Kinetics and Mechanism of the Arase-Hoshi R2BH-Catalyzed Alkyne Hydroboration: Alkenylboronate Generation via B-H/C-B Metathesis

Article abstract of DOI:10.1021/jacs.9b10114

The mechanism of R₂BH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ ¹⁹F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labeling (¹⁰B/²H), and density functional theory (DFT) calculations. For the Cy₂BH-catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-Markovnikov addition product ArCH = CHBCy₂. Irreversible and turnover-rate limiting reaction with pinacolborane (k ≈ 7 × 10^-3 M^-1 s^-1) regenerates Cy₂BH and releases E-Ar-CH═CHBpin. Two irreversible events proceed in concert with turnover. The first is a Markovnikov hydroboration leading to regioisomeric Ar-C(Bpin)═CH₂. This is unreactive to pinacolborane at ambient temperature, resulting in catalyst inhibition every ～10² turnovers. The second is hydroboration of the alkenylboronate to give ArCH₂CH(BCy₂)Bpin, again leading to catalyst inhibition. 9-BBN behaves analogously to Cy₂BH, but with higher anti-Markovnikov selectivity, a lower barrier to secondary hydroboration, and overall lower efficiency. The key process for turnover is B-H/C-B metathesis, proceeding by stereospecific transfer of the E-alkenyl group within a transient, μ-B-H-B bridged, 2-electron-3-center bonded B-C-B intermediate.

Full text of DOI:10.1021/jacs.9b10114

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Article
Kinetics and Mechanism of the Arase-Hoshi R2BH-Catalyzed Alkyne
Hydroboration: Alkenylboronate generation via B-H/C-B Metathesis
Eduardo Nieto-Sepulveda, Andrew D. Bage, Louise A Evans, Thomas
A. Hunt, Andrew G. Leach, Stephen P Thomas, and Guy C. Lloyd-Jones
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10114 • Publication Date (Web): 26 Oct 2019
Downloaded from pubs.acs.org on October 27, 2019
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Kinetics and Mechanism of the Arase-Hoshi R2BH-Catalyzed Alkyne
Hydroboration: Alkenylboronate generation via B-H/C-B Metathesis.
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ò
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Eduardo Nieto-Sepulveda, Andrew D. Bage, Louise A. Evans, Thomas A. Hunt,Õ Andrew G. Leach,
†
†
Stephen P. Thomas*, and Guy C. Lloyd-Jones*,
† EaStChem, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK
Õ Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.
‡ School of Health Sciences, Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK
ABSTRACT: The mechanism of R2BH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ
19F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labelling (10B/2H), and density functional theory
(DFT) calculations. For the Cy2BH catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-
Markovnikov addition product ArCH=CHBCy2. Irreversible and turnover-rate limiting reaction with pinacolborane (k ~7´10-3 M-1s-
1) regenerates Cy2BH and releases E-Ar-CH=CHBpin. Two irreversible events proceed in concert with turnover. The first is a Mar-
kovnikov hydroboration leading to regioisomeric E-Ar-CH(Bpin)=CH2. This is unreactive to pinacolborane at ambient temperature,
resulting in catalyst inhibition every ~102 turnovers. The second is hydroboration of the alkenylboronate to give
ArCH2CH(BCy2)Bpin, again leading to catalyst inhibition. 9-BBN behaves analogously to Cy2BH, but with higher anti-Markovnikov
selectivity, a lower barrier to secondary hydroboration, and overall lower efficiency. The key process for turnover is B-H/C-B me-
tathesis, proceeding by stereospecific transfer of the E-alkenyl group within a transient, µ-B-H-B bridged, 2-electron-3-centre bonded
B-C-B intermediate.
INTRODUCTION
Burke's E-1-Bpin-2-MIDA ethene,13l enantioenriched geminal si-
lylboronates,13m and at multikilo-scale in the preparation of an
alkenylboronate for cyclopropanation.13n However, despite diverse
and extensive application of the Arase-Hoshi hydroboration, re-
markably little mechanistic detail has emerged regarding why it is
highly effective in many cases,13 e.g. Scheme 1, yet fails in others.14
Alkenylboron reagents are ubiquitous in synthesis and pre-eminent
in stereospecific cross-coupling reactions to generate alkenes. In
such reactions, selection of the appropriate reagent can be crucial.1
For example, although vinylboronic acid is not especially prone to
protodeboronation,2 in solution,2b it does polymerize3 and self-con-
dense,4 making protected forms more readily handled.5 Alkenyl-
boronates are valued for their stability,6 and as intermediates in the
synthesis of alkenyl-boronic acid,7a -trifluoroborate,7b -tin,7c and -
aluminium reagents,7d alkenyl iodonium salts,7e allyl boronates,7f
epoxyboronates,7g and cyclopropylboronates.7h
Scheme 1. Selected applicationsof Arase-Hoshi hydroboration.13cln
O
H
B
1pin
O
O
B
(ref 13n)
(ref 13c)
H
O
Cl
30 ºC
5 mol% Cy2BH
Cl
Alkyne hydroboration allows regio- and stereo-selective synthesis
of alkenylboron reagents.8 Although many B-H species hydrobo-
rate alkynes at ambient temperature,8 1,3,2-dioxaborinanes,9a and
1,3,2-dioxaborolanes, such as catecholborane (1cat)9b and pinacol-
borane (1pin),9c are inert.9 This has prompted the development of
numerous catalysts,10,11 and initiators,12 for the process,8 including
Ca, Ti, Zr, Fe, Ru, Ni, Co, Rh, Ir, Cu, Au and Ag com-
plexes/salts,10a-t carboxylic acids,10u amides,10v NaOH,10w Et3P,10x
Al hydrides and alkyls,10yz and a wide range of boron species.11a-o
94 %
