Easy and efficient copper-catalyzed synthesis of bicyclic pyrimidinones under mild conditions

Article abstract of DOI:10.1055/s-0030-1258803

A simple and efficient copper-catalyzed method has been developed for synthesis of bicyclic pyrimidinones containing six-, seven-, eight-membered rings under mild conditions. The protocol uses readily available 2-bromocycloalk-1-enecarboxylic acids, amidines, and guanidines as the starting materials, copper-catalyzed cascade couplings provide the corresponding bicyclic pyrimidinones without addition of any ligand or additive, and the method is of economical and practical advantages. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258803

LETTER
2611
Easy and Efficient Copper-Catalyzed Synthesis of Bicyclic Pyrimidinones
under Mild Conditions
S
ynthesis of Bicyc
i
lic Pyrimidin
G
ones uo,a Haijun Yang,a Hongxia Liu,b Yuyang Jiang,b Hua Fu*a
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
b
Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Received 22 July 2010
medicinal activities.1 Therefore, it is very desirable to de-
velop readily preparation of pyrimidinone derivatives.
Abstract: A simple and efficient copper-catalyzed method has
been developed for synthesis of bicyclic pyrimidinones containing
six-, seven-, eight-membered rings under mild conditions. The pro-
tocol uses readily available 2-bromocycloalk-1-enecarboxylic ac-
ids, amidines, and guanidines as the starting materials, copper-
catalyzed cascade couplings provide the corresponding bicyclic
pyrimidinones without addition of any ligand or additive, and the
method is of economical and practical advantages.
There are several known preparative routes to pyrimidone
dervatives.9–11 For example, de Meijere and co-workers
have developed an approach to such compounds by way
of Michael addition of amidines to methyl 2-chloro-2-
cyclopropylideneacetate,12a with ring-enlarging rear-
rangement to yield cyclobutene-annelated pyrimidinones,
which subsequently undergo thermal cyclobutene ring
opening followed by Diels–Alder reaction.12b Thermal
cyclobutene ring opening of the latter at 175 °C followed
by regioselective Diels–Alder cycloaddition with phenyl
vinyl sulfone gives the 2-aryl-6-(phenylsulfonyl)-5,6,7,8-
tetrahydroquinazolinone derivatives.12c However, the
substrate scope is very limited for the construction of
bicyclic pyrimidinones by the above method. The wide
applications of bicyclic pyrimidinone derivatives as bio-
logical and medicinal active molecules have stimulated
our research into the development of new strategy for
their synthesis. Recently, copper-catalyzed Ullmann N-
Key words: copper, cascade reaction, bicyclic pyrimidinone, nitro-
gen heterocycle, synthetic method
The pyrimidinones and their derivatives are ubiquitous in
natural products, pharmaceuticals, and functional materi-
als.1 For example, research at Merck has led to the identi-
fication of raltegravir potassium (A in Figure 1),2 a potent
and well-tolerated HIV-1 integrase inhibitor that targets
strand transfer, the second of two catalytic cycles mediat-
ed by the integrase enzyme.3 Bicyclic pyrimidones have
been identified as potent HIV integrase inhibitors en-
dowed with desirable preclinical features, and amongst
them hexahydropyrimido[1,2-a]azepine-2-carboxamide
derivative proved particularly interesting.4 Very recently,
Muraglia and co-workers have developed a new kind of
bicyclic pyrimidinones as potent and orally bioavailable
HIV-1 integrase inhibitors (IC50 = 12 nM for compound B
in Figure 1).5 5,8-Dideaza-5,6,7,8-tetrahydrofolic acid (C
in Figure 1) and 2-substituted tetrahydroquinazolinones
have attracted considerable attention in chemistry6 and bi-
ology.7 A wide range of biological activities have been
discovered for such compounds, such as anticancer activ-
ity, antimicrobial activity against Streptococcus faecium,
inhibition of dihydrofolate reductase and thymidilate syn-
thase,8 as well as an ability to be good substrates for par-
tially purified mouse liver folylpolyglutamate
synthetase.9 Compound D in Figure 1 was found to be a
highly potent inhibitor of poly(ADP-ribose) polymerase-
1 (PARP-1).10 On the other hand, the substituted 4(3H)-
pyrimidinones are the key intermediates to the preparation
of the bioactive pyrimidines that are of wide biological or
O
Me
O–K+
F
N
O
N
N
H
H
N
N
N
O
O
A
O
OH
F
N
H
N
N
O
N
Me
O
B
Me
N
O
Me
NH
N
NH2
H
N
O
O
C
HN
HO
OH
O
N
O
NH
O
N
D
SYNLETT 2010, No. 17, pp 2611–2616
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258803; Art ID: W11510ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Examples of biologically or medicinally active pyrimi-
dones

