Facile syntheses of 2-substituted 3-cyanochromones

Article abstract of DOI:10.1016/j.tetlet.2012.05.031

A simple and general route to 3-cyanochromones containing various substituents on position 2 of the ring is developed. The method is based on condensation of 3-(2-hydroxyphenyl)-3-oxopropionitrile with acid chlorides or anhydrides in pyridine at room temp

Full text of DOI:10.1016/j.tetlet.2012.05.031

Tetrahedron Letters 53 (2012) 3630–3632
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Tetrahedron Letters
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Facile syntheses of 2-substituted 3-cyanochromones
K. S. Levchenko a, , I. S. Semenova b, V. N. Yarovenko b, P. S. Shmelin a, M. M. Krayushkin b
⇑
a Central Science Research Institute of Technology ‘Technomash’, 4 Ivana Franko St., Moscow 121108, Russia
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Pr., Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and general route to 3-cyanochromones containing various substituents on position 2 of the
ring is developed. The method is based on condensation of 3-(2-hydroxyphenyl)-3-oxopropionitrile with
acid chlorides or anhydrides in pyridine at room temperature.
Received 30 March 2012
Revised 26 April 2012
Accepted 3 May 2012
Available online 11 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Substituted 3-cyanochromones
3-(2-Hydroxyphenyl)-3-oxopropionitrile
3-Hetaryl-2-(2-hydroxybenzoyl)
acrylonitriles
Acylation
3-Cyanochromones are of interest as antifungal agents1 and no-
vel telomerase inhibitors.2 In addition, they are precursors of a
number of 2-substituted chromone-3-carboxylic acids,3 which
are known as inhibitors of p56lCk tyrosine kinase,4 and chro-
mone-3-carbaldehydes,5 which exhibit cytotoxic, anti-Helicobac-
ter pylori, urease inhibitory, and anti-HIV activity.6 The presence
of the cyano group at position 3 allows further functionalization
of chromones or the design of new heterocyclic compounds.7–10
Several routes to 3-cyanochromones are described in the litera-
ture, however, these methods only enable the synthesis of products
with a limited set of substituents, particularly, at position 2 of the
chromone. For example, 3-cyano derivatives were synthesized by
substitution of chlorine in 3-chloro-2-phenylchromones with cop-
per cyanide.2,11–13 These reactions proceeded under reflux in N-
methylpyrrolidone at 200–220 °C, and were limited by the availabil-
ity of 3-halochromones. 3-Cyanochromones can also be synthesized
by cyanationof 2-alkyl-3-bromochroman-4-ones with the use of the
SmI2/KHMDS/TsCN system at ꢀ78 °C, followed by oxidation of the
resulting 2-alkyl-3-cyanochroman-4-ones with DDQ on reflux in
1,4-dioxane for 12 h to give 2-alkyl-3-cyanochrom-4-ones.14 2-
Unsubstituted 3-cyanochromones were synthesized by refluxing a
benzene solution of sulfuric acid and O-methyl oximes, which were
produced by the reaction of chromone-3-carbaldehydes with
O-methylhydroxylamine.15
b-bromo-a-alkylthiocinnamonitriles with various substituted
methyl salicylates followed by treatment with AlCl3/PhNO2 at
150 °C.5 It should be noted that methods for the synthesis of
3-cyanochromones containing heterocyclic moieties at position 2
are lacking in the literature.
In the present study, we report a simple and general route to
various 2-substituted 3-cyanochromones containing alkyl, aryl, or
heterocyclic substituents at position 2 (Scheme 1). In the first step,
readily available 20-hydroxyacetophenone was converted into the
corresponding dimethylaminomethylene derivative 2 in quantita-
tive yield under reflux in DMF–DMA. Compound 2 was then
refluxed in ethanol with hydroxylamine hydrochloride to give 2-
(isoxazol-5-yl)phenol 3 in 80% yield. Upon treatment with aque-
ous-ethanolic NaOH solution at room temperature, the isoxazole
ring in compound 3 was cleaved to form 3-(2-hydroxyphenyl)-
3-oxopropionitrile (4) in 75% yield.16 The synthesis of target ni-
triles 6a,b was performed according to a method previously used
by us for the synthesis of 3-acyl-2-hetarylchromones 10.17,18 In
this method, b-diketone 7 (Scheme 2) underwent an aldol conden-
sation with various aldehydes at room temperature or with slight
heating to form a mixture of compounds 8 and 9, which give 3-
acyl-2-substituted chromones 10 upon oxidation with selenium
dioxide in refluxing 1,4-dioxane. Using this approach we prepared
condensation products 5 in 70–80% yield. The latter were easily
oxidized to give compounds 6 in 52–75% yield.
In 2003, a method was developed for the synthesis of 3-cyano-2-
phenylchromones (in 35–65% yields) involving the reaction of
It should be noted that the aldol condensation of aldehydes with
nitrile 4 is complete in 15 min at room temperature,19 which is
much faster20 compared to the corresponding reaction with dike-
tones 7, which is complete within 6–12 h. This fact is indicative of
⇑
Corresponding author. Tel.: +7 499 144 6835; fax: +7 499 144 7595.
E-mail address: ntc_technology@socket.ru (K. S. Levchenko).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.031

