Allenes through Horner-Wadsworth-Emmons olefination of alkenylphosphonates

Article abstract of DOI:10.1080/10426500212268

Mono- and di-substituted allenes 5 were synthesized by successive Horner-Wadsworth-Emmons olefination starting from methylene-bisphosphonate 1 and two carbonyl compounds. The key to success is KH or KH-18-crown-6 as a base for the second HWE olefination o

Full text of DOI:10.1080/10426500212268

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Phosphorus, Sulfur, and Silicon and the Related
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Allenes through Horner-Wadsworth-Emmons
Olefination of Alkenylphosphonates
a
a
a
Yasuo Nagaoka , Hideki Inoue & Kiyoshi Tomioka
a
Graduate School of Pharmaceutical Sciences , Kyoto University , Yoshida, Sakyo-ku, Kyoto,
Japan
Published online: 27 Oct 2010.
To cite this article: Yasuo Nagaoka , Hideki Inoue & Kiyoshi Tomioka (2002) Allenes through Horner-Wadsworth-Emmons
Olefination of Alkenylphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:6-7, 1843-1846, DOI:
10.1080/10426500212268
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1843–1846
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DOI: 10.1080/10426500290093432
ALLENES THROUGH
HORNER-WADSWORTH-EMMONS OLEFINATION
OF ALKENYLPHOSPHONATES
Yasuo Nagaoka, Hideki Inoue, and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto, Japan
(Received July 29, 2001; accepted December 25, 2001)
Mono- and di-substituted allenes 5 were synthesized by succes-
sive Horner-Wadsworth-Emmons olefination starting from methylene-
bisphosphonate 1 and two carbonyl compounds. The key to success is
KH or KH-18-crown-6 as a base for the second HWE olefination of
hydroxyalkenylphosphonates 4.
Keywords: Allene; 18-crown-6; double olefination; Horner-Wadsworth-
Emmons reaction; phosphonate
1
We have been engaged in the chemistry of lithium phosphonates in
which Baylis-Hillmann type products 4 were obtained upon LDA treat-
ment of alkenylphosphonates 3 with aldehydes and subjected to Horner-
Wadsworth-Emmons (HWE) olefination using NaH as a base, giving
2
the corresponding allenes 5 in up to 72% yields. Allenes are recent fo-
cus of versatile class of intermediates in a variety of organic synthetic
3
0
processes. The major allene synthesis relies on a SN2 replacement of
4
propargylic leaving groups and others involve dehydrohalogenation of
5
6
vinylic halides, reductive elimination of halogenated cyclopropanes,
and so on.7
� 10
Our synthesis is conceptually different from these and
2
is advantageous in the retrosynthetic simplicity. Two sp and one sp
carbon atoms of allene functionality are constructed by sequential dou-
ble HWE olefinations of the three components, methylenebisphospho-
nate 1 with two carbonyl compounds as shown in Scheme 1.11 Real-
ization of this scenario is critically dependent on the efficacy of the
second HWE olefination of hydroxyalkenylphosphonate 4, because the
We gratefully acknowledge financial support from Japan Society for Promotion of
Science and the Ministry of Education, Science, Sports and Culture, Japan.
Address correspondence to Yasuo Nagaoka, Faculty of Engineering, Kansai Univer-
sity, Suita, Osaka 564-8680, Japan. E-mail: ynagaoka@ipcku.kansai-u.ac.jp
1
843

