A convenient access to 3-cyanoflavones

Article abstract of DOI:10.1016/j.tetlet.2003.10.072

Reaction of β-bromo α-alkylthiocinnamonitriles with various substituted methyl salicylates followed by treatment with AlCl ₃/PhNO₂ provides 3-cyanoflavones.

Full text of DOI:10.1016/j.tetlet.2003.10.072

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9283–9285
A convenient access to 3-cyanoflavones
Fre´de´ric Lassagne* and Francis Pochat
Laboratoire de Chimie Organique, Universite´ de Rennes 1, Bat 7, Campus de Beaulieu, 35042 Rennes, France
Received 1 September 2003; revised 7 October 2003; accepted 13 October 2003
Abstract—Reaction of b-bromo a-alkylthiocinnamonitriles with various substituted methyl salicylates followed by treatment with
AlCl3/PhNO2 provides 3-cyanoflavones.
© 2003 Elsevier Ltd. All rights reserved.
Several C-3 substituted flavones have been found to
play an important role in a number of biological pro-
cesses: the most representative of them are flavonols
which are reported to have antiviral and antibiotic
effects as well as antioxidant properties.
mmol), methyl salicylate 2 (7.2 mmol) and anhydrous
potassium carbonate (6.5 mmol) in dry DMSO (10 mL)
was stirred overnight at 70–80°C. After pouring into
cold water, diethyl ether extraction and washing with 1
M NaOH solution, compounds 3 (Z/E mixture) were
isolated in good yields (70–90%) as shown in Table 1.
Among the numerous C-3 functionalized flavones
described in the literature1 only one example of a
substituted 3-cyanoflavone has been reported, as a by-
product from a reaction starting from a 3-(a-hydroxy-
benzyl) flavone.2
The conversion of 3 into 3-cyanoflavones 4 was carried
out as follows. To a stirred solution of precursor 3 (1.5
mmol) in dry nitrobenzene at 150°C (50 mL, inner
temp.) was added dropwise, over 2 min, a nitrobenzene
solution of AlCl3 (0.88 M, 5.5 mmol, 5.3 mL). After
stirring for a further 5 min at the same temperature, the
mixture was poured into cold 10% HCl solution,
extracted with CH2Cl2 and washed with NaHCO3 solu-
tion and water until neutral pH. The solvents were
evaporated and the residual solid was purified on a
silica gel column eluted with CH2Cl2/AcOEt in the
range (v/v) 90/10 to 98/2. Compounds 4a–h were
obtained (Table 1). Selected data for 4d: IR (w, KBr,
cm−1): 2225 (CꢀN), 1651 (CꢁO). Anal. found C, 75.87;
H, 5.74; N, 4.26%; calc. for C21H19NO3 C, 75.66; H,
More recently, we have found a novel route to 3-
cyanoflavones 4 by reacting b-bromo a-ethylthio cinna-
monitrile 1 with methyl salicylate 2 and the subsequent
treatment of precursor 3 with AlCl3 (Scheme 1).
Compounds of type 1, readily obtained in good yields
(70–80%) following the literature method,3 react in
alkaline medium with methyl salicylate4 2 to give the
substitution products 3 as Z, E mixtures which can be
further used as such. These reactions were performed
using the following general procedure: a mixture of 1 (6
1
5.74; N, 4.20%. H NMR (300 MHz, CDCl3) l 8.17
Scheme 1.
Keywords: b-bromo a-ethylthiocinnamonitrile; methyl methoxysalicylate; 2-(2-cyano-2-(ethylthio-1-arylvinyloxy))-benzoic acid methyl ester;
aluminium chloride; 3-cyanoflavones; 3-formylflavones.
* Corresponding author. Fax: 02-23-23-62-98; e-mail: frederic.lassagne@univ-rennes1.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.072

