Microwave-assisted synthesis of highly functionalized guanidines on soluble polymer support

Article abstract of DOI:10.1016/j.tetlet.2012.05.074

An efficient method for the N,N′-di(Boc)-protected guanidines containing piperazine and homopiperazine scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carbamate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer support. In this manner, highly functionalized guanidines were obtained after cleavage from the support. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine components. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer support, this method provides an efficient route to access highly functionalized guanidines.

Full text of DOI:10.1016/j.tetlet.2012.05.074

Tetrahedron Letters 53 (2012) 3959–3962
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of highly functionalized guanidines on
soluble polymer support
⇑
Chih-Hau Chen, Chieh-Li Tung, Chung-Ming Sun
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
An efficient method for the N,N0-di(Boc)-protected guanidines containing piperazine and homopiperazine
scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carba-
mate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via depro-
tonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer
support. In this manner, highly functionalized guanidines were obtained after cleavage from the support.
The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine com-
ponents. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the
substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer
support, this method provides an efficient route to access highly functionalized guanidines.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 30 March 2012
Revised 10 May 2012
Accepted 15 May 2012
Available online 19 May 2012
Keywords:
Carbamate-protected guanidines
Microwave irradiation
Soluble polymer support
Introduction
H
N
Br
Guanidines are one of the most privileged structural motifs fre-
quently occurring in natural products,1 and have been widely rec-
ognized as useful building blocks for the synthesis of various
biologically active compounds.2 The compelling biological activi-
ties of guanidine derivatives have been ascribed to their ability
to recognize receptors by a variety of non-covalent interactions,
H2N
N
HO
OH
H
O
N
HN
2X-
NH2
O
H2N
O
HO
H
N
NH
H
N
COOH
O
HN
H2N
O
HN
NH
N
N
NH2
OH
OH
H
HN
OH
including hydrogen-bonding, electrostatic, and p-stacking associa-
tions.3 As important variants, heterocycles substituted guanidines
exhibit a broad range of intriguing biological activities such as
cytotoxic,4 antifungal,5 antiviral,6 antimicrobial,7 anticancer,8 and
antimalarial4,5 activities. Saxitoxin (STX, Fig. 1), the causative
agents of paralytic shellfish poisoning (PSP), is potent neurotoxins
produced by dinoflagellates.9 Dragmacidin E was isolated from
Spongosortes sp. and exhibited potent serine-threonine protein
phosphatase inhibitory activity.10 Ptilomycalin A displays promis-
ing anticancer and antiviral activities.11 Zanamivir was syntheti-
cally derived influenza inhibitor.12 The tremendous therapeutic
potential of this class of compounds has sparked our interest in
the synthesis of guanidine with piperazine scaffold and their ana-
log to further explore their biological application.13 Compared to
other heterocycles syntheses,14 the synthetic approach to incorpo-
rate guanidine moiety is limited.15 Therefore, the development of a
mild and efficient synthesis for the rapid construction of highly
substituted guanidines is important. Methods wherein guanidines
could be further functionalized with a variety of electrophiles to
(+)-Saxitoxin (STX)
dragmacin E
zanamivir
O
O
H
H
N
O
N
NH2
NH2
10
N
H
N
H
O
ptilomycalin A
Figure 1. Various types of biologically active heterocycles containing guanidine
frameworks.
give a more highly substituted guanidine are referred to as a gua-
nidinylation. There are very few methods that are employed for the
further functionalization of protected guanidines. Batey and
co-workers developed a phase-transfer catalyzed alkylation of
guanidines for the synthesis of substituted guanidines.16 The most
commonly used method involves the reaction of guanidine with a
primary or secondary alcohol under Mitsunobu conditions.17 The
advent of microwave-assisted organic synthesis has contributed
significantly to the development of eco-compatible methodologies
to save both energy and resources.18 The polyethylene glycol
⇑
Corresponding author.
E-mail address: cmsun@mail.nctu.edu.tw (C.-M. Sun).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.074

