Double heteroannulation reactions of 1-naphthol with alkyl- and arylmethylidene derivatives of malononitrile dimer

Article abstract of DOI:10.1016/j.tetlet.2015.02.081

The synthesis of 7H-benzo[7,8]chromeno[2,3-b]pyridine derivatives from the reactions of arylmethylidene derivatives of malononitrile dimer with 1-naphthol is described.

Full text of DOI:10.1016/j.tetlet.2015.02.081

Accepted Manuscript
Double heteroannulation reactions of 1-naphthol with alkyl- and arylmethyli-
dene derivatives of malononitrile dimer
Ivan N. Bardasov, Anastasiya U. Alekseeva, Denis L. Mihailov, Oleg V. Ershov,
Dmitry A. Grishanov
PII:
S0040-4039(15)00362-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.081
TETL 45951
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 August 2014
12 December 2014
18 February 2015
Please cite this article as: Bardasov, I.N., Alekseeva, A.U., Mihailov, D.L., Ershov, O.V., Grishanov, D.A., Double
heteroannulation reactions of 1-naphthol with alkyl- and arylmethylidene derivatives of malononitrile dimer,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.081
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Double heteroannulation reactions of 1-naphthol with alkyl- and arylmethylidene
derivatives of malononitrile dimer
Ivan N. Bardasov,* Anastasiya U. Alekseeva, Denis L. Mihailov, Oleg V. Ershov, Dmitry A.
Grishanov

Double heteroannulation reactions of 1-naphthol with alkyl- and arylmethylidene
derivatives of malononitrile dimer
Ivan N. Bardasov a,*, Anastasiya U. Alekseeva a, Denis L. Mihailov a, Oleg V. Ershov a, Dmitry
A. Grishanov b
aUlyanov Chuvash State University, Moskovsky pr. 15, Cheboksary 428015, Russia
bKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
Leninskii prosp. 31, Moscow 119991, Russia
Abstract — The synthesis of 7H-benzo[7,8]chromeno[2,3-b]pyridine derivatives from the
reactions of arylmethylidene derivatives of malononitrile dimer with 1-naphthol is described.
Keywords: Heterocyclic compounds; Cyano compounds; One-pot reactions; Pyridine; Pyran;
Double heteroannulation reactions; Michael addition.
*
Corresponding
bardasov.chem@mail.ru.
author.
Tel.:
+79083030163;
fax:
+78352450279;
e-mail:
It is known that the reactions of α,β-unsaturated nitriles with 1-naphthols leads to 4H-
benzo[h]chromene derivatives.1 The 4H-benzo[h]chromene fragment is part of many
biologically active compounds;2 examples include: antimitotic and microtubule destabilizing
activity,1f, 2a anticancer activity,1f, 2a-c antitubercular2d-e and antimicrobial activity,2e-f and
neuroprotective activity for potential treatment of Alzheimer's disease.2g
In order to synthesize new functionally substituted 4H-benzo[h]chromenes, we have used
arylmethylidene derivatives of malononitrile dimer 1,3 reactions of which with active methylene
compounds were reported to be useful for the synthesis of fused heterocyclic structures.3,4 It was
found that the reactions of compounds 1 with 1-naphthol gave 7-aryl-8,10-diamino-7H-
benzo[7,8]chromeno[2,3-b]pyridine-9-carbonitriles 2a-f in 37-60% yields (Scheme 1 and Table
1).5
Ar
NH2
CN
CN
CN
B
Ar
+
OH
CN
CN
CN
OH
NH2
1a-f
A
Ar
NH2
Ar
NH2
N
CN
CN
CN
NH2
O
O
NH2
2a-f
B
Scheme 1. Synthesis of 7-aryl-8,10-diamino-7H-benzo[7,8]chromeno[2,3-b]pyridine-9-
carbonitriles 2a-f.
Table 1. Synthesis of 7-aryl-8,10-diamino-7H-benzo[7,8]chromeno[2,3-b]pyridine-9-
carbonitriles 2a-f.
Substrate
Ar
C6H5
2-ClC6H4
3-O2NC6H4
Product
2a
2b
Yielda (%)
52
60
56
1a
1b
1c
2c

