Alcohol-Initiated Dinitrile Cyclization in Basic Media: A Route Toward Pyrazino[1,2-a]indole-3-Amines

Alexey A. Festa; Nikita E. Golantsov; Olga A. Storozhenko; Alexey N. Shumsky; Alexey V. Varlamov; Leonid G. Voskressensky

doi:10.1055/s-0036-1591529

Synlett, Table of Contents

Synlett 2018; 29(07): 898-903
DOI: 10.1055/s-0036-1591529

letter

Alcohol-Initiated Dinitrile Cyclization in Basic Media: A Route Toward Pyrazino[1,2-a]indole-3-Amines

Authors

Alexey A. Festa

^aPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russian Federation Email: lvoskressensky@sci.pfu.edu.ru
Nikita E. Golantsov

^aPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russian Federation Email: lvoskressensky@sci.pfu.edu.ru
Olga A. Storozhenko

^aPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russian Federation Email: lvoskressensky@sci.pfu.edu.ru
Alexey N. Shumsky

^bN. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences (IBCP), Kosygin St., 4, 119334 Moscow, Russian Federation
Alexey V. Varlamov

^aPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russian Federation Email: lvoskressensky@sci.pfu.edu.ru
Leonid G. Voskressensky *

^aPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russian Federation Email: lvoskressensky@sci.pfu.edu.ru

Abstract

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Abstract

A selective route to the formation of 1-alkoxypyrazino[1,2-a]indole-3-amines through alcohol-initiated dinitrile cyclization, starting from N-(cyanomethyl)indole-2-carbonitriles under basic conditions, was discovered. The resulting compounds were shown to be unstable in solution, and a three-component reaction of the dinitrile, alcohol, and aromatic aldehyde was used to overcome the problem.

Key words

pyrazinoindoles - cyclization - dinitriles - domino reaction - multicomponent reaction - transition-metal free

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References

References and Notes
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38 1-Methoxypyrazino[1,2-a]indole-3-amine (3a); Typical Procedure Na₂CO₃ (2.0 mmol) was added to a stirred solution of dinitrile 2a (1.0 mmol) in MeOH (2.5 mL) at reflux, and the mixture was vigorously stirred at reflux for 1 h. The mixture was then cooled to r.t. and the resulting precipitate was collected by filtration, washed with H₂O (3 × 10 mL), and dried in air to give a yellow solid; yield: 0.170 g (80%); mp 134 °С (dec.). IR (KBr): 3377; 3272 cm^–1. ¹H NMR (600 MHz, DМSО-d ₆): δ = 4.04 (s, 3 H, OMe), 4.93 (s, 2 H, NH₂), 6.84 (s, 1 H, H-10), 7.23–7.25 (m, 2 H, H-7, H-8), 7.47 (s, 1 H, H-4), 7.76–7.78 (m, 1 H, H-6), 7.90–7.91 (m, 1 H, H-9). ¹³C NMR (150 MHz, DМSО-d ₆): δ = 53.8 (OCH₃), 90.8 (C-4), 92.1 (C-10), 111.9 (C-9), 120.7 (C-10a), 121.4 (C-8), 122.3 (C-7), 122.4 (C-6), 127.4 (C-9a), 129.7 (C-5a), 140.8 (C-3), 155.7 (C-1). ESI-MS: m/z = 214 [M + H]⁺. Anal. Calcd for C₁₂H₁₁N₃O (213.09): C 67.59; H 5.20; N 19.71. Found: C 67.45; H 5.23; N 19.62.
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40 2-{(E)-[(1-Ethoxypyrazino[1,2-a]indol-3-yl)imino]methyl}phenol (4d); Typical Procedure A solution of dinitrile 1a (1 mmol, 181 mg) and salicylaldehyde (0.83 mmol, 0.088 mL) in EtOH (5 mL) at reflux was treated with K₂CO₃ (2 mmol, 276 mg). After 3 h of vigorous stirring at reflux, the precipitate was collected by filtration, washed with H₂O (3 × 10 mL) and EtOH (1 mL), and dried in air to give a yellow solid; yield: 173 mg (63%); mp 199 °С. IR (KBr): 3430, 3336 cm^–1. ¹H NMR (600 MHz, DMSO-d ₆): δ = 1.47 (t, J = 7.1, 3 H), 4.67 (q, J = 7.1, 2 H), 6.92–6.97 (m, 2 H), 7.10 (s, 1 H), 7.32–7.41 (m, 3 H), 7.66 (dd, J = 7.7, 1.5, 1 H), 7.85 (d, J = 7.7, 1 H), 8.29 (d, J = 8.1, 1 H), 8.85 (s, 1 H), 9.36 (s, 1 H), 12.97 (s, 1 H). ¹³C NMR (150 MHz, DМSО-d ₆): δ = 14.8, 62.8, 96.7, 110.8, 112.7, 117.1, 119.7, 120.3, 122.7, 122.9, 123.3, 124.1, 128.6, 132.2, 132.6, 132.9, 137.2, 155.8, 158.6, 160.4. ESI-MS: m/z = 332 [M + H]⁺. Anal. Calcd for C₂₀H₁₇N₃O₂ (331.37): C 72.49; H 5.17; N 12.68. Found: C 72.31; H 5.14; N 12.45.
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42 X-ray diffraction data for 4d were collected on a Bruker APEX DUO diffractometer [λ(MoKα) = 0.71073 Å, ω-scans, 2θ < 56°]. Yellow crystals of C₂₀H₁₇N₃O₂ at 120(2) K are monoclinic, space group P2₁/c, a = 17.855(3), b = 5.7930(8), c = 15.267(2) Å, β = 96.335(3)°, V = 1569.5(4) Å3, Z = 4 (Z′ = 1), d_calc = 1.402 g cm^–3. Intensities of 3789 independent reflections (R_int = 0.0876) out of 17025 collected were used in structure solution and refinement. The structure was solved by direct methods and refined by the full-matrix least-squares technique against F² in anisotropic approximation. The hydrogen atom connected to the oxygen atom was found from difference Fourier synthesis and refined isotropically. Other hydrogen atoms were placed in calculated positions and refined in the riding model with U_iso(H) equal to 1.5 U_eq(Cm) and 1.2 U_eq(Ci) of the connected methyl and other carbon atoms. The refinement converged to R₁ = 0.0499 [calculated for 2473 observed reflections with I > 2σ(I), wR₂ = 0.1015, and GOF = 0.999]. All calculations were performed with the SHELX software package (see Ref. 43). Atomic coordinates, bond lengths and angles, and thermal parameters have been deposited at the Cambridge Crystallographic Data Center with the accession number CCDC 1580729, and can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures.
43 Sheldrick GM. Acta Crystallogr., Sect. C 2015; 71: 3

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