Beyond benzyl grignards: Facile generation of benzyl carbanions from styrenes

Article abstract of DOI:10.1002/chem.201200642

Benzylic functionalization is a convenient approach towards the conversion of readily available aromatic hydrocarbon feedstocks into more useful molecules. However, the formation of carbanionic benzyl species from benzyl halides or similar precursors is far from trivial. An alternative approach is the direct reaction of a styrene with a suitable coupling partner, but these reactions often involve the use of precious-metal transition-metal catalysts. Herein, we report the facile and convenient generation of reactive benzyl anionic species from styrenes. A Cu^I-catalyzed Markovnikov hydroboration of the styrenic double bond by using a bulky pinacol borane source is followed by treatment with KOtBu to facilitate a sterically induced cleavage of the C-B bond to produce a benzylic carbanion. Quenching this intermediate with a variety of electrophiles, including CO₂, CS₂, isocyanates, and isothiocyanates, promotes C-C bond formation at the benzylic carbon atom. The utility of this methodology was demonstrated in a three-step, two-pot synthesis of the nonsteroidal anti-inflammatory drug (±)-flurbiprofen. Make or break: The facile generation of benzyl anion equivalents from styrenes has been achieved by using a Cu-catalyzed hydroboration in conjunction with sterically induced cleavage of the C-B bond with tBuOK. Quenching this reactive intermediate with heteroallene electrophiles yields benzylic C-C bond formation (see scheme), and the utility of this methodology has been demonstrated by a synthesis of the nonsteroidal anti-inflammatory drug (±)-flurbiprofen. Copyright

Full text of DOI:10.1002/chem.201200642

FULL PAPER
DOI: 10.1002/chem.201200642
Beyond Benzyl Grignards: Facile Generation of Benzyl Carbanions
from Styrenes
R. David Grigg, Jared W. Rigoli, Ryan Van Hoveln, Samuel Neale, and
Jennifer M. Schomaker*[a]
Abstract: Benzylic functionalization is
convenient approach towards the
catalysts. Herein, we report the facile
and convenient generation of reactive
benzyl anionic species from styrenes. A
CuI-catalyzed Markovnikov hydrobora-
tion of the styrenic double bond by
using a bulky pinacol borane source is
followed by treatment with KOtBu to
facilitate a sterically induced cleavage
a
À
conversion of readily available aromat-
ic hydrocarbon feedstocks into more
useful molecules. However, the forma-
tion of carbanionic benzyl species from
benzyl halides or similar precursors is
far from trivial. An alternative ap-
proach is the direct reaction of a sty-
rene with a suitable coupling partner,
but these reactions often involve the
use of precious-metal transition-metal
of the C B bond to produce a benzylic
carbanion. Quenching this intermediate
with a variety of electrophiles, includ-
ing CO2, CS2, isocyanates, and isothio-
À
cyanates, promotes C C bond forma-
tion at the benzylic carbon atom. The
utility of this methodology was demon-
strated in a three-step, two-pot synthe-
sis of the nonsteroidal anti-inflammato-
ry drug (Æ)-flurbiprofen.
Keywords: benzyl anion · carban-
ions · carboxylation · cleavage reac-
tions
·
Cu catalysis
· domino
reactions
Introduction
The reaction of a carbanion with an electrophile is one of
the most general approaches employed for the formation of
[1]
À
new C C bonds. Certain types of carbanionic species are
difficult or inconvenient to prepare and many synthetic
chemists opt for more indirect approaches to construct these
bonds. An excellent example is the benzyl anion, which
could undergo reactions with heteroallene electrophiles to
yield a number of valuable bioactive molecules (Figure 1).
