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. Toxicol. 2004, 337, 427 2004, 12, 4633 N+ NCO2CH2CH3 esterase + NH N 2016, 119, 41 N N N N O O O Sydnone Imines Molsidomine Linsidomine NO NO R - can be directly lithiated at C4 (Li-halogen exchange fails) N CN 3 N+ 4 N –NO N CN N CN - synthesized by Greco in 1962 N N N - - stabilized by N-acylimino groups O then 2 O 5 NH - can undergo ring-opening reactions at neutral pH tautomerization O O 1 C4 Lithiation (Sydnone imines) Synthesis of sydnone imines:

1 1 1 First reported successful synthesis R R Li R E N+ n-BuLi N+ E+ N+ Greco, C. V.; Nyberg, W. H.; Cheng, C. C. J. Med. Chem. 1962, 5, 899. THF + N NR2 N NR2 E = ArCHO, MeO2Cl N NR2 n-Pr O –78 ºC O O 2 30 – 83% NaNO ON HCl + R = acyl 1 HN CN 2 N CN N unstable above R = Cy, 1-morpholine n-Pr HCl n-Pr MeOH N - –78 ºC 95% O NH 1 TMSCl, MeI, and allyl Br (2 steps) white crystalline R SR 1. S do not react under + 8 powder N these conditions Pharmaceuticals featuring sydnone imines 2. MeI or H2O N 2 O NR 58 – 89% R = n-Bu, N O N O Mendeleev Commun. 1 - - i-Pr, NMe2 Bn N+ NH Bn N+ N 2009, 19, 322 NH2 NHPh Cross Coupling of Sydnone imines Me Me O Me 3 1 1 R X 1 3 mesocarb R Li R Cu R R + + Pd(PPh)3 (5 mol%) + feprosidnine (Sidnocarb) amphetamine N CuBr N N (Sydnophen) dopamine reuptake inhibitor; N 2 N 2 THF, rt N 2 stimulant O NR O NR O NR amphetamine pro drug R3 = aryl, vinyl stable under X = Br, I Mendeleev Commun. 2000, 10, 181reflux for several hours 30 – 65% R1 = Cy, 1-morpholine Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17

Münchnone (See Gordon W. Gribble, Gianatassio, 2014 for more examples) Multicomponent synthesis of münchnones (Palladium-catalyzed)

- hydrolysis prone; often generated in situ CO (1 atm) 1 2 1 R R1 R R R 3 + 4 - C4-electron withdrawing groups O [Pd], iPr NEt MeOH N N 2 N MeO C N R3 stabilize münchnone/enable isolation + 2 - 3 Bu NBr, 2 O - electrophilic at C2 2 R Cl 4 3 - O 5 R H MeCN/THF, 55 ºC R O O R2 O 1 - nucleophilic at C4 1 - cannot be lithiated at C2/C4 R = aryl, R3 = aryl, alkyl 31 – 91% alkyl, Bn R1 Synthesis and reactions of münchnones Arndtsen and coworkers, J. Am. Chem. Soc. 2003, 125, 1474 R2 = aryl 3 ROH RO2C N R First reported synthesis O R1 CO (4 atm) R1 R2 38 – 86% R2 O [Pd(allyl)Cl]2 (5 mol%) N+ 3 Lawson, A.; Miles, D. H. Chem. Ind. (London) 1958, 461. R N OR tBuP(2-biphenyl) R4 R5 5 4 R3 O- R R R2 (15 mol%) O O Dehydration with DCC: 38 – 72% O O Bu NBr, Ac2O J. Org. Chem. 1979, 44, 977 4 O- Dehydration with EDCI: MeCN, 65 ºC R1 R3 N N+ N Me Synth. Commun. 1986, 16, 357. Angew. Chem. Int. Ed. 2008, 47, 5430. R2 Huisgen Pyrrole Synthesis ([3+2] cycloadditions with alkynes) For mechanistic analysis of these reactions, Angew. Chem. Int. Ed. Engl. 1964, 3, 136. see Chem. Eur. J. 2016, 22, 15945 1 Ph R Ph O O 1 2 Ph Multicomponent synthesis of münchnones (via Ugi Reaction) Ac2O - R R + O 2 HO C N Ph N R 4 5 2 55 ºC 1 2 N R3 CHO R R 5 4 J. Am. Chem. Soc. 1995, Me R , R = CO2R, 1 R R Me “a few minutes” Me R CO2H HCl 117, 7842 Ph Ar, alkyl, H J. Am. Chem. Soc. 1996, 90% yellow Ph NC 2 THF, 55 ºC 1 3 118, 2574 needles R NH2 or R N R [3+2] Cycloadditions with other Dipolarophiles PhMe, 100 ºC 2 “If DMAD is unable to ambush a R suspected mesoionic heterocycle, BnO (EROS article) 13 – 63% BnO BnO then the later most probably has not BnO been generated!” –Gordon Gribble BnO TsCN N BnO From acylamino chromium carbene complexes N CO2H Ts N CONH2 DCC, iPr2NEt MeO C CO Me BnO N Cr(CO) O Cr(CO) DMAD (2 equiv.) 2 2 BnO O Helv. Chim. Acta. BnO O 5 5 1997, 80, 1443 OBn + n-BuLi; PhCOCl CO (30 psi) OBn OBn HN Ph Ph N Ph dark, THF Ph Ph 4 –78 ºC, THF N R 53% 23% Me Me rt, 2 days N Me R4 12 – 90% NSO Ph 3 1 J. Am. Chem. Soc. 2000, 122, 7398 90% 2 R N R J. Chem. Res. (S) 1991, 188 2 O- R Ar Ring chain tautomerization O N N+ ArN2BF4 Bronberger and Huisgen, CO2Me CO2Me 3 1 PhCOCl, Ph R + R 3 1 Tet. Lett. 1984, 25, 65 O Me N R N R Me OTBS DMAD + CO Me 2 2 CO2Me 2 R 4 R R4 N Tet. Lett. 1988, N N R P Tet. Lett. 1986, 27, 4419 PhOC MeOC P 29, 2027 9% R4 Regitz and coworkers, 36% 3 1 Chem. Ber. 1987, 120, 1809 PCl R N R TMS R2 Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17

