Enamines, reaction with carbenes

Many carbenes add to cumulated systems, that is, allenes, to give alkyHdenecy-clopropanes in a synthetically useful reaction. Thus, allene itself reacts with ethoxycarbonylcarbene to give the ethyl ester of 2-methylenecyclopropane-l-carboxylic acid. 3-Methylbuta-l,2-diene (dimethylallene) has been proposed as a useful probe for carbene multiplicity since singlets add to the more substituted double bond, whereas triplets add to the 1,2-bond (Scheme 5.38). Carbenes react with enamines in the normal way accompanied by a ring expansion that generates ketones via rearrangement of the initially formed aminocyclopropane (Scheme 5.39). 

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). 

Reaction of a,/MJnsaturated Fischer Carbene Complexes with Alkenes, Butadienes, Enamines, and Imines... 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

In isolated examples, reactions of specific amides and thioamides with dihalo-carbenes can take unusual pathways. Thus, for example, using procedure 7.1.1, A,A-dialkylamides are converted into a-chloromethylene derivatives of the amides [48]. The initial step in which the carbene attacks the carbonyl oxygen atom is the same as for the dehydration of the A-alkyl amides, but subsequent steps, for which there is evidence from 2H/ H labelling experiments, lead to the formation of an enamine and further reaction with the carbene (Scheme 7.34). 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

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. 

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). 

The results of a series of reactions of Fischer carbene complexes with enynes are summarized in Tables 1 and 2. Cyclopropane synthesis is accomplished in the alkoxy series (Y = OMe) by the generation of a mixture of geometric isomers of enol ethers, whereas in the dialkyl-amino series, ketones are directly obtained after hydrolysis of the enamines. Higher yields have been obtained using the amino analog pentacarbonyl(l-pyrrolidinoethylidene)chromium [Y = N(CH2)J. - ... 

The carbene complex starting materials mentioned above include an enamine structure which is coupled with an alkyne. Vice versa, the coupling of alkynylcarbene complexes with enamines leads to cyclopentanoid products as well. The complementary reaction of tungsten alkynylcarbene complex 59 with enamine... 

Cyclopentanoids may also arise from the reaction of alkenylcarbene complexes with enamines. As shown in Scheme 33, tungsten carbene 66 reacts with enamines 67 and 68 to afford the enol ethers 69 which give cyclopentenone 70 upon acidic hydrolysis. [83] The formation of 69 generates two carbon-carbon bonds and three stereogenic centers with remarkable regio- and stereoselectivity. The reaction of enamine 67 results in a racemic mixture of 70 the chiral enamine 68, however, adds to carbene complex 66 to give enantiomerically enriched (87% e.e.) cyclopentenone 70. 

The potential of Fischer carbene complexes in the construction of complex structures from simple starting materials is nicely reflected in the next example. Thus, the reaction of alkenylcarbene complexes of chromium and tungsten with cyclopentanone and cyclohexanone enamines allows the di-astereo- and enantioselective synthesis of functionalised bicyclo[3.2.1]octane and bicyclo[3.3.1]nonane derivatives [12] (Scheme 44). The mechanism of this transformation is initiated by a 1,4-addition of the C -enamine to the alkenylcarbene complex. Further 1,2-addition of the of the newly formed enamine to the carbene carbon leads to a metalate intermediate which can... 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

Enamine formation occurs by the thermolysis of diazo compounds (Scheme 150)67 109,278 284 288,304 332 453 454 via a carbene-like intermediate.284 332 When R1 = Ph, it enters into competition with hydrogen migration,284,332 and the electrophilic character of the carbene enhances the migration of the dimethylaminophenyl more than the phenyl.332 When triazoline synthesis is carried out at temperatures higher than that at which thermolysis of diazo compounds occurs, enamines are obtained exclusively, as in the addition of phenyl azide to cinnamic nitriles and ketones, with phenyl migration dominating in the nitrile.284 Enamine is also formed quantitatively in the reaction of ethyl diazoacetate with benzylideneaniline at 110°C.455... 

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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