Carbene, cyclopropyl

The addition of carbene to a 3-(halopropyl)-5//-dibenz[7>./]azepine 5 (X = Cl, Br) in a Simmons—Smith reaction is more complex and results in a mixture of the tetracycle 6 (6%), its cyclopropano derivative 7 (48 %), the 5-allyl derivative 8 and the (cyclopropyl)methyl compound 9, the latter two products in a combined yield of 12%.31... 

Other examples of [2C+2S+1C0] cycloaddition reactions have been described by Herndon et al. by the use of chromium cyclopropyl(methoxy)carbenes. These complexes react with alkynes releasing ethene and forming cyclopenta-dienone derivatives, which evolve to cyclopentenone derivatives in the presence of chromium(O) and water [122] (Scheme 76). This reaction has been extended to intramolecular processes and also to the synthesis of some natural products [123]. These authors have also described another process involving a formal [2C+2S+1C0] cycloaddition reaction. Thus, the reaction of methyl and cyclo-propylcarbene complexes with phenylacetylene derivatives does not afford the expected benzannulated products, and several regioisomers of cyclopentenone derivatives are the only products isolated [124] (Scheme 76). 

Alkoxycarbene complexes with unsaturation in the alkyl side chain rather than the alkoxy chain underwent similar intramolecular photoreactions (Eqs. 10 and 11) [60]. Cyclopropyl carbene complexes underwent a facile vinyl-cyclopropane rearrangement, presumably from the metal-bound ketene intermediate (Eqs. 12 and 13) [61]. A cycloheptatriene carbene complex underwent a related [6+2] cycloaddition (Eq. 14) [62]. 

Reactions of cyclopentyne with alkenes gives [2+2] cycloadduct with complete retention of stereochemistry (Scheme 24) [120], Laird and Gilbert observed the expected [2+2] cycloadduct along with the polycyclic adduct in the reaction of norbomyne with 2,3-dihydropyran (Scheme 24) [121], and located a cyclopropyl-carbene intermediate [122],... 

PTC has been extensively used for making cyclopropyl derivatives. The most common reaction involves generation of dichlorocarbene from chloroform, using NaOH and a quaternary ammonium hydroxide. The carbene subsequently reacts with an alkene in high yield. Hydrolysis of dichlorocarbene, normally rapid in the presence of water, is minimal. An interesting and very efficient example of a Michael addition to produce a cyclopropyl derivative is shown in Scheme 4.26. 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

The presence of a cyclopropyl moiety in the carbene complexes makes them useful for synthesis. The cyclopropylcarbene complexes 95 undergo a cycloaddition reaction with alkynes to give the cyclopentenones 96 [51]. The reaction course is explained as being metallacyclopentene fragmentation. (Scheme 34)... 

Photoelimination of nitrogen from diazirines, for example, proceeds via carbene intermediates. 3-tert-Butyldiazirine (395) is converted into the cyclopropane 396 and the alkene 397 with the formation of the carbene insertion product being favored from the singlet state.328 3-Cyclopropyl-3-chlorodiazirine (398) has similarly been converted to the carbene 399 which undergoes both rearrangement to l-chlorocyclobutene(400)329 and addition... 

The elusive diazoalkenes 6 and 14 are unlikely to react with methanol as their basicity should be comparable to that of diphenyldiazomethane. However, since the formation of diazonium ions cannot be rigorously excluded, the protonation of vinylcarbenes was to be confirmed with non-nitrogenous precursors. Vinyl-carbenes are presumedly involved in photorearrangements of cyclopropenes.21 In an attempt to trap the intermediate(s), 30 was irradiated in methanol. The ethers 32 and 35 (60 40) were obtained,22 pointing to the intervention of the al-lylic cation 34 (Scheme 10). Protonation of the vinylcarbene 31 is a likely route to 34. However, 34 could also arise from protonation of photoexcited 30, by way of the cyclopropyl cation 33. The photosolvolysis of alkenes is a well-known reaction which proceeds according to Markovnikov s rule and is, occasionally, associated with skeletal reorganizations.23 Therefore, cyclopropenes are not the substrates of choice for demonstrating the protonation of vinylcarbenes. 

Aryl(cyclopmpyl)carbenes. The potential of the cyclopropyl group for conjugation 70 suggests that the nucleophilicity of carbenes should not be strongly... 

Surprising is the absence of evidence for additional stability of 85 over 83. Electron donation from the electron-rich a bonds of the cyclopropyl ring to the carbene s vacant p orbital is widely believed to stabilize cyclopropylcarbenes.4 One would therefore expect 85, with an additional cyclopropyl substituent, to react more slowly than either parent carbene 83 or dimethylcarbene, but all three lifetimes are comparable. The lifetimes of 83-85 need to be redetermined in inert (fluorocarbon) solvents in order to reveal their innate differences. Note, however, that the effect of cyclopropyl substitution is apparent upon comparison of 83 (r 24 ns) to MeCH (r < 0.5 ns).89110... 

