Aluminium-Catalyzed C(sp)?H Borylation of Alkynes

Article abstract of DOI:10.1002/anie.202106216

Historically used in stoichiometric hydroalumination chemistry, recent advances have transformed aluminium hydrides into versatile catalysts for the hydroboration of unsaturated multiple bonds. This catalytic ability is founded on the defining reactivity of aluminium hydrides with alkynes and alkenes: 1,2-hydroalumination of the unsaturated π-system. This manuscript reports the aluminium hydride catalyzed dehydroborylation of terminal alkynes. A tethered intramolecular amine ligand controls reactivity at the aluminium hydride centre, switching off hydroalumination and instead enabling selective reactions at the alkyne C?H σ-bond. Chemoselective C?H borylation was observed across a series of aryl- and alkyl-substituted alkynes (21 examples). On the basis of kinetic and density functional theory studies, a mechanism in which C?H borylation proceeds by σ-bond metathesis between pinacolborane (HBpin) and alkynyl aluminium intermediates is proposed.

Full text of DOI:10.1002/anie.202106216

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Accepted Article
Title: Aluminium-Catalyzed C(sp)−H Borylation of Alkynes
Authors: Dominic R Willcox, Daniel M De Rosa, Jack Howley, Abigail
Levy, Alan Steven, Gary S Nichol, Carole A Morrison, Michael
J Cowley, and Stephen P Thomas
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202106216
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Aluminium-Catalyzed C(sp)−H Borylation of Alkynes
Dominic R. Willcox,[a]+ Daniel M. De Rosa,[a]+ Jack Howley,[a] Abigail Levy,[a] Alan Steven,[b] Gary S.
Nichol,[a] Carole A. Morrison,[a] Michael J. Cowley,*[a] and Stephen P. Thomas*[a]
[a]
D. R. Willcox, D. M. De Rosa, J. Howley, A. Levy, Dr. G. S. Nichol, Prof. C. Morrison, Dr. M. J. Cowley, Dr. S. P. Thomas
EaStCHEM School of Chemistry
University of Edinburgh
Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom
E-mail:
Stephen.Thomas@ed.ac.uk
Michael.Cowley@ed.ac.uk
[b]
Dr. A. Steven
AstraZeneca Pharmaceutical Technology and Development
Macclesfield Campus, Cheshire, SK10 2NA, United Kingdom
+ Authors contributed equally
Supporting information for this article is given via a link at the end of the document.
Abstract: Historically used in stoichiometric hydroalumination
chemistry, recent advances have transformed aluminium hydrides
into versatile catalysts for the hydroboration of unsaturated multiple
bonds. This catalytic ability is founded on the defining reactivity of
aluminium hydrides with alkynes and alkenes: 1,2-hydroalumination
of the unsaturated π-system. This manuscript reports the aluminium-
hydride catalyzed dehydroborylation of terminal alkynes. A tethered
intramolecular amine ligand controls reactivity at the aluminium
hydride centre, switching off hydroalumination and instead enabling
selective reactions at the alkyne C–H σ-bond. Chemoselective C‒H
borylation was observed across a series of aryl- and alkyl substituted
alkynes (21 examples). On the basis of kinetic and density functional
theory studies, a mechanism in which C–H borylation proceeds by σ-
bond metathesis between pinacolborane (HBpin) and alkynyl
aluminium intermediates is proposed.
alumination. The resulting alkynyl aluminium species react with
HBpin to provide alkynyl boronic esters and regenerate the
aluminium hydride. This C–H borylation is complementary to the
typical reactivity of transition metal catalysts with HBpin and
alkynes, which overwhelmingly results in hydroboration.[8]
Scheme 1. (a) Stoichiometric hydroalumination of alkynes. (b) Catalytic
aluminium-hydride reactivity with alkynes. (c) Hydroalumination versus C–H
alumination of alkynes.
