A new chiral organosulfur catalyst for highly stereoselective synthesis of epoxides

Article abstract of DOI:10.1002/adsc.200800453

A new chrial organosulfide was synthesized through an unexpected Wagner-Meerwein rearrangement. This organosulfide could catalyze the epoxidation reaction of various aromatic aldehydes smoothly with benzyl bromide to give trans-diaryl epoxides in satisfactory yields (60-84%) with excellent diastereoselectivities (trans:cis=95:5-100:0) and good to excellent enantioselectivities (86-96% ee).

Full text of DOI:10.1002/adsc.200800453

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DOI: 10.1002/adsc.200800453
A New Chiral Organosulfur Catalyst for Highly Stereoselective
Synthesis of Epoxides
Yuan Gui,a Jian Li,a Chang-Shan Guo,a Xin-Liang Li,a Zhi-Feng Lu,a
and Zhi-Zhen Huanga,*
a
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, Peopleꢀs Republic of China
Fax : (+86)-25-8368-6231; e-mail: huangzz@nju.edu.cn
Received: July 22, 2008; Published online: October 16, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800453.
Abstract: A new chrial organosulfide was synthe-
sized through an unexpected Wagner–Meerwein re-
arrangement. This organosulfide could catalyze the
epoxidation reaction of various aromatic aldehydes
smoothly with benzyl bromide to give trans-diaryl
epoxides in satisfactory yields (60–84%) with excel-
lent diastereoselectivities (trans:cis=95:5–100:0)
and good to excellent enantioselectivities (86–96%
ee).
nocatalyst to undergo the epoxidation reaction, fur-
nishing trans-stilbene oxides with moderate enantio-
metric excesses (about 74% ee).[4] Metzner et al. suc-
cessfully developed epoxidations catalyzed by C2-sym-
metrical thiolanes to give trans-diaryl epoxides with
excellent enantioselectivities (up to 96% ee).[5] How-
ever, the diastereoselective excesses are 66–88% in
most cases.[5] Goodmanꢀs group also utilized C2-sym-
metrical chiral sulfides to catalyze asymmetric epoxi-
dation, and a couple of good examples, the trans-2,3-
diphenyl epoxide with 97% ee and trans-2-(4-fluoro-
benzenyl)-3-phenyl epoxide with 98% ee were ob-
tained.[6] Neverthless, the yields of the two epoxides
are only 41% and 19%, respectively. Therefore, it is
still a challenge to find new organosulfur catalysts for
epoxidations to achieve not only excellent enantiose-
Keywords: chiral organosulfides; diastereoselectiv-
ity; enantioselectivity; epoxidation; organocatalysis
In the last decade, organocatalysis has undergone lectivities but also excellent diastereoselectivities.
great advances and become a powerful tool for the Initially, cheap d-camphor was chosen as a starting
synthesis of important optically active building material to undergo oxidation with selenium dioxide,
blocks.[1] It is well known that chiral epoxides are one reaction with methylmagnesium iodide, and another
of the most important synthetic building blocks owing oxidation with lead tetraacetate, leading to diketone 3
to their versatile chemical transformations and signifi- in a satisfactory yield similar to that reported in the
cant biological activities. Recently, the chiral ylide literature (Scheme 1).[7] Then it was found that dike-
route has become one of the most important strat- tone 3 could react stereoselectively with sodium boro-
egies for optically active epoxides because it combines hydride to give diol 4 as major product in a reasona-
the formation of a carbon-carbon bond and an epoxi- ble yield. After the mesylation of 4 and the successive
dation into one reaction.[2–6] Although there are many nucleophilic substitution of dimesylate 5 with sodium
reports on employing chiral sulfides to catalyze epoxi- sulfide nonahydrate in DMSO at 100–1058C, we iso-
dation reactions via sulfonium ylides, very successful lated desired chiral organosulfide 6 in 37% yield as
cases are still limited.[2a,3–6] Aggarwal et al. found that major product and an unkown liquid. The configura-
chiral sulfonium ylides could be formed by the reac- tions of the two carbons connected with two hydroxy
tion of sulfides with diazo compounds under the catal- groups, respectively, in diol 4 should be opposite to
ysis of CuACHTUNGTRENNUNG(acac)2 or Rh2ACHTUGNTERN(NUGN OAc)4, affording an elegant the configurations of that connected to sulfur in orga-
synthesis of trans-diaryl epoxides in high yields with nosulfide 6 due to the SN2 reaction initiated by sulfide
excellent distereoselectivities and enantioselectivities anion.[5] The structure of organosulfide 6 was deduced
(up to 94% ee).[3] In these processes, although novel from its oxide 7 by single crystal X-ray diffraction.[8a]
sulfides were used as organocatalysts, metal com- Because the spot of the unkown liquid on TLC after
plexes were also neccessarily employed.[1b,2a,3] Daiꢀs exposure to iodine vapor is very close to the spot of
1
group reported a camphor-derived sulfide as an orga- organosulfide 6, the H NMR spectrum of the liquid
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Scheme 1. Synthesis of chiral organosulfide 6.
