Enantiospecific Alkynylation of Alkylboronic Esters

Article abstract of DOI:10.1002/anie.201600599

Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction. The process involves use of α-lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel-type reactions has not previously been explored. The resulting functionalized 1,1-disubstituted alkenes undergo facile base-mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl-protected alkynes can be formed by simply introducing a suitable carbon- or silicon-based electrophile after the base-mediated 1,2-elimination reaction. Enantiospecific alkynylation: Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction to give alkynes in high yield and essentially complete enantiospecificity.

Full text of DOI:10.1002/anie.201600599

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International Edition: DOI: 10.1002/anie.201600599
German Edition: DOI: 10.1002/ange.201600599
Boronic Ester Reactions
Enantiospecific Alkynylation of Alkylboronic Esters
Yahui Wang, Adam Noble, Eddie L. Myers, and Varinder K. Aggarwal*
Abstract: Enantioenriched secondary and tertiary alkyl pina-
colboronic esters undergo enantiospecific deborylative alky-
nylation through a Zweifel-type alkenylation followed by a 1,2-
elimination reaction. The process involves use of a-lithio vinyl
bromide or vinyl carbamate species, for which application to
Zweifel-type reactions has not previously been explored. The
resulting functionalized 1,1-disubstituted alkenes undergo
facile base-mediated elimination to generate terminal alkyne
products in high yield and excellent levels of enantiospecificity
over a wide range of pinacolboronic ester substrates. Further-
more, along with terminal alkynes, internal and silyl-protected
alkynes can be formed by simply introducing a suitable
carbon- or silicon-based electrophile after the base-mediated
1,2-elimination reaction.
S
tereoselective methods for the synthesis of alkynes[1,2] have
received renewed interest as a result of their considerable
synthetic utility across an array of modern reactions, including
click reactions with azides,[3] gold-catalyzed cycloisomeriza-
tion,[4] and enyne/diyne metathesis.[5] Alkyne-substituted
stereocenters can be installed with high enantioselectivity
by a number of methods, including the asymmetric addition of
acetylides to carbonyls,[6] transformation of chiral aldehydes
or ketones into the corresponding alkynes,[7] and copper-
catalyzed allylic substitution reactions.[8] As an alternative, we
considered stereospecific conversion of chiral alkylboronic
esters into alkynes because alkylboronic esters themselves are
versatile intermediates that can be readily prepared with high
enantioselectivity using a variety of methods,[9] including by
a lithiation–borylation method developed within our labora-
tory.[10]
Scheme 1. Alkynylation of alkyl boron species.
this approach is only applicable to symmetric trialkylboranes
(BR3)[13,14] and borinic esters (BR2OR),[15] which suffer from
a number of drawbacks, including difficulty in preparing an
enantioenriched form, poor stability, and the poor atom
economy of subsequent transformations (two R groups are
wasted in borane transformations). As such, the majority of
examples involve simple, non-chiral boron reagents and the
only enantiospecific examples utilize secondary borinic esters
that require lengthy syntheses.[15d,e] Furthermore, these meth-
ods are not applicable to direct synthesis of terminal alkynes
and cannot be used to access alkynes with a-quaternary
stereocenters.
