2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides: IV.* Synthesis of 1-alkyl(aryl)-4-amino-6-iodo-3-oxo- 1,3-dihydrofuro[3,4-c]pyridine-7- carbonitriles

Article abstract of DOI:10.1134/S107042801208012X

The reaction of sodium 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with hydroiodic acid at heating led to the formation of 1-alkyl(aryl)-4-amino-6-iodo- 3-oxo-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitriles.

Full text of DOI:10.1134/S107042801208012X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 8, pp. 1107−1110. © Pleiades Publishing, Ltd., 2012.
Original English Text © Ya.S. Kayukov, S.V. Karpov, I.N. Bardasov, O.V. Kayukova, O.V. Ershov, O.E. Nasakin, 2012, published in Zhurnal Organicheskoi
Khimii, 2012, Vol. 48, No. 8, pp. 1109−1112.
2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides: IV.*
Synthesis of 1-alkyl(aryl)-4-amino-6-iodo-3-oxo-
1,3-dihydrofuro[3,4-с]pyridine-7-carbonitriles
Ya. S. Kayukova, S. V. Karpova, I. N. Bardasova, O. V. Kayukovab,
O. V. Ershova, and O. E. Nasakina
a I.N.Ul’yanov Chuvash State University, Cheboksary, 428015 Russia
e-mail: kaukovyakov@mail.ru
b Chuvash Agriculchural Academy, Cheboksary, Russia
Received February 27, 2012
Abstract—The reaction of sodium 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with hydroiodic acid at heating led
to the formation of 1-alkyl(aryl)-4-amino-6-iodo-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitriles.
DOI: 10.1134/S107042801208012X
2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides Iа–Ig are
promising initial compounds for the synthesis of various
heterocyclic compounds [1–5]. It was shown [1] that
the reaction of propenides I with HI depending on the
applied solvent made it possible to obtain derivatives
either of pyridine II or of dihydrofurane III. In both
cases the reaction products are capable of further hetero-
cyclization providing fused systems including furan and
pyridine rings. The polyfunctional compounds based on
the furo[3,4-с]pyridine system are of interest as potential
pharmaceuticals since many among them exhibit diverse
physiological action [6–11].
a short (1–3 min) boiling of propenides Iа–Ig with concn.
HI. As a result furo[3,4-c]pyridines IVа–IVg were ob-
tained in 58–84% yields.
The structure of compounds IVа–IVg was derived
from the analysis of 1Н NMR and mass spectra and was
consistent with the data of IR spectroscopy and elemental
analysis. In the 1Н NMR spectra the amino group at the
pyridine ring gives rise to two broadened singlets in the
range 7.37–8.94 ppm. Similar pattern of signals from
the amino group was formerly described for 2-amino-6-
iodopyridines in [1]. The proton of the furan ring in the
1Н NMR spectra of the aryl and the tert-butyl derivatives
appears as a singlet in the region 5.49–6.96 ppm, and
in the spectra of compounds IVa, IVb it is observed as
a quartet and a triplet respectively. The protons of the
methylene unit in compound IVb are diastereotopic and
appear as two multiplets.
The research showed that 2-iodopyridines II did not
react with hydrogen halides, but dihydrofuranes III at
heating to boiling with hydroiodic acid underwent fast
transformation into 1-alkyl(aryl)-4-amino-6-iodo-3-
oxo-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitriles IV.
Since the dihydrofurans III formed by the reaction of
propenides I with HI in water solution we investigated
the possibility to synthesize furo[3,4-с]pyridines IV
by a direct reaction proceeding from propenides I. To
this end we studied the effect of the reaction conditions
(temperature, duration, HI concentration) in the system
propenide Iа–Ig–HI. The best results were obtained at
In this process the formation of two position isomers is
possible, IV and A, that differ by the reciprocal location
of the amino group and the iodine atom with respect to
the rest part of the molecule. In keeping with TLC and
1Н NMR spectra only one of the possible isomers forms
in the reaction, and its structure was derived from the
analysis of the 13С NMR spectrum of compound IVd.
