New HA 14-1 analogues: Synthesis of 2-amino-4-cyano-4H-chromenes

Article abstract of DOI:10.1016/j.tetlet.2010.09.090

The synthesis of 2-amino-4-cyano-4H-chromene derivatives as new HA 14-1 analogues by a simple and efficient method is reported. In addition, the reaction of 2-amino-2H-chromene-3-carbonitriles, salicylaldehydes and amines results in the formation of new c

Full text of DOI:10.1016/j.tetlet.2010.09.090

Tetrahedron Letters 51 (2010) 6270–6274
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Tetrahedron Letters
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New HA 14-1 analogues: synthesis of 2-amino-4-cyano-4H-chromenes
⇑
Leila Moafi, Somayeh Ahadi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2-amino-4-cyano-4H-chromene derivatives as new HA 14-1 analogues by a simple and
efficient method is reported. In addition, the reaction of 2-amino-2H-chromene-3-carbonitriles, salicylal-
dehydes and amines results in the formation of new chromeno[2,3-d]pyrimidine derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 June 2010
Revised 28 August 2010
Accepted 20 September 2010
Available online 15 October 2010
Keywords:
Multicomponent
Chromene
Malononitrile
Chromeno[2,3-d]pyrimidine
Salicylaldehyde
Multicomponent reactions (MCRs), in which multiple reactions
are combined into a single synthetic operation have been used
extensively to form carbon–carbon bonds in synthetic chemistry.1,2
Such reactions offer a wide range of possibilities for the efficient
construction of highly complex molecules in a single step, thus
avoiding complicated purification operations and allowing savings
of both solvents and reagents.3,4 Heterocycles containing the chro-
mene moiety show interesting features that make them attractive
targets for MCRs.
Therefore, numerous studies have reported the synthesis of new
analogues of HA 14-1 (see general structure, Fig. 1).16–19
Multicomponent reactions of salicylaldehydes, malononitrile
and various nucleophiles have attracted the interest of researchers
in order to prepare different analogues of HA 14-1. The synthesis
of indolyl chromenes was reported by Shanthi and Perumal using in-
doles as the nucleophiles.20 A recent publication described the prep-
aration of new chromene phosphonic acid diethyl esters by reaction
of salicylaldehydes, malononitrile and triethyl phosphite.21
Chromenes constitute a major class of naturally occurring com-
pounds, and interest in their chemistry continues because of their
utility as biologically active agents.5,6 They occur widely in plants,
including edible vegetables and fruits.7 Synthetic chromene ana-
logues have been developed over the years, and some of them have
been employed as pharmaceuticals,8 including antifungal9 and
antimicrobial agents.10 2-Aminochromenes are employed as pig-
ments,11 cosmetics, agrochemicals12 and are major constituents
of many natural products.
As part of our program aimed at developing new methods for
the preparation of heterocyclic compounds,22–30 we report an effi-
cient and simple synthesis of new analogues of HA 14-1.
Iminochromenes 3a–n were prepared via Knoevenagel conden-
sation of salicylaldehydes 1a–g and malononitrile (2a) or cyanoacet-
amide (2b) using the known procedure.31,32 In order to prepare new
HA 14-1 analogues, we carried out the reaction of iminochromenes
3a–n with trimethylsilyl cyanide (4) (TMSCN) in the presence of
LiClO4 (15 mol %) as the catalyst which afforded 2-amino-4-cyano-
Recently, 4H-chromene (1, Fig. 1) (HA 14-1) was discovered,
and was found to display binding activity for the surface pocket
of the Bcl-2 protein (IC50 = 9 lM) and it induces apoptosis of tumor
R2
EtO2C
CN
cells.13 Bcl-2 and a family of related proteins regulate apoptosis or
programmed cell death, and are implicated in a number of human
diseases such as cancer.14,15 Specifically, Bcl-2 can contribute to
neoplastic cell expansion by preventing normal cell turnover
caused by physiological cell death mechanisms. The discovery of
Bcl-2 binding compound 1 provides a promising lead for the
development of new analogues as potential anti-cancer agents.
