Reduction of carboxylic esters to ethers with triethyl silane in the combined use of titanium tetrachloride and trimethylsilyl trifluoromethanesulfonate

Article abstract of DOI:10.1016/S0040-4020(01)00420-3

Aliphatic acyclic and cyclic ethers are prepared on treatment of their corresponding carboxylic esters and lactones with triethylsilane in the presence of titanium tetrachloride and trimethylsilyl trifluoromethanesulfonate.

Full text of DOI:10.1016/S0040-4020(01)00420-3

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 5353±5359
Reduction of carboxylic esters to ethers with triethyl silane in the
combined use of titanium tetrachloride and trimethylsilyl
tri¯uoromethanesulfonate
Michihisa Yato, Koichi Hommap and Akihiko Ishida
Medicinal Chemistry Research Laboratory, Tanabe Seiyaku Co. Ltd., 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
Received 17 August 2000; accepted 10 April 2001
AbstractÐAliphatic acyclic and cyclic ethers are prepared on treatment of their corresponding carboxylic esters and lactones with
triethylsilane in the presence of titanium tetrachloride and trimethylsilyl tri¯uoromethanesulfonate. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
nic acid gave the corresponding methyl ether in only 7%
yield, reduction of the secondary and tertiary butyl esters
gave ethers in 41 and 76% yields, respectively. Tsurugi et al.
also achieved the conversion of carboxylic esters to ethers
with trichlorosilane ,Cl3SiH) under g-irradiation.2 Only
alkyl aliphatic carboxylates could be reduced to the corre-
sponding ethers in good yields. Recent work of Cutler and
his co-workers have established the process of manganese
acetyl complexes catalyzed hydrosilylation of carboxylic
esters, however, only esters of straight-chain carboxylic
acids have cleanly yielded their corresponding ethers.3
In previous papers, we have already reported that cyclic
ethers are prepared from lactones on treatment with silyl
The reduction of carboxylic esters to the corresponding
alcohols, for example, with lithium aluminium hydride
,LiAlH4), has been a widely used synthetic method,
however there are a few reports on the reduction of
carboxylic esters to ethers. Pettit and his co-workers have
reported the reduction of carboxylic esters to ethers with
boron tri¯uoride etherate and metal hydride, sodium boro-
hydride ,NaBH4), in diglymeÐtetrahydrofuran being the
most satisfactory.1 The yields of ethers are greatly corre-
lated with the bulkiness of the ester alcohol groups in such
reductions. While reduction of the methyl ester of 5b-chola-
Table 1. Reduction of 1a with Et3SiH in the presence of TiCl4 and TMSOTf or AgOTf
Entry
Et3SiH
,mol)
TiCl4
,mol)
TMSOTf
,mol)
AgOTf
,mol)
TMSCI
,mol)
Yield ,%)
2a
1a
1
2
3
4
5
6
7
8
5.0
5.0
5.0
5.0
3.0
5.0
5.0
5.0
3.0
1.5
1.5
1.5
1.5
±
±
±
±
±
±
±
±
3.0
3.0
±
±
±
±
±
±
±
3.0
27
35
65
81
58
±
61
54
14
±
±
88
±
0.5
1.5
3.0
3.0
3.0
±
1.5
1.5
63
76
±
±
Keywords: triethylsilane; titanium tetrachloride; trimethylsilyl tri¯uoromethanesulfonate.
Corresponding author. Fax: 181-48-433-2610; e-mail: k-homma@tanabe.co.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00420-3

5354
M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
Table 2. Reduction of esters with Et3SiH in the presence of TiCl4 and TMSOTf
aThe product was 4-phenylbutanol ,3). 1d was recovered in 41% yield.
bThe product was 4-phenylbutanol ,3). 1e was recovered in 51% yield.
cThe product was 4-phenylbutanol ,3).
d1p was recovered in 13% yield.
nucleophiles by promotion of trityl salt such as triphenyl-
methylium hexachloroantimonate ,TrSbCl6), or by the
catalyst system of antimony pentachloride ,SbCl5) with
chlorotrimethylsilane ,TMSCl) and tin,II) iodide ,SnI2).4
In the case of acyclic esters, however, these catalysts are
unable to promote such reduction effectively.
presence of titanium tetrachloride ,TiCl4) and trimethylsilyl
tri¯uoromethanesulfonate ,TMSOTf).
2. Results and discussion
To begin with the reduction of methyl 4-phenylbutylate
,1a) using 5.0 mol equiv. of Et3SiH and 3.0 mol equiv. of
TiCl4 in dichloromethane was carried out. Reaction gave
desired methyl ether ,2a) in only 27% yield, along with
In this paper, we would like to report a convenient synthesis
of several acyclic and cyclic ethers from the corresponding
carboxylic esters, with triethylsilane ,Et3SiH) in the

M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
5355
Table 3. Synthesis of b-amino ether ,5) by the reduction of aromatic ketone ,4) with Et3SiH in the presence of TiCl4 and TMSOTf
Entry
Substrate
Et3SiH ,mol)
TiCl4 ,mol)
TMSOTf ,mol)
Yield ,%)
5
6
7
1
2
3
4
5
,R)-4
,S)-4
,R)-4
,S)-4
rac-4
5.0
5.0
3.0
3.0
3.0
3.0
3.0
1.5
1.5
3.0
6.0
6.0
3.0
3.0
±
71
75
±
±
±
±
±
87
84
25
±
±
±
±
38
recovery of 1a in 61% yield ,Table 1, entry 1). We then
examined the reduction of 1a using Et3SiH in the presence
of TiCl4 and TMSOTf or AgOTf, in expectation of in situ
formation of titanium tri¯ate species, under several con-
ditions. Results were summarized in Table 1.