Lewis-acid catalyzed cycloadditions CF R4 R1 3 1 N OH O R N DMF 3 rt N R4NH R R2 N Ph R3 2 N Org. Lett. 2002, 40 – 88% 2 CO H 4, 3533 O TMSCl R 2 O R1 1 1 HO NR1COR2 O R O CH2Cl2 TFAA, pyr. R CF3 2 + PhNHNH2 PhH O - 51 – 78% 4 HO C N R N + O R 2 N N 1 1 reflux N M R R R2 O- N CF3 2 O 46 – 95% R R2 3 J. Am. Chem. Soc. 3 4 R Kawase and Koiwai, Chem. Pharm. Bull. 2008, 56, 433 Ph azlactone R R N 2004, 126, 12776 1 AgOAc (cat.) R R2 CO2H DCE 15 – 95% O N COR2 3 rt Ph3PCH2R Br, SMe3I, 1. NH4OAc, DMF 14 – 70% n-BuLi; AcOH, n-BuLi; AcOH, 2. POCl , pyr. OH 3 Ph N For Au-catalyzed enantioselective [3+2] cycloaddition see: 80 ºC 80 ºC N CF Toste and coworkers, J. Am. Chem. Soc. 2007, 129, 12638 H 3 3 R CF MeS CF3 Münchnones As Nucleophiles 3 CF3 N TFAA, pyr. N 2 O R2 R 2 Tet. Lett. 1993, N N R N DMAP, 80 ºC R CF 1 O 3 CF3 34, 859 R1 R 1 46 – 87% O R Kawase and coworkers,Kawase and coworkers,Kawase and coworkers, CO2H N Org. Lett. 2010, Tet. Lett. 2012, Chem. Pharm. Bull. 53, 2782 O OH 12, 4776 2001, 49, 461 R O TFAA Tet. Lett. 1994, 100 ºC R N CF3 81 – 88% H 35, 149 O Complex structures synthesized via münchnones R R O O O TFAA, pyr. N R’ N Ph NHPh OBn R PhH N R R’ Me Me HO2C O 52 – 98% CF N R’ = tBu, Ph O 3 N N J. Chem. Soc. Chem. Commun. 1992, 1076 F Me F Me O Et Münchnones As Electrophiles: Reactions of C4 N trifluoroacylated münchnones HO H HO atorvastatin (–)-rhaznilam HMG-CoA O Lipitor HO reductase HO Me 18 O CO H inhibitor CO H CF3 H O 2 2 N+ 2 CF3 18 1,4-dioxane Ph N Ph O OH Lopchuk and Gribble, Tokuyama and coworkers, U.S. Pat. Appl. 0239857 A1, 2005 O 60 ºC Me OH 95% Tet. Lett. 2015, 56, 3208. Tetrahedron 2015, 71, 3619 Also see: OPRD, 2008, 12, 1183 Kawase and coworkers, Tet. Lett. 1998, 39, 6189 Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17 Münchnone imine Thiomünchnone R + N + - synthesized by Gotz and Zale in 1970 S - synthesized by Potts in 1977 NH- - can be lithiated unlike the parent münchone O O- - reports of reactions with thiomünchnones are incredibly O limited Synthesis and reactions of münchnone imines Synthesis and reactions of thiomünchnones O R2 TFA, + TFAA N O NC N R1 R1 NCOCF - R2 O 3 HO HS Ph Ph 2 CO H Ph O + Tetrahedron 1970, 26, 3185 2 Bu R 2 NaOH DIC S R CHO + N PhMe, - Ph Br MeOH HO2C S Ph Ph O O Bu Bu Li 1 - reflux + n-BuLi R O NCOCF3 79% N N+ CuI; J. Org. Chem. 1977, 42, 1633 S 1 - – 90 ºC, THF R2COCl O Ph R O NCOCF3 R1 NCOCF - O 3 2 cod Pd(PPh ) Bu R Ph 3 4 N+ 32% Mendeleev Commun. 2003, 13, 215 (6.25 mol%) THF 1 - Tet. Lett. 2000, 41, 1687 R O NCOCF3 Montréalone [4+2] vs. [3+2] Reactivity O PR3 BF - - synthesized by Arndtsen in 2007 4 2 3 Ph Ar EtO2C R + R - bulky PR3 unit allows for highly regioselective cycloaddition + N N CO2Et compared to münchnone/offers opportunity for asymmetric O R1 cycloadditions Ph O NH2 DMF, rt N Ph Ph H Synthesis of Montréalone Ph O proposed structure HBF4 J. Org. Chem. 1979, 44, 111. Ph NC N Ph 1 R4 R5 4 R5 R Ph O R Ar Ph Ar N O P O PR3 + CO2Et HN DBU N 2 3 2 O R + R R3 H R Cl CHCl N R3 R2 - DMF, rt O CO Et 3 N Ph O NH 2 R1 R1 + HBF Ph 4 J. Am. Chem. Soc. 2007, 129, 297 24 – 91% Oxamünchnone confirmed by X-ray Eur. J. Org. Chem. 1999, 297. O+ - synthesized by Burk in 1980 R4 R - Hamaguchi and Nagai indicated utility of oxamünones for - For computational N N O O cycloaddition chemistry (furan synthesis) analysis 3 R2 - form stable adducts with olefin cycloaddition partners of 1,3-dipolar R N cycloadditions X Synthesis and reactions of oxamünchnone R1 n of munchnone X = O, S, CH2 derivatives: Synthesis of imidazoles from Enantioselective synthesis of Ar MeO2C CO2Me O O J. Am. Chem. Soc. Montréalone pyrollines with a chiral BINOL-derived [Pd] O+ DMAD Ar 2013, 135, 17349 phosphite from Montréalone O Ph J. Org. Chem. 2015, 80, 2709 PhMe, 80 ºC Ph O- Ar O Ph N O Org. Lett. 2014, 16, 1056 2 J. Chem. Soc., Chem. Commun. 1985, 190 Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17

