The synthesis of N-acetylserotonin

Synthesis of tryptamines by the Fischer method using synthetic precursors and latent forms of amino-butanal (review)

“…In contrast to the aminobutanal acetals, which were used in the synthesis of tryptamines [24, 142,215], use of the trimer of both pyrrolidine [226] and piperideine [230] in the Fischer reaction led to unsatisfactory results, which may be explained by their instability in the acidic medium and the need for milder conditions. The success in the use of the trimers of pyrroline 3 in place of aminobutanal acetals in the synthesis of other heterocyclic compounds [33] makes it possible to hope for its successful future application for the synthesis of tryptamines.…”

“…Indolization takes place readily in dilute mineral acids and also in 25% acetic acid at 85°C (Table 11), and in the last case the reaction products are easier to purify than in the Fischer reaction with ZnCl 2 [142]. In order to facilitate the isolation of the crystalline hydrochlorides of the tryptamines in some cases it is necessary to use several equivalents of HCl, while addition of the acid at the beginning of the reaction can have a negative effect on the yield of the tryptamine [140].…”

“…HCl [242]; 53a → 55a R = 5-OH; R 1 = Me, R 2 = R 3 = H (~100% d ); 3.4 atm H 2 , Pd/C, quantitatively [242]; 53b R = 4,6-F 2 , 5-OMe; R 1 = Me, R 2 = R 3 = H (59% b ); 90% HCO 2 H; 53b → 55b (54% b ) LiAlH 4 [125]; 53c R = 4,6-F 2 , 5-OMe; R 1 = R 2 = H, R 3 = Me (39% b ); 90% HCO 2 H; 53c → 55c (43% b ) LiAlH 4 [125]; 55d-h R 1 = Me, R 2 = CO 2 Et, R 3 =H, d R = H (20% c ); e R = OBn (47% d ); f R = Me (86% d ); g R = Cl (13% d ); h R = F (34% d ); 1) AcOH; 2) 10% SSA -2-PrOH, 1-10 h, ∆; 3) Ni-Ra, H 2 , 10 atm; one-pot [243]; 54a R = H, R 3 = CO 2 Me (40% b ); THF, HCl, ∆, 35 min [86,87]; 54i → 55i R = H, R 1 = R 2 = H, R 3 = CO 2 Me (95% b in the form of the N-Ac derivative); H 2 , 3.4 atm, 20 h, Ni-Ra; Ac 2 O [86,87]; 55i (40% b ); Fischer synthesis from aminobutanal 7c, THF, HCl, ∆, 35 min [86,87]; 54a-d R 3 = H, a R = 5-OBn (61% b ); b R = 5-OMe (67% b ); c R = 5-OEt (51% b ); d R = 7-OMe (11% b ); 50% AcOH, 80°C, 2 h 30 min [215]; 54 → 55 see also the preparative methods in [244] (LiAlH 4 ) and [245] (H 2 , Ni-Ra) Catalytic hydrogenation of the indoles 54 in the presence of alkylamines leads to N-alkyltryptamines [246,247]. In the presence of a benzyl group it is possible to combine catalytic reduction with debenzylation [242].…”

“…The production of aminoacetals by the action of an excess of mmonia on halo acetals is well known (e.g., see [91,131] 4 Ti -NaBH 4 , 1:4:2:1.5, absolute diglyme, 60°C [139] 68% a by the reduction of methoxycarbonylaminobutanal meth of compound 19b, is used in the biomimetic synthesis of arious alkaloids with an indolizidine fragment [32]. Alk = Me (57% а ), Pd/C, H 2 , 114 atm [138]; 18 Alk = Et (92%), ratio of reagen It is also known that the acetal 18 is produced with a yield of 45% a by exhaustive methylation with methyl iodide followed by demethylation of the quaternary salt by boiling in ethanolamine [140]. N-Methylaminobutanal was obtained with a yield of di yl acetal with lithium aluminum hydride [129].…”

“…The yield of the tryptamine 41a in 8% trifluoroacetic acid was somewhat lower, while in 8% hydrochloric acid the reaction was complicated by the formation of aniline derivatives. The tryptamine 41b was formed with the smaller yield when the reaction was carried out in 25% acetic acid [140], while the synthesis of the tryptamine 41a was complicated by the formation of side products [77]. …”