Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds

Article abstract of DOI:10.1021/jacs.6b03963

The stereospecific cross-coupling of secondary boronic esters with sp² electrophiles (Suzuki-Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel-Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C-C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp²)-C(sp³) and an adjacent C-B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Full text of DOI:10.1021/jacs.6b03963

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Article
Development of Enantiospecific Coupling of Secondary
and Tertiary Boronic Esters with Aromatic Compounds.
Marcin Odachowski, Amadeu Bonet, Stéphanie Essafi, Philip Conti-
Ramsden, Jeremy N. Harvey, Daniele Leonori, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03963 • Publication Date (Web): 06 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
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Development of Enantiospecific Coupling of Secondary and
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Marcin Odachowski,a Amadeu Bonet,a$ Stephanie Essafi,a Philip Conti-Ramsden,a Jeremy N.
Harvey,a†* Daniele Leonori, a,b,‡* and Varinder K. Aggarwala*
a
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom. b School of Chemis-
try, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.
KEYWORDS stereospecific, organoboron, boronic ester, synthetic methods, transition metal–free coupling, quater-
nary centres, computational chemistry, DFT
ABSTRACT: The stereospecific cross-coupling of secondary boronic esters with sp2 electrophiles (Suzuki-Miyaura reac-
tion) is a long-standing problem in synthesis but progress has been achieved in specific cases using palladium catalysis.
However, related couplings with tertiary boronic esters are not currently achievable. In order to address this general prob-
lem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl
lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an
electron from the aromatic ring or react in a Friedel-Crafts-type manner, respectively, generating a cationic species, which
would trigger 1,2-migration of the boron substituent, creating the new C-C bond. Elimination (preceded by further oxida-
tion in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was
examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled
the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different
steric demands and functional groups (esters, azides, nitriles, alcohols, ethers). The reaction also worked well with other
electron rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position.
Conditions were also found in which the B(pin)- moiety could be retained in the product, ortho to the boron substituent.
This protocol, which created a new C(sp2)-C(sp3) and an adjacent C-B bond, was again applicable to a range of secondary
and tertiary boronic esters. In all cases the coupling reaction occurred with complete stereospecificity. Computational
studies verified the competing processes involved and were in close agreement with the experimental observations.
1. Introduction
The cross coupling of organoboron derivatives with C-sp2
electrophiles, the Suzuki-Miyaura reaction, is one of the
most broadly used reactions with applications that span
materials, pharmaceuticals and agrochemicals.1,2 Its mild
reaction conditions, functional group tolerance, broad
SCHEME 1. The Suzuki-Miyaura Cross-Coupling of
Aliphatic Organoborons
scope and scalability are features which have contributed
Ar
[Pdº(L)]
Ar–X
R1
to its extensive use in both academic and industrial set-
tings.2 There is currently a strong impetus to extend this
reaction to sp3–sp2 cross-coupling as it offers new strate-
gic disconnections for the rapid assembly of chiral (3D)
molecules.3,4 However, such a coupling reaction has
proved challenging.5,6 This is because the desirable fea-
tures of the high configurational stability of the C–B bond
which enables boronic esters to be isolated and purified
also renders them relatively unreactive and further activa-
tion is required in order to engage them in the key
transmetalation step of the catalytic cycle.7,8 Furthermore,
competing β-hydride elimination can also occur from the
aliphatic organo-Pd(II) species which can have an impact
on both yield and stereoselectivity.
R
reductive
elimination
oxidative
addition
Ar
PdII
Ar–PdII–X
R1
R1
R
βꢀhydride
elimination
R
+
Ar–H
transmetalation
R2 R2
B
R2 R2
B
X
R1
R
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Despite these inherent difficulties, examples of Pd-
SCHEME 3. Molander’s Stereoselective Cross-
Coupling of Aliphatic Organoborons
catalyzed sp2–sp3 cross-coupling of chiral organoborons
have been reported.5,6,9-20 Pioneering work by Crudden
showed that benzylic pinacol boronic esters and diben-
zylic neopentyl boronic esters could be coupled with high
stereospecificity with retention of configuration with aryl
iodides.21-23 Liao found that the stereospecific coupling of
dibenzylic organoborons could be rendered invertive us-
ing the potassium trifluoroborate salt in place of the neo-
pentyl boronic ester (which occurred with retention).24
Molander and Hall employed internal activating groups
to promote the coupling of chiral potassium trifluorobo-
rates with inversion of configuration.25-28 Suginome devel-
oped a unique stereospecific cross-coupling of benzylic α-
amino boronic esters that, depending on the addition of a
Bronsted or a Lewis acid, occurred with inversion or re-
tention of configuration.29-32 More recently, Biscoe report-
ed the first stereoinvertive cross-coupling of unactivated
secondary potassium trifluoroborates.33
1
2
3
4
5
6
7
8
O
O
Ph
Ph
N
N
BF3K
Me
Ar
+
Ar–Br
[Irꢀphotocatalyst]
[Niºꢀcatalyst]
visible light
Ph
Ph
Me
52%
75% ee
racemic
None of the transition metal-based processes have been
applied to tertiary boronic esters and their application to
secondary boronic esters are rather substrate specific,
limiting the applicability of the methodology. This is be-
cause the transition metal-catalyzed processes are espe-
cially sensitive to steric effects. Indeed, the assembly of
all-carbon quaternary stereogenic centres by Suzuki-
Miyaura cross-coupling has not been reported.5,6
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We have recently developed an alternative non-transition
metal-mediated strategy for the stereospecific cross-
coupling of secondary and tertiary boronic esters with
complete retention of configuration (Scheme 4).36 Our
protocol relies on the formation of a chiral boronate
complex that upon addition of N-bromo-succinimide
(NBS) undergoes a reaction cascade comprising SEAr, 1,2-
metallate rearrangement and elimination. This chemistry
was inspired by reactions developed more than 40 years
ago on simple and symmetrical boranes.37-43 In this paper
we provide a full account of this work, describing its gen-
esis, mechanistic and DFT studies as well as illustrating
the full scope of the coupling reaction.
SCHEME 2. The Suzuki-Miyaura Stereospecific Cross-
Coupling of Aliphatic Secondary Organoborons
Crudden
Stereoretentive coupling of chiral benzylic and di-benzylic boronic esters
Ar2
B(pin)
[Pdº]
[Pdº]
Ar2–I
Ar3–I
+
Ar1
Ar1
Me
Ar1
Ar1
Me
Ar3
Ar2
B(neo)
+
Ar2
Liao
Stereoinvertive coupling of chiral di-benzylic boronic esters
BF3K
Ar2
[Pdº]
Ar3
Ar2
Ar3–I
+
SCHEME 4. Planned Coupling Protocol
Ar1
Ar1
[Br+]
Molander and Hall
Stereoinvertive coupling of chiral
Li
R2 B(pin)
R1
NBS
Ar
R1
β-C=O trifluoroborates
Ar
R2
+
B(pin)
Ar
O
BF3K
R
O
Ar
[Pdº]
R
+
Ar–I
R2
R
R
X
X
R
R1
chiral boronic ester electron rich
arylated product
• tertiary centres
• quaternary centres
• secondary
• teriary
aryllithium
via stereospecific
SEAr–1,2-metallate
rearrangement
Suginome
Stereoretentive and invertive coupling of chiral benzylic
α-amino boronic esters
B(pin)
NHAc
B(pin)
NHAc
Ar2
[Pdº]
Ar2–Br
Ar2–Br
+
+
Ar1
Ar1
Zr(OiPr)4•iPrOH
Ar1
Ar1
NHAc
Ar2
2. Design Plan
[Pdº]
NHAc
PhOH
At the outset, we reasoned that a possible way to achieve
a transition metal-free stereospecific cross-coupling of
boronic esters would be to exploit the inherent nucleo-
philicity of an aryl-boronate complex I (Scheme 5A - left).
