Metal-Free Regio- and Chemoselective Hydroboration of Pyridines Catalyzed by 1,3,2-Diazaphosphenium Triflate

Article abstract of DOI:10.1021/jacs.7b09754

N-Heterocyclic phosphenium triflates (NHP-OTf) 1 serve as efficient catalysts for the regio- and chemoselective hydroboration of pyridines under ambient condition with good functional group tolerance. Mechanistic studies indicate that a boronium salt, [(Py)₂·Bpin]OTf 4, is generated concomitant with NHP-H 5 via hydride abstraction from HBpin by 1 in the initial reaction step. Hydride reduction of the activated pyridine in [(Py)₂·Bpin]OTf 4 by NHP-H 5 affords the 1,4-hydroboration product selectively. Thus, the phosphenium species act as a hydrogen transfer reagent in the catalytic cycle.

Full text of DOI:10.1021/jacs.7b09754

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Metal-Free Regio- and Chemoselective Hydroboration of Pyridines
Catalyzed by 1,3,2-Diazaphosphenium Triflate
‡
Bin Rao, Che Chang Chong, and Rei Kinjo*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
637371, Singapore
*
S Supporting Information
ABSTRACT: N-Heterocyclic phosphenium triflates (NHP-
OTf) 1 serve as efficient catalysts for the regio- and
chemoselective hydroboration of pyridines under ambient
condition with good functional group tolerance. Mechanistic
studies indicate that a boronium salt, [(Py) ·Bpin]OTf 4, is
2
generated concomitant with NHP-H 5 via hydride abstraction
from HBpin by 1 in the initial reaction step. Hydride reduction of the activated pyridine in [(Py) ·Bpin]OTf 4 by NHP-H 5
2
affords the 1,4-hydroboration product selectively. Thus, the phosphenium species act as a hydrogen transfer reagent in the
catalytic cycle.
INTRODUCTION
■
Dihydropyridine (DHP) derivatives are ubiquitous in naturally
occurring molecules, biologically active agents such as NADH
nicotinamide adenine dinucleotide), and pharmaceutically
important molecules such as Hantzsch esters. Hence, the
development of efficient methodologies for the construction of
a DHP skeleton has attracted considerable interest in synthetic
chemistry. While the reduction of preactivated pyridines with
strong reductants is utilized as the conventional synthetic
(
1
1e,f,2
approach to 1,2- or 1,4-DHP derivatives,
several catalytic
protocols for the direct reduction of pyridines have been
described in recent years. Among them, the systems employing
mild reducing reagents such as silanes and boranes instead of
H gas are considered to be efficacious because they may
2
circumvent the use of highly flammable and highly pressurized
hydrogen gas, as well as the obstacle of over-reduction to
3
,4
Figure 1. (a) Synthesis of 1,2- and 1,4-DHP derivatives by catalytic
reduction of pyridines with boranes and silanes. (b) Examples of the
reported catalysts for the hydroboration of pyridines. (c) Present work.
produce undesired piperidine derivatives (Figure 1a).
Since the seminal work by Harrod and co-workers in 1998,
several catalytic hydrosilylation reactions using metal catalysts
5
6
,7
or B(C F ) have been described.
Meanwhile, the first
6
5 3
metal-free protocol, for regioselective hydroboration of
pyridines has still remained undeveloped.
catalytic hydroboration of pyridines (Figure 1b) was reported
by the Hill group in 2011, in which the use of the magnesium8
catalyst I produced both 1,2- and 1,4-DHP derivatives.
Suginome and co-workers showed that 1,2-hydroboration o9f
pyridines took place in the presence of a rhodium catalyst, II.
In 2014, pyridine hydroboration with a complete 1,2-
regiospecificity was achieved by Marks and Delferro et al.
Recently, we have reported that N-heterocyclic phosphane
13
(
NHP-H) featuring the umpolung P−H bond catalyzes
various reactions involving transfer hydrogenation of unsatu-
rated bonds with ammonia-borane, hydroboration of carbonyls,
14
and CO reduction. Mechanistic studies revealed that the
2
Lewis acidity of the P center in NHP-H as well as the property
of NHP-H as a strong hydride donor is essential to achieve
these catalytic reactions. We reasoned that the Lewis acidity of
the P center can be enhanced in the form of phosphenium
10
with an organolanthanide catalyst, III. For regioselective 1,4-
hydroboration of pyridines, Gunanathan et al. reported that a
11
ruthenium catalyst, IV, was effective. Wang and Li et al.
