An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea with alkyl and aryl amines under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2008.03.158

An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea 5 with alkyl and aryl amines under mild conditions has been developed. In the presence of NaH as a base, trifluoroacetic anhydride (TFAA)

Full text of DOI:10.1016/j.tetlet.2008.03.158

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3687–3690
An efficient method for the synthesis of disubstituted thioureas
via the reaction of N,N0-di-Boc-substituted thiourea with alkyl
and aryl amines under mild conditions
Biaolin Yin *, Zhaogui Liu, Mingjun Yi, Jiancun Zhang*
Guangzhou Institute of Biomedicine and Health, The Chinese Academy of Sciences, Guangzhou, 510663 China
Received 11 November 2007; revised 21 March 2008; accepted 26 March 2008
Available online 6 April 2008
Abstract
An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N0-di-Boc-substituted thiourea 5 with alkyl and
aryl amines under mild conditions has been developed. In the presence of NaH as a base, trifluoroacetic anhydride (TFAA) reacted with
5 providing intermediate 6, which then reacted with amines giving thioureas 7 in excellent yields. This reaction conditions tolerated other
functional groups such as amide, ester, enol ether and hydroxyl groups.
Ó 2008 Elsevier Ltd. All rights reserved.
Thioureas have attracted much attention due to their
bioactivities as pharmaceutics and pesticides. A variety of
thiourea derivatives and their metal complexes exhibit
analgesic,1 anti-inflammatory,2 antimicrobial,3 anticancer4
and antifungal activities.5 Moreover, thioureas are impor-
tant building blocks in the synthesis of heterocycles. For
example, 2-amino-1,3-thiazoles can be readily prepared
through the condensation of thioureas with a-halocarbonyl
compounds.6 Likewise, arylthioureas can be transformed
into benzothiazoles upon treatment with bromine.7 Other
examples include the synthesis of iminothiazolines,8 thio-
hydantoins,9 1,3,5-triazine10 and 2-amino-oxazo-lidines.11
Therefore, the synthesis of novel thioureas and the devel-
opment of new methods for their preparation are of great
importance in searching bioactive molecules as well as in
synthetic chemistry.
of a strong acid,12 aryl isothiocyanates with amines fol-
lowed by basic hydrolysis,13 isothiocyanates with ammonia
or amines,14 primary amines with carbon disulfide in the
presence of mercury acetate and aqueous ammonia15 and
unsubstituted thioureas with primary alkyl amines at high
temperature.16 Recently, several other new methods for the
preparation of substituted thioureas have also been
reported.17 However, many reported methods suffer from
drawbacks and limitations related to harsh reaction condi-
tions such as high reaction temperature, long reaction time,
the use of a strong acid or base and noxious reagents such
as hydrogen sulfide and carbon disulfide. Therefore, the
development of a mild, efficient and environmentally
benign method is highly desirable. Herein, we report a
novel, mild and efficient method for the preparation of
disubstituted thioureas via the reaction of N,N0-di-Boc-
substituted thiourea with alkyl and aryl amines.
To date, a variety of methods for the preparations of
thioureas have been documented, including the reaction
of alkali metal thiocyanates with amines in the presence
Recently, Charette and others reported the generation of
imino 3 and iminium 4 triflates via the reaction of amide
with triflic anhydride in the presence of a base. Those tri-
flates can further react with a series of nucleophiles, such
as alcohols, amines, aminothiols, H2S and H218O to give
the corresponding esters, amidines, thiazolines, thioamides
and 18O-labelled amides (Scheme 1).18 Although this kind
*
Corresponding authors. Tel.: +86 020 32290423; fax: +86 020
32290423 (B.Y).
E-mail addresses: yin_biaolin@gibh.ac.cn (B. Yin), zhang_jiancun@
gibh.ac.cn (J. Zhang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.158

3688
B. Yin et al. / Tetrahedron Letters 49 (2008) 3687–3690
Table 1
O
OTf
OTf
O
Optimization of the reaction conditions
Tf2O
R2
R2
+
R2
R2
R1
N
R1
N
+
R3
R1
N
H
R1
N
H
Pyridine
S
S
BnNH2
R3
Boc
Boc
Boc
Bn
N
H
N
H
N
H
N
H
reaction conditions
THF, overnight
1
2
3
4
Nu-
esters; amidines; thiazolines;
thioamides;18O-labeled amides.
