New chiral sulfoxide ligands possessing a phosphano or phosphanoamino functionality in palladium-catalyzed asymmetric allylic nucleophilic substitution reactions

Article abstract of DOI:10.1016/S0040-4020(00)00393-8

New chiral sulfoxide ligands possessing a phosphano or phosphanoamino functionality as an alternative coordinating element were developed, and their usefulness was demonstrated by applying them to palladium-catalyzed asymmetric allylic nucleophilic substitution reactions. The structure of the catalyst precursor coordinated by the chiral phosphino sulfoxide was determined by X-ray crystallographic analysis. The possible mechanism for the asymmetric induction using these chiral ligands was proposed on the basis of the stereochemical outcome obtained. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00393-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4701±4710
New Chiral Sulfoxide Ligands Possessing a Phosphano or
Phosphanoamino Functionality in Palladium-Catalyzed
Asymmetric Allylic Nucleophilic Substitution Reactions
*
Kunio Hiroi, Yoshio Suzuki, Ikuko Abe and Ryoko Kawagishi
Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,
Sendai, Miyagi 981-8558, Japan
Received 2 March 2000; accepted 8 May 2000
AbstractÐNew chiral sulfoxide ligands possessing a phosphano or phosphanoamino functionality as an alternative coordinating element
were developed, and their usefulness was demonstrated by applying them to palladium-catalyzed asymmetric allylic nucleophilic substitu-
tion reactions. The structure of the catalyst precursor coordinated by the chiral phosphino sulfoxide was determined by X-ray crystal-
lographic analysis. The possible mechanism for the asymmetric induction using these chiral ligands was proposed on the basis of the
stereochemical outcome obtained. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
palladium complexes,12 [312] cycloaddition reactions,13
and allene formation with chiral sul®nates.14 Several years
ago, we extended our project to catalytic asymmetric synth-
esis with chiral ligands focused on chiral organosulfur func-
tionality, and developed new chiral ligands bearing chiral
organosulfur groups.15 We describe in this report details of
our recent work on asymmetric synthesis with chiral sulf-
oxide ligands bearing a b-phosphano or phosphanoamino
function as another coordinating element.16
The increasing practical usefulness of catalytic asymmetric
synthesis has received much attention in recent years,1 espe-
cially in the pharmaceutical ®eld, for the preparation of
biologically active chiral compounds. Currently, much
interest is being focused on new ef®cient chiral ligands.
Hitherto, various types of chiral ligands, possessing stereo-
controllable coordinating elements such as phosphane,2
phosphite,3 amine,4 oxygen (alcohol or ether),5 sulfenyl
functions,6 and so on, have been developed. The design
and development of new chiral ligands that effect bond
formation in a highly enantioselective fashion stand as
important and challenging tasks in modern asymmetric
synthesis. There have been some issues published related
to asymmetric synthesis with chiral ligands bearing organo-
sulfur functions; however, few reports have appeared
concerning asymmetric synthesis with chiral ligands bear-
ing chiral organosulfur groups such as sul®nyl7 and sulfox-
imine functions8 as sole chiral sources.
Results and Discussion
Synthesis of chiral sulfoxide ligands
Chiral b-phosphanoethyl p-tolyl sulfoxide (R)-1 was
prepared by a Michael addition of lithium diphenylphos-
phide to (R)-p-tolyl vinyl sulfoxide,17 however, the b-phos-
phano sulfoxide was too labile at room temperature to be
isolated in complete purity, presumably due to the facile
conversion into the corresponding phosphane oxide 1b by
the intramolecular redox reaction via 1a (Scheme 1).
We have taken much interest in the participation of chirality
in a chiral sul®nyl function in transition metal-catalyzed
reactions, and extensive efforts have been made for the
development of asymmetric synthetic methodologies with
chiral organosulfur compounds such as cyclopropane±
cyclobutane9 and -cyclopentene rearrangements,10 intramo-
lecular ene reactions,11 nucleophilic substitutions of p-allyl-
Chiral o-phosphanophenyl sulfoxides (S)-5a,b were obtain-
able from 2-¯uoroiodobenzene (2) and readily available
chiral sul®nates. Lithiation of 2 with n-butyllithium
followed by sul®nylation with (Ss)-3a18 or -3b19 produced
(S)-4a or -4b, respectively. Phosphanylation of (S)-4a or -4b
with potassium diphenylphosphide (KPPh2)20 gave (S)-5a,b.
Other chiral (3, 4, or 5-substituted-2-phosphano)phenyl
sulfoxides (S)-8a±d were prepared from 6a±d in a similar
procedure to that mentioned above. Chiral sulfoxides (S)-
10a and (R)-10b were readily obtained starting from
Keywords: asymmetric induction; catalysis; palladium and compounds;
sulfoxides.
* Corresponding author. Tel.: 181-22-234-4181; fax: 181-22-275-2013;
e-mail: khiroi@tohoku-pharm.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00393-8

4702
K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
with compete retention of the chirality without conversion
into the phosphane oxide (only quite a small amount of the
corresponding phosphane oxide (11b) was detected by
HPLC analysis). However, upon heating in re¯uxing THF
a more rapid irreversible transformation of (S)-5b into 11b
was observed with almost complete retention of the enan-
tiomeric excess value as shown in Fig. 1, plotted by HPLC
analysis with Chiralpak AD in accordance with elapse of
reaction time. The complete retention of the enantiomeric
excess value under the thermal condition means that the
transformation reaction should be irreversible. Thus, with
chiral o-phosphinophenyl sulfoxides as ligands, it should be
desirable to perform the reactions at rather low temperature,
at least below 508C (Scheme 3).
Scheme 1.
2-bromoaniline. The reaction of 2-bromoaniline with
chlorodiphenylphosphane was carried out in re¯uxing ben-
zene in the presence of triethylamine to give 9. Treatment of
9 with n-butyllithium followed by sul®nylation with (Ss)-3a
or -3b produced (S)-10a or (R)-10b in good yields, respec-
tively (Scheme 2).
