Chiral sulfoxide ligands bearing nitrogen atoms as stereocontrollable coordinating elements in palladium-catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1016/S0957-4166(98)00394-2

Palladium-catalyzed asymmetric allylic alkylations were studied by using chiral sulfoxide ligands bearing nitrogen atoms as coordinating elements, such as chiral α-sulfinylacetamides, β or γ-amino sulfoxides, and β- sulfinyl sulfonamides. The effects of t

Full text of DOI:10.1016/S0957-4166(98)00394-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3797–3817
Chiral sulfoxide ligands bearing nitrogen atoms as
stereocontrollable coordinating elements in palladium-catalyzed
asymmetric allylic alkylations1
Kunio Hiroi,∗ Yoshio Suzuki, Ikuko Abe, Yutaka Hasegawa and Kenji Suzuki
Department of Synthetic Organic Chemistry, Tohoku College of Pharmacy, 4-4-1 Komatsushima, Aoba-ku, Sendai,
Miyagi 981-8558, Japan
Received 10 August 1998; accepted 21 September 1998
Abstract
Palladium-catalyzed asymmetric allylic alkylations were studied by using chiral sulfoxide ligands bearing
nitrogen atoms as coordinating elements, such as chiral α-sulfinylacetamides, β or γ-amino sulfoxides, and β-
sulfinyl sulfonamides. The effects of the chiral sulfinyl functions on the asymmetric induction were demonstrated.
Use of (S)-2-pyrrolidinophenyl p-tolyl sulfoxide or (S)-2-(N-butyl-N-methylaminomethyl)phenyl p-tolyl sulfoxide
as chiral ligands in the palladium-catalyzed asymmetric allylic alkylations provided the highest enantioselectivity
(50 or 58% e.e., respectively) among chiral sulfoxide ligands examined by us. The participation of the sulfinyl
groups in these catalytic asymmetric reactions is rationalized, and the mechanism for the asymmetric induction is
proposed on the basis of the stereochemical outcome obtained. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Asymmetric synthetic reactions have received much attention in recent years for the preparation of
chiral biologically active compounds, and many methodologies for asymmetric carbon–carbon bond
formation have been developed.2 Quite recently, catalytic asymmetric synthesis has received much
attention3 for the practical synthesis of homochiral compounds, especially in the pharmaceutical field,
and transition metal-catalyzed asymmetric reactions with many kinds of chiral ligands such as phosphi-
nes, phosphonites, amines, and alcohols have been reported.4
Over the course of a decade we have so far studied the stereochemistry of transition metal-catalyzed
reactions of chiral systems such as chiral allyl esters5 and cyclopropane compounds bearing chiral
sulfinyl groups.6 These continuous works have always stimulated much interest in the participation of
chiral sulfinyl functionality to transition metal catalysts,7 and successively extensive efforts have been
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00394-2

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devoted to the development of new chiral ligands bearing chiral organosulfur functionalities as sole chiral
sources.8
2. Results and discussion
Few reports have been published concerning asymmetric synthesis with chiral organosulfur ligands
bearing chiral sulfinyl9 or sulfinamide groups10 as sole chiral sources. We describe in this article
details of our studies on the palladium-catalyzed asymmetric allylic alkylations using the chiral sulfinyl
functionality11 in ligands such as chiral α-sulfinylacetamides, β or γ-amino sulfoxides, and β-sulfinyl
sulfonamides.
2.1. Synthesis of chiral sulfoxide ligands
Chiral sulfoxide ligands which were examined in this report were obtained as follows. Chiral 2-(p-
toluenesulfinyl)acetamides (R)-2a–c were prepared by the amidation of (R)-2-(p-toluenesulfinyl)acetic
acid 112 via the corresponding methyl carbonate (Scheme 1).
Scheme 1.
Chiral β-aminoethyl sulfoxides (R)-5a–h were readily obtained in good yields (90–100%) by Michael
additions13 of the corresponding secondary amines 4a–h to (R)-p-tolyl vinyl sulfoxide 314 in MeOH at
50°C for 2 h (Scheme 2) except for N,N-diphenylamide (R)-5h (lithium N,N-diphenylamide, prepared
from N,N-diphenylamine and n-butyllithium, was reacted with (R)-3 in THF at room temperature). The
results are listed in Table 1.
Scheme 2.
Other β-amino sulfoxides, o-aminophenyl sulfoxides (S)-8a–d, were prepared starting from commer-
cially available 2-bromoaniline 6 as follows. (S)-2-(N,N-Dimethylamino)phenyl p-tolyl sulfoxide 8a was
obtained by reductive N-methylation of 6 with formaline and NaBH3CN15 followed by the sulfinylation
of the carbanion (generated by treating N,N-dimethyl-2-bromoaniline 7a with butyllithium) with (−)-
menthyl (S)-p-toluenesulfinate (Scheme 3). Similarly, o-(cyclic amino)phenyl sulfoxides (S)-8b,c were
synthesized via intramolecular N,N-dialkylation of 6 with 1,4-dibromobutane or 1,5-dibromopentane
followed by the same sulfinylation of 7b,c as described above. 2-(Sulfonamido)phenyl sulfoxides (S)-
8d–g were prepared in similar sequences by N-sulfonylation of 6 followed by N-methylation and then
subsequent sulfinylation of 7d–g with (−)-menthyl (S)-p-toluenesulfinate.

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Table 1
Synthesis of chiral β-amino sulfoxides (R)-5a–h by Michael additions of 4a–h to chiral vinyl sulfoxide
(R)-3a)
Scheme 3.
Chiral 2-(aminomethyl)phenyl sulfoxides (S)-12a–g were prepared by amidation of readily available
2-bromobenzoyl chloride 9 with secondary amines followed by reduction of the amides 10a–g with
BH3·THF and sulfinylation of the amines 11a–g produced with (−)-menthyl (S)-p-toluenesulfinate in
the same way as mentioned earlier (Scheme 4).
Chiral 2-(p-toluenesulfinyl)benzenesulfonamide (S)-15 was obtained by amidation of readily available
2-bromobenzenesulfonyl chloride 13 followed by sulfinylation of sulfonamide 14 with (−)-menthyl (S)-
p-toluenesulfinate.

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Scheme 4.
2.2. Palladium-catalyzed asymmetric allylations with chiral sulfoxide ligands
Initially, palladium-catalyzed asymmetric allylations16 of t-butyl 2-methylacetoacetate 16 were studied
using chiral α-sulfinylacetamides (R)-2a–c as chiral ligands. The reactions of the carbanion of 16 [gene-
rated by treatment with NaH (1.0 equiv.)] with allyl acetate (1.5 equiv.) were carried out in the presence of
[PdCl(π-allyl)]2 (0.03 equiv.) and (R)-2a–c (0.12 equiv.) to give t-butyl (S)-2-allyl-2-methylacetoacetate
17 (Scheme 5) with considerably low enantiomeric excess (e.e.). The e.e. of the product 17 was
determined on the basis of the optical rotation of 17 obtained (the optical rotation of homochiral (S)-
(−)-17: [α]D −22.7 (CHCl3).17 A linear relationship between the e.e. of the product 17 and its rotation
was confirmed by 1H-NMR analysis of the allylation product with a chiral shift reagent [europium tris[3-
(trifluoromethylhydroxymethylene)-(+)-camphorate] (Eu(tfc)3)] The results are summarized in Table 2.
The highest enantioselectivity (50%) was obtained with (R)-2c in 1,2-dimethoxyethane (DME).
Scheme 5.
The low enantioselectivity observed with the above acetamide ligands would arise presumably from the
rather poor coordinating ability of the amide nitrogen atom to the palladium catalyst. Therefore, it seems
difficult to form chelates of (R)-2a–c with palladium. Thus, we chose chiral β-aminoethyl sulfoxides as
chiral ligands, which would be expected to be more efficient for the formation of chelates owing to the
increased coordination ability of the β-amino groups to palladium.
Palladium-catalyzed asymmetric allylations18 of 16 were studied using chiral β-aminoethyl sulfoxides
(R)-5a–h obtained above as chiral ligands. Studies on asymmetric allylations of the sodium enolate of
16 [generated by treatment with NaH (1.0 equiv.)] with allyl acetate (1.5 equiv.) were carried out using
[PdCl(π-allyl)]2, Pd(OAc)2, Pd(dba)2, or Pd2(dba)3·CHCl3 (0.03 or 0.06 equiv.) as a catalyst and (R)-5a
(0.12 equiv.) as a chiral ligand in DME, tetrahydrofuran (THF), ether (Et2O), or toluene, giving optically
active allylated compound 1719 with a rather unexpectedly low e.e. The results are summarized in Table 3.