yield, which was accompanied by 2,3-dihydrogenated
product in 30% yield ,entry 12). Although Cutler's method,
using manganese acetyl complexes, gave satisfactory results
only for straight-chain esters, our reduction using TiCl4 and
TMSOTf gave good results in the case of carboxylic esters
derived from branched carboxylic acids ,1m and n, entries
13 and 14). Moreover, this reaction has been applicable to
the reduction of lactones ,1o and p) to give desired cyclic
ethers in good yields ,entries 15 and 16).
The reaction has been accelerated by the combined use of
TiCl4 and TMSOTf ,entries 2±4). When the reduction was
carried out using 1.5 mol equiv. of TiCl4 and 3.0 mol equiv.
of TMSOTf, the reaction has proceeded smoothly and the
yield of 2a has been improved to 81% ,entry 4). In the
reaction using small excess amounts of Et3SiH ,3.0 mol
equiv.), the yield of 2a has been reduced to 58% ,entry 5).
Moreover, TMSOTf alone did not promote this reaction at
all ,entry 6).
The application is noted on Table 3 for the synthesis of
b-amino ether by the reduction of methyl 4-,4-chlorophe-
nyl)-2-methoxycarbonylamino-4-oxobutanoate ,4). The
ester ,4) was easily prepared by Friedel±Crafts acylation
of chlorobenzene with N-,methoxycarbonyl)aspartic
anhydride.6
In the reaction using TiCl4 and AgOTf ,2 equiv. with
respect to TiCl4), which has been reported to generate
dichlorobis,tri¯uoromethanesulfonato)titanium ,TiCl2,OTf)2)
in situ,5 the yield of 2a was a 63% ,entry 7). When TMSCl
,2 equiv. with respect to TiCl4) was added to the combi-
nation of TiCl4 and AgOTf, the yield of 2a has been
improved to 76% ,entry 8). These results suggested the
titanium species generated in situ from TiCl4 and AgOTf
were identical with those generated from TiCl4 and
TMSOTf, and TMSCl played important role in the reduc-
tion of carboxylic esters to ethers. Study for details in the
reaction mechanism is now under way.
When the reduction of 4 was carried out using 5.0 mol
equiv. of Et3SiH in the presence of TiCl4, reduction of
both carbonyl moieties, ester and ketone groups took
place to give the desired b-amino ethers ,5) in 71%
,.99% ee) yield for ,R)-isomer from ,R)-4 and 75%
,.99% ee) yield for ,S)-isomer from ,S)-4 without racemi-
zation,7 respectively ,entries 1 and 2). On the other hand, in
the case of the reduction of 4 using 3.0 mol equiv. of
Et3SiH, only the ketone moiety was reduced into methylene
to give ,6) in 87% ,.99% ee) yield for ,R)-isomer from
,R)-4 and in 84% ,.99% ee) yield for ,S)-isomer from ,S)-4
without racemization,7 respectively ,entries 3 and 4). We
have already reported that the reduction of 4 using Et3SiH
and TiCl4 gave 6 in 25% yield along with 4-chlorinated
product ,7) in 38% yield ,entry 5).6 These results suggest
that the addition of TMSOTf into the Et3SiH±TiCl4 system
prevents the chlorination of intermediate cation.
Next, we examined the reduction of various carboxylic
esters under the condition shown in entry 4 in Table 1.
These results were summarized in Table 2. Reduction of
carboxylic esters derived from primary alcohols ,1a±c)
gave corresponding ethers in good yields ,entries 1±3),
however, in the case of carboxylic esters derived from
branched alcohols ,1d and e) and phenyl ester ,1f), reaction
product was 4-phenylbutanol ,3) instead of desired ethers.
Substituents such as bromo ,1h), nitro ,1i) and methoxy
,1k) group were inert for this hydrosilylation ,entries 8, 9
and 11). In the case of the substrate which contains indole
ring, this reaction gave corresponding ether in moderate
In conclusion, we have developed ef®cient methods for the
preparation of aliphatic acyclic and cyclic ethers by the new
reduction of their corresponding carboxylic esters with
triethyl silane promoted through the combination of TiCl4
and TMSOTf. Although there are a few effective reduction
methods for converting carboxylic esters to ethers, this new

5356
M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
reduction proceeds smoothly even if the substrates are
carboxylic esters of branched carboxylic acids, and is
successfully applicable to the synthesis of optically active
b-amino ethers.
