Reductive Heterocyclization of 2-Cyanobenzophenones by the Action of NaBH4. New Efficient Synthesis of 3-Arylphthalides

Article abstract of DOI:10.1134/S1070428018040085

The reduction of 2-cyclopropylcarbonyl-, 2-(thiophen-2-yl)carbonyl-, and 2-arylcarbonylbenzonitriles with sodium tetrahydridoborate afforded 3-cyclopropyl-, 3-(2-thiophen-2-yl)-, and 3-arylphthalides, respectively, in high yields. Under analogous conditions, 3-cyanobenzophenones were converted to the corresponding 3-cyanobenzhydrols.

Full text of DOI:10.1134/S1070428018040085

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 4, pp. 568–572. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © S.S. Mochalov, A.N. Fedotov, E.V. Trofimova, N.S. Zefirov, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 4,
pp. 568–571.
Reductive Heterocyclization of 2-Cyanobenzophenones
by the Action of NaBH4. New Efficient
Synthesis of 3-Arylphthalides
S. S. Mochalov, A. N. Fedotov,* E. V. Trofimova, and N. S. Zefirov†
Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
*e-mail: fed@org.chem.msu.ru
Received May 21, 2017
Abstract—The reduction of 2-cyclopropylcarbonyl-, 2-(thiophen-2-yl)carbonyl-, and 2-arylcarbonylbenzo-
nitriles with sodium tetrahydridoborate afforded 3-cyclopropyl-, 3-(2-thiophen-2-yl)-, and 3-arylphthalides,
respectively, in high yields. Under analogous conditions, 3-cyanobenzophenones were converted to the corre-
sponding 3-cyanobenzhydrols.
DOI: 10.1134/S1070428018040085
We previously described [1] an attempt to synthe-
size 3-arylpthalimides (practically important hetero-
cyclic compounds) starting from 2-acylbenzonitriles.
For this purpose, we planned to accomplish successive
transformation of initial nitriles A first to amides B and
then to o-carbamoylbenzhydrols C and cyclization of
the latter to target 3-arylphthalimidines D (Scheme 1).
However, 2-cyanobenzophenones A turned out to be-
have anomalously even in the hydrolysis stage. Unlike
3-aroylbenzonitriles which were converted in the
system CF3COOH–H2SO4 to the corresponding benz-
amides1 with high yields, and the carbonyl func-
tionality therein remained unchanged, 2-aroylbenzo-
nitriles under the same conditions gave rise to 3-aryl-3-
hydroxyphthalimidines E. Thus, the aroyl substituent
in the ortho position with respect to the cyano group
in the initial benzonitrile is subject to intramolecular
interaction during the hydrolysis process, so that the
formation of target benzamides C becomes impossible.
The failure to convert 2-cyanobenzophenones to
3-arylphthalimidines D prompted us to try to obtain
the latter from the same benzonitriles but in a dif-
ferent way.
cyclopropane ring in the presence of concd. H2SO4
generates benzylic cation G which is incapable of
interacting with the cyano group because of its linear
structure. Modification of the cyano group via addition
of sulfuric acid thereto gives imidate group (structure
H), so that the intramolecular interaction between the
cationic center and modified cyano group becomes
possible. The subsequent closure of five-membered
ring and hydrolysis yield final structure J (Scheme 2).
We presumed that analogous scheme of formation
of 3-substituted phthalimidines is possible in reactions
of benzonitriles with an ortho-substituent capable of
generating benzylic cation under similar conditions.
Taking into account that benzyl alcohols in acidic
medium are readily converted to carbenium ions, we
made an attempt to synthesize 2-cyanobenzhydrols and
study their behavior under the conditions ensuring the
transformation of 2-cyclopropylbenzonitriles [2]. We
planned to obtain the required 2-cyanobenzhydrols by
reduction of the carbonyl group in 2-cyanobenzo-
phenones with NaBH4; it is known that this reducing
agent is inactive toward cyano group.
