A novel one-pot three-component tandem Michael/aldol/Horner-Wadsworth-Emmons (HWE) reaction of lithium alkylselenolates with 1-alkynylphosphine oxides and aldehydes: Facile synthesis of selenium-substituted allenes

Article abstract of DOI:10.1039/b304527g

The one-pot tandem Michael/aldol/Horner-Wadsworth-Emmons (HWE) reaction of lithium alkylselenolates, 1-al-kynylphosphine oxides and aldehydes in THF provides a new general access to selenium-substituted allenes with good to excellent yields.

Full text of DOI:10.1039/b304527g

A novel one-pot three-component tandem
Michael/aldol/Horner–Wadsworth–Emmons (HWE) reaction of lithium
alkylselenolates with 1-alkynylphosphine oxides and aldehydes: facile
synthesis of selenium-substituted allenes†
Xian Huang*ab and Zheng-Chang Xionga
a Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, P. R. China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P. R. China
Received (in Cambridge, UK) 25th April 2003, Accepted 20th May 2003
First published as an Advance Article on the web 11th June 2003
The one-pot tandem Michael/aldol/Horner–Wadsworth–
Emmons (HWE) reaction of lithium alkylselenolates, 1-al-
kynylphosphine oxides and aldehydes in THF provides a
new general access to selenium-substituted allenes with good
to excellent yields.
BuSeLi with diphenyl-phenylethynylphosphine oxide (1a) in
THF was investigated. When the mixture of n-BuSeLi and 1a in
THF was stirred for 2 hours at rt, only a complex mixture was
obtained while 22% of 1a was recovered and no Michael adduct
was observed. This could be ascribed to the fact that the Michael
adduct 4a is a good nucleophile itself12 which can further react
with 1a. To our surprise, when p-chlorobenzaldehyde (3a) was
added to the mixture of n-BuSeLi and 1a in THF one hour after
the addition of 1a, we got the allene 5a in 38% yield (Table 1,
entry 2). Shortening the time during the addition of 1a and 3a or
dropping the reaction temperature of Michael addition can
minimize the side reaction and improve the yield of 5a
dramatically (Table 1). When 3a was added 0.5 hour after the
addition of 1a at 0 °C with stirring for a further hour at rt, the
yield of 5a was increased to 74% (Table 1, entry 4). It is
noteworthy that no adduct of n-BuSeLi to p-chlorobenzalde-
hyde (3a) was detected during the reaction. This suggests that n-
BuSeLi can react with 1a selectively in the presence of 3a. Thus
we can carry out the tandem reaction by adding the 1a and 3a in
one portion.
In an effort to optimize this process by adding the 1a and 3a
in one portion, a range of different reaction temperatures and
solvents were investigated. The results are summarized in Table
2. From Table 2, it should be noted that reaction temperature
and solvent were crucial for the success of the reaction. When
the reaction was carried out at 225 °C, the HWE reaction could
not proceed efficiently (entry 1). If the reaction temperature
dropped to 240 °C, the HWE reaction did not occur at all, only
the Michael/aldol adduct (6a) was obtained in 34% yield with
recovered 1a in the yield of 57% (entry 2). When 1a and 3a were
added to the solution of n-BuSeLi in THF at 225 °C, the
reaction was complete within 30 min to afford 5a in the yield of
82% after warming the reaction mixture to rt in 20 min (entry 3).
