Solvent-free synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-ones catalyzed by BiCl3: A green route to a privileged backbone

Article abstract of DOI:10.1002/ejoc.201500227

An extensive array of 4H-pyrido[1,2-a]pyrimidin-4-ones have been synthesized from commercially available 2-aminopyridines and β-oxo esters with excellent yields under solvent-free conditions. The reaction, catalyzed by cheap and nontoxic BiCl₃,

Full text of DOI:10.1002/ejoc.201500227

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500227
Solvent-Free Synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-ones Catalyzed by BiCl3:
A Green Route to a Privileged Backbone
Irwan I. Roslan,[a] Qiu-Xuan Lim,[a] Aijuan Han,[a] Gaik-Khuan Chuah,*[a] and
Stephan Jaenicke*[a]
Keywords: Bismuth / Green chemistry / Solvent-free reactions / Cyclization / Heterocycles
An extensive array of 4H-pyrido[1,2-a]pyrimidin-4-ones have
been synthesized from commercially available 2-amino-
pyridines and β-oxo esters with excellent yields under sol-
vent-free conditions. The reaction, catalyzed by cheap and
nontoxic BiCl3, proceeds with short reaction times under mild
conditions and normal atmosphere. Only water and alcohol
are formed as co-products in this green reaction.
Introduction
4H-Pyrido[1,2-a]pyrimidin-4-one is a privileged scaffold
that appears in many fused heterocyclic compounds, which
fulfill Lipinski’s rule of fives for orally active drugs with
good bioavailability.[1] Thus, it is not surprising that several
derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one possess bio-
logical activities,[2] and this skeletal structure can be found
in drugs with anti-asthmatic, anti-cancer, anti-depressant,
anti-hypertensive, anti-malarial, anti-microbial, anti-oxi-
dant, anti-ulcerative, tranquillizing, and analgesic proper-
ties as well as a human leukocyte elastase inhibitor
(Scheme 1).[3] 4H-Pyrido[1,2-a]pyrimidin-4-ones are also
used as photographic sensitizers, curing agents for polyiso-
cyanates, dyes for acrylic nylon and polyester fibres, organic
blue-emitting compounds and as synthetic intermediates.[4]
The traditional method to construct 4H-pyrido[1,2-a]-
Scheme 1. Drugs possessing the 4H-pyrido[1,2-a]pyrimidin-4-ones
skeleton.
pyrimidin-4-ones from 2-aminopyridines and various β-oxo chloromethyl ketones and 2-aminopyridines under reflux in
esters requires high reaction temperatures of 150–200 °C ethanol but obtained low to moderate yields of up to 81%
and corrosive acidic reagents like polyphosphoric acid, sul- only.[9] Solid-phase synthesis of 4H-pyrido[1,2-a]pyrimidin-
furic acid or phosphoryl chloride.[5] Cassis et al. reported a 4-ones could be carried out at 90 °C but still required the
noncorrosive synthesis of 2-aminopyridines with Meldrum’s use of acetic acid as a cosolvent with DMF and long reac-
acid, but the reaction required a temperature of 250 °C.[6] tion times of 16 h.[10] Use of activated 1,4-enediones and
Besides oxo esters, (2-alkoxymethylene)malonic esters, 3- Cu(OAc)2·H2O as catalyst enabled the synthesis of 4H-pyr-
alkoxyacrylic esters, succinic esters and glutaric esters are ido[1,2-a]pyrimidin-4-ones at 80 °C with good to moderate
used with 2-aminopyridines.[7] More recent syntheses allow yields of up to 91% after 6 h.[11] We envisioned that by re-
for lower reaction temperatures but still require harsh acidic placing corrosive Brønsted acids with a mild, moisture- and
conditions or activated starting materials that have to be air-stable Lewis acid like Bi(OTf)3 or BiCl3, the reaction
synthesized.[8] Recently, Bonacorso et al. formed 4H- between 2-aminopyridines and β-oxo esters could be made
pyrido[1,2-a]pyrimidin-4-ones using β-alkoxyvinyl tri- to proceed under more benign conditions and thereby offer
an environmentally friendly alternative. Bismuth catalysis
[a] Department of Chemistry, National University of Singapore
has gained attention over the past decade due to an increas-
ing focus on green chemistry.[12] Although bismuth is a
heavy metal, it is not carcinogenic.[13] Bismuth salts are
nontoxic and are, in fact, rated with lower toxicity than
even NaCl.[14] They are cheap, readily available and easy to
handle, being moisture- and air-stable.
