Stereoselective synthesis of 3,5-dialkyl-3,5-dihydro-3,5-diphenyl-4H- pyrazol-4-ones

Article abstract of DOI:10.1055/s-2005-916008

We report stereoselective five-step syntheses of cis-3-ethyl-3,5-dihydro-3, 5-diphenyl-5-methyl-4H-pyrazol-4-one (cis-1b) and trans-3,5-diethyl-3,5-dihydro- 3,5-diphenyl-4H-pyrazol-4-one (trans-1c). The key synthon was 1,3-diphenylpent-2-en-1-one (5b) synthesized in a new one-pot crossed aldol/dehydration reaction of acetophenone with propiophenone using titanium(IV) chloride/tributylamine, followed by treatment with methanesulfonyl chloride and triethylamine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-916008

PAPER
2901
Stereoselective Synthesis of 3,5-Dialkyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-
4-ones
Stereoselective
Sy
n
nthesis of 3,5
d
-Dialkyl-3,5
r
-dihydro
e
-3,5-diphen
y
yl-4
H
-pyrazol-4-o
G
nes . Moiseev, Douglas C. Neckers*
Center for Photochemical Sciences, Bowling Green State University, Bowling Green, OH 43403, USA
Fax +1(419)3720366; E-mail: neckers@photo.bgsu.edu
Received 12 April 2005; revised 30 May 2005
yl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-one (cis- or
Abstract: We report stereoselective five-step syntheses of cis-3-
ethyl-3,5-dihydro-3,5-diphenyl-5-methyl-4H-pyrazol-4-one (cis-
1b) and trans-3,5-diethyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-
one (trans-1c). The key synthon was 1,3-diphenylpent-2-en-1-one
trans-1c, respectively). The key step in the synthesis of
cis-1b and cis-1c should be synthesis of 1,3-diphenylpent-
2-en-1-one (5b, b-ethyl chalcone) using a crossed aldol/
(5b) synthesized in a new one-pot crossed aldol/dehydration reac- dehydration reaction of acetophenone and propiophe-
tion of acetophenone with propiophenone using titanium(IV) chlo-
ride/tributylamine, followed by treatment with methanesulfonyl
chloride and triethylamine.
none. Reaction of triethylaluminum with a racemic
mixture of (4S,5S)- and (4R,5R)-5-ethyl-4,5-dihydro-3,5-
diphenyl-1-tosyl-1H-pyrazol-4-ol [(4S,5S)- and (4R,5R)-
Key words: stereoselective synthesis, 3,5-dialkyl-3,5-dihydro-3,5-
3b], instead of trimethylaluminum, should lead to the ste-
diphenyl-4H-pyrazol-4-ones, b-alkyl chalcones, crossed aldol/de-
reoselective addition of an ethyl group to give cis-3,5-di-
hydration, heterocyclic compounds
ethyl-4,5-dihydro-3,5-diphenyl-3H-pyrazol-4-ol (cis-2c),
the oxidation of which would afford cis-1c.
While b-alkyl chalcones 5 are well-known organic syn-
The cis- and trans-3,5-dihydro-3,5-dimethyl-3,5-diphe-
thons for the preparation of biologically active heterocy-
nyl-4H-pyrazol-4-ones1 (cis- and trans-1a, respectively)
are the only known cis- and trans-3,5-dialkyl-3,5-diaryl-
clic compounds,5 only b-methyl chalcone6 (5a) is easily
available by self-condensation of acetophenone in the
presence of Lewis acids. In addition, the known methods
3,5-dihydro-4H-pyrazol-4-ones (1) and are potential pre-
cursors for allenes,2 functionalized cyclopropanones3 and
for the synthesis of b-alkyl chalcones with differing sub-
stituents at the b-position and/or at the benzene rings are
complicated.7 Although crossed aldol/dehydration is a
simple and classical way to synthesize the latter, self-con-
densation of the reacting ketones, especially when both
reactants have enolizable hydrogens and close pKa (e.g.,
acetophenone and propiophenone) is a problem. Howev-
cyclopropylidenes4 (Scheme 1).
Retrosynthetic analysis of cis- or trans-1a suggests a chal-
lenging stereospecific synthesis of other derivatives of 1.
