N-Phosphano nitrogen-containing five-membered aromatic chiral α-sulfoxides as new chiral ligands in asymmetric palladium-catalyzed allylic alkylation: Stereoelectronic effects of the substituents on the aromatic rings

Article abstract of DOI:10.1016/j.tet.2003.12.067

New chiral ligands, N-diphenylphosphano nitrogen-containing five-membered aromatic compounds bearing chiral sulfinyl groups as the sole chiral source has been developed. The structure of a palladium intermediate derived from the new chiral sulfoxide ligand was determined as a palladium complex with a five-membered chelate ring formed by coordination of the phosphano group and the sulfinyl sulfur atom involved. The stereoelectronic effects of substituents on the aromatic rings are discussed.

Full text of DOI:10.1016/j.tet.2003.12.067

Tetrahedron 60 (2004) 2155–2162
N-Phosphano nitrogen-containing five-membered aromatic chiral
a-sulfoxides as new chiral ligands in asymmetric palladium-
catalyzed allylic alkylation: stereoelectronic effects of the
substituents on the aromatic rings
a,*
a
Kunio Hiroi, Ikuo Izawa, Toshiya Takizawa and Ken-ichi Kawai
a
b
a
Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai,
Miyagi 981-8558, Japan
Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
b
Received 4 November 2003; accepted 17 December 2003
Abstract—New chiral ligands, N-diphenylphosphano nitrogen-containing five-membered aromatic compounds bearing chiral sulfinyl
groups as the sole chiral source has been developed. The structure of a palladium intermediate derived from the new chiral sulfoxide ligand
was determined as a palladium complex with a five-membered chelate ring formed by coordination of the phosphano group and the sulfinyl
sulfur atom involved. The stereoelectronic effects of substituents on the aromatic rings are discussed.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
sulfur or oxygen atoms in the chiral sulfoxides to metal
catalysts. In the protocol of our plan, we employed pyrrole
or indole skeletons as main frameworks of ligands for the
conformational fixation, in which chiral sulfinyl groups
were incorporated at the 2 or 7 positions, resultantly
providing five- or six-membered chelates 2 and 3 by
coordination of phosphano groups. We will discuss
sterically and, or electronically the effects of substituents
introduced on the skeletons (Scheme 1).
Catalytic asymmetric synthesis has attracted much attention
in recent years for the efficient preparation of optically
active compounds, particularly for a facile entry to chiral
biologically active compounds and chiral pharmaceuticals.
A number of asymmetric synthetic methodologies for
1
2
carbon–carbon bond formation have been developed, and
various types of chiral ligands for the catalytic asymmetric
synthesis have been devised so far, by utilizing chiral
amines, amides, alcohols, phophines, biaryls with axial
chirality, and so on. However, hitherto few precedents of
4
chiral sulfoxide ligands have appeared.
On these lines, we have developed novel chiral sulfoxide
ligands consisting of N-phosphano nitrogen-containing five-
membered aromatics, and demonstrate the usefulness of the
ligands in terms of reactivity of the catalysts with the
ligands and the resultant enantioselectivity.
3
Quite recently, we have developed novel several chiral
sulfoxide ligands which are useful for transition metal-
catalyzed asymmetric carbon–carbon bond formation.
5
2. Results and discussion
For further development of new chiral ligands possessing
chiral sulfinyl groups as sole chiral sources, we have utilized
phosphanoamino groups as other coordination sites besides
chiral sulfinyl groups. In these cases, the formation of
several chelates 1a–d will be possible by coordination of
nitrogen or phosphano groups in the phosphanoamines and
2.1. Synthesis of chiral pyrrolyl and indolyl sulfoxide
ligands
Novel chiral N-phosphanopyrrolyl and -indolyl aryl sulf-
oxides were prepared as follows. a-Sulfinylation of N-t-
6
butoxycarbonylpyrroles 4a,b and indoles 8a–d with
7
(
2)-menthyl (S)-p-toluene-, 1-naphthalene-, or 2-meth-
Keywords: Asymmetric synthesis; Palladium and compounds; Alkylation;
Indoles; Pyrroles; Sulfoxides.
8
oxy-1-naphthalenesulfinates (5a–c) was carried out at
278 8C in THF for 24 h using lithium diisopropylamide to
give the corresponding a-sulfinylated pyrroles (S)-6a–d
*
Corresponding author. Tel.: þ81-22-234-4181x2531; fax: þ81-22-275-
2
013; e-mail address: khiroi@tohoku-pharm.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.067

2156
K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
Scheme 1.
and indoles (S)-9a–e. Upon treatment with n-butyllithium
followed by the reaction with chlorodiphenylphosphane,
catalysts with the ligands and the resultant enantioselec-
tivity. Introduction of two methyl groups at the 3- and
5-positions of the pyrrole ring in (S)-7c improved
dramatically the chemical yield and the e.e. of the products;
the palladium-catalyzed reaction of (^)-14 with sodium
malonate using (S)-7d as a ligand in THF at 220, 245, or
278 8C for 2, 7, or 20 h gave (S)-15 with 65, 80, or 83% e.e.
in excellent yields (97 and 96%), respectively, although in a
little lower chemical yield (32%) at 278 8C.
(
(
S)-6a–d and (S)-9a–e were converted into (S)-7a–d and
S)-10a–e, respectively.
