Unexpected formation of benzofuran derivatives in the C-amidoalkylation of p-cresol with 4-chloro-N-(2,2-dichloro-2-phenylethylidene)benzenesulfonamide

Article abstract of DOI:10.1007/s10593-012-0919-0

The C-amidoalkylation of p-cresol with 4-chloro-N-(2,2-dichloro-2- phenylethylidene)benzenesulfon-amide in the presence of H₂SO ₄, oleum, or a mixture of H₂SO₄ and P ₄O₁₀ was studied for the first time. It was shown that the reaction not only leads to the targeted 4-chloro-N-[2,2-dichloro-1-(2-hydroxy- 5-methylphenyl)-2-phenylethyl]benzenesulfonamide but is also accompanied by unexpected formation of the heterocyclic derivatives 4-chloro-N-(5-methyl-2- phenyl-1-benzofuran-3-yl)benzenesulfonamide and 5-methyl-3-phenyl-2-benzofuran- 2(3H)-one.

Full text of DOI:10.1007/s10593-012-0919-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 11, February, 2012 (Russian Original Vol. 47, No. 11, November, 2011)
UNEXPECTED FORMATION OF BENZOFURAN
DERIVATIVES IN THE C-AMIDOALKYLATION
OF p-CRESOL WITH 4-CHLORO-N-(2,2-DICHLORO-
2-PHENYLETHYLIDENE)BENZENESULFONAMIDE*
V. Yu. Serykh1, I. B. Rozentsveig1**, G. N. Rozentsveig1, and K. A. Chernyshev1
The C-amidoalkylation of p-cresol with 4-chloro-N-(2,2-dichloro-2-phenylethylidene)benzenesulfon-
amide in the presence of H2SO4, oleum, or a mixture of H2SO4 and P4O10 was studied for the first time. It
was shown that the reaction not only leads to the targeted 4-chloro-N-[2,2-dichloro-1-(2-hydroxy-
5-methylphenyl)-2-phenylethyl]benzenesulfonamide but is also accompanied by unexpected formation of
the heterocyclic derivatives 4-chloro-N-(5-methyl-2-phenyl-1-benzofuran-3-yl)benzenesulfonamide and
5-methyl-3-phenyl-2-benzofuran-2(3H)-one.
Keywords: benzofurans, p-cresol, imines, sulfonamides, C-amidoalkylation, acid catalysis,
heterocyclization, nucleophilic addition.
Due to the presence of strong electron-withdrawing substituents the polychloro aldehyde N-sulfonyl-
imines possess enhanced electrophilicity and are highly active in reactions with various nucleophilic reagents.
This makes it possible to synthesize effectively various derivatives of the sulfonamide series [1].
We are systematically studying the amidoalkylation of aromatic and heteroaromatic compounds by the
polychloro aldehyde sulfonylimines [1-7] since the amidopolychloroethylated derivatives of arenes and
hetarenes are used as convenient reagents for production of functionalized sulfonamido-substituted acyclic and
O-, N-, and S-heterocyclic compounds [8-12].
In a continuation of this work, we have investigated the C-amidoalkylation of p-cresol with 4-chloro-
N-(2,2-dichloro-2-phenylethylidene)benzenesulfonamide (1), which is a typical available representative of
activated electron-deficient sulfonylimines [1].
It was found that in the presence of concentrated H2SO4, oleum, or the H2SO4–P4O10 mixture derivatives
of the benzofuran series 4-chloro-N-(5-methyl-2-phenyl-1-benzofuran-3-yl)benzenesulfonamide (3) and
5-methyl-3-phenyl-2-benzofuran-2(3H)-one (4) are unexpectedly formed along with the desired C-amidoalkylation
product 4-chloro-N-[2,2-dichloro-1-(2-hydroxy-5-methylphenyl)-2-phenylethyl]benzenesulfonamide (2).
_______
*Dedicated to Academician M. G. Voronkov on his 90th birthday.
**To whom correspondence should be addressed, e-mail: i_roz@irioch.irk.ru.
1A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky St.,
Irkutsk 664033, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1617-1622, November, 2011.
Original article submitted April 28, 2011.
0009-3122/12/4711-1339©2012 Springer Science+Business Media, Inc.
1339

