Acetoacetanilides as masked isocyanates: Facile and efficient synthesis of unsymmetrically substituted ureas

Article abstract of DOI:10.1021/ol101474f

Figure Presented. A general and practical method for the preparation of unsymmetrically substituted ureas has been developed. By the reactions of acetoacetanilides with various amines including primary/secondary amines, a series of substituted aryl ureas were achieved in high yields. Acetoacetanilide substrates can be considered as masked reagents that liberate reactive isocyanates in situ.

Full text of DOI:10.1021/ol101474f

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4220-4223
Acetoacetanilides as Masked
Isocyanates: Facile and Efficient
Synthesis of Unsymmetrically
Substituted Ureas
Ying Wei, Jing Liu, Shaoxia Lin, Hongqian Ding, Fushun Liang,* and
Baozhong Zhao
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, China
liangfs112@nenu.edu.cn
Received May 20, 2010
ABSTRACT
A general and practical method for the preparation of unsymmetrically substituted ureas has been developed. By the reactions of acetoacetanilides
with various amines including primary/secondary amines, a series of substituted aryl ureas were achieved in high yields. Acetoacetanilide
substrates can be considered as masked reagents that liberate reactive isocyanates in situ.
Substituted ureas have received considerable attention due to
their wide range of applications in agriculture, petrochemicals,
Scheme 1
.
Structures of Biologically Important Substituted
Ureas
medicine, and biology and as important intermediates and
bifunctional organocatalysts in organic synthesis.1-3 For ex-
ample, Diuron (A) (Scheme 1) is a commercially available
herbicide mainly used to control weeds on hard surfaces.4
Structurally simple urea B, incorporating a morpholine ring,
was found to be very effective in the treatment of chronic
(1) For reviews on substituted ureas, see: (a) Gallou, I. Org. Prep.
Proced. Int. 2007, 4, 355. (b) Bigi, F.; Maggi, R.; Sartori, G. Green Chem.
2000, 2, 140. (c) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ.
Chem. ReV. (Engl. Ed.) 1985, 54, 249. (d) Matsuda, K. Med. Res. ReV.
1994, 14, 271
.
(2) Selected examples on substituted ureas as intermediates in organic
synthesis, see: (a) Gao, J.; Li, H.; Zhang, Y.; Zhang, Y. Green Chem. 2007,
9, 572. (b) Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567. (c) Clayden,
J.; Dufour, J.; Grainger, D. M.; Helliwell, M. J. Am. Chem. Soc. 2007,
129, 7488. (d) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
44, 6367. (e) Yu, S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill,
myelogenous leukemia.5 Unsymmetrically substituted urea
C has been shown to be a potent HIV-1 protease inhibitor6
and D as a receptor tyrosine kinase (RTK) inhibitor.7
The conventional methods reported for the urea synthesis
are essentially based on phosgene,8 phosgene substitutes,9
D. R. J. Org. Chem. 2009, 74, 9539
.
(3) Selected examples on urea-based bifunctional organocatalysts in
organic synthesis, see: (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
(4) Cabrera, A.; Cox, L.; Velarde, P.; Koskinen, W. C.; Cornejo, J. J.
Agric. Food Chem. 2007, 55, 4828.
.
(5) Cao, P.; Huang, X.; Ding, H.; Ge, H.; Li, H.; Ruan, B.; Zhu, H.
Chem. BiodiVersity 2007, 4, 881.
10.1021/ol101474f  2010 American Chemical Society
Published on Web 09/01/2010

