A Facile one-pot benzylation of sodium enolates using trifluoromethanesulfonic anhydride and diphenyl sulfoxide

Article abstract of DOI:10.1248/cpb.53.476

A facile one-pot C-benzylation of various sodium enolates derived from methyl malonate, β-ketoesters, a β-cyanoester, a β-cyanosulfone, ketones and a carboxylic ester is reported. Reaction of alkoxydiphenylsulfonium salts formed by treating various benzyl alcohols with diphenyl sulfide bis(trifluoromethanesulfonate) (derived from trifluoromethanesulfonic anhydride and diphenyl sulfoxide) proceeded smoothly, and the corresponding C-benzylated products were afforded in good to high yields.

Full text of DOI:10.1248/cpb.53.476

4
76
Chem. Pharm. Bull. 53(5) 476—480 (2005)
Vol. 53, No. 5
A Facile One-Pot Benzylation of Sodium Enolates Using
Trifluoromethanesulfonic Anhydride and Diphenyl Sulfoxide
a
a
a
,a,b
Tomofumi TAKUWA, Tomofumi MINOWA, Hidehiko FUJISAWA, and Teruaki MUKAIYAMA*
a
Center for Basic Research, The Kitasato Institute; 6–15–5 (TCI) Toshima, Kita-ku, Tokyo 114–0003, Japan: and
Kitasato Institute for Life Science, Kitasato University; 5–9–1 Shirokane, Minato-ku, Tokyo 108–8641, Japan.
b
Received October 1, 2004; accepted March 4, 2005; published online March 10, 2005
A facile one-pot C-benzylation of various sodium enolates derived from methyl malonate, b-ketoesters, a b-
cyanoester, a b-cyanosulfone, ketones and a carboxylic ester is reported. Reaction of alkoxydiphenylsulfonium
salts formed by treating various benzyl alcohols with diphenyl sulfide bis(trifluoromethanesulfonate) (derived
from trifluoromethanesulfonic anhydride and diphenyl sulfoxide) proceeded smoothly, and the corresponding C-
benzylated products were afforded in good to high yields.
Key words C-benzylation; diphenyl sulfoxide; trifluoromethanesulfonic anhydride
Alkylation of metal enolates is one of the most fundamen- tive sulfonium intermediate, which in turn reacts with amines
12,13)
tal and frequently used reactions in organic synthesis. This to afford aziridines or b,g-unsaturated amines.
There-
reaction is generally accomplished by treating various metal fore, formation of an alkoxy diphenyl sulfonium intermediate
enolates with alkylating reagents such as alkyl halides or was anticipated upon treatment of an alcohol with diphenyl
alkyl sulfonates. Such reactions of metal enolates derived sulfide bis(trifluoromethanesulfonate). Initially, reaction of 4-
1)
2)
3)
from ketones, esters, and b-keto esters with alkyl halides methoxybenzyl alcohol with sodium dimethyl malonate was
afford a mixture of mono-, di- and poly-alkylated products, studied as a model system; that is, the diphenyl alkoxy sulfo-
even when one equivalent each of base and alkylating nium intermediate was generated by adding 1.2 eq of 4-
reagent are used. For example, O-monobenzylated, C- methoxybenzyl alcohol to a mixture of trifluoromethanesul-
monobenzylated and C-dibenzylated products (5 : 45 : 50) fonic anhydride and diphenyl sulfoxide in tetrahydrofuran
were obtained by benzylation of ethyl acetate with benzyl (THF) at ꢀ78 °C. After stirring the mixture for 30 min,
4)
bromide in dimethyl sulfoxide.
3.0 eq of freshly-prepared sodium enolate of dimethyl mal-
C-Alkylation of active methylene compounds with alco- onate was continuously added and then the reaction mixture
hols has recently been accomplished in a redox reaction sys- was slowly warmed to room temperature. After aqueous
5)
tem by Mitsunobu-type reactions, and Tsunoda and co- work up, dimethyl (4-methoxybenzyl)malonate was obtained
6)
workers have also reported efficient methods for alkylation in 35% yield (Chart 2).
of active methylene compounds. However, with benzyl alco-
In order to improve the efficiency of the reaction, opti-
hol, it is reported that the concomitant double alkylation mization of the reaction conditions was attempted. First, the
7)
and/or an ether forming-reaction takes place. Thus, it is im- effects of various solvents were examined (Table 1). When
portant to develop an efficient approach to this type of reac- solvents such as MeCN, CH Cl , hexane and dimethylform-
2
2
tion, since C-monobenzylation of enolates is an important amide (DMF) were used, the desired product was not de-
area of synthetic organic chemistry.