These species are very easy to prepare by the addition of
aryllithiums (e.g. 2-lithiofuran) to boronic esters and are
both chemically and configurationally stable. In order to
trigger a stereospecific 1,2-metallate rearrangement, a
positive charge needs to be generated at the aromatic B-
bearing carbon. Inspired by the work of Suzuki, Negishi
and Levy on the coupling of symmetrical boranes,37-45 we
reasoned that addition of a suitable electrophile would
generate the cation II by SEAr. This was expected to trig-
ger a 1,2-migration and following elimination would give
the aryl-coupled product III stereospecifically. However,
whilst feasible, this approach was not without concern
since our previous studies on the reactivity of related aryl
Biscoe
Stereoinvertive coupling of chiral trifluoroborates
BF3K
Ar
[Pdº]
Ar–Cl
+
Me
Et
Me
Et
Single electron processes have also been used for the con-
struction of sp2-sp3 bonds and Molander successfully ex-
plored the application of dual photoredox and Niº cataly-
sis for the coupling of secondary benzylic trifluoroborates
and aryl bromides.34,35 Despite the moderate enantioselec-
tivity achieved in the single example reported (52% yield,
75:25 e.r.), this exciting approach opens new avenues for
exploration.
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Journal of the American Chemical Society
etane boronic ester 1q and 1r were obtained by Cu(I)-
boronates towards electrophilic reagents (e.g. NBS, I2,46
iminium ions,47 Selectfluor48) showed that they efficiently
serve as chiral nucleophiles and undergo electrophilic
substitution with inversion of stereochemistry (SE2inv) at
the sp3 carbon (Scheme 5B).49 We therefore considered an
alternative mode of activation. In particular, we envisaged
that treatment of I with an appropriate oxidant would
deliver the radical cation IV by SET oxidation (Scheme 5A
- right).50,51 This was expected to trigger a 1,2-migration,
and, following a 2nd oxidation (from the radical interme-
diate V) and elimination, would deliver the arylated
product III again with retention of stereochemistry.
catalyzed borylation as reported by Ito58 and Marder.59
(3B) Nitrile 1s was synthesized according to Yun’s β-
boration protocol.60 (4) 2-B(pin)-N-Boc-pyrrolidine 1t
was prepared by asymmetric lithiation of N-Boc-
pyrrolidine and quenching with i-PrOB(pin) as described
by Whiting.61 (5) 1,2-Bis-boronic ester 1u was prepared by
asymmetric Morken-Nishiyama diboration.62,63
1
2
3
4
5
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60
SCHEME 6. Synthesis of Secondary and Tertiary Bo-
ronic Esters.
1. Lithiation-borylation
SCHEME 5. Proposed Pathways for Coupling (A) and
Potential Competing Reactions (B)
O
OCb
asymmetric lithiation
(pin)B R3
iꢀPr2N
O
via
(pin)B
R3
R1
R2
then R3–B(pin)
R1 R2
R1 R2
1a-d, 1f-g, 1p-t
A) Proposed pathways for stereospecific coupling of boronic esters
boronate complex
B(pin)
+
Secondary:
Li
R
R1
1a [er 98:2] :1 R1 = PhCH2CH2
1b [er 96:4] :1 R1 = Me
R2 = H
R3 = Me
3 = CH2CH2ꢀpꢀOMeꢀPh
R3 = iꢀPr
O
1e–
2e–
R
2 = H
R
1c [er 97:3] : R1 = PhCH2CH2
1d [er 96:4] : R1 = (CH2)2CHC(CH3)2
R2 = H
2 = H
R
R
3 = CH2CH2ꢀpꢀOMeꢀPh
1e [er 92:8] : R1 = CH2CH2CO2tꢀBu R2 = H
R3 = PhCH2CH2
ox•–
ox
1f [er 96:4] : R1 = (CH2)4N3
R2 = H
R3 = CH2CH2ꢀpꢀOMeꢀPh
E+
E
B(pin)
R1
B(pin) Li
R1
B(pin)
R1
O
O
O
SEAr
oxidation
Tertiary:
R
1g [er 99:1] :1 R1 = PhCH2CH2
1h [er 99:1] :1 R1 = Ph
1i [er 99:1] : R1 = Ph
1j [er 99:1] : R1 = Ph
1k [er 99:1] : R1 = Ph
R2 = Me
R2 = Me
R2 = Me
R2 = Me
R3 = Et
R
R
II
IV
R3 = Et
chiral boronate
R3 = iꢀBu
R3 = pꢀBrꢀPh
complex (I)
1,2-Shift
R2 = CH(CH2)2 R3 = Me
2. Hydroboration
B(pin)
R1
HB(pin), CuCl
O
B(pin)
Stereospecific
Transition
Metal-Free
Coupling
1,2-Shift
(R,R,S,S)-TangPhos, NaOtꢀBu
R
V
A)
B)
Ph
Ph
toluene, rt, 12h
71 %
1l
ox
[er 93:7]
oxidation
Method 1
HB(cat) then pinacol
ox•–
R
R
Nu–
B(pin)
R1
Nu–
Method 2
B(pin)
HBBr2•DMS then pinacol
B(pin)
R1
1m-n, 1o-p
R1
elimination
elimination
E
B(pin)
O
O
O
B(pin)
R
R
R
H
III
H
B) Reaction of aryl boronate complexes with electrophiles
H
H
CF3
1o: R = H [dr >99:1]
1p: R = TBS [dr >99:1]
1n
RO
1m
[dr >99:1]
H
[dr >99:1]
B(pin)
Br
NBS
F3C
Ph
B(pin) Li
B(pin) Li
3,5ꢀ(CF3)2ꢀC6H3Li
B(pin)
3. Cu(I)-catalyzed borylation
Method 1
Ph
(R)-21
SE2inv
O
85%, 100% es
X
B2(pin)2, Cu(I)X, Xantphos, KOtꢀBu
A)
Ph
R
R1
X = Cl, I
B(pin)
B(pin)
MeO
Method 2
(S)-1a
4ꢀ(MeO)ꢀC6H4Li
B2(pin)2, Cu(I)I, PPh3, LiOMe
Br
1r
NBS
1q [dr >99:1]
Ph
B2(pin)2, CuCl, NaOt-Bu
(S,R)ꢀJosiPhos, MeOH
(R)-21
Ph
SE2inv/SET
B(pin)
CN
50%, 90% es
B)
CN
Ph
Ph
THF, rt, 18 h
85%
3. Synthesis of Boronic Esters
1s
[er 98:2]
All of the required boronic esters were prepared using five
general protocols as described in Scheme 6 and the Sup-
porting Information. (1) Secondary and tertiary boronic
esters 1a-k were prepared by lithiation-borylation meth-
odology developed by us.52-55 (2) Benzylic boronate 1l was
prepared by enantioselective hydroboration as reported
by Yun,56 whereas carene -, pinene- and cholesterol-based
substrates (1m-n and 1o-p) were prepared by diastereose-
lective hydroboration as described by Renaud57 and in situ
trans-esterification with pinacol. (3A) Menthyl and ox-
4. Asymmetric lithiation
secꢀBuLi, (–)ꢀsparteine, Et2O, –78 ºC
B(pin)
N
N
Boc
1t
then iꢀPrOB(pin)
Boc
88%
[er 95:5]
5. Enantioselective diboration
B2(pin)2, Pt(dba)3, L*
Ar
Ar
Ar
O
P
O
Bpin
O
O
Ph
Bpin
Ph
Ph
1u
MeCN, 60 °C
79%
[er 97:3]
Ar
Ar = 3,5ꢀ(iꢀPr)2ꢀC6H3
L*
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4. Results and Discussion
4.1 Oxidative couplings
complex 22 obtained by addition of p-MeO-phenyllithium
1
2
3
4
5
6
7
8
to 1a also failed to deliver the desired product. This was
particularly surprising as (i) boronic ester 1a efficiently
underwent intramolecular arylation with 2-lithiofuran
(2a) and (ii) the p-MeO-phenyl group can be readily oxi-
dized by DDQ.64
We began our studies with the addition of 2-lithiofuran to
secondary boronic ester 1a and explored a variety of oxi-
dants covering a wide range of electrochemical potential
(Scheme 7A). Out of all the oxidants tested, DDQ (2,3-
dichloro-5,6-dicyano-1,4-benozquinone) was found to be
uniquely effective, resulting in complete reaction after
just 5 min at –78 ºC (entry 1). Furthermore the process
was completely stereospecific (100% es). At this point a
range of enantioenriched secondary and tertiary boronic
esters were tested under the optimized reaction condi-
tions (Scheme 7B). In general, secondary dialkyl boronic
esters 1a, 1c and 1e reacted well and the corresponding
products 2a, 2c and 2e were obtained in high yields and
complete stereospecificity. This initial screening showed
that the process tolerated increased steric hindrance on
the boronic ester and ester functional groups. The meth-
odology was also applied to hindered cyclic terpene-
derived boronic esters 1m-n giving the desired products
2m-n in high yields and complete diastereospecificity.
