A general synthesis of benzofuran-2-thiolates via intramolecular addition of phenolates to alkynethiolates

Article abstract of DOI:10.1039/a704025c

4-(ortho-Hydroxyaryl)-1,2,3-thiadiazoles can be transformed into benzofuran-2-thiolates via an intramolecular cyclization.

Full text of DOI:10.1039/a704025c

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A general synthesis of benzofuran-2-thiolates via intramolecular addition of
phenolates to alkynethiolates
Bart D’hooge, Stefan Smeets, Suzanne Toppet and Wim Dehaen*
Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Leuven (Heverlee), Belgium
N
4-(ortho-Hydroxyaryl)-1,2,3-thiadiazoles can be trans-
N
S
formed into benzofuran-2-thiolates via an intramolecular
R
COMe
OH
R
cyclization.
i, ii
R′
R′
OH
1,2,3-Thiadiazoles 1, unsubstituted at the 5-position, are cleanly
decomposed into alkynethiolates 2 under the influence of strong
bases such as organolithium reagents, sodamide, sodium
hydride and potassium tert-butoxide.1 These alkynethiolates are
interesting reagents which have been alkylated and acylated at
sulfur, and converted with nucleophiles into derivatives of the
thioketenes 3 which result from protonation at carbon of 2.1,2
Another possibility is the combination of alkynethiolate 2 with
thioketene 3 to give a dithiafulvene 4. The dimer 42 will be
formed in protic solvents or when no efficient nucleophile is
present to trap the thioketene 3 (Scheme 1).
5a–c
6a–c
iii
iii
N
N
S
R
R
SR′′
O
R′
OR′′
R′
7a
8a–e
Scheme 2 Reagents and conditions: i, EtO2CNHNH2; ii, SOCl2; iii, base,
RBX, acetone, reflux
The method of Hurd and Mori3 gives access to 5-unsubsti-
tuted 1,2,3-thiadiazoles 1, and consists of reacting methyl
ketones successively with ethyl carbazate (or tosylhydrazide)
and thionyl chloride. This procedure was used to obtain
4-(orthohydroxyaryl)-1,2,3-thiadiazoles 6a–c from the aceto-
phenones 5a–c in 37–74% overall yield.4 We wanted to use the
alkylation of phenol 6a as a means to attach the 1,2,3-thiadi-
azole group to other molecules.5 However, the thiadiazole 6a
proved to be susceptible to relatively weak bases, such as
potassium carbonate, and in the presence of alkylating agents
the unexpected thioethers 8a–c were formed in high yields
instead of the O-alkylated thiadiazoles 7. Only with the very
reactive methyl iodide is some O-alkylated product 7a formed.
The formation of 7a can be suppressed by adding the alkylating
agent after the decomposition is completed. (Scheme 2, Table
1).
phenyl protons at the 3, 4 and 5 positions moved upfield by 0.42,
0.34 and 0.64 ppm, respectively, whereas the 6-H was little
affected (Dd +0.17 ppm). Slow nitrogen evolution was
1
observed, and after a period of 21 h the H NMR spectrum
corresponded to a 1:1 mixture of compounds 9 and 13. The 5-H
of the 1,2,3-thiadiazole ring of 9 was partially deuterated under
these conditions, proving the intermediacy of the 1,2,3-thiadi-
azol-5-yl anion 10. After 93 h the reaction was completed and
the NMR spectrum showed a clean absorption pattern of
benzofuran-2-thiolate7 with dH 5.98 (3-H), 6.81, 6.90 (5-H and
6-H) and 7.06 (4-H and 7-H), with no detectable impurities
present. When the same reaction was followed by NMR
spectroscopy in [2H6]DMSO, the alkynethiolate 11 (48%) was
observed after 15 min, together with the phenolate 9 (35%) and
benzofuran 13 (17%). Compound 11 showed peaks in the 13C
NMR spectrum at d 71.8 (d) and 101.2 (s) for the alkyne
carbons (respectively b and a to sulfur). After 3 h the phenolate
9 had disappeared and the spectrum showed a 1:1 mixture of 11
and 13. The 13C NMR spectrum of thiolate 13 had peaks at
173.9 (d, 2JCH 9 Hz) and 99.1 (d, 1JCH 173 Hz) for the C-2 and
C-3 carbons of the benzofuran, respectively. After one week,
the transformation to benzofuranthiolate 13 was complete and
the reaction could be treated with methyl iodide to give an
immediate and quantitative reaction, affording the sulfide 8a.
From this it follows that an alternative pathway where, in the
first step, the alkynethiolate 11 is alkylated, followed by
The mechanism of this unusual reaction was elucidated by
1
following the decomposition of 6a by H NMR (400 MHz)
spectroscopy. Thus, a solution of compound 6a in CD3CN was
treated with aqueous tetrabutylammonium hydroxide at room
temperature. Initially, the phenolate 9 was present as indicated
by the disappearance of the phenolic OH at dH 9.69 (as
compared to the spectrum without base) and the downfield shift
of the thiadiazole 5-H from dH 9.20 to 9.76. In addition, the
S
RCH2
C
Nu
NuH
Table 1 Products and yields from the reactions of 6a–c with base and
alkylating agents
R
H
R
H
Base
H +
R
C
C
S–
C C S
N
S
Yield (%)a
N
Starting
material
1
2
3
R
RA
RBX
Products
7
8
6a
6a
6a
6b
6c
H
H
H
OH
H
H
H
H
H
MeI
BnCl
C16H33Br
7a + 8a
8b
8c
8d
8e
43
0
0
0
0
56
91
97
92
46
R
H
R
H
S
S
C
16H33Br
OH
C16H33Br
4
Scheme 1
a Isolated yields after chromatographic separation.
Chem. Commun., 1997
1753

