Copper(II)-catalyzed synthesis of pyrimidines from propargylic alcohols and amidine: A propargylation-cyclization-oxidation tandem reaction

Article abstract of DOI:10.1055/s-0030-1259954

A new approach to the tandem synthesis of 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines from propargylic alcohols with amidine is described. This reaction is catalyzed by 20 mol% Cu(OTf)² to give pyrimidines in moderate to good yields v

Full text of DOI:10.1055/s-0030-1259954

LETTER
1179
Copper(II)-Catalyzed Synthesis of Pyrimidines from Propargylic Alcohols and
Amidine: A Propargylation–Cyclization–Oxidation Tandem Reaction
P
yrimidines from Prop
i
argylic
n
A
lcohols and
Ami
L
dine in, Qing-zhen Chen, Yu Zhu, Xin-liang Chen, Ji-jun Cai, Ying-ming Pan, Zhuang-ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005 Fujian, P. R. of China
Fax +86(592)2180318; E-mail: zpzhan@xmu.edu.cn
Received 31 December 2010
substituted pyrimidines directly from propargylic alco-
Abstract: A new approach to the tandem synthesis of 2,4-disubsti-
hols with amidine using copper(II) triflate as the catalyst.
tuted or 2,4,6-trisubstituted pyrimidines from propargylic alcohols
with amidine is described. This reaction is catalyzed by 20 mol%
Cu(OTf)2 to give pyrimidines in moderate to good yields via a pro-
pargylation–cyclization–oxidation tandem sequence.
Not only can the reaction be carried out under mild condi-
tions, giving water as the only byproduct and oxidized by
atmospheric air, but also all of the propargylic alcohols
used are readily available.
Key words: pyrimidine, propargylation, amidine, copper, annula-
tion
Table 1 Optimization of Reaction Conditionsa
OH
NH
20 mol% Cu(OTf)2, air
NH2
solvent, reflux
N
Pyrimidine is a very important heterocyclic unit featuring
prominently in pharmaceuticals, agrochemicals, biologi-
cally active molecules, and novel materials.1 Accordingly,
considerable attention has been paid to develop efficient
methods for its synthesis.2 Two general strategies are
commonly used for the preparation of substituted pyri-
midines: 1) functionalization of existing pyrimidine-con-
taining precursors by introduction of new substituents,
and 2) formation of a new pyrimidine ring through
cyclization of acyclic substrates.3 Among cyclization
approaches, the classical condensation of N–C–N frag-
ments, most often amidines or guanidines, with 1,3-dicar-
bonyl derivatives or their equivalents still remains the
most powerful synthetic tool.4 More recently, the applica-
tion of alkynones and propargylic compounds in the as-
sembly of pyrimidines has been attracting substantial
attention from both academia and industry.5 Müller and
co-workers demonstrated a one-pot preparation of 2,4-
disubtituted pyrimidines from TMS-ynones and amidini-
um salt.5h,i Bagley also described a microwave-assisted
oxidation–heteroannulation sequence for the construction
of 2,4-disubstituted pyrimidines from propargylic alco-
hols and amidines.5j In the latter case, however, only two
synthetic examples were reported, and an excessive oxi-
dant (MnO2, 10 equiv) was required to convert the prop-
argylic alcohols completely into the alkynones. Thus,
development of more general, efficient as well as eco-
nomic methodologies for the synthesis of pyrimidines is
in high demand.
+
Ph
Ph
Ph
N
3a
Ph
2
TMS
1a
Entry
1
Catalyst
–
Solvent
Time (h) Yield (%)b
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
24
24
24
3.5
1.5
24
24
24
40
25
53
52
87
21
41
45
0
2
BiCl3
3
InCl3
4
FeCl3
5
Cu(OTf)2
Bi(OTf)3
Zn(OTf)2
AgOTf
PTSA
6
7
8
9
0.2
10
11
12
13
14
15
16
CF3COOH
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
PhCl
PhCl
CH3CN
DCE
24
8
0
78c
57
71
55
0
24
24
18
24
8
CH3NO2
DCM
PhMe
78
As the results of development on the transition-metal-
catalyzed propargylic substitution reactions in our group,6
herein we wish to report a highly efficient propargylation–
cyclization–oxidation tandem reaction for the synthesis of
a Reaction conditions: catalyst (20 mol%), 1a (0.5 mmol, 1.0 equiv),
and 2 (1 mmol, 2 equiv) in a solvent (2 mL) at refluxing temperature.
b Isolated yields.
c 10 mol% Cu(OTf)2.
In the initial study, we chose the propargylic alcohol 1a
and benzamidine 2 as the substrates. The reaction was run
in the absence of any catalyst, using chlorobenzene as the
solvent. A low yield of pyrimidine 3a was obtained after
SYNLETT 2011, No. 8, pp 1179–1183
Advanced online publication: 18.04.2011
DOI: 10.1055/s-0030-1259954; Art ID: W21010ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

