Synthesis of chiral sulfinyl-substituted 1-indolyl enones and asymmetric conjugate addition by an arylcopper reagent

Article abstract of DOI:10.1248/cpb.52.733

The asymmetric conjugate addition of arylcopper reagents to chiral 1-[2-(p-tolylsulfinyl)]indolyl and 1-[3-(p-tolylsulfinyl)]indolyl enones was examined. With the 2-sulfinyl-indolyl derivatives, the reaction of the arylcopper reagent gave high diastereoselectivities (81-88% de's) to afford the adducts in excellent yields, although the similar addition reaction of the 3-sulfinyl derivatives afforded poor diastereoselectivities.

Full text of DOI:10.1248/cpb.52.733

June 2004
Chem. Pharm. Bull. 52(6) 733—738 (2004)
733
Synthesis of Chiral Sulfinyl-Substituted 1-Indolyl Enones and Asymmetric
Conjugate Addition by an Arylcopper Reagent
Yoshitsugu ARAI,* Makoto KASAI, and Yukio MASAKI
Gifu Pharmaceutical University; 5–6–1 Mitahora-higashi, Gifu 502–8585, Japan.
Received February 16, 2004; accepted March 11, 2004; published online March 11, 2004
The asymmetric conjugate addition of arylcopper reagents to chiral 1-[2-(p-tolylsulfinyl)]indolyl and 1-[3-
(p-tolylsulfinyl)]indolyl enones was examined. With the 2-sulfinyl-indolyl derivatives, the reaction of the arylcop-
per reagent gave high diastereoselectivities (81—88% de’s) to afford the adducts in excellent yields, although the
similar addition reaction of the 3-sulfinyl derivatives afforded poor diastereoselectivities.
Key words chiral indolyl sulfoxide; conjugate addition; aryl copper reagent; diastereoselectivity
We have recently reported that the conjugate addition of reagent. It is known that 3-lithio derivative, generated from
a,b-unsaturated enones 1, derived from a chiral sulfinyl aux- 1-(benzenesulfonyl)indole by an alkyllithium, readily under-
iliary 2, proceeds smoothly to give the adduct 3 with high di- goes C(3)→C(2) migration of lithium to produce the 2-lithio
astereoselectivity (3 vs. 4).1) It is noted that the major adduct indole during the reaction.3) Selective C-3 lithiation of 1-(tri-
3 was treated with an alkoxide to afford the ester 5 (or 6), isopropylsilyl)indole was thus attempted by the procedure ac-
along with efficient recovery of the sulfoxide 2 without any cording to the literature method.2) After treatment of 1-(tri-
loss of optical purity (Chart 1).
isopropylsilyl)indole with 1.5 eq of t-butyllithium and
In connection with asymmetric synthesis using chiral sul- N,N,Nꢁ,Nꢁ-tetramethylethylenediamine (1.8 eq) in hexane at
foxides, we were intrigued by the use of chiral 2- and 3- 0 °C for 3 h followed by addition of (Ss)-(ꢂ)-l-menthyl p-
sulfinyl indolyl enones 7 and 8 as for conjugate addition re- toluenesulfinate (ꢂ78 °C for 1 h) in THF, a considerable
actions (Chart 2). In contrast to pyrrole sulfoxide 1, steric in- amount of undesired product 10 (30% yield) was produced
teractions between the H-7 of the indole ring and the N-sub- by migration of the triisopropylsilyl group.2) The desired
stituent (ꢀthe enoyl group) of 7 and 8 may influence the con- compound 11 was also isolated as the minor product (17%
formational flexibility of the transition structure. We here de- yield) under the conditions. Additionally, exposure of 11 ob-
scribe the synthesis of 7 and 8 and their conjugate additions tained to tetrabutylammonium fluoride afforded 9 with low
with organocuprates.
enantiomeric excess (ee; 34% ee).
Chiral auxiliary 9 for the synthesis of 7 commenced from
Therefore, we sought an alternative route to 9 via the 3-
1-(triisopropylsilyl)indole, which provides selectively the iodoindole 12 as shown in Chart 3. Kondo et al.3) reported
C(3)-lithiated indole2) by the action of an alkyllithium that the use of ethylmagnesium bromide effects iodine–metal
(i.e., magnesium) exchange reaction of 12 to afford the 3-
magnesio indole without extensive rearrangement to the 2-
magnesio species.
In fact, treatment of 12 with ethylmagnesium bromide in
THF at 0 °C followed by addition of (Ss)-(ꢂ)-l-menthyl p-
toluenesulfinate produced the 3-sulfinyl indole 13 in 78%
Chart 1
Chart 2
Chart 3
∗ To whom correspondence should be addressed. e-mail: araiy@gifu-pu.ac.jp
© 2004 Pharmaceutical Society of Japan

734
Vol. 52, No. 6
tion of the 2-lithio species,4,5) after which was quenched with
(ꢂ)-l-menthyl p-toluenesulfinate to give the sulfoxide 15 in
74% yield. Alkaline hydrolysis of 15 afforded the requisite 2-
sulfinyl indole 14 (ꢃ99% ee) in quantitative yield.
yield. No 2-sulfinyl product was detected in the reaction mix-
ture. Although chiral HPLC analysis of 13 was unsuccessful
due to decomposition of a sample through the column, the
sulfoxide 9, after which was treated with base, showed high
enantiomeric excess (99% ee) on chiral HPLC. Incorporation
of an enone group into 9 was carried out by the method pre-
viously described.1) Treatment of 9 with (E)-cinnamoyl- and
crotonyl chloride in the presence of sodium hydride afforded
7a and 7b, respectively, in 77% and 58% yields. With
crotonyl chloride (contaminated with (Z)-1-butenoyl chlo-
ride), the minor product, the 1-[(Z)-1-butenoyl]indole was
readily removed after recrystallization of the crude product.
On the other hand, the synthesis of the key precursor 14
for 8 was achieved starting from 1-(benzenesulfonyl)indole
(Chart 4). Treatment of 1-(benzenesulfonyl)indole with 1 eq
of lithium diisopropylamide (LDA) resulted in ready forma-
In a similar manner to the reaction (9→7), the sulfoxides
8a and 8b were obtained in good yields. Having obtained the
sulfoxides 7 and 8, we first examined the conjugate addition
of 7 with an arylcopper reagent. In the previous results,1) it
had been shown that these reagents for conjugate additions of
1 afford better results in diastereoselectivity and yields than
the use of the cuprates derived from organolithiums.6) There-
fore, the reaction was carried out by the diarylcuprate [pre-
pared from an aryl Grignard reagent (6 eq) and Cu(I) (3 eq)]
at ꢂ30 °C for 1 h. When the reaction was conducted by a
smaller amount of the organocuprate, the reaction was often
incomplete within several hours. The results are summarized
in Table 1.
Disappointingly, the diastereoselectivities were poor, re-
sulted in the production of nearly equal amounts of two di-
astereoisomers 16 and 17. In all cases, diastereoisomers 17
were produced in favor to 16. The diastereoselectivity and
absolute stereochemistry were determined by chiral HPLC
analysis of the methyl esters 5 and 61) obtained by methanol-
ysis of the crude product mixture.