Initial 2-cyanobenzophenones 2a–2k were synthe-
sized by nucleophilic substitution of bromine in
2-bromobenzophenones by the action of copper(I)
cyanide in DMF (Rosenmund–von Braun reaction;
Scheme 3). Initially, we examined the reduction with
NaBH4 of benzophenone 2l in which the cyano group
is located in the meta position with respect to the car-
According to the data of [2], 2-cyclopropylbenzo-
nitriles can be converted to 3-ethylphthalimidines by
the action of concentrated sulfuric acid. Opening of the
†
Deceased.
1
This study was performed specially to compare with the behavior
of 2-aroylbenzonitriles under the given hydrolysis conditions.
568

REDUCTIVE HETEROCYCLIZATION OF 2-CYANOBENZOPHENONES
569
Scheme 1.
OH
CF3COOH–H2SO4
R1
R3
or CF3COOH
NH
R2
O
O
R3
R1
R2
E
CN
O
OH
R3
R3
(1) CF3COOH–H2SO4
(2) H2O
R1
R2
R1
R2
A
NaBH4
CONH2
CONH2
B
C
R3
R1
R2
CF3COOH, 20°C
NH
O
D
Scheme 2.
Me
Me
Me
H2SO4
H2SO4
NH
NH
OSO3H
X
CN
X
CN
X
X
OSO3H
F
G
H
I
Et
H2O, 0°C
NH
X
O
J
bonyl group. This reaction afforded with high yield
benzhydrol 3 with the cyano group being unchanged
(Scheme 4). Unlike nitrile 2l, ortho-cyanobenzo-
phenones 2a–2k behaved differently under analogous
conditions. The reaction gave 3-arylphthalides 4a–4k
rather than the corresponding 2-cyanobenzhydrols 5a–
5k (Scheme 5). Thus, the close position of the cyano
group to the carbonyl substituent is the crucial factor
preventing formation of benzhydrols 5a–5k in the re-
duction of 2-cyanobenzophenones 2a–2k with NaBH4.
Scheme 6 illustrates a probable mechanism of forma-
tion of 3-arylphthalides 4a–4k under the given condi-
tions. In the first stage, the addition of tetrahydrido-
borate ion to the carbonyl group of 2 gives boron
alkoxide K, which is likely to facilitate intramolecular
ring closure via nucleophilic attack on the C≡N carbon
atom with formation of intermediate L. Treatment of
Scheme 3.
O
O
R1
R2
R1
R2
110–120°C, 12 h
R3
R3
Br
CN
1a–1k
2a–2k
R1R2 = OCH2CH2O, R3 = cyclo-C3H5 (a), thiophen-2-yl (b),
Ph (c), 4-MeC6H4 (d), 2-ClC6H4 (e); R1 = R2 = OMe, R3 =
4-MeC6H4 (f); R1 = R2 = H, R3 = Ph (g), 4-MeC6H4 (h),
4-MeOC6H4 (i), 4-BrC6H4 (j), 1,4-benzodioxan-6-yl (k).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

MOCHALOV et al.
570
Scheme 4.
O
OH
(1) NaBH4, EtOH
(2) 2 N HCl
NC
O
O
NC
O
O
2l
3
Scheme 5.
OH
CN
O
(1) NaBH4, EtOH
(2) 2 N HCl
(3) H2O, 100°C
R3
O
(1) NaBH4, EtOH
(2) 2 N HCl
R1
R2
R1
R1
R2
R3
R3
R2
CN
O
5a–5k
2a–2k
4a–4k
R1R2 = OCH2CH2O, R3 = cyclo-C3H5 (a), thiophen-2-yl (b), Ph (c), 4-MeC6H4 (d), 2-ClC6H4 (e); R1 = R2 = OMe, R3 = 4-MeC6H4 (f);
R1 = R2 = H, R3 = Ph (g), 4-MeC6H4 (h), 4-MeOC6H4 (i), 4-BrC6H4 (j), 1,4-benzodioxan-6-yl (k).
Scheme 6.