38 Kg
O
1cat
H
B
TBSO
OTBS
TBSO
OTBS
O
H
THF, 21 ºC
10 mol% Cy2BH
then NaOH
OTBDPS Me
OTBDPS Me
B(OH)2
97%
H
O
1pin
N
N
B
10 mol% Cy2BH
B
In 1995, Arase and Hoshi reported that Cy2BH and 9-BBN both
efficiently catalyze the regioselective cis-hydroboration of alkynes
with 1cat in THF at ambient temperature.11d The process was later
extended to hydroboration with 1pin, allowing preparation of E-
alkenyl pinacolboronates in good yield,11f without contamination
by metal catalysts. Over the last two decades, the Arase-Hoshi
R2BH-catalyzed alkyne hydroboration11d-g has been deployed ex-
tensively,13 for example in the synthesis of Dictyostatin,13a Man-
delalide A,13b (-)-FR182877,13cd Amphidinolide V,13e (+)-Herbox-
idiene,13f (-)-Bafilomycin A1,13gh Aigialomycin D,13i 1α,25-dihy-
droxyvitamin D analogues,13j Lejimalide B and analogues,13k
O
B
(ref 13l)
O
O
O
O
THF, 85 ºC
84%
O
O
O
O
RESULTS AND DISCUSSION
1. Prior Studies. In their seminal report,11df Arase and Hoshi sug-
gested general mechanism I, Scheme 2, to account for the catalytic
effect of R2BH on alkyne hydroboration. The mechanism is analo-
gous to that proposed in 1990 by Periasamy for catalysis by
[H3B·N(Ph)Et2]11ac and was primarily based on two known stoichi-
ometric processes: the hydroboration of alkynes by dialkyl-
boranes,15 and the thermal redistribution of trialkyl boranes with
borate esters,10v,16 including o-phenylene borate,16b and 1cat.10v
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Thermal redistribution of boranes with borates is catalyzed by B-H
hydroboration, hydroboration, dehydroboration sequence
1
2
3
4
5
6
7
8
boranes.16d It may proceed by B-H/C-B metathesis (pathway Ia), as
suggested by Köster,16d or by alkoxy ligand exchange (B-O/C-B
metathesis; pathway Ib), as suggested by Brown,16b or by analogous
processes where R = H.17
(2®4®5®3; mechanism II) provides a pathway for catalysis.18 In-
dependently prepared 5pinAr is an efficient catalyst for the alkyne
hydroboration process; however, tests for dehydroboration from
5pinAr proved negative.11j This led to the suggestion that Ar3B, or
5pinAr, or analogous RBAr2 species, exert catalysis through the
Lewis-acid polarization19 of the alkyne to facilitate the direct addi-
tion of the pinacolborane 1pin B-H, cis across a formally zwitteri-
onic intermediate (6, mechanism III).11j Vasko, Kamer, and Aldrich
recently reported on alkyne hydroboration catalyzed by a dime-
thylxanthene-based frustrated Lewis pair (FLP).11o It was eluci-
dated that the active catalyst is generated in two stages: the FLP
Scheme 2. Mechanisms I-IV for R2BH/BR3-catalyzed alkyne (2)
hydroboration with a generic 1,3,2-dioxaborolane (1). Key prod-
uct-generating steps are indicated on the left-hand side of each cy-
cle. R = H, alkyl or Ar; L = neutral ligand, e.g. solvent.
O
B
(a) B-H/C-B
R
B
H
O
O
Mechanism I
Ar
9
H
B
O
R
H
Ar
10
11
12
13
14
15
16
17
18
19
20
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22
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E-3
H
H
O
B
R
R
undergoes metathesis with 1pin to generate a (C6F5)2(H)B PAr3
×
2
Ar
complex, and this then reacts with the alkyne (2) to generate E-4 (R
= R = C6F5). By analogy to prior work,11j E-4 was assumed to un-
dergo hydroboration to generate 5pinAr and thus initiate mechanism
III.11o An additional process to be considered is one in which a
borenium–borohydride ion-pair (7, mechanism IV) is generated by
hydride transfer from 1,3,2-dioxaborolane 1 to R3B. Borenium-cat-
alyzed hydroborations involving NHC species are well-de-
scribed.20 Propagation of Arase-Hoshi catalysis by mechanism IV
would require H-transfer to alkyne adduct 8, within the ion-pair
(pathway IVa), or by a chain-reaction involving 1 (pathway IVb).
Mechanisms III and IV are partially analogous to that proposed by
Ingleson for the addition of Lewis-base adducts of 9-BBN to al-
kynes,21 however, the latter proceeds with overall trans addition of
B and H.22
metathesis
H
B
R
B
O
R
H
O
Ar
O
B
R
B
R
E-4
Ar
(x 2)
1
B-O/C-B
(b)
H
H
O
B
R
B
H
Mechanism II
O
R
H
Ar
E-3
Ar
H
H
R
2
R
O
H
B
R
R
H
R
B
H
B
H
B
Ar
H
R
Ar
O
Ar
O
B
dehydroboration
E-4
H
H
H
O
H
B
Herein we report on a mechanistic investigation of Arase-Hoshi hy-
droboration catalysis,11d-g Scheme 1, employing Cy2BH, and 9-
BBN, with 1pin. We have focussed in particular on the mode of ad-
dition of 1pin to p-fluorophenylacetylene (2) with the aim of distin-
guishing stepwise 1,2-addition involving metathesis (mechanism
I), from direct cis-1,2-addition then dehydroboration (mechanism
II), from direct cis-1,2-addition (mechanism III), from stepwise
1,2-addition, that does not involve C-B bond formation with the
catalyst (mechanism IV).
5
O
O
1
R
O
B
H
Mechanism III
Ar
B
R
O
R
Ar
cis-addition
E-3
H
(e.g. 5)
d-
H
d+
B
2
H
d+
O
H
B
O
Ar
d-
R
2. Elimination of 'Uncatalyzed' Reactions. There are conflict-
ing reports in the literature regarding the direct hydroboration of
alkynes by 1,3,2-dioxaborolanes (1)9 Thus, although it is widely
O
O
Ar
B
R
H
R
BR3
6
1
9b
accepted that 1cat is relatively unreactive to simple alkynes, fre-
quently requiring heating under solvent-free conditions,23 pinacol-
(a) ion-pair
O
B
Mechanism IV
R
B
H
9c
borane, 1pin
,
is sometimes reported to react efficiently with al-
d-
R3B
R
kynes at ambient temperature in solution.9c,24,,25 1,3,2-Dioxaboro-
lanes (1) can undergo disproportionation,26 especially in the pres-
ence of nucleophilic Lewis bases,26a to generate borates and BH3.
