Microwave-irradiated transition-metal catalysis: Rapid and efficient dehydrative carbon-carbon coupling of alcohols with active methylenes

Article abstract of DOI:10.1055/s-2008-1067020

A rapid and highly productive synthetic microwave-irradiation protocol for transition-metal-catalyzed carbon-carbon coupling of a wide range of benzylic/allylic alcohols with β-diones, β-keto esters, and dialkyl malonates is reported. In a representative

Full text of DOI:10.1055/s-2008-1067020

PAPER
1717
Microwave-Irradiated Transition-Metal Catalysis: Rapid and Efficient
Dehydrative Carbon–Carbon Coupling of Alcohols with Active Methylenes
M
icrowave-Irr
r
adiatedT
i
ransit
n
ion-Meta
l
Ca
i
talysisvasarao Arulananda Babu,a,b Makoto Yasuda,a,b Yasunori Tsukahara,b Tomohisa Yamauchi,b Yuji Wada,b,c
Akio Baba*a,b
a
Department of Applied Chemistry, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68797387; E-mail: baba@chem.eng.osaka-u.ac.jp
Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
b
c
2-12-1-S1-43 Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Received 28 January 2008; revised 8 February 2008
conventional heating conditions.9,10 Despite these rapid
developments, perhaps due to the poor leaving ability of
the hydroxy group and the low activation of the alcohols
by catalysts, in most of these methods a very long heating
Abstract: A rapid and highly productive synthetic microwave-
irradiation protocol for transition-metal-catalyzed carbon–carbon
coupling of a wide range of benzylic/allylic alcohols with b-diones,
b-keto esters, and dialkyl malonates is reported. In a representative
screening of transition-metal catalysts, salts of Zn, Cu, Fe, Sc, Ru, period (5 h to 24 h, for a moderate to very good yield) and
often a special solvent, e.g., nitromethane9c–h or dichlo-
Pt, Ta, and Mo were found to furnish the coupling products. In light
romethane,10a were essential. In some cases, stoichiomet-
of the results obtained, among all of these catalysts copper(II) tri-
flate was found to be relatively more effective compared to other
ric or excess amounts10 of Lewis acids (BF3·OEt2),10a or
catalysts even in the case of a less reactive benzyl alcohol or diester.
Brønsted acids (AcOH7d or HCO2H10b) and alcohols or ac-
Interestingly, these MW-irradiated reactions are performed in a
tive methylene compounds9d were required even when us-
more or less MW-transparent medium, such as toluene, having a
very low tand, or under neat conditions.
ing extended heating periods.9,10 Hence, new and
efficiently accelerated catalytic protocols with a wide
range of applicability and operational simplicity are ex-
tremely desirable for this exigent C–C coupling.
Key words: alcohols, alkylations, catalysis, C–C coupling, dicar-
bonyl compounds, microwave irradiation, transition metals
Taking impetus from the efficient, well-known MW-ac-
celerated transition-metal-catalyzed C–C and C–N cou-
pling reactions,1–3 we envisaged the significant coupling
of alcohols with active methylene compounds under MW-
irradiated metal catalysis.
Driving chemical reactions by microwave irradiation is
recognized as, more or less, an ecofriendly alternative to
conventional heating methods.1,2 Especially, the celebrat-
ed transition-metal-based reactions under conventional
heating, e.g., Suzuki–Miyaura,3a Migita–Kosugi–Stille,3b
Negishi,3c Heck,3d Sonogashira3e C–C and Buchwald–
Hartwig3f C–N coupling reactions, are very well-emerg-
ing transformations at superior speeds under MW
irradiation1–3 than with conventional heating conditions.
This is, perhaps, because the rate and efficiency is very
high in MW-irradiated protocols, which are cleaner than
conventional heating methods.1–3
To the best of our knowledge there exists no report on the
MW-irradiated cross dehydrative C–C coupling of active
methylene compounds with alcohols as nucleophiles.1–3
Herein, we report a synthetically essential and highly pro-
ductive MW-induced transition-metal-catalyzed coupling
of alcohols with active methylene compounds.
At first, we examined the transition-metal catalysts under
MW irradiation with toluene as the medium by using the
reactive combination of diphenylmethanol (1a) and
acetylacetone (2a) (100 °C, 15 min, Table 1). Several
transition-metal catalysts were found to be promising can-
didates, including, fortunately, some of the common and
inexpensive metals such as copper, zinc, and iron. Several
other representative transition-metal catalysts salts, listed
in Table 1, were ineffective.
