Org. Synth. 1998, 75, 69
DOI: 10.15227/orgsyn.075.0069
2-(4-METHOXYPHENYL)-2-CYCLOHEXEN-1-ONE: PREPARATION OF 2-IODO-2-CYCLOHEXEN-1-ONE AND SUZUKI COUPLING WITH 4-METHOXYPHENYLBORONIC ACID
[
2-Cyclohexen-1-one, 2-(4-methoxyphenyl)- and 2-Cyclohexen-1-one, 2-iodo-)]
Submitted by Frederic S. Ruel, Matthew P. Braun, and Carl R. Johnson
1
.
Checked by Alain Zakarian and David J. Hart.
1. Procedure
Caution! This procedure involves volatile and toxic reagents and should be conducted in an efficient fume hood.
A.
2-Iodo-2-cyclohexen-1-one
. A 500-mL, three-necked, round-bottomed flask equipped with a 1.5-in. Teflon-coated magnetic stirring bar, glass stopper, 50-mL addition funnel, and a reflux condenser is charged with a 1:1 mixture of 75 mL of anhydrous diethyl ether
(Note 1) and 75 mL of pyridine
. With vigorous stirring,
53 g (0.21 mol) of iodine
(Note 2) is added slowly. At the completion of the addition, the dark brown mixture is stirred an additional 10-20 min until complete dissolution is obtained.
The addition funnel is charged with
9.53 mL (9.46 g, 98.4 mmol) of 2-cyclohexen-1-one
(Note 3). After addition of approximately 2 mL of the enone, the flask is quickly immersed in an ice bath
(Note 4) and the remainder of the enone is added dropwise to the cooled, stirred, dark-brown solution over a 10-min period. At the completion of the addition, the ice bath is removed and the mixture is stirred an additional 2.5 hr. The reaction mixture is poured into a 1-L separatory funnel and the round-bottomed flask is washed with two
200-mL portions of diethyl ether
that are added to the separatory funnel. The mixture is washed successively with two
150-mL portions of 2N hydrochloric acid
to remove pyridine
(Note 5), three
150-mL portions of aqueous 20%
sodium thiosulfate (Na2S2O3)
(Note 6) and
100 mL of brine
. The resulting organic phase is dried over anhydrous
magnesium sulfate
, filtered, and evaporated at reduced pressure to give a yellow-orange solid.
This material is recrystallized from
diethyl ether/pentane (2:1) to give 15.1 g (69%) of
2-iodo-2-cyclohexen-1-one
as a pale yellow solid, mp 48.5-49°C
(Note 7). If desired, an additional 2.4 g (11%; mp 48-49°C) can be isolated by concentration of the mother liquor, column chromatography of the residue on
40 g of silica gel
eluting with a mixture of
10%
ethyl acetate in petroleum ether
, and recrystallization of the collected iodoenone from pentane.
B.
2-(4-Methoxyphenyl)-2-cyclohexen-1-one
. A 500-mL, round-bottomed flask, equipped with a 1.5-in. Teflon-coated magnetic stirring bar and an argon inlet adaptor, is charged with
10.02 g (45.1 mmol) of 2-iodo-2-cyclohexen-1-one
,
10.69 g (70.4 mmol, 1.56 eq) of 4-methoxyphenylboronic acid
(Note 8),
16.72 g (72.1 mmol, 1.6 eq) of silver(I) oxide (Ag2O)
(Note 9),
0.85 g (2.8 mmol, 6 mol %) of triphenylarsine
(Note 10),
0.53 g (1.4 mmol, 3 mol %) of palladium(II) bis(benzonitrile)dichloride
(Note 11),
200 mL of tetrahydrofuran (THF) and 25 mL of water (Note 12). The reaction mixture, flushed with argon, is stirred for 1 hr and then quenched by the addition of
125 mL of saturated aqueous ammonium chloride
. After the solution is stirred for 1 hr, the resulting two-phase mixture is poured into a 2-L separatory funnel. The upper (organic) and lower (aqueous) phases are separated. The aqueous phase is extracted twice with
300-mL portions of diethyl ether
. The combined organic phases are washed successively with two 500-mL portions of water and
200 mL of brine
. The resulting organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure to give a pale yellow solid.
The resulting product is purified by column chromatography on
90 g of silica gel
eluting with a mixture of
30%
ethyl acetate in petroleum ether
(Note 13). The chromatographed material is further purified by recrystallization from
diethyl ether/pentane (2:1) to give 7.1 g (78%) of
2-(4-methoxyphenyl)-2-cyclohexen-1-one
as a pale yellow solid, mp 58-59°C
(Note 14). An additional 1.6 g (18%; mp 58-59°C) can be isolated by concentration of the mother liquor and column chromatography of the residue on
30 g of silica gel
eluting with a mixture of
10%
ethyl acetate in petroleum ether
.
2. Notes
1.
Unless otherwise indicated, the solvents are reagent grade and are used without further purification.
2.
Iodine certified A.C.S. was purchased from Fisher Scientific Company
.
3.
2-Cyclohexen-1-one (97%) was purchased from Aldrich Chemical Company, Inc.
Caution! This chemical is highly toxic; glove protection is recommended.
4.
The reaction is exothermic. The first addition of 2 mL of the enone is necessary to avoid formation of aggregates that occurs if the mixture is cooled before this initial addition is made.
5.
These first washes are very important; less acidic washes can promote reversal of the reaction from
pyridine left in the medium.
6.
These washes remove the brown color of the upper (organic) phase. The aqueous solution of
sodium thiosulfate is 20% by weight.
7.
Spectral data for
2-iodo-2-cyclohexen-1-one follow:
1H NMR (300 MHz, CDCl
3) δ: 2.07 (quint, 2 H, J = 6.3), 2.43 (dt, 2 H, J = 5.4, 5.8), 2.64 (apparent t, 2 H, J = 6.3), 7.76 (t, 1 H, J = 4.5)
;
13C NMR (75.5 MHz, CDCl
3) δ: 22.7, 29.8, 37.1, 103.7, 159.5, 192.1
.
8.
4-Methoxyphenylboronic acid can be purchased from Aldrich Chemical Company, Inc.
9.
Silver(I) oxide, 99+%, was purchased from Aldrich Chemical Company, Inc.
10.
Triphenylarsine, 97%, was purchased from Aldrich Chemical Company, Inc.
11.
Palladium(II) bis(benzonitrile)dichloride was purchased from Aldrich Chemical Company, Inc.
12.
The dissolution of all solid chemicals may be slightly exothermic but this does not cause any build-up of pressure.
13.
Insoluble by-products could be removed by hot filtration but with a significant loss of product. Chromatography is advised to optimize the isolated yield.
14.
This material gave a satisfactory combustion analysis. Characterization data for
2-(4-methoxyphenyl)-2-cyclohexen-1-one follow:
1H NMR (300 MHz, CDCl
3) δ: 2.09 (quint, 2 H, J = 6.3), 2.5-2.6 (m, 4 H), 3.80 (s, 3 H), 6.88 (d, 2 H, J = 8 Hz), 6.98 (t, 1 H, J = 4.5), 7.26 (d, 2 H, J = 8 Hz)
;
13C NMR (75.5 MHz, CDCl
3) δ: 22.9, 26.5, 39.0, 55.2, 113.4, 128.9, 129.7, 139.6, 146.9, 159.0, 198.2
; Anal. calcd for C
13H
14O
2: C, 77.20; H, 6.97. Found: C, 77.09; H, 7.01.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Cycloalkenones are ubiquitous as reactive intermediates and bioactive materials. Modification of a simple cycloalkenone by addition of a carbon substituent at the α-position should be a useful transformation, but one that is not readily accomplished by conventional enone chemistry. α-Substituted cycloalkenones could of themselves be of interest, but perhaps, of more general importance would be their use as intermediates for the production of substituted cycloalkanones or α,β-disubstituted cycloalkanones by a subsequent conjugate addition procedure.
2 These strategies avoid many of the limitations attendant to the trapping of enolates with carbon electrophiles. The method of Kim involving treatment of enones with the combination of a
dimethyl acetal
,
pyridine and trimethylsilyl triflates results in α-(1-methoxyalkyl)enones.
3 The metallation of α-bromoenones masked as ketals for α-functionalizations has been developed by Smith.
4
This preparation illustrates an efficient two-step process for the transformation of a cycloalkenone to the corresponding α-substituted derivative. The first step involves the installation of an α-iodo substituent by a process thought to involve nucleophilic addition of
pyridine,
iodine capture of the resulting enolate, and pyridine-promoted elimination of
pyridine.
5 The resulting vinyl iodides are superior to other vinyl halides as participants in a variety of transition-metal catalyzed coupling reactions, illustrated here by the Suzuki coupling with an arylboronic acid. Other coupling partners that have been investigated in the laboratories of the submitters include alkenes, vinyl metals,
6 arylstannanes,
7 and alkyl-9-BBN's.
2
Prior to our original report
7 on this method, acceptable and general preparative routes to α-iodocycloalkenones had not been described. Treatment of a β-substituted cycloalkenone with
trimethylsilyl azide
and a mixture of
iodine and
pyridine sequentially in
dichloromethane has now been reported as a method for the preparation of β-substituted-α-iodocycloalkenones.
8 The combination of
iodine and
pyridinium dichromate has also been reported to provide α-iodoenones from enones
9 as well as from ethynyl carbinols.
9,10 Some successes have also been achieved with enones and
iodine azide (IN3)11
and
iodine/ceric ammonium nitrate
.
12,13,14 The submitters' first variant
5 of the present procedure used
carbon tetrachloride
as a solvent. In this procedure this solvent has been replaced with the more benign
diethyl ether.
The Suzuki coupling of
2-iodo-2-cyclohexen-1-one and
4-methoxyphenylboronic acid is achieved using
silver(I) oxide as a suspension in aqueous
THF as the base. Unlike earlier reports,
15,16,17 in which up to 6 equiv of Ag
2O were used, we have found that 1.6 equiv is completely effective. Under these mild conditions, rapid conversion can be achieved at room temperature for a large variety of sensitively functionalized partners in near quantitative yields (see Table).
18
TABLE
2-ARYL-2-CYCLOALKENONES FROM 2-IODO-2-CYCLOALKENONES
|
|
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-(4-Methoxyphenyl)-2-cyclohexen-1-one:
2-Cyclohexen-1-one,2-(4-methoxyphenyl)- (10);
(63828-70-6)
2-Iodo-2-cyclohexen-1-one:
2-Cyclohexen-1-one, 2-iodo- (8,9);
(33948-36-6)
4-Methoxyphenylboronic acid:
Benzeneboronic acid, p-methoxy- (8),
Boronic acid,(4-methoxyphenyl)- (9);
(5720-07-0)
Pyridine (8,9);
(110-86-1)
Iodine (8,9);
(7553-56-2)
2-Cyclohexen-1-one, HIGHLY TOXIC (8,9);
(930-68-7)
Sodium thiosulfate:
Thiosulfuric acid, disodium salt (8,9);
(7772-98-7)
Silver(I) oxide:
Silver oxide (8);
Silver oxide (Ag2O) (9);
(20667-12-3)
Triphenylarsine:
Arsine, triphenyl- (8,9);
(603-32-7)
Palladium(II) bis(benzonitrile)dichloride:
Palladium, bis(benzonitrile)dichloro- (8,9);
(14220-64-5)
Copyright © 1921-, Organic Syntheses, Inc. All Rights Reserved