Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of Benzyl Halides and Boronic Acids via 1,2-Metalate Shift

Article abstract of DOI:10.1021/jacs.8b00380

Cross-coupling of organoboron compounds with electrophiles (Suzuki-Miyaura reaction) has greatly advanced C-C bond formation and has been well received in medicinal chemistry. During the past 50 years, transition metals have played a central role throughout the catalytic cycle of this important transformation. In this process, chemoselectivity among multiple carbon-halogen bonds is a common challenge. In particular, selective oxidative addition of transition metals to alkyl halides rather than aryl halides is difficult due to unfavorable transition states and bond strengths. We describe a new approach that uses a single organic sulfide catalyst to activate both C(sp³) halides and arylboronic acids via a zwitterionic boron "ate" intermediate. This "ate" species undergoes a 1,2-metalate shift to afford Suzuki coupling products using benzyl chlorides and arylboronic acids. Various diaryl methane analogues can be prepared, including those with complex and biologically active motifs. The reactions proceed under transition-metal-free conditions, and C(sp²) halides, including aryl bromides and iodides, are unaffected. The orthogonal chemoselectivity is demonstrated in the streamlined synthesis of highly functionalized diaryl methane scaffolds using multi-halogenated substrates. Preliminary mechanistic experiments suggest both the sulfonium salt and the sulfur ylide are involved in the reaction, with the formation of sulfonium salt being the slowest step in the overall catalytic cycle.

Full text of DOI:10.1021/jacs.8b00380

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Article
A Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction
of Benzyl Halides and Boronic Acids via 1,2-Metallate Shift
Zhiqi He, Feifei Song, Huan Sun, and Yong Huang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2018
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A Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of
Benzyl Halides and Boronic Acids via 1,2-Metallate Shift
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Zhiqi He, Feifei Song, Huan Sun and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen, 518055, China
Supporting Information Placeholder
ABSTRACT: Crossꢀcoupling of organoboron compounds with electrophiles (SuzukiꢀMiyaura reaction) have greatly advanced CꢀC bond
formation and well received in medicinal chemistry. During the last 50 years, transition metals play a central role throughout the catalytic
cycle of this important transformation. In this process, chemoselectivity among multiple carbonꢀhalogen bonds is a familiar challenge. In
particular, selective oxidative addition of transition metals to alkyl halides rather than aryl halides is difficult due to unfavorable transition
states and bond strengths. We describe a new approach that uses a single organic sulfide catalyst to activate both C(sp3)ꢀhalides and aryl
boronic acids via a zwitterionic boron “ate” intermediate. This “ate” species undergoes a 1,2ꢀmetallate shift to afford Suzuki coupling
products using benzyl chlorides and aryl boronic acids. Various diaryl methane analogues can be prepared, including those with complex
and biologically active motifs. The reactions proceed under transitionꢀmetalꢀfree conditions and C(sp2)ꢀhalides, including aryl bromides
and iodides, are unaffected. The orthogonal chemoselectivity is demonstrated in the streamlined synthesis of highly functionalized diaryl
methane scaffolds using multiꢀhalogenated substrates. Preliminary mechanistic experiments suggest both the sulfonium salt and the sulfur
ylide are involved in the reaction, with the formation of sulfonium salt being the slowest step in the overall catalytic cycle.
would be an ideal entry point towards an transitionꢀmetalꢀfree
crossꢀcoupling strategy that does not require an OA step. So far,
no such strategy for crossꢀcoupling reactions has been reported.8
The approach described here is redoxꢀneutral throughout the cataꢀ
lytic cycle. It replaces toxic and expensive late transition metals
with more environmentally sustainable small molecule catalysts
that introduce complementary selectivity for carbonꢀcarbon bond
synthesis and potentially reverse the selectivity of C(sp3) over
C(sp2).
INTRODUCTION
Transitionꢀmetalꢀcatalyzed crossꢀcoupling of carbonꢀhalides
and carbonꢀboronic acids/esters is a dominant strategy for carbonꢀ
carbon bond synthesis in modern chemistry.1 Over 60% carbonꢀ
carbon bond forming processes in medicinal chemistry are now
accomplished using the SuzukiꢀMiyaura crossꢀcoupling reaction.2
Palladium and nickel are the most effective metals in this remarkꢀ
able transformation, which has three sequential catalytic segments:
oxidative addition (OA), transmetallation (TM) and reductive
elimination (RE).3 The procedure, however, has several limitaꢀ
tions. In order to maintain appreciable concentrations of lowꢀ
valent transition metals throughout the course of these reactions,
an oxidative environment, such as ambient atmosphere, is often
avoided. 3c, 4 More significantly, OA into C(sp2)ꢀX bonds is more
facile than with their C(sp3) counterparts5 and as a result, crossꢀ
coupling reactions involving alkyl halides have limited tolerance
of C(sp2)ꢀX bonds, especially aryl iodides and bromides. This
inadequacy presents a difficult problem for syntheses using subꢀ
strates containing several halogen atoms and extra steps are often
needed to replace halogens with more distinguishable groups.
