Synthesis of 5-acyl-6-[2-hydroxy-3-(amino)propylamino]-1,3-dialkyl-1H- pyrimidine-2,4-diones

Article abstract of DOI:10.1039/b509775d

A stepwise synthetic approach involving substitution of 6-chloro-1,3-dialkyluracils (5 and 6) with 3-(tert-amino)-2-hydroxypropylamines and subsequent acylation at C5 of uracil has been used to synthesize pyrimidinediones 27-33 in 61-89% overall yield. Th

Full text of DOI:10.1039/b509775d

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A R T I C L E
Synthesis of 5-acyl-6-[2-hydroxy-3-(amino)propylamino]-1,3-dialkyl-
1H-pyrimidine-2,4-diones†
Palwinder Singh,*a Kamaldeep Paula and Wolfgang Holzerb
a Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, India.
E-mail: palwinder_singh_2000@yahoo.com; Fax: +91-183-2258819; Tel: +91-183-2258802,
ext. 3495
b Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse-14, A-1090, Wein,
Austria
Received 11th July 2005, Accepted 31st August 2005
First published as an Advance Article on the web 26th September 2005
A stepwise synthetic approach involving substitution of 6-chloro-1,3-dialkyluracils (5 and 6) with
3-(tert-amino)-2-hydroxypropylamines and subsequent acylation at C5 of uracil has been used to synthesize
pyrimidinediones 27–33 in 61–89% overall yield. The conformational aspects of the new molecules based upon NMR
data have been discussed.
Introduction
One major objective of organic synthesis is to design and
synthesize molecules with potential bioactivities. Multi-drug
resistance (MDR) is a major limiting factor in the develop-
ment of drug candidates. In recent years, the development of
means to control MDR has become important – even more
important than the development of new drug molecules. It
is well established that MDR comes into play due to the
over-expression of p-glycoprotein (p-gp).1,2 A number of MDR
modulators are being used along with the drugs which bind
competitively to p-gp and thereby inhibit the p-gp-mediated
transport of drug molecules out of the cell.1–3 Propafenone (1a)
Scheme 1
and its derivatives (1b–g), as well as its heterocyclic analogues
that have pyrazole in place of benzene13 have been extensively
in DMF using K2CO3 as base gave a solid compound [M+
explored4–12,13 for their MDR-modulating properties. Most of the
◦
m/z 191], in 40% yield (lit.14 14%), mp 163–64 C (lit.15 mp
MDR modulators have appropriately placed aromatic ring(s)
164–165 ◦C), which was identified as 1,3-dimethylpyrido[2,3-
and a basic tertiary nitrogen. Uracil, a unique molecule due
d]pyrimidin-2,4-dione (4) by comparison with reported data
to its functionalities and reactivity pattern, is widespread in
(Scheme 2). This is probably a result of epichlorohydrin reacting
natural as well as synthetic systems. The pyrimidinedione
at C5 of the uracil followed by epoxide ring-opening by the
ring constitutes the basic skeleton of a number of clinically
6-NH2 group and oxidation/dehydrogenation.
used drugs, many of which face the problem of multi-drug
resistant organisms. The use of uracil-based MDR modulators
can create competition between the MDR modulators and
anti-cancer drugs for binding to p-gp, reducing the level of
multi-drug resistance. The acceptability of the uracil moiety in
biological systems and the presence of a greater number of H-
binding sites in comparison to propafenone(s) prompted us to
design and synthesize pyrimidinedione-based molecules (2a–g).
These molecules could be considered as structural analogues of
Scheme 2
propafenone (1a), formed by replacement of the benzene moiety
and the ethereal oxygen of propafenone with pyrimidinedione
and NH respectively (Scheme 1).
In another synthetic approach, 6-amino-5-benzoyl-1,3-
dimethyluracil16 failed to react with epichlorohydrin under
various reaction conditions, using e.g. K2CO3, potassium tert-
butoxide, triethylamine, NaH and NaOH as bases in CH3CN,
DMF and methanol.
Results and discussion
Therefore, an alternative approach was followed, whereby
1,3-dialkyl-6-chlorouracils (5, 6) were made to react with
hydroxy amines 7.17,18 6-Chloro-1,3-dimethyluracil (5) (10 mmol)
on refluxing with 3-morpholino-2-hydroxypropylamine (7a)
(10 mmol) in absolute ethanol in the presence of Na2CO3 gave
8 as yellow oil (87%), [M+ + 1, m/z 299] (Scheme 3). In the
1H NMR spectrum of 8, most of the protons are magnetically
non-equivalent and the spectrum shows a 4H multiplet at d 2.43–
2.48, a 2H multiplet at d 2.63, two 1H double double doublets
at d 3.00 and 3.21, two 3H singlets at d 3.29 and 3.40, a broad
1H signal (exchangeable with D2O) at d 3.35, a 4H multiplet at
Herein we present the syntheses of the new designed pyrimidine-
2,4-dione derivatives 2a–g. The conformational features of some
of the molecules have been described on the basis of coupling
constants of various protons in the 1H NMR spectra, and NOE
experiments.
A direct approach for the syntheses of compounds 2a–g by the
reaction of epichlorohydrin with 1,3-dimethyl-6-aminouracil (3)
† Electronic supplementary information (ESI) available: 1H NMR
spectra of 12 and 18. See DOI: 10.1039/b509775d
3 9 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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appear at d 2.43 (the energy-minimized structure of 8 also shows
that Hd and the equatorial proton of C16 are in close proximity).
The geminal coupling constant of each proton of the ddd (JHb
)
–H
c
is 12.6 Hz. The proton at d 3.21 (Hb) shows a coupling of 3.6 Hz
with Hd and a coupling of 3.9 Hz with NH (Ha) proton. The
proton at d 3.00 (Hc) shows a 6.9 Hz coupling with Hd and
a coupling of 6.6 Hz with the NH (Ha) proton. On the basis
of the dependence of coupling constant on dihedral angle, it
is predicted that Ha, Hb, and Hd are syn to each other, while
the proton Hc is anti to the Ha and Hd protons. Based upon
these NMR investigations, configurations of the chiral carbon
center present in compound 8 have been shown in Fig. 1a ; its
energy-minimized structure (Fig. 1b) also corresponds to the
structure predicted from the NMR data. It seems that the part
of the substituent at C6 near to the uracil ring i.e., the NH–C8–
C9 fragment, shows slow conformational changes on the NMR
scale, while the distal part of the chain (C10 and the morpholine
moiety) is flexible.
In similar reactions, the 6-chloro-1,3-dialkyluracils 5 and 6,
on reaction with appropriately synthesized amino alcohols 7a–
c, provide respective uracil derivatives 9–13 in 76–84% yields
(Scheme 3). The 1H NMR spectra of 9–13 show similar coupling
features to those for 8. In compounds 11–13, the benzylic
protons at N1 and N3 appear as doublets with a strong geminal
coupling constant of 15 Hz.
Heating of a mixture of 8 and benzoic anhydride (2 equiv.)
in a microwave oven for 3 minutes, after work-up and column
chromatography, gave a yellow oil in 95% yield, [M+ + 1 m/z
403], which contained a benzoyl group. The downfield shift of
the Hd proton to d 5.42 (presence of the electron-withdrawing
group on C9), the absence of an exchangeable (OH) proton in
the region d 3–4, and the appearance of an ester absorption
peak at 1709 cm−1 in the IR spectrum support the formation of
compound 14. (Scheme 4).
Scheme 3
d 3.72, a 1H multiplet at d 4.0, a singlet at d 4.81 and a broad 1H
triplet (exchangeable with D2O) at d 5.21. The assignments of
these signals to specific protons have been made on the basis of
coupling constants of various signals, their decouplings, NOE
and H–13C HETCOR NMR experiments. Decoupling of the
1
multiplet at d 4.0 converts the two double double doublets to
their respective double doublets, and the most upfield signal at d
2.44 is converted to a singlet, which shows that the 1H multiplet
at d 4.0 belongs to Hd and that the 4H multiplet at d 2.43–2.48
contains the 2 C10 protons (Fig. 1a). On D2O exchange, the
signal at d 5.21 disappears and the two double double doublets
are converted to two double doublets. This indicates that the
exchangeable signal at d 5.21 belongs to NH (Ha) and two double
double doublets at d 3.00 and 3.21 belong to the Hc and Hb
protons at C8, and that the appearance of the double double
doublets is due to geminal coupling and two vicinal couplings
with the CH and NH protons. Decoupling of the 4H signal at d
3.72 transforms the left part of the multiplet at d 2.43–2.48 to a
singlet. This shows that the 4H multiplet at d 2.43–2.48 contains
the two protons at C12/C16 and that the signal at d 3.72 belongs
to the 4 protons at C13 and C15. These assignments have also
been confirmed by the 1H–13C HETCOR NMR spectrum. The
other two protons of C12/C16 appear at d 2.63 as a multiplet.
The observation of an NOE between Hd and the multiplet signal
at d 2.63 indicates that the equatorial protons of the C12/C16
carbons appear at d 2.63, while the axial protons of C12/C16
Scheme 4
The chemical shifts to all the protons of 14 have been assigned
on the basis of decoupling, NOE and 1H–13C HETCOR NMR
experiments. The C8 protons appear as double double doublets
at d 3.41 and 3.53 (Fig. 2) as in compound 8. In contrast
to compound 8, the C10 protons appear as a doublet at d
2.77, not overlapping with the C12/C16 protons. Similarly,
Fig. 1 a) NMR spectral assignment and relative configurations at NH,
C8 and C9 of 8. b) Energy-minimized structure of 8.19
Fig. 2 NMR spectral assignment of 14.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5
3 9 5 9

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compounds 9–13 on treatment with benzoic anhydride under
microwave irradiation provide compounds 15–19 in excellent
yield (Scheme 4).