However, the generation of these reactive species is far
from trivial and suffers from more than just the expected
functional group incompatibility. Direct deprotonation at
a benzylic position often leads to competing metallation of
the aromatic ring, and the oxidative additions of metals, in-
cluding Mg, Zn, Cd, and Mn, to benzyl halides are problem-
atic due to the competitive formation of bibenzyl prod-
ucts.[2,3] Thus, the formation of benzyl carbanions has tradi-
tionally relied on the use of toxic main-group precursors, in-
cluding benzylselenides, benzylstannanes, benzyltellurides
and benzylmercury compounds, or on the cleavage of
benzyl–oxygen and benzyl–sulfur bonds with lithium.[2g,4,5]
Figure 1. Bioactive molecules containing benzylic functionalization.
Results and Discussion
A more convenient and environmentally friendly approach
for the synthesis of benzyl carbanions might involve generat-
ing a benzyl anion from an olefin precursor, perhaps via
a benzyl boronic ester intermediate. This could minimize
single-electron pathways and the subsequent formation of
homocoupling byproducts that plague current methods.
Benzyl carbon atoms have been previously functionalized
by the treatment of benzyl boronic esters with strong bases
to give borates, which undergo subsequent reactions with
a variety of electrophiles.[6] These elegant methods, devel-
oped by Matteson, Aggarwal, Crudden, and others, rely on
the use of pyrophoric, and in some cases very specific, orga-
nolithium bases. The desired products cannot be accessed di-
rectly from styrene; however, the transfer of chirality from
an enantioenriched boronic ester to the product with excel-
[a] R. D. Grigg, J. W. Rigoli, R. Van Hoveln, S. Neale,
Prof. J. M. Schomaker
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
Fax : (+1)608-265-4534
E-mail: schomakerj@chem.wisc.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200642.
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lent fidelity is a nice feature of these systems.[6] In our case,
the products of interest contain highly acidic protons at the
benzylic position, which avoids the need for an asymmetric
approach. In fact, on an industrial scale, flurbiprofen and
ibuprofen are prepared and utilized as the racemates. If res-
olution is necessary, flurbiprofen can be treated with (R,R)-
thiomicamine and the undesired enantiomer is recycled.[7]
Currently, this approach is much more economical than uti-
lizing existing asymmetric syntheses of the molecule.
Table 1. Initial optimization of the benzylic anion formation and quench-
ing with CO2.
Entry
Base
Solvent
T [8C]
RT
Yield (1a/2a/3a) [%][a]
1
2
3
4
5
6
7
8
9
NaOtBu
KHMDS
CsF
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
THF
THF
THF
hexane
Et2O
THF
THF
THF
THF
THF
65:17:trace
70:0:30
100:0:0
65:16:18
trace:86:10
9:75:16
RT
RT
0
À40
À40
À78
À15
0
À
We hypothesized that C C bond formation at a benzyl
carbon might be facilitated under mild conditions by using
the combination of a bulky boronic ester and a bulky alkox-
ide base. Attack of the base at the boronic ester boron atom
would generate the boronate, which could then undergo het-
25:62:12
trace:60:23
trace:56:26
0:82:trace
À
erolytic C B bond cleavage to generate a highly reactive
benzyl carbanion.[8] Initial confirmation was provided by the
treatment of a primary benzylic boronic ester with potassi-
um tert-butoxide (KOtBu) in the presence of CO2 [Eq. (1);
Bpin=pinacolborane (4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane), IPr=2,6-di(isopropylphenyl)imidazolium]. Continued
experimentation demonstrated that the Cu species was not
necessary to promote the carboxylation reaction. In addi-
tion, this transformation proved to be chemoselective, as
a non-benzylic boronic ester did not yield the desired car-
boxylic acid product [Eq. (2)]. Herein, we report the synthe-
10
RT, À78
[a] Yields were derived from 1H NMR spectroscopy and are based on bi-
benzyl as the internal standard.