The latter is a known catalyst for alkyne hydroboration,11mn and
thus impure or aged solutions, of 1pin, or those prepared in situ from
pinacol and H3B·SMe2,9c can contain sufficient BH3 to undergo ef-
ficient but indirect (i.e. catalyzed)11n reaction with alkynes. We be-
gan by confirming25 that, in the absence of a deliberately introduced
catalyst,10,11 1pin does not react with alkyne 2 in solution at 23 °C,
or undergo disproportionation to generate B2pin3 + BH3, and hy-
droboration products thereof. Of a range of solvents explored, a
mixture of dioxane and CHCl3 (1%) emerged as highly effective at
O
O
R
Ar
H
(a)
L
H
d+
E-3
B
O
H
B
(b)
O
O
1
H
Ar
O
O
B
R3BH
O
O
7
B
O
8
B
O
B
O
L
Ar
R3BH
H
H
O
(b) chain
L
Ar
H
2
Ar
H
Whilst the mechanism under Arase-Hoshi catalysis conditions has
not been explored, a number of studies on related alkyne hydrobo-
rations using 1pin, that are catalyzed or initiated12 by [Ar(3–n)BHn]
species have been reported.11i-j,l,n Detailed NMR spectroscopic
studies by Oestreich11i revealed that Ar3B catalyzed hydroboration,
where Ar = 3,5-(CF3)2C6H3), involves in situ Ar3B / 1pin redistribu-
tion to generate a range of species, including dimers of Ar2BH, and
ArBH2. These were proposed to be the active catalysts for alkyne
hydroboration via mechanism I. In contrast, Stephan and Glorius,
found that alkyne hydroboration catalyzed by B(C6F5)3, and by
HB(C6F5)2, involved generation of alkyldiaryl borane intermedi-
ates, including diboryl 5pinAr (Scheme 2, Mechanism II, R = C6F5)
that was isolated and characterized as an isonitrile complex.11j Al-
kyl boranes undergo thermal dehydroboration,17 and a three-stage
stabilizing 1pin,
27 and there was no detectable reaction of 1pin with
2 (600 mM) over a period of 24 hours at ambient temperature (99.9
% 2, 19F NMR spectroscopy; >99% 1pin, <0.2 % B2pin3, 11B NMR
spectroscopy).
3. In situ 19F NMR Spectroscopic Analysis. Addition of Cy2BH
to the stable solution of 1pin and 2 induces catalytic hydroboration,
Scheme 3. Endpoint 19F NMR spectroscopic analysis indicates that
the product mixture contains E-3pin (93%) and three minor compo-
nents, linear alkenylborane E-4Cy (0.3 %), branched alkenylborane
iso-4Cy (1.2 %), and 1,1-diborylalkane 5pinCy (5.4%). Variation of
the catalyst loading led to changes in the relative proportions of the
endpoint reaction products. Diboryl 5pinCy, the product of formal
double hydroboration,28 was always generated in quantities directly
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proportional to the Cy2BH catalyst loading. In contrast, higher
Cy2BH loadings led to reduced quantities of E-3pin
loading, and that 1,1-diborylalkane 5pinCy primarily accumulates af-
1
2
3
4
5
6
7
8
.
ter 2 has been consumed, we sought to test whether E-4Cy and 5pinCy
are intrinsic to the catalytic cycle (e.g. in mechanisms I and II), or
are peripheral to the cycle, e.g. generated by non-productive side
reactions. Preparation of d4-2, in which the aromatic ring is perdeu-
terated, results in an upfield shift (Dd = 0.5 ppm) in the 19F NMR
spectra of d4-2, relative to 2, and analogously into any products
thereof. This facilitates detailed interrogation of mechanisms I-IV,
by way of isotope-entrainment.31
Scheme 3. HBCy2-catalyzed hydroboration of alkyne 2, together
with intermediates and side-products detected by 19F-NMR spec-
troscopy after 12 h at 23 °C.
O
H
B
1pin, 1 equiv.
O
B
O
H
O
Ar
Ar
6.8 mol% Cy2BH
dioxane
E-3pin 93.2%
2, 600 mM
O
B
H
9
Ar = p-F-C6H4
CHCl3 (1% v/v)
23 °C, 12 h, >99%
O
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
p-F-C6D4
1. 1pin (2 equiv.)
Cy
H
Cy
5 mol% Cy2BH
d4-E-3pin
B
p-F-C6H4
d0-2
+
Ar
Cy
Ar
Cy
Cy
O
H
B
dioxane, 23 °C
CHCl3 (1% v/v)
O
H
B
B
H
Cy
H
B
O
Ar
O
p-F-C6H4
2. at 26 % conversion
d0-E-3pin
d4-2 (1 equiv.)
5pinCy 5.4%
E-4Cy 0.3%
iso-4Cy 1.2%
Δ!F = 0.5 ppm
80
In situ 19F NMR spectroscopic monitoring of the reaction evolu-
tion, Scheme 3, indicates that the branched alkenylborane iso-4Cy
is generated in concert with product E-3pin, in a constant ratio of
1:89±1. In contrast, alkenylborane E-4Cy is generated transiently,
reaching a maximum pseudo steady-state concentration after a
short induction period. Increased catalyst loadings result in directly
proportional increases in the concentration of transient alkenyl-
borane E-4Cy.29 In contrast, diboryl 5pinCy is present in low concen-
trations until >99% of alkyne 2 has been consumed. At this stage,
the concentration of product (E-3pin) becomes constant, the concen-
tration of alkenylborane E-4Cy decays to zero, and diboryl 5pinCy ap-
pears in direct inverse proportion to the decay in E-4Cy. Identical
kinetics were obtained in the absence of CHCl3 (1%).30 Changing
from dioxane to THF as solvent had negligible impact on the tem-
poral concentrations of the species detected by 19F NMR spectros-
copy (2, E-3pin, E-4Cy, iso-4Cy, and 5pinCy). Standard graphical anal-
ysis of the concentration of 2 during its Cy2BH-catalyzed reaction
(Scheme 3) with 1pin, and systematic variation in the concentrations
of all three components led to an empirical rate equation d[3pin]/dt
» kobs[Cy2BH]0[1pin]t, consistent with all four mechanisms (I-IV),
under specific constraints.
d4/d0-2
70
60
d4/d0-E-4Cy
isotope entrainment
50
40
30
20
10
0
d4/d0-iso-4Cy
d4/d0-E-3pin
d4/d0-5pinCy
20
30
40
50
60
70
80
90
100
conversion / %
BPin
H
Ar
H
Ar
mech. II
mechs. III, IV
mech. I
or
BR3
R3BH
The generation of E-4Cy, iso-4Cy and 1,1-diborylalkane 5pinCy were
further investigated by stoichiometric reactions. In the absence of
1pin, 1 equiv. of (Cy2BH)n reacted instantly with 2 to give E-4Cy and
iso-4Cy in an 89/1 ratio. Addition of 1 equiv. 1pin to the mixture
cleanly generated 1,1-diborylalkane 5pinCy from E-4Cy, Scheme 4.
The same product (5pinCy) was also cleanly generated on reaction of
isolated purified E-3pin with 1 equiv. HBCy2. Deconvolution of the
direct versus indirect pathways from E-4Cy to 5pinCy (Scheme 4) was
achieved by isotopic labelling, vide infra.