Mechanistically, OA into C(sp2)ꢀhalide bonds is concerted and
generally facile, while metallation of C(sp3)ꢀhalides is disfavored
both for electronic reasons such as low reduction potential of
alkyl halides6 and stereochemical reasons, specifically steric hinꢀ
drance and lack of orbital stabilization from neighboring sp3ꢀ
carbons (Fig. 1a). 7 A general solution to these limitations associꢀ
ated with OA requires a distinct mechanistic approach that does
not involve an OA step.
In addition to OA, transition metals are also essential for the
remaining catalytic cycle of crossꢀcoupling reactions.3a Subseꢀ
quent to OA, a new carbonꢀcarbon bond is constructed following
a sequence of TM followed by RE. Organic boron compounds are
the most general partners with a carbonꢀmetal bond for TM, due
to wellꢀbalanced reactivity and wide tolerance to functional
groups.3b Interestingly, organoboron compounds are known to
form carbonꢀcarbon bonds via a nonꢀtransmetallation pathway.9
Boronic acids and esters are mild Lewis acids that are able to
accept a lone pair of electrons from carbon anions to form anionic
boronꢀcentered “ate” complexes (Fig. 1b). When the carbon anion
also contains a leaving group X, the resulting “ate” complex unꢀ
dergoes a stereospecific 1,2ꢀmetallate shift forming a new CꢀC
bond.10 This 1,2ꢀcarbon shift was first discovered in 1956 by
Brown et al. in the hydroborationꢀ oxidation reaction11 and was
subsequently reported in 1968 by Hooz and Linke for CꢀC bond
synthesis.12 We hypothesized that this unique reactivity of boron
could be harnessed to replace the TM and RE steps in transitionꢀ
metalꢀcatalyzed crossꢀcoupling reactions.
Unlike transition metals, organic nucleophiles are inherently seꢀ
lective towards alkyl halides in SN2 substitution reactions. Analoꢀ
gous reactions with aryl halides (SNAr) are far more difficult. This
textbook chemistry is an excellent example of complementary
activation of C(sp3)ꢀhalide bonds using organic molecules, and
The key issue is to identify a catalyst capable of linking the halꢀ
ide activation step, an SN2 substitution, with a carbonꢀcarbon
bond formation step, a 1,2ꢀmetallate shift. The essential boron
“ate” complex is the link between these two steps. Boron “ate”
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complexes are normally generated by nucleophilic addition of a
carbon anion to a organoboron and this particular carbon also
should be electrophilic so as to trigger subsequent 1,2ꢀmigration.
details), K4P2O7 exhibits the best overall balance of activity and
basicity. A major sideꢀproduct of this reaction was decomposition
of 1a as a result of hydrolysis by the boronic acid (2a) and the
base. Significant quantities of the corresponding benzyl alcohol
and dibenzyl ether were observed. In addition, the αꢀcarbons of
cat. 1 are susceptible to deprotonation upon sulfonium formation.
This can be followed by [2.3]ꢀsigmatropic rearrangement to cause
decomposition and deactivation of the catalyst.15a A similar beꢀ
havior was observed for the six membered cyclic sulfide (cat. 2).
The acyclic dialkyl sulfide (cat. 3) showed poor catalytic activity
and triphenylphosphine sulfide (cat. 4), thiourea (cat. 5 and 6)
and carbamimidothioate (cat. 7) led to poor conversions due to
the instability of those sulfides under the reaction conditions. (For
detailed discussions, see Supplementary Information). Next, in
order to avoid αꢀdeprotonation, diaryl sulfides were examined.
Although diphenyl sulfide (cat. 8) yielded merely 10% of the
crossꢀcoupling product (3aa), side reactions such as the decompoꢀ
sition of benzyl bromide and the sulfide catalyst were suppressed.
Increased catalytic activity was observed for cyclic diaryl sulfides.
