Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: Lead identification and SAR of 3- and 4-substituted derivatives

Article abstract of DOI:10.1021/jm990383f

Through computationally directed broad screening, a novel 1,5- diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC

Full text of DOI:10.1021/jm990383f

1034
J . Med. Chem. 2000, 43, 1034-1040
Novel 1,5-Dip h en ylp yr a zole Non n u cleosid e HIV-1 Rever se Tr a n scr ip ta se
In h ibitor s w ith En h a n ced Activity ver su s th e Dela vir d in e-Resista n t P 236L
Mu ta n t: Lea d Id en tifica tion a n d SAR of 3- a n d 4-Su bstitu ted Der iva tives
Michael J . Genin,*,† Carolyn Biles,† Barb J . Keiser,§ Susan M. Poppe,‡ Steven M. Swaney,‡ W. Gary Tarpley,‡
Yoshihiko Yagi,§ and Donna L. Romero†
Combinatorial and Medicinal Chemistry Research, Infectious Diseases Research, and Discovery Technologies,
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001
Received J uly 26, 1999
Through computationally directed broad screening, a novel 1,5-diphenylpyrazole (DPP) class
of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered.
Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC50 ) 2.3 µM)
and delavirdine-resistant P236L (IC50 ) 1.1 µM) reverse transcriptase (RT). Also, PNU-32945
has an ED50 for inhibition of viral replication in cell cultures of 0.1 µM and was shown to be
noncytotoxic with a CC50 > 10 µM. Structure-activity relationship studies on the 3- and
4-positions of PNU-32945 led to interesting selectivity and activity within the class. In
particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant
(IC50 ) 0.65 µM), whereas it is essentially inactive versus the wild-type enzyme (IC50 > 50
µM). Furthermore, this compound was significantly more active versus the P236L mutant than
delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues
are discussed.
In tr od u ction
The well-known ability of the human immunodefi-
ciency virus (HIV) to efficiently generate resistance to
both protease inhibitors and reverse transcriptase in-
hibitors (RTIs) has compelled researchers in these areas
to develop novel analogues with enhanced activity
against such mutants. The discovery of the bis(het-
eroaryl)piperazine (BHAP) class of nonnucleoside RTIs
at Pharmacia & Upjohn led to the development of
against the P236L mutant revealed three structurally
delavirdine mesylate (1) which is currently being mar-
keted as Rescriptor (delavirdine mesylate tablets) for
the treatment of patients suffering from HIV infection
distinct classes as inhibitors. The alkylaminopiperidine
BHAPs (AAP-BHAP)3 and the pyrimidine thioethers5
have been shown to have very good activity against both
P236L RT in vitro and mutant viral replication in cell
cultures.3,5 The third class, exemplified by the diphen-
ylpyrazole (DPP) PNU-32945, 2, also has activity against
the P236L mutant and thus served as a lead for
structure-activity relationship (SAR) studies.
and AIDS.1 The major reverse transcriptase (RT) mu-
tant selected by serial HIV-1 passage in vitro in the
presence of increasing concentrations of delavirdine
contains a proline-to-leucine substitution at residue 236
of RT (P236L).2 This single mutation confers strong
resistance to delavirdine (P236L IC50 ) 18 µM versus
wild-type (WT) IC50 ) 0.26 µM). Interestingly, the
P236L mutant is sensitized to other nonnucleoside RTIs
such as nevirapine and Merck’s L-697,661.3 Thus, we
were interested in developing new analogues with
enhanced activity versus the P236L mutant. Therefore,
a search for a new class of nonnucleoside RTIs with the
desired activity profile was initiated in order to discover
a novel entity with activity against delavirdine-resistant
virus.
Ch em istr y
On first examination of PNU-32945 we decided to
determine whether the nitrile moiety was critical for
activity. Thus, 1,5-diphenyl-3-methylpyrazole analogues
containing various substituents at the 4-position were
synthesized as outlined in Scheme 1. Several analogues
were prepared by derivatizing the readily available 1,5-
diphenyl-3-methylpyrazole (4), which was prepared as
a single regioisomer in excellent yield by condensing
1-benzoylacetone (3) with phenylhydrazine (Scheme 1).
Vilsmeier formylation6 of 4 provided the aldehyde 5,
which was reduced to the alcohol and alkylated to give
6. In addition, the aldehyde was subjected to a J ones
oxidation7 and Wittig olefination8 to provide the acid
and olefin derivatives 7 and 8, respectively. Also,
bromination of 4 gave high yields of the aryl bromide 9
which readily underwent metal-halogen exchange with
Previously, a computationally directed broad screen
of the Pharmacia & Upjohn chemical repository led to
the discovery of several structurally diverse inhibitors
of the WT RT enzyme.4 Evaluation of these compounds
* To whom correspondence should be addressed. Tel: 616-833-9869.
Fax: 616-833-2516. E-mail: michael.j.genin@am.pnu.com.
† Combinatorial and Medicinal Chemistry Research.
‡ Infectious Diseases Research.
§ Discovery Technologies.
10.1021/jm990383f CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/09/2000

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 1035
Sch em e 1
Sch em e 2
t-BuLi followed by quench with alkyl halides and methyl
isocyanate to afford the alkyl and amide analogues 10-
12. The amide derivative was further converted to the
thioamide 13 with Lawesson’s reagent.9
Scheme 2. Dianion generation by treatment of 24 with
sodamide followed by carbon dioxide quench provided
the labile â-keto acid 25 in good yield.10 This acid could
be quickly converted to the regioisomeric pyrazoles 26
and 27 by treatment with phenylhydrazine in refluxing
methanol in low yields. This mixture was then treated
with LAH to yield the alcohols 28 and 29 which were
separated by chromatography.11 The alcohol 29 was in
turn methylated to provide the ether 30.
Alternatively, treatment of diketo acid 25 with diazo-
methane12 afforded the more stable ester 31 which was
converted to the pyrazole 32. This material was then
transformed into the amide analogues 35 and 36. The
primary carboxamide was further converted to the
nitrile 37 with Lawesson’s reagent.9
Another route to the desired 4-substituted pyrazole
analogues involved functionalization of 1-benzoylacetone
prior to pyrazole ring formation (Scheme 1). Thus,
1-benzoylacetone was deprotonated with cesium carbon-
ate and reacted with various alkyl halides to afford
diketo intermediates that were converted to the desired
pyrazoles as shown. The ester 17 was further converted
to the alcohol 18, acid 19, and primary carboxamide 20
congeners via standard chemistry. Finally, the acetylene
analogue 22 was hydrogenated to afford the 4-propyl
derivative 23.
