A facile and practical one-pot 'catch and release' synthesis of substituted guanidines

Article abstract of DOI:10.1016/j.tetlet.2009.06.113

A 'catch and release' two-step one-pot protocol has been developed for the facile and practical synthesis of substituted guanidines from thioureas and various amines utilizing readily available brominated polystyrene resin.

Full text of DOI:10.1016/j.tetlet.2009.06.113

Tetrahedron Letters 50 (2009) 5145–5148
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile and practical one-pot ‘catch and release’ synthesis
of substituted guanidines
*
Ying Wang , Daryl R. Sauer, Stevan W. Djuric
High-Throughput Organic Synthesis Group, Medicinal Chemistry Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064-6113, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A ‘catch and release’ two-step one-pot protocol has been developed for the facile and practical synthesis
of substituted guanidines from thioureas and various amines utilizing readily available brominated poly-
styrene resin.
Received 3 June 2009
Revised 24 June 2009
Accepted 26 June 2009
Available online 1 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The functionality of guanidines has been found in many natural
products and medicinally interesting molecules mainly due to
their basicity and hydrogen-bonding properties. They are impor-
tant pharmacophores in various therapeutic areas with biological
activities ranging from antimicrobial, antiviral, antifungal to neu-
rotoxic.1 As a result, methods have been developed for the synthe-
sis of guanidines both in solution and on solid support.2 Solid
phase synthesis offers the unique advantage that excess reagents
or resins can be used to drive the reaction to completion thus sim-
plifying purification. However, most of the known solid phase
methods for guanidine synthesis either involve lengthy prepara-
tion of the specially designed linkers, or leave the generated guani-
dine with a ‘handle’ after cleavage, which in many cases may not
be desirable.2a,3
Me
NH
R'NH2
S
NHR'
NH
MeI
S
-MeSH
RHN
NH2
RHN
RHN
Solid Phase Version
S
R'NH2
X
NHR''
NH
S
RHN
NH2
Release
Catch
RHN
RHN
NH
Scheme 1. Guanidine formation through S-methylisothiourea in solution and on
solid support.
In connection with ongoing research efforts, we needed a direct
and practical synthetic method that would allow us to access the
guanidine moiety from diverse sets of amines and thiourea scaf-
folds using readily available reagents. The method should also be
amenable for library automation. Here we report a facile and prac-
tical method we have developed for the synthesis of substituted
guanidines.
Typically, the synthesis of guanidines involves treating of an
amine or amine equivalent with an electrophilic amidine species.
The most commonly used such species is S-alkylisothiourea, in par-
ticular, S-methyl isothiourea. With this method, guanidines can be
easily synthesized from amines and thioureas in a two-step pro-
cess (Scheme 1). The advantages of this method are that no extra
coupling reagent is needed, mild reaction conditions are utilized,
and in many cases, high yields of the final products can be obtained
with diverse amines. However, the major drawback of this method
is the generation of noxious and toxic methyl mercaptan, which is
unpleasant to work with and not suitable for high throughput
Table 1
Determination of the loading of benzylthiourea 3
S
Br
H2N
N
1
S
H
HN
N
3
Or
H
CH2Cl2/DMF = 2:1
50°C
4
Cl
2
Entry
Equiv of the resin relative to 3
Resin 1a (4 h)
Resin 2a (30 h)
1
2
3
0.8
1
1.5
100%b
91%
69%b
56%
100%c
83%c
a
All percentages are determined based on the limiting reagents.
Percentages are determined based on the consumption of the resin.
Percentages are determined based on the consumption of 3.
b
c
* Corresponding author. Tel.: +1 847 935 3058; fax: +1 847 935 5212.
E-mail address: Wang.Ying@abbott.com (Y. Wang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.113