On the other hand, under the conditions, the reaction of the
2-sulfinyl indoles 8 gave moderate to high diastereoselectivi-
ties to afford 18 as the major products (Table 2). Although,
with the cinnamoyl derivative 8a, an alkylcuprate
(Me2Cu·MgBr·MgBrI) provided low diastereoselectivity
(59% de; entry 1, Table 2), addition reaction of di-o-tolyl-
and di-p-tolylcuprates to 8a gave high diastereoselectivities
(84—86% de’s). The reaction of the crotonoyl derivatives 8b
also gave high diastereoselectivities (entries 4—6, Table 2).
The reaction mechanism of the highly diastereoselective
Chart 4
Table 1. Conjugate Addition of an Arylcopper Reagent to 3-Sulfinyl-Substituted Indolyl Enones 7a)
Major
product
Isolated
yield (%)
Entry
Substrate
Organocopper reagent
ee/%b) of ester 5 or 6
de/%c) of 16 vs. 17
1
2
3
4
5
7a
7a
7b
7b
7b
(2-MeC6H4)2CuMgBr·MgBrI
(4-MeC6H4)2CuMgBr·MgBrI
Ph2CuMgBr·MgBrI
(2-MeC6H4)2CuMgBr·MgBrI
(4-MeC6H4)2CuMgBr·MgBrI
17acꢀ
17adꢀ
17baꢀ
17bcꢀ
17bdꢀ
99
99
99
94
96
16
4
19
33
34
6cꢀꢄent-6cꢀ
6dꢀꢄent-6dꢀ
5bꢀꢄent-5bꢀ
5cꢀꢄent-5cꢀ
5dꢀꢄent-5dꢀ
16
4
19
33
34
16acꢀꢄ17acꢀ
16adꢀꢄ17adꢀ
16baꢀꢄ17baꢀ
16bcꢀꢄ17bcꢀ
16bdꢀꢄ17bdꢀ
a) The reaction was carried out at ꢂ30 °C for 1 h in tetrahydrofuran. Sulfoxide 7 with 98—99% ee was employed for the reaction. b) Enantiomeric excess of 5 and 6 was
determined by chiral HPLC analysis. c) Diastereoisomeric excess was determined by chiral HPLC analysis of 5 and 6, since the C(3) methine protons of two diastereoisomeric
products were not well-resolved in the 1H-NMR spectrum. Absolute configuration at the C(3) position of the major product was determined by comparison with the chiral HPLC
behavavior (retention times) of the methyl ester (5 and 6) obtained by methanolysis.
Table 2. Conjugate Addition of Organocopper Reagent to 2-Sulfinyl-Substituted Indolyl Enones 8a)
Major
product
Isolated
yield (%)
Entry
Substrate
Organocopper reagent
ee/%b) of ester 5 or 6
de/%c) of 18 vs. 19
1
2
3
4
5
6
8a
8a
8a
8b
8b
8b
Me2CuMgBr·MgBrI
18abꢀ
18acꢀ
18adꢀ
18baꢀ
18bcꢀ
18bdꢀ
94
96
98
99
96
98
58
84
84
85
88
81
5bꢀꢃent-5bꢀ
5cꢀꢃent-5cꢀ
5dꢀꢃent-5dꢀ
ent-5bꢀꢃ5bꢀ
6cꢀꢃent-6cꢀ
6dꢀꢃent-6dꢀ
59
84
86
86
88
81
18abꢀꢃ19abꢀ
18acꢀꢃ19acꢀ
18adꢀꢃ19adꢀ
18baꢀꢃ19baꢀ
18bcꢀꢃ19bcꢀ
18bdꢀꢃ19bdꢀ
(2-MeC6H4)2CuMgBr·MgBrI
(4-MeC6H4)2CuMgBr·MgBrI
Ph2CuMgBr·MgBrI
(2-MeC6H4)2CuMgBr·MgBrI
(4-MeC6H4)2CuMgBr·MgBrI
a) The reaction was carried out by 2—3 eq of Cu(I) and 4—6 eq of an aryl Grignard reagent at ꢂ30 °C for 2 h in tetrahydrofuran. Sulfoxide 8 with 98—99% ee was em-
ployed for the reaction. b) Enantiomeric excess was determined by chiral HPLC. c) Diastereoisomeric excess was determined by 1H-NMR analysis [the methine protons at
C(3)] of the crude products and/or by ee values from chiral HPLC analysis of 5 and 6. Absolute configuration of the C(3) position of the major product was determined by compari-
son with the chiral HPLC behavavior (retention times) of 5 and 6.

June 2004
735
Fig. 1
Fig. 2
cation by washing with phosphate buffer, pH 7.5, according to the literature
method.11) TLC analyses were performed using Merck precoated silica
60F254 plates (0.2 mm). Column chromatography was carried out on Merck
silica (70—230 mesh) or Merck silica (230—400 mesh). Chiral HPLC
analyses were performed using a chiral column (4.6ꢅ250 mm). Peak ratios
conjugate addition of 8 induced by the chiral sulfinyl moiety
is consistent with previous proposals.1) Generally, the pre-
ferred orientation of the S→O group of the a,b-unsaturated
sulfoxide moiety is coplanar with the carbon–carbon double
bond [S(O)–CꢀC–].1) Since it is assumed that the conjugate by HPLC were determined with an integrator (Shimadzu Chromatopac C-
R6A). Grignard reagents (THF solution) were purchased commercially and
addition takes place via the s-cis conformation of the enone
diluted with THF to the appropriate concentrations, and titrated12) prior to
group (N–C(O)–CꢀC–), a diarylcopper reagent, which
use.
would be dimeric7,8) could attack preferentially from the
3-[(Ss)-(p-Tolylsulfinyl)]-1-(triisopropylsilyl)indole (11) To a cooled
solution of 1-(triisopropylsilyl)indole13) (175 mg, 0.64 mmol) and
N,N,Nꢁ,Nꢁ-tetramethylethylenediamine (0.17 ml, 1.15 mmol) in dry hexane
(10 ml) at 0 °C was added t-BuLi (2.6 ml of a 0.37 mol dmꢂ3 solution in
hexane, 0.96 mmol) and the mixture was stirred for 3 h at the same tempera-
ture. After being cooled to ꢂ78 °C, a solution of (Ss)-(ꢂ)-l-menthyl p-tolu-
enesulfinate (377 mg, 1.28 mmol) in dry THF (10 ml) was added. The mix-
ture was stirred for 1 h at the same temperature and then quenched with a
saturated NH4Cl solution and the aqueous layer was extracted with Et2O
(30 mlꢅ3). The combined extracts were washed with brine, dried, and con-
centrated. The crude product was purified by flash chromatography on silica
using hexane–AcOEt (5 : 1) as eluent to give 10 (80 mg, 30%) and 11
(46 mg, 17%). Sulfoxide 10: mp 174—176 °C (from AcOEt); 1H-NMR
(270 MHz) d 1.19 (9H, d, Jꢀ7.5, Me), 1.25 (9H, d, Jꢀ7.5, Me), 1.6—1.8
(3H, m, CH), 2.37 (3H, s, Me), 6.9—7.0 (1H, m, ArH), 7.1—7.35 (2H, m,
ArH), 7.24 (2H, d, Jꢀ8.1, p-Tol), 7.4—7.5 (1H, m, ArH), 7.53 (2H, d,
Jꢀ8.1, p-Tol), 8.71 (1H, s, NH). Sulfoxide 11: mp 130—132 °C (from
Et2O/hexane); 1H-NMR (270 MHz) d 1.14 (9H, d, Jꢀ7.7, Me), 1.15 (9H, d,
Jꢀ7.7, Me), 1.6—1.8 (3H, m, CH), 2.37 (3H, s, Me), 7.0—7.1 (1H, m,
C(3)-Re face of transition state A, affording 18 as shown in
Fig. 1. The transition state B would be unstable due to a
steric 1,5-interaction9) between the C(7) hydrogen and the
hydrogen in the a,b-enone substituent.
