Expeditious synthesis of 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones

Article abstract of DOI:10.1016/j.tet.2007.06.115

A convenient synthesis of new 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones from the Baylis-Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to ac

Full text of DOI:10.1016/j.tet.2007.06.115

Tetrahedron 63 (2007) 9448–9455
Expeditious synthesis of 5,6,7,8-tetrahydro-imidazo-
[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido-
[1,2-a]pyrimidin-2-ones*
*
Richa Pathak and Sanjay Batra
Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Received 27 February 2007; revised 12 June 2007; accepted 28 June 2007
Available online 10 July 2007
Abstract—A convenient synthesis of new 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-
a]pyrimidin-2-ones from the Baylis–Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to
achieve the syntheses of title compounds involved generation of diamines from different Baylis–Hillman derivatives followed by treatment
with cyanogen bromide at reflux temperature to trigger a double intramolecular cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of an amino alkyl ester on the Baylis–Hillman adduct of ac-
rylonitrile followed by reduction of the nitrile function would
lead to a diamino system, which may be cyclized with cyan-
ogen bromide to yield the annulated [1,2-a]pyrimidine-2-
ones. On the other hand, the alkylation of a primary allyl
amine,5 generated from the acetyl derivative of Baylis–
Hillman adducts, with alkyl haloacetate should lead to an
allyl amino alkyl ester. Subsequently, reducing the nitrile to
amine would also furnish a diamino framework, which should
undergo a double intramolecular cyclization by reaction with
cyanogen bromide to afford an annulated [1,2-a]pyrimidin-2-
one system. Alternatively, acetates can be subjected to
Michael addition with amino alkyl ester followed by reduction
of nitrile group and successive cascade cyclizations with cyan-
ogen bromide. It was reasoned that this strategy might be ex-
tended to the synthesis of pyrimido[1,2-a]pyrimidin-2-ones.
In principle, primary allyl amine afforded from the acetyl
derivative of Baylis–Hillman adducts of acrylonitrile would
undergo SN2 reaction with the acetyl derivative of Baylis–
Hillman adduct of acrylate to yield a product, which may
serve as substrate for the synthesis of the desired heterocyclic
system. Herein, we describe the details of our successful
attempts toward expeditious synthesis of a variety of annu-
lated [1,2-a]pyrimidin-2-ones involving these approaches.
The versatility of Baylis–Hillman derivatives for the con-
struction of diverse heterocyclic frameworks is stupendous.
This is apparent by a recent surge in the number of publica-
tions describing synthetic methodologies toward this objec-
tive.1 One of our interests in this area concerns achieving
practical synthesis of heterocyclic systems from Baylis–
Hillman derivatives containing a nitrile group.2 We have
been especially interested in the synthesis of ring systems in-
corporating guanidine functionality. In this context, recently,
we have reported the solid-phase synthesis of annulated pyr-
imidinones from the Baylis–Hillman adducts via Michael
addition of alkanediamines followed by cyanogen bromide-
mediated cyclization of the diamine and finally base-
promoted cyclative cleavage.3 The adoption of this strategy
on the solid-phase chemistry was a direct outcome of our
unsuccessful attempt to carry out the Michael addition of
alkanediamines onto the Baylis–Hillman acetates in solution-
phase as it invariably led to the formation of the polymeric
products. Intriguingly, imidazo-pyrimidinone system is not
very well represented in the literature though some of the
derivatives bearing this moiety have been reported to display
significant bioactivities.4 With the aim to diversify the syn-
thesis of annulated [1,2-a]pyrimidin-2-ones in solution-phase,
we decided to utilize the derivatives of Baylis–Hillman
adduct of acrylonitrile. Conceptually, the Michael addition
2. Results and discussion
*
2.1. Synthesis of 6-(hydroxy-substituted phenyl-methyl)-
5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones
CDRI communication no. 7163. A part of this work was presented as
poster at ACS-CSIR conference from 6–9 January 2006 at NCL, Pune.
Keywords: Baylis–Hillman; 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyrimidin-
2-ones; 3,4,6,7,8,9-Hexahydro-pyrimido[1,2-a]pyrimidin-2-ones; Cyano-
gen bromide.
* Corresponding author. Tel.: +91 522 2262411–18x4368; fax: +91 522
2623405/2623938; e-mail: batra_san@yahoo.co.uk
We initiated our studies from the Baylis–Hillman adduct of
acrylonitrile 1a, which was easily obtained by following
standard procedure.2a Subsequent reaction of glycine ester
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.115

R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
9449
with 1a at reflux temperature for 12 h gave the correspond-
ing product 2a as diastereoisomeric mixture (1:1) in excel-
lent yield (Scheme 1). Hydrogenating 2a in the presence
of Raney-Ni for 3 h afforded the desired diamine 3a. The
diamine 3a being unstable in nature was immediately sub-
jected to reaction with cyanogen bromide in absolute ethanol
at reflux temperature to yield the substituted imidazo[1,2-
a]pyrimidine-2-one 4a as hydrobromide salt in good yield
(Scheme 1). The generality of this reaction protocol was
evident from the synthesis of several analogs 4b–g. The
spectroscopic data especially the UV spectra of compounds
4a–g supported the assigned structure to be the 5,6,7,8-tetra-
hydro-imidazo[1,2-a] pyrimidine-2-ones.4a
generated via a reported procedure,5 was treated with ethyl
iodoacetate in THF in the presence of K2CO3 for 1.5 h to
yield a mixture of two products (Scheme 2). These products
were isolated in 4 and 58% yields and were established to be
7 and 8, respectively (Scheme 2). Alternatively, the treat-
ment of amine 6 with ethyl bromoacetate yielded the desired
secondary amine 8 in 63% yield with only traces of 7, though
the reaction was completed in 15 h. Hydrogenating the allyl
amine 8 with Raney-Ni gave the diamino derivative 9 in
good yield. The product 9 was immediately treated with cy-
anogen bromide in absolute alcohol at reflux temperature to
furnish the product 10 (Scheme 2). Encouraged with these
results, we decided to extend the utility of this method to
the synthesis of substituted imidazo[1,2-a]pyrimidin-
2-ones from the substrate afforded by the SN2 reaction of
glycine ester and the acetyl derivative of Baylis–Hillman
adduct. Therefore, the acetates 5c,g were treated with
glycine ester in the presence of DABCO in a THF/water
system (1:1, v/v) to furnish corresponding products 11c,g
(Scheme 3). Reduction of the nitrile group with Raney-Ni
in 11c,g led to the isolation of diamines 12c,g, respectively.
Treatment of diamines 12c,g with cyanogen bromide in
absolute ethanol at reflux temperature afforded the desired
5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-2-one 13c,g as
diastereoisomeric mixture in 1:1 ratio.
