Transition-metal-free BF3-mediated oxidative and non-oxidative cross-coupling of pyridines

Article abstract of DOI:10.1002/anie.201400750

We report a BF₃-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF₃· OEt₂ as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines. Oxidative or non-oxidative - That is the question! Pyridines bearing a substituent at position 4 readily undergo a BF₃-mediated oxidative coupling at position 2 with a wide range of alkynyllithium compounds. In contrast, 4-cyano- or 4-chloropyridines undergo a novel BF₃-mediated cross-coupling at position 4 with alkylmagnesium reagents. The combination of the two transition-metal-free procedures allows the preparation of a broad range of pyridines.

Full text of DOI:10.1002/anie.201400750

Angewandte
Chemie
DOI: 10.1002/anie.201400750
BF3-Mediated Coupling
Transition-Metal-Free BF3-Mediated Oxidative and Non-Oxidative
Cross-Coupling of Pyridines**
Quan Chen, Thierry Leꢀn, and Paul Knochel*
Dedicated to the MPI fꢁr Kohlenforschung on the occasion of its centenary
Abstract: We report a BF3-mediated direct alkynylation of
pyridines at C(2) by using a variety of alkynyllithium reagents
(oxidative cross-coupling). Moreover, we have developed
a novel transition-metal-free cross-coupling method between
alkylmagnesium reagents and 4-substituted pyridines, such as
isonicotinonitrile and 4-chloropyridine, by employing
BF3·OEt2 as a promoter. The combination of these methods
enabled us to efficiently prepare a range of di-, tri-, and
tetrasubstituted pyridines.
F
unctionalization of the pyridine scaffold is an important
synthetic task, since polyfunctional pyridines are widely used
for pharmaceutical and biological applications.[1] Transition-
metal-catalyzed cross-coupling methods have been used
extensively to functionalize the pyridine skeleton.[2,3] How-
ever, the use of Pd or Ni catalysts has some drawbacks, such as
the toxicity or price of the metal and the need for ligands.
Recently, we reported that 3-substituted pyridines of type
1 undergo BF3-mediated[4] oxidative cross-coupling reac-
tions[5,6] at position 4 with various alkyl- and arylmagnesium
or -zinc reagents to give 3,4-disubstituted pyridines of type 3
via a tentative intermediate of type 2 (Scheme 1).[7] These
reactions are remarkably regioselective and proceed almost
only at position 4. We wondered which reaction course would
be observed if position 4 of the pyridine ring was occupied by
a substituent. Herein, we report a new BF3-mediated oxida-
tive cross-coupling of pyridines of type 4 with alkynyllithium
derivatives 5 via a tentative intermediate 6, which leads to 2,4-
disubstituted pyridines of type 7. As a guideline for predicting
this regioselectivity, it should be noticed that the complex-
ation of the pyridine nitrogen atom with BF3 makes posi-
tions 2, 4, and 6 of the pyridine ring especially electrophilic,
thus favoring the formation of new carbon–carbon bonds at
these positions.
Scheme 1. BF3-mediated oxidative and non-oxidative cross-coupling of
pyridines.
attractive cross-coupling procedure which doesn’t require
either an oxidative step or a transition-metal catalyst but
proceeds through an addition-elimination step mediated by
BF3·OEt2. This method allows the direct substitution of X
(X = CN, Cl) in pyridines of type 4 with various alkyl groups
from Grignard reagents via the tentative intermediate 8 to
afford products of type 9.[8] We will demonstrate that these
new reactions allow a convenient functionalization of the
pyridine scaffold to obtain various di-, tri-, and tetrasubsti-
tuted pyridines.[9]
As a typical example, a 4-substituted pyridine, isonicoti-
nonitrile (4a), was treated with BF3·OEt2 (1.1 equiv, THF,
08C, 15 min). After subsequent addition of triisopropylsilyl-
ethynyllithium (5a, 1.5 equiv, À308C, 1 h) and rearomatiza-
tion with chloranil (2.0 equiv, 258C, 2 h), the 2,4-disubstituted
pyridine 7a was isolated in 81% yield (Scheme 2).
The overall result may also be governed by steric effects.
In the course of this work, we discovered an even more
[*] Dipl.-Chem. Q. Chen, Dr. T. Leꢀn, Prof. Dr. P. Knochel
Department of Chemistry
Ludwig-Maximilians-Universitꢁt Mꢂnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢂnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC-227763), and Sonderforschungbereich
(SFB-749) of the German Science Foundation (DFG) for financial
support. We also thank BASF AG (Ludwigshafen) and Rockwood
Lithium (Frankfurt) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400750.
Scheme 2. BF3-mediated addition of the alkynyllithium compound 5a
to isonicotinonitrile (4a).
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Table 1: Direct alkynylation of pyridine derivatives using various alkynyllithium compounds.
