Copper-powder-catalyzed synthesis of pyrimidines from β-bromo α,β-unsaturated ketones and amidine hydrochlorides

Article abstract of DOI:10.1055/s-0034-1380410

Abstract β-Bromo α,β-unsaturated ketones are coupled and cyclized with amidine hydrochlorides in the presence of a catalytic amount of copper powder along with a base to give the corresponding pyrimidines in good yields.

Full text of DOI:10.1055/s-0034-1380410

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1081–1084
letter
1081
Y. Jiao et al.
Letter
Synlett
Copper-Powder-Catalyzed Synthesis of Pyrimidines from β-Bro-
mo α,β-Unsaturated Ketones and Amidine Hydrochlorides
Yang Jiao
R
O
Son Long Ho
Chan Sik Cho*
Cu powder
HN
NH2
N
R
+
•HCl
K3PO4, DMF
110 °C, 24 h
N
R'
R'
Br
Department of Applied Chemistry, Kyungpook National University,
Daegu 702-701, Republic of Korea
23–77%
cscho@knu.ac.kr
Received: 14.12.2014
Accepted after revision: 29.01.2015
Published online: 20.02.2015
from α-methylene-group-containing ketones by bromina-
tion under Vilsmeier–Haack conditions,12 and the products
can serve as valuable building blocks for the construction of
various cyclic compounds.13 Among such cyclization reac-
tions, we have shown that β-bromo α,β-unsaturated ke-
tones are carbonylatively cyclized to (Z)-alkylidenefura-
nones under carbon monoxide pressure in the presence of a
palladium catalyst.14 It was also demonstrated that β-bro-
mo α,β-unsaturated ketones are coupled and cyclized with
arylhydrazines to give 3-substituted 1-aryl-1H-pyrazoles in
the presence of a palladium catalyst.15 Under these circum-
stances, with an effort to develop another heterocyclic com-
pounds using β-bromo α,β-unsaturated ketones, herein we
describe a promising route for the synthesis of pyrimidines
by copper-powder-catalyzed coupling and cyclization of β-
bromo α,β-unsaturated ketones with amidine hydrochlo-
rides.
The results of several attempted coupling and cycliza-
tion of 1-(2-bromocyclohex-1-enyl)hexan-1-one (1a) with
benzamidine hydrochloride (2a) for the optimization of re-
action conditions are listed in Table 1. It is known by Lin et
al. that β-bromo α,β-unsaturated aldehydes react with ami-
dine hydrochlorides in the presence of a base to give pyrim-
idines.16 However, similar treatment of β-bromo α,β-unsat-
urated ketone 1a with 2a did not afford 4-pentyl-2-phenyl-
5,6,7,8-tetrahydroquinazoline (3a) at all (Table 1, entry 1).
No additional activity for the formation of 3a was observed
with copper(I) iodide along with cesium carbonate, and the
starting 1a was recovered intact (Table 1, entry 2). Further
addition of L-proline as ligand produced 3a in 51% isolated
yield (Table 1, entry 3). Surprisingly, when the reaction was
performed in the presence of copper powder without fur-
ther addition of a ligand, 3a was formed in 66% yield with
the complete conversion of 1a (Table 1, entry 4). The yield
of 3a was affected by the molar ratio of 2a to 1a, a higher
molar ratio [2a]/[1a] = 1.5, resulting in a slightly increased
DOI: 10.1055/s-0034-1380410; Art ID: st-2014-u1029-l
Abstract β-Bromo α,β-unsaturated ketones are coupled and cyclized
with amidine hydrochlorides in the presence of a catalytic amount of
copper powder along with a base to give the corresponding pyrimidines
in good yields.
Key words copper, coupling, cyclization, heterocycles, hetero-
geneous catalysis
It is known that pyrimidine plays an important role as a
basic scaffold in the design of compounds exhibiting a wide
spectrum of biological activities, such as anticancer,1 anti-
malarial,2 antitumor,3 antiproliferative,4 sodium hydrogen
exchanger-1 (NHE-1) inhibitor properties.5 Thus, many
pyrimidine-containing compounds have been synthesized
and tested for biological activity.6,7 In connection with this
report, Truong et al. reported that 2-iodobenzaldehydes re-
act with amidine hydrochlorides in the presence of cop-
per(I) iodide to afford quinazolines via condensation and C–
N coupling.8 Fu and Jiang have shown that 2-bromophenyl-
ketones as well as 2-bromobenzaldehydes react with ami-
dine hydrochlorides in the presence of copper(I) iodide and
L-proline to give quinazolines.9 Such a similar coupling and
condensation was also exemplified by the palladium-cata-
lyzed reaction of β-halo α,β-unsaturated aldehydes with
amidine hydrochlorides to give pyrimidines.10 However, no
reports for the reaction of β-halo α,β-unsaturated ketones
with amidine hydrochlorides were observed.
