Facile, catalyst-free cascade synthesis of sulfonyl guanidines: Via carbodiimide coupling with amines

Article abstract of DOI:10.1039/c8cc08564a

An expeditious catalyst-free cascade coupling of N,N-dibromoarylsulfonamides with isonitriles and amines via carbodiimide intermediates has been developed. The protocol represents an elegant pathway for sulfonyl guanidines at room temperature within a short time with high yields and wide substrate scope. The carbodiimide intermediate could also be isolated in an appreciable yield.

Full text of DOI:10.1039/c8cc08564a

ChemComm
View Article Online
View Journal
COMMUNICATION
Facile, catalyst-free cascade synthesis of sulfonyl
guanidines via carbodiimide coupling with amines†
Cite this:DOI: 10.1039/c8cc08564a
Debojit Hazarika, Arun Jyoti Borah and Prodeep Phukan
*
Received 26th October 2018,
Accepted 4th January 2019
DOI: 10.1039/c8cc08564a
rsc.li/chemcomm
An expeditious catalyst-free cascade coupling of N,N-dibromoaryl-
Recent methods for acyclic guanidine synthesis involve transition
sulfonamides with isonitriles and amines via carbodiimide inter- metal catalyzed cascade reactions of organic azides with isonitriles
mediates has been developed. The protocol represents an elegant leading to the formation of carbodiimides followed by reaction with
pathway for sulfonyl guanidines at room temperature within a short an amine (Scheme 1a).8 Oxidative isocyanide insertion with amines
time with high yields and wide substrate scope. The carbodiimide in the presence of cobalt catalysts is an alternate pathway to generate
intermediate could also be isolated in an appreciable yield.
substituted guanidines (Scheme 1b).9 In some other approaches,
cyanamide can directly provide the CN2 core during the synthesis of
trisubstituted guanidines (Scheme 1c).10 Although these reported
protocols effectively provide the synthesis of N,N0,N00-substituted
guanidines, they require catalytic and oxidative reaction conditions.
N,N-Dibromoarylsulfonamides are an important class of organic
reagents in various organic transformations.11 In continuation of our
effort with such reagents,7b,12 herein, we are reporting an expeditious
method for the synthesis of N,N0,N00-tri-substituted acyclic guan-
idines utilizing N,N-dibromoarylsulfonamides without using
any catalyst. This has been achieved through an in situ generated
carbodiimide intermediate at room temperature (Scheme 1d).
The guanidine core is a common functionality in natural products,
pharmaceuticals, agrochemicals, catalysts, superbases and super-
potent sweeteners.1 In view of their importance and usefulness,
the development of an efficient pathway for the synthesis of substi-
tuted guanidines has attracted great interest from organic as well as
medicinal chemists. The synthesis of acyclic guanidines has been
well explored by classical methods that are based on transformation
of electrophilic guanylation reagents like thioureas, isothioureas,
amidine sulfonic acids, cyanamides, carbodiimides, triflyl guani-
dines, and carboximidamide derivatives as reagents.2 Many of these
methods usually suffer from harsh reaction conditions, multistep
pathways, limited substrate scope, and/or expensive catalysts. A
straightforward route for the synthesis of di-, tri-, and tetra-
substituted guanidines involves the reaction of amines with electro-
philic thiourea derivatives as guanylation reagents where carbo-
diimides are thought to be the intermediate.3 Catalytic direct
guanylation of amines with symmetrical and unsymmetrical carbo-
diimides seems to be an alternative to prepare N-substituted guan-
idines.4 Nevertheless, the preparation of carbodiimide is tedious and
strict conditions are necessary along with the requirement of a
transition metal catalytic system.5 Yeung reported a method for
the synthesis of guanidines via bromo-functionalization of olefin
using NBS in the presence of a cyanamide as both a solvent and a
reagent.6 However, due to the presence of bromine at the a-position,
the reaction undergoes subsequent cyclization,7 which limits its
applicability in acyclic guanidine synthesis.
Department of Chemistry, Gauhati University, Gopinath Bordoloi Nagar,
Guwahati-781014, Assam, India. E-mail: pphukan@yahoo.com,
pphukan@gauhati.ac.in
† Electronic supplementary information (ESI) available. CCDC 1882434. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc08564a
Scheme 1 Cascade synthesis of N,N0,N00-substituted guanidines.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
Table 2 Substrate scope of aminesa
Isolable intermediates and the exclusion of metal catalysts for
the synthesis of carbodiimide are the notable advantages of the
present protocol.