The reaction proceeds while the reagents are stirred in CCl4 without heating and is in all cases
accompanied by the formation of 4-chlorobenzenesulfonamide, the lowest yield of which (8%) was obtained
when the process was carried out in the presence of the H2SO4–P4O10 mixture.
OH
Cl
Cl
Ph
H2SO4–P4O10
CCl4
N
+
ArSO2
Me
1
Cl
Cl
Ph
OH
ArSO2HN
Me
NHSO2Ar
Ph
Ph
Me
Me
+
+
O
O
O
3
4
2
Ar = 4-ClC6H4
The structure of compounds 2-4, formed in the reaction of the imine 1 with p-cresol, was proved by full
1
13
1
assignment of all the signals in the H and C NMR spectra using H–13C HSQC, 1H–13C HMBC, and NOESY
two-dimensional correlation experiments (Fig. 1, 2). Thus, cross peaks between the protons of the methyl group
and the H-4 and H-6 protons of the cresol ring were observed in the NOESY spectra of the C-amidoalkylation
product 2, and this indicates their spatial proximity. The H-4 proton also has a cross peak with the H-3 proton,
which in turn correlates with the OH group, while the H-6 proton correlates with the NH group. Thus, the
obtained data reliably confirm the structure of compound 2.
O
Cl
S
N
H
C
H
O
CCl2
OH
H
1
4
2
6
5
3
H
H3C
H
Fig. 1. The cross peaks in the NOESY spectrum confirming the structure of compound 2.
O
Cl
S
H
N
O
H
3
2
H
Me
H
3a
O
7a
4
4
H
5
3a
7a
3
7
6
5
H
6
7
Me
2
H
O
O
H
H
3
4
Fig. 2. The cross peaks in the 1H–13C HMBC spectra (3JC,H) confirming the structure of compounds 3 and 4.
1340