During the course of our continuing studies directed to-
wards transition-metal-catalyzed cyclization reactions of
β-bromo α,β-unsaturated aldehydes and their derivatives,
we have identified several new methods for the synthesis of
carbo- and heterocyclic compounds.11 β-Bromo α,β-unsatu-
rated aldehydes and their derivatives are readily prepared
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1081–1084

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Y. Jiao et al.
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formation of 3a (Table 1, entry 5). Among the bases exam-
ined under the employed conditions, tripotassium phos-
phate was shown to be the base of choice and cesium car-
bonate exhibited nearly the same activity as tripotassium
phosphate (Table 1, entries 5–9). On the other hand, many
reactions have been carried out with microwave irradiation
to speed up the reaction rate and to obtain an acceptable
yield of product in minutes.17 When 1a was treated with 2a
in N,N-dimethylformamide at 150 °C for 30 minutes in the
presence of copper powder and tripotassium phosphate
under microwave irradiation (100 W initial power), 3a was
formed in 54% yield with 86% conversion of 1a (Table 1, en-
try 10). However, the isolation of 3a from crude mixture
met with failure since 1a and 3a are exactly same Rf value
on TLC under various eluents. The molar distribution of the
mixture of 1a and 3a was calculated from the intensity of
the clearly separated protons in the 1H NMR spectrum. As a
result, the best result in terms of both product yield and
complete conversion of 1a was accomplished by the stan-
dard set of reaction conditions shown in entry 5 of Table
1.18
coupling and cyclization of 1a with acetamidine hydrochlo-
ride (2b) also proceeded to give the corresponding pyrimi-
dine 3b in good yield. With other easily available cyclic β-
bromo α,β-unsaturated ketones 1b and 1c, it was possible
to introduce substituents such as isopropyl and phenyl at
position 4 of pyrimidines 3c–f under the employed condi-
tions. Methyl-substituted six-membered β-bromo α,β-un-
saturated ketone 1d was also coupled and cyclized with 2b
to give the corresponding pyrimidine 3g in similar yield.
With cyclic β-bromo α,β-unsaturated ketones 1e–h having
various ring sizes, the corresponding coupled and cyclized
pyrimidines 3h–k were also invariably formed irrespective
of ring sizes on 1e–h. Similar treatment of acyclic β-bromo
α,β-unsaturated ketones 1i and 1j with 2 under the em-
ployed conditions also afforded the coupled and cyclized
products 3l and 3m, however, though not yet understood,
the yield was lower than that when previously described
cyclic β-bromo α,β-unsaturated ketones were used.
Table 2 Copper-Powder-Catalyzed Synthesis of Pyrimidines 3 from β-
Bromo-α,β-Unsaturated Ketones 1 and Amidines 2a
R1
O
Table 1 Optimization of Conditions for the Reaction of 1a with 2a
Cu powder
HN
NH2
R1
N
+
•HCl
O
R2
K3PO4, DMF
110 °C, 24 h
N
R2
Br
HN
NH2
•HCl
N
2a R2 = Ph
2b R2 = Me
3
+
1
Ph
N
Ph
Br
1a
3a
2a
Ketone
Product
Yield
(%)
Entrya
[2a]/[1a]
Catalyst
Base
Solvent
Yield (%)
O
1b
2c
3c,d
4
1.1
1.1
1.1
1.1
1.5
1.5
1.5
1.5
1.5
1.1
–
Et3N
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0
0
CuI
CuI
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cs2CO3
Cs2CO3
K3PO4
K3PO4
K2CO3
NaOt-Bu
Cs2CO3
NaOAc
K3PO4
N
51
66
76
19
38
73
13
54
N
3a R2 = Ph
3b R2 = Me
R2
Br
1a
76
69
5
6
O
7
8
N
9
N
3c R2 = Ph
3d R2 = Me
R2
Br
10e
1b
68
56
a Reaction conditions: 1a (0.5 mmol), copper catalyst (0.05 mmol), base
(1.5 mmol), solvent (3 mL), 110 °C, 24 h, unless otherwise stated.
b Et3N (0.75 mL), 1,4-dioxane (5 mL), 5 h.