9
Sulfinylation of 7-bromoindole (11) (derived from 2-
bromonitrobenzene upon treatment with vinylmagnesium
bromide) with (Ss)-5c using n-butyllithium followed by
N-phosphanation of (R)-12 with chlorodiphenylphosphane
gave (R)-13 (Scheme 2).
In the case of indole systems the substituents at the
5-positions of the indole rings in 10a,b were marginally
effective for the reactivity. Introduction of electron-donat-
ing groups (methoxy group) at the 5-positions of the indoles
improved electronically the reactivity to provide slightly
higher chemical yield (87–90%) with a little lower
enantioselectivity, as shown in Table 1, in comparison
with those by (S)-10a. Introduction of a methyl group at the
2.2. Palladium-catalyzed asymmetric reactions with
chiral sulfoxide ligands
The effects of the new chiral sulfoxide ligands thus obtained
were studied in the palladium-catalyzed asymmetric
alkylation of (^)-14 with dimethyl malonate. The reactions
of (^)-14 with sodium dimethyl malonate (generated by
treating with sodium hydride) were carried out in THF at
C position, however, was not so effective in achieving high
5
2
78 8C in the presence of [PdCl(p-allyl)] (0.03 equiv.) and
2
efficiency in terms of the chemical yield and the enantio-
selectivity, providing a slightly lower chemical yield of
(S)-15 with slightly lower e.e.
a chiral ligand (S)-7a–c (0.06 equiv.) to give (S)-15 with
moderate e.e. Incorporation of a methoxy group at the C2
position of the naphthalene ring in the sulfoxide provided
high enantioselectivity of (S)-15, presumably due to steric
effects of the methoxy substituent. The highest e.e. (74 and
Introduction of a methyl group at the 3-position of the
indole ring ((S)-10e) provided the highest enantioselectivity
(93%) of (S)-15, presumably owing to the steric control in
the conformational equilibrium of the vicinal chiral sulfinyl
group.
8
2
3%) of (S)-15 was obtained with (S)-7c at 245 and
78 8C, respectively, although in a little lower chemical
yield (Scheme 3).
The replacement of the pyrrole skeleton in (S)-7 with an
indolyl function ((S)-10) in the chiral sulfoxide ligands
provided a similar stereochemical result. The reaction of
Interestingly, the existence of a methoxy group on the
naphthalene ring in the sulfinyl groups of (S)-10c was also
highly effective in achieving high enantioselectivity and
chemical yield, in contrast with those by (S)-10d.
(
^)-14 with sodium malonate in THF at 0, 220, or 245 8C
using (S)-10a gave (S)-15 with 56, 60, or 73% e.e.,
respectively, in high yield (81–92%); similarly the reaction
in DME at the same temperature afforded (S)-15 with 59, 65,
or 73% e.e., respectively, in high yield (83–94%).
Use of another indolyl sulfoxide (R)-13 as a ligand provided
(S)-15 in 76% yield with a slightly lower enantioselectivity,
as listed in Table 1.
Unambiguous effects of electron-donating groups on the
pyrrole and indole rings of the chiral ligands were observed,
resulting in remarkable improvement of the reactivity of the
The molecular structure of the chiral sulfoxide ligand
((S)-10a)-palladium [PdCl ·(CH CN) ] complex was
determined as a five-membered chelate 16 formed by
2
3
2

K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
2157
Scheme 2.
coordination of the sulfinyl sulfur atom and the phosphano
group to the palladium catalyst, as shown in Figure 1, by the
X-ray crystallographic analysis. In comparison with a
palladium complex of (S)-2-(diphenylphosphano)phenyl
5
f
2-methoxy-1-naphthyl sulfoxide reported by us previously,
the molecular structure indicates that the bond lengths
Figure 1. Crystallographic data (ORTEP drawing) for (S)-16. Selected bond
˚
distance (A) and angles (deg): Pd(1)–S(1) 2.229(4), Pd(1)–P(1) 2.222(4),
Pd(1)–Cl(1) 2.338(4) Pd(1)–Cl(2) 2.299(4), N(1)–P(1) 1.716(12), S(1)–
C(1) 1.716(12) S(1)–Pd(1)–P(1) 88.85(14), S(1)–Pd(1)–Cl(1) 89.42(14).
Scheme 3.

2158
K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
a
Table 1. Palladium-catalyzed asymmetric alkylations of 14 using chiral ligands (S)-7, (S)-10, and (R)-13
Ligand
Solvent
Reaction temp.
Reaction time
(h)
Yield (%) of
(S)-15
e.e. (%) of
b
(S)-15
(8C)
(
S)-7a
THF
THF
THF
THF
THF
THF
THF
DME
DME
THF
THF
THF
THF
THF
THF
DME
DME
DME
THF
THF
THF
DME
DME
DME
THF
THF
THF
THF
THF
DME
DME
DME
THF
THF
THF
THF
THF
0
3
24
8
1
4
8
23
2
7
2
76
72
89
70
78
40
7
17
24
29
45
53
74
83
40
55
65
80
83
56
60
73
59
65
73
52
55
65
56
61
65
57
61
31
32
36
37
36
48
74
82
93
32
41
220
220
0
220
240
278
0
220
220
245
278
0
220
245
0
220
245
0
220
245
0
220
245
220
245
0
220
245
0
(
(
S)-7b
S)-7c
68
53
97
96
32
92
92
81
94
91
83
91
81
43
79
72
61
90
87
88
57
29
82
45
32
93
83
68
93
76
(
(
S)-7d
7
20
80
4
21
80
4
21
13
13
21
13
13
21
2
S)-10a
(
S)-10b
(
(
S)-10c
S)-10d
8
3
14
14
3
14
18
10
16
24
2
220
245
220
245
278
220
245
(
(
S)-10e
R)-13
16
a
The reactions of 14 with carbanion of dimethyl malonate (generated by treating with NaH (2.0 equiv.) were carried out in THF or DME in the presence of
PdCl(p-allyl)] (0.03 equiv.) and a chiral ligand (S)-7, (S)-10, or (R)-13 (0.06 equiv.).
