Magnesium-catalyzed hydroboration of pyridines

Article abstract of DOI:10.1021/om2008138

Reaction of catalytic quantities of a β -diketiminato n-butylmagnesium complex with pinacol-borane in the presence of pyridine derivatives provides facile access to borylated dihydropyridines. The reaction is applicable to a wide range of monocyclic and fused-ring pyridine derivatives and catalytic turnover is proposed to occur through a well-defined sequence of Mg-H/pyridine dearomatization and Mg-N/B-H sigma bond metathesis steps.

Full text of DOI:10.1021/om2008138

Communication
pubs.acs.org/Organometallics
Magnesium-Catalyzed Hydroboration of Pyridines
Merle Arrowsmith, Michael S. Hill,* Terrance Hadlington, Gabriele Kociok-Kohn,
̈
and Catherine Weetman
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: Reaction of catalytic quantities of a β-diketiminato n-butylmagnesium
complex with pinacol−borane in the presence of pyridine derivatives provides facile
access to borylated dihydropyridines. The reaction is applicable to a wide range of
monocyclic and fused-ring pyridine derivatives and catalytic turnover is proposed to
occur through a well-defined sequence of Mg−H/pyridine dearomatization and Mg−
N/B−H sigma bond metathesis steps.
Scheme 1
earomatization of pyridine and its fused-ring derivatives
can provide access to a plethora of functionalized
D
molecules primed for further transformations.1 Although it
has long been known that stoichiometric addition reactions of
alkali-metal hydrides and alkyls give rise to reducing
dihydropyridide derivatives,2 the harsh conditions employed
and the relative instability of the dearomatized products does
not necessarily lend itself to extension to a more attractive
catalytic regime. Reports of homogeneous catalytic trans-
formations of this nature are very scarce and are limited to
an initial report of titanocene-based pyridine hydrosilylation by
Harrod and a very recent description of a ruthenium-centered
process by Nikonov and co-workers.3 Our own recent efforts
have concentrated upon the use of heavier alkaline-earth
elements, primarily Mg and Ca, in heterofunctionalization
catalyses more conventionally the preserve of less abundant
transition and rare-earth metals.4 While much of this work was
inspired by previous observations in the chemistry of trivalent
lanthanide derivatives, we have found that in many cases the
reduced charge density of the similarly d0 divalent alkaline-earth
centers results in divergent or, in many cases, complementary
reactivity. For example, Diaconescu and co-workers have shown
that a wide range of organometallic and hydrido group 3 and
lanthanide derivatives are capable of consecutive o-CH
activation and C−C coupling of N-heterocycles.5 In contrast,
the β-diketiminato n-butylmagnesium complex I (Scheme 1)
reacts cleanly with PhSiH3 in the presence of pyridine
derivatives to yield simple dearomatized dihydropyridide
species,6 presumably through the intermediacy of the
previously reported hydrido magnesium complex [HC{(Me)-
CN(2,6-iPr2C6H3)}2MgH]2.7 Although this dearomatization
reactivity was readily extended to a variety of substituted and
fused-ring pyridine derivatives, all attempts to incorporate these
species into a catalytic scenario such as that illustrated where E
= R3Si (R = alkyl, aryl, hydrido) in Scheme 1 were
unsuccessful.8 We have postulated that the necessary polarized
Si−H/Mg−N metathesis transition state (inset, Scheme 1) is
disfavored by the presence of additional strongly coordinating
pyridine molecules, which effectively impede interaction with
the relatively nonbasic phenylsilane.
