Extension of the Willgerodt-Kindler reaction: Protected carbonyl compounds as efficient substrates for this reaction

Article abstract of DOI:10.1016/j.tetlet.2004.03.130

Nitrogen derivatives of carbonyl compounds such as oximes, hydrazones, and semicarbazones were found to be excellent candidates for the Willgerodt-Kindler reaction. They can be used directly in a solvent-free reaction, under both classical and microwave conditions, to give the corresponding thiomorpholides in good yields.

Full text of DOI:10.1016/j.tetlet.2004.03.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4167–4169
Extension of the Willgerodt–Kindler reaction: protected carbonyl
compounds as efficient substrates for this reaction
Hossein Reza Darabi,a,* Kioumars Aghapoora and Mahmoud Tajbakhshb
aChemistry and Chemical Engineering Research Center of Iran, Organic Chemistry, PO Box 14335-186, Tehran, Iran
bDepartment of Chemistry, University of Mazandaran, Babolsar, Iran
Received 24 January 2004; revised 13 March 2004; accepted 22 March 2004
Abstract—Nitrogen derivatives of carbonyl compounds such as oximes, hydrazones, and semicarbazones were found to be excellent
candidates for the Willgerodt–Kindler reaction. They can be used directly in a solvent-free reaction, under both classical and
microwave conditions, to give the corresponding thiomorpholides in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
to our best knowledge, have not been studied in the
literature. Although they are useful protecting groups, a
disadvantages of these derivatives are the conditions
required for their cleavage and regeneration to the
parent carbonyl compound. In general, when faced with
the problem of preparing a thioamide from the corre-
sponding carbonyl group in a polyfunctional molecule,
its preservation throughout the entire sequence of syn-
thetic reactions is necessary. On the other hand, the
regeneration of a carbonyl group from a protected
derivative may result in a decrease of the total yield of
the reaction sequence together with an additional step.
Moreover, during the regeneration of a carbonyl group
the selection of the appropriate reagent, which is inert to
other functional groups in the molecule can be a sig-
nificant problem. Therefore, it is of interest to determine
whether a derivative of a carbonyl compound can be
subjected directly to the Willgerodt–Kindler reaction
conditions to give the corresponding thiomorpholides.
Recent studies on the Willgerodt–Kindler reaction in
our laboratory1–5 have been directed toward its further
development in synthesis. This reaction is a well known
method for the synthesis of thioamides.6 In the original
Willgerodt–Kindler reaction, ketones and aldehydes
were found to react with sulfur and secondary amines to
give terminal thioamides as a result of consecutive oxi-
dations and rearrangements. Thioamides have often
appeared in the literature as versatile intermediates in
medical and organic chemistry.7–11 Very recently, we
reported the direct and fast conversion of thiomorpho-
lides into the corresponding thioesters.12
NY
O
N
R
Sulfur, morpholine
n
X
X
S
1
Herein we report the direct synthesis of thiomorpholides
2 and 3 from protected aldehydes and ketones using
optimized reaction conditions. The crude reaction mix-
tures were directly analyzed by GC–MS and/or sub-
jected to column chromatography. All the products were
2, n = 0
3, n = 0
Y = OH, N(CH3)2, NHCONH2
R = H, CH3
The present study is focused on Willgerodt–Kindler
reactions of nitrogen derivatives of carbonyl compounds
such as oximes, hydrazones, and semicarbazones which,
1
characterized by H NMR and MS spectral data and
were similar to those reported in the literature. The
reaction conditions and yields of the products 2 and 3
are given in Table 1.
Keywords: Protected carbonyl compounds; Willgerodt–Kindler reac-
tion; Thiomorpholides; Solvent-free conditions.
In conclusion, we have shown that the Willgerodt–Kindler
reaction can be conducted with a variety of substrates, as
shown in Table 1. Although the yields from the carbonyl
* Corresponding author. Tel.: +98-218036144; fax: +98-218037185;
e-mail: darabi@ccerci.ac.ir
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.130

