N1-Alkylated 3,4-dihydropyrimidine-2(1H)-ones: Convenient one-pot selective synthesis and evaluation of their calcium channel blocking activity

Article abstract of DOI:10.1016/j.ejmech.2008.10.002

It has been found that selective N1-alkylation of 3,4-dihydropyrimidine-2(1H)-ones can be achieved under solvent-less, mild phase transfer catalytic (PTC) conditions with tetrabutylammonium hydrogen sulfate and 50% aqueous NaOH as the catalyst and base, r

Full text of DOI:10.1016/j.ejmech.2008.10.002

European Journal of Medicinal Chemistry 44 (2009) 1997–2001
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
N1-Alkylated 3,4-dihydropyrimidine-2(1H)-ones: Convenient one-pot selective
synthesis and evaluation of their calcium channel blocking activity
,
a
b
b
b
Kamaljit Singh a , Divya Arora , Elizabeth Poremsky , Jazmyne Lowery , Robert S. Moreland
*
a Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143 005, India
b Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been found that selective N1-alkylation of 3,4-dihydropyrimidine-2(1H)-ones can be achieved
under solvent-less, mild phase transfer catalytic (PTC) conditions with tetrabutylammonium hydrogen
sulfate and 50% aqueous NaOH as the catalyst and base, respectively. The procedure is tolerant to
substitutional variation at key diversity points on the pyrimidinone moiety.
Received 31 March 2008
Received in revised form
22 September 2008
Accepted 2 October 2008
Available online 11 October 2008
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords:
Phase transfer catalysis
N-Alkylation
Biginelli dihydropyrimidinones
Regioselective
Tetrabutylammonium hydrogen sulfate
Vascular smooth muscle
1. Introduction
(S > O > N)-1,4-dihydropyrimidines [5] (Fig. 2) mimic the activity
of 1,4-DHPs. Also it has been found that ortho and/or meta
Drugs of three different chemical categories
–
1,4-dihy-
aromatic substitution, ester alkyl group were major determinants
of in vitro potency. DHPM 1 has been identified as a lead with R-
enantiomer [8] both more potent as well as long lasting and
compares most favorably with the long-acting DHP derivative
amlodipine 2, in spontaneously hypertensive rats.
dropyridines (DHP) (e.g., nifedipine), phenylalkylamines (e.g.,
verapamil) and benzothiazepines (e.g., diltiazem) represent the
most studied organic calcium channel blockers and are used in the
treatment of cardiovascular disorders including hypertension [1].
They are known to bind to three different, but allosterically linked,
sites on the a1 subunit of the calcium channel. The biological
activity of these compounds, in particular symmetrical 1,4-DHPs
bearing equivalent substituents at C-2/C-6 and esters at C-3/C-5,
arises due to the structural features such as an axial aromatic ring
at C-4, the plane of which bisects the boat conformation of the
DHP ring. A similar binding model has been proposed [2] for
a closely related, unsymmetrical dihydropyrimidinones (DHPMs)
(Fig. 1), which possess an inherent chiral centre at C-4 by virtue of
unsymmetrical substituent modifications. A variety of DHPM have
been synthesized and examined for their calcium channel block-
ing properties using various synthetic routes. In general accord
with structure–activity relationships, established for 1,4-DHP
calcium channel blockers [3,4], it has been found that N3-(alkyl,
acyl, carbamate, sulfonyl, ureido) [5–9] substituted-2-hetero
HCl
F3C
i-PrO2C
O
S
N
Cl
CO2Me
EtO2C
O
N
O
F
R
H2N
Me
N
H
N
H
Me
2
1
Intrigued by such investigations, we undertook synthetic
manipulation of C-6, N-3 and C-4 positions of DHPMs [10–12], as
well as investigations of the calcium channel binding properties of
a number of these derivatives. Investigations in the calcium
channel binding properties of the N-1 substituted DHPM deriva-
tives which bear a close similarity with some biologically active
molecules [13,14] has not thus far been undertaken. Herein, we
report a general route to N-1 substituted DHPMs as well as
* Corresponding author. Tel.: þ91 183 2258853; fax: þ91 183 2258819/20.