The absence of catalytic reactivity for the silane-based
systems led us to turn our attention to commercially available
boranes as a source of hydride in the hope that the Lewis acidic
boron center would more effectively compete for access to the
Mg−N bond. We have previously described that the reaction of
9-borabicyclo[3.3.1]nonane (9-BBN) with a β-diketiminato
calcium diphenylamide provided clean access to a calcium
hydride species which was isolated as a dialkylborohydride
through interaction with a further 1 equiv of 9-BBN.9 A similar
NMR-scale reaction performed in d8-toluene between the
Received: August 30, 2011
Published: October 18, 2011
© 2011 American Chemical Society
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Table 1. Dearomatization−Hydroboration of Pyridine Derivatives with Pinacol−Borane Catalyzed by Compound I
a
b
Relative to a tetrakis(trimethylsilyl)silane internal standard in C6D6. After addition of another 1 equiv of pinacol−borane and heating at 70 °C for
c
d
a further 2 days. The solution turns dark red and red crystals form rapidly, depleting the catalyst in solution. On the basis of 3-methylnicotinate.
e
f
g
Isolated by recrystallization of the crude reaction mixture from hexanes at −30 °C. Isolated by vacuum distillation. Three equivalents of
h
1
pinacolborane. 88% conversion of 3-cyanopyridine; 60% to N,N′,N′-{B(OCMe2)2}3-3-aminomethyl-1,2- and -1,4-dihydropyridine. H NMR shifts
of the remaining 22% of dearomatized reaction products are attributed to partially reduced intermediates.
alternative reagent pinacol−borane (HBpin) and the β-
diketiminato magnesium butyl complex I proceeded instanta-
neously at room temperature. The 11B NMR spectrum of this
reaction mixture displayed a single resonance at around 37
ppm, ascribed to the n-butyl boronic acid pinacol ester (n-
Although attempts to obtain analytically pure bulk samples of
compound 1 were frustrated by the presence of variable
quantities of the n-BuBpin byproduct, some insight into the
nature of this problem and the identity of the magnesium
hydride species in solution was provided by the use of DOSY
NMR spectroscopy. The resonances attributed to compound 1
and the n-BuBpin byproduct displayed similar diffusion
coefficients at 298 K and converged to an identical value at
218 K. We interpret these observations to indicate the
formation of a labile magnesium-coordinated {n-BuHBpin}−
anion in solution in a manner reminiscent of that observed in
our previously reported studies of calcium amide reactivity with
9-BBN. In solution, it is likely that various magnesium and
boron hydride species are in exchange, a proposal further
supported by the outcome of a single-crystal X-ray study. This
latter analysis resulted from a few crystals obtained from a
similar reaction performed between the magnesium n-butyl
species I and an excess of the HBpin reagent. Although these
1
BuBpin), while the H NMR spectrum revealed evidence for
the clean formation of a single magnesium-containing
compound, 1. A single 1H resonance observed at 4.71 ppm
was ascribed to the methine in the β-diketiminate backbone,
and a resonance with an identical relative integration at 3.9 ppm
was tentatively assigned to a magnesium hydride through
comparison to Jones’ previously reported and silane-derived
hydride species [HC{(Me)CN(2,6-iPr2C6H3)}2MgH]2.7
A
single 12H resonance ascribed to the methyl groups of the
pinacol backbone was also observed to be shifted from that in
the starting material to around 1.0 ppm, indicating that the
HBpin had been cleanly converted to n-BuBpin by both the 11
NMR and the H NMR spectral data.
B
1
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11B
crystals diffracted very weakly, providing only 66% of the
complete data and consequently high residuals (R1 = 0.1031),
the connectivity of the molecule was unambiguous and revealed
a dimeric structure in which the magnesium centers are bridged
by μ-Mg−H−Mg and O−B−O bridging interactions provided
by the hydride and H2Bpin borohydride anions (see Figure S1
in the Supporting Information).
consumption of the pinacol−borane doublet resonance (δ
11
31.6 ppm) and the formation of a BH3 quartet at δ B −9.0 ppm
11B
and a new singlet at δ
25.7 ppm, resulting from
decomposition of the borane.
Hydroboration of 2-picoline led to exclusive formation of the
1,4-dihydropicoline, albeit in moderate yield even after
extensive periods of heating at 70 °C. Examination of the 11B
NMR data, however, showed formation of the same pinacol−
borane decomposition byproduct as observed with 4-DMAP.