or isocyanates.10 These approaches have been demonstrated
to be particularly efficient for symmetrical ureas. However,
phosgene and isocyanates are toxic, unstable, and expensive
to handle. In this regard, direct utilization of in situ formed
isocyanates represents an attractive strategy toward efficient
synthesis of ureas, especially more challenging unsymmetri-
cally substituted ureas.1a,11
Scheme 2. Initial Investigation
In our research on the synthetic potential of R,R-disub-
stituted ꢀ-ketoamides12 bearing both electrophilic and nu-
cleophilic centers toward various carbo- and heterocycles,13
we presented the amine-mediated ring-opening reactions of
doubly EWG-activated cyclopropanes and subsequent recy-
clization, which afford fully functionalized pyridin-2(1H)-
ones.13a In our continued work, the reaction of 1-acetyl-1-
carbamoyl cyclopropane (1a) with L-proline was explored
(Scheme 2). To our surprise, the expected ring-opening
product 4 was not observed. Instead, an unsymmetric N-aryl
urea14,15 was achieved in high efficiency, which provides a
straightforward, simple, and efficient synthesis of unsym-
metrically substituted ureas via in situ formation of isocy-
anates.16 A careful literature search revealed that reactions
of acetoacetanilides and primary amines have been reported
by Bigi et al.17 It was noteworthy that, in their reactions,
the reaction conditions require high temperatures (180 °C)
and a zeolite catalyst, and only symmetric N,N′-dialkyl17a
(aryl17b) ureas were prepared (eq 1). By contrast, a catalyst-
free reaction of acetoacetanilides and primary/secondary
amines was developed under milder conditions in our work
(eq 2). Herein, we wish to communicate the results.
(6) Matzen, L.; van Amsterdam, C.; Rautenberg, W.; Greiner, H. E.;
Harting, J.; Seyfried, C. A.; Bo¨ttcher, H. J. Med. Chem. 2000, 43, 1149.
(7) 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.
(8) (a) Babad, H.; Zeiler, A. G. Chem. ReV. 1973, 73, 75. (b) Smith,
M. B.; March, J. March’s AdVanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed; Wiley: New York, 2001; p 1191; (c)
Kno¨lker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2497.
Initially, optimization of the reaction conditions was con-
ducted (Table 1). It was found that both the solvent and
(9) Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937.
(10) The reaction of isocyanates with various nucleophiles has been
extensively reported in the literature, see: (a) Ozaki, S. Chem. ReV. 1972,
72, 457. (b) Braunstein, P.; Nobel, D. Chem. ReV. 1989, 89, 1927. For the
utilization of isocyanate towards the synthesis of eight-membered cyclic
ureas via [6 + 2] cycloaddition, reaction with 2-vinylazetidines has been
reported. See: (c) Koya, S.; Yamanoi, K.; Yamasaki, R.; Azumaya, I.; Masu,
H.; Saito, S. Org. Lett. 2009, 11, 5438. For the reaction of isocyanatobenzene
with lithiated chiral diamine towards chiral ureas, see: (d) Ko¨hn, U.; Gu¨nther,
W.; Go¨rls, H.; Andersa, E. Tetrahedron: Asymmetry 2004, 15, 1419.
(11) For recent examples for the preparation of ureas via in situ formation
of isocyanate, see: (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,
Table 1. Optimization of the Reaction Conditionsa
entry
2a (equiv)
solvent
t (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
2.2
2.2
2.2
1.2
1.2
1.2
1.2
CH2Cl2
THF
xylene
xylene
toluene
DMF
rt
60
120
120
115
120
100
8
8
3.5
3.5
3.5
7
0
0
92
92
90
trace
0
1340
.
(12) For selected representative reactions from ꢀ-ketoamides, see: (a)
Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc. 2009,
131, 11660. (b) Lie´by-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am.
Chem. Soc. 2005, 127, 17176. (c) Zhou, C.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2007, 129, 5828. (d) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong,
D. Org. Lett. 2008, 10, 345. (e) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115.
(f) Ramanjulu, J. M.; DeMartino, M. P.; Lan, Y.; Marquis, R. Org. Lett.
2010, 12, 2270.
H2O
8
a Reactions were carried out on a 1.0 mmol scale in 2 mL of solvent.
b Yield of isolated product.
(13) (a) Liang, F.; Cheng, X.; Liu, J.; Liu, Q. Chem. Commun. 2009,
3636. (b) Cheng, X.; Liang, F.; Shi, F.; Zhang, L.; Liu, Q. Org. Lett. 2009,
11, 93. (c) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org. Chem. 2006, 71, 8006.
(d) Zhao, L.; Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org. Chem. 2006, 71,
1094.
temperature have a large effect on the reaction. Whether at room
temperature in CH2Cl2 or at 60 °C in THF for 8 h, the reactions
of acetoacetanilide 1a and L-proline 2a (2.2 equiv) could not
give satisfactory results (entries 1 and 2). To our delight, at
120 °C in xylene (2.0 mL) for 3.5 h, the reaction of acetoac-
(14) For N-aryl urea preparation: Lukin, K. A.; Hsu, M. C.; Fernando,
D. P.; Kotecki, B. J.; Leanna, M. R. U.S. Pat. Appl.US2007244178
.
(15) More recently, ortho-directed C-H bond activation and cross-
coupling of aryl ureas have emerged. For representative examples, see: (a)
Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem., Int. Ed. 2010,
49, 781. (b) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am.
Chem. Soc. 2010, 132, 4978. (c) Houlden, C. E.; Hutchby, M.; Bailey, C. D.;
Gair Ford, J.; Tyler, S. N. G.; Gagne´, M. R.; Lloyd-Jones, G. C.; Booker-
(16) Examples for the formation of isocyanates from amides under Pd
catalysis, see: (a) Furata, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.; Tanaka,
K.; Kan, T. Org. Lett. 2007, 9, 183. (b) Donati, L.; Michel, S.; Tillequin,
F.; Poree´, F.-H. Org. Lett. 2010, 11, 156.
Milburn, K. I. Angew. Chem., Int. Ed. 2009, 48, 1830
.
Org. Lett., Vol. 12, No. 19, 2010
4221

