Electrophilic Carbenes

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1 Electrophilic Carbenes The reaction of so-called stabilized diazo compounds with late transition metals produces a metal carbene intermediate that is electrophilic. The most common catalysts are Cu(I) triflate and h(ii) aceate and related complexes. thers include Pd(II) salts and h 6 (C) 16. These intermediates engage in very rich chemistry, often as part of cascade processes. 1 cyclopropanation 1 + L n M This resonance structure shows why these carbenes are electrophilic 1 ML n no change in oxidation state 1 ML n 2 C Z Z = C,,, S, Si Z carbonyl ylide formation insertion reactions + L n M ML n ML n a new carbene for further reactions

2 Diazo Formation While diazo alkanes are normally reactive and unstable, those that are conjugated to electron-withdrawing groups (typically carbonyls) are often quite stable. Several methods available for their production. Diazo transfer reactions sulfonyl azide = ketone, nitro ester, amide S 2 3 Et 3 K 2 C LMDS, TF CF 3 C 2 C 2 CF 3 78 ºC 1 J. rg. Chem. 1990, 55, CF 3 Ms 3, Et 3 2, C 3 C 1 2 C 2 a. Et 2 CCl, Et 3 Cl Ca b. C 2

3 Cyclopropanation If formed in the presence of an olefin, the carbene can form cyclopropanes. Both inter- and intramolecular reactions are possible. Because the carbenes are electrophilic, the react much faster with electron-rich olefins. X + C 2 Et catalyst C 2 Et X = C 2 Br, C 2 Cl,, Bu, Ac, Et, Bu, i-pr, t-bu, C 2 =C, C 2 =C, C 2 =Ct-Bu, C=C, C=CCl, C=C, C=C catalyst = h 2 (Ac) 4, CuCl P(i-Pr) 3, h 6 (C) 16, PdCl 2 (C) 2 X rder of reactivity: electron-rich > "neutral" >> electron poor β-substitution on olefin slows reactivity & cis > trans Alkene geometry is maintained, but little stereoselectivity for diazo-bearing carbon ther reactive groups: dienes, alkynes, aromatic rings, and heteroaromatic rings Asymmetric reactions are possible with chiral ligands on h and Cu catalysts. Intramolecular reactions usually prefer to form 5-membered rings. With polyenes, the regioselectivity is usually good, but can depend on catalyst choice.

4 Cyclopropanation K 2 C 3 Bu 4 Br BrC 2 C=C pbsa, DBU C 3, 40 ºC 82% C 2 Cl 2, 0 ºC 83% a. KMDS, TF C, LiBr 78 ºC C 2 Et 1% h 2 (ct) 4 b. TBDPSCl DMAP, imidazole 38% TBDPS C 2 Cl 2, rt 70% 83:17 dr C 2 Et thiophenol BF 3 Et 2 C 2 Et TBDPS C 2 Cl 2 78 ºC 90%, 10:1 dr TBDPS S J. rg. Chem. 1997, 62, 194.

5 Cyclopropanation h 2 [5(S)-MEPY] 4 C 2 Cl 2, 80%, 92% ee J. Am. Chem. Soc. 2001, 123, C h h h 2 [5(S)-MEPY] 4 4 a. C 3 C(Et) 3 EtC 2, Δ 65% b. aq. a 90% a. (CCl) 2 b. C 2 C CuS 4 cyclohexane, Δ 52% (from acid) Li 3 81% J. Chem. Soc., Perkin Trans , 2583

6 Cyclopropanation With appropriate substitution patterns, cascade reactions are possible 2 C + TBS h 2 (Ac) 4 C 2 Cl 2, Δ 94% J. rg. Chem. 1991, 56, C TBS TBS 2 C Boc Boc + TBS C 2 1% h 2 (S-PTAD) 4 2,2-dimethylbutane 50 ºC 69%, 96% ee C 2 TBS J. Am. Chem. Soc. 2007, 129, C 2 TBDPS h 2 (Ac) 4 rg. Lett. 2003, 5, C 2 Cl 2 50% TBDPS C C 2

7 Ylide Formation The electrophilic nature of the carbenes means they are also capable of reacting with Lewis basic groups such as carbonyls, ethers, and sulfides. This will form an ylide structure. If appropriate functionality is present, other reactions will take place (cycloadditions, rearrangements). Intramolecular formation of ylides are most common. X cat. X [2,3]-rearrangements TBDPS ylide TBDPS Cu(acac) 2 TF, Δ 75% TBDPS rg. Lett. 2004, 6, oxonium ylide >95:5 TBDPS δ δ +

8 Ylide Formation S C 2 h 2 (Ac) 4 C 6 6, Δ 77% J. Chem. Soc., Perkin Trans , S C 2 2 C S + C 2 racemic J. Am. Chem. Soc. 2010, 132, % h 2 (S-DSP) 4 pentane, 0 ºC 50 70% yield 92 98% ee C 2 Stevens-type rearrangement S C 2 Et h 2 (Ac) 4 S C 2 Et S C 2 Et C 6 6, Δ 55% Chem. Commun. 1986, 651.

