Dihydridoboranes: Selective Reagents for Hydroboration and Hydrodefluorination

Article abstract of DOI:10.1021/acs.orglett.9b02515

The preparation of a new series of dihydridoboranes supported by N,N-chelating ligands, [R₂NCH₂CH₂NAr]^- (R = alkyl, Ar = aryl), is reported. These new boranes react selectively with carbonyls, imines, and a series of electron-deficient fluoroarenes. The reactivity is complementary to recognized reagents such as pinacolborane, catecholborane, NHC-BH₃, and borane (BH₃) itself. Selectivities are rationalized by invoking both open- A nd closed-chain forms of the reagents as part of equilibrium mixtures.

Full text of DOI:10.1021/acs.orglett.9b02515

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dihydridoboranes: Selective Reagents for Hydroboration and
Hydrodefluorination
Nicholas A. Phillips, James O’Hanlon, Thomas N. Hooper, Andrew J. P. White,
and Mark R. Crimmin*
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City, London W12 0BZ, U.K.
S
* Supporting Information
ABSTRACT: The preparation of a new series of dihydridoboranes
supported by N,N-chelating ligands, [R2NCH2CH2NAr]− (R =
alkyl, Ar = aryl), is reported. These new boranes react selectively
with carbonyls, imines, and a series of electron-deficient
fluoroarenes. The reactivity is complementary to recognized
reagents such as pinacolborane, catecholborane, NHC−BH3, and
borane (BH3) itself. Selectivities are rationalized by invoking both
open- and closed-chain forms of the reagents as part of equilibrium
mixtures.
oranes are an integral aspect of 21st century synthesis.
BReactivity patterns of three-coordinate boranes are
dictated by the availability of the p-orbital on boron. For
example, borane, BH3, is an exceptional reagent for the
selective reduction and hydroboration of unsaturated mole-
cules. Similarly, pinacolborane (HBpin) and catecholborane
(HBcat), while often requiring catalysis to achieve practical
reaction rates, have found widespread application in synthetic
chemistry. The success of these latter reagents has been in part
driven by their stability and ease of handling along with the use
of reaction products as partners in Suzuki−Miyaura cross-
coupling reactions.1
Recently, there has been a growing appreciation of new
Figure 1. Boranes in synthesis: comparison of borane- and
reactivity of boranes determined by the nucleophilicity of the
B−H bond pair of electrons.2 For example, Curran and co-
workers have pioneered the use of BH3·NHC (NHC = N-
heterocyclic carbene) adducts as robust reagents capable of
reacting with a number of electrophiles.3 As dissociation of the
NHC from BH3·NHC to form BH3 is highly unfavorable, it has
been hypothesized the hydridic character of B−H bonds
determines the reactivity. In line with this suggestion BH3·
NHC reacts selectively with aliphatic halides and sulfonates in
preference to alkenes and carbonyl functional groups.4 Only in
the presence of a suitable promoter or catalyst (AcOH, HNTf2,
I2 or silica gel) is the hydroboration of unsaturated CC and
CX bonds observed (X = O, NR) due to the formation of a
more reactive borenium intermediate.5−8
In this paper, we report a new class of dihydridoboranes,
prepared through a simple and scalable synthetic approach
(Figure 1). These new boranes are highly chemoselective
reagents for the hydroboration of carbonyl functional groups.
They are also effective for the hydrodefluorination of electron
deficient fluoroarenes. The observed chemoselectivities are
complementary to those established for BH3 with carbonyls
reacting in preference to alkenes in both intra- and
borohydride-type reactivity.
intermolecular competition experiments. Furthermore, the
reactions occur in the absence of promoters or catalysts,
providing a broader scope of intrinsic reactivity than BH3·
NHC while still allowing reactions to be conducted in apolar
solvents. We ascribe these results to the hemilability of the
ligand system on the borane. Hence, our new reagents capture
both modes of established reactivity of three- and four-
coordinate boranes and offer new opportunities to tune
selectivities.
Despite broad and growing applications of boranes, the
preparation and exploitation of dihydridoboranes, reagents
containing two reactive hydrides, remains neglected.9 The
i
exception is Pr2NBH2 which has an established chemistry
due to its facile preparation from amine-borane dehydrogen-
ation.10 The paucity of studies can be traced back to two key
points: (i) nonligated species tend to aggregate to form dimers
Received: July 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02515
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Letter
Figure 2. (a) Preparation of dihydridoboranes 3a−f. (b) Structures of 3c, 3e, and 3f in the solid state.