This indicates that the HWE reaction can proceed smoothly at rt.
On the other hand, THF was proved to be the most efficient
solvent for the preparation of selenium-substituted allene (entry
3). When the reaction was performed in benzene and diethyl
ether, we obtained the Michael/aldol product (6a) exclusively in
63% and 51% yield, respectively (entries 4, 5).
The tandem reaction is of current interest because it offers a
convenient and economical way to prepare desired organic
molecules.1 The Michael addition and the aldol reaction are
acknowledged as useful tools for constructing complex organic
molecules, and combining the two reactions in one pot has been
a focus of organic chemistry.2
Allenes show unique reactivity in organic synthesis due to the
presence of the cumulated CNC double bonds.3 Many studies
have been performed on their preparation and reactivity.4,5
Heteroatom-substituted allenes have also received attention.6
Selenium-substituted allenes are known as isolable compounds
or reactive intermediates.7 However, the difficulty in preparing
this kind of compound has limited their application in organic
synthesis. Thus, it is highly desirable to develop a convenient
method to synthesize this kind of compound.
The selenolates are good nucleophiles for Michael addition
reaction8 and several selenolate anion-triggered Michael/aldol
tandem reactions have been intensively studied.9 Recently, our
group has reported the stereoselective Michael/aldol tandem
reaction of phenylselenomagnesium bromide with acetylenic
sulfones and aldehydes to afford (Z)-b-phenylseleno-a-(p-
tolylsulfonyl)allylic alcohols.10 On the other hand, the Horner–
Wadsworth–Emmons (HWE) reaction of b-phosphonato alk-
oxides is the most general procedure to construct the CNC
double bond; the cumulated CNC double bonds of allenes can
also be constructed by the HWE reaction of b-phosphonoallyl
alcohols.11 Thus, we envisaged that if the p-tolylsulfonyl group
in the above tandem reaction is replaced by a phosphono group,
the Michael/aldol intermediates, b-phosphonoallyl alkoxides,
may undergo HWE olefination reaction leading to the selenium-
substituted allenes as the final products (Scheme 1). Herein, we
wish to report our preliminary results for the Michael/aldol/
Horner–Wadsworth–Emmons (HWE) tandem reaction.
We first studied the reaction of (n-BuSe)2 with n-BuLi in
solvents such as THF, ether and benzene. BuLi (1.5 M in
hexane) was added to the solution of (n-BuSe)2 in the above
solvents with stirring at rt. After 0.5 hour, the reaction mixtures
were trapped with PhCH2Br. The n-BuSeCH2Ph was formed in
a yield of > 99%. This shows that the n-BuSeLi can be
generated quantitatively from (n-BuSe)2 on treatment with n-
BuLi in the above solvents. Then the Michael addition of n-
Table 1 Two-step tandem reaction under various conditions a
Michael addition
Aldol/HWE reaction
Yield (%)b
Entry
T/°C
Time/h
T/°C
Time/h
5a
1
2
3
4
rt
rt
rt
0
0.5
1
2
rt
rt
rt
rt
1
1
1
1
63
38
16
74
0.5
Scheme 1
a The reaction was carried out using 1a (1.0 mmol), 2 (1.0 mmol) and 3a
(1.0 mmol). b Isolated yield.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b3/b304527g/
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CHEM. COMMUN., 2003, 1714–1715
This journal is © The Royal Society of Chemistry 2003

