Burns Group Meeting Carbene Generation Sajan Patel

Carbene Geometry: Sulfonyl Hydrazones:

Bent Linear Bamford-Stevens R hν R R Na(s) + HO OH R photosensitizer triplet or singlet NHTs NaOEt N N2

Simplified MO Diagram: >60 °C R1 R2 R1 R2

linear, sp bent, sp2 occurs faster with o-nitrophenylsulfonyl instead of Ts, but gives a comparable yield R py is orthogonal R R Shapiro p p p x y y R

N2 HOR N2 H px mixes in R2 s character R2 R R R 2 σ 1 R1

Triplet vs. Singlet Reactivity: in protic solvents, diazos can decompose to olefins

Fukuyama Triplet - stepwise mechanism TsHN-NHTs O DBU O + R R N Me Me Me Me Br 2 RO THF, 0 °C RO

Singlet - concerted mechanism 52-90%

TsHN-NHTs + O DBU O R R Me Me Me Me Br N2 Ph THF, 21 °C Ph Persistent Linear Carbenes: Persistent Bent Carbenes: 94%

CF3 J. Am. Chem. Soc., 1967, 89 (22), 5736-5737 Ph Br Ph J. Chem. Soc., 1952, 0, 4735-4740 N N Ad Ad Ad Ad J. Am. Chem. Soc., 1959, 81 (20), 5512-5513

F3C J. Org. Chem., 1963, 28 (3), 870-872 Br Org. Lett., 2007, 9 (16), 3195-3197 Alkenes from Tosylhydrazones, John Wiley and Sons, 2011 1 Burns Group Meeting Carbene Generation Sajan Patel

Triazoles: Dimroth Rearrangement

N N N CONH CONH2 EWG 2 N N N N EWG N NH Me N Me N N N N R NH R NHEWG N 2 R NH2 N N

EWG = -CN, -NO2, -SO2R Me Me

1 - equilibirum favors side with EWG on excocyclic nitrogen - Me H NMR signals coalesce at 88 °C - conversion proceeds more rapidly with an EWG at N1 (160 °C)

CO Me 2 CO2Me R 1) 0.5% Rh (S-NTTL) Ph Ph 4 2 4 O 1,2-DCE, 65 °C N + R N R3 4 N N N N 2) K CO , H O, R N N R 2 3 2 2 1 N R2 MeOH, 21 °C R3 Cl Cl 59-92% R1 = SO2Me or SO2C8H17 >20:1 dr - lone pair repulsion promotes diazo formation 8-98% ee

NMs CO Me CO2Me 2 Ms 1% Rh2(OAc)4 N Et3SiH SiEt3 1% Rh2(S-NTTL)4 N N + N N DCM, 21 °C N N 1,2-DCE, 60 °C Ph R R Ph R = H, no reaction R = Cl, 88% 82% >30:1 dr 97% ee

J. En. In. Med. Chem., 2002, 17 (6), 359-367 Tetrazoles: Angew. Chem., 2013, 125, 10228-10231 J. Am. Chem. Soc., 2009, 131, 18034-18035 R N 3% Rh2(S-TCPTTL)4 Angew. Chem. Int. Ed., 2007, 46, 4757-4759 N2 N Tf 3 eq R HN N Tf2O, TTBP Tf Adv. Het. Chem., 1974, 16, 33-85 N N N Bull. Soc. Chim. Belg., 1990, 99 (4) ECH, 0 °C Ph [3+2] cycloaddition Ph N Bull Soc. Chim. Belg., 1981, 90 (6) Ph J. Chem. Soc. Perkin Trans., 1972, 0, 2623-2630 Angew. Chem. Int. Ed., 2018, 57, 5497-5500 46-88% 22-99% ee 3 Burns Group Meeting Carbene Generation Sajan Patel

Sulfonium and Sulfoxonium Ylides:

n + 1 Cycloaddition Corey-Chaykovsky Reaction O O Me NaH, CuI N O Me O O Me + N S Ph O S + Ph O DMF, 0-21 °C, 2 h Me R R DMSO R R R R R = H, 71% R = Me, 64%

