Strategy for the synthesis of pyrimidine derivatives: NbCl 5-mediated cycloaddition of alkynes and nitriles

Article abstract of DOI:10.1021/om300669s

Intermolecular cycloadditions of alkynes (terminal alkynes and internal alkynes) with aryl nitriles were successfully achieved, using an NbCl ₅ complex, to give substituted pyrimidine derivatives in high yields with excellent chemo- and regioselectivity.

Full text of DOI:10.1021/om300669s

Communication
pubs.acs.org/Organometallics
Strategy for the Synthesis of Pyrimidine Derivatives: NbCl5‑Mediated
Cycloaddition of Alkynes and Nitriles
Yasushi Satoh, Kaoru Yasuda, and Yasushi Obora*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan
S
* Supporting Information
ABSTRACT: Intermolecular cycloadditions of alkynes (terminal
alkynes and internal alkynes) with aryl nitriles were successfully
achieved, using an NbCl5 complex, to give substituted pyrimidine
derivatives in high yields with excellent chemo- and regioselectivity.
yrimidine derivatives are an important class of aza-
heterocyclic compounds.1 Pyrimidine derivatives are key
structures in many natural products and biologically active
substances, including minoxidil, thiamine, meridianin D, and
pyrimethamine (Figure 1).1 In addition, some pyrimidines are
methods for preparing pyrimidine derivatives. Previously,
Martinez, Hanack, and co-workers reported the reaction of
alkynes and nitriles to afford trisubstituted pyrimidine
derivatives by using a strong acid such as CF3SO3H.4h
Alternatively, transition-metal-mediated/-catalyzed [2 + 2 +
2] intermolecular cycloaddition of alkynes and nitiriles is one of
the most efficient, simple, and atom-economical methods for
preparing pyrimidine derivatives. However, such a cyclo-
addition reaction exclusively afforded pyridines, not pyrimidines
(Scheme 1, previous work).6
P
Scheme 1. Transition-Metal-Catalyzed or -Mediated
Reactions of Alkynes and Nitriles
Figure 1. Biologically active compounds.
used in polymer and supramolecular chemistry.2,3 These
compounds have therefore attracted much attention from
synthetic chemists for use in efficient syntheses.4,5
Since Brugnatelli synthesized pyrimidines,4a many synthetic
organic chemists have studied preparations of pyrimidine
derivatives. Many of the reported reactions are synthetic
methods that do not use transition metals, such as
condensations of N−C−N fragments and ketones, condensa-
tions of formamidine acetate with ketones,4b and reactions of
N-vinylamides with nitriles.4c Various other synthetic methods
for the synthesis of pyrimidine derivatives have been reported,
such as transition-metal-mediated or -catalyzed condensation
reactions of amidines with propargylic alcohols5a and three-
component coupling reactions of functionalized enamines,
triethyl orthoformate, and potassium aryltrifluoroborates with
pyrimidine chlorides.5d
Recently, we reported that low-valent Nb catalysts
(NbCl3(DME)7 and NbCl5/hydrosilane system8d) are useful
for cycloaddition reactions of terminal alkynes, internal alkynes,
and alkenes to give 1,3-cyclohexadienes.8
In this paper, we report a simple strategy for the NbCl5-
mediated synthesis of tri- and tetrasubstituted pyrimidine
derivatives using excellently chemoselective and highly
regioselective intermolecular cycloaddition reactions of one
alkyne molecule and two nitrile molecules (Scheme 1, this
work).
Initially we chose 4-octyne (1a) and benzonitrile (2a) as
model substrates and performed intermolecular cycloaddition
Intermolecular cycloaddition of one alkyne molecule and two
nitrile molecules is one of the simplest and atom-economical
Received: July 18, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om300669s | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
a
reactions using various transition-metal catalysts (Table 1). For
instance, 1a (1 mmol) was reacted with 2a (2 mmol) in the
Table 2. Scope of Reaction of Alkynes 1 with Aryl Nitrile 2
a
Table 1. Optimization of the Model Reaction
b
entry
Lewis acid (amt (equiv))
yield of 3a (%)
c
1
NbCl5 (0.2)
NbCl5 (0.2)
NbF5 (0.2)
TaCl5 (0.2)
ZrCl4 (0.2)
AlCl3 (0.2)
FeCl3 (0.2)
CeCl3 (0.2)
NbCl5 (1.2)
NbCl5 (1.2)
10
2
3
4
5
6
7
8
9
21
12
9
trace
12
trace
d
n.d.
50
e
10
86 (79)
a
Reaction conditions: 1a (1 mmol), 2a (2 mL) and Lewis acid
b
(amount based on 1a) at 60 °C for 22 h under Ar (entries 2−8). GC
