2,4,6-Trisubstituted pyrimidine derivatives as pregnancy interceptive agents

Article abstract of DOI:10.1016/j.bmc.2005.01.020

A series of 2,4,6-trisubstituted pyrimidine derivatives was synthesized and evaluated for their in vivo pregnancy interceptive activity in hamsters. Out of the 17 compounds synthesized three compounds showed 100% activity at a dose of 10 mg/kg.

Full text of DOI:10.1016/j.bmc.2005.01.020

Bioorganic & Medicinal Chemistry 13 (2005) 1893–1899
2,4,6-Trisubstituted pyrimidine derivatives
as pregnancy interceptive agents
Anu Agarwal,a Brijesh Kumar,b Purshottam K. Mehrotrac and Prem M. S. Chauhana,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow, India
bSophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow, India
cDivision of Endocrinology, Central Drug Research Institute, Lucknow, India
Received 7 December 2004; revised 14 January 2005; accepted 14 January 2005
Available online 2 February 2005
Abstract—A series of 2,4,6-trisubstituted pyrimidine derivatives was synthesized and evaluated for their in vivo pregnancy intercep-
tive activity in hamsters. Out of the 17 compounds synthesized three compounds showed 100% activity at a dose of 10 mg/kg.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
triazoles, isoquinolines and tetrahydro pyridines had
been earlier evaluated as pregnancy interceptive
agents.3–10
Interest in the development of non-steroidal post coital
or morning after pills dates back to early sixties. In
the late 50s the progesterone–estrogen combination pills
with 21 days continuous use in a month were introduced
for birth control. The pregnancy interceptive drugs ap-
pear to manifest its contraceptive action primarily by
producing a synchrony between ovum transport and
uterine preparation for its reception and do not affect
the hypothalamo-pitutary ovarian axis or the embryo.
The logical approach therefore is to develop need based
agents that would not disturb pituitary or ovarian func-
tion but prevent pregnancy by interfering with the pre-
implantation effects. The knowledge that a critical
balance between estrogen and progesterone is essential
for the development of fertilized ovum and preparation
of uterus for implantation is utilized to develop the
envisaged contraceptive. Some others designed and syn-
thesized non-steroidal estrogen antagonists with week
estrogenic activity aimed to prevent pregnancy by dis-
turbing the delicate ratio between estrogen and proges-
terone at the uterine level but without interfering with
their synthesis or peripheral levels.1,2
2. Chemistry
Dihydro-a-ionone 1 was reacted with different aldehydes
(a–n, Fig. 1) in the presence of potassium hydroxide in
methanol to afford the corresponding chalcones 2a–n.
In case of 2o dihydro-a-ionone was refluxed with in-
dole-3-carboxaldehyde in the presence of piperidine in
methanol to afford the chalcone 2o. The chalcones 2a–
o were further cyclized with guanidine hydrochloride
in the presence of sodium isopropoxide (synthesized in
situ by adding sodium metal in isopropanol) to afford
the 2,4,6-trisubstituted pyrimidines 3a–o as shown in
(Scheme 1). Compound 3a was further reacted
with 1-(2-chloro-ethyl)-pyrrolidine and 1-(2-chloro-
ethyl)-piperidine in the presence of potassium carbonate
and tetra butyl ammonium iodide to afford 4a and 4b
respectively (Scheme 2). The substitution took place
only at the phenolic hydroxyl and not at the amino
group (amino group is less basic due to the pyrimidine
ring).
Based on this concept a variety of heterocyclic molecules
such as thiazoles, oxadiazoles, pyrazoles, isoxazoles,
3. Biological activity
Keywords: Pregnancy interceptive; Pyrimidines; a-Ionone.
Syrian golden hamsters of the instituteÕs animal colony
weighing 85–120 g were used. Animals were maintained
in air-conditioned quarters at 21 2 °C and 60–70%
*
Corresponding author. Tel.: +91 522 2212411–18x4332; fax: +91
522 2623405; e-mail addresses: prem-chauhan-2000@yahoo.com;
premsc58@hotmail.com
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.01.020

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A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
Table 1. Pregnancy interceptive activity in hamsters by subcutaneous
route
R
O
O
N
a
R
b
N
Compd no
Dose
Activity (%)
NH2
3a
3b
3c
3d
3e
3f
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
100
100
100
50
0
1
2 (a-o)
3 (a-o)
Scheme 1. Reagents and conditions: (a) for 2a–n different aldehydes,
KOH, methanol, 0 °C–rt, 12 h. For 2o: indole-3-carboxaldehyde,
piperidine, methanol, reflux, 12 h. (b) Guanidine hydrochloride,
sodium isopropoxide, isopropanol, reflux, 8 h.
50
0
3g
3h
3i
30
50
40
0
R
3j
3k
3l
i
j
a
OH
Me
Me
0
3m
3n
3o
4a
4b
0
0
OMe
OMe
50
50
50
b
c
Me
k
NMe2
OMe
adding olive oil to them and then the ethanol was evap-
orated on a water bath. Mated females were injected (sc)
with compounds in respective dosage on days 4–8 post-
coitum (pc) and autopsied on day 12pc. The numbers of
implantations, resorbing foetuses and or endometrial
scars were recorded. Potentiality percentage was calcu-
lated by dividing the number of animals showing resorb-
ing foetuses, dead foetuses or endometrial scars against
the animals showing normal/live embryos. Animals with
no sign of implantation or having apparently normal
looking uteri and the absence of corpora lutea were
not included. Activity of all tested compounds is shown
in Table 1.
O
O
d
e
l
S
N
OMe
m
CH3
Br
OMe
n
o
f
N
CH3
MeO
g
h
N
H
OCH2Ph
4. Results and discussion
Figure 1.
The present study has furnished a new lead as it is evi-
dent from the pregnancy interceptive activity of com-
pounds. The structures of the active compounds
indicate that the environment around the phenyl ring
governs the ability of the compounds to evoke biore-
sponse. When the R group was 4-hydroxy phenyl the
compound 3a showed 100% activity in hamsters. On
substituting the hydroxy group with methoxy group
(3b) the activity was retained. On introduction of one
more methoxy group at the 3-position (3c) it again
showed 100% activity. When the R group was piperonal
(3d) having two oxygen atoms similar to 3,4-dimethoxy
phenyl 3c the activity reduced to 50%. These results indi-
cate the importance of oxygen atom with flexible groups
in the molecule. When 2-ethyl pyrrolidine (4a) and 2-
ethyl piperidine (4b) was attached to the oxygen atom
at 4-position activity reduced to 50%. These results indi-
cate the importance of oxygen atom with limited bulk at
the 4-position of the phenyl ring. With R having 4-meth-
oxy naphthalene (3e) the activity reduced to 0% due to
the steric bulk. With R as 3-methoxy phenyl (3f) the
activity reduced to 50% and when the phenyl ring had
methoxy group at 2-position (3g) the activity diminished
completely. These results emphasize the importance of
methoxy group at 4-position. When the methoxy group
O
N
n
N
a
3a
N
4a: n = 0
4b: n = 1
NH2
Scheme 2. Reagents and conditions: (a) 1-(2-chloro-ethyl)-pyrrolidine
or 1-(2-chloro-ethyl)-piperidine K2CO3, tetrabutylammonium iodide,
acetone, reflux, 5 h.
humidity, with a regulated photoperiod (14 h light, 10 h
dark) and uniform husbandry conditions were used.
