Studies of the condensation of sulfones with ketones and aldehydes

Article abstract of DOI:10.1021/jo051947s

The condensation of ketones or aldehydes with sulfunes was shown to give a variety of products. Condensation of 2-methylcyclohexanone with dimethyl sulfone using potassium t-butoxide as base gave useful yields of 1,2- dimethylenecyclohexane. Under the same conditions, cycloheptanone, 3-methyl-2-butanone, and 2-bulanone were converted to dienes. Remarkably, these reaction conditions converted acetophenone into p-terphenyl (10%) and (E)-1,4-diphenyl-3-penten-1-one (44%). Propiophenone was converted to 2′-methyl-p-terphenyl (61%). Using α-tetralone produced 1-methynaphthalene and naphthalene. No reaction took place with β-tetralone. Using diethyl sulfone with α-tetralone lead to pure naphthalene. Condensation of isobutyraldehyde and dimethyl sulfone using potassium t-butoxide gave isoprene in low yield. Using benzaldehyde and benzyl phenyl sulfone in N,N-dimethylcinnamide gave 1,2-diphenyl-1- phenylsulfonylethylene, N,N-dimethylcinnamide, and a complex condensation product. Only 1,2-diphenyl-1-phenylsulfonylethylene was obtained when the solvent was THF.

Full text of DOI:10.1021/jo051947s

Studies of the Condensation of Sulfones with Ketones and Aldehydes
Michael E. Garst,† Lloyd J. Dolby,* Shervin Esfandiari, Rachel A. Okrent, and
Alfred A. Avey
Organic Consultants, Inc., 132 East Broadway, Suite 107, Eugene, Oregon 97401
Orgcon2@Mindspring.com
ReceiVed September 16, 2005
The condensation of ketones or aldehydes with sulfones was shown to give a variety of products.
Condensation of 2-methylcyclohexanone with dimethyl sulfone using potassium t-butoxide as base gave
useful yields of 1,2-dimethylenecyclohexane. Under the same conditions, cycloheptanone, 3-methyl-2-
butanone, and 2-butanone were converted to dienes. Remarkably, these reaction conditions converted
acetophenone into p-terphenyl (10%) and (E)-1,4-diphenyl-3-penten-1-one (44%). Propiophenone was
converted to 2′-methyl-p-terphenyl (61%). Using R-tetralone produced 1-methynaphthalene and
naphthalene. No reaction took place with â-tetralone. Using diethyl sulfone with R-tetralone lead to pure
naphthalene. Condensation of isobutyraldehyde and dimethyl sulfone using potassium t-butoxide gave
isoprene in low yield. Using benzaldehyde and benzyl phenyl sulfone in N,N-dimethylacetamide gave
1,2-diphenyl-1-phenylsulfonylethylene, N,N-dimethylcinnamide, and a complex condensation product.
Only 1,2-diphenyl-1-phenylsulfonylethylene was obtained when the solvent was THF.
Introduction
to achieve. In our hands, the reaction gave very poor yields
and a noteworthy stench. On consideration of the proposed
mechanism, it appeared to us that the reaction might go better
by substituting dimethyl sulfone for dimethyl sulfoxide. We were
pleased to find that the condensation of 2-methylcyclohexanone
with dimethyl sulfone using potassium t-butoxide in N,N-
dimethylacetamide (DMAC) gave useful yields of 1,2-dimeth-
ylenecyclohexane (eq 1). The crude 1,2-dimethylenecyclohexane
The critical step of a recent synthesis required 1,2-dimeth-
ylenecyclohexane (1a). The Diels-Alder condensation of 1a
with methyl acrylate gives the required octalin intermediate 2a
with the double bond in the desired position. Most reported
preparations of 1,2-dimethylenecyclohexane are several steps
and are not readily adapted to large-scale synthesis.1,2 One report
claims good yields of 1a from condensation of dimethyl
sulfoxide with 2-methylcyclohexanone.1b However, the pub-
lished yields from this synthesis were higher than we were able
† Allergan Inc., 2525 DuPont Drive, Mail Code RD3D, Irvine, California
92612.
(1) (a) Bailey, W. J.; Golden, H. R. J. Am. Chem. Soc. 1953, 75, 4780.
(b) Arenz, T.; Vostell, M.; Frauenerath, H. Synlett 1991, 23. (c) Bloomquist,
A. T.; Longone, D. T. J. Am. Chem. Soc. 1957, 79, 3916. (d) Bartlett, P.
D.; Wingrove, A. S.; Owyang, R. J. Am. Chem. Soc. 1968, 90, 6067. (e)
Van Straten, J. W.; van Norden, J. J.; van Schaik, T. A. M.; Franke, G. T.;
de Wolf, W. H.; Bickelhaupt, F. Recl.: J. R. Neth. Chem. Soc. 1978, 105.
(f) Quin, L. D.; Leimert, J.; Miller, R. W.; McPhail, A. T. J. Org. Chem.
1979, 44, 6. (g) Block, E.; Aslam, M. Org. Synth. Coll. Vol. VIII, 1993,
212.
is contaminated with impurities which are difficult to separate.
However, the toluene solution of the crude diene 1a was used
directly in the Diels-Alder reaction with methyl acrylate and
the desired adduct was readily purified. This sequence gave
1,2,3,4,5,6,7,8-octahydro-2-naphthoic acid1a (2a) in 49% yield
based on 2-methylcyclohexanone.
(2) Bailey, W. J.; Golden, H. R. J. Am. Chem. Soc. 1957, 79, 6516.
10.1021/jo051947s CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/13/2005
J. Org. Chem. 2006, 71, 553-556
553

Garst et al.
yield (%)
TABLE 1. Summary of Diene Synthesis and Diels-Alder Reactions
ketone/aldehyde
diene
yield (%)/method
dienophile
product
2-methylcyclohexanone
3-methyl-2-butanone
2-butanone
isobutyraldehyde
2-methylcycloheptanone
1a
3
5
11
1b
A
methyl acrylate
methyl acrylate
2a
4
49
36
ca. 40/A
26/A
7.5/B
42/A
maleic anhydride
2b
30
SCHEME 1
We have made a preliminary study of the scope of this
reaction by using various ketones and aldehydes with three
sulfones.
Results and Discussion
Reaction of Ketones with Dimethyl Sulfone. A study of
reaction conditions was carried out for the synthesis of diene
1a. First, a variety of solvents were explored. N-methylpyrroli-
done, DMSO, DMAC, DMF, glyme, and diglyme gave similar
results. However, a poor yield (<10%) was obtained in refluxing
THF: this is most likely due to the lower reaction temperature.
To test this hypothesis, two identical reactions in DMAC were
run at 100 and 90 °C giving the diene 1a in yields of 60% and
40%, respectively. DMAC was chosen as the solvent simply
because it is easily removed by aqueous extraction.
Treatment of 2-butanone under identical conditions gave
isoprene (5) in 26% yield after distillation (eq 2).
The scope of this reaction was explored by studying variations
in ring size and substituents for cyclic ketones. The reaction
was further examined with several aromatic and acyclic ketones.
The reaction of cyclohexanone and dimethyl sulfone with
potassium t-butoxide in DMAC was expected to give 3-meth-
ylenecyclohexene. The reaction gave a mixture of four com-
pounds by GC analysis. Analysis of the mixture by UV, NMR,
and GC/MS showed all four of the compounds to be isomers
of the molecular formula C7H10.3 It appears that the expected
product is formed and suffers double-bond isomerization under
the strongly basic reaction conditions. Unfortunately, no reaction
occurred when potassium carbonate was used as the base.
However, the diene products obtained from dimethyl sulfone
and cyclohexanone are markedly different from the product
obtained with dimethyl sulfoxide and cyclohexanone which was
identified as 2-methylenecyclohexyl methanesulfenate.1b This
result shows that the products obtained with dimethyl sulfoxide
are not derived from contaminating dimethyl sulfone. The
reaction of 2,6-dimethylcyclohexanone with dimethyl sulfone
and potassium t-butoxide in DMAC gave a mixture of seven
unidentified compounds. Similarly, the reaction of 2-methyl-
cyclopentanone gave no useful products. However, under the
same conditions, 2-methylcycloheptanone gave 1,2-dimethyl-
enecycloheptane1e,g (1b), isolated as the Diels-Alder adduct
of maleic anhydride (5-oxatricyclo[7.5.0.0 3,7 ]tetradec-1(9)-
ene-4,6-dione, 2b) in 30% overall yield (Table 1). These
conditions, when applied to 3-methyl-2-butanone, gave 2,3-
dimethyl-1,3-butadiene (3, Scheme 1). To get an estimate of
the yield, a portion of the crude product was treated with methyl
acrylate to give 3,4-dimethylcyclohex-3-ene carboxylate (4)4 in
36% yield. This reaction is thus quite convenient for producing
a solution of 2,3-dimethyl-1,3-butadiene (3) to use in Diels-
Alder condensations if an alternative to the pinacol procedure
is needed.5
When a solution of R-tetralone and dimethyl sulfone in
DMAC was treated with potassium t-butoxide, a 9:1 mixture
of 1-methylnaphthalene (6) and naphthalene (7) was obtained
in 85% combined yield (eq 3). The origin of the naphthalene
was explored in connection with the study of the condensation
of R-tetralone with diethyl sulfone, a reaction which gives
naphthalene (7) exclusively (vide infra).
However, when â-tetralone was used instead of R-tetralone,
no reaction took place. It appears that â-tetralone is converted
to the enolate under the reaction conditions, and there is not a
high enough concentration of dimethyl sulfone anions and free
â-tetralone to give a reaction.
Surprisingly, when propiophenone was treated with dimethyl
sulfone and potassium t-butoxide in DMAC, 2′-methyl-p-
terphenyl (8)6 was formed in 61% yield (eq 4). That 8 is indeed
the product was confirmed by X-ray crystallography. Formation
of 8 requires two molecules of propiophenone and one carbon
from dimethyl sulfone as well as a two-electron oxidation.
(3) Spangler, C. W.; Hartford, T. W. J. Chem. Soc., Perkin Trans. I 1976,
16, 1792.
(4) Inukai, T.; Kasai, M. J. Org. Chem. 1965, 30, 3567.
(5) Allen, C. F. H.; Bell, A. Org. Synth. Coll. Vol III, 312.
(6) Sidorova, N. G.; Nikonovich, S. D. Zh. Obshch. Khim. 1960, 30,
921; Chem. Abstr. 1960, 55, 6451f.
554 J. Org. Chem., Vol. 71, No. 2, 2006

Condensation of Sulfones with Ketones and Aldehydes
TABLE 2. Summary of Reactions with Aromatic Ketones and Aldehydes with Various Sulfones
compound
sulfone
product
method
yield (%)
propiophenone
acetophenone
Me2SO2
Me2SO2
8
9
A
A
61
9
10
44
85
87
R-tetralone
Me2SO2
Et2SO2
benzyl phenyl sulfone
Me2SO2
Et2SO2
9:1 ratio of 6/7
7
NR
NR
A
A
A
A
A
B
R-tetralone
R-tetralone
â-tetralone
2-methylcyclohexanone
benzaldehyde
no useful product
benzyl phenyl sulfone
12
13
14
12
7.8
57
25
benzaldehyde
benzyl phenyl sulfone
Ba
78
a THF solvent.
SCHEME 2
dimethyl sulfone, which is more acidic than diethyl sulfone,
causes more condensation and less alkylation of the enolate to
take place.
Only starting materials were recovered from the attempted
condensation of R-tetralone with benzyl phenyl sulfone using
potassium t-butoxide in DMAC. We conclude that the anion
derived from benzyl phenyl sulfone is too stable to react with
a sluggish ketone. However, benzyl phenyl sulfone does
condense with the more reactive benzaldehyde (vide infra).
Reaction of Aldehydes with Sulfones. The reaction of
isobutyraldehyde and dimethyl sulfone with potassium t-
butoxide in DMAC gave 2-methyl-1,3-butadiene (5) in 7.5%
yield after distillation. The reaction of n-heptanal and dimethyl
sulfone under these conditions did not afford 1,3-octadiene.
However, benzaldehyde and benzyl phenyl sulfone in the
presence of potassium t-butoxide in DMAC gave a mixture of
1,2-diphenyl-1-phenylsulfonylethylene (12),10 N,N-dimethyl-
cinnamide (13),11 and a condensation product (14) derived from
one molecule of each of the three organic materials in the
reaction mixture (eq 6). The structure of compound 14 was
Under the same reaction conditions, acetophenone and
dimethyl sulfone gave p-terphenyl (9)7 and E-1,4-diphenyl-3-
penten-1-one (10)8 (Scheme 2).
Formation of p-terphenyl must involve two molecules of
acetophenone and requires two carbons from dimethyl sulfone.
A plausible mechanism involves ketone 10 as an intermediate.
Ketone 10 would be expected to lead to a mixture of the 2,5-
diphenyl-1,3,5-hexatrienes, which in turn would give terphenyl
upon cyclization and oxidation.
Reaction of Ketones with Diethyl Sulfone and Benzyl
Phenyl Sulfone. Reaction of 2-methylcyclohexanone and diethyl
sulfone with potassium t-butoxide in DMAC did not give any
useful products. As noted before, when R-tetralone was treated
with dimethyl sulfone, 1-methylnaphthalene (6) and naphthalene
(7) were formed in the ratio of 9:1 (eq 3, Table 2). However,
when R-tetralone was treated with diethyl sulfone, only naph-
thalene was formed in 87% yield.
In an attempt to determine the intermediate in this reaction,
R-tetralone was converted to 1-methoxy-3,4-dihydronaphthalene
(11)9 with 1,2-dimethoxypropane in the presence of p-TsOH.
When 11 was treated with potassium t-butoxide in DMAC,
naphthalene was formed in nearly quantitative yield (eq 5).
obtained by X-ray crystallography.
When this reaction was carried out in THF instead of DMAC,
only 12 was formed in 78% yield.
Experimental Section
General. Gas chromatography was performed on a capillary
column (HP-1 30 m × 0.32 mm and 0.25 µm film) with flame
ionization detection or on a megabore column (HP-5 10 m × 0.53
mm and 2.53 µm film) with thermal conductivity detection. NMR
spectra were obtained on a 300 MHz or on a 60 MHz, in CDCl3
with 1% TMS, instrument. All reactions were performed under
nitrogen. Column chromatography was performed on flash silica
From this result, it appears that the enolate of R-tetralone is
alkylated on oxygen by diethyl sulfone to give 1-ethoxyl-3,4-
dihydronaphthalene which would lead to naphthalene. Using
(7) Carnelley, T. J. Chem. Soc. 1880, 37, 701.
(8) Koppes, M. J. C. M.; Crabbendam, A. M.; Cerfontain, H. Recl. TraV.
Chim. Pays-Bas 1988, 107, 676.
(9) (a) Motohashi, S.; Satomi, M.; Fujimoto, Y.; Tatsuno, T. Synthesis
1982, 12, 1021. (b) Ortholand, J.-Y.; Vicart, N.; Greiner, A. J. Org. Chem.
1995, 60, 1880.
(10) Hellman, H.; Erbele, D. Ann. 1963, 662, 188.
(11) Staudinger, H.; Kon, N. Liebigs Ann. Chem. 1911, 384, 38.
J. Org. Chem, Vol. 71, No. 2, 2006 555

Garst et al.
gel (60 Å, 32-63 µ). All reagents and solvents were purchased
from commercial suppliers and used as received without further
purification.
potassium t-butoxide (53.76 g, 0.48 mol), and DMAC (200 mL).
The solution was then heated on a steam bath. When the internal
temperature reached 90 °C, a solution of isobutyraldehyde (14.4 g,
0.2 mol) in DMAC (50 mL) was added dropwise over a period of
30 min. Volatile product began to collect in the receiving flask,
which was cooled in an ice-methanol bath. Distillation was
complete after 1 h. The distillate (8 g) was washed with ice cold
water (1 × 5 mL) and 1 M HCl (1 × 5 mL) and filtered through
1 PS paper to give 1.0 g of 2-methyl-1,3-butadiene (5) (7.5%).
Method A. General Procedure for Condensations of Ketones
with Dimethyl Sulfone as Exemplified by Preparation of 1,2-
Dimethylenecyclohexane. A mechanically stirred solution of
2-methylcyclohexanone (208 g, 1.86 mol) and dimethyl sulfone
(419.5 g, 4.28 mol) in DMAC (2750 mL) was heated on a steam
bath to 75 °C. Powdered potassium t-butoxide (500 g, 4.46 mol)
was added all at once. The inside temperature rose to 98 °C upon
addition, and heating continued for 2 h. The GC analysis of the
reaction showed the reaction to be complete. The reaction was
cooled to room temperature in an ice bath, diluted with water (2
L), and extracted with toluene (3 × 1 L). The toluene solution could
be processed to isolate the primary condensation products or used
directly in a Diels-Alder reaction.
Acknowledgment. We thank Prof. Marilyn Olmstead of the
Chemistry Department of the University of California, Davis,
for the crystal structure determinations.
Supporting Information Available: Text giving experimental
details, characterization of new compounds, and X-ray crystal-
lographic files for 8 and 14 in CIF format is presented. This material
is available free of charge via the Internet at http://pubs.acs.org.
Method B as Exemplified by Preparation of 2-Methyl-1,3-
butadiene. A 500 mL three-necked flask fitted with a distillation
head with an efficient condenser, mechanical stirrer, and thermo-
meter was charged with dimethyl sulfone (43.2 g, 0.46 mol),
JO051947S
556 J. Org. Chem., Vol. 71, No. 2, 2006