Soluble polymer-supported synthesis of N, N-di(Boc)-protected guanidines

Article abstract of DOI:10.1055/s-1998-1989

A novel method for soluble, inexpensive polymer-supported synthesis of internal guanidines with piperazine and piperidine scaffolds has been developed. We carried out a preliminary study on the reactivity of N,N-bis-Boc-1-guanylpyrazole 1, N,N-bis-Boc-thiourea 2 and N,N-di-(tert-butoxycarbonyl)-S-methylisothiourea 3 with resin bound diamines in liquid phase. Guanidines are liberated from the polymer support in high yields and good purity by simple precipitation and washing. This liquid-phase method proves to be a useful tool for constructing guanidine libraries containing a diamine moiety.

Full text of DOI:10.1055/s-1998-1989

December 1998
SYNLETT
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Soluble Polymer-Supported Synthesis of N, N-di(Boc)-Protected Guanidines
Jing-Ying Shey, Chung-Ming Sun*
Department of Chemistry, National Dong Hwa University, Shou-Feng, Hualien 974, TAIWAN
Fax: (886)- 3-8661487. E-mail: cmsun@cc.ndhu.edu.tw
Received 22 September 1998
Abstract: A novel method for soluble, inexpensive polymer-supported
synthesis of internal guanidines with piperazine and piperidine scaffolds
has been developed. We carried out a preliminary study on the reactivity
of N,N-bis-Boc-1-guanylpyrazole 1, N,N-bis-Boc-thiourea 2 and N,N-
It is known that the guinidino group is a key structural element in many
medicinally interesting molecules. They are frequently found in
5
compounds possessing broad biological activities, including
6
hypertensive and neurological effects. Consequently, a general method
di-(tert-butoxycarbonyl)-S-methylisothiourea
3
with resin bound
for the rapid multiple synthesis of guanidine containing compounds
would be of great value for drug discovery and lead optimization.
diamines in liquid phase. Guanidines are liberated from the polymer
support in high yields and good purity by simple precipitation and
washing. This liquid-phase method proves to be a useful tool for
constructing guanidine libraries containing a diamine moiety.
1-3
Combinatorial organic synthesis on solid support has already been
regarded as an important tool for the synthesis of a large number of
pharmaceutically interesting compounds. In combination with high
throughput screening, this technology may dramatically accelerate drug
lead discovery. While most of the libraries thus established have been
synthesized on solid support, liquid-phase combinatorial synthesis
(LPCS) provides an interesting approach, where molecules are prepared
Classical synthesis of guanidines usually requires reaction of an amine
with an electrophilic amidine species. The most commonly used
guanylating reagents are derivatives of pyrazole-1-carboxamidine 1,
7
protected thiourea 2 and S-alkylisothioureas 3. Solid-phase synthesis of
8
guanidines has been recently reported by Pfizer’s group , and solution-
4
on a liquid, soluble polymer-poly(ethylene glycol). This polymer
phase synthesis of polyazapyridinocyclophanes containing guanidine
support, in contrast to an insoluble matrix, is soluble in most organic
solvents and has a strong tendency for precipitation in particular
solvents. In order to meet all requirements of a stepwise synthesis
without intermediate purification, this support should be stable during
all stages of synthesis. Upon reaction, the product remains covalently
bound to the support, and purification can be accomplished after
precipitation simply by filtering and washing away the unreacted low-
molecular-weight, solution-phase reagents.
9
functionality has also been studied. We describe here our preliminary
results on the liquid-phase method for the synthesis of substituted
guanidine libraries (Table 1). The basic synthetic route is outlined in
Scheme 1.
When applied to scaffold analogs synthesis, this approach requires that
the polymer-diamine templates are soluble under conditions of
guanylation but insoluble during the workup of reaction mixtures. The

