Sterically congested, roofed β-iminodisulfides as new chiral ligands for palladium-catalyzed, asymmetric allylic alkylation

Article abstract of DOI:10.1248/cpb.58.1419

The preparation of a new class of roofed β-iminodisulfides from sterically congested, conformationally rigid chiral 2-thiazolidinones is described. A functional survey of palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate proved that symmetrical roofed β-iminodisulfides are efficient chiral ligands, showing enantioselectivity opposite that associated with chiral roofed β-iminothioether ligands.

Full text of DOI:10.1248/cpb.58.1419

October 2010
Communication to the Editor
Chem. Pharm. Bull. 58(10) 1419—1421 (2010)
1419
By contrast, one study suggested that b-aminodisulfides,
the dimeric form of b-aminothiols, showed poor reactivity
and enantioselectivity when used as chiral ligands for the
palladium-catalyzed asymmetric allylic alkylation reaction.13)
Generally, chiral b-aminodisulfide ligands have received lit-
tle attention in the field of catalytic asymmetric synthesis.
Therefore, additional investigation of b-aminodisulfides as
chiral ligands is intriguing.16)
We previously reported that conformationally rigid and
sterically bulky chiral “roofed” 2-iminothioethers, which
were prepared by thermal [4ϩ2] cycloaddition of a simple 5-
membered heterocycle, 2-thiazolone, to cyclic dienes, fol-
lowed by optical resolution and ring-cleavage, showed excel-
lent yields and enantioselectivities for the palladium-cat-
alyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate
with dimethyl malonate.15) Based on this result, we envisaged
that the dimer of this unique skeleton would show similar re-
sults.
b
Sterically Congested, “Roofed” -
Iminodisulfides as New Chiral Ligands
for Palladium-Catalyzed, Asymmetric
Allylic Alkylation
Hirofumi MATSUNAGA, Ryoh TOKUDA,
Makoto NAKAJIMA, and Tadao ISHIZUKA*
Faculty of Medical and Pharmaceutical Sciences, Kumamoto
University; 5–1 Oe-honmachi, Kumamoto 862–0973, Japan.
Received June 22, 2010; accepted July 29, 2010; published online
July 30, 2010
The preparation of a new class of “roofed” b-iminodisulfides
from sterically congested, conformationally rigid chiral 2-thia-
zolidinones is described. A functional survey of palladium-cat-
alyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl
acetate with dimethyl malonate proved that symmetrical
“roofed” b-iminodisulfides are efficient chiral ligands, showing
In this paper, we wish to describe the preparation and ap-
enantioselectivity opposite that associated with chiral “roofed” plication of sterically congested “roofed” b-iminodisulfides
b-iminothioether ligands.
as efficient chiral ligands for palladium-catalyzed asymmet-
ric allylic alkylation.
Key words b-iminodisulfide; asymmetric allylic alkylation; b-iminoth-
Starting from the “roofed” cis-2-aminothiol (2), which was
readily obtained from the chiral 2-thiazolidinone (1)17) by hy-
drolytic ring cleavage with Ba(OH)2 in ethanol under reflux,
ioether; palladium-catalyzed; opposite stereoselectivity
Palladium-catalyzed asymmetric allylic alkylation is a aerial oxidation of 2 in ethanol afforded the chiral and sym-
well-studied organic chemistry protocol, because it is a pow- metrical “roofed” b-aminodisulfide (3). Disulfide exchange
erful tool for enantioselective formation of carbon–carbon between the symmetrical b-aminodisulfide (3) and a dialkyl
and carbon–heteroatom bonds.1—7) Similar to other chiral disulfide in the presence of RhH(Ph3P)4 as a catalyst18,19) af-
catalyst systems, the enantioselectivity of this reaction forded a unsymmetrical disulfide (4). Both b-aminodisulfides
mostly depends on the character of the chiral ligand that is (3, 4) were subsequently treated with aryl aldehyde in the
coordinated to palladium. Therefore, various chiral ligands presence of molecular sieves to yield the corresponding sym-
have been developed and discovery of novel chiral ligands metrical and unsymmetrical b-iminodisulfide (5, 6), respec-
for this reaction remains an important research goal.
