A convenient synthesis of 2,2′-bipyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.07.153

Picolinates 7 were prepared from the corresponding α-chloro-β-keto-esters 6. Esters 7 were converted into 2,2′-bipyridine derivatives 10 via triazines 9 using an aza Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2007.07.153

Tetrahedron Letters 48 (2007) 6974–6976
A convenient synthesis of 2,20-bipyridine derivatives
Alexander Gehre,a Stephen P. Stanfortha,* and Brian Tarbitb
aSchool of Applied Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK
bVertellus Specialities Chemicals UK Ltd, Seal Sands Road, Seal Sands, Middlesbrough, TS2 1UB, UK
Received 18 May 2007; revised 17 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Picolinates 7 were prepared from the corresponding a-chloro-b-keto-esters 6. Esters 7 were converted into 2,20-bipyridine
derivatives 10 via triazines 9 using an aza Diels–Alder reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
In a series of previous Letters,1–4 we have described the
synthesis of triazines 3 from readily available amidraz-
ones 1 and hydrated a,b-diketo-esters 2 or their
equivalents (Scheme 1). These triazines 3 reacted with
2,5-norbornadiene 5 affording pyridine derivatives 4 in
an inverse electron-demand aza Diels–Alder reaction.
Alternatively, pyridines 4 could be prepared directly
from a mixture of amidrazones 1, a,b-diketo-esters 2
and 2,5-norbornadiene 5 in a convenient ‘one-pot’
reaction.
In this Letter we describe an alternative synthesis of
a,b-diketo-esters 2 and their application to the prepara-
tion of 2,20-bipyridine derivatives. 2,20-Bipyridine deriv-
atives were chosen as targets because of their current
interest as ligands in a wide range of contemporary
metal-catalysed processes.7
The oxidation of a-hydroxy-b-keto-esters 8 (Scheme 2)
was envisaged as a suitable method for the synthesis of
compounds 2 and picolinate esters 7 were chosen as suit-
able precursors of compounds 8. Picolinates 7 were
readily prepared from picolinic acid and a-chloro-b-
keto-esters 6 under basic conditions in good overall
yield.8 Furthermore, compounds 7 did not require puri-
fication and could be used directly in subsequent reac-
tions. The facile cleavage of picolinate esters in the
presence of copper salts is well known9 and this reaction
was used to generate a-hydroxy-b-keto-esters 8 in situ.
Thus, when picolinates 7 were treated with copper(II)
acetate, compounds 8 were initially formed and were
subsequently oxidised by the excess copper(II) acetate
yielding the required a,b-diketo-esters 2. After washing
the reaction mixture with Na2EDTA to remove copper
salts, solutions of compounds 2 could then be reacted
with amidrazone 1 (R1 = 2-pyridyl) giving triazines
9. Triazines 9 have been converted into the correspond-
ing 2,20-bipyridines 10 by an aza Diels–Alder reaction
but it is more convenient to transform a,b-diketo-esters
2 directly into 2,20-bipyridines 10.10 Thus, after reacting
picolinates 7 with copper(II) acetate, the resulting
a,b-diketo-esters 2 were dissolved in ethanol and
amidrazone 1 (R1 = 2-pyridyl) and 2,5-norbornadiene
5 were added. After heating at reflux the required 2,20-
bipyridines 10 were obtained.
In our preliminary work,1–3 a,b-diketo-esters 2 were
prepared by a diazo-transfer reaction between commer-
cially available b-keto-esters and tosyl azide giving the
corresponding diazo-compounds [R2COC(N2)CO2Et].
These diazo-compounds were subsequently treated
t
with BuOCl affording a,b-diketo-esters 2.5 From a
manufacturing perspective, the large scale use of these
diazo-compounds would not be attractive and their
replacement by other a,b-diketo-ester equivalents would
be highly desirable. Alternative methods of preparing
a,b-diketo-esters 2 similarly have other drawbacks: for
example, a,b-diketo-esters are commonly prepared by
ozonolysis of phosphorane precursors [R2COC(@PPh3)-
CO2Et]6, which generates large quantities of triphenyl-
phosphine oxide as an unwanted by-product. In view
of these limitations, the preparation of a-acetoxy-a-
chloro-b-keto-esters as a,b-diketo-ester 2 equivalents
was developed and published in a preliminary form.4
Keywords: 2,20-Bipyridines; 1,2,4-Triazines; Aza Diels–Alder reaction.
*
Corresponding author. Tel.: +44 191 2274784; fax: +44 191
2273519; e-mail: steven.stanforth@unn.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.153

A. Gehre et al. / Tetrahedron Letters 48 (2007) 6974–6976
6975
Scheme 1. Synthesis of pyridines 4.
Scheme 2. Synthesis of bipyridines 10. Reagents and conditions: (i) picolinic acid, KHCO3, DMF, rt; (ii) Cu(OAc)2, MeOH, CH2Cl2 then
Na2EDTA; (iii) amidrazone 1 (R1 = 2-pyridyl), EtOH, reflux; (iv) amidrazone 1 (R1 = 2-pyridyl), 5, EtOH, reflux.
6. Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687–
701.
In summary, picolinates 7 are readily prepared and can
be used as convenient sources of a,b-diketo-esters 2.
2,20-Bipyridines 10 can be prepared from the reaction
of compounds 2, amidrazone 1 (R1 = 2-pyridyl) and
2,5-norbornadiene 5. This methodology compliments
our other studies directed at the preparation and appli-
7. See, for example: (a) Malkov, A. V.; Baxendale, I. R.;
Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.;
Mansfield, D. J.; Valko, M.; Kocˇovsky´, P. Organometal-
lics 2001, 20, 673–690; (b) Puglisi, A.; Benaglia, M.;
Annunziata, R.; Bologna, A. Tetrahedron Lett. 2003, 44,
2947–2951; (c) Fletcher, N. C. J. Chem. Soc., Perkin
Trans. 1 2002, 1831–1842; (d) Malkov, A. V.; Pernazza,
D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani, P.;
Kocˇovsky´, P. J. Org. Chem. 2003, 68, 4727–4742; (e)
Bouet, A.; Heller, B.; Papamicae¨l, C.; Dupas, G.; Oude-
yer, S.; Marsais, F.; Levacher, V. Org. Biomol. Chem.
2007, 1397–1404.
cation of readily available a,b-diketo-esters
2
equivalents.4
Acknowledgements
We thank Vertellus Specialities Chemicals UK Ltd for
generous financial support and the EPSRC mass spec-
trometry service (Swansea) for high resolution mass
spectra.
8. Ethyl 2-picolinoyl-3-oxo-3-phenylpropanoate 7 (R2 = Ph):
To a stirred ice-cold solution of picolinic acid (13.6 g;
110 mmol) in DMF (150 mL) was added KHCO3 (8.84 g,
88.3 mmol). After warming to room temperature, com-
pound 6 (R2 = Ph) (10.0 g; 44.1 mmol) was added and
the solution was left stirring at room temperature until
the reaction was judged complete by TLC (8 days). The
solution was poured into water (100 mL), extracted with
CH2Cl2 and the combined organic fractions were washed
with water (4 · 200 mL), dried (MgSO4) and evaporated
giving the product (12.7 g, 96%) as a viscous orange liquid.
IR: mmax/cmꢀ1 2984, 1748 (C@O), 1694 (C@O), 1598,
1583, 1450, 1372, 1237, 1128, 1023, 748, 703. 1H NMR:
(270 MHz, CDCl3) d = 8.81 (ddd, 1H, J = 1.0, 1.7 and
4.7 Hz, Py–H), 8.20 (ddd, 1H, J = 1.0, 1.2 and 7.9 Hz, Py–
H), 8.09 (m, 2H, Ph–H), 7.86 (ddd, 1H, J = 1.7, 7.7 and
7.9 Hz, Py–H), 7.64 (tt, 1 H, J = 1.4 and 7.3 Hz, Ph–H),
7.55–7.48 (m, 3H, Py–H and Ph–H), 6.64 (s, 1H,
References and notes
1. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron
Lett. 2002, 43, 6015–6017.
2. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron
Lett. 2003, 44, 693–694.
3. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron
2004, 60, 8893–8897.
4. Altuna-Urquijo, M.; Stanforth, S. P.; Tarbit, B. Tetrahe-
dron Lett. 2005, 46, 6111–6113.
5. Detering, J.; Martin, H.-D. Angew. Chem., Int. Ed. Engl.
1988, 27, 695–698.

6976
A. Gehre et al. / Tetrahedron Letters 48 (2007) 6974–6976
9. Sammakia, T.; Jacobs, J. S. Tetrahedron Lett. 1999, 40,
CHOPic), 4.30 (q, 2H, J = 7.2 Hz, ester–CH2–), 1.24 (t,
3H, J = 7.2 Hz, ester–CH3) ppm. 13C NMR: (68 MHz,
CDCl3) d = 189.30 (CO), 164.95 (CO), 163.58 (CO),
150.43 (CH), 146.67 (CH), 137.21 (CH), 134.41 (CH),
134.26 (C), 129.42 (CH), 128.92 (CH), 127.60 (CH), 125.97
(CH), 75.31 (CH), 62.77 (CH2), 14.01 (CH3) ppm. HRMS
(EI): calcd for C17H15NO5 (M+H)+: 314.1023. Found:
2685–2688.
10. Typical procedures: Ethyl 6-phenyl-[2,20]-bipyridine-5-car-
boxylate 10 (R2 = Ph):
A mixture of compound 7
(R2 = Ph) (1.00 g; 3.32 mmol), Cu(OAc)2 (1.32 g;
6.63 mmol; 2.0 equiv) and ethanol (2 mL) in DCM
(50 mL) was stirred at room temperature for one day.
The reaction was diluted with hexanes (20 mL) and
washed with Na2EDTA (0.1 M aqueous solution) until
the aqueous phase remained colourless. The organic phase
was dried over MgSO4, filtered and evaporated. The
resulting oil was taken up in ethanol (50 mL), compound 1
(R1 = 2-pyridyl) (361 mg; 2.65 mmol; 0.8 equiv) and 2,5-
norbornadiene 5 (2.9 mL; 26.5 mmol; 8.0 equiv) were
added and the solution was heated at reflux under a
nitrogen atmosphere for 2 days. After cooling to room
temperature the mixture was poured onto water and
extracted with CH2Cl2. The organic layer was washed with
water, dried (MgSO4) and evaporated. The crude mixture
was purified by column chromatography (silica gel: diethyl
ether) giving the product (570 mg; 71%) identical with an
authentic sample.3 Ethyl 6-propyl-[2,20]-bipyridine-5-car-
boxylate 10 (R2 = nPr): Using a similar procedure to that
described above, compound 10 (R2 = nPr) (59%) was
obtained, identical with an authentic sample.3
314.1021.
Ethyl
2-picolinoyl-3-oxo-3-hexanoate
7
(R2 = nPr): Using a similar procedure to that described
above compound 7 (R2 = nPr) (95%) was obtained as a
viscous orange liquid. IR: mmax/cmꢀ1 2968, 1732 (C@O),
1128. 1H NMR: (270 MHz, CDCl3) d = 8.82 (ddd, 1H,
J = 1.0, 1.7 and 4.7 Hz, Py–H), 8.23 (ddd, 1H, J = 1.0, 1.2
and 7.9 Hz, Py–H), 7.89 (ddd, 1H, J = 1.7, 7.7 and 7.9 Hz,
Py–H), 7.54 (ddd, 1H, J = 1.2, 4.7 and 7.7 Hz, Py–H) 5.81
(s, 1H, CHOPy), 4.33 (q, 2H, J = 7.2 Hz, ester–CH2–),
2.77 (t, 2 H, J = 7.2 Hz, CH3–CH2–CH2–), 1.70 (sextet,
2H, J = 7.2 Hz, CH3–CH2–CH2–), 1.33 (t, 3H, J = 7.2 Hz,
ester–CH3), 0.96 (t, 3H, J = 7.2 Hz, propyl–CH3) ppm.
13C NMR: (68 MHz, CDCl3) d = 199.55 (CO), 164.48
(CO), 163.66 (CO), 150.41 (CH), 146.73 (C), 137.21 (CH),
127.60 (CH), 125.88 (CH), 78.33 (CH), 62.72 (CH2), 41.84
(CH2), 16.70 (CH2), 14.13 (CH3), 13.58 (CH3) ppm.
HRMS (EI): calcd for C14H17NO5 (M+H)+: 280.1179.
Found: 280.1180.