Ph
O
c 20 h
d
L-Proline (0.1 mmol) was added as ligand.
e Reaction conditions: 150 °C, 30 min, microwave irradiation (100 W initial
power).
N
Ph
N
R2
Br
1c
3e R2 = Ph
3f R2 = Me
77
47
After the reaction conditions had been optimized, vari-
ous known β-bromo α,β-unsaturated ketones 1 were sub-
jected to the reaction with amidine hydrochlorides 2 in or-
der to investigate the reaction scope, and several represen-
tative results are summarized in Table 2.12,14,15,19–21 The
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1081–1084

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Table 2 (continued)
Ketone
ing from readily available ketones and amidine hydrochlo-
rides.22 Further study of synthetic applications to heterocy-
cles starting from ketones is in progress.
Product
Yield
(%)
O
Acknowledgment
N
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science and Technology (2010-0007563).
Br
N
1d
3g
57
70
67
60
O
References and Notes
N
(1) Xie, F.; Zhao, H.; Zhao, L.; Lou, L.; Hu, Y. Bioorg. Med. Chem. Lett.
2009, 19, 275.
(2) Joffe, A. M.; Farley, J. D.; Linden, D.; Goldsand, G. Am J. Med.
1989, 87, 332.
(3) Xie, F.; Li, S.; Bai, D.; Lou, L.; Hu, Y. J. Comb. Chem. 2007, 9, 12.
(4) Wang, S.; Wood, G.; Meades, C.; Griffiths, G.; Midgley, C.;
McNae, I.; McInnes, C.; Anderson, S.; Jackson, W.; Mezna, M.;
Yuill, R.; Walkinshaw, M.; Fisher, P. M. Bioorg. Med. Chem. Lett.
2004, 14, 4237.
(5) Atwal, K. S.; O’Neil, S. V.; Ahmad, S.; Doweyko, L.; Kirby, M.;
Dorso, C. R.; Chandrasena, G.; Chen, B.-C.; Zhao, R.; Zahler, R.
Bioorg. Med. Chem. Lett. 2006, 16, 4796.
(6) Lagoja, I. M. Chemistry & Biodiversity 2005, 2, 1.
(7) Undheim, K.; Benneche, T. In Comprehensive Heterocyclic Chem-
istry II; Vol. 6; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 93.
(8) Truong, V. L.; Morrow, M. Tetrahedron Lett. 2010, 51, 758.
(9) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun. 2008,
6333.
Br
N
Me
1e
3h
O
N
Br
N
1f
3i
O
N
Br
N
1g
3j
O
(10) Gogoi, J.; Gogoi, P.; Benbaruah, P.; Boruah, R. C. Tetrahedron Lett.
2013, 54, 7136.
N
Br
(11) (a) Cho, C. S.; Patel, D. B.; Shim, S. C. Tetrahedron 2005, 61, 9490.
(b) Cho, C. S.; Shim, H. S. Tetrahedron Lett. 2006, 47, 3835.
(c) Cho, C. S.; Patel, D. B. Tetrahedron 2006, 62, 6388. (d) Cho, C.
S.; Kim, J. U.; Choi, H.-J. J. Organomet. Chem. 2008, 693, 3677.
(e) Cho, C. S.; Kim, H. B.; Lee, S. Y. J. Organomet. Chem. 2010, 695,
1744. (f) Cho, C. S.; Kim, H. B. J. Organomet. Chem. 2011, 696,
3264. (g) Bae, Y. K.; Cho, C. S. Synlett 2013, 24, 1848. (h) Ho, S. L.;
Cho, C. S. Synlett 2013, 24, 2705. (i) Bae, Y. K.; Cho, C. S. Appl.
Organomet. Chem. 2014, 28, 225.
(12) (a) Arnols, Z.; Holly, A. Collect. Czech. Chem. Commun. 1961, 26,
3059. (b) Coates, R. M.; Senter, P. D.; Baker, W. R. J. Org. Chem.
1982, 47, 3597.