tively (Chart 1).20)
We initially tested the catalytic activity of the symmetrical
Chiral b-aminosulfides and their derivatives,8,9) which are
principally prepared from the corresponding 2-amino alco- “roofed” b-iminodisulfide 5a–Pd(II) complex, prepared in
hols and/or a-amino acids, are used less frequently in this re- situ. The Pd(II)-catalyzed allylic alkylation of 1,3-diphenyl-
action system. However, Anderson et al.,10,11) Page and col- 2-propenyl acetate (7) with dimethyl malonate under stan-
leagues,12) Braga et al.,13,14) and Tokuda et al.15) have re- dard conditions, in the presence of N,O-bis(trimethylsilyl)ac-
ported good to excellent chemical yields and enantioselectiv- etamide (BSA) as a base and a catalytic amount of KOAc in
ities using these compounds, indicating that chiral b- CH2Cl2, did not proceed well, and gave the corresponding
aminosulfides have potential as effective chiral ligands.
product (8) in only 6% yield and 12% ee (Table 1, entry 1).
Chart 1
∗ To whom correspondence should be addressed. e-mail: tstone@gpo.kumamoto-u.ac.jp
© 2010 Pharmaceutical Society of Japan

1420
Vol. 58, No. 10
Table 1. Palladium-Catalyzed Asymmetric Allylic Alkylation with b-Iminodisulfide Type Ligand
Time
(h)
Yielda)
(%)
eeb)
(%)
Time
(h)
Yielda)
(%)
eeb)
(%)
Entry Ligand
Base
Solvent
CH2Cl2
Entry Ligand
Base
Solvent
1
2
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
BSA/KOAcc)
24
24
24
24
24
24
24
24
24
12
24
24
6
9
12 (S)
48 (R)
—
36 (R)
—
15 (S)
38 (S)
50 (S)
26 (S)
50 (S)
—
13
14
15
16
17
18
19
20
21
22
23
24
5a
5a
5a
6a
6a
6a
6b
6b
6b
9
Cs2CO3
Cs2CO3
THF
24
24
1
Trace
Trace
97
—
—
24 (S)
—
—
—
—
—
52 (S)
—
—
BSA/KOAcc) Toluene
MeCN
DMSO
CH2Cl2
DMSO
DMSO
CH2Cl2
DMSO
DMSO
CH2Cl2
DMSO
MeCN
3
4
5
6
BSA/KOAcc)
BSA/KOAcc)
BSA/KOAcc)
NaH
THF
Trace
18
NR
5
17
14
46
98
Trace
Trace
Cs2CO3
MeCN
DMSO
CH2Cl2
Toluene
THF
MeCN
DMSO
CH2Cl2
Toluene
BSA/KOAcc)
NaH
24
24
24
24
24
24
24
24
NR
Trace
Trace
NR
Trace
6
NR
NR
93
Cs2CO3
7
8
9
NaH
NaH
NaH
NaH
Cs2CO3
Cs2CO3
BSA/KOAcc)
NaH
Cs2CO3
10
11
12
BSA/KOAcc)
Cs2CO3
9
10
—
Cs2CO3
0.25
83 (R)
a) Isolated yields. b) Determined by HPLC (Daicel CHIRALPAK AD-H,
hexane : i-PrOHϭ19 : 1, flow 1.0 ml/min). c) KOAc 5 mol%.
Table 2. Palladium-Catalyzed Asymmetric Allylic Alkylation with Sym-
metrical b-Iminodisulfide Ligands Using NaH as Base in DMSO
Based on our previous success with a “roofed” b-imino-
thioether–Pd(II) complex, we investigated the effects of vari-
ous solvents (i.e., toluene, tetrahydrofuran (THF), MeCN and
dimethyl sulfoxide (DMSO)). Unfortunately, none of
them gave yields greater than 20% (entries 2—5).
We next examined the effects of a base on this reaction.
Using NaH as a base, the reaction proceeded sluggishly in
CH2Cl2, toluene or THF (less than 17%, entries 6—8), and
moderate product yield (46%) was observed using MeCN
(entry 9). To our surprise, excellent yield and 50% ee were
obtained in DMSO (entry 10). The effect of DMSO on the
reaction rate was dramatically enhanced in the presence of
Cs2CO3 as a base. Although 97% yield was achieved after
only 1 h, the selectivity was not as good (24% ee, entry 15).
Catalytic activity of the unsymmetrical “roofed” b-imin-
odisulfides (6a, 6b)–Pd(II) complexes were also tested, but,
Entry
Ligand
Time (h)
Yielda) (%)
eeb)
1
2
3
4
5
5a
5b
5c
5d
5e
12
24
24
24
24
98
47
61
57
85
50 (S)
55 (S)
72 (S)
67 (S)
16 (S)
a) Isolated yields. b) Determined by HPLC (Daicel CHIRALPAK AD-H,
hexane : i-PrOHϭ19 : 1, flow 1.0 ml/min).
unfortunately, negative results were observed (entries 16— 5-Pd(II)-catalyzed asymmetric allylic alkylation is not clear,
21). It is intriguing that the symmetrical “non-roofed” b- considering both early work using “roofed” b-iminothioether
iminodisulfide 9, prepared from (S)-phenylglycine, did not 10 and the results of the present study, the most plausible hy-
work as a chiral ligand in this reaction system (entry 23). 21)
It should be noted that almost all of the alkylated products
pothesis for this reaction is depicted in Fig. 1.22)
Thus, there are two possible diastereomeric p-allylic palla-
8 resulting from use of the symmetrical “roofed” b-imin- dium complexes—11 (M-type) and 12 (W-type). Steric re-
odisulfide 5a showed the (S)-configuration, while use of the pulsion between the disulfide moiety of the 2-iminothioether
“roofed” b-iminothioether 10 produced the (R)-configuration ligand and the phenyl ring of the p-allyl substrate appears
(entry 24).
greater than that from the “roof ” moiety of the ligand, ren-
Table 2 summarizes the optimization of the imino moiety dering the intermediate (12) more feasible than 11. Nucle-
of the symmetrical b-iminodisulfide ligand (5a—e) in the ophilic attack at the p-allyl complex would occur at a trans-
presence of NaH in DMSO. Although p-substituted benzyl- position relative to the sulfur atom, which is a better electron
idene ligands showed lower activities than the N-benzylidene acceptor, to preferentially give the (S)-alkylated product (8).
compound (5a), they showed higher enantioselectivities (en-
In conclusion, a new “roofed” b-iminodisulfide appeared
tries 2—4). The results obtained using electron-withdrawing to work as a chiral ligand for the palladium-catalyzed allylic
substituents (p-Cl, p-NO2) were superior to those obtained alkylation of 1,3-diphenyl-2-propenyl acetate with good
using an electron-donating substituent (p-Me), and p- enantioselectivity, but in the opposite configuration resulting
chlorobenzylidene ligand gave the best selectivity (72% ee). from use of the b-iminothioether ligand. This is the first re-
The 9-anthranylmethylidene moiety, which showed the high- port that b-iminodisulfide itself has the potential to provide a
est ee value for the b-iminothioether-Pd(II) system,15) unique chiral environment. Additional studies are currently
showed lower selectivity (16% ee).
in progress.
While the precise mechanism of “roofed” b-iminodisulfide

October 2010
1421
Fig. 1. Plausible Asymmetric Induction Process of Palladium-Catalyzed Asymmetric Allylic Alkylation via p-Allylpalladium Complex Intermediate
References and Notes
128.5, 130.7, 135.9, 141.7, 143.0, 144.3, 145.8, 160.5. MS (FAB) m/z:
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2000, 379—381 (2000).
737 (MH)ϩ; HR-MS Calcd for C50H45N2S2 (MH)ϩ 737.0969, Found
737.3024. Compound (5c): colorless amorphous solid; [a]D ϩ467.6°
(cϭ0.42, CHCl3); 1H-NMR (300 MHz, CDCl3) d: 1.59 (6H, s), 1.79
(6H, s), 2.99 (2H, d, Jϭ8.7 Hz), 3.40 (2H, d, Jϭ8.7 Hz), 6.91—7.46
(24H, m), 7.93 (2H, s); 13C-NMR (100 MHz, CDCl3) d: 15.7, 17.0,
46.4, 47.1, 69.9, 78.2, 121.3, 121.4, 122.5, 123.0, 125.5, 125.9, 125.9,
126.1, 128.9, 129.7, 134.2, 136.8, 141.6, 142.9, 144.2, 145.7, 158.8.
MS (FAB) m/z: 827 (MNa)ϩ; HR-MS Calcd for C50H42Cl2N2S2Na
(MNa)ϩ 827.2064, Found 827.2060. Compound (6b): colorless amor-
phous solid; [a]D ϩ394.8° (cϭ1.00, CHCl3); 1H-NMR (400 MHz,
CDCl3) d: 1.64 (3H, s), 2.14 (3H, s), 3.07 (1H, d, Jϭ8.7 Hz), 3.39 (1H,
d, Jϭ8.7 Hz), 3.65 (2H, s), 7.06—7.38 (16H, m), 7.57—7.61 (2H, m),
8.05 (1H, s); 13C-NMR (100 MHz, CDCl3) d: 15.6, 17.3, 43.6, 46.5,
47.1, 68.1, 78.0, 121.3, 121.4, 122.5, 123.0, 125.3, 125.8, 125.95,
126.02, 126.9, 128.2, 128.49, 128.54, 129.2, 130.7, 135.9, 137.6,
141.4, 143.2, 144.2, 145.8, 160.6. MS (FAB) m/z: 492 (MH)ϩ; HR-MS
Calcd for C32H30NS2 (MH)ϩ 491.9940, Found 492.1820.
21) We speculate that “roofed” b-iminodisulfides 5 have cis-fused imino
and disulfide moiety with fixed conformation and therefore bidentate
site would coordinate to Pd easily and tightly to show the higher cat-
alytic activity than other b-iminosulfides. To the contrary, the direction
of the binding site of “non-roofed” b-iminodisulfide 9 is not confor-
mationally fixed and also has diverse chelation patterns with Pd, thus,
possibly showing less reactivity.
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22) It has been known that the oxidative addition of disulfides into Pd(0)
gives the thiopalladium species and dialkyl disulfides show lower reac-
tivity or instability than diaryl disulfides.23,24) To check the state of the
disulfide ligand 5a in the presence of Pd(0) species, DTNB (5,5Ј-
dithiobis(2-nitrobenzoic acid)), commonly used to quantify the con-
centration of thiol groups in a sample, was added to the mixture of lig-
and 5a, [Pd(C3H5)Cl]2 (0.5 eq) and allylacetate 7 (2 eq) in THF, fol-
lowed by the addition of 3 eq of NaCH(CO2Me)2 in THF at 20 °C. The
solution acquired the same color as it did when dibenzyl disulfide was
used in place of 5a. However, different color was acquired when ben-
zylmercaptane was added in place of 5a. This difference was qualita-
tive by visual check and did not show the exact state of the catalyst
and/or ligand. However, this results seemed to be the indirect evidence
for non-participation of thiolate from disulfide 5a and Pd(0) in the re-
action. In addition, the stability of disulfide 5a was also supported by
the fact that the treatment of diaminodisulfide 3 with NaBH4 in EtOH
gave none of the corresponding aminothiol 2.
16) b-Aminodisulfides have proven to be effective catalysts for the enan-
tioselective addition of of diethylzinc to aldehyde, providing chiral
secondary alcohols in high ees. In this case, the catalytically active
species have been shown to be thiazazincolidines, derived from the
cleavage of the disulfide bond by diethylzinc. See: Braga A. L.,
Galetto F. Z., Rodrigues O. E. D., Silveira C. C., Paixão M. W., Chiral-
ity, 20, 839—845 (2008).
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1159—1168 (2006).
20) Spectroscopic data of the typical 2-iminodisulfide ligands (5a, 5c, 6b)
are as follows. Compound (5a): colorless amorphous solid; [a]D
1
ϩ821.0° (cϭ1.00, CHCl3); H-NMR (500 MHz, CDCl3) d: 1.60 (6H, 23) Zanella R., Ros R., Graziani M., Inorg. Chem., 12, 2736—2738
s), 1.77 (6H, s), 3.04 (1H, d, Jϭ8.5 Hz), 3.44 (1H, d, Jϭ8.5 Hz),
(1973).
6.88—6.90 (2H, m), 7.03—7.44 (20H, m), 7.53—7.55 (4H, m), 7.99 24) Nishiyama Y., Kawamatsu H., Sonoda N., J. Org. Chem., 70, 2551—
(2H, s); 13C-NMR (125 MHz, CDCl3) d: 15.5, 16.9, 46.4, 47.1, 69.8,
78.2, 121.1, 121.4, 122.5, 122.9, 125.3, 125.7, 125.7, 126.0, 128.4,
2554 (2005).