Reductive alkylation of thioureas: A highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas

Article abstract of DOI:10.1016/j.tetlet.2004.08.182

A highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas by the reductive alkylation of N-monosubstituted thioureas with aldehydes is described. N-Monosubstituted thioureas can in turn be synthesized by the reductive amination of thiourea with an appropriate aldehyde. This reductive alkylation methodology was also extended to carbamates.

Full text of DOI:10.1016/j.tetlet.2004.08.182

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8091–8093
Reductive alkylation of thioureas: a highly practical synthesis of
unsymmetrical N,N0-disubstituted thioureas
*
Lech Ciszewski, Daquiang Xu, Oljan Repic and Thomas J. Blacklock
ˇ
Process R&D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA
Received 2 July 2004; revised 25 August 2004; accepted 25 August 2004
Available online 21 September 2004
Abstract—A highly practical synthesis of unsymmetrical N,N0-disubstituted thioureas by the reductive alkylation of N-monosubsti-
tuted thioureas with aldehydes is described. N-Monosubstituted thioureas can in turn be synthesized by the reductive amination of
thiourea with an appropriate aldehyde. This reductive alkylation methodology was also extended to carbamates.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Molecules containing symmetrical or unsymmetrical
N,N0-disubstituted thioureas are of biological interest.
Several methods are reported for the synthesis of sym-
metrical thioureas but additional synthetic approaches
for unsymmetrical thioureas are still desirable.1 In a
development program we needed to develop an efficient
and economical synthesis of N,N0-disubstituted thio-
ureas, which prompted us to investigate a convenient
method for their synthesis. In continuation of our work
on the reductive amination of urea,2 we rationalized that
a straightforward approach to unsymmetrical thiourea
would be the stepwise reductive amination of thioureas
with aldehydes. In this paper we report our results on
the development of a highly practical method for the
synthesis of unsymmetrical N,N0-disubstituted thioureas
To test the synthetic feasibility of our approach we first
studied the reductive amination3 of thiourea itself with
4-tert-butylbenzaldehyde since N-(4-tert-butyl)benzyl
thiourea (1) was a precursor to our target molecule.
Thus, treatment of thiourea with 4-tert-butylbenzalde-
hyde in acetic acid in the presence of TMS–Cl afforded
the corresponding imine that was reduced with sodium
borohydride4 to afford N-(4-tert-butyl)benzyl thiourea
(1) in 65% yield. Use of TMS–Cl was important in this
reaction to obtain good yields since without it the yield
of 1 reduced to almost half. Similarly, 4-methoxybenz-
aldehyde gave N-(4-methoxy)benzyl thiourea (2) in 50%
yield. These results demonstrated that our previously
reported methodology for the reductive amination of
urea was also applicable to thiourea.
S
CHO
1. TMS-Cl, AcOH
2. NaBH4, rt
S
N
H
NH2
+
H2N
NH2
R
R
1: R = t-Bu
2: R = OCH3
by the reductive amination of N-monoalkylated thio-
ureas with aldehydes in the presence of trimethylsilyl
chloride as the dehydrating agent and sodium borohy-
dride in acetic acid as the reducing agent.
With these results in hand, we next studied the reductive
amination of N-(4-tert-butyl)benzyl thiourea (1) with 4-
methoxybenzaldehyde in the presence of TMS–Cl as the
dehydrating agent and sodium borohydride as the
reducing agent in acetic acid. It afforded the desired
unsymmetrical N,N0-disubstituted thiourea (3) in 76%
yield (Table 1, entry 1). To test the scope and limitations
of these conditions5 we next studied the reductive
*
Corresponding author. Tel.: +1 862 778 8319; fax: +1 973 781
2188; e-mail: lech.ciszewski@pharma.novartis.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.182

