Organoborane catalyzed regioselective 1,4-hydroboration of pyridines

Article abstract of DOI:10.1021/jacs.5b03147

A bulky organoborane Ar^F₂BMe (Ar^F = 2,4,6-tris(trifluoromethyl)phenyl, 1) has been synthesized. In C₆D₆ solution this organoborane and pyridine form a frustrated Lewis pair. Under mild conditions, 1 can efficiently catalyze 1,4-hydroboration of a series of pyridines. This reaction is highly chemo- and regioselective. The reaction intermediate, a boronium complex [Py₂Bpin][Ar^F₂B(H)Me] (3), was characterized in solution by NMR spectroscopy, which was also confirmed by DFT calculation.

Full text of DOI:10.1021/jacs.5b03147

Communication
pubs.acs.org/JACS
Organoborane Catalyzed Regioselective 1,4-Hydroboration of
Pyridines
Xiaoting Fan, Junhao Zheng, Zhen Hua Li,* and Huadong Wang*
Collaborative Innovation Center of Chemistry for Energy Material, Shanghai Key Laboratory of Molecular Catalysis and Innovative
Material, Department of Chemistry, Fudan University, Handan Road 220, Shanghai, 200433, China
S
* Supporting Information
Hill et al. investigated the hydroboration of pyridines catalyzed
ABSTRACT: A bulky organoborane ArF BMe (ArF
=
by a Mg(II) complex, which affords mixtures of 1,2- and 1,4-
dihydropyridine derivatives.7 Subsequently, the groups of
Suginome8 and Marks9 discovered that 1,2-hydroboration
products can be obtained when Rh(I) or La(III) complexes are
used as a catalyst. It is believed that the metal-hydride species are
involved in these metal-catalyzed pyridine hydroborations and
the facile insertion of the pyridine CN bond into the M−H
bond is responsible for the observed 1,2-selectivity.
2
2,4,6-tris(trifluoromethyl)phenyl, 1) has been synthesized.
In C6D6 solution this organoborane and pyridine form a
frustrated Lewis pair. Under mild conditions, 1 can
efficiently catalyze 1,4-hydroboration of a series of
pyridines. This reaction is highly chemo- and regioselec-
tive. The reaction intermediate, a boronium complex
[Py2Bpin][ArF B(H)Me] (3), was characterized in sol-
2
ution by NMR spectroscopy, which was also confirmed by
The recent emerging chemistry of frustrated Lewis pairs
(FLPs) provides a conceptually different strategy for reduction of
unsaturated organic substrates.10−12 Noticeably, the group of Du
stereoselectively hydrogenated substituted pyridines to piper-
idines with C6F5CH2CH2B(C6F5)2 as the catalyst.13 The
Stephan group also described the 1,4-hydrosilylation of 2-
phenylquinoline catalyzed by B(C6F5)3.14 Furthermore, the
Crudden group reported that borenium complexes can catalyze
the 1,4-hydroboration of acridine.15 Nevertheless, the reduction
of unsubstituted pyridine with FLPs has not been achieved.16
This could be due to the lack of steric protection around the
nitrogen atom of pyridine, which can coordinate to the Lewis
acid of FLPs and deactivate the catalysts. Apparently, employing
a bulky organoborane would hinder such an interaction, thus
keeping the FLP reactivity in the reaction system. In our recent
report,17 we have demonstrated that bulky 2,4,6-tris(trifluoro-
DFT calculation.
1,4-Dihydropyridines represent an important class of bioactive
molecules.1,2 In addition, its derivatives are widely applied as
reducing reagents for organic synthesis.3 One of the common
routes to the synthesis of 1,4-dihydropyridines consists of
stoichiometric nucleophilic addition to pyridines or pyridinium
salts. However, such a method requires preactivating pyridines
and often leads to regioisomeric mixtures.1 As an alternative,
catalyzed reduction of pyridines could provide a straightforward
approach for the synthesis of 1,4-dihydropyridines. Whereas
hydrogenation of pyridines needs to overcome the problem of
overreduction,4 the approaches employing milder reducing
reagents, such as silanes and boranes, have been recently
introduced. The Nikonov5 and Oesterich6 groups reported that
Ru(II) complexes can selectively catalyze 1,4-hydrosilylation of
pyridines. On the other hand, effective 1,4-hydroboration of
pyridines still remains elusive (Scheme 1). In an earlier report,
methyl)phenyl (ArF) substituted organoborane HBArF can
2
form FLPs with a series of amines, such as NEt3 and 1,4-
diazabicyclo[2.2.2]octane (DABCO), which can effectively
activate H2, alkynes, and CO2. Thus, we decided to investigate
the reactivity of ArF substituted organoboranes in pyridine
hydroboration reactions.
Scheme 1. Recent Advances in Hydroboration of Pyridines
First we examined HBArF as the catalyst for pyridine
2
hydroboration. Pinacolborane (HBpin) was chosen as the
hydroboration reagent. When 10 mol % of HBArF was added
2
to a 1:1 mixture of HBpin and pyridine in C6D6 at room
temperature, no hydroboration product was observed after 24 h.
