Synthesis of dienol ethers using the phosphine-catalyzed alkyne isomerization reaction

Article abstract of DOI:10.1055/s-0030-1259700

A series of -alkoxy-substituted electron-deficient alkynes were isomerized to the corresponding dienol ethers using phosphine catalysis. Both Ph ₃P and a polymer-supported phosphine were found to be useful in this context. This methodology represents a general procedure for the synthesis of push-pull' -alkoxy dienones. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259700

LETTER
989
Synthesis of Dienol Ethers Using the Phosphine-Catalyzed Alkyne Isomeriza-
tion Reaction
Synthesis of
Dienol
Et
i
hers chael Yunyi Fu, Jiawen Guo, Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: phtoy@hku.hk
Received 8 November 2010
vated alkynes. A survey of the literature indicated that
Abstract: A series of d-alkoxy-substituted electron-deficient
alkynes were isomerized to the corresponding dienol ethers using
phosphine catalysis. Both Ph3P and a polymer-supported phosphine
were found to be useful in this context. This methodology repre-
while KOH has been used instead of a secondary amine to
open a pyridinium salt to form the glutaconaldehyde po-
tassium salt, such dienol ethers are relatively rare, and it
sents a general procedure for the synthesis of ‘push-pull’ d-alkoxy appears that no general procedure exists for their stereo-
selective synthesis.11,12 Importantly, our strategy would
dienones.
allow for the synthesis of both dienones and dienoates
since alkynones and alkynonates are suitable substrates
for the isomerization reaction. Thus, if our concept proved
feasible, it could be used to efficiently prepare a range of
potentially useful building blocks for organic synthesis in
an organocatalytic and highly stereoselective manner
(Scheme 2).
Key words: organocatalysis, polymer-supported catalyst, alkyne
isomerization, dienes, enol ethers, triphenylphosphine
Nearly two decades ago, and virtually simultaneously, the
groups of Lu1 and Trost2 reported the stereoselective
Ph3P-catalyzed isomerization of alkynones into the corre-
sponding E,E-dienones (Scheme 1).3 Shortly thereafter
Rychnovsky and Kim reported that the use of PhOH as a
weakly acidic co-catalyst allowed less activated
alkynoates to be similarly isomerized.4 Since then such
isomerization reactions have been used in a variety of
contexts,5 especially natural product synthesis.6
CHO
+ R2NH
R2N
N+
A
X–
Zincke aldehydes
CHO
glutaconaldehyde K+ salt
+ KOH
K+–
O
N+
O
O
–
Ph3P (cat.)
SO3
R2
R1
R2
Δ
O
O
R1
R2
R1O
R2
Scheme 1 Alkynone isomerization reactions catalyzed by Ph3P
R1O
"push–pull" dienol ethers
1
R1 = allyl, aryl or benzyl
2 = alkoxy, alkyl or aryl
We recently reported a bifunctional polymer bearing both
phosphine and phenol groups and its use as a catalyst for
Morita–Baylis–Hillman reactions.7 This material was
subsequently used to catalyze the isomerization of a vari-
ety of alkynoates to the corresponding 2E,4E-dienoates,8,9
and during the course of this later work it occurred to us
that the reported substrate scope for such isomerization re-
actions was rather limited. All of the alkynone and
alkynoate substrates described in the literature possessed
alkyl substituents at the d-position (R1 in Scheme 1). To
the best of our knowledge, no examples of isomerization
substrates bearing heteroatom substituents at this position
have been described in the literature. Furthermore, we
noted the great synthetic utility of Zincke aldehydes
(Scheme 2) recently reported by Vanderwal and co-work-
ers,10 and wondered if analogous ‘push-pull’ dienol ethers
could be prepared via isomerization of the corresponding
d-alkoxy-substituted electron-withdrawing-group-acti-
R
Scheme 2
In order to test our hypothesis, we set out to synthesize a
series of substrates of the general structure 1 in a straight-
forward manner. As a starting point we treated 2a13 with
n-BuLi (1.2 equiv) at low temperature to generate the cor-
responding acetylide ion, which was reacted directly with
a range of aldehydes (1.2 equiv) to afford the correspond-
ing propargyl alcohols. These were in turn oxidized using
PDC (2.5 equiv) at room temperature to afford the desired
ketones 1a–f (Scheme 3).14 Additionally, aryl ether 2b15
and allyl ether 2c16 were prepared according to literature
procedures and converted into 1g and 1h, respectively,
using similar methodology (Scheme 4). Thus a range of d-
benzyloxy, -phenoxy, and -allyloxy alkynones was pre-
pared in short order.
Once the synthesis of substrates 1a–h was complete, we
examined the isomerization of 1a using both triphe-
nylphosphine (Ph3P) and JandaJel-triphenylphosphine
SYNLETT 2011, No. 7, pp 0989–0991
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259700; Art ID: W01510ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