Instead, the poor diastereoselectivities in the reaction of 7
reflect that the chiral sufinyl group remote from the reaction
site would not participate in the addition reaction. The rea-
sons for reversal in the observed selectivity (17 produced in
slightly preference to 16) should reflect that the syncoplanar
orientation (transition structure D) of the S→O group with
the C(2)–C(3) double bond in the indole ring is preferred
(Fig. 2).10)
In summary, we have shown that asymmetric 1,4-addition
of arylcopper reagents to the chiral 2-sulfinyl-substituted in-
dolyl enone proceeds smoothly to give the addition product
with high diastereoselectivity in high yield. With the indolyl ArH), 7.1—7.2 (1H, m, ArH), 7.26 (2H, d, Jꢀ8.1, p-Tol), 7.4—7.5 (2H, m,
ArH), 7.49 (2H, d, Jꢀ8.1, p-Tol), 7.68 (1H, s, H-2).
To a solution of 11 (25 mg, 0.06 mmol) obtained in dry THF (4 ml) was
added Bu4NF·3H2O (38 mg) in dry THF (1 ml) at 0 °C. The mixture was
stirred for 1 h at the same temperature and then diluted with Et2O (5 ml).
sulfoxide, 1,6-asymmetric induction has been achieved, and
the chiral auxiliary was efficiently recovered without any loss
of optical purity.
After the usual work-up, the product was purified by column chromatogra-
Experimental
phy on silica using hexane–AcOEt (1 : 2) as eluent to give 9 (23 mg, 82%).
The ee of 9 obtained showed 34% by chiral HPLC (vide infra).
The symbol Ss expresses that the absolute configuration of the sulfinyl
center is S. Melting points were determined with a Yanaco micro melting
point apparatus and are uncorrected. Boiling point for bulb-to-bulb distilla-
1-Benzenesulfonyl-3-[(Ss)-(p-tolylsulfinyl)]indole (13) To an ice-
cooled solution of 1-benzenesulfonyl-3-iodoindole5) 12 (3.88 g, 10.1 mmol)
tion indicates bath temperature. IR spectra were recorded as film or KBr in dry THF (25 ml) at 0 °C was added EtMgBr (26.5 ml of a 0.46 mol dmꢂ3
disk on a Perkin-Elmer Spectrum One FT-IR spectrometer. NMR spectra solution in THF, 12.2 mmol) and the mixture was stirred for 0.5 h at the
were measured in CDCl3 solution with tetramethylsilane as internal stan- same temperature, and allowed to stand at room temperature for 0.5 h. After
dard, on a JEOL JNM-GX270 or EX-400 spectrometer. The following ab- being cooled to 0 °C, a solution of (Ss)-(ꢂ)-l-menthyl p-toluenesulfinate
breviations are used: singlet (s), doublet (d), triplet (t), quartet (q), doublet of
(3.59 g, 12.2 mmol) in dry THF (30 ml) was added. The mixture was stirred
doublets (dd), doublet of dq (ddq), multiplet (m), and broad (br). J-Values at 0 °C overnight in the dark. The reaction mixture was then quenched with a
are given in Hz. Mass spectra were taken with a JEOL JMS-D300 or JMS- diluted NaHCO3 solution and the aqueous layer was extracted with Et2O
SX102A spectrometer. Optical rotations were recorded on a JASCO DIP- (50 mlꢅ3). The combined extracts were washed with brine, dried, and con-
360 digital polarimeter. Extracts were dried over anhydrous MgSO4 before
evaporation of solvents on a rotary evaporator under reduced pressure. Dry
centrated. The crude product was purified by flash chromatography on silica
using hexane–AcOEt (20 : 1→15 : 1→1 : 1) as eluent to give 13 (3.13 g,
THF and diethyl ether were freshly distilled from sodium benzophenone 78%). mp 153—154 °C (from EtOAc); [a]D21 ꢆ97.4° (cꢀ1.1, CHCl3) for
ketyl prior to use. m-Chloroperbenzoic acid (m-CPBA) was used after purifi- 99% ee (SsꢃRs). IR cmꢂ1 (KBr) 1372 (NSO2), 1044 (S→O). 1H-NMR

736
Vol. 52, No. 6
(270 MHz) d 2.38 (3H, s, Me), 7.16 (1H, dt, Jꢀ8.1, 0.9, ArH), 7.25—7.35 was determined by chiral HPLC analysis of the methyl esters1) (5bꢀ : ent-
(3H, m, ArH), 7.4—7.65 (6H, m, ArH), 7.9—8.0 (3H, m, ArH), 8.01 (1H, s,
5cꢀꢀ42 : 58, 16% ee) by methanolysis (vide infra). After recrystallization of
H-2). 13C-NMR (67.5 MHz) d 21.1, 113.6, 120.4, 124.0, 124.9 (2C), 125.3, the product mixture, the product ratio changed to 81 : 9 (62% de) by judging
125.7, 125.8, 126.8 (2C), 127.9, 129.4 (2C), 129.8 (2C), 134.3, 135.4, 137.3, from chiral HPLC of the esters (61% ee).
139.7, 141.5. EI-MS m/z 395 (Mꢆ), 379, 347, 238, 223, 206. Anal. Calcd for
1-[(S)-3-Phenyl-3-(o-tolyl)propanoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole
C21H17NO3S2: C, 63.79; H, 4.33; N, 3.54. Found: C, 63.69; H, 4.27; N, 3.64.
3-[(Ss)-(p-Tolylsulfinyl)]indole (9) To a solution of sulfonamide 13 ꢆ63.2° (cꢀ1.0, CHCl3) for ꢈ98% ee (SsꢃRs), 62% de (3Sꢃ3R after recrys-
(2.76 g, 6.98 mmol) in dioxane (70 ml) was added 4% aq. NaOH (50 ml,
w/v) and the mixture was stirred at room temperature for 2 h in the dark. The
reaction mixture was then extracted with Et2O (50 mlꢅ3). The combined ex- Jꢀ7.5, CH2), 5.02 (1H, t, Jꢀ7.5, PhCH), 7.1—7.35 (14H, m, ArH), 7.55—
(17acꢀ) mp 194—197 °C (from AcOEt/hexane) (3Sꢆ3R mixture). [a]D22
tallization). IR cmꢂ1 (KBr) (3Sꢆ3R mixture). 1718 (CꢀO), 1036 (S→O).