1424
LETTERS
SYNLETT
After the reactions were completed, the PEG-bound guanidines were
precipitated by the addition of an ice cold solution of t-butyl methyl
ether and were recrystallized from hot ethanol if necessary. This workup
step should then furnish compounds in analytically pure form before
resin cleavage. No attempts were made to optimize the reaction
conditions and all reagents were used directly without further
purification. Treatment of guanylated products with KCN in methanol
resulted in a very efficient cleavage from polymer support to provide the
desired compounds (7~9) in high yield (80~98%) and high purity
(72~98%). Compounds were characterized by electron spray mass
Scheme 1
solubility of the reactants and polymer support allows reaction kinetics
control similar to those observed in solution chemistry. Our liquid-phase
method then retains two crucial advantages of solid-phase synthesis, i.e.
addition of excess reagents and simple product purification.
1
spectrometry and H NMR confirming that in each reaction the major
In order to evaluate the relative reactivity of guanylating reagents in the
liquid-phase combinatorial synthesis, we carried out the reaction of
polymer bound amines (4~6) with various reagents (1~3) under
compound had a molecular ion corresponding to the appropriate
product. Further deprotection of di-Boc-guanidines (Scheme 2) has been
carried out in trifluoroacetic acid/methylene chloride solution (50 %) at
25°C in quantitative yield.
10
several conditions (A~D) in methylene chloride. Results are
summarized in Table 1. As can be seen, the aminoguanylation reaction
proceeds smoothly at ambient temperature to give the corresponding
products after resin cleavage (except entries 5,9). The reaction of PEG-
supported primary amine 4 with N,N-bis(Boc)-1-guanylpyrazole 2 was
performed successfully at room temperature in 20 hr, since 1-pyrazolyl
substituent represents a good leaving group (entry 1, procedure A).
Course of reaction was easily followed by TLC analysis (observation of
It is worthy to note that, in contrast to the various restrictions on the
analysis of reaction development in solid-phase synthesis, liquid-phase
synthesis allows routine analytical instruments (UV, IR, NMR, TLC) to
monitor reaction progress without following
a cleave-&-analyze
technique. This non-destructive approach to monitoring reaction
progress makes the LPCS method even more valuable.
1
decreasing 2) and was conveniently estimated by H NMR without any
In summary, a novel liquid phase synthesis of guanidines containing
piperazine and piperidine derivatives has been developed. All four
resin cleavage. The polymer bound secondary amines 5 and 6 proved to
be less reactive (entries 5,9), since the addition of 2 to them did not
result in the isolation of any desired products even under more forcing
conditions of elevated temperature (e.g. refluxing toluene). It is clear
that sterically crowded amines (5,6) may hinder the approach of center
amidine carbon. Therefore, reactions using 1 were proven less efficient.
reactions (linker attachment, S 2 reaction, guanylation and resin
N
cleavage) involved are highly efficient in giving the desired compounds
in high yields and good purity just by simple precipitation and washing.
This method of synthesis is versatile and produces compounds with
known pharmacophoric scaffolds, and which are thus ideally suited for
combinatorial library generation. Further exploration of this technology
is ongoing and will be reported in later papers.
A
different protocol (procedure B) was then developed for
guanidinylation using the combination of reagent and
2
diisopropylcarbodiimide (DICDI). This process worked very well at
room temperature even with steric bulk amines such as 5 and 6 (entries
6,10). Use of guanylating agent 2 in the presence of mercuric chloride
and triethylamine (procedure C) also provided a very efficient route for
the bis-protected guanidines formation of amino compounds (entries
3,7,11). Without addition of triethylamine, the reaction proceeded
slowly. Formation of insoluble mercuric sulfide was easily removed by
using fluted filter paper before precipitation and washing. Although
Acknowledgements: we thank the National Science Council of Taiwan
for general financial support.
References and Notes
(1) Terrett, N. K.; Gardener, M.; Gordon, D. W.; Kobylecki, R.
Tetrahedron 1995, 30, 8135.
11
7a
Bergeron and Cook reported that complete reaction of a primary
amine with commercially available reagent in solution-phase
(2) Myers, P. L.; Greene, J. W.; Teig, S. L. Todays Chemist at Work
1997, 6, 46.
3
chemistry, our treatment of 3 with polymer bound amine 4 failed to
deliver the corresponding guanidine under several harsh conditions.
However, we found that N,N-di(Boc)-S-methylisothiourea 3 reacted
(3) Borman, S. Chemical & Engineering News 1998, April 6, 47.
(4) Han, H.; Wolfe, M.; Brenner, S.; Janda, K. Proc. Natl. Acad. Sci.
USA, 1995, 92, 6419.
with amines (4~6) readily by the catalysis of HgCl to produce
2
(5) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66, 119.
corresponding guanyl products (entries 4,8,12). Although the exact
intermediates for this mercuric chloride- or DICDI-promoted guanidine
formation are unknown, the possible in-situ generated bis-Boc-
carbodiimide 13 may be the reactive species.
(6) (a) Mori, A.; Cohen, B. D.; Lowenthal, A. Historical, Biological,
Biochemical, and Clinical Aspects of the Naturally Occurring
Guanidino Compounds; Plenum: New York, 1983. (b) Gilman,
Scheme 2

December 1998
SYNLETT
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A. G.; Goodman, L. S.; Gilman, A.; Eds; The Pharmacological
Basis of Therapeutics, 6 Edition.; Macmillan Co.: New York,
(10) Polymer supported amines (4~6) were synthesized by treating
th
MeO-PEG (MW: 5000) with 4-chloromethyl benzoyl chloride
1980; p 180. (c) Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee,
S.; Garvey, E. P.; Salter, M.; Duffy, C.; Burnette, T. C.; Furfine, E.
S. J. Med. Chem. 1998, 412, 2858.
(1.2 equiv, CH Cl , 24 h, R.T.) to give the resin bound benzyl
2 2
chloride via ester linkage. The resulting polymer-supported
benzylic halide reacted readily with several templates (4-
(aminomethyl)piperidine, piperazine and homopiperazine) in the
(7) (a) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579. (b)
Verdini, A. S.; Lucietto, P.; Fossati, G.; Giordani, C. Tetrahedron
Lett. 1992, 33, 6541. (c) Poss, M. A.; Iwanowicz, E.; Reid, J. A.;
Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933.
presence of Et N at room temperature. These nucleophilic
3
substitution reactions were monitored using proton NMR for the
disappearance
of
polymer-bound
benzylic
protons
(MeOPEGCOPh-CH -Cl) at 4.58 ppm. After the reactions were
2
(8) Robinson, S.; Roskamp, E. J. Tetrahedron 1997, 53, 6697.
completed, the PEG-bound products (4~6) were precipitated by
the addition of t-butyl methyl ether and after drying the products
were ready for the next synthetic step.
(9) An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. D.
Tetrahedron 1998, 54, 3999.
(11) Bergeron, R. J.; McMannis, J. S. J. Org. Chem. 1987, 52, 1700.