6
8
–Cy2BH
R3B, 1pin
Cy2BH
H
BCy2
H
H
BPin
BCy2
Ar
Ar
Bpin
5pinCy
0→48 % d4
Ar
H
Cy2BH
2
1pin
Ar
E-4Cy
0→71% d4
E-3pin
0→50% d4
0→71% d4
HBCy2
(direct)
H-Bpin (1pin
)
BCy2
iso-4Cy
0→52 % d4
H
Ar
Scheme 4. Stoichiometric hydroboration of alkenylboron spe-
cies.15,28 See text for full discussion of direct versus indirect reac-
Figure 1. Isotope entrainment into the catalytic cycle, confirming
on-cycle productivity of intermediate E-4Cy (® E-3pin) and its indi-
rect conversion to 5pinCy via E-3pin. Open circles: experimental data
(19F NMR spectroscopy) for d4-incorporation (%) versus net con-
version of d4/d0-2 + d4/d0-4Cy into d4/d0-E-3pin, d4/d0-iso-4Cy, and
d4/d0-5pinCy (%). Solid lines: simulation of d4-incorporation based
on the kinetic model in Figure 3. Conditions: 1pin (600 mM), 2 (295
mM), Cy2BH, (30 mM), dioxane/CHCl3 (99:1) at 296 K, with d4-2
(297 mM), added at 26% conversion.
tion pathways from E-4Cy to 5pinCy
.
O
O
HB
HB
O
O
1pin
1pin
H
BCy2
E-4Cy
O
direct
indirect
dioxane
296 K
Ar
B
Cy2B
Ar
O
H
CHCl3
(1% v/v)
metathesis
H
Addition of d4-2 (0.5 equiv.) to a reaction of 2 (0.5 equiv.) and 1pin
(1 equiv.) undergoing turnover (Cy2BH, 5 mol%) induces an iso-
topic perturbation. At the point of addition (26 % total conversion)
the d4/d0-isotope ratio in the substrate pool 2, is immediately raised
from 0% to 71%-d4. In situ 19F NMR spectroscopic monitoring of
the subsequent evolution of the d4/d0-isotope ratios (%) in 2, E-4Cy,
5pinCy
Ar = p-F-C6H4
Cy2BH
hydroboration
O
B
H
O
Ar
E-3pin
4. Validation of Alkenylborane E-4 as an On-Cycle Inter-
mediate. Having identified that E-4Cy is generated at a pseudo
steady-state concentration that corresponds to the Cy2BH catalyst
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iso-4Cy, E-3pin, and 5pinCy, as a function of conversion, Figure 1, re- However, two factors corrupt this analysis: i) for mechanism I, re-
1
2
3
4
5
6
7
8
veals numerous features:
peated catalytic turnover of Cy2BH generates E-3pin with a different
label distribution to the first turnover, see lower section to Scheme
5; and ii) reversible generation of µ-H borane dimers, scrambles the
B-H/D labelling patterns in 1pin / Cy2BH. Neither problem is solved
by stoichiometric reaction between E-4Cy and 1pin, because 1,1-di-
borylalkane 5pinCy is rapidly generated from Cy2BH + E-4Cy
(Scheme 4) when there is no alkyne (2) present.
i) There are no significant reversible reactions connecting 2 with
any intermediates or products, on or off cycle: 2 remains 71%-d4
throughout.
ii) The isotope ratio in transient intermediate E-4Cy grows, in ad-
vance of all other species except for 2 (which undergoes a step-
change at the point of addition) and soon approaches the same level
as 2, i.e. 71%-d4.
To bypass these complications, we conducted single turnover anal-
ysis32 via sequential-additions of Cy2BH (cat.), then RCºCH (R ¹
Ar), then 1pin, to the alkyne 2. As illustrated schematically in the
lower section of Scheme 5, this effects in situ generation of E-4Cy
and its conversion to E-3pin, with the regenerated Cy2BH catalyst
being sequestered in further turnover that converts RCºCH to E-
3'pin via E-4'Cy. The E-3pin emerging from the first turnover is then
separated, and analyzed by 1H and 10/11B NMR spectroscopy, and
by MS.
iii) The isomeric alkenylborane iso-4Cy, generated in low propor-
tion (1.2 % of total product), also accumulates d4, at a slower rate
than E-4Cy, but in advance of E-3pin. It eventually reaches 52%-d4;
this value corresponds exactly to that predicted for irreversible gen-
eration of iso-4Cy from 2, as an inert product.
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
iv) Product E-3pin accumulates d4 after addition of d4-2, rising to
50%-d4 after a short induction period. The accumulation of d4 in E-
3pin is thus dependent on the growth of d4 in an intermediate that
connects it (mechanisms I, II) with the substrate 2. Thus, E-3pin is
not generated directly from 2, or transiently complexed 2, mecha-
nisms III, IV).
Scheme 5. H and B migrations (red, blue) under catalytic condi-
tions during the first, and all subsequent turnovers, during conver-
sion of on-cycle intermediate E-4Cy to E-3pin by 1pin. Coloring illus-
trates differentiation of B-H/C-B metathesis (Ia), B-O/C-B metath-
esis (Ib), and syn-dehydroboration (II) mechanisms.
Cy
v) On complete consumption of 2, the intermediate, E-4Cy under-
goes decay, but retains its isotope ratio throughout (71%-d4); it is
thus generated and consumed irreversibly.
H
B
O
O
Cy
H
Ar
H
BCy2
E-4Cy
1pin
vi) 1,1-Diborylalkane 5pinCy is present in low quantities (0.5%)
throughout the first 95 % of the reaction evolution, during which
the isotope ratio in 5pinCy rises from 0 to 30%-d4. In the final stage
B
H
Ar
2
H
Ar = p-F-C6H4
II
I(a)
1pin
1pin
of reaction evolution there is a surge in the concentration of 5pinCy
,
I(b)
1pin
where it is generated in inverse proportion to the decay in E-4Cy (~5
mol%). However, the isotope ratio maximum in 5pinCy is 48%-d4,
demonstrating that that 5pinCy is not generated via turnover of E-4Cy
(71%-d4) (mechanism II), but from E-3pin (≤50%-d4) - i.e. the 'indi-
rect' route, Scheme 4.
