This paper reviews literature over 25 years’ activity on phosphoryl carbanion reagents and shows that these compounds are powerful tools in organic chemistry. The main target of this review is to outline some of the reactive peculiarities that make this class of compounds powerful tools in the synthesis of 5- and 6-heterocyclic compounds and/or substituted heterocycle phosphor esters. The importance of these latter compounds in pharmacology is also discussed.
Turk J Chem (2016) 40: 225 247 ă ITAK ˙ c TUB ⃝ Turkish Journal of Chemistry http://journals.tubitak.gov.tr/chem/ doi:10.3906/kim-1502-56 Review Article Wittig–Horner reagents: powerful tools in the synthesis of 5-and 6-heterocyclic compounds; shedding light on their application in pharmaceutical chemistry Rizk Elsayed KHIDRE1,2,∗, Wafaa Mahmoud ABDOU1 Chemical Industries Division, National Research Centre, Dokki, Giza, Egypt Department of Chemistry, Faculty of Science, Jazan University, Jazan, Saudi Arabia Received: 09.02.2015 • Accepted/Published Online: 22.06.2015 • Final Version: 02.03.2016 Abstract: This paper reviews literature over 25 years’ activity on phosphoryl carbanion reagents and shows that these compounds are powerful tools in organic chemistry The main target of this review is to outline some of the reactive peculiarities that make this class of compounds powerful tools in the synthesis of 5- and 6-heterocyclic compounds and/or substituted heterocycle phosphor esters The importance of these latter compounds in pharmacology is also discussed Key words: Phosphonyl carbanions reagents, phospha-Michael (P-Michael) addition, Perkin-type reaction, fivemembered heterocycles, six-membered heterocycles, nucleophiles Introduction Organophosphorus compounds, in parallel, are noteworthy for their biological activity, 1−4 especially when they are associated with various heterocycles One of the most important of these bioactive heterocycles are the substituted heterocycle phosphor esters and/or heterocycles containing phosphorus groups In spite of their importance, methods for the direct synthesis of these types of heterocycles are quite limited 7,8 With this aim, our group and others investigated for over 25 years the usefulness of phosphoryl carbanions (also known as Wittig–Horner (WH) or Wadsworth–Horner–Emmons (WHE) reagents) in the construction of several fiveand six-membered heteroring systems Related substituted heterocycle phosphor esters and/or heterocycles containing phosphorus groups were reported This review article describes the progress over last three decades in the chemistry of phosphoryl carbanions, showing their synthetic usefulness as versatile building blocks in the construction of five- or six-membered heterocycles (Scheme 1) and in connection to our previous review articles 9−14 The classification is based upon the size of the heterocyclic rings (five-membered and six-membered rings) and the number of heteroatoms in the given molecule regardless of the site of attack by the reagent There are, however, some exceptions to this classification, some of which will emerge in the subsequent discourse Heterocyclic derivatives, on the other hand, are of great importance in pharmaceutical chemistry The main purpose of this review is to represent a survey of the utility of phosphonyl carbanions in the synthesis of 5- and 6-heterocyclic compounds and provide useful and up-to-date data for chemists Furthermore, pharmacological applications of the produced heterocycles are discussed ∗ Correspondence: rizkkhidre@yahoo.com 225 KHIDRE and ABDOU/Turk J Chem O OR S P OR O P OR OR O S H N 16 NH P O HO 15 NH2 