An umpolung approach to the hydroboration of pyridines: A novel and efficient synthesis of: N -H 1,4-dihydropyridines

Article abstract of DOI:10.1039/c9sc05627k

The first inverse hydroboration of pyridine with a diboron(4) compound and a proton source has been realized under simple basic and catalyst-free conditions. This process consists of a formal boryl anion addition to pyridine, which produces an N-boryl pyridyl anion complex, and the subsequent protonation of the anion complex. This process enables a simple and efficient method for the synthesis of multi-substituted N-H 1,4-dihydropyridine (1,4-DHP) derivatives that are difficult to prepare using established methods. Furthermore, this method allows for facile preparation of 4-deuterated 1,4-DHPs from an easily accessible deuterium ion source. This inverse hydroboration reaction represents a new mode for pyridine functionalization.

Full text of DOI:10.1039/c9sc05627k

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An umpolung approach to the hydroboration of
pyridines: a novel and efficient synthesis of N-H
1,4-dihydropyridines†
Cite this: DOI: 10.1039/c9sc05627k
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have been paid for by the Royal Society
of Chemistry
*
Huan Yang, Li Zhang, Fei-Yu Zhou and Lei Jiao
The first inverse hydroboration of pyridine with a diboron(4) compound and a proton source has been
realized under simple basic and catalyst-free conditions. This process consists of a formal boryl anion
addition to pyridine, which produces an N-boryl pyridyl anion complex, and the subsequent protonation
of the anion complex. This process enables a simple and efficient method for the synthesis of multi-
substituted N-H 1,4-dihydropyridine (1,4-DHP) derivatives that are difficult to prepare using established
methods. Furthermore, this method allows for facile preparation of 4-deuterated 1,4-DHPs from an
easily accessible deuterium ion source. This inverse hydroboration reaction represents a new mode for
pyridine functionalization.
Received 7th November 2019
Accepted 23rd November 2019
DOI: 10.1039/c9sc05627k
rsc.li/chemical-science
we envisioned that if the hydroboration of pyridine could be
inverse in its polarity, a novel approach to DHPs might be
Introduction
realized. This could not only bring about a conceptually new
hydroboration process, but also expand the scope of pyridine
reduction. Herein, we report such an umpolung approach to
pyridine hydroboration, in which a formal addition of a boryl
anion to pyridine occurred rst, and the formed Meisenheimer
complex was then protonated to form the 1,4-DHP derivative
Dihydropyridine (DHP) represents an important class of
heterocyclic skeletons which prevalently exist in biologically
active agents, pharmaceutically important molecules, and
synthetically useful organic reductants, such as nicotinamide
adenine dinucleotide (NADH) and Hantzsch ester (HEH).1
Owing to their potential medicinal properties and broad
application as reducing agents, 1,4-DHP derivatives have
attracted great interest in terms of their synthesis.2 Reduction of
pre-activated pyridines using strong inorganic reductants
(Scheme 1a)3 and the Hantzsch cyclocondensation (Scheme 1b)4
are two conventional synthetic methods of 1,4-DHPs. In recent
years, an array of catalytic reduction reactions of pyridines
employing milder reducing reagents such as boranes and
silanes have been developed (Scheme 1c).5,6 In these reactions,
pyridine coordinates to a Lewis acid center under catalytic
conditions, and then the hydride addition occurs at the C4 (or
C2) position of the in situ activated pyridine.
These hydroboration and hydrosilylation protocols provided
ideal and exible approaches to DHPs from easily available
pyridine derivatives utilizing either metal- or organocatalysis.
Despite these achievements, alternative methodologies that
could produce N-H DHPs in a highly efficient and regioselective
manner are still in high demand. Opposite to the Lewis acid
activation–hydride addition mode involved in these protocols,
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua
University, Beijing 100084, China. E-mail: Leijiao@mail.tsinghua.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
additional information, and characterization data. CCDC 1935576. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c9sc05627k
Scheme 1 Methods for the synthesis of 1,4-dihydropyridines (1,4-
DHPs).
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(Scheme 1d). This anion formation–protonation sequence
enables an efficient approach to a variety of N-H 1,4-DHPs,
which are not easily accessible by conventional methods.
