Unprecedented single-pot protocol for the synthesis of N1, C6-linked bicyclic 3,4-dihydropyrimidinones via lithiation of Biginelli compounds

Article abstract of DOI:10.1016/j.tet.2008.10.001

4-Aryl/alkyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives readily undergo metalation at the C6 methyl (vinylogous ester) position along with two acidic NHs upon treatment with n-butyllithium at -10 °C. The trianion of DHPMs thus obtained react smoothly with various terminal dibromoalkanes to afford N1, C6-linked bicyclic DHPM derivatives, which represent key structural features of the medicinally potent marine alkaloids such as batzelladine A and crambescin A.

Full text of DOI:10.1016/j.tet.2008.10.001

Tetrahedron 64 (2008) 11718–11723
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Unprecedented single-pot protocol for the synthesis of N1, C6-linked bicyclic
3,4-dihydropyrimidinones via lithiation of Biginelli compounds
*
Kamaljit Singh , Sukhdeep Singh
Organic Synthesis Laboratory, Department of Applied Chemical Sciences & Technology, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Aryl/alkyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one ester derivatives readily undergo metalation at
the C6 methyl (vinylogous ester) position along with two acidic NHs upon treatment with n-butyllithium
at ꢀ10 ꢁC. The trianion of DHPMs thus obtained react smoothly with various terminal dibromoalkanes to
afford N1, C6-linked bicyclic DHPM derivatives, which represent key structural features of the medici-
nally potent marine alkaloids such as batzelladine A and crambescin A.
Received 8 August 2008
Received in revised form
24 September 2008
Accepted 1 October 2008
Available online 10 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli compounds
Lithiation
Bicyclic DHPMs
Batzelladine alkaloids
Anti-HIV
1. Introduction
because of interesting pharmacological1 and structural2 profiles.
Apart from their structural similarity with the calcium channel
Functionalized 3,4-dihydropyrimidin-2(1H)ones (DHPMs, Bigi-
nelli compounds 1) represent a class of heterocyclic system that has
attracted a considerable interest of organic and medicinal chemists
blockers of the 1,4-dihydropyridine category such as nifedipine 2,
this scaffold constitute an important structural component of
medicinally potent marine alkaloids such as batzelladine alkaloids,
O
H
O
H
H
H
H
O
R1
NO2
O
R2
R2
N
N
4
O
H
C9H19
H
C7H15
EtO
Me
5
6
3NH
2
1
Me
N
H
N
H
Me
N
N
H
MeO
Me
OMe
Me
H
N
X
H
N
H
Batzelladine A
3
Batzelladine B
4
DHPM 1
1 = alkyl/ aryl
X = O, S, NH
Nifedipine
2
R
NH
NH
R3
NH2
NH
N
O
N
O
O
(CH2)6
R2
=
H
N
NH2
NH
Crambescin A (R3 = C9H19
H
N
H
O
O
H2N
NH2
)
5
6
Sch575948 (R3 = C5H11
)
* Corresponding author. Tel.: þ91 183 2258853; fax: þ91 2258819 20.
E-mail address: kamaljit19in@yahoo.co.in (K. Singh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.001

K. Singh, S. Singh / Tetrahedron 64 (2008) 11718–11723
11719
R1
O
R1
O
R1
O
lithium base
dielectrophile
EtO
LiH2C
NLi
EtO
NH
EtO
Me
NH
(Y-CH2(CH2)n-Y)
N
Li
X
N
( )n
X
N
H
X
7
1
Scheme 1. Proposed hypothesis for synthesis of bicyclic DHPM 7.
which are obtained from bright red Caribbean sponge Batzella
species.3 Among the various fragments obtained from methanolic
extracts of this sponge, batzelladine A 3 and B 4 inhibit the binding
of HIV surface glycoprotein gp120 to the CD4 receptor of human
T-cells and therefore are of therapeutic interest for the treatment of
HIV-AIDS.3 The tricyclic framework of 3/4, their side chains R2 as
well as other biologically important natural products such as
crambescin A4 (crambine A 5) and Sch575948 65 contain a bicyclic
unit reminiscent of an iminopyrimidine having N1, C6-link through
a three-carbon bridge.
Synthesis of this important bicyclic system has gained
considerable attention in the recent past in order to develop a total
synthesis of 3 and its analogues. Although a general approach to
link N1 and C6 positions of Biginelli DHPMs is still elusive, step-
wise building6 of a pyrrolo-pyrimidine structure, which serves as
a template for further modification to produce bicyclic guanidine
fragment of batzelladine A has been adopted. We recently reported
on highly regioselective functional elaboration of DHPM core at key
C6, C4, N3, N1 positions. Herein we report that N1, C6-positions of 1
could be linked in a single step to obtain bicyclic analogues 3–6 and
offer a practical and synthetically useful route.
temperature, whereby instead of 7a or 8a, 9a was isolated in 35%
yield, along with unreacted 1a. Compound 9a could be readily
transformed to 4-methyl-4,7-dihydro-1H,3H-furo[3,4-d]pyrimidin-
2,5-dione11 and when independently reacted with the metalated
1a, led to the exclusive formation of dimeric DHPM 8a.
O
Me
NH
EtO
O
Me
NH
O
Me
NH
N
H
O
Condition A
EtO
EtO
Me
H
O
N
N
O
N
H
O
HN
OEt
8a
1a
7a
Me
O
Condition B
Condition A
i. n-BuLi (3.5 eq.)
THF/N2/-10 °C to r.t.,3 h
ii. 1,2-dibromoethane (3.0 eq.)
THF/N2/-10 °C to r.t., 12 h
iii. sat. NH4Cl (aq.)/ r.t.
Condition B
i. n-BuLi (3.5 eq.)
O
Me
NH
THF/N2/-10 °C to r.t.,3 h
ii. 1,2-dibromethane (3.0 eq.)
THF/N2/-78 °C, 30 min.
EtO
Br
N
H
O
iii. sat. NH4Cl (aq.)/ -78 °C
9a
Scheme 2. Reaction of 1a with 1,2-dibromoethane under different conditions.
2. Results and discussion
In order to circumvent the formation of dimeric DHPM 8a and
improve the yield of 7a, various other bases such as LDA or
combination of n-BuLi with TMEDA, K-OBut, NaH, HMPA were used
(Table 1), but the formation of 8a could not be avoided and using
3.5 equiv of n-BuLi 7a was obtained in maximum of 35% yield. Even
changing 1,2-dibromoethane with 1,2-dichloroethane, 1-bromo-2-
chloroethane,12 and 2-chloroethanol toluene-4-sulfonate failed to
Lithiation of a number of dihydropyrimidinones derivatives 1
with selected lithium bases and quenching with a variety of hard7/
soft8 electrophiles led to the regioselective elaboration of key di-
versity oriented (C6 and N3) positions of the DHPM core. While
nucleophiles regioselectively add at the C4 position to offer C4
elaborated 1 in a synthetically useful manner.9 It was expected that
under appropriate lithiation conditions if more than 3 equiv of
a base are employed to deprotonate 1, in situ generation of
tri-lithiated (N1, N3, and C6) species could be envisaged, which
upon treatment with a dihaloalkane might lead to the formation of
N1, C6-linked bicyclic DHPM 7 (Scheme 1). It would also offer an
opportunity to probe the effect of hydrocarbon chain length
intercepting the two electrophilic centers of the dielectrophile on
the reaction pathway.
Table 1
Condition optimization for the synthesis of bicyclic DHPM 7a
O
Me
NH
O
Me
NH
i. base (equiv.)
EtO
EtO
Me
-10 °C to r.t., 3 h
8a
ii. 1,2-dielectrophile
-10 °C to r.t., 12 h
N
O
N
H
O
1a
7a
DHPM 1a (Scheme 2) was treated with 3.5 equiv of freshly
prepared n-BuLi (2.1 N in hexane) in anhydrous THF at ꢀ10 ꢁC,
under a blanket of dry nitrogen gas followed by stirring at room
temperature for 3 h. The resultant colored anionic suspension was
subsequently quenched with 3.0 equiv of 1,2-dibromoethane at
ꢀ10 ꢁC, which upon stirring for 12 h at room temperature furnished
7a in 35% yield (Table 1). However, the formation of 7a was ac-
companied by formation of a dimeric DHPM 8a in 55% yield. Evi-
dently, intramolecular cyclization (through N1 anion) of the
initially formed C6-elaborated 3-bromopropyl derivative, due to
excess equivalent of base may result in the formation of DHPM 7a.
The dimeric species 8a could arise through the in situ formation of
6-bromomethyl DHPM 9a (Scheme 2) through bromination of C6
methyl of 1a by 1,2-dibromoethane.10 In turn, 9a could serve as an
electrophile to quench a part of metalated 1a to furnish the dimer
8a. To provide an unequivocal support to the proposed mechanism,
and in order to isolate 9a, the above reaction was quenched at
ꢀ78 ꢁC followed by subsequent stirring for 30 min at the same
Entry
Base (equiv)
Electrophile
Product
Isolated
yield (%)a
1
2
3
4
5
6
n-BuLi (1.1)
n-BuLi (2.1)
n-BuLi (3.5)
n-BuLi (4.0)
n-BuLi (3.5)
n-BuLi (3.5)
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dichloroethane
1-Bromo-2-
d
d
7a
7a
7a
7a
d
d
35b
28b
Trace
10
chloroethane
2-Chloroethanol
7
n-BuLi (3.5)
d
d
toluene-4-sulfonate
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
1,2-Dibromoethane
8
9
10
11
12
13
LDA (3.5)
LDA (4.0)
n-BuLi/TMEDA (3.5)
n-BuLi/K(OBu)t (3.5)
n-BuLi/NaH (3.5)
n-BuLi/HMPA (3.5)
7a
7a
d
d
7a
7a
23b
15b
d
d
20b
26b
a
After chromatographic purification.
More than 50% of starting DHPM gets converted into dimer 8a.
b

11720
K. Singh, S. Singh / Tetrahedron 64 (2008) 11718–11723
Table 2
Reaction of metalated DHPMs 1b–d with 1,2-dibromoethane
O
O
R1
EtO
NH
O
R1
O
R1
N
i. n-BuLi/THF/N2
-10 °C to r.t.,3 h
N
H
O
EtO
Me
NH
EtO
NH
H
O
N
ii. 1,2-dibromoethane (3.0eq.)
THF/N2/-10 °C to r.t., 12 h
N
H
X
X
HN
OEt
R1
1
7
8
Entry
DHPM
R/X
Equiv of n-BuLi
Product (isolated yield %)a
7
8
1
2
3
1b
1c
1d
Ph/O
H/O
Ph/S
3.5
4.5
3.5
7b (30)
7c (15)
7d (15)
8b (50)
8c (48)
d
a
After chromatographic purification.
further improve the yield of 7a (Table 1). Several other experiments
using prolonged lithiation time, inverse addition of reactants, high
dilution, and change in solvent did not show any appreciable
improvement in the yield of 7a. Inverse addition was also plagued
by the formation of precipitates of anionic species, which even
upon dilution did not run very smoothly through cannula making
the procedure impracticable.
To determine the scope and limitations of this reaction, we
subsequently studied the reaction of 1b (R1¼Ph, X¼O, Table 2) with
1,2-dibromoethane under the same set of conditions. Both bicyclic
7b and dimeric 8b DHPM derivatives were obtained in 30% and 50%
yield, respectively13 (Table 2). However, DHPM 1c (R1¼H, X¼O,
Table 2) furnished 7c (15%) and 8c (48%), respectively, even upon
increasing the equivalent of the base from 3.5 to 4.5 equivalent.13
Use of rather reactive pyrimidine-2-thione derivative 1d (R¼Ph,
X¼S, Table 2) furnished a complex mixture of products, out of
which the N1, C6-linked bicyclic DHPM 7d was obtained in only 15%
yield.
Further, in order to monitor the effect of hydrocarbon chain
length of the dielectrophile on the reaction profile, the metalated
DHPM 1a was treated with 1,3-dibromopropane under optimized
conditions. However, only one product i.e., N1, C6-linked bicyclic
DHPM analogue 7e was obtained in 71% yield (Table 3). In the event
of dibromoalkanes other than 1,2-dibromoethane the formation of
8-type dimer is not probable. Apart from a reactive alkyl halide, 1,2-
dibromoethane is a potent source of electrophilic bromine for
bromination of carbanions,10,14 a feature not feasible when the two
bromines are intercepted by methylenes in excess of two. A similar
reaction of metalated 1b with 1,3-dibromopropane also furnished
the corresponding N1, C6-linked DHPM derivative 7f in 74% yield.
However, when the reaction was stirred at ꢀ10 ꢁC only for 30 min,
instead of 12 h at rt (Table 3), the C6-bromobutyl derivative of
DHPM 9b was obtained in 75% yield. By increasing the chain length
further, e.g., using 1,4-dibromobutane as dielectrophile for
quenching metalated 1b, in addition to the N1, C6-linked product
7g (28%), C6-bromopentyl DHPM derivative 9c was obtained in 58%
yield. However, the reaction of metalated DHPM 1b with higher
homologues of the dielectrophile, such as 1,5-dibromopentane and
1,6-dibromohexane, only led to C6-elaborated products 9d and 9e
in 68% and 72% yields, respectively. The formation of N3 alkylated
product was not detected in any case, which is well in agreement
with our previous findings wherein N3 lithiated DHPM derivatives
were found to reactive exclusively with hard electrophiles,7 only
whereas least acidic C6 methyl anion preferentially reacted with
soft electrophiles.8
Thus whereas, all attempts to isolate C6-elaborated 3-bromo-
propyl DHPM in the reaction of 1a with 1,2-dibromoethane failed
owing to the favorable proximity of the nucleophilic N1 anion and
electrophilic bromopropyl center leading to instant cyclization to
the five membered ring of the thermodynamically more stable 7a,
the derivative 9c could be isolated and cyclized to the corre-
sponding 7g. However, the greater flexibility of the long alkyl
Table 3
Effect of dielectrophile chain length on formation of bicyclic DHPM 7
NaH/THF
R1
R1
N
O
R1
O
O
n = 2, 3
i. n-BuLi/THF/N2
EtO
NH
-10 °C to r.t.,3 h
EtO
NH
EtO
Me
NH
ii. BrCH2(CH2)nBr (3.0 eq.)
THF/N2/-10 °C to r.t., 12 h
N
H
O
O
N
H
O
Br
( )n
7
( )n
9
1
Entry
DHPM
R1
Electrophile BrCH2(CH2)nBr
Product (isolated yield %)a
7
9
1
2
3
4
5
1a
1b
1b
1b
1b
Me
Ph
Ph
Ph
Ph
n¼2
n¼2
n¼3
n¼4
n¼5
7e (71)
7f (74)
7g (28)
d
d
9b (0)b
9c (58)b
9d (68)
9e (72)
d
a
After chromatographic purification.
Electrophile addition at ꢀ10 ꢁC followed by stirring for 30 min and quenching at rt furnish 9b in 75% and 9c 73% yields, exclusively.
b

K. Singh, S. Singh / Tetrahedron 64 (2008) 11718–11723
11721
chains in 9d and 9e did not affect cyclization to the corresponding
bicyclic DHPM derivatives.
room temperature and stirring was continued for additional 12 h,
to complete the reaction, after which a saturated aqueous solution
of NH4Cl was introduced to terminate the reaction. The reaction
was extracted with ethyl acetate (3ꢂ25 ml) treated in sequence
with brine and water. The extracts were dried over anhydrous
Na2SO4 and the mixture concentrated under reduced pressure. The
products were isolated by flash chromatography using silica gel-G
(60–120 mesh) and mixtures of ethyl acetate and hexane as eluent.
For preparing samples for micro-analytical analysis, crystallization
was done using combinations of dry DCM and hexane or methanol
and petroleum ether (40–60 ꢁC).
To supplement the yield of the desired N1, C6-linked DHPM
derivatives 7f and 7g, each of the corresponding C6-bromoalkyl
products 9b and 9c were cyclized. Thus, C6-bromobutyl DHPM 9b
upon treatment with 2.1 equiv of NaH in THF at 0 ꢁC furnished 7f
(TLC monitoring) in 72% yield. Similarly, C6-bromopentyl DHPM 9c
was also transformed to the corresponding N1, C6-linked DHPM 7g
in 55% yield, using relatively harsh reaction conditions as this re-
action was required to be refluxed for 2 h. However, reaction of C6-
bromohexyl DHPM 9d and C6-bromoheptyl DHPM 9e derivatives
remained unaffected even upon prolonged treatment with NaH.
The following compounds have been prepared.
3. Conclusions
4.2.1. 3-Methyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]-
pyrimidine-4-carboxylic acid ethyl ester 7a
Thus, we have found that using n-BuLi (3.5 equiv) at ꢀ10 ꢁC
DHPM derivatives upon metalation and subsequent reaction with
dielectrophiles furnish N1, C6-linked bicyclic DHPM derivatives,
which constitute an important structural feature of alkaloids. The
hydrocarbon chain length flanked by two halides guides the
cyclization to the N1, C6-linked bicyclic DHPMs. Thus using
BrCH2(CH2)nBr, for n¼1 to n¼3 cyclization proceeds in the reaction
itself, however, if n exceeds 3 i.e., n¼4, 5; N1, C6-linked DHPM
derivatives are not formed even if treated with a base, separately.
This single-pot approach furnish access to N1, C6-linked DHPM
derivatives in moderate yields.
Yield: 35%; amorphous white solid; mp (CH2Cl2/hexane) 141 ꢁC;
[Found: C, 59.01; H, 7.32; N, 12.24. C11H16N2O3 requires: C, 58.92; H,
7.14; N, 12.51%.] Rf (40% ethyl acetate/hexane) 0.24; nmax (KBr) 3275,
1685, 1665 cmꢀ1 1H (300 MHz, CDCl3) 1.27 (3H, d, J 6.6 Hz, CH3),
;
1.29 (3H, t, J 7.2 Hz, CH3), 2.02–2.04 (2H, m, CH2), 3.12–3.22 (2H, m,
CH2), 3.70–3.72 (2H, m, CH2), 4.18–4.20 (2H, m, –OCH2), 4.40–4.43
(1H, m, C4-H), 5.11 (1H, br, D2O exchangeable, N3-H); 13C (75 MHz,
CDCl3) 14.4, 21.3, 24.0, 31.9, 46.5, 47.9, 59.8, 153.1, 165.7; m/z 224
(Mþ).
4.2.2. 1-Oxo-3-phenyl-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]-
pyrimidine-4-carboxylic acid ethyl ester 7b
4. Experimental
Yield: 30%; crystalline solid; mp (CH2Cl2/hexane) 185 ꢁC;
[Found: C, 67.23; H, 6.33; N, 10.04. C16H18N2O3 requires: C, 67.13; H,
6.29; N, 9.79%.] Rf (50% ethyl acetate/hexane) 0.3; nmax (KBr) 3200,
4.1. General information
1670, 1655 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.18 (3H, t, J 7.2 Hz, CH3),
Melting points were determined in open capillaries and are
uncorrected. 1H/13C NMR (300/75 MHz as well as 200/50 MHz;
CDCl3þDMSO-d6/TFA) spectra were recorded using commercial
deuterated solvents on multinuclear spectrometer Jeol FT-AL-300
instrument using tetramethylsilane as internal standard. Data are
2.04–2.07 (2H, m, CH2), 3.10–3.13 (1H, m, CH), 3.24–3.26 (1H, m,
CH), 3.77–3.79 (2H, m, CH2), 4.07–4.09 (2H, m, OCH2), 5.32 (1H, br,
D2O exchangeable, N3-H), 5.40 (1H, d, J 3.0 Hz, C4-H), 7.26–7.29
(5H, m, ArH); 13C (75 MHz, CDCl3)
d 14.2, 21.3, 32.1, 46.7, 55.8, 59.9,
126.4, 127.8, 128.6, 129.5, 152.1; m/z 286 (Mþ).
reported as follows: chemical shifts (d, ppm), multiplicity [singlet
(s), doublet (d), double doublet (dd), triplet (t), quartet (q), AB
quartet (ABq), broad (br), and multiplet (m)], coupling constant
[Hz], integration. Mass spectra (MS) were recorded on Bruker
Daltonics esquire 3000 spectrometer. IR spectra were recorded on
Shimadzu FTIR 8400 S spectrophotometer. Elemental analyses
were performed on FLASH EA 1112 (Thermo electron corporation)
analyzer.
Thin layer chromatography (TLC) was performed on Merck
(60F254, 0.2 mm) using an appropriate solvent system. The chro-
matograms were visualized under UV light. Separation of various
products was carried out by flash chromatography on silica gel
(60–120 mesh). All solvents and electrophiles were dried with
appropriate reagents before use. Reactions were run under a blan-
ket of dry nitrogen gas in a sealed (rubber septum, Aldrich) round-
bottomed flasks. Organometallic reagents were added using
cannula. The low temperature (ꢀ10 ꢁC and ꢀ78 ꢁC) was attained in
Dewar flasks using organic solvent–liquid N2 slush.
4.2.3. 1-Oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]-pyrimidine-4-
carboxylic acid ethyl ester 7c
Yield: 15%; white solid; mp (CH2Cl2/hexane) 132 ꢁC; [Found: C,
56.98; H, 6.52; N, 13.24. C10H14N2O3 requires: C, 57.14; H, 6.66; N,
13.33%.] Rf (45% ethyl acetate/hexane) 0.5; nmax (KBr) 3100, 1670,
1665 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.28 (3H, t, J 7.2 Hz, CH3), 1.97–
1.99 (2H, m, CH2), 3.09–3.11 (2H, m, CH2), 3.69 (2H, t, J 7.2 Hz, CH2),
4.16 (2H, s, C4), 4.17 (2H, q, J 7.2 Hz, OCH2), 4.88 (1H, br, D2O ex-
changeable, N3-H); 13C (75 MHz, CDCl3)
d 14.4, 21.3, 31.8, 41.5, 46.4,
59.8, 102.1, 153.1, 165.7; m/z 210 (Mþ).
4.2.4. 3-Phenyl-1-thioxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]-
pyrimidine-4-carboxylic acid ethyl ester 7d
Yield: 15%; yellow crystalline solid; mp (CH2Cl2/hexane) 178 ꢁC;
[Found: C, 63.29; H, 6.24; N, 9.05; S 10.60. C16H18N2O2S requires: C,
63.57; H, 5.96; N, 9.27; S, 10.59%.] Rf (35% ethyl acetate/hexane) 0.5;
nmax (KBr) 3165, 1645, 1610 cmꢀ1; 1H (300 MHz, CDCl3)
d 1.18 (3H, t,
J 7.2 Hz, CH3), 2.04–2.06 (2H, m, CH2), 3.09–3.11 (1H, m, CH), 3.31–
3.34 (1H, m, CH), 4.08–4.11 (4H, m, 2ꢂCH2), 5.37 (1H, d, J 3.0 Hz, C4-
H), 6.95 (1H, br, D2O exchangeable, N3-H), 7.26–7.30 (m, 5H, ArH);
4.2. General procedure
To a suspension of DHPM 1 (5 mmol) in dry THF (50 ml) under
a blanket of dry N2, 2.1 N n-BuLi (17.5 mmol, 8.33 ml) was added
drop-wise at ꢀ10 ꢁC. After the addition, reaction mixture was
warmed to room temperature and stirred for additional 3 h until
colored anionic species was generated. To this solution, appropriate
dielectrophile (dibromoalkane) (15 mmol), dissolved in 10 ml dry
THF was added drop-wise using cannula at 10 ꢁC. Upon addition of
the electrophile, the red color was quenched in most of the cases,
indicating the consumption of the anions. Reaction was warmed to
13C (75 MHz, CDCl3)
d 14.1, 21.0, 32.1, 52.1, 55.7, 60.3, 100.7, 126.6,
128.2, 128.8, 142.9, 149.3, 165.3, 175.4; m/z 302 (Mþ).
4.2.5. 3-Methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-pyrido[1,2-c]-
pyrimidine-4-carboxylic acid ethyl ester 7e
Yield: 71%; light brown solid; mp (CH2Cl2/hexane) 72 ꢁC;
[Found: C, 60.31; H, 7.32; N, 11.34. C12H18N2O3 requires: C, 60.50; H,
7.56; N, 11.76%.] Rf (45% ethyl acetate/hexane) 0.5; nmax (KBr) 3260,
1695, 1645 cmꢀ1; 1H (300 MHz, CDCl3)
d 1.23 (3H, d, J 6.3 Hz, CH3),

11722
K. Singh, S. Singh / Tetrahedron 64 (2008) 11718–11723
1.27 (3H, t, J 7.2 Hz, CH3), 1.74–1.77 (2H, m, CH2), 3.00–3.03 (1H, m,
CH), 3.12–3.14 (1H, m, CH), 3.55–2.57 (2H, m, CH2), 3.79–3.81 (2H,
m, CH2), 4.14–4.16 (2H, m, OCH2), 4.32–4.34 (1H, m, C4-H), 5.10 (1H,
4.3. Trapping of intermediates 9a and 9b
To a suspension of DHPM 1 (5 mmol) in 50 ml dry THF under
a blanket of dry N2, 2.1 N n-BuLi (8.33 ml, 17.5 mmol) was added
drop-wise at ꢀ10 ꢁC. After the addition, reaction mixture was
warmed to room temperature and stirred for additional 3 h. For
trapping 9a, the reaction was shifted to ꢀ78 ꢁC and 1,2-dibromo-
ethane (1.3 ml, 15 mmol), dissolved in 10 ml dry THF was added
drop-wise. Stirring was continued at the same temperature for
additional 30 min, after which a saturated aqueous solution of
NH4Cl was introduced at ꢀ78 ꢁC. However, for synthesis of 9b the
second step was executed at ꢀ10 ꢁC, by using 1,3-dibromopropane
(15 mmol) and stirring was continued for 30 min at rt. The reaction
was treated with brine and extracted with ethyl acetate (3ꢂ25 ml).
The extracts were dried over anhydrous Na2SO4 and the mixture
concentrated under reduced pressure. The product was isolated by
flash chromatography using silica gel-G (60–120 mesh) and
mixtures of ethyl acetate/hexane as eluent.
br, D2O exchangeable, N3-H); 13C (75 MHz, CDCl3)
d 14.3, 18.7, 21.7,
23.4, 25.3, 40.5, 46.1, 59.8, 103.1, 132.4, 154.7, 165.9; m/z 238 (Mþ).
4.2.6. 1-Oxo-3-phenyl-2,3,5,6,7,8-hexahydro-1H-pyrido[1,2-c]-
pyrimidine-4-carboxylic acid ethyl ester 7f
Yield: 74%; amorphous white solid; mp (CH2Cl2/hexane) 132 ꢁC;
[Found: C, 67.89; H, 6.85; N, 9.63. C17H20N2O3 requires: C, 68.0; H,
6.66; N, 9.33%.] Rf (45% ethyl acetate/hexane) 0.7; nmax (KBr) 3180,
1655, 1608 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.16 (3H, t, J 7.2 Hz, CH3),
1.72–1.74 (3H, m, CH2 and CH), 1.86–1.88 (1H, m, CH), 3.06–3.08
(1H, m, CH), 3.21–3.23 (1H, m, CH), 3.63–3.65 (1H, m, CH), 3.83–
3.85 (1H, m, CH), 4.07 (2H, q, J 7.2 Hz, OCH2), 5.36 (1H, s, C4-H), 5.36
(1H, br, D2O exchangeable, N3-H), 7.26–7.28 (5H, m, ArH); 13C
(50 MHz, CDCl3)
d 14.1, 18.7, 21.8, 25.4, 40.6, 54.2, 59.9, 101.7, 126.2,
127.8, 128.7, 143.7, 151.2, 153.1, 165.8; m/z 300 (Mþ).
4.2.7. 1-Oxo-3-phenyl-1,2,3,5,6,7,8,9-octahydropyrimido[1,6-a]-
azepine-4-carboxylic acid ethyl ester 7g
4.3.1. 5-Ethoxycarbonyl-6-(bromomethyl)-4-methyl-3,4-
dihydropyrimidin-2(1H)-one 9a
Yield: 28%; amorphous white solid; mp (CH2Cl2/hexane) 136 ꢁC;
[Found: C, 68.67; H, 7.27; N, 9.19. C18H22N2O3 requires: C, 68.78; H,
7.00; N, 8.91%.] Rf (35% ethyl acetate/hexane) 0.7; nmax (KBr) 3100,
Yield: 35%; amorphous brown solid; mp (CH2Cl2) 137 ꢁC;
[Found: C, 39.18; H, 4.87; N, 9.91. C9H13N2O3Br requires: C, 38.98; H,
4.69; N, 10.10%.] Rf (60% ethyl acetate/hexane) 0.4; 1H (300 MHz,
1685, 1660 cmꢀ1
;
1H (300 MHz, CDCl3)
d
1.18 (3H, t, J 7.2 Hz, CH3),
CDCl3) d 1.31 (3H, t, J 7.2 Hz, CH3), 1.30 (3H, d, J 6.6 Hz, CH3), 4.21–
1.72–1.74 (6H, m, 3ꢂCH2), 2.92–2.94 (1H, m, CH), 3.43–3.45 (1H, m,
CH), 3.86–3.88 (2H, m, CH2), 4.09 (2H, q, J 7.2 Hz, OCH2), 5.36 (1H, d,
J 3.3 Hz, C4-H), 5.45 (1H, br, D2O exchangeable, N3-H), 7.24–7.26
4.23 (2H, m, OCH2), 4.41–4.43 (1H, m, C4-H), 4.57 (2H, ABq, J
10.5 Hz, CH2Br), 5.71 (1H, br, D2O exchangeable, N3-H), 8.05 (1H, br,
D2O exchangeable, N1-H); 13C (75 MHz, CDCl3)
d 14.3, 21.3, 31.8,
(5H, m, ArH); 13C (75 MHz, CDCl3)
d
14.0, 26.7, 28.3, 28.7, 28.8, 43.2,
46.5, 47.9, 59.7, 104.7, 144.4, 153.0, 165.6; m/z 277 (Mþ).
53.9, 60.1, 103.3, 126.2, 127.7, 128.6, 143.3, 153.6, 154.5, 166.1; m/z
314 (Mþ).
4.3.2. 5-Ethoxycarbonyl-6-(4-bromobutyl)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 9b
4.2.8. 1,2-Bis-[(5-ethoxycarbonyl-4-methyl-3,4-dihydropyrimidin-
2(1H)-one)-6-yl]ethane 8a
Yield: 75%; white solid; mp (CH2Cl2/hexane) 141 ꢁC; [Found: C,
53.65; H, 5.71; N, 7.07. C17H21N2O3Br requires: C, 53.54; H, 5.51; N,
7.34%.] Rf (45% ethyl acetate/hexane) 0.4; nmax (KBr) 3100, 1690,
Yield: 55%; amorphous white solid, did not melt up to 300 ꢁC;
[Found: C, 55.03; H, 6.83; N,13.97. C18H26N4O6 requires: C, 54.82; H,
1630 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.15 (3H, t, J 7.2 Hz, CH3), 1.77–
6.59; N, 14.21%.] nmax (KBr) 3260, 1680, 1625 cmꢀ1
;
1H (300 MHz,
1.79 (2H, m, CH2), 1.93–1.95 (2H, m, CH2), 2.75 (2H, t, J 7.5 Hz, CH2),
3.41 (2H, t, J 6.Hz, CH2), 4.06 (2H, q, J 7.2 Hz, OCH2), 5.40 (1H, d, J
2.7 Hz, C4-H), 5.61 (1H, br, D2O exchangeable, N3-H), 7.27–7.29 (5H,
m, ArH), 8.04 (1H, br, D2O exchangeable, N1-H); 13C (75 MHz,
CDCl3þTFA)
d
1.31 (6H, t, J 7.2 Hz, 2ꢂCH3), 1.33 (6H, d, J 6.3 Hz,
2ꢂCH3), 2.84–2.86 (2H, m, CH2), 3.03–3.05 (2H, m, CH2), 4.23–4.25
(4H, m, 2ꢂOCH2), 4.50–4.52 (2H, m, 2ꢂC4-H), 7.13 (2H, br, D2O
exchangeable, N3-H), 8.43 (2H, br, D2O exchangeable, N1-H); 13C
CDCl3)
d 14.0, 26.7, 30.7, 32.2, 33.1, 55.8, 60.0, 101.3, 126.5, 128.0,
(75 MHz, CDCl3þTFA)
d
14.0, 18.3, 23.3, 29.1, 47.5, 60.7, 104.4, 112.8,
128.7, 143.6, 149.7, 153.2, 165.2; m/z 381 (Mþ).
116.6, 147.1, 156.4, 165.1; m/z 394 (Mþ).
4.3.3. 5-Ethoxycarbonyl-6-(5-bromopentyl)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 9c
4.2.9. 1,2-Bis-[(5-ethoxycarbonyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one)-6-yl]ethane 8b
Yield: 58%; white solid; mp (CH2Cl2/hexane) 153 ꢁC; [Found: C,
54.97; H, 6.09; N, 7.31. C18H23N2O3Br requires: C, 54.68; H, 5.82; N,
7.08%.] Rf (35% ethyl acetate/hexane) 0.4; nmax (KBr) 3185, 1665,
Yield: 50%; amorphous white solid, did not melt up to 300 ꢁC;
[Found: C, 64.60; H, 5.51; N,10.53. C28H30N4O6 requires: C, 64.86; H,
5.79; N, 10.81%.] nmax 3210, 1680, 1640 cmꢀ1
;
1H (300 MHz,
1615 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.15 (3H, t, J 7.2 Hz, CH3), 1.55–
CDCl3þTFA)
d
1.14 (6H, t, J 7.2 Hz, 2ꢂCH3), 3.07–3.09 (2H, m, CH2),
1.57 (4H, m, 2ꢂCH2), 1.86–1.88 (2H, m, CH2), 2.71–2.73 (2H, m, CH2),
3.40 (2H, t, J 6.6 Hz, CH2), 4.06 (2H, q, J 7.2 Hz, OCH2), 5.39 (1H, d, J
2.7 Hz, C4-H), 5.70 (1H, br, D2O exchangeable, N3-H), 7.27–7.29 (5H,
m, ArH), 8.20 (1H, br, D2O exchangeable, N1-H); 13C (75 MHz,
3.19–3.21 (2H, m, CH2), 4.07 (4H, q, J 7.2 Hz, 2ꢂ–OCH2), 5.51 (2H, d, J
3.0 Hz, 2ꢂC4-H), 7.29 (10H, m, ArHþ2H, D2O exchangeable, N3-H),
8.58 (2H, br, D2O exchangeable, N1-H); 13C NMR (75 MHz,
CDCl3þTFA)
d
13.6, 29.2, 55.5, 61.6, 103.2, 108.8, 112.5, 116.3, 120.1,
CDCl3) d 14.0, 27.1, 27.7, 31.4, 32.1, 33.6, 55.6, 60.0, 100.99, 126.5,
126.5, 141.6, 147.4, 155.2, 165.7; m/z 518 (Mþ).