Since the 4-ethylpyrazole congener 11 retained sig-
nificant activity and selectivity for P236L mutant versus
WT RT (vide infra), this moiety was held constant while
varying the 3-methyl substituent. The 1-ethyl-1-ben-
zoylacetone intermediate 24 was prepared as shown in
Biology
The DPPs prepared above were tested in vitro for
their ability to inhibit WT and P236L RT at three
concentrations, and IC50s were determined for active

1036 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Brief Articles
Ta ble 1. Activitya of Delavirdine Mesylate, 2 (PNU-32945),
Nevirapine, and L-697,661 in Vitro versus WT and Mutant
(P236L) HIV-1 RT
more selective for the P236L enzyme (P236L IC50 ) 0.65
µM versus WT IC50 > 50 µM).
IC50 (µM)
Con clu sion
ED50 (µM) CC50 (µM)
compound
WT P236L PBMC/D34 PBMC/D34
Through broad screening of the Pharmacia & Upjohn
chemical library a novel 1,5-diphenylpyrazole class of
NNRTIs has been discovered with enhanced activity
against delavirdine-resistant P236L RT versus the WT
enzyme. Structure-activity relationship studies on the
3- and 4-positions led to interesting selectivity and
activity within the class. In particular, the 3-hydroxy-
ethyl-4-ethyl congener 29 is a potent inhibitor of P236L
RT, whereas it is essentially inactive versus the WT
enzyme. Furthermore, this compound was significantly
more active versus the P236L mutant than delavirdine.
1 (delavirdine mesylate) 0.26 18.0
2 (PNU-32945)
nevirapine
0.0001
0.1
0.01-0.1
>10
>10
>10
>10
2.31
3.1
0.8
1.14
0.32
L-697,661
0.11 <0.0001
a
Data shown were generated as described previously in ref 3.
analogues as described by us previously.3 The inhibitory
activities of 1,5-diphenyl-3-methylpyrazole analogues
varied at the 4-position are summarized in Table 2. The
majority of these analogues exhibited little or no inhibi-
tory activity versus either RT enzyme. However, the
4-ethyl, 4-propyl, and 4-propargyl congeners 11, 23, and
22 possessed good activity. Furthermore, these ana-
logues exhibit higher selectivity for P236L inhibition
versus WT than the lead PNU-32945. In fact the ethyl
analogue 11 was much more selective for the P236L
mutant (IC50 ) 0.52 µM) than the WT RT (IC50 ) 14.5
µM). The 4-methyl and 4-isopropyl analogues 10 and
21, however, were poorly active versus both enzymes
indicating the importance of size and shape of the
4-substituent. Replacement of the purely aliphatic
moieties with more polar substituents also led to losses
in activity. For example, both amide and thioamide
analogues 12 and 13 were poor RTIs. Likewise, the
methoxymethyl, hydroxyethyl, and carboxylate com-
pounds 6, 18, and 19 lost some or all RT inhibitory
activity.
Exp er im en ta l Section
Gen er a l. Melting points were determined on a Thomas-
Hoover apparatus and are uncorrected. 1H NMR spectra were
recorded on a Bruker AM-300 spectrometer. Chemical shifts
are reported in δ units (ppm) relative to TMS as internal
standard. Mass spectra and combustion analyses were ob-
tained by the Structural, Analytical and Medicinal Chemistry
Department of Pharmacia & Upjohn, Inc. Unless otherwise
indicated all reactions were conducted in commercially avail-
able anhydrous solvents under a nitrogen atmosphere in oven-
dried glassware. Chromatography was carried out on EM
Science 230-400 mesh ASTM silica gel. Elemental analyses
were within (0.4% of calculated values. Biological assays were
performed as described previously in ref 3.
1,5-Diph en yl-3-m eth ylpyr azole (4). Phenylhydrazine (13.3
g, 0.12 mol), 1-benzoylacetone (20 g, 0.12 mol), and NaOAc‚
3H2O (10.1 g, 0.074 mol) were mixed together in EtOH (150
mL) and H2O (75 mL). The reaction was refluxed for 3 h,
concentrated in vacuo, and partitioned between Et2O and H2O.
The aqueous layer was extracted with Et2O and the combined
extracts were washed with 1 N NaOH, brine, and dried (Na2-
SO4). Removal of solvent in vacuo yielded 28.4 g (99%) of an
orange oil that was used without further purification: 1H NMR
(300 MHz, CDCl3) δ 2.55 (s, 3 H), 6.48 (s, 1 H), 7.36-7.49 (m,
10 H); HRMS (EI) calcd for C16H14N2 234.1157, found 234.1150.
Since the 4-ethylpyrazole congener 11 retained sig-
nificant activity, the 4-ethyl moiety was held constant
while the substitution at the 3-position was varied
(Table 3). As was seen above, most of these analogues
lost activity against both enzymes with the noted
exception of the hydroxyethyl analogue 29. This com-
pound had comparable activity to 11, but it was much
Ta ble 2. Inhibitory Activities of 1,5-Diphenyl-3-methylpyrazole Analogues Varied at the 4-Position against WT and Mutant (P236L)
HIV-1 RTa
% inhibition
compound
1 µM
10 µM
P236L
50 µM
P236L
IC50 (µM)
no.
R
WT
37
0
4
P236L
WT
WT
WT
P236L
2
6
7
-CH2CN
-CH2OCH3
-COOH
47
0
0
71
0
0
77
18
1
90
14
1
93
50
4
2.31 ( 0.25
1.14 ( 0.12
8
-CHdCH2
-CH3
-CH2CH3
3.6
0
1-2
5
0
0
0
11
21
0
50
15
0
12
0
0
10
0
42
7
0
0
26
3
81
0
0
8
0
0
8
80
56
18
0
67
3
0
0
3
48
6
72
49
59
36
94
0
0
28
0
29
13
93
71
10
11
12
13
18
19
20
21
22
23
14.5 ( 10.6
0.52 ( 0.06
1.54 ( 0.26
-CONHCH3
-CSNHCH3
-CH2CH2OH
-CH2CO2H
-CH2CONH2
-CH(CH3)2
-propargyl
-CH2CH2CH3
0
36
18
37
31
0
0
14
0
38
4
13.4 ( 6.2
a
Data shown were generated as described previously in ref 3.