K. S. Levchenko et al. / Tetrahedron Letters 53 (2012) 3630–3632
3631
O
O
O
O
N
N
(i)
(iii)
(ii)
(iv)
N
OH
OH
OH
OH
1
2
4
3
O
O
O
N
N
(v)
R
OH
R
5a, b
6a, b
Scheme 1. Reagents and conditions: (i) DMF–DMA reflux, 1 h; (ii) NH2OHꢁHCl, EtOH, reflux, 2 h; (iii) NaOH, EtOH/H2O (1:3), rt 24 h; (iv) thiophene-2-carboxaldehyde or
furfural, piperidine, EtOH, rt, 15 min; (v) SeO2, 1,4-dioxane, reflux.
O
O
R1
R1
O
O
R
O
O
O
R2
O
(ii)
R1
O
O
(i)
R1
8
R
R
R2
OH
7
10
R = Alkyl, Br,H;
R1, R2 = Aryl or hetaryl
R
OH R2
9
Scheme 2. Reagents and conditions: (i) R2CHO, piperidine, EtOH, rt (6–12 h) or heating (0.5–3 h); (ii) SeO2, 1,4-dioxane, reflux.
versatile and enabled the synthesis of various 3-cyanochromones
6a–l, including previously unavailable 2-hetaryl-substituted exam-
ples 6a–c, in good to high yields (Table 1).
In summary, we have developed a general and simple method
for the synthesis of a range of 2-alkyl-, 2-aryl-, and 2-hetaryl-3-
cyanochromones in good to excellent yields. The method does
not require the use of expensive reagents or chromatographic puri-
fication of the reaction products.
O
O
O
O
O
N
N
N
(i)
OH
R
4
O
6a-l
R
11
Scheme 3. Reagents and conditions: (i) RCOCl, pyridine, rt 1–3 h.
Acknowledgements
the higher activity of the methylene group in nitrile derivatives 4
compared to that in diketones 5. This encouraged us to synthesize
esters 11 in expectation of spontaneous cyclization to cyanochro-
mones 6a–l (Scheme 3).
The authors are grateful to OJSC CSRIT «Technomash» for finan-
cial support, and Dr. E. P. Grebennikov and Dr. A. U. Bochkov for
helpful suggestions.
In fact, the acylation of nitrile 4 with acid chlorides in pyridine
at room temperature afforded the target nitriles in 49–90% yields.
It should be noted that the reaction products did not require chro-
matographic purification and pure products could be obtained by
simple crystallization, for example, from ethanol. The method is
Supplementary data
Supplementary data (characterization data of synthesized com-
pounds) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.05.031. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
Table 1
Isolated yields and melting points of compounds 6a–la.
Entry
R
Product
Mp (°C)
Yield (%)
1
2
3
4
5
6
7
8
Furan-2-yl
Thien-2-yl
5-Methylthien-2-yl
Ph
2-Cl-C6H4
4-Cl-C6H4
2-F-C6H4
4-F-C6H4
2-Me-C6H4
Me
6a
6b
6c
6d
6e
6f
6g
6h
6i
166–168
198–200
149–151
165–166
150–152
203–205
189–191
209–211
165–167
192–194
123–125
189–190
82
64
60
90
67
78
63
70
61
References and notes
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10
11
12
6j
6k
6l
65 (70)b
(54)b
49
Et
CH2Ph
a
The corresponding acid chloride (1.05 mmol) was added to nitrile 4 (1 mmol) in
pyridine (1.5 mL). After stirring at rt, the mixture was poured into water. The
precipitate that formed was washed with water, dried, and if required, crystallized
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b
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0.208 mmol) or thiophene-2-carboxaldehyde (0.24 g, 0.208 mmol) in EtOH.
After stirring for 15 min, the precipitate that formed was filtered, washed with
cold EtOH, and dried in air. A pure yellow product was obtained.
3-Furan-2-yl-2-(2-hydroxybenzoyl)acrylonitrile (5a). Yield 380 mg (80%); mp
118–120 °C. 1H NMR (300.13 MHz, CDCl3): d 11.34 (s, 1H), 8.11 (d, J = 8.1 Hz,
1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.53–7.58 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.99 (t,
J = 7.6 Hz, 1H), 6.72 (d, J = 3.1 Hz, 1H).
2-(2-Hydroxybenzoyl)-3-(thien-2-yl)acrylonitrile (5b). Yield 70%; mp 112–
114 °C. 1H NMR (300.13 MHz, CDCl3): 11.33 (s, 1H), 8.28 (s, 1H), 8.11 (d,
J = 8.0 Hz, 1H), 7.91 (d, J = 3.4 Hz, 1H), 7.87 (d, J = 4.8 Hz 1H), 7.56 (t, J = 7.6 Hz,
1H), 7.28 (m, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H).
General procedure for the oxidation of 5. SeO2 (2 mmol) was added to a
solution of 5a or 5b (1 mmol) in 1,4-dioxane and the resulting mixture was
refluxed until completion of the reaction (TLC monitoring). Column
chromatographic separation afforded products 6a and 6b in 75% and 52%
yields, respectively.
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16. 3-(2-Hydroxyphenyl)-3-oxopropanenitrile (4). Mp 108–109 °C. 1H NMR
(300.13 MHz, CDCl3): d 11.36 (s, 1H), 7.54–7.58 (m, 2H), 6.94–7.05 (m, 2H),
4.17 (s, 2H). 13C NMR (75.47 MHz, CDCl3): d 192.68 (C@O), 162.76 (C-OH),
138.18 (C-40), 129.45 (C-60), 119.80 (C-50), 119.2 (C-30), 117.70 (C-10), 113.40
(CN), 29.70 (C-2).
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19. General procedure for the preparation of 5: One drop of piperidine was added
to
a mixture of ketonitrile 4 (322 mg, 0.2 mmol) and furfural (0.2 g,