O O P OR N S OR S 14 R O N N O OR P OR OO 13 N OR N N N P N OR H O O (RO)2P O O P OR OR O OR O P OR N N H O R HN H N O P OR RO OR RO P O RO O O P RO 12 O N N Ph 11 10 OR P OR O NH O P OR O OR O P OR OR O H N N P CN O O OR Scheme Synthesis of five-membered heterocycles 2.1 Five-membered heterocycles with one heteroatom 2.1.1 Pyrroles and their fused systems Phosphonyl carbanions 17 were reacted with amine 18 in refluxed toluene containing p -toluenesulfonic acid (PTSA) to give phosphorylpyrrolidin-2-ones 21 in high yields via formation of intermediates imines 19 and enamines 20 followed by lactamization (Scheme 2) 15 δ -Amino-β -keto-phosphonates 22 were treated with 4-acetamidobenzenesulfonyl azide (4-ABSA) in the presence of NaH to afford δ -amino- α -diazo-β -ketophosphonates 23 Stereoselective intramolecular cyclization of the latter compounds gives pyrrolidine-2-phosphonates 24 Olefination reaction of 24 gives 2-ethylidene pyrrolidine 25 in good yields (Scheme 3) 16 Hydroxypyrroles 29 were obtained, in excellent yields, by reaction of oxime 26a,b with α -phosphorylvinyl-p -tolylsulfoxide 27 in DMF containing NaH via intermediates 28 (Scheme 4) 17 226 KHIDRE and ABDOU/Turk J Chem O EtO P EtO CO2Et + O R2NH2 R1 17 PTSA EtO O P CO2Et EtO N R R1 18 O OEt P OEt R1 N -EtOH O 19 EtO O P CO2Et H EtO N R R1 R 21 20 R1 = Me, n-Bu, Ph, 3,4-(OMe) 2C6H3 R2 = n-hexyl, benzyl Scheme Boc NH O R Boc i) NaH O NH O ii) 4-ABSA P(OMe)2 R1 22 23 N2 O O Rh2(OAc)4 CH2Cl2 O P(OMe) R1 O i) base P(OMe)2 R1 R2 N N Boc ii) R CHO Boc 24 25 R = n-Bu, t-Bu, Ph ; R = Me, n-Pr, n-C6H13 Boc = t-buty carboxylate Scheme O O N S Me + EtO P R R EtO CH2 O OH 26a, R = Me b, R = Ph NaH 27, R1 = 4-MeC6H4 O Me O P(OEt) S R R N O O 28 O S R1 Me R N OH 29 Scheme Indol-2-yl methylphosphonate 33 and 1,4-dihydroquinolin-2-ylphosphonate 34 were synthesized by reaction of 3-phenyl-[2,4]-benzoxazine-1-one 30 with diethyl vinylphosphonate 31a (Scheme 5) 18 227 KHIDRE and ABDOU/Turk J Chem O O N P OEt COPhOEt 32 30 O OEt OEt P OEt O + N COPh 33, 41% O EtO P EtO 31a O LiH/DMF N Ph O OEt N P OEt PhOC O 34, 27% Scheme N -aryl- α -phosphonylglycine derivatives 37 were formed by reaction of ethyl 2-diazophosphonylacetate 35 and substituted aromatic aniline 36 in toluene in the presence of catalytic Rh (OAc) at reflux temperature, while the Wittig–Horner reaction of 37 with o -iodobenzaldehydes 38 in CH Cl gave Z− olefinic adducts 39 in high yields Intramolecular cyclization of 39 in DMF in the presence of PdCl and KOAc gave 2-ethyl indole carboxylates 40 in good yields (Scheme 6) 19,20 O P(OEt)2 EtO2C NH2 Rh2(OAc)4 Y + N2 O P(OEt)2 35 EtO2C NH toluene Y 37 36 X CHO I 37 + X Base CH2Cl r.t 38 EtO2C NH 39 I X EtO2C PdCl2 N KOAc, DMF 40 Y Y X = H, 6-NO2, 5-OMe; Y = 4-CO2Et, 4-CH2CO2Et, 3,4-OCH2O-, 2-Br Scheme Intramolecular cyclization of N -((diphenylphosphoryl)methyl)aniline 41 in THF containing either BuLi at –78 ◦ C 17 or LDA 21 afforded indole-2-diphenylphosphine oxides 42 in high yields (Scheme 7) X R1 n-BuLi/THF N PO R2 Ph or LDA Ph 41 N R2 O P Ph Ph 42 R1 = CONEt2, R2 = i-Pr, propynyl; X = OH R1 = CN, R2 = Me, i-Pr, PhCH2; X = NH2 Scheme 3-Formyl pyrrolidine 43 was treated with triethyl phosphonoacetate 31a in THF to yield pyrrolidine 228 KHIDRE and ABDOU/Turk J Chem acrylate 44 Hydrogenation, and hydrolysis followed by intramolecular cyclization of 44 gave aminopyrrolizidine 45 (Scheme 8) 22 Bn N Ac Bn N Ac N Ac O EtO P + EtO CHO THF, base CO2Me 31b 43 CO2Me N Ac 44 Bn NH i) H2-Pd/C N ii) H3O iii) cyclization O 45, 61% Scheme In the same fashion, (1,2-bis(benzyloxy)-5-methylhexahydro-1H -pyrrolizin-3-yl)methyl