E-mail address: kamaljit19in@yahoo.co.in (K. Singh).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.10.002

1998
K. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1997–2001
corresponding N1,N3-disubstituted products could be detected in
( non-essential)
right hand side
some cases, ethyl-1,2,3-trimethyl-2-oxo-4-(phenyl)-3,4-dihydrop-
yrimidine-5-carboxylate 5 was obtained in 8–10% isolated yield
along with 4a. It has also been found that neither of R1, R2, R3 or R4
has influenced the regioselectivity or yield of the desired N-1
alkylated products.
X= syn
X
Phenyl up
(antagonist)
N
H
Hydrogen bond
H
O
The structures of the newly synthesized compounds have been
established on the basis of elemental analysis and spectroscopic
techniques and are presented in Section 5.
Me
R
O
left- hand side
(essential)
cis corbonyl
Fig. 1. Proposed receptor-bound dihydropyrimidine conformation (antagonist).
3. Biological results and discussion
screening results of some of the representative compounds for their
calcium channel blocking activity.
The study of N-1 substituted DHPMs facilitates supplementing
information about structure requirements important to
biological activity. It also affords to expand the existing structure–
activity relationships, and, potentially to discover additional
structure modifications consistent with improved biological
activity.
2. Chemistry
The available route of N-1 alkylation of DHPMs using N-
substituted ureas face limitation owing to low yields and the
requirement of a number of urea derivatives, which are not avail-
able commercially [15]. With the failure of the standard alkylation
conditions to show selectivity in N-1 alkylation, the use of Mitsu-
nobu-type reaction conditions furnishes N-1 alkylated DHPMs, but
reagents used are reasonably expensive [16]. But the method is
attractive in so far as the formation of mixtures of N-1/N-3 alkylated
DHPMs [17] is avoided.
The newly synthesized compounds were screened for their
calcium channel blocking activity based on their ability to relax
a
membrane depolarization induced contraction of vascular
smooth muscle. Swine carotid arteries were obtained from a local
slaughterhouse and transported to the laboratory in an ice-cold
MOPS buffered physiological salt solution (PSS). The PSS contained,
in mM: 140 NaCl, 4.7 KCl, 1.2 MgSO4, 1.6 CaCl2, 1.2 Na2HPO4, 2 3-[N-
morpholino] propane sulfonic acid (MOPS, pH 7.4), 5 D-glucose, and
Recently, we have revealed that Biginelli DHPMs can be regio-
selectively substituted (acylation and alkoxycarbonylation) [11] at
the N-3 position, with a wide variety of electrophiles. Use of
a similar methodology through reaction of DHPMs with a base (LDA
or n-BuLi/ꢀ78 ꢁC/THF) followed by quenching with electrophiles
such as iodomethane [10,11] or CH-acidic compounds [10,11] such
as ethyl bromoacetate or ethyl 2-bromopropionate, resulted in
rather indiscriminate attack at C-6 methyl/N-1/N-3 positions
resulting in mixture of products. PTC has been established as
a versatile method especially for N-alkylation reaction of various
types of heterocyclic moieties [18]. We have found that a one-pot
N1-alkylation of DHPMs 3 could be achieved in high yields, under
solvent-free conditions employing tetrabutylammonium hydrogen
sulfate and 50% aqueous NaOH as the catalyst and base (Scheme 1),
respectively.
The present protocol of N-1 alkylation not only preserves the
simplicity of synthetic operation but also furnished remarkable
selectivity (over N-3) in alkylation reaction, furnishing the products
in moderate to high yields. The reaction can be performed under
relatively simple reaction conditions by stirring together, an
appropriate DHPM, electrophile and 50% aqueous sodium
hydroxide solution at ambient temperature for specific time
(Table 1), without using a solvent. After the reaction is over, the
excess electrophile can even be recovered through phase separa-
tion and reused. The results presented in Table 1 indicate the scope
and generality of the method, which is efficient not only from the
point of view of the substituents of the DHPM core, but also with
respect to the alkylating agent. Although trace amounts of the
0.02 Na2-ethylenediaminetetraacetic acid (EDTA). Arteries were
cleaned of connective tissue, and then dissected free of both intima
and adventitia leaving a thin medial layer for experimentation.