1180
M. Lin et al.
LETTER
24 hours (Table 1, entry 1). The reaction was further test- in 74% yield (Table 2, entry 7). Obviously, electron-rich
ed in the presence of various Lewis acids such as BiCl3, propargylic alcohols provided the desired products in
InCl3, FeCl3, Cu(OTf)2, Bi(OTf)3, Zn(OTf)2, and AgOTf. higher yields than electron-poor propargylic alcohols. In-
ternal propargylic alcohols 1c and 1d (R2 = Ph, n-Bu)
were also subjected to the reaction conditions, and the de-
sired pyrimidines were obtained in moderate yields
We found that 20 mol% copper(II) triflate could efficient-
ly promote the tandem reaction at reflux for 1.5 hours, and
the desired product 3a was isolated in 87% yield (Table 1,
entry 5). With other Lewis acids, the tandem reaction pro-
(Table 2, entries 3 and 4). The reaction of terminal prop-
argylic alcohol 1b (R2 = H) with 2 afforded 3a in moder-
ceeded slowly to afford pyrimidines 3a in low yields
ate yield after a somewhat longer reaction time (Table 2,
(Table 1, entries 2–4 and 6–8). It is worth noting that
entry 2). Additionally, propargylic alcohols 1e, 1f,and 1i
Bi(III) catalysts had a negative effect on this reaction
(Table 1, entries 1, 2, and 6). A slower reaction rate and
lower yield was observed when the catalytic amount of
Cu(OTf)2 was decreased to 10 mol% (Table 1, entry 11).
Brønsted acids, such as PTSA and TFA, failed to catalyze
the tandem reaction (Table 1, entries 9 and 10). In addi-
tion, it was found that the solvent played a crucial role in
this tandem reaction (Table 1, entries 5 and 12–16). Ace-
(R1 = 1-naphthyl and 2-thienyl) readily underwent this
tandem reaction to afford the substituted pyrimidines 3e
and 3i in moderate to good yields (Table 2, entries 5, 6,
and 9). Similarly, propargylic alcohol 1j also afforded
moderate yield of pyrimidine 3j (Table 2, entry 10). How-
ever, the results suggested that the aliphatic propargylic
alcohols, such as substrate 1k (R1 = CH3, R2 = Ph), failed
to afford the substituted pyrimidine.
tonitrile, 1,2-dichloroethane, nitromethane, and toluene as
solvents were also able to facilitate the reaction. However, Instability of the propargylic cation intermediate probably
the use of chlorobenzene obviously reduced the reaction made the tandem reaction less favorable. For the aromatic
time and improved the yield (Table 1, entries 12–14 and propargylic alcohols, the reaction was completed under
16). Dichloromethane failed to promote this reaction mild conditions. No added oxidant was needed, and oxy-
(Table 1, entry 15). The results of solvents screening gen in the air was sufficient to ensure formation of pyri-
showed that the reaction rate was influenced by various midines. A wide range of secondary propargylic alcohols
factors such as boiling point and polarity. Among these bearing not only terminal alkyne groups but also internal
factors, the boiling point of solvents might be a main fac- alkyne groups could effectively be employed, and a num-
tor. However, the detailed mechanism was still not clear.
ber of functional groups, such as bromo, methoxy, and cy-
clohexenyl, were tolerated under the reaction conditions.
With the optimal conditions, the substrate scope of this
tandem reaction was examined. As depicted in Table 2, a We next examined the reaction of propargylic alcohol 1a
variety of propargylic alcohols underwent this tandem re- under the optimized conditions in the absence of amidine.
action to give the corresponding substituted pyrimidines No oxidation of alcohol was observed. Thus, we speculat-
in moderate to good yields. Various secondary phenyl- ed that this reaction underwent a new procedure other than
substituted propargylic alcohols 1a–c were examined. ‘oxidation–heteroannulation’ mechanism.5j–l On the other
The propargylic alcohol 1a (R2 = TMS) gave the most de- hand, we have demonstrated a propargylation–cyclo-
sirable result, providing the substituted primidines in isomerization tandem reaction of propargylic alcohols
good yield (Table 2, entry 1). Propargylic alcohol 1h pos- and amides to provide oxazoles.6c We therefore hypothe-
sessing an electron-donating group at the aryl ring sized that the reaction of propargylic alcohols and benz-
(R1 = 4-MeOC6H4) reacted smoothly with amidine af- amidine would undergo a similar process. As a working
fording the pyrimidine 3h in 91% yield (Table 2, entry 8). hypothesis, we propose the following mechanism for the
However, the substrate 1g (R1 = 4-BrC6H4) containing a pyrimidine ring formation (Scheme 1). First, Cu(OTf)2-
weakly electron-deficient aryl ring was also successfully induced SN1 substitution of propargyl alcohol 1 leads to 6,
employed in the tandem reaction to give the pyrimidine 3g which upon intramolecular nucleophilic attack of amidine
Ph
OH
Ph
20 mol% Cu(OTf)2
PhCl, reflux, air
N
N
+
R1
H2N
NH
R1
R2
R2
1
2
3
+
aromatization air
Ph
Cu2
2
Ph
Cu2+
+
HN
R1
NH
HO
R1
6-endo-dig
HN
R1
N
R1
R2
R2
R2
R2
H+
Cu2+
5
6
7
Scheme 1 Mechanistic rationale for Cu(II)-catalyzed tandem synthesis of pyrimidines
Synlett 2011, No. 8, 1179–1183 © Thieme Stuttgart · New York