3 Science Drive 3, Singapore 117543
E-mail: chmsj@nus.edu.sg
chmcgk@nus.edu.sg
http://www.chemistry.nus.edu.sg/people/academic_staff/
jaenicke.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500227.
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SHORT COMMUNICATION
We hereby report a bismuth(III)-catalyzed solvent-free Table 2. Scope of the reaction.[a]
synthesis of 4H-pyrido[1,2-a]pyrimidin-4-one and its ana-
logues from readily available and inexpensive starting mate-
rials, i.e., 2-aminopyridines and β-oxo esters. The reaction
can be carried out neat, requiring only short reaction times
and low temperatures to access a wide scope of products.
Water and alcohols are formed along with the desired prod-
uct.
Results and Discussion
Initially, several solvents were tested for the reaction be-
tween methyl acetoacetate (1) and 2-aminopyridine (2)
using 5 mol-% of Bi(OTf)3 as the catalyst (Table 1, En-
tries 1–4). The best yield of 88% was obtained in toluene.
Following previous literature on solvent-free bismuth-cata-
lyzed reactions,[15] we tried a neat reaction and were de-
lighted that the reaction proceeded with Ͼ 99% yield
(Table 1, Entry 5). A blank without catalyst was also con-
ducted, but only traces of 3aa were formed, confirming that
bismuth(III) salts are necessary to catalyze the reaction
(Table 1, Entry 6). Other bismuth(III) salts were screened
for the reaction, and BiCl3 was found to give Ͼ 99% yield
of 3aa (Table 1, Entries 7–8). In comparison, only traces of
the product were observed with InCl3 or ZnCl2 as catalyst
(Table 1, Entries 9–10). Because of its much lower cost com-
pared to Bi(OTf)3, BiCl3 was chosen as the catalyst in fur-
ther optimization studies.
Table 1. Optimization parameters for BiIII-catalyzed syntheses of
4H-pyrido[1,2-a]pyrimidin-4-ones.[a]
Entry
Solvent
Catalyst
T
[°C]
t
[h]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
dioxane
NO2Me
H2O
toluene
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
–
Bi(OAc)3
BiCl3
InCl3
ZnCl2
BiCl3
BiCl3
BiCl3
BiCl3
100
100
100
100
100
100
100
100
100
100
100
100
100
80
8
8
8
8
8
8
8
8
5
5
5
3
1
3
3
37 (28)
38 (28)
41 (35)
88 (85)
100 (100)
traces
21(10)
100 (99)
traces
–
–
–
–
–
–
–
–
–
–
–
0
99 (98)
97 (95)
85 (82)
75 (70)
52 (46)
BiCl3
50
[a] Reaction conditions: 2 (0.5 mmol), 1 (2.0 equiv.) and catalyst
(0.025 mmol) in 4 mL of solvent. [b] Yield determined by GC
analysis; isolated yields in parentheses.
[a] Reaction conditions: 2 (0.5 mmol), 1 (1.0 mmol) and BiCl3
(0.025 mmol) neat at 100 °C for 3 h. Percentage isolated yields. [b]
The ethyl carboxylate derivative is used instead of the methyl carb-
oxylate. [c] Reaction was carried out in 4 mL of toluene.
Reducing the reaction time from 8 to 3 h did not affect
the reaction, but a further decrease to 1 h resulted in a sig-
nificant drop of the yield of 3aa to 85% (Table 1, Entries 8,
2
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Synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-ones
11–13). Lowering of the reaction temperature from 100 to ceeded with a high yield of 94% of 3an with 2-aminothi-
80 and 50 °C led to a reduction in yield to 75 and 52%, azole, only traces of 3ao were formed with 2-aminopyrimid-
respectively (Table 1, Entries 13–15). Hence, the reaction ine (Table 2, 3an and 3ao). This could be due to the induc-
can be carried out with high yields of 3aa by using tive effect of the additional N-atom on the pyrimidine ring,
0.5 mmol of 2, 2 equiv. of 1, and 5 mol-% BiCl3 (relative to which reduces the nucleophilicity of the NH2 group.