5146
Y. Wang et al. / Tetrahedron Letters 50 (2009) 5145–5148
automated library production. To circumvent this problem and
take advantage of this synthetic route, a corresponding ‘catch
and release’ solid phase version was designed (Scheme 1).4 In this
approach, there’s no additional ‘handle’ required for the thiourea
scaffold, as the resin is attached through the sulfur atom. Subse-
quently, the ‘SH’ group is retained by the polymeric solid support
upon displacement by amines.
For our initial studies, we chose to examine the guanidination of
benzylthiourea with aminomethylcyclohexane. Both brominated
and chlorinated polystyrene resins 1 and 2 were tested in the first
loading step (Table 1). Initial experiments showed that the reaction
proceeded faster in a CH2Cl2–DMF (2:1) solvent system than in
DMF, which was used to facilitate the dissolution of the thioureas.
Addition of base, such as diisopropylethylamine, did not facilitate
S
S
+
i) CH2Cl2/DMF = 2:1
50°C , 4h
H2N
N
HN
N
Br
H
H
4
1
3
not isolated
NH
NH2
( 2.5 eq)
(ii)
HN
N
H
CH2Cl2/DMF = 2:1
50°C, 13h
5
85%
Scheme 2. One-pot synthesis of guanidine 5.
Table 2
One-pot synthesis of N,N0-disubstituted guanidines
i)
4-6 h
NH
S
Br
R
R'
R
N
H
NH2
N
N
H
H
ii)
2.5 eq R'NH2, 20h
CH2Cl2/DMF = 2:1, 50°C
Entry
1
Thiourea
Amine
Producta
Yield (%)
80
S
HN
N
NH
HN
N
H2N
N
NH2
N
N
H
H
H
NH
NH2
2
3
99
84
N
N
H
H
O
O
HO
NH
NH2
HO
N
N
H
H
NH
O
4
5
6
7
82
97
82
43
N
N
H
H
NH2
O
NH
O
O
NH2
O
O
N
N
H
H
NH
F
NH2
F
N
N
H
H
NH
HO
NH
HO
NH2
N
H

Y. Wang et al. / Tetrahedron Letters 50 (2009) 5145–5148
5147
Table 2 (continued)
Entry
Thiourea
Amine
Producta
Yield (%)
H
H
N
NH
NH
N
S
O
H2N
8
9
75
42
80
69
O
HN
NH2
H
N
H2N
HN
H
S
N
NH
10
N
NH2
NH
N
H
H
N
NH2
H
NH
H2N
11
N
H
N
H
O
O
a
Products were isolated as their TFA salt and the purities of the compounds thus obtained were greater than 95% as determined by 1H NMR and LC–MS.
the reaction. As shown in Table 1, the brominated resin afforded
higher loadings in all cases examined with much shorter reaction
time (4 h vs 30 h).5 Thus, resin 1 was used throughout our study.
Especially noteworthy is that with 1.5 equiv of the brominated re-
sin, the thiourea substrate was completely loaded onto the resin in
4 h.
guanidines were obtained. Trisubstituted guanidines could also
be obtained from N,N-disubstituted thioureas in our two-step
one-pot procedure, albeit with longer loading time and higher
equivalents of amines (Table 4).
In summary, a facile and practical two-step one-pot ‘catch and
release’ method has been developed for the synthesis of substi-
tuted guanidines with good to excellent yields. The protocol uses
readily available resin under mild reaction conditions with maxi-
mal use of the thiourea substrate. Furthermore, the process can
be easily adapted to library production in a simple and straightfor-
ward manner.
The loaded resin 4 could be washed, dried and stored for the
second displacement step if desired. More conveniently, a one-
pot procedure was developed without the need to isolate the
loaded resin 4 (Scheme 2). Thus, adding 1.5 equiv of resin 1 to a
solution of benzylthiourea at 50 °C afforded the loaded resin 4 after
4 h as indicated by the complete disappearance of the benzylthiou-
rea in the solution. Subsequently 2.5 equiv of amine was added and
the resulting mixture was heated at 50 °C. After 13 h, the resin was
filtered off and washed with additional CH2Cl2–DMF. Guanidine 5
was isolated with a 85% yield as its TFA salt after HPLC purification.
The advantages of this approach are threefold. First, the method
ensures the complete loading of the thiourea substrate, which
makes the maximum use of the substrate. Second, the reaction
can be conveniently monitored by traditional methods such as
TLC and LC–MS, as the completion of the loading step is indicated
by the disappearance of the thiourea substrate. Third, by eliminat-
ing the washing and drying step, this one-pot process dramatically
cuts down compound or library production time. Also the capture
of the ‘SH’ group by the resin makes the synthesis less odorous.
This procedure worked well with a broad spectrum of primary
amines to generate N,N0-disubstituted guanidines as illustrated in
Table 2. All the thiourea substrates used in Table 2 were com-
pletely loaded onto the resin in 6 h. Amines were then added to
the resulting solutions and the reaction was continued for another
20 h before work-up. The yields range from fair to excellent (42–
99%).
Table 3
Synthesis of trisubstituted guanidines from thiourea and secondary amines
i)
S
NH
(1.5 eq.)
Br
CH2Cl2/DMF = 2:1, 50°C
R'
N
NH2
ii)
N
N
H
H
R
2.5 eq. NHRR', 1.5 eq. HgCl2
CH3CH2CH2OH,90°C, 20 h
Entry
1
Amine
Producta
Yield (%)
76
O
NH
N
H
N
N
H
O
NH
2
3
70
82
51
N
H
N
N
H
NH
N
H
N
Secondary amines also reacted with thiourea under these two-
step one-pot conditions, although the yield was low and the reac-
tion time needed for the second displacement step was signifi-
cantly longer. However, when resin 4 was washed and dried, and
then reacted with amines in the presence of 1.5 equiv HgCl2 in
methoxyethanol for the displacement step, the corresponding tri-
substituted guanidines were obtained in fair to good yields (Table
3). A simple filtration after the reaction removed the resin and the
mercury salts altogether. With anilines, only low yields of the
N
H
NH
HN
N
H
N
4
a
Products were isolated as their TFA salt and the purities of the compounds thus
obtained were greater than 95% as determined by 1HNMR and LC–MS.