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 1037
Ta ble 3. Inhibitory Activities of 1,5-Diphenyl-4-ethylpyrazole Analogues Varied at the 3-Position against WT and Mutant (P236L)
HIV-1 RTa
% inhibition
compound
1 µM
P236L
10 µM
P236L
50 µM
P236L
IC50 (µM)
no.
R
WT
WT
WT
WT
P236L
11
27
29
30
32
33
34
35
-CH3
2
0
0
22
5
1
50
0
58
15
21
6
42
0
18
29
20
3
81
13
84
47
41
8
67
0
42
33
34
7
94
14
95
71
55
12
52
72
14.5 ( 10.6
>50
0.52 ( 0.06
-CH2CO2H
-CH2CH2OH
-CH2CH2OCH3
-CH2CO2CH3
-CH2CONHMe
-CH2CONH2
-CH2CN
0.65 ( 0.10
12
2
16
14
18
15
29
46
39
39
a
Data shown were generated as described previously in ref 3.
Anal. Calcd for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found:
C, 81.52; H, 6.05; N, 11.72.
278.1055, found 278.1071. Anal. Calcd for C17H14N2O2‚H2O:
C, 68.91; H, 5.44; N, 9.45. Found: C, 68.75; H, 4.87; N, 8.94.
1,5-Dip h en yl-3-m et h yl-4-vin ylp yr a zole (8). Methyltri-
phenylphosphonium bromide (0.55 g, 1.52 mmol) was dissolved
in 3 mL of THF and cooled to -20 °C. Then 0.95 mL of
n-butyllithium (1.6 M in hexane, 1.52 mmol) was added and
the reaction was stirred 30 min and then warmed to 0 °C. Then
compound 5 (0.20 g, 0.76 mmol) dissolved in 2 mL of THF was
added and the reaction was stirred 1 h at 0 °C. It was poured
into water, extracted with EtOAc, dried over Na2SO4, filtered
1,5-Dip h en yl-3-m eth yl-4-for m ylp yr a zole (5). Compound
4 (12.2 g, 52.2 mmol) was dissolved in 26 mL of DMF and
heated to 90 °C. Then 10.0 mL of phosphorus oxychloride (65.2
mmol) was added dropwise and stirring was continued for 7
h. The reaction was not complete by TLC, so an additional 26
mL of DMF and 10 mL of phosphorus oxychloride were added
at room temperature. After addition, the reaction was heated
to 90 °C for 2 h and then cooled to 0 °C and quenched by the
cautious addition of ice chips and water. Then 130 mL of 2 N
NaOH was added (to pH 5.5-6.0) and the mixture was
extracted with EtOAc (4×). The organic layers were washed
with water, brine, dried over Na2SO4 and concentrated in
vacuo. Recrystallization from CH3OH afforded 10.15 g (74%)
of the title aldehyde: mp 135-137 °C; 1H NMR (300 MHz,
CDCl3) δ 9.71 (s, 1 H), 7.38-7.28 (m, 3 H), 7.26-7.12 (m, 7
H), 2.56 (s, 3 H). Anal. Calcd for C17H14N2O1: C, 77.84; H, 5.38;
N, 10.68. Found: C, 77.53; H, 5.53; N, 10.77.
1,5-Dip h en yl-3-m eth yl-4-m eth oxym eth ylp yr a zole (6).
Compound 5 (1.0 g, 3.81 mmol) was dissolved in 2 mL of THF
and cooled to 0 °C. Then 1.91 mL of LAH (1.0 M in THF, 1.91
mmol) was added and the reaction was stirred 30 min. Then
the reaction was quenched by the dropwise addition of 0.072
mL of water, 0.072 mL of 10% NaOH, and 0.22 mL of water.
The reaction was filtered through Celite, and concentrated in
vacuo. Purification by flash chromatography (50% EtOAc/
hexane) provided 0.87 g (86%) of the intermediate alcohol. This
material (0.40 g, 1.52 mmol) was dissolved in 7.5 mL of THF
and cooled to 0 °C. Then 0.12 g of NaH (30% dispersion in
mineral oil, 1.54 mmol) was added and the reaction was stirred
15 min. Then iodomethane (0.96 mL, 1.54 mmol) was added
and the reaction was warmed to room temperature for 3 h.
Then it was cooled to 0 °C, quenched by the dropwise addition
of water, and extracted with CHCl3. The organic layers were
dried over Na2SO4, concentrated in vacuo and purified by flash
column chromatography (15% EtOAc/hexane) to afford 0.236
g (56%) of the title pyrazole as an oil: 1H NMR (300 MHz,
CDCl3) δ 7.47 (m, 3 H), 7.36 (m, 7 H), 4.38 (s, 2 H), 3.50 (s, 3
H), 2.56 (s, 3 H). Anal. Calcd for C18H18N2O‚0.1H2O: C, 77.17;
H, 6.55; N, 10.00. Found: C, 77.17; H, 6.43; N, 9.93.
through
a plug of silica gel and concentrated in vacuo.
Purification by flash column chromatography (5% EtOAc/
hexane) provided 0.16 g (82%) of the title pyrazole: mp 111-
1
112 °C; H NMR (300 MHz, CDCl3) δ 7.43 (m, 3 H), 7.32 (m,
7 H), 6.59 (dd, J ) 11.6, 18.0 Hz, 1 H), 5.48 (dd, J ) 1.5, 18.0
Hz, 1 H), 5.23 (dd, J ) 1.5, 11.6 Hz, 1 H), 2.60 (s, 3 H); MS
m/z 260 (M + H). Anal. Calcd for C18H16N2‚0.1H2O: C, 82.48;
H, 6.23; N, 10.69. Found: C, 82.53; H, 6.21; N, 10.61.
1,5-Dip h en yl-3-m eth yl-4-br om op yr a zole (9). Compound
4 (5 g, 21.3 mmol) was dissolved in acetic acid (55 mL) and
cooled in an ice bath. Bromine (4.1 g, 25.6 mmol) was added
dropwise while stirring under N2. After 30 min the reaction
was diluted with 1 N NaOH (100 mL) and extracted with
CHCl3. The extracts were washed with brine and dried (Na2-
SO4). Removal of solvent in vacuo gave a light brown oil which
was homogeneous by TLC and NMR. This material was used
without further purification 6.6 g (99%): 1H NMR (300 MHz,
CDCl3) δ 2.32 (s, 3 H), 7.08-7.42 (m, 10 H).
