A novel atom-efficient, one-pot synthesis of sulfonylguanidines and sulfamoylguanidines

Article abstract of DOI:10.1016/j.tetlet.2011.04.031

An expedient one-pot procedure for the atom-efficient production of a variety of sulfonylguanidines and sulfamoylguanidines under mild conditions is described. The route constitutes an important alternative to current methods.

Full text of DOI:10.1016/j.tetlet.2011.04.031

Tetrahedron Letters 52 (2011) 3198–3200
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel atom-efficient, one-pot synthesis of sulfonylguanidines
and sulfamoylguanidines
⇑
Jos H.M. Lange , Stefan Verhoog, Hans J. Sanders, Arnold van Loevezijn, Chris G. Kruse
Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient one-pot procedure for the atom-efficient production of a variety of sulfonylguanidines and
sulfamoylguanidines under mild conditions is described. The route constitutes an important alternative
to current methods.
Received 2 March 2011
Revised 28 March 2011
Accepted 8 April 2011
Available online 19 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The guanidine moiety constitutes a key structural element in
many biologically active compounds1 and natural products.2 Sulfo-
nylguanidines have been applied as precursors in the synthesis of
peptide ‘tweezer’3 receptors4,5 and as chiral organocatalysts for
the Michael reaction.6 Moreover, sulfonylguanidines such as the
racemic antiulcer agent osutidine,7 and the closely related acyl-
guanidines, exemplified by the sodium–calcium exchange blocker
benzamil,8 and the antithrombotic factor Xa inhibitor,9 BMS-
344577, are of pharmaceutical interest. The cannabinoid CB1
antagonistic10 pyrazoline-1-carboxamidines,11 including the anti-
obesity agent ibipinabant,12 can be considered as sulfonylguani-
dine derivatives wherein one of the guanidine nitrogen atoms is
part of a heterocyclic ring (Fig. 1).
Several synthetic approaches to sulfonylguanidines and acyl-
guanidines have been described.6,11–14 In general, an electrophilic
guanylating agent is synthesized from a thiourea. In the final step
of the synthetic sequence, the thiourea is coupled with a nucleo-
philic amine in the presence of a Hg(II) salt, EDC, the Mukaiyama
reagent, 2,4-dinitrofluorobenzene or iodine.15 The required N-sul-
fonylthioureas are either synthesized from a sulfonamide and an
isothiocyanate in the presence of a base, or are obtained by the
reaction of a sulfonylisothiocyanate and an amine. An alternative
route4,5 to sulfonylguanidines started from an amine which was
converted with thiophosgene into the corresponding isothiocya-
nate, and further converted by reaction with a second amine into
the corresponding thiourea. The thiourea obtained was then
O
Cl
HN
N
O
N
OH
H
H
O
O
N
N
HN
NH2
N
O
N
N
S
N
N
O
H
N
O
S
H2N
HO
N
N
O
N
HN
NH
Cl
O
N
NH2
S
O
NMe2
O
Cl
osutidine
benzamil
BMS-344577
ibipinabant
Figure 1. Examples of sulfonylguanidines and acylguanidines of pharmaceutical interest.
⇑
Corresponding author. Tel.: +31 (0)294 479731, fax: +31 (0)294 477138.
E-mail addresses: jos.lange@abbott.com, jos.lange@kpnmail.nl (J.H.M. Lange).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.031

J. H. M. Lange et al. / Tetrahedron Letters 52 (2011) 3198–3200
3199
R2
R1
R1
R2
R2
R1
R1
R2
N
N
a
b, c
d
N
N
O
S
R1R2NH
R3
R3
R3
R3
N
S
N
N
O
H
N
SH
N
S
H
R4
1
2
3
4
5
Scheme 1. Reagents and conditions: (a) R3N@C@S, CH3CN, N2, rt, 2 h, except for 5h (20 h); (b) CH3I, rt, 18 h; (c) concentration in vacuo; (d) R4SO2NH2, KHCO3, MeCN, reflux,
22 h, except for 5d and 5i (72 h).
methylated in the presence of NH4PF6 and subsequently coupled
with a sulfonamide in the presence of a base to produce the desired
sulfonylguanidine.
cycloalkyl-, and heterocycloalkyl-sulfonamides. In general, the
observed yields of the sulfonylguanidine derivatives of general for-
mula 5 from 1 were high. In this context it should be noted that the
applied one-pot procedure encompasses three consecutive
chemical conversions.