2.2. Synthesis of 6-benzyl-5,6,7,8-tetrahydro-imid-
azo[1,2-a]pyrimidin-2-ones and 6-Methyl-5-phenyl-
5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones
In order to increase the scope of this strategy, it was decided
to carry out similar reactions with the acetyl derivative of
the Baylis–Hillman adducts of acrylonitrile. In view of our
earlier observation that during the reaction of the acetyl de-
rivatives of the Baylis–Hillman adducts large excess of pri-
mary amine has to be used,5 we decided to avoid the reaction
of glycine ester directly with 5. Therefore, the allyl amine 6,
Scheme 1.
Scheme 2.
Scheme 3.

9450
R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
2.3. Synthesis of 7-substituted phenyl-methyl-3-methyl-
4-substituted phenyl-3,4,6,7,8,9-hexahydro-pyr-
imido[1,2-a]pyrimidin-2-ones
13c,g, and 24–27 was deactivated prior to use by adding
12 mL of water per 100 g of silica gel. Compounds 2a–g,
4a–g, 13c,g, and 24–27 were obtained as diastereoisomeric
mixture in 1:1 ratio as evident from the 1H NMR of the crude
products.
Buoyed by the success of our strategy for the generation of
a variety of imidazo[1,2-a]pyrimidinone system, we decided
to investigate the synthesis of pyrimido[1,2-a]pyrimidin-2-
ones. In principle, SN2 reaction between the primary allyl
amine 6 and the acetyl derivative of Baylis–Hillman adduct
of acrylate would yield a suitable starting substrate for the
desired motif. Hence, treatment of compounds 6a–c with
14 and 15 in the presence DABCO in a THF/water system
(1:1, v/v) furnished the products 16–19 in excellent yields
(Scheme 4). Hydrogenation of 16–19 with Raney-Ni and
subsequent treatment of the diamine 20–23 with cyanogen
bromide in absolute ethanol gave the desired 3,4,6,7,8,9-
hexahydro-pyrimido[1,2-a]pyrimidin-2-ones 24–27 in mod-
erate yields as diastereoisomeric mixture in 1:1 ratio.
4.2. General procedure for the preparation of 2a–g
To a stirred solution of appropriate compound from 1a–g
(3.16 mmol) in MeOH (5 mL) were added Et3N
(6.3 mmol, 0.65 mL) and glycine methyl ester hydrochloride
(4.74 mmol, 0.6 g). The reaction mixture was heated at
reflux temperature till the completion of reaction (monitored
by TLC, ca. 12 h). Thereafter, methanol was removed in
vacuo and the residue was extracted with EtOAc
(3ꢀ25 mL) and water (40 mL). The organic layers were
combined, dried over Na2SO4, and concentrated to afford
crude products, which were purified via silica gel column
chromatography using hexane/EtOAc (60:40, v/v) to yield
the pure products.
3. Conclusions
4.2.1. (2-Cyano-3-hydroxy-3-phenyl-propylamino)-ace-
tic acid methyl ester (2a). Yield: 92% as colorless oil;
Rf¼0.4 (hexane/EtOAc, 60:40); nmax (neat) 1739 (CO2Me),
In summary, we have demonstrated convenient and practical
strategies for the synthesis of differently substituted new
annulated 5,6,7,8-tetrahydro-imidazo[1,2-a] pyrimidine-2-
ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-
2-ones from the derivatives of Baylis–Hillman adducts of
acrylonitrile.
1
2245 (CN), 3331 (NH, OH) cmꢁ1; H NMR (200 MHz,
CDCl3) d 2.71 (br s, 2H, 2ꢀNH), 2.92–3.10 (m, 4H,
2ꢀCH2NH), 3.19–3.25 (m, 2H, 2ꢀCH), 3.50 (s, 2H,
CH2CO), 3.53 (s, 2H, CH2CO), 3.75 (s, 6H, 2ꢀOCH3),
5.07 (d, 1H, J¼3.0 Hz, CHOH), 5.08 (d, 1H, J¼3.0 Hz,
CHOH), 7.33–7.47 (m, 10H, 2ꢀ5ArH); 13C NMR
(75 MHz, CDCl3) d 43.5, 49.5, 50.3, 52.1, 53.1, 53.6, 71.9,
73.3, 74.1, 120.1, 121.1, 121.4, 127.7, 127.8, 128.0, 128.2,
129.8, 129.4, 130.1, 142.6, 142.8, 143.1, 166.0, 174.1;
mass (FAB+) m/z¼249 (M++1); Anal. Calcd for
C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C,
63.13; H, 6.28; N, 11.35.
4. Experimental
4.1. General
Melting points are uncorrected and were determined in cap-
illary tubes on an apparatus containing silicon oil. IR spectra
were recorded using Perkin–Elmer Spectrum RX I FTIR
1
spectrophotometer. H NMR and 13C NMR spectra were
4.2.2. (2-Cyano-3-hydroxy-3-naphthalen-2-propyl-
amino)-acetic acid methyl ester (2b). Yield: 83% as color-
less oil; Rf¼0.6 (hexane/EtOAc, 60:40); nmax (neat) 1739
recorded either on a Bruker DPX-200 FT or Bruker Avance
DRX-300 spectrometers, using TMS as an internal standard
(chemical shifts in d values, J in Hz). The ESMS were
recorded on MICROMASS LC–MS system and FABMS
were recorded on JEOL/SX-102 spectrometer. Elemental
analyses were performed on Carlo Erba 108 or Elementar
Vario EL III microanalyzer. The HRMS spectra were re-
corded as EI-HRMS. The HPLCs were performed on RP
C-18 column (250ꢀ4.5 mm, 5mm) using a gradient of 10–
100% methanol containing 0.1% TFA and water in 25 min
at a flow rate of 1 mL/min on Agilent 1100. The silica gel
used for column chromatography of compounds 4a–g, 10,
(CO2Me), 2244 (CN), 3451 (NH, OH) cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 2.92–3.06 (m, 4H, 2ꢀCH2NH),
3.16–3.23 (m, 2H, 2ꢀCH), 3.42–3.50 (m, 4H, 2ꢀCH2CO),
3.78 (s, 6H, 2ꢀOCH3), 5.23 (d, 1H, J¼2.8 Hz, CHOH),
5.29 (d, 1H, J¼2.8 Hz, CHOH), 7.49–7.52 (m, 6H,
2ꢀ3ArH), 7.81–7.93 (m, 8H, 2ꢀ4ArH); 13C NMR
(50 MHz, CDCl3) d 11.3, 14.6, 40.1, 41.3, 48.5, 49.7, 50.5,
50.7, 52.5, 60.9, 61.6, 73.7, 74.3, 76.9, 77.5, 78.2, 119.1,
119.6, 124.0, 124.2, 125.6, 126.7, 126.8, 128.6, 128.9,
133.6, 133.7, 138.3, 172.6; mass (ES+) m/z¼299 (M++1);
Scheme 4.