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H. R. Darabi et al. / Tetrahedron Letters 45 (2004) 4167–4169
Table 1. The direct synthesis of thiomorpholides from derivatives of carbonyl compounds
Yield (%)b
Conventional heatingc
Ref.
Entry
Substrates 1
Productsa
MWd (min)
70 (7)
S
NOH
a
b
c
65
72
83
3
3
3
M
H
S
NN(CH3)2
79 (10)
72 (5)
M
H
S
NNHCONH2
H
M
S
NOH
H
d
e
43
75
48 (7)
80 (7)
14
15
M
OMe
OMe
NOH
H
S
MeO
Cl
MeO
M
S
NN(CH3)2
H
f
60
55
70 (10)
72 (7)
1
Cl
M
S
NNHCONH2
H
g
14
M
O2N
O2N
NNHCONH2
CH3
h
71
60 (7)13
1
M
S
NOH
CH3
Cl
i
61
41
55
55 (7)
44 (7)
57 (7)
1
Cl
M
S
NNHCONH2
MeO
H3C
j
1
MeO
H3C
M
CH3
S
NN(CH3)2
CH3
k
14
M
S
NN(CH3)2
S
l
65
73 (10)
1
H
M
a M ¼ morpholine.
b Yields are based on GC analysis.
c The reaction time is 3 h at 100 °C.
d MW ¼ microwave irradiation.
derivatives in comparison with the analogous ketones and
aldehydes under the same reaction conditions are slightly
lower,1–3;6 the method is applicable to polyfunctional mol-
ecules due to its wide range of functional group toleration.
2. General procedure
2.1. Caution
Experiments should be carried out in an efficient
hood to avoid exposure to noxious hydrogen sulfide
vapors.
Further studies of the Willgerodt–Kindler reactions of
new substrates are in progress in our laboratory.

H. R. Darabi et al. / Tetrahedron Letters 45 (2004) 4167–4169
4169
5. Darabi, H. R.; Aghapoor, K.; Nakhshab, L. Z. Natur-
forsch., in press.
2.2. Solvent-free reaction under conventional heating
6. Brown, E. V. Synthesis 1975, 358, and references cited
therein.
In a typical experiment, a mixture of substrate 1
(1 mmol), sulfur (4 mmol), and morpholine (6 mmol)
was refluxed for 3 h. After cooling, the reaction product
2 or 3 was purified by silica gel column chromatography
[petroleum ether–ethyl acetate (4:1)] and recrystallized
from ethanol. The products 2 or 3 were generally pure as
judged by TLC, GC–MS, and NMR analysis.
7. (a) Padwa, A.; Scott Beall, L.; Heidelbaugh, T. M.; Liu,
B.; Sheehan, S. M. J. Org. Chem. 2000, 65, 2684; (b) May,
P. J.; Bradley, M.; Harrowven, D. C.; Pallin, D. Tetrahe-
dron Lett. 2000, 41, 1627; (c) Harrowven, D. C.; Lucas, M.
C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 4443; (d)
Metzner, P. Synthesis 1992, 1185.
8. Spatola, A. F. In Chemistry and Biochemistry of Amino
acids, Peptides and Proteins; Weinstein, B., Ed.; Marcel
Dekker: New York, 1983; Vol. 7, pp 267–357, and
references cited therein.
2.3. Solvent-free reaction under microwave heating
9. Hoeg-Jensen, T.; Olsen, C.; Holm, A. J. Org. Chem. 1994,
59, 1257.
10. Katritzky, A. L.; Moutou, J. L.; Yang, Z. Synlett 1995, 99.
11. Murguia, M. C.; Rossi, R. A. Tetrahedron Lett. 1997, 38,
1335.
In a typical experiment, a mixture of substrate 1
(0.1 mmol), sulfur (0.4 mmol), and morpholine
(0.6 mmol) in an open pyrex glass flask was exposed to
microwave irradiation at 650 W between 5 and 10 min.16
The workup was performed using an identical procedure
to that described above.
12. Darabi, H. R.; Aghapoor, K.; Tabar-heydar, K. Monatsh
Chem. 2004, 135, 79.
13. Full details of the Willgerodt–Kindler reaction of 1h and
other semihydrazones under both microwave and conven-
tional heating and possible reaction pathways are con-
tained in a manuscript soon to be submitted.
14. Tominaga, Y.; Matsuoka, Y.; Oniyama, Y.; Uchimura,
Y.; Komiya, H.; Hirayama, M.; Kohra, S.; Hosomi, A. J.
Heterocycl. Chem. 1990, 27, 647.
15. Campaine, E.; Pragnell, M.; Haff, F. J. Heterocycl. Chem.
1968, 5, 141.
16. The microwave oven used for this study was a domestic
National model NN-6755 with seven power settings (90–
900 W).
References and notes
1. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtah-
edi, M. M. Tetrahedron Lett. 1999, 40, 7549.
2. Darabi, H. R.; Aghapoor, K.; Tabar-heydar, K. Phospho-
rus, Sulfur and Silicon 2002, 177, 1189.
3. Aghapoor, K.; Darabi, H. R.; Nooshabadi, M.; Tabar-
heydar, K. Phosphorus, Sulfur and Silicon 2002, 177, 1183.
4. Aghapoor, K.; Darabi, H. R.; Tabar-heydar, K.; Nakh-
shab, L. Sulfur Lett. 2002, 25, 259.