Scheme 1
Scheme 2a
a Reagents and conditions: (a) (i) KOH, EtOH, reflux, 90 min;
(ii) H+, >95%. (b) Diphenylphosphoryl azide, Et3N, DMF, 0 °C
to rt. (c) MeOH, BnOH or t-BuOH, heat (6a, 59% from 4; 6b,
86% from 4; 6c, 74% from 4). (d) 10% Pd/C, 40 psi H2, MeOH,
rt, 90 min, 75%. (e) KOH, ethylene glycol, 115 °C, 90 min, 59%.
and practical synthesis for the preparation of 1-substituted
2-aminopyrrole-3-carbonitriles.
heteroaromatic aglycons have been shown to possess a
variety of biological activities. The conventional synthesis
of 5:6 [d]-fused 4-aminopyrimidines (B) is based on the
annulation of five-membered-ring o-aminonitriles. The o-
aminocyano-azoles (A) react with isocyanate equivalents
followed by a base-promoted cyclization or react with
aldehyde equivalents followed by an amination-cyclization
to afford the [d]-fused 4-aminopyrimidines, e.g., purines,
pyrazolo[3,4-d]pyrimidines, and pyrrolo[2,3-d]pyrimidines.
(Scheme 1)
However, there is one major exception, i.e., the 5,6-
unsubstituted pyrrolo[2,3-d]pyrimidines (B, X ) Y ) CH).
This 5:6 fused [d]pyrimidine ring system (Scheme 1) has in
general been synthesized from the appropriate pyrimidines
(C)18,19 instead of pyrroles, because of the lack of viable
pyrrole precursors, e.g., 1 and 2.
Our first approach was based on functional group ma-
nipulations from existing pyrrole derivatives. Ethyl 1-benzyl-
3-cyanopyrrole-2-carboxylate21 (3) was saponified to the
corresponding acid (4).21 The acid was reacted with diphe-
nylphosphoryl azide to afford the acyl azide (5), which then
underwent a Curtius rearrangement in the presence of an
excess amount of alcohols to give the corresponding car-
bamates23 (6a-c). Carbamates are widely used protecting
groups for amines, and a removal of the carbamates should
give the desired 1-benzyl-2-amino-3-cyanopyrrole (1a).24 The
desired product 1a25 was obtained from either a base
hydrolysis of 6a or a catalytic hydrogenolysis of the Cbz-
masked precursor 6b. (Scheme 2)
A direct synthesis of 2-amino-3-cyanopyrroles from acy-
clic precursors was also explored. Attempts to prepare the
(23) 1-Benzyl-2-methoxycarbonylamino-3-cyanopyrrole (6a). To a
solution of 1-benzyl-3-cyanopyrrole-2-carboxylic acid21 (4, 7.04 g, 31.12
mmol) in N,N-dimethylformamide (75 mL) at 0 °C was added diphe-
nylphosphoryl azide (DPPA, 7.65 mL, 9.72 g, 35.30 mmol, 1.1 equiv), and
triethylamine (4.75 mL, 3.42 g, 33.80 mmol, 1.1 equiv). The solution was
allowed to stir at room temperature for 6 h. Methanol (7 mL) was added,
and the reaction mixture was heated at 65 °C for 8 h. The solvents were
evaporated in vacuo, and then the resulting residue was dissolved in EtOAc
(140 mL). The solution was extracted with 1 N aqueous HCl solution (3 ×
80 mL), washed with saturated aqueous NaHCO3 solution (3 × 80 mL),
dried over anhydrous MgSO4, and then concentrated to dryness. The residue
was recrystallized from ethanol to give 6a (4.695 g, 18.39 mmol, 59%):
mp 140-142 °C (EtOH); 1H NMR (DMSO-d6, 500 MHz) δ 9.57 (bs, 1 H,
NH), 7.36-7.28 (m, 3 H), 7.16-7.15 (m, 2 H), 6.87 (d, 1 H, J ) 2.9 Hz),
6.46 (d, 1 H, J ) 3.3 Hz), 5.05 (s, 2 H), 3.63 (s, 3 H, CH3); 13C NMR
(DMSO-d6, 125 MHz) δ 155.8, 137.6, 133.6, 129.4 (CH), 128.5 (CH), 128.2
(CH), 121.3 (CH), 116.7, 110.4 (CH), 89.0, 53.3 (CH3), 50.0 (CH2); IR
(KBr, cm-1) 3281, 3141, 3125, 2226, 1735, 1679, 1570, 1507. Anal. Calcd
for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found: C, 65.94; H, 5.08;
N, 16.30.
A perusal of the literature revealed that only a few
synthetic routes had been reported for the synthesis of
2-aminopyrrole-3-carbonitriles (1) and the corresponding
3-carboxylates (2). Toja et al. has reported the synthesis of
ethyl 2-aminopyrrole-3-carboxylate, which is currently the
most feasible route toward this rather unstable pyrrole
derivative.20 2-Aminopyrrole-3-carbonitriles were anticipated
to be more stable because of the strong electron-withdrawing
effect of the 3-cyano group. However, the only routes for
preparing 2-aminopyrrole-3-carbonitriles were limited to
special orientations and required multistep elaboration from
commercially available materials.21,22 These restrictions
prompted us to initiate studies designed to provide a facile
(24) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 503-550 (7. Protection
for the Amino Group-Carbamates).
(25) 2-Amino-1-benzyl-3-cyanopyrrole (1a). Purified by flash column
chromatography (Hex/EtOAc ) 7:3, Rf ) 0.27) and recrystallized from
Hex/EtOAc: mp 104-106 °C (Hex/EtOAc); 1H NMR (CDCl3, 500 MHz)
δ 7.40-7.32 (m, 3H), 7.13-7.11 (m, 2 H), 6.24 (d, 1 H, J ) 3.4 Hz), 6.17
(d, 1 H, J ) 3.4 Hz), 4.95 (s, 2 H), 3.84 (bs, 2 H, NH2); 13C NMR (CDCl3,
125 MHz) δ 145.1, 136.2, 129.6 (CH), 128.6 (CH), 127.1 (CH), 118.1,
116.7 (CH), 108.6 (CH), 76.1, 50.0 (CH2); IR (KBr, cm-1) 3375, 3325,
2187, 1636, 1548, 1505; MS (EI/70 eV) m/z 91 (100), 197 (41) (M+); HRMS
calcd for C12H11N3 (M+) 197.0953, found 197.0952. Anal. Calcd for
C12H11N3: C, 73.07; H, 5.62; N, 21.30. Found: C, 73.00; H, 5.58; N, 21.47.
(18) Winkeler, H. D.; Seela, F. Chem. Ber. 1980, 113, 2069-2080.
(19) Duffy, T. D.; Wibberley, D. G. J. Chem. Soc., Perkin Trans. 1 1974,
1921-1929.
(20) Toja, E.; Tarzia, G.; Ferrari, P.; Tuan, G. J. Heterocycl. Chem. 1986,
23, 1555-1560.
(21) Huisgen, R.; Laschtuvka, E. Chem. Ber. 1960, 93, 65-81.
(22) Sonoda, M.; Kuriyama, N.; Tomioka, Y.; Yamazaki, M. Chem.
Pharm. Bull. 1982, 30, 2357-2363.
2858
Org. Lett., Vol. 6, No. 17, 2004