whereas LiOtBu was completely ineffective (data not
shown). KOtBu was the superior base (Table 1, entries 5–
10), with the use of potassium hexamethyldisilazide
(KHMDS) (Table 1, entry 2) providing none of the desired
2a product. The addition of the appropriate crown ethers to
the reaction mixture did not improve the results. A variety
of fluoride sources known to form boronate complexes from
boronic esters (KF, tetra-n-butylammonium fluoride
(TBAF), tris(dimethylamino)sulfonium difluorotrimethylsili-
cate (TASF) and CsF, Table 1, entry 3) were also unsuccess-
ful, perhaps due to their lack of steric bulk. The optimal sol-
vents for the reaction were ethereal in nature, with the use
of diethyl ether at À408C providing an 86% yield of 2a
(Table 1, entry 5), and the use of THF providing a yield of
75% (Table 1, entry 6). Dioxane and 1,2-dimethoxyethane
(DME) gave 2a in moderate yields, but were not as effec-
tive as THF or diethyl ether. Noticeable temperature effects
were also apparent, particularly in relation to the amount of
protodeboronated 3a that was produced in the reaction.[11]
Although conversion to 2a was observed at temperatures
as low as À788C (Table 1, entry 7), complete conversion of
the starting material did not occur until the temperature
reached À158C (Table 1, entry 8). The increase in conver-
sion at higher temperatures (Table 1, entries 8 and 9) came
at the expense of an increased amount of byproduct 3a,
which resulted from the removal of the acidic proton of the
product 2a by unreacted anionic species present in the mix-
ture. With this protodeboronation pathway in mind, the op-
timal reaction conditions utilized base–substrate mixing at
room temperature followed by cooling the solution to
À788C before addition of CO2 (Table 1, entry 10). This
minimized the undesired protodeboronation and provided
higher and more consistent yields in subsequent studies.
With an optimized method in hand for the carboxylation
of the benzylic boronic esters, the scope of the reaction was
explored. Both 1- and 2-naphthylene-derived boronic esters
1a and 1b were converted to the corresponding carboxylic
À
sis and C C bond-forming reactions of highly reactive
benzyl anion equivalents from styrenes by using a one-pot
Cu-catalyzed hydroboration followed by simple treatment
with KOtBu and a heteroallene electrophile.
A secondary pinacol-based boronic ester 1a, accessed
from a Cu-catalyzed Markovnikov hydroboration of 1-vinyl-
napthalene, was chosen for initial studies to determine
À
whether sterically induced C B bond cleavage to produce
a benzyl anion could be accomplished (Table 1).[9] Yun and
co-workers have described an enantioselective version of
this highly regioselective hydroboration reaction, but we
were able to employ CuCl in conjunction with a bis(diphe-
nylphosphino)benzene (DPPBz) ligand to accomplish the
racemic reaction (see the Experimental Section and Sup-
porting Information for further details). CO2 was employed
as the electrophile because this readily available and inex-
pensive C1 source would lead to the formation of phenyl-
acetic acids, such as 2a.[10] The identity of both the anion
and the cation proved important. NaOtBu (Table 1, entry 1)
resulted in the incomplete conversion of 1a to the product,
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Benzyl Carbanions from Styrenes
FULL PAPER
À
Table 2. Substrate scope for the sterically induced C B bond cleavage by
using CO2 as the electrophile.
Table 3. One-pot hydroboration/carboxylation of styrenes.
[a] HBpin (1.2 equiv), CuCl (3.0 mol%), bis(diphenylphosphino)benzene
(DPPBz, 3.0 mol%), NaOtBu (6.0 mol%), THF.
entries 5–8) generally proceeded in high yields and did not
require cooling to À788C prior to electrophile addition. Al-
though isothiocyanates reacted smoothly with the 4-CO2Me-
containing substrate at À788C (Table 4, entries 2–4, com-
pounds 5c, 5 f, and 5i), isocyanates tended to competitively
form oligomers, which resulted in diminished yields
(Table 4, entries 5–8, compounds 6c, 6 f, 6i, and 6l). These
functionalizations could also be accomplished in a single pot
from the styrene precursors, as illustrated for the syntheses
of 4b (Table 4, entry 1), 5a (Table 4, entry 2), and 6a
(Table 4, entry 5).
