A simple metal-free synthesis of 2-substituted pyridine-4,5-dicarboxylates and their N-oxides

Article abstract of DOI:10.1016/j.tet.2012.04.013

Herein a simple, metal-free synthesis of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted pyridine 3,4-dicarboxylates and their N-oxides from the corresponding methyl ketones in good to excellent yield, demonstrated with 22 examples in each case, is described. The method complements the current coupling reactions of 2-heterocyclic organometallic reagents.

Full text of DOI:10.1016/j.tet.2012.04.013

Tetrahedron 68 (2012) 4719e4731
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Tetrahedron
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A simple metal-free synthesis of 2-substituted pyridine-4,5-dicarboxylates and
their N-oxides
*
ꢀ
ꢀ
ꢀ
ꢀ
Jure Bezensek, Benjamin Prek, Uros Groselj, Marta Kasunic, Jurij Svete, Branko Stanovnik
ꢀ
ꢀ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein a simple, metal-free synthesis of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted
pyridine 3,4-dicarboxylates and their N-oxides from the corresponding methyl ketones in good to ex-
cellent yield, demonstrated with 22 examples in each case, is described. The method complements the
current coupling reactions of 2-heterocyclic organometallic reagents.
Received 26 January 2012
Received in revised form 16 March 2012
Accepted 2 April 2012
Available online 9 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
In this communication we report a simple, metal-free synthesis
of dimethyl 2-substituted pyridine-4,5-dicarboxylates and their N-
Pyridines and their N-oxides with aromatic or heteroaromatic
substituents are an important class of compounds, which have
found applications in medicinal chemistry.1 Among them are many
biologically active compounds,2 such as Streptonigrin,3 Glyvec,4
and Rosuvastatin,5 and many natural products.6 They are found
also in MAP inhibitors,7 and among P,N-ligands, used as catalysts in
asymmetric reactions.8,9
oxides as an extension of the enaminone methodology recently
developed in our laboratory. These have a broad applicability in the
synthesis of numerous heterocyclic systems,18 including natural
products and their analogs,19 in the regiospecific [2þ2]cycloaddi-
tions with electron-poor acetylenes and further transformations of
cycloadducts into highly substituted heterocyclic systems.20
There are many methods for the preparation of pyridines de-
scribed in the literature.10 Arylearyl bond formation is one of the
most important tools of modern organic synthesis. These bonds are
often found in natural products, such as alkaloids, as well as in
numerous biologically active parts of pharmaceutical and agro-
chemical species, in polyaromatics used as organic conductors and
semiconductors, and in ligands in asymmetric catalysis.11 Palla-
dium catalyzed reactions are powerful and useful tools for the
synthesis of heterocycles, especially for the formation of CeC bonds
in aryl and heteroaryl substituted heterocycles.12e14 In this context,
the Suzuki reaction has a special significance.14 An attractive al-
ternative is a mild Negishi cross-coupling of 2-heterocyclic orga-
nozinc reagents with aryl and heteroaryl chlorides,15 which
complements reactions with other 2-heteroarylorganometallic re-
agents.16 Direct arylation and alkylation of nitropyridine N-oxides
with Grignard reagents,17a and arylation of arene and N-hetero-
arenes with diaryliodonium salts without the use of transition
metal catalysts17b have been reported recently. Furthermore, the
down side of the use of organometallic reagents in pharmaceutical
industry is their ever increasing cost, i.e., the progressive shortage
of lithium, and the strict regulation regarding the residual traces of
metals left in the final products.
2. Results and discussion
Polysubstituted butadienes, i.e., dimethyl 2-[(dimethylamino)
methylene]-3-(2-substituted) succinates 3, have been prepared
from alkyl, aryl, and heteroaryl methyl ketones 1 by treatment with
N,N-dimethylformamide dimethyl acetal (DMFDMA) or tert-
butoxybis(dimethylamino)methane (Bredereck’s reagent) to give
the corresponding 3-(dimethylamino)-1-substituted-prop-2-en-1-
ones 2, followed by microwave assisted [2þ2]cycloaddition to di-
methyl acetylenedicarboxylate (DMAD), as reported previously.21
Polysubstituted aminobutadienes 3 prepared according to this
procedure are isomeric to the aminobutadienes formed by the
Michael addition. Consequently, they represent an alternative group
of intermediates for the preparation of isomerically substituted
pyridine derivatives, which cannot be obtained by the Bohl-
manneRahtz22 synthesis. With this fact in mind, we decided to
study the scope and limitations of this procedure. Compounds 3,
dissolved in MeOH, were treated with ammonium acetate (10-fold
excess) at room temperature for 5e120 h to give dimethyl 2-
substituted pyridine-4,5-dicarboxylates 4aes in 44e86% yield,
while treatment with hydroxylamine hydrochloride (1.5 equiv) in
MeOH for 2e120 h at room temperature gave the corresponding 2-
substituted 4,5-bis(methoxycarbonyl)-pyridine N-oxides 5aes in
45e96% yield. In this manner, alkyl, alkenyl, cyclopentenyl, styryl,
phenyl, substituted phenyl, ferrocenyl, pyrrol-2-yl, pyrrol-3-yl,
* Corresponding author. E-mail address: branko.stanovnik@fkkt.uni-lj.si (B.
Stanovnik).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.013

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4720
furan-3-yl, thiophen-3-yl, substituted thiophen-3-yl, indol-3-yl,
thiazol-2-yl, pyrid-2-yl, pyrazin-2-yl, and other substituents have
been introduced at position 2 in pyridine or pyridine N-oxide
(Scheme 1, Table 1).
N. The structures of compounds 4hej,l,m, 5j,k, 8b, and 9b were
confirmed by X-ray analyses (Figs. 1e3).
4. Conclusion
Finally, the scope of this methodology was tested with di- and
triacetyl-benzenes. Thus treatment of 1,3-(6a), 1,4-diacetyl-(6b) or
1,3,5-triacetylbenzene (6c) with DMFDMA furnished enaminones
7aec, respectively, followed by [2þ2]cycloaddition of DMAD to
give the corresponding succinates 8aec. Lastly, cyclization of 8aec
with ammonium acetate yielded pyridine derivatives 9aec, re-
spectively, whereas cyclization with hydroxylamine hydrochloride
produced the expected pyridine N-oxides 10aec, both in moderate
to good yields (61e87%) (Scheme 2). Compounds 9aec and 10aec
could potentially be used in coordination and dendrimer chemistry.
The exclusive formation of pyridine and pyridine N-oxides upon
cyclization of succinate derivatives 3 and 8 with ammonium acetate
and hydroxylamine hydrochloride, respectively, could be attributed
to the following facts: (i) under acidic conditions, the order of re-
activity of the functional groups attached to the butadiene scaffolds
3 and 8 is the following: CH]CHeNMe2 (masked formyl group)>
ketone group>CO2Me,18d thus first the protonated dimethylamino
group is substituted by the nucleophile employed (‘NH3, NH2OH’),
followed by cyclocondensation with the ketone group, (ii) the suc-
cinate derivatives 3 and 8 in the solid state (see X-ray structures in
Figs.1e3 in Ref. 21b) are not planar (conjugated) but bent around the
C(2)eC(3) single bond (torsion angles ranging from 50 to 62ꢀ) due to
severe steric repulsion in the planar conformation, which conve-
niently puts the amino group of the C]CeNH2 and C]CeNHeOH
group, respectively, in a position suitable for attack on the carbonyl
group (assuming a free rotation around the C(2)eC(3) single bond,
In conclusion, we have described a simple, metal-free synthesis
of 2-alkyl-, 2-cycloalkyl, 2-aryl-, and 2-heteroaryl-substituted pyr-
idine 3,4-dicarboxylates and their N-oxides from the corresponding
methyl ketones in good to excellent yield demonstrated with 22
examples with correct elemental analyses. This method comple-
ments the current reactions of the coupling of 2-heterocyclic or-
ganometallic reagents and tolerates a broad substituent scope in
position 2 of the pyridine ring.
5. Experimental
5.1. General
Melting points were determined on a Kofler micro hot stage and
on an SRS OptiMelt MPA100-Automated Melting Point System. NMR
spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for
1H and 75.5 MHz for 13C, and a Bruker UltraShield 500 plus at
500 MHz for 1H and 126 MHz for 13C, using DMSO-d6 and CDCl3 with
TMS as the internal standard, as solvents. Mass spectra were recor-
ded on an AutoSpecQ spectrometer and Agilent 6224 Accurate Mass
TOF LC/MS, IR spectra on a PerkineElmer Spectrum BX FTIR spec-
trophotometer. Microanalyses were performed on a PerkineElmer
CHN Analyser 2400 II. Column chromatography (CC) was performed
on silica gel (Fluka, Silica gel 60, particle size: 0.035e0.070 mm).
Methyl ketones 1aes and 6a,b, N,N-dimethylformamide di-
methyl acetal, tert-butoxy bis(dimethylamino)methane, are com-
mercially available (SigmaeAldrich). 1,10,100-(Benzene-1,3,5-triyl)
triethanone (6c) was prepared following the literature procedure.23
Compounds 3d,f,jeo,qes have been described previously,21
compound 4f was prepared according to the procedure described
in the literature.24
€
for the fulfillment of the BurgieDunitz trajectory) (Scheme 3).
3. Structure determination
The structures of the new compounds were determined by 1H
and 13C NMR spectroscopy, HRMS and microanalyses for C, H, and
Scheme 1. Synthesis of 2-substituted pyridine-4,5-dicarboxylates 4 and the corresponding pyridine N-oxides 5 from methyl ketones 1.