5
7a
a
Entry Reaction conditions
Yield
(%)
Nu- = alcohols, amines, aminothiols, H2S or H218O
1
2
BnNH2 (1.1 equiv)/rt
Ac2O (1.1 equiv)/pyridin (1.2 equiv)e/0 °C then
BnNH2/rt
0b
58
Scheme 1. Generation of imino 3 and iminium 4 triflates and their further
transformations.
3
4
5
6
7
8
9
MsC (1.1 equiv)/pyridine (1.2 equiv)/0 °C then
BnNH2 (1.1 equiv)/rt
TsCl (1.1equiv)/pyridine (1.2equiv)/0 °C then BnNH2 50
(1.1 equiv)/rt
TFAA (1.1 eq)/pyridine (1.2 equiv)/0 °C then BnNH2 78
(1.1 equiv)/rt
Tf2O (1.1 equiv)/DIEA (1.2 equiv)/0 °C then BnNH2 25
(1.1 equiv)/rt
Tf2O (1.1 equiv)/NMM (1.2 equiv)/0 °C then BnNH2 32
(1.1 equiv)/rt
TFAA (1.1 equiv)/NaH (1.2 equiv)/0 °C then BnNH2 91
(1.1 equiv)/rt
TFAA (1.1 equiv)/NaH (1.2 equiv)/0 °C then BnNH2 73
(2.2 equiv)/rt
60
of reaction with an amide has been extensively used in
organic synthesis, to the best of our knowledge, little explo-
ration has been conducted with thiocarbonyl compunds. In
view of the fact that the properties of triflates and thiotri-
flates are quite different, we envisioned that some new
information could be obtained when the substrate is a thio-
carbonyl compound. Initially, N,N0-di-Boc-substituted
thiourea, prepared from thioureas according to a literature
method,19 was chosen as the substrate, and benzylamine as
the nucleophile. After treatment of 5 with Tf2O (1.1 equiv)
and pyridine (1.2 equiv) at 0 °C for 1 h, followed by the
addition of benzylamine (1.1 equiv), no expected guanidine
derivative 6 was produced; instead, thiourea 7a was formed
in moderate yield (64%). 20 This unexpected but useful
result nonetheless provides a novel method for the prepara-
tion of disubstituted thioureas under mild conditions
(Scheme 2). Further efforts were made to adjust the reac-
tion variants such as activator, base, reaction temperature
and the amount of amine to optimize the conditions. The
results are summarized in Table 1.
It was found that if BnNH2 was used alone, the reaction
did not produce thiourea 7a at room temperature over-
night, but guanidine 6 was formed in 75% yield (entry 1).
When other activators such as Ac2O, MsCl and TsCl are
used, the yields were lower (entries 2–4) and TFAA (triflu-
oroacetic anhydride) as an activator gave rise to a little
higher yield (entry 5). Meanwhile, other organic bases such
as DIEA (N,N-diisopropylethylamine) or NMM (N-meth-
ylmorpholine) were used, 7a was formed in lower yields
along with many other unidentified by-products. To our
delight, when NaH was used as a base to deprotonate
and TFFA as an activator, the reaction yield was increased
to 91% (entry 8). Surprisingly, increasing the amount of
BnNH2 (2.2 equiv, entry 9) led to a lower yield (73%) along
with some deprotected by-product of 7a (11%), possibly
a
Isolated yield.
Guanidine was the only product isolated.
b
due to the deprotection of the Boc group in the presence
of excessive BnNH2.
Based on the results, we concluded that TFAA (1.1
equiv)/NaH (1.2 equiv)/0 °C then BnNH2 (1.1 equiv)/rt
in THF solvent are suitable conditions for this conversion.
The scope of the reaction was then examined with different
amines, and the results are summarized in Table 2. As can
be seen, all primary amines worked well with 5 affording
the desired compounds 7b–7f in excellent yields (entries
1–4). It is also worth noting that under these reaction con-
ditions, functional groups such as amide, ester, enol ether
and hydroxyl are tolerated. Cyclic five or six-membered
ring amines also afford the desired thioureas in good yields
(entries 5–8). Importantly, under this condition, no epimer-
1
ization of compound 7i was observed based on H NMR.
