An easy and versatile synthesis of ureas from 2-benzylaminopyrimidine

Article abstract of DOI:10.1016/j.tetlet.2008.09.171

A general procedure for the easy and versatile synthesis of ureas from 2-benzylaminopyrimidine is described. This methodology involves the preparation of a highly reactive carbamoyl chloride intermediate that can be further reacted with a high variety of different amines, including highly hindered secondary amines and deactivated anilines with excellent yields. Furthermore, this smooth procedure is compatible with a second functionality on the amine.

Full text of DOI:10.1016/j.tetlet.2008.09.171

Tetrahedron Letters 49 (2008) 7171–7173
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An easy and versatile synthesis of ureas from 2-benzylaminopyrimidine
a
b,
Michiel Van Gool a, , José M. Bartolomé , Gregor J. Macdonald
*
*
a Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen-Cilag, Neuroscience Medicinal Chemistry Department, Jarama 75, 45007 Toledo, Spain
b Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica N.V., Neuroscience Medicinal Chemistry Department,
Turnhoutseweg 30, B2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2008
Revised 26 September 2008
Accepted 30 September 2008
Available online 2 October 2008
A general procedure for the easy and versatile synthesis of ureas from 2-benzylaminopyrimidine is
described. This methodology involves the preparation of a highly reactive carbamoyl chloride intermedi-
ate that can be further reacted with a high variety of different amines, including highly hindered second-
ary amines and deactivated anilines with excellent yields. Furthermore, this smooth procedure is
compatible with a second functionality on the amine.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Ureas
2-Benzylaminopyrimidine
Triphosgene
As part of one of our Neuroscience Drug Discovery programs,
we were interested in the synthesis of a highly diverse set of urea
derivatives of 2-alkylamino pyrimidines. For the development of a
methodology amenable for the high-throughput parallel synthesis
of the desired final compounds, 2-benzylaminopyrimidine 11 was
selected as a suitable model system (Scheme 1).
O
N
NH
N
LG
N
N
N
The most classical approach involving the reaction of 1 with iso-
cyanates was rapidly discarded—Firstly, due to the low reactivity of
2-benzylaminopyrimidine 1 under all reaction conditions investi-
gated2 and secondly, because of the limited diversity of commer-
cially available isocyanates that would limit the diversity of the
set of final compounds. Consequently, a different strategy for the
preparation of compounds 3 following an indirect approach was
considered. This strategy involves the formation of a reactive inter-
mediate 2 that by further reaction with amines would afford the
desired urea derivatives 3 (Scheme 1). This two-step methodology
offers a number of advantages, such as a larger and more diverse
set of commercial building blocks (amines vs isocyanates) and ac-
cess to tetrasubstituted ureas, not possible via the classical route.
Our first attempt consisted of reacting 1 with 1,10-carbonyldi-
imidazole (CDI), followed by addition of the amine, according to
a previously described procedure for similar compounds.3 How-
ever, this approach failed and no final compounds were detected
in any of the different conditions tried,4 probably due again to
the low reactivity of our aminopyrimidine model hampering the
formation of intermediate 2.
1
2
LG = Leaving Group
O
N
N
NR1R2
N
3
Scheme 1.
Finally, our last attempt targeted the preparation of 2 according
to a similar procedure described for the synthesis of [1,2,4]triazolo-
[1,5-a]pyrimidinium betaines from 2-alkylaminopyrimidines.5
Thus, reaction of 1 with triphosgene in dichloromethane at room
temperature followed by addition of ethylamine furnished desired
compound 3a (Scheme 2, Table 1) in an excellent yield. Further-
more, here it is shown that the intermediate 4 is sufficiently
* Corresponding authors. Tel.: +34 925 245 750; fax: +34 925 245 771 (M.V.G.).
E-mail address: mvgool2@prdes.jnj.com (M. Van Gool).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.171

7172
M. Van Gool et al. / Tetrahedron Letters 49 (2008) 7171–7173
Table 1
O
Synthesis of final compounds 3a–l produced via Scheme 2
NH
N
ii)
Cl
Entry
Amine
Reaction timea
10 min
Isolated yield
81b
i) Triphosgene
Et3N, CH2Cl2
N
N
N
N
3a
NH2
NH2
3b
3c
3d
10 min
10 min
10 min
81b
88b
83b
1
4
HO
O
NH2
NH2
R
1
HN
R
2
O
O
O
N
3e
3f
10 min
10 min
85b
82b
NH2
N
NR1R2
O
N
N
H
N
NH2
O
O
3a-l
NH
Scheme 2.