etanilide 1a (1.0 mmol) and L-proline 2a (2.2 equiv) proceeded
cleanly to give a white solid after workup and purification. The
product was characterized as N-phenylpyrrolidine-1-carboxa-
mide 3a (92% yield, entry 3) on the basis of its spectral and
analytical data (see the Supporting Information). The structure
of 3a was further confirmed by the X-ray single-crystal
diffraction (Figure 1).18 The feed amount of L-proline was
recovered, which is consistent with the possible mechansim
described later.
Since parent 3-oxo-N-phenylbutanamide gave satisfactory
results, we thus start directly from commercially available
substrates to investigate the scope with respect to the amide
motif and amine (Tables 2 and 3). First of all, a series of 3-oxo-
Table 2. Reactions of Different Acetoacetanilides and L-Prolinea
entry
1
R1
time (h)
3
yield (%)b
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1e
1f
1g
1h
1i
2-OmePh
4-OmePh
2-MePh
4-MePh
2,4-Me2Ph
2-ClPh
3.0
3.5
3.0
3.5
3.0
3.5
3.5
3.5
3.5
7
3b
3c
3d
3e
3f
3g
3h
3i
86
80
83
82
85
80
78
81
91
0
Figure 1. ORTEP drawing of 3a.
4-ClPh
5-Cl-2-OmePh
2-pyridyl
Bn
reduced to be 1.2 equiv with a similar yield (entry 4). The
reaction in toluene gave a comparable yield (entry 5). Only a
trace amount of 3a was observed when highly polar DMF was
used as the solvent under otherwise identical conditions (entry
6). Water was also tested but proved to be inert (entry 7).
Obviously, nonpolar solvents like toluene and xylene are
favorable for substituted urea formation.
Having established the optimal conditions for the forma-
tion of unsymmetrically substituted urea 3a, a series of
reactions based on various substituted acetamides and
L-proline were carried out at 120 °C in xylene, with the aim
to explore the influence of the substituents on the acetamide
substrates on the reactions (Figure 2).19 As a result, the
1j
1k
3j
3k
a Reactions were carried out on a 1.0 mmol scale in 2 mL of xylene at
120 °C with 1 (1.0 equiv) and 2 (1.2 equiv). b Yield of isolated product.
N-arylbutanamides 1b-i were reacted with L-proline 2a under
conditions identical to those for 3a in Table 1 (entry 4). It was
observed that all the reactions proceeded smoothly to afford
the corresponding unsymmetrically substituted aryl ureas 3b-i
in good to excellent yields (Table 2, entries 1-8). Heteroaryl
urea 3j was prepared in 91% yield from 3-oxo-N-(pyridin-2-
yl)butanamide 1j19b (entry 9). When 3-oxo-N-alkylbutanamide
substrate such as 3-oxo-N-benzylbutanamide 1k was used, the
reaction did not give the desired product (entry 10).20
Then, various amines including sencondary amines and
primary amines were subjected to the reaction sequences (Table
Table 3. Reactions of 3-Oxo-N-phenylbutanamide and Various
Aminesa
Figure 2. Effect of substituents on the acetamide substrates.
entry
2
time (h)
3
yield (%)b
1
2
3
4
5
6
7
8
piperidine
3.0
3.0
3.0
3.5
4.0
4.0
4.0
5.0
3l
95
92
95
87
60
72
78
0c
2-methylpiperidine
morpholine
pyrrolidine
diethylamine
benzylamine
aniline
3m
3n
3a
3o
3p
3q
3r
reactions of acetoacetanilides containing various substituents
at the R-position, such as cyclopentyl, ethyl, methyl, or
hydrogen, proceeded efficiently, giving urea 3a in good to
excellent yields (80-93%). However, N-methyl-N-phenyl
counterparts and N-phenylacetamide failed to react with
L-proline under identical conditions with intact substrates
ammonia
a Reactions were carried out on a 1.0 mmol scale in 2 mL of xylene at
120 °C with 1 (1.0 equiv), and 2 (1.2 equiv). b Yield of isolated product.
c NH4OAc (10.0 equiv) was used as the ammonia source, and the reaction
was performed under sealed conditions.
(17) (a) Bigi, F.; Frullanti, B.; Maggi, R.; Sartori, G.; Zambonin, E. J.
Org. Chem. 1999, 64, 1004. (b) Bigi, F.; Maggi, R.; Sartori, G.; Zambonin,
E. Chem. Commun. 1998, 513.
4222
Org. Lett., Vol. 12, No. 19, 2010

