Endocyclic enamines

Deuterium exchange at the /2-carbon yields, for a given secondary amine, the following reactivity for the ketone substrate120 cyclopentanone (47) cycloheptanone (49) cyclohexanone (48). 

Endocyclic enamines may be combined with / -functional groups leading to cyclic /2-phospholene sulphide enamines130 (60), cyclic /2-ketoenamines131,132 (61), 3-(pyrrolidi-n-l-yl)-5,6-dihydro-4//-thiopyran 1,1-dioxide133 (62) and 3-amino-5,6-dihydro-4//-pyran134 (63). 

Pyrrolidine enamines of cyclic ketones have been prepared from cyclobutanone to cyclononanone. In the reaction of unsymmetrical 2-methyl or 2-phenyl cyclohexanone with pyrrolidine, of the two regio isomers 50a and 50b the less substituted enamine (50a) is formed preferentially . This is in contrast to the behaviour of enol derivatives, where the most stable regio isomer is the more substituted one. The reason for the destabilization of 50b is the steric interference of the 2-substituent with a CH2 group of the pyrrolidine ring in a coplanar cis arrangement at the C=C double bond. 

Secondary amines used for reactions with cyclic ketones may be aziridine (52X azetidine (53), pyrrolidine (54), piperidine (55), hexamethylenimine (56), morpholine (57), //-methylpiperazinc (58) and acyclic amines like dimethyla-mine (59). The general order of electrophilic attack of enamines as dependent on the nature of the amine moiety decreases in the sequence pyrrolidine (54) dimethylamine (59) hexamethylenimine (56) piperidine (55) sk azetidine (53) morpholine (57). This sequence seems to parallel the magnitude of conjugative interaction between the amino group and the C=C double bond as indicated by the H NMR chemical shift of the hydrogen at the jS-carbon. 

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The dehydrobromination and dequaternization of l,l,3-trimethyl-2-bromomethylpyrrolidinium bromide (158) has been accomplished by dry distillation from potassium acetate (123). Since the product was isolated as the perchlorate salt, no conclusion can be drawn as to whether the original reaction mixture contained the exocyclic enamine (159) or the endocyclic enamine (160) ora mixture of both. 

A wide variety of more complex endocyclic enamines are thus made available as synthetic intermediates. 

ENDOCYCLIC ENAMINE SYNTHESIS JV-METHYL- 2- PHENYL- A -TETRA-HYDROPYRIDINE, 54, 93 Enol acetates, acylation of,... 

The preparation of macrocyclic diimines and endocyclic enamines are represented by the procedures for the formation of 1,10-DIAZA-CYCLOOCTADECANE and N-METHYL-2-PHENYL-A2-TETRA-HYDROPYRIDINE. Other procedures representative of alkylation reactions and aromaticity (TRI-i-BUTYLCYCLOPROPENYL FLUOROBORATE) round out a volume of tested experimental procedures of general value. 

ENDOCYCLIC ENAMINE SYNTHESIS N-METHYL-2-PHENYL-A2-TETRAHYDROPYRIDINE... 

Another application of this strategy is the construction of cyclic systems bearing 1,4-dissonant relationships. For example, the synthesis of the hasubanan alkaloid ring system 35. reported in 1972 by Evans [24], involves the Diels-Alder cycloaddition of a dienyl sulphoxide 32 with an endocyclic enamine 33, followed by a [2,3]-sigmatropic rearrangement of the resulting cycloadduct 34 (Scheme 5.21). 

An interesting strategy for pyrrolidine a,/3-functionalization has been developed <2005T1221>, starting from readily available endocyclic enamine derivatives. A two-step heteroannulation procedure involving iodoetherification of A -acyl-2-pyrrolines 216 giving 217 followed by radical cyclization gave access to the bicyclic compounds 218 which can be used in further transformations to form substituted pyrrolidines 219 and 220 (Scheme 22). 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

In addition to acyclic and monocyclic enamines, bicyclic and tricyclic enamines also undergo cycloaddition with dihalocarbenes. Endocyclic enamines , such as pyrrole and indole, add dichforocarbene and the adducts rapidly undergo ring cleavage to afford 3-chloropyridine and 3-chloroquinoline, respectively, in moderate yields (c/. Section 4.7.3.9).75-77... 

