Stereoselective Synthesis of Z-α,β-Unsaturated Sulfones Using Peterson Reagents

Article abstract of DOI:10.1021/acs.orglett.5b03008

New Peterson reagents were prepared by introducing alkyloxy groups on the silicon atom in order to fix the conformation of the sulfone anion. The reagents 1d and 1e reacted with a variety of aldehydes after the treatment with Li-base to give Z-α,β-unsaturated sulfones with up to >99:1 selectivity in good to excellent yields. For the reaction with aliphatic aldehydes, CPME (cyclopentyl methyl ether) is the choice of solvent, while DME (1,2-dimethoxyethane) gave higher selectivity for the reaction with aromatic aldehydes.

Full text of DOI:10.1021/acs.orglett.5b03008

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Z‑α,β-Unsaturated Sulfones Using
Peterson Reagents
Kaori Ando,* Tomohiro Wada, Miho Okumura, and Hiroshi Sumida
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: New Peterson reagents were prepared by introducing
alkyloxy groups on the silicon atom in order to fix the conformation of
the sulfone anion. The reagents 1d and 1e reacted with a variety of
aldehydes after the treatment with Li-base to give Z-α,β-unsaturated
sulfones with up to >99:1 selectivity in good to excellent yields. For
the reaction with aliphatic aldehydes, CPME (cyclopentyl methyl ether) is the choice of solvent, while DME (1,2-
dimethoxyethane) gave higher selectivity for the reaction with aromatic aldehydes.
α,β-Unsaturated sulfones1 are useful substrates in stereospecific
conformation of the sulfone anion, we planned to introduce an
alkyloxy group on the silicon atom of the Peterson reagent. The
anion derived from 1 would be expected to have a chelate
structure. When that anion reacts with aldehyde, two plausible
transition structures C1 and C2 could potentially arise.
Moreover, if R′ is large, the structure C1 would suffer from
steric repulsion between the R group of the aldehyde and the
R′ group on the silicon atom. Thus, reaction occurs via C2 to
give D, from which Z-α,β-unsaturated sulfone 2 would be
obtained via the intermediate E.13 In order to test this working
hypothesis, the reagents 1 were prepared and the reactions of 1
with a variety of aldehydes were studied. Here, we wish to
report the Z-selective preparation of α,β-unsaturated sulfones
using new Peterson reagents 1.
reactions for the construction of chiral centers, such as the
Michael reaction,2 epoxidation,3 and the Heck reaction.4 In
addition, some vinyl sulfones are known as cysteine protease
inhibitors5 and neuroprotective agents for Parkinson’s disease
therapy.6 Therefore, the stereodefined synthesis of carbon−
carbon double bonds with high selectivity is critically important.
Although it is rather easy to obtain the thermodynamically
stable E-α,β-unsaturated sulfones, there is no general method to
obtain Z-isomers. For special cases, iodosulfonylation of
terminal alkynes followed by reductive cleavage of the C−I
bond,7 nucleophilic addition of thiols to acetylene followed by
oxidation,8 and others9 were reported. Mori and co-workers
reported stereoselective epoxidation of Z-α,β-unsaturated
sulfones having a chiral center at the γ-position, and the
products were elegantly transformed to trans-fused tetrahy-
dropyran rings which are frequently encountered cyclic units of
marine toxins.3 Unfortunately, they prepared the starting Z-α,β-
unsaturated sulfones by the Peterson reaction10 of
Me3SiCH2SO2Ph with chiral aldehydes as a 1:1 mixture (Z/
E) following Ley’s procedure.11 The reason for this non-
stereoselectivity seems to be the presence of two conformers A
and B for the sulfone anions12 (Scheme 1). In order to fix the
In order to see the effects of the alkyloxy group, the reaction
of the reagents 1 with n-octanal was performed (Table 1).