In order to get C5-benzoylated products, alternative reaction
conditions were tried. Treatment of 8 with benzoyl chloride in
chloroform/Na2CO3 or dioxan/Ca(OH)2 gave compound 14 in
92% and 81% yields respectively; no C5-benzoylated product
was formed. Compounds 9–13 also undergo a similar type of
reaction to give the respective compounds 15–19 (Scheme 4,
conditions b and c). Therefore, under all the reaction conditions
shown in Scheme 4, compounds 8–13 underwent regioselective
benzoylation at OH. However, on treatment with benzoyl
chloride in pyridine, 8 gave an oily product [M+ + 1 m/z
507]. The mass difference of 208 units from 8 indicated that
two benzoyl groups had been introduced. The conspicuous
1
absence of the C5 proton in the d 4–5 region of the H NMR
spectrum indicated the formation of compound 20 (Scheme 5).
The downfield shifting of NH protons to d 9.6 in compound 20
must be due to strong intramolecular H-bonding with the C O
Scheme 6
=
group at C5.
Scheme 5
Similarly, refluxing of 9–13 with benzoyl chloride in pyridine
gave the compounds 21–25, respectively (Scheme 5). Compound
8 also underwent diacylation with 3-phenylpropionyl chloride in
pyridine to gave compound 26 in 60% yield, [M+ + 1 m/z 563]
(Scheme 5).
In order to achieve the target 5-benzoylated-6-substituted
uracils, the hydrolysis of compounds 20–26 was carried out.
On treatment with 2 N NaOH, compound 20 gave a yellowish
oil [M+ + 1 m/z 403]. The molecular mass is 104 units less than
20, which clearly indicates the removal of one benzoyl group. Its
1H NMR spectrum shows an exchangeable broad 1H triplet at d
9.50, another exchangeable proton at d 2.79, and the absence of
the C5 proton in the d 4–5 region, along with the other signals.
The Hd proton appears at d 3.91 (similar to the Hd proton of
8). Based upon NMR spectral data, formation of compound 27
was confirmed (Scheme 6). The downfield shift of NH proton to
Fig. 3 a) 1H NMR spectral assignments of various protons in 27.
The chemical shifts and splitting pattern are given in parentheses. b)
Energy-minimized structure of 27.
on adjacent carbons of uracil, similar to the groups present
on adjacent carbons of benzene in propafenone, has been
achieved.
=
d 9.50 is due to strong intramolecular H-bonding with the C O
group at C5.
Experimental
The energy-minimized structure of 27 shows the close prox-
˚
imity of the NH proton to the carbonyl oxygen at C5 (1.85 A)
General
(Fig. 3b). The chemical shifts and splitting pattern of the protons
of 27 are shown in Fig. 3a. Similarly, the hydrolysis of 21–26 gave
compounds 28–33 respectively (Scheme 6).
All melting points are uncorrected. Column chromatography
was carried out using silica gel (60–120 mesh). All eluents were
1
distilled prior to use. The H NMR spectra were recorded on
Bruker 300 MHz and JEOL JNM 300 MHz NMR spectrome-
ters, and 13C NMR spectra at 75 MHz on the same spectrometers
in deuterated chloroform; chemical shifts are quoted in ppm
against tetramethylsilane, and coupling constants in Hertz.
In 13C NMR spectral data, +ve signals correspond to CH3
Conclusion
A stepwise synthesis leads to the formation of 5-benzoyl-6-
substituted pyrimidin-2,4-diones in moderate to high yields.
The target of introducing acyl and hydroxy amine groups
3 9 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5

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and CH carbons and −ve signals correspond to CH2 carbons
in the DEPT-135 NMR spectrum. The FAB mass spectra
were recorded on a JEOL SX 102/DA-6000 Mass Spectrom-
eter/Data System using argon/xenon (6 kV, 10 mA) as the FAB
gas. Infrared spectra were recorded on an FTIR Shimadzu 8400
spectrometer on a thin dispersed film (from chloroform).
3JH
= 4.8 Hz, 3JH
= 4.5 Hz, Hb), 3.30 (3H, s, NCH3), 3.35
–H
–H
a
d
b
b
(1H, bs, OH, exchanges with D2O), 3.37 (3H, s, NCH3), 4.01
(1H, m, Hd), 4.81 (1H, s, C5-H), 5.98 (1H, bs, Ha, exchanges
with D2O); dC(75.4 MHz, CDCl3, Me4Si): 23.6 (−ve, C13,14), 27.8
(+ve, NCH3), 28.6 (+ve, NCH3), 47.7 (−ve, C8), 54.4 (−ve,
C12,15), 60.0 (−ve, C10), 65.5 (+ve, C9), 75.4 (+ve, C5), 151.9
(C2), 153.3 (C6), 163.2 (C4); H–13C HETCOR: The 2 × ddd
1
6-(2-Hydroxy-3-morpholin-4-ylpropylamino)-1,3-dimethyl-1H-
pyrimidin-2,4-dione (8)
at d 3.11 and 3.19 belong to one carbon at d 47.7. The carbon
signal at d 54.4 corresponds to two proton signals: a multiplet at
d 2.61 and part of a multiplet at d 2.77–2.84. The carbon signal
at d 60.0 corresponds to two proton signals, a dd at d 2.56 and
part of multiplet at d 2.77–2.84; m/z (FAB) 283 (M+ + 1).
A solution of 6-chloro-1,3-dimethyluracil (1.745 g, 10 mmol),
3-morpholino-2-hydroxypropylamine (1.47 g, 10 mmol) and
sodium carbonate (1.06 g, 10 mmol) in absolute ethanol (10 ml)
was refluxed. After 7–10 h of refluxing, the reaction mixture was
filtered while hot and concentrated under vacuum. The residue
was purified by column chromatography using CHCl3–MeOH
(7 : 3) as eluent, giving rise to 8 (2.25 g, 87%) as a yellowish
oil. (Found: C, 52.51; H, 7.55; N, 18.65. C13H22N4O4 requires C,
52.34; H, 7.43; N, 18.78%); mmax (CHCl3)/cm−1: 3200 (NH), 1613,
1,3-Dibenzyl-6-(2-hydroxy-3-morpholin-4-ylpropylamino)-1H-
pyrimidin-2,4-dione (11)
According to the preparation of 8, 11 was obtained from 6
(3.105 g, 10 mmol) as a yellowish oil. Yield: 3.4 g, 78%; (Found:
C, 66.60; H, 6.75; N, 12.45. C25H30N4O4 requires C, 66.65; H,
6.71; N, 12.44%); mmax (CHCl3)/cm−1: 3378 (NH), 1627, 1691
=
1692 (C O); dH(300 MHz, CDCl3, Me4Si) 2.44 (2H, m, C10-H2),
2
2.46 (2H, m, C12-H2/C16-H2), 2.63 (2H, m, C12-H2/C16-H2),
=
(C O); dH(300 MHz, CDCl3, Me4Si) 2.09 (1H, dd, J = 12.6 Hz,
2
3
3
3J = 10.2 Hz, C10-H), 2.21 (1H, dd, 2J = 12.6 Hz, 3J = 3.9 Hz,
3.00 (1H, ddd, JH
= 12.6 Hz, JH
= 7.0 Hz, JH
=
–H
–H
–H
c a
c
c
d
b
6.6 Hz, Hc), 3.21 (1H, ddd, 2JH
= 12.6 Hz, 3JH
= 3.9 Hz,
C10-H), 2.29 (2H, m, C12-H2, C16-H2), 2.55 (2H, m, C12-H2,
–H
–H
a
c
b
3JH
= 3.6 Hz, Hb), 3.29 (3H, s, NCH3), 3.35 b(1H, bs, OH,
2
3
C16-H2), 2.81 (1H, dt, J = 12.6 Hz, J = 5.4 Hz, Hc), 3.12
–H
d
b
2
3
exchanges with D2O), 3.40 (3H, s, NCH3), 3.72 (4H, m, C13-
H2, C15-H2), 4.00 (1H, m, Hd), 4.81 (1H, s, C5-H), 5.21 (1H,
t, J = 4.2 Hz, Ha, exchanges with D2O); dC(75.4 MHz, CDCl3,
Me4Si): 27.8 (+ve, NCH3), 28.7 (+ve, NCH3), 46.8 (−ve, C8),
53.8 (−ve, C12,16), 62.0 (−ve, C10), 63.9 (+ve, C9-H), 66.8 (−ve,
C13,15), 75.8 (+ve, C5), 151.8 (C2), 153.2 (C6), 163.1 (C4); 1H–
13C HETCOR: The 1H NMR signal at d 2.43–2.48 corresponds
to the two carbon signals at d 53.8 (C12,16) and 62.0 (C10). The
1H NMR signal at d 2.63 also corresponds to the carbon signal
at d 53.8 (C12, C16). The 2 × ddd at d 3.00 and 3.21 correspond
to one carbon at d 46.8 (C8). NOE: irradiation of the 1H signal
at d 5.21 shows an NOE between N1-CH3 and Hd. Irradiation
of the 1H signal at d 4.00 shows an NOE between the protons
at d 5.21 and 2.63; m/z (FAB) 299 (M+ + 1).
