Bromodimethylsulfonium bromide (BDMS)-mediated Lossen rearrangement: Synthesis of unsymmetrical ureas

Article abstract of DOI:10.1016/j.tetlet.2012.03.129

Bromodimethylsulfonium bromide (BDMS) was found to be a very efficient reagent for Lossen rearrangement of hydroxamic acids to the corresponding isocyanates which were subsequently trapped in situ with various amines to afford unsymmetrical ureas in good to excellent yields (64-89%). The protocol is experimentally simple, mild, and represents valuable alternative to the existing methods for in situ activation of hydroxamic acids promoting Lossen rearrangement.

Full text of DOI:10.1016/j.tetlet.2012.03.129

Tetrahedron Letters 53 (2012) 2890–2893
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Tetrahedron Letters
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Bromodimethylsulfonium bromide (BDMS)-mediated Lossen rearrangement:
synthesis of unsymmetrical ureas
Deepak K. Yadav a, Arvind K. Yadav b, Vishnu P. Srivastava b, Geeta Watal a, Lal Dhar S. Yadav b,
⇑
a Alternative Therapeutics Unit, Drug Development Division, Medicinal Research Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
b Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bromodimethylsulfonium bromide (BDMS) was found to be a very efficient reagent for Lossen rearrange-
ment of hydroxamic acids to the corresponding isocyanates which were subsequently trapped in situ
with various amines to afford unsymmetrical ureas in good to excellent yields (64–89%). The protocol
is experimentally simple, mild, and represents valuable alternative to the existing methods for in situ
activation of hydroxamic acids promoting Lossen rearrangement.
Received 3 March 2012
Revised 28 March 2012
Accepted 30 March 2012
Available online 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Bromodimethylsulfonium bromide (BDMS)
Lossen rearrangement
Hydroxamic acids
Isocyanates
Unsymmetrical ureas
Unsymmetrical urea derivatives have attracted significant inter-
est due to their extensive applications in agriculture, petrochemi-
cals, pharmaceuticals, and biology.1 For example, Diuron (A) is a
commercially accessible herbicide primarily used to eradicate
weeds on hard surfaces (Fig. 1).2 Structurally simple urea (B), pos-
sessing a morpholine ring, has displayed very effective role in the
treatment of chronic myelogenous leukemia.3 Similarly, substi-
tuted urea (C) proved to be a potent HIV-1 protease inhibitor4
and (D) a receptor tyrosine kinase (RTK) inhibitor (Fig. 1).5 Urea
derivatives also impart important function in organic synthesis as
intermediates and bifunctional organocatalysts.6
The synthesis of urea derivatives traditionally requires reagents
based on either phosgene7 and phosgene surrogates,8 or starting
directly from isocyanates.9 These approaches are particularly com-
petent for symmetrical urea derivatives. However, phosgene and
isocyanates are noxious, unstable, and require special care for
handling. In this regard, direct utilization of in situ-generated iso-
cyanates offers a convenient entry into urea derivatives, especially
O
Cl
Cl
O
N
N
N
N
H
O
Antileukemic agent (B)
Diuron (A)
OMe
N
O
CF3
O
N
O
Cl
N
H
O
N
H
N
NMe
N
H
N
H
HN
HIV-1 Protease inhibitor (C)
RTK- inhibitor (D)
Figure 1. Biologically relevant unsymmetrical urea motifs.
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.129

