Microwave-assisted transamidation of ureas

Article abstract of DOI:10.1016/j.tetlet.2016.02.103

An effective microwave-assisted urea formation from cyclopentyl- or isopropyl-substituted ureas is described. This novel transamidation methodology provided ureas IIa-IIq in good yields via microwave irradiation of the cyclopentyl- or isopropyl-substitute

Full text of DOI:10.1016/j.tetlet.2016.02.103

Tetrahedron Letters 57 (2016) 1941–1943
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Tetrahedron Letters
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Microwave-assisted transamidation of ureas
⇑
Tammy C. Wang , Jennifer X. Qiao
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective microwave-assisted urea formation from cyclopentyl- or isopropyl-substituted ureas is
described. This novel transamidation methodology provided ureas IIa–IIq in good yields via microwave
irradiation of the cyclopentyl- or isopropyl-substituted ureas with excess (5–10 equiv) of amines at
150 °C in THF/DMSO.
Received 22 January 2016
Revised 25 February 2016
Accepted 26 February 2016
Available online 3 March 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted
Urea formation
Transamidation
Cyclopentyl urea
The urea functional group is a common and useful building
block in the preparation of pharmaceutically active candidates
and natural products.1 Ureas are also commonly employed link-
ages in or between scaffolds as bioisosteres of carbamates or
amides in drug discovery. Numerous classical synthetic pathways
have been developed to generate ureas through isocyanates,2a,b
activated carbamate intermediates3 and carboxylic acid
derivaties.4 The application of microwave-assisted organic synthe-
atom with pyrrolidine. Herein we report the first synthesis of ureas
via transamidation of isopropyl or cyclopentyl urea I with excess
amines (5–10 equiv) in THF or a 1:1 mixture of THF/DMSO under
microwave irradiation at 150 °C (Table 1). Cyclopentyl or isopropyl
ureas are final compounds and/or advanced intermediates of two
in-house drug discovery programs.6a–e The cyclopentyl urea
analogs gave good in vitro potency but poor metabolic
stability.6a–c This methodology allowed us to promptly screen
different cyclopentyl urea replacements with structurally diverse
amines in a timely fashion.
sis in urea formation via the aforementioned synthetic methods is
5a,b
also well studied.
Symmetrical ureas were also generated by
reacting aromatic amines with ethyl acetoacetate promoted by
zeolite HSZ-3602c or by reacting amine using binary CO2/water as
reaction media2d or by aromatic amines or hydrazines with urea
devoid of solvents either under conventional heating in the
presence of catalytic zinc chloride2e,2f or under microwave
irradiation.2g
Initially, we planned to form compound 2 via the displacement
of 2-Cl-pyridine analog 16a upon heating pyrrolidine (neat) at
150 °C under microwave irradiation. After 1500 s, the reaction gave
an unexpected product 3 (88% yield) with no trace of 2 found
(Fig. 1). Compound 3 is a product of both transamidation of cyclo-
pentyl urea with pyrrolidine and displacement of the chlorine
Table 1 shows the results of primary amines (e.g., entries
4–12) and secondary amines (e.g., entries 13–14) with different
bulky groups on one side of the urea group and a cyclopentyl
or an isopropyl group on the other side. However, the less bulky
group Ie in entry 6 also gave the desired product cleanly in good
yields. Transamidation also showed good yields with weak ami-
nes (calcd. pKa = 7 for entries 4–6 and pKa = 6 for entry 8). Under
microwave irradiation, the chirality of the structure remains
unchanged based on the chiral purity analysis of IIa in entry 4.
All reactions were performed in 1500 s. For reactions with
isolated yields under 70% (e.g., entry 4), the only other side pro-
duct observed from LCMS of the reaction mixture was the unre-
acted starting cyclopentyl urea Ib. Increasing the temperature or
prolonging the reaction irradiation time could lead to completion
of reaction.
Upon obtaining good yields for the transamidation of ureas with
primary and secondary amines, we conducted a few studies on the
scope of the transamidation reaction. For example, using
⇑
Corresponding author. Tel.: +1 609 252 7556; fax: +1 609 252 7446.
E-mail address: Tammy.Wang@bms.com (T.C. Wang).
http://dx.doi.org/10.1016/j.tetlet.2016.02.103
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

1942
T. C. Wang, J. X. Qiao / Tetrahedron Letters 57 (2016) 1941–1943
Table 1
Transamidation of ureas Ia–g with primary and secondary amines under microwave
irradiation
N
HN
O
HN
F
N
R1
N
H
H
N
H
N
2 (5-10 equiv)
NHR1R
N
Cl
F3C
HN
O
R2
R
R
mw at 150 oC, 1500 sec.
