Transition-metal-free BF3-mediated regioselective direct alkylation and arylation of functionalized pyridines using grignard or organozinc reagents

Article abstract of DOI:10.1021/ja401146v

A formal regioselective cross-coupling of various pyridines with alkyl and aryl groups can be achieved by a BF₃·OEt₂-mediated addition of Grignard or organozinc reagents to pyridines bearing various substituents (chloro, bromo, cyano, vinyl, phenyl, carbethoxy, nitro, etc.) followed by an oxidative aromatization mediated by chloranil. Good regioselectivity and wide functional group tolerance make this method very versatile for the preparation of polyfunctional pyridines. No transition-metal catalyst is required in these coupling reactions.

Full text of DOI:10.1021/ja401146v

Communication
pubs.acs.org/JACS
Transition-Metal-Free BF3‑Mediated Regioselective Direct Alkylation
and Arylation of Functionalized Pyridines Using Grignard or
Organozinc Reagents
Quan Chen, Xavier Mollat du Jourdin, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
Scheme 1. Selective Addition of a Grignard Reagent to 1a
ABSTRACT: A formal regioselective cross-coupling of various
pyridines with alkyl and aryl groups can be achieved by a
BF3·OEt2-mediated addition of Grignard or organozinc reagents
to pyridines bearing various substituents (chloro, bromo, cyano,
vinyl, phenyl, carbethoxy, nitro, etc.) followed by an oxidative
aromatization mediated by chloranil. Good regioselectivity and
wide functional group tolerance make this method very versatile
for the preparation of polyfunctional pyridines. No transition-
metal catalyst is required in these coupling reactions.
yridines are an important class of N-heterocycles including
1
2
BF3 facilitates this addition reaction considerably, and without this
Lewis acid, no reaction occurs.15
Pmany bioactive compounds and functional materials. The
direct functionalization of these heterocyclic scaffolds has been
achieved by numerous methods, including C−H activation,3
radical reaction,4 and directed metalation.5 Nevertheless, these
approaches always require the addition of catalytic or
stoichiometric amounts of transition metals, most of which are
expensive and nonenvironmentally benign. Besides, such
transition-metal catalyzed procedures are frequently accompa-
nied by side reactions such as homocoupling and β-hydride
elimination. Moreover, especially for the pharmaceutical
industry, the removal of harmful transition-metal contamination
is often costly and difficult.6
To avoid using transition metals, oxidative Chichibabin-type
two-step strategies (nucleophilic addition followed by oxidative
aromatization) represent one of the most expedient methods for
the direct functionalization of pyridine derivatives.7 Yet, a pre-
activation of the pyridine ring such as N-oxidation, N-acylation, or
N-alkylation is usually required.8 Especially for hard nucleophiles
such as organolithium, Grignard, and organozinc reagents, the
nucleophiles add mostly to the C(2)-position of the pyridine
ring. The formation of a small but not negligible amount of a
4-substituted product is often observed, lowering somewhat the
synthetic value of these methods.9 As a solution, we report a novel
transition-metal-free BF3·OEt210 mediated regioselective synthesis
of 4-substituted pyridine derivatives using LiCl activated
Grignard11 or organozinc reagents.12
The presence of LiCl has a beneficial effect since the addition
of EtMgCl·LiCl provides the product (4b) in 94% NMR yield
(NMR determination with internal standard calibration). In the
absence of LiCl, EtMgCl furnishes the desired product (4b) in
only 67% NMR yield (Table 1, entry 1). A range of primary and
secondary alkylmagnesium derivatives add in the presence of LiCl to
3-chloropyridine (1a) to furnish regiospecifically the 4-substituted
products (4c−f) in 70−94% yield (entries 2−5). Notably, even a
tertiary alkyl group such as a tert-butyl group can be introduced to
nicotinonitrile (1b) in 70% yield (entry 6). In order to exclude a
radical pathway, we used hex-5-en-1-ylmagnesium chloride (5) as
a radical clock, but no cyclized product was obtained and only
the linear substituted pyridine (4h) was obtained in 76% NMR
yield (entry 7). Several other 3-substituted pyridines such as
3-bromopyridine (1c), ethyl nicotinate (1d), 3-phenylpyridine (1e),
and 3-vinylpyridine (1f) add iPrMgCl·LiCl, leading to the desired
4-substituted pyridines (4i−l) in 47−79% yield (entries 8−11).
i
Also, 2-chloropyridine (1g) adds PrMgCl·LiCl in the C(4)-
position to afford the corresponding disubstituted pyridine (4m) in
76% NMR yield. Interestingly, the 2-chloro substituent is inert under
these conditions (entry 12). Similarly, a 1,2,3-trisubstituted pyridine
(4n) can be readily prepared in 93% isolated yield (entry 13).
