A high yielding, one-pot synthesis of substituted ureas from the corresponding amines using Mitsunobu's reagent

Article abstract of DOI:10.1007/s00706-007-0776-1

A Mitsunobu-based protocol has been developed for the synthesis of symmetrically and unsymmetrically substituted ureas from a variety of primary and secondary amines using gaseous carbon dioxide, in good to excellent yields. This protocol is mild and efficient compared to other reported methods.

Full text of DOI:10.1007/s00706-007-0776-1

Monatsh Chem 139, 267–270 (2008)
DOI 10.1007/s00706-007-0776-1
Printed in The Netherlands
A High Yielding, One-pot Synthesis of Substituted Ureas
from the Corresponding Amines Using Mitsunobu’s Reagent#
Devdutt Chaturvedi1;ꢀ, Nisha Mishra2, and Virendra Mishra2
1
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, U.P., India
2
Synthetic Research Laboratory, Department of Chemistry, B.S.A. College, Mathura, U.P., India
Received July 28, 2007; accepted August 2, 2007; published online February 12, 2008
# Springer-Verlag 2008
Summary. A Mitsunobu-based protocol has been developed mation of amines through catalytic carbonylation to
for the synthesis of symmetrically and unsymmetrically
produce disubstituted ureas provides an alternative en-
substituted ureas from a variety of primary and secondary
vironmental benign method and has been investigated
amines using gaseous carbon dioxide, in good to excellent
over many years using various kinds of metallic cat-
yields. This protocol is mild and efficient compared to other
alysts [12]. However, these methods failed due to the
reported methods.
problems of regenerating the catalysts from the prod-
ucts. Moreover, their formation using CO2 employed
Keywords. Mitsunobu’s reagent; Carbon dioxide; Amines;
Substituted ureas.
harsh reaction conditions, such as long reaction times,
use of expensive strongly basic reagents, tedious
work-up, and low yields [13]. Consequently, there is
Introduction
Substituted ureas are very important class of com- continued interest in developing new and convenient
pounds that display a wide range of interesting appli- methods for the synthesis of substituted ureas using
cations [1]. They have extensively been used as mild reaction conditions.
agrochemicals [2], pharmaceuticals [3], intermedi-
Our group [14] has been engaged over several years
ates in organic synthesis [4], for protection of amino with the development of new methods for the syn-
groups [5], and as linkers in combinatorial chemistry thesis of carbamates, dithiocarbamates and related
[6]. These uses require their preparation by conve- compounds using cheap, abundantly available, and
nient and safe methodology. Traditionally, their syn- safe reagents like CO2 and CS2. Recently, we have
thesis involves a reaction of amines with phosgene reported [15] the synthesis of carbamates, dithiocar-
[7], its derivatives [8], carbonyl-imidazoles [9], or bamates, O,S-dialkyl-dithiocarbonates (xanthates),
carbon monoxide [10] using various kinds of metal and dialkyl carbonates from the corresponding alco-
and non-metal catalysts. Moreover, a process for pre- hols using Mitsunobu’s reagent. Based on our recent
paring 1,3-disubstituted ureas through reacting a cy- work, we report herein a chemoselective, highly effi-
clic carbonic acid ester with an amine over a proper cient, and mild synthesis of symmetrical and unsym-
catalyst was disclosed [11]. However, This method metrical ureas from corresponding amines using
is too expensive to use on a large scale. The transfor- Mitsunobu’s reagent.
#
This paper is dedicated to Dr. Nitya Anand for his constant
inspiration for research.
Corresponding author. E-mail: ddchaturvedi002@yahoo.
Results and Discussion
ꢀ
co.in
We carried out the synthesis of substituted sym-
metrical and unsymmetrical ureas by mild carba-