R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
9451
Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39.
Found: C, 68.29; H, 5.90; N, 9.57.
71.8, 116.7, 118.0, 119.8, 120.7, 126.6, 126.8, 127.1,
127.2, 128.5, 127.7, 131.2, 131.8, 137.9, 138.0, 170.7,
170.9; mass (ES+) m/z¼267 (M++1); Anal. Calcd for
C13H15FN2O3$H2O: C, 54.92; H, 6.03; N, 9.85. Found, C,
55.12; H, 5.88; N, 10.05.
4.2.3. (2-Cyano-2-hydroxy-3-p-tolyl-propylamino)-acetic
acid methyl ester (2c). Yield: 92% as colorless oil; Rf¼0.5
(hexane/EtOAc, 60:40); nmax (neat) 1739 (CO2Me), 2245
1
(CN), 3322 (NH, OH) cmꢁ1; H NMR (300 MHz, CDCl3)
4.2.7. [2-Cyano-3-(2,4-dichloro-phenyl)-3-hydroxy-3-
propylamino]-acetic acid methyl ester (2g). Yield: 81%
as colorless oil; Rf¼0.7 (hexane/EtOAc, 60:40); nmax
d 2.36 (s, 6H, 2ꢀCH3), 2.56 (br s, 2H, 2ꢀNH), 2.91–3.06
(m, 6H, 2ꢀCH and 2ꢀCH2NH), 3.48–3.50 (m, 4H,
2ꢀCH2CO), 3.75 (s, 6H, 2ꢀOCH3), 5.00 (d, 1H,
J¼4.7 Hz, CHOH), 5.03 (d, 1H, J¼4.6 Hz, CHOH), 7.20
(d, 4H, J¼8.0 Hz, 2ꢀArH), 7.33 (d, 4H, J¼8.0 Hz,
2ꢀ4ArH); 13C NMR (75 MHz, CDCl3) d 12.9, 19.9, 38.6,
39.7, 47.0, 48.0, 48.8, 49.0, 50.8, 59.2, 72.1, 72.5, 117.4,
117.8, 124.5, 124.9, 128.0, 136.1, 136.9, 137.1, 170.9,
171.0; mass (ES+) m/z¼263 (M++1); Anal. Calcd for
C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
63.82; H, 7.05; N, 10.51.
(neat) 1740 (CO2Me), 3430 (NH, OH) cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 3.08–3.20 (m, 4H, 2ꢀCH2NH),
3.37–3.50 (m, 6H, 2ꢀCH and CH2CO), 3.75 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 5.42 (d, 1H, J¼4.6 Hz,
CHOH), 5.50 (d, 2H, J¼4.6 Hz, CHOH), 7.36–7.40 (m,
4H, ArH), 7.56–7.61 (m, 1H, ArH), 7.78–7.82 (m, 1H,
ArH); 13C NMR (75 MHz, CDCl3) d 35.6, 36.9, 46.2,
48.9, 51.0, 60.1, 69.3, 70.0, 116.6, 126.2, 126.9, 127.9,
128.1, 128.3, 128.6, 129.6, 136.3, 170.7, 170.9; mass
(ES+) m/z¼317 (M++1), 319 (M++3); Anal. Calcd for
C13H14Cl2N2O3: C, 49.23; H, 4.45; N, 8.83. Found: C,
49.28; H, 4.20; N, 8.86.
4.2.4. [3-(2-Bromo-phenyl)-2-cyano-3-hydroxy-propyl-
amino]-acetic acid methyl ester (2d). Yield: 93% as color-
less oil; Rf¼0.5 (hexane/EtOAc, 60:40); nmax (neat) 1717
(CO2Me), 2200 (CN), 3463 (NH, OH) cmꢁ1
;
1H NMR
4.3. General procedure for the preparation of
3a–g, 9, 12c,g, and 20–23
(200 MHz, CDCl3) d 2.93–3.22 (m, 4H, 2ꢀCH2NH),
3.23–3.32 (m, 2H, 2ꢀCH), 3.41 (s, 2H, CH2CO), 3.60 (d,
2H, J¼0.5 Hz, CH2CO), 3.75 (s, 3H, OCH3), 3.77 (s, 3H,
OCH3), 5.37 (d, 1H, J¼1.4 Hz, CHOH), 5.48 (d, 1H,
J¼3.0 Hz, CHOH), 7.20–7.25 (m, 2H, ArH), 7.39–7.60
(m, 4H, ArH), 7.82–7.89 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3) d 35.5, 37.0, 45.9, 48.8, 49.0, 50.9, 71.3,
71.9, 116.6, 117.9, 119.8, 120.7, 126.6, 126.8, 127.1,
127.2, 128.5, 128.7, 131.2, 131.8, 137.8, 138.0, 170.7,
170.8; mass (ES+) m/z¼328 (M+), 330 (M++2); Anal. Calcd
for C13H15BrN2O3: C, 47.72; H, 4.62; N, 8.56. Found: C,
47.97; H, 4.78; N, 8.22.
A mixture of appropriate compound from 2a–g, 8 or 11c,g,
16–19 (2.0 mmol) and Raney-Ni (0.1 g wet) in methanol
(10 mL) was subjected to hydrogenation at 40 psi in the
Parr assembly for 3 h. The catalyst was filtered through
a pad of Celite and the filtrate was concentrated. The residue
was used directly for further reactions.
4.4. General procedure for the preparation of 4a–g, 10,
13c,g, and 24–27
To a stirred solution of appropriate diamines from 3a–g, 9,
12c,g or 20–23 (1.98 mmol) in absolute EtOH (15 mL)
was added CNBr (2.97 mmol, 0.315 g) and the reaction mix-
ture was heated at reflux temperature for 8 h (36–48 h for
20–23). Ethanol was removed from the mixture and the
residue was subjected to silica gel column chromatography
using (CHCl3/MeOH, 90:10, v/v) as the eluant to furnish
the pure products as hydrobromide salts.
4.2.5. [3-(2-Chloro-phenyl)-2-cyano-2-hydroxy-3-propyl-
amino]-acetic acid methyl ester (2e). Yield: 89% as color-
less oil; Rf¼0.6 (hexane/EtOAc, 60:40); nmax (neat) 1740
(CO2Me), 3430 (NH, OH) cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 2.93–3.20 (m, 4H, 2ꢀCH2NH), 3.37–3.44 (m,
2H, 2ꢀCH), 3.50 (s, 2H, CH2CO), 3.60 (s, 2H, CH2CO),
3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 5.45 (d, 1H,
J¼4.2 Hz, CHOH), 5.53 (d, 2H, J¼4.3 Hz, CHOH), 7.32–
7.42 (m, 5H, ArH), 7.62–7.66 (m, 1H, ArH), 7.83–7.87
(m, 2H, ArH); 13C NMR (75 MHz, CDCl3) d 36.1, 37.3,
38.6, 38.9, 45.9, 48.6, 49.0, 50.9, 68.5, 69.2, 116.8, 118.1,
126.0, 126.1, 126.9, 127.9, 128.1, 128.3, 128.5, 129.6,
130.6, 136.7, 170.9; mass (ES+) m/z¼283 (M++1), 285
(M++3); Anal. Calcd for C13H15ClN2O3: C, 55.23; H,
5.35; N, 9.91. Found: C, 55.01; H, 5.54; N, 10.11.