Compared to boranes and borinic esters, boronic esters
[BR(OR)2] are atom-economic substrates, which are easier to
prepare and handle; however, they do not undergo alkyny-
lation reactions owing to the reversibility of alkynyl boronate
complex formation.[15c] Here, the addition of electrophiles
leads to trapping of the acetylide and recovery of the boronic
ester starting material (Scheme 1B, pathway (i)).[16] In con-
trast, vinyl boronate complexes of alkylboronic esters are
much more stable with respect to fragmentation and undergo
facile electrophile-induced 1,2-migration and deboronation
The Suzuki–Miyaura reaction could potentially be used to
transform boronic esters into alkynes in conjunction with an
alkynyl halide. However, the use of chiral boronic acids/esters
in such cross-coupling reactions is not known; the only
reported examples are those that utilize primary sp3-, sp2-, and
sp-type boron species, which are compounds that undergo
facile transmetalation.[11,12] Another attractive method
involves electrophile-induced 1,2-migration of an alkynyl
boronate followed by deboronation (Scheme 1A). However,
[*] Dr. Y. Wang, Dr. A. Noble, Dr. E. L. Myers, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201600599.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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by the so-called Zweifel olefination.[17] We questioned
into 4a, prompted us to conduct the transformation at a lower
whether alkynes could be generated using a variant of this
transformation by implementing suitably functionalized vinyl
anions that would allow the resulting substituted alkene
(Zweifel product) to undergo elimination and thereby
unmask the alkyne (Scheme 1B, pathway (ii)).[18] Such
a method would enable the use of readily available alkylbor-
onic esters to prepare chiral alkynes that are not easily
accessed using established methods. Herein, we report the
development of an alkynylation method that enables enan-
tiospecific transformation of structurally diverse secondary
and tertiary pinacolboronic esters into terminal and internal
alkynes.
To test our strategy, we started with commercially
available vinyl bromide 2a, which can be lithiated at the a-
position with LDA at low temperature.[19] Initially, we focused
on optimizing conditions for the preparation of bromoalkene
intermediate 3a (Table 1). Treatment of a THF solution of
temperature (À958C) and increase the relative amounts of
vinyl bromide and LDA used (2.0 equiv). Under these
conditions, conversion into 3a was improved and 4a was not
detected (entry 4, Table 1). Finally, conducting the reaction in
Et2O, whilst adding both vinyl bromide and LDA as solutions
in THF[21] (Et2O/THF 3:2) gave a 96% conversion to 3a
(entry 6, Table 1). Use of this mixture of solvents was superior
to exclusive use of either THF or Et2O, the latter leading to
complete recovery of starting material (entries 5 and 7,
Table 1).
Once an efficient process was established for generating
the 1,1-bromoalkylalkene 3a, we investigated a variety of
conditions for effecting dehydrobromination. Our attempts to
unmask the alkyne in situ, by addition of basic reagents after
treatment with I2/MeOH, only led to isolation of 3a.
However, subsequent work-up and treatment of a solution
of crude 3a with either TBAF (5.0 equiv, DMF, 608C, 1 h)[22]
or LDA (2.6 equiv, THF, À788C to RT)[23] led to isolation of
alkyne 6a in good yield and with complete enantiospecificity
(Scheme 2). Using the optimized conditions, we converted
a variety of enantioenriched secondary boronic esters 1 into
their corresponding alkynyl derivatives 6 (Scheme 2). The
transformation occurred cleanly in the presence of cyclo-
propyl, alkene, azide, electron-rich aryl, silyl ether, and tert-
butyl ester functional groups, and showed essentially com-
Table 1: Optimization of conditions for generating 1,1-bromoalkyl-
alkenes from alkylboronic esters.
Entry[a]
LDA/2a
T [8C]
Solvent
I2
3a:1a:4a[b]
(x equiv)
(y equiv)
1
2
3
4
1.3
1.3
1.3
2.0
2.0
2.0
2.0
À78
À78
À78
À95
À95
À95
À95
THF
TBME
Et2O
Et2O
THF
Et2O
Et2O
1.5
1.5
1.5
2.2
2.2
2.2
2.2
49:51:0
79:18:3
81:14:5
87:13:0
91:9:0
5[c]
6[c]
7[d]
96:4:0
0:100:0
[a] Reactions were conducted using 1a (0.15 mmol) in solvent (1.0 mL;
not including the solvent used to add 2a and LDA); I2 was added as
a solution in MeOH (2.0 mL). [b] Ratio determined by GC-MS analysis of
the crude reaction mixture. [c] Using LDA (0.86m in THF). [d] Using 2a
(1.0m in Et2O). TBME=tert-butyl methyl ether; pin=pinacol; LDA=
lithium diisopropylamide.
vinyl bromide (2a, 1.3 equiv) and secondary boronic ester 1a
at À788C with LDA (1.3 equiv) presumably generated vinyl-
boronate 5, which, after addition of a methanolic solution of I2
(1.5 equiv) and subsequent warming to room-temperature,
gave the required alkene 3a together with starting material 1a
in a circa 1:1 ratio (entry 1, Table 1). Switching the solvent to
less coordinating TBME (tert-butyl methyl ether) or Et2O
(albeit with some THF present owing to 2a being added as
a 1.0m solution in THF) led to increased conversion to 3a.
However, small amounts of insertion product 4a, a compound
formed by 1,2-migration of vinylboronate 5, were also
detected (entries 2 and 3, Table 1).[20] The significant amounts
of 1a recovered (likely because of the instability of 1,1-
lithiobromoethene)[19b,d,e] and competing rearrangement of 5
Scheme 2. Scope of alkynylation of secondary boronic esters. Reactions
were carried out with 1 (0.30 mmol), 2a (1.0m in THF, 0.60 mmol),
LDA (0.86m in THF, 0.60 mmol), I2 (0.66 mmol), and TBAF·3H2O
(1.5 mmol). [a] LDA (0.86m in THF, 0.75 mmol) was used instead of
TBAF for dehydrobromination. [b] TIPSCl was added after dehydrobro-
mination with LDA. The higher yield of 6h’ was attributed to the
volatility of 6h. TBAF=tetra-n-butylammonium fluoride; TBDPS=tert-
butyldiphenylsilyl; TBS=tert-butyldimethylsilyl; TIPS=triisopropylsilyl;
PMP=para-methoxyphenyl.
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plete enantiospecificity. The alkynylation method was also
successfully applied to hindered boronic ester 1h, derived
from menthol, leading to alkynes 6h/6h’.
Alkynylation of tertiary boronic esters was more chal-
lenging. Using conditions optimized for the alkenylation of
secondary boronic esters, only 42% of substrate 1j was
converted into vinyl bromide 3j, and significant amounts of
insertion product 4j and starting material were also detected
(10% and 48%, respectively; Scheme 3). Presumably,
Scheme 3. Zweifel reaction of tertiary benzylic boronic esters.
Scheme 4. Alkynylation of tertiary and hindered secondary boronic
esters. Reactions were carried out with 1 (0.3 mmol), 2b (0.4 mmol),
LDA (0.4 mmol), I2 (0.4 mmol), and tBuLi (0.75 mmol). [a] 2b
(1.2 mmol) and LDA (1.2 mmol) were used.
increased steric hindrance close to the boron atom slows
both vinyl boronate formation and subsequent electrophilic
activation, thus allowing decomposition of the vinyllithium
reagent and 1,2-migration of the vinyl boronate to become
competing reaction pathways. In an effort to diminish side-
reactions, we investigated the use of vinyl carbamate 2b
(readily prepared from THF, nBuLi, and CbCl (Cb = N,N-
iPr2NCO))[24] in place of vinyl bromide 2a. We anticipated
that the corresponding vinyllithium species would be more
stable with respect to decomposition, and that the poorer
leaving-group ability of the carbamate would engender slower
1,2-migration and faster electrophilic activation of the
corresponding vinyl boronate. Indeed, treating a THF solu-
tion of vinyl carbamate 2b and tertiary boronic ester 1j with
LDA (À788C, 1 h) followed by I2/MeOH gave the 1,1-O-
carbamoylalkylalkene 3j’ with excellent conversion
(Scheme 3).
Dehydro-O-carbamoylation was effected using either
tBuLi/Et2O or LDA/THF to give the corresponding alkyne
derivative 6j in good yield (89% and 88% yield, respectively,
from 1j in 100% es; Scheme 4). Other enantioenriched
tertiary boronic esters, including alkene-bearing, diaryl, and
non-benzylic substrates, were converted into their alkyne
derivatives in good yield and with complete enantiospecificity
(6k–m, Scheme 4). Sterically hindered secondary boronic
esters, such as cyclopropyl substrate 1b and cholesterol
derivative 1o, were transformed into the corresponding
alkyne derivatives 6b and 6o[25] in good yield and enantio-/
diastereospecificity using the vinyl carbamate technique. By
comparison, boronic esters 1b and 1o produced low to
moderate yields when vinyl bromide was used as the reagent.
