(Z)-Selective Wittig and Corey-Chaykovsky reactions of propargyl ylides using trialkylgallium bases

Article abstract of DOI:10.1016/j.tetlet.2008.03.086

Trialkylgalliums deprotonated propargylphosphonium salts and propargylsulfonium salts to form propargyl ylides. The resulted organogallium intermediates underwent the Wittig reaction and the Corey-Chaykovsky reaction with aldehydes giving (Z)-enynes and (

Full text of DOI:10.1016/j.tetlet.2008.03.086

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3492–3495
(Z)-Selective Wittig and Corey–Chaykovsky reactions
of propargyl ylides using trialkylgallium bases
Yoshio Nishimura, Takao Shiraishi, Masahiko Yamaguchi *,
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
Received 21 February 2008; revised 12 March 2008; accepted 17 March 2008
Available online 24 March 2008
Abstract
Trialkylgalliums deprotonated propargylphosphonium salts and propargylsulfonium salts to form propargyl ylides. The resulted
organogallium intermediates underwent the Wittig reaction and the Corey–Chaykovsky reaction with aldehydes giving (Z)-enynes
and (Z)-epoxides predominantly. The use of an appropriate trialkylgallium is essential for the stereoselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Phosphorous and sulfur ylides, which are conveniently
generated by the treatment of onium salts with bases, are
a group of compounds used in organic synthesis. Their
reactions with aldehydes or ketones give olefins and epox-
ides, respectively, the Wittig1 and the Corey–Chaykovsky
reaction.2 Strong alkali metal bases such as butyllithium,
sodium amides, or potassium hydride have been used for
the generation of ylides, and these ylides exhibited different
reactivity and the selectivity depending on the base. The
base effect in the E/Z selectivity of the Wittig reaction is
a well-documented example. Whereas lithium bases gave
mixtures of (E)- and (Z)-isomers, sodium or potassium
bases showed high (Z)-selectivity.3 The observations were
explained by the presence or absence of the interactions
of the alkali metal cations and ylides.4 It can therefore be
expected that the use of other metal bases will exhibit still
different reactivity and selectivity. However, such method
has been unexplored, because the organometallic reagents
other than alkali metal derivatives were considered not
basic enough to deprotonate the a-position of the onium
groups.
Previously, we reported a method to use trialkylgalliums
for the deprotonation of ketones.5 The reagent exhibited
notable regioselectivity in the enolization of unsymmetrical
ketones, which the conventional alkali metal bases did not.
It was therefore considered interesting to extend the meth-
odology to the deprotonation of other organic compounds,
and described here is the ylide formation reactions of phos-
phonium and sulfonium salts. Relatively high (Z)-selectiv-
ity was observed for the Wittig and the Corey–Chaykovsky
reaction using an appropriate trialkylgallium base
(Scheme 1).
When (3-triethylsilyl-2-propynyl)triphenylphosphonium
bromide 1 (2.0 equiv), trimethylgallium (2.0 equiv), and
benzaldehyde 2 were treated in THF at room temperature
for 1 h, 1-triethylsilyl-4-phenyl-3-buten-1-yne
3
was
obtained in 93% yield in a ratio Z:E = 74:26 (Table 1, entry
1). The reactions with triethyl-, triisopropyl-, and tri(t-
butyl)gallium gave (E)-3 with lower selectivities (entries
H
Me3Ga
Ph3P
Br
+
+
R'CHO
R'CHO
R'
R'
R
R
R
H
O
t
-Bu3Ga
*
Me2S
Br
Corresponding author. Tel.: +81 22 795 6812; fax: +81 22 795 6811.
E-mail address: yama@mail.pharm.tohoku.ac.jp (M. Yamaguchi).
WPI Advanced Institute for Materials Research, Tohoku University,
Aoba, Sendai, Japan.