In contrast, more hindered acyclic secondary amines did
not lead to the desired products under these conditions
(entry 9). Less nucleophilic primary arylamines also afford
the desired products in excellent yields (entries 10 and 11).
With aminophenol, only the thiourea product was isolated
and no thiocarbamate was observed (entry 11). Similar to
the acyclic secondary alkyl amines, acyclic secondary aryl-
amines did not afford the desired product (entry 12). The
reaction of 5 with phenyl hydrazine afforded exclusively
the thiohydrozone product 7n (entry 13).
In summary, an efficient method for the synthesis of
mono- and N,N-disubstituted thioureas has been devel-
oped. This method involves the reaction of N,N0-di-Boc-
substituted thiourea with amines in the presence of NaH
and TFAA. This method can proceed under mild condi-
NHBn
1)Tf2O(1.1 eq)
Pyridine (1.2 eq)
0 oC/THF
Boc
Boc
Boc
S
N
H
N
6
0%
Boc
Boc
N
H
N
H
S
2)BnNH2/r.t.
Bn
5
N
H
N
H
7a 64%
Scheme 2. Reaction of 5 with benzyl amine using Tf2O as an activator.

B. Yin et al. / Tetrahedron Letters 49 (2008) 3687–3690
3689
Table 2
Table 2 (continued)
Synthesis of thioureas via the reaction of 5 with amines21
Entry
12
R1R2NH
Product
Yield
(%)
S
1)NaH (1.2 eq)/TFAA(1.1 eq)
S
/THF/0 o
Boc
C
Boc
NHMe
Boc
N
H
N
H
N
H
NR1R2
N
NHBoc
2) R1R2NH(1.1 eq)/ r.t.
0
5
7b~7n
S
7m
PhHNHN
Entry R1R2NH
Product
Yield
(%)
NHBoc
13
85
NHNH2
S
7n
S
1
H2N
94
BocHN
AcO
N
H
7b
tions, and fuctionalized thioureas can be readily prepared.
Not only primary alkyl amine but also secondary alkyl
amine and primary arylamine substituted thioureas can
be obtained in high yield. Importantly, no symmetric
disubstituted thioureas formation was observed under the
reaction conditions. Further studies including the detailed
mechanism and the reaction of N,N0-di-Boc-substituted
thiourea with other nucleophiles such as alcohols, stable
carbanions to synthesize diverse thiocarbamates and thio-
amide derivatives are under way and will be reported in
due course.
O
O
OEt
AcO
OEt
2
78
AcHN
AcHN
NHBoc
HN
7c
NH2
S
O
OAc
O
OAc
AcO
O
AcO
O
OMe
OMe
3
88
AcO
AcHN
AcO
S
AcHN
NH
Ph
NHBoc
NH2
7d
Acknowledgment
S
This work was supported by the Grant-in-Aid for Scien-
tific Research from the Municipal Government of
Guangzhou.
Ph
OH
4
5
6
7
82
84
90
82
BocHN
N
OH
H2N
H
7e
S
References and notes
NH
N
NHBoc
NHBoc
7f
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S
O
NH
O
N
7g
S
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Rodrigues, J.; Rosival, B. V.; Verde, L. C.; Souza, N.; Ivo, V.; Carlito,
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HO
HO
OMe
N
8
9
89
OMe
N
H
O
S
NHBoc
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O
7i
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278; (b) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Synthesis 2002, 75.
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11. Heinelt, U.; Schultheis, D.; Jager, S.; Iindenmaire, M.; Pollex, A.;
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Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M.
J.; Powell, E. T.; Molinari, A. J. Synthesis 1988, 456.