The C–C coupling reaction of alkyl halides and pseudoha-
lides with active methylene compounds is an important
protocol in organic syntheses.4–7 Generally, these process-
es require the use of a stoichiometric amount of base.
Strikingly, organic chemists have envisioned the catalytic
addition of alkenes6 or alcohols7 with active methylene
compounds as an ingenious atom-economical8 green pro-
tocol. Water is the only byproduct if alcohol is employed
(as compared to HX in the case of alkyl halides4) and al-
cohols are abundantly available.
Next, in the reaction using low reactive 4-bromobenzyl al-
cohol (1b) with 1,3-diphenylpropane-1,3-dione (2b), the
catalytic activity of copper(II) triflate is apparently higher
than that of scandium, zinc, and iron (Table 2) affording
3b in 63% yield. The effect of MW is also obvious be-
cause the low efficiency under thermal heating. Although
scandium(III) triflate9e and iron(III) chloride9d catalysts
were effective with more reactive substrates 1a and 2a,
In this extremely demanding task, initially we, and subse-
quently others, have reported Lewis or Brønsted acid cat-
alyzed C–C coupling reactions using alcohols under
SYNTHESIS 2008, No. 11, pp 1717–1724
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.04.2008
DOI: 10.1055/s-2008-1067020; Art ID: F02208SS
© Georg Thieme Verlag Stuttgart · New York

1718
S. A. Babu et al.
PAPER
did not effect the reaction in polar solvents, such as etha-
nol, dimethyl sulfoxide, N,N-dimethylformamide, which
are usually employed to readily achieve higher tempera-
tures, and gave no product (Table 3). Other polar solvents
such as tetrahydrofuran, chloroform, and acetone were
less favorable. It was observed that even nonpolar sol-
vents such as methylcyclohexane and hexane gave com-
parable yields to ethyl acetate and acetonitrile.
Analogously, the nonpolar solvent toluene afforded 3a in
excellent yield, which is comparable to chlorinated sol-
vents such as 1,2-dichloroethane and chlorobenzene. Nat-
urally, toluene was selected as an ecofriendly solvent.
Table 1 MW-Irradiated Reaction of 1a with 2a: Screening of Metal
Catalystsa
O
O
OH
O
O
MW irradiation
+
Ph
Ph
catalyst (5 mol%),
toluene, 100 °C, 15 min
1a
(1 mmol)
2a
(1.2–1.5 mmol)
Ph
Ph
3a
Catalyst
none
Yield (%) of 3a
0b
0
NiBr2
WCl4
To attain higher temperatures that effect the chemical re-
actions of organic functional groups, MW irradiations are
usually performed in polar media that has a permanent di-
pole moment and high tand factor.11a,b These characteris-
tics are essential requirements for an efficient absorption
of MW and the generation of heat (temperature) to effect
the chemical reactions of functional groups present in the
solvent medium. However, the MW-irradiated coupling
reaction of alcohol 1a with 2a was effective even in a
more or less MW transparent nonpolar media (with a very
low tand factors) such as hexane, methylcyclohexane, or
toluene (Table 3).11c This is perhaps because of: (a) a low
absorption of MW by these solvents, and (b) relatively en-
hanced direct contact of MW with the functional groups
of reactants (alcohol, ketone, and catalyst) themselves
having a permanent dipole moment that might effected the
coupling reaction (similar to neat reaction conditions).1–3,11d
Additionally, in hexane or methylcyclohexane a slightly
higher yield of product 3a was observed using MW than
under oil bath heating.11e Since the theoretical aspects of
heating by MW is still a topic of research,1–3 it could be
speculated that either one or both components of MW
(electric and magnetic) could be activating the substrates
in a medium with a low tand factor.
0
c
SnCl2
0
c
CoCl2
0
ZrCl4
CrCl2
LaCl3
MnCl2
NbCl5
0
0
0
0
0
c
Pd(PPh3)4
RhCl(PPh3)3
YCl3
0
0
0
HfCl4
0
AgClO4
8
d
Zn(OTf)2
30
80
95
99
99
98
98
99
RuCl3
d
ZnBr2
Taking impetus from these results, the generality of this
MW-irradiated coupling was demonstrated for a high ef-
ficiency using a variety of 1,3-diones and alcohols
(Table 4).11f From the point of convenience and efficient
productivity, copper, zinc, and iron catalysts were em-
ployed in the coupling reactions. The iron(III) chloride
catalyzed reactions of diarylmethanols 1a,c with dione 2a
under solvent-free conditions gave 3a,c in quantitative
yields (Table 4, entries 1 and 2). 1-Phenylethanol (1d) ef-
fectively reacted with the diketones 2a and 2b in the pres-
ence of copper(II) triflate and zinc(II) bromide,
respectively (Table 4, entries 3 and 4). Then, the cou-
plings of allylic alcohols 1e,f, with 2a,b were effected by
copper(II) triflate, scandium(III) triflate, zinc(II) bromide,
and iron(III) chloride catalysts to give the respective prod-
ucts effectively (Table 4, entries 5–8). The highly enoliz-
able cyclic dione 2c was MW irradiated with 1a in the
presence of copper(II) triflate to give 3i with an all-carbon
quaternary center (Table 4, entry 9).