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3801
Table 2
Palladium-catalyzed asymmetric allylation of 16 with chiral α-sulfinylacetamide ligands (R)-2a–ca)
Table 3
Studies on palladium-catalyzed asymmetric allylation of 16 with a chiral β-aminoethyl sulfoxide
ligand (R)-5aa)
The use of [PdCl(π-allyl)]2 in DME or Et2O gave (S)-(−)-17 with slightly higher e.e., however the
allylation in THF provided (R)-(+)-17.
Use of other chiral sulfoxides (R)-5b–h as chiral ligands was carried out in the same system under
similar reaction conditions with [PdCl(π-allyl)]2 (0.03 equiv.) in THF or DME at 0, −20°C, or room
temperature. The results obtained are summarized in Table 4. Among the chiral sulfoxide ligands
examined, a slightly higher (S)-selectivity of the product 17 was observed with (R)-5f,g. It should be
noted that the marked solvent effects on the stereochemistry of the reaction product were observed in this

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Table 4
Palladium-catalyzed asymmetric allylation of 16 with chiral β-aminoethyl and o-aminophenyl sulfo-
xide ligands (R)-5b–h and 8a,ba)
asymmetric allylation: the allylation of 16 with (R)-5b–h in DME gave (S)-(−)-17, whereas the reaction
with (R)-5c in THF afforded (R)-(+)-17.
In order to improve the enantioselectivity further, stereochemical fixation of the conformation of
the ligands was employed by means of introducing phenyl rings into the chiral ligand systems for the
facile formation of intermediary cyclic palladium complexes mentioned later. Thus, use of chiral o-
aminophenyl (S)-8a–g, o-(aminomethyl)phenyl (S)-12a–g, and o-(aminosulfonyl)phenyl p-tolyl sulfoxi-
des (S)-15 as ligands was studied in the palladium-catalyzed reactions. The allylations of sodium enolate
of 16 with allyl acetate (1.5 equiv.) were carried out at −20°C in THF, Et2O, or DME in the presence
of [PdCl(π-allyl)]2 (0.03 equiv.) and (S)-8a,b (0.12 equiv.) to produce (S)-(−)-17. The results obtained
are summarized in Table 4. In contrast with the results with (R)-5a–h, as we expected, the rather high
enantioselectivity of the product (S)-17 was obtained in all cases examined with (S)-8a,b. With these
ligands, solvent effects on the enantioselectivity were observed, which is quite different from the results
with β-aminoethyl sulfoxides (R)-5a–h, with no change of the absolute configuration of the product 17
even in THF with (S)-8b, as shown in Table 4.
Studies on palladium-catalyzed asymmetric alkylation of 1,3-diphenyl-2-propenyl acetate 18 with
dimethyl malonate sodium enolate were carried out at 50°C in the presence of [PdCl(π-allyl)]2, Pd(dba)2,
or Pd(OAc)2 (0.06 equiv.), and chiral o-aminophenyl sulfoxides (S)-8a–c or chiral 2-(sulfonamido)phenyl
sulfoxides (S)-8d–g. The results are summarized in Table 5. The alkylation of 18 with dimethyl malonate
using chiral ligands (S)-8a–c produced (S)-19 with extremely low e.e. (13–19%), whereas the reactions
with sulfonamide ligands (S)-8d–g gave (S)-19 with an increasing e.e. (22–38%). The e.e. of the product
19 was calculated by HPLC analysis with Chiralpak AD.19 When the sulfonamide ligands (S)-8d–g were
replaced by another sulfonamide (S)-15, the alkylation of 18 with sodium malonate afforded (S)-19 with
25 and 28% e.e (Scheme 6). It seems quite understandable that despite the rather crucial difference in
the stereochemical situation around the sulfonamide groups in the ligands, the degree of the asymmetric
induction observed was quite similar to that with (S)-8d–g.

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3803
Table 5
Palladium-catalyzed asymmetric allylic alkylation of 18 with dimethyl malonate using chiral sulfoxide
ligands (S)-8a–g or (S)-15a)
Scheme 6.
The use of chiral ligands (S)-12a–g bearing one-carbon longer chain substituents between the amino
and the phenyl groups in the alkylation of 18 with dimethyl malonate in THF at room temperature
provided (S)-19 with rather low e.e. The highest enantioselectivity (58%) of (S)-19 was obtained with
(S)-12c, as shown in Table 6. It indicates that six-membered π-allylpalladium intermediates derived from
(S)-12a–g might presumably be sterically less effective in asymmetric induction than five-membered
intermediates obtained from (S)-8a–g, as mentioned later, although the coordination ability of the
nitrogen groups in (S)-12a–g to the palladium catalysts would be stronger than that of the nitrogen in
(S)-8a–g.
2.3. The mechanism of the asymmetric reaction
The mechanism for this asymmetric induction with these chiral sulfoxide ligands is rationalized on the
basis of the stereochemical outcome obtained. A five-membered palladacyclic π-allylpalladium complex
20a (Scheme 7) would be formed as an intermediary reactive allylating species by the participation
of the sulfinyl sulfur lone pair9 and the nitrogen atom of the chiral β-aminoethyl sulfoxides (R)-5a–h
used, resulting in the creation of a new chiral environment designated in 21a. The sodium enolate of
acetoacetate 16 would react with 20a via the nucleophilic substitution of 16A or 16B with 21a (from the

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
Table 6
Palladium-catalyzed asymmetric allylic alkylation of 18 with dimethyl malonate using chiral sulfoxide
ligands (S)-12a–ga)
back side of the palladium catalyst) in sterically preferred fashion to give (S)-17. When THF was used as
the solvent, different stereochemical results were obtained in some cases (R)-5a,c. In these cyclic amino
ligands, the five-membered complexes would be transformed, via 20b formed by the participation of the
THF oxygen atom due to the steric strain induced by the five-five- or five-six-membered spiro structure,
into sterically relieved six-membered intermediates 20c,d. A six-membered π-allylpalladium complex
20c would be preferred to 20d because of the steric interference between the p-tolyl group and the allyl
part in 20d, providing the new chiral environment shown in 21b. Thus, the reaction of sodium enolate 16
with allyl acetate in THF would proceed via the nucleophilic substitution of 16C or 16D with 21b (from
the back side of the palladium catalyst) in a sterically preferred manner, giving (R)-17.
Scheme 7.
In the case of (S)-8a–g, rather higher enantioselectivity was obtained, presumably due to the sterically

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3805
fixed structure of the intermediary palladium complex 22, which provides a chiral environment designa-
ted in 23 (Scheme 8). The reaction of the sodium enolate of 16 with this palladium complex 22 would
proceed via the nucleophilic substitution of 16A or 16B with 23 from the back side of the palladium
catalyst in sterically preferred fashion, to give (S)-17.
Scheme 8.
The mechanism of the asymmetric alkylations of 18 using chiral ligands (S)-8a–g or (S)-12a–g
is rationalized as follows. The reactions would proceed via chiral π-allylpalladium complexes 24
(Scheme 9) involving five-membered chelates9 derived from a palladium catalyst and (S)-8a–g. In the
equilibrium of the allylic systems in the chelates, 24b would be sterically preferred to 24a because of the
existence of the steric hindrance between the p-tolyl and the phenyl group in the allylic systems in 24a.
Therefore, the nucleophile (malonate sodium enolate) would attack at the allylic site (c) in 24b from the
back side of the palladium to produce (S)-19. However, the precise reason for the preference of the allyl
terminus (c) in the attack of the nucleophile is not clear at the present time.
Scheme 9.
In the cases of sulfonamide ligands (S)-8d–g bearing bulky substituents, 25a would be preferentially
formed due to the steric repulsion between the sulfonamide substituents (R2) and the phenyl groups at
the allyl terminus in 25b. The reaction of malonate sodium enolate would occur at the allylic site (b) in
25a trans to the better π-acceptor,20 which is the sulfinyl sulfur atom in the current case, from the back
side of the palladium, affording (S)-19. This explanation would also be supported by the fact that the
increasing steric bulk of the R2 group in 25 (e.g. (S)-8g) provided the higher enantioselectivity of (S)-19.
Likewise when using (S)-12a–g as chiral ligands, π-allylpalladium complexes 26 (Scheme 10)
involving six-membered chelates9 would be formed. In the equilibrium of these six-membered palladium
complexes 26a,b, 26b would be preferred to 26a due to the steric interference between the p-tolyl
and the substituents (Rs) on the amino groups. The nucleophile (sodium malonate) would react at the
allyl terminus (c) affording (S)-19. In the case of the sulfonamide ligand (S)-15, presumably, the π-
allylpalladium complex 27 involving a similar six-membered chelate with the sulfinyl sulfur and the
sulfonamide nitrogen atom21 would be created, instead of formation of the palladium complex chelating
with the sulfinyl sulfur atom and the sulfonyl oxygen atom (if the reaction proceeds via the chelates, the

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
predicted stereochemistry of the product is in conflict with that observed). Similarly, the stereoisomer
27b would be preferred to 27a in the equilibrium of the palladium complex 27a,b because of similar
steric reasons to those mentioned above. The preferential attack of the nucleophile at the allyl terminus
(c) would result in the formation of (S)-19.
Scheme 10.
The precise reason for the preference of the allyl terminus (c) in the attack of the nucleophile is not
so clear at the present time, however, presumably it will be due to the steric interference of the large
substituents at the nitrogen group in the reaction of the nucleophile at the allyl terminus (d).
Thus, the new chiral sulfoxides described herein were demonstrated to serve as chiral ligands in the
palladium-catalyzed reactions of 16 and 18, giving optically active products 17 and 19 with moderate
enantioselectivity.
3. Experimental
Infrared (IR) spectra were obtained in the indicated state with a JASCO DR-81 Fourier transform
IR spectrometer. NMR spectra were determined in the indicated solvent with JEOL JNM-LA 400
(1H-NMR; 400 MHz, 13C-NMR; 100 MHz) and JEOL EX-270 (1H-NMR; 270 MHz, 13C-NMR; 67.8
MHz) high-resolution NMR spectrometers; chemical shifts are given in ppm from tetramethylsilane as
an internal standard. Splitting patterns are designated as s, singlet; bs, broad singlet; d, doublet; dd,
doublet of doublets; t, triplet; quint, quintet; m, multiplet. Mass spectra were taken on a JEOL JMS-
DX 303/JMA-DA 5000 system. High performance liquid chromatography (HPLC) was performed with
a Tosoh UV-8010 CCPM (column: Daicel Chiralpak AD, hexane:i-PrOH=20:1, 0.5 ml/min, 254 nm).
Optical rotations were measured with a JASCO DIP-370 polarimeter. Flash column chromatography was
performed with Merck silica gel 60 (230–400 mesh). Thin layer or thick layer plates (preparative TLC)
were made of Merck silica gel 60PF-254 activated by drying at 140°C for 3.5 h.
3.1. Synthesis of chiral 2-(p-toluenesulfinyl)acetamide derivatives
3.1.1. (R)-N,N-Diisopropyl-2-(p-toluenesulfinyl)acetamide 2a
Methyl chloroformate (1.39 g, 13.8 mmol) was added to a solution of (R)-p-toluenesulfinylacetic acid
1 (911 mg, 4.6 mmol) and triethylamine (1.39 g, 13.8 mmol) in THF (15 ml) at 0°C, and the reaction
mixture was stirred at 0°C for 2 h. The reaction solution was diluted with ether and filtered. The filtrate
was evaporated in vacuo. A solution of the crude product obtained in THF (2 ml) was added at 0°C to a
solution of diisopropyl amine (768 mg, 7.6 mmol) and triethylamine (697 mg, 6.9 mmol) in THF (5 ml)
and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was then diluted