However, secondary benzylic, α-amino and tertiary bo-
ronic esters 1l, 1t and 1g failed. Furthermore the boronate
4.1.1 DFT Calculations & Proposed Mechanism of
Oxidative Couplings
9
The surprising difference in behavior of these boronate
complexes prompted us to try to understand the cause of
the unsuccessful couplings (Scheme 8). Analysis of the
different failed reactions revealed that 2-B(pin)-furan [or
p-MeO-C6H4-B(pin)] was the major product and using
boronic ester 1g, we were able to isolate olefin 23 (as a
mixture of regioisomers) (Scheme 8A). The formation of
these products suggested to us that preferential SET oxi-
dation of the sp3-C–B bond over the aromatic unit was
occurring which would generate the 2-B(pin)-furan, the
radical anion of DDQ and a stable tertiary (or secondary
benzylic) radical which could ultimately give the olefins
23. This proposed mechanism implied a surprising
chemoselectivity in the DDQ oxidation step whereby sec-
ondary (non-benzylic) boronate complexes react at the
furyl unit (Scheme 8B, Path A), whereas the sp3 C–B bond
is oxidized in the cases of secondary benzylic and tertiary
substrates (Path B). In order to analyze this further we
performed computational studies. DFT calculations based
on model i-Pr boronate 24 showed the HOMO, and hence
the site for SET, in species such as the boronate complex I
to be mostly localized on the sp3 C–B bond. DFT geome-
try optimization of the radical produced by SET led to
spontaneous C–B bond breaking with formation of a radi-
cal. While it does provide an explanation for the unsuc-
cessful couplings, this predicted behavior is inconsistent
with (i) the observed stereospecific coupling with the di-
alkyl secondary boronic esters and (ii) the retention of the
cyclopropane unit in example 2m. This led us to consider
a different mechanism that did not involve SET. In fact,
DDQ is known to be a strong electrophile with a Mayr
reactivity parameter of –3.59, comparable to a tropylium
ion.65 Thus, a mechanism similar to the one delineated for
the electrophilic quench in Scheme 5A might be opera-
tive. As described in Scheme 8C, SEAr from the boronate
complex ate-1a with DDQ would give intermediate 25,
which, upon stereospecific 1,2-rearrangement and elimi-
nation would account for the successful formation of 2a
with retention of stereochemistry. DFT studies showed
that DDQ could indeed react via this pathway after initial
formation of the encounter complex 26•DDQ. The low
calculated barriers for this mechanism are consistent with
the fact that reaction with DDQ is complete in minutes at
–78 °C and it is proposed that in the successful arylation
cases this pathway is followed (see SI for more details).
10
11
12
13
14
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21
22
23
24
25
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41
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45
46
47
48
49
50
51
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59
60
SCHEME 7. Reaction Optimization and Substrate
Scope with DDQ.a
A) Oxidant screening
nꢀBuLi, THF, –78 ºCꢀrt
Oxidant
B(pin) Li
B(pin)
O
O
O
then
, –78 °C
2a
Ph
(R)ꢀ1a
Ph
[er 98:2]
Ph
Entry
Oxidant
T (ºC)
time
Yield (%)
es (%)b
1
2
3
4
5
6
7
8
DDQ
DDQ
chloranil
Mn(OAc)3
Cu(OAc)2
CAN
–78
0
5 minꢀ1 h
5 min
82
20
0
0
0
0
0
0
100
100
–
–
–
–
–
–
–78ꢀrt
–78ꢀrt
–78ꢀrt
–78ꢀrt
–78ꢀrt
–78ꢀrt
5 minꢀ16 h
5 minꢀ16 h
5 minꢀ16 h
5 minꢀ16 h
5 minꢀ16 h
5 minꢀ16 h
WCl6
(pꢀBrꢀPh)3N•+
B) Scope and limitations of the process
• Successful couplings:
• secondary nonꢀbenzylic boronic esters
CO2tꢀBu
O
O
O
O
O
Ph
2a
Ph
2c
Ph
2e
2m
58%
2n
62%
dr > 20:1
100% ds
82%
67%
71%
er 98:2
100% es
er 97:3
100% es
er 96:4
100% es
dr > 20:1
100% ds
• Unsuccessful couplings:
• αꢀN, benzylic, tertiary boronic esters and other electron rich aromatics
MeO
B(pin)
B(pin)
B(pin)
B(pin)
O
O
O
Boc
Ph
N
Ph
Ph
While this mechanism would fully explain the successful
couplings reported in Scheme 8B, a unified mechanistic
picture would still imply a remarkable ability of DDQ to
serve as an electrophile or a one-electron oxidant depend-
ing on the furyl-boronate substitution pattern: secondary
ate-1l
ate-1g
ate-1t
22
a Reaction conditions: furan (1.2 equiv.), n-BuLi (1.2 equiv.) in
→
THF (0.3 M) at –78 ºC rt for 1 h, then 1a (1.0 equiv.) in THF
(0.3 M) at –78 ºC then oxidant (1.5 equiv.) in THF (0.3 M).b
Determined by chiral HPLC analysis.
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Journal of the American Chemical Society
lar B3LYP-D2 calculations were used to predict free ener-
non-benzylic substrates would undergo SEAr (Path C)
while secondary benzylic and tertiary would undergo sp3
C–B bond SET oxidation (Path D). We believe that in the
latter cases Path D operates owing to the greater ease of
removal of an electron from the benzylic sp3 C–B bond
leading to a more stable benzylic or tertiary radical and
we performed further calculations using the model iso-
propyl and benzylic boronate complexes 24 and ate-1l.