Informative carbon signals are those of the pyridine ring
in the positions 3 and 5. According to the calculations
_______________
* For Communication III, see [1].
1107

KAYUKOV et al.
1108
H
R
O
R
O
R
O
NH2
NC
CN
I
NC
CN
NC
HI, s-C4H9OH
2HI, H2O
_I2
CN
CN CN
CN
H2N
N
Iа_Ig
IIIа_IIIg
II
H
O
H
O
H
R
R
O
R
NH2
NH2
_
H+
NC
NC
I
NH2
NH
NC
I
CN
CN
N
NH+
NH
H
I
H
H
O
O
R
R
O
R
H2O, H+
NC
H2N
NC
O
O
NH2
NC
I
NH
NH2
_NH4
+
N
I
I
N
N
IVа_IVg
A
R = CH3 (a), C2H5 (b), t-C4H9 (c), C6H5 (d), 3-ClC6H4 (e), 4-ClC6H4 (f), 2,4-Cl2C6H3 (g).
performed using the data on the effect of the functional
groups on the displacement of the chemical shifts in the
13С NMR spectra of the pyridine ring [12], the signals of
atoms С3а and С7 of compound IVd differ insignificantly
(107.4 and 107.8 ppm respectively). Analogous calcula-
tions for the alternative structure А give values 124.9
(С3а) and 90.3 ppm ( С7). In the 13С NMR spectrum of
furopyridine IVd signals 102.59 and 99.4 ppm correspond
to atoms С3а and С7 in agreement with the structure IVd.
tors, among them also on the halogen nature, and no such
studies concerned HI. Only several publications concern
the results of HI reaction with α,ω-dinitriles [15–18], also
with unsymmetrical ones [17, 18]. We believe that the
direction of the reaction depends not only on the basicity,
but also on the electrophilic properties of the cyano group.
In the dicyanomethylene fragment it is higher for on the
one hand it is less affected by the deactivating influence
of the amino group, and on the other hand two adjacent
cyano groups mutually increase the reactivity of each
other. Therefore the addition of HI occurs regioselectively
to the cyano groups of the dicyanomethylene fragment.
It is followed by the heterocyclization and isomerization
involving the formation of the aromatic system of the
pyridine ring, and the amino group at the furan ring is
converted into imino group. The latter easily hydrolyses
under the reaction conditions.
The most probable sequence of transformations con-
sists in the primary formation of a dihydrofuran interme-
diate. In this stage also the reduction takes place. This is
confirmed by the possibility to isolate dihydrofurans III
as the main reaction product if the reaction mixture is not
subjected to boiling. Thus obtained dihydrofurans III re-
act at boiling with HI converting into furo[3,4-с]pyridines
IV. In dihydrofuranе III two types of cyano groups are
present: cyano groups of the dicyanomethylene fragment
and of enaminonitrile fragment. The regioselectivity of re-
actions between α,ω-dinitriles and hydrogen halides was
investigated in [13–18]. It was suggested that the halogen
added to the cyano group bound to an sp2-hybridized
carbon atom. In [13] the regioselectivity was regarded as
related to the basicity of the cyano groups, but it was also
shown in [13] that the reaction depended on many fac-
EXPERIMENTAL
The reaction progress was monitored and the purity of
compounds synthesized was checked by TLC on Silufol
UV-254 plates (development under UV irradiation in io-
dine vapor, and at the thermal decomposition). IR spectra
were recorded from thin films or mulls in mineral oil
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 8 2012

2-ACYL(AROYL)-1,1,3,3-TETRACYANOPROPENIDES: IV
1109
on an IR Fourier spectrophotometer FSM-1202. 1Н and
13C NMR spectra were registered on a spectrometer
Bruker DRX-500 at operating frequencies 500.13 and
125.76 МHz respectively, solvent DMSO-d6, internal ref-
erence TMS. Mass spectra were obtained on an instrument
Simadzu GCMS-QP2010S DI (electron impact, 70 eV).