Na2SO4. After removal of the solvent, the oily residue was
puri®ed by column chromatography on silica gel ,eluent:
hexane±AcOEtˆ4:1) to afford 0.92 g ,70%) of 1l as pale
yellow oily semi solid. IR ,Nujol): 1729, 1456, 1447, 1363,
1
1176 cm21. APCI-MS m/z: 376 ,M11MeOH). H NMR
,CDCl3) d: 2.69 ,2H, t, Jˆ8.1 Hz), 3.00 ,2H, t, Jˆ
8.1 Hz), 3.67 ,3H, s), 7.21±7.55 ,8H, m), 7.85 ,2H, d, Jˆ
8.4 Hz), 7.99 ,1H, d, Jˆ8.2 Hz). Anal. calcd for
C18H18NO4S: C, 62.77; H, 5.27; N, 4.07; S, 9.31. Found:
C, 62.95; H, 5.31; N, 4.20; S, 9.44.
3. Experimental
3.1. General
All melting points were taken in open capillary tubes on a
melting point apparatus ,Buchi 535) without correction. IR
spectra were taken with an Analect RFX-65 spectrophoto-
3.1.2. '^)-a-Benzyl-g-butyrolactone '1o). To a solution of
benzaldehyde ,2.00 g, 18.7 mmol) and g-butyrolactone
,3.22 g, 37.4 mmol) in toluene ,40 ml) was added sodium
methoxide ,1.32 g, 24.5 mmol) at 2108C. After being
stirred at the same temperature for 5 min, then at room
temperature for 1.5 h, the mixture was diluted with AcOEt
,30 ml). To this mixture was added dropwise conc. H2SO4
,1.35 ml) and H2O ,20 ml) in an ice bath. The organic layer
was washed with sat. NaHCO3 solution, H2O and brine, and
dried over Na2SO4. After removal of the solvent, the residue
was washed with i-Pr2O to afford 2.64 g ,80%) of ,^)-a-
benzylidene-g-butyrolactone as colourless crystals, mp
116±1178C. IR ,Nujor): 1737, 1649 cm21. EI-MS m/z:
1
meter. H NMR spectra were measured with a Gemini
,Varian, 300 MHz), or a JNM GSX-400 ,JEOL, 400 MHz)
spectrometer with tetramethylsilane ,TMS) as an internal
standard. The mass spectra ,MS), atmospheric pressure
chemical ionization mass spectra ,APCI-MS), electrospray
ionization mass spectra ,ESI-MS), electrical ionization
mass spectra ,EI-MS), and FAB-MS were obtained with a
SSQ7000C ,Finnigan MAT Inc.), an INCOS 50 ,Finnigan
MAT Inc.) or a JMS-HX 100 ,JEOL) spectrometer. Optical
rotations were measured on a Horiba SEPA-200 digital
polarimeter. HPLC analysis was done with a Hitachi 638-
30 ,ultraviolet detection). Elemental analyses were obtained
by using a Perkin±Elmer 2400, a Yanagimoto MT-3 or a
YEW ion chromato IC-7000. Chromatography was
performed using pre-coated Merck silica gel 60 GF254
plates, and Kanto silica gel 60 N ,100±210 mesh) powder.
In general, reactions were carried out in dry solvents under
an argon atmosphere. Unless otherwise mentioned, all
carboxylic esters were synthesized from the corresponding
carboxylic acids and alcohols in a usual manner.
1
174 ,M1), 129, 115. H NMR ,CDCl3) d: 3.26 ,2H, dt,
Jˆ3.0, 7.3 Hz), 4.47 ,2H, t, Jˆ7.3 Hz), 7.37±7.54 ,5H,
m), 7.58 ,1H, t, Jˆ3.0 Hz). Anal. calcd for C11H10O2: C,
75.84; H, 5.79. Found: C, 75.81; H, 5.78.
A mixture of ,^)-a-benzylidene-g-butyrolactone ,2.00 g,
11.5 mmol) and 10% Pd/C ,210 mg) in EtOH ,40 ml)±
MeOH ,10 ml) was stirred vigorously under 1 atm. H2 for
2 h. Catalyst was removed by ®ltration. The solvent was
removed in vacuo to afford 2.00 g ,99%) of ,^)-a-benzyl-
g-butyrolactone ,1o) as a colourless oil. IR ,Neat): 1769,
1454, 1375, 1204, 1185, 1149, 1023 cm21. GC±MS m/z:
3.1.1. Methyl 3-'1-phenylsulfonylindol-3-yl)-propionate
'1l). SOCl2 ,0.67 g, 5.63 mmol) was added dropwise to
MeOH ,10 ml) in an ice bath and the mixture was stirred
at room temperature for 30 min. To this mixture was added
3-indole propionic acid ,0.91 g, 4.81 mmol) at the same
temperature. After being stirred at room temperature for
3 h, solvent was concentrated in vacuo. The residue was
extracted with AcOEt. The AcOEt was washed with sat.
NaHCO3 solution and brine, and dried over Na2SO4. After
removal of the solvent, the oily residue was puri®ed by ¯ash
column chromatography on silica gel ,eluent: hexane±
AcOEtˆ2:1) to afford 0.97 g ,99%) of methyl 3-,3-indo-
lyl)-propionate as a colourless oil. IR ,Neat): 3411, 1725,
1457, 1436, 1339, 1269, 1226, 1201, 1163 cm21. APCI-MS
m/z: 204 ,MH1). 1H NMR ,CDCl3) d: 2.73 ,2H, dd, Jˆ8.7,
7.3 Hz), 3.11 ,2H, dd, Jˆ8.7, 7.3 Hz), 6.99±7.01 ,1H, m),
7.09±7.22 ,2H, m), 7.33±7.37 ,1H, m), 7.58±7.62 ,1H, m),
7.96 ,1H, brs).
