Synthesis of guanidines via the I2 mediated desulfurization of N,N′-di-Boc-thiourea

Article abstract of DOI:10.1016/j.tetlet.2019.150970

The I₂ mediated desulfurization of N,N′-di-Boc-thiourea was developed. Various primary amines, including sterically and electronically deactivated primary amines, were transformed into the corresponding bis-Boc protected guanidines under mild conditions.

Full text of DOI:10.1016/j.tetlet.2019.150970

Accepted Manuscript
Synthesis of guanidines via the I2 mediated desulfurization of N,N′ -di-Boc-
thiourea
Hao-Jie Rong, Cui-Feng Yang, Tao Chen, Yong-Qiang Wang, Bin-Ke Ning
PII:
S0040-4039(19)30721-X
https://doi.org/10.1016/j.tetlet.2019.150970
150970
DOI:
Article Number:
Reference:
TETL 150970
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 June 2019
17 July 2019
22 July 2019
Please cite this article as: Rong, H-J., Yang, C-F., Chen, T., Wang, Y-Q., Ning, B-K., Synthesis of guanidines via
the I2 mediated desulfurization of N,N′ -di-Boc-thiourea, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.150970
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Synthesis of guanidines via the I2 mediated
desulfurization of N,N′-di-Boc-thiourea
Hao-Jie Rong, Cui-Feng Yang, Tao Chen, Yong-Qiang Wang and Bin-Ke Ning
R
NH
S
I2 (1.2 eq.), NEt3 (2.4 eq.)
PhMe, 0 °C
R
Boc
Boc
Boc
Boc
+
NH2
N
N
N
N
H
H
H
R = alkyl, benzyl, aryl
52-98% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of guanidines via the I2 mediated desulfurization of N,N′-di-Boc-
thiourea
Hao-Jie Rong a,b, Cui-Feng Yang a, Tao Chena, Yong-Qiang Wangb and Bin-Ke Ninga,c
aModern Chemistry Research Institute of Xi’an, Xi’an 710065, China
bDepartment of Chemistry&Materials Science, Northwest University, Xi’an 710069, China
cState Key Laboratory of Fluorine & Nitrogen Chemicals, Xi’an 710065, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The I2 mediated desulfurization of N,N′-di-Boc-thiourea was developed. Various primary
amines, including sterically and electronically deactivated primary amines, were transformed
into the corresponding bis-Boc protected guanidines under mild conditions.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Iodine
Primary amines
N,N′-di-Boc-thiourea
Guanidines
Guanidine-containing compounds are found in many natural
products and pharmaceuticals.1-5 For example, Rosuvastatinis,
which has been used to treat high cholesterol, is one of the best
selling drugs in the United States,6 and Bupirimate, developed by
ICI, is used for the treatment of powdery mildew.7 Additionally,
guanidines have also been used as peptide mimetics,
organocatalysts, organobases, fluorescent probes, and ionic
liquids.8 Typically, guanidines are prepared from thioureas,9-11
the I2 mediated desulfurization of N,N′-di-Boc-thiourea was
envisioned.
Previous work:
R1 R2
S
R2 R1
N
HgCl2 or CuCl2
+
+
Boc
Boc
N
H
N
H
N
H
(1a)
(1b)
(1c)
Boc
Boc
Boc
N
N
H
isothioureas,12-14
carbodiimides,15-16
and
pyrazole-1-
R1 R2
N
carboximidamides.17-18 Among them, N,N′-di-Boc-thiourea 2,19-20
which possess high reactivity and can be easily removed from the
product, has been widely used for the guanylation of amines.21-26
However, substrates with a strong nucleophilic amino group are
typically required in this methodology.19 Subsequently, the
method was improved by Kim and co-workers,27 who reported
that the desulfurization process can be promoted in the presence
of Hg(II) or Cu(II). Under their conditions, both sterically and
electronically deactivated amines were transformed to the
corresponding guanidines (Scheme 1a). Next, Lipton28 and co-
workers reported the Mukaiyama’s reagent mediated
desulfurization of N,N′-di-Boc-thiourea 2 for the guanylation of
unreactive amines and resign-bound amines (Scheme 1b).
Meanwhile, other desulfurization reagents such as NIS or
cyanuric chloride (TCT) were also developed for the
desulfurization of N,N′-di-Boc-thiourea 2 (Scheme 1c, 1d).29
Despite significant progress in the desulfurization of N,N′-di-
Boc-thiourea, a practical and efficient desulfurization strategy is
still required for the guanylation of amines.
N
CH3
Cl
O
S
R2 R1
I
Boc
Boc
Boc
Boc
Boc
Boc
N
H
N
H
N
H
N
N
H
R1 R2
N
S
R2 R1
O
N
I
+
N
H
Boc
Boc
N
N
N
N
H
H
H
Cl
R1 R2
N
N
N
S
(TCT)
R2 R1
Cl
N Cl
+
Boc
Boc
Boc
Boc
N
H
(1d)
N
N
N
N
H
H
H
This work:
R
R
N
NH
S
I
2 (1.2 eq), NEt3 (2.4 eq)
PhMe, 0 °C
Boc
Boc
Boc
+
NH2
N
N
H
N
H
H
3
1
2
Scheme 1. Guanylation of amines using N,N′-di-Boc-thiourea.
Initially, we chose the guanylation of aniline 1a as the model
reaction to optimize the reaction conditions (Table 1). After a
careful screening of solvents and bases, it was found that using
PhMe as the solvent and NEt3 as the base gave the desired
product in 92% yield.
I2 is a commercially available oxidant30-36 which is widely used
in organic synthesis. Recently, the I2 mediated desulfurization of
arylsulfonyl-protected thioureas was reported for the synthesis of
guanidines and the guanidine-containing quinazolinone
heterocyclic skeleton.37-29 Inspired by this work, the possibility of

