Last modified on 12 October 2011, at 19:23

Intermolecular C-H insertions of carbenoids

Intermolecular C-H insertions of carbenoids involve insertion of the carbon atom of metal carbenoids into sp3-hybridized C-H bonds. The net results are C-H functionalization and the formation of new carbon-carbon and carbon-hydrogen bonds.[1]

Introduction

Metal carbenoids are highly electrophilic species containing a metal-carbon double bond. They undergo bond insertion chemistry with electron-rich π and σ bonds. The insertion of metal carbenoids into carbon-carbon π bonds, which affords cyclopropanes, is a heavily studied reaction with considerable synthetic utility.[2] Although carbenoid insertion into carbon-hydrogen σ bonds is less developed than cyclopropanation, the ability of C-H insertion to rapidly introduce complexity into simple organic precursors has encouraged continued study of the reaction (Eq. 1).

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Metal carbenoids may be classified according to the nature of the substituents attached to the carbenoid carbon (Eq. 2). Because metal carbenoids are electrophilic, attaching electron-withdrawing groups increases the reactivity (and decreases the selectivity) of the carbenoid. The earliest carbenoids studied were derived from diazoacetate esters and possessed a single electron-withdrawing or acceptor group. Carbenoids that possess two acceptor groups attached to the carbenoid carbon are more reactive and less selective than those containing a single acceptor group, and selectivity for a single C-H bond is difficult to achieve using this class of carbenoids. Donor/acceptor carbenoids, which possess one withdrawing and one donating group attached to the carbenoid carbon, offer a good balance of stability and reactivity and are most often used to effect highly site-selective and stereoselective C-H insertion reactions.

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Although copper, silver, and rhodium complexes have all been employed as catalysts for carbenoid insertion reactions, enantioselective C-H insertions are typically accomplished with chiral rhodium carboxylate complexes. Some of the most popular complexes are shown in Eq. 3.

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Mechanism and Stereochemistry

Prevaling Mechanism

During the early development of C-H insertion reactions with carbenoids, the mechanism of insertion was largely speculative. In recent years, the prevailing mechanism of carbenoid insertion into C-H bonds has been corroborated by theoretical[3] and mechanistic[4] studies (Eq. 4).

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After weak coordination of the reactive C-H bond to the carbenoid carbon, insertion takes place in a single concerted but asynchronous step. Hammett studies and theoretical work have confirmed that the transition state for insertion (which is the turnover-limiting step of the reaction) resembles a hydride transfer from the substrate. Partial positive charge exists on the sp3 carbon atom in the transition state, suggesting that nearby electron-donating groups should increase the rate of C-H insertion. α-Oxygen, α-nitrogen, β-silyl, vinyl, and aryl substituents have all been shown to activate C-H bonds for carbenoid insertion reactions.

C-H Insertion/Cope Rearrangement of Vinyl-substituted Carbenoids

In reactions with allylic C-H bonds, vinyl-substituted donor/acceptor carbenoids undergo a simultaneous C-H insertion/Cope rearrangement process (Eq. 5).[5] Because the direct C-H insertion product is (generally) more thermodynamically stable than the product of combined insertion and rearrangement, the mechanism of this process cannot involve insertion to form a discrete intermediate followed by Cope rearrangement. The high stereoselectivity of this process suggests a concerted, chair-like transition state for the combined insertion and rearrangement step.

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Diastereoselectivity of Substrate-controlled Insertions

Diastereoselective insertion may take place when chiral substrates are used. Although acceptor and acceptor/acceptor carbenoids are often too reactive to react with good diastereoselectivity, donor/acceptor carbenoids frequently provide high yields of a single diastereomer. Diastereoselectivity is highest when the reactive sp3 carbon is substituted with groups of significantly different size. A transition-state model has been proposed to explain the observed diastereoselectivity of insertions with aryl-substituted donor/acceptor carbenoids (Eq. 6).[6]

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The alkoxy moiety of the ester group is proposed to project from the plane of the carbenoid, leading the small group to occupy the space near the ester. The large group occupies a relatively open region of space between the ester and aryl groups.

Scope and Limitations

Acceptor Carbenoids

Acceptor complexes suffer from some issues with carbene dimerization and side reactions. However, bulky catalysts have addressed this problem to some extent. In substrates containing steric bias, selective C-H insertion can be achieved. For instance, in the example below, the tertiary positions possess the right balance of steric and electronic factors to react selectively in the presence of a bulky copper borohydride catalyst.[7]

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Electron-donating groups, such as α-oxygen atoms, help bias C-H bonds for insertion. In the example below, only the 2-position of tetrahydrofuran reacts because of the stabilizing effect of the α-oxygen on the transition state for insertion.[8]

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Acceptor/acceptor Carbenoids

Acceptor/acceptor carbenoids are often too reactive to undergo selective C-H insertion. In the presence of π bonds, they often effect cyclopropanation reactions in addition to C-H insertion, as shown in Eq. 9. Selectivity for C-H insertion is even worse under copper(I) catalysis.[9] Furthermore, bulky metal catalysts do little to address the problem, as a number of examples fail to extrude nitrogen gas from the starting diazo compounds.[7]

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Aryl-substituted Donor/acceptor Carbenoids

Donor/acceptor carbenoids often provide a balance of selectivity and reactivity that leads to high yields of a single C-H insertion product. In the example in Eq. 10, replacement of hydrogen with phenyl on the carbenoid leads to a substantial increase in yield.[10]