1
176 ,M1), 147, 91. H NMR ,CDCl3) d: 1.92±2.06 ,1H,
m), 2.19±2.30 ,1H, m), 2.75 ,1H, dd, Jˆ13.4, 9.5 Hz),
2.79±2.90 ,1H, m), 3.26 ,1H, dd, Jˆ13.4, 3.5 Hz), 4.14
,1H, dt, Jˆ9.2, 6.6 Hz), 4.23 ,1H, dt, Jˆ9.1, 3.2 Hz),
7.19±7.34 ,5H, m). Anal. calcd for C11H12O2: C, 74.98;
H, 6.86. Found: C, 74.82; H, 7.01.
3.1.3. 4-Phenyl-6-hexanolide '1p). The mixture of
4-phenylcyclohexanone ,1.2 g, 6.9 mmol) and mCPBA
,1.8 g, 8.4 mmol) in CHCl3 ,24 ml) was stirred at room
temperature for 20 h. The reaction mixture was diluted
with AcOEt, washed with sat. NaHCO3 solution, H2O and
brine, and dried over Na2SO4. After removal of the solvent,
the residue was recrystallized from AcOEt±hexane to afford
1.05 g ,80%) of 1p as colourless needles, mp 100±1018C.
IR ,Nujol): 1743, 1457, 1389, 1247, 1174, 1150 cm21. EI-
MS m/z: 190 ,M1), 148, 117, 91. 1H NMR ,CDCl3) d: 1.78±
1.92 ,1H, m), 2.00±2.20 ,3H, m), 2.71±2.90 ,3H, m), 4.31
,1H, ddd, Jˆ13.4, 9.5, 1.5 Hz, 6-H), 4.40 ,1H, ddd, Jˆ15.6,
4.9, 2.6 Hz, 6-H), 7.16±7.27 ,3H, m, aromatic), 7.29±7.36
,2H, m, aromatic). Anal. calcd for C12H14O2: C, 75.76; H,
7.42. Found: C, 75.76; H, 7.45.
To a suspension of NaH ,0.17 g, 4.25 mmol) in DMF ,5 ml)
was added dropwise a solution of methyl 3-,3-indolyl)-
propionate ,0.77 g, 3.79 mmol) in DMF ,8 ml) in an ice
bath and the mixture was stirred at the same temperature
for 1 h. To this mixture was added dropwise a solution of
PhSO2Cl ,0.81 g, 4.59 mmol) in DMF ,2 ml) at the same
temperature. After being stirred at room temperature over
night, the mixture was poured into ice water. The aqueous
layer was extracted with AcOEt. The combined organic
layer was washed with H2O and brine, and dried over
3.1.4. 'R)-Methyl 4-'4-chlorophenyl)-2-methoxycarbonyl-
amino-4-oxobutanoate ''R)-4). SOCl2 ,1.5 g, 12.6 mmol)
was added dropwise to a solution of ,R)-4-,4-chlorophenyl)-
2-methoxycarbonylamino-4-oxobutanoic acid6 ,2.3 g, 8.2

M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
5357
mmol) in MeOH ,35 mL) at 08C. The mixture was stirred at
08C for 16 h. The reaction mixture was concentrated in
vacuo. The residue was extracted with AcOEt. The AcOEt
was washed with sat. NaHCO3 solution and brine, and dried
over Na2SO4. After removal of the solvent, the residue was
puri®ed by column chromatography on silica gel. Elution
with AcOEt±hexane ,1:2) gave 1.8 g ,75%; .99% ee) of
7.1 Hz), 7.14±7.19 ,3H, m), 7.24±7.30 ,2H, m). Anal.
calcd for C12H18O: C, 80.85; H, 10.18. Found: C, 81.13;
H, 9.98.
3.2.2. 4-Phenylbutyl butyl ether '2c). This compound was
obtained from 1c in 79% yield as a colourless oil. IR ,Neat):
1496, 1453, 1373, 1115 cm21. GC±MS m/z: 206 ,M1), 132,
1
,R)-4 as a colourless oil. IR ,Neat): 3359, 1726, 1687 cm21
.
117, 104, 91. H NMR ,CDCl3) d: 0.92 ,3H, t, Jˆ6.4 Hz),
APCI-MS m/z: 302 and 300 ,MH1). H NMR ,DMSO-d6)
d: 3.45±3.48 ,2H, m, 3-H), 3.54 ,3H, s, NHCO2Me), 3.64
,3H, s, CO2Me), 4.57±4.65 ,1H, m, 2-H), 7.57±7.66 ,1H, m,
NH), 7.62 ,2H, d, Jˆ8.8 Hz, aromatic), 7.97 ,2H, d, Jˆ
8.8 Hz, aromatic). Anal. calcd for C13H14NO5Cl: C, 52.10;
H, 4.71; N, 4.67; Cl, 11.83. Found: C, 52.22; H, 4.91; N,
4.42; Cl, 11.57.