benzoate 48 was synthesized from the reaction of pyrrolidine-2-carbaldehyde 46 with diethyl acetyl methylenephosphonate 31d to yield adduct 47, followed by hydrogenation and intramolecular cyclization (Scheme 9) 23−25 BnO BnO OBn O + BzOH2C N CHO 46 CBz EtO P EtO COMe 31d cyclization 47 N CBz O Me BnO Pd-C/H2 BzO OBn BnO N BzO 48 Me Scheme 2.1.2 Furans and thiophenes and their fused systems Cyclopropane phosphonate 50a,b and 3-(thiophen-2-yl)pent-2-enedinitrile 51a,b were prepared from the reaction of 3(2-thienyl)acrylonitrile 49a,b with cyano methylene phosphonate 31e in THF containing NaH at reflux In addition, phosphono-substituted furan 52c was also isolated from 49a (Scheme 10) 26 229 KHIDRE and ABDOU/Turk J Chem EtO EtO CN S P O CN 31e R NaH, THF, ref lux 49a, R = CO2Et b, R = CN S NC CN CN R OEt + P OEt S O R + EtO P O CH2CN EtO NC 51a (22%) 52c (26%) b ( 28%) S O 50a (23%) b (46%) Scheme 10 Similarly, treatment of 49a with phosphonoacetate 31c afforded phosphono-substituted furans 173 and 174 (Scheme 11) 26 CN S CO2Et EtO O EtO P CO2Et 31c THF, NaH,ref lux S EtO2C O (EtO) 2P 49a S CN + O O EtO P EtO EtO2C 53 (41%) CN O CO2Et 54 ( 23%) Scheme 11 Diethyl (1,7-dioxaspiro-[4.4]nona-3,8-dien-9-yl)phosphonate 57 was recently obtained from reaction of 2-acetylfuran 55 with diethyl vinylphosphonate 31a in DMF containing lithium hydride (Scheme 12) 27 O Me Me O 55 O + Me P(OEt)2 LiH/DMF Me O - Me Me O O O +CH 31a 56 O P(OEt) 57, 67% O P(OEt) Scheme 12 Knoevenagel condensation reaction of oxathiolone 58 with α -phosphonyl carbanions 31b,c,e in refluxed ethanol in the presence of EtONa followed by sequential alkylation gave benzothien-3-ylphosphonates 60 in 66% yield (Scheme 13) Benzothienylphosphonate esters 60a–c showed significant antimicrobial activity against a panel of representative gram-positive pathogenic microorganisms, gram-negative microorganisms, and fungi 28 230 KHIDRE and ABDOU/Turk J Chem O HO O S 58 P(OEt)2 + O EtONa HO O S R 31b,c,e RO O 59A HO P(OEt)2 OH R O S O 59B Na P(OEt)2 Alkylation - H2O R = CO2Me; b, R = CO2Et; c, R = CN R O EtO P(OEt) S 60 O Scheme 13 2.2 Synthesis of five-membered heterocycles with more than one heteroatom 2.2.1 Pyrazoles and their fused systems [3+2] Cycloaddition reaction of diazomethane with vinyl-1,2-butadienylphosphonates 61a,b yielded pyrazole3-phosphonates 63a,b (Scheme 14) 29 Me C Me C C C RO P Me RO O 61a, R = Me b, R = Et + CH2N2 Me C C RO P O N RO 62 N H H Me RO RO P O HN N 63a,b Me Scheme 14 Pyrazolinyl-3-phosphonate 66 and diazaphosphole 67 were prepared in 27% and 44% yields, respectively, from the reaction of 2-diazo-1,3-indandione 64 with phosphonoacetate 31b,c in a mixture of LiOH/H O/CHCl at reflux On the other hand, spiroindene-2,3‘-pyrazolyl phosphonate 69 and spiro diazaphosphole 70 were yielded from the reaction of 64 with cyanomethylphosphonate 31e (Scheme 15) 30 Similarly, spiro[indene-2,3‘-pyrazol]-5‘-yl)phosphonate 72 was synthesized in 72% yield by treatment of diazoketone 64 with diethyl vinylphosphonate 31a under phase-transfer catalysis conditions (Scheme 16) 30 Spiroindene-2,3‘-pyrazolinyl phosphonates (66, 69, and 72) and spiro diazaphospholes (67, 70) showed more significant antimicrobial activity towards tested organisms (bacteria and fungi) Furthermore, the phosphole derivatives (67 and 70) are more active than the phosphonate derivatives (66, 69, and 72) 30 231 KHIDRE and ABDOU/Turk J Chem O N O Et NN CO2R O P EtO OEt N O N NO O Li CHP(OEt)2 65 CO2R LiOH/H2O/CHCl O 31b, R = Me c, R = Et 64 EtO EtO P 31e O Alkylation OH- O P OEt O O OEt 66, 27% + O Et N N P CO2R O O OEt 67, 44% O CN LiOH/H2O/CHCl3 