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4721
Table 1
(2.0 equiv) and the mixture was stirred in a closed vessel under
microwave irradiation (300 W) at an automatically controlled
constant temperature (CEM Corporation Discover microwave unit)
or at room temperature. After cooling to room temperature, volatile
compounds were evaporated in vacuo and the residue was purified
with column chromatography using mixtures of EA/PE as a mobile
phase. Fractions containing the product were combined and
evaporated in vacuo.
The 2-substituted pyridine-4,5-dicarboxylates 4 and the corresponding pyridine N-
oxides 5 prepared from methyl ketones 1
Entry
R
Yield (%)
a
b
c
Et
Pr
79
81
95
79
67
74
47
82
96
5.2.1. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-(2-
oxobutylidene)succinate (3a). Prepared from (E)-1-(dimethyla-
mino)pent-1-en-3-one (2a) (656 mg, 5.2 mmol), 80 ꢀC, 5 min,
chromatography (ethyl acetate/petroleum ether¼1:1). Yield: 1.11 g
tBu
d
e
f
9721a
70
70
75
45
71
(79%) of yellow oil. 1H NMR (CDCl3, 300 MHz):
d 1.05 (3H, t,
J¼7.3 Hz, CH3); 2.58 (2H, q, J¼7.3 Hz, CH2); 2.87 (6H, s, NMe2); 3.63
75
(3H, s, COOMe); 3.79 (3H, s, COOMe); 7.01 (1H, s, CH); 7.67 (1H, s,
CH). 13C NMR (CDCl3, 75.5 MHz):
d 8.3, 37.2, 43.4, 51.5, 53.1, 91.4,
7521a
6722
131.6, 137.3, 153.5, 169.0, 169.1, 201.5. EI-HRMS: m/z¼270.1337
(MHþ); C13H20NO5 requires: m/z¼270.1341 (MHþ); nmax (NaCl)
2976, 2950, 2904, 1720, 1692, 1686, 1603, 1432, 1284, 1241, 1217,
g
76
32
76
86
72
67
1122, 1088, 1029, 958, 871, 803, 778 cmꢁ1
.
5.2.2. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-(2-
oxopentylidene)succinate (3b). Prepared from (E)-1-(dimethyla-
mino)hex-1-en-3-one (2b) (141 mg, 1.0 mmol), 80 ꢀC, 5 min,
chromatography (ethyl acetate/petroleum ether¼1:1). Yield:
h
230 mg (81%) of yellow oil. 1H NMR (CDCl3, 300 MHz):
d 0.90 (3H, t,
i
83
55
48
45
44
47
46
75
80
J¼7.4 Hz, CH3); 1.62 (2H, s, J¼7.4 Hz, CH2); 2.43 (2H, m, CH2); 2.92
(6H, s, NMe2); 3.68 (3H, s, COOMe); 3.79 (3H, s, COOMe); 6.85 (1H, s,
j
6921a
9121b
1621b
CH); 7.51 (1H, s, CH). 13C NMR (CDCl3, 75.5 MHz):
d 14.1, 19.1, 39.7,
43.4, 51.7, 52.9, 104.4, 126.4, 143.0, 152.3, 165.6, 168.2, 196.8. EI-
HRMS: m/z¼284.1491 (MHþ); C14H22NO5 requires: m/
z¼2784.1492 (MHþ); nmax (NaCl) 2955, 1719, 1633, 1587, 1433, 1402,
k
l
1354, 1323, 1247, 1197, 1126, 1061, 1018, 969, 889, 806 cmꢁ1
.
5.2.3. (2E,3E)-Dimethyl 2-(3,3-dimethyl-2-oxobutylidene)-3-((dime-
thylamino)methylene)succinate (3c). Prepared from (E)-1-(dime-
thylamino)-4,4-dimethylpent-1-en-3-one (2c) (155 mg, 1.0 mmol),
80 ꢀC, 8 min, chromatography (ethyl acetate/petroleum ether¼1:1).
Yield: 282 mg (95%) of yellowish oil. 1H NMR (CDCl3, 500 MHz):
m
n
7021b
78
83
78
81
d
1.17 (9H, s, tBu); 2.87 (6H, s, NMe2); 3.60 (3H, s, COOMe); 3.79 (3H,
7021b
s, COOMe); 7.36 (1H, s, CH); 7.65 (1H, s, CH). 13C NMR (CDCl3,
126 MHz):
d 26.4, 42.9, 44.4, 51.1, 52.8, 90.8, 129.0, 137.8, 152.7,
168.8, 168.9, 205.5. EI-HRMS: m/z¼298.1648 (MHþ); C15H24NO5
requires: m/z¼298.1649 (MHþ); nmax (NaCl) 2953, 1732, 1693, 1660,
1557, 1540, 1433, 1398, 1267, 1240, 1218, 1088, 1046, 975, 943, 887,
o
p
8621a
54
46
93
54
803, 772 cmꢁ1
.
67
5.2.4. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-((E)-2-
oxo-4-phenylbut-3-en-1-ylidene)succinate (3e). Prepared from
q
r
7521a
6721a
4621a
80
47
72
65
56
74
(1E,4E)-1-(dimethylamino)-5-phenylpenta-1,4-dien-3-one
(2e)
(402 mg, 2.0 mmol), 60 ꢀC, 2ꢂ5 min, chromatography (ethyl ace-
tate/petroleum ether¼1:1). Yield: 478 mg (70%) of red oil. 1H NMR
(CDCl3, 300 MHz):
d 2.87 (6H, s, NMe2); 3.62 (3H, s, COOMe); 3.82
(3H, s, COOMe); 6.81 (1H, d, J¼16.1 Hz, CH); 7.17 (1H, s, CH);
7.36e7.39 (3H, m, 3ꢂ Ph); 7.50e7.60 (4H, m, 2ꢂ CHþ2Ph). 13C NMR
s
(CDCl3, 75.5 MHz): d 43.0, 51.2, 52.8, 91.8, 126.5, 128.3, 129.0, 130.5,
131.6, 134.6, 137.7, 143.6, 152.3, 168.5, 168.6, 190.3. EI-HRMS: m/
z¼344.1494 (MHþ); C19H22NO5 requires: m/z¼344.1498 (MHþ);
nmax (NaCl) 2982, 1731, 1645, 1584, 1565, 1470, 1433, 1424, 1387,
5.2. General procedure for the synthesis of (2E,3E)-dimethyl
2-((dimethylamino)methylene)-3-(2-substituated)succinates
3aec,e,gei,p and 8c
1328, 1222, 1174, 1127, 1087, 880, 827, 746, 702 cmꢁ1
.
5.2.5. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-(2-(2-
fluorophenyl)-2-oxoethylidene)succinate (3g). Prepared from (E)-3-
(dimethylamino)-1-(2-fluorophenyl)prop-2-en-1-one (2g) (274 mg,
1.4 mmol), 100 ꢀC, 15 min, chromatography (ethyl acetate/
To a solution of (E)-3-(dimethylamino)-1-substituted-prop-2-
en-1-one 2aec,e,gei,p and 7c (0.78e5.2 mmol) in MeCN
(1e4 mL) was added excess dimethyl acetylenedicarboxylate

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
Scheme 2. Synthesis of di- and trisubstituted benzenes with pyridine and pyridine N-Oxide derived substituents.
J¼254.1 Hz), 168.4, 168.9, 188.3 (d, J¼2.3 Hz). EI-HRMS: m/
C20
O3
z¼336.1245 (MHþ); C17H19NO5F requires: m/z¼336.1247 (MHþ);
nmax (NaCl) 1722,1694,1610,1547,1482,1450,1434,1401,1273,1246,
1217, 1089, 1043, 958, 866, 849, 802, 768 cmꢁ1
.
O4
C19
O2
C5
C9
C7
C8
C1
5.2.6. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-(2-oxo-2-
(perfluorophenyl)ethylidene)succinate (3h). Prepared from (E)-3-
(dimethylamino)-1-(perfluorophenyl)prop-2-en-1-one (2h) (403 mg,
1.5 mmol), 100 ꢀC, 30 min, chromatography (ethyl acetate/petroleum
ether¼1:2). Yield: 194 mg (32%) of red oil.1H NMR (CDCl3, 500 MHz):
C16
O15
C11
C12
O6
C14
C10
d
2.89 (6H, s, NMe2); 3.65 (3H, s, COOMe); 3.82 (3H, s, COOMe); 7.01
N13
C17
(1H, t, J¼1.8 Hz, CH); 7.80 (1H, s, CH). 13C NMR (CDCl3, 126 MHz):
C18
d
43.9, 51.7, 53.2, 92.8, 116.2 (tm, J¼17.0 Hz), 126.1, 137.7 (dm,
J¼254.9 Hz), 142.3, 142.6 (d, J¼258.6 Hz), 144.2 (d, J¼252.1 Hz), 155.5,
168.4, 168.8, 180.3. EI-HRMS: m/z¼408.0847 (MHþ); C17H15NO5F5
requires: m/z¼408.0865 (MHþ); nmax (NaCl) 1728, 1692, 1651, 1606,
1519, 1497, 1435, 1400, 1323, 1247, 1218, 1155, 1093, 988, 898, 800,
Fig. 1. ORTEP view of butadiene 8b.
petroleum ether¼1:1). Yield: 356 mg (76%) of red oil. 1H NMR
764 cmꢁ1
.
(CDCl3, 300 MHz):
d 2.88 (6H, s, NMe2); 3.58 (3H, s, COOMe); 3.82
(3H, s, COOMe); 7.11 (1H, ddd, J1¼10.7 Hz, J2¼8.3 Hz, J3¼1.0 Hz, 1ꢂ
Ph); 7.1 (1H, td, J1¼7.6 Hz, J2¼1.1 Hz, 1ꢂ Ph); 7.40 (1H, d, J¼2.7 Hz,
CH); 7.48 (1H, dddd, J1¼8.3 Hz, J2¼7.4 Hz, J3¼5.1 Hz, J4¼1.9 Hz, 1ꢂ
5.2.7. (2E,3E)-Dimethyl 2-((dimethylamino)methylene)-3-(2-(2-
nitrophenyl)-2-oxoethylidene)succinate (3i). Prepared from (E)-3-
(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one (2i) (440 mg,
2.0 mmol), 100 ꢀC, 20 min, chromatography (ethyl acetate/petro-
leum ether¼1:1). Yield: 631 mg (83%) of red oil. 1H NMR (CDCl3,
Ph), 7.59 (1H, s, CH); 7.64 (1H, td, J1¼7.6 Hz, J2¼1.8 Hz, 1ꢂ Ph). 13
C
NMR (CDCl3, 75.5 MHz):
124.3 (d, J¼3.6 Hz), 127.4 (d, J¼12.3 Hz), 129.8 (d, J¼4.5 Hz), 130.4 (d,
d
43.2, 51.1, 52.8, 92.1, 116.4 (d, J¼22.7 Hz),
J¼2.3 Hz), 133.9 (d, J¼8.9 Hz), 139.1 (d, J¼1.2 Hz), 153.2, 160.9 (d,
300 MHz):
d 2.91 (6H, s, NMe2); 3.57 (3H, s, COOMe); 3.79 (3H, s,

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4723
C9
C9
O4
O6
C5
N2
F2
N1
F1
O3
C3
O4
O5
C8
C4
C3
C12
C11
C4
C8
O3
C7
C11
C13
C10
C15
C12
C13
C5
C1
O1
F3
C6
C10
C14
C2
O2
C2
C6
O1
C15
C7
C14
C1
N1
F4
O2
F5
4h
4i
C16
C19
C17
C9
O3
C8
C7
C15
O2
C18
O4
C14
C6
C5
Fe1
C13
C4
C8
N1
N2
C2
O1
C9
C3
C11
C10
O1
O3
C10
C1
C1
C12
C3
C12
C2
C6
C14
C13
C4
C11
O4
N1
C5
O2
C7
4j
4l
O14
C6
C38
O3
C12
C32
C25
C7
O10
C20
O1
C9
O16
C33
C21
C8
C31
C6
C3
C12
O2
O4
C11
C29
C30
C17
C4
N7
N1
O2
C10
C5
N1
C28
C35
C34
C8
O19
O22
C26
C9
C23
C2
C13
C1
O4
O3
C27
C37
C5
C15
C24
O11
C36
O18
4j
9b
Fig. 2. ORTEP view of pyridines 4hej,l,m.
C9
O2
C16
C7
O4
C15
C5
O5
C17
C18
C6
C11
C12
O1
N1
C8
O3
Fe1
C11
C2
C4
C8
C10
C1
C3
C13
C19
C1
C3
C12
N2
C14
C10
C14
C2
O4
O2
C13
N1
O3
C6
C4
C9
C5
O5
C7
O1
5j
5k
Fig. 3. ORTEP view of pyridine N-oxides 5j,k.