Increasing the reaction temperature systematically led to
reduced turnover and faster degradation of the catalyst and
the pinacol−borane substrate. For 2,6-dimethylpyridine the
formation of the kinetic 1,2-dihydropyridine was entirely
prevented and no catalysis was observed (entry 6). Similarly,
no conversion to the dearomatized products was observed with
2-phenylpyridine and 2,2′-bipyridine, although a rapid color
change of the latter reaction mixture to dark red and formation
of highly insoluble red crystals was indicative of stoichiometric
dearomatization of the substrate.
Addition of 1 equiv of pinacol−borane (HBpin) and pyridine
to a solution of I resulted in the formation of an orange
solution, which provided a 1H NMR spectrum effectively
identical with that observed for previously reported magnesium
dihydropyridide species.6 Addition of a further 1 equiv of
HBpin resulted in the observation of a new 12H singlet
resonance at ca. δ 1 ppm in the 1H NMR spectrum, which was
attributed to the formation of dearomatized and hydroborated
pyridine (HPyBpin). This inference was confirmed by the 11B
NMR spectrum, which revealed a new singlet resonance at 27.1
ppm assigned to the HPyBpin product. While representative
uncatalyzed reactions of either pyridine or isoquinoline with
HBpin provided little evidence, 0% (70 °C) and 3% (20 °C)
conversion, respectively, for hydroboration, reactions employ-
ing a catalytic quantity of I (5−10 mol %) proceeded smoothly
under mild (25−70 °C) conditions (Table 1). The reactions
with quinoline and isoquinoline (Table 1, entries 11 and 12)
proceeded cleanly at room temperature and low catalyst
loading (5 mol %) within several hours to afford the N-Bpin-
1,2-dihydroquinoline derivatives in excellent yield. In contrast,
hydroboration of unsubstituted pyridine and its methyl and
phenyl derivatives required heating at 70 °C overnight and
catalyst loadings of 10 mol % to achieve similar conversions.
Mixtures of the N-borylated 1,2- and 1,4-dihydropyridines were
observed, distinguishable by their characteristic methylene
The catalytic system did not show any functional group
tolerance toward aldehyde or ester functionalities (entries 14
and 15). Instead of forming the dearomatized species, pinacol−
borane was seen to add across the carbonyl double bond and to
stoichiometrically cleave the methoxy group in the case of 3-
methylnicotinate. Although addition of another 1 equiv of
pinacol−borane to the reaction mixture with 3-pyridinecarbox-
aldehyde and subsequent heating at 80 °C for several days
resulted in the formation of small amounts of dearomatized
1
products (<5%), observed by H and 11B NMR spectroscopy,
decomposition side reactions rapidly depleted the amount of
active catalyst in solution. Similar reactivity was observed with
4-cyanopyridine (entries 17a,b) wherein the CN unit was
completely reduced by 2 equiv of pinacol−borane at room
temperature. Upon addition of a third 1 equiv of pinacolborane
and heating to 80 °C, however, the solution turned a deep blue
1
resonances which appeared in the H NMR spectra at ca. δ
4.0−4.2 and 2.6−2.9 ppm, respectively. In the cases of pyridine
(entries 1a−d), 3-picoline (entry 3), and 3,5-lutidine (entry 5)
the 1,4-adducts were formed as the major product (52−63%).
Variation of the reaction temperature for the hydroboration of
pyridine allowed the 1,4-adduct to be obtained almost
quantitatively at 80 °C (entry 1a) as the thermodynamic
product.6 Performing the reaction at 35 °C, however, did not
provide selective conversion to the 1,2-adduct (entry 1d).
Rather, an equimolar mixture of the 1,2- and 1,4-dihydropyr-
idines was obtained. The reaction did not proceed in significant
yields at lower temperature.