3960
C.-H. Chen et al. / Tetrahedron Letters 53 (2012) 3959–3962
HN
NH
NH
O
O
PEG
pyridine, CH2Cl2
MW, 10 min
CH2Cl2
or
O
PEG
+
+
Cl
Cl
OH
MW, 5 min
Cl
HN
2
1
O
NBoc
O
guanidinylating
PEG
PEG
+
reagents
NH
N
NHBoc
O
O
A-E
N
N
n
n
3
n = 1, 2
4
n = 1, 2
NBoc
NBoc
NBoc
NBoc
O
O
RX, NaH, CH2Cl2
0°C, 3 h
KCN, MeOH
r.t. 12 hrs
PEG
N
N
N
O
H3CO
R
R
N
n
n
5
n = 1, 2
Scheme 1. Synthesis of Boc-guanidine derivatives.
6
n = 1, 2
support is suitable for energy dissipation with microwaves.19 The
incorporation of microwave irradiation with PEG supported organ-
ic synthesis greatly accelerates the library synthesis and simplifies
the purification steps in multistep organic synthesis. In this report,
we present highly efficient guanylation and guanidinylation for the
synthesis of highly substituted guanidines on soluble polymer sup-
port under microwave irradiation.
guanylating reagents comprising N,N0-di-tert-butoxycarbonyl-1H-
pyrazole-1-carboxamidine A,15a N,N0-di-tert-butoxycarbonylthiou-
rea B, N,N0-protected S-methylisothiourea C, triflylguanidine deriv-
ative D, and bis-Boc-benzotriazole-carboxamidine E (Fig. 2).20 The
feasibility of these guanylating reagents was first attempted at
room temperature. A comparison of the yields and purities of
guanylation of the PEG linked cyclic diamines 3 with guanylating
reagents A–E is shown in Figure 3. The desired guanylation adducts
were unsuccessful in the case of agent A. However, guanylating re-
agents B–E react efficiently with PEG immobilized benzylpiperi-
zine and benzyldiazepane to afford Boc-protected guanidines in
good yields and purities. The benzotriazole-based reagents E com-
paratively analyzed and proved to be the most efficient one as the
guanylating reagent which leads to a quantitative conversion of
the PEG supported amines into the guanidines in excellent yield
within 6 h at room temperature. The same transformation with
guanylating reagent E is also performed in an open vessel micro-
wave reactor which needed only 7 min to furnish the same product
to show a substantial enhancement of the reaction efficiency. The
reactivities of these guanylating reagents are proposed to be
dependent on the properties of leaving groups that may enhance
the electrophilicity of the amidine carbon.20c The mechanism of
the guanylation of 3 was speculated through a highly electrophilic
intermediate, bis(Boc)carbodiimide.
Results and discussion
A synthetic route toward the highly functionalized Boc-guani-
dines of piperazine and homopiperazine is described in Scheme 1.
Monohydroxyl functionalized PEG (MW 5000) was employed as a
soluble support for a multistep synthetic sequence. PEG is allowed
to react first with di-electrophile, 4-chloromethyl benzoyl chloride
under basic condition. The formation of ester bond in a refluxing
condition required 48 h in dichloromethane which was brought
down to 10 min under open vessel microwave irradiation leading
to polymer conjugates 2 (Scheme 1). Accordingly, PEG conjugate
2 was purified by precipitation with diethyl ether. The progress
of the PEG supported reaction was directly monitored through reg-
ular proton NMR spectroscopy without releasing the intermediate
from the support. The piperazinyl and diazepanyl moiety are intro-
duced to the immobilized benzyl chloride 2 by a nucleophilic sub-
stitution reaction toward the targeted guanidine skeleton. This
reaction was completed in 5 min in a microwave cavity at 100 °C.
It took 16 h to complete in oil-based refluxing condition to afford
polymer conjugate 3. It is noteworthy to mention that the nucleo-
philic substitution with piperazine or diazepane did not cleave the
ester bond of the polymer linkage site even under harsh micro-
wave condition.
The next challenge was the synthesis of substituted guanidine
derivatives from PEG conjugate 4 through nucleophilic substitu-
tion. To extend the scope of the present process, the PEG linked
guanidine derivatives were planned to react with electrophiles to
furnish extra scaffold diversity to provide highly substituted guani-
dine derivatives. The NH alkylation of the PEG linked guanidine 4 is
expected to be laborious. Since, the NH is hindered by the Boc func-
tionality sterically and the nucleophilicity of the nitrogen may be
dispersed by the guanidine due to resonance effect. PEG supported
With the PEG attached benzyldiamine 3 in hand, we explored
the viability and efficiency of the guanylation reaction with various
N
O
O
CH3
N
S
N
S
S
N
F3C
BocHN
N
N
BocHN
NHBoc
BocN
NHBoc
NHBoc
BocN
NHBoc
NHBoc
BocN
A
B
C
D
E
condition for A: 1.2 eq. of A in CH2Cl2 (r.t.; 8 h)
B
B
condition for : 1.2 eq. of and 1.2 eq. DICDI in CH2CI2 (r.t.; 18 h)
C
C
condition for : 1.2 eq. of , 2 eq of HgCI2 and 3 eq. of Et3N in CH2CI2 (r.t.; 40 h)
D
D
condition for : 1.2 eq. of , and 3 eq. of Et3N in CH2CI2 (r.t.; 10 h)
E
E
condition for : 1.2 eq. of , and 3 eq. of Et3N in CH2Cl2 (r.t.; 6 h or MW; 7 min)
Figure 2. Reagents and conditions for the synthesis of N,N0-diprotected guanidines.

