Synthese directe d'indoles anti-hypertensifs

A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1,R2)‐2‐Thioxoacetyl)‐phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives: A Novel Synthesis of Intermediate (1‐Acetyl‐1H‐indol‐3‐yl)malononitrile/cyanoacetates

“…Such relatively low reactivity of acetylindoxyl 1 in the Gewald reaction is akin to that of cyclopentanone [32]. It is not surprising since this species as well as its benzene-substituted derivatives, as a rule, are not easily available even via the Fischer reaction because of side processes [40]. So, we decided to use 1-acetyl-3-indolylmalononitrile 14a and 3-indolylcyanoacetates 14c-e with the COMe/ COOEt/H moiety at the ring nitrogen (N-1), respectively, instead of acetylindoxyl 1 and the corresponding activehydrogen nitriles.…”

“…So, we decided to use 1-acetyl-3-indolylmalononitrile 14a and 3-indolylcyanoacetates 14c-e with the COMe/ COOEt/H moiety at the ring nitrogen (N-1), respectively, instead of acetylindoxyl 1 and the corresponding activehydrogen nitriles. The latter are known to be applied in the syntheses of biologically active compounds [40]. Among malononitrile derivatives only ylidenemalononitriles are known to be successfully used in the Gewald reaction instead of ketones [32], whereas, as far as we know, such type of fully heteroaromatic nitriles as 14 has not been tested in the reaction.…”

“…In some cases, 3indolylcyanoacetates with the unsubstituted ring nitrogen atom were isolated as a byproduct in low (8-12%) yields. It is not surprising since this species as well as its benzene-substituted derivatives, as a rule, are not easily available even via the Fischer reaction because of side processes [40]. It should also be noted that Nenitzescu and Raileanu attempted to obtain 1-acetyl-3-indolylcyanoacetic acid by condensation of acetylindoxyl 1 with cyanoacetic acid but failed; they also did not observe the formation of 3-indolylcyanoacetic acid [41].…”

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

“…-Pr) 2 NLi, -78°С, THF [117]; e R 1 R 2 = (CH 2 ) 5 ; 71-79% a ; (i-Pr) 2 NLi, -78°С, THF [117] f R 1 = H, R 2 = CO 2 Me (32% а ); NaH, DMF -PhH [86,87] [126] 385 H (43% б ) [127], with an eightfold excess of MeNO 2 yield 62% а [128]; b-h R = Me The acetal 15 was also obtained [129] by hydrolysis (57% a ) of the methoxycarbonyl derivative, synthesized by the Hoffmann rearrangement (69% a ) from dimethoxyglutaramide (obtained in turn by a multistage synthesis from caprolactam [130]). 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].…”

“…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].…”