Enantiospecific sp2–sp3 Coupling of ortho- and para-Phenols with Secondary and Tertiary Boronic Esters

Article abstract of DOI:10.1002/anie.201710777

The coupling of ortho- and para-phenols with secondary and tertiary boronic esters has been explored. In the case of para-substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph₃BiF₂ or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (?)-4-(1,5-dimethylhex-4-enyl)-2-methyl phenol. For ortho-substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho-lithiation and borylation gave the coupled product, again with complete stereospecificity.

Full text of DOI:10.1002/anie.201710777

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Accepted Article
Title: Enantiospecific sp²-sp³ Coupling of o- and p-Phenols with
Secondary and Tertiary Boronic Esters
Authors: Claire Margaret Wilson, Venkataraman Ganesh, Adam Noble,
and Varinder Kumar Aggarwal
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710777
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10.1002/anie.201710777
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Enantiospecific sp2-sp3 Coupling of o- and p-Phenols with
Secondary and Tertiary Boronic Esters
Claire M. Wilson,† Venkataraman Ganesh,† Adam Noble and Varinder K. Aggarwal*
Abstract: The coupling of o- and p-phenols with secondary and
tertiary boronic esters has been explored. In the case of p-substituted
phenols, after reaction of a dilithio phenolate species with a boronic
ester, subsequent treatment with Ph3BiF2 or Martin’s sulfurane gave
the coupled product with complete enantiospecificity. The
methodology was applied to the synthesis of the broad spectrum
antibacterial natural product (–)-4-(1,5-dimethylhex-4-enyl)-2-methyl
phenol. For o-substituted phenols, initial incorporation of
a
benzotriazole on the phenol oxygen was required. Subsequent ortho-
lithiation and borylation gave the coupled product, again with
complete stereospecificity.
Phenols are ubiquitous motifs in pharmaceuticals, agrochemicals
and polymers, and are important constituents of plant metabolites
possessing an array of interesting biological activities.[1] Chiral
phenolic groups, bearing benzylic stereocenters, are also found
in a range of currently marketed drugs and agrochemicals
(Scheme 1a).[2] Installation of the benzylic stereocenter would
ideally be accomplished by a stereospecific cross-coupling
reaction between a halo-phenol and a chiral organometallic
reagent. However, sp2-sp3 cross-couplings, such as the Suzuki-
Miyaura reaction,[3] of secondary and tertiary aliphatic
organometallic reagents remain a significant challenge.[4] We
have worked on a conceptually different approach to such cross-
couplings and recently reported a high yielding, stereospecific
method for the coupling of aryl lithiums with chiral secondary and
tertiary boronic esters (Scheme 1b).[5,6] The reaction occurs via a
boronate complex which undergoes stereospecific 1,2-migration
upon activation by an electrophilic halogenating agent, with
subsequent elimination of the boron and halide groups leading to
the coupled product. This mode of activation proved to be highly
efficient for a variety of electron-rich heteroaromatics (e.g. furan,
thiophene, indole, benzofuran) and electron-rich aromatics,
provided they were substituted with donor groups at the meta-
position. The meta donor group and the electron-rich boronate
worked synergistically to promote electrophilic reaction on the
aromatic ring.[5a,5b] Positioning the donor group in the para-
position pushes electron density onto the sp3 carbon of the
boronate complex, resulting in selective reaction via an SE2
pathway, rather than an SEAr pathway (eg Scheme 1c, LHS).[5b,7]
Scheme1. sp2-sp3 coupling of aromatics and proposed coupling of phenols
To address this limitation, we considered the counterintuitive use
of the even more electron-rich para-phenolates for our coupling
strategy (Scheme 1c). Although paradoxically this should strongly
promote reaction at the sp3 carbon (SE2 pathway), we reasoned
that the nucleophilic properties of the phenolate oxygen would
lend themselves to identifying activating reagents that could
trigger the desired 1,2-migration of the boronate complex. Herein,
we report our success in achieving this goal with two distinct
methods for the stereospecific coupling of both ortho- and para-
substituted phenols with secondary and tertiary boronic esters.
Initially, we focused on coupling para-substituted phenols.
We began our studies by establishing the conditions required to
promote the 1,2-migration of the boronate complex 1a, which was
[a]
Dr. C. M. Wilson, Dr. V. Ganesh, Dr. A. Noble, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol,
Cantock’s Close, Bristol, BS8 1TS, United Kingdom
E-mail: v.aggarwal@bristol.ac.uk
†
Authors Contributed Equally
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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easily prepared by reaction of boronic ester 1 with 2 equivalents
of sBuLi. A broad range of promoters were investigated, including
phenol oxidizing reagents [e.g. single electron oxidants: Fremy’s
salt, CAN, DDQ, and two-electron oxidants: PhI(OAc)2)], aliphatic
alcohol oxidizing reagents (e.g. Swern-type conditions, MnO2),
dehydrating reagents (e.g. Martin’s sulfurane, Burgess reagent),
phenolate alkylation reagents (e.g. Ph3BiF2) and other oxophilic
reagents (e.g. Ph3PCl2, SO2Cl2). Although most were
unsuccessful (see SI for full details), we were delighted to find that
Martin’s sulfurane (3, Ph2S[OC(CF3)2Ph]2,[8] Method A) and
triphenylbismuth difluoride (4, Ph3BiF2,[9] Method B) gave the
desired coupling product in good yield.
Scheme 3. A possible mechanism for the coupling promoted by 3 and 4.
(OMe, 7g) or electron-withdrawing groups (F, CF3; 7h, 7i). In
most cases, Martin’s sulfurane (Method A) gave higher yields than
Ph3BiF2 (Method B).
Having demonstrated that a wide range of phenols could be
employed in this cross-coupling reaction, we then explored the
scope of the boronic esters using Martin’s sulfurane (Method A,
Table 2). Primary, secondary and tertiary boronic esters were all
successfully coupled, giving high yields of the desired products
with excellent enantiospecificity (es). Both benzylic and non-
benzylic boronic esters could be used, as well as highly hindered
secondary and tertiary boronic esters. Chiral secondary boronic
Scheme 2. Optimization of reaction conditions. Reaction Conditions: ArBpin 1
(0.20 mmol, 1.0 equiv), sBuLi (0.20 mmol, 1.0 equiv), Promoter (as in table
above), 0 °C to rt, 16 h. Yields were determined using 1H NMR with 1,3,5-
trimethoxybenzene as an internal standard. DDQ = 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; Fremy’s salt
phenyliodine bis(trifluoroacetate);
bis(trifluoromethyl)benzyloxy]diphenylsulfur.
=
disodium nitrosodisulfonate; PIFA
=
Martin’s sulfurane bis[α,α-
=
esters bearing alkenyl (8i), cyclopropyl (8j), TBS ether (8k), azido
Table 1. Substrate scope of p-bromophenols for sp2-sp3 coupling with 6.a
A plausible mechanism for the reaction of 1a with promoters
3 and 4 is presented in Scheme 3. The key step in both the cases
is believed to be the functionalization of the phenolate oxygen of
boronate complex I by the promoters 3 and 4 giving intermediates
IIa and IIb respectively. This triggers 1,2-migration with the
reduction of SIV to SII in IIa and BiV to BiIII in IIb, leading to the
quinone intermediate III. Subsequent rearomatization by
elimination of Bpin from III leads to the coupled products. The
success of the two reagents may be ascribed to their hindered
nature which leads to preferential reaction at the unhindered
phenolate over the much more hindered boronate.
Having established two protocols for triggering the key 1,2-
migration step, we turned our attention to linking them with in situ
boronate formation from alkyl boronic esters. Dianionic boronate
complex VI was generated by the reaction of boronic ester 6 with
dilithiated aryl species V, which was prepared from the
corresponding
p-bromophenols
5
through
sequential
deprotonation with MeLi followed by lithium-halogen exchange
with tBuLi.[10] The optimized coupling reaction conditions were
then applied to a range of p-bromophenols 5a-i (Table 1). Using
benzylic boronic ester 6 as our standard, p-bromophenol 5a gave
the desired coupling product 7a in 62% yield with Martin’s
sulfurane (3) as the promoter and 44% with Ph3BiF2 (4).Additional
methyl substituents could be introduced on the phenol at the 2- or
3-position (7b, 7c) as well as the 2,6- and 3,5-positions (7d, 7e),
albeit with a reduction in yield in the case of the sterically more
demanding cases. 1-Naphthol could also be used in the coupling
reaction (7f) as could phenols bearing electron-donating groups
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10.1002/anie.201710777
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Table 2. Substrate scope of chiral boronic esters for enantiospecific sp2-sp3 coupling with p-bromophenolsa
(8l), acetal (8m) and carbamate (8n) functionalities were
smoothly converted to the corresponding phenol derivatives 9i-n
in good yields (68-37%) and with excellent enantiospecificity. In
addition, the natural product-derived boronic esters 8o and 8q,
gave the desired coupling products 9o-q efficiently (58-50%) with
complete diastereospecificity.
To further highlight the utility of this coupling reaction, we
applied it to the synthesis of the natural product (–)-4-(1,5-
dimethylhex-4-enyl)-2-methylphenol (9r), a compound active
against a broad spectrum of gram-positive (MIC:16-32 μg/mL)
and gram-negative bacteria including methicillin-resistant S.
aureus and vancomycin-resistant E. faecium.[11] Phenol 9r is also
a key intermediate in the total synthesis of (+)--herbertenol.[12]
Treatment of enantioenriched boronic ester 8r[13] with dilithiated
5b followed by Martin’s sulfurane gave the natural product 9r in
57% yield with 100% enantiospecificity.
We postulated that a convenient solution to the poor
reactivity of the ortho-substituted phenolate would be to
incorporate an efficient leaving group on the phenolic oxygen prior
to boronate complex formation. We selected a benzotriazole (Bt)
group as it can be easily introduced,[14] is compatible with
organolithium reagents,[15] and is a good leaving group.[16]
However, we were also aware that boronate complexes
possessing good leaving groups at the ortho-position were prone
to undergo elimination leading to benzyne formation,[17]
potentially competing process.
a
Having successfully developed an enantiospecific cross-
coupling reaction for the synthesis of para-substituted phenols,
we wished to extend the methodology to ortho-phenols. However,
our attempts with o-bromophenol 10 using the previous strategy
of dilithiation/boronate complex formation and activation with
Martin’s sulfurane only gave a trace amount of the desired product
14a (Scheme 4). While activation with Ph3BiF2 gave the coupled
product in significantly higher yield (31%) all attempts to improve
upon this were unsuccessful. We believe that the increased steric
demand of the phenolate 11 inhibits reaction with the bulky
promotors. This prompted us to investigate an alternative strategy
that would avoid the requirement of reacting a sterically hindered
phenolate with an activating group.
Scheme 4. Attempts towards ortho-functionalization using o-bromophenol
o-Bromophenoxybenzotriazoles
10a-d
were
easily
prepared in one step by reaction of Ar2I+OTf- with
hydroxybenzotriazole (HOBt).[14] Lithium-halogen exchange of
10a with nBuLi and treatment with boronic ester 6 gave the
corresponding boronate complex (see 13, Table 3). To our delight,
upon warming to room temperature the 1,2-migration proceeded
to give the ortho-functionalized phenol 14a in 53% yield with
100% es. Both electron-rich (10b) and electron-deficient
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Table 3. Substrate scope of Ar-OBt and chiral boronic esters for enantiospecific sp2-sp3 coupling to access ortho-functionalized phenols.
phenoxybenzotriazoles (10c,d) gave the coupled products 14b-d
in good yields (41-82%). A range of chiral secondary and tertiary
boronic esters were tested to explore the scope of this
methodology. With simple secondary and tertiary boronic esters,
2-bromophenoxybenzotiazole 10a reacted smoothly under the
standard reaction conditions to give the desired products 15a-d in
22-68% yield. The use of strongly electron-withdrawing
substituents (CF3) on the aromatic ring or sterically demanding
tertiary pinacol boronic esters (e.g. to give 15c) resulted in poor
yield (10-15%) with considerable recovery of the starting boronic
esters (see SI for details). For tertiary boronic esters, exchanging
the pinacol ligand for a less bulky neopentyl glycol gave the
coupled product (15c) in slightly improved yield (22%). Other
functionalized secondary boronic esters gave the corresponding
products bearing alkenyl (15e), azido (15f), and carbamate (15h)
functionalities, as well as a menthol-derived boronic ester (15g),
all with complete stereospecificity.
Y. Wang, Dr. C. Sandford and Dr. M. Odachowski for valuable
discussion and contributing boronic esters.
Keywords: boronic esters • synthetic methods • phenol •
arylation • carbon-carbon bond formation.
[1]
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[5]
In conclusion, we have developed a general method for the
enantiospecific coupling of boronic esters with ortho- and para-
substituted phenols. For hindered ortho-substituted phenols, a
pre-incorporated leaving group (benzotriazole) was required to
promote 1,2-migration of the corresponding boronate complex.
For the less hindered para-substituted phenols 1,2-migration was
triggered using Martin’s sulfurane or Ph3BiF2. The substrate
scope was found to be broad, with excellent functional group
tolerance demonstrated over a range of boronic ester and phenol
coupling partners. This methodology provides an important
extension to the growing range of aromatics that can partake in
stereospecific transition metal-free cross-coupling[5] of highly
hindered secondary and tertiary boronic esters and will likely find
broad utility for the synthesis of challenging chiral phenol
derivatives.
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Am. Chem. Soc. 2017, 139, 9519-9522.
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2011, 133, 16794-16797; b) K. Feeney, G. Berionni, H. Mayr, V. K.
Aggarwal, Org. Lett. 2015, 17, 2614-2617. Reaction of p-MeO-
arylboronate complexes with electrophiles result in the addition of
electrophiles to the sp3-carbon-boron bond through an SE2 inversion
pathway or a SET pathway.
[8]
[9]
a) S. S. Pooppanal, Synlett 2009, 850-851; b) Z. Wang, in
Comprehensive Organic Name Reactions and Reagents, John Wiley &
Sons, Inc., 2010.
Acknowledgements
We acknowledge financial support from the EPSRC
(EP/I038071/1) and ERC (670668). VG thanks the RS for the
Newton International Fellowship. We thank Dr. Eddie Myers, Dr.
M. Drapeau, T. Ollevier, Electronic Encyclopedia of Reagents for Organic
Synthesis: Triphenylbismuth Difluoride, 2014.
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Entry for the Table of Contents (Please choose one layout)
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The coupling of o- and p-phenols with
boronic esters has been explored. In
the case of p-bromophenols, after
reaction of the dilithio aryl species with
the boronic ester, treatment with
Ph3BiF2 or Martin’s sulfurane gave the
coupled product with complete
enantiospecificity (es). In the case of o-
C. M. Wilson, V. Ganesh, A. Noble and
V. K. Aggarwal*
Page No. – Page No.
Enantiospecific sp2-sp3 Coupling of
o- and p-Phenols with Secondary and
Tertiary Boronic Esters
phenols, initial incorporation of
a
benzotriazole on the phenol oxygen
was required. Subsequent o-lithiation
and borylation gave the coupled
product, again with complete es.
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