Palladium-catalyzed asymmetric reactions with chiral
b-phosphano or -phospanoamino sulfoxide ligands
The palladium-catalyzed asymmetric allylic alkylations of
(^)-1,3-diphenyl-2-propenyl acetate (13) with dimethyl
malonate sodium enolate (generated by treating with NaH)
were studied using (S)-5a,b and (S)-8a-d as chiral ligands.
The reactions of (^)-13 with sodium malonate were carried
out in THF, DME, CH3CN, or DMSO at room temperature
for 6±10 h in the presence of [PdCl(p-allyl)]2, Pd(OAc)2,
Pd(dba)2, or Pd2(dba)3´CHC13 (0.06 equiv.) and (S)-5a
(0.12 equiv.), producing (S)-14a in good yields with mod-
erate enantiomeric excess (e.e.) (22±46%). The reaction of
(^)-13 with dimethyl malonate was also accomplished by
using N,O-bis(trimethylsilyl)acetamide (BSA)21 (3.0 equiv.)
and a catalytic amount of sodium acetate, instead of sodium
hydride, giving (S)-14a in 81% yield with 44% e.e. The
palladium-catalyzed reactions of (^)-13 with dimethyl malo-
nate using (S)-8a±d as a ligand gave (S)-14a with rather low
e.e., similar to the results obtained with (S)-5a. These results
show, not as expected, that the marked electronic and steric
In contrast to (R)-1, chiral o-phosphanophenyl sulfoxides
were obtained with retention of the chirality on the sul®nyl
functions. The reason for this unexpected stability of the
chirality is rationalised by the lower reactivity of the
aromatic phosphano functions compared with that of the
aforementioned phosphanoethyl group in (R)-1.
Thus, we executed detailed studies on the thermal stability
of chiral o-phosphanophenyl sulfoxides. The chiral sulfox-
ide (S)-5a was extremely stable at room temperature,
however under heating in THF it was partially converted
into the corresponding phosphane oxide 11a. The time-
course of the conversion of (S)-5a into 11a was listed in
Table 1. Comparatively, the chiral sulfoxide (S)-5b was
concluded to be very stable in THF at room temperature
Scheme 2.

K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
4703
150
Table 1. The thermal conversion of sulfoxide (S)-5a into phosphane oxide 11a (a solution of (S)-5a in THF was heated under re¯ux)
Reaction time (h)
2
4
18
20
24
30
40
50
70
90
130
Product 11aa ratio (%)
e.e. (%)a of (S)-5a
±
100
±
99
3.2
96
3.5
95
3.7
96
4.3
98
4.5
96
4.6
96
5.0
96
5.7
96
7.5
96
9.6
96
a The product 11a ratio and the e.e. of (S)-5a obtained were determined by HPLC analysis with Chiralpak OJ (iPrOH/hexane 1:9) (the retention time of (R)-
5a, (S)-5a, and 11a; 14, 18 and 34 min, respectively, ¯ow rate 0.5 ml/min.) in accordance with elapse of the reaction time.
effects of the methyl or vicinal alkoxy groups could not be
detected. However, a chiral sul®nyl compound (S)-5b with a
bulky substituent was demonstrated to serve as a highly
ef®cient chiral ligand in the palladium-catalyzed reactions,
providing an extremely high degree of asymmetric induc-
tion. The reactions of (^)-13 with sodium malonate were
carried out in THF at 220 or 2408C in the presence of
[PdCl(p-allyl)]2 (0.03 equiv.) and (S)-5b (0.06 equiv.) to
afford (S)-14a in good yields with 75% e.e. The use of
PdC12(CH3CN)2 (0.03 equiv.) and (S)-5b (0.06 equiv.) in
the reaction at 2208C in THF improved the e.e. (82%) of
the product (S)-14a. The e.e. and the absolute con®guration
of the product 14a were determined by HPLC analysis with
Chiralpak AD.22 The results obtained under other various
reaction conditions are summarized in Table 2 (Scheme 4).
same result as that obtained under the normal reaction
conditions with PdCl2(CH3CN)2 and (S)-5b.
With chiral b-phosphanoamino sulfoxides as chiral ligands,
marked stereoelectronic effects were observed. The palla-
dium-catalyzed reactions of (^)-13 with dimethyl malonate
sodium enolate were carried out in the presence of
[PdCl(p-allyl)]2 (0.06 equiv.) and the chiral ligand (S)-10a
(0.12 equiv.) in THF at room temperature to give (S)-14a
with 45% e.e. Use of other palladium catalysts such as
Pd(OAc)2, Pd(dba)2, and Pd2(dba)3´CHCl3 gave (S)-14a
with rather low e.e. (24, 31, and 39%, respectively). Rather
unequivocal solvent effects were observed in this catalytic
reaction. The above reactions of (^)-13 with sodium malo-
nate catalyzed by [PdCl(p-allyl)]2 were carried out in DME,
toluene, benzene, acetonitrile, or DMSO to give (S)-14a
with 44, 28, 23, 19, or 8% e.e., respectively, as listed in
Table 4. The effect of the molar ratio of [PdCl(p-allyl)]2
to (S)-10a was studied in the reaction of (^)-13 with sodium
malonate in THF at room temperature. The 1:4 to 1:8 molar
ratios of [PdCl(p-allyl)]2 to (S)-10a provided higher enan-
tioselectivity (43 and 49%, respectively) of (S)-14a.
The asymmetric allylic amination of (^)-13 under palla-
dium catalysis with (S)-5b provided a high degree of asym-
metric induction. Enantioselectivity of (R)-14b as high as
85% e.e. was observed when the reactions of (^)-13 with
benzylamine were carried out in toluene at 08C in the
presence of [PdCl(p-allyl)]2 (0.06 equiv.) and (S)-5b
(0.12 equiv.). The e.e. and the absolute con®guration of
the product 14b were determined by HPLC analysis with
Chiralcel OD.23 The results obtained under other various
reaction conditions are summarized in Table 3. As shown
in Table 3, unequivocal solvent effects on the asymmetric
induction were observed; with DMSO, DMF, or acetonitrile
as solvent, a very poor e.e. of (R)-14b was obtained.