(13) (a) Brahma, S.; Ray, J. K. Tetrahedron 2008, 64, 2883. (b) Jana, R.;
Chatterjee, I.; Samanta, S.; Ray, J. K. Org. Lett. 2008, 10, 4795.
N
1h
3k
60
23
35
O
N
Ph
Br
O
Ph
N
Ph
1i
3l
Ph
Ph
N
Ph
Br
Ph
N
(c) Karthikeyan,
P.;
Meena Rani,
A.;
Saiganesh,
R.;
Balasubramanian, K. K.; Kabilan, S. Tetrahedron 2009, 65, 811.
(d) Samanta, S.; Jana, R.; Ray, J. K. Tetrahedron Lett. 2009, 50,
6751. (e) Nandi, S.; Ray, J. K. Tetrahedron Lett. 2009, 50, 6993.
(f) Jana, R.; Paul, S.; Biswas, A.; Ray, J. K. Tetrahedron Lett. 2010,
51, 273. (g) Samanta, S.; Yasmin, N.; Kundu, D.; Ray, J. K. Tetrahe-
dron Lett. 2010, 51, 4132. (h) Yasmin, N.; Ray, J. K. Synlett 2010,
924. (i) Paul, S.; Gorai, T.; Koley, A.; Ray, J. K. Tetrahedron Lett.
2011, 52, 4051.
1j
3m
a Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), copper powder (0.05
mmol), K3PO4 (1.5 mmol), DMF (3 mL), 110 °C, 24 h.
In summary, it has been shown that β-bromo α,β-unsat-
urated ketones react with amidine hydrochlorides in the
presence of copper powder along with a base to give the
corresponding pyrimidines. The present reaction provides a
new method for synthesizing the pyrimidine scaffold start-
(14) Cho, C. S.; Kim, H. B. Catal. Lett. 2010, 140, 116.
(15) Lee, H. K.; Cho, C. S. Appl. Organomet. Chem. 2012, 26, 570.
(16) Yan, S.; Tang, Y.; Yu, F.; Lin, J. Helv. Chim. Acta 2011, 94, 487.
(17) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave
Synthesis for Organic Chemists; Wiley-VCH: Weinheim, 2009.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1081–1084

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(18) Performing the reaction on a larger scale (6 times) resulted in a
slightly decreased yield of 3a (71%).
(19) (a) Murai, M.; Yoshida, S.; Miki, K.; Ohe, K. Chem. Commun.
2010, 46, 3366. (b) Ryan, S. J.; Candish, L.; Martínez, I.; Lupton,
D. W. Aust. J. Chem. 2011, 64, 1148.
(m, 2 H), 2.62 (s, 3 H), 2.76–2.89 (m, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 14.11, 21.86, 22.64, 25.76, 28.18, 28.97, 30.42, 32.09,
32.22, 32.88, 34.55, 123.80, 164.07, 164.69, 168.64. HRMS (EI):
m/z [M+] calcd for C15H24N2: 232.1939; found: 232.1941.
2-Methyl-4-pentyl-6,7-dihydro-5H-cyclopenta[d]pyrimi-
dine (3h)
(20) Luo, Y.; Herndon, J. W. Organometallics 2005, 24, 3099.
(21) Pyrimidines 3 – General Procedure
Oil; yield 72 mg (70%). 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J =
7.0 Hz, 3 H), 1.33–1.37 (m, 4 H), 1.66–1.69 (m, 2 H), 2.08–2.14
(m, 2 H), 2.64 (t, J = 8.0 Hz, 2 H), 2.67 (s, 3 H), 2.89 (t, J = 7.5 Hz,
2 H), 2.96 (t, J = 8.0 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ =
14.14, 22.12, 22.67, 25.91, 28.17, 28.26, 31.96, 34.31, 35.86,
129.26, 165.52, 166.07, 174.25. Anal. Calcd for C13H20N2: C,
76.42; H, 9.87; N, 13.71. Found: C, 76.28; H, 9.80; N, 13.75.