The enantiomeric excess (e.e.) of (S)-15 was determined by the HPLC analysis with Chiralpak AD.
[
2
b
between the nitrogen-phosphane and the sulfur-aromatic
1
dimethyl malonate) attacks the g-carbon in the allyl
terminus of 17b trans to the better p-accepting atom,
which is the phosphano group in the present case, giving
(S)-15. The remarkable increase in enantioselectivity by the
2-methoxy-1-naphthyl sulfoxide (S)-7c and (S)-10c over
that by (S)-7b and (S)-10d is rationalized presumably by the
planar fixation of the conformation of the aromatic carbon–
sulfur bond in the intermediate ascribed to the dipole–
dipole repulsion between the sulfinyl S–O bond and the
methoxy group.
carbon atoms are slightly shorter, and the Pd–Cl bond
2
length is a little longer, compared with the Pd–Cl bond,
owing to the electronic (p-accepting) effects of the
phosphorus atom; however, the bond angles between the
Pd–P–N and the Pd–S–C are very similar to those in
the 2-(diphenylphosphano)phenyl sulfoxide–palladium
complex.
2.3. The mechanism for the asymmetric induction with
chiral N-phosphano pyrrolyl and indolyl sulfoxides as
chiral ligands
A six-membered palladium complex 18 formed by
coordination of the sulfinyl sulfur atom and the
phosphano group in (R)-13 provided slightly lower
enantioselectivity in the allylic alkylations, presumably
due to the less effective steric environment involved in
the complex (Scheme 4).
The mechanism of the asymmetric induction in these
asymmetric alkylations with new chiral ligands is rational-
ized on the basis of the stereochemical results and the
molecular structure of the intermediary palladium complex
as follows. In the conformational equilibrium of p-allyl-
palladium complexes derived from the intermediary palla-
dium-chiral ligand complexes, an M-typed p-allyl
intermediate 17b is sterically preferred to W-typed 17a
because of the existence of steric interference between the
aryl substituent on the sulfinyl group and the phenyl of the
g-allyl system in 17a. The nucleophile (the carbanion of
3. Conclusion
Thus, evidently it should be concluded that these novel
chiral sulfoxide ligands developed by us are very useful
as chiral ligands in palladium-catalyzed asymmetric

K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
2159
Scheme 4.
alkylation, and the introduction of the electron-donating
substituents on the aromatic rings enables us to improve
remarkably the reactivity of the intermediary complexes and
the enantioselectivity by the stereoelectronic effects. Our
present work is one of the most useful asymmetric synthetic
methods with high efficiency using chiral sulfoxides as the
sole chiral sources in the ligands, involving studies on the
stereoelectronic effects of the substituents on the pyrrole and
indole skeletons and the structural determination of an
intermediary palladium complex with a chiral b-phosphano
sulfoxide.
(607 mg, 6.0 mmol) in THF (10 ml) was added to the flask.
A 1.56 M butyllithium solution in hexane (4.0 ml,
6.0 mmol) was added to the above solution at 278 8C and
the mixture was stirred at the same temperature for 30 min.
A solution of tert-butyl 1-pyrrolecarboxylate (4a) (1.0 g,
6.0 mmol) in THF (5 ml) was added to the above solution.
After the mixture had been stirred at 278 8C for 1.5 h, a
solution of (2)-menthyl (S)-p-toluenesulfinate (5a)
(883 mg, 3.0 mmol) in THF (10 ml) was added and the
reaction mixture was further stirred at 278 8C for 24 h.
The reaction solution was diluted with ether, quenched with
a saturated aqueous NH Cl, and washed with a saturated
4
4
. Experimental
aqueous NaCl. The organic layers were combined, dried
over anhydrous Na SO , and concentrated in vacuo. The
2
4
4
.1. General
residual oil was subjected to flash column chromatography
ethyl acetate–hexane 1:1) to give (S)-6a (369 mg, 60%
(
yield).