They were provided pelleted diet (Lipton India Ltd)
and ad lib. tap water. The guidelines for care and use
of animals approved by the institute were strictly fol-
lowed. Regularly cyclic females in the proestrus stage
were mated with coeval males (3:1 ratio) of respective
species in sterile plastic cages overnight. The presence
of spermatozoa in the vaginal smear on the following
morning was considered as day 1 of gestration. For test-
ing pregnancy interceptive efficacy the compounds were
administered to mated hamsters on days 4–8 postcoi-
tum. Compounds were administered subcutaneously
(sc) by initially solubilizing them in 100% ethanol and

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
1895
in 3f was substituted with 3-benzyloxy (3h) group the
activity reduced to 30%. These results indicate the
importance of steric bulk. When R was 4-methyl phenyl
(3i) the activity was 50% but when another methyl group
was introduced at 3-position (3j) the activity reduced to
40%. When the R group was 3-thiophene (3l) it did not
showed any activity. When the R group was indole (3o)
it showed a activity of 50%, but when it was N-methyl
indole (3m) and N-methyl-5-bromo-indole (3n) the
activity diminished completely. These results emphasize
the importance of free indolic NH in the molecule.
6.94 (d, 2H, J = 8.1 Hz), 6.68 (d, 1H, J = 15.8 Hz),
5.31 (t, 1H, J = 4.1 Hz), 2.69 (t, 2H, J = 5.2 Hz), 1.99–
2.01 (m, 2H), 1.82–1.86 (m, 1H), 1.76 (s, 3H), 1.67–
1.71 (m, 2H), 1.55–1.59 (m, 2H), 0.99 (s, 3H), 0.87
(s, 3H). 13C (CDCl3, 50 MHz): 201.2, 154.1, 148.8,
143.2, 135.9, 130.2, 122.2, 122.1, 121.7, 113.5, 49.4,
41.1, 36.7, 31.8, 28.2, 26.3, 24.4, 24.1, 23.7.
6.1.2. 1-(4-Methoxy-phenyl)-5-(2,6,6-trimethyl-cyclohex-
2-enyl)-pent-1-en-3-one. Viscous oil (2b), yield 92%; MS
313 (M+1); IR (KBr) 3420, 3212, 2932, 1712, 1484,
1
1280 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.53
(d, 1H, J = 16.2 Hz), 7.47 (d, 2H, J = 8.2 Hz), 6.91 (d,
2H, J = 8.2 Hz), 6.65 (d, 1H, J = 16.2 Hz), 5.38 (t, 1H,
J = 4.6 Hz), 3.84 (s, 3H, OCH3), 2.67 (t, 2H), 1.99 (m,
2H), 1.85 (m, 1H), 1.75 (s, 3H), 1.71 (m, 2H), 1.56 (m,
2H), 0.99 (s, 3H), 0.86 (s, 3H). 13C (CDCl3, 50 MHz):
200.9, 156.3, 149.5, 143.4, 136.3, 130.4, 122.5, 122.1,
121.8, 113.4, 56.6, 49.2, 41.2, 36.7, 31.9, 28.1, 26.4,
24.37, 24.1, 23.8.
5. Conclusion
Out of the 17 synthesized, 2,4,6-trisubstituted pyrimi-
dines, three compounds showed 100% activity at
10 mg/kg and six compounds showed 50% activity at
10 mg/kg. The compounds showed a good structure–
activity relationship. These results suggest that struc-
tural modification in these compounds at the R position
help the molecule to reach the uterus and show the activ-
ity. These findings are significant because the search for
new chemical structures for the development of a once a
month contraceptive is highly desirable.
6.1.3. 1-(3,4-Dimethoxy-phenyl)-5-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-pent-1-en-3-one. Viscous oil (2c), yield: 79%;
MS 343 (M+1); IR (KBr) 3452, 3218, 2926, 1711, 1476,
1
1268 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.58
(d, 1H, J = 15.8 Hz), 7.48 (s, 1H), 7.36 (d, 1H,
J = 8.4 Hz), 6.78 (d, 1H, J = 8.4 Hz), 6.56 (d, 1H,
J = 15.8 Hz), 5.33 (t, 1H, J = 4.1 Hz), 3.97 (s, 3H,
OMe), 3.92 (s, 3H, OMe), 2.71 (t, 2H, J = 5.4 Hz),
1.98–2.01 (m, 2H), 1.84–1.87 (m, 1H), 1.76 (s, 3H),
1.69–73 (m, 2H), 1.55–1.59 (m, 2H), 0.99 (s, 3H), 0.88
(s, 3H). 13C (CDCl3, 50 MHz): 200.5, 162.4, 161.5, 143.4,
143.1, 129.2, 123.8, 122.5, 121.1, 116.2, 112.1, 56.9,
56.6, 49.2, 40.8, 33.6, 31.9, 30.5, 28.2, 24.5, 24.1, 23.7.
6. Experimental details
IR spectra were recorded on Beckman Aculab-10, Per-
kin Elmer 881 and FTIR 8210 PC, Scimadzu spectro-
photometers either on KBr discs or in neat. Nuclear
magnetic resonance (NMR) spectra were recorded on
either Bruker Avance DRX-300 MHz or Bruker DPX
200 FT spectrometers using TMS as an internal refer-
ence. FAB mass spectra were recorded on JEOL SX
102/DA 6000 mass spectrometer using Argon/Xenon
(6 KV, 10 mA) as the FAB gas. Chemical analysis were
carried out on Carlo-Erba-1108 instrument. The melting
points were recorded on an electrically heated melting
point apparatus and are uncorrected.
6.1.4. 1-Benzo[1,3]dioxo-5-yl-5-(2,6,6-trimethyl-cyclohex-
2-enyl)-pent-1-en-3-one. Viscous oil (2d), yield 81%; MS
327 (M+1); IR (KBr) 3442, 3218, 2936, 1708, 1496,
1
1294 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.84
(d, 1H, J = 17.4 Hz), 7.16 (s, 1H), 7.04 (d, 1H,
J = 8.4 Hz), 6.83 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H,
J = 17.4 Hz), 6.11 (s, 2H), 5.35 (t, 1H, J = 4.2 Hz),
2.67 (t, 2H, J = 5.2 Hz), 1.97–2.01 (m, 2H), 1.83–1.89
(m, 1H), 1.75 (s, 3H), 1.65–1.73 (m, 2H), 1.58–1.64 (m,
2H), 0.98 (s, 3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz):
202.1, 150.2, 148.6, 145.4, 139.8, 136.4, 122.6, 121.8,
121.4, 118.5, 114.2, 94.6, 49.4, 38.7, 33.1, 31.9, 30.5,
28.0, 24.5, 24.0, 23.5.
6.1. General procedure for the synthesis of compounds 2a–n
To a solution of dihydro-a-ionone 1 (1 equiv) in 50 mL
of methanol or ethanol was added potassium hydroxide
(1.5 equiv) in 5 mL of water over a period of 30 min at
0 °C–rt. Then the corresponding aldehyde (1.1 equiv)
was added slowly to the reaction mixture. The reaction
mixture was stirred at room temperature for 12 h. The
solvent was removed from the reaction mixture under
reduced pressure. Water was added and the aqueous
phase was extracted with ethyl acetate. The organic
phases were dried over anhydrous Na2SO4, filtered
and concentrated. The crude product was purified by
flash chromatography on silica gel (hexane/ethyl acetate
90:10) to afford the pure compound.