The higher enantioselectivity was obtained by using 2-
methoxy-1-naphthyl sulfoxide (R)-10b, and the results are
summarized in Table 4. The reaction of (^)-13 with sodium
malonate catalyzed by [PdCl(p-allyl)]2 and (R)-10b
produced (R)-14a with 97% e.e. The effects of the molar
ratio of the palladium catalyst to the ligand used were extre-
mely remarkable. In particular, the 1:8 molar ratio of
[PdCl(p-allyl)]2 to (R)-10b resulted in the highest enantio-
selectivity of (R)-14a. The reason for this high ef®ciency is
not clear at the present time. It should also be remarked that
the absolute con®guration of the product 14a obtained by
the palladium-catalyzed reaction of (^)-13 with dimethyl
malonate using (R)-10b was inversed from that obtained
with (S)-10a. However, the reaction in DMSO gave (S)-
14a with low e.e. This indicates that the sul®nyl function-
ality would participate in this palladium-catalyzed reaction
via coordination to the catalyst to result in the stereocontrol
of the product. The result of this high enantioselectivity was
the most highly selective example among the asymmetric
The catalyst precursor (12) derived from (S)-5b and
PdC12(CH3CN)2 was isolated by recrystallization from
CH2Cl2-Et2O. The structure was determined by X-ray crys-
tallographic analysis as shown in Fig. 2. The palladium-
catalyzed reactions of (^)-13 with sodium malonate using
the isolated palladium complex 12 as a catalyst gave the
Figure 1. Convertion ratio of (S)-5b to 11b upon heating in re¯uxing THF.
(W)(S)-5b; (S) 11b.
Scheme 3.

4704
K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
Table 2. Palladium-catalyzed asymmetric allylic alkylation of 13 with dimethyl malonate using (S)-5a,b or 8a±d (the reactions of 13 with carbanion of
dimethyl malonate (generated by treating with NaH (1.2 equiv.)) were carried out in the presence of a palladium catalyst (0.06 equiv.) and chiral ligands (S)-
5a,b or 8a-d (0.12 equiv.))
Entry
Ligand
Catalyst
Solvent
Reaction temp. (8C)
Reaction time (h)
Yield (%) of (S)-14a
e.e (%) of (S)-14aa
1
2
3
4
5
6
7
8
(S)-5a
[PdCl(p-allyl)]2
Pd(OAc)2
Pd(dba)2
THF
THF
THF
THF
DME
CH3CN
DMSO
CH2Cl2
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
rt
0
220
220
220
220
245
220
220
rt
0
rt
rt
rt
10
10
10
6
10
10
10
6
10 min
3
4
8
8
72
70
75
73
72
77
84
34
15
38
24
22
39
46
44
65
75
75
70
82
75
75
52
13
15
21
36
22
36
36
20
38
28
Pd2(dba)3´CHCl3
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
PdCl2(CH3CN)2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
39
81b
73
9
(S)-5b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
75
72c
72d
71e
59
THF
DME
Toluene
DMSO
CH3CN
THF
CH2Cl2
CH2Cl2
CH2Cl2
THF
8
3
74
73
64
70
30 min
10 min
12
12
12
12
12
4
24
61
(S)-8a
(S)-8b
(S)-8c
(S)-8d
89c
58c
73b
67
0
rt
rt
rt
CH2Cl2
THF
CH2Cl2
83b
53
rt
12
92b
a The enantiomeric excess (e.e.) of (S)-14a was calculated by HPLC analysis with Chiralpak AD.22
b Reacted in the presence of BSA (3.0 equiv.) and a catalytic amount of NaOAc.
c The catalyst [PdCl(p-allyl)]2 (0.01 equiv.) was used.
d The catalyst [PdCl(p-allyl)]2 (0.005 equiv.) was used.
e The catalyst PdCl2(CH3CN)2 (0.03 equiv.) was used.
synthetic reactions reported previouly, by means of chiral
organosulfur ligands as the sole chiral sources.
The mechanism for the asymmetric induction with
chiral b-phosphano and b-phosphanoamino sulfoxides
as chiral ligands
The mechanism for the asymmetric induction with chiral o-
phosphanophenyl sulfoxide ligands is proposed on the basis
of the stereochemical results obtained. A ®ve-membered
chelated p-allylpalladium complex would be formed by
Scheme 4.
Table 3. Palladium-catalyzed asymmetric allylic amination of 13 with benzylamine using chiral sulfoxide ligands (S)-5a,b (the reactions of 13 with benzyl-
amine (2.0 equiv.) were carried out in THF in the presence of a catalyst (0.06 equiv.) and chiral ligands (S)-5a,b (0.12 equiv.))
Entry
Ligand
Catalyst
Solvent
Reaction temp. (8C)
Reaction time (h)
Yield (%) of (R)-14b
e.e.(%) of (R)-14ba
1
2
3
4
5
6
7
8
(S)-5a
(S)-5b
[PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
Pd2(dba)3´CHCl3
Pd(dba)2
THF
THF
THF
THF
THF
THF
THF
DMSO
DMF
CH3CN
DME
Toluene
Toluene
Toluene
50
50
rt
37
24
96
65
98
144
168
65
38
16
23
20
20
92
56
84
55
59
37
20
29
85
64
72
66
91
85
51
30
74
75
66
79
76
72
10
12
3
50
50
50
50
50
50
50
50
50
rt
Pd(OAc)2
PdCl2(CH3CN)2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
PdCl(p-allyl)]2
9
10
11
12
13
14
74
50
70
85
0
a The enantiomeric excess (e.e.) of (R)-14b was calculated by HPLC analysis with Chiralcel OD.23

K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
4705
ence between the large substituent (p-toly or 2-methoxy-1-
naphthyl) on the chiral sulfoxide and the phenyl group in the
allyl terminus in 15a. The nucleophile (sodium malonate or
benzylamine) attacks preferentially the allyl terminus trans
to the better p-acceptor,24 which is the phosphane group in
the current case, despite the steric effect by the bulky substi-
tuent (2-methoxy-1-naphthyl), affording (S)-14a or (R)-14b,
respectively (Scheme 5).