HN
O
O
THF/DMSO (1:1)
N
150 oC mw, 1500 sec.
HN
2 (notobserved)
Urea II
Urea I
F3C
neat
N
F
N
CF3
Cl
H
H
N
N
H
F
HN
H
H
N
N
N
N
H
N
1
O
N
N
N
O
O
O
O
F3C
F3C
F3C
HF2CF2CO
Ia
Ib
F
Ic
F
F
F
3 (88%yield)
Figure 1. Discovery of transamidation of urea 1 to urea 3.
O
F
H
N
F
H
N
H
N
H
N
O
O
F
F3C
Id
HF2CF2CO
Ie
F
5–10 equiv of morpholine, urea 1 selectively underwent transami-
dation reaction without displacing the chlorine atom (entry 15,
Table 2). Functional groups such as carboxylic acid (entry 16),
alcohol (entries 17 and 19), and dihydrofuran-2(3H)-one (entry 18)
were also tolerated.
Therefore, in contrast to the classical stepwise synthetic
pathway to urea formation, we utilized isopropyl or cyclopentyl
ureas as stable intermediates for the transamidation, thereby
providing a rapid method for high-throughput synthesis and
optimization. Although the mechanism of the transamidation
of ureas was not studied, we propose that microwave irradia-
tion facilitated the bond-breaking process of the presumably
weaker C–N bond, which was on the less hindered urea side,
and thus formed an isocyanate intermediate that contained
O
O
F
H
H
N
N
N
N
H
HO
H
N
O
HF2CF2CO
If
F
Ig
CF3
Entry Urea I R1R2NH
Urea II
Isolated yield*,a (%)
60
H2N
H
N
H
N
CF3
CF3
CF3
CF3
CF3
CF3
4
58
6
Ib
Ig
Ie
Ic
Id
Id
R
O
IIa
IIb
IIc
H2N
H2N
H
N
H
N
R
78
81
85
77
79
O
the relatively bulky group. In fact, LCMS showed
a small
H
N
H
N
amount of the corresponding isocyanate formed when heating
Ia in the absence of an amine under the same reaction condi-
tions (described in Table 1). Interestingly, no un-reacted start-
ing ureas were identified by LCMS after 1500 s. in any of the
reactions except entry 4 shown in Tables 1 and 2. Microwave
irradiation is the key for these high-yielding transamidation
reactions. For example, under conventional heating at 150 °C
for 4 h, urea Ia reacted with 5–10 equiv of 2,2,2,-trifluo-
roethanamine to give only 11% of the transamidated product.
After heating for 12 more hours, 41% of the transamidated pro-
duct was formed along with 45% of the cleaved bulky left-hand
amine (R-NH2) and 14% of unreacted urea Ia. Increasing the
temperature to 200 °C under conventional heating led to
decomposition.
In summary, we described a novel one-step synthesis of ureas
via the transamidation of the cyclopentyl or isopropyl ureas with
excess amines (5–10 equiv) under microwave irradiation at
150 °C. Moreover, amines can be elaborated with functional groups
such as carboxylic acid and alcohol with no putative effect. Gener-
alization of this methodology and study of the reaction mechanism
and scopes such as using aryl/heteroaryl amines will be
investigated.
R
O
NH2
H
N
H
N
7
R
O
IId
F3C
H2N
H
N
H
N
CF3
8
R
O
IIe
H2N
H2N
H
N
H
N
F
R
9
F
F
F
O
IIf
H
N
H
N
F
F
F
R
R
F
10
Id
If
80
93
98
O
O
IIg
H2N
H
N
H
N
11
12
IIh
IIi
H2N
HN
H
N
H
N
R
If
N
O
N
O
Bn
Bn
H
N
N
N
O
13
14
Ia
Ia
84
88
R
R
O
O
IIj
H
N
H
N
Acknowledgements
IIk
The authors would like to thank Dr. Feng Qiu for structural con-
firmation of compound 3 and Dr. Ruth R. Wexler for reviewing the
manuscript and valuable suggestions.
*
Yields refer to isolated and chromatographically pure products. All products
exhibited spectral data and HRMS consistent with their structures.
a ,7 General reaction method—urea precursor I (1 equiv), amine (5–10 equiv), THF/
DMSO (1:1, 0.12 M), 150 °C mw, 1500 s.