In the case of endocyclic enamines, the imines from the triazoline decomposition are one-carbon, ring-contracted products (Scheme 179).30,39,225,510,511 Application of the reaction to cholestanonepyrrolidine... 

Tetrahydropyridines are endocyclic enamines and can react readily with numerous electrophiles at the 5-position and nucleophiles at the 6-position. An example of this reactivity is a three-component reaction of iV-benzyloxycarbonyl-l,2,3,4-tetrahydropyridine 185, which reacts with primary carbamates in the presence of iodine to give 2-amino-3-iodopiperidines 186, with a toor-relationship between the substituents (Scheme 49). Tetrahydropyridine 185 also reacts with sodium azide in methanol in the presence of ceric ammonium nitrate to give 3-azido-2-methoxypiperidine 187, which can be isolated or reacted with nucleophiles in the presence of BF3-OEt2 to give 3-azido-2-alkylpiperidines 188 in which the relationship between the substituents is cis <2005T1221>. 

A very interesting comparative X-ray diffraction study of six N-cyclic endocyclic enamines 77147 and 78 to 82 was performed by Dunitz and coworkers144. Structural formulae and nomenclature of these enamines are presented in Scheme 2. In addition, 1,1,2-trimorpholinoethene148 (83) is included. Relevant heavy atom distances of the enamino groups are given in Table 1 and angles in Table 2. These structures (77-83) cover enamines mainly of cyclohexene with pyrrolidino, piperidino and morpholino substituents. 

Diels-Alder addition of the endocyclic enamine (40) to the moderately electron-deficient ( )-l,3-di-enyl sulfoxide (39) proceeded smooAly without loss of the nitrogen atom. Subsequent 2,3-sigmatropic... 

This reaction has been developed by Stevens for a refined access to various alkaloid families. Equation 29 shows the short synthesis of mesembrine, where methyl vinyl ketone is annulated to the endocyclic enamine. The precursors for the imines are usually cyclopropyl aldehydes and the corresponding amines or cyclopropyl nitriles combined with suitable organometallics as demonstrated in a simple myosmine synthesis (equation 30). Additional examples will not be discussed here since excellent review articles exist on this topic ... 

The rare-earth metal-catalyzed cyclization of aminoalkenes, aminoalkynes and aminodienes generally produces exclusively the exocyclic hydroamination products. The only exception was found in the cyclization of homopropargylamines leading to the formation of the endocyclic enamine product via a 5-endo-dig hydroamination/cyclization (32) [142], most likely due to steric strain in a potential four-membered ring exocyclic hydroamination product. Interestingly, the 5-endo-dig cyclization is still preferred even in the presence of an alkene group that would lead to a 6-exo hydroamination product [142]. 

There is speculation that long-term exposure to cyclic tertiary amines such as cocaine, phencyclidine, and phenothiazines may result in biochemical lesions through the formation of reactive metabolites. This premise is supported by the induction of a parkinsonian state by MPTP. Although the initial product of microsomal oxidation is an electrophilic endocyclic iminium intermediate which is thought to be the reactive species primarily responsible for neurotoxicity, there is now evidence that the iminium is in equilibrium with the endocyclic enamine and that the latter is transformed to reactive species. The presence of iminium- detoxifying enzymes in cytosolic and microsomal fractions suggests that rapid inactivation of the iminium... 

Evidence for oxidative metabolism of the endocyclic enamines has been obtained for both 1-BP and PCP. In a previously reported (Masumoto et al. 1991) preparative scale metabolism of 1-BP, it was found that in addition to the C -C. coupled dimer 3, small amounts of l-benzyl-3- piperidol (l-BP-3-ol), l-benzyl-4-piperidol (l-BP-4-ol), and 1-benzyl-3-piperidone (l-BP-3-one) were obtained (figure 5). It was further found that cyanide reduced greatly the levels of l-BP-3-one metabolite but not the l-BP-3-ol metabolite, suggesting that 1-BP-3-one is generated principally from the initial metabolite (1-BP-Im ) rather than from oxidation of l-BP-3-ol (Masumoto et al. 1991 Sayre et al. 1991). Consistent with this notion is the finding of relatively large amounts of the corresponding 3-one in the... 

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