C.-H. Chen et al. / Tetrahedron Letters 53 (2012) 3959–3962
3961
guanidine 4 was treated with sodium hydride and electrophiles in
dichloromethane. Gratifyingly, polymer supported substituted
guanidine conjugate 5 was obtained in 3 h through deprotonation
and nucleophilic substitution. It is worth to mention that the ester
functionality of the electrophiles remains intact under the strongly
basic condition during the nucleophilic substitution (entries 6d, 6f,
6j, and 6l). Compared with previous reports,16,17 we have demon-
strated the guanidinylation protocol that is compatible with a wide
range of substrates and additional phase-transfer-catalysts or cou-
pling reagents are not needed. The cleavage of the polymer support
from compound 5 was carried out by using a 1% potassium cyanide
solution in methanol. The polymer was precipitated out by addi-
tion of a cold ether solution and the filtrates were concentrated
to obtain polymer-free substituted guanidine derivatives 6 with
high purities and yields (Table 1).21 The results summarized in Ta-
ble 1 show some representative examples to demonstrate the suc-
cessful access of guanidinylation and N-alkylation to the
substituted Boc-guanidine derivatives with manifold appendages.
In current synthetic approach, we have successfully integrated
the advantages of PEG with microwave synthesis to afford a rapid
synthesis of substituted Boc-guanidine derivatives with high puri-
ties and yields.
Conclusion
An efficient method for the alkylation of N-dicarbamate-pro-
tected guanidines using a variety of alkyl halides has been ex-
plored. Under this procedure, the acidic N-carbamate hydrogen is
deprotonated using basic conditions and subsequently alkylation
to yield highly functionalized guanidines. This protocol provides
Figure 3. Yields and purities of isolated N,N0-diprotected guanidines
reaction of (i) PEG immobilized benzylpiperizine and (ii) PEG immobilized
benzyldiazepane with guanylating reagents A–E.
6 upon
Table 1
Synthesis of substituted guanidine derivatives
Entry
Amine
RX
HPLC purityc (%)
91
Isolate yielda (%)
82
Br
HN
NH
NH
6a
HN
6b
6c
95
97
86
87
Br
Br
HN
HN
NH
NH
O
6d
6e
79
93
71
84
Cl
Br
OCH3
Br
HN
HN
NH
NH
O
6f
97
87
OCH3
Br
NH
NH
NH
NH
6g
6h
6i
91
89
97
82
80
87
HN
HN
HN
HN
Br
Br
O
6j
69 (29)b
88
62
79
Cl
Br
OCH3
Br
NH
NH
6k
HN
HN
O
6l
92
83
OCH3
a
b
c
Yields were determined on weight of purified samples.
The yields in the parentheses represent unreacted starting material.
HPLC purities were determined with crude samples.