Hydroboration of 4-picoline (entry 4) principally yielded the
1,2-dihydropicoline (81%). The formation of the 1,4-adduct as
the minor product (19%) contrasts with stoichiometric
reactions of compound 1 with phenylsilane and 2 equiv of 4-
picoline, which exclusively afforded the 1,2-dihydro-4-methyl-
pyridide magnesium complex at 70 °C.8 Similarly, 4-phenyl-
pyridine quantitatively yielded the 1,2-dihydropyridine, without
formation of the 1,4-adduct being observed (entry 8). This may
be a steric effect from the larger phenyl substituent, which
prevents isomerization of the 1,2-dihydropyridide complex to
the 1,4-dihydropyridide. It is also notable that hydroboration of
4-phenylpyridine occurred much faster than that of 4-picoline,
suggesting a strong inductive effect of the pyridine ring
substituents upon hydroboration rates. Despite successful
stoichiometric dearomatization of 4-dimethylaminopyridine
(4-DMAP) with phenylsilane, the reaction did not afford
significant conversion under catalytic conditions (entry 13).
After 3 days at 80 °C, however, examination of the 11B NMR
spectrum of the crude reaction mixture showed complete
1
color and monitoring of the reaction by H NMR showed very
slow conversion to the fully reduced 1,2-dihydropyridine. In
contrast, the reaction of 3-cyanopyridine with 3 equiv of
pinacol−borane at room temperature led to a mixture of mainly
1,4-dihydropyridines showing no, partial, or full reduction of
the CN functional group. Heating this sample at 70 °C gave
the fully reduced N,N′N′-{B(OCMe2)2}3-3-aminomethyl-1,4-
dihydropyridine as the major product (entry 16).
For those reactions that proceeded cleanly (entries 1, 3−5, 8,
and 10−12), scale up allowed the isolation of the 1,2- and 1,4-
adduct mixtures, either by recrystallization from hexanes at −30
°C or by vacuum distillation, yielding low-melting colorless
solids or thick colorless oils which were thermally stable at
temperatures up to 170 °C. All dearomatized products were
highly air- and moisture-sensitive and decomposed rapidly
when left exposed to air or water. Monitoring of a sample of N-
Bpin-1,2-dihydroquinoline in C6D6 exposed to air showed the
rapid formation of NH-1,2-dihydroquinoline, characterized by a
1
broad H NMR NH resonance integrating for one proton at
2.61 ppm. This species then slowly decomposed to the
rearomatized quinoline starting material. The fate of the
pinacol−borane fragment during these decomposition reactions
became apparent through X-ray analysis of single crystals of
originally analytically pure (by NMR) N-Bpin-1,2-dihydroqui-
noline, which underwent decomposition upon contact with the
open atmosphere. This analysis (Figure S2, Supporting
Information) revealed the still dearomatized NH-1,2-dihydro-
quinoline cocrystallized with the previously reported bis-
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boryloxide [O(Bpin)2],10 formed presumably through sequen-
tial hydrolysis of N-Bpin-1,2-dihydroquinoline and condensa-
tion of two molecules of Bpin(OH). Analysis of the 11B NMR
spectra of hydroboration products of other pyridine derivatives
left exposed to moisture evidenced similar decomposition with
formation of the related dihydropyridine and [O(Bpin)2]
11
(singlet at δ 25.0 ppm).
B
Preliminary observations of the reactivity of the N-Bpin-
substituted pyridines reported herein indicate similar, but
possibly more selective, reactivity with electrophiles to those
described for analogous N-silylated derivatives.3b For example,
benzophenone was reacted with a sample of the mixed N-Bpin-
1,2- and N-Bpin-1,4-dihydropyridine products generated as
described by entry 1d in Table 1. Under these conditions only
the N-borylated 1,2-dihydropyridine (ca. 50%) of the sample
was rearomatized with consequent hydroboration of the
benzophenone (Figure S3, Supporting Information). We are
continuing to study the mechanisms and selectivity of this
reactivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, and a CIF file giving full experimental details,
NMR spectra, and crystallographic data for cocrystallized [NH-
1,2-dihydroquinoline][O(Bpin)2]. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: msh27@bath.ac.uk.
■
ACKNOWLEDGMENTS
We thank the EPSRC (U.K.) for funding.
■
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