6
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
The sulfinylations of tert-butyl 2,4-dimethyl-1-pyrrolecar-
boxylate (4b), tert-butyl 1-indolecarboxylate (8a), tert-butyl
5-methyl-1-indolecarboxylate (8b), tert-butyl 5-methoxy-1-
indolecarboxylate (8c), tert-butyl 3-methyl-1-indolecarboxyl-
ate (8d) with (Ss)-5a, (2)-menthyl (S)-1-naphthalenesulfi-
1
a JOEL EX-270 ( H NMR; 270 MHz) high-resolution NMR
spectrometer; chemical shifts are given in ppm from
tetramethylsilane as an internal standard. Splitting patterns
are designated as s, singlet; d, doublet; dd, doublet of
doublets; m, multiplet. Mass spectra were taken on a JOEL
JMS-DX 303/JMA-DA 5000 system. High performance
liquid chromatography (HPLC) was performed with a
Tosoh UV-8010 CCPM (column: Dicel Chiralpak AD
nate
(5b)
or
(2)-menthyl
(S)-2-methoxy-1-
naphthalenesulfinate (5c) were carried out in the same
way as described above to give (S)-2-pyrrolyl 1-naphthyl
sulfoxide (6b), (S)-2-pyrrolyl 2-methoxy-1-naphthyl sulf-
oxide (6c), (S)-3,5-dimethyl-2-pyrrolyl 2-methoxy-1-
naphthyl sulfoxide (6d), (S)-2-indolyl 2-methoxy-
1-naphthyl sulfoxide (9a), (S)-5-methyl-2-indolyl 2-meth-
oxy-1-naphthyl sulfoxide (9b), (S)-5-methoxy-2-indolyl
2-methoxy-1-naphthyl sulfoxide (9c), (S)-5-methoxy-2-
indolyl 1-naphthyl sulfoxide (9d), and (S)-3-methyl-2-
indolyl 2-methoxy-1-naphthyl sulfoxide (9e), respectively.
(
hexane/i-PrOH 20:1), 0.5 ml/min, 254 nm). Optical
rotations were measured at 24 8C with a JASCO DIP-370
polarimeter. X-ray diffraction analysis was carried out on a
Rigaku RAXIS-IV diffractometer. Flash column chroma-
tography 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 8C for 3.5 h.
4
.1.2. Compound (S)-6b. Yield 47%. [a] þ472.48 (c¼0.3,
D
film
21
4
.1.1. (S)-2-Pyrrolyl p-tolyl sulfoxide (6a). A 100 ml two-
CHCl ). IR nmax cm : 3227, 3020, 1418, (pyrrole), 1016
3
(sulfoxide). H NMR (270 MHz, CDCl ) d: 6.16–6.19 (1H,
3
1
necked flask equipped with a septum inlet and magnetic
stirring bar was flushed with argon, and maintained under a
positive pressure of argon. A solution of diisopropylamine
m, Ar-H), 6.65–6.68 (1H, m, Ar-H), 6.82–6.86 (1H, m,
Ar-H), 7.45–8.01 (6H, m, Ar-H), 8.35 (1H, dd, J¼1.2,

2160
K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
þ
mass determination: 241.0558 (calcd for C H NOS:
6
.1 Hz, Ar-H), 8.92 (1H, s, NH). MS m/z 241 (M ). Exact
7.80 (1H, d, J¼8.2 Hz, Ar-H), 7.98 (1H, d, J¼9.0 Hz,
Ar-H), 8.86 (1H, d, J¼8.0 Hz, Ar-H), 9.11 (1H, s, NH). MS
1
4 11
þ
for C H NO S: 335.0980).
2
41.0561).
m/z 335 (M ). Exact mass determination: 335.0961 (calcd
2
0
17
2
4
CHCl ). IR n
.1.3. Compound (S)-6c. Yield 37%. [a] þ86.58 (c¼2.5,
D
film
21
cm : 3447, 3018, 1431, (pyrrole), 1026
max
4.1.10. (S)-N-(Diphenylphosphano)-2-pyrrolyl p-tolyl
sulfoxide (7a). A 25 ml two-necked flask equipped with a
septum inlet and a magnetic stirring bar was flushed with
argon, and maintained under a positive pressure of argon.
3
1
(
s, –OCH ), 6.15–6.18 (1H, m, Ar-H), 6.39–6.42 (1H, m,
sulfoxide). H NMR (270 MHz, CDCl ) d: 4.07 (3H,
3
3
Ar-H), 6.94–6.97 (1H, m, Ar-H), 7.25–7.57 (3H, m, Ar-H),
7
.79–7.98 (2H, m, Ar-H), 8.80 (1H, dd, J¼0.9, 7.7 Hz, Ar-H),
þ
nation: 271.0693 (calcd for C H NO S: 271.1669).
9
.95 (1H, s, NH). MS m/z 271 (M ). Exact mass determi-
A solution of 6a (369 mg, 1.80 mmol) in THF (10 ml) was
added to the flask. A 1.56 M butyllithium solution in hexane
1
5
13
2
(1.3 ml, 1.98 mmol) was added at 278 8C to the above
4
CHCl ). IR n
.1.4. Compound (S)-6d. Yield 29%. [a] þ46.18 (c¼1.0,
solution and the mixture was stirred at the same temperature
for 45 min. A solution of chlorodiphenylphosphane
(ClPPh ) (477 mg, 2.16 mmol) in THF (5 ml) was added
to the above solution. After the mixture was stirred at the
same temperature for 2 h, the reaction solution was diluted
with ether and filtered through celite. The filtrate was
concentrated in vacuo. The crude product was subjected to
flash column chromatography (ethyl acetate–hexane 2:3) to
give (S)-7a (48 mg, 64% yield).
D
film
21
cm : 3443, 3018, 1431, (pyrrole), 1022
max
3
1
(
CH ), 2.25 (3H, s, CH ), 4.14 (3H, s, –OCH ), 5.72 (1H, d,
sulfoxide). H NMR (270 MHz, CDCl ) d: 2.18 (3H, s,
3
2
3
3
3
J¼2.8 Hz, Ar-H), 7.31–7.95 (5H, m, Ar-H), 8.77 (1H, dd,
þ
J¼0.8, 7.7 Hz, Ar-H), 8.9 (1H, s, NH). MS m/z 299 (M ).
