Synthesis of 5,6-dicyanobenzofurans based on 4-bromo-5-nitrophthalonitrile

Article abstract of DOI:10.1016/j.mencom.2009.11.013

A new stereoselective method for the synthesis of substituted 5,6-dicyanobenzofurans by activated aromatic nucleophilic replacement of a bromine atom and a nitro group in 4-bromo-5-nitrophthalonitrile has been developed.

Full text of DOI:10.1016/j.mencom.2009.11.013

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 332–333
Synthesis of 5,6-dicyanobenzofurans
based on 4-bromo-5-nitrophthalonitrile
Sergei I. Filimonov,a Zhanna V. Chirkova,a Igor G. Abramov,a
Alexander S. Shashkov,b Sergey I. Firgangb and Galina A. Stashina*b
a Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 0852 44 0729;
e-mail: filimonovsi@ystu.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: galina_stashina@chemical-block.com
DOI: 10.1016/j.mencom.2009.11.013
A new stereoselective method for the synthesis of substituted 5,6-dicyanobenzofurans by activated aromatic nucleophilic replace-
ment of a bromine atom and a nitro group in 4-bromo-5-nitrophthalonitrile has been developed.
Owing to the diversity of practical applications of benzo-
furans,1,2 interest in this class of heterocycles remains high.3,4
N
Br
ONa
O
Although diverse methods are known to synthesise these com-
pounds, information on syntheses of benzofurans with electron-
withdrawing substituents is relatively scarce,5–7 and only three
papers on the synthesis of ortho-dicarbonitriles containing the
benzofuran moiety are available. Two syntheses of dicyanobenzo-
furans are based on a high-temperature reaction of brominated
derivatives with metal cyanides,8,9 and nucleophilic replacement
of the nitro group in 4-nitrophthalonitrile with dimedone10 at
100 °C is used in one case. Note that substituted ortho-dicarbo-
nitriles are precursors for synthesising phthalocyanines,11–13
hexazocyclanes14 and other compounds containing anhydride,
imide, isoindoline and tetrazole moieties.
+
O
R
R1
N
O
N
1
2a–f
R1
O
R1
O
ONa
O
N
N
N
N
R
R
R
R1
O
ONa
O
N
O
O
N
O
3a–f
We have developed a new method for the synthesis of
substituted 5,6-dicyanobenzofurans 4a–f by activated aromatic
nucleophilic replacement of a bromine atom and a nitro group15,16
in 4-bromo-5-nitrophthalonitrile (BNPN) 1 with sodium salts of
1,3-diketones 2a–f† (Scheme 1). The reaction occurs at 25–35 °C
in DMF and requires 12–20 h to be completed (the reaction
time decreases to 2 h in case of aliphatic substituents). The
reaction yield exceeds 75%, which is attributable to the high
reactivity of BNPN in strongly basic media. The behaviour of this
substrate in SNAr reactions was considered previously.11–14,17–19
In reactions with mono- and bifunctional O-, N-, S-nucleo-
philes, the reactive bromine atom was first replaced in this
compound an then the nitro group; as a result, a wide range of
derivatives were obtained with diverse aliphatic, aromatic and
heterocyclic substituents.
A specific feature of this method is that sodium salts of
1,3-dicarbonyl compounds 2a–f were used not only as reagents
but also as deprotonating agents; therefore, they were needed in
a two-fold molar excess. Attempts to decrease the amount of
compounds 2a–f using other bases (TEA, K2CO3, NaOH and
MeONa) resulted in a considerable decrease in the yields of
target benzofurans 4a–f. This reaction was carried out in DMSO,
DMF, acetonitrile and ethanol; however, the best results were
obtained in DMF.
O
a R = R1 = Me
b R = Me, R1 = OEt
c R = Ph, R1 = OEt
d R = Me, R1 = 4-MeOC6H4
e R = Me, R1= 4-MeC6H4
f R = Me, R1= 2-thienyl
R1
R
N
O
N
4a–f
Scheme 1
immediately after the formation, it undergoes deprotonation to
give an O-nucleophile.