6.1.5. 1-(4-Methoxy-naphthalen-1-yl)-5-(2,6,6-trimethyl-
cyclohex-2-enyl)-pent-1-en-3-one. Viscous oil (2e), yield
85%; MS 363 (M+1); IR (KBr) 3452, 3218, 2936, 1711,
1
1486, 1268 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm)
8.12 (dd, 1H, J = 7.6, 2.5 Hz), 7.94 (dd, 1H, J = 7.4,
2.8 Hz), 7.56 (d, 1H, J = 16.2 Hz), 7.26–7.30 (m, 3H),
6.64 (d, 1H, J = 8.2 Hz), 6.54 (d, 1H, J = 15.6 Hz), 5.32
(t, 1H, J = 4.2 Hz), 4.02 (s, 3H, 3OMe), 2.71 (t, 2H,
J = 5.2 Hz), 1.98–2.01 (m, 2H), 1.84–1.89 (m, 1H), 1.77
(s, 3H), 1.64–1.70 (m, 2H), 1.58–1.62 (m, 2H), 0.99 (s,
3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz): 200.8, 156.8,
143.8, 136.4, 132.1, 129.7, 128.2, 127.5, 126.3, 125.7,
125.6, 122.8, 121.7, 121.1, 111.5, 56.5, 49.3, 42.1, 38.6,
33.1, 31.9, 30.6, 28.1, 24.1, 23.5.
6.1.1. 1-(4-Hydroxy-phenyl)-5-(2,6,6-trimethyl-cyclohex-
2-enyl)-pent-1-en-3-one. Viscous oil (2a), yield: 76%; MS
298 (M+1); IR (KBr) 3426, 3214, 2938, 1708,
1
1476, 1274 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm)
7.86 (d, 2H, J = 8.1 Hz), 7.56 (d, 1H, J = 15.8 Hz),

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A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
6.1.6. 1-(3-Methoxy-phenyl)-5-(2,6,6-trimethyl-cyclohex-
2-enyl)-pent-1-en-3-one. Viscous oil (2f), yield 89%; MS
313 (M+1); IR (KBr) 3442, 3218, 2936, 1708, 1496,
5.32 (t, 1H, J = 4.1 Hz), 2.71 (t, 2H, J = 5.2 Hz), 1.98–
2.01 (m, 2H), 1.85–1.89 (m, 1H), 1.76 (s, 3H), 1.66–
1.74 (m, 2H), 1.58–1.64 (m, 2H), 0.99 (s, 3H), 0.87 (s,
3H). 13C (CDCl3, 50 MHz): 200.1, 144.6, 140.2, 138.5,
136.4, 135.2, 130.4, 128.6, 124.9, 121.4, 121.1, 49.5,
38.7, 33.2, 31.9, 30.6, 28.1, 25.2, 24.1, 23.4, 20.3, 20.1.
1
1294 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.58
(d, 1H, J = 16.1 Hz), 7.38 (s, 1H), 7.31 (d, 1H,
J = 8.3 Hz), 7.15 (dd, 1H, J = 7.2, 2.6 Hz), 6.98 (d, 1H,
J = 8.4 Hz), 6.76 (d, 1H, J = 16.1 Hz), 5.36 (t, 1H, J =
4.4 Hz), 2.69 (t, 2H, J = 4.6 Hz), 1.97–2.0 (m, 2H),
1.82–1.84 (m, 1H), 1.74 (s, 3H), 1.66–1.68 (m, 2H),
1.53–1.57 (m, 2H), 0.99 (s, 3H), 0.88 (s, 3H). 13C
(CDCl3, 50 MHz): 201.1, 159.18, 143.4, 139.2, 137.26,
130.2, 122.1, 121.4, 119.1, 116.1, 115.1, 49.12, 41.1,
36.9, 31.6, 28.1, 26.9, 24.4, 24.1, 23.8.
6.1.11. 1-(4-Dimethylamino-phenyl)-5-(2,6,6-trimethyl-
cyclohex-2-enyl)-pent-1-en-3-one. Viscous oil (2k), yield
75%; MS 326 (M+1); IR (KBr) 3445, 3215, 2924, 1709,
1484, 1264 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d
(ppm) 7.53 (d, 1H, J = 15.6 Hz), 7.45 (d, 2H,
J = 8.3 Hz), 6.69 (d, 2H, J = 8.3 Hz), 6.54 (d, 1H,
J = 15.6 Hz), 5.39 (t, 1H, J = 4.6 Hz), 3.02 (s, 6H,
NMe2), 2.65 (t, 2H, J = 4.5 Hz), 1.98–2.01 (m, 2H),
1.84 (m, 1H), 1.76 (s, 3H), 1.74 (m, 2H), 1.54 (m, 2H),
0.98 (s, 3H), 0.86 (s, 3H). 13C (CDCl3, 50 MHz):
200.9, 152.28, 143.6, 136.26, 130.42, 122.54, 121.8,
121.22, 112.25, 48.88, 40.43, 40.99, 36.77, 31.5, 28.02,
26.82, 24.39, 24.06, 23.87.
6.1.7. 1-(2-Methoxy-phenyl)-5-(2,6,6-trimethyl-cyclohex-
2-enyl)-pent-1-en-3-one. Viscous oil (2g), yield 88%; MS
313 (M+1); IR (KBr) 3442, 3218, 2936, 1708, 1496,
1
1294 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.61
(d, 1H, J = 16.2 Hz), 7.56 (d, 1H, J = 8.2 Hz), 7.16
(dd, 1H, J = 7.4, 2.6 Hz), 6.96 (d, 1H, J = 8.4 Hz), 6.86
(dd, 1H, J = 7.6, 2.8 Hz), 6.75 (d, 1H, J = 16.2 Hz),
5.35 (t, 1H, J = 4.2 Hz), 3.84 (s, 3H, 3OMe), 2.70 (t,
2H, J = 5.1 Hz), 1.98–2.01 (m, 2H), 1.82–1.88 (m, 1H),
1.76 (s, 3H), 1.64–1.74 (m, 2H), 1.54–1.59 (m, 2H),
0.98 (s, 3H), 0.89 (s, 3H). 13C (CDCl3, 50 MHz):
201.4, 159.2, 143.6, 139.4, 137.3, 130.4, 122.4, 121.2,
119.2, 116.4, 115.2, 49.2, 41.1, 36.8, 31.5, 28.2, 26.9,
24.5, 24.1, 23.8.
6.1.12. 1-Thiophen-2-yl-5-(2,6,6-trimethyl-cyclohex-2-
enyl)-pent-1-en-3-one. Viscous oil (2l), yield 74% (2l)
MS 289 (M+1); IR (KBr) 3441, 3208, 2928, 1714, 1486,
1
1252 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.78
(s, 1H), 7.52 (d, 1H, J = 15.6 Hz), 7.46 (s, 1H,
J = 4.2 Hz), 7.26 (d, 1H, J = 4.2 Hz), 6.54 (d, 1H,
J = 15.6 Hz), 5.32 (t, 1H, J = 4.1 Hz), 2.70 (t, 2H,
J = 5.4 Hz), 1.98–2.03 (m, 2H), 1.85–1.9 (m, 1H), 1.77
(s, 3H), 1.66–1.72 (m, 2H), 1.58–1.62 (m, 2H), 0.98 (s,
3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz): 200.2, 143.2,
140.6, 135.8, 126.5, 126.1, 125.6, 121.3, 120.8, 49.3,
38.6, 33.1, 31.9, 30.5, 28.0, 24.4, 24.0, 23.4.