Alkyne hydroalumination is a textbook application of main group
species for organic synthesis.[1] The intermediate alkenyl
aluminium compounds are rarely isolated, but rather treated in
situ with electrophiles to give functionalized alkenes.[2] Recently,
we[3] and others[4] have rendered these reactions catalytic and
increased the breadth of aluminium catalysis beyond Ziegler-
Natta processes, reduction (Meerwein-Ponndorf-Verley) and
Lewis acid catalysis.[5]
Aluminium-catalyzed hydroboration combines the prototypical
alkyne hydroalumination with
a turnover step that uses
pinacolborane (HBpin) to provide boronic esters and regenerate
the aluminium hydride catalyst. However, these reactions were
limited to the preparation of alkenyl- and alkyl boronic esters.[3–4]
We thus sought to develop Al–C bond forming reactivity of
aluminium hydrides that is not based on hydroalumination, and
open aluminium catalysis to the synthesis of other classes of
boronic ester.[6] Particularly promising in this regard was the work
of Roesky and Zhu, who reported an Al/N frustrated Lewis pair for
the stoichiometric dehydrogenative alumination of heterocycles
and alkynes.[7]
To
favour
dehydrogenative
C–H
alumination
over
Here, we report an aluminium-catalyzed dehydrogenative C–H
borylation. Using the in situ generated tethered Lewis pair catalyst
1a, we ‘switch off’ alkyne hydroalumination to favour C–H
hydroalumination, we designed the aluminium dihydride 1a by
adapting principles from previously reported aluminium- and
1
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boron-based intramolecular FLPs.[7,9] Our hypothesis was that the
rigid aromatic backbone bearing a ‘hard’ amine donor ortho to the
aluminium centre would increase the basicity of the aluminium
hydrides, and quench the Lewis acidity of the aluminium centre.
A boron analogue of the aluminium dihydride 1a reacts with
alkynes by hydroboration,[9b] reflecting the low barrier for that
reaction (compared to deprotonation). We carried out preliminary
DFT calculations [ωB97XD/6-311++G(d,p)] to examine the
relative barriers to alkyne hydroalumination and dehydrogenative
C–H alumination. Computationally, the anilino-ligand of the alane
1a provides substantial energetic discrimination between the two
pathways, with the activation barrier for hydroalumination being
9.1 kcal mol-1 higher than that predicted for C–H alumination
(Scheme 1, c).
Table 2. Scope of C–H borylation of terminal alkynes and their applications.
The prediction of good discrimination between the two
possible pathways encouraged us to seek experimental
verification. We have previously used alkylalanes and HBpin to
generate catalytically-active aluminium hydrides under reaction
conditions.[3] Adopting the same concept, we prepared the
dimethylalane 1b in 54% yield by reaction of 2-lithio-N,N-
dimethylaniline with Me2AlCl, as a precursor to the dihydride 1a.
The dimethylalane 1b is a pre-catalyst for C–H borylation of
alkynes, generating dihydride 1a in situ. Reaction of 1-ethynyl-4-
fluoro-benzene with HBpin in the presence of dimethylalane 1b
(10 mol%) gave only trace amounts of alkynyl boronic ester 3 at
room temperature (Table 1). At higher temperatures, we observed
formation of alkynyl boronic ester 3 (30%), dihydrogen and
significant hydroboration (entries
2 and 3). That alkyne
hydroboration was competitive with C–H borylation seemed at
odds with the predicted large barrier to hydroalumination by 1a
(Scheme 1, c). Furthermore, Roesky and Zhu reported high
selectivity for dehydrogenative alumination of alkynes with a
related aluminium dihydride.[7] We postulated that the
hydroboration product could instead be the result of hidden BH3-
catalyzed hydroboration.[10] Monitoring the reaction of 1b with
HBpin by 11B NMR spectroscopy revealed signals attributable to
BH3 (SI section 2.3). The same was observed when monitoring
catalytic reactions.
Table 1. Catalyst optimization.
Entry
Conditions
3 (%)
trace
30
4 (%)
trace
8
1
2
3
4
5
6
r.t.