The subsequent intramolecular nucleophilic replacement of
the nitro group in intermediate 3a–f by the O-nucleophilic
centre formed in situ completes the formation of target 5,6-di-
cyanobenzofurans 4a–f. Note that, due to the tautomerism of
the double bond, cyclisation of intermediate 3 can produce two
isomers of 2-Me or 3-Ac-benzofurans 4a,b,d–f; however, the
reaction occurs stereoselectively under the conditions used to
give only one 2-Me isomer in all cases, which was proved by
13C NMR spectroscopy (the methyl proton signal at d 14–15 ppm).
This follows from an analysis of 13C NMR chemical shifts for
compound 4a (the only compound with an acetyl substituent)
with the following values for methyl carbons: d 15.27 (2-Me)
and 30.75 (3-Ac), respectively.
We believe that the formation of the benzofuran ring in 4a–f
starts with an attack of nucleophilic reagent 2a–f at the BNPN
carbon atom bound to the bromine atom to give intermediate
3a–f.20 The formation of C–C bonds in electron-deficient
aromatic compounds was considered by Artamkina et al.21
Compound 3 is not accumulated in the reaction mixture; instead,
The structures of compounds 4a–f were confirmed by a
combination of IR- and NMR-spectroscopic and mass-spectro-
metric data. Typical signals in H NMR spectra include two
signals of phthalonitrile protons at about d 8.5 ppm and a
methyl group signal at about d 2.55–2.86 ppm. Furthermore, the
13C NMR spectra of benzofurans 4a,d–f contain a characteristic
1
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 332–333
signal of the carbonyl carbon in the region of d 180–190 ppm,
References
whereas the signal of the carbonyl carbon of the ester group in
compounds 4b,c is observed in the region of d 160–164 ppm.
Compound 4c is the only one in the presented series that has a
phenyl substituent at the 2-position. Its structure was confirmed
by an analysis of data of a NOESY spectrum containing medium-
intensity cross-peaks of ethyl group protons with one of the
protons of the phthalonitrile ring and the phenyl substituent.
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4
5
6
†
IR spectra were measured on a Perkin-Elmer RX-1 spectrometer in the
range of 700–4000 cm–1 using suspensions of substances in Vaseline oil.
Mass spectra were obtained using a FINNIGAN MAT.INCOS 50 mass
spectrometer; the ionization energy was 70 eV. NMR spectra were recorded
on a Bruker DRX-500 instrument at 30 °C for solutions in [2H6]DMSO.
7
8
1
Signals of residual protons of the solvent in H NMR spectra (dH 2.50)
or the signal of [2H6]DMSO in 13C spectra (dC 39.5) were used as
references for chemical shift measurements.
9
I. G. Farbenind, German Patent, 742392, 1935 (in German).
BNPN (1) was synthesised using a published procedure.17 The sodium
salts of 1,3-dicarbonyl compounds 2a–f were synthesised by the proce-
dure reported elsewhere.22
10 M. P. Roze, E. L. Berzhin’sh and O. Ya. Neiland, Zh. Org. Khim., 1987,
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Khim., 1998, 68, 860 (Russ. J. Gen. Chem., 1998, 68, 813).
General procedure for the synthesis of compounds 4a–f. Compound
2a–f (4.4 mmol) was added to a solution of BNPN (2.0 mmol) in 3 ml
of DMF, the mixture was stirred for 2–20 h at 25–35 °C and poured into
10 ml of 1% hydrochloric acid solution. The resulting resinous preci-
pitate was extracted with CH2Cl2, thoroughly washed with water, and
chromatographed on silica gel using a hexane–dichloromethane mixture
(1:2) as the eluent. The eluent was evaporated; the resulting precipitate
was filtered off and recrystallised from ethanol.
3-Acetyl-2-methyl-1-benzofuran-5,6-dicarbonitrile 4a: yield 61%,
mp 205–207 °C. 1H NMR, d: 2.66 (s, 3H, Me), 2.87 (s, 3H, 2-Me), 8.56
(s, 1H, 7-H), 8.57 (s, 1H, 4-H). 13C NMR, d: 15.27 (2-Me), 30.75 (3-Ac),
109.67 (C-5), 110.13 (C-6), 115.99 (CºN), 116.11 (CºN), 116.87 (C-3),
117.72 (4-C), 127.74 (7-C), 130.19 (C-3a), 152.86 (C-7a), 168.09 (C-2),
193.12 (C=O). IR (n/cm–1): 2234 (CºN), 1666 (C=O), 1286 (C–O–C).
