Rhodium-catalyzed synthesis of 2,3-diaryl-1,4-diketones via oxidative coupling of benzyl ketones using α-thioketone oxidizing reagent

Article abstract of DOI:10.1016/j.tetlet.2012.12.107

RhH(PPh₃)₄ and 1,2-bis(diphenylphosphino)benzene (dppBz) catalyzed the oxidative coupling reaction of aryl benzyl ketones giving 2,3-diaryl-1,4-diketones in high yields. 3,3-Dimethyl-1-methylthio-2-butanone was used as the oxidizing

Full text of DOI:10.1016/j.tetlet.2012.12.107

Tetrahedron Letters 54 (2013) 1298–1301
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Tetrahedron Letters
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Rhodium-catalyzed synthesis of 2,3-diaryl-1,4-diketones via oxidative
coupling of benzyl ketones using
a-thioketone oxidizing reagent
⇑
⇑
Mieko Arisawa , Guangzhe Li, Masahiko Yamaguchi
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
RhH(PPh3)4 and 1,2-bis(diphenylphosphino)benzene (dppBz) catalyzed the oxidative coupling reaction of
aryl benzyl ketones giving 2,3-diaryl-1,4-diketones in high yields. 3,3-Dimethyl-1-methylthio-2-buta-
none was used as the oxidizing reagent, which was converted to 3,3-dimethyl-2-butanone and dimethyl
disulfide. Rhodium enolates were catalytically formed from ketones, which underwent oxidative cou-
pling using an organosulfur reagent.
Received 1 November 2012
Revised 19 December 2012
Accepted 26 December 2012
Available online 3 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,3-Diaryl-1,4-diketone
Benzyl ketone
a-Thioketone
Oxidative coupling
Rhodium-catalyzed reaction
2,3-Diaryl-1,4-diketones are important synthetic intermediates
for five-membered ring heteroarenes such as furans, pyrroles, and
thiophenes.1 They are synthesized by the oxidative coupling of me-
tal enolate in the presence of stoichiometric amounts of oxidants
such as titanium, iron, and halogen reagents,2 as well as by the
for 6 h under an argon atmosphere, ( )- and meso-1,2,3,4-tetra-
phenyl-1,4-butanediones 3 were obtained in 62% and 5% yields
based on 2, respectively (Scheme 2). 3,3-Dimethyl-2-butanone
was obtained in 60% yield, and no coupling product derived from
2 was formed. Thus, 1 was selectively coupled to give 3, and 2 serves
as the oxidizing reagent. X-ray analysis of the major product
coupling reaction using metal enolates and
a
-halo ketones.3 Both
methods employ stoichiometric amounts of metal reagents for
enolate formation and/or coupling. It is thus considered interesting
to determine whether such coupling can be conducted from
ketones by a catalytic method using an organic oxidizing reagent
under mild conditions. We previously reported the rhodium-
catalyzed
a-methylthiolation reaction of 1,2-diphenylethanone
using organic methylthiolation reagent, which indicated that
rhodium enolate could formally be oxidized by organosulfur
compounds.4 Described in this study is the rhodium-catalyzed
oxidative coupling reaction of aryl benzyl ketones giving 2,3-
diaryl-1,4-diketones (Scheme 1). 3,3-Dimethyl-1-methylthio-2-
butanone was used as the oxidizing reagent, which was converted
to 3,3-dimethyl-2-butanone and dimethyl disulfide. Rhodium eno-
lates were catalytically formed from ketones, which underwent
oxidative coupling using an organosulfur reagent.
Scheme 1.
When 1,2-diphenylethanone 1 (5 equiv) was reacted with 3,3-di-
methyl-1-methylthio-2-butanone 2 in the presence of RhH(PPh3)4
(10 mol %) and dppBz (20 mol %) in refluxing chlorobenzene (1 M)
⇑
Corresponding authors. Tel.: +81 22 795 6814; fax: +81 22 795 6811 (M.A.); tel.:
+81 22 795 6812; fax: +81 22 795 6811 (M.Y.).
E-mail addresses: arisawa@m.tohoku.ac.jp (M. Arisawa), yama@m.tohoku.ac.jp
(M. Yamaguchi).
Scheme 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.107