The ratio of C- or O-alkylation strongly depends on the
nature of the alkylating reagent. Alkoxydiphenyl sulfonium
species are known as efficient alkylating reagents in reactions
with carbon nucleophiles. Similarly, sulfonium salts derived
from dialkylsulfoxides and trifluoromethanesulfonic anhy-
dride have been utilized previously in Swern-type oxida-
8
)
9)
10)
tion, sulfilimine synthesis, and glycosylation reactions.
Here, we describe a facile one-pot C-benzylation using triflu-
11)
oromethanesulfonic anhydride and diphenyl sulfoxide.
Chart 1
Results and Discussion
Generation of an alkoxy sulfonium intermediate was first
attempted using the bromodiphenyl sulfonium salt derived
from diphenyl sulfide and bromine (Chart 1); that is, 1.0 eq
of bromine was added to diphenyl sulfoxide in
dichloromethane at ꢀ78 °C. After stirring the mixture for
10 min, 4-methoxybenzyl alcohol and freshly-prepared
sodium enolate of dimethyl malonate were continuously
added, followed by slow warming to room temperature. How-
ever, the desired product was not obtained. We have previ-
ously reported that diphenyl sulfide bis(trifluoromethanesul-
fonate) reacts with styrene to generate the corresponding ac-
Chart 2
∗
To whom correspondence should be addressed. e-mail: mukaiyam@abeam.ocn.ne.jp
© 2005 Pharmaceutical Society of Japan

May 2005
477
Table 1. Effects of Various Solvents
Table 3. The Amount of Sodium Enolate
a)
a)
Entry
Solvent Yield (%)
Entry
Solvent Yield (%)
a)
Entry
Nucleophile
COOMe
Equivalent
Yield (%)
b
1
2
3
4
THF
35
5
6
7
8
CH Cl
ND )
57
2
2
b)
Et O
ND
ND
ND
Toluene
Hexane
DMF
1
2
3
1.5
2.0
3.0
25
68
97
2
t
b)
b)
b)
BuOMe
ND
Na
ꢁ
COOMe
b)
CH CN
ND
3
a) Isolated yields. b) Desired product was not detected.
a) Isolated yields.
®
Table 2. Effect of Bases as a Scavenger in Benzylation
sons for the particular effect of proton sponge remain un-
clear.
Next, the appropriate amount of nucleophile was exam-
ined (Table 3). Yields were lowered by decreasing the
amount of nucleophile, and at least 3.0 eq of nucleophile
were necessary for preparation of the desired product in high
yield. This result indicates that the nucleophiles are proto-
nated by TfOH trapped with the base and by excess benzyl
alcohol. In all cases, dibenzylated and O-benzylated products
were not detected under these conditions.
The effects of alcohols and nucleophiles were then exam-
ined under the optimized reaction conditions. The effects of
benzyl alcohol substituents were examined using the sodium
enolate of dimethyl malonate as a model nucleophile (Table
Yield
Yield
(%)
Entry
Base
Entry
Base
a)
a)
(%)
b)
1
2
3
4
5
None
CsF
57
54
58
65
6
7
8
9
10
DBU
N,N-Dimethylaniline
Pyridine
Trace
Trace
77
53
97
Cs CO3
2
K CO3
2,6-Lutidine
Proton Sponge
2
®
c)
Triethylamine Trace
4
). All reactions were performed using the same reaction
a) Isolated yields. b) 1,8-Diazabicyclo[5.4.0]undec-7-ene. c)
time, and it was found that various benzyl alcohols can be ef-
fectively employed in the reaction. For benzyl alcohols with
electron-donating groups, the desired products were obtained
tected. Similar results were obtained when ethereal solvents in high yields (Entries 3—6). Furthermore, the correspond-
t
such as Et O and BuOMe were used. In contrast, the reac- ing C-benzylated products were obtained in good to high
2
tion proceeded smoothly when toluene was used as solvent, yields when benzyl alcohols with electron-withdrawing
and the desired product was obtained in 57% yield (Entry 6). groups were used (Entries 8—12). In contrast, the desired
During this reaction, TfOH was generated as the reaction of product was not detected for a secondary benzyl alcohol such
the diphenyl sulfonium intermediate and 4-methoxybenzyl as 1-phenylethanol (Entry 13).