Finally, alkyl and benzyl halides were also suitable elec-
trophiles for benzylic functionalization (Table 5). MeI,
iPrBr, and BnBr (Bn=benzyl) were all successfully coupled
to 1a in yields of 60, 59, and 67%, respectively (Table 5,
compounds 7a, 7b, and 7c). In the case of iPrBr, this repre-
sented a convenient approach to the coupling of two secon-
dary carbon atoms at a benzylic position by using an inex-
pensive Cu catalyst.
Other electrophiles, including aldehydes, ketones, ketenes,
and the Bestmann ylide (Ph3P=C=C=O), exhibited varying
degrees of success in reactions with the anionic benzyl spe-
cies generated from 1a.[13] The reaction of the benzyl anion
with ketones and aldehydes did not result in exclusive addi-
tion to the carbonyl, but rather in the significant competing
formation of the enolate. Oligomerization was observed in
all attempts to utilize ketenes or the Bestmann ylide as the
electrophile.
[a] The entire reaction was performed at À788C. [b] The acid was esteri-
fied prior to isolation. [c] The entire reaction was performed at À458C.
acids 2a and 2b in 82 and 75% yields, respectively
(Table 2). A tertiary boronic ester 1c was also converted
smoothly to the tertiary carboxylic acid 2c (Table 2) in good
yield. Additional substitution at the b-position of the olefin
was tolerated, as shown by the formation of 2d (Table 2);
thus it was not necessary to utilize a terminal olefin. Other
aromatic systems based on biphenyl systems successfully
gave the carboxylic acids 2g and 2h (Table 2). The success
of the carboxylation was greatly improved by using elec-
tron-withdrawing groups on the styrenyl and phenanthryl
systems, examples include 2e–2j (Table 2). Ketone and ester
groups survived the reaction conditions provided the tem-
perature of the base–substrate mixing step was lowered
(products 2e and 2i, Table 2).
The simplicity of the carboxylation conditions allowed the
reaction to be telescoped with a Cu-catalyzed hydroboration
to achieve
a
convenient hydrocarboxylation process
(Table 3).[9a,12] The hydroboration was conducted by using
either toluene or THF as the solvent, then the reaction mix-
ture was transferred by cannula to a solution of KOtBu in
THF at the appropriate temperature. Alternatively, the
KOtBu was added to the hydroboration mixture to achieve
a one-pot process. Gratifyingly, the carboxylation was com-
patible with the hydroboration process and the overall
yields for the two-step, one-pot reaction approached those
observed for the one-step conversion of the isolated boronic
ester into the carboxylic acid product.
The utility of our methodology was demonstrated in
a short synthesis of flurbiprofen (Scheme 1). This molecule
Other heteroallenes, including isocyanates, isothiocya-
nates, and CS2, were suitable electrophiles for the reaction
(Table 4). Conditions for the CO2 carboxylation could be ex-
tended to CS2 for the preparation of dithiocarboxylic acids
in good isolated yields (Table 4, entry 1). Reactions with iso-
thiocyanates (Table 4, entries 2–4) and isocyanates (Table 4,
Scheme 1. A short synthesis of (Æ)-flurbiprofen. a) HBpin (1.2 equiv),
CuCl (3.0 mol%), bis(diphenylphosphino)benzene (3.0 mol%), NaOtBu
(6.0 mol%), >95:5 regioselectivity.
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J. M. Schomaker et al.
Table 4. One-pot hydroboration/carboxylation of other heteroallene electrophiles.
been considered as a treatment for metastatic
prostate cancer and analogues of this molecule
have been explored for the treatment of Alzheim-
erꢁs disease.[15,16] The commercially available 4-
bromo-2-fluorobiphenyl (8) was cross-coupled with
a vinyl boronic ester to give a 91% yield of the
olefin precursor (9) for the key reaction step. Our
one-pot Cu-catalyzed hydroboration/carboxylation
proceeded in 83% yield to provide flurbiprofen
(10) in a three-step, two-pot process from a com-
mercially available starting material (Scheme 1).