O
Ar
H
H
Cy
H
O
H
B
O
H
O
B
B
Ar
BCy2
O
O
Cy
B
H
Cy2B
(x 2)
Ar
H
H
H
After complete consumption of 2, addition of further 2 to the sys-
tem (comprising E-3pin, iso-4Cy, 5pinCy, and 1pin) does not result in
generation of E-4Cy, or recovery of any significant turnover, or per-
turbation in the isotope ratios of E-3pin, iso-4Cy, 5pinCy, confirming
that all of observed species are generated irreversibly under the
conditions of catalysis. Together with the empirical rate equation,
the isotope entrainment analysis (Figure 1) eliminates mechanisms
II, III and IV; and places considerable constraints on I in terms of
(lack of) reversibility at all stages. Inclusion of these constraints, as
illustrated in the simplified mechanism I at the bottom of Figure 1,
allows quantitative prediction of the isotope ratios as function of
conversion when the resting state is E-4Cy; see solid lines passing
through data points in Figure 1, generated using the holistic kinetic
model described below.
5. Single-Turnover 10B,2H-analysis of Metathesis Pathways.
Attention was next focussed on the productive turnover of E-4Cy by
1pin to give Cy2BH + E-3pin. In common to metathesis mechanisms
Ia and Ib, Scheme 2, is the retention of the cis-H in E-4Cy in the
product E-3pin; see upper left-hand side of Scheme 5 where the cis-
H in both E-4Cy and E-3pin is colored red. This provides simple dif-
ferentiation of mechanism I from mechanism II. In the latter, the
cis-H in E-4Cy is eliminated via syn-stereospecific dehydroboration
during generation of E-3pin; see upper right-hand side of Scheme 5,
where the liberated Cy2BH has B-H colored red. The two pathways
for metathesis (Ia, 1b) are differentiated from each other by the bo-
ron atom in E-4Cy (colored red in the upper part of Scheme 5) which
is transferred into Cy2BH in mechanism Ia, but retained in E-3pin in
mechanism Ib.
I(b)
II
I(a)
O
O
H
H
O
H
B
B
O
O
B
O
Ar
Ar
Ar
E-3pin
E-3pin
H
H
E-3pin
H
Cy2BH
Cy2BH
Cy2BH
first turnover
R
H
R
H
R
H
H
H
H
BCy2
BCy2
BCy2
R
R
R
H
H
H
I(a)
II
1pin
E-4’Cy
1pin
I(b)
1pin
O
H
all subsequent turnovers
B
O
R ≠ Ar
R
E-3’pin
H
Commercially-available D3B·THF was reacted with cyclohexene
to generate (dn-Cy2)BD in situ. Control experiments (see SI) indi-
cated 90% B-D. Single turnover analysis, using pentyne to se-
quester Cy2BH and 1pin, gave E-3pin that was 90 % deuterated at cis-
H, Scheme 6. This is fully consistent with metathesis pathways Ia
and Ib, and eliminates mechanism II. Labelling of the boron inter-
mediates required development of a reliable synthesis of stable so-
lutions of pure [10B]-1pin, ≥ 97% 10B, in dioxane/CHCl3, Scheme 6
lower; see SI for full details. With [10B]-1pin in hand, single-turno-
ver, followed by isolation of E-3pin and analysis by 10B/11B NMR
spectroscopy using natural abundance ArBF3K as an internal refer-
ence, indicated that [10B]-E-3pin (≥ 97% 10B) is generated. This re-
sult is fully consistent with metathesis pathway Ia, and eliminates
B-O/C-B metathesis (alkoxy ligand exchange, pathway Ib),
Scheme 6.
In principle then, it is simple to distinguish mechanisms Ia, Ib, and
II by 1H/2H and 10B/11B labelling of the Cy2BH catalyst and reagent
1pin, and analysis of the isotopic provenance of cis-H and B in the
product E-3pin, as illustrated by red/blue coloring in Scheme 5.
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Journal of the American Chemical Society
by 1pin (DG‡calc.= 25.7 kcal mol-1) and that 5pinCy is generated irre-
Scheme 6. Single-turnover analysisa of E-3pin generated from
b
Cy2BD + 1pin and Cy2BH + 10B-1pin
.
versibly: dehydroboration to regenerate E-3pin + Cy2BH, DG‡
=
1
calc.
29 kcal mol-1. These features render generation of iso-4Cy and 5pinCy
Ar = p-F-C6H4
2
Ar
H
2
1. pentyne
(10 equiv.)
catalyst termination steps, at ambient temperature.
Cy
O
B
D
3
4
dioxane, 296 K
D
Cy2BD
B
Cy
O
Ar
CHCl3
Ar
2. d0-1pin
90 % B-D
(1% v/v)
H
E-4Cy
5
6
7
8
excess
H
Ar = p-F-C6H4
O
H
[2H]-E-3pin
TS2→E-3pin
B
TS2→E-3pin
direct
1pin
O
90 % D
77.8
52.3
direct
Ar
H
Ar
E-3pin
B-H /C-B
metathesis
(pathway Ia)
Cy2BH
Cy2B
2
H
TS2→iso-4
Ar
H
2
9
1. pentyne
(10 equiv.)
Cy
O
H
H
dioxane, 296 K
Ar
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
k1
E-4Cy
H
10B
Cy2BH
B
Cy
O
TS2→E-4
Ar
CHCl3
2. [10B]-1pin Ar
E-9pinCy
H
(1% v/v)
E-4Cy
H
1 equiv.
46.1
(49.1)
Cy2BH
[
10B1]-E-3pin
k2
+ 2
TSiso-4→iso-9
31.2
ii
TLS 1pin
>97 % 10B
i
32.2
(34.5)
10B(OH)3
(o-tol)3Pꢀ10BH3
20.5
(20.0)
H
Cy2B
+ Cy2BH
+ 1pin
+ 2
aAnalyses by H and 10/11B NMR spectroscopy, and MS; see SI.
bConditions: i) iPrOH, 3 equiv. CaH2, 4 equiv. 90 °C; distill 60 °C,
40-60 mBar; then LiAlH4 0.8 equiv, o-tol3P, 1.5 equiv. THF, 0 °C;
then Rochelle salt, aq.; then 3% aq. H2O2; 52-72% ii) pinacol, 0.77
equiv., dioxane / CHCl3 (1%), 57 °C, 16h, then distil, 40°C, 60-90
mBar; 1.09 M solution in dioxane / CHCl3, 50% yield from pinacol.
1
H
BCy2
H
(R2BH)2
TS4→9
Ar
TS9→3
E-9pinCy
TS3→5
19.7
(18.5)
iso-4
Ar
18.3
(19.6)
TS2→E-4
16.7
(17.7)
17.1
(16.2)
5.5
(4.7)
(15.5)
TS4→5’
13.3
(16.3)
0.0
H
-0.6
(1.7)
5(R2B)2
(-11.9)
Ar
O
O
H
B
BCy2
5pinR2B
Ar
H
Ar
O
H
6. Mechanism and Kinetics of Cy2BH Catalysis via Alkenyl
B-H/C-B Metathesis (pathway Ia). The full catalytic cycle for
Mechanism Ia was explored using the M06L/6-311++G** level of
theory, which had previously been found effective for the protode-
boronation reaction.33 All calculations were performed in Gauss-
ian09,34 with dioxane solvation incorporated via a polarizable con-
tinuum model (PCM) single point at the same level of theory. Free
energy corrections were computed with 'goodvibes'35 at T = 298
and standard state concentration of 1M. Geometries and energies
(including a description of the low energy conformations) are pro-
vided as supporting information.