In order to evaluate the optimum conditions, an initial investiga-
tion was carried out for the reaction of TsNBr2 (1a) and tert-butyl
isonitrile (2a) with diethylamine. After a systematic study of the
reaction parameters, we have found that the simple combination of
TsNBr2 (1 equivalent) and isonitrile (1 equivalent) with diethylamine
(1 equivalent) in the presence of a weak base K2CO3 (2 equiv.) in
MeCN at room temperature provided the desired product N-(tert-
butylamino-diethylaminomethylene)-4-methylbenzenesulfonamide
(4a) in 84% yield (Table 1, entry 1) within 30 min of reaction time.
The base played a crucial role in this transformation and in its
absence the product was isolated only in 21% yield (entry 2). The use
of potassium fluoride was not found to be very effective in improving
the reaction yield (57%, entry 5). While DCM could provide the
product in an acceptable yield (entry 6, 47%), THF or 1,4-dioxane was
found to have a diminishing effect on the reactivity (entries 7 and 8).
With the optimum reaction conditions in hand, we first inves-
tigated the scope of amines. The results are presented in Table 2.
Secondary amines, being better nucleophiles, exhibited higher
reactivity for the transformation. For example, amines such as
dimethylamine, dipropylamine, dibutylamine and dioctylamine
provided the desired trisubstituted guanidine product in excellent
yield (82–87%, 4a–4e, Table 2). Cyclic diamines such as pyrrolidine
(3f), piperdines (3g–3h) and morpholine (3i) also exclusively under-
went the guanylation process affording the corresponding products
in 74–81% yields. Gratifyingly, secondary amines containing active
functional sites like hydroxyl, alkene and alkyne could also produce
the desired products in high yields (4j–4m, 65–72%). In particular,
the tolerance of the alkene and alkyne moiety is spectacular as it is
very sensitive to produce bromointermediates in the presence of
TsNBr2.11b It should be noted that compounds 4j–4l provide a
handle for further transition metal-catalyzed synthetic applications.
In addition, the expected product 4n could be isolated in 79% yield
when N-methylbenzylamine was used.
We have also investigated the suitability of the primary aromatic
amines including heterocyclic amines under the standard reaction
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a–3n (0.5 mmol)-
K2CO3 (1 mmol), 3o–3w (0.5 mmol)-KF (1 mmol), CH3CN (4 mL), rt;
isolated yields. 3 equiv. KF. 2–4 equiv. KF.
b
c
Table 1 Optimization of the reaction conditionsa
conditions to produce the trisubstituted guanidines. It was observed
that with K2CO3 the reactivity of aromatic amines is not impressive.
However, with the use of a fluoride base, KF, we were able to isolate
the desired product in moderate yield (22–57%, 4o–4v). The fluoride
ion is expected to either increase the nucleophilicity of the aromatic
amine or activate the possible carbodiimide intermediate.
The scope of N,N-dibromoarylsulfonamides is wide and tri-
substituted guanidines could be produced in high yields irres-
pective of the electronic nature and position of the substituents
on the benzene ring of the dibromoarylsulfonamides (74–84%,
5a–5i). The halo functionalities are well tolerated (F, Cl, and Br)
and exhibited high reactivity highlighting the potential of this
process in combination with further conventional transforma-
Entry
Variation from ‘‘standard conditions’’
Yieldb (%)
1
2
3
4
5
6
7
8
None
Without K2CO3
84
21
46
54
57
47
Trace
Trace
Using 1 equiv. K2CO3
Using 1.5 equiv. K2CO3
KF instead of K2CO3
CH2Cl2 instead of CH3CN
THF instead of CH3CN
1,4-Dioxane instead of CH3CN
a
Standard conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), K2CO3
(1 mmol) in CH3CN (4 mL) at room temperature for 30 min. b Isolated yields. tions (Table 3).
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
Table 3 Substrate scope of N,N-dibromoarylsulfonamidesa
to afford the desired guanidines exclusively in high yields (6f–6o,
73–82%). We have also confirmed the structure of 6m by X-ray
analysis. The X-ray structural analysis reveals that the CQNNs and
C–NH(tBu) bond distances are nearly the same (1.333 Å and 1.338 Å,
respectively). The reactivity of the carbodiimide intermediate is very
fast with the amines and in the course of the observations we did not
observe formation of any byproduct via its degradation. An impor-
tant aspect of the present protocol is its amenability to gram-scale
applications (77% for 4a, pl. see the ESI†).