D. K. Yadav et al. / Tetrahedron Letters 53 (2012) 2890–2893
2891
the more synthetically challenging unsymmetrically substituted
ureas.10
The Lossen rearrangement basically involves the conversion of
O
O
R1
R1
N
C
O
S
N
Br
-DMSO
4
an O-activated hydroxamic acid into the corresponding isocyanate
intermediate. Ensnaring of the isocyanate intermediate with appo-
site amines provides the derivatives of urea. However, the Lossen
rearrangement has received comparatively little attention as a
general synthetic method since its original publication.11 The rea-
sons for its limited use appear to be associated with complicated
experimental procedure and the competing formation of self-
condensation byproducts has been partially addressed by
ingenious innovations.10b,12 Thus, development of an alternative
method circumventing such limitations should be welcomed
among chemical communities. To overcome the dimerization13
associated with the classical Lossen rearrangement, it would be
desirable to initiate the rearrangement on the ‘activated
O-hydroxamate’, after the complete consumption of the hydroxa-
mic acid. Thus, the quest for reagents which activate hydroxamic
acids via the formation of ‘activated O-hydroxamate’ under mild
conditions is ongoing and there is wide scope for developing novel
methods utilizing mild and efficient methodology.
Bromodimethylsulfonium bromide (BDMS), first explored by
Meerwein,14 is a very inexpensive commercially available and
easily manageable reagent with intriguing properties making its
execution exceedingly attractive in organic synthesis.15 This com-
pound can act either as a source of molecular bromine or bromoni-
um ions, or bromine radicals or bromide ions as well as dehydrating
agent.15a,16 Interestingly, in most of these cases the use of BDMS of-
fered advantages compared to other classical methods in terms of
cost, yield, and mildness. Thus, in the light of these results, sighting
new applications for BDMS in organic synthesis are of interest.
Herein, we report a simple and efficient process for the synthesis
of unsymmetrical urea derivatives employing BDMS as a proficient
promoter for Lossen rearrangement (Scheme 1).
3
R2
R3
Br
S
HN
5
Br
2
Base
R2
R3
BDMS
H
N
O
N
R1
OH
R1
O
N
H
1
6
Scheme 2. A plausible reaction pathway for Scheme 1.
Table 1
Optimization of reaction conditions for the synthesis of unsymmetrical urea via
BDMS-promoted Lossen rearrangementa
O
H
N
H
N
OH
1. BDMS, Solvent, Base
2. 4-MePhNH2, 9 h
N
H
O
5a
6a
1a
Entry
Solventb
Basec
Temp (°C)
Yieldd (%)
1
2
3
4
5
6
7
8
9
10
11
12e
13
DCM
Toluene
THF
EtOAc
CH3CN
CH3CN
CH3CN
CH3CN
DCE
NMM
NMM
NMM
NMM
Pyridine
DIPA
Reflux
80
Reflux
Reflux
80
<20
45
72
48
74
71
80
70
89
74
28
64f
36
80
80
80
80
80
40
80
80
DIPEA
TEA
NMM
NMM
NMM
NMM
NMMg
Recently, our research group has illustrated the utility of BDMS
in hydroxyl group activation of oximes via formation of O-
activated oximates intermediate leading to the synthetic nitriles
and amides.16 These reports and our recent study17 toward reac-
tions involving migration to electron-deficient nitrogen atom have
prompted us to investigate the possible use of BDMS as a reagent
enabling the Lossen rearrangement directly from commercially
available hydroxamic acids 1 via the formation of O-activated
hydroxamate intermediates 3 to afford isocyanates 4. These isocy-
anates could be easily captured in situ with appropriate amines 5
to give unsymmetrical ureas 6 (Scheme 2).
CH3CN
DCE
DCE
DCE
a
Reaction conditions: 1a (1 mmol), BDMS 2 (1.3 mmol), base (2.6 mmol), 5a
(1.2 mmol). For experimental details, see Ref. 18.
b
2 mL was used.
Base was added at 0 °C.
Yields of the isolated pure compound.
BDMS (1.0 mmol) was used.
Self-condensed diphenylurea was also isolated in 27% yield.
NMM (1.3 mmol) was used.
c
d
e
f
g
Initially, a pilot reaction was performed to synthesize 1-phenyl-
3-p-tolylurea 6a from commercially available benzhydroxamic acid
1a and p-tolylamine 5a chosen as model substrates and optimizing
the general procedure with respect to solvents, bases, and reaction
conditions. Thus, benzhydroxamic acid 1a was treated with BDMS
2 in the presence of different bases in various organic solvent fol-
lowed by the addition of p-tolylamine 5a and the progress of the
reaction was monitored by TLC. The experimental data for screening
conditions are compiled in Table 1. To our amazement, we observed
rapid and selective access to 1-phenyl-3-p-tolylurea 6a from ben-
zhydroxamic acid 1a (1 mmol) and p-tolylamine 5a using BDMS
(1.3 mmol) and NMM (2.6 mmol) in DCE at 80 °C (Table 1, entry 9).
The above reaction condition was appropriate for the rearrangement
and successive trapping of isocynate intermediate 4a with amine 5a
because when lowering the reaction temperature from 80 to 40 °C
and decreasing the amount of BDMS and NMM, the yield of 6a was
noticeably reduced (Table 1, entries 11–13).
Having established the optimized reaction conditions, the gen-
erality and scope of the protocol were demonstrated across a range
of hydroxamic acids 1 and amines 5 to access various unsymmet-
rical urea derivatives (Table 2). As evident from Table 2, both aro-
matic and aliphatic hydroxamic acids were equally applicable to
undergo Lossen rearrangement and ensuing reaction with amines
either aromatic or aliphatic in nature. Electron-rich aromatic
hydroxamic acids afforded the desired products in relatively high
yield in short time as compared with aromatic hydroxamic acids
bearing electron-withdrawing group (Table 2, entries 14–17). This
observation is in accordance with the expectation that the rate of
rearrangement would be proportional to the electron density on
the migrating group.19
Br
R2
R3
O
Br
H
N
S
1.
2.
, Base
, 0 to 80 oC
N
R1
OH
R1
N
H
R2
HN
O
R3
Scheme 1. Synthesis of unsymmetrical ureas utilizing BDMS.

