Synthesis of substituted 1,8-naphthyridine-3-carboxylates from Baylis-Hillman adducts of substituted 2-chloronicotinaldehydes

Article abstract of DOI:10.1002/hlca.200800352

A series of substituted 1,8-naphthyridine-3-carboxylates were synthesized for the first time from the Baylis-Hillman adducts obtained from 2-chloronicotinaldehyde derivatives. Three methods were adopted to synthesize 1,8-naphthyridine-3-carboxylates, of w

Full text of DOI:10.1002/hlca.200800352

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Synthesis of Substituted 1,8-Naphthyridine-3-carboxylates from
Baylis – Hillman Adducts of Substituted 2-Chloronicotinaldehydes
by Puli Narendera), Mettu Ravindera), Partha Sarathi Sadhua), Bhimapaka China Raju*b),
Chilukuri Rameshc), and Vaidya Jayathirtha Rao*a)c)
a) Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad-500607, India
b) Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad-500607, India (phone: þ 914027161541; fax: þ 914027160757;
e-mail: chinarajuiict@yahoo.co.in)
c) National Institute of Pharmaceutical Education & Research, Balanagar, Hyderabad-500037, India
A series of substituted 1,8-naphthyridine-3-carboxylates were synthesized for the first time from the
Baylis – Hillman adducts obtained from 2-chloronicotinaldehyde derivatives. Three methods were
adopted to synthesize 1,8-naphthyridine-3-carboxylates, of which the azide-reduction route (Scheme 5)
gave the best yields compared to the other attempted methods (Schemes 2 and 3).
1. Introduction. – Naphthyridines are an important class of pharmaceutically active
compounds, and their chemistry has been reviewed since their evaluation [1]. A large
number of 1,8-naphthyridines were reported to exhibit antimicrobial [2a], antitumor
[2b – d], anti-inflammatory [2e], and diuretic activities [2f]. Many other 1,8-naphthyr-
idines have been found to be active as antiallergics [3a], local anaesthetics [3b],
antiplatelet agents [3c], anticonvulsants [3d], and antihypertensives [3e]. The 1,8-
naphthyridine derivatives were also reported to be associated with the property of
inhibiting secretion of acid in stomach known as a gastric antisecretary [4], and also
used for the treatment of memory disorders, in particular Alzheimerꢀs disease [5].
Some new 1,8-naphthyridine derivatives have recently been patented as plant-growth
regulators, fungicides, bactericides, herbicides, insecticides, and nematicides [6].
Arylnaphthyridines have been reported as potent mGlu5-receptor antagonists [7]. In
addition to medicinal applications, 1,8-naphthyridines have been employed in the study
of bioorganic and bioorganometallic processes (for a recent example, see [8]) and in
organometallic [9] applications.
A survey of the literature shows that there are two general methods available for
the preparation of 1,8-naphthyridines, namely the Skraup and the Friedlꢀnder reaction.
The former is a powerful method for the synthesis of quinolines and many
naphthyridines [10]. However, it is very much substrate-dependent and not suitable
for the preparation of 2-substituted 1,8-naphthyridines [11]. On the other hand, the
Friedlꢀnder reaction is one of the most important methods for synthesizing pyridines,
quinolines, and naphthyridines [12], but one of its major drawbacks is that unsym-
metrical ketones give both regioisomeric products, generally with little or no selectivity.
ꢁ 2009 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Moreover, both methods for the synthesis of 1,8-naphthyridines require high reaction
temperatures and prolonged reaction times, and suffer from low product yields. Thus, in
view of their immense biological importance, the development of a simple, convenient,
and environmentally compatible synthesis of 1,8-naphthyridines is very much desirable.
In continuation of our work on the study of N-containing heterocyclic compounds
[13], we report herein a novel, simple, and efficient route for the synthesis of
substituted 1,8-naphthyridine-3-carboxylates from Baylis – Hillman adducts, which are
often difficult to obtain by other routes.
2. Results and Discussion. – 2.1. Baylis – Hillman Actates. The Baylis – Hillman
reaction is a useful method for CꢀC bond-formation from activated vinyl and CO
substrates [14]. Chemical transformation of the Baylis – Hillman adducts or their
derivatives into useful heterocyclic compounds have been studied recently by us and
other groups [13][15]. Thus, we have reported new Baylis – Hillman adducts derived
from 2-chloronicotinaldehydes (¼2-chloropyridine-3-carboxaldehydes) [13b,d], and
the transformation of these adducts into the quinoline skeleton [13c] is a useful entry to
quinoline chemistry.
