Tris(2,4,6-trifluorophenyl)borane: An Efficient Hydroboration Catalyst

Article abstract of DOI:10.1002/chem.201703109

The metal-free catalyst tris(2,4,6-trifluorophenyl)borane has demonstrated its extensive applications in the 1,2-hydroboration of numerous unsaturated reagents, namely alkynes, aldehydes and imines, consisting of a wide array of electron-withdrawing and donating functionalities. A range of over 50 borylated products are reported, with many reactions proceeding with low catalyst loading under ambient conditions. These pinacol boronate esters, in the case of aldehydes and imines, can be readily hydrolyzed to leave the respective alcohol and amine, whereas alkynyl substrates result in vinyl boranes. This is of great synthetic use to the organic chemist.

Full text of DOI:10.1002/chem.201703109

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Accepted Article
Title: Tris(2,4,6-trifluorophenyl)borane: An Efficient Hydroboration
Catalyst
Authors: James Lawson, Lewis Wilkins, and Rebecca Melen
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Tris(2,4,6-trifluorophenyl)borane: An Efficient Hydroboration
Catalyst
James R. Lawson,[a]‡ Lewis C. Wilkins[a]‡ and Rebecca L. Melen[a]*
Abstract: The metal-free catalyst tris(2,4,6-trifluorophenyl)borane
has demonstrated its extensive applications in the 1,2-hydroboration
of numerous unsaturated reagents, namely alkynes, aldehydes and
imines consisting of a wide array of electron withdrawing- and
donating-functionalities. A range of over 50 borylated products are
reported, with many reactions proceeding with low catalyst loading
under ambient conditions. These pinacol boronate esters, which in the
case of aldehydes and imines can be readily hydrolyzed to leave the
respective alcohol and amine whilst alkynyl substrates result in vinyl
boranes which is of great synthetic use to the organic chemist.
The hydroboration reaction has been rigorously explored,
with many historic examples utilizing transition metal catalysts
such as rhodium, palladium and platinum.[1] More recently, the
use of metal-free catalysts, often derived from p-block elements,[2]
has been developed however, cases of alkaline earth metal
centred catalysts have also been documented with good
success[3] allowing access to a wider variety of borylated
Scheme 1. Previous catalytic hydroboration reactions and this work.
substrates without the necessity of removing trace-metal
impurities.[4] Indeed, many hydroboration reactions are often
atom-efficient, utilizing hydroboranes such as pinacol borane
(HBPin),[5] Piers’ borane (HB(C6F5)2)[6] or 9-BBN.[7] The resulting
borylation process more often yields the syn-hydroboration
product, however, the trans-hydroboration has been reported in
the literature (Scheme 1, top).[8] The hydroboration of carbon–
carbon double- and triple-bonds provides access to synthetically
useful borylated molecules which are readily functionalized
further through cross-coupling reactions such as the Suzuki
reaction.[9] In other work, the hydroboration of alkenes and imines
with HBPin was found to be catalyzed by the functionalized
triarylborane tris[3,5-bis(trifluoromethyl)phenyl] borane (BArF3),
which was found to be a superior catalyst to the archetypical
Lewis acid B(C6F5)3 (Scheme 1, middle).[10] It has also been
shown that the catalytic hydroboration of alkynes is achievable
using Piers’ borane (HB(C6F5)2) as a catalyst.[11] Whilst metal
catalyzed hydroborations of aldehydes[12] and imines[13] have
been described, metal-free alternatives are seldom reported.[14] In
addition to those reactions described above, the hydroboration of
C=O and C=N bonds results in borylated alcohols and amines,
respectively which can in turn undergo hydrolysis to generate the
free alcohol and amine, thus providing a simple synthetically
accessible pathway for heteroatom double bond reduction.
In this work we sought a new, metal-free catalytic protocol
for the hydroboration of a wide variety of C–X (X = C, N, O)
multiple bonds. Our goal was to identify a highly Lewis acidic
boron-based catalyst that presented no competing reactivity when
exposed to a broad array of substrates featuring various
functional groups. Early in our studies, tris(2,4,6-
trifluorophenyl)borane (2,4,6-BArF ) showed great potential for
9
this task.[15] When combined with phenylacetylene in a 1:1 molar
ratio, NMR spectroscopic studies showed no 1,1-carboboration of
the alkyne, as is observed with other Lewis acidic triaryl boranes
such as B(C6F5)3.[16] Heating at 60 °C for 120 h still did not induce
any reactivity, showcasing this catalysts lack of side-reaction.
Additionally, there was no evidence of ligand redistribution
between the HBPin reagent and the catalyst as has been
identified previously, presumably due to the presence of the o-
fluorine atoms on the phenyl rings.[10a] Thus, 2,4,6-BArF was
selected for screening to probe its effectiveness as a catalyst for
hydroboration.