2892
D. K. Yadav et al. / Tetrahedron Letters 53 (2012) 2890–2893
Table 2
Synthesis of unsymmetrical ureas 6 via BDMS-promoted Lossen rearrangementa
R2
R3
O
H
N
N
1. BDMS, NMM
R1
OH
R1
N
H
R2
2.
O
HN
5
1
R3
6
DCE, 0 ºC to 80 ºC
Entry
1
Hydroxamic acid 1 R1
Amine 5
Productb
6
Time (h)
9.0
Yieldc (%)
89
NH2
H
N
H
N
Ph
O
NH
2
H
N
H
N
2
3
Ph
Ph
8.5
8.0
86
85
O
O
NH
H
N
H
N
2
O
O
NH
H
N
H
N
2
4
5
Ph
Ph
9.5
9.0
72
78
O
O
O
Cl
Cl
NH2
H
N
H
N
Cl
Cl
NH
H
N
H
N
2
6
Ph
9.5
77
Cl
Cl
NH
H
N
H
N
2
7
8
9
Ph
Ph
Ph
12
72
70
74
O N
2
O
O
NO2
F
NH
H
N
H
N
2
9.5
7.0
F
NH
H
N
N
N
O
NH2
H
N
H
N
10
Me
8.0
83
O
H
N
NH
O
11
12
13
14
Cyclohexyl
tBu
9.0
9.0
8.5
7.5
80
80
78
84
O
O
O
N
NH
O
H
N
O
NH
H
H
N
2
N
Ph
O
NH
O
H
N
O
N
4-MeC6H4
O

