Investigation of the [1,5]-hydride shift as a route to nitro-Mannich cyclisations

Abstract

Conditions were found for the [1,5]-hydride shift nitro-Mannich reaction that led to the synthesis of 2,3-disubstituted tetrahydroquinolines. Two simple cyclic amine substrates gave diastereomerically pure rearranged products in 65 and 90% yields by refluxing in HFIP. A more general procedure used Gd(OTf)3 as a catalyst and successfully rearranged other cyclic and acyclic amines in 42-84% yield with diastereomeric ratios of 75:25 to >95:5 in favour of the antidiastereoisomer (9 examples). Two examples of sulfur containing heterocycles gave lower yields of 9 and 25%. Electron withdrawing substituents were shown to have a deleterious effect on the success of the reaction. The results indicated the limitation of the [1,5]-hydride shift nitro-Mannich reaction with respect to the stability of the intermediate iminium ion.

peri-Interactions in 1,8-bis(dimethylamino)naphthalene ortho-ketimine cations facilitate [1,5]-hydride shift: selective synthesis of 1,2,3,4-tetrahydrobenzo[h]quinazolines

“…21 Subsequently, the acid-catalyzed variant ( 3 → 5 ) of this cyclization was developed leading to a significant increase in the rate and yields in comparison with the thermal variant. 22–26 For the mentioned reactions (Scheme 1), there are three main factors that are favorable for the tert -amino effect: (1) the effective pyrrolidine-based hydride-donating part: the tert -amino effect in general is more pronounced for amines with secondary or tertiary carbon substituents 14,27,28 while the simple NMe group does not produce good results, even if the hydride-acceptor is an active N -alkylated Schiff base as in 6 (Scheme 2); 29 (2) increased hydride-accepting ability of the C(R 1 )NR 2 group due to the accepting (CF 3 , CO 2 Et) or at least not donating (H) nature of the substituent R 1 ; and (3) relatively high hydrolytic stability of the precursor imines 1 and 4 because of the presence of the R 2 substituent in comparison with N -unsubstituted imines (R 2 = H).…”

“…[5][6][7][8][9][10] Thus, the intramolecular hydride shift in ortho-substituted derivatives of N-alkylated anilines (also referred to as the tert-amino effect 11,12 ) has gained vast application for the synthesis of nitrogen heterocycles. [13][14][15][16][17] In the framework of this work, quinazolines, possessing prominent biological activity, [18][19][20] are of particular interest.…”

“…(1) the effective pyrrolidine-based hydride-donating part: the tert-amino effect in general is more pronounced for amines with secondary or tertiary carbon substituents 14,27,28 while the simple NMe group does not produce good results, even if the hydride-acceptor is an active N-alkylated Schiff base as in 6 (Scheme 2); 29 (2) increased hydride-accepting ability of the C(R 1 )vNR 2 group due to the accepting (CF 3 , CO 2 Et) or at least not donating (H) nature of the substituent R 1 ; and (3) relatively high hydrolytic stability of the precursor imines 1 and 4…”

“…30 On the one hand, 7 has a poor hydride donor NMe group. 14,27,28 On the other hand, the ketimino group in 7 bares EDGs (e.g. Alk, 4-OMeC 6 H 4 , and tienyl) on the carbon atom suppressing the hydride accepting ability.…”

1,5-Hydride-Shift-Triggered Cyclization for the Synthesis of Unsymmetric Julolidines

“…[9][10][11][12][13][14] Such reactions allow tetrahydroquinoline derivatives to be obtained in a straightforward and redox-neutral manner (Scheme 1, previous work). 15 Significant progress in this area is associated with Lewis acid (LA) catalysis, 12,15 especially with the enantioselective procedure developed by Seidel's group, 16 which has allowed various applications involving alternative hydride acceptors [17][18][19][20][21][22][23][24][25] as well as the use of donating groups with shorter or longer tethers. [26][27][28][29][30] Assembly of julolidines via a 1,5-hydride-shift-triggered cyclization could be of benefit due to the unambiguous regioselectivity of hydride transfer and the straightforward access to unsymmetrically substituted derivatives 1 (Scheme 1, this work).…”