2-Methyl-4-pentyl-6,7,8,9-tetrahydro-5H-cyclo-
To a 5 mL screw-capped vial was added β-bromo α,β-unsatu-
rated ketone 1 (0.5 mmol) and amidine hydrochloride 2 (0.75
mmol), together with copper powder (Shinyo Pure Chemicals
Co., 0.05 mmol), K3PO4 (1.5 mmol), and DMF (3 mL). The reac-
tion mixture was stirred at 110 °C for 24 h. The mixture was
then cooled to r.t. and filtered through a short column of silica
gel (EtOAc) to remove inorganic salts. Removal of the solvent
left a crude mixture, which was separated by TLC [silica gel 60
GF254 (Merck), EtOAc–hexane] to give desired products. Except
for known 3e23 and 3l,24 all new products were characterized
spectroscopically as shown below.
hepta[d]pyrimidine (3i)
Oil; yield 78 mg (67%). 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J =
7.0 Hz, 3 H), 1.31–1.42 (m, 4 H), 1.57–1.71 (m, 6 H), 1.84–1.90
(m, 2 H), 2.62 (s, 3 H), 2.72–2.79 (m, 4 H), 2.92–2.95 (m, 2 H). 13
C
4-Pentyl-2-phenyl-5,6,7,8-tetrahydroquinazoline (3a)
Oil; yield 107 mg (76%). 1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J
= 7.1 Hz, 3 H), 1.34–1.45 (m, 4 H), 1.76–1.91 (m, 6 H), 2.69–2.74
(m, 4 H), 2.90–2.93 (m, 2 H), 7.39–7.47 (m, 3 H), 8.38–8.41 (m, 2
H). 13C NMR (100 MHz, CDCl3): δ = 14.28, 22.51, 22.80, 22.86,
24.71, 27.51, 32.06, 32.91, 34.34, 128.08, 128.54, 129.89,
138.77, 161.19, 165.16, 168.71. HRMS (EI): m/z [M+] calcd for
NMR (100 MHz, CDCl3): δ = 14.12, 22.65, 25.79, 26.00, 27.43,
27.77, 29.42, 32.05, 32.34, 35.72, 38.78, 129.66, 164.08, 166.87,
171.16. HRMS (EI): m/z [M+] calcd for C15H24N2: 232.1939;
found: 232.1940.
2-Methyl-4-pentyl-5,6,7,8,9,10-hexahydrocy-
cloocta[d]pyrimidine (3j)
Oil; yield 74 mg (60%). 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J =
7.1 Hz, 3 H), 1.33–1.47 (m, 8 H), 1.63–1.73 (m, 4 H), 1.76–1.82
(m, 2 H), 2.64 (s, 3 H), 2.68–2.72 (m, 2 H), 2.78–2.81 (m, 2 H),
2.86–2.89 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.18, 22.73,
25.53, 25.91, 25.94, 26.47, 29.54, 30.39, 30.50, 32.23, 34.90,
35.10, 127.16, 164.74, 167.83, 169.37. HRMS (EI): m/z [M+]
calcd for C16H26N2: 246.2096; found: 246.2095.
C19H24N2: 280.1939; found: 280.1941.
2-Methyl-4-pentyl-5,6,7,8-tetrahydroquinazoline (3b)
Oil; yield 75 mg (69%). 1H NMR (400 MHz, CDCl3): δ = 0.89–0.92
(m, 3 H), 1.33–1.41 (m, 4 H), 1.61–1.68 (m, 2 H), 1.80–1.88 (m, 4
H), 2.60–2.68 (m, 4 H), 2.62 (s, 3 H), 2.80–2.83 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 14.14, 22.37, 22.67, 22.75, 24.41, 25.81,
28.21, 32.14, 32.53, 34.58, 124.23, 164.08, 164.96, 168.75.
HRMS (EI): m/z [M+] calcd for C14H22N2: 218.1783; found:
218.1782.
4-Isopropyl-2-phenyl-5,6,7,8-tetrahydroquinazoline (3c)
Solid; yield 86 mg (68%); mp 82–83 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.30 (d, J = 6.5 Hz, 6 H), 1.83–1.89 (m, 4 H), 2.72–
2.74 (m, 2 H), 2.90–2.92 (m, 2 H), 3.19 (sept, J = 6.5 Hz, 1 H),
7.38–7.46 (m, 3 H), 8.44–8.46 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 21.32, 22.42, 22.90, 24.32, 30.71, 33.02, 124.47,
128.07, 128.44, 129.86, 138.88, 161.13, 165.27, 172.71. HRMS
(EI): m/z [M+] calcd for C17H20N2: 252.1626; found: 252.1624.