60 °C
80 °C
50
14
20
8
Yields determined by 1H NMR spectroscopy using 1,3,5-trimethyoxybenzene as
an internal standard (isolated yields in parentheses). Reaction conditions:
substrate (1.0 mmol), HBpin (1.2 mmol), 1,5-hexadiene (0.8 mmol), 1b (0.1
80 °C with 0.1 equiv. 1,5-COD
80 °C with 1.0 equiv. 1,5-COD
80 °C with 0.8 equiv. 1,5-hexadiene
72
a
b
mmol), CHCl3 (1.0 mL), 80 °C, and 16 h. 0.5 mmol of substrate. Yield
determined by 19F NMR spectroscopy with fluorobenzene as an internal
standard. c 20 mol% 1b.
89
90
3
To suppress the unwanted reaction of BH3 with the substrate, we
investigated the addition of dienes as BH3 traps (see SI section
2.2). Reaction in the presence of 0.1 equivalents of 1,5-
cyclooctadiene (COD) showed the formation of cylcooctenyl-B-9-
Yields determined by 19F NMR spectroscopy using fluorobenzene as an internal
standard 1,5-COD = 1,5-cyclooctadiene.
2
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BBN, and increased selectivity for the C–H borylation product
(72:20, Table 1, entry 4). Using 1 equivalent of COD further
improved the yield and selectivity (entry 5). 1,5-Hexadiene[11]
gave the greatest selectivity (entry 6, see also SI section 2.2).
Control reactions confirm that pre-catalyst 1b is responsible
for C−H borylation. Reactions in the absence of 1b led only to
recovery of starting materials. The bifunctional alane-amine
structure of 1b is required for C–H borylation: neither PhAlMe2
alone nor in combination with an external amine (N,N-
dimethylaniline) are active for catalytic C−H borylation.
corresponding to the formation of 10% of borylated product
(Scheme 2). The total consumption of substrate during the initial
period was always equivalent to the catalyst loading (see SI 8.2).
Accompanying this, we observed the generation of CH4 by 1H and
13C NMR spectroscopy, and MeBpin in the 11B NMR spectrum.
Using D-4-fluorophenylacetylene d1-2k, DCH3 was observed. The
simultaneous observation of methane and MeBpin suggests two
concurrent pathways for pre-catalyst activation. We thus
examined in turn the stoichiometric reactivity of the dimethylalane
pre-catalyst 1b with alkyne and HBpin.
We next examined the substrate scope of the Al-catalyzed
C–H borylation (Table 2). Ortho-, meta-, and para-substituted
arylalkynes 3b-d showed equal reactivity and selectivity for C–H
borylation over hydroboration. Anisole and aniline derivatives 3f-
g, competing Lewis bases, did not perturb reactivity or selectivity.
Reaction of dialkyne 3h proceeded to give the diborylated species.
A CF3 group led to substantially reduced reactivity (3i), which was
not observed for aryl chloride or fluoride substituents (3j-k).
Chemoselectivity was maintained with a thiophene-substituted
alkyne 3l and an internal alkene 3o. Ethynylcyclopropane 3q
reacted without observable ring-opening, and the trimethylsilyl
group in 3r was retained. An alkyl chloride 3s, thiol ether 3t and
ether 3u were all tolerated with no substitution or elimination
observed. The synthetic utility of the alkynyl boronic esters was
Scheme 3. (a) Formation and reactivity of tris(phenylacetylide)aluminium-N,N-
dimethylaniline 6. (b) Formation and reactivity of 1b-HBpin adduct 7. (c)
Proposed catalyst activation pathways. Thermal ellipsoids shown at 50%
probability level. Hydrogen atoms except B–H omitted. aYield determined by
comparison to N,N-dimethylaniline. [23]
demonstrated by Carboni-Lindsey reaction with
a
1,2,4,6-
tetrazine[12] to give
a
pyridazine 4. and BH3-catalyzed
hydroboration to give a diborylated alkene 5.[10a]
Under reaction conditions there are two possibilities for
generating the active aluminium dihydride catalyst 1a from the
dimethyl pre-catalyst 1b. Al/B exchange with two equivalents of
HBpin would generate 1a and MeBpin.[3] Alternatively,
deprotonation of the alkyne by 1b would generate methane[13] and
a bis(alkynyl)aluminium compound which could enter the catalytic
cycle after Al/B exchange.
