Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17 Definitions: Examples of mesoionic compounds: Mesoionic compounds are “five membered heterocycles which cannot be satisfactorily represented by any one covalent or dipolar structure, but only has hybrids of polar R R R R O+ structures…they possess a sextet of electrons.” N+ N+ N+ N+ O- – Ollis and Stanforth, Tetrahedron, 1985, 41, 2239 N - N - - N O O O NH- O O O NH Betaines are compounds that bear a positively charged cationic functional group (such R sydnone sydnone imine as a quaternary ammonium group) and a negatively charged functional group (such as a münchnone münchnone imine isomünchnone carboxylate). R1 R1 S- Mesomeric betaines are neutral conjugated molecules which can be represented by S+ R + N+ N+ dipolar structures in which both the positive and negative charges are delocalized within N+ S the π-system O- N - N O- N O- O O N N R S i. acyclic (1,3- and 1,5-dipoles) R2 R2 ii. conjugated heterocyclic mesomeric betaines thioisomünchnone thiomünchnone iii. cross-conjugated heterocyclic mesomeric betaines iv. pseudo-cross-conjugated heterocyclic mesomeric betaines Other common mesoionic compounds: Zwitterionic compounds are neutral molecules with both positive and negative charges O PR3 (amino acids). O+ S+ O+ 2 3 1 3 O R + R R R R - - - N Me O O O N+ + - + 4 R O S S 1 N CO2 N R N R R2 N - Me Me + oxamünchnone 1,3-dithiolium-4-olate 1,3-dithiolium-4-olate Montréalone O O 5 N R R O- Outline: mesoionic betaine acyclic mesomeric betaine conjugated heterocyclic (azomethine ylide) mesomeric betaine I. Sydnones: synthesis and reactions Some of the key figures in the II. Münchnones: synthesis and reactions chemistry of mesoionic compounds: O O III. Isomünchnones: synthesis and reactions R IV. Assorted mesoionic compounds N+ +H N CO - N+ 3 2 Topics not covered in great detail or at all: N O- R N O- R R I. Mesoionic carbene ligands II. Related mesomeric betaine compounds cross-conjugated heterocyclic pseudo-cross-conjugated zwitterion mesomeric betaine heterocyclic Kenneth Turnbull Masami Kawase mesomeric betaine Resonance structures of a sydnone (mesoionic): R R R R H N+ N+ N+ N - - N - N N N O O O O O O O O R R R H + Gordon Gribble Rolf Huisgen Manfred Regitz Albert Padwa Bruce Arndtsen N N N (Gianatassio, (Hafensteiner, (Krawczuk, - - N - N - N - 2014) 2004) 2009) O+ O O+ O O+ O Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17 Sydnones 1. MBT, PhMe, 1. HBr, NaNO2 O- - often crystalline solids (can be purified by recrystallization) H2N reflux S Me 2. p-NO2BnBr Br + R H - typically stable at room temperature S Me 2. Et3N (cat.) + 3. m-CPBA 3 N 4 - conc. acid or heat can result in decomposition via decarboxylation to N Me O 77% N Me 2 N O- hydrazine derivatives; relatively stable to hydrolysis CO H O O 5 - C4 pK = 18 – 20 2 (3 steps) CO PNB 1 a 2 - discovered in Sydney, Australia S Synthesis of sydnones: S N Br O3; P(OMe)3 Br SCHO AcOCHO, Br S S EtOAc Me PPh Me First reported synthesis 3 N N Earl, J. C.; Mackney, A. W. J. Chem. Soc. 1935, 899. N –70 ºC, 72% then reflux O Me O Me O (3 steps) Ph CO2PNB 42% CO2PNB CO2PNB ON PhN + NaNO Ac2O HN CO2H 2 N CO2H N rt N O J. Org. Chem. Ar HCl Ar O N - 2004, 69, 5850 - can use isoamyl nitrite 73% O O for acid sensitive substrates: proposed correct structure Synthesis 1988, 1011 structure Br S 1. MgBr , Et N; Ac O O O 2 3 2 N One-pot Synthesis N N –20 ºC to 0 ºC N Ar Br CHO + N Ar DBH, NaNO2 N N N CO H N+ Synthesis, O 2. Zn dust, 2 Ac O, CH Cl N Br phosphate H 2 2 2 2006, (2 steps) CO2H NaO C S 0 - 5 ºC N - O buffer (pH 6.5) 2 O O Me 1123 80 – 94% Me Reactions of sydnones: DBH β-lactamase Related compounds: inhibitor Pyrazole Synthesis (Cycloadditions with Alkynes) N N N (Wyeth) -O R3 R4 R4 R3 First reported by O O + N N S O R3 