Consider, for example, synthesis of cis- or trans-3-ethyl-
3,5-dihydro-5-methyl-3,5-diphenyl-4H-pyrazol-4-one
(cis- or trans-1b, respectively) and cis- or trans-3,5-dieth-
4
HO
3
H
5
O
HO
N
H
Oxidation
Ar'
R'
Ar'
Ar
R
Ar'
R'
Ar
R
Ar
R
N
N
N
Hydrazone
formation
N
N
Ring
closure
Alkyl
addition
Ts
cis-1
2
3
O
Ar
O
Ar
R
O
O
H
O
Ar
Ar'
R
R
Ar
CH3
Ar'
Aldol / dehydration
reaction
trans-4
5
a: Ar = Ar' = Ph, R = R' = Me
b: Ar = Ar ' = Ph, R = Et, R' = Me
c: Ar = Ar' = Ph, R = R' = Et
Scheme 1 Retrosynthetic analysis of cis-1a, cis-1b, and cis-1c
SYNTHESIS 2005, No. 17, pp 2901–2905
x
x.
x
x
.
2
0
0
5
Advanced online publication: 26.08.2005
DOI: 10.1055/s-2005-916008; Art ID: M02605SS
© Georg Thieme Verlag Stuttgart · New York

2902
A. G. Moiseev, D. C. Neckers
PAPER
er, one-pot Mukaiyama8 crossed aldol condensation of tri- over two steps. When the one-pot synthesis was used for
methylsilyl enol ethers of acetophenone with various the self-aldol/dehydration reaction of acetophenone, it af-
ketones afforded in situ crossed aldol products, which forded 5a in 50% yield. The 1H NMR spectra of 5a and 5b
were dehydrated using trifluoroacetic acid.7e In this man- contain allylic hydrogen at 7.15 ppm, which is character-
ner, we report a Mukaiyama-related crossed aldol conden- istic for (E)-b-alkyl chalcones.7c The main side reaction
sation between acetophenone and propiophenone, which during the crossed aldol/dehydration reactions is titani-
was successfully accomplished using titanium(IV) chlo- um-induced polymerization of 5a and 5b.
ride and tributylamine to provide selectively 3-hydroxy-
We improved on the literature synthesis1 of the racemic
mixture (4S,5S)- and (4R,5R)-4,5-dihydro-5-methyl-3,5-
diphenyl-1-tosyl-1H-pyrazol-4-ol [(4S,5S)- and (4R,5R)-
3a], obtaining these in higher yield (59%) and in less time
1,3-diphenylpentan-1-one in 86% yield.9 We found that
reaction of the latter in situ with methanesulfonyl chloride
and triethylamine (–78 °C → r.t.) gave 5b in a one-pot
procedure (Scheme 2).
by heating trans-4a with tosylhydrazine at 70 °C, fol-
lowed by treatment with dry hydrogen chloride. Reaction
of cis-4a with tosylhydrazine under the same conditions
O
Ph
R
and with a longer reaction time gave the racemic mixture
(4S,5R)- and (4R,5S)-4,5-dihydro-5-methyl-3,5-diphenyl-
1-tosyl-1H-pyrazol-4-ol [(4S,5R)- and (4R,5S)-3a] stereo-
selectively in 50% yield. With this improved procedure,
the reaction of trans-4b with tosylhydrazine gave (4S,5S)-
and (4R,5R)-3b in 61% yield. Reaction of the latter with
trimethylaluminum over three days afforded 3-ethyl-4,5-
dihydro-5-methyl-(cis-3,5-diphenyl)-3H-pyrazol-4-ol (cis-
2b) stereoselectively. Ultimately, Jones oxidation of cis-
2b gave cis-1b in 4% overall yield.
O
O
O
R
H
H
a
b
O
Ph
R
O
O
+
Ph
CH3
R
Ph
Ph
Ph
Ph
Ph
H
5
trans-4
cis-4
c
HO
H
N
O
HO
N
H
d
e
Ph
R'
Ph
Ph
R
Ph
R'
Ph
R
Ph
R
N
N
N
N
Ts
The reaction of (4S,5S)- and (4R,5R)-3b with triethylalu-
minum should lead to cis-2c stereoselectively with subse-
quent oxidation affording cis-1c. However, reaction of
(4S,5S)- and (4R,5R)-3b with triethylaluminum at 75 °C
for a week gave 70% conversion into the addition product.
