Synthesis of unsaturated organotrifluoroborates via Wittig and Horner-Wadsworth-Emmons olefination

Article abstract of DOI:10.1021/jo060863w

The stereoselective synthesis of unsaturated organotrifluoroborates by using the Wittig and Horner-Wadsworth-Emmons olefination is described. These reactions were general for both alkyl- and aryltrifluoroborates. The synthesis of di- and trisubstituted ol

Full text of DOI:10.1021/jo060863w

Synthesis of Unsaturated Organotrifluoroborates via Wittig and
Horner-Wadsworth-Emmons Olefination
Gary A. Molander* and Ruth Figueroa
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed April 25, 2006
The stereoselective synthesis of unsaturated organotrifluoroborates by using the Wittig and Horner-
Wadsworth-Emmons olefination is described. These reactions were general for both alkyl- and
aryltrifluoroborates. The synthesis of di- and trisubstituted olefins was achieved by using formyl- and
acetyl-substituted organotrifluoroborates. The products were isolated in moderate to excellent yield. The
Wittig reaction with nonstabilized ylides was performed under salt free conditions in most cases to obtain
the Z-isomer. The E-isomer was accessed by using preformed stabilized ylides. The Horner-Wadsworth-
Emmons reaction also gave the E-isomer as expected.
Introduction
Wittig4 and Horner-Wadsworth-Emmons4a,d,5 (HWE) reac-
tions have been widely used in synthesis as a means of
elaborating the carbon skeleton and introducing further func-
tionality into organic substrates. The generality and high
stereoselectivity of these reactions constitute two desirable
features offered by these protocols. Additionally, the double
bond geometry can be predicted and controlled by choosing
the appropriate reagents and reaction conditions. These char-
acteristics make these reactions attractive for the assembly of
olefinated organoboron compounds, reagents that could subse-
quently be utilized in further carbon-carbon bond forming
reactions via transition metal catalyzed reactions (e.g., Suzuki-
Miyaura coupling).6
Organoboron compounds are becoming increasingly impor-
tant components of transition metal catalyzed organic transfor-
mations, but the synthesis of functionalized organoboron
compounds can be challenging because of the incompatibility
of the methods employed to generate the organoboron moiety
with other substituents. For example, although catalyzed and
uncatalyzed hydroboration reactions1,2 as well as the transmeta-
lation of organolithium and Grignard reagents3 are often used
to prepare organoboron derivatives, competitive side reactions
with existing, sensitive functionalities in the substrate can limit
the use of these methods. These limitations make the installation
of added functionality to an existing organoboron compound
attractive, but this approach is rarely feasible and has not often
been employed for obvious reasons. Thus, boronic acids are
relatively strong Bronsted acids, while organoboranes and
boronate esters are Lewis acidic. All of these classes of
organoborons are thus susceptible to reaction with nucleophiles
and bases that are often required for carbon-carbon bond-
forming reactions and functional group transformations.
To the best of our knowledge, no examples of Wittig or HWE
reactions have been reported with use of suitably functionalized
boronic acid derivatives, undoubtedly because of the presence
(4) Reviews: (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89,
863. (b) Vedejs, E.; Peterson, M. J. In Topics in Stereochemistry; Eliel, E.
L., Wilen, S. H., Eds.; John Wiley & Sons: New York, 1994; Vol. 21, p
1. (c) Vedejs, E.; Peterson, M. J. In AdVances in Carbanion Chemistry;
Snieckus, V., Ed.; JAI Press Inc.: New York, 1996; Vol. 2, pp 1-86. (d)
Edmonds, M.; Abell, A. In Modern Carbonyl Olefination Methods and
Applications; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004;
pp 1-17.
(1) Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983, 2,
1311.
(2) (a) Burgess, K.; Ohlmeyer, M. J. Chem. ReV. 1991, 91, 1179. (b)
Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909. (c) Kabalka, G.
W.; Narayana, C.; Reddy, N. K. Synth. Commun. 1994, 24, 1019. (d)
Ma¨nnig, D.; No¨th, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 878. (e) Evans,
D. A.; Muci, A. R.; Stu¨rmer, R. J. Org. Chem. 1996, 61, 3224.
(3) Matteson, D. S. Tetrahedron 1989, 45, 1859.
