Palladium-catalyzed intramolecular arylation of pyrimidines: a novel and expedient avenue to benzannulated pyridopyrimidines

Article abstract of DOI:10.1016/j.tet.2009.01.107

A new efficient protocol for the synthesis of benzannulated pyrido[2,3-d]- and pyrido[3,2-d]pyrimidines has been successfully accomplished via the palladium-catalyzed intramolecular arylation of C-H bond of pyrimidine moiety. The methodology has also been

Full text of DOI:10.1016/j.tet.2009.01.107

Tetrahedron 65 (2009) 2751–2756
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Palladium-catalyzed intramolecular arylation of pyrimidines: a novel
and expedient avenue to benzannulated pyridopyrimidines
*
K.C. Majumdar , B. Sinha, P.K. Maji, S.K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new efficient protocol for the synthesis of benzannulated pyrido[2,3-d]- and pyrido[3,2-d]pyrimidines
has been successfully accomplished via the palladium-catalyzed intramolecular arylation of C–H bond of
pyrimidine moiety. The methodology has also been extended to the synthesis of pyrimido[5,4,-c]iso-
quinoline-2,4,6(1H,3H,5H)-trione derivatives in excellent yields.
Received 24 December 2008
Received in revised form 29 January 2009
Accepted 29 January 2009
Available online 6 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Intramolecular arylation reaction
Palladium acetate
Pyridopyrimidine derivatives
1. Introduction
catalyzed intra- and intermolecular arylation of the C–H bond of
a heteroaromatic compounds is of considerable interest due to its
Heterocycles containing pyrimidine as purine analogues,1–5 es-
pecially pyrido[2,3-d]pyrimidines, an important biologically sig-
nificant annulated pyrimidines connected with purine pteridines
system,6–8 are of great synthetic interest due to their wide
biological and pharmacological activities. The potential utilities of
such compounds have been identified in, virtually, all of the major
therapeutic areas as many of them are found to exhibit antifolate,
antibacterial, antimicrobial, anti-inflammatory, antileishmanial,
anticonvulsants, diuretic and antiaggressive activities.9–15 More-
over, pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,5H)-trione moiety has
gained particular prominence in the field of chemotherapy as it
exhibits both the properties of the biologically significant 4-hy-
droxy-2-pyridone and of uracil in one ring system.16–18 Several
approaches aimed towards the synthesis of these classes of com-
pounds are available in the literature.19–26 However, the corre-
sponding benzannulated analogues of pyrido[2,3-d]- and
pyrido[3,2-d]pyrimidines have remained unexplored for their
biological activities, which may be due to the lack of general syn-
thetic route for these classes of heteroaromatics from easily ac-
cessible precursors.
significant utility in organic synthesis.32–43 Although several aspects
of intra- and intermolecular arylation strategies to alkenes and al-
kynes have been extensively investigated as it corresponds to ver-
satile and general route to numerous oxa- and aza-heterocycles,44–48
surprisingly, limited examples of palladium-catalyzed arylation
to heterocyclic moieties are available in the literature.49–53
However, the reactions lack in generality due to the problem of
selectivity as well as harsh reaction conditions.54–58 In the
present study, we wish to report a mild, efficient and high
yielding ligand free palladium-catalyzed regioselective intra-
molecular vinyl C–H arylation strategy for the construction of a
new class of benzannulated pyridopyrimidine derivatives of
biological interest.
2. Results and discussion
The requisite cyclization precursors, 5-[N-(2-bromobenzyl)-
N-methylamino]-1,3-dimethyluracils (3a–d) and 6-[N-(2-bromo-
benzyl)-N-methylamino]-1,3-dimethyluracils (6a,b) for the present
investigations were synthesized in excellent yields as depicted in
Scheme 1. The compounds 3a–d were obtained starting from easily
available 5-bromouracil (1) according to our earlier published
procedure59 involving N-benzylation of 5-[N-methylamino]-
1,3-dimethyluracil (2) under classical alkylation condition. In
contrast, the synthesis of compound 6a,b directly by the N-ben-
zylation of 6-[N-methylamine]-1,3-dimethyluracil miserably failed
to give any product. However, a reverse procedure, i.e., refluxing
In recent years palladium-catalyzed reactions have become one
of the most successful and straightforward methods for the con-
struction of ring system as it offers an efficient entry from relatively
simple precursors to cyclic compounds.27–31 In particular, palladium
* Corresponding author. Tel.: þ91 33 2582 8750; fax: þ91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.107

2752
K.C. Majumdar et al. / Tetrahedron 65 (2009) 2751–2756
Table 1
2-bromobenzyl-N-methylamine (5) with 6-chlorouracil (4) in
EtOH afforded the compounds 6a,b in 89% and 92% yields, re-
spectively (Scheme 1).
Optimization study of palladium-catalyzed intramolecular C–H arylation of 5-((2-
bromobenzyl)(methyl)amino)-1,3-dimethylpyrimidine-2,4(1H,3H)-dionea
O
Me
N
O
Me
N
Me
O
Me
O
Pd(0)
N
N
1
O
O
O
R1
NH
R
N
Br
Base, TBAB
Solvent
Temp., time
N
Me
3a
N
Me
7a
Me
O
Br
Me
O
Me
O
N
N
N
(i)
(ii)
Br
N
N
N
R2
Me
1
Me
3
Me
2
Entry Catalyst
Mol (%) Base
Temp (ꢀC) Time (h) Solvent Yield (%)
a R1 = Me, R2 = H
a R1 = Me
b R1 = Et
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2 10
Pd(OAc)2 10
Pd(OAc)2 10
5
5
KOAc
KOAc
KOAc
K2CO3
K2CO3 100
K2CO3 100
KOAc
KOAc
KOAc
90
90
90
90
48
48
24
24
12
12
18
24
72
DMF
CH3CN
DMF
DMF
CH3CN
DMF
Toluene 42
DMF
DMF
15
10
30
25
38
0
b R1 = Me, R2 = OMe
c R1 = Et, R2 = H
d R1 = Et, R2 = OMe
R1
HN
PdCl2
5
O
N
R2
O
Pd(OAc)2 10
Pd(OAc)2 10
Pd(OAc)2 10
100
140
rt
Me
O
Me
Br
91
0
N
(iii)
R2
Br
N
+
Cl
O
N
N
a
The amount of base and TBAB used in all cases is 2.5 mmol and 0.6 mmol,
Me
4
Me R1
6
respectively.
5
a R1 = Me, R2 = H
(entry 2, Table 1, yield 10%). Change of base (K2CO3, entry 4, Table 1)
did not have any pronounced effect on the chemical yield as only
25% of the compound 7a was isolated using 10 mol % of Pd(OAc)2.
The use of PdCl2 also resulted no reaction (entry 6, Table 1). How-
ever, the use of 10 mol % of Pd(OAc)2 in DMF with KOAc as a base
b R1 = Me, R2 = OMe
Scheme
1. Reagents
and
conditions:
(i)
R1NH2,
reflux,
1 h
(ii)
R2
(iii) EtOH, reflux, 6-10 h.
, K2CO3 (anhyd.), acetone (dry), 8 h
Br
Br
Table 2
Synthesisa of 5-alkyl-1,3-dimethyl-5,6-dihydropyrimido[5,4-c]isoquinoline-2,4-
(1H,3H)-diones (7b–d) and 5-alkyl-2,4-dimethyl-5,6-dihydropyrimido[4,5-c]-
isoquinoline-1,3(1H,3H)-diones
During the course of our continued interest in the synthesis of
substituted and condensed heteroaromatics, we have developed
different novel synthetic methodologies based on free radical cy-
clizations60–63 and sigmatropic rearrangements64–67 pathways.
While attempting to synthesize this particular class of benzannu-
lated pyridopyrimidine derivatives by free radical pathway,59,68 we
observed that the reaction suffered from the mode of cyclizations
(5-exo-trig vs 6-endo-trig) along with unwanted oxidation of the
cyclized product59 (Fig. 1). In view of that, we turned our attention
to examining the possibility of using the palladium catalyzed
intramolecular arylation reaction strategy for the synthesis of this
fused pyrimidine annulated heterocycles.
In order to gain rapid insight in to the feasibility of the key cy-
clization, the amine 3a, chosen as a representative substrate, was
treated with Pd(OAc)2 (5 mol %) as catalyst, tetra-n-butylammo-
nium bromide (TBAB) as additive and potassium acetate as base in
DMF at 90 ꢀC (entry 1, Table 1) for 48 h and the desired pyr-
Entry
Starting material
Product
Yieldb (%)
O
Me
N
O
N
Me
N
Me
O
Me
O
N
N
1
Br
89
N
Me
Me
7b
OMe
OMe
3b
O
Et
N
O
Et
N
Me
O
Me
O
N
O
N
2
3
4
87
81
95
Br
N
Me
7c
N
Me
3c
O
Et
Et
Me
O
N
Me
O
N
idopyrimidine
compound
1,3,5-trimethyl-5,6-dihydropyr-
N
N
imido[5,4-c]isoquinoline-2,4(1H,3H)-dione (7a) was isolated in
very poor yield (15%). An optimization of the reaction condition was
needed to improve the chemical yield of the transformation. The
intramolecular cyclization of 3a was also examined in CH3CN as
solvent, which also resulted in poor conversion to compound 7a
Br
N
N
Me
7d
Me
3d
OMe
OMe
OMe
OMe
O
O
N
Me
O
Me
O
Br
N
N
O
Me
N
N
N
N
O
Me
N
Me
O
Me Me
6a
Me Me
8a
Me
O
Bu3SnH
N
N
N
(6-endo-trig)
Br
N
Me
N
Me
O
N
O
N
Me
O
Me
O
N
Br
N
Me
N
O
5
92
O
Me
N
O
N
N
Me
O
O
Me
O
Bu3SnH
N
Me Me
6b
Me Me
8b
I
(5-exo-trig)
N
N
a
Me
Me
All the reactions were carried out using Pd(OAc)2 (10 mol %), KOAc (2.5 mmol),
TBAB (0.60 mmol) and DMF (15 ml) at 140 ꢀC for 24 h.
b
Figure 1.
Isolated yield.

K.C. Majumdar et al. / Tetrahedron 65 (2009) 2751–2756
2753
Table 3
Synthesis of pyrimido[5,4-c]isoquinoline-2,4,6(1H,3H,5H)-triones (12a–f)
O
R3
N
R3
NH
O
R3
N
O
O
Cl
R1
O
O
R1
O
O
R1
O
(i)
N
(ii)
N
N
I
+
I
N
R2
12
N
N
R2
9
R2
10
11
Entry
1
Starting material
Product
Time (h)
Yielda (%)
O
O
Me
N
Me
Me
O
O
Me
O
N
O
N
N
N
N
N
N
N
N
N
N
3
95
I
N
Me
11a
N
Me
12a
O
Et
N
O
Et
N
Me
O
O
O
O
O
Me
O
O
O
O
O
2
3
4
5
3
5
8
4
94
90
96
95
I
N
Me
11b
N
Me
12b
O
Me
N
O
Me
N
Et
O
Et
O
I
N
Et
11c
N
Et
12c
O
Et
N
O
Et
N
Et
O
Et
O
I
N
Et
12d
N
Et
11d
O
Me
N
O
Me
N
Me
O
Me
O
I
I
N
Et
12e
N
Et
11e
O
Et
N
O
Et
N
Me
O
O
Me
O
O
N
N
6
5
91
N
N
Et
11f
Et
12f
Reagents and conditions: (i) see Ref. 14; (ii) Pd(OAc)2 (10 mol %), TBAB (0.60 mmol), KOAc (2.5 mmol), DMF (15 ml), 100 ꢀC.
a
Isolated yield.
(2.5 mmol) showed excellent conversion of 3a to 7a (yield: 91%) at
140 ꢀC (entry 8, Table 1). It is noteworthy that the temperature has
a pronounced effect on the cyclization as the conversion rate of 3a
was observed only 30% when 10 mol % of Pd(OAc)2 was utilized at
90 ꢀC for 24 h (entry 3, Table 1).
The intramolecular arylation reaction was applied to various
substituted 5-[N-(2-bromobenzyl)-N-methylamino]-1,3-dimethyl-
uracils (3b–d) and 6-[N-(2-bromobenzyl)-N-methylamino]-1,3-
dimethyluracils (6a,b) utilizing optimized reaction conditions.
In general, excellent yields (81–95%) of cyclized compounds, 5-alkyl-
1,3-dimethyl-5,6-dihydropyrimido[5,4-c]isoquinoline-2,4(1H,3H)-
diones (7b–d) and 5-alkyl-2,4-dimethyl-5,6-dihydropyrimido
[4,5-c]isoquinoline-1,3(2H,4H)-diones (8a,b) were obtained from
substrates 3b–d and 6a,b, respectively (Table 2).
triones (12a–f), structural analogues of biologically important
pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,5H)-trione. The precursor
amides, 11a–f, were synthesized by following the procedure de-
veloped in our laboratory.68 The amide 11a was initially subjected
to intramolecular arylation reaction utilizing our optimized re-
action condition (Table 2). Unfortunately, the cyclization using
10 mol % of Pd(OAc)2 as catalyst at 140 ꢀC for 4 h was found to be
inefficient as very poor yield of the cyclized product was obtained
(isolated yield of 12a: 10%) leaving no starting material in the
reaction mixture. Therefore, a further optimization study was
needed. It was observed that at 100 ꢀC with 10 mol % of Pd(OAc)2
in DMF, an excellent conversion of compound 11a to 12a (yield
95%) was effected. By employing this new optimized reaction
condition,
a
variety
of
pyrimido[5,4-c]isoquinoline-
We next sought to extend the scope of this methodology into
the construction of pyrimido[5,4-c]isoquinoline-2,4,6(1H,3H,5H)-
2,4,6(1H,3H,5H)-triones (12b–f) were prepared in 90–96% yield
(Table 3).

2754
K.C. Majumdar et al. / Tetrahedron 65 (2009) 2751–2756
A plausible catalytic cycle for the formation of compound 7
4.2.1. 5-((2-Bromobenzyl)(ethyl)amino)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (3c)
from the amine 3 is outlined in Scheme 2. Initial oxidative ad-
dition of palladium(0) to 3 generates the aryl-palladium in-
termediate 13, which undergoes insertion into the double bond
Yield: 95%; sticky liquid; Rf¼0.43 (30% EtOAc/pet. ether); IR
(KBr) nmax: 752, 1453, 1651, 1699, 2925 cmꢁ1; UV (EtOH) lmax: 215,
305 nm; 1H NMR (CDCl3, 400 MHz): dH¼0.98 (t, J¼7.0 Hz, 3H,
–NCH2CH3), 3.07 (q, J¼7.1 Hz, 2H, –NCH2CH3), 3.27 (s, 3H, –NCH3),
3.33 (s, 3H, –NCH3), 4.18 (s, 2H, –NCH2), 6.70 (s, 1H, ]CH), 7.06–7.10
(m,1H, ArH), 7.21–7.25 (m,1H, ArH), 7.41–7.43 (dd, J¼1.4, 7.6 Hz,1H,
ArH), 7.48–7.50 (dd, J¼1.1, 7.9 Hz, 1H, ArH); HRMS Calcd for
C15H18N3O2Br: 352.0655 [MþþH], 354.0636 [MþþHþ2]. Found:
352.0625 [MþþH], 354.0625 [MþþHþ2].
of pyrimidine to generate
s-arylpalladium complex 14. Finally,
the product is obtained via reductive elimination of H-[Pd]-Br
from the palladium complex 14. The palladium(0) species are
regenerated by the base induced proton abstraction from
H-[Pd]-Br.
Pd(II)
3
Base-H
4.2.2. 5-((2-Bromo-5-methoxybenzyl)(ethyl)amino)-1,3-
Pd(0)
dimethylpyrimidine-4(1H,3H)-dione (3d)
Base
Oxidative
Yield: 94%; sticky liquid; Rf¼0.35 (30% EtOAc/pet. ether); IR
(KBr) nmax: 754, 1466, 1651, 1700, 2924 cmꢁ1; UV (EtOH) lmax: 208,
306 nm; 1H NMR (CDCl3, 400 MHz): dH¼0.99 (t, J¼7.1 Hz, 3H,
–NCH2CH3), 3.07 (q, J¼7.1 Hz, 2H, –NCH2CH3), 3.27 (s, 3H, –NCH3),
3.32 (s, 3H, –NCH3), 3.78 (s, 3H, –OCH3), 4.14 (s, 2H, –NCH2), 6.64
(dd, J¼3.1, 8.6 Hz, 1H, ArH), 6.74 (s, 1H, ]CH), 7.04 (d, J¼3.0 Hz, 1H,
ArH), 7.36 (dd, J¼3.4, 8.8 Hz, 1H, ArH); HRMS Calcd for
C16H20N3O3Br: 382.0761 [MþþH], 384.0742 [MþþHþ2]. Found:
382.0781 [MþþH], 384.0781 [MþþHþ2].
O
R1
N
addition
H [Pd] Br
N
Br
[Pd] Br
O
N
[
]
Pd
R1
O
7
R2
Insertion
13
N
Reductive
Elimination
N
N
O
H
R2
14
4.3. General procedure for the preparation of amines 6a,b
Scheme 2. General mechanistic approach of the intramolecular arylation reaction.
A mixture of 2-bromobenzyl-N-methylamine (5) (5 mmol) and
6-chlorouracil (5 mmol) was refluxed in dry EtOH (25 ml) on
a water bath for 6–10 h. The reaction mixture was cooled and EtOH
was removed. The residual mass was extracted with CH2Cl2
(3ꢂ10 ml). The CH2Cl2 extract was washed with water (2ꢂ10 ml)
and dried (Na2SO4). The residual mass after removal of the solvent
(CH2Cl2) was subjected to column chromatography over silica gel
using petroleum ether/ethyl acetate as eluant to give compound
(6), which were purified by crystallization from CH2Cl2.
3. Conclusion
In conclusion, we have developed a mild and efficient route for
the construction of a new class of benzannulated pyrido[2,3-d]-
and pyrido[3,2-d]pyrimidines as well as pyrimido[5,4-c]iso-
quinoline-2,4,6(1H,3H,5H)-triones via palladium-catalyzed intra-
molecular arylation of C–H bond of pyrimidine moiety under
ligand free condition. The methodology, as compared to our
previously reported free radical pathway, is observed to be ex-
cellent for the arylation of both at C-5 and C-6 C–H bonds of the
pyrimidine heterocycles. All the reactions are clean and high
yielding. The scope and generality of this methodology have been
successfully demonstrated by synthesizing a variety of pyrimidine
derivatives.
4.3.1. 6-((2-Bromobenzyl)(methyl)amino)-1,3-dimethyl
pyrimidine-2,4(1H,3H)-dione (6a)
Yield: 89% as yellow solid; mp 117–119 ꢀC; Rf¼0.40 (40% EtOAc/
pet. ether); IR (KBr) nmax: 762, 1439, 1649, 1697, 2955 cmꢁ1; UV
(EtOH) lmax: 214, 279 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.65 (s,
3H, –NCH3), 3.32 (s, 3H, –NCH3), 3.37 (s, 3H, –NCH3), 4.16 (s, 2H,
–NCH2), 5.30 (s, 1H, ]CH), 7.18–7.21 (m, 1H, ArH), 7.32 (d, J¼4.2 Hz,
2H, ArH), 7.57 (d, J¼7.8 Hz, 1H, ArH); HRMS Calcd for C14H16N3O2Br:
338.0499 [MþþH], 340.0479 [MþþHþ2]. Found: 338.0530 [MþþH],
340.0517 [MþþHþ2].
4. Experimental section
4.1. General
Melting points were determined in an open capillary and are
uncorrected. IR spectra were recorded on a Perkin–Elmer L
120-000A spectrometer (nmax in cmꢁ1) on KBr disks. UV absorp-
tion spectra were recorded in EtOH on a Shimadzu UV-2401PC
spectrophotometer (lmax in nm). 1H NMR and 13C NMR spectra
were recorded on a Bruker DPX-300 and Bruker DPX-400 spec-
trometer in CDCl3 with TMS as internal standard. HRMS were
recorded on a QTOF Micro YA 263 instrument at the Indian As-
sociation for the Cultivation of Science, Kolkata. Silica gel [(60–
120 mesh), Spectrochem, India] was used for chromatographic
separation. Silica gel G [E-Merck (India)] was used for TLC. Pe-
troleum ether refers to the fraction boiling between 60 ꢀC and
80 ꢀC.
4.3.2. 6-((2-Bromo-5-methoxybenzyl)(methyl)amino)-1,3-
dimethylpyrimidine-2,4(1H,3H)-dione (6b)
Yield: 92% as yellow solid; mp 109–111 ꢀC; Rf¼0.30 (40% EtOAc/
pet. ether); IR (KBr) nmax: 763, 1441, 1664, 1697, 2947 cmꢁ1; UV
(EtOH) lmax: 206, 280 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.66 (s,
3H, –NCH3), 3.32 (s, 3H, –NCH3), 3.36 (s, 3H, –NCH3), 3.78 (s, 3H,
–OCH3), 4.10 (s, 2H, –NCH2), 5.31 (s, 1H, ]CH), 6.72–6.75 (dd, J¼3,
8.7 Hz, 1H, ArH), 6.88 (d, J¼2.9 Hz, 1H, ArH), 7.45 (d, J¼8.6 Hz, 1H,
ArH); HRMS Calcd for C15H18N3O3Br: 368.0604 [MþþH], 370.0585
[MþþHþ2]. Found: 368.0625 [MþþH], 370.0547 [MþþHþ2].
4.4. General procedure for the preparation of compound
7a–d and 8a,b
A mixture of TBAB (tetra-n-butylammonium bromide) (0.19 g,
0.60 mmol) and KOAc (0.23 g, 2.5 mmol) in dry and degassed DMF
(25 ml) under nitrogen atmosphere was stirred well for about
20 min. Compounds 3a–d (0.6 mmol) and Pd(OAc)2 (10 mol %) were
added to it. The reaction mixture was stirred at 140 ꢀC for 24 h and
4.2. General procedure for the preparation of amines 3a–d
Compounds 3a–d were prepared following our published
procedure.59

K.C. Majumdar et al. / Tetrahedron 65 (2009) 2751–2756
2755
allowed to cool to room temperature. It was diluted with water
(50 ml) and extracted with CH2Cl2 (3ꢂ15 ml). The organic extract
was washed with hydrochloric acid [1 N, 15 ml], water (20 ml) and
saturated brine solution (20 ml). It was dried overanhydrous Na2SO4
and filtered. The residual mass after removal of the solvent was
subjectedtocolumn chromatographyoversilicagelusingpetroleum
ether/ethyl acetate as eluant. The crude products obtained were
purified by crystallization from CH2Cl2/hexane mixture.
(EtOH) lmax¼206, 312 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.59 (s,
3H, –NCH3), 3.43 (s, 3H, –NCH3), 3.56 (s, 3H, –NCH3), 3.81 (s, 3H,
–OCH3), 4.13 (s, 2H, –NCH2), 6.68 (d, J¼2.6 Hz, 1H, ArH), 6.85 (dd,
J¼2.7, 8.8 Hz, 1H, ArH), 8.37 (d, J¼8.7 Hz, 1H, ArH); 13C NMR (CDCl3,
75.5 MHz): dC¼28.5, 32.2, 39.2, 54.9, 55.7, 99.5, 112.1, 112.9, 122.0,
126.4, 129.8, 152.1, 154.5, 158.9, 161.7; HRMS Calcd for C15H17N3O3:
288.1343 [MþþH]. Found: 288.1309 [MþþH].
4.5. General procedure for the preparation of compound 12a–f
4.4.1. 1,3,5-Trimethyl-5,6-dihydropyrimido[5,4-c]isoquinoline-
2,4(1H,3H)-dione (7a)
A mixture of TBAB (tetra-n-butylammonium bromide) (0.19 g,
0.60 mmol) and KOAc (0.23 g, 2.5 mmol) in dry and degassed DMF
(15 ml) was well stirred about 20 min. Compounds 11a–d
(0.6 mmol) and Pd(OAc)2 (10 mol %) were added to it. The mixture
was stirred at 100 ꢀC for 3–8 h and allowed to cool to room tem-
perature. It was diluted with water (50 ml) and extracted with
CHCl3 (3ꢂ10 ml). The organic extract was washed with hydro-
chloric acid [1 N, 15 ml], water (25 ml) and saturated brine solution
(25 ml). It was dried over anhydrous Na2SO4 and filtered. The re-
sidual mass after removal of the solvent was subjected to column
chromatography using petroleum ether/ethyl acetate as eluant over
silica gel. The crude product was purified by crystallization from
CH2Cl2/hexane mixture.
Yield: 91% as white solid; mp 147–150 ꢀC; Rf¼0.35 (40% EtOAc/
pet. ether); IR (KBr) nmax: 744, 1452, 1643, 1688, 2950 cmꢁ1; UV
(EtOH) lmax: 206, 344 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.51 (s,
3H, –NCH3), 3.32 (s, 3H, –NCH3), 3.58 (s, 3H, –NCH3), 4.04 (s, 2H,
–NCH2), 7.26 (d, J¼7.8 Hz, 1H, ArH), 7.38–7.40 (m, 1H, ArH),
7.43–7.47 (m, 1H, ArH), 7.48 (d, J¼7.8 Hz, 1H, ArH); HRMS Calcd for
C14H15N3O2: 280.1062 [MþþNa]. Found: 280.1062 [MþþNa].
4.4.2. 8-Methoxy-1,3,5-trimethyl-5,6-dihydropyrimido[5,4-c]
isoquinoline-2,4(1H,3H)-dione (7b)
Yield: 89% as white solid; mp 155–158 ꢀC; Rf¼0.21 (30% EtOAc/
pet. ether); IR (KBr) nmax: 755, 1456, 1645, 1731, 2951 cmꢁ1; UV
(EtOH) lmax: 209, 344 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.58 (s,
3H, –NCH3), 3.42 (s, 3H, –NCH3), 3.56 (s, 3H, –NCH3), 3.87 (s, 3H,
–OCH3), 4.01 (s, 2H, –NCH2), 6.78 (d, 1H, J¼2.4 Hz, ArH), 6.88 (dd,
J¼2.5, 8.6 Hz, 1H, ArH), 8.41 (d, J¼8.7 Hz, 1H, ArH); HRMS Calcd for
C15H17N3O3: 288.1343 [MþþH]. Found: 288.1303 [MþþH].
4.5.1. 1,3,5-Trimethylpyrimido[5,4-c]isoquinoline-2,4,6
(1H,3H,5H)-trione (12a)
Yield: 95% as white solid; mp 171–173 ꢀC; Rf¼0.28 (40% EtOAc/
pet. ether); IR (KBr) nmax¼741, 1461, 1656, 1708, 2959 cmꢁ1; UV
(EtOH) lmax¼222, 350, 480 nm; 1H NMR (CDCl3, 400 MHz):
dH¼3.45 (s, 3H, –NCH3), 3.75 (s, 3H, –NCH3), 4.02 (s, 3H, –NCH3),
7.72–7.77 (m, 2H, ArH), 7.97 (d, J¼7.8 Hz, 1H, ArH), 8.56 (dd, J¼1.4,
7.9 Hz, 1H, ArH); HRMS calcd for C14H13N3O3: 272.1035 [MþþH].
Found: 272.1457 [MþþH].
4.4.3. 5-Ethyl-1,3-dimethyl-5,6-dihydropyrimido[5,4-c]
isoquinoline-2,4(1H,3H)-dione (7c)
Yield: 87% as cream coloured solid; mp 149–151 ꢀC; Rf¼0.30
(30% EtOAc/pet. ether); IR (KBr) nmax: 758, 1462, 1654, 1731,
; UV (EtOH) lmax:
2920 cmꢁ1 219, 353 nm; 1H NMR (CDCl3,
300 MHz): dH¼0.85 (t, J¼7.1 Hz, 3H, –NCH2CH3), 2.96 (q, J¼7.0 Hz,
2H, –NCH2CH3), 3.42 (s, 3H, –NCH3), 3.59 (s, 3H, –NCH3), 4.12 (s, 2H,
–NCH2), 7.26 (d, J¼1.9 Hz,1H, ArH), 7.35–7.49 (m, 3H, ArH); 13C NMR
(CDCl3, 75.5 MHz): dC¼13.7, 28.2, 37.6, 44.4, 51.7, 123.3, 124.1, 125.9,
126.4, 127.2, 130.1, 133.5, 138.1, 152.4, 161.0; HRMS Calcd for
C15H17N3O2: 272.1394 [MþþH]. Found: 272.1398 [MþþH].
4.5.2. 5-Ethyl-1,3-dimethylpyrimido[5,4-c]isoquinoline-
2,4,6(1H,3H,5H)-trione (12b)
Yield: 94% as white solid; mp 95–97 ꢀC; Rf¼0.30 (40% EtOAc/pet.
ether); IR (KBr) nmax¼759, 1466, 1647, 1696, 2932 cmꢁ1; UV (EtOH)
lmax¼222, 258, 355 nm; 1H NMR (CDCl3, 400 MHz): dH¼1.40 (t,
J¼6.8 Hz, 3H, –NCH2CH3), 3.45 (s, 3H, –NCH3), 3.73 (s, 3H, –NCH3),
4.68 (q, J¼6.8 Hz, 2H, –NCH2CH3), 7.69–7.78 (m, 2H, ArH), 7.94 (d,
J¼7.5 Hz,1H, ArH), 8.55 (dd, J¼1.5, 7.8 Hz,1H, ArH); 13C NMR (CDCl3,
75.5 MHz): dC¼15.0, 28.9, 40.7, 41.7, 118.4, 124.8, 127.8, 128.7, 129.1,
130.4, 130.6, 131.5, 152.0, 157.4, 160.5; HRMS Calcd for C15H15N3O3:
286.1186 [MþþH]. Found: 286.1297 [MþþH].
4.4.4. 5-Ethyl-8-methoxy-1,3-dimethyl-5,6-dihydropyrimido-
[5,4-c]isoquinoline-2,4(1H,3H)-dione (7d)
Yield: 81% as light brown solid; mp 132–134 ꢀC; Rf¼0.32 (40%
EtOAc/pet. ether); IR (KBr) nmax: 756, 1464, 1645, 1732, 2924 cmꢁ1
;
UV (EtOH) lmax: 210, 352 nm; 1H NMR (CDCl3, 400 MHz): dH¼0.85
(t, J¼7.1 Hz, 3H, –NCH2CH3), 2.88 (q, J¼7.1 Hz, 2H, –NCH2CH3), 3.36
(s, 3H, –NCH3), 3.46 (s, 3H, –NCH3), 3.83 (s, 3H, –OCH3), 3.93 (s, 2H,
–NCH2), 6.76 (d, J¼2.4 Hz,1H, ArH), 6.87 (dd, J¼2.6, 8.7 Hz,1H, ArH),
7.39 (d, J¼8.6 Hz, 1H, ArH); HRMS Calcd for C16H19N3O3: 324.1324
[MþþNa]. Found: 324.1324 [MþþNa].
4.5.3. 1,3-Diethyl-5-methylpyrimido[5,4-c]isoquinoline-
2,4,6(1H,3H,5H)-trione (12c)
Yield: 90% as white solid; mp 115–118 ꢀC; Rf¼0.35 (40% EtOAc/
pet. ether); IR (KBr) nmax¼761, 1451, 1648, 1697, 2970 cmꢁ1; UV
(EtOH) lmax¼222, 255, 352 nm; 1H NMR (CDCl3, 400 MHz): dH¼1.27
(t, J¼7.0 Hz, 3H, –NCH2CH3), 1.37 (t, J¼6.9 Hz, 3H, –NCH2CH3), 4.01
(s, 3H, –NCH3), 4.05 (q, J¼7.0 Hz, 2H, –NCH2CH3), 4.22 (q, J¼6.9 Hz,
2H, –NCH2CH3), 7.69–7.78 (m, 2H, ArH), 7.91 (d, J¼8 Hz, 1H, ArH),
8.55 (dd, J¼1.4, 7.9 Hz, 1H, ArH); 13C NMR (CDCl3, 75.5 MHz):
dC¼12.7, 14.3, 34.2, 37.4, 47.3, 119.8, 124.4, 128.0, 128.4, 129.1, 129.7,
130.3, 131.7, 151.7, 157.4, 160.9; HRMS Calcd for C16H17N3O3:
322.1168 [MþþNa]. Found: 322.1152 [MþþNa].
4.4.5. 2,4,5-Trimethyl-5,6-dihydropyrimido[4,5-c]isoquinoline-
1,3(2H,4H)-dione (8a)
Yield: 95% as white solid; mp140–143 ꢀC; Rf¼0.46 (40% EtOAc/
pet. ether); IR (KBr) nmax¼749, 1455, 1635, 1688, 2918 cmꢁ1; UV
(EtOH) lmax¼205, 311 nm; 1H NMR (CDCl3, 400 MHz): dH¼2.62 (s,
3H, –NCH3), 3.43 (s, 3H, –NCH3), 3.51 (s, 3H, –NCH3), 4.08 (s, 2H,
–NCH2), 7.11 (d, J¼7 Hz, 1H, ArH), 7.20–7.24 (m, 1H, ArH), 7.33–7.35
(m, 1H, ArH), 8.43 (d, J¼7.9 Hz, 1H, ArH); HRMS Calcd for
C14H15N3O2: 280.1062 [MþþNa]. Found: 280.1090 [MþþNa].