4-FC6H4
3,4-(H3CO)2C6H3
3,4,5-(H3CO)3C6H2
50
40
37
1d
1e
1f
2d
2e
2f
a Yield of isolated product.
The first stage of the reaction is thought to involve the formation of the Michael adduct
A, which undergoes intramolecular heterocyclization to give 2-aminochromene B. The proximity
of the amino and cyano groups leads to formation a pyridine ring via intramolecular nucleophilic
addition and formation of compound 2.
In recent years, one-pot reactions have gained significant attention, and have been used
for the synthesis of poly- and heterofunctional compounds. This strategy lowers the number of
steps, as well as the reagents, thereby reducing the energy consumption of the process, and
increases the total yields of the products. The application of a one-pot synthesis (Scheme 2 and
Table 2)6,7 allowed us to use aliphatic aldehydes as substrates; the synthesis of compounds 1 with
such substrates has not been described in the literature. Compounds 1g,j were synthesized from
isobutyraldehyde and isovaleraldehyde8 in 12-62% yields. The structures of compounds 2a-k
were confirmed by IR, and NMR spectroscopy and mass spectrometry.7
Scheme 2. One pot synthesis of 7-aryl- and 7-alkyl-8,10-diamino-7H-
benzo[7,8]chromeno[2,3-b]pyridine-9-carbonitriles 2a-k.
Table 2. One pot synthesis of 7-aryl- and 7-alkyl-8,10-diamino-7H-benzo[7,8]chromeno[2,3-
b]pyridine-9-carbonitriles 2a-k.
R
C6H5
Product
2a
2b
2c
2d
2e
Yielda (%)
43
62
37
54
35
30
17
26
13
12
27
2-ClC6H4
3-O2NC6H4
4-FC6H4
3,4-(H3CO)2C6H3
3,4,5-(H3CO)3C6H2
(CH3)2CH
C3H7
CH3
(C2H5)2CH
C5H11
a Yield of isolated product.
2f
2g
2h
2i
2j
2k
An unusual Michael initiated ring closure (MIRC) reaction, which features in the process
of the tandem double ring-closing, occurs in Schemes 1 and 2.9
In summary, in this paper we have described a one-pot synthesis of new derivatives of
7H-benzo[7,8]chromeno[2,3-b]pyridine, which represents another example of the double
heteroannulation reactions of Michael adducts (DHARMA) using the malononitrile dimer.3,
4a,b,d,e, 10
Acknowledgement
This work was carried out in the framework of the baseline of the State Assignment of the
Ministry of Education and Science of the Russian Federation №872.

References and notes
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Lyshchikov, A. N. Russ. J. Org. Chem. 2014, 50, 244–250.
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5. Typical procedure for the preparation of 7-aryl-8,10-diamino-7H-benzo[7,8]chromeno[2,3-
b]pyridine-9-carbonitriles 2. A mixture of 1-naphthol (10 mmol), 2-amino-4-arylbuta-1,3-
diene-1,1,3-tricarbonitrile (1) (10 mmol) and Et2NH (11 mmol) in EtOH (10 mL) was heated
at reflux temperature with vigorous stirring for 1 h. After cooling, the resulting precipitate
was filtered and washed with EtOH. Compound 2a. mp 267-268 ºС (dec.); 1H NMR (500.13
MHz, DMSO-d6): δ 5.44 (1Н, s, СН), 6.44 (2Н, s, NН2), 6.60 (2H, s, NH2), 7.14 (1Н, t, J =
7.6 Hz, С6Н5), 7.25 (2Н, t, J = 7.6 Hz, С6Н5), 7.29 (1Н, d, J = 8.5 Hz, СН), 7.35 (2Н, d, J =
7.4 Hz, С6Н5), 7.56 (1H, t, J = 7.5 Hz, СН), 7.62 (2H, t, J = 8.4 Hz, СН), 7.89 (1H, d, J =
8.1 Hz, СН), 8.22 (1H, d, J = 8.3 Hz, СН). 13C NMR (125.76 MHz, DMSO-d6): 38.36,
71.02, 90.24, 116.35, 119.48, 120.58, 123.24, 123.47, 126.15, 126.44, 126.53, 126.59,
127.17, 127.62, 128.53, 132.58, 143.99, 145.19, 156.82, 159.04, 159.73. IR (mineral oil,
cm–1): 3459, 3342, 3291 (NH2), 2206 (CN). MS (EI, 70 eV): m/z (%) 364 [M]+ (27), 287
[M–77]+ (100). Anal. Calcd for C23H16N4O: C, 75.81; H, 4.43; N, 15.38. Found: C, 75.63;
H, 4.50; N, 15.50.
6. Typical
one-pot
procedure
for
the
preparation
7-aryl-8,10-diamino-7H-
benzo[7,8]chromeno[2,3-b]pyridine-9-carbonitriles 2. A mixture of 1-naphthol (10 mmol),
aromatic aldehyde (10 mmol) and malononitrile dimer sodium salt (10 mmol) in EtOH (10
mL) was heated at reflux temperature with vigorous stirring for 1 h. After cooling, the
resulting precipitate was filtered and washed with EtOH.
7. Typical
one-pot
benzo[7,8]chromeno[2,3-b]pyridine-9-carbonitriles 2. A mixture of 1-naphthol (10 mmol),
procedure
for
the
preparation
7-alkyl-8,10-diamino-7H-
aliphatic aldehyde (10 mmol) and malononitrile dimer sodium salt (10 mmol) in a solution