5148
Y. Wang et al. / Tetrahedron Letters 50 (2009) 5145–5148
Table 4
the compounds are also included. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.06.113.
Synthesis of trisubstituted guanidines from N,N-disubstituted thiourea and primary
amines
i)
(1.7 eq.)
Br
References and notes
NHR
NH
NH2
S
12 h
N
N
1. (a) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66, 119; (b) Mori, A.;
Cohen, B. D.; Lowenthal, A. Guanidines, Historical, Biological, Biochemical, and
Clinical Aspects of the Naturally Occurring Guanidino Compounds; Plenum: New
York, 1985; (c) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339.
ii)
3 eq. RNH2, 24h
CH2Cl2/DMF = 2:1, 50°C
2. (a) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V.
Tetrahedron 1998, 54, 15063; (b) Wilson, L. J.; Klopfenstein, S. R.; Li, M.
Tetrahedron Lett. 1999, 40, 3999–4002; (c) Linton, B. R.; Carr, A. J.; Orner, B. P.;
Hamilton, A. D. J. Org. Chem. 2000, 65, 1566; (d) Wu, Y.; Hamilton, S. K.;
Wilkinson, D. E.; Hamilton, G. S. J. Org. Chem. 2002, 67, 7553; (e) Poss, M. A.;
Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933; (f)
Sandin, H.; Swanstein, M.; Wellner, E. J. Org. Chem. 2004, 69, 1571; (g)
Rasmussen, C. R.; Villani, F. J., Jr.; Reynolds, B. E.; Plampin, J. N.; Hood, A. R.;
Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Howse, R. M., Jr.;
Molinari, A. J. Synthesis 1988, 6, 460; (h) Dodd, D. S.; Wallace, O. B. Tetrahedron
Lett. 1998, 39, 5701.
3. (a) Ghosh, A. K.; Hol, W. J.; Fan, E. J. Org. Chem. 2001, 66, 2161–2164; (b) Kilburn,
J. P.; Lau, J.; Jones, R. C. F. Tetrahedron 2002, 58, 1739–1743; (c) Drewry, D. H.;
Gerritz, S. W.; Linn, J. A. Tetrahedron Lett. 1997, 38, 3377–3380; (d) Kearney, P.
C.; Fernandez, M.; Flygare, J. A. Tetrahedron Lett. 1998, 39, 2663–2666.
4. For some recent ‘catch and release’ examples, see: (a) Strohmeier, G. A.; Kappe,
C. O. Angew. Chem., Int. Ed. 2004, 43, 621–624; (b) Porcheddu, A.; Giampaolo, G.;
De Luca, L.; Ruda, A. M. J. Comb. Chem. 2004, 6, 105–111; (c) Larsen, S. D.;
Stachew, C. F.; Clare, P. M.; Cubbage, J. W.; Leach, K. L. Bioorg. Med. Chem. Lett.
2003, 13, 3491–3495; (d) Marugg, J. L.; Neitzel, M. L.; Tucker, J. Tetrahedron Lett.
2003, 44, 7537–7540; (e) Adams, G. L.; Graybill, T. L.; Sanchez, R. M.; Maggaard,
V. W.; Burton, G.; Rivero, R. A. Tetrahedron Lett. 2003, 44, 5041–5045.
5. The resin was purchased from Novabiochem (Cat. No. 01-64-0400). The loading
of the resin used in this study is 1.06 mmol/g. The loading of the thiourea was
determined by calibration of the HPLC traces of the solution using internal
standard and was further confirmed by 13C-GELMAS experiments. See
Supplementary data for details.
Entry Amine
Producta
Yield
(%)
OH
HN
OH
1
82
77
H2N
N
N
NH
HN
NH
2
H2N
a
Products were isolated as their TFA salt and the purities of the compounds thus
obtained were greater than 95% as determined by 1H NMR and LC–MS.
Acknowledgements
We thank Jan Waters for the NMR spectroscopic analysis and
Dr. Michael Ochse and Dr. Adrian Hobson for helpful discussions.
Supplementary data
Synthetic procedures, 1H NMR, 13C NMR and Masspec data of all
the compounds are provided. Spectra of 1H NMR and 13C NMR of all