2) as catalyst, neat, at 100 °C for 3 h.
A plausible mechanism for the reaction (Figure 1) is pro-
Next, the scope of the reaction under the optimized con- posed. In the first step, a molecule of BiCl3 complexes to 1
ditions was investigated (Table 2). Essentially quantitative through the carbonyl group of the ketone moiety. This en-
yields were obtained when β-oxo thioesters and β-oxo hances the electrophilicity of the carbonyl functionality and
amides were treated with 2 (Table 2, 3aaЈЈ and 3aaЈЈЈ). The promotes the nucleophilic addition of the amino group of
reaction proceeded well with ethyl carboxylates of β-oxo 2, forming intermediate A with release of one HCl mol-
esters (Table 2, 3aaЈ). Excellent yields were also obtained ecule. A ring-closing condensation reaction forms interme-
with bulkier substituents at the C-2 position of the desired diate B with release of MeOH. Abstraction of the α-H atom
product, although the yield was slightly lower when a as HCl and transfer of the oxygen atom to the bismuth
phenyl substituent was used (Table 2, 3ba–3ea). Interest- center generate BiOCl intermediate C and release the prod-
ingly, reactions of 2 with diethyl 2-methyl-3-oxosuccinate uct 3aa. The BiCl3 catalyst is regenerated by the reaction of
and diethyl 3-oxopentanedioate gave good to excellent C with the 2 equiv. of HCl formed during the reaction, and
yields (Table 2, 3fa and 3ga). However, when ethyl 4-chloro- the cycle can be repeated.
acetoacetate was used as the substrate, good yields of 3ha
were obtained only when the reaction mixture was diluted
with toluene. Under solvent-free conditions, the chloro sub-
stituent was replaced by an ethoxy group. Pleasingly, a good
yield of 81% was obtained with a trifluoromethyl substitu-
ent at the C-2 position (Table 2, 3ia). Introduction of a CF3
moiety frequently enhances certain biological, chemical and
physical properties and increases lipophilicity and bioavail-
ability.[16] Hence, it is found in pharmaceutical compounds
such as Sorafenib and Leflunomide.[17] We were elated that
even with substituents at the C-3 position, the reaction gave
excellent yields (Table 2, 3ja–3ma).
A comparison between the yields for 3ea and 3la with
the substituent at C-2 and C-3 position, respectively, sug-
gests that steric factors are more prominent for bulky R1
than R2 in 1. The reaction also proceeded smoothly with
various cyclic β-oxo esters to form the corresponding prod-
ucts in good to excellent yields (Table 2, 3na–3pa).
Several substituted 2-aminopyridines were also treated
with 1 under the optimized conditions. Excellent yields were
obtained with substrates bearing a methyl group at C-3, C-
4, C-5 or C-6 of the 2-aminopyridine structural motif and
Figure 1. Proposed mechanism for the BiIII-catalyzed formation of
4H-pyrido[1,2-a]pyrimidin-4-ones.
even for an ethyl group at the C-4 position (Table 2, 3ab–
3af). Substrates with a halogen substituent at the C-5 posi-
tion of 2-aminopyridine gave high yields of 95–97%
(Table 2, 3ag–3aj). The reaction also proceeded well with
To further explore the usefulness of this method, the syn-
an OH or CO2Et group at the C-3 position to form 3ak thesis of 3ma was scaled up by using 15 mmol of aminopyr-
and 3am with 97 and 86% yield, respectively. However, only idine 2 and 2 equiv. of ethyl 2-benzyl-3-oxobutanoate
a moderate yield of 65% of 3al was obtained when the (Scheme 2). An isolated yield of 89% of white needle-like
strongly electron-withdrawing NO2 group was present at crystals of 3ma was obtained after workup and recrystalli-
the C-5 position. Furthermore, while the reaction pro- zation.
Scheme 2. Scaled-up synthesis of 3ma.
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I. I. Roslan, Q.-X. Lim, A. Han, G.-K. Chuah, S. Jaenicke
SHORT COMMUNICATION
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Conclusions
We have developed an efficient new method to 4H-pyr-
ido[1,2-a]pyrimidin-4-ones using BiCl3 as catalyst. The re-
action applies to a wide spectrum of β-oxo esters as well as
the 2-aminopyridine substrates. These starting compounds
are cheap and commercially available. Excellent yields are
obtained in a short reaction time under mild reaction con-
ditions without needing any solvent or an inert atmosphere.