4.5.4. 1,3,5-Triethylpyrimido[5,4-c]isoquinoline-2,4,6
(1H,3H,5H)-trione (12d)
Yield: 96% as white solid; mp 192–194 ꢀC; Rf¼0.34 (40% EtOAc/
pet. ether); IR (KBr) nmax¼761, 1459, 1651, 1697, 2942 cmꢁ1; UV
(EtOH) lmax¼223, 260, 354 nm; 1H NMR (CDCl3, 400 MHz): dH¼1.29
(t, J¼7.0 Hz, 3H, –NCH2CH3), 1.36 (t, J¼6.9 Hz, 3H, –NCH2CH3), 1.41
(t, J¼6.8 Hz, 3H, –NCH2CH3), 4.06 (q, J¼7.0 Hz, 2H, –NCH2CH3), 4.21
4.4.6. 8-Methoxy-2,4,5-trimethyl-5,6-dihydropyrimido[4,5-c]
isoquinoline-1,3(2H,4H)-dione (8b)
Yield: 92% as white solid; mp 152–154 ꢀC; Rf¼0.28 (30% EtOAc/
pet. ether); IR (KBr) nmax¼754, 1461, 1646, 1692, 2921 cmꢁ1; UV

2756
K.C. Majumdar et al. / Tetrahedron 65 (2009) 2751–2756
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(q, J¼6.9 Hz, 2H, –NCH2CH3), 4.66 (q, J¼6.8 Hz, 2H, –NCH2CH3),
7.68–7.77 (m, 2H, ArH), 7.89 (d, J¼7.9 Hz, 1H, ArH), 8.54 (dd, J¼1.4,
7.9 Hz, 1H, ArH); HRMS Calcd for C17H19N3O3: 314.1499 [MþþH].
Found: 314.1428 [MþþH].
4.5.5. 1-Ethyl-3,5-dimethylpyrimido[5,4-c]isoquinoline-
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2,4,6(1H,3H,5H)-trione (12e)
Yield: 95% as white solid; mp 165–167 ꢀC; Rf¼0.32 (40% EtOAc/
pet. ether); IR (KBr) nmax¼759, 1456, 1647, 1697, 2976 cmꢁ1; UV
(EtOH) lmax¼221, 253, 354 nm; 1H NMR (CDCl3, 400 MHz): dH¼1.28
(t, J¼7.0 Hz, 3H, –NCH2CH3), 3.75 (s, 3H, –NCH3), 4.03 (s, 3H,
–NCH3), 4.08 (q, J¼6.9 Hz, 2H, –NCH2CH3), 7.70–7.80 (m, 2H, ArH),
7.98 (d, J¼7.8 Hz, 1H, ArH), 8.57 (dd, J¼1.4, 7.8 Hz, 1H, ArH); HRMS
Calcd for C15H15N3O3: 286.1186 [MþþH]. Found: 286.1191 [MþþH].
4.5.6. 1,5-Diethyl-3-methylpyrimido[5,4-c]isoquinoline-
2,4,6(1H,3H,5H)-trione (12f)
30. Blame, G.; Bougssi, D.; Monteiro, N. In Hand Book of Organopalladium Chemistry
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35. Majumdar, K. C.; Pal, A. K.; Taher, A.; Debnath, P. Synthesis 2007, 1707.
36. Arai, N.; Takahashi, M.; Mitani, M.; Mori, A. Synlett 2006, 3170.
37. Karimi, B.; Enders, D. Org.
Yield: 91% as white solid; mp 180–182 ꢀC; Rf¼0.35 (40% EtOAc/
pet. ether); IR (KBr) nmax¼760, 1459, 1646, 1698, 2936 cmꢁ1; UV
(EtOH) lmax¼222, 260, 354 nm; 1H NMR (CDCl3, 400 MHz): dH¼1.27
(t, J¼7.0 Hz, 3H, –NCH2CH3), 1.41 (t, J¼6.8 Hz, 3H, –NCH2CH3), 3.73
(s, 3H, –NCH3), 4.08 (q, J¼7.0 Hz, 2H, –NCH2CH3), 4.68 (q, J¼6.8 Hz,
2H, –NCH2CH3), 7.69–7.78 (m, 2H, ArH), 7.91 (d, J¼7.8 Hz, 1H, ArH),
8.55 (dd, J¼1.3, 7.9 Hz, 1H, ArH); HRMS Calcd for C16H17N3O3:
300.1343 [MþþH]. Found: 300.1346 [MþþH].
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Acknowledgements
We thank the CSIR (New Delhi) and DST (New Delhi) for fi-
nancial assistance. Three of us (P.K.M. and S.K.C., B.S.) are thankful
to UGC (New Delhi) and CSIR (New Delhi) for their fellowships.
44. Cropper, E. L.; White, A. J. P.; Ford, A.; Hii, K. K. J. Org. Chem. 2006, 71, 1732.
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