Direct and improved access to unsymmetrically functionalized bipyridines by a stille-type cross-coupling reaction

Article abstract of DOI:10.1081/SCC-120015770

The Stille-type cross-coupling reaction on mesylate, tosylate, and triflate allowed synthesis of symmetrical but also interesting unsymmetrical monofunctionalized 2′2′-bipyridines in possible multigram scales.

Full text of DOI:10.1081/SCC-120015770

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Direct and Improved Access to Unsymmetrically
Functionalized Bipyridines by a Stille-Type Cross-
Coupling Reaction
Julien Mathieu a & Alain Marsura a
a Groupe d'Etude des Vecteurs Supramoléculaires du Médicament , Université Henri
Poincaré-Nancy I , Nancy, France
Published online: 17 Aug 2006.
To cite this article: Julien Mathieu & Alain Marsura (2003) Direct and Improved Access to Unsymmetrically Functionalized
Bipyridines by a Stille-Type Cross-Coupling Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:3, 409-414, DOI: 10.1081/SCC-120015770
To link to this article: http://dx.doi.org/10.1081/SCC-120015770
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 3, pp. 409–414, 2003
Direct and Improved Access to Unsymmetrically
Functionalized Bipyridines by a Stille-Type
Cross-Coupling Reaction
*
Julien Mathieu and Alain Marsura
Groupe d’Etude des Vecteurs Supramoleculaires
du Medicament, Universite Henri Poincare-Nancy I,
Nancy, France
ABSTRACT
The Stille-type cross-coupling reaction on mesylate, tosylate, and
triflate allowed synthesis of symmetrical but also interesting unsym-
metrical monofunctionalized 2020-bipyridines in possible multigram
scales.
Key Words: Stille-type reaction; Bipyridines multigram scale
synthesis.
*Correspondence: Alain Marsura, Groupe d’Etude des Vecteurs Supramoleculai-
res du Medicament, UMR CNRS-UHP 7565, Universite Henri Poincare-Nancy I,
5 rue A. Lebrun, BP 403, 54001, Nancy, France; Fax: 33(0)383682345; E-mail:
alain.marsura@pharma.u-nancy.fr.
409
DOI: 10.1081/SCC-120015770
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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410
Mathieu and Marsura
In the course of our ongoing research of new bis-heterocycle synthesis,
the selective obtention of monofunctionalized systems remains a synthetic
challenge until today to gain a simpler way for corresponding heterocyclic
cryptate synthesis in bulk than the one previously published.[1a] A survey
of the literature revealed a recent high interest on Stille-type cross-coupling
methods using either tributyltin-picoline[1b] or tributyltin-diazines[2a,2b]
and sometimes triflates[3] to obtain symmetrical or unsymmetrical bis-
heterocyclic units by stannylation of corresponding halides, followed by
a palladium-catalysed reaction.
Here, we report a new two-step efficient coupling reaction between
tributyltin-2-picoline 6 and (het) pyridyl mesylate, tosylate, and triflate
2–4. The tributyl(6-methyl-2-pyridyl)-stannane 6 was prepared in a high
yield (86%) by Br–Li exchange transmetallation from 2-bromo-6-methyl
pyridine5followedbystannylationwithtributyltinchloride(THF,À78ꢀC).
2-Methylsulphonyl 2, 2-( p-toluenesulphonyle) 3, and 2-trifluoromethyl-
sulphonyl-4-carboxymethyl-6-methyl pyridin 4 were prepared in good
yields from 2-hydroxy-4-carboxymethyl-6-methyl pyridine by classical
reactions[4a,4b] except 3 for which a recent modification was used.[4c]
Under our conditions[5]; (Sch. 1) the cross-coupling reaction between
the stannane 6 and sulphonates 2–4 leads to 2,20-bipyridines 7 and 8.
As mentioned in Table 1, the mesylate 2 and tosylate 3 afforded a mixture
of 7 and 8 in almost equivalent percentage indicating competitive
homocoupling and heterocoupling. Note that reactions (realized in
triplicate) with the tosylate gave a better yield (93%) than with the
mesylate (67%). However, only heterocoupling occurs in the reaction
with the triflate 4, giving the monofunctionalized bipyridine 7 in a good
yield (78%).
Scheme 1.

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Stille-Type Cross-Coupling Reaction
Table 1. Preparation of 2,20-bipyridines.
411
Starting Product
Yields (%)a 7
Yields (%)a 8
2
3
4
31
53
78
36
40
0
Reactions realized from 2 mmol of 5.
aIsolated yields.
In summary, we have demonstrated a Stille-type cross-coupling that
works with 2-picolinyl mesylate or tosylate and is shown to be a simple
and competitive method to afford monofunctionalized bis-heterocycles.
This methodology potentially improves the synthesis of monofunctiona-
lized supramolecules as e.g., heterocyclic cryptates.
EXPERIMENTAL
General
All compounds gave satisfactory spectral data (1H and 13C NMR)
and new compounds gave satisfactory elemental analyses.
4-Carbomethoxy-6-methyl-2-methanesulphonyloxypyridine 2: To
4-carbomethoxy-6-hydroxy-2-methylpyridine (5 g, 29.9 mmol) in dry
pyridine (50 mL) at 0ꢀC under Ar was added methanesulphonyl chloride
(3.5 mL, 44.8 mmol). The solution was stirred at room temperature for
3 h and then was poured into a separatory funnel containing H2O
(40 mL). The mixture was extracted with CH2Cl2 (3 Â 60 mL), then com-
bined organic fractions were dried over MgSO4. Filtration and concen-
tration in vacuo, followed by chromatography on silica gel (elution:
CH2Cl2/MeOH, 97:3), gave a solid. Yield: 5.8 g (85%). M.p. 48–49ꢀC.
1H NMR (CDCl3): ꢀ ¼ 7.69 (s, 1H), 7.45 (s, 1H), 3.95 (s, 3H), 3.51 (s, 3H),
2.59 (s, 3H). 13C NMR (CDCl3): ꢀ ¼ 164.3, 159.1, 157.2, 142.0, 121.6,
112.2, 52.9, 40.8, 23.9. C9H11NO5S; 0.2 H2O requires: C, 43.44; H, 4.62;
N, 5.63. Found: C, 43.63; H, 4.47; N, 5.50.
4-Carbomethoxy-6-methyl-2-p-toluenesulphonyloxypyridine 3: To
4-carbomethoxy-2-hydroxy-6-methylpyridine (5 g, 29.9 mmoles) and
Et3N (4.3 mL, 31.0 mmol) in CH2Cl2 (150 mL) at 60ꢀC under Ar was
added dropwise a solution of p-toluenesulphonyl chloride (recrystallized

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412
Mathieu and Marsura
in hexane) (5.91 g, 31.0 mmol) in CH2Cl2 (50 mL). After the mixture was
stirred at 60ꢀC for 8 h. Then the mixture was washed with H2O
(3 Â 50 mL). The organic phase was dried over MgSO4, and the solvent
was removed in vacuo. The crude product was purified by chromatogra-
phy on aluminium oxide gel (elution: CH2Cl2), gave a white powder.
1
Yield: 8.2 g (85%). H NMR (CDCl3): ꢀ ¼ 7.78 (d, J ¼ 8.2 Hz, 2H), 7.63
(s, 1H), 7.45 (s, 1H), 7.37 (d, J ¼ 8.0 Hz, 2H), 3.95 (s, 3H), 2.49 (s, 3H),
2.47 (s, 3H). 13C NMR (CDCl3): ꢀ ¼ 165.2, 159.8, 157.6, 146.1, 142.4,
134.3, 130.2, 129.5, 122.1, 112.7, 53.1, 24.0, 21.9.
4-Carbomethoxy-6-methyl-2-trifluoromethanesulphonyloxypyridine 4:
To 4-carbomethoxy-2-hydroxy-6-methylpyridine (1 g, 6.0 mmol) in dry
pyridine (40 mL) at 0ꢀC under Ar was rapidly added trifluoromethanesul-
phonic anhydride (1.21 mL, 7.2 mmol). The solution was stirred at 0ꢀC for
20 min and then was poured into a separatory funnel containing H2O
(40 mL). The mixture was extracted with CH2Cl2 (3 Â 30 mL), then
combined organic fractions were dried over MgSO4. Filtration and
concentration in vacuo, followed by chromatography on silica gel (elution:
CH2Cl2/acetone, 99:1), gave a colorless oil. Yield: 1.47 g (76%). 1H NMR
(CDCl3): ꢀ ¼ 7.78 (s, 1H), 7.50 (s, 1H), 3.97 (s, 3H), 2.61 (s, 3H). 13C NMR
(CDCl3): ꢀ ¼ 164.5, 160.8, 156.3, 143.3, 123.9, 119.2 (q, JCF ¼ 1240 Hz),
112.3, 53.2, 23.9. C9H8F3NO5S, CH2Cl2 requires: C, 31.27; H, 2.62;
N, 3.65. Found: C, 31.14; H, 2.33; N, 4.01.
6-Methyl-2-tributylstannylpyridine 6: To 2-bromo-6-methylpyridine
(2.5 g, 14.54 mmol) in anhydrous THF (35 mL) at À78ꢀC under Ar was
added dropwise n-butyllithium (10 mL, 16 mmol; 1.6 M in hexane). After
the solution was stirred at À78ꢀC for 90 min, tributyltinchloride (4.73 mL,
17.45 mmol) was added, and the mixture was allowed to warm to room
temperature. Water (15 mL) was poured into the reaction mixture, and the
phases were separated. The aqueous layer was extracted with diethylether
(3 Â 20 mL). The combined organic phases were dried over MgSO4, and
the solvent was removed in vacuo. The resulting oil was purified by chro-
matography on aluminium oxide gel (elution: hexanes/acetone, 99.5:0.5)
to furnish a colorless oil. Yield: 4.78 g (86%). 1H NMR (CDCl3): ꢀ ¼ 7.34
(t, J ¼ 7.4 Hz, 1H), 7.21 (d, J ¼ 7.4 Hz, 1H), 6.98 (d, J ¼ 7.6 Hz, 1H), 2.57
(s, 3H), 1.66–1.52 (m, 6H), 1.41–1.32 (m, 6H), 1.22–1.09 (m, 6H), 1.07–0.87
(m, 9H). 13C NMR (CDCl3): ꢀ ¼ 173.7, 159.3, 134.0, 130.0, 122.2, 29.1,
27.5, 13.8, 10.0.
4-Methoxycarbonyl-6,60-dimethyl-2,20-bipyridine 7 and 6,60-dimethyl-
2,20-bipyridine 8: To a solution of 2-methyl-6-tributylstannylpyridine
(764 mg, 2 mmol) in xylol (15 mL) under Ar were added PdCl2(PPh3)2
(70 mg, 0.1 mmol, 5 mol%), PPh3 (52 mg, 0.2 mmol, 10 mol%) and the

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Stille-Type Cross-Coupling Reaction
413
appropriate heteroaromatic compound (2 mmol). The mixture was
refluxed for 24 h. After cooling at r.t., the mixture was poured into a
saturated solution of EDTA (2Naþ) (15 mL). The aqueous layer was
extracted with CH2Cl2 (3 Â 30 mL). The combined organic phases were
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by chromatography on silica gel (Elution: hexane/
acetone, 95:5), gave two products: 4-methoxycarbonyl-6,60-dimethyl-2,20-
bipyridine 7: M.p.: 116–117ꢀC. 1H NMR (CDCl3): ꢀ ¼ 8.72 (s, 1H), 8.20 (d,
J ¼ 7.8 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J ¼ 7.8 Hz, 1H), 7.18 (d, J ¼ 7.6 Hz,
1H), 3.98 (s, 3H), 2.72 (s, 3H), 2.69 (s, 3H). 13C NMR (CDCl3): ꢀ ¼ 166.8,
159.6, 158.7, 157.7, 155.6, 139.2, 137.7, 124.1, 122.8, 118.9, 118.9, 52.7,
24.8. C14H14N2O2, 0.5 H2O requires: C, 66.92; H, 6.02; N, 11.15; Found:
C, 66.66; H, 5.78; N, 10.81. 6,60-dimethyl-2,20-bipyridine 8: 1H NMR
(CDCl3): ꢀ ¼ 8.20 (d, J ¼ 7.8 Hz, 2H), 7.69 (t, J ¼ 7.6 Hz, 2H), 7.15 (d,
J ¼ 7.6 Hz, 2H), 2.64 (s, 6H). 13C NMR (CDCl3): ꢀ ¼ 158.5, 156.6, 137.6,
123.7, 118.8, 24.9.
ACKNOWLEDGMENTS
This work was supported by the CNRS and the French Ministere
de la Recherche. We thanks Mrs. N. Marshall for correcting the
manuscript.
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414
Mathieu and Marsura
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Received in the Netherlands January 21, 2002