Lewis acid promoted benzylic cross-couplings of pyridines with aryl bromides

Article abstract of DOI:10.1002/anie.201103074

Either ZnCl₂, Sc(OTf)₃, or BF₃OEt ₂ can promote the palladium-catalyzed arylation of methylpyridines and related heterocycles (see example). The complexation of the Lewis acid to the nitrogen atom in the heteroc

Full text of DOI:10.1002/anie.201103074

Communications
DOI: 10.1002/anie.201103074
Arylation Reactions
Lewis Acid Promoted Benzylic Cross-Couplings of Pyridines with Aryl
Bromides**
Stꢀphanie Duez, Andreas K. Steib, Sophia M. Manolikakes, and Paul Knochel*
The functionalization of pyridines and related heterocycles is
very important because of their biological properties and
relevance to material science.[1] The benzylic arylation of
pyridines, in particular, is a challenging synthetic problem.
Palladium-catalyzed arylations of 2-picoline involving direct
[2]
À
C H activation have no generality, and only few examples
have been reported. Thus, azaarenes bearing electron-with-
drawing groups may be arylated at 1008C with a Pd catalyst.[3]
Several alternative procedures involving the fragmentation of
a 2-(2-pyridyl)ethanol,[4] the arylation of N-oxides,[5] and
N-iminopyridinium ylides[6] have been described. These
methods, although displaying generality, require modified
N-heterocyclic precursors.[4–6] In addition, whereas 2-picoline
(1a) can be functionalized in this way, the arylation of
Scheme 1. Lewis acid (LA) promoted benzylic cross-coupling.
4-picoline (2a) has not been described. The difficulty in
forming a new carbon–carbon bond with metalated 2-picoline
(3; or 4-picoline) may be due to the nature of the palladium
complexes[7] (4a–c) resulting from the reaction with ArPdX
(Scheme 1). We anticipate that all of these possible structures
are reluctant to undergo a reductive elimination because of
the chelation of the heterocyclic nitrogen with the Pd center.
Hartwig and co-workers have already shown that palladium-
catalyzed aminations are accelerated by a Lewis acid (BEt3).[8]
Nolan and co-workers have also reported that reductive
eliminations of Pd complexes are accelerated by AlCl3.[9]
We envisioned that the presence of an appropriate Lewis
acid (LA) complexing the nitrogen atom of the heterocycle
may lead to a new Pd intermediate such as 5, which would
then undergo fast reductive elimination leading to the cross-
coupling product 6. Similar behavior may be expected for the
arylation of 4-picoline (Scheme 1). The beneficial effect of
Lewis acids in the additions of 2-picoline to imines and enones
has already been demonstrated.[10,11] Thus, we directed our
attention toward the use of bases (Met-base) bearing a Lewis
acidic metal center for the metalation. Recently, we have
reported a kinetically highly active LiCl-solubilized TMP
base (TMP = 2,2,6,6-tetramethylpiperidyl): TMPZnCl·LiCl
(7) displays high chemoselectivity in various directed zinca-
tions of arenes and heterocycles.[12,13] Besides, 7 proved to be
an excellent base for the generation of nitrile and ester
enolates.[13,14] We have also demonstrated that 7 is compatible
with additional strong Lewis acids (MgCl2, BF3·OEt2) and
forms frustrated Lewis pairs.[15] Herein, we report that Lewis
acids such as ZnCl2, MgCl2, BF3·OEt2 , and Sc(OTf)3 in
combination with TMPZnCl·LiCl promote efficiently the
Negishi cross-coupling[16] of various methyl-substituted
N-heterocycles.
Thus, the zincation of 2-picoline (1a) with 7 (2.0 equiv)[17]
gives the zincated picoline 8a. Its cross-coupling with
5-bromoindole (9a, 0.8 equiv) in the presence of 2 mol%
Pd(OAc)2 and 2–4 mol% SPhos[18] affords the desired pyri-
dine 6a in 86% yield (in Scheme 2). Such cross-coupling
reactions can be extended to various substituted aryl bro-
mides (9b–d) leading to products 6b–d in 66 to 95% yield
(Table 1, entries 1–3). Also, 2-substituted pyridines such as
1b,c are metalated with 7 under the same conditions and react
[*] Dr. S. Duez, M. Sc. A. K. Steib, M. Sc. S. M. Manolikakes,
Prof. Dr. P. Knochel
Department Chemie, Ludwig Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank BASF AG
(Ludwigshafen), Chemetall GmbH (Frankfurt), and Heraeas
(Hanau) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103074.
Scheme 2. Palladium-catalyzed direct cross-coupling of picolines 1a
and 2a.
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Angew. Chem. Int. Ed. 2011, 50, 7686 –7690