(5) Walker, B. J. In Organophosphorus Reagents in Organic Synthesis;
Gadogan, J. I. G., Ed.; Academic Press: London, UK, 1979; pp 155-205.
(6) (a) Miyaura, N.: Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 49-97. (c) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
10.1021/jo060863w CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/06/2006
J. Org. Chem. 2006, 71, 6135-6140
6135

Molander and Figueroa
TABLE 1. Optimization of Wittig Reaction Conditions
of the acidic protons in these species. On the other hand, the
Wittig and HWE reactions using aromatic boronate esters with
stabilized ylides and phosphonates have been reported to a very
limited extent,7,8 but these transformations suffer because of the
presence of the pinacol unit, which adds to the expense and
detracts from the atom economy of the overall process.
entry
ylide (equiv)
solvent
yielda (%)
Z:Eb
The current contribution focuses on the employment of the
Wittig and HWE reactions to functionalize the more robust
potassium organotrifluoroborates. Potassium organotrifluorobo-
rates are unique and versatile organoboron compounds.9 They
can be easily prepared by the addition of inexpensive KHF2 to
a variety of organoboron intermediates.10 These organoboron
substrates are crystalline powders stable to both air and moisture.
The utility of potassium organotrifluoroborates has been dem-
onstrated by their application in Suzuki-Miyaura-type coupling
reactions,9 rhodium-catalyzed 1,4 additions,11 and allylation
reactions,12 making them highly attractive synthetic reagents.
The interest in the synthesis of unsaturated potassium organ-
otrifluoroborates, in particular, has been reinforced upon the
development of methods for epoxidation13 and dihydroxylation14
of these substrates while preserving the trifluoroborate unit.
1
2
3
4
1.0
1.1
1.1
1.5
THF/DMF
CH3CN/THF
DMF
27
0
34
72
1.5:1
2:1
4:1
DMF
a Isolated yields. b Based on H NMR.
1
ease of isolation of the product. To have complete conversion
of the starting material was important not only to demonstrate
the efficiency of the process, but also because the separation of
product and starting trifluoroborate proved quite difficult.
Traditionally, the ylide is generated by using NaHMDS in
THF, which provides salt-free conditions and higher Z-selectivi-
ties than the corresponding lithium bases.4a,15 However, most
potassium organotrifluoroborates have poor solubility in THF.
After testing the solubility of formyltrifluoroborate 1a in various
solvents amenable to the Wittig reaction, the highest concentra-
tion was achieved with DMF.
Results and Discussion
Initial studies were directed toward the Wittig reaction of
both formyl- and acetyl-substituted organotrifluoroborates with
nonstabilized ylide reagents. The anionic character of this
reaction provided information about the tolerance of the
trifluoroborate to the reaction conditions. The goal was to
develop a general method that would allow use of both
aryltrifluoroborates and alkyltrifluoroborates.
The reaction between 4-formylphenyltrifluoroborate (1a) and
an ethyltriphenylphosphonium bromide-derived ylide (3) was
chosen to develop the method. Organotrifluoroborate 1a was
prepared by adding KHF2 to the corresponding boronic acid.10
Because the conditions to generate the ylide were well-known,
attention was directed toward other aspects of the reaction. This
included the ability of the reaction to reach completion and the
The Wittig reaction was initially performed with standard
conditions: a solution of the aldehyde in a mixture of THF and
DMF was added to a solution of the in situ generated ylide,
followed by an aqueous workup. As shown in Table 1 entry 1,
the product was isolated in poor yield. This result was attributed
to the high solubility of the product in DMF. A mixture of CH3-
CN/THF was then used (entry 2), but the poor solubility of 1a
in these solvents led to no reaction. The first reaction conditions
1
were then reevaluated. Analysis of the reaction by H NMR
revealed that the reaction had reached completion. Therefore,
the isolation of the organotrifluoroborate needed to be improved.