R
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.086

Y. Nishimura et al. / Tetrahedron Letters 49 (2008) 3492–3495
3493
Table 1
Table 2
Effect of trialkylgalliums on the Wittig reaction
The Wittig reaction of propargyl ylide using trimethylgallium
H
H
Me3Ga (2.0 eq)
Base (2.0 eq)
Ph3P
Ph3P
Br
+
R'CHO
+
PhCHO
R'
R
SiEt3
1 (2.0 eq)
R
Ph
SiEt3
THF, 0 ºC
Br
THF, rt, 1 h
2.0 eq
2
(Z)-3
Entry
R
R0
Time (h) Yield (%) Z:E
Entry
Base
Me3Ga
Yield (%) 3
Z:E
1
2
3
4
5
6a
7
8
9
SiEt3
Ph
7
10
24
10
11
24
92
86
94
82
89
71
87
84
83
94
62
63
45
72
53
80:20
78:22
85:15
85:15
81:19
88:12
81:19
81:19
84:16
84:16
78:22
77:23
78:22
76:24
85:15
1
93
92
71
66
71
91
87
43
22
74:26
80:20
76:24
11:89
67:33
28:72
39:61
17:83
32:68
2a
3b
4
p-CH3C6H4
p-ClC6H4
n-C6H13
c-C6H11
t-Bu
NaN(SiMe3)2/Me3Ga
NaN(SiMe3)2
BuLi/Me3Ga
BuLi
Et3Ga
i-Pr3Ga
5b
6c
7
t-BuMe2SiO(CH2)5 10
PhCO2(CH2)5
n-C6H13
n-C6H13
n-C6H13
n-C6H13
c-C6H11
13
20
20
8
4
4
8
9
SiBu3
Sii-Pr3
SiMe3
t-Bu3Ga
10
11b
12c
13c
14c
15c
a
a
The reaction was conducted at 0 °C.
1 was treated with alkali metal bases at 0 °C for 1 h, and then Me3Ga
b
n-C6H13
and 2 were added.
c
1 was treated with butyllithium at 0 °C for 1 h, and then 2 was added.
c-C6H11
n-C6H13
c-C6H11
4
4
7–9). In order to know the effect of the gallium reagent, an
ylide was prepared from 1 beforehand by sodium bis(tri-
methylsilyl)amide or butyllithium (1.0 equiv), and was
reacted with benzaldehyde (1.0 equiv) in the presence of
trimethylgallium (entries 3 and 5). The reaction proceeded
with (Z)-selectivity in ratios similar to the reaction using
trimethylgallium (entry 1). The results confirmed the
importance of trimethylgallium for (Z)-selectivity. It was
later found that the reaction at 0 °C enhanced the selecti-
vity to 80:20 (entry 2).
The reaction was applied to various propargylphospho-
nium salts and aldehydes, and (Z)-enynes were obtained in
good stereoselectivity (Table 2). The electron-withdrawing
group at the p-position of benzaldehyde enhanced the
(Z)-selectivity (entry 3). A bulky aliphatic aldehyde showed
higher (Z)-selectivity than less a-substituted aldehydes
(entries 4–6). Propargylphosphonium salts with alkyl
groups at the terminal carbon also underwent the (Z)-selec-
tive reactions in moderate yields at 60 °C (entries 12–15),
which may be due to relatively low acidity of the propargyl
protons of these substrates compared to the silyl
derivatives.
The synthesis of (Z)-enynes by the olefination of
aldehydes has attracted a considerable interest, and
Yamamoto developed the (Z)-selective Peterson reaction
using disilylated propargyl Grignard or titanium reagents
derived from 1,3-bis(trialkylsilyl)propynes.6 In general,
the Wittig reaction of propargylphosphonium salts gives
(E)-enynes as the major product,7 and (Z)-selective reac-
tion is rare restricted to the reaction of aldehydes possess-
ing five-membered cyclic ether ring.8 The present method
can be useful for the synthesis of (Z)-enynes using phos-
phonium salts, which is more convenient to prepare than
the propargylsilanes.