3g
3h
20 min
20 min
92b
90b
NH
activated to react with a high diversity of amines under mild con-
ditions allowing the preparation of the desired urea derivatives 3
with good to excellent overall yields. This procedure has proven
to be general enough to allow the easy synthesis of tri- and tetra-
substituted urea derivatives of 2-benzylaminopyrimidine includ-
ing those compounds from reaction with highly sterically
hindered secondary amines and deactivated anilines.
N
3i
7 h
80b
NH
NH2
Reaction of 2-benzylaminopyrimidine 1 with a slight excess
(0.4 equiv) of triphosgene in the presence of triethylamine6
(2.4 equiv) in dichloromethane7 at room temperature afforded
after 10 min of incubation, the carbamoyl chloride 4. The forma-
tion of this intermediate was confirmed by LC/MS analysis of the
reaction mixture. Thus, a mixture of carbamoyl chloride 4 and its
corresponding methyl carbamate (formed by reaction of 4 with
the methanol used as eluent) was observed. Subsequent addition
of the corresponding amines, either aliphatic or aromatic
(1.6 equiv), furnished desired urea derivatives 3a–l (Table 1).8 In
most of the examples, total conversion to the final product was
observed after few minutes of reaction time. Only when either
a highly hindered amine (diisopropylamine 3i) or a deactivated
aniline (4-cyanoaniline 3l) was used, longer reaction times of 7
hours and 1 h, respectively, were required. Final yields after stan-
dard work-up and purification ranged from a good 72% to an
excellent 92%, and were not affected by the reactivity of the
amines used.9 Furthermore, this mild methodology is compatible
with the presence of a second functionality in the amine (3c–f)
that may be subject for a further derivatization. Noteworthy in
the case of 2-aminoethanol, no reaction of the hydroxyl group
was observed (3c). Additionally, as shown in examples 3g–i, this
procedure allows the straightforward formation of tetrasubstitut-
ed ureas.
In conclusion, here we have reported a general procedure that
allows the easy and versatile synthesis of ureas from 2-benzyl-
aminopyrimidine. This methodology involves the preparation of a
highly reactive carbamoyl chloride intermediate that can be
further reacted with a high variety of different amines, including
highly hindered secondary amines and deactivated anilines with
excellent yields. Furthermore, this smooth procedure is compatible
with a second functionality on the amine. Further exploration of
this procedure on other low reactive systems is currently in
progress, and will be reported in due course.
3j
10 min
10 min
1 h
73c
72c
80d
NH2
NH2
3k
O
3l
NC
a
Reaction time after addition of the corresponding amine.
Yield after chromatographic purification.
Yield after chromatographic purification and crystallization from acetonitrile.
Yield after chromatographic purification and crystallization from methanol.
b
c
d
Acknowledgments
The highly valuable collaboration and help of Mr. Alberto
Fontana with the generation of the reported analytical data is
gratefully acknowledged.
References and notes
1. Cherng, Y. J. Tetrahedron 2002, 58, 887–890.
2. Reaction of 1 with ethyl and phenyl isocyanate (1 or 5 equiv of isocyanate) was
tested using dichloromethane, tetrahydrofuran and toluene as solvents at
temperatures ranging from room temperature to 110 °C. Addition of a base to
the reaction media (diisopropylethylamine) was also investigated. Under all the
reactions conditions tried no satisfactory amounts of desired products 3a or 3j
respectively were obtained.
3. Keizer, H. M.; Sijbesma, R. P.; Meijer, E. W. Eur. J. Org. Chem. 2004, 12, 2553–
2555.
4. Compound
1 was reacted with CDI at temperatures ranging from room
temperature to 65 °C followed by addition of ethylamine and aniline and
further reaction at temperatures ranging between room temperature and 50 °C
in either chloroform or tetrahydrofuran as solvents.
5. Marley, H.; Wright, S. H. B. J.; Preston, P. Chem. Soc., Perkin Trans. I 1989, 10,
1727–1733.

M. Van Gool et al. / Tetrahedron Letters 49 (2008) 7171–7173
6. When diisopropylethylamine was added similar results were obtained but no ESI-HRMS m/z calcd for
7173
C
15H17N4O3 [MH]+ 301.1301. Found: 301.1321.
reaction at all was observed when an inorganic base (K2CO3) was used.