Intact medial strips of swine carotid artery (7 ꢂ 0.7 mm) were
suspended between a Grass FT.03 force transducer and a stationary
clip in water-jacketed organ baths. The strips were equilibrated in
PSS at 37 ꢁC, pH 7.4 and bubbled with 100% O2 for 90–120 min. A
passive force of w2 g was applied to all tissues. This passive force
sets the muscle at a length that approximates Lo, the length at
which maximal active force is generated. During the equilibration
period, tissues were maximally contracted with 110 mM KCl
(equimolar substitution for NaCl) several times until similar levels
of force were attained.
The equilibrated vascular strips were contracted with 110 mM
KCl containing PSS, allowed to achieve a stable level of force and
then subjected to the cumulative addition of calcium channel
blocker (1 mM to 30 mM) or DMSO as a vehicle control. Data are
presented (Fig. 3) as a percent of the initial maximal response to
110 mM KCl at each dose of compound.
The calcium channel blockers were compared against nifedipine
for their ability to relax a membrane depolarization induced
contraction which is almost exclusively dependent on the influx of
extra-cellular calcium [19]. The novel compounds and nifedipine
were tested across a concentration range of 1
Nifedipine completely relaxed the KCl-induced contraction with an
IC50 in the 10 M range. In contrast compounds 4b–4g and 5
maximally relaxed the KCl-induced contractions by only 40% with
IC50s ranging from 100 to 300 M.
mM to 30 mM.
m
m
2/3-NO2,2-CF3,2-Cl
X
i-Pr >Et >Me
CO2 alkyl, CO alkyl, SO2alkyl,CONH alkyl, alkyl
R1OOC
Me
R2
N
N
H
W
S>O>N
Fig. 2. General structure–activity relationship of 1,4-dihydropyrimidine calcium channel blockers.

K. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1997–2001
1999
120
Ar/R1
NH
O
Ar/R1
NH
O
R2O
R2O
(i) cat. n-Bu4NHSO4
100
80
60
40
20
0
R3
N
H
O
50% NaOH
R3
N
O
(ii) R4X, (0°C to RT)
R4
4
3
Scheme 1. N-1 Alkylation of Biginelli DHPMs under phase transfer catalytic conditions.
Nifedipine
4b
4c
4d
4e
4f
4. Conclusions
Thus an efficient protocol for the selective N1-alkylation of 3,4-
dihydropyrimidin-2(1H)-ones using PTC, under mild solvent-free
reaction conditions is presented. The method holds potential for
the preparation of 4 in multi-gram scale as has been achieved in
case of 4a in this investigation. Among the novel compounds tested
very minor calcium channel blocking activity was observed as
compared to nifedipine in a screen using relaxation of a membrane
depolarized vascular tissue as the end-point.
4g
5
1
3
10
30 100 300 1000 300010,000 Final
[compound] in uM
Fig. 3. Medial strips from the swine carotid artery were contracted with 110 mM KCl-
PSS and then subjected to the cumulative addition of calcium channel blocker to
determine their potential for relaxation. Nifedipine and 6 novel calcium channel
blockers (4b–4g and 5) were tested.
5. Experimental
Melting points were determined by open capillaries and are
uncorrected. 1H and 13C NMR spectra were recorded on JEOL FT-
NMR AL-300 MHz spectrophotometer using TMS as an internal
standard. The mass spectra were recorded on Esquire 3000-00037
mass spectrophotometer. The elemental analysis was done on
Thermo Flash EA 112. The purity of the compounds was checked by
thin layer chromatography (TLC) on silica gel plates using n-hexane
and ethyl acetate as solvent system. Analyses indicated by the
symbols of the elements were within ꢃ0.4% of the theoretical
values.
stirred to complete the reaction (TLC). The reaction was neutralized
using aqueous hydrochloric acid solution (1 N). Extractive workup
with ethyl acetate furnished corresponding 4/5 which were further
purified using column chromatography on silica gel (60–120 mesh).
The characterization data of the compounds is given below.