alcohol progressed. Thus, the reaction was examined in the
It was noted that the desired product was not detected
presence of various bases, in order to capture TfOH as it was when the reaction was carried out in the absence of diphenyl
formed. The effects of these bases are shown in Table 2. sulfoxide (Table 4, Entry 2). This indicates that the reaction
When solid bases such as cesium fluoride, cesium carbonate does not proceed via nucleophilic substitution of benzyl tri-
and potassium carbonate were used, the results were similar fluoromethanesulfonate (generated from benzyl alcohol and
to the reaction carried out in the absence of base. Therefore, trifluoromethanesulfonic anhydride) by the nucleophile.
organic bases such as Et N, 1,8-diazabicyclo[5.4.0]undec-7-
Several nucleophiles were further examined (Table 5) and
3
ene (DBU), and PhNMe were chosen so that the reaction the desired products were obtained in excellent yields with
2
could be performed in a homogeneous system. However, b-keto esters (Entries 2, 3). When the sodium enolate of
only a trace amount of the desired product was detected with methyl cyanoacetate was used as a nucleophile, the corre-
these bases. This indicates that preferential nucleophilic at- sponding product was obtained in good yield with 4.0 eq of
tack by the amine on diphenyl sulfide bis(trifluoromethane- nucleophile (Entry 4), and the sodium salt of (phenylsul-
sulfonate) occurred faster than formation of the alkoxy fonyl)acetonitrile also worked effectively in the reaction
diphenyl sulfonium intermediate, since these amine bases are (Entry 5). Similarly, the reaction proceeded smoothly with
more nucleophilic than alcohols. In order to reduce this ef- sodium enolates derived from various ketones, using 4.0—
fect, the reaction was performed using weaker amine nucle- 6.0 eq of nucleophile (Entries 6—9). Furthermore, a sodium
ophiles, such as pyridine and 2,6-lutidine. With pyridine, the enolate derived from a carboxylic ester also served as a nu-
desired product was obtained in 77% yield, while a yield cleophile in the reaction, again using 4.0 eq of nucleophile
similar to that in the absence of bases was obtained with 2,6- (Entry 10).
litidine. Furthermore, the reaction proceeded smoothly to af-
Next, the effect of the counter cation in the metal enolates
ford the C-benzylated product in an almost quantitative yield was investigated (Table 6). With lithium or potassium eno-
®
when proton sponge was used as a base, although the rea- lates generated from acetophenone, the desired product was

4
78
Vol. 53, No. 5
Table 4. Various Benzyl Alcohol Derivatives in Benzylation Reactions
a)
a)
Entry
1
Alcohol
Product
Yield (%)
94
Entry
8
Alcohol
Product
Yield (%)
2
—
1
7
74
88
74
84
76
b)
c)
2
ND
9
8
9
3
4
97
88
1
1
1
0
1
2
3
10
11
5
6
4
5
85
85
c)
1
3
—
ND
7
6
83
a) Isolated yields. b) The reaction was carried out without diphenyl sulfoxide. c) Desired product was not detected.
Table 5. Investigation of Other Sodium Enolates
a)
a)
Entry
Nucleophile
Product
Yield (%)
94
Entry
Nucleophile
Product
Yield (%)
c)
1
2
3
6
7
8
78
c,d)
96
95
b,d)
Quant.
95
b)
d,e)
4
5
70
9
84
b,d)
79
10
98
1
a) Isolated yields. b) 4.0 eq of nucleophiles were used. c) 5.0 eq of nucleophiles were used. d) Yields were determined by H-NMR. e) 6.0 eq of nucleophiles were
used.
obtained in 38% or 30% yields, respectively. In contrast, the sulfoxide were used, but the reaction did not proceed at all
reaction proceeded smoothly and afforded the desired prod- (Chart 3). This suggests that the reaction is limited to the pri-
uct in good yield in the presence of a sodium enolate nucle- mary benzyl alcohol at present (Table 4, Entry 13). The reac-
ophile.
tion mechanism is assumed to be that shown in Chart 4. Ini-
Finally, the reaction was attempted using other alcohols tially, diphenyl sulfoxide is activated by trifluoromethanesul-
that were not simple benzyl alcohols. For example, phenethyl fonic anhydride to form a sulfonium complex A. Reaction of
alcohol was used for alkylation of the sodium enolate gener- the benzyl alcohol with A in situ affords an active oxosulfo-
ated from isopropyl acetate, but the corresponding product nium trifluoromethanesulfonate B, which in turn reacts with
was not detected. To increase the reactivity of the alkoxy sul- a nucleophile to give the corresponding C-benzylated prod-
fonium intermediate, alkoxy dialkyl sulfonium salts of uct.