7. Tetrahydrofuran and acetonitrile were also investigated as solvents, furnishing
similar results.
Compound 3e: syrup; 1H NMR (CDCl3) d 1.41 (s, 9H) 2.85–2.98 (m, 3H) 3.42–
3.51 (m, 2H) 3.51–3.60 (m, 2H) 5.47 (s, 2H) 6.84 (t, J = 4.77 Hz, 1H) 7.17 (s, 1H)
7.25 (t, J = 7.46 Hz, 2H) 7.36 (d, J = 7.46 Hz, 2H) 8.49 (d, J = 4.98 Hz, 2H) 10.35 (br
s, 1 H); 13C NMR (CDCl3) d 28.55 (CH3) 34.88 (CH3) 38.78 (C) 39.27 (C) 47.15
(CH2) 47.91 (C) 48.73 (C) 114.09 (CH) 126.73 (CH) 127.64 (CH) 128.27 (CH)
139.40 (C) 156.33 (C) 157.26 (CH) 159.94 (C); ESI-HRMS m/z calcd for
C20H28N5O3 [MH]+ 386.2192. Found: 386.2171. Compound 3f: white solid; mp
208.6 °C; 1H NMR (CDCl3) d 1.89 (s, 3H) 3.40–3.49 (m, 2H) 3.55 (q, J = 5.87 Hz,
2H) 5.47 (s, 2H) 6.75 (br s, 1H) 6.88 (t, J = 4.87 Hz, 1H) 7.18 (s, 1H) 7.25 (t,
J = 7.36 Hz, 2H) 7.34 (d, J = 7.05 Hz, 2H) 8.51 (d, J = 4.77 Hz, 2H) 10.48 (t,
J = 5.39 Hz, 1H); 13C NMR (CDCl3) d 23.32 (CH3) 40.03 (CH2) 41.37 (CH2) 47.29
(CH2) 114.42 (CH) 126.84 (CH) 127.48 (CH) 128.33 (CH) 139.19 (C) 157.33 (CH)
157.55 (C) 159.80 (C) 170.88 (C); ESI-HRMS m/z calcd for C16H20N5O2 [MH]+
314.1617. Found: 314.1627. Compound 3g: white solid; mp 107.4 °C; 1H NMR
(CDCl3) d 3.38 (m, 8H) 5.10 (s, 2H) 6.73 (t, J = 4.87 Hz, 1H) 7.20–7.35 (m, 3H) 7.43
(d, J = 7.26 Hz, 2H) 8.42 (d, J = 4.77 Hz, 2H); 13C NMR (CDCl3) d 45.38 (CH2) 50.21
(CH2) 66.46 (CH2) 113.30 (CH) 127.67 (CH) 128.60 (CH) 128.98 (CH) 137.97 (C)
157.20 (C) 158.31 (CH) 160.69 (C); ESI-HRMS m/z calcd for C16H19N4O2 [MH]+
299.1508. Found: 299.1517. Compound 3h: white solid; mp 86.4 °C; 1H NMR
(CDCl3) d 2.12 (br s, 4H) 2.18 (s, 3H) 3.40 (br s, 4H) 5.09 (s, 2H) 6.72 (t,
J = 4.77 Hz, 1H) 7.21–7.27 (m, 1H) 7.31 (t, J = 7.26 Hz, 2H) 7.43 (d, J = 7.05 Hz,
2H) 8.41 (d, J = 4.77 Hz, 2H); 13C NMR (CDCl3) d 44.89 (CH2) 46.09 (CH3) 50.22
(CH2) 54.55 (CH2) 113.17 (CH) 127.53 (CH) 128.54 (C) 128.97 (CH) 138.10 (C)
157.14 (C) 158.26 (CH) 160.79 (C); ESI-HRMS m/z calcd for C17H22N5O [MH]+
312.1824. Found: 312.1836. Compound 3i: syrup; 1H NMR (CDCl3) d 0.93–1.20
(m, 12H) 3.41–3.75 (m, 2H) 4.94–5.17 (m, 2H) 6.67 (t, J = 4.77 Hz, 1H) 7.20–7.36
(m, 3H) 7.45 (d, J = 7.05 Hz, 2H) 8.38 (d, J = 4.77 Hz, 2H); 13C NMR (CDCl3) d
20.13 (CH + CH3) 49.95 (CH2) 112.65 (CH) 127.57 (CH) 128.52 (CH) 129.70 (CH)
138.04 (C) 156.31 (C) 158.12 (CH) 161.33 (C); ESI-HRMS m/z calcd for C18H25N4O