1H-NMR (270 MHz) d 2.34 (3H, s, Me), 2.37 (3H, s, Me), 3.69 (2H, d,
tracts were washed with saturated brine (30 ml), dried, and concentrated to
7.65 (2H, m, ArH), 7.97 (1H, s, H-2), 8.35—8.4 (1H, m, ArH). 13C-NMR
give 9 (1.73 g, 97%) as a pale yellow solid. mp 131—133 °C (dec.) (from (67.5 MHz) d 19.9, 21.4, 42.2, 42.4, 117.2, 119.6 (2C), 124.5, 125.5 (2C),
AcOEt); [a]D23 ꢆ44.8° (cꢀ1.0, CHCl3) for 99% ee (SsꢃRs). IR cmꢂ1 (KBr)
3569 (NH), 1019 (S→O). H-NMR (270 MHz) d 2.38 (3H, s, Me), 6.95— 131.0, 136.4, 136.7, 140.2, 140.8, 141.9, 142.0, 142.7, 169.5. EI-MS m/z
7.05 (1H, m, ArH), 7.05—7.4 (3H, m, ArH), 7.18 (1H, d, Jꢀ2.9, H-2), 7.26 477 (Mꢆ), 461, 239, 181. Anal. Calcd for C31H27NO2S: C, 77.97; H, 5.70; N,
(2H, d, Jꢀ8.3, p-Tol), 7.54 (2H, d, Jꢀ8.3, p-Tol), 10.36 (1H, br s, NH). 13C- 2.93. Found: C, 77.76; H, 5.54; N, 2.89.
126.1, 126.2, 126.3 (2C), 126.7, 126.8, 128.0 (2C), 128.7 (2C), 130.1 (2C),
1
NMR (67.5 MHz) d 21.2, 112.6, 115.8, 119.0, 121.2, 123.2, 123.6, 125.0
Typical Procedure for Alcoholysis of Adduct To a solution of the
(2C), 129.7 (2C), 130.0, 137.3, 140.0, 140.6. EI-MS m/z 255 (Mꢆ), 239, crude mixture of 16acꢀ and 17acꢀ (30 mg, 0.06 mmol), obtained by the reac-
207. Anal. Calcd for C15H13NOS: C, 70.58; H, 5.13; N, 5.49. Found: C, tion of 7a (ꢈ98% ee), in dry THF (4 ml) cooled in an ice-bath was added
70.57; H, 5.16; N, 5.56.
NaOMe (1.0 ml of a 0.1 mol dmꢂ3 solution in MeOH, 0.1 mmol) dropwise.
After being stirred for 1 h at that temperature, the mixture was quenched
with a saturated NH4Cl solution and the aqueous layer was extracted with
Et2O (10 mlꢅ3). The extracts were washed with brine, dried, and concen-
For determination of the enantiomeric excess of 9, an analytical sample of
9 and ent-9 (ꢀthe enantiomer of 9) was prepared by the following sequence.
Treatment of 9 with Zn–TiCl4 afforded the corresponding sulfide, which was
oxidized with m-CPBA to produce (ꢇ)-9 (mp 138—140 °C; lit.14) mp trated. The crude product was purified by column chromatography on silica
120.5—121.5 °C). Since a pair of peaks was resolved by chiral HPLC, the ee using hexane–AcOEt (4 : 1→0 : 1) as eluent to give the esters 5cꢀ and ent-
(99%) of the product was confirmed. Chiral HPLC: Chiralpak AS-H,
254 nm, hexane–2-propanol: 6 : 1; 1.0 ml/min; 9: 80.9 min, ent-9: 98.5 min.
5cꢀ1) (12 mg, 78%, ent-5cꢀ-enriched) and the sulfinyl indole 9 (12 mg, 75%,
ꢈ98% ee). Chiral HPLC: Chiralcel OD-H, 254 nm, hexane–2-propanol:
1-(E)-Cinnamoyl-3-[(Ss)-(p-tolylsulfinyl)]indole (7a) Sulfinyl indole 9 100 : 1; 1.0 ml/min; ent-5cꢀ: 14.1 min, 5cꢀ: 20.3 min.
(549 mg, 2.15 mmol) in dry THF (15 ml) was added dropwise to an ice-
cooled suspension of NaH (129 mg, 60% dispersion in mineral oil,
3.22 mmol) in dry THF (5 ml) and the mixture was then stirred at room tem-
1-[(S)-3-Phenyl-3-(p-tolyl)propanoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole
(17adꢀ) In a similar manner, the products 16adꢀ and 17adꢀ was obtained in
99% yield. Methanolysis of the crude mixture afforded 5dꢀ and ent-5dꢀ
perature for 1 h. The mixture was cooled to 0 °C and (E)-cinnamoyl chloride (48 : 52, 4% ee, 79% yield) and 9 (84% yield, 99% ee). Chiral HPLC: Chi-
(537 mg, 3.22 mmol) in dry THF (15 ml) was added to the mixture. After
being stirred for 1.5 h, the mixture was quenched with diluted NaHCO3
(20 ml) and the aqueous layer was extracted with Et2O (15 mlꢅ3). The com-
bined extracts were washed with saturated brine (30 ml), dried, and concen-
trated to give 7a (641 mg, 77%) as a solid. mp 203—205 °C (from AcOEt);
ralcel OD-H, 254 nm, hexane–2-propanol: 100 : 1; 0.5 ml/min; 5dꢀ: 17.1 min,
ent-5dꢀ: 35.1 min.
17adꢀ: mp 147—148 °C (from Et2O/hexane) (3Sꢆ3R mixture). [a]D23
ꢆ2.7° (cꢀ1.0, CHCl3) for 98% ee (SsꢃRs), 11% de (3Rꢃ3S after recrystal-
1
lization). IR cmꢂ1 (KBr) (3Sꢆ3R mixture) 1723 (CꢀO), 1038 (S→O). H-
[a]D24 ꢂ156° (cꢀ1.0, THF) for 98% ee (SsꢃRs). IR cmꢂ1 (KBr) 1701
NMR (270 MHz) d 2.29 (3H, s, Me), 2.37 (3H, s, Me), 3.70 (2H, d, Jꢀ7.3,
1
(CꢀO), 1035 (S→O). H-NMR (270 MHz) d 2.39 (3H, s, Me), 7.15—7.5 CH2), 4.79 (1H, t, Jꢀ7.3, PhCH), 7.35—7.5 (14H, m, ArH), 7.60 (2H, d,
(8H, m, ArHꢆCHꢀ), 7.65—7.75 (5H, m, ArH), 8.05 (1H, d, Jꢀ15.4,
Jꢀ8.1, p-Tol), 7.99 (1H, s, ArH), 8.35—8.4 (1H, m, ArH). 13C-NMR
CHꢀ), 8.20 (1H, s, ArH), 8.52 (1H, d, Jꢀ8.4, ArH). 13C-NMR (100 MHz) d (67.5 MHz) d 20.9, 21.4, 42.0, 46.0, 117.2, 119.5, 119.6, 124.4, 125.3, 125.5
21.4, 116.1, 117.3, 119.7, 124.5, 125.6 (3C), 126.3, 126.4, 128.6 (3C), 129.2 (2C), 125.6, 126.3, 126.7, 127.5 (2C), 127.6 (2C), 128.7 (2C), 129.5 (2C),
(2C), 130.1 (2C), 131.3, 134.0, 137.0, 140.3, 142.0, 148.3, 164.1. EI-MS 130.1 (2C), 136.4, 136.7, 140.0, 140.2, 141.9, 143.3, 169.5. EI-MS m/z 477
m/z 385 (Mꢆ), 369, 131, 103. Anal. Calcd for C24H19NO2S: C, 74.79; H, (Mꢆ), 461, 239, 181. Anal. Calcd for C31H27NO2S: C, 77.97; H, 5.70; N,
4.97; N, 3.63. Found: C, 74.69; H, 4.91; N, 3.56.