Me NH HN O Me S + O R1 O O Me R R DMSO R R 10% Cu(Tol-BINAP) R1 S R (Tol-BINAP)Cu R Me 1 Na2CO3 3 NH N N O N N N R2 O O Cl Me R3 R2 R2 Me S + R R DMSO O 2 TIPSO CO2R OTIPS 2.5 % CuOTf O R4 2 6% L* R1 CO2R + S O R3 R4 DCM, 21 °C, 24 h R1 N Cyclopropanation (Sulfonium Ylides) 2 R3

PhOC O Me cat. [Cu] O + S + COPh Ph Me Ph PhOC

Trost, CuSO4 5% major product

Julia, Cu(pentacac)2 86% not observed

H O O Ph 2% Rh2(5S-MEPY)4 in all cases, diazo compounds show S O higher yields but comparable diastereo- O Ph DCE, 82 °C and enantioselectivity H 40%, 69% ee 4 Burns Group Meeting Carbene Generation Sajan Patel

N-H Insertion (Sulfoxonium Ylides)

O O Me S O O O Me S 1% [Ir(cod)Cl]2 N Boc Me Me ring expansion of lactams DMSO, 21 °C DCM, 21 °C N BnO2C NHBoc CO2Bn BnO2C Boc 97%

CO Et CO2Et 2 CO2Et F 5 steps 1% [Ir(cod)Cl]2 - selective CRTH2 antagonist N N N - potential treatment of respiratory disease H PhMe/DMF, 85 °C, 6 h O S O N S O O Me Me Me O 83% MK-7246 49% overall yield

O Cbz Cbz S I O N O N Cbz Cbz O O O N O N 8 steps t BuOK [Ir(cod)Cl]2 N N Me S N H H N NBoc NBoc DMSO Me H PhMe, 80 °C H NBoc NHBoc O O O3SO O 87% MK-7655 10% overall yield ß-lactamase inhibitor

Sulfur Ylides in Organic Synthesis and Transition Metal Catalysis, Springer, 2017 J. Chem. Soc., Chem. Commun., 1993, 0, 1434-1435 Org. Lett., 2018, 20, 2464-2467 Org. Lett., 2017, 19, 5256-5259 5 Burns Group Meeting Carbene Generation Sajan Patel

C-H Insertion (Sulfonium and Sulfoxonium Ylides)

- poor relation of N-H Insertion - dimerization is the key challenge - sulfur ylides are more nucleophilic than diazos and will attack metal carbenoids more readily

O O O 2% Rh2(5S-MEPY)4 Ph O S DCE, 82 °C Ph 9%

O S Me O 1% [Ir(cod)Cl] Me 2 Ph + Ph O DCM, 21 °C O O

not observed 94%

ß-oxido Carbenoids: Tetrahedron, 1987, 43 (1), 3-38 Bull. Chem. Soc. Jpn., 1977, 50 (6), 1592-1595 - superior selectivity for single-homologation than the Büchner-Curtius-Schlotterbeck reaction J. Org. Chem., 1970, 35 (8)

Br Br Li O Li O O HO n Li O Li Me Br Br BuLi (2 eq) Br Me Me

Me Me

i Br 1) PrMgBr BnMgCl NBS 2) ∆ O Ph O Ph OH OH Ph

6 Burns Group Meeting Carbene Generation Sajan Patel

Dihalogenated Alkanes and Alkenes: Dichloroalkenes

Simmons-Smith R3 Cl R R 5-10% [Ni], Zn 1 R1 + 3 R 2 CH2I2 + 2 Zn 2 (ICH2)ZnI (ICH2)2Zn + ZnI2 Cl 2 Et2O, DMA 21 °C, 24 h R2

