Copper powder-catalyzed coupling and cyclization of 1-bromoallyl bromides with amidine hydrochlorides leading to pyrimidines

Article abstract of DOI:10.1080/00397911.2017.1287276

1-Bromoallyl bromides are coupled and cyclized with amidine hydrochlorides in DMF at 130 °C in the presence of a catalytic amount of copper powder along with K₃PO₄ to give pyrimidines in moderate to good yields.

Full text of DOI:10.1080/00397911.2017.1287276

Copper Powder-Catalyzed Coupling and Cyclization of 1-Bromoallyl Bromides with
Amidine Hydrochlorides Leading to Pyrimidines
Ha Kyeong Lee1, Ho-Sang Sohn2, Chan Sik Cho1
1Department of Applied Chemistry, Kyungpook National University, Daegu, South Korea
2Department of Materials Science and Metallurgical Engineering, Kyungpook National
University, Daegu, South Korea
Address correspondence to Chan Sik Cho, Department of Applied Chemistry, Kyungpook
National University, Daegu 702-701, South Korea E-mail: cscho@knu.ac.kr
Abstract
1-Bromoallyl bromides are coupled and cyclized with amidine hydrochlorides in DMF at
130 oC in the presence of a catalytic amount of copper powder along with K3PO4 to give
pyrimidines in moderate to good yields.
Graphical Abstract
KEYWORDS: Amidine hydrochlorides; 1-bromoallyl bromides; pyrimidines; C-N bond
formation; copper powder
1

INTRODUCTION
It is known that pyrimidines show a broad spectrum of biological activities such as
anticancer, antimalarial, antitumor, antiproliferative, sodium hydrogen exchanger-1
(NHE-1) inhibitor properties.[1-5] Thus, many pyrimidine-containing compounds have
been synthesized and tested for biological activity.[6] Among pyrimidine syntheses, in
connection with this report, Gogoi and Benbaruah have shown that -halo-
-
unsaturated aldehydes are coupled and cyclized with amidine hydrochlorides in the
presence of a palladium catalyst to give pyrimidines.[7] Such a similar coupling and
cyclization was also exemplified by the copper(I) iodide-catalyzed reaction of 2-
halobenzaldehydes and 2-halophenylketones with amidine hydrochlorides to give
quinazolines.[8,9] As part of our continuing studies on copper-catalyzed cyclization
reactions,[10-13] we also reported on copper powder-catalyzed synthesis of pyrimidine
scaffold from -bromo-
-unsaturated ketones and amidine hydrochlorides via such a
coupling and cyclization.[14] The present work arose during the course of the application
of such a coupling and cyclization protocol to the reaction with 1-bromoallyl bromides.
Herein this report describes a copper powder-catalyzed coupling and cyclization of 1-
bromoallyl bromides with amidine hydrochlorides leading to pyrimidines.[15]
2

RESULTS AND DISCUSSION
The results of several attempted coupling and cyclization of 1-bromo-2-
(bromomethyl)cyclohex-1-ene (1a) with benzamidine hydrochloride (2a) for the
optimization of reaction conditions are listed in Table 1. Treatment of 1a with 2
equivalents of 2a in DMF at 130 oC for 8 h in the presence of copper powder and K3PO4
gave the coupled and cyclized product 2-phenyl-5,6,7,8-tetrahydroquinazoline (3a) in
only 35% isolated yield with complete conversion of 1a, which was monitored until 1a
had disappeared on TLC (entry 1). However, performing the reaction by stepwise
procedure shown in experimental section afforded an increased yield of 3a with nearly no
formation of side products (entries 2 and 3). The molar ratio of [2a]/[1a] affected the
yield of 3a and the yield increased with the increase of the molar ratio up to 2 (entries 3
and 4). Higher molar ratio of [2a]/[1a] = 3 resulted in rather decreased yield of 3a along
with the formation of several unidentifiable products (entry 5). Among the bases
examined under the employed conditions, K3PO4 was shown to be the base of choice
(entries 2-4, 6-14). The reaction did not proceed at all without the addition of either
copper powder or base (entries 15 and 16). As a result, after further tuning with reaction
temperature and other copper salts (entries 10-13), the best result in terms of both product
3

yield and complete conversion of 1a was accomplished using the standard set of reaction
conditions shown in entry 3 of Table 1.
After the reaction conditions had been established, various 1-bromoallyl bromides 1,
which are readily available from the corresponding ketones, were treated with amidine
hydrochlorides 2 to investigate the scope of reaction and several representative results are
summarized in Table 2. The six-membered bromoallyl bromides 1b and 1c also reacted
with amidine hydrochloride 2a to give the corresponding pyrimidines 3b and 3c.
However, the product yield was lower than when 1a was subjected to the reaction with 2a.
With cyclic bromoallyl bromides 1d-f having various ring sizes, the corresponding
coupled and cyclized products 3d-f were also formed in 41-59% yields. To test for the
effect of the position of bromide and bromomethyl group on benzo-fused six-membered
bromoallyl bromides 1g and 1h were employed. Even though the coupling and
cyclization took place irrespective of the position, higher product yield was observed
with 1h. 3-Bromo-4-(bromomethyl)-1,2-dihydronaphthalene (1h) was also coupled and
cyclized with acetamidine hydrochloride (2b) to give 3-methyl-5,6-
dihydrobenzo[f]quinazoline (3i) in 54% yield. Similar treatment of 2-bromobenzyl
4