MS, m/z (%): 224 (M+, 30), 209 (M+ – Me, 100), 181 (M+ – Ac, 4).
Found (%): C, 69.42; H, 3.57; N, 12.52. Calc. for C13H8N2O2 (%): C,
69.64; H, 3.60; N, 12.49.
Ethyl 5,6-dicyano-2-methyl-1-benzofuran-3-carboxylate 4b: yield 54%,
mp 129–132 °C. 1H NMR, d: 1.39 (t, 3H, Et, J 7.0 Hz), 2.83 (s, 3H, 2-Me),
4.40 (q, 2H, CH2, J 7.0 Hz), 8.45 (s, 1H, 7-H), 8.62 (s, 1H, 4-H). 13C NMR,
d: 13.96 (Me), 14.22 (2-Me), 60.88 (CH2), 108.71 (C-5), 109.73 (C-6),
110.11 (C-3), 115.89 (CºN), 115.97 (CºN), 117.85 (C-4), 127.15 (C-7),
129.83 (C-3a), 152.98 (C-7a), 161.78 (C=O), 168.97 (C-2). IR (n/cm–1):
2235 (CºN), 1716 (C=O), 1285 (C–O–C). MS, m/z (%): 254 (M+, 53),
239 (M+ – Me, 2), 226 (M+ – Et + H, 100), 209 (M+ – OEt, 82), 181
(M+ – COOEt, 25). Found (%): C, 66.27; H, 3.73; N, 11.06. Calc. for
C14H10N2O3 (%): C, 66.14; H, 3.96; N, 11.02.
13 S. A. Siling, S. V. Shamshin, A. B. Grachev, O. Yu. Tsiganova, V. I. Yuzhakov
,
I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, A. G. Vitukhnovsky,
A. S. Averjushkin and B. C. Lap, Oxidation Commun., 2000, 4, 481.
14 I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova, V. V.
Plakhtinskii and M. S. Belysheva, Mendeleev Commun., 2001, 80.
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Nitro Group, Wiley, New York, 1991.
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Russian Patent, 2167855, 2001.
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M. B. Abramova, Mendeleev Commun., 2000, 78.
19 I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova and
V. V. Plachtinsky, Heterocycles, 2001, 55, 1161.
20 P. P. Onys’ko, N. V. Proklina, V. P. Prokopenko and Yu. G. Golobov,
Zh. Org. Khim., 1985, 21, 1647 [J. Org. Chem. USSR (Engl. Transl.),
1985, 21, 1504].
21 G. A. Artamkina, S. V. Kovalenko, I. P. Beletskaya and O. A. Reutov,
Usp. Khim., 1990, 59, 1288 (Russ. Chem. Rev., 1990, 59, 750).
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Received: 6th May 2009; Com. 09/3335
Ethyl 5,6-dicyano-2-phenyl-1-benzofuran-3-carboxylate 4c: yield 69%,
mp 187–190 °C. 1H NMR, d: 1.34 (t, 3H, Et, J 7.0 Hz), 4.38 (q, 2H, CH2,
J 7.0 Hz), 7.58 (t, 2H, Ph, J 7.7 Hz), 7.64 (t, 1H, Ph, J 7.7 Hz), 8.00 (d,
2H, Ph, J 7.7 Hz), 8.52 (s, 1H, 7-H), 8.66 (s, 1H, 4-H). 13C NMR, d:
13.76 (Me), 61.23 (CH2), 108.56 (C-5), 110.28 (C-6), 110.42 (C-3), 115.90
(CºN), 116.03 (CºN), 118.31 (C-4), 127.02 (C-1'), 128.34 (C-3', C-5'),
128.44 (C-4'), 129.56 (C-2', C-6'), 130.78 (C-7), 131.78 (C-3a), 153.16
(C-7a), 161.39 (C=O), 164.21 (C-2). IR (n/cm–1): 2232 (CºN), 1727
(C=O), 1222 (C–O–C). MS, m/z (%): 316 (M+, 79), 288 (M+ – Et + H,
34), 271 (M+ – OEt, 100), 244 (271 – HCN, 29), 215 (244 – 29, 87).
Found (%): C, 72.18; H, 3.55; N, 8.83. Calc. for C19H12N2O3 (%): C,
72.15; H, 3.82; N, 8.86.