9284
F. Lassagne, F. Pochat / Tetrahedron Letters 44 (2003) 9283–9285
Table 1.
R1
R2
R3
R4
3 (Z/E mixture)
4
5
Yield (%)
mp (°C)
Yield (%)
mp (°C)
Yield (%)
mp (°C)
a
b
c
d
e
f
H
H
Me
tBu
Cl
OMe
OCH2O
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
85
86
75
70
70
81
85
90
58–68
64–70
76–80
128–132
80–94
90–100
100–110
98–104
54
64
61
60
65
63
50
35a
157–158b
209–210c
182–183
173–174
221–222
224–225
202–203
269–270
55
–
60
–
–
–
151–152d
–
158–159
–
–
–
–
–
OMe
OMe
OMe
OMe
OMe
OMe
OMe
g
h
–
–
H
a Cyclization occurred at 100°C and the lower yield of flavone 4h was explained by the concomitant formation of the phenolic compound 4%h
(R1=R3=OMe, R2=H, R4=OH) in 15% yield. Data for 4%h: mp=232–233°C. EIMS: m/z found 323.0799 (M+); calc. for C18H13NO5: m/z
1
323.0794 (M+). H NMR (500 MHz, DMSO) l 11.97 (1H, s, OH), 8.11 (2H, d, J=8.7 Hz, H-2%, 6%), 7.23 (2H, d, J=8.7 Hz, H-3%, 4%), 6.86 (1H,
d, J=1.75 Hz, H-6), 6.50 (1H, d, J=1.75 Hz, H-8), 3.91 (3H, s, MeO), 3.89 (3H, s, MeO). 13C NMR (125 MHz, DMSO) l 178.83 (CꢁO), 171.25
(C-2), 166.68 (C-7), 164.00 (C-4%), 161.09 (C-5), 156.93 (C-8a), 131.50 (C-2%, 6%), 121.94 (C-1%), 115.08 (C-3%, 5%), 114.67 (CꢀN), 103.44 (C-4a),
99.71 (C-6), 94.57 (C-3), 94.34 (C-8), 56.89 (MeO), 56.31 (MeO).
b mp (lit.2)=151–152°C.
c mp (lit.2)=202–203°C.
d mp (lit.6)=152°C.
(1H, d, J=8.8 Hz, H-5), 8.07 (2H, J=8.6 Hz, H-2%, 6%),
7.62 (2H, d, J=8.6 Hz, H-3%, 5%), 7.05 (1H, dd, J=8.8
and 2.2 Hz, H-6), 6.97 (1H, d, J=2.2 Hz, H-8), 3.97
(3H, s, OMe), 1.4 (9H, s, tBu). 13C NMR (75 MHz,
CDCl3) l 173.43 (CꢁO), 170.46 (C-2), 165.18 (C-7),
157.30 (C-4%), 157.13 (C-8a), 128.51 (C-2%,6%),127.41 (C-
5), 127.18 (C-1%), 126.12 (C-3%,5%), 115.68 (C-6), 115.53
(C-4a), 114.45 (CꢀN), 100.76 (C-8), 97.46 (C-3), 56.15
(MeO), 35.29 (Cqu tBu), 31.03 (CH3). EIMS: m/z
333.1363 (M+).
(C-2), 164.75 (C-7), 157.4 (C-8a), 143.07 (C-4%), 129.94
(C-2%, 6%), 129.27 (C-3%, 5%), 127.92 (C-1%), 127.70 (C-5),
117.96 (C-4a), 117.30 (C-3), 115.17 (C-6), 100.69 (C-8),
55.98 (MeO), 21.70 (CH3).
In summary, this paper describes the first simple and
efficient method for the synthesis of substituted 3-
cyanoflavones and
a corresponding access to 3-
formylflavones, which could be of interest as starting
materials for preparation of novel heterocyclic systems.
We observed that no reaction occurs without the pres-
ence of AlCl3, the cyclisation is easier when electron-
donating groups are in either the ortho or para position
relative to the ester moiety. We suppose that the first
step involves complexation of the carbonyl by AlCl3
which increases the electropositivity of the carbon
atom. A Mannich-type reaction of the enol ether moi-
ety should then close the six-membered ring, releasing
methoxide which could in turn assist the elimination of
the ethylthio group, thereby restoring aromaticity.
Acknowledgements
Thanks to M. Utjes for her support, and S. Sinbandhit
and P. Guenot for recording NMR and mass spectra.
References
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Furthermore, these 3-cyanoflavones can be converted
to 3-formylflavones 5, by the reduction of the nitrile
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compounds 5a and 5c (Table 1). Selected data for 5c:
1H NMR (300 MHz, CDCl3) l 10.15 (1H, s, CHO),
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3. The bromo compounds 1 were prepared as follows:
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F. Lassagne, F. Pochat / Tetrahedron Letters 44 (2003) 9283–9285
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