and higher oligomers9 and (ii) ligated species tend to undergo
intramolecular reactions in preference to intermolecular
reactions leading to decomposition.11−14
Although one series of apparently stable dihydridoboranes
bearing six and seven-membered chelate rings is known,15 to
the best of our knowledge, investigations have been limited to
their preparation and structural characterization. The addition
of N-aryl-N′,N′-dialkyl-1,2-ethanediamine16 pro-ligands 1a−f
to a freshly prepared solution of Me2S·BH2Br results in the
instant precipitation of 2a−f as cream solids from Et2O
solution.14 The salts 2a−f could be recrystallized from
dichloromethane in good yields (60−69%) and can be
deprotonated by the addition of triethylamine to a stirring
suspension of the ammonium salt in toluene. Filtration and
crystallization at −30 °C yielded the neutral boranes 3a−f in
75−84% (Figure 2). Infrared data reveal symmetric and
asymmetric ν(B−H) stretches for 3a−f in the range 2192−
2294 cm−1. 11B NMR chemical shifts for 3a−f range between
−2.8 and +2.1 ppm and in certain cases are resolved as triplets
1
with JB−H ∼ 110 Hz.
The structures of 3c, 3e, and 3f are represented in Figure 2.
In 3c, the 3,5-xylyl ring is coplanar with the B−N framework
whereas in 3e and 3f, the mesityl ring rotates into a position
orthogonal to the B−N framework suggesting reduced
delocalization of the nitrogen lone pair into the aromatic
system in the solid state structure. The length of the C−N(sp2)
bonds (3c, 1.372(4) Å; 3e, 1.412(2) Å; 3f, 1.418(2) Å) and
B−N(sp2) bonds (3c, 1.523(5) Å; 3e, 1.512(3) Å, 3f, 1.506(2)
Å) are consistent with only negligible BN π-character (see
Supporting Information). The pendant amine is weakly
associated with boron displaying a long B−N(sp3) interaction
in the solid state (3c, 1.622(6) Å; 3e, 1.625(4) Å; 3f, 1.641(3)
Å; cf. 1.564(6) Å in BH3·NH317). The data show that while
these dihydridoboranes can be described as a four-coordinate,
the B−N(sp3) interaction is expected to be weaker than the
B−N(sp2) interaction.17
Boranes 3a−f are effective stoichiometric reagents for
reduction and hydroboration of a number of organic substrates
in the absence of a catalyst (Figure 3). Hence, 3c and 3e were
found to react with aldehydes, ketones, enones, and imines
under mild conditions (25 °C) to form the corresponding
alcohols and amines following an acidic workup. Hydride
transfer to a series of electron-deficient fluorocarbons and
iodocarbons was also achieved but required elevated temper-
atures of 80 °C (Figure 4). These reactions proceed directly to
yield the corresponding hydrodehalogenation products. For
Figure 3. Reaction of dihydridoboranes 3a−f with carbonyls. (a) 1:1
stoichiometry, 0.2 M in C6D6 solvent. (b) NMR yields measured by
comparison to 1-fluorohexane as an internal standard, isolated yields
in parentheses. (c) Yields report for hydroborated intermediate prior
to workup.
the fluoroarenes, the regioselectivity is consistent with that
established for nucleophilic aromatic substitution pathways. In
these reactions, the mesityl-substituted borane 3e reacts faster
than the 3,5-xylyl analogue 3c (see the Supporting
Information).
Under more forcing conditions (100 °C) slow reactions
were observed between 3e with esters, amides, alkynes,
alkenes, and nitriles. However, reduction of these substrates
does not proceed beyond modest conversion before the on-set
of a decomposition pathway of 3e involving methane
elimination.18 The restriction in the functional group scope
highlights the chemoselective nature of these reagents, a facet
that is borne out in competition experiments.
The hydroboration of CO bonds of aldehydes and
ketones with 3e was found to occur selectively in the presence
of esters, alkenes, an N-phenyl imine, an aryl bromide, and
B
DOI: 10.1021/acs.orglett.9b02515
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carbonyl species.19 Only using an expensive Rh- or Ir- catalyst
has the chemoselective reduction of carbonyls with HBCy2
been achieved.20 Dihydridoborane 3e was applied to the
selective reduction of the isomers of (+)-dihydrocarvone
(Figure 5b).
These new boranes display two contrasting modes of
activity, acting as hydride transfer reagents with electron-
deficient halocarbons but hydroborating agents with carbonyl
and imine functional groups. The latter pathway is not typical
of four-coordinate boranes. In order to probe the origin of
selectivity a series of DFT studies were conducted using the
B3PW91 functional and 6-311+G* basis-set. Dispersion
(GD3BJ) and solvation (PCM, benzene) effects were
considered in the optimization processes. The discussion is
limited to reactions of 3e (Figure 6).