Table 1. Optimization of the asymmetric epoxidation cata-
lyzed by organosulfide 6.[a]
is analogous to that of 6 and the molecule weight of
the liquid is equal to that of 6 according to mass spec-
tra data, we presumed that the liquid might be an
isomer of organosulfide 6. Thus, the reaction of the
liquid with benzyl bromide and silver tetrafluorobo-
rate was perfomed at room temperature, and the ex-
pected sulfonium salt 9 was obtained in 87% yield. Fi-
nally, the unkown liquid was determined to be orga-
nosulfide 8 by single crystal X-ray diffraction of its
salt 9.[8b]
By lowering the temperature in the reaction of di-
mesylate 5 with sodium sulfide from 100–1058C to
65–708C,[5c] the yield of organosulfide 6 was increased
to 55%. With the novel organosulfide 6 in hand, we
examined the epoxidation reaction of benzaldehyde
10a with benzyl bromide under the catalysis of orga-
nosulfide 6. It was found that when sodium hydroxide
or potassium hydroxide and tetrabutylammonium
iodide (TBAI) were employed, respectively, as a base
and an additive for halogen exchange and phase-
transfer catalysis,[5b] organosulfide 6 could catalyze
the epoxidation reaction smoothly in MeCN-H2O (9:1
v/v) at room temperature to give desired diphenyl ep-
oxide 11a in good yields with excellent trans diaste-
reoselectivities (entries 5 and 6, Table 1). However,
Entry Solvent (9:1
v/v)
Base
Yield
[%][b]
trans/
ee
cis[c]
[%][d]
1
2
3
4
5
6
t-BuOH/H2O NaOH 54
i-PrOH/H2O NaOH 50
98:2
98:2
9
11
–
–
19
15
[e]
[e]
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
Cs2CO3 trace
K2CO3 trace
NaOH 78
–
–
[e]
[e]
99:1
99:1
KOH
80
[a]
Reaction temperature was 20–258C and reaction time
was 40 h. Other conditions are similar to the general pro-
cedure for epoxides in Experimental Section.
Isolated yields.
[b]
[c]
[d]
1
Determined by HNMR or GC.
Enantiomeric excesses of trans isomers were determined
by chiral HPLC using a Chiracel OD-H column.
Not determined.
[e]
the enantioselectivities were rather low under various rearrangement reaction by raising the reaction tem-
reaction conditions. (Table 1). perature and decreasing the amount of sodium sulfide
Owing to the poor enantioselectivities of the epoxi- in the nucleophilic substitution, and found that when
dation catalyzed by chiral organosulfide 6, we turned the reaction of dimesylate 5 with sodium sulfide nona-
our attention to chiral organosulfide 8. The organosul- hydrate was performed in DMF at 140–1508C and the
fide 8 was a Wagner–Meerwein rearrangement prod- amount of sodium sulfide nonahydrate was decreased
uct from dimesylate 5. The quartenary carbon adja- from about 2 equiv. to about 1 equiv., the organosul-
cent to the secondary carbon cation in 12 might pro- fide 8 could be obtained as major product in a yield
mote a 1,2-carbon shift to form a more stable tertiary of 41% with the organosulfide 6 in 13% yield in the
carbon cation as in 13 (Scheme 2). We improved the two-step sequence (Scheme 3).
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Chiral Organosulfur Catalyst for Highly Stereoselective Synthesis of Epoxides
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Table 2. Optimization of the asymmetric epoxidation cata-
lyzed by organosulfide 8.[a]
Entry Mol% Solvent/
Base
Yield
[%][c]
trans/ ee
8
H2O[b]
cis[d]
[%][e]
1
2
3
4
5
6
7
10
10
10
10
10
10
5
t-BuOH
i-PrOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NaOH 51
NaOH 48
NaOH 70
98:2
98:2
99:1
99:1
88
87
93
91
Scheme 2. Simplified scheme of the rearrangement to form
organosulfide 8.