S
0
NH
(n-Bu)2N
NHBoc
7j
H
N
NHBoc
10
11
91
81
NH2
S
7k
HO
HO
H
N
NHBoc
NH2
S
7l

3690
B. Yin et al. / Tetrahedron Letters 49 (2008) 3687–3690
14. Moor, M. L.; Crossely, F. S. Org. Synth. Coll. Vol. III 1955, 617.
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(m, 5H), 4.86 (d, 2H, J = 5.6 Hz), 1.47 (s, 9H). 13C NMR (400 MHz,
CDCl3) d 179.8, 151.8, 136.5, 128.8, 128.0, 127.9, 83.8, 49.5, 28.1. ESI-
MS m/z (265, M+ꢀH). Anal. Calcd for C13H18N2O2S: C, 58.62; H,
6.81; N, 10.52; S, 12.04. Found: C, 58.44; H, 6.86; N, 10.64; S, 12.33.
21. Typical procedure for thioureas formation (7c): To a mixture of N,N0-
di-Boc-substituted thiourea (552 mg, 2 mmol) and THF (20 mL) was
added 60% NaH (95 mg, 2.4 mmol) at 0 °C. The reaction mixture was
stirred at the same temperature for 1 h, then TFAA (370 lL,
2.2 mmol) was added and the stirring continued for additional 1 h.
Then amine (2.2 mmol) was added and the resulting reaction mixture
was stirred at room temperature overnight. Ten millilitre of H2O was
added to quench the reaction and the mixture was extracted with
EtOAc (15 mL ꢁ 3). The combined organic layers were dried over
MgSO4, and the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography to afford
compound 7c. Solid, mp 104–105 °C. IR (KBr): mmax: 3485, 2931,
16. Erickson, J. G. J. Org. Chem. 1956, 21, 483.
´
`
17. (a) Vazquez, J.; Bemes, S.; Reyes, Y.; Moya, M.; Sharma, P.; Alvarez,
´
C.; Gutierrez, R. Synthesis 2004, 1955; (b) Katritzky, A. R.;
Kirichenko, N.; Rogovoy, B. V.; Kister, J.; Tao, H. Synthesis 2004,
1799; (c) Ciszewski, L.; Xu, D.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 2004, 45, 8091; (d) Mitsuo, K.; Masato, S.; Keiko,
T.; Tadashi, A. Tetrahedron Lett. 2005, 46, 5841.
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Angew. Chem., Int. Ed. Engl. 1981, 20, 879; (b) Sisti, N. J.; Fowler, F.
W.; Grierson, D. S. Synlett 1991, 816; (c) Thomas, E. W. Synthesis
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Guerrini, A. J. Org. Chem. 1996, 61, 8480; (e) Sisti, N. J.; Zeller, E.;
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A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499; (h) Charette, A. B.;
Chua, P. J. Org. Chem. 1998, 63, 908; (i) Charette, A. B.; Chua, P.
Synlett 1998, 163; (j) Charette, A. B.; Chua, P. Tetrahedron Lett.
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1725, 1719, 1633, 1557, 1433, 1297, 1031, 774, 659 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) d 9.89 (d, J = 6.4 Hz, 1H), 7.94 (s, 1H), 6.67 (s,
1H), 6.32 (d, J = 8.4 Hz, 1H), 5.60 (d, J = 8.8 Hz, 1H), 4.87–4.84 (m,
1H), 4.41–4.36 (m, 1H), 4.24–4.18 (m, 2H), 3.00 (dd, J = 6.0 Hz,
J = 18.0 Hz), 2.49–2.42 (m, 1H), 2.09 (s, 3H), 1.93 (s, 3H), 1.48 (s,
9H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 181.1,
170.9, 165.2, 151.3, 135.3, 130.7, 84.4, 71.9, 61.3, 53.9, 53.0, 30.4, 28.0,
23.3, 21.0, 20.9, 14.2; ESI-MS m/z (444, M++H). Anal. Calcd for
19. Exposito, A.; Femandez-Suarez, M.; Iglesias, T.; Munoz, L.; Riguera,
R. J. Org. Chem. 2001, 66, 4206.
20. Spectral data for compound 7a: Solid, mp 147–148 °C. IR (KBr): mmax
:
C
19H29N3O7S: C, 51.45; H, 6.59; N, 9.47; S, 7.23. Found: C, 51.67; H,
3446, 3172, 2971, 1668, 1534, 1250, 1206, 1150, 964, 918, 750 cmꢀ1
.
6.33; N,9.50; S, 7.10.
1H NMR (400 MHz, CDCl3): d 9.97 (s, 1H), 7.94 (s, 1H), 7.38–7.29