TABLE 1. Physicochemical Characteristics of Compounds 2-4
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
С
H
Cl
N
S
2
3
4
C21H18Cl3NO3S
C21H16ClNO3S
C15H12O2
53.31
53.58
63.35
63.39
80.12
80.34
3.90
3.85
4.02
4.05
5.42
5.39
22.78
22.59
8.84
8.91
2.96
2.98
3.58
3.52
6.90
6.81
7.98
8.06
132-134
189-191
65-67
68
23
8
—
—
—
The assignment of the C-4–C-7 and also the C-3a–C-7a carbon atoms in compounds 3 and 4 is easily
made by the joint use of data on the direct and long-range correlation of the H-4, H-6, and H-7 protons with the
respective carbon atoms using the 1H–13C HSQC and 1H–13C HMBC methods optimized for spin–spin coupling
constants of 10 Hz (Fig. 2). A question common to the given compounds is the position of the benzene ring in
the benzofuran ring. Thus, in the 1H–13C HMBC spectrum of compound 3, there are cross peaks for the protons
of the NH group and the o-H atom of the benzene ring with carbon atom, resonating at 151.0 ppm, for which the
other interactions are absent. In the case if this carbon atom were at position 3 of the benzofuran ring, a cross
peak would be observed with the H-4 proton, but its absence makes it possible to conclude that the given carbon
atom (151.0 ppm) is at position 2. The H-4 proton does in fact have a cross peak with the carbon atom at 112.8
ppm, for which additional interactions are absent. Consequently, the given carbon atom must be assigned as C-3.
Similarly, for the benzofuranone 4, it is possible to observe long-range interaction of the H-4 proton and o-H
TABLE 2. Spectral Characteristics of Compounds 2-4.
Com- IR spectrum,
pound
1H NMR spectrum, δ, ppm (J, Hz)
13C NMR spectrum, δ, ppm
ν, сm–1
1165,
2.00 (3Н, s, CH3);
20.2 (CH3); 60.9 (СНCCl2);
95.7 (CCl2); 114.1 (C-3);
120.9 (C-1); 126.3 (C-5);
127.5 (o-С Ph); 127.5 (m-С Ph);
127.9 (o-С Ar); 128.1 (m-С Ar);
129.0 (p-С Ph, C-4); 129.2 (C-6);
136.6 (p-С Ar); 139.3 (i-С C6H4);
140.0 (i-С Ph); 152.7 (C-2)
2
1360 (SO2), 5.70 (1Н, d, 3J = 10.7, СНCCl2);
3275 (NH)
6.32 (1Н, d, 3J = 8.2, Н-3);
6.67 (1Н, dd, 3J = 8.2, 4J = 1.8, Н-4);
7.03 (1Н, d, 4J = 1.8, Н-6);
7.22 (2H, AA'BB', J(AB) = J(A'B') = 8.7,
J(AA') = 4.6, J(BB') = 4.2, m-Н Ar);
7.32 (1Н, m, р-H Ph);
7.34 (2Н, m, o-H Ph); 7.40 (2H,
AA'BB', J(AB) = J(A'B') = 8.7, J(AA') = 4.6,
J(BB') = 4.2, o-Н Ar);
7.57 (2Н, m, m-H Ph);
8.46 (1Н, d, 3J = 10.7, NH);
9.13 (1H, s, OH)
1170,
2.24 (3H, s, CH3);
20.6 (CH3); 110.9 (С-7);
3
6.54 (1Н, d, 4J = 1.6, Н-4);
7.10 (1Н, dd, 3J = 8.4, 4J = 1.6, Н-6);
7.40 (2Н, m, o-Н Ph);
112.8 (C-3); 118.9 (C-4);
125.9 (m-С Ph); 126.3 (C-6);
127.1 (C-5); 128.4 (o-С Ph);
128.6 (С-3a); 128.8 (o-С Ar);
128.9 (i-С Ph); 129.2 (m-С Ar);
132.0 (p-С Ph); 137.9 (p-С Ar);
139.2 (i-С С6Н4); 150.5 (С-7а);
151.0 (С-2).
1380 (SO2),
3300 (NH)
7.41 (1Н, m, p-Н Ph);
7.44 (1Н, d, 3J = 8.4, Н-7);
7.48 (2H, AA'BB', J(AB) = J(A'B') = 8.7,
J(AA') = 4.6, J(BB') = 4.2, m-Н Ar);
7.62 (2H, AA'BB', J(AB) = J(A'B') = 8.7,
J(AA') = 4.6, J(BB') = 4.2, o-Н Ar);
7.91 (2Н, m, m-Н Ph); 10.12 (1Н, s, NH)
1057 (С–О), 2.28 (3Н, s, СН3); 4.79 (1Н, s, Н-3);
21.1 (СН3); 50.0 (C-3); 110.5 (C-7);
128.2 (p-С Ph); 128.3 (o-С Ph);
129.2 (m-С Ph); 135.4 (i-С Ph);
125.8 (C-4); 127.1 (C-3a);
129.8 (C-6); 134.2 (C-5);
151.9 (C-7а); 175.4 (C-2)
4
6.96 (1Н, d, 4J = 1.3, H-4);
1487,
7.10 (1Н, dd, 3J = 8.3, 4J = 1.3, H-6);
1802 (С=О)
7.18 (2Н, m, o-Н Ph);
7.28 (1Н, m, p-Н Ph);
7.32 (2Н, m, m-Н Ph);
7.34 (1Н, d, 3J = 8.3, H-7).
1341