M. Arisawa et al. / Tetrahedron Letters 54 (2013) 1298–1301
1299
Table 1
Effect of methylthio transfer reagent
O1
O2
Entry
Thiolating reagents
Yield of 3 (%)
(( )-3:meso-3)
58 (14:1)
O
a,b
43 (14:1)
Ph
1
2
( )-3
38 (9:1)c,b
26 (7:1)d,b
SMe
Figure 1. Thermal ellipsoid plot of ( )-3 at 50% probability.
O
69 (12:1)
Ph
SMe
67 (12:1)
60 (7:1)b
16 (7:1)e
3
4
62 (13:1)f
5
6
n.d.g
48 (11:1)h
Scheme 3.
7
8
55 (14:1)h
19 (10:1)
( )-3 confirmed the structure (Fig. 1).5 ( )-3, 1H NMR (CDCl3) d 5.39;
meso-3, d 5.78. No reaction occurred in the absence of the rhodium
complex or dppBz.
(MeS)2
a
b
c
Concentration, 1 M.
Using 1 (2 equiv).
Concentration, 0.5 M.
Concentration, 0.25 M.
Using 1 (1 equiv).
Ad = adamantyl.
This reaction was found to proceed via a-methylthioketone 4c.
When 1 (2 equiv) was reacted with 2-hexylthio-1,2-diphenyletha-
none 4a in the presence of RhH(PPh3)4 (5 mol %) and dppBz
(10 mol %) in 1 M refluxing chlorobenzene for 6 h, 3 was obtained
in 45% yield [( )-3:meso-3 = 15:1] which was accompanied by di-
hexyl disulfide in 90% yield (Scheme 3). In order to obtain insights
into the mechanisms of such a reaction, 1 and 4a were each sub-
jected to the reaction. The reaction of 1 under the same conditions
gave 3 in 3%, and that of 4a gave 3 in 5% yield. The results showed
that 3 was formed by the combination of 1 and 4a. When 1,2-di-
phenyl-2-phenylthio-1-ethanone 4b was used instead of 4a, the
yield of 3 decreased to 14%, which indicated a higher efficiency
of alkylthio derivatives (4a, 4c) than that of an arylthio derivative
(4b).
d
e
f
g
h
Not detected.
Using 1 (3 equiv).
diphenyl-1,4-butanedione 8 (10%). The products were accompa-
nied by the recovery of 6 (48%), 1 (42%), and dimethyl disulfide
(50%) (Scheme 4). A rapid methylthio transfer occurred between
6 and 4c.4,6
Returning to the coupling reaction of 1, the effect of the
oketone as the oxidizing reagent was examined (Table 1). The
reaction of -methylthiopropiophenone gave 3 in 43% yield. When
the concentration was decreased from to 0.25 M in this
reaction, the yield of 3 decreased and a small amount of 2-
methylthio-1,2-diphenylethanone 4c (14%) was formed (entry 1).
2-Methyl-2-methylthiopropiophenone,
thio-2-butanone 2, and 1-adamantyl-2-methylthio-1-ethanone
gave 3 in high yields (entries 2–4). In these reactions, no coupling
product of 1 and
1/2 was changed from 1 to 2 and 5, the yields of 3 increased to
60% and 67%, respectively (entry 3). In contrast to the above
thioketones, -methylthio-p-cyanoacetophenone did not give 3
a-thi-
a
Since the present reaction contained coupling of a ketone and
1
an
a-thioketone, cross coupling was examined (Scheme 4). The
reaction of an equimolar amount of 2-(p-methoxyphenyl)-1-phe-
nyl-1-ethanone 6 and 4c in refluxing chlorobenzene for 6 h in
the presence of RhH(PPh3)4 (10 mol %) and dppBz (20 mol %) gave
a statistical mixture of 2-(p-methoxyphenyl)-1,3,4-triphenyl-1,4-
butanedione 7 (24%), 3 (13%), and 2,3-di(p-methoxyphenyl)-1,4-
3,3-dimethyl-1-methyl-
a-thioketone was formed. When the molar ratio
a-
a
(entry 5). This may be due to the relatively acidic nature of
p-cyanoacetophenone and is consistent with the low yield of 3 ob-
tained using dimethyl disulfide (entry 8). Note that 2-[(methyl-
thio)methyl]-benzothiazole and 2-[(methylthio)methyl]-benzoxazole
could also be used as oxidizing reagents giving 3 in 48% and 55%
yields, respectively (entries 6 and 7). Several organosulfur compounds
can be used as oxidizing reagents in this coupling reaction.
1,2-Diaryl-1-ethanones 9 possessing either p-electron-donating
groups or p-electron-withdrawing groups on an aryl moiety
Scheme 4.