1.30±1.42 ,2H, m), 1.50±1.74 ,6H, m), 2.63 ,2H, t, Jˆ
7.7 Hz), 3.40 ,2H, q, Jˆ6.4 Hz), 3.42 ,2H, t, Jˆ7.7 Hz),
7.13±7.19 ,3H, m), 7.24±7.30 ,2H, m). Anal. calcd for
C14H12O: C, 81.50; H, 10.75. Found: C, 81.31; H, 10.67.
1
3.2.3. 2-Phenylethyl methyl ether '2g). This compound
was obtained from 1g in 40% yield as a colourless oil. IR
,Neat): 1496, 1454, 1383, 1154 cm21. GC±MS m/z: 136
1
,M1), 104, 91, 45. H NMR ,CDCl3) d: 2.89 ,2H, t, Jˆ
3.1.5. 'S)-Methyl 4-'4-chlorophenyl)-2-methoxycarbonyl-
amino-4-oxobutanoate ''S)-4). This compound was
obtained from ,S)-4-,4-chlorophenyl)-2-methoxycarbonyl-
amino-4-oxobutanoic acid6 in 95% ,.99% ee) yield as a
colourless oil. IR ,Neat): 3359, 1726, 1687 cm21. APCI-MS
7.1 Hz), 3.36 ,3H, s), 3.61 ,2H, t, Jˆ7.1 Hz), 7.20±7.33
,5H, m). Anal. calcd for C9H12O: C, 79.37; H, 8.88.
Found: C, 79.55; H, 8.76.
1
m/z: 302 and 300 ,MH1). H NMR ,DMSO-d6) d: 3.45±
3.2.4. 2-'4-Bromophenyl)ethyl methyl ether '2h). This
compound was obtained from 1h in 80% yield as a colour-
3.48 ,2H, m, 3-H), 3.54 ,3H, s, NHCO2Me), 3.64 ,3H, s,
CO2Me), 4.57±4.65 ,1H, m, 2-H), 7.57±7.66 ,1H, m, NH),
7.62 ,2H, d, Jˆ8.8 Hz, aromatic), 7.97 ,2H, d, Jˆ8.8 Hz,
aromatic). Anal. calcd for C13H14NO5Cl: C, 52.10; H, 4.71;
N, 4.67; Cl, 11.83. Found: C, 52.08; H, 4.74; N, 4.57; Cl,
11.67. Chiral HPLC analysis was carried out under the
following conditions: column, chiralcel OD-R ,4.6£
150 mm); eluent, MeCN±H2O ,7:13), 0.5 mL/min; detec-
tor, 254 nm; retention time, ,R)-4 ,26 min), ,S)-4 ,24 min).
less oil. IR ,Neat): 1489, 1382, 1117, 1072, 1011 cm21
.
GC±MS m/z: 216 and 214 ,M1), 171 and 169, 135, 45.
1H NMR ,CDCl3) d: 2.83 ,2H, t, Jˆ7.0 Hz), 3.34 ,3H, s),
3.58 ,2H, t, Jˆ7.0 Hz), 7.10 ,2H, d, Jˆ8.4 Hz), 7.41 ,2H, d,
Jˆ8.4 Hz). Anal. calcd for C9H11BrO: C, 50.26; H, 5.15; Br,
37.15. Found: C, 50.11; H, 5.34; Br, 37.21.
3.2.5. 2-'4-Nitrophenyl)ethyl methyl ether '2i). This
compound was obtained from 1i in 72% yield as a colourless
oil. IR ,Neat): 1506, 1462, 1344, 1153 cm21. GC±MS m/z:
3.2. Reduction of esters or lactones '1) with Et3SiH±
TiCl4±TMSOTf
1
181 ,M1), 151, 45. H NMR ,CDCl3) d: 2.98 ,2H, t, Jˆ
6.5 Hz), 3.35 ,3H, s), 3.65 ,2H, t, Jˆ6.5 Hz), 7.39 ,2H, d,
Jˆ8.8 Hz), 8.15 ,2H, d, Jˆ8.8 Hz). Anal. calcd for
C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.43;
H, 6.17; N, 7.81.
The general procedure is exempli®ed by the reduction of
methyl 4-phenylbutanoate ,1a). To a solution of TiCl4
,240 mg, 1.27 mmol) in CH2Cl2 ,1.5 ml) was added drop-
wise a solution of TMSOTf ,581 mg, 2.61 mmol) in CH2Cl2
,1 ml) in an ice bath. After being stirred at room temperature
for 4 h, a solution of 1a ,147 mg, 0.83 mmol) and Et3SiH
,485 mg, 4.17 mmol) in CH2Cl2 ,2 ml) was added in an ice
bath. After being stirred at room temperature for 20 h, the
reaction mixture was poured into ice-water. The aqueous
layer was extracted with AcOEt. The combined organic
layer was washed with H2O and brine, and dried over
Na2SO4. After removal of the solvent, the oily residue was
subjected to silica gel preparative TLC ,eluent: hexane±
AcOEtˆ20:1) to afford 110 mg ,81%) of 4-phenylbutyl
methyl ether ,2a) as a colourless oil. IR ,Neat): 1603,
1496, 1453, 1387, 1152 cm21. GC±MS m/z: 164 ,M1),
3.2.6. 3-Phenylpropyl methyl ether '2j). This compound
was obtained from 1j in 75% yield as a colourless oil. IR
,Neat): 1496, 1454, 1386, 1155 cm21. GC±MS m/z: 150
1
,M1), 117, 91, 45. H NMR ,CDCl3) d: 1.84±1.94 ,2H,
m), 2.69 ,2H, t, Jˆ7.5 Hz), 3.34 ,3H, s), 3.39 ,2H, t,
Jˆ6.4 Hz), 7.15±7.21 ,3H, m), 7.26±7.31 ,2H, m). Anal.
calcd for C10H14O: C, 79.96; H, 9.39. Found: C, 80.15; H,
9.53.