In contrast to the cyclopropyl- and cyclobutylhalo- (and acetoxy)carbenes, the cyclopentylhalo- and acetoxycarbenes (91), and their corresponding benzo derivatives, the indanylcarbenes (94), prefer 1,2-H shifts over 1,2-C shifts Eqs. 35 and 36.115 In the absence of strain relief to drive ring expansion, as with the cyclobutylcarbenes, 17, where kc exceeds ku, the 1,2-H shift is preferred.115... 

Further work by Trost established the involvement of metallacarbenoid species.292,293 A dimer product 307, incorporating a cyclopropyl group, was observed in the reaction of 304 in the presence of the highly electron-deficient palladole catalyst 305 (Scheme 78). This transformation is the signature of an intermediate of type 306. This chemistry could be rendered useful by playing with other unsaturated bonds as the carbene acceptor, and a variety of polycyclic adducts such as 308 could be synthesized. 

The discovery of carbene and carbenoid additions to olefins was the major breakthrough that initiated the tapping of this structural resource for synthetic purposes. Even so, designed applications of cyclopropane chemistry in total syntheses remain limited. Most revolve around electrophilic type reactions such as acid induced ring opening or solvolysis of cyclopropyl carbinyl alcohol derivatives. One notable application apart from these electrophilic reactions is the excellent synthesis of allenes from dibromocyclopropanes 2). 

Some fragmentation reactions from cyclopropyl carbenes and aziridine derivatives are as follows ... 

Under suitable conditions, carbon atoms react with olefines to form allenes 46 presumably via intermediate cyclopropyl carbenes viz. 

Evidently a large part of the energy liberated in the approach of the carbon atom to ethylene will go into this normal mode — which is the one required for conversion of 30 to 31. Unless the interconversion of vibrational energy is incredibly efficient, one would then expect the initially formed 30 to be converted to 31 even at the lowest temperatures. The fact that allene is formed at -190° is not therefore surprising. On the other hand the existence of a large barrier between 30 and 31 would prohibit rearrangement of 30 if formed under milder conditions free cyclopropyl carbenes do not rearrange to allenes if formed by conventional methods in solution 49). 

Cyclohexylidene carbene and cyclopentylidene carbene have been generated by the base-induced decomposition of the appropriate 1 -(A-acety 1-jV-nitroso-aminomcthyl)cycloalkan-l-ol in the presence of Aliquat [47-49] and they have been shown to react in high yield with electron rich alkenes (see Section 7.3). Cyclopropylmethylidene, di(cyclopropyl)methylidene, and isopropylidene carbenes have been generated by an analogous route [49]. 

Both acridone and dibenzo[6,/]azepine produce unexpected products (Scheme 7.39) when reacted with dimethylvinylidene carbene (7.1.18.A). Acridone reacts initially at the nitrogen atom to produce the 10-(3,3-dimethylallenyl) derivative (13%) and a pyrroloacridone (10%) which, if the structure is correct, could be derived from the allene by sigmatropic shifts [16]. The dibenzoazepine reacts as expected to produce a cyclopropyl derivative but, under the reaction conditions, the adduct rearranges spontaneously to yield a 1,6-methanodibenzo[b,/]cyclo-prop [J]azepine, the structure of which was confirmed by X-ray crystallography [17]. 

The reductive cyclization of readily available enol phosphates of 1,3-dicarbonyl compounds bearing pendant olefinic units has been explored [66,67]. The chemistry is exceptionally interesting, and provides a unique route to structures possessing a cyclopropyl unit which is suitable for structural elaboration. The reaction occurs in a manner wherein the phosphate-bearing carbon behaves like a carbene that adds to the pendant alkene to form a cyclopropane. While this provides a useful way of viewing the transformation, mechanistic studies indicate that a carbene is not an actual intermediate. Examples are portrayed in Table 11. 

Fig. 2.32. Possible mechanism of the formation of cyclopentenones and cycloheptadienones from alkoxy(cyclopropyl)carbene complexes [373],...

The formation of cycloheptadienones from alkoxy(cyclopropyl)carbene complexes and alkynes (Entry 5, Table 2.24) [388,389] proceeds essentially by the same mechanism as the Dotz benzannulation reaction (see Figure 2.32). The cyclopropyl group participates in the electrocyclic rearrangement as the equivalent of a vinyl group. 

Both thermal (120 °C at 0.005r) and photochemical decomposition of the tosylhy-drazone salt (21) were proposed to proceed by initial formation of the cyclopropyl-carbene followed by fragmentation to biradicals (22) and (23), which proceeded to 1- and 2-vinylnaphthalene and benzobarrelene (24). ... 

Quite a wide variety of alkenes have been subjected to this carbene addition [148] the products are multifunctional small ring molecules which may not only be reduced to simple vinylcyclopropanes, but to various substituted cyclopropyl-acetylenes and cyclopropylideneacetates which are particularly useful and versatile building blocks for organic synthesis [155],... 

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