Efficient synthesis of dihydropyrido[4,3-d]pyrimidines by microwave-promoted three-component aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2012.11.018

A microwave-promoted solvent- and catalyst-free aza-Diels-Alder reaction is described. 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil reacts with aldehyde and amine inside a microwave reactor to produce dihydropyrido[4,3-d]pyrimidine derivatives in excellent yield and within a very short time.

Full text of DOI:10.1016/j.tetlet.2012.11.018

Accepted Manuscript
Efficient synthesis of dihydropyrido[4,3-d]pyrimidines by microwave-promo‐
ted three-component aza-Diels–Alder reaction
Manas M. Sarmah, Rupam Sarma, Dipak Prajapati, Wenhao Hu
PII:
S0040-4039(12)01939-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.018
TETL 42110
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 September 2012
1 November 2012
5 November 2012
Please cite this article as: Sarmah, M.M., Sarma, R., Prajapati, D., Hu, W., Efficient synthesis of dihydropyrido[4,3-
d]pyrimidines by microwave-promoted three-component aza-Diels–Alder reaction, Tetrahedron Letters (2012), doi:
http://dx.doi.org/10.1016/j.tetlet.2012.11.018
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Efficient synthesis of dihydropyrido[4,3-d]pyrimidines by microwave-
promoted three-component aza-Diels–Alder reaction
Manas M. Sarmaha, Rupam Sarmaa,b, Dipak Prajapatia and Wenhao Huc
aMedicinal Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat,
Assam 785006, India
bDepartment of Chemistry, Nalbari College, Nalbari, Assam 781335, India
cDepartment of Chemsitry, East China Normal University, Shanghai 200062, P R China
*Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011
E-mail address: dr_dprajapati2003@yahoo.co.uk
Keywords:
Aza-Diels-Alder reaction (ADA)
Pyrido[4,3-d]pyrimidine
Multi-component reaction (MCR)
Green Chemistry
Abstract
A microwave-promoted solvent- and catalyst-free aza-Diels-Alder reaction is
described. 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil reacts with aldehyde and amine
inside a microwave reactor to produce dihydropyrido[4,3-d]pyrimidine derivatives in
excellent yield and within a very short time.
The hetero Diels-Alder reaction is widely recognized as a powerful tool for the
construction of six membered heterocycles of biological as well as synthetic significance.1
Developing a Diels−Alder reaction strategy for generation of the target molecules has
become an intriguing and inspirational criteria for numerous synthetic groups as it ensures
excellent atom-economy of the reaction.2 Although the asymmetric3 and nonasymmetric4
versions of the aza-Diels−Alder (ADA) reaction has been studied under various catalytic
conditions, not much effort is directed toward developing catalyst- and solvent-free
techniques. In particular, multi-component ADA reactions5 involving in situ generation of
either the diene or dienophile or both is a challenging area that needs to be explored further.
The pyrimidine core has always attracted much attention as compounds containing this
structural motif are known to exhibit diverse pharmaceutical potency. The building block of
numerous natural products as well as the purine bases of DNA and RNA also contains the
pyrimidine unit.6 Fused pyrimidine systems, in particular pyridopyrimidines, exhibit
bioactivities such as antimicrobial, antibacterial, antifolate, anti-inflammatory, insecticidal,
antiviral and anticancer activities.7 Although the preparation and studies about the
pharmacological activities of pyrido[2,3-d]- and pyrido[3,2-d]pyrimidines have been carried
out in detail, construction of pyrido[4,3-d]pyrimidines9 is a relatively less studied area.
Therefore, development of mild and rapid approaches towards pyrido[4,3-d]pyrimidines,10