Isomünchnone Imidosulfoxides as isomünchnone precursors via Pummerer R O- Rearrangement/Deprotonation J. Org. Chem. 2000, 65, 2368 + - synthesized and isolated by Ibata in 1974 N O O R1 O- - typically not isolable/stable (EWG stabilizes) O O O + - primarily used in cycloaddition chemistry S+ N O S R2 N R3 R2 N R3 R2 SR3 1 O 1 R R A B Synthesis of isomünchnones O O SR3 R1 OAc Ac O O Initial Synthesis and Isolation N 2 B Hamaguchi, M.; Ibata, T. Tet. Lett. 1974, 4475 R1N A 1 B 2 NO2 R A R CO Me 2 O SEt O O O O O 1. NaIO4/RuCl3 OTf Me O- Ac O, TsOH (cat.) 2 2. BF3•OEt2 N Cu(acac)2 + S CO2Me O N N Et N 3. (TfO) NPh, NEt N heat PhMe, 90 ºC 2 3 2 15 min 74% (3 steps) Ar O N O 51% CO2Me Me NO2 O O Ar red crystalline material N N air-stable for weeks N N 1. H2, PtO2 N SnBu3

2. NaOMe, Pd2dba3 (10 mol%) MeOH TFP (20 mol%) Reactions of isomünchnones 85% CO2Me CO2Me THF, reflux, 70% [3+2] Cycloadditions formal synthesis (Goldberg and Lipkin, i. Intramolecular H Me O O J. Org. Chem. 1972, 37, 1823) Rh OAc Me Ac 2 4 O Strategy was applied to other alkaloids N Ac in same publication: PhMe, reflux BnN Bn N 74% 2 O Maier and Evertz, Tet. Lett. 1988, 29, 1988 O O Me Me ii. intermolecular N Ph Ph OMe N N O N O O O H N N O O H O Ac O O O O O 1.2:1 (±)-anagryine onychine dielsiquinone endo:exo N Rh2OAc4 Me Me N Me + 78% O N Me N PhH, 80 ºC - N H N2 O H DMAD MeO2C CO2Me 85% H OCN Me H N Me Padwa and coworkers, Tet. Lett. 1989, 30, 4077 3 O OH H O H HN (±)-lupinine (±)-pumiliotoxin C (±)-costaclavin Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17