2612
Q. Guo et al.
LETTER
arylations have made great progress,13 and the N-arylation
strategy has been used to make N-heterocycles.14 Unfor-
tunately, these methods sometimes cannot be used to con-
struct functionalized molecules because the reaction
temperature is still too high, so it is highly desirable to de-
velop milder copper-catalyzed methods. Recently, we15
and other groups16 have developed copper-catalyzed N-
arylations at room temperature, and the results showed
that efficiency of the copper-catalyzed coupling reactions
highly depended on the involvement of the suitable
ligands. In continuation of our endeavors to develop cop-
per-catalyzed cross-couplings17 and synthesis of N-het-
erocycles,18 herein, we report an easy and efficient
copper-catalyzed synthesis of bicyclic pyrimidinones
without addition of any ligand or additive under mild con-
ditions.
Table 1 Copper-Catalyzed Synthesis of 2-Propyl-5,6,7,8-tetrahyd-
roquinazolin-4(3H)-one via Cascade Coupling of 2-Bromocyclohex-
1-enecarboxylic Acid with Butyramidine Hydrochloridea
O
COOH
Br
HN
NH2⋅HCl
cat., base
solvent, r.t., 1 h
NH
+
N
1a
2c
3c
Entry
1
Catalyst
CuSO4
CuI
Base
Solvent
Yield (%)b
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
dioxane
DMSO
EtOAc
toluene
H2O
2
65
3
CuBr
Cu2O
–
42
4
63
At first, 2-bromocyclohex-1-enecarboxylic acid and bu-
tyramidine hydrochloride were used as the model sub-
strates to optimize reaction conditions including the
catalysts, bases, and solvents under nitrogen atmosphere.
As shown in Table 1, four copper catalysts were screened
at room temperature in the presence of two equivalents of
Cs2CO3 (relative to amount of 2-bromocyclohex-1-ene-
carboxylic acid) in DMF (entries 1–4), and CuI showed
the best activity (entry 2). No target product was obtained
in the absence of copper catalyst (entry 5). Other bases,
K2CO3 and K3PO4, were tested, and Cs2CO3 was the most
effective base (compare entries 2, 6, and 7). The cascade
coupling yield decreased as amount of base reduced (com-
pare entries 2 and 8), and the reaction did not work in the
absence of base (entry 9). The effect of solvents was also
investigated (compare entries 2, 10–15), and DMF pro-
vided the highest yield (entry 2). Only trace amount of py-
rimidinone 3a was observed under air (entry 16).
5
tracec
53
6
CuI
7
CuI
trace
47d
trace
46
8
CuI
9
CuI
10
11
12
13
14
15
16
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuI
trace
40
CuI
CuI
0
CuI
0
CuI
25
CuI
DMF
tracee
a Reaction conditions: 2-bromocyclohex-1-enecarboxylic acid (0.5
mmol), butyramidine hydrochloride (0.6 mmol), catalyst (0.025
mmol for Cu2O; 0.05 mmol for the others), base (1 mmol), solvent (1
mL) at r.t. (ca. 25 °C) under a nitrogen atmosphere.
b Isolated yield.
We investigated the scope of copper-catalyzed cascade re-
actions of 2-bromocycloalk-1-enecarboxylic acids with
amidines and guanidines under our optimized conditions
(10 mol% CuI as the catalyst, 2 equiv of Cs2CO3 as the
base, and DMF as the solvent).19 As shown in Table 2, the
amidines were converted into the products in good yields
c No addition of catalyst.
d Base (0.5 mmol).
at room temperature, and cyclopropanecarboxamidine e Under air.
and isonicotinamidine exhibited higher reactivity than
catalyzed Ullmann-type couplings by us18 and other
groups.20 Finally, coupling of the carboxyl and amino of
amidino in IV affords the target product 3.21
other amidines. Guanidines also provided the correspond-
ing bicyclic pyrimidinones in moderate to good yields
when temperature was raised to 40 or 50 °C (entries 6, 7
13, and 19). For the 2-bromocycloalk-1-enecarboxylic ac-
ids containing six-, seven-, and eight-membered rings,
their reactive activity did not show any notable difference.
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of bicyclic py-
rimidinones containing six-, seven-, and eight-membered
rings. The cascade reactions of 2-bromocycloalk-1-ene-
carboxylic acids with amidines or guanidines were per-
formed well under very mild conditions (r.t. to 50 °C)
without addition of any ligand or additive, and the target
products were obtained in good yields. The present meth-
od provides opportunity for screening of diverse and use-
ful biological and medicinal molecules.
A possible formation mechanism of bicyclic pyrimidino-
nes was proposed in Scheme 1. Coordination of 2-bro-
mocycloalk-1-enecarboxylic acid with CuI first forms I in
the presence of base (Cs2CO3). Oxidative addition of I
yields II, and complexation of II with amidine or guani-
dine gives coordinate III, and reductive elimination of III
provides N-arylation product IV releasing copper cata-
lyst. The ortho substituent effect were found in copper-
Synlett 2010, No. 17, 2611–2616 © Thieme Stuttgart · New York