furo[3,4-c]pyridine-7-carbonitrile (IVd). Yield 84%,
mp 267–269°С (decomp.). IR spectrum, ν, cm–1: 3343,
3222 (NH2), 2224 (C≡N), 1755 (C=O). 1Н NMR spec-
trum, δ, ppm: 6.71 s (1H, СH), 7.35–7.37 m (2Harom),
7.42–7.46 m (3Harom), 7.66 s (1H, NH2), 8.88 s (1H,
NH2). 13С NMR spectrum, δ, ppm: 80.87 (С1), 99.40
(С7), 102.59 (С3а), 116.42 (СN), 128.35 (o-Ph), 128.85
(m-Ph), 129.89 (p-Ph), 130.62 (С6), 133.01 (Ph), 155.88
(С7а), 163.79 (С4), 167.99 (С3). Mass spectrum, m/z (Irel,
%): 278 (2) [M + 1]+, 277 (10) [M]+, 250 (4), 127 (48),
116 (27), 105 (40), 90 (12). Found, %: C 44.81; H 2.28;
N 11.24. C14H8IN3O2. Calculated, %: C 44.59; H 2.14;
N 11.14. М 376.97.
4-Amino-6-iodo-1-methyl-3-oxo-1,3-dihydro-
furo[3,4-c]pyridine-7-carbonitrile (IVа). With 15 ml
of concn. HI was thoroughly triturated 1.03 g (5 mmol)
of propenide Iа, then the reaction mixture was heated at
100°С for 1–3 min, the mixture was cooled and diluted
with 10 ml of cold water. The separated oily substance
was isolated by decanting and triturated at heating with
10 ml of ethanol. The dispersion obtained was filtered,
the precipitate was washed with ethanol till the removal
of iodine, then it was recrystallized from glacial actic acid
(25 ml). Yield 1.23 g (78%), mp 244–246°С. IR spectrum,
ν, cm–1: 3342, 3261 (NH2), 2223 (CN), 1748 (C=O).
1Н NMR spectrum, δ, ppm: 1.57 д (3H, CH3, 3J 6.8 Hz),
5.74 к (1H, CH, 3J 6.8 Hz), 7.55 s (1Н, NH2), 8.79 s (1Н,
NH2). Mass spectrum, m/z (Irel, %): 316 (9) [M]+, 315
(89) [M]+, 188 (57) [M – I]+, 127 (76) [I]+, 117 (58), 90
(100). Found, %: C 34.72; H 1.95; N 13.79. C9H6IN3O2.
Calculated, %: C 34.31; H 1.92; N 13.34. М 314.95.
4-Amino-1-(3-chlorophenyl)-6-iodo-3-oxo-1,3-
dihydrofuro[3,4-c]pyridine-7-carbonitrile (IVe). Yield
(71%), mp 244–246°С (decomp.). IR spectrum, ν, cm–1:
3371, 3211 (NH2), 2221 (C≡N), 1753 (C=O). 1Н NMR
spectrum, δ, ppm: 6.73 s (1H, СH), 7.37 д (1Harom, 3J 7.7
Hz), 7.47 t (1H, C6H4, 3J 7.7 Hz), 7.53–7.55 m (1Harom),
7.67 s (1H, NH2), 8.90 (1H, NH2). Mass spectrum, m/z
(Irel, %): 413 (2) 411 (6) [M]+, 213 (15), 178 (23), 177
(20), 151 (28), 139 (48), 127 (59), 116 (22), 113 (35),
111 (71), 90 (36), 75 (100). Found, %: C 40.48; H 1.69;
N 10.17. C14H7ClIN3O2. Calculated, %: C 40.85; H 1.71;
N 10.21. М 410.93.
Compounds IVb–IVg were obtained similarly.
