Herein, we developed the first heterogeneous catalyzed fluorination of aliphatic acids and the first heterogeneous catalyzed trifluoromethylation of boronic acids using the successfully
LITERATURE REVIEW
Introduction of fluorine into organic scaffolds
Previous studies showed different methods to introduce fluorine into organic molecules using various fluorinating reagents as the fluorine transfer sources In general, there are three ultimate mechanisms of fluorination reactions as following:
The first fluorinating reagent used for fluorination was fluorine gas, the strongest elemental oxidant known [11] Subsequent reagents such as hypofluorites, fluoroxysulfates and perchloryl fluoride were also utilized as fluorine generating sources However, using aforementioned reagents coped with their high reactivity resulting in the difficulty of C-F bond formation [12] Xenon fluoride then exhibited the more stable reactivity than above reagents, but its high oxidizing potential restricted the substrate scope with limited functional group tolerance [13]
Continuously, the development of N-fluoro reagent classes including N- fluorobis(phenyl)sulfonimide (NFSI) [14] and related analogs [14, 15], N- fluoropyridinium salts [16], and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo
5 [2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, F-TEDA-BF 4 ) [17] became the vital leap in fluorine chemistry due to their air-setup stability, regioselectivity and functional group tolerance (Figure 1.3)
Figure 1.3 Some common N-fluoro reagent classes as fluorine sources [14-17]
Both main group organometallics and transition-metal organometallics can be fluorinated electrophilically to obtain aryl fluorides Compared to the former, the latter could afford aryl fluorides with an enhanced substrate scope as well as wider pathways of mechanism that help improving the expansion of electrophilic fluorination so far
However, the development of stable, direct and functional group tolerant C-F bond formation based upon electrophilic pathways still remains challenging
Scheme 1.1 Electrophilic fluorination of aryl boronic acids and trifluoroborates [18]
Fluorinated arenes could be obtained by the reaction between aryl metal reagents namely aryl-tin , -mercury , -lead , -germanium , -silicon , and -boron and fluorine gas, hypofluorites, fluoroxysulfates, and xenon difluoride High reactivity of reagents, nevertheless, limited the substrate scope, especially the functional group tolerance
The generation of N-flouro reagents has overcome the limitations of the high reactivity of reagents and become the important reagents in fluorination currently Cazorla group conducted the conversion of aryl nucleophiles such as aryl boronic acids and
6 trifluoroborates into corresponding aryl fluorides in high yield under the facile, mild condition (Scheme 1.1) Such aryl nucleophiles could undergo single electron transfer affording protodemetallation byproducts [18]
Scheme 1.2.Fluorination of aryl Grignard reagents [19-21]
Fluorination of Grignard substrates with N-fluoro reagents generated corresponding adducts but was limited in scope due to the basicity and nucleophilicity of Grignard compounds Undesired protodemetallation byproducts could be reduced by the change of solvents and reagent equivalent (Scheme 1.2) [19-21]
Scheme 1.3 Transition metal catalyzed fluorinations with directing groups [22, 23]
The earliest transition metal catalyzed aromatic fluorination was conducted via utilizing an ortho-directing group The conversion of C-H bond to C-F bond was obtained, but the broad functional group tolerance was limited due to the necessity of coordinating groups (Scheme 1.3) [22, 23]
Moreover, electrophilic fluorination reactions of aryl stannanes [24], boronic acids [25], and silanes [26] was developed using silver as transition metal catalyst The C-F bond formation was assumed to proceed via the multimetallic, high valent silver
7 intermediacy generated by the oxidation of silver (I) complexes with oxidant and the adduct was afforded by reductive elimination (Scheme 1.4)
Scheme 1.4 Fluorination of aryl stannanes, boronic acids and silanes [24-26]
Unactivated alkenes were also fluorinated by the use of Palladium as catalyst, which was described by Liu and co-workers Intramolecular aminofluorination of unactivated alkenes gave C-F bond formation in moderate to high yield, whereas the Pd-catalyzed intermolecular fluoroamination of styrenes yielded the corresponding adducts with a limited scope of starting substrate (Scheme 1.5) [27, 28]
Scheme 1.5 Pd-catalyzed Aminofluorination of Unactivated Alkenes [27, 28]
Alternative approach in fluorination reaction is the sp 3 C-H bond fluorination
Nucleophiles employed in the fluorination reactions of aliphatic compounds were often carbanions in ZKLFKWKHILUVWPROHFXOHVXVHGZHUHFDUERQ\OGHULYDWLYHV7KHĮ- fluorination of carbonyl derivatives with strong oxidizing fluorinating reagents, namely gaseous fluorine [29], alkyl hypofluorite [30], perchloryl fluoride [31],