of EtOH/H2O (20%, 10 mL) was refluxed for 10 min. After cooling, the resulting precipitate
was filtered and washed with EtOH. Compound 2g. mp 276-277 ºС (dec.); 1H NMR (500.13
MHz, DMSO-d6): δ 0.55 (3Н, d, J = 6.7 Hz, СН3), 0.95 (3Н, d, J = 6.9 Hz, СН3), 1.89-1.97
(1Н, m, СН), 4.18 (1Н, d, J = 3.8 Hz, CН), 6.45 (2H, s, NH2), 6.65 (2H, s, NH2), 7.27 (1Н,
d, J = 8.4 Hz, СН), 7.54-7.61 (2Н, m, СН), 7.68 (1Н, d, J = 8.4 Hz, СН), 7.94 (1Н, d, J =
7.7 Hz, СН), 8.18 (1Н, d, J = 8.2 Hz, СН). 13C NMR (125.76 MHz, DMSO-d6): 16.98,
19.80, 33.72, 38.38, 71.00, 90.44, 116.70, 117.22, 120.43, 122.27, 123.02, 126.09, 126.19,
127.18, 127.55, 132.63, 146.56, 156.71, 159.40, 160.53. IR (mineral oil, cm–1): 3459, 3342,
3291 (NH2), 2206 (CN). MS (EI, 70 eV): m/z (%) 330 [M]+ (2), 287 [M–43]+ (100). Anal.
Calcd for C20H18N4O: C, 72.71; H, 5.49; N, 16.96. Found: C, 72.60; H, 5.62; N, 16.74.
8. Typical procedure for the preparation of 4-alkyl-2-aminobuta-1,3-diene-1,1,3-
tricarbonitriles 1. A mixture of aliphatic aldehyde (10 mmol), malononitrile dimer (10
mmol) and piperidine acetate (1 mmol) in i-PrOH (10 mL) was heated at reflux temperature
with vigorous stirring for 20 min. After cooling, cold H2O (20 mL) was added, and the
resulting precipitate was filtered, washed with H2O and then recrystallized from a mixture of
1
H2O:i-PrOH. Compound 1g. mp 158-159 ºС (dec.); H NMR (500.13 MHz, DMSO-d6): δ
1.10 (6Н, d, J = 6.6 Hz, 2СН3), 2.78-2.85 (1Н, m, CН), 7.20 (1H, d, J = 10.2 Hz, СН), 8.94
(1Н, s, NН2), 9.05 (1Н, s, NН2). IR (mineral oil, cm–1): 3382, 3338, 3220 (NH2), 2220, 2208
(CN). MS (EI, 70 eV): m/z (%) 186 [M]+ (58), 171 [M–15]+ (80). Anal. Calcd for C10H10N4:
C, 64.50; H, 5.41; N, 30.09. Found: C, 64.59; H, 5.50; N, 29.91. Compound 1j. mp 267-268
1
ºС (dec.); H NMR (500.13 MHz, DMSO-d6): δ 0.87 (6Н, t, J = 7.5 Hz, 2СН3), 1.36-1.45
(2Н, m, CН2), 1.53-1.61 (2H, m, CH2), 2.37-2.44 (1Н, m, СН), 7.12 (1Н, d, J = 10.8 Hz,
СН), 8.91 (1Н, s, NН2), 9.09 (1Н, s, NН2). IR (mineral oil, cm–1): 3327, 3181 (NH2), 2222,
2209 (CN). MS (EI, 70 eV): m/z (%) 214 [M]+ (18), 199 [M–15]+ (25), 185 [M–29]+ (39).
Anal. Calcd for C12H14N4: C, 67.27; H, 6.59; N, 26.15. Found: C, 67.34; H, 6.77; N, 25.89.
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