- usually requires alcohol directing group 50-99%

Cu-Zn Cl Cl OH + CH2I2 OH 5-10% [Ni], Zn TsN NMP H OH OH TsN Me Me 65% Cu-Zn 90% ee + CH I O 2 2 O Alternative Strategy, Primary Vinyl Triflates O O

R R H t R 1 Fritsch-Buttenberg-Wiechell Rearrangement 1 KO Bu 1 R3

0 °C R2 R2 OTf R2 R H H 3 R H R R temperature must be kept low to prevent FBW decomposition

Dibromoalkenes

Ar Ar Ar Ar Ar Br Ar Ar Ar NiI2, Li, naphthalene [Ni] = + Ar Ar + C C Ar Br THF Ar Ar Ar Ar Ar Ar Ar

Ar = Ph 23% 0% 23% Chem. Rev., 2004, 104, 3795-3849 Ar = p-Me-C H 10% 11% trace 6 4 Chem. Lett., 1988, 149-152 J. Am. Chem. Soc., 2017, 139, 11686-11689 Science, 2019, 363, 857-862 7 Burns Group Meeting Carbene Generation Sajan Patel

Angew. Chem. Int. Ed. Engl., 1992, 31, 274-285 J. Am. Chem. Soc., 1994, 116, 93-98 J. Am. Chem. Soc., 1988, 110, 6566-6568 Org. Lett., 2006, 8 (17), 3659-3662

8 Burns Group Meeting Carbene Generation Sajan Patel

Aziridinylimines:

- alternative to tosyl hydrazones - cleaved thermally, good for base-sensitive substrates

Ph NHTs N NaH, ∆ N2 ∆ N N Ph

Albert Eschenmoser, ETH Zürich

H N N ∆ N taut. N

Ph

N2 N ∆ ∆ Albert Padwa, Emory University N Ph Ph C C CH Ph C C CH

Ph

Ph O-H insertion ROH

Ph

Ph C C CH2OR CH CH RO

R = OMe, 60% 2 : 3

Helv. Chim. Acta., 1972, 55, 1276 R = OiPr, 52% 5 : 1 Tet. Lett., 1979, 46, 4425-4428 Tet. Lett., 1991, 32 (8), 983-986 2 Burns Group Meeting Carbene Generation Sajan Patel

Diazo Transfer: Kristensen Modification

Seyferth-Gilbert Homologation - uses bench-stable diazo transfer agent - convenient, scalable

O O KOtBu O O H P O + OMe R1 R2 P OMe O O R1 R2 THF, -78 °C O O OMe N OMe R H 2 S P N N3 OMe R OMe Bestman-Ohira Modification MeCN, K CO MeOH N 2 3 N2 good for base-sensitive substrates, such as enolizable aldehydes Pd-Catalyzed Cross-Coupling of Diazoacetates O O O P K CO + OMe 2 3 5% Pd(PPh ) , Et N OMe R 3 4 3 H CO Et n CO Et R H N MeOH, 21 °C 2 Bu4NBr 2 2 + EtO2C I N2 acetone, 35 °C CO2Et N2 48-86% MeO O O O P via P OMe OMe OMe OMe 10% Pd(PPh3)4, DBU n H CO2Et Bu NBr Ar CO2Et N2 N2 4 Ar I + N MeCN, 45 °C N in situ generation of Bestman-Ohira Reagent 2 2 0-80% O O O Hydrazones as Acyl Anions P O O OMe O O OMe R H 2.5% Pd (dba) S P 2 3 N3 OMe R R 5% DPEphos R R OMe MeOH MeCN, K CO NaOtBu 2 3 N2 NH NH N Me Ph Br + N N and/or N Ph dioxane H 80 °C, 24 h Ph H C-arylation N-arylation

R = tBu, 98% (C-arylation) R = Boc, no reaction R = Bz, no reaction R = Ph, 91% (N-arylation) Synthesis, 2004, 1, 59-62 J. Am. Chem. Soc., 2006, 128, 14800-14801 J. Org. Chem., 2014, 79, 9423-9426 J. Am. Chem. Soc., 2007, 129, 8708-8709 9