phenethyl alcohol and di-p-nitrophenyl or di-tert-butylphenyl

May 2005
479
Table 6. Other Metal Enolate
perimental procedure (Table 4, Entry 3) is described: to a stirred solution of
diphenyl sulfoxide (0.20 mmol) in toluene (1.0 ml) under an argon atmo-
sphere was added a trifluoromethanesulfonic anhydride (0.20 mmol) at
ꢀ
78 °C. After stirring for 30 min a solution of 4-methoxybenzyl alcohol
®
(0.24 mmol) and proton sponge (0.24 mmol) in toluene (0.8 ml) was added,
and the reaction mixture was stirred for further 30 min. Fleshly prepared
14)
sodium salt of dimethyl malonate dissolved in THF (0.4 M, 1.5 ml) was
added and the reaction mixture was slowly warmed up to room temperature.
After stirring for 2 h, the reaction mixture was quenched with water (5 ml)
and the aqueous layer was extracted with ethyl acetate (30 ml). The organic
a)
Entry
Metal
Yield (%)
layers were collected and dried (MgSO ). After filtration and evaporation of
4
1
2
3
Li
Na
K
38
78
30
the solvdent, the resulted residue was purified by preparative TLC to afford
compound 1 in 97% yield as a colorless oil.
Dimethyl (4-Methoxybenzyl)malonate (1)
15)
ꢀ1
IR (neat) cm : 3779,
1
2
360, 1743, 1249, 1218. H-NMR (270 MHz, CDCl ) d: 3.14 (2H, d,
3
a) Isolated yields.
Jꢂ7.8 Hz), 3.61 (1H, d, Jꢂ7.8 Hz), 3.68 (6H, s), 3.75 (3H, s), 6.79 (2H, d,
Jꢂ8.7 Hz), 7.19 (2H, d, Jꢂ8.7 Hz). C-NMR (68 MHz, CDCl ) d: 34.0,
2.6 (ꢃ2), 53.9, 55.2, 113.8, 129.6 (ꢃ2), 129.7 (ꢃ2), 158.2, 169.1 (ꢃ2).
Dimethyl Benzylmalonate (2)
442, 1234. H-NMR (270 MHz, CDCl ) d: 3.21 (2H, Jꢂ7.9 Hz, d), 3.64—
1
3
3
5
16)
ꢀ1
IR (neat) cm : 2360, 2337, 1743,
1
1
3
3
1
3
.67 (1H, m), 3.68 (6H, s), 7.16—7.29 (5H, m). C-NMR (68 MHz, CDCl )
3
d: 34.8, 52.6 (ꢃ2), 53.6, 126.7, 128.4 (ꢃ2), 128.6 (ꢃ2), 137.6, 169.0 (ꢃ2).
1
7)
ꢀ1
Dimethyl (3-Methoxybenzyl)malonate (3)
IR (neat) cm : 3586,
1
2
3
(
337, 1743, 1265. H-NMR (270 MHz, CDCl ) d: 3.17 (2H, d, Jꢂ7.8 Hz),
.62—3.65 (1H, m), 3.67 (6H, s), 3.75 (3H, s), 6.71—6.75 (3H, m), 7.16
3
Chart 3
1
3
1H, t, Jꢂ7.8 Hz). C-NMR (68 MHz, CDCl ) d: 34.8, 52.6 (ꢃ2), 53.5,
3
5
5.1, 112.1, 114.3, 120.9, 129.4, 139.1, 159.5, 169.0 (ꢃ2).
1
8)
ꢀ1
Dimethyl (4-Methylbenzyl)malonate (4)
IR (neat) cm
: 2360,
1
1
(
743, 1442, 1226, 809. H-NMR (270 MHz, CDCl ) d: 2.29 (3H, s), 3.16
2H, d, Jꢂ7.8 Hz), 3.63 (1H, t, Jꢂ7.9 Hz), 3.68 (6H, s), 7.06 (4H, s). C-
3
13
NMR (68 MHz, CDCl ) d: 21.1, 34.4, 52.6 (ꢃ2), 53.7, 128.5 (ꢃ2), 129.1
3
(
ꢃ2), 130.7, 136.2, 169.1 (ꢃ2).
19)
ꢀ1
Dimethyl (4-Isopropylbenzyl)malonate (5)
IR (neat) cm : 2962,
1
2
337, 1743, 1434, 823. H-NMR (270 MHz, CDCl ) d: 1.21 (2H, d,
3
Jꢂ6.9 Hz), 2.80—2.90 (1H, m), 3.18 (2H, d, Jꢂ7.8 Hz), 3.62—3.65 (1H,
m), 3.68 (6H, s), 7.10 (4H, m). C-NMR (68 MHz, CDCl ) d: 24.0 (ꢃ2),
3
1
3
3
3.7, 34.4, 52.5 (ꢃ2), 53.7, 126.5, (ꢃ2), 128.5 (ꢃ2), 134.9, 147.2, 169.1
(
ꢃ2).
