Cascade imination, Buchwald-Hartwig cross coupling and cycloaddition reaction: Synthesis of pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1039/c5ra00725a

A novel and efficient palladium catalyzed method was developed for the synthesis of wide range of pyrido[2,3-d]pyrimidines, using readily available β-bromovinyl/aryl aldehydes and 6-amino-1,3-dialkyluracils as the starting materials with good yields. This reaction proceeds via cascade imination/Buchwald-Hartwig cross coupling/cycloaddition reactions under microwave irradiation and solvent free conditions. This journal is

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Cascade imination, Buchwald-Hartwig cross coupling and cycloaddition
reaction: synthesis of pyrido[2,3-d]pyrimidines
Pallabi Saikia, Gitarthi Sharma, Sanjib Gogoi,* Romesh C Boruah*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
couple of advantages such as decreased reaction time, high yield
50 of products and enhancement of the chemoꢀ, regioꢀ and
stereoselectivity of the reactions. Several novel transitionꢀmetal
catalyzed reactions are known in the literature which have been
performed under microwave heating.8 As a part of our ongoing
research interests in the synthesis of biologically important Nꢀ
55 containing heterocycles, utilizing βꢀbromovinyl/aryl aldehydes as
the versatile synthons,9 herein, we wish to report an efficient Pd
catalyzed synthesis of pyrido[2,3ꢀd]pyrimidines using βꢀ
halovinyl/aryl aldehydes and 6ꢀaminoꢀ1,3ꢀdialkyluracils as the
starting materials in solventꢀfree conditions under microwave
60 irradiation.
A novel and efficient palladium catalyzed method was
developed for the synthesis of wide range of pyrido[2,3-
d]pyrimidines, using readily available β-bromovinyl/aryl
aldehydes and 6-amino-1,3-dialkyluracils as the starting
10 materials with good yields. This reaction proceeds via cascade
imination/Buchwald-Hartwig cross coupling/cycloaddition
reactions under microwave irradiation and solvent free
conditions.
The pyrido[2,3ꢀd]pyrimidine heterocycles are of tremendous
15 biological importance due to their wide range of biological
properties such as antiꢀinflammatory, analgesic, antihypertensive,
antiviral, antimicrobial, antiasthmatic and anticancer activities.1
Some of the biologically active pyrido[2,3ꢀd]pyrimidine
derivatives are shown in Figure 1. In view of their very high
20 biological and pharmaceutical importances, synthesis of these
pyrido[2,3ꢀd]pyrimidine derivatives have received considerable
attentions in the literature. Typically, these heterocycles were
synthesized by the reaction of 6ꢀaminouracils with α,βꢀ
unsaturated carbonyl compounds,2 Meldrum’s acid derivatives3
25 3ꢀchloroꢀ2ꢀpropeniminium salts4 and electronꢀrich enamines5.
Moreover, multiꢀcomponent reactions were used to obtain these
heterocycles.6 Recently, Kolos and coworkers reported an elegant
synthetic method for pyrido[2,3ꢀd]pyrimidines by the reaction of
3ꢀ(hetero)aroylacrylic acids or their methyl esters with 6ꢀaminoꢀ
30 1,3ꢀdimethyluracil.7 In spite of various reports for the synthesis of
pyrido[2,3ꢀd]pyrimidines, there is still lack of a facile and
environmentally benign general strategy for the synthesis of these
important fused heterocycles.
We started our studies by examining the reaction of βꢀ
bromovinyl aldehyde 1a (1.0 mmol), with equimolar amount of
6ꢀaminoꢀ1,3ꢀdimethyluracil (2a, 1.0 mmol). To our delight,
heating the reaction mixture at 120 oC for 12 hours in presence of
65 PdCl2 (2.5 mol %), K2CO3 (1.1 mmol) and PPh3 (5.0 mol %),
afforded pyrido[2,3ꢀd]pyrimidine derivative 3a in 54% yield
(Table 1, entry 1), which was fully characterized by 1H NMR, 13
C
NMR and mass spectroscopy. Screening of other palladium
catalysts, such as PdCl2(PPh3)2, Pd(dppf)Cl2, Pd(OAc)2 and
70 Pd(TFA)2, revealed Pd(OAc)2 as the most effective catalyst to
synthesize 3a (Table 1, entries 2ꢀ5). Then we studied the effect of
ligand on this cascade reaction. The ligand xantphos turned out to
be the best ligand amongst the screened ligands (dppf, 1,10ꢀphen)
to carry out this reaction under thermal conditions (Table 1,
75 entries 6ꢀ8). This reaction provided inferior results when the base
K2CO3 was replaced with base Na2CO3 or Cs2CO3 or NaOtBu
(Table 1, entries 9ꢀ11). Moreover, screening of solvents such as
DMSO and CH3CN provided lower yield of 3a (Table 1, entries
12ꢀ13). In order to curtail the reaction time when we studied the
80 influence of microwave (MW) irradiation (700 W, 120 oC, 14
bar), we observed a significant reduction in reaction time from 12
hours to 5 minutes to perform this reaction in DMF (Table 1,
entry 14). Subsequently, because of the various advantages of
solventꢀfree reactions,10 we performed the reaction under solvent
85 free condition. Gratifyingly, under this condition we obtained
slight increase of 3a to 91% in 5 minutes of reaction time under
microwave irradiation (Table 1, entry 15). Our attempt to perform
the reaction without catalyst could not provide 3a under the
solvent free condition (Table 1, entry 16).
35
40
45
90
With the optimized reaction conditions in hand (Table 1, entry
11), we then explored the feasibility of the reaction by selecting
some representative βꢀhalovinyl/aryl aldehydes 1a-m and 6ꢀ
Chemical reactions performed under Microwave heating have
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Table 1. Optimization of the reaction conditions for the synthesis of 3aa
To the best of our knowledge, this is the first example of Cꢀ5
alkylation of 6ꢀaminoꢀ1,3ꢀdialkyluracils via cascade
Pd catalyst (2.5 mol %)
ligand (5 mol %),
base (1.1 equiv)
O
O
imination/coupling/cycloaddition reaction which finally leads to
45 the formation of pyrido[2,3ꢀd]pyrimidines.
Br
CHO
N
N
+
Table 2. Synthesis of pyrido[2,3ꢀd]pyrimidine derivativesa
solvent/neat
thermal/MW (700 W)
H2N
N
O
N
N
O
1a
2a
3a
Entry
Pd catalyst
PdCl2
Solvent
Ligand
Thermal/
MW
3a
(%)b
54
47
50
72
61
64
84
69
77
72
63
71
49
87
91
0
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
DMF
Neat
PPh3
PPh3
PPh3
PPh3
PPh3
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
MW
50
PdCl2(PPh3)2
Pd(dppf)Cl2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
dppf
xantphos
1,10ꢀphen
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
ꢀ
9c
10d
11e
12
13
14
15
16
55
MW
MW
60
Neat
aAll reactions were performed in presence of K2CO3 (1.1 equiv) for 12
5
hours (thermal) or for 5 minutes (microwave) unless otherwise
c
mentioned; bIsolated yield. Na2CO3 (1.1 equiv) was used. dCs2CO3 (1.1
equiv) was used. eNaOtBu (1.1 equiv) was used.