Subsequent Jones oxidation of the latter gave mostly
cis-2
cis-1
(S,S)- 3
a: R = R' = Me
b: R = Et, R' = Me
Scheme 2 (a) 1. TiCl4, Bu3N, CH2Cl2, –78 °C; 2. MsCl, Et3N, –78
°C → r.t.; (b) 30% H2O2, 8% NaOH, MeOH, r.t.; (c) 1. tosylhydra-
zine, isobutyric acid, CH2Cl2, 70 °C; 2. HCl (g), 0 °C; (d) AlMe3, to- trans-1c along with trans-5-ethyl-3,5-dihydro-3,5-diphe-
nyl-3-vinyl-4H-pyrazol-4-one (trans-1d) (16%, 1H NMR
luene, 75 °C; (e) CrO3, H2SO4, H2O, acetone, 0 °C
spectroscopy) (Scheme 3).
Unfortunately, purification of 5b led to the nonconjugated
(E,Z)-1,3-phenylpent-3-en-1-one. Treatment of crude 5b
with hydrogen peroxide in alkaline methanol, similar to
the process used with 1,3-diphenylbut-2-en-1-one (5a),10
gave a mixture of cis- and trans-(3-ethyl-3-phenyloxiran-
2-yl)(phenyl)methanone (cis- and trans-4b) in 22% yield
Most likely, the vinyl derivative trans-1d formed from the
same intermediate (6, Scheme 3) as the diethyl-substitut-
ed compound trans-1c. The lower reactivity of (4S,5S)-
and (4R,5R)-3b with triethylaluminum in comparison
with trimethylaluminum can be explained in terms of the
steric hindrance in 6 for facial delivery of the ethyl group.
Ts
Et
Et
Ts
N
Et
Et
Ph
Ph
N
Ph
N
N
N
Al(Et)3
Ph
N
N
N
H
H
Ph
Ph
CH2
H
O
H
OH
Ph
OH
CH
Ph
+
OH
Et
Et Al
Et
trans-2c
trans-2d
3b
6
CrO3
H2SO4
acetone
Et
Et
N
N
N
Ph
Ph
N
+
Ph
Ph
O
O
CH
Et
CH2
trans-1c
trans-1d
Scheme 3 Synthesis of trans-1c
Synthesis 2005, No. 17, 2901–2905 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 3,5-Dialkyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-ones
2903
tion was extracted with CH2Cl2 (3 × 100 mL), and the organic layer
was dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, hexane–EtOAc 9:1) to afford 0.61 g of trans-4b and 0.4
g of cis-4b (22% yield over two steps).
We synthesized cis- and trans-1a using a modified litera-
ture synthesis1 in order to differentiate them spectroscop-
1
ically. Both cis- and trans-1a have almost the same H
NMR spectra. However, these isomers are easily differen-
tiated by UV spectroscopy because the extinction coeffi-
cient of cis-1a (lmax = 354 nm) is almost twice as high as
that of trans-1a. In comparison, the extinction coefficient
of cis-1b (lmax = 357 nm) is close to the extinction coeffi-
cient of cis-1a. As evidence that the trans-1c (lmax = 361
nm) was obtained, its extinction coefficient is almost the
same as that of trans-1a.
cis-4b
mp 117–119 °C.
Rf = 0.23 (hexane–EtOAc, 9:1).
1H NMR (300 MHz, CDCl3): d = 7.82 (dd, J = 7.4, 3.3 Hz, 2 H),
7.53 (t, J = 6.6 Hz, 1 H), 7.41 (t, J = 8.3 Hz, 2 H), 7.15–7.29 (m, 5
H), 4.36 (s, 1 H), 2.35–2.49 (m, 1 H), 1.92–2.05 (m, 1 H), 1.01 (t,
J = 7.5 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 8.8, 30.5, 64.8, 68.2, 126.8,
127.8, 127.9, 128.1, 128.6, 133.4, 135.4, 135.7, 192.8.
In conclusion, cis-1b was synthesized in five steps. How-
ever, the reaction of (4S,5S)- and (4R,5R)-3b with trieth-
ylaluminum with subsequent oxidation of the formed
addition product gave, instead of the expected cis-1c,
trans-1c (along with 16% trans-1d) in 2% overall yield. A
novel one-pot crossed aldol/dehydration reaction was de-
veloped affording 5b in 40–50% yield. This procedure
might be used for the synthesis of further b-alkyl chal-
cones.
MS (EI, 70 eV): m/z (%) = 252 (2) [M+], 223 (95), 117 (39), 105
(100), 91 (32), 77 (74).