8 fluoroxysulfate [32], and XeF 2 [33] commonly gave desired fluorinated products, but there were a limited substrate scope and byproducts afforded due to the strong oxidizing potential of reagents By contrast, the usage of N-fluoro reagents as less reactive, more functional group tolerant electrophilic fluorinating reagents resulted in the stable, selective fluorination in mild conditions
Scheme 1.6 Two steps for fluorination of ketones with N-fluoro reagent of
Obviously, Erik Fuglseth group conducted a fluorination of acetophenol derivatives with three routes using various conditions The results showed that route A gave products in moderate to high yields depending upon the electronic properties of substituents In this route, the acetophenones were converted into the corresponding trimethylsilyl enol ethers followed by fluorination with SelectFluor to yield desired fluorinated products (Scheme 1.6) [34]
Scheme 1.7 Fluorination of ketones with N-fluoro reagent SelectFluor [35]
Another specific research was carried out in 2009 by Gaj Stavber group They carried out a direct, regioVHOHFWLYH IOXRULQDWLRQ RI YDULRXV F\FOLF DQG DF\FOLF NHWRQHV WR Į- fluoroketones with water as medium and SelectFluor (F-TEDA-BF 4 ) as fluorinating reagent in presence of inexpensive amphiphile sodium dodecyl sulfate (SDS) as a promoter (Scheme 1.7) [35]
The conversion of aliphatic C-H bond to C-F bond still remain challenges so far due to the high electronegativity of elemental fluorine as well as the high hydration energy of
9 fluoride anion Therefore, the number of articles about the fluorination of aliphatic C- H bond still remains limited In 2000, Chambers and co-workers conducted the fluorination of saturated systems utilizing fluoride solution and SelectFluor as fluorine sources without catalyst However, the reaction gave corresponding products in low to moderate yield on various substituents [36]
Scheme 1.8 Transition metal catalyst for aliphatic C-F bond formation [22]
The usage of transition metal catalysts has been useful for selective, efficient fluorination of aliphatic C-H bond The first research using transition metal catalyst was proceed by Sanford and co-workers in 2006, which was the palladium-catalyzed fluorination of 8-methylquinoline using the electrophilic N-fluoro reagent This transformation was attributed to occur via the high-valent palladium fluoride intermediates followed by the C-F bond-forming reductive elimination (Scheme 1.8) [22]
Scheme 1.9 Ion (II) catalyzed fluorination of benzylic substrates [37]
Introduction of trifluoromethyl group (CF 3 group) into organic compounds
Trifluoromethyl group is significantly different from methyl group over chemical properties To illustrate, the methylation reaction of Grignards is rather facilely done and they can be reacted with ketones to form tertiary alcohols in excellent yields On the contrary, to the same conditions, trifluoromethylation of them furnished low
20 transformation of unstable Grignards and their reaction with ketones generated low yield trifluoromethylated alcohols due to the concomitant formation of sideproducts (Scheme 1.24) [58-60]
Scheme 1.24 The difference between methyl group and trifluoromethyl group [58-60]
The early trifluoromethylation was developed by Swarts in 1892, which employing SbF 5 as fluorine transfer reagent to access benzotrifluoride from benzotrichloride [61]
The reaction under the harsh conditions witnessed several sideproducts due to steps to replace chlorides by fluorides In 1968, McLoughlin and Thrower first conducted the fluoroalkylation of iodoaromatic compounds to afford fluoroalkylaromatic ones under the interaction of perfluoroalkylhalides (R f X) as nucleophilic reagent and copper, generating fluoroalkylcopper intermediate [62] The low yield and limited substrate scope are the disadvantages of this method, but the discovery of fluoroalkyl copper intermediate in this transformation became seminal to date (Scheme 1.25)
Scheme 1.25 Route via fluoroalkylcopper intermediate by McLoughlin and Thrower [62]
Previous studies set forth various approaches to introduce the trifluoromethyl group into organomolecules Like methods for fluorination, the developed tools for
21 trifluoromethylation of organic molecules employed numerous reagents to attach CF 3 group to different substrates The problems of group tolerance and the selectivity still remain in these reactions In this part, we categorize the developed methods into three major groups according to the corresponding mechanism, as following:
The electrophilic trifluoromethylating reagents widely used in trifluoromethylation UHDFWLRQV DUH K\SHUYDOHQW LRGRQLXP VDOWV 7RJQLảV UHDJHQWV DQG VXQIRQLXP VDOWV 8PHPRWRảV UHDJHQWV 7KH HDUO\ GHYHOopment of iodonium salt was conducted by Yagupolski et al [63] and was extensively studied by Umemoto and co-workers, who showed that (perfluoroalkyl)-phenyliodonium triflates (Figure 1.5, reagent 1) were the unrivalled equivalent of R f + and they were applied to the syntheses of various nucleophiles such as carbanions, enolates, alkenes, silyl enol ethers, aromatics [64]