KOH
71
[f]
[f]
Cs2CO3 trace
K2CO3 trace
NaOH 58
NaOH 74
NaOH 63
NaOH 60
–
–
–
–
[f]
[f]
98:2
99:1
99:1
99:1
92
90
93
88
8
20
10
9[g]
10[h] 10
[a]
Reaction temperature was 20–258C and reaction time
was 40 h. Other conditions are similar to the general pro-
cedure for epoxides in Experimental Section.
Solvent/H2O: v:v=9:1.
[b]
[c]
[d]
[e]
Isolated yields.
Determined by HNMR or GC.
1
Scheme 3. Synthesis of chiral organosulfide 8.
Enantiomeric excesses of trans isomers were determined
by chiral HPLC using a Chiracel OD-H column.
Not determined.
Reaction temperature: 08C.
No TBAI was used.
[f]
With the new organosulfide 8 in hand, we chose
benzaldehyde 10a as a model substrate to probe the
reaction conditions for asymmetric epoxidation.
When t-BuOH/H2O (9:1 v/v), sodium hydroxide and
[g]
[h]
TBAI were employed as solvent, base and additive, crease of the ee value was observed (entry 9, Table 2).
respectively, we were pleased to find that organosul- It was further found that without TBAI, both the
fide 8 could catalyze the epoxidation reaction of ben- yield and enantioselectivity of the epoxidation were
zaldehyde 10a readily with benzyl bromide to give the decreased (compare entries 3 and 10, Table 2). Thus,
desired diphenyl epoxide 11a in a moderate yield the optimal reaction conditions were as follows: the
with excellent diastereoselectivity and good enantio- reaction was performed at room temperature, the sol-
selectivity (entry 1, Table 2). Encouraged by this vent was CH3CN/H2O (9:1 v/v), the base was sodium
result, we examined other solvents in the reaction. hydroxide, TBAI was employed as an additive and
Using i-PrOH/H2O (9:1 v/v) as solvent led to similar the amount of organosulfide 8 was 10 mol%.
yield, diastereoselectivity and enantioselectivity
After the optimal reaction conditions were estab-
(entry 2, Table 2). To our delight, when MeCN/H2O lished, various aromatic aldehydes 10a–i were exam-
(9:1 v/v) was employed as a solvent, both the yield ined in the asymmetric epoxidation. It was found that
and the enantioselectivity were improved remarkably organosulfide 8 at 10 mol% loading could catalyze
(entry 3, Table 2). The effect of bases on yields was the epoxidation of aromatic aldehydes 10a–i smoothly
also studied. Using potassium hydroxide led to a simi- with benzyl bromide via a chiral sulfonium ylide,
lar yield, diastereoselectivity and enantioselectivity as giving the desired trans-diaryl epoxides 11a–i with sat-
those using sodium hydroxide (entries 3 and 4, isfactory yields (60–84%) in 40 h (entries 1–9,
Table 2). When weak bases such as cesium carbonate Table 3). Almost solely trans isomers of epoxides
and potassium carbonate were employed, only a trace were obtained in most cases for the aromatic alde-
amount of trans-diphenyl epoxide 11a was obtained hydes 10a–i. Moreover, various aromatic aldehydes
(entries 5 and 6, Table 2). As compared to the 10 could result in good to excellent enantioseletivities
mol% loading, using 20 mol% of organosulfide 8 led (88–96% ee) and among them, 4-methylbenzaldehyde
to a slight decrease of enantioselectivity while there led to the highest enantioselectivity (entries 1–9,
was a slight increase in yield (compare entries 3 and Table 3). For the asymmetric epoxidation of bezalde-
8, Table 2). When the reaction temperature was de- hyde 10a with benzyl bromide, the chiral sulfide 8 as
creased from room temperature to 08C, the epoxida- an organocatalyst could result in both excellent enan-
tion reaction proceeded slowly, and no significant in- tioselectivity (93% ee) and excellent diastereoselectiv-
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Yuan Gui et al.
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Table 3. Scope of the epoxidation of aldehydes 11 under the
catalysis of orgaosulfide 8.[a]
leraldehyde or isovaleraldehyde led to moderate
enantioselectivities.