TaI5
H2PtCl6·6 H2O
Sc(OTf)3
d
Cu(OTf)2
FeCl3
a Irradiations were performed in a Biotage Initiator, sealed tube and
the temperature ramped to that stated and held there for 15 min at nor-
mal absorption.
b 20 min.
c 3 mol%.
d 110 °C.
they were not effective in the case of a less reactive benzyl
alcohol 1b, with the exception of copper(II) triflate.
Next, we screened solvents congenial to MW irradiation
for the coupling reaction of diphenylmethanol (1a) with
acetylacetone (2a). The copper(II) triflate catalyst system
Synthesis 2008, No. 11, 1717–1724 © Thieme Stuttgart · New York

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Microwave-Irradiated Transition-Metal Catalysis
1719
Table 2 MW-Irradiated and Conventional Heating Reactions of 1b with 2b
O
O
OH
O
O
Ph
Ph
+
Ph
Ph
Br
Br
3b
1b
2b
Conditionsa
Catalyst (5 mol%)
Time (min)
Yield (%)
MW, chlorobenzene, 135 °C
MW, chlorobenzene, 135 °C
MW, chlorobenzene, 135 °C
MW, chlorobenzene, 135 °C
MW, chlorobenzene, 135 °C
chlorobenzene, 100 °C
Cu(OTf)2
Sc(OTf)3
Zn(OTf)2
FeCl3
30
45
45
45
45
45
45
63b
29
0
0c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
50
<20d
0d
toluene, 110 °C
a See footnote a in Table 1, very high absorption, reactions were carried out using 1b and 2b (1 mmol each), catalyst (5 mol%), solvent (2.5 mL).
b 1.5 mmol of 1b was used.
c 4-Chlorobenzyl alcohol or benzyl alcohol was used instead of 1b.
d Oil bath heating.
Table 3 Screening of Solvents Suitable for MW Irradiationa
O
O
OH
O
O
MW irradiation
+
Ph
Ph
Cu(OTf)2 (3 mol%),
Ph
Ph
solvent (2.5–3 mL), 15 min
1a
2a
(1.2–1.5 mmol)
3a
(1 mmol)
Solvent
tandb
Temp (°C)
Time (min)
Yield (%)
MW
Oil bath
EtOHc
DMSOc
DMFc
0.941
0.825
0.161
0.091
0.127
0.101
0.059
0.054
0.062
0.062
0.047
0.040
0.020
100
150
150
65
15
15
15
15
15
12
15
15
3
0
0
0
c
CHCl3
<10
98
DCEc
90
chlorobenzenec
EtOAcc
110
85
90
67
acetonec
60
<10
70
MeCNc
90
50
75
MeCNc
90
15
15
15
15
3
79
THFc
70
<10
>98
55
<10
>98
48
toluened
110
70
hexaned
methylcyclohexaned
methylcyclohexaned
–
90
53
32
e
e
–
90
15
84
69
a Irradiations performed in a Biotage Initiator, sealed tube and the temperature ramped to that stated and held there for allotted time.
b Values of tand factor as reported.11a,b
Reactions performed under very high absorption.
d Reactions performed under normal absorption.
e tand value not available.