268
D. Chaturvedi et al.
mation of amines with gaseous carbon dioxide in
the presence of Mitsunobu’s reagent. We assume
that the unstable carbamic acid 1 [16] generated
from an amine and CO2 reacts with the Mitsunobu
zwitterion 2 formed from Ph3P and diethyl azodi-
carboxylate, to furnish the stabilized zwitter-ionic
species 3, which in turn would react with a second
molecule of desired amine to form the highly re-
active ionic species 4. This ionic species 4 would
further undergo electronic rearrangement to afford
the desired substituted urea derivative as shown in
Scheme 1. Various symmetrical and unsymmetrical
substituted urea derivatives were prepared in high
yields and their spectroscopic confirmation was
achieved from the reported values as mentioned
in Table 1.
Conclusion
Scheme 1
We have developed a convenient and efficient proto-
col for the one-pot, four-component coupling of var-
ious primary and secondary amines via a Mitsunobu
zwitterion. This reaction generates the correspond-
ing substituted ureas in high yields. Furthermore,
this method exhibits substrate versatility, mild reac-
tion conditions, and experimental convenience. This
Scheme 2
Table 1. Conversion of amines into substituted areas of general formula 1a
Entry
R1
R2
R3
R4
Time=h
Yieldb=%
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
n-Hexyl
2-Phenethyl
Benzyl
n-Octyl
i-Amyl
n-Dodecyl
Cyclohexyl
n-Butyl
H
H
H
H
H
H
H
n-Hexyl
2-Phenethyl
Benzyl
n-Octyl
i-Amyl
n-Dodecyl
Cyclohexyl
n-Butyl
H
H
H
H
H
H
2
2
2.5
2
2.5
1
2.5
3
4
4
4
2.5
2
2.5
3
3
4
94
96
85
96
84
98
81
84
88
90
86
82
93
86
76
83
80
81
[17]
[18]
[17]
[18]
[17]
[19]
[17]
[19]
[13c]
[13c]
[13c]
[18]
[17]
[17]
[17]
[17]
[17]
[17]
H
n-Butyl
n-Butyl
R1 ¼ R2 ¼ Piperidine
R1 ¼ R2 ¼ Pyrolidine
R1 ¼ R2 ¼ Morpholine
R3 ¼ R4 ¼ Piperidine
R3 ¼ R4 ¼ Pyrolidine
R3 ¼ R4 ¼ Morpholine
1-Methylbenzyl
H
H
H
H
H
H
H
1-Methylbenzyl
H
H
H
H
n-Hexyl
p-Methoxybenzyl
p-Anisidine
n-Hexyl
n-Dodecyl
p-Methoxybenzyl
p-Anisidine
n-Propyl
n-Propyl
Cyclohexyl
Cyclohexyl
R3 ¼ R4 ¼ Pyrolidine
n-Propyl
n-Propyl
3
a
All the products were characterized by IR, NMR, and mass spectral data
Isolated yields
b

One-pot Synthesis of Substituted Ureas
269
Eyermann CJ, Chang CH, Emmett G, Holler ER,
Daneker WF, Li RH, Markwalder JA, Seiz SP, Sharpe
TR, Bacheler LT, Rayner MM, Klabe RM, Shum LY,
Winslow DL, Kornhauser DM, Jackson DA, Erickson-
Viitanen S, Hodge CN (1996) J Med Chem 39: 3514
[4] a) Hegarty AF, Drennan LJ (1995) In: Katrizky AR,
Methocohn, O, Rees CW (eds) Comprehensive Organic
Functional Group Transformations. Pergamon, Oxford,
6: 499; b) Vishnyakova TP, Golubeva EV, Glebova EV
(1985) Russ Chem Rev 54: 249
[5] Greene TW, Wuts PGM (1999) Protective Groups in
Organic Synthesis, 3rd edn. John Wiley and Sons Inc.,
New York
[6] a) Mensal M, Gutschow M (2005) Tetrahedron Lett 46:
2231; b) Fattori D, Andrea PD, Porcelloni M (2003)
Tetrahedron Lett 44: 811; c) Curtet S, Langlois MM
(1999) Tetrahedron Lett 40: 8563
synthesis protocol is believed to offer a more general
method for the formation of C–N bonds essential to
numerous organic syntheses.
Experimental
Chemicals were procured from Merck, Aldrich and Fluka
chemical companies. Reactions were carried out under an
atmosphere of nitrogen. IR spectra (4000–200 cmꢁ1) were
recorded on Bomem MB-104-FTIR spectrophotometer where
as NMRs were scanned on AC-300F, NMR (300 MHz), in-
strument using CDCl3 and some other deuterated solvents and
TMS as internal standard. Elemental analysis were made by
Carlo-Erba EA 1110-CNNO-S analyzer and agreed favorably
with calculated values.
[7] a) Pri-Bar I, Alper H (1990) Can J Chem Rev Can Chem
68: 1544; b) Smith MB, March J (2001) Advanced
Organic Chemistry. Reactions, Mechanisms, and Struc-
ture, 5th edn. Wiley Interscience, New York, Chichester,
Brisbane, Toronto, Singapore
[8] a) Nowick JS, Holmes DL, Noronha G, Smith EM,
Nguyen TM, Huang SL (1996) J Org Chem 61: 3929;
b) Guichard G, Semety V, Didierjean C, Asubry A,
Briand JP, Rodriguez M (1999) J Org Chem 64: 8702
[9] Batey RA, Santhakumar V, Yoshina-Ishii C, Taylor SD
(1998) Tetrahedron Lett 39: 6267
Typical Experimental Procedure
N,N0-Di-n-hexylurea (1) n-Hexylamine (1cm3, 7.56 mmol)
was taken in 25cm3 dry DMSO and gaseous CO2 was bubbled
through it for 30min at room temperature. To this, a mixture
of 1.98 g triphenylphosphine (7.56 mmol) and 1.31cm3 diethyl
azodicarboxylate (7.56 mmol) was added slowly in 2–3 small
portions. Next, 1 cm3 n-hexylamine (7.56 mmol) was added.
The reaction was stirred at room temperature until completion
(2h) as confirmed by TLC. The reaction mixture was then
poured into 50 cm3 distilled water and extracted with ethyl
acetate thrice. The organic layer was separated and dried over
anhydrous sodium sulfate and then concentrated to afford
1.62g (94%) N,N0-di-n-hexylurea identical in all respects with
those described in Ref. [17].
[10] a) McCusker JE, Main AD, Johnson KS, Grasso CA,
McElwee-White L (2000) J Org Chem 65: 5216; b)
Bassoli A, Rindone B, Tollari S, Chioccara F (1990) J
Mol Catal 60: 41
[11] US Patent. 5902899, May 11, 1999
[12] a) Gupte SP, Chaudhuri RV (1988) J Catal 114: 246; b)
Mulla SAR, Rode CV, Kelkar AA, Gupte SP (1997) J
Mol Catal A Chem 122: 103; c) Basoli A, Rindone B,
Tollari S, Chioccara F (1990) J Mol Catal 60: 41; c)
Dombeck BD, Angelici R (1977) J Organomet Chem
134: 203; d) Yoshida T, Kambe N, Murai S, Sonoda N
(1986) Tetrahedron Lett 27: 2037; e) Sonoda N,
Yasuhara T, Kondo K, Ikeda T, Tsutsumi S (1971) J
Am Chem Soc 93: 6344; f) Sonoda N (1993) Pure Appl
Chem 65: 699 g) McCusker JE, Main AD, Johnson KS,
Grasso CA, White ME (2000) J Org Chem 65: 5216; h)
McCusker JE, Qian F, McElwee-White L (2000) J Mol
Catal A Chem 159: 11
Acknowledgements
The authors thank Dr. Suprabhat Ray for his fruitful sugges-
tions and the SIAF Division of CDRI for providing spectro-
scopic and analytical data.
References
[1] a) Jayakumar R, Nanjundan S, Prabaharan M (2006)
Reactive and Functional Polymers 66: 299; b) Lam PYS,
Jadhav PK, Eyermann, CJ, Hodge CN, Ru Y, Bacheler
LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang
CN, Weber PC, Jackson DA, Sharp TR, Erickson-
Viitanen S (1994) Science 263: 380; c) Schiere JB, Nell
AJ (1993) Animal Food Sci Technol 43: 135
[2] a) Chauhan YS, Apphun A, Singh VK, Dwivedi BS
(2004) Field Crops Res 89: 17; b) Abad A, Lloveras J,
Michelena A (2004) Field Crops Res 87: 257
[13] a) Yamazaki N, Hisaki F, Iguchi T (1974) Tetrahedron
Lett 13: 119; b) Morimoto Y, Fujiwara W, Taniguchi H,
Hori Y, Nagano Y (1986) Tetrahedron Lett 27: 1809;
c) Tai CC, Huck MJ, McKoon EP, Woo T, Jessop PG
(2002) J Org Chem 67: 9070
`
[14] a) Chaturvedi D, Kumar A, Ray S (2002) Synth Com-
mun 32: 2651; b) Chaturvedi D, Ray S (2005) Lett
Org Chem 2: 742; c) Chaturvedi D, Ray S (2005) J
Sulfur Chem 26: 365; d) Chaturvedi D, Ray S (2006)
Monatsh Chem 137: 201; e) Chaturvedi D, Ray S
(2006) Monatsh Chem 137: 311; f) Chaturvedi D,
Ray S (2006) Monatsh Chem 137: 459; g) Chaturvedi
[3] a) Frezza M, Castang S, Estephane J, Soulere L,
Deshayes C, Chantegrel B, Nasser W, Queneau Y,
Reverchon S, Doutheau A (2006) Bioorg Med Chem
14: 4781; b) Li G, Hasvold LA, Tao ZF, Wang GT,
Waltney SL II, Patel J, Kovar P, Credo RB, Chen Z,
Zhang H (2006) Bioorg Med Chem Lett 16: 2293; c)
Lam PYS, Ru Y, Jhadhav PK, Aldrich PE, Delucca GV,

270
D. Chaturvedi et al.: One-pot Synthesis of Substituted Ureas
D, Ray S (2006) Monatsh Chem 137: 465; h) Chaturvedi
D, Ray S (2006) J Sulfur Chem 27: 265; i) Chaturvedi D,
Ray S (2006) Monatsh Chem 137: 1219; j) Chaturvedi
D, Mishra N, Mishra V (2007) Monatsh Chem 138:
57; k) Chaturvedi D, Mishra N, Mishra V (2006) Chin
Chem Lett 17: 1309; l) Chaturvedi D, Mishra N, Mishra
V (2007) J Sulfur Chem 28: 39
Tetrahedron Lett 48: 149; d) Chaturvedi D, Mishra N,
Mishra V (2007) Tetrahedron Lett 48: 5043
[16] Chaturvedi D, Ray S (2007) Current Org Chem 11:
987
[17] Enquest PA, Nilsson P, Edin J, Larhed M (2005) Tetra-
hedron Lett 46: 3335
[18] Bigi F, Frullanti B, Maggi R, Sartori G, Zambonin E
(1999) J Org Chem 64: 1004
[19] Shi F, Deng Y, Sima T, Yang H (2001) Tetrahedron Lett
42: 2161
[15] a) Chaturvedi D, Kumar A, Ray S (2003) Tetrahedron
Lett 44: 7637; b) Chaturvedi D, Ray S (2006) Tetrahe-
dron Lett 47: 1307; c) Chaturvedi D, Ray S (2007)