6.1.8. 1-(3-Benzyloxy-phenyl)-5-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-pent-1-en-3-one. Viscous oil (2h), yield 78%;
(2h) MS 389 (M+1); IR (KBr) 3448, 3212, 2926, 1712,
1484, 1262 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d
(ppm) 7.56 (d, 1H, J = 15.8 Hz), 7.48 (s, 1H), 7.42 (d,
1H, J = 8.6 Hz), 7.26–7.34 (m, 6H), 6.94 (d, 1H,
J = 8.5 Hz), 6.58 (d, 1H, J = 15.8 Hz), 5.34 (t, 2H,
J = 4.2 Hz), 5.16 (s, 2H, OCH2), 2.70 (t, 2H,
J = 5.6 Hz), 1.98–2.02 (m, 2H), 1.84–1.88 (m, 1H), 1.75
(s, 3H), 1.65–1.72 (m, 2H), 1.58–1.64 (m, 2H), 0.99 (s,
3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz): 200.4, 158.2,
144.2, 139.7, 136.6, 136.1, 128.8, 128.4, 128.2, 127.7,
121.2, 120.8, 120.1, 117.4, 113.7, 70.7, 49.4, 38.7, 33.1,
31.9, 30.5, 28.0, 24.5, 24.0, 23.5.
6.1.13. 1-(1-Methyl-1H-indol-2-yl)-5-(2,6,6-trimethyl-
cyclohex-2-enyl)-pent-1-en-3-one. Viscous solid (2m),
yield 87%; MS 336 (M+1); IR (KBr) 3452, 3218, 2936,
1
1711, 1486, 1268 cmÀ1; H NMR (CDCl3, 200 MHz) d
(ppm) 7.93 (d, 1H, J = 8.6 Hz), 7.78 (d, 1H,
J = 16.1 Hz), 7.36 (s, 1H), 7.33 (d, 1H, J = 8.5 Hz),
7.28–7.32 (m, 2H), 6.79 (d, 1H, J = 16.1 Hz), 5.35 (t,
2H, J = 4.2 Hz), 3.79 (s, 3H, NCH3), 2.72 (t, 2H,
J = 5.2 Hz), 1.98–2.01 (m, 2H), 1.84–1.89 (m, 1H), 1.77
(s, 3H), 1.65–1.75 (m, 2H), 1.56–1.61 (m, 2H), 0.99 (s,
3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz): 201.2, 136.8,
136.2, 135.8, 129.9, 125.5, 123.2, 121.8, 121.3, 120.8,
120.1, 112.6, 111.8, 49.3, 41.4, 36.2, 33.1, 32.1, 28.1,
26.2, 24.4, 24.1, 23.4.
6.1.9. 1-p-Tolyl-5-(2,6,6-trimethyl-cyclohex-2-enyl)-pent-
1-en-3-one. Viscous oil (2i), yield 95%; MS 297 (M+1);
1
IR (KBr) 3426, 3206, 2928, 1709, 1486, 1272 cmÀ1; H
NMR (CDCl3, 200 MHz) d (ppm) 7.54 (d, 1H, J =
16.1 Hz), 7.42 (d, 2H, J = 8.2 Hz), 7.18 (d, 2H,
J = 8.2 Hz), 6.64 (d, 1H, J = 16.1 Hz), 5.32 (t, 1H,
J = 4.1 Hz), 2.46 (s, 3H, CH3), 2.68 (t, 2H, J = 5.6 Hz),
1.99–2.01 (m, 2H), 1.82–1.86 (m, 1H), 1.75 (s, 3H),
1.69–1.73 (m, 2H), 1.54–1.58 (m, 2H), 0.99 (s, 3H),
0.87 (s, 3H) 13C (CDCl3, 50 MHz): 200.1, 144.54,
142.4, 136.38, 132.2, 128.5, 124.8, 118.4, 117.2, 49.1,
40.98, 36.4, 31.8, 28.2, 26.3, 24.46, 24.14, 23.81, 20.28.
6.1.14. 1-(5-Bromo-1-methyl-1H-indol-2-yl)-5-(2,6,6-tri-
methyl-cyclohex-2-enyl)-pent-1-en-3-one. Viscous solid
(2n), yield 89%; MS 415 (M+1); IR (KBr) 3452, 3218,
2936, 1711, 1486, 1268 cmÀ1
;
1H NMR (CDCl3,
200 MHz)
d (ppm) 8.38 (s, 1H), 7.78 (d, 1H,
J = 16.1 Hz), 7.65 (s, 1H), 7.32 (d, 1H, J = 8.6 Hz),
7.18 (d, 1H, J = 8.6 Hz), 6.79 (d, 1H, J = 16.1 Hz),
5.32 (t, 2H, J = 4.2 Hz), 3.80 (s, 3H, NCH3), 2.71 (t,
2H, J = 5.4 Hz), 1.97–2.01 (m, 2H), 1.84–1.89 (m, 1H),
1.78 (s, 3H), 1.65–1.74 (m, 2H), 1.56–1.61 (m, 2H),
0.99 (s, 3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz):
201.1, 136.6, 136.3, 135.8, 129.8, 125.5, 123.2, 122.8,
122.1, 121.4, 118.2, 112.5, 111.7, 49.4, 41.4, 36.3, 33.1,
32.2, 28.1, 26.2, 24.4, 24.1, 23.4.
6.1.10. 1-(3,4-Dimethyl-phenyl)-5-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-pent-1-en-3-one. Viscous oil (2j), yield 85%;
MS 311 (M+1); IR (KBr) 3412, 3228, 2928, 1709, 1496,
1
1284 cmÀ1; H NMR (CDCl3, 200 MHz) d (ppm) 7.58
(d, 1H, J = 15.8 Hz), 7.58 (s, 1H), 7.51 (d, 1H, J = 8.2
Hz), 7.04 (d, 1H, J = 8.2 Hz), 6.76 (d, 1H, J = 15.8 Hz),

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
1897
6.2. 1-(1H-Indol-2-yl)-5-(2,6,6-trimethyl-cyclohex-2-
enyl)-pent-1-en-3-one (2o):
2.66 (t, 2H, J = 4.6 Hz), 1.98 (m, 2H), 1.84 (m, 1H),
1.75 (s, 3H), 1.71 (m, 2H), 1.55 (m, 2H), 0.99 (s, 3H),
0.87 (s, 3H); 13C (CDCl3, 50 MHz): 170.1, 169.6,
167.1, 162.6, 143.4, 130.2, 129.2, 122.9, 115.1, 110.4,
56.5, 49.3, 42.1, 33.6, 31.8, 30.6, 28.1, 24.4, 24.1, 23.8.
