Auto-tandem catalysis: Synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones via copper-catalyzed aza-Michael addition-aerobic dehydrogenation-intramolecular amidation

Article abstract of DOI:10.1039/c3cc38131e

A copper-catalyzed domino synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones has been developed from 1,4-enediones and 2-aminoheterocycles with air as the oxidant. The Royal Society of Chemistry 2013.

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Auto-tandem catalysis: synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones
via copper-catalyzed aza-Michael addition–aerobic dehydrogenation–
intramolecular amidation
Yan Yang, Wen-Ming Shu, Shang-Bo Yu, Fan Ni, Meng Gao, An-Xin Wu*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A copper-catalyzed synthesis of 4H-pyrido[1,2-a]pyrimidin-4-
ones has been developed from 1,4-enediones and 2-
aminoheterocycles with air as the oxidant. Copper catalyst in
10 this reaction could promote three mechanistically distinct
transformations of aza-Michael addition, aerobic
dehydrogenation and intramolecular amidation.
Scheme 1 Proposed reaction route
Nitrogenꢀcontaining heterocycles are ubiquitous in natural
products and pharmaceutical drugs,1 therefore, considerable
15 attention has been paid to their efficient synthetic methods.2
Recently, an increasing number of Nꢀheterocycles have been
prepared by copperꢀcatalyzed aerobic oxidative C–N
formation strategy, which has incomparable advantages in
atom economy, bond forming efficiency and environmental
20 benignity.3 Meanwhile, autoꢀtandem catalysis involving two
or more mechanistically different transformations promoted
by a single catalyst has attracted much interests of chemists,
which could greatly improve the catalyst utilization
efficiency.4 Inspired by these excellent synthetic strategies,
25 we suppose that it would be a highly efficient method for
synthesis of Nꢀheterocycles by incorporating the copperꢀ
catalyzed aerobic oxidative C–N formation into autoꢀtandem
catalysis reactions.
50
Initially, 1,4ꢀenedione 1a and 2ꢀaminopyridine 2a were
chosen as model substrates to optimize the reaction conditions.
Fortunately, the desired product 3aa was obtained in 58%
yield when the reaction was conducted in DMF with 0.05
o
equiv of Cu(OAc)2ꢁH2O as catalyst under air at 80 C (Table 1,
55 entry 1). Much to our satisfaction, by increasing the catalyst
loading to 0.2 equiv, product 3aa was obtained in 87% yield
(entry 3). When the reaction was conducted in absence of
copper catalyst, no desired product was obtained (entry 4).
When the reaction was conducted under nitrogen, only 9%
60 yield was obtained (entry 5). These results indicated that
copper catalyst and air are necessary for this reaction. When
the reaction was conducted at lower or higher temperature (60
or 100 oC), decreased yields were obtained (entries 6–7).
Other copper catalysts and solvents were then screened under
65 air at 80 oC, but no better results were obtained (entries 8–20).
With this optimized result in hand, we next explored the
scope of this reaction. Based on our previously reported crossꢀ
coupling reaction of 1,3ꢀdicarbonyl compounds and methyl
ketones,7 a series of diversely substituted 1,4ꢀenediones 1
70 were prepared. As shown in Table 2, we first examined the
scope of this reaction for R1 substituents. For example,
substrates with electronꢀneutral (–H, –Me), electronꢀ
donating(–OMe), electronꢀwithdrawing (–NO2) and sterically
hindered (1ꢀnaphthyl, 2ꢀnaphthyl) R1 substituents could be
75 smoothly transformed into their corresponding products in
good to high yields (Table 2, entries 1–6; 71–88%). To our
delight, moderate to high yields were obtained with
halogenated and hydroxylated R1 substituents (entries 7–10;
52–86%). The heteroaryl groups for R1 were also investigated,
80 such as 2ꢀfuryl, 2ꢀbenzofuryl and 3ꢀthienyl groups, their
corresponding products were also obtained in high yields
(entries 11–13; 83–89%). Much to our satisfaction, when R1
was unsaturated (E)ꢀPhꢀ(CH=CH)ꢀ group, its corresponding
The 4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀone skeleton is
a
30 privileged scaffold in medicinal chemistry, which has shown
broad biological activities, such as antipsychotic, antiallergic,
antidepressant, the tranquillizing agent, antihypertensive and
antiulcerative.5 However, only limited methods are available
for their synthesis, which usually need wasteꢀproducing
35 leaving groups (–NR, –OR, –SCH3, –SOCH3,–Cl, –Br, –I) and
suffer from high temperature, strong acids or bases.6 Herein,
we would like to report a highly efficient method for synthesis
of 4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones from 1,4ꢀenediones and
2ꢀaminopyridines by copperꢀpromoted autoꢀtandem catalysis
40 strategy (Scheme 1).
a Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. E-mail: chwuax@mail.ccnu.edu.cn
45 † Electronic Supplementary Information (ESI) available: General
experimental procedures and characterization data for all compounds. See
DOI: 10.1039/b000000x/
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Table 1. Optimization of the Reaction Conditiona
35 Table 2. Scope of unsymmetrical 1,4ꢀenediones 1a
Entry Catalyst (equiv)
Solvent
Temp
(oC)
80
80
80
80
80
60
100
80
80
80
80
80
80
80
80
80
Yield
(%)b
58
Yield
Entry
1
R1
R2
R3
3
(%)b
1
2
3
Cu(OAc)2ꢁH2O (0.05)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
87
88
82
71
80
82
85
86
84
52
89
88
83
74
Cu(OAc)2ꢁH2O (0.1)
Cu(OAc)2ꢁH2O (0.2)
—
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
CuBr2 (0.2)
72
4ꢀMeꢀPh
4ꢀOMeꢀPh
4ꢀNO2ꢀPh
1ꢀnaphthyl
2ꢀnaphthyl
4ꢀClꢀPh
4ꢀBrꢀPh
4ꢀFꢀPh
4ꢀOHꢀPh
2ꢀfuryl
2ꢀbenzofuryl
3ꢀthienyl
(E)ꢀPhꢀ
(CH=CH)ꢀ
Ph
87
d
4
—
5c
6
9
78
82
54
48
83
46
74
72
70
82
79
60
56
72
66
7
8
9
CuCl2 (0.2)
10
11
12
13
14
15
16
17
18
19
20
CuSO4 (0.2)
CuO (0.2)
CuBr (0.2)
CuCl (0.2)
Cu2O (0.2)
CuI (0.2)
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
Cu(OAc)2ꢁH2O (0.2)
DMSO
CH3CN
C2H5OH
CH3NO2
1,4ꢀdioxane
15
16
17
18
19
20
1o
1p
1q
1r
1s
1t
4ꢀOMeꢀPh
4ꢀNO2ꢀPh
4ꢀClꢀPh
4ꢀFꢀPh
2ꢀfuryl
CH3
Et
Et
Me
Me
Et
3oa
3pa
3qa
3ra
3sa
3ta
79
75
81
78
87
91
80
78
80
80
Ph
Ph
Ph
Ph
Ph
Et
a
Unless otherwise specified, all reaction were carried out using 1a (0.5
a Reaction was carried out using 1 (1.0 mmol, 1.0 equiv), 2a (1.1 mmol,
1.1 equiv) and Cu(OAc)2ꢁH2O (0.2 mmol, 0.2 equiv) in 5 mL DMF at 80
oC under air. b Isolated yields.
mmol, 1.0 equiv), 2a (0.55 mmol, 1.1 equiv) and catalysts (0.2 equiv) in
2.5 mL solvent under air for 6 h. b Isolated yields. c Under N2. d No desired
products were obtained.
product was obtained in good yield (entry 14; 74%). As to the
substituents R2, various electrondonating (–OMe), electronꢀ
withdrawing (–NO2), and halogenated substituents (–Cl, –F)
were compatible with the reaction condition, and their
corresponding products were obtained in high yields (entries
15–18; 75–81%).8 To our delight, when R2 was 2ꢀfuryl group
or methyl group, the reaction proceeded cleanly to give the
Table 3. Scope of 2ꢀaminoheterocycles 2a
5
10 desired products with excellent yields (entries 19–20; 87–
91%).
We next examined the scope of this reaction for 2ꢀ
aminopyridines 2 (Table 3). When they were substituted with
methyl group at 3ꢀ, 4ꢀ or 5ꢀ positions, the corresponding
15 products were obtained in good to high yields (74–85%; 3ab–
3ad). To our delight, halogenꢀsubstituted 2ꢀaminopyridines
(5ꢀCl, 5ꢀBr) could also afford the desired products in good
yields (58–64%; 3ae–3af). Gratifyingly, when 2ꢀ
aminobenzothiazole was used as substrate, the reaction
20 performed very well and the corresponding product 3ag was
obtained in good yield (71%; 3ag).