Scheme 2. Reaction profile using 4-fluorophenylacetylene 2k, monitored by 19
F
NMR spectroscopy.
Using 19F NMR spectroscopy, we monitored the reaction of 4-
fluorophenylacetylene 2k with HBpin in the presence of 10 mol%
pre-catalyst 1b at 80 °C (Scheme 2). In the initial stages of the
reaction, alkyne consumption and product formation were rapid.
After this initial period, the rate of reaction decreased. In the first
10 minutes, approximately 10% of the substrate was consumed,
Reaction of pre-catalyst 1b with excess phenylacetylene rapidly
generated the tris-acetylide species 6, which was structurally
characterized (Scheme 3, a). The formation of the tris-acetylide 6
results from protonolysis of all Al–C bonds in 1b, generating
methane and N,N-dimethylaniline, which coordinates to the
aluminium centre. Under catalytic conditions this would generate
3
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methane (as observed) and an alkynyl-aluminium species which
would then undergo Al/B exchange with HBpin to generate the
product 3a. Treatment of the tris-acetylide 6 with HBpin gave
alkynyl boronic ester 3a in a reduced yield (39%). The tris-
acetylide 6 is not catalytically active, presumably because the
dimethyl-aniline unit is no longer covalently attached to the
aluminium centre.
calculations, with pathway (a) having a much higher barrier to
activation (28.7 kcal mol-1) compared to the alkyne-deprotonation
pathway (b) (18.7 kcal mol-1) (Figure 1).
From our initial kinetic study, it is clear that catalyst
activation generates product more rapidly than under steady-state
conditions. Thus, alkyne deprotonation is more rapid from the
dimethyl aluminium pre-catalyst 1b than the dihydride catalyst 1a,
in line with the expected reactivity differences of alkyl- and
hydrido-aluminium compounds.[14]
Dividing the reaction into two phases, we determined rates
for the initiation phase with rate k1 and ‘turnover’ phase with rate
k2. Using time-normalization kinetics,[15] the order of the reaction
in each component was determined for the ‘turnover’ phase (k2)
(Scheme 4, a). The reaction was found to be 1st order with respect
to alkyne, and 2nd order with respect to catalyst, suggesting the
active catalyst 1a exists in solution largely as a dimer, [1a]2, which
is reacting directly with alkyne in the rate-limiting step.
Figure 1. DFT-computed free energies for the two possible catalyst activation
pathways of 1a. (Energies calculated at ωB97XD/6-311++G(d,p) on ωB97XD/6-
31+G(d,p)-optimised structures).
Scheme 4. (a) Reactant orders from variable time normalization analysis
(VTNA). (b) Kinetic isotope effect with D-4-fluorophenylacetylene d1-2k and
DBpin.
Figure 2. Crystal structure of dihydride oligomer 8. Thermal ellipsoids shown at
50% probability level. Hydrogen atoms except Al–H omitted.[23]
With HBpin, pre-catalyst 1b gave the adduct 7 at room
temperature, indicated by the observation of a signal in the 11B
1
NMR spectrum at δ 6.0 (d, JB–H = 135 Hz). Crystallography
revealed coordination of the amine of 1b to the boron centre of
HBpin. The aluminium centre is maintained as four-coordinate by
coordination of an HBpin oxygen. Heating 7 to 80 ºC generated
MeBpin; we infer corresponding formation of the Al–H
functionality. When 7 is heated in the presence of alkyne, rapid
formation of borylated alkyne 3, MeBpin and CH4 occurs, as
observed in catalysis (Scheme 3, b).
Based on these observations, we propose that catalyst
activation occurs through two distinct and concurrent pathways to
give the common Al–H catalyst 1a. In pathway (a), Al/B exchange
with HBpin generates MeBpin and Al–H functionality. In pathway
(b), deprotonation of the alkyne by 1b generates methane and
alkynyl-aluminium species which can undergo Al/B exchange with
HBpin, generating product and the Al–H catalyst 1a (Scheme 3,
c). Both of these pathways were found to be viable by DFT
Consistent with the presence of an oligomeric catalyst species
under reaction conditions,[16] attempts to isolate the dihydride 1a
(by reaction of 2-lithio-N,N-dimethylaniline with H2AlCl), gave a
tetrameric aluminium species 8. The alane 8 is formally a tetramer
of 1a (i.e. the molecular formulae of 8 and 4[1a] are the same).
