Reactions carbene insertion

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

An unprecedented carbene insertion reaction was observed on reaction of the cationic re-arene ruthenium amidinates with trimethylsilyldiazo-methane (Scheme 145, TFPB = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate). 

The highly reactive species methylene inserts into C—H bonds,both aliphatic and aromatic,though with aromatic compounds ring expansion is also possible (see 15-62). This version of the reaction is useless for synthetic purposes because of its nonselectivity (see p. 248). This contrasts with the metal carbene insertion reaction, which can be highly selective, and is very useful in synthesis. Alkylcarbenes usually rearrange rather than give insertion (p. 249), but, when this is impossible. 

There are numerous examples of metal carbene insertion reactions, usually requiring a catalyst. " The C—H insertion reactions of metal carbenes can be highly selective. Intramolecular insertion reactions are very versatile and tolerate a... 

Owing to the high reactivity of the intermediates involved, intermolecular carbene insertion reactions are not very selective. The distribution of products from the photolysis of diazomethane in heptane, for example, is almost exactly that expected on a statistical basis.211... 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

The a-osmiumdiazo compound 91 decomposes in a thermal reaction to yield the metallacyclic complex 93 (130). This resembles the electrophilic carbene insertion reaction forming OsCl(CO)2(PPh2C6H4CHCl) (PPh3) (77) (see Section V,D,2), and we suggest that a similar insertion reaction of an electrophilic, cationic osmium carbyne 92 is the key step in this transformation. An X-ray structure determination has confirmed the formulation of 93. 

Since alkyllithium compounds and their carbanions have an isoelectronic structure with alkoxides, their reaction behavior with carbenes is expected to be similar to that of alkoxides, showing enhanced reactivity in both C-H insertion and hydride abstraction.35 In this reaction, the hydride abstraction cannot be followed by recombination and, therefore, can be differentiated from the insertion. Indeed, the reaction of alkyllithium compounds 70 or nitrile anions (see Section IV.B) with ethyl(phenylthio)carbenoid, which is generated by the reaction of 1-chloropropyl sulfide 69 with BuLi, takes place at the -position of 70 more or less in a similar manner giving both insertion product 71 and hydride abstraction products 72 and 73, respectively. This again supports a general rule C-H bonds at the vicinal position of a negatively charged atom are activated toward carbene insertion reactions (Scheme 22). 

One report of a secondary /3-deuterium KIE for a carbene insertion reaction has appeared recently. Pascal and Mischke (1991) found that the /3-deuterium KIE for the insertion of dichlorocarbene into the benzylic C—H bond of cumene (reaction (39)) was (kH/kD)p = 1.250 and 1.22 when the KIE was based on GC-MS analyses and H nmr, respectively. 

The initial question was whether the active catalyst is copper metal, copper(I), or copper(II), because all metal precursors gave results. Without the proper control of the valence state and the ligand environment the selectivities for the copper catalysed cyclopropanations (or carbene insertion reactions) have remained low or inconsistent for a long period of time. It was only in the sixties that a more systematic study of these issues was started. Several divalent copper salts were successfully used, but Kochi and Salomon [1] showed with the use of Cu(I)OTf that most likely copper(I) was the actual species needed for this reaction. 

The mechanism proposed for carbene-abstraction and carbene-insertion reactions is based on the calculations of Dewar (MINDO/2) and Hoffmann (extended Hiickel) Hoffmann dealt only with the concerted reactions of singlet carbenes, whereas Dewar discussed both singlet and triplet carbene reactions. The calculations of Dewar s ) for the reaction of triplet methylene with methane gave the following results ... 

The reaction is predicted to be exothermic by 86 kcal/mol with an activation energy of 10 kcal/mol. The former is not unreasonable given that a lone pair (on the carbene) has been exchanged for a CC bond. The latter is in line with the observation that (singlet) carbene insertion reactions are known to be very fast. 

