Synthesis of functionalized pyrazines and quinoxalines from Nef-isocyanide adducts and 1,2-diamines

Article abstract of DOI:10.1002/hlca.201100299

Alkyl 3-(alkylamino)-5,6-dicyanopyrazine-2-carboxylates and alkyl 3-(alkylamino)quinoxaline-2-carboxylates were obtained in good yields by treatment of Nef-isocyanide adducts with 1,2-diamines in MeCN. Copyright

Full text of DOI:10.1002/hlca.201100299

Helvetica Chimica Acta – Vol. 95 (2012)
169
Synthesis of Functionalized Pyrazines and Quinoxalines from Nef-Isocyanide
Adducts and 1,2-Diamines
by Issa Yavari*, Ramin Pashazadeh, and Reza Hosseinpour
Chemistry Department, Tarbiat Modares University, P.O. Box 14115 – 175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
Alkyl 3-(alkylamino)-5,6-dicyanopyrazine-2-carboxylates and alkyl 3-(alkylamino)quinoxaline-2-
carboxylates were obtained in good yields by treatment of Nef-isocyanide adducts with 1,2-diamines in
MeCN.
Introduction. – The synthetic interest in isocyanides is traditionally associated with
their interaction with aldehydes and ketones as disclosed in the Ugi and Passerini
reactions [1][2]. Discovered much earlier by Nef [3], the reaction of isocyanides with
acyl chlorides is, however, less documented [4 – 7]. This reaction gives imidoyl chloride
intermediates, which can be either hydrolyzed to ketoamides or trapped to form
various cyclic adducts [4]. In contrast to the Ugi and Passerini reactions, the interaction
between isocyanides and acyl chlorides often requires heating to give adducts in
moderate yields [8]. More efficient Nef-type reactions could be accomplished with
highly electrophilic acid derivatives such as trifluoroacetic anhydride [9] or acyl
bromides, which were shown to be more reactive than the corresponding chlorides [10].
Results and Discussion. – As part of our current studies on the development of new
routes to synthesis of imidoyl chlorides [11 – 14] and quinoxalines [15], here we report a
new one-pot synthesis of pyrazines and quinoxalines with imidoyl chloride intermedi-
ates. Thus, the Nef isocyanide adducts 3, obtained from alkyl chlorooxalates 1 with
isocyanides 2, reacts at room temperature with 2,3-diaminomaleonitrile (¼(Z)-2,3-
diaminobut-2-enedinitrile; 4) and benzene-1,2-diamine (5) to give alkyl 3-(alkyl-
amino)-5,6-dicyanopyrazine-2-carboxylates 6 and alkyl 3-(alkylamino)quinoxaline-2-
carboxylates 7 in moderate-to-good yields (Scheme 1 and Table).
1
The structures of compounds 6 and 7 were deduced from their IR, and H- and
1
13C-NMR data. For example, the H-NMR spectrum of 6a in CDCl3 exhibited three
singlets readily recognized as arising from tBu (d(H) 1.50), MeO (d(H) 3.98), and NH
(d(H) 8.91) H-atoms. The 1H-decoupled 13C-NMR spectrum of 6a exhibited ten signals
in agreement with the proposed structure. The 1H- and 13C-NMR spectra of 6b – 6d are
similar to those for 6a, except for the signals of the alkyl groups.
A plausible pathway may be proposed to rationalize product formation (Scheme 2).
Presumably, the Nef isocyanide adduct 3, formed from acid chloride 1 and isocyanide 2,
is attacked by 4 to form the intermediate 8, which then undergoes an intramolecular
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

170
Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1
Table. Conversions of 4 and 5 to 6 and 7, Respectivelya)
Amine
R
Rꢂ
Product
Yield [%]
4
4
4
4
5
5
5
Me
Me
Et
Et
Et
t-Bu
Cyclohexyl
t-Bu
Cyclohexyl
Cyclohexyl
t-Bu
6a
6b
6c
6d
7a
7b
7c
57
72
75
86
84
72
62
Et
Me
Cyclohexyl
a) For the reaction, see Scheme 1.
Scheme 2
cyclization reaction to afford 9. This intermediate is converted to 6 by H-atom shift and
elimination of H2O.
In summary, we have developed a simple, one-pot synthesis of functionalized 3-
(alkylamino)-5,6-dicyanopyrazines and 3-(alkylamino)quinoxalines by treatment of
Nef isocyanide adducts with 1,2-diamines in MeCN. Short reaction times and readily
available starting materials are the main advantages of this protocol.