Recently, we disclosed16 an improved synthetic route to ibipin-
abant from inexpensive, commercially available reagents with a
high degree of atom-efficiency.17
However, in some cases, the one-pot reaction was more trou-
blesome. These specific cases are discussed in more detail below.
The last step, reaction with dansylamide, in the synthesis of 5d
appeared to proceed more slowly than in the other cases and gave
rise to the concomitant formation of some impurities. By prolong-
ing the reaction time to 72 h and subjecting the crude 5d obtained
to flash chromatographic purification followed by recrystallization
(EtOH), pure 5d was isolated in a moderate yield of 49%. It was ob-
served that in the first stage of the attempted synthesis of 5f the
addition of sterically demanding N-tert-butylisopropylamine to
methyl isothiocyanate did not take place at ambient or elevated
temperatures. This initial step also proceeded slowly in the synthe-
sis of 5h which could be rationalized by invoking the low nucleo-
philicity19 of aromatic N-methyl-p-anisidine. However, coupling of
the p-anisidine to methyl isothiocyanate could be achieved by
increasing the reaction time from two to 20 h, thereby eventually
leading to a satisfactory overall yield of pure 5h (70%). Further-
more, it was observed that the rate of conversion from 4i into 5i
was significantly slower than in the other studied cases, leading
to a modest isolated yield of 5i. For the small and polar compounds
5l and 5m modest yields (ꢀ40%) were initially obtained. It was
observed that in the final washing step a significant amount of
the crude product was lost in the extraction process. This could
be overcome by eliminating the extraction/washing step from
These encouraging results warranted an additional study direc-
ted at the scope of this expedient methodology as well as to further
improvements of the experimental procedures involved. In partic-
ular, we attempted to develop a novel one-pot protocol18 for the
efficient production of a variety of sulfonylguanidines and sulfa-
moylguanidines by the consecutive reaction of a secondary amine
with an isothiocyanate, methyl iodide, and a sulfonamide or sulf-
amide. The use of mild reaction conditions constituted the main
point of attention herein since this would enable the inclusion of
additional sensitive functionalities without the need for compli-
cated protecting group strategies. A diverse set of commercially
available reagents were compiled for this purpose in order to pre-
pare a range of 16 sulfonylguanidines 5a–5p. Our results are sum-
marized in Scheme 1 and Table 1.
In order to gain more insight into the scope of the guanylation
reaction a variety of R1–R4 substituents were used in different
combinations. For example, the set of applied secondary amines
R1R2NH consisted of either dialkylamines, having different degrees
of steric demand, monocyclic amines with varying ring sizes and
fused bicyclic tetrahydroisoquinoline, benzylic, or aromatic
amines. The reagents R3–N@C@S were selected from alkyl-, cyclo-
alkyl-, benzyl-, and phenyl-isothiocyanates. Finally, the sulfona-
mides R4SO2NH2 consisted of (substituted) aryl-, heteroaryl-,
Table 1
One-pot synthesis of guanidines 5a–5p
Compound
R1
R2
R3
R4
Yield (%)
83
Compound
R1
R2
R3
R4
Yield (%)
30
5a
–(CH2)4–
Me
Ph
5i
–(CH2)4–
Ph
Ph
Cl
5b
5c
–(CH2)5–
–(CH2)6–
Bn
93
5j
–(CH2)4–
–(CH2)4–
t-Bu
Ph
Ph
67
n-Pr
68
5k
c-Hexyl
83
Cl
Cl
S
5d
Bn
49
5l
–(CH2)4–
Me
Me
95
N
5e
5f
El
El
Me
Me
Me
Ph
Ph
Ph
57
0
5m
5n
5o
–(CH2)4–
–(CH2)4–
–(CH2)4–
Me
Me
Me
70
76
84
t-Bu
Bn
i-Pr
Me
N
5g
84
NH2
Cl
OMe
N
5h
Me
Et
70
5p
–(CH2)4–
Me
97

3200
J. H. M. Lange et al. / Tetrahedron Letters 52 (2011) 3198–3200
7. Tsuji, S.; Kawano, S.; Tsujii, M.; Kawai, N.; Gunawan, E. S.; Sun, W. H.; Hori, M.
Arzneimittelforschung 2001, 51, 46–50.