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1720
S. A. Babu et al.
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Table 4 MW-Irradiated Coupling of Alcohols with 1,3-Dionesa
O
O
OH
O
O
MW irradiation
R2
R3
+
Ph
R1
R2
R3
toluene, MtXn, T °C, time
Ph
R1
Entry
Alcohol
Dione
Catalyst (mol%)
Temp (°C)
Time (min) Product
Yield (%)
O
O
R
OH
O
O
1
2
FeCl3 (5)
FeCl3 (5)
110
110
20
20
3a: 99b
3c: 98b
Ph
R
Ph
1a: R = Ph
1c: R = 4-Tol
2a
3a: R = Ph
3c: R = 4-Tol
O
O
O
R
O
OH
R
R
3
4
Cu(OTf)2 (5)
ZnBr2 (5)
110
110
25
25
3d: 75
3e: 92
R
Ph
Ph
2a: R = Me
2b: R = Ph
1d
3d: R = Me
3e: R = Ph
O
O
R
R
OH
5
6
7
2a
2a
2b
Cu(OTf)2 (3)
Sc(OTf)3 (3)
ZnBr2 (5)
110
110
110
15
15
35
3f: 67
3f: 75
3g: 77
1e
3f: R = Me
3f: R = Me
3g: R = Ph
O
O
OH
8
9
2a
FeCl3 (3)
90
1
90
Ph
Ph
Ph
Ph
1f
3h
O
O
O
COMe
Ph
1a
Cu(OTf)2 (5)
110
30
85c
Ph
2c
3i
a See footnote a in Table 3, all reactions were carried out using 1 (1 mmol) and 2 (1–1.2 mmol) under normal absorption.
b Neat reaction performed using 2a (1.5 mmol).
c Chlorobenzene was used under very high absorption.
Table 5 shows the reactions of alcohols with a variety of tries 8–10). Similarly, an allylic alcohol 1f with diethyl
b-keto esters or dialkyl malonate; these are less reactive malonate (2i) gave 3s (Table 5, entries 11 and 12).
than 1,3-diones. The reaction of b-keto esters 2d,g were
Next, to find the relatively high acceleration and efficien-
promoted by convenient metal catalysts such as copper,
cy under MW irradiation, we performed a preliminary
iron, and zinc (Table 5, entries 1, 4, 5, 6, and 7). The
comparison between conventional heat and MW-irradiat-
iron(III) chloride catalyzed reaction of 2d with 1a in neat
ed settings using b-keto esters. Representative examples
are shown in Table 6. The iron(III) chloride catalyzed re-
action of diphenylmethanol (1a) and ethyl 2-methyl-3-
oxobutanoate (2f) was completed in one minute to give 3l
in 81% yield under MW irradiation, while conventional
heating gave the same product in 35% yield. The reaction
of 1-phenylethanol (1d) and b-keto ester 2d gave a similar
result for 3t in six minutes (44% and 10%). Analogously,
conditions gave 3j quantitatively (Table 5, entry 1). The
coupling reactions of alcohol 1a with 2e,f were also cata-
lyzed by scandium(III) triflate (Table 5, entries 2 and 3).
The a-substituted b-keto esters 2f,g afforded the products
3l,m with an all-carbon quaternary center (Table 5, entries
3 and 4). Another less common, demanding reaction is the
coupling of an alcohol with the diesters dimethyl or dieth-
yl malonate 2h,i. The scandium(III) triflate or copper(II)
the coupling of 1a and highly enolizable cyclic keto ester
triflate catalyzed MW-irradiated reactions of diesters 2h,i
2j showed the same trend in 8 minutes (40% and 0%) in
with 1a,g,c gave 3p–r in very good yields (Table 5, en-
giving 3u. The coupling of alcohol 1a with a diester 2i is
difficult for the copper(II) triflate or scandium(III) triflate
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Microwave-Irradiated Transition-Metal Catalysis
1721
Table 5 Coupling of Alcohols with b-Keto Esters or Dialkyl Malonates under MWa
O
O
O
O
OH
R1
R2
OR4
MW irradiation
+
R3
Ph
R2
OR4
Ph
toluene, cat. (X mol%)
R1
R3
Entry Alcohol
b-Keto ester
or dialkyl malonate
MtXn
(mol%)
Temp
(°C)
Time
(min)
Product
Yield
(%)
O
O
OH
O
O
Me
OEt
1
FeCl3 (5)
110
110
110
110
20
25
5
(98)b
Ph
Ph
OEt
Ph
Ph
1a
2d
3j
O
O
O
O
MeO
OMe
2
3
4
1a
1a
1a
Sc(OTf)3 (3)
Sc(OTf)3 (3)
FeCl3 (5)
65
82
95
MeO
OMe
Ph
O
Ph
2e
3k
O
O
O
O
OEt
OEt
OEt
Me
Ph
Me
Ph
Ph
2f
3l
O
Ph
COOEt
O
20
2g
3m
Ph
OH
Ph
78c
83c
COOEt
5
6
2g
2g
ZnBr2 (5)
Zn(OTf)2 (5)
110
110
15
15
O
Ph
Ph
1f
3n
O
O
OEt
Ph
7
8
1f
2d
Cu(OTf)2 (3)
Sc(OTf)3 (5)
110
135
5
90c
Ph
3o
O
O
OH
O
O
MeO
OMe
15
71d
Ph
C6H4Cl-p
MeO
OMe
Ph
R
2h
1g
3p,q
3p: R = 4-ClC6H4
OH
9
2h
Sc(OTf)3 (5)
Cu(OTf)2 (5)
135
135
15
15
3q: R = 4-Tol
78d
71d
Ph
tol-p
1c
O
O
O
O
EtO
3r
OEt
OEt
10
1a
1f
EtO
OEt
Ph
O
Ph
O
2i
11
12
Sc(OTf)3 (5)
ZnBr2 (5)
20
15
72d
69d
EtO
2i
135
Ph
Ph
3s
a See footnote a, Table 3, all reactions were carried out using 1 (1 mmol) and 2 (1–1.1 mmol) under normal absorption.
