Cyclopropanation of enamines

Enamines are readily formed from ketones and therefore constitute an accessible class of substituted olefins. The dichlorocyclopropanation reaction of enamines has not been a preparatively useful one in the past. However, when the reaction is conducted under phase transfer conditions, moderate to excellent yields of the dichlorocarbene adducts can be obtained [34, 35]. A variety of enamines have been subjected to phase transfer cyclopropanation and the results are recorded in Table 2.3. 

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Apart from these findings, the limited application of ZnCl2 (cyclopropanation of some cyclic 1,3-dienes, isoprene and ethyl vinyl ether 4S-49)) and copper(II) acetyl-acetonate (cyclopropanation of enamines 50)) still stand alone. 

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

Attempts to induce cyclopropanation of enamines by carbene transfer from the tungsten complex (332) were unsuccessful. Under a high pressure of carbon monoxide, a combined addition of the carbene and CO led to formation of ketones (333) and (334). ... 

The thermal [1] or photochemical [5] isomerization of N-silylated allylamine in the presence of Fe(CO)5 provides the corresponding N-silylated enamines 7a and 7b. Z-enamine 7b does not react in any of the examined cycloadditions. The cyclopropanation of E-enamine 7a with methyl diazoacetate under copper(I) catalysis provides the donor-acceptor-substituted cyclopropane 9 [1], which can be converted in good yield into the interesting dipeptide 10 [6]. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Chiral enamines have been used as ligands for Cu(I) in the enantioselective cyclopropanation of styrene (66). Copper(I) complexes of the quinolinyl ligand 94 provides modest enantioselectivities, although cis-trans selectivity is very low. 

In several synthetic studies, cyclopropane derivatives were used as synthones or building elements for ring enlargement steps, e.g. reaction of enamines with cyclopropenone [65], synthesis of 2,3-dihydro-l,4-diazepine by thermal isomerization of 1,2-diamino-cyclopropanes [32] [66], and preparation of 3-amino-fulvenes from methylencyclopropenes with alkynamines [67]. 

Substituted bicyclo[ . 1.0]alkanes may also be obtained by condensation of secondary amines with 2-haloketones. A variety of nucleophilic reactions can be carried out on the intermediate cyclopropaniminium salt 116251 (Scheme 108). Competing alkene scission and cyclopropanation occurs on reaction of enamines with pentacarbonyl-chromium carbene complexes252 (Scheme 109). N-Silylated allylamines and their derived N-silylated enamines undergo rhodium or copper catalysed cyclopropanation by methyl diazoacetate253 (Scheme 110). 

Cyclopropanes have also been obtained by reaction of enamines with a-chloro electrophilic alkenes. After Michael addition the chlorine undergoes nucleophilic displacement by the regenerated enamine or enolate anion260,261 (Scheme 112). Bicy-clo[ 1.1.0] butanes may be obtained by cycloaddition of trimethyl ethylenetricarboxylate followed by a base catalysed displacement of the amine moiety262 (Scheme 113). 

Anodic oxidation of enamines in NaCN-MeOH with iodide ion as mediator provides ring-fused cyclopropane aminonitriles with the nitrile group exclusively in exo position [Eq. (29)] [256]. This reaction is possibly an electrocyclic ring closure of an intermediate allyl cation LXXIII. 

A number of atypical reactions of enamines have been developed. For example, hydroboration-oxida-tion affords stereochemically defined, vicinal amino alcohols (equation 26). Similarly, enamines have been shown to undergo reaction with diazomethane to form substituted cyclopropanes. These materials can be further transformed to a alkylated ketones by thermolysis followed by hydrolysis (equation 27). ... 

Cyclopropanation products 59 of enamines rearrange to a-methyl or a-ethyl ketones 60 when heated in aqueous methanol in sealed tubes or when refluxed in aqueous methanol in the presence of 10% palladium on charcoal. ... 

Instead of PdCOAc), other catalysts such as PdCl, PdCl 2 PhCN and [(ri -CjHjlPdCl] can be used without significant loss of activity . Comparison of the PdfOAcIj/CHjNj reagent with the CuCl/CH N system reveals some complementary behavior Cyclopropanation of carbonyl-substituted alkenes works well with palladium, but fails with the copper catalyst. The same was true for cyclopropanation of a P-arylenamine , although other enamines and 1,2-enediamines underwent the expected reaction with CuCl/CH N. In intramolecular competition... 

Interestingly, enamines attack the terminal olefinic carbon of l,l-bis(ethoxycarbonyl)-2-vinylcyclopropane (42), with ring opening of the cyclopropane ring, in contrast to sodiomalonic ester which attacks the more substituted cyclopropane carbon. With diethyl cyclopropylmethylideneraalonate (43) reaction occurs at the jff-carbon and the cyclopropyl ring remains intact (Scheme 27). Titanium tetrachloride catalyses the highly diastereoselective addition of enamines to 2,2-dimethoxyethyl crotonate. ... 

The conditions reported by the Qin group for the intermolecular cyclopropanation of 3-substituted hexahydropyrroloindole provided unsuccessful results (Table 4.3, entry 3) [65, 69]. Furthermore, no conversion was observed using Cu(OTf)2, CuOTf, IMF copper(l) 27 or IMes gold(I) 15 complexes as catalysts (Table 4.3, entries 3-7) [116, 117]. Only starting material was recovered under the optimized conditions. This is probably due to the higher steric hindrance of the indole III-35, in comparison with methyl l//-indole-l-carboxylate, preventing the nucleophilic attack of the enamine moiety. 

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