We estimated the free energy of activation ΔG* for one-
electron oxidation of the boronate in the encounter com-
plex 26•DDQ with Marcus theory, 66,67 using DFT (B3LYP)
calculations to obtain the parameters needed (see the SI
for details of this Marcus theory modeling and other
computations). This yielded ΔG* of 4.7 kcal mol–1 for R =
Me, and 2.5 kcal mol for R = Ph (Scheme 8E)). Also, regu-
gies of activation ΔG* for SEAr starting from 26•DDQ,
which were 3.7 kcal mol–1 in both cases. Hence, as shown
in Scheme 8D, reaction through Path C in the encounter
complex 26•DDQ is favored by 1.0 kcal mol–1 for the iso-
propyl case (consistent with the successful coupling with
secondary alkyl substrates), whereas reaction through
Path D is favored by 1.2 kcal mol–1 for the benzylic sub-
strate (accounting for the lack of coupling in such cases).
The uncertainties in the Marcus theory calculations mean
that this agreement with experiment is in part fortuitous,
but the conclusion that both SEAr and SET are facile, and
that the latter proceeds more readily from 26•DDQ, is
more robust.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 8. Experimental observations and proposed mechanism for unsuccessful couplings
A) C–B Bond oxidation – Experimental evidences and Proposed mechansim for not succesful couplings
2ꢀLiꢀfuran
THF, –78 ºC
via
Et B(pin)
B(pin)
• oxidation
• Hꢀatom abstraction
O
+
+
B(pin)
B(pin)
O
then DDQ
–78 ˚C, 5 min
O
Ph
Ph
Ph
[DDQ]•–
Ph
DDQ
1g
23
ate-1g
B) C–B Bond oxidation – DFT studies
DDQ
B(pin)
O
Me
B(pin)
not detected
O
Me
Me
Me
furyl ring oxidation
Path A
DDQ
B(pin)
Me
O
Me
DDQ
24
B(pin)
O
+
possible
oxidation
sites
Me
Me
Me
Me
CN
B(pin)
O
sp3 C–B bond oxidation
Path B
furyl boronate complex HOMO
C) Proposed mechanism for successful couplings – SEAr
Nu–
CN
CN
O
O
CN
O
B(pin)
B(pin)
B(pin)
Me
Cl
Cl
CN
CN
O
O
O
O
Cl
Cl
O
O
1,2-shift
SEAr
elimination
Cl
Cl
Ph
Ph 2a
O
Ph
ate-1a
25 Ph
E) SET vs SEAr pathway – energy diagram
D) SET vs SEAr pathway – DFT studies
ꢀGTHF, –78 °C
kcal mol–1
Path D
Path C
NC
O
O
CN
O
4.7
Cl
Cl
3.7
DDQ
ꢀG*
B(pin)
Me
B(pin)
O
2.5
ꢀG‡
–78 ºC
R
R
Me
0.0
26•DDQ
R = Me (24)
R = Ph (ate-1l)
NC
O
R = Me
R = Ph
CN
R = Me
SET (Path D)
SEAr (Path C)
Cl
O
Cl
CN
O
O
O
Ph
O
Me
CN
H
Cl
Cl
CN
CN
B(pin)
R = Ph
B(pin)
Me
E
O
O
Cl
B(pin)
Me
R
Me
B(pin)
Me
O
R
Me
Cl
R
O
26•DDQ
4.2 Electrophile-mediated couplings
strategy further. As described in Scheme 9, we subjected
boronate complex ate-1a (obtained by addition of 2-
lithiofuran to boronic ester 1a) to a range of electrophiles
and identified NBS to be highly effective at both –78 and
0 ºC (entries 3 and 4). Under these reaction conditions
Our initial study on the DDQ-mediated arylation of chiral
boronic esters revealed that the electrophile-promoted
pathway was feasible and so we decided to evaluate this
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Journal of the American Chemical Society
Page 6 of 16
product 2a was obtained in 92% yield and complete ste- well and afforded the desired products in high yields and
1
2
3
4
5
6
7
8
reospecificity with retention of configuration.
with complete retention of stereochemistry (2l-2t). Fur-
thermore, we found that the stereospecific coupling was
compatible with the following functional groups: ester 2e,
azide 2f, nitrile 2s, a trisubstituted double bond 2d and an
unprotected hydroxyl group 2o. The oxetanyl organobo-
ronic ester 1r also coupled effectively under our standard
conditions providing the first example of an oxetanyl or-
ganoboron being engaged in a C–C coupling reaction.68
This moiety is gaining in popularity as it is emerging as a
privileged pharmacophore in medicinal chemistry. In par-
ticular, Carreira has shown that 3,3-disubstituted oxetanes
are effective polar replacements for carbonyl and gem-
dimethyl groups in drug-like molecules.69
Finally, we evaluated the use of other electron rich het-
eroaromatics as coupling partners and found that the re-
action scope was quite broad. Thus, the coupling reaction
was applicable to the following lithiated heterocycles: C-3
furan 3e, C-2 benzofuran 4e, C-2 N-methyl pyrrole 5b, C-2
N-methyl indole 6a and 6q, C-2 thiophene 7a and 7q, and
C-2 benzothiophene 8b. In some cases, N-
iodosuccinamide (NIS) was found to be superior to NBS
as the latter caused the bromination of the electron rich
aromatic ring of the reaction product. However, attempts
to carry out the coupling with indoles bearing other
groups on nitrogen failed, as did coupling of C-3 N-
methyl indole. Moreover, reaction with 2-lithio-5-
methylfuran resulted in low yield. The power of this ap-
proach for the simple modification of natural products
was showcased by the successful coupling of cholesterol-
B(pin) 1o with 2-lithiofuran and 2-lithio-N-methyl-indole
(2o and 6p). Furthermore, by using 1,2-bis-boronic ester
1u a stereospecific di-arylation process was developed
affording 2u in 58% yield and complete es.
SCHEME 9. Optimization of Reaction Conditions for
Electrophile-Promoted Couplings.a
nꢀBuLi, THF, –78 ºC to rt
E+
B(pin)
B(pin)
O
O
2a
O
then
, –78 °C
Ph
(R)ꢀ1a
ate-1a
Ph
9
Ph
[er 98:2]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
E+
T (ºC)
time
Yield (%)
es (%)b
1
2
3
4
5
6
I2
NIS
NBS
NBS
NCS
–78
–78
–78
0
–78
–78
1 h
1 h
1 h
1 h
1 h
1 h
39
42
91
92
61
nd
nd
100
100
nd
TCCA
trace
nd
a Reaction conditions: furan (1.2 equiv.), n-BuLi (1.2 equiv.) in
→
THF (0.3 M) at –78 °C rt for 1 h, then 1a (1.0 equiv.) in THF
(0.3 M) at –78 °C then electrophile (1.2 equiv.) in THF (0.3
M).b Determined by chiral HPLC analysis. TCCA = trichloroi-
socyanuric acid.