b Neat reaction done using 2d (1.5 mmol).
c ds ratio 1:1.
d Chlorobenzene was used under very high absorption.
Synthesis 2008, No. 11, 1717–1724 © Thieme Stuttgart · New York

1722
S. A. Babu et al.
PAPER
Table 6 Attempts for Comparing the Efficiency and Rate Acceleration in MW and Conventional Heat Settingsa
O
O
O
O
OH
R1
MW or thermal
R2
OEt
+
R3
Ph
R2
OEt
Ph
toluene (2.5 mL), cat.
R1
R3
Entry ROH
Dione or ester
Catalyst (mol%) Temp (°C) Time
Product
Yieldb (%)
MW
Thermal
O
O
O
O
OH
Me
Me
OEt
1
2
FeCl3 (5)
FeCl3 (5)
110
110
60 sec
6 min
81
35
Me
OEt
OEt
Ph
Ph
Me
Ph
3l
Ph
1a
2f
O
O
O
O
OH
Me
OEt
44
40
10
Me
Ph
Ph
Me
2d
1d
3t
Ph
O
O
COOEt
O
Ph
OEt
3
1a
FeCl3 (3)
90
8 min
trace
2j
3u
O
O
O
O
4
5
1a
1a
Cu(OTf)2 (5)
Sc(OTf)3 (5)
135c
135c
15 min
15 min
71
93
traced
EtO
OEt
EtO
OEt
Ph
Ph
2i
3r
3r
2i
32e (5)f
a See footnote a in Table 3, normal absorption, reactions were carried out using 1 and 2 (1 mmol each).
b Preheated oil bath was used.
c Chlorobenzene was used under very high absorption.
d Oil bath heating at 100 °C in toluene or chlorobenzene for 20 min.
e Oil bath reaction in toluene at 100 °C for 30 min.
f Oil bath reaction in chlorobenzene at 100 °C for 20 min.
performed. Reactions were carried out either under MW irradiation
in a sealed tube or under thermal heating in an inert atmosphere. So-
lutions were dried with anhydrous MgSO4. Reagents were added to
the reaction flask through syringe. Analytical TLC was performed
on silica plates and components were visualized by observation un-
catalyzed conventional heating reaction and furnishes
only trace amounts of 3s. In contrast, the MW-irradiation
protocol gave 3s in 71% or 93% yield, respectively, in just
15 minutes (Table 6). These investigations apparently re-
vealed that the rate acceleration and efficiency in MW ir-
radiation are far better than conventional heating
conditions.
1
der I2 or UV light. Yields were determined from H NMR spectra
using internal standards or after isolation by column chromatogra-
1
phy. Ratios of diastereomers were determined from H NMR of
crude reaction mixture.
Compounds 3a–h,12–18 3j,19 3m,20 3o,21 3r,22 3s,23 and 3t15 have
been previously reported in the literature.
In conclusion, a synthetically essential, rapid and efficient
MW-irradiated transition-metal-catalyzed C–C coupling
of benzylic or allylic alcohols with b-dicarbonyls has been
established. This green protocol offers easy and unlimited
access for the coupling products.