demonstrated the first metal-free 1,4-hydroboration reaction of
+
15
cation NHP , which may be used as a hydride transfer reagent
F
F
pyridines using a bulky organoborane, Ar BMe V [Ar = 2,4,6-
2
12
tris(trifluoromethyl)phenyl]. Despite these pioneering stud-
ies, it is clear that an efficient catalytic system, in particular, the
Received: September 12, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b09754
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
F
12
in the hydroboration reaction of pyridines. Herein we report
in addition to B(Me)Ar , we straightforwardly prepared 4
2
that a catalytic amount of N-heterocyclic phosphenium triflates
from pyridine, HBpin, and triflic acid in CD CN, and the solid-
3
(
NHP-OTf) 1 effectively promotes the selective hydroboration
of pyridines under ambient conditions (Figure 1c).
state structure was determined by X-ray diffraction analysis
1
11
(Scheme 2a). The H and B NMR data of 4 are identical to
RESULTS AND DISCUSSION
We embarked our investigation with hydroboration of pyridine
a employing 1a as the catalyst, prior to which we confirmed by
stoichiometric reactions that neither HBpin nor pyridine 2a
interacts with 1a (Figures S1 and S2).
mol % 1a, a mixture of pyridine 2a and 4,4,5,5-tetramethyl-
,3,2-dioxaborolane (HBpin) in CD CN was stirred at room
■
Scheme 2. (a) Synthesis and the Solid-State Structure of 4;
(b) Stoichiometric Reactions between 4 and HBpin or 5; (c)
Attempt of Hydroboration of 2a in the Presence of 10 mol %
4
2
1
5a,b
In the presence of 10
1
3
temperature (Scheme 1a). After 6 h, more than 90% conversion
Scheme 1. (a) Hydroboration of Pyridine 2a Catalyzed by
1
a; (b) Proposed Reaction Mechanism
those observed during the reaction (Figure S3), confirming that
4
is generated as a key intermediate in the catalytic reaction.
The presence of 4 during the reaction was further confirmed in
the HRMS (Figure S3). Boronium 4 did not react with HBpin,
whereas treatment of 4 with a stoichiometric amount of NHP-
H 5 at room temperature afforded NHP-OTf 1a and
hydroboration product 3a quantitatively (Scheme 2b). Since
no direct reaction takes place between Py 2a and NHP-H 5
(
Figure S5), the pyridine in boronium 4 must be activated.
Crudden et al. demonstrated that a borenium catalyst promotes
hydroboration of imines with HBpin and proposed that the
boron-activated iminium ion [(imine)·Bpin] is reduced by
+
of 2a was confirmed, and 1,4-DHP 3a was formed as the major
product concomitant with a trace amount of 1,2-DHP 3a′.
When the reaction was monitored by NMR spectroscopy
18
HBpin with assistance from the Lewis base DABCO. In order
to check whether a similar process is involved in our catalytic
cycle, the reaction of Py 2a and HBpin in the presence of 10
mol % 4 was examined. Even at 50 °C, no reaction was
observed, confirming that boronium 4 itself does not serve as
the catalyst to promote the hydroboration of pyridine (Scheme
2c). We have also confirmed that a similar reaction proceeded
(
Figure S3), we detected a set of resonances at 8.87 ppm (4H),
.32 ppm (2H), 7.85 ppm (4H), and 1.09 ppm (12H) in the
8
1
H NMR spectrum, as well as a singlet at 7.26 ppm in the 11
B
NMR spectrum, which should correspond to the activated
pyridine intermediate. Because the phosphenium moiety of 1a
does not form the Lewis adduct with pyridine 2a (Figure S2),
we envisaged that the activated pyridine intermediate is the
between [(2-PhPy) ·Bpin]OTf and NHP-H 5 to afford the
2
corresponding hydroboration product 1-Bpin-2-phnyldihydro-
pyridine (Figure S8), suggesting that irrespective of the
bulkiness of the pyridine substrates, the borane-bis(pyridine)
species is a key intermediate in the catalytic cycle.