Figure 1.5 Hypervalent iodine perfluoroalkyl reagents [63-67]
However, the development had one drawback until recentlly: the failure in the preparation of trifluoromethyl aryliodonium salts, possibly due to the instability of synthetic intermediate [65]
The successful preparation of stable trifluoromethyl phenyliodonium salts were discovered by Togni and co-workers, who also successfully prepared various classes of hypervalent iodine derivatives, and those reagents have been commonly employed since the first application, especially reagent 2 and 3 (Figure 1.5, reagents 2-8) [66, 67]
22 Scheme 1.265HDFWLYLW\RIDOFRKRO7RJQLảVUHDJHQWYLDYDULRXVH[DPSOHV[65]
Reagent 3 is considered as alcohol CF 3 -reagent, which is much better soluble in organic solvents than reagent 2 Its reactivity was firstly evaluated with cyclic ȕ-keto esters DQGĮ-nitro esters in the presence of CuCl as catalyst under mild conditions to IRUPFRUUHVSRQGLQJĮ-trifluoromethylated esters in moderate to high yields However, The reaction faced the complicated handling, expensive agents, hard isolation of products and limited substrate scope (Scheme 1.26, reaction 1 and 2) [68]
A variety of arenes and N-heteroarenes reacted with reagent 3 to form desired products with the attachment of CF 3 group into the position adjacent to nitrogen or activated groups on the benzene ring (Scheme 1.26, reaction 3 and 4) Additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethylsilyl)silyl chloride are necessary for some substrates [69] This protocol described a wide range of substrates, but the low yields and low selectivity were the main disadvantages in this reaction
Ritter-type trifluoromethylation of azoles using reagent 3 under the catalysis of HNTf 2 was described (Scheme 1.26, reaction 5) [70] The reaction exhibited the suitability with a number of substituted groups on starting materials, and was the first development for the direct coupling of nitrogen and CF 3 , affording the desired products in moderate yields However, the generation of various byproducts lowered the selectivity of the method
23 In the effort of trifluoromethylating the S-hydrogen phosphorothioates, Togni and co- workers conducted the reaction with the presence of reagent 3 in CDCl 3 at room temperature [71] This method gave the desired products in moderate yields, exhibited the compatibility with alkyl groups and oppositely with alkylchloro groups on phosphorothioates Nevertheless, the reaction required extra steps, complicated handling (Scheme 1.26, reaction 6)
MacMillan and co-workers described the enantioselective trifluoromethylation of DOGHK\GHV WR OLEHUDWH HQDQWLRHQULFKHG Į-formyl trifluoromethylated products in the productive merger of imidazolidinone and Lewis acids CuCl The approach allowed to afford the desired products in high yield of 70 to 87% and high enantioselective excess (ee) of ca 97% (Scheme 1.26, reaction 7) [72]
Furthermore, the primary and secondary aryl and alkylphosphanes reacted with reagent 3 to give the desired products in moderate to good yields under direct, mild and readily conditions The limited range of substrates and the low yield are the limitations of this protocol However, the method allowed the preparation of trifluoromethylphosphanes bond to ferrocenyl cores which are the ligands for transition metals in a number of oxidation reactions (Scheme 1.26, reaction 8) [65, 68]
Scheme 1.27 The low yields in trifluoromethylation of phenols using reagent 2 [73]
Similar to reagent 3, acid CF 3 -reagent 2 has been widely employed in several approaches for O-trifluoromethylation of various organic compounds The earliest study was the trifluoromethylation of phenols which formed the desired products in very low yields (Scheme 1.27) [73]
24 Scheme 1.28 Reactivity of acid CF 3 -reagent 2 via various examples [65]
Although the failure in O-trifluoromethylation of phenols, reagent 2 has shown the efficiency in trifluoromethylation of aliphatic alcohols in the presence of the zinc (II) salt [74], sulfonic acids in the presence of strong Bronsted acid [75] (Scheme 1.28) [65]
TogniảV reagent 2 was also employed to attach CF 3 synthon to unactivated terminal olefins, described by Buchwald group They successfully synthesized the organic molecules containing allylic CF 3 functional group in moderate to good yield utilizing catalyst of copper (I) The mechanism was also probed, yet the details in the transformation was not elucidated despite numerous studies were conducted They generally surmised that the trifluoromethylation hurdled complex pathways and the further efforts must be done to clarify the mechanism (Scheme 1.29) [76]
Scheme 1.29 Copper (I) catalyzed-allylic trifluoromethylation of unactivated olefins [76]
Another popular electrophilic CF 3 reagent used in the trifluoromethylation of organic frameworks is Yagupolski-8PHPRWRảVUHDJHQWZKLFKHDUO\GLVFRYHUHGE\