The aqueous workup combined with the attempt to precipitate
the organotrifluoroborate from the organic solution was per-
ceived to be the major part of the difficulty. Having these factors
in mind, the reaction was repeated with only DMF to dissolve
the organotrifluoroborate (entry 3). Additionally, instead of an
aqueous workup, the salts (NaBr) were removed by filtration
and the filtrate was concentrated in vacuo. The residue was
washed with CH2Cl2, which dissolved the organic impurities
including triphenylphosphine oxide, but not the organotrifluo-
roborate. The trifluoroborate remained as a precipitate that could
be collected and purified by recrystallization. These modifica-
tions led to a small improvement in the isolated yield. The
filtration to remove NaBr was considered to be a second
impediment to success, because some of the product was filtered
off as well. Inorganic salts produced in the formation of ylides
have previously been removed by filtration prior to reaction
with the carbonyl.4a,16 To simplify the technique further, a stock
solution of the ylide was prepared, the salt formed in the ylide
was allowed to settle, and the filtration step was eliminated by
siphoning off the solution above the precipitate. These salt-free
conditions and isolation techniques gave the final product in
72% yield after recrystallization (entry 4). The preservation of
(7) Wittig: (a) Lautens, M.; Mancuso, J. J. Org. Chem. 2004, 69, 3478.
(b) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69, 4607. Wittig-
Horner under Masamune conditions: (c) Kobayashi, Y.; Tokoro, Y.;
Watatani, K. Tetrahedron Lett. 1998, 39, 7537. (d) Kobayashi, Y.; Tokoro,
Y.; Watatani, K. Eur. J. Org. Chem. 2000, 3825.
(8) HWE or Horner-Emmons-Wittig: (a) Schmidt, U.; Leitenberger,
V.; Griesser, H.; Schmidt, J.; Meyer, R. Synthesis 1992, 1248. (b) Park, K.
C.; Yoshino, K.; Tomiyasu, H. Synthesis 1999, 2041. (c) Busnel, O.;
Carreaux, F.; Carboni, B.; Pethe, S.; Goff, S. V.-L.; Mansuy, D.; Boucher,
J.-L. Bioorg. Med. Chem. 2005, 13, 2373. (d) Gopalarathnam, A.; Nelson,
S. G. Org. Lett. 2006, 8, 7.
(9) Reviews: (a) Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2003, 4313.
(b) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49.
(10) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020. (b) Vedejs, E.; Fields, S. C.; Hayashi,
R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc.
1999, 121, 2460.
(11) (a) Batey, R. A.; Thadani, A. N. Org. Lett. 1999, 1, 1683. (b)
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2002, 3552. (c)
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett. 2002, 43, 6155.
(d) Navarre, L.; Pucheault, M.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett.
2005, 46, 4247.
(12) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett.
1999, 40, 4289. (b) Batey, R. A.; Thadani, A. N.; Smil, D. V. Synthesis
2000, 990. (c) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4, 3827. (d)
Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44, 8051. (e) Li,
S.-W.; Batey, R. A. Chem. Commun. 2004, 12, 1382.
the trifluoroborate unit was demonstrated by using 11B and 19
NMR.
F
(13) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125,
11148.
(14) Molander, G. A.; Figueroa, R. Org. Lett. 2006, 8, 75.
(15) Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1976,
109, 1694.
(16) Anderson, R. J.; Henrick, C. A. J. Am. Chem. Soc. 1975, 97, 4327.
6136 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Unsaturated Organotrifluoroborates
TABLE 2. Wittig Reaction with Various Potassium
Organotrifluoroborates
yielding. Application of the developed conditions was extended
to heteroaryltrifluoroborates 1e and 1f (entries 5 and 6). The
corresponding unsaturated organotrifluoroborates were isolated
in good yield with high Z-selectivity.
The Wittig reaction of ketones is more difficult because of
the decrease in reactivity of the carbonyl group. These trans-
formations required harsher reaction conditions as well as longer
reaction times.18 However, the use of ketones is relevant for
the introduction of a higher degree of substitution in the double
bond. Therefore, it was important to demonstrate that potassium
organotrifluoroborates with trisubstituted olefins could be
prepared by using the corresponding ketones. Indeed, the
reaction of potassium 4-acetylphenyltrifluoroborate (1g)19 gave
the olefination product in moderate yield and good selectivity
with use of the same reaction conditions as those reported for
the formyl substrates.