The Baylis – Hillman adducts 2a – 2j were now synthesized similarly [13b,d] from
the substituted 2-chloronicotinaldehydes 1a – 1f with ethyl or methyl acrylate (¼ethyl
or methyl prop-2-enoate) in very good yields (Scheme 1). The allyl acetate derivatives
3a – 3j of these adducts were then efficiently obtained by treatment with either AcCl/
pyridine or Ac2O/Et3N (cat. DMAP (¼ N,N-dimethylpyridin-4-amine)) [16]. All the
new compounds were well characterized by spectral data.
Scheme 1
It was anticipated that the acetate derivatives 3 are convertible into primary-
allylamine derivatives, which could easily lead to the formation of substituted 1,8-
naphthyridines via an SNAr reaction, the allylamine moiety acting as a nucleophile and
substituting the Cl-atom at the pyridine ring even under moderate conditions. This

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assumption prompted us to look for an efficient synthesis of allylamine derivatives from
the Baylis – Hillman acetates 3. Thus the primary-allylamines were generated from 3 by
using different nucleophiles such as i) p-toluenesulfonamide (¼4-methylbenzenesul-
fonamide), ii) ammonium acetate, and iii) sodium azide followed by reduction.
2.2. Reaction of Acetate Derivatives 3 with p-Toluenesulfonamide: The reaction of
the Baylis – Hillman acetates 3a – 3j with p-toluenesulfonamide (TsNH2) [15a][17] in
the presence of K2CO3 in dimethylformamide as solvent at 40 – 508 gave the substituted
1,8-naphthyridine-3-carboxylates 4a – 4j in 55 – 64% yield (Scheme 2). With the aid of
K2CO3, TsNH2 generates the nucleophile that undergoes Michael addition to the
exocyclic C¼C bond of acetates 3 and subsequent migration of the C¼C bond with the
simultaneous ejection of the AcO group to give the rearranged sulfonamide derivatives
TsNHOH2C(COOR)¼CHPy. This reaction is also known as tandem nucleophilic-
addition – elimination reaction (SN2’) [18][19]. The intermediates could not be
isolated, and subsequently the TsNH moiety again generates a nucleophile with the
aid of K2CO3, which can now attack in an SNAr reaction at C(2) of the pyridine ring
followed by elimination of Clꢀ to give the 1,2-dihydro-1-tosyl-1,8-naphthyridine-3-
carboxylates. The latter are then converted into the 1,8-naphthyridine-3-carboxylates 4
by the elimination of p-toluenesulfonic acid under normal elimination-reaction
conditions.
Scheme 2
2.3. Reaction of Acetate Derivatives 3 with Ammonium Acetate. The Baylis – Hill-
man acetates 3a – 3j were treated with NH4OAc in anhydrous MeOH at room
temperature for 1 – 2 h to obtain the substituted 1,8-naphthyridine-3-carboxylates 4a –
4j in 20 – 26% yield (Scheme 3). The primary-allylamine derivatives were not isolated
as they underwent the aromatic nucleophilic substitution reaction (SNAr) as soon as
they were formed, yielding the 1,2-dihydro-1,8-naphthyridine-3-carboxylates in low
yields due to the formation of by-products [20]. Presumably, the formed 1,2-dihydro-
1,8-naphthyri-

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 3
dine-3-carboxylates underwent an auto-oxidation during the workup procedure to yield
the 1,8-naphthyridine-3-carboxylates 4.
However, we observed the formation of allylic-alcohol derivative 5a [21] when the
Baylis – Hillman acetate 3a reacted with ammonium acetate in the presence of aqueous
MeOH (containing 5% of H2O) (Scheme 4). OH Ions may attack the exocyclic C¼C
bond instead of ammonium ions when MeOH containing H2O was used.
Scheme 4
2.4. Reaction of Acetate Derivatives 3 with NaN3. We have also developed another
method to synthesize the substituted 1,8-naphthyridine-3-carboxylates 4a – 4j by
converting first the Baylis – Hillman acetates 3a – 3j to the primary allyl azide
derivatives 6a – 6j. Thus, after formation of the corresponding salts in the presence of
DABCO (¼1,4-diazabicyclo[2.2.2]octane) in aqueous THFat room temperature, NaN3
was added to give 6a – 6j in 80 – 92% yield within 5 min, which were identified by
spectroscopic analysis (Scheme 5). Reduction of 6a – 6j with triphenylphosphine in the
presence of water for 14 – 16 h by the Staudinger reaction [22] gave the 1,8-
naphthyridine-3-carboxylates 4a – 4j in 72 – 88% yield via the corresponding primary-
allylamine derivatives which underwent immediately SNAr reaction (!1,2-dihydro-1,8-
naphthyridine-3-carboxylates) followed by auto-oxidation.