3.2.7. 3-'4-Methoxyphenyl)propyl methyl ether '2k).
This compound was obtained from 1k in 89% yield as a
colourless oil. IR ,Neat): 1512, 1463, 1299, 1246, 1177,
1118, 1037 cm21. GC±MS m/z: 180 ,M1), 148, 121, 91,
1
132, 117, 104, 91, 45. H NMR ,CDCl3) d: 1.56±1.74
1
77, 45. H NMR ,CDCl3) d: 1.81±1.91 ,2H, m), 2.63 ,2H,
,2H, m), 2.63 ,2H, t, Jˆ7.5 Hz), 3.32 ,3H, s), 3.39 ,2H, t,
Jˆ7.9 Hz), 7.14±7.19 ,3H, m), 7.24±7.30 ,2H, m). Anal.
calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.15; H,
9.83.
dd, Jˆ7.3, 8.1 Hz), 3.34 ,3H, s), 3.38 ,2H, t, Jˆ6.4 Hz),
3.79 ,3H, s), 6.83 ,2H, d, Jˆ8.8 Hz), 7.10 ,2H, d Jˆ
8.8 Hz). Anal. calcd for C11H16O2: C, 73.11; H, 8.99.
Found: C, 73.30; H, 8.95.
3.2.1. 4-Phenylbutyl ethyl ether '2b). This compound was
obtained from 1b in 78% yield as a colourless oil. IR ,Neat):
1495, 1453, 1377, 1353, 1127, 1112 cm21. GC±MS m/z:
3.2.8. 3-'1-Phenylsulfonylindol-3-yl)propyl methyl ether
'2l). This compound was obtained from 1l in 43% yield as a
yellow oil. IR ,Neat): 1447, 1369, 1175, 1119 cm21. APCI-
MS m/z: 362 ,M11MeOH), 347 ,M11NH4), 330 ,MH1).
1H NMR ,CDCl3) d: 1.89±1.99 ,2H, m), 2.72±2.77 ,2H, m),
1
178 ,M1), 132, 117, 104, 91, 59. H NMR ,CDCl3) d:
1.19 ,3H, t, Jˆ7.1 Hz), 1.57±1.74 ,4H, m), 2.64 ,2H, t,
Jˆ7.5 Hz), 3.42 ,2H, t, Jˆ6.2 Hz), 3.46 ,2H, q, Jˆ

5358
M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
3.34 ,3H, s), 3.39 ,2H, t, Jˆ6.2 Hz), 7.20±7.34 ,3H, m),
7.38±7.45 ,2H, m), 7.47±7.54 ,2H, m), 7.83±7.88 ,2H, m),
7.99 ,1H, dt, Jˆ8.1, 0.9 Hz). Anal. calcd for C18H19NO3S:
C, 65.63; H, 5.81; N, 4.25; S, 9.73. Found: C, 65.46; H, 6.01;
N, 4.33; S, 9.91.
amino-4-,4-chlorophenyl)butyl methyl ether ,,R)-5) as
20
colourless crystals, mp 43.5±458C. [a]D ˆ13.28 ,c 0.5,
CHCl3). IR ,Neat): 3350, 1691 cm21. APCI-MS m/z: 274
1
and 272 ,MH1, 1:3). H NMR ,CDCl3) d: 1.75±1.87 ,2H,
m, 3-H), 255±2.73 ,2H, m, 4-H), 3.33 ,3H, s, OMe), 3.39
,2H, d, Jˆ3.9 Hz, 1-H), 3.68 ,3H, s, CO2Me), 3.72±3.85
,1H, m, 2-H), 4.81±4.95 ,1H, m, NH), 7.12 ,2H, d, Jˆ
8.4 Hz, aromatic), 7.24 ,2H, d, Jˆ8.4 Hz, aromatic). Anal.
calcd for C13H18NO3Cl: C, 57.46; H, 6.68; N, 5.15; Cl,
13.05. Found: C, 57.40; H, 6.55; N, 5.03; Cl, 13.01.
3.2.9. 2-Isobutyl 4-phenylbutyl ether '2m). This com-
pound was obtained from 1m in 72% yield as a colourless
oil. IR ,Neat): 1447, 1369, 1175, 1119 cm21. GC±MS m/z:
1
206 ,M1), 131, 104. H NMR ,CDCl3) d: 0.89 ,6H, d,
Jˆ6.8 Hz), 1.57±1.75 ,4H, m), 1.85 ,1H, sept, Jˆ6.6 Hz),
2.64 ,2H, t, Jˆ7.7 Hz), 3.15 ,2H, d, Jˆ6.8 Hz), 3.42 ,2H, t,
Jˆ6.2 Hz), 7.14±7.19 ,3H, m), 7.24±7.31 ,2H, m). Anal.
calcd for C14H22O: C, 81.50; H, 10.75. Found: C, 81.59; H,
10.75.
