Alkynyl Moiety for Triggering 1,2-Metallate Shifts: Enantiospecific sp2–sp3 Coupling of Boronic Esters with p-Arylacetylenes

Article abstract of DOI:10.1002/anie.201703894

The enantiospecific coupling of secondary and tertiary boronic esters to aromatics has been investigated. Using p-lithiated phenylacetylenes and a range of boronic esters coupling has been achieved by the addition of N-bromosuccinimide (NBS). The alkyne functionality of the intermediate boronate complex reacts with NBS triggering the 1,2-migration of the group on boron to carbon giving a dearomatized bromoallene intermediate. At this point elimination and rearomatization occurs with neopentyl boronic esters, giving the coupled products. However, using pinacol boronic esters, the boron moiety migrates to the adjacent carbon resulting in formation of ortho boron-incorporated coupled products. The synthetic utility of the boron incorporated product has been demonstrated by orthogonal transformation of both the alkyne and boronic ester functionalities.

Full text of DOI:10.1002/anie.201703894

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Title: Alkynyl Moiety for Triggering 1,2-Metallate Shifts: Enantiospecific
sp2-sp3 Coupling of Boronic Esters with p-Arylacetylenes
Authors: Varinder Kumar Aggarwal
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Alkynyl Moiety for Triggering 1,2-Metallate Shifts: Enantiospecific
sp2-sp3 Coupling of Boronic Esters with p-Arylacetylenes
Venkataraman Ganesh,[a] Marcin Odachowski[a] and Varinder K. Aggarwal*[a]
Abstract: The enantiospecific coupling of secondary and tertiary
boronic esters to aromatics has been investigated. Using p-lithiated
phenylacetylenes and a range of boronic esters coupling has been
achieved by the addition of N-bromosuccinimide (NBS). The alkyne
functionality of the intermediate boronate complex reacts with NBS
triggering the 1,2-migration of the group on boron to carbon giving a
dearomatized bromoallene intermediate. At this point elimination and
rearomatization occurs with neopentyl boronic esters, giving the
coupled products. However, using pinacol boronic esters, the boron
moiety migrates to the adjacent carbon resulting in formation of ortho
boron-incorporated coupled products. The synthetic utility of the boron
incorporated product has been demonstrated by orthogonal
transformation of both the alkyne and boronic ester functionalities.
For over half a century, cross-coupling reactions, particularly the
Suzuki–Miyaura reaction, have been widely used in synthesis
with applications spanning pharmaceuticals, agrochemicals and
materials.[1] However, although extraordinarily useful for sp2–sp2
coupling, this reaction shows rather limited scope for aliphatic
boron reagents. Primary organoboron reagents work well, but
apart from a few specific examples[2] (chiral) secondary and
tertiary boronic esters do not. Recently, we reported a unique
approach to the stereospecific sp2-sp3 coupling of boronic esters
by exploiting the reaction of boronate complexes with
electrophiles (Scheme 1a).[3] The coupling reaction worked well
with electron rich heteroaromatics and aromatics bearing donor
groups in the meta-position. However, without such features no
coupling occurred and bromination at the sp3 center occurred
instead (Scheme 1a).[4]
In order to broaden the substrate scope to an even greater range
of aromatics, we envisaged the introduction of a functional group
exo to the aromatic ring that would be more reactive than the sp3
center, and still trigger the 1,2-metallate shift. We considered the
use of alkynes because they should react with electrophiles in the
desired way and because of the ease with which they can be
Scheme 1. General mechanism of metal catalyzed sp2-sp3 coupling of boronic
esters.
transformed into
a
variety of other functional groups.[5]
Furthermore, alkynes are an important substituent in their own
right owing to their prominence in natural products and as a site
for rapid and site-selective conjugation, through a variety of Click
reactions.[6] We hypothesized that treatment of the TMS-
phenylacetylene derived boronate complex (C) with NBS should
result in bromination of the alkyne[7] which would trigger 1,2-
metallate shift[8] leading to
a
dearomatized bromoallene
intermediate (D) (Scheme 1b).[8] Upon reaction with a nucleophile,
elimination and rearomatisation would result.[5]
In this paper, we describe the realization of this hypothesis. To
test our idea, we chose cyclohexyl pinacol boronic ester (CyBpin,
1a) and TMS-p-bromophenylacetylene (2a) as standard
substrates. Treatment of bromoalkyne 2a with n-BuLi in THF at -
78 C followed by CyBpin gave boronate complex 3a. Subsequent
addition of NBS in MeOH afforded a mixture of products
comprising the desired coupled product 4a (40%), a product with
boron incorporation in the ortho-position 4b (52%) as well as a
[a]
Dr. V. Ganesh, Dr. M. Odachowski and Prof. V. K. Aggarwal
School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom.
E-mail: v.aggarwal@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201703894
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5) and again found that iPrOH/MeCN was optimal here too, giving
the highest ratio, leading to a 76% yield of 4b (entry 4). In
THF/MeCN the reaction predominantly favored the undesired sp3
bromination pathway, showing the need for an alcohol co-solvent
(entry 3).
In order to promote the formation of the de-borinated coupled
product 4a, we needed to promote nucleophilic attack at the boron
atom and so decided to tune the steric environment around the
boron center with a variety of diol ligands. Of the diols tested, the
least hindered neopentyl glycol gave the highest selectivity for the
coupled product 4a (82%) with minimal amounts of 4b and 5
(entry 8). With increasing steric hindrance around boron, an
increasing proportion of the boron incorporation product 4b was
observed. Additional solvent screening showed that in TFE/THF,
the sp3 bromination pathway could be eliminated (entry 9).
Using the optimized conditions for creating boron-free products
we explored the substrate scope of the aromatic component,
employing a range of arylalkynes with a standard secondary
boronic ester 6a obtained in 96:4 er using our lithiation-borylation
methodology.[9] With simple p-bromophenylalkyne 2a, the
reaction furnished the expected coupled product 7a in 92% yield
and with 100% enantiospecificity. With alkyl substituents in the
ortho- (2b) and meta-positions (2c) the desired product 7b and 7c
were obtained in 85% and 86% yield respectively. Similarly, the
naphthylalkyne 2d also afforded the expected coupled product 7d
in good yield (89%) (minor amounts (~5%) of boron incorporation
was observed in all cases). Electron-donating substituents on the
aromatic ring (2e and 2f) smoothly afforded the coupled products
7e and 7f in excellent yields (82 and 90% respectively). However,
the introduction of electron-withdrawing groups such as fluoro
(2g) or trifluoromethoxy (2h) on the aromatic ring favoured the
direct sp3 bromination pathway (~9:1) with neopentyl boronic
Scheme 2. General scheme and optimization of reaction conditions.a
small amount of 5 (6%) along with Cy-Br formed through the direct
bromination at the sp3 carbon (Scheme 2, entry 1). At this point,
we decided to optimize the reaction conditions to maximize the
formation of either 4a or 4b, initially focusing on the maximally
functionalized boron-incorporated product 4b. We had previously
observed such products when coupling electron-rich aromatics
with boronic esters and found that iPrOH/MeCN gave the best
ratio.[3b] We therefore carried out a brief solvent study (entries 2-
Table 1. Scope of NBS mediated coupling of phenylacetylenes with secondary
boronic ester.a
esters, so the corresponding pinacol boronic esters were tested.
Table 2. Scope of NBS mediated coupling of Bneop esters with 2a.a
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In comparison to pinacol, it is known that neopentyl boronic esters
promote undesired SE2 reaction at the sp3 carbon.[10] Pleasingly,
with 2g, and the pinacol boronic ester 9a the coupled product 7g
was obtained in 71% yield. With trifluoromethoxy 2h, the desired
product 7h was obtained in a modest yield of 32% together with
undesired direct bromination at the sp3 carbon (in 2:3 ratio) and
minor amounts of boron incorporated products (~10%). With other
phenylacetylenes 2b-c and 2f, the reaction proceeded smoothly
to provide the corresponding products 10ab, 10ac and 10af in
good yields. In the case of 2c and 2f, a regioisomeric mixture of
products (10ac1-c2 and 10af1-f2) were observed. With other
t
electron-withdrawing groups (e.g. CF3, CN, CO2 Bu, F and OCF3)
on the aromatic ring, in MeCN/iPrOH solvent, bromination at the
sp3 carbon was favored (>95%) over bromination of the
deactivated phenylacetylene.
t
strongly electron withdrawing groups e.g. CF3, CN, CO2 Bu
bromination of the sp3 carbon dominated over the attack on the
deactivated aromatic ring. A dimethylacetal functionality 2i
(representing a masked aldehyde) reacted efficiently with the
corresponding neopentyl boronic ester to provide the coupled
product 7i in 66% yield. In all cases the reactions occurred with
complete enantiospecificity.
We then turned our attention to the scope of 2 and 3 neopentyl
boronic esters in our coupling chemistry (Table 2). Secondary
boronic esters bearing alkyl, alkenyl, cyclopropyl and silyl ether
functionalities 6a-d and natural product-derived boronic ester 6e
smoothly converted to the corresponding coupled product 7a, 8b-
e in good yields and 100% es. Other commonly occurring
functional groups were tolerated in the boronic ester including
azide (6f) and carbamate (6g). With tertiary neopentyl boronic
esters 6h and 6i, the reaction proceeded smoothly to furnish the
coupled products 8h and 8i in 43% and 79% yield respectively.
We then turned to exploring the scope for the boron incorporation
using pinacol boronic esters using the identified conditions
(Scheme 2, entry 4). Reaction of boronic ester 9a with 2a gave
the expected boron-incorporated product 10a in 78% yield with
100% es. On a gram-scale under standard reaction conditions,
The scope of secondary pinacol boronic esters was also
investigated. An array of aromatic, 2o and 3o boronic esters
bearing phenyl, alkyl, alkenyl, cyclopropyl, ester, azido, silylether,
nitrile and amide[11] functional groups 9b-j all worked well
furnishing the products 10b-j in good yield (52-81%) and 100%
es. Natural product-derived boronic esters 9k and 9l were
transformed exclusively to the boron incorporated product 10k
and 10l in 88% and 76% yields, respectively with complete
diastereospecificity.
The mechanism that accounts for the generation of the boron-free
and boron-incorporated products is shown in Scheme 3.
Following the formation of boronate complex I, the reaction with
NBS leads to the bromoallene intermediate II. If the boronic ester
is unhindered, subsequent attack by MeOH at boron promotes
elimination leading to product Va (Path a). In contrast, if the
boronic ester is hindered, nucleophilic attack is less favored,
especially with iPrOH as solvent, and migration of the boron to the
adjacent carbon occurs instead, relieving steric encumbrance and
eliminating bromide. This leads to carbocation intermediate IV,
which then eliminates to the product Vb (Path b).
Table 3. Scope of NBS mediated coupling of boronic esters with phenylacetylenes providing boron incorporated products.
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lead to the coupled product or to the coupled product bearing an
ortho boronic ester. The maximally functionalised product is
highly versatile as each functional group can be transformed
chemoselectively making it an ideal intermediate in synthesis.
Acknowledgements
VG thanks the RS for a Newton International Fellowship. We
thank EPSRC (EP/I038071/1) for financial support. We thank C.
Sandford, Dr. Y. Wang, Dr. J. J. Wu, A. Fawcett, Dr. C. Gracía-
Ruiz, G. Casoni & Dr. R. Armstrong for discussions and preparing
certain boronic esters. We thank Prof. H. Ito for assistance with
boronic ester 9i. We thank Dr. Eddie Myers for useful discussions.
Keywords: sp2-sp3 Coupling • 1,2-Metallate rearrangement •
Organoboron • Stereospecific reactions• Phenylacetylenes
Scheme 3. Plausible mechanism for sp2-sp3 coupling and boron incorporation;
[1]
[2]
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Suzuki, Angew. Chem. Int. Ed. 2011, 50, 6722-6737; Angew. Chem.
2011, 123, 6854–6869.
The boron incorporated products provide a rich source of
functionality which can be chemoselectively converted into a
range of diverse products (Scheme 4). Using K2CO3/MeOH the
orthogonal deprotection of the TMS group was achieved providing
the terminal alkyne 11a in 87% yield.[12] Hydration of 10a with 20
mol% triflic acid in TFE furnished ketone 11b in 76% yield.[13]
Under standard CuAAC conditions,[14] 11a was transformed to the
corresponding triazole product 11c in 85% yield. Oxidation of the
boronic ester with H2O2/NaOH and hydroxylamine sulfonic acid
(HSA)[15] gave the desired phenol 11d and aniline 11e in 90 and
62% respectively. Under standard Sonagashira conditions with
iodobenzene, 11a smoothly converted to the functionalized
alkyne 11f in 90% yield.
(a) D. Imao, B. W. Glasspoole, V. r. S. Laberge, C. M. Crudden, J. Am.
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Diane, M. R. Biscoe, J. Am. Chem. Soc. 2014, 136, 14027-14030; (e) D.
Leonori, V. K. Aggarwal, Angew. Chem. Int. Ed. 2015, 54, 1082-1096;
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Alkenes can also be used in place of alkynes but reactions are not as
clean or high yielding (48% yield) as the bromohydrin methyl ether was
also formed from further bromination of the alkene and trapping by MeOH.
See SI for details.
[6]
(a) J. Lam, Chemistry and biology of naturally-occurring acetylenes and
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Compounds (NOARC), Elsevier, 1988; (b) H. C. Kolb, M. G. Finn, K. B.
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[9]
Scheme 4. Synthetic transformations of product 10a.
[10] K. Feeney, G. Berionni, H. Mayr, V. K. Aggarwal, Org. Lett. 2015, 17,
2614-2617.
In summary, we have successfully developed an efficient
enantiospecific sp2-sp3 coupling of a range of aromatic alkynes
with a broad range of enantioenriched boronic esters. The alkyne
acts as a reactive handle for reaction with NBS which triggers the
coupling process. Importantly, conditions were found which either
[11] K. Kubota, Y. Watanabe, H. Ito, Adv. Synth. Catal. 2016, 358, 2379-2384.
[12] U. Dutta, S. Maity, R. Kancherla, D. Maiti, Org. Lett. 2014, 16, 6302-6305.
[13] W. Liu, H. Wang, C.-J. Li, Org. Lett. 2016, 18, 2184-2187.
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[14] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B.
Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210-216.
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2553.
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Entry for the Table of Contents (Please choose one layout)
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The enantiospecific coupling of
secondary and tertiary boronic esters
to aromatics has been investigated.
Using p-lithiated phenylacetylenes and
a range of boronic esters coupling has
been achieved by the addition of NBS.
By tuning the steric environment
around boron, the coupled product with
or without boron can be targeted. The
boron containing product is highly
versatile as each functional group can
be transformed chemoselectively.
V. Ganesh, M. Odachowski, and V. K.
Aggarwal*
Page No. – Page No.
Alkynyl Handle to Promote 1,2-
Metallate Shifts: Enantiospecific sp2-
sp3 Coupling of Boronic Esters with
Phenylacetylenes
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