Exact mass determination: 299.0961 (calcd for
C H NO S: 299.0980).
2
0
17
2
4
CHCl ). IR n
.1.5. Compound (S)-9a. Yield 41%. [a] þ245.28 (c¼1.5,
D
film
max
21
cm : 3441, 3016, 1508, 1467 (indole),
The phosphanations of (S)-6b–d, (S)-9a–d, or (R)-12 were
carried out in the same way as described above to give (S)-
N-(diphenylphosphano)-2-pyrrolyl 1-naphthyl sulfoxide
(7b), (S)-N-(diphenylphosphano)-2-pyrrolyl 2-methoxy-1-
naphthyl sulfoxide (7c), (S)-3,5-dimethyl-N-(diphenylphos-
phano)-2-pyrrolyl 2-methoxy-1-naphthyl sulfoxide (7d),
3
1
1
024 (sulfoxide). H NMR (270 MHz, CDCl ) d: 4.04 (3H,
3
s, –OCH ), 6.58 (1H, dd, J¼0.9, 1.1 Hz, Ar-H), 7.04–7.63
3
(7H, m, Ar-H), 7.81–8.02 (2H, m, Ar-H), 8.78–8.81 (1H,
m, Ar-H), 9.43 (1H, s, NH). MS m/z 321 (M ). Exact mass
þ
determination: 321.0780 (calcd for C H NO S:
1
9
15
2
3
21.0824).
(S)-N-(diphenylphosphano)-2-indolyl
2-methoxy-1-
naphthyl sulfoxide (10a), (S)-N-(diphenylphosphano)-5-
methyl-2-indolyl 2-methoxy-1-naphthyl sulfoxide (10b),
(S)-N-(diphenylphosphano)-5-methoxy-2-indolyl 2-meth-
oxy-1-naphthyl sulfoxide (10c), (S)-N-(diphenylphos-
phano)-5-methoxy-2-indolyl 1-naphthyl sulfoxide (10d),
(S)-N-(diphenylphosphano)-3-methyl-2-indolyl 2-meth-
oxy-1-naphthyl sulfoxide (10e), and (R)-N-(diphenylphos-
phano)-7-indolyl 2-methoxy-1-naphthyl sulfoxide (13),
respectively.
4
CHCl ). IR n
.1.6. Compound (S)-9b. Yield 50%. [a] þ40.38 (c¼2.53,
D
film
max
21
cm : 3211, 3011, 2943, 1431 (indole),
3
1
1
022 (sulfoxide). H NMR (270 MHz, CDCl ) d: 2.38 (3H,
3
s, CH ), 4.04 (3H, s, –OCH ), 6.49–6.50 (1H, dd, J¼0.8,
3
3
0
.8 Hz, Ar-H), 7.06 (1H, d, J¼1.2 Hz, Ar-H), 7.26–8.02
(7H, m, Ar-H), 8.80 (1H, d, J¼1.2 Hz, Ar-H), 9.32 (1H, s,
NH). MS m/z 335 (M ). Exact mass determination:
þ
3
35.0978 (calcd for C H NO S: 355.0980).
20 17 2
4
CHCl ). IR n
.1.7. Compound (S)-9c. Yield 35%. [a] þ149.58 (c¼0.9,
4.1.11. Compound (S)-7a. [a] þ41.48 (c¼1.3, CHCl ). IR
D
D
3
film
max
21
film
21
cm : 3443, 3018, 1508, 1467 (indole),
n
cm : 3460, 3053, 1435, (pyrrole), 1045 (sulfoxide).
max
3
1
1
1
026 (sulfoxide). H NMR (270 MHz, CDCl ) d: 3.77 (3H,
3
H NMR (270 MHz, CDCl ) d: 2.32 (3H, s, CH ), 6.25–
3 3
s, –OCH ), 4.02 (3H, s, –OCH ), 6.49 (1H, dd, J¼0.8,
6.28 (1H, m, Ar-H), 6.53–6.56 (1H, m, Ar-H), 6.61–6.64
(1H, m, Ar-H), 7.09–7.51 (14H, m, Ar-H). MS m/z 389
(M ). Exact mass determination: 389.1024 (calcd for
3
3
1.3 Hz, Ar-H), 6.85–6.94 (1H, m, Ar-H), 7.23–8.05 (7H,
m, Ar-H), 8.78–8.81 (1H, m, Ar-H), 9.45 (1H, s, NH). MS
þ
C H NOPS: 389.1003).
þ
for C H NO S: 351.0929).
m/z: 331 (M ). Exact mass determination: 351.0957 (calcd
2
3 20
2
0
17
3
4
.1.12. Compound (S)-7b. Yield 61%. [a] þ272.48
D
film
21
4
CHCl ). IR n
.1.8. Compound (S)-9d. Yield 65%. [a] þ22.98 (c¼2.09,
(c¼0.6, CHCl ). IR n
cm : 3437, 3057, 1435, (pyrrole),
max
D
3
film
max
21
1
cm : 3011, 2856, 1508, 1448 (indole),
1043 (sulfoxide). H NMR (270 MHz, CDCl ) d: 6.11–6.16
3
3
1
1
s, –OCH ), 6.84–6.89 (2H, m, Ar-H), 6.89–6.96 (1H, d,
020 (sulfoxide). H NMR (270 MHz, CDCl ) d: 3.78 (3H,
(2H, m, Ar-H), 6.61–6.63 (1H, m, Ar-H), 7.16–7.70 (14H,
m, Ar-H), 7.83 (1H, d, J¼8.1 Hz, Ar-H), 7.92 (1H, d,
J¼8.1 Hz, Ar-H), 8.40 (1H, d, J¼7.3 Hz, Ar-H). MS m/z
3
3
J¼17.5 Hz, Ar-H), 7.15–7.19 (1H, d, J¼8.9 Hz, Ar-H),
þ
7
.50–8.08 (6H, m, Ar-H), 8.35–8.38 (1H, dd, J¼1.2,
425 (M ). Exact mass determination: 425.0986 (calcd for
þ
mass determination: 321.0820 (calcd for C H NO S:
1
.2 Hz, Ar-H), 8.61 (1H, s, NH). MS m/z: 321 (M ). Exact
C H NOPS: 425.1003).
