VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY NGUYEN THI HONG ANH USING IONIC LIQUID AS SOLVENT FOR COUPLING, AND HALOGEN EXCHANGE REACTION
LITERATURE REVIEW
IONIC LIQUIDs (ILs)
Ionic liquids (ILs) have been played extensive roles in the fields of synthesis, catalysis, extraction, electrochemistry, etc Welton reported that ILs are not new, and some of the ILs such as [EtNH3][NO3] was first described in 1914 [9, 10] Until the 1970s and 1980s, ionic liquids obtained through the mixing of alkyl-substituted imidazolium and pyridinium cations with halide/trihalogenoaluminate anions were initially developed for use as electrolytes in battery applications [11, 12] Additionally, the imidazolium halogenaluminate salts have important physical properties, such as viscosity, melting point, and acidity adjusted by changing the alkyl substituent and the imidazolium(pyridinium)/halide (halogenoaluminate) ratios [13] However, two major drawbacks for applications of ILs were moisture sensitivity and acidity/basicity In 1992, Wilkes and Zaworotko obtained ionic liquids with weakly neutral coordinating anions such as hexafluorophosphate (PF6 -) and tetrafluoroborate (BF4 -), opening up a renaissance of the rich chemistry of molten salts and the much wider range of their applications [14] Recently, the combination of the cation 1-ethyl-3-methylimidazolium and the smaller anion tetrachloroaluminate to form 1-ethyl-3-methylimidazolium tetrachloroaluminate and the related alkylhalogenoaluminate(III) ionic liquids had been widely studied by the time 2001 As 2004, 1,3-dialkyl imidazolium salts were the most popular and investigated classes of room temperature ionic liquids [15, 16]
ILs are a subset of molten salts with melting points (Tm) below 373 o K
In Walden’s original paper on The European Article Numbering system, he described a class of materials as “water-free salts” which melt at relatively low temperatures, about up to 100 °C [17] With the continuous efforts of some chemists, ILs have not only become increasingly popular as an extraction media
Page 2 but also widely as “green solvents”, which are regarded as powerful alternatives to the volatile organic compounds (VOCs) in the field of organic synthesis
Furthermore, the task-specific ionic liquids (TSILs) where a functional group is covalently tethered to the cation or anion (or both) of the ionic liquid, are the latest generation of ionic liquids The incorporation of this functionality should imbue the ionic liquid with a capacity not only as a reaction media but also as a reagent or catalyst in some reactions or processes [18] The environmental interest has centered on the usage of ionic liquids as “greener” alternatives to volatile organic solvents The ionic liquids have been attractive as potential solvents due to they exhibit very low vapor pressures under ambient conditions and thus are non-volatile solvents [19] Due to the application as green solvents for many reactions, ionic liquids have also become effective catalysts, co- catalysts, ligand sources and other industrial applications with more advantages in comparison with conventional solvents
Table 1-1 Comparison of properties of ionic liquids with organic solvents [20,
Properties Organic solvents Ionic liquids
Catalytic ability Common and tunable Rare
Chirality Common and tunable Rare
Vapor pressure Negligible under normal condition
Obeys the Clausius- Clapeyron Equation Flammability Usually nonflammable Usually flammable Solvation Strongly solvating Weakly solvating
Limited range of solvents available
Polarity Polarity concept questionable Conventional polarity concepts apply
Cost Two to one hundred times greater than ILs
Properties Organic solvents Ionic liquids
Recyclability Economic imperative Green imperative
ILs consist of cations and anions, they exhibit the dual functionality Some common cations are used for ionic liquids such as ammonium, sulfonium, phosphonium, imidazolium, pyridinium, picolinium, pyrrolidinium, thiazolium, oxazolium, pyrazolium The common anions are BF4 , PF6 - , SbF6 , ZnCl3 , CuCl2 , SnCl3 , N(CF3SO2)2 , N(C2F5SO2)2 , N(FSO2)2 , C(CF3SO2)3 , CF3CO2 , CF3SO3 , and CH3SO3 [22, 23]
Figure 1-1 Chemical structures of cations in ionic liquids [22, 23]
Nowadays, ionic liquids are interdisciplinary tools for chemists, physicists, biologists, engineers, and simulators using them to tackle important scientific problems This has been spurred by green chemistry movement due to ionic liquid solvents can be integrated into existing systems [24]
Room temperature ionic liquids are generated by the use of bulk organic cations associated with inorganic or organic anions [25] Additionally, the fact that many ionic liquids can be synthesized by a suitable combination of anions and cations This unlimited range means ionic liquids being described as
“designer solvents”[26] Their properties can be adjusted and controlled by suitable choice of cations and anion ILs exhibit many properties which make them potentially attractive media for homogeneous catalysis such as [27]:
No vapor pressure which facilitates product separation by distillation
Ability to dissolve a wide range of organic, inorganic and organometallic compounds
The attractive solvents for catalytic hydrogenations, carbonylations, hydroformylations, and aerobic oxidations with H2, CO and O2
Immiscibility in some organic solvents, e.g alkanes, and, hence, can be used in two-phase systems
Polarity and hydrophilicity/lipophilicity can be readily adjusted by changing cation/anion and thus ILs have been referred as ‘designer solvents’ [28]
Chloroaluminate ions-based ILs are usually strong Lewis, Franklin and Bronsted acids that can replace for hazardous acids such as HF in several acid-catalyzed reactions
Almost ILs can be preserved for a long time without decomposition
Figure 1-2 Applications of ionic liquids [29]
Figure 1-3 Structure of 1-alkyl-3-methylimidazolium-based ionic liquids[4, 30]
The first ILs, such as organo-aluminate ILs, have a limited range of applications because they were unstable to air and water Furthermore, these ILs were not inert towards various organic compounds [16] After the first reports on the synthesis and applications of air stable ILs such as 1-n-butyl-3- methlyimidazolium tetrafluoroborate ([BMIM]BF4) and 1-n-butyl-3- methlyimidazolium hexafluorophosphate ([BMIM]PF6), the number of air and water stable ILs have started to increase rapidly
Researchers have discovered that ILs are more than just green solvents
They have found several applications such as replacing them with volatile organic solvents, making new materials, effective heat conducting , support for enzyme-catalyzed reactions, host for a variety of catalysts, purification of gases, homogenous and heterogeneous catalysis, biological reactions media and removal of metal ions [30] The number of researches on ILs and their specific
Page 6 applications are increasing rapidly in the literature For example, the 1-ethyl-3- methylimidazolium cation has been the most widely studied until 2001
Nowadays, 1,3-dialkyl imidazolium salts are the most popularly used and investigated class of ILs The asymmetric 1,3-dialkylimidazolium salts are the most intensively investigated to start generating a low-melting salt of any particular anion [19, 31, 32]
1.1.3 Synthesis of Ionic Liquids 1.1.3.1 Standard route to 1-alkyl-3-methylimidazolium-based ionic liquids
The most common reactions for synthesis of almost ionic liquids were via salt metathesis reactions However, attempts to a great challenge in the synthesis of high purity ILs had led to the continuous development in new synthetic routes and purification procedures
Figure 1-4 shows the most widely procedure for preparation of ionic liquids, by taking 1-alkyl-3-methylimidazolium-based ionic liquids as an example
Similarly, other types of cations, notably pyridinium systems could be prepared through this process
Figure 1-4 Typical procedure for synthesis of 1-alkyl-3-methylimidazolium- based ionic liquids [33]
1.1.3.2 Microwave-assisted preparation of ILs
In comparison with the preparation of ILs using conventional heating (oil bath at 80 o C), the similar synthesis was carried out using microwave (MW) irradiation under solvent-free conditions Interestingly, the result reported that MW-assisted chemical process offered favorable features in contrast to the limitation in the conventional approach Particularly, the reaction required only a few minutes to afford reasonable yield while the conventional heat needed several hours to take place Another noticeable advantage of the microwave supported method was the use of only stoichiometric amount of reactants under solvent-free condition in comparison to a large excess of alkyl halides/organic solvents in the conventional heat [34] Additionally, the purity of products from MW-assisted method is higher than that of conventional one However, to overcome the drawbacks that the reaction occurred in the opened container, Khadilkar and Rebeiro investigated a new method using a closed pressure reactor [35]
It is critical to pay much attention to the purification of ILs in order to avoid the possible interactions between reactants and impurities and to prevent the nature of these solvents from altering [36] ILs possess a unique range of physico-chemical properties such as such as negligible vapor pressure, large liquidus range, high thermal stability, high ionic conductivity, large electrochemical window, and ability to solvate compounds of widely varying polarity However, several described properties are now subjected to controversy: e.g electrochemical window, long-term thermal stability, polarity and volatility under certain conditions [37] Bulk physical and chemical properties of ILs will be discussed in the following part
Melting point is a very important property of ILs because ILs have a large liquids range determined by their low melting points as well as high decomposition
Page 8 points, and the solubility of ILs in water or organic solvents is strongly correlated with their melting points Melting point of ILs is governed by van der Waals forces and electrostatic interaction force and the impact of the two forces play different roles on different kinds of ILs They have relatively low melting points, ideally below the ambient temperature due to bulky organic cations in ionic liquids It was illustrated in Table 1-2 that the reduction in melting points can be approached by enhancing the size of the anion, or that of the cation
Table 1-2 Melting points (°C) and thermochemical radii of the anions (Å) for
Na + and [EMIM] + salts The ionic radii of the cations are 1.2 Å (Na + ) and 2 x 2.7 Å ([EMIM] + , non-spherical) [38]
In addition, the symmetry of the ions remarkably influences on the melting points of correspondent ILs To be more specific, raising the symmetry in the ions increases the ion–ion packing in the crystal cell leading to an increase in the melting point On the contrary, low-symmetric ions distort the Coulombic charge distribution causing the reducing of melting points It can be explained that the ionic liquids containing large asymmetric cations have low melting points
Another factor makes the difference in melting point is the degree of branching
Table 1-3 illustrates that the melting point increases with the increasing the degree of chain branching for alkyl chain in imidazolium [38]
Table 1-3 Melting points for isomeric [BMIM]PF6 and [PMIM]PF6 ionic liquids, with various degree of branching in the alkyl substituent [38]
N(1)- Substitution Melting point ( o C) n-Butyl 6.4 sec-Butyl 83.3 tert-Butyl 159.7 n-Propyl 40
Ionic liquids as solvents
A majority of common solvents have potential health hazards although they are extensively utilized For example, approximately half of 189 hazardous air pollutants regulated by Clean Air Act Amendment of U.S (1990) are VOCs including solvents such as dichloromethane [46] The VOCs are the workhorses
Page 13 of industrial chemistry in the pharmaceutical and petrochemical areas [47] The physical and chemical properties of ILs are varied by changing the alkyl chain length on the cation and the anion types For example, Huddleston et al [39] concluded that the density of ILs increases with a decrease in the alkyl chain length on the cation and an increase in the molecular weight of the anion The composition and the specific properties of these liquids depend on the type of cation and anion in the IL structure By combining various kinds of cation and anion structures, it is estimated that 1018 ILs can be designed [30, 44]
The unique properties of ILs and the ability to design their properties by choice of anion, cation and substituents create many more processing options, alternative to the ones of conventional solvents The most important advantage of the use of these ionic liquids as solvents was the facile separation of the products from the reaction by simple decanting (in most of the cases) and the recovered ionic catalyst solution
Moreover, in various cases, ionic liquids have been shown to promote reactions which are difficult or do not occur in conventional organic solvents For chemical reactions carried out in conventional solvents, the solvent must be isolated from the products by evaporation In addition, there are some chemicals that can decompose under high temperature of heating Therefore, ILs seem to be potentially good solvents for many chemical reactions in the cases where distillation is not practical, or water insoluble or thermally sensitive products are the components of a chemical reaction Although, ILs are not considered to be distilled due to their low volatility, Earle et al [37] showed that many ionic liquids, especially bistriflamide ILs, can be distilled at 200–300 o C and low pressure without decomposition
A solvent is generally characterized by macroscopic physical constants
“bulk properties” such as vapor pressure, boiling point, density, cohesive pressure, relative permittivity e.g “dielectric constants”, surface tension, refractive index The large number of studies have been devoted to the characterization of ILs “bulk”
As solvents, ILs posses several advantages over conventional organic solvents,
Page 14 which make them environmentally compatible [10, 48-55]:
ILs have the ability to dissolve many different organic, inorganic and organometallic materials
ILs are highly polar ILs consist of loosely coordinating bulky ions ILs do not evaporate since they have very low vapor pressures ILs are thermally stable, approximately up to 300 o C
Most of ILs have a liquid window of up to 200 o C which enables wide kinetic control
ILs have high thermal conductivity and a large electrochemical window ILs are immiscible with many organic solvents
ILs are nonaqueous polar alternatives for phase transfer processes The solvent properties of ILs can be tuned for a specific application by varying the anion cation combinations
The polarity is one of the most important properties for characterizing the solvent effect in chemical reactions [56] It is also the property which has probably been the most widely discussed in the case of ILs There is no single parameter and direct measurement that can characterize the IL polarity The difficulty in the case of ILs is to find a suitable soluble probe which measures the polarity parameters as independently as possible of the other influences of the solvent [57, 58] This is probably the scale that has been applied to the greatest number of ILs [57, 59]
Figure 1-5 Normalised solvent polarity scale (ET(30) = 0.00 for Me4Si and
The first example of Heck reaction in ionic liquid was reported by Kaufmann et al in 1996 [60] Butyl trans-cinnamate was produced in high yield by reaction of bromobenzene with butyl acrylate in molten tetraalkylammonium and tetraalkylphosphonium bromide salts No formation of palladium metal was observed and the product was obtained by distillation from the ionic liquid (Scheme 1-1)
Scheme 1-1 Pd-catalyzed Heck reaction in ionic liquid [60]
1.2.2 Reaction of bromobenzene with butyl acrylate in molten tetraalkylammonium and tetraalkylphosphonium bromide salts (Suzuki reaction)
Suzuki cross-coupling reactions using Pd(PPh3)4 as catalyst in
Page 16 [BMIM]BF4 have been reported by Mathews and co-workers [61] The best suitable conditions were achieved by pre-heating the aryl halide to 110 °C in the ionic liquid with the Pd-complex The arylboronic acid and Na2CO3 were later added to start the reaction Several advantages over the reaction as performed under the conventional Suzuki conditions were described This work has clearly shown that ionic liquid offers a significantly enhanced activity in formation of the homo-coupling aryl by-product Moreover, the ionic catalyst layer could be reused after extraction of the products with ether and removal of the by-products (NaHCO3 and NaXB(OH)2) with excess water No deactivation was observed with this procedure over three further reaction cycles
Scheme 1-2 Pd-catalyzed Suzuki cross-coupling reaction in a [BMIM]BF4 ionic liquid [61]
As known, it is very difficult to recycle the liquid inorganic acid catalysts which need to be neutralized after the reaction Moreover, large amounts of volatile organic solvents and liquid inorganic acids cause the pollution when discharge to the environment Consequently, a Brứnsted acidic ionic liquid, 1- methylimidazolium tetrafluoroborate ([HMIM]BF4) was used as a recyclable catalyst and solvent in the esterification of carboxylic acids with alcohols, for example [62] Recently, the heteropoly anion-based Brứnsted acidic ionic liquids were successfully prepared for esterification of oleic acid for biodiesel application