Compound 4a. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 90%, mp ¼ 170 ꢁC, 1H NMR (CDCl3)
: 1.18 (t, 3H, J ¼ 7.2 Hz,
d
ester-CH3), 2.51 (s, 3H, CH3), 3.23 (s, 3H, NCH3), 4.10 (q, 2H,
J ¼ 7.2 Hz, ester-CH2), 5.38 (d, 2H, J ¼ 2.7 Hz, CH), 5.52 (s, NH,
exchanged with D2O), 7.23–7.29 (m, 5H, ArH); 13C NMR (CDCl3)
d:
14.1, 16.4, 30.2, 53.8, 60.1,104.1,126.1,127.7,128.6, 143.3,148.5,153.9
and 166.0. Anal. C15H18N2O3: C, 65.69; H, 6.56; N, 10.21. Found: C,
65.72; H, 6.96; N, 10.52; MS: m/z 274 (Mþ).
5.1. General procedure for the synthesis of ethyl-1,6-dimethyl-2-
oxo-4-(phenyl)-3,4-dihydropyrimidine-5-carboxylate (4a–q/5)
Compound 4b. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 87%; mp ¼ 118 ꢁC (dichloromethane); 1H (CDCl3)
d: 1.17 (t,
To a mixture of DHPM 3 (5.26 mmol), tetrabutylammonium
hydrogen sulfate (5.21 mmol) and an electrophile (0.16 mol) in
a round bottomed flask, aqueous NaOH solution (2.0 ml, 50% w/v)
was added slowly with stirring at 0 ꢁC. After stirring for half an
hour, the reaction mixture was shifted to room temperature and
3H, J ¼ 6.9 Hz, ester-CH3), 1.21 (t, 3H, J ¼ 7.2 Hz, CH3), 2.53 (s, 3H,
CH3), 3.70–3.94 (m, 2H, NCH2), 4.08 (q, 2H, J ¼ 6.9 Hz, ester-CH2),
5.35 (d, 2H, J ¼ 2.7 Hz, CH), 5.63 (s, NH, exchanged with D2O), 7.21–
7.29 (m, 5H, ArH); 13C NMR (CDCl3)
d: 13.6,14.4,15.3, 37.1, 53.4, 59.5,
103.8, 125.7, 127.1, 128.0, 143.1, 148.0, 152.9 and 165.6. Anal.
C16H20N2O3: C, 66.66; H, 6.94; N, 9.72. Found: C, 66.94; H, 6.96; N,
9.92; MS: m/z 288 (Mþ).
Table 1
N-1 Alkylation of 3,4-dihydropyrimidinones 3 using PTC.a
Compound 4c. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 92%; mp ¼ 108 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.86 (t,
Productb R1
R2
R3
R4X
Reaction Time (h) Yield (%)
4ac
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C2H5 CH3 CH3I
C2H5 CH3 C2H5Br
3
3
3
3
3
4
5
5
5
5
4
4
3
3
3
4
5
90
87
92
85
95
85
80
75
72
77
82
81
80
81
79
83
89
3H, J ¼ 7.2 Hz, ester-CH3), 1.15 (m, 3H, CH3), 1.13–1.19 (m, 2H, CH2),
2.51 (s, 3H, CH3), 3.48–3.89 (m, 2H, NCH2), 4.08 (m, 2H, ester-CH2),
5.35 (d, 2H, J ¼ 3.0 Hz, CH), 5.86 (s, NH, exchanged with D2O), 7.22–
C2H5 CH3 n-C3H7Br
C2H5 CH3 n-C4H9Br
C2H5 CH3 n-C5H11
C2H5 CH3 n-C10H21Br
C2H5 CH3 CH2]CHCH2Br
C2H5 CH3 Br (CH2) 4 Br
C2H5 CH3 Br (CH2) 5 Br
C2H5 CH3 Br (CH2) 6Br
C2H5 CH3 n-C4H9Br
7.29 (m, 5H, ArH); 13C NMR (CDCl3)
d: 10.9, 14.0, 15.9, 22.9, 44.0,
53.6, 59.9, 104.3, 126.1, 127.4, 128.4, 143.4, 148.7, 153.7 and 166.1.
Anal. C17H22N2O3: C, 67.54; H, 7.28; N, 9.27. Found: C, 67.72; H, 7.38;
N, 9.42; MS: m/z 302 (Mþ).