(prepared from TMPMgCl·LiCl[19] and ZnCl2) leads to even
faster cross-couplings (at least six times faster). However, the
reaction is complicated by increased amounts of diarylation[20]
making the general use of this Lewis acid unattractive. A
further hint showing the importance of Lewis acids for the
tentative Pd intermediate of type 5 (Scheme 1) is found in the
cross-coupling reaction of picolines (1a or 2a) with electron-
deficient aryl bromides. Substrates like 4-bromobenzonitrile
(9j) and ethyl 4-bromobenzoate (9k) gave disappointing
results in the presence of either ZnCl2 or MgCl2 as Lewis
acids. Therefore, we screened[21] other powerful alternative
Lewis acids[22] such as ScCl3, Sc(OTf)3,[23] Yb(OTf)3,[24] and
Y(OTf)3.[22a] Thus, the direct cross-coupling of zincated
2-picoline (8a) with 4-bromobenzonitrile (9j) gave no
product (even after additional ligands for the Pd catalyst
were screened).[25] However, in the presence of 10 mol%
Sc(OTf)3, an efficient palladium-catalyzed cross-coupling
took place and afforded the coupling product 6g in 87%
yield (Scheme 3). Similarly, 4-picoline (2a) gave the cross-
Table 1: Direct benzylic cross-coupling of 2- and 4-picoline derivatives.
Entry Picoline[a]
Aryl Br
Product
Yield [%][b]
À
1
2
3
1a (3)
1a (6)
1a (6)
9b: R=4-OMe 6b: R=4-OMe
95
78
66
9c: R=4-F
9d: R=3-Cl
6c: R=4-F
6d: R=3-Cl
4
1b (20)
1c (11)
9b
9b
6e
6 f
99
92
5[e]
6
7
8
9
2a (1)
2a (1)
2a (1)
2a (1)
2a (1)
9b
10b: R=4-OMe
10c: R=3-Me
98[c]
82
9 f: R=3-Me
9g: R=4-NMe2 10d: R=4-NMe2
9h: R=4-OH
9i: R=4-OPiv
70
10e: R=4-OH
10 f: R=4-OPiv
84[c]
81[c]
10
11
12
2b (1)
2b (1)
9 f
10g
10h
69[d]
9a
69
Scheme 3. Sc(OTf)3-catalyzed cross-coupling of 2-picoline (1a) and
4-picoline (2a) with electron-poor aryl bromides 9j and k.
13
10b (3)
9b
10i
93
[a] Reaction time (h) for the arylation in brackets. [b] Yield of isolated
analytically pure product. [c] Pd(OCOCF3)2 was used as the Pd source.
[d] 2 mol% Pd(OAc)2, 4 mol% PCy3 was used. [e] TBDMS=tert-butyldi-
methylsilyl.
coupling product 10j only in 41% yield without Sc(OTf)3, but
the addition of 10 mol% Sc(OTf)3 increased the cross-
coupling yield to 78% (Scheme 3). The effect of Sc(OTf)3
may be best explained by an acceleration of the reductive-
elimination step in the cross-coupling as a result of the
complexation of Sc(OTf)3 to the heterocyclic nitrogen (see
11a,b, Scheme 3). It is anticipated that electron-withdrawing
substituents lead to Pd intermediates of type 4 (Scheme 1)
which are especially reluctant to undergo reductive elimina-
tion. We expect the effect of a Lewis acid to be crucial in these
cases. Thus, the cross-couplings of picolines 1a and 2a with
various electron-deficient aryl bromides (9j–l) are dramati-
cally improved by the presence of 10 mol% Sc(OTf)3 and the
cross-coupling products 6h and 10k–l are obtained in 75–85%
yield. In the absence of Sc(OTf)3, the yields of the cross-
coupling are between 0 and 51% (Table 2, entries 1–3).
Following the mild zincation of picolines and efficient
subsequent cross-coupling, we were set to tackle regioselec-
tivity issues in the arylation of dimethylpyridines. Thus, we
with 4-bromoanisole (9b) to provide the desired products
(6e,f) in very high yields (92–99%, Table 1, entries 4 and 5).
To our knowledge, no arylation of 4-picoline (2a) has
been reported in the literature. However, the smooth
zincation of 2a with 7 (1.5 equiv) proceeds readily, and the
palladium-catalyzed cross-coupling of 8b with various aryl
bromides (9b, 9e–i) furnishes the 4-substituted pyridines 10a–
f in 70 to 98% yield (Scheme 2 and Table 1, entries 6–10).
2-Chloro-4-methylpyridine (2b) similarly reacts and produces
the arylated products 10g and 10h in 69% yield (Table 1,
entries 11 and 12). Cross-coupling of the 4-substituted pyri-
dine (10b) with 4-bromoanisole (9b) leads to the desired
product (10i) in high yield (entry 13). These smooth cross-
couplings may be explained by the role that ZnCl2 plays as a
Lewis acid. Interestingly, the use of TMPZnCl·MgCl2·2LiCl
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Table 2: Effect of Sc(OTf)3 on the benzylic cross-coupling of 2- and
Table 3: Selective benzylic cross-couplings of lutidines with various aryl
4-picoline with electron-deficient electrophiles.
bromides, chlorides, and a triflate.
Picoline[a]
Aryl Br
Product[b]
Entry Lutidine
Aryl X
Product
Yield
[%][a]
À
À
Entry
1
1a
9k
6h: 85% (31)[c]
1
2
3
12a
12a
12a
9b
9 f
13b: R=4-OMe 90
13c: R=3-Me
13d: R=4-CF3
91
88
9m: R=4-CF3
2
3
2a
9j
10k: 75% (0)[c]
4
5
6
7
8
9
10
12c
12c
12c
12c
12c
12c
12c
9b
9i
15b: R=4-OMe 92[b]
15c: R=4-OPiv 82[b]
15d: R=4-CN
2a
9l
10l: 78% (51)[c]
9j
77[b]
[a] Conditions: 508C, 1 h. [b] Yield of isolated analytically pure product.
[c] Yield of isolated product when the reaction was performed without
Sc(OTf)3.
9n: X=OTf, R=4-OMe 15b: R=4-OMe 98[b]
9o: X=Br, R=2-OMe
9p: X=Cl, R=3-OMe
9q: X=Cl, R=4-CF3
15e: R=2-OMe 92[b]
15 f: R=3-OMe 86[b]
15g: R=4-CF3
88[b]
examined the arylation of 2,3-, 3,4-, and 2,4-lutidines (12a–c).
With 2,3-lutidine (12a), zincation with 7 occurs exclusively at
position 2, leading after palladium-catalyzed arylation with
4-bromo-N,N-dimethylaniline (9g) to the disubstituted pyri-
dine (13a) in 85% yield (Scheme 4). Further arylations are
[a] Yield of isolated analytically pure product. [b] BF3·OEt2 was added
prior to TMPZnCl·LiCl.
cross-coupling with ethyl 4-bromobenzoate (9k) to the
pyridine (15a) in 82% yield. This reactivity is general and
several typical aryl bromides, chlorides, and a triflate
(9b,i,j,n–q) undergo regioselective arylations at position 4 to
provide products 15b–g in 77–98% yield (Table 3, entries 4–
10).[27]
Finally, we briefly examined the arylation of methyl-
substituted quinolines (16a,b) and isoquinoline (16c). With 7
zincation is rapid, and the subsequent palladium-catalyzed
arylation proceeds well with various aryl bromides (Scheme 5
and Table 4, entries 1–8). In the case of Negishi cross-
couplings with aryl bromides bearing an acidic proton, the
use of Pd(OCOCF3)2 introduced by Oshima and Yorimitsu[4]
Scheme 4. Selective cross-couplings of lutidines 12a–12c.[28]
described in Table 3, entries 1–3. In the case of 3,4-lutidine
(12b), completely regioselective metalation occurs at posi-
tion 4 leading after a cross-coupling with 4-bromoanisole (9b)
to the disubstituted pyridine 14 in 92% yield (Scheme 4). The
regioselective arylation of 2,4-lutidine (12c) is more challeng-
ing since the direct zincation with 7 produces a 2:1 mixture of
[15a,26]
regioisomers. However, the addition of BF3·OEt2
prior
to 7 directs the zincation only at position 4 since the
complexation of 12c with BF3·OEt2 at the heterocyclic
nitrogen hampers the metalation by 7 at position 2 for steric
factors. Thus the zincation occurs at position 4 leading after
Scheme 5. Cross-coupling of quinolines 16a–c with aryl bromides.
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Angew. Chem. Int. Ed. 2011, 50, 7686 –7690