The apparent generation of a highly reactive
benzylic carbanion by using KOtBu as a relatively
weak base was quite surprising. The presence of
the boronic ester might lower the pKa of the ben-
zylic proton sufficiently to allow direct deprotona-
tion by KOtBu. However, the conversion of a terti-
ary boronic ester 1c to the corresponding carbox-
ylic acid 2c (Table 1) occurred in good yield. Addi-
tionally, if an enantioenriched tertiary boronic
ester 11 was subjected to the reaction conditions,
racemic 12 was obtained (Eq. (3)), indicating sig-
Entry
1
Electrophile
CS2
Product
Ar
Yield
[%]
4a
4b
4b
4c
1-naphthyl
4-PhC6H4
4-PhC6H4
81
66
62[a]
81
4-CO2MeC6H4
5a
5a
1-naphthyl
1-naphthyl
4-PhC6H4
92
81[a]
90
2
Ph-NCS
5b
5c[b]
4-CO2MeC6H4
89
5d
5e
1-naphthyl
4-PhC6H4
4-CO2MeC6H4
91
91
81
3
4
p-MeOC6H4-NCS
p-FC6H4-NCS
5 f[b]
5g
5h
1-naphthyl
4-PhC6H4
4-CO2MeC6H4
88
85
80
5i[b]
6a
6a
1-naphthyl
1-naphthyl
4-PhC6H4
81
À
nificant cleavage of the C B bond prior to electro-
70[a]
74
5
Ph-NCO
phile attack. Additional evidence that the reaction
proceeded through a benzyl carbanionic species in-
cluded the improved product yields obtained from
substrates with electron-withdrawing groups on the
aromatic ring. This suggested that stabilization of
a benzyl anion was important to the success of the
reaction.
6b
6c[b]
4-CO2MeC6H4
44
6d
6e
1-naphthyl
4-PhC6H4
4-CO2MeC6H4
87
83
46
6
7
8
p-MeOC6H4-NCO
p-FC6H4-NCO
Cy-NCO
6 f[b]
6g
6h
1-naphthyl
4-PhC6H4
4-CO2MeC6H4
91
87
47
A proposed polar mechanism for the sterically
induced bond cleavage is illustrated in
Scheme 2.[17] Reaction of the base with the boron
atom in 13 yields the expected boronate complex
6i[b]
6j
6k
1-naphthyl
4-PhC6H4
4-CO2MeC6H4
92
83
26
À
14. A sterically induced cleavage of the C B bond
6l[b]
would give the presumed benzyl anion 15, which
then reacts rapidly with the electrophile. The ne-
cessity of employing two equivalents of base is not
[a] Yields for the one-pot reaction by using styrene as the substrate. [b] Reaction con-
ducted at À788C.
Table 5. One-pot hydroboration/carboxylation of alkyl halide electrophi-
les.[a]
clear; however, the formation of 17 may help to facilitate
the reaction by driving the equilibrium in the desired direc-
tion.
[a] Yields were derived from 1H NMR spectroscopy and are based on
1,1,2,2-tetrachloroethane as an internal standard.