aminoꢀ1,3ꢀdialkyluracils 2a-b (Table 2). The βꢀaryl substituted βꢀ
bromovinyl aldehydes (1bꢀd) with electron donating and
65
10 electronꢀwithdrawing groups such as methyl, chloro and nitro
present in the aromatic ring reacted smoothly with 6ꢀaminoꢀ1,3ꢀ
dimethyluracil 2a to afford pyrido[2,3ꢀd]pyrimidines 3bꢀd11 in
77ꢀ93% yields. Thus, this reaction indicated diversity in
functional group tolerance. Similarly, the heterocycle substituted
15 βꢀbromovinyl aldehyde 1e reacted with 2a under the optimized
reaction conditions to afford 7ꢀfuryl substituted pyrido[2,3ꢀ
d]pyrimidine 3e in 84% yield. The cyclic βꢀbromovinyl
aldehydes 1fꢀh were also converted to pyrido[2,3ꢀd]pyrimidines
3fꢀh12 in good yields (85ꢀ90%). Because of the importance of
20 steroids fused with heterocycles,13 we attempted to extend the
scope of this reaction with steroidal βꢀbromovinyl aldehydes. As
shown in Table 2, the cascade reactions of steroidal βꢀbromovinyl
aldehydes 1i-j with 2a were tested under the above reaction
conditions to afford corresponding steroidal pyrido[2,3ꢀ
25 d]pyrimidines 3i-j in 73ꢀ78% yields. In addition, the reactions of
βꢀbromovinyl aldehydes 1a and 1e with 6ꢀaminoꢀ1,3ꢀ
dipropyluracil 2b proceeded smoothly to provide pyrido[2,3ꢀ
d]pyrimidines 3k-l in 74ꢀ86% yields. Next, we carried out the
reaction of orthoꢀbromobenzaldehydes 1kꢀm with 2a under the
30 optimized reaction condition to provide the aryl fused pyrido[2,3ꢀ
d]pyrimidines 3m-o in 72ꢀ79% yields. The formation of isomer 3
was proved by comparison of new spectral and physical data with
those reported in the literature for compound 3b.11b
70
aReaction conditions: A grinded mixture of βꢀbromovinyl/aryl aldehydes
(1.0 mmol), 6ꢀaminoꢀ1,3ꢀdialkyluracils (1.0 mmol), Pd(OAc)2 (2.5
75 mol%), xantphos (5.0 mol%) and K2CO3 (1.1 mmol) was irradiated in a
o
closed vessel in a Synthos 3000 microwave reactor at 700 Watt (120 C
and 14 bar) for 5 minutes; Isolated yields.
80
85
Scheme 1. Proposed mechanism for the formation of 3
The formation of pyrido[2,3ꢀd]pyrimidine 3 is envisaged to
35 occur via a mechanism which is shown in Scheme 1. First, the
aldehyde 1 reacts with 6ꢀaminoꢀ1,3ꢀdialkyluracil 2 to produce
imine 4a, which on subsequent BuchwaldꢀHartwig cross coupling
reaction with another molecule of 2 affords intermediate 4b.
Then, rearrangement of electron generates probably azadiene
40 intermediate 4c, which on sixꢀelectron cyclization and subsequent
elimination of one molecule of 2 affords the final compound 3.
Conclusions
In conclusion, we have developed a novel environmentally
90 benign procedure for the efficient synthesis of biologically
important pyrido[2,3ꢀd]pyrimidines. A variety of βꢀhalovinyl/aryl
aldehydes undergo this reaction with 6ꢀaminoꢀ1,3ꢀdialkyluracils
in presence of palladium catalyst under microwave irradiation via
cascade imination/coupling/cycloaddition. Several features such
2
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Acknowledgements
70
75
80
Pallabi Saikia thanks UGC, New Delhi for the award of Senior
Research Fellowship (CSIRꢀSRF). We are grateful to Director,
CSIRꢀNEIST for his keen interests. We gratefully acknowledge
financial support from CSIRꢀORIGIN (CSC0108), CSIRꢀACT
(CSC0301) and CSIRꢀINSPIRE (CSC0107) projects.
5
7
8
Notes and references
10 Medicinal Chemistry Division, NorthꢀEast Institute of Science and
Technology, Jorhat, Assam 785 006, India. Tel.: +91 3762372948; fax:
+913762370011; skgogoi1@gmail.com; rc_boruah@yahoo.co.in
† Electronic Supplementary Information (ESI) available: [Copies of 1H
9
NMR,
13C
NMR
spectra
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