16
borane-pyridine complex 4 in the form of a boronium. Hence,
we propose a B−H bond activation mechanism (Scheme 1b),
in which the initial step is the formation of Py·Bpin·OTf and
NHP-H 5 via the activation of the B−H bond of HBpin by 1a
and 2a. After immediate complexation of Py·Bpin·OTf with the
To gain insight into the features of the reaction
intermediates, we performed a theoretical study using a DFT
method (Scheme 3). The calculated free energy shows that
second Py to afford the boronium [(Py) ·Bpin]OTf 4, one of
2
+
the activated pyridines in 4 would be reduced via the H transfer
from NHP-H 5 to furnish 3a/3a′ along with the release of 1a
and 2a. Note that the catalytic organic reactions involving
formation of Py·Bpin·OTf from Py·Bpin is exergonic with ΔG
−1
= −8.3 kcal·mol . [(Py) ·Bpin]OTf 4 formed by coordination
2
of the second pyridine to Py·Bpin·OTf is found to be slightly
more stable than Py·Bpin·OTf, which is in line with our NMR
observation (Figure S3). Natural bond orbital (NBO) analysis
reveals that the charges at the para position of the activated
17
phosphenium species are extremely rare, and to the best of
our knowledge, this result represents not only the first
phosphenium catalysis but also the first selective pyridine
hydroboration using a phosphorus-based catalyst.
pyridines in Py·Bpin·OTf and [(Py) ·Bpin]OTf 4 are
2
In order to support the proposed reaction mechanism, we
performed several control reactions. First, we attempted the
preparation and isolation of 4. While Li and Wang et al.
comparable, although they are slightly more electronegative
+
than that in Py·Bpin . Because of the small free energy gap
between Py·Bpin·OTf and [(Py) ·Bpin]OTf 4, as well as the
2
+
F
−
described that boronium [(Py) ·Bpin] with [HB(Me)Ar ]
comparable electrophilic nature of their activated pyridine
moieties, the reaction pathway via a hydride transfer from
NHP-H 5 to Py·Bpin·OTf may also be plausible in the actual
2
2
F
[
Ar = 2,4,6-tris(trifluoromethyl)phenyl] as the counterion
decomposed at room temperature to yield pyridine 2a and 3a
B
DOI: 10.1021/jacs.7b09754
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Journal of the American Chemical Society
Article
Scheme 3. Calculated Free Energy Differences (ΔG) in Py·
bearing small ethyl groups, formation of 1,2-DHP product 3a′
was apparently increased (entry 8). By contrast, the employ-
ment of 1d and 1e led to highly selective reactions, and 1e was
found to be the best catalyst for the reaction (entries 9 and 10).
Note that the solid-state structure of 1e determined by an X-ray
diffractometry reveals the ion-separated form of 1e, confirming
+
Bpin , Py·Bpin·(OTf), and [(Py) ·Bpin]OTf 4 and the
2
Charges (in Parentheses) at the Selected para- and ortho-
Carbon Atoms of the Activated Pyridines
2
3
the pronounced phosphenium (σ λ ) feature rather than
3
3
tricoordinate phosphorus triflate (σ λ ) (see the SI). We have
also investigated the effect of the X group of the catalysts using
1
f−1i bearing BF , Cl, F, and OAc, respectively (entries 11−
4
1
4). While 1f (X = BF ) exhibited a similar catalytic activity to
4
that of 1e (X = OTf), the reaction with 1g (X = Cl) required a
longer reaction time. No reactions at all were observed with 1h
(X = F) and 1i (X = OAc), demonstrating the significant effect
of the X group of the catalyst.
catalytic reaction. The charges at the ortho carbon atoms in
both Py·Bpin·(OTf) and [(Py) ·Bpin]OTf 4 are more positive
2
compared with those at the para position, suggesting that the
selective formation of 1,4-DHP derivative 3a is most likely due
to steric factors rather than electronic effects. A kinetic study
confirms that the reaction is first order for catalyst 1a but zeroth
order for both HBpin and pyridine 2a (Figures S9−S14).
Having a mechanistic understanding in mind, we briefly
investigated the reaction conditions (Table 1). Without any
Having the optimized conditions in hand, we examined the
scope of the catalytic reaction with various pyridine substrates
(Table 2). Pyridines bearing either a methyl or phenyl group at
the meta position afforded single products in high yields (3b
99%, 3c 96%, 3d 91%). Electron-withdrawing substituents such
as ester, acetyl, cyano, and amide groups greatly promoted the
reaction rate, and hydroboration completed within 1 h to afford
the corresponding 1,4-DHP products in high yields (3e 99%, 3f
a
9
0%, 3g/3g′/3g″ 98%, 3h 95%). Note that these unsaturated
Table 1. Optimization of Reaction Conditions
functional groups were tolerated under the reaction conditions
8
,14b,19
despite their potentially reducible property.