4.4.1. 6-(Hydroxy-phenyl-methyl)-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidin-2-one (4a). Yield: 57% as
a brown oil; Rf¼0.3 (CHCl3/MeOH, 90:10); nmax (neat)
1658 (CONH), 3370 (NH, OH) cmꢁ1
;
1H NMR
(200 MHz, DMSO-d6) d 2.32–2.49 (m, 2H, 2ꢀCH), 2.76–
2.89 (m, 4H, 2ꢀCH2N), 3.11–3.23 (m, 4H, 2ꢀCH2NH),
3.56 (s, 4H, 2ꢀCH2CO), 5.03 (d, 1H, J¼3.6 Hz, CHOH),
5.11 (d, 1H, J¼3.5 Hz, CHOH), 7.48–7.61 (m, 4H, ArH),
7.88–7.93 (m, 6H, ArH); 13C NMR (50 MHz, DMSO-d6)
d 37.1, 37.5, 42.9, 43.5, 49.9, 51.6, 69.6, 72.6, 125.3,
126.7, 126.9, 127.3, 127.8, 128.4, 128.6, 143.5, 144.2,
158.5, 158.7, 172.2, 172.5; mass (ES+) m/z¼246 (M++1);
lmax¼226 nm; HR-EIMS Calcd for C13H15N3O2:
245.1164, found: 245.1166.
4.2.6. [2-Cyano-3-(2-fluoro-phenyl)-3-hydroxy-propyl-
amino]-acetic acid methyl ester (2f). Yield: 79% as color-
less oil; Rf¼0.5 (hexane/EtOAc, 60:40); nmax (neat) 1734
(CO2Me), 2233 (CN), 3437 (NH, OH) cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 2.28 (br s, 2H, 2ꢀNH), 2.95–3.14
(m, 6H, 2ꢀCH2NH and CH), 3.49 (s, 2H, CH2CO), 3.57
(s, 2H, CH2CO), 3.74 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
5.37 (d, 1H, J¼2.6 Hz, CHOH), 5.38 (d, 1H, J¼2.6 Hz,
CHOH), 7.01–7.11 (m, 2H, ArH), 7.21–7.32 (m, 4H,
ArH), 7.58–7.59 (m, 2H, ArH); 13C NMR (75 MHz,
CDCl3) d 35.6, 37.1, 45.8, 48.7, 48.9, 50.8, 50.9, 71.1,
4.4.2. 6-(Hydroxy-naphthalen-2-yl-methyl)-5,6,7,8-tetra-
hydro-imidazo[1,2-a]pyrimidin-2-one (4b). Yield: 62% as
a brown oil; Rf¼0.5 (CHCl3/MeOH, 90:10); nmax (neat) 1661
(CONH), 3427 (NH, OH) cmꢁ1 1H NMR (200 MHz,
;

9452
R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
DMSO-d6) d 2.26–2.28 (m, 2H, 2ꢀCH), 3.05–3.19 (m, 4H,
2ꢀCH2N), 3.46–3.74 (m, 4H, 2ꢀCH2NH), 3.75 (s, 4H,
2ꢀCH2CO), 4.87 (d, 1H, J¼4.2 Hz, CHOH), 4.92 (d, 1H,
J¼4.2 Hz, CHOH), 7.42–7.52 (m, 6H, ArH), 7.75–7.86
(m, 8H, ArH); 13C NMR (50 MHz, DMSO-d6) d 37.3,
37.8, 41.4, 41.9, 42.5, 43.0, 51.6, 52.0, 73.3, 73.9, 126.4,
127.2, 129.1, 129.7, 130.1, 130.7, 131.5, 131.8, 132.0,
133.2, 133.4, 138.3, 138.9, 146.7, 147.1, 158.0, 158.7,
177.6, 178.3; mass (ES+) m/z¼296 (M++1); lmax¼224 nm;
HR-EIMS Calcd for C17H17N3O2: 295.1321, found:
295.1325.
(300 MHz, DMSO-d6) d 2.98–3.16 (m, 6H, 2ꢀCH and
2ꢀCH2N), 3.51–3.62 (m, 4H, 2ꢀCH2NH), 3.77 (s, 4H,
2ꢀCH2CO), 5.42 (d, 1H, J¼4.5 Hz, CHOH), 5.45 (d, 1H,
J¼4.5 Hz, CHOH), 7.05–7.12 (m, 2H, ArH), 7.23–7.36
(m, 4H, ArH), 7.58–7.59 (m, 2H, ArH); 13C NMR
(50 MHz, DMSO-d6) d 38.5, 38.8, 41.7, 41.9, 42.3, 43.0,
51.6, 52.1, 73.0, 73.5, 126.7, 127.0, 127.3, 128.6, 129.1,
129.4, 130.0, 136.9, 140.4, 158.1, 158.7, 172.2, 173.1;
mass (ES+) m/z¼264 (M++1); lmax¼226 nm; HR-EIMS
Calcd for C13H14FN3O2: 263.1070, found: 263.1074.
4.4.7. 6-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-5,6,7,8-
tetrahydro-imidazo[1,2-a]pyrimidin-2-one (4g). Yield:
88% as a white solid; mp 248–250 ꢂC; Rf¼0.6 (CHCl3/
MeOH, 90:10); nmax (KBr) 1662 (CONH), 3367 (NH, OH)
4.4.3. 6-(Hydroxy-p-tolyl-methyl)-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidin-2-one (4c). Yield: 89% as a color-
less oil; Rf¼0.4 (CHCl3/MeOH, 90:10); nmax (neat) 1662
(CONH), 3409 (NH, OH) cmꢁ1
;
1H NMR (300 MHz,
cmꢁ1 1H NMR (300 MHz, DMSO-d6) d 2.24–2.26 (m,
;
DMSO-d6) d 2.30 (s, 6H, 2ꢀCH3), 2.80–2.83 (m, 2H,
2ꢀCH), 3.06–3.11 (m, 4H, 2ꢀCH2N), 3.27–3.43 (m, 4H,
2ꢀCH2NH), 3.83 (s, 4H, 2ꢀCH2CO), 4.64 (d, 1H, J¼
4.4 Hz, CHOH), 4.69 (d, 1H, J¼4.4 Hz, CHOH), 7.18 (d,
4H, J¼8.0 Hz, ArH), 7.27 (d, 4H, J¼8.0 Hz, ArH), 7.78
(br s, 2H, 2ꢀNH), 10.78 (s, 2H, 2ꢀOH); 13C NMR
(75 MHz, DMSO-d6) d 21.2, 24.6, 24.7, 43.5, 43.9, 45.3,
45.8, 47.0, 47.8, 55.2, 56.3, 63.7, 76.5, 77.1, 130.3, 131.4,
132.7, 132.9, 140.5, 142.1, 144.0, 161.7, 161.9, 173.9,
175.8; mass (ES+) m/z¼260 (M++1); lmax¼220 nm; HR-
EIMS Calcd for C14H17N3O2: 259.1321, found: 259.1349.