26 20
1
9
15
2
3
21.0823).
4.1.13. Compound (S)-7c. Yield 60%. [a] þ79.78 (c¼1.3,
D
film
21
CHCl ). IR n
3
cm : 3422, 3059, 1435, (pyrrole), 1026
max
1
4
CHCl ). IR n
.1.9. Compound (S)-9e. Yield 4.6%. [a] þ51.68 (c¼0.6,
(sulfoxide). H NMR (270 MHz, CDCl ) d: 3.74 (3H,
3
D
film
max
21
cm : 1504, 1448 (indole), 1020
sulfoxide). H NMR (270 MHz, CDCl ) d: 2.32 (3H,
s, –OCH ), 6.23–6.26 (1H, m, Ar-H), 6.54–6.57 (1H, m,
3
3
1
(
s, –CH ), 4.05 (3H, s, –OCH ), 7.05–7.62 (7H, m, Ar-H),
Ar-H), 6.61–6.64 (1H, m, Ar-H), 6.86–7.81 (15H, m,
þ
3
Ar-H), 9.08 (1H, d, J¼8.7 Hz, Ar-H). MS m/z 455 (M ).
3
3

K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
2161
Exact mass determination: 455.1138 (calcd for
C H NO PS: 455.1109).
inlet and magnetic stirring bar was flushed with argon, and
maintained under positive pressure of argon. A solution of
2
7
22
2
7-bromoindole (11)9 (294 mg, 1.5 mmol) in THF (10 ml)
4
.1.14. Compound (S)-7d. Yield 46%. [a] þ118.98
was added at 278 8C to the flask. A 1.56 M n-butyllithium
solution in hexane (2.0 ml, 3.0 mmol) was added to the
above solution and the mixture was warmed to 0 8C during
3 h. A solution of (2)-menthyl sulfinate, (Ss)-2c, (360 mg,
1.0 mmol), in THF (5 ml) was added. After the mixture was
stirred at 0 8C for 24 h, the reaction was quenched with a
D
film
21
(
c¼1.2, CHCl ). IR n
cm : 3620, 3020, 1425, (pyrrole),
max
3
1
1
s, CH ), 2.23 (3H, s, CH ), 3.71 (3H, s, –OCH ), 5.90 (1H,
032 (sulfoxide). H NMR (270 MHz, CDCl ) d: 2.18 (3H,
3
3
3
3
s, Ar-H), 6.78–7.66 (15H, m, Ar-H), 9.28–9.31 (1H, m,
Ar-H). MS m/z 483 (M ). Exact mass determination:
4
þ
83.1425 (calcd for C H NO PS: 483.1422).
saturated aqueous NH Cl, and the mixture was diluted with
4
2
9
26
2
ether. The solution was washed with a saturated aqueous
NH Cl and a saturated aqueous NaCl, dried over anhydrous
4
.1.15. Compound (S)-10a. Yield 59%. [a] þ209.68
D
4
film
max
21
(c¼0.9, CHCl ). IR n cm : 3439, 3009, 1508, 1467
(indole), 1026 (sulfoxide). H NMR (270 MHz, CDCl ) d:
Na SO , and concentrated in vacuo. The crude product was
2
3
4
1
subjected to flash column chromatography (ethyl acetate–
hexane 1:1) to give 12 (308 mg, 64% yield).
3
4
.01 (3H, s, –OCH ), 6.57–8.02 (20H, m, Ar-H), 8.80 (1H, d,
3
þ
nation: 505.1302 (calcd for C H NO PS: 505.1266).
J¼9.5 Hz, Ar-H). MS m/z 505 (M ). Exact mass determi-
4.1.22. Compound 12. [a] þ486.48 (c¼0.9, CHCl ). IR
3
1
24
2
D
3
film
max
21
n cm : 3427, 3018, 1508, 1431 (indole), 1022
(sulfoxide). H NMR (270 MHz, CDCl ) d: 3.85 (3H,
1
4
.1.16. Compound (S)-10b. Yield 55%. [a] 255.68
D
3
film
max
21
(
c¼2.05, CHCl ). IR n
cm : 3400, 3053, 2928, 1508,
1
s, –OCH ), 6.56–6.58 (1H, m, Ar-H), 6.86–7.99 (9H, m,
3
3
1
CDCl ) d: 2.33 (3H, s, CH ), 3.77 (3H, s, –OMe), 6.44–
467 (indole), 1026 (sulfoxide). H NMR (270 MHz,
Ar-H), 8.77 (1H, d, J¼8.7 Hz, Ar-H), 10.19 (1H, s, NH).
þ
(calcd for C H NO S: 321.0824).