In conclusion, we have synthesized two new chiral
organosulfides 6 and 8 using cheap d-camphor as
starting material. Among them, the chiral organosul-
fide
8 was synthesized through an unexpected
Wagner–Meerwein rearrangement. It was found that
the organosulfide 8 could catalyze the epoxidation re-
action of various aromatic aldehydes smoothly with
benzyl bromide to give trans-diaryl epoxides in satis-
factory yields (60–84%) with excellent diastereoselec-
tivities (trans:cis=95:5–100:0) and good to excellent
enantioselectivities (86–96% ee). Therefore, organo-
sulfide 8 has better catalytic functions in comparison
with the other organosulfides summarized in ref.[10]
The studies on the utility of the chalcogenides having
a novel structure like 8 in organocatalyzed epoxida-
tions, cyclopropanations and aziridinations with excel-
lent diastereoselectivies and enantioselectivies are un-
derway.
Entry R
11 Yield trans/ ee
[%][b] cis[c] [%][d]
Configuration
1
C6H5
a
b
c
d
e
f
70
67
60
78
65
84
76
80
71
68
65
53
57
51
99:1 93
99:1 96
98:2 90
100:0 94
96:4 93
100:0 88
100:0 88
97:3 90
98:2 86
95:5 86
99:1 85
87:13 85
75:25 73
80:20 71
R,R
R,R
R,R
R,R
R,R
R,R
R,R
R,R
S,S
2
3
4
5
6
7
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-FC6H4
g
h
i
j
k
l
8
9
2,4-Cl2C6H3
4-NO2C6H4
2-Furyl
E-Styryl
Cyclohexyl
10
11
12
S,R
R,R
R,R
R,R
R,R
13[e] CH
(CH2)3
m
n
14[e]
ACHTUNGTRENNUNG(CH3)2CHCH2
Experimental Section
[a]
For detailed reaction conditions, see the general procedure
for epoxides in Experimental Section.
Isolated yields.
Determined by HNMR or GC.
Enantiomeric excesses of trans isomers were determined by
chiral HPLC using a Chiracel OD-H column.
General Procedure for Epoxides
[b]
[c]
[d]
1
To the solution of chiral organosulfide 8 (6.0 mg, 0.03 mmol)
in MeCN/H2O (3 mL, 9:1v/v) was added aldehyde
(0.30 mmol), benzyl bromide (77 mg, 0.45 mmol), n-Bu4NI
(108 mg, 0.30 mmol) and NaOH (24 mg, 0.60 mmol).The re-
action mixture was stirred at 20–258C for 40 h. Filtration
and evaporation gave a residue that was purified by prepa-
rative TLC or column chromatography, affording the de-
sired epoxide 11a–n.
[e]
15 mol% of 8 was employed and the reaction time was 48 h.
ity (98% de), which was rarely reported in the litera-
ture.[10] The absolute configurations of the epoxides
11a–n were assigned by comparison of the results of
optical rotation and chiral HPLC with those of known
compounds and all (R, R)-isomers of 11a–h are dex-
trorotatory in EtOH.[3d,4] Furyl aldehyde 10j as a het-
eroaromatic aldehyde also underwent the epoxidation
reaction readily, giving a similar yield, diastereoselec-
tivity and enantioselctivity (entry 10, Table 3). The
configuration of 2-(4-nitrophenyl)-3-phenyl epoxide
11i was reversed and the configuration of 2-(2-furyl)-
Supporting Information
1
Preparations, analytical data, H and 13C NMR spectra of 3–
6, 8, 9 and 11a–n and chiral HPLC diagrams of 11a–n are
available as Supporting Information.
Acknowledgements
3-phenyl epoxide 11j is the same as that in most We thank the National Natural Science Foundation of China
for financial support of the project (20572042).
diaryl epoxides 11a–h although it was designated
(2S,3R) (entries 9 and 10, Table 3).[3d,9]
As compared to many epoxidations of aromatic al-
dehydes, only a small amount of examples involved References
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tion of aliphatic aldehydes smoothly with benzyl bro-
mide to furnish 2-alkyl-3-phenyl epoxides 11l–n in
reasonable yields with moderate diastereoselectivities
(entries 12–14, Table 3). Among them, cyclohexane-
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Adv. Synth. Catal. 2008, 350, 2483 – 2487

Chiral Organosulfur Catalyst for Highly Stereoselective Synthesis of Epoxides
COMMUNICATIONS
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