a
N
8. Hirsh, A. J.; Sabater, J. R.; Zamurs, A.; Smith, R. T.; Paradiso, A. M.; Hopkins, S.;
Abraham, W. M.; Boucher, R. C. J. Pharmacol. Exp. Ther. 2004, 311, 929–938.
9. Shi, Y.; Li, C.; O’Connor, S. P.; Zhang, J.; Shi, M.; Bisaha, S. N.; Wang, Y.; Sitkoff,
D.; Pudzianowski, A. T.; Huang, C.; Klei, H. E.; Kish, K.; Yanchunas, J., Jr.; Liu, E.
C.-K.; Hartl, K. S.; Seiler, S. M.; Steinbacher, T. E.; Schumacher, W. A.; Atwal, K.
S.; Stein, P. D. Bioorg. Med. Chem. Lett. 2009, 19, 6882–6889.
N
O
Me
Me
N
N
N
S Me
H
10. (a) Janero, D. R.; Makriyannis, A. Expert Opin. Emerg. Drugs 2009, 14, 43–65; (b)
Lange, J. H. M.; Kruse, C. G. Chem. Rec. 2008, 8, 156–168; (c) Högenauer, E. K.
Exp. Opin. Ther. Patents 2007, 17, 1457–1476; (d) Lange, J. H. M.; Kruse, C. G.
Drug Discovery Today 2005, 10, 693–702; (e) Lange, J. H. M.; Kruse, C. G. Curr.
Opin. Drug Discov. Devel. 2004, 7, 498–506.
6a
4a
Scheme 2. (a) C6H5CONHNa, THF, reflux, 22 h (12%).
11. (a) Lange, J. H. M.; Coolen, H. K. A. C.; van der Neut, M. A. W.; Borst, A. J. M.;
Stork, B.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2010, 53, 1338–1346; (b)
Lange, J. H. M.; den Hartog, A. P.; van der Neut, M. A. W.; Kruse, C. G. Bioorg.
Med. Chem. Lett. 2009, 19, 5675–5678; (c) Lange, J. H. M.; van Stuivenberg, H.
H.; Veerman, W.; Wals, H. C.; Stork, B.; Coolen, H. K. A. C.; McCreary, A. C.;
Adolfs, T. J. P.; Kruse, C. G. Bioorg. Med. Chem. Lett. 2005, 15, 4794–4798.
12. Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H. H.; Dijksman, J. A. R.;
Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker, K.; McCreary, A. C.; Veerman,
W.; Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog, A. P.; de Jong, N. M. J.; Adolfs,
T. J. P.; Hoogendoorn, J.; Kruse, C. G. J. Med. Chem. 2004, 47, 627–643.
13. Zhang, J.; Shi, Y.; Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett. 2002, 43, 57–59.
14. (a) Shi, Y.; Li, C.; O’Connor, S. P.; Zhang, J.; Shi, M.; Bisaha, S. N.; Wang, Y.;
Sitkoff, D.; Pudzianowski, A. T.; Huang, C.; Klei, H. E.; Kish, K.; Yanchunas, J.;
Liu, E. C.-K.; Hartl, K. S.; Seiler, S. M.; Steinbacher, T. E.; Schumacher, W. A.;
Atwal, K. S.; Stein, P. D. Bioorg. Med. Chem. Lett. 2009, 19, 6882–6889; (b)
Martin, N. I.; Liskamp, R. M. J. J. Org. Chem. 2008, 73, 7849–7851; (c) Shepherd,
J.; Gale, T.; Jensen, K. B.; Kilburn, J. D. Chem. Eur. J. 2006, 12, 713–720; (d)
Gluszok, S.; Goossens, L.; Depreux, P.; Hénichart, J.-P. Tetrahedron Lett. 2006, 47,
6087–6090; (e) Jensen, K. B.; Braxmeier, T. M.; Demarcus, M.; Frey, J. G.;
Kilburn, J. D. Chem. Eur. J. 2002, 8, 1300–1309; (f) Zhang, J.; Shi, Y. Tetrahedron
Lett. 2000, 41, 8075–8078; (g) Bonnat, M.; Bradley, M.; Kilburn, J. D.