C6H5
C6H5
Compound 4d. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 85%; mp ¼ 110 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.91 (t,
C6H4OCH3
C6H3(OCH3) 2 C2H5 CH3 n-C4H9Br
CH3
C5H11
C6H5
CH3
3H, J ¼ 7.2 Hz, ester-CH3), 1.17 (t, 3H, J ¼ 7.2 Hz, CH3), 1.29 (m, 2H,
CH2), 1.55 (m, 2H, CH2), 2.56 (s, 3H, CH3), 3.53–3.96 (m, 2H, NCH2),
4.09 (q, 2H, J ¼ 7.2 Hz, ester-CH2), 5.35 (d,1H, J ¼ 2.7 Hz, CH), 5.42 (s,
NH, exchanged with D2O), 7.23–7.29 (m, 5H, ArH); 13C NMR (CDCl3)
C2H5 CH3 n-C4H9Br
C2H5 CH3 n-C4H9Br
CH3 CH3 n-C4H9Br
CH3 CH3 n-C4H9Br
C2H5 C6H5 n-C4H9Br
d: 13.7, 14.0, 16.0, 19.9, 25.6, 37.8, 54.1, 60.1, 126.2, 128.6, 143.1, 143.4
CH3
and 194.3. Anal. C18H24N2O3: C, 68.35; H, 7.59; N, 8.86. Found: C,
a
Tetrabutylammonium hydrogen sulfate was employed as catalyst. Reactions
68.17; H, 7.38; N, 8.52; MS: m/z 316 (Mþ).
were considerably slow when tetraethylbenzylammonium chloride was employed.
b
Compound 4e. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
Trace amounts of N1,N3-dialkylated products were also formed in some cases.
Corresponding N1,N3-dimethyl derivative 5 was also isolated in 8–10% yield.
yield: 95%; mp ¼ 121 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.88
c

2000
K. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1997–2001
(t, 3H, J ¼ 7.2 Hz, ester-CH3), 1.76 (t, 3H, J ¼ 7.2 Hz, CH3), 1.27 (m, 4H,
2 ꢂ CH2), 2.52 (s, 3H, CH3), 3.58–3.91 (m, 2H, NCH2), 4.09 (q, 2H,
J ¼ 6.9 Hz, ester-CH2), 5.30 (s, NH, exchanged with D2O), 5.35 (s, 1H,
OCH3), 3.78 (s, 1H, OCH3), 4.06 (q, 2H, J ¼ 7.2 Hz, ester-CH2), 5.56 (d,
1H, CH), 5.64 (broad, NH, exchanged with D2O), 6.35 (dd, 1H,
J ¼ 6.0 Hz, ArH), 6.45 (d, 1H, J ¼ 2.1 Hz, ArH), 6.99 (d, 1H, J ¼ 8.4 Hz,
CH), 7.26–7.30 (m, 5H, ArH); 13C NMR (CDCl3)
d: 13.9,14.1,16.0, 22.3,
ArH); 13C NMR (CDCl3)
d: 13.6, 14.0, 15.9, 19.8, 32.0, 42.1, 48.0, 55.2,
28.8, 29.5, 42.6, 54.0, 60.1, 104.4, 126.2, 127.7, 128.6, 143.4, 148.7,
153.4 and 166.1. Anal. C19H26N2O3: C, 69.09; H, 7.87; N, 8.48. Found:
C, 69.38; H, 7.96; N, 8.71; MS: m/z 330 (Mþ).
59.9, 98.6, 102.3, 103.4, 122.1, 126.8, 150.0, 154.0, 157.8, 160.4 and
166.2. Anal. C20H28N2O5: C, 63.82; H, 7.44; N, 7.44. Found: C, 63.75;
H, 7.37; N, 7.66; MS: m/z 376 (Mþ).