4.2.1 Couplings between chiral secondary boronic
esters with 5-membered ring heterocycles
We then decided to evaluate the scope of this transition
metal-free cross-coupling strategy. As described in
Scheme 10, a broad range of boronic esters was evaluated
with electron rich 5-membered ring aryllithiums. In gen-
eral, secondary dialkyl substituted boronic esters reacted
very well with 2-furyllithium giving the desired products
in high yields and complete es. Pleasingly, secondary ben-
zylic and pyrrolidinyl boronic esters 1l and 1t also reacted
SCHEME 10. Scope of Electrophile-Mediated Coupling of Secondary Alkylboronic Esters with 5-Membered Het-
eroaromatics.a
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lithiation (see SI)
NBS
R2
1
2
3
4
5
6
7
B(pin)
X
X
X
B(pin)
1 h
R1
then
, 0 ºC
R1 R2
R1 R2
N3
CO2tꢀBu
O
O
O
O
O
O
O
O
O
Ph
8
Ph
2ab
92%
er 98:2
100% es
Ph
2cc
92%
er 97:3
PMP
2db
94%
er 92:8
Ph
PMP
2fb
71%
er 96:4
100% es
9
2ec
2lc
93%
er 93:7
100% es
2mb
77%
dr 99:1
2nc
82%
dr 99:1
100% ds
2qc
80%
dr 99:1
100% ds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90%
er 96:4
100% es
100% es
100% es
100% ds
CO2tꢀBu
CO2tꢀBu
CN
O
O
O
O
O
N
O
N
N
N
Ph
Boc
Ph
Ph
PMP
Ph
2rb
38%
2sd
90%
er 98:2
2tc
74%
3ec
85%
4ec
66%
5bc,e
47%
er 96:4
100% es
6ac,e
86%
6qc,e
65%
dr 99:1
100% ds
er 93:7
96% es
er 96:4
100% es
er 96:4
100% es
er 98:2
100% es
100% es
H
H
O
H
H
O
S
S
S
H
H
H
H
HO
TBSO
PMP
Ph
2ub
58%
er 97:3
100% es
H
O
H
N
Ph
7ac
7qc
65%
8bc
55%
2oc
78%
6pc,e
75%
dr 99:1
100% ds
92%
er 98:2
100% es
dr 99:1
100% ds
er 96:4
100% es
dr 99:1
100% ds
a Reaction conditions: see Scheme 9. b NBS added at 0 ºC. c NBS added at –78 ºC. d NBS added at –100 ºC. e NIS was used instead
of NBS. $ Electrophile added at –100 °C.
4.2.2 Couplings between chiral secondary boronic
esters with 6-membered ring aromatics
ulated by the reaction media, we now believe that the
increased polarity of the mixed solvent system to be the
reason for the improved selectivity.71 Under these reaction
conditions 9a was isolated in 83% yield. When the reac-
tion was tested with a single methoxy group in the aro-
matic unit (using 3-MeO-C6H4–Li) no product 11a was
observed under standard reaction conditions (entry 3) but
following addition of NBS in MeOH, a mixture of 11a, 11aa
and 21 in 69:29:3 ratio was obtained (entry 4). We there-
fore reasoned that in order to maximize the beneficial
effect of MeOH a complete solvent exchange was re-
quired. Thus, after formation of the boronate complex in
THF at –78 ºC the solvent was removed under high vacu-
um at 0 ºC. MeOH was then added and the mixture was
cooled to –78 ºC prior to NBS addition. Under these con-
ditions the desired product 11a was obtained with com-
plete selectivity and isolated in 72% yield (entry 5).
As shown in Scheme 11B, a broad range of electron rich
benzene derivatives was evaluated. The following lithiat-
ed benzene derivatives coupled successfully with both
secondary dialkyl as well as benzylic boronic esters fur-
nishing products in high yield and complete stereospeci-
ficity: 3,5-dimethoxy (9a, 9q, 9l), 3-N,N-dimethylamino
(10a, 10q), and 3-methoxy (11a, 11l). Disubstituted elec-
tron rich aromatics e.g. 2,3- or 3,4-dimethoxy (12b and
13b) aryllithiums also worked but lower yields were ob-
served in these cases as a result of competing ipso substi-
tution (giving the aryl bromide and starting boronic ester)
Having evaluated the ability of chiral secondary bo-
ronic esters to undergo the stereospecific NBS-coupling
with electron rich heteroaromatics, we moved on to the
more challenging 6-membered ring electron rich aromat-
ics. As their corresponding boronate complexes are com-
petent sp3-nucleophiles (SE2inv, see Scheme 5B),46-49 the
reactions conditions had to be modified to promote reac-
tion on the aromatic ring (Scheme 11A).
We started our investigation using the 3,5-(MeO)2-
C6H3–Li, taking advantage of the synergistic effect of all 3
donor groups of the boronate complex promoting bro-
mination on the aromatic ring at the para position.70 This
would be followed by stereospecific 1,2-metallate rear-
rangement and elimination. As shown in Scheme 11A
when the reaction was performed using the standard
conditions a mixture of the desired product 9a, the
B(pin)-incorporated product 9aa (see Section 4.3) and the
alkyl bromide 21 was obtained in a 81:6:13 ratio as deter-
mined by crude GC analysis (entry 1). As compound 9aa
arises from an incomplete nucleophilic elimination step,
we repeated the reaction adding NBS in MeOH, in order
to promote the elimination pathway (MeOH could act as
the nucleophile). Pleasingly, this simple modification of
the reaction conditions completely suppressed the for-
mation of both 9aa and 21 (entry 2). As SEAr can be mod-
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Journal of the American Chemical Society
Page 8 of 16
and competing reaction at the sp3 carbon (giving bromide
out a meta donor group, e.g. phenyllithium, bromination
at the sp3 carbon dominated and no arylation was ob-
served. With a weak meta donor group, e.g. 3-
methylphenyllithium, ~3:1 mixture of 2-bromo-4-
phenylbutane and the desired coupled product were ob-
tained showing the lower limit of the aromatic group that
can be employed.
We have previously found that benzylic boronate com-
plexes are better nucleophiles at the sp3 carbon of the
boronate than their non-benzylic counterparts. This
competing undesired reaction could account for the lower
yields of the desired arylation obtained in the benzylic
versus the non-benzylic substrates e.g. compare 9a/9l,
11a/11l, 18b/18l.
The cholesterol B(pin) 1o reacted well with the electron
rich aryllithiums giving products 9o and 10p in high yield
and complete diastereospecificity.
1
2
3
4
5
6
7
8
21). Pleasingly Br substitution e.g. at C-5 was tolerated
giving 14b in good yield and complete es. The coupling
was successful with the weakly nucleophilic naphthyl
(both at C-1 and C-2) and the phenanthryl moiety giving
products 15a, 16b and 17b. Furthermore, the coupling was
also successful with weakly donating aromatics e.g. 3,5-
dimethylphenyl and 2-lithio-6-methoxypyridine, giving
products 18b and 20b, respectively.
However, not all aromatics worked, due to competing
processes. If bromination occurs on the aromatic ring, the
desired arylation takes place but competing reaction can
also occur at the sp3 carbon of the boronate complex.
