Aqueous Wittig reactions of semi-stabilized ylides. A straightforward synthesis of 1,3-dienes and 1,3,5-trienes

Article abstract of DOI:10.1016/j.tetlet.2009.07.133

A direct synthesis of 1,3-dienes and 1,3,5-trienes from the reaction of semi-stabilized ylides and a range of saturated and unsaturated aldehydes is reported in water as solvent, employing sodium hydroxide as base. The water-soluble phosphine oxide side p

Full text of DOI:10.1016/j.tetlet.2009.07.133

Tetrahedron Letters 50 (2009) 5737–5740
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Aqueous Wittig reactions of semi-stabilized ylides. A straightforward
synthesis of 1,3-dienes and 1,3,5-trienes
*
James McNulty , Priyabrata Das
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct synthesis of 1,3-dienes and 1,3,5-trienes from the reaction of semi-stabilized ylides and a range
of saturated and unsaturated aldehydes is reported in water as solvent, employing sodium hydroxide as
base. The water-soluble phosphine oxide side product is removed simply by aqueous partitioning of the
organic products.
Received 10 July 2009
Revised 24 July 2009
Accepted 27 July 2009
Available online 6 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Tamura,7d,e Schlosser,7f and others7g using mixed aryl/alkyl and al-
kyl-substituted phosphines were shown to provide higher levels of
The development of green, environmentally benign synthetic
protocols has been a subject of significant concern over the past
few years both in academia and in industry.1 In particular, sol-
vent-free reactions and reactions in water are of increasing inter-
est. Water is extremely inexpensive, is easy to process, and is
environmentally benign.2 Water has been generally ignored as a
medium for organic reactions due to substrate solubility problems
and real or perceived reagent incompatibilities. Nonetheless, or-
ganic reactions carried out in water often exhibit a rate-enhancing
effect in spite of poor solubility of the substrates in water.3,4 In
addition, reactions traditionally conducted under strictly anhy-
drous conditions, such as the Wittig olefination, have been demon-
strated to occur in aqueous media in limited cases. In this Letter we
report the first examples of the aqueous Wittig reaction of trialkyl-
allylphosphonium salt-derived semi-stabilized ylides allowing for
the successful synthesis of a range of functionalized 1,3-dienes
and 1,3,5-trienes in water.
(E)-olefin stereoselectivity. Other recent related methods for the
synthesis of conjugated alkenes include the use of ylides derived
from arsonium salts,7h in addition to a variety of metal-catalyzed
cross-coupling processes.7i
We recently reported the first examples of the Wittig reaction
involving trialkylphosphine-derived semi-stabilized benzylidenyl
ylides in water.8 Water has been used previously as the reaction
medium for the Wittig reaction of stabilized ylides9 giving unsatu-
rated esters. The reaction of triphenyl-substituted benzylidenyl
ylides with aldehydes has also been reported in water,10 providing
stilbenes with poor configurational selectivity and requiring chro-
matographic purification to remove triphenylphosphine oxide. To
our knowledge, the use of trialkyl allylidenyl ylides has not hereto-
fore been performed in aqueous media. In our recent report,8 tri-
ethylbenzyl phosphonium salts were converted chemoselectively
to the benzylidenyl phosphorane in water using simply sodium
or lithium hydroxide as base. These ylides were shown to react
with a range of aldehydes yielding stilbenes and 1-phenylalkenes
in high yield. The major advantages of this process are the high
(E)-olefin stereoselectivity and the easy separation of the water-
soluble triethylphosphine oxide from the organic product which
generally precipitated from the aqueous solution.
The synthesis of functionalized 1,3-dienes and homologous
polyenes is a central concern in synthetic organic chemistry. The
1,3-diene sub-unit is itself found in a wide range of bioactive mate-
rials including terpenoids, fatty acid-derived lipids, pheromones,
and polyketides.5 In addition, functionalized 1,3-dienes are of cen-
tral importance as the 4p-component in Diels–Alder cycloaddition
and other reactions, leading to a wide array of complex intermedi-
ates.6 The Wittig olefination reaction of a triphenylallylidenyl ylide
with a carbonyl compound, conducted under anhydrous condi-
tions, is possibly the most general method available for preparing
functionalized 1,3-dienes, Figure 1.7a–c While the use of triphenyl-
phosphine-derived ylides (R0 = Ph) generally results in poor (E):(Z)
stereoselection, subsequent methods advanced by Vedejs,7d
2. Results and discussion
We first investigated the aqueous Wittig reaction of ylides de-
rived from the three different trialkylallyl-phosphonium salts
shown in Figure 1. These salts were pre-formed by the reaction
of the corresponding tertiary phosphine with allyl bromide.12 The
salts were dissolved in aqueous sodium hydroxide (4 equiv) and
3,4,5-trimethoxybenzaldehyde was added. The reaction went
to completion within one hour at 70 °C yielding the desired
1-phenyl-1,3-diene. Both the isolated chemical yield and the
* Corresponding author. Tel.: +1 905 525 9140x27393; fax: +1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.133

5738
J. McNulty, P. Das / Tetrahedron Letters 50 (2009) 5737–5740
R'
R'
R'
P+
MeO
NaOH, H2O
70 °C, 1 Hr
Br
MeO
OMe
5e
MeO
MeO
O
+ R'3P=O
R' = ethyl, n-butyl, iso-butyl
OMe
Phosphonium Salt
Product
% Yield
80
E:Z
P+
Br
MeO
MeO
5.5:4.5
OMe
MeO
MeO
82
85
4: 1
9:1
-
P
Br
Br
+
OMe
OMe
MeO
MeO
P
+
-
Figure 1. Screening the Wittig reaction of various trialkylallyl phosphonium salts using sodium hydroxide in water.
(E)-stereoselectivity of the resulting diene were shown to be high-
est for the triethylallyl-derived ylide. The triethylallylphosphoni-
um bromide was next screened in the aqueous Wittig reaction
with a range of aromatic aldehydes, solely in aqueous sodium
hydroxide under the conditions described above. The overall re-
sults of this investigation are summarized in Table 1.
unsaturated and aliphatic aldehydes, the results of which are sum-
marized in Table 2. The unsaturated aldehydes allowed ready ac-
cess to the corresponding 1,3,5-trienes from
a variety of
skeletons including monoterpenoid, aliphatic, and aromatic cases
and this appears to be very general. Isolated yields were in the
80% range with good to high (E) stereoselectivity being observed.
Most interestingly, the enolizable aliphatic aldehydes dihydrocin-
namaldehyde and dodecanal were also observed to react selec-
tively with the allyl ylide generated under these aqueous basic
conditions. Only traces of polar impurities were observed and the
corresponding 1,3-dienes were isolated in 73% and 70% yields,
respectively. This chemoselectivity favoring olefination over po-
tential homo-aldol or Cannizaro-type products under conditions
that are classically known to effect these reactions is startling.
We have postulated that this chemoselectivity is due to the forma-
tion of phosphonium salt-stabilized micelles that effectively parti-
tion the organic materials from the aqueous basic environment
during the reaction. Ylide formation occurs at the interface, and
delivery of the neutral ylide and olefination take place in the or-
ganic interior of the micelle.
In many cases, the product diene oils-out or precipitates from
the aqueous media during the reaction or upon cooling. The dienes
were partitioned between dichloromethane and water and ran
through a short column of silica to effect isolation of the (E):(Z)
mixture. In a few cases the individual stereoisomers were readily
separable. The isolated yields of the 1,3-dienes were high in all
cases investigated. The (E):(Z)-stereoselectivity of the aqueous
Wittig reaction was also generally high, and in accord with earlier
results conducted in THF using t-BuOK or n-BuLi as base.7c,e The
reaction of the triethylallylidenyl ylide with benzaldehyde was
also carried out at room temperature, giving the 1,3-diene with
70% conversion after 3 h. Analysis of this crude product showed
the formation of the dienes in the same 4:1 (E):(Z) ratio as reported
in Table 1, indicating that the configurational selectivity observed
is not subject to any significant thermodynamic isomerization un-
der the reactions conditions or subsequent silica gel chromatogra-
phy. The general reaction proved applicable to a wide range of
hetero-substituted aromatic aldehydes, including ortho-substi-
tuted derivatives. The reactions of both 2-chloro benzaldehyde
and 2-fluoro benzaldehyde resulted in higher (Z)-stereoselectivity
than initially anticipated. The increased (Z)-stereoselectivity and
anamolous effects of 2-halo benzaldehyde derivatives have been
reported previously.11
3. Conclusion
In conclusion, the Wittig reaction of ylides derived from trialkyl-
allyl phosphonium salts has been demonstrated for the first time in
water using sodium hydroxide as base. Ylide formation occurs
exclusively through deprotonation at the allylic position. The
resulting ylides were shown to react with a series of aromatic,
unsaturated, and enolizable aliphatic aldehydes yielding a structur-
ally diverse range of useful 1,3-dienes and 1,3,5-trienes. The reac-
tion is observed to be very chemoselective for olefination
The aqueous Wittig reaction of ylides derived from triethylallyl-
phosphonium bromide was next investigated with a series of a,b-