R3
R3
O
R3
O
R1
R2
BH3
R1
R2
R1
R2
NaBH4, EtOH
EtOH
HCl
O
N
2a–2k
BH3
NH
NH
K
L
M
R3
R1
H2O, 100°C, 0.5 h
O
R2
O
4a–4k
the reaction mixture with 2 N aqueous HCl yields
iminofuran structure M which is unstable [3] and is
readily hydrolyzed further to final products 4a–4k.
lyzer. The melting points were determined using
an Electrothermal 1A9100 digital melting point appa-
ratus. The products were isolated, and their purity was
checked, by chromatography on Al2O3 of Brockmann
activity grade II using diethyl ether–chloroform–pe-
troleum ether (40–70°C), 1:1:3 or 1:1:2, as eluent.
Thus, the observed reductive heterocyclization of
2-cyanobenzophenones can be regarded as a novel
efficient method of synthesis of 3-substituted
phthalides. The synthetic potential of this method is
likely to be determined only by the accessibility of
initial 2-acylbenzonitriles.
Aroylbenzonitriles 2a–2l were synthesized from
the corresponding 2-bromobenzophenones 1a–1k and
3-bromobenzophenone 1l according to the procedure
described in [1]. Their physical constants and spectral
parameters were in agreement with published data [1].
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
3-[(1,4-Benzodioxan-6-yl)(hydroxy)methyl]-
benzonitrile (3). 3-Cyanobenzophenone 2l, 1 mmol,
was added with stirring over a period of 0.5 h to a sus-
pension of 0.04 g (1 mmol) of NaBH4 in 5 mL of
ethanol, and the mixture was stirred for 1 h at 40–50°C
and was left to stand for 24 h at 20°C. The mixture was
treated with 2 N aqueous HCl until weakly acidic reac-
tion, poured into 150 mL of water, and extracted with
VXR-400 spectrometer at 400.13 MHz using CDCl3 or
DMSO-d6 as solvent; the chemical shifts were meas-
ured relative to the residual proton signal of the solvent
(CHCl3) or tetramethylsilane (DMSO-d6). The mass
spectra (electron impact, 70 eV) were recorded on
a Finnigan MAT Incos-50 instrument. The elemental
analyses were determined with a Vario-11 CHN ana-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

REDUCTIVE HETEROCYCLIZATION OF 2-CYANOBENZOPHENONES
571
diethyl ether. The extract was dried over CaCl2 and
evaporated, and the residue was subjected to prepara-
tive thin-layer chromatography on Al2O3 using diethyl
ether–chloroform–petroleum ether (40–70°C), 1:1:2,
as eluent. Yield 0.25 g (94%), oily material. H NMR
spectrum (CDCl3), δ, ppm: 4.25 m (4H, OCH2CH2O),
5.74 s (1H, CHOH), 6.10 s (1H, OH), 6.83 m (3H,
4.31 m (4H, OCH2CH2O), 6.26 s (1H, 8-H), 6.75 s
(1H, Harom), 7.24–7.28 m (2H, Harom), 7.35–7.38 m
(3H, Harom), 7.40 s (1H, Harom). Mass spectrum, m/z
(Irel, %): 268 (78) [M]+, 239 (23), 191 (26), 168 (32),
163 (100), 152 (10), 139 (90), 134 (31), 127 (12), 105
(32), 89 (12), 77 (84), 74 (24), 69 (18), 63 (36), 50
(90), 39 (19). Found, %: C 71.55, 71.77; H 4.18, 4.26.
C16H12O4. Calculated, %: C 71.64; H 4.51. M 268.27.
1
H
arom), 7.43 m (1H, Harom), 7.54 d (1H, Harom, J =
7.6 Hz), 7.62 d (1H, Harom, J = 7.8 Hz), 7.69 s (1H,
arom). Found, %: C 71.82, 71.98; H 4.68, 4.81;
8-(4-Methylphenyl)-2,3-dihydrofuro[3,4-g][1,4]-
benzodioxin-6(8H)-one (4d). Yield 79%, mp 145–
H
1
N 5.06, 5.12. C16H13NO3. Calculated, %: C 71.90;
H 4.90; N 5.24.