2-Methyl-3-(4-methylbenzoyl)benzofuran-5,6-dicarbonitrile 4e: yield
61%, mp 195–198 °C. 1H NMR, d: 2.47 (s, 3H, Me'), 2.52 (s, 3H, 2-Me),
7.40 (d, 2H, 5'-H, 3'-H, J 8.0 Hz), 7.72 (d, 2H, 2'-H, 6'-H, J 8.0 Hz),
8.15 (s, 1H, 7-H), 8.64 (s, 1H, 4-H). 13C NMR, d: 14.95 (2-Me), 21,31
(Me'), 109.77 (C-5), 109.92 (C-6), 116.22 (2CºN), 116.53 (C-3), 117.98
(C-7), 127.28 (C-4), 129.34 (C-5', C-3'), 129.48 (C-2', C-6'), 131.40
(C-1'), 135.13 (C-3a), 144.23 (C-4'), 153.44 (C-7a), 166.33 (C-2), 189.13
(C=O). IR (n/cm–1): 2235 (CºN), 1642 (C=O), 1288 (C–O–C). MS, m/z
(%): 300 (M+, 99), 285 (M+ – Me, 100), 209 (M+ – PhMe, 67), 181
(M+ – COPhMe, 9), 119 (COPhMe, 68). Found (%): C, 76.13; H, 3.80;
N, 9.25. Calc. for C19H12N2O2 (%): C, 76.00; H, 4.03; N, 9.33.
2-Methyl-3-(thien-2-ylcarbonyl)benzofuran-5,6-dicarbonitrile 4f: yield
53%, mp 170–173 °C. 1H NMR, d: 2.68 (s, 3H, 2-Me), 7.26 (t, 1H, 4'-H,
J 3.6 Hz, J 4.8 Hz), 7.85 (d, 1H, 3'-H, J 3.6 Hz), 8.21 (d, 1H, 5'-H,
J 4.8 Hz), 8.32 (s, 1H, 7-H), 8.68 (s, 1H, 4-H). 13C NMR, d: 14.76 (2-Me),
109.80 (C-5), 109.92 (C-6), 116.23 (CºN), 116.27 (CºN), 116.58 (C-3),
118.01 (C-7), 127.25 (C-4'), 128.98 (C-4), 131.06 (C-3a), 136.10 (C-5'),
136.86 (C-3'), 143.21 (C-2'), 153.40 (C-7a), 165.26 (C-2), 180.79 (C=O).
IR (n/cm–1): 2234 (CºN), 1622 (C=O), 1291 (C–O–C). MS, m/z (%):
292 (M+, 100), 277 (M+ – Me, 8), 209 (M+ – thienyl, 26), 111 (thienyl-
carbonyl, 99). Found (%): C, 65.77; H, 2.78; N, 9.74. Calc. for C16H8N2O2S
(%): C, 65.74; H, 2.76; N, 9.58.
3-(4-Methoxybenzoyl)-2-methylbenzofuran-5,6-dicarbonitrile 4d: yield
64%, mp 163–166 °C. 1H NMR, d: 2.55 (s, 3H, Me), 3.89 (s, 3H, OMe),
7.07 (d, 2H, 5'-H, 3'-H, J 8.8 Hz), 7.80 (d, 2H, 2'-H, 6'-H, J 8.8 Hz),
8.10 (s, 1H, 7-H), 8.56 (s, 1H, 4-H). 13C NMR, d: 14.84 (2-Me), 55.70
(OMe), 109.66 (C-5), 109.83 (C-6), 114.21 (C-5', C-3'), 116.25 (2CºN),
116.61 (C-3), 117.95 (C-7), 127.24 (C-4), 130.16 (C-3a), 131.80 (C-2',
C-6'), 131.52 (C-1'), 153.43 (C-7a), 163.69 (C-4'), 165.62 (C-2), 187.80
(C=O). IR (n/cm–1): 2230 (CºN), 1647 (C=O), 1265 (C–O–C). MS, m/z
(%): 316 (M+, 100), 301 (M+ – Me, 30), 285 (M+ – OMe, 100), 273
(M+ – Ac, 6), 135 (COPhOMe, 57). Found (%): C, 72.27; H, 3.73; N,
8.90. Calc. for C19H12N2O3 (%): C, 72.15; H, 3.82; N, 8.86.
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