Tetrahedron Lett. 1996, 37, 5409–5412; (h) Deprez, P.; Vevert, J.-P. Synth.
Commun. 1996, 4299–4310; (i) Himbert, G.; Schwickerath, W. Liebigs Ann.
Chem. 1982, 12, 2105–2118.
the reaction procedure in these two cases. The reaction mixtures
obtained which contained crude 5l and 5m were diluted with a
small amount of ethyl acetate and the remaining solid material
(mostly KHCO3 salt) was removed by filtration. Subsequently, the
filtrate was concentrated and subjected to flash chromatographic
purification. This specific modification led to a significant increase
in chemical yield for both 5l (95%) and 5m (70%), respectively.
In general, the atom-efficiencies of the one-pot conversions of 1
into 5 were high. In our set of compounds, 5a–5p the atom-effi-
ciency ranged from 54% for the smallest molecule 5l to 74% for
the largest compound 5d.
In addition, we attempted to prepare the acylguanidine 6a via
an analogous one-pot protocol by reaction of the in situ formed
4a with benzamide. However, the desired product 6a was not
formed in this reaction which could be rationalized by invoking
insufficient nucleophilicity of the carboxamide under the neutral
reaction conditions. After a brief survey of the reaction conditions
we succeeded in preparing 6a by the addition of three molar equiv-
alents of benzamide sodium salt (prepared from benzamide and
NaH in THF) to a solution of in situ formed 4a in anhydrous THF
(Scheme 2). However, this procedure furnished 6a in a disappoint-
ingly low 12% yield. The use of potassium hexamethyldisilazide
(KHDMS) as an alternative base did not improve the yield in this
particular reaction. Since the analogous reaction of 4a with 1-car-
bamylpiperidine did not proceed at all, it was decided to abandon
this alternative synthetic approach for the synthesis of acylguani-
dine derivatives.
15. (a) Qin, C.; Li, J.; Fan, E. Synlett 2009, 2465–2468. and references cited therein;
(b) Flemer, S.; Madalengoitia, J. S. Synthesis 2007, 1848–1860. and references
cited therein.
16. Lange, J. H. M.; Sanders, H. J.; van Rheenen, J. Tetrahedron Lett. 2011, 52, 1303–
1305.
17. Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246.
18. Yields refer to isolated pure products unless otherwise noted and were not
optimized. Selected data for compounds 5a, 5b, and 6a. Synthesis of compound
5a: The one-pot experiment was carried out in oven-dried glassware under a
nitrogen atmosphere. A solution of pyrrolidine (0.36 g, 5.00 mmol) in CH3CN
(3 ml) was added dropwise to a stirred solution of methyl isothiocyanate
(0.47 ml, 5.50 mmol) in CH3CN (10 ml, anhydrous puresolve™) under cooling in
an ice-bath to keep the reaction temperature below 10 °C. The ice-bath was
removed and stirring was continued at room temperature for 2 h to furnish a
yellow-colored solution of the intermediate 2a. The nitrogen flow was stopped
(to prevent evaporation of volatile CH3I in the subsequent reaction), a CaCl2 tube
was fitted for protection against moisture and CH3I (0.62 ml, 10.0 mmol) was
added in one portion. Stirring was continued at room temperature for 18 h after
which TLC analysis [eluent: EtOAc/hexanes 1:1 (v/v)] showed full conversion of
2a into 3a. The solvent and excess CH3I were removed in vacuo and CH3CN
(10 ml) was added in order to dissolve the resulting dark-yellow solid. KHCO3
(0.70 g, 7.00 mmol) and benzenesulfonamide (0.83 g, 5.25 mmol) were added
successively and the resulting mixture was stirred at reflux temperature for 22 h.
