Efficient synthesis of thiobenzanilides by Willgerodt-Kindler reaction with base catalysts

Article abstract of DOI:10.1055/s-2007-991073

Willgerodt-Kindler reaction between anilines and benzaldehydes readily proceeded in the presence of catalytic amount of Na₂S·9H ₂O to give thiobenzanilides in moderate to good yields. The base catalyst was also available for preparation of primary thiobenzamide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991073

LETTER
2687
Efficient Synthesis of Thiobenzanilides by Willgerodt–Kindler Reaction with
Base Catalysts
B
ase-Assisted Wil
e
lgerodt–Kindler Reaction Okamoto,a,b Takakazu Yamamoto,a Takaki Kanbara*b,c
a
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
b
Tsukuba Research Center for Interdisciplinary Materials Science (TIMS), University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba 305-8573,
Japan
c
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba 305-8573, Japan
Fax +81(29)8534490; E-mail: kanbara@ims.tsukuba.ac.jp
Received 2 July 2007
H
N
Ph
Ph
Abstract: Willgerodt–Kindler reaction between anilines and benz-
aldehydes readily proceeded in the presence of catalytic amount of
Na2S·9H2O to give thiobenzanilides in moderate to good yields. The
base catalyst was also available for preparation of primary thio-
benzamide.
base (cat.)
base (cat.)
Ph-NH2 + Ph-CHO + S8
Ph
S
S
H2N
NH3 (aq) + Ph-CHO + S8
Key words: sulfur, catalysis, condensation, aromatic amines, thio-
amides
Scheme 1
thiobenzanilides in low to moderate yields (15% and 39%
yields, respectively, as shown in Scheme 2); these results
are consistent with reported literatures.5a,c The first step of
the WK reaction is considered to involve cleavage of the
S–S bond of elemental sulfur caused by nucleophilic at-
tack of amine to form polysulfide anions in a reversible
way.4 The less basic amines, such as aniline, lead to only
little formation of the polysulfide anions. In contrast, ad-
dition of a small amount (5 mol%) of Na2S·9H2O in the
reaction mixtures improved the reaction as shown in
Scheme 2.
Thioamides have been used in the field of medical and
organic chemistry1,2 and aromatic thioamides have been
notably valuable building blocks for preparation of bio-
logically relevant five- and six-membered heterocycles.
Thioamides have also attracted recent attention in inclu-
sion chemistry, transition-metal coordination chemistry,
and materials science.3
The Willgerodt–Kindler (WK) reaction is extensively
used to synthesize various thioamides.1f,4 However, to our
knowledge, there have been only a few reports on the
preparation of aromatic thioamides such as thiobenz-
anilide using the WK reaction,5 and the yields have been
low unless severe reaction conditions or microwave
techniques are employed.6
Na2S·9H2O
(5 mol%)
H
N
Ph
Ph-NH2 + Ph-CHO + S8
Ph
DMF
S
115 °C, 12 h
under N2
66%
Thiobenzanilide and its derivatives have generally been
prepared by thionation of the corresponding benzanilides
with Lawesson’s reagent or P2S5.7 To eliminate the limi-
tations of the WK reaction, we have carried out the modi-
fication of the reaction conditions and found that addition
of catalytic amount of base such as Na2S·9H2O was effi-
cient for the preparation of thiobenzanilides. There have
been a few reports that addition of bases raised yields in
WK reactions,8 however, a usability of base catalysts for
synthesis of thiobenzanilides has not been examined. We
report here the efficient modification of WK reaction for
preparation of thiobenzanilides, as shown in Scheme 1.
The synthetic protocol is also available for preparation of
primary thiobenzamide.
(15% without base)
Na2S·9H2O
(5 mol%)
H
N
PMP
PMP-NH2 + PMP-CHO + S8
PMP
DMF
S
115 °C, 12 h
under N2
66%
(39% without base)
Scheme 2
To optimize the reaction conditions, the WK reaction of
benzaldehyde and aniline with sulfur was carried out
under various conditions. As shown in Table 1, the WK
reaction of benzaldehyde and aniline with sulfur smoothly
proceeded by the addition of Na2S·9H2O as the base
catalyst. The yield increased with an increase in the base
content, and 91% yield was attained with 15 mol% of
Na2S·9H2O. The yield was comparable to reported yields
for WK reaction using microwave tequnique.6 Use of
other bases such as t-BuOK, DMAP, and Et3N gave
thiobenzanilide in moderate (40–62%) yields.
