Copper-Catalyzed One-pot Synthesis of Pyrimidines from Amides, N,N′-dimethylformamide dimethylacetal, and Enamines

Article abstract of DOI:10.1002/adsc.201700234

A versatile copper catalyzed one-pot synthesis of diversely substituted pyrimidines directly from amides, N,N′-dimethylformamide dimethylacetal (DMF?DMA) and enamines has been established. The reaction involved the two C?N bonds and one C?C bond formation by formal [2+1+3] annulation approach to pyrimidines. This protocol is based on the use of readily available primary amides, DMF?DMA and enamines to install di- and tri-substituted pyrimidine structure with diverse functionality in one-pot manner, which makes this strategy to be appealing for the medicinal chemistry. (Figure presented.).

Full text of DOI:10.1002/adsc.201700234

Title: Copper-Catalyzed One-pot Synthesis of Pyrimidines from
Amides, DMF–DMA and Enamines
Authors: Hitesh Jalani, Wangshui Cai, and hongjian Lu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700234
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10.1002/adsc.201700234
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed One-pot Synthesis of Pyrimidines from
Amides, N,N′-dimethylformamide dimethylacetal, and
Enamines
Hitesh B. Jalani,a Wangshui Caia and Hongjian Lua,*
a
Institute of Chemistry & BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
E-mail:hongjianlu@nju.edu.cn
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
the synthesis of structurally diverse pyrimidines from
Abstract. A versatile copper catalyzed one-pot synthesis of
diversely substituted pyrimidines directly from amides, readily available materials.
N,N′-dimethylformamide dimethylacetal (DMF–DMA) and
enamines has been established. The reaction involved the
two C–N bonds and one C–C bond formation by formal
[2+1+3] annulation approach to pyrimidines. This protocol
is based on the use of readily available primary amides,
DMF–DMA and enamines to install di- and tri-substituted
pyrimidine structure with diverse functionality in one-pot
manner, which makes this strategy to be appealing for the
medicinal chemistry.
Figure 1. Selected Examples Containing Pyrimidine Core
Keywords:Pyrimidine; DMF–DMA; Enamine; Copper
Over the past few years, novel methodologies
utilizing copper-catalyzed transformations have been
developed.[10a-b] Such methods provide significant
benefits to the synthesis of variety of heterocycles,
Pyrimidines are one of the biologically important
heterocycles, which are present in various natural
because
copper
salts
are
inexpensive
products,[1]
synthetic
intermediates,[2]
environmentally-benign and possess low toxicity[10c-f]
and therefore are widely used in organic synthesis. In
addition, many amide building blocks are available[11]
and their use in the construction of various
heterocycles is common. To the best of our
knowledge, the use of primary amides for the
construction of pyrimidine using a formal [2+1+3]
annulation approach (Scheme 1b) has not been
reported to date. Continuing our efforts in the
application of enamines to the synthesis of various
heterocycles,[12] we report in this update a copper-
catalyzed, one-pot synthesis of pyrimidines directly
from primary amides, N,N′-dimethyl formamide
dimethylacetal (DMF–DMA) and enamines. The
reaction involves the formation of an N-acylamidine
pharmaceuticals[3] (Figure 1) and other materials of
interest.[4] Recently, pyrimidines are also used as
directing groups for the study of C–H activation
reactions.[5] In view of the importance of pyrimidines
in the diverse fields, various synthetic methods have
been developed for the concise and efficient synthesis
of substituted pyrimidines. One of the common
approaches is Pinner’s pyrimidine synthesis (Eq 1,
Scheme 1a),[6] which involves the reaction of
amidines (N–C–N) with 1,3-dicarbonyl compounds
(C–C–C). Synthetic variants of the 1,3-dicarbonyl
compounds have also been employed for the
synthesis of pyrimidines, for example the Morita-
Baylis-Hillman reaction.[7] A second interesting
approach involves the conversion of N-vinyl or N-
aryl amides with nitriles to the subsequent pyrimidine
or quinazoline[8] (Eq 2, Scheme 1a). Nevertheless, the
availability of numerous methods,[9] the long-lasting
interest and utility of the pyrimidine scaffold has led
further interest in the development of new synthetic
routes, particularly more efficient, versatile and
straightforward approaches using various catalysts for
1
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10.1002/adsc.201700234
Advanced Synthesis & Catalysis
1, entry 1). We then began the optimization of
reaction conditions for this one-pot reaction.
Considering the valuable contributions of various
metal catalysts in the synthesis of heterocyclic
systems, we carried out the reaction of the enamine
(3a) and N-acylamidine prepared in situ with the
copper catalysts as shown in Table 1, including
copper iodide, copper bromide, copper (I) chloride,
copper (II) chloride, copper acetate and copper
trifluoroacetate. Among them, copper acetate (20
mol%) was found to be the best, delivering 82%
Scheme 1. Structural Fragment-based Pyrimidine Synthesis
1
conversion based on H NMR (Table 1,entry 12).