MS m/z 321 (M ). Exact mass determination: 321.0862
3
3
6
8
.47 (1H, d, J¼8.7 Hz, Ar-H), 6.62–7.70 (18H, m, Ar-H),
2
0
17
2
þ
mass determination: 519.1411 (calcd for C H NO PS:
.90 (1H, d, J¼8.7 Hz, Ar-H). MS m/z 519 (M ). Exact
4.2. Palladium-catalyzed asymmetric nucleophilic
substitution reactions of 1,3-diphenyl-2-propenyl acetate
3
2
26
2
5
19.1422).
(14) with chiral N-(diphenylphosphino) sulfoxide
ligands. General procedure
4
.1.17. Compound (S)-10c. Yield 52%. [a] þ244.68
D
film
max
21
(c¼0.8, CHCl ). IR n cm : 3450, 3018, 1510, 1431
(indole), 1035 (sulfoxide). H NMR (270 MHz, CDCl ) d:
3
1
A 25 ml two-necked flask equipped with a septum inlet and
a magnetic stirring bar, and containing sodium hydride
(60% oil dispersion, 37 mg, 0.912 mmol), was flushed with
argon, and maintained under a positive pressure of argon. A
solution of dimethyl malonate (120 mg, 0.912 mmol) in
THF (2.5 ml) was added at 0 8C to the above flask and
stirred for 15 min. Another 25 ml two-necked flask
equipped with a septum inlet and a magnetic stirring bar,
and containing di-m-chlorobis (p-allyl) dipalladium
[PdCl(CH vCHCH )] (5 mg, 0.014 mmol) and chiral
3
3
.76 (3H, s, –OCH ), 3.78 (3H, s, –OMe), 6.46 (2H, d,
3
J¼1.5 Hz, Ar-H), 6.64–7.70 (17H, m, Ar-H), 8.91–8.94 (1H,
þ
determination:535.1380(calcdfor C H NO PS: 535.1371).
d, J¼8.7 Hz, Ar-H). MS m/z 535 (M ). Exact mass
3
2
26
2
4
.1.18. Compound (S)-10d. Yield 58%. [a] þ104.658
D
film
21
(
(
c¼2.06, CHCl ). IR n
cm : 3055, 3001, 2831, 1431
max
3
1
indole), 1033 (sulfoxide). H NMR (270 MHz, CDCl ) d:
3
3
6
.72 (3H, s, –OCH ), 6.55–6.56 (1H, d, J¼2.5 Hz, Ar-H),
3
2
2 2
.62 (1H, d, J¼0.5 Hz, Ar-H), 6.76 (1H, d, J¼1.8 Hz,
N-(diphenylphosphano) sulfoxide ligands (0.028 mmol)
was flushed with argon, and maintained under a positive
pressure of argon. A solution of (^)-1,3-diphenyl-2-
propenyl acetate (14) (115 mg, 0.456 mmol) in THF
(1 ml) was added at room temperature to the above solution,
and the mixture was stirred at room temperature for 30 min.
The solution was added to the above solution including
sodium dimethyl malonate, and the reaction mixture was
stirred under the conditions listed in Table 1. The reaction
solution was diluted with ether, and the solution was washed
Ar-H), 6.94 (1H, d, J¼2.1 Hz, Ar-H), 7.02–7.90 (16H, m,
Ar-H), 8.12–8.15 (1H, d, J¼8.4 Hz, Ar-H). MS m/z 505
þ
C H NO PS: 505.1265).
(
M ). Exact mass determination: 505.1198 (calcd for
3
1
24
2
4
.1.19. Compound (S)-10e. Yield 17%. [a] þ66.68
D
film
max
21
(c¼1.2, CHCl ). IR n cm : 3177, 2959, 1506, 1450
(indole), 1020 (sulfoxide). H NMR (270 MHz, CDCl ) d:
3
1
3
2
.29 (3H, s, CH ), 3.94 (3H, s, CH ), 7.08–7.63 (13H, m,
3 3
Ar-H), 7.79–7.98 (6H, m, Ar-H), 8.85 (1H, d, J¼8.9 Hz,
with a saturated aqueous NH Cl and a saturated aqueous
4
þ
19.1420 (calcd for C H NO PS: 519.1422).
Ar-H). MS m/z 519 (M ). Exact mass determination:
5
NaCl, dried over anhydrous Na SO , and concentrated in
2
4
vacuo. The crude product was subjected to preparative TLC
ether–hexane 1:4) to give optically active diethyl (1,3-
3
2
26
2
(
1
0
4
CHCl ). IR n
.1.20. Compound 13. Yield 58%. [a] þ9.08 (c¼1.2,
diphenyl-2-propenyl) propanedioate (15). The e.e. of
product was determined by HPLC analysis with Chiralpak
AD (i-PrOH–hexane 1:20, flow rate 0.5 ml/min, retention
time; 28 min (R), 38 min (S)). The results are summarized in
Table 1.