O N NO Li CHP(OEt)2 O CN 68 N N Alkylation + P(OEt)2 O NH2 O 69, 38% OH- O Et N N P CN O O OEt 70, 33% Scheme 15 O N N + 64 O Alkylation O P(OEt) LiOH/H2O/CHCl O H N N 31a O O Et N N O 72 O P(OEt) 71 O P(OEt)2 Scheme 16 Vilsmeier–Haack reaction of phosphonyl ethylene hydrazones 73 gave 1-phenyl-4-diethoxyphosphonylpyrazoles 74 in 46%–81% yields (Scheme 17) 31 EtO O EtO P R NHPh N EtO O P R EtO 73 DMF/POCl3 46-81% 74 N N Ph R = H, Me, Ph Scheme 17 Cyclization of β -hydrazonophosphonates 75 into their corresponding 4-phosphonopyrazoles 76 was achieved via their reaction with triethyl orthoformate in xylene containing a few drops of glacial acetic acid (Scheme 18) 32,33 232 KHIDRE and ABDOU/Turk J Chem R R R HC(OEt)3 P N O AcOH/xylene NH R 68-94% 75 R O R P R2 N N 76 R1 R = Ph, OEt; R1 = Me, Ph, CH2CF3; R2 = Me, CH(Me) 2, Ph Scheme 18 2.2.2 Oxazole and its fused systems In a recent report, 2-azido-4,6-di-tert-butylphenol 77 was reacted with diethyl vinylphosphonate 31a in sodium ethanolate solution under reflux to give 2-benzoxazole phosphonate 78 in 74% yield via a coupling cyclization reaction of 77 with 31a in one step with tandem NH alkylation and extrusion of nitrogen Similarly, benzoxazole phosphonates 79 (72%) were formed from the reaction of the azide 77 with saturated WHE reagents 31 (Scheme 19) 34 O P (OEt)2 31a Et O N P OEt OEt O 78 EtONa -N2 N3 O P (OEt)2 OH Et O N P OEt OEt O R1 R1 31 EtONa -N2 77 79 R1 = SMe, -C(S)NH2, C(O)Me, Ph, 4-ClC6H4, CN, CO2Me, CO2Et Scheme 19 Stereoselective 1,3-dipolar cycloaddition of allyldiphenylphosphine oxides 80 with nitrile oxides 81 afforded ∆2 -isoxazolines 82 (Scheme 20) 35,36 O Ph P Ph R 80 Ph + R C N O Ph P O O N R 81 R2 82 R1 = H, Me, Et, n-Pr, i-Pr R2 = Me, Et, n-Pr, hexyl, Ph, CO2Et, (CH2)nCO2Me (n = 2,3) Scheme 20 233 KHIDRE and ABDOU/Turk J Chem Treatment of diethyl phosphonoacetates 31b,c with triketoindane-2-oxime 83 in EtOH/EtONa at reflux temperature yielded spiroindene-2,3’-isoxazolidinylphosphonate 85 and adduct 86 Compound 83 was treated with (methylthio)methylphosphonate 31f,g in EtOH/EtONa at reflux to give diethyl(3-ethoxy 4-oxo4-hydroindeno[2,1-d][1,3]oxazol-2yl)phosphonate 88 (Scheme 21) Compounds 85, 86, and 88 were screened against some gram-positive bacteria, gram-negative bacteria, and fungi Compound 85 showed feeble activity against gram-positive bacteria Compounds 86 and 88 displayed no activity against the tested bacteria Compound 86 is moderately active against D specifera at 780 µ g/cm while compounds 85 and 88 are more active against D specifera at 780 µ g/cm Compounds 85 and 88 registered 100% spore germination inhibition of F oxysporum at 320 µ g/cm 37 O P (OEt)2 O P(OEt)2 O O CO2R 31b,c NH O O 84 EtOH/EtONa R = Me, Et O NOH 83 O P (OEt)2 O OR -ROH Alkylation O P(OEt)2 N SR O O 87 EtOH/EtONa R = Me, Et O OEt O P OEt O NO Et RO2C 86, 35% 85, 36% O SR 31f ,g O OEt O P OEt O O N O Et O -RSH N Alkylation O 88, 72% OEt OEt P OEt O Scheme 21 Oxazolophosphonate 91 and the diolefin 90 were obtained from the reaction of 2-(hydroxyimino)-1,3diphenylpropane-1,3-dione 89 with phosphoacetonitrile 31c (Scheme 22) 38 O Ph NOH Ph O (EtO) 2PCH2CN 31e CHCN NOH Ph CHCN O 89 PhOC Ph Ph 90, (19%) + HN O OEt NC P O OEt 91, (41%) Scheme 22 The reaction between alloxan-5-oxime derivatives 92 with thiomethylphosphonates 44f,g to give the corresponding fused substituted [1,3]oxazolo[4,5-d]2-pyrimidinylphosphonate 93 was reported Triazaspiro[4,5]dec3-en-4-ylphosphonate 94 and [1,3]oxazolo[4,5-d ]pyrimdin-2-ylidene ethylphosphonate 95 were obtained from the reaction of 92 with allyl phosphonates 31h (Scheme 23) 