2
Tetrahedron
Table 1. Optimization of the reaction conditions.a
NEt3
R
NEt3
H2N
BocN
H
H
R
Ph
-S, -I-
HN
C
BocN
NBoc
NH2
BocN
NHBoc
S
NH
C
NBoc
Boc
Boc
Boc
Boc
BocN
NHBoc
+
S
S
I
N
N
N
N
I
I
H
H
H
Scheme 2. Proposed mechanism.
2
3a
1a
Entry
1
Solvent
DMF
Base
NEt3
Yield (%)
83
In conclusion, the I2 mediated oxidative desulfurization of
thioureas to prepare guanidine derivatives was developed.
Various amines, including electronically and sterically
deactivated amines, were transformed to the protected guanidines
under readily accessible conditions.
2
3
4
EtOH
PhMe
PhMe
NEt3
NEt3
77
87
81
K2CO3
5
6
PhMe
PhMe
Py
75
92
Acknowledgments
NEt3
This Project was funded by China Postdoctoral Science Foundation.
a
2
1a
(19 mg, 0.2
Reagents and conditions: thiourea (66 mg, 0.24 mmol), amine
mmol), base (0.48 mmol), solvent (2 mL), I2 (61 mg, 0.24 mmol), rt; b0 C.
References and notes
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5. 1871-1907.
Table 2. Synthesis of guanidines using I2 and N,N′-di-Boc-
thiourea.a
R
N
S
NH
NHBoc
Boc
Boc
R
Boc
N
N
NH2
+
H
H
1
(0.2 mmol)
2
(0.24 mmol)
3
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OMe
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NHBoc
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96%
N
NHBoc
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NHBoc
b
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Zong-Ying, L.; Xiao-Ying, H.; Yuan-Yuan, Z.; Xiu-Li, D.,
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92%
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CF3 Boc
HN
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NHBoc
86%
12.
Pattarawarapan, M.; Jaita, S.; Wangngae, S.; Phakhodee, W.,
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Boc
Boc
N
N
NHBoc
NHBoc
N
NHBoc
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b
b
b
3e,
3f,
3g,
3h,
61%
62%
65%
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OMe
Boc
HN
HN
HN
HN
Boc
Boc
Boc
N
F
N
NHBoc
83%
NHBoc
NHBoc
N
NHBoc
N
NHBoc
82%
3i,
3j,
3k,
3l,
76%
94%
HN
CF3
HN
HN
HN
Boc
Boc
Boc
N
NHBoc
N
N
NHBoc
N
NHBoc
3n,
83%
3m,
77%
3o,
3p,
61%
52%
a
1
2
Reagents and conditions: amine (0.2 mmol), thiourea (0.24 mmol), NEt3 (0.48 mmol), PhMe
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4053-4054.
b2
(2 mL), I2 (0.24 mmol), 0 C;
(0.48 mmol), NEt3 (0.96 mmol), I2 (0.48 mmol)
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Various primary anilines (3a-g), benzylic (3h-j) and aliphatic
(3k-p) amines with different substitution were tested. The desired
guanidines were obtained in 52-98% yield. Due to the unstable
nature of the reactive intermediates, the yield decreased slightly
when sterically or electronically deactivated amines (3d-g, 3n-p)
were used (Table 2). However, no product was detected when
using secondary amines. The free guanidines can be prepared by
simple deprotection of the Boc-protected guanidine according to
the literature method.19
Base on previous reports,29, 37-40 a plausible mechanism for this
reaction was proposed: the oxidative desulfurization of thiourea 2
mediated by I2 in the presence of NEt3 generates the
corresponding carbodiimide in situ. Then, the carbodiimide is
attacked by the amine to form the desired protected guanidines
(Scheme 2).
29. Dardonville, C.; Goya, P.; Rozas, I.; Alsasua, A.; Martı́n, M. I.; Borrego,
M. J., Biorg. Med. Chem. 2000, 8, 1567-1577.
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2980.

3
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Click here to remove instruction text...
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4
Tetrahedron
The I2 Mediated Desulfurization of N,N′-di-Boc-
thiourea was firstly developed.
A practical protocol by using N,N′-di-Boc-thiourea
and iodine as guanylating reagents.
Wide substrate scope with 52-98% yield.