Scheme 5
3. Conclusion. – We developed for the first time an efficient route for the synthesis
of substituted 1,8-naphthyridine-3-carboxylates under mild conditions in high yields via
the Baylis – Hillman adducts. Three methods were adopted to synthesize the 1,8-

Helvetica Chimica Acta – Vol. 92 (2009)
963
naphthyridine-3-carboxylates 4a – 4j, of which the azide/triphenylphosphine method
was the best when compared to the p-toluenesulfonamide or ammonium acetate
procedure.
The authors thank the Director and Head of the Organic Chemistry Division-II, IICT, for constant
encouragement. P. N. , M. R., and P. S. thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, for the fellowships.
Experimental Part
1. General. The chemicals NaN3, DABCO, Ph3P, p-toluenesulfonamide, and all the solvents were
obtained commercially. The Baylis – Hillman adducts were synthesized according to our earlier-reported
method [13c]. Column chromatography (CC): silica gel (SiO2; 60 – 120 mesh). M.p.: Mettler-Temp
apparatus; uncorrected. IR Spectra: Perkin-Elmer-1600 FT-IR spectrometer; ˜n in cmꢀ1 1H- and
.
13C-NMR Spectra: Gemini-200 and Bruker-Avance-300 spectrometers; chemical shifts d in ppm rel. to
Me4Si as an internal standard, J in Hz. EI-MS: 7070 H spectrometers with a direct inlet system; at 70 eV;
in m/z (rel. %).
2. 1,8-Naphthyridine-3-carboxylates 4a – 4j by the p-Toluenesulfonamide Method: General Procedure.
To a stirred soln. of the Baylis – Hillman acetate, 3a (0.566 g, 2 mmol) in DMF were added p-
toluenesulfonamide (1.71 g, 10 mmol) and K2CO3 (1 g, 10 mmol), and the mixture was stirred at 40 – 508
for 4 h (TLC monitoring). Then the mixture was poured into cold 10% HCl soln. and extracted with Et2O
(3 ꢁ 50 ml), the combined Et2O layer dried (Na2SO4) and concentrated, and the obtained residue
subjected to CC (silica gel, hexane/AcOEt 6 :4): 4a as solid in 64% yield.
3. 1,8-Naphthyridine-3-carboxylates 4a – 4j by the Ammonium Acetate Method: General Procedure.
To a soln. of 3a (0.283 g, 1 mmol) in anh. MeOH (10 ml) was added NH4OAc (0.616 g, 8 mmol) in one
portion under N2. The mixture was stirred at r.t. (TLC monitoring). After completion of the reaction, the
mixture was diluted with CHCl3 (30 ml) and filtered to remove excess of NH4OAc. The filtrate was
concentrated and the residue subjected to CC (SiO2, hexane/AcOEt 5 :5): pure 4a as solid in 26% yield.
4. Allyl Azide Derivatives 6a – 6j: General Procedure. To the stirred soln. of 3a (0.283 g, 1 mmol) in
THF/H2O 1:1 (4 ml) was added DABCO (0.112 g, 1 mmol). After 10 min, NaN3 (0.1 g, 1.5 mmol) was
added under stirring, and after 5 min, the mixture was extracted with AcOEt (2 ꢁ 20 ml), the org. layer
dried (NaSO4) and concentrated, and the residue subjected to CC (SiO2, hexane/AcOEt 98 :2): 6a
(0.23 g, 92%).
5. Reduction of Azide Derivatives 6a – 6j to 1,8-Naphthyridine-3-carboxylates 4a – 4j: General
Procedure. To a stirred soln. of 6a (0.23 g, 0.9 mmol) in THF (5 ml) was added Ph3P (0.365 g, 1.4 mmol)
and allowed to stir at r.t. for 1 h (!dark yellow mixture). Thereafter, H2O (50 ml) was added and the
reaction allowed to proceed for further 14 h (TLC monitoring). Then the solvent was evaporated, the
residue extracted with AcOEt, the AcOEt soln. washed with H2O (2 ꢁ 20 ml), dried (Na2SO4), and
concentrated and the obtained residue subjected to CC (SiO2, hexane/AcOEt 4 :6): 4a in 88% yield.