2.93. Found: C, 77.76; H, 5.76; N, 2.98.
1-[(E)-2-Butenoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole (7b) Crotonamide 7b
was obtained after recrystallization in 58% yield from 9 (2.87 g) and
crotonyl chloride (1.77 ml, contaminated by isocrotonyl chloride) in a man-
ner similar to the procedure for 7a, except for the reaction time (3.5 h): mp
118—119 °C (from hexane–AcOEt); geometrical purity ꢃ99%; [a]D22
ꢆ11.4° (cꢀ1.0, CHCl3) for ꢃ99% ee (SsꢃRs). IR cmꢂ1 (KBr) 1694 (CꢀO),
1036 (S→O). 1H-NMR (270 MHz) d 2.08 (3H, dd, Jꢀ7.0, 1.7, Me), 2.38
1-[(R)-3-(Phenyl)butanoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole (17baꢀ)
The reaction of 7b with diphenylcuprate afforded the products 16baꢀ and
17baꢀ which were treated with sodium methoxide to give a mixture of ent-
5bꢀ and 5bꢀ (40.7 : 59.3, 19% ee, 90% yield) and 9 (91% yield, 99% ee).
Chiral HPLC: Chiralcel OD-H, 254 nm, hexane–2-propanol: 100 : 1;
1.0 ml/min; ent-5bꢀ: 13.3 min; 5bꢀ: 6.3 min.
17baꢀ: mp 53—55 °C (from Et2O/hexane) (3Sꢆ3R mixture), [a]D20 ꢆ7.1°
(3H, s, Me), 6.72 (1H, dq, Jꢀ14.8, 1.7, CHꢀ), 7.15—7.41 (6H, m, (cꢀ1.0, CHCl3) for 99% ee (SsꢃRs), 2% de (3Rꢃ3S, after recrystallization).
ArHꢆCHꢀ), 7.64 (2H, d, Jꢀ8.2, p-Tol), 8.07 (1H, s, ArH), 8.46 (1H, d,
IR cmꢂ1 (KBr) 1733 (CꢀO), 1037 (S→O). 1H-NMR (270 MHz) d 1.45 (3H,
Jꢀ8.4, ArH). 13C-NMR (100 MHz) d 18.7, 21.4, 117.2, 119.6, 121.5, 124.4, d, Jꢀ7.0, Me), 2.38 (3H, s, Me), 3.17 (1H, dd, Jꢀ16.1, 7.5, C(O)CHH),
125.2, 125.4 (3C), 126.1, 126.6, 130.1 (2C), 136.9, 140.2, 141.9, 148.7, 3.29 (1H, dd, Jꢀ16.1, 6.2, C(O)CHH), 3.5—3.65 (1H, m, PhCH), 7.1—7.4
163.8. EI-MS m/z 323 (Mꢆ), 307, 275, 239, 207, 69. EI-HR-MS Calcd for
(10H, m, ArH), 7.61 (2H, d, Jꢀ8.1, p-Tol), 7.91 (1H, s, H-2), 8.43 (1H, s,
C19H17NO2S: 323.0980. Found: 323.0989. Anal. Calcd for C19H17NO2S· ArH). 13C-NMR (100 MHz) d 21.4, 21.8, 36.0, 44.1, 117.1, 119.6, 124.3,
1/4H2O: C, 69.62; H, 5.38; N, 4.27. Found: C, 69.60; H, 5.46; N, 4.30. No 125.2, 125.3 (2C), 125.4, 126.2, 126.3, 126.7 (2C), 128.7 (3C), 130.0 (2C),
satisfactory elemental analysis was obtained due to ready absorption of
water.
136.6, 140.1, 141.9, 145.1, 170.0. EI-MS m/z 401 (Mꢆ), 385, 353, 239, 207,
105. Anal. Calcd for C25H23NO2S: C, 74.79; H, 5.78; N, 3.49. Found: C,
Typical Procedure for Preparation of 16 and 17 from 7 (Table 1, 74.70; H, 6.05; N, 3.14.
Entry 1) To a sonicated suspension of Cu(I)I (297 mg, 1.6 mmol) in dry
1-[(R)-3-(o-Tolyl)butanoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole (17bcꢀ) mp
THF (10 ml) cooled at ꢂ10 °C was added o-tolylmagnesium bromide (31 ml 139—141 °C (from Et2O) (3Sꢆ3R mixture), [a]D20 ꢆ0.75° (cꢀ2.0, CHCl3)
of a 0.10 mol dmꢂ3 solution in THF, 3.1 mmol) dropwise. After 0.5 h, a
cooled solution of 7a (200 mg, 0.52 mmol, 99% ee) in dry THF (10 ml) was
added dropwise at ꢂ30 °C, and the yellow solution was stirred for 1 h at the
same temperature. The reaction mixture was then quenched with a saturated
for 99% ee (SsꢃRs), 33% de (3Rꢃ3S, after recrystallization). IR cmꢂ1 (KBr)
1725 (CꢀO), 1035 (S→O). 1H-NMR (270 MHz) d 1.39 (3H, d, Jꢀ7.0, Me),
2.38 (3H, s, Me), 2.41 (3H, s, Me), 3.21 (1H, dd, Jꢀ16.5, 8.1, CHH), 3.28
(1H, dd, Jꢀ16.5, 5.9, CHH), 3.7—3.9 (1H, m, MeCH), 7.1—7.4 (9H, m,
NH4Cl solution and the aqueous layer was extracted with Et2O (30 mlꢅ3). ArH), 7.61 (2H, d, Jꢀ8.4, ArH), 7.95 (1H, s, H-2), 8.43 (1H, d, Jꢀ8.8,
The combined extracts were washed with brine, dried, and concentrated. The
crude product was purified by flash chromatography on silica using
hexane–AcOEt (20 : 1→2 : 1) as eluent to give a mixture of 16acꢀ and 17acꢀ
(246 mg, 99%). Signals for 16acꢀ and 17acꢀ were not adequately resolved in
ArH). 13C-NMR (100 MHz) d 19.5, 21.4, 21.5, 30.8, 43.4, 117.1, 119.6,
124.4, 125.0 (2C), 125.4 (2C), 126.3 (2C), 126.4, 126.5 (2C), 130.1 (2C),
130.7, 135.2, 136.6, 140.0, 141.9, 143.4, 170.1. EI-MS m/z 415 (Mꢆ), 399,
239, 207, 119. Anal. Calcd for C26H25NO2S: C, 75.16; H, 6.07; N 3.37.
Found: C, 74.98; H, 6.05; N 3.36.
1
the H-NMR spectrum of the product mixture; therefore, the product ratio

June 2004
737
judged by that of 14.