Scheme 1-3 Brứnsted acidic ionic liquid 1-methylimidazolium tetrafluoroborate: a green catalyst and recyclable medium for esterification [62]
The use of ILs as versatile solvent/catalysts could overcome disadvantages of solid catalysts For instance, some acidic ILs are prepared by the reaction of neutral nucleophiles n-butyl imidazole or triphenylphosphine with 1,4- butanesultone or 1,3-propanesultone, respectively The usage of these ILs provided a good product selectivity as well as reaction yields and the ease of catalyst/substrate separation Moreover, ILs can dissolve many organic and inorganic substrates and they also readily recycled [63] Additionally, ILs that exhibited both as solvent and as co-catalyst in transition metal catalysis were formed by treatment of a halide salt with a Lewis acid (such as chloroaluminate or chlorostannate melts) This could be explained that the Lewis acidity or basicity, which was always present (at least latently), resulted in strong interactions with the catalyst complex It was noted that the Lewis acidity of an ionic liquid was used to convert the neutral catalyst precursor into the corresponding cationic active form For example, the activation of Cp2TiCl2 in acidic chloroaluminate melts [64]:
It is well known that alkylaluminum(III) compounds react vigorously with protons to deliver the corresponding alkane The using of ionic liquids derived from ethylaluminium(III) dichloride could prevent the cationic side reaction
Alkylaluminum(III) compounds can be used as alkylating agents which allowed a greater number of potential catalysts to be used [19]
It appeared that transition metal-catalyzed hydrogenation reactions in ionic liquids were particularly promising based on several factors: (1) the large number of ionic hydrogenation catalysts were available [65] and (2) the solubility of many alkenes and the availability of hydrogen in many ionic liquids appeared to be sufficiently high to achieve good reaction rates It was noteworthy that the diffusion of hydrogen into ionic liquids was found to be relatively fast, the ease of its transfer from the gas phase into the melt is of special importance [66]
Page 18 In 1996, Suarez and co-workers investigated the Rh-catalyzed hydrogenation of cyclohexene in 1-n-butyl-3-methylimidazolium ([BMIM]) tetrafluoroborate [33] and Farve dissolved the cationic “Osborn complex”
[Rh(nbd)(PPh3)2][PF6] (nbd = norbornadiene) in ionic liquids with weakly coordinating anions (e.g., [PF6] – , [BF4] – , and [SbF6] – ) and used the obtained ionic catalyst solutions for the biphasic hydrogenation of 1-pentene [67] (Scheme 1- 4) Although the reactants had the limited solubility in the catalyst phase, the rates of hydrogenation in [BMIM][SbF6] were five times faster than that of reaction in acetone
Scheme 1-4 Biphasic hydrogenation of 1-pentene with the cationic “Osborn complex” [Rh(nbd)(PPh3)2][PF6] (nbd = norbornadiene) in ionic liquids with weakly coordinating anions [67]
Although there were already a highly efficient aqueous or organic biphasic industrial process for the hydroformylation of olefins, these could only be used with short-chain (≤ 5C) olefins However, ionic liquids present the higher solubilities for the higher olefins, and offered the possibility of replacing the water layer and extending the usefulness of the biphasic technique
The hydroformylation of 1-hexene in a variety of ionic liquids with imidazolium and pyrrrolidinium cations and different anions was carried out by Favre and co-workers [67] Initially they introduced the rhodium as [Rh(CO)2(ACAC)] with four equivalents of the charged phosphine TPPMS (triphenylphosphine-3-monosulfonate) and measured the turnover frequency of the catalyst in the different ionic liquids For the [BF4] − , [PF6] − , [CF3SO3] − , and [CF3CO2] − ionic liquids they found that the turnover frequency (TOF) of the reaction was dependent upon the solubility of the 1-hexene in the ionic liquid,
Reactions Literature review
The development of novel methodologies for the synthesis of biologically active heterocyclic compounds has been attracted more and more attention by organic chemists [71, 72] Amongst heterocyclic compounds, coumarin derivatives are becoming popular due to their important pharmacological properties such as anti-inflammatory, antioxidant, antiallergic, antithrombotic,
Page 20 anti-HIV, autophagy inhibitors and anticancer activities [73-80] They have been used commonly as additives in food and cosmetics and in the preparation of insecticides, optical brighteners, dispersed fluorescent and laser dyes [81, 82]
Coumarin was synthesized via Pechmann reaction with acidic catalysis It is considered as effective, simple and common reaction to synthesize various derivatives of coumarin [83] However, the co-catalytic acid can cause problems of environmental pollution as well as the difficulty of reusing catalyst [84] In 2013, Shaterian and Aghakhanizadeh used 2-pyrrolidonium; imidazolium ionic liquids with bronsted acid hydrogensulfate anion such as ([HNMP][HSO4]) [A],
N-methyl-2-pyrrolidonium hydrogen sulfate ([NMP][HSO4]) [B], N-methyl-2- pyrrolidonium dihydrogen phosphate ([NMP][H2PO4]) [C], (4-sulfobutyl)tris (4- sulfophenyl)phosphonium hydrogen sulfate [D], and triphenyl(propyl-3-sulfonyl) phosphonium toluenesulfonate [E] as catalysts for the condensation reaction between phloroglucinol and β-Pechmann ketoesterda high efficiency under normal conditions (Scheme 1-6) [85]
Scheme 1-6 The reaction between β-ketoester phloroglucinol in ILS [85]
Besides well-known procedures including Pechmann and Perkin reactions, recently coumarins were also synthesized via the condensation between salicylaldehydes and active methylene compounds using acidic as well as basic catalysts [75-77, 81, 86, 87]
In recent years, Sm (III) was used as a catalyst transplant operation in C-C response to the carbon skeleton, aldol condensation reaction Bahekar and Shinde performed Pechmann condensation reaction using Sm (III) in the absence of a solvent for the reaction of ethyl acetoacetate and phenols to form coumarin derivatives (Scheme 1-7) [88] The reaction reached an average yield with difficulty of recovered catalyst
Scheme 1-7 The reaction of phenol derivatives with ethyl acetoacetate under the catalyst Sm (NO3)3.6H2O [88]
Then, in 2011, Karami and Kiani conducted the reaction between β- Pechmann condensation and ketoesters phenol derivatives in ZrOCl2.8H2O/SiO2 as a catalyst in Lewis solvent for a short time about 5-80 minutes, and the reaction yields gained from 75 to 99% (Scheme 1.8) [83] Then catalyst was recovered by filtration, then washed with chloroform and dried for reusage
Scheme 1-8 The reaction between β-ketoesters and phenol derivatives under the catalytic Lewis ZrOCl2.8H2O/SiO2 [83]
In 2009, Shi and co-workers synthesized novel 3-acetoacetylcoumarin derivatives by reaction between substituted salicylaldehyde and 4-hydroxy-6- methyl-2H-pyran-2-one via Konevenagel condensation in good yields using [BMIM]Br as a catalyst at 90 o C [89]
Scheme 1-9 The reaction between substituted salicylaldehyde and 4-hydroxy-6- methyl-2H-pyran-2-one [89]
In 2015, Mi and colleagues conducted a synthesis of 3-acyl-4-aryl coumarins via metal-free tandem oxidative acylation/cyclization between alkynoates with aldehydes The reaction was achieved by the addition of an acyl radical to alkynes and a C–H bond functionalization to form simultaneously two new C–C bonds [90]
Scheme 1-10 Reaction oxidative acylation/cyclization between alkynoates with aldehydes [90]
In 2015, Gadakh and co-workers used Rh-catalyst for synthesis of coumarin derivatives from phenolic acetates and acrylates via C–H bond activation The addition of formic acid as reducing agent led to the high yield for synthesis of coumarin derivatives with NaOAc as a base [91]
Scheme 1-11 Synthesis of coumarin derivatives from phenolic acetates and acrylates via C–H bond activation [91]
In 2006, Rao and Sivakumar conducted the condensation of α-aroylketene dithioacetals and 2-hydroxyarylaldehydes for facile synthesis of a combinatorial library of 3-aroylcoumarins in the presence of piperidine as a catalyst [92]
Scheme 1-12 Condensation of α-aroylketene dithioacetals and 2- hydroxyarylaldehydes [92]
Benzodiazepines are an important class of aza heterocycles with biological activities and therapeutic functions Among derivatives of benzodiazepine class, 1,5-benzodiazepines has extensively been used as anticonvulsant, anti-anxiety, antiviral, antitumor, psychosis, antipyretic, and anti-inflammatory agents [93-96]
Moreover, they are also known as the precursors in the preparation of triazoles and oxadiazoles [97-99] With their wide applications, a large number of
Page 23 methodologies for the synthesis of 1,5-benzodiazepines have been developed
In 2008, Silva and co-workers synthesized 1,2,4,5-tetrahydro-1,4- benzodiazepin-3-ones in a one-pot reaction with two-step synthesis under a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant Two pathways were accessible; both routes utilize bifunctional, o- nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B) [100]
Scheme 1-13 Synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones [100]
One of simple and efficient protocols commonly studied is the direct condensation of 1,2-phenylenediamines and ketones in the presence of an acid catalyst [101]
Scheme 1-14 Synthesis of 2,3-dihydro-1-H-1,5-benzodiazepine from o- phenylenediamine and acetophenone [101]
The uses of various catalysts, such as polyphosphoric acid, MgBr2, Sc(OTf)3, InBr3, H3BO3, polymer-supported FeCl3, SiO2/ZnCl2, MgO/POCl3, CH3COOH under microwave irradiation for the cyclocondensation to synthesize 1,5-benzodiazepines were reported [97, 98, 102-105]
However, many of these processes have remained several shortcomings including prolonged reaction time, low selectivity, harsh reaction condition, and complex work-up procedures Therefore, there is still a need of convenient and practical methods for the synthesis of substituted 1,5-benzodiazepines under mild
Page 24 reaction conditions with economic viability and high yield
1.3.2 Carbon-Nitrogen coupling 1.3.2.1 Synthesis of substituted piperidines (N-arylation)
Recently, the N-arylation of piperidine has been intensely studied due to pharmacological activities (i.e., antibacterial, antiviral, anti-inflammatory, anti- allergic) of compounds containing the N-aryl heterocyclic amine moiety [106]
Most of methods for the formation of aryl-nitrogen bond from aryl halide and amine are based on transition metal-catalyzed systems [106-109] Interestingly, with aryl halides activated by electron-withdrawing groups such as -NO2, -CN, and -CF3, N-arylation can occur by nucleophilic aromatic substitution without the presence of expensive transition metal catalysts [110-112] However, long reaction times or vigorous conditions of elevated temperature, high pressure, microwave assistance and the support of other bases are required to obtain acceptable yields [110, 113, 114] Therefore, the development of more efficient and facile protocols for preparation of N-aryl substituted piperidines is still a great challenge For aryl halide containing the electron-withdrawing groups (-NO2, -CN, -COCH3 ) and no secondary amines, reactions can occur easily under the nucleophilic aromatic substitution in presence of polar solvents and a strong base without a catalyst [115] However, carbon-nitrogen coupling reaction was performed successfully on the aryl halide and less reactive amines with palladium complex/copper complex as a catalyst [115, 116] In 2011, Fors and Buchwald reported the usage of Pd catalyst based on two biarylphosphine ligands for C−N cross-coupling reactions [116]
Scheme 1-15 Pd catalyst based on two biarylphosphine ligands for C−N cross- coupling reactions [116]
AIMS AND OBJECTIVES
Over the last two decades, ILs have emerged as a new class of green solvents with a number of outstanding properties that outperform conventional solvents As a result, It’s applications have been continuously investigated so that they can adapt well in chemistry area as well as in the normal life This was the reason why this study focused on the synthesis of ILs and the application of ILs in organic synthesis Especially, the conventional heating methods have been replaced by microwave-assisted chemical processes in order to enhance the yield associated with reducing the time of the reaction
Additionally, the nucleophile reactions were conducted in ILs with the same polarization of organic solvents To favor an S N 2 reaction, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile To prevent this interference, polar, aprotic solvents such as acetone, DMF or DMSO should be used Ionic liquids like polar apotic solvents so that they could be used in nucleophilic reaction without any limitation as conventional solvents Till today, a large number of ILs have been reported; however, room temperature ILs (Imidazolium based-cations) possessed the advantages in comparison with the other ILs
Therefore, the first aim of the study is to synthesize imidazolium based ILs with bromide and hexaflorophosphate anions under the assistance of microwave
After the synthesis of imidazolium based ILs, the second aim of this thesis is to attempt towards the applications of imidazolium based ILs as solvents for coupling reactions and halogen exchange reaction These prepared ILs for coupling reactions are expected to achieve better results comparing with the previous reports: catalyst-free reaction and green free-solvents with high conversion and mild condition in a short time
Specially, in halogen exchange reports, only transfer from aryl bromide to iodide Thus, in this thesis, we want to transform the aryl iodide to aryl bromide using Cu (I) catalyst in ILs solvent without other catalysts
EXPERIMENTAL
Materials and instrumentation
Na2SO4 China 99.0% n-Butanol Merck 99.8%
Piperidine Merck 99.0% p-Xylene Merck 99.0% p-Xylene Merck 99.0%
Chemicals were purchased from Sigma-Aldrich and Merck, and used as received without further purification 1 H and 13 C NMR spectra were recorded using a Bruker AV 500 spectrometer at The Vietnam Academy of Science and Technology (VAST) 18 Hoang Quoc Viet, Cau Giay, Ha Noi Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 17-A, GC Shimadzu 2010 Plus equipped with a flame ionization detector (FID) and an DB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 àm) at Ho Chi Minh city university of technology The temperature program for GC analysis is described in appendix 44 Conversion of products were calculated by GC with appropriate internal standards (Appendix 45) GC–MS analyzes were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 àm) with electron impact ionization mode at Hoan Vu analytical laboratory (HCMC) 215 Phan Anh, Binh Tri Dong, Binh Tan, HCM The temperature program for GC–MS analysis was from 60 to 280 o C at 10 o C/min and held at 280 o C for 2 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library
Synthesis of ionic liquids
2.2.1 Preparation of 1-alkyl-3-methylimidazolium bromide
In a typical reaction for preparation of [BMIM]Br, 20 mL (0.225 mol) of 1-methylimidazole was mixed with 30 mL (0.273 mol) of 1-bromobutane in a 250 mL round bottom flask equipped with a flux condenser The mixture was then irradiated in a microwave oven (Sanyo – EM S2086W – 800W) at 80 W, and stirred vigorously during the reaction time by the magnetic stirrer The irradiation was paused every 10 seconds so that the mixture can be quenched to prevent over heating The irradiation was repeated for a total time of 3 minutes (6 minutes for 1-bromohexane, 9 minutes for 1-bromooctane) After completion of reaction, the resulting mixture was cooled down to room temperature, then washed with ethyl acetate three times, and with diethyl ether three times to separate the starting materials as well as undesired products The residue of volatile solvents was removed by a vacuum rotary evaporation at 50 o C to afford 53.02 g of product
The ionic liquids [HMIM]Br and [OMIM]Br were synthesized with the same procedure mentioned above to form 56.81 g and 62.81 g ionic liquids, respectively
Scheme 2-1 The synthesis of 1-alkyl-3-methylimidazolium bromide
Figure 2-1 The synthesis of 1-alkyl-3- methylimidazolium bromide
1) Ethyl acetate 3x20 mL 2) Diethyl ether 3x20 mL Undesired materials
-Microwave 80 w -Vigorously stirring -Stop irradiating every 10 seconds
20 mL methylimidazole x (mL) of 1-bromoalkane
Bromobutane x0 mL Bromohexane x@ mL Bromooctane xP mL
2.2.2 Preparation of 1-alkyl-3-methylimidazolium hexafluorophosphate
Scheme 2-2 The formation of 1-alkyl-3-methylimidazolium hexafluorophosphate by anion metathesis In a typical procedure for preparation of [BMIM] PF6; 40 mL (0.272 mol) of hexafluorophosphoric acid was added to a plastic conical flask containing 50 mL of cold distilled water This mixture was stirred and immersed in an ice bath for 30 minutes and then cooled down to 05 o C (mixture I) The mixture of [BMIM] Br (50 g, 0.228 mol) with 50 mL of cold distilled water was also stirred and immersed in another ice bath for 30 minutes (mixture II) Next, the mixture I was added dropwise to mixture II The resulting mixture was continuously stirred and cooled for 24 hours After that, the upper acidic aqueous layer was almost separated by decanting and the resulting mixture was washed by cold water until the almost excess acid was removed The acidity was tested by pH paper The excess water was removed by a vacuum rotary evaporation at 70 o C to afford 50.78 g of product