In the case of quinoline, the addition of iPrMgCl·LiCl occurs with
good regioselectivity to afford the 4-substituted quinolines (4o−q)
in 78−86% isolated yield (entries 14−16). Yet, <10% of the corres-
ponding 2-substituted quinolines16 have also been isolated.17
To expand the scope of this reaction, we have investigated the
use of alkylzinc reagents12c for the nucleophilic addition. The
addition of OctZnBr·MgCl2·LiCl to nicotinonitrile (1b) led to an
Thus, treatment of 3-chloropyridine (1a) with BF3·OEt2 (1.1
equiv, THF, 0 °C, 15 min) affords the Lewis pair (2). Subsequent
addition of iPrMgCl·LiCl (1.2 equiv, −50 °C, 0.5 h) leads to the
tentative intermediate (3), which was conveniently aromatized
by the low toxic13 chloranil14 (2.0 equiv, 25 °C, 2 h) affording the
3-chloro-4-isopropylpyridine (4a) in 89% isolated yield. The
regioisomeric 2-substitution product is not observed (Scheme 1).
Received: February 1, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja401146v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Direct Alkylation of Pyridine Derivatives Using
Grignard Reagents
Scheme 2. Selective Addition of an Organozinc Reagent to
Nicotinonitrile
Thus, a variety of functionalized zinc reagents react under
these conditions and highly functionalized products were
obtained in 60−93% yield. Remarkably, functionalized mixed
diorganozinc reagents with an acetoxy, a carbethoxy,19 or a cyano
group can be prepared and used without problems (Table 2).
Table 2. Direct Alkylation of Pyridine Derivatives Using
Alkylzinc Reagents
a
b
2MgX2·LiCl is omitted for clarity. Isolated yields of analytically pure
c
products. The reaction was carried in an 8 mmol scale.
Next, we have examined the arylation of functionalized
pyridines (Table 3). Here, arylmagnesium reagents proved to
give the best results and a smooth addition is obtained with a variety
of Grignard reagents leading to polyfunctional 4-arylated pyridines
(7a−n; 42−99%). Remarkably, a number of functional groups are
tolerated in the starting pyridines such as an ester (entries 1−4), an
amide (entries 5), a ketone (entry 6), a nitro8g (entry 7), and a cyano
group (entries 8−14). In a large scale (8 mmol) reaction,
2-chloromethylphenylmagnesium bromide20 adds to ethyl nicotinate
(1d) and leads to the pyridine (7d) in 83% isolated yield (entry 4).
Both Grignard reagents with electron-withdrawing (entry 9) or
-donating groups (entry 10) afford 4-arylated pyridines (7i and 7j) in
high yields. Even a bulky Grignard reagent such as mesitylmagnesium
bromide reacts efficiently with nicotinonitrile (1b) and furnishes the
4-mesitylnicotinonitrile (7k) in 98% isolated yield (entry 11). For a
4-substituted starting pyridine such as isonicotinonitrile (1o), the
addition of a Grignard reagent cannot occur at C(4) but proceeds
at C(2) and furnishes the corresponding product in acceptable yields
(entries 12 and 13). Finally, 2-chloronicotinonitrile (1p) is converted to
the 1,2,3-trisubstituted pyridine (7n) in 57% isolated yield (entry 14).
To introduce a more functionalized aryl group, p-EtO2C−
C6H4MgCl·LiCl (9) was prepared in situ via an iodine/magnesium
exchange.11a In a reversed addition procedure, a mixture of
a
Isolated yields of analytically pure products. NMR yields are
b
given in parentheses. The reaction is performed with EtMgCl.
c
The low isolated yield is caused by a difficult chromatographical
separation.
unsatisfactory reaction with uncompleted conversion. However,
by forming the mixed diorganozinc reagent OctZntBu, readily
prepared by adding BuMgCl to OctZnBr·MgCl2·LiCl, we
t
obtained a fast and quantitative addition to nicotinonitrile (1b)
at −50 °C. After oxidative treatment with chloranil, the desired
4-substituted pyridine (6a) was obtained in 99% yield (Scheme 2).