Anal. Calcd for C22H29N3O: C, 75.18; H, 8.32; N,
11.96. Found: C, 75.12; H, 8.54; N, 11.87.
A solution of dihydro-a-ionone 1 (1.0 equiv), indole-3-
carboxaldehyde (1.1 equiv) and piperidine (1.5 equiv)
was refluxed in 50 mL of methanol or ethanol for
12 h. The solvent was removed from the reaction mix-
ture under reduced pressure. Water was added and the
aqueous phase was extracted with ethyl acetate. The or-
ganic phases were dried over anhydrous Na2SO4, filtered
and concentrated. The crude product was purified by
flash chromatography on silica gel (hexane/ethyl acetate,
60:40) to afford the pure compound.
6.3.3. 4-(3,4-Dimethoxy-phenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-2-enyl)-ethyl]-pyrimidin-2ylamine (3c). White
solid, yield: 62%, mp 109–111 °C; MS 382 (M+1); IR
(KBr) 3445, 3169, 2936, 1647, 1579, 1342, 1245 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.64 (s, 1H), 7.54
(d, 1H, J = 8.6 Hz), 6.93 (d, 1H, J = 8.6 Hz), 6.85 (s,
1H), 5.34 (t, 1H, J = 4.1 Hz), 5.07 (s, 2H, NH2), 3.98 (s,
3H, OMe), 3.94 (s, 3H, OMe), 2.70 (t, 2H, J = 5.2 Hz),
1.98–2.01 (m, 2H), 1.84–1.88 (m, 1H), 1.75 (s, 3H),
1.69–72 (m, 2H), 1.54–1.58 (m, 2H), 0.99 (s, 3H), 0.87
(s, 3H). 13C (CDCl3, 50 MHz): 170.1, 169.6, 167.1,
162.6, 161.7, 143.4, 130.2, 124.2, 122.9, 116.4, 115.1,
110.4, 56.9, 56.5, 49.3, 42.1, 33.6, 31.8, 30.6, 28.1, 24.5,
24.1, 23.8. Anal. Calcd for C23H31N3O2: C, 72.41; H,
8.19; N, 11.01. Found: C, 72.68; H, 8.04; N, 11.22.
Viscous solid, yield 82%; MS 322 (M+1); IR (KBr) 3452,
1
3218, 2936, 1711, 1486, 1268 cmÀ1; H NMR (CDCl3,
200 MHz) d (ppm) 8.76 (s, 1H, NH), 7.92 (d, 1H,
J = 8.7 Hz), 7.82 (d, 1H, J = 16.1 Hz), 7.53 (s, 1H),
7.43 (d, 1H, J = 8.2 Hz), 7.32–7.26 (m, 2H), 6.85 (d,
1H, J = 16.1 Hz), 5.36 (t, 2H, J = 4.1 Hz), 2.71 (t, 2H,
J = 5.2 Hz), 1.97–2.01 (m, 2H), 1.85–1.89 (m, 1H), 1.78
(s, 3H), 1.65–1.75 (m, 2H), 1.57–1.63 (m, 2H), 0.98 (s,
3H), 0.86 (s, 3H). 13C (CDCl3, 50 MHz): 202.1, 137.9,
137.4, 136.2, 130.6, 125.8, 123.8, 122.1, 121.9, 121.4,
120.8, 113.8, 112.6, 49.2, 41.4, 33.1, 32.0, 28.1, 26.1,
24.4, 24.1, 23.5.
6.3.4. 4-Benzo[1,3]dioxo-5-yl-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethyl]-pyrimidin-2-ylamine (3d). White solid,
yield: 60%, mp 126-128 °C; MS 366 (M+1); IR (KBr)
6.3. General procedure for the synthesis of comounds 3a–o
3436, 3168, 2927, 1654, 1552, 1338, 1248 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.39 (s, 1H), 7.26
(d, 1H, J = 8.2 Hz), 7.06 (d, 1H, J = 8.2 Hz), 6.92 (s,
1H), 6.14 (s, 2H), 5.33 (t, 1H, J = 4.1 Hz), 2.69 (t, 2H,
J = 5.2 Hz), 1.98–2.01 (m, 2H), 1.83–1.88 (m, 1H), 1.76
(s, 3H), 1.66–1.74 (m, 2H), 1.58–1.64 (m, 2H), 0.99 (s,
3H), 0.87 (s, 3H). 13C (CDCl3, 50 MHz): 173.4, 169.6,
167.2, 151.6, 149.4, 140.7, 136.8, 123.2, 121.8, 120.2,
115.6, 107.4, 94.8, 49.3, 38.7, 33.2, 31.9, 30.5, 28.0,
24.4, 24.0, 23.5. Anal. Calcd for C22H27N3O2: C, 72.30;
H, 7.45; N, 11.50. Found: C, 72.52; H, 7.28; N, 11.67.
To a solution of 1.1 equiv of guanidine hydrochloride in
50 mL of isopropanol, 1.1 equiv of sodium metal was
added. The reaction mixture was refluxed for 2 h and
then different chalcones (2a–n, 1.0 equiv) were added
to it and refluxed for 8 h. The solvent was removed from
the reaction mixture under reduced pressure. Water was
added and the aqueous phase was extracted with ethyl
acetate. The organic phases were dried over anhydrous
Na2SO4, filtered and concentrated. The crude product
was purified by flash chromatography on silica gel (hex-
ane/ethyl acetate 80:20) to afford the pure compound.
6.3.5. 4-(4-Methoxy-naphthalen-1-yl)-6-[2-(2,6,6-tri-
methyl-cyclohex-2-enyl)-ethyl]-pyrimidin-2ylamine (3e).
6.3.1. 4-{2-Amino-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethyl]-pyrimidin-4-yl}phenol (3a). White solid, yield:
68%, mp 144–146 °C; MS 338 (M+1); IR (KBr) 3454,
White solid, yield: 65%, mp 119–120 °C; MS (M+1); IR
(KBr) 3464, 3179, 2936, 1658, 1574, 1342, 1252 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 8.35 (dd, 1H,
J = 4.4 Hz), 8.20 (dd, 1H, J = 4.5 Hz), 7.56–7.40 (m,
3H), 6.86 (d, 1H, J = 8.2 Hz), 6.73 (s, 1H), 5.33 (t, 1H,
J = 4.2 Hz), 5.26 (s, 2H, NH2), 4.03 (s, 3H, 3OMe),
2.73 (t, 2H, J = 5.1 Hz), 1.97–2.00 (m, 2H), 1.84–1.88
(m, 1H), 1.79 (s, 3H), 1.63–1.70 (m, 2H), 1.57–1.64 (m,
2H), 0.99 (s, 3H), 0.87 (s, 3H). 13C (CDCl3, 50 MHz):
172.8, 168.0, 163.6, 156.9, 136.4, 132.0, 129.7, 128.0,
127.5, 126.2, 125.8, 125.6, 122.7, 121.2, 111.5, 103.6,
56.0, 49.4, 42.1, 38.6, 33.1, 31.9, 30.6, 28.0, 24.0, 23.5.