bromide (1i) with 2a under the employed conditions also afforded 2-phenylquinazoline
(3j) in 62 yield.
The reaction seems to proceed via an initial formation of intermediate 4 or 5 by N-
allylation or copper-catalyzed N-vinylation between 1 and 2. Subsequent ring closure of
both intermediates by such similar C-N bond formation produces dihydropyrimidine 6,
which triggers aromatization to give pyrimidine 3. It appears that the N-vinylation takes
place via a sequence such as oxidative addition of vinyl carbon-bromide bond to copper
powder to produce vinylcopper(II), vinylamidocopper(II) formation by ligand exchange,
and reductive elimination of vinylamidocopper(II). A similar catalytic pathway has
already been proposed in copper-catalyzed coupling and cyclization of o-
bromobenzylbromides with benzamidines.[15]
CONCLUSION
In summary, it has been shown that 1-bromoallyl bromides 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 starting from readily available ketones and amidine
5

hydrochlorides. Further study of synthetic applications to heterocycles starting from
ketones is in progress.
EXPERIMENTAL
1H and 13C NMR (500 and 125 MHz) spectra were recorded on a Bruker Avance III 500
spectrometer using TMS as an internal standard. Melting points were determined on a
Standford Research Inc. MPA100 automated melting point apparatus. The isolation of
pure products was carried out via thin layer (silica gel 60 GF254, Merck) chromatography.
All known 1-bromoallyl bromides 1 were prepared by the reported method.[16-19] Copper
powder (100 mesh, 99.5%) was purchased from Strem. Commercially available organic
and inorganic compounds were used without further purification.
General Procedure (Taking The Synthesis Of 3b As An Example)
To a stirred DMF (2 mL) solution of 2a (0.094 g, 0.6 mmol) and K3PO4 (0.191 g, 0.9
mmol) in a 5 mL screw-capped vial (Wheaton) was added dropwise DMF (2 mL)
solution of 1b (0.080 g, 0.3 mmol) over 20 min and the resulting mixture was allowed to
react at 80 oC for 1 h. After charging with Cu powder (0.002 g, 0.03 mmol), the reaction
mixture was heated to react at 130 oC for 8 h. The reaction mixture was cooled down to
6

room temperature and filtered through a short silica gel column (ethyl acetate) to
eliminate inorganic salts. Removal of the solvent left a crude mixture, which was
separated by thin-layer chromatography (silica gel, ethyl acetate-hexane mixture) to give
pyrimidine 3b.
6-Methyl-2-Phenyl-5,6,7,8-Tetrahydroquinazoline (3b)
Yield (28 mg, 42%). Solid. mp 89-90 oC (hexane-chloroform). Rf = 0.39 (hexane-EA
10:1). 1H NMR (500 MHz, CDCl3) δ 1.05 (d, J = 6.6 Hz, 3H), 1.43-1.51 (m, 1H), 1.81-
1.90 (m, 1H), 1.92-1.97 (m, 1H), 2.28-2.34 (m, 1H), 2.74-2.98 (m, 3H), 7.36-7.41 (m,
3H), 8.29-8.31 (m, 2H), 8.37 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7, 28.8, 30.7,
32.0, 34.1, 127.6, 128.1, 128.7, 130.3, 138.3, 157.3, 162.4, 166.1. Anal Calcd for
C15H16N2: C 80.32; H 7.19; N 12.49. Found: C 80.11; H 7.10; N 12.59. HRMS (EI) Anal
Calcd for C15H16N2 (M+): 224.1313. Found: 224.1315.
FUNDING
This research was supported by Research Assistant (HK Lee) Program of Kyungpook
National University.
7

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9

Table 1. Optimization of conditions for the reaction of 1a with 2aa.
Entry Cu catalyst [2a]/[1a] Base
Temp (oC) Time (h)b Yield (%)
1c
2
Cu powder 2.0
Cu powder 2.0
Cu powder 2.0
Cu powder 1.0
Cu powder 3.0
Cu powder 2.0
Cu powder 2.0
Cu powder 1.0
Cu powder 2.0
Cu powder 2.0
Cu powder 1.0
Cu powder 2.0
Cu powder 2.0
Cu powder 1.0
Cu powder 2.0
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
130
130
130
130
130
8
4
8
8
8
8
4
8
8
4
8
8
4
8
8
8
20
8
35
51
63
42
35
44
25
31
41
22
34
5
3
4
5
6
NaOtBu 130
NaOtBu 130
NaOtBu 130
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
-
130
130
130
130
130
130
130
130
100
130
10
11
12
13
14
15
16d
17
18
5
4
0
-
2.0
Cu powder 2.0
CuI 2.0
K3PO4
K3PO4
K3PO4
0
24
24
10

19
20
CuCl
CuO
2.0
2.0
K3PO4
K3PO4
130
130
8
8
53
50
aExcept as noted, all reactions were carried out by stepwise procedure as shown in
Experimental section.
bReaction time after charging with Cu powder.
cA 5 mL screw-capped vial was charged with all reagents and the reaction mixture was
stirred at 130 oC for 8 h.
dIn the absence of Cu powder.
11

Table 2. Cu powder-catalyzed synthesis of pyrimidines 3 from 1-bromoallyl bromides 1
and amidine hydrochlorides 2a
1-Bromoallyl bromides 1 Amidine hydrochlorides 2 Pyrimidines 3
Yield (%)
63
2a
42
42
47
59
41
2a
2a
2a
2a
2a
24
79
2a
2a
12

54
62
2b
2a
3i
a All reactions were carried out with 1 (0.3 mmol), 2 (0.6 mmol), Cu powder (0.03 mmol),
K3PO4 (0.9 mmol) and DMF (4 ML) at 130 C for 8 h.
13

Scheme 1. Reaction pathway.
14