especially under catalyst- and solvent-free conditions, is highly desired because of their
biological significance.
In recent years, we have been involved in developing microwave-assisted organic
synthesis (MAOS)11 for generation of nitrogen containing heterocyclic compounds.12 In the
current scenario, where tackling the environmental and economic aspects of a reaction is the
greatest concern for a chemist, we have successfully shown that microwave is an excellent
alternative for carrying out catalyst- and solvent-free reactions. Further, it has been
demonstrated that urea can be effectively employed as a readily available nitrogen source for
the incorporation of a single nitrogen atom into a ring system under microwave
conditions.12c,d Herein, we report an efficient three-component solvent- and catalyst-free
ADA reaction for the synthesis of pyrido[4,3-d]pyrimidines under microwave irradiation.
Preliminary studies were directed to investigate the reaction between 6-[2-
(dimethylamino)vinyl]-1,3-dimethyl uracil with an aldehyde and an amine under microwave
irradiation. Initially reaction of 6-[2-(dimethylamino)vinyl]-1,3-dimethyl uracil 1a was
carried out with one equivalent of p-chlorobenzaldehyde 2a and p-chloroaniline 3a at 400 W
inside a microwave reactor in the absence of any catalyst under various solvent systems, and
the results obtained are summarized in Table 1 (Scheme 1).
Scheme 1
It was observed that in most of the organic solvents the reactants were reluctant to
participate in the reaction (Table 1, entries 1-7). In dimethylformamide solvent, only trace
amount of product formation was observed (Table 1, entry 8). Further, the reaction did not
take place when water was employed as the reaction medium (Table 1, entry 9) and the
starting material was recovered quantitatively. However, when the reactants were irradiated
0
at 400 W and 160 C for 10 min under neat conditions (Table 1, entry 10), the product 5,6-
di(4-chlorophenyl)-1,3-dimethyl-5,6-dihydropyrido[4,3-d]pyrimidine-2,4-dione
4a
was
obtained in 70 % yield.
Table 1 Optimisation for the synthesis of 4a under MW irradiationa

Entry
Solvent
Time (min) Yield (%)b
1
2
3
4
5
15
15
15
12
12
n.r.
n.r.
n.r.
n.r.
n.r.
Acetonitrile
Ethanol
Methanol
Chloroform
Toluene
6
Nitrobenzene
Acetic acid
10
5
n.r.
n.r.
trace
n.r.
70
7
8
Dimethylformamide 10
9
Water
Neat
10
10
10
aReaction conditions: compound 1a (1 mmol), p-chlorobenzaldehyde 2a (1 mmol) and p-
chloroaniline 3a (1 mmol) were irradiated at 550 Watt for 10 min in absence of any solvent
in a microwave reactor. bIsolated yield.
We were excited to observe that the reaction proceeded under neat conditions, as
solventless reactions are always desirable because of environmental constrains. Optimization
of the microwave conditions revealed that the yield could be increased to 91% when the
0
reactants are irradiated at 550 W and 160 C for 12 min in absence of any catalyst. Using
these optimised conditions, the scope of the reaction was then investigated with a number of
different aldehydes 2 and amines 3 and the results obtained are summarized in Table 2
(Scheme 2).13
Scheme 2
The yield of the reaction was found to be excellent when different aromatic aldehydes
and amines were employed in the reaction (Table 2, entries 1-24). Aldehydes and amines
with electron donating as well as withdrawing groups participated in the reaction smoothly.
Moreover, the reaction was successful with heteroaromatic aldehydes such as furfuraldehyde
and thiophenealdehyde (Table 2, entries 21-24). When the dimethylamine group of 1 was
substituted with morpholine, we were pleased to find that smooth reaction occurred with
comparable yields (Table 2, entries 2,4,6 etc). In all cases, formation of an imine byproduct in
trace amount from the aldehyde and amine was detected which could be easily eliminated by
column chromatography. Unfortunately, the reaction failed when tried with alkyl aldehydes
and alkyl amines. However, ethyl glyoxylate was observed to react smoothly with aromatic
aldehydes and products were obtained in excellent yields (Table 2, entries 25-27).

