Synthesis of highly substituted 4H-pyrido[1,2- A ]pyrimidines via a one-pot three-component condensation reaction

Article abstract of DOI:10.1021/co400086u

A one-pot three-component reaction, involving condensation of 2-aminopyridines, aldehydes, and ketones/aldehydes under trifluoromethanesulfonic acid catalysis, provides rapid access to highly substituted novel 4H-pyrido[1,2-a]pyrimidines.

Full text of DOI:10.1021/co400086u

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Article
Synthesis of Highly Substituted 4H-Pyrido[1,2-a]pyrimidines
via a One-Pot Three-Component Condensation Reaction
Kai Yang, Jinbao Xiang, Guochen Bao, Qun Dang, and Xu Bai
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400086u • Publication Date (Web): 05 Aug 2013
Downloaded from http://pubs.acs.org on August 9, 2013
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Synthesis of Highly Substituted 4HꢀPyrido[1,2ꢀ
a]pyrimidines via a OneꢀPot ThreeꢀComponent
Condensation Reaction
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Kai Yang, Jinbao Xiang*, Guochen Bao, Qun Dang*, and Xu Bai
The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical
Sciences and The College of Chemistry, Jilin University, 1266 Fujin Road, Changchun, Jilin
130021, P. R. China
KEYWORDS: MCRs, multicomponent reactions, threeꢀcomponent reaction, 2ꢀaminopyridine,
4Hꢀpyrido[1,2ꢀa]pyrimidine
ABSTRACT: A oneꢀpot threeꢀcomponent reaction, involving condensation of 2ꢀaminopyridines,
aldehydes and ketones/aldehydes under trifluoromethanesulfonic acid catalysis, provides rapid
access to highly substituted novel 4Hꢀpyrido[1,2ꢀa]pyrimidines.
INTRODUCTION
Pyridopyrimidines are an important class of nitrogenꢀcontaining heterocycles since many of
them exhibit a plethora of interesting biological activities.1–10 For example, pyrido[1,2ꢀ
a]pyrimidine constitutes the core structure of some marketed drugs, including the antiasthmatic
agent pemirolast,11 the tranquilizer pirenperone,12 and the antiallergic agent barmastine.13 Other
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pyrido[1,2ꢀa]pyrimidine derivatives are known for their antidepressant,14 gastrointestinal
protective,15 neurotropic and stressꢀprotecting,16 and anticancer properties.17
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Over the past decades, a number of approaches to the synthesis of 4Hꢀpyrido[1,2ꢀ
a]pyrimidines have been described, and these methodologies focused on the traditional twoꢀ
component condensation of 2ꢀaminopyridines with a variety of bifunctional electrophiles.10,18–26
Multicomponent reactions (MCRs) have emerged as powerful methods for creating molecular
complexity and diversity, and are recognized as important tools for a successful drug discovery
program to access drugꢀlike molecules in a rapid and efficient manner.27–31 However,
multicomponent reactions for the synthesis of 4Hꢀpyrido[1,2ꢀa]pyrimidines are scarce in
general.32,33 To the best of our knowledge, there is no report on the synthesis of 4ꢀalkyl/aryl
substituted 4Hꢀpyrido[1,2ꢀa]pyrimidines via MCRs.
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The Biginelli reaction is a commonly used threeꢀcomponent reaction involving oneꢀpot
condensations of urea, aldehydes, and βꢀketoesters.34 Recently, we reported a versatile threeꢀ
component reaction of 4ꢀaminopyrimidines, aldehydes and βꢀketoesters leading to 4Hꢀ
pyrimido[1,6ꢀa]pyrimidines (Scheme 1).35 As part of our ongoing efforts to develop
methodologies to prepare libraries of novel heterocycles,36–41 we set out to discover and develop
novel reactions to extend the scope of the wellꢀknown Biginelli reaction through the use of
readily available ketones/aldehydes in place of βꢀketoesters (active methylene compound) in 2ꢀ
aminopyridine systems as shown in Scheme 2. Herein, the details of these studies are presented.
Scheme 1. Threeꢀcomponent reaction of 4ꢀaminopyrimidines, aldehydes and βꢀketoesters
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Scheme 2. Threeꢀcomponent reaction of 2ꢀaminopyridines 1, aldehydes 2 and ketones/aldehydes
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RESULTS AND DISCUSSION
Initially, 2ꢀaminopyridine 1{1}, 4ꢀchlorobenzaldehyde 2{1}, and cyclohexanone 3{1} were
selected to investigate the reaction conditions suitable to generate product 4{1,1,1} (Scheme 3).