Table 1. Peterson Reaction of 1 with n-Octanal
entry
R3Si, 1
base (equiv)
yield (%)
Z/E
1
2
3
4
5
(tBuO)Ph2Si, 1a
Ph3Si, 3
n-BuLi (0.9)
n-BuLi (0.9)
n-BuLi (0.9)
LiHMDS (1.3)
LiHMDS (1.3)
92
32
89
91
71
81:19
22:78
64:36
79:21
76:24
(tBuO)Me2Si, 1b
1a
Scheme 1. Our Working Hypothesis for a New Peterson
Reagent
(Et2CHO)Ph2Si, 1c
When the (t-BuO)Ph2Si reagent 1a14,15 was treated with n-BuLi
(0.9 equiv)16 in THF at 0 °C for 30 min and the resulting anion
reacted with n-octanal at 0 °C, α,β-unsaturated sulfone 2a was
obtained with 81:19 Z-selectivity in 92% yield (entry 1 in Table
1). For comparison, the same reaction was performed using
Ph3SiCH2SO2Ph 3 instead of 1a. The alkene 2a was obtained in
32% yield with 22:78 E-selectivity (entry 2). Thus, we had
Received: October 17, 2015
Published: December 4, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b03008
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Organic Letters
Letter
succeeded in the selective preparation of Z-2a by introducing a
t-BuO group on the silicon atom of the Peterson reagent. The
(t-BuO)Me2Si reagent 1b gave lower 64:36 selectivity by the
same procedure (entry 3). The Z-selectivity of the (Et2CHO)-
Ph2Si reagent 1c using LiHMDS (1.3 equiv) was also lower
than that of 1a (entries 4 and 5), and the yield of 1c was low
probably due to the low stability of 1c. From this screening, 1a
looked to be the most promising reagent tested here.
Further optimization of the reaction conditions was
performed using 1a. When 1a was treated with n-BuLi (1.3
equiv) in THF at 0 °C and the anion reacted with
benzaldehyde at −78 °C, 2b was obtained in 93% yield with
90:10 Z-selectivity (entry 1 in Table 2). Although the use of
the reaction with p-chlorobenzaldehyde using LiHMDS (1.3
equiv) at room temperature gave 1:99 E-selectivity in 17%
yield. The selectivity dropped to 82:18 at lower temperature in
90% yield (entry 7). Next, the reactions of 1a with aliphatic
aldehydes were studied. The reaction with n-octanal was also
performed at 0 °C and gave 79:21 selectivity (entry 8).
Interestingly, lower selectivity was obtained at both −20 °C and
room temperature (entries 9 and 10). The highest selectivity
was obtained by using n-BuLi (0.9 equiv) at 0 °C (81:19, 92%
yield) (entry 11). The reaction of 1a with cyclohexanecarbal-
dehyde gave 2f in 97% yield with 94:6 Z-selectivity (entry 12).
In the same procedure, the reactions with 2-methylpentanal 4g
and 2-ethylhexanal 4h gave the corresponding alkenes with
94:6 and 96:4 Z-selectivity (entries 13 and 14). The reactions
with more hindered 4i and pivalaldehyde gave 2i and 2j with
74:26 and 69:31 Z-selectivity, respectively (entries 15 and 16).
In addition, the reaction with trans-2-hexenal 4k gave a
moderate selectivity (86:14, entry 17). Thus, we succeeded in
preparing Z-2 by the reaction of 1a with α-branched aldehydes
highly selectively. However, there is still room for improvement
for other types of aldehydes.
Table 2. Peterson Reactions of 1a with Aldehydes
entry
4, R
conditions
2, yield (%)
Z/E
a
1
Ph
Ph
Ph
−78 °C, 1 h
−78 °C, 1 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
−78 to 0 °C
0 °C, 2 h
−20 °C, 2 h
rt, 2 h
2b, 93
2b, 76
2b, 81
2c, 86
2d, 61
2e, 73
2e, 90
2a, 91
2a, 96
2a, 70
2a, 92
2f, 97
2g, 85
2h, 85
2i, 73
2j, 55
2k, 76
90:10
90:10
91:9
The effect of the substituent on the aryl sulfones were also
studied as shown in Scheme 2. When the reaction with
2
3
4
5
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-ClC6H4
n-C7H15
n-C7H15
n-C7H15
n-C7H15
c-Hex
91:9
Scheme 2. Effects of the Substituent on Aryl Sulfones
88:12
86:14
82:18
79:21
76:24
74:26
81:19
94:6
b
6
7
8
9
10
a,b
11
12
13
14
15
16
17
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 3 h
0 °C, 4 h
0 °C, 2 h
4g
94:6
4h
96:4
4i
74:26
69:31
86:14
a,b
t-Bu
benzaldehyde was performed at −78 °C, the Z/E ratios were
90:10, 87:13, 92:8, and 85:15 for the reagent having X = H, Cl,
Me, OMe, respectively. The p-tolyl sulfone reagent gave the
highest Z-selectivity (92:8) in a good yield (80%). A similar
trend was observed for the reaction with n-octanal. Thus, the
selectivity was slightly improved by using the p-tolyl sulfone
reagent. In other words, our new method will be useful for
various aryl sulfones due to the small substituent effect.