1,5-Dip h en yl-3,4-d im et h ylp yr a zole (10). Compound 9
(0.5 g, 1.6 mmol) was dissolved in dry THF (5 mL) and cooled
to -78 °C under N2. Then t-BuLi (1.7 M, 1.9 mL, 3.2 mmol)
was added slowly. The reaction was stirred for 10 min after
which time MeI (0.5 mL, 8.0 mmol) was added dropwise.
Stirring was continued at -78 °C for 45 min before the reaction
was allowed to warm to room temperature and quenched with
H2O. The reaction was partitioned between 1 N NaHCO3 and
CHCl3. The organic layer was dried (Na2SO4) and concentrated
in vacuo to a residue which was chromatographed on a 2 × 40
cm column with hexane/Et2O (9:1). The product was isolated
as a colorless oil in a yield of 0.17 g (43%): 1H NMR (300 MHz,
CDCl3) δ 2.04 (s, 3 H), 2.35 (s, 3 H), 7.13-7.36 (m, 10 H);
HRMS calcd for C17H16N2 248.1313, found 248.1320. Anal.
Calcd for C17H16N2: C, 82.23; H, 6.50; N, 11.28. Found: C,
82.32; H, 6.60; N, 11.31.
1,5-Dip h en yl-3-m eth ylp yr a zole-4-ca r boxylic Acid (7).
Compound 5 (0.53 g, 2.0 mmol) was dissolved in 16 mL of
acetone and 5 mL of J ones’ reagent was added. The reaction
was stirred 30 min at room temperature, poured into water,
and extracted with hexane. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in
vacuo to afford 0.53 g (96%) of the title acid: mp 195-200 °C;
1H NMR (300 MHz, CDCl3) δ 7.27 (m, 3 H), 7.20 (m, 5 H),
7.08 (m, 2 H), 2.54 (s, 3 H); HRMS calcd for C17H14N2O2
1,5-Dip h en yl-3-m eth yl-4-eth ylp yr a zole (11). Compound
9 (0.5 g, 1.6 mmol) was dissolved in dry THF (5 mL) and cooled
to -78 °C under N2. Then t-BuLi (1.7 M, 1.9 mL, 3.2 mmol)
was added slowly. The reaction was stirred for 10 min after
which time EtI (0.26 mL, 3.2 mmol) was added dropwise.
Stirring was continued at -78 °C for 45 min and the reaction

1038 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Brief Articles
was allowed to warm to room temperature and quenched with
H2O. The reaction was partitioned between 1 N NaHCO3 and
CHCl3. The organic layer was dried (Na2SO4) and concentrated
in vacuo to an oil which was chromatographed on a 2 × 45 cm
column with hexane/Et2O (9:1). The product was isolated as a
colorless oil in a yield of 0.25 g (60%): 1H NMR (300 MHz,
CDCl3) δ 1.30 (t, J ) 7.6 Hz, 3 H), 2.56 (s, 3 H), 2.66 (q, J )
7.55 Hz, 2 H), 7.32-7.54 (m, 10 H); HRMS calcd for C18H18N2
262.1470, found 262.1477. Anal. Calcd for C18H18N2: C, 82.41;
H, 6.92; N, 10.68. Found: C, 82.01; H, 6.84; N, 10.50.
was removed and the residue partitioned between Et2O and
H2O. The organic layer was dried (Na2SO4) and concentrated
to an oil which was chromatographed on a 4 × 30 cm column
with EtOAc/hexane (1:3). The product was isolated as a
1
colorless oil: 0.80 g (61%); H NMR (300 MHz, CDCl3) δ 2.31
(s, 3 H), 3.39 (s, 2 H), 3.65 (s, 3 H), 7.10-7.22 (m, 7 H), 7.26-
7.32 (m, 3 H); HRMS calcd for C19H18N2O2 306.1368, found
306.1369.
1,5-Diph en yl-3-m eth yl-4-(2-h ydr oxyeth yl)pyr azole (18).
Compound 17 (0.64 g, 2.1 mmol) was dissolved in dry THF
1,5-Dip h en yl-3-m et h yl-4-(N-m et h ylfor m id o)p yr a zole
(12). Compound 9 (0.5 g, 1.6 mmol) was dissolved in dry THF
(5 mL) and cooled to -78 °C under N2. Then t-BuLi (1.7 M,
1.9 mL, 3.2 mmol) was added slowly. The reaction was stirred
for 10 min after which time methylisocyanate (0.1 mL, 1.6
mmol) was added dropwise. Stirring was continued at -78 °C
for 45 min and the reaction was allowed to room temperature
before being quenched with H2O. The reaction was partitioned
between 1 N NaHCO3 and CHCl3. The organic layer was dried
(Na2SO4) and concentrated in vacuo to a residue which was
crystallized from CHCl3 in a yield of 0.34 g (73%): mp 133-
(15 mL) and cooled to -78 °C. While stirring under N2
a
solution of LAH (1 M, 2.1 mL) was added and the reaction
was allowed to warm to room temperature and quenched with
H2O (0.12 mL), 15% NaOH (0.12 mL), and H2O (0.36 mL). The
solid was filtered off and the filtrate was partitioned between
CHCl3 and H2O. The organic layer was washed with brine and
dried (Na2SO4). Removal of solvent gave a yellow oil which
was chromatographed on a 2 × 40 cm column with EtOAc/
hexane (1:2). The product was isolated as a white foam in a
yield of 0.44 g (75%): mp 108-109 °C; 1H NMR (300 MHz,
CDCl3) δ 1.75 (br s, 1 H), 2.34 (s, 3 H), 2.68 (t, J ) 7.0 Hz, 2
H), 3.64 (t, J ) 7.0 Hz, 2 H), 7.11-7.24 (m, 7 H), 7.28-7.32
(m, 3 H); HRMS calcd for C18H18N2O 278.1419, found 278.1420.
Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06.
Found: C, 77.53; H, 6.63; N, 9.93.