1-[(R)-3-(p-Tolyl)butanoyl]-3-[(Ss)-(p-tolylsulfinyl)]indole (17bdꢀ)
mp 124—126 °C (from Et2O/light petroleum) (3Sꢆ3R mixture), [a]D21
ꢂ11.5° (cꢀ2.0, CHCl3) for 99% ee (SsꢃRs), 51% de (3Rꢃ3S after recrys-
tallization). IR cmꢂ1 (KBr) 1740 (CꢀO), 1035 (S→O). 1H-NMR (270 MHz)
d 1.42 (3H, d, Jꢀ7.0, Me), 2.32 (3H, s, Me), 2.37 (3H, s, Me), 3.14 (1H, dd,
Jꢀ16.1, 7.5, CHH), 3.26 (1H, dd, Jꢀ17.1, 6.4, CHH), 3.4—3.6 (1H, m,
MeCH), 7.10—7.35 (9H, m, ArH), 7.60 (2H, d, Jꢀ8.1, p-Tol), 7.90 (1H, s,
H-2), 8.42 (1H, d, Jꢀ8.2, ArH). 13C-NMR (100 MHz) d 21.0, 21.4, 21.9,
35.6, 44.3, 117.1, 119.6, 124.4, 125.3 (2C), 125.4 (2C), 126.3, 126.6 (3C),
129.4 (2C), 130.1 (2C), 136.3, 136.7, 140.1, 141.9, 142.1, 170.1. EI-MS m/z
415 (Mꢆ), 399, 239, 207, 119. EI-HR-MS Calcd for C26H25NO2S: 415.1614.
Found: 415.1606. Anal. Calcd for C26H25NO2S·1/3H2O: C, 74.14; H, 6.06;
N, 3.33. Found: C, 74.10; H, 6.00; N 3.31.
Typical Procedure for Preparation of 18 and 19 from 8 (Table 2,
Entry 3) To a sonicated suspension of Cu(I) (295 mg, 1.55 mmol) in dry
THF (10 ml) cooled at ꢂ10 °C was added p-tolylmagnesium bromide
(3.1 mmol, 31 ml of a 0.10 mol dmꢂ3 solution in THF) dropwise. After 0.5 h,
a solution of 8a (200 mg, 0.52 mmol, 98% ee) in dry THF (10 ml) was added
dropwise at ꢂ30 °C, and the yellow solution was stirred for 2 h at the same
temperature. The reaction mixture was then quenched with a saturated
NH4Cl solution and the aqueous layer was extracted with Et2O (30 mlꢅ3).
The combined extracts were washed with brine, dried, and concentrated. The
crude product was purified by flash chromatography on silica using
hexane–AcOEt (20 : 1→1 : 1) as eluent to give a mixture of 18adꢀ and 19adꢀ
(230 mg, 94%). Since the diastereoisomers 18adꢀ and 19adꢀ were not ade-
1
quately resolved in the H-NMR spectrum, the product ratio (18adꢀ, 19adꢀ)
1-Benzenesulfonyl-2-[(Ss)-(p-tolylsulfinyl)]indole (15) Butyllithium
(2.3 ml of a 1.57 mol dmꢂ3 solution in hexane, 3.42 mmol) was added slowly
to an ice-cooled solution of diisopropylamine (0.48 ml, 3.42 mmol) in dry
THF (15 ml) under an argon atmosphere. After being stirred at the same
temperature for 0.5 h, 1-(benzenesulfonyl)indole5) (800 mg, 3.11 mmol) in
dry THF (20 ml) was added to the solution at ꢂ78 °C. After being stirred for
1 h, (Ss)-(ꢂ)-l-menthyl p-toluenesulfinate (1.1 g, 3.73 mmol) in dry THF
(10 ml) was added. The reaction mixture was stirred at the same temperature
overnight and quenched with saturated NH4Cl (50 ml). The organic phase
was separated and the aqueous layer was extracted with Et2O (10 mlꢅ3).
The combined extracts were washed with saturated brine (10 ml), dried, and
concentrated. The residue was purified by flash chromatography on silica
with hexane–EtOAc (6 : 1) to give 15 (906 mg, 74%) as a solid: mp 175—
176 °C (from EtOAc); [a]D23 ꢆ32.8° (cꢀ1.0, CHCl3) for 99% ee (SsꢃRs). IR
was determined by chiral HPLC analysis of the methyl esters (5dꢀ and ent-
5dꢀꢀ92 : 8, 84% ee) by methanolysis. Chiral HPLC of the ester derived after
recrystallization of the product mixture showed 89% ee.
1-[(R)-3-Phenyl-3-(p-tolyl)propanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole
(18adꢀ) mp 174—177 °C (from AcOEt) (3Sꢆ3R mixture), [a]D22 ꢂ25.0°
(cꢀ1.0, CHCl3) for 98% ee (SsꢃRs), 91% de (3Rꢃ3S after recrystalliza-
tion). IR cmꢂ1 (KBr) 1694 (CꢀO), 1048 (S→O). 1H-NMR (270 MHz) d
2.31 (3H, s, Me), 2.33 (3H, s, Me), 3.68 (2H, d, Jꢀ7.1, CH2), 4.71 (1H, t,
Jꢀ7.1, PhCH), 7.0—7.75 (18H, m, ArH). 13C-NMR (100 MHz) d 21.0,
21.4, 43.6, 45.5, 113.0, 114.2, 122.7, 123.9, 125.9, 126.6, 126.7 (2C), 127.4
(2C), 127.6 (2C), 128.7, 129.3 (2C), 129.4, 129.6 (2C), 129.9, 136.0, 136.5,
140.0, 141.3, 142.5, 143.3, 145.5, 169.4. EI-MS m/z 477 (Mꢆ), 461, 239,
207, 181. Anal. Calcd for C31H27NO2S: C, 77.97; H, 5.70; N, 2.93. Found:
C, 77.82; H, 5.64; N, 2.94.
1
cmꢂ1 (KBr) 1374, 1176 (NSO2), 1055 (S→O). H-NMR (270 MHz) d 2.30
1-[(R)-3-(Phenyl)butanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole (18abꢀ)
The reaction of 8a with diphenylcuprate afforded the product 18abꢀ as the
major diastereoisomer. mp 153—156 °C (from hexane/light petroleum)
(3Sꢆ3R mixture), [a]D22 ꢆ22.9° (cꢀ0.6, CHCl3) for 98% ee (SsꢃRs), 68%
de (3Rꢃ3S after recrystallization). IR cmꢂ1 (KBr) 1690 (CꢀO), 1051
(3H, s, Me), 7.25—7.6 (9H, m, ArH), 7.75—7.85 (4H, m, ArH), 8.02 (1H, d,
Jꢀ8.4, ArH). 13C-NMR (100 MHz) d 21.5, 114.1, 114.4, 122.1, 124.4,
126.4, 126.7 (2C), 127.0 (2C), 128.9, 129.3 (2C), 130.0 (2C), 134.4, 137.1,
138.5, 141.6, 142.5, 143.8. EI-MS m/z 395 (Mꢆ), 379, 347, 238, 223, 206.
Anal. Calcd for C21H17NO3S2: C, 63.79; H, 4.33; N, 3.54. Found: C, 63.70;
H, 4.32; N, 3.43.