J. McNulty, P. Das / Tetrahedron Letters 50 (2009) 5737–5740
5739
Table 1
Table 1 (continued)
Synthesis of 1-phenyl-1,3-dienes 5 from aromatic aldehydes 4 using the aqueous
Wittig reaction12
R–CHO
1,3-Diene
Yield
85
(E):(Z)
-
F
X
Et
1) NaOH, H2O
F
O
X
R
Et3P
+
R
Et P
7:3
R
+
O
Et
1
2
3
2)
5a-m
5k
R'
H
4a-m
O
O
O
O
O
R–CHO
1,3-Diene
Yield
80
(E):(Z)
83
87
3.5:1
4:1
O
5l
4:1
3:1
H
5a
O
O
O
O
5m
81
85
95
H
5b
MeO
MeO
Table 2
Synthesis of polyenes from trialkylallylidenyl ylides with unsaturated and enolizable
aliphatic aldehydes
O
MeO
MeO
MeO
MeO
R–CHO
Polyene
Yield
(E):(Z)
8.5:1.5
H
5c
O
5n
80
9:1
3:1
H
O
H
5d
Br
Br
O
MeO
MeO
H
78
9:1
MeO
MeO
H
O
85
9:1
5e
5o
OMe
OMe
H
Cl
Cl
O
5p
80
80
79
3:2
7:3
4:1
6
6
90
92
1.1:1
4:1
O
H
5f
O
H
O
H
H
5g
5q
BnO
BnO
O
O
O
90
9.5:0.5
H
5h
5r
F
F
O
O
O
O
O
85
85
4:1
H
73
70
4:1
4:1
H
5i
5s
O
H
8.5:1.5
O
5j
N
N
H
9
5t
9

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J. McNulty, P. Das / Tetrahedron Letters 50 (2009) 5737–5740
8. McNulty, J.; Das, P. Eur. J. Org. Chem. 2009, 4031–4035.
under conditions where competing homo-aldol or Cannizaro dis-
proportionation reactions might be anticipated. Further studies
on the mechanism of this simple, chemoselective polyene synthesis
and applications on the reactions of other trialklylphosphine-de-
rived semi-stabilized ylides in aqueous media are under underway.
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Acknowledgments
We thank NSERC, Cytec Canada Inc. and McMaster University
for financial support of this work.
12. Representative procedure: Synthesis of allyl-triethylphosphonium-bromide:
Into a flame-dried flask was added triethylphosphine (1 mL, 6.80 mmol) in
dry dichloromethane (6.8 mL) under argon at 0 °C. To this was added allyl
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6H); 3.36 (dd, JPH = 16.8 Hz, JHH = 8.4 Hz, 2H); 5.2–5.8 (m, 3H); 13C NMR
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1 and 2: Synthesis of 5e: Into a flame-dried flask,
containing a magnetic stirring bar, was weighed allyl-triethylphosphonium
bromide (238 mg, 1 mmol) and distilled water (0.4 mL) was added to make a
2.5 M solution. The contents of the flask were stirred for 15 min at room
temperature whereupon powdered NaOH (160 mg, 4.0 mmol) was added
slowly. After 2 min 3,4,5-trimethoxybenzaldehyde (196.2 mg, 1 mmol) was
added slowly to the reaction flask. The contents of the flask were stirred
vigorously at 70 °C for 1 h. The oil bath was removed and the flask was left
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