(1H, dt, J = 12.6 Hz, J = 5.7 Hz, Hb), 3.67 (4H, m, C13-
H2, C15-H2), 3.82 (1H, m, Hd), 4.82 (1H, s, C5-H), 4.93 (1H,
d, J = 16.6 Hz, PhCH2), 5.15 (1H, d, J = 14.0 Hz, PhCH2),
5.18 (1H, d, J = 14.0 Hz, PhCH2), 5.37 (1H, d, J = 16.6 Hz,
PhCH2), 7.24–7.48 (10H, m, 2 × Ph); dC(75.4 MHz, CDCl3,
Me4Si): 44.3 (−ve, PhCH2), 45.7 (−ve, C8), 46.0 (−ve, PhCH2),
53.5 (−ve, C12,16), 61.2 (−ve, C10), 63.6 (+ve, C9), 66.8 (−ve,
C13,15), 76.3 (+ve, C5), 126.6 (+ve, ArCH), 127.3 (+ve, ArCH),
128.2 (+ve, ArCH), 128.3 (+ve, ArCH), 128.6 (+ve, ArCH),
129.2 (+ve, ArCH), 135.1 (ArC), 137.6 (ArC), 152.2 (C2), 153.0
1
(C6), 162.6 (C4); H–13C HETCOR: 2 × dd at d 2.09 and 2.21
correspond to carbon signal at d 61.2, two multiplets at d 2.29
and 2.55 belong to carbon signal at d 53.5, 2 × dt at d 2.81 and
3.12 correspond to carbon signal at d 45.7, two doublets at d
4.93 and 5.37 belong to carbon signal at d 46.0 and two doublets
at d 5.15 and 5.18 belong to carbon signal at d 44.3; m/z (FAB)
451 (M+ + 1).
6-(2-Hydroxy-3-piperidin-1-ylpropylamino)-1,3-dimethyl-1H-
pyrimidin-2,4-dione (9)
According to the preparation of 8, 9 was obtained from 5
(1.745 g, 10 mmol) as a yellowish oil. Yield: 2.15 g, 84%; (Found:
C, 56.71; H, 7.95; N, 18.72. C14H24N4O3 requires C, 56.74; H,
8.16; N, 18.90%); mmax (CHCl3)/cm−1: 3220 (NH), 1632, 1692
1,3-Dibenzyl-6-(2-hydroxy-3-piperidin-1-ylpropylamino)-1H-
pyrimidin-2,4-dione (12)
According to the preparation of 8, 12 was obtained from 6
(3.105 g, 10 mmol) as a yellowish oil. Yield: 3.3 g, 77%; (Found:
C, 69.52; H, 7.15; N, 12.44. C26H32N4O3 requires C, 69.62; H,
7.19; N, 12.49%); mmax (CHCl3)/cm−1: 3296 (NH), 1635, 1689
=
(C O); dH(300 MHz, CDCl3, Me4Si) 1.46 (2H, m, C14-H2),
1.57 (4H, m, C13-H2, C15-H2), 2.36 (2H, m, C12-H2/C16-H2),
2
2.38 (2H, d, J = 6 Hz, C10-H2), 2.57 (2H, m, C12-H2/C16-
H2), 3.00 (1H, dt, 2JH
= 12.6 Hz, 3JH
= 6.3 Hz, 3JH
=
–H
–H
–H
c a
c
c
d
b
=
(C O); dH(300 MHz, CDCl3, Me4Si): 1.43 (2H, m, C14-H2),
2
3
4.2 Hz, Hc), 3.16 (1H, dt, JHb = 12.6 Hz, JHb
= 4.2 Hz,
–H
–H
d
c
1.54 (4H, m, C13-H2, C15-H2), 2.08 (1H, dd, 2J = 12.3 Hz, 3J =
3JH
= 4.2 Hz, Hb), 3.29 (3H, s, NCH3), 3.40 (3H, s, NCH3),
–H
a
2
3
b
=
9.9 Hz, C10-H), 2.18 (1H, dd, J = 12.6 Hz, J 3.9 Hz, C10-H),
2.23 (2H, m, C12-H2/C16-H2), 2.50 (2H, m, C12-H2/C16-H2),
2.80 (1H, dt, 2J = 12.6 Hz, 3J = 5.4 Hz, Hc), 3.10 (1H, dt,2J =
12.0 Hz, 3J = 4.2 Hz, Hb), 3.82 (1H, m, Hd), 4.82 (1H, s, C5-H),
4.93 (1H, d, J = 16.5 Hz, PhCH2), 5.15 (1H, d, J = 14.1 Hz,
PhCH2), 5.18 (1H, d, J = 14.1 Hz, PhCH2), 5.35 (1H, d, J =
16.5 Hz, PhCH2), 7.25–7.46 (10H, m, 2 × Ph); dC(75.4 MHz,
CDCl3, Me4Si): 23.9 (−ve, C14), 25.7 (−ve, C13,15), 44.3 (−ve,
PhCH2), 45.9 (−ve, C8), 46.0 (−ve, PhCH2), 54.6 (−ve, C12,16),
61.3 (−ve, C10), 63.6 (+ve, C9), 76.1 (+ve, C5), 126.6 (+ve,
ArCH), 127.2 (+ve, ArCH), 128.2 (+ve, ArCH), 128.3 (+ve,
ArCH), 128.5 (+ve, ArCH), 129.2 (+ve, ArCH), 135.1 (ArC),
137.7 (ArC), 152.2 (C2), 153.2 (C6), 162.8 (C4); m/z (FAB) 449
(M+ + 1).
3.50 (1H, bs, OH, exchanges with D2O), 3.98 (1H, m, Hd),
4.81 (1H, s, C5-H), 5.44 (1H, t, J = 4.2 Hz, Ha, exchanges
with D2O); dC(75.4 MHz, CDCl3, Me4Si): 24.0 (−ve, C14), 26.0
(−ve, C13,15), 27.8 (+ve, NCH3), 28.7 (+ve, NCH3), 47.2 (−ve,
C8), 54.9 (−ve, C12,16), 62.4 (−ve, C10), 63.9 (+ve, C9), 75.7
(+ve, C5), 151.9 (C2), 153.3 (C6), 163.1(C4); m/z (FAB) 297
(M+ + 1).
6-(2-Hydroxy-3-pyrrolidin-1-ylpropylamino)-1,3-dimethyl-1H-
pyrimidin-2,4-dione (10)
According to the preparation of 8, 10 was obtained from 5
(1.745 g, 10 mmol) as a yellowish oil. Yield: 2.05 g, 84%; (Found:
C, 55.43; H, 7.75; N, 19.75. C13H22N4O3 requires C, 55.30; H,
7.85; N, 19.84%); mmax (CHCl3)/cm−1: 3200 (NH), 1613, 1692
=
(C O); dH(300 MHz, CDCl3, Me4Si) 1.81 (4H, m, C13-H2, C14-
1,3-Dibenzyl-6-(2-hydroxy-3-pyrrolidin-1-yl-propylamino)-1H-
pyrimidin-2,4-dione (13)
H2), 2.56 (1H, dd, 2J = 12.3 Hz, 3J = 4.8 Hz, C10-H), 2.61 (2H,
m, C12-H2/C15-H2), 2.77–2.84 (3H, m, 2H of C12-H2/C15-
H2, 1H of C10), 3.11 (1H, ddd, JH
4.8 Hz, JH
2
3
= 12.3 Hz, JH
=
According to the preparation of 8, 13 was obtained from 6
(3.105 g, 10 mmol) as a yellowish oil. Yield: 3.2 g, 76%; (Found:
–H
–H
d
c
c
b
3
2
= 4.2 Hz, Hc), 3.19 (1H, dt, JHb = 12.3 Hz,
–H
–H
c
c
a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5
3 9 6 1

View Article Online
2
3
C, 69.01; H, 7.05; N, 12.85. C25H30N4O3 requires C, 69.10; H,
3.56 (2H, dd, J = 9.2 Hz, J = 6.2 Hz, C10-H2), 5.07 (1H, s,
C5-H), 5.57 (1H, m, Hd), 7.16 (1H, bt, J = 6.0 Hz, Ha), 7.53–8.03
(5H, m, Ph); dN(30.4 MHz, CDCl3): 117.4 (N1), 142.9 (N3), 73.8
(N7), 50.7 (N11); dC(75.4 MHz, CDCl3, Me4Si): 21.0 −ve, C14),
22.1 (−ve, C13,15), 27.1 (+ve, NCH3), 29.5 (+ve, NCH3), 42.9
(−ve, C8), 53.1 (−ve, C12,16), 56.2 (−ve, C10), 66.8 (+ve, C9),
74.2 (+ve, C5), 128.6 (+ve, ArCH), 129.2 (ArC), 129.6 (+ve,
6.96; N, 12.89%); mmax (CHCl3)/cm−1: 3016 (NH), 1627, 1689
=
(C O); dH(300 MHz, CDCl3, Me4Si): 1.93 (4H, m, C13-H2,
C14-H2), 2.34 (1H, dd, 2J = 12.0 Hz, 3J = 2.4 Hz, C10-H), 2.48
(1H, dd, 2J = 11.4 Hz, 3J = 3.9 Hz, C10-H), 2.54 (2H, m, C12-
H2/C15-H2), 2.64 (2H, m, C12-H2/C15-H2), 2.92 (1H, m, Hc),
3.07 (1H, m, Hb), 3.87 (1H, m, Hd), 4.82 (1H, s, C5-H), 4.97 (1H,
d, J = 16.4 Hz, PhCH2), 5.09 (1H, d, J = 14.0 Hz, PhCH2), 5.13
(1H, d, J = 16.4 Hz, PhCH2), 5.33 (1H, d, J = 14.0 Hz, PhCH2),
5.62 (1H, bs, Ha), 7.21–7.54 (10H, m, 2 × Ph); dC(75.4 MHz,
CDCl3, Me4Si): 23.0 (−ve, C13,14), 44.3 (−ve, PhCH2), 45.4 (−ve,
C8), 45.7 (−ve, PhCH2), 54.6 (−ve, C12,15), 58.3 (−ve, C10),
64.5 (+ve, C9), 75.6 (+ve, C5), 126.0 (+ve, ArCH), 127.2 (+ve,
ArCH), 127.7 (+ve, ArCH), 128.0 (+ve, ArCH), 128.3 (+ve,
ArCH), 128.8 (+ve, ArCH), 135.4 (ArC), 137.5 (ArC), 152.0
(C2), 153.1 (C6), 163.2 (C4); m/z (FAB) 435 (M+ + 1).
