Borane-Catalyzed, Chemoselective Reduction and Hydrofunctionalization of Enones Enabled by B-O Transborylation

Article abstract of DOI:10.1021/acs.orglett.1c00446

The use of stoichiometric organoborane reductants in organic synthesis is well established. Here these reagents have been rendered catalytic through an isodesmic B-O/B-H transborylation applied in the borane-catalyzed, chemoselective alkene reduction and formal hydrofunctionalization of enones. The reaction was found to proceed by a 1,4-hydroboration of the enone and B-O/B-H transborylation with HBpin, enabling catalyst turnover. Single-turnover and isotopic labeling experiments supported the proposed mechanism of catalysis with 1,4-hydroboration and B-O/B-H transborylation as key steps.

Full text of DOI:10.1021/acs.orglett.1c00446

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Letter
Borane-Catalyzed, Chemoselective Reduction and
Hydrofunctionalization of Enones Enabled by B−O Transborylation
Kieran Nicholson, Thomas Langer, and Stephen P. Thomas*
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ABSTRACT: The use of stoichiometric organoborane reductants in
organic synthesis is well established. Here these reagents have been
rendered catalytic through an isodesmic B−O/B−H transborylation
applied in the borane-catalyzed, chemoselective alkene reduction and
formal hydrofunctionalization of enones. The reaction was found to
proceed by a 1,4-hydroboration of the enone and B−O/B−H
transborylation with HBpin, enabling catalyst turnover. Single-turnover
and isotopic labeling experiments supported the proposed mechanism
of catalysis with 1,4-hydroboration and B−O/B−H transborylation as
key steps.
Scheme 1
hemoselective reductions are an important tool in the
1
Csynthesis of natural products and pharmaceutical targets.
The ability to selectively reduce one functional group over
another removes the requirement of protecting groups and
results in elegant and atom-economical syntheses. The
chemoselective reduction and reductive functionalization of
enones at the alkene are of interest, as the resulting ketones are
found in a wide array of biologically active compounds.2−6
The chemoselective reduction of enones at the CC bond
is dominated by transition-metal catalysis using hydro-
genation,7−12 transfer hydrogenation,13−27 and silanes28−39 as
the terminal reductants (Scheme 1a). Main-group strategies for
enone reduction have generally focused on carbonyl reduction,
most notably using borohydride reagents40 and the CBS
catalyst to give enantioenriched allylic alcohols.41 Several
stoichiometric, main-group methods for the reduction of the
enone CC bond have been reported, including the use of
hydride reagents42 and selenium-43 and sulfur-derived
reductants.44
Main-group strategies for the reduction of enones to
saturated ketones include the use of dihydropyridines,45−48
frustrated Lewis pairs,49,50 bismuth catalysis,51 and phosphoric
acid catalysis using hydroboranes52 and hydrosilanes53−55 as
the terminal reductants. However, these methods generally
have a limited substrate scope with respect to chemoselectivity
over reducible functional groups, require the multistep
synthesis of catalysts, or suffer from limited sustainability of
the reaction conditions.49−55 Alternatively, hydroboranes such
as catecholborane (HBcat), dicyclohexylborane (HBCy2), and
9-borabicyclo[3.3.1]nonane (H-B-9-BBN) can be used as
stoichiometric reductants for the reduction of enones by 1,4-
hydroboration, which, following hydrolysis, gives the saturated
ketones (Scheme 1b).56,57 Significantly, the resulting boron
enolate can be trapped by electrophiles, offering further
synthetic value.58
Received: February 5, 2021
Published: March 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00446
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2498−2504
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Main-group catalysis offers an underutilized and sustainable
alternative to transition-metal catalysis; however, the redox
chemistry of transition metals is not readily translated to main-
group species. Although excellent progress has been made to
impart the entrenched methods of catalysis on the main-group,
the use of oxidative addition and reductive elimination remain
limited beyond the d-block.59 Recently, transborylation has
offered a new approach to main-group catalysis, where
controlled and directed isodesmic ligand interchange is
exploited for catalyst turnover and has enabled previously
stoichiometric reagents to be used as catalysts.60−62
Scheme 2
B−O/B−H transborylation has been used to render the
Midland reduction catalytic.63 If a suitable, secondary organo-
borane catalyst could be identified, then it was postulated that
B−O/B−H transborylation could be extended to the chemo-
selective reduction of enones with HBpin as a turnover reagent
and terminal reductant (Scheme 1c). 1,4-Hydroboration of an
enone by a secondary organoborane would give a dialkyl boron
enolate that could undergo B−O/B−H transborylation with
HBpin to give a Bpin-enolate and regenerate the secondary
borane catalyst. Hydrolysis of the Bpin-enolate on workup
would give the saturated ketone. Alternatively, the Bpin-
enolate could be trapped by an electrophile, resulting in a
reductive α-functionalization of the enone.