MW Irradiated Transition-Metal-Catalyzed Dehydrative C–C
Coupling of Alcohols with Nucleophiles; General Procedure
To a dry sample tube closed by a septum containing a magnetic
bead, alcohol (1 mmol) and b-dicarbonyl compound (1–1.1 mmol)
were added under an inert atmosphere. Then an appropriate solvent
(toluene or other solvent, see the appropriate Table) and catalyst
were added. The sample tube was sealed with a cap and then sub-
jected to MW irradiation (See Tables for the appropriate catalyst,
temperature, and time). After the period of irradiation, the mixture
was poured into a separating funnel containing H2O (2–3 mL) and
extracted with Et2O (3 ×). The combined organic layers were dried
and concentrated to afford the crude mixture, which was then puri-
fied by column chromatography. Yields of products were deter-
MW irradiations were carried out in a Biotage Initiator, in a sealed
tube (supplied by Biotage) and the temperature ramped to that stat-
ed and held there for allotted time (see the Tables 1– 6 for the type
of absorption was set for each solvent). IR spectra were recorded as
thin films or KBr pellets on a Horiba FT-720 spectrophotometer. 1H
and 13C NMR spectra were recorded on Jeol JNM-GSX-270 or 400
(270/67.9 or 400/100 MHz) spectrometers, respectively with TMS
as internal standard. Carbon types were determined in DEPT 13C
NMR or OFR spectral analyses. MS spectra were recorded on a Jeol
JMS-DS303 spectrometer. Column chromatography was performed
on silica gel (100–200 mesh, Wako silica gel) or flash column was
Synthesis 2008, No. 11, 1717–1724 © Thieme Stuttgart · New York

PAPER
Microwave-Irradiated Transition-Metal Catalysis
1723
mined after isolation by column chromatography or from 1H NMR
spectra using an internal standard.
13C NMR (100 MHz, CDCl3): d = 204.5, 171.6, 141.1, 140.5, 129.9,
129.7, 128.2, 128.0, 126.6, 126.5, 65.0, 61.6, 53.6, 26.9, 18.2, 13.6.
GC-MS (EI): m/z (%) = 310 (M+, 0.02), 292 (29.6), 221 (11.7), 219
(13.33), 168 (13.9), 167 (100), 165 (17.0), 152 (8.1), 115 (6.9).
HRMS (EI): m/z [M]+ calcd for C20H22O3: 310.1569; found:
310.1577.
Transition-Metal-Catalyzed Dehydrative C–C Coupling of Al-
cohols with Nucleophiles Using Conventional Heating; General
Procedure
To a dry round-bottom flask were added the alcohol (1 mmol) and
b-dicarbonyl compound (1–1.1 mmol) under an inert atmosphere.
Then the appropriate solvent (toluene or other solvent) (2.5 mL) and
catalyst were added. The flask was then dipped into a preheated oil
bath (See Tables for appropriate catalyst, temperature and time).
After the appropriate time, the mixture was cooled with a r.t. water
bath and poured into a separating funnel containing H2O (2–3 mL)
and extracted with Et2O (3 ×). The combined organic layers were
dried and concentrated to afford the crude mixture. Yields of prod-
ucts were determined after isolation by column chromatography or
from 1H NMR spectra using an internal standard.
Ethyl 1-(1,3-Diphenylallyl)-2-oxocyclopentanecarboxylate (3n)
Isolated as a mixture of diastereomers (ds 70:30); colorless thick oil.
IR (CDCl3): 1751, 1724, 1600, 1492 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.15 (m, 10 H), 6.52–6.34
(m, 2 H), 4.53 (d, J = 8.8 Hz, 1 H)*, 4.43 (d, J = 8.8 Hz, 1 H), 4.17–
4.07 (m, 2 H)*, 3.98 (q, J = 7.2 Hz, 2 H),2.73–2.70 (m, 1 H), 2.40–
1.68 (s, 5 H), 1.18 (t, J = 7.2 Hz, 3 H)*, 1.04 (t, J = 7.2 Hz, 3 H).
*Minor isomer.
13C NMR (100 MHz, CDCl3): d = 213.3, 213.1*, 168.9, 168.8*,
139.6, 139.4*, 136.8, 133.0, 132.8*, 129.6, 128.8, 128.4*, 124.4,
128.3, 128.2, 128.32, 127.4, 127.4*, 66.2, 66.2*, 61.7*, 61.5, 52.8,
51.9*, 38.8, 38.6*, 29.9, 28.5*, 19.7, 19.4*, 14.0*, 13.8. *Minor
isomer.
Diethyl 2-Benzhydrylmalonate (3r); Typical Procedure for
Gram-Scale Preparation
Diphenylmethanol (2 g, 10.8 mmol), diethyl malonate (1.75 g, 10.8
mmol), and Cu(OTf)2 (195 mg, 5 mol%) in chlorobenzene (15 mL)
were subjected to MW irradiation using a CEM discover MW ma-
chine for a hold period of 20 min at 110 °C (the temperature ramped
to that stated in 9 min). After irradiation, the mixture was subjected
to the usual workup procedure as given above to afford 3r (2.39 g,
67%).