ꢀ1
Dimethyl (1-Naphthylmethyl)malonate (6) IR (neat) cm : 3070,
337, 1743, 1442, 786. H-NMR (270 MHz, CDCl ) d: 3.68 (6H, s), 3.73
1
2
3
Chart 4
(2H, d, Jꢂ5.0 Hz), 3.87 (1H, t, Jꢂ7.5 Hz), 7.36 (2H, m), 7.50 (2H, m), 7.73
(
1H, dd, Jꢂ6.3, 3.3 Hz), 7.85 (1H, d, Jꢂ7.6 Hz), 8.01 (1H, d, Jꢂ8.2 Hz).
1
3
C-NMR (68 MHz, CDCl ) d: 32.0, 52.59, 52.61 (ꢃ2), 123.0, 125.3, 125.6,
3
Conclusion
1
26.2, 127.0, 127.6, 128.9, 131.3, 133.5, 133.8, 169.2 (ꢃ2). Anal. Calcd for
A new and efficient one-pot C-benzylation reaction of var- C H O : C, 70.57; H, 5.92. Found: C, 70.61; H, 5.88.
1
6
16
4
20)
ꢀ1
ious sodium enolates was established using new benzylating
reagents generated in situ from diphenyl sulfoxide, trifluo-
romethanesulfonic anhydride and benzyl alcohols. Further
study of this type of alkylation reaction is currently in
progress.
Dimethyl (4-Nitrobenzyl)malonate (7)
IR (neat) cm : 3370, 2946,
1
1
743, 1342. H-NMR (270 MHz, CDCl ) d: 3.20 (2H, d, Jꢂ7.9 Hz), 3.59—
3
3
.61 (1H, m), 3.59 (6H, s), 7.26 (2H, d, Jꢂ8.9 Hz), 8.02 (2H, d, Jꢂ8.9 Hz).
13
C-NMR (68 MHz, CDCl ) d: 34.4, 52.5, 52.8 (ꢃ2), 123.7 (ꢃ2), 125.3,
3
1
29.6 (ꢃ2), 145.2, 168.4 (ꢃ2).
2
1)
ꢀ1
Dimethyl (4-Chlorobenzyl)malonate (8)
IR (neat) cm : 3756,
1
2
337, 1743, 848, 817. H-NMR (270 MHz, CDCl ) d: 3.60 (2H, d,
3
Experimental
Jꢂ7.8 Hz), 3.62 (1H, t, Jꢂ7.8 Hz), 3.68 (6H, s), 7.11 (2H, d, Jꢂ8.1 Hz),
1
3
All melting points were determined on a Yanagimoto micro melting point
7.22 (2H, d, Jꢂ8.2 Hz). C-NMR (68 MHz, CDCl ) d: 34.1, 52.6 (ꢃ2),
3
apparatus (Yanaco MP-S3) and were uncorrected. Infrared (IR) spectra were 53.4, 128.6 (ꢃ2), 130.0 (ꢃ2), 132.5, 136.0, 167.8 (ꢃ2).
1
ꢀ1
recorded on a Horiba FT 300 FT-IR spectrometer. H-NMR spectra were
Dimethyl (3-Chlorobenzyl)malonate (9) IR (neat) cm : 2954, 2337,
recorded on a JEOL EX270 (270 MHz) spectrometer; chemical shifts (d) are 1743, 1442, 1025. H-NMR (270 MHz, CDCl ) d: 3.17 (2H, d, Jꢂ7.8 Hz),
1
3
13
reported in parts per million relative to tetramethylsilane. Splitting patterns
3.63 (1H, t, Jꢂ7.8 Hz), 3.69 (6H, s), 7.04—7.30 (4H, m). C-NMR
are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, (68 MHz, CDCl ) d: 34.4, 52.7 (ꢃ2), 53.3, 126.9, 127.0, 128.8, 129.7,
3
1
3
broad. C-NMR spectra were recorded on a JEOL EX270 (68 MHz) spec-
trometer with complete proton decoupling. Chemical shifts are reported in
parts per million relative to tetramethylsilane with the solvent resonance as
134.2, 139.6, 168.7 (ꢃ2). FAB-HR-MS m/z: 257.0585 (Calcd for
C H ClO : 257.0575).