The Wittig reaction of alkyl aldehydes with nonstabilized
ylides was subsequently investigated. These reactions are usually
very efficient and highly selective for the generation of the
Z-isomer because of the increase in reactivity as compared with
aromatic aldehydes. The synthesis of the formylalkyltrifluo-
roborate 1h was achieved by the hydroboration of the com-
mercially available acrolein diethyl acetal (13), using the
Snieckus reagent,20 followed by deprotection and further treat-
ment of the intermediate with KHF2 (eq 1). The reaction between
alkyltrifluoroborate 1h and the nonstabilized ylide 4 proceeded
as expected (entry 8).
The Wittig reactions with ylide 4 containing a nitrile group
demonstrated the efficient use of functionalized ylides. In
subsequent studies, further functional group compatibility was
investigated (Table 3). Thus, ylide 14 was reacted with 1a to
afford the unsaturated organotrifluoroborate with an acetal
functionality (entry 1). The lower Z/E selectivity observed in
this reaction was not surprising and can be attributed to the
known effect of having an oxide functionality in the ylide.21
The preparation of the unsaturated organotrifluoroborate 18
containing an amino group surprisingly proved to be more
difficult (entry 2). When NaHMDS was used to generate the
ylide 15 and only 1 equiv of the ylide was used, the reaction
did not reach completion. After surveying the amount of ylide
required, it was found that 2 equiv were needed. However, the
organotrifluoroborate isolated was contaminated with tri-
phenylphosphine oxide. The problems in the isolation of 18 were
attributed to the significant amount of byproducts in the reaction.
These results led to the use of n-BuLi as the base to generate
ylide 15, thus eliminating the amine byproduct. In this manner,
the Wittig reaction was accomplished with only 1.1 equiv of
the ylide, and the product was isolated in 82% yield. The lower
and reverse selectivity of the reaction can be attributed to two
factors: the reaction is no longer under salt-free conditions (the
a Isolated yields. b Contaminated with 3.2% of the starting trifluoroborate.
1
1
c Based on H NMR. d Based on the H NMR detection limit.
The optimized reaction and isolation conditions were then
utilized to study the substrate scope (Table 2). The use of a
functionalized ylide in the studies was attractive as a means to
increase molecular complexity. Consequently, 3-cyanopropyl-
triphenylphosphonium bromide17 was used to prepare the nitrile-
containing ylide 4, and this ylide was employed as a standard
partner with various organotrifluoroborates.
The positional effect of the organotrifluoroborate unit in the
aromatic ring relative to the reactive formyl group was first
studied. Formylaryltrifluoroborates 1a, 1b, and 1c were allowed
to react with ylide 4 (entries 1, 2, and 3). Each reaction
proceeded in excellent yield. Isolation of the product from the
para- and meta-substituted organotrifluoroborates with almost
the same stereoselectivity demonstrated that there is no differ-
ence in the electronic effect of the trifluoroborate at these
positions, and that the reduction in selectivity of the ortho-
substituted trifluoroborate 1b is therefore due to steric effects
(A1,3-strain). The Wittig reaction of the more substituted
formylaryltrifluoroborate 1d was also very selective and high
(18) Vedejs, E.; Cabaj, J.; Peterson, M. J. J. Org. Chem. 1993, 58, 6509.
(19) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(20) Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed.
2003, 42, 3399.
(17) Bressy, C.; Bruye`re, D.; Bouyssi, D.; Balme, G. ARKIVOC 2002,
5, 127.
(21) Maryanoff, B. E.; Reitz, A. B.; Duhl-Emscoiler, B. A. J. Am. Chem.
Soc. 1985, 107, 217.