BR2
B
-12.0
(-11.6)
BCy2
H
E-4Cy
B
Cy
O
Cy
Ar
BR2
E-9Cy
+ Cy2BH
+ 2
E-3pin
+ Cy2BH
+ 1pin
+ 2
H
H
Ar
+ 2 Cy2BH
5(R2B)2
BPin
-32.8
H
H
+ 2
+ 1pin
+ 2
E-4Cy
5pinR2B
+ Cy2BH
+ Cy2BH
B-H / C-B metathesis
(pathway Ia)
+ 2
+ E-3pin
1pin
TS4→9
E-3pin
The calculated barrier for the direct (uncatalyzed) reaction of 1pin
with 2 is very high (DG‡calc.= 46 kcal mol-1), consistent with the
requirement for catalysis.11j,m,o,25 For catalysis by Cy2BH, the rest-
ing state was found to be E-4Cy. Metathesis by 1pin (k2) is calculated
to be turnover-rate limiting (DG‡calc.= 19.7 kcal mol-1; Figure 2), in
excellent agreement with the experimental rate of turnover,
DG‡exp.= 20.3 kcal mol-1. Rapid capture of the liberated Cy2BH by
2 (DG‡calc.= 14 kcal mol-1), completes the cycle, which is thus con-
sistent with the empirical rate-equation in which the turnover fre-
quency is first order in both 1pin and [BCy2]tot. The B-H/C-B me-
tathesis (pathway Ia) is calculated to proceed in a step-wise manner
involving a transient µ-H bridged intermediate (E-9pinCy) where a
B-C-B assembly is midpoint between transfer of the alkene from
one boron to the other, with retention of E-configuration (see lower
section of Figure 2). Intermediate E-9pinCy is somewhat analogous
to a number of isolated B-C-B and Al-C-Al complexes.36 In a de-
tailed study of a closely related structure, Holthausen and Wagner
determined the bonding in this type of intermediate to involve two
2-electron-3-centre ('2e3c') bonds.36a The first employs the 1s or-
bital of the bridging hydrogen while the second employs an sp2
hybrid orbital from the bridging carbon, see schematic illustration
at the bottom Figure 2. In accordance with the nature of these pre-
viously described structures, the double bond is almost unperturbed
in the intermediate E-9pinCy (C=C 1.36 Å, C=C-H 116˚).
k2 (TLS)
TS9→3
+
+
DGTSCy calc. = 19.7
(exp. = 20.3)
E-4Cy
Cy2B
E-9pinCy
Cy2BH
Bpin
H
Bpin
Cy2B
1.35 Å
H
1.35 Å
H
1.36 Å
H
H
H
H
119 °
Ar
117 °
Ar
116 °
Ar
Figure 2. Upper: free energies (kcal mol-1, M06L/6-311++G**
PCM (dioxane, single point with M06L/6-311++G**) standard
state, 1M, 298 K) of species in the reaction of 1pin with 2 to generate
E-3pin, via intermediates E-4Cy and E-9pinCy. Kinetically disfavored
and inhibition pathways in grey; values in parentheses are for the
analogous process with 9-BBN. Lower: calculated structures (H at-
oms on cyclohexyl and pinacolyl groups omitted for clarity) for the
B-H/C-B metathesis process, with schematic illustration of the key
orbitals and 2-electron-3-centre bonds.36a
With a more detailed mechanistic picture in hand, the full reaction
evolution, as determined by in situ 19F NMR spectroscopy, was ex-
plored across a range of initial concentrations. The kinetic model
outlined in Figure 3, satisfactorily accounts for the temporal con-
centrations of all species detected by 19F-NMR spectroscopy,
Scheme 3, including generation of side product iso-4Cy and the sec-
ondary process that indirectly converts E-4Cy to 5pinCy, via 3pin, pre-
dominantly after complete consumption of 2. The optimization of
the model includes isotope entrainment of d4-2 into the catalytic
cycle, see solid lines through datapoints in Figure 1. Five key fea-
tures emerge from the analysis:
Whilst the thermodynamic driving force for overall hydroboration
(2 +1pin ® E-3pin) is substantial37 (DGcalc.= –33 kcal mol-1), that for
the metathesis step E-4Cy + 1pin ® E-3pin + Cy2BH is low. The cal-
culations, see Figure 2, also confirm that the disfavored Markovni-
kov hydroboration product iso-4Cy has a large barrier to metathesis
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Journal of the American Chemical Society
i) The rate of hydroboration of alkyne 2 by Cy2BH (k1) is far greater
Page 6 of 11
BR2
BR2
Ar
1
than the rate of reaction of E-4Cy with 1pin (k2), leading to E-4Cy
Bpin
5pinBR2
Ar
iso-4BR2
being the dominant catalyst species throughout the reaction.
2
3
4
5
6
7
8
9
ii) The selectivity for anti-Markovnikov hydroboration (k1/k3) of 2
by Cy2BH is moderate, leading to catalyst inhibition via generation
of iso-4, occurring on average, once in every 89 turnovers.
k4
k3
E-3pin
2
Bpin
E-3pin
R2BH
Ar
H
Ar
iii) The rate of hydroboration of 2 by Cy2BH (k1) is around three
orders of magnitude faster than E-3pin (k4), leading to the majority
of 5pinCy being generated in the very last stages of reaction, when
all of the alkyne 2 has been consumed.
iv) The impact of Cy2BH aggregation,38 which is extensive in the
absence of alkyne 2, is negligible, due to the low concentration of
free borane.
2
k0
(R2BH)2
k2
k1
H
B
1pin
BR2
BR2
E-4BR2
k5
R2BH
O
O
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
Ar
Ar
BR2
5(BR2)2
v) Generation of iso-4Cy and 5pinCy reduces the yield of E-3pin. In
principle, the highest yield of E-3pin attainable under these condi-
tions is 98.5%, by use of 1.25 mol% Cy2BH. This value assumes
no catalyst deactivation pathways other than generation of iso-4Cy
k0 = 10-3 s-1
k1 ≥ 3 M-1 s-1
catalysis by Cy2BH
conc. / M
0.6
k2 = 6.6 ×10-3 M-1 s-1
and 5pinCy
.