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Table 4: Cross-couplings of quinolines with various aryl bromides.
Entry Quinoline[a]
Aryl X
Product
Yield [%][b]
À
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2
3
4
5
16a (1)
16a (1)
16a (1)
16a (2)
16a (2)
9g
9j
9l
17b: R=4-NMe2 93
17c: R=4-CN
17d: R=3-CF3
17e: R=4-OH
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72
9h
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6
7
8
16b (1)
16b (1)
16b (1)
9 f
9m
9t: R=3-F
18b: R=3-Me
18c: R=4-CF3
18d: R=3-F
96
86
95
[a] Reaction time (h) for the arylation in brackets. [b] Yield of the isolated
analytically pure product. [c] 2 equiv TMPZnCl·LiCl, 2 mol% Pd-
(OCOCF3)2 , and 4 mol% SPhos were used.
was advantageous and ensured high yields and fast cross-
couplings (Table 4, entries 4 and 5). The arylation of
2-methylquinoline (16b) is best performed with the Xant-
phos[29] ligand since the formation of diarylation by-products
can be avoided (Table 4, entries 6–8).
In summary, we have reported the direct palladium-
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(pyridines, quinolines, and isoquinoline) promoted by
ZnCl2, Sc(OTf)3 , or BF3·OEt2. The action of these Lewis
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nitrogen which facilitates the reductive elimination of the Pd
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2,4-lutidine metalation. The possibility of improving related
Pd cross-couplings by the addition of Lewis acids is currently
under investigation in our laboratory.
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Published online: June 30, 2011
Keywords: cross-coupling · metalation · pyridine · zinc
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Communications
TMPZnCl·MgCl2·LiCl instead of in 6 h in the presence of
TMPZnCl·LiCl (7) but led to less product 6d (61%) owing to
the formation of 17% of diarylated product.
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PEPPSI,[31] [Pd(PPh3)4], and [PdCl2(dppf)] did not give satisfac-
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