Helvetica Chimica Acta – Vol. 95 (2012)
171
Experimental Part
General. All chemicals were obtained commercially and used without further purification. M.p.:
Electrothermal-9100 apparatus. IR Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR
spectra: Bruker DRX-500 Avance instrument at 500.1 and 125.7 MHz, resp.; d in ppm, J in Hz. MS:
Finnigan-MAT-8430EI-MS mass spectrometer; at 70 eV; in m/z (rel. %). Elemental analyses: Vario EL
III CHNOS elemental analyzer.
General Procedure for Synthesis of Compounds 6 and 7. Isocyanide 2 (1.0 mmol) was added to acyl
chloride 1 (1 mmol) under solvent-free conditions at r.t., and the mixture was stirred for 10 min, then
MeCN (2 ml) and 1,2-diamine (4 or 5, 1 mmol) were added. The mixture was stirred for 2 – 4 h at r.t. and
then concentrated under reduced pressure. The crude compound was purified by flash column
chromatography (hexane/AcOEt 4 :1) to give the product.
Methyl 3-[(tert-Butyl)amino]-5,6-dicyanopyrazine-2-carboxylate (6a). Yellow powder. Yield: 0.15 g
(57%). M.p. 175 – 1778. IR (KBr): 3329 (NH); 2354, 2223 (CN), 1704 (C¼O). 1H-NMR: 1.50 (s, t-Bu);
3.98 (s, MeO); 8.91 (s, NH). 13C-NMR: 29.6 (Me3C); 55.2 (Me3C); 55.3 (MeO); 114.4 (CN); 115.0 (CN);
118.6 (C); 129.0 (C); 136.0 (C); 154.2 (C); 166.4 (C¼O). EI-MS: 259 (5, Mþ), 244 (65), 212 (24), 184
(57), 170 (14), 77 (28), 59 (47), 57 (100). Anal. calc. for C12H13N5O2 (259.11): C 55.59, H 5.05, N 27.01;
found: C 55.80, H 5.21, N 26.87.
Methyl 5,6-Dicyano-3-(cyclohexylamino)pyrazine-2-carboxylate (6b). Yellow powder. Yield: 0.20 g
(72%). M.p. 135 – 1378. IR (KBr): 3329 (NH); 2223, 2354 (CN); 1704 (C¼O), 1204. 1H-NMR: 1.27 – 2.02
(m, 5 CH2); 4.03 (s, MeO); 4.06 – 4.08 (m, CHN); 8.73 (d, J ¼ 6.3, NH). 13C-NMR: 24.3 (2 CH2); 25.1
(CH2); 31.9 (2 CH2); 50.2 (CH); 53.7 (MeO); 113.0 (CN); 113.6 (CN); 117 (C); 127.2 (C); 135.6 (C);
152.5 (C); 164.8 (C¼O). EI-MS: 285 (23, Mþ), 270 (1), 242 (35), 228 (100), 210 (39), 196 (29), 182 (32),
155 (9), 81 (38), 55 (86). Anal. calc. for C14H15N5O2 (285.12): C 58.94, H 5.30, N 24.55; found: C 59.18, H
5.53, N 24.26.
Ethyl 3-[(tert-Butyl)amino]-5,6-dicyanopyrazine-2-carboxylate (6c). Yellow powder. Yield: 0.20 g
(75%). M.p. 170 – 1728. IR (KBr): 3323 (NH), 2228 (CN), 1699 (C¼O), 1206. 1H-NMR: 1.43 (t, J ¼ 7.1,
Me); 1.50 (s, t-Bu); 4.44 (q, J ¼ 7.1, CH2O); 8.94 (s, NH). 13C-NMR: 15.4 (Me); 29.6 (Me3C); 55.2
(Me3C); 64.8 (CH2O); 114.5 (CN); 115.1 (CN); 118.6 (C); 129.4 (C); 135.8 (C); 154.2 (C); 166.0 (C¼O).
EI-MS: 273 (12, Mþ), 258 (53), 212 (17), 184 (20), 170 (8), 69 (12), 57 (100). Anal. calc. for C13H15N5O2
(273.12): C 57.13, H 5.53, N 25.63; found: C 56.87, H 5.41, N 25.82.
Ethyl 5,6-Dicyano-3-(cyclohexylamino)pyrazine-2-carboxylate (6d). Yellow powder. Yield: 0.25 g
