A convenient synthesis of pyridine and 2,2′-bipyridine derivatives

Article abstract of DOI:10.1016/j.tet.2008.11.090

α-Chloro-α-acetoxy-β-keto-esters 9 were readily prepared from β-keto-esters 6 in good overall yields. These compounds reacted as α,β-diketo-ester equivalents 2 with amidrazones 1 yielding triazines 3, generally in good yields. Picolinates 10 provided an alternative source of α,β-diketo-ester equivalents 2 when treated with copper(II) acetate. A 'one-pot' reaction of the α,β-diketo-ester equivalents 2 with amidrazones 1 in the presence of 2,5-norbornadiene 5 in boiling ethanol yielded the pyridines 4 and 2,2′-bipyridines 4 (R¹=2-pyridyl) directly without the need to isolate the corresponding triazines 3. Triazine 3c reacted with the aza-dienophiles 13 and 17 affording the products 16 and 18, respectively, in good yields.

Full text of DOI:10.1016/j.tet.2008.11.090

Tetrahedron 65 (2009) 975–984
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convenient synthesis of pyridine and 2,20-bipyridine derivatives
,
b
Marta Altuna-Urquijo a, Alexander Gehre a, Stephen P. Stanforth a , Brian Tarbit
*
a School of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
b Vertellus Specialities UK Ltd, Seal Sands Road, Seal Sands, Middlesbrough TS2 1UB, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Chloro-
These compounds reacted as
generally in good yields. Picolinates 10 provided an alternative source of
when treated with copper(II) acetate. A ‘one-pot’ reaction of the -diketo-ester equivalents 2 with
a
-acetoxy-
b
-keto-esters 9 were readily prepared from
b
-keto-esters 6 in good overall yields.
Received 24 September 2008
Received in revised form 11 November 2008
Accepted 27 November 2008
Available online 3 December 2008
a
,b
-diketo-ester equivalents 2 with amidrazones 1 yielding triazines 3,
-diketo-ester equivalents 2
a,b
a,b
amidrazones 1 in the presence of 2,5-norbornadiene 5 in boiling ethanol yielded the pyridines 4 and 2,20-
bipyridines 4 (R1¼2-pyridyl) directly without the need to isolate the corresponding triazines 3. Triazine
3c reacted with the aza-dienophiles 13 and 17 affording the products 16 and 18, respectively, in good
yields.
Keywords:
Pyridines
2,20-Bipyridines
1,2,4-Triazines
Ó 2008 Elsevier Ltd. All rights reserved.
a,b-Diketo-esters
Aza Diels–Alder reaction
1. Introduction
pyridyl) from readily available amidrazones 1 and hydrated a,b-
diketo-esters 2 or their equivalents (Scheme 1) and this work has
recently been extended to allow the preparation of 2,20:6,200-ter-
pyridines.12f The reaction of amidrazones 1 and compounds 2 in
ethanol at reflux yielded triazine derivatives 3, which, in the
presence of 2,5-norbornadiene 5, afforded products 4 via the in-
verse electron-demand aza Diels–Alder when the group R1 is
electron-deficient (CO2Et or 2-pyridyl). Thus, compounds 4 are
readily accessible in a convenient ‘one-pot’ reaction from ami-
Pyridine derivatives occupy a central position in modern
heterocyclic chemistry particularly in the pharmaceutical and ag-
rochemical fields. Consequently new and efficient methods for the
preparation of this important heterocyclic ring system are of con-
temporary interest.1 2,20-Bipyridine2 and its derivatives have also
been the subject of numerous studies, principally because of their
well-developed coordination chemistry.3 Many applications of
2,20-bipyridine derivatives have been reported in fields such as
supramolecular chemistry,4 artificial photosynthesis systems,5 lu-
minescent sensor materials6 and non-linear optical materials.7
When the 2,20-bipyridine framework bears pendent chiral sub-
stituents, they have been studied as potential ligands in metal-
catalysed asymmetric reactions.8 The aza Diels–Alder reaction has
become an important and versatile method for the preparation of
pyridine derivatives and several recent reviews have discussed the
scope and application of this useful reaction.9 1,2,4-Triazines10 have
been frequently used as 2-azadienes and they have been reacted
with a variety of aza-dienophiles, including the acetylene equiva-
lent 2,5-norbornadiene,2,11 yielding pyridine and 2,20-bipyridine
derivatives.
drazones 1 (R1¼CO2Et or 2-pyridyl). The hydrated
a
,
b
-diketo-esters
-keto-
2 were originally prepared from commercially available
b
esters by a diazo-transfer reaction giving the corresponding diazo-
compounds [R2COC(N2)CO2Et] and subsequent treatment of these
with t-BuOCl.13 From a manufacturing perspective, the large scale
use of these diazo-compounds would not be attractive and their
replacement by other
desirable. Alternative methods of preparing
similarly have other drawbacks: for example, a,b
a
,b
-diketo-ester equivalents would be highly
-diketo-esters 2
-diketo-esters are
a,b
commonly prepared by ozonolysis of phosphorane precursors
[R2COC(]PPh3)CO2Et],14 which generates large quantities of tri-
phenylphosphine oxide as an unwanted by-product. In view of
these limitations, this paper reports two alternative methods of
In a series of previous publications,12 we have described the
synthesis of triazines 3, pyridines 4 and 2,20-bipyridines 4 (R1¼2-
preparing a,b-diketo-ester equivalents 2 and describes how these
reactants can be used for the synthesis of triazine 3 and pyridine 4
derivatives. Some of this work have been published in a preliminary
form,12d,e and this paper gives a full description of the work and
also describes how our earlier studies have been extended.
* Corresponding author. Tel.: þ44 191 2274784; fax: þ44 191 2273519.
E-mail address: steven.stanforth@unn.ac.uk (S.P. Stanforth).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.090

976
M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
NH2
NH2
O
O
CO2Et
R2
N
CO2Et
R2
N
EtOH, reflux
36-100%
N
Compounds 3 and 4:
R1 R2
R1
R1
N
1
2
3
a
b
c
d
e
f
2-pyridyl Ph
2-pyridyl Me
2-pyridyl n-Pr
2-pyridyl i-Bu
(ii) 31-95%
5
Ph
Ph
Ph
n-Pr
Ph
n-Pr
Ph
g
h
i
Me
CO2Et
R2
(i)
Me
SMe
SMe
22-96%
R1
N
j
n-Pr
4
Scheme 1. Synthesis of triazines 3 and pyridines 4. Reaction conditions: (i) EtOH, reflux, 2,5-norbornadiene 5 (compounds 4a–d); (ii) xylene reflux or 1,2-dichlorobenzene, 140 ꢀC,
2,5-norbornadiene 5 (compounds 4e–j).
Table 1
Synthesis of triazines 3
2. Discussion
We have prepared the
rivatives 9a–d as representative examples of
equivalents (Scheme 2). The readily available
d were treated with sulfuryl chloride15 yielding the
keto-esters 7a–d. Treatment of these products with a mixture of
acetic acid and triethylamine in dimethylformamide at room tem-
perature yielded the acetates 8a–d (85–100%). Chlorination of
acetates 8a–d with sulfuryl chloride afforded novel compounds
9a–d (77–98%) as oils that did not require further purification.
We were also interested in examining the alcohols 11 as potential
a
-chloro-
a
-acetoxy-
b
a,b
-keto-ester de-
-diketo-ester
-keto-esters 6a–
-chloro-
Triazine 3
R1
R2
Methoda and yield (%)
A
B
C
D
b
a
b
c
d
e
f
g
h
i
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
Ph
Ph
Me
Me
SMe
Ph
97
37
98
d
95
d
79
d
80
52
d
51
90
92
65
d
71
54
d
65
d
d
58
58
63
d
43
58
d
d
d
d
64
92
a
b-
Me
n-Pr
i-Bu
Ph
n-Pr
Ph
n-Pr
Ph
n-Pr
82
93
54
43
100
100
j
SMe
a
,b
-diketo-ester 2 precursors (Scheme 3). Hydrolysis of the acetates
a
8 could give alcohols 11, which might then be oxidised to the a,b-
Method A: no pre-treatment of compounds 9. Method B: pre-treatment of
compounds 9 with EtOH/HCl. Method C: pre-treatment of compounds 9 with
ethanolic methylamine. Method D: from picolinates 10.
diketo-esters 2. In order to avoid this two-step sequence, picolinates
10a–d were prepared in good yield by reacting the appropriate
chloro-derivatives 7 with picolinic acid under basic conditions as
shown in Scheme 3. The facile cleavage of picolinates in the presence
of copper salts is well known16 and this property would allow the
solution with a range of amidrazones 1. Amidrazone 1 (R1¼2-pyr-
idyl) was prepared from 2-cyanopyridine and hydrazine hydrate.18
Amidrazones 1 (R1¼Ph, Me) were prepared in situ by reaction of
the corresponding amidine hydrochlorides with hydrazine hydrate
and amidrazone 1 (R1¼SMe) was synthesised as its HI salt by
methylation of thiosemicarbazide.19 The resulting 1,2,4-triazine
derivatives 3 were isolated with the best yields being obtained
when at least 2 equiv of amidrazone 1 was used (Table 1, method
A). The work-up for this reaction was straightforward; the solvent
direct conversion of picolinates 10 into their corresponding
a,b-
diketo-esters 2. Thus, in the presence of Cu(OAc)2, picolinates 10
would be expected to give alcohols 11, which would then be oxidised
in situ by Cu(OAc)217 into the corresponding
a
,
b
-diketo-esters 2.
In order to assess whether compounds 9 were suitable
diketo-ester equivalents they were reacted in boiling ethanol
a,b-
AcO
CO2Et
R2
Cl
CO2Et
R2
AcO
O
CO2Et
R2
CO2Et
R2
(i)
(ii)
(iii)
Cl
O
O
O
6
7
8
9
Compounds 6-9: a R2 = Ph; b R2 = Me; c R2 = n-Pr;d R2 = i-Bu
Scheme 2. Synthesis of compounds 9. Reaction conditions: (i) SO2Cl2, CH2Cl2, 0 ꢀC to rt; (ii) Et3N, AcOH, DMF, rt; (iii) SO2Cl2, CH2Cl2, 0 ꢀC to rt.