2H, 2ꢀCH), 2.76–2.79 (m, 4H, 2ꢀCH2N), 3.35–3.42 (m,
4H, 2ꢀCH2NH), 3.88 (s, 4H, 2ꢀCH2CO), 4.99 (d, 1H,
J¼3.9 Hz, CHOH), 5.01 (d, 1H, J¼3.9 Hz, CHOH), 6.10
(s, 2H, 2ꢀNH), 7.50–7.53 (m, 2H, ArH), 7.60–7.69 (m,
4H, ArH), 10.86 (s, 2H, 2ꢀOH); 13C NMR (75 MHz,
DMSO-d6) d 36.5, 36.8, 40.6, 41.9, 42.6, 50.7, 51.4,
67.6, 69.1, 126.7, 127.6, 128.0, 128.7, 129.0, 129.8,
131.0, 138.9, 156.8, 158.0, 170.9, 172.1; mass (ES+)
m/z¼314 (M++1); lmax¼230 nm; HR-EIMS Calcd for
C13H12Cl2N3O2: 313.0385, found: 313.0389.
4.4.8. 6-Benzyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimi-
din-2-one (10). Yield: 48% as a brown oil; Rf¼0.4 (CHCl3/
4.4.4. 6-[(2-Bromo-phenyl)-hydroxy-methyl]-5,6,7,8-
tetrahydro-imidazo[1,2-a]pyrimidin-2-one (4d). Yield:
66% as colorless oil; Rf¼0.4 (CHCl3/MeOH, 90:10); nmax
MeOH, 90:10); nmax (neat) 1660 (CONH), 3362 (NH) cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 2.20–2.41 (m, 1H, CH), 2.67–
2.71 (m, 2H, CH2N), 3.12–3.45 (m, 4H, ArCH2 and
CH2NH), 3.88 (s, 2H, CH2CO), 6.52 (br s, 1H, NH), 7.16–
7.38 (m, 5H, ArH); 13C NMR (50 MHz, DMSO-d6) d 45.9,
57.1, 73.9, 75.9, 76.3, 133.1, 134.3, 135.4, 137.3, 138.2,
145.3, 163.2, 177.4; mass (ES+) m/z¼230 (M++1);
lmax¼222 nm; HR-EIMS Calcd for C13H14N3O: 229.1215,
found: 229.1218.
(neat) 1658 (CONH), 3370 (NH, OH) cmꢁ1 1H NMR
;
(300 MHz, DMSO-d6) d 2.30–2.36 (m, 2H, 2ꢀCH), 3.02–
3.29 (m, 8H, 2ꢀCH2N and 2ꢀCH2NH), 3.67 (s, 4H,
2ꢀCH2CO), 4.87 (d, 1H, J¼4.4 Hz, CHOH), 4.89 (d, 1H,
J¼4.4 Hz, CHOH), 7.22–7.27 (m, 2H, ArH), 7.42–7.46
(m, 2H, ArH), 7.54–7.58 (m, 4H, ArH); 13C NMR
(50 MHz, DMSO-d6) d 37.6, 37.9, 39.5, 40.7, 41.8, 42.1,
52.0, 52.6, 71.2, 71.9, 121.6, 125.4, 126.8, 127.6, 128.2,
129.0, 129.8, 133.0, 142.2, 158.0, 172.1, 172.6; mass
(ES+) m/z¼324 (M++1); lmax¼226 nm; HR-EIMS Calcd
for C13H14BrN3O2: 323.0269, found: 323.0265.
4.4.9. 6-Methyl-5-p-tolyl-5,6,7,8-tetrahydro-imidazo[1,2-
a]pyrimidin-2-one (13c). Yield: 52% as a brown oil; Rf¼0.5
(CHCl3/MeOH, 90:10); nmax (neat) 1668 (CONH), 3357
1
(NH) cmꢁ1; H NMR (200 MHz, CDCl3) d 0.83 (d, 3H,
4.4.5. 6-[(2-Chloro-phenyl)-hydroxy-methyl]-5,6,7,8-
tetrahydro-imidazo[1,2-a]pyrimidin-2-one (4e). Yield: 83%
as white solid; mp 272–274 ꢂC; Rf¼0.5 (CHCl3/MeOH,
J¼6.6 Hz, CH3), 0.88 (d, 3H, J¼6.6 Hz, CH3), 2.36 (s,
6H, 2ꢀArCH3), 2.53–2.56 (m, 2H, 2ꢀCHCH2), 3.03–3.15
(m, 4H, 2ꢀCH2NH), 3.76 (s, 2H, CH2CO), 3.77 (s, 2H,
CH2CO), 4.44 (d, 2H, J¼5.2 Hz, 2ꢀCHPh), 6.98 (d, 4H,
J¼8.0 Hz, 2ꢀ2ArH), 7.23 (d, 4H, J¼8.0 Hz, 2ꢀ2ArH);
13C NMR (75 MHz, CDCl3) d 13.4, 14.6, 19.8, 29.6, 33.1,
39.5, 42.0, 51.6, 58.5, 61.5, 125.7, 126.1, 127.7, 128.2,
128.5, 132.0, 133.9, 137.0, 165.7, 182.9; mass (ES+)
m/z¼244 (M++1); lmax¼225 nm; HR-EIMS Calcd for
C14H17N3O: 243.1372, found: 243.1365.
90:10); nmax (KBr) 1648 (CONH), 3415 (NH, OH) cmꢁ1
;
1H NMR (300 MHz, DMSO-d6) d 2.32–2.34 (m, 2H,
2ꢀCH), 2.83–2.97 (m, 4H, 2ꢀCH2N), 3.25–3.32 (m, 4H,
2ꢀCH2NH), 4.01 (s, 4H, 2ꢀCH2CO), 5.05 (d, 1H, J¼
4.5 Hz, CHOH), 5.09 (d, 1H, J¼4.5 Hz, CHOH), 7.16–
7.31 (m, 6H, ArH), 7.58–7.60 (m, 2H, ArH), 7.87 (br s,
2H, 2ꢀNH), 10.89 (br s, 2H, 2ꢀOH); 13C NMR (50 MHz,
DMSO-d6) d 37.6, 38.2, 40.2, 40.9, 41.7, 42.5, 51.4, 51.9,
69.0, 69.8, 127.7, 128.7, 129.0, 129.4, 129.7, 130.1, 131.2,
133.9, 140.8, 158.0, 158.6, 172.1, 172.9; mass (ES+)
m/z¼280 (M++1); lmax¼222 nm; HR-EIMS Calcd for
C13H14ClN3O2: 279.0775, found: 279.0778.