The reaction was conducted using 3.0 equiv of phosphonium salt and
10.0 equiv of Me3Ga.
b
The reaction was conducted using 3.0 equiv of phosphonium salt and
3.0 equiv of Me3Ga.
c
The reaction was conducted using 4.0 equiv of Me3Ga at 60 °C.
reaction of sulfonium ylides with aldehydes, the Corey–
Chaykovsky reaction, generally gave (E)-epoxides, and an
exception was reported using propargyltelluride.9,10 Tri-
alkylgallium method turned out to be effective for the
(Z)-selective Corey–Chaykovsky reaction of propargyl-
sulfonium ylide, which is generally easier to prepare than
the corresponding tellurides.
(3-Triethylsilyl-2-propynyl)dimethylsulfonium bromide
4 (3.0 equiv), tri(t-butyl)gallium (2.5 equiv), and cyclohex-
anecarboxaldehyde 5 were treated in chlorobenzene at
room temperature for 3 h, and (Z)-1-triethylsilyl-4-cyclo-
hexyl-1-buten-3-yne epoxide 6 (Z:E = 93:7) was obtained
in 70% yield (Table 3, entry 4). The use of trimethylgallium,
triethylgallium, and triisopropylgallium showed lower (Z)-
selectivity (entries 1–3).11 The effect of bulkiness in the tri-
alkylgalliums for the (Z)-stereoselectivity is reverse in the
Corey–Chaykovsky and the Wittig reaction.
Table 3
Effect of trialkylgalliums on the Corey–Chaykovsky reaction
H
O
R3Ga (2.5 eq)
Me2S
+
c-C6H11CHO
c-C6H11
SiEt3
4 (3.0 eq)
Br
PhCl, rt, 6 h
SiEt3
5
(Z)-6
Entry
R3Ga
Yield (%) 6
Z:E
1
2
3
4a
a
Me3Ga
Et3Ga
i-Pr3Ga
t-Bu3Ga
87
62
30
70
48:52
56:44
75:25
93:7
The ylide formation of propargylsulfonium salts using
trialkylgalliums was next examined in order to compare
the reactivity with the propargylphosphonium salts. The
The reaction was conducted for 3 h.

3494
Y. Nishimura et al. / Tetrahedron Letters 49 (2008) 3492–3495
Table 4
H
D
Base (1.0 eq.)
THF, rt, 1 h
DCl
The Corey–Chaykovsky reaction of a propargylsulfonium salt using tri(t-
butyl)gallium
Ph3P
Br
Ph3P
X
SiEt3
SiEt3
rt, 10 min
1-d
1
H
O
t
-Bu3Ga (2.5 eq)
PhCl, rt, 3 h
Me3Ga No deuteration
Me2S
Br
R
+
RCHO
BuLi
82%-d
D
SiEt3
SiEt3
H
4 (3.0 eq)
Base (1.0 eq.)
PhCl, rt, 1 h
DCl
Me2S
Br
Me2S
Entry
R
Yield (%)
Z:E
SiEt3
SiEt3
rt, 10 min
X
1
2
3
4
Ph
70
75
68
68
70
79
66
90:10
92:8
93:7
92:8
93:7
93:7
94:6
4-d
4
p-ClC6H4
p-BrC6H4
o-MeC6H4
c-C6H11
n-C6H13
PhCH2CH2
No deuteration
68%-d
t
-Bu3Ga
BuLia
a in THF at 0 ºC.
5
6a
7a
a
Scheme 3.
The reaction was conducted using 4.0 equiv of sulfonium salt and
also the deprotonation process. When 1 was reacted with
trimethylgallium (1.0 equiv) at room temperature for 1 h
followed by quenching with 10 M deuterium chloride in
D2O (5.0 equiv) at the same temperature for 10 min, no
deuteration occurred in the recovered 1. It was confirmed
that the use of butyllithium gave 1-d in a quantitative yield
with 82%-d (Scheme 3). The results indicated that tri-
methylgallium deprotonated 1 only in the presence of an
aldehyde, which may be due to the enhanced basicity
of trimethylgallium by the coordination to aldehyde. A
similar observation was obtained with a sulfonium salt.
In summary, (Z)-selective Wittig reaction and Corey–
Chaykovsky reaction of propargyl ylides were developed
using trialkylgallium base. The ligand effect on the gallium
metal played an important role in the stereoselectivity.
3.0 equiv of t-Bu3Ga.
