Angewandte
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As shown, the ability to incorporate diverse N-activating
groups allows subsequent derivatization of the dihydropyr-
idine. The structure of the amide 11 was confirmed by X-ray
analysis.
pyridine was a suitable substrate is particularly noteworthy
since these reagents readily participate in cross-coupling
reactions. Thus their successful application highlights the
mildness of the method while retaining the 2-chloro group for
subsequent chemistry. This reaction was also applied to
quinoline 4-boronic esters, giving good yields for these
substrates (21, 36, 48). Expansion of this methodology to 5-
and 7-borono-quinolines and 6-borono-isoquinoline was only
modestly successful (49–51). Additionally, the 2-pyridyl
boronic esters were too unstable for the current reaction
conditions,[7b] thus providing large amounts of protodebory-
lated pyridines.
Typical oxidations of boronic esters require peroxides, so
the facile oxidation shown in Table 1 was surprising.[12] The
rate of this oxidation is insensitive to the nature of activating
group (both steric and electronic), but qualitatively depen-
dent on the substituent at the 4-position (Ph > primary alkyl >
tertiary alkyl). These observations suggest a radical mecha-
nism. Indeed, trialkyl boranes are known to react with oxygen
to generate alkyl radicals.[15] However, we observed no ring
opening of the cyclopropyl ring in 42, which indicates that the
lifetime of any radical must be short.
Hall and co-workers previously prepared tetrahydropyr-
idines featuring an allylic boronic ester, and they showed that
such compounds participated in allylation reactions.[16] By
contrast, the 4-boryl-4-dihydropyridine products described
here are unknown reagents. Therefore we next explored their
synthetic utility. For example, addition of the allyl boronate to
benzaldehyde generated the desired homoallylic alcohol (Æ)-
52 with good yield and diastereoselectivity (Scheme 3a).[17]
Hydrogenation of (Æ)-52 gave the trisubstituted piperidine
(Æ)-53 while oxidation provided the disubstituted pyridine 54,
Upon treatment of the dihydropyridine with oxygen and
base, rapid formation of the substituted pyridine was
observed.[13] A broad range of substituted pyridines and
quinolones were synthesized as highlighted in Table 1.
Primary, secondary, and tertiary alkyl lithium reagents were
successfully used, as were aryl and alkynyl lithium species.
Optically active lithiated Boc-pyrrolidine was an excellent
substrate, thus leading to the pyridines 26–28 in high yields
and high enatiomeric ratios.[14] To introduce functionalized
nucleophiles, we explored the use of aryl and alkyl zinc
reagents. Ester, bromo, and cyano groups were all accom-
modated (29–31). Although the reaction worked well with
aryl zinc halides, the analogous reaction using alkyl zinc
reagents proved more difficult. Accordingly, we used a mixed
zinc reagent derived from the zinc chloride and tert-butyl
magnesium chloride and achieved good yields of the ester
32.[5] Additionally, alkyl, aryl, and vinyl Grignard reagents
provided the pyridines in high yields. Two cyclopropyl
Grignard reagents were incorporated without any evidence
of ring opening (41, 42). Overall, the reaction is notable for its
ability to 1) incorporate sp3-, sp2-, and sp-hybridized carbon
nucleophiles, 2) accommodate organolithium, organozinc,
and organomagnesium reagents, and 3) introduce electro-
philic functional groups including nitriles and esters.
This coupling not influenced by the substitution on the
pyridine ring itself. Electron-donating and electron-with-
drawing groups were tolerated at the 2- and 3-positions (17–
20, 27–28, 34–35, 43–46). The observation that the 2-chloro-
Table 1: Substrate scope for preparation of substituted pyridines.[a]
[a] Typical conditions: het-B(pin) (1 equiv, 0.3 mmol), R-M (1.1 equiv), À788C, CCl3COCl (2 equiv), À78 to À408C; 10% NaOH (aq.), RT, O2 balloon.
[b] Yield of isolated product. [c] Typical conditions: (À)sparteine (1.3 equiv, 0.39 mmol), sBuLi (1.3 equiv, 0.39 mmol), N-Boc pyrrolidine (1.3 equiv,
0.39 mmol); het-B(pin) (1 equiv, 0.3 mmol), À788C, CCl3COCl (3.5 equiv), À788C; saturated aq. Na2CO3 RT, O2 balloon. het-B(pin)=heteroaryl
pinacol boronic ester.
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Angew. Chem. Int. Ed. 2016, 55, 2205 –2209