Iodine-mediated guanidine formation through arylsulfonyl-activated thioureas

Article abstract of DOI:10.1055/s-0029-1217825

Reaction of arylsulfonyl thioureas with amines to form guanidines can be efficiently promoted through the use of iodine, instead of conventional reagents such as the Mukaiyama reagent or EDC. The general scope and limitations of the reaction are probed.

Full text of DOI:10.1055/s-0029-1217825

LETTER
A
Iodine-Mediated Guanidine Formation through Arylsulfonyl-Activated
Thioureas
G
uanidine Forma
u
tion
f
rom
A
i
ctivated
y
Thiourea
s
ing Qin,a Jizhen Li,*a Erkang Fan*b
a
College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, P. R. of China
Fax 0086(431)88499179; E-mail: ljz@jlu.edu.cn
b
Biomolecular Structure Center, Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
Fax +1(206)6857002; E-mail: erkang@u.washington.edu
Received 27 April 2009
low cost, and low toxicity reagent.12 Herein, we wish to
report our investigation of iodine as a desulfurization re-
agent to promote guanidine formation using Pbf-activated
thioureas.
Abstract: Reaction of arylsulfonyl thioureas with amines to form
guanidines can be efficiently promoted through the use of iodine,
instead of conventional reagents such as the Mukaiyama reagent or
EDC. The general scope and limitations of the reaction are probed.
Key words: iodine, guanidine, arylsulfonyl thiourea, desulfuriza- Pbf-activated thioureas 3 were conveniently prepared in
tions, aminations
high yield (Scheme 1) in dichloromethane according to
reported procedures7c,9 from alkyl or aryl amines, includ-
ing secondary amines, with the highly reactive Pbf-
isothiocyanate. Pbf-isothiocyanate may be easily obtained
by treatment of Pbf-Cl with Bu4NNCS directly7c or from
Pbf-NH2 treated with KOH and CS2 followed by triphos-
gene in toluene, similar to the preparation of Pmc-isothio-
cyanate.11
Guanidine functional groups play essential roles in bio-
logical systems, natural products and synthetic pharma-
ceuticals.1 Consequently, many reagents have been
developed to prepare protected or unprotected
guanidines.2 One of the common strategies used for the
construction of the guanidine functionality is transforma-
tion from thioureas. Such reactions are usually promoted
through reaction with EDC,3 Hg(II),4 the Mukaiyama re-
agent (2-chloro-1-methylpyridinium iodide),5 or 2,4-dini-
trofluorobenzene.3 In all these cases the thiourea needs to
be substituted by electron-withdrawing groups such as ar-
yl, acyl, or alkoxycarbonyl groups in order to achieve high
yields.6 We have previously reported the synthesis of
N¢,N¢¢-disubstituted or oligomeric guanidines through the
use of Mukaiyama reagent or EDC-mediated condensa-
tion with Pbf-activated thiourea (Pbf: 2,2,4,6,7-penta-
The thioureas 3 thus obtained were treated with a diverse
array of amines 4 (R3R4NH) to produce N-Pbf-N¢,N¢¢-di-
substituted guanidines in the presence of iodine (Table 1).
A general procedure is described here. At room tempera-
ture, solid iodine (3 equiv) was added slowly to a stirring
mixture of thiourea 3 (1 equiv) and DIPEA (3 equiv) in an
aprotic solvent such as THF. Iodine dissolved immediate-
ly and the reaction mixture became a purple clear solution.
This was followed by addition of 4. While most guanidine
products were formed within two hours (monitored by
TLC), the reactions were still maintained overnight in or-
der to allow slower reactions to proceed more completely
for yield comparison. In our experience, heating or chang-
ing solvent to DMF or CH2Cl2 did not significantly
change the product yield. The desired guanidines 5 were
afforded as white solids after silica gel chromatography
using ethyl acetate and petroleum ether as eluent.13
methyl-dihydrobenzofuran-5-sulfonyl).7
Furthermore,
this approach provides efficient access to heterocycles
such as 1,5-disubstituted 2-(N-alkylamino)imidazolidin-
4-ones8 and 2-(N-alkylamino)pyrimidin-4-one deriva-
tives.9 The method of using Pbf-activated thiourea was
also applied to the preparation of NG-substituted L-argin-
ine analogues that are suitable for solid-phase peptide syn-
thesis.10 Similarly, other acid-sensitive arylsulfonyl
activation groups such as Pmc could be incorporated into
the guanidine synthesis (Pmc: 2,2,5,7,8-pentamethylchro-
man-6-sulfonyl).11 The strong activating ability of the Pbf
group prompted us to investigate whether a milder and
less toxic reagent could be used for the guanidine forma-
tion reaction, which is believed to proceed through de-
sulfurization and a carbodiimide intermediate. The ability
of iodine to act as a desulfurization reagent in the cycliza-
tion of N-2-pyridylmethyl thioamides or benzothiazoles
attracted our attention because iodine is an easy to handle,
S
CH2Cl2
Pbf
R1
R1R2NH
Pbf NCS
N
N
R2
+
0–5 °C, 0.5–2 h
H
1
2
3
Pbf
R3R4NH (4, 3 equiv)
N
R1
N
R4
DIPEA (3 equiv), I2 (3 equiv)
N
R3
THF, r.t.
R2
5
O
S
Pbf =
O
SYNLETT 2009, No. x, pp 000A–000D
x
x
.xx.
2
0
0
9
O
Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1217825; Art ID: W06109ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

B
C. Qin et al.
LETTER
The results of the iodine-mediated guanidine formation is dine (Table 1, entries 3, 8, 10, and 15). Fourth, N¢,N¢-di-
shown in Table 1. There are several findings in our results substituted N-Pbf-thioureas (R1 and R2 ≠ H) failed to
that are worth noting. First, in general, the iodine-promot- afford guanidines under our reaction conditions, suggest-
ed reaction of Pbf-thioureas with both primary and sec- ing that thioureas incompatible with the pathway of gen-
ondary amines produced the desired guanidines in good erating a carbodiimide intermediate would not work
yields (Table 1, entries 1, 2, 4, 6, 9, 11, and 13–15). Sec- (Table 1, entries 20 and 21). This result was consistent
ond, reactions with ethanolamine or b-amine acid esters with guanidinylation reactions of other activated thio-
gave lower, but still reasonable, yields (Table 1, entries 7, ureas in general using EDC or the Mukaiyama reagent, in-
and 16–18). This result showed that the reaction can easily cluding guanidinylation by Pmc-thiourea with EDC.11
tolerate a range of substituted functional groups such as
The desulfurization ability of iodine in the guanidinyla-
hydroxy or ester groups on the amine or the thiourea moi-
tion process of Pbf-activated thioureas was compared to
eties. Third, aromatic amines with a strong electron-with-
those of the Mukaiyama reagent and EDC. As shown in
drawing substituent, such as a nitro group, failed to
Table 1 (entries 1, 4, 5, 7, 12, and 17–19), in general, io-
undergo the guanidine formation reaction (Table 1, en-
dine produced similar yields to those obtained from reac-
tries 5 and 12). The result suggested that aromatic amines
tions promoted by either EDC or the Mukaiyama reagent.
must possess sufficient nucleophilicity to form the guani-
Table 1 Conversion of Pbf-thiourea and Amines into Guanidines
Entry
R1R2NH
(2)
Thiourea R3R4NH
Product
(5)
Yield with
iodine
Yield with
EDC
Yield with
Mukaiyamareagent
(%)a
(3)
(4)
(%)a
(%)a
1
2
n-BuNH2
n-BuNH2
n-BuNH2
n-BuNH2
n-BuNH2
i-BuNH2
i-BuNH2
i-BuNH2
PhNH2
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
piperidine
5a
5b
5c
5d
94b
83
67
57
0
99
96
–
c
BnNH2
–
3
4-MeOC6H4NH2
n-BuNH2
–
–
4
55
0
73
0
5
2-ClC6H4NH2
Et2NH
6
5e
5f
5g
5h
5i
89
88
73
78
77
71b
0
–
–
7
HO(CH2)2NH2
4-MeOC6H4NH2
BnNH2
84
–
74
–
8
9
–
–
10
11
12
13
14
15
16
PhNH2
4-MeOC6H4NH2
morpholine
4-O2NC6H4NH2
pyrrolidine
BnNH2
–
–
PhNH2
5j
–
–
PhNH2
0
0
BnNH2
5k
5l
90
86
70
67
–
–
BnNH2
–
–
BnNH2
PhNH2
5h
5m
–
–
BnNH2
Bn[MeCO2(CH2)2]NH
(HCl salt)
–
–
17
18
BnNH2
BnNH2
3d
3d
HO(CH2)2NH2
5n
5o
60
54
56
70
50
85
EtO2C(CH2)2NH2
(HCl salt)
19
EtO2C(CH2)2NH2
(HCl salt)
3e
BnNH2
5o
63
79
90
20
21
piperidine
3f
BnNH2
0b
0b
–
–
–
–
Ph(Me)NH
3g
n-BuNH2
a Isolated yield.
b Solvent: CH2Cl2.
c Not performed.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

LETTER
Guanidine Formation from Activated Thioureas
C
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In the case of reactions involving substrates with an ester
group, iodine-promoted reactions gave slightly lower, but
still reasonable, yields (entries 18 and 19 gave 54–63% for
iodine vs 70–90% for EDC or the Mukaiyama reagent).
Thus, we can conclude that, in general, iodine can replace
EDC or the Mukaiyama reagent as an alternative low cost
and low toxicity reagent in guanidinylation reactions with
Pbf-activated thiourea.
Other thiourea guanidinylation reagents such as N,N¢-
bis(Boc)thiourea and N-phenyl-N¢-benzyl thiourea14 were
also studied under our reaction conditions. However,
guanidine products were not formed. The result shows
that Pbf activates thiourea sufficiently enough to allow the
use of iodine as a mild desulfurization reagent. We also
believe that other arylsulfonyl-activated thioureas, for ex-
ample Pmc-thiourea,15 could achieve similar results using
iodine in place of EDC or the Mukaiyama reagent.
In summary, iodine was found for the first time to be use-
ful for the construction of guanidines from readily acces-
sible Pbf-activated thioureas under mild conditions. Thus,
iodine can be used as an economical and less toxic alter-
native to traditional reagents such as EDC or the
Mukaiyama reagent. Application of this method for the
synthesis of biologically active guanidine-containing het-
erocycles is currently under way in our group.
(7) (a) Li, J. Z.; Zhang, G. T.; Zhang, Z. S.; Fan, E. J. Org.
Chem. 2003, 68, 1611. (b) Zhang, Z. S.; Fan, E. J. Org.
Chem. 2005, 70, 8801. (c) Zhang, Z. S.; Pickens, J. C.; Hol,
W. G. J.; Fan, E. Org. Lett. 2004, 6, 1377. (d) Zhang, Z. S.;
Carter, T.; Fan, E. Tetrahedron Lett. 2003, 44, 3063.
(8) Li, J. Z.; Zhang, Z. F.; Fan, E. Tetrahedron Lett. 2004, 45,
1267.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(9) Li, J. Z.; Kou, J. P.; Luo, X. Y.; Fan, E. Tetrahedron Lett.
2008, 49, 2761.
(10) Martin, N. I.; Liskamp, R. M. J. J. Org. Chem. 2008, 73,
Acknowledgment
7849.
This project is supported by funding from the State Key Laboratory
of Applied Organic Chemistry, Lanzhou University, and the Scien-
tific Research Foundation for the Returned Overseas Chinese Scho-
lars, State Education Ministry, P. R. of China.
(11) Flemer, S.; Madalengoitia, J. S. Synthesis 2007, 12, 1848.
(12) (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T.
Org. Lett. 2006, 8, 5621. (b) Downer-Riley, N. K.; Jackson,
Y. A. Tetrahedron 2007, 63, 10276. (c) Kobayashi, K.;
Miyamoto, K.; Yamase, T.; Nakamura, D.; Morikawa, O.;
Konishi, H. Bull. Chem. Soc. Jpn. 2006, 79, 1580. (d) Kim,
I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron Lett. 2007,
48, 8976. (e) Kobayashi, K.; Hashimoto, K.; Shiokawa, T.;
Morikawa, O.; Konishi, H. Synthesis 2007, 6, 0824.
(13) [N-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-
sulfonyl)-N¢-(2-ethoxycarbonylethyl)-N¢¢-benzyl
guanidine (5o): Iodine (0.0928 g, 0.35 mmol) was added to
a solution of thiourea 3e (0.0495 g, 0.12 mmol) dissolved in
THF (4 mL), followed by DIPEA (0.0491 g, 0.35 mmol).
After 10 min, BnNH2 (0.0388 g, 0.35 mmol) was added to
the mixture, and the reaction mixture was stirred overnight
at room temperature. The residue obtained after evaporation
of the solvent was separated by silica gel column (petroleum
ether–EtOAc) to afford 5o as a white solid (0.0364 g, 63%).
MS: m/z = 502.3 [M + H]+. 1H NMR (300 MHz, CDCl3):
d = 1.20–1.25 (t, J = 7.2 Hz, 3 H), 1.47 (s, 6 H), 2.10 (s,
3 H), 2.46–2.48 (d, J = 5.7 Hz, 2 H), 2.50 (s, 3 H), 2.58 (s,
3 H), 2.95 (s, 2 H), 3.44–3.50 (m, 2 H), 4.03–4.10 (m, 2 H),
4.30–4.32 (m, 2 H), 7.18–7.20 (m, 2 H), 7.29–7.31 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 12.4, 14.1, 17.9, 19.2, 21.0,
28.6, 33.9, 36.9, 43.2, 45.4, 60.9, 86.3, 117.3, 124.4, 127.1,
127.8, 127.8, 132.3, 133.2, 138.4, 154.7, 158.6, 172.7. Anal.
Calcd for C26H35N3O5S: C, 62.25; H, 7.03; N, 8.38. Found:
C, 62.14; H, 7.12; N, 8.57.
References and Notes
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Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

D
C. Qin et al.
LETTER
(14) (a) Poss, M. A.; Iwanowicz, E.; Reid, J.; Lin, J.; Gu, Z.
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Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

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