The ionic liquids [HMIM] PF6 and [OMIM] PF6 were synthesized with the same procedure mentioned above to form 59.2 g and 70.3 g of products, respectively
Figure 2-2 The synthetic procedure of 1-alkyl-3- methylimidazolium hexafluorophosphate ionic liquids
50 mL H2O each time until neutral
BMIMBr xP g HMIMBr xU g OMIMBr xb.5 g
Studied Reaction
Scheme 2-3 Synthesis of coumarin from salicylaldehyde and methyl acetoacetate Unless otherwise stated, salicylaldehyde (0.11 mL, 1.0 mmol) and diphenyl ether (0.1 mL) as the internal standard in [BMIM]Br ionic liquid (4.0 mL) were introduced into a 50 mL glass vessel Methyl acetoacetate at pre- determined molar ratio (3eq) was added, and the mixture was then stirred at 100 oC for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL) from the reaction mixture at different time intervals, and quenching with water (1 mL) The organic components were extracted into diethyl ether (3 mL), dried over Na2SO4 and analyzed by gas chromatography (GC) with reference to diphenyl ether, and then main product (3-acetylcoumarin) was identified by GC- MS, NMR For investigation of [BMIM]Br recycling, after the reaction, the resulting mixture was cooled to room temperature and extracted with diethyl ether (5 x 10 mL) to remove the organic components The ionic liquid layer was evaporated under vacuum (50 o C, 10 mmHg) for 1 h to remove any excess solvent and then reused in further reaction under identical conditions to those of the first run Reaction conversion was calculated by following formula (1)
S1, S2: Peak area of substrate and internal standard, respectively t0: Time of beginning tx: Time of withdrawing the sample
Page 47 The survey factors affect on reaction conversion
Molar ratio between salicylaldehyde/methyl acetoacetate = 1.0/1.0, 1.0/2.0 and 1.0/3.0
These two factors are the basic conditions affecting the reaction which should be investigated during the experiment The two factors were associated with the below chemicals and solvents Temperature 100 o C and molar ratio between salicylaldehyde/methyl acetoacetate 1.0/3.0 was chosen for future experiments
Alkyl chain length of ionic liquids: [BMIM]Br, [HMIM]Br, [OMIM]Br
Ionic liquid anions: [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvents: [BMIM]Br, DMF, DMSO, n-butanol, toluene, p- xylene
Scheme 2-4 The cyclocondensation reaction of 1,2-phenylenediamine with acetone to form 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine The [HMIM]Br ionic liquid was applied as catalyst for the cyclocondensation of 1,2-phenylenediamine and ketones to obtain 1,5- benzodiazepine derivatives In a typical experiment, a pre-determined amount of [HMIM]Br was added to the flask containing a mixture of 1,2-phenylenediamine (0.108 g, 1.0 mmol), acetone (3.7 mL, 50 mmol) and diphenyl ether (0.1 mL) as the internal standard The catalyst concentration was calculated based on the molar ratio of [HMIM]Br/1,2-phenylenediamine The reaction mixture was then stirred at required temperature for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL) from the reaction mixture at different time intervals, and quenching with water (1.0 mL) The organic components were
Page 48 extracted by diethyl ether (3 mL), dried over Na2SO4 and analyzed by gas chromatography (GC) with reference to 4-bromoanisole, and then main product (2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine) was identified by GC-MS, NMR To investigate the recyclability of [HMIM]Br catalyst, after completion, the reaction mixture was diluted with water (10 mL), and extracted with diethyl ether (3 x 10 mL) to remove the organic compounds The aqueous layer consisting of the ionic liquid was distilled under vacuum (80 o C, 10 mmHg) for 1 h to remove water to obtain [HMIM]Br ionic liquid, which could be reused
Reaction conversion was calculated by formula (1)
The survey factors affect on reaction conversion
Molar ratio of ILs/1,2-phenylenediamine: 0.0/0.0, 1.0/1.0, 3.0/1.0, 5.0/1.0,
Molar ratio between acetone/1,2-phenylenediamine = 60/1.0, 50/1.0,
Ionic liquids: [HMIM]Br, [BMIM]Br, [OMIM]Br, [BMIM]PF6,
Other catalysts: CH3COOH, Zn (NO3)2, n-butanol , [HMIM]Br and water
2.3.3 Synthesis of 1-(4-nitrophenyl)piperidine derivatives
Scheme 2-5 The N-arylation between 4-bromonitrobenzenes and heterocyclic amines in ionic liquids Unless otherwise stated, 4-bromonitrobenzene (0.202 g, 1 mmol), and 4- bromoanisole (0.1 mL) as the internal standard in [HMIM]Br ionic liquid (4.0 mL) were introduced into a 50 mL glass vessel Piperidine at pre-determined molar ratio was added, and the mixture was then stirred at required temperature for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL)
Page 49 from the reaction mixture at different time intervals, quenching with diethyl ether (2 mL), filtering through a short silica gel pad, drying over Na2SO4, analyzing by GC with reference to 4-bromoanisole, and then main product (1-(4- nitrophenyl)piperidine) was identified by GC-MS, NMR Reaction conversion was calculated by formula (1)
The survey factors affect on reaction conversion
Alkyl chain length of ILs: [BMIM]Br, [HMIM]Br, [OMIM]Br
Molar ratio between the two reactants: 1-bromo-4-nitrobenzene/piperidine
Ionic liquid anions: [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvents: [BMIM]Br, DMF, DMSO, NMP, n-butanol, toluene
The halogen in 4-nitrophenyl halide: F, Cl, Br and I
2.3.4 Synthesis of 1-[2-(N-morpholino)ethyl]-2-methylindole derivatives
Scheme 2-6 The reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in the [BMIM]PF6 ionic liquid In a typical reaction, a solution of 1-(N-morpholino)-2-chloroethane hydrochloride in ionic liquid was added dropwise under a magnetic stirrer for an interval of time The products were extracted into n-hexane, and the solvent was then removed by a rotavapor at 30 o C Reaction progress was monitored by GC, and then product (1-(2-(N-morpholino)ethyl)-2-methylindole) was identified by GC-MS The reaction yield was calculated based on GC analysis and the mass of
Page 50 the product mixture The product was also purified by recrystallization to achieve isolated yield, and analyzed by GC-MS and NMR
The factors affect the reaction conversion:
The reagent molar ratio 1-(N-morpholino)-2-chloroethane hydrochloride/
The molar ratio base KOH/2-methylindole: 1.0/0.0, 1.0/1.0, 1.0/2.0, 1.0/3.0, 1.0/4.0, 1.0/5.0, 1.0/6.0
Several kinds of base: Triethyl amine; Na2CO3, K3PO4.3H2O, K2CO3,
The molar ratio [BMIM]PF6/2-methylindole: 40.0/1.0, 60.0/1.0, 80.0/1.0,
Several kinds of ionic liquid: [BMIM]Br, [HMIM]Br, [OMIM]Br,
[BMIM]PF6, [HMIM]PF6, [OMIM]PF6
The recovery and reuse of ILs
Scheme 2-7 The reaction between 2,5-hexadione and amine in the [BMIM]PF6 ionic liquid Unless otherwise stated, 2,5-hexadione (0.12 mL, 1 mmol), and p-xylene (0.1 mL) as the internal standard in [BMIM]PF6 ionic liquid (3 mL) were introduced into a 100 mL glass vessel Amine was added, and the mixture was then stirred at required temperature for 60 min Reaction conversion was monitored by withdrawing 0.1 mL aliquots from the reaction mixture at different time intervals, quenching with diethyl ether (2 mL), filtering through a short silica gel pad, drying over Na2SO4, analyzing by GC with reference to p-xylene, and then main products (1-benzyl-2,5-dimethyl-1H-pyrrole and 1-(4-
Page 51 methoxyphenyl)-2,5-dimethyl-1H-pyrrole) were identified by GC-MS, NMR
Reaction conversion was calculated by formula (1)
The survey factors affect the reaction conversion:
The reagent molar ratio (amine/dione): 1/1, 1/1.1, and 1/1.2
The molar of ionic liquid: 14 mmol, 19 mmol, 24 mmol
The alkyl chain length in cation of ionic liquid: [BMIM]PF6, [HMIM]PF6,
Some conventional organic solvents: [BMIM]PF6, Toluene, dichloromethane, ethyl acetate, methanol
The recovery and reuse of ILs
Scheme 2-8 Reaction between 4'-iodoacetophenoneand copper(I) bromide Aryl iodide (0.1 mmol) and copper(I) halide (0.2mmol) were added into a 4 mL vial Diphenyl ether (5.2 mg, used as internal standard) and solvent (0.4 mL) were then added to the vial in succession The resulting reaction mixture was stirred at 140 C for 8 h At interval of time, an aliquot (0.1 mL) was withdrawn from the reaction mixture and quenching with water (0.5 mL) The organic components were extracted by ethyl acetate (2.5 mL), dried over anhydrous Na2SO4, and analyzed by GC with reference to diphenyl ether Yield of product was calculated by formula (2) Products were isolated and confirmed by GC-MS and NMR
Where: mPr (mg): Mass of 4'-bromoacetophenone obtained
Page 52 mPr’(mg): Calculated mass of 4'-bromoacetophenone when yield 100%
SPr: Peak area of 4'-bromoacetophenone in sample SIS: Peak area of diphenyl ether in sample mIS (mg): Mass of diphenyl ether in sample
The factors affect the reaction conversion:
The molar ratio (Aryl iodide/copper(I) halide): 1:0.5, 1:1.5, 1:2, 1:2.3 and
Several kinds of solvents: [BMIM]Br, [HMIM]Br, [OMIM]Br, diglymer,
Several kinds of catalysts: copper(I) bromide, iron(II) chloride, zinc(II) chloride, nickel(II) chloride, sodium bromide, mixture of silver nitrate and potassium bromide
Aryl iodide derivatives: 4'-iodoacetophenone, 4-Bromoanisole, 4- bromotoluene, 4’-chloroacetophenone, 4-chloroanisole, 1-chloro-4- fluorobenzene
The recovery and reuse of ILs
RESULTS AND DISCUSSION
The synthesis of ionic liquids
3.1.1 The synthesis of [AMIM]Br
The [AMIM]Br ionic liquid products were immiscible with starting material solution, as a result of that, the formation of these ionic liquids could be monitored visibly in the reaction The phenomenon of the synthetic process is that the initial mixture was clear, then became opaque, and finally returned to transparent mixture Compared to the conventional method, the microwave assisted synthesis of ionic liquid afforded very high yield with short reaction time It was explained by the efficient heating effect of the electromagnetic radiation [52] Ionic liquids are molecular dipoles, which can absorb very easily the microwave energy They are normally randomly orientated, but under the influence of microwave they rotate themselves according to the external electric field [110] The rapid oscillation of the external electric field causes Molecular dipoles to realign themselves continuously This suitable condition in the collision of dipoles, consequently heat is generated Microwave irradiation therefore produces effective internal heating by direct coupling of microwave energy with the molecules that are present in the reaction mixture In addition, the irradiation was paused every 10 seconds to prevent the formation of a local overheating and undesired products because ILs strongly absorb the microwave energy [106] As expected, it was observed that using microwave in the synthesis of [AMIM]Br ionic liquids obtained the very high yield as well as the remarkable acceleration of the reaction rate Indeed, [AMIM] ionic liquids were prepared with the yields of over 90% only within several minutes Meanwhile, these synthesis under conventional condition consumed more than 12 hours to achieve the similar conversion [111] Besides it was also noted that these alkylation reactions were carried out in the solvent–free conditions and avoided the use of a large excess of alkyl halide These advantages are promising to lead to the
Page 54 economic and environmental benefits In summary, the above suitable condition implied that microwave technique could make the synthesis of ionic liquid not only faster but also greener as well as more convenient
The synthesis of [BMIM]Br could afford over 96% of yield compared to about 92% and 91% in case of [HMIM]Br and [OMIM]Br, respectively The results showed that increasing the length of alkyl chain corresponded to a decrease in reaction yields It was explained that the reduction of the inductive effect (+I) caused the reduction of the positive density of the carbon next to bromine atom when increasing the alkyl chain length of [AMIM]Br This reduction led to decrease in reactivity in substitution reaction, and the decline of microwave energy absorbability Additionally, it was also found that in order to achieve the similar yields, the irradiation time was obviously lengthened when increasing the length of the alkyl chain Indeed, the total irradiation time in the case of [BMIM]Br, [HMIM]Br and [OMIM]Br were 3, 6 and 9 minutes, respectively
Figure 3-1 The yield of synthetic process of [AMIM]Br ILs
Table 3-1 The yield of [AMIM]Br synthesis
30 (0.273) m[BMIM]Br experiment (g) 52.4 53.04 53.61 m[BMIM]Br theory (g) 55.18
40 (0.279) m[HMIM]Br experiment (g) 56.74 57.04 56.65 m[HMIM]Br theory (g) 61.66
50 (0.282) m[OMIM]Br experiment (g) 62.41 62.89 63.12 m[OMIM]Br theory (g) 68.66
The structures of [AMIM]Br ILs were characterized by NMR and MS The detailed results are described below
1 H NMR (500 MHz, DMSO-d6): δ = 0.86 (t, J=7.0 Hz, 3H; CH 3), 1.24 (m, 2H;
CH 2CH3), 1.75 (m, 2H; CH 2 CH2CH3), 3.87 (s, 3H; N-CH 3 ), 4.20 (m, 2H; N- CH 2 ), 7.78 (t, J=2.0 Hz, 1H; N-CH=C), 7.86 (t, J=2.0 Hz, 1H; N-CH=C), 9.37
13 C NMR (125 MHz, DMSO-d6): δ = 13.18 (C-CH3), 18.66 (CH2), 31.31 (CH2), 35.74 (N-CH3), 48.39 (N-CH2), 122.18 (C=C-N), 123.45 (C=C-N), 136.44 (N-
Figure 3-2 The structure of [BMIM]Br IL
The procedure for preparation of [HMIM]Br was described in the subsection 2.2.1 with 1-bromohexane as a precursor
1 HNMR (500 MHz, DMSO-d6): = 0.85 (t, J=1.5 Hz, 3H, CH3); 1.26 (m, 6H, CH2CH2CH2); 1.78 (m, 2H, CH2); 3.86 (s, 3H, N–CH3); 4.17 (t, J=7.5 Hz, 2H,
13 C NMR (125 MHz, DMSO-d6): = 13.74 (C–CH3); 21.77 (CH2); 25.05 (CH2); 29.27 (CH2); 30.46 (CH2); 35.71 (N–CH3); 48.69 (N–CH2); 122.19 (C=C–N); 123.50 (C=C–N); 136.44 (N–C=N) (Appendix 5)
The above analytical results confirm the structure and purity of the prepared ionic liquid [HMIM]Br
Figure 3-3 The structure of [HMIM]Br IL
The procedure for preparation of [OMIM]Br was described in the subsection 2.2.1 with 1-bromooctane as a precursor
1 H NMR (500 MHz, DMSO-d6): = 0.84 (t, J=5.0 Hz, 3H, CH3); 1.20 (m, 10H, CH2CH2CH2CH2CH2); 1.78 (m, 2H, CH2); 3.87 (s, 3H, N–CH3); 4.18 (t, J= 7.5
Hz, 2H, N–CH2); 7.76 (m, 1H, N–CH=C); 7.83 (m, 1H, N–CH=C); 9.30 (s,1H,N–CH=N) (Appendix 7)
13 C NMR (125 MHz, DMSO-d6): = 13.81 (C–CH3); 21.93 (CH2); 25.39 (CH2); 28.23 (CH2); 28.36 (CH2); 35.68 (N–CH3); 48.65 (N–CH2); 122.17(C=C–
The above analytical results confirm the structure and purity of the prepared ionic liquid [OMIM][Br]
Figure 3-4 The structure of [OMIM]Br IL
3.1.2 The synthesis of [AMIM]PF 6
Table 3-2 The yield of synthetic process of [AMIM]PF6
50 (0.228) m[BMIM]PF6 experiment (g) 50.53 50.78 51.02 m[BMIM]PF6 theory (g) 64.79
55 (0.223) m[HMIM]PF6 experiment (g) 59.47 59.00 59.12 m[HMIM]PF6 theory (g) 69.47
62.5 (0.227) m[OMIM]PF6 experiment (g) 69.89 70.34 70.54 m[OMIM]PF6 theory (g) 77.28
Figure 3-5 The yield of synthetic process of [AMIM]PF6 ILs
It has often been observed the detectable amount of HF is associated with a slow hydrolysis of [PF6] - in the presence of water [163] For this reason, the preparation of [AMIM]PF6 should be carried out in a plastic flask Cooling the starting materials before reaction was necessarily required because of the very high toxicity and strong vapor character of hexafluorophosphoric acid Moreover, the anion exchange between [AMIM]Br and HPF6 is an exothermic reaction, the reaction mixture should be therefore immersed in an ice bath during reaction time to limit the overheating as well as the vaporization of HPF6 In addition, cooling the reaction mixture also facilitated the phase separation, thus accelerated the reaction rate
The [AMIM]PF6 ionic liquids are negligibly soluble in water, therefore, the resulting mixture was washed with cooled water to achieve higher yield The yield of the synthetic process of [AMIM]PF6 increased with an increase in the alkyl chain length Actually, the synthesis of [OMIM]PF6 could achieve over 90% compared to about 82% and 78% in the case of [HMIM]PF6 and [BMIM]PF6, respectively The reduction of the [AMIM]PF6 solubility in water corresponding to the increase in the alkyl chain length could be the suitable explanation for the obtained results
3.1.3 [AMIM]PF 6 ILs characterization 3.1.3.1 [BMIM]PF 6 IL
The procedure for preparation of [BMIM]PF6 was described in the subsection 2.2.2 with 1-butyl-3-methylimidazolium bromide as a precursor
1 H NMR (500 MHz, DMSO-d6): δ = 0.91 (t, J=7,5 Hz, 3H, CH3); 1.27 (m, 2H, CH2CH3); 1.77 (m, 2H, CH2CH2CH3); 3.85 (s, 3H, N–CH3); 4.16 (t,
J=7.0 Hz, 2H, N-CH2); 7.67 (m, 1H, N–CH=C); 7.73 (m, 1H, N-CH=C); 9.07 (s, 1H, N-CH=N) (Appendix 10)
13 C NMR (125 MHz, DMSO-d6): δ = 13.14 (C–CH3); 18.71 (CH2); 31.28 (CH2); 35.65 (N–CH3); 48.51 (N-CH2); 122.19 (C=C-N); 123.54(C=C-N);
MS (ESI): m/z = 139 [C8H15N2] + ; m/z = 423 [([C8H15N2] + )2PF6 -] + The above analytical results confirm the structure and purity of the prepared ionic liquid [BMIM]PF6 (Appendix 12).
Figure 3-6 The structure of [BMIM]PF6 IL
The procedure for preparation of [HMIM]PF6 was described in the subsection 2.2.2 with 1-hexyl-3- methylimidazolium bromide as a precursor
1 H NMR (500 MHz, DMSO-d6): δ = 0.87 (t, J= 1.5 Hz, 3H, CH3); 1.26 (m, 6H, CH2CH2CH2); 1.78 (m, 2H, CH2); 3.85 (s, 3H, N–CH3); 4.15 (t, J= 7.0 Hz, 2H, N-CH2); 7.67 (m, 1H, N–CH=C); 7.73 (m, 1H, N-CH=C); 9.07(s, 1H, N-CH=N) (Appendix 13).