9 Ylide Formation Dipolar Cycloadditions Addition of carbonyls will for a carbonyl ylide. These are 1,3-dipoles that can undergo cycloaddition reactions with electron deficient olefins/alkynes. h 2 (Ac) Et 4 one diastereomer C Et 6 6, 50 ºC 95% 2 C 2 Et C 2 Et J. rg. Chem. 1998, 63, 556. PMP TBDPS PMP h 2 (Ac) 4 CF 3, 100 ºC 73% Angew. Chem. Int. Ed. 2006, 45, TBDPS t-bu 2 C TMS C 2 t-bu TBDPS MM + h 2 (Ac) 4 C 6 6, Δ 72% t-bu 2 C t-bu 2 C Ac MM TBDPS TMS Angew. Chem. Int. Ed. 2003, 42, 5351.

10 Insertion eactions h(ii) catalysts promote the insertion of diazoalkanes into C,,, S, and Si bonds. Likely involves a three-center transition state. Chiral ligands can be used for enantioselective reactions. Intramolecular reactions generally favor 5-membered ring formation. Fluorinated carboxylate ligands on the metal promote insertion into aromatic C bonds. General order of reactivity for C bonds: 2º > 1º 3º, but is catalyst dependent Electron-withdawing groups deactivate C bonds, electron-donating groups activate Proposed transition state: J. Am. Chem. Soc. 1993, 115, 958. C + ML n C C C ML n C C This mechanism implies that the insertion reaction is stereospecific C 2 Et h 2 (CC 3 F 7 ) 4 C 2 Cl 2, rt then Et 3, TIPSTf 91% C 2 Et With h 2 (Ac) 4 a mixture was obtained TIPS with benxylix C insertion.

11 Insertion eactions n h 2 (4(S)-MACIM) 4 cis:trans = 99: % ee n 62 75% Ac C 2 4(S)-MACIM J. Am. Chem. Soc. 1994, 116, equiv + h 2 (S-PTAD) 4 2,2-di--butane, Δ 83%, 92% ee P()() 2 P()() 2 rg. Lett. 2006, 8, Br + C 2 J. rg. Chem. 2002, 67, h 2 (S-DSP) 4 2,2-di--butane 50 ºC 56%, 94% ee C 2 Br

12 Insertion eactions insertions C 2 J. rg. Chem. 1991, 56, h 2 (ct) 4 EtAc/hexane Δ C 2 insertions 1. h 2 (Ac) 4 C 6 6, 80 ºC 96% 2. 2 Cr 4 Et 2, rt Tetrahedron Lett. 1995, 36, Et 2 C P()(Et) 2 a TF, rt 86% (2 steps) C 2 Et Si insertions Z/E = 96:4 C 2 h 2 (Ac) 4 2 Si C 2 Cl 2, rt 75% Tetrahedron Lett. 1994, 35, Si Z/E = 95:5 C 2

13 tathesis with Alkynes nce formed, h carbenoids can undergo "metathesis"-type chemistry with alkynes. This generates a new h carbene that can undergo other processes, such as those we have already discussed. hl n hl n hl n h 2 (Ac) 4 C 2 Cl 2, rt 95% Tetrahedron Lett. 1991, 32, h 2 (Ac) 4 C 2 Cl 2, rt 97% Tetrahedron Lett. 1993, 34, 7853.

14 itrenoid Intermediates Much like metal-catalzyed decomposition of diazo compounds produces carbenoid intermediates, it is also possible to generate nitrenoid intermediates. This typically involves the in situ oxidation of a non-basic primary nitrogen atom (sulfonamide, amide, carbamate, urea, etc.). 2 C 2 t-bu one enantiomer 5% h 2 (esp) 2 S I(Ac) 2, Mg 2 C 2 Cl 2, 40 ºC 90% 5% h 2 (Ac) 4 I(Ac) 2, Mg C 2 Cl 2, 40 ºC 82% 5% h 2 (Ac) 4 I(Ac) 2, Mg C 2 Cl 2, 40 ºC Angew. Chem. Int. Ed. 2001, 40, 598. J. Am. Chem. Soc. 2004, 126, S C 2 t-bu one enantiomer 2 C carbonyl groups prefer 5 membered rings, sulfonyls prefer 6 membered rings. intermolecular are possible: J. Am. Chem. Soc. 2007, 129, 562. esp C 2

15 itrenoid Intermediates 2 S h 2 (Ac) 4 I(Ac) 2 Mg S BF 3 Et 2 S C 2 Cl 2 quant. C 2 Cl 2 68% TBS TBS TBS TBS rg. Lett. 2007, 9, ther types of reactions are possible besides C insertions Tces Tces 2 TBDPS h 2 (esp) 2 I(Ac) 2 Mg TBDPS CCl 3 C 2 Cl 2, 40 ºC 61% Ac CCl 3 J. Am. Chem. Soc. 2008, 130,