4k
a
b
n-BuLi was used as base. 0.9 equiv of base was used.
LiHMDS instead of n-BuLi gave the same selectivity at −78 °C,
slightly higher selectivity (91:9) was obtained at 0 °C (entries 2
and 3). It is unclear why the Z-selectivity is higher at the higher
temperature. Since the use of NaHMDS and KHMDS at −78
°C gave 2b with Z/E = 76:24 and 35:65 ratio, respectively, it is
important to use Li base. The use of toluene as solvent gave
lower selectivity (Z/E = 36:64) in 40% yield along with the
recovered 1a (40%) at −78 °C. The reaction of 1b, 1c, and 3
with benzaldehyde gave 2b with Z/E = 46:54 (62% yield),
51:49 (67% yield), and 21:79 (64% yield), respectively. The
reactions of 1a with p-tolualdehyde and p-anisaldehyde under
the same conditions as entry 3 gave the corresponding alkenes
2c and 2d with 91:9 and 88:12 Z-selectivity, respectively
(entries 4 and 5). The reaction with p-chlorobenzaldehyde
under the same conditions (1.3 equiv of LiHMDS at 0 °C for 2
h) gave 2e with 58:42 Z-selectivity (62% yield). When the same
reaction was performed by using LiHMDS (0.9 equiv), an
86:14 ratio was obtained in 73% yield (entry 6). It seems that
both decomposition and isomerization of 2e occur in the
presence of excess base at 0 °C or higher temperature. In fact,
In order to improve the Z-selectivity, we prepared the
reagents having alkoxyalkyloxy groups on the silicon atom,
which were expected to have a stronger chelate structure when
they were treated with Li base (Scheme 3). Monoprotection of
3-methylbutane-1,3-diol followed by the reaction with Ph2SiCl2
gave 5. The reaction of the crude silyl chlorides 5 with the
anion derived from PhSO2Me gave 1d and 1e in good yields.
Scheme 3. Preparation of New Peterson Reagents 1d,e,f
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DOI: 10.1021/acs.orglett.5b03008
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Organic Letters
Letter
The reagent 1f was obtained from commercially available 1-
methoxy-2-methyl-2-propanol by the same procedure.
Table 4. Peterson Reactions of 1e with Aliphatic Aldehydes
When 1d was treated with n-BuLi (0.9 equiv) in THF at 0
°C for 15 min followed by the addition of n-octanal at 0 °C, Z-
2a was obtained in 79% yield and 82:18 ratio (entry 1 in Table
3). In toluene, the selectivity was improved to 92:8 and the use
entry
4, R
conditions
2, yield (%)
Z/E
Table 3. Peterson Reactions of 1d−f with n-Octanal
1
2
3
4
5
n-C7H15
4l
−78 °C, 2 h
−78 °C, 2 h
0 °C, 2 h
−78 °C, 3 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 3 h
0 °C, 2 h
−78 °C, 3 h
0 °C, 2 h
rt, 2 h
2a, 85
2l, 92
2l, 92
2m, 64
2f, 97
2f, 84
2g, 90
2h, 91
2i, 68
2i, 75
2i, 69
2j, 79
2j, 92
2j, 76
2k, 90
2k, 83
97:3
96:4
4l
93:7
Ph(CH2)2
c-Hex
c-Hex
4g
94:6
99:1
a
6
99:1
7
8
9
99:1
entry
1
solvent
conditions
yield (%)
Z/E
4h
>99:1
91:9
a
1
1d
1d
1d
1d
1d
1d
1e
1e
1e
1f
THF
0 °C, 2 h
0 °C, 4 h
0 °C, 1 h
−78 °C, 3 h
0 °C, 2 h
−78 °C, 3 h
0 °C, 2 h
0 °C, 2 h
−78 °C, 2 h
0 °C, 2 h
0 °C, 2 h
79
60
84
77
80
78
69
90
85
56
80
82:18
92:8
91:9
93:7
93:7
95:5
92:8
93:7
97:3
80:20
4i
a
a
2
toluene
toluene
toluene
CPME
CPME
toluene
CPME
CPME
toluene
toluene
10
4i
90:10
91:9
a
3
11
4i
b
4
12
13
t-Bu
t-Bu
t-Bu
4k
88:12
86:14
89:11
92:8
5
b
a
6
14
0 °C, 2 h
0 °C, 2 h
−78 °C, 2 h
7
8
9
15
16
4k
94:6
a
1d was used instead of 1e.