After cooling to room temperature, 2 N NaOH was added and the mixture was
extracted with EtOAc (3 ꢁ 20 ml). The combined organic layers were washed
with brine (20 ml), dried (Na2SO4), and evaporated in vacuo to give a pale brown
oil. The crude 5a was purified by flash chromatography (gradient elution: EtOAc/
hexanes 1:1, EtOAc/hexanes 3:1, EtOAc) to furnish N-(benzenesulfonyl)-N0-
methylpyrrolidine-1-carboximidamide (5a) as a white solid (1.09 g, 83% yield).
Melting point: 95–97 °C. 1H NMR (400 MHz, CDCl3): d 1.82–1.92 (m, 4H), 2.85 (d,
J = 5.3 Hz, 3H), 3.43–3.50 (m, 4H), 6.77 (br s, 1H), 7.40–7.50 (m, 3H), 7.90 (dd,
J = 8 and 2 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 25.32, 31.58, 49.20, 125.86,
128.52, 131.10, 144.67, 158.34. HR-MS (ES+): calcd for C12H18N3O2S (M+H)+
In conclusion, an efficient one-pot procedure for the atom-
efficient production of a variety of sulfonylguanidines and sulfa-
moylguanidines under mild reaction conditions is described. The
outlined synthetic methodology has a broad applicability, but ste-
rically demanding amines R1R2NH appear to limit the scope.
Acknowledgments
Willem Gorter and Hugo Morren are gratefully acknowledged
for analytical support.
Supplementary data
Supplementary data (selected analytical data for compounds
5c–5e and 5g–5p) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.031.
268.1120;
found:
268.1105.
N0-Benzyl-N-[(4-chlorobenzene)sulfonyl]
piperidine-1-carboximidamide (5b). Melting point: 136–138 °C. 1H NMR
(400 MHz, CDCl3): d 1.53–1.67 (m, 6H), 3.30–3.37 (m, 4H), 4.26 (d, J = 6 Hz,
2H), 7.01 (br t, J = 6 Hz, 1H), 7.15–7.21 (m, 2H), 7.30–7.38 (m, 5H), 7.65 (br d,
J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 24.19, 25.57, 48.93, 48.93, 49.99,
127.40, 127.59, 128.11, 128.80, 128.98, 136.91, 137.49, 142.39, 160.05. HR-MS
References and notes
1. Saczewski, F.; Balewski, L. Expert Opin. Ther. Patents 2009, 19, 1417–1448.
2. Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva, A. E.; Romminger, S.;
Morais, R. P.; Bandeira, K.; Mizuno, C. M. Nat. Prod. Rep. 2010, 27, 1871–1907.
3. Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71–102.
4. (a) Shepherd, J.; Gale, T.; Jensen, K. B.; Kilburn, J. D. Chem. Eur. J. 2006, 12, 713–
720; (b) Bonnat, M.; Bradley, M.; Kilburn, J. D. Tetrahedron Lett. 1996, 37, 5409–
5412.
(ES+): calcd for
C
19H23N3O2S35Cl (M+H)+ 392.1200; found: 392.1200. N-
[(Methylimino)(pyrrolidin-1-yl)methyl]benzamide (6a). Melting point: 199–
202 °C. 1H NMR (400 MHz, CDCl3): d 1.92–1.99 (m, 4H), 2.97 (d, J = 4.8 Hz, 3H),
3.52–3.59 (m, 4H), 7.10–7.33 (m, 1H), 7.34–7.44 (m, 3H), 8.17 (br d, J = 8 Hz, 2H).
13C NMR (100 MHz, CDCl3): d 25.39, 30.34, 48.10, 127.68, 128.87, 130.34, 138.82,
162.31. HR-MS (ES+): calcd for C13H18N3O (M+H)+ 232.1450; found: 232.1463.
19. Henderson, W. A.; Schultz, C. J. J. Org. Chem. 1962, 27, 4643–4646.
5. Jensen, K. B.; Braxmeier, T. M.; Demarcus, M.; Frey, J. G.; Kilburn, J. D. Chem. Eur.
J. 2002, 8, 1300–1309.
6. Thai, K.; Gravel, M. Tetrahedron: Asymmetry 2010, 21, 751–755.