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3807
with ether, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was subjected to preparative TLC (chloroform:methanol=10:1) to
give (R)-2a (277 mg, 21% yield).
The reactions of the methyl carbonate derived from (R)-1 (4.6 mmol) with diphenylamine (1.28 g, 7.6
mmol), or dicyclohexylamine (1.38 g, 7.6 mmol) were carried out using the same procedure as described
above to give (R)-N,N-diphenyl-, or N,N-dicyclohexyl-2-(p-toluenesulfinyl)acetamide 2b,c, respectively.
2a: [α]D +95 (c=0.6, CHCl3). IR νmfilamx cm−1: 1634 (amide), 1595 (aromatic), 1042 (S_O). 1H-NMR
(270 MHz; CDCl3) δ: 1.06 (d, J=6.6 Hz, 3H, CH3), 1.18 (d, J=6.8 Hz, 3H, CH3), 1.33 (dd, J=10.4,
6.8 Hz, 6H, (CH3)2), 2.41 (s, 3H, C6H4CH3), 3.44–3.52 (m, 2H, CH), 3.85 (quint, J=6.8 Hz, 1H, CH),
3.70 (d, J=13.7 Hz, 1H, CH), 4.03 (d, J=13.7 Hz, 1H, CH), 7.47 (AB system, J=8.0 Hz, 4H, C6H4CH3).
13C-NMR (67.8 MHz; CDCl3) δ: 20.4, 20.9, 21.1, 21.4, 46.4, 49.7, 64.1, 124.6, 129.8, 163.1. m/z: 281
(M+). Exact mass determination: 281.1450 (calcd C15H23NO2S: 281.1405).
1
2b: 42% yield. [α]D +45 (c=4.1, CHCl3). IR νmfilamx cm−1: 1633 (amide), 1600 (aromatic). H-NMR
(270 MHz; CDCl3) δ: 0.98–1.46 (m, 12H, (CH2)3×2), 1.52–1.77 (m, 8H, (CH2)2×2), 2.20–2.30 (m, 2H,
CH×2), 2.41 (s, 3H, C6H4CH3), 3.73 (d, J=13.7 Hz, 1H, CH), 4.05 (d, J=13.7 Hz, 1H, CH), 7.29–7.33
(m, 2H, ArH), 7.62–7.65 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 20.4, 23.1, 23.7, 24.1, 24.2,
24.3, 24.5, 25.3, 25.5, 28.8, 29.8, 63.3, 123.6, 128.8, 163.1. m/z: 361 (M+). Exact mass determination:
361.2105 (calcd C21H31NO2S: 361.2076).
2c: 18% yield. [α]D +92 (c=3.6, CHCl3). IR νmfilamx cm−1: 1664 (amide), 1595 (aromatic), 1049 (S_O).
1H-NMR (270 MHz; CDCl3) δ: 2.43 (s, 3H, C6H4CH3), 3.68 (d, J=13.7 Hz, 1H, CH), 4.03 (d, J=13.7
Hz, 1H, CH), 7.05–7.34 (m, 10H, (C6H5)2), 7.46 (AB system, J=8.2 Hz, 4H, C6H4). 13C-NMR (67.8
MHz; CDCl3) δ: 21.5, 63.1, 126.1, 126.7, 128.85, 128.9, 130.0, 164.2. m/z: 349 (M+). Exact mass
determination: 349.1114 (calcd C21H19NO2S: 349.1158).
3.2. Synthesis of β-amino sulfoxide derivatives
3.2.1. (R)-2-(Pyrrolidino)ethyl p-tolyl sulfoxide 5a
A solution of (R)-p-tolyl vinyl sulfoxide 3 (220 mg, 1.3 mmol) in methanol (10 ml) was added at 0°C
to a solution of pyrrolidine (188 mg, 2.6 mmol) in methanol (2 ml) and the reaction mixture was stirred
at 50°C for 2 h. The reaction solution was concentrated in vacuo. The crude product was subjected to
preparative TLC (chloroform:methanol=15:1) to give (R)-5a (162 mg, 99% yield).
Michael additions of other secondary amines 4b–g to (R)-3 were carried out using the same procedure
as described above to give (R)-2-piperidino-, (R)-2-(hexamethyleneamino)-, (R)-2-morpholino-, (R)-2-
(N,N-diethylamino)-, (R)-2-(N-methyl-N-cyclohexylamino)-, and (R)-2-(N-methyl-N-butylamino)ethyl
p-tolyl sulfoxide 5b–g, respectively.
1
(R)-5a: [α]D +140 (c=11.4, acetone). IR νmfilamx cm−1: 1600 (aromatic), 1040 (S_O). H-NMR (270
MHz; CDCl3) δ: 1.73–1.84 (m, 4H, (CH2)2), 2.42 (s, 3H, CH3), 2.50–2.58 (m, 4H, CH2NCH2),
2.61–3.04 (m, 4H, (CH2)2), 7.43 (AB system, J=7.9 Hz, 4H, C6H4). 13C-NMR (67.8 MHz; CDCl3)
δ: 21.4, 23.5, 49.0, 54.0, 56.9, 124.2, 129.9. m/z: 237 (M+). Exact mass determination: 237.1187 (calcd
C13H19ONS: 237.1193).
1
(R)-5b: 90% yield. [α]D +141 (c=8.6, acetone). IR νmfilamx cm−1: 1597 (aromatic), 1043 (S_O). H-
NMR (270 MHz; CDCl3) δ: 1.40–1.59 (m, 6H, (CH2)3), 2.22–2.45 (m, 4H, CH2NCH2), 2.47–2.81 (m,
2H, NCH2), 2.86–3.83 (m, 2H, CH2S), 7.42 (AB system, J=7.9 Hz, 4H, C6H4). 13C-NMR (67.8 MHz;
CDCl3) δ: 20.7, 23.6, 25.2, 51.0, 53.6, 54.4, 123.5, 129.2. m/z: 251 (M+). Exact mass determination:
251.1323 (calcd C14H21NOS: 251.1344).