6. Data of 4a – 4j, 6a, 6d – 6f, 6j, and 5a. Methyl 6-Methyl-1,8-naphthyridine-3-carboxylate (4a). Yield
88%1). M.p. 274 – 2768. IR (KBr): 3396, 2922, 1663, 1426, 1375, 1028, 762, 697. 1H-NMR (200 MHz,
(D6)DMSO): 9.42 (s, 1 H); 8.99 (s, 1 H); 8.79 (s, 1 H); 8.09 (s, 1 H); 3.98 (s, 3 H); 2.57 (s, 3 H). EI-MS:
202 (100, Mþ), 171 (92), 143 (45), 116 (60), 89 (40). Anal. calc. for C11H10N2O2: C 65.34, H 4.98, N 13.85;
found: C 65.35, H 4.99, N 13.89.
Methyl 6-Ethyl-1,8-naphthyridine-3-carboxylate (4b). Yield 78%1). M.p. 282 – 2848. 1H-NMR
(200 MHz, CDCl3): 9.57 (s, 1 H); 9.08 (s, 1 H); 8.8 (s, 1 H); 8.02 (s, 1 H); 4.01 (s, 3 H); 2.94 (q, J ¼
7.17, 2 H); 1.42 (t, J ¼ 7.17, 3 H). 13C-NMR (75 MHz, CDCl3): 165.2; 157.2; 152.3; 139.3; 138.9; 135.1;
124.0; 121.3; 52.5; 29.6; 25.9; 14.8. EI-MS: 216 (100, Mþ), 201 (60), 185 (80), 174 (15), 157 (20), 130 (45).
Anal. calc. for C12H12N2O2: C 66.65, H 5.59, N 12.95; found: C 66.68, H 5.68, N 12.88.
1
)
Yields of 4a – 4j from 3a – 3j according to the method of Scheme 5.

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Helvetica Chimica Acta – Vol. 92 (2009)
Methyl 6-(4-Methoxyphenyl)-1,8-naphthyridine-3-carboxylate (4c). Yield 72%1). M.p. 296 – 2988.
1H-NMR (200 MHz, CDCl3): 9.57 (s, 1 H); 9.00 (s, 1 H); 8.61 (s, 1 H); 8.34 (s, 1 H); 7.60 (br. s, 4 H); 4.02
(s, 3 H); 3.86 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 166.7; 160.1; 150.3; 137.2; 134.2; 133.9; 129.0; 128.7;
128.4; 128.2; 128.1; 127.4; 114.8; 55.3; 52.3. EI-MS: 294 (Mþ). Anal. calc. for C17H14N2O3: C 69.38, H 4.79,
N 9.52; found: C 69.32, H 4.74, N 9.32.
Methyl 6-Methyl-7-phenyl-1,8-naphthyridine-3-carboxylate (4d). Yield 74%1). M.p. 285 – 2878. IR
(KBr): 3060, 2924, 1721, 1611, 1429, 1254, 1103, 699. 1H-NMR (200 MHz, CDCl3): 9.55 (s, 1 H); 8.78 (s,
1 H); 8.10 (s, 1 H); 7.48 – 7.67 (m, 5 H); 3.98 (s, 3 H); 2.53 (s, 3 H). EI-MS: 278 (23, Mþ), 277 (100), 247
(8), 218 (10), 190 (7). Anal. calc. for C17H14N2O2: C 73.37, H 5.07, N 10.07; found: C 73.22, H 5.12, N
10.19.
Dimethyl 1,8-Naphthyridine-2,6-dicarboxylate (4e). Yield 88%1). M.p. 312 – 3158. IR (KBr): 2958,
1720, 1441, 1341, 1228, 1141, 1099, 775. 1H-NMR (200 MHz, CDCl3): 9.69 (s, 1 H); 9.0 (s, 1 H); 8.8 (d, J ¼
7.95, 1 H); 8.34 (d, J ¼ 7.95, 1 H); 4.08 (s, 3 H); 4.05 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 166.4; 165.8;
148.8; 148.4; 139.3; 138.6; 129.3; 128.3; 123.0; 121.3; 52.9; 52.3. EI-MS: 246 (100, Mþ). Anal. calc. for
C12H10N2O4: C 58.54, H 4.09, N 11.38; found: C 58.23, H 4.46, N 10.98.