3). For secondary cyclic amines such as piperidine, 2-meth-
ylpiperidine, morpholine, and pyrrolidine, the reactions were
highly efficient, and the desired ureas 3l-n and 3a were
obtained in excellent yields (entries 1-4). Acyclic secondary
amines like diethylamine gave the corresponding urea 3o in
moderate yield (entry 5). Primary amines are also efficient for
the explored reactions. In the cases of primary aliphatic amines
such as benzylamine, and primary aromatic amine such as
aniline, the corresponding ureas 3p and 3q were prepared in
72% and 78% yields, respectively (entries 6 and 7).21 However,
the reaction of 1a and ammonia could not give the desired urea
3r (entry 8). It should be noted that all the crude products 3
could be purified simply by recrystallization from n-hexane,
which provides a convenience for large-scale synthesis of useful
ureas. Gram-scale preparation of compounds 3a and 3l have
been achieved in respective yields of 86% and 91% in our
laboratory. Clearly, the present protocol provides a general,
efficient, and practical pathway to construct unsymmetrically
substituted aryl ureas. Moreover, the protocol meets the need
for library synthesis.
Scheme 4. Possible Mechanism for the Formation of Ureas 3
2 and acetoacetanilide 1 occurrs to give intermediate I,
followed by the formation of an iminium ion intermediate
II via the loss of one molecule of water. Then, decarboxy-
lation might take place, giving key intermediate III.22 Finally,
an isocyanate intermediate IV would be generated via the
elimination of acetone enamine,23 which, in turn, is captured
in situ by the pyrrolidine (from the hydrolysis of acetone
enamine)24 nucleophile, giving the aryl urea 3.25,26
In conclusion, we have developed a practical and efficient
protocol for the production of substituted ureas by the reactions
of acetoacetanilides with various amines via in situ generated
isocyanate intermediates. The reaction features readily available
starting materials, wide scope, mild conditions, and high effi-
ciency and is phosgene- and catalyst-free. Further work on the
synthetic application of the ureas is ongoing in our laboratory.
In addition to N-nucleophiles, the reactions of O/S-nucleo-
philes like BnOH, PhOH, BnSH, and PhSH with acetoaceta-
nilides were also examined, but proved to be inert, even though
additional amine like triethylamine (1.2 equiv) or pyrrolidine
(0.2 equiv) was introduced to the reaction system (Scheme 3).
Scheme 3
.
Reactions of Acetoacetanilides with
O/S-Nucleophiles
Acknowledgment. Financial support by NSFC (20972027)
and Training Fund of NENU’S Scientific Innovation Project
(NENU-STC08013 and STB07007) is greatly acknowledged.
Note Added after ASAP Publication. The graphic in
Table 3 was missing in the pdf file of the version published
ASAP September 1, 2010; this has been corrected and
reposted September 3, 2010.
To clarify the decarboxylation involved in the reaction
leading to urea (Table 2), we performed a control reaction
of L-proline with acetophenone in xylene at 130 °C. As a
result, distinct decarboxylation was observed.22 On the basis
of all the results described, a possible mechanism for the
efficient one-pot transformation into substituted ureas was
proposed, as depicted in Scheme 4 (with L-proline as an
example). Initially, a nucleophilic addition between amine
Supporting Information Available: Experimental details
and characterization for all new compounds and crystal
structure data (CIF files). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101474F
(22) Decarboxylation of R-amino acids proceeds under conditions such
as in the presence of ketone catalyst in hydrocarbon solvents like xylene or
tetralin. For references, see: (a) Takano, S.; Nishimura, T.; Ogasawara, K.
Heterocycles 1977, 6, 1167. (b) Hashimoto, M.; Eda, Y.; Osanai, Y.; Iwai,
T.; Aoki, S. Chem. Lett. 1986, 893. (c) Zheng, L.; Yang, F.; Dang, Q.; Bai,
X. Org. Lett. 2008, 10, 889.
(18) CCDC 771468 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(19) All the acetoacetanilide derivatives were either commercially
available or prepared according to the procedure reported. See: (a) Zhang,
Z.; Zhang, Q.; Sun, S.; Xiong, T.; Liu, Q. Angew. Chem., Int. Ed. 2007,
46, 1726. (b) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431.
(20) Complex products were observed in the reaction. The lack of the
reactivity of N-alkyl acetoacetanilides is probably due to their relatively
high pKa values of the N-H.
(23) Mukaiyama, T.; Tokizawa, M.; Nohira, H.; Takei, H. J. Org. Chem.
1961, 26, 4381.
(24) Actually, a quite large amount of gas bubbles evolved from the reaction
of proline with acetoacetanilides, supposed as CO2 and gaseous acetone.
(25) Obviously, the formation of the iminium ion intermediate II facilitates
both the decarboxylation and the enamine elimination processes.
(26) We would like to thank the reviewers for valuable comments on
the manuscript.
(21) Other amines such as ethanol amine, aminopyridine, and t-butylamine
were also tried but led to complex mixtures.
Org. Lett., Vol. 12, No. 19, 2010
4223