Results and discussion
Reaction design
Our idea for realizing the inverse pyridine hydroboration orig-
inated from our previous discovery that 4-phenylpyridine (1)
efficiently catalyses the borylation of aryl halides with bis(pi-
nacolato)diboron (B2pin2),7a as well as the related mechanistic
studies.7b It was found that the reaction of pyridine 1, B2pin2,
and a methoxide anion led to the formation of a trans-2H,20H-
[2,20-bipyridine]-1,10-diide borate complex 2 (Scheme 2). DFT
calculation suggested that the reaction between pyridine 1,
diboron, and methoxide rst led to the formation of an N-boryl
pyridyl Meisenheimer anion (Int-B) through heterolytic cleavage
of the B–B bond in the bis-coordinated diboron(4) (Int-A), which
was then trapped by another molecule of 1 to form complex 2.
Although Int-B was not observed experimentally, we envisioned
to attempt trapping of this proposed anionic intermediate by
protonation, which might produce product 3 and thus realize
an intriguing umpolung of the conventional pyridine hydro-
boration process. Further hydrolysis of 3 might afford N-H 1,4-
DHP product 4 (Scheme 2). If realized, such an inverse pyridine
hydroboration process would represent a novel mode of pyri-
dine reduction, and bring about new opportunities for the
synthesis of 1,4-DHP derivatives.
Fig. 1 Partial crude 1H NMR spectra of the 4-PhPy/B2pin2/MeOK
reaction system protonated with different amounts of methanol.
and 6.37 ppm (doublet, 2H), respectively. Interestingly, with 1.3
equiv. of MeOH, another set of peaks of dearomatized pyridine
appeared at 4.21 ppm (broadened triplet, 1H), 4.12 ppm
(multiplet, 2H), and 6.15 ppm (dd, 2H), respectively (Fig. 1b),
which became the only dearomatized species when excess
MeOH was used (Fig. 1c). The coupling pattern of these peaks
was in agreement with that of the desired 1,4-DHP molecule,
and gas chromatography-mass spectrometry (GC-MS) analysis
of the reaction mixture also detected the peak of the 1,4-DHP
product (m/z ¼ 157 for Mc+).
Proof-of-concept and mechanistic understanding
We set out to test this hypothesis by employing methanol as
a proton source. The reaction between pyridine 1, MeOK, and
B2pin2 was carried out in the presence of 18-crown-6 and varied
1
amounts of methanol in tetrahydrofuran (THF). H NMR anal-
ysis of the crude reaction mixture showed that when 1.1
equivalent of MeOH was employed, a set of peaks related to
dearomatized pyridine emerged (Fig. 1a). Their coupling
pattern tted well with a 4-hydro-4-phenylpyridyl motif, in
which the protons in the R–CH(CH]CH)2N moiety showed up
at 4.25 ppm (broadened triplet, 1H), 3.89 ppm (multiplet, 2H),
When excess deuterated methanol (MeOD) was employed,
the methine peak at 4.21 ppm decreased due to deuteration,
and the peaks at 4.12 and 6.15 ppm became a doublet because
deuterium replaces the coupling protons on both NH and
methane positions (Fig. 1d). This observation, together with the
GC-MS analysis of the product [m/z ¼ 159 for (M-d2)c+], sup-
ported the assignment of the 1,4-DHP structure. These experi-
mental ndings served as direct evidence for the formation of
the N-boryl pyridyl Meisenheimer anion (Int-B) in the
diboron(4)/pyridine/base system, and the regioselective
protonation at its C4 position brought about a novel approach
to 1,4-DHP derivatives. Because the present reaction is distinct
from the established hydroboration protocols in terms of the
reaction mechanism, it could be regarded as an inverse hydro-
boration process.
In order to gain further understanding regarding the
formation of the key intermediate Int-B and the regioselective
protonation at its C4-position, we performed DFT calculations.
In our previous study, the B–B bond cleavage transition state
Scheme 2 Design of the inverse hydroboration of pyridine based on
our previous mechanistic study.
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Table 1 Optimization of reaction conditionsa
(TS1$K) starting from the bis-coordinated diboron(4)8 has been
located.7b In the present study, we analysed the change of NBO
charge distribution during the B–B bond breaking event (Int-
A$K / TS1$K, Scheme 3). It was found that during this process,
negative charge transferred from the MeOBpin part (le part, in
blue) to the N-borylpyridine part (right part, in red), and the
NBO charge on C4 of the pyridine ring evolved from ꢀ0.001 to
ꢀ0.213, implying a heterolytic cleavage of the B–B bond with
a pair of electrons going to the forming N-boryl pyridyl Mei-
senheimer anion Int-B. The whole process could be viewed as
a formal addition of a boryl anion to pyridine, which served as
the key step of the inverse pyridine hydroboration. We noted
that in the phosphine-catalysed b-selective hydroboration
Entry
Diboron(4)
Base
Solvent
Conversionb
1
2
3
4
5
6
7
B2pin2
B2neo2
B2eg2
B2eg2
B2eg2
B2eg2
B2eg2
MeOK
MeOK
MeOK
MeONa
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
THF
THF
THF
MeCN
17%
63%
96%
78%
91%
73%
71%
´
´
reaction with B2pin2 developed by Gulyas and Fernandez,
a mechanism involving a similar formal boryl anion addition
towards conjugated electron-decient substrates was
proposed.9 The regioselectivity of the subsequent protonation
step was also analysed using the DFT calculated HOMO and the
corresponding orbital composition of Int-B (Scheme 3). It was
found that C4 of the pyridine ring had the largest contribution
to the HOMO of anion Int-B, which was supported by both the
plot of HOMO and the calculated molecular orbital composition
using the NAO method. This could account for the observed
regioselectivity in the protonation step, which exhibited pref-
erence to the formation of 1,4-DHP over 1,2-DHP.