All of the products obtained were characterized by IR, NMR and mass spectrometry.
Additionally, the structure of compound 1,3-dimethyl-5,6-diphenyl-5,6-dihydropyrido[4,3-
d]pyrimidine-2,4-dione 4h was confirmed by X-ray single-crystal analysis (Figure 1).14
Figure 1 Ortep diagram of compound 4h drawn with 30% probability ellipsoid.
Table 2 Substrate scope for the synthesis of 5,6-diaryl-5,6-dihydropyrido[4,3-d]pyrimidine
derivatives 4a-la

Uracil (R1)
Aldehyde
Amine
Yield (%)b
Entry
Product
Time (min)
Cl
Cl
O
H2N
OHC
-NMe2
-morpholine
91
88
1
2
Me
12
13
N
N
N
Cl
Cl
4a
4b
N
O
Me
OCH3
O
N
N
H2N
OHC
Me
-NMe2
-morpholine
80
84
3
4
14
12
OCH3
O
Me
Cl
CH3
O
H2N
Me
OHC
OHC
82
85
-NMe2
-morpholine
N
N
N
5
6
14
12
CH3
Cl
N
O
4c
Me
Br
OC2H5
O
Me
H2N
N
83
80
-NMe2
-morpholine
7
8
12
13
N
O
OC2H5
4d
4e
Br
Me
Cl
Br
O
H2N
Me
OHC
85
80
-NMe2
-morpholine
9
10
13
15
N
N
N
Br
Cl
Cl
N
O
Me
Cl
F
O
H2N
Me
OHC
OHC
82
79
-NMe2
-morpholine
11
12
12
14
N
F
N
O
4f
4g
4h
Me
O
Br
H2N
Me
78
75
-NMe2
-morpholine
13
14
14
15
N
N
N
Br
N
O
Me
O
N
N
Me
H2N
OHC
OHC
77
80
-NMe2
-morpholine
15
16
15
12
O
Me
Cl
OCH3
O
Me
H2N
N
N
80
81
-NMe2
-morpholine
17
18
12
14
N
O
OCH3
Cl
4i
Me

aReaction conditions: compound 1 (1 mmol), aldehyde 2 (1 mmol) and amine 3 (1 mmol)
were irradiated at 550 Watt in absence of any solvent in a microwave reactor. bIsolated yield.
In the next step, we set out to examine and compare the effect of microwave irradiation
with conventional heating on the outcome of this three-component reaction.15 Accordingly,
equimolar amount of the reactants 6-[2-(dimethylamino)vinyl]-1,3-dimethyl uracil 1a, p-
chlorobenzaldehyde 2a and p-chloroaniline 3a were refluxed in various solvents under
thermal heating. The results of this study are summarized in Table 3.
Table 3 Solvent study of the reaction under thermal conditiona

aReaction conditions: compound 1a (1 mmol), p-chlorobenzaldehyde 2a (1 mmol) and p-
chloroaniline 3a (1 mmol) were refluxed under air in absence of any catalyst. bIsolated yield.
As is evident from Table 3, except dimethylformamide, in all other organic solvents
examined, the reaction either gave negligible yield or did not proceed at all (Table 3, entries
1-6). The reaction also failed when water was employed as the reaction medium (Table 3,
entry 9). When the reactants were heated in absence of any solvent at the boiling point of
0
dimethylformamide solvent (154 C), the reaction proceeded with very little yield (Table 3,
entry 8). No significant change was observed on continuation of the reaction for longer time.
Formation of the imine byproduct was observed along with the desired pyridopyrimidine
product when the reaction was carried out in dimethylformamide solvent. At this stage, we
became interested to see whether the reaction actually proceeds via a formal [4+2] pathway.
To investigate this, we reacted 6-[2-(dimethylamino)vinyl]-1,3-dimethyl uracil 1a with pre-
formed imine 5a generated from p-chlorobenzaldehyde 2a and p-chloroaniline 3a under
refluxing conditions by employing DMF as solvent (Scheme 3).
Cl
O
O
Me
Me
CH
N
Cl
DMF, reflux
12 h
Cl
N
N
N
Cl
N
N
NMe2
O
O
5a
Me
Me
1a
4a (95 %)
Scheme 3
Formation of the expected product 5,6-di(4-chlorophenyl)-1,3-dimethyl-5,6-
dihydropyrido[4,3-d]pyrimidine-2,4-dione 4a was observed with minor improvement in yield
as compared to the three-component reaction. This shows that the three-component
transformation proceed via a concerted two-step pathway. The first step involves in situ
formation of an imine from aldehyde and amine and in the second step, the imine undergoes
[4+2] ADA cycloaddition with the pyrimidine diene system followed by elimination of
dimethylamine to yield the pyrido[4,3-d]pyrimidine derivative as final product.

