Novel two-step, one-pot synthesis of primary acylureas

Article abstract of DOI:10.1016/j.tetlet.2010.09.003

A new procedure for the synthesis of primary acylureas from cyanamide and a variety of carboxylic acids is described. Under mild reaction conditions, the products were obtained in good yield from commercially available starting materials.

Full text of DOI:10.1016/j.tetlet.2010.09.003

Tetrahedron Letters 51 (2010) 5843–5844
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel two-step, one-pot synthesis of primary acylureas
⇑
Zili Xiao, Michael G. Yang , Andrew J. Tebben, Michael A. Galella, David S. Weinstein
Research & Development, Britstol-Myers Squibb Company, Route 206 & Provinceline Road, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2010
Revised 1 September 2010
Accepted 2 September 2010
Available online 8 September 2010
A new procedure for the synthesis of primary acylureas from cyanamide and a variety of carboxylic acids
is described. Under mild reaction conditions, the products were obtained in good yield from commer-
cially available starting materials.
Published by Elsevier Ltd.
Both primary acylureas and primary amides are relatively
hydrophilic moieties, which have been used as metabolically stable
bioisosteres of carboxylates. However, primary acylureas, unlike
primary amides, have the potential to form intramolecular hydro-
gen bonds as shown in Figure 1.1 As a result of such interactions,
small molecules derived from primary acylureas are likely to exhi-
bit better permeability in cell-based assays than their primary
amide counterparts. Because of their greater metabolic stability,
aqueous solubility, and permeability, primary acylureas represent
important functional groups in the field of medicinal chemistry.
Few studies have been reported for the synthesis of functional-
ized primary acylureas,2 and better synthetic protocols which are
efficient and do not require harsh reaction conditions are needed.
One procedure recently reported in the literature (Eq. 1, Fig. 2)
could potentially produce compound 4a from 3a (Eq. 2, Fig. 2).
However, in our hands when the reaction was carried out at a high
temperature (130 °C) for 10–24 h, only 17% of the desired product
was isolated after repeated attempts (Eq. 2, Fig. 2). In this Letter,
we report an efficient and general alternative method for the
synthesis of primary acylureas from a variety of commercially
available carboxylic acids (Eq. 3, Fig. 2).
H
H
O
O
N
N
H
4a: trans
-5.36
+5.36
kcal/mol
kcal/mol
O
O
H
N
N
H
H
crystal structure of the trans isomer (4a)
4a: cis
Figure 1. Evidence of intromolecular hydrogen bonding in 4a.
O
O
NH2
Synlett 2004, 8, 1355
(1)
OH
N
H
O
2
1
CF3
80% yield
1 equiv. O=C(NH2)2
Our study began with the coupling reaction of 3a and cyana-
mide (Table 1, entry 1). We envisioned that the cyanamide
would readily couple with the carboxylic acid in the presence
of BOP (1.2 equiv) and DIEA (3 equiv), and that the hydrolysis
step could then be performed in the same flask. Despite the lack
of literature reports on the hydrolysis of N-acylcyanamide to the
toluene azeotropic
reflux, 9-24h
F3C
B(OH)2
5 or 10 mol%
O
O
NH2
corresponding primary acylurea, we speculated that such
a
OH
N
H
O
4a
transformation could be accomplished under acidic conditions.3
In our first attempt, 4a was isolated in 37% yield (Table 1, entry
1). It is worth noting that mild heating was often necessary to
hydrolyze the N-acylcyanamide, although higher reaction tem-
peratures did not improve the yield. We were able to improve
the reaction yield dramatically by allowing a longer reaction
time in both steps (entry 1 vs entry 2, Table 1). Based on these
(2)
(3)
3a
Our result
17% yield
NH2
O
O
1. NH2CN/BOP/DIEA
R
N
H
O
R
OH
2. 12 N HCl (in one-pot)
4
3
high yields
⇑
Corresponding author. Tel.: +1 609 252 3234; fax: +1 609 252 7863.
E-mail address: michael.yang@bms.com (M.G. Yang).
Figure 2. Recent studies on the synthesis of primary acylureas.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.09.003