J. Org. Chem, Vol. 71, No. 16, 2006 6137

Molander and Figueroa
TABLE 4. Wittig Reaction with Various Stabilized Ylides
TABLE 3. Wittig Reaction with Various Unstabilized Ylides
a 14 and 16 were generated with NaHMDS. 15 was generated with
1
n-BuLi. b Isolated yield. c Based on H NMR.
a Isolated yields. b Reaction time was 20 h. c Contaminated with 1% of
1
starting trifluoroborate. DMF only as solvent. d Based on H NMR.
reaction contained soluble lithium salts)4 and the possible
participation of the amino group.20 The synthesis of trisubstituted
organotrifluoroborates can be efficiently accomplished by using
branched ylides such as 16, whereupon the product was isolated
in 84% yield (entry 3).
It also shows the stability of the trifluoroborate unit under these
mildly anionic conditions.
The method was also extended to the use of formyl-
substituted alkyltrifluoroborates as shown in eq 2. Alkyltri-
The success of the Wittig reaction of formyl- and acetyl-
substititued organotrifluoroborates with nonstabilized ylides
provided a motivation to explore the reaction with stabilized
ylides. Carbonyl-stabilized ylides have been recognized as
valuable synthetic tools to access E-olefins with high selectivity.4
The reaction conditions that are often utilized employ preformed
ylides or in situ generation of the ylide with mild bases.
Considering the initial isolation problems observed in the
reaction with nonstabilized ylides, the use of preformed
stabilized ylides was more practical. In this way, the removal
of inorganic or organic salts was eliminated, and furthermore,
some of the preformed stabilized ylides are commercially
available. Toluene and benzene are commonly used in these
reactions to allow higher reaction temperatures. Once again,
DMF was also used as a cosolvent to ensure the solubility of
the starting trifluoroborates. The combination of benzene and
DMF in a 1:1 ratio at 90 °C with a slight excess of the preformed
stabilized ylides proved to be excellent reaction conditions
(Table 4). Isolation of the products was then further simplified.
The reaction mixtures were concentrated and washed with CH2-
Cl2 to give the product as a pure, insoluble solid that was
separated by filtration (recrystallization was not needed).
Potassium 4-formylphenyltrifluoroborate (1a) was again used
to evaluate different stabilized ylides under the indicated reaction
conditions. The synthesis of R,â-unsaturated potassium phen-
yltrifluoroborates bearing a nitrile, ketone, ester, and Weinreb
amide functional group was conducted in moderate to excellent
yields by using ylides 20,22 21, 22, and 23, respectively. All
the reactions proceeded smoothly in a short period of time except
for the reaction with ylide 21, which required 20 h. The longer
reaction time required by ylide 21 has been attributed to a lower
reactivity that results from higher stabilization of the nucleophile.4b
Additionally, the use of benzene is not required in the reaction.
This was demonstrated in the synthesis of organotrifluoroborate
27, wherein DMF was used as the only solvent. These results
demonstrate the synthetic merit of this transformation to
introduce valuable functionalities in the organotrifluoroborates.
fluoroborate 1h was reacted with methoxycarbonylmethylene-
phosphorane (22) to yield the product in 56% yield. The
observed yield and stereoselectivity were lower than those for
the aryltrifluoroborates. The reduced selectivity was not surpris-
ing because of the higher reactivity of alkanals. In this case,
the trifluoroborate unit showed some degradation as demon-
strated by the presence of inorganic salts in the 19F NMR of
the product. Nevertheless, these results demonstrated the
generality of the reaction for both the organotrifluoroborate and
the ylide.
After completing the Wittig reactions, studies were initiated
toward the application of the Horner-Wadsworth-Emmons
olefination of appropriately functionalized potassium organo-
trifluoroborates. It was important to demonstrate that either of
the two olefination tools could be utilized to synthesize
unsaturated organotrifluoroborates, and to demonstrate the use
of both alkyl- and aryltrifluoroborates in the HWE reaction. This
reaction offers the advantage that higher E-selectivity can be
achieved in many cases compared to the Wittig reaction. The
solubility of the byproducts of the HWE reaction in water was
anticipated to facilitate isolation and purification of the elabo-
rated trifluoroborates.
The previous studies on the Wittig reaction provided a basic
set of information useful in the exploration of the HWE
olefination. Thus, the starting trifluoroborate would be added
in DMF to the phosphonate carbanion solution. The phosphonate
carbanion was generated in situ following standard conditions.
Preliminary studies with aldehyde 1a and phosphonates 29 and
30 were helpful in the development of isolation conditions. In
both cases, partial precipitation of the product was observed.
Unfortunately, the precipitated products were contaminated with
6138 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Unsaturated Organotrifluoroborates
TABLE 5. HWE Reaction with Various Organotrifluoroborates and Phosphonates
1
1
a Isolated yields. b Contaminated with 4-6% of phosphonate species. c Based on H NMR. d Based on the H NMR detection limit.
the phosphate byproduct [(EtO2)PdO(OLi)]. Nevertheless,
advantage was taken of this phenomenon. Further precipitation
of the organotrifluoroborate could be induced to separate the
solid mixture from the excess phosphonate. Isolation of the
organotrifluoroborate could then be achieved by taking advan-
tage of the water solubility of the phosphate combined with
the Batey and Quach cation exchange reaction to generate
tetrabutylammonium organotrifluoroborates.23 By using this
strategy, the tetrabutylammonium salts migrated into the organic
phase, and the phosphate byproduct remained in the aqueous
phase.
Once the reaction and isolation conditions were optimized,
the scope of the HWE olefination with use of aryltrifluoroborates
was studied (Table 5). The conditions developed were general
for various phosphonates (entries 1-4). The lower selectivity
observed with phosphonate 29 can be attributed to the higher
reactivity of the anion as compared with the more stabilized
phosphonate 30 combined with the smaller steric influence of
the cyano group. The synthesis of the styrylphenyltrifluoroborate
35 proceeded in good yield by using the semistabilized
carbanion from phosphonate 31. The use of the branched
phosphonate 32 was important from the point of view of
introducing more substitution in the olefin. Indeed, the trisub-
stituted organotrifluoroborate 36 was prepared in 65% yield.
This yield was achieved after removal of the excess phosphonate
32 by extraction with an aqueous solution of KOH. Some of
the products trapped a small percent of the phosphonates, but
the remains of these starting materials could be easily removed
by this simple extraction protocol.
Formylheteroaryltrifluoroborates could also be used to syn-
thesize the corresponding R,â-unsaturated compounds (entries
5 and 6). The use of formylalkyltrifluoroborate 1h proceeded
with high selectivity but in lower yield (entry 7).
Conclusion
Although organoborons (particularly boronic acids and bo-
ronate esters) are playing an increasing role in the synthesis of
organic molecules via transition metal catalyzed processes, in
general these reagents are synthesized in one synthetic step and
transformed immediately without further functional group
elaboration. This is due in large part to the Bronsted and Lewis
acidic properties of these materials. Because of this, practitioners
(22) Prepared according to a procedure reported by: Mauduit, M.;
Kouklovsky, C.; Langlois, Y. Tetrahedron Lett. 1998, 39, 6857.
(23) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
J. Org. Chem, Vol. 71, No. 16, 2006 6139

Molander and Figueroa
ylmethylenetriphenylphosphorane (22) (368 mg, 1.1 mmol), DMF
(1.0 mL), and benzene (1.0 mL) was heated to 90 °C (oil bath
temperature) for 2 h.24 The reaction mixture was concentrated
overnight under high vacuum.25 CH2Cl2 was added to the resulting
solid mixture and the slurry was stirred for about 3 min. The solids
were collected by filtration, washed with three small portions of
CH2Cl2, and dried under high vacuum to yield 210.4 mg (78%) of
a white solid. Mp >220 °C; IR (KBr) νmax 1712 (CdO), 1640 (Cd
C), 1216 (C-O) cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.59 (d,
J ) 15.9 Hz, 1H), 7.43 (d, J ) 6.9 Hz, 2H), 7.39 (d, J ) 6.8 Hz,
2H), 6.49 (d, J ) 15.9 Hz, 1H), 3.70 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 167.0, 146.0, 131.9 (2C), 130.7, 126.6 (2C), 115.1,
51.3; 19F NMR (470 MHz, DMSO-d6) δ -140.1; 11B NMR (128
MHz, DMSO-d6) δ 2.42; HRMS (m/z) [M - K]- calcd for C10H9-
BF3O2 229.0648, found 229.0644. The Z/E ratio was 1:39 based
on the integration of peaks at 5.85 and 6.49 ppm, respectively.
General Procedure for the Horner-Wadsworth-Emmons
Reaction: Preparation of (E)-Tetrabutylammonium 4-(2-Cy-
anovinyl)phenyltrifluoroborate (33). The reaction was performed
under a N2 atmosphere in a two-necked round-bottomed flask. The
cation exchange was performed in an open atmosphere in a round-
bottom flask. To a solution of diethyl cyanomethylphosphonate
(0.20 mL, 213 mg, 1.2 mmol) in THF (1.9 mL) was added 1.6 M
n-BuLi (0.75 mL, 1.2 mmol) in hexanes at 0 °C (ice-water bath).
The resulting solution was stirred for 0.5 h. Then, a solution of
potassium 4-formylphenyltrifluoroboratae (1a) in DMF (1.0 mL)
was added via syringe. The solution was kept for 1.5 h at 0 °C.26
The ice bath was removed and the mixture was stirred for another
2 h. To the mixture was added hexanes and Et2O in an alternate
fashion until no more precipitation was observed. The solid was
washed with two small portions of both hexanes and Et2O. To a
mixture of the solid in H2O (0.4 mL) and CH2Cl2 (3.0 mL) was
added a solution of 40 wt % n-Bu4NOH (0.62 mL, 1.0 mmol) in
H2O. The biphasic solution was stirred for 0.5 h. The layers were
separated. The aqueous layer was extracted with two small portions
of CH2Cl2. The combined organic layers were washed with two
small portions of H2O, dried (MgSO4), and concentrated under high
vacuum to yield 305 mg (70%) of a yellow solid. Mp 95-96 °C;
IR (CH2Cl2) νmax 2213 (CtN), 1614 (CdC) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.65 (d, J ) 7.7 Hz, 2H), 7.36 (d, J ) 16.6 Hz,
1H), 7.30 (d, J ) 7.6 Hz, 2H), 5.80 (d, J ) 16.6 Hz, 1H), 3.07-
3.00 (m, 8H), 1.53-1.46 (m, 8H), 1.35 (sextet, J ) 7.3 Hz, 8H),
0.95 (t, J ) 7.3 Hz, 12H); 13C NMR (125 MHz, CDCl3) δ 152.2,
132.4 (2C), 130.8, 125.9 (2C), 119.0, 93.1, 58.4 (4C), 23.7 (4C),
are severely limited in their approach to complex molecule
synthesis by the chemical characteristics of the reagents
themselves.
The tetracoordinate nature of organotrifluoroborates shields
them from reactions with Lewis bases and nucleophiles under
normal reaction conditions. Remote functionality can thus be
transformed under anionic conditions, leaving the valuable
carbon-boron bond intact for eventual coupling processes.
Consequently, the sensitivity of the boron moiety itself is largely
removed from consideration in synthetic schemes, and potential
retrosynthetic analyses to target molecules can be greatly
expanded.
In the current demonstration of this approach, the stereo-
selective synthesis of unsaturated potassium organotrifluorobo-
rates via the Wittig and Horner-Wadsworth-Emmons reaction
was accomplished in moderate to excellent yields. The estab-
lished reaction conditions allow the isolation of the products as
stable solids with high purity. Thus, relatively simple orga-
noboron substructures can be elaborated by olefination, increas-
ing molecular complexity while retaining the valuable carbon-
boron bond for subsequent transformations.
Experimental Section
General Procedure for the Wittig Reaction with Nonstabilized
Ylides: Preparation of (Z)-Potassium 4-(4-Cyanobut-1-enyl)-
phenyltrifluoroborate (5).
A mixture of 3-cyanopropyltri-
phenylphosphonium bromide17 (821 mg, 2.00 mmol) in THF (2.0
mL) was cooled to 0 °C (ice-water bath). To the slurry was added
1.0 M NaHMDS in THF (2.0 mL, 2.0 mmol). The resulting orange
to red solution was stirred for 30 min. The ice bath was removed
and the stirring was stopped. The mixture was allowed to settle
(∼1 h) until the precipitate (NaBr) completely separated from the
solution. To a mixture of potassium 4-formylphenyltrifluoroborate
(1a) (212 mg, 1.0 mmol) in DMF (1.0 mL) was added the ylide
solution (2.2 mL, 1.1 mmol) via syringe at -78 °C. (Note: If the
solution freezes the flask can be removed from the bath until
everything goes in solution, and then returned to the bath.) After
the solution was stirred for 1 h, the ice bath was removed and
stirring was continued for another 2 h. The mixture was concen-
trated under high vacuum overnight until almost all the DMF and
HMDS was removed. To the residue was added CH2Cl2, and the
mixture was stirred until there was an evident separation of a solid.
The solid was collected by suction filtration and washed with three
small portions of CH2Cl2 to afford the crude product as a brown
solid. The solid was stirred in a solution of 10% MeOH in acetone.
Then, Et2O was added until no more precipitation was observed.
The precipitate was collected, washed with small portions of Et2O,
and dried under high vacuum to yield 215 mg (82%) of a yellow
solid. Mp 186-188 °C; IR (KBr) νmax 3062 (dC-H), 2252 (Ct
N), 1606 (CdC) cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.33 (d,
J ) 7.6 Hz, 2H), 7.04 (d, J ) 7.5 Hz, 2H), 6.48 (d, J ) 11.5 Hz,
1H), 5.50 (dt, J ) 11.5, 6.5 Hz, 1H), 2.64-2.59 (m, 4H); 13C NMR
(125 MHz, DMSO-d6) δ 133.0, 131.9 (2C), 131.3, 126.64, 126.62
(2C), 120.4, 24.2, 16.7; 19F NMR (470 MHz, DMSO-d6) δ -139.6;
11B NMR (128 MHz, DMSO-d6) δ 2.20; HRMS (m/z) [M - K]-
calcd for C11H10BF3N 224.0858, found 224.0853. The Z/E ratio
was 28:1 based on the integration of peaks at 5.50 and 6.12 ppm,
respectively.
19.5 (4C), 13.5 (4C); 19F NMR (470 MHz, CDCl3) δ -142.6; 11
B
NMR (128 MHz, CDCl3) δ 1.69. HRMS (m/z) [M-nBu4N]- calcd
for C9H6BF3N 196.0545, found 196.0547. The Z/E ratio was 1:9
based on the integration of peaks at 5.30 and 5.80 ppm, respectively.
Acknowledgment. We thank the National Institutes of
Health (GM 35249), Amgen, and Merck for their generous
support. Frontier Scientific is acknowledged for their generous
donation of boronic acids. Dr. Rakesh K. Kohli at the University
of Pennsylvania is acknowledged for the determination of high-
resolution mass spectra of the organotrifluoroborates.
Supporting Information Available: Complete experimental
details and copies of all NMR spectra (1H,13C, 19F, and 11B). This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO060863W
Anal. Calcd for C11H10BF3KN: C, 50.21; H, 3.83. Found: C,
49.87; H, 3.99.
General Procedure for the Wittig Reaction with Stabilized
Ylides: Preparation of (E)-Potassium 4-(2-(Methoxycarbonyl)-
vinyl)phenyltrifluoroborate (26). A mixture of potassium 4-formyl-
phenyltrifluoroborate (1a) (212 mg, 1.0 mmol), methoxycarbon-
(24) The reaction begins heterogeneous and becomes homogeneous as
it reaches 90 °C and remains homogeneous until completion.
(25) Complete removal of DMF is required to facilitate isolation of the
product. Slight heating (50 °C) can be used to facilitate DMF removal.
(26) At this stage partial precipitation of the product was observed.
6140 J. Org. Chem., Vol. 71, No. 16, 2006