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
Scheme 3. Proposed formation of pyridines and pyridine N-oxides.
COOMe); 7.16 (1H, s, CH); 7.44e7.47 (2H, m, CHþ1ꢂ Ph), 7.58 (1H, td,
J1¼7.7 Hz, J2¼1.6 Hz, 1ꢂ Ph); 7.67 (1H, td, J1¼7.5 Hz, J2¼1.3 Hz, 1ꢂ
Ph); 8.03 (1H, dd, J1¼8.1 Hz, J2¼1.3 Hz, 1ꢂ Ph). 13C NMR (CDCl3,
volatile components were evaporated in vacuo and products were
purified by column chromatography and crystallized from the ap-
propriate solvents.
75.5 MHz):
d 42.6, 50.7, 52.5, 90.8, 123.7, 128.8, 130.0, 130.8, 133.3,
136.1, 139.5, 146.4, 153.2, 167.6, 168.0, 190.6. EI-HRMS: m/
z¼363.1201 (MHþ); C17H19N2O7 requires: m/z¼363.1192 (MHþ);
nmax (NaCl) 1723, 1695, 1684, 1654, 1617, 1603, 1527, 1435, 1399,
5.3.1. Dimethyl 6-ethylpyridine-3,4-dicarboxylate (4a). Prepared
from
(2E,3E)-dimethyl
2-[(dimethylamino)methylene]-3-[2-
oxobutylidene]succinate (3a) (989 mg, 3.7 mmol) and NH4OAc
(2.83 g, 37 mmol), stirred for 24 h, chromatography (petroleum
ether/ethyl acetate¼1:1); yield: 655 mg (79%) of yellow oil. 1H NMR
1346, 1261, 1088, 1044, 956, 856, 795 cmꢁ1
.
5.2.8. (2E,3E)-Dimethyl 2-(2-(1-(tert-butoxycarbonyl)-1H-indol-3-
yl)-2-oxoethylidene)-3-((dimethylamino)methylene)succinate
(3p). Prepared from (E)-tert-butyl 3-(3-(dimethylamino)acryloyl)-
1H-indole-1-carboxylate (2p) (354 mg, 1.1 mmol), 70 ꢀC, 10 min,
chromatography (ethyl acetate/petroleum ether¼1:2). Yield:
(300 MHz, CDCl3):
d
1.33 (3H, t, J1¼7.5 Hz, CH3); 2.93 (2H, q,
J1¼7.5 Hz, CH2); 3.93 (3H, s, COOCH3); 3.95 (3H, s, COOCH3); 7.36
(1H, s, pyridine); 9.02 (1H, s, pyridine). 13C NMR (75.5 MHz, CDCl3):
d
13.4, 31.3, 52.7, 53.1, 120.3, 122.2, 141.6, 150.1, 165.5, 167.3, 167.9.
ESI-HRMS: m/z¼224.0923 (MHþ); C11H14NO4 requires: m/
z¼224.0929 (MHþ); nmax (NaCl) 2971, 2953, 2883, 2842, 2359, 2330,
1734, 1595, 1553, 1457, 1435, 1384, 1297, 1205, 1137, 1075, 990,
348 mg (67%) of red oil. 1H NMR (CDCl3, 500 MHz):
d 1.71 (9H, s,
tBu); 2.90 (6H, s, NMe2); 3.62 (3H, s, COOMe); 3.85 (3H, s, COOMe);
7.33 (1H, td, J1¼7.5 Hz, J2¼1.2 Hz, indole); 7.35e7.41 (1H, m, indole);
7.46 (1H, s, CH); 7.55 (1H, s, CH), 8.11 (1H, d, J¼8.2 Hz, indole);
963 cmꢁ1
.
8.29e8.37 (2H, m, 2ꢂ indole). 13C NMR (CDCl3, 126 MHz):
d
28.3,
5.3.2. Dimethyl 6-propylpyridine-3,4-dicarboxylate (4b). Prepared
from (2E,3E)-dimethyl 2-((dimethylamino)methylene)-3-(2-
oxopentylidene)succinate (3b) (230 mg, 0.85 mmol) and NH4OAc
(654 mg, 8.5 mmol), stirred for 5 days, chromatography (ethyl ac-
etate/petroleum ether¼1:2); yield: 135 mg (67%) of yellow oil. 1H
43.2, 51.4, 53.2, 85.7, 91.5, 115.2, 120.8, 122.7, 124.5, 125.8, 127.7,
131.4, 133.2, 135.8, 136.9, 149.3, 153.1, 169.0, 169.1, 187.3. EI-HRMS:
m/z¼457.1967 (MHþ); C24H29N2O7 requires: m/z¼457.1969
(MHþ); nmax (NaCl) 2982, 2949, 1744, 1693, 1643, 1603, 1584, 1540,
1450, 1435, 1372, 1309, 1271, 1242, 1191, 1144, 1087, 1044, 956, 882,
NMR (CDCl3, 300 MHz):
d
0.98 (3H, t, J¼7.4 Hz, CH3); 1.79 (2H,
851, 767 cmꢁ1
.
sextet, J¼7.2 Hz, CH2); 2.86 (2H, t, J¼7.5 Hz, CH2); 3.93 (3H, s,
COOCH3); 3.95 (3H, s, COOCH3); 7.32 (1H, s, pyridine); 9.00 (1H, d,
5.2.9. (2E,20E,200E,3E,30E,300E)-Hexamethyl 3,30,300-(benzene-1,3,5-
triyltris(2-oxoethan-2-yl-1-ylidene))tris(2-((dimethylamino)methy-
lene)succinate) (8c). Prepared from (2E,20E,200E)-1,10,100-(benzene-
1,3,5-triyl)tris(3-(dimethylamino)prop-2-en-1-one) (7c) (290 mg,
0.78 mmol), 100 ꢀC, 20 min, chromatography (ethyl acetate). Yield:
J¼0.5 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 13.8, 22.7, 40.4,
52.8, 53.1, 120.8, 122.1, 141.1, 150.3, 165.7, 166.9, 167.4. ESI-HRMS: m/
z¼238.1072 (MHþ); C12H16NO4 requires: m/z¼238.1079 (MHþ);
nmax (NaCl) 2959, 1733, 1596, 1555, 1436, 1380, 1297, 1207, 1139,
1075, 979, 895, 873, 824, 796, 769, 686 cmꢁ1
.
233 mg (38%) of red oil. 1H NMR (CDCl3, 300 MHz):
d 2.90 (18H, s,
3ꢂ NMe2); 3.57 (9H, s, 3ꢂ COOMe); 3.85 (9H, s, 3ꢂ COOMe); 7.53
5.3.3. Dimethyl 6-(tert-butyl)pyridine-3,4-dicarboxylate
(4c). Prepared from (2E,3E)-dimethyl 2-(3,3-dimethyl-2-
(3H, s, CH); 7.57 (3H, s, CH); 8.52 (1H, s, CH). 13C NMR (CDCl3,
75.5 MHz):
d
43.3, 51.3, 53.0, 92.1, 127.2, 131.5, 138.8, 140.4, 153.4,
oxobutylidene)-3-((dimethylamino)methylene)succinate (3c) (298
mg, 1.0 mmol) and NH4OAc (770 mg, 10.0 mmol), stirred for 5 days,
chromatography (ethyl acetate/petroleum ether¼1:5); yield:
168.4, 168.6, 189.1. EI-HRMS: m/z¼796.2929 (MHþ); C39H46N3O15
requires: m/z¼796.2929 (MHþ); nmax (NaCl) 1724, 1685, 1654, 1604,
1559, 1541, 1435, 1400, 1245, 1216, 1188, 1090, 1043, 953, 894, 837,
187 mg (74%) of colorless oil. 1H NMR (CDCl3, 500 MHz):
d
1.39 (9H,
790 cmꢁ1
.
s, Bu); 3.93 (3H, s, COOCH3); 3.96 (3H, s, COOCH3); 7.48 (1H, s,
t
pyridine); 9.03 (1H, s, pyridine). 13C NMR (CDCl3, 126 MHz):
d 30.0,
52.9, 53.2, 97.9, 117.4, 121.7, 141.3, 149.9, 165.9, 167.9, 174.1. ESI-
HRMS: m/z¼252.1231 (MHþ); C13H18NO4 requires: m/z¼252.1230
(MHþ); nmax (NaCl) 2957, 2869, 1734, 1592, 1559, 1435, 1364, 1295,
5.3. General procedure for the synthesis of dimethyl 2-
substituted pyridine-4,5-dicarboxylates
1257, 1194, 1138, 1068, 975, 880, 822, 801, 776 cmꢁ1
.
NH4OAc (10-fold excess) was added to a solution of (2E,3E)-di-
methyl 2-[(dimethylamino)methylene]-3-(2-substituted)succinates
(0.29e3.70 mmol) in MeOH (10 mL). The reaction mixture was
stirred from 5 h to 5 days at room temperature and after that
5.3.4. Dimethyl 6-(cyclopent-1-en-1-yl)pyridine-3,4-dicarboxylate
(4d). Prepared from (2E,3E)-dimethyl 2-[2-(cyclopent-1-en-1-yl)-

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4725
2oxoethylidene]-3-[(dimethylamino)methylene]succinate
(3d)
requires: C, 62.28; H, 4.18; N, 4.84. Found C, 62.29; H, 4.23; N, 4.74);
ESI-HRMS: m/z¼290.0820 (MHþ); C15H13FNO4 requires: m/
z¼290.0829 (MHþ); nmax (KBr) 2955, 1738, 1720, 1614, 1589, 1556,
1493, 1451, 1435, 1368, 1317, 1302, 1274, 1243, 1232, 1139, 1083,
(307 mg, 1 mmol) and NH4OAc (771 mg, 10 mmol), stirred for 24 h,
chromatography (petroleum ether/ethyl acetate¼5:1), crystallized
from and ethyl acetate/petroleum ether; yield: 183 mg (70%) of
light brown solid. Mp 115.4e118.2 ꢀC. 1H NMR (300 MHz, CDCl3):
1049, 963, 956, 912, 867, 821, 772, 755 cmꢁ1
.
d
2.05 (2H, m, CH2); 2.59 (2H, m, CH2); 2.80 (2H, m, CH2); 3.92 (3H, s,
COOCH3); 3.95 (3H, s, COOCH3); 6.79 (1H, m, CH); 7.48 (1H, s,
pyridine); 9.01 (1H, s, pyridine). 13C NMR (75.5 MHz, CDCl3):
23.3,
5.3.8. Dimethyl 6-(perfluorophenyl)pyridine-3,4-dicarboxylate
(4h). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(perfluorophenyl)ethylidene)succinate (3h) (92 mg,
0.23 mmol) and NH4OAc (180 mg, 2.30 mmol), stirred for 4 h, chro-
matography (ethyl acetate/petroleum ether¼1:8). Crystallized from
ethyl acetate/petroleum ether; yield: 65 mg (86%) of white solid. Mp
d
32.3, 33.8, 52.7, 53.0, 118.1, 121.6, 135.8, 141.3, 142.6, 150.5, 158.5,
165.5, 167.5. (C14H15NO4 requires: C, 64.36; H, 5.79; N, 5.36. Found
C, 63.96; H, 5.74; N, 5.26); ESI-HRMS: m/z¼262.1084 (MHþ);
C14H16NO4 requires: m/z¼262.1079 (MHþ); nmax (KBr) 2950, 2943,
2844, 2369, 1733, 1619, 1594, 1537, 1436, 1398, 1350, 1291, 1254,
86.7e88.5 ꢀC.1H NMR (CDCl3, 500 MHz):
(3H, s, COOCH3); 7.71 (1H, s, pyridine); 9.18 (1H, s, pyridine). 13C NMR
(CDCl3, 126 MHz):
d 3.98 (3H, s, COOCH3); 3.99
1196, 1138, 1080, 959 cmꢁ1
.
d
53.4, 53.6, 106.5 (td, J1¼3.8 Hz, J2¼15.8 Hz),124.3,
5.3.5. (E)-Dimethyl 6-styrylpyridine-3,4-dicarboxylate
(4e). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
125.4, 138.1 (dm J¼253.9 Hz),141.2,142.1 (dm, J¼257.7 Hz),144.9 (dm,
J¼252.9 Hz), 150.5, 151.0, 165.4, 166.1. 19F NMR (CDCl3, 470.9 MHz):
ꢁ142.4, ꢁ151.4, ꢁ160.8. (C15H8F5NO4 requires: C, 49.88; H, 2.23; N,
3.88. Found C, 49.64; H, 2.23; N, 3.83); ESI-HRMS: m/z¼362.0441
(MHþ); C15H9F5NO4 requires: m/z¼361.0446 (MHþ); nmax (KBr) 1740,
1724, 1654, 1636, 1552, 1529, 1500, 1443, 1365, 1303, 1274, 1195, 1140,
lene)-3-((E)-2-oxo-4-phenylbut-3-en-1-ylidene)succinate
(3e)
(230 mg, 0.67 mmol) and NH4OAc (515 mg, 6.7 mmol), stirred for 2
days, chromatography (ethyl acetate/petroleum ether¼1:1). Crys-
tallized from ethyl acetate/petroleum ether; yield: 150 mg (75%) of
yellow solid. Mp 73.4e75.7 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
3.90
1087, 1065, 991, 979, 897, 829, 766, 717 cmꢁ1
.
(3H, s, COOCH3); 3.95 (3H, s, COOCH3); 7.15 (1H, d, J¼16.2 Hz, CH);
7.28e7.39 (3H, m, Ph); 7.47 (1H, s, pyridine), 7.54e7.57 (2H, m, Ph);
7.74 (1H, d, J¼16.2 Hz, CH); 9.03 (1H, s, pyridine). 13C NMR (CDCl3,
5.3.9. Dimethyl 6-(2-nitrophenyl)pyridine-3,4-dicarboxylate
(4i). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-(2-nitrophenyl)-2-oxoethylidene)succinate (3i) (601 mg,
1.66 mmol) and NH4OAc (1278 mg, 16.6 mmol), stirred for 1 day,
precipitated from reaction mixture; yield: 289 mg (55%) of white
75.5 MHz):
d 52.7, 53.1, 119.7, 122.1, 126.2, 127.6, 128.9, 129.3, 135.9,
136.5, 141.7, 150.9, 159.3, 165.4, 167.3. (C17H15NO4 requires: C, 68.68;
H, 5.09; N, 4.71. Found C, 68.59; H, 4.88; N, 4.71); ESI-HRMS: m/
z¼298.1081 (MHþ); C17H16NO4 requires: m/z¼298.1079 (MHþ);
nmax (KBr) 3043, 3030, 3958, 1740, 1720, 1635, 1563, 1546, 1431,
1379, 1287, 1258, 1191, 1133, 1073, 967, 880, 825, 792, 756, 720,
solid. Mp 125.7e127.7 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.969 (3H, s,
COOCH3); 3.972 (3H, s, COOCH3); 7.58e7.64 (2H, m, Ph); 7.67e7.73
(2H, m, pyridineþPh); 7.96e7.99 (1H, m, Ph); 9.07 (1H, d, J¼0.6 Hz,
691 cmꢁ1
.
pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 53.2, 53.5, 121.2, 124.2,
125.0,130.4,131.4,132.9,134.1,141.6,149.2, 150.6,159.4,165.5,166.7.
(C15H12N2O6 requires: C, 56.96; H, 3.82; N, 8.86. Found C, 57.07; H,
3.76; N, 8.81); ESI-HRMS: m/z¼317.0789 (MHþ); C15H13N2O6 re-
quires: m/z¼317.0774 (MHþ); nmax (KBr) 2955, 1738, 1726, 1593,
1551, 1532, 1435, 1362, 1297, 1260, 1195, 1137, 1104, 1078, 959, 910,
5.3.6. Dimethyl 6-phenylpyridine-3,4-dicarboxylate (4f). Prepared
from (2E,3E)-dimethyl 2-((dimethylamino)methylene)-3-(2-oxo-2-
phenylethylidene)succinate (3f) (590 mg, 1.86 mmol) and NH4OAc
(1432 mg, 18.6 mmol), stirred for 2 days, chromatography (ethyl
acetate/petroleum ether¼1:3). Crystallized from ethyl acetate/pe-
troleum ether; yield: 340 mg (67%) of white solid. Mp 73.9e76.9 ꢀC
873, 849, 825, 782, 757, 709 cmꢁ1
.
(Ref. 22: mp 72e73 ꢀC). 1H NMR (CDCl3, 300 MHz):
d
3.95 (3H, s,
5.3.10. Dimethyl 6-(ferrocenyl)pyridine-3,4-dicarboxylate
(4j). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-ferrocenyl-2-oxoethylidene)succinate (3j) (201 mg,
0.49 mmol) and NH4OAc (377 mg, 4.9 mmol), stirred for 3 days,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallized
from ethyl acetate/petroleum ether; yield: 89 mg (48%) of red solid.
COOCH3); 3.97 (3H, s, COOCH3); 7.45e7.52 (3H, m, Ph); 7.88 (1H, d,
J¼0.7 Hz, pyridine); 8.03e8.65 (2H, m, Ph); 9.13 (1H, d, J¼0.7 Hz,
pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 52.9, 53.3, 118.5, 122.8,
127.5, 129.1, 130.5, 137.5, 141.8, 150.9, 160.9, 165.7, 167.4. (C15H13NO4
requires: C, 66.41; H, 4.83; N, 5.16. Found C, 66.71; H, 4.71; N, 5.14);
ESI-HRMS: m/z¼272.0919 (MHþ); C15H14NO4 requires: m/
z¼272.0923 (MHþ); nmax (KBr) 3065, 3020, 2958, 1740, 1720, 1593,
1555, 1478, 1442, 1365, 1290, 1259, 1184, 1142, 1083, 949, 893, 827,
Mp 128.4e131.4 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.92 (3H, s,
COOCH3); 3.96 (3H, s, COOCH3); 4.06 (5H, s, ferrocene); 4.51 (2H, t,
J¼1.8 Hz, ferrocene); 4.98 (2H, t, J¼1.8 Hz, ferrocene); 7.44 (1H, d,
J¼0.7 Hz, pyridine); 8.96 (1H, d, J¼0.7 Hz, pyridine). 13C NMR
795, 772, 752, 689 cmꢁ1
.
(CDCl3, 75.5 MHz):
d 52.7, 53.2, 68.2, 70.1, 71.4, 81.4, 117.6, 120.5,
5.3.7. Dimethyl 6-(2-fluorophenyl)pyridine-3,4-dicarboxylate
(4g). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
141.2, 150.9, 164.8, 165.8, 167.8. (C19H17NO4Fe requires: C, 60.18; H,
4.52; N, 3.69. Found C, 59.85; H, 4.45; N, 3.56); ESI-HRMS: m/
z¼380.0601 (MHþ); C19H18NO4Fe requires: m/z¼380.0585 (MHþ);
nmax (KBr) 3123, 3072, 3043, 3017, 2956, 1742, 1722, 1595, 1539,
1496, 1460, 1432, 1387, 1294, 1258, 1195, 1137, 1109, 1062, 1007, 957,
lene)-3-(2-(2-fluorophenyl)-2-oxoethylidene)succinate
(3g)
(191 mg, 0.57 mmol) and NH4OAc (438 mg, 5.7 mmol), stirred for 2
days, chromatography (ethyl acetate/petroleum ether¼1:1). Crys-
tallized from ethyl acetate/petroleum ether; yield: 125 mg (76%) of
907, 888, 835, 824, 795, 769, 685 cmꢁ1
.
yellow solid. Mp 133.6e135.7 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.96
(3H, s, COOCH3); 3.97 (3H, s, COOCH3); 7.18 (1H, ddd, J1¼1.1 Hz,
J2¼8.2 Hz, J3¼11.6 Hz, Ph); 7.28 (1H, td, J1¼1.2 Hz, J2¼7.6 Hz, Ph);
7.43 (1H, dddd, J1¼1.9 Hz, J2¼5.0 Hz, J3¼7.0 Hz, J3¼8.2 Hz, Ph); 8.00
(1H, dd, J1¼0.8 Hz, J2¼1.3 Hz, pyridine); 8.07 (1H, td, J1¼1.8 Hz,
J2¼7.9 Hz, Ph); 9.16 (1H, d, J¼0.7 Hz, pyridine). 13C NMR (CDCl3,
5.3.11. Dimethyl 6-(1-methyl-1H-pyrrol-2-yl)pyridine-3,4-
dicarboxylate (4k). Prepared from (2E,3E)-dimethyl 2-[(dimethyla-
mino)methylene]-3-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxoethylidene]
succinate (3k) (291 mg, 0.9 mmol) and NH4OAc (694, 9 mmol), stirred
for 24 h, chromatography (petroleum ether/ethyl acetate¼5:1),
crystallized from and ethyl acetate/petroleum ether; yield: 112 mg
(45%) of white solid. Mp 105.8e107.8 ꢀC. 1H NMR (300 MHz, CDCl3)
75.5 MHz):
d
53.0, 53.2, 116.6 (d, J¼22.9 Hz), 122.4 (d, J¼11.0 Hz),
123.2, 124.9 (d, J¼3.6 Hz), 125.8 (d, J¼10.9 Hz), 131.3 (d, J¼2.4 Hz),
132.0 (d, J¼8.8 Hz), 141.4 (d, J¼0.4 Hz), 150.6, 160.9 (d, J¼251.6 Hz),
d
3.91 (s, 3H, COOCH3); 3.95 (s, 3H, COOCH3); 4.02 (s, 3H, NCH3); 6.18
165.5, 167.1. 19F NMR (CDCl3, 470.9 MHz):
d
ꢁ112.0. (C15H12FNO4
(dd, 1H, J1¼2.7 Hz, J2¼3.9 Hz, pyrrole) 6.76 (m, 2H, pyrrole); 7.62 (d,