1
844
Y. Nagaoka et al.
SCHEME 1
first olefination of methylenebisphosphonate 1 to 3 through 2 is a well-
1
2
established high yield process. We describe herein the high yield HWE
olefination of alkenylphosphonate 3 with a wide range of carbonyl com-
pounds. The accurate selection of a base for HWE olefination of 4 was
the key for success.
It readily comes to an answer that olefination of 4 requires forma-
2
tion of an unfavorable phosphooxetane that involves one sp carbon in
the four-membered ring. Furthermore, the 120 degree bond angle by
2
the sp carbon is a significantly unfavorable factor in intramolecular
nucleophilic attack of an alcoholic oxygen nucleophile to P O phospho-
rous electrophile to form the four-membered ring. The analysis leads to
suggestion that olefination of 4 requires efficient activation of a nucle-
ophilic alcoholic oxygen. However, strong base is likely to deprotonate
allene protons to result in isomerization into alkyne and diene. We be-
gan our studies to find an appropriate base for olefination of 4.
1
2
We set 4a (R = Ph, R = t-Bu, R = Et or i-Pr) as an olefination testing
1
2
hydroxyphosphonate to allene 5a (R = Ph, R = t-Bu), because 4a and
a are the most simple alcohol and allene with regard to abstractable
protons (Table I). The lithium alkoxide, generated by treating 4a
5
(
R = Et) with 1 equiv of BuLi in THF, was the least reactive alkoxide
to afford 5a in 30% yield along with concomitant formation of insepa-
rable complex mixture after 5 h under reflux (Entry 1 in Table I). The
excellent conversion was achieved by treating the potassium alkoxide,
�
formed with KH, in THF at 60 C for 5 min to give 5a in 92% yield (En-
try 3 in Table I). The reaction of 4a (R = Et, i-Pr) can be performed at
�
much lower temperature (0 C) for 0.5 h by further addition of 0.1 equiv
of 18-crown-6 to give 5a in the same 92% yield (Entry 6 in Table I). At
�
the higher reaction temperature (60 C) for 5 min and in the presence of
1
7
equiv of 18-crown-6, the major product was the isomerized alkyne in
5% yield (Entry 4 in Table I). Isomerization of 5a could be prevented by
�
lowering reaction temperature to 0 C affording 5a in 89% yield (Entry 5

Allenes Through Horner-Wadsworth-Emmons Olefination
1845
TABLE I Base Dependency of Olefination Efficacy of 4a
1
8-crown-6
(equiv)
Temp
( C)
Time
(min)
Yield (%)
5
�
Entry
R
Base
1
2
3
4
5
6
7
8
9
Et
Et
Et
i-Pr
i-Pr
i-Pr
Et
Et
Et
BuLi
NaH
KH
KH
KH
KH
KDA
KHMDS
Reflux
50
60
60
0
0
60
25
150
40
300
30
5
30
72
92
25
89
92
41
88
55
62
70
1.0
1.0
0.1
5
15
30
60
15
80
15
10
a
KOH
1
1
0
1
Et
Et
t-BuOKb
t-BuOCs
60
a
DMSO was used as a solvent.
b
1
.5 equiv.
in Table I). The effects of 18-crown-6 are apparent and favorable for the
olefination through nucleophilic activation of the potassium alkoxide.
Other potassium bases were less effective than KH (Entries 7–10 in
Table I). The softer base, t-BuOCs was less effective than KH (Entry 11
in Table I). Thus we could find KH and KH-18-crown-6 as suitable ole-
fination bases for 4a.
The conditions found above were successfully applicable to olefi-
nation of other hydroxyphosphonates 4 as summarized in Table II.
1
2
TABLE II Effects of Substituents R and R on the Reaction of 4
1
8-crown-6
(equiv)
Temp
( C)
Time
(min)
Yield (%)
5
R1
Ph
Ph
Ph
Ph
Ph
Ph
R2
t-Bu
c-Hex
Ph(CH2)2
Me
Me
Ph
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph
�
Entry
4
1
2
3
4
5
6
7
8
9
a
b
c
d
d
e
f
g
h
i
0.1
0
60
60
60
0
60
60
60
60
60
30
10
20
20
60
40
20
60
10
60
92
61
71
40
73
17
79
77
42
55
0.1
t-Bu
c-Hex
H
0.1
1.0
1
0
t-Bu

1
846
Y. Nagaoka et al.
The olefination proceeded smoothly to give the corresponding allenes
b–d in good yields even when methine, methylene, and methyl groups
5
2
(
R ) are adjacent to the allene function (Entries 2–5 in Table II). Es-
pecially, KH-crown base improved the reaction yield to 73% from 40%
2
even when R is a methyl group that is readily deprotonated (Entry 5
in Table II). When methylene is at one end of the allene such as 5f–h
2
(
R = Ph(CH2)2), the reaction proceeded smoothly to afford the allenes
in relatively high yields (Entries 7–9 in Table II).
In conclusion, mono- and di-substituted allenes were efficiently syn-
thesized by successive Horner-Wadsworth-Emmons olefinations start-
ing from methylenebisphosphonate 1 and two carbonyl compounds.
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