13 C NMR (125 MHz, DMSO-d6): δ = 13.71 (C–CH3); 21.80 (CH2); 25.09(CH2);
Page 61 The above analytical results confirm the structure and purity of the prepared ionic liquid [HMIM]PF6
Figure 3-7 The structure of [HMIM]PF6 IL
The procedure for preparation of [OMIM]PF6 was described the in subsection 2.2.2 with 1-octyl-3- methylimidazolium bromide as a precursor
1 H NMR (500 MHz, DMSO-d6): δ = 0.860 (t, J= 3.0 Hz, H, CH3); 1.265 (m, 10H,CH2CH2CH2CH2CH2); 1.783 (m, 2H, CH2); 3.845 (s, 3H, N–CH3); 4.145 (t, J=2.0 Hz,H, N-CH2); 7.674 (m, 1H, N–CH=C); 7.741 (m, 1H, N-CH=C); 9.076 (s, 1H, N-CH=N) (Appendix 16)
13 C NMR (125 MHz, DMSO-d6): δ = 13.830 (C–CH3); 21.978 (CH2); 25.427 (CH2); 28.258(CH2); 28.389 (CH2); 29.297 (CH2); 31.090 (CH2); 35.657 (N- CH3); 48.750 (N-CH2), 122.191 (C=C-N); 123.534 (C=C-N); 136.422 (N-C=N) (Appendix 17)
The above analytical results confirm the structure and purity of the prepared ionic liquid [OMIM]PF6
Figure 3-8 The structure of [OMIM]PF6 IL
Page 62 Imidazolium ionic liquid not only acts as acid-base but also can be viewed as a non-protonated polar solvent The polarization of ionic liquids varies according to their structure As known, S N 2 substitution reactions and condensation reactions are often required acid-base catalysis and strongly influenced by the solvents S N 2 reactions was effected by the nucleophile, solvent and leaving group It is usually performed in organic solvents To favor S N 2 mechanism, protic solvents such as water and alcohols should be avoided Since the hydrogen atom in a polar protic solvent is highly positively charged, it can interact with the anionic nucleophile which would negatively affect a S N 2 reaction To prevent this interference, polar, aprotic solvents such as acetone, DMF or DMSO without acidic protons-accelerating S N 2 reaction by solvating the cation thus making the nucleophile more available to react The effect of solvents on the rate of S N 2 nucleophilic substitution reactions was increased in the order of DMSO I in the N-arylation reactivity is carbon- halogen bond polarity which increases from I to F [110, 112, 114, 188]
Figure 3-25 Effect of the halogen in 4-nitrophenyl halide on the reaction conversion
3.4.6 Reusability of Ionic liquid [BMIM]Br
As mentioned earlier, the application of ionic liquids as “greener” alternatives is due to the feasible reusability of ionic liquid solvent which is stated to be important in the view of green chemistry [4] In our work, the ionic liquid solvent was therefore investigated for the recoverability and recyclability in the N-arylation of piperidine with 4-bromonitrobenzene over seven successive runs
The reaction was carried out in [BMIM]Br at 90 o C with the reagent molar ratio of piperidine and 4-bromonitrobenzene 3.0: 1.0 After the reaction, the product and unreacted starting materials were separated from the reaction mixture by extraction with diethyl ether The ionic liquid solvent was then washed several times with diethyl ether, and then reused in a further reaction under condition which is identical to those of the first run Interestingly, it was found that the ionic liquid could be reused several times without a significant decrease in the efficiency with the conversion of more than 93% at the seventh run (Figure 3-26)
Figure 3-26 Ionic liquid recycling study for the N-arylation reaction between piperidine and 4-bromonitrobenzene
Table 3-5 The reaction conversions of the optimized synthetic conditions for N- arylation reaction
Alkyl chain length [BMIM]Br; [HMIM]Br; [OMIM]Br
Molar ratio between 1-bromo-4- nitrobenzene/piperidine 1.0/1.5; 1.0/2.0; 1.0/2.5 and 1.0/3.0 Ionic liquid anion [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvent [BMIM]Br, DMF, DMSO, n-butanol, toluene, NMP The recovery and reuse of ILs 7 runs
1 H NMR (500 MHz, CDCl3): δ = 1.68 (s, 6H, -CH2- CH2); 3.34 (s, 4H, -CH2- N); 6.78 (m, Jo=6.0 Hz, Jm=3.5 Hz, 2H, =CH-C); 8.07 (m, Jo=4.5 Hz, Jm=2.0 Hz, 2H, =CH-C) (Appendix 25)
Page 84 The above analytical results confirm the structure of 1-(4-nitrophenyl)piperidine
Figure 3-27 The structure of 1-(4-nitrophenyl)piperidine
In summary, we developed a convenient and environmentally friendly N-aryl piperidine synthesis using the imidazolium-based ionic liquid as a green solvent in the absence of a transition metal catalyst Ionic liquid-mediated reaction proceeded smoothly to 94% conversion in comparison with the case of conventional organic solvents under the same conditions (Figure 3-24)
Interestingly, it was found that the C(aryl)-N coupling reaction in [BMIM]Br gave a selectivity for 4-bromonitrobenzene that was higher than that for the corresponding 2-isomer whereas 3-isomer was inactive Current research in our laboratory has focused on investigation of promoting role and high recyclability of ionic liquids for a wide range of organic transformations The suitable condition for N-aryl piperidine synthesis with [BMIM]Br IL as solvent was at temperature of 90 o C, reagent ratio 1 to 3 and reaction time of 3 h The reaction mechanism for ILs assisted synthesis of N-aryl piperidine was presented in
Figure 3-35 Moreover, the addition of ILs in the reaction also increases the selectivity of the product, which is reflected by GC and NMR analysis results
Scheme 3-4 Possible mechanism for the formation of 1-(4- nitrophenyl)piperidine derivative reaction
The synthesis of 1-(2-(N-morpholino)ethyl)-2-methylindole derivatives (Reaction 4)
In the N-alkylation of indole, a strong base is required to generate the anion on the nitrogen atom, facilitating the alkylation reaction with the alkyl halide [196, 197] The reaction also requires a base to convert the ammonium salt to the corresponding amine N-alkylation of indole reaction was conducted by Le and
Page 85 co-workers in 2004 [140], in this study, [BMIM]BF4 was used as solvent Here, we wished to conduct the N-alkylation of indole reaction in easy synthesis solvent and with high reaction yield The [BMIM]PF6 ionic liquid was evaluated for their suitability as reaction solvent initially for the reaction between 1-(N- morpholino)-2-chloroethane hydrochloride and 2-methylindole to form 1-(2-(N- morpholino)ethyl)-2-methylindole as the principal product (Scheme 3-5)
Scheme 3-5 The reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in the [BMIM]PF6 ionic liquid
3.5.1 Effect of the reaction time
Initial studies focused on the effect of the reaction time on the reaction yield, at room temperature using 1-(N-morpholino)-2-chloroethane hydrochloride : 2-methylindole molar ratio of 1.2: 1, KOH: 2-methylindole molar ratio of 3: 1 and [BMIM]PF6: 2-methylindole molar ratio of 60: 1 It was found that the reaction could afford 64% yield within 7 h Increasing reaction time to 8 h lead to an enhancement of only 1% yield (Figure 3-28) Therefore, 7 h was chosen as reaction time for further experiments
Figure 3-28 Effect of reaction time on the product yield
3.5.2 Effect of 1-(N-morpholino)-2-chloroethane hydrochloride : 2- methylindole molar ratio
Another factor that could effect the yield of the reaction was the 1-(N- morpholino)-2-chloroethane hydrochloride: 2-methylindole molar ratio It was previously reported that the N-alkylation of indole in conventional solvents could proceed well using the alkyl halide : indole molar ratio in the range of 1: 1 to 2: 1 [198-200] The studies then addressed the effect of 1-(N-morpholino)-2- chloroethane hydrochloride : 2-methylindole molar ratio in the range of 1: 1 to 1.6: 1 It was observed that increasing this molar ratio from 1: 1 to 1.2: 1 lead to an enhancement in reaction yield from 42% to 64% (Figure 3-29) Using higher reagent molar ratio was found to be unnecessary as the reaction yield was not improved further Therefore,1-(N-morpholino)-2-chloroethane hydrochloride: 2- methylindole molar ratio of 1.2: 1 was used in further experiments
As mentioned earlier, a strong base is required to generate the anion on the nitrogen atom, facilitating the N-alkylation reaction with the alkyl halide [196,
Figure 3-29 Effect of 1-(N-morpholino)-2-chloroethane hydrochloride: 2- methylindole molar ratio
3.5.3 Effect of KOH: 2-methylindole molar ratio
The reaction also requires a base to convert the ammonium salt to the corresponding amine It was therefore decided to investigate the effect of KOH : 2-methylindole molar ratio on the yield of the product The reaction was carried out using 1-(N-morpholino)-2-chloroethane hydrochloride: 2-methylindole molar ratio of 1.2: 1, and [BMIM]PF6: 2-methylindole molar ratio of 60:1 in 7 h It was observed that best yield (73%) was achieved at the KOH: 2-methylindole molar ratio of 4:1 A yield of only 9% was obtained for the reaction using less than a stoichiometric amount of base relative to 2-methylindole, while the reaction yield could be improved to 32% and 64% for the KOH: 2-methylindole molar ratio of 2: 1 and 3: 1, respectively (Figure 3-30) In the N-alkylation of indole, a strong base is required to generate the anion on the nitrogen atom, facilitating the alkylation reaction with the alkyl halide [196, 197] The reaction also requires a base to convert the ammonium salt to the corresponding amine Indeed, it was previously reported that the N-alkylation of indole in DMSO could proceed well using KOH: indole molar ratio of 3.9: 1 [68]
Figure 3-30 Effect of KOH: 2-methylindole molar ratio
Conventionally, this reaction was carried out in DMF or DMSO, in the presence of a strong base such as NaH, NaNH2, CH3ONa, KOH, or NaOH [198, 201] However, NaH, NaNH2 and CH3ONa are not only expensive but also require an anhydrous medium A mixture of aqueous NaOH and a phase transfer catalyst was previously found to be effective for the N-alkylation of indole [196]
Sukata previously reported the N-alkylation reactions of indole and pyrrole in ionic liquids using K2CO3 as a base [163, 199] The reaction was therefore carried out using different bases, including triethylamine, Na2CO3, K3PO4.3H2O, K2CO3, KOH, NaOH, and CH3COONa
Figure 3-31 Effect of different bases to reaction yield of N-alkylation of indole
It was found that trimethylamine, Na2CO3, K3PO4, K2CO3 and CH3COONa were ineffective for the reaction, with less than 5% yields KOH was the most suitable base with 73% yield being achieved for the reaction, while the reaction using NaOH could afford a yield of 50% (Figure 3-31) Indeed, KOH was reported to be the base of choice for several indole N-alkylation reactions [198, 199, 202]
3.5.5 Effect of the reaction temperature
With these suitable conditions in mind, we then decided to investigate the effect of the temperature on the reaction yield The reaction was carried out at different temperature, using 1-(N-morpholino)-2-chloroethane hydrochloride: 2- methylindole molar ratio of 1.2: 1, KOH: 2-methylindole molar ratio of 4: 1, and [BMIM]PF6: 2-methylindole molar ratio of 60 : 1 Interestingly, it was found that increasing the reaction temperature resulted in a significant drop in reaction yield The reaction at room temperature afforded a yield of 73%, while the yield decreased to 66% for the reaction at 40 o C Moreover, a yield of only 23% was observed for the reaction carried out at 90 o C (Figure 3-32)
Figure 3-32 Effect of reaction temperature
Indeed, it was previously reported that several indole N-alkylation reactions were successfully carried out in conventional solvents at room temperature [198-201] The significant drop in the reaction yield at high temperature could be rationalized based on the formation of by-products
However, the problem still needs further studies to elucidate a complete reaction pathway
3.5.6 Effect of [BMIM]PF 6 : 2-methylindole molar ratio
The amount of the solvent used for the reaction could be of extreme importance, especially for the case of ionic liquids because of their unique properties It was therefore necessary to investigate the effect of [BMIM]PF6 : 2- methylindole molar ratio on the reaction yield The reaction was carried out at different [BMIM]PF6: 2-methylindole molar ratios, using 1-(N-morpholino)-2- chloroethane hydrochloride : 2-methylindole molar ratio of 1.2: 1, and KOH: 2- methylindole molar ratio of 4: 1 It was observed that decreasing the [BMIM]PF6: 2-methylindole molar ratio from 60: 1 to 40: 1 could increase the reaction yield from 73% to 75% From experimental points of view, it should be noted that decreasing this ratio to less than 40: 1 resulted in difficulties in stirring
Page 91 due to the high viscosity of the ionic liquid Increasing this ratio to higher than 60: 1 was found to be slightly less effective for the reaction, with 70% yield being achieved at the ratio of 120: 1 (Figure 3-33)
Figure 3-33 Effect of [BMIM]PF6: 2-methylindole molar ratio
3.5.7 Effect of different ionic liquid solvents
It was previously reported that several imidazolium-based ionic liquids had polarities similar to those of polar aprotic solvents such as DMSO, DMF [163] As mentioned earlier, the reaction between 1-(N-morpholino)-2- chloroethane hydrochloride and 2-methylindole was conventionally carried out in a dipolar aprotic solvent such as DMF or DMSO, and nonpolar solvents were not suitable for the reaction [5,6] The reaction was also carried out in other imidazolium-based ionic liquids, including [HMIM]PF6, and [OMIM]PF6 It was found that increasing the alkyl chain resulted in a drop slightly in the reaction yield, with 73.8% and 73% being achieved for the case of [HMIM]PF6 and [OMIM]PF6, respectively This could be rationalized based on the fact that increasing the length of the alkyl group would decrease the polarity of the ionic liquid solvent, though the difference between butyl, hexyl and octyl groups were not significant Interestingly, it was observed that [BMIM]Br, [HMIM]Br, [OMIM]Br ionic liquids were ineffective for the reaction (Figure 3-34) This can
Page 92 explained that the polarization of these ionic liquids is not as great as the ionic liquids with PF6 anions, so dissolving the solid base is not good However, the problem still needs further studies to clarify the effect of anion in the ionic liquid structure
Figure 3-34 Effect of different ionic liquid solvents
3.5.8 Solvent [BMIM]PF 6 recycling studies
Ionic liquids have been considered as green solvents not only due to their non-volatile nature, minimizing emission of toxic organic compounds, but also because of their reuse and recyclability [2, 44] We therefore investigated the
Synthesis of pyrrole derivatives (Reaction 5)
Scheme 3-6 The Paal-Knorr cyclocondensation between 2,5-hexanedione and amines in ionic liquids Polar solvents are well-known for Paal-Knorr reaction [204] They make the polar starting materials increase their solubility However, the polarity of solvents causes a rise in the polarity of C=O double bond which is a suitable condition in increasing the positive density of carbon atom next to oxygen, thus, accelerates the reaction rate [126, 204] The polarity of many ILs is similar to those of short chain alcohol, or polar aprotic solvents DMF, DMSO [44, 205]
Therefore, ILs are suitable solvents for Paal-Knorr pyrrole synthesis and immiscible with non-polar, and less polar organic solvents Diethyl ether can be therefore used to separate non-polar compound from ILs by extraction
[AMIM]PF6 ILs are the preferred choices in view of green chemistry because of their remarkable reusability
3.6.1 The effect of reagent molar ratio
Figure 3-37 The effect of reagent molar ratio on the Paal Knorr reaction conversion
Figure 3-37 shows that a small change in the molar ratio of reactants led to a significant change in the reaction rate Actually, the Paal Knorr reaction using the benzylamine: 2,5-hexanedione molar ratio of 1:1.2 achieved the conversion of more than 80% after the first ten minutes compared with about 70% and 54% in case of 1:1.1 and 1:1, respectively As a reason for this result, the molar ratio of reactants is one of the main influences on the reaction rate The results show that the higher molar ratio of reactants was, the faster the reaction rate would be observed [206] For the first ten minutes, the conversion was increased by 80%, and then an increase of only 14% for the next period In all cases, the high conversion was also obtained with short reaction time Indeed, the conversion was almost complete after 40 minutes
3.6.2 The effect of the amount of ionic liquid
In purpose of investigating the influence of ionic liquid amount on the reaction conversion, the Paal-Knorr condensation was carried out with a variety of ionic liquid : benzylamine molar ratio It was observed that the reaction rate of Paal Knorr procedure declined dramatically when raising the ionic liquid : benzylamine molar ratio The conversions of 81%, 58%, 38% were achieved
Page 97 after 10 minutes corresponding to the using molar ratio of 14:1, 19:1, 24:1, respectively (Figure 3-38) The process using the ratio of 14:1 afforded the conversion of almost 100% after only 30 minutes while the similar conversion could not be obtained in cases of 19:1 and 24:1 molar ratio even after 50 minutes
As mentioned above, the explanation was based on the fact that the concentration of reactants impacted on the reaction rate Increasing the volume of ionic liquid caused a drop in the reactant concentration leading to a decrease in the reaction rate In summary, the ionic liquid : benzylamine molar ratio of 14:1 would be used to optimize the conversion of Paal-Knorr procedure
Figure 3-38 The influence of the used amount of ionic liquid
3.6.3 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion
Figure 3-39 The influence of some kinds of ionic liquids on the reaction conversion
The Paal Knorr reaction was conducted in different imidazolium hexafluorophosphate ionic liquids including [BMIM]PF6, [HMIM]PF6 and [OMIM]PF6 It was found that increasing the length of the alkyl chain on the imidazolium ring led to a slight drop in the reaction conversion (Figure 3-39)
The Paal- Knorr reaction carried out in the [BMIM]PF6 afforded 81% conversion after 10 minutes compared to 77% in case of [HMIM]PF6 and 69% in case of [OMIM]PF6 It was also observed that the conversion of 100% could be obtained after only 30, 40 and 50 minutes when using [BMIM]PF6, [HMIM]PF6 and [OMIM]PF6 as solvents, respectively These suitable condition could be rationalized on the fact that increasing the length of the alkyl chain would decrease the polarity of the solvent resulting in a slight drop in the reaction rate
This is due to the increase in the alkyl chain length on the imidazolium ring corresponded to a rise in the viscosity of ionic liquid [207] and also caused a decrease in reaction rate Practically, the viscosity of [BMIM]PF6, [HMIM]PF6, [OMIM]PF6 are 450 Cps, 585 Cps, 682 Cps at 25 o C, respectively [1] Anyway,
Page 99 the absolute conversion could be achieved after 60 min in three cases of ionic liquid In summary, [BMIM]PF6 could be considered as an efficient solvent for the Paal-Knorr reaction and would be employed for further studies
3.6.4 The effect of organic solvents
To determine whether the ionic liquid was an essential factor to obtain the high conversion of Paal-Knorr condensation, the same reactions were carried out in a variety of traditional solvents As seen from Figure 3-40, there is a sufficient decrease in conversion when changing from polar solvents to less polar and non- polar ones Among different organic solvents used in these experiments, [BMIM]PF6 ionic liquid gave the highest reaction conversion After 30 minutes, the reaction reached a completes conversion On the contrary, the Paal–Knorr condensations decreased in dichloromethane and toluene, in which the conversion only reached 52% and 21% for dichloromethane and toluene, respectively, after 60 minutes Likewise, common polar solvents such as methanol and ethyl acetate also performed a better reaction conversion than those of non-polar ones The conversion of 94% and 78% were corresponded to the methanol and ethyl acetate, respectively These can be explained by the fact that the decrease in the polarity of solvent causes troubles for the reaction rate as presented above This demonstrated that [BMIM]PF6 ionic liquid played a key role in accelerating the rate of the Paal-Knorr pyrrole synthesis
Figure 3-40 The effect of other organic solvents on the reaction conversion