ArCH), 133.6 (+ve, ArCH), 151.4 (C2), 153.1 (C6), 161.6 (C4),
+
=
165.2 (C O); m/z (FAB) 401 (M + 1).
Benzoic acid 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-ylamino)-1-(pyrrolidin-1-ylmethyl)ethyl ester (16).
According to the preparation of 14, 16 was obtained from 10
(2.82 g, 10 mmol) as a white solid. Yield: 4.45 g, 90%; mp 180–
82 ◦C; (Found: C, 62.12; H, 6.80; N, 14.55. C20H26N4O4 requires
C, 62.16; H, 6.78; N, 14.50%); mmax (KBr)/cm−1: 3288 (NH),
=
1720, 1662 (C O); dH(300 MHz, CDCl3, Me4Si): 1.91 (4H, m,
C13-H2, C14-H2), 3.07 (3H, s, NCH3), 3.22 (4H, m, C12-H2,
Benzoic acid 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(morpholin-4-
ylmethyl)ethyl ester (14)
2
3
C15-H2), 3.23 (3H, s, NCH3), 3.48 (2H, dd, J = 8.4 Hz, J =
2
3
6.0 Hz, C8-H2), 3.59 (2H, dd, J = 6.0 Hz, J = 4.2 Hz, C10-
H2), 5.04 (1H, s, C5-H), 5.54 (1H, m, Hd), 7.15 (1H, t, J =
6.0 Hz, Ha), 7.50–8.05 (5H, m, Ph); 1D TOCSY: irradiation of
the multiplet at d 5.54 (Hd) shows signals at d 3.48 (C8-H2), 3.58
(C10-H2) and 7.15 (NH) indicating that these protons are part
of a one-spin system; dC(75.4 MHz, CDCl3, Me4Si): 22.6 (−ve,
C13,14), 27.1 (+ve, NCH3), 29.5 (+ve, NCH3), 42.8 (−ve, C8),
54.2 (−ve, C12,15), 54.3 (−ve, C10), 67.9 (+ve, C9), 74.1 (+ve,
C5), 128.6 (+ve, ArCH), 129.2 (ArC), 129.7 (+ve, ArCH), 133.6
Compound 8 (2.98 g, 10 mmol), on mixing with benzoic
anhydride (4.52 g, 20 mmol) was heated in a microwave oven for
3 min. After stirring with a saturated solution of NaHCO3, the
reaction mixture was extracted with CHCl3. Removal of CHCl3
left a thick liquid which was purified by column chromatography
using chloroform–methanol (8 : 2) as eluents, to give 14
(3.8 g, 95%) as a yellowish oil. (Found: C, 59.60; H, 6.55; N,
13.95. C20H26−N1 4O5 requires C, 59.69; H, 6.51; N, 13.92%); mmax
=
(+ve, ArCH), 151.4 (C2), 153.1 (C6), 161.6 (C4), 165.2 (C O);
=
(CHCl3)/cm : 3438 (NH), 1709, 1672 (C O); dH(300 MHz,
m/z (FAB) 387 (M+ + 1).
CDCl3, Me4Si): 2.62 (4H, m, C12-H2, C16-H2), 2.77 (2H, d, J =
6.0 Hz, C10-H2), 3.30 (3H, s, NCH3), 3.40 (3H, s, NCH3), 3.40
(1H, merged with NCH3, Hc), 3.53 (1H, dt, 2J = 12.9 Hz, 3J =
4.2 Hz, Hb, on D2O exchange it becomes a dd with coupling
constants of 12.9 and 4.2 Hz), 3.72 (4H, t, J = 4.8 Hz, C13-H2,
C15-H2), 4.88 (1H, s, C5-H), 5.42 (1H, m, Hd), 6.06 (1H, bt,
J = 5.4 Hz, Ha), 7.47–8.01 (5H, m, Ph); dC(75.4 MHz, CDCl3,
Me4Si): 27.7 (+ve, NCH3), 28.9 (+ve, NCH3), 47.3 (−ve, C8),
54.4 (−ve, C12,16), 60.8 (−ve, C10), 66.8 (−ve, C13,15), 69.9
(+ve, C9), 75.6 (+ve, C5), 128.7 (+ve, ArCH), 129.0 (ArC), 129.8
(+ve, ArCH), 133.9 (+ve, ArCH), 151.9 (C2), 152.8 (C6), 163.0
Benzoic acid 2-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-ylamino)-1-(morpholin-4-ylmethyl)ethyl ester (17).
According to the preparation of 14, 17 was obtained from 11
(4.50 g, 10 mmol) as a yellowish oil. Yield: 4.5 g, 82%; (Found:
C, 69.32; H, 6.15; N, 10.15. C32H34N4O5 requires C, 69.30; H,
6.18; N, 10.10%); mmax (CHCl3)/cm−1: 3300 (NH), 1710, 1629
=
(C O); dH(300 MHz, CDCl3, Me4Si): 2.47 (2H, m, C12-H, C16-
H), 2.50 (2H, d, J = 7.2 Hz, C10-H and C12-H/C16-H), 2.57
(2H, d, J = 5.4 Hz, C10-H and C12-H/C16-H), 3.29 (1H, ddd,
3
3
2JH
= 13.2 Hz, J(H
= 5.1 Hz, JH
= 3.3 Hz, Hc),
–H
–H
)
–H
c a
c
c
d
b
2
3
3
3.44 (1H, ddd, JHb = 13.2 Hz, JHb
= 4.2 Hz, JHb
=
1
13
1
–H
–H
–H
a
c
d
=
(C4), 167.3 (C O); H– C HETCOR: The H NMR signal at d
3.40 corresponds to two carbon signals at d 28.9 and 47.3, and
the 1H signal at d 3.53 also corresponds to a carbon signal at d
47.3. NOE: irradiation of the 1H signal at d 6.06 shows an NOE
between N1-CH3 and Hd; m/z (FAB) 403 (M+ + 1).
3.6 Hz, Hb), 3.61 (4H, t, J = 4.5 Hz, C13-H2, C15-H2), 4.97
(1H, s, C5-H), 5.11 (2H, d, J = 16.8 Hz, N1-CH2Ph), 5.15
(2H, s, N3-CH2Ph), 5.26 (1H, m, C9-Hd), 7.15–7.46 (15H, m,
3 × Ph); dC(75.4 MHz, CDCl3, Me4Si): 44.2 (−ve, PhCH2), 45.8
(−ve, PhCH2), 45.9 (−ve, C8), 54.2 (−ve, C12,16), 59.6 (−ve,
C10), 66.7 (−ve, C13,15), 69.9 (+ve, C9), 76.5 (+ve, C5), 126.0
(+ve, ArCH), 127.2 (+ve, ArCH), 128.0 (+ve, ArCH), 128.3
(+ve, ArCH), 128.5 (+ve, ArCH), 128.6 (+ve, ArCH), 129.1
(+ve, ArCH), 129.2 (ArC), 134.8 (ArC), 137.6 (ArC), 152.0
Alternative procedures
(i) A mixture of 8 (2.98 g, 10 mmol), benzoyl chloride (1.405 g,
10 mmol) and sodium carbonate (1.06 g, 10 mmol) in 10 ml of
chloroform was refluxed for 5 h. After cooling and filtration,
the solvent was removed under vacuum and the crude residue
was purified by column chromatography using chloroform–
methanol as eluent.
(ii) A mixture of 8 (10 mmol), benzoyl chloride (10 mmol)
and Ca(OH)2 in dioxan was refluxed until the completion of
the reaction (TLC). After filtration, the solvent was removed
under vacuum and the crude residue was purified by column
chromatography using chloroform–methanol as eluent.
1
13
=
(C2), 152.8 (C6), 162.6 (C4), 166.5 (C O); H– C HETCOR:
The carbon signal at d 54.2 shows cross-peaks with three proton
signals at d 2.47, 2.50 and 2.57, and the carbon signal at d 59.6
also shows a cross-peak with the proton signals at d 2.50 and
2.57. The 2 × ddd at d 3.29 and 3.44 show cross-peaks with the
carbon signal at d 45.9. The 1H NMR signals at d 5.11 and 5.15
correspond to the carbon signals at d 45.8 and 44.2 respectively;
m/z (FAB) 555 (M+ + 1).
Benzoic acid 2-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-ylamino)-1-(piperidin-1-ylmethyl)ethyl ester (18).