a
Reaction conditions: 4-PhPy (0.36 mmol, 1 equiv.), diboron(4) (1.1
equiv.), base (1.1 equiv.), MeOH (11 equiv.), solvent (2 mL), sealed
b
tube, 30 ꢁC for 4.5 h. Determined by 1H NMR analysis. B2pin2
¼
bis(pinacolato)diboron; B2neo2
B2eg2 ¼ bis(ethylene glycolato)diboron.
¼
bis(neopentyl glycolato)diboron;
Acetonitrile was also proved to be a suitable solvent, although
the yield of 4 was lower than that in THF solvent (entry 7).
Subsequently, the scope of this reaction was tested by
employing various pyridine substrates. In general, this reaction
exhibits a broad substrate scope with respect to the pyridine
substrate, affording 1,4-DHP derivatives with different substi-
tution patterns in moderate to good yields (Table 2). Although
their structures were far from complex, many of these N-H 1,4-
DHPs were synthesized for the rst time, emphasizing the
synthetic value of the present protocol. Generally, the yields of
these rather air-labile products were quantied by 1H NMR
analyses of the reaction mixtures, and pure products could be
obtained by ash column chromatography on basic alumina
under an inert atmosphere. However, 4-substituted-1,4-DHPs
were difficult to purify because they underwent rapid oxida-
tion back to pyridine substrates (4, 6a, and 6b). Electron-
withdrawing substituents, such as amide, ester, and cyano
groups, were proved benecial to the hydroboration process,
affording the 1,4-DHP products in good yields.10 Of special note,
this inverse hydroboration protocol tolerated the active
hydrogen in the pyridine substrates (e.g., 5b and 5c), which
complements the traditional hydroboration methods. Multi-
substituted pyridines, such as 2,5-, 3,4-, and 3,5-disubstituted
ones (5h-l), were all compatible substrates. Interestingly, for
a nicotinate substrate bearing a 4-methoxy substitution (5m),
hydroboration occurred twice to afford 1,4-DHP product 6f
when 2.2 equivalents of B2eg2 and base were employed, due to
the elimination of the methoxy group. In all cases, the hydro-
boration occurred selectively at the 1,4-position, and no 1,2-
DHP product was obtained.
Optimization of reaction conditions and substrate scope
With this proof-of-concept in hand, we set out to search for
suitable reaction conditions for practical synthesis of 1,4-DHP
(Table 1). First, diboron(4) compounds with different steric
hindrances were attempted, and it was found that the less hin-
dered diboron(4) exhibits better reactivity (entries 1–3), with
bis(ethylene glycolato)diboron (B2eg2) leading to the best NMR
yield of 4-phenyl-1,4-dihydropyridine (4). A brief screen of bases
indicated that MeONa, Cs2CO3, and K2CO3 were all compatible,
and among them Cs2CO3 was the optimal one (entries 4–6).
The successful umpolung of the pyridine hydroboration
allowed for facile access to a series of 4-deuterated 1,4-DHPs.
1,4-DHPs are prevalently used as hydride and/or electron
donors in organic chemistry, and 4-deuterium substituted 1,4-
DHPs are always employed as ideal mechanistic probes and
organic deuteride transfer reagents. However, following the
Scheme 3 Mechanism of the formation of Meisenheimer complex
Int-B and its highest occupied molecular orbital (HOMO) from DFT
calculation.
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Table 2 Inverse hydroboration of pyridinesa
Table 3 Synthesis of 4-deuterated 1,4-DHP derivativesa
a
Reaction conditions: pyridine substrate (1 equiv.), B2eg2 (1.1 equiv.),
Cs2CO3 (1.1 equiv.), MeOD (22 equiv.), sealed tube, 50 ꢁC for 14 h.