MS-FAB: m/z (%) = 371 (M+ + Na, 77), 193 (100).
HRMS-FAB: m/z [M + Na]+ calcd for C23H24NaO3: 371.1623;
found: 371.1626.
Dimethyl 2-[(4-Chlorophenyl)phenylmethyl]malonate (3p)
Mp 87–89 °C (hexane–Et2O).
IR (CDCl3): 1754, 1735, 1492, 1434 cm–1.
2-Acetyl-2-benzhydrylcyclohexanone (3i)
Mp 131–133 °C (hexane–Et2O).
IR (CDCl3): 1697, 1596, 1492, 1446 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.28–7.16 (m, 9 H), 4.75 (d,
J = 12.4 Hz, 1 H), 4.32 (d, J = 12.4 Hz, 1 H), 3.56 (s, 3 H), 3.53 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 167.8, 167.7, 140.5, 139.7, 132.7,
129.0, 128.8, 128.7, 127.5, 127.1, 57.0, 52.7, 52.6, 50.3.
GC-MS (EI): m/z (%) = 332 (M+, 32.5), 274 (28.0), 273 (27.9), 272
(80.4), 271 (13.0), 241 (45.2), 203 (31.4), 201 (100), 165 (57.9).
1H NMR (400 MHz, CDCl3): d = 7.23–7.12 (m, 10 H), 5.47 (s, 1 H),
2.81–2.76 (m, 1 H), 2.53–2.49 (m, 1 H), 2.22–2.14 (m, 1 H), 1.91–
1.08 (m, 5 H), 1.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 208.5, 204.3, 140.7, 140.2, 130.4,
130.2, 128.4, 128.0, 126.8, 126.4, 73.4, 53.2, 42.3, 31.1, 26.9, 25.2,
22.2.
GC-MS (CI): m/z (%) = 307 (M+ + H, 0.48), 263 (3.3), 245 (4.6),
168 (14.1), 167 (100), 141 (2.8).
HRMS (EI): m/z [M]+ calcd for C18H17ClO4: 332.0815; found:
332.0819.
HRMS (CI): m/z [M + H]+ calcd for C21H23O2: 307.1698; found:
307.1695.
Dimethyl 2-[(4-Methylphenyl)phenylmethyl]malonate (3q)
Mp 104–106 °C (hexane–Et2O).
IR (CDCl3): 1754, 1735, 1454, 1434 cm–1.
Methyl 2-Benzhydryl-4-methoxy-3-oxobutanoate (3k)
Mp 89–91 °C (hexane–Et2O).
IR (CDCl3): 1754, 1727, 1496, 1454 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.31–7.13 (m, 10 H), 4.81 (d,
J = 12.4 Hz, 1 H), 4.70 (d, J = 12.4 Hz, 1 H), 3.90 (d, J = 18.0 Hz,
1 H), 3.68 (d, J = 18.0 Hz, 1 H), 3.51 (s, 3 H), 3.18 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.28–7.24 (m, 4 H), 7.17–7.15 (m,
3 H), 7.06 (d, J = 7.6 Hz, 2 H), 4.73 (d, J = 12.4 Hz, 1 H), 4.34 (d,
J = 12.4 Hz, 1 H), 3.55 (s, 3 H), 3.53 (s, 3 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.1, 168.1, 141.3, 138.1, 136.4,
129.3, 128.6, 127.6, 127.5, 126.8, 57.2, 52.6, 52.5, 50.7, 21.0.
13C NMR (100 MHz, CDCl3): d = 201.7, 167.5, 141.3, 140.8, 128.8,
128.6, 128.0, 127.4, 127.0, 126.8, 77.6, 59.2, 59.1, 52.5, 50.6.
GC-MS (EI): m/z (%) = 312 (M+, 23.3), 253 (15.0), 252 (50.0), 221
(28.8), 181 (100), 178 (13.7), 165 (24).
GC-MS (CI): m/z (%) = 313 (M+ + H, 0.36), 295 (2.3), 294 (6.2),
209 (5.6), 168 (13.4), 167 (100).
HRMS (EI): m/z [M]+ calcd for C19H20O4: 312.1362; found:
312.1362.
HRMS (CI): m/z [M + H]+ calcd for C19H21O4: 313.1440; found:
313.1444.
Ethyl 1-Benzhydryl-2-oxocyclohexanecarboxylate (3u)
Colorless thick oil.
IR (CDCl3): 1712, 1600, 1496, 1450 cm–1.