4.4.10. 5-(2,4-Dichloro-phenyl)-6-methyl-5,6,7,8-tetrahy-
dro-imidazo[1,2-a]pyrimidin-2-one (13g). Yield: 57% as
a brown oil; Rf¼0.7 (CHCl3/MeOH, 90:10); nmax (neat)
1660 (CONH), 3350 (NH) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d 0.83 (d, 3H, J¼6.4 Hz, CH3), 0.88 (d, 3H,
J¼6.4 Hz, CH3), 2.23–2.40 (m, 2H, 2ꢀCH–CH2), 2.49–
2.71 (m, 4H, 2ꢀCH2NH), 3.67 (s, 2H, CH2CO), 3.73 (s,
2H, CH2CO), 4.07 (d, 1H, J¼1.4 Hz, CHPh), 4.13 (d, 1H,
J¼1.4 Hz, CHPh), 7.03–7.09 (m, 2H, 2ꢀArH), 7.30–7.47
4.4.6. 6-[(2-Fluoro-phenyl)-hydroxy-methyl]-5,6,7,8-tet-
rahydro-imidazo[1,2-a]pyrimidin-2-one (4f). Yield: 74%
as colorless oil; Rf¼0.5 (CHCl3/MeOH, 90:10); nmax
(neat): 1676 (CONH), 3436 (NH, OH) cmꢁ1 1H NMR
;

R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
9453
(m, 2H, 2ꢀArH), 7.53 (s, 1H, ArH), 7.55 (s, 1H, ArH); 13
C
7.65 (m, 4H, ArH), 10.54 (br s, 2H, 2ꢀNH); 13C NMR
(50 MHz, CDCl3) d 14.4, 51.9, 61.4, 61.5, 111.0, 118.4,
121.8, 125.8, 125.9, 127.0, 128.4, 129.6, 129.9, 130.5,
NMR (75 MHz, CDCl3) d 11.9, 13.2, 14.2, 15.1, 28.4, 29.3,
32.9, 34.7, 39.7, 42.5, 44.5, 51.5, 58.2, 61.1, 126.8, 127.0,
127.4, 127.6, 127.8, 128.2, 128.3, 133.6, 133.8, 134.6,
170.4, 180.7; mass (ES+) m/z¼298 (M++1); lmax¼223 nm;
HR-EIMS Calcd for C13H13Cl2N3O: 297.0436, found:
297.0438.
131.2, 131.9, 136.8, 141.4, 143.2, 145.3, 166.2; lmax
221 nm; mass (ES+) m/z¼436 (M++1); HR-EIMS Calcd
¼
for C22H21ClF3N3O: 435.1325, found: 435.1321.
4.5. Typical procedure for the preparation of 8
4.4.11. 7-Benzyl-3-methyl-4-phenyl-3,4,6,7,8,9-hexa-
hydro-pyrimido[1,2-a]pyrimidin-2-one (24). Yield: 63%
as colorless oil; tR¼19.3 min; nmax (neat) 1688 (CONH),
To a stirred solution of 6 (6.33 mmol, 1.0 g) in THF (50 mL)
was added K2CO3 (9.49 mmol, 1.31 g) followed by ethyl
iodoacetate (7.59 mmol, 0.89 mL) and the reaction was
allowed to continue for 1.5 h at room temperature.
Thereafter, the reaction mixture was quenched with water
(50 mL) and extracted with EtOAc (3ꢀ30 mL). The organic
layers were combined, dried (Na2SO4), and evaporated un-
der vacuo to yield a residue. This crude product was purified
via silica gel column chromatography using hexane/EtOAc
(90:10, v/v) to afford 7 followed by hexane/EtOAc (80:20,
v/v) to furnish 8.
1
3412 (NH) cmꢁ1; H NMR (200 MHz, CDCl3) d 0.84–
0.97 (m, 3H, CH3), 1.05–1.33 (m, 3H, CH3), 2.19–2.42
(m, 2H, 2ꢀCH), 2.49–2.75 (m, 4H, 2ꢀCH2), 2.96–3.35
(m, 10H, 2ꢀ2CH2 and CH), 3.43–3.67 (m, 2H, 2ꢀCH),
3.92–4.09 (m, 1H, CH), 4.11–4.29 (m, 1H, CH) 7.05–7.36
(m, 20H, ArH), 10.61 (br s, 2H, 2ꢀNH); 13C NMR
(50 MHz, CDCl3) d 12.5, 33.3, 37.4, 43.5, 50.06, 51.38,
60.8, 66.3, 67.2, 68.7, 76.9, 77.6, 78.2, 127.0, 127.3,
128.5, 129.4, 138.5, 139.5, 157.6, 177.8; lmax¼215 nm;
mass (ES+) m/z¼334 (M++1); HR-EIMS Calcd for
C21H23N3O: 333.1841, found: 333.1840.
4.5.1. [(3-Cyano-4-phenyl-but-3-enyl)-ethoxycarbonyl-
amino]-acetic acid ethyl ester (7). Yield: 4% as colorless
oil; Rf¼0.8 (hexane/EtOAc; 80:20); nmax (neat) 1736
4.4.12. 3-Methyl-7-(4-methyl-benzyl)-4-phenyl-3,4,6,7,
8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (25).
Yield: 56% as colorless oil; tR¼18.1 min; nmax (neat) 1690
(2ꢀCO2Et), 2218 (CN) cmꢁ1
;
1H NMR (200 MHz,
CDCl3) d 1.29 (t, 6H, J¼7.1 Hz, 2ꢀCH2CH3), 3.65 (s, 4H,
CH2), 3.77 (s, 2H, CH2), 4.20 (q, 4H, J¼7.1 Hz,
2ꢀCH2CH3), 7.23 (s, 1H, ]CH), 7.42–7.44 (m, 3H,
ArH), 7.78–7.80 (m, 2H, ArH); mass (ES+) m/z¼331
(M++1); Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.42; H, 6.59; N, 8.66.