HRMS (EI): m/z calcd for C17H16O2: 252.1150; found: 252.1150.
trans-4b
mp 59–61 °C.
Rf = 0.38 (hexane–EtOAc, 9:1).
IR (neat): 3063, 2976, 2935, 2879, 1682, 1596, 1448, 1398, 1226,
940, 841, 747, 696, 662 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (dd, J = 7.7, 3.3 Hz, 2 H),
7.63 (t, J = 6.9 Hz, 1 H), 7.35–7.55 (m, 7 H), 4.15 (s, 1 H), 2.09–
2.19 (m, 1 H), 1.58–1.69 (m, 1 H), 0.91 (t, J = 7.5 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 9.4, 23.8, 67.1, 67.5, 125.9,
128.1, 128.3, 128.8, 128.9, 133.9, 135.7, 138.8, 193.1.
Thin-layer chromatography was performed using commercially
prepared silica gel plates (polyester backed, 200-mm) and visualiza-
tion was effected with short wavelength UV light (254 nm) and/or
cerium soln [(NH4)6Mo4O24 (4.12 g), Ce(SO4)2·H2O (1.12 g), concd
H2SO4 (10 mL), and H2O (100 mL)]. Column chromatography was
performed using silica gel (60-Å, 32–63 mm). All 1H and 13C NMR
spectra were recorded at 300 and 75.5 MHz in CDCl3 at 20 °C.
Chemical shifts were recorded as d values in ppm. The Bu3N and
Et3N were distilled over NaOH and were stored over NaOH. Ace-
tophenone, propiophenone and MsCl were distilled prior to use, and
CH2Cl2 was distilled over CaH2. Toluene was distilled over Na prior
to use.
MS (EI, 70 eV): m/z (%) = 252 (2) [M+], 223 (95), 117 (39), 105
(100), 91 (32), 77 (74).
HRMS (EI): m/z calcd for C17H16O2: 252.1151; found: 252.1150.
(4S,5S)- and (4R,5R)-4,5-Dihydro-5-methyl-3,5-diphenyl-1-
tosyl-1H-pyrazol-4-ol [(4S,5S)- and (4R,5R)-3a, Racemic
Mixture]:
1,3-Diphenylpent-2-en-1-one (5b):
To a solution of acetophenone (10 g, 83 mmol) in CH2Cl2 (110 mL)
at –78 °C was added dropwise a 1 M solution of TiCl4 in CH2Cl2
(100 mL, 100 mmol) followed by Bu3N (22 g, 119 mmol). The mix-
ture was stirred for 1.5 h at this temperature. Then, propiophenone
(12.5 g, 93 mmol) was added dropwise and resulting solution was
stirred at –78 °C for 2.5 h. After adding MsCl (21 g, 183 mmol) and
Et3N (9.4 g, 93 mmol) dropwise, the mixture was allowed to warm
to r.t. and was stirred for 3 h. Then, the mixture was worked up with
a mixture of CH2Cl2 (200 mL), ice (1000 g), and H2O (200 mL). The
organic layer was separated off and the aqueous layer was extracted
with CH2Cl2 (600 mL). The combined organic layers were washed
with 0.15 M NaHCO3 soln (3 × 200 mL), dried (Na2SO4), and evap-
orated under reduced pressure. The residue was purified by flash
column chromatography (silica gel, firstly with hexane, then hex-
ane–CH2Cl2 1:1) to afford 22 g (according to GC/MS and 1H NMR
spectroscopic data) of a mixture of 5b, propiophenone, and the non-
conjugated (E,Z)-1,3-diphenylpent-3-en-1-one). It was not possible
to completely purify 5b, therefore, crude 5b was used in the next
step; the presence of impurities did not influence the epoxidation re-
action.
To a solution of trans-4a (0.13 g, 0.5 mmol) in CH2Cl2 (1 mL) at r.t.
was added tosylhydrazine (0.13 g, 0.7 mmol) and isobutyric acid
(0.52 g, 5.9 mmol). The resulting solution was heated to 70 °C and
kept at this temperature for 20 min in a closed vial. According to
TLC (hexane–EtOAc, 3:1), the starting compound had reacted to
form the tosylhydrazone of trans-4a (Rf = 0.3). Then, dry HCl was
passed through the mixture at 0 °C to form (4S,5S)- and (4R,5R)-3a
(Rf = 0.17). The mixture was worked up with H2O (5 mL) and ex-
tracted with CH2Cl2 (15 mL). The organic layer was dried (Na2SO4)
and evaporated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane–EtOAc 3:1) to afford
(4S,5S)- and (4R,5R)-3a as a viscous orange oil; yield: 0.13 g
(59%).
