A facile synthesis of imino-protected cyclic guanidine derivatives from diamines

Article abstract of DOI:10.1016/j.cclet.2011.07.008

A convenient one-step synthesis of five-membered or six-membered imino-protected cyclic guanidine via an intramolecular ring-closure reaction of alkyl diamine (2a-2g) with 1, 3-diamino-protected methylisothiourea (1a and 1b) was established and investigated. Amino guanidine such as 3-(2-aminoethyl)-1, 2-dibenzyloxycarbonylguanidine (4a) has been proved to be the intermediate of the reaction via utilizing mono-protected diamine as starting material. The intramolecular ring closure of 4a results in 2- benzyloxycarbonyliminoimidazolidine (3a). This new one-step synthesis has advantages of simple condition, easy workup procedure and reasonable yield.

Full text of DOI:10.1016/j.cclet.2011.07.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1399–1402
www.elsevier.com/locate/cclet
A facile synthesis of imino-protected cyclic guanidine
derivatives from diamines
*
Jian Hai Yuan, Xiao Xiao Yang , Hao Lin, De Xin Wang
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Received 19 April 2011
Available online 12 October 2011
Abstract
A convenient one-step synthesis of five-membered or six-membered imino-protected cyclic guanidine via an intramolecular
ring-closure reaction of alkyl diamine (2a–2g) with 1, 3-diamino-protected methylisothiourea (1a and 1b) was established and
investigated. Amino guanidine such as 3-(2-aminoethyl)-1, 2-dibenzyloxycarbonylguanidine (4a) has been proved to be the
intermediate of the reaction via utilizing mono-protected diamine as starting material. The intramolecular ring closure of 4a results
in 2-benzyloxycarbonyliminoimidazolidine (3a). This new one-step synthesis has advantages of simple condition, easy workup
procedure and reasonable yield.
# 2011 Xiao Xiao Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Intramolecular cyclization; 1, 4-Nucleophilic addition; Alkyldiamines; Cyclic guanidine
The guanidine group is a very important alkalinous pharmacophore. A variety of molecules with diverse structure
containing single or multiple guanidine units have been isolated from microorganisms or natural plants, many of which
possess antimicrobial or cytotoxic activity [1,2]. Therefore, incorporation and derivation of guanidino group in certain
compound may benefit their bioactivity. Generally, the typical synthesis of guanidine-containing compounds involves
treatment of an amine with an electrophilic guanidinylating reagent [3]. Several guanidinylating reagents have been
employed frequently such as pyrazole-1-carboxamidine, S-alkylisothiourea and protected thiourea derivatives [4–7].
Cyclic guanidines synthesis was reported by Rapport by reacting diamines with S, S-dimethyl-N-tosyliminodithio-
carbonimidate [8], which turned out to be an alternative way to the classical method of reacting cyanogen bromide with
diamines to afford five-membered 2-iminoimidazolidine and six-membered 3, 4, 5, 6-tetrahydropyrimidine rings [9].
Recently, in the context of developing peptidomimetic inhibitors in our ongoing research, we need to synthesize
series of aminoalkyl guanidine. Initially, referred to reported method for synthesis aminoalkylguanidine [7], we
attempt to synthesize 1-(3-aminopropyl)-2, 3-dibenzoxycarbonylguanidine (4a) by treating bis(benzyloxy-carbonyl)-
2-methylisothiourea (1a) [10] ethylenediamine (2a). However, an unexpected compound was found as the only
product of the reaction. By analyzing mass spectrum and NMR data, the product turned out to be 2-
benzyloxycarbonyliminoimidazolidine (3a) which has been reported by Rapoport [11] with 3.7% yield using benzyl
chloroformate (Cbz-Cl) and 2-iminoimidazolidine as reaction materials (Scheme 1). This result inspired us to develop
* Corresponding author.
E-mail address: yangxx@imm.ac.cn (X.X. Yang).
1001-8417/$ – see front matter # 2011 Xiao Xiao Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.07.008