Conclusion
A convenient method for generating benzyl anions from
styrenes has been demonstrated. This approach avoids the
tedious and often capricious preparation of secondary and
tertiary benzylic Grignard or organolithium reagents, and
is a nonsteroidal anti-inflammatory drug (NSAID) used for
the treatment of the inflammation and pain caused by oster-
oarthritis and rheumatoid arthritis.[14] (R)-Flurbiprofen has
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Benzyl Carbanions from Styrenes
FULL PAPER
mixture was then diluted with THF to yield an overall solvent composi-
tion of 3:2 toluene/THF. A solution of KOtBu (2.2 equiv) in THF
(0.22m) was added and the reaction mixture was stirred for 15 min. The
flask was cooled to À788C, evacuated, and backfilled with CO2 three
times (CO2 was supplied through a Schlenk line). The mixture was
warmed to room temperature, stirred for 1 h, quenched with HClACHTUNGTRENNUNG(1m),
and then extracted with several portions of dichloromethane. The com-
bined organic layers were dried over Na2SO4 and the volatile compounds
were removed under reduced pressure. The crude residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate gradient).
Preparation of dithiocarboxylic acids from benzyl boronic esters: KOtBu
(2.20 mmol, 2.2 equiv) and THF (8 mL) were placed in a Schlenk flask
(100 mL) under an inert atmosphere. The flask was cooled to the appro-
priate temperature (RT, À45 or À788C) before a solution of the boronic
ester (1.0 mmol, 1.0 equiv) in THF (2 mL) was added by cannula or sy-
ringe. The solution was allowed to stir for 10 min. The flask was then
cooled to À788C and the reaction mixture was treated with CS2
(5.00 mmol, 5 equiv). The flask was allowed to warm to room tempera-
ture and stirred for 1 h. The reaction was quenched with a solution of
NH4OH (5%) and then extracted with one portion of diethyl ether. The
aqueous phase was acidified with concentrated HCl and extracted with
dichloromethane. The combined organic layers were washed with brine,
dried over Na2SO4, and the volatile compounds were removed under re-
duced pressure. The crude residue was purified by column chromatogra-
phy on silica gel (hexanes/ethyl acetate gradient).
Scheme 2. A potential polar mechanism for sterically induced bond cleav-
age.
exhibits greater functional-group tolerance. The mild nature
of the method allows a one-pot transformation of styrene
derivatives to a number of valuable motifs, including phenyl-
acetic acids and amides. A three-step, two-pot synthesis of
flurbiprofen from commerically available starting materials
was accomplished in 76% overall yield, demonstrating the
utility of this method. The chemoselective nature of the ster-
ically induced bond cleavage could also prove to be a power-
ful method for sequential transformations of molecules con-
Reaction of isothiocyanates or isocyanates with benzyl boronic esters:
KOtBu (2.20 mmol, 2.2 equiv) and THF (8 mL) were placed in a Schlenk
flask (100 mL) under an inert atmosphere. The flask was cooled to the
appropriate temperature (RT, À45 or À788C) and a solution of the bor-
onic ester (1.0 mmol, 1.0 equiv) in THF (2 mL) was added by cannula or
syringe. The solution was allowed to stir for 10 min, then kept at the tem-
perature necessary to generate the reactive anionic intermediate. The iso-
thiocyanate or isocyanate (1.10 mmol, 1.10 equiv) was then rapidly inject-
ed into the reaction mixture either neat or as a THF solution. The mix-
ture was stirred for 1 min prior to the addition of saturated NH4Cl
(10 mL). The aqueous mixture was extracted with several portions of di-
chloromethane, and the combined organic layers were washed with brine,
dried over Na2SO4, and the volatile compounds were removed under re-
duced pressure. The crude residue was then purified by column chroma-
tography on silica gel, or was recrystallized from hexanes/ethyl acetate.
À
taining multiple C B bonds obtained through previously de-
scribed diborylations of olefins and allenes.[18] Future work
is focused on employing this method in diasteroselective
tandem one-pot diborylation/functionalization reactions of
olefins, dienes, and allenes.
Experimental Section
Reaction of alkyl halides with benzyl boronic esters: The boronic ester
(0.4 mmol, 1.0 equiv) was dissolved in dry THF (4 mL) and treated with
KOtBu (0.880 mmol, 2.2 equiv). The solution was stirred at room temper-
ature for 10 min prior to injection of the alkyl halide (2.0 mmol, 5 equiv).