(4S,5R)- and (4R,5S)-4,5-Dihydro-5-methyl-3,5-diphenyl-1-
tosyl-1H-pyrazol-4-ol [(4S,5R)- and (4R,5S)-3a, Racemic
Mixture]:
The synthesis of (4S,5R)- and (4R,5S)-3a from cis-4a was similar to
that of (4S,5S)- and (4R,5R)-3a.
Yield: 0.11 g (50%).
cis-andtrans-(3-Ethyl-3-phenyloxiran-2-yl)(phenyl)methanone
(cis- and trans-4b):
To the stirred heterogeneous solution of crude 5b (4.00 g) in MeOH
(50 mL) was added dropwise 30% aq H2O2 (4.85 g, 43 mmol) and
8% NaOH (5.18 g, 10 mmol) at 0 °C. The mixture was allowed to
warm to r.t. and was stirred for 2 d. Then, the mixture was poured
into a mixture of ice (100 g) and H2O (100 mL). The resulting solu-
(4S,5S)- and (4R,5R)-5-Ethyl-4,5-dihydro-3,5-diphenyl-1-tosyl-
1H-pyrazol-4-ol [(4S,5S)- and (4R,5R)-3b]:
The synthesis of (4S,5S)- and (4R,5R)-3b from trans-4b was similar
to that of (4S,5S)-and (4R,5R)-3a.
Yield: 0.13 g (61%); mp 63–66 °C.
Synthesis 2005, No. 17, 2901–2905 © Thieme Stuttgart · New York

2904
A. G. Moiseev, D. C. Neckers
PAPER
IR (neat): 3516, 1598, 1496, 1448, 1344, 1160, 1066, 763, 668 cm–1.
HRMS-CI: m/z [M+ + H] calcd for C18H18N2O: 279.1497; found:
279.1495.
1H NMR (300 MHz, CDCl3): d = 7.90 (dd, J = 5.3, 3.0 Hz, 2 H),
7.64 (dd, J = 6.8, 1.5 Hz, 2 H), 7.39 (t, J = 3.0 Hz, 3 H), 7.16–7.31
(m, 7 H), 5.23 (d, J = 8.1 Hz, 1 H), 2.68–2.81 (m, 1 H), 2.44–2.56
(m, 1 H), 2.40 (s, 3 H), 1.55 (d, J = 8.1 Hz, 1 H), 1.01 (t, J = 7.5 Hz,
3 H).
13C NMR (75.5 MHz, CDCl3): d = 8.5, 21.5, 29.6, 78.9, 81.3, 127.2,
127.4, 127.8, 128.4, 128.5, 128.6, 129.1, 130.0, 130.1, 135.5, 137.0,
143.4, 152.6.
trans-3,5-Diethyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-one
(trans-1c):
To stirred solution of (4S,5S)- and (4R,5R)-3b (0.5 g, 1.2 mmol) in
dry toluene (5 g) at 0 °C was added dropwise 1.9 M Et3Al soln (6.5
mL, 12 mmol). The mixture was allowed to warm to r.t. (20 °C) and
then was heated to 75 °C. The mixture was kept at this temperature
for a week, after which it was added dropwise to mixture of H2O
(100 mL), ice (100 g), and CH2Cl2 (100 mL). Then 6 M HCl (30
mL) was added dropwise to the resulting solution. The aqueous lay-
er was extracted with CH2Cl2 (300 mL), and the organic layer was
dried (Na2SO4) and evaporated under reduced pressure. The residue
was purified by preparative TLC (silica gel, hexane–EtOAc 9:1) to
afford 0.053 g of trans-2c (along with 17% of trans-2d according to
MS (EI, 70 eV): m/z (%) = 420 (21) [M+], 265 (75), 236 (26), 155
(11), 132 (49), 115 (23), 104 (100).
HRMS (EI): m/z calcd for C24H24N2O3S: 420.1508; found:
420.1506.
3-Ethyl-4,5-dihydro-5-methyl-(cis-3,5-diphenyl)-3H-pyrazol-4-
ol (cis-2b):
1
the H NMR spectrum) and 0.151 g of (4S,5S)- and (4R,5R)-3b
(70% conversion). To a solution of trans-2c (0.05 g, 0.2 mmol) in
acetone (1.9 mL) at 0 °C was added dropwise Jones reagent for 2 h.