Thus, the
hydroboration reaction proceeded with a remarkable chemo-
selectivity. Halogen (Cl, Br, I) groups were also well tolerated
to afford the products in good yields (3i/3i′ 94%, 3j/3j′ 98%,
3k/3k′ 99%), in which a slight formation of 1,2-DHP products
was observed. When treating 3,5-dicholoropyridine 2l, a single
product (3l) was obtained in 94% yield, and the solid-state
structure was confirmed by X-ray diffractometry. Pyridine
substrates with alkynyl and akenyl groups could also smoothly
generate 1,4-DHP products (3m 96%, 3n 98%, 3o 98%).
Interestingly, when 3-methoxyl and amino pyridine 2p and 2q
were employed, 1,4-DHP and 1,2-DHP products were obtained
in 1:2 and 1:4 ratios, respectively. The reversed regioselectivity
is probably due to the strong electron-donating property of the
b
entry
catalyst
solvent
T (°C)
time (h)
yield (%) ratio
1
2
3
4
5
6
7
8
9
CD CN
28
28
28
28
28
28
70
28
28
28
28
28
28
28
24
6
0
3
1a
1a
1a
5
CD CN
90 (15:1)
80 (11:1)
10
3
CDCl3
C D
18
24
24
12
12
12
12
12
12
24
48
48
6
6
CD CN
<5
3
1b
1b
1c
1d
1e
1f
CD CN
0
3
CD CN
91(>20:1)
78 (5:1)
92 (>20:1)
96 (>20:1)
94 (>20:1)
92 (15:1)
0
3
10
methoxy and amino groups. It is salient to mention that Lewis
CD CN
3
F
acidic borane B(Me)Ar 2 could not promote the hydroboration
CD CN
3
12
reaction of 3-methoylpyridine 2p. Moreover, while it has been
1
1
1
1
1
0
1
2
3
4
CD CN
3
concluded in previous reports that with the ruthenium and
CD CN
3
10,11
organolanthanide catalysts,
2-substituted pyridines did not
1g
1h
1i
CD CN
3
undergo hydroboration because of steric hindrance, 2-picoline
r and 2,3-dimethylpyridine 2s were readily transformed to the
corresponding 1,4-DHP products with our system (3r 90%, 3s
1%). Significantly, NHP-OTf 1e exhibited catalytic activity for
hydroboration of 2-arylpyridines 2t and 2u to generate 3t/3t′
CD CN
3
2
CD CN
0
3
a
Reaction conditions: pyridine (0.20 mmol), HBpin (0.21 mmol),
solvent (0.40 mL). Catalyst loading is 5 mol % relative to pyridine.
Yields and 3a/3a′ ratio were determined by H NMR spectroscopy
9
b
1
(
95%) and 3u/3u′ (97%), respectively. This result is in stark
using methyltriphenylsilane as an internal standard.
contrast to Crudden’s rhodium catalysis, in which 2-
arylpyrindes afforded o-C−H borylation products via dehydro-
20
catalysts, no reaction was observed (entry 1). The use of a polar
solvent such as CD CN gave the best result with high yield and
genation. Note that the Ru catalyst IV did not promote the
11
hydroboration of 2-substituted pyridines. In addition, the
3
good product selectivity, whereas the catalytic process was
substrates 2c, 2p, and 2t did not undergo hydroboration with
1
2
remarkably inhibited in nonpolar C D (entries 2−4). When
the B-based catalyst V. With benzannulated substrate
quinoline 2v, 1,2-DHP product 3v′ was formed as the major
product. When 4-(pyridin-3-yl)benzaldehyde 2w was em-
ployed, single 1,4-DHP 3w was obtained in 94% yield via
hydroboration of both aldehyde and pyridine moieties. Double
hydroboration of pyrimidine 2x proceeded cleanly, and 3x was
obtained in 91% yield. We observed no reactions with 2-
substitued pyridines with a strong electron-withdrawing group
6
6
NHP-H 5 was employed, only a trace amount of product was
detected after 24 h at room temperature (entry 5). While no
reaction proceeded with catalyst 1b at room temperature, 3a
was selectively formed in good yield under heating conditions
at 70 °C, probably due to the steric effect of bulky Dipp groups
on the N atoms in 1b (entries 6 and 7). We also examined the
catalytic activity of benzannulated NHP-OTf (1c−1e). With 1c
C
DOI: 10.1021/jacs.7b09754
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Journal of the American Chemical Society
Article
a
Table 2. Scope of Pyridine Substrates
no hydroboration product was obtained presumably due to the
intolerance of the nitro group.