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J.H. Yuan et al. / Chinese Chemical Letters 22 (2011) 1399–1402
H
N
NHCbz
NCbz
H N
2
4a
S
NHCbz
NH
2
MeCN, r.t.
H N
+
2
NCbz
1a
NCbz
2a
HN NH
3a
Scheme 1. Reaction of N-Cbz protected methylisothiourea and ethylenediamine.
a simple and convenient synthetic method of compound 3a and then try to apply it to prepare other substituted five-
membered or six-membered cyclic guanidine derivatives.
We introduced two guanidinylating reagents 1a and 1b to react with aliphatic diamine 2a–g at ambient
temperature to afford corresponding 2-alkyloxycarbonyliminoimidazolidine derivatives 3a–i (Table 1) [12]. The
yields ranged from moderate to high depending on the structure of the aliphatic diamine. For diamine with two
primary amino (ethylenediamine 2a and 1, 3-propylenediamine 2e), the reaction condition was mild, and usually
the product 3a and 3e could be precipitated gradually during reaction (acetonitrile as solvent) with high yield.
However, for diamines with single or two secondary amino groups (Table 1, entry 3, 7–9), the yields were
improved while the reaction time being extended or the reaction proceeding at 70 8C. We found that tert-
butoxycarbonyl (Boc)-protected group was less beneficial for this reaction than benzyloxycarbonyl(Cbz)-
protected group (entry 8, 9). For example, compound 3h was obtained with lower yield than 3a via treating the
same diamine 2a with compound 1b and 1a respectively. For the synthesis of 3h and 3i, our findings are generally
correspondent with the results of Botta’s group [7], in which 3h was obtained by heating 1-(2-aminoethyl)-2, 3-di-
Boc-guanidine and 3i by reacting 2e with 1-(trifluoromethanesulfonyl)-2, 3-di-Boc-guanidine in tetrahydrofuran.
However, under our reaction condition, cyclic guanidine 3h was obtained directly as the major product rather than
via separable linear form intermediate.
The mechanism of the labile property of guanidinylethylamine 4a was proposed and shown in Scheme 2. We
presumed that two 1, 4-nucleophilic addition-elimination occurred subsequently when compound 1a was treated with
Table 1
Results and yields of the synthesis of imino-protected cyclic guanidine derivatives.a
NR
NHR
1
S
2
MeCN
r.t.
R
NHR
1
N
+
R HN
2
n
N R
n
NR
(2a-g)
1a: R=Cbz
1b: R=Boc
3a-i
Entry
Diamine 2
n
R1
R2
Compound 1
R
Product 3
Yield (%)
Mp (8C)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
1
1
1
1
2
2
2
1
2
H
H
H
H
a
a
a
a
a
a
a
b
b
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
a
b
c
d
e
f
91
180–182
55–57
52–54
–
CH3
73
58, 79b
CH2CH3
CH3
H
c
CH3
H
70
90
192–194
39–41
56–58
H
CH3
CH3
H
72
g
a
e
CH3
H
g
h
i
56, 76b
54, 86b
57, 89b
205d
176d
H
H
a
Reaction condition: 1 mmol of diamine was reacted with 0.5 mmol of compound 1 in MeCN at ambient temperature.
The yields were improved by heating at 70 8C for 2 h after stirring for 2 h at room temperature.
The compound was achieved as colourless oil.
b
c
d
The compound decomposed at this temperature.

J.H. Yuan et al. / Chinese Chemical Letters 22 (2011) 1399–1402
1401
NH
2
HN
N
H
N
H N
2
S
NH
S
O
NH
2
2
NH
H
N
H
N
_
2a
O
CH SH
O
3
O
N
O
O
O
O
N
O
O
O
O
1a
4a
O
O
O
intramolecular
cyclization
H
O
N
HN
O
O
O
NH
2
N
+
N
H
H
N
N
O
4d
NH
3a
Scheme 2. Proposed mechanism for the synthesis of cyclic imino-protected guanidine derivatives 3.
diamine 2a. Firstly, an intermolecular reaction took place between 1a and diamine 2a, and one methanethiol left
during this process, and then another 1, 4-nucleophilic addition-elimination proceeded intramolecularly, in which 3a
was afforded by losing one benzyl carbamate.
To confirm this mechanism, firstly, 4c (the hydrochloride of linear molecule 4a) was prepared via reacting
ethylenediamine with Boc2O, then guanidinylating by compound 1a and finally removing Boc with hydrochloride
saturated ethyl acetate. Thereafter, 4c was stirred with 1 equiv. N-methylmorpholine (NMM) in THF at room
temperature. As 4a was forming, its free amino group immediately attacked the quaternary electrophilic carbon atom
of enamine bond to afford 3a as the target product (Scheme 3). The benzyl carbamate 4d generated as byproduct has
also been confirmed not only by HPLC via co-injection crude product with standard benzyl carbamate (Fig. 1), but also
by 1H NMR and HRMS after separation. Thus these results provided solid evidence of the mechanism which indicates
the linear molecule 4a with a free amino was labile and the linear molecule 4a could be the intermediate of the
reaction.
In conclusion, we developed a simple and novel method for the synthesis of 2-iminoimidazolidine and 2(1H)-
iminotetrahydropyrimidine derivatives. Compared to the classical method reported [7], the reaction condition of our
method was facile and mild, and it was easily operated with moderate to high yields. Furthermore, the mechanism of
this reaction was illustrated and testified by preparing 4c and then treating 4c with NMM to afford 3a. The result that 4c
could be transformed to product 3a when its amino was liberated by NMM strongly supported the mechanism we
proposed. In addition, all compounds we synthesized in this paper were characterized by HRMS(ESI) and 1H NMR,
data are included in supporting information.
Boc
NH
H
N
(1) Boc O
2
HCl/EtOAc
NHCbz
NCbz
H N
2
NH
2
(2) 1a, MeCN, r.t.
2a
4b
.
NCbz
HCl
NH
2
NH
2
H
H
N
NMM
N
NHCbz
NCbz
4a
NHCbz
HN NH
NCbz
3a
4c
Scheme 3. The proof of the proposed mechanism.

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J.H. Yuan et al. / Chinese Chemical Letters 22 (2011) 1399–1402
Fig. 1. HPLC co-injection of crude product with benzyl carbamate standard: crude product (A), crude product mix with benzyl carbamate standard
(B), compound 3a (C), benzyl carbamate standard (D), gradient of solvent B (E) [13].
Acknowledgments
We thank Project 81001366 supported by NSFC and basic scientific research foundation of Institute of Materia
Medica (No. 2009CHX07) for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2011.07.008.
References
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[12] General procedure for the synthesis of cyclic imino-protected guanidine derivatives (3): To a solution of 1 mmol alkyldiamine in MeCN,
0.5 mmol compound 1a or 1b in MeCN was added dropwise and stirred at ambient temperature for the appropriate amount of time as indicated
in Table 1. The progress of the reaction was monitored by TLC. After completion, compound 3a and 3e could be precipitated from MeCN as
pure products upon TLC examination. Other compound could be obtained via the following procedure: MeCN was removed in vacuo after
reaction was completed, and EtOAc was added to take up the residue. The EtOAc solution was transferred to separation funnel, and then
washed with water and brine each for 3 times subsequently. The organic layer was dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by silica column chromatograph using 1% MeOH/DCM as eluent. Characterization of 2-
benzoxycarbonyliminoimidazolidine (3a): 1H NMR (400 MHz, CDCl3): d 7.66 (s, 2H, NH), 7.28-7.38 (m, 5H, Ph-H), 5.15 (s, 2H, Ph-CH2-O),
3.62 (s, 4H, –CH2CH2–); MS (ESI): m/z 220.1527 [M+H]+, 439.2047 [2M+H]+; HRMS (ESI): calcd. for C11H14N3O2 [M+H]+ 220.1065, found
220.1081.
[13] HPLC conditions: solvent A: water with 0.1%TFA; solvent B: acetonitrile with 0.1%TFA; column: Chromasil C18 reverse-phase, 4.6 Â 15 cm,
5 mm; gradient: linear from 5% B to 95% B over 10 min, then 95% B for 1 min, and 5% B for 2 min. Wavelength used for detection: 214 nm.