E-3pin
k1 = 89 k3
vi) Unlike 9-BBN, vide infra, competing hydroboration of E-4Cy by
Cy2BH is negligible: 5(Cy)2 was not detected under the reaction con-
ditions (≤0.1 %; k1/k5 ≥ 2.7´103).
2
0.5
k1 = 2×103 k4
k1 ≥ 3×103 k5
conc. / mM
50
0.4
0.3
0.2
0.1
7. Catalysis by 9-BBN. Unlike the air-sensitive, in situ-prepared
suspension of (Cy2BH)n,38 the related secondary borane (9-BBN)2,
is commercially-available as a crystalline solid, and as a readily-
handled solution in THF. Although the majority of applications of
(9-BBN)2 catalysis in Arase-Hoshi alkyne hydroboration have em-
ployed 1cat; it is also effective with 1pin and has recently been used
by Werner in the synthesis of E-stilbenes;39 see SI for further ex-
amples. In situ 19F-NMR spectroscopic analysis of the reaction of
alkyne 2 with 1pin catalyzed by (9-BBN)2, revealed a similar but not
2
40
30
20
10
0
[Cy2BH]0
5pinCy
iso-4Cy
E-4Cy
0.0
0
0
10
20
time / ks
30
40
10
20
30
40
identical set of intermediates to those found for Cy2BH. In situ 11
B
time / ks
NMR spectroscopic analysis also confirmed that the free 9-BBN is
predominantly dimeric (K0 <1.4´10-4 M; k0 ~1 ´10–3 s-1)40 under
the reaction conditions. Independent reaction of alkyne 2 with 9-
BBN generated E-49BBN and the double hydroboration28 product
5(9BBN)2, which was also detected (0.8%) during catalytic turnover.
k0 >10-3 s-1
catalysis by 9-BBN
conc. / M
0.6
K0 <1.4×10-4
M
(K0)0.5k1 = 1 ×10-3 M-2.5 s-1
k2 = 1.6 ×10-2 M-1 s-1
k2 > 400 k3
2
0.5
0.4
0.3
0.2
0.1
0.0
Reaction of isolated E-3pin with 9-BBN generated 5pin9BBN
.
k1 = 4.6 k4
k1 = 2.9 k5
conc. / mM
The catalytic cycle involving 9-BBN, generated by reversible dis-
sociation from (9-BBN)2, was also explored using the M06L/6-
311++G** level of theory, and the computed energies (see values
in parentheses in Figure 2 and further detail of inhibition processes)
used to guide simulation of the full reaction evolution, as deter-
mined by in situ 19F NMR spectroscopy, at two (9-BBN)2 loadings.
Hydroboration catalyzed by (9-BBN)2 (Figure 3, lower graphs) has
a distinct profile, with three key points identified by computational
and kinetic analysis:
E-3pin
100
80
60
40
20
0
[9BBN]0
5pinBBN
E-49BBN
5(9-BBN)2
30
0
10
20
30
0
10
20
i) Dimerization of the free 9-BBN (k-0) leads to a low pseudo
steady-state concentration of E-49BBN. Higher catalyst concentra-
tions result in decreased selectivity (k2/k5) for E-3pin over 5(9BBN)2
(165/1 at 3 mol%; 75/1 at 6.8 mol% (9-BBN)2). Increasing the
[1pin]0/[2]0 ratio leads to less 5(9BBN)2 generation; however, with this
substrate (2), this is only a minor inhibition pathway.
time / ks
time / ks
Figure 3. Temporal evolution of 2 (600 mM) + 1pin (606 mM) at
296 K, in dioxane, containing 1 % v/v CHCl3 stabilizer, after addi-
tion of (Cy2BH)n, 3.5 mol% (upper graphs) and (9-BBN)2, 6.8
mol% (lower graphs). Open circles experimental data (in situ 19F
NMR spectroscopy). Solid lines: simulations according to the ki-
netic models shown. For Cy2BH, k0 represents quasi-irreversible
reactive dissolution of its suspension. For the 9-BBN simulation,
K0 represents a upper limit based on 11B NMR spectroscopic anal-
ysis; the absolute rate constants should not be applied in isolation.
See SI for full details.
ii) The anti-Markovnikov selectivity (k1/k3) in hydroboration of 2
by 9-BBN is high (>400/1) leading to negligible inhibition.
iii) The rate of hydroboration of the product E-3pin by 9-BBN (k4;
to generate 5pin9BBN) competes significantly with hydroboration of
2 (k1/k4~5), leading to irreversible inhibition throughout the reac-
tion, Figure 3. This reduces the maximum yield of E-3pin under
these conditions to 65 %, using 11 mol% (9-BBN)2.
8. Catalyst Inhibition in Arase-Hoshi Hydroboration.
The secondary boranes Cy2BH and 9-BBN catalyse Arase-Hoshi
hydroboration of alkyne 2 with different efficiencies. As discussed
above, the dominant 'on-cycle' catalytic species for the reaction is
identified as Ar-CH=CH-BR2 (E-4), generated by irreversible anti-
Markovnikov addition of the borane R2BH to the alkyne (2). The
relatively low barrier to irreversible reaction of E-4 with 1pin (~20
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Journal of the American Chemical Society
proceeding via a fleeting intermediate in which the alkene is pin-
kcal mol-1) allows the overall process to undergo turnover at ambi-
1
2
3
4
5
6
7
8
ent temperature. For both catalyst systems, a number of competing
and irreversible hydroborations by R2BH proceed in concert with
turnover. These include Markovnikov hydroboration of the alkyne
(to generate iso-4), addition to the on-cycle intermediate (E-4) to
generate 5(R2B)2, and addition to the net hydroboration product (E-
3pin) to generate 5pinR2B, all of which lead to catalyst inhibition and
reduced yields.. As a result, the two catalysts Cy2BH and 9-BBN
have different optimum catalyst loadings; these reflect a compro-
mise between total conversion of alkyne 2, and overall yield of E-
3pin. Conducting the reaction at higher temperatures and in different
solvents will change selectivity and may also facilitate turnover of
what are inhibited species at ambient temperature in dioxane.
cered between two boron centres, by way of a µ-B-H-B bridge and
a 2-electron-3-centre ('2e3c') B-C-B bond; Figure 2 and Scheme 7.