In order to demonstrate the scope of this reaction, the study was then extended to the Paal-Knorr reaction of aromatic primary amine (4- methoxyaniline) For Paal-Knorr pyrrole synthesis, the low conversion was archived for arylamines, the reason is free electrons in the N conjugated to an aromatic ring system, so that the arylamines need additional conditions for reaction In the mechanism of the Paal-Knorr pyrrole synthesis reported by Mothana and Boyd, it was confirmed that different conditions (temperature, solvent and substitution of amine) affected the rate of pyrrole formation [208]
Accordingly, initial screenings addressed the effect of temperature on the reaction conversion It was previously reported that the Paal-Knorr condensation could occur in the temperature range from 25 o C to 100 o C with a wide variety of different reagents and catalysts [163] In particular, several studies with aniline derivatives, high temperature or microwave irradiation was required [121, 123, 127, 209, 210] The Paal-Knorr reaction was carried out in [BMIM]PF6 with 1.5 equivalent of 4-methoxyaniline as starting material at 60, 80, and 100 o C It was found that the conversions of 43, 56, and 68% were achieved after 6 h for temperature of 60, 80 and 100 o C, respectively (Figure 3-41) However, it was
Page 101 also observed that employing too high temperature could lead to acceleration of oxidation of arylamines For this reason, increasing the reaction temperature to higher than 100 o C was unnecessary for the reaction, although the reaction rate could be higher
Figure 3-41 Effect of temperature on the reaction conversions of 4- methoxyaniline as amine
The reactions were carried out at 100 o C using [BMIM]PF6 as a solvent
The reaction of the 4-methoxyaniline gave 99% conversion after 4 h In earlier reports, it was well known that less basic aromatic amines needed longer reaction time and harsher conditions for the formation of corresponding pyrroles [211, 212]
Table 3-7 Reaction of 2,5-hexanedione with amines
3.6.6 The reusability of [BMIM]PF 6 ionic liquid
Halogen exchange reaction (Reaction 6)
The halogen exchange reactions between aryl iodides and copper(I) halides were conducted to produce corresponding aryl bromides or aryl chlorides The reaction between 4'-iodoacetophenone and copper(I) bromide to form 4'- bromoacetophenone was investigated under various parameters, namely molar ratios, temperature, and solvents (Scheme 3-7)
Scheme 3-7 The halogen exchange reactions In addition, to expand the applicability of copper(I) halide reactions with different aryl iodides and aryl bromides were proceeded An important advantage of this work is the use of copper(I) halides, which are more economical than nickel and ruthenium compounds [153, 161]
3.7.1 Effect of time reaction on reaction yield
The effect of reaction time on the reaction yield was carried out at 140 o C using the molar ratio of aryl iodides: copper(I) bromide 1: 2 with biphenyl ether as an internal standard and [BMIM]Br as solvent It was found that the reaction could afford a reasonable yield within 8 h, with a yield of 92.4% being observed under this condition Increasing reaction time to 24 h led to an enhancement of less than 1 % yield (Figure 3-44) Therefore, 8 h of the reaction time was chosen for further experiments
Figure 3-44 Effect of the reaction time on yield of 4'-bromoacetophenone reaction
3.7.2 Effect of 4'-iodoacetophenone/copper(I) bromide molar ratios on the reaction yield
The reagents ratio is an important factor that should be taken into accounts when investigating the copper-mediated halogen exchange reaction Initial studies about reagents ratio effect provided by performing the reaction at 140 C for 8 h, using 0.1 mmol of 4'-iodoacetophenone in 1 mL ILs The examined 4'- iodoacetophenone/copper(I) bromide molar ratios were: 1:0.5; 1:1.5; 1:2; 1:2.3 and 1:2.5
With 0.5; 1.5 equiv of copper(I) bromide being used, approximately 50% of the reactant was converted to the product When 2.0 equiv of copper(I) bromide was employed, the yield of more than 90% was obtained (Figure 3-45)
The yield increasing from the ratio of 1:0.5, 1:1.5, to 1:2.0 and decreased from 1:2.0 to 1:2.5, the maximum yield was 91% with the ratio of 1:2.0 It is supposed that 4'-iodoacetophenone was rapidly reacted with copper(I) bromide to form 4'- bromoacetophenone Therefore, the exceeded amount of copper(I) bromide was not required in transforming 4'-iodoacetophenone into 4'-bromoacetophenone
The result showed that this reaction has high bromide ion utilization efficiency
Figure 3-45 Effect of molar ratio between 4'-iodoacetophenone/CuBr on the reaction yield A reagent ratio range of 1:1 to 1:2 was previously employed by Arvela and Leadbeater in the halogen exchange reaction using nickel(II) salts as reagents [161] Indeed, 2 equiv of NiBr2 could be used for the bromination, and 1 equiv of NiCl2 could be used for the chlorination Barthzy and co-workers used 1.5 equiv of thallium fluoride (TlF) to achieve relatively high efficiency [153]
However, the toxic and expensive TlF made a considerable drawback of this approach Generally, the molar ratio of 1:2.0 in our work gave the highest the reaction conversion Therefore, 2.0 equiv of copper(I) bromide was chosen for further experiments
3.7.3 Effect of temperature on the reaction yield
Obviously, temperature plays an important role in many organic transformations Therefore, in the second step, we decided to evaluate the effect of temperature on the product yield The halogen exchange reactions were carried out using 0.1 mmol of 4'-iodoacetophenone and 2.0 equiv of copper(I) bromide in 0.4 mL [BMIM]Br, at 120, 130, 140 and 150 C, respectively The result in figure 3-50 noticed that at 140 C, the reaction yield reached the value of 92.4% at 8 hours However, the reaction temperatures were decreased to 120 C and 130 C resulted in the reaction yields were 9.4% and 36.1%, respectively It was believed that the temperature provided the energy for the dissociation of iodine
Page 108 atom from C-I bond but increasing the reaction temperature to 150 C resulted in a slight drop in reaction yield (76.4%)
Figure 3-46 Effect of temperature on reaction yield
In the first attempt for nickel-mediated halogen exchange reaction, Cramer and Coulson performed the reaction at 210 C [160] An enhanced system was developed by Arvela and Leadbeater, the reaction was carried out at 170 C under microwave irradiation [161] Recently, several reports showed that halide exchange reaction could be conducted under milder condition Barthzy and co- workers investigated the halide exchange with 16-electron ruthenium(II) complexes at room temperature to form fluorinated arenes [153] In conclusion, the reaction temperature of 140 C gave the reaction yield to be comparable to previous approaches Therefore, we decided to use 140 o C temperature for further experiments
3.7.4 Effect of solvents on the reaction yield
The influence of solvents on the halogen exchange reaction were also studied In this study, [BMIM]Br, [HMIM]Br, [OMIM]Br, diglymer, DMF, NMP and DMA were tested for the copper-mediated halogen exchange The reactions were performed at 140 C for 8 h using 0.1 mmol of 4'- iodoacetophenone and 2.0 equiv of copper(I) bromide in 0.4 mL solvent
Figure 3-47 Effect of solvents on reaction yield
The result in Figure 3-47 indicated that [BMIM]Br was the most effective solvent for this reaction High yield up to 92.4% was achieved for [BMIM]Br after 8 hours in comparison with other solvents, which afforded only from 46% to 84.3% yield All of the examined solvents could be used for this reaction
However, [BMIM]Br would be the solvent of choice for further studies The conventional halide exchange using NiCl2 as catalyst was carried out in ethanol solution [160] The work of Arnold and co-workers involved the use of dichloromethane as solvent for the halogen exchange reaction [213] In 2010, Watson and co-workers reported the palladium catalytic conversion of aryl triflates to aryl fluorides [156] They discovered that the use of cyclohexane suppressed the formation of undesired isomer It is supposed that using different solvents might accelerate or slow down the transformation of reaction
3.7.5 Effect of different catalysts on the reaction yield
The next step to determine the effect of other catalysts was performed for the comparison with copper(I) halides The reactions were carried out at 140 C for 8 hours using 0.1 mmol of 4'-iodoacetophenone and 2.0 equiv of metal halide in 0.4 mL [BMIM]Br
Figure 3-48 Effect of catalysts on the reaction yield
The result indicated in (Figure 3-48) that none of catalysis, except for copper bromide could be used for this reaction There was no trace of product when using iron(II) chloride, zinc(II) chloride, nickel(II) chloride, sodium bromide, mixture of silver nitrate and potassium bromide It was also noticed that copper(II) bromide gave lower product yield than copper(I) bromide This might due to the less reactivity of copper(II) bromide compared with copper(I) bromide It was previously reported that only a few halogen sources could be used for the halogen exchange reaction, most of them proceeded thought a copper- or nickel-based system Palladium-based system was previously shown to be ineffective for this type of reaction [151] Experimental suitable condition showed that the halogenated agent CuBr performed well in 1-butyl-3- methylimmidazolium bromide solvent
3.7.6 Effect of aryl halide substituents on the reaction yield
Synthesis of coumarin derivatives from phenolic acetates and acrylates
In 2006, Rao and Sivakumar conducted the condensation of α-aroylketene dithioacetals and 2-hydroxyarylaldehydes for facile synthesis of a combinatorial library of 3-aroylcoumarins in the presence of piperidine as a catalyst [92]
Scheme 1-12 Condensation of α-aroylketene dithioacetals and 2- hydroxyarylaldehydes [92]
Benzodiazepines are an important class of aza heterocycles with biological activities and therapeutic functions Among derivatives of benzodiazepine class, 1,5-benzodiazepines has extensively been used as anticonvulsant, anti-anxiety, antiviral, antitumor, psychosis, antipyretic, and anti-inflammatory agents [93-96]
Moreover, they are also known as the precursors in the preparation of triazoles and oxadiazoles [97-99] With their wide applications, a large number of
Page 23 methodologies for the synthesis of 1,5-benzodiazepines have been developed
In 2008, Silva and co-workers synthesized 1,2,4,5-tetrahydro-1,4- benzodiazepin-3-ones in a one-pot reaction with two-step synthesis under a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant Two pathways were accessible; both routes utilize bifunctional, o- nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B) [100]
Scheme 1-13 Synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones [100]
One of simple and efficient protocols commonly studied is the direct condensation of 1,2-phenylenediamines and ketones in the presence of an acid catalyst [101]
Scheme 1-14 Synthesis of 2,3-dihydro-1-H-1,5-benzodiazepine from o- phenylenediamine and acetophenone [101]
The uses of various catalysts, such as polyphosphoric acid, MgBr2, Sc(OTf)3, InBr3, H3BO3, polymer-supported FeCl3, SiO2/ZnCl2, MgO/POCl3, CH3COOH under microwave irradiation for the cyclocondensation to synthesize 1,5-benzodiazepines were reported [97, 98, 102-105]
However, many of these processes have remained several shortcomings including prolonged reaction time, low selectivity, harsh reaction condition, and complex work-up procedures Therefore, there is still a need of convenient and practical methods for the synthesis of substituted 1,5-benzodiazepines under mild
Page 24 reaction conditions with economic viability and high yield
1.3.2 Carbon-Nitrogen coupling 1.3.2.1 Synthesis of substituted piperidines (N-arylation)
Recently, the N-arylation of piperidine has been intensely studied due to pharmacological activities (i.e., antibacterial, antiviral, anti-inflammatory, anti- allergic) of compounds containing the N-aryl heterocyclic amine moiety [106]
Most of methods for the formation of aryl-nitrogen bond from aryl halide and amine are based on transition metal-catalyzed systems [106-109] Interestingly, with aryl halides activated by electron-withdrawing groups such as -NO2, -CN, and -CF3, N-arylation can occur by nucleophilic aromatic substitution without the presence of expensive transition metal catalysts [110-112] However, long reaction times or vigorous conditions of elevated temperature, high pressure, microwave assistance and the support of other bases are required to obtain acceptable yields [110, 113, 114] Therefore, the development of more efficient and facile protocols for preparation of N-aryl substituted piperidines is still a great challenge For aryl halide containing the electron-withdrawing groups (-NO2, -CN, -COCH3 ) and no secondary amines, reactions can occur easily under the nucleophilic aromatic substitution in presence of polar solvents and a strong base without a catalyst [115] However, carbon-nitrogen coupling reaction was performed successfully on the aryl halide and less reactive amines with palladium complex/copper complex as a catalyst [115, 116] In 2011, Fors and Buchwald reported the usage of Pd catalyst based on two biarylphosphine ligands for C−N cross-coupling reactions [116]
Scheme 1-15 Pd catalyst based on two biarylphosphine ligands for C−N cross- coupling reactions [116]
In the 1990s, the teams of Buchwald and Hartwig developed a new method to form the connective carbon-nitrogen The coupling reaction was done between aryl halides and amines catalyzed by palladium complexes [117, 118]
This is an effective way to implement carbon-coupling reaction between aryl halide containing no withdrawing electronic groups and weak amine base
Buchwald–Hartwig described carbon-nitrogen coupling reaction mechanism SNAr under the palladium catalyst (Scheme 1-16) The reaction generated acid HX which destroyed the catalytic activity of Pd(0), therefore, it needed to have the involvement of a consumer base as agent HX In addition, the base will instead form a complex with palladium, creating an stable state
Scheme 1-16 Mechanism Buchwald-Hartwig reaction [116]
Page 26 In 2011, Jiao and co-workers conducted Ullmann amination of aryl halides with copper powder-catalyst under organic solvent- and ligand-free [119]
Scheme 1-17 Ullmann amination of aryl halides with aqueous methylamine
Then in 2015, Zhou and co-workers used CuI/Oxalic diamide as catalyst for coupling reaction of (hetero)aryl chlorides and amines The reaction proceeds at 120 °C with K3PO4 as the base in DMSO to afford a wide range of (hetero)aryl amines in good to excellent yields [120]
Scheme 1-18 CuI/Oxalic diamide catalyzed coupling reaction of (hetero)aryl chlorides and amines[120]
Pyrroles are an important class of heterocyclic compounds, contributing to the structural skeleton of several natural products, synthetic pharmaceuticals, and functional materials [121, 122] One of the most common methods to achieve pyrroles is the Paal-Knorr reaction between 1,4-dicarbonyl compounds and primary amines [123] Conventionally, the Paal-Knorr condensation could be catalyzed by many catalysts, such as layered zirconium phosphate and zirconium sulfophenyl phosphonate, zeolite, Fe 3+ -montmorillonite, aluminum oxide, and ruthenium (III) chloride [121-124] However, toxic and volatile organic solvents used for this reaction, which caused several undesirable economic and environmental aspects as well as health and safety issues From the view of green chemistry, a more environmentally benign approach should be developed for the reaction
Page 27 Paal-Knorr reaction which occurs between a dione and a primary amine (or ammonia) is the most popular method to synthesize pyrroles (Scheme 1-19) [125] The mechanism of this reaction was studied in 1995 by Amarnath [125]
This research focused on explaining which intermediate was formed in the reaction, and then proposed an appropriate mechanism However, the mechanism for this reaction is still not deeply understood The widely agreed mechanism is recommended in Scheme 1-19 [125, 126] There are supposed to be three different pathways for Paal-Knorr mechanism, including the first one from compounds 1 to 2, 3, 4, and 5, or the second from compounds 1 to 2, 6, 9, 4, and 5, and the last from compounds 1 to 2, 6, 7, 4, and 5 However, any pathway containing the formation of enamine (compounds number 8 and 9) before the cyclization must be ruled out because the stereochemical configuration suitable condition cannot match the true product Additionally, any pathway containing the cyclization of imine (compound number 6 in the third pathway) must also be dismissed because the intermediate stability is opposite to the practical result
Therefore, the only appropriate mechanism should be the first pathway, where there is no water elimination occur before the rate-determined step, the cyclization
Scheme 1-19 Mechanism of Paal-Knorr reaction [125, 126]
Danks also studied microwave-assisted Paal-Knorr reaction in 1999 [127]
Page 28 The suitable condition showed that the synthesis of pyrroles by reaction of hexane-2,5-dione with primary amines occurred in less than two minutes under microwave activation
Scheme 1-20 Microwave assisted synthesis of pyrrole [127]
In a study of Paal-Knorr reaction, Zhang and his co-workers investigated the ultrasound-assisted synthesis of pyrroles in the presence of zirconium chloride as catalyst under solvent-free condition [128] Compared with known methods, this new method provides an easy access to various substituted pyrroles with excellent yields in short times The suitable conditions are shown in Table 1-5
Table 1-5 The ultrasound-assisted synthesis of substituted pyrroles in the presence of ZrCl4 under solvent-free condition [128]
Entry Amine Time (min) Yield (%)
Sreekumar and Padmakumar had carried out the preparation of pyrroles and pyrazoles by an interMolecular reaction of and diketones with primary amines or hydrazine derivatives respectively under zeolite catalysis [129] The suitable reaction conditions are listed in Table 1-6
Scheme 1-21 Paal-knorr catalyzed by zeolite [130]
Table 1-6 Comparison of the yield of various Pyrrole derivatives over different zeolites [130]
Page 30 In 2011, Pasha’s group found that lead oxide was an effective catalyst for the one pot synthesis of substituted pyrroles for the Paal–Knorr reaction [130]
The authors reported a simple and efficient way for the preparation of substituted pyrroles via condensation of -diketone and differently substituted primary amines using nano lead oxide as a catalyst under solvent-free condition The recyclability of nano PbO was also investigated, and it could be recycled three times without distinct loss of activity [130] The suitable reaction conditions were presented in Table 1-7
Table 1-7 Paal–Knorr reaction of acetonylacetone and aniline under different reaction conditions [130]
Solvent free Solvent free Solvent free Acetonitrile
RT RT RT RT RT RT RT
63 81 90 89 a Isolated yields, b Catalyst was reused for three times
In 2013, Yan and co-workers synthesized pyrroles from α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Scheme 1-22 Reaction between α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Page 31 In 2011, Tsuji and co-workers conducted synthesis of furans and pyrroles via cyclization of α-propargyl-β-keto esters with Indium-catalyst [132]
Scheme 1-23 Cyclization of α-propargyl-β-keto esters with Indium-catalyst
In 2010, Maiti and co-workers conducted a simple and direct synthesis of functionalized pyrroles: iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
Scheme 1-24 Iron(III)-catalyzed four-component coupling reaction of 1,3- dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
1.3.2.3 Synthesis of pravadoline derivatives (Nucleophilic substitution reaction)
The nucleophilic substitution S N 2 means that two molecules are involved in the actual transition state:
Scheme 1-25 Mechanism of nucleophilic substitution S N 2 [134]
The factor to be considered in substitution reactions is the solvent To favor an SN2 mechanism, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile, they hinder the backside attack necessary for the concerted reaction