1
135 °C; H NMR (300 MHz, CDCl3) δ 2.57 (s, 3 H), 2.70 (d, J
) 4.8 Hz, 3 H), 5.10 (br, 1 H), 7.10-7.14 (m, 2 H), 7.21-7.26
(m, 5 H), 7.36-7.38 (m, 3 H); HRMS calcd for C18H17N3O
291.1372, found 291.1379. Anal. Calcd for
0.1H2O: C, 73.75; H, 5.91; N, 14.33. Found: C, 73.69; H, 5.92;
N, 14.25.
C18H17N3O‚
4-(1,5-Dip h en yl-3-m et h ylp yr a zolyl)a cet ic Acid (19).
Compound 17 (0.10 g, 0.33 mmol) was dissolved in THF (10
mL) and 1 N NaOH (5 mL) was added. The reaction was
stirred overnight and partitioned between 1 N HCl and CHCl3.
The aqueous layer was extracted with CHCl3 and the combined
extracts were washed with brine and dried (Na2SO4). Removal
of solvent gave an oil which was chromatographed on a 2 ×
40 cm column with EtOAc/hexane/HOAc (30:60:1). The acid
was isolated as a white foam in a yield of 80 mg (85%): mp
1,5-Dip h en yl-3-m et h yl-4-(N-m et h ylt h iofor m a m id o)-
p yr a zole (13). Compound 12 (0.24 g, 0.82 mmol) and Lawes-
son’s reagent (0.17 g, 0.41 mmol) were refluxed in dry toluene
under N2 for 2 h. The solvent was removed in vacuo and the
residue was chromatographed on a 2 × 40 cm column with
EtOAc/hexane (1:2). The product was isolated and crystallized
1
from EtOAc/hexane to yield 0.1 g (40%): mp 174-175 °C; H
1
NMR (300 MHz, CDCl3) δ 2.67 (s, 3 H), 3.15 (d, J ) 4.94 Hz,
3 H), 7.08 (br s, 1 H), 7.25-7.48 (m, 10 H); HRMS calcd for
161-162 °C; H NMR (300 MHz, CDCl3) δ 2.30 (s, 3 H), 3.37
(s, 2 H), 7.09-7.19 (m, 7 H), 7.25-7.27 (m, 3 H), 10.3 (br, 1
H); HRMS calcd for C18H16N2O2 292.1212, found 292.1207.
Anal. Calcd for C18H16N2O2‚1.2H2O: C, 68.86; H, 5.91; N, 8.92.
Found: C, 69.18; H, 5.66; N, 8.53.
C
C
18H17N3S 307.1143, found 307.1139. Anal. Calcd for
18H17N3S: C, 70.33; H, 5.57; N, 13.67. Found: C, 70.32; H,
5.64; N, 13.65.
Meth yl 3-Acetyl-4-oxo-4-p h en ylbu ta n oa te (14). 1-Ben-
zoylacetone (2.5 g, 15.4 mmol) was dissolved in acetone (30
mL) and cooled to 0 °C. Cesium carbonate (15.4 mmol) was
added and the enolate was allowed to warm to room temper-
ature. Methyl bromoacetate (1.5 mL, 15.4 mmol) was added
and the reaction was refluxed for 5 h. Water (50 mL) was
added and the reaction was concentrated in vacuo and
extracted with CHCl3. The extracts were washed with brine
and dried (Na2SO4). Removal of solvent gave a yellow oil which
was chromatographed on a 4 × 30 cm column to yield pure
product as a colorless oil 2.9 g (82%): 1H NMR (300 MHz,
CDCl3) δ 2.11 (s, 3 H), 2.85-3.02 (m, 2 H), 3.59 (s, 3 H), 4.97
(t, J ) 7.03 Hz, 1 H), 7.36-7.47 (m, 2 H), 7.52-7.58 (m, 1 H),
7.94-7.98 (m, 2 H).
2-Isobu tyl-1-p h en yl-1,3-bu ta n ed ion e (15). Following the
procedure for the preparation of 14, but starting with benzoyl-
acetone (10.0 g, 61.7 mmol), 2-iodopropane (9.2 mL, 92.5 mmol)
and cesium carbonate (20.1 g, 61.7 mmol) stirring at 55 °C for
18 h and workup as above. The crude product was purified by
chromatography (2% EtOAc/hexane) to provided 3.17 g (15%)
of the title diketone as an oil.
2-Acetyl-1-p h en yl-4-p en tyn -1-on e (16). Following the
procedure for the preparation of 14, but starting with benzoyl-
acetone (5.0 g, 30.83 mmol), propargyl bromide (5.15 mL, 46.2
mmol) and cesium carbonate (30.83 mmol), stirring 72 h at
room temperature, and purifying by chromatography (5%
EtOAc/hexane) provided 3.78 g (61%) of the title diketone as
an oil: 1H NMR (300 MHz, CDCl3) δ 8.01 (m, 2 H), 7.62 (m, 1
H), 7.48 (m, 2 H), 4.71 (t, J ) 7.9 Hz, 1 H), 2.93 (ddd, J ) 2.6,
7.9, 17.2 Hz, 1 H), 2.78 (ddd, J ) 2.6, 7.9, 17.2 Hz, 1 H), 2.19
(s, 3 H), 2.00 (t, J ) 2.6 Hz, 1 H).
2-(3-Met h yl-1,5-d ip h en yl-1H -p yr a zol-4-yl)a cet a m id e
(20). Compound 2 (200 mg, 0.73 mmol) was placed in 37% HCl
(0.5 mL) and heated to 40 °C for 2 h. The mixture was poured
into water and extracted with EtOAc. The extracts were
washed with 1 N NaOH and dried (Na2SO4). Removal of
solvent gave a residue that was crystallized from EtOAc/
hexane to give 160 mg (75%): mp 129-130 °C; 1H NMR (400
MHz, CDCl3) δ 2.38 (s, 3 H), 3.40 (s, 2 H), 5.45 (br s, 1 H),
5.62 (br s, 1 H), 7.18-7.27 (m, 7 H), 7.35-7.37 (m, 3 H); MS
m/z 292 (M + H). Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88;
N, 14.42. Found: C, 74.03; H, 5.89; N, 14.32.