Lithium bromide, ferric dichloride, ferric trichloride
and indium trichloride all failed to produce
pyrimidines. The reaction catalyzed by hydrated
catalysts such as nickel chloride, zinc acetate and p-
toluene sulfonic acid afforded pyrimidines with low
yields.
followed by a copper-catalyzed cyclization of this N-
acylamidine with enamine, producing pyrimidines.
Table 1. Optimization of Reaction Conditions[a]
Table 2. Substrate Scope for Amides[a,b]
entry
1
Catalyst (20 mol %)
No Catalyst
CuI
temp (°C) solvent yield[b] (%)
120
120
120
120
120
120
120
120
120
120
120
100
100
100
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
23
51
2
3
CuBr2
39
4
CuCl
42
5
CuCl2
35
6
LiBr
trace
trace
trace
trace
26
7
FeCl2
8
FeCl3
9
InCl3
10
11
12
13
14
NiCl2.6H2O
Zn(OAc)2.2H2O
Cu(OAc)2
Cu(OTf)2
TsOH
31
82 (76[c])
75 (70[c])
21
[a]1a (0.2 mmol), 2 (0.24 mmol) and 3a (0.3 mmol) in 2 ml
solvent and 4Å molecular sieve (250 mg) for 6 h.
[b]Conversion based on crude 1H NMR. [c] Isolated yield.
DMF-DMA is known as an electrophilic one
carbon synthon. When it reacts with amide
functionality, it gives N-acylamidine. The formation
of N-acylamidine[13-15] requires excess DMF-DMA (3-
4 equv.) and high reaction temperatures (100-120oC).
In order to simplify the pyrimidine synthesis, first we
optimized the N-acylamidine reaction conditions. We
observed that the reaction of benzamide with 1.2
o
equivalents of DMF-DMA at 60 C for 2-3 hours
(Table 1) could proceed quantitatively, as determined
1
by H NMR. Once the optimization of the synthesis
of the N-acylamidine was successfully achieved, we
commenced our study for the synthesis of
pyrimidines by subjecting benzamide (1a), DMF-
DMA (2), and t-butyl-3-amino crotonate (3a) in the
presence of various catalysts and solvents in one-pot
reaction (Table 1 and Supporting Information). In our
first attempt the reaction was carried out without any
catalyst, and the expected pyrimidine product 4a was
[a]1 (0.2 mmol), 2 (0.24 mmol), 3 (0.3 mmol) and
Cu(OAc)2 (0.04 mmol) in 2 mL solvent and 4 Å molecular
sieve (250 mg). [b]Isolated yield.
1
formed in 23% yield as assessed by H NMR (Table
2
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10.1002/adsc.201700234
Advanced Synthesis & Catalysis
Having established the optimal reaction conditions
optimized reaction conditions (Table 3). Alkyl-3-
aminobut-2-enoate containing different alkyloxy
groups such as methyl, ethyl and t-butyl provided the
corresponding 2-aryl-4-alkyl-pyrimidines with good
yields (4s-4u). When enamine substrates having
isobutyl, cyclohexyl, phenyl, and 2-fluorophenyl
group used in this study, the corresponding products
were formed with moderate yields (4v-4y). With the
heterocyclic substrate ethyl (Z)-3-amino-3-(thiophen-
2-yl) acrylate, the pyrimidine (4z) was obtained in
59% yield. The present method provides a simple and
easy preparation of ethyl 4-(chloromethyl)-2-phenyl
pyrimidine-5-carboxylate (4a′) in 69% yield. The
method failed, however, to generate pyrimidines from
enamines, such as 4-amino-2H-chromen-2-one and 1-
(t-butyl)-5-ethyl-3-aminopent-2-enedioate. It was
also observed that DMF-DMA was useful for the
pyrimidine synthesis while other acetal such as
DMA-DMA (N,N′-dimethylacetamide dimethylacetal)
were not successful, probably due to steric hindrance.
in hand, various mono, di and tri substituted aromatic
amides were subjected to the copper-catalyzed
cyclization reaction in order to examine the electronic
and steric effects of the substituents on the aryl
amides (1) (Table 2). The results indicated that
reaction of amides incorporating different halogen
group, such as –Cl, –Br, –I and –F proceeded with
good yields (4b-f). The reaction of aryl amides with
electron-donating groups, such as phenyl, methoxy,
amino and methyl group on the aryl ring, gave
moderate yields (4g-j). Electron-withdrawing groups,
such as CF3, NO2 group containing benzamide
resulted in moderate to good yield (4k-n). In addition
to various benzamides, 2-naphthamide gave the
corresponding pyrimidine derivative 4o with 61%
yield. Moreover, the thiophene derivates 4p and 4q
were obtained in reasonable yield when
benzo[b]thiophene-2-carboxamideand5-methyl
thiophene-2-carboxamidewere used as the substrates.