8092
L. Ciszewski et al. / Tetrahedron Letters 45 (2004) 8091–8093
amination of several N-monoalkylated thioureas with
various aldehydes and the results are described in
Table 1.6 In all cases the isolated yields were excellent
but are unoptimized.
In summary, we have developed a highly practical syn-
thesis of unsymmetrical N,N0-disubstituted thioureas
by the reductive alkylation of N-monosubstituted thio-
ureas with aldehydes. N-Monosubstituted thioureas
can in turn be synthesized by the reductive amination
of thiourea with an appropriate aldehyde. This reductive
alkylation methodology was also extended to
carbamates.
We have further extended the synthetic utility of this
methodology to the reductive amination of carbamates7
and the results are reported in Table 2.6
Table 1. Unsymmetrical N,N0-disubstituted thioureas
S
1. TMS-Cl, AcOH
2. NaBH4, rt
S
+
R'-CHO
N
H
R'
R
N
H
R
N
H
NH2
Entry
1
Thiourea
Aldehyde
Product
Yield (%)
72
S
S
CHO
N
H
N
H
N
NH2
H
CH3O
t-Bu
OCH3
OCH3
t-Bu
t-Bu
3
S
S
CHO
N
H
N
H
N
NH2
2
3
4
5
6
66
76
93
87
82
H
t-Bu
H3CO
3
S
S
S
CHO
N
N
H
N
H
NH2
NH2
H
CH3O
OCH3
t-Bu
4
S
CHO
N
H
N
H
N
H
t-Bu
t-Bu
t-Bu
5
S
S
CHO
CHO
N
H
N
H
N
H
NH2
t-Bu
O2N
O2N
6
S
S
N
N
H
H3C
H
N
H
NH2
H3C
t-Bu
7
Table 2. N-Alkylated carbamates
O
1. TMS-Cl, AcOH
2. NaBH4, rt
O
R
+
R'-CHO
R
R'
O
N
H
O
NH2
Entry
1
Carbamate
Aldehyde
Product
Yield (%)
74
O
8
CHO
CHO
O
O
O
N
H
NH2
O
t-Bu
t-Bu
t-Bu
O
O
N
H
2
79
O
NH2
t-Bu
9

L. Ciszewski et al. / Tetrahedron Letters 45 (2004) 8091–8093
8093
room temperature and stirred overnight. To the resulting
suspension was added sodium borohydride (1.51g,
0.04mol) over 30min at 23–30ꢁC. Completion of the
reaction was monitored by HPLC. Water (70mL) was
added to the reaction mixture at room temperature and
concentrated (150mbar, 45–50ꢁC) to collect 150mL of a
mixture of acetic acid and water. To the suspension was
added 6N NaOH (80mL) over 10min at 24–30ꢁC to adjust
the pH to 10. After stirring the mixture at room temper-
ature for 30min the crude product was collected by
filtration, washed with water (2 · 50mL). The crude prod-
uct was recrystallized from a mixture of heptane and ethyl
acetate.
Acknowledgements
The authors would like to express their appreciation to
Dr. Mahavir Prashad for his editorial assistance in the
preparation of this manuscript.
References and notes
1. (a) Herr, R. J.; Kuhler, L. L.; Meckler, H.; Opalka, C. J.
Synthesis 2000, 1569–1574; (b) Ballabeni, M.; Ballini, R.;
Bigi, F.; Maggi, R.; Parrini, M.; Predieri, G.; Sartori, G.
J. Org. Chem. 1999, 64, 1029–1032; (c) Ramadas, K.;
Janarthanan, N.; Velmathi, S. Synth. Commun. 1997, 27,
2255–2260; (d) Boas, U.; Jakobsen, H. J. Chem. Soc.,
Chem. Commun. 1995, 1995–1996; (e) Duceppe, J. S.;
Gauthier, J. J. Heterocycl. Chem. 1984, 21, 1685–1687; (f)
Ramadas, K.; Srinivasa, N.; Janarthanan, N. Tetrahedron
Lett. 1993, 34, 6447–6450.
4. Use of sodium triacetoxyborohydride in this reaction gave
similar results as obtained with sodium borohydride sug-
gesting that the actual reducing agent is sodium triacetoxy-
borohydride.
5. Typical procedure for unsymmetrical N,N0-disubstituted
thioureas: The procedure was essentially the same as
described above in Ref. 3 using N-alkyl thiourea (0.017mol),
and aldehyde (0.02mol), followed by trimethylsilyl chloride
(0.051mol) and sodium borohydride (0.034mol).
6. All the compounds gave satisfactory spectral data.
7. Typical procedure for N-alkylated carbamates: The proce-
dure was essentially the same as described above in Ref. 3
using carbamate (0.01mol) and aldehyde (0.015mol), fol-
lowed by trimethylsilyl chloride (0.03mol) and sodium
borohydride (0.03mol).
ˇ
2. Xu, D.; Ciszewski, L.; Li, T.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 1998, 39, 1107–1110.
3. Typical procedure for N-monoalkylated thioureas: To a
suspension of thiourea (15.25g, 0.2mol) in acetic acid
(150mL) was added an aldehyde (0.02mol) at room
temperature. The suspension was warmed to 60–65ꢁC to
obtain a solution. The resulting solution was cooled to
45ꢁC, and trimethylsilyl chloride (7.61mL, 0.06mol) was
added during 3min. The reaction mixture was cooled to