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4726
1H, J1¼0.6 Hz, pyridine); 8.99 (d, 1H, J1¼0.6 Hz, pyridine). 13C NMR
18.5 mmol), stirred for 2 days, chromatography (ethyl acetate/
petroleum ether¼1:3). Crystallized from ethyl acetate/petroleum
ether; yield: 302 mg (54%) of yellow solid. Mp 94.7e97.8 ꢀC. 1H
(75.5 MHz, CDCl3):
d 37.9, 52.6, 53.1, 108.6, 113.9, 118.3, 119.9, 129.1,
130.5, 141.5, 150.3, 155.8, 165.7, 167.7. (C14H14N2O4 requires: C, 61.31;
H, 5.14; N, 10.21. Found C, 61.13; H, 5.15; N, 10.21); ESI-HRMS: m/
z¼275.1034 (MHþ); C14H15N2O4 requires: m/z¼275.1032 (MHþ); nmax
(KBr) 3412, 2994, 2369, 2344,1749,1712,1685,1654,1636,1617,1595,
NMR (CDCl3, 300 MHz):
d 2.43 (3H, s, CH3); 2.65 (3H, s, CH3); 3.94
(3H, s, COOCH3); 3.96 (3H, s, COOCH3); 7.02 (1H, d, J¼1.1 Hz,
thiophene); 7.57 (1H, d, J¼0.7 Hz, pyridine), 9.09 (1H, d, J¼0.7 Hz,
1534, 1458, 1303, 1272, 1249, 1141, 1097, 958 cmꢁ1
.
pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 15.4, 15.6, 53.1, 53.5,
120.2, 121.5, 126.6, 135.4, 136.5, 139.4, 141.7, 150.9, 159.0, 165.9,
167.8. (C15H15NO4S requires: C, 59.00; H, 4.95; N, 5.59. Found C,
59.03; H, 4.80; N, 4.57); ESI-HRMS: m/z¼306.0806 (MHþ);
C15H16NO4S requires: m/z¼306.0800 (MHþ); nmax (KBr) 3069,
3006, 2950, 2920, 1739, 1718, 1639, 1592, 1541, 1487, 1432, 1373,
1343, 1302, 1277, 1248, 1194, 1139, 1074, 1015, 959, 897, 878, 845,
5.3.12. Dimethyl 6-(1-methyl-1H-pyrrol-3-yl)pyridine-3,4-
dicarboxylate (4l). Prepared from (2E,3E)-dimethyl 2-[(dimethyla-
mino)methylene]-3-[2-(1-methyl-1H-pyrrol-3-yl)-2-oxoethylidene]
succinate (3l) (352 mg, 1.1 mmol) and NH4OAc (847 mg, 11 mmol),
stirred for
5 days, chromatography (petroleum ether/ethyl
acetate¼7:1), crystallized from ethyl acetate; yield: 131 mg (44%) of
824, 795, 768, 737 cmꢁ1
.
light yellow solid. Mp 105.2e108.3 ꢀC. 1H NMR (300 MHz, CDCl3):
d
3.66 (s, 3H, NCH3); 3.90 (s, 3H, COOCH3); 3.94 (s, 3H, COOCH3); 6.63
5.3.16. Dimethyl 6-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)pyridine-
3,4-dicarboxylate (4p). Prepared from (2E,3E)-dimethyl 2-(2-(1-
(tert-butoxycarbonyl)-1H-indol-3-yl)-2-oxoethylidene)-3-((dime-
thylamino)methylene)succinate (3p) (348 mg, 0.67 mmol) and
NH4OAc (516 mg, 6.7 mmol), stirred for 2 day, chromatography
(ethyl acetate/petroleum ether¼1:10). Crystallized from ethyl ace-
tate/petroleum ether; yield: 127 mg (46%) of yellow solid. Mp
(m, 2H, pyrrole); 7.34 (t,1H, J1¼1.9 Hz, pyrrole); 7.48 (d,1H, J1¼0.6 Hz,
pyridine); 8.97 (d, 1H, J1¼0.6 Hz, pyridine). 13C NMR (75.5 MHz,
CDCl3): d 36.6, 52.5, 52.9, 107.6, 116.2, 119.6, 123.2, 123.7, 123.8, 141.8,
151.0, 158.4, 165.6, 167.9. (C14H14N2O4 requires: C, 61.31; H, 5.14; N,
10.21. Found C, 61.16; H, 5.22; N, 10.12); ESI-HRMS: m/z¼275.1021
(MHþ); C14H15N2O4 requires: m/z¼275.1032 (MHþ); nmax (KBr) 3460,
2361, 2343, 1740, 1715, 1636, 1599, 1540, 1437, 1298, 1218, 1139,
135.4e138.1 ꢀC. 1H NMR (CDCl3, 500 MHz):
d 1.70 (9H, s, Boc); 3.97
973 cmꢁ1
.
(3H, s, COOCH3); 4.00 (3H, s, COOCH3); 7.39 (2H, dqd, J1¼1.3 Hz,
J2¼7.3 Hz, J3¼14.7 Hz, indole); 7.48 (1H, d, J¼0.4 Hz, pyridine),
8.22e8.25 (2H, m, indole); 8.43e8.45 (1H, m, indole); 9.18 (1H, d,
5.3.13. Dimethyl 6-(furan-3-yl)pyridine-3,4-dicarboxylate
(4m). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-(furan-3-yl)-2-oxoethylidene)succinate (3m) (315 mg,
1.0 mmol) and NH4OAc (770 mg, 10.0 mmol), stirred for 2 days,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallized
from ethyl acetate/petroleum ether: yield: 203 mg (78%) of
J¼0.4 Hz, pyridine). 13C NMR (CDCl3, 126 MHz):
d 28.2, 52.8, 53.2,
84.8, 115.3, 118.6, 119.5, 121.3, 121.9, 123.8, 125.3, 126.9, 127.7, 136.2,
141.5, 149.3, 160.9, 157.5, 165.5, 167.5. (C22H22N2O6 requires: C,
64.38; H, 5.40; N, 6.83. Found C, 64.43; H, 5.19; N, 6.70); ESI-HRMS:
m/z¼411.1606 (MHþ); C22H23N2O6 requires: m/z¼411.1551 (MHþ);
nmax (KBr) 1734, 1717, 1636, 1549, 1455, 1436, 1395, 1373, 1291, 1271,
brownish solid. Mp 92.7e94.2 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.94
(3H, s, COOCH3); 3.97 (3H, s, COOCH3); 6.57 (1H, dd, J1¼1.8 Hz,
J2¼3.5 Hz, furan); 7.22 (1H, dd, J1¼0.7 Hz, J2¼3.5 Hz, furan); 7.59
(1H, dd, J1¼0.7 Hz, J2¼1.7 Hz, furan), 7.80 (1H, d, J¼0.6 Hz, pyridine);
1240,1207, 1159, 1108, 1057, 1018, 989, 955, 879, 821, 766, 750 cmꢁ1
.
5.3.17. Dimethyl 6-(1,3-thiazol-2-yl)pyridine-3,4-dicarboxilate
(4q). Prepared from (2E,3E)-dimethyl 2-[(dimethylamino)methy-
lene]-3-[2-oxo-2-(thiazol-2-yl)ethylidene]succinate (3q) (447 mg,
1.37 mmol) and NH4OAc (1.056 g, 13.7 mmol), stirred for 24 h,
chromatography (petroleum ether/ethyl acetate¼4:1), crystallized
from ethyl acetate; yield: 306 mg (80%) of light brown solid. Mp
9.04 (1H, d, J¼0.7 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 52.9,
53.2, 112.0, 112.8, 116.4, 122.0, 142.1, 145.1, 151.1, 152.3, 152.4, 165.4,
167.3. (C13H11NO5 requires: C, 59.77; H, 4.24; N, 5.36. Found C,
60.05; H, 4.08; N, 5.34); ESI-HRMS: m/z¼262.0715 (MHþ);
C13H12NO5 requires: m/z¼262.0715 (MHþ); nmax (KBr) 1739, 1718,
1604, 1577, 1548, 1490, 1438, 1352, 1299, 1282, 1257, 1193, 1138,
128.0e130.8 ꢀC. 1H NMR (300 MHz, CDCl3):
d 3.96 (s, 3H, COOCH3);
1093, 1011, 956, 919, 883, 851, 825, 796, 762, 733 cmꢁ1
.
3.98 (s, 3H, COOCH3); 7.54 (d, 1H, J1¼3.3 Hz, thiazole); 7.97 (d, 1H,
J1¼3.3 Hz, thiazole); 8.36 (d, 1H, J1¼0.6 Hz, pyridine); 9.03 (d, 1H,
5.3.14. Dimethyl 6-(thiophen-3-yl)pyridine-3,4-dicarboxylate
(4n). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(thiophen-3-yl)ethylidene)succinate (3n) (162 mg,
0.5 mmol) and NH4OAc (385 mg, 5.0 mmol), stirred for 3 days,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallized
from ethyl acetate/petroleum ether; yield: 115 mg (83%) of yellow
J1¼0.6 Hz, pyridine). 13C NMR (75.5 MHz, CDCl3):
d 53.0, 53.2, 117.9,
123.2, 124.9, 141.9, 144.8, 150.6, 154.3, 165.2, 166.5, 167.0.
(C12H10N2O4S requires: C, 51.79; H, 3.62; N, 10.07. Found C, 51.69; H,
3.55; N, 10.01); ESI-HRMS: m/z¼279.0446 (MHþ); C12H11N2O4S
requires: m/z¼279.0446 (MHþ); nmax IR (KBr) 3462, 3103, 2994,
2359, 1740, 1720, 1636, 1589, 1551, 1437, 1414, 1374, 1298, 1275,
solid. Mp 101.3e104.6 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
3.95 (3H, s,
1242, 1134, 1084, 957, 921 cmꢁ1
.
COOCH3); 3.98 (3H, s, COOCH3); 7.43 (1H, dd, J1¼3.0 Hz, J2¼5.1 Hz,
thiophene);7.70 (1H, dd, J1¼1.3 Hz, J2¼5.1 Hz, thiophene); 7.73 (1H, d,
J¼0.7 Hz, pyridine), 8.06 (1H, dd, J1¼1.3 Hz, J2¼3.0 Hz, thiophene);
5.3.18. Dimethyl 6-(pyridn-2-yl)pyridine-3,4-dicarboxylate
(4r). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(pyridin-2-yl)ethylidene)succinate (3r) (126 mg,
0.4 mmol) and NH4OAc (308 mg, 4.0 mmol), stirred for 3 days,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallized
from ethyl acetate/petroleum ether; yield: 51 mg (47%) of white
9.08 (1H, d, J¼0.7 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 52.9,
53.2, 118.1, 122.1, 126.3, 126.4, 127.0, 140.6, 141.9, 151.0, 156.7, 165.5,
167.4. (C13H11NO4S requires: C, 56.31; H, 4.00; N, 5.05. Found C,
56.25; H, 3.92; N, 5.00); ESI-HRMS: m/z¼278.0489 (MHþ);
C13H12NO4S requires: m/z¼278.0487 (MHþ); nmax (KBr) 3110, 2947,
2844,1733,1595,1546,1528,1520,1445,1436,1421,1336,1290,1237,
1206, 1140, 1095, 1077, 955, 914, 898, 879, 849, 824, 809, 784,
solid. Mp 109.7e111.8 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.94 (3H, s,
COOCH3); 3.95 (3H, s, COOCH3); 7.34 (1H, ddd, J1¼1.1 Hz, J2¼4.8 Hz,
J3¼7.5 Hz, Py); 7.82 (1H, td, J1¼1.8 Hz, J2¼7.8 Hz, Py); 8.44 (1H, d,
J¼8.0 Hz, Py); 8.61 (1H, d, J¼0.6 Hz, pyridine); 8.68 (1H, ddd,
J1¼0.9 Hz, J2¼1.7 Hz, J3¼4.8 Hz, Py); 9.09 (1H, d, J¼0.6 Hz, pyridine).
727 cmꢁ1
.
5.3.15. Dimethyl 6-(2,5-dimethylthiophen-3-yl)pyridine-3,4-
dicarboxylate (4o). Prepared from (2E,3E)-dimethyl 2-((dimethy-
lamino)methylene)-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethy-
lidene)succinate (3o) (650 mg, 1.85 mmol) and NH4OAc (1430 mg,
13C NMR (CDCl3, 75.5 MHz):
d 53.0, 53.2, 119.3, 122.0, 124.4, 125.0,
137.3, 141.9, 149.6, 150.4, 154.4, 159.5, 165.7, 167.2. (C14H12N2O4 re-
quires: C, 61.76; H, 4.44; N, 10.29. Found C, 61.61; H, 4.33; N, 10.20);
ESI-HRMS: m/z¼273.0868 (MHþ); C14H13N2O4 requires: m/

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4727
z¼273.0868 (MHþ); nmax (KBr) 3065, 6007, 2951, 1736, 1719, 1585,
(C33H27N3O12ꢂH2O requires: C, 58.67; H, 4.33; N, 6.22. Found C,
58.80; H, 4.03; N, 6.16); ESI-HRMS: m/z¼658.1649 (MHþ);
C33H28N3O12 requires: m/z¼658.1673 (MHþ); nmax (KBr) 3009,
2956, 1730, 1638, 1617, 1590, 1556, 1436, 1367, 1351, 1303, 1243,
1549, 1460, 1440, 1370, 1298, 1282, 1227, 1196, 1133, 1097, 994, 966,
930, 870, 826, 785, 747, 685 cmꢁ1
.
5.3.19. Dimethyl 6-(pyrazin-3-yl)pyridine-3,4-dicarboxylate
(4s). Prepared from (2E,3E)-dimethyl 2-[(dimethylamino)methy-
lene]-3-(2-oxo-2-(pyrazin-2-yl)ethylidene)succinate (3s) (159 mg,
0.5 mmol) and NH4OAc (385 mg, 5 mmol), stirred for 3 days,
chromatography (petroleum ether/ethyl acetate¼5:1), crystallized
from ethyl acetate; yield: 98.5 mg (72%) of white solid. Mp
1196, 1141, 1092, 1068, 975, 882, 826, 795, 770, 697 cmꢁ1
.
5.4. General procedure for the synthesis of 2-substittued 4,5-
bis(methoxycarbonyl)-pyridine 1-oxides
NH2OHꢂHCl (1.5-fold excess) was added to a solution of (2E,3E)-
dimethyl 2-[(dimethylamino)methylene]-3-(2-substituted)succinates
(0.23e3.07 mmol) in MeOH (10 mL). The reaction mixture was
stirred from 2 h to 5 days at room temperature and after that vol-
atile components were evaporated in vacuo and products were
purified by column chromatography and crystallized from appro-
priate solvents.
150.2e152.8 ꢀC. 1H NMR (300 MHz, CDCl3):
d 3.98 (s, 3H, COOCH3);
3.99 (s, 3H, COOCH3); 8.58 (s, 1H, pyridine); 8.66 (m, 2H, pyrazine);
9.15 (s, 1H, pyridine); 9.70 (d, 1H, J1¼1.5 Hz, pyrazine). 13C NMR
(75.5 MHz, CDCl3): d 53.1, 53.3, 119.6, 125.2, 141.9, 144.1, 144.2, 146.7,
149.4, 150.5, 157.6, 166.8, 168.7. (C13H11N3O4 requires: C, 57.14; H,
4.06; N, 15.38. Found C, 57.01; H, 4.00; N, 15.36); ESI-HRMS: m/
z¼274.0824 (MHþ); C13H12N3O4 requires: m/z¼274.0828 (MHþ);
nmax IR (KBr) 2961, 1745, 1718, 1654, 1559, 1436, 1268, 1294, 1100,
5.4.1. 2-Ethyl-4,5-bis(methoxycarbonyl)pyridine 1-oxide
(5a). Prepared from (2E,3E)-dimethyl 2-[(dimethylamino)methy-
lene]-3-(2-oxobutylidene)succinate (3a) (311 mg, 1.2 mmol) and
NH2OHꢂHCl (125 mg, 1.8 mmol), stirred for 2 h, chromatography
(petroleum ether/ethyl acetate¼1:1); yield: 123 mg (47%) of yellow
1017, 794 cmꢁ1
.
5.3.20. Tetramethyl 6,60-(1,3-phenylene)bis(pyridine-3,4-
dicarboxylate) (9a). Prepared from (2E,20E,3E,30E)-tetramethyl
3,30-(1,3-phenylenebis(2-oxoethan-2-yl-1-ylidene))bis(2-((dime-
thylamino)methylene)succinate)) (8a) 834 mg, 1.5 mmol) and
NH4OAc (2310 mg, 30.0 mmol), stirred for 3 days, chromatography
(ethyl acetate). Crystallized from ethyl acetate/petroleum ether;
yield: 604 mg (87%) of brownish solid. Mp 147.1e150.3 ꢀC. 1H NMR
oil.1H NMR (300 MHz, CDCl3)
d
1.34 (t, 3H, J1¼7.5 Hz, CH3); 2.95 (q, 2H,
J1¼7.5 Hz, CH2);3.98(s, 3H, COOCH3);3.99(s, 3H, COOCH3);7.63(s,1H,
pyridine); 8.46 (s, 1H, pyridine). 13C NMR (75.5 MHz, CDCl3):
d
10.2,
23.5, 53.2, 53.4, 124.5, 126.3, 128.5, 139.3, 156.1, 164.3, 164.9. ESI-
HRMS: m/z¼240.0876 (MHþ); C11H14NO5 requires: m/z¼240.0872
(MHþ); nmax IR (NaCl): 3416, 2953, 2842, 2364, 2330,1734,1723,1617,
(CDCl3, 300 MHz):
d 3.98 (6H, s, COOCH3); 4.00 (6H, s, COOCH3);
7.64 (1H, t, J¼7.8 Hz, Ph); 8.00 (2H, d, J¼0.7 Hz, pyridine), 8.18 (2H,
1537, 1431, 1307, 1294, 1274, 1241, 1186, 1131, 1060, 963 cmꢁ1
.
dd, J1¼1.8 Hz, J2¼7.8 Hz, Ph); 8.77 (1H, t, J¼1.6 Hz, Ph); 9.18 (2H, d,
J¼0.7 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
d
53.1, 53.4, 118.7,
5.4.2. 4,5-Bis(methoxycarbonyl)-2-propylpyridine 1-oxide
(5b). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxopentylidene)succinate (3b) (868 mg, 3.07 mmol) and
NH2OHꢂHCl (320 mg, 4.6 mmol), stirred for 2 h, chromatography
(ethyl acetate/petroleum ether¼1:1); yield: 640 mg (82%) of yellow
123.2, 126.4, 129.4, 129.9, 138.4, 142.0, 151.0, 160.2, 165.6, 167.4.
(C24H20N2O8 requires: C, 62.07; H, 4.34; N, 6.03. Found C, 61.99; H,
4.17; N, 5.99); ESI-HRMS: m/z¼465.1299 (MHþ); C24H21N2O8 re-
quires: m/z¼465.1298 (MHþ); nmax (KBr) 3007, 2955, 1744, 1724,
1594, 1557, 1436, 1369, 1305, 1291, 1266, 1195, 1139, 1085, 963, 882,
oil. 1H NMR (CDCl3, 300 MHz):
d
1.04 (3H, t, J¼7.4 Hz, CH3); 1.78 (2H,
859, 824, 795, 777, 690 cmꢁ1
.
sextet, J¼7.5 Hz, CH2); 2.90 (2H, t, J¼7.5 Hz, CH2); 3.93 (3H, s,
COOCH3); 3.94 (3H, s, COOCH3); 7.63 (1H, s, pyridine); 8.46 (1H, s,
5.3.21. Tetramethyl 6,60-(1,4-phenylene)bis(pyridine-3,4-
dicarboxylate) (9b). Prepared from (2E,20E,3E,30E)-tetramethyl
3,30-(1,4-phenylenebis(2-oxoethan-2-yl-1-ylidene))bis(2-((dime-
thylamino)methylene)succinate) (8b) (439 mg, 0.79 mmol) and
NH4OAc (1217 mg, 15.8 mmol), stirred for 3 days, precipitated from
reaction mixture; Crystallized from ethyl acetate; yield: 239 mg
(65%) of brownish solid. Mp 184.7e186.9 ꢀC. 1H NMR (CDCl3,
pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 13.8, 19.1, 32.2, 53.1, 53.3,
125.4, 126.1, 128.6, 139.3, 154.7, 164.3, 164.7. ESI-HRMS: m/
z¼254.1030 (MHþ); C12H16NO5 requires: m/z¼254.1028 (MHþ);
nmax (NaCl) 3123, 3040,2958, 2875, 1734, 1616, 1534, 1435, 1402,
1296, 1241, 1049, 970, 913, 867, 804, 769, 671 cmꢁ1
.
5.4.3. 2-(tert-Butyl)-4,5-bis(methoxycarbonyl)pyridine 1-oxide
(5c). Prepared from (2E,3E)-dimethyl 2-(3,3-dimethyl-2-
300 MHz):
J¼0.6 Hz, pyridine), 8.22 (4H, s, Ph); 9.17 (2H, d, J¼0.6 Hz, pyridine).
13C NMR (CDCl3, 126 MHz):
53.1, 53.4, 118.7, 123.3, 128.1, 139.3,
d 3.98 (6H, s, COOCH3); 4.00 (6H, s, COOCH3); 7.97 (2H, d,
oxobutylidene)-3-((dimethylamino)methylene)succinate (3c) (282
mg, 0.95 mmol) and NH2OHꢂHCl (99 mg, 1.4 mmol), stirred for
24 h, chromatography (ethyl acetate/petroleum ether¼1:1); yield:
d
142.0, 151.1, 159.9, 165.7, 167.4. (C24H20N2O8 requires: C, 62.07; H,
4.34; N, 6.03. Found C, 61.87; H, 4.18; N, 5.94); ESI-HRMS: m/
z¼465.1317 (MHþ); C24H21N2O8 requires: m/z¼465.1298 (MHþ);
nmax (KBr) 3008, 2959, 1728, 1713, 1591, 1551, 1479, 1435, 1325, 1307,
1270, 1248, 1198, 1146, 1126, 1086, 962, 899, 852, 785, 748,
245 mg (96%) of yellowish oil. 1H NMR (CDCl3, 500 MHz):
d
1.51 (9H,
t
s, Bu); 3.93 (3H, s, COOCH3); 3.94 (3H, s, COOCH3); 7.72 (1H, s,
pyridine); 8.34 (1H, s, pyridine). 13C NMR (CDCl3, 126 MHz):
d 26.7,
36.6, 53.3, 53.5, 124.3, 125.9, 128.8, 141.4, 160.3, 164.6, 165.2. ESI-
HRMS: m/z¼268.1182 (MHþ); C13H18NO5 requires: m/z¼268.1179
(MHþ); nmax (NaCl) 2957, 1732, 1610, 1537, 1489, 1436, 1306, 1277,
687 cmꢁ1
.
5.3.22. Hexamethyl 6,60,600-(benzene-1,3,5-triyl)tris(pyridine-3,4-
dicarboxylate) (9c). Prepared from (2E,20E,200E,3E,30E,300E)-hexam-
ethyl 3,30,300-(benzene-1,3,5-triyltris(2-oxoethan-2-yl-1-ylidene))
tris(2-((dimethylamino)methylene)succinate) (8c) (230 mg,
0.29 mmol) and NH4OAc (670 mg, 8.7 mmol), stirred for 1 day,
precipitated from reaction mixture; Crystallized from ethyl acetate/
petroleum ether; yield: 122 mg (64%) of brownish solid. Mp
1240, 1200, 1136, 1116, 1037, 970, 912, 804, 776, 665 cmꢁ1
.
5.4.4. 2-(Cyclopent-1-en-1-yl)-4,5-bis(methoxycarbonyl)pyridine 1-
oxide (5d). Prepared from (2E,3E)-dimethyl 2-[2-(cyclopent-1-en-
1-yl)-2-oxoethylidene]-3-[(dimethylamino)methylene]succinate
(3d) (432 mg, 1.4 mmol) and NH2OHꢂHCl (146 mg, 2.1 mmol),
stirred for 24 h, chromatography (petroleum ether/ethyl
acetate¼1:1), crystallized from ethyl acetate/petroleum ether;
yield: 291 mg (75%) of yellow solid. Mp 124.0e126.2 ꢀC. 1H NMR
215.3e217.4 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.99 (9H, s, COOCH3);
4.02 (9H, s, COOCH3); 8.10 (3H, d, J¼0.7 Hz, pyridine), 8.89 (3H, s,
Ph); 9.20 (3H, d, J¼0.7 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
(300 MHz, CDCl3):
2.67e2.72 (m, 2H, cyclopentene); 2.78e2.84 (m, 2H, cyclopentene);
d
2.00 (pent, 2H, J1¼7.8 Hz, cyclopentene);
d
53.1, 53.5, 118.8, 123.6, 128.0, 139.2, 142.2, 151.1, 159.5, 165.6, 167.3.