Interestingly, when we used formamide, instead of
aromatic amide, the present procedure successfully
gave the methyl 4-methylpyrimidine-5-carboxylate
4r with 72% yield, a di-substituted pyrimidine
compound, thus demonstrating the diversity of the
present procedure.
Table 3. Substrate Scope for Enaminesa,b
Figure 2. The Possible Reaction Pathway
The possible reaction mechanism pathway has
been described in Figure 2. Initially, the nucleophilic
substitution reaction of amide with DMF-DMA will
result into the formation of N-acylamidine 5.[16]
Considering the characteristics of enamines, which
can mostly react as C-nucleophile[17] the reaction
pathway is regarded as nucleophilic reaction of
double bond of enamine with the N-acylamidine. The
lone pair of electron of nitrogen of N,N′-
dimethylamine group possibly assisting the oxygen of
carbonyl of N-acylamidine 5 to coordinate with
copper acetate to form 6. The double bond of
enamine 3 attacks the highly electrophilic amidines
carbon attached to the electron pulling quaternary
nitrogen of 6 and forms 7 which further led to 8 with
the formation of AcOH. Further protonation of the
nitrogen of N,N’-dimethyl amine and make it again
quaternary nitrogen to form the 9, which then
cyclized to 10 with the removal of N,N′-dimethyl
amine and AcOH. This further aromatized to afford
the pyrimidine 4. This pathway is regioselective and
led to predominantly 2-arylpyrimidine confirmed by
X-ray single crystal structure[18] of 4n. Here the
possibility of the attack of amino group of enamine 3
on the quaternary nitrogen of 6 is ruled out by the fact
that if it would have happened, then it may form 6-
arylpyrimidine.
[a]1 (0.2 mmol), 2 (0.24 mmol), 3 (0.3 mmol) and
Cu(OAc)2 (0.04 mmol) in 2 mL solvent and 4Å molecular
sieve (250 mg). [b]Isolated yield.
Encouraged by the good tolerance of amide groups
in this reaction, we subjected different enamines to
this one-pot reaction and found that the enamines
were successfully converted into the corresponding
pyrimidines in moderate to good yields under the
3
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10.1002/adsc.201700234
Advanced Synthesis & Catalysis
To an oven dried Schlenk tube was charged with amide
(0.2 mmol), DMF-DMA (0.24 mmol) and DCE (2.0 mL).
The tube was closed with Teflon cap and placed in a
preheated oil bath at 60 ℃. After consumption of the
starting material (approx. 2-4 hours, monitored by TLC)
4Å molecular sieve (250 mg), Cu(OAc)2 (0.04 mmol) and
enamine (0.3 mmol) were charged and the reaction was
heated at 100 ℃ for 6-18 hours. After completion of
reaction (monitored by TLC PE/EA10:1), the mixture was
filtered through celite and washed with DCM. Organic
layer was then concentrated and the resulting residues were
purified by silica gel column chromatography (petroleum
ether/ethyl acetate) to afford the pure product.
With pyrimidine core in hand, we were interested
to explore the functional transformation reactions of
this newly synthesized pyrimidine scaffold (Scheme
2). The reaction of pyrimidine 4e with naphthalen-1-
boronic acid under the standard Suzuki cross
coupling reaction conditions gave the pyrimidine 4ea
with 78% yield, appended with a bulky naphthalene
core at the 4th position of the phenyl directly attached
to the pyrimidine ring (Scheme 2). Although the
transition metal-catalyzed decarboxylative carbon–
carbon bond formation reactions of aromatic
carboxylic acid are well established,[19-20] there are
few reports on the decarboxylative carbon–carbon
bond formation reactions of hetero-aromatic systems
mainly for activated systems such as thiophene, furan
and especially for highly privilege scaffold such as
pyrimidine are very few.[20] The palladium catalyzed
decarboxylative C-5 allylation of 4xa with ally
bromide was achieved to form the allyl pyrimidine,
4xb with 61% yield. Such pyrimidine bearing allyl
group could be useful for further functionalization.
Furthermore, the carboxylic acid 4xa can be
converted to isocyanate intermediate via Curtis
rearrangement of acyl azides. The resulting
isocyanate intermediate can serve as the precursor for
various useful amino compounds, such as urea (4xc)
Acknowledgements
We are grateful for financial support by the National Natural
Science Foundation of China (21472085) and Qing Lan
Project.We thank Heifei Zhang, Hongmio Wu and Lizheng Yang
for their support in HRMS and 19F-NMR analysis.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201700234
Advanced Synthesis & Catalysis
UPDATE
Copper-Catalyzed One-pot Synthesis of
Pyrimidines from Amides, DMF-DMA and
Enamines
Adv. Synth. Catal. Year, Volume, Page – Page
Hitesh B. Jalani, Wangshui Cai and Hongjian Lu*
6
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