1,5-Dip h en yl-3-m eth yl-4-isop r op ylp yr a zole (21). Com-
pound 15 (1.0 g, 4.90 mmol), phenylhydrazine (0.48 mL, 4.90
mmol) and sodium acetate (0.66 g, 4.90 mmol) were placed in
6 mL of ethanol and 3 mL of water and heated to reflux for
2.5 h. Then the reaction was cooled to room temperature,
poured into water, extracted with CHCl3, dried over Na2SO4
and concentrated in vacuo. Purification by flash column
chromatography (5% methyl tert-butyl ether/hexane) afforded
0.30 g (22%) of the title pyrazole: mp 79-80 °C; 1H NMR (300
MHz, CDCl3) δ 7.30 (m, 3 H), 7.13 (m, 7 H), 2.85 (m, 1 H),
2.42 (s, 3 H), 1.21 (d, J ) 7.1 Hz, 6 H); HRMS calcd for
C
C
19H20N2 276.1626, found 276.1617. Anal. Calcd for
19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.35; H,
7.29; N, 10.03.
1,5-Dip h en yl-3-m eth yl-4-p r op a r gylp yr a zole (22). Com-
pound 16 (0.51 mg, 2.54 mmol), phenylhydrazine (0.25 mL,
2.54 mmol) and sodium acetate (0.35 g, 2.54 mmol) were placed
in 3.3 mL of ethanol and 1.7 mL of water and heated to reflux
for 4 h. Then an additional 0.05 mL of phenylhydrazine was
added and the reaction was refluxed a further 3 h. Then the
reaction was cooled to room temperature, and poured into
water, and adjusted to pH 2 with 1 N HCl. The mixture was
extracted with CHCl3, dried over Na2SO4 and concentrated in
vacuo. Purification by flash column chromatography (2% CH3-
Meth yl (4-(1,5-Diph en yl-3-m eth yl)pyr azolyl)acetate (17).
Phenylhydrazine (0.84 mL, 8.5 mmol) and methyl 3-acetyl-4-
oxo-4-phenylbutanoate (14) (1.0 g, 4.27 mmol) were dissolved
in MeOH (50 mL) and refluxed under N2 for 4 h. The solvent

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 1039
OH/toluene) afforded 0.51 g (74%) of the title pyrazole as an
oil: 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 3 H), 7.25 (m, 5 H),
3.37 (d, J ) 2.8 Hz, 2 H), 2.49 (s, 3 H), 2.11 (t, J ) 2.8 Hz, 1
H); HRMS calcd for C19H16N2 272.1313, found 272.1311. Anal.
Calcd for C19H16N2‚0.15CHCl3: C, 79.25; H, 5.61; N, 9.65.
Found: C, 79.28; H, 5.63; N, 9.74.
temperature and quenched. The precipitate was filtered off
and the filtrate was partitioned between CHCl3 and 1 N
NaHCO3. The organic layer was dried (Na2SO4) and the solvent
was removed in vacuo. The residue was purified on a 2 × 30
cm column with EtOAc/hexane (1:2). The low Rf material 29
was isolated (75 mg, 39%) as was the high Rf isomer 28 (50
o
1
mg, 26%). 29: mp 100-101 C; H NMR (300 MHz, CDCl3) δ
1.01 (t, J ) 7.6 Hz, 3 H), 2.37 (q, 7.5 Hz, 2 H), 2.87 (t, J ) 5.7
Hz, 2 H), 3.41 (br, 1 H), 3.98 (br, 2 H) 7.08-7.19 (m, 7 H),
7.25-7.29 (m, 3 H); HRMS calcd for C19H20N2O 292.1576,
found 292.1582. Anal. Calcd for C19H20N2O‚0.25H2O: C, 76.88;
H, 6.96; N, 9.44. Found: C, 77.02; H, 6.85; N, 9.31.
1,5-Dip h en yl-3-m et h yl-4-p r op ylp yr a zole (23). Com-
pound 22 (0.19 g, 0.71 mmol) was dissolved in 25 mL of ethanol
and 90 mg of 10% palladium on carbon was added. The
reaction was hydrogenated on a Parr shaker for 2 h at 40 psi.
Filtration and concentration afforded 0.18 g (90%) of the title
pyrazole: 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 3 H), 7.16
(m, 7 H), 2.38 (t, J ) 7.6 Hz, 2 H), 2.34 (s, 3 H), 1.46 (sextet,
J ) 7.6 Hz, 2 H), 0.85 (t, J ) 7.6 Hz, 3 H); HRMS calcd for
1
28: mp 123-124 °C; H NMR (300 MHz, CDCl3) δ 1.03 (t,
J ) 7.53 Hz, 3 H), 1.66 (br, 1 H), 2.54 (q, 7.54 Hz, 2 H), 2.82
(t, J ) 7.13 Hz, 2 H), 3.49 (t, J ) 7.09 Hz, 2 H), 7.17-7.36 (m,
8 H), 7.54-7.58 (m, 2 H); HRMS calcd for C19H20N2O 292.1576,
found 292.1576. Anal. Calcd for C19H20N2O‚0.2H2O: C, 77.10;
H, 6.95; N, 9.46. Found: C, 77.28; H, 6.85; N, 9.44.
C
19H20N2 276.1626, found 272.1617.
2-Acetylben zoph en on e (24). 1-Benzoylacetone (20 g, 0.123
mol) was dissolved in acetonitrile (300 mL) and cesium
carbonate (40.2 g, 0.123 mol) was added followed by EtI (14.8
mL, 0.184 mol). The reaction was heated at 55 °C for 5 h before
being diluted with H2O. The reaction was concentrated in
vacuo and extraxted with CHCl3 (3×). The extracts were dried
(Na2SO4) and concentrated to an oil. Purification on a 5 × 45
cm column with EtOAc/Hex (1:9) yielded 21 g (90%) of product
as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.83 (m, 2
H), 7.45 (m, 1 H), 7.33 (m, 2 H), 4.20 (t, J ) 7.1 Hz, 1 H), 1.98
(s, 3 H), 1.88 (m, 2 H), 0.80 (t, J ) 7.1 Hz, 3 H).
3,5-Dik eto-4-eth yl-5-p h en ylp en ta n oic Acid (25). Com-
pound 24 (4.3 g, 22.6 mmol) was added dropwise to a mixture
of NaNH2 (3.1 g, 79.6 mmol) in liquid NH3 (150 mL). The
yellow solution was stirred for 1 h at room temperature under
N2 with a dry ice acetone gas condenser on top of the flask to
recondense the evaporating NH3. Et2O (50 mL) was added and
the NH3 was evaporated on a steam bath under a stream of
N2. This was replaced with anhydrous Et2O. The ether solution
was heated on the steam bath for 5 min after the NH3 had
evaporated to ensure its complete removal. While stirring at
room temperature CO2 gas was bubbled into the ether solution
of the dianion for 30 min. The reaction was poured into an ice
solution of 6 N HCl and extracted with Et2O. The organic
extracts were dried (Na2SO4) and the solvent was removed to
yield 4.7 g (89%) of the acid as a light orange solid. This
material due to its extreme instability was refrigerated and
used without further purification.