The tert-butyl group plays in all these reactions the role of a non-
transferable ligand.18 It should be noticed that although the tert-butyl
group bears 9 β-hydrogens, no significant β-hydride elimination is
observed in these reactions, since no transition metal is present. This
enables us to avoid using more expensive nontransferable ligands
such as neopentyl, neophyl,18b or trimethylsilylmethyl,18a,c which
bears no β-hydrogen.
B
dx.doi.org/10.1021/ja401146v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Direct Arylation of Pyridine Derivatives Using
Grignard Reagents
Scheme 4. Double Addition to Nicotinonitriles Using
a
a 1,4-Dimagnesiated Aromatic Reagent
a
Yield based on Grignard reagent.
1 equiv of tBuMgCl is used to deprotonate the amide nitrogen and 2
equiv of BF3·OEt2 are added, leading to the tentative intermediate 13.
Both alkyl and aryl Grignard reagents react with 13, and the desired
products (14−15) are obtained in good yields (Scheme 5).
Scheme 5. Direct Alkylation and Arylation of Nicotinamide
To explore some mechanistic details of this reaction, 3-
i
chloropyridine (1a) was reacted with premixed PrMgCl·LiCl
and EtMgCl·LiCl in equal amounts. Interestingly, the bulkier
isopropyl adduct (4a) is mainly formed (eq 1). It indicates that,
rather than steric effects, the nucleophilicity and aggregation of
the Grignard reagents play a more important role in these
additions to pyridines. Besides, more electron-deficient ethyl
nicotinate (1d) undergoes the addition of the Grignard reagent
more readily (ca. 4 times) than 3-chloropyridine (1a) (eq 2).
a
b
Isolated yields of analytically pure products. The reaction was
carried in a 8 mmol scale.
nicotinonitrile (1b) and BF3·OEt2 was added to the Grignard
reagent 9 to furnish a dual-functionalized pyridine (7o) in 86%
isolated yield (Scheme 3).
Scheme 3. Selective Addition of a Functionalized Grignard
Reagent to Nicotinonitrile
In summary, we have developed a transition-metal-free
BF3·OEt2-mediated functionalization of pyridines with function-
alized alkyl and aryl groups. An excellent C(4)-regioselectivity
makes this method a complement to previously reported ones.
This reaction is practical and can be performed at a larger scale
with no decrease in yield. Further mechanistic and synthetic
studies are underway in our laboratory.
ASSOCIATED CONTENT
Nicotinonitrile oligomers are usually used as functional
materials, but their synthesis is always complex.21 Surprisingly,
with the aid of BF3·OEt2, a dimagnesiated species (10)11b reacts
with 2 equiv of nicotinonitrile and affords a fluorescent
compound 11 in one step (Scheme 4).
Also, nicotinamides are widely used as building blocks for many
pharmaceuticals. However, the direct functionalization of nicotina-
mides always relies on transition-metal catalyzed procedures.3f,22 Here,
■
S
* Supporting Information
1
Full experimental details, H and 13C spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
paul.knochel@cup.uni-muenchen.de
■
C
dx.doi.org/10.1021/ja401146v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
2005, 7, 5059. N-Alkylation: (q) Loska, R.; Mak
̧
osza, M. J. Org. Chem.
Notes
2007, 72, 1354. Others: (r) Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang,
M. Org. Lett. 2001, 3, 2807. (s) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7,
5535.
(9) (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel,
J. J. Am. Chem. Soc. 2001, 123, 11829. (b) Legault, C.; Charette, A. B. J.
Am. Chem. Soc. 2003, 125, 6360.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Fonds der Chemischen Industrie and the
European Research Council (ERC-227763) and Sonderfor-
schungbereich (SFB-749) of the German Science Foundation
(DFG) for financial support and Rockwood Lithium (Frankfurt)
for the generous gift of chemicals.
(10) (a) Maruyama, K.; Yamamoto, Y. J. Am. Chem. Soc. 1977, 99,
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