The reaction of benzaldehyde with aniline and 4-anisidine
in the presence of sulfur under the conditions of the
conventional WK reaction afforded the corresponding
SYNLETT 2007, No. 17, pp 2687–2690
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
The reaction conditions of entry 9 in Table 1 were applied
for various aromatic amines and aldehydes,9 and the
DOI: 10.1055/s-2007-991073; Art ID: U06207ST
© Georg Thieme Verlag Stuttgart · New York

2688
K. Okamoto et al.
LETTER
Table 1 WK Reaction of Aniline with Benzaldehydea
results are summarized in Table 2. Na2S·9H2O was effi-
cient for the preparation of several thiobenzanilides. Di-
substituted aromatic thioamides, which could not be
prepared by the conventional WK reaction, were obtained
in moderate yields (entries 5 and 6). Na2S·9H2O was also
effective for the reaction of heteroaromatic amines and
aldehydes (entries 8–10 and 12). New compounds (entries
8, 10, and 11) were characterized by NMR spectroscopy
and elemental analysis.10
Entry
Base
Time (h) Yield (%)b
1
2
–
12
12
12
12
12
4
15
40
42
62
55
32
66
83
91
88
Et3N, 5 mol%
3
DMAP, 5mol%
t-BuOK, 5 mol%
Na2S·9H2O, 1 mol%
Na2S·9H2O, 5 mol%
Na2S·9H2O, 5 mol%
Na2S·9H2O, 10 mol%
Na2S·9H2O, 15 mol%
Na2S·9H2O, 20 mol%
4
5
Scheme 3 shows a plausible role for Na2S·9H2O in the
WK reaction. The suspension of elemental sulfur in the
DMF solution of aniline remained unreacted because of
the poor nucleophilicity of aniline. The addition of a small
amount of Na2S·9H2O into the reaction mixture of sulfur
with aniline caused a color change of the reaction system,
from pale yellow to deep blue. Therefore, the base catalyst
is considered to initiate the nucleophilic cleavage of the
elemental sulfur ring to give the polysulfide anions as
depicted in Scheme 3.
6
7
12
12
12
12
8
9
10
a Reaction conditions: aniline (6.0 mmol), benzaldehyde (4.0 mmol)
and sulfur (5.0 mmol) in DMF (4 mL) at 115 °C.
b Isolated yield.
Table 2 WK Reaction of Aromatic Amines, Arylaldehydes, and Sulfur with Catalytic Amount of Na2S·9H2Oa
Entry
Amine
Aldehyde
Product
Yield (%)b
91 (15)
S
S
CHO
NH2
1
N
H
OMe
NH2
CHO
2
3
92 (40c)
78 (7)
N
H
MeO
S
S
CHO
CHO
CHO
NH2
N
H
MeO
MeO
MeO
OMe
NH2
4
88 (39)
48 (0e)
N
H
MeO
MeO
OHC
S
S
NH2
5d
N
H
N
H
S
CHO
NH2
6d
40 (0e)
40 (0e)
N
H
H
N
OHC
S
NO2
S
NH2
CHO
7f
N
H
O2N
Synlett 2007, No. 17, 2687–2690 © Thieme Stuttgart · New York

LETTER
Base-Assisted Willgerodt–Kindler Reaction
2689
Table 2 WK Reaction of Aromatic Amines, Arylaldehydes, and Sulfur with Catalytic Amount of Na2S·9H2Oa (continued)
Entry
8
Amine
Aldehyde
Product
Yield (%)b
70 (51)
S
S
S
N
NH2
CHO
N
H
N
N
NH2
CHO
CHO
9
10
11f
12
65 (15)
45 (6)
N
H
N
N
N
NH2
N
H
S
CHO
NH2
51 (0e)
88 (71)
N
H
NC
NC
N
S
NH2
N
CHO
N
H
a Reaction was carried out in analogy with entry 9 in Table 1.
b Isolated yield; the data obtained in the absence of base is shown in parentheses.
c From ref. 5c.
d Aniline (3 equiv) was used.
e Not detected by TLC.
f Na2S·9H2O (5 mol%) was used.
initiator
slow
in moderate yield under microwave irradiation.1f The
addition of the base catalyst was also effective for the WK
reaction of benzaldehyde with aqueous ammonia,12 and
the yield was improved as shown in Scheme 4.