1,5-Dip h en yl-3-(2-m eth oxyeth yl)-4-eth ylp yr a zole (30).
Compound 29 (210 mg, 0.70 mmol) was dissolved in dry THF
at 0 °C. Sodium hydride (60%, 30 mg, 0.77 mmol) was added
and the reaction was stirred 15 min. MeI (0.048 mL, 0.77
mmol) was added and stirring was continued at 0 °C for 30
min and allowed to warm to room temperature. The reaction
was quenched with water and worked up to give an oil which
was chromatographed on a 2 × 40 cm column with EtOAc/
hexane (1:9). The product was isolated as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 1.09 (t, J ) 7.53 Hz, 3 H), 2.47 (q,
J ) 7.55 Hz, 2 H), 3.02 (t, J ) 7.57 Hz, 2 H), 3.42 (s, 3 H),
3.81 (t, J ) 7.68 Hz, 2 H), 7.16-7.25 (m, 7 H), 7.30-7.33 (m,
3 H); HRMS calcd for C20H22N2O 306.1732, found 306.1741.
Anal. Calcd for C20H22N2O‚0.5H2O: C, 76.16; H, 7.35; N, 8.88.
Found: C, 76.02; H, 7.32; N, 8.41.
Meth yl 3,5-Diketo-4-eth yl-5-ph en ylpen tan oate (31). Ex-
cess trimethylsilyldiazomethane (2 M) was added to 25 (2.0
g, 8.54 mmol) followed by benzene (10 mL) and methanol (20
mL). The reaction was stirred at room temperature for 1 h
and the solvent was removed in vacuo. The residue was
chromatographed on a 2 × 45 cm column with EtOAc/hexane
(1:9). The product was isolated as an oil in a yield of 0.9 g
(48%): 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J ) 7.41 Hz, 3
H), 1.91-2.02 (m, 2 H), 3.46 (s, 2 H), 3.57 (s, 3 H), 4.52 (t, J )
6.86 Hz, 1 H), 7.37-7.48 (m, 2 H), 7.52-7.57 (m, 1 H), 7.89-
7.94 (m, 2 H).
2-(1,5-Dip h en yl-4-eth ylp yr a zole)a cetic Acid (27) a n d
5-(3-Dip h en yl-4-et h ylp yr a zole)a cet ic Acid (26). Com-
pound 25 (2.0 g, 8.54 mmol) was placed in a flask. Methanol
(20 mL) was added quickly followed by phenylhydrazine (3.4
mL, 17.1 mmol). The reaction was refluxed under N2 for 3 h
and concentrated in vacuo. The residue was partitioned
between 1 N HCl and CHCl3. The aqueous layer was extracted
with CHCl3 and the combined extracts were back extracted
with 1 M NaHCO3. The NaHCO3 was acidified with 6 N HCl
and extracted with CHCl3. The extracts were dried (Na2SO4)
and the solvent was removed in vacuo to give the product as
a mixture of isomers. These were separated on a 2 × 40 cm
column with EtOAc/hexane/HOAc (30:60:1). The desired prod-
uct 27 (low Rf) was isolated as a solid in a yield of 0.8 g (31%):
mp 208-209 °C; 1H NMR (300 MHz, CDCl3) δ 1.00 (t, J ) 7.6
Hz, 3 H), 2.37 (q, 7.6 Hz, 2 H), 3.79 (s, 2 H), 7.07-7.28 (m, 10
H); HRMS calcd for C19H18N2O2 306.1368, found 306.1367.
Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.28; H, 5.94; N, 9.14.
Meth yl 2-(1,5-Diph en yl-4-eth yl-3-pyr azolyl)acetate (32).
Compound 31(0.90 g, 3.62 mmol), phenylhydrazine (0.53 mL,
5.43 mmol), and NaOAc‚3H2O (0.49 g, 3.6 mmol) were refluxed
in methanol for 3 h. The solvent was evaporated and the
residue was partitioned between EtOAc and H2O. The organic
layer was washed with brine and dried (Na2SO4). Removal of
solvent gave an oil which was purified on a 2 × 40 cm column
with EtOAc/hexane (1:9) to yield 0.46 g (40%): 1H NMR (300
MHz, CDCl3) δ 0.98 (t, J ) 7.49 Hz, 3 H), 2.39 (q, J ) 7.53 Hz,
2 H), 3.67 (s, 3 H), 3.73 (s, 2 H), 7.06-7.17 (m, 7 H), 7.23-
7.27 (m, 3 H); HRMS calcd for C20H20N2O2 320.1525, found
320.1516. Anal. Calcd for C20H20N2O2‚H2O: C, 73.33; H, 6.40;
N, 8.55. Found: C, 73.70; H, 5.91; N, 8.16.
1,5-Dip h en yl-3-(N-m et h ylm et h ylca r b oxa m id o)-4-et h -
ylp yr a zole (33). Compound 32 (77.0 mg, 2.4 mmol) was
dissolved in methanol (5 mL) and methylamine (40%/H2O) (5
mL) was added and the reaction was capped tightly and stirred
overnight. The solvent was removed in vacuo and the residue
was chromatographed with EtOAc/hexane to give 50 mg (7%)
of pure product as an oil: 1H NMR (300 MHz, CDCl3) δ 0.98
(t, J ) 7.53 Hz, 3 H), 2.37 (q, J ) 7.57 Hz, 2 H), 2.72 (d, J )
4.81 Hz, 3 H), 3.62 (s, 2 H), 6.80 (br s, 1 H), 7.07-7.26 (m, 10
H); HRMS calcd for C20H21N3O 319.1685, found 319.1680.
Anal. Calcd for C20H21N3O‚1.0H2O: C, 71.19; H, 6.87; N, 12.45.
Found: C, 70.81; H, 6.54; N, 12.41.