9
Initially, the hydroboration of phenylacetylene was studied
due to its long-standing use as a model reagent for this
transformation[17] with the conversion being measured by in situ
multinuclear NMR spectroscopy. To offer contrast to our chosen
catalyst, it was compared against other fluorinated triaryl boranes,
including B(C6F5)3, tris(2,6-difluorophenyl)borane (2,6-BArF ) as
6
[a]
Dr. J. R. Lawson, Mr. L. C. Wilkins, Dr. R. L. Melen
School of Chemistry, Cardiff University, Main Building, Park Place,
Cardiff, Cymru/Wales, CF10 3AT, U.K.
E-mail: MelenR@cardiff.ac.uk
Authors provided equal contribution to this work.
Supporting Information (SI) available: Details of syntheses, NMR
spectra and crystallographic data of all structures. For SI and
crystallographic data in CIF or other electronic format see DOI:
http://doi.org/10.17035/d.2017.0038516225
well as the non-fluorinated triphenylborane (entry 1–3, Table 1).
Initial hydroborations were carried out at 5 mol% catalyst loading,
where it was discovered that 2,4,6-BArF9 facilitated hydroboration
of phenylacetylene within 5 h (entry 4, Table 1). This borane
showed superior reactivity when compared to that of the
archetypal Lewis acid, B(C6F5)3, which failed to reach completion
after 18 h giving just 59% conversion (entry 1, Table 1). The less
‡
†
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Lewis acidic 2,6-BArF6 borane showed only slight improvements
over B(C6F5)3, with 62% conversion (entry 2, Table 1) and BPh3
demonstrated just 31% conversion (entry 3, Table 1). Despite the
molecular structure of 2,4,6-BArF9 and 2,6-BArF6 differing only by
the substitution of a p-F atom, work by Alcarazo has elucidated
their relative Lewis acidities in the series; B(C6F5)3 (100%) > 2,4,6-
BArF9 (70%) > 2,6-BArF9 (56%) which perhaps sheds light on the
observed conversions for entries 2 and 4 (Table 1).[15] Following
this, solvent effects were probed with THF, Et2O and toluene
being used in addition to CH2Cl2 (entry 4–7, Table 1). Comparable
results were garnered in toluene (entry 5, Table 1) as in CH2Cl2
however, no reaction was observed with coordinating solvents
most likely due to the sequestration of the borane catalyst (entry
6–7, Table 1). CH2Cl2 was chosen over toluene to facilitate more
convenient purification of the product. Finally, catalyst and HBPin
loading was explored (entry 8–13, Table 1). It was noted that the
catalyst could be lowered to 2 mol% without significant deleterious
impact on the conversion, equally, increasing to 10 mol% only had
slight positive impact on the rate of reaction leading to full
conversion after 4 h. Whilst a stoichiometric amount of HBPin
yielded quantitative conversion in this system, 1.2 equivalents of
HBPin were used going forward to facilitate maximum conversion
in subsequent reactions, in addition, any unreacted excess HBPin
is readily removed in vacuo. Additionally, catecholborane (HBCat)
was trialled as an alternative borylation reagent using the
established catalytic procedure which garnered the vinylboronate
ester in slightly lower conversions of 85% after 6 h (entry 14,
Table 1).
Simple aryl and alkyl substituted terminal alkynes proceeded
rapidly to the hydroboration products 1a–d at ambient
temperature giving good to excellent isolated yields of 71–99%.
Propargyl esters were found to react exclusively with the alkyne
functionality in good yields (55–77%), with no observable
reduction of the ester moiety (1e–h). Furthermore, propargyl
acrylate was reacted to give 1i with exclusive hydroboration of the
alkyne over the alkene in 87% yield. The generation of 1l from the
diyne featuring both terminal and internal alkynes displayed
selective hydroboration of the terminal triple-bond over the
internal unit. In a bid to expand the scope of this reaction,
reagents exclusively featuring internal alkynes were targeted next.
Combinations of alkynes featuring aryl and alkyl termini were
successfully hydroborated to give 1m–p with some of the best
isolated yields of 80–96%. Of particular note, the use of
asymmetric internal alkynes led to
a single regioisomer
predominating in products 1m and 1o (Scheme 2). In situ NMR
spectroscopic studies indicate that the two regioisomers were
formed in a ca. 10:1 ratio preferring a geminal methyl/borane
configuration. Storing saturated CH2Cl2 solutions of 1k and 1p
gave croppings of colorless crystals which could be measured by
X-ray crystallography to determine the trans-alkene molecular
structure as a result of the syn-addition reaction, the trans-alkene
(Figure 1). Alkenyl substrates were also attempted however were
met with more limited success than their alkynyl counterparts in
contrast to the work of Oestreich et al.[10a]
Table 1. Reaction condition optimization.
Entry
Catalyst
Load.
(mol%)
5
borane
(equiv.)
Solv.