Yields of the 1,4-DHP products were determined by 1H NMR analysis
of the reaction mixture using DMSO as the internal standard (isolated
yields are shown in parentheses). THF as the solvent. MeCN as the
solvent. MeONa was used instead of Cs2CO3. MeOK and 18-crown-
b
c
d
e
f
6 (1.1 equiv. both) were used instead of Cs2CO3. The reaction was
conducted at 65 ꢁC.
a
Reaction conditions: pyridine substrate (1 equiv.), B2eg2 (1.1 equiv.),
Cs2CO3 (1.1 equiv.), MeOH (11 equiv.), sealed tube, 50 ꢁC for 14 h.
Yields of the 1,4-DHP products were determined by 1H NMR analysis
of the reaction mixture using DMSO as the internal standard (isolated
yields are shown in parentheses). THF as the solvent. MeCN as the
solvent. MeONa was used instead of Cs2CO3. MeOK and 18-crown-
dihydropyridine (6d-d). Interestingly, double inverse hydro-
boration of pyridine 5m has been successfully utilized to
prepare 4,4-dideuterated 1,4-DHP 6f-d2. These results demon-
strate that our method can provide a straightforward synthetic
approach to a series of 4-deuterated 1,4-DHP derivatives, where
easily available and inexpensive MeOD was used as the deute-
rium source.
Further experiments were also performed to reveal the
limitations of the present protocol (Fig. 2). We found that
halogenated pyridines 5n and 5o, 3-triuoromethylpyridine
(5p), 2-substituted pyridines 5q and 5r, tetrasubstituted
b
c
d
e
f
6 (1.1 equiv. each) were used instead of Cs2CO3. The reaction was
conducted at 65 ꢁC.
established synthetic methods (Scheme 1a–c), less accessible
deuteride reagents (e.g., NaBD4 and DBpin) and deuterated
aldehydes should be employed to prepare 4-deuterated 1,4-
DHPs, while the present inverse hydroboration protocol only
requires a readily available D+ source for the same task. The
result shown in Fig. 1d has already demonstrated this, although
the deutero ratio was still not satisfactory with only 2.2 equiv. of
MeOD. To our delight, by employing 22 equiv. of MeOD, 1,4-
DHPs with high deuterium incorporation at the 4-position were
obtained (Table 3).
It was found that most pyridine substrates described in
Table 2 could be transformed to the desired 4-deuterated 1,4-
DHPs in moderate to good yields with excellent deuterium
incorporation (up to >98%) at the C4 position. Furthermore, the
structure of the 1,4-DHP product was unambiguously
conrmed using the XRD structure of 3-cyano-4-deuterated-1,4-
Fig. 2 Unsuccessful substrates for the inverse hydroboration.
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compatibility. A great advantage of this protocol is that 4-
deuterated 1,4-DHPs could be easily prepared using easily
available MeOD as the deuterium source. The produced 1,4-
DHP derivatives are complementary to previously known ones,
and can act as useful organic hydride/deuteride donors.
Conflicts of interest
The authors declare no competing nancial interest.
Acknowledgements
We acknowledge the nancial support from the National Key
Research and Development Plan (grant no. 2017YFA0505200)
and the National Natural Science Foundation of China (grant
no. 21772110 and 21822304). The technology platform of the
CBMS and the Tsinghua Xuetang Talents Program are
acknowledged for providing instrumentation and computa-
tional resources.
Scheme 4 The use of the produced 1,4-DHPs in asymmetric hydride/
deuteride transfer reaction.
pyridine 5s, and other pyridine-embedded heterocycles, such as
quinoline (5t), isoquinoline (5u) and acridine (5v), were not
compatible with this inverse hydroboration protocol. They
either exhibited a low reactivity, or produced a complex mixture
of products under the reaction conditions.
Notes and references
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Potential use of the 1,4-DHP product
1,4-DHPs are typical organic hydride donors in hydride transfer
reactions.1g In particular, Hantzsch ester (HEH) is the most
prevalently used hydride donor in asymmetric hydride transfer
reactions. Since many of the newly synthesized 1,4-DHPs are
structurally unprecedented in the literature, we are curious
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A
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Conclusions
In conclusion, the umpolung of pyridine hydroboration has
been realized for the rst time by utilizing the diboron(4)/
pyridine/base system in a transition-metal-free manner. The
key steps include a base-promoted formal addition of a boryl
anion to pyridine, and the subsequent protonation of the
produced N-boryl pyridyl anion complex. This inverse hydro-
boration process enables a simple and efficient method for the
synthesis of 1,4-dihydropyridine derivatives from pyridines, and
features broad substrate scope and good functional group
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´
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