39 234 KHIDRE and ABDOU/Turk J Chem O EtO P EtO R O N O NOH O SR R1 N OEt P O N O OEt R1 93 O 31f ,g R = Me, Et H N H N R1 O 92 R1 = H, Me O EtO P EtO 31h R1 N OH N O O N R 94 O P O EtO OEt R1 Me + O O Et N N R1 O EtO P O EtO N 95 Scheme 23 2.2.3 Thiazole and oxaphosphole and their fused systems 5-Benzylidene-4-thiazolidines 96 was reacted with phosphonoacetates 31b,c in EtOH/EtONa at room temperature to yield diethyl 6-benzylidene-3,5-dioxotetrahydro-2H -thiazolo[2,3-b ]thiazol-2-ylphosphonate 97 Fused phosphonopyranones 99 together with olefins 98 were regioselectivity synthesized when the above reaction occurred at reflux temperature (Scheme 24) 40 O NH S Ph S O EtO P EtO O O r.t CO2R Ph N O P OEt OEt S S 97 (58%) EtONa/EtOH O 96 N ref lux Ph CO2R S CO2R 98, 30% O + O O P EtO OEt Ph Et N S S 99, 30% Scheme 24 On the other hand, compound 96 was reacted with phosphonoacetonitrile 31f in DMF containing LiH at reflux temperature to afford Michael addition product 100 along with thiazolo[2,3- b]thiazolo-phosphonate 101 (Scheme 25) 40 235 KHIDRE and ABDOU/Turk J Chem O Ph O NH2 O O CN O O (EtO)2PCH2CN NH P OEt N + EtO P 31f S OEt S S EtO Ph S Ph 101, 40% 100, 25% NH S S 96 Scheme 25 Treatment of phosphonyl carbanions 31b,c,f with 1-(5-methylfuran-2-yl)ethanone 102, in DMF containing LiH under reflux, afforded oxaphospholes 104 (55%–48.2% yield) along with phosphonate 103 (17%–22.6% yield) (Scheme 26) 28 O Me Me O O + O + P(OEt)2 Me OH P - EtOH OEt O LiH/DMF Me P(OEt)2 /- H2O R 31b,c,f 102 O Me R 103 O Me O O P OEt Me R OEt O A Me R 104 R = CN, CO2Me, CO2Et Scheme 26 2.2.4 Triazoles and diazaphosphole and their fused systems One pot reaction of methoxyimine 105, phosphonyl acetohydrazide 106, and aromatic or/and heterocycles aldehyde gave 1,2,4-triazoles 107 in moderate to excellent yields (Scheme 27) 41 n N OMe (n = 0,1,2) 105 + O O P NH2 + N EtO H EtO n EtONa RCHO 106 N toluene R N N 107 R = Ph, 4-MeOC6H4, 4-NCC6H4, 4-ClC6H4, thiazol-2-yl, pyrid-2-yl, thien-2-yl Scheme 27 Hydrazonyl halides 108 were reacted with WH reagents 31c,f in NaOEt at room temperature to yield diazaphospholes 109 via cyclization followed by hydrolysis of intermediates B and C, respectively (Scheme 28) 42 236 KHIDRE and ABDOU/Turk J Chem EtO O P R EtO 31c,f H R1 N N Cl Ph NaOEt 108 R1 H N NHPh -EtOH R P OEt OEt O B H N R1 R H N N Ph N Ph Hydrolysis R P O P O R HO OEt C 109 R1 = CO2Et, Ph, COPh; R = CO2Et, CN Scheme 28 Diazoketone 64 was reacted with diethyl (methylthio)methylphosphonate 31g to yield spiro[1,2,4-diazaphosphole3,2‘-indene]-1‘,3‘-dione-4-oxide 110 along with indeno-[2,1-e ][4,1,2]oxadiazin-9(1H) -one 111 (Scheme 29) 30 Compound 110 showed more significant antimicrobial activity than the unphosphorylated oxadiazine 111 O N N + O 64 O P(OEt)2 LiOH/H O/CHCl SMe 31g a) -EtOH or - (EtO)2POH b) Alkylation O Et N N P SMe O O OEt 110, 49% O + Et N O N SMe 111, 17% Scheme 29 Nucleophilic addition of HWE reagents 31b,c,f to 1,2,4-triazole-3-thiol-4-aminoarylidenes 112 in DMF containing LiH yielded β -amino-phosphonates 113 (≈ 55% yield) and thiadiazoles 114 On the other hand, thiadiazoles 114 were, however, exclusively obtained in 75%–80% yield when the reaction (112 and the same WHE reagents) proceeded in MeOH/MeONa containing a catalytic amount of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (Scheme 30) 43 Compounds 114 showed more significant antimicrobial activity, with minimal inhibitory concentration (MIC) of 54–140 and 22–143 mmol L −1 and minimal bactericidal concentration (MBC) values of 70–439 and 44–268 mmol L −1 compared with MIC/MBC for ciprofloxacin of 48–386 (MIC, mmol