1
(S→O). H-NMR (270 MHz) d 1.13 (3H, d, Jꢀ6.8, Me), 2.34 (3H, s, Me),
3.09 (1H, dd, Jꢀ16.5, 9.0, C(O)CHH), 3.27 (1H, dd, Jꢀ16.5, 4.7,
C(O)CHH), 3.35—3.5 (1H, m, PhCH), 7.1—7.4 (8H, m, ArH), 7.5—7.7
(6H, m, ArH). 13C-NMR (100 MHz) d 21.2, 21.4, 35.4, 45.6, 113.2, 114.1,
122.7, 123.8, 125.8, 126.6, 126.7 (2C), 127.0 (2C), 128.7 (2C), 129.7 (2C),
129.8, 136.5, 141.7, 142.7, 145.2, 145.3, 170.0. EI-MS m/z 401 (Mꢆ), 385,
239, 207, 105. Anal. Calcd for C25H23NO2S: C, 74.79; H, 5.78; N, 3.49.
Found: C, 74.53; H, 5.77; N, 3.38.
1-[(S)-3-(Phenyl)butanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole (19baꢀ)
The reaction of 8b with dimethylcuprate afforded the product 19abꢀ as the
major diastereoisomer. mp 163—165 °C (from Et2O) (3Sꢆ3R mixture),
[a]D24 ꢂ35.7° (cꢀ0.8, CHCl3) for ꢈ99% ee (SsꢃRs), 90% de (3Sꢃ3R after
recrystallization). IR cmꢂ1 (KBr) 1685 (CꢀO), 1057 (S→O). 1H-NMR
(270 MHz) d 1.26 (3H, d, Jꢀ6.8, Me), 2.32 (3H, s, Me), 3.21 (1H, dd,
Jꢀ16.5, 8.3, C(O)CHH), 3.28 (1H, dd, Jꢀ16.5, 5.7, C(O)CHH), 3.43 (1H,
ddq, Jꢀ8.3, 6.6, 5.7, CH), 7.1—7.4 (9H, m, ArH), 7.55—7.75 (5H, m,
ArH). 13C-NMR (100 MHz) d 21.4, 21.7, 35.3, 45.5, 113.1, 114.2, 122.7,
123.8, 125.8, 126.5, 126.6 (2C), 126.8 (2C), 128.6 (2C), 129.6 (2C), 129.9,
136.5, 141.5, 142.6, 145.3, 145.5, 170.0. EI-MS m/z 401 (Mꢆ), 385, 239,
207. Anal. Calcd for C25H23NO2S: C, 74.79; H, 5.78; N, 3.49. Found: C,
74.55; H, 5.84; N, 3.37.
1-[(S)-3-(p-Tolyl)butanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole (18bdꢀ)
The reaction of 8b with di-p-tolylcuprate afforded the product 18bdꢀ as the
major diastereoisomer. mp 148—150 °C (from hexane/Et2O) (3Sꢆ3R mix-
ture); [a]D23 ꢂ41.8° (cꢀ0.7, CHCl3) for ꢃ99% ee (SsꢃRs), 95% de (3Sꢃ3R
after recrystallization). IR cmꢂ1 (KBr) 1694 (CꢀO), 1057 (S→O). 1H-NMR
(270 MHz) d 1.23 (3H, d, Jꢀ6.8, Me), 2.33 (3Hꢅ2, s, Me), 3.18 (1H, dd,
Jꢀ16.3, 8.4, CHH), 3.22 (1H, dd, Jꢀ16.3, 5.5, CHH), 3.37 (1H, ddq,
Jꢀ8.4, 6.8, 5.5, MeCH), 7.0—7.2 (6H, m, ArH), 7.3—7.4 (2H, m, ArH),
7.55—7.75 (5H, m, ArH). 13C-NMR (100 MHz) d 21.0, 21.4, 21.7, 34.9,
45.7, 113.0, 114.2, 122.6, 123.8, 125.8, 126.5 (2C), 126.8 (2C), 129.3 (2C),
129.6 (2C), 129.9, 136.1, 136.5, 141.4, 142.3, 142.7, 145.5, 170.0. EI-MS
m/z 415 (Mꢆ), 399, 239, 207. Anal. Calcd for C26H25NO2S: C, 75.16; H,
6.07; N, 3.37. Found: C, 74.98; H, 6.09; N, 3.36.
Methanolysis of the crude product afforded the esters (6dꢀ and ent-6dꢀ,
92% yield) with recovery of the auxiliary 14 (94% yield, ꢃ99% ee). Methyl
(S)-3-(p-Tolyl)butanoate (6dꢀ): A colorless oil, bp 130—140 °C/9.3 hPa;
[a]D23 ꢆ29.5° (cꢀ1.5, CHCl3) for 87% ee. Chiral HPLC: Chiralpak AS-H,
254 nm, hexane–2-propanol: 800 : 1; 1.0 ml/min; 6dꢀ: 7.8 min, ent-6dꢀ:
10.2 min. Chiral ester ent-6dꢀ is a known compound; however, the optical ro-
tation was not mentioned.15)
2-[(Ss)-(p-Tolylsulfinyl)]indole (14) Sulfoxide 14 was obtained in 99%
yield from 15 (603 mg) in a manner similar to the procedure for 11, except
for the reaction time (overnight): mp 165—166 °C (from Et2O); [a]D23
ꢆ20.3° (cꢀ2.1, CHCl3) for 99% ee (SsꢃRs). IR cmꢂ1 (KBr) 3569 (NH),
1029 (S→O). 1H-NMR (270 MHz) d 2.39 (3H, s, Me), 6.86 (1H, dd, Jꢀ2.1,
0.7, H-3), 7.1—7.2 (1H, m, ArH), 7.2—7.4 (2H, m, ArH), 7.29 (2H, d,
Jꢀ8.1, p-Tol), 7.58 (2H, d, Jꢀ8.1, p-Tol), 7.55—7.7 (1H, m, ArH), 9.54
(1H, br s, NH). 13C-NMR (100 MHz) d 21.3, 106.6, 112.4, 120.6, 121.6,
124.5, 124.9 (2C), 126.9, 130.0 (2C), 136.4, 138.1, 140.0, 141.6. EI-MS m/z
255 (Mꢆ), 239, 207. Anal. Calcd for C15H13NOS: C, 70.58; H, 5.13; N, 5.49.
Found: C, 70.31; H, 5.08; N, 5.44. Enantiomeric excess of 14 was deter-
mined by chiral HPLC analysis. A racemic sample for analytical chiral
HPLC was prepared in a similar manner to the procedure described earlier.
Chiral HPLC: Chiralpak AS, 254 nm, hexane–2-propanol: 9 : 1; 1.0 ml/min;
14: 43.0 min, ent-14: 48.9 min.
1-(E)-Cinnamoyl-2-[(Ss)-(p-tolylsulfinyl)]indole (8a) The cinnamoyl
amide 8a was obtained in 58% yield from 14 (386 mg, 98% ee) and (E)-cin-
namoyl chloride (378 mg) in a manner similar to the procedure for 7a, ex-
cept for the reaction time (overnight): mp 121—123 °C (from Et2O); [a]D22
ꢂ145° (cꢀ1.0, CHCl3) for 98% ee (SsꢃRs). IR cmꢂ1 (KBr) 1678 (CꢀO),
1
1049 (S→O). H-NMR (270 MHz) d 2.33 (3H, s, Me), 7.21 (2H, d, Jꢀ8.2,
p-Tol), 7.25—7.5 (5H, m, ArH), 7.32 (1H, d, Jꢀ15.8, CHꢀ), 7.55—7.75
(5H, m, ArH), 7.68 (2H, d, Jꢀ8.2, p-Tol), 7.83 (1H, d, Jꢀ15.8, CHꢀ). 13C-
NMR (67.5 MHz) d 21.7, 113.8, 114.8, 118.8, 122.9, 124.1, 126.2, 127.0
(2C), 128.9 (2C), 129.5 (2C), 129.6, 130.1 (2C), 131.6, 134.4, 137.6, 142.1,
142.4, 144.6, 147.9, 164.8. EI-MS m/z 385 (Mꢆ), 369, 239, 207, 131, 103.