The potential energy surface for the reaction of 3e with the
4-position of pentafluoropyridine is presented in Figure 6. This
reaction is calculated to proceed from the closed-chain isomer
of 3e-close. Initial association of the substrate forms a weakly
bound encounter complex Int-1 (ΔG° = 2.2 kcal mol−1) in
which the electron-deficient aromatic forms a π−π stacking
interaction with the aryl group of the borane. HDF then
proceeds by a concerted SNAr mechanism through TS-1A
(ΔG⧧ = 18.4 kcal mol−1). This transition state leads directly to
Int-2A (ΔG° = −57.7 kcal mol−1), an encounter complex of
the reaction products which is slightly more stable than the
separated products (ΔG° = −56.6 kcal mol−1). The formation
of the new B−F bond provides a significant thermodynamic
driving force for the reaction. There is no defined
Meisenheimer intermediate; rather, IRC calculations show
that TS-1A decays by first formation of the C−H bond then
scission of the C−F bond and migration of the fluoride ion to
the boron center. This mechanism predicts the observed
regiochemistry and nucleophilic attack of 3e-close on C5F5N
at the 2-position (TS-1B, ΔG⧧ = 24.4 kcal mol−1) or 3-
position (TS-1C, ΔG⧧ = 27.4 kcal mol−1) occurs by transition
states that are higher in energy than TS-1A (Supporting
Information). Further calculations suggest that the open-chain
isomer 3e-open does not participate in hydride transfer as the
corresponding transition state is inaccessible (>50 kcal mol−1)
under the reaction conditions.
Figure 4. Reaction of dihydridoboranes 3c/3e with (a) fluoroarenes
and (b) iodocarbons. (a) 1:1 stoichiometry, 0.2 M in C6D6 solvent.
(b) NMR yields measured by comparison to 1-fluorohexane as an
internal standard.
perfluorinated aromatics (Figure 5a). The selectivity is
complementary to known neutral boranes, as while BH3 reacts
nonselectively with both unsaturated CC and CO bonds,
the hindered borane HBCy2 has been shown to selectively
react with alkenes and alkynes in the presence of a range of
The direct hydroboration of benzaldehyde with 3e requires
access to a partially vacant p-orbital on boron. In line with this
hypothesis, BH3·DMAP, one of the most nucleophilic hydrides
of the four-coordinate series,21 shows negligible reaction with
benzaldehyde at 25 °C after 24 h (DMAP = 4-
(dimethylamino)pyridine). Hence, 3e-close is unlikely to be
the active species involved in hydroboration.
Ring-opening of 3e must be accessible under the reaction
conditions. DFT calculations show that ring-opening of 3e-
close to form 3e-open is only modestly endergonic (+1.1 kcal
mol−1) with a low barrier transition state for dissociation of the
dimethylamino group (TS-2 = 12.1 kcal mol−1). Variable-
temperature 11B NMR studies provided support for reversible
ring-opening and an equilibrium between open and close chain
forms. Upon cooling a sample of 3e in toluene-d8 from 298 to
193 K, the 11B NMR resonance shifts from δ = +2.6 ppm to
−3.3 ppm, suggesting a shift in the equilibrium position toward
1
the closed form. Across this temperature range one set of H
NMR chemical shifts are observed for the ligand environment,
with those adjacent to boron showing a strong dependence of
chemical shift on temperature (see the Supporting Informa-
tion). The findings suggest that the sample remains the in fast-
Figure 5. (a) Intermolecular and (b) intramolecular competition
reactions showing the preference for hydroboration of carbonyl
functional groups. All reactions conducted with borane 3e data in blue
are the selectivity for the blue highlighted substrate as a percentage.
C
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Figure 6. (a) Calculated reaction pathways for hydride transfer and ring-opening with 3e. B3PW91 functional and 6-311+G* basis-set with GD3BJ
dispersion and PCM solvent corrections. Values in kcal mol−1. (b) QTAIM molecular graph showing noncovalent interactions in TS-1A.
Notes
exchange equilibrium at all temperatures, with the data
representing a time-average of ring-opened and ring-closed
forms.
The authors declare no competing financial interest.
Multinuclear NMR data (.mnova, .mnpub) and a coordinate
file for the optimized DFT structures (.mol2) are available
through an open-access repository. DOI: 10.14469/hpc/6000.
While it is highly likely that the hydroboration of carbonyls
and imines originates from 3e-open, we are yet to fully resolve
the mechanism of this pathway. Preliminary evidence,
including the unusual selectivity for carbonyl over alkene
functional groups, suggests that it is likely more complicated
than a concerted hydroboration step. A more detailed
mechanistic study will be required to comment further on
the role(s) that the open and closed forms of the borane play
in this mechanism.
ACKNOWLEDGMENTS
■
We are grateful to the Royal Society for provision of a
University Research Fellowship (M.R.C.) and the ERC
(FluoroFix: 677367) for generous funding.
In summary, the preparation of a new series of
dihydridoboranes supported by N,N-chelating ligands is
reported. They react selectively with carbonyls, imines, and a
series of electron-deficient fluoroarenes. Selectivities are
complementary to established reagents, including borane itself.
The data suggest that open- and closed-chain forms of these
boranes may be in equilibrium in solution due to reversible
ligand dissociation. These boranes are likely to offer new
opportunities in synthesis and catalysis which exploit their
tunable properties.
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