Compound 4f. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
Compound 4m. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 85%; mp ¼ 103 ꢁC (dichloromethane); 1H (CDCl3)
d
: 0.88 (t,
yield: 80%; mp ¼ 85 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.94 (t, 3H,
3H, J ¼ 6.9 Hz, ester-CH3), 1.17 (t, 3H, J ¼ 7.2 Hz, CH3), 1.25 (s, 16H,
8 ꢂ CH2), 2.52 (s, 3H, CH3), 3.52–3.95 (m, 2H, NCH2), 4.08 (q, 2H,
J ¼ 7.2 Hz, ester-CH2), 5.35 (s, 1H and NH, exchanged with D2O),
J ¼ 6.9 Hz, ester-CH3), 1.20–1.65 (m, 7H, CH3 and 2 ꢂ CH2), 2.46 (s,
3H, CH3), 3.46–3.98 (m, 2H, NCH2), 4.14–4.22 (m, 2H, ester-CH2),
4.30–4.33 (m, 1H, CH), 5.04 (broad, NH, exchanged with D2O); 13C
7.23–7.29 (m, 5H, ArH); 13C NMR (CDCl3)
d
: 14.1, 16.1, 22.6, 29.2,
NMR (CDCl3) d: 13.7, 14.2, 15.7, 19.9, 23.1, 31.9, 42.0, 45.9, 59.8, 106.0,
29.8, 31.8, 42.7, 60.1, 67.1, 90.3, 126.2, 128.6, 148.7, 165.8, 175.7 and
180.7. Anal. C24H36N2O3: C, 72.00; H, 9.00; N, 12.00. Found: C, 72.15;
H, 9.17; N, 12.11; MS: m/z 400 (Mþ).
148.4, 154.4 and 166.1. Anal. C13H22N2O3: C, 61.41; H, 8.66; N, 11.02.
Found: C, 61.15; H, 8.79; N, 10.95; MS: m/z 254 (Mþ).
Compound 4n. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
Compound 4g. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 81%; mp ¼ 70 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.90 (m,
yield: 80%; mp ¼ 122 ꢁC (dichloromethane); 1H (CDCl3)
d
: 1.16 (t,
6H, 2 ꢂ CH3), 1.22–1.63 (m, 15H, 6 ꢂ CH2 and CH3), 2.45 (s, 3H, CH3),
3H, J ¼ 7.2 Hz, ester-CH3), 2.50 (s, 3H, CH3), 4.09 (q, 2H, J ¼ 7.2 Hz,
ester-CH2), 4.40 (q, 2H, J ¼ 21.3 Hz, CH2), 5.13 (t, 2H, J ¼ 18.0 Hz,
CH2), 5.39 (s, 1H, CH), 5.69 (broad, NH, exchanged with D2O), 5.79–
3.43–3.95 (m, 2H, NCH2), 4.13–4.22 (m, 3H, ester-CH2 and CH), 5.17
(s, NH, exchanged with D2O); 13C NMR (CDCl3)
d: 13.6, 13.8, 14.1,
15.8, 19.9, 22.4, 24.0, 31.3, 31.8, 36.6, 42.0, 49.8, 59.8, 105.1, 148.6,
154.5 and 166.2. Anal. C17H29N2O3: C, 66.01; H, 9.38; N, 9.06. Found:
C, 66.00; H, 9.27; N, 9.10; MS: m/z 309 (Mþ).
5.91 (m, 1H, CH), 7.27–7.29 (m, 5H, ArH); 13C NMR (CDCl3)
d: 14.0,
15.9, 44.8, 53.9, 60.1, 104.2, 116.0, 126.2, 127.6, 128.5, 133.9, 143.3,
148.8 and 166.0. Anal. C17H20N2O3: C, 68.00; H, 6.66; N, 9.33. Found:
C, 68.14; H, 6.44; N, 9.11; MS: m/z 300 (Mþ).
