Tricyclic enamines

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... 

An alternative route (Scheme 48) was used by Dolby et al. (160) to prepare the tricyclic enamine (225). A Vilsmeier reaction between 3,4-methylenedioxy-A yV-dimethylbenzamidc (232), and pyrrole gave the amide (233) in 80% yield. Reduction with sodium borohydride provided the benzyl pyrrole (234), which... 

Yet another method has been described (162) (Scheme 50) for the preparation of the tricyclic enamine (225). /V-Alkylation of ethyl pyrrole-2-carbox-ylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156) but contrasting with the report of Dolby et al. (160). 

The catalyst Ir/(l a,S,S) 44 has been successfully applied to the synthesis of chiral tricyclic amines (Scheme 8.21). The hydrogenation of tricyclic enamine such as... 

Scheme 8.21 Asymmetric hydrogenation of tricyclic enamines with lr/(Ro,S,S) 44.

An attempt to prepare cephalotaxine and 11-hydroxycephalotaxine from chiral precursors by means of a ring expansion of isoquinoline derivatives prepared by the Pictet-Spengler condensation was made by Hudlicky in 1981 (70,71) as shown in Scheme 37. Acid 210 was prepared by condensation of biogenic amines 208 (X = H or OH) with the pyruvate 209. Borane reduction to the corresponding alcohols 211, followed by acid-catalyzed solvolysis, led to the tricyclic enamines 212 and 213 (77). This approach was modeled on the biogenetic condensation of amines with pyruvates to generate 1,1-disubstituted tetrahydroisoquinolines, ubiquitous in alkaloid biogenesis (70). 

In an attempt to gain insight into the pharmacophore moiety of the ergot alkaloids, aza-transposed ergolines were synthesized [55] with the nitrogen atom in the 9-position by alkylation-amination of a tricyclic enamine in the presence of ethyl a,a,-bis(dibromomethyl)acetate, triethylamine, and methyl-amine which led to the construction of the azatransposed ergoline. 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

A 3,4,8,9-tetrahydropyrido[2,l-c][l,4]thiazine 336 and a benzo(A)-l,4-thiazine 335 was isolated from the reaction mixture of enaminone 334 and 2-(3-chlorobenzylidene)acetylacetate (99T7915). Reactions of enamines 334 and 337 with DMAD in MeOH yielded addition products 338 and 339 and bi- and tricyclic derivatives 340 and 341, respectively. The latters could be obtained in quantitative yields when the addition products 338 and 339 were heated in refluxing MeOH. 

In a typical example of aliphatic cyclizations, already discussed in Section 5.2, the enamine 675 is alkylated by silylated methyl 4-chloroacetoacetate 747 a [2] to give, via 760 and subsequent ehmination of pyrrolidine, the unsaturated bicycHc /9-ke-toester 761 in, as yet, only 30-40% yield [1]. Analogously, the bicycHc system 1408 with an additional 6-keto group is silylated to 1409 and cyclized via 1410, in an overall yield of 42%, to the tricyclic capnellene intermediate 1411 [3] (Scheme 9.1). An alternative synthesis of bicyclic compounds Hke 761 is given elsewhere [3 a]. 

Thiopyranopyrrolizines can be prepared readily from the enamine 170 upon treatment with DMAD. Alternatively, heating of the thiacyclooctadiene derivative 171 in methanol gives the same tricycle 172, but this time as a 5 2 mixture with the (Z,E)-isomer of the precursor 171. These reactions probably involve the the intermediacy of an unstable cyclobutene and/or a zwitterionic diene, as shown in Scheme 51 <1984JA1341>. 

The enamine 141 can be cyclized to the [l,2,4]triazolopyridopyrimidine 142 upon treatment with sodium ethoxide (Scheme 40) <2002M1297>. This fused tricyclic system may also be obtained, like the pteridine analogue (cf. Scheme 38), from the reaction of hydrazonoyl halides and pyridopyrimidines such as 143, and also by treatment of the triazolopyrimidine 144 with dimethylformamide dimethylacetal (DMF-DMA) dimethylacetal and subsequent ring closure <2003MOL333, 2003HAC491> (Scheme 41). Another series of triazolopyridopyrimidines, for example, 146, can be prepared from a hydrazine-substituted pyridopyrimidine 145, in two ways either directly by reaction with an acid chloride, or via a derived hydrazone (Scheme 42) <1996MI585>. 

These cyclizations normally involve a carbonyl group. The enamine 109 undergoes a reaction with oxalyl chloride to give an intermediate product 110, which is then cyclized upon treatment with HC1 leading to the angular tricyclic compound 111 in excellent yield (Scheme 11) <1995EJM525>. 

The mechanism of this conversion was formulated to occur by an initial addition of the ammonia at position 2 and of the anion of the keto compound (or the enamine) at position 6, i.e., formation of 124. It is of course possible that this addition pattern can be reversed addition of the ammonia at position 6 and of the anion at position 2. In both addition products an internal cyclization occurs by attack of the nitrogen of the amino group on the keto function, yielding the tricyclic intermediate 125. Aromatization occurs by loss of A-methyl-a-nitroacetamide (Scheme III.62). 

The mechanism of the formation of tricyclic intermediates 56 and 57 is also the important and conflicting matter. For example, Quiroga et al. [83] showed that these MCRs, the most probable, proceed via preliminary Knoevenagel condensation and Michael addition (Scheme 26). At the same time they rejected another pathway including the generation of enamine 60, because no reaction was observed between it and aromatic aldehyde when their mixture was refluxed in ethanol. 

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