Pleasingly, double alkynylation of 1,2-bis(boronic ester) 1n
was also achieved to give 1,2-diyne 6n in high yield and
enantiospecificity. However, application of the alkynylation
procedure to allylic boronic ester 1p failed because the
intermediate vinyl boronate complex reacted with iodine as
an allylic metal reagent, leading to fragmentation.[10f]
The alkynylation of secondary benzylic boronic esters
presented additional challenges owing to the enhanced acidity
of the sp3 benzylic center. Under the optimized conditions
enantioenriched substrate 1q was converted into vinyl
carbamate intermediate 3q’ in excellent yield. However,
t
subsequent elimination with BuLi resulted in significant
racemization, with the alkyne product 6q being formed in
78% yield but with only 22% es (entry 1, Table 2). We
t
hypothesized that the excess BuLi present after elimination
resulted in post-reaction racemization and that this process
could be prevented by reducing the amount of base used.
t
Indeed, reducing the stoichiometry of BuLi from 2.5 to
1.1 equivalents led to much improved enantiospecificity
(essentially complete), albeit with a concomitant reduction
in yield (entries 1–4, Table 2). Interestingly, use of LDA
resulted in considerably higher levels of racemization
(entries 5 and 6, Table 2).
Finally, we wished to demonstrate the versatility of the
alkynylation method by extending it to the synthesis of
internal and protected alkynes. This was achieved by taking
advantage of the acetylide intermediate, which formed upon
elimination of bromide or carbamate en route to the alkyne
and could be trapped with a variety of electrophiles. For
example, carbon electrophiles produced internal alkynes 7
and 8, whereas silyl chlorides generated alkyne 9; all in very
high yield (Scheme 5).
In summary, enantioenriched secondary and tertiary
boronic esters can be alkynylated in good yield and with
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Table 2: Alkynylation of secondary benzylic boronic esters.
Keywords: alkynes · alkynylation · boronic esters ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4270–4274
Angew. Chem. 2016, 128, 4342–4346
Entry[a]
Base (x equiv)
conv. [%][b] yield [%][b] e.r.[c]
es [%]
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1
2
3
4
5
6
tBuLi
tBuLi
tBuLi
tBuLi
LDA
(2.5)
(2.0)
(1.5)
(1.1)
(2.5)
(1.1)
>99
>99
75
60
>99
49
78
70
60
43 (37)
87
61:39 22
76:24 53
95:5
98:2
50:50
92
98
0
LDA
39
63:37 27
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Scheme 5. Trapping of intermediate acetylides with electrophiles.
high levels of enantiospecificity using a method involving
a Zweifel-type olefination followed by a 1,2-elimination
reaction. Either vinyl carbamates or vinyl bromides can be
employed; the former demonstrates a broader substrate
scope (applicable to secondary and tertiary boronic esters),
whereas the latter can be eliminated using mild base (TBAF).
Owing to the variety of functional groups into which alkynes
can be transformed, we believe that these methods signifi-
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organic molecules could be prepared from boronic ester
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We acknowledge financial support from a Horizon 2020
Marie Skłodowska-Curie Fellowship (EMTECS/652890) and
the EPSRC (EP/I038071/1). We thank Dr. Daniel Blair,
Alexander Fawcett, Christopher Sandford and Marcin Oda-
chowski for valuable discussions and for preparing boronic
esters. We thank Dr. Hazel Sparkes for X-ray analysis of 6o.
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[25] X-ray crystallography of the cholesterol-derived product 6o
allowed us to confirm that the alkynylation of boronic esters
proceeds with retention of stereochemistry. CCDC 1439386
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[16] This pathway was predominant in our initial investigations of the
reaction of alkynyl boronates of pinacol boronic esters with I2.
Received: January 19, 2016
Published online: March 2, 2016
4274 www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 4270 –4274