Dimethyl (2-Chlorobenzyl)malonate (10) IR (neat) cm : 2954, 2360,
1
2
14
4
ꢀ
1
1
the internal standard (CDCl ; d 77.0 ppm). High-resolution mass spectra
2337, 1743, 1473. H-NMR (270 MHz, CDCl ) d: 3.25 (2H, d, Jꢂ7.8 Hz),
HR-MS) were recorded on a JEOL-700T mass spectrometer. Elemental 3.61 (6H, s), 3.77 (1H, t, Jꢂ7.8 Hz), 7.07—7.17 (3H, m), 7.24—7.27 (1H,
3
3
(
1
3
analyses were performed on vario EL III (elementar), DX-500 (DIONEX)
and UV2200 (SHIMADZU). Analytical TLC was performed on Merck pre-
coated TLC plates (silica gel 60 GF254, 0.25 mm). Silica-gel column chro-
matography was carried out on Merck silica gel 60 (0.063—0.200 mm).
m). C-NMR (68 MHz, CDCl ) d: 32.8, 51.2, 52.6 (ꢃ2), 126.7, 128.4,
129.5, 131.2, 134.0, 135.1, 168.9 (ꢃ2). FAB-HR-MS m/z: 257.0579 (Calcd
for C H ClO : 257.0575).
Dimethyl (2-Fluorobenzyl)malonate (11)
3
1
2
14
4
2
2)
ꢀ1
IR (neat) cm : 3710,
1
Preparative thin-layer chromatography (PTLC) was carried out on silica-gel 2352, 1743, 1234. H-NMR (270 MHz, CDCl ) d: 3.23 (2H, d, Jꢂ7.9 Hz),
Wacogel B-5F. Solvents were freshly distilled when dry solvents were 3.67 (6H, s), 3.73 (1H, t, Jꢂ7.8 Hz), 6.95—7.04 (2H, m), 7.14—7.24 (2H,
3
1
3
needed. Other reagents were purchased from Tokyo Kasei Kogyo, Kanto m). C-NMR (68 MHz, CDCl ) d: 28.6, 51.8, 52.6 (ꢃ2), 115.1, 115.4,
3
Chemical, Aldrich Chemical or Merck, and were used after purification by
distillation or recrystallization.
124.0, 128.6, 128.7, 131.1, 168.9 (ꢃ2).
Methyl 2-Benzyl-3-oxobutanoate (12)
2
3)
ꢀ1
IR (neat) cm : 2337, 1735,
1
Typical Experimental Procedure for Benzylation of Enolates The ex- 1434, 1211. H-NMR (270 MHz, CDCl ) d: 2.17 (3H, s), 3.15 (2H, d,
3

4
80
Vol. 53, No. 5
1
3
Jꢂ7.7 Hz), 3.68 (3H, s), 3.79 (1H, t, Jꢂ7.7 Hz), 7.15—7.30 (5H, m). C- References and Notes
NMR (68 MHz, CDCl ) d: 29.8, 34.0, 52.5, 61.1, 111.2, 126.6 (ꢃ2), 128.6
1) Waring A. J., “Comprehensive Organic Chemistry,” ed. by Stoddart J.
F., University of Sheffield, Oxford, 1979, pp. 1017—1104.
2) Sutherland I. O., “Comprehensive Organic Chemistry,” ed. by Suther-
land I. O., University of Liverpool, Oxford, 1979, pp. 869—956.
3) Brown J. M., “Comprehensive Organic Chemistry,” ed. by Sutherland
I. O., University of Liverpool, Oxford, 1979, pp. 779—814.
4) le Noble W. J., Puerta J. E., Tetrahedron Lett., 7, 1087—1090 (1966).
5) Mitsunobu O., Yamada M., Mukaiyama T., Bull. Chem. Soc. Jpn., 40,
935—939 (1967).
6) Tsunoda T., Ozaki F., Itô S., Tetrahedron Lett., 35, 5081—5082
(1994).
7) Tsunoda T., Nagaku M., Nagino C., Kawamura Y., Ozaki F., Hioki H.,
Itô S., Tetrahedron Lett., 36, 2531—2534 (1995).
3
(
ꢃ2), 137.9, 169.3, 202.2.
