Cyclization of Ketones with Nitriles under Base: A General and Economical Synthesis of Pyrimidines

Article abstract of DOI:10.1021/acs.orglett.8b01324

A facile, general, and economical synthesis of diversely functionalized pyrimidines has been realized under basic conditions via the copper-catalyzed cyclization of ketones with nitriles. The reaction proceeds via a novel pathway involving the nitriles ac

Full text of DOI:10.1021/acs.orglett.8b01324

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cyclization of Ketones with Nitriles under Base: A General and
Economical Synthesis of Pyrimidines
Lebin Su, Kang Sun, Neng Pan, Long Liu, Mengli Sun, Jianyu Dong,* Yongbo Zhou,*
and Shuang-Feng Yin
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
S
* Supporting Information
ABSTRACT: A facile, general, and economical synthesis of
diversely functionalized pyrimidines has been realized under
basic conditions via the copper-catalyzed cyclization of ketones
with nitriles. The reaction proceeds via a novel pathway
involving the nitriles acting as electrophiles and consecutive
C−C bond and two C−N bond formations and shows broad
substrate scope and good tolerance of many important
functional groups. This strategy represents a new platform for constructing pyrimidine structures.
yrimidines are fundamental structural motifs found in many
kinds of functional compounds, such as natural products,
achieved by the reactions of nitriles with N-vinylamides and
alkynes (Scheme 1, eqs 1 and 2).6,7
P
drugs, bioactive molecules, supramolecules, and biogenetic and
photophysical materials (Figure 1).1,2 Numerous pyrimidine-
Scheme 1. Synthesis of Substituted Pyrimidines from Nitriles
Figure 1. Representative pyrimidine compounds.
containing functional compounds have been synthesized by
using simple pyrimidines as basic chemical raw materials.
Therefore, pyrimidines are consumed in large quantities in the
biological, medical, and chemical industries, and their facile,
general, and economical synthesis holds extreme significance.
Traditionally, pyrimidine structures are constructed by the
condensation of amidines with 1,3-dicarbonyl compounds or
surrogates.3 In recent years, numerous attempts have been made
toward the synthesis of pyrimidines in the pursuit of less
expensive and more readily available nitrogen sources, more
convenient 1,3-dicarbonyl equivalents, milder reaction con-
ditions, and more facile operational procedures, as well as
improving access to more structurally diverse pyrimidines.3−5 In
these regards, readily available nitriles have been employed as
nitrogen sources, instead of amidines. Notable advances are
Ketones are abundant, structurally diverse, and inexpensive
chemicals, and the reaction of ketones with nitriles would be an
ideal strategy for the synthesis of pyrimidines. In 1985, Zielinski8
first reported the treatment of two nitriles with one ketone for the
synthesis of pyrimidines in the presence of phosphoryl chloride.
In later years, many improvements to the reaction have been
made by the use of Tf2O (Scheme 1, eq 3).9 However, serious
shortcomings remain. Anhydrous conditions are required, and a
stoichiometric amount of Tf2O is rather expensive. Furthermore,
because of the release of a strong organic acid, TfOH, functional
groups containing lone pairs of electrons, such as NH2, OH,
Received: April 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thiophene, and pyridine, are not tolerated. These drawbacks
restrict the application of these methods.
With the optimal conditions in hand, we next examined the
scope of the substrates, and the results are summarized in
Scheme 2. The reaction of acetonitrile 2a with aromatic ketones
To achieve a facile, general, and economical synthesis of
pyrimidines, we developed a novel approach for accessing
pyrimidines from ketones and nitriles via copper catalysis.
(Scheme 1, eq 4). The reaction proceeds under basic conditions
by using nitriles as electrophiles, which is quite different from the
a
Scheme 2. Substrate Scope
known methods that nitriles are used as nucleophiles.6−9
A
variety of 2,4,6-trisubstituted pyrimidines are efficiently con-
structed with good tolerance for many functional groups,
especially thiophene, pyridine, OBn, SMe, NH2, and OH.
As shown in Table 1, a 62% yield of 2,4-dimethyl-6-
phenylpyrimidine 3a was produced by the treatment of
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
cat.