O
N
CO2Et
R2
Cl
CO2Et
R2
CO2Et
R2
O
O
HO
O
(i)
(ii)
CO2Et
R2
[O]
O
O
O
11
7
2
10
a R2 = Ph; b R2 = Me; c R2 = n-Pr;d R2 = i-Bu
Scheme 3. Synthesis of picolinates 10 and their conversion into intermediates 2. Reaction conditions: (i) picolinic acid, KHCO3, DMF, rt; (ii) Cu(OAc)2 aq, rt.

M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
977
Table 2
The four methods A–D described above were then assessed in
a ‘one-pot’ synthesis of some selected 2,20-bipyridine derivatives 4
(Table 2). When 2 equiv of amidrazone 1 (R1¼2-pyridyl) was
‘One-pot’ synthesis of 2,20-bipyridines 4
Pyridine 4
R1
R2
Methoda and yield (%)
reacted with the a-chloro-a-acetoxy-b-keto-ester derivatives 9 in
A
B
C
D
the presence of an excess of 2,5-norbornadiene 5 in ethanol at
reflux, the 2,20-bipyridine derivatives 4 were produced generally in
moderate yield (method A) except when R1¼Me and a poor yield of
2,20-bipyridine 4b was obtained. Prior reaction of selected exam-
a
b
c
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
Ph
Me
n-Pr
i-Bu
50
22
63
49b
80
d
96
d
68
d
71
d
59
45
80
61c
d
a
ples of a-chloro-a-acetoxy-b-keto-ester derivatives 9 with either
Method A: no pre-treatment of compounds 9. Method B: pre-treatment of
compounds 9 with EtOH/HC1. Method C: pre-treatment of compounds 9 with
ethanolic methylamine. Method D: from picolinates 10.
ethanolic hydrogen chloride (method B) or ethanolic methylamine
(method C) gave improved yields of the corresponding 2,20-bipyr-
idines 4, whereas the appropriate picolinates 10 produced mode-
rate yields of compounds 4c and 4d but a good yield of compound
4a. It is interesting to note that when R2¼i-Bu, an inseparable
mixture of regioisomers 4d and 12 was formed in methods A and C.
In contrast to triazine 3 (R1¼2-pyridyl), triazines 3 (R1¼Ph, Me,
SMe) were not expected to be sufficiently reactive to undergo the
inverse electron-demand aza Diels–Alder reaction with 2,5-nor-
bornadiene 5 in boiling ethanol solution at a convenient rate be-
cause of the electronic nature of the R1 groups. Triazines 3e–h were
therefore reacted with 2,5-norbornadiene 5 in xylene at reflux
yielding the pyridine derivatives 4e–h (31–95%), respectively. The
reaction of triazines 3i and 3j with 2,5-norbornadiene 5 proceeded
in hot (140 ꢀC) 1,2-dichlorobenzene yielding 2,20-bipyridines 4i
(88%) and 4j (64%), respectively (Scheme 1). Surprisingly, these two
triazines also reacted in neat, boiling 2,5-norbornadiene 5 (bp
89 ꢀC) over 2 days giving products 4i (64%) and 4j (66%) together
with some unreacted starting material.
Triazines 3i and 3j were oxidised by meta-chloroperbenzoic acid
(MCPA) affording the corresponding sulfoxides 3k and 3l (Scheme
4). As anticipated, the electron-deficient sulfoxide group allowed
these compounds to react with 2,5-norbornadiene 5 in boiling
ethanol giving pyridines 4k and 4l. These two pyridine derivatives
were also prepared by oxidation of pyridines 4i and 4j, respectively,
with 1 equiv of NaBO3$4H2O. In order to introduce a group that
might eventually be replaced by nucleophiles, sulfone 4m (93%)
was prepared from pyridine derivative 4j and an excess of
NaBO3$4H2O.
b
Mixture of 4d/12 (2:1).
Mixture of 4d/12 (3:1)
c
Bu-i
N
CO2Et
N
12
.
was evaporated and the residue was taken up into dichloro-
methane, washed with water, and after drying and evaporating the
organic layer, triazines 3 were obtained generally in good yield. Low
yields were only obtained when either R1 or R2 was a methyl group.
We reasoned that in the reaction of the amidrazones 1 with the
chloro- -acetoxy- -keto-ester derivative 9a, 1 equiv of amidrazone
1 might have reacted at the acetate carbonyl group resulting in de-
acylation and subsequent collapse of the resulting -chloro- -hy-
droxy- -keto-esters to the -diketo-esters 2 by loss of hydrogen
chloride. If this was the case, then it might be possible to convert
compounds 9 into their corresponding -diketo-esters 2 prior to
reaction with amidrazones 1. The -chloro- -acetoxy- -keto-ester
a-
a
b
a
a
b
a,b
a,b
a
a
b
derivatives 9 were therefore treated with saturated ethanolic
hydrogen chloride solution to induce de-acylation by transesteri-
fication and then 1 equiv of an amidrazone 1 was added. Under
these conditions the triazines 3 were produced (Table 1, method B),
generally in good yield. Alternatively, these a-chloro-a-acetoxy-b-
keto-ester derivatives 9 could be pre-treated with ethanolic me-
thylamine prior to addition of 1 equiv of an amidrazone 1 (Table 1,
method C) and in this case moderate to good yields of triazines 3
were obtained.
Additional functionality can be introduced into the pyridine-
ring by using, for example, enamines20 and enol-ethers21 as the
aza-dienophiles (Scheme 5). Thus, triazine 3c was reacted in boiling
ethanol with an excess of 2,3-dihydrofuran 13 giving the 2,20-
bipyridine derivative 16 (64%) after reaction of the intermediate 14
with additional 2,3-dihydrofuran 13. The regioselectivity of the
cycloaddition process was expected from results previously
obtained with this dienophile.12c Thus, if the alternative
regioisomer 15 had been formed, intramolecular lactonisation
In order to determine the suitability of picolinates 10 as a,b-
diketo-esters they were treated with an excess of Cu(OAc)2. After
washing with the disodium salt of EDTA, amidrazones 1 (R1¼2-
pyridyl or SMe) and ethanol were added and after heating at reflux
the appropriate triazines 3 were produced in moderate to good
yields (Table 1, method D).
CO2Et
R2
N
N
CO2Et
R2
N
N
CO2Et
R2
N
N
(ii)
(i)
Me
Me
65-91%
75-88%
S
N
MeS
S
O
O
3i R2 = Ph
3k R2 = Ph
3l R2 = n-Pr
4k R2 = Ph
(v)
3j R2 = n-Pr
4l R2 = n-Pr
64-88%
CO2Et
Pr-i
CO2Et
R2
(iv)
(iii)
Me
93%
72-78%
MeSO2
N
S
N
4i R2 = Ph
4m
4j R2 = n-Pr
Scheme 4. Synthesis of sulfoxide and sulfone derivatives. Reaction conditions: (i) MCPA; (ii) 2,5-norbornadiene 5, EtOH, reflux; (iii) NaBO3$4H2O, 1.05–1.10 equiv; (iv) NaBO3$4H2O,
2.5 equiv; (v) 2,5-norbornadiene 5, 1,2-dichlorobenzene, 140 ꢀC.

978
M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
O
O
O
OH
O
H
EtOH, reflux
N2
CO2Et
Prn
CO2Et
Prn
13
CO2Et
H
N
13
N
N
N
Prn
N
N
N
N
CO2Et
Prn
N
14
16
N
3c
N
OH
N
EtOH, rt
N2
CO2Et
Prn
CO2Et
Prn
CO2Et
Prn
17
H
N
AcOH
N
N
N
N
N
15
18
N
H
Scheme 5. Formation of 2,20-bipyridines 16 and 18.
would have been expected to occur. With enamine 17 as the
dienophile, the 2,20-bipyridine derivative 18 (84%) was obtained.
This reaction proceeded at room temperature and after the initial
cycloaddition process acetic acid was added to the reaction mixture
to assist the elimination of pyrrolidine.
dried (MgSO4) and evaporated giving a-chloro-b-keto-esters 7,
which were used in the subsequent reactions without need for
purification.
4.2.1. Ethyl 2-chloro-3-oxo-3-phenylpropanoate 7a15
Compound 7a was prepared from ethyl benzoylacetate 6a (1.0 g,
5.2 mmol) using the general procedure. Yield (1.03 g, 88%) as
3. Conclusion
a yellow oil; 1H NMR: (CDCl3)
d
8.02 (d, 2H, J¼7 Hz, Ph–H), 7.65 (t,
1H, J¼7 Hz, Ph–H), 7.50 (t, 2H, J¼7 Hz, Ph–H), 5.67 (s, 1H, –CHCl),
4.28 (q, 2H, J¼7 Hz, –OCH2CH3), 1.23 (t, 3H, J¼7 Hz, –OCH2CH3).
We have demonstrated that the
ter derivatives 9 and picolinates 10 are readily prepared and that
they are effective -diketo-ester equivalents. These compounds
are useful intermediates for the synthesis of 1,2,4-triazines 3 and
hence 2,20-bipyridines 4 via an aza Diels–Alder reaction. The
transformation of starting materials 9 and 10 into 2,20-bipyridines 4
can often be carried out in a ‘one-pot’ reaction without the need to
isolate the triazine 3 intermediates.
a-chloro-a-acetoxy-b-keto-es-
a,b
4.2.2. Ethyl 2-chloro-3-oxohexanoate 7c15
Compound 7c was prepared from ethyl butyrylacetate 6c (20 g,
0.12 mol) using the general procedure. Yield (21.95 g, 90%) as
a yellow liquid; 1H NMR: (CDCl3)
d 4.74 (s, 1H, –CHCl), 4.23 (q, 2H,
J¼7 Hz, –OCH2CH3), 2.65–2.60 (m, 2H, –CH2–), 1.59 (sextet, 2H,
–CH2–), 1.25 (t, 3H, J¼7 Hz, –OCH2CH3), 0.87 (t, 3H, J¼7 Hz, –CH3).
4. Experimental
4.1. General
4.2.3. Ethyl 2-chloro-5-methyl-3-oxohexanoate 7d
Compound 7d was prepared from ethyl 5-methyl-3-oxohex-
anoate 6d22 (12.0 g; 69.7 mmol) using the general procedure. Yield
(14.6 g, 100%) as a pale yellow liquid (86:14 keto/enol mixture); IR:
nmax/cmꢁ1 2962, 1729 (C]O), 1252, 1181, 1022; 1H NMR (CDCl3):
1H NMR (270 MHz) and 13C NMR (67.5 MHz) spectra were
recorded on a Joel JNM EX270 instrument. Elemental analysis was
performed by the Department of Chemistry at the University of
Newcastle. High-resolution mass spectra were performed by the
EPSRC mass spectrometry service at the University of Wales,
Swansea. Melting points are reported uncorrected as determined
on a Stuart SMP1 melting point apparatus. Infrared spectra were
obtained using a diamond anvil on a Perkin Elmer 1000 spectro-
photometer. Thin layer chromatography was performed on Merck
plastic foil plates pre-coated with silica get 60F254. Silica gel for
column chromatography was Merck silica gel 60. Ethyl 2-chloro-
acetoacetate 7b was commercially available.
d
12.43 (s, 1H, OH enol form), 4.75 (s, 1H, pCHCl), 4.29 (q, 2H, enol
form, J¼7.2 Hz, –OCH2CH3), 4.28 (q, 2H, keto form, J¼7.2 Hz,
–OCH2CH3), 2.70 (d, 2H, enol form, J¼7.2 Hz, –CH2Pr-i), 2.59 and
2.56 (2d, 2H, keto form, J¼7.2 Hz, –CH2Pr-i), 2.19 (nonet, 1H,
J¼6.7 Hz, 5-H overlapping enol and keto forms, –CH2CHMe2), 1.31
(t, 3H, overlapping enol and keto forms, J¼7.2 Hz, –OCH2CH3), 0.99
and 0.96 (2d, 6H, enol form, J¼7.2 Hz, –CH2CHMe2), 0.94 and 0.93
(2d, 6H, keto form, J¼7.2 Hz, –CH2CHMe2); 13C NMR (CDCl3) (keto
form): d 198.5 (CO), 165.1 (CO), 63.2 (CH2CH3), 61.3 (CH), 47.7 (CH2),
24.3 (CH), 22.4, 22.3 (CH3), 14.0 (CH3); HRMS (ESI) for C9H16ClO3
[MþH]þ: m/z calcd: 207.0782; measured: 207.0781.
4.2. Preparation of
procedure15
a-chloro-b-keto-esters 7: general
4.3. Preparation of
procedure23
a-acetoxy-b-keto-esters 8: general
To a stirred ice-cold solution of the appropriate b-keto-ester 6 in
CH2Cl2 (10 mL) was added slowly sulfuryl chloride (1.1 equiv). After
stirring for 1 h at room temperature the solution was washed with
a saturated solution of sodium carbonate, the organic layer was
To a stirred ice-cold solution of glacial acetic acid (10 mL,
0.18 mol) in DMF (50 mL) was added slowly NEt3 (10 mL, 0.10 mol).
After warming to room temperature, the appropriate
a-chloro-

M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
979
b
-keto-ester 7 (0.02–0.03 mol) was added and the solution was left
4.4.3. Ethyl 2-acetoxy-2-chloro-3-oxohexanoate 9c
stirring at room temperature for 20 h. The solution was poured into
water, extracted twice with CH2Cl2 and the combined organic ex-
tracts were dried (MgSO4) and evaporated affording a-acetoxy-b-
Compound 9c was prepared from compound 8c (4.0 g, 18 mmol)
using the general procedure. Yield (4.62 g, 98%) as a yellow oil.
Analytical data (IR, 1H NMR, HRMS) for this compound has been
reported previously by us.12d
keto-ester 8. These compounds were all used in the subsequent
reactions without the need for purification.
4.4.4. Ethyl 2-acetoxy-2-chloro-5-methyl-3-oxohexanoate 9d
Compound 9d was prepared from compound 8d (4.97 g,
21.6 mmol) and SO2Cl2 (1.91 mL, 23.8 mmol) using the general
procedure. Yield (5.45 g, 95%) as a yellow oil; IR: nmax/cmꢁ1 2965,
4.3.1. Ethyl 2-acetoxy-3-oxo-3-phenylpropanoate 8a24a,b
Compound 8a was prepared from compound 7a (5.0 g,
0.02 mol) using the general procedure. Yield (5.24 g, 95%) as a yel-
low liquid; 1H NMR: (CDCl3)
d
8.00 (d, 2H, J¼7 Hz, Ph–H), 7.64 (t,1H,
1735 (C]O), 1247, 1200, 1090, 1021; 1H NMR (CDCl3):
d 4.32 (q, 2H,
J¼7 Hz, Ph–H), 7.50 (t, 2H, J¼7 Hz, Ph–H), 6.34 (s, 1H, –CHOAc), 4.24
(q, 2H, J¼7 Hz, –OCH2CH3), 2.22 (s, 3H, –OCOCH3), 1.20 (t, 3H,
J¼7 Hz, –OCH2CH3).
J¼7.2 Hz, –OCH2CH3), 2.77–2.70 (m, 2H, –CH2Pr-i), 2.30–2.15 (m,
1H, –CHMe2), 2.24 (s, 3H, –COCH3),1.31 (t, 3H, J¼7.2 Hz, –OCH2CH3),
1.00–0.94 (m, 6H, –CHMe2); 13C NMR (CDCl3):
d 196.2 (CO), 167.7
(CO), 163.5 (CO), 63.9 (CH2), 45.5 (CH2), 24.1 (CH), 22.4 (CH3), 22.2
(CH3), 20.9 (CH3), 13.9 (CH3) (the C-2 carbon was not sufficiently
intense to be located); HRMS (ESI) for C11H21ClNO5 [MþNH4]þ: m/z
calcd: 282.1103; measured: 282.1104.
4.3.2. Ethyl 2-acetoxy-3-oxobutanoate 8b23,24a,b,25
Compound 8b was prepared from compound 7b (10.0 g,
60.8 mmol) using the general procedure. Yield (9.67 g, 85%) as
a yellow liquid; 1H NMR (CDCl3):
d 5.50 (s, 1H, –CHOAc), 4.29 (q, 2H,
J¼7.2 Hz, –OCH2CH3), 2.36 (s, 3H, –COCH3), 2.24 (s, 3H, –OCOCH3),
4.5. Preparation of picolinates 10
1.32 (t, 3H, J¼7.2 Hz, –OCH2CH3).
The preparation of picolinates 10a and 10c and full analytical
data for these two compounds have been described in our previous
communication.12e Picolinates 10b and 10d were prepared using
a similar procedure. Compound 10b (77% yield); 93:7 keto/enol
mixture; IR: nmax/cmꢁ1 2986, 1727 (C]O), 1290, 1244, 1215, 1126,
4.3.3. Ethyl 2-acetoxy-3-oxohexanoate 8c24b,26
Compound 8c was prepared from compound 7c (5.0 g,
27 mmol) using the general procedure. Yield (5.0 g, 90%) as a yellow
liquid; 1H NMR: (CDCl3)
d
5.50 (s, 1H, –CHOAc), 4.19 (q, 2H, J¼7 Hz,
–OCH2CH3), 2.57 (t, 2H, J¼7 Hz, –CH2–), 2.14 (s, 3H, –OCOCH3), 1.56
(sextet, 2H, J¼7 Hz, –CH2–), 1.22 (t, 3H, J¼7 Hz, –OCH2CH3), 0.84 (t,
3H, J¼7 Hz, –CH3).
1092, 749, 700; 1H NMR (CDCl3):
d 12.35 (s, 1H, OH enol form), 8.82
(ddd, 2H, overlapping keto and enol forms, J¼1.0, 1.7 and 4.7 Hz,
Py–H), 8.23 (ddd 2H, overlapping keto and enol, J¼1.0, 1.2 and
7.9 Hz, Py–H), 7.90 (ddd, 2H, overlapping keto and enol forms, J¼1.7,
7.7 and 7.9 Hz, Py–H), 7.55 (ddd, 2H, overlapping keto and enol
forms, J¼1.2, 4.7 and 7.7 Hz, Py–H), 5.81 (s, 1H, 2-H keto form,
–CHOCO–), 4.34 (q, 2H, keto form, J¼7.2 Hz, –OCH2CH3), 4.33 (q, 2H,
enol form, J¼7.2 Hz, –OCH2CH3), 2.47 (s, 3H, keto form, –COCH3),
2.39 (s, 3H, enol form, –COCH3), 1.34 (t, 3H, keto form, J¼7.2 Hz,
–OCH2CH3), 1.33 (t, 3H, enol form, J¼7.2 Hz, –OCH2CH3); 13C NMR
4.3.4. Ethyl 2-acetoxy-5-methyl-3-oxohexanoate 8d25
Compound 8d was prepared from compound 7d (5.0 g,
24.2 mmol) using the general procedure. Yield (5.67 g, 100%) as
a yellow liquid; 1H NMR (CDCl3):
d 5.46 (s, 1H, pCHOAc), 4.27 (q, 2H,
J¼7.2 Hz, –OCH2CH3), 2.53 (d, 2H, J¼6.7 Hz, –CH2Pr-i), 2.22 (s, 3H,
–OCOCH3), 2.19 (nonet, J¼6.7 Hz, 1H, –CH2CHMe2), 1.30 (t, 3H,
J¼7.2 Hz, –OCH2CH3), 0.93 and 0.90 (2d, 6H, J¼6.7 Hz, –CH2CHMe2).
(CDCl3) keto form:
d
197.2 (CO), 164.3 (CO), 163.6 (CO), 150.4 (CAr),
146.6 (CAr), 137.2 (CAr), 127.6 (CAr), 125.9 (CAr), 78.6 (CH), 62.8 (CH2),
27.5 (CH3), 14.1 (CH3); HRMS (ESI) for C12H14NO5 [MþH]þ: m/z
calcd: 252.0866; measured: 252.0866. Compound 10d: (80% yield);
IR: nmax/cmꢁ1 2961, 1725 (C]O), 1308, 1290, 1245, 1192, 1130, 1092,
4.4. Preparation of
general procedure
a-acetoxy-a-chloro b-keto-esters 9:
To a stirred ice-cold solution of the appropriate
a
-acetoxy-
b
-
749, 702; 1H NMR (CDCl3):
d
8.82 (ddd, 1H, J¼1.0, 1.7 and 4.7 Hz, Py–
keto-ester 8 (2 mmol) in CH2Cl2 (5 mL) was added slowly sulfuryl
chloride (2.2 mmol unless otherwise stated). After stirring at room
temperature for 1 h, the solution was washed with a saturated
solution of sodium carbonate, dried (MgSO4) and evaporated
H), 8.23 (ddd, 1H, J¼1.0, 1.2 and 7.9 Hz, Py–H), 7.89 (ddd, 1H, J¼1.7,
7.7 and 7.9 Hz, Py–H), 7.54 (ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–H),
5.79 (s, 1H, –CHOCO–), 4.33 (q, 2H, J¼7.2 Hz, –OCH2CH3), 2.67 and
2.66 (2d, 2H, J¼6.7 Hz, –CH2Pr-i), 2.26 (nonet, J¼6.7 Hz, 1H,
–CH2CHMe2), 1.33 (t, 3H, J¼7.2 Hz, –OCH2CH3), 0.98 and 0.96 (2d,
yielding crude
a-acetoxy-a-chloro-b-keto-ester 9. These com-
pounds were all used in the subsequent reactions without the need
for purification.
6H, J¼6.7 Hz, –CHMe2); 13C NMR (CDCl3) keto form:
d 199.0 (CO),
164.4 (CO), 163.6 (CO), 150.4 (CAr), 146.7 (CAr), 137.2 (CAr), 127.6 (CAr),
125.9 (CAr), 78.6 (CH), 62.7 (CH2), 48.7 (CH2), 24.2 (CH), 22.5 (CH3),
22.4 (CH3), 14.1 (CH3); HRMS (ESI) for C15H20NO5 [MþH]þ: m/z
calcd: 294.1336; measured: 294.1332.
4.4.1. Ethyl 2-acetoxy-2-chloro-3-oxo-3-phenylpropanoate 9a
Compound 9a was prepared from compound 8a (0.5 g, 2 mmol)
using the general procedure. Yield (0.44 g, 77%) as a yellow oil.
Analytical data (IR, 1H NMR, HRMS) for this compound has been
reported previously by us.12d
4.6. Synthesis of triazines 3
4.6.1. Ethyl 5-phenyl-3-(2-pyridyl)-1,2,4-triazine-6-carboxylate 3a
Method A. To a stirred solution of amidrazone 1 (R1¼2-pyridyl)
(0.6 g. 4.25 mmol) in ethanol (20 mL) was added compound 9a
(0.5 g, 1.7 mmol) in one portion. The solution was then stirred un-
der reflux for 2 h, allowed to cool to room temperature and poured
into water (20 mL). The mixture was extracted several times with
CH2Cl2 and the combined organic extracts were washed with water,
dried (MgSO4) and evaporated giving compound 3a as an orange oil
(0.52 g, 97%); IR: nmax/cmꢁ1 1735 (C]O), 1489, 1281, 1173 and 697;
4.4.2. Ethyl 2-acetoxy-2-chloro-3-oxobutanoate 9b
Compound 9b was prepared from compound 8b (4.0 g,
21.3 mmol) and SO2Cl2 (1.88 mL, 23.4 mmol) using the general
procedure. Yield (3.83 g; 81 %) as a yellow liquid; IR: nmax/cmꢁ1
2987, 1733 (C]O), 1370, 1252, 1199, 1086, 1042, 1011; 1H NMR
(CDCl3):
d
4.33 (q, 2H, J¼7.2 Hz, –OCH2CH3), 2.50 (s, 3H, –CH3), 2.24
(s, 3H, –CH3), 1.32 (t, 3H, J¼7.2 Hz, –OCH2CH3); 13C NMR (CDCl3):
d
194.5 (CO), 167.7 (CO), 163.3 (CO), 90.0 (C), 64.0 (CH2), 24.8 (CCH3),
20.8 (CCH3), 13.9 (CH2CH3); HRMS (ESI) for C8H12ClO5 [MþH]þ: m/z
1H NMR: (CDCl3)
Py–H), 7.95 (dt, 1H, J¼8 and 2 Hz, Py–H), 7.87 (dd, 2H, J¼8 and 2 Hz,
d
8.95 (d, 1H, J¼5 Hz, Py–H), 8.72 (d, 1H, J¼8 Hz,
calcd: 240.0633; measured: 240.0632.

980
M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
Ph–H), 7.57–7.53 (m, 4H, Ph–H and Py–H), 4.42 (q, 2H, J¼8 Hz,
–OCH2CH3), 1.30 (t, 3H, J¼7 Hz, –OCH2CH3); 13C NMR: (CDCl3)
2H, propyl–CH2–), 1.94–1.80 (m, 2H, propyl–CH2–), 1.49 (t, 3H,
J¼7 Hz, propyl–CH3), 1.04 (t, 3H, J¼7 Hz, –OCH2CH3); 13C NMR:
d
165.2 (CO), 162.5 (C), 156.8 (C), 152.2 (C), 150.7 (CH), 150.4 (C),
(CDCl3) d 164.2 (CO), 163.8 (C), 162.7 (C), 152.2 (C), 150.8 (CH), 149.9
137.3 (CH), 134.3 (C), 131.8 (CH), 129.1 (CH), 129.0 (CH), 126.1 (CH),
124.9 (CH), 63.0 (CH2), 13.9 (CH3); HRMS (EI): m/z calcd for
C17H15N4O2 [MþH]þ: 307.1190, measured: 307.1188.
(C), 137.3 (CH), 126.1 (CH), 125.0 (CH), 62.9 (CH2), 37.2 (CH2), 22.5
(CH2), 14.2 (CH3), 14.1 (CH3); HRMS (EI): m/z calcd for C14H17N4O2
[MþH]þ: 273.1346, measured: 273.1345. Anal. Calcd for
C14H16N4O2: N 20.57, C 61.75, H 5.92. Found: N 20.38, C 61.39, H
6.05.
Method B. A solution of compound 9a (0.5 g, 1.7 mmol) in sat-
urated ethanolic HCl (5 mL) was stirred at room temperature for
16 h. The solvent was evaporated giving compound 2a as a yellow
oil (0.41 g). A portion of this oil (0.25 g, 0.9 mmol) was added in one
portion to a stirred solution of amidrazone 1 (R1¼2-pyridyl) (0.12 g,
0.9 mmol) in ethanol (20 mL). The solution was then stirred under
reflux for 2 h, allowed to cool to room temperature and poured into
water (20 mL), The mixture was extracted several times with
CH2Cl2 and the combined organic extracts were washed with water,
dried (MgSO4) and evaporated giving compound 3a as an orange oil
(0.26 g, 95%), identical with an authentic sample.
4.6.4. Ethyl 5-isobutyl-3-(2-pyridyl)-1,2,4-triazine-6-
carboxylate 3d
Using the general procedures (methods C and D), triazine 3d
was prepared in the yields shown in Table 1. Triazine 3d was
obtained as orange crystals, mp 80–83 ꢀC after column chroma-
tography over silica gel [eluent: ethyl acetate/petroleum ether bp
60–80 ꢀC (2:1)]; IR: nmax/cmꢁ1 2955, 2928, 2868, 1723 (C]O), 1505,
1248, 1137, 1051, 785, 744; 1H NMR (CDCl3):
d
8.94 (ddd, 1H, J¼1.0,
Method C. To a stirred solution of compound 9a (0.5 g, 1.7 mmol)
in ethanol (3 mL) was added a solution of 33 wt % methylamine in
ethanol (0.43 mL, 3.5 mmol). After stirring for 1 h at room tem-
perature, amidrazone 1 (R1¼2-pyridyl) (0.24 g, 1.7 mmol) was
added in one portion. The solution was then stirred under reflux for
2 h, allowed to cool to room temperature and poured into water
(20 mL). The mixture was extracted several times with CH2Cl2, and
the combined organic extracts were washed with water, dried
(MgSO4) and evaporated. The crude mixture was purified by col-
umn chromatography over silica gel [eluent: ethyl acetate/petro-
leum ether bp 60–80 ꢀC (6:4)] giving compound 3a (0.35 g, 64%),
identical with an authentic sample.
Method D. A mixture of compound 10a (1.00 g, 3.32 mmol),
Cu(OAc)2 (1.32 g, 6.63 mmol), methanol (20 mL) and CH2Cl2
(50 mL) was stirred at room temperature for 1 day. The reaction
was diluted with hexane (20 mL) and the organic fraction was
washed with Na2EDTA (0.1 M aqueous solution) until the aqueous
phase remained colourless. The organic phase was dried (MgSO4)
and evaporated. The resulting oil was taken up in ethanol (50 mL)
and amidrazone 1 (R1¼2-pyridyl) (361 mg, 2.65 mmol) was added.
The solution was stirred under reflux for 1 day, allowed to cool to
room temperature, poured into water and extracted with CH2Cl2.
The combined organic layers were washed with water, dried
(MgSO4) and evaporated. The crude mixture was purified by col-
umn chromatography over silica gel [ethyl acetate/diethyl ether
(1:1)] giving compound 3a (513 mg, 64%) identical with an au-
thentic sample.
1.7 and 4.7 Hz, Py–H), 8.72 (ddd, 1H, J¼1.0, 1.2 and 7.9 Hz, Py–H),
7.95 (ddd, 1H, J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.51 (ddd, 1H, J¼1.2, 4.7
and 7.7 Hz, Py–H), 4.57 (q, 2H, J¼7.2 Hz, –OCH2CH3), 3.15 (d, 2H,
J¼7.2 Hz, –CH2Pr-i), 1.50 (t, 3H, J¼7.2 Hz, –OCH2CH3), 2.36–2.21 (m,
1H, –CH2CHMe2), 0.99 (d, 6H, J¼6.7 Hz, –CHMe2); 13C NMR (CDCl3):
d
164.3 (CO), 163.1 (CAr), 162.5 (CAr), 152.3 (CAr), 150.4 (CAr), 150.8
(CAr), 137.3 (CAr), 126.0 (CAr), 125.0 (CAr), 62.9 (CH2), 43.3 (CH2), 29.1
(CH), 22.5 (CH3),14.3 (CH3); HRMS (ESI) for C15H19N4O2 [MþH]þ: m/z
calcd: 287.1503; measured: 287.1504.
4.6.5. Ethyl 3,5-diphenyl-1,2,4-triazine-6-carboxylate 3e27
Method A. To a stirred, ice-cold solution of benzamidine hy-
drochloride hydrate (0.8 g, 5.1 mmol) in ethanol (10 mL) was added
drop-wise hydrazine hydrate (0.25 mL, 5.1 mmol). After stirring at
0 ꢀC for 15 min, the mixture was warmed to room temperature and
stirred for another 15 min. Compound 9a (0.57 g, 2 mmol) and
triethylamine (0.52 mL, 3.8 mmol) were slowly added. The solution
was stirred under reflux for 20 h, cooled to room temperature and
poured into water (10 mL). The mixture was extracted several times
with CH2Cl2 and the combined organic extracts were washed with
water, dried (MgSO4) and evaporated giving compound 3e as a red
oil (0.5 g, 82%); IR: nmax/cmꢁ1 1734 (C]O), 1275, 1151 and 688; 1H
NMR: (CDCl3)
d
8.67 (dd, 2H, J¼8 and 2 Hz, Ph–H), 8.12–8.04 (m, 3H,
Ph–H), 7.87 (dd, 2H, J¼8 Hz, Ph–H), 7.51–7.59 (m, 3H, Ph–H), 4.44 (q,
2H, J¼7 Hz, –OCH2CH3), 1.30 (t, 3H, J¼7 Hz, –OCH2CH3); HRMS (EI):
m/z calcd for C18H16N3O2 [MþH]þ: 306.1237, measured: 306.1238.
Method B. To a stirred, ice-cold solution of benzamidine hydro-
chloride hydrate (0.2 g, 1.27 mmol) in ethanol (5 mL) was added
drop-wise hydrazine hydrate (0.06 mL, 1.27 mmol). After stirring at
0 ꢀC for 15 min, the mixture was warmed to room temperature and
stirred for another 15 min, and compound 2a (0.2 g, 0.89 mmol)
(prepared from compound 9a and saturated ethanolic HCl as de-
scribed above in Section 4.6.1, Method B) and triethylamine
(0.12 mL, 0.9 mmol) were slowly added. The resulting solution was
stirred under reflux for 20 h, cooled to room temperature and
poured into water (10 mL). The mixture was extracted several times
with CH2Cl2 and the combined organic extracts were washed with
water, dried (MgSO4) and evaporated yielding compound 3e (80%),
identical with an authentic sample.
4.6.2. Ethyl 5-methyl-3-(2-pyridyl)-1,2,4-triazine-6-carboxylate 3b
Using the general procedure (method A), the crude product was
purified by column chromatography (ethyl acetate; Rf¼0.15)
yielding triazine 3b (786 mg; 36%) as an orange wax, which turned
brown on standing; IR: nmax/cmꢁ1 1725 (C]O), 1517, 1250, 1141; 1H
NMR: (CDCl3)
d
8.94 (ddd, 1H, J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.77
(ddd, 1H, J¼1.0, 1.2 and 7.9 Hz, Py–H), 7.96 (ddd, 1H, J¼1.7, 7.7 and
7.9 Hz, Py–H), 7.52 (ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–H), 4.58 (q,
2H, J¼7.2 Hz, –OCH2CH3), 2.98 (s, 3H, Ar–CH3), 1.51 (t, 3H, J¼7.2 Hz,
–OCH2CH3); 13C NMR: (CDCl3)
d 164.0 (CO), 162.5 (C), 161.2 (C), 151.9
(C), 150.8 (CH), 136.8 (CH), 125.8 (CH), 125.0 (CH), 124.1 (C), 62.9
(CH2), 23.3 (CH3), 14.2 (CH3); HRMS (EI): m/z calcd for C12H13N4O2
[MþH]þ: 245.1033, measured: 245.1030.
4.6.6. Ethyl 3-phenyl-5-propyl-1,2,4-triazine-6-carboxylate 3f
Using the general procedures (methods A and B), triazine 3f was
prepared in the yields shown in Table 1. Recrystallisation from
ethanol gave the pure compound 3f (0.50 g, 93%) as a yellow solid,
mp 58–60 ꢀC; IR: nmax/cmꢁ1 1718 (C]O), 1506, 1259 and 1115; 1H
4.6.3. Ethyl 5-propyl-3-(2-pyridyl)-1,2,4-triazine-6-carboxylate 3c
Using the general procedures, triazine 3c was prepared by
methods A–D in the yields given in Table 1. Compound 3c was
produced as an orange solid, mp 68–70 ꢀC; IR: nmax/cmꢁ1 1721
NMR: (CDCl3)
d
8.62 (dd, 2H, J¼8 and 2 Hz, Ph–H), 7.51–7.59 (m, 3H,
(C]O), 1506, 1247 and 1138; 1H NMR: (CDCl3)
Py–H), 8.72 (d, 1H, J¼8 Hz, Py–H), 7.94 (dt, 1H, J¼8 and 2 Hz, Py–H),
7.50 (m, 1H, Py–H), 4.55 (q, 2H, J¼8 Hz, –OCH2CH3), 3.24–3.17 (m,
d
8.93 (d, 1H, J¼5 Hz,
Ph–H), 4.55 (q, 2H, J¼7 Hz, –OCH2CH3), 3.17–3.11 (m, 2H, propyl–
CH2–), 1.90 (sextet, 2H, J¼8 Hz, propyl–CH2–), 1.49 (t, 3H, J¼7 Hz,
–OCH2CH3), 1.07 (t, 3H, J¼7 Hz, propyl–CH3); 13C NMR: (CDCl3)

M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
981
d
164.3 (CO), 163.3 (C), 163.1 (C), 148.7 (C), 134.3 (C), 132.4 (CH),
ethanol (0.43 mL, 3.5 mmol). After stirring for 1 h at room tem-
perature, amidrazone 1 (R1¼SMe$HCl) (0.41 g, 1.7 mmol) and so-
dium bicarbonate (0.18 g, 2 mmol) were added in one portion. The
solution was then stirred under reflux for 2 h, allowed to cool to
room temperature, poured into water (20 mL) and extracted with
CH2Cl2. The combined organic extracts were washed with water,
dried (MgSO4) and evaporated affording compound 3i (0.28 g, 58%),
identical with an authentic sample.
129.0 (2ꢂCH), 62.7 (CH2), 36.9 (CH2), 21.3 (CH2), 14.3 (CH3), 14.0
(CH3); HRMS (EI): m/z calcd for C15H18N3O2 [MþH]þ: 272.1394,
measured: 272.1397. Anal. Calcd for C15H17N3O2: N 15.49, C 66.40, H
6.32. Found: N 15.81, C 66.43, H 6.22.
4.6.7. Ethyl 3-methyl-5-phenyl-1,2,4-triazine-6-carboxylate 3g28
Method A. To a stirred ice-cold solution of acetamidine hydro-
chloride hydrate (0.48 g, 5 mmol) in ethanol (10 mL) was added
drop-wise hydrazine hydrate (0.25 mL, 5 mmol). After stirring at
0 ꢀC for 15 min, the mixture was allowed to warm to room tem-
perature, stirred for another 15 min, and compound 9a (0.57 g,
2 mmol) and triethylamine (0.52 mL, 3.8 mmol) were slowly added.
The solution was stirred under reflux for 20 h, allowed to cool to
room temperature and poured into water (10 mL). The mixture was
extracted with CH2Cl2 and the combined organic fractions were
washed with water, dried (MgSO4) and evaporated giving com-
pound 3g (0.26 g, 54%) as an orange oil; IR: nmax/cmꢁ1 1736 (C]O),
4.6.10. Ethyl 3-methylthio-5-propyl-1,2,4-triazine-6-carboxylate 3j
Using similar procedures to those described above for the
preparation of compound 3i, compound 3j was prepared by
methods A–C in the yields reported in Table 1. Compound 3j was
obtained as an orange oil; IR: nmax/cmꢁ1 1723 (C]O), 1496, 1210
and 1182; 1H NMR: (CDCl3)
d
4.50 (q, 2H, J¼7 Hz, –OCH2CH3), 3.06–
2.98 (m, 2H, propyl–CH2–), 2.70 (s, 3H, –SCH3), 1.79 (sextet, 2H,
J¼7 Hz, propyl–CH2–), 1.46 (t, 3H, J¼7 Hz, propyl–CH3), 1.02 (t, 3H,
J¼7 Hz, –OCH2CH3); 13C NMR: (CDCl3)
d 174.8 (CO), 164.1 (C), 162.7
1506, 1259, 1137 and 693; 1H NMR: (CDCl3)
d
7.76 (dd, 2H, J¼8 and
(C), 146.2 (C), 62.5 (CH2), 36.8 (CH2), 21.3 (CH2), 14.2 (CH3), 14.0
(CH3), 13.9 (CH3); HRMS (EI): m/z calcd for C10H16N3O2S [MþH]þ:
242.0958, measured: 242.0959.
2 Hz, Ph–H), 7.58–7.51 (m, 3H, Ph–H), 4.40 (q, 2H, J¼7 Hz,
–OCH2CH3), 2.99 (s, 3H, –CH3), 1.27 (t, 3H, J¼7 Hz, –OCH2CH3); 13C
NMR: (CDCl3)
d 167.4 (CO), 165.3 (C), 156.1 (C), 149.3 (C), 134.4 (C),
131.7 (CH), 129.0 (CH),128.9 (CH), 62.9 (CH2), 23.9 (CH3), 13.9 (CH3);
HRMS (EI): m/z calcd for C13H14N3O2 [MþH]þ: 244.1081, measured:
244.1082.
4.7. Synthesis of pyridines 4a–d
The methods A–D that were described for the preparation of the
triazines 3 in Section 4.6 above were followed except that 2,5-
norbornadiene 5 (5–10 equiv) was added to the reaction mixture
and the mixture was heated at reflux overnight. The yields of
products are given in Table 2.
4.6.8. Ethyl 3-methyl-5-propyl-1,2,4-triazine-6-carboxylate 3h
Using the general procedures (methods A and B), triazine 3h
was prepared in the yields shown in Table 1. Chromatography over
silica gel [eluent: petroleum ether bp 60–80 ꢀC/ethyl acetate (6:4)]
gave the desired product 3h as a yellow oil; IR: nmax/cmꢁ1 1728
4.7.1. Ethyl 6-phenyl[2,20]bipyridyl-5-carboxylate 4a
Chromatography over silica gel [eluent: ethyl acetate/petroleum
ether bp 60–80 ꢀC (6:4)] gave compound 4a as an orange oil,
identical with an authentic sample.12c
(C]O), 1515, 1260 and 1094; 1H NMR: (CDCl3)
d
4.52 (q, 2H, J¼7 Hz,
–OCH2CH3), 3.04–2.98 (m, 2H, propyl–CH2–), 2.90 (s, 3H, –CH3),
1.78 (sextet, 2H, J¼8 Hz, propyl–CH2–), 1.46 (t, 3H, J¼7 Hz,
–OCH2CH3), 1.02 (t, 3H, J¼7 Hz, propyl–CH3); 13C NMR: (CDCl3)
d
167.7 (CO), 164.3 (C), 162.7 (C), 148.8 (C), 62.7 (CH2), 36.8 (CH2),
4.7.2. Ethyl 6-methyl[2,20]bipyridyl-5-carboxylate 4b
23.9 (CH2), 22.7 (CH3), 14.2 (CH3), 14.0 (CH3); HRMS (EI): m/z calcd
for C10H16N3O2 [MþH]þ: 210.1237, measured: 210.1236.
Column chromatography over silica gel (diethyl ether/
hexanes¼4:1; Rf¼0.41) yielded compound 4b as white needles, mp
77–79 ꢀC; lit.29: 80 ꢀC (from ethanol); 1H NMR (CDCl3):
d 8.71 (ddd,
4.6.9. Ethyl 3-methylthio-5-phenyl-1,2,4-triazine-3-carboxylate 3i
1H, J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.51 (ddd, 1H, J¼1.0, 1.2 and 7.9 Hz,
Py–H), 8.34 (d, 1H, J¼8.2 Hz, Py–3H or Py–4H), 8.29 (d, 1H, J¼8.2 Hz,
Py–3H or Py–4H), 7.84 (ddd, 1H, J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.35
(ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–H), 4.41 (q, 2H, J¼7.2 Hz,
–OCH2CH3), 2.93 (s, 3H, –CH3), 1.43 (t, 3H, J¼7.2 Hz, –OCH2CH3).
Method A. To
a stirred solution of compound 9a (0.5 g,
1.75 mmol) and sodium bicarbonate (0.41 g, 4.9 mmol) in EtOH
(20 mL) was added amidrazone 1 (R1¼SMe$HCl) (4.4 mmol, 1.02 g).
The solution was then stirred under reflux for 2 h, allowed to cool to
room temperature, poured into water (20 mL) and extracted with
CH2Cl2. The combined organic extracts were washed with water,
dried (MgSO4) and evaporated yielding compound 3i (0.37 g, 80%)
as a red solid, mp 62–64 ꢀC; IR: nmax/cmꢁ1 1727 (C]O), 1483, 1224
4.7.3. Ethyl 6-propyl[2,20]bipyridyl-5-carboxylate 4c
Chromatography over silica gel [eluent: ethyl acetate/petroleum
ether bp 60–80 ꢀC (6:4)] gave the desired product 4c as an orange
oil, identical with an authentic sample.12c
and 1210; 1H NMR: (CDCl3)
d
7.74 (d, 2H, J¼8 Hz, Ph–H), 7.50–7.53
(m, 3H, Ph–H), 4.40 (q, 2H, J¼7 Hz, –OCH2CH3), 2.75 (s, 3H, –SCH3),
1.27 (t, 3H, J¼7 Hz, –OCH2CH3); 13C NMR: (CDCl3)
d
174.4 (CO), 165.1
4.7.4. Ethyl 6-isobutyl[2,20]bipyridyl-5-carboxylate 4d and ethyl 5-
isobutyl[2,20]bipyridyl-6-carboxylate 12
Compound 4d was obtained as a brown oil after chromatogra-
phy over silica gel [eluent: diethyl ether/hexane (1:2)]. In methods
A and C an inseparable mixture of 4d and 12 was produced in the
ratios given in Table 2. Compound 4d: IR: nmax/cmꢁ1 3057, 2957,
2930, 2870, 1719 (C]O), 1583, 1555, 1254, 1093, 1052, 770, 744; 1H
(C), 155.8 (C), 146.9 (C), 134.2 (C), 131.8 (CH), 129.0 (CH), 128.9 (CH),
62.7 (CH2), 14.0 (CH3), 13.9 (CH3); HRMS (EI): m/z calcd for
C13H14N3O2S [MþH]þ: 276.0801, measured: 276.0800.
Method B. To a solution of amidrazone 1 (R1¼SMe$HCl) (0.2 g,
0.9 mmol) and sodium bicarbonate (0.09 g, 1.17 mmol) in ethanol
(15 mL) was added in one portion compound 2a (0.25 g, 1.1 mmol)
(prepared from compound 9a and saturated ethanolic HCl as de-
scribed in Section 4.6.1, method B). The solution was then stirred
under reflux for 2 h, allowed to cool to room temperature, poured
into water (20 mL) and extracted with CH2Cl2. The combined or-
ganic extracts were washed with water, dried (MgSO4) and evap-
orated giving compound 3i (0.22 g, 90%), identical with an
authentic sample.
NMR (CDCl3):
d
8.70 (ddd, 1H, J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.52
(ddd, 1H, J¼1.0, 1.2 and 7.9 Hz, Py–H), 8.30 (d, 1H, J¼8.2 Hz, Py–3H
or Py–4H), 8.27 (d, 1H, J¼8.2 Hz, Py–3H or Py–4H), 7.84 (ddd, 1H,
J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.34 (ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–
H), 4.40 (q, 2H, J¼7.2 Hz, –OCH2CH3), 3.16 (d, 2H, J¼6.7 Hz, –CH2Pr-
i), 2.26 (nonet, J¼6.7 Hz, 1H, –CH2CHMe2), 1.43 (t, 3H, J¼7.2 Hz,
–OCH2CH3), 0.99 (d, 6H, J¼6.7 Hz, –CHMe2); 13C NMR (CDCl3):
Method C. To a stirred solution of compound 9a (0.5 g, 1.7 mmol)
in ethanol (3 mL) was added a solution of 33 wt % methylamine in
d
167.1 (CO), 162.1 (CAr), 157.3 (CAr), 155.7 (CAr), 149.3 (CAr), 139.4
(CAr), 137.1 (CAr), 125.8 (CAr), 124.3 (CAr), 121.9 (CAr), 117.7 (CAr), 61.3

982
M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
(CH2CH3), 45.3 (CH2Pr-i), 29.1 (CHMe2), 22.7 (CH3), 14.3 (CH2CH3);
HRMS (ESI): m/z calcd for C17H21N2O2 [MþH]þ: 285.1598, mea-
propyl–CH3); HRMS (EI): m/z calcd for C12H18NO2 (MþH)þ:
208.1332, measured: 208.1334.
sured: 285.1598. Compound 12: 1H NMR (CDCl3):
d 8.70 (ddd, 1H,
J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.58 (ddd, 1H, J¼1.0, 1.2 and 7.9 Hz, Py–
H), 8.42 (d, 1H, J¼8.2 Hz, Py–3H or Py–4H), 8.33 (d, 1H, J¼8.2 Hz,
Py–3H or Py–4H), 7.85 (ddd, 1H, J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.36
(ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–H), 4.43 (q, 2H, J¼7.2 Hz,
–OCH2CH3), 2.54 (d, 2H, J¼6.9 Hz, –CH2Pr-i), 2.30–2.15 (m, 1H,
–CH2CHMe2), 1.31 (t, 3H, J¼7.2 Hz, –OCH2CH3), 0.89 (d, 6H,
J¼6.7 Hz, –CHMe2).
4.8.5. Ethyl 6-methylthio-2-phenylpyridine-3-carboxylate 4i
Method A. A stirred solution of triazine 3i (2.00 g, 7.26 mmol)
and 2,5-norbornadiene 5 (27.4 mL, 254 mmol, 35.0 equiv) in 1,2-
dichlorobenzene (100 mL) was heated to 140 ꢀC under a nitrogen
atmosphere for 1 day. After cooling to room temperature, the sol-
vent was evaporated and the residue purified by column chroma-
tography over silica gel [eluent: ethyl acetate/hexanes (1:4);
Rf¼0.32] giving compound 4i (1.75 g, 88%) as an orange liquid; IR:
nmax/cmꢁ1 2982, 2928, 1710 (C]O), 1567, 1427, 1385, 1281, 1265,
4.8. Synthesis of pyridines 4e–m and 14 and 18
1152, 1130, 1046, 764, 697; 1H NMR (CDCl3):
d
7.92 (d, 1H, J¼8.2 Hz,
Py–4H), 7.58–7.40 (m, 5H, Ph–H), 7.18 (d, 1H, J¼8.2 Hz, Py–5H), 4.13
4.8.1. Ethyl 2,6-diphenylpyridine-3-carboxylate 4e30
(q, 2H, J¼7.2 Hz, –OCH2CH3), 2.61 (s, 3H, –SCH3), 1.05 (t, 3H,
A solution of compound 3e (0.43 g, 1.4 mmol) and 2,5-norbor-
nadiene 5 (1.5 mL, 14 mmol) in xylene (15 mL) was heated at reflux
overnight. The solvent was evaporated and the residue was purified
by column chromatography over silica gel [eluent: ethyl acetate/
petroleum ether bp 60–80 ꢀC (2:8)] giving compound 4e (0.19 g,
44%) as a brown oil; IR: nmax/cmꢁ1 1714 (C]O), 1573, 1289, 1140,
J¼7.2 Hz, –OCH2CH3); 13C NMR (CDCl3):
d
168.2 (CO), 162.6 (CAr),
158.9 (CAr), 140.3 (CAr), 137.7 (CAr), 128.9 (CAr), 128.7 (CAr), 128.0
(CAr), 122.3 (CAr), 119.2 (CAr), 61.3 (CH2CH3), 13.8 (CH3), 13.3 (CH3);
HRMS (ESI) for C15H16NO2S [MþH]þ: m/z calcd: 274.0896; mea-
sured: 274.0894.
Method B. In neat 2,5-norbornadiene 5 (50 equiv) at reflux for 2
days compound 4i (64%), identical with an authentic sample, was
obtained together with recovered triazine 3i (8%).
758, 691; 1H NMR: (CDCl3)
d
8.18 (d, 1H, J¼8 Hz, Py–H), 8.12 (dd, 2H,
J¼8 and 2 Hz, Ph–H), 7.78 (d, 1H, J¼8 Hz, Py–H), 7.65 (dd, 2H, J¼8
and 2 Hz, Ph–H), 7.48–7.42 (m, 6H, Ph–H), 4.18 (q, 2H, J¼7 Hz,
–OCH2CH3), 1.07 (t, 3H, J¼7 Hz, –OCH2CH3); HRMS (EI): m/z calcd
for C20H18NO2 [MþH]þ: 303.1254, measured: 303.1258.
4.8.6. Ethyl 6-methylthio-2-propylpyridine-3-carboxylate 4j
Method A. A stirred solution of triazine 3j (100 mg, 414 mmol)
and 2,5-norbornadiene 5 (0.45 mL, 4.17 mmol, 10.1 equiv) in 1,2-
dichlorobenzene (5 mL) was heated to 140 ꢀC under a nitrogen
atmosphere for 1 day. After cooling to room temperature, the sol-
vent was evaporated and the residue purified by column chroma-
tography [eluent: ethyl acetate/hexanes (1:4); Rf¼0.55] yielding
compound 4j (63 mg, 64%) as a yellow liquid; IR: nmax/cmꢁ1 2962,
2931, 2872, 1718 (C]O), 1575, 1441, 1375, 1260, 1144, 1094; 1H NMR
4.8.2. Ethyl 6-phenyl-2-propylpyridine-3-carboxylate 4f
Compound 4f was synthesised from triazine 3f (0.1 g,
0.37 mmol) in xylene following the procedure described above for
the preparation of compound 4e from compound 3e. Chromato-
graphy over silica gel [eluent: ethyl acetate/petroleum ether bp 60–
80 ꢀC (2:8)] gave the desired product 4f (0.05 g, 31%) as a yellow oil.
IR nmax/cmꢁ1 1719 (C]O), 1582, 1261, 1088; 1H NMR: (CDCl3)
d
8.22
(CDCl3):
d
7.97 (d, 1H, J¼8.2 Hz, Py–4H), 7.04 (d, 1H, J¼8.2 Hz, Py–
(d, 1H, J¼8 Hz, Py–H), 8.05 (dd, 2H, J¼8 and 2 Hz, Ph–H), 7.61 (d, 1H,
J¼8 Hz, Py–H), 7.46 (t, 2H, J¼7 Hz, Ph–H), 7.15 (t, 1H, J¼7 Hz, Ph–H),
4.39 (q, 2H, J¼7 Hz, –OCH2CH3), 3.25–3.18 (m, 2H, propyl–CH2–),
1.88–1.80 (m, 2H, propyl–CH2–), 1.42 (t, 3H, J¼7 Hz, –OCH2CH3),
3H), 4.34 (q, 2H, J¼7.2 Hz, –OCH2CH3), 3.15–3.09 (m, 2H, propyl–
CH2–), 2.59 (s, 3H, –SCH3), 1.84–1.70 (m, 2H, propyl–CH2–), 1.39 (t,
3H, J¼7.2 Hz, –OCH2CH3), 1.00 (t, 3H, J¼7.2 Hz, propyl–CH3); 13C
NMR (CDCl3): d
166.8 (CO), 163.6 (CAr), 163.0 (CAr), 138.1 (CAr), 120.6
1.04 (t, 3H, J¼7 Hz, propyl–CH3); 13C NMR: (CDCl3)
d
166.9 (CO),
(CAr), 118.1 (CAr), 61.0 (CH2CH3), 39.0 (CH2), 22.8 (CH2), 14.4 (CH3),
14.3 (CH3), 13.2 (CH3); HRMS (ESI) for C12H18NO2S [MþH]þ: m/z
calcd: 240.1053; measured: 240.1052.
163.4 (C), 158.9 (C), 139.4 (CH), 138.7 (C), 129.6 (CH), 128.9 (CH),
127.4 (CH), 123.8 (C), 117.2 (CH), 61.3 (CH2), 39.2 (CH2), 23.1 (CH2),
14.4 (CH3), 14.3 (CH3); HRMS (EI): m/z calcd for C17H20NO2 [MþH]þ:
270.1489, measured: 270.1490.
Method B. In neat 2,5-norbornadiene 5 (45 equiv) at reflux for 2
days compound 4j (66%), identical with an authentic sample, was
obtained together with recovered triazine 3j (8%).
4.8.3. Ethyl 2-methyl-6-phenylpyridine-3-carboxylate 4g1e
Compound 4g was synthesised from compound 3g (0.18 g,
0.74 mmol) following the procedure described above for the
preparation of compound 4e. Chromatography over silica gel [elu-
ent: ethyl acetate/petroleum ether bp 60–80 ꢀC (2:8)] gave the
desired product 4g (0.17 g, 95%) as a brown oil; IR: nmax/cmꢁ1 1715
4.8.7. Ethyl 6-methanesulfoxy-2-phenylpyridine-3-carboxylate 4k
Method A. To a stirred, ice-cold solution of triazine 3i (0.26 g,
0.9 mmol) in CH2Cl2 (15 mL) was added 80% 3-chloroperbenzoic
acid (0.21 g, 1.2 mmol) and the mixture was stirred 1 h at 0 ꢀC and
then 1 h at room temperature. The reaction mixture was poured
into water (10 mL), the organic layer was separated and washed
with a saturated solution of NaHCO3 (2ꢂ15 mL), dried (MgSO4) and
evaporated under giving compound 3k as a red oil (0.25 g, 91%),
which was used without further purification; 1H NMR: (CDCl3)
(C]O), 1278, 1136, 765, 696; 1H NMR: (CDCl3)
d
8.02 (d, 1H, J¼8 Hz,
Py–H), 7.50 (dd, 2H, J¼8 and 2 Hz, Ph–H), 7.45–7.38 (m, 3H, Ph–H),
7.19 (d, 1H, J¼8 Hz, Py–H), 4.12 (q, 2H, J¼7 Hz, –OCH2CH3), 2.65 (s,
3H, –CH3), 1.02 (t, 3H, J¼7 Hz, –OCH2CH3); HRMS (EI): m/z calcd for
C15H16NO2 [MþH]þ: 242.1176, measured: 242.1173.
d
7.88 (d, 2H, J¼7 Hz, Ph–H), 7.63–7.51 (m, 3H, Ph–H), 4.45 (q, 2H,
J¼7 Hz, –OCH2CH3), 3.15 (s, 3H, –SOCH3) and 1.27 (t, 3H, J¼7 Hz,
–OCH2CH3). A solution of compound 3k (0.17 g, 0.6 mmol) and 2,5-
norbornadiene 5 (0.65 mL, 6 mmol) in ethanol (15 mL) was stirred
under reflux and an atmosphere of nitrogen for 12 h and then
allowed to cool to room temperature. The solvent was evaporated
and water (10 mL) was added to the residue. The mixture was
extracted with CH2Cl2 and the combined organic extracts were
dried (MgSO4) and evaporated giving compound 4k (0.13 g, 75%) as
an orange oil after chromatography over silica gel [eluent: CH2Cl2/
methanol (9:1)]; IR: nmax/cmꢁ1 1718 (C]O), 1281, 1085, 1047, 698;
4.8.4. Ethyl 6-methyl-2-propylpyridine-3-carboxylate 4h
Compound 4h was synthesised from compound 3h (0.15 g,
0.72 mmol) following the procedure described above for the
preparation of compound 4e. Chromatography over silica gel [elu-
ent: ethyl acetate/petroleum ether bp 60–80 ꢀC (2:8)] gave the
desired product 4h (0.1 g, 67%) as a brown oil; IR: nmax/cmꢁ1 1721
(C]O), 1250, 1095; 1H NMR: (CDCl3)
d
8.06 (d, 1H, J¼8 Hz, Py–H),
7.04 (d, 1H, J¼8 Hz, Py–H), 4.36 (q, 2H, J¼7 Hz, –OCH2CH3–), 3.10–
3.00 (m, 2H, propyl–CH2–), 2.60 (s, 3H, –CH3), 1.72–1.63 (m, 2H,
propyl–CH2–), 1.39 (t, 3H, J¼7 Hz, –OCH2CH3), 1.01 (t, 3H, J¼7 Hz,
1H NMR: (CDCl3)
d
8.33 (d, 1H, J¼8 Hz, Py–H), 8.09 (d, 1H, J¼8 Hz,

M. Altuna-Urquijo et al. / Tetrahedron 65 (2009) 975–984
983
Py–H), 7.57–7.44 (m, 5H, Ph–H), 4.20 (q, 2H, J¼7 Hz, –OCH2CH3),
2.93 (s, 3H, –SOCH3), 1.08 (t, 3H, J¼7 Hz, –OCH2CH3); 13C NMR
evaporation of the solvent, the residue was purified by column
chromatography over silica gel [eluent: diethyl ether/hexanes
(9:1); Rf¼0.33] yielding compound 16 (233 mg, 64%) as a brown oil;
IR: nmax/cmꢁ1 2960, 2873, 1718 (C]O), 1252, 1184, 1091, 1034; 1H
(CDCl3): d
168.06 (CO), 167.45 (CAr), 158.73 (CAr), 139.92 (CAr), 138.80
(CAr), 129.42 (CAr), 128.74 (CAr), 128.34 (CAr), 117.26 (CAr), 62.02
(CH2), 41.33 (CH3), 13.73 (CH3) (one aryl signal was not sufficiently
intense to be located); HRMS (EI): m/z calcd for C15H16N3O3S
[MþH]þ: 290.0845, measured: 290.0846.
NMR (CDCl3):
d
8.66 (ddd, 1H, J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.17 (s,
1H, Py–4H), 7.88 (ddd, 1H, J¼1.0, 1.5 and 7.9 Hz, Py–H), 7.82 (ddd,
1H, J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.31 (ddd, 1H, J¼1.5, 4.7 and 7.7 Hz,
Py–H), 5.10–5.03 (m, 1H, pCH–), 4.40 (q, 2H, J¼7.2 Hz, –OCH2CH3),
3.85 and 3.65 (dt, 2H, J¼6.7 and 9.0 Hz, –CH2CH2–), 3.82–3.74 (m,
2H, –OCH2–), 3.19 (t, 2H, J¼6.7 Hz, –CH2CH2–), 3.18–3.13 (m, 2H,
propyl–CH2–), 2.04–1.70 (m, 6H, aliphatic–H), 1.43 (t, 3H, J¼7.2 Hz,
–OCH2CH3), 1.01 (t, 3H, J¼7.4 Hz, propyl–CH3); 13C NMR (CDCl3):
Method B. A suspension of NaBO3$4H2O (59 mg; 383 mmol;
1.05 equiv) in glacial acetic acid (2.5 mL) was heated to 50–60 ꢀC
and compound 4i (100 mg; 366 mol) was added. The mixture was
m
stirred for 4 h, allowed to cool to room temperature and filtered.
The filtrate was evaporated yielding compound 4k (83 mg, 78%)
identical with an authentic sample.
d
167.0 (CO), 160.4 (CAr), 158.4 (CAr), 157.8 (CAr), 148.5 (CAr), 141.7
(CAr), 136.8 (CAr), 130.7 (CAr), 124.7 (CAr), 123.1 (CAr), 103.7 (CH), 67.1
(CH2), 66.9 (CH2), 61.3 (CH2CH3), 38.7 (CH2), 32.4 (CH2), 32.4 (CH2),
23.4 (CH2), 14.4 (CH3), 14.3 (CH3) (one aromatic and one aliphatic
carbon could not be located); HRMS (ESI) for C22H29N2O4 [MþH]þ:
m/z calcd: 385.2122; measured: 385.2118.
4.8.8. Ethyl 6-methanesulfoxy-2-propylpyridine-3-carboxylate 4l
Method A. Compound 3l (65%) was obtained as a red oil by ox-
idation of compound 3j following the procedure described above
for the preparation of compound 3k from compound 3i and was
used without further purification; 1H NMR: (CDCl3)
d 4.54 (q, 2H,
J¼7 Hz, –OCH2CH3), 3.18–3.11 (m, 2H, –CH2–), 3.08 (s, 3H, –SOCH3),
1.83 (sextet, 2H, J¼8 Hz, propyl–CH2–), 1.46 (t, 3H, J¼7 Hz,
–OCH2CH3), 1.02 (t, 3H, J¼7 Hz, propyl–CH3). A solution of com-
pound 3l (0.63 g, 2.4 mmol) and 2,5-norbornadiene 5 (2.65 mL,
24 mmol) in ethanol (15 mL) was stirred at reflux under an atmo-
sphere of nitrogen for 12 h and then allowed to cool to room
temperature. The reaction mixture was worked-up as described
above for the synthesis of compound 4k giving compound 4l
(0.55 g, 88%) as an orange oil; IR: nmax/cmꢁ1 1721 (C]O), 1262,
4.8.11. Ethyl 3-propyl-1-(pyridin-2-yl)-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carboxylate 18
A solution of triazine 3c (128 mg, 470
mmol) and 1-cyclo-
pentenylpyrrolidine (76 L, 521 mol, 1.11 equiv) in ethanol (5 mL)
m
m
was stirred at room temperature for 1 h. Glacial acetic acid (0.5 mL)
was added and the mixture was stirred for another hour. NaOH
(1 M, 15 mL) was then added to the mixture and the organic layer
was separated and the aqueous layer was extracted with
dichloromethane (2ꢂ5 mL). The combined organic extracts were
dried (MgSO4) and the solvent evaporated yielding compound 18
(122 mg, 84%) as a brown oil; IR: nmax/cmꢁ1 2961,2873, 1717 (C]O),
1568, 1555, 1255, 1231, 1116, 1093, 1024, 743; 1H NMR (CDCl3):
1095, 1065; 1H NMR: (CDCl3)
d
8.38 (d, 1H, J¼8 Hz, Py–H), 7.93 (d,
1H, J¼8 Hz, Py–H), 4.41 (q, 2H, J¼7 Hz, –OCH2CH3), 3.15–3.07 (m,
2H, propyl–CH2–), 2.87 (s, 3H, –SOCH3), 1.74 (sextet, 2H, J¼8 Hz,
propyl–CH2–), 1.42 (t, 3H, J¼7 Hz, –OCH2CH3), 0.99 (t, 3H, J¼7 Hz,
d
8.68 (ddd, 1H, J¼1.0, 1.7 and 4.7 Hz, Py–H), 8.25 (ddd, 1H, J¼1.0, 1.2
propyl–CH3); 13C NMR (CDCl3):
d
168.2 (CO), 166.0 (CAr), 163.7 (CAr),
and 7.9 Hz, Py–H), 7.80 (ddd, 1H, J¼1.7, 7.7 and 7.9 Hz, Py–H), 7.27
(ddd, 1H, J¼1.2, 4.7 and 7.7 Hz, Py–H), 4.42 (q, 2H, J¼7.2 Hz,
–OCH2CH3), 3.38 (t, 2H, J¼7.7 Hz, –CH2CH2CH2–), 3.06 (t, 2H,
J¼7.7 Hz, –CH2CH2CH2–), 3.01–2.95 (m, 2H, propyl–CH2–), 2.09 (dt,
2H, 18H, J¼7.7 and 7.7 Hz), 1.82 (m, 2H, propyl–CH2–), 1.42 (t, 3H,
J¼7.2 Hz, –OCH2CH3), 1.01 (t, 3H, J¼7.4 Hz, propyl–CH3); 13C NMR
140.4 (CAr), 126.7 (CAr), 116.3 (CAr), 61.8 (CH2), 41.2 (CH3), 38.5 (CH2),
22.9 (CH2), 14.3 (CH3), 14.1 (CH3); HRMS (EI): m/z calcd for
C12H18NO3S [MþH]þ: 256.1002, measured: 256.1001.
Method B. Following a similar procedure to that described above
in Section 4.8.7, method B for the synthesis of compound 4k,
compound 4l (72%) was obtained, identical with an authentic
sample.
(CDCl3): d
168.5 (CO), 158.2 (CAr), 157.9 (CAr), 155.9 (CAr), 152.0 (CAr),
148.6 (CAr), 137.0 (CAr), 136.5 (CAr), 124.3 (CAr), 123.5 (CAr), 123.0
(CAr), 61.2 (CH2CH3), 38.4 (CH2), 33.0 (CH2), 32.9 (CH2), 25.1 (CH2),
23.4 (CH2), 14.4 (CH3), 14.3 (CH3); HRMS (ESI) for C19H23N2O2
[MþH]þ: m/z calcd: 311.1754; measured: 311.1750.
4.8.9. Ethyl 6-methylsulfonyl-2-propylpyridine-3-carboxylate 4m
A suspension of NaBO3$4H2O (1.61 g, 10.5 mmol, 2.50 equiv) in
glacial acetic acid (50 mL) was heated to 50–60 ꢀC and pyridine 4j
(1.00 g; 4.18 mmol) was added. The mixture was stirred for 2 h,
allowed to cool to room temperature and filtered. A saturated,
aqueous solution of NaHCO3 (200 mL) was added to the filtrate and
the mixture was extracted with dichloromethane (200 mL). The
organic phase was separated and washed sequentially with a satu-
rated aqueous solution of NaHCO3 and water (200 mL each), dried
(MgSO4) and evaporated yielding compound 4m (1.06 g, 93%) as
a yellow oil; IR: nmax/cmꢁ1 2964, 2935, 2875, 1724 (C]O), 1309,
Acknowledgements
We thank Vertellus Specialities UK Ltd for generous financial
support and the EPSRC mass spectrometry service (Swansea) for
high-resolution mass spectra.
References and notes
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d
8.37 (d, 1H, J¼8.2 Hz, Py–
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