1300
M. Arisawa et al. / Tetrahedron Letters 54 (2013) 1298–1301
Table 2
Synthesis of 2,3-diaryl-1,4-diketones
Entry
Ar
R
Yield of 10 (%)
(( )-10:meso-10)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
H (1)
H (1)
67 (12:1)
50 (5:1)a
57 (>20:1)
71 (6:1)
66 (6:1)
50 (6:1)
41 (6:1)
Cl (9a)
Me (9b)
OMe (9c)
H (9d)
H (9e)
Ph
4-Tol
4-t-BuC6H4
Figure 2. Possible mechanism.
coupling product 3 and methanethiol are liberated by reductive
elimination with the regeneration of rhodium catalyst. Thiol is oxi-
dized with a trace amount of oxygen, forming dimethyl disulfide
and water (Cycle II). Overall, the oxidative coupling of 1 gave prod-
a
In air.
reacted with 2 giving 2,3-diaryl-1,4-diketones 10 in high yields un-
der an argon atmosphere (Table 2, entries 1–5). All the compounds
gave racemic derivatives as the major products, the structures of
which were determined by 1H NMR similarly to that of 3. The
selectivity may be ascribed to the thermodynamic stabilities of
the racemic compounds. When meso-3 was treated with
RhH(PPh3)4 (10 mol %) and dppBz (20 mol %) in refluxing chloro-
benzene for 3 h, an 8:1 mixture of ( )-3 and meso-3 was obtained.
No reaction occurred in the absence of the rhodium complex.
This reaction converts 1 and 2 to 3, 11, and dimethyl disulfide,
and is formally oxidative coupling of 3. Consequently, two reaction
modes are conceivable regarding the stoichiometry (Scheme 5).
uct 3.
a-Thioketone 2 and oxygen are used as the oxidizing re-
agents and converted to the ketone 11, dimethyl disulfide, and
water. The mechanism explains the need for either 2 or 4c in the
present reaction.
In summary, RhH(PPh3)4 and dppBz catalyzed the oxidative
coupling reaction of aryl benzyl ketones giving 2,3-diaryl-1,4-dike-
tones in high yields. 3,3-Dimethyl-1-methylthio-2-butanone was
used as the oxidizing reagent, which was converted to 3,3-di-
methyl-2-butanone and dimethyl disulfide. The rhodium-cata-
lyzed method can be used for the oxidative coupling of organic
compounds using an organosulfur oxidizing reagent under mild
conditions.
Two molecules of ketone and one molecule of
to form one molecule of the coupling product, one molecule of
the reduced -thioketone, 0.5 molecules of disulfide, and water:
-Thioketone and oxygen are oxidizing reagents (reaction mode
a-thioketone react
a
Typical experimental procedures
a
1). Alternatively, two molecules of thioketone and two molecules
of ketone react to give one molecule of the coupling product, two
In a two-necked flask were placed 1 (1.25 mmol, 245.3 mg),
RhH(PPh3)4 (10 mol %, 28.8 mg), and dppBz (20 mol %, 22.3 mg)
under an argon atmosphere. Dry chlorobenzene (0.25 mL) was
added, and the solution was heated at reflux for 30 min. Then,
molecules of the reduced
a-thioketone, and one molecule of disul-
fide: -Thioketone is the oxidizing reagent (reaction mode 2). That
a
the yield of 1,4-diketones often exceeds 50% is explained by the
reaction mode 1. It was previously found that the rhodium com-
plex catalyzes the oxidation of thiols in the presence of a small
amount of oxygen.7 That the reaction was not inhibited in air
may be explained by the reaction mode 1 (Table 2, entry 2).
A possible mechanism of the reaction follows (Fig. 2). The reac-
tion involves two catalytic cycles: oxidation of 1 to 4c using 2 (Cy-
cle I); coupling of 1 and 4c giving 3 (Cycle II). The rhodium
intermediate A formed from the ketone 1 undergoes ligand ex-
change and hydrogen transfer to 2 giving 11. The resulting methyl-
thiorhodium intermediate B shows equilibrium of the regeneration
of the rhodium complex and the formation of 4c (Cycle I). The elec-
tron-rich rhodium intermediate B reacts with another molecule of
1 to give a high-valence rhodium intermediate C, and the C–C
3,3-dimethyl-1-methylthio-2-butanone
2 (0.25 mmol, 36.6 mg)
was added, and the mixture was heated at reflux for 6 h. The sol-
vent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel giving ( )-
3 (60.7 mg, 62%) and meso-3 (5.1 mg, 5%).
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research (No. 21229001) and the GCOE program from JSPS. M.A.
expresses her appreciation to the financial supports from the
Grant-in-Aid for Scientific Research (No. 22689001), Japan Science
Technology Agency, and also to the Asahi Glass Foundation.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.107.
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