LETTER
Pyrimidines from Propargylic Alcohols and Amidine
1181
nitrogen at the Cu-activated triple bond of alkyne produces pargylic alcohol, furnishing the propargylic cation 5, but
cyclic dihydropyrimidine intermediate 7 (6-endo-dig). also activated the triple bond rendering the cyclization
Then, the dihydropyrimidine 7 can aromatize to the pyri- process more facile.
midine ring via oxidation by air. It was noteworthy that
the Cu(OTf)2 acted as a bifunctional catalyst, not only did
it assist in the leaving of the hydroxyl group from the pro-
Table 2 Synthesis of Substituted Pyrimidines 37 from Propargylic Alcohols 1 and Amidine 2a
R1
NH
OH
20 mol% Cu(OTf)2
air, PhCl, reflux
N
+
R1
Ph
NH2
R2
N
Ph
R2
1
2
3
Entry
Propargylic alcohol
Product
Time (h)
1.5
Yield (%)b
87
Ph
N
1
1a R1 = Ph, R2 = TMS
1b R1 = Ph, R2 = H
1c R1 = Ph, R2 = Ph
N
Ph
Ph
3a
Ph
N
2
3
6
3
68
79
N
3a
Ph
N
Ph
N
Ph
3c
OMe
Ph
4
5
6
1d R1 = 2-MeOC6H4, R2 = n-Bu
1e R1 = 1-naphthyl, R2 = TMS
1f R1 = 1-naphthyl, R2 = H
24
1.5
6
75
89
69
N
N
3d
3e
3e
N
N
Ph
N
N
Ph
Synlett 2011, No. 8, 1179–1183 © Thieme Stuttgart · New York