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(R)-5c: 93% yield. [α]D +141 (c=1.9, acetone). IR νmfilamx cm−1: 1597 (aromatic), 1044 (S_O). 1H-NMR
(270 MHz; CDCl3) δ: 1.57–1.61 (m, 8H, (CH2)4), 2.41 (s, 3H, CH3), 2.62–2.66 (m, 4H, CH2NCH2),
2.67–3.01 (m, 4H, (CH2)2), 7.42 (AB system, J=7.9 Hz, 4H, C6H4). 13C-NMR (67.8 MHz; CDCl3) δ:
21.2, 26.8, 50.6, 54.9, 56.0, 124.0, 129.7. m/z: 265 (M+). Exact mass determination: 265.1534 (calcd
C15H23ONS: 265.1500).
1
(R)-5d: 93% yield. [α]D +122 (c=1.9, acetone). IR νmfilamx cm−1: 1600 (aromatic), 1040 (S_O). H-
NMR (270 MHz; CDCl3) δ: 1.42–1.64 (m, 4H, CH2NCH2), 2.37–2.51 (m, 4H, CH2OCH2), 2.42 (s, 3H,
CH3), 2.53–2.92 (m, 2H, NCH2), 3.00–3.04 (m, 2H, SCH2), 7.32 (d, J=7.9 Hz, 2H, ArH), 7.54 (d, J=8.2
Hz, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.4, 24.0, 25.6, 51.6, 54.3, 54.6, 124.2, 130.0. m/z: 253
(M+). Exact mass determination: 253.1061 (calcd C13H19NO2S: 253.1037).
1
(R)-5e: 97% yield. [α]D +173 (c=5.7, acetone). IR νmfilamx cm−1: 1597 (aromatic), 1043 (S_O). H-
NMR (270 MHz; CDCl3) δ: 1.01 (t, J=7.0 Hz, 6H, CH3×2), 2.41 (s, 3H, CH3), 2.54 (q, J=6.9 Hz,
4H, CH2×2), 2.65–2.93 (m, 4H, (CH2)2), 7.32 (d, J=7.9 Hz, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3)
δ: 11.5, 21.2, 27.6, 45.5, 46.7, 55.2, 123.9, 129.7. m/z: 239 (M+). Exact mass determination: 239.1378
(calcd C13H21NOS: 239.1344).
(R)-5f: [α]D +149 (c=3.5, acetone). IR νmfilamx cm−1: 1558 (aromatic), 1046 (S_O). 1H-NMR (270 MHz;
CDCl3) δ: 1.04–1.79 (m, 10H, (CH2)5), 2.26 (s, 3H, NCH3), 2.36–2.45 (m, 1H, CH), 2.40 (s, 3H, CH3),
2.60–3.06 (m, 4H, (CH2)2), 7.31 (d, J=6.9 Hz, 2H, ArH), 7.54 (dd, J=8.2, 1.2 Hz, 2H, ArH). 13C-NMR
(67.8 MHz; CDCl3) δ: 21.2, 25.7, 25.8, 26.1, 28.1, 28.7, 37.4, 46.6, 56.6, 62.8, 123.9, 129.7. m/z: 279
(M+). Exact mass determination: 279.1692 (calcd C16H25NOS: 279.1657).
1
(R)-5g: 93% yield. [α]D +161 (c=2.7, acetone). IR νmfilamx cm−1: 1597 (aromatic), 1046 (S_O). H-
NMR (270 MHz; CDCl3) δ: 0.88–0.93 (m, 3H, CH3), 1.26–1.46 (m, 4H, (CH2)2), 2.23 (s, 3H, NCH3),
2.33–2.39 (m, 2H, NCH2), 2.42 (s, 3H, CH3), 2.54–2.95 (m, 4H, (CH2)2), 7.30 (d, J=7.9 Hz, 2H,
ArH), 7.54 (dd, J=8.2, 2.0 Hz, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 14.0, 20.5, 21.4, 29.3, 42.0,
50.4, 55.6, 57.3, 124.2, 129.9. m/z: 253 (M+). Exact mass determination: 253.1491 (calcd C14H23NOS:
253.1500).
3.2.2. (R)-2-(N,N-Diphenylamino)ethyl p-tolyl sulfoxide 5h
A 1.5 M hexane solution of n-butyllithium (0.5 ml, 0.72 mmol) was added at 0°C to a solution of
N,N-diphenylamine (122 mg, 0.72 mmol) in THF (2 ml). The mixture was stirred at 0°C for 30 min.
Then, a solution of (R)-3 (100 mg, 0.6 mmol) in THF (2 ml) was added to the above solution. The
reaction mixture was stirred at room remperature for 20 h. The reaction solution was diluted with ether,
washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude product was subjected to preparative TLC (ether:hexane=3:1) to give (R)-5h (135 mg, 39% yield).
1
(R)-5h: [α]D +59.2 (c=6.8, acetone). IR νmfilamx cm−1: 1590 (aromatic), 1040 (S_O). H-NMR (270
MHz; CDCl3) δ: 2.41 (s, 3H, CH3), 2.93–3.18 (m, 2H, NCH2), 3.94–4.29 (m, 2H, SCH2), 6.93–6.99 (m,
6H, ArH), 7.22–7.32 (m, 6H, ArH), 7.45–7.47 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.4,
45.2, 54.0, 121.2, 122.0, 123.9, 129.5, 130.0. m/z: 345 (M+). Exact mass determination: 335.1340 (calcd
C21H21NOS: 335.1389).
3.3. Synthesis of chiral 2-(amino- or 2-sulfonamido)phenyl sulfoxide derivatives
3.3.1. N-(2-Bromophenyl)pyrrolidine 7b
A solution of 2-bromoaniline 6 (100 mg, 0.59 mmol) in toluene (2 ml) was added to a solution of 1,4-
dibromopentane (153 mg, 0.71 mmol) and triethylamine (175 mg, 1.77 mmol) in toluene (1 ml) and the
reaction mixture was stirred at reflux for 6 h. It was then diluted with ether, washed with saturated aqueous

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3809
NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was subjected to
preparative TLC (ether:hexane=1:5) to give 7b (77 mg, 57% yield).
The reaction of 6 (100 mg, 0.59 mmol) with 1,5-dibromobutane (163 mg, 0.71 mmol) was carried out
using the same procedure as described above to give N-(2-bromophenyl)piperidine 7c.
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1
7b: IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.91–1.96 (m, 4H, (CH2)2),
max
3.32–3.37 (m, 4H, N(CH2)2), 6.70–6.76 (m, 1H, ArH), 6.89–6.92 (m, 1H, ArH), 7.15–7.21 (m, 1H,
ArH), 7.48–7.51 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 25.0, 51.2, 117.9, 121.2, 127.7, 134.5.
m/z: 225 (M+). Exact mass determination: 225.0194 (calcd C10H12NBr: 225.0153).
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1
7c: 58% yield. IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.52–1.60 (m, 2H,
max
CH2), 1.70–1.78 (m, 4H, (CH2)2), 2.92–2.96 (m, 4H, N(CH2)2), 6.82–6.87 (m, 1H, ArH), 7.00–7.03 (m,
1H, ArH), 7.20–7.26 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 24.2, 26.2, 53.3, 120.9, 123.8,
128.1, 133.7. m/z: 239 (M+). Exact mass determination: 239.0310 (calcd C11H14NBr: 239.0301).
3.3.2. N-(2-Bromophenyl)benzenesulfonamide
Benzenesulfonyl chloride (1.23 g, 6.98 mmol) was added to a solution of 6 (1.00 g, 5.81 mmol) and
pyridine (1.17 g, 17.44 mmol) in dichloromethane (5 ml) at 0°C, and the reaction mixture was stirred at
0°C for 1 h. The reaction solution was diluted with ether, washed with saturated aqueous NaHCO3 and
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ether:hexane=1:1) to give N-(2-bromophenyl)benzenesulfonamide
(1.44 g, 79% yield).
The reactions of 6 (1.00 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.33 g, 6.98 mmol), 4-
methoxybenzenesulfonyl chloride (1.44 g, 6.98 mmol), or 1-naphthalenesulfonyl chloride (1.58 g,
6.98 mmol) were carried out using the same procedure as described above to give the corresponding
sulfonamides.
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1
IR ν
cm−1: 3220 (NH), 1590 (aromatic), 1465, 1160 (SO2NH). H-NMR (270 MHz; CDCl3)
max
δ: 1.59 (bs, 1H, NH), 6.94–7.00 (m, 2H, ArH), 7.25–7.31 (m, 2H, ArH), 7.38–7.45 (m, 4H, ArH),
7.51–7.69 (m, 2H, ArH), 7.73–7.78 (m, 4H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 122.9, 126.5, 127.3,
128.6, 129.0, 132.6, 133.3. m/z: 311 (M+). Exact mass determination: 310.9631 (calcd C12H10NO2SBr:
310.9616).
3.3.3. N-(2-Bromophenyl)-p-toluenesulfonamide
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1
31% yield. IR ν
cm−1: 1597 (aromatic), 1381, 1169 (SO2NH). H-NMR (270 MHz; CDCl3) δ:
max
1.58 (bs, 1H, NH), 2.47 (s, 3H, CH3), 7.08–7.11 (m, 1H, ArH), 7.27–7.29 (m, 2H, ArH), 7.31–7.35 (m,
2H, ArH), 7.61–7.64 (m, 1H, ArH), 7.85–7.88 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.6,
127.8, 129.0, 129.1, 131.4, 133.7, 134.1. m/z: 325 (M+). Exact mass determination: 324.9801 (calcd
C13H12NO3SBr: 324.9772).
3.3.4. N-(2-Bromophenyl)-4-methoxybenzenesulfonamide
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1
82% yield. IR ν
cm−1: 1590 (aromatic), 1370, 1160 (SO2NH). H-NMR (270 MHz; CDCl3) δ:
max
3.80 (s, 3H, OCH3), 6.84–6.89 (m, 3H, ArH), 6.92–6.98 (m, 1H, NH), 7.22–7.29 (m, 1H, ArH), 7.40 (dd,
J=8.1, 1.5 Hz, 1H, ArH), 7.63–7.71 (m, 3H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 55.6, 114.2, 115.8,
122.7, 126.3, 128.5, 129.5, 130.3, 132.6, 134.8. m/z: 341 (M+). Exact mass determination: 340.9709
(calcd C13H12NO3SBr: 340.9721).