ꢀ
1
Methyl 2-Benzyl-4-methyl-3-oxopentanoate (13) IR (neat) cm
:
1
2
954, 2329, 1743, 1712. H-NMR (270 MHz, CDCl ) d: 0.85 (3H, d,
Jꢂ6.9 Hz), 1.03 (3H, d, Jꢂ6.8 Hz), 1.09—1.24 (3H, m), 2.54—2.65 (1H,
m), 3.13 (2H, d, Jꢂ7.6 Hz), 3.92 (1H, t, Jꢂ7.6 Hz), 4.12 (2H, q, Jꢂ7.1 Hz),
.13—7.30 (5H, m). C-NMR (68 MHz, CDCl ) d: 14.1, 17.7, 19.8, 34.4,
1.4, 58.7, 61.4, 126.5, 128.4 (ꢃ2), 128.8 (ꢃ2), 138.3, 168.9, 208.3. FAB-
3
13
7
4
3
HR-MS m/z: 249.1496 (Calcd for C H O : 249.1485).
1
5
21
3
ꢀ1
Methyl 2-Cyano-3-phenylpropanoate (14) IR (neat) cm
:
2962,
1
2
252, 1751, 1265, 755. H-NMR (270 MHz, CDCl ) d: 3.15 (2H, ddd,
3
Jꢂ28.0, 13.9, 8.4 Hz), 3.66 (1H, dd, Jꢂ8.4, 5.8 Hz), 3.70 (3H, s), 7.17—
.30 (5H, m). C-NMR (68 MHz, CDCl ) d: 35.8, 39.6, 53.5, 115.9, 127.7,
28.8 (ꢃ2), 128.9 (ꢃ2), 135.1, 165.8. FAB-HR-MS m/z: 188.0715 (Calcd
13
7
1
3
8) Hendrickson J. B., Schwartzman S. M., Tetrahedron Lett., 16, 273—
276 (1975).
9) Coburn M. D., Hayden H. H., Synthesis, 1986, 490—492 (1986).
for C H NO : 188.0712).
11
10
2
2
4)
ꢀ1
3
-Phenyl-2-(phenylsulfonyl)propanenitrile (15)
IR (neat) cm
:
1
2
1
7
1
1
930, 2220, 1320, 1160. H-NMR (270 Hz, CDCl ) d: 3.08 (1H, dd, Jꢂ13.6, 10) Garcia B. A., Poole J. L., Gin D. Y., J. Am. Chem. Soc., 119, 7597—
3
1.7 Hz), 3.58 (1H, dd, Jꢂ13.6, 3.9 Hz), 4.08 (1H, dd, Jꢂ11.7, 3.9 Hz),
7598 (1997).
13
.21—8.06 (10H, m). C-NMR (68 MHz, CDCl ) d: 32.7, 59.4, 113.72, 11) Takuwa T., Onishi J. Y., Matsuo J., Chem. Lett., 33, 8—9 (2004).
3
28.2, 128.6, 129.1 (ꢃ2), 129.2 (ꢃ2), 129.7 (ꢃ2), 130.6, 133.5, 135.4, 12) Matsuo J., Yamanaka H., Kawana A., Mukaiyama T., Chem. Lett., 32,
35.5.
,3-Diphenylpropan-1-one (16)
392—393 (2003).
25)
ꢀ1
1
IR (neat) cm : 2352, 2337, 1689, 13) Yamanaka H., Matsuo J., Kawana A., Mukaiyama T., Chem. Lett., 32,
1
1
596. H-NMR (270 MHz, CDCl ) d: 2.99 (2H, t, Jꢂ7.7 Hz), 3.23 (2H, t,
626—627 (2003).
3
1
3
Jꢂ7.7 Hz), 7.04—7.51 (9H, m), 7.86—7.90 (2H, m). C-NMR (68 MHz,
14) Sodium enolates were prepared by adding sodium hydride in THF (Ta-
bles 1—4 and Table 5, Entries 1—5) or sodium hexamethyldisi-
lazanide in THF (Table 5, Entris 6—10, Tables 6 and 7) to THF solu-
tion of the corresponding carbonyl compounds.
CDCl ) d: 30.2, 40.5, 126.0, 127.9 (ꢃ2), 128.3, 128.4 (ꢃ2), 128.5 (ꢃ2),
3
1
2
32.9 (ꢃ2), 136.7, 141.1, 199.0.
26)
ꢀ1
2
-Methyl-1,3-diphenylpropan-1-one (17)
IR (neat) cm : 2360,
1
337, 1681, 1450, 971. H-NMR (270 MHz, CDCl ) d: 1.13 (3H, d, 15) House H. O., Larson J. K., Muller H. C., J. Org. Chem., 33, 961—968
3
Jꢂ6.9 Hz), 2.62 (1H, dd, Jꢂ13.6, 7.9 Hz), 3.10 (1H, dd, Jꢂ13.6, 6.4 Hz),
(1968).