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–
SC16H33
O
N
H
O
OH
Base
6a
COMe
i–iii
S
N
9
Cl
14
15
–
OH
N
OH
O
C
–N2
Scheme 4 Reagents and conditions: i, EtO2CNHNH2; ii, SOCl2; iii, K2CO3,
16H33Br, acetone, reflux
–
C
C
S
S
H
–
S
N
10
11
12
similar strategy from 2-acetyl-1-naphthol 14. The chlorine was
introduced on the electron rich naphthol at the stage of the
Hurd–Mori reaction (Scheme 4).3
Financial support from the University is gratefully acknow-
ledged. B. D. thanks the I.W.T. for a predoctoral fellowship.
MeI
–
SMe
S
O
O
8a
13
Scheme 3
Footnote and References
* E-mail: wim.dehaen@chem.kuleuven.ac.be
intramolecular phenolate addition,8 can be excluded (Scheme
3).
1 R. Raap and R. G. Micetich, Can. J. Chem., 1968, 46, 1057; G. L’abbe´,
W. Dehaen and B. Haelterman, J. Chem. Soc., Perkin Trans. 1, 1994,
2203.
2 R. Mayer, B. Hunger, R. Prousa and A. K. Mu¨ller, J. Prakt. Chem., 1967,
35, 294; A. Shafiee and I. Lalezari, J. Heterocycl. Chem., 1973, 10,
11.
3 C. D. Hurd and R. I. Mori, J. Am. Chem. Soc., 1955, 77, 5359; R. N.
Butler and D. A. O’Donoghue, J. Chem. Soc., Perkin Trans. 1, 1982,
1223.
4 The synthesis of compound 6 has been reported before in a patent without
experimental data: J. M. Muchowski and J. H. Fried, US Pat., 3 940 407,
1976; Chem. Abstr., 1976, 85, P63072a.
5 For instance, we used the isomeric 4-(4-hydroxyphenyl)-1,2,3-thiadi-
azole in a convergent synthesis of dendrimers: G. L’abbe´, B. Haelterman
and W. Dehaen, Bull. Soc. Chim. Belg., 1996, 105, 419.
6 The compounds 7a, 8b–e and 15 are new and were fully characterized by
IR, mass, 1H NMR and 13C NMR spectroscopy. Benzofuran 8a has been
prepared before: B. Capon and S. Q. Lew, Tetrahedron, 1992, 48,
7823.
7 P. C. Montevecchi and M. L. Navacchia, J. Org. Chem., 1995, 60, 6455;
M. Wierzbich, G. Kirsch, D. Cagniant, M. Liebermann and T. W.
Schafer, Chim. Ther., 1977, 12, 557.
It is most unusual that a weak base such as phenolate would
be capable of abstracting the 5-thiadiazole hydrogen. We found
that the decomposition reaction to alkynethiolate 2 also occurs,
although at a much slower rate (several days), when equal
amounts of phenol and 4-phenyl-1,2,3-thiadiazole 1 are reacted
in refluxing acetone in the presence of equivalent amounts of
potassium carbonate and benzyl chloride. There is no observ-
able reaction when only 1, potassium carbonate and benzyl
chloride are present, proving the intermediacy of the phenolate
anion. Here, the major products are the known2 dimeric
dithiafulvalene 4 and benzyl phenyl ether. It is interesting to
note that no dimers have been detected in the reactions starting
from 6a–c. Apparently, intramolecular phenolate addition is
much more effective than the intermolecular dimerization
process.
The generality of the reaction was investigated by reacting
the 2,4-dihydroxyphenyl- and 2,5-dihydroxyphenyl-thiadi-
azoles 6b and 6c with hexadecyl bromide under the same
reaction conditions. In the presence of one equivalent of
alkylating agent, only the S-monoalkylated products 8d and 8e,
respectively, were formed in fair to excellent yields (Scheme 1,
Table 1). The chloronaphthofuran 15 was produced following a
8 F. Weselly and E. Zbiral, Liebigs Ann. Chem., 1957, 605, 98.
Received in Liverpool, UK, 9th June 1997; 7/04025C
1754
Chem. Commun., 1997