[MH]+ 313.2028. Found: 313.2046. Compound 3j: white solid; mp 162.1 °C; 1H
NMR (CDCl3) d 5.55 (s, 2H) 6.88 (t, J = 4.87 Hz, 1H) 7.07 (t, J = 7.46 Hz, 1H) 7.15–
7.22 (m, 1H) 7.22–7.29 (m, 2H) 7.32 (t, J = 7.88 Hz, 2H) 7.42 (d, J = 7.46 Hz, 2H)
7.61 (d, J = 7.46 Hz, 2H) 8.54 (d, J = 4.77 Hz, 2H) 12.63 (s, 1H); 13C NMR (CDCl3) d
47.13 (CH2) 114.42 (CH) 120.62 (CH) 123.71 (CH) 126.92 (CH) 127.87 (CH)
128.36 (CH) 129.10 (CH) 138.98 (C) 139.13 (C) 153.49 (C) 157.34 (CH) 159.76
(C); ESI-HRMS m/z calcd for C18H17N4O [MH]+ 305.1402. Found: 305.1397.
Compound 3k: white solid; mp 151.8 °C; 1H NMR (CDCl3) d 3.78 (s, 3H) 5.54 (s,
2H) 6.82–6.91 (m, 3H) 7.15–7.21 (m, 1H) 7.26 (t, J = 7.46 Hz, 2H) 7.42 (d,
J = 7.46 Hz, 2H) 7.50 (d, J = 8.71 Hz, 2H) 8.53 (d, J = 4.98 Hz, 2H) 12.42 (br s, 1H);
13C NMR (CDCl3) d 47.11 (CH2) 55.68 (CH3) 114.28 (2 ꢀ CH) 122.41 (CH) 126.88
(CH) 127.90 (CH) 128.33 (CH) 132.05 (C) 139.22 (C) 153.73 (C) 156.14 (C) 157.30
(CH) 159.78 (C); ESI-HRMS m/z calcd for C19H19N4O2 [MH]+ 335.1508. Found:
335.1497. Compound 3l: white solid; mp 196.2 °C; 1H NMR (CDCl3) d 5.55 (s, 2H)
7.00 (t, J = 4.87 Hz, 1H) 7.17–7.25 (m, 1H) 7.24–7.32 (m, 2H) 7.41 (d, J = 7.26 Hz,
2H) 7.60 (d, J = 8.71 Hz, 2H) 7.74 (d, J = 8.71 Hz, 2H) 8.61 (d, J = 4.77 Hz, 2H)
13.07 (s, 1H); 13C NMR (CDCl3) d 47.24 (CH2) 106.26 (C) 114.87 (CH) 119.36 (C)
120.18 (CH) 127.12 (CH) 127.82 (CH) 128.43 (CH) 133.34 (CH) 138.58 (C) 143.23
(C) 153.14 (C) 157.46 (CH) 159.52 (C); ESI-HRMS m/z calcd for C19H16N5O [MH]+
330.1355. Found: 330.1368.
8. General procedure: To a solution of 1 (100 mg, 0.54 mmol) and triethylamine
(0.18 ml, 1.30 mmol) in CH2Cl2 (3 ml)
a solution of triphosgene (64 mg,
0.216 mmol) in CH2Cl2 (1 ml) was added. The reaction mixture was stirred at
room temperature for 10 min and then the corresponding amines (0.864 mmol)
were added. After completion of the reaction (reaction times are shown in Table
1), the corresponding mixtures were diluted with CH2Cl2 (25 ml) and washed
with 10% NH4Cl aqueous solution. The organic layers were separated, dried
(Na2SO4), filtered and evaporated under vacuum. The residues thus obtained
were purified by Flash silica gel column chromatography (eluent CH2Cl2/MeOH
gradient from 100/0 to 98/2). The desired fractions were collected and
evaporated yielding the urea derivatives 3a–l. Compounds 3j–l were further
crystallized from CH3CN (3j,k) or MeOH (3l).