S
S
S
S
S
S
S
S
NH2
fast
S
S
S
Na2S·9H2O (cat.)
H2N
Ph
S
S
S
S2–
S92–, S82–, S72–···Sx
polysulfide anion
2–
NH3 (aq) + PhCHO + S8
S
(Na2S)
DMF
115 °C, 12 h
under N2
S
S
with 1 mmol cat., 49%
(18% without cat.)
Scheme 3
Scheme 4
There have been numerous investigations concerning the
reaction of elemental sulfur in amines or ammonia,11 how-
ever, the behavior and the fate of sulfur in those media
have not yet been fully elucidated. From changes of the
absorption spectra and conductivity of those media, Davis
et al. suggested that the color change of the reaction media
results from the formation of polysulfide anions and that
the related ions were generated by the initial nucleophilic
attack of amines on the sulfur ring.11a
In summary, we succeeded in improving the preparation
of thiobenzanilides and primary thiobenzamide by the
WK reaction under mild conditions. The base catalyst was
applicable for the preparation of various thiobenzanilides,
and the results will contribute to the expanded use of the
WK reaction.
Acknowledgment
Na2S·9H2O was also usable for the preparation of primary
thiobenzamide. In contrast to extensive study on the reac-
tion of elemental sulfur with ammonia,11e only a few re-
ports concerning the WK reaction of benzaldehyde with
ammonia were reported; the reaction gave thiobenzamide
The authors gratefully thank Dr. T. Koizumi of Tokyo Institute of
Technology for useful discussion. The authors are grateful to the
Chemical Analysis Center of University of Tsukuba, for measure-
ments of NMR spectra and elemental analysis.
Synlett 2007, No. 17, 2687–2690 © Thieme Stuttgart · New York

2690
K. Okamoto et al.
LETTER
1,4-Bis(anilinothiocarbonyl)benzene (Table 2, entry 6):
yellow powder; mp 280–281 °C, lit.2a 280–282 °C.
N-(4-Nitrophenyl)thiobenzamide (Table 2, entry 7):
yellow powder; mp 145–146 °C, lit.13 145 °C.
N-(4-Pyridyl)thiobenzamide (Table 2, entry 8): yellow
powder; mp 187–188 °C. 1H NMR (400 MHz, DMSO-d6):
d = 11.99 (s, 1 H), 9.59 (d, J = 6.4 Hz, 2 H), 8.00 (d, J = 6.4
Hz, 2 H), 7.78 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H),
7.47 (t, J = 7.6 Hz, 2 H). 13C{1H} NMR (100 MHz, DMSO-
d6): d = 199.35, 150.17, 146.64, 142.78, 130.99, 128.00,
127.37, 116.67. Anal. Calcd for C12H10N2S: C, 67.26; H,
4.70; N, 13.07; S, 14.96. Found: C, 67.32; H, 4.52; N, 13.15;
S, 14.88.
References and Notes
(1) (a) Jagodziński, T. S. Chem. Rev. 2003, 103, 197.
(b) Klingele, M. H.; Brooker, S. Eur. J. Org. Chem. 2004,
3422. (c) Murai, T.; Aso, H.; Tatematsu, Y.; Itoh, Y.; Niwa,
H.; Kato, S. J. Org. Chem. 2003, 68, 8514. (d) Ach, D.;
Reboul, V.; Metzner, P. Eur. J. Org. Chem. 2002, 2573.
(e) Ares, J. J. Synth. Commun. 1991, 21, 625. (f) Zbruyev,
O. I.; Stiasni, N.; Kappe, C. O. J. Comb. Chem. 2003, 5,
145. (g) Murai, T. Top. Curr. Chem. 2005, 251, 247.