Substitution on the aromatic ring which pushes electron
density onto boron (i.e. o- and p-donor groups) favors the
latter process. This explains why 2- or 4- methoxyphenyl-
a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
lithium
were
not
effective
whereas
3-
methoxyphenyllithium, giving 11a, was successful. With-
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SCHEME 11. Optimization (A) and Scope (B) for Coupling of Secondary Boronic Esters to 6-Membered Electron
Rich Aromatics.a
1
2
A) NBS coupling with 6-membered ring heterocycles: Optimizationa,b
3
R
4
5
6
7
MeO
R
R
OMe
R
OMe
nꢀBuLi, THF, –78 ºC to rt
NBS
B(pin)
MeO
B(pin)
B(pin)
Br
solvent, –78 ºC, 1 h
Br
then
, –78 ºC
Ph
Ph
Ph
Ph
(R)ꢀ1a
9a : R = OMe
11a : R = H
9aa : R = OMe
11aa: R = H
[er 98:2]
21
Ph
8
9
[Br+]
Entry
R
Solvent
Br
R
R
Br
MeO
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SEAr
1,2ꢀshift
9a
9aa 21
9a
11a
Nu–
MeO
Ph
MeO
B(pin)
B(pin)
1
2
OMe
OMe
THF
THF, NBS
added in MeOH
81
6
13
B(pin)
99 (83%)
11a
<1
<1
Ph
Ph
vs
Br
11aa 21
MeO
R
B(pin)
MeO
R
3
4
5
H
H
H
THF
<1
68
99 (72%)
<1
29
<1
<1
3
<1
9aa
11aa
THF, NBS added in MeOH
THF then solvent
switch to MeOH
H
B(pin)
B–
Ph
Ph
B) Scope of the process with secondary boronic esters
R
NBS
MeOH, –78 ºC, 1h
lithiation (see SI)
R
R
R3
(pin)B
B(pin)
then
H/Br
R1 R2
R1 R2
, –78 ºC
R1 R2
MeO
OMe
MeO
OMe
MeO
OMe
NMe2
NMe2
OMe
OMe
Ph
Ph
Ph
Ph
Ph
9a
83%
9q
84%
dr 99:1
100% ds
9l
64%
er 97:3
100% es
10ac
65%
er 98:2
100% es
10qc
70%
11a
72%
er 98:2
100% es
11l
43%
er 97:3
er 98:2
100% es
dr 99:1
100% ds
100% es
OMe
OMe
OMe
OMe
Br
OMe
PMP
PMP
Ph
Ph
PMP
PMP
12b
46%
er 96:4
100% es
13b
51%
14b
81%
er 98:2
100% es
15a
89%
er 98:2
16bd
62%
17b
53%
er 96:4
100% es
er 96:4
100% es
er 96:4
100% es
100% es
OMe
H
H
N
H
H
H
H
H
H
H
PMP
Ph
PMP
PMP
10pc
68%
dr 99:1
9o
91%
RO
TBSO
18b
83%
18l
21%
19b
17%
20be
58%
er 96:4
100% es
H
dr 99:1
100% ds
100% ds
er 96:4
100% es
MeO
OMe
NMe2
a
Re-
action conditions: for lithiation conditions see SI; boronic ester (1.0 equiv.) in THF (0.3 M) at –78 °C then solvent switch to
MeOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78 °C, 1h. b Optimization perfomed with GC-MS, isolated yields in parentheses.
c NIS used instead of NBS. d Reaction performed at –15 °C, e DBDMH (1,3-dibromo-5,5-dimethylhydantoin) used instead of NBS.
4.2.3 Couplings of chiral tertiary boronic esters
the potential to solve this unmet synthetic challenge. As
shown in Scheme 12, a range of tertiary alkyl and benzylic
boronic esters with both 5- and 6-membered ring aryllith-
iums were found to work well. Trialkyl, benzylic, and di-
benzylic boronic esters 1g–k were coupled with 2-
furyllithium in high yields and complete es furnishing
products 2g–k. The chemistry was also extended to 2-
lithiobenzofuran giving 4g and 4h. Electron rich 6-
membered aryllithiums were evaluated next. In the case
Having evaluated the use of secondary boronic esters in
the NBS-mediated stereospecific cross-couplings meth-
odology, we moved to the more challenging tertiary bo-
ronic esters, a class of substrates for which transition
metal–based methodologies are currently not available.5,6
As our approach goes through a distinct mechanistic
pathway, we were keen to explore if our methodology had
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Page 10 of 16
b
c
°C, 1h.
Reaction performed at -15 °C,
DBDMH (1,3-
of the 3,5-dimethoxy-phenyllithium both alkyl and ben-
zylic substrates were successful and the desired products
9g and 9h were obtained in high yield and complete es.
The coupling was successful with other electron rich ar-
omatics such as 3-methoxy-phenyllithium (11h), 1- and 2-
naphthyllithium (15g and 16g), 6-methoxy 2-lithio-
pyridine (20g) and 3,5-dimethyl-phenyllithium (18g). A
remarkable example is the successful coupling with the
weakly electron rich aromatic, 3-methyl-phenyllithium
which gave product 19g in 46% yield and complete es. We
rationalized the success of this example with the in-
creased steric congestion offered by the three alkyl groups
that slows down the rate of sp3 halogenation enabling
reaction at the aromatic ring to compete more favorably.
1
2
3
4
5
6
7
8
dibromo-5,5-dimethylhydantoin) used instead of NBS.
4.3 Stereospecific arylation-B(pin) incorporations
During the optimization of the NBS-mediated coupling of
secondary boronic esters and 6-membered ring aryllithi-
ums we observed the unexpected formation of products
where the B(pin) group was incorporated into the aro-
matic ring (Scheme 11A, see entry 1 and 4). This observa-
tion set the stage for the development of a unique ortho-
borylation- -coupling reaction. Mechanistically we believe
this product arises from an incomplete nucleophilic
B(pin)-elimination reaction from intermediate 27
(Scheme 13A). This would lead to a nucleophilic 1,2-
Wagner-Meerwein shift of the B(pin) moiety forming the
more stable carbocation 28. Final deprotonation would
furnish the B(pin)-incorporated product 18aa. Based on
this mechanism, we speculated that whilst a polar solvent
(e.g. MeOH) was required to facilitate the SEAr we needed
to reduce its ability to serve as a nucleophile in order to
favor the 1,2-Wagner-Meerwein shift.71 We therefore test-
ed the sterically hindered alcohol i-PrOH in place of
MeOH and the ratio of 18a:18aa:21 was improved to 5:88:7
as determined by GC-MS. Furthermore by using a 1:1 i-
PrOH–CH3CN solvent mixture we were able to selectively
obtain product 18aa and to isolate it in 90% yield. With
the optimized reaction conditions we evaluated the scope
of this novel coupling reaction. As described in Scheme
13B, a variety of aryllithiums reacted well providing the
desired products in good yields and complete es (9ba,
11ba, 15ba, 18aa,). We were pleased to see that tertiary
groups were compatible as well and delivered remarkably
high yields furnishing very sterically congested quater-
nary scaffolds (9ga, 18ga). It was also possible to perform
this reaction on heterocyclic substrate such as benzothio-
phene (8ba). We believe that this particular result is a
very attractive tool for introducing neighboring function-
alities in a single transformation. Moreover, the B(pin)
moiety serves as a useful handle for further functionaliza-
tion either by transition metal catalysis or the protocol
described herein.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 12. Coupling of Tertiary Boronic Esters.a
Ar
R2 Ar
R1
NBS
lithiation (see SI)