Padwa’s Approach to Lysergic Acid Thioisomünchnone J. Org. Chem. 1995, 60, 2704 - O R O Ph N+ HO2C Me MeO2C Me S NNHTs N N MeO2C Me N Ph S N S 2 H H H S O- O NH Ph COCl N+ H Et N, 12h N O H N R 3 rt N N R NH NH 86% NR Initial Synthesis and Isolation deep-red needles Potts, K. T.; Murphy, P. J. Chem. Soc., Chem. Commun. 1984, 1348 m.p. 256 – 259 lysergic acid paspalic acid For preparation via diazothioamides with Rh, see: Padwa and coworkers, Heterocycles, 1993, 35, 367. Me O- O O O + N Padwa’s total synthesis of alloyohimbane N OMe J. Org. Chem. 2000, 65, 2684 O CO2Me NH Me N2 - N O S N N N H N H R H O + isomünchnone + N H N S O H H H Cl 1. O3; NaBH4 OH alloyohimbane Br 2. MnO2 1. H2CrO4 NHMe 3. Wittig 2. CDI; MeNH2 1. Wittig NH 81% 47% 2. OH- O N N O (3 steps) (2 steps) N 3. LDA, CBr4 N N Bz Bz H S Bz CHO 4. (COCl)2 Cl S MeO2C 54% 1. ClCOCH2CO2Me 93% 5 Br PhMe, rt, N H (4 steps) 2. MsN3 (2 steps) then 100 ºC H H 75% 1. Ra-Ni 42% O (2 steps) O O O O 2. LAH Me MeO C Me alloyohimbane N 2 N MeO2C Rh (pfb) O H 2 4 N OMe 1,3-thiazolium-4-thiolate (6 mol%) S Ph O Me N2 R S- CH Cl , rt R S- S 2 2 N N+ DMAD CO2Me 93% N+ 1. ROTs N 47 – 72% N Ph Ph 2. NaH, S8, DMF Ph Ph N NBz Bz S S R Ph MeO2C Me S 30 – 48% CO2Me Bz O N (2 steps) 1. BF3•OEt2 H R = Me, Et, Bn S MeO2C Me 2. N Chem. Pharm. Bull. 1984, 32, 4637 NaSH 44% formed in 33% MeOH Cl OPh when Rh2(OAc)4 was - used 3. Bu SnH, R O R OMe 3 4% NH + + AIBN, Δ (3 steps) N Me3OBF4 N NBz paspalic acid S 78% S Baran Group Meeting Jacob T. Edwards Mesoionic Compounds 3/25/17

1,3-dithiolium-4-olates Key References: Synthesis O- Gotthardt and Christl, Tet. Lett. 1968, 4743 S+ The Chemistry of Heterocyclic Compounds, Volume 60: Oxazoles: Ph S Ac2O O- Synthesis, Reactions, and Spectroscopy, Part A (edited by David C. + S BF3•OEt2 S Palmer) HO2C S Ph 85 – 90% Ph S Ph Heterocycles synthesized from 1,3-dithiolium-4-olates The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic tBu Applications of 1,3-Dipolar Cycloaddition Chemistry Toward R Ph Heterocycles and Natural Products (Edited by Albert Padwa) P N tBu Metalation of Azoles and Related Five-Membered Ring Heterocycles Ph S Ph S Ph tBu (Topics in Heterocyclic Chemistry) (Edited by Gordon W. Gribble) Chem. Ber. 1987, 120, 1809 Bull. Soc. Chim. Fr. 1997, 134, 927 Interconversion of mesionic compounds Souizi and Robert, Synthesis, 1982, 1059 Souizi and coworkers, J. Chem. Soc., Chem. Commun. 1993, 998.

S- - O- Ph Ph X S+ + CS2 S+ N C X N N PhH, heat PhH, heat N Y S N R S R 82 – 95% Y S 82 – 95% Y Y = CH , O Y = CH2 1,3-dithiolium- 2 1,3-dithiolium- R= Ar 1,3-thiazolium- 4-thiolate R= Me, Et, Ph, Ar 4-olate X = O, S 4-thiolate O S S S NPh Y N S R N R S S O O 1,3-oxathiolium-4-olates isolable Synthesis O- Gotthardt and coworkers, Angew. Chem. Int. Ed. Engl. 1975, 14, 422 S+ O- Ph S CO2Me Ac O S+ CO2Me O 2 HO2C O R R Ph 34% O R = pip. R O Ph not isolable; 4-COCF3 derivatives can be isolated 1,3,2-oxathiazolium-5-olates Synthesis O- Gotthardt, Chem. Ber. 1972, 105, 188 tBu Ph O- P + N O Ph DCC N S Ph S NO N O+ HO2C S S Chem. Ber. 1987, 120, 1809