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C.-H. Chen et al. / Tetrahedron Letters 53 (2012) 3959–3962
12. von Itzstein, M.; Wu, W. Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Phan, T.
V.; Smythe, M. L.; White, H. F.; Oliver, S. W.; Colman, P. M.; Varghese, J. N.;
Ryan, D. M.; Woods, J. M.; Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C.
R. Nature 1993, 363, 418–423.
13. Yellol, G. S.; Chung, T. W.; Sun, C. M. Chem. Commun. 2010, 46, 9170–9172.
14. Kemp, J. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 7, p 469513.
15. (a) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579–582; (b) Yu, Y.; Ostresh, J.
M.; Houghten, R. A. J. Org. Chem. 2002, 67, 3138–3141; (c) Santana, A. G.;
Francisco, C. G.; Suárez, E.; González, C. C. J. Org. Chem. 2010, 75, 5371–5374;
(d) Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett. 2001, 3,
1133–1136.
an alternate method for the alkylation of protected guanidines
from those currently utilized. In addition, the need for stoichiome-
tric amounts of costly reactive coupling reagents is circumvented.
An attractive feature of this methodology is that few byproducts
are generated and at the end of the reaction, simple workup fol-
lowed by filtration gives high yields of the desired products. The
efficiency of parallel synthesis was greatly enhanced by combining
the advantages of microwave synthesis and a soluble polymer
support.
16. Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003, 68, 2300–2309.
17. (a) Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.; Goodman, M. J. Org.
Chem. 1998, 63, 8432–8439; (b) Vaidyanathan, G.; Zalutsky, M. R. J. Org. Chem.
1997, 62, 4867–4869.
18. Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794–806.
19. Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J. Tetrahedron Lett. 2000, 41,
6371–6375.
Acknowledgments
The authors thank the National Science Council of Taiwan for
the financial assistance and the authorities of the National Chiao
Tung University for providing the laboratory facilities. This Letter
is particularly supported by ‘Aim for the Top University Plan’ of
the National Chiao Tung University and Ministry of Education,Tai-
wan, ROC.
20. Musiol, H.; Moroder, L. Org. Lett. 2001, 3, 3859–3861.
21. General procedures for synthesis of 6: (All microwave experiments performed in
CEM discover microwave system at the frequency of 2450 Hz and 0–300 W
power in open vessel system.) The polymer support (PEG 5000; 10.0 g,
1.0 equiv, 2.0 mmol) in toluene (25 mL) was treated with 4-(chloromethyl)
benzoyl chloride 1 (567.0 mg, 1.5 equiv, 3.0 mmol) in toluene (25 mL) and
pyridine (791.0 mg, 5.0 equiv, 10.0 mmol) under microwave irradiation at
200 W for 10 min to afford amide 2. The reaction mixture was diluted with
slow addition of excess cold ether (50 mL). The precipitated amide conjugate
was filtered through a fritted funnel, washed with ether, and then dried.
Piperazine (4.31 g, 5.0 equiv, 50.0 mmol) or Homopiperazine (5.01 g, 5.0 equiv,
50.0 mmol) were added to a solution of 2 (10.31 g, 1.0 equiv, 2.0 mmol) in
dichloromethane. The reaction mixture was stirred under microwave
irradiation at 120 W for 5 min and after completion; the reaction mixture
was passed through a thin layer of celite to remove salt. The solution was
concentrated by rotary evaporation and diluted with slow addition of an excess
of cold ether. The precipitated conjugate was filtered through a fritted funnel
and washed with ether to afford 3. N,N0-di-tert-butoxycarbonyl-1H-
benzo[d][1,2,3]triazole-1-carboximidamide (0.47 g, 1.3 equiv, 1.3 mmol) was
added to a solution of 3 (5.20 g, 1.0 equiv, 1.0 mmol) in dichloromethane
(30 mL). After stirring for 10 min, triethylamine (0.30 g, 3.0 equiv, 3.0 mmol)
was added and it was treated under microwave irradiations at 150 W for
7 min. The solution was concentrated by rotary evaporation and diluted with
slow addition of an excess of cold ether. The precipitated guanidine conjugate
was filtered through a fritted funnel and washed with ether to afford 4. To a
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.074.
References and notes
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solution of
4 (1.09 g, 1.0 equiv, 0.2 mmol) and alkyl halide (3.0 equiv,
0.6 mmol) in dichloromethane (10 mL) under nitrogen, sodium hydride
(0.024 g, 5.0 equiv, 1.0 mmol) was added and the reaction mixture was
stirred at 0 °C for 3 h. After completion, the reaction mixture was washed
with cold ether. The precipitate was filtered and dried well to furnish the PEG
bound quanidine 5 in excellent yield. To a solution of 5 in methanol (10 mL),
KCN (0.1 g) was added and stirred for 48 h. After the quenching procedure, the
crude products 6 were obtained. The filtrate was dried and subjected to HPLC
analysis which depicts high purity. The title compounds 6 were obtained in
good to excellent overall yield after column chromatography purification.
Compound 6e: 1H NMR (300 MHz, CDCl3) d 7.91 (d, J = 8.4 Hz, 2H), 7.81 (m, 4H),
7.49 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 5.25 (b, 1H), 3.89 (m, 4H), 3.07 (m, 6H),
2.63 (b, 2H), 2.05 (b, 2H), 1.55 (s, 9H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) d
167.3, 160.0, 154.1, 152.8, 134.2, 133.7, 133.4, 130.0, 129.3, 129.1, 128.8, 128.4,
128.0, 127.7, 126.7, 126.6, 115.8, 115.0, 82.3, 79.9, 62.6, 52.5, 51.4, 28.8, 28.6;
IR (neat): 2922, 2851, 1721; MS (FAB-MS) m/z: 617 (M+H)+; HRMS : calcd for
C
35H44N4O6 m/z : 616.3261; found 617.3341 (M+H)+.