R2 B(pin)
Ar–Br/H
R2 B(pin)
then
R
MeOH, –78 ºC, 1h
R
R1
R
R1
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Br
2g
89%
er 99:1
100% es
2h
83%
er 99:1
2i
76%
er 99:1
100% es
2j
94%
er 99:1
100% es
2k
53%
er 98:2
99% es
100% es
OMe
OMe
MeO
MeO
O
O
Ph
Ph
Ph
Ph
4g
4h
9g
9h
66%
64%
78%
63%
er 99:1
100% es
er 99:1
100% es
er 99:1
100% es
er 99:1
100% es
MeO
Ph
11hc
47%
Ph
Ph
Ph
15g
75%
16gb
49%
18g
66%
er 99:1
100% es
er 99:1
100% es
er 99:1
100% es
er 98:2
100% es
OMe
N
Ph
18h
24 %
Ph
Ph
19g
46%
er 99:1
100% es
20gc
60%
er 99:1
100% es
a
Reaction conditions: for lithiation conditions see SI; bo-
ronic ester (1.0 equiv.) in THF (0.3 M) at –78 °C then solvent
switch to MeOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78
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SCHEME 13. Method for Retaining the Boronic Ester in the Coupling Reaction
1
2
A) Optimization of the arylation-B(pin) incorporation process
3
4
5
6
solvent switch
then NBS
nꢀBuLi, THF, –78 ºC to rt
B(pin)
B(pin)
B(pin)
Br
Br
then
, –78 ºC
Ph
Ph
Ph
Ph
1a
18a
18aa
21
7
8
9
Ph
Br
Entry
Solvent switch to
18aa
18aaa
21a
Br
1
2
3
4
5
6
–
MeOH
iꢀPrOH
<1
<1
37
88 (55%)
55 (47%) 47
53
99
3
7
60 (60%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
vs
Nu–
B(pin)
B(pin)
5
3
42
2
H
B(pin)
CH3CN
CH3CN–MeOH (1:1)
CH3CN–i-PrOH (1:1)
5
4
Base
Ph
Ph
Ph
Ph
94 (90%)
27
28
B) Scope of the stereospecific arylation-B(pin) incorporation processb
R
R
solvent switch to
CH3CN–iꢀPrOH (1:1)
lithiation (see SI)
R
B(pin)
R3
R3
(pin)B
(pin)B R3
then NBS
CH3CN–i-PrOH (1:1)
0 ºC, 1h
H/Br
R1 R2
R1 R2
then
, –78 ºC
R1 R2
OMe
MeO
OMe
OMe
2.7
1
MeO
B(pin)
B(pin)
S
B(pin)
B(pin)
(pin)B
(pin)B
PMP
B(pin)
PMP
PMP
Ph
Ph
Ph
PMP
9ba
38%
er 96:4
11ba
55%
15ba
72%
18aa
90%
er 98:2
100% es
9ga
46%
er 99:1
18ga
83%
er 99:1
100% es
8ba
46%
er 96:4
100% es
er 96:4
100% es
er 96:4
100% es
100% es
100% es
a GC conversion, isolated yield in brackets. b Reaction conditions: for lithiation conditions see SI; boronic ester (1.0 equiv.)
in THF (0.3 M) at –78 °C then solvent switch to CH3CN–i-PrOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78 °C, 1h.
4.4 Trends in reactivity
SCHEME 14. Main Competing Processes which De-
termine the Outcome of the Coupling Reaction Illus-
trate Trends in Reactivitya
The successful outcome of the coupling reaction is de-
pendent on a number of factors but the extent of compet-
ing reactions at the sp3 carbon versus the aromatic ring
appears to dominate in many cases. Considering these
two factors only, trends in reactivity can be readily un-
derstood (Scheme 14). For tertiary and secondary non-
benzylic boronates, as the aromatic becomes less electron
rich, the yield for the coupled product declines since re-
action of NBS at the less electron rich aromatic becomes
increasingly less favored. Comparing benzylic secondary
2l, 9l, 11l and 18l) and tertiary (2h, 9h, 11h and 18h) prod-
ucts the same trend is observed. In addition, the in-
creased resistance to reactions at the sp3 carbon of the
tertiary alkyl substrates leads to increased yields of cou-
pled products compared to the corresponding secondary
substrates (cf. 19g and 19b).
SE2inv – Path B
SEAr – Path A
[Br+]
Ar
Ar
vs
B(pin)
R1
B(pin)
R
R
R1
[Br+]
• highly electron rich Ar
• not influenced by sterics
• not influenced by Ar
• sterically accessible sp3ꢀC
electronꢀrichness of aromatic group
SEAr
SE2inv – not affected
MeO
O
MeO
B(pin)
B(pin)
B(pin)
B(pin)
Ph
Ph
Ph
Ph
2a
92%
9a
83%
18b
83%
19b
17%
MeO
O
MeO
B(pin)
Et
B(pin)
Et
B(pin)
Et
B(pin)
Et
Ph
Ph
Ph
Ph
2g
89%
9g
78%
18g
66%
19g
46%
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Page 12 of 16
a Yields for arylation process.
A) Reaction of boronate complex 24 with NBS
[Br+]
1
4.5 DFT and React-IR studies
2
3
4
5
6
7
8
9
Path A
SEAr
Path B
SE2inv
O
Br
B(pin)
+
B(pin)
24
O
O
Additional DFT calculations were performed for the elec-
trophilic reactions with NBS. Using the same model iso-
propyl boronate anionic complex 24, two mechanisms
were considered: one involves electrophilic addition at
the aromatic ring (Path A, SEAr), whereas the other in-
volves electrophilic attack at the sp3 C–B bond (Path B –
SE2inv) (Scheme 15A). In both cases, transition states
were located (Scheme 15B), involving near-linear N–Br–C
arrangements corresponding to nucleophilic substitution
at bromine. For Path B, the TS leads directly to succin-
imide anion and the bromoalkyl species with release of
boronate ester. For Path A, electrophilic attack of the
bromine triggered migration of the alkyl group in the
same reaction step, without further barrier. The migra-
tion is already well under way at the TS. The discrete cat-
ionic intermediate II (Scheme 5A) is never actually
formed but is nevertheless a useful species to consider
when formulating the overall process. This TS is the sig-
nificantly more stable one with the furyl model boronate
complex, consistent with the observed high yields for
alkylated furan. Additional calculations were performed
using 3,5-dimethylphenyl and phenyl substrates. The TS
for Path B has almost the same free
[Br+]
B) Transition state analysis – B3LYP-D2/6-31+G(d)
Path A: concerted SEAr and 1,2-shift
O
O
O
O
N
N
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
O
B(pin)
B(pin)
Br
O
Path B
O
O
N
O
B(pin)
+
Br
Br
N
+
O
O
B(pin)
O
C) Activation energies and solvent effects – B3LYP-D2/6-31+G(d)
Boronate complexes
O
B(pin)
B(pin)
B(pin)
SCHEME 15. DFT Calculations of the Main Compet-
ing Processes Illustrating Trends in Reactivity
Solvent
Path A
Path B
THF
THF
17.8
15.4
MeOH
16.0
THF
21.7
13.9
6.7
15.3
16.2
energy in all three cases, but the barrier height for Path A
increases sharply for these less nucleophilic aryl groups
(Scheme 15C). In the case of phenyl, the barrier is now
much higher than for oxidation of the C–B bond – con-
sistent with experiment. For 3,5-dimethylphenyl, the
SE2inv (Path B) is predicted to be strongly favored in THF
as observed. However, in MeOH the two barriers are al-
most the same, although experimentally Path A is fa-
vored. The TS for path A is much more polar than the
reactants, so the solvation free energy for the TS is large
compared to that for reactants. This helps to explain why
more polar solvents favor path A over path B. Also, con-
sidering the uncertainties in continuum models of solva-
tion free energy, one must bear in mind that the calculat-
ed free energy for this TS is likely somewhat inaccurate.