Under these conditions, a vari-
ety of 4-substituted pyridines (4;
X = CN, Cl, Br, Ar, or R) react with
Entry Substrate
Alkinyllithium
reagent
Product
Yield
[%][a]
various
alkynyllithium
com-
pounds[10] bearing an alkyl (5b and
5c), aryl (5e and 5g), silyl (5d), or
alkenyl substituent (5 f) to afford
the expected functionalized pyri-
dines 7b–k in yields of 53–89%
(Table 1, entries 1–10). No coupling
product 7b was detected in the
absence of BF3·OEt2 (Table 1,
entry 1). Notably, the presence of
an electron-withdrawing substitu-
ent at position 4 is not required,
and an aryl or a tert-butyl substitu-
ent at position 4 lead to the
expected products 7i–k in yields of
53–63% (Table 1, entries 8–10). In
the case of 4e, the addition occurs at
position 6 (rather than at posi-
tion 2) as a result of the steric
hindrance of the carbethoxy group.
In the absence of a substituent at
position 4, we still observed a reac-
tion at positions 2 or 6. Thus, 2-
cyanopyridine (10a) reacts with the
alkynyllithium compound 5h at
position 6 to furnish the 2,6-disub-
stituted pyridine 11 in 66% yield.
When electron-withdrawing sub-
stituents are present at position 3,
a smooth alkynylation occurs at
position 2 to give the 2,3-disubsti-
tuted pyridines 12a–c in yields of
69–82% (Table 1, entries 12–14).[11]
The coupling reaction also proceeds
well when electron-rich 3-picoline
(1d) is used as the substrate, yet
surprisingly it takes place at the
more crowded C(2)-position and
a 2,3-disubstituted product (12d) is
obtained (Table 1, entry 15). Even
pyridine itself (13) undergoes the
coupling reaction with the lithium
reagent 5 f and gives 2-substituted
product 14 in 66% yield (Table 1,
entry 16).
1
89(0)[b]
2
3
71
89[c]
4
71
5
6
7
77
82
75
8
9
63
53
10
11
61
66
A double functionalization at
positions 2 and 6 can also be readily
achieved. Thus, isonicotinonitrile
(4a) is alkynylated at position 2 by
our standard procedure, which
results in the formation of 7l and
7m in yields of 65 and 76%, respec-
tively. The addition of a second
alkynyllithium reagent in the pres-
ence of BF3·OEt2 followed by oxi-
dative rearomatization furnishes
1a:
X=Cl
1b:
X=Br
1c: X=I
12a:
X=Cl
12b:
12
13
74
82
X=Br
14
12c: X=I 69
2
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Table 1: (Continued)
tallic reagents such as alkynyl-
lithium compounds 5 f and 5h or
2-thienylmagnesium halide
Entry Substrate
Alkinyllithium
reagent
Product
Yield
[%][a]
undergo an oxidative cross-cou-
pling at position 6 to afford the
tetrasubstituted pyridines 18a–c in
yields of 53–89% (Scheme 4).
Treating isonicotinonitrile (4a)
in the presence of BF3·OEt2 with an
alkylmagnesium reagent com-
plexed with lithium chloride
instead of an alkynyllithium
resulted in the formation of an
unexpected 4-substituted product
of type 9 (Scheme 1). Thus, the
treatment of 4a with BF3·OEt2 at
15
16
64
66
[a] Yields of isolated, analytically pure products. [b] Reaction performed in the absence of BF3·OEt2.
[c] TMS=trimethylsilyl.
08C followed by the addition of c-HexMgBr·LiCl (1.2 equiv)
at À508C leads to a very fast cross-coupling reaction (within
30 min) to afford the 4-substituted pyridine 9a in 71% yield
(Scheme 5).
The BF3-mediated cross-coupling can be extended to
various primary and secondary organomagnesium reagents to
afford the 4-substituted pyridines 9b–e in 46–89% yield
(Table 2). The substitution does not occur without the
assistance of BF3·OEt2 (Table 2, entry 1). Interestingly, 2-
chloro-4-cyanopyridine (19), which could in principle
undergo a cross-coupling at position 2 (the 2-chloro substitu-
ent is a good leaving group),[12] reacts smoothly at position 4
to give chloropyridine 9e as the only detectable product in
46% yield (Table 2, entry 4). To evaluate the difference in
reactivity between a chloro and a cyano substituent in such
BF3-mediated cross-coupling reactions, we submitted a 1:1
mixture of 4a and 4b to a BF3-mediated cross-coupling with c-
HexMgBr·LiCl. We found that the cyano group is a better
leaving group, and leads within 30 min to the full consumption
of 4a and the formation of the desired product 9a in 94%
yield. The chloropyridine 4b could be recovered in 81% yield
(Scheme 5). The higher reactivity of the isonicotinonitrile
(4a) may be explained by the mesomeric acceptor properties
of the cyano group compared to the mesomeric donor
properties of the chloro substituent (acid cyanides are also
more electrophilic than acid chlorides).[13]
Scheme 3. BF3-mediated direct alkynylation leading to the preparation
of 2,4,6-trisubstituted pyridines. Reaction conditions: a) BF3·OEt2
(1.1 equiv, THF, 08C, 15 min); b) 5h (1.5 equiv, À308C, 1 h); c) chlor-
anil (2.0 equiv, 258C, 2 h); d) 5d (1.5 equiv, À308C, 1 h); e) 5e
(1.5 equiv, À308C, 1 h); f) 5 f (1.5 equiv, À308C, 1 h); g) 5g (1.5 equiv,
À308C, 1 h).