According to the preparation of 14, 18 was obtained from 12
(4.48 g, 10 mmol) as a yellowish oil. Yield: 4.4 g, 80%; (Found: C,
Benzoic acid 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-ylamino)-1-(piperidin-1-ylmethyl)ethyl ester (15).
According to the preparation of 14, 15 was obtained from 9
(2.96 g, 10 mmol) as a white solid. Yield: 3.7 g, 91%; mp 202–
204 ◦C; (Found: C, 62.99; H, 7.10; N, 13.92. C21H28N4O4 requires
C, 62.98; H, 7.05; N, 13.99%); mmax (KBr)/cm−1: 3218 (NH), 1710,
71.75; H, 6.50; N, 10.15. C33H36N4O4 requires C, 71.72; H, 6.57;
−1
=
N, 10.14%); mmax (CHCl3)/cm : 3033 (NH), 1715, 1631 (C O);
dH(300 MHz, CDCl3, Me4Si): 1.37 (2H, m, C14-H2), 1.50 (4H,
=
1699 (C O); dH(300 MHz, CDCl3, Me4Si): 1.77 (2H, m, C14-
m, C13-H2, C15-H2), 2.44 (4H, m, C12-H2, C16-H2), 2.56 (2H,
H2), 2.49 (4H, m, C13-H2, C15-H2), 3.00 (2H, m, C12-H2/C16-
H2), 3.38 (2H, m, C12-H2/C16-H2), 3.07 (3H, s, NCH3), 3.24
(3H, s, NCH3), 3.46 (2H, dd, 2J = 9.6 Hz, 3J = 6.0 Hz, C8-H2),
dd, 2J = 8.2 Hz, 3J = 5.8 Hz, C10-H2), 3.33 (1H, ddd, 2JH
=
–H
c
12.3 Hz, 3JH
= 8.4 Hz, 3JH
= 3.9 Hz, Hc), 3.44 (1H, dbdd,
–H
–H
a
c
d
c
2JH
= 12.3 Hz, 3JH
= 6.3 Hz, 3JH
= 4.2 Hz, Hb), 4.96
–H
–H
–H
a
b
c
d
b
b
3 9 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5

View Article Online
(1H, s, C5-H), 5.12 (2H, s, PhCH2), 5.14 (2H, s, PhCH2), 5.27
(1H, m, C9-Hd), 7.19–7.90 (15H, m, 3 × Ph); dC(75.4 MHz,
CDCl3, Me4Si): 23.8 (−ve, C14), 25.5 (−ve, C13,15), 44.2 (−ve,
PhCH2), 45.7 (−ve, PhCH2), 46.2 (−ve, C8), 55.3 (−ve, C12,16),
60.0 (−ve, C10), 69.9 (+ve, C9), 76.4 (+ve, C5), 126.1 (+ve,
ArCH), 127.2 (+ve, ArCH), 127.9 (+ve, ArCH), 128.3 (+ve,
ArCH), 128.5 (+ve, ArCH), 128.6 (+ve, ArCH), 129.0 (+ve,
ArCH), 129.2 (ArC), 129.7 (+ve, ArCH), 133.6 (+ve, ArCH),
NCH3), 34.6 (+ve, NCH3), 48.8 (−ve, C8), 55.4 (−ve, C12,16),
59.1 (−ve, C10), 70.6 (+ve, C9), 94.1 (C5), 127.8 (+ve, ArCH),
127.9 (+ve, ArCH), 128.5 (+ve, ArCH), 129.2 (ArC), 129.7
(+ve, ArCH), 131.0 (+ve, ArCH), 133.5 (+ve, ArCH), 141.3
=
(ArC), 151.5 (C2), 160.1 (C6), 161.4 (C4), 165.9 (C O), 195.3
=
(C O); 2D TOCSY, HMBC and HSQC experiments of this
compound also confirm all the above assignments to various
protons and carbons; m/z (FAB) 505 (M+ + 1).
135.0 (ArC), 137.6 (ArC), 152.1 (C2), 152.9 (C6), 162.6 (C4),
Benzoic acid 2-(5-benzoyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(pyrrolidin-1-ylmethyl)ethyl
ester (22). According to the preparation of 20, 22 was obtained
from 10 (2.82 g, 10 mmol) as a yellowish oil. Yield: 3.4 g, 65%;
(Found: C, 66.12; H, 6.10; N, 11.52. C27H30N4O5 requires C,
66.11; H, 6.16; N, 11.42%); mmax (CHCl3)/cm−1: 3328 (NH),
+
=
166.4 (C O); m/z (FAB) 553 (M + 1).
Benzoic acid 2-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-ylamino)-1-(pyrrolidin-1-ylmethyl)ethyl ester (19).
According to the preparation of 14, 19 was obtained from 13
(4.34 g, 10 mmol) as a yellowish oil. Yield: 4.73 g, 75%; (Found:
=
C, 71.55; H, 6.80; N, 10.55. C32H34N4O4 requires C, 71.35; H,
1710, 1670 (C O); dH(300 MHz, CDCl3, Me4Si): 1.95 (4H,
m, C13-H2, C14-H2), 2.87 (2H, dd, J = 8.4 Hz, J = 6.0 Hz,
−1
2
3
=
6.36; N, 10.40%); mmax (CHCl3) (cm ): 3233 (NH), 1710 (C O);
dH(300 MHz, CDCl3, Me4Si): 1.81 (4H, m, C13-H2, C14-H2),
2.92 (2H, dd, 2J = 7.2 Hz, 3J = 3.2 Hz, C10-H2), 3.30 (4H, m,
C12-H2, C15-H2), 3.55 (2H, dd, 2J = 7.5 Hz, 3J = 5.6 Hz, C8-
H2), 4.82 (1H, s, C5-H), 5.07 (2H, d, J = 15.2 Hz, PhCH2), 5.28
(2H, d, J = 14.4 Hz, PhCH2), 5.43 (1H, m, Hd), 7.25–7.37 (15H,
m, 3 × Ph); dC(75.4 MHz, CDCl3, Me4Si): 23.2 (−ve, C13,14), 44.3
(−ve, PhCH2), 45.6 (−ve, C8), 45.7 (−ve, PhCH2), 55.6 (−ve,
C12,15), 58.5 (−ve, C10), 70.1 (+ve, C9), 75.9 (+ve, C5), 126.2
(+ve, ArCH), 126.8 (+ve, ArCH), 127.2 (+ve, ArCH), 127.7
(+ve, ArCH), 127.9 (+ve, ArCH), 128.0 (+ve, ArCH), 128.3
(+ve, ArCH), 128.8 (+ve, ArCH), 129.0 (ArC), 135.4 (ArC),
C10-H2), 3.10 (3H, s, NCH3), 3.15 (4H, m, C12-H2, C15-H2),
2
3
3.24 (3H, s, NCH3), 3.60 (2H, dd, J = 8.4 Hz, J = 6.5 Hz,
C8-H2), 5.44 (1H, m, Hd), 7.51–8.01 (10H, m, 2 × Ph), 9.52 (1H,
t, J = 6.0 Hz, Ha); dC(75.4 MHz, CDCl3, Me4Si): 22.5 (−ve,
C13,14), 27.3 (+ve, NCH3), 29.0 (+ve, NCH3), 46.8 (−ve, C8),
55.2 (−ve, C12,15), 58.3 (−ve, C10), 69.9 (+ve, C9), 94.1 (C5),
127.3 (+ve, ArCH), 127.6 (+ve, ArCH), 128.7 (+ve, ArCH),
129.5 (ArC), 129.7 (+ve, ArCH), 131.8 (+ve, ArCH), 132.5
(+ve, ArCH), 141.6 (ArC), 151.5 (C2), 158.1 (C6), 161.8 (C4),
+
=
=
165.2 (C O), 194.8 (C O); m/z (FAB) 491 (M + 1).
Benzoic acid 2-(5-benzoyl-1,3-dibenzyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(morpholin-4-ylmethyl)ethyl
ester (23). According to the preparation of 20, 23 was obtained
from 11 (4.50 g, 10 mmol) as a yellowish oil. Yield: 4.5 g,
68%; (Found: C, 71.00; H, 5.80; N, 8.71. C39H38N4O6 requires
C, 71.11; H, 5.81; N, 8.51%); mmax (CHCl3)/cm−1: 3386 (NH),
=
137.5 (ArC), 152.0 (C2), 153.1 (C6), 163.2 (C4), 166.5 (C O);
m/z (FAB) 539 (M+ + 1).