D
film
max
21
cm : 3412, 2988, 1506, 1433 (indole),
3
1
1
s, –OCH ), 6.18–6.25 (2H, m, Ar-H), 6.63–7.72 (17H, m,
024 (sulfoxide). H NMR (270 MHz, CDCl ) d: 3.26 (3H,
3
3
Ar-H), 8.31 (1H, dd, J¼1.0, 6.8 Hz, Ar-H), 8.90–8.94 (1H,
þ
05.1412 (calcd for C H NO PS: 505.1266).
m, Ar-H). MS m/z 505 (M ). Exact mass determination:
5
4.3. Structure determination of Pd-(S)-10a complex (16)
by X-ray diffraction
3
1
24
2
4
(
.1.21. (R)-7-Indolyl 2-methoxy-1-naphthyl sulfoxide
12). A 50 ml two-necked flask equipped with a septum
A reaction mixture of (S)-10a (30 mg, 0.06 mmol) and

2162
K. Hiroi et al. / Tetrahedron 60 (2004) 2155–2162
PdCl ·(CH CN) (18 mg, 0.06 mmol) in EtOH (3 ml) was
2
Seyden-Penne, J. Chiral auxiliaries and ligands in asymmetric
synthesis; Wiley: New York, 1995.
3
2
stirred at room temperature for 15 min. The yellowish
precipitates (16 mg, 40% yield) were collected and
recrystallized from CH Cl –hexane.
4. (a) Allen, J. V.; Bower, J. F.; Williams, J. M. J. Tetrahedron:
Asymmetry 1994, 5, 1895–1898. (b) Tokunoh, R.; Sodeoka,
M.; Aoe, K.; Shibasaki, M. Tetrahedron Lett. 1995, 36, 8035.
(c) Chelucci, G.; Berta, D.; Saba, A. Tetrahedron 1997, 53,
3843–3848.
2
2
A palladium complex (16) with (S)-9a was obtained as
yellow prisms.
5
. (a) Hiroi, K.; Suzuki, Y. Heterocycles 1997, 46, 77–81. (b)
Hiroi, K.; Suzuki, Y.; Abe, I.; Hasegawa, Y.; Suzuki, K.
Tetrahedron: Asymmetry 1998, 9, 3797–3817. (c) Suzuki, Y.;
Abe, I.; Hiroi, K. Heterocycles 1999, 50, 89–94. (d) Hiroi, K.;
Suzuki, Y.; Abe, I. Chem. Lett. 1999, 149–150. (e) Hiroi, K.;
Suzuki, Y. Tetrahedron Lett. 1998, 39, 6499–6502. (f) Hiroi,
K.; Suzuki, Y.; Kawagishi, R. Tetrahedron Lett. 1999, 40,
715–718. (g) Hiroi, K.; Suzuki, Y.; Abe, I. Tetrahedron:
Asymmetry 1999, 10, 1173–1188. (h) Hiroi, K.; Suzuki, Y.;
Abe, I.; Kawagishi, R. Tetrahedron 2000, 56, 4701–4710. (i)
Hiroi, K.; Suzuki, Y.; Kaneko, Y.; Kato, F.; Abe, I.;
Kawagishi, R. Polyhedron 2000, 19, 525–526. (j) Hiroi, K.;
Watanabe, K.; Abe, I.; Koseki, M. Tetrahedron Lett. 2001, 42,
7617–7619. (k) Watanabe, K.; Hirasawa, T.; Hiroi, K. Chem.
Pharm. Bull. 2002, 50, 372–379.
Diffraction intensities were collected from a crystal of
dimensions 0.30£0.15£0.10 mm on a Rigaku AFC-7 FOS
four-circle diffractometer. Of the total 2852 unique reflec-
tions (complete for 2u,136.18, 1895 satisfied the criterion
F.3s (F) and only these were used in the solution and
refinement of the structure. Crystal data C H NO SCl PPd,
1
3
24
2
2
M¼682.88, orthorhombic, space group P2 2 2 , a¼13.263
1
1 1
˚
˚
3
(
7), b¼17.366 (8), c¼12.090 (6) A, V¼2784.7 (2) A , Z¼4,
2
3
Dc¼1.629 g cm , F(000)¼1376, Cu Ka X-radiation
˚
(
graphite monochromator), l¼1.54178 A.
Lists of atomic parameters, bond length, and bond angles
have been deposited to the Cambridge Crystallographic
Data Centre.
6
. (a) Arai, Y.; Masuda, Y.; Masaki, Y. Chem. Lett. 1997, 145.
(b) Arai, Y.; Masuda, Y.; Masaki, Y. J. Chem. Soc., Perkin
Trans. 1 1999, 2165–2170.
References and notes
7. Ordoney, M.; Rosa, V. G.; Labastida, V.; Llera, J. M.
Tetrahedron: Asymmetry 1996, 7, 2675–2686.
1
2
3
. (a) In Catalytic asymmetric synthesis; Ojima, I., Ed.; VCH:
New York, 1993. (b) Noyori, R. Asymmetric catalysis in
organic synthesis; Wiley: New York, 1994.
8. Pyne, S. G.; Hayipour, A.; Prabakaran, K. Tetrahedron Lett.
1994, 35, 645–648.
9. David, R. D.; Jeremy, G.; David, A. L. Synlett 1992, 79–80.
10. (a) Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y.
Tetrahedron Lett. 1986, 27, 191–194. (b) Yamaguchi, M.;
Shima, T.; Yamagishi, T.; Hida, M. Tetrahedron: Asymmetry
1991, 2, 663–666.
. (a) Brunner, H. Synthesis 1988, 645. (b) Blystone, S. L. Chem.
Rev. 1989, 89, 1663. (c) Ojima, I.; Clos, N.; Bastos, C.
Tetrahedron 1989, 45, 6901–6939.
. (a) Sawamura, M.; Ito, Y. Chem. Rev. 1992, 92, 857–871. (b)