Steroidal dienamines

Steroidal A -dienamines are formed with a high degree of selectivity in the presence of 17- or 20-ketones. Preparation of morpholine and pyrrolidine enamines is achieved by azeotropic removal of water with or without a catalyst. Pyrrolidine enamines are also formed efficiently by addition of the base to the hot solution of the ketone in methanol followed by immediate cooling. ... 

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

By analogy with the kinetic protonation of steroidal zl -enolate anions with weak acids such as acetic acid, which proceeds at the C-4 atom, since the maximum negative charge resides at this position (54,55), the kinetic protonation of the -dienamines with weak acids also occurs at this... 

The alkylation of dienamines has not been studied extensively. Thus the dienamine (44) is reported (43,44) to alkylate at Cj with methyl iodide to give the iminium salt (45), which on hydrolysis gives the alkylated a,)3-unsatur-ated ketone (46). Similar dienamines prepared from A -2-oko steroids. On the other hand, are reported to undergo only N alkylation (45). 

Alkylation of dienamines with alkyl halides has been found to take place at the oc carbon (288-290). The reaction was used in the synthesis of steroid analogs (291). 

Fluorination.1 This reagent effects regio- and stereospecific fluorination of the electron-rich steroid dienamine (2) to give the (axial) 6(l-fluoro-4-cholestenone-3 (3). In the added presence of Cu(acac)2, reaction of 2 with 1 results in 6a-fluoro-4-cholestenone-3 (10%) and 6,6-difluoro-4-cholestenone-3 (15%) as the only products. 

Enamines have been used for blocking steroidal ketones.32,79 82 a,/3-Unsaturated ketones afford dienamines.59,82,83... 

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

Ionized primary enamines of low energy may also be reaction intermediates in the loss of ammonia. Scheme 34 shows a mechanism proposed for the extensive loss of ammonia from low-energy ionized 3-amino steroids. Enamine 63 may lose ammonia after two successive 1,4 H-transfers. The participation of the H at C(5) has been established by D-labelling42. Only higher energy ions lead to m/z 82 fragment ions through the ionized dienamine 64,... 

Steroidal dienamines of the conessine and cholestane series have been regio- and stereoselectively reduced by NaBH4, in the presence of acetic acid, on the a,/ -double bond to give the corresponding 3/ -amino derivative113,114 (Scheme 85). 

The same was observed for steroidal dienamines having a carbonyl group at C-17157 and for enamino esters which were reduced by LiAlH4 at the keto and ester functions, respectively, leading in the latter case to saturated pyran and furan derivatives158,159 (Scheme 111). 

Indolo-steroids have been obtained by -coupling of steroid dienamines with dia-zonium salts in dimethylformamide followed by Fischer-indole cyclization of the resulting hydrazone39 (Scheme 37). In methylene chloride the /Fcoupled product 75 was obtained, cyclization of which gave indazoles 74 and 762a. The oxidative role of dimethyl sulphoxide in the formation of 76 was attributed to nucleophilic attack by the solvent on 75 leading to intermediates 77 and 78, with elimination of dimethyl sulphide (Scheme 38). 

A flexible method uses the condensation of suitable dienamine systems with appropriate aromatic derivatives. This is illustrated in the reaction of the dienamine (168) with the salt (169), yielding the heterocyclic steroid (170), which is then reduced to its tetrahydro-derivative (171). ... 

As shown in Scheme 49, the cyclohexylimine of 10-methyl-l(9)-octalin-2-one has been methylated at C-3 via the kinetically formed cross-conjugated dienamine anion (95) or monomethylated at C-1 via the thermodynamically more stable extended anion (96). Steroidal and simpler enones have also been monoalkylated at the a-position via their corresponding hetero- or homo-annular extended dienamine anions. Likewise, a-alkylations are the rule for liAiated a,3-unsaturated aldimines. The thermodynamically controlled procedure for the synthesis of a-methyl a,3-unsaturated ketones is a vast improvement over conventional methodology using extended metal dienolates where a,a-dimethylation is a severe... 

Furano-steroids 80 and 3-oxa-A-norsteroids 79 have been prepared by reaction of a-bromoketones with steroid dienamines (Scheme 39). 

The total synthesis of conessine by Marshall and Johnson - is treated further in a general article on the total synthesis of steroids. The 3j -dimethyl-amino-group is introduced by reduction (NaBH4-acetic acid) of the dienamine (43) obtained from A -conanen-3-one. It is by this method, followed by catalytic... 

Treatment of the dienamine (432 n = 1) with m-methoxyphenyldiazonium-fluoroborate gives the 6,7-diaza-steroid (474) in one step, or the aza-derivative (475) which can be converted quantitatively to (474). 

With dienamines which are constrained in a ring as in the steroids 36 simple diformylation occurs (Eq. The benzfulvene 37 and similar fulvenes may... 

The following Section deals with protective groups that have been used almost exclusively in the steroid field. Moreover it applies mostly to derivatives of a,/3-unsaturated ketones, so that properly speaking and for the most part dienol and dienamine derivatives are discussed. 

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