Anal. Calcd for C26H31N3O: C, 77.77; H, 7.78; N,
10.46. Found: C, 77.86; H, 7.69; N, 10.42.
3162, 2928, 1646, 1578, 1325, 1227 cmÀ1 1H NMR
;
(CDCl3, 200 MHz) d (ppm) 8.06 (d, 2H, J = 8.7 Hz),
7.12 (d, 2H, J = 8.7 Hz), 6.87 (s, 1H), 5.32 (t, 1H,
J = 4.2 Hz), 5.09 (s, 2H, NH2), 2.71 (t, 2H,
J = 4.6 Hz), 1.98–2.01 (m, 2H), 1.83–1.86 (m, 1H), 1.77
(s, 3H), 1.71–1.75 (m, 2H), 1.52–1.58 (m, 2H), 0.98 (s,
3H), 0.86 (s, 3H); 13C (CDCl3, 50 MHz): 170.4, 169.3,
167.2, 157.8, 143.1, 130.6, 129.9, 123.2, 115.6, 108.2,
49.2, 42.1, 33.6, 31.8, 30.6, 28.1, 24.4, 24.1, 23.8. Anal.
Calcd for C21H27N3O: C, 74.74; H, 8.06; N, 12.45.
Found: C, 74.62; H, 8.18; N, 12.62.
6.3.2. 4-(4-Methoxy-phenyl)-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethyl]-pyrimidin-2ylamine (3b). White solid,
yield: 72%, mp 106–108 °C; MS 352 (M+1); IR (KBr)
6.3.6. 4-(3-Methoxy-phenyl)-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethyl]-pyrimidin-2ylamine (3f). Creamish col-
oured solid, yield: 61%, mp 68–70 °C; MS 352 (M+1); IR
3460, 3175, 2931, 1642, 1576, 1336, 1233 cmÀ1
;
1H
(KBr) 3456, 3174, 2926, 1648, 1571, 1348, 1248 cmÀ1
;
NMR (CDCl3, 200 MHz) d (ppm) 7.99 (d, 2H,
J = 8.9 Hz), 7.01 (d, 2H, J = 8.9 Hz), 6.86 (s, 1H), 5.34
(t, 1H, J = 4.8 Hz), 5.04 (s, 2H, NH2), 3.89 (s, 3H),
1H NMR (CDCl3, 200 MHz) d (ppm) 7.58 (s, 1H),
7.50 (d, 1H, J = 8.5 Hz), 7.35 (dd, 1H, J = 7.6, 3.0 Hz),
7.01 (d, 1H, J = 8.5 Hz), 6.87 (s, 1H), 5.34 (t, 1H,

1898
A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
J = 4.7 Hz), 5.21 (s, 2H, NH2), 3.87 (s, 3H, 3OMe), 2.71
(t, 2H, J = 4.9 Hz), 1.98–2.00 (m, 2H), 1.84–1.86 (m,
1H), 1.78 (s, 3H), 1.70–1.74 (m, 2H), 1.55–1.57 (m,
2H), 0.98 (s, 3H), 0.86 (s, 3H). 13C (CDCl3, 50 MHz):
173.3, 165.6, 163.7, 160.4, 139.6, 136.4, 130.1, 121.1,
119.9, 116.6, 112.7, 107.1, 57.2, 50.1, 38.6, 33.1, 31.9,
29.4, 27.8, 24.8, 23.9, 23.6. Anal. Calcd for
C22H29N3O: C, 75.18; H, 8.32; N, 11.96. Found: C,
75.34; H, 8.46; N, 11.77.
1H NMR (CDCl3, 200 MHz) d (ppm) 7.77 (s, 1H),
7.69 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 8.4 Hz), 6.87
(s, 1H), 5.34 (t, 1H, J = 4.6 Hz), 5.02 (s, 2H, NH2),
2.70 (t, 2H, J = 5.3 Hz), 1.97–2.01 (m, 2H), 1.85–1.89
(m, 1H), 1.78 (s, 3H), 1.65–1.75 (m, 2H), 1.57–1.63 (m,
2H), 0.98 (s, 3H), 0.86 (s, 3H). 13C (CDCl3, 50 MHz):
173.2, 165.9, 163.8, 139.6, 137.3, 136.5, 135.7, 130.4,
128.6, 124.9, 121.12, 106.7, 49.5, 38.7, 33.1, 31.9, 30.6,
28.0, 25.3, 24.1, 23.5, 20.3, 20.2. Anal. Calcd for
C23H31N3: C, 79.04; H, 8.94; N, 12.02. Found: C,
79.24; H, 8.79; N, 11.92.
6.3.7. 4-(2-Methoxy-phenyl)-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethyl]-pyrimidin-2ylamine (3g). light yellow
solid, yield: 54%, mp 60–62 °C; MS 352 (M+1); IR
6.3.11. 4-(Dimethylamino-phenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-2-enyl)-ethyl]-pyrimidin-2ylamine (3k). White
solid, yield: 67%, mp 118–120 °C; MS 365 (M+1); IR
(KBr) 3472, 3179, 2938, 1649, 1584, 1346, 1239 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.78 (d, 1H,
J = 8.4 Hz), 7.35 (dd, 1H, J = 7.8, 2.6 Hz), 7.1 (d, 1H,
J = 8.4 Hz), 7.01 (dd, 1H, J = 7.4, 2.8 Hz), 6.96 (s,
1H), 5.33 (t, 1H, J = 4.2 Hz), 5.04 (s, 2H, NH2), 3.86
(s, 3H, 3OMe), 2.70 (t, 2H, J = 5.3 Hz), 1.97–2.00 (m,
2H), 1.86-1.88 (m, 1H), 1.77 (s, 3H), 1.67–1.70 (m,
2H), 1.57–1.59 (m, 2H), 0.99 (s, 3H), 0.88 (s, 3H). 13C
(CDCl3, 50 MHz): 173.5, 165.3, 163.7, 160.5, 139.4,
136.4, 130.4, 121.3, 119.8, 116.6, 112.8, 107.4, 56.2,
49.9, 38.7, 33.4, 31.9, 29.8, 27.8, 24.8, 23.8, 23.7. Anal.
Calcd for C22H29N3O: C, 75.18; H, 8.32; N, 11.96.
Found: C, 75.26; H, 8.44; N, 11.82.
(KBr) 3445, 3169, 2936, 1647, 1579, 1342, 1245 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.64 (d, 2H,
J = 8.4 Hz), 6.75 (d, 2H, J = 8.4 Hz), 6.88 (s, 1H), 5.34
(t, 1H, J = 4.2 Hz), 3.03 (s, 6H, NMe2), 2.71 (t, 2H,
J = 5.2Hz), 1.98–2.01 (m, 2H), 1.84–1.88 (m, 1H), 1.75
(s, 3H), 1.69–72 (m, 2H), 1.54–1.58 (m, 2H), 0.99 (s,
3H), 0.87 (s, 3H). 13C (CDCl3, 50 MHz): 173.2, 165.9,
163.4, 152.5, 136.5, 130.5, 122.6, 121.8, 112.4, 107.4,
49.2, 40.4, 40.9, 36.7, 31.4, 28.1, 26.7, 24.4, 24.1, 23.8.
Anal. Calcd for C23H32N4: C, 75.78; H, 8.85; N, 15.37.
Found: C, 75.82; H, 8.54; N, 15.48.