First, the previously reported conditions for the pyrimidine system was studied, only 41% yield
of the desired product 4{1,1,1} was obtained by heating 0.5 equiv CF3SO3H, 1.0 equiv 1{1}, 3.0
equiv 2{1} and 3.0 equiv 3{1} for 46 hours at 110 oC; another product was also isolated and
identified as compound 5{1,1,1} (13%).42 The above results prompted us to screen for an
optimized condensation condition, and the results are summarized in Table 1. Treatment of
compound 1{1} (1.0 equiv) with compounds 2{1} (1.1 equiv) and 3{1} (1.1 equiv) in the
presence of CF3SO3H (0.5 equiv) in refluxing acetonitrile for 130 hours gave the desired product
4{1,1,1} in 45% yield and side product 5{1,1,1} in 17% yield (entry 2, table 1). Variation of
solvents (entries 3–5, table 1) did not lead to significant improvement in the yield of compound
4{1,1,1}, but using toluene as the solvent did shorten the reaction time possibly due to the higher
reaction temperature (entry 5, table 1). Next, other acids, including pTsOH, TFA, AcOH, and
PPA, were screened but neither did produce higher yield of compound 4{1,1,1} nor reduce the
amount of side product 5{1,1,1} (entries 6–9, table 1). Reaction concentration was also
investigated: conducting the reaction at a dilute concentration of compound 1{1} (0.5 M, entry
10, table 1) or under a solventꢀfree condition (entry 11, table 1) did not increase the yield of
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compound 4{1,1,1}. Formation of the side product 5{1,1,1} indicates that two molecules of
aldehyde 2{1} participated in the reaction, therefore optimization of the stoichiometry of
reactants could minimize the formation of compound 5{1,1,1} leading to the higher yield of
product 4{1,1,1}. As expected, increasing ketone 3{1} produced more desired product 4{1,1,1}
and less side product 5{1,1,1} (entries 13–15, table 1), while reducing the amount of ketone 3{1}
led to even more side product 5{1,1,1} (entry 12, table 1). An acceptable condition was
discovered as heating a mixture of 0.5 equiv CF3SO3H, 1.0 equiv 1{1}, 1.1 equiv 2{1}, and 3.0
equiv 3{1} in toluene for 21 hours at reflux (entry 14, table 1), which gave product 4{1,1,1} in
69% yield and only 8% of side product 5{1,1,1}. Therefore the reaction condition of entry 14
was applied to further studies.
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Scheme 3. Threeꢀcomponent reaction of 2ꢀaminopyridine 1{1}, 4ꢀchlorobenzaldehyde 2{1} and
cyclohexanone 3{1}
Table 1. Optimization of the threeꢀcomponent reactiona
2{1} 3{1} acid
(eq) (eq) (0.5 eq)
temp. [1{1}] time 4{1,1,1}/5{1,1,1}
(oC) (yield, %)b
(M) (h)
entry
solvent
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3.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
3.0
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1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.5
2.0
3.0
5.0
CF3SO3H none
110
ꢀꢀ
46
41/13
2
CF3SO3H CH3CN reflux 2.0
130 45/17
120 39/16
3
CF3SO3H EtOH
CF3SO3H DMF
reflux 2.0
110 2.0
4
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43/12
10/50c
56/14
69/8
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CF3SO3H toluene reflux 2.0
6
pTsOH
TFA
toluene reflux 2.0
toluene reflux 2.0
toluene reflux 2.0
toluene reflux 2.0
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8
AcOH
PPA
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CF3SO3H toluene reflux 0.5
CF3SO3H none 110 ꢀꢀ
CF3SO3H toluene reflux 2.0
CF3SO3H toluene reflux 2.0
CF3SO3H toluene reflux 2.0
CF3SO3H toluene reflux 2.0
58/6
a All reactions were conducted with 1.0 mmol of 1{1}. b Isolated yield. c Yield based on
cyclohexanone 3{1}.
To explore the scope of this oneꢀpot threeꢀcomponent reaction, various 2ꢀaminopyridines
1{1−4}, aldehydes 2{1−15} and ketones/aldehydes 3{1−9} were employed under the above
optimized reaction conditions (Scheme 2, Figure 1). The results are summarized in Table 2 and
Table 3.