L −1 ) and 55–396 for (MBC mmol L −1 ) and MIC/MBC for chloramphenicol of 70–439 (MIC, mmol L −1 ) and 65–619 (MBC mmol L −1 ) against a panel of gram-positive and gram-negative bacterial pathogens: Klebsiella pneumoniae 2011E, Pseudomonas aeruginosa 6065 Y, Escherichia coli BW54, Escherichia coli BW55, Acinetobacter haemolyticus BW62, Stenotrophomonas maltophilia D457R, Staphylococcus epidermis 887E, Bacillus cereus ATCC 11778, Staphylococcus aureus ATCC 29213, and Sarcina lutea 43 Synthesis of six-membered heterocycles 3.1 Synthesis of six-membered heterocycles with one heteroatom 3.1.1 Pyridines and pyrans and their fused systems Diethyl 1-cyano-2-ethoxyvinylphosphonate 117 was reacted with cyclobutenyl amine 115 in a mixture of DMF and THF (1:1) containing sodium hydride to afford pyridine-3-carbonitriles 119 (Scheme 31) 44 237 KHIDRE and ABDOU/Turk J Chem N N N SH N OEt + EtO P R2 O R1 112 HS DMF/LiH N N 31 MeOH/MeONa/DDQ /-H2 O P OEt OEt N R2 + N H R1 113 S R N R2 N N NH P OEt O OEt 114 S R N R2 N N NH P OEt 114 O OEt R1= 4-Me2NC6H4, 4-ClC6H4; R2 = CO2Me, CO2Et, CN Scheme 30 R1 115 COCF3 NaH NH2 20 oC R1 COCF3 EtO 117 O P(OEt)2 CN R COCF3 O P(OEt)2 CN N H 118 - EtONa NH 116 CF3 R1 R1 = C4H7, C6H11 CN N 119 (48-60%) Scheme 31 Reaction of β -fluoroamidinium salt 120 with acetyl methylene phosphonate 31e in DMF containing t -BuOK gave the 1,3-butadienylphosphonates 121 in good yields The latter compound was treated with ammonia to afford pyridin-3-ylphosphonate 122 in 60% yield (Scheme 32) 45 F Et 2N N Et Et I 120 EtO O P COMe EtO 31e t-BuOK, DMF - Et2NH F Et 2N 121 COMe OEt P OEt O NH3 F N O OEt P OEt Me 122 Scheme 32 2-(hydroxyimino)-1,3-Diphenylpropane-1,3-dione 89 was reacted with diethyl phosphonoacetates 31b,c to yield oxazolophosphonate 123a,b (20%) and phosphono-1-ethoxypyridinone 126a,b (32%) (Scheme 33) 38 238 KHIDRE and ABDOU/Turk J Chem O Ph NOH Ph EtO O P CO R EtO 31b,c -H2O OEt PhOC N O OEt Ph P RO2C O OEt 126a,b (32%) -ROH Ph PhOC HN RO2C O OEt P OEt O 123a,b ( 20%) LiOEt O O 89 Ph O Ph NOH CO2R Ph O OEt RO2C P OEt 125 NOH + 31b,c Ph CO2R 124 Scheme 33 Quinolinyl phosphonate 129 and 2-aminoquinolin-3-ylphosphonate 132 along with 1H -indol-2-ylphosphonate 133 were synthesized from the reaction of 3-phenyl-2,4-benzoxazine-1-one 30 with phosphonoacetate 31b,c and phosphonoacetonitrile 31e, respectively (Scheme 34) 18 O EtO P CO R EtO 31b,c LiH/DMF O O O N O OEt P OEt CO2R Ph O Li 127 128 O N 30 Ph O EtO P CN EtO 31e LiH/DMF O OEt P OEt O CN O Li N Ph 130 O OEt P OEt CO2R O NH Li COPh O OEt P OEt CN NH Li 131 COPh -ROH OEt O OEt P OEt O N COPh 129, 64% O OEt P OEt N NH2 COPh 132, 37% -HCN OEt OEt P OEt N O COPh 133, 24% O Scheme 34 4-(p -tolyl)-2,3-Benzoxazine-1-one 134 was treated with phosphonyl carbanion 31a–c,e to give the substituted isoquinoline derivative 136 and 138, via intermediates 135 and 138, respectively (Scheme 35) 18 239 KHIDRE and ABDOU/Turk J Chem O R O EtO P OEt O N 31b,c,e R R R 135 134, R = 4-MeC6H4 O EtO P OEt O 31a O OEt P OEt O NOH OEt P OEt NOH O O OEt P O OEt - H2O R N R 136, R = CO2Me, CO2Et, CN O - H 2O R 137 OEt P OEt N O R 138 Scheme 35 2-(phenylmethylene)-1,3-Diphenylpropanedione 139 was reacted with phosphonyl carbanion 140 in the presence of NaH and/or NaOEt to afford substituted pyran-3-ylphosphonate 142 via intermolecular 1:4 addition followed by intramolecular cyclization 141 (Scheme 36) 46 O Ph Ph O 139 EtO EtO P + O Ph O Me O Me Me Toluene/NaH or EtONa/EtOH O OEt O P OEt OBu-t Ph Ph OH 140 Ph O 141 - (CH3)3COH Ph O OEt P OEt O Ph Ph O O 142 Scheme 36 3.2 Synthesis of six-membered heterocycles with more than one