4-Amino-1-(4-chlorophenyl)-6-iodo-3-oxo-1,3-
dihydrofuro[3,4-c]pyridine-7-carbonitrile (IVf). Yield
(68%), mp 220–224°С (decomp.). IR spectrum, ν, cm–1:
3369, 3231 (NH2), 2221 (C≡N), 1754 (C=O). 1Н NMR
spectrum, δ, ppm: 6.74 s (1H, СH), 7.44 m (АА'BB',
2Нarom, 3J 8.4 Hz), 7.51 m (АА'BB', 2Нarom, 3J 8.4 Hz),
7.68 s (1H, NH2), 8.89 (1H, NH2). Mass spectrum, m/z
(Irel, %): 413 (3) 411 (8) [M]+, 151 (19), 139 (36), 127
(63), 116 (12), 113 (25), 111 (63), 90 (21). Found, %:
C 40.78; H 1.73; N 10.24. C14H7ClIN3O2. Calculated,
%: C 40.85; H 1.71; N 10.21. М 410.93.
4-Amino-1-ethyl-6-iodo-3-oxo-1,3-dihydrofuro-
[3,4-c]pyridine-7-carbonitrile (IVb). Yield 67%, mp
238–240°С. IR spectrum, ν, cm–1: 3326, 3204 (NH2),
1
2225 (C≡N), 1750 (C=O). Н NMR spectrum, δ, ppm:
3
0.88 t (3H, CH3, J 7.3 Hz), 1.76–1.86 m (1H, CH2),
2.21–2.22 m (1H, CH2), 5.69 d.d (1H, CH, 3J 7.3, 3.4 Hz),
7.56 с (1H, NH2), 8.79 с (1H, NH2). Mass spectrum,
m/z (Irel, %): 330 (9) [M + 1]+, 329 (94) [M]+, 301 (6)
[M – 28]+, 300 (99) [M – 29]+, 127 (95) [I]+, 116 (47),
117 (44), 90 (85), 55 (100). Found, %: C 36.61; H 2.53;
N 12.81. C10H8IN3O2. Calculated, %: C 36.50; H 2.45;
N 12.77. М 328.97.
4-Amino-1-(2,4-dichlorophenyl)-6-iodo-3-oxo-1,3-
dihydrofuro[3,4-c]pyridine-7-carbonitrile (IVg). Yield
(58%), mp 290–292°С (decomp.). IR spectrum, ν, cm–1:
3372, 3211 (NH2), 2222 (C≡N), 1751 (C=O). 1Н NMR
spectrum, δ, ppm: 6.96 s (1H, СH), 7.43 br.s (1H, NH2),
7.50–7.51 m (1Нarom), 7.74 s (1Нarom), 7.81 s (1H, 1Нarom),
8.94 (1H, NH2). Mass spectrum, m/z (Irel, %): 449 (1),
448 (1), 447 (10) 446 (2), 445 (15) [M]+, 177 (17), 176
(23), 175 (33), 173 (53), 148 (23), 147 (45), 146 (13),
145 (58), 127 (100), 117 (51), 116 (73), 90 (19). Found,
%: C 37.75; H 1.41; N 9.29. C14H6Cl2IN3O2. Calculated,
%: C 37.70; H 1.36; N 9.42. М 444.89.
4-Amino-1-(tert-butyl)-6-iodo-3-oxo-1,3-
dihydrofuro[3,4-c]pyridine-7-carbonitrile (IVc).
Yield 73%, mp 236–238°С (decomp.). IR spectrum, ν,
cm–1: 3251 (NH2), 2223 (C≡N), 1752 (C=O). 1Н NMR
spectrum, δ, ppm: 0.98 s [9H, С(CH3)3], 5.49 s (1H, CH),
7.57 s (1Н, NH2), 8.80 s (1Н, NH2). Mass spectrum, m/z
(Irel, %): 357 (3) [M]+, 301 (21), 173 (5), 116 (8), 117 (7),
90 (11), 57 (100). Found, %: C 40.73; H 3.41; N 11.83.
C12H12IN3O2. Calculated, %: C 40.36; H 3.39; N 11.77.
М 357.00.
4-Amino-6-iodo-3-oxo-1-phenyl-1,3-dihydro-
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KAYUKOV et al.
9. Abe, H.,Arai,Y.,Aoyagi, S., and Kibayashi, C., Tetrahedron
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