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2-Aminopyridines 1:
4
5
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7
NH2
N
NH2
NH2
NH2
N
N
N
N
Cl
EtO2C
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{1}
{3}
{2}
{4}
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Aldehydes 2:
O
O
O
O
O
O
O
Me
O
Me
Cl
MeO
Me
O2N
{1}
{2}
{5}
{3}
{4}
{6}
{7}
O
O
O
O
O
O
O
S
N
{8}
{9}
{12}
{15}
{10}
{11}
{13}
{14}
Ketones/aldehydes 3:
O
O
O
O
O
{1}
{5}
{2}
{3}
{4}
O
O
O
O
{6}
{7}
{8}
{9}
Figure 1. Diversity elements employed during library synthesis. 2ꢀAminopyridines 1{1−4},
aldehydes 2{1−15}, and ketones/aldehydes 3{1−9}
Table 2. Threeꢀcomponent reaction of 2ꢀaminopyridines 1{1−4}, aldehydes 2{1−14} and
cyclohexanone 3{1}a
entry 1{1−4}
2{1−14}
time (h)
product
yield (%)b
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1
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{3}
{4}
{2}
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4{1,2,1}
4{1,1,1}
4{1,3,1}
4{1,4,1}
4{1,5,1}
4{1,6,1}
4{1,7,1}
4{1,8,1}
4{1,9,1}
4{1,10,1}
4{1,11,1}
4{1,12,1}
4{1,13,1}
4{1,14,1}
4{2,1,1}
4{3,1,1}
4{4,1,1}
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2
{1}
3
{3}
4
{4}
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5
{5}
6
{6}
7
{7}
8
{8}
9
{9}
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{10}
{11}
{12}
{13}
{14}
{1}
{1}
{1}
a
Reagents and conditions: CF3SO3H (0.5 equiv), 1{1−4} (1.0 equiv), 2{1−14} (1.1 equiv),
and 3{1} (3.0 equiv) in toluene, reflux. b Isolated yield.
The scope of aldehydes (R2CHO) was investigated using cyclohexanone and results are
disclosed in Table 2. Various benzaldehydes are suitable substrates leading to the desired
products in good to high yields (entries 1–7, Table 2). Both electronꢀwithdrawing and electronꢀ
donating groups are tolerated although 2ꢀmethylbenzaldehyde (entry 6, Table 2) gave slightly
lower yield compared to benzaldehyde (entry 1, Table 2), indicating possible steric hindrance
effects. Other aryl and heteroaryl aldehydes (entries 8–10, Table 2) are also tolerated but gave
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the desired products in lower yields compared to benzaldehyde (entry 1, Table 2). Aliphatic
aldehydes were also studied and the desired products were obtained in good to high yields. It is
interesting to note that simple straight chain aliphatic aldehydes gave moderate yields (entries 11
and 12, Table 2), while cyclic aliphatic aldehydes produced excellent yields (entries 13 and 14,
Table 2). To test the electronic effects for the substituents of the 2ꢀaminopyridines, both electronꢀ
donating and electronꢀwithdrawing groups were tested (entries 15–17, Table 2). Tuning the
electron density of the 2ꢀamino group had little effect on product yields, but it appears that the
reaction proceeded faster when there is an electronꢀdonating group on 2ꢀaminopyridines (entry
15 vs. entries 16 and 17, Table 2). Having completed the investigation of the scope of aldehydes
2{1−14}, various carbonyl compounds 3{2−9} were studied and results are summarized in
Table 3.
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Table 3. Scope of the threeꢀcomponent reaction of 2ꢀaminopyridine 1{1}, aldehydes 2{1} or
2{14−15} and ketones/aldehydes 3{2−9}a
entry 2{1}/2{14−15} 3{2−9}
time (h)
24
product
yield (%)b
1
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{1}
{1}
{1}
{1}
{1}
{1}
{2}
{3}
{4}
{5}
{6}
{7}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,1,6}
4{1,1,7}
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0
24
84
41
26
62c
43c
168
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{14}
{15}
{1}
{6}
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16
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4{1,14,6}
4{1,15,6}
4{1,1,8}
4{1,1,9}
65c
62d
0
8
{6}
{8}
{9}
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{1}
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a
Reagents and conditions (except designated): CF3SO3H (0.5 equiv), 1{1} (1.0
b
equiv), 2{1} (1.1 equiv), and 3{2−5} or 3{8−9} (3.0 equiv) in toluene, reflux.
c
Isolated yield. CF3SO3H (0.5 equiv), 1{1} (1.0 equiv), 2{1} or 2{14} (2.0 equiv),
and 3{6−7} (1.1 equiv) in toluene, reflux. d CF3SO3H (0.5 equiv), 1a (1.0 equiv), and
phenylacetaldehyde (4.1 equiv) in toluene, reflux.