Use of dibenzothiophene (cat. 9) yielded 21% of 3aa with 40% of
the halide remaining. We hypothesized that the low yield was a
result of attenuated nucleophilicity of cat. 9 due to aromaticity
that tends to delocalize electron lone pairs on the sulfur atom.
Generally a more nucleophilic sulfide would favor the sulfonium
salt formation. Molecules such as thianthrene (cat. 10) are not
fully aromatic and a transannular heteroatom further increases the
nucleophilicity of such compounds. Indeed, an improved yield
was obtained for cat. 10ꢀcat. 13. Nꢀbenzylation was observed for
catalysts containing a NH group, and more nucleophilic selenium
analogues failed to catalyze the crossꢀcoupling reaction. Cat. 14
decomposed rapidly under the conditions of the reaction.
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Besides halideꢀsubstituted anions, typical donor/acceptor species
13
are carbenes12,
and ylides.14 Organic sulfides are both good
nucleophiles and effective leaving groups. They react with alkyl
halides in the presence of a base to give sulfur ylides,15 and reacꢀ
tion of a sulfur ylide with boron will generate a zwitterionic boron
“ate” complex. Pioneering work by Aggarwal and coꢀworkers
demonstrated that the 1,2ꢀmetallate shift occurs readily in elecꢀ
tronꢀrich borane “ate” complexes with sulfide as the leaving
9
16
group.14,
However, carbon migration from less electronꢀrich
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“ate” complexes, those derived from boronic acids or esters for
example, has not been reported.17 Our primary mission therefore
is to identify a sulfide that is sufficiently nucleophilic to generate
boron “ate” complexes from boronic acids, and also competent to
trigger subsequent 1,2ꢀshifts. The migratory product, alkyl boꢀ
ronic acids, would undergo in situ protodeboronation to give the
final crossꢀcoupled product. We believe fine tuning the electronics
of the sulfide might yield a competent catalyst for this purpose.
We next focused on fine tuning the structure of cat. 12 in an atꢀ
tempt to further improve the nucleophilicity while avoiding Nꢀ
benzylation of the catalyst. When a less nucleophilic NꢀBoc cataꢀ
lyst (cat. 15) was used, noticeably lower catalytic activity was
observed. Introduction of electronꢀdonating amino groups into the
phenyl rings (cat. 16) failed to enhance the yield as ammonium
salt formation was very rapid under the reaction conditions. The
Nꢀmethylated catalyst (cat. 17) afforded 52% yield of 3aa, but in
this case, ammonium salt formation was still observed. The use of
a less basic phenylꢀsubstituted nitrogen (cat. 18) improved the
yield to 62%. The best conversion was with cat. 20, which affordꢀ
ed 68% of the desired product. Under these optimized reaction
conditions, hydrolysis of bromide (1a) could not be completely
suppressed, but use of the corresponding chloride (4a) solved this
problem and in this case, the crossꢀcoupling occurred smoothly in
80% isolated yield. In the absence of cat. 20, no crossꢀcoupling
occurred, ruling out a possible direct SN2 displacement mechaꢀ
nism.18 Cat. 20 belongs to a wellꢀknown family of photosensitizꢀ
ers,19 and consequently, the reaction was tested in dark, but the
crossꢀcoupling was not affected.
With the optimized reaction conditions in hand, we surveyed
the substrate scope of benzyl chlorides and aryl boronic acids
(table 1). This transitionꢀmetalꢀfree protocol tolerates various
aromatic substituents in the benzyl chlorides and both electronꢀ
rich and electronꢀpoor functional groups were tested, leading to
moderate to good yields. Benzyl chlorides with electronꢀpoor
substituents react more slowly, despite being better electrophiles
for SN2 reactions. This observation is consistent with Aggarwal
and Harvey’s finding, that SN2 substitution of these compounds
with electronꢀneutral sulfides is slow.20 Potassium bromide
proved to be an effective coꢀcatalyst that accelerates the formation
of the sulfonium salt via in situ halogen exchange. Highly elecꢀ
tronꢀdeficient benzyl chlorides, including pentafluorobenzyl chloꢀ
ride, react smoothly with phenyl boronic acid using 20 mol% KBr.
Orthoꢀ, metaꢀ, and paraꢀmethylbenzyl chlorides reacted with
Figure 1. Transition-metal-catalyzed vs Sufide-Catalyzed
Suzuki cross-coupling. M = transition metal; X = halogen.