Time
(h)
Conv.a
(%)
1
2
B(C6F5)3
2,6-BArF
HBPin (1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
18
59
5
5
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1)
HBPin (1.2)
HBPin (2)
HBPin (5)
HBCat (1.2)
18
18
5
62
31
99
99
0
6
3
BPh3
4
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
2,4,6-BArF
5
9
9
9
9
9
9
9
9
9
9
9
5
5
5
6
5
18
18
18
6
7
5
Et2O
0
8
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
99
99
99
99
99
99
85
9
2
10
11
12
13
14
10
2
4
6
2
6
2
5
2
6
a Conversion measured via in situ 1H NMR spectroscopy.
With optimized reaction conditions for the hydroboration of
phenylacetylene in hand using HBPin as the borylation reagent,
the reaction scope was expanded to a range of terminal alkynes.
Scheme 2. Hydroboration of various internal and terminal alkynes. Conditions
for given isolated yield noted.
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Figure 1. Solid-state structure of 1k and 1p. Thermal ellipsoids shown at 50%
probability. C: black, H: white, O: red, B: yellow green, Si: grey. Disordered
pinacol unit of 1k modelled over multiple sites with solvent molecules omitted
for clarity.
The 1,2-hydroboration of aldehydes was then examined,
beginning with benzaldehyde (Scheme 3). Using the optimized
reaction conditions established previously, it was observed via
multinuclear NMR spectroscopy that the aldehyde was
completely consumed within 1 hour at room temperature.
Removal of volatiles in vacuo, and redissolution in CDCl3 gave
multinuclear NMR data confirming the hydroborated
benzaldehyde (2a) as the sole product. Following this, the
hydroboration reaction was extended to several other aldehydes
to explore the functional group tolerance (Scheme 3). Beginning
with substituted benzaldehydes, it was observed that electron
withdrawing groups (including p-NO2, o-CN, p-F and p-CF3) and
electron-donating groups such as OMe could be included in both
the ortho- and para-positions with little impingement on reactivity
(2a–m). Heteroarenes (2o–p) were tolerated under comparable
conditions to other substituents, indicating that potential
sequestration of the borane or catalyst by the coordinating
heteroatom is a reversibly facile process. Fused aryl systems
(2n), alkyl substituents (2q–s) as well as cyclic aliphatics (2t) were
all tolerated explicating the generality of this synthetic
methodology. It was, however, found that elevated temperature
were required to achieve full conversion for most substrates,
notably ortho-substituted benzaldehydes and some electron-
withdrawing functionalities with slightly longer reaction times
being noted.
Scheme 3. Hydroboration of aldehydes. Conditions indicated to reach
quantitative conversion by in situ 1H NMR spectroscopy.
Following aldehydes, C=N bond hydroboration was
investigated, beginning with N-benzylideneaniline. It was once
again observed that hydroboration occurred rapidly using the
same reaction conditions, with exclusive product formation as
observed by multinuclear NMR spectroscopy, showing full
conversion of the imine to the borolanamine 3a within 4 h. Indeed,
other recent studies in the group have shown similar results when
using
tris(3,5-bis(trifluoromethyl)phenyl)borane
in
imine
reductions with good yields being reported.[10b] Expansion of the
substrate scope required a library of imines, which were readily
synthesized using literature procedures.[18] Hydroboration of
these various imines was readily achieved, featuring aryl groups
substituted with alkyl, fused aryl, electron withdrawing- and
donating-groups, as well as variance on the nitrogen atom
(Scheme 4). It was noted that electron-rich R1 aryl groups gave
the corresponding aminoborane again in quantitative yields (3b–
e) with the analogous electron-poor moieties performing equally
as well (3f–g). Moreover, functionalization of the R2 unit had little
impact on reactivity whereby aliphatic groups were tolerated well,
generating the borylated products 3i–l quantitatively in as little as
4 h at 60 °C. Sterically encumbered 2,6-diethylphenyl and 2,4,6-
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trimethylphenyl substituted amines (3m–n) performed well with
other functionalities such as p-CF3 and o-F (3o–p) posing no
obstacle. Some borylated amine products were found to be
sensitive to protodeboration upon work-up, and as such were fully
hydrolyzed to the secondary amine for the purpose of NMR
analysis (3d–g, 3p).
Acknowledgements
RLM would like to acknowledge the EPSRC (grant number
EP/N02320X/1) for funding. RLM would like to acknowledge Prof.
Dr. Martin Oestreich for advice in the preparation of this
manuscript.
Keywords: Catalysis • Metal-free • Boron • Hydroboration • Lewis
acids
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Scheme 4. Hydroboration of imines. Conditions indicated to reach quantitative
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9
reagent for the hydroboration of a wide variety of substrates. This
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reactions requiring low catalyst loading and relatively mild
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The use of tris(2,4,6-trifluorophenyl)
borane in the metal-free 1,2-syn-
hydroboration of various unsaturated
moieties such as alkynes, aldehydes
and imines generates a plethora of
over 50 borylated products with
many reactions proceeding with low
catalyst loading under ambient
conditions.
James R. Lawson, Lewis C. Wilkins
and Rebecca L. Melen*
Tris(2,4,6-trifluorophenyl)borane: An
Efficient Hydroboration Catalyst
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