the 2,4,6-trisubstituted pyridines (15a–c) in
yields of 60–74% (Scheme 3).
Moreover, highly functionalized tetrasub-
stituted pyridines were obtained from nicoti-
nonitrile (1e) by a sequence of several
oxidative cross-coupling reactions. The first
carbon–carbon bond formation occurs at
position 4 as expected,[7] which leads to the
disubstituted pyridine 16 in 95% yield. Posi-
tions 2 and 6 of 16 can be readily differ-
entiated since the cyano group strongly acti-
vates position 2. Therefore, the addition of
the alkynyllithium reagent 5j in the presence
of BF3·OEt2 produces only the 2,3,4-trisubsti-
tuted pyridine 17 in 88% yield after treatment
Scheme 4. BF3-mediated polyfunctionalization of nicotinonitrile (1e) for the preparation of
with chloranil. Finally, a range of organome- 2,3,4,6-tetrasubstituted pyridines.
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Scheme 5. BF3-mediated substitution of isonicotinonitrile (4a) and 4-
chloropyridine (4b) by c-HexMgBr·LiCl. The yields of the competition
experiment were determined by GC using n-undecane as an internal
standard.
Table 2: Non-oxidative cross-coupling of isonicotinonitrile (4a) or 4-
chloropyridine (4b) using Grignard reagents.
Entry Substrate
Grignard reagent Product
Yield [%][a]
Scheme 6. Consecutive BF3-mediated alkynylation and substitution for
the preparation of 2,4-disubstituted pyridines.
1
89(0)[b]
proceeds with alkynyllithium reagents and affords 2- or 6-
substituted pyridines after oxidative rearomatization. On
another hand, the cross-coupling procedure leads to the
substitution at position 4 of a chloro or cyano substituent by
an alkylmagnesium reagent. Neither method requires the use
of a transition-metal catalyst. Extension to other N-hetero-
cycles and applications to the synthesis of natural products is
currently underway.
2
3
4
c-PentMgCl·LiCl
63
72(76)[c]
46
iPrMgCl·LiCl
Received: January 23, 2014
Published online: && &&, &&&&
[a] Yields of isolated, analytically pure products. [b] Reaction performed
in the absence of BF3·OEt2. [c] 4-Chloropyridine (4b) was used as the
substrate.
Keywords: alkynyllithium compounds · BF3 · chloranil ·
.
cross-coupling · nitrogen heterocycles
To demonstrate the versatility of our methods we have
combined the two new functionalization procedures of
pyridines (oxidative and non-oxidative cross-coupling reac-
tions) to produce various 2,4-disubstituted pyridines of type
20. Thus, isonicotinonitrile (4a) and 4-chloropyridine (4b)
were treated with the alkynyllithium reagents 5b,j,i in the
presence of BF3·OEt2, which led after oxidative workup with
chloranil to the 2-alkynylated pyridines 7n–p in yields of 73–
84%. After these oxidative cross-coupling reactions, we
performed a BF3-mediated cross-coupling with various alkyl-
magnesium reagents, which afforded the 2,4-disubstituted
pyridines 20a–c in yields of 66–88% by substitution of the
chloro or cyano substituent (Scheme 6). Interestingly, the 2,6-
dialkynylisonicotinonitriles 15a–c (Scheme 3) do not undergo
these cross-coupling reactions and only starting materials are
recovered, thus indicating that the complexation of BF3 at the
pyridine nitrogen atom (and not at the cyano nitrogen atom)
is crucial for the success of this substitution reaction.
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Communications
BF3-Mediated Coupling
Q. Chen, T. Leꢁn,
P. Knochel*
&&&& — &&&&
Transition-Metal-Free BF3-Mediated
Oxidative and Non-Oxidative Cross-
Coupling of Pyridines
Oxidative or non-oxidative—That is the
question! Pyridines bearing a substituent
at position 4 readily undergo a BF3-
mediated oxidative coupling at position 2
with a wide range of alkynyllithium com-
pounds. In contrast, 4-cyano- or 4-
chloropyridines undergo a novel BF3-
mediated cross-coupling at position 4
with alkylmagnesium reagents. The com-
bination of the two transition-metal-free
procedures allows the preparation of
a broad range of pyridines.
6
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