A possible mechanistic pathway for the generation of guanidine
is illustrated in Scheme 2. The reaction is believed to proceed via the
formation a carbodiimide intermediate (III). The initial step of the
reaction is the abstraction of Br+ ions from TsNBr2 by the base
resulting in the formation of intermediate I,12a which subsequently
reacts with isonitrile to form carbodiimide intermediate III. To con-
firm the formation of carbodiimide, we have carried out a reaction
between N,N-dibromoarylsulfonamides (1) and isonitrile (2a). Grati-
fyingly, we could isolate carbodiimide 7 in a moderate to high yield.
A simple mixing of the sulfonamide with isonitrile in dichloro-
methane, at room temperature furnished the corresponding carbo-
diimide. To validate the method, we have synthesized a few
more carbodiimides and the results are presented in Scheme 3
(entries 7a–e). The structure of carbodiimides 7 was confirmed
by analysing the NMR and HRMS data.
After isolating carbodiimide successfully, we intended to
testify our proposed mechanism by reacting an isolated carbo-
diimide with an amine. When carbodiimide 7a (intermediate III)
was treated with diethyl amine in the presence of two equiva-
lents of potassium carbonate in acetonitrile or CH2Cl2 at room
temperature, the corresponding guanidine 4a was produced in
63–90% yield (Scheme 4).
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
K2CO3 (1 mmol), CH3CN (4 mL), rt, 30 min; isolated yields.
After having success in implementing our process for various
amines and dibromoarylsulfonamides, we extended the reaction to
check the compatibility of various sulfonamides with different iso-
cyanides and secondary amines. These experiments generated a
library of N-sulfonyl guanidines (Table 4). While investigating the
scope of isocyanides under the optimal conditions, it was found that
isocyanopentane, isocyanocylohexane, 2-isocyanopropane, ethyl
isocyanoacetate and aryl isocyanide worked well to furnish the
desired products 6a–e in high yields (70–83%). The reactions of
dibromoarylsulfonamides with different amines proceeded smoothly
Table 4 Scope of isonitriles and compatibility of various N,N-dibromo-
arylsulfonmaides with different secondary aminesa
Having established a convenient procedure for acyclic guanidine
derivatives, we further focused on utilizing it for the synthesis of
molecules with biological importance. When propargylguanidine
4j was subjected to an Ag-catalyzed hydroamination process in
the presence of acetic acid in DCM, the reaction generated an
imidazolidinone derivative (8, Scheme 5), which is a common
Scheme 2 Proposed mechanism for the synthesis of sulfonyl guanidines.
Scheme 3 Synthesis of carbodiimide from N,N-dibromoarylsulfonamides.
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1 mmol), CH2Cl2
(4 mL), rt, 30 min; isolated yields.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), K2CO3
(1 mmol), CH3CN (4 mL), rt, 30 min; isolated yields.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
Tetrahedron, 2001, 57, 1671; (c) M. C. de Souza, W. P. de Macedo, M. C. M.
da Silva, G. C. de, O. Ramos and H. G. Alt, Phosphorus, Sulfur Silicon Relat.
Elem., 2004, 179, 1047; (d) S. Cunha and M. T. Rodrigues, Tetrahedron Lett.,
ˆ
´
2006, 47, 6955; (e) H. Esteves, A. de Fatima, R. de P. Castro, J. R. Sabino,
F. Macedo, Jr. and T. O. Brito, Tetrahedron Lett., 2015, 56, 6872.
4 Selected examples: (a) T.-G. Ong, G. P. A. Yap and D. S. Richeson, J. Am.
Chem. Soc., 2003, 125, 8100; (b) F. Montilla, A. Pastor and A. Galindo,
J. Organomet. Chem., 2004, 689, 993; (c) W.-X. Zhang, M. Nishiura and
Z. Hou, Synlett, 2006, 1213; (d) H. Shen, H.-S. Chan and Z. Xie, Organo-
metallics, 2006, 25, 5515; (e) T.-G. Ong, J. S. O’Brien, I. Korobkov and D. S.
Richeson, Organometallics, 2006, 25, 4728; ( f ) Q. Li, S. Wang, S. Zhou,
G. Yang, X. Zhu and Y. Liu, J. Org. Chem., 2007, 72, 6763; (g) W.-X. Zhang,
M. Nishiura and Z. Hou, Chem. – Eur. J., 2007, 13, 4037; (h) W.-X. Zhang,
D. Li, Z. Wang and Z. Xi, Organometallics, 2009, 28, 882; (i) X. Zhu, Z. Du,
F. Xu and Q. Shen, J. Org. Chem., 2009, 74, 6347; ( j) C. Alonso-
Scheme 4 Synthesis of 4a from the isolated carbodiimide.
´
´
Moreno, F. Carrillo-Hermosilla, A. Garces, A. Otero, I. Lopez-Solera,
´
˜
A. M. Rodrıguez and A. Antinolo, Organometallics, 2010, 29, 2789;
(k) R. E. Looper, T. J. Haussener and J. B. C. Mack, J. Org. Chem.,
2011, 76, 6967; (l) S. Pottabathula and B. Royo, Tetrahedron Lett.,
ˇ
2012, 53, 5156; (m) D. Tan, C. Mottillo, A. D. Katsenis, V. Strukil and
ˇˇ ´
T. Friscic, Angew. Chem., Int. Ed., 2014, 53, 9321; (n) L. Xu, W.-X.
Zhang and Z. Xi, Organometallics, 2015, 34, 1787.
Scheme 5 Synthetic utility of acyclic guanidine.
5 Synthesis of carbodiimide: for a review: (a) A. Williams and I. T. Ibrahim,
Chem. Rev., 1981, 81, 589; representative examples: (b) C. L. Stevens,
C. H. Singhal and A. B. Ash, J. Org. Chem., 1967, 32, 2895; (c) T. Saegusa,
Y. Ito and T. Shimizu, J. Org. Chem., 1970, 35, 3995; (d) F. Palacios,
C. Alonso, D. Aparicio, G. Rubiales and J. M. de los Santos, Tetrahedron,
structural motif in both synthetic and natural bioactive compounds
of medicinal relevance.13 We have also synthesized a seven-
membered cyclic guanidine (10, Scheme 5) through a diallylation
and ring metathesis sequence from 4l to generate a 1,3-diazepine
derivative. The structure of 10 was further confirmed by hydrolyzing
it to a known compound (pl. see ESI†).14
In summary, we have developed a catalyst-free protocol for the
synthesis of sulfonyl guanidines by treating N,N-dibromoarylsulfon-
amides with isonitrile and amine in the presence of a base. The
reaction works very fast at room temperature to produce the
corresponding guanidine within a short time. Chemoselectivity of
the procedure has been demonstrated by using substrates having
functionalities like hydroxyl, alkene and alkyne to afford the desired
sulfonyl guanidines. The synthesis and isolation of the carbodiimide
intermediate under mild and catalyst-free conditions are remarkable
achievements of the present method. Guanidine products were
successfully transformed to core structures of biologically active
molecules.
¨
2007, 63, 523; (e) R. E. Cowley, N. A. Eckert, J. Elhaık and P. L. Holland,
Chem. Commun., 2009, 1760; ( f ) N. P. Mankad, P. Mu¨ller and
J. C. Peters, J. Am. Chem. Soc., 2010, 132, 4083; (g) J. J. Scepaniak, R. P.
Bontchev, D. L. Johnson and J. M. Smith, Angew. Chem., Int. Ed., 2011,
50, 6630; (h) R. E. Cowley, M. R. Golder, N. A. Eckert, M. H. Al-Afyouni
and P. L. Holland, Organometallics, 2013, 32, 5289; (i) E. Kogut, H. L.
Wiencko, L. Zhang, D. E. Cordeau and T. H. Warren, J. Am. Chem. Soc.,
2005, 127, 11248; ( j) C. A. Laskowski and G. L. Hillhouse, Organo-
metallics, 2009, 28, 6114; (k) Y. M. Badiei, A. Krishnaswamy, M. M.
Melzer and T. H. Warren, J. Am. Chem. Soc., 2006, 128, 15056; (l) K. Shin,
Y. Baek and S. Chang, Angew. Chem., Int. Ed., 2013, 52, 8031.
6 L. Zhou, J. Chen, J. Zhou and Y.-Y. Yeung, Org. Lett., 2011, 13, 5804.
7 (a) L. Zhou, J. Zhou, C. K. Tan, J. Chen and Y.-Y. Yeung, Org. Lett.,
2011, 13, 2448; (b) K. K. Rajbongshi, I. Saikia, L. D. Chanu, S. Roy
and P. Phukan, J. Org. Chem., 2016, 81, 5423.
