Cyclopropanes reactions with enamines

A titanium-methylene complex was readily generated from CH2CI2 by treatment with TiCLt and magnesium metal. This generation of active titanium-methylene complex 445 was useful for cyclopropane formation with enamines 446 or amides 447 to give aminocyclopropanes 448 and 449, respectively, in good yields (Scheme 1.210) [294]. TiCU worked catalyticaUy in the reaction with enamines 446, while substoichiometric amounts of TiClq were necessary for the reaction with amides 447. 

The similarity between the reactions of alkenes and cyclopropanes is further demonstrated by the reactions of electrophilic cyclopropanes and cyclopropenes with enamines. Cyclopropylcyanoester74, when treated with the pyrrolidine enamine of cyclohexanone, undergoes what would be a 1,2 cycloaddition in the analogous alkene case, but is actually a 1,3 cycloaddition here, to form adduct 75 (90). A similar reaction between the... 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

Novel methods for functionalizing piperidines at the 3- and 4-positions were also introduced. Mete and co-worker synthesized 3-diazo-piperidin-2-one and characterized its reactivity in transition-metal catalyzed reactions, particularly H-X insertion reactions and cyclopropanation reactions <02T3137>. Christoffers and co-workers developed an asymmetric Michael addition reaction with a chirally modified 4-piperidone-enamine. They were able to create a quaternary carbon center in >95% de and elaborate the compound on through classical means to the functionalized piperidine 107 (Scheme 21) <02EJ01505>. 

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). 

Diazo-l,l,l-trifluoro-3-nitropropane reacts with enamines. This reaction goes through the intermediacy of a cyclopropane derivative which hydrolyzes to the corresponding ketone 47. ... 

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). ... 

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. ... 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Sol 9. (d) Aldehydes and ketones having a-protons react with secondary amines to form enamines. The enamine formed in the first step undergoes cyclopropanation reaction at the double bond with dichlorocarbene that is generated by a-elimination of HCl from chloroform. This product undergoes ring expansion to furnish 2-chlorocyclohex-2-en-l-one (I). 

The reaction of carbene complexes with enamines has been found to give cyclopropanes in low yield (Dorter et at., 1974). Reaction of carbene complexes with l-vinyl-2-pyrrolidone in the absence of added CO pressure gives alkene scission products (Dorrer and Fischer, 1974a), whereas at high CO pressure products possibly derived from ketenes are obtained (Dorrer and Fischer, 1974b) (see Scheme 11). 

Development of such a catalytic cascade process requires a stable and electron-rich carbon species as a nucleophile, which should be compatible with electrophihc aldehyde functionality in one of the chemical entities 144 (Schane 1.53) [90]. Undesired reaction of 144 with the catalyst to produce an iminium or aiamine could significantly complicate the cascade process. Potentially, the iminium 144a could undergo reversible intramolecular cyclopropanation and thus slow down the desired cascade process. Moreover, the enamine 144b could participate in the Michael reaction with iminium 144c. 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

The Simmons-Smith reaction has been used as the basis of a method for the indirect a methylation of a ketone. The ketone (illustrated for cyclohexanone) is first converted to an enol ether, an enamine (16-12) or silyl enol ether (12-22) and cyclopropanation via the Simmons-Smith reaction is followed by hydrolysis to give a methylated ketone. A related procedure using diethylzinc and diiodomethane allows ketones to be chain extended by one carbon. In another variation, phenols can be ortho methylated in one laboratory step, by treatment with Et2Zn and... 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

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