3
.61—3.72 (1H, m), 7.08—7.22 (5H, m), 7.34—7.50 (3H, m), 7.83—7.86 16) Elinson M. N., Feducovich S. K., Zakharenkov A. A., Ugrak B. I.,
1
3
(
1
2H, m). C-NMR (68 MHz, CDCl ) d: 17.5, 39.4, 42.8, 126.1, 128.1 (ꢃ2),
Nikishin G. I., Lindeman S. V., Struchkov J. T., Tetrahedron, 51,
5035—5046 (1995).
IR (neat) cm : 2360, 17) Bradly R., Jeffrey S., Christpher S., Phosphorus, Sulfur and Silicon
and the Related Elements, 177, 1881—1884 (2002).
3
28.2 (ꢃ2), 128.4 (ꢃ2), 128.9 (ꢃ2), 132.7, 136.3, 139.8, 203.5.
2
7)
ꢀ1
2
,2-Dimethyl-1,3-diphenylpropan-1-one (18)
1
2
7
1
1
329, 2673, 1457. H-NMR (270 MHz, CDCl ) d: 1.23 (6H, s), 3.00 (2H, s),
3
13
.01—7.47 (10H, m). C-NMR (68 MHz, CDCl ) d: 26.2 (ꢃ2), 46.3, 48.8, 18) Chuang C., Wang S., Tetrahedron, 54, 10043—10052 (1998).
3
26.3, 127.3 (ꢃ2), 127.90 (ꢃ2), 127.94, 128.2, 128.5, 130.4, 130.5, 132.7, 19) Matheson R. C., WO200021941 (2000).
37.8, 209.3.
,4-Dimethyl-1-phenylpentan-3-one (19)
20) Palmer B. D., Lee Ho H., Johnson P., Baguley B. C., Wickham G.,
Wakelin L. P. G., McFadyen W. D., Denny W. A., J. Med. Chem., 33,
3008—3014 (1990).
2
5)
ꢀ1
4
IR (neat) cm
: 2352,
1
1
(
704, 1095, 694. H-NMR (270 MHz, CDCl ) d: 1.10 (9H, s), 2.75—2.90
3
1
3
4H, m), 7.16—7.36 (5H, m). C-NMR (68 MHz, CDCl ) d: 26.4 (ꢃ3), 21) Matoba K., Yamazaki T., Chem. Pharm. Bull., 31, 2955—2956 (1983).
3
3
0.1, 38.5, 44.1, 125.9 (ꢃ2), 127.7, 128.3 (ꢃ2), 141.4, 214.7.
22) Boiadjiev S. E., Lightner D. A., J. Phys. Org. Chem., 12, 751—757
(1999).
28)
ꢀ1
Isopropyl 3-Phenylpropanoate (20)
IR (neat) cm : 3880, 2337,
1
1
727, 1110. H-NMR (270 MHz, CDCl ) d: 1.19 (6H, d, Jꢂ6.4 Hz), 2.57
23) Sundar N., Bhat S. V., Synthetic Commun., 28, 2311—2316 (1998).
3
(
(
2H, t, Jꢂ7.8 Hz), 2.93 (2H, t, Jꢂ7.8 Hz), 4.92—5.03 (1H, m), 7.17—7.36 24) Fujii M., Nakamura K., Mekata H., Oka S., Ohno A., Bull. Chem. Soc.
13
5H, m). C-NMR (68 MHz, CDCl ) d: 21.9 (ꢃ2), 31.1, 36.3, 67.7, 126.1,
Jpn., 61, 495—500 (1988).
25) Dieter R. K., Sharma R. R., Yu H., Gore V. K., Tetrahedron, 59,
3
1
28.2 (ꢃ2), 128.3 (ꢃ2), 140.5, 172.3.
1
083—1094 (2003).
Acknowledgments This study was supported by in part by the Grant of
26) Nudelman N. S., García G. V., J. Org. Chem., 66, 1387—1394 (2001).
27) Barluenga J., Aguilar E., Olano B., Fustero S., J. Org. Chem., 53,
1741—1744 (1988).
28) Kunishima M., Kawachi C., Morita J., Terao K., Iwasaki F., Tani S.,
Tetrahedron, 55, 13159—13170 (1999).
the 21st Century COE Program, Ministry of Education, Culture, Sports, Sci-
ence and Technology. The authors wish to thanks to Yamanouchi Pharma-
ceutical Co., Ltd. for mass spectrometry analysis and elemental analysis.