This is the first direct experimental evidence for R2BH generation
from an alkenylboron proceeding via B-C-B transfer (mechanism
Ia),16d rather than by alkoxy ligand exchange (mechanism Ib).16a
The process is directly analogous to the mechanism for redistribu-
tion reactions of alkylboranes proposed by Köster in the 1960s,16d
and the B-Ar-B species isolated and characterized in great detail by
Holthausen and Wagner.36a It is also related to the generation of
arylboronate products in the FLP-catalyzed borylation of het-
eroarenes,41 the 1pin-mediated liberation of Ar2BH and Ar2BH2
from Ar3B species,11i and to Ar2BH liberation from a dimethylxan-
thene-based FLP.11o The kinetic and mechanistic details elucidated
herein, will aid in the rational selection of conditions for application
of Arase-Hoshi hydroboration,13,14 as well as in the design of new
selective boron-catalyzed reactions and processes.
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 7. Arase-Hoshi catalysis by Cy2BH versus 9-BBN.11df,13,37
R2B
k3
no direct
(uncatalyzed)
reaction
iso-4
O
B
H
Ar
H
Ar
O
2
H
H
R2BH
1pin
inhibition
______________________
ASSOCIATED CONTENT
9-BBN more
regio-selective
k1
H
O
H
BR2
B
O
Ar
Ar
H
Supporting Information: Additional discussion, experimental
procedures, kinetic data and analysis, computational details, char-
acterization data and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
E-3pin
H
E-4
1pin
O
O
slower with
Cy2BH
k2
R2BH
R2BH
slower with
Cy2BH
H
B
k5
k4
H
Ar
int. E-9
B
H
BR2
BR2
H
BR2
AUTHOR INFORMATION
R
R
H
B
O
Ar
Ar
O
B-H / C-B metathesis
with retention
of configuration
Corresponding Authors
inhibition
inhibition
guy.lloyd-jones@ed.ac.uk, stephen.thomas@ed.ac.uk
(pathway Ia)
Author contributions
ò E.N.S. and A.D.B. contributed equally to this work.
For 1pin + E-4, the B-H/C-B-metathesis proceeds at a similar rate
with 9-BBN (k2 ~2 ´10-2 M-1s-1) as compared to Cy2B (k2 ~7´10-3
M-1s-1), but with the addition of R2BH across the alkyne 2 proceed-
ing with considerably higher regioselectivity (9-BBN, k1/k3 > 400;
Cy2B, , k1/k3 ~89), Scheme 7. Ostensibly, this suggests 9-BBN to
be the superior catalyst. Indeed, many of the early applications of
Arase-Hoshi hydroboration employed 9-BBN with 1cat.13 However,
9-BBN has a higher propensity than Cy2BH to undergo secondary
Notes
The authors declare no competing financial interest.
Funding Sources
G.C.L.-J. and E.N.S. thank CONACYT for generous support.
S.P.T. thanks the Royal Society for a University Research Fellow-
ship. S.P.T. and A.B.D. thank AstraZeneca and the EPSRC for a
CASE award. The research leading to these results has received
funding from the European Research Council under the European
Union's Seventh Framework Programme (FP7/2007-2013) / ERC
grant agreement n° [340163].
hydroboration28 (k4, E-3pin ® 5pin9BBN; and k5, E-49BBN ® 5(9BBN)2
)
leading to an earlier onset of termination of turnover. Hindered al-
kyne substrates that inhibit B-H/C-B-metathesis by 1, or those
bearing B-coordinating groups that can direct secondary hydrobo-
ration,14 will exacerbate catalyst termination. Lack of turnover of
intermediates analogous to E-4, by 1pin or 1cat explains why some
alkynes that fail to undergo Arase-Hoshi catalysis, readily undergo
stoichiometric hydroboration with 9-BBN,14c or Cy2BH,14a and
then direct cross-coupling.
ACKNOWLEDGMENT
AGL thanks the EPSRC and National Chemical Database Service
for access to the Cambridge Structural Database. We thank Mat-
thew Harper (Bristol) for technical assistance in the early phases
of this work, and Jeremy Harvey (Bristol, Leuven) for preliminary
calculations and valuable mechanistic discussion.
CONCLUSIONS
In 1990, Periasamy described modest acceleration of alkyne hy-
droboration by catecholborane 1cat, in the presence of
[H3B·N(Ph)Et2]11ac Five years later, Arase and Hoshi demonstrated
that dialkyl boranes (R2BH) are very efficient catalysts for alkyne
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(12) Initiators can function by inducing disproportionation (see
reference 26) of the 1,3,2-dioxaborolane (1), leading to generation
of BH3, a known catalyst for Arase-Hoshi alkyne hydroboration
(see references 11m,n). It is thus not clear for the examples in ref-
erences 10 and 11, which additives are genuine (pre)-catalysts, and
which are initiators.
(13) Selected examples of the application of Arase-Hoshi R2BH-
catalyzed alkyne hydroboration in synthesis: (a) Jägel, J.; Maier,
M. E. An Efficient Synthesis of the C1-C9 Segment of Dictyostatin.
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6537. (c) Evans, D. A.; Starr, J. T. A cycloaddition cascade ap-
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bayashi, J. i. Total Synthesis and Biological Evaluation of Am-
phidinolide V and Analogues. Chem. Eur. J. 2009, 15, 4011-4029.
(14) Examples of failed Arase-Hoshi R2BH-catalyzed alkyne
hydroboration: (a) Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng,
N.; Roush, W. R. Studies on the Synthesis of Apoptolidin A. 1.
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son, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.;
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Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M.; Vetelino, A. B.; Schlesinger, H. I. Hydrides of Boron. III. Dimethoxyborine.
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(29) In situ protonolyis of iso-4 / E-4pin with pinacol caused turn-
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(22) The products from Arase-Hoshi hydroboration, as far as we
aware, always correspond to a net cis addition of H and B.
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Chloride sources, such as CH2Cl2, HCl, Bu4NCl, which
possibly quench borenium intermediates in the disproportionation
mechanisms elucidated by Marder (see reference 26a), also proved
effective. Indeed, as little as 15 ppm CHCl3 induces a noticeable
increase in the lifetime of dioxane solutions of (MeO)2BH (Burg,
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(37) The analogous hydroboration process shown at the top of
Scheme 1 liberates 36.8 kcal mol-1, according to in situ reaction
calorimetry, see ref 13n.
(38) (Cy2BH)n is only sparingly soluble in ether solvents:
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GRAPHICAL ABSTRACT
O
O
H
B
B
2-e-3-centre
bonds
H
Ar
H
Cy Cy
O
H
H
BCy2
B
O
Ar
+ HBpin
Ar
+ Cy2BH
H
H
‡
∆G calc = 19.7 kcal mol-1
‡
∆G exp = 20.3 kcal mol-1
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