5844
Z. Xiao et al. / Tetrahedron Letters 51 (2010) 5843–5844
Table 1
Primary acylureas 4a–k produced via Eq. 3 in Figure 2
Entry
Acids 3
Reaction conditions step 1a?step 2b
Ureas 4 (Yield %)c
1
2
3
4
5
6
7
8
9
Benzoic acid 3a
Benzoic acid 3a
rt/3 h?50 °C/6 h (Method A)
rt/16 h?50 °C/16 h (Method B)
B
B
B
B
4a (37)
4a (84)
4b (74)
4c (71)
4d (77)
4e (65)
4f (77)
4g (72)
4h (31)
4i (88)
4j (86)
4k (71)
4-Methoxybenzoic acid 3b
4-Chlorobenzoic acid 3c
4-Isopropyl benzoic acid 3d
6-Methylnicotinic acid 3e
2-Fluorobenzoic acid 3f
rt/16 h?rt/16 h (Method C)
3-Nitrobenzoic acid 3g
C
C
C
B
B
1H-Indole-3-carboxylic acid 3h
Cyclohexanecarboxylic acid 3i
(S)-2-Phenylbutanoic acid 3j
1-Phenylcyclopropane carboxylic acid 3k
10
11
12
a
b
c
The reactions were conducted in DMF with 1 equiv of 3, 1.5 equiv of cyanamide, 1.2 equiv of BOP, and 3 equiv of DIEA.
Concentrated HCl (12 N) was added.
For detailed purification procedures see Ref. 4.
observations, the reaction times of entry 2 were used throughout
the remainder of the study.4 Reactions went smoothly at room
temperature for entries 7–10 (Table 1).
Acknowledgment
The authors thank Dr. John V. Duncia, Dr. Douglas G. Batt and
Dr. Joel C. Barrish for their valuable suggestions on preparation of
this manuscript.
A broad range of acids has been studied for this reaction and
representative results are summarized in Table 1. For substituted
benzoic acids, both electron donating (entries 3–5) and withdraw-
ing groups (entries 7 and 8) were well tolerated. The reaction
yields ranged from 71% to 77%. It is worth mentioning that the
coupling reaction of 4-nitrobenzoic acid with cyanamide was not
successful under the current reaction conditions. However, hetero-
cyclic carboxylic acids such as 6-methylnicotinic acid (3e) and 1H-
indole-3-carboxylic acid (3h) were converted into the desired
products 4e and 4h in 65% and 31% yields, respectively (entries 6
and 9). The reaction also worked well with aliphatic carboxylic
acids. In the case of cyclohexanecarboxylic acid (3i), the reaction
gave 4i in excellent yield (entry 10). (S)-2-Phenylbutanoic acid
(3j) provided the corresponding acylurea 4j in 86% yield (entry
11). The sterically hindered 1-phenylcyclopropane carboxylic acid
(3k) was well tolerated to give 4k in 71% yield (entry 12).
In summary, we have developed a novel method for the syn-
thesis of primary acylureas from cyanamide and a variety of car-
boxylic acids. The combination of mild reaction conditions and
wide substrate scope makes this protocol both useful and prac-
tical. Currently, this methodology has been successfully applied
in our medicinal chemistry efforts to generate biologically active
primary acylurea derivatives. These results will be reported in
due course.
References and notes
1. Computer modeling and the crystal structure suggest that the trans isomer is
the preferred conformation. The initial conformational energies for both
rotomers were minimized using the OPLSAA-2005 force field in Macromodel
(version 9.7, Schrodinger, LLC, New York, NY, 2009). Ab initio minimized
conformations were then generated within Jaguar (version 7.6, Schrodinger, LLC,
New York, NY, 2009) at the B3LYP/6-31G** level of theory in vacuum. Final
energies were calculated using the SM8 solvation model with the M06-2X/6-
31** basis set as implemented within Jaguar.
2. (a) Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004, 8, 1355–1358; (b) Seiller,
B.; Heins, D.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51(40), 10901–10912;
(c) Maynert, E. W.; Washburn, E. J. Org. Chem. 1950, 15, 259–261; For the
synthesis of second and tertiary acylureas see: (d) Wodka, D.; Robbins, M.; Lan, P.;
Martinez, R. L.; Athanasopoulos, J.; Makara, G. M. Tetrahedron Lett. 2006, 47, 1899.
3. For a related study on hydrolysis of N-acylcyanamide see: Perronnet, J.; Jacques,
P.; Taliani, L. J. Heterocycl. Chem. 1981, 18, 433–435.
4. Typical reaction procedure: A mixture of the acid 3 (1 mmol, 1 equiv), BOP
(1.2 equiv), cyanamide (1.5 equiv), and DIEA (3 equiv) in DMF (1.2 mL) was
stirred at rt for 16 h. To the reaction mixture, 12 N HCl (1 mL) was added and
then stirred at 50 °C or rt for additional 16 h. After cooling, the precipitate was
collected by filtration, washed with water, and vacuum dried to yield the
desired compounds. The purities of the final compounds ranged from 98% to
100% by HPLC analysis. Representative example of 4K 1H NMR (400 MHz,
DMSO-d6) d ppm: 8.25 (1H, s), 7.72 (1H, s), 7.23–7.49 (6H, m), 1.43–1.55 (2H,
m), 1.08–1.25 (2 H, m). 13C NMR (400 MHz, DMSO-d6) d ppm: 15.61, 31.37,
127.86, 128.86, 130.01, 138.56, 152.97, 174. 22.