CuI
base
temp (°C) conv (%) yield (%)
1
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
t-BuONa
t-BuOK
KOH
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
110
90
86
78
97
88
90
85
89
82
35
100
100
90
93
95
<5
0
62
53
39
82
68
45
21
16
nd
nd
nd
nd
38
11
18
nd
nd
nd
80
46
2
CuCl
3
CuBr
4
CuCl2
CuBr2
Cu(OAc)2
Cu(OH)2
CuO
5
6
7
8
9
ZnCl2
AgOTf
FeCl3
10
11
12
13
14
15
16
17
18
19
20
CoBr2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
Na2Co3
Et3N
0
NaOH
NaOH
100
60
a
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mL), CuCl2 (20 mol %),
a
Reaction conditions: 1a (0.3 mmol), catalyst (0.06 mmol, 20 mol %),
base (0.6 mmol, 2 equiv) in CH3CN 2a (0.6 mL) for 24 h under N2.
Conversion of 2a. GC yields using n-tridecane as an internal
NaOH (0.6 mmol), at 120 °C for 24 h under N2. Isolated yield is
b
c
given. 48 h. 30 h.
b
c
standard.
with electron-withdrawing substituents such as F (3b), CF3 (3c),
and Cl (3d) provided high isolated yields (82−87%) of the
corresponding products. In comparison, slightly lower yields
(65−72%) were observed when the aromatic ring had electron-
donating substituents (3e−h). This electronic effect is attributed
to the fact that the electron-withdrawing (donating) groups
facilitate (disfavor) the formation of enolic intermediate I (vide
infra). Reactive functional groups, such as SO2Me (3i), OBn
(3j), and NH2 (3k,l), were also well-tolerated in this reaction,
and the desired products were produced in 67−84% yields.
Notably, phenolic OH group, which is sensitive to base, was also
compatible; although, 3m was isolated in only 57% yield.
Sterically hindered polycyclic aromatic ketones also reacted
efficiently with 2a and produced the corresponding pyrimidines
in good yields (3n and 3o). Heteroaromatic ketones that contain
thiophene and pyridine were also good substrates and afforded
desired products 3p and 3q in 77% and 75% yields, respectively.
Functional groups such as NH2, OH, and pyridine are very
acetophenone 1a with acetonitrile 2a at 120 °C in the presence
of 20 mol % of CuI and 2.0 equiv of NaOH (Table 1, entry 1). In
our investigation of the Cu salts (Table 1, entries 1−8), CuCl2
gave the highest yield (82%). Cu(OH)2 and CuO showed low
catalytic efficiencies in this reaction (Table 1, entries 7 and 8),
which could probably be attributed to their poor solubility. Other
metal catalysts such as ZnCl2, AgOTf, FeCl3, and CoBr2 were
also tested; however, no desired product was obtained (Table 1,
entries 9−12). The screening of the bases revealed that NaOH
played a unique role in this transformation; both stronger bases
and weaker bases gave very low yields of 3a (Table 1, entries 13−
17). In the absence of NaOH, the reaction did not take place
(Table 1, entry 18). A comparable yield (80%) was observed at
130 °C. However, when the reaction temperature was lowered to
110 °C, only 46% yield of 3a was obtained (Table 1, entries 19
and 20).
B
DOI: 10.1021/acs.orglett.8b01324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
important and are frequently found in functional pyrimidine
derivatives.1a−d The known methodologies that require Tf2O or
Lewis acids are not compatible with these functional groups.6−9
The developed reaction was also successfully applied to
aliphatic ketones. For example, the treatment of 4-phenylbutan-
2-one with 2a afforded the corresponding product 3r in 71%
yield. When the sterically hindered ketones adamantanone and 1-
cyclohexylethanone were subjected to the reaction system, the
desired products were furnished in moderate yields (3s, 51%; 3t,
47%). Beside acetonitrile, other aromatic and aliphatic nitriles,
such as benzonitrile, 4-methylbenzonitrile, 3-methylbenzonitrile,
and pentanenitrile were good substrates for this transformation,
giving the desired products in good to excellent yields (3u−zc,
65−93%). Heteroaryl nitrile 3-thiophenecarbonitrile also reacted
smoothly with 1-(4-fluorophenyl)ethanone, and 3zd was
produced in 92% yield.
(Scheme 4, eq 2). Indeed, 6a could be smoothly converted
into the target product 3a under the optimal conditions (83%
yield) and even under copper-free conditions (82% yield,
Scheme 4, eq 3). These results illustrate that enaminone 6a
probably served as the reaction intermediate in this annulation
reaction, and a copper catalyst was essential for converting the
ketones to enaminones.12a This finding also indicates that
structurally diverse 2,4,6-trisubstituted pyrimidines could be
constructed by employing nitriles and enaminones as starting
materials under copper-free conditions.