1H and 11B NMR analysis revealed that HBArF and pyridine
2
form a classical Lewis adduct in the reaction mixture, suggesting
that the steric protection of the boron center in HBArF is not
2
enough to prohibit the coordination of pyridine. Therefore, we
decided to replace the hydride substituent with a methyl group,
which would increase the steric bulkiness of the organoborane.
Additionally, the decreased Lewis acidity of such an organo-
borane could also disfavor the coordination of pyridine. ArF BMe
2
Received: February 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b03147
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(1) was synthesized by treating ArF BF with MeMgBr in
toluene/ether solution at room temperature (Scheme 2). After
molecule of pyridine.15,19 Indeed, mixing an equimolar amount
of 1 and HBpin with 2 equiv of pyridine in C6D6 at rt resulted in
the formation of 3 (Scheme 3).20 Attempts to isolate pure 3 have
2
Scheme 2. Synthesis of 1
Scheme 3. Reaction of Pyridine, 1, and HBpin in 2:1:1 Ratio
so far met with failure. 3 decomposed in C6D6 at rt to yield
pyridine, 1, and 2a. Kinetic studies of the decomposition of 3 in
C6D6 by monitoring 1H NMR revealed that this reaction is a first-
order reaction. The activation parameters ΔH‡, ΔS‡, and ΔG‡ at
298 K are estimated to be 22.9 1.3 kcal mol−1, 5.6 4.4 cal K−1
mol−1, and 21.2 2.6 kcal mol−1, respectively. The slight positive
value of ΔS‡ implies that the pyridine molecule does not
completely dissociate from the boron center in the transition
state.
recrystallization, the organoborane 1 could be obtained in 63%
yield and was fully characterized by NMR and elemental analysis.
1
Upon mixing 1 with 10 equiv of pyridine, the H, 19F and 11B
NMR spectra obtained in C6D6 at rt remained unchanged, which
indicates an FLP is formed between 1 and pyridine. When 10 mol
% of 1 was employed as the catalyst, pyridine readily reacts with
an equimolar amount of HBpin in C6D6, quantitatively yielding
1,4-dihydropyridine 2a as the only regioisomer within 16 h
(Table 1). Two other highly Lewis acidic organoboranes,
The hydroboration of pyridine was further investigated by
DFT(M06-2X) calculations (Figure 1).21 Initially, HBpin and
Table 1. Screening of Organoborane Catalysts
a
entry
organoborane
none
yield [%]
b
1
2
3
4
5
0
b
ArF BH
0
2
b
1
99(87)
b
B(C6F5)3
0
c
B(C6Cl5)3
40
a
1
Yields were determined by H NMR analysis (C6D6 as solvent), and
isolated yields for preparative scale syntheses (toluene as solvent) are
b
c
given in parentheses. 10 mol % of catalyst was employed. 20 mol %
of catalyst was employed.
Figure 1. Gibbs free energy profile at 298 K for the reaction between
pyridine, HBpin, and 1.
B(C6F5)3 and B(C6Cl5)3,18 were also tested as the catalyst.
The former yielded no hydroboration product, and the latter
only provided a moderate yield even with 20 mol % loading of the
catalyst.
pyridine form a loosely coordinating complex,22 which also
interacts with the ArF moiety of 1 through a weak van der Waals
interaction. Subsequently, the B−H bond of HBpin is activated
through synergetic interaction of both pyridine and 1 to afford
While monitoring the hydroboration of pyridine by 1H NMR
spectroscopy, we observed that catalyst 1 was converted to an
intermediate 3 during the reaction process. A set of resonances
(8.12(d), 6.88(t), 6.68(t) ppm) from the pyridine moiety, a
singlet signal (0.84 ppm) corresponding to the Bpin fragment,
the borenium [PyBpin][ArF B(H)Me] (IM2), which needs to
2
overcome a free energy barrier of 9.2 kcal mol−1. Then a molecule
of pyridine coordinates to the borenium IM2 to generate the
boronium 3, and this step is almost barrierless.23 The next step is
and two singlets at 8.17 and 0.58 ppm from the ArF BMe moiety
hydride transfer from the [ArF B(H)Me]− anion to the 4-
2
2
1
were observed in the H NMR spectrum. Integration of these
position of the pyridine ring of 3, followed by decoordination of
pyridine to form 2a and 1. In agreement with the experimental
observation, the hydride-transfer step is found to be the rate-
determining step and proceeds via the transition state TS2 with a
18.6 kcal mol−1 free energy barrier, which is comparable with the
experimental value. We also calculated the free energy barrier for
the formation of the 1,2-dihydropyridine derivative from 3,
which is 3.9 kcal mol−1 higher than TS2. This is possibly due to
the large steric repulsion between Bpin and ArF moieties.