T. C. Wang, J. X. Qiao / Tetrahedron Letters 57 (2016) 1941–1943
1943
Table 2
W.; Hua, L.; Hou, Z. ACS Sust. Chem. Eng. 2014, 2, 1147; (e) Pasha, M.; Reddy, M.
Synth. Commun. 2009, 39, 2928; (f) Huo, Q.; Margolese, D.; Stucky, G. Chem.
Mater. 1996, 8, 1147; (g) Mojtahedi, M.; Saidi, M. R.; Bolourtchian, M. J. Chem.
Res. (S) 1999, 710.
Transamidation of ureas with functionalized amines under microwave irradiation
R1
N
H
N
H
N
H
N
NHR1R2 (5-10 equiv)
(1:1)
3. (a) Flyes, T. M.; James, T. D.; Pryhitka, A.; Zojsji, M. J. Org. Chem. 1993, 58, 7456;
(b) Lamothe, M.; Perez, M.; Colovray-Gotteland, V.; Halazy, S. Synlett 1996, 507.
4. Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164.
5. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
6. (a) Harikrishnan, L. S.; Finlay, H. J.; Qiao, J. X.; Kamau, M. G.; Jiang, J.; Wang, T. C.;
Li, J.; Cooper, C. B.; Poss, M. A.; Adam, L. P.; Taylor, D. S.; Chen, A. Y. A.; Yin, X.;
Sleph, P. G.; Yang, R. Z.; Sitkoff, D. F.; Galella, M. A.; Nirschl, D. S.; Van Kirk, K.;
Miller, A. V.; Huang, C. S.; Chang, M.; Chen, X.-Q.; Salvati, M. E.; Wexler, R. R.;
Lawrence, R. M. J. Med. Chem. 2012, 55, 6162; (b) Miller, M. M.; Liu, Y.; Jiang, J.;
Johnson, J. A.; Kamau, M.; Nirschl, D. S.; Wang, Y.; Harikrishnan, L.; Taylor, D. S.;
Chen, A. Y. A.; Yin, X.; Seethala, R.; Peterson, T. L.; Zvyaga, T.; Zhang, J.; Huang, C.
S.; Wexler, R. R.; Poss, M. A.; Lawrence, R. M.; Adam, L. P.; Salvati, M. E. Bioorg.
Med. Chem. Lett. 2012, 22, 6503; (c) Qiao, J. X.; Wang, T. C.; Adam, L. P.; Chen, Al.
Y.-A.; Taylor, D. S.; Yang, R. Z.; Zhuang, S.; Sleph, P. G.; Li, J. P.; Li, D.; Yin, X.;
Chang, M.; Chen, X.-Q.; Shen, H.; Li, J.; Smith, D.; Wu, D.-R.; Leith, L.;
Harikrishnan, L. S.; Kamau, M. G.; Miller, M. M.; Bilder, D.; Rampulla, R.; Li, Y.-
X.; Xu, C.; Lawrence, R. M.; Poss, M. A.; Levesque, P.; Gordon, D. A.; Huang, C. S.;
Finlay, H. J.; Wexler, R. R.; Salvati, M. E. J. Med. Chem. 2015, 58, 9010; (d)
L’Heureux, A.; Hiebert, S.; Hu, C.; Lam, P. Y. S.; Lloyd, J.; Pi, Z.; Qiao, J. X.;
Thibeault, C.; Tora, G. O.; Yang, W.; Wang, Y.; Wang, T. C.; Bowsher, M. S.; Ruel,
R. PCT Int. Appl. 2014, WO 2014022343 A1, 20140206; (e) Qiao, J. X.; Wang, T. C.;
Hiebert, S.; Hu, C. H.; Schumacher, W. A.; Spronk, S. A.; Clark, C. G.; Han, Y.; Hua,
J.; Price, L. A.; Shen, H.; Chacko, S. A.; Everlof, G.; Bostwick, J. S.; Steinbacher, T.
E.; Li, Y.-X.; Huang, C. S.; Seiffert, D. A.; Rehfuss, R.; Wexler, R. R.; Lam, P. Y. S.
ChemMedChem 2014, 9, 2327.