According to TLC (silica gel, hexane–EtOAc 9:1), trans-2c (Rf =
0.52) reacted completely to form trans-1c (Rf = 0.47). The mixture
was quenched with i-PrOH (2 mL), and the precipitate was filtered
off and washed with acetone (5 mL). The solvent was evaporated
and H2O (5 mL) was added to the residue. The aqueous solution was
extracted with CH2Cl2 (10 mL), and the organic layer was dried
(Na2SO4) and evaporated under reduced pressure. The residue was
purified by preparative TLC (silica gel, hexane–EtOAc 9:1) to af-
ford 0.033 g of trans-1c (along with 16% trans-1d) as a white solid
in 14% yield over the last two steps.
To a stirred solution of (4S,5S)- and (4R,5R)-3b (0.6 g, 1.4 mmol)
in dry toluene (6 g) under an argon atmosphere at 0 °C was added
dropwise 2 M Me3Al in toluene (7.8 mL, 17 mmol). The mixture
was allowed to warm to r.t. and was then heated to 75 °C and kept
at this temperature for 3 d. According to TLC (hexane–EtOAc, 3:1),
the starting compound (Rf = 0.17) was consumed forming cis-2b.
The mixture was worked up with a mixture of CH2Cl2 (25 mL), ice
(25 g), and H2O (25 mL). Then, 6 M HCl (30 mL) was added drop-
wise to the mixture and the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL). The organic layer was dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane–EtOAc 9:1)
to afford cis-2b as a yellowish solid; yield: 0.15 g (38%); mp 111–
112 °C.
mp 69–72 °C.
1H NMR (300 MHz, CDCl3): d = 7.60–7.69 (m, 4 H), 7.29–7.39 (m,
6 H), 2.10–2.22 (m, 2 H), 1.84–1.96 (m, 2 H), 0.67 (t, J = 7.5 Hz, 6
H).
IR (neat): 3441, 2976, 2926, 1600, 1493, 1445, 1379, 1052, 1027,
753, 693 cm–1.
13C NMR (75.5 MHz, CDCl3): d = 8.6, 32.7, 90.3, 125.5, 126.2,
1H NMR (300 MHz, CDCl3): d = 7.26–7.40 (m, 10 H), 4.13 (d, J =
5.7 Hz, 1 H), 1.94–2.01 (m, 1 H), 1.63 (s, 3 H), 1.34–1.41 (m, 1 H),
1.06 (d, J = 5.7 Hz, 1 H), 0.84 (t, J = 7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 8.8, 22.9, 32.6, 79.1, 95.8, 100.0,
125.0, 127.1, 127.2, 128.0, 128.7, 128.9, 136.8, 145.4.
MS (EI, 70 eV): m/z (%) = 252 (6) [M+ – N2], 221 (26), 205 (7), 178
(7), 143 (25), 128 (22), 115 (37), 105 (83), 91 (100), 77 (51), 44
(100).
127.9, 128.1, 128.8, 130.2, 136.4.
MS (EI, 70 eV): m/z (%) = 264 (14) [M+ – N2], 235 (21), 207 (100),
178 (60), 129 (28), 91 (33).
UV/Vis (MeCN): lmax (e) = 361 nm (154).
HRMS-CI: m/z [M+ + H] calcd for C19H20N2O: 293.1654; found:
293.1649.
UV/Vis (MeCN): lmax (e) = 341 nm (204).
HRMS-CI: m/z [M+ + H] calcd for C18H20N2O: 281.1654; found:
Acknowledgment
We gratefully acknowledge Anton A. Shakhmin (REU student) for
help with the synthesis of cis-1b, Dr. Thomas H. Kinstle and Dr.
Sergey Voskresensky for fruitful discussions, and the McMaster
Endowment for support of this research.
281.1659.
cis-3-Ethyl-3,5-dihydro-5-methyl-3,5-diphenyl-4H-pyrazol-4-
one (cis-1b):
The procedure used for the Jones oxidation of cis-2b was similar to
that reported for the synthesis of cis-1a.1
References
Yield: 0.14 g (96%); mp 58–61 °C.
(1) Pirkle, W. H.; Hoover, D. J. J. Org. Chem. 1980, 45, 3407.
(2) Pirkle, W. H.; Kalish, R. J. Am. Chem. Soc. 1967, 89, 2781.