4-Isopropyl-2-methyl-5,6,7,8-tetrahydroquinazoline (3d)
Oil; yield 53 mg (56%). 1H NMR (400 MHz, CDCl3): δ = 1.22 (d, J =
6.5 Hz, 6 H), 1.82–1.85 (m, 4 H), 2.62 (s, 3 H), 2.67–2.69 (m, 2 H),
2.80–2.82 (m, 2 H), 3.14 (quint, J = 6.5 Hz, 1 H). 13C NMR (100
MHz, CDCl3): δ = 21.21, 22.38, 22.92, 24.17, 26.02, 30.43, 32.75,
123.23, 164.39, 164.83, 172.89. HRMS (EI): m/z [M+] calcd for
2-Methyl-4-pentyl-5,6,7,8,9,10,11,12,13,14-decahydrocyclo-
dodeca[d]pyrimidine (3k)
Oil; yield 91 mg (60%). 1H NMR (400 MHz, CDCl3): δ = 0.91 (m, J
= 7.1 Hz, 3 H), 1.31–1.72 (m, 20 H), 1.81–1.88 (m, 2 H), 2.62 (s, 3
H), 2.66–2.76 (m, 6 H). 13C NMR (100 MHz, CDCl3): δ = 14.18,
22.48, 22.75, 23.12, 25.21, 25.88, 26.04, 26.57, 26.90, 27.42,
27.83, 28.57, 29.62, 32.23, 32.26, 35.01, 127.49, 164.22, 168.80,
169.20. HRMS (EI): m/z [M+] calcd for C20H34N2: 302.2722;
found: 302.2719.
2-Methyl-4-pentyl-5,6-diphenylpyrimidine (3m)
Solid; yield 55 mg (35%); mp 62–64 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.70–0.74 (m, 3 H), 1.09–1.14 (m, 4 H), 1.49–1.57
(m, 2 H), 2.51–2.55 (m, 2 H), 2.74 (s, 3 H), 7.00–7.02 (m, 2 H),
7.08–7.14 (m, 3 H), 7.19–7.24 (m, 5 H). 13C NMR (100 MHz,
CDCl3): δ = 14.07, 22.45, 26.36, 29.25, 31.93, 35.71, 127.62,
127.97, 128.53, 128.63, 129.37, 129.78, 130.48, 136.74, 138.76,
164.17, 166.47, 169.65. HRMS (EI): m/z [M+] calcd for C22H24N2:
316.1939; found: 316.1938.
C12H18N2: 190.1470; found: 190.1467.
2-Methyl-4-phenyl-5,6,7,8-tetrahydroquinazoline (3f)
Oil; yield 53 mg (47%). 1H NMR (400 MHz, CDCl3): δ = 1.71–1.76
(m, 2 H), 1.89–1.94 (m, 2 H), 2.67–2.69 (m, 2 H), 2.71 (s, 3 H),
2.91–2.94 (m, 2 H), 7.40–7.46 (m, 3 H), 7.50–7.52 (m, 2 H). 13C
NMR (100 MHz, CDCl3): δ = 22.51, 22.93, 25.91, 26.66, 32.58,
124.43, 128.43, 128.75, 129.00, 138.53, 164.57, 165.48, 166.46.
HRMS (EI): m/z [M+] calcd for C15H16N2: 224.1313; found:
224.1311.
2,6-Dimethyl-4-pentyl-5,6,7,8-tetrahydroquinazoline (3g)
Oil; yield 66 mg (57%). 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J =
7.1 Hz, 3 H), 1.12 (d, J = 6.6 Hz, 3 H), 1.31–1.50 (m, 5 H), 1.61–
1.69 (m, 2 H), 1.82–1.97 (m, 2 H), 2.17–2.25 (m, 1 H), 2.61–2.66
(22) A reviewer suggested that the present reaction might be toler-
ant of several functional groups such as hydroxy, amino, and
ester. However, it is difficult to examine such functional-group
compatibility at present since the synthetic course of the start-
ing 1 uses Grignard reagents as a step. Thus, further application
of this method to the synthesis of such functional-group-con-
taining pyrimidines needs more elaborate plans.
(23) Herrera, A.; Martínez-Álvarez, R.; Chioua, M.; Sánchez, Á.;
Molero, D.; Chioua, R. Magn. Reson. Chem. 2002, 40, 293.
(24) Herrera, A.; Martínez-Álvarez, R.; Chioua, M.; Chioua, R.;
Sánchez, Á. Tetrahedron 2002, 58, 10053.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1081–1084

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