a
10
11
1f
79:21
b
Table 5. Peterson Reactions of 1e with Aromatic Aldehydes
a
n-BuLi (0.9 equiv) was used instead of LiHMDS (1.3 equiv). Base
was added at −78 °C.
of LiHMDS instead of n-BuLi at −78 °C gave 93:7 Z-selectivity
(entries 2−4). In cyclopentyl methyl ether (CPME), the Z-
selectivity was further improved to 95:5 (entry 6). In order to
see the effect of alkoxy group, R′O, the same reaction was
performed using the methoxy reagent 1e to give Z-2a with 97:3
selectivity in 85% yield (entry 9). The reaction of the one
carbon shorter reagent 1f gave 2a with inferior Z-selectivity
(80:20) even in toluene solvent (entry 10). Thus, extremely
high Z-selectivity (97:3) was obtained from the reaction of 1e
with n-octanal, which reacted with 1a to give 2a in moderate Z-
selectivity (entry 11 in Table 2).
The examples summarized in Table 4 demonstrate the
versatility and the scope of our new reagent 1e for the synthesis
of Z-α,β-unsaturated sulfones 2 with various aliphatic
aldehydes. Not only n-octanal but also β-branched aldehyde,
citronellal 4l, and 3-phenylpropionaldehyde reacted with 1e at
−78 °C to give 2l and 2m with high Z-selectivity (96:4 and
94:6, entries 2 and 4). The reactions of 1e with α-branched
aldehydes, cyclohexanecarbaldehyde, 4g, and 4h gave 2 with
more than 99:1 Z-selectivity in 90−97% yields even at 0 °C
(entries 5, 7, and 8). A similar result was obtained with 1d
(99:1, 84% yield, entry 6). The reaction with more hindered
aldehyde 4i gave slightly lower selectivity (91:9) in 68% yield
(entry 9). The reaction of 1d with 4i gave similar results, and
the selectivity was slightly higher at −78 °C (entries 10 and
11). With more bulky pivalaldehyde, 2j was obtained with
88:12 selectivity from 1e and 89:11 selectivity from 1d (entries
12−14). The reaction with α,β-unsaturated aldehyde, trans-2-
hexenal 4k gave Z-2k with 94:6 Z-selectivity in 83% yield
(entry 16).
entry
4, R
solvent
conditions
2, yield (%)
Z/E
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CPME
THF
−78 °C, 3 h
0 °C, 1 h
−78 °C, 1 h
0 °C, 1 h
−78 °C, 1 h
−78 °C, 3 h
−55 °C, 3 h
−55 °C, 3 h
−55 °C, 3 h
−55 °C, 4 h
2b, 76
2b, 76
2b, 97
2b, 71
2b, 54
2b, 35
2b, 90
2c, 96
2d, 67
2e, 64
87:13
90:10
90:10
92:8
THF
a
4
a
THF
5
THF
89:11
74:26
94:6
6
toluene
DME
DME
DME
DME
7
8
p-MeC6H4
p-MeOC6H4
p-ClC6H4
94:6
9
93:7
10
87:13
a
1d was used instead of 1e.
−78 °C, 2b was obtained in 76% yield and 87:13 Z-selectivity
(entry 1). Since the selectivity is moderate under the best
conditions for aliphatic aldehydes, further optimization of the
reaction conditions was performed. In THF, slightly higher
90:10 Z-selectivity was obtained at both 0 and −78 °C (entries
2 and 3). Under the same conditions, 1d gave 92:8 selectivity at
0 °C and 89:11 selectivity at −78 °C (entries 4 and 5). The Z-
selectivity further improved to 94:6 in 1,2-dimethoxyethane
(DME) at −55 °C, giving the products in 90% yield (entry 7).
By using this procedure, p-tolualdehyde and p-anisaldehyde
gave the corresponding alkenes with 94:6 and 93:7 Z-
selectivity, respectively (entries 8 and 9). The selectivity was
dropped to 87:13 for the reaction with p-chlorobenzaldehyde
(entry 10).