R3
Br
CO2Et
NH2
R1
O
NH2
O
New synthetic targets
(1)
HA 14-1
⇑
Corresponding author. Tel.: +98 21 29903104; fax +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
Figure 1. HA 14-1 and designed analogues.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.090

L. Moafi et al. / Tetrahedron Letters 51 (2010) 6270–6274
6271
CN
Y
Refs 31
and 32
Y
CHO
Y
X
TMSCN (4)
X
+
NC
X
OH
LiClO4 (15 mol%)
EtOH
O
NH
O
NH2
60-83%
X=CN
X= CONH2 2b
2a
83-93%
5a-n
1a-g
3a-n
Scheme 1.
Table 1
Two-step synthesis of 2-amino-4-cyano-4H-chromenes 5
Table 1 (continued)
Yielda
(%)
Yieldb
(%)
Entry Product
Time
(h)
Yielda
(%)
Yieldb
(%)
Entry Product
Time
(h)
CN
CN
Me
CN
NH
CONH2
1
3
93
89
87
85
82
80
87
83
12
5
80
81
78
47
44
41
O
O
NH2
2 5a
5l
OMe
CN
CN
Br
CN
NH
CONH2
NH2
2
3.5
13
4.5
O
O
2 5b
5m
CN
CN
O2N
CN
CONH2
NH2
3
4
14
4
O
NH2
O
MeO
5c
5n
CN
a
Two-step method.
Three-component method.
MeO
b
CN
NH
4
7
O
2 5d
4H-chromenes 5a–n in good yields after 3–7 h in EtOH at room tem-
perature (Scheme 1). The results are summarised in Table 1.
To develop a one-pot, three-component synthesis of 2-amino-4-
cyano-4H-chromenes 5a–n, we studied the reaction of salicylalde-
hydes 1a–g, malononitrile (2a) or cyanoacetamide (2b) and TMSCN
(4) under similar conditions (LiClO4, EtOH) (Scheme 2).33 As indi-
cated in Table 1, the desired products were obtained in good yields
with 2a, and moderate yields with 2b after 24 h. It is noteworthy
that without LiClO4 the products were obtained in only trace
amounts, even after 48 h.
The nature of these compounds as 1:1:1 adducts was apparent
from their mass spectra, which displayed, in each case, the molec-
ular ion peak at appropriate m/z values. Compounds 5a–n are sta-
ble solids the structures of which were established by IR, 1H and
13C NMR spectroscopy and elemental analysis.
CN
Me
CN
NH
5
6
6
5
3
83
80
77
91
80
79
73
49
O
2 5e
CN
Br
CN
6
O
NH2
5f
CN
O2N
CN
7
O
NH
2 5g
CN
To further explore the potential of this three-component proto-
col for fused aminochromene synthesis, we replaced salicylalde-
hyde 1 with 2-hydroxynaphthalene-1-carboxaldehyde (6) and
obtained 3-amino-1H-benzo[f]chromenes 7a, and b as the prod-
ucts in good yields (Scheme 3).
CONH2
NH2
8
O
5h
OMe
CN
To the best of our knowledge, this procedure provides the first
example of an efficient and three-component synthesis of 2-ami-
no-4-cyano-4H-chromenes.
Mechanistically, it is reasonable to assume that product 5 re-
sults from initial Knoevenagel condensation of salicylic aldehydes
1 and cyano compound 2 and subsequent Pinner reaction (8?9).
Next, the resulting intermediate 9 could be attacked by TMSCN 4
to produce the product 5 (Scheme 4).21
During our investigation on the synthesis of new chromene
derivatives, we found that reaction of 2-imino-2H-chromene-3-car-
bonitrile (3a), salicylaldehyde (1a) and amines 10a–e, under similar
conditions, afforded 2-[4-(alkylamino)-5H-chromeno[2,3-b]pyrim-
idin-2-yl]phenols 11a–e in good yields after 15 h (Table 2).34
Although we have not established an exact mechanism for the
formation of chromenopyridines 11, a possible explanation is pro-
CONH2
9
5
5
6
83
85
88
50
48
51
O
NH2
CN
5i
CONH2
NH2
10
O
MeO
5j
CN
MeO
CONH2
NH2
11
O
5k

6272
L. Moafi et al. / Tetrahedron Letters 51 (2010) 6270–6274
CN
O
Y
CHO
Y
X
LiClO4 (15 mol%)
EtOH, 24 h
+
NC
X
+ TMSCN
OH
NH2
1
2
4
5
Scheme 2.