proton of the benzene ring with the carbon atom at 50.0 ppm, which corresponds to a shift of the carbon atom of
the methine fragment; on the other hand, for the H-4 proton the cross peak with the carbonyl carbon atom
(175.4 ppm) is absent, indicating that the benzene ring is located at the C-3 carbon atom. Thus, the proposed
structure of benzofuran 3 and benzofuranone 4 is fully confirmed.
The structure of compounds 2-4 is also confirmed by the data of IR spectroscopy and elemental analysis
(Tables 1 and 2).
We assumed that the benzofuran 3 is formed as a result of intramolecular heterocyclization of the
C-amidoalkylation product 2. This suggestion was confirmed by an additional experiment: when stirred in the
presence of H2SO4–P4O10 compound 2 was completely converted into benzofuran 3 after 5 h.
Evidently, during acid catalysis protonation of the starting azomethine 1 proceeds with formation of the
amidoalkyl carbocation A, which reacts with p-cresol to give the amidoalkylation product 2. Substitution here
takes place selectively at the ortho position to the hydroxyl group of p-cresol. Compound 2 enters into further
heterocyclization on account of substitution of the chlorine atom of the dichloromethylene group with formation
of the cyclic intermediate B, which is dehydrochlorinated to the final benzofuran 3.
The ease of these processes is probably determined by the effect of the benzene ring, which facilitates
substitution of the chlorine atom at the benzylic position, by the intramolecular nature of the substitution, and by
the gain of energy as a result of formation of the thermodynamically stable heteroaromatic structure.
Cl
Cl
Ph
OH
ArSO2HN
Me
NHSO2Ar
Ph
Me
4-MeC6H4OH
Cl
+
Cl
Ph
H
H+
3
N
1
– HCl
ArSO2
– HCl
Cl
O
2
B
A
Ar = 4-ClC6H4
The most likely path to formation of the benzofuranone 4 probably includes nucleophilic addition of
p-cresol to the azomethine group with formation of the O-adduct C, which undergoes hydrolytic transformations
with elimination of 4-chlorobenzenesulfonamide presumably as shown in the scheme. It is possible that some of
these processes are realized during the work-up of the synthesis. The ability of polychloro aldehydes
sulfonylimines to form O-adducts of type C has been described in the literature [1].
O
Cl
O
Cl
Ph
H
N
H
N
Ph
ArSO2
ArSO2
OH
O
1
+
– 2HCl
Me
C
Ph
OH
Ph
O
Me
Me
4
OH
OH
– ArSO2NH2
– H2O
O
Ar = 4-ClC6H4
1342

Thus, it has been demonstrated for the first time that heterocyclic compounds of the 3-amidobenzofuran
and benzofuran-3-one series can be synthesized by the reaction of N-(2,2-dichloro-2-phenylethyl-
idene)arenesulfonamide and p-cresol. It should be noted that 3-amino- and 3-amidobenzofuran compounds
exhibit biological activity [13-16] and are important reagents [14-17]. For this reason it is of current interest to
improve further the new synthetic approach to 3-sulfonamidobenzofurans of type 3 based on the transformations
of available reagents, which are activated electron-deficient polychloroacetaldehyde sulfonylimines and para-
substituted phenols. Moreover, study of the benzofuran ring formation mechanism is of fundamental interest.
EXPERIMENTAL
1
The IR spectra were obtained on a Bruker IFS instrument using KBr pellets. The H and 13C NMR
spectra were obtained on a Bruker DPX-400 spectrometer (400 and 100 MHz) with HMDS as internal standard.
Merck silica gel (0.063-0.200 mm, pH 6.5-7.5) was used for column chromatography.
Imine 1 was synthesized by the method described in [18] from 4-chloro-N,N-dichloro-
benzenesulfonamide and phenylacetylene.
Procedure for the Synthesis of Compounds 2-4. A mixture of p-cresol (0.54 g, 5 mmol), imine 1
(1.82 g, 5 mmol), P4O10 (0.28 g, 1 mmol), and 96% H2SO4 (0.55 ml, ~10 mmol) in CCl4 (10 ml) was stirred for 5
h. The reaction mixture was then mixed with 100 ml of water. The precipitated mixture of products was
separated, washed with 10% ammonia (20 ml) to remove the 4-chlorobenzenesulfonamide (formed with a yield
of 0.08 g (8%)) and again with water, and dried in vacuum. Compounds 2-4 were isolated from the mixture by
column chromatography (eluent 1:1 CHCl3–petroleum ether). Properties of the obtained compounds are
presented in Tables 1 and 2.
Synthesis of Benzofuran 3 from Compound 2. A mixture of compound 2 (0.47 g, 1 mmol), P4O10
(0.28 g, 1 mmol), and 96% H2SO4 (0.55 ml, ~10 mmol) in CCl4 (10 ml) was stirred for 5 h. The reaction mass
was then mixed with 50 ml of water, and the precipitate was filtered off, dried in vacuum, and recrystallized
from CHCl3.
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