Furthermore, the existence of the vicinal phosphanoamino
functions in the chiral sul®nyl ligands was demonstrated to
be most essential for the improvement of the enantioselec-
tivity, in comparison with the cases of the vicinal amino and
phosphano sul®nyl ligands. This high enantioselectivity
arises presumably from the formation of a sterically control-
lable six-membered transition state as described below.
The mechanism of this asymmetric synthesis induced by the
chirality of the chiral sul®nyl group is rationalized as
follows. The phosphorus and sulfur atoms in the chiral phos-
phanoamino ligand (S)-10a have rather strong coordination
ability to palladium catalysts, forming six-membered p-
allylpalladium intermediates 16a±d, in which 16a,b
would be more sterically preferred to 16c,d, because of
the existence of 1,3-diaxial steric interference between the
tolyl group and the phenyl group in 16c,d. In the conforma-
tional equilibrium between 16a and 16b, 16b would be
preferred to 16a which has steric interference between the
Figure 2. Molecular structure (ORTEP drawing) of 12 with the omission of
two molecules of CH2Cl2 included.
coordination of the phosphano group and the sul®nyl sulfur
function to palladium. In the conformational equilibrium of
the ®ve-membered chelate, the conformer 15b would be
preferred to 15a because of the existence of steric interfer-
Table 4. The palladium-catalyzed asymmetric alkylation of 13 with (S)-10a or (R)-10b (the reaction of 13 with dimethyl malonate sodium enolate (generated
by treating with NaH (1.2 equiv.)) were carried out in the presence of [PdCl(p-allyl)]2 (0.06 equiv.) and chiral ligands (S)-10a or (R)-10b)
Entry
Ligand
Ratio of
Pd/ligand
Solvent
Reaction temp.
(8C)
Reaction time
(h)
Yield (%)
of 14aa
e.e.(%) of 14ab
(Abs. con®gn.)
1
2
3
4
5
6
7
8
(S)-10a
1:1
1:2
1:4
1:8
1:2
1:2
1:2
1:2
1:1
1:2
1:2
1:4
1:8
1:2
1:2
1:4
1:4
1:2
THF
THF
THF
THF
DME
Toluene
CH3CN
DMSO
THF
THF
THF
THF
THF
DME
DME
Toluene
Toluene
DMSO
rt
rt
rt
rt
rt
rt
rt
rt
0
0
rt
0
0
0
55
24
55
62
47
40
17
17
110
110
48
110
132
40
76
110
35
26 (39)
22 (70)
18 (51)
27 (42)
33 (72)
12 (75)
59 (87)
50 (90)
26 (59)
29 (82)
41 (87)
33 (94)
49 (90)
41 (92)
46 (80)
26 (67)
34 (51)
83
39 (S)
45 (S)
43 (S)
49 (S)
44 (S)
28 (S)
19 (S)
8 (S)
67 (R)
73 (R)
53 (R)
70 (R)
97 (R)
75 (R)
71 (R)
81 (R)
67 (R)
11 (S)
9
(R)-10b
10
11
12
13
14
15
16
17
18
rt
0
rt
rt
3
a The corrected yields of 14a based on the recovered starting material are described in parentheses.
b The enantiomeric excess (e.e.) of 14a was calculated by HPLC analysis with Chiralpak AD.22
Scheme 5.

4706
K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
Scheme 6.
Scheme 7.
tolyl group and the phenyl substituent in the allylic system.
In general, nucleophilic attack would be preferred at the
allyl terminus in 16a±d trans to the better p-acceptor,24
which is the phosphorus group in the current case, resulting
in the formation of the corresponding intermediates 17a±d,
respectively. The nucleophile (malonate carbanion) would
attack preferentially the allylic site trans to the phosphorus
group in the sterically most preferred p-allylpalladium
complex 16b, producing (S)-14a via 17b (Scheme 6).
using chiral sulfoxides as the sole chiral sources, involving
studies on the thermal stability of chiral b-phosphano sulf-
oxides with the elapse of the reaction time and the structural
determination of an intermediary palladium complex with a
chiral b-phosphano sulfoxide.
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
a JEOL JNM-LA 400 (1H NMR; 400 MHz) and JEOL EX-
270 (1H NMR; 270 MHz) high-resolution NMR spectro-
meter; chemical shifts are given in ppm from tetramethylsi-
lane as an internal standard. Splitting patterns are designated
as s, singlet; bs, broad singlet; d, doublet; dd, doublet of
doublets; ddd, double doublet of doublets; t, triplet; dt,
triplet of doublets; td, doublet of triplets; 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: Dicel Chiralpak AD (hexane/i-PrOH 20:1) or
Chiralcel OD (hexane/i-PrOH 200:1), 0.5 ml/min,
254 nm). Optical rotations were measured at 248C with a
JASCO DIP-370 polarimeter. X-Ray diffraction analysis
was carried out on a Rigaku RAXIS-IV diffractometer.
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 1408C for 3.5 h.
Surprisingly, the ligand (R)-10b with the larger substituent,
the 2-methoxy-1-naphthyl group, was highly effective in the
asymmetric induction via the p-allylpalladium complex,
controlling the stereochemistry of the product. Since,
presumably, the steric crowding by the large naphthyl
group would disturb the alkylation at the allylic site trans
to the phosphorus group in the sterically preferred 18b,
similarly as mentioned above, in the equilibrium of 18a,b,
the preferential alkylation at the allylic site syn to the phos-
phorus group in 18b would occur to give (R)-14a (Scheme
7).
Conclusion
Thus, chiral o-phosphanophenyl sulfoxides and 2-(phos-
phanoamino)phenyl sulfoxides were demonstrated to serve
as ef®cient chiral ligands in the palladium-catalyzed allylic
nucleophilic substitution reactions. It should be noted that
chiral 2-(diphenylphosphanoamino)phenyl 2-methoxy-1-
naphthyl sulfoxide was the most ef®cient ligand among
the known ligands bearing a chiral organosulfur function-
ality as the sole chiral source. Our present work is the ®rst
report related to asymmetric synthesis with high ef®ciency
(S)-2-Fluorophenyl p-tolyl sulfoxide (4a). A 1.06 M
cyclohexane solution of sec-butyllithium (sec-BuLi) (3 ml,

K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
4707
2.70 mmol) was added at 2788C to a solution of 2-¯uoro-
iodobenzene (2) (500 mg, 2.25 mmol) in THF (4 ml), and
the reaction mixture was stirred at 2788C for 1 h. A solution
of (2)-menthyl (Ss)-p-toluenesul®nate (3a)18 (728 mg,
2.47 mmol) in THF (8 ml) was added to the above solution,
and the reaction mixture was stirred at room temperature for
3 h. The reaction solution was diluted with ether and the
solution was washed with 10% aqueous HCl, saturated
aqueous NaHCO3 and saturated aqueous NaCl, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
product was subjected to preparative TLC (ether/
hexaneˆ3:1) to give (S)-4a (353 mg, 67% yield).
solution was washed with 10% aqueous HCl, saturated
aqueous NaHCO3, and saturated NaCl, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude
product was subjected to preparative TLC (ether/hex-
aneˆ1:1) to give (S)-7c (502 mg, 74% yield).
The sul®nations of 2-¯uoro-1-benzyloxybenzene were
carried out in the same way as described above to give
(S)-2-¯uoro-3-benzyloxyphenyl p-tolyl sulfoxide (7d).
®lm
max
(S)-7c. [a]Dˆ2318 (cˆ1.5, CHCl3). IR n
cm21: 1600
(aromatic), 1020 (SO). NMR (270 MHz; CDCl3) d: 2.36
(s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.98±7.05 (m, 7H,
ArH), 7.23±7.28 (m, 3H, ArH), 7.44 (dd, Jˆ5.6, 1.6 Hz,
1H, ArH), 7.58±7.61 (m, 2H, ArH). MS m/z: 264 (M1).
HRMS: 264.0582 (Calcd C25H21OPS: 264.0620).
The sul®nylations of 2, 3-bromo-4-¯uorotoluene (6a) or 4-
bromo-3-¯uorotoluene (6b) with (Ss)-3a or (2)-menthyl
(Ss)-2-methoxy-1-naphthalenesul®nate (3b)19 were carried
out in the same way as described above to give (S)-2-¯uoro-
phenyl 2-methoxy-1-naphthyl sulfoxide (4b), (S)-2-¯uoro-
3-tolyl p-tolyl sulfoxide (7a) or (S)-2-¯uoro-4-tolyl p-tolyl
sulfoxide (7b), respectively.
®lm
(S)-7d. 37% yield. [a]Dˆ2718 (cˆ6.5, CHCl3). IR n
max
cm21: 1600 (aromatic), 1040 (SO). NMR (270 MHz;
CDCl3) d: 2.36 (s, 3H, CH3), 5.08 (d, Jˆ1.3 Hz, 2H,
CH2), 7.03±7.09 (m, 1H, ArH), 7.17±7.50 (m, 9H, ArH),
7.60 (d, Jˆ7.6 Hz, 2H, ArH). MS m/z: 340 (M1). HRMS:
340.0975 (Calcd C25H21OPS: 340.0934).
®lm
max
(S)-4a. [a]Dˆ2778 (cˆ1.2, acetone). IR n
cm21: 1595
(aromatic), 1040 (SO). NMR (400 MHz; CDCl3) d: 2.36 (s,
3H, CH3), 7.00±7.05 (m, 1H, ArH), 7.25±7.27 (m, 2H,
ArH), 7.31±7.44 (m, 2H, ArH), 7.59±7.60 (m, 2H, ArH),
7.91±7.95 (m, 1H, ArH). MS m/z: 234 (M1). HRMS:
234.0515 (Calcd C13H11OFS: 234.0527).
(S)-(Diphenylphosphano)phenyl p-tolyl sulfoxide (5a). A
0.5 M THF solution of potassium diphenylphosphide
(KPPh2)20 (commercially available) (2 ml, 1.16 ml) was
added at room temperature to a solution of (S)-4a
(181 mg, 0.77 mmol) in THF (4 ml), and the reaction
mixture was stirred at room temperature for 30 min. The
reaction solution was diluted with ether and ®ltered through
Celite. The ®ltrate was concentrated in vacuo and the resi-
due was subjected to preparative TLC (ether/hexaneˆ3:1)
to give (S)-5a (268 mg, 87% yield).
®lm
max
(S)-4b. 74% yield. [a]Dˆ11768 (cˆ6.5, acetone). IR n
cm21: 1595 (aromatic), 1035 (SO). NMR (270 MHz;
CDCl3) d: 3.87 (s, 3H, CH3), 6.84±6.94 (m, 1H, ArH),
7.21 (d, Jˆ9.1 Hz, 1H, ArH), 7.30±7.40 (m, 3H, ArH),
7.48±7.54 (m, 1H, ArH), 7.76 (dt, Jˆ8.2, 0.7 Hz, 1H,
ArH), 7.94 (d, Jˆ9.1 Hz, 1H, ArH), 8.14±8.24 (m,1H,
ArH), 8.66 (d, Jˆ8.6 Hz, 1H, ArH). MS m/z: 300 (M1).