To prevent this interference, polar, aprotic solvents such as acetone, DMF (dimethylformamide), or DMSO should be used [134]
Pd catalyst based on two biarylphosphine ligands for C−N cross-
In the 1990s, the teams of Buchwald and Hartwig developed a new method to form the connective carbon-nitrogen The coupling reaction was done between aryl halides and amines catalyzed by palladium complexes [117, 118]
This is an effective way to implement carbon-coupling reaction between aryl halide containing no withdrawing electronic groups and weak amine base
Buchwald–Hartwig described carbon-nitrogen coupling reaction mechanism SNAr under the palladium catalyst (Scheme 1-16) The reaction generated acid HX which destroyed the catalytic activity of Pd(0), therefore, it needed to have the involvement of a consumer base as agent HX In addition, the base will instead form a complex with palladium, creating an stable state
Scheme 1-16 Mechanism Buchwald-Hartwig reaction [116]
Page 26 In 2011, Jiao and co-workers conducted Ullmann amination of aryl halides with copper powder-catalyst under organic solvent- and ligand-free [119]
Scheme 1-17 Ullmann amination of aryl halides with aqueous methylamine
Then in 2015, Zhou and co-workers used CuI/Oxalic diamide as catalyst for coupling reaction of (hetero)aryl chlorides and amines The reaction proceeds at 120 °C with K3PO4 as the base in DMSO to afford a wide range of (hetero)aryl amines in good to excellent yields [120]
Scheme 1-18 CuI/Oxalic diamide catalyzed coupling reaction of (hetero)aryl chlorides and amines[120]
Pyrroles are an important class of heterocyclic compounds, contributing to the structural skeleton of several natural products, synthetic pharmaceuticals, and functional materials [121, 122] One of the most common methods to achieve pyrroles is the Paal-Knorr reaction between 1,4-dicarbonyl compounds and primary amines [123] Conventionally, the Paal-Knorr condensation could be catalyzed by many catalysts, such as layered zirconium phosphate and zirconium sulfophenyl phosphonate, zeolite, Fe 3+ -montmorillonite, aluminum oxide, and ruthenium (III) chloride [121-124] However, toxic and volatile organic solvents used for this reaction, which caused several undesirable economic and environmental aspects as well as health and safety issues From the view of green chemistry, a more environmentally benign approach should be developed for the reaction
Page 27 Paal-Knorr reaction which occurs between a dione and a primary amine (or ammonia) is the most popular method to synthesize pyrroles (Scheme 1-19) [125] The mechanism of this reaction was studied in 1995 by Amarnath [125]
This research focused on explaining which intermediate was formed in the reaction, and then proposed an appropriate mechanism However, the mechanism for this reaction is still not deeply understood The widely agreed mechanism is recommended in Scheme 1-19 [125, 126] There are supposed to be three different pathways for Paal-Knorr mechanism, including the first one from compounds 1 to 2, 3, 4, and 5, or the second from compounds 1 to 2, 6, 9, 4, and 5, and the last from compounds 1 to 2, 6, 7, 4, and 5 However, any pathway containing the formation of enamine (compounds number 8 and 9) before the cyclization must be ruled out because the stereochemical configuration suitable condition cannot match the true product Additionally, any pathway containing the cyclization of imine (compound number 6 in the third pathway) must also be dismissed because the intermediate stability is opposite to the practical result
Therefore, the only appropriate mechanism should be the first pathway, where there is no water elimination occur before the rate-determined step, the cyclization
Scheme 1-19 Mechanism of Paal-Knorr reaction [125, 126]
Danks also studied microwave-assisted Paal-Knorr reaction in 1999 [127]
Page 28 The suitable condition showed that the synthesis of pyrroles by reaction of hexane-2,5-dione with primary amines occurred in less than two minutes under microwave activation
Scheme 1-20 Microwave assisted synthesis of pyrrole [127]
In a study of Paal-Knorr reaction, Zhang and his co-workers investigated the ultrasound-assisted synthesis of pyrroles in the presence of zirconium chloride as catalyst under solvent-free condition [128] Compared with known methods, this new method provides an easy access to various substituted pyrroles with excellent yields in short times The suitable conditions are shown in Table 1-5
Table 1-5 The ultrasound-assisted synthesis of substituted pyrroles in the presence of ZrCl4 under solvent-free condition [128]
Entry Amine Time (min) Yield (%)
Sreekumar and Padmakumar had carried out the preparation of pyrroles and pyrazoles by an interMolecular reaction of and diketones with primary amines or hydrazine derivatives respectively under zeolite catalysis [129] The suitable reaction conditions are listed in Table 1-6
Scheme 1-21 Paal-knorr catalyzed by zeolite [130]
Table 1-6 Comparison of the yield of various Pyrrole derivatives over different zeolites [130]
Page 30 In 2011, Pasha’s group found that lead oxide was an effective catalyst for the one pot synthesis of substituted pyrroles for the Paal–Knorr reaction [130]
The authors reported a simple and efficient way for the preparation of substituted pyrroles via condensation of -diketone and differently substituted primary amines using nano lead oxide as a catalyst under solvent-free condition The recyclability of nano PbO was also investigated, and it could be recycled three times without distinct loss of activity [130] The suitable reaction conditions were presented in Table 1-7
Table 1-7 Paal–Knorr reaction of acetonylacetone and aniline under different reaction conditions [130]
Solvent free Solvent free Solvent free Acetonitrile
RT RT RT RT RT RT RT
63 81 90 89 a Isolated yields, b Catalyst was reused for three times
In 2013, Yan and co-workers synthesized pyrroles from α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Scheme 1-22 Reaction between α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Page 31 In 2011, Tsuji and co-workers conducted synthesis of furans and pyrroles via cyclization of α-propargyl-β-keto esters with Indium-catalyst [132]
Scheme 1-23 Cyclization of α-propargyl-β-keto esters with Indium-catalyst
In 2010, Maiti and co-workers conducted a simple and direct synthesis of functionalized pyrroles: iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
Scheme 1-24 Iron(III)-catalyzed four-component coupling reaction of 1,3- dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
1.3.2.3 Synthesis of pravadoline derivatives (Nucleophilic substitution reaction)
The nucleophilic substitution S N 2 means that two molecules are involved in the actual transition state:
Scheme 1-25 Mechanism of nucleophilic substitution S N 2 [134]
The factor to be considered in substitution reactions is the solvent To favor an SN2 mechanism, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile, they hinder the backside attack necessary for the concerted reaction
To prevent this interference, polar, aprotic solvents such as acetone, DMF (dimethylformamide), or DMSO should be used [134]
Page 32 In 2003, Kim and co-workers investigated the reactivities in the nucleophilic fluorination of 2-(3-methanesulfonyloxypropyl)naphthalene in the presence of 1-n-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) The fluorination using higher periodic alkali as CsF was completed in 20 min, with 95% conversion without any byproducts Moreover, they also carried out various nucleophilic substitutions of mesyloxyalkane 1 and 2-(3-bromopropyl) naphthalene at the primary aliphatic position using the potassium halides, acetate, cyanide, and alkoxides, respectively, in the presence of ionic liquids with 90% of major products [135]
Scheme 1-26 Nucleophilic substitution reaction of naphthalene derivatives and nucleophiles in ionic liquids [135]
In 2015, Jadhav and co-workers also conducted nucleophilic hydroxylation in water media promoted by a hexa-ethylene glycol-bridged dicationic ionic liquid (HexaEG-DHIM) with 86-96% conversion HexaEG- DHIM enhanced significantly the nucleophilicity of water [136]
Scheme 1-27 Nucleophilic hydroxylation in water media promoted by a hexa- ethylene glycol-bridged dicationic ionic liquid [136]
Pravadoline or (4-methoxyphenyl)(2-methyl-1-(2-(4-morpholinyl)ethyl) 1-H-indole-3-yl) methanone with similar derivatives is a drug that had been started the development from 1980 Pravadoline is an anti-inflammatory and analgesic drug with an IC50 of 4.9 àM and a Ki of 2511 nM Today, pravadoline derivatives and structurally similar compounds are still interested in the study of different chemists [137, 138] 1-(2-(N-morpholino)ethyl)-2-methylindole is used as a starting material for the synthesis of pravadoline, which is one of the non-
Page 33 steroidal anti-inflammatory drugs [68] It is conventionally synthesized by the nucleophilic substitution reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in a dipolar aprotic solvent such as DMF or DMSO [137, 139] in the presence of a base such as potassium hydroxide or sodium hydroxide
In 2004, Le conducted N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom at nitrogen atom and the alkyl halides was accomplished in ionic liquids [140]
Scheme 1-28 N-Alkylation of heterocyclic compounds [140]
In addition to nucleophilic reaction, many other methods to synthesize indoles e.g 3-iodoindoles was prepared by the Pd/Cu-catalyzed coupling of N,N- dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization in 2006 [141]
Scheme 1-29 Coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst [141]
Mechanism of Paal-Knorr reaction [125, 126]
Danks also studied microwave-assisted Paal-Knorr reaction in 1999 [127]
Page 28 The suitable condition showed that the synthesis of pyrroles by reaction of hexane-2,5-dione with primary amines occurred in less than two minutes under microwave activation
Scheme 1-20 Microwave assisted synthesis of pyrrole [127]
In a study of Paal-Knorr reaction, Zhang and his co-workers investigated the ultrasound-assisted synthesis of pyrroles in the presence of zirconium chloride as catalyst under solvent-free condition [128] Compared with known methods, this new method provides an easy access to various substituted pyrroles with excellent yields in short times The suitable conditions are shown in Table 1-5
Table 1-5 The ultrasound-assisted synthesis of substituted pyrroles in the presence of ZrCl4 under solvent-free condition [128]
Entry Amine Time (min) Yield (%)
Sreekumar and Padmakumar had carried out the preparation of pyrroles and pyrazoles by an interMolecular reaction of and diketones with primary amines or hydrazine derivatives respectively under zeolite catalysis [129] The suitable reaction conditions are listed in Table 1-6
Scheme 1-21 Paal-knorr catalyzed by zeolite [130]
Table 1-6 Comparison of the yield of various Pyrrole derivatives over different zeolites [130]
Page 30 In 2011, Pasha’s group found that lead oxide was an effective catalyst for the one pot synthesis of substituted pyrroles for the Paal–Knorr reaction [130]
The authors reported a simple and efficient way for the preparation of substituted pyrroles via condensation of -diketone and differently substituted primary amines using nano lead oxide as a catalyst under solvent-free condition The recyclability of nano PbO was also investigated, and it could be recycled three times without distinct loss of activity [130] The suitable reaction conditions were presented in Table 1-7
Table 1-7 Paal–Knorr reaction of acetonylacetone and aniline under different reaction conditions [130]
Solvent free Solvent free Solvent free Acetonitrile
RT RT RT RT RT RT RT
63 81 90 89 a Isolated yields, b Catalyst was reused for three times
In 2013, Yan and co-workers synthesized pyrroles from α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Scheme 1-22 Reaction between α-amino carbonyl compounds and aldehydes with I2-catalyst [131]
Page 31 In 2011, Tsuji and co-workers conducted synthesis of furans and pyrroles via cyclization of α-propargyl-β-keto esters with Indium-catalyst [132]
Scheme 1-23 Cyclization of α-propargyl-β-keto esters with Indium-catalyst
In 2010, Maiti and co-workers conducted a simple and direct synthesis of functionalized pyrroles: iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
Scheme 1-24 Iron(III)-catalyzed four-component coupling reaction of 1,3- dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
1.3.2.3 Synthesis of pravadoline derivatives (Nucleophilic substitution reaction)
The nucleophilic substitution S N 2 means that two molecules are involved in the actual transition state:
Scheme 1-25 Mechanism of nucleophilic substitution S N 2 [134]
The factor to be considered in substitution reactions is the solvent To favor an SN2 mechanism, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile, they hinder the backside attack necessary for the concerted reaction
To prevent this interference, polar, aprotic solvents such as acetone, DMF (dimethylformamide), or DMSO should be used [134]
Page 32 In 2003, Kim and co-workers investigated the reactivities in the nucleophilic fluorination of 2-(3-methanesulfonyloxypropyl)naphthalene in the presence of 1-n-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) The fluorination using higher periodic alkali as CsF was completed in 20 min, with 95% conversion without any byproducts Moreover, they also carried out various nucleophilic substitutions of mesyloxyalkane 1 and 2-(3-bromopropyl) naphthalene at the primary aliphatic position using the potassium halides, acetate, cyanide, and alkoxides, respectively, in the presence of ionic liquids with 90% of major products [135]
Scheme 1-26 Nucleophilic substitution reaction of naphthalene derivatives and nucleophiles in ionic liquids [135]
In 2015, Jadhav and co-workers also conducted nucleophilic hydroxylation in water media promoted by a hexa-ethylene glycol-bridged dicationic ionic liquid (HexaEG-DHIM) with 86-96% conversion HexaEG- DHIM enhanced significantly the nucleophilicity of water [136]
Scheme 1-27 Nucleophilic hydroxylation in water media promoted by a hexa- ethylene glycol-bridged dicationic ionic liquid [136]
Pravadoline or (4-methoxyphenyl)(2-methyl-1-(2-(4-morpholinyl)ethyl) 1-H-indole-3-yl) methanone with similar derivatives is a drug that had been started the development from 1980 Pravadoline is an anti-inflammatory and analgesic drug with an IC50 of 4.9 àM and a Ki of 2511 nM Today, pravadoline derivatives and structurally similar compounds are still interested in the study of different chemists [137, 138] 1-(2-(N-morpholino)ethyl)-2-methylindole is used as a starting material for the synthesis of pravadoline, which is one of the non-
Page 33 steroidal anti-inflammatory drugs [68] It is conventionally synthesized by the nucleophilic substitution reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in a dipolar aprotic solvent such as DMF or DMSO [137, 139] in the presence of a base such as potassium hydroxide or sodium hydroxide
In 2004, Le conducted N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom at nitrogen atom and the alkyl halides was accomplished in ionic liquids [140]
Scheme 1-28 N-Alkylation of heterocyclic compounds [140]
In addition to nucleophilic reaction, many other methods to synthesize indoles e.g 3-iodoindoles was prepared by the Pd/Cu-catalyzed coupling of N,N- dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization in 2006 [141]
Scheme 1-29 Coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst [141]
Aryl halides are highly versatile synthetic intermediates which have many applications in organic chemistry [142] Aryl halides also present in many natural products [143, 144] Moreover, many top selling pharmaceuticals contain chlorine and fluorine atoms (Figure 1-6) due to the useful medical properties of halide functional groups The halogenation of aromatic rings can enhance the physical and biological properties in pharmaceutical and agrochemical candidates [145]
Figure 1-6 Top pharmaceuticals containing chloride and fluoride functional groups [145]
Among these halides, chlorides and bromides are highly versatile intermediates [115, 146, 147] They are essential components of many pharmaceutical and bioactive compounds Therefore, the development of convenient and efficient methods for the selective synthesis of aryl and heteroarylchlorides and bromides has attracted an increasing attention [148-150]
The synthesis of aryl halides has been developed for decades In general, the two common preparatory routes to aryl halides are: (1) direct halogenation, and (2) via nucleophilic aromatic substitution reaction (SNAr) The properties of aryl halides are highly dependent on the nature of the halogen atom [151] The bond
Page 35 strength of the C–X bond decreases significantly as the size of the halogen atom increases from fluorine to iodine (Table 1-8)
Table 1-8 Bond dissociation energies of aryl halides [151]
Bond Dissociation energies (kJ.mol -1 )
Aryl iodides and bromides are generally more reactive than chlorides and fluorides Aryl chlorides and fluorides, in contrast, are generally relatively inert and they are much more commonly found in pharmaceuticals and agrochemicals, where they are introduced to modify the physical and biological properties of aromatic rings Therefore, it would be useful to have a general method for interconverting between the different halogen derivatives Recently, metal- mediated halogen exchange (or halide exchange) of aryl halides has attracted considerable attention (Scheme 1-30) [152, 153] Halogen exchange has been expected to be one of the most convenient and efficient methods for the synthesis of aryl and heteroaryl halides
Scheme 1-30 Metal-mediated halogen exchange of aryl halides
Metal activation of carbon–halogen bonds has received an incredible amount of attention in the last few decades with the development of transition- metal-catalyzed organic transformations [154]
In 2010, an attractive set of conditions for the halogenation of a wide range of simple arenes using substituted succinimide as halogen source and
Page 36 gold(III) chloride as catalyst was reported (Scheme 1-31) [155] Excellent yields of up to 99% were obtained The high efficiency of these reactions was attributed to the dual role of gold in activating both the succinimide component (as a traditional Lewis acid) and the arene through the formation of an aryl- gold(III)complex However, the expensive gold(III) catalyst limits the use of this method [155]
Scheme 1-31 Halogenation with N-halosuccinimide and gold(III) catalyst [155]
Recently, metal-mediated nucleophilic aromatic substitution is a potential field of research which aims for the replacement of the conventional Sandmeyer synthesis In 2009, Watson and co-workers reported the formation of aryl fluorides from aryl triflates with palladium(II) complex (Scheme 1-32) [156]
One year later, they succeeded in converting aryl triflates into chlorides and bromides (Scheme 1-33) [149]
Scheme 1-32 Conversion of aryl triflates into aryl fluorides [156]
Scheme 1-33 Conversion of aryl triflates into aryl chlorides and bromides [149]
The transformation of aryl triflates exhibits a wide substrate scope and tolerates a number of functional groups, allowing the introduction of fluorine, chlorine and bromine atoms into highly functionalized organic molecules
Despite these advantages, a few limitations still remain including reaction conditions, the use of complex ligand and treatment of expensive palladium(II) complexes
Page 37 Another nucleophilic aromatic substitution approach is halogen exchange, which was a convenient and efficient methods for the synthesis of aryl and heteroaryl halides
Reaction between α-amino carbonyl compounds and aldehydes with I 2 -
Page 31 In 2011, Tsuji and co-workers conducted synthesis of furans and pyrroles via cyclization of α-propargyl-β-keto esters with Indium-catalyst [132].
Cyclization of α-propargyl-β-keto esters with Indium-catalyst [132]
In 2010, Maiti and co-workers conducted a simple and direct synthesis of functionalized pyrroles: iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133].
Iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133]
1.3.2.3 Synthesis of pravadoline derivatives (Nucleophilic substitution reaction)
The nucleophilic substitution S N 2 means that two molecules are involved in the actual transition state:
Scheme 1-25 Mechanism of nucleophilic substitution S N 2 [134]
The factor to be considered in substitution reactions is the solvent To favor an SN2 mechanism, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile, they hinder the backside attack necessary for the concerted reaction
To prevent this interference, polar, aprotic solvents such as acetone, DMF (dimethylformamide), or DMSO should be used [134]
Page 32 In 2003, Kim and co-workers investigated the reactivities in the nucleophilic fluorination of 2-(3-methanesulfonyloxypropyl)naphthalene in the presence of 1-n-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) The fluorination using higher periodic alkali as CsF was completed in 20 min, with 95% conversion without any byproducts Moreover, they also carried out various nucleophilic substitutions of mesyloxyalkane 1 and 2-(3-bromopropyl) naphthalene at the primary aliphatic position using the potassium halides, acetate, cyanide, and alkoxides, respectively, in the presence of ionic liquids with 90% of major products [135]
Scheme 1-26 Nucleophilic substitution reaction of naphthalene derivatives and nucleophiles in ionic liquids [135]
In 2015, Jadhav and co-workers also conducted nucleophilic hydroxylation in water media promoted by a hexa-ethylene glycol-bridged dicationic ionic liquid (HexaEG-DHIM) with 86-96% conversion HexaEG- DHIM enhanced significantly the nucleophilicity of water [136]
Scheme 1-27 Nucleophilic hydroxylation in water media promoted by a hexa- ethylene glycol-bridged dicationic ionic liquid [136]
Pravadoline or (4-methoxyphenyl)(2-methyl-1-(2-(4-morpholinyl)ethyl) 1-H-indole-3-yl) methanone with similar derivatives is a drug that had been started the development from 1980 Pravadoline is an anti-inflammatory and analgesic drug with an IC50 of 4.9 àM and a Ki of 2511 nM Today, pravadoline derivatives and structurally similar compounds are still interested in the study of different chemists [137, 138] 1-(2-(N-morpholino)ethyl)-2-methylindole is used as a starting material for the synthesis of pravadoline, which is one of the non-
Page 33 steroidal anti-inflammatory drugs [68] It is conventionally synthesized by the nucleophilic substitution reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in a dipolar aprotic solvent such as DMF or DMSO [137, 139] in the presence of a base such as potassium hydroxide or sodium hydroxide
In 2004, Le conducted N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom at nitrogen atom and the alkyl halides was accomplished in ionic liquids [140]
Scheme 1-28 N-Alkylation of heterocyclic compounds [140]
In addition to nucleophilic reaction, many other methods to synthesize indoles e.g 3-iodoindoles was prepared by the Pd/Cu-catalyzed coupling of N,N- dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization in 2006 [141]
Scheme 1-29 Coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst [141]
Aryl halides are highly versatile synthetic intermediates which have many applications in organic chemistry [142] Aryl halides also present in many natural products [143, 144] Moreover, many top selling pharmaceuticals contain chlorine and fluorine atoms (Figure 1-6) due to the useful medical properties of halide functional groups The halogenation of aromatic rings can enhance the physical and biological properties in pharmaceutical and agrochemical candidates [145]
Figure 1-6 Top pharmaceuticals containing chloride and fluoride functional groups [145]
Among these halides, chlorides and bromides are highly versatile intermediates [115, 146, 147] They are essential components of many pharmaceutical and bioactive compounds Therefore, the development of convenient and efficient methods for the selective synthesis of aryl and heteroarylchlorides and bromides has attracted an increasing attention [148-150]
The synthesis of aryl halides has been developed for decades In general, the two common preparatory routes to aryl halides are: (1) direct halogenation, and (2) via nucleophilic aromatic substitution reaction (SNAr) The properties of aryl halides are highly dependent on the nature of the halogen atom [151] The bond
Page 35 strength of the C–X bond decreases significantly as the size of the halogen atom increases from fluorine to iodine (Table 1-8)
Table 1-8 Bond dissociation energies of aryl halides [151]
Bond Dissociation energies (kJ.mol -1 )
Aryl iodides and bromides are generally more reactive than chlorides and fluorides Aryl chlorides and fluorides, in contrast, are generally relatively inert and they are much more commonly found in pharmaceuticals and agrochemicals, where they are introduced to modify the physical and biological properties of aromatic rings Therefore, it would be useful to have a general method for interconverting between the different halogen derivatives Recently, metal- mediated halogen exchange (or halide exchange) of aryl halides has attracted considerable attention (Scheme 1-30) [152, 153] Halogen exchange has been expected to be one of the most convenient and efficient methods for the synthesis of aryl and heteroaryl halides
Scheme 1-30 Metal-mediated halogen exchange of aryl halides
Metal activation of carbon–halogen bonds has received an incredible amount of attention in the last few decades with the development of transition- metal-catalyzed organic transformations [154]
In 2010, an attractive set of conditions for the halogenation of a wide range of simple arenes using substituted succinimide as halogen source and
Page 36 gold(III) chloride as catalyst was reported (Scheme 1-31) [155] Excellent yields of up to 99% were obtained The high efficiency of these reactions was attributed to the dual role of gold in activating both the succinimide component (as a traditional Lewis acid) and the arene through the formation of an aryl- gold(III)complex However, the expensive gold(III) catalyst limits the use of this method [155]
Scheme 1-31 Halogenation with N-halosuccinimide and gold(III) catalyst [155]
Recently, metal-mediated nucleophilic aromatic substitution is a potential field of research which aims for the replacement of the conventional Sandmeyer synthesis In 2009, Watson and co-workers reported the formation of aryl fluorides from aryl triflates with palladium(II) complex (Scheme 1-32) [156]
One year later, they succeeded in converting aryl triflates into chlorides and bromides (Scheme 1-33) [149]
Scheme 1-32 Conversion of aryl triflates into aryl fluorides [156]
Scheme 1-33 Conversion of aryl triflates into aryl chlorides and bromides [149]
The transformation of aryl triflates exhibits a wide substrate scope and tolerates a number of functional groups, allowing the introduction of fluorine, chlorine and bromine atoms into highly functionalized organic molecules
Despite these advantages, a few limitations still remain including reaction conditions, the use of complex ligand and treatment of expensive palladium(II) complexes
Page 37 Another nucleophilic aromatic substitution approach is halogen exchange, which was a convenient and efficient methods for the synthesis of aryl and heteroaryl halides
In 1993, Bayraktaroglu and co-workers succeeded in converting aryl bromides and iodides into chlorides by using hypochlorite salt and phase-transfer catalyst in generally good yields (Scheme 1-34) [157] These routes were alternate approaches with use of zeolites [158] or photolysis [159], for only low yields of the desired product and a number of by-products
Scheme 1-34 Halogen exchange with phase-transfer catalyst
In 2001, Barthazy and his co-workers demonstrated the catalytic halide exchange for the fluorination of moderately activated organic bromides and iodides by ruthenium(II) complexes (Scheme 1-35) [153] The alkyl halides (bromides and iodides) were converted to the fluoro-analogues in the presence of thallium(I) fluoride as the fluoride source, the yields ranged between 31% and 83% However, the products of aryl halides were not reported This method was also suffered from several disadvantages, including the use of toxic and expensive thallium(I) fluoride and the treatment of ruthenium(II) complexes
Scheme 1-35 Fluorination by halide exchange with ruthenium(II) complex [153]
Nickel-mediated halogen exchange reactions were first reported by Cramer and Coulson in 1975 [160] In 2003, Arvela and Leadbeater presented the halide exchange of aryl halides facilitated by microwave and conventional heat using nickel(II)halides as reagents (Scheme 1-36) [161] Reactions were fast and could be performed without the need for exclusion of air and water
However, high temperature (170 C) and stoichiometric amount of toxic nickel(II) salts were required for high reaction yields
Scheme 1-36 Halide exchange of aryl halides using nickel(II) salts [161]
Nucleophilic hydroxylation in water media promoted by a hexa-ethylene glycol-bridged dicationic ionic liquid [136]
ethylene glycol-bridged dicationic ionic liquid [136]
Pravadoline or (4-methoxyphenyl)(2-methyl-1-(2-(4-morpholinyl)ethyl) 1-H-indole-3-yl) methanone with similar derivatives is a drug that had been started the development from 1980 Pravadoline is an anti-inflammatory and analgesic drug with an IC50 of 4.9 àM and a Ki of 2511 nM Today, pravadoline derivatives and structurally similar compounds are still interested in the study of different chemists [137, 138] 1-(2-(N-morpholino)ethyl)-2-methylindole is used as a starting material for the synthesis of pravadoline, which is one of the non-
Page 33 steroidal anti-inflammatory drugs [68] It is conventionally synthesized by the nucleophilic substitution reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole in a dipolar aprotic solvent such as DMF or DMSO [137, 139] in the presence of a base such as potassium hydroxide or sodium hydroxide
In 2004, Le conducted N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom at nitrogen atom and the alkyl halides was accomplished in ionic liquids [140]
Scheme 1-28 N-Alkylation of heterocyclic compounds [140]
In addition to nucleophilic reaction, many other methods to synthesize indoles e.g 3-iodoindoles was prepared by the Pd/Cu-catalyzed coupling of N,N- dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization in 2006 [141]
Scheme 1-29 Coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst [141]
Aryl halides are highly versatile synthetic intermediates which have many applications in organic chemistry [142] Aryl halides also present in many natural products [143, 144] Moreover, many top selling pharmaceuticals contain chlorine and fluorine atoms (Figure 1-6) due to the useful medical properties of halide functional groups The halogenation of aromatic rings can enhance the physical and biological properties in pharmaceutical and agrochemical candidates [145]
Figure 1-6 Top pharmaceuticals containing chloride and fluoride functional groups [145]
Among these halides, chlorides and bromides are highly versatile intermediates [115, 146, 147] They are essential components of many pharmaceutical and bioactive compounds Therefore, the development of convenient and efficient methods for the selective synthesis of aryl and heteroarylchlorides and bromides has attracted an increasing attention [148-150]
The synthesis of aryl halides has been developed for decades In general, the two common preparatory routes to aryl halides are: (1) direct halogenation, and (2) via nucleophilic aromatic substitution reaction (SNAr) The properties of aryl halides are highly dependent on the nature of the halogen atom [151] The bond
Page 35 strength of the C–X bond decreases significantly as the size of the halogen atom increases from fluorine to iodine (Table 1-8)
Table 1-8 Bond dissociation energies of aryl halides [151]
Bond Dissociation energies (kJ.mol -1 )
Aryl iodides and bromides are generally more reactive than chlorides and fluorides Aryl chlorides and fluorides, in contrast, are generally relatively inert and they are much more commonly found in pharmaceuticals and agrochemicals, where they are introduced to modify the physical and biological properties of aromatic rings Therefore, it would be useful to have a general method for interconverting between the different halogen derivatives Recently, metal- mediated halogen exchange (or halide exchange) of aryl halides has attracted considerable attention (Scheme 1-30) [152, 153] Halogen exchange has been expected to be one of the most convenient and efficient methods for the synthesis of aryl and heteroaryl halides
Scheme 1-30 Metal-mediated halogen exchange of aryl halides
Metal activation of carbon–halogen bonds has received an incredible amount of attention in the last few decades with the development of transition- metal-catalyzed organic transformations [154]
In 2010, an attractive set of conditions for the halogenation of a wide range of simple arenes using substituted succinimide as halogen source and
Page 36 gold(III) chloride as catalyst was reported (Scheme 1-31) [155] Excellent yields of up to 99% were obtained The high efficiency of these reactions was attributed to the dual role of gold in activating both the succinimide component (as a traditional Lewis acid) and the arene through the formation of an aryl- gold(III)complex However, the expensive gold(III) catalyst limits the use of this method [155]
Scheme 1-31 Halogenation with N-halosuccinimide and gold(III) catalyst [155]
Recently, metal-mediated nucleophilic aromatic substitution is a potential field of research which aims for the replacement of the conventional Sandmeyer synthesis In 2009, Watson and co-workers reported the formation of aryl fluorides from aryl triflates with palladium(II) complex (Scheme 1-32) [156]
One year later, they succeeded in converting aryl triflates into chlorides and bromides (Scheme 1-33) [149]
Scheme 1-32 Conversion of aryl triflates into aryl fluorides [156]
Scheme 1-33 Conversion of aryl triflates into aryl chlorides and bromides [149]
The transformation of aryl triflates exhibits a wide substrate scope and tolerates a number of functional groups, allowing the introduction of fluorine, chlorine and bromine atoms into highly functionalized organic molecules
Despite these advantages, a few limitations still remain including reaction conditions, the use of complex ligand and treatment of expensive palladium(II) complexes
Page 37 Another nucleophilic aromatic substitution approach is halogen exchange, which was a convenient and efficient methods for the synthesis of aryl and heteroaryl halides
In 1993, Bayraktaroglu and co-workers succeeded in converting aryl bromides and iodides into chlorides by using hypochlorite salt and phase-transfer catalyst in generally good yields (Scheme 1-34) [157] These routes were alternate approaches with use of zeolites [158] or photolysis [159], for only low yields of the desired product and a number of by-products
Scheme 1-34 Halogen exchange with phase-transfer catalyst
In 2001, Barthazy and his co-workers demonstrated the catalytic halide exchange for the fluorination of moderately activated organic bromides and iodides by ruthenium(II) complexes (Scheme 1-35) [153] The alkyl halides (bromides and iodides) were converted to the fluoro-analogues in the presence of thallium(I) fluoride as the fluoride source, the yields ranged between 31% and 83% However, the products of aryl halides were not reported This method was also suffered from several disadvantages, including the use of toxic and expensive thallium(I) fluoride and the treatment of ruthenium(II) complexes
Scheme 1-35 Fluorination by halide exchange with ruthenium(II) complex [153]
Nickel-mediated halogen exchange reactions were first reported by Cramer and Coulson in 1975 [160] In 2003, Arvela and Leadbeater presented the halide exchange of aryl halides facilitated by microwave and conventional heat using nickel(II)halides as reagents (Scheme 1-36) [161] Reactions were fast and could be performed without the need for exclusion of air and water
However, high temperature (170 C) and stoichiometric amount of toxic nickel(II) salts were required for high reaction yields
Scheme 1-36 Halide exchange of aryl halides using nickel(II) salts [161]
The work of Arvela and Leadbeater on nickel catalysis exhibited a wide range of substrate scope and high efficiency [161] However, the elevated temperature, stoichiometric amount, and the treatment of the toxic nickel faced difficulties for industrial scale
Copper salts are known to possess low toxicity and more abundant than corresponding nickel salts In 2002, Klapars and Buchwald succeeded in converting aryl bromide into iodide by using Copper-catalyst (Scheme 1-37) [162]
Scheme 1-37 Copper-mediated halogen exchange of aryl halides [162]
Over the last two decades, ILs have emerged as a new class of green solvents with a number of outstanding properties that outperform conventional solvents As a result, It’s applications have been continuously investigated so that they can adapt well in chemistry area as well as in the normal life This was the reason why this study focused on the synthesis of ILs and the application of ILs in organic synthesis Especially, the conventional heating methods have been replaced by microwave-assisted chemical processes in order to enhance the yield associated with reducing the time of the reaction
Metal-mediated halogen exchange of aryl halides
Metal activation of carbon–halogen bonds has received an incredible amount of attention in the last few decades with the development of transition- metal-catalyzed organic transformations [154]
In 2010, an attractive set of conditions for the halogenation of a wide range of simple arenes using substituted succinimide as halogen source and
Page 36 gold(III) chloride as catalyst was reported (Scheme 1-31) [155] Excellent yields of up to 99% were obtained The high efficiency of these reactions was attributed to the dual role of gold in activating both the succinimide component (as a traditional Lewis acid) and the arene through the formation of an aryl- gold(III)complex However, the expensive gold(III) catalyst limits the use of this method [155].