8 (a) Z. Zhang, Z. Li, B. Fu and Z. Zhang, Chem. Commun., 2015, 51, 16312;
(b) Z.-Y. Gu, Y. Liu, F. Wang, X. Bao, S.-Y. Wang and S.-J. Ji, ACS Catal.,
2017, 7, 3893; (c) Z. Zhang, B. Huang, G. Qiao, L. Zhu, F. Xiao, F. Chen,
B. Fu and Z. Zhang, Angew. Chem., Int. Ed., 2017, 56, 4320; (d) G. Qiao,
Z. Zhang, B. Huang, L. Zhu, F. Xiao and Z. Zhang, Synthesis, 2018, 330.
9 T.-H. Zhu, S.-Y. Wang, T.-Qi. Wei and S.-J. Ji, Adv. Synth. Catal., 2015,
357, 823.
Financial support from SERB, India (Grant No. EMR/2016/
007883) is gratefully acknowledged. We thank SAIF, GU and
Dr Ranjit Thakuria for providing single crystal X-ray data and
analysis. DH thanks UGC, India for the BSR fellowship.
10 (a) J. Li and L. Neuville, Org. Lett., 2013, 15, 6124; (b) K. Tsubokura,
T. Iwata, M. Taichi, A. Kurbangalieva, K. Fukase, Y. Nakao and
K. Tanaka, Synlett, 2014, 1302; (c) J. Li, H. Wang, Y. Hou, W. Yu,
S. Xu and Y. Zhang, Eur. J. Org. Chem., 2016, 2388.
11 (a) I. Saikia, A. J. Borah and P. Phukan, Chem. Rev., 2016, 116, 6837;
(b) K. K. Rajbongshi, A. J. Borah and P. Phukan, Synlett, 2016, 1618.
12 Selected examples: (a) I. Saikia, B. Kashyap and P. Phukan, Chem.
Commun., 2011, 47, 2967; (b) A. J. Borah and P. Phukan, Chem. Commun.,
2012, 48, 5491; (c) P. Phukan, P. Chakraborty and D. Kataki, J. Org.
Chem., 2006, 71, 7533; (d) I. Saikia, P. Chakraborty, M. J. Sarma,
M. Goswami and P. Phukan, Synth. Commun., 2015, 45, 211; (e) K. K.
Rajbongshi, D. Hazarika and P. Phukan, Tetrahedron, 2016, 72, 4151;
( f ) D. Hazarika and P. Phukan, Tetrahedron, 2017, 73, 1374; (g) K. K.
Rajbongshi, D. Hazarika and P. Phukan, Tetrahedron Lett., 2015, 56, 356;
(h) D. C. Loukrakpam and P. Phukan, Tetrahedron Lett., 2017, 58, 4855;
(i) D. Hazarika and P. Phukan, Tetrahedron Lett., 2018, 59, 4593.
13 (a) J. P. Wolfe, Eur. J. Org. Chem., 2007, 571; (b) M. J. Gainer, N. R. Bennett,
Y. Takahashi and R. E. Looper, Angew. Chem., Int. Ed., 2011, 50, 684;
(c) B. A. Hopkins and J. P. Wolfe, Angew. Chem., Int. Ed., 2012, 51, 9886;
(d) K. Shen and Q. Wang, Chem. Sci., 2017, 8, 8265; (e) M. Nagamoto,
T. Nishimura and H. Yorimitsu, Synthesis, 2017, 4272; ( f ) F. Xu,
S. A. Shuler and D. A. Watson, Angew. Chem., Int. Ed., 2018, 57, 12081.
14 E. Kanno, K. Yamanoi, S. Koya, I. Azumaya, H. Masu, R. Yamasaki
and S. Saito, J. Org. Chem., 2012, 77, 2142.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) R. G. S. Berlinck, A. C. B. Burtoloso and M. H. Kossuga, Nat. Prod. Rep.,
2008, 25, 919; (b) A. F. Pozharskii, A. T. Soldatenkov and A. R. Katritzky,
Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry,
Biochemistry and Applications, Wiley, 2nd edn, 2011; (c) D. Castagnolo,
S. Schenone and M. Botta, Chem. Rev., 2011, 111, 5247.
2 (a) J. C. Manimala and E. V. Anslyn, Eur. J. Org. Chem., 2002, 3909;
(b) A. R. Katritzky and B. V. Rogovoy, ARKIVOC, 2005, 49; (c) C. Alonso-
˜
Moreno, A. Antinolo, F. Carrillo-Hermosilla and A. Otero, Chem. Soc.
Rev., 2014, 43, 3406; (d) W.-X. Zhang, L. Xu and Z. Xi, Chem. Commun.,
2015, 51, 254.
3 Selected examples: (a) J. Zhang and Y. Shi, Tetrahedron Lett., 2000, 41, 8075;
(b) S. Cunha, M. B. Costa, H. B. Napolitano, C. Lariucci and I. Vencato,
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019