In summary, we have developed a microwave-promoted aza-Diels-Alder reaction
strategy for the construction of pyrido[4,3-d]pyrimidine derivatives. A range of aromatic and
heteroaromatic aldehydes and amines have been shown to participate in the reaction when
carried out inside a microwave reactor in absence of any solvent or catalyst. This
methodology offers a new approach for the synthesis of pyrido[4,3-d]pyrimidine from simple
starting materials with excellent atom-economy. Overall, this one-pot, three-component, two-
step technique is simple, efficient and provides an alternative toward removing organic
solvents from organic synthesis.
Acknowledgements
We thank DST, New Delhi for financial support to this work. RS thanks CSIR, New
Delhi for a research fellowship. We also thank the Director, NEIST, Jorhat for his keen
interest and constant encouragement.
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13. 6-[2-(Dimethylamino)vinyl]-1,3-dimethyluracil 1a (1 mmol), p-chlorobenzaldehyde 2a
(1 mmol) and p-chloroaniline 3a (1 mmol) were irradiated in a closed vessel in the
absence of any solvent in a Synthos 3000 microwave reactor at 550 W, 160 °C, and 12
bar for 12 min. The crude product mixture was dissolved in chloroform and directly
column chromatographed using 2:3 ethyl acetate/hexane as the eluent to get pure 1,3-
dimethyl-5,6-di(4-chlorophenyl)-5,6-dihydropyrido[4,3-d]pyrimidine-2,4-dione 4a.
Compound 4a: Brown solid; m.p. 92-93 0C; 1H NMR (CDCl3, 300 MHz) δ 7.42-7.24 (m,
8H, arom.), 6.97 (d, J = 7.59 Hz, 1H, -CH=CH-), 6.31 (s, 1H, CH), 5.51 (d, J = 7.38 Hz,
1H, -CH=CH-), 3.42 (s, 3H, NCH3), 3.36 (s, 3H, NCH3); 13C NMR (CDCl3, 75 MHz) δ

161.0, 151.7, 144.0, 142.4, 139.1, 139.6, 133.8, 129.9, 129.4, 128.9, 126.9, 119.5, 96.4,
92.3, 57.5, 31.0, 28.3; IR (CHCl3, cm-1) 1691.9, 1648.5, 1541.1, 1489.3, 754.2; MS
(GCMS, m/z) 414 [M]+; Anal. Calcd for C21H17Cl2N3O2: C, 60.88; H, 4.14; N, 10.14.
found: C, 60.80; H, 4.11; N, 10.07. Similarly, reaction of 1b was carried out with
different aldehydes and amines to obtain products 4b-n.
14. CCDC-882057 contains the supplementary crystallographic data for compound 4h.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
15. 6-[2-(Dimethylamino)vinyl]-1,3-dimethyluracil 1a (1 mmol), p-chlorobenzaldehyde 2a
(1 mmol) and p-chloroaniline 3a (1 mmol) were refluxed in a round bottom flask under
air till the reaction goes to completion. After the reaction is complete, as indicated by
TLC, the solvent was distilled off under reduced pressure and the product purified by
column chromatographed using 2:3 ethyl acetate/hexane as the eluent to get pure 1,3-
dimethyl-5,6-di(4-chlorophenyl)-5,6-dihydropyrido[4,3-d]pyrimidine-2,4-dione 4a.

Efficient synthesis of dihydropyrido[4,3-d]pyrimidines by microwave-
promoted three-component aza-Diels-Alder reaction
Manas M. Sarmaha, Rupam Sarmaa,b Dipak Prajapatia, and Wenhao Huc
aMedicinal Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat,
Assam 785006, India
bDepartment of Chemistry, Nalbari College, Nalbari, Assam 781335, India
cEast China Normal University, Shanghai, P R China
 Corresponding author. fax: +91-376-237-0011; e-mail: dr_dprajapati2003@yahoo.co.uk