Org. Synth. 2002, 79, 84
DOI: 10.15227/orgsyn.079.0084
(R)-3-PHENYLCYCLOHEXANONE
[
Cyclohexanone, 3-phenyl-, (R)-
]
Submitted by Tamio Hayashi, Makoto Takahashi, Yoshiaki Takaya, and Masamichi Ogasawara
1
.
Checked by Timothy B. Durham and Marvin J. Miller.
1. Procedure
Caution! All reactions should be conducted in a well-ventilated hood.
(R)-(+)-3-Phenylcyclohexanone
(1).
Method A. A 500-mL, two-necked, round-bottomed
flask, fitted with a magnetic stirring bar, rubber
septum, and a reflux condenser attached to a gas-flow
adapter with a stopcock, is charged with
12.2 g (100 mmol) of phenylboronic
acid
(Notes 1, 2),
300 mg (0.482
mmol) of (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
[(R)-BINAP] (Notes 3, 4), and
103 mg
(0.399 mmol) of acetylacetonatobis(ethylene)rhodium(I)
(Note 5), and the flask is flushed with nitrogen.
To the flask are added
3.86 g (3.90
mL, 40.2 mmol) of 2-cyclohexenone
(Note 6),
200 mL of 1,4-dioxane
(Note 7), and 20 mL of water via syringe, and the entire orange
mixture is immersed in a oil bath preheated to 120°C and heated
at 105°C for 3 hr. After the solvent is cooled to room temperature, it is removed
under reduced pressure on a rotary evaporator. After concentration
of the initial reaction mixture on a rotary evaporator, the
residue is dissolved in
diethyl ether
(100 mL). The resulting solution is transferred to a 500-mL
separatory funnel and washed with 1.2 M hydrochloric
acid (HCl, 100 mL) followed by
5%
sodium hydroxide (NaOH) solution (100 mL).
The aqueous washes are separately extracted with
diethyl
ether (30 mL each). The ether layers are combined
and washed with saturated
sodium chloride
solution (100 mL), dried over anhydrous
magnesium sulfate
, filtered, and the filtrate concentrated
on a rotary evaporator to give a brown oil. The oil is filtered
through silica (200 mL) with
hexanes (500 mL) followed by
diethyl ether (400 mL)
on a 4-cm φ column. Fractions of eluent (20 mL) are collected and those containing
the product as determined by TLC are combined and concentrated on a rotary
evaporator to give a brown oil that is distilled under reduced pressure
(0.5 mm) to give 5.77 g (83% yield) of
(R)-3-phenylcyclohexanone
(1)
(Note 8) as a colorless oil. The enantiomeric purity is 98.6%
ee, which is determined by HPLC analysis using a chiral stationary phase column (Note 9).
Method B. A dry, 200-mL, two-necked, round-bottomed
flask fitted with a magnetic stirring bar, rubber
septum, and a reflux condenser attached to a gas-flow
adapter with a stopcock, is flushed with nitrogen.
The flask is charged with
3.95 g (25.2
mmol) of bromobenzene
(Note 10) and
12.5 mL
of dry diethyl ether
(Note 11)
via syringe, and cooled to 0°C in an ice-water bath. At this
temperature,
16.7 mL (25.1 mmol)
of a 1.50 M solution of n-butyllithium
in hexane
(Note 12) is added.