heteroatom 3.2.1 Pyridazines, oxazines, and oxathiines and their fused systems 2-Diazotrifluoroacetoacetate 143 was allowed to react with phosphonyl carbanion reagents 31c,e in acetonitrile to give olefinic adduct 144a,b Reductive cyclization of 144a using triphenylphosphine yielded pyridazines 146 (Scheme 37) 47 240 KHIDRE and ABDOU/Turk J Chem O N2 F3C + CO2Et 143 O EtO P CH2R1 EtO H i) LiCl ii) EtN(i-Pr)2 31c,e OEt PPh3 only 144a F3C O N N CO2Et 145 R2 N2 F3C CO2Et 144a, R = CO2Et b, R = CN OEt PPh3 - Ph3PO N N F3C 146 CO2Et Scheme 37 When compound 83 was reacted with diethyl cyanomethylphosphonate 31e, indeno-[1,2-b ][1,4]oxazin3yl)phosphonate 148 together with indeno[2,1-d][1,3]-oxazole-2-carbonitrile 150 was obtained (Scheme 38) Compound 148 showed more significant antifungal activity against D specifera and F oxysporum 37 O O O P (OEt)2 O O P(OEt)2 N C CN -H2O OH NOH O 83 OH 147 CN 31e O EtOH/EtONa O -(EtO)2P(O)O NH O 149 NH O P OEt O OEt NH 148, 48% -H2 N CN O 150, 21% CN Scheme 38 In a systematic study, the behavior of indandione oxime 83 towards diethyl vinylphosphonate 31a was reported and indeno[1,2-b ][1,4]oxazin-3-yl)phosphonate 153 along with indeno[a]pyrrole 150 was obtained (Scheme 39) 37 Barbituric acid-5-oximes 92 were reacted with phosphonyl carbanion reagents 31b,c to afford the pyrimidino[4,5-b][1,4]oxazin-3yl)phosphonate 156 and spiro[pyrimidine[5,3‘][1,2]oxazole]-4‘yl)phosphonate 158 via intermediates 155 and 157, respectively Moreover, [1,4]oxazino[3,2-d]pyrimidin-2,4-dione phosphonates 160 were obtained via Perkin-type condensation of 92 with phosphonoacetonitrile 31f (Scheme 40) 39 241 KHIDRE and ABDOU/Turk J Chem O P (OEt) O O 31a NOH EtOH/EtONa O 151 83 O N O P O EtO OEt + N O O 152 -H2O -(EtO)2P(O)O Alkylation O O NH O P OEt O OEt 153, 46% O P(OEt) O OEt N 154, 14% Scheme 39 O O OEt P N OEt O O N OH OR R1 155 R1 EtO O P CO2R EtO NOH 31b,c EtONa/EtOH O -H2O R1 O N O N R1 92 O R1 O N NH O CO2R N O P OEt R O OEt 157 EtO O P CN EtO 31f R1 O N O O N N R1 OH P OEt OEt CN 159 N O R1 O N N R1 O R1 O O OEt P OEt O O N N N R1 156, 35% R1 N -ROH O O Et NO N OH Alkylation R1 O P O EtO OEt 158, 28% H O OEt N P OEt O NH2 160, 74% R1 = H, Me Scheme 40 Similarly, pyrimido[4,5-b][1,4]oxazin-6-ylphosphonate 162 via intermediate 161, and pyrrolo-[3,2-d]pyrimidine-2,4-dione 165 were obtained from the reaction between compound 92 and vinylphosphonate 31a (Scheme 41) 39 242 KHIDRE and ABDOU/Turk J Chem + O R1 O N O R1 O EtO P EtO 31a N N R1 O NOH N R1 O O R 92 R = H, Me N O O Et O O O N P OEt R1 N -H2O N P OEt OEt OEt Alkylation O N O O R1 162, 43% 161 O O N N O R1 163 O -(EtO) 2PO R P OEt OEt O N O N N R 164 O Alkylation O R1 O N OEt N N R1 165, 21% Scheme 41 Diethyl vinylphosphonate 31a was reacted with oxime 89 to give [1,4]oxazinephosphonate 167 via intermediate 166 (Scheme 42) 38 O EtO P OEt 31a O Ph N(O) CH2 PhOC NOH Ph OEt P OEt O 166 Ph LiH O 89 -H2O PhOC Ph O N OEt P OEt O 167, 70% O Scheme 42 6-Hydroxybenzo[ d][1,3]oxathiol-2-one 58 was reacted with diethyl vinylphosphonate 31a in EtONa solution to furnish 1,4-benzoxathiin-2-ylphosphonate 168 in 64% yield via a cycloaddition reaction and tandem OH-alkylation as displayed in Scheme 43 28 O HO O + S 58 P(OEt)2 O EtONa/ Alkylation 31a EtO Me O S O P(OEt)2 O 168, 64% Scheme 43 243 KHIDRE and ABDOU/Turk J Chem In the same fashion, 1,4-benzoxathiin-2yl-methylphosphonate 169 was obtained from the reaction between 58 and allylphosphonate 31h (Scheme 44) 28 O HO P(OEt) O S 58 O Me P(OEt)2 EtONa/ + O CH=CH2 A CH Me EtO O Alkylation CH2P(OEt)2 O S B 31h O 169, 66% Scheme 44 Benzoxathiinphosphonates 168 and 169 