As shown in Scheme 5, a variety of nitriles worked well with
enaminones, producing the corresponding pyrimidines in good
a
Scheme 5. Synthesis of Highly Substituted Pyrimidines
Considering the synthetic usefulness of this reaction, we
further illustrated its scalability. When the reaction was scaled up
to 9 mmol (gram scale), the desired product 3y was isolated in
82% yield (Scheme 3, eq 1). Because methyl heteroarenes are
Scheme 3. Synthetic Utility
good substrates for C(sp3)−H activation,10 the direct oxidation
of 4-(4-fluorophenyl)-2,6-dimethylpyrimidine 3b was inves-
tigated, and the selective methyl oxidation product, aldehyde 4,
was obtained in 72% yield (Scheme 3, eq 2).11
Several control experiments were performed to elucidate the
mechanism of this reaction. The reaction of 1a with ethanamide
5 did not give the desired product, suggesting that the
cycloaddition of 1a with a primary amide via hydroxylation of
a nitrile is not involved (Scheme 4, eq 1). The reaction of
acetophenone 1a with acetonitrile at 100 °C for 12 h resulted in a
12% GC yield of (Z)-3-amino-1-phenylbut-2-en-1-one 6a
a
Reaction conditions: 6 (0.3 mmol), 2 (0.6 mL), and NaOH (0.3
mmol), at 120 °C for 16 h under N2. Isolated yield is given.
to excellent yields. Aromatic nitriles (3zh−zk) (78−84%) are
more reactive than alkyl nitriles (3ze−zg) (66−73%), which is
probably due to the stronger electrophilicity of the C−N triple
bonds of aromatic nitriles (vide infra). Cyanamide underwent the
annulation reaction with 6a to provide 2-amino-substituted
pyrimidine 3zl in 90% yield. A heteroaryl nitrile, exemplified by
3-thiophenecarbonitrile, also reacted efficiently with 6a, giving
the desired product 3zm in 76% yield. In addition, aliphatic
enaminone (Z)-4-aminopent-3-en-2-one reacted effectively with
3-methylbenzonitrile to afford the desired pyrimidine 3zn in 92%
yield. Thus, a concise approach for accessing highly substituted
pyrimidines from two different nitriles with a ketone via
enaminone has been developed, and these products cannot be
accessed by the known reaction systems.8,9
Scheme 4. Control Experiments
On the basis of the results of the above studies and the
literature reports,5,12 a plausible reaction pathway was proposed
as shown in Scheme 6. First, enolic intermediate I is formed via
the dehydration of ketone 1 with NaOH, which nucleophilically
attacks the carbon atom of nitrile 2 that has been activated by
CuCl2 to produce imine intermediate II via C−C bond
formation. The isomerization of II gives enaminone III.5b,c
Dehydrogenation of III results in negative enaminone ion IV,
which then nucleophilically attacks another equivalent of nitrile
C
DOI: 10.1021/acs.orglett.8b01324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have developed a facile, general, and efficient
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NaOH, and CuCl2. This new procedure is applicable to a wide
range of substrates, including aromatic, heteroaromatic, and
aliphatic ketones and nitriles, and is tolerant of many important
functional groups, especially thiophene, pyridine, OBn, SMe,
NH2, and OH. The reaction proceeds via a novel pathway, in
which the nitriles act as electrophiles, and consecutive C−C
bond and two C−N bond formations are involved. This simple
and economical protocol represents a new platform for the
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01324.
Experimental procedures, full spectroscopic data, and 1H
and 13C spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: djyustc@hotmail.com.
*E-mail: zhouyb@hnu.edu.cn.
ORCID
(8) Zielinski, W. Heterocycles 1985, 23, 1639.
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Chem. 1992, 57, 1627. (b) Pardo, Z. D.; Olsen, G. L.; Fernandez-Valle,
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Yongbo Zhou: 0000-0002-3540-8618
Notes
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2012, 134, 2706. (c) Herrera, A.; Martínez-Alvarez, R.; Ramiro, P.;
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
́
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Financial support from the NSF of China (Grant Nos. 21573065,
21706058, and 21273066) and the NSF of Hunan Province
(2016JJ1017 and 2018JJ3031) is much appreciated.
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DOI: 10.1021/acs.orglett.8b01324
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