3.3.2. 'S)-2-Methoxycarbonylamino-4-'4-chlorophenyl)-
butyl methyl ether ''S)-5). This compound was obtained
from ,S)-4 in 75% ,.99% ee) yield as colourless crystals,
20
mp 43.5±458C. [a]D ˆ23.28 ,c 0.5, CHCl3). IR ,Neat):
3350, 1705 cm21. APCI-MS m/z: 274 and 272 ,MH1,
1:3). H NMR ,CDCl3) d: 1.75±1.87 ,2H, m, 3-H), 2.55±
1
3.2.10. 2,2-Dimethylpropyl 4-phenylbutyl ether '2n).
This compound was obtained from 1n in 65% yield as a
2.73 ,2H, m, 4-H), 3.33 ,3H, s, OMe), 3.39 ,2H, d, Jˆ
3.9 Hz, 1-H), 3.68 ,3H, s, CO2Me), 3.72±3.85 ,1H, m,
2-H), 4.81±4.95 ,1H, m, NH), 7.12 ,2H, d, Jˆ8.4 Hz,
aromatic), 7.24 ,2H, d, Jˆ8.4 Hz, aromatic). Anal. calcd
for C13H18NO3Cl: C, 57.46; H, 6.68; N, 5.15; Cl, 13.05.
Found: C, 57.18; H, 6.59; N, 5.36; Cl, 12.89. Chiral
HPLC analysis was carried out under the following con-
ditions: column, chiralpak AD ,4.6£250 mm); eluent:
hexane±EtOH ,9:1), 1.0 mL/min; detector, 220 nm; reten-
tion time, ,R)-5 ,14 min), ,S)-5 ,9 min).
colourless oil. IR ,Neat): 1447, 1369, 1175, 1119 cm21
.
1
GC±MS m/z: 220 ,M1). H NMR ,CDCl3) d: 0.90 ,9H,
s), 1.56±1.76 ,4H, m), 2.64 ,2H, t, Jˆ7.3 Hz), 3.42 ,2H, t,
Jˆ6.3 Hz), 7.14±7.20 ,3H, m), 7.25±7.30 ,2H, m). Anal.
calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.58; H,
10.98.
3.2.11. 3-Benzyltetrahydrofuran '2o). This compound
was obtained from 1o in 67% yield as a colourless oil. IR
,Neat): 3416, 1453, 1239, 1083, 1048, 1016 cm21. GC±MS
m/z: 162 ,M1), 92, 70. 1H NMR ,CDCl3) d: 1.56±1.68 ,1H,
m), 1.94±2.05 ,1H, m), 2.44±2.59 ,1H, m), 2.68±2.71 ,2H,
m), 3.46 ,1H, dd, Jˆ8.4, 6.8 Hz), 3.72±3.94 ,3H, m), 7.15±
7.23 ,3H, m), 7.25±7.32 ,2H, m). Anal. calcd for C11H14O:
C, 81.44; H, 8.70. Found: C, 81.42; H, 8.75.
3.3.3. Preparation of methyl 4-'4-chlorophenyl)-2-
'methoxycarbonylamino)-butanoate ''R)-6). To a solu-
tion of TiCl4 ,214 mg, 1.13 mmol) in CH2Cl2 ,1.5 ml) was
added dropwise
a
solution of TMSOTf ,514 mg,
2.31 mmol) in CH2Cl2 ,1 ml) in an ice bath. After being
stirred at room temperature for 4 h, a solution of ,R)-4
,223 mg, 0.74 mmol) and Et3SiH ,266 mg, 2.29 mmol) in
CH2Cl2 ,2 ml) was added in an ice bath. After being stirred
at room temperature for 20 h, the reaction mixture was
poured into ice-water. The aqueous layer was extracted
with AcOEt. The combined organic layer was washed
with H2O and brine, and dried over Na2SO4. After removal
of the solvent, the oily residue was subjected to silica gel
preparative TLC ,eluent: hexane±AcOEtˆ2:1) to afford
184 mg ,87%; .99% ee) of ,R)-methyl 4-,4-chloro-
phenyl)-2-,methoxycarbonylamino)butanoate ,,R)-6) as a
3.2.12. 4-Phenyloxepane '2p). This compound was
obtained from 1p in 40% yield as a colourless oil. IR
,Neat): 1492, 1451, 1136, 1123 cm21. GC±MS m/z: 176
1
,M1), 132, 117, 104, 91. H NMR ,CDCl3) d: 1.77±1.99
,6H, m, 3-H, 5-H, 6-H), 2.75±2.85 ,1H, m, 4-H), 3.64±3.79
,2H, m, 2-H or 7-H), 3.85±3.94 ,2H, m, 7-H or 2-H), 7.15±
7.23 ,3H, m, aromatic), 7.27±7.33 ,2H, m, aromatic). Anal.
calcd for C12H16O: C, 81.77; H, 9.15. Found: C, 81.53; H,
9.26.