1182
M. Lin et al.
LETTER
Table 2 Synthesis of Substituted Pyrimidines 37 from Propargylic Alcohols 1 and Amidine 2a (continued)
R1
NH
OH
20 mol% Cu(OTf)2
air, PhCl, reflux
N
+
R1
Ph
NH2
R2
N
Ph
R2
1
2
3
Entry
Propargylic alcohol
Product
Time (h)
Yield (%)b
Br
7
1g R1 = 4-BrC6H4, R2 = TMS
3
74
N
N
Ph
3g
OMe
8
1h R1 = 4-MeOC6H4, R2 = TMS
1.5
91
N
N
Ph
3h
S
9
10
11
1i R1 = 2-thienyl, R2 = TMS
1j R1 = Ph, R2 = 1-cyclohexenyl
1k R1 = Me, R2 = Ph
2
4.5
24
85
73
0
N
N
Ph
3i
Ph
N
N
Ph
3j
N
N
Ph
3k
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), and Cu(OTf)2 (0.1 mmol) in chlorobenzene (2 mL) at reflux.
b Isolated yields.
We also sought to extend the substrate to alkenyl-substi- dominant (more rapid) oxidation process, 3l was fur-
tuted propargyl alcohol 1l (Scheme 2). Interestingly, it nished as the main product. Such a result provided an
was found that the expected product 3l was obtained along additional support for the propargylation–cyclization–
with a double-bond-hydrogenated product 4. We specu- oxidation mechanism.
lated that the dihydropyrimidine intermediate 7l was first
In summary, we have developed a Cu(OTf)2-catalyzed
formed via substitution–cyclization sequence as described
tandem reaction of propargylic alcohols with amidine,
above (Scheme 1).
providing a general and facile approach to 2,4-disubstitut-
Then, this dihydropyrimidine could aromatize to the cor- ed or 2,4,6-trisubstituted pyrimidines. The copper salt as
responding pyrimidine ring 3l or 4 through two competi- catalyst, broad substrates scope, operational simplicity,
tive aromatization processes: 1) oxidation by the air, and mild reaction conditions, no added oxidant, and minimal
2) migration of the exocyclic double bond. Thus, with the
Synlett 2011, No. 8, 1179–1183 © Thieme Stuttgart · New York

LETTER
Pyrimidines from Propargylic Alcohols and Amidine
1183
Ph
oxidation
(by air)
N
N
Ph
Ph
3l (58%)
OH
NH
20 mol% Cu(OTf)2
PhCl, reflux, 2 h
aromatization
HN
N
+
Ph
Ph
NH2
Ph
Ph
TMS
1l
2
7l
N
N
double-bond shift
Ph
4 (16%)
Scheme 2 Cu(II)-catalyzed formation of pyrimidines from alkenyl propargyl alcohol 1l and amidine 2
Comprehensive Heterocyclic Chemistry III, Vol. 8;
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This work was supported by the National Natural Science Founda-
tion of China (No. 21072159), Science & Technology Bureau of
Xiamen (No. 3502Z20093007) and NFFTBS (No. J1030415).
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To a solution of propargylic alcohol 1 (0.5 mmol) and
amidine 2 (1 mmol) in PhCl (2 mL), Cu(OTf)2 (0.1 mmol)
was added, and it was stirred at reflux. When the reaction
was completed (monitored by TLC), the solvent was
removed under vacuum, and then the residue was further
purified by silica gel column chromatography (PE and
EtOAc) to afford pyrimidine.
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