6.3.8. 4-(3-Benzyloxy-phenyl)-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethyl]-pyrimidin-2-ylamine (3h). White solid,
yield: 59%, mp 96–98 °C; MS 428 (M+1); IR (KBr)
6.3.12. 4-Thiophen-2-yl-6-[2-(2,6,6-trimethyl-cyclohex-2-
enyl)-ethyl]-pyrimidin-2-ylamine (3l). Creamish coloured
solid, yield: 65%, mp 101–102 °C; MS (M+1); IR (KBr)
3442, 3164, 2939, 1648, 1554, 1345, 1236 cmÀ1
;
1H
3442, 3164, 2939, 1648, 1554, 1345, 1236 cmÀ1 1H
;
NMR (CDCl3, 200 MHz) d (ppm) 7.65 (s, 1H), 7.57
(d, 1H, J = 8.4 Hz), 7.31–7.46 (m, 6H), 7.09 (d, 1H,
J = 8.2 Hz), 6.87 (s, 1H), 5.34 (t, 2H, J = 4.1 Hz), 5.14
(s, 2H, OCH2), 5.03 (s, 2H, NH2), 2.71 (t, 2H,
J = 5.4 Hz), 1.99–2.02 (m, 2H), 1.84–1.89 (m, 1H), 1.77
(s, 3H), 1.66–1.74 (m, 2H), 1.57–1.64 (m, 2H), 0.99 (s,
3H), 0.87 (s, 3H). 13C (CDCl3, 50 MHz): 173.4, 165.5,
163.7, 159.6, 139.7, 137.3, 136.4, 130.1, 129.0, 128.4,
127.9, 121.2, 120.2, 117.5, 113.9, 107.1, 70.6, 49.4,
38.7, 33.1, 31.9, 30.5, 28.0, 24.5, 24.0, 23.5. Anal. Calcd
for C28H33N3O: C, 78.65; H, 7.78; N, 9.83. Found: C,
78.78; H, 7.43; N, 9.57.
NMR (CDCl3, 200 MHz) d (ppm) 8.00 (s, 1H), 7.61 (s,
1H, J = 4.2 Hz), 7.38 (d, 1H, J = 4.2Hz), 6.76 (s, 1H),
5.34 (t, 1H, J = 4.2 Hz), 5.21 (s, 2H, NH2), 2.68 (t, 2H,
J = 5.5 Hz), 1.98–2.02 (m, 2H), 1.84–1.89 (m, 1H), 1.76
(s, 3H), 1.66–1.73 (m, 2H), 1.58–1.63 (m, 2H), 0.99 (s,
3H), 0.87 (s, 3H). 13C (CDCl3, 50 MHz): 173.4, 163.7,
161.2, 141.2, 136.4, 126.7, 126.6, 126.3, 121.2, 106.8,
49.3, 38.6, 33.1, 31.9, 30.5, 28.0, 24.4, 24.0, 23.4. Anal.
Calcd for C19H25N3S: C, 69.68; H, 7.69; N, 12.83; S,
9.79. Found: C, 69.84 H, 7.94; N, 12.65; S, 9.86.
6.3.13. 4-(1-Methyl-1H-indol-3-yl)-6-[2-(2,6,6-trimethyl-
cyclohex-2-enyl)-ethyl]-pyrimidin-2-ylamine (3m). White
solid, yield: 68%, mp 130–132 °C; MS 375 (M+1); IR
6.3.9. 4-p-Tolyl-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethyl]-pyrimidin-2ylamine (3i). White solid, yield: 74%,
mp 112–114 °C; MS 336 (M+1); IR (KBr) 3460, 3175,
(KBr) 3442, 3164, 2939, 1648, 1554, 1345, 1236 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 8.35 (d, 1H,
J = 8.6 Hz), 7.77 (s, 1H), 7.37 (d, 1H, J = 8.5Hz),
7.23–7.27 (m, 2H), 6.86 (s, 1H), 5.34 (t, 2H,
J = 4.2 Hz), 4.96 (s, 2H, NH2), 3.84 (s, 3H, N–CH3),
2.69 (t, 2H, J = 5.3 Hz), 1.98–2.01 (m, 2H), 1.84–1.90
(m, 1H), 1.78 (s, 3H), 1.65–1.73 (m, 2H), 1.56–1.64 (m,
2H), 0.98 (s, 3H), 0.88 (s, 3H). 13C (CDCl3, 50 MHz):
172.0, 163.6, 162.9, 138.3, 136.6, 131.3, 126.5, 122.8,
122.0, 121.4, 121.1, 114.5, 110.1, 106.5, 49.4, 38.7,
33.6, 33.1, 31.9, 30.6, 28.1, 24.5, 24.1, 23.5. Anal. Calcd
for C24H30N4: C, 76.97; H, 8.09; N, 14.96. Found: C,
76.68; H, 8.34; N, 14.63.
1
2931, 1642, 1576, 1336, 1233 cmÀ1; H NMR (CDCl3,
200 MHz) d (ppm) 7.56 (d, 2H, J = 8.4 Hz), 7.32 (d,
2H, J = 8.4 Hz), 6.84 (s, 1H), 5.33 (t, 1H, J = 4.2 Hz),
2.48 (s, 3H, CH3), 2.71 (t, 2H, J = 5.4 Hz), 1.98–2.01
(m, 2H), 1.82–1.86 (m, 1H), 1.76 (s, 3H), 1.69–1.72 (m,
2H), 1.54–1.58 (m, 2H), 0.99 (s, 3H), 0.88 (s, 3H). 13C
(CDCl3, 50 MHz): 172.84, 165.86, 163.42, 144.2,
137.67, 133.4, 128.7, 118.5, 117.4, 107.62, 49.2, 40.96,
36.46, 31.82, 28.24, 26.35, 24.46, 24.18, 23.78, 20.24.
Anal. Calcd for C22H29N3: C, 78.76; H, 8.71; N, 12.53.
Found: C, 78.82; H, 8.98; N, 12.64.
6.3.10. 4-(3,4-Dimethyl-phenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-2-enyl)-ethyl]-pyrimidin-2ylamine (3j). White
6.3.14. 4-(5-Bromo-1-methyl-1H-indol-3-yl)-6-[2-(2,6,6-
trimethyl-cyclohex-2-enyl)-ethyl]-pyrimidin-2-ylamine
(3n). White solid, yield: 71%, mp 200–202 °C; MS 454
(M+1); IR (KBr) 3436, 3148, 2928, 1651, 1552, 1354,
solid, yield: 70%, mp 124–125 °C; MS 349 (M+1); IR
(KBr) 3456, 3174, 2932, 1652, 1590, 1352, 1242 cmÀ1
;

A. Agarwal et al. / Bioorg. Med. Chem. 13 (2005) 1893–1899
1899
1
1228 cmÀ1; H NMR (CDCl3, 200 MHz) 8.56 (s, 1H),
2H), 1.57–1.61 (m, 2H), 1.50 (t, 4H, J = 4.1 Hz), 0.98
(s, 3H), 0.87 (s, 3H). 13C: 170.4, 169.3, 167.2, 157.8,
143.1, 130.6, 129.9, 123.2, 115.6, 108.2, 49.2, 42.1,
33.6, 31.8, 30.6, 28.1, 24.4, 24.1, 23.8. Anal. Calcd for
C28H33N3O: C, 74.61; H, 8.81; N, 12.89. Found: C,
74.79; H, 8.62; N, 12.61.