(2) (a) Petrova, D.; Jakopčić, K. Croat. Chem. Acta 1976, 48,
319. (b) Downer, N. K.; Jackson, Y. A. Org. Biomol. Chem.
2004, 2, 3039. (c) Mathis, C. A.; Wang, Y.; Holt, D. P.;
Huang, G.-F.; Debnath, M. L.; Klunk, W. E. J. Med. Chem.
2003, 46, 2740.
N-(3-Pyridyl)thiobenzamide (Table 2, entry 9): yellow
powder; mp 140–141 °C, lit.14 140–141 °C.
(3) (a) Inoue, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron Lett.
2003, 44, 5167. (b) Akaiwa, M.; Kanbara, T.; Fukumoto, H.;
Yamamoto, T. J. Organomet. Chem. 2005, 690, 4192.
(c) Okamoto, K.; Kanbara, T.; Yamamoto, T.; Wada, A.
Organometallics 2006, 25, 4026. (d) Kagaya, S.; Sato, E.;
Masore, I.; Hasegawa, K.; Kanbara, T. Chem. Lett. 2003, 32,
622.
(4) (a) Kindler, K. Justus Liebigs Ann. Chem. 1923, 431, 187.
(b) Carmack, M.; Spielman, M. A. Org. React. (N. Y.) 1946,
3, 83. (c) Brown, E. V. Synthesis 1975, 358; and references
cited therein.
(5) (a) Böttcher, B.; Bauer, F. Justus Liebigs Ann. Chem. 1950,
568, 218. (b) Tandel, S.; Bliznets, I.; Ebinger, K.; Ma, Y.-A.;
Bhumralkar, D.; Thiruvazhi, M. Tetrahedron Lett. 2004, 45,
2321. (c) Pelova, R.; Kozhukharova, A. Nauchni Trudove
Plovdiv. Univ. Paisii Khilendarski, Khim 1982, 20, 79.
(6) Bulavka, V. N. Proceedings of ECSOC-8, The Eight
International Electronic Conference on Synthetic Organic
Chemistry; MDPI: Basel, 2004, E008.
(7) (a) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697.
(b) Curphey, T. J. J. Org. Chem. 2002, 67, 6461.
(8) (a) Poupaert, J. H.; Bouinidane, K.; Renard, M.; Lambert, D.
M.; Isa, M. Org. Prep. Proced. Int. 2001, 33, 335.
(b) Moghaddam, F. M.; Boinee, H. Z.; Taheri, S. J. Sulfur
Chem. 2004, 25, 407.
(9) Experimental Procedure (Table 1, entry 9): Na2S·9H2O
(216 mg, 15 mol%) was added to a mixture of sulfur (160
mg, 5 mmol as elemental sulfur) and aniline (0.55 mL, 6
mmol) in DMF (4 mL), and the suspension was stirred at
115 °C for 0.5 h under nitrogen. After the mixture was
cooled to r.t., benzaldehyde (0.41 mL, 4 mmol) was added,
and was stirred at 115 °C for 12 h under nitrogen. After
cooling to r.t., the resulting solution was quenched with sat.
aq NH4Cl solution (50 mL) and extracted with CHCl3 (50
mL). The organic fraction was thoroughly washed with H2O
(2 × 50 mL) and dried with anhyd Na2SO4. After
concentration, the resulting crude product was purified by
chromatography on silica gel with CHCl3 to afford N-
phenylthiobenzamide as a yellow powder (780 mg, 91%
yield); mp 99 °C, lit.7 99 °C.
N-(6-Quinolyl)thiobenzamide (Table 2, entry 10): orange
powder; mp 177–179 °C. 1H NMR (400 MHz, DMSO-d6):
d = 12.03 (s, 1 H), 8.90 (br, 1 H), 8.56 (br, 1 H), 8.38 (d, J =
8.0 Hz, 1 H), 8.05–8.11 (m, 2 H), 7.89 (d, J = 7.6 Hz, 2 H),
7.53–7.56 (m, 2 H), 7.49 (t, J = 7.6 Hz, 2 H). 13C{1H} NMR
(100 MHz, DMSO-d6): d = 199.81, 151.99, 147.55, 144.08,
139.55, 137.49, 132.50, 130.65, 129.67, 129.29, 129.08,
128.86, 123.41, 123.00. Anal. Calcd for C16H12N2S: C,
72.70; H, 4.58; N, 10.60; S, 12.13. Found: C, 72.62; H, 4.51;
N, 10.60; S, 11.97.