Table 2
Synthesis of 2-(chromenopyrimidin-2-yl)phenols 11
NR2
CN
CHO
LiClO4 (15 mol%)
EtOH, 15 h
N
OH
+
NH
R2NH
+
O
OH
O
N
3a
1a
10a-e
11a-e
Entry
1
Product
Yield (%)
NMe2
N
OH
74
O
N
11a
11b
N
N
2
79
N
OH
O
O
N
3
77
N
OH
O
N
11c
H
N
N
N
4
80
N
OH
O
11d
N
N
5
76
N
OH
O
11e
posed in Scheme 5. The reaction is initiated by nucleophilic attack of
amines 10 on the cyano group of 3a. Next, cyclization with salicylal-
dehyde (1a), followed by tautomerization afforded the products 11.
In conclusion, we have described a facile three-component
method for the synthesis of 2-amino-4-cyano-4H-chromenes by
reaction of salicylaldehydes, malononitrile or cyanoacetamide
and TMSCN at room temperature. Furthermore, a new synthesis
of 2-(chromeno[2,3-b]pyrimidin-2-yl)phenol derivatives by the
one-pot condensation of 2-imino-2H-chromene-3-carbonitrile,
salicylaldehyde and amines has been reported.

L. Moafi et al. / Tetrahedron Letters 51 (2010) 6270–6274
6273
X
CHO
NC
NH2
OH
LiClO4 (15 mol%)
+
NC
X
+ TMSCN
O
EtOH, 24 h
6
2
4
X=CN
X=CONH2 7b
7a
90%
52%
Scheme 3.
Y
CHO
Y
Y
TMSCN
X
X
LiClO4
EtOH
+
NC
X
4
5
OH
CN
OH
O
NH
LiClO4
1
2
8
9
Scheme 4.
CHO
OH
NR2
NR2
CN
N
OH
NH
+
NH
R2NH
O
O
NH
O
N
3a
10
H shift
11
Scheme 5.
22. Bazgir, A.; Mohammadi Khanaposhtani, M.; Abolhasani Soorki, A. Bioorg. Med.
Chem. Lett. 2008, 18, 5800.
Acknowledgement
23. Bazgir, A.; Seyyedhamzeh, M.; Yasaei, Z.; Mirzaei, P. Tetrahedron Lett. 2007, 48,
8790.
24. Sayyafi, M.; Seyyedhamzeh, M.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64,
2375.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
25. Ghahremanzadeh, R.; Imani Shakibaei, G.; Bazgir, A. Synlett 2008, 1129.
26. Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. Tetrahedron 2009, 65, 2005.
27. Dabiri, M.; Azimi, S. C.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64, 7307.
28. Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem. 2009, 11, 341.
29. Ghahremanzadeh, R.; Ahadi, S.; Sayyafi, M.; Bazgir, A. Tetrahedron Lett. 2008,
49, 4479.
30. Ghahremanzadeh, R.; Sayyafi, M.; Ahadi, S.; Bazgir, A. J. Comb. Chem. 2009, 11,
393.
31. Borisov, A. V.; Dzhavakhishvili, S. G.; Zhuravel, I. O.; Kovalenko, S. M.;
Nikitchenko, V. M. J. Comb. Chem. 2007, 9, 5.
References and notes
1. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169.
2. Tietze, L. F.; Modi, A. Med. Chem. Res. 2000, 20, 304.
3. Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427.
4. List, B.; Castello, C. Synlett 2001, 1687.
5. Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765.
6. Kumar, P.; Bodas, M. S. Org. Lett. 2000, 2, 3821.
32. Volmajer, J.; Toplak, R.; Leban, I.; Le Marechal, A. M. Tetrahedron 2005, 61, 7012.
33. Typical procedure for the preparation of 2-amino-4H-chromene-3,4-dicarbonitrile
(5a). A mixture of 2-hydroxybenzaldehyde (1 mmol), malononitrile (1 mmol),
TMSCN (1 mmol) and LiClO4 (15 mol %) in EtOH (5 ml) was stirred for 24 h (the
progress of the reaction was monitored by TLC). After completion, the mixture
was filtered and the precipitate washed with H2O (2 Â 5 ml) and the residue
recrystallised from EtOH to afford pure 5a. Grey powder (82%); mp: 180 °C
7. Curini, M.; Cravotto, G.; Epifano, F.; Giannone, G. Curr. Med. Chem. 2006, 13,
199.
8. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887.
9. Tangmouo, J. G.; Meli, A. L.; Komguem, J.; Kuete, V.; Ngounou, F. N.; Lontsi, D.;
Beng, V. P.; Choudhary, M. I.; Sondengam, B. L. Tetrahedron Lett. 2006, 47, 3067.
10. Kraus, G. A.; Kim, I. J. Org. Chem. 2003, 68, 4517.
11. Ellis, G. P. In The Chemistry of Heterocyclic Compounds. Chromenes, Chromanes,
and Chromones; Weissberger, A., Taylor, E. C., Eds.; John Wiley: New York,
1977; pp 11–141. Chapter II.
12. Hafez, E. A.; Elnagdi, M. H.; Elagamey, A. G. A.; El-Taweel, F. M. A. A.
Heterocycles 1987, 26, 903.
13. Wang, J. L.; Liu, D.; Zhang, Z.; Shan, S.; Han, X.; Srinvasula, S. M.; Croce, C. M.;
Alnemeri, E. S.; Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124.
14. Adams, J.; Cory, S. Science 1998, 281, 1322.
(dec). IR (KBr) (m
max/cmÀ1): 3385, 3320, 2193, 1654. MS (EI, 70 eV) m/z: 197
(M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.35 (1H, s, CH), 7.10–7.45 (4H,
m, H-Ar), 7.53 (2H, s, NH2). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 27.4, 47.7,
115.0, 117.2, 119.4, 120.2, 125.9, 129.1, 130.8, 148.6, 161.8. Anal. Calcd for
C11H7N3O: C, 67.00; H, 3.58; N, 21.31. Found: C, 66.89; H, 3.50; N, 21.38. 2-
Amino-6-methyl-4H-chromene-3,4-dicarbonitrile (5e). Grey powder (83%); mp:
165–168 °C. IR (KBr) (m
max/cmÀ1): 3380, 3321, 2197, 1651. MS (EI, 70 eV) m/z:
211 (M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 2.28 (3H, s, CH3), 5.27 (1H, s,
CH), 6.98–7.21 (3H, m, H-Ar), 7.48 (2H, s, NH2). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 20.5, 27.5, 47.7, 114.5, 116.9, 119.5, 120.3, 125.0, 131.3, 135.3, 146.6,
161.9. Anal. Calcd for C12H9N3O: C, 68.24; H, 4.29; N, 19.89. Found: C, 68.11; H,
4.35; N, 19.80. 2-Amino-4-cyano-5-methoxy-4H-chromene-3-carboxamide (5i).
15. Thompson, C. B. Science 1995, 267, 1456.
16. Yavari, I.; Djahaniani, H.; Nasiri, F. Tetrahedron 2003, 59, 9409.
17. Costa, M.; Areias, F.; Abrunhosa, L.; Venâncio, A.; Proença, F. J. Org. Chem. 2008,
73, 1954.
18. Yu, N.; Aramini, J. M.; Germann, M. W.; Huang, Z. Tetrahedron Lett. 2000, 41,
6993.
19. Grée, D.; Vorin, S.; Manthati, V. L.; Caijo, F.; Viault, G.; Manero, F.; Juin, P.; Grée,
R. Tetrahedron Lett. 2008, 49, 3276.
20. Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007, 48, 6785.
21. Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009, 917.
Grey powder; mp: 220 °C (dec). IR (KBr) (m
max/cmÀ1): 3464, 3307, 2228, 1660.