The reaction was applied to several aldehydes, and both
aliphatic and aromatic aldehydes gave (Z)-epoxides pre-
dominantly (Table 4).
Both the ylides formed from phosphonium salts and sul-
fonium salts using trialkylgallium bases exhibited (Z)-selec-
tivity. It is interesting to consider the stereoselectivity of
these two reactions and the effect of the alkyl groups in
the gallium-derived bases.4 A hypothesis is presented in
Scheme 2. Thus, ylide addition to aldehydes can be consid-
ered to take place with the anti-configuration of carbonyl
oxygen coordinated with trialkylgallium and the onium
group. In case of phosphonium ylide reaction, the lack of
the gauche interactions between aldehyde R and ethynyl
group would favor the transition state A rather than B.
Then, the cis-elimination provided (Z)-enynes. In case of
sulfonium ylides, the gauche interactions between the gal-
lium t-butyl group and the ethynyl group became serious
at the addition step, and the transition state C was favored
over D. The trans-elimination provided (Z)-epoxides.
The interaction of carbonyl oxygen and trialkylgallium
affected not only the addition process as noted above but
Acknowledgment
Y.N. thanks JSPS for financial support (No. 18850004).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.086.
Ph3P
GaMen
GaMen
R'
O
O
H
cis-elimination
References and notes
R
R'
R
H
PPh3
H
R
H
1. Reviews: (a) Abell, A.; Edmonds, M. In Modern Carbonyl Olefination;
Takeda, T., Ed.; Wiley-VCH: Weinhelm, Germany, 2004, Chapter 1,
p 1; (b) Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999,
3049; (c) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A.
Liebigs Ann. Chem. 1997, 1283; (d) Kelly, S. E. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, Chapter 3.1, p 729; (e) Maryanoff, B. E.; Reitz,
A. B. Chem. Rev. 1989, 89, 863; (f) Maercker, A. Org. React. 1965, 14,
270.
2. Reviews: (a) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611; (b) Aggarwal, V. K. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidel-
berg, 1999; Vol. 2, Chapter 18.3, p 679; (c) Dai, L.-X.; Hou, X.-L.;
Zhou, Y.-G. Pure Appl. Chem. 1999, 71, 369; (d) Li, A.-H.; Dai,
R'
A
Ga(t-Bu)n
Ga(
t
-Bu)n
trans-elimination
R'
R'
O
O
O
H
H
H
H
R
R
R
R'
SMe2
SMe2
C
Ga(
t
-Bu)n
R'
GaMen
R'
O
O
H
H
H
R
R
H
SMe2
PPh3
´
L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341; (e) Aube, J. In
D
B
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Scheme 2.
Pergamon Press: Oxford, 1991; Vol. 1, Chapter 3.2, p 819.

Y. Nishimura et al. / Tetrahedron Letters 49 (2008) 3492–3495
3495
3. For example: (a) Reitz, A. B.; Nortey, S. O.; Jordan, A. D., Jr.;
Mutter, M. S.; Maryanoff, B. E. J. Org. Chem. 1986, 51, 3302; (b)
Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J. Am. Chem.
Soc. 1985, 50, 217; (c) Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org.
Chem. 1980, 45, 4262; (d) Bergelson, L. D.; Barsukov, L. I.;
Shermyakin, M. M. Tetrahedron 1967, 23, 2709; (e) Schlosser, M.;
Christmann, K. F. Liebigs Ann. Chem. 1967, 708, 1; (f) Bergelson, L.
D.; Vaver, V. A.; Barsukov, L. I.; Shemyakin, M. M. Tetrahedron
Lett. 1964, 2669.
4. Recent works on the mechanisms of the Wittig and Corey–Chaykov-
sky reactions: (a) Edwards, D. R.; Du, J.; Crudden, C. R. Org. Lett.
2007, 9, 2397; (b) Rabiette, R.; Richardson, J.; Aggarwal, V. K.;
Harvey, J. M. J. Am. Chem. Soc. 2006, 128, 2394; (c) Rabiette, R.;
Richardson, J.; Aggarwal, V. K.; Harvey, J. M. J. Am. Chem. Soc.