147°C (from EtOH). H NMR spectrum (CDCl3), δ,
ppm: 2.36 s (3H, CH3), 4.31 m (4H, OCH2CH2O),
6.25 s (1H, 8-H), 6.75 s (1H, Harom), 7.16 d (2H, Harom
,
Reductive heterocyclization of 2-acylbenzoni-
triles 2a–2k by the action of NaBH4 (general proce-
dure). Compound 2a–2k, 1 mmol, was added with
stirring over a period of 0.5 h to a suspension of 0.04 g
(1 mmol) of NaBH4 in 5 mL of ethanol, and the
mixture was heated to 40–50°C, kept for 1 h at that
temperature, and left to stand for 24 h at 20°C. The
mixture was treated with 2 N aqueous HCl, poured into
150 mL of water, refluxed for 0.5 h, and purged with
air over a period of 1 h to remove residual ethanol. The
precipitate was filtered off and recrystallized from
an appropriate solvent or purified by preparative thin-
layer chromatography on Al2O3. We thus isolated
3-arylphthalides 4a–4k; compounds 4g, 4h, and 4j
were described previously [4, 5].
J = 8.1 Hz), 7.19 d (2H, Harom, J = 8.1 Hz), 7.42 s (1H,
Harom). Mass spectrum, m/z (Irel, %): 282 (100) [M]+,
267 (37), 182 (12), 163 (87), 153 (21), 139 (21), 119
(23), 107 (14), 91 (44), 77 (20), 69 (13), 63 (40), 50
(66), 39 (35). Found, %: C 72.11, 72.40; H 4.77, 4.85.
C17H14O4. Calculated, %: C 72.33; H 5.00. M 282.30.
8-(2-Chlorophenyl)-2,3-dihydrofuro[3,4-g][1,4]-
benzodioxin-6(8H)-one (4e). Yield 73%, mp 143–
1
144°C (from EtOH). H NMR spectrum (CDCl3), δ,
ppm: 4.30 m (4H, OCH2CH2O), 6.81 s (1H, 8-H),
3
4
6.97 s (1H, Harom), 7.13 d.d (1H, Harom, J = 7.8, J =
1.5 Hz), 7.21–7.31 m (2H, Harom), 7.41 s (1H, Harom),
3
4
8.16 d.d (1H, Harom, J = 7.9, J = 1.3 Hz). Mass
spectrum, m/z (Irel, %): 302 (100) [M]+, 267 (7), 238
(6), 223 (21), 202 (10), 191 (26), 173 (9), 163 (99),
151 (6), 139 (77), 126 (10), 111 (17), 75 (25), 69 (10),
63 (15), 50 (43). Found, %: C 63.28, 63.52; H 3.43,
3.51. C16H11ClO4. Calculated, %: C 63.48; H 3.66.
M 302.71.
8-Cyclopropyl-2,3-dihydrofuro[3,4-g][1,4]benzo-
dioxin-6(8H)-one (4a). Yield 69%, mp 142–143°C
1
(purified by chromatography). H NMR spectrum
(CDCl3), δ, ppm: 0.55–0.76 m (4H) and 1.08 m (1H)
(C3H5), 4.39 m (4H, OCH2CH2O), 4.75 d (1H, 8-H, J =
7.3 Hz), 6.98 s (1H, Harom), 7.36 s (1H, Harom). Mass
spectrum, m/z (Irel, %): 232 (23) [M]+, 204 (10), 191
(25), 176 (20), 163 (91), 148 (9), 135 (9), 107 (15),
103 (15), 77 (22), 74 (12), 69 (21), 63 (25), 53 (14), 50
(53), 39 (100). Found, %: C 67.42, 67.53; H 5.18,
5.31. C13H12O4. Calculated, %: C 67.23; H 5.43.
M 232.24.
