Reactivity and regioselectivity in Stille couplings of 3-substituted 2,4-dichloropyridines

Article abstract of DOI:10.1016/j.tetlet.2010.11.108

The influence of substituents at C-3 of 2,4-dichloropyridines on their reactivity and regioselectivity in Pd-catalyzed cross-couplings is studied. As a model reaction, the (Ph₃P)₂PdCl₂-catalyzed Stille coupling between 2-furyl(tributyl)tin and pyridines is chosen. Increased electron-withdrawing ability of a substituent at the pyridine 3-position improves the overall reactivity. Absolute selectivity for coupling at C-2 is achieved with an amino group at C-3, and the selectivity is totally reversed when the amino group is exchanged for a nitro substituent.

Full text of DOI:10.1016/j.tetlet.2010.11.108

Tetrahedron Letters 52 (2011) 523–525
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity and regioselectivity in Stille couplings of 3-substituted
2,4-dichloropyridines
⇑
Abhijit Datta Khoje, Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
The influence of substituents at C-3 of 2,4-dichloropyridines on their reactivity and regioselectivity in Pd-
Received 28 September 2010
Revised 11 November 2010
Accepted 19 November 2010
Available online 24 November 2010
3 2 2
catalyzed cross-couplings is studied. As a model reaction, the (Ph P) PdCl -catalyzed Stille coupling
between 2-furyl(tributyl)tin and pyridines is chosen. Increased electron-withdrawing ability of a substi-
tuent at the pyridine 3-position improves the overall reactivity. Absolute selectivity for coupling at C-2 is
achieved with an amino group at C-3, and the selectivity is totally reversed when the amino group is
exchanged for a nitro substituent.
Keywords:
Pyridine
Ó 2010 Elsevier Ltd. All rights reserved.
Regioselectivity
Substituent effect
Stille coupling
The pyridine ring is present in numerous natural products,
drugs, and other molecules of interest in both physical and life sci-
ences. Hence selective and efficient functionalization of pyridines
structures of the products 2–4 were determined by NMR spectros-
copy, especially HMBC and/or selective NOE spectroscopy (Fig. 1).
Conversion of 2,4-dichloropyridine (1a) at ambient temperature
was slow and the major coupling product was the 2-furylpyridine
2a. No regioisomer 3a was observed, but some disubstituted prod-
uct 4a was formed. When the temperature was raised to 55 °C or
even 90 °C, the conversion and the formation of disubstituted
product 4a were increased.
1
is of synthetic importance. A number of halopyridines are readily
available and these may serve as important synthetic intermedi-
ates, especially in substitution and coupling reactions. It is still
regarded as difficult to predict a priori the regioselectivity in nucle-
ophilic displacement reactions performed on di- or trihalopyri-
dines when the halogens are located at the activated 2-, 4-, and
Compound 1b, which contains an electron-donating amino
group at the pyridine 3-position, required an elevated temperature
in order to react, and the coupling occurred with complete conver-
sion and selectivity at 90 °C to give the 2-furylpyridine 2b.
Good selectivity was difficult to achieve in the couplings of
amide 1c, aldehyde 1d, ester 1e, and nitrile 1f. The 2-substituted
isomers 2 were the major products, but (except for the nitrile 1f)
conversion at ambient temperature was relatively slow, especially
for the amide, and the regioisomer 3 and/or the dicoupled product
4 were generally observed. The nitrile 1f reacted with fairly good
selectivity at ambient temperature. Unfortunately, selectivity was
not improved when the reaction temperature was reduced. A Suzu-
ki coupling of the nitrile 1f was previously reported to take place
2
6
-positions. Palladium-catalyzed cross-coupling reactions are
3
important for functionalization of haloaryls or heteroaryls. Except
for one example of a Suzuki coupling on 2,4-dichloro-3-cyanopyr-
idine,4 Pd-catalyzed couplings on 2,4-dichloropyridines tend to
5
give the 2-substituted product as the major isomer. 2,4,6-Trib-
romopyridines react preferably at the
a-positions in Sonogashira
couplings, and this has been explained due to ‘a directing role by
6
the ring nitrogen’. However, there are relatively few examples of
couplings on such substrates, and no systematic study of reactivity
and selectivity has been reported.
We herein describe a study examining the influence of substit-
uents at the 3-position of 2,4-dichloropyridines in cross-couplings.
4
The (Ph
3
P)
2
PdCl
2
-catalyzed Stille couplings between 2-furyl(tribu-
mainly at C-4.
7
tyl)tin and pyridines 1a–h were investigated (Scheme 1, Table 1).
5
d
4
Compound 1a was commercially available and pyridines 1b, 1c,
5
d
8
9
1
g, 1h, and 1i were readily available by literature methods. The
syntheses of pyridines 1d, 1e, and 1f are shown in Scheme 2. The
⇑
Corresponding author. Tel.: +47 228 57019; fax: +47 228 55507.
E-mail address: l.l.gundersen@kjemi.uio.no (L.-L. Gundersen).
3 3 2 2
Scheme 1. (a) 2-(Bu Sn)furan, (Ph P) PdCl , DMF; see also Table 1.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.108