7.71 (s, 1H), 7.38 (d, 1H, J = 8.6 Hz), 7.21 (d, 1H,
J = 8.6 Hz), 6.77 (s, 1H), 5.35 (t, 2H, J = 4.3 Hz), 4.97
(s, 2H, NH2), 3.83 (s, 3H, N–CH3), 2.69 (t, 2H,
J = 5.3 Hz), 1.98–2.01 (m, 2H), 1.84–1.90 (m, 1H), 1.78
(s, 3H), 1.64–1.72 (m, 2H), 1.57–1.64 (m, 2H), 0.99 (s,
3H), 0.89 (s, 3H). 13C (CDCl3, 50 MHz): 172.4, 163.5,
162.8, 138.4, 136.5, 131.4, 126.5, 122.8, 122.4, 122.1,
117.4, 114.4, 110.1, 106.5, 49.4, 38.6, 33.6, 33.1, 31.9,
30.6, 28.1, 24.5, 24.1, 23.5. Anal. Calcd for C24H29BrN4:
C, 63.57; H, 6.45; N, 12.36. Found: C, 63.68; H, 6.58; N,
12.52.
6.4.2. 4-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-6-[2-(2,6,6-
trimethyl-cyclohex-2-enyl)-ethyl]-pyrimidin-2-ylamine
(4b). White solid, yield: 85%, mp 104–106 °C; MS (M+1);
IR (KBr) 3445, 3156, 2928, 1636, 1548, 1342, 1234 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.96 (d, 2H,
J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz), 6.84 (s, 1H), 5.33
(t, 1H, J = 4.2 Hz), 5.17 (s, 2H, NH2), 4.20 (t, 2H,
J = 4.8 Hz), 3.36 (t, 2H, J = 4.8 Hz), 2.82 (t, 2H,
J = 5.6Hz), 2.72 (t, 4H, J = 4.8 Hz), 1.98–2.02 (m, 2H),
1.84–1.89 (m, 1H), 1.77 (s, 3H), 1.66–1.72 (m, 2H),
1.57–1.62 (m, 2H), 1.55 (m, 6H), 0.99 (s, 3H), 0.88 (s,
3H). 13C (CDCl3, 50 MHz): 170.6, 169.4, 167.5, 157.8,
143.2, 130.6, 129.9, 123.3, 115.6, 108.2, 82.6, 65.2,
49.4, 44.5, 42.1, 33.6, 31.8, 30.6, 28.1, 26.2, 25.7, 24.4,
24.1, 23.8. Anal. Calcd for C28H33N3O: C, 74.96; H,
8.99; N, 12.49. Found: C, 74.78; H, 8.68; N, 12.57.
6.3.15. 4-(1H-Indol-2-yl)-6-[2-(2,6,6-trimethyl-cyclohex-
2-enyl)-ethyl]-pyrimidin-2-ylamine (3o). White solid, yield
71%, mp decomposes at 126 °C; MS 361 (M+1); IR (KBr)
3456, 3168, 2938, 1656, 1568, 1338, 1248 cmÀ1; 1H NMR
(CDCl3, 200 MHz) d (ppm) 9.12 (s, 1H, NH), 8.35 (d,
1H, J = 8.7 Hz), 7.83 (s, 1H), 7.40 (d, 1H, J = 8.4 Hz),
7.26–7.21 (m, 2H), 6.87 (s, 1H), 5.33 (t, 2H,
J = 4.0 Hz), 5.14 (s, 2H, NH2), 2.71 (t, 2H, J = 5.4 Hz),
1.98–2.01 (m, 2H), 1.85–1.89 (m, 1H), 1.77 (s, 3H),
1.66–1.75 (m, 2H), 1.54–1.63 (m, 2H), 0.99 (s, 3H), 0.88
(s, 3H). 13C (CDCl3, 50 MHz): 172.1, 163.5, 163.2,
137.4, 136.5, 126.9, 125.8, 123.2, 121.8, 121.7, 121.1,
116.0, 112.1, 106.8, 49.4, 38.6, 33.1, 31.9, 30.6, 28.1,
24.56, 24.0, 23.5. Anal. Calcd for C23H28N4: C, 76.63;
H, 7.83; N, 15.54. Found: C, 76.46; H, 7.64; N, 15.42.
Acknowledgements
A.A. thanks the Council of Scientific and Industrial Re-
search (India) for the award of fellowship. We are also
thankful to S.A.I.F., CDRI, Lucknow for providing
spectroscopic data. Thanks are also due to Mrs. Shakti
Kitchlu for her help in evaluating the biological activity
of compounds. CDRI communication No 6664.
6.4. General procedure for the synthesis of comounds 4a
and b
To a solution of 1.0 equiv of 3a in acetone, 1.2 equiv of
1-(2-chloro-ethyl)-pyrrolidine (for 4a), 2.0 equiv of
K2CO3 and 1.1 equiv of tetrabutyl ammonium iodide
was taken and the reaction mixture was refluxed for a
period of 5h. The reaction mixture was filtered from sin-
tered funnel to filter out K2CO3 and the solvent was re-
moved under reduced pressure. Water was added and
the aqueous phase was extracted with ethyl acetate.
The organic phases were dried over anhydrous Na2SO4,
filtered and concentrated. The crude product was puri-
fied by flash chromatography on silica gel (hexane/ethyl
acetate 70:30) to afford the pure compound.
References and notes
1. Kamboj, V. P.; Ray, S.; Dhawan, B. N. Drugs Today 1992,
28, 227.
2. Singh, M. M. Med. Res. Rev. 2001, 21, 302.
3. Mehrotra, P. K.; Neelima; Bhaduri, A. P.; Kamboj, V. P.
Ind. J. Med. Res. 1986, 83, 614–617.
4. Neelima; Mehrotra, P. K.; Bhaduri, A. P.; Kamboj, V. P.
Ind. J. Med. Res. 1987, 86, 256–259.
5. Singh, M. M.; Mehrotra, P. K.; Agnihotri, A. Contracep-
tion 1987, 36, 239–250.
6. Mukherjee, A.; Akhtar, M. S.; Sharma, V. L. J. Med.
Chem. 1989, 32, 2297–2300.
7. Shukla, R.; Mehrotra, P. K.; Dwivedi, A.; Kamboj, V. P.
Contraception 1992, 45, 605–612.
8. Winters, G.; Oddaso, G.; Conti, M.; Galliani, G. Eur. J.
Med. Chem. 1984, 19, 215–218.
9. Mehrotra, P. K.; Shukla, R.; Dwivedi, A. Contraception
1991, 43, 507–519.
10. Mehrotra, P. K.; Kitchlu, S.; Batra, S. Contraception 2001,
64, 187–191.
6.4.1. 4-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-6-[2-(2,6,6-
trimethyl-cyclohex-2-enyl)-ethyl]-pyrimidin-2-ylamine
(4a). White solid, yield: 82%, mp 98–100 °C; MS (M+1);
IR (KBr) 3448, 3158, 2930, 1648, 1542, 1336, 1238 cmÀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 7.97 (d, 2H,
J = 8.6 Hz), 7.00 (d, 2H, J = 8.6 Hz), 6.84 (s, 1H), 5.29
(t, 1H, J = 4.2 Hz), 5.0 (s, 2H, NH2), 4.22 (t, 2H,
J = 5.1 Hz), 3.12 (t, 2H, J = 5.1 Hz), 2.76 (t, 2H,
J = 5.4 Hz), 2.68 (t, 4H, J = 4.2 Hz), 1.99–2.02 (m,
2H), 1.84–1.89 (m, 1H), 1.75 (s, 3H), 1.66–1.71 (m,