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
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3.93 (s, 3H, COOCH3); 3.94 (s, 3H, COOCH3); 7.63 (s, 1H, pyridine);
7.91e7.94 (m, 1H, cyclopentene); 8.49 (s, 1H, pyridine). 13C NMR
(95 mg, 0.23 mmol) and NH2OHꢂHCl (25 mg, 0.35 mmol), stirred for
2 days, chromatography (ethyl acetate/petroleum ether¼1:2). Crys-
tallized from ethyl acetate/petroleum ether; yield: 43 mg (67%) of
(75.5 MHz, CDCl3):
d 22.2, 34.5, 35.0, 53.2, 53.4, 125.2, 126.3, 126.6,
132.3, 140.9, 142.6, 146.8, 164.3, 165.1. (C14H15NO5 requires: C,
60.64; H, 5.45; N, 5.05. Found C, 60.51; H, 5.45; N, 5.03); ESI-HRMS:
m/z¼278.1021 (MHþ); C14H16NO5 requires: m/z¼278.1028 (MHþ);
nmax IR (KBr) (cmꢁ1): 3550, 3472, 3276, 3051, 2950, 2358, 1742,
1723, 1635, 1609, 1533, 14,734, 1426, 1295, 1233, 1138, 1066,
white solid. Mp 120.8e122.8 ꢀC. 1H NMR (CDCl3, 500 MHz):
d
3.95
(3H, s, COOCH3);4.00(3H, s, COOCH3);7.89 (1H, s, pyridine);8.50(1H,
s, pyridine). 13C NMR (CDCl3, 126 MHz):
53.6, 53.9, 106.5 (td,
d
J1¼4.2 Hz, J2¼17.4 Hz), 125.0, 129.8, 132.7, 138.1 (dm J¼251.0 Hz),
139.2, 139.9, 143.5 (dm, J¼234.6 Hz), 145.0 (dm, J¼249.7 Hz), 163.6,
164.1. 19F NMR (CDCl3, 470.9 MHz): ꢁ137.4, ꢁ150.3, ꢁ161.3.
(C15H8F5NO5 requires: C, 47.76; H, 2.14; N, 3.37. Found C, 47.72; H,
2.06; N, 3.70); ESI-HRMS: m/z¼378.0388 (MHþ); C15H9F5NO5 re-
quires: m/z¼378.0395 (MHþ); nmax (KBr) 1737,1657,1529,1500,1437,
1398,1319,1307,1273,1247,1205,1136,1038, 992, 968, 913, 866, 821,
965 cmꢁ1
.
5.4.5. (E)-4,5-Bis(methoxycarbonyl)-2-styrylpyridine 1-oxide
(5e). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-((E)-2-oxo-4-phenylbut-3-en-1-ylidene)succinate
(3e)
(478 mg, 1.4 mmol) and NH2OHꢂHCl (146 mg, 2.1 mmol), stirred
804, 735, 695, 670 cmꢁ1
.
for 3 h, precipitated from reaction mixture; yield: 198 mg (45%) of
white solid. Mp 157.2e158.8 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
3.94
5.4.9. 4,5-Bis(methoxycarbonyl)-2-(2-nitrophenyl)pyridine 1-oxide
(3H, s, COOCH3); 3.95 (3H, s, COOCH3); 7.35e7.42 (3H, m, Ph);
7.55e7.62 (3H, m, PhþCH); 7.73 (1H, d, J¼16.7 Hz, CH); 7.97 (1H, s,
pyridine), 8.46 (1H, s, pyridine). 13C NMR (CDCl3, 75.5 MHz):
(5i). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-(2-nitrophenyl)-2-oxoethylidene)succinate
(3i)
(440 mg,1.2 mmol) and NH2OHꢂHCl (125 mg,1.8 mmol), stirred for
d
53.3, 53.4, 117.3, 123.0, 126.7, 127.7, 128.2, 129.1, 130.0, 135.7,
12 h, precipitated from reaction mixture; yield: 187 mg (47%) of
138.2, 140.1, 149.7, 164.2, 165.0. (C17H15NO5 requires: C, 65.17; H,
4.83; N, 4.47. Found C, 65.29; H, 4.89; N, 4.45); ESI-HRMS: m/
z¼314.1019 (MHþ); C17H16NO5 requires: m/z¼314.1028 (MHþ);
nmax (KBr) 1734, 1726, 1653, 1625, 1576, 1525, 1432, 1406, 1293,
1269, 1261, 1235, 1151, 1126, 1056, 687, 960, 904, 884, 799, 761,
white solid. Mp 170.9e172.3 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.94
(3H, s, COOCH3); 3.98 (3H, s, COOCH3); 7.45 (1H, dd, J1¼1.4 Hz,
J2¼7.5 Hz, Ar); 7.70 (1H, dd, J1¼1.6 Hz, J2¼7.8 Hz, Ar); 7.78 (1H, dd,
J1¼1.4 Hz, J2¼7.5 Hz, Ar); 7.87 (1H, d, J¼0.6 Hz, pyridine); 8.20 (1H,
dd, J1¼1.2 Hz, J2¼8.1 Hz, Ar); 8.42 (1H, d, J¼0.6 Hz, pyridine). 13C
715, 691 cmꢁ1
.
NMR (CDCl3, 75.5 MHz): d 53.4, 53.7,124.8,126.3, 126.4, 126.6, 131.0,
131.6, 132.0, 139.4, 148.8, 149.7, 164.2, 164.3. (C15H12N2O7 requires:
C, 54.22; H, 3.64; N, 8.43. Found C, 54.26; H, 3.48; N, 8.38); ESI-
HRMS: m/z¼665.1353 (2 MHþ); C30H25N4O14 requires: m/
z¼665.1362 (2 MHþ); nmax (KBr) 1736, 1717, 1653, 1624, 1531, 1430,
1398, 1356, 1319, 1298, 1282, 1250, 1134, 1071, 958, 917, 859, 802,
5.4.6. 4,5-Bis(methoxycarbonyl)-2-phenylpyridine 1-oxide
(5f). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-phenylethylidene)succinate (3f) (419 mg,
1.32 mmol) and NH2OHꢂHCl (139 mg, 2.0 mmol), stirred for 4 h,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallized
from ethyl acetate/petroleum ether; yield: 268 mg (71%) of white
777, 731, 698 cmꢁ1
.
solid. Mp 120.5e121.8 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
3.86 (3H, s,
5.4.10. 2-(Ferrocenyl)-4,5-bis(methoxycarbonyl)pyridine 1-oxide
(5j). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-ferrocenyl-2-oxoethylidene)succinate (3j) (340 mg,
0.82 mmol) and NH2OHꢂHCl (85 mg, 1.23 mmol), stirred for 1 day,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallized
from ethyl acetate/petroleum ether; yield: 149 mg (46%) of red
COOCH3); 3.89 (3H, s, COOCH3); 7.39e7.44 (3H, m, Ph); 7.74e7.77
(2H, m, Ph); 7.78 (1H, s, pyridine); 8.44 (1H, pyridine). 13C NMR
(CDCl3, 75.5 MHz):
d 53.1, 53.4, 126.1, 127.4, 128.5, 129.2, 129.4,
130.5, 131.0, 140.4, 150.7, 164.2, 164.4. (C15H13NO5 requires: C,
62.72; H, 4.56; N, 4.88. Found C, 62.81; H, 4.42; N, 4.85); ESI-HRMS:
m/z¼286.0718 (MꢁHꢁ); C15H12NO5 requires: m/z¼286.0721
(MꢁHꢁ); nmax (KBr) 1740, 1723, 1610, 1533, 1452, 1434, 1397, 1306,
1277, 1231, 1126, 1070, 1029, 954, 911, 877, 801, 783, 763, 718,
solid. Mp 148.6e151.2 ꢀC. 1H NMR (CDCl3, 500 MHz):
d 3.95 (3H, s,
COOCH3); 3.96 (3H, s, COOCH3); 4.18 (5H, s, ferrocene); 4.57 (2H, t,
J¼1.5 Hz, ferrocene); 5.23 (2H, t, J¼1.5 Hz, ferrocene); 7.81 (1H, s,
pyridine); 8.46 (1H, s, pyridine). 13C NMR (CDCl3, 126.0 MHz):
690 cmꢁ1
.
d
53.4, 53.5, 70.2, 70.3, 71.6, 74.3, 124.6, 125.9, 126.6, 141.93, 153.2,
5.4.7. 2-(2-Fluorophenyl)-4,5-bis(methoxycarbonyl)pyridine 1-oxide
(5g). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-(2-fluorophenyl)-2-oxoethylidene)succinate (3g) (191 mg,
0.57 mmol) and NH2OHꢂHCl (59 mg, 0.86 mmol), stirred for 4 h,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallized
from ethyl acetate/petroleum ether; yield: 126 mg (72%) of yellow
164.6, 165.4. (C19H17NO5Fe requires: C, 57.75; H, 4.34; N, 3.54.
Found C, 57.86; H, 4.07; N, 3.58); ESI-HRMS: m/z¼396.0536
(MHþ); C19H18NO5Fe requires: m/z¼396.0534 (MHþ); nmax (KBr)
3085, 2953, 1733, 1609, 1533, 1506, 1456, 1435, 1399, 1372, 1300,
1225, 1212, 1134, 1098, 1036, 1001, 962, 880, 825, 800,
774,668 cmꢁ1
.
solid. Mp 132.0e134.5 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.92 (3H, s,
COOCH3); 3.97 (3H, s, COOCH3); 7.18e7.24 (1H, m, Ph); 7.24e7.30 (1H,
m, Ph); 7.46e7.53 (1H, m, Ph); 7.58 (1H, td, J1¼1.7 Hz, J2¼7.4 Hz, Ph);
7.85 (1H, s, pyridine); 8.50 (1H, s, pyridine). 13C NMR (CDCl3,
5.4.11. 4,5-Bis(methoxycarbonyl)-2-(1-methyl-1H-pyrrol-2-yl)pyri-
dine 1-oxide (5k). Prepared from (2E,3E)-dimethyl 2-[(dimethyla-
mino)methylene]-3-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxoethylidene]
succinate (3k) (512 mg, 1.6 mmol) and NH2OHꢂHCl (167 mg,
2.4 mmol), stirred for 24 h, chromatography (petroleum ether/ethyl
acetate¼1:1), crystallized from petroleum ethyl acetate/ether; yield:
342 mg (75%) of dark brown solid. Mp 110.7e116.3 ꢀC. 1H NMR
75.5 MHz):
d
53.2, 53.5,116.2 (d, J¼21.3 Hz),119.3 (d, J¼14.2 Hz),124.3
(d, J¼3.6 Hz),125.4,128.6 (d, J¼2.1 Hz),130.6,131.0 (d, J¼2.3 Hz),132.5
(d, J¼8.6 Hz), 139.9, 146.9, 160.1 (d, J¼252.1 Hz), 164.1, 164.2. 19F NMR
(CDCl3, 470.9 MHz): ꢁ116.9. (C15H12FNO5 requires: C, 59.02; H, 3.96;
N, 4.59. Found C, 59.22; H, 4.07; N, 4.35); ESI-HRMS: m/z¼306.0774
(MHþ); C15H13FNO5 requires: m/z¼306.0778 (MHþ); nmax (KBr) 3045,
2959, 1746, 1719, 1623, 1608, 1581, 1529, 1484, 1453, 1425, 1314, 1288,
(300 MHz, CDCl3) d 3.67 (s, 3H, NCH3); 3.91 (s, 3H, COOCH3); 3.95 (s,
3H, COOCH3); 6.22 (dd,1H, J1¼2.6 Hz, J2¼3.8 Hz, pyrrole); 6.47 (dd,1H
J1¼1.8 Hz, J2¼3.8 Hz, pyrrole); 6.84e6.86 (m,1H, pyrrole); 7.77 (d,1H,
J1¼0.3 Hz, pyridine); 8.47 (d, 1H, J1¼0.3 Hz, pyridine). 13C NMR
1256, 1239, 1134, 1073, 965, 926, 818, 773, 755, 745, 664 cmꢁ1
.
(75.5 MHz, CDCl3):
d 36.1, 53.1, 53.4, 108.9, 114.4, 123.9, 125.9, 126.7,
5.4.8. 4,5-Bis(methoxycarbonyl)-2-(perfluorophenyl)pyridine 1-
oxide (5h). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)
methylene)-3-(2-oxo-2-(perfluorophenyl)ethylidene)succinate (3h)
128.5,129.0,140.0,145.0,164.2,164.4. (C14H14N2O5 requires: C, 57.93;
H, 4.86; N, 9.65. Found C, 57.72; H, 4.87; N, 9.61); ESI-HRMS: m/
z¼291.0985 (MHþ); C14H15N2O5 requires: m/z¼291.0981 (MHþ); nmax