RESULTS AND DISCUSSION
We began our investigation with benzyl bromide (1a) and 4ꢀ
methoxyl boronic acid (2a) as coupling partners (Fig. 2). The
desired diaryl methane crossꢀcoupling product (3aa) was obtained
in 22% GC yield, when tetrahydrothiophene (cat. 1) and K4P2O7
were tested as the catalyst and the base, respectively. Among most
inorganic bases examined (see Supplementary Information for
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similar efficiency, but the reaction was noticeably slower for 2,5ꢀ
steric effects.
dimethylbenzyl chloride (table 1, product 3ga), possibly due to
1
cat. ( 20 mol % )
2 equiv K4P2O7
2
3
4
5
Br
+
(HO)2B
OMe
OMe
MeCN, 110°C, 24h
1a
2a (1.5eq)
3aa
S
N
S
6
7
S
P
N
Ph
Ph
S
S
Ph
8
cat. 1
cat. 2
cat. 3
cat. 4
cat. 5
9
3aa: 22%; 1a: 7%
3aa: 24%; 1a: 5%
3aa:13 %; 1a: 2%
3aa: 5%; 1a: 12%
3aa: 7%; 1a: <1%
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S
N
S
S
N
Ph
N
Ph
N
.
S
S
S
HCl
O
cat. 6
3aa: 5%; 1a: 3%
cat. 7
3aa: 6%; 1a: 14%
cat. 8
3aa: 10%; 1a: 50%
cat. 9
3aa: 21%; 1a: 40%
cat. 10
3aa: 28%; 1a: 23%
Boc
N
H
N
H
N
O
S
OMe
Se
Se
S
S
S
cat. 11
3aa: 47%; 1a: 16%
cat. 12
3aa: 41%; 1a: 2%
cat. 13
3aa: 40%; 1a: 0%
cat. 14
3aa: <1%; 1a:<1%
cat. 15
3aa: 19%; 1a: 23%
Bz
N
Me
N
Ph
N
Ph
N
Ar
N
OMe
OMe
N
S
N
S
S
S
S
cat. 16
3aa: 19%; 1a: <1%
cat. 17
3aa: 52%; 1a: 4%
cat. 18
3aa: 62%; 1a: 5%
cat. 19
3aa: 67%; 1a: 2%
cat. 20, Ar = p-anisole
3aa: 68%; 1a: 2%
cat. ( 20 mol % )
2 equiv K4P2O7
Cl
Cl
+
(HO)2B
2a (1.5eq)
OMe
OMe
OMe
MeCN, 110°C, 48h
4a
4a
3aa: 86% (80%)a
without cat. 20
2 equiv K4P2O7
+
(HO)2B
2a (1.5eq)
OMe
MeCN, 110°C, 48 h
3aa: < 1%
Figure 2. Discovery of a Sulfide Catalyst Enabling Transition-Metal-Free sp3-sp2 cross-coupling. Reactions were conducted using
0.5 mmol benzyl halide 1a, 0.75 mmol 4ꢀmethoxyphenylboronic acid 2a, 20 mol% catalyst, 1 mmol K4P2O7 in 1 mL acetonitrile under Ar
at 110 °C for 24 h. Yield was determined by GC using biphenyl as internal standard. a 0.5 mL acetonitrile was used. The number in parenꢀ
theses
reflects
the
isolated
yield.
Compatibility with halogens was surveyed next. Aryl fluorides,
chlorides, bromides and iodides were all unaffected, regardless of
their positions on the aromatic ring (Table 1, products 3ha-3na).
These results clearly demonstrate the complementary reactivity
compared to transitionꢀmetalꢀcatalyzed reactions.
talysis. Aliphatic boronic acids, for example hexylboronic acid
and cyclohexylboronic acid, are poor coupling partners under
current conditions. Trace amounts of products were found by GC.