To provide insight into the reaction mechanism, a control
experiment was performed (Scheme 2). When 2ꢀaminoꢀ6ꢀ
methylpyridine 2h was used as substrate, only the C–N
25 coupling product 4ah was obtained with 68% yield, which
may be due to the steric hindrance of 6ꢀmethyl group (Scheme
2a). In contrary, when the reaction was conducted in absence
of copper catalyst, no desired product 4ah was obtained
(Scheme 2b). These results clearly confirmed that
30 Cu(OAc)2ꢁH2O could efficiently catalyze the intermolecular
C–N bond formation via azaꢀMichael addition–aerobic
dehydrogenation. To further verify copper catalyst was
necessary for the intramolecular cyclization via amide bond
formation, we first obtained the C–N coupling
a
Reaction was carried out using 1a (1.0 mmol, 1.0 equiv), 2 (1.1 mmol,
40 1.1 equiv) and Cu(OAc)2ꢁH2O (0.2 mmol, 0.2 equiv) in 5 mL DMF at 80
oC under air. b Isolated yield.
intermediate 4ea in 17% yield when 1,4ꢀenedione 1e was
treated with 2ꢀaminopyridine 2a in presence of 0.05 equiv of
Cu(OAc)2ꢁH2O under air for 2 h.8 When 4ea was used as
45 substrate, a quantitative yield of 3ea was obtained with 0.2
equiv of Cu(OAc)2ꢁH2O as catalyst for 3 h (Scheme 2c). In
contrary, only trace of 3ea was obtained in absense of
Cu(OAc)2ꢁH2O (Scheme 2d). These results clearly confirmed
that Cu(OAc)2ꢁH2O could efficiently catalyze the
50 intramolecular cyclization via amide bond formation.
Based on the previous studies, a possible reaction
mechanism was proposed in scheme 3 with 1a and 2a as an
example. The azaꢀMichael addition of 1a with 2a under Cu(II)
catalysis would first generate intermediate A, which then
2
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undergoes copperꢀcatalyzed aerobic dehydrogenation reaction 30 It’s noteworthy that copper catalyst in this reaction could
to generate E/Z isomers of intermediate B.9 The Eꢀisomer of
intermediate could undergo isomerization reaction to
generate its Zꢀisomer through intermediate C, and finally it
could afford the product 3aa through copper catalyzed
promote three mechanistically distinct transformations of azaꢀ
Michael addition, aerobic dehydrogenation and intramolecular
amidation. Wide substrate scope, mild reaction condition, and
air as oxidant are also significant advantages of this reaction.
B
5
intramolecular amide bond formation. Because the reaction 35 Further application of this method is underway in our
was conducted under air atmosphere, the formed Cu(I) species
in this reaction could be oxidized by air to Cu(II), so that the
reaction can be catalytic in Cu with air as terminal oxidant.
laboratory.
We thank the National Natural Science Foundation of
China (Grant 21032001 and 21272085). We also thank Dr.
Chuanqi Zhou for his help in performing HRMS analysis and
10 It’s noteworthy that Cu(OAc)2ꢁH2O played two critical roles
in this reaction, which could not only catalyze the 40 Dr. Xianggao Meng for performing Xꢀray diffraction analysis.
intermolecular C–N bond formation through azaꢀMichaial
addition/aerobic dehydrogenation, but also catalyze the
subsequent intramolecular cyclization via amide bond
15 formation.
Notes and references
1
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Chemistry of Heterocycles: Structure, Reactions, Syntheses, and
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For some recent reviews and examples on Nꢀheterocycle synthesis
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Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464–3484;
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2
45
50
55
60
65
70
75
80
85
90
95
100
3
4
Scheme 2. Control experiments
5
Scheme 3. Proposed reaction mechanism
20
Considering the γꢀdiketone functional group in products
could easily undergo further transformation, we treated 3aa
with hydrazine hydrate in DMF, and a novel fused heterocycle
5aa was readily prepared in 81% yield (eq. 1). It's noteworthy
that this novel fused heterocycle scaffold of 5aa has never
6
25 been reported before.
7
8
M. Gao, Y. Yang, Y. D. Wu, C. Deng, L. P. Cao, X. G. Meng, and
A. X. Wu, Org. Lett., 2010, 12, 1856–1859.
CCDC 905791 (3qa) and 905792 (4ea) contain the supplementary
crystallographic data for this paper. For more details, see Supporting
Information.
D. Wang, Y. Shiraishi and T. Hirai, Chem. Commun., 2011, 47,
2673–2675.
In conclusion, we have developed a novel copper
catalyzed synthesis of 4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones from
1,4ꢀenediones and 2ꢀaminoheterocycles with air as the oxidant.
9
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Auto-tandem catalysis: synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones via
copper-catalyzed aza-Michael addition–aerobic dehydrogenation–intramolecular
amidation
A copper-catalyzed synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones has been developed from
1,4-enediones and 2-aminoheterocycles with air as the oxidant. The copper catalyst in this reaction
could promote three mechanistically distinct transformations of aza-Michael addition, aerobic
dehydrogenation and intramolecular amidation.