The other regioisomer 26 (high Rf) was isolated in a yield
of 0.4 g (15%): mp 153-154 °C; 1H NMR (300 MHz, CDCl3) δ
11.40 (br, 1 H), 7.52 (m, 2 H), 7.32-7.05 (m, 8 H), 3.46 (s, 2
H), 2.43 (q, J ) 7.6 Hz, 2 H), 0.94 (t, J ) 7.6 Hz, 3 H); HRMS
calcd for C19H18N2O2 306.1368, found 306.1368. Anal. Calcd
for C19H18N2O2‚0.2H2O: C, 73.62; H, 5.98; N, 9.04. Found: C,
73.59; H, 5.82; N, 9.02.
1,5-Dip h en yl-3-(2-h yd r oxyeth yl)-4-eth ylp yr a zole (29)
an d 1,3-Diph en yl-4-eth yl-5-(2-h ydr oxyeth yl)pyr azole (28).
A mixture of 27 and 26 (0.20 g, 0.65 mmol) was dissolved in
dry THF (10 mL) and cooled to -78 °C. A solution of 1 M LAH
(0.65 mL) was added and the reaction was warmed to room
2-(1,5-Diph en yl-4-eth yl-3-pyr azolyl)acetam ide (34). Com-
pound 32 (40 mg, 0.12 mmol) was dissolved in a saturated
solution of NH3/MeOH. The reaction was capped tightly and
stirred overnight. Reaction was not complete therefore NH3
gas was bubbled in for 1 h and the reaction was stirred an

1040 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Brief Articles
Tarpley, W. G.; Thomas, R. C. Targeting Delavirdine/Atevirdine
Resistant HIV-1: Identification of (Alkylamino)piperidine-
Containing Bis(heteroaryl)piperazines as Broad Spectrum HIV-1
Reverse Transcriptase Inhibitors. J . Med. Chem. 1996, 39,
3769-3789.
additional 2 days while capped tightly. The solvent and excess
NH3 were removed in vacuo and the residue was crystallized
from MeOH/Et2O to yield 30 mg (85%): mp 215-216 °C; H
1
NMR (300 MHz, CDCl3) δ 1.09 (t, J ) 7.61 Hz, 3 H), 2.46 (q,
J ) 7.54 Hz, 2 H), 3.72 (s, 3 H), 5.45 (br s, 1 H), 6.95 (br s, 1
H), 7.15-7.26 (m, 7 H), 7.30-7.36 (m, 3 H); HRMS calcd for
(4) Romero, D. L.; Busso, M.; Tan, C.-K.; Reusser, F.; Palmer, J .
R.; Poppe, S. M.; Aristoff, P. A.; Downey, K. M.; So, A. G.;
Resnick, L.; Tarpley, W. G. Nonnucleoside reverse transcriptase
inhibitors that potentially block human immunodeficiency virus
type 1 replication. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8806-
8810.
(5) Wishka, D. G.; Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis,
J . M.; Hosley, J . D.; Adams, W. J .; Seest, E. P.; Castle, T. M.;
Dolak, L. A.; Keiser, B. J .; Yagi, Y.; Azhwarsamy, J .; Schlachter,
S. T.; Murphy, M. J .; Cleek, G. J .; Nugent, R. A.; Poppe, S. M.;
Swaney, S. M.; Han, F.; Watt, W.; White, W. L.; Poel, T.-J .;
Thomas, R. C.; Voorman, R. L.; Stefanski, K. J .; Stehle, R. G.;
Tarpley, W. G.; Morris, J . (-)-6-Chloro-2-[(1furo[2,3-c]pyridin-
5-yl-ethyl)thio]-4-pyrimidinamine, PNU-142721, a New Broad
Spectrum HIV-1 Non-Nucleoside Reverse Transcriptase Inhibi-
tor. J . Med. Chem. 1998, 41, 1357-1360.
(6) Smith, G. F. Indoles. Part I. The Formylation of Indole and Some
Reactions of 3-Formylindole. J . Chem. Soc. 1954, 3842-3846.
(7) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.; Marinovic,
N. Sesquiterpene Lactones: Total Synthesis of (()-Vernolepin
and (()-Vernomenin J . Am. Chem. Soc. 1977, 99, 5773-5780.
(8) Nicoloau, K. C.; Barnette, W. E.; Ma, P. A Remarkably Simple,
Highly Efficient, and Stereoselective Synthesis of Steroids and
Other Polycyclic Systems. Total Synthesis of Estra-1,3,5(10)-
trien-17-one via Intramolecular Capture of o-Quinodimethanes
Generated by Cheletropic Elimination of SO2. J . Org. Chem.
1980, 45, 1463-1470.
C
19H19N3O 305.1528, found 305.1532. Anal. Calcd for C19H19-
N3O‚0.5H2O: C, 72.59; H, 6.41; N, 13.37. Found: C, 72.53; H,
6.03; N, 13.34.
1,5-Diph en yl-3-cya n om eth yl-4-eth ylp yr a zole (35). Com-
pound 34 (0.10 g, 0.33 mmol) and Lawesson’s reagent (0.13 g,
0.33 mmol) were dissolved in dry toluene and heated to ruflux
under N2 for 2 h. The solvent was evaporated in vacuo and
the residue was chromatographed on a 2 × 30 cm column with
EtOAc/hexane (1:9). The product was isolated as a white solid
which crystallized from Et2O in a yield of 84 mg (89%): mp
99-100 °C; 1H NMR (300 MHz, CDCl3) δ 1.33 (t, J ) 7.62 Hz,
3 H), 2.72 (q, J ) 7.55 Hz, 2 H), 4.02 (s, 2 H), 7.34-7.48 (m, 7
H), 7.52-7.55 (m, 3 H); HRMS calcd for C19H17N3 287.1422,
found 287.1422. Anal. Calcd for C19H17N3: C, 79.42; H, 5.96;
N, 14.62. Found: C, 79.29; H, 6.14; N, 14.45.
Ack n ow led gm en t. We thank the Structural, Ana-
lytical and Medicinal Chemistry Department of Phar-
macia & Upjohn for mass spectral and combustion
analysis data.
Refer en ces
(1) Romero, D. L. Atevirdine Mesylate. Drugs Future 1994, 19 (1),
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Reagents. Tetrahedron 1985, 41, 5061-5087.
(10) Hauser, C. R.; Harris, T. M. Condensations at the Methyl Group
Rather than the Methylene Group of Benzoyl- and Acetylacetone
Through Intermediate Dipotassio Salts. J . Am. Chem. Soc. 1958,
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