Ethyl 6-Methyl-1,8-naphthyridine-3-carboxylate (4f). Yield 82%1). M.p. 282 – 2858. IR (KBr): 3396,
1
2922, 1663, 1426, 1375, 1028, 762, 697. H-NMR (200 MHz, CDCl3): 9.52 (s, 1 H); 9.0 (s, 1 H); 8.78 (s,
1 H); 8.0 (s, 1 H); 4.42 (q, J ¼ 7.17, 2 H); 2.51 (s, 3 H); 1.39 (t, J ¼ 7.17, 3 H). EI-MS: 216 (100, Mþ), 199
(33), 183 (33), 152 (8), 77 (10). Anal. calc. for C12H12N2O2: C 66.65, H 5.59, N 12.95; found: C 66.62, H
5.68, N 12.81.
Ethyl 6-Ethyl-1,8-naphthyridine-3-carboxylate (4g). Yield 80%1). M.p. 286 – 2898. IR (KBr): 3390,
1
2982, 1690, 1490, 1390, 1028, 762, 697. H-NMR (200 MHz, CDCl3): 9.52 (s, 1 H); 8.83 (s, 1 H); 8.36 (s,
1 H); 8.13 (s, 1 H); 4.42 (q, J ¼ 7.21, 2 H); 2.92 (q, J ¼ 7.21, 2 H); 1.41 (t, J ¼ 7.21, 3 H); 1.31 (t, J ¼ 7.21,
3 H). EI-MS: 230 (100, Mþ). Anal. calc. for C13H14N2O2: C 67.81, H 6.13, N 12.17; found: C 67.78, H 6.08,
N 12.14.
Ethyl 6-Phenyl-1,8-naphthyridine-3-carboxylate (4h). Yield 84%1). M.p. 240 – 2428. IR (KBr): 3060,
2924, 1721, 1611, 1426, 1254, 1103, 699. 1H-NMR (200 MHz, CDCl3): 9.55 (s, 1 H); 8.78 (s, 1 H); 8.46 (s,
1 H); 8.10 (s, 1 H); 7.42 – 7.67 (m, 5 H); 4.38 (q, J ¼ 7.17, 2 H); 1.43 (t, J ¼ 7.17, 3 H). 13C-NMR (75 MHz,
CDCl3): 166.2; 150.5; 137.4; 137.3; 134.4; 134.0; 129.1; 128.9; 128.7; 128.4; 128.2; 127.2; 127.1; 61.1; 14.3.
EI-MS: 278 (100, Mþ), 249 (64), 183 (65), 137 (10), 128 (10). Anal. calc. for C17H14N2O2: C 73.36, H 5.07,
N 10.07; found: C 73.42, H 5.09, N 10.45.
Ethyl 6-Methyl-7-phenyl-1,8-naphthyridine-3-carboxylate (4i). Yield 82%1). M.p. 282 – 2858. IR
(KBr): 2927, 1706, 1613, 1407, 1257, 1106, 783. 1H-NMR (200 MHz, CDCl3): 9.6 (s, 1 H); 8.8 (s, 1 H); 8.12
(s, 1 H); 7.75 – 7.45 (m, 5 H); 4.51 (q, J ¼ 7.21, 2 H); 2.60 (s, 3 H); 1.50 (t, J ¼ 7.21, 3 H). 13C-NMR
(50 MHz, CDCl3): 165.6; 156.0; 152.7; 139.6; 138.7; 133.2; 131.7; 129.4; 129.2; 129.0; 128.2; 124.1; 120.5;
61.7; 20.6; 14.3. EI-MS: 292 (40, Mþ), 291 (100), 263 (75), 247 (10), 218 (11). Anal. calc. for C18H16N2O2:
C 73.95, H 5.51, N 9.58; found: C 73.99, H 5.66, N 9.64.
6-Ethyl 2-Methyl-1,8-naphthyridine-2,6-dicarboxylate (4j). Yield 88%1). M.p. 314 – 3168. IR (KBr):
3023, 2954, 1742, 1712, 1324, 1280, 1173, 1093, 783. 1H-NMR (200 MHz, CDCl3): 9.78 (d, J ¼ 2.93, 1 H);
8.91 (d, J ¼ 2.93, 1 H); 8.48 (d, J ¼ 8.08, 1 H); 8.38 (d, J ¼ 8.08, 1 H); 4.50 (q, J ¼ 7.34, 2 H); 4.09 (s, 3 H);
1.50 (t, J ¼ 7.34, 3 H). 13C-NMR (50 MHz, CDCl3): 165.3; 164.2; 156.4; 154.4; 152.7; 139.8; 139.4; 125.7;
122.9; 122.7; 62.1; 53.2; 14.3. EI-MS: 260 (3, Mþ), 230 (17), 215 (10), 202 (100), 174 (42), 160 (10), 128
(8), 101 (6). Anal. calc. for C13H12N2O4: C 60.40, H 4.65, N 10.76; found: C 60.35, H 4.68, N 10.68.