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3.3.5. N-(2-Bromophenyl)-1-naphthalenesulfonamide
77% yield. IR νmfilamx cm−1: 1590 (aromatic), 1330, 1160 (SO2NH). 1H-NMR (270 MHz; CDCl3) δ: 1.58
(bs, 1H, NH), 6.83–6.89 (m, 1H, ArH), 7.21–7.30 (m, 2H, ArH), 7.46–7.49 (m, 1H, ArH), 7.55–7.68 (m,
3H, ArH), 7.88–8.05 (m, 2H, ArH), 8.21–8.26 (m, 1H, ArH), 8.65–8.68 (m, 1H, ArH). 13C-NMR (67.8
MHz; CDCl3) δ: 114.9, 121.4, 124.0, 124.4, 125.8, 127.0, 128.4, 129.1, 130.4, 132.6, 135.0. m/z: 361
(M+). Exact mass determination: 360.9770 (calcd C16H12NSBr: 360.9772).
3.3.6. N-(2-Bromophenyl)-N-methylbenzenesulfonamide 7d
A 25 ml two-necked flask equipped with a septem inlet and a magnetic stirring bar, and containing
sodium hydride (50% oil dispersion; 133 mg, 2.78 mmol) was flushed with argon, and maintained under
a positive pressure of argon. A solution of N-(2-bromophenyl)benzenesulfonamide (433 mg, 2.78 mmol)
in THF (4 ml) was added to the above flask. The mixture was stirred at 0°C for 30 min. A solution
of iodomethane (394 mg, 2.78 mmol) in THF (4 ml) was added the above solution, and the mixture
was stirred at room temperature for 4 h. The reaction solution was diluted with ether, washed with
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ether:hexane=1:1) to give 7d (331 mg, 79% yield).
The N-methylation of other sulfonamide derivatives was carried out using the same procedure as
described above to give N-(2-bromophenyl)-N-methyl-p-toluenesulfonamide 7e, N-(2-bromophenyl)-N-
methyl-4-methoxybenzenesulfonamide 7f, or N-(2-bromophenyl)-N-methyl-1-naphthalenesulfonamide
7g, respectively.
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7d: IR ν
cm−1: 1590 (aromatic), 1340, 1175 (SO2). 1H-NMR (270 MHz; CDCl3) δ: 3.20 (s, 3H,
max
CH3), 7.11–7.27 (m, 3H, ArH), 7.51–7.63 (m, 4H, ArH), 7.78–7.82 (m, 2H, ArH). 13C-NMR (67.8
MHz; CDCl3) δ: 38.3, 124.7, 126.9, 127.8, 128.2, 128.9, 129.8, 130.7, 132.8, 134.0, 139.0. m/z: 325
(M+). Exact mass determination: 324.9791 (calcd C13H12NO2SBr: 324.9772).
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7e: 97% yield. IR ν
cm−1: 1593 (aromatic), 1165 (SO2). 1H-NMR (270 MHz; CDCl3) δ: 2.44 (s,
max
3H, C6H4CH3), 3.18 (s, 3H, NCH3), 6.92–6.99 (m, 1H, ArH), 7.11–7.38 (m, 4H, ArH), 7.59–7.78 (m,
3H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.6, 38.3, 122.5, 126.3, 127.3, 128.7, 129.7, 130.5, 132.6,
134.0. m/z: 339 (M+). Exact mass determination: 338.9958 (calcd C14H14NO2SBr: 338.9929).
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1
7f: 81% yield. IR ν
cm−1: 1590 (aromatic), 1340, 1160 (SO2). H-NMR (400 MHz; CDCl3) δ:
max
3.17 (s, 3H, NCH3), 3.82 (s, 3H, OCH3), 6.88 (dd, J=6.8, 2.2 Hz, 1H, ArH), 6.96–6.98 (m, 2H, ArH),
7.11–7.20 (m, 1H, ArH), 7.25–7.30 (m, 1H, ArH), 7.37–7.42 (m, 1H, ArH), 7.60–7.76 (m, 2H, ArH).
13C-NMR (100 MHz; CDCl3) δ: 38.3, 55.6, 114.1, 115.8, 122.6, 124.8, 126.3, 128.2, 129.5, 130.1, 132.6,
134.0. m/z: 357 (M+). Exact mass determination: 356.9854 (calcd C14H14NO3SBr: 356.9857).
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1
7g: 78% yield. IR ν
cm−1: 1590 (aromatic), 1345, 1180 (SO2). H-NMR (270 MHz; CDCl3) δ:
max
3.25 (s, 3H, CH3), 7.11–7.31 (m, 3H, ArH), 7.45–7.67 (m, 4H, ArH), 7.88–7.91 (m, 1H, ArH), 8.18 (dd,
J=7.4, 1.3 Hz, 1H, ArH), 8.58 (dd, J=6.6, 1.6 Hz, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 38.7,
124.0, 125.9, 126.8, 127.8. 128.1, 128.6, 129.7, 130.7, 131.7, 133.9, 134.5. m/z: 375 (M+). Exact mass
determination: 374.9959 (calcd C17H14NO2SBr: 374.9929).
3.3.7. (S)-2-(N,N-Dimethylamino)phenyl p-tolyl sulfoxide 8a
A 1.64 M pentane solution of tert-butyllithium (0.8 ml, 1.3 mmol) was added at −78°C to a solution
of 2-bromo-N,N-dimethylaniline 7a15 (253 mg, 1.2 mmol) in THF (3 ml), and the reaction mixture
was stirred at −78°C for 1 h. A solution of (−)-menthyl (S)-p-toluenesulfinate (395 mg, 1.3 mmol) in
THF (3 ml) was added to the above solution, and the reaction mixture was stirred at 0°C for 6 h. The
reaction solution was diluted with ether, and the solution was washed with saturated aqueous NH4Cl and

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3811
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ether:hexane=3:1) to give (S)-8a (168 mg, 52% yield).
The sulfinylation of N-(2-bromophenyl)pyrrolidine 7b and -piperidine 7c was carried out using the
same procedure as described above to give (S)-2-(pyrrolidino)phenyl or (S)-2-(piperidino)phenyl p-tolyl
sulfoxide 8b,c, respectively.
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1
8a: [α]D −96 (c=5.5, acetone). IR ν
cm−1: 1588 (aromatic), 1032 (S_O). H-NMR (270 MHz;
max
CDCl3) δ: 2.33 (s, 3H, CH3), 2.61 (s, 6H, (CH3)2), 7.08–7.20 (m, 1H, ArH), 7.25–7.38 (m, 4H, ArH),
7.40–7.48 (m, 1H, ArH), 7.53–7.56 (m, 1H, ArH), 7.94–9.97 (m, 1H, ArH). 13C-NMR (67.8 MHz;
CDCl3) δ: 21.3, 44.9, 120.9, 124.7, 125.1, 125.5, 129.4, 131.5. m/z: 259 (M+). Exact mass determination:
259.1069 (calcd C15H17NOS: 259.1031).
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8b: 31% yield. [α]D −101 (c=1.0, acetone). IR ν
cm−1: 1590 (aromatic), 1020 (S_O). 1H-NMR
max
(270 MHz; CDCl3) δ: 1.83–2.03 (m, 4H, (CH2)2), 2.33 (s, 3H, C6H4CH3), 3.11–3.19 (m, 2H, NCH2),
3.41–3.51 (m, 2H, NCH2), 6.84 (dd, J=1.0, 8.2 Hz, 1H, ArH), 6.93–6.99 (m, 1H, ArH), 7.30 (AB system,
J=8.2 Hz, 4H, C6H4), 7.26–7.40 (m, 1H, ArH), 7.85 (dd, J=7.9, 1.6 Hz, 1H, ArH). 13C-NMR (67.8
MHz; CDCl3) δ: 21.3, 25.5, 52.1, 116.7, 120.1, 125.3, 126.3, 129.6, 131.7. m/z: 285 (M+). Exact mass
determination: 285.1187 (calcd C17H19NOS: 285. 1232).
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8c: 43% yield. [α]D −110 (c=1.0, acetone). IR ν
cm−1: 1595 (aromatic), 1020 (S_O). 1H-NMR
max
(270 MHz; CDCl3) δ: 1.55–1.70 (m, 6H, (CH2)3), 2.33 (s, 3H, C6H4CH3), 2.44–2.52 (m, 2H, NCH2),
3.03–3.10 (m, 2H, NCH2), 7.08 (dd, J=7.7, 1.3 Hz, 1H, ArH), 7.38 (AB system, J=8.0 Hz, 4H, C6H4),
7.27–7.41 (m, 2H, ArH), 7.97–8.00 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.4, 23.9, 26.0,
121.3, 124.6, 125.3, 125.9, 129.4, 131.5. m/z: 299 (M+). Exact mass determination: 299.1344 (calcd
C18H21NOS: 299.1328).
3.3.8. (S)-N-Methyl-N-[2-(p-toluenesulfinyl)phenyl]benzenesulfonamide 8d
A 1.14 N cyclopentane solution of sec-butyllithium (1.7 ml, 1.79 mmol) was added at −78°C to a
solution of N-(2-bromophenyl)-N-methylbenzenesulfonamide 7d (292 mg, 0.90 mmol) in THF (6 ml),
and the reaction mixture was stirred at −78°C for 1 h. A solution of (−)-menthyl (S)-p-toluenesulfinate
(527 mg, 1.79 mmol) in THF (7 ml) was added to the above solution, and the reaction mixture was
stirred at room temperature for 6 h. The reaction solution was diluted with ether and the solution was
washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was subjected to preparative TLC (ether:hexane=2:1) to give
(S)-8d (98 mg, 28% yield).
The sulfinylations of N-(2-bromophenyl)-N-methyl-p-toluenesulfonamide 7e, N-(2-bromophenyl)-N-
methyl-4-methoxybenzenesulfonamide 7f, or N-(2-bromophenyl)-N-methylnaphthalene-1-sulfonamide
7g, N-cyclohexyl-N-isopropyl-2-bromobenzenesulfonamide 14 were carried out using the same proce-
dure as described above to give (S)-N-methyl-N-[2-(p-toluenesulfinyl)phenyl]-p-toluenesulfonamide 8e,
(S)-N-methyl-N-[2-(p-toluenesulfinyl)phenyl]-4-methoxybenzenesulfonamide 8f, or (S)-N-methyl-N-[2-
(p-toluenesulfinyl)phenyl]-1-naphthalenesulfonamide 8g, respectively.
1
(S)-8d: [α]D −243 (c=2.0, CHCl3). IR νmfilamx cm−1: 1590 (aromatic), 1170 (SO2), 1050 (S_O). H-
NMR (270 MHz; CDCl3) δ: 2.31 (s, 3H, C6H4CH3), 3.30 (s, 3H, NCH3), 7.10–7.18 (m, 4H, ArH),
7.29–7.39 (m, 3H, ArH), 7.47–7.50 (m, 1H, ArH), 7.52–7.68 (m, 3H, ArH), 7.72–7.78 (m, 1H, ArH), 8.29
(dd, J=1.2, 7.9 Hz, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3, 38.6, 125.4, 125.8, 127.3, 128.2,
129.3, 129.7, 130.0, 130.7. m/z: 385 (M+). Exact mass determination: 385.0795 (calcd C20H19NO3S2:
385.0807).
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(S)-8e: 35% yield. [α]D −48 (c=13.1, acetone). IR ν
cm−1: 1590 (aromatic), 1160, 1340 (SO2),
max
1020 (S_O). 1H-NMR (270 MHz; CDCl3) δ: 2.31 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.27 (s, 3H, NCH3),