Halogenation with N-halosuccinimide and gold(III) catalyst [155]
Recently, metal-mediated nucleophilic aromatic substitution is a potential field of research which aims for the replacement of the conventional Sandmeyer synthesis In 2009, Watson and co-workers reported the formation of aryl fluorides from aryl triflates with palladium(II) complex (Scheme 1-32) [156]
One year later, they succeeded in converting aryl triflates into chlorides and bromides (Scheme 1-33) [149]
Scheme 1-32 Conversion of aryl triflates into aryl fluorides [156]
Scheme 1-33 Conversion of aryl triflates into aryl chlorides and bromides [149]
The transformation of aryl triflates exhibits a wide substrate scope and tolerates a number of functional groups, allowing the introduction of fluorine, chlorine and bromine atoms into highly functionalized organic molecules
Despite these advantages, a few limitations still remain including reaction conditions, the use of complex ligand and treatment of expensive palladium(II) complexes
Page 37 Another nucleophilic aromatic substitution approach is halogen exchange, which was a convenient and efficient methods for the synthesis of aryl and heteroaryl halides
In 1993, Bayraktaroglu and co-workers succeeded in converting aryl bromides and iodides into chlorides by using hypochlorite salt and phase-transfer catalyst in generally good yields (Scheme 1-34) [157] These routes were alternate approaches with use of zeolites [158] or photolysis [159], for only low yields of the desired product and a number of by-products
Scheme 1-34 Halogen exchange with phase-transfer catalyst
In 2001, Barthazy and his co-workers demonstrated the catalytic halide exchange for the fluorination of moderately activated organic bromides and iodides by ruthenium(II) complexes (Scheme 1-35) [153] The alkyl halides (bromides and iodides) were converted to the fluoro-analogues in the presence of thallium(I) fluoride as the fluoride source, the yields ranged between 31% and 83% However, the products of aryl halides were not reported This method was also suffered from several disadvantages, including the use of toxic and expensive thallium(I) fluoride and the treatment of ruthenium(II) complexes
Scheme 1-35 Fluorination by halide exchange with ruthenium(II) complex [153]
Nickel-mediated halogen exchange reactions were first reported by Cramer and Coulson in 1975 [160] In 2003, Arvela and Leadbeater presented the halide exchange of aryl halides facilitated by microwave and conventional heat using nickel(II)halides as reagents (Scheme 1-36) [161] Reactions were fast and could be performed without the need for exclusion of air and water
However, high temperature (170 C) and stoichiometric amount of toxic nickel(II) salts were required for high reaction yields
Scheme 1-36 Halide exchange of aryl halides using nickel(II) salts [161]
The work of Arvela and Leadbeater on nickel catalysis exhibited a wide range of substrate scope and high efficiency [161] However, the elevated temperature, stoichiometric amount, and the treatment of the toxic nickel faced difficulties for industrial scale
Copper salts are known to possess low toxicity and more abundant than corresponding nickel salts In 2002, Klapars and Buchwald succeeded in converting aryl bromide into iodide by using Copper-catalyst (Scheme 1-37) [162]
Scheme 1-37 Copper-mediated halogen exchange of aryl halides [162]
Over the last two decades, ILs have emerged as a new class of green solvents with a number of outstanding properties that outperform conventional solvents As a result, It’s applications have been continuously investigated so that they can adapt well in chemistry area as well as in the normal life This was the reason why this study focused on the synthesis of ILs and the application of ILs in organic synthesis Especially, the conventional heating methods have been replaced by microwave-assisted chemical processes in order to enhance the yield associated with reducing the time of the reaction
Additionally, the nucleophile reactions were conducted in ILs with the same polarization of organic solvents To favor an S N 2 reaction, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile To prevent this interference, polar, aprotic solvents such as acetone, DMF or DMSO should be used Ionic liquids like polar apotic solvents so that they could be used in nucleophilic reaction without any limitation as conventional solvents Till today, a large number of ILs have been reported; however, room temperature ILs (Imidazolium based-cations) possessed the advantages in comparison with the other ILs
Therefore, the first aim of the study is to synthesize imidazolium based ILs with bromide and hexaflorophosphate anions under the assistance of microwave
After the synthesis of imidazolium based ILs, the second aim of this thesis is to attempt towards the applications of imidazolium based ILs as solvents for coupling reactions and halogen exchange reaction These prepared ILs for coupling reactions are expected to achieve better results comparing with the previous reports: catalyst-free reaction and green free-solvents with high conversion and mild condition in a short time
Specially, in halogen exchange reports, only transfer from aryl bromide to iodide Thus, in this thesis, we want to transform the aryl iodide to aryl bromide using Cu (I) catalyst in ILs solvent without other catalysts
Na2SO4 China 99.0% n-Butanol Merck 99.8%
Piperidine Merck 99.0% p-Xylene Merck 99.0% p-Xylene Merck 99.0%
Chemicals were purchased from Sigma-Aldrich and Merck, and used as received without further purification 1 H and 13 C NMR spectra were recorded using a Bruker AV 500 spectrometer at The Vietnam Academy of Science and Technology (VAST) 18 Hoang Quoc Viet, Cau Giay, Ha Noi Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 17-A, GC Shimadzu 2010 Plus equipped with a flame ionization detector (FID) and an DB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 àm) at Ho Chi Minh city university of technology The temperature program for GC analysis is described in appendix 44 Conversion of products were calculated by GC with appropriate internal standards (Appendix 45) GC–MS analyzes were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 àm) with electron impact ionization mode at Hoan Vu analytical laboratory (HCMC) 215 Phan Anh, Binh Tri Dong, Binh Tan, HCM The temperature program for GC–MS analysis was from 60 to 280 o C at 10 o C/min and held at 280 o C for 2 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library
2.2.1 Preparation of 1-alkyl-3-methylimidazolium bromide
In a typical reaction for preparation of [BMIM]Br, 20 mL (0.225 mol) of 1-methylimidazole was mixed with 30 mL (0.273 mol) of 1-bromobutane in a 250 mL round bottom flask equipped with a flux condenser The mixture was then irradiated in a microwave oven (Sanyo – EM S2086W – 800W) at 80 W, and stirred vigorously during the reaction time by the magnetic stirrer The irradiation was paused every 10 seconds so that the mixture can be quenched to prevent over heating The irradiation was repeated for a total time of 3 minutes (6 minutes for 1-bromohexane, 9 minutes for 1-bromooctane) After completion of reaction, the resulting mixture was cooled down to room temperature, then washed with ethyl acetate three times, and with diethyl ether three times to separate the starting materials as well as undesired products The residue of volatile solvents was removed by a vacuum rotary evaporation at 50 o C to afford 53.02 g of product
The ionic liquids [HMIM]Br and [OMIM]Br were synthesized with the same procedure mentioned above to form 56.81 g and 62.81 g ionic liquids, respectively
Scheme 2-1 The synthesis of 1-alkyl-3-methylimidazolium bromide
Figure 2-1 The synthesis of 1-alkyl-3- methylimidazolium bromide
1) Ethyl acetate 3x20 mL 2) Diethyl ether 3x20 mL Undesired materials
-Microwave 80 w -Vigorously stirring -Stop irradiating every 10 seconds
20 mL methylimidazole x (mL) of 1-bromoalkane
Bromobutane x0 mL Bromohexane x@ mL Bromooctane xP mL
2.2.2 Preparation of 1-alkyl-3-methylimidazolium hexafluorophosphate
Scheme 2-2 The formation of 1-alkyl-3-methylimidazolium hexafluorophosphate by anion metathesis In a typical procedure for preparation of [BMIM] PF6; 40 mL (0.272 mol) of hexafluorophosphoric acid was added to a plastic conical flask containing 50 mL of cold distilled water This mixture was stirred and immersed in an ice bath for 30 minutes and then cooled down to 05 o C (mixture I) The mixture of [BMIM] Br (50 g, 0.228 mol) with 50 mL of cold distilled water was also stirred and immersed in another ice bath for 30 minutes (mixture II) Next, the mixture I was added dropwise to mixture II The resulting mixture was continuously stirred and cooled for 24 hours After that, the upper acidic aqueous layer was almost separated by decanting and the resulting mixture was washed by cold water until the almost excess acid was removed The acidity was tested by pH paper The excess water was removed by a vacuum rotary evaporation at 70 o C to afford 50.78 g of product
The ionic liquids [HMIM] PF6 and [OMIM] PF6 were synthesized with the same procedure mentioned above to form 59.2 g and 70.3 g of products, respectively
Figure 2-2 The synthetic procedure of 1-alkyl-3- methylimidazolium hexafluorophosphate ionic liquids
50 mL H2O each time until neutral
BMIMBr xP g HMIMBr xU g OMIMBr xb.5 g
Scheme 2-3 Synthesis of coumarin from salicylaldehyde and methyl acetoacetate Unless otherwise stated, salicylaldehyde (0.11 mL, 1.0 mmol) and diphenyl ether (0.1 mL) as the internal standard in [BMIM]Br ionic liquid (4.0 mL) were introduced into a 50 mL glass vessel Methyl acetoacetate at pre- determined molar ratio (3eq) was added, and the mixture was then stirred at 100 oC for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL) from the reaction mixture at different time intervals, and quenching with water (1 mL) The organic components were extracted into diethyl ether (3 mL), dried over Na2SO4 and analyzed by gas chromatography (GC) with reference to diphenyl ether, and then main product (3-acetylcoumarin) was identified by GC- MS, NMR For investigation of [BMIM]Br recycling, after the reaction, the resulting mixture was cooled to room temperature and extracted with diethyl ether (5 x 10 mL) to remove the organic components The ionic liquid layer was evaporated under vacuum (50 o C, 10 mmHg) for 1 h to remove any excess solvent and then reused in further reaction under identical conditions to those of the first run Reaction conversion was calculated by following formula (1)
S1, S2: Peak area of substrate and internal standard, respectively t0: Time of beginning tx: Time of withdrawing the sample
Page 47 The survey factors affect on reaction conversion
Molar ratio between salicylaldehyde/methyl acetoacetate = 1.0/1.0, 1.0/2.0 and 1.0/3.0
These two factors are the basic conditions affecting the reaction which should be investigated during the experiment The two factors were associated with the below chemicals and solvents Temperature 100 o C and molar ratio between salicylaldehyde/methyl acetoacetate 1.0/3.0 was chosen for future experiments
Alkyl chain length of ionic liquids: [BMIM]Br, [HMIM]Br, [OMIM]Br
Ionic liquid anions: [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvents: [BMIM]Br, DMF, DMSO, n-butanol, toluene, p- xylene
Conversion of aryl triflates into aryl chlorides and bromides [149]
The transformation of aryl triflates exhibits a wide substrate scope and tolerates a number of functional groups, allowing the introduction of fluorine, chlorine and bromine atoms into highly functionalized organic molecules
Despite these advantages, a few limitations still remain including reaction conditions, the use of complex ligand and treatment of expensive palladium(II) complexes
Page 37 Another nucleophilic aromatic substitution approach is halogen exchange, which was a convenient and efficient methods for the synthesis of aryl and heteroaryl halides
In 1993, Bayraktaroglu and co-workers succeeded in converting aryl bromides and iodides into chlorides by using hypochlorite salt and phase-transfer catalyst in generally good yields (Scheme 1-34) [157] These routes were alternate approaches with use of zeolites [158] or photolysis [159], for only low yields of the desired product and a number of by-products.
Halogen exchange with phase-transfer catalyst
In 2001, Barthazy and his co-workers demonstrated the catalytic halide exchange for the fluorination of moderately activated organic bromides and iodides by ruthenium(II) complexes (Scheme 1-35) [153] The alkyl halides (bromides and iodides) were converted to the fluoro-analogues in the presence of thallium(I) fluoride as the fluoride source, the yields ranged between 31% and 83% However, the products of aryl halides were not reported This method was also suffered from several disadvantages, including the use of toxic and expensive thallium(I) fluoride and the treatment of ruthenium(II) complexes.
Fluorination by halide exchange with ruthenium(II) complex [153]
Nickel-mediated halogen exchange reactions were first reported by Cramer and Coulson in 1975 [160] In 2003, Arvela and Leadbeater presented the halide exchange of aryl halides facilitated by microwave and conventional heat using nickel(II)halides as reagents (Scheme 1-36) [161] Reactions were fast and could be performed without the need for exclusion of air and water
However, high temperature (170 C) and stoichiometric amount of toxic nickel(II) salts were required for high reaction yields
Halide exchange of aryl halides using nickel(II) salts [161]
The work of Arvela and Leadbeater on nickel catalysis exhibited a wide range of substrate scope and high efficiency [161] However, the elevated temperature, stoichiometric amount, and the treatment of the toxic nickel faced difficulties for industrial scale
Copper salts are known to possess low toxicity and more abundant than corresponding nickel salts In 2002, Klapars and Buchwald succeeded in converting aryl bromide into iodide by using Copper-catalyst (Scheme 1-37) [162]
Scheme 1-37 Copper-mediated halogen exchange of aryl halides [162]
Over the last two decades, ILs have emerged as a new class of green solvents with a number of outstanding properties that outperform conventional solvents As a result, It’s applications have been continuously investigated so that they can adapt well in chemistry area as well as in the normal life This was the reason why this study focused on the synthesis of ILs and the application of ILs in organic synthesis Especially, the conventional heating methods have been replaced by microwave-assisted chemical processes in order to enhance the yield associated with reducing the time of the reaction
Additionally, the nucleophile reactions were conducted in ILs with the same polarization of organic solvents To favor an S N 2 reaction, protic solvents such as water and alcohols should be avoided Since these hydrogen bonding solvents are able to strongly solvate the nucleophile To prevent this interference, polar, aprotic solvents such as acetone, DMF or DMSO should be used Ionic liquids like polar apotic solvents so that they could be used in nucleophilic reaction without any limitation as conventional solvents Till today, a large number of ILs have been reported; however, room temperature ILs (Imidazolium based-cations) possessed the advantages in comparison with the other ILs
Therefore, the first aim of the study is to synthesize imidazolium based ILs with bromide and hexaflorophosphate anions under the assistance of microwave
After the synthesis of imidazolium based ILs, the second aim of this thesis is to attempt towards the applications of imidazolium based ILs as solvents for coupling reactions and halogen exchange reaction These prepared ILs for coupling reactions are expected to achieve better results comparing with the previous reports: catalyst-free reaction and green free-solvents with high conversion and mild condition in a short time
Specially, in halogen exchange reports, only transfer from aryl bromide to iodide Thus, in this thesis, we want to transform the aryl iodide to aryl bromide using Cu (I) catalyst in ILs solvent without other catalysts
Na2SO4 China 99.0% n-Butanol Merck 99.8%
Piperidine Merck 99.0% p-Xylene Merck 99.0% p-Xylene Merck 99.0%
Chemicals were purchased from Sigma-Aldrich and Merck, and used as received without further purification 1 H and 13 C NMR spectra were recorded using a Bruker AV 500 spectrometer at The Vietnam Academy of Science and Technology (VAST) 18 Hoang Quoc Viet, Cau Giay, Ha Noi Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 17-A, GC Shimadzu 2010 Plus equipped with a flame ionization detector (FID) and an DB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 àm) at Ho Chi Minh city university of technology The temperature program for GC analysis is described in appendix 44 Conversion of products were calculated by GC with appropriate internal standards (Appendix 45) GC–MS analyzes were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 àm) with electron impact ionization mode at Hoan Vu analytical laboratory (HCMC) 215 Phan Anh, Binh Tri Dong, Binh Tan, HCM The temperature program for GC–MS analysis was from 60 to 280 o C at 10 o C/min and held at 280 o C for 2 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library
2.2.1 Preparation of 1-alkyl-3-methylimidazolium bromide
In a typical reaction for preparation of [BMIM]Br, 20 mL (0.225 mol) of 1-methylimidazole was mixed with 30 mL (0.273 mol) of 1-bromobutane in a 250 mL round bottom flask equipped with a flux condenser The mixture was then irradiated in a microwave oven (Sanyo – EM S2086W – 800W) at 80 W, and stirred vigorously during the reaction time by the magnetic stirrer The irradiation was paused every 10 seconds so that the mixture can be quenched to prevent over heating The irradiation was repeated for a total time of 3 minutes (6 minutes for 1-bromohexane, 9 minutes for 1-bromooctane) After completion of reaction, the resulting mixture was cooled down to room temperature, then washed with ethyl acetate three times, and with diethyl ether three times to separate the starting materials as well as undesired products The residue of volatile solvents was removed by a vacuum rotary evaporation at 50 o C to afford 53.02 g of product
The ionic liquids [HMIM]Br and [OMIM]Br were synthesized with the same procedure mentioned above to form 56.81 g and 62.81 g ionic liquids, respectively
Scheme 2-1 The synthesis of 1-alkyl-3-methylimidazolium bromide
Figure 2-1 The synthesis of 1-alkyl-3- methylimidazolium bromide
1) Ethyl acetate 3x20 mL 2) Diethyl ether 3x20 mL Undesired materials
-Microwave 80 w -Vigorously stirring -Stop irradiating every 10 seconds
20 mL methylimidazole x (mL) of 1-bromoalkane
Bromobutane x0 mL Bromohexane x@ mL Bromooctane xP mL
2.2.2 Preparation of 1-alkyl-3-methylimidazolium hexafluorophosphate
Scheme 2-2 The formation of 1-alkyl-3-methylimidazolium hexafluorophosphate by anion metathesis In a typical procedure for preparation of [BMIM] PF6; 40 mL (0.272 mol) of hexafluorophosphoric acid was added to a plastic conical flask containing 50 mL of cold distilled water This mixture was stirred and immersed in an ice bath for 30 minutes and then cooled down to 05 o C (mixture I) The mixture of [BMIM] Br (50 g, 0.228 mol) with 50 mL of cold distilled water was also stirred and immersed in another ice bath for 30 minutes (mixture II) Next, the mixture I was added dropwise to mixture II The resulting mixture was continuously stirred and cooled for 24 hours After that, the upper acidic aqueous layer was almost separated by decanting and the resulting mixture was washed by cold water until the almost excess acid was removed The acidity was tested by pH paper The excess water was removed by a vacuum rotary evaporation at 70 o C to afford 50.78 g of product
The ionic liquids [HMIM] PF6 and [OMIM] PF6 were synthesized with the same procedure mentioned above to form 59.2 g and 70.3 g of products, respectively
Figure 2-2 The synthetic procedure of 1-alkyl-3- methylimidazolium hexafluorophosphate ionic liquids
50 mL H2O each time until neutral
BMIMBr xP g HMIMBr xU g OMIMBr xb.5 g
Scheme 2-3 Synthesis of coumarin from salicylaldehyde and methyl acetoacetate Unless otherwise stated, salicylaldehyde (0.11 mL, 1.0 mmol) and diphenyl ether (0.1 mL) as the internal standard in [BMIM]Br ionic liquid (4.0 mL) were introduced into a 50 mL glass vessel Methyl acetoacetate at pre- determined molar ratio (3eq) was added, and the mixture was then stirred at 100 oC for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL) from the reaction mixture at different time intervals, and quenching with water (1 mL) The organic components were extracted into diethyl ether (3 mL), dried over Na2SO4 and analyzed by gas chromatography (GC) with reference to diphenyl ether, and then main product (3-acetylcoumarin) was identified by GC- MS, NMR For investigation of [BMIM]Br recycling, after the reaction, the resulting mixture was cooled to room temperature and extracted with diethyl ether (5 x 10 mL) to remove the organic components The ionic liquid layer was evaporated under vacuum (50 o C, 10 mmHg) for 1 h to remove any excess solvent and then reused in further reaction under identical conditions to those of the first run Reaction conversion was calculated by following formula (1)
S1, S2: Peak area of substrate and internal standard, respectively t0: Time of beginning tx: Time of withdrawing the sample
Page 47 The survey factors affect on reaction conversion
Molar ratio between salicylaldehyde/methyl acetoacetate = 1.0/1.0, 1.0/2.0 and 1.0/3.0
These two factors are the basic conditions affecting the reaction which should be investigated during the experiment The two factors were associated with the below chemicals and solvents Temperature 100 o C and molar ratio between salicylaldehyde/methyl acetoacetate 1.0/3.0 was chosen for future experiments
Alkyl chain length of ionic liquids: [BMIM]Br, [HMIM]Br, [OMIM]Br
Ionic liquid anions: [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvents: [BMIM]Br, DMF, DMSO, n-butanol, toluene, p- xylene
Scheme 2-4 The cyclocondensation reaction of 1,2-phenylenediamine with acetone to form 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine The [HMIM]Br ionic liquid was applied as catalyst for the cyclocondensation of 1,2-phenylenediamine and ketones to obtain 1,5- benzodiazepine derivatives In a typical experiment, a pre-determined amount of [HMIM]Br was added to the flask containing a mixture of 1,2-phenylenediamine (0.108 g, 1.0 mmol), acetone (3.7 mL, 50 mmol) and diphenyl ether (0.1 mL) as the internal standard The catalyst concentration was calculated based on the molar ratio of [HMIM]Br/1,2-phenylenediamine The reaction mixture was then stirred at required temperature for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL) from the reaction mixture at different time intervals, and quenching with water (1.0 mL) The organic components were
Page 48 extracted by diethyl ether (3 mL), dried over Na2SO4 and analyzed by gas chromatography (GC) with reference to 4-bromoanisole, and then main product (2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine) was identified by GC-MS, NMR To investigate the recyclability of [HMIM]Br catalyst, after completion, the reaction mixture was diluted with water (10 mL), and extracted with diethyl ether (3 x 10 mL) to remove the organic compounds The aqueous layer consisting of the ionic liquid was distilled under vacuum (80 o C, 10 mmHg) for 1 h to remove water to obtain [HMIM]Br ionic liquid, which could be reused
Reaction conversion was calculated by formula (1)
The survey factors affect on reaction conversion
Molar ratio of ILs/1,2-phenylenediamine: 0.0/0.0, 1.0/1.0, 3.0/1.0, 5.0/1.0,
Molar ratio between acetone/1,2-phenylenediamine = 60/1.0, 50/1.0,
Ionic liquids: [HMIM]Br, [BMIM]Br, [OMIM]Br, [BMIM]PF6,
Other catalysts: CH3COOH, Zn (NO3)2, n-butanol , [HMIM]Br and water
2.3.3 Synthesis of 1-(4-nitrophenyl)piperidine derivatives
Scheme 2-5 The N-arylation between 4-bromonitrobenzenes and heterocyclic amines in ionic liquids Unless otherwise stated, 4-bromonitrobenzene (0.202 g, 1 mmol), and 4- bromoanisole (0.1 mL) as the internal standard in [HMIM]Br ionic liquid (4.0 mL) were introduced into a 50 mL glass vessel Piperidine at pre-determined molar ratio was added, and the mixture was then stirred at required temperature for 3 h Reaction conversion was monitored by withdrawing aliquots (0.1 mL)
Page 49 from the reaction mixture at different time intervals, quenching with diethyl ether (2 mL), filtering through a short silica gel pad, drying over Na2SO4, analyzing by GC with reference to 4-bromoanisole, and then main product (1-(4- nitrophenyl)piperidine) was identified by GC-MS, NMR Reaction conversion was calculated by formula (1)
The survey factors affect on reaction conversion
Alkyl chain length of ILs: [BMIM]Br, [HMIM]Br, [OMIM]Br
Molar ratio between the two reactants: 1-bromo-4-nitrobenzene/piperidine
Ionic liquid anions: [BMIM]Br, [BMIM]PF6, [BMIM]BF4
Reaction solvents: [BMIM]Br, DMF, DMSO, NMP, n-butanol, toluene
The halogen in 4-nitrophenyl halide: F, Cl, Br and I
2.3.4 Synthesis of 1-[2-(N-morpholino)ethyl]-2-methylindole derivatives