(86%). M.p. 154 – 1568. IR (KBr): 3330 (NH), 2355, 2226 (CN), 1693 (C¼O), 1196. 1H-NMR: 1.47 – 1.99
(m, 5 CH2); 1.42 (t, J ¼ 7.1, Me); 4.05 (m, CHN); 4.43 (q, J ¼ 7.1, CH2O); 8.76 (d, J ¼ 6.8, NH).
13C-NMR: 14.0 (Me); 24.2 (2 CH2); 25.3 (CH2); 31.9 (2 CH2); 50.1 (CH); 63.2 (CH2O); 113.0 (CN); 113.6
(CN); 117.2 (C); 127.5 (C); 135.4 (C); 152.5 (C); 164.4 (C¼O). EI-MS: 299 (21, Mþ), 270 (13), 242 (91),
210 (20), 170 (42), 81 (37), 69 (44), 55 (100). Anal. calc. for C15H17N5O2 (299.14): C 60.19, H 5.72, N
23.40; found: C 60.32, H 5.84, N 23.15.
Ethyl 3-(Cyclohexylamino)quinoxaline-2-carboxylate (7a). Pale yellow powder. Yield: 0.25 g (84%).
M.p. 89 – 918. IR (KBr): 3357 (NH), 1690 (C¼O), 1458, 1214. 1H-NMR: 1.37 – 2.08 (m, 5 CH2); 1.44 (t,
J ¼ 7.1, Me); 4.14 – 4.20 (m, CH); 4.49 (q, J ¼ 7.1, CH2O); 7.28 (t, J ¼ 8.2, CH); 7.54 (t, J ¼ 8.3, CH); 7.60
(d, J ¼ 8.4, CH); 7.90 (d, J ¼ 8.3, CH); 7.94 (d, J ¼ 7.3, NH). 13C-NMR: 15.6 (Me); 26.1 (2 CH2); 27.2
(CH2); 33.9 (2 CH2); 50.0 (CH); 63.8 (CH2O); 124.9 (C); 125.7 (CH); 127.4 (CH); 131.6 (CH); 133.8
(CH); 136.8 (C); 145.8 (C); 152.7 (C); 167.6 (C¼O). EI-MS: 299 (22, Mþ), 242 (16), 170 (50), 155 (11),
145 (100), 129 (30), 81 (22), 69 (65), 55 (74). Anal. calc. for C17H21N3O2 (299.16): C 68.20, H 7.07, N
14.04; found: C 67.94, H 7.21, N 13.92.
Ethyl 3-[(tert-Butyl)amino]quinoxaline-2-carboxylate (7b). Pale yellow powder. Yield: 0.19 g
1
(72%). M.p. 80 – 828. IR (KBr): 3364 (NH), 1698 (C¼O), 1460, 1212. H-NMR: 1.46 (t, J ¼ 7.0, Me);
1.52 (s, t-Bu); 4.49 (q, J ¼ 7.0, CH2O); 7.31 (t, J ¼ 7.8, CH); 7.57 (t, J ¼ 7.35, CH); 7.65 (d, J ¼ 8.0, CH);
7.91 (d, J ¼ 8.3, CH); 8.05 (s, NH). 13C-NMR: 15.6 (Me); 30.1 (Me3C); 53.2 (Me3C); 63.8 (CH2O); 125.8
(CH); 127.8 (CH); 131.6 (CH); 131.9 (C); 133.7 (CH); 136.5 (C); 145.2 (C); 153.1 (C); 167.8 (C¼O). EI-
MS: 273 (6, Mþ), 184 (39), 170 (23), 141 (51), 125 (29), 83 (84), 69 (29), 57 (100). Anal. calc. for
C15H19N3O2 (273.33): C 65.91, H 7.01, N 15.37; found: C 66.08, H 7.14, N 15.46.

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Helvetica Chimica Acta – Vol. 95 (2012)
Methyl 3-(Cyclohexylamino)quinoxaline-2-carboxylate (7c). Pale yellow powder. Yield: 0.17 g
(62%). M.p. 115 – 1178. IR (KBr): 3433 (NH), 1691 (C¼O). 1H-NMR: 1.24 – 2.09 (m, 5 CH2); 4.22 – 4.24
(m, CH); 4.05 (s, MeO); 7.17 – 7.91 (m, CH); 7.93 (d, J ¼ 8.4, NH). 13C-NMR: 24.6 (2 CH2); 25.8 (CH2);
32.5 (2 CH2); 53.2 (CH); 54.0 (MeO); 124.5 (C); 125.0 (CH); 127.5 (CH); 130.1 (CH); 133.1 (CH); 136.3
(C); 145.1 (C); 153.4 (C); 167.5 (C¼O). EI-MS: 285 (4, Mþ), 228 (4), 129 (12), 118 (27), 97 (16), 81 (42),
69 (100), 56 (95). Anal. calc. for C16H19N3O2 (285.15): C 67.35, H 6.71, N 14.73; found: C 67.18, H 6.84, N
14.91.
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Received July 26, 2011