HRMS: 300.0620 (Calcd C17H13O2FS: 300.0640).
The phosphanations of (S)-4 or 7a±d, were carried out in the
same way as described above to give (S)-2-(diphenyl-
phosphano)phenyl 2-methoxy-1-naphthyl sulfoxide (5b),
(S)-2-(diphenylphosphano)-3-tolyl p-tolyl sulfoxide (8a),
(S)-2-(diphenylphosphano)-4-tolyl p-tolyl sulfoxide (8b),
(S)-2-(diphenylphosphano)-3-methoxyphenyl p-tolyl sulf-
oxide (8c), (S)-3-benzyloxy-2-(diphenylphosphano)phenyl
p-tolyl sulfoxide (8d), respectively.
®lm
(S)-7a. 79% yield. [a]Dˆ2228 (cˆ1.1, CHCl3). IR n
max
cm21: 1595 (aromatic), 1040 (SO). NMR (270 MHz;
CDCl3) d: 2.329 (s, 3H, CH3), 2.33 (s, 3H, CH3), 6.82
(dd, Jˆ10.6, 0.7 Hz, 1H, ArH), 7.09 (dd, Jˆ1.5, 0.6 Hz,
1H, ArH), 7.23 (dd, Jˆ8.6, 0.6 Hz, 2H, ArH), 7.55±7.58
(m, 2H, ArH), 7.73±7.78 (m, 1H, ArH). MS m/z: 248
(M1). HRMS: 248.0652 (Calcd C14H13OFS: 248.0671).
(S)-5a. Mp 1248C (colorless prisms; recrystallized from
®lm
max
®lm
max
(S)-7b. 49% yield. [a]Dˆ1268 (cˆ1.4, CHCl3). IR n
CHCl3/hexane). [a]Dˆ21388 (cˆ1.1, acetone). IR n
1
cm21: 1590 (aromatic), 1042 (SO). NMR (270 MHz;
CDCl3) d: 2.37 (s, 3H, CH3), 2.38 (s, 3H, CH3), 6.87±
6.94 (m, 1H, ArH), 7.15±7.21 (m, 1H, ArH), 7.26 (t,
Jˆ4.0 Hz, 2H, ArH), 7.57±7.60 (m, 2H, ArH), 7.67±7.70
(m, 1H, ArH). MS m/z: 248 (M1). HRMS: 248.0721 (Calcd
C14H13OFS: 248.0671).
cm21: 1595 (aromatic), 1040 (SO). H NMR (270 MHz;
CDCl3) d: 2.24 (s, 3H, CH3), 6.93±7.06 (m, 5H, ArH),
7.14±7.37 (m, 9H, ArH), 7.44 (d, Jˆ8.2 Hz, 2H, ArH),
7.55±7.61 (m, 1H, ArH), 8.14±8.18 (m, 1H, ArH).
13C NMR (67.8 MHz; CDCl3) d: 21.3, 124.1, 124.3,
126.3, 126.4, 128.1, 128.2, 128.4, 128.5, 128.8, 129.4,
130.5, 132.0, 133.1, 133.3, 133.4, 133.6, 134.3, 134.4,
135.0, 135.3, 135.5, 135.6, 141.0, 141.8. MS m/z: 400
(M1). HRMS: 400.1051 (Calcd C25H21OPS: 400.1043).
(S)-2-Fluoro-3-methoxyphenyl p-tolyl sulfoxide (7c). A
solution of 2-¯uoroanisole (200 mg, 1.59 mmol) and
N,N,N0,N00,N00-pentamethyldiethylenetriamine (PMDTA)
(329 mg, 1.90 mmol) in THF (5 ml) was added at 2788C
to a 1.56 M hexane solution of n-butyllithium (n-BuLi)
(1 ml, 1.90 mmol), and the reaction mixture was stirred at
2788C for 2 h. A solution of (Ss)-3a (559 mg, 1.90 mmol)
in THF (5 ml) was added to the above solution, and the
reaction mixture was stirred at room temperature for 12 h.
The reaction solution was diluted with ether, and the
(S)-5b. Mp 2038C (colorless prisms; recrystallized from
CHCl3/hexane). 73% yield. [a]Dˆ11308 (cˆ1.9, acetone).
®lm
max
IR n
cm21: 1595 (aromatic), 1035 (SO). NMR
(270 MHz; CDCl3) d: 3.48 (s, 3H, CH3), 6.16±6.23 (m,
2H, ArH), 6.63 (d, Jˆ9.2 Hz, 1H, ArH), 6.76±6.82 (m,
2H, ArH), 6.93±7.04 (m, 4H, ArH), 7.17±7.26 (m, 3H,
ArH), 7.32±7.39 (m, 2H, ArH), 7.47 (d, Jˆ9.1 Hz, 1H,

4708
K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
ArH), 7.55±7.70 (m, 3H, ArH), 8.47±8.52 (m, 1H, ArH),
8.88 (dd, Jˆ7.7, 0.8 Hz, 1H, ArH). 13C NMR (67.8 MHz;
CDCl3) d: 56.6, 110.7, 113.1, 113.7, 120.5, 123.3, 123.9,
124.0, 127.1, 127.4, 127.5, 127.6, 127.8, 128.0, 128.1,
128.2, 128.3, 128.4, 129.0, 129.2, 131.0, 132.3, 132.4,
132.6, 132.8, 133.1, 134.1, 134.6, 134.9. MS m/z: 466
(M1). HRMS: 466.1156 (Calcd C29H23O2PS: 466.1191).
Jˆ7.5, 1.0 Hz, 1H, ArH), 7.19±7.56 (m, 14H, ArH), 7.75
(ddd, Jˆ12.7, 6.8, 1.5 Hz, 2H, ArH), 8.44 (d, Jˆ12.0 Hz,
1H, ArH). MS m/z: 415 (M1). 13C NMR (100 MHz; CDCl3)
d: 21.3, 120.4, 120.5, 124.7, 126.1, 126.3, 128.1, 128.2,
128.3, 128.4, 128.6, 129.5, 130.8, 131.1, 131.2, 131.7,
131.8, 131.9, 132.0, 132.1, 132.6, 132.8, 139.6, 140.8,
142.8. HRMS: 415.1160 (Calcd C25H22NOPS: 415.1107).
®lm
max
(S)-8a. 50% yield. [a]Dˆ2568 (cˆ3.1, CHCl3). IR n
(R)-10b. Mp 1438C (colorless prisms; recrystallized from
CHCl3/hexane). 33% yield. [a]Dˆ11478 (cˆ1.1, acetone).
cm21: 1591 (aromatic), 1024 (SO). NMR (400 MHz;
CDCl3) d: 2.24 (s, 3H, CH3), 2.43 (s, 3H, CH3), 6.89±
7.01 (m, 5H, ArH), 7.14±7.34 (m, 9H, ArH), 7.44±7.46
(m, 2H, ArH), 7.98±7.99 (m, 1H, ArH). MS m/z: 414
(M1). HRMS: 414.1223 (Calcd C26H23O4PS: 414.1207).
®lm
max
IR n
cm21: 1590 (aromatic), 1020 (SO). NMR
(400 MHz; CDCl3) d: 1.41 (bs, H, NH), 3.77 (s, 3H,
CH3), 6.76±6.89 (m, 1H, ArH), 6.96±7.22 (m, 6H, ArH),
7.34±7.56 (m, 7H, ArH), 7.81±8.00 (m, 5H, ArH), 8.67±
1
8.74 (m, 1H, ArH). C NMR (100 MHz; CDCl3) d: 56.7,
®lm
max
(S)-8b. 51% yield. [a]Dˆ2728 (cˆ2.3, CHCl3). IR n
112.2, 113.3, 114.1, 120.0, 120.1, 121.0, 122.6, 123.0,
124.7, 125.5, 127.2, 127.3, 127.8, 128.6, 128.7, 128.8,
128.9, 129.0, 129.3, 130.8, 131.3, 131.4, 132.0, 132.1,
132.2, 132.3, 132.4, 135.4. MS m/z: 481 (M1). HRMS:
481.1266 (Calcd C29H24O2PNS: 481.1279).
cm21: 1584 (aromatic), 1026 (SO). NMR (400 MHz;
CDCl3) d: 2.24 (s, 3H, CH3), 2.25 (s, 3H, CH3), 6.78±
6.79 (m, 1H, ArH), 6.97±7.01 (m, 4H, ArH), 7.18±7.44
(m, 11H, ArH), 8.02 (dd, Jˆ8.1, 3.7 Hz, 1H, ArH). MS m/
z: 414 (M1). HRMS: 414.1200 (Calcd C26H23OPS:
414.1207).
2-(2-Methoxy-1-naphthylsulfanyl)phenyl diphenylphos-
phane oxide (11b).
A solution of (S)-5b (30 mg,
®lm
(S)-8c. 71% yield. [a]Dˆ2118 (cˆ1.2, CHCl3). IR n
0.08 mmol) in THF (8 ml) was stirred under heating at
re¯ux. The reaction solution was concentrated in vacuo
and the residue was subjected to preparative TLC (ethyl
acetate/hexaneˆ5:1) to give 11b (3.0 mg, 10% yield).
max
cm21: 1580 (aromatic), 1020 (SO). NMR (400 MHz;
CDCl3) d: 2.22 (s, 3H, CH3), 3.27 (s, 3H, CH3), 6.81±6.89
(m, 2H, ArH), 6.91 (d, Jˆ0.7 Hz, 1H, ArH), 6.98 (d,
Jˆ7.8 Hz, 2H, ArH), 7.04±7.08 (m, 2H, ArH), 7.14±7.18
(m, 1H, ArH), 7.24±7.35 (m, 5H, ArH), 7.52 (d, Jˆ8.1 Hz,
2H, ArH), 7.68 (t, Jˆ8.1 Hz, 1H, ArH), 7.97 (ddd, Jˆ7.8,
3.2, 1.0 Hz, 1H, ArH). MS m/z: 430 (M1). HRMS: 430.1187
(Calcd C26H23O2SP: 430.1156).
®lm
max
11a. IR n
cm21: 1600 (aromatic). NMR (270 MHz;
CDCl3) d: 2.31 (s, 3H, CH3), 7.03±7.16 (m, 6H, ArH),
7.28±7.38 (m, 2H, ArH), 7.44±7.57 (m, 6H, ArH), 7.73±
7.79 (m, 4H, ArH). MS m/z: 400 (M1). HRMS: 400.1011
(Calcd C25H21OPS: 400.1051).
®lm
max
(S)-8d. 48% yield. [a]Dˆ2588 (cˆ1.3, CHCl3). IR n
cm21: 1580 (aromatic), 1030 (SO). NMR (270 MHz;
CDCl3) d: 2.29 (s, 3H, CH3), 4.68 (d, Jˆ1.5 Hz, 2H,
CH2), 6.65±6.68 (m, 2H, ArH), 6.92±7.39 (m, 13H, ArH),
7.47±7.58 (m, 3H, ArH), 7.67 (dd, Jˆ6.4, 1.8 Hz, 2H, ArH),
7.74±7.80 (m, 1H, ArH), 8.36 (ddd, Jˆ8.0, 2.7, 0.8 Hz, 1H,
ArH). MS m/z: 506 (M1). HRMS: 506.1443 (Calcd
C32H27O2SP: 506.1469).
11b. 88% yield. IR n
cm21: 1601 (aromatic). NMR
®lm
max
(270 MHz; CDCl3) d: 3.31 (s, 3H, CH3), 6.52 (d,
Jˆ9.0 Hz, 1H, ArH), 6.68 (dd, Jˆ6.8, 1.2 Hz, 2H, ArH),
6.94±7.00 (m, 2H, ArH), 7.04±7.08 (m, 1H, ArH), 7.20±
7.49 (m, 9H, ArH), 7.52±7.65 (m, 2H, ArH), 7.84 (dt,
Jˆ16.8, 1.5 Hz, 1H, ArH), 8.75±8.78 (m, 1H, ArH), 8.95
(d, Jˆ8.5 Hz, 1H, ArH). MS m/z: 467 (M111). HRMS:
466.1146 (Calcd C29H23O2PS: 466.1156).
(S)-N-(Diphenylphosphano)-2-(p-toluenesul®nyl)aniline
(10a). A 1.08 M cyclohexane solution of sec-BuLi (2 ml,
1.85 mmol) was added at 2788C to a solution of 2-bromo-
N-(diphenylphosphano)aniline (9) (300 mg, 0.84 mmol) in
THF (3 ml), and the reaction mixture was stirred at 2788C
for 1 h. A solution of (Ss)-3a (372 mg, 1.26 mmol) in THF
(3 ml) was added to the above solution, and the reaction
mixture was stirred at room temperature for 6 h. The
reaction mixture was diluted with ether, and the solution
was ®ltered through Celite. The ®ltrate was concentrated
in vacuo and the residue was subjected to preparative
TLC (ethyl acetate/hexaneˆ3:1) to give (S)-10a (601 mg,
52% yield). The sul®nylation of 9 with (Ss)-3b was carried
out in the same way as described above to give (R)-N-
(diphenylphosphano)-2-(2-methoxy-1-naphthylsul®nyl)ani-
line (10b).
The chelate of palladium with (S)-5b
(S)-5b (30 mg, 0.06 mmol) and bis(acetonitrile)dichloro-
palladium [PdCl2(CH3CN)2] (18 mg, 0.06 mmol) were
dissolved in CH2Cl2 (3 ml) at room temperature by stirring
for 10 min, and the solution was concentrated in vacuo,
yielding a product, [PdCl2-(S)-5b]´2CH2Cl2 (42 mg, 40%
yield), which was recrystallized from ether-dichloro-
methane (5:1). The structure of the chelate obtained was
determined by X-ray crystallographic analysis. The princi-
pal crystallographic parameters of the product are as
follows: C31H27O2PSCl6Pd; Fwˆ813.70; monoclinic;
Ê
Ê
space group P21(#4); aˆ9.466(1) A, bˆ17.136(2)A,
Ê
Ê 3
cˆ11.180(1)A, bˆ107.99(1)8; Vˆ1724.9(3) A ; Zˆ2;
21
Ê
Dcˆ1.567 g/cm3; Mo Ka; lˆ0.71070 A, mˆ11.37 cm
;
(S)-10a. Mp 2058C (colorless prisms; recrystallized from
F(000)ˆ816. The colorless prismatic crystal with dimen-
sions of 0.15£0.10£0.10 mm was used for data collection.
The structure was re®ned to a ®nal Rˆ0.038, Rwˆ0.049 for
2985 re¯ections, I.3s(I).
®lm
max
CHCl3/hexane). [a]Dˆ2548 (cˆ0.7, acetone). IR n
cm21:1600 (aromatic), 1020 (SO). NMR (400 MHz;
CDCl3) d: 1.65 (bs, 1H, NH), 2.44 (s, 3H, CH3), 6.96 (td,

K. Hiroi et al. / Tetrahedron 56 (2000) 4701±4710
4709
Palladium-catalyzed asymmetric nucleophilic substitu-
tion reactions of 1,3-diphenyl-2-propenyl acetate (13)
with chiral sulfoxide ligands.
HPLC analysis with a chiral column, Chiralcel OD (hexane/
i-propanolˆ200:1).23 The results obtained are listed in
Table 3.
General procedure A. A 25 ml two-necked ¯ask
equipped with a septem inlet and a magnetic stirring
bar, and containing sodium hydride (50% oil dispersion,
23 mg, 0.48 mmol), was ¯ushed with argon, and main-
tained under a positive pressure of argon. A solution of
dimethyl malonate (63 mg, 0.48 mmol) in THF (3 ml)
was added at 08C to the above ¯ask. Another 25 ml
two-necked ¯ask equipped with a septem inlet and a
magnetic stirring bar, and containing di-m-chlorobis-
(p-allyl)dipalladium ([PdCl(CH2vCHCH2)]2) (4 mg,
0.01 mmol) and chiral sulfoxide ligands (0.02 mmol),
was ¯ushed with argon, and maintained under a posstive
pressure of argon. A solution of (^)-1,3-diphenyl-2-pro-
penyl acetate (13) (100 mg, 0.40 mmol) in THF (3 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 Tables
2 and 4. The reaction solution was diluted with ether,
and the solution was washed with saturated aqueous
NH4Cl and saturated aqueous NaCl, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude
product was subjected to preparative TLC (ethyl ace-
tate/hexaneˆ1:7) to give optically active diethyl (1,3-
diphenyl-2-propenyl) propanedioate (14).22 The e.e.
and the absolute con®guration of the product were
determined by HPLC analysis with a chiral column,
Chiralpak AD (hexane/i-propanolˆ20:1).22 The results
obtained are listed in Tables 2 and 4.
Acknowledgements
The present work was supported by a Grant-in-Aid for
Scienti®c Research from the Ministry of Education,
Science, Sports and Culture, Japan.
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(BSA)21
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The reaction mixture was diluted with ether. The organic
layer was washed 10% aqueous sodium hydroxide and satu-
rated aqueous NaCl, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was subjected to
preparative TLC (ethyl acetate/hexaneˆ1:7) to give 14a.22
The results obtained are listed in Table 2.
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30 min, were added successively a solution of (^)-13
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amine (68 mg, 0.64 mmol) in THF (3 ml). The reaction
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tive TLC (ether/hexaneˆ1:4) to give optically active N-ben-
zyl-1,3-diphenyl-2-propenylamine (14b).23 The e.e. and the
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