Methyl (2E)-2-(Azidomethyl)-3-(2-chloro-5-methylpyridin-3-yl)prop-2-enoate (6a). Yield 92%. M.p.
82 – 848. 1H-NMR (200 MHz, CDCl3): 8.22 (s, 1 H); 7.90 (s, 1 H); 7.58 (s, 1 H); 4.02 (s, 2 H); 3.92 (s, 3 H);
2.39 (s, 3 H). EI-MS: 266 (100, Mþ), 224 (76), 210 (23).
Methyl (2E)-2-(Azidomethyl)-3-(2-chloro-5-methyl-6-phenylpyridin-3-yl)prop-2-enoate (6d). Yield
91%. M.p. 110 – 1128. 1H-NMR (200 MHz, CDCl3): 7.95 (s, 1 H); 7.68 (s, 1 H); 7.60 – 7.42 (m, 5 H); 4.08 (s,
2 H); 3.93 (s, 3 H); 2.43 (s, 3 H). EI-MS: 342 (100, Mþ), 300 (66), 286 (45), 258 (12).
Methyl 5-[(1E)-2-(Azidomethyl)-3-methoxy-3-oxoprop-1-en-1-yl]-6-chloropyridine-2-carboxylate
1
(6e). Yield 92%. M.p. 119 – 1218. H-NMR (200 MHz, CDCl3): 8.09 (d, J ¼ 8.08, 1 H); 7.91 (d, J ¼ 8.08,
1 H); 7.90 (s, 1 H); 3.99 (s, 3 H); 3.97 (s, 2 H). EI-MS: 310 (100, Mþ), 295 (76), 253 (65), 225 (36).

Helvetica Chimica Acta – Vol. 92 (2009)
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Ethyl (2E)-2-(Azidomethyl)-3-(2-chloro-5-methylpyridin-3-yl)prop-2-enoate (6f). Yield 84%. M.p.
95 – 968. 1H-NMR (200 MHz, CDCl3): 8.21 (s, 1 H); 7.89 (s, 1 H); 7.58 (s, 1 H); 4.36 (q, J ¼ 7.43, 2 H); 4.02
(s, 2 H); 2.39 (s, 3 H); 1.41 (t, J ¼ 7.43, 3 H). EI-MS: 280 (100, Mþ), 238 (76), 224 (23).
Methyl 5-[(1E)-2-(Azidomethyl)-3-ethoxy-3-oxoprop-1-en-1-yl]-6-chloropyridine-2-carboxylate
(6j). Yield 90%. 1H-NMR (200 MHz, CDCl3): 8.09 (d, J ¼ 8.08, 1 H); 7.93 (d, J ¼ 8.08, 1 H); 7.90 (s,
1 H); 4.35 (q, J ¼ 7.34, 2 H); 3.98 (s, 3 H); 3.97 (s, 2 H); 1.39 (t, J ¼ 7.34, 3 H).
Methyl (2E)-3-(2-Chloro-5-methylpyridin-3-yl)-2-(hydroxymethyl)prop-2-enoate (5a). Yield 75%.
1
M.p. 152 – 1558. IR (KBr): 3314, 2956, 1708, 1021. H-NMR (200 MHz, CDCl3): 8.16 (s, 1 H); 7.74 (s,
1 H); 7.52 (s, 1 H); 4.28 (s, 2 H); 3.81 (s, 2 H); 2.30 (s, 3 H); 1.60 (br. s, OH). EI-MS: 241 (100, Mþ). Anal.
calc. for C11H12NClO3: C 54.67, H 5.00, N 5.79; found: C 54.69, H 5.12, N 5.82.
REFERENCES
[1] V. P. Litvinov, Russ. Chem. Rev. 2004, 73, 637; W. W. Paudler, R. R. Sheets, Adv. Heterocycl. Chem.
1983, 33, 147.
[2] a) G. R. Rao, K. Mogilaiah, B. Sreenivasulu, Indian J. Chem., Sect. B 1996, 35, 339; b) S. K.
Srivastava, M. Jaggi, A. T. Singh, A. Madan, N. Rani, M. Vishnoi, S. K. Agarwal, R. Mukherjee,
A. C. Burman, Bioorg. Med. Chem. Lett. 2007, 17, 6660; c) Y. Tsuzuki, K. Tomita, Y. Sato, S.
Kashimoto, K. Chiba, Bioorg. Med. Chem. Lett. 2004, 12, 3189; d) S.-X. Zhang, K. F. Bastow, Y.
Tachibana, S.-C. Kuo, E. Hamel, A. Mauger, V. L. Narayanan, K.-H. Lee, J. Med. Chem. 1999, 42,
4081; e) T. Kuroda, F. Suzuki, T. Tamura, K. Ohmori, H. Hosoe, J. Med. Chem. 1992, 35, 1130;
f) D. K. J. Gorecki, E. M. Hawes, J. Med. Chem. 1977, 20, 124.
[3] a) S.-C. Kuo, S.-Y. Tsai, H.-T. Li, C.-H. Wu, K. Ishii, H. Nakamura, Chem. Pharm. Bull. 1988, 36,
4403; b) P. L. Ferrarini, C. Mori, N. Tellini, Farmaco 1990, 45, 385; c) P. L. Ferrarini, M. Badawneh,
F. Franconi, C. Manera, M. Miceli, C. Mori, G. Saccomanni, Farmaco 2001, 56, 311; d) J. T. Leonard,
R. Gangadhar, S. K. Gnanasam, S. Ramachandran, M. Sarvanan, S. K. Sridhar, Biol. Pharm. Bull.
2002, 25, 798; e) P. L. Ferrarini, C. Mori, M. Badawneh, V. Calderone, R. Greco, C. Manera, A.
Martinelli, P. Nieri, G. Saccomanni, Eur. J. Chem. 2000, 35, 815.
[4] A. A. Santilli, A. C. Scotese, R. F. Bauer, S. C. Bell, J. Med. Chem. 1987, 30, 2270.
[5] V. P. Litvinov, Adv. Heterocycl. Chem. 2006, 91, 189.
[6] A. S. Noravyan, E. G. Paronikyan, S. A. Vartanyan, Khim.-Farm. Zh. 1985, 19, 790; V. P. Litvinov,
S. V. Roman, V. D. Dyachenko, Russ. Chem. Rev. (Engl. Transl.) 2000, 69, 201; L. Chrzastek, B.
Mianowska, W. Sliwa, Aust. J. Chem. 1994, 47, 2129; B. Bachowska, T. Zujewska, Arkivoc 2001, (vi),
77.
[7] P. Galatsis, K. Yamagata, J. A. Wendt, C. J. Connolly, J. W. Mickelson, B. J. Milbank, S. E. Bove, C. S.
Knauer, R. M. Brooker, C. E. Augelli-Szafran, R. D. Schwarz, J. J. Kinsora, K. S. Kilgore, Bioorg.
Med. Chem. Lett. 2007, 17, 6525.
[8] K. Nakatani, S. Sando, I. Saito, Bioorg. Med. Chem. 2001, 9, 2381; K. Nakatani, S. Sando, I. Saito, J.
Am. Chem. Soc. 2001, 122, 2172; C. H. Nguyen, C. Marchand, S. Delage, J.-S. Sun, H. Garestier, C.
´ `
Helene, E. Bisagni, J. Am. Chem. Soc. 1998, 120, 2501; Y. Zhou, Y. Xiao, X. Qian, Tetrahedron Lett.
2008, 49, 3380.
[9] C. He, J. L. DuBois, B. Hedman, K. O. Hodgson, S. J. Lippard, Angew. Chem., Int. Ed. 2001, 40, 1484;
C.-M. Che, C.-W. Wan, K.-Y. Ho, Z.-Y. Zhou, New. J. Chem. 2001, 25, 63; R. Ziessel, A. Harriman, A.
El-ghayoury, L. Douce, E. Leize, H. Nierengarten, A. Van Dorsselaer, New J. Chem. 2000, 24,
729.
[10] Y. Hamada, I. Takeuchi, Yakugaku Zasshi 2000, 120, 206.
[11] Y. Hamada, I. Takeuchi, Chem. Pharm. Bull. 1971, 19, 1857.
[12] C.-C. Cheng, S.-J. Yan, ꢃThe Friedlꢄnder Synthesis of Quinolinesꢀ, in ꢃOrganic Reactionsꢀ, Vol. 28,
Ed. W. C. Dauben, J. Wiley & Sons, New York, 1982, p. 37; D.-Q. Yang, F. Lꢂ, W. Guo, Chin. J. Org.
Chem. 2004, 24, 366; P. G. Dormer, K. K. Eng, R. N. Farr, G. R. Humphrey, J. C. McWilliams, P. J.
Reider, J. W. Sager, R. P. Volante, J. Org. Chem. 2003, 68, 467.

966
Helvetica Chimica Acta – Vol. 92 (2009)
[13] a) B. Gangadasu, P. Narender, S. B. Kumar, M. Ravinder, B. Anada Rao, C. Ramesh, B. C. Raju, V. J.
Rao, Tetrahedron 2006, 62, 8398; b) P. Narender, B. Gangadasu, M. Ravinder, U. Srinivas, G. Y. S. K.
Swamy, K. Ravikumar, V. J. Rao, Tetrahedron 2006, 62, 954; c) P. Narender, U. Srinivas, M.
Ravinder, B. Anand Rao, C. Ramesh, K. Harakishore, B. Gangadasu, U. S. N. Murthy, V. J. Rao,
Bioorg. Med. Chem. 2006, 14, 4600; d) P. Narender, U. Srinivas, B. Gangadasu, S. Biswas, V. J. Rao,
Bioorg. Med. Chem. Lett. 2005, 15, 5378; e) P. Narendar, B. Gangadasu, C. Ramesh, B. C. Raju, V. J.
Rao, Synth. Commun. 2004, 34, 1097; f) K. Srinivas, U. Srinivas, V. J. Rao, K. Bhanuprakash, K. H.
Kishore, U. S. N. Murthy, Bioorg. Med. Chem. Lett. 2005, 15, 1121.
[14] D. Basavaiah, K. V. Rao, R. J. Reddy, Chem. Soc. Rev. 2007, 36, 1581; V. Singh, S. Batra, Tetrahedron
2008, 64, 4511; D. Basavaiah, P. D. Rao, R. S. Hyma, Tetrahedron 1996, 52, 8001; E. Ciganek,
ꢃOrganic Reactionsꢀ, Vol. 51, John Wiley & Sons, New York, 1997, pp. 201 – 350; S. E. Drewes,
G. H. P. Roos, Tetrahedron 1988, 44, 4653; P. Langer, Angew. Chem., Int. Ed. 2000, 39, 3049.
[15] a) J. N. Kim, H. J. Lee, K. Y. Lee, H. S. Kim, Tetrahedron Lett. 2001, 42, 3737; b) J. N. Kim, K. Y. Lee,
H. S. Kim, T. Y. Kim, Org. Lett. 2000, 2, 343; c) O. B. Familoni, P. T. Kaye, P. J. Klaas, Chem.
Commun. 1998, 2563; d) D. Basavaiah, R. M. Reddy, N. Kumaragurubaran, D. S. Sharada,
Tetrahedron 2002, 58, 3693.
[16] D. Basavaiah, M. Krishnamacharyulu, R. S. Hyma, P. K. S. Sarma, N. Kumaragurubaran, J. Org.
Chem. 1999, 64, 1197; P. L. H. Mason, N. D. Emslie, Tetrahedron 1994, 50, 12001.
[17] Y. M. Chung, H. J. Lee, S. S. Hwang, J. N. Kim, Bull. Korean Chem. Soc. 2001, 22, 799.
[18] M. Grignon-Dubois, F. Diaba, M.-C. Grellier-Marly, Synthesis 1994, 800; F. Diaba, C. Le Houerou,
M. Grignon-Dubois, P. Gerval, J. Org. Chem. 2000, 65, 907; F. Diaba, I. Lewis, M. Grignon-Dubois, S.
Navarre, J. Org. Chem. 1996, 61, 4830.
[19] D. E. Minter, P. L. Stotter, J. Org. Chem. 1981, 46, 3965; F. W. Fowler, J. Org. Chem. 1972, 37, 1321;
D. L. Comins, A. H. Abdullah, J. Org. Chem. 1982, 47, 4315.
[20] K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horagushi, Chem. Commun. 2004, 470;
V. Singh, R. Pathak, S. Kanojiya, S. Batra, Synlett 2005, 2465.
[21] D. Basavaiah, K. Padmaja, T. Satyanarayana, Synthesis 2000, 1662 and ref. cit. therein; D. Basavaiah,
A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811; H. S. Kim, T. Y. Kim, K. Y. Lee, Y. M.
Chung, H. J. Lee, J. N. Kim, Tetrahedron Lett. 2000, 41, 2613.
[22] H. Staudinger, E. Hauser, Helv. Chim. Acta 1921, 4, 861; A. Patra, A. K. Roy, S. Batra, A. P. Bhaduri,
Synlett 2002, 1819; Y. G. Gololobov, I. N. Zhumurova, L. F. Kashukin, Tetrahedron 1981, 37, 437.
Received September 12, 2008