The reactions of 1e with aromatic aldehydes are summarized
in Table 5. When 1e was treated with LiHMDS (1.3 equiv) in
CPME at 0 °C followed by the addition of benzaldehyde at
In summary, we have developed new Peterson reagents for
the synthesis of Z-α,β-unsaturated sulfones, which are useful
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DOI: 10.1021/acs.orglett.5b03008
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Organic Letters
Letter
(7) (a) Truce, W. E.; Muldoon, C. A.; Sinclar, J. J. Org. Chem. 1971,
36, 1727. (b) Edwards, G. L.; Muldoon, C. A.; Sinclair, D. J.
Tetrahedron 1996, 52, 7779.
(8) Truce, W. E.; Simms, J. A. J. Am. Chem. Soc. 1956, 78, 2756.
(9) Ohnuma, T.; Hata, N.; Fujiwara, H.; Ban, Y. J. Org. Chem. 1982,
47, 4713.
(10) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (b) Staden, L. F.;
Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195.
(11) Craig, D.; Ley, S. V.; Simpkins, N. S.; Whitham, G. H.; Prior, M.
J. J. Chem. Soc., Perkin Trans. 1 1985, 1949.
(12) The metallated carbon is nearly pyramidal in PhSCH2Li and
nearly planar in PhSOCH2Li, and PhSO2CH2Li is in an intermediate
hybridization state. See: (a) Chassaing, G.; Marquet, A. Tetrahedron
1978, 34, 1399. (b) Chassaing, G.; Marquet, A. J. Organomet. Chem.
1982, 232, 293. (c) Ohno, A.; Higaki, M.; Oka, S. Bull. Chem. Soc. Jpn.
1988, 61, 1721. In addition, our DFT study (B3LYP/6-31G*) on the
anion derived from 1a shows strong interactions with both one of the
sulfone oxygens and the metallated carbon, which caused the
carbanion carbon to have a rather flat pyramidal structure. The
energy difference between two conformers A and B is only 0.1 kcal/
mol.
synthetic intermediates in organic synthesis. In order to fix the
conformation of the sulfone anion, we introduced an alkyloxy
group on the silicon atom of the Peterson reagents. The
reaction of the (t-BuO)Ph2Si reagent 1a with a variety of
aldehydes gave Z-α,β-unsaturated sulfones with 69−96%
selectivity in moderate to high yields. On the other hand, the
Ph3Si reagent 3 showed moderate E-selectivity. Further
improvement was obtained by the introduction of alkoxyalky-
loxy reagents 1d and 1e, which showed high Z-selectivity
(generally 93−99% Z-selectivity) for a variety of aldehydes.
This is the first Z-selective synthesis of α,β-unsaturated sulfones
from aldehydes and can be applied to a broad range of
substrates. Investigations into the detailed reaction mechanism
and the synthetic applications of this methodology are actively
being studied in this laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
This material is available free of charge via the Internet. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b03008.
(13) Kawashima, T.; Iwama, N.; Okazaki, R. J. Am. Chem. Soc. 1992,
114, 7598.
(14) The reagent 1a was prepared in 91% yield from the reaction of
MeSO2Ph and (t-BuO)Ph2SiCl, which was prepared by following the
literature procedure: Gillard, J. W.; Fortin, R.; Morton, H. E.; Yoakim,
C.; Quesnelle, C. A.; Daignault, S.; Guindon, Y. J. Org. Chem. 1988, 53,
2602.
(15) The nitrile reagent (t-BuO)Ph2SiCH2CN was reported to give
Z-α,β-unsaturated nitriles: Kojima, S.; Fukuzaki, T.; Yamakawa, A.;
Murai, Y. Org. Lett. 2004, 6, 3917.
(16) When 1.3 equiv of n-BuLi was used and the reaction with n-
octanal was performed at 0 °C, only a trace amount of 2a was
obtained. When isolated 2a (Z/E = 85:15) was treated with n-BuLi
(0.2 equiv) in THF at 0 °C for 3 h, 7% of 2a (Z/E = 82:18) was
recovered along with deconjugated sulfones and some Michael
addition products.
Experimental procedures, compound characterization
1
data, H NMR spectra of compounds 1a−f, 3, 1a(p-
Me), 1a(p-MeO), 1a(p-Cl), and 2a−m, and 13C NMR
spectra of compounds 1a,b,d−f, 3, and 2a−m (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ando@gifu-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Natsuhisa Oka (Gifu University) for his
assistance with the high-resolution mass spectra analysis. This
work was supported financially by a Grant-in-Aid for Scientific
Research on Innovative Areas.
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