Anal. Calcd for C24H19NO2S: C, 74.79; H, 4.97; N, 3.63. Found: C, 74.40;
H, 4.90; N, 3.54. The ee of 8a was estimated as 98% as judged by that of 14.
1-Crotonoyl-2-[(Ss)-(p-tolylsulfinyl)]indole (8b) Crotonamide 8b was
obtained in 68% yield from 14 (2.40 g, ꢈ98% ee) and crotonyl chloride
(1.35 ml) in a manner similar to the procedure for 8a, except for the reaction
time (6.5 h): mp 132—133 °C (from AcOEt/hexane); geometrical purity
94%; [a]D24 ꢂ58.2° (cꢀ1.1, CHCl3) for ꢈ98% ee (SsꢃRs). IR cmꢂ1 (KBr)
1680 (CꢀO), 1045 (S→O). 1H-NMR (270 MHz) d 2.05 (3H, dd, Jꢀ7.0, 1.7,
Me), 2.34 (3H, s, Me), 6.72 (1H, dq, Jꢀ15.2, 1.7, CHꢀ), 7.1—7.4 (5H, m,
ArHꢆCHꢀ), 7.55—7.75 (5H, m, ArH). 13C-NMR (100 MHz) d 18.8, 21.4,
112.8, 114.4, 122.5, 123.5, 123.7, 125.6, 126.7 (2C), 129.5, 129.7 (2C),
136.9, 141.7, 142.4, 144.6, 148.3, 164.2. EI-MS m/z 323 (Mꢆ), 307, 239,
207, 132, 69. Anal. Calcd for C19H17NO2S: C, 70.57; H, 5.30; N, 4.33.
Found: C, 70.41; H, 5.32; N, 4.21. The ee of 8b was estimated as ꢈ98% as

738
1-[(R)-3-Phenyl-3-(o-tolyl)propanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole
Vol. 52, No. 6
1614 (2001).
(18acꢀ) The reaction of 8a with di-o-tolylcuprate afforded the product
18acꢀ as the major diastereoisomer. mp 118—121 °C (from light petro-
leum/AcOEt) (3Sꢆ3R mixture). [a]D22 ꢂ49.9° (cꢀ1.0, CHCl3) for 99% ee
(SsꢃRs), 91% de (3Rꢃ3S after recrystallization). IR cmꢂ1 (KBr) 1709
(CꢀO), 1041 (S→O). 1H-NMR (270 MHz) d 2.25 (3H, s, Me), 2.30 (3H, s,
Me), 3.61 (1H, dd, Jꢀ17.1, 6.8, C(O)CHH), 3.71 (1H, dd, Jꢀ17.1, 6.8,
C(O)CHH), 4.91 (1H, dd, Jꢀ7.8, 6.8, PhCH), 7.00 (2H, d, Jꢀ7.8, p-Tol),
7.0—7.7 (14H, m, ArH), 7.44 (2H, d, Jꢀ7.8, p-Tol). 13C-NMR (100 MHz) d
19.8, 21.4, 41.9, 43.9, 113.0, 114.1, 122.7, 123.9, 125.5, 125.9, 126.1, 126.4,
126.5 (2C), 126.6, 127.9 (2C), 128.7 (2C), 129.6 (2C), 129.9, 130.8, 136.4,
136.6, 140.5, 141.2, 142.3, 142.6, 145.5, 169.4. EI-MS m/z 477 (Mꢆ), 461,
239, 207, 181. Anal. Calcd for C31H27NO2S: C, 77.97; H, 5.70; N, 2.93.
Found: C, 77.66; H, 5.99; N, 2.79.
2) Matsuzono M., Fukuda T., Iwao M., Tetrahedron Lett., 42, 7621—
7623 (2001).
3) Kondo Y., Yoshida A., Sato S., Sakamoto T., Heterocycles, 42, 105—
108 (1996).
4) Kano S., Sugino E., Shibuya S., Hibino S., J. Org. Chem., 46, 2979—
2981 (1981).
5) Sailnier M. G., Gribble G. W., J. Org. Chem., 47, 757—761 (1982).
6) Melnyk O., Stephen E., Pourcelot G., Cresson P., Tetrahedron, 48,
841—850 (1992).
7) van Koten G., Noltes J. G., J. Am. Chem. Soc., 101, 6593—6599
(1979).
8) Hofstee H. K., Boersma J., van der Kerk G. J. M., J. Organomet.
Chem., 144, 255—261 (1978).
1-[(S)-3-(o-Tolyl)butanoyl]-2-[(Ss)-(p-tolylsulfinyl)]indole (18bcꢀ) mp
139—140 °C (from hexane/Et2O); [a]D24 ꢂ57.4° (cꢀ2.0, CHCl3) for ꢃ99%
ee (SsꢃRs), ꢃ99% de (3Sꢃ3R after recrystallization). IR cmꢂ1 (KBr) 1694
(CꢀO), 1054 (S→O). 1H-NMR (270 MHz) d 1.23 (3H, d, Jꢀ6.8, Me), 2.29
(3H, s, Me), 2.30 (3H, s, Me), 3.22 (2H, d, Jꢀ6.8, CH2), 3.67 (1H, sextet,
Jꢀ6.8, MeCH), 7.05—7.4 (8H, m, ArH), 7.5—7.75 (5H, m, ArH). 13C-
NMR (100 MHz) d 19.4, 21.4, 21.5, 30.4, 45.0, 113.0, 114.1, 122.7, 123.8,
9) Tourwé D., De Cock E., Van Binst G., J. Org. Chem., 46, 5321—5324
(1981).
10) Tietze L. F., Schuffenhauer A., Schreiner P. R., J. Am. Chem. Soc., 120,
7952—7958 (1998).
11) Schwartz N. N., Blumbergs J. H., J. Org. Chem., 29, 1976—1979
(1964).
12) Gilman H., Cartledge F. K., J. Organomet. Chem., 2, 447—454 (1964).
124.8, 125.8, 126.1, 126.4, 126.7 (2C), 129.6 (2C), 129.9, 130.6, 135.2, 13) Beswick P. J., Grennwood C. S., Mowlem T. J., Nechvatal G., Widdow-
136.5, 141.4, 142.5, 143.5, 145.5, 170.1. EI-MS m/z 415 (Mꢆ), 399, 239,
son D. A., Tetrahedron, 44, 7325—7334 (1988).
207. Anal. Calcd for C26H25NO2S: C, 75.16; H, 6.07; N, 3.37. Found: C, 14) Greenhouse R. J., Muchowski J. M., US Patent, 4654360, 1987.
75.00; H, 6.10; N, 3.29.
15) For (R)-ester, see: Cabaret D., Capillon J., Guett J. P., J. Organomet.
Chem., 113, 215—224 (1976).
References and Notes
1) Arai Y., Ueda K., Xie J., Masaki Y., Chem. Pharm. Bull., 49, 1609—