Ethyl 2-Benzhydryl-2-methyl-3-oxobutanoate (3l)
Colorless thick oil.
IR (CDCl3): 1712, 1496, 1450, 1230 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.13 (m, 10 H), 5.27 (s, 1 H),
4.05–3.93 (m, 2 H), 2.05 (s, 3 H), 1.52 (s, 3 H), 1.01 (t, J = 6.8 Hz,
3 H).
1H NMR (400 MHz, CDCl3): d = 7.42–7.12 (m, 10 H), 5.08 (s, 1 H),
3.93–3.72 (m, 2 H), 2.39–2.65 (m, 1 H), 2.45–2.37 (m, 2 H), 1.95–
1.47 (m, 5 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.2, 170.6, 140.8, 140.4, 130.6,
130.2, 127.8, 126.5, 126.3, 65.8, 61.2, 54.0, 41.8, 34.8, 26.7, 22.6,
13.4.
Synthesis 2008, No. 11, 1717–1724 © Thieme Stuttgart · New York

1724
S. A. Babu et al.
PAPER
MS-FAB: m/z (%) = 359 (M+ + Na, 48), 167 (100).
HRMS-FAB: m/z [M + Na]+ calcd for C22H24NaO3: 359.1623;
Organomet. Chem. 1989, 361, C57. (e) Alkylation in AcOH
(15 mL) using allyl alcohol, see: Mukhopadhyay, M.; Iqbal,
J. Tetrahedron Lett. 1995, 36, 6761. Using allylic acetates,
for example, see: (f) Tanaka, Y.; Mino, T.; Akita, K.;
Sakamoto, M.; Fujita, T. J. Org. Chem. 2004, 69, 6679.
(8) (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003,
1379. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(9) (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. Int. Ed.
2006, 45, 793. In the course of this work the following
reports (using MeNO2 solvent) appeared very recently:
(b) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett.
2007, 9, 825. (c) Kischel, J.; Mertins, K.; Michalik, D.;
Zapf, A.; Beller, M. Adv. Synth. Catal. 2007, 349, 865.
(d) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72,
5161. (e) Huang, W.; Wang, J.; Shen, Q.; Zhou, X.
Tetrahedron Lett. 2007, 48, 3969. (f) Brønsted acids in
heptane see: Motokura, K.; Nakagiri, N.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. J. Org. Chem. 2007, 72, 6006.
(g) Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-Gutierrez, J.
M.; Rodriguez, F. Org. Lett. 2007, 9, 2027. (h) Surfactant
system, see: Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9,
311.
(10) (a) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002,
1823. (b) Gullickson, G. C.; Lewis, D. E. Aust. J. Chem.
2003, 56, 385. (c) Takahashi, H.; Kashiwa, N.; Kobayashi,
H.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2002,
43, 5751. (d) Coote, S. J.; Davies, S. G.; Middlemiss, D.;
Naylor, A. Tetrahedron Lett. 1989, 30, 3581. (e) Khalaf, A.
A.; Roberts, R. M. J. Org. Chem. 1972, 37, 4227.
(11) (a) The ability of a specific substance to convert
electromagnetic energy into heat at a given frequency and
temperature is determined by the so-called loss factor tand,
see ref. 1a. (b) Gabriel, C.; Gabriel, S.; Grant, E. H.;
Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
27, 213. (c) Some other reactions for MW irradiation in
toluene are also known, see refs 1–3. (d) At this stage,
perhaps we cannot ignore the point that the reaction in
solvents having coordinating ability (with the catalyst)
might decrease the activation of the catalyst in MW
irradiation. We thank the referee for indicating this point.
(e) Exceptionally, in the case of toluene, no difference was
noted for the highly reactive substrates 1a/2a at this high
temperatures. (f) We used toluene because of its higher
boiling point than other nonpolar solvents and naturally,
toluene was selected as an ecofriendly solvent.
(12) 3a,d: Marquet, J.; Moreno-mañas, M. Synthesis 1979, 348.
(13) 3b: Karban, J. W.; Aparicio, M. K.; Palacios, R. R.;
Richardson, K. A.; Klausmeyer, K. K. Acta Crystallogr.
Sect. E 2004, 60, o2043.
found: 359.1627.
Acknowledgment
We thank the financial supports by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science,
and Technology, and Nippon Steel Chemical Co., Ltd, Japan. We
thank Mr. H. Moriguchi, Faculty of Engineering, for MS spectra.
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Synthesis 2008, No. 11, 1717–1724 © Thieme Stuttgart · New York