The tetramer 8 can be considered a hydride-bridged dimer of an
AlH3 adduct of a bis(anilino)aluminium hydride (Figure 2). Each
4
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aluminium centre in the tetramer 8 is 5-coordinate. The tetramer
alkyne to form the zwitterionic acetylide 9, necessitating cleavage
of a bridging Al–H bond. Subsequent H2 elimination precedes Al/B
exchange which occurs by σ-bond metathesis (as during catalyst
activation), regenerating the bridged aluminium dihydride [1a]2.
As main group compounds continue to find increasing use
as catalysts[21] chemists will need new strategies to control
reactivity at the main-group centre, mirroring the journey to
establish ligand design principles in transition-metal chemistry.[22]
Here, we have shown how a pendant amine functionality can alter
the preference of aluminium for hydroalumination of alkynes and
instead enable selective catalytic functionalization of the C‒H σ
bonds. Our findings suggest new principles for ligand design in
the growing field of aluminium-catalyzed functionalization.[3–4] We
8
is catalytically competent for dehydrogenative alkyne
hydroboration, though a significant level of hydroboration was
observed, presumably catalyzed by AlH3 released from the
tetramer 8.[3] Using DFT [ωB97XD/6-311++G(d,p)]), we
calculated the relative energies of the catalyst 1a, dimeric catalyst
[1a]2, [anilino]2AlH·AlH3, and its hydride-bridged dimer 8. All four
compounds were within 4.4 kcal mol-1 of each other (see SI 9.5).
Returning to the kinetic studies, we sought preliminary
evidence for the operative catalytic mechanism beyond the
catalyst activation stage. We determined kinetic isotope effects in
the “turnover” phase of the reaction (i.e. k2) using both DBpin and
D-4-fluorophenylacetylene (d1-2k), substituting each reagent in
turn and then both together (Scheme 4, b). Both the B–H and C–
are currently undertaking
a detailed mechanistic study to
2
H bond KIE values are small (kH/kD B‒H 1.5; C‒H 1.4). H NMR
establish the precise nature of the catalytic cycle in this reaction.
spectra during these experiments excluded isotopic scrambling
between starting materials as an explanation for the small isotope
effects.[17]
Acknowledgements
We can readily exclude σ-bond metathesis of Al–C and B–
H bonds as the rate-limiting step in the C–H borylation of alkynes
by the catalyst 1a since: i) the reaction is zero order in HBpin and,
ii) kH/kD(B‒H), at 1.5, is substantially smaller than expected for a
process in which σ-bond metathesis is rate-limiting.[18] We instead
explain the observed value of kH/kD(B‒H) as a Al‒H/Al‒D isotope
effect, since HBpin generates Al–H functionality during activation
and in the catalytic cycle (see below).
S.P.T. thanks the Royal Society for a University Research
Fellowship (URF/R/191015). D.R.W. and S.P.T. thank the Royal
Society for funding a PhD studentship (RGF/EA/180218). M.J.C.,
S.P.T. and D.M.D.R. thank AstraZeneca, the EPSRC and
CRITICAT CDT for funding a PhD studentship (EP/LO161419/1).
We acknowledge the EaStCHEM Research Computing Facility
and the Edinburgh Compute and Data Facility for access to
software and high-performance computing resources. This
project has received funding from the European Research
Council (ERC) under the European Union's Horizon 2020
research and innovation programme (grant agreement no. ERC‐
2016‐STG‐716315).
Scheme 5. Proposed catalytic cycle.
Keywords: aluminium • borylation • catalysis • σ-bond
metathesis • main-group
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[18]
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10.1002/anie.202106216
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The aluminium-hydride catalyzed dehydroborylation of terminal alkynes is reported. By using a tethered intramolecular amine Lewis
base as a ligand at the aluminium hydride centre, reactivity is controlled, switching off hydroalumination and instead enabling
selective reactions at the alkyne C–H σ-bond.
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