(3) (a) Adam, W.; Fuss, A.; Mazenod, F. P.; Quast, H. J. Am.
Chem. Soc. 1981, 103, 998. (b) Quast, H.; Fuss, A. Angew.
Chem., Int. Ed. Engl. 1981, 20, 291. (c) Sandler, W.;
Wrobel, R.; Komnick, P.; Rademacher, P.; Muchall, H. M.;
Quast, H. Eur. J. Org. Chem. 2000, 1, 91.
(4) (a) Berson, J. A. Acc. Chem. Res. 1978, 446. (b) Crawford,
R. J.; Tokunaga, H. Can. J. Chem. 1974, 52, 4033.
(5) (a) Kidwai, M.; Misra, P. Synth. Commun. 1999, 29, 3237.
(b) Sachchar, S. P.; Singh, A. K. J. Indian Chem. Soc. 1985,
62, 142. (c) Kiyoshi, T.; Katsuya, N.; Nobukiyo, K.;
Takashi, T.; Takehiro, O.; Hachiro, S.; Masaaki, M. Chem.
Pharm. Bull. 1997, 45, 987.
IR (neat): 3054, 2984, 2918, 1763, 1597, 1490, 1443, 1073, 1027,
775, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.54 (m, 4 H), 7.33–7.44 (m, 6 H),
2.15–2.35 (m, 1 H), 1.90–2.10 (m, 1 H), 1.55 (s, 3 H), 0.74 (t, J =
7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 8.7, 24.4, 31.8, 86.7, 90.1, 125.4,
125.5, 128.1, 128.8, 128.9, 136.7, 137.0, 214.8.
MS (EI, 70 eV): m/z (%) = 250 (20) [M+ – N2], 234 (63), 222 (24),
193 (100), 178 (57), 128 (14), 91 (33).
UV/Vis (MeCN): lmax (e) = 357 nm (269).
Synthesis 2005, No. 17, 2901–2905 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 3,5-Dialkyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-ones
2905
(6) (a) Wayne, W.; Adkins, H. In Organic Synthesis, Vol. 3;
(8) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett.
1973, 1011. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J.
Am. Chem. Soc. 1974, 96, 7503. (c) Mukaiyama, T. Angew.
Chem., Int. Ed. Engl. 1977, 16, 817.
(9) (a) Tanabe, Y.; Matsimoto, M.; Higashi, T.; Misaki, T.; Itoh,
T.; Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron
2002, 58, 8269. (b) Yoshida, Y.; Hayashi, R.; Sumihara, H.;
Tanabe, Y. Tetrahedron Lett. 1997, 38, 8727.
(10) (a) Hasegawa, E.; Ishiyama, K.; Horaguchi, T.; Shimizu, T.
J. Org. Chem. 1991, 56, 1631. (b) Wasserman, H. H.;
Aubrey, N. E.; Zimmerman, H. E. J. Am. Chem. Soc. 1953,
75, 96. (c) Domagala, J. M.; Bach, R. D. J. Am. Chem. Soc.
1979, 44, 3168.
Wiley: New York, 1955, 367. (b) Calloway, N. O.; Green,
L. D. J. Am. Chem. Soc. 1937, 59, 809. (c) Mazza, L. J.;
Guarna, A. Synth. Commun. 1980, 41. (d) Labadie, J. W.;
Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634.
(e) Lyle, R. E.; DeWitt, E. J.; Nichols, N. M.; Cleland, W. J.
Am. Chem. Soc. 1953, 75, 5959. (f) Karger, M. H.; Mazur,
Y. J. Org. Chem. 1971, 36, 540. (g) Lutz, R. E.; Slade, L. T.
J. Org. Chem. 1961, 26, 4888.
(7) (a) Takeda, T.; Kabasawa, Y.; Fujiwara, T. Tetrahedron
1995, 51, 2515. (b) Pelter, A.; Ward, R. S.; Ohlendorf, D.;
Ashdown, D. H. J. Tetrahedron 1979, 35, 531. (c) Brunner,
M.; Maas, G. Synthesis 1995, 957. (d) Cox, C. D.; Breslin,
M. J.; Mariano, B. J. Tetrahedron Lett. 2004, 45, 1489.
(e) Bouhlel, E.; Hassine, B. B. Synth. Commun. 1992, 15,
2183.
Synthesis 2005, No. 17, 2901–2905 © Thieme Stuttgart · New York