Benzoic acid 2-(5-benzoyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-pyrimidin-4-ylamino)-1-(morpholin-4-ylmethyl)ethyl
ester (20). A mixture of 8 (2.98 g, 10 mmol) and benzoyl
chloride (2.81, 20 mmol) in pyridine (10 ml) was refluxed at
115 ◦C for 4 h. The solvent was removed under vacuum and
treated with a saturated solution of sodium bicarbonate to
remove traces of benzoic acid. The aqueous part was extracted
with ether and dried over anhydrous sodium sulfate. Removal
of the solvent provided a crude product which was purified by
column chromatography using hexane–ethyl acetate (3 : 7) as
eluent giving rise to compound 20 (3.2 g, 62%) as a yellowish
oil; (Found: C, 64.12; H, 6.05; N, 11.20. C27H30N4O6 requires
C, 64.02; H, 5.97; N, 11.06%); mmax (CHCl3)/cm−1: 3209 (NH),
=
1716, 1635 (C O); dH(300 MHz, CDCl3, Me4Si): 2.30 (4H, m,
C12-H2, C16-H2), 2.41 (2H, d, J = 5.6 Hz, C10-H2), 3.41 (1H,
ddd, 2JH
= 12.4 Hz, 3JH
= 9.0 Hz, 3JH
= 4.4 Hz, Hc),
–H
–H
–H
c a
c
c
d
b
2
3
3
3.59 (1H, ddd, JH
= 12.4 Hz, JH
= 8.4 Hz, JHb
=
–H
–H
–H
a
c
d
4.0 Hz, Hb), 3.86 (4bH, t, J = 4.5 Hz, C1b3-H2, C15-H2), 5.05 (2H,
d, J = 16.2 Hz, PhCH2), 5.10 (2H, d, J = 14.4 Hz, PhCH2), 5.11
(1H, m, Hd), 7.01–8.04 (20H, m, 4 × Ph); dC(75.4 MHz, CDCl3,
Me4Si): 44.3 (−ve, PhCH2), 46.8 (−ve, PhCH2), 46.9 (−ve, C8),
54.4 (−ve, C12,16), 59.2 (−ve, C10), 66.2 (−ve, C13,15), 69.6
(+ve, C9), 94.2 (C5), 126.2 (+ve, ArCH), 126.5 (+ve, ArCH),
127.0 (+ve, ArCH), 127.3 (+ve, ArCH), 127.5 (+ve, ArCH),
127.9 (+ve, ArCH), 128.4 (+ve, ArCH), 128.6 (+ve, ArCH),
129.1 (ArC), 129.5 (+ve, ArCH), 130.0 (+ve, ArCH), 131.1
(+ve, ArCH), 131.5 (+ve, ArCH) 131.8 (ArC), 133.0 (ArC),
=
1655, 1719 (C O); dH(300 MHz, CDCl3, Me4Si): 2.50 (4H, m,
C12-H2, C16-H2), 2.63 (2H, d, J = 6.6 Hz, C10-H2), 3.19 (3H, s,
NCH3), 3.56 (3H, s, NCH3), 3.62 (4H, t, J = 4.5 Hz, C13-H2,
C15-H2), 3.69 (2H, m, C8-H2), 5.31 (1H, m, Hd), 7.39–7.95
(10H, m, 2 × Ph), 9.62 (1H, t, J = 5.4 Hz, Ha, exchanges with
D2O)); dC(75.4 MHz, CDCl3, Me4Si): 28.1 (+ve, NCH3), 34.8
(+ve, NCH3), 48.4 (−ve, C8), 54.2 (−ve, C12,16), 58.7 (−ve,
C10), 66.8 (−ve, C13,15), 70.6 (+ve, C9), 94.5 (C5), 127.8 (+ve,
ArCH), 128.5 (+ve, ArCH), 129.1 (ArC), 129.7 (+ve, ArCH),
131.1 (+ve, ArCH), 133.6 (+ve, ArCH), 141.2 (ArC), 151.5
=
137.1 (ArC), 152.0 (C2), 162.9 (C6), 165.6 (C4), 174.7 (C O),
195.3 (C O); m/z (FAB) 659 (M + 1).
Benzoic acid 2-(5-benzoyl-1,3-dibenzyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(piperidin-1-ylmethyl)ethyl
ester (24). According to the preparation of 20, 24 was obtained
from 12 (4.48 g, 10 mmol) as a yellowish oil. Yield: 4.27 g,
65%; (Found: C, 73.12; H, 6.30; N, 8.85. C40H40N4O5 requires
C, 73.15; H, 6.14; N, 8.53%); mmax (CHCl3)/cm−1: 3200 (NH),
+
=
=
=
(C2), 160.5 (C6), 161.3 (C4), 166.1 (C O), 195.5 (C O); m/z
(FAB) 507 (M+ + 1).
=
Benzoic acid 2-(5-benzoyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(piperidin-1-ylmethyl)ethyl
ester (21). According to the preparation of 20, 21 was
obtained from 9 (2.96 g, 10 mmol) as a yellowish oil. Yield:
5.1 g, 61%; (Found: C, 66.52; H, 6.40; N, 11.10. C28H32N4O5
requires C, 66.65; H, 6.39; N, 11.10%); mmax (CHCl3)/cm−1: 3230
1725, 1633 (C O); dH(300 MHz, CDCl3, Me4Si): 1.40 (2H, m,
C14-H2), 1.49 (4H, m, C13-H2, C15-H2), 2.44 (4H, m, C12-H2,
C16-H2), 2.62 (2H, d, J = 6.3 Hz, C10-H2), 3.66 (1H, dd,
3
2J = 10.8 Hz, J = 8.1 Hz, C8-H), 3.88 (1H, d, J = 13.5 Hz,
C8-H), 5.11 (2H, d, J = 15.9 Hz, PhCH2), 5.16 (2H, d, J =
13.2 Hz, PhCH2), 5.32 (1H, m, Hd), 7.21–8.02 (20H, m, 4 ×
Ph), 14.30 (1H, bs, Ha, exchanges with D2O); dC(75.4 MHz,
CDCl3, Me4Si): 23.2 (−ve, C14), 24.5 (−ve, C13,15), 44.1 (−ve,
PhCH2), 45.0 (−ve, PhCH2), 45.1 (−ve, C8), 54.9 (−ve, C12,16),
60.2 (−ve, C10), 68.2 (+ve, C9), 94.4 (C5), 125.9 (+ve, ArCH),
126.3 (+ve, ArCH), 126.9 (+ve, ArCH), 128.3 (+ve, ArCH),
128.5 (+ve, ArCH), 128.6 (+ve, ArCH), 128.9 (ArC), 129.0
(+ve, ArCH), 129.2 (+ve, ArCH), 129.3 (+ve, ArCH), 129.8
(+ve, ArCH), 130.9 (ArC), 133.8 (ArC), 137.7 (ArC), 148.3
=
(NH), 1720, 1656 (C O); dH(300 MHz, CDCl3, Me4Si): 1.41
(2H, m, C14-H2), 1.52 (4H, m, C13-H2, C15-H2), 2.42 (2H, m,
C12-H2/C16-H2), 2.51 (2H, m, C12-H2/C16-H2), 2.61 (2H,
2
3
dd, J = 3.6 Hz, J = 1.2 Hz, C10-H2), 3.21 (3H, s, NCH3),
3.58 (3H, s, NCH3), 3.66 (2H, m (distorted triplet), J = 5.1 Hz,
C8-H2), 5.30 (1H, m, Hd), 7.33–7.98 (10H, m, 2 × Ph), 9.63
(1H, t, J = 6.4 Hz, Ha, exchanges with D2O); dC(75.4 MHz,
CDCl3, Me4Si): 23.9 (−ve, C14), 25.9 (−ve, C13,15), 28.0 (+ve,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5
3 9 6 3

View Article Online
=
=
(C2), 151.1 (C6), 157.3 (C4), 162.6 (C O), 194.3 (C O); m/z
to the carbon signal at d 61.1. The signals at d 3.21 and 3.47
correspond to the carbon signal at d 50.3; m/z (FAB) 403
(M + 1).
(FAB) 657 (M+ + 1).
Benzoic acid 2-(5-benzoyl-1,3-dibenzyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-ylamino)-1-(pyrrolidin-1-ylmethyl)ethyl
ester (25). According to the preparation of 20, 25 was
obtained from 13 (4.34 g, 10 mmol) as a yellowish oil. Yield:
3.9 g, 62%; (Found: C, 72.72; H, 5.60; N, 8.55. C39H38N4O5
requires C, 72.88; H, 5.96; N, 8.72%); mmax (CHCl3)/cm−1: 3345
5-Benzoyl-6-(2-hydroxy-3-piperidin-1-ylpropylamino)-1,3-
dimethyl-1H-pyrimidin-2,4-dione (28). According to the
preparation of 27, 28 was obtained from 21 (2.52 g, 5 mmol) as
a yellowish oil. Yield: 2.6 g, 61%; (Found: C, 63.01; H, 6.98; N,
14.02. C21H28−N1 4O4 requires C, 63.00; H, 7.00; N, 14.00%); mmax
=
(CHCl3)/cm : 3131 (NH), 1647 (C O); dH(300 MHz, CDCl3,
=
(NH), 1710, 1660 (C O); dH(300 MHz, CDCl3, Me4Si): 1.80
2
3
Me4Si): 1.47 (2H, m, C14-H2), 1.58 (4H, m, C13-H2, C15-H2),
2.55 (2H, m, C12-H2/C16-H2), 2.67 (2H, m, C12-H2/C16-H2),
2.79 (2H, d, J = 5.1 Hz, C10-H2), 2.90 (1H, bs, OH, exchanges
(4H, m, C13-H2, C14-H2), 2.63 (2H, dd, J = 7.2 Hz, J =
3.0 Hz, C10-H2), 2.79 (2H, m, C12-H2/C15-H2) 2.90 (2H, m,
C12-H2/C15-H2), 3.08 (2H, dd, 2J = 7.5 Hz, 3J = 3.8 Hz,
C8-H2), 5.07 (2H, d, J = 16.8 Hz, PhCH2), 5.12 (2H, d, J =
14.8 Hz, PhCH2), 5.41 (1H, m, Hd), 7.07–7.91 (20H, m, 4 × Ph),
8.61 (1H, bs, Ha, exchanges with D2O); dC(75.4 MHz, CDCl3,
Me4Si): 23.8 (−ve, C13,14), 44.1 (−ve, PhCH2), 45.2 (−ve, C8),
45.7 (−ve, PhCH2), 56.0 (−ve, C12,15), 58.9 (−ve, C10), 69.1
(+ve, C9), 94.6 (C5), 126.2 (+ve, ArCH), 126.4 (+ve, ArCH),
126.8 (+ve, ArCH), 127.2 (+ve, ArCH), 127.4 (+ve, ArCH),
127.7 (+ve, ArCH), 127.9 (+ve, ArCH), 128.0 (+ve, ArCH),
128.3 (+ve, ArCH), 128.5 (ArC), 128.8 (+ve, ArCH), 129.0
with D2O), 3.03 (1H, ddd, 2JH
= 12.3 Hz, 3JH
= 7.4 Hz,
–H
d
–H
–H
d
c
c
b
3JH a = 4.0 Hz, Hc), 3.20 (1H, ddd, 2JH c = 12.3 Hz, 3JH
=
–H
–H
c
b
b
5.4 Hz, 3JH
= 4.2 Hz, Hb), 3.30 (3H, s, NCH3), 3.42 (3H, s,
–H
a
b
NCH3), 4.09 (1H, m, Hd), 7.36–8.03 (5H, m, Ph), 8.59 (1H, bs,
Ha); dC(75.4 MHz, CDCl3, Me4Si): 23.5 (−ve, C14), 26.1 (−ve,
C13,15), 28.2 (+ve, NCH3), 34.8 (+ve, NCH3), 49.8 (−ve, C8),
55.1 (−ve, C12,16), 60.1 (−ve, C10), 64.3 (+ve, C9), 94.3 (C5),
127.8 (+ve, ArCH), 127.9 (+ve, ArCH), 131.0 (+ve, ArCH),
=
141.3 (ArC), 151.8 (C2), 160.3 (C6), 161.3 (C4), 195.3 (C O);
m/z (FAB) 401 (M+ + 1).