To investigate the scope and limitation of this novel metal-free
catalytic system, we tested a variety of substituted pyridines
signals revealed that the molar ratio of the pyridine, Bpin, and
ArF BMe moieties is 2:1:1. The 11B NMR spectrum of the
2
reaction showed two signals (one singlet at 6.8 ppm and one
doublet at −15.6 ppm (JHB = 77 Hz)) besides the signals from
HBpin and 2a. While the singlet signal is consistent with the
formation of a boronium cation,15 the doublet signal suggests the
existence of a hydridoborate anion. Based on this NMR analysis,
the intermediate 3 is assigned as [Py2Bpin][ArF B(H)Me],
2
which possibly arises from the activation of HBpin by the
pyridine/1 pair and the subsequent coordination of another
B
DOI: 10.1021/jacs.5b03147
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(Table 2).24 For 3-substitued pyridines, we noticed that electron-
donating substituents decrease the activity of the catalyst (entries
bromopyridine, which is not basic enough to activate the H−B
bond of HBpin.28 An attempt to extend this catalyst system to 4-
substituted pyridines was not successful. No hydroboration
product was observed for 4-picoline (entry 12). We also
examined a few lutidines and found that only 2,3-lutidine can
be reduced to the corresponding dihydropyridine (entries 13−
15).
Table 2. Substrate Scope of 1 Catalyzed Hydroboration of
Pyridines with HBpin
To demonstrate the synthetic application of N-boryl-1,4-
dihydropyridines, we converted 3-bromopyridine to the
corresponding N-benzoyl-1,4-dihydropyridine 4 in a one-pot
manner (Scheme 4). Treatment of in situ formed N-boryl-3-
Scheme 4. Synthesis of 4
bromo-1,4-dihydropyridine with tBuOLi29 and subsequently
with benzoyl chloride resulted in the formation of 4 in 64% yield.
It is noteworthy that 4 could not be accessed through common
methods, such as Birch reduction30 or Hantzsch synthesis.31
Fowler reduction, which involves direct reduction of pyridinium
salts with NaBH4, can only provide 1,4-dihydropyridine adducts
as a minor product.32
In conclusion, we have developed an efficient regioselective
1,4-hydroboration of pyridines catalyzed by a bulky organo-
borane 1. This reaction is metal-free and shows excellent chemo-
and regioselectivity under mild conditions. The key to this
hydroboration reaction is that 1 is bulky enough to form FLP
with pyridine. Experimental and theoretical mechanism studies
reveal that the reaction pathway is different from those catalyzed
by transition or lanthanide metal complexes and the key
intermediate is a boronium complex 3, which has been observed
by NMR spectroscopy. Efforts to extend the application of bulky
organoboranes in FLP chemistry are currently underway.
a
1
Yields were determined by H NMR analysis (C6D6 as solvent), and
isolated yields for preparative scale syntheses (toluene as solvent) are
given in parentheses. Reaction was carried out at 60 °C.
b
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization of the products, and
theoretical calculation details. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
1 and 2). 3-Picoline requires an elevated temperature to obtain a
moderate yield, and the 3-methoxylpyridine is completely
unreactive. When the substituents at the 3-position are
electron-withdrawing functionalities, 1,4-hydroborated products
can be obtained in good to excellent yields (entries 4−7). For
example, bromo and iodo substituents, which are often sensitive
to dehalogenation by transition metal catalysts, were found to be
compatible with the catalytic system (entries 4 and 5). Moreover,
Lewis basic substituents, including the strongly coordinating
cyano group, did not inhibit the reaction at all and no reduction
of the CO or CN bond was observed (entries 6 and 7).
Remarkably, the ethynyl moiety, which is prone to reduction25 or
deprotonation26 by transition metal or lanthanide complexes,
remained untouched under the reaction conditions (entry 8),
highlighting the excellent chemoselectivity of this metal-free
catalyst system. For 2-substituted pyridines, only 2-picoline can
be quantitatively hydroborated (entry 9). Both phenyl and
bromo substitution at the 2-position suppressed the reaction
completely (entries 10 and 11). Whereas the former might be too
sterically demanding for effective B−H activation,27 the latter
could be attributed to the substantially decreased basicity of 2-
AUTHOR INFORMATION
■
Corresponding Authors
*huadongwang@fudan.edu.cn
*lizhenhua@fudan.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Shanghai Science and Technology
Committee (Shanghai Rising-Star Program 13QA1400500),
Shanghai Leading Academic Discipline Project (B108), the
National Nature Science Foundation of China (21102018,
21273042, 21372048), and the National Basic Research Program
of China (2011CB808505) is gratefully acknowledged. We also
thank the High Performance Computer Center of Fudan
University for the allocation of computing time.
C
DOI: 10.1021/jacs.5b03147
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Journal of the American Chemical Society
Communication
(19) Dureen, M. A.; Lough, A.; Gilbert, T. M.; Stephan, D. W. J. Am.
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(20) When equimolar amounts of 1, pyridine, and HBpin were
combined in C6D6, 3 was the only major product with unreacted 1 and
HBpin remaining in the solution.
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DOI: 10.1021/jacs.5b03147
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX