α-(3-Pyridyl)malonates: preparation and synthetic applications

Article abstract of DOI:10.1016/j.tet.2007.09.026

Alkylation of aromatic rings is a major challenge in organic syntheses since more complex carbon skeletons can be constructed. The alkylation of pyridine by nucleophilic aromatic substitution of the nitro group in methyl 3-nitro-4-pyridylcarboxylate (1) w

Full text of DOI:10.1016/j.tet.2007.09.026

Tetrahedron 63 (2007) 11893–11901
a-(3-Pyridyl)malonates: preparation and synthetic applications
*
ꢀ
Freddy Tjosas, Nina Marie Pettersen and Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology NTNU, Sem Saelands vei 8, N-7491 Trondheim, Norway
Received 8 June 2007; revised 29 August 2007; accepted 13 September 2007
Available online 22 September 2007
Abstract—Alkylation of aromatic rings is a major challenge in organic syntheses since more complex carbon skeletons can be constructed.
The alkylation of pyridine by nucleophilic aromatic substitution of the nitro group in methyl 3-nitro-4-pyridylcarboxylate (1) with malonic
ester is reported. The versatility of the a-(3-pyridyl) malonic ester product (3) is demonstrated by the formation of a number of new 3-alkylated
pyridines and new fused bis-heterocycles. cis 2-Halomethyl-4-(3-pyridyl)tetrahydrofuran products were selectively prepared. Exact 1H and
13C NMR assignments of practically all products were obtained by a series of NMR experiments.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
nitration method,4 an investigation of the chemistry of nitro-
pyridines is now in progress in our laboratories.
As a general fact, aromatic substrates are very unreactive
towards nucleophilic substitution. However, substitution is
accelerated by electron-withdrawing groups ortho or para
to the leaving group. A nitrogen atom in the ring is also
activating. Surprisingly, the nitro group, which is not gener-
ally lost in aliphatic systems, is a particularly good leaving
group in nucleophilic aromatic substitutions.1,2
The formation of new C–C bonds is a major challenge in
organic syntheses since more complex carbon skeletons
can be constructed. Alkylation of aromatic rings is therefore
an important transformation. The classical malonate aryl-
ation is based on the a-arylation of malonic esters followed
by hydrolysis and decarboxylation. Activated aryl halides
like nitroaryl halides generally give good results. Corre-
spondingly, copper catalysed5 and palladium catalysed
a-arylation of malonic esters6 have been reported.
These effects and the synthetic potential for the replacement
of a nitropyridine group have been demonstrated by our
results for the nucleophilic aromatic substitution of the nitro
group in 3-nitro-4-carboxylate (1) since the pyridyl aromatic
system in combination with the anion stabilising carbonyl
group in ortho position makes the 3-nitro substituent
a good leaving group. We have previously obtained promis-
ing results from the nucleophilic aromatic substitution of the
nitro group in methyl 3-nitropyridyl carboxylate 1 by hetero-
atom nucleophiles, see below.3 Oxygen, nitrogen, sulfur and
fluoride nucleophiles were tested to yield the new products
2a–e.
Based on our experience with the useful leaving group abi-
lity of the nitro group in carboxylate 1, we have investigated
3-nitropyridyl carboxylate (1) as a potential substrate for
malonate arylation. The versatility of the a-(3-pyridyl)
malonic ester product (3) is hereby demonstrated by the
formation of new 3-alkylpyridines (5–10, 16), and new bis-
heterocycles (11a, 11b, 13, 14, 15). cis 2,4-(3-Pyridyl)tetra-
hydrofurano products (17a, 17b) were prepared from the
decarboxylated allyl bromide product 8. Our results are
discussed below.
CO2Me
NO2
CO2Me
R
2a R = N3
2b R = OMe
2c R = OPh
2d R = SPh
2e R = F
i), ii), iii) iv) or v)
2. Results and discussion
N
N
1
2
2.1. a-(3-Pyridyl) malonic esters
i) NaN3 ii) MeOH, NaH iii) PhOH, NaH iv) PhSH, NaH v) CsF, DMSO
We have succeeded in carrying out for the first time, the nu-
cleophilic aromatic substitution of the pyridine nitro group
in 3-nitropyridyl carboxylate (1) with a carbon nucleophile.
We thus obtained the methyl a-(3-pyridyl) malonic esters
(3a, see Scheme 1) in 55% yield by nucleophilic aromatic
substitution of 1 with dimethyl malonate and Cs2CO3. The
ethyl ester product (3b) was prepared (24%) by diethyl
malonate and NaH. The general experience was that a higher
Based on the fact that a number of substituted 3-nitro-
pyridines have been readily available through an improved
Keywords: Pyridylmalonate; Nitropyridines; 3-Alkylpyridine; Bis-hetero-
cycles; cis 2-Halomethyl-4-(3-pyridyl)tetrahydrofuran.
* Corresponding author. Tel.: +47 73594094; fax: +47 73594256; e-mail:
anne.fiksdahl@chem.ntnu.no
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.026

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F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
CO2Me
CO2Me
NO2
CO2Me
CO2Me
N
7'
N
1
MW
CH2(CO2Me)2
55 %
MeO2C
Cs2CO3, DMSO
CO2Me
CO2Me
CO2Me
MeO2C
CO2Me
- CO2
NaOMe
89 %
110 °C, 16 hrs,
MeO2C
CO2R
CO2R
CO2Me
NO2
or MW, 10 min
N
N
CO2Me
60 %
5
7
RO2C
+
N
N
CO2R
3a R = Me
3b R = Et
CO2Me
MeO2C
N
MeO2C
CO2Me
CO2Me
4a R = Me
4b R = Et
- CO2
Br
- CO2
MW
CsCl, DMSO
MW 6 min
55 %
Cs2CO3, THF
Pd(PPh3)4,PPh3
N
6
5 min
81 %
20 min
43 %
8
94 %
CO2Me
CO2Me
CH3
CO2Me
CO2Me
N
9
N
10
N
8'
Scheme 1.
yield of 3b would be expected by using Cs2CO3 as a base.
Additionally, the formation of minor amounts of the
6-substituted products 4a and 4b could be observed. These
products may be formed by oxidative nucleophilic substitu-
tion, a reaction that is well known for nitroarenes and
nucleophiles.7
a number of reactions.10 In this work, MW promoted decar-
boxylation reactions were successful and afforded higher
yields of 7 and 8 than conventional heating. For the conver-
sion of the tetraester 5 to the triester 7 (60%) the reaction
time was drastically reduced from 16 h to 10 min (360 W).
Correspondingly, the decarboxylation of 6 to 8 (55%) was
carried out in 6 min by MW irradiation (360 W). In contrast
to conventional heating, minor amounts of additional prod-
ucts were also isolated. Based on NMR and GC–MS, the
new by-products were supposed to be the di-decarboxylated
compounds 70 and 80, respectively. MW decarboxylation of
the malonic ester intermediate 3a similarly afforded homo-
chinchomeric acid dimethyl ester (9)11 in 81% yield in
5 min. Irradiation (90 W) of 3a for 10 min gave a mixture
of 9 (34%) and methyl 3-methyl-4-pyridylcarboxylate (10,
17%). However, the di-decarboxylated product 10 was the
single product after 20 min irradiation and was readily
isolated (43%). The decarboxylation products 9/10 were
never obtained by conventional heating.
2.2. 3-Alkylpyridines
3-Alkylpyridines are related to nicotinic acid (niacin) and
nicotinamide, the essential component in the pyridine
nucleotides, the NAD and NADP coenzymes. A series of
3-alkylated pyridine compounds have previously been stud-
ied for their pharmacological activity. We have used the
pyridylmalonate (3a) as a key intermediate for the prep-
aration of a series of new 3-alkylpyridines.
Alkylation of the malonic ester 3a by a Michael addition
with methyl acrylate afforded the tetraester intermediate 5
in 89% yield, while the allylproduct 6 was obtained in
94% yield by the Pd catalysed reaction with allyl bromide.
Similar allyl bromide reactions are known to afford con-
siderably lower yields without palladium catalysis.8 The
following decarboxylation of 5 and 6 gave the 3-pyridyl-
alkylated products 7 and 8. Depending on the temperature,
similar decarboxylation reactions have been reported to
give mono- or di-decarboxylated products, selectively.9 We
did not observe any formation of the di-decarboxylation
products 70 and 80 after 16 h heating at 110 ꢀC.
2.3. Bis-heterocycles
The pyridylmalonate (3a) and homochinchomeric acid
dimethyl ester (9) were key precursors for the preparation
of a number of new ring closure products (11a, 11b, 13,
14, 15, 17a, 17b), as shown in Schemes 2–5.
CO2Me
MeO2C
CO2Me
CO2Me
O
O
R
NaCl, DMSO
CO2Me RCOCl
Recent development in microwave-accelerated (MW) orga-
nic syntheses has shown that the method offers the great
advantage of enhanced reaction rates. The products are often
produced in increased yields and in higher purity by such re-
actions compared to conventional heating methods. We have
experienced that MW irradiation has been successful for
Δ
110 °C
81%
N
N
31-39%
N
3a
9
11a R = CH2Ph
11b R = Ph
One-pot: 24 - 31%
Scheme 2.

F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
11895
The preparation of the 2,6-naphthyridine derivative 15
includes the amination of the isocoumarine analogue (11b)
for the formation of 3-phenyl-2,6-naphthyridin-1(2H)-one
(14).23 We obtained the 2,6-naphthyridin-1(2H)-one (14)
in 43% yield from 11b and NH3 and prepared the
2,6-naphthyridine derivative (15) (49%) from 14 by POCl3
reaction.24 The chloro substituent may be removed by
hydrogenation or used in subsequent transformations such
as amination or palladium catalysed cross-coupling re-
actions. 1-Halo-2,6-naphthyridines forms a-adducts at C-1
with KNH2/NH3 and the method has been used for the prep-
aration of 1-amino-2,6-naphthyridines.25 The reaction repre-
sents an alternative to Chichibabin amination to prepare
1-amino derivatives.21 1-Halo-2,6-naphthyridines can now
readily be prepared by the present procedure via pyridylmal-
onate (3a). Non-substituted 2,6-naphthyridin-1(2H)-one has
previously been prepared by cyclisation of 4-pyridylnitrile
derivatives21 or by palladium catalysed cross-coupling
reactions.26
O
O
Ph
Ph
O
O
Ph
O
HO2C
hydrolysis
NaBH4
20%
N
N
N
11b
12
13
Scheme 3.
Cl
O
O
POCl3
N
NH3
O
NH
N
N
N
Ph
Ph
Ph
11b
Scheme 4.
15
14
An one-pot preparation of the vinylic d-lactone products
11a/11b by direct condensation of pyridylmalonate (3a)
with benzoyl and phenylacetyl chloride and subsequent cyc-
lisation afforded 3-benzyl- and 3-phenyl-pyrano[4,3-c]pyri-
din-1-one (11a, 11b, see Scheme 2) in 24 and 31% yields,
respectively. A step-wise procedure was also successful,
giving corresponding total yields (25, 32%) but also easier
work-up and product isolation compared to the direct
condensation of 9 with acyl chloride. The step-wise yields
are given in Scheme 2. A similar strategy has been applied,
using homophthalic acid, for the preparation of natural
products and compounds with biological activity.12–17 The
3-substituted pyrano[4,3-c]pyridin-1-ones (11a, 11b) are
N-heterocyclic isocoumarin analogues. Similar products
have previously been prepared from halopyridines by palla-
dium-catalysed cross-coupling reactions.18,19
2.4. Pyridyltetrahydrofurans
Tetrahydrofurans are in general used as intermediates in syn-
thesis of biologically active compounds and the ring system
is found in many naturally occuring compounds. Being
nicotine-related compounds, the 3-alkylpyridyl systems are
of special interest. 5-(3-Pyridyl)tetrahydrofuran-2-yl ana-
logues have been studied as drug candidates and as modula-
tors of smoking or nicotine ingestion and lung cancer.33
2-(Aminomethyl)-5-(2-pyridyl)tetrahydrofurans have been
patented for treating of central nervous system disorders,34
while 2-(aminomethyl)-4-phenyltetrahydrofurans are used
in the preparation of agrochemical fungicides35 and have
been studied as potential antidepressants.36
An one-pot alkaline hydrolysis, hydride reduction and
cyclodehydration of 11b gave the saturated d-lactone, 3,4-
dihydro-1H-pyrano[4,3-c]pyridin-1-one (13, 20%). The
reaction proceeds through the 3-(2-oxo-2-phenylethyl)-4-
pyridinecarboxylic acid (12) intermediate and the reduction
product of 12, which underwent spontaneous cyclisation to
13 (Scheme 3).15,20
The decarboxylated allyl bromide product 8 was used as
substrate for the preparation of the tetrahydrofuran ring
closure products 17a and 17b, as shown in Scheme 5.
Hydride reduction of 8 afforded the diol 16 (51%). Com-
pound 16 is a g-hydroxyolefin and underwent NBS bromo-
etherification to give the brominated 5-ring cyclic ether
product (17a) in 40% yield. This bromoetherification
method has previously been used for the preparation of small
and medium-sized cyclic bromomethyl ethers.27 Due to the
presence of two primary alcohol groups in substrate 17, the-
oretically, either the 5-ring (17a) or the 7-ring product (170a)
Several multi-step syntheses of 2,6-naphthyridine (15) have
been described.11,21,22 Based on our simple three-step synthe-
sis of homochinchomeric acid (9) from methyl 4-pyridinecar-
boxylate,3,4 a new procedure is proposed for the preparation of
2,6-naphthyridine derivative (15, see Scheme 4).
CH2X
CH2R
O
HOCH2
N
Reactions of γ -OH olefin:
*
*
O
CH2OH
NBS
HOCH2 CH2OH
MeO2C
CO2Me
N
bromoetherification
17'a,b
17a X = Br
17b X = I
LiAlH4
iodoetherification
N
N
I2
16
HOCH2
8
hydroalkoxylation
O
N
18
Scheme 5.

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F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
could be formed. Neither of the products (17a, 170a) could
NOESY NMR studies of 17b were also in exact agreement
with the data for 17a discussed above.
1
be excluded from the H and 13C NMR spectra, but HSQC
and HMBC experiments showed that the most favourable
5-ring ether product 17a was formed. A displacement of
the halide in 17a with alkylamine would give the cor-
responding 2-(aminomethyl)-5-(2-pyridyl)tetrahydrofuran,
a well known structural moiety in pharmaceuticals.34–36
Consequently, all the identical NOESY interactions for 17a
and 17b indicate that both the tetrahydrofuran rings are
formed by cis ring closure and that the cyclisations for the
formation of products 17a and 17b are proceeding through
similar reaction mechanisms and intermediates. The tetra-
hydrofuran moiety may be prepared via the bromonium/
iodonium ion intermediate followed by an exo-tet ring
closure. The direct exo-trig alcohol intramolecular attack
on the double bond by addition of the halide electrophile
would represent an alternative mechanism. Radical photo-
chemical mechanisms are reported as well.30 2,4-Disubsti-
tuted tetrahydrofurans have been reported to be formed by
cyclisation reactions as 5:1 mixtures of cis/trans iodo- and
bromomethyl diastereomers.31 Computational and experi-
mental studies have shown that 5-exo-trig cyclisations of
sterically hindered 4-penten-1-oxyl radicals form diastere-
meric mixtures, but cis 2,4-disubstituted tetrahydrofurans
are the major products.32 To the best of our knowledge, there
are no reports on diastereospecific formation of single cis
2,4-disubstituted tetrahydrofurans.
A second chiral centre is formed by the tetrahydrofuran ring
closure. Only one single diastereomer was formed, as shown
by NMR. The ring configuration was studied by NOESY
NMR experiments. The observed strong interactions be-
tween the tetrahydrofuran protons H-2 and H-4, Ha-3 and
H-2, Ha-3 and H-4 indicated that a cis ring closure had taken
place (see Fig. 1). Additional confirmation of the cis ring
configuration is based on a series of observed NOESY inter-
actions between H-4/Ha-5, Hb-3/Hb-5, Hb-3/CH2Br and
Hb-5/CH2Br. cis H-2/H-4 was stronger than the Hb-3/Hb-5
NOESY interaction, indicating a closer proximity between
H-2 and H-4 (‘axial’) than Hb-3 and Hb-5 (‘semi-axial’) in
the five-membered ring. As a consequence, the cis Ha-3
and Ha-5 would be ‘equatorial’ and thus explain the
absence of a NOESY interaction between them. The cis con-
figuration was also supported by the absence of any NOESY
interaction between H-4 and CH2Br. A trans ring configura-
tion may have been demonstrated by a possible NOESY in-
teraction between H-4 and the protons of the bromomethyl
substituent in the 2-position. Interactions between the py-
CH2OH group and H-4 as well as pyridine-H-2 and Hb-3
and Hb-5, respectively, indicate the conformation shown
below.
The observed selective cis ring closures would proceed
through cis intermediates to give the single cis products, hav-
ing both large groups (pyridyl and CH2X) at the same side of
the new tetrahydrofuran ring. This cis configuration would
be favoured, since the least steric hindrance can be obtained
by a di-equatorial arrangement of the two large groups to
avoid unfavourable 1,3-diaxial interactions. The fact that
the formation of only cis tetrahydrofuran rings takes place
in our case, may be due to the additional directing effect
and the stabilisation affected by the pyridine nitrogen atom
on the bromination/iodination agents or bromonium/
iodonium intermediates. Such stabilisation would only be
enabled by cis intermediates and cis ring closures to give
the cis product.
It is well known that g-hydroxyolefins can undergo hydro-
alkoxylation by I2 catalysis.28 However, for non-sterically
hindered double-bonds using stoichiometric amounts of
iodine, the competing reaction would be iodoetherification.
The two alternative products for substrate 16 would there-
fore be the 2-methyltetrahydrofuran product 18 or the iodo-
methyl product 17b. The outcome of the reaction was that no
hydroalkoxylation had taken place, explained by the lack of
steric hindrance of the substrate double-bond. Thus the iodo-
substituted product 17b (24%) was isolated and the 7-ring
product (170b) was not observed. Hydroalkoxylation may
also be carried out with Pt catalysis.29 However, no 2-methyl-
tetrahydrofuran product (18) was obtained by this method
either. Except for the predicted effects of the iodine, in par-
ticular the characteristic low 13C NMR frequency of the
CH2I carbon (d 9.4), all NMR data (1H, 13C NMR, HSQC,
HMBC) of the iodoproduct 17b were in accordance with
the corresponding data for the bromoproduct 17a. Detailed
3. Conclusion
Our results demonstrate that the nitropyridine/a-pyridyl-
malonate pathway may represent a convenient strategy
both for the preparation of 3-alkylated pyridines and for
the synthesis of more complex carbon skeletons, such as
fused bis-heterocycles.
a-(3-Pyridyl)malonic esters (3a,b) have been prepared by
nucleophilic aromatic substitution of the nitro group in
methyl 3-nitro-4-pyridylcarboxylate (1) by malonate. The
versatility of the a-pyridylmalonate product (3) has been
demonstrated by the simple transformations of 3a into a
series of new 3-alkylpyridines (5–10, 16). Furthermore, new
bis-heterocycles such as the N-heterocyclic isocoumarin
analogue 3-substituted-pyrano[4,3-c]pyridin-1-one (11a, 11b),
the d-lactone 3,4-dihydro-1H-pyrano[4,3-c]pyridin-1-one
(13), the 2,6-naphthyridin-1(2H)-one (14) and the 2,6-
naphthyridine derivative (15) were readily prepared from
a-pyridylmalonate (3a) in few steps by subsequent intra-
molecular reactions. cis 2-Halomethyl-4-(3-pyridyl)tetra-
hydrofurano products 17a and 17b were selectively
prepared from the decarboxylated allyl bromide product 8.
H2
HO
CH2
H4
Ha
Ha
Br / I
H3b
H
H
O
H
5
Hb
H
N
17a-b
Figure 1.

F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
11897
NMR experiments (DEPT, COSY, HMBC, APT, HSQC,
NOESY) were used for structure identification and H and
preparation of 3a from 1 and dimethyl malonate. However,
Cs2CO3 was replaced by NaH. As for 3a/4a, flash chromato-
graphy (Et2O) afforded two products, the 3-substituted (3b)
and the 6-substituted (4b). Compound 3b was obtained as
1
13C NMR assignments of practically all products.
1
Bioassay screening of the products are in progress.
a crystalline product (220 mg, 24%), pure by H and 13C
NMR. Rf 0.35 (Et2O); mp 64–65 ꢀC; IR nmax: 3019 (m),
1
2960 (w), 1732 (s), 1282 (w), 1216 (s), 758 (s) cmꢁ1; H
4. Experimental
4.1. General
NMR (400 MHz, CDCl3): dH 1.29 (6H, t, J 7.1 Hz, CH3),
3.92 (3H, s, OCH3), 4.27 (2H, q, J 7.1 Hz, CHBH), 4.26
(2H, q, J 7.1 Hz, CHAH), 5.52 (1H, s, CH), 7.80 (1H, dd, J
5.0, 0.5 Hz, H-5), 8.71 (1H, s, H-2), 8.72 (1H, d, J 5.0 Hz,
H-6); 13C NMR (100 MHz, CDCl3): dC 14.1, 52.8, 53.5,
62.1, 123.5, 128.4, 136.7, 150.0, 151.8, 166.0, 167.6; MS:
m/z 295 (M+, 2%), 263 (11), 249 (96), 235 (10), 221 (61),
218 (41), 204 (46), 189 (51), 177 (20), 163 (26), 149 (69),
134 (100), 120 (14), 106 (53), 92 (13); HRMS: calcd for
C14H17NO6: 295.1056; obsd 295.1055.
Chemicals: Cs2CO3 (99.9%), NaH (95%), POCl3 (99%),
LiAlH4 (95%), methyl isonicotinate (98%) (Aldrich); meth-
yl acrylate, Pd(PPh3)4, phenylacetylchloride, benzoylchlor-
ide, NaBH4 (Fluka); allyl bromide (99%), acetic anhydride
(99%) (Acros); diethyl malonate (99%) (Acros); PPh3,
NaCl (p.a.), CsCl (p.a.), NBS (Merck); NH3 (25% in water,
VWR), I2 (Acf chemiefarma); NaS2O3 (p.a., KeboLab);
dimethyl malonate (97%, Janssen Chimica). Solvents: DMSO,
4.1.3. 2-(4-Methoxycarbonyl-3-nitro-6-pyridyl)-pro-
panedioic acid dimethyl ester (4a). Minor amounts of the
title compound, pure by NMR, were isolated by flash chro-
matography (Et2O) from the crude product mixture of 4a
Et2O, THF, EtOAc, CH2Cl2, pentane, (p.a. VWR). H/13C
1
NMR: Bruker Avance DPX 300 and 400 MHz spectrome-
ters, chemical shifts are reported in parts per million down-
field from TMS. J values are given in hertz. MS: Finnigan
MAT 95 XL (EI/70 eV). IR: Nicolet 20SXC FT-IR spectro-
photometer. All melting points are uncorrected, measured on
a Griffin apparatus. Flash chromatography: Silica (SDS,
1
and 3a described above (186 mg, 18%). Rf 0.2 (Et2O); H
NMR (400 MHz, CDCl3): dH 3.82 (6H, s, OCH3), 3.99
(3H, s, OCH3), 5.10 (1H, s, CH), 7.85 (1H, s, H-5), 9.16
(1H, s, H-2); 13C NMR (100 MHz, CDCl3): dC 53.4 (malo-
nate-OCH3), 53.8 (py-ester-OCH3), 59.6 (malonate-CH),
123.3 (C-5), 135.7 (C-4), 142.3 (C-3), 144.7 (C-2), 158.2
(C-6), 163.7 (py-C]O), 166.4 (malonate-C]O); NMR as-
signments are based on COSY, HMBC and HSQC experi-
ments; MS: m/z 312 (M+, 7%), 307 (17), 280 (40), 269
(65), 254 (67), 222 (52), 209 (55), 181 (60); HRMS: calcd
for C12H12N2O8: 312.0504; obsd 312.0601.
˚
60 A, 40–63 mm). Microwave irradiation was performed in
a household microwave oven (Elram M8017NP-CF), modi-
fied with a reflux condenser, at ‘Low’ (90 W) or ‘Medium’
(360) power of max 800 W output. Methyl 3-nitro-4-pyridi-
necarboxylate (1) was prepared from methyl 4-pyridine-
carboxylate by nitration according to the literature.4
4.1.1. 2-(4-Methoxycarbonyl-3-pyridyl)-propanedioic
acid dimethyl ester (3a). A solution of 1 (600 mg,
3.3 mmol), in DMSO (25 mL) was added drop-wise to
a stirred solution of Cs2CO3 (1.21 g, 3.7 mmol, 1.1 equiv)
and diethyl malonate (0.60 mL, 5.25 mmol, 1.6 equiv) in
DMSO (15 mL) under nitrogen atmosphere during 30 min
at 150 ꢀC. After additional stirring at 150 ꢀC a saturated
solution of NH4Cl (100 mL) was added and the product
was extracted by diethyl ether. Flash chromatography
(Et2O) afforded two products, the 3-substituted (3a) and
the 6-substituted (4a). Compound 3a: 484 mg, 55%; Rf
0.35 (Et2O); mp 78.2–78.5 ꢀC; IR (film) nmax: 3019 (m),
1735 (m), 1437 (w), 1282 (w), 1215 (s), 1221 (s), 1092
4.1.4. 2-(4-Methoxycarbonyl-3-nitro-6-pyridyl)-pro-
panedioic acid diethyl ester (4b). Minor amounts of 4b
were isolated by flash chromatography (Et2O) from the
crude product mixture of 4b and 3b described above
(67 mg, 7.5%). Rf 0.2 (Et2O); 1H NMR (400 MHz,
CDCl3): dH 1.29 (6H, t, J 7.1 Hz, CH3), 3.99 (3H, s,
OCH3), 4.27 (2H, q, J 7.1 Hz, CHHB), 4.26 (2H, q, J
7.1 Hz, CHAH), 5.07 (1H, s, CH), 7.87 (1H, s, H-5), 9.16
(1H, s, H-2); 13C NMR (100 MHz, CDCl3): dC 14.0, 53.8,
60.2, 62.7, 123.5, 135.8, 142.3, 144.7, 158.6, 163.9, 166.1.
4.1.5. Trimethyl 1-(4-(methoxycarbonyl)pyridin-3-yl)-
propane-1,1,3-tricarboxylate (5). A solution of 3a
1
(m) cmꢁ1; H NMR (400 MHz, CDCl3): dH 3.80 (6H, s,
OCH3), 3.93 (3H, s, OCH3), 5.56 (1H, s, malonate-CH),
7.80 (1H, d, J 4.9 Hz, H-5), 8.69 (1H, s, H-2), 8.73 (1H, d,
J 4.9 Hz, H-6); 13C NMR (100 MHz, CDCl3): dC 52.8 (py-
ester-OCH3), 53.0 (malonate-CH), 53.1 (malonate-OCH3),
123.5 (C-5), 128.2 (C-4), 136.6 (C-3), 150.2 (C-6), 151.9
(C-2), 166.0 (py-C]O), 168.0 (malonate-C]O); NMR
assignments are based on DEPT, HMBC and HSQC experi-
ments; MS: m/z 267 (M+, 6%), 235 (100), 207(79), 204 (89),
180 (41), 164 (55), 150 (21), 134 (39), 106 (12); HRMS:
calcd for C12H13NO6: 267.0743; obsd 267.0699. Anal.
Calcd for C12H13NO6: C, 53.93; H, 4.90; N, 5.24. Found:
C, 53.73; H, 4.94; N, 5.26.
(52 mg, 0.2 mmol), methyl acrylate (51 mL, 0.57 mmol)
and NaOMe (0.15 M, 13 mL, 0.02 mmol) in MeOH
(2 mL) was stirred at room temperature for 68 h. Flash chro-
matography (Et2O) afforded an oily product (61 mg, 89%),
pure by H and 13C NMR. Rf 0.25 (Et2O); IR (film) nmax
1
:
3003 (w), 2955 (m), 1735 (s), 1588 (w), 1436 (s), 1363
1
(w), 1283 (s), 1218 (m), 1174 (m), 1106 (m) cmꢁ1; H
NMR (400 MHz, CDCl3): dH 2.37 (2H, t, J 8.0 Hz, propyl
3-CH2), 2.79 (2H, t, J 8.0 Hz, propyl 2-CH2), 3.53 (3H, s,
terminal ester OCH3), 3.69 (6H, s, malonate esters OCH3),
3.81 (3H, s, py-ester OCH3), 7.65 (1H, d, J 5.0 Hz, H-5),
8.37 (1H, s, H-2), 8.62 (1H, d, J 5.0 Hz, H-6); 13C NMR
(100 MHz, CDCl3): dC 30.3 (C-2, CH2), 30.5 (C-3, CH2),
51.7 (terminal ester OCH3), 52.8 (py-ester OCH3), 53.2
(malonate esters OCH3), 61.3 (C-1, quart. C), 123.9 (C-5),
131.4 (C-3), 138.4 (C-4), 149.8 (C-6), 150.3 (C-2), 166.9
4.1.2. 2-(4-Methoxycarbonyl-3-pyridyl)-propanedioic
acid diethyl ester (3b). The title product was prepared
from 1 and diethyl malonate as described above for the

11898
F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
(py-ester C]O), 169.8 (malonate ester C]O), 172.9 (ter-
minal ester C]O); NMR assignments are based on DEPT,
COSY, HMBC, APT and HSQC experiments; MS (CI):
m/z 354 (M+1, 77%), 322 (45), 267 (37), 236 (100), 230
(40), 202 (28); MS (EI) m/z 353 (M+, 2%), 322 (78), 294
(53), 267 (86), 262 (38), 236 (100), 235 (92), 202 (88),
174 (62), 162 (74); HRMS: calcd for C16H19NO8:
353.1111; obsd 353.1107.
C]O); NMR assignments are based on DEPT, COSY,
HMBC, APT and HSQC experiments; MS: m/z 295 (M+,
2%), 263 (75), 235 (31), 217 (21), 203 (15), 190 (31), 176
(22), 162 (44), 160 (23), 150 (31), 144 (37), 134 (20), 111
(26), 99 (19); HRMS: calcd for C14H17NO6: 295.1056;
obsd 295.1058.
4.1.8. Methyl 3-(4-methoxy-4-oxobutyl)isonicotinate (70).
Minor amounts of 70 (3–5%) were isolated by flash chroma-
tography (Et2O/n-pentane 4:1) from a mixture with 7, pure
4.1.6. 1-(4-Methoxycarboxyl-3-pyridyl)-1,1-di(methoxy-
solution of 3a (1.34 g,
1
carbonyl)-3-butene (6).
A
by NMR; H NMR (400 MHz, CDCl3): dH 1.95 (2H, t, J
5.02 mmol, 1 equiv) and Cs2CO3 (1.96 g, 6.93 mmol,
1.2 equiv) in dry THF (20 mL) was stirred for 15 min under
nitrogen atmosphere. Allyl bromide (0.60 mL, 6.0 mmol,
1.4 equiv), Pd(PPh3)4 (0.28 g, 0.25 mmol, 0.05 equiv) and
PPh3 (0.12 g, 0.61 mmol, 0.1 equiv) in dry THF (20 mL)
was stirred for 15 min. The allyl bromide solution was trans-
ferred to the malonate solution by syringe in an inert pres-
sure system and the reaction was stirred for 1 h at room
temperature before a saturated solution of NH4Cl (30 mL)
was added. The product was extracted by ethyl acetate. Flash
chromatography (Et2O) afforded an oily product (1.45 g,
7.6 Hz, CH2-20), 2.39 (2H, t, J 7.6 Hz, CH2-30), 2.99 (2H,
t, J 7.6 Hz, CH2-10), 3.67 (3H, s, terminal ester OCH3),
3.93 (3H, s, py-ester-OCH3), 7.67 (1H, d, J 5.2 Hz, py-
H-5), 8.58 (1H, J 5.2 Hz, py-H-6), 8.58 (1H, s, py-H-2).
4.1.9. 2-(4-Methoxycarboxyl-3-pyridyl)-4-pentenoic acid
methyl ester (8). The title product was preferentially pre-
pared by MW irradiation. A solution of 6 (860 mg,
2.80 mmol), CsCl (1.42 g, 8.4 mmol, 3 equiv) in water
(0.6 mL, 12 equiv) and DMSO (25 mL) was irradiated at
‘medium’ power (360 W) for 6 min. The solution was
cooled, added water (30 mL) and extracted with ethyl ace-
tate (3ꢂ30 mL). An oily product was obtained (382 mg,
1
94%), pure by H and 13C NMR. Rf 0.4 (Et2O); IR (film)
nmax: 3004 (w), 2954 (s), 1735 (s), 1638 (w), 1588 (w),
1435 (s), 1284 (s), 1215 (s), 1105 (m), 963 (m), 928 (m),
1
55%), pure by H and 13C NMR; IR (film) nmax: 3019 (s),
1
858 (m) cmꢁ1; H NMR (400 MHz, CDCl3): dH 8.66 (1H,
2954 (m), 1732 (s), 1642 (w), 1436 (m), 1412 (w), 1280
(s), 1215 (s), 1170 (m), 1103 (m), 924 (m) cmꢁ1; 1H NMR
(400 MHz, CDCl3): dH 8.69 (1H, s, py-H-2), 8.63 (1H, d, J
5.2 Hz, py-H-6), 7.69 (1H, dd, J 5.2, 1.3 Hz, py-H-5), 5.7
(1H, m, H-4, –CH]), 5.05 (2H, m, H-5, terminal ]CH2),
4.54 (1H, t, J 7.4 Hz, H-2), 3.87 (3H, s, py-ester OCH3),
3.74 (3H, s, ‘malonate’ OCH3), 2.96 (1H, m, H-3, –CH2–),
2.60 (1H, m, H-3, –CH2–); 13C NMR (100 MHz, CDCl3):
dC 36.4 (CH2), 45.2 (methin CH), 51.3 (‘malonate ester’
OCH3), 52.2 (pyridyl ester OCH3), 117.2 (terminal
]CH2), 122.8 (py-C-5), 133.0 (py-C-3), 134.2 (penten-
C-4; –CH]), 136.2 (py-C-4), 148.4 (py-C-6), 150.9 (py-
C-2), 165.9 (py-ester C]O), 172.4 (‘malonate’ ester
C]O); NMR assignments are based on COSY, HMBC
and APT experiments; MS: m/z 249 (M+, 7%), 248 (29),
247 (63), 216 (89), 189 (66), 188 (95), 156 (100), 144
(34), 130 (97), 128 (42) 103 (30). Anal. Calcd for
C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.44;
H, 6.13; N, 5.65.
d, J 5.0 Hz, H-6), 8.50 (1H, s, H-2), 7.7 (1H, d, J 5.0 Hz,
H-5), 5.77 (1H, m, H-30, –CH]), 5.00 (2H, d, J 12.8 Hz,
H-40, terminal ]CH2), 3.87 (3H, s, py-ester OCH3), 3.74
(6H, s, 2ꢂmalonate OCH3), 3.27 (2H, dd, J 7.2, 0.8 Hz,
H-20, –CH2–); 13C NMR (100 MHz, CDCl3): dC 39.6
(CH2), 52.6 (py-Me-ester), 52.9 (two malonate-Me-ester),
62.0 (quart. C), 119.3 (terminal ]CH2), 123.5 (C-5),
131.7 (C-3), 133.0 (allyl –CH]), 138.8 (C-4), 149.3 (C-
6), 150.7 (C-2), 167.6 (py-ester-C]O), 169.7 (two malo-
nate-ester-C]O); NMR assignments are based on DEPT,
COSY, HMBC and HSQC experiments; MS: m/z 307 (M+,
5%), 275 (59), 247 (77), 216 (100), 188 (89), 156 (90).
HRMS: calcd for C15H17NO6: 307.1056; obsd 307.1069.
Anal. Calcd for C15H17NO6: C, 58.63; H, 5.58; N, 4.56.
Found: C, 58.18; H, 5.77; N, 4.44.
4.1.7. Dimethyl 2-(4-(methoxycarbonyl)pyridin-3-yl)-
pentanedioate (7). The title product was preferentially pre-
pared by MW irradiation. A solution of 5 (130 mg,
0.37 mmol) and NaCl (64 mg, 1.11 mmol) in DMSO
(4 mL) was irradiated at ‘medium’ power (360 W) for
4.1.10. Methyl 3-(but-3-enyl)isonicotinate (80). Minor
amounts of 80 (2–3%) were isolated by flash chromatography
(Et2O/n-pentane 4:1) from a mixture with 8, pure by H
1
1
10 min to afford an oily product (87 mg, 60%), pure by H
1
and 13C NMR. Alternatively, some lower yields were ob-
tained by conventional heating of the reaction mixture for
16 h at 110 ꢀC; IR (film) nmax: 3001 (w), 2954 (s), 1731
(s), 1590 (w), 1437 (s), 1281 (s), 1171 (m), 1104 (m),
NMR and GC–MS. Rf 0.5 (Et2O/n-pentane 4:1), H NMR
(400 MHz, CDCl3): dH 2.37 (2H, q, J 6.8 Hz, CH2-20),
3.04 (2H, t, J 7.2 Hz, CH2-10), 3.93 (3H, s, py-ester-
OCH3), 5.02 (2H, m, C-40; terminal ]CH2), 5.82 (1H, m,
C-30; –CH]), 7.66 (1H, d, J 5.2 Hz, py-H-5), 8.56 (1H, d,
J 5.2 Hz, py-H-6), 8.57 (1H, s, py-H-2); GC–MS: m/z 291
(M+, 13%), 176 (6), 159 (100), 150 (34), 131 (19), 92 (36).
1
1003 (w), 853 (w), 724 (m) cmꢁ1; H NMR (400 MHz,
CDCl3): dH 2.16 (1H, m, H-20), 2.36 (2H, m, H-30), 2.55
(1H, m, H-20), 3.64 (3H, s, terminal ester OCH3), 3.67
(3H, s, ‘malonate ester’ OCH3), 3.93 (3H, s, py-ester
OCH3), 4.51 (1H, t, J 7.6 Hz, H-10), 7.71 (1H, d, J 4.8 Hz,
H-5), 8.65 (1H, d, J 4.8 Hz, H-6), 8.68 (1H, s, H-2); 13C
NMR (100 MHz, CDCl3): dC 27.9 (C-20), 31.9 (C-30), 44.9
(C-10), 51.7 (terminal ester OCH3), 52.4 (‘malonate ester
OCH3’), 52.8 (py-ester OCH3), 123.6 (C-5), 133.6 (C-3),
136.8 (C-4), 149.3 (C-6), 151.4 (C-2), 166.3 (py-ester
C]O), 172.9 (‘malonate’ ester C]O), 173.1 (terminal ester
4.1.11. Methyl (4-methoxycarboxyl-3-pyridine)acetate
(homochinchomeric acid dimethyl ester) (9).11 MW
decarboxylation was carried out as described above for the
preparation of 8. Irradiation of the solution of 3a (150 mg,
0.54 mmol) and CsCl (3 equiv) in water (12 equiv) and
DMSO (10 mL) at ‘low’ power (90 W) for 5 min afforded
9 in 81% yield, pure by 1H and 13C NMR, after flash

F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
11899
chromatography (ethyl acetate/n-pentane 4:1). Rf 0.5 (Et2O);
IR (film) nmax: 3002 (w), 2954 (m), 1732 (s), 1591 (w), 1437
(m), 1281 (s), 1105 (m), 1001 (m), 997 (m), 724 (s); 1H NMR
(300 MHz, CDCl3): dH 3.71 (3H, s, side chain OCH3), 3.91
(3H, s, py-ester OCH3), 4.01 (2H, s, CH2), 7.80 (1H, d,
J 5.2 Hz, H-5), 8.58 (1H, s, H-2); 8.69 (1H, d, J 5.2 Hz,
H-6), 13C NMR (75 MHz, CDCl3): dC 37.5 (CH2), 52.4 (side
chain OCH3), 52.8 (py-ester OCH3), 123.8 (C-5), 130.0
(C-3), 137.0 (C-4), 150.0 (C-6), 153.3 (C-2), 166.3 (pyr-
ester C]O), 171.3 (side chain C]O); NMR assignments
are based on DEPT, HSQC and HMBC experiments; MS:
m/z 209 (M+, 2%), 177 (100), 149 (53), 120 (22), 92 (27).
HRMS: calcd for C10H11NO4: 209.0688; obsd 209.0688.
Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70.
Found: C, 56.76; H, 5.39; N, 6.66.
m/p-Ph-H), 7.67 (2H, dd, J 0.7, 5.5 Hz, o-Ph-H), 8.06 (1H,
dd, J 5.1, 0.8 Hz, py-H-5), 8.88 (1H, d, J 5.1 Hz, py-H-6),
9.11 (1H, s, py-H-2); 13C NMR (75 MHz, CDCl3): dC 98.7
(pyrano-C-4, –CH]), 121.6 (py-C-5), 125.6 (py-C-4),
127.6 (p-Ph-CH), 129.1/129.5 (o-/m-Ph-CH), 131.4 (py-
C-3), 135.2 (Ph-C-1), 148.4 (py-C-6), 149.0 (py-C2),
155.9 (pyrano-C-3), 160.9 (pyrano-C]O); NMR assign-
ments are based on DEPT, COSY and HMBC experiments;
MS: m/z 223 (M+, 100%), 195 (70), 167 (11), 166 (11),
139 (17), 105 (17).
4.1.15. 3-Phenyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-
1-on (13). A solution of 11b (34 mg, 0.15 mmol) in a solu-
tion of KOH (5%, 5 mL) and ethanol (2.5 mL) was heated
to reflux for 4 h, cooled and NaBH4 (23 mg, 0.60 mmol)
was added. The reaction was stirred at room temperature
for 24 h. After the addition of acetic anhydride (0.3 mL,
3 mmol) the solution was heated to reflux for further 2 h,
cooled, water was added (15 mL) and the mixture stirred
for 24 h. Dichloromethane extraction (3ꢂ15 mL) and flash
chromatography (ethyl acetate/pentane added 2.5% NEt3;
4.1.12. Methyl 3-methyl-4-pyridinecarboxylate (10).30 By
prolonged MW irradiation time (10 min, 90 W, see prepara-
tion of 9 above), 9 and methyl 3-methyl-4-pyridylcarboxy-
late (10) were isolated in 34 and 17% yields, respectively.
Irradiation for 20 min afforded only 10. Purification by chro-
1
1
matography (Et2O) afforded 30% yield, pure by H NMR.
1:2) yielded the product (7 mg, 20%), pure by H and 13C
Compound 10: Rf 0.55 (Et2O); 1H NMR (400 MHz,
CDCl3): dH 2.55 (3H, s, py-CH3), 3.90 (3H, s, OCH3),
7.66 (1H, d, J 5.2 Hz, H-5), 8.53 (1H, d, J 5.2 Hz, H-6),
8.55 (1H, s, H-2); MS: m/z 151 (M+, 10%), 150 (31), 149
(100), 134 (121), 125 (11), 123 (10), 119 (13), 111 (19),
97 (27).
NMR; IR (film) nmax: 3064 (w), 2918 (w), 1724 (s), 1572
(m), 1494 (m), 1453 (m), 1425 (m), 1413 (m), 1349 (s),
1286 (s), 1244 (s), 1200 (m), 1160 (w), 1101 (m), 1007
(s), 883 (w), 852 (m) cmꢁ1 1H NMR (400 MHz, CDCl3):
dH 8.78 (1H, d, J 5.0 Hz, py-H-6), 8.72 (1H, s, py-H-2),
7.96 (1H, d, J 5.0 Hz, py-H-5), 7.44 (5H, m, Ph-H), 5.61
(1H, dd, J 12.0, 3.0 Hz, pyrano-H-3), 3.35 (1H, dd, J 16.5,
12.0 Hz, pyrano-H-4), 3.32 (1H, dd, J 1.5, 3.0 Hz, pyrano-
C-4); 13C NMR (100 MHz, CDCl3): dC 32.4 (pyrano-
H-4; CH2), 80.4 (pyrano-C-3, CH), 122.6 (py-C-5), 126.1
(o-Ph-C), 128.4 (p-Ph-C), 128.9 (m-Ph-C), 130.1 (py-C-3),
132.6 (py-C-4), 137.7 (Ph-C-1), 149.2 (py-C-6), 149.8
(py-C-2), 163.6 (pyrano-C]O); NMR assignments are
based on HSQC and HMBC experiments; MS: m/z 225
(M+, 17%), 119 (100), 105 (13), 91 (42); HRMS: calcd for
C14H11NO2: 225.0790; obsd 225.0794.
4.1.13. 3-Benzylpyrano[4,3-c]pyridin-1-one (11a). A solu-
tion of 3a (140 mg, 0.52 mmol) and phenylacetyl chloride
(416 mL, 3.14 mmol, 6 equiv) was stirred at 200 ꢀC for
2 h. To the solution were added NaHCO3 (saturated solution,
30 mL) and ethyl acetate (30 mL) and the mixture was
stirred for additional 5 min before the product was isolated
by extraction. Flash chromatography (CH2Cl2) afforded an
off-white crystalline product (CH2Cl2) (30 mg, 24%), pure
1
13
by H and C NMR. Rf 0.05 (CH2Cl2); mp 72–72.5 ꢀC;
IR nmax: 3019 (m), 2918 (w), 1740 (s), 1654 (m), 1560
(w), 1480 (w), 1454 (m), 1417 (m), 1262 (w), 1215 (s),
4.1.16. 3-Phenyl-2,6-naphthyridin-1(2H)-one (14).21 The
title compound was prepared in 43% yield from 11b and
1
1139 (w), 1054 (m), 850 (w) cmꢁ1; H NMR (400 MHz,
1
CDCl3): dH 3.86 (2H, s, benzylic CH2), 6.21 (1H, t,
J 0.7 Hz, pyrano-CH]), 7.28–7.38 (5H, m, Ph), 7.98
(1H, d, J 5.4 Hz, py-H-5), 8.69 (1H, d, J 5.4 Hz, py-H-6),
8.77 (1H, s, py-H-2); 13C NMR (100 MHz, CDCl3): dC
40.1 (benzylic CH2), 100.9 (pyrano-C-4, –CH]), 121.3
(py-C-5), 125.6 (py-C-4), 127.6 (p-Ph-CH), 129.1/129.5
(o-/m-Ph-CH), 131.4 (py-C-3), 135.2 (Ph-C-1), 148.4
(py-C2/C-6), 159.5 (pyrano-C-3), 161.3 (pyrano-C]O); NMR
assignments are based on APT, HSQC and HMBC experi-
ments; MS: m/z 237 (M+, 100%), 209 (30), 208 (15), 180
(12), 146 (30), 118 (15), 91 (39); HRMS: calcd for
C15H11NO2: 237.0790; obsd 237.0790.
NH3 as described in literature,23,24 pure by H and 13C
NMR; H NMR (400 MHz, CDCl3): dH 6.85 (1H, s, H-4),
1
8.14 (1H, d, J 5.2 Hz, H-8), 8.68 (1H, d, J 5.2 Hz, H-7),
9.06 (1H, d, J 0.8 Hz, H-5); 13C NMR (100 MHz, CDCl3):
dC 101.4 (C-4), 119.5 (C-8), 126.2 (o-Ph-C), 129.4 (p-Ph-
C), 129.5 (C-4a), 130.1 (m-Ph-C), 133.2 (Ph-C-1),133.7
(C-8a), 141.6 (C-3), 146.2 (C-7), 150.1 (C-5), 162.7 (C-1);
NMR assignments are based on DEPT, COSY, APT,
HSQC and HMBC experiments.
4.1.17. 1-Chloro-3-phenyl-2,6-naphthyridine (15). The
title compound was prepared from 14 and POCl3 as described
in literature25 to afford an off-white crystalline product
(EtOAc) (49%), pure by 1H and 13C NMR; mp 145.0–
145.4 ꢀC; IR nmax: 3063 (w), 1615 (w), 1566 (s), 1478 (s),
1453 (m), 1317 (s), 1257 (s), 1224 (m), 1150 (s), 989 (m),
876 (m), 850 (m), 827 (m) cmꢁ1; 1H NMR (600 MHz, ace-
tone-d6): dH 9.50 (1H, s, H-5), 8.78 (1H, d, J 5.4 Hz, H-7),
8.55 (1H, d, J 1.0 Hz, H-4), 8.21 (2H, m, Ph-o-H), 8.06
(1H, dd, J 5.4, 1.0 Hz, H-8), 7.52–7.55 (2H, m, Ph-m-H),
7.47–7.49 (1H, m, Ph-p-H); 13C NMR (150 MHz, acetone-
d6): dC 153.5 (C-5), 152.4 (C-3), 150.7 (C-1), 146.7 (C-7),
4.1.14. 3-Phenylpyrano[4,3-c]pyridin-1-one (11b).18 The
title compound was prepared from 3a and benzoyl chloride
as described above for 11a. afforded the pale yellow crystal-
1
line product (CH2Cl2, 31%), pure by H and 13C NMR. Rf
1
0.05 (CH2Cl2); H NMR (300 MHz, CDCl3): dH7.01 (1H,
s, pyrano-C-4, –CH]), 7.48 (3H, m, m/p-Ph-H), 7.87 (2H,
dd, J 1.7, 5.1 Hz, o-Ph-H), 8.06 (1H, d, J 4.9 Hz, py-H-5),
8.76 (1H, d, J 4.9 Hz, py-H-6), 8.98 (1H, s, py-H-2); corre-
sponding data in DMSO-d6: dH 7.55 (4H, m, H-4 and

11900
F. Tjosꢀas et al. / Tetrahedron 63 (2007) 11893–11901
138.0 (Ph-C-1), 134.1 (C-40), 130.4 (Ph-C-4), 129.8 (Ph-C-
3/5), 128.9 (C-80), 127.5 (Ph-C-2/6), 118.1 (C-8), 115.9
(C-4); NMR assignments are based on HSQC and HMBC
experiments; MS: m/z 242/240 (M+, 32/100%), 105 (46),
177 (14), 151 (18), 102 (14); HRMS: calcd for
C14H9N2Cl: 240.0454; obsd 240.0449.
(py-C-5), 134.4 (py-C-3), 147.1 (py-C-6), 147.8 (py-C-2),
148.4 (py-C-4); NMR assignments are based on APT,
HSQC, HMBC and NOESY experiments. The following
NOESY NMR interactions were observed: H-2/H-4, Ha-3/
H-2, Ha-3/H-4, H-4/Ha-5, Hb-3/Hb-5, Hb-3/CH2Br, Hb-5/
CH2Br, CH2OH/H-4, py-H-2/Hb-3, py-H-2/Hb-5. MS: m/z
273/271 (M+, 1%), 252/254 (4), 234/236 (5), 208/210 (2),
178 (10), 174 (13), 160 (44), 156 (31), 143 (100), 132
(95), 117 (98), 106 (44), 91 (25); HRMS: calcd for
C11H14NO279Br: 271.0208; obsd 271.0202. Anal. Calcd
for C11H14NO2Br: C, 48.55; H, 5.19; N, 5.15. Found: C,
48.45; H, 5.04; N, 5.23.
4.1.18. 2-(4-Hydroxymethyl-3-pyridyl)-4-penten-1-ol
(16). A solution of 8 (725 mg, 2.9 mmol) in dry THF
(12 mL) was drop-wise added to a solution of LiAlH4
(165 mg, 4.38 mmol) in dry THF (13 mL) at 0 ꢀC. The reac-
tion was stirred at room temperature for 2 h, cooled to 0 ꢀC
and diethyl ether (25 mL) was added, followed by a NH4Cl
solution (saturated, 40 mL) and water (40 mL). The product
was extracted from basic solution by diethyl ether
(3ꢂ50 mL) and yielded 17 (287 mg, 51%), pure by 1H and
13C NMR; IR (film) nmax: 3682 (w), 3620 (w), 3400 (br),
3019 (s), 2976 (m), 1523 (w), 1421 (m), 1216 (s), 1046
4.1.20. cis-Tetrahydro-2-iodomethyl-4-(4-hydroxy-
methyl-3-pyridyl)-furan (17b). A solution of the diol 16
(80 mg, 0.4 mmol) in dichloromethane (5 mL) was stirred
at room temperature for 24 h after the addition of I2
(50 mg, 0.2 mmol, 0.5 equiv).31 The solvent was decanted
and the solid precipitate was dissolved in dichloromethane
(5 mL) and acetone (10 mL) and Na2S2O3 (5% solution,
25 mL) was added. The crude product was extracted with di-
chloromethane (5ꢂ30 mL)) and flash chromatography (1%
methanol in dichloromethane) yielded the product (32 mg,
24%), pure by 1H and 13C NMR. Rf 0.05 (acetone/n-pentane
1:2); IR (film) nmax: 3682 (w), 3620 (w), 2975 (m), 1520 (w),
1
(m), 928 (m) cmꢁ1; H NMR (600 MHz, CDCl3): dH 8.32
(1H, s, py-H-2), 8.22 (1H, d, J 5.4 Hz, py-H-6), 7.24 (1H,
d, J 5.4, 1.3 Hz, py-H-5), 5.65 (1H, dd, J 17.0, 10.2 Hz,
H-4, –CH]), 5.15 (1H, dd, J 17.0, 1.8 Hz, H-5, terminal
]CHaHb), 4.98 (1H, dd, J 10.2, 1.8 Hz, H-5, terminal
]CHaHb), 4.78 (1H, d, J 13.0 Hz, py-CHaHbOH), 4.47
(1H, d, J 13.0 Hz, py-CHaHbOH), 3.90 (1H, dd, J 10.0,
4.8 Hz, ‘malonate’-CHaHbOH), 3.62 (1H, dd, J 10.0,
9.4 Hz, ‘malonate’-CHaHbOH), 3.46 (2H, s, 2ꢂOH), 3.19
(1H, m, H-2), 2.46 (1H, m, H-3, –CHaHb-C), 2.39 (1H, m,
H-3, –CHaHb-C); 13C NMR (100 MHz, CDCl3): dC 36.0
(C-3), 40.9 (C-2), 61.6 (py-CH2OH), 66.5 (C-1, CH2OH),
117.2 (C-5, ]CH2), 123.0 (py-C-5), 135.2 (C-4, –CH]),
136.5 (py-C-3), 147.2 (py-C-6), 147.7 (py-C-2), 148.8 (py-
C-4); NMR assignments are based on APT, HSQC and
HMBC experiments; MS: m/z 193 (M+, 1%), 180 (6), 170
(4), 164 (13), 157 (14), 145 (66), 134 (39), 130 (49), 117
(66), 106 (100), 91 (68); HRMS: calcd for C11H15NO2:
193.1103; obsd 193.1094. Anal. Calcd for C11H15NO2; C,
68.37; H, 7.82; N, 7.25. Found: C, 68.10; H, 7.68; N, 7.15.
1
1422 (w), 1215 (s), 1046 (m), 929 (m) cmꢁ1; H NMR
(400 MHz, CDCl3): dH 8.56 (1H, s, py-H-2), 8.41 (1H, d, J
4.8 Hz, py-H-6), 7.39 (1H, d, J 4.8 Hz, py-H-5), 4.76 (2H,
s, py-CH2OH), 4.21 (1H, dd, J 8.4, 7.7 Hz, H-5, CHaHb),
4.13 (1H, m, H-2), 3.96 (1H, dd, J 8.4, 8.2 Hz, H-5, CHaHb),
3.72 (1H, m, H-4), 3.35 (1H, dd, J 11.6, 5.8 Hz, side chain
CHaHb I), 3.38 (1H, dd, J 11.6, 5.8 Hz, side chain CHaHb
I), 2.59 (1H, m, H-3, CHaHb), 1.88 (1H, m, H-3, CHaHb);
13C NMR (100 MHz, CDCl3): dC 9.4 (CH2I), 39.3 (C-3),
40.6 (C-4), 61.3 (py-CH2OH), 74.0 (C-5), 79.0 (C-2),
121.7 (py-C-5), 134.4 (py-C-3), 147.3 (py-C-6), 147.9 (py-
C-2), 148.0 (py-C-4); NMR assignments are based on
APT, HSQC, HMBC and NOESY experiments. The follow-
ing NOESY NMR interactions were observed: H-2/H-4,
Ha-3/H-2, Ha-3/H-4, H-4/Ha-5, Hb-3/Hb-5, Hb-3/CH2I,
Hb-5/CH2I, CH2OH/H-4, py-H-2/Hb-3, py-H-2/Hb-5. MS:
m/z 319 (M+, 5%), 271 (3), 192 (12), 178 (22), 178 (22),
160 (30), 143 (100), 91 (13); HRMS: calcd for
C11H14NO2I: 319.0069; obsd 319.0061. Anal. Calcd for
C11H14NO2I: C, 41.40; H, 4.42; N, 4.39. Found: C, 41.49;
H, 4.51; N, 4.29.
4.1.19. cis-Tetrahydro-2-bromomethyl-4-(4-hydroxy-
methyl-3-pyridyl)-furan (17a). A solution of the diol 16
(88 mg, 0.45 mmol) in THF (2 mL) and water (0.15 mL)
was cooled to ꢁ78 ꢀC and NBS (89 mg, 0.50 mmol,
1.1 equiv) was added.37 After 2 h of stirring, the temperature
was raised to room temperature. Water (30 mL) was added
and the crude product was extracted with ethyl acetate
(3ꢂ15 mL). Flash chromatography (10% methanol in di-
chloromethane) yielded the product (50 mg, 40%), pure by
1H and 13C NMR. Rf 0.1 (acetone/n-pentane 1:1); IR (film)
nmax: 3682 (w), 3619 (w), 3018 (s), 2975 (m), 1600 (m),
1521 (w), 1477 (w), 1419 (m), 1215 (s), 1046 (m), 928
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