showed more significant antimicrobial activity than some known drugs ciprofloxacin and ketoconazole (standards) against a panel of representative gram-positive pathogenic microorganisms, gram-negative microorganisms, and fungi 28 3.2.2 Oxaphosphinine, diazaphosphinine, and thiadiazine and their fused systems Phosphonates 171 and oxaphosphinine oxides 173 were synthesized, in almost equal yields, by reaction of 5-bromo-2-acetylthiophene 170 with phosphonyl carbanion 31b,c,e in dry DMF containing LiH under reflux temperature (Scheme 45) 27 The antiinflammatory activity in vivo of compound 173 was examined at 50 mg/kg body weight and displayed inhibitory activities, which were equivalent to that of the standard indomethacin at 100 mg/kg 27 O Me Br S O 170 EtO O R P EtO 31b,c,e - HBr R O S (EtO)2P Me 171 Me Me Br S OH P OEt OEt O R 172 R = CO2Me, CO2Et, CN - EtOH Br S R O OEt P O 173 Scheme 45 Enamine phosphonates 174 was reacted with nitriles to afford 1,5,2-diazaphosphine-2-oxides 175 While highly stable hydrogen-bonded amine-dihydrodiazaphosphinine adducts 176 were synthesized either by addition of diisopropyl amine to diazaphosphine oxide 175 or by the reaction of phosphonate 174 with nitriles in the presence of lithium diisopropylamine (LDA) (Scheme 46) 48 244 KHIDRE and ABDOU/Turk J Chem ( i-Pr)2HN O OEt P OEt i) LDA R2 NH2 ii) R3CN R1 R2 i) B ii) R uLi CN O OEt P N R1 R2 N H 175 R3 N R H 176 NH ( iPr) 174 O OEt P N R1 R1 = H, Me, Ph R2 = C2F5, CF3, Ph, 2-f uryl, 2-pyridyl R3 = CF3, C2F5, C7H5, 2-furyl, 2-pyridyl Scheme 46 Reactions between 1,2,4-triazole-3-thiol-4-aminoarylidenes 115 and diethyl [methyl(thioalkyl)]phosphonates methanolic sodium methoxide in the presence catalytic amount of DDQ yielded thiadiazine-2-phosphonates 177 (≈ 72% yield) As displayed in Scheme 47, compounds 177 were formed via elimination of the alkylthiol motif from intermediate 176, followed by intramolecular cyclization (Scheme 47) 43 N N N SH SH OEt + EtO SR2 P N R O MeOH/MeONa N N DDQ 115 R2S O N P OEt OEt N H R 176 -R2SH -H2 O OEt P N N OEt N N R H 177 S R1 = 4-Me2NC6H4, 4-ClC6H4; R2 = Me, Et Scheme 47 1,2,4-Triazole-3-thiol-4-aminoarylidenes 115 were reacted with diethyl(2-methylallyl)phosphonate 178 in MeOH/MeONa/DDQ solution to give the fused thiadiazine-5-methylphosphonates 180a,b in ≈75% yield According to the mechanism outlined in Scheme 48, Michael addition by imine 115 onto the isomerized ylide form of the phosphonate reagent resulted in the formation of final products 180 via tandem loss of the H molecule from the initially formed intermediate 179 43 Conclusion Phosphoryl carbanions (WHE) are versatile and convenient intermediates for construction of many types of five- and six-membered heterocycles This survey attempted to summarize the synthetic potential of phosphoryl carbanions, as starting precursors, in the synthesis of 5- and 6-membered heterocycles since 1985 245 KHIDRE and ABDOU/Turk J Chem N N N SH N 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Quinolinyl phosphonate 129 and 2-aminoquinolin-3-ylphosphonate 132 along with 1H -indol-2-ylphosphonate 133 were synthesized from the reaction of 3-phenyl-2,4-benzoxazine-1-one 30 with phosphonoacetate... onto the isomerized ylide form of the phosphonate reagent resulted in the formation of final products 180 via tandem loss of the H molecule from the initially formed intermediate 179 43 Conclusion... diethyl(2-methylallyl)phosphonate 178 in MeOH/MeONa/DDQ solution to give the fused thiadiazine-5-methylphosphonates 180a,b in ≈75% yield According to the mechanism outlined in Scheme 48, Michael addition by imine 115 onto