Commonly used boranes 1a−c for the stoichiometric 1,4-
hydroboration of enones were assessed as potential catalysts
for the chemoselective alkene reduction of enones using
chalcone 2a as a model substrate and HBpin as the turnover
reagent (Scheme 2a). The commercially available [H-B-9-
BBN]2 1c achieved the best results, giving dihydrochalcone 3a
without any observed ketone reduction. Equal catalytic activity
was observed in several solvent systems including EtOAc,
THF, and toluene. EtOAc was chosen for further study due to
the high product yield and its status as a “green” solvent.64
Cyclic enones, such as cyclohexenone, were unreactive,
presumably due to the inability to orientate into the s-cis
conformation required for 1,4-hydroboration. In accordance
with previous reports,65 α,β-unsaturated esters and amides
were unreactive. (See Table S2.)
a
For further details of the optimization reaction conditions, see Table
1
S1. H NMR yields were calculated from the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard.
To support the proposed mechanism of catalysis, isotopic
labeling experiments were conducted (Scheme 2). The use of
D-Bpin resulted in deuterium incorporation solely at the β-
position, consistent with 1,4-hydroboration of the enone by D-
B-9-BBN D1-1c, generated by B−O/B−D transborylation
(Scheme 2b). The mechanism of B−O/B−H transborylation
was investigated with 10B-enriched H-10Bpin in a single-
turnover experiment with the O-B-9-BBN enolate 4a. The
resulting O-Bpin-enolate 10B-5a was obtained with complete
10B incorporation, showing that the B−O bond of the O-B-9-
BBN enolate 4a was exchanged alongside catalyst regeneration
rather than a ligand redistribution, which would break the B−
C bonds (Scheme 2c).
Having optimized the reaction conditions and confirmed the
mechanism through isotopic labeling, the reaction was applied
to a diverse scope of enones (Scheme 3). Dihydrochalcone, 3a,
was isolated in high yield (92%) with complete chemo-
selectivity for alkene reduction and without the formation of
any allylic alcohol observed. The reaction tolerated the
presence of an excellent array of reducible functional groups
including ester 3b (91%) and 3e (74%), nitrile 3c (52%),
alkyne 3d (68%), nitro 3f (82%), and alkene 3g (55%)
substituents. These functionalities react with stoichiometric
borane reagents and can be reduced by transition-metal-
catalyzed hydrogenation or transfer hydrogenation.66 A benzyl
ether 3h (73%) was retained during the alkene reduction,
demonstrating orthogonality to Pd/H2, which cleaves benzyl
ethers by hydrogenolysis. The inclusion of heteroaromatic
structures was tolerated, including pyridine 3i (65%),
thiophenes 3j (82%) and 3k (57%), and furan 3l (89%)
groups. In the case of pyridine 3i, a 2-bromo substituent was
required to prevent the coordination and deactivation of the
borane catalyst. Aryl halides were also tolerated with substrates
bearing fluoro 3m (93%), chloro 3n (92%), bromo 3o (85%)
and 3p (86%), and iodo 3q (90%) substituents all chemo-
selectively reduced at the alkene without any deleterious side
reactions. This is notable because halide-substituted substrates
can be challenging using transition-metal catalysis due to
unwanted oxidative addition and protodehalogenation.67
The Lewis acidic catalyst achieved good yields in the
presence of substrates bearing Lewis basic functionalities such
as a thioether 3r (87%), dimethylamino 3y (96%), and an
ether 3s (87%) groups. Several dimethoxydihydrochalcones
3t−3w were isolated in good yields with complete selectivity
for alkene reduction. A substrate bearing an unprotected
phenol 3x was successfully reduced (88%) using in situ
protection with an additional equivalent of HBpin. The
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a
Scheme 3. Substrate Scope
a
b
Reaction conditions: [H-B-9-BBN]2 4 mol %, HBpin (1.2 equiv) EtOAc, 40 °C, 16 h, then SiO2 (0.5 g, excess). Isolated as an inseparable
c
mixture with starting material. (See the SI for details.) An additional equivalent of HBpin was added.
protection prevented the nonproductive reaction of the
catalyst, H-B-9-BBN, with the alcohol.