In previous work,72 we have shown based on calibration
with very accurate coupled cluster calculations that
B3LYP with dispersion corrections, as used here, yields
reasonably accurate results for similar boronate chemis-
try. However, it should also be noted that conformational
complexity, treatment of the lithium counterion, and
modeling of solvation introduces further sources of error.
The boronate reaction with NBS could be followed by
React-IR.73 The boronate complex was prepared and
cooled to –78 °C and the mixture monitored by React-
IR.74 Addition of NBS in MeOH over 60 seconds resulted
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tion at the ipso position then competing ipso bromina-
in rapid consumption of the ate complex ate-9a, essen-
1
2
3
4
5
6
7
8
tially instantaneously, indicating that the reaction was
extremely rapid (Scheme 16). The low free energy barrier
calculated for the reaction with the furan boronate com-
plex suggests that reaction with NBS should be very rapid
at –78 °C, and indeed, reaction was observed to occur in
less than a minute for the dimethoxyphenyl boronate,
which should have a similar reactivity.
tion occurred returning the boronic ester (e.g. 2-
lithioindole was successful but the 3-lithioindole failed)
(Scheme 17).
SCHEME 17. Reactions with 5-Membered Ring Aromatics
R1
[Br+]
(pin)B
X
Br
R
[Br+]
R1
R
vs
9
B(pin)
R1
SCHEME 16. React-IR Studies of Reaction at –78 °C
X
X
X
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[Br+]
R
ipsoꢀsubstitution
OMe
MeO
OMe
NBS
MeO
B(pin)
The coupling reaction was also applicable to 6-membered
ring aromatics provided they had donor groups in the
meta position. The meta donor group together with the
(electron rich) boronate worked synergistically, promot-
ing bromination on the aromatic ring. If the donor group
was para to the boronate it promoted bromination at the
sp3 carbon instead and no coupled product was obtained.
This competing reaction was increasingly observed when
weaker meta donors on the 6-membered ring were em-
ployed e.g. using 3-methylaryllithium. The coupling reac-
tions with 6-membered ring aromatics required different
conditions: it was found that solvent exchange from THF
to MeOH led to improved yields of the desired coupling
product. Using these conditions, a range of 6-membered
ring aromatics, including 1- and 2-naphthalenes were suc-
cessfully coupled to secondary and tertiary boronic esters.
Solvent choice played a major role in the outcome of the
coupling reaction. Using MeCN-iPrOH, we found that the
B(pin)- moiety was retained in the product, ortho to the
boron substituent. We believe this arises from a 1,2-
Wagner-Meerwein shift of the B(pin) group which re-
lieves steric hindrance followed by loss of a proton. Again
this protocol, which created a new C(sp2)-C(sp3) and an
adjacent C-B bond, was applicable to a range of secondary
and tertiary boronic esters.
MeOH, –78 ºC
Ph
ate-9a
IR band: 1588 cm–1
Ph
9a
IR band: 1570 cm–1
ate-9a –1588 cm–1
9a –1570 cm–1
addition
of NBS
5. Conclusions
We set out to explore two different pathways by which
boronate complexes derived from an aliphatic secondary
or tertiary boronic ester and 2-furyllithium could react
with either an oxidant or an electrophile to give a coupled
product stereospecifically. Of the oxidants tested, DDQ
was uniquely effective but it only worked with a limited
range of secondary boronic esters; benzylic and tertiary
boronic esters were ineffective. From analysis of the
products obtained from the unsuccessful reactions and
from DFT studies we concluded that in those cases DDQ
oxidized the aliphatic C-B bond leading to a relatively
stable (benzylic or tertiary) radical. In the cases of non-
benzylic aliphatic secondary boronic esters which did
react successfully, DDQ acted as an electrophile – not an
oxidant, triggering 1,2-migration and subsequent elimina-
tion. NBS was a better electrophile than DDQ as it was
less prone to oxidize the aliphatic C-B bond. This reagent
was applicable to a broad range of secondary and tertiary
boronic esters with very different steric demand and tol-
erated a range of functional groups (esters, azides, ni-
triles, alcohols, and ethers). It was also applicable to a
range of electron rich heteroaromatics including pyrrole,
indole, thiophene, benzofuran and benzothiophene. It
was important that the NBS-mediated bromination oc-
curred at the ortho or para position of the aromatic ring
in relation to the boronate; if the electronics favored reac-
SCHEME 18. Reactions with 6-Membered Ring Aromatics.
promotes reaction
at aromatic
Br
EDG
EDG
MeOH
MeOH
B(pin)
R1
R
R1
R
[Br+]
EDG
EDG
mꢀEDG and boronate
promote reaction
on aromatic
pꢀEDG promotes
B(pin)
R1
vs
B(pin)
reaction at sp3ꢀC
R
R
R1
[Br+]
Br
EDG
EDG
i-PrOH
B(pin)
B(pin)
R1
promotes reaction
at aromatic but does
not capture B(pin)
R
R
R1
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All of the coupling reactions occurred with complete ste-
reospecificity.
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1
2
3
4
5
6
7
8
DFT calculations supported the mechanistic scenario put
forward and the very low barriers calculated for addition
of NBS to electron rich aromatics were commensurate
with the almost instantaneous reaction observed by Re-
act-IR at -78 °C. Interestingly, no cationic intermediates
are involved during the process; the 1,2-migration occurs
as the NBS reacts with the aromatic ring.
9
The methodology described provides a new way of cou-
pling secondary and tertiary boronic esters with electron
rich aromatics. Since there are a growing number of prac-
tical methods for making aliphatic secondary and tertiary
boronic esters with very high enantioselectivity, this new
stereospecific method should find wide application. Even
in the cases where racemic or achiral substrates are used
the absence of costly or difficult-to-remove transition
metals, which are often avoided at late stage processes of
drug manufacture, are further attractive features of the
methodology.
10
11
12
13
14
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16
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18
19
20
21
22
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46
47
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49
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60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1
Experimental procedures, H and 13C NMR spectra, HPLC
traces, React-IR plots (PDF).
DFT calculations (PDF).
AUTHOR INFORMATION
Corresponding Author
v.aggarwal@bristol.ac.uk;
daniele.leonori@manchester.ac.uk
jeremy.harvey@chem.kuleuven.be
Current Addresses
†
JNH: Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium.
‡ DL: School of Chemistry, University of Manchester, Oxford
Road, Manchester M13 9PL, UK.
$
AB: Department of Chemistry, University of Hull, Cotting-
ham Road, Hull, HU6 7RX, UK.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
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Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
(35) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G.
A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896.
We thank EPSRC (EP/I038071/1) and the European Research
Council (FP7/2007ꢀ2013, ERC grant no. 246785) for financial
support. A. B. thanks the Marie Curie Fellowship program (EC
FP7 No 329578).
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Li
R2 B(pin)
Ar
Ar
R2
+
NBS
R2
or
R
R1
Ar
B(pin)
R1
R
R1
R
stereospecific
transition metal-free
coupling
chiral
boronic ester
chiral
7
aryllithium
arylated product
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9
• full scope
• DFT studies
• ReactꢀIR studies
• high ee
• stable
• easy to make
• high modularity
• easy to make
• many available
• high ee
• widespread motif
• all Cꢀstereogenic centres
• incorporation of B(pin)
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