R4 Huisgen: Me + Angew. Chem. Int. Ed. N N R2 N R2 N R2 N N [3+2] N N Engl. 1962, S S –CO 1, 48 NaO2C NaO2C R1 2 R1 R1 BRL–42715 SB-206999Z For discussion on regiochemistry of sydnone cycloadditions, see: Tetrahedron, 2010, 66, 553 Sydnones on process scale: Org. Process Res. Dev. 2006, 10, 712. Cycloadditions with Alkenes H NO NaNO2 TFAA + N N N N decomp. O 3 4 O - R R further reactions CO H CO H PhMe exotherm. at O R3 R4 2 aq. HCl 2 ([3+2], 58% 180 ºC O 4 quant. - 2 O R –CO2 2.5 kg decomp. O R 2 N pyrazoline 2 N [3+2] N R3 R N exotherm. at R N N formation, O 1,2-diethoxyethane R1 1 oxidation, etc) 68 ºC 1 R 120 – 125 ºC R O OEt 5h, ca. 1.5:1 O - O O O Me KOH/EtOH O+ O N N N N N N or KOEt/EtOH N + N N + + + CO K CO2Et xylenes N N 2 [selective N N N N reflux N hydrolysis] 41% (desired) 65% (20:1:1) CO2Et desired 81% CO2Et Tet. Lett. 1989, 35, 4625 For cycloheptenone: 4:1:1 (70%) Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17 Other Heterocycles Accessed via Cycloadditions of Sydnones N3 Side Chain Lithiation + Ph E Yield (%) PCl Me Ph allyl Br 67 R3 Regitz and coworkers, n-BuLi Li Ph E+ E Ph TMS N+ + ClCO2Me 21 or P Chem. Ber. THF N+ N TMSCl 36 tBu P 1987, 1809 N - –90 ºC N - 70 2 N O O N - O CO2 R N Tet. Lett. 1986, O O O 80 27, 4415 p-ClPhCHO 1 PhCOMe 12 R Syn. Lett. 1998, 667. PhCOPh 70 -O Russ. Chem. Bull. 1998, 47, 1725. + N Dilithiation O Kato and coworkers, O N Ph R R2 N J. Chem .Soc., Perkin OH OMe N DMF, Li R N COR reflux, 30% Trans. 1 - 1 1993, 1055 O R RCO2R’ Li Me E tBu tBu + + + tBu N 71 – 95% N then E+ N R2 O N E+ = TMSCl, Br N - N tBu N O- 2 O Synthesis, 1996, O I , (SPh) , DMF O tBu 1 Bull. Soc. Chim. Fr. 1183 2 2 ortho-directed lithiation N R with n-BuLi 59 – 86% N 1997, 134, 927 from (requires TMEDA) CH2Cl2, N (2 equiv.) reflux, 42 –80% 3-(2-bromophenyl)sydnone THF, –78 ºC Synth. Commun. C4 Acylation tBu 2009, 39, 2852 -O -O -O O+ O+ ClSO NCO O+ C4 Magnesiation K10 clay, Ac2O 2 O O Ph N 110 ºC N MeCN N N N N N+ R = aryl, 25 – 86% R = aryl, Bn Me H2N R R 55 – 81% R N - EtMgBr O O Synth. Commun. 1996, Synth. Commun. 1998, THF Ph MgBr Ph E E+ = 26, 2757 28, 931 30 ºC N+ E+ + H O, CO , C4 Halogenation N 2 2 - - - Ph Br Mg N - N Ac2O, Me2CO O O O + O O- + + + N MeI O O O PhICl2 O Br2 O N - Et O J. Het. Chem. 1972, 9, 123 N N N O O 2 Cl N Et3N, CH2Cl2 N AcOH, NaOAc Br N Bull. Chem. Soc. Jpn. 1957, 30, 210 53 – 88% 77% Cross coupling reactions of sydnones R rt R R ICl 1 Liebigs Ann. 1997, 70 – 92% Synth. Comm. 1996, R1 Cu R Li R1 ZnCl AcOH, NaOAc + 2613 26, 1441 + CuBr N ZnCl2 + -O N N N O+ N - O- N - O O O O O I N C4 Lithiation N (Het)Ar X Ph R Mendeleev Comm. (Het)Ar X Mendeleev Comm. + N 1992, 2, 60 Pd(PPh ) (5 mol%) Pd(PPh3)4 (5 mol%) 1992, 2, 60 n-BuLi 3 4 42 – 92% N 42 – 92% O- 1 1 O Et2O Ph Li Ph E R Br R Ar R1 + + + + ArX –20 ºC N E+ N+ E = N (Het)ArB(OR’2)2 N N+ Ph Br CO2, Ph2PCl, N Pd(OAc) , PPh N - N - O- PdCl2(PPh3)2 (5 mol%) N O- 2 3 N - + O O (MeS)2, (PhSe)2 O O K CO , wet DMF O N n-BuLi O O CsF, DME/H2O, 2 3 O 130 ºC, w Synthesis 2009, 650 N O- Et2O Bull. Chem. Soc. Jpn. µ O –50 ºC 1959, 32, 282. Bull. Chem. Soc. Jpn. 1986, 59, 483 J. Org. Chem. 2009, 74, 396 J. Het. Chem. 1966, 3, 391. Bull. Chem. Soc. Jpn. 1986, 59, 487 For Sonagashira coupling: Synth. Commun. 2003, 33, 2209 Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17 Medicinal Chemistry Investigations of Sydnones O Cl O H S N O N Me N O PMB NH- N + NCO Et + N- N N 2 N N N+ N N Ph N N O2N Cl N N+ N H O O O- O N+ Ar Me N + O N - - O Molsidomine Linsidomine Pirsidomine SYD-1 O N O vasodilator active metabolite O N of Molsidomine 2 Activation mechanism of Molsidomine (NO release) anti-carcinoma broad-spectrum antibacterial activity anti-oxidant Basic Clin. N O N O NO Arch Pharm. Pharm. Med. Chem. Bioorg. Med. Chem. - NH Pharmacol.