The reaction tolerated the inclusion of aryl, alkyl , and
naphthyl substituents (3z−3ad) to give the corresponding
ketones in high yields. The presence of electron-withdrawing
trifluoromethyl substituents 3ae (58%) and 3af (64%) resulted
in reduced chemoselectivity and thus reduced yield, with
elevated levels of 1,2-hydroboration observed (3ae = 8%, 3af =
14%). Presumably, this occurred due to the electron-with-
drawing substituent causing a lowering of the LUMO energy
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and thus biasing chemoselectivity, although this effect was not
observed in the reaction of other substrates bearing electron-
withdrawing groups. The chemoselective reduction was
applied to molecules of pharmaceutical interest, and a
derivative of the anti-inflammatory Nabumetone 3ah was
chemoselectively reduced in good yield (84%). 16-Dihydro-
pregnenolone acetate, a precursor to four pharmaceuticals on
the WHO Model List of Essential Medicines,68 was reduced in
good yield to pregnenolone acetate 3ag (80%). This strategy
provides an alternative to the Pd/H2 approach used in the
Marker degradation,69 a semisynthesis of progesterone.
To further expand the synthetic utility of this reduction
protocol and exploit the O-Bpin-enolate 5a, a range of
electrophiles were screened for telescope reactivity to interpret
this and achieve a formal hydrofunctionalization of the enone.
(Scheme 4a).
Scheme 4
The catalytic generation of boron enolates demonstrated
comparable reactivity to that of stoichiometric enolate
generation.57 Several reductively functionalized chalcone
derivatives were prepared by this method. 1,4-Hydroboration
of enones has previously been reported to give (Z)-
enolates,56,65 and the generation of syn aldol products (6a
82% > 20:1 d.r., 6b 86% 5:1) is consistent with this. The
reaction was also applicable to bromination (6c 76%)
reactions.
Finally, the transborylation strategy for chemoselective
enone reduction was applied to the total synthesis of
Moskachan B (Scheme 4b).70 Enone 7c, readily prepared
from safrole in three steps, underwent chemoselective 1,4-
reduction with H-B-9-BBN/HBpin to give Moskachan B.
Using in situ 11B NMR spectroscopy and the isotopic
labeling studies, a mechanism was proposed (Scheme 4c). The
dissociation of [H-B-9-BBN]2 (δ11B = 28 ppm) to a solvent-
coordinated monomer followed by 1,4-hydroboration on the
enone gives the O-B-9-BBN-enolate 4a (56 ppm), which
undergoes an isodesmic B−O/B−H transborylation with
HBpin to regenerate the H-B-9-BBN catalyst and give a O-
Bpin-enolate 5a (22 ppm). Hydrolysis of the O-Bpin enolate
5a gives the saturated ketone 3, or reaction with an
electrophile gives the formal hydrofunctionalization product.
In summary, we have demonstrated the application of B−O/
B−H transborylation as a turnover strategy for the chemo-
selective reduction of enones, thus enabling previously
stoichiometric borane reductants to be used as catalysts and
providing a main-group alternative to transition-metal catalysis
for this transformation. Catalysis showed excellent functional
group tolerance and wide applicability with chemo- and
regioselective alkene reduction in all cases. The synthetic
applicability was extended by intercepting the intermediate O-
Bpin-enolates with electrophiles for the diastereoselective
formation of C−C bonds through aldol-type reactions and
formal hydrofunctionalizations. The use of DBpin as the
stoichiometric turnover reagent supported the proposed
pathway of 1,4-hydroboration by incorporation of the
deuterium in the β-position of the ketone. Single-turnover
experiments with H-10Bpin showed that a B−O/B−H
transborylation was occurring as the key turnover step for
catalyst regeneration.
a
For details of the telescope reactions for the hydrofunctionalization
of enones, see the SI.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00446.
General experimental information, experimental setup
and procedures, reaction monitoring, NMR spectra, and
associated references (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
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Stephen P. Thomas − EaStCHEM School of Chemistry,
University of Edinburgh, Edinburgh EH9 3FJ, United
Kingdom; orcid.org/0000-0001-8614-2947;
Email: stephen.thomas@ed.ac.uk
Authors
Kieran Nicholson − EaStCHEM School of Chemistry,
University of Edinburgh, Edinburgh EH9 3FJ, United
Kingdom
Thomas Langer − Pharmaceutical Technology &
Development, Chemicals Development U.K., AstraZeneca,
Macclesfield SK10 2NA, United Kingdom
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00446
Author Contributions
K.N. carried out all of the practical work. K.N. and S.P.T.
devised the concept. T.L. and S.P.T. supervised the work. All
authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.P.T. acknowledges the Royal Society for a University
Research Fellowship (URF/R/191015). S.P.T. and K.N.
thank AstraZeneca and the EPSRC for an iCASE PhD
studentship.
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