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
7.11–7.18 (m, 4H, ArH), 7.26–7.39 (m, 4H, ArH), 7.50–7.60 (m, 3H, ArH), 8.02 (d, J=0.8 Hz, 1H, ArH).
6.78–7.74 (m, 12H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3, 21.7, 38.5, 125.2, 125.8, 127.1, 127.9,
129.1, 129.6, 131.1, 131.3. m/z: 385 (M+). Exact mass determination: 385.0807 (calcd C20H19NO3S2:
385.0837).
(S)-8f: 29% yield. [α]D −128 (c=1.7, CHCl3). IR νmfilamx cm−1: 1580 (aromatic), 1170 (SO2), 1050
1
(S_O). H-NMR (270 MHz; CDCl3) δ: 2.31 (s, 3H, C6H4CH3), 3.25 (s, 3H, NCH3), 3.91 (s, 3H,
C6H4OCH3), 6.93 (dd, J=2.6, 8.7 Hz, 1H, ArH), 7.10–7.23 (m, 5H, ArH), 7.29–7.39 (m, 2H, ArH),
7.51–7.70 (m, 3H, ArH), 7.77 (dd, J=2.6, 4.8 Hz, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3,
38.4, 56.0, 109.7, 110.2, 116.6, 125.6, 127.2, 128.0, 129.3, 129.8, 131.4, 132.2. m/z: 436 (M+1). Exact
mass determination: 435.0998 (calcd C24H21NO3S2: 435.0963).
(S)-8g: 25% yield. [α]D −37 (c=2.6, CHCl3). IR νmfilamx cm−1: 1580 (aromatic), 1160 (SO2), 1045
1
(S_O). H-NMR (270 MHz; CDCl3) δ: 2.31 (s, 3H, C6H4CH3), 3.30 (s, 3H, NCH3), 6.96–7.96 (m,
11H, ArH), 7.86–8.03 (m, 1H, ArH), 8.19–8.26 (m, 1H, ArH), 8.41–8.67 (m, 2H, ArH). 13C-NMR (67.8
MHz; CDCl3) δ: 21.2, 38.3, 119.9, 124.6, 125.8, 126.0, 127.6, 127.9, 128.1, 128.3, 129.3, 129.7, 130.0,
130.5, 132.4, 134.2, 134.5, 134.9, 135.2. m/z: 415 (M+). Exact mass determination: 415.0902 (calcd
C21H21NO4S2: 415.0912).
3.4. Synthesis of chiral 2-(aminomethyl)phenyl sulfoxides derivatives
3.4.1. Bromobenzoic acid pyrrolidine amide 10a
A solution of 2-bromobenzoyl chloride 9 (1.29 g, 5.87 mmol) in dichloromethane (10 ml) was added at
0°C to a solution of pyrrolidine (500 mg, 7.04 mmol) and triethylamine (1.19 g, 4.56 mmol) in dichloro-
methane (10 ml), and the reaction mixture was stirred at room temperature for 2 h. It was then diluted
with chloroform, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude product was subjected to flash column chromatography (ether:hexane=2:1) to give
10a (1.49 g, 97% yield).
The reactions of 9 (1.00 g, 4.56 mmol) with N-methylisopropylamine (399 mg, 5.47 mmol),
N-methyl-n-butylamine (476 mg, 5.47 mmol), N-methylcyclohexylamine (618 mg, 5.47 mmol), N-
cyclohexylisopropylamine (771 mg, 5.47 mmol), N,N-dicyclohexylamine (990 mg, 5.47 mmol), or N,N-
dibenzylamine (1.08 g, 5.47 mmol) were carried out using the same procedure as described above to give
2-bromo-N-methyl-N-isopropylbenzamide 10b, 2-bromo-N-methyl-n-butylbenzamide 10c, 2-bromo-N-
methyl-N-cyclohexylbenzamide 10d, 2-bromo-N-cyclohexyl-N-isopropylbenzamide 10e, 2-bromo-N,N-
dicyclohexylbenzamide 10f, or 2-bromo-N,N-dibenzylbenzamide 10g, respectively.
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1
10a: IR ν
cm−1: 1630 (amide), 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.85–2.17 (m,
max
4H, (CH2)2), 3.16–3.21 (m, 2H, CH2), 3.64–3.69 (m, 2H, CH2), 7.20–7.38 (m, 3H, ArH), 7.55–7.58 (m,
1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 24.6, 25.9, 45.5, 48.0, 118.8, 127.5, 127.7, 130.2, 132.8,
139.7, 167.4. m/z: 253 (M+). Exact mass determination: 253.0096 (calcd C11H12NOBr: 253.0102).
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10b: 99% yield. IR ν
cm−1: 1637 (amide), 1590 (aromatic). 1H-NMR (270 MHz; CDCl3) δ: 1.08
max
(d, J=6.6 Hz, 3H, CH3), 1.23 (d, J=6.8 Hz, 3H, CH3), 2.98 (s, 3H, NCH3), 3.68 (quint, J=6.6 Hz, 1H,
CH), 7.19–7.27 (m, 2H, ArH), 7.32–7.38 (m, 1H, ArH), 7.54–7.60 (m, 1H, ArH). 13C-NMR (67.8 MHz;
CDCl3) δ: 20.4, 25.5, 29.3, 49.9, 119.0, 127.5, 127.8, 129.9, 132.9, 139.3, 168.4. m/z: 255 (M+). Exact
mass determination: 255.0247 (calcd C11H14NOBr: 255.0259).
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1
10c: 99% yield. IR ν
cm−1: 1630 (amide), 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ:
max
0.98 (t, J=7.2 Hz, 3H, CH3), 1.39–1.76 (m, 6H, (CH2)3), 3.10 (s, 3H, NCH3), 7.19–7.27 (m, 2H,
ArH), 7.32–7.38 (m, 1H, ArH), 7.54–7.59 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 25.6, 27.0,

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3813
30.9, 58.5, 118.9, 119.0, 126.9, 127.3, 127.4, 127.6, 129.7, 132.6, 139.0. m/z: 269 (M+). Exact mass
determination: 269.0384 (calcd C12H16NOBr: 269.0415).
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1
10d: 99% yield. IR ν
cm−1: 1630 (amide), 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ:
max
1.43–1.94 (m, 10H, (CH2)5), 3.01 (s, 3H, NCH3), 4.56–4.65 (m, 1H, CH), 7.18–7.27 (m, 2H, ArH),
7.31–7.38 (m, 1H, ArH), 7.53–7.60 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 25.5, 25.7, 27.0,
30.7, 30.9, 58.5, 119.0, 127.3, 127.4, 127.6, 129.7, 132.7, 139.2, 168.7. m/z: 295 (M+). Exact mass
determination: 295.0563 (calcd C14H18NOBr: 295.0551).
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10e: 99% yield. IR ν
cm−1: 1640 (amide), 1590 (aromatic). 1H-NMR (270 MHz; CDCl3) δ: 1.05
max
(d, J=6.6 Hz, 3H, CH3), 1.22 (d, J=6.6 Hz, 3H, CH3), 1.44–2.16 (m, 10H, (CH2)5), 2.97–3.14 (m, 1H,
CH), 3.58 (quint, J=6.6 Hz, 1H, CH), 7.14–7.22 (m, 2H, ArH), 7.27–7.34 (m, 1H, ArH), 7.53–7.56 (m,
1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 20.6, 20.8, 25.2, 25.6, 26.6, 29.9, 31.1, 51.2, 118.8, 126.5,
127.5, 129.4, 132.8, 168.3. m/z: 323 (M+). Exact mass determination: 323.0889 (calcd C16H22NOBr:
323.0885).
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10f: 86% yield. IR ν
cm−1: 1635 (amide), 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ:
max
1.18–2.04 (m, 20H, (CH2)5×2), 2.57–2.70 (m, 2H, CH×2), 2.57–2.70 (m, 2H, CH×2), 7.39–7.49 (m,
2H, ArH), 7.75–7.83 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 22.5, 26.6, 30.0, 33.1, 52.9, 122.9,
127.4, 130.0, 132.5, 166.9. m/z: 363 (M+). Exact mass determination: 363.1242 (calcd C19H26NOBr:
363.1198).
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1
10g: 86% yield. IR ν
cm−1: 1630 (amide), 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ:
max
4.12–4.18 (m, 2H, CH2), 4.29–5.32 (m, 2H, CH2), 7.10–7.15 (m, 2H, ArH), 7.20–7.39 (m, 11H, ArH),
7.56–7.58 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 46.6, 50.8, 119.5, 127.5, 127.6. 127.7, 127.8,
128.5, 128.8, 129.0, 130.3, 133.0, 135.8, 169.7. m/z: 379 (M+). Exact mass determination: 379.0619
(calcd C21H18NOBr: 379.0572).
3.4.2. N-(2-Bromobenzyl)pyrrolidine 11a
A solution of 10a (743 mg, 2.93 mmol) in THF (5 ml) was added at 0°C to a 1 M borane–THF
complex solution (15 ml, 15.0 mmol), and the reaction mixture was stirred at reflux for 6 h. Then, after
cooling, a solution of methanol (15 ml) and 10% potassium hydroxide (5 ml) was added. The reaction
mixture was stirred at reflux for a further 1 h. The solution was concentrated in vacuo. It was then diluted
with chloroform and washed with saturated aqueous NaCl. The organic layer was separated, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was subjected to preparative TLC
(ethyl acetate:hexane=1:4) to give 11a (384 mg, 55% yield).
The reduction of N-2-bromobenzamide derivatives 10b–g with a borane–THF complex solution was
carried out using the same procedure as described above to give N-methyl-N-isopropyl- 11b, N-butyl-N-
methyl- 11c, N-cyclohexyl-N-methyl- 11d, N-cyclohexyl-N-isopropyl- 11e, N,N-dicyclohexyl- 11f, or
N,N-dibenzyl-2-bromobenzylamine 11g, respectively.
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1
11a: IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.78–1.82 (m, 4H, (CH2)2),
max
2.57–2.62 (m, 4H, (CH2)2), 3.74 (s, 2H, CH2), 7.05–7.11 (m, 1H, ArH), 7.24–7.27 (m, 1H, ArH),
7.46–7.68 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 23.7, 54.2, 59.5, 124.0, 127.1, 128.0, 130.4,
132.4. m/z: 239 (M+). Exact mass determination: 239.0348 (calcd C11H14NBr: 239.0310).
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1
11b: 78% yield. IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.09 (d, J=6.6 Hz,
max
6H, CH3×2), 2.18 (s, 3H, NCH3), 2.94 (quint, J=6.6 Hz, 1H, CH), 3.59 (s, 3H, NCH3), 7.04–7.10 (m,
1H, ArH), 7.23–7.29 (m, 1H, ArH), 7.47–7.52 (m, 2H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 18.0,
36.7, 53.8, 57.1, 127.1, 128.0, 130.6, 132.5, 139.3. m/z: 241 (M+). Exact mass determination: 241.0426
(calcd C11H16NBr: 241.0466).
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1
11c: 90% yield. IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 0.88–0.93 (m, 3H,
max