4-Cyano-N-phenylthiobenzamide (Table 2, entry 11):
orange powder; mp 130–131 °C. 1H NMR (400 MHz,
DMSO-d6): d = 12.01 (s, 1 H), 7.91–7.93 (br, 4 H), 7.83 (d,
J = 8.0 Hz, 2 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.29 (t, J = 8.0 Hz,
1 H). 13C{1H} NMR (100 MHz, DMSO-d6): d = 195.16,
146.14, 139.47, 131.96, 128.42, 127.95, 126.42, 123.74,
118.27, 112.54. Anal. Calcd for C14H10N2S: C, 70.56; H,
4.23; N, 11.76. Found: C, 70.85; H, 4.45; N, 11.71.
N-Phenyl-2-pyridinethioamide (Table 2, entry 12):
orange-yellow powder; mp 45 °C, lit.15 45 °C.
(11) (a) Davis, R. E.; Nakshbendi, H. F. J. Am. Chem. Soc. 1962,
84, 2085. (b) McMillan, F. H.; King, J. A. J. Am. Chem. Soc.
1948, 70, 4143. (c) Vineyard, B. D. J. Org. Chem. 1967, 32,
3833. (d) MacColl, R.; Windwer, S. J. Phys. Chem. 1970,
74, 1261. (e) Sato, R.; Sato, T.; Segawa, K.; Takikawa, Y.;
Takizawa, S.; Oae, S. Phosphorus, Sulfur Silicon Relat.
Elem. 1979, 7, 213.
(12) Preparation of Thiobenzamide (Scheme 4): Na2S·9H2O
(244 mg, 1 mmol) was added to a mixture of sulfur (160 mg,
5 mmol as elemental sulfur) and 28% aq NH3 (3 mL, ca. 44
mmol) in DMF (4 mL), and the suspension was stirred at
115 °C for 0.5 h under nitrogen. After the mixture was
cooled to r.t., benzaldehyde (0.41 mL, 4 mmol) was added,
and stirred at 115 °C for 12 h under nitrogen. After cooling
to r.t., the resulting solution was quenched with sat. aq
NH4Cl solution (50 mL) and extracted with CHCl3 (50 mL).
The organic fraction was thoroughly washed with H2O (2 ×
50 mL) and dried with anhyd Na2SO4. After concentration,
the resulting crude material was purified by chromatography
on silica gel with CHCl3–Et2O (100:0–20:80) to afford
thiobenzamide as a pale yellow powder (270 mg, 49%
yield); mp 118 °C, lit.7b 117–118 °C.
(10) N-(4-Methoxyphenyl)thiobenzamide (Table 2, entry 2):
yellow powder; mp 135 °C, lit.7 135 °C.
4-Methoxy-N-phenylthiobenzamide (Table 2, entry 3):
yellow powder; mp 154 °C, lit.7 153–154 °C.
4-Methoxy-N-(4-methoxyphenyl)thiobenzamide
(Table 2, entry 4): yellow powder; mp 148 °C, lit.7 148 °C.
1,3-Bis(anilinothiocarbonyl)benzene (Table 2, entry 5):
yellow powder; mp 243–244 °C, lit.2a 242–244 °C.
(13) Reynaud, P.; Moreau, R. C.; Samama, J. P. Bull. Soc. Chim.
Fr. 1965, 12, 3623.
(14) Couture, A.; Grandclaudon, P. Synthesis 1985, 5, 533.
(15) Mazumder, U. K.; Gupta, M.; Karki, S. S.; Bhattacharya, S.;
Rathinasamy, S.; Sivakumar, T. Bioorg. Med. Chem. 2005,
13, 5766.
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