7. General procedure for urea transamidation: In a 2-mL Personal Chemistry Smith
Process conical vial, cyclopentyl urea was mixed with amine (5–10 equiv) in a
mixture of THF/DMSO (1:1, v/v). Microwave reactions were carried out in a
Personal Chemistry Emrys Optimizer model microwave reactor. Typical
reactions were run using 300 W of power for 150–300 s. and approximately
100 W of power until the final experiment time reached 1200 s. The
temperature was measured with an IR probe and maintained at 150 °C. The
resulting mixture was diluted in EtOAc, washed with 1 N HCl and filtered.
Solvents were evaporated under vacuum, and the residue was purified by
chromatography or preparative HPLC.
8. Typical procedure exemplified by the synthesis of 1-[(1R)-1-(4-fluoro-3-
methoxyphenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-
3-(2,2,2-trifluoroethyl)urea (IIb, Table 1, entry 5): In a 2 mL Personal Chemistry
Smith Process conical vial, 3-cyclopentyl-1-[(1R)-1-(4-fluoro-3-methoxyphenyl)-
1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl] Ig (20 mg,
0.035 mmol) was mixed with 2,2,2,-trifluoroethanamine (19.48 mg,
0.177 mmol) in a 1:1 mixture of THF/DMSO (0.3 mL). The reaction mixture
was stirred for 1500 s. under microwave irradiation at 150 °C. The reaction
mixture was diluted with EtOAc (2 mL) and washed with 1 N HCl (1 mL), then
dried over Na2SO4. The solution was filtered and the solvent was evaporated
under reduced pressure. The crude product was purified via silica
chromatography using hexane/EtOAc as the mobile phase to provide the
desired product IIb as a white solid (18 mg, 78% yield). HRMS: C26H21F9N2O3
calcd for [M+H]: 581.14815, found: 581.14771. 1H NMR (500 MHz, METHANOL-
d4) d 7.26–7.13 (m, 3H), 7.10 (d, J = 9.9 Hz, 1H), 7.06–6.94 (m, 3H), 6.82–6.73 (m,
4H), 6.70 (br. s., 1H), 6.46–6.14 (m, 1H), 4.03 (d, J = 12.7 Hz, 1H), 3.93–3.74 (m,
3H), 3.70 (s, 3H). 13C NMR (125 MHz, METHANOL-d4): d 164.04 (d, J = 244.40),
158.85 (m), 152.83 (d, J = 245.8 Hz), 152.40 (d, J = 7.9 Hz), 150.71 (d, J = 11.8 Hz),
148.51 (d, J = 10.9 Hz), 142.38 (m), 137.85, 132.28, 128.79, 127.79, 126.36 (q,
J = 278.5 Hz), 120.60 (d, J = 6.6 Hz), 118.12 (tt, J = 271.8, 28.5 Hz), 117.74 (m),
116.42 (d, J = 18.8 Hz), 114.14, 113.78 (d, J = 23.5 Hz), 109.49 (tt, J = 250.1,
40.8 Hz), 108.86 (d, J = 25.8 Hz), 65.74 (m), 56.72, 44.80, 41.90 (q, J = 34.7 Hz).
Anal. Calcd for C26H21F9N2O3: C, 53.80; H, 3.61; F, 29.46; N, 4.83. Found: C,
53.88; H, 3.60; F, 27.43; N, 4.86.
R2
R
R
O
O
THF/DMSO
150 oC mw, 1500 sec.
Urea II
Urea I
Entry Urea I
R1R2NH
Urea II
Isolated yielda
(%)
Cl
N
O
HN
O
H
N
H
N
Cl
N
H
N
N
O
15
16
O
81
88
F3C
F3C
1
IIl
F
F
OH
O
F
A
OH
H
O
H
N
F
H
N
H
N
N
O
H2N
O
20
A
F
IIm
F
HO
HN
CF3
HO
CF3
F
F
A
H
N
H
H
N
N
N
O
O
17
74
A
Ic
IIn
F
F
O
H2N
CF3
CF3
O
O
F
A
F
H
N
O
H
N
H
N
H
N
O
18
19
73
86
O
A
Ic
IIo
F
F
HO
NH
Cl
Cl
OH
H
N
O
H
N
H
N
N
N
N
O
F3C
F3C
IIp
Ia
F
F
A = –OCF2CF2H.
a
General reaction method—urea precursor (1 equiv), amine (5–10 equiv),
THF/DMSO (1:1, 0.12 M), mw 150 °C, 1500 s.
Supplementary data
Supplementary data (spectroscopic data for compounds IIa–IIq)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.02.103.
References and notes
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