MS (EI, 70 eV) m/z: 245 (M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.84 (3H,
s, CH3), 5.29 (1H, s, CH), 6.87 (3H, br s, H-Ar and NH2), 7.09–7.18 (2H, m, H-Ar),
8.12 (2H, s, NH2). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 27.0, 56.3, 69.6,
113.0, 118.2, 119.8, 121.0, 125.4, 138.7, 147.8, 160.2, 170.2. Anal. Calcd for
C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.65; H, 4.59; N, 17.03. 2-

6274
L. Moafi et al. / Tetrahedron Letters 51 (2010) 6270–6274
Amino-6-bromo-4-cyano-4H-chromene-3-carboxamide (5m). Cream powder;
mp: 138 °C (dec). IR (KBr)
max/cmÀ1): 3460, 3311, 2221, 1663. MS (EI,
70 eV) m/z: 294 (M++2), 292 (M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.32
(1H, s, CH), 6.89 (2H, br s, NH2), 7.10–7.61 (3H, m, H-Ar), 8.10 (2H, s, NH2). 13
reaction was monitored by TLC). After completion, the mixture was filtered and
the precipitate washed with H2O (2 Â 5 ml) and EtOH (5 ml) to afford pure
(m
product 11a. White powder (74%); mp: 177–179 °C. IR (KBr) (m
max/cmÀ1):
C
3427, 3048, 1608. MS (EI, 70 eV) m/z: 319 (M++1). 1H NMR (300 MHz, DMSO-
d6): dH (ppm) 3.18 (6H, s, N(CH3)2), 4.15 (2H, s, CH2), 6.88 (2H, br s, H-Ar), 7.12
(2H, br s, H-Ar), 7.27 (3H, br s, H-Ar), 8.22 (1H, br s, H-Ar), 13.36 (1H, s, OH).
Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.58; H,
5.28; N, 13.07. (Due to the very low solubility of product 11a, we were unable
NMR (75 MHz, DMSO-d6): dC (ppm) 26.8, 69.4, 116.9, 119.3, 119.8, 120.6,
131.3, 133.4, 148.6, 159.9, 169.9. Anal. Calcd for C11H8BrN3O2: C, 44.92; H,
2.74; N, 14.29. Found: C, 44.83; H, 2.69; N, 14.23. 3-Amino-1H-
benzo[f]chromene-1,2-dicarbonitrile (7a). Grey powder; mp: 219 °C (dec). IR
(KBr) (
m
max/cmÀ1): 3379, 3310, 3196, 2187, 1651. MS (EI, 70 eV) m/z: 247 (M+).
to obtain
chromeno[2,3-d]pyrimidin-2-yl]phenol (11b). White powder (79%); mp: 168–
a
13C NMR spectrum for this product). 2-[4-(Piperidin-1-yl)-5H-
1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.85 (1H, s, CH), 7.29–8.08 (8H, m, H-
Ar and NH2). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 25.4, 48.3, 107.6, 117.2,
119.5, 119.9, 123.2, 126.2, 128.5, 129.1, 129.8, 131.0, 131.7, 146.9, 161.6. Anal.
Calcd for C15H9N3O4: C, 72.87; H, 3.67; N, 16.99. Found: C, 72.75; H, 3.58; N,
16.91.
170 °C. IR (KBr) (m
max/cmÀ1): 3416, 3064, 2933, 1608. MS (EI, 70 eV) m/z: 359
(M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.69 (6H, s, 3CH2), 3.48 (4H, s,
2CH2), 3.99 (2H, s, CH2), 6.89–6.95 (2H, m, H-Ar), 7.13–7.20 (2H, m, H-Ar),
7.26–7.39 (3H, m, H-Ar), 8.26 (1H, d, 3JHH = 6.0 Hz, H-Ar), 13.28 (1H, s, OH). 13
C
34. Typical procedure for the preparation of 2-[4-(dimethylamino)-5H-chromeno[2,3-
d]pyrimidin-2-yl]phenol (11a). A mixture of 2-hydroxybenzaldehyde (1 mmol),
2-imino-2H-chromene-3-carbonitrile (1 mmol), dimethylamine (1 mmol) and
LiClO4 (15 mol %) in EtOH (5 ml) was stirred for 15 h (the progress of the
NMR (75 MHz, DMSO-d6): dC (ppm) 24.3, 25.3, 26.0, 49.2, 97.8, 116.8, 117.8,
118.6, 119.3, 120.6, 125.0, 128.6, 129.1, 129.5, 133.3, 150.4, 160.3, 161.0, 163.8,
146.8. Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C, 73.43;
H, 5.81; N, 11.76.