LETTER
Synthesis of Bicyclic Pyrimidinones
2613
O
O
O
O
Cs2CO3
CsI
O
OH
CuI
+
Cu
Cu
( )n
( )n
Br
( )n
Br
Br
n = 1–3
II
1
I
O
HN
NH2
O
N
O
O
2
OH
NH2
Cu
Br
R
NH
( )n
HN
III
( )n
IV
( )n
NH2
H2O
N
R
CuBr
3
R
R
Scheme 1 Possible formation mechanism of bicyclic pyrimidinones
Table 2 Copper-Catalyzed Synthesis of Bicyclic Pyrimidinonesa
O
COOH
HN
NH2⋅HCl
CuI, Cs2CO3, DMF
temp. N2
NH
+
Br
R
N
R
n
n
2
n = 1–3
3
1
COOH
Br
COOH
Br
COOH
Br
1a
1c
1b
Entry
2
Time (h)
Product (3)
Yield (%)b
O
HN
NH2⋅HCl
NH
1
2
80
N
2a
3a
O
HN
NH2⋅HCl
NH
NH
NH
2
3
2
1
66
65
N
2b
3b
O
HN
NH2⋅HCl
NH2⋅HCl
N
2c
3c
HN
O
4
5
2
3
62
84
N
Ph
3d
2d
O
HN
NH2⋅HCl
NH
N
N
N
2e
3e
Synlett 2010, No. 17, 2611–2616 © Thieme Stuttgart · New York

2614
Q. Guo et al.
LETTER
Table 2 Copper-Catalyzed Synthesis of Bicyclic Pyrimidinonesa (continued)
O
COOH
HN
NH2⋅HCl
CuI, Cs2CO3, DMF
temp. N2
NH
+
Br
R
N
R
n
n
2
n = 1–3
3
1
COOH
Br
COOH
Br
COOH
Br
1a
1c
1b
Entry
2
Time (h)
2
Product (3)
Yield (%)b
O
HN
NH2⋅HCl
NH2
60c
NH
NH
6
7
N
NH2
2f
3f
O
HN
NH2 ⋅H2SO4
2
45d
N
O
6
N
N
O
2g
2a
3g
O
NH
8
0.5
71
N
O
3h
3i
NH
NH
NH
9
10
11
2b
2c
2d
2
2
2
72
67
75
N
O
N
O
3j
N
O
Ph
3k
NH
12
13
2e
2f
3
2
80
N
N
3l
O
N
65c
NH
NH2
3m
Synlett 2010, No. 17, 2611–2616 © Thieme Stuttgart · New York

LETTER
Synthesis of Bicyclic Pyrimidinones
2615
Table 2 Copper-Catalyzed Synthesis of Bicyclic Pyrimidinonesa (continued)
O
COOH
HN
NH2⋅HCl
CuI, Cs2CO3, DMF
temp. N2
NH
+
Br
R
N
R
n
n
2
n = 1–3
3
1
COOH
Br
COOH
Br
COOH
Br
1a
1c
1b
Entry
2
Time (h)
0.5
Product (3)
Yield (%)b
O
NH
14
2a
82
N
O
3n
3o
3p
3q
NH
NH
NH
NH
15
16
17
2b
2c
2d
2
2
1
73
63
78
N
O
N
O
N
O
Ph
18
19
2e
2f
3
2
82
N
N
3r
3s
O
N
76c
NH
NH2
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.05 mmol), Cs2CO3 (1 mmol), DMF (3 mL) at r.t. (ca. 25 °C) under a nitrogen atmo-
sphere.
b Isolated yield.
c Reaction temperature (40 °C).
d Conditions: 2g (0.35 mmol), reaction temperature 50 °C.
No. 2007AA02Z160) and the Key Subject Foundation from Beijing
Department of Education (XK100030514).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
Acknowledgment
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This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20972083), Chinese 863 Project (Grant
Synlett 2010, No. 17, 2611–2616 © Thieme Stuttgart · New York

2616
Q. Guo et al.
LETTER
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(19) General Procedure for the Synthesis of Compounds 3a–s
A two-neck round-bottom flask was charged with a
magnetic stirrer, evacuated and backfilled with nitrogen.
Amidine hydrochloride or guanidine hydrochloride 2a–f
(0.6 mmol) or bis(guanidine)sulfate (2g, 0.35 mmol), CuI
(0.05 mmol, 9.5 mg), Cs2CO3 (1 mmol, 326 mg), and DMF
(1 mL) were added under nitrogen atmosphere. After a 15
min stirring, 2-bromocycloalk-1-enecarboxylic acid (1, 0.5
mmol) was added to the flask. The mixture was allowed to
stir under nitrogen atmosphere at the shown temperature for
some time (see Table 2). After completion of the reaction,
the mixture was concentrated with the aid of a rotary
evaporator. The residue was purified by column chroma-
tography on silica gel using PE–EtOAc or CH2Cl2–MeOH as
eluent to provide the desired product.
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