5
24
A. D. Khoje, L.-L. Gundersen / Tetrahedron Letters 52 (2011) 523–525
Table 1
Stille coupling between pyridines 1 and 2-furyltri(butyl)tin
Substrate
R
R1
Temp (°C)
Time (h)
Product ratioa
Isolated yield (%)
%
1
% 2
% 3
% 4
1
1
1
1
1
1
1
1
1
a
a
a
b
c
H
H
H
NH
CONH
CONH
CHO
CHO
CO
H
H
H
H
H
H
H
H
H
rt
18
18
18
1
18
18
18
7
54
42
39
0
87
12
13
17
22
37
39
45
100
13
56
65
47
54
0
0
0
0
0
22
11
12
0
9
19
16
0
22, 2a
b
55
90
90
rt
55
rt
—
—
b
2
70, 2b
b
2
0
—
—
b
c
2
10
11
24
24
c
d
d
e
64, 2d
b
0
rt
—
2
Me
18
35, 2e
1
—
8, 4e
b
1
1
e
f
CO Me
2
CN
H
H
0
rt
7
18
25
0
50
82
0
13
25
5
61, 2f
1
—
—
2, 3f
b
1
1
1
1
f
CN
H
H
H
Cl
0
rt
0
7
1
4
2.5
19
0
0
53
13
6
20
76
92
87
8
11
2
b
g
g
h
NO
NO
NO
2
d
2
2
76, 3g
73, 3h
e
0
0
2
11
a
b
c
Determined from the 1H NMR spectra of the crude products.
No product isolated in pure form.
Contained 9% of 3d.
d
e
Contained 4% of 2g.
The structure of the difurylpyridine could not be determined with absolute certainty.
due to the fact that the isomers 3 were formed by direct nucleo-
1
5
philic substitution rather than a Pd-catalyzed cross-coupling.
However the nitropyridine 1g did not react at all with 2-furyl(trib-
1
6
utyl)tin alone.
In summary, the increased electron-withdrawing ability of a
substituent at the 3-position of 2,4-dichloropyridines increases
the overall reactivity in Pd-catalyzed Stille couplings. The nature
of the C-3 substituent strongly influences the regioselective out-
come of the reaction. Complete selectivity for the 2-position can
be achieved with an amine group at the pyridine 3-position, and
the selectivity is completely reversed if the amine group is ex-
changed for a nitro substituent. When a substituent with elec-
tron-withdrawing ability other than a nitro group is attached to
C-3, there is a preference for coupling at C-2, but extensive fine-
tuning of the reaction conditions would be required to achieve
complete regioselectivity, which is beyond the scope of this initial
study.
Scheme 2. Reagents and conditions: (a) (1) LDA, (2) DMF, THF, À78 °C; (b)
CF CO) O, Et N, CH Cl , 0 °C; (c) MeI, DBU, MeCN.
(
3
2
3
2
2
Figure 1. Structure elucidation of compounds 2 and 3. The highlighted bonds show
the most important HMBC correlations and the curly arrow the most important
enhancement observed from selective NOE.
Acknowledgments
The Norwegian Research Council is gratefully acknowledged for
a grant to A.D.K. (KOSK II, project number 177368) as well as for
partial financing of the Bruker Avance instruments used in this
study.
The most interesting finding in this study was that the regiose-
lectivity was completely reversed for the 3-nitropyridines 1g and
h. Herein coupling took place at C-4 almost exclusively, even with
1
compound 1h where exchangeable chlorides are present at both
a
-
References and notes
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13b
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6
.
.
7
To a solution of 1 (1.00 mmol) in DMF (3 mL) was added (PPh
3 2 2
) PdCl (21 mg,
0
.030 mmol) under an N atm and the reaction mixture was stirred for 5 min,
2
before 2-furyl(tributyl)tin (0.32 mL, 1.0 mmol) was added. The resulting
mixture was stirred for the time and at the temperature given in Table 1.
H
2
O
(40 mL) was added and the aqueous mixture extracted with EtOAc
(
2 Â 30 mL). The combined organic phases were washed with brine (30 mL),
1
dried (MgSO
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) and evaporated in vacuo. The H NMR spectrum of the crude
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.
.
9
1
16. The reaction was performed as described above,7 but without (PPh
The reaction mixture was stirred at ambient temperature for 18 h.
3 2 2
) PdCl .