This reaction apparently proceeds by way of the normal phosphonate condensation product, the diazoalkylidene, which then spontaneously loses nitrogen to form the transient alkylidene car-bene. Careful work showed that, after statistical corrections were applied, the reactivity of a C-H bond toward insertion was approximately 0.003 for primary C-H bonds (methyl), 1.0 for secondary C-H bonds (methylene), 7.5 for benzylic (methylene) C-H bonds and 18.6 for tertiary C-H bonds. These relative reactivities are very similar to those previously observed for intramolecular C-H insertion by an alkylidene carbenoid generated from a vinyl bromide27. It was shown subsequently that the alkylidene carbene insertion reaction proceeds with retention of absolute configuration28. Using this approach, (l )-3-dimethyl-3-phenyl-l-cyclopentene and (i )-4-methyl-4-phenyl-2-cyclohexcnonc were prepared in high enantiomeric purity. 

The LFP method has been used to determine absolute rate constants for intermol-ecular carbene insertion reactions. Given the more convenient diazirine precursor (14) available for CgHsCCl, as opposed to the phenanthrene precursor (15) of CCI2, as well as the directly observable character of CeHsCCl, LFP studies have focused on... 

Occasionally the cyclopropylidene to allene isomerization cannot take place for structural reasons. If, for example, the expected allene would be very highly strained, as is the case for certain cyclic allenes, then the reaction is forced to follow an alternative path. A case in point is provided by 1-alkyl-7,7-dibromonorcaranes which undergo a carbene insertion reaction when treated with methyl lithium to provide bicyclobutanes rather than allene derivatives. 

A rather unique synthetic example based on the well-known pyrrole-pyridine carbene insertion reaction involves the following ring expansion.16... 

An interesting Fe-catalyzed SN2 -like carbene insertion reaction using diazo compounds and allyl sulfides (the Doyle-Kirmse reaction) was reported by Carter and Van Vranken in 2000 [20], Various allyl thioethers were reacted with TMS-diazomethane in the presence of catalytic amounts of Fe(dppe)Cl2 to furnish the desired insertion products with moderate levels of stereocontrol [Equation (7.6), Scheme 7.14]. The products obtained serve as versatile synthons in organic chemistry, e.g. reductive desulfurization furnishes lithiated compounds that can be used in Peterson-type oleftnations to yield alkenes [Equation (7.7), Scheme 7.14] [21]. 

Analogous transannular carbene insertion reactions have also been reported as illustrated in Eq. (37). Both 9-noradamantanone,23) and N-methyl-9-aza-noradamantane124 have been prepared in this manner. 

Dehydroadamantanes are most readily obtained from either carbene insertion reactions or from 1,3-reductive eliminations. Pyrolysis of the dry sodium salt of the tosylhydrazone of adamantanone gives good yields of 2,4-dehydroada-mantane 133>. The unstable 1,3-dehydroadamantane is obtained from the treatment of 1,3-dibromoadamantane with sodium (Eq. (43)) 134>. 

In CHEC-II(1996), carbene insertion reactions into the N-H bond to form a fused-ring azetidinone warranted a separate section. In the last decade, the popularity to this approach to bicyclic systems seems to have markedly declined. Nevertheless, dirhodium tetraacetate and rhodium octanoate were used to generate the corresponding bicyclic compounds from the diazo compounds 241 (R2 = H and /3-Me), respectively, via the carbene intermediates. In the latter case, the produced enol was esterified and then the ester group replaced with a hydroxymethyl substituent to give derivatives 242 in a one-pot process <2001JCM166, 1999TL427>. 

An attempt to generate an amino-aryl carbene 154 from the alkylated phenanthridinium salt 153 (Equation 78) <2006TL531> was unsuccessful due to steric interactions. The actual reaction with a variety of strong, sterically hindered bases/nucleophiles is shown (Equations 79-81). The mesityllithium products proved that a carbene intermediate is not possible. Unlike /-butyl alcohol and hexamethyldisilazane, trimethylbenzene, the conjugate acid of mesityllithium, is not prone to carbene insertion reactions. Electronically this is explained by the planar nature of 153 which serves to lower the lowest unoccupied molecular orbital (LUMO) energy of the iminium moiety. 

Activation by silicon of a P-C-H bond to an intramolecular carbene insertion reaction is exemplified by the silicon-directed Bamford-Stevens reaction.68 For example, thermal decomposition of P-trimethylsilyl /V-aziridinyl imines 72 in toluene (Scheme 8) [with or without Rh2(OAc)4 catalyst] results in the formation of allylic silanes 73 as major or exclusive products by the preferential insertion of the carbene intermediate into the C-H bond P to the silicon substituent. 

---