To demonstrate the robustness of our catalytic process, we
performed the reaction with 5 mmol of pyridine 2f at the
standard conditions (Scheme 4). After 1 h, 3f was formed
Scheme 4. Further Transformation of 3f
t
nearly quantitatively, which was further treated with BuOLi
followed by benzoyl choloride in a one-pot manner to afford N-
9
,21
benzoyl-1,4-dihydropydine 6 in 81% yield (0.92 g).
Moreover, by acylation with 2-iodobenzoyl chloride to give
the crude product 7 and subsequent intramolecular Heck
reaction, a new heterocyclic product 8 was obtained in 35%
total yield from 2f. These results demonstrate that our catalysis
may provide a straightforward synthetic approach to function-
alize 1,4-DHP derivatives from pyridine substrates under mild
1d
conditions.
CONCLUSIONS
After more than 50 years since the discovery of dicoordinate
phosphorus species by Dimroth and Hoffmann, we have
demonstrated that phosphenium species can be utilized as a
catalyst. We have shown the unique performance of NHP-OTf
■
22
1
as a regio- and chemoselective catalyst for hydroboration of
pyridines. The reaction has been achieved under metal-free and
ambient conditions, and various pyridine substrates involving
those not available in previous reports were well tolerated in
our system. Mechanistic studies suggest that (i) the initial step
involves the hydride transfer from HBpin to NHP cation to
generate a boronium, [(Py) ·Bpin]OTf 4, the structure of
2
which was decisively confirmed by X-ray diffraction analysis,
and (ii) the second step is reduction of the activated pyridine in
4
by NHP-H 5. Thus, diazaphophenium plays a pivotal role as a
a
hydride transfer reagent during the selective pyridine
hydoboration reaction.
Reaction conditions: pyridine substrates (0.20 mmol), HBpin (0.21
mmol), CD CN (0.40 mL), 1e (5 mol %). NMR yields and ratios of
regioisomers (1,4-DHP:1,2-DHP) are determined by H NMR
spectroscopy using methyltriphenylsilane as an internal standard.
Isolated yield is in parentheses. 0.42 mmol of HBpin was used. Due
to the poor solubility of the product 3x in CD CN, only the isolated
yield was determined.
3
1
ASSOCIATED CONTENT
Supporting Information
■
b
c
*
S
3
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b09754.
Experimental section (PDF)
2
ya,b, 2,6-lutidine 2yc, 4-picoline 2yd, and 4-dimethylamino-
Crystallographic data in CIF format (CIF)
pyridine 2ye, which was probably on account of the electronic
(CIF)
(CIF)
(CIF)
and steric factors on the pyridine skeleton and in line with the
10−12
trends observed in previous reports.
With substrates 2yf,
D
DOI: 10.1021/jacs.7b09754
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Journal of the American Chemical Society
Article
(
13) (a) Gudat, D. Dalton Trans. 2016, 45, 5896−5907.
AUTHOR INFORMATION
Corresponding Author
rkinjo@ntu.edu.sg
ORCID
Rei Kinjo: 0000-0002-4425-3937
Present Address
C.C.C.) Energetics Research Institute, Nanyang Technolog-
ical University, 50 Nanyang Avenue, Singapore 639798,
Singapore.
■
(
̈ ̈
́
b) Puntigam, O.; Konczol, L.; Nyulaszi, L.; Gudat, D. Angew.
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Nieger, M.; Du Mont, W.-W. J. Am. Chem. Soc. 2006, 128, 3946−3955.
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5819. (b) Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed.
2015, 54, 190−194. (c) Chong, C. C.; Kinjo, R. Angew. Chem., Int. Ed.
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‡
(
Angew. Chem., Int. Ed. 2014, 53, 3342−3346. Other most related
phosphorus catalyses: (e) Lin, Y.-C.; Hatzakis, E.; McCarthy, S. M.;
Reichl, K. D.; Lai, T.-Y.; Yennawar, H. P.; Radosevich, A. T. J. Am.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Nanyang Technological University
NTU) and Ministry of Education, Singapore (MOE2015-T1-
01-029:RG9/15), for financial support. We also thank Dr.
Rakesh Ganguly and Dr. Li Yongxin (NTU) for assistance with
X-ray crystallographic analysis.
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DOI: 10.1021/jacs.7b09754
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX