Regioselective formation of hydroxy lactams from pyridine-2,3-dicarboximides and their cyclodehydration to pyrido[2′,3′:3,4]pyrrolo-fused heterocyclic systems

Abstract

Grig nard reactions of pyridine-2,3-dicarboximides involve attack at the carbonyl group closer to the pyridine nitrogen atom to give 7-hydroxypyrrolo[3,4-b] pyridin-5(7H) -one derivatives. Reduction of the same imides with sodium borohydride gives mixtures of regiosomeric hydroxy lactams, in which the 7-hydroxypyrrolo[3,4-6] pyridin-5-ones are the major components. Hydroxy lactams derived by either of these two methods from pyridine-2,3-dicarboximides containing N-bentyl, N-2phenylet hyl, N-2-( indol-3-yl)ethyl, or Nbiphenyl -2-yl su bstituents are cyclised by heating in trifluoroacetic or polyphosphoric acid to give derivatives of new pyrido[2',3':3,4] pyrrolo-fused heterocyclic systems. Intramolecular amidoalkylation via the acid-catalysed cyclodehydration of a-hydroxy lactams provides a very general procedure for the construction of fused heterocyclic systems.' Structures (2x8) are illustrative of the fused isoindole ring systems obtained in this way from N-substituted hydroxyphthalimidines (1) or, in some cases, by a double cyclisation in a 0 0 (2) n = 1, R = Ph (3)n = 2 , R = H , P h (4) n = 2, R = ph (5) n = 3, R = H, Me,Ph (6) R = H, Ph, PhCH2

Zinc‐Catalyzed Selective Reduction of Cyclic Imides with Hydrosilanes: Synthesis of ω‐Hydroxylactams

“…2-benzyl-5,6-dibromo-3- 1, 145.4, 137.3, 132.5, 129.3, 128.5, 128.0, 127.8, 127.4, 127.2, 125.2, 79.7, 42.4 5, 167.6, 144.0, 132.1, 131.2, 129.4, 123.2, 122.9, 81.7, 60.5, 38.6, 31.6 3, 167.9, 144.1, 132.1, 131.6, 129.3, 123.3, 122.9, 82.6, 37.2, 35.9, 35.6, 32.7 4, 154.6, 144.6, 132.1, 131.6, 129.5, 123.2, 123.0, 82.3, 79.8, 57.5, 52.6, 43.4, 42.5, 39.6, 28.4, 26.0, 23.8; HR-MS-ESI: m/z = 390.2379, calculated for C 21 H 31 N 3 O 4 (M + H) + : 390.2393. 6,7-Dihydro-7-hydroxy-6-(phenylmethyl)-5H-pyrrolo [3,4-b]pyridin-5-one (2l): [33] Pale yellow solid; yield: 230.6 mg (96%); mp 184. 8, 163.9, 152.8, 137.5, 131.2, 128.5, 127.8, 127.2, 125.2, 124.7, 80.8, 42.2. cis - 13 C NMR (100 MHz, CDCl 3 ): d = 175.…”

Methods for the construction of [1,2]isoindolo-condensed benzazepines, benzazocines, quinolines, and isoquinolines. 2. Isoindoloquinolines, isoindoloisoquinolines. (Review)

“…Thus, the lactams are converted under acidic conditions into the corresponding isoindoloquinolines 87a-f and 79 [28,[32][33][34] and their aza analogs 87g,h [35]. The reaction takes place through the formation of the N-acyliminium cation 86.…”

“…Intramolecular alkylation, taking place through the acid-catalyzed cyclization of α-hydroxylactams, is a convenient method for the construction of condensed heterocycles [28,[32][33][34][35]. Thus, the lactams are converted under acidic conditions into the corresponding isoindoloquinolines 87a-f and 79 [28,[32][33][34] and their aza analogs 87g,h [35].…”

“…The reaction takes place through the formation of the N-acyliminium cation 86. The initial hydroxylactams 85 were synthesized by reduction of the respective lactams or by condensation of primary amines with the corresponding 3-halogen-substituted phthalic anhydrides [28,[32][33][34][35]. [29,30] described for the synthesis of compounds 87.…”

Practical Outcome of Azaphthalimide Reduction with Zn/AcOH at Various Temperatures

“…3-6)-the classes of compounds that can also exert various biological effects [8] or serve as valuable intermediates en route to more complex fused heterocyclic systems [9]. However, when we became interested in synthetic development of screening compound libraries based on these two core structures, we were faced with the surprising lack of methods described in the literature for high-yielding and chemoselective reduction of azaphthalimides (the typically used sodium borohydride often provides complex and difficult-to-separate mixtures of products [9][10][11][12], with some improvement offered by the use of a magnesium perchlorate additive [13]). Additionally, there seem to be no reports in the literature on the reductive manipulation of 5azaphthalimides.…”