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
CH3), 1.21–1.39 (m, 2H, CH2), 1.41–1.57 (m, 2H, CH2), 2.22 (s, 3H, NCH3), 2.40–2.46 (m, 2H, NCH2),
3.56 (s, 2H, CH2), 7.05–7.29 (m, 1H, ArH), 7.24–7.29 (m, 1H, ArH), 7.45–7.53 (m, 2H, ArH). 13C-NMR
(67.8 MHz; CDCl3) δ: 14.1, 20.6, 29.6, 42.3, 57.8, 61.5, 127.2, 128.2, 130.8, 132.6. m/z: 255 (M+). Exact
mass determination: 255.0601 (calcd C12H18NBr: 255.0623).
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1
11d: 81% yield. IR ν
cm−1: 1595 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.05–1.39 (m, 6H,
max
(CH2)3), 1.79–1.98 (m, 4H, (CH2)2), 2.23 (s, 3H, NCH3), 2.42–2.51 (m, 1H, CH), 3.65 (s, 2H, CH2),
7.04–7.10 (m, 1H, ArH), 7.23–7.29 (m, 1H, ArH), 7.47–7.52 (m, 2H, ArH). 13C-NMR (67.8 MHz;
CDCl3) δ: 26.1, 26.4, 28.8, 37.6, 57.5, 63.1, 127.1, 128.0, 130.6, 132.5. m/z: 281 (M+). Exact mass
determination: 281.0743 (calcd C14H20NBr: 281.0779).
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1
11e: 81% yield. IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.02 (d, J=6.6 Hz,
max
6H, CH3×2), 1.18–1.26 (m, 6H, (CH2)3, 1.43–1.81 (m, 4H, (CH2)2), 2.47–2.55 (m, 1H, CH), 3.08 (quint,
J=6.6 Hz, 1H, CH), 3.72 (s, 2H, CH2), 7.00–7.06 (m, 1H, ArH), 7.22–7.28 (m, 1H, ArH), 7.45 (dd, J=7.9,
1.2 Hz, 1H, ArH), 7.68–7.71 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.0, 26.3, 31.7, 48.7, 49.6,
58.3, 126.9, 127.4, 130.1, 132.0. m/z: 309 (M+). Exact mass determination: 309.1058 (calcd C16H24NBr:
309.1092).
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1
11f: 90% yield. IR ν
cm−1: 1590 (aromatic). H-NMR (270 MHz; CDCl3) δ: 1.02–1.77 (m, 20H,
max
(CH2)5×2), 2.52–2.59 (m, 2H, CH×2), 3.77 (s, 2H, CH2), 7.00–7.06 (m, 1H, ArH), 7.22–7.28 (m, 1H,
ArH), 7.43–7.47 (m, 1H, ArH), 7.69–7.72 (m, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 26.2, 26.4,
31.9, 50.3, 58.4, 126.9, 127.4, 130.1, 132.0. m/z: 349 (M+). Exact mass determination: 349.1406 (calcd
C19H28NBr: 349.1405).
11g: 78% yield. IR νmfilamx cm−1: 1600 (aromatic). 1H-NMR (270 MHz; CDCl3) δ: 3.60 (s, 4H, CH2×2),
3.68 (s, 2H, CH2), 7.06–7.19 (m, 1H, ArH), 7.21–7.50 (m, 12H, ArH), 7.69–7.73 (m, 1H, ArH). 13C-
NMR (67.8 MHz; CDCl3) δ: 57.3, 58.2, 124.2, 126.7, 126.8, 128.1, 128.6, 128.1, 128.6, 130.3, 132.5.
m/z: 365 (M+). Exact mass determination: 365.0774 (calcd C21H20NBr: 365.0779).
3.4.3. (S)-2-(Pyrrolidinomethyl)phenyl p-tolyl sulfoxide 12a
A 1.04 M cyclopentane solution of sec-butyllithium (0.5 ml, 0.50 mmol) was added at −78°C to a
solution of N-(2-bromobenzyl)pyrrolidine 11a (100 mg, 0.42 mmol) in THF (3 ml), and the reaction
mixture was stirred at −78°C for 1 h. A solution of (−)-menthyl (S)-p-toluenesulfinate (147 mg, 0.50
mmol) in THF (3 ml) was added to the above solution, and the mixture was stirred at 0°C for 6 h. The
reaction solution was diluted with ether and the solution was washed with saturated aqueous NH4Cl and
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ether:hexane=3:1) to give (S)-12a (87 mg, 70% yield).
The sulfinylations of N-isopropyl-N-methyl-2-bromobenzylamine 11b, N-butyl-N-methyl-2-
bromobenzylamine 11c, N-cyclohexyl-N-methyl-2-bromobenzylamine 11d, N-cyclohexyl-N-
isopropyl-2-bromobenzylamine 11e, N,N-dicyclohexyl-2-bromobenzylamine 11f, N,N-dibenzyl-
2-bromobenzylamine 11g were carried out using the same procedure as described above to give
(S)-2-(N-isopropyl-N-methyl-, (S)-2-(N-butyl-N-methyl-, (S)-2-(N-cyclohexyl-N-methyl-, (S)-2-(N-
cyclohexyl-N-isopropyl-, (S)-2-(N,N-dicyclohexyl-, or (S)-2-(N,N-dibenzylaminomethyl)phenyl p-tolyl
sulfoxide 12b–g, respectively.
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(S)-12a: [α]D −109 (c=4.7, acetone). IR ν
cm−1: 1590 (aromatic), 1030 (S_O). H-NMR (270
max
MHz; CDCl3) δ: 1.61–1.71 (m, 4H, (CH2)2), 2.28–2.49 (m, 4H, N(CH2)2), 2.35 (s, 3H, C6H4CH3), 3.33
(d, J=13.2 Hz, 1H, NCH), 3.87 (d, J=13.2 Hz, 1H, NCH), 7.18–7.53 (m, 7H, ArH), 8.03–8.07 (m, 1H,
ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3, 23.4, 53.2, 57.5, 128.3, 128.9, 129.5, 130.4. m/z: 299 (M+).
Exact mass determination: 299.1344 (calcd C18H21NOS: 299.1351).
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1
(S)-12b: 41% yield. [α]D −124 (c=3.9, acetone). IR ν
cm−1: 1590 (aromatic), 1030 (S_O). H-
max