D. K. Yadav et al. / Tetrahedron Letters 53 (2012) 2890–2893
2893
Table 2 (continued)
Entry
Hydroxamic acid 1 R1
Amine 5
NH
Productb
6
Time (h)
7.0
Yieldc (%)
O
H
N
O
O
O
N
15
16
4-MeOC6H4
87
71
64
O
O
NH
NH
O
H
N
N
4-ClC6H4
14
18
O
Cl
O
H
N
N
17
4-NO2C6H4
O
O N
2
a
See Ref. 18 for general procedure.
b
c
All the products are known compounds10,12 and were characterized by comparison of their mp and spectral data with those of reported in the literature.
Yields of pure isolated products after column chromatography.
8. Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937.
In outline, we have exposed the efficacy and generality of bro-
9. (a) Ozaki, S. Chem. Rev. 1972, 72, 457; (b) Braunstein, P.; Nobel, D. Chem. Rev.
1989, 89, 1927; (c) Koya, S.; Yamanoi, K.; Yamasaki, R.; Azumaya, I.; Masu, H.;
Saito, S. Org. Lett. 2009, 11, 5438.
10. (a) Lebel, H.; Leogane, O. Org. Lett. 2006, 8, 57170; (b) Dube, P.; Noah, F.; Nathel,
F.; Vetelino, M.; Couturier, M.; Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.;
Hardink, M. Org. Lett. 2009, 11, 5622; (c) Peterson, S. L.; Stucka, S. M.; Dinsmore,
C. J. Org. Lett. 2010, 12, 1340.
11. (a) Yale, H. L. Chem. Rev. 1943, 33, 209; (b) Bauer, L.; Exner, O. Angew. Chem., Int.
Ed. Engl. 1974, 13, 376.
12. (a) Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org.
modimethylsulfonium bromide (BDMS) as a versatile reagent pro-
moting Lossen rearrangement at moderately low temperature. This
procedure could be useful in order to avoid the safety problem of
phosgene-based7,8 approaches for the in situ preparation of isocy-
anates and their ensuing reaction with amines. Additionally, the
prominent features of the present protocol are the simple opera-
tion, ready accessibility of the reagent, its cost effectiveness, and
higher yields in relatively short reaction times. Thus, this method-
ology for Lossen rearrangement would be a practical alternative to
the existing protocols for the synthesis of N,N0-disubstituted
unsymmetrical ureas.
Chem. 1998, 63, 10040; (b) Hamon, F.; Prie, G.; Lecornue, F.; Papot, S.
.
Tetrahedron Lett. 2009, 50, 6800; (c) Wallace, R. G.; Barker, J. M.; Wood, M. L.
Synthesis 1990, 1143; (d) Salomon, C. J.; Breuer, E. J. Org. Chem. 1997, 62, 3858.
13. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291.
14. (a) Meerwein, H.; Zenner, K. F.; Gipp, R. Justus Liebigs Ann. Chem. 1965, 67, 688;
(b) Olah, G. A.; Vankar, Y. D.; Arvanaghi, M.; Surya Prakash, G. K. Synthesis 1979,
720.
15. (a) Choudhury, L. H.; Pravin, T.; Khan, A. T. Tetrahedron 2009, 65, 9513; (b)
Khan, A. T.; Parvin, T.; Choudhury, L. H. . J. Org. Chem. 2008, 73, 8398; (c) Das, B.;
Ravikanth, B.; Thirupathi, P.; Rao, B. V. Tetrahedron Lett. 2006, 47, 5041; (d) Das,
B.; Srinivas, Y.; Holla, H.; Laxminarayana, K.; Narender, R. Tetrahedron Lett.
2007, 48, 6681; (e) Yadav, D. K.; Patel, R.; Srivastava, V. P.; Watal, G.; Yadav, L.
D. S. . Tetrahedron Lett. 2010, 51, 739.
Acknowledgments
We sincerely thank the SAIF, Punjab University, Chandigarh, for
providing spectra. One of us (A.K.Y.) is grateful to the CSIR, New
Delhi, for the award of a Junior Research Fellowship.
16. (a) Yadav, L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2009, 50, 5532; (b)
Yadav, L. D. S.; Garima; Srivastava, V. P. Tetrahedron Lett. 2010, 51, 5701.
17. Srivastava, V. P.; Patel, R.; Garima; Yadav, L. D. S. Chem. Commun. 2010, 46,
5808.
18. General procedure for the synthesis of unsymmetrical urea derivatives 6: To a
solution of hydroxamic acid 1 (1 mmol) in DCE (2 mL) at 0 °C under nitrogen
atmosphere, N-methylmorpholine (NMM) (2.6 mmol) then bromodi-
References and notes
1. (a) Gallou, I. Org. Prep. Proced. Int. 2007, 4, 355; (b) Moreau, J. J. E.; Vellutini, L.;
Man, M. W. C.; Bied, C. Chem. Eur. J. 2003, 9, 1559; (c) Bigi, F.; Maggi, R.; Sartori,
G. Green Chem. 2000, 2, 140; (d) Matsuda, K. Med. Res. Rev. 1994, 14, 271.
2. Cabrera, A.; Cox, L.; Velarde, P.; Koskinen, W. C.; Cornejo, J. J. Agric. Food Chem.
2007, 55, 4828.
3. Cao, P.; Huang, X.; Ding, H.; Ge, H.; Li, H.; Ruan, B.; Zhu, H. Chem. Biodivers.
2007, 4, 881.
4. Matzen, L.; van Amsterdam, C.; Rautenberg, W.; Greiner, H. E.; Harting, J.;
Seyfried, C. A.; Bottcher, H. J. Med. Chem. 2000, 43, 1149.
5. Wilhelm, S. M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.;
Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.;
Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.;
Voznesensky, A.; Riedl, B.; Post, L. E.; Bollag, G.; Trail1, P. A. Cancer Res. 2004, 64,
7099.
6. (a) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187; (b) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367; (c) Lubkoll, J.; Wennemers,
H. Angew. Chem., Int. Ed. 2007, 46, 6841; (d) Wei, Q.; Gong, L.-Z. Org. Lett. 2010,
12, 1008; (e) Yu, S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill, D. R. J. Org.
Chem. 2009, 74, 9539.
methylsulfonium bromide
mixture was stirred at 0 °C for 2 h. The amine
2
(BDMS) (1.3 mmol) were added and the
(1.2 mmol) was then
5
added and the temperature of reaction mixture was raised to 80 °C and
stirred at the same temperature for 7–18 h (Table 2). Upon completion of
the reaction as indicated by TLC, the reaction mixture was cooled to rt and
acidified with 2 mL HCl (0.1 N) and the solution was extracted with DCM
(2 ꢀ 10 mL) and EtOAc (1 ꢀ 10 mL). The combined organic phase was dried
over MgSO4, filtered, and evaporated under reduced pressure. The resulting
crude product was purified by silica gel column chromatography using a
gradient mixture of hexane/ethyl acetate as eluent to give the corresponding
pure urea derivatives 6. All the products are known compounds and were
characterized by the comparison of their mp and spectral data with those of
reported in the literature.10,12
19. Swenson, J. S.; Davis, A. M.; Deyo, R. A.; Graham, B. W.; Jahn, E. P.; Mattice, J. D.
J. Org. Chem. 1973, 38, 3956.
7. (a) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75; (b) Smith, M. B.; March, J.,
5th ed. In March’s Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure; Wiley: New York, 2001; (c) Knolker, H.-J.; Braxmeier, T.;
Schlechtingen, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2497.