We suspect the aromatic πꢀelectrons of arylboronic acids particiꢀ
pate and facilitate the 1,2ꢀmetallate shift process via a phenonium
type intermediate. Although sp3 CꢀB bonds are more nucleophilic
than sp2 CꢀB bonds, the lack of πꢀelectrons might require signifiꢀ
cantly higher activation energy for 1,2ꢀalkyl shift. In addition,
alkylboronic acids are more prone to protodeboronation under the
reaction conditions. Heteroaryl substrates containing basic nitroꢀ
gens are not tolerated due to Nꢀbenzylation. Dihydrobenzofuran
(3ar), indoline (3as), and quinolinone (3at) containing boronics
gave the desired products in moderate to good yields. Structurally
complex and biologically active motifs are well tolerated in this
transitionꢀmetalꢀfree sp2ꢀsp3 CꢀC bond coupling reactions. For
example, substrates containg bazedoxifene (3wu), celecoxib (3yv)
and androsterone (3rw) as sidechains reacted with synthetically
useful efficiency to yield novel drug analogues (Table 1, products
3wu, 3yv and 3rw). Interestingly, ketones did not interfere with
the sulfur ylide intermediate. The antilipidemic drug beclobrate
was prepared using 4ꢀchlorobenzyl chloride and the correspondꢀ
We next studied the scope of arylboronic acids. The reaction
shows preference to electronꢀrich arylboronic acids. Paraꢀ
methoxy, paraꢀdiphenylamino, and 9ꢀphenanthracenyl substrates
afford the corresponding coupling products in 80%, 81% and 84%
yield, respectively. Analogs with electronꢀdonating methyl, pheꢀ
nyl and sulfide groups give moderate yields. For highly electronꢀ
rich arylboronic acids, K2CO3 sometimes works better as the base.
Arylboronic acids with strong electronꢀwithdrawing groups give
low conversions, despite being stronger Lewis acids that would
react faster with the sulfur ylide intermediate. Protodeboronation
of the arylboronic acids and hydrolysis of the benzyl halides were
predominant. During the cationotropic 1,2ꢀmetallate shift, these
electronꢀdeficient aryl groups are not nucleophilic enough to atꢀ
tack the sulfide leaving group on the adjacent, sp3ꢀhybridized
carbon center. On the other hand, mildly electronꢀwithdrawing
halogen substituents are tolerated, providing additional handles
for crossꢀcoupling cascades with the help of transition metal caꢀ
ing
arylboronic
acid.
Table 1. Substrate Scope of the Transition-Metal-Free C(sp3)-C(sp2) Cross-Coupling Reaction.
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Unless otherwise specified, reactions were performed using 0.5 mmol substituted benzyl chlorides, 0.75 mol arylboronic acid, 1 mmol
a
K4P2O7 and 0.1 mmol cat. 20 in 0.5 mL acetonitrole at 110 ºC for 48 h. Isolated yield. The number in parentheses reflects the GC yield.
0.1 mmol KBr was used as coꢀcatalyst. b 1 mmol arylboronic acid was used. c 1 mmol K2CO3 was used as base instead of K4P2O7. d Run
at 130 ºC. e 0.25 mmol benzyl chloride, 0.375 mmol boronic acid and 40% cat. 20 was used in 0.3M MeCN. f 30% cat. 20 was used. g 0.25
mmol boronic acid and 0.375 mmol benzyl chloride was used in 0.4 mL acetonitrile/1,4ꢀdioxane (v/v=1/1)
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Figure 3. Modular synthesis of diaryl methane scaffolds using sequential cross-coupling reactions.
Figure 4. Mechanistic experiments
Unsymmetrical diarylmethanes are prevalent structural motifs
in natural products and pharmaceutical agents.21 Consequently,
the sulfide catalyzed crossꢀcoupling reactions were applied in the
synthesis of several structurally sophisticated diarylmethane scafꢀ
folds The exclusive selectivity of alkyl chloride over aryl bromide
and aryl iodide led us to test modular crossꢀcoupling reactions
using cascades of organo and transitional metal catalysis (Figure
3). Substrates containing multiple halogens were employed. The
sulfideꢀcatalyzed C(sp3)ꢀC(sp2) crossꢀcoupling was carried out
first. The remaining C(sp2)ꢀhalide bonds are further functionalized
using transition metal catalysis. The reaction between halide (4j)
and 3ꢀchloroꢀ4ꢀmethoxyꢀphenylboronic acid affords, in 61% yield,
compound 5, which contains one aryl bromide and one aryl chloꢀ
ride. Selective functionalization of the aryl bromide was accomꢀ
plished using palladiumꢀcatalyzed BuchwaldꢀHartwig aminaꢀ
tion/ether formation or Suzuki coupling.22 The less reactive aryl
chloride was converted to aryl and heteroaryl groups by Suzuki
coupling. The highly functionalized diarylmethane analogs (7, 8,
9) were prepared in a threeꢀstep sequence, a modular approach
which allows rapid generation of diversified libraries of diarylmeꢀ
thanes using multiꢀhalogenated substrates.
arene that could be generated by protodeboronation. This possible
reaction pathway was tested using benzyl chloride and anisole. It
was found that only less than 1% of the crossꢀcoupling product
was detected, regardless as to whether or not a base or a sulfide
was used (Figure 4a). These negative results suggest that neither
benzyl chloride nor its sulfonium salt is electrophilic enough to
react with anisole directly. Arylboronic esters were commonly
used to generate boron “ate” complexes by reacting with lithium
or Grignard reagents. These substrates fail to react under our
standard crossꢀcoupling conditions (Figure 4b). The increased
steric effect and decreased Lewis acidity might prevent addition
of a soft nucleophilic such as a sulfur ylide.