2005, 127, 13468; (d) Aggarwal, V. K.; Harvey, J. M.; Richardson, J.
J. Am. Chem. Soc. 2002, 124, 5747; (e) Lindvall, M. K.; Koskinen, A.
M. P. J. Org. Chem. 1999, 64, 4596; (f) Bangerter, F.; Karpf, M.;
Meier, L. A.; Rys, P.; Skrabal, P. J. Am. Chem. Soc. 1998, 120,
10653; (g) Yamataka, H.; Nagase, S. J. Am. Chem. Soc. 1998, 120,
7530.
Tetrahedron 2005, 61, 2607; (b) Liu, S. H.; Hu, Q. Y.; Xue, P.; Wen,
T. B.; Williams, I. D.; Jia, G. Organometallics 2005, 24, 769; (c) Vong,
B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E. A. Angew. Chem.,
Int. Ed. 2004, 43, 3947; (d) Kuramachi, K.; Nagata, S.; Itaya, H.;
Matsubara, Y.; Sunoki, T.; Uchiro, H.; Takao, K.; Kobayashi, S.
Tetrahedron 2003, 59, 9743; (e) Boeckman, R. K., Jr.; Zhang, J.;
Reeder, M. R. Org. Lett. 2002, 4, 3891; (f) Smith, A. B., III; Minbiole,
K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,
10942; (g) Boland, M.; Schroer, N.; Sieler, C. Helv. Chim. Acta 1987,
70, 1025.
8. (Z)-Selective Wittig reaction of propargylphosphonium salts: (a)
Wang, Z.-M.; Tian, S.-K.; Shi, M. Chirality 2000, 12, 581; (b) Ahmed,
M.; Barley, G. C.; Hearn, M. T. W.; Jones, S. E. R. H.; Thaller, V.;
Yates, J. A. J. Chem. Soc., Perkin Trans. 1 1974, 1981.
9. (a) Zhou, Z.-L.; Huang, Y.-Z.; Shi, L.-L. J. Org. Chem. 1992, 57,
6598; (b) Zhou, Z.-L.; Huang, Y.-Z.; Shi, L.-L.; Hu, J. J. Chem. Soc.,
Chem. Commun. 1992, 986.
10. (Z)-Selective aziridination reactions of imines with propargylsulfoni-
um salts were reported: (a) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.; Hou,
X.-L.; Xia, L.-J.; Lin, L. J. Org. Chem. 1998, 63, 4338; (b) Li, A.-H.;
Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin, L. Angew.
Chem., Int. Ed. 1997, 36, 1317; (c) Wang, D.-K.; Dai, L.-X.; Hou,
X.-L. Chem. Commun. 1997, 1231.
11. A referee suggested to conduct the reaction using other bases. Use of
NaN(SiMe3)2, KN(SiMe3)2, t-BuOK, NaH, KOH, K2CO3, and
Cs2CO3 did not give epoxide 6 by reacting at rt, and formed
decomposed products derived from 4. In contrast, butyllithium and
LDA gave 6 in 43% (Z:E = 98:2) and 47% (Z:E = 97:3) yields,
respectively. The origin of the metal effect on the stereochemistry is a
subject of interest in future.
5. (a) Nishimura, Y.; Yamaguchi, M. Chem. Commun. 2008, 35; (b)
Nishimura, Y.; Miyake, Y.; Amemiya, R.; Yamaguchi, M. Org. Lett.
2006, 8, 5077; (c) Nishimura, Y.; Amemiya, R.; Yamaguchi, M.
Tetrahedron Lett. 2006, 47, 1839.
6. (a) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H.
Bull. Chem. Soc. Jpn. 1984, 57, 2768; (b) Corey, E. J.; Rucker, C.
¨
Tetrahedron Lett. 1982, 23, 719; (c) Yamakado, Y.; Ishiguro, M.;
Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc. 1981, 103, 5568.
7. Examples of the Wittig reaction of propargylphosphonium salts: (a)
Kobayashi, Y.; Fukuda, A.; Kimachi, T.; Ju-ichi, M.; Takemoto, Y.