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3815
NMR (270 MHz; CDCl3) δ: 0.99 (d, J=2.5 Hz, 3H, CH3), 1.01 (d, J=2.3 Hz, 3H, CH3), 1.96 (s, 3H,
NCH3), 2.35 (s, 3H, C6H4CH3), 2.88 (quint, J=7 Hz, 1H, CH(CH3)2), 3.37 (d, J=13.4, 1H, CH), 3.80 (d,
J=13.4, 1H, CH), 7.37 (AB system, J=8.3 Hz, 4H, C6H4), 7.32–7.47 (m, 3H, ArH), 7.94–7.97 (m, 1H,
ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 17.3, 21.3, 34.7, 52.9, 55.7, 125.7, 125.9, 129.5, 129.6, 130.4.
m/z: 301 (M+). Exact mass determination: 301.1501 (calcd C18H23NOS: 301.1477).
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(S)-12c: 11% yield. [α]D −109 (c=1.7, acetone). IR ν
cm−1: 1590 (aromatic), 1035 (S_O). H-
max
NMR (270 MHz; CDCl3) δ: 0.87 (m, 3H, (CH2)3CH3), 1.18–1.53 (m, 4H, CH2(CH2)2CH3), 2.03 (s, 3H,
NCH3), 2.28–2.34 (m, 2H, NCH2 (CH2)2)2, 2.35 (s, 3H, C6H4CH3), 3.28 (d, J=13.4 Hz, 1H, CH), 3.75
(d, J=13.4 Hz, 1H, CH), 7.37 (AB system, J=8.1 Hz, 4H, C6H4), 7.31–7.51 (m, 3H, ArH), 7.97–8.00 (m,
1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 14.0, 20.6, 21.3, 28.8, 41.1, 57.1, 59.4, 125.6, 126.0, 128.5,
129.6, 130.5. m/z: 425 (M+). Exact mass determination: 425. 1788 (calcd C28H27NOS: 425.1813).
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(S)-12d: 64% yield. [α]D −121 (c=8.6, acetone). IR ν
cm−1: 1590 (aromatic), 1030 (S_O). H-
max
NMR (270 MHz; CDCl3) δ: 1.12–1.25 (m, 6H, (CH2)3), 1.75–1.78 (m, 4H, CH(CH2)2), 2.02 (s, 3H,
NCH3), 2.34 (s, 3H, C6H4CH3), 2.39–2.43 (m, 3H, NCH3), 3.44, (d, J=13.5 Hz, 1H, CH), 3.88 (d,
J=13.5 Hz, 1H, CH), 7.37 (AB system, J=8.2 Hz, 4H, C6H4), 7.34–7.42 (m, 3H, ArH), 7.90–7.93 (m,
1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.2, 25.9, 26.2, 28.1, 35.8, 55.7, 62.5, 125.6, 125.7, 128.3,
129.4, 129.5, 130.4. m/z: 341 (M+). Exact mass determination: 341.1813 (calcd C21H27NOS: 341.1800).
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1
(S)-12e: 93% yield. [α]D −27 (c=10.3, acetone). IR ν
cm−1: 1590 (aromatic), 1035 (S_O). H-
max
NMR (270 MHz; CDCl3) δ: 0.93 (d, J=6.6 Hz, 3H, CH3), 0.96 (d, J=6.4 Hz, 3H, CH3), 1.00–1.26
(m, 6H, (CH2)3), 1.43–1.76 (m, 4H, CH(CH2)2), 2.36 (s, 3H, C6H4CH3), 2.98 (quint, J=6.6 Hz, 1H,
CH(CH3)), 3.52 (d, J=16.0 Hz, 1H, CH), 3.58 (d, J=16.0 Hz, 1H, CH), 7.36 (AB system, J=8.2 Hz, 4H,
C6H4), 7.40–7.43 (m, 2H, ArH), 7.71 (dd, J=5.4, 5.6 Hz, 1H, ArH), 7.95 (dd, J=5.7, 3.6 Hz, 1H, ArH).
13C-NMR (67.8 MHz; CDCl3) δ: 20.1, 21.3, 31.0, 32.0, 45.4, 48.2, 57.7, 124.2, 126.1, 127.4, 128.9,
129.8, 130.6. m/z: 369 (M+). Exact mass determination: 369.2126 (calcd C23H31NOS: 369.2093).
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(S)-12f: 57% yield. [α]D −19 (c=2.4, acetone). IR ν
cm−1: 1590 (aromatic), 1025 (S_O). H-
max
NMR (270 MHz; CDCl3) δ: 0.94–1.25 (m, 12H, (CH2)3×2), 1.52–1.75 (m, 8H, NCH(CH2)2×2), 2.35
(s, 3H, C6H4CH3), 2.38–2.59 (m, 2H, NCH×2), 3.56, (d, J=16.0 Hz, 1H, CH), 3.89 (d, J=16.0 Hz, 1H,
CH), 7.36 (AB system, J=8.2 Hz, 4H, C6H4). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3, 26.1, 26.2, 26.3,
31.3, 31.6, 46.0, 57.9, 124.2, 126.2, 127.3, 128.9, 129.8, 130.6. m/z: 409 (M+). Exact mass determination:
409.2439 (calcd C26H35NOS: 409.2462).
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(S)-12g: 54% yield. [α]D −48 (c=5.2, acetone). IR ν
cm−1: 1590 (aromatic), 1030 (S_O). H-
max
NMR (270 MHz; CDCl3) δ: 2.34 (s, 3H, C6H4CH3), 3.39–3.73 (m, 6H, N(CH2)3), 7.24 (AB system,
4H, J=8.4 Hz, C6H4), 7.20–7.34 (m, 12H, C6H5×2), 7.67–7.70 (m, 1H, ArH), 7.96–7.99 (m, 1H, ArH).
13C-NMR (67.8 MHz; CDCl3) δ: 21.4, 54.0, 57.9, 124.6, 126.1, 127.1, 128.3, 128.9, 129.7, 129.9, 130.9,
137.7, 138.6. m/z: 425 (M+). Exact mass determination: 425.1788 (calcd C28H27NOS: 425.1813).
3.5. Synthesis of chiral 2-(p-toluenesulfinyl)benzenesulfonamide derivatives
3.5.1. N-Cyclohexyl-N-isopropyl-2-bromobenzenesulfonamide 14
A solution of 2-bromobenzenesulfonyl chloride 13 (500 mg, 1.96 mmol) in dichloromethane (5 ml)
was added to a solution of N-isopropylcyclohexylamine (332 mg, 2.35 mmol) and pyridine (393 mg)
in dichloromethane (5 ml) at 0°C, and the reaction mixture was stirred at room temperature for 6 h.
The reaction solution was diluted with ether, and washed with saturated aqueous NaHCO3 and saturated
aqueous NaCl. The ethereal layers were combined, dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was subjected to preparative TLC (ether:hexane=1:1) to give 14 (334 mg, 48%
yield).

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K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
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14: IR ν
cm−1: 1590 (aromatic), 1325, 1160 (SO2N). H-NMR (270 MHz; CDCl3) δ: 1.05–1.23
max
(m, 2H, CH2), 1.29 (d, J=6.9 Hz, 6H, CH3×2), 1.51–1.84 (m, 8H, (CH2)4), 3.44–3.55 (m, 1H, CH), 3.91
(quint, J=6.9 Hz, 1H, CH), 7.27–7.48 (m, 2H, ArH), 7.70 (dd, J=7.7, 1.5 Hz, 1H, ArH), 8.14–8.17 (m,
1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 22.5, 25.3, 26.6, 32.9, 49.7, 58.2, 120.1, 127.4, 131.9, 133.0,
135.6. m/z: 359 (M+). Exact mass determination: 359.0576 (calcd C15H22NO2SBr: 359.0555).
3.5.2. (S)-N-Cyclohexyl-N-isopropyl-2-(p-toluenesulfinyl)benzenesulfonamide 15
The reaction was carried out using the same procedure as described in Section 3.3.8.
(S)-15: 60% yield. [α]D −109 (c=4.3, CHCl3). IR νmfilamx cm−1: 1590 (aromatic), 1150 (SO2), 1040
1
(S_O). H-NMR (270 MHz; CDCl3) δ: 1.15–1.85 (m, 10H, (CH2)5), 1.26 (dd, J=6.8 Hz, 6H,
CH(CH3)2), 2.32 (s, 3H, C6H4CH3), 3.26–3.36 (m, 1H, NCH(C5H10)), 3.76 (quint, J=6.8 Hz, 1H,
CH(CH3)2), 7.20 (d, J=7.9 Hz, 2H, ArH), 7.54–7.75 (m, 4H, ArH), 7.89 (d, J=1.3 Hz, 1H, ArH),
8.31 (d, J=1.3 Hz, 1H, ArH). 13C-NMR (67.8 MHz; CDCl3) δ: 21.3, 21.6, 22.6, 25.2, 26.5, 32.0, 32.9,
125.7, 125.8, 129.2, 129.7, 130.9, 133.2. m/z: 419 (M+). Exact mass determination: 419.1584 (calcd
C22H29NO3S2: 419.1589).
3.6. Palladium-catalyzed asymmetric allylations of 2-methylacetoacetate 17 with chiral ligands
3.6.1. General procedure A
A 25 ml two-necked flask equipped with a septem inlet and a magnetic stirring bar, and containing
sodium hydride (50% oil dispersion, 21 mg, 0.34 mmol), was flushed with argon, and maintained under
a positive pressure of argon. A solution of tert-butyl 2-methylacetoacetate 17 (100 mg, 0.58 mmol) in
THF (1 ml) was added at 0°C to the above flask. The mixture was stirred at 0°C for 30 min. Another
25 ml two-necked flask equipped with a septem inlet and a magnetic stirring bar, and containing di-
µ-chlorobis(π-allyl)dipalladium ([PdCl(CH2_CHCH2)]2) (6 mg, 0.02 mmol), was flushed with argon,
and maintained under a positive pressure of argon. A solution of allyl acetate (88 mg, 0.87 mmol) and a
chiral ligand (R)-2a–c, 5a–h, or (S)-8a,b (0.07 mmol) in THF (2 ml) was added at room temperature to
the above solution and the mixture was stirred at room temperature for 1 h. The solution was added to the
above solution including sodium enolate of 17, and the reaction mixture was stirred under the conditions
listed in Tables 2–4. The reaction solution was diluted with ether, and the solution was washed with
saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude product was subjected to preparative TLC (ether:hexane=1:2) to give optically active
tert-butyl 2-allyl-2-methylacetoacetate 18.17 The results obtained are listed in Tables 2–4.
3.6.2. General procedure B
A solution of a chiral ligand (S)-8a–g, 12a–g, or 15 (0.038 mmol) and [PdCl(π-allyl)]2 (7 mg, 0.019
mmol) in THF (1 ml) was stirred under argon for 1 h, then a solution of racemic (E)-1,3-diphenyl-2-
propenyl acetate 18 (80 mg, 0.32 mmol) in THF (1 ml) was added. To the mixture was added dropwise
a solution of sodium dimethyl malonate in THF (3 ml), generated by treating dimethyl malonate (51
mg, 0.39 mmol) with NaH (50% oil dispersion, 18 mg, 0.38 mmol). After stirring at 50°C under
argon for 20–48 h, the reaction mixture was diluted with ether. The organic layer was washed with
saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude product was subjected to preparative TLC (ethyl acetate:hexane=1:7) to give (S)-
(1,3-diphenyl-2-propenyl)propanedioate 19.19 The e.e. and the absolute configuration of the product 19
were determined by HPLC analysis with a chiral column, Chiralpak AD (hexane:i-propanol=20:1). The
results obtained are listed in Tables 5 and 6.

K. Hiroi et al. / Tetrahedron: Asymmetry 9 (1998) 3797–3817
3817
Acknowledgements
The present work was supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
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