1
(CONH), 3431 (NH) cmꢁ1; H NMR (200 MHz, CDCl3)
d 0.87–0.93 (m, 3H, CH3), 1.24–1.29 (m, 3H, CH3), 2.32
(s, 3H, CH3), 2.35 (s, 3H, CH3), 2.60–2.74 (m, 2H,
2ꢀCH), 2.85–3.37 (m, 12H, 2ꢀ3CH2), 3.59–3.78 (m, 2H,
2ꢀCH), 3.92–4.01 (m, 1H, CH), 4.05–4.13 (m, 1H, CH),
6.89–7.22 (m, 18H, 2ꢀ9ArH), 10.50 (br s, 2H, 2ꢀNH);
13C NMR (50 MHz, CDCl3) d 12.5, 17.3, 17.7, 21.5, 33.4,
37.6, 39.4, 43.7, 50.2, 127.0, 128.2, 128.4, 129.2, 130.1,
133.9, 134.4, 136.4, 138.8, 157.8, 178.3; lmax¼224 nm;
mass (ES+) m/z¼348 (M++1); HR-EIMS Calcd for
C22H25N3O: 347.1998, found: 347.1999.
4.5.2. (3-Cyano-4-phenyl-but-3-enyl)-carbamic acid eth-
yl ester (8). Yield: 58% as colorless oil; Rf¼0.7 (hexane/
EtOAc; 80:20); nmax (neat) 1738 (CO2Et), 2213 (CN)
cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 1.30 (t, 3H,
J¼7.2 Hz, CH2CH3), 1.97 (br s, 1H, NH), 3.48 (s, 2H,
CH2), 3.63 (d, 2H, J¼1.2 Hz, CH2), 4.23 (q, 2H,
J¼7.2 Hz, CH2CH3), 7.13 (s, 1H, ]CH), 7.42–7.46 (m,
3H, ArH), 7.76–7.78 (m, 2H, ArH); 13C NMR (75 MHz,
CDCl3) d 12.9, 53.5, 57.1, 57.2, 60.0, 106, 107.1, 117.1,
127.7, 129.4, 131.7, 144.0, 144.9, 169.0; mass (ES+) m/z¼
245 (M++1); Anal. Calcd for C14H16N2O2: C, 68.83; H,
6.60; N, 11.47. Found: C, 69.17; H, 6.47; N, 11.66.
4.4.13. 3-Methyl-4-phenyl-7-(4-trifluoromethyl-benzyl)-
3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one
(26). Yield: 68% as colorless oil; tR¼21.1 min; nmax (neat)
1683 (CONH), 3409 (NH) cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d 0.86–0.96 (m, 3H, CH3), 1.09–1.36 (m, 3H,
CH3), 2.03–2.19 (m, 2H, 2ꢀCH), 2.58–2.79 (m, 4H,
2ꢀCH2), 3.13–3.42 (m, 4H, 2ꢀCH2), 3.72–4.21 (m, 6H,
2ꢀCH2 and 2ꢀCH), 7.32–7.49 (m, 10H, ArH), 7.57–7.73
(m, 8H, ArH) 10.32 (br s, 2H, 2ꢀNH); 13C NMR
(50 MHz, CDCl3) d 14.3, 15.5, 43.8, 44.8, 47.2, 51.6, 56.5,
61.9, 64.3, 66.3, 104.4, 114.7, 117.3, 126.6, 128.5, 129.5,
130.8, 132.0, 144.4, 145.1, 148.5, 173.0; lmax¼222 nm;
mass (ES+) m/z 402 (M++1); HR-EIMS Calcd for
C22H22F3N3O: 401.1715, found: 401.1718.
4.6. General procedure for the of preparation of 11c,g
To a solution of appropriate acetate6 from 5c,g (2.5 mmol) in
a THF/H2O system (10 mL, 1:1, v/v) was added DABCO
(0.42 g, 3.76 mmol) at room temperature and the mixture
was stirred for 10 min. Simultaneously, in another flask to
the solution of glycine methyl ester hydrochloride (0.47 g,
3.75 mmol) in H2O (5 mL) was added Et3N (0.52 mL,
5.0 mmol) and the mixture was stirred for 10 min. This mix-
ture was then added dropwise to the flask containing the ace-
tate and the reaction was continued at room temperature for
1.5 h. The THF was removed from the reaction mixture and
the residue was extracted with EtOAc (2ꢀ20 mL) and water
(25 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo to afford the crude product. Puri-
fication of the crude product via column chromatography
over silica gel with hexane/EtOAc (85:15, v/v) furnished
the pure products.
4.4.14. 7-(4-Chloro-benzyl)-3-methyl-4-(4-trifluoro-
methyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-
a]pyrimidin-2-one (27). Yield: 67% as colorless oil;
tR¼21.8 min; nmax (neat): 1686 (CONH), 3457 (NH)
1
cmꢁ1; H NMR (300 MHz, CDCl3) d 0.85–0.97 (m, 3H,
CH3), 1.30–1.38 (m, 3H, CH3), 2.21–2.46 (m, 2H, 2ꢀCH),
2.53–2.80 (m, 6H, 2ꢀCH2 and 2ꢀ1H of CH2), 2.83–3.29
(m, 6H, 2ꢀCH2 and 2ꢀ1H of CH2), 3.60–3.72 (m, 2H,
2ꢀCH), 4.01–4.10 (m, 1H, CH), 4.15–4.24 (m, 1H, CH),
6.84–7.03 (m, 4H, ArH), 7.19–7.40 (m, 8H, ArH), 7.58–

9454
R. Pathak, S. Batra / Tetrahedron 63 (2007) 9448–9455
4.6.1. (2-Cyano-1-p-tolyl-allylamino)-acetic acid methyl
ester (11c). Yield: 76% as colorless oil; Rf¼0.6 (hexane/
EtOAc; 85:15); nmax (neat) 1737 (CO2Me), 2226 (CN)
3.47 (s, 2H, CH2NH), 4.14 (q, 2H, J¼7.2 Hz, CH2CH3),
4.76 (s, 1H, CHNH), 6.01 (s, 1H, ]CH2), 6.39 (s, 1H,
]CH2), 6.97 (s, 1H, ]CH), 7.19–7.42 (m, 7H, ArH), 7.64
(d, 2H, J¼8.0 Hz, ArH); 13C NMR (75 MHz, DMSO-d6)
d 12.8, 13.0, 50.4, 59.8, 108.6, 117.0, 124.1, 124.2, 124.6,
125.3, 126.7, 127.5, 127.6, 127.9, 128.2, 128.5, 128.6,
129.1, 131.8, 139.8, 143.0, 143.7, 164.5; mass (ES+) m/z¼
361 (M++1); Anal. Calcd for C23H24N2O2: C, 76.64; H,
6.71; N, 7.77. Found: C, 76.68; H, 6.50; N, 7.66.
1
cmꢁ1; H NMR (200 MHz, CDCl3) d 1.88 (br s, 1H, NH),
2.35 (s, 3H, CH3), 3.36 (d, 2H, J¼2.5 Hz, CH2CO), 3.71
(s, 3H, OCH3), 4.41 (s, 1H, CH), 5.98 (s, 1H, ]CH2),
6.09 (s, 1H, ]CH2), 7.17 (d, 2H, J¼8.0 Hz, ArH), 7.28 (d,
2H, J¼8.0 Hz, ArH); 13C NMR (75 MHz, CDCl3) d 19.9,
46.7, 50.7, 63.4, 116.2, 125.0, 126.0, 128.4, 128.8, 134.3,
137.2, 171.2; mass (ES+) m/z¼245 (M++1); Anal. Calcd
for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
69.11; H, 6.66; N, 11.55.