Compound 4o. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 79%; mp ¼ 97 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.90 (t, 3H,
Compound 4h. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
J ¼ 7.2 Hz, ester-CH3), 1.23–1.59 (m, 4H, 2 ꢂ CH2), 2.52 (s, 3H, CH3),
3.56–3.92 (m, 2H, NCH2), 3.63 (s, 3H, OCH3), 5.35 (d, 1H, J ¼ 3.0 Hz,
CH), 5.71 (broad, NH, exchanged with D2O), 7.22–7.33 (m, 5H, ArH);
yield: 75%; mp ¼ 140 ꢁC (dichloromethane); 1H (CDCl3)
d: 1.17 (t,
3H, J ¼ 7.2 Hz, ester-CH3), 1.69–1.80 (m, 4H, 2 ꢂ CH2), 2.54 (s, 3H,
CH3), 3.38 (t, 2H, J ¼ 6.3 Hz, CH2Br) 3.62–3.97 (m, 2H, NCH2), 4.10 (q,
2H, J ¼ 6.9 Hz, ester-CH2), 5.37 (s, 1H and NH, exchanged with D2O),
13C NMR (CDCl3)
d: 13.6, 15.9, 19.7, 31.7, 42.1, 51.1, 53.2, 104.1, 125.9,
127.4, 128.4, 143.2, 149.1, 153.9 and 166.5. Anal. C17H22N2O3: C,
67.54; H, 7.28; N, 9.27. Found: C, 67.52; H, 7.39; N, 9.10; MS: m/z
302 (Mþ).
7.23–7.31 (m, 5H, ArH); 13C NMR (CDCl3)
d: 14.0, 15.9, 28.2, 29.5,
33.0, 41.3, 53.5, 60.1, 104.8, 126.0, 127.6, 128.5, 143.2, 148.3, 153.7
and 166.0. Anal. C18H23N2O3Br: C, 54.68; H, 5.82; N, 7.08. Found: C,
54.38; H, 5.82; N, 7.01; MS: m/z 395 (Mþ).
Compound 4p. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 83%; mp ¼ 72 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.94 (t,
Compound 4i. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
3H, J ¼ 7.0 Hz, ester-CH3), 1.22 (d, 3H, J ¼ 7.0 Hz, CH3), 1.29–1.58
(m, 4H, 2 ꢂ CH2), 2.46 (s, 3H, CH3), 3.46–3.93 (m, 2H, NCH2), 3.71
(s, 3H, OCH3), 4.29–4.34 (m, 1H, CH), 5.69 (broad, NH, exchanged
yield: 72%; mp ¼ 122 ꢁC (dichloromethane); 1H (CDCl3)
d: 1.17 (t,
3H, J ¼ 7.2 Hz, ester-CH3), 1.37–1.87 (m, 6H, 3 ꢂ CH2), 2.52 (s, 3H,
CH3), 3.35 (t, 2H, J ¼ 6.9 Hz, CH2Br), 3.57–3.91 (m, 2H, NCH2), 4.10
(q, 2H, J ¼ 7.2 Hz, ester-CH2), 5.36 (s, 1H and NH, exchanged with
with D2O); 13C NMR (CDCl3)
d: 13.5, 15.6, 19.7, 22.8, 31.7, 41.8,
45.5, 50.9, 105.5, 148.6, 154.3 and 166.4. Anal. C12H20N2O3: C,
60.00; H, 8.33; N, 11.66. Found: C, 60.13; H, 8.19; N, 11.59; MS: m/z
240 (Mþ).
D2O), 7.23–7.30 (m, 5H, ArH); 13C NMR (CDCl3)
d: 14.0, 16.0, 25.1,
28.8, 32.2, 33.2, 42.1, 53.5, 60.1, 104.7, 126.1, 127.5, 128.5, 143.4,
148.5, 153.6 and 166.0. Anal. C19H25N2O3Br: C, 55.74; H, 6.11; N,
6.84. Found: C, 55.88; H, 6.02; N, 6.94; MS: m/z 409 (Mþ).
Compound 4j. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
Compound 4q. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 89%; mp ¼ 118 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.68–0.86
(m, 6H, ester-CH3 and CH3), 1.00–1.13 (m, 2H, CH2), 1.25–1.44 (m,
5H, CH3 and CH2), 2.89–3.71 (m, 2H, NCH2), 3.83 (q, 2H, J ¼ 7.0 Hz,
ester-CH2), 4.39–4.43 (m, 1H, CH), 5.37 (broad, NH, exchanged with
yield: 77%; mp ¼ 128 ꢁC (dichloromethane); 1H (CDCl3)
d: 1.17 (t,
3H, J ¼ 7.2 Hz, ester-CH3), 1.22–1.84 (m, 8H, 4 ꢂ CH2), 2.52 (s, 3H,
CH3), 3.38 (t, 2H, J ¼ 6.9 Hz, CH2Br), 3.59–3.91 (m, 2H, NCH2), 4.10
(q, 2H, J ¼ 6.9 Hz, ester-CH2), 5.37 (s, 1H and NH, exchanged with
D2O), 7.20–7.41 (m, 5H, ArH); 13C NMR (CDCl3)
d: 13.4, 13.5, 19.6,
23.3, 31.6, 43.3, 46.5, 59.6, 107.3, 127.9, 128.1, 128.5, 129.0, 134.6,
149.8, 154.4 and 165.4. Anal. C18H24N2O3: C, 68.35; H, 7.59; N, 8.86.