Table 2 One-pot tandem reaction under various conditionsa
with other aromatic or aliphatic aldehydes or a,b-unsaturated
aldehydes. The results are summarized in Table 3.
As can be seen in Table 3, all the aromatic aldehydes give the
selenium-substituted allenes in good yields. The aliphatic
aldehydes and a,b-unsaturated aldehydes can also provide the
selenium-substituted allenes in moderate yield (entries 5, 13). In
the case of s-BuSeLi, an inseparable 1 : 1 ratio of diastereoi-
Yield (%)b
1
somers 5k (determined by 400 MHz H NMR spectra) was
Entry
Solvent
T/°C
Time/h
5a
6a
1a
obtained (entry 11).
In summary, we have developed an efficient one-pot three-
1
2
3
4
5
THF
THF
THF
Et2O
225
5
5
1
2
2
29
—
82
—
—
36
34
—
51
63
28
57
—
32
19
240
component
Michael/aldol/Horner–Wadsworth–Emmons
225–rt
225–rt
rt
(HWE) tandem reaction of lithium alkylselenolates with
1-alkynylphosphine oxides and aldehydes, which provides a
convenient synthesis of selenium-substituted allenes. This
method possesses the advantages of readily available starting
materials, easy manipulation, mild reaction conditions and good
yields of products. Further application of selenium-substituted
allenes in organic synthesis is now in progress in our
laboratory.
Benzene
a The reaction was carried out using 1a (1.0 mmol), 2 (1.0 mmol) and 3a
(1.0 mmol). b Isolated yield.
In order to confirm the Michael/aldol adduct as the reaction
intermediate and the effect of the solvent, we transformed the
Michael/aldol adduct (6a), b-phosphonoallyl alcohol, to lithium
b-phosphonoallyl alkoxide by treating 6a with n-BuLi at 278
°C in THF and in ether. When the solution of lithium b-
phosphonoallyl alkoxide in THF was warmed to room tem-
perature, it eliminated diphenylphosphinate spontaneously
within 20 min to afford the selenium-substituted allene in 86%
yield. However, no selenium-substituted allene was obtained
and most of the material was recovered when the solution of
lithium b-phosphonoallyl alkoxide in ether was stirred at rt for
1 hour and quenched with NH4Cl saturated solution (Scheme
2).
Further investigation showed that other lithium alkylseleno-
lates such as s-BuSeLi, i-PrSeLi can also react with 1-alkynyl-
phosphine oxides and aldehydes to give the selenium-substi-
tuted allenes smoothly in good yields. However, the reaction did
not occur with the use of lithium phenylselenolate.
The present reaction conditions were compatible with the
reaction of aromatic or aliphatic 1-alkynylphosphine oxides
This work was supported by the National Natural Science
Foundation of China (20272050).
Notes and references
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Scheme 2
Table 3 Synthesis of selenium-substituted allenesa
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Time/
min
Yieldb
Product (%)
Entry R1
R2
R3
1
2
3
4
5
C6H5
n-Bu p-ClC6H4
n-Bu C6H5
n-Bu p-CH3OC6H4
30
30
40
5a
5b
5c
5d
5e
5f
82
80
87
83
63
89
84
82
86
81
82
85
59
77
71
73
C6H5
C6H5
C6H5
C6H5
C6H5
n-Bu p-(CH3)2NC6H4 40
n-Bu n-C3H7
i-Pr p-CH3OC6H4
60
40
25
25
30
6
7
CH3OCH2 n-Bu C6H5
5g
5h
5i
8
9
CH3OCH2 n-Bu p-ClC6H4
CH3OCH2 n-Bu p-CH3OC6H4
10
11
12
13
14
15
16
CH3OCH2 n-Bu p-(CH3)2NC6H4 30
5j
CH3OCH2 s-Bu p-ClC6H4
CH3OCH2 i-Pr p-ClC6H4
CH3OCH2 n-Bu C6H5CHNCH
n-C5H11
n-C5H11
n-C5H11
25
25
40
50
50
50
5kc
5l
8 P. L. Fuchs and T. F. Braish, Chem. Rev., 1986, 86, 903.
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Mitsudera, S. Asano, S. Kidera and A. Kakehi, J. Org. Chem., 1999, 64,
6353.
5m
5n
5o
5p
n-Bu C6H5
n-Bu p-ClC6H4
n-Bu p-CH3OC6H4
10 (a) X. Huang and M. Xie, J. Org. Chem., 2002, 67, 8895; (b) X. Huang
and M. Xie, Org. Lett., 2002, 4, 1331.
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a The reaction was carried out by adding a solution of 1 (1.0 mmol) and 3
(1.0 mmol) in THF (4 ml) to a solution of 2 (1.0 mmol) in THF (6 ml) at 225
°C, then the reaction mixture was warmed to rt in 20 min and stirred for the
time given in the Table at rt. The RSeLi was generated from (RSe)2 on
treatment with n-BuLi at rt. b Isolated yield of 5. c 5k d.r.
= 1 : 1
(determined by 400 MHz 1H NMR spectra).
12 Y. Nagaoka and K. Tomioka, Org. Lett., 1999, 1, 1467.
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