In order to further understand the mechanistic details of this
sulfur ylide mediated transformation, a number of experiments
were carried out. The sulfonium salts of cat. 20 is unstable. The
corresponding benzyl sulfonium salt of cat. 11 (compound 12)
was prepared by heating the sulfide and excess benzyl bromide in
the presence of TMSOTf. Interestingly, treating compound 12
with pꢀmethoxyphenylboronic acid (2a) and K4P2O7 led to the
desired crossꢀcoupling product 3aa in 51% yield at room temperaꢀ
ture. In sharp contrast, the reaction between 2a and benzyl broꢀ
mide only afforded 1% of product 3aa using cat. 20 at room temꢀ
perature. These results suggest the sulfonium is likely involved in
An alternative mechanism for this benzyl chlorideꢀaryl boronic
acid coupling reaction would be FriedelꢀCrafts benzylation by an
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the catalytic cycle and its formation is the slowest step that reꢀ
quires heating. The sulfur ylide formation, boron “ate” complex
formation, 1,2ꢀmetallate shift and protodeboronation are all facile
steps that occur smoothly at room temperature. HRMS of the
reaction mixture also suggests the concentration of the sulfonium
is very low (see SI).
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is financially supported by the National Natural Sciꢀ
ence Foundation of China (21702008 for Z. H. and 21572004 for
Y. H.), Guangdong Province Special Branch Program
(2014TX01R111), and Shenzhen Basic Research Program
(JCYJ20160226105602871).
The sulfur ylide of compound 12 can be obtained by using
LiHMDS ꢀ20 ºC in toluene, which appears as a bright yellow
solution. Isolation of the pure ylide was unsuccessful and selfꢀ
dimerization to stilbene was the major decomposition pathway.
Direct transfer of the crude ylide solution into a suspension of 2a
in toluene led to immediate color quenching. The crossꢀcoupling
product 3aa slowly formed in 55% yield after 24 hours at room
temperature. (Figure 4d, entry 1, 2). Stilbene was formed in 14%
yield based on compound 12. When boroxine was used, 3aa was
obtained in 27% yield. We propose that the reduced yield was due
to the increased stereo effect of boroxine. These results suggest
the sulfide ylide is likely the key intermediate, and the rapid color
fading indicates the formation of the “ate” complex is very fast at
room temperature. During our substrate scope survey (Table 1),
no stilbene formation was observed, indicating the sulfur ylide
was formed in low concentration. This observation is consistent
with our proposal that the sulfonium salt formation is the rateꢀ
limiting step for this reaction. The final protodeboronation has
been reported to be facile for diarylmethyl boronic acids.13
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Employing electron deficient boroxines resulted in low converꢀ
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CONCLUSION
In summary, after nearly half a century of domination of transiꢀ
tion metals in the Suzuki reaction, an alternative transitionꢀmetalꢀ
free strategy is developed for C(sp3)ꢀC(sp2) crossꢀcoupling reacꢀ
tions between benzyl chlorides and arylboronic acids. The excluꢀ
sive chemoselectivity of alkyl over aryl halides is complementary
to transitionꢀmetalꢀcatalyzed processes. The reaction proceeds
through a novel catalytic cycle: sulfonium salt, sulfur ylide, boron
“ate” complex, 1,2ꢀmetallate shift and protodeboronation. This
approach eliminates possible C(sp2)ꢀC(sp2) coupling reactions for
substrates with multiple aryl halide substituents and enables a
modular synthesis of unsymmetrical diarylmethanes using a seꢀ
quential crossꢀcoupling technique. We anticipate this new strategy
will significantly widen the paradigm for crossꢀcoupling reactions.
Supporting Information
Experimental procedures, analytical and spectroscopic data for
new compounds, copies of NMR spectra. This material is availaꢀ
ble free of charge via the Internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author
huangyong@pkusz.edu.cn
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