As evident from Table 3, acyclic ketones (R3COCH2R4) are also compatible for the current
reactions to yield the expected products (entries 1, 3 and 4, Table 3) with the exception of
acetophenone. The reaction of acetophenone led to complex reaction mixtures which might be
due to the instability of product 4{1,1,3} under the current reaction conditions. It is noteworthy
that the reaction also can be extended to aliphatic aldehydes, although moderate yields were
obtained for reactions involving phenylacetaldehyde and pentanal (entries 5–7, Table 3).43 The
selfꢀcondensation reactions of phenylacetaldehyde on treatment with 2ꢀaminopyridine 1{1} was
also investigated, which produced the desired product 4{1,15,6} in 62% yield (entry 8, Table 3).
The case of cyclopentanone was surprising and failed to give the desired product 4{1,1,8} (entry
9, Table 3). On the other hand, the reaction of cycloheptanone proceeded smoothly to form the
desired product 4{1,1,9} in good yield (entry 10, Table 3). To unambiguously identify the
structures of compound 4, compound 4{1,1,6} Xꢀray crystallographic analysis was performed
(Figure 2).44
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Figure 2. ORTEP diagram of compound 4{1,1,6}
Mechanistically, several reaction pathways could be envisioned to generate products 4 in the
current MCR. After carefully examination of our experimental results and considering existing
literature reports,21,24,43,45–47 we propose two potential mechanistic pathways as shown in Scheme
4 to account for the current multicomponent reactions. The first step of the current MCR is the
formation of intermediate 6 through CF3SO3H promoted Knoevenagel condensation of aldehyde
2 and ketone/aldehyde 3. Intermediate 6 was indeed detected and identified in the reaction
mixture by mass spectroscopy and TLC analysis during the reaction. Subsequently, 2ꢀ
aminopyridine 1 can react with intermediate 6 via two reaction pathways. For pathway a,
condensation of 2ꢀaminopyridine 1 with intermediate 6 under acidꢀcatalyzed conditions to give
imine 7,21,24 and then imine 7 underwent an intramolecular cyclization reaction to generate
product 4. On the other hand, it is plausible that the current MCR could follow reaction pathway
b: Michael addition by the nucleophilic pyridine ring N atom of intermediate 6 to afford ketone
intermediate 8,45 then an intramolecular cyclization of the imine group of intermediate 8 onto the
keto moiety to give 9, and finally an acidꢀcatalyzed elimination of water to afford product 4.
Scheme 4. Proposed reaction mechanism
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CONCLUSIONS
In summary, we have demonstrated that 2ꢀaminopyridines, aldehydes and ketones/aldehydes
undergo a productive threeꢀcomponent reaction to provide 4Hꢀpyrido[1,2ꢀa]pyrimidines in
moderate to high yields. This new MCR proved to have a broad scope since many aliphatic
aldehydes, aromatic aldehydes, heterocyclic aldehydes, cyclic ketones and acyclic ketones are
suitable substrates for the current MCR. Moreover, the current MCR is operationally simple
therefore this new methodology should allow the rapid assembly of heterocyclic scaffolds with
highly substituted 4Hꢀpyrido[1,2ꢀa]pyrimidines. This synthetic methodology complements the
wellꢀknown Biginelli reaction and existing pyridine chemistry by allowing access to libraries of
the pyridineꢀfused heterocycles.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, full characterization data, copies of LCꢀ
MSꢀELSD and NMR spectra for all products, and crystallographic data of 4{1,1,6} (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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*Tel: +86ꢀ431ꢀ85188955; Fax: +86ꢀ431ꢀ85188900; Eꢀmail: jbxiang@jlu.edu.cn,
qdang@jlu.edu.cn
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Funding Sources
This work was supported by National Natural Science Foundation of China (No. 20902036 and
81072526), the Basic Scientific Research Fund of Jilin University, and Changchun Discovery
Sciences, Ltd.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank Mr. Xuyang Luo for NMR measurements.
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