Bicyclic carbene

Since the reactive substructure of cA-2-(l,3-butadienyl)cyclopropylidene is contained in the bicyclic carbene 124, there is a possibility that a carbene-carbene rearrangement occurs together with 1,5-carbon migration. Analysis of the probable reaction pathways allows one to conclude that 1,5-C-migration (124 - 132) in the fixed c -l,3-butadienyl fragment of structure 124 is impossible. The 1,3-carbon migration (124 - 130) which takes place instead is mechanistically analogous to the vihylcyclopropylidene-cyclopentylidene... 

Smaller cyclic olefins react with dibromocarbene to give the gem-dibromo-bicyclic systems, but these have not been reported to give allenes on reaction with methyl- or n-butyllithium. One possible reason may be the severe ring strain of cyclic allenes with less than seven carbon atoms. For example, Moore and Ward [14] found that 7,7-dibromobicyclo[4.1.0]heptane reacts with methyllithium to give bicyclic carbene intermediates which can be trapped with olefins (Eq. 4). 

For various mono- and bicyclic carbenes, e. g., benzocycloheptenylidenes (Kirmse et al., 1981 Kirmse and Sluma, 1988 Kirmse et al., 1993a) and cyclopentenylidenes (Kirmse et al., 1985), product and label distribution were compatible with mechanism (a), but not with mechanism (b). The photolytic reactivity of diazomethane with the four aliphatic alcohols, mentioned above, is in contradiction to the gas-phase acidities of these alcohols Gaseous er butanol is the strongest acid among them (see Blair et al., 1973 Arnett et al., 1974), but according to Kerr et al. s... 

A handful of more elaborate M(III) monocarbonyls have also been prepared, by a variety of routes. For instance, the H2O ligand in each of the iridacy-cloheptatriene complexes 338,503,504 and 340 (Section III-B.l, Scheme 23, II-C.l, Chart 12) has been displaced by CO to afford 681-683 and 553 respectively, the latter also being obtained by carbonylation of the bicyclic carbene 341 (Scheme 23)." " " " ... 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

Intermediate 37 can be transformed into ( )-thienamycin [( )-1)] through a sequence of reactions nearly identical to that presented in Scheme 3 (see 22— 1). Thus, exposure of /(-keto ester 37 to tosyl azide and triethylamine results in the facile formation of pure, crystalline diazo keto ester 4 in 65 % yield from 36 (see Scheme 5). Rhodium(n) acetate catalyzed decomposition of 4, followed by intramolecular insertion of the resultant carbene 3 into the proximal N-H bond, affords [3.2.0] bicyclic keto ester 2. Without purification, 2 is converted into enol phosphate 42 and thence into vinyl sulfide 23 (76% yield from 4).18 Finally, catalytic hydrogenation of 23 proceeds smoothly (90%) to afford ( )-thienamycin... 

Non-heteroatom-stabilised Fischer carbene complexes also react with alkenes to give mixtures of olefin metathesis products and cyclopropane derivatives which are frequently the minor reaction products [19]. Furthermore, non-heteroatom-stabilised vinylcarbene complexes, generated in situ by reaction of an alkoxy- or aminocarbene complex with an alkyne, are able to react with different types of alkenes in an intramolecular or intermolecular process to produce bicyclic compounds containing a cyclopropane ring [20]. 

Carbene complexes which have an all-carbon tether between the diene and the dienophile react via intramolecular Diels-Alder reaction to give the corresponding bicyclic compound. The stereoselectivities of these reactions are comparable to those observed for the Lewis acid-catalysed reactions of the corresponding methyl esters and much higher than those of the thermal reactions of the methyl esters which are completely unselective. Moreover, the ris-sub-stituted complexes undergo endo-selective reactions where the corresponding reaction of the ester fails [109] (Scheme 61). 

The resulting carbene complex 41b bears a hetero substituent and shows activity in the ring-opening/cross metathesis of strained bicyclic alkenes and... 

Ring expansion of tetrahydrofurans to dihydropyrans results when their 2-W-aziiidinyl imines are heated <96CC909> and when their 2-ca-alkyl bromides are treated with Ag20 in a nucleophilic acidic solvent <96JCS(P1)413>. Alkyl carbenes and bicyclic oxonium ion intermediates are invoked, respectively. 

From the reactions presented in this section one can conclude that cyclic acetal formation via addition to a carbene intermediate is a general reaction for type I cleavage of cyclobutanones, tricyclic compounds, and certain bridged bicyclics as minor products. No acetal has been isolated from photolyses of cyclopentanones or cyclohexanones except for the special case of an a-sila ketone previously discussed. 

However, more recent work indicates that some bicyclic systems do indeed yield cyclic acetals from addition to carbene intermediates,<34,35>... 

The equilibrium interconversion between an ethylene phosphite and a bicyclic spirophosphorane is shown to proceed by the insertion of the phosphite into the labile O-H bond of the hydroxyethyl ester. The mechanism is similar to the insertion of carbenes or nitrenes. Energy relationships of reaction intermediates were studied by MO RHF, MP2(full), MP4SDTQ, and DFT calculations. In most cases, they predicted that hydroxyethyl ethylene phosphates were more stable than the strained spirophosphoranes, which is not supported by the experimental evidence. The best correspondence to experimental data was obtained by DFT calculations with Perdew-Wang correlation functions <2003JST35>. 

The methyl substitution in carbenes lb-d has a pronounced influence on the yield of the bicyclic isomers 3 24,74 Thus, visible light irradiation of the 2,6-dimethylated carbene lb rapidly and with very high yield produces the cyclopropene 3b (Scheme 7).The yield is significantly higher than in the case of the parent system 3a. In contrast, methyl substitution in 3-position as in lc drastically reduces the yield of the cyclopropene 3c to approximately 10%. 

Table 4. The B3LYP/6-31G(d) Energies of Bicyclic Compounds 3a,b,d, and of the Transition Structures for their Formation Relative to Carbenes 1 a,b,d...

Our approach to the synthesis of model compounds, suited for the generation of carbenes, which are bound to the bridgehead of a strained bicyclic system, used the facile synthesis of [n.l.ljpropellanes, which we developed some years ago. Starting from substituted allyl chlorides 35, dibromocarbene addi-... 

The stereochemistry of products 27 (Table 6, entries 2, 3, and 4) can be explained distinctly on the same basis that alkyl substituents R1, R2 are positioned in quasi equatorial positions in the transition structure. Exclusive formation of the all-cis isomer in the reaction of cyclohexyl acetate (entry 5) is further evidence to support the oxido-carbene interaction in a double-chaired bicyclic structure 28, as depicted in Scheme 13, Eq. 1. 

A rhodium-catalyzed intramolecular C-H functionalization has been employed for the synthesis of bicyclic imidazoles. The alkene acts as an anchor to the metal, directing the C-H functionalization process, which involves the formation of an Rh(l) carbene intermediate (Equation (118)).107... 

This catalytic tandem carbene addition-bicyclization of enynes has been very recently applied to the synthesis of fluorinated bicyclo[ .0.l]-amino esters.176... 

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