990
M. Y. Fu et al.
LETTER
O
Table 1 Isomerization of 1a–h to 3a–h Using Ph3P and JJ-PPh3
1. n-BuLi, THF, –78 °C
2. RCHO
O
R
O
BnO
3. PDC, CH2Cl2, r.t.
BnO
1a R = phenyl, 52%
1b R = C6H4-4-Cl, 65%
1c R = 2-furyl, 58%
1d R = 2-thienyl, 54%
1e R = methyl, 74%
1f R = nonyl, 45%
R2
Ph3P or JJ-PPh3
2a
R1O
R2
R1O
PhMe, Δ
3a–h
1a–h
Entry Substrate Product
Yield (%)a
Ph3P JJ-PPh3
Scheme 3 Synthesis of isomerization substrates 1a–f
O
O
1
2
1a
1b
90
86
BnO
Ph
O
PhO
1. n-BuLi, THF, –78 °C
2. PhCHO
3a
2b
Ph
or
3. PDC, CH2Cl2, r.t.
RO
1g R = phenyl, 56%
1h R = allyl, 56%
BnO
93
88
O
2c
Cl
3b
Scheme 4 Synthesis of isomerization substrates 1g–h
O
O
O
S
3
4
1c
94
83
90
85
(JJ-PPh3),17–20 a heterogeneous polymer-supported phos-
phine that we have previously reported. Gratifyingly, our
initial studies were successful, and we were able to quick-
ly identify optimal reaction conditions for the formation
of 3a from 1a as being the use of 0.2 equivalents of phos-
phine catalyst in hot toluene (1 M, 80 °C; Table 1, entry
1). In this reaction the use of Ph3P and JJ-PPh3 afforded
essentially the same yield of isolated product (90% vs.
86%, respectively), with the later having the advantage
that it could be separated from 3a by simple filtration.21
We then applied these reaction conditions to substrates
1b–h using both Ph3P and JJ-PPh3 as the catalyst. As be-
fore, in all cases these nucleophilic phosphine catalysts af-
forded similar yields of the corresponding dienol ether
products 3b–h (entries 2–8). It should be noted that the
isomerization of phenyl ether 1g to 3g was stopped after
three hours in order to minimize byproduct formation. De-
spite the shorter reaction time for these experiments, high
yield of 3g was obtained in both cases. For the reactions
catalyzed by Ph3P, the products were purified by silica gel
chromatography. When the reactions were performed us-
ing JJ-PPh3, the phosphine catalyst was removed by filtra-
tion, and then further purification was performed if
necessary.
BnO
3c
1d
BnO
3d
O
O
O
5
6
7
8
1e
1f
75
64
62b
91
67
61
59b
84
BnO
3e
BnO
(CH2)8Me
3f
1g
1h
PhO
Ph
Ph
3g
O
AllylO
3h
a Isolated yield of 1.0 mmol scale reactions with 0.2 mmol catalyst
(Ph3P or JJ-PPh3) in toluene (1 M, 80 °C) for 18 h.
b Reaction time: 3 h.
In summary, we have developed a short synthesis of 5-
alkoxy-2E,4E-dienones based on the phosphine-catalyzed
isomerization of electron-deficient alkynes. This repre-
sents the first general, organocatalytic, and stereoselective
method for the synthesis of such dienol ether compounds,
and we are currently examining their synthetic utility in
the context of complex molecule synthesis.
P. R. of China (Project No. HKU 704108P). Technical assistance
from Julia Hermeke, Jinni Lu, Yan Teng, and Xuanshu Xia is also
acknowledged.
References and Notes
(1) (a) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993,
1921. (b) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001,
34, 535.
(2) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(3) For reviews of phosphine catalysis, see: (a) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (b) Ye,
L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140.
(c) Marinetti, A.; Voituriez, A. Synlett 2010, 174. (d) Wei,
Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005.
Acknowledgement
This research was supported financially by the University of Hong
Kong and the Research Grants Council of the Hong Kong S. A. R,
Synlett 2011, No. 7, 989–991 © Thieme Stuttgart · New York

LETTER
Synthesis of Dienol Ethers
991
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(21) General Reaction Procedure
To a solution of 1 (1.0 mmol) in toluene (1 mL) was added
Ph3P or JJ-PPh3 (0.2 mmol). The reaction vial was then
shaken at 80 °C for 18 h. At this time, the reaction mixture
was either concentrated and purified by silica gel chromatog-
raphy (for Ph3P) or filtered and concentrated in vacuo (for
JJ-PPh3). All products 3 were characterized by 1H NMR and
13C NMR spectroscopy.
Synlett 2011, No. 7, 989–991 © Thieme Stuttgart · New York

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