The solution was stirred for 1 min before an aliquot of saturated aqueous
NH4Cl was added to quench the reaction. The reaction mixture was ex-
tracted with portions of dichloromethane, the combined organic layers
were washed with brine, dried over MgSO4, and filtered. The volatile
compounds were removed under reduced pressure and the residue was
purified by column chromatography (hexanes/ethyl acetate gradient).
The characterization data of the isolated products were consistent with
those reported previously.
General procedures:
Transition-metal-free carboxylation of benzyl boronic esters: KOtBu
(2.20 mmol, 2.2 equiv) and THF (8 mL) were placed in a Schlenk flask
(100 mL) under an inert atmosphere. The flask was cooled to the desired
temperature (RT, À45 or À788C) before a solution of the boronic ester
(1.0 mmol, 1.0 equiv) in THF (2 mL) was added by cannula or syringe.
The reaction mixture was stirred for 10 min, then cooled to À788C. The
flask was evacuated and backfilled with CO2 three times (CO2 was sup-
plied by using a Schlenk line). The flask was allowed to warm to room
temperature under a CO2 atmosphere (1atm) and was stirred for 3 h.
The reaction was then quenched with HCl (1m) and extracted with sever-
al portions of dichloromethane. The combined organic layers were
washed with brine, dried over Na2SO4, and the volatile compounds were
removed under reduced pressure. The crude residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate gradient). In
some cases, the insolubility of the carboxylic acid in the organic phase ne-
cessitated the addition of several equivalents of methyl iodide prior to
the aqueous quench. The corresponding methyl ester was then isolated
by extraction and purified by column chromatography on silica gel.
Acknowledgements
The authors thank Dr. Charles Fry of the University of Wisconsin–Madi-
son for assistance with NMR spectroscopy. Funding was provided by
start-up funds from the University of Wisconsin–Madison. The NMR fa-
cilities at UW–Madison are funded by the NSF (CHE-9208463, CHE-
9629688) and the NIH (RR08389-01).
One-pot hydrocarboxylation of styrenes by a Cu-catalyzed hydroboration/
carboxylation: In a glovebox, a mixture of CuCl (0.03 equiv), bis(diphe-
nylphosphino)benzene (0.033 equiv), and NaOtBu (0.03 equiv) was sus-
pended in dry toluene (0.33m). The flask was tightly sealed and the mix-
ture was removed from the glovebox and stirred for 10 min at RT.
4,4,5,5-TetramethylACHTUNGTRENNUNG[1,3,2]dioxaborolane (1.1 equiv) was added and the re-
action mixture was stirred for an additional 10 min. The desired styrene
substrate (1 equiv) in toluene was added by syringe. The reaction flask
was placed in a pre-heated oil bath at 658C and stirred overnight. The
[1] M. Smith, J. March, Marchꢀs Advanced Organic Chemistry: Reac-
tions, Mechanisms, and Structure, 6th ed., Wiley, New York, 2007,
p. 1329.
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J. M. Schomaker et al.
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À
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Received: February 27, 2012
Published online: && &&, 2012
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Benzyl Carbanions from Styrenes
FULL PAPER
Benzyl Carbanions
R. D. Grigg, J. W. Rigoli,
R. Van Hoveln, S. Neale,
J. M. Schomaker* ............ &&&& — &&&&
À
Make or break: The facile generation
of benzyl anion equivalents from styr-
enes has been achieved by using a Cu-
catalyzed hydroboration in conjunction
with sterically induced cleavage of the
allene electrophiles yields benzylic C
C bond formation (see scheme), and
the utility of this methodology has
been demonstrated by a synthesis of
the nonsteroidal anti-inflammatory
drug (Æ)-flurbiprofen.
Beyond Benzyl Grignards: Facile
Generation of Benzyl Carbanions from
Styrenes
À
C B bond with tBuOK. Quenching
this reactive intermediate with hetero-
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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