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The major product of C-H insertions depends on a subtle interplay between steric and electronic factors. In the reaction of isohexane, both the electronically favored tertiary position and a sterically favored secondary position react to give a mixture of products (Eq. 11). The use of 2-methylbutane instead of 2-methylpentane leads exclusively to functionalization of the tertiary position.[11]

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Although benzylic positions are electronically activated toward C-H insertion, competing double cyclopropanation of the aromatic ring is a problem in reactions of these substrates. Only secondary benzylic positions possess the right balance of steric and electronic factors to favor formation of the C-H insertion product (Eq. 12).[4]

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Although α-heteroatoms encourage insertion through a resonance effect, β-heteroatoms may discourage insertion through an inductive effect. Thus, dimethoxyethane undergoes insertion selectively at its methyl groups, which are more electron rich than the methylene groups.[12]

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Vinyl-substituted Donor/acceptor Carbenoids

Vinyldiazoacetates undergo the combined C-H insertion/Cope rearrangement when combined with allylic substrates. Experiments have shown that insertion and rearrangement are concerted, as heating converts the observed product to the product of direct C-H insertion. A small amount (10-15%) of product derived from divinylcyclopropane rearrangement is also observed.[13]

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Synthetic Applications

C-H insertion reactions employing α-diazo esters are synthetically useful because they complement many reactions of carbonyl compounds at the α position. The electronic preferences of metal carbenoids are opposite to the preferences of electrophiles used in reactions of enolates. For instance, while tertiary alkyl halides such as adamantyl bromide do not participate in enolate alkylation chemistry, the insertion of metal carbenoids into tertiary C-H bonds is an electronically favored process. In the example in Eq. 15, the product of C-H insertion was carried on to synthesize a complex for enantioselective C-H insertion reactions.[14]

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C-H insertion reactions build up molecular complexity very rapidly, reducing the number of synthetic steps required to reach complex targets. For example, the drug ritalin may be synthesized from N-Boc-piperidine and methyl diazophenylacetate in only two steps.[15]

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Comparison to Other Methods

C-H functionalization is a rapidly developing field involving a variety of mechanistic paradigms. Insertions of carbenoids involve an "outer-sphere" mechanism in which the metal does not participate directly in the insertion event. Palladium-based methods, on the other hand, operate by an "inner-sphere" mechanism that involves insertion of the metal center into the reactive C-H bond.[16]

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When a synthesis warrants the use of a C-H insertion process, a choice between the intermolecular and intramolecular variants must be made. Because of site selectivity issues associated with the earliest C-H insertion reactions, intramolecular methods were developed before intermolecular methods. A variety of stereoselective and site-selective intramolecular C-H insertion methods exist. However, additional synthetic steps may be required to prepare tethered compounds for intramolecular reactions. The example below, from a synthesis of imperanene, gave higher yield and better stereoselectivity than the corresponding intermolecular insertion reaction in a related synthesis, but the synthesis involving intramolecular insertion required far more synthetic steps than the intermolecular route.[17][18]

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Experimental Conditions and Procedure

Typical Conditions

Intermolecular C-H insertion reaction should be carried out under an inert atmosphere using anhydrous conditions. Typically, a solution of the diazo compound is added slowly (dropwise) to a stirred solution of the catalyst and substrate. Great care should be taken when handling diazo compounds, as they are both toxic and explosive.

Example Procedure[4]

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A degassed solution of methyl phenyldiazoacetate (1 mmol) in anhydrous cyclohexane (10 mL) was added dropwise over 90 min to a stirred, degassed solution of Rh2(S-DOSP)4 (0.01 mmol) in anhydrous cyclohexane (5 mL) at 10º. The solution was stirred at 10º for an additional 15 min and then immediately warmed to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (98% petroleum ether/2% Et2O) to afford the product shown (80% yield): 95% ee (Chiralcel-OD, 99.4% hexane/0.6% 2-propanol, 1.0 mL/min, 254 nm; tR = 8.6 and 10.4 min); [α]23D = –35.1º (c 0.57, CDCl3); IR (neat) 3028, 2926, 2850, 1735, 1497 cm–1; 1H NMR (CDCl3) δ 7.31–7.22 (m, 5 H), 3.64 (s, 3 H), 3.22 (d, J = 10.6 Hz, 1 H), 203–1.97 (m, 1 H), 1.81–1.56 (m, 4 H); 1.32–1.01 (m, 5 H), 0.87–0.70 (m, 1 H).

References

  1. Davies, H. M. L.; Pelphrey, P. M.; Org. React. 2011, 75, 75. doi: (10.1002/0471264180.or075.02)
  2. (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1. doi: (10.1002/0471264180.or057.01) (b) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. doi: (10.1002/0471264180.or058.01)
  3. Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
  4. a b c Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165.
  5. Davies, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5472.
  6. Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001, 617, 47.
  7. a b Caballero, A.; Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2003, 125, 1446.
  8. Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2002, 124, 896.
  9. Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725.
  10. Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.; Stafford, D. G. Tetrahedron Lett. 1998, 39, 4417.
  11. Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
  12. Davies, H. M. L.; Yang, J. Adv. Synth. Catal. 2003, 345, 1133.
  13. Davies, H. M. L.; Stafford, D. G.; Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41, 2035.
  14. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett 2006, 8, 3437.
  15. Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A.; J. Am. Chem. Soc. 1999, 121, 6509.
  16. Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542.
  17. Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941.
  18. Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org. Chem. 2002, 67, 2954.