5,6-Dimethoxy-3-(4-methylphenyl)-2-benzo-
furan-1(3H)-one (4f). Yield 66%, mp 156–157°C
1
(from EtOH). H NMR spectrum (DMSO-d6), δ, ppm:
2.33 s (3H, CH3), 3.79 s (3H, OCH3), 3.87 s (3H,
OCH3), 6.51 s (1H, 3-H), 6.90 s (1H, Harom), 7.17 d
(2H, Harom, J = 8.1 Hz), 7.22 d (2H, Harom, J = 8.1 Hz),
7.33 s (1H, Harom). Mass spectrum, m/z (Irel, %): 284
(19) [M]+, 269 (6), 182 (6), 165 (100), 152 (7), 139 (6),
119 (15), 91 (12), 77 (6), 63 (7), 50 (6), 39 (6). Found,
%: C 71.93, 72.08; H 5.56, 5.74. C17H16O4. Calculated,
%: C 71.82; H 5.67. M 284.31.
8-(Thiophen-2-yl)-2,3-dihydrofuro[3,4-g][1,4]-
benzodioxin-6(8H)-one (4b). Yield 64%, mp 152–
1
153°C (purified by chromatography). H NMR spec-
trum (CDCl3), δ, ppm: 4.32 m (4H, OCH2CH2O),
6.54 s (1H, HTh), 6.90 s (1H, Harom), 7.01 m (1H, HTh),
7.14 d (1H, HTh, J = 2.6 Hz), 7.35 d (1H, HTh,
J = 4.0 Hz), 7.41 s (1H, Harom). Found, %: C 61.08,
61.21; H 3.29, 3.42. C14H10O4S. Calculated, %:
C 61.30; H 3.67.
3-(4-Methoxyphenyl)-2-benzofuran-1(3H)-one
(4i). Yield 82%, mp 115–117°C (purified by chroma-
1
tography). H NMR spectrum (CDCl3), δ, ppm: 3.82 s
(3H, OCH3), 6.39 s (1H, 2-H), 6.91 d.d (2H, Harom, 3J =
4
3
4
7.2, J = 1.9 Hz), 7.19 d.d (2H, Harom, J = 7.2, J =
3
4
8-Phenyl-2,3-dihydrofuro[3,4-g][1,4]benzodi-
oxin-6(8H)-one (4c). Yield 88%, mp 167–168°C (from
1.9 Hz), 7.33 d.d (1H, Harom, J = 7.6, J = 0.9 Hz),
7.57 m (1H, Harom), 7.67 m (1H, Harom), 7.97 d (1H,
Harom, J = 7.6 Hz). Mass spectrum, m/z (Irel, %): 240
1
EtOH). H NMR spectrum (CDCl3), δ, ppm: 4.26–
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MOCHALOV et al.
572
(86) [M]+, 209 (22), 195 (28), 181 (32), 165 (40), 152
(61), 135 (99), 104 (100), 92 (19), 77 (75), 63 (34), 51
(42), 44 (17), 39 (25). Found, %: C 75.01, 75.21;
H 5.02, 5.15. C15H12O3. Calculated, %: C 74.99;
H 5.03. M 240.26.
This study was performed under financial support
by the Council for Grants at the President of the
Russian Federation (project no. NSh 10268.2016.3).
REFERENCES
3-(2,3-Dihydro-1,4-benzodioxan-6-yl)-2-benzo-
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Zefirov, N.S., Russ. J. Org. Chem., 2018, vol. 54, no. 3,
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furan-1(3H)-one (4k). Yield 66%, mp 136–137°C
1
(from EtOH). H NMR spectrum (CDCl3), δ, ppm:
4.26 m (4H, OCH2CH2O), 6.32 s (1H, 3-H), 6.75–
6.79 m (2H, Harom), 6.88 d (1H, Harom, J = 8.2 Hz),
7.35 d (1H, Harom, J = 7.6 Hz), 7.57 m (1H, Harom),
7.67 m (1H, Harom), 7.96 d (1H, Harom, J = 7.7 Hz).
Mass spectrum, m/z (Irel, %): 268 (45) [M]+, 168 (32),
163 (29), 152 (6), 139 (40), 133 (14), 128 (16), 113
(7), 104 (100), 87 (12), 77 (86), 63 (44), 51 (92), 43
(12), 39 (26). Found, %: C 71.55, 71.79; H 4.28, 4.37.
C16H12O4. Calculated, %: C 71.64; H 4.51. M 268.27.
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