127.9, 128.7, 143.6, 150.1, 165.2; m/z 395 (Mþ).
4.2.10. 1,2-Bis-[(5-ethoxycarbonyl-3,4-dihydropyrimidin-2(1H)-
one)-6-yl]ethane 8c
4.3.4. 5-Ethoxycarbonyl-6-(6-bromohexyl)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 9d
Yield: 48%; amorphous white solid, did not melt up to 300 ꢁC;
[Found: C, 52.18; H, 5.91; N, 15.39. C16H22N4O6 requires: C, 52.45; H,
Yield: 68%; white solid; mp (CH2Cl2/hexane) 121 ꢁC; [Found: C,
55.93; H, 6.25; N, 6.90. C19H25N2O3Br requires: C, 55.74; H, 6.11; N,
6.84%.] Rf (25% ethyl acetate/hexane) 0.5; nmax (KBr) 3205, 1685,
6.01; N, 15.30%.] nmax 3230, 1745, 1675 cmꢀ1
;
1H (300 MHz,
CDCl3þTFA)
d
1.30 (6H, t, J 7.2 Hz, 2ꢂCH3), 2.93–2.95 (4H, m,
1632 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.15 (3H, t, J 7.2 Hz, CH3), 1.42–
2ꢂCH2), 4.22 (4H, q, J 7.2 Hz, 2ꢂ–OCH2), 4.23 (4H, s, 2ꢂC4-CH2),
144 (4H, m, 2ꢂCH2), 1.62–1.64 (2H, m, CH2), 1.83–1.85 (2H, m, CH2),
2.71–2.73 (2H, m, CH2), 3.39 (2H, t, J 6.6 Hz, CH2), 4.07 (2H, q, J
7.2 Hz, OCH2), 5.39 (1H, s, C4-H and 1H, D2O exchangeable, N3-H),
7.13 (1H, br, D2O exchangeable, N3-H), 7.30 (5H, m, ArH); 13C
6.81 (2H, br, D2O exchangeable, N3-H), 8.23 (2H, br, D2O ex-
changeable, N1-H); 13C (75 MHz, CDCl3þTFA)
d 13.9, 29.3, 41.0, 61.4,
98.5, 112.6, 116.4, 148.4, 156.5, 159.9, 160.5, 165.5; m/z 366 (Mþ).

K. Singh, S. Singh / Tetrahedron 64 (2008) 11718–11723
11723
(75 MHz, CDCl3)
d
14.0, 27.7, 27.9, 28.4, 31.5, 32.5, 33.9, 55.6, 59.9,
Reference and notes
100.8, 126.5, 127.8, 128.6, 143.8, 150.6, 153.7, 165.3; m/z 410 (Mþ).
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4.3.5. 5-Ethoxycarbonyl-6-(7-bromoheptyl)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 9e
Yield: 72%; white solid; mp 111 ꢁC (CH2Cl2/hexane); [Found: C,
56.83; H, 6.63; N, 6.71. C20H27N2O3Br requires: C, 56.60; H, 6.36; N,
6.60%.] Rf (20% ethyl acetate/hexane) 0.4; nmax (KBr) 3180, 1665,
1615 cmꢀ1 1H (300 MHz, CDCl3)
; d 1.15 (3H, t, J 7.2 Hz, CH3), 1.42–
1.44 (6H, m, 3ꢂCH2), 1.60–1.62 (2H, m, CH2), 1.82–1.84 (2H, m, CH2),
2.70–2.72 (2H, m, CH2), 3.38 (2H, t, J 6.6 Hz, CH2), 4.07 (2H, q, J
7.2 Hz, OCH2), 5.39 (1H, d, J 2.7 Hz, C4-H), 5.68 (1H, br, D2O ex-
changeable, N3-H), 7.27–7.29 (5H, m, ArH), 7.85 (1H, br, D2O ex-
changeable, N1-H); 13C (75 MHz, CDCl3)
d 14.0, 27.9, 28.0, 28.3, 29.1,
31.6, 32.6, 33.8, 55.6, 59.9, 100.9, 126.5, 127.9, 128.7, 143.7, 150.4,
165.3; m/z 424 (Mþ).
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Acknowledgements
The authors thank Dr. K. A. Suri, Deputy Director, Institute of
Integrated Medicine, Jammu for his help for getting mass spectro-
metric data and Chemistry Department, Guru Nanak Dev University
for micro analytical data. Financial support of CSIR (01(1960)/04/
EMR-II) and UGC (31-53/2005/SR), New Delhi is gratefully
acknowledged.
12. Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125–4149.
13. Electrophilic addition at ꢀ78 ꢁC, followed by subsequent quenching at same
temperature after 30 min, leads to the corresponding C6 brominated DHPM
analogous instead of N1, C6 linked product.
14. Greene, A. E.; Muller, J.-C.; Ourisson, G. J. Org. Chem. 1974, 39, 186–191.