(ArC), 135.4 (ArC), 137.5 (ArC), 152.8 (C2), 153.3 (C6), 163.2
(C4), 163.0 (C O), 194.6 (C O); m/z (FAB) 643 (M + 1).
+
=
=
5-Benzoyl-6-(2-hydroxy-3-pyrrolidin-1-ylpropylamino)-1,3-
dimethyl-1H-pyrimidin-2,4-dione (29). According to the
preparation of 27, 29 was obtained from 22 (2.45 g, 5 mmol) as
a yellowish oil. Yield: 1.25 g, 65%; (Found: C, 66.40; H, 6.70; N,
14.51. C20H26−N1 4O4 requires C, 66.32; H, 6.73; N, 14.50%); mmax
3-Phenyl-propionic acid 2-[1,3-dimethyl-2,6-dioxo-5-(3-
phenylpropionyl)-1,2,3,6-tetrahydropyrimidin-4-ylamino)-1-
(morpholin-4-ylmethyl)ethyl ester (26). According to the
preparation of 20, 26 was obtained from 8 (2.98 g, 10 mmol) as
a yellowish oil by using 3-phenylpropionyl chloride. Yield: 3.4 g,
60%; (Found: C, 66.12; H, 6.80; N, 9.70. C31H38N4O6 requires
C, 66.17; H, 6.81; N, 9.96%); mmax (CHCl3)/cm−1: 3243 (NH),
=
(CHCl3)/cm : 3335 (NH), 1700, 1680 (C O); dH(300 MHz,
CDCl3, Me4Si): 1.97 (4H, m, C13-H2, C14-H2), 2.85 (2H, dd,
2J = 8.4 Hz, 3J = 6.0 Hz, C10-H2), 2.90 (4H, m, C12-H2,
C15-H2), 3.25 (3H, s, NCH3), 3.40 (3H, s, NCH3), 3.44 (2H, dd,
2J = 8.4 Hz, 3J = 6.5 Hz, C8-H2), 3.99 (1H, m, Hd), 7.46–7.95
(5H, m, Ph), 9.60 (1H, t, J = 6.0 Hz, Ha): dC(75.4 MHz, CDCl3,
Me4Si): 22.8 (−ve, C13,14), 28.1 (+ve, NCH3), 29.1 (+ve, NCH3),
47.0 (−ve, C8), 55.4 (−ve, C12,15), 58.9 (−ve, C10), 64.9 (+ve,
C9), 94.8 (C5), 127.1 (+ve, ArCH), 129.7 (+ve, ArCH), 130.8
=
1700, 1650 (C O); dH(300 MHz, CDCl3, Me4Si): 2.29–2.43
(6H, m, C10-H2, C12-H2, C16-H2), 2.70 (2H, dt, J = 7.8 Hz,
6.9 Hz, CH2), 2.92 (4H, m, 2 × CH2), 3.31 (3H, s, NCH3), 3.32
2
(2H, m, CH2), 3.40 (3H, s, NCH3), 3.50 (2H, dd, J = 8.0 Hz,
3J = 4.2 Hz, C8-H2), 3.60 (4H, t, J = 4.5 Hz, C13-H2, C15-H2),
5.12 (1H, m, Hd), 7.15–7.30 (10H, m, 2 × Ph), 11.68 (1H, t, J =
5.4 Hz, Ha, exchanges with D2O); dC(75.4 MHz, CDCl3, Me4Si):
28.1 (+ve, NCH3), 30.6 (+ve, NCH3), 30.7 (−ve, CH2), 35.3
(−ve, CH2), 35.6 (−ve, CH2), 36.5 (−ve, CH2), 47.6 (−ve, C8),
54.0 (−ve, C12,16), 58.2 (−ve, C10), 66.5 (−ve, C13,15), 69.4
(+ve, C9), 94.9 (C5), 125.7 (+ve, ArCH), 126.3 (+ve, ArCH),
128.2 (+ve, ArCH), 128.4 (+ve, ArCH), 128.5 (+ve, ArCH),
(+ve, ArCH), 141.8 (ArC), 151.7 (C2), 159.1 (C6), 161.1 (C4),
+
=
194.8 (C O); m/z (FAB) 387 (M + 1).
5-Benzoyl-1,3-dibenzyl-6-(2-hydroxy-3-morpholin-4-ylpropyl-
amino)-1H-pyrimidin-2,4-dione (30). According to the
preparation of 27, 30 was obtained from 23 (3.29 g, 5 mmol) as
a yellowish oil. Yield: 2.25 g, 81%; (Found: C, 69.28; H, 6.32; N,
10.04. C32H34−N1 4O5 requires C, 69.31; H, 6.31; N, 10.10%); mmax
140.0 (ArC), 141.8 (ArC), 151.3 (C2), 161.6 (C4), 162.7 (C6),
+
=
=
172.0 (C O), 200.4 (C O); m/z (FAB) 563 (M + 1).
=
(CHCl3)/cm : 3231 (NH), 1637 (C O); dH(300 MHz, CDCl3,
Me4Si): 2.17 (2H, m, C10-H2), 2.20 (2H, m, C12-H2/C16-H2),
5-Benzoyl-6-(2-hydroxy-3-morpholin-4-ylpropylamino)-1,3-
dimethyl-1H-pyrimidin-2,4-dione (27). Compound 20 (2.53 g,
5 mmol) was stirred with 2 N aqueous sodium hydroxide (10 ml)
in ethanol (10 ml) at room temperature for 2 h. Extraction with
ether, drying over sodium sulfate and solvent removal afforded
a thick liquid which was purified by column chromatography
using ethyl acetate–methanol (8 : 2) as eluent to give 27
(1.82 g, 89%) as a yellowish oil. (Found: C, 59.68; H, 6.40;
N, 13.85. C20H26N4O5 requires C, 59.70; H, 6.46; N, 13.93%);
mmax (CHCl3)/cm : 3393 (NH), 1638, (C O); dH(300 MHz,
CDCl3, Me4Si): 2.33 (2H, m, C12-H2/C16-H2), 2.34 (2H,
m, C10-H2), 2.58 (2H, m, C12-H2/C16-H2), 2.79 (1H, bs,
2
2.46 (2H, C12-H2/C16-H2), 2.87 (1H, ddd, JH
= 12.6 Hz,
–H
c
–H
c
3JH
= 6.3 Hz, 3JH
= 4.2 Hz, Hc), 3.08 (1H, bdt, 2JH
=
–H
–H
c
d
c
a
b
3
3
12.92 Hz, JH
= 3.6 Hz, JH
= 4.0 Hz, Hb), 3.60 (4H,
–H
–H
a
d
t, J = 4.6 Hzb, C13-H2, C15-H2)b, 3.66 (1H, m, Hd), 5.12 (2H,
d, J = 16.2 Hz, PhCH2), 5.30 (2H, d, J = 14.4 Hz, PhCH2),
7.17–7.77 (15H, m, 3 × Ph); dC(75.4 MHz, CDCl3, Me4Si): 44.3
(−ve, PhCH2), 48.6 (−ve, PhCH2), 49.6 (−ve, C8), 53.3 (−ve,
C12,16), 60.8 (−ve, C10), 64.5 (−ve, C13,15), 66.3 (+ve, C9),
92.9 (C5), 125.9 (+ve, ArCH), 126.4 (+ve, ArCH), 127.0 (+ve,
ArCH), 128.0 (+ve, ArCH), 128.2 (+ve, ArCH), 128.8 (ArC),
129.2 (+ve, ArCH), 129.8 (+ve, ArCH), 133.4 (+ve, ArCH),
−1
=
134.1 (+ve, ArCH), 137.5 (ArC), 140.2 (ArC), 151.4 (C2), 156.5
2
OH, exchanges with D2O), 3.21 (1H, ddd, JH
= 12.6 Hz,
–H
c
+
b
=
(C6), 161.1 (C4), 194.4 (C O); (FAB) m/z 555 (M + 1).