The ice-water bath is removed and the mixture is stirred at
room temperature for 1 hr. The flask is cooled to −78°C in a dry ice-acetone
bath, and
2.59 g (24.9 mmol)
of trimethoxyborane
(Note 13)
is added dropwise over a period of 10 min via syringe. The mixture is stirred at −78°C
for 30 min and slowly warmed to room temperature by removal of the dry ice-acetone
bath. In a second flask, a 100-mL, two-necked, round-bottomed
flask, equipped with a magnetic stirring bar, rubber
septum, and a gas-flow adapter with a stopcock,
are placed
74.7 mg (0.120 mmol)
of (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
[(R)-BINAP] (Notes 3, 4), and
25.8 mg
(0.100 mmol) of acetylacetonatobis(ethylene)rhodium(I)
(Note 5). After the flask is flushed with nitrogen,
50 mL of 1,4-dioxane
is added via syringe, and the mixture is stirred at room temperature for 10 min. To
the first flask containing the phenylborate reagent,
Lithium phenyltrimethoxyborate
, are added successively, via
syringe
0.975 g (10.1 mmol)
of 2-cyclohexenone
(Note 6),
0.54 mL of water, and the catalyst solution from the second flask. The entire mixture
is heated in an oil bath at 100°C for 12 hr. After the solvent
is cooled to room temperature, it is removed under reduced pressure on a rotary
evaporator. The dark brown residue is diluted with
diethyl
ether (100 mL) and transferred to a 500-mL
separatory funnel. The ether solution is washed with
10%
hydrochloric acid (100 mL) and
5% aqueous sodium hydroxide
(100 mL). The aqueous layers are extracted with
diethyl ether (30 mL each).
The organic layers are combined, washed with aqueous saturated
sodium
chloride (100 mL), and dried over anhydrous
magnesium sulfate
. The solvent
is removed under reduced pressure on a rotary evaporator to
give a brown oil, which is dissolved in
5 mL
of diethyl ether
and chromatographed on silica gel
[4 cm Φ,
200 mL of silica gel
(Note 14)]. Elution with
500
mL of hexane
(Note 15)
followed by elution with
400 mL of diethyl
ether
gives crude
3-phenylcyclohexanone
(1), collected as 20-mL
fractions and combined.
Distillation under reduced pressure (bp 125-130°C
at 0.5 mm) gives 1.55 g
(88.1% yield) of
(R)-3-phenylcyclohexanone
(1)
(Note 8) as a colorless oil. The enantiomeric purity is 98.3%
ee, which is determined by HPLC analysis using a chiral stationary phase column (Note 9).
2. Notes
1.
Phenylboronic acid
was purchased from Tokyo Kasei Kogyo Co., Ltd.
and
used as received.
2.
The use of
2.5 equiv (to 2-cyclohexenone)
of
phenylboronic acid
is
important for a high yield. With
1.0 equiv of phenylboronic
acid
, the yield is less than
70%.
3.
(R)-BINAP is commercially available from
Aldrich Chemical Company, Inc.
, although the submitters
have prepared it according to the reported procedures.
2
4.
This molar ratio (1.2 : 1) of BINAP to the
rhodium(I)
is required for high enantioselectivity. With a 1 : 1 ratio, the enantioselectivity
is usually 1 or 2% lower.
5.
Acetylacetonatobis(ethylene)rhodium(I)
is commercially available from Strem Chemicals, Inc.
,
although the submitters have prepared it according to a reported procedure.
3
6.
2-Cyclohexenone
was purchased from Tokyo Kasei Kogyo Co., Ltd.
and
distilled before use.
7.
1,4-Dioxane was
purchased from Wako Pure Chemical Industries, Ltd.
and distilled from
benzophenone ketyl
before use.
8.
Specific rotation value of
1:
[α]D
20+21° (CHCl3, c 0.96)
[literature rotation for (
R)-
1 (98.7% ee);
4
[α]D
20+20.5° (c
0.58, CHCl3)]. The spectra are as follows:
1H NMR (500 MHz, CDCl
3) δ:
1.77 (qdd, 1 H, J = 12.6, 4.4, 3.3), 1.85 (qd, 1 H, J = 12.3, 3.3),
2.07 (dm, 1 H, J = 13.1), 2.14 (ddq, 1 H, J = 12.7, 6.0, 3.1),
2.37 (tdd, 1 H, J = 12.6, 6.3, 1.1), 2.45 (dm, 1 H, J = 14.5),
2.52 (td, 1 H, J = 12.4, 1.1), 2.59 (ddt, 1 H, J = 14.0, 4.5, 2.0),
3.00 (tt, 1 H, J = 11.9, 3.8), 7.19-7.25 (m, 3 H), 7.32
(t, 2 H, J = 7.5)
;
13C
NMR (125 MHz, CDCl
3) δ: 24.88, 32.10, 40.46,
44.04, 48.21, 126.01, 126.03,
128.06, 143.86, 209.80
.
9.
The column contained Daicel Chiralcel OD-H (eluent,
hexane/
2-propanol
= 98/2).
10.
Bromobenzene was
purchased from Kanto Chemical Company Inc.
, and used
as received.
11.
Diethyl ether was
purchased from Nacalai Tesque Company Inc.
, and distilled
from
benzophenone ketyl
before
use.
12.
n-Butyllithium
in hexane was purchased from Kanto Chemical Company
Inc.
, and used as received.
13.
Trimethoxyborane (trimethyl
borate) was purchased from Wako Pure Chemical Industries, Ltd.
and used as received.
14.
Silica gel 60 100-210 μm (Kanto
Chemical Company Inc.) was used.
15.
Biphenyl
as a by-product is removed by this elution.
3. Discussion
Conjugate addition of organometallic reagents to electron-deficient olefins constitutes
one of the versatile methodologies for forming carbon-carbon bonds. Although considerable
efforts have been made to develop efficient chiral catalytic systems for asymmetric
conjugate addition, the successful examples are rare in terms of enantioselectivity,
catalytic activity, and generality.
5 In 1997, Miyaura and co-workers
6
found that a
phosphine-rhodium complex catalyzes the 1,4-addition
of aryl- and alkenylboronic acids to α,β-unsaturated ketones giving β-substituted
ketones. Based on this finding, the submitters developed rhodium-catalyzed, asymmetric,
1,4-addition reactions of organoboron reagents to electron-deficient olefins. High
enantioselectivity has been achieved in the reaction of α,β-unsaturated
ketones with aryl- and alkenylboronic acids, which was carried out in
dioxane/H2O
at 100°C in the presence of a
rhodium catalyst generated from
acetylacetonatobis(ethylene)rhodium(I)
and
(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(BINAP).
7 Both acyclic and cyclic enones gave the
corresponding optically active ketones of over 90% ee. In place of isolated organoboronic
acids, 2-alkenyl-1,3,2-benzodioxaboroles, readily accessible by hydroboration of alkynes
with
catecholborane
,
8 and arylborates, generated by
reaction of aryllithiums with
trimethoxyborane
,
9 can also be used for the asymmetric
1,4-addition. α,β-Unsaturated esters
10 and 1-alkenylphosphonates
11 undergo the
rhodium-catalyzed asymmetric addition of organoboron derivatives to give the corresponding
1,4-addition products of over 90% ee. The submitters also studied some basic factors,
including reaction temperature, solvent, rhodium precursor, and chiral ligand, which
are capable of affecting the enantioselectivity and catalytic activity.
12
Some of the optically active products obtained by the rhodium-catalyzed, asymmetric,
1,4-addition of aryl- and alkenylboronic acids or their derivatives are shown in Figure
1.
Figure 1. Products obtained by the rhodium-catalyzed asymmetric 1,4-addition [(S)-BINAP
is used]
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(R)-3-Phenylcyclohexanone:
Cyclohexanone,
3-phenyl-, (R)- (9); (34993-51-6)
Phenylboronic acid:
Benzeneboronic acid
(8);
Boronic acid, phenyl- (9); (98-80-6)
(R)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
[(R)-BINAP]:
Phosphine oxide, [1,1'-binaphthalene]-2,2'-diylbis[diphenyl-,
(R)- (11); (94041-16-4)
Acetylacetonatobis(ethylene)rhodium (1):
Rhodium,
bis(ethylene)(2,4-pentanedionato)- (8);
Rhodium, bis(η2-ethene)(2,4-pentanedionato-O,O'-
(9); (12082-47-2)
Cyclohexenone: HIGHLY TOXIC:
2-Cyclohexen-1-one
(8,9); (930-68-7)
Bromobenzene:
Benzene, bromo-
(8,9); (108-86-1)
Butyllithium:
Lithium, butyl-
(8,9); (109-72-8)
Trimethoxyborane: ALDRICH;
Trimethyl
borate:
Boric acid, trimethyl ester (8,9); (121-43-7)
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