yields except for the value in the parentheses. Reaction conditions: 1a
c
(1 mmol), 2a (2 mmol), and NbCl5 (0.2 mmol) in 1,2-dichloroethane
d
e
(1 mL) at 60 °C for 22 h under Ar. Not detected by GC. The
reaction was performed by adding NbCl5 (0.2 mmol) in six portions
every 2 h over 22 h ((0.2 mmol/2 h)6).
presence of NbCl5 (0.2 mmol) in 1,2-dichloroethane (1 mL) at
60 °C for 22 h. 2,4-Diphenyl-5,6-n-dipropylpyrimidine (3a)
was obtained in 10% yield with excellent chemoselectivity
(Table 1, entry 1). When 2 mL of 2a was used instead of 1,2-
dichloroethane, 3a was obtained in 21% yield (entry 2).
To optimize the reaction, we compared NbCl5 with different
metal salts (NbF5, TaCl5, ZrCl4, AlCl3, FeCl3, and CeCl3)
(entries 3−8). The catalyst precursor significantly influenced
the reaction activity. The best results for the model cyclo-
addition reaction were observed in the presence of an NbCl5
catalyst. We tried to increase the yield of 3a. In one of many
attempts, we tried a stoichiometric reaction; this gave 3a in 50%
yield (entry 9). We succeeded in obtaining 3a in 86% yield by
adding NbCl5 (0.2 mmol) to the reaction mixture six times
every 2 h (entry 10). Surprisingly, 1,2,3,4,5,6-hexapropylben-
zene from cyclotrimerization of 4-octyne was not formed in the
present reaction.9 Here, low-valent Nb compounds such as
NbCl3(DME)7,8did not afford 3a at all under these conditions.
Under the optimized reaction conditions, i.e., Table 1, entry
10, we investigated the scope of the reaction using various
alkynes (Table 2). For instance, the internal alkynes 4-octyne
(1a), 3-hexyne (1b), and 5-decyne (1c) participated in the
reaction and the corresponding pyrimidine derivatives (3a−c)
were obtained in 72−82% isolated yields with excellent chemo-
and regioselectivities (entries 1−3).
a
Reaction conditions: see optimized conditions (Table1, entry 10).
Isolated yields. Not detected by GC. The values in parentheses
b
c
d
show the selectivity (%) of 2,4,6-substituted adducts.
However, when 1-phenyl-1-propyne (1g) was used, 3g was
obtained in 76% yield with >99% regioselectivity. The reactions
of trimethylsilylacetylene and ethyl propiolate did not afford the
products 3.
We next investigated the scope of the reaction with terminal
alkynes. The reaction was successful using terminal alkynes
with n-octyl, phenyl, and cyclohexyl groups. The terminal
alkynes 1-decyne (1h), phenylacetylene (1i), and cyclo-
hexylacetylene (1j) gave the corresponding desired products
(3h−j) in 50−74% yields with >95% regioselectivity and
excellent chemoselectivity (entries 8−10). In addition, 4-
methylbenzonitrile (2b) and 4-fluorobenzonitrile (2c) were
also employed in the reaction, affording the corresponding
products (entries 11 and 12). The reaction of an aliphatic
nitrile such as octanonitrile or trimethylsilyl cyanide proved to
be sluggish under these conditions.
However, the reaction with diphenylacetylene (1d) did not
give any of the corresponding pyrimidine (3d; entry 4). The
regioselectivities of the desired products from the reactions of
unsymmetrical alkynes (1e−g) and 2a were influenced by
electronic effects on the unsymmetrical internal alkynes (entries
5−7). For instance, 2-pentyne (1e) and 4-methyl-2-pentyne
(1f) gave the corresponding products in good yields as a
mixture of regioisomers (3e,f and 3e′,f′); these were
characterized by 1H and 13C NMR spectroscopy, and the
resonances were assigned using 2D-HMQC and HMBC.
B
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Organometallics
Communication
On the basis of these experiments, we propose the reaction
mechanism shown in Scheme 2. The reaction initiates NbCl5-
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, ALCA from Japan Science
and Technology Agency (JST), and MEXT-Supported
Program for the Strategic Research Foundation at Private
Universities (2010−2014).
Scheme 2. Plausible Mechanism for the Reaction of
Phenylacetylene (1i) and Benzonitrile (2a)
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* Supporting Information
Text, figures, and tables giving experimental and character-
1
ization data and original H, 13C, HMQC, and HMBC NMR
spectra for products 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: obora@kansai-u.ac.jp.
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The authors declare no competing financial interest.
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