Found: C, 68.17; H, 7.44; N, 8.70; MS: m/z 316 (Mþ).
D2O), 7.23–7.33 (m, 5H, ArH); 13C NMR (CDCl3)
d: 14.0, 15.9, 25.7,
27.6, 29.4, 32.4, 33.6, 42.2, 53.3, 60.0, 104.5, 126.0, 127.4, 128.4,
143.3, 148.6, 153.7 and 166.0. Anal. C20H27N2O3Br: C, 56.73; H, 6.38;
N, 6.61. Found: C, 56.79; H, 6.37; N, 6.66; MS: m/z 423 (Mþ).
Compound 4k. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
Compound 5. White solid; Rf: 0.5 (60% ethyl acetate/hexane);
yield: 10%; mp ¼ 55 ꢁC (dichloromethane); 1H (CDCl3)
d: 1.23 (t, 3H,
J ¼ 7.2 Hz, ester-CH3), 2.47 (s, 3H, CH3), 2.91 (s, 3H, NCH3), 3.26 (s,
yield: 82%; mp ¼ 120 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.92 (t,
3H, NCH3), 4.12 (q, 2H, J ¼ 7.2 Hz, ester-CH2), 5.24 (s, 1H, CH), 7.21–
3H, J ¼ 7.2 Hz, ester-CH3), 1.17 (t, 3H, J ¼ 7.0 Hz, CH3), 1.26–1.61 (m,
4H, 2 ꢂ CH2), 2.51 (s, 3H, CH3), 3.58–3.90 (m, 2H, NCH2), 3.78 (s, 3H,
OCH3), 4.08 (q, 2H, J ¼ 7.0 Hz, ester-CH2), 5.31 (s, 1H, CH), 5.34
(broad, NH, exchanged with D2O), 6.81 (d, 2H, J ¼ 8.6 Hz, ArH), 7.16
7.31 (m, 5H, ArH); 13C NMR (CDCl3)
d: 14.1, 16.5, 30.9, 34.3, 60.0,
60.7, 103.5, 126.5, 127.7, 128.5, 140.9, 141.1, 153.7 and 165.9. Anal.
C16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.92; H, 7.13; N,
10.25; MS: m/z 288 (Mþ).
(d, 2H, J ¼ 8.8 Hz, ArH); 13C NMR (CDCl3)
d: 13.7, 14.1, 16.0, 19.9, 31.8,
42.3, 53.4, 55.2, 60.0, 104.7, 113.8, 127.4, 135.8, 148.3, 153.5, 159.0
and 166.2. Anal. C19H26N2O4: C, 65.89; H, 7.51; N, 8.09. Found: C,
66.00; H, 7.37; N, 8.25; MS: m/z 346 (Mþ).
Acknowledgements
Financial support from CSIR (01(1960)/04/EMR-II) and UGC (31-
53/2005/SR), New Delhi is gratefully acknowledged. DA thanks
CSIR, New Delhi for research fellowship. This study was also sup-
ported in part by funds from National Institutes of Health grants HL
37945 and DK 57252 to RSM.
Compound 4l. White solid; Rf: 0.5 (45% ethyl acetate/hexane);
yield: 81%; mp ¼ 105 ꢁC (dichloromethane); 1H (CDCl3)
d: 0.88 (t,
3H, J ¼ 7.2 Hz, ester-CH3), 1.11 (t, 3H, J ¼ 6.9 Hz, CH3), 1.22–1.54 (m,
4H, 2 ꢂ CH2), 2.60 (s, 3H, CH3), 3.44–4.01 (m, 2H, NCH2), 3.73 (s, 1H,

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