3
3JH
= 6.3 Hz, JH
= 5.7 Hz, Hc), 3.26 (3H, s, NCH3),
–H
–H
a
c
d
c
2
3
3
3.47 (1H, dt, JH
= 12.9 Hz, JH
= 4.2 Hz, J(Hb–Hd)
=
5-Benzoyl-1,3-dibenzyl-6-(2-hydroxy-3-piperidin-1-ylpropyl-
amino)-1H-pyrimidin-2,4-dione (31). According to the
preparation of 27, 31 was obtained from 24 (3.28 g, 5 mmol) as
a yellowish oil. Yield: 2.2 g, 80%; (Found: C, 71.52; H, 6.49; N,
10.12. C33H36−N1 4O4 requires C, 71.73; H, 6.52; N, 10.14%); mmax
–H
–H
a
c
4.2 Hz, Hb), 3.54b(3H, s, CH3), 3.64 (b4H, m, C13-H2, C15-H2),
3.91 (1H, m, Hd), 7.37–7.54 (5H, m, Ph), 9.50 (1H, t, J =
4.5 Hz, Ha); dC(75.4 MHz, CDCl3, Me4Si): 28.1 (+ve, NCH3),
34.8 (+ve, NCH3), 50.3 (−ve, C8), 53.6 (−ve, C12,16), 61.1
(−ve, C10), 65.4 (+ve, C9), 66.7 (−ve, C13,15), 94.4 (C5), 127.7
(+ve, ArCH), 127.9 (+ve, ArCH), 131.1 (+ve, ArCH), 141.5
=
(CHCl3)/cm : 3330 (NH), 1640 (C O); dH(300 MHz, CDCl3,
Me4Si): 1.49 (2H, m, C14-H2), 1.67 (4H, m, C13-H2, C15-H2),
1
13
=
(ArC), 151.7 (C2), 160.6 (C6), 161.4 (C4), 195.8 (C O); H– C
HETCOR: The two multiplets at d 2.33 and 2.58 correspond to
the carbon signal at d 53.6. The 2H multiplet at d 2.34 belongs
2.18 (2H, m, C12-H2/C16-H2), 2.69 (2H, m, C12-H2/C16-H2),
2
2.70 (2H, d, J = 6.8 Hz, C10-H2), 3.01 (1H, ddd, JH
=
–H
c
b
12.3 Hz, 3JH
= 7.4 Hz, 3JH
= 3.8 Hz, Hc), 3.14 (1H, ddd,
–H
–H
a
c
d
c
3 9 6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5

View Article Online
2JH
= 12.3 Hz, 3JH
= 4.2 Hz, 3JH
= 4.2 Hz, Hb), 3.96
ArCH), 128.5 (+ve, ArCH), 141.9 (ArC), 151.4 (C2), 161.7
–H
–H
–H
a
b
c
d
(1H, m, Hd), 5.06 (2H,bd, J = 14.8 Hz, PhCH2), 5.17 (2H, d, J =
16.2 Hz, PhCH2), 7.11–7.52 (15H, m, 3 × Ph); dC(75.4 MHz,
CDCl3, Me4Si): 22.6 (−ve, C14), 23.8 (−ve, C13,15), 44.0 (−ve,
PhCH2), 45.2 (−ve, PhCH2), 46.2 (−ve, C8), 54.5 (−ve, C12,16),
60.6 (−ve, C10), 63.1 (+ve, C9), 93.2 (C5), 125.9 (+ve, ArCH),
126.9 (+ve, ArCH), 127.6 (+ve, ArCH), 128.3 (+ve, ArCH),
128.5 (+ve, ArCH), 128.8 (ArC), 129.2 (+ve, ArCH), 130.9
(+ve, ArCH), 133.4 (+ve, ArCH), 137.5 (ArC), 144.5 (ArC),
(C4), 162.7 (C6), 200.4 (C O); m/z (FAB) 431 (M + 1).
b
+
=
Acknowledgements
We thank CSIR (New Delhi) and DST (New Delhi) for financial
assistance. DST (New Delhi) is also acknowledged for the FIST
programme. Thanks are due to CDRI (Lukhnow) for running
the mass spectra and elemental analysis. The authors are highly
thankful to Prof. Subodh Kumar (Guru Nanak Dev University)
for fruitful discussions on this topic.
=
151.1 (C2), 155.0 (C6), 157.1 (C4), 194.2 (C O); m/z (FAB)
553 (M+ + 1).
5-Benzoyl-1,3-dibenzyl-6-(2-hydroxy-3-pyrrolidin-1-yl-propyl-
amino)-1H-pyrimidin-2,4-dione (32). According to the
preparation of 27, 32 was obtained from 25 (3.16 g, 5 mmol) as
a yellowish oil. Yield: 2.02 g, 75%; (Found: C, 71.32; H, 6.32; N,
10.38. C32H34−N1 4O4 requires C, 71.37; H, 6.31; N, 10.40%); mmax
References
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385–415.
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=
(CHCl3)/cm : 3231 (NH), 1652 (C O); dH(300 MHz, CDCl3,
Me4Si): 1.93 (4H, m, C13-H2, C14-H2), 2.67 (2H, dd, 2J =
3
7.0 Hz, J = 3.8 Hz, C10-H2), 2.81 (2H, m, C12-H2/C15-H2),
2.90 (2H, m, C12-H2/C15-H2), 3.13 (2H, dd, 2J = 8.0 Hz, 3J =
4.2 Hz, C8-H2), 4.11 (1H, m, Hd), 5.23 (2H, d, J = 15.9 Hz,
PhCH2), 5.52 (2H, d, J = 14.1 Hz, PhCH2), 7.19–7.72 (15H, m,
3 × Ph): dC(75.4 MHz, CDCl3, Me4Si): 24.0 (−ve, C13,14), 44.1
(−ve, PhCH2), 45.4 (−ve, C8), 45.9 (−ve, PhCH2), 56.5 (−ve,
C12,15), 59.9 (−ve, C10), 62.8 (+ve, C9), 93.6 (C5), 126.2 (+ve,
ArCH), 126.8 (+ve, ArCH), 127.2 (+ve, ArCH), 127.7 (+ve,
ArCH), 127.9 (+ve, ArCH), 128.0 (+ve, ArCH), 128.3 (+ve,
ArCH), 128.5 (ArC), 128.8 (+ve, ArCH), 135.4 (ArC), 137.5
7 P. Chiba, S. Burghofer, E. Richter, B. Tell, A. Moser and G. Ecker,
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589–596.
=
(ArC), 152.2 (C2), 153.8 (C6), 158.2 (C4), 194.8 (C O); m/z
(FAB) 539 (M+ + 1).
11 G. Ecker, M. Huber, D. Schmid and P. Chiba, Mol. Pharmacol., 1999,
6-(2-Hydroxy-3-morpholin-4-ylpropylamino)-1,3-dimethyl-5-
(3-phenylpropionyl)-1H-pyrimidin-2,4-dione (33). According
to the preparation of 27, 33 was obtained from 26 (2.81 g,
5 mmol) as a yellowish oil. Yield: 1.55 g, 72%; (Found: C,
56, 791–796.
12 D. Annibali, G. Ecker, W. Fleishhacker, T. Helml, W. Holzer and
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41, 4001–4011.
61.35; H, 6.87; N, 13.01. C22H30N4O5 requires C, 61.39; H,
−1
=
6.97; N, 13.02%); mmax (CHCl3)/cm : 3313 (NH), 1680 (C O);
14 T.-L. Su and K. A. Watanabe, J. Heterocycl. Chem., 1984, 21, 1543–
2
3
dH(300 MHz, CDCl3, Me4Si): 2.53 (2H, dd, J = 8.1 Hz, J =
3.0 Hz, C10-H2), 2.64 (2H, m, C12-H2/C16-H2), 2.77 (2H, m,
C12-H2/C16-H2), 2.95 (2H, t, J = 7.4 Hz, CH2), 3.32 (3H, s,
NCH3), 3.33 (1H, merged with NCH3, Hc), 3.42 (2H, t, J =
1547.
15 A. C. Mclean and F. S. Spring, J. Chem. Soc., 1949, 2582–2585.
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and L. Goldman, J. Am. Chem. Soc., 1946, 68, 1291–1293.
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1259.
2
7.4 Hz, CH2), 3.48 (3H, s, NCH3), 3.53 (1H, dt, J = 12.6 Hz,
3J = 4.2 Hz, 3J = 3.9 Hz, Hb), 3.80 (4H, m, C13-H2, C15-H2),
4.02 (1H, m, Hd), 7.16–7.25 (5H, m, Ph), 11.77 (1H, t, J =
4.2 Hz, NHa); dC(75.4 MHz, CDCl3, Me4Si): 28.1 (+ve, NCH3),
30.9 (−ve, CH2), 36.4 (+ve, NCH3), 44.6 (−ve, CH2), 50.5
(−ve, C8), 53.7 (−ve, C12,16), 61.4 (−ve, C10), 65.5 (+ve, C9),
66.0 (−ve, C13,15), 94.9 (C5), 125.7 (+ve, ArCH), 128.2 (+ve,
19 The energy minimizations and theoretical predictions of MDR
modulating properties were performed using the BioMed CaChe
Worksystem Pro 6.1 molecular modeling software.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 5 8 – 3 9 6 5
3 9 6 5