Wittig reaction of formyl-substituted organotrifluoroborates and stabilized phosphonium ylides in an aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2007.11.205

The synthesis of unsaturated organotrifluoroborates using the Wittig alkenation is described. These transformations to disubstituted alkenes were achieved by using formyl-substituted organotrifluoroborates and stabilized ylides using water as a solvent. T

Full text of DOI:10.1016/j.tetlet.2007.11.205

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Tetrahedron Letters 49 (2008) 1266–1268
Wittig reaction of formyl-substituted organotrifluoroborates
and stabilized phosphonium ylides in an aqueous medium
a,
b
*
Gary A. Molander , Roberta A. Oliveira
a Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, United States
b Departamento de Quimica Fundamental, Universidade Federal de Pernambuco, Recife-PE 50670-901, Brazil
Received 12 September 2007; accepted 26 November 2007
Available online 5 December 2007
Abstract
The synthesis of unsaturated organotrifluoroborates using the Wittig alkenation is described. These transformations to disubstituted
alkenes were achieved by using formyl-substituted organotrifluoroborates and stabilized ylides using water as a solvent. The products
were isolated in moderate to excellent yields and the reaction gave preferentially the E-isomer.
Ó 2007 Published by Elsevier Ltd.
Green technology is a topic that is receiving significant
attention because of environmental issues.1 The develop-
ment of methods focusing on environmentally benign reac-
tion media has been particularly prominent.2 Thus,
advances in the development of aqueous biphase catalysis3
and the use of supercritical fluids,4 ionic liquids,5 and fluo-
rous media6 continue to be important areas of investigation.
Wittig7 and Horner–Wadsworth–Emmons7a,8 (HWE)
reactions have been widely used in synthesis as a means
of elaborating the carbon skeleton and introducing further
functional groups into organic substrates. The generality
and high stereoselectivity of these reactions constitute
two desirable features offered by these protocols. Addition-
ally, the double bond geometry can generally be predicted
and controlled by choosing the appropriate reagents and
reaction conditions. Many novel and useful adaptations
of the Wittig reaction have been described in the literature,
including those employing microwaves,9 sonication,10 light
irradiation,11 ionic liquids,12 silica,13 lithium salts,14 ben-
zoic acid,15 surfactants,16 phase transfer catalysts,17 cyclo-
dextrins,18 and high temperatures19 or pressures,20 as well
as those employing solvent free conditions.21
The use of water as a solvent for Wittig reactions has also
been reported in the reaction between aldehydes and stabi-
lized or semistabilized phosphorus ylides.22 In addition to
their environmental benefits, these protocols sometimes
provide higher yields and similar diastereoselectivities22d
when compared to reactions performed in organic solvents.
Organotrifluoroborates have proven to be robust surro-
gates for boronic acids and boronate esters in Suzuki cou-
pling reactions, providing many advantages over the latter
reagents.23 One of the major benefits is the ability to ela-
borate upon the structure of a simple, functionalized
organotrifluoroborate, increasing its molecular complexity
while maintaining the valuable carbon–boron bond for
subsequent transformation. Recently, our group described
the synthesis of unsaturated potassium organotrifluoro-
borates via the Wittig and Horner–Wadsworth–Emmons
reaction of the corresponding trifluoroborato-substituted
benzaldehydes.24 The complementary process, that is, gen-
eration and reaction of potassium [(trifluoroboratophenyl)
methyl]triphenylphosphonium ylides with aldehydes, was
also described as a novel synthetic method for creating
functionalized alkenes.25
Herein, we report the Wittig reaction of formyl-substi-
tuted organotrifluoroborates with commercially available,
carbonyl-stabilized ylide reagents in an aqueous medium.26
In addition to being more environmentally sound, the use of
*
Corresponding author. Tel.: +1 215 573 8604; fax: +1 215 573 7165.
E-mail address: gmolandr@sas.upenn.edu (G. A. Molander).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.205

G. A. Molander, R. A. Oliveira / Tetrahedron Letters 49 (2008) 1266–1268
1267
preformed stabilized ylides avoids the removal of inorganic
or organic salts during the reaction work-up, facilitating the
isolation of the potassium organotrifluoroborate products.
The trifluoroborato-substituted aldehydes were pre-
pared from the corresponding boronic acids following a lit-
erature procedure.27 In initial efforts to evaluate different
stabilized ylides we used potassium 2-formylphenyltrifluo-
roborate as a model substrate. The reaction was studied
using standard conditions: 2-formylphenyltrifluoroborate
(1.0 mmol) in conjunction with diverse ylides (1.5 mmol)
in water (2 mL). In all the cases, the desired alkene was iso-
lated in low yield in incomplete reactions when the reaction
was conducted at room temperature, owing to the poor sol-
ubility of the reagents. Complete consumption of the start-
ing material was critical not only for the overall efficiency
of the method, but also because separation of the product
from the organotrifluoroborate starting material is quite
difficult. When the reactions were heated to 90 °C, 1H
and 13C NMR analysis of the reactions revealed that the
reaction was complete after 12 h. To isolate the products,
the water was removed under vacuum and the triphenyl-
phosphine oxide and excess ylide were removed by tritura-
tion with dichloromethane followed by washing the
mixture with acetone. In this manner, the remaining
alkene-functionalized organotrifluoroborates 3 were all
obtained in moderate to good yields as stable white solids
(Table 1).28
organotrifluoroborates 1b–g. The results are depicted in
Table 2.
The desired products were obtained in moderate to good
yields for a variety of functionalized substrates and substi-
tution patterns, including
a
heterocyclic aldehyde.
Although the degree of diastereoselection proved to be
highly variable and substrate-dependent, in all the cases
the E-isomer was predominant. The lack of high diastereo-
selectivity is not uncommon in similar Wittig-type reac-
tions performed in aqueous media.2a–c
For the most part these trends in diastereoselection
translated when the conditions were applied to 1-(triphenyl-
phosphoranylidene)acetone 2b, although somewhat lower
yields and selectivities were observed (Table 3). This might
be attributed to the lower reactivity of the ylide that results
from greater stabilization of the nucleophile.7,26 Curiously,
aldehyde 1f, which gave essentially a single diastereomeric
enoate on reaction with the corresponding ylide (Table 2,
entry 5), gave a nearly 1:1 mixture of E and Z enone
products (Table 3, entry 5).
In summary, we have demonstrated the use of formyl-
substituted organotrifluoroborates with carbonyl-stabilized
Table 2
Reaction of formyl-substituted organotrifluoroborates 1b–g with methyl
(triphenylphosphoranylidene)acetate 2a in water at 90 °C
2a
KF3B
CO2Me
KF3B Ar CHO
Ar
With the optimized conditions for the formation of the
alkenes in hand, we examined the scope of the aqueous
Wittig reaction for the synthesis of alkene-functionalized
organotrifluoroborates using methyl (triphenylphosphor-
anylidene)acetate 2a and various formyl-substituted
H2O, 90 oC, 12 h
1b-g
4b-g
Entry
KF3B–Ar-CHO
BF3K
E:Zb
Yielda (%)
1
1b
Only E
70:30
82
Table 1
CHO
Reaction of 2-formylphenyltrifluoroborate 1a with different stabilized
ylides 2a–d in water at 90 °C
CHO
2
1c
1d
1e
1f
80
BF3K
BF3K
KF3B
R
CHO
2a-d
H2O, 90 oC, 12 h
BF3K
F
1a
3
4
5
6
65:35
67:33
Only E
65:35
67
65
86
70
3a-d
Entry
1
Ylide
E:Zb
Yielda (%)
85
OHC
OMe
2a
80:20
85:15
75:25
60:40
Ph3P
Ph3P
CHO
BF3K
O
O
O
O
2
3
2b
90
MeO
KF3B
OMe
N
2c
2d
65
CHO
Me
Ph3P
Ph3P
O
KF3B
4
61c
CN
1g
CHO
S
a
Yield is given for the isolated product, >95% purity unless indicated.
E/Z ratios were determined by 1H NMR.
92% pure by NMR.
a
b
c
Yield is given for the isolated product, >95% pure by NMR.
E/Z ratios were determined by 1H NMR.
b

1268
G. A. Molander, R. A. Oliveira / Tetrahedron Letters 49 (2008) 1266–1268
Table 3
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28. Typical procedure: A mixture of formyl-substituted organotrifluorob-
orates 1a–e (1.0 mmol) and the appropriate carbonyl-stabilized ylide
2a–d (1.5 mmol) was added to a flask followed by the addition of
water (2.0 mL). The mixture was heated to 90 °C for 12 h. After this
period, the water was removed in vacuo and the residue was washed
with dichloromethane (3 Â 5.0 mL) and acetone (2 Â 5 mL). The
products were obtained as white solids after drying under high
vacuum.
We thank the National Institutes of Health (GM35249),
Merck Research Laboratories and Amgen for their gener-
ous support. R.A.O. is also thankful to CNPq (Brazil)
for her fellowship.
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