4.7.3. 2-[(2-Cyano-3-phenyl-allylamino)-(4-trifluoro-
methyl-phenyl)-methyl]-acrylic acid ethyl ester (18).
Yield: 89% as colorless oil; Rf¼0.8 (hexane/EtOAc;
85:15); nmax (neat) 1714 (CO2Et), 2214 (CN), 3343 (NH)
4.6.2. [2-Cyano-1-(2,4-dichloro-phenyl)-allylamino]-ace-
tic acid methyl ester (11g). Yield: 81% as colorless oil;
Rf¼0.8 (hexane/EtOAc; 85:15); nmax (neat) 1732
cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 1.26 (t, 3H,
J¼7.2 Hz, CH2CH3), 3.54 (s, 2H, CH2NH), 4.16 (q, 2H,
J¼7.2 Hz, CH2CH3), 4.84 (s, 1H, CHNH), 6.04 (s, 1H,
]CH2), 6.46 (s, 1H, ]CH2), 7.04 (s, 1H, ]CH), 7.41–
7.51 (m, 3H, ArH), 7.56–7.63 (m, 4H, ArH), 7.72–7.77
(m, 2H, ArH); 13C NMR (75 MHz, DMSO-d6) d 12.8,
50.3, 59.8, 59.9, 109.3, 116.8, 124.3, 125.4, 126.7, 127.9,
128.8, 130.3, 135.1, 139.8, 141.6, 143.6, 164.6; mass
(ES+) m/z¼415 (M++1); Anal. Calcd for C23H21F3N2O2:
C, 66.66; H, 5.11; N, 6.76. Found: C, 66.50; H, 4.88; N, 6.92.
1
(CO2Me), 2216 (CN) cmꢁ1; H NMR (200 MHz, CDCl3)
d 3.38 (d, J¼5.6 Hz, 2H, CH2CO), 3.74 (s, 3H, OCH3),
4.94 (s, 1H, CH), 6.05 (s, 1H, ]CH2), 6.13 (s, 1H,
]CH2), 7.31–7.42 (m, 2H, ArH), 7.61–7.66 (d, 1H,
J¼8.4 Hz, ArH); 13C NMR (75 MHz, CDCl3) d 46.6, 50.8,
62.9, 115.8, 124.4, 127.5, 127.9, 129.4, 133.2, 135.8,
171.1; mass (ES+) m/z¼299 (M++1), 301 (M++3); Anal.
Calcd for C13H12Cl2N2O2: C, 52.19; H, 4.04; N, 9.36.
Found: C, 51.87; H, 3.95; N, 9.29.
4.7.4. 2-[[3-(4-Chloro-phenyl)-2-cyano-allylamino]-(4-
trifluoromethyl-phenyl)-methyl]-acrylic acid ethyl ester
(19). Yield: 78% as colorless oil; nmax (neat) 1720
4.7. General procedure for the preparation of 16–19
To a stirred solution of appropriate acetate from 14 and 15
(5.2 mmol) in THF/H2O (5 mL, 1:1, v/v) system was added
DABCO (7.8 mmol, 0.87 g,) at room temperature and the re-
action mixture was allowed to stir for 5 min. This was fol-
lowed by dropwise addition of a solution of appropriate
allyl amine from 6a–c (5.2 mmol) in THF (5 mL) and the re-
action was allowed to proceed till completion (as analyzed
by TLC, ca. 1 h). Thereafter excess THF was evaporated
in vacuo and the residue was extracted with EtOAc
(3ꢀ30 mL) and water 50 mL. The organic layers were com-
bined, dried (Na2SO4), and evaporated in vacuo to obtain
a residue, which was purified via silica gel column chroma-
tography using hexane/EtOAc (85:15, v/v) to yield the pure
product.
(CO2Et), 2214 (CN), 3400 (NH) cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 1.27 (t, 3H, J¼7.2 Hz, CH2CH3),
3.53 (d, 2H, J¼2.1 Hz, CH2NH), 4.20 (q, 2H, J¼7.5 Hz,
CH2CH3), 4.82 (s, 1H, CHNH), 6.01 (s, 1H, ]CH2), 6.45
(s, 1H, ]CH2), 7.00 (s, 1H, ]CH), 7.37 (d, 2H,
J¼8.4 Hz, ArH), 7.47–7.70 (m, 4H, ArH), 7.68 (d, 2H,
J¼8.4 Hz, ArH); mass (ES+) m/z¼449 (M++1); Anal. Calcd
for C23H20ClF3N2O2: C, 61.54; H, 4.49; N, 6.24. Found: C,
61.68; H, 4.50; N, 6.56.
Acknowledgements
One of the authors (R.P.) gratefully acknowledges the finan-
cial assistance from CSIR, New Delhi in the form of fellow-
ship. This work was supported by the financial grant from
DST, New Delhi.
4.7.1. 2-[(2-Cyano-3-phenyl-allylamino)-phenyl-methyl]-
acrylic acid ethyl ester (16). Yield: 68% as colorless oil;
Rf¼0.5 (hexane/EtOAc; 85:15); nmax (neat) 1713 (CO2Et),
2212 (CN), 3340 (NH) cmꢁ1; 1H NMR (200 MHz, CDCl3)
d 1.24 (t, 3H, J¼7.2 Hz, CH2CH3), 3.53 (s, 2H, CH2NH),
4.17 (q, 2H, J¼7.2 Hz, CH2CH3), 4.79 (s, 1H, CHNH),
6.01 (s, 1H, ]CH2), 6.41 (s, 1H, ]CH2), 7.05 (s, 1H,
]CH), 7.27–7.46 (m, 8H, ArH), 7.74–7.77 (m, 2H, ArH);
13C NMR (75 MHz, CDCl3) d 12.9, 13.1, 43.3, 50.3, 52.2,
59.8, 108.9, 117.2, 124.5, 126.5, 127.3, 127.4, 127.6,
128.3, 129.0, 132.0, 133.7, 139.4, 140.5, 142.8, 165.0,
166.7; mass (ES+) m/z¼347 (M++1). Anal. Calcd for
C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.41;
H, 6.20; N, 7.92.
References and notes
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4.7.2. 2-[(2-Cyano-3-p-tolyl-allylamino)-phenyl-methyl]-
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Rf¼0.6 (hexane/EtOAc; 85:15); nmax (neat) 1712 (CO2Et),
2217 (CN), 3399 (NH) cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.21 (t, 3H, J¼7.2 Hz, CH2CH3), 2.38 (s, 3H, ArCH3),

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