20
colourless oil. [a]D ˆ245.88 ,c 1.1, CHCl3). IR ,Neat):
3.3. Reduction of methyl 4-'4-chlorophenyl)-2-methoxy-
carbonylamino-4-oxobutanoate '4) with Et3SiH±TiCl4±
TMSOTf
3335, 1725, 1533 cm21. APCI-MS m/z: 288 and 286
1
,MH1, 1:3). H NMR ,CDCl3) d: 1.86±2.01 ,1H, m, 3-H),
2.09±2.23 ,1H, m, 3-H), 2.60±2.70 ,2H, m, 4-H), 3.70 ,3H,
s, NHCO2Me), 3.73 ,3H, s, CO2Me), 4.34±4.46 ,1H, m,
2-H), 5.20±5.33 ,1H, m, NH), 7.11 ,2H, d, Jˆ8.4 Hz,
aromatic), 7.25 ,2H, d, Jˆ8.4 Hz, aromatic). Anal. calcd
for C13H16NO4Cl: C, 54.65; H, 5.64; N, 4.90; Cl, 12.41.
Found: C, 54.39; H, 5.45; N, 4.66; Cl, 12.13.
3.3.1. Preparation of 'R)-2-methoxycarbonylamino-4-'4-
chlorophenyl)butyl methyl ether ''R)-5). To a solution of
TiCl4 ,330 mg, 1.74 mmol) in CH2Cl2 ,2 ml) was added
dropwise a solution of TMSOTf ,782 mg, 3.52 mmol) in
CH2Cl2 ,1 ml) in an ice bath. After being stirred at room
temperature for 4 h,
a solution of ,R)-4 ,174 mg,
3.3.4. 'S)-Methyl 4-'4-chlorophenyl)-2-'methoxycarbon-
ylamino)butanoate ''S)-6). This compound was obtained
from ,S)-6 in 84% ,.99% ee) yield as a colourless oil.
0.58 mmol) and Et3SiH ,358 mg, 3.08 mmol) in CH2Cl2
,2 ml) was added in an ice bath. After being stirred at
room temperature for 20 h, the reaction mixture was poured
into ice-water. The aqueous layer was extracted with
AcOEt. The combined organic layer was washed with
H2O and brine, and dried over Na2SO4. After removal of
the solvent, the oily residue was subjected to silica gel
preparative TLC ,eluent: hexane±AcOEtˆ2:1) to afford
112 mg ,71%; .99% ee) of ,R)-2-methoxycarbonyl-
20
[a]D ˆ145.68 ,c 1.1, CHCl3). IR ,Neat): 3335, 1725,
1
1533 cm21. APCI-MS m/z: 288 and 286 ,MH1, 1:3). H
NMR ,CDCl3) d: 1.86±2.01 ,1H, m, 3-H), 2.09±2.23 ,1H,
m, 3-H), 2.60±2.70 ,2H, m, 4-H), 3.70 ,3H, s, NHCO2Me),
3.73 ,3H, s, CO2Me), 4.34±4.46 ,1H, m, 2-H), 5.20±5.33
,1H, m, NH), 7.11 ,2H, d, Jˆ8.4 Hz, aromatic), 7.25 ,2H, d,

M. Yato et al. / Tetrahedron 57 (2001) 5353±5359
5359
3. Mao, Z.; Gregg, B. T.; Cutler, A. R. J. Am. Chem. Soc. 1995,
117, 10139±10140.
Jˆ8.4 Hz, aromatic). Anal. calcd for C13H16NO4Cl: C,
54.65; H, 5.64; N, 4.90; Cl, 12.41. Found: C, 54.83; H,
5.61; N, 4.74; Cl, 12.49. Chiral HPLC analysis was carried
out under the following conditions: column, chiralpak AD
,4.6£250 mm); eluent: hexane±EtOH ,4:1), 1.0 mL/min;
detector, 220 nm; retention time, ,R)-6 ,8 min), ,S)-6
,12 min).
4. Homma, K.; Takenoshita, H.; Mukaiyama, T. Bull. Soc. Chem.
Jpn 1990, 63, 1898±1915.
5. ,a) Noftle, R. E.; Cady, G. H. Inorg. Chem. 1966, 5, 2182±
2185. ,b) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama,
T. Bull. Chem. Soc. Jpn 1993, 66, 1516±1527. ,c) Miyashita,
M.; Shiina, I.; Mukaiyama, T. Bull. Chem. Soc. Jpn 1994, 67,
210±215. ,d) Yoshida, Y.; Hayashi, R.; Sumihara, H.; Tanabe,
Y. Tetrahedron Lett. 1997, 38, 8727±8730.
References
6. ,a) Yato, M.; Homma, K.; Ishida, A. Heterocycles 1995, 41,
17±20. ,b) Yato, M.; Homma, K.; Ishida, A. Heterocycles 1998,
49, 233±254.
1. ,a) Pettit, R. G.; Piatak, D. M. J. Org. Chem. 1962, 27, 2127±
2130. ,b) Pettit, R. G.; Kasturi, T. R. J. Org. Chem. 1961, 26,
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7. Optical purity of the products was determined with HPLC
analysis. See Section 3.