This green reaction forms only water and alcohol as co-
products. A mechanism has been proposed based on a tan-
dem nucleophilic addition and ring-closing condensation
reaction.
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Experimental Section
General Procedure for Formation of 4H-Pyrido[1,2-a]pyrimidin-4-
ones: A 5 mL round-bottomed flask was charged with methyl
acetoacetate (1) (107.9 μL, 1 mmol), 2-aminopyridine (2) (47.1 mg,
0.5 mmol) and BiCl3 (7.9 mg, 0.025 mmol). The reaction mixture
was stirred at 100 °C for 3 h. The mixture was taken up in a mini-
mal amount of ethanol and filtered. The filtrate was purified by
column chromatography with a short column, using ethyl acetate
and hexane (9:1, v/v) as eluent to afford clear needle-like crystals
of 3aa in essentially 100% yield.
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2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(3aa):
1H
NMR
(300 MHz, CDCl3): δ = 8.93 (d, J = 7.2 Hz, 1 H), 7.64 (t, J =
7.4 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.03 (t, J = 6.6 Hz, 1 H),
6.24 (s, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (300 MHz, CDCl3): δ
= 165.1, 157.6, 150.5, 136.1, 127.0, 125.6, 114.9, 103.1, 24.5 ppm.
HRMS (ESI): calcd. for C9H9N2O [M – H]+ 161.0709, found
161.0712.
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General Procedure for the Scaled-up Synthesis of 3ma: A 50 mL
round-bottomed flask was charged with ethyl 2-benzyl-3-oxo-
butanoate (6.38 mL, 30 mmol), 2-aminopyridine (2) (1.41 g,
15 mmol) and BiCl3 (237 mg, 0.75 mmol). The reaction mixture
was stirred at 100 °C for 5 h. The mixture was diluted with a mini-
mal amount of ethanol and filtered. The filtrate was purified by
column chromatography using ethyl acetate/hexane (2:3, v/v) as
eluent and further recrystallization with ethanol, providing 3ma as
white needle-like crystals in 89% yield.
[6]
[7]
[8]
Examples of recent syntheses of 4H-pyrido[1,2-a]pyrimidin-4-
one and its derivatives: a) W. Engen, T. E. O’Brien, B. Kelly, J.
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3-Benzyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(3ma):
1H
NMR (300 MHz, CDCl3): δ = 8.82 (d, J = 4.5 Hz, 1 H), 7.35 (s, 2
H), 7.24–6.96 (m, 5 H), 6.82 (s, 1 H), 3.97 (s, 2 H), 2.36, (s, 3 H)
ppm. 13C NMR (300 MHz, CDCl3): δ = 161.6, 157.5, 148.0, 139.3,
134.5, 127.8, 127.8, 126.6, 125.6, 125.1, 114.3, 114.1, 31.7, 22.4
ppm. HRMS (ESI) calcd. for C16H15N2O [M – H]+: 251.1179,
found 251.1174.
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Synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-ones
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Received: February 16, 2015
Published Online: ᭿
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5

Job/Unit: O50227
/KAP1
Date: 04-03-15 13:26:00
Pages: 6
I. I. Roslan, Q.-X. Lim, A. Han, G.-K. Chuah, S. Jaenicke
SHORT COMMUNICATION
Heterocycle Synthesis
4H-Pyrido[1,2-a]pyrimidin-4-ones, a privi-
leged backbone for developing drugs with
good oral bioavailability, are easily synthe-
sized by a solvent-free BiCl3-catalyzed tan-
dem reaction with an expanded scope and
excellent yields.
I. I. Roslan, Q.-X. Lim, A. Han,
G.-K. Chuah,* S. Jaenicke* .............. 1–6
Solvent-Free Synthesis of 4H-Pyrido[1,2-a]-
pyrimidin-4-ones Catalyzed by BiCl3: A
Green Route to a Privileged Backbone
Keywords: Bismuth / Green chemistry / Sol-
vent-free reactions / Cyclization / Hetero-
cycles
6
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Eur. J. Org. Chem. 0000, 0–0