9. Analytical data: Melting points were determined in open capillary tubes on a
Mettler FP62 apparatus and are uncorrected. NMR spectra were recorded on a
Bruker DPX-400 with standard pulse sequences operating at 400 MHz for 1H
NMR and at 101 MHz for 13C NMR. Chemical shifts (d) are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS). High-resolution mass
spectra were recorded on a Micromass LCT Time of Flight mass spectrometer
configured with an electrospray ionization source, maintained at 140 °C, using
nitrogen as the nebulizer gas and Lockmass device for mass calibration using
Leucine-Enkephaline as standard substance. Spectra were acquired in positive
ionization mode by scanning from 100 to 750 in 0.5 s using a dwel time of 0.1 s.
The capillary needle voltage was 2.5 kV and the cone voltage was 20 V. Data
acquisition was performed with MassLynk-Openlynx software. Compound 3a:
white solid; mp 78.9 °C; 1H NMR (CDCl3) d 1.25 (t, J = 7.26 Hz, 3H) 3.38–3.50 (m,
2H) 5.47 (s, 2H) 6.82 (t, J = 4.77 Hz, 1H) 7.12–7.21 (m, 1H) 7.25 (t, J = 7.46 Hz,
2H) 7.38 (d, J = 7.67 Hz, 2H) 8.47 (d, J = 4.77 Hz, 2H) 10.13 (br s, 1H); 13C NMR
(CDCl3) d 15.39 (CH3) 35.77 (CH2) 47.14 (CH2) 113.91 (CH) 126.69 (CH) 127.78
(CH) 128.24 (CH) 139.61 (C) 156.02 (C) 157.18 (CH) 160.08 (C); ESI-HRMS m/z
calcd for C14H17N4O [MH]+ 257.1402. Found: 257.1413. Compound 3b: white
solid; mp 78.8 °C; 1H NMR (CDCl3) d 4.64 (d, J = 5.60 Hz, 2H) 5.50 (s, 2H) 6.81 (t,
J = 4.87 Hz, 1H) 7.14–7.21 (m, 1H) 7.22–7.29 (m, 3H) 7.29–7.43 (m, 6H) 8.45 (d,
J = 4.77 Hz, 2H) 10.53–10.71 (m, 1H); 13C NMR (CDCl3) d 44.94 (CH2) 47.33 (CH2)
114.09 (CH) 126.79 (CH) 127.26 (CH) 127.57 (CH) 127.81 (CH) 128.31 (CH)
128.75 (CH) 139.47 (2 ꢀ C) 156.34 (C) 157.27 (CH) 160.03 (C); ESI-HRMS m/z
calcd for C19H19N4O [MH]+ 319.1559. Found: 319.1571. Compound 3c: syrup; 1
H
NMR (CDCl3) d 3.45 (br s, 1H) 3.56 (q, J = 5.04 Hz, 2H) 3.78 (t, J = 4.98 Hz, 2H)
5.46 (s, 2H) 6.83 (t, J = 4.87 Hz, 1H) 7.17 (s, 1H) 7.25 (t, J = 7.57 Hz, 2H) 7.35 (d,
J = 7.46 Hz, 2H) 8.48 (d, J = 4.77 Hz, 2H) 10.47–10.56 (m, 1H); 13C NMR (CDCl3) d
43.80 (CH2) 47.33 (CH2) 63.13 (CH2) 114.30 (CH) 126.82 (CH) 127.67 (CH)
128.31 (CH) 139.25 (C) 157.32 (CH) 157.56 (C) 159.86 (C); ESI-HRMS m/z calcd
for C14H17N4O2 [MH]+ 273.1352. Found: 273.1358. Compound 3d: white solid;
mp 76.7 °C; 1H NMR (CDCl3) d 3.76 (s, 3H) 4.21 (d, J = 5.39 Hz, 2H) 5.47 (s, 2H)
6.85 (t, J = 4.87 Hz, 1H) 7.12–7.21 (m, 1H) 7.25 (t, J = 7.46 Hz, 2H) 7.37 (d,
J = 7.46 Hz, 2H) 8.51 (d, J = 4.77 Hz, 2H) 10.72 (t, J = 4.66 Hz, 1H); 13C NMR
(CDCl3) d 42.98 (CH2) 47.32 (CH2) 52.36 (CH3) 114.38 (CH) 126.81 (CH) 127.68
(CH) 128.30 (CH) 139.19 (C) 156.31 (C) 157.33 (CH) 159.84 (C) 171.19 (C);