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4729
IR (KBr) 3545, 3483, 3420, 3092, 2945, 2366, 2344, 1739, 1725, 1617,
1560,1522, 1438, 1322, 1301, 1233, 1130, 1082, 991 cmꢁ1
139.9, 140.4, 147.9, 164.4, 164.6. ESI-HRMS: m/z¼322.0743 (MHþ);
C15H16NO5S requires: m/z¼322.0749 (MHþ); nmax (KBr) 2954, 2921,
1731, 1612, 1528, 1507, 1435, 1338, 1301, 1239, 1129, 1058, 962, 916,
.
5.4.12. 4,5-Bis(methoxycarbonyl)-2-(1-methyl-1H-pyrrol-3-yl)pyri-
dine 1-oxide (5l). Prepared from (2E,3E)-dimethyl 2-[(dimethyla-
mino)methylene]-3-[2-(1-methyl-1H-pyrrol-3-yl)-2-oxoethylidene]
succinate (3l) (736 mg, 2.3 mmol) and NH2OHꢂHCl (237 mg,
3.5 mmol), stirred for 3 days, chromatography (ethyl acetate), crys-
tallized from ethyl acetate/petroleum ether; yield: 539 mg, (80%) of
white-yellow solid. Mp 146.5e148.8 ꢀC. 1H NMR (300 MHz, CDCl3):
849, 802, 775, 736, 708 cmꢁ1
.
5.4.16. 2-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)-4,5-bis(methoxyc-
arbonyl)pyridine 1-oxide (5p). Prepared from (2E,3E)-dimethyl 2-(2-
(1-(tert-butoxycarbonyl)-1H-indol-3-yl)-2-oxoethylidene)-3-((dime-
thylamino)methylene)succinate (3p) (116 mg, 0.26 mmol) and
NH2OHꢂHCl (27.0 mg, 0.33 mmol), stirred for 3 days, precipitated from
reaction mixture; yield: 60mg(54%) ofwhite solid. Mp 155.5e158.4 ꢀC.
d
3.71 (s, 3H, NCH3); 3.92 (s, 3H, COOCH3); 3.93 (s, 3H, COOCH3); 6.63
(dd, 1H, J1¼1.8 Hz, J2¼3.0 Hz, pyrrole); 6.68e6.70 (m, 1H, pyrrole);
1H NMR (CDCl3, 500 MHz):
d 1.70 (9H, s, Boc); 3.97 (3H, s, COOCH3);
7.90 (s, 1H, pyridine); 8.44 (t, 1H, J1¼1.8 Hz, pyrrole); 8.54 (s, 1H,
3.98 (3H, s, COOCH3); 7.38 (1H, td, J1¼1.0 Hz, J2¼8.0 Hz, indole); 7.43
(1H, td, J1¼1.0 Hz, J2¼8.5 Hz, indole); 7.82 (1H, d, J¼7.8 Hz, indole); 8.27
(1H, s, pyridine), 8.34 (1H, d, J¼8.2 Hz, indole); 8.61 (1H, s, pyridine);
pyridine). 13C NMR (75.5 MHz, CDCl3):
d 36.6, 53.0, 53.1, 108.1, 113.9,
122.5, 123.1, 123.7, 127.5, 128.1, 140.9, 146.7, 164.3, 165.7. (C14H14N2O5
requires: C, 57.93; H, 4.86; N, 9.65. Found C, 57.78; H, 4.86; N, 9.61);
ESI-HRMS: m/z¼291.0983 (MHþ); C14H15N2O5 requires: m/
z¼291.0981 (MHþ); nmax IR (KBr) 3555, 3493, 3415, 3235, 3105, 2961,
2362, 2342,1740,1719,1608,1539,1473,1442,1372,1303,1280,1216,
9.05 (1H, s, indole). 13C NMR (CDCl3,126 MHz):
d 28.3, 53.5, 53.6, 85.2,
109.9, 116.1, 119.8, 124.0, 125.4, 125.7, 126.6, 127.2, 127.6, 131.1, 135.5,
140.7,145.6,149.2,164.4,165.1. (C22H22N2O7 requires: C, 61.97; H, 5.20;
N, 6.57. Found C, 62.23; H, 5.16; N, 6.58); ESI-HRMS: m/z¼427.1489
(MHþ); C22H23N2O7 requires: m/z¼427.1500 (MHþ); nmax (KBr) 3071,
2957, 1743, 1732, 1612, 1533, 1454, 1399, 1344, 1310, 1296, 1242, 1147,
1172, 1133, 1069, 941 cmꢁ1
.
5.4.13. 2-(Furan-3-yl)-4,5-bis(methoxycarbonyl)pyridine 1-oxide
(5m). Prepared from (2E,3i)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-(furan-3-yl)-2-oxoethylidene)succinate (3m) (315 mg,
1.0 mmol) and NH2OHꢂHCl (104 mg, 1.5 mmol), stirred for 4 h,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallized
from ethyl acetate/petroleum ether; yield: 216 mg (78%) of grayish
1126, 1064, 1028, 960, 854, 835, 781, 762, 748 cmꢁ1
.
5.4.17. 4,5-Bis(methoxycarbonyl)-2-(thiazol-2-yl)pyridine 1-oxide
(5q). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(thiazol-2-yl)ethylidene)succinate (3q) (162 mg,
0.5 mmol) and NH2OHꢂHCl (52.0 mg, 0.75 mmol), stirred for 4 h,
chromatography (ethyl acetate/petroleum ether¼1:1); yield: 95 mg
(65%) of brown solid. Mp 148.8e156.0 ꢀC. 1H NMR (CDCl3,
solid. Mp 128.4e129.7 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.95 (3H, s,
COOCH3); 3.96 (3H, s, COOCH3); 6.64 (1H, dd, J1¼1.8 Hz, J2¼3.5 Hz,
furan); 7.65 (1H, dd, J1¼0.6 Hz, J2¼1.8 Hz, furan); 8.07 (1H, dd,
J1¼0.6 Hz, J2¼3.5 Hz, furan), 8.25 (1H, s, pyridine); 8.52 (1H, s,
300 MHz):
J¼3.1 Hz, thiazole); 8.18 (1H, d, J¼3.1 Hz, thiazole); 8.61 (1H, s,
pyridine), 8.97 (1H, s, pyridine). 13C NMR (CDCl3, 75.5 MHz):
53.5,
d 3.97 (3H, s, COOCH3); 3.98 (3H, s, COOCH3); 7.67 (1H, d,
pyridine). 13C NMR (CDCl3, 75.5 MHz):
d
53.3, 53.4, 113.0, 118.4,
d
122.5, 126.6, 127.0, 140.7, 141.5, 144.3, 145.3, 164.1, 165.0. (C13H11NO6
requires: C, 56.32; H, 4.00; N, 5.05. Found C, 56.35; H, 3.84; N, 4.99);
ESI-HRMS: m/z¼278.0663 (MHþ); C13H12NO6 requires: m/
z¼278.0665 (MHþ); nmax (KBr) 3126, 2953, 1722, 1613, 1536, 1502,
1458, 1435, 1388, 1308, 1291, 1267, 1242, 1192, 1158, 1131, 1083, 998,
53.7, 124.2, 124.8, 127.8, 128.7, 139.6, 143.6, 144.2, 153.9, 164.0, 164.6.
(C12H10N2O5S requires: C, 48.98; H, 3.43; N, 9.52. Found C, 49.04; H,
3.46; N, 9.44); ESI-HRMS: m/z¼295.0385 (MHþ); C12H11N2O5S re-
quires: m/z¼295.0389 (MHþ); nmax (KBr) 2708, 1719, 1618, 1535,
1506, 1465, 1431, 1395, 1315, 1281, 1233, 1193, 1130, 1080, 1059,
962, 935, 903, 892, 834, 805, 777, 769, 720, 670 cmꢁ1
.
1002, 960, 915, 881, 804, 774 cmꢁ1
.
5.4.14. 4,5-Bis(methoxycarbonyl)-2-(thiophen-3-yl)pyridine 1-oxide
(5n). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(thiophen-3-yl)ethylidene)succinate (3n) (79 mg,
0.24 mmol) and NH2OHꢂHCl (25.5 mg, 0.37 mmol), stirred for 4 h,
chromatography (ethyl acetate/petroleum ether¼1:1); yield: 57 mg
(81%) of red solid. Mp 121.5e123.5 ꢀC. 1H NMR (CDCl3, 300 MHz):
5.4.18. 4,5-Bis(methoxycarbonyl)-[2,20-bipyridine] 1-oxide
(5r). Prepared from (2E,3E)-dimethyl 2-((dimethylamino)methy-
lene)-3-(2-oxo-2-(pyridin-2-yl)ethylidene)succinate (3r) (126 mg,
0.4 mmol) and NH2OHꢂHCl (42 mg, 0.6 mmol), stirred for 3 h,
chromatography (ethyl acetate/petroleum ether¼1:1); yield: 64 mg
(56%) of brown oil. 1H NMR (CDCl3, 300 MHz):
d 3.95 (3H, s,
d
3.95 (3H, s, COOCH3); 3.96 (3H, s, COOCH3); 7.43 (1H, dd,
COOCH3); 3.97 (3H, s, COOCH3); 7.40 (1H, ddd, J1¼0.9 Hz, J2¼4.8 Hz,
J3¼7.5 Hz, Py); 7.85 (1H, td, J1¼1.8 Hz, J2¼7.9 Hz, Py); 8.51 (1H, s,
pyridine); 8.70 (1H, s, pyridine); 8.76 (1H, d, J¼4.7 Hz, Py); 8.94 (1H,
J1¼3.1 Hz, J2¼5.2 Hz, thiophene); 7.65 (1H, dd, J1¼1.3 Hz, J2¼5.2 Hz,
thiophene); 8.06 (1H, s, pyridine), 8.54 (1H, s, pyridine); 8.99 (1H,
dd, J1¼1.3 Hz, J2¼3.1 Hz, thiophene). 13C NMR (CDCl3, 75.5 MHz):
d, J¼8.1 Hz, pyridine). 13C NMR (CDCl3, 75.5 MHz):
d 53.2, 53.5,
d
53.3, 53.5, 125.5, 125.8, 126.7, 127.0, 127.5, 130.5, 131.1, 141.2, 145.7,
125.2, 125.5, 126.5, 128.3, 129.9, 136.7, 141.0, 148.1, 148.6, 149.8,
164.3, 164.6. ESI-HRMS: m/z¼289.0814 (MHþ); C14H13N2O5 re-
quires: m/z¼289.0824 (MHþ); nmax (KBr) 3127, 3047, 3002, 2955,
1731, 1615, 1584, 1458, 1430, 1308, 1269, 1225, 1130, 1099, 1080,
164.2, 164.9. (C13H11NO5S requires: C, 53.24; H, 3.78; N, 4.78. Found
C, 53.25; H, 3.82; N, 4.73); ESI-HRMS: m/z¼294.0429 (MHþ);
C13H12NO5S requires: m/z¼294.0436 (MHþ); nmax (KBr) 3122, 3097,
2950, 1721, 1612, 1525, 1437, 1384, 1309, 1239, 1208, 1184, 1134,
1011, 989, 956, 905, 874, 795, 781, 742, 714, 664 cmꢁ1
.
1070, 1012, 966, 910, 872, 813, 803, 775, 726, 699, 666 cmꢁ1
.
5.4.19. 4,5-Bis(methoxycarbonyl)-2-(pyrazin-2-yl)pyridine 1-oxide
(5s). Prepared from (2E,3E)-dimethyl 2-[(dimethylamino)methy-
lene]-3-[2-oxo-2-(pyrazin-2-yl)ethylidene]succinate (3s) (462 mg,
1.5 mmol) and NH2OHꢂHCl (156 mg, 2.25 mmol), stirred for 24 h,
chromatography (ethyl acetate), crystallized from ethyl acetate;
yield: 322 mg (74%) of white-yellow solid. Mp 130.8e132.6 ꢀC. 1H
5.4.15. 2-(2,5-Dimethylthiophen-3-yl)-4,5-bis(methoxycarbonyl)pyr-
idine 1-oxide (5o). Prepared from (2E,3E)-dimethyl 2-((dimethyla-
mino)methylene)-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethylid-
ene)succinate (3o) (521 mg, 1.45 mmol) and NH2OHꢂHCl
(152.0 mg, 2.18 mmol), stirred for 2 h, chromatography (ethyl ac-
etate/petroleum ether¼1:1); yield: 434 mg (93%) of yellow oil. 1H
NMR (300 MHz, CDCl3):
d 3.96 (s, 3H, COOCH3); 3.99 (s, 3H,
NMR (CDCl3, 500 MHz):
d
2.41 (3H, s, CH3); 2.44 (3H, s, CH3); 3.93
COOCH3); 8.52 (s, 1H, pyridine); 8.70 (d, 2H, J1¼0.9 Hz, pyrazine);
(3H, s, COOCH3); 3.97 (3H, s, COOCH3); 6.88 (1H, d, J¼1.0 Hz, thio-
8.74 (dd, 1H, J1¼1.5 Hz, J2¼2.4 Hz, pyrazine); 10.19 (s, 1H, pyridine).
phene); 7.70 (1H, s, pyridine), 8.51 (1H, s, pyridine). 13C NMR (CDCl3,
13C NMR (75.5 MHz, CDCl3):
d 53.3, 53.6, 126.4, 128.2, 130.8, 140.8,
126 MHz):
d
14.9, 15.3, 53.3, 53.6, 125.7, 126.1, 127.5, 129.3, 136.9,
144.2, 144.3, 145.8, 146.3, 146.7, 164.0, 164.2. (C13H11N3O5 requires:

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J. Bezensek et al. / Tetrahedron 68 (2012) 4719e4731
4730
C, 53.98; H, 3.83; N, 14.53. Found C, 53.83; H, 3.78; N, 14.45);
ESI-HRMS: m/z¼290.0785 (MHþ); C13H12N3O5 requires: m/
z¼290.0777 (MHþ); nmax IR (KBr) 3545, 3116, 2950, 2366,1739,1717,
hydrogen atoms using SHELXL-97 was employed.28 All H atoms
were initially located in difference Fourier maps. Methyl H atoms
were subsequently treated as riding atoms in geometrically ideal-
ized positions with bond lengths CeH 0.96 A and Uiso(H)¼
1610, 1488, 1458, 1384, 1314, 1288, 1249, 1202, 1143, 1096, 971 cmꢁ1
.
ꢁ
1.5Ueq(C). Rotations of the methyl groups were allowed whereas
their tilting was not permitted. The coordinates and Uiso’s of other
non-methyl hydrogen atoms were refined independently.
Figures depicting the structures were prepared by ORTEP3.29
CCDC 859534e859542 contain the supplementary crystallo-
graphic data for structures 4hej,l,m, 5jek, 8b, and 9b, respectively.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
5.4.20. 6,60-(1,3-Phenylene)bis(3,4-bis(methoxycarbonyl)pyridine 1-
oxide) (10a). Prepared from (2E,20E,3E,30E)-tetramethyl 3,30-(1,3-
phenylenebis(2-oxoethan-2-yl-1-ylidene))bis(2-((dimethylamino)
methylene)succinate) (8a) (518 mg, 0.9 mmol) and NH2OHꢂHCl
(188 mg, 2.7 mmol), stirred for 2 h, precipitated from reaction
mixture; Crystallized from ethyl acetate/petroleum ether; yield:
337 mg (75%) of white solid. Mp 196.5e198.9 ꢀC. 1H NMR (CDCl3,
500 MHz): d 3.94 (6H, s, COOCH3); 3.98 (6H, s, COOCH3); 7.66 (1H, t,
J¼7.8 Hz, Ph); 7.90 (2H, s, pyridine), 7.97 (2H, d, J¼7.8 Hz, Ph); 8.31
(1H, s, Ph); 8.53 (2H, s, pyridine). 13C NMR (CDCl3, 1265 MHz):
Acknowledgements
d
53.4, 53.7, 126.6, 127.6, 128.9, 130.0, 130.2, 131.4, 131.5, 140.5, 150.0,
164.2, 164.4. (C24H20N2O10 requires: C, 58.07; H, 4.06; N, 5.64.
Found C, 58.13; H, 3.89; N, 5.58); ESI-HRMS: m/z¼497.1184 (MHþ);
C24H21N2O10 requires: m/z¼497.1196 (MHþ); nmax (KBr) 3039, 2955,
1734,1716,1636,1614,1536,1439,1396,1371,1310,1278,1239,1194,
Financial support from the Slovenian Research Agency through
grants P0-0502-0103, P1-0179, and J1-6689-0103-04 are gratefully
acknowledged. We also thank the Krka d.d. (Novo mesto, Slovenia)
and Lek d.d., a Sandoz Company (Ljubljana, Slovenia) for financial
support.
1140, 1077, 1031, 979, 960, 907, 859, 826, 802, 774, 725, 699 cmꢁ1
.
5.4.21. 6,60-(1,4-Phenylene)bis(3,4-bis(methoxycarbonyl)pyridine 1-
oxide) (10b). Prepared from (2E,20E,3E,30E)-tetramethyl 3,30-(1,4-
phenylenebis(2-oxoethan-2-yl-1-ylidene))bis(2-((dimethylamino)
methylene)succinate) (8b) (472 mg, 0.85 mmol) and NH2OHꢂHCl
(177 mg, 2.55 mmol), stirred for 2 h, precipitated from reaction
mixture; Crystallized from DMF/H2O; yield: 359 mg (85%) of yel-
References and notes
1. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4,
2337.
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Gulyas, B.; Brennum, L. T.; Fardec, L.; Wikstroma, H. V. Bioorg. Med. Chem. 2005,
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4. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature 2002, 1, 493.
lowish solid. Mp 242.8e245.7 ꢀC. 1H NMR (CDCl3, 500 MHz):
(6H, s, COOCH3); 3.99 (6H, s, COOCH3); 7.91 (2H, s, pyridine), 8.00
(4H, s, Ph); 8.53 (2H, s, pyridine). 13C NMR (CDCl3, 75.5 MHz):
53.5,
d 3.96
d
5. Quirk, J.; Thornton, M.; Kirkpatrick, P. Nature 2003, 2, 769.
53.7, 126.5, 127.6, 129.5, 130.1, 133.0, 140.7, 150.0, 164.2, 164.4.
(C24H20N2O10 requires: C, 58.07; H, 4.06; N, 5.64. Found C, 58.19; H,
4.17; N, 5.70); ESI-HRMS: m/z¼497.1176 (MHþ); C24H21N2O10 re-
quires: m/z¼497.1196 (MHþ); nmax (KBr) 3108, 3053, 1732, 1719,
1637, 1612, 1526, 1453, 1433, 1307, 1289, 1242, 1202, 1135, 1078, 962,
6. (a) Karwno, L. B. S.; Angerhofer, C. K.; Tsauri, S.; Padmarinata, K.; Pezzuto, J. M.;
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930, 884, 849, 807, 771, 710, 690 cmꢁ1
.
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16. Luzung, M. R.; Patel, J. S.; Yin, J. J. Org. Chem. 2010, 75, 8330.
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5.4.22. 6,60,600-(Benzene-1,3,5-triyl)tris(3,4-bis(methoxycarbonyl)
pyridine 1-oxide) (10c). Prepared from (2E,20E,200E,3E,30E,300E)-hex-
amethyl 3,30,300-(benzene-1,3,5-triyltris(2-oxoethan-2-yl-1-ylidene))
tris(2-((dimethylamino)methylene)succinate) (8c) (190 mg, 0.24
mmol) and NH2OHꢂHCl (75.0 mg, 1.1 mmol), stirred for 12 h, pre-
cipitated from reaction mixture; yield: 104 mg (61%) of brownish
solid. Mp 230.1e233.2 ꢀC. 1H NMR (CDCl3, 500 MHz):
COOCH3); 4.97 (9H, s, COOCH3); 7.96 (3H, s, pyridine), 8.47 (3H, s, Ph);
8.53 (3H, s, pyridine). 13C NMR (CDCl3, 126 MHz):
53.5, 53.8, 126.9,
d 3.95 (9H, s,
d
127.7, 130.4, 131.8, 132.1, 140.6, 149.1, 164.1, 164.3. (C33H27N3O15ꢂH2O
requires: C, 54.78; H, 4.04; N, 5.81. Found C, 54.88; H, 3.77; N, 5.76);
ESI-HRMS: m/z¼706.1508 (MHþ); C33H28N3O12 requires: m/
z¼706.1515 (MHþ);nmax (KBr) 1755,1720,1701,1623,1527,1468,1393,
1374, 3950, 1236, 1193, 1092, 1068, 1024, 901, 793, 769 cmꢁ1
.
5.5. X-ray structure analysis for compounds 4hej,l,m, 5jek,
8b, and 9b
For X-ray structure determination, the crystals of the afore-
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