Facile and selective synthesis of chloronicotinaldehydes by the Vilsmeier reaction

Article abstract of DOI:10.1016/j.tet.2006.06.026

Eleven enamides were prepared by adopting different procedures. The various enamides prepared were subjected to Vilsmeier reaction using (i) POCl₃/DMF; (ii) diphosgene/DMF; (iii) triphosgene/DMF leading to the formation of various multisubstituted chloronicotinaldehydes. Studies carried out indicate that Vilsmeier reagent concentration and the replacement of POCl₃ by diphosgene or triphosgene, provides excellent selectivity and higher yields. Under modified reaction conditions one can get only chloronicotinaldehydes and not the chloropyridines as products. The various advantages in using diphosgene and triphosgene are illustrated. The mechanism of formation of chloronicotinaldehyde was discussed.

Full text of DOI:10.1016/j.tet.2006.06.026

Tetrahedron 62 (2006) 8398–8403
Facile and selective synthesis of chloronicotinaldehydes
by the Vilsmeier reaction
B. Gangadasu, P. Narender, S. Bharath Kumar, M. Ravinder, B. Ananda Rao,
*
Ch. Ramesh, B. China Raju and V. Jayathirtha Rao
Organic Chemistry Division II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 007, Andhra Pradesh, India
Received 16 January 2006; revised 30 May 2006; accepted 8 June 2006
Available online 7 July 2006
Abstract—Eleven enamides were prepared by adopting different procedures. The various enamides prepared were subjected to Vilsmeier
reaction using (i) POCl3/DMF; (ii) diphosgene/DMF; (iii) triphosgene/DMF leading to the formation of various multisubstituted chloronico-
tinaldehydes. Studies carried out indicate that Vilsmeier reagent concentration and the replacement of POCl3 by diphosgene or triphosgene,
provides excellent selectivity and higher yields. Under modified reaction conditions one can get only chloronicotinaldehydes and not the
chloropyridines as products. The various advantages in using diphosgene and triphosgene are illustrated. The mechanism of formation of
chloronicotinaldehyde was discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2-chloropyridines, pyridones, and quinolines using en-
amides under Vilsmeier reaction conditions.12 This led us to
conduct a systematic investigation on the feasibility of cycli-
zation of enamides under Vilsmeier conditions to synthesize
chloronicotinaldehydes. These chloronicotinaldehydes are
very good precursors for the synthesis of arachidonic acid
metabolite heterocyclic analogues 8-HETE.13,14 Our con-
tinuing interest in the synthesis of heterocycles for biological
activity15 led us to report a facile and an efficient method for
the synthesis of various substituted chloronicotinaldehydes
(pyridine-3-carboxaldehyde) from enamides. Studies carried
out on the formation of chloronicotinaldehydes in Vilsmeier
reactions dramatically improved the selectivity and yield by
using diphosgene/triphosgene compared to classical method
of using POCl3 in the formation of Vilsmeier reagent.
Among heterocyclic compounds, pyridine and its derivatives
are important compounds and are present in many biological
systems.1,2 Among the various applications of these pyridine
derivatives, the pharmaceutical and agrochemical3 applica-
tions are more important. Extensive studies have been car-
ried out on the synthesis of pyridine compounds owing to
their wide importance as drugs, biologically active natural
products, and for other various applications. Introducing
a formyl group into the aromatic ring system of pyridine is
particularly significant, considering the lack of reactivity
of pyridines toward electrophilic substitution reactions com-
pared to benzenoids. The formyl group present on the pyri-
dine ring opens up the possibility of carrying out a diverse
range of functional group transformations. Furthermore,
chloronicotinaldehydes are very good precursors for annula-
tion of a wide variety of heterocyclic ring systems.
2. Results and discussion
Vilsmeier reaction was initially used for the formylation of
activated aromatic substrates and carbonyl compounds;4 it
is now used as a powerful synthetic tool for the construction
of many heterocyclic compounds5–10 such as quinolines,
indoles, quinozolines, and pyridines. The synthesis of
various substituted chloronicotinaldehydes using Vilsmeier
reaction have been much less reported in the literature.11,12
Meth-Cohn and Westwood reported the synthesis of
Various enamides (1–11; Scheme 1) were prepared for the
purpose of synthesizing various chloronicotinaldehydes
(12–22; Scheme 1). Enamides 1–5 were synthesized by con-
densing appropriate aldehyde with benzylamine16 to form
initially a Schiff base and followed by acetylation17 using
acetic anhydride and triethylamine. Aldol condensation of
benzaldehyde/p-methoxybenzaldehyde with acetone pro-
vided an a,b-unsaturated ketones, which were converted
into the corresponding oximes and subsequent treatment
11
using PCl5 afforded enamides 6 and 7. Enamide 8 was
Keywords: Enamides; Vilsmeier reaction; Diphosgene/triphosgene; Chloro-
nicotinaldehydes; Selectivity; Mechanism.
* Corresponding author. Tel.: +91 40 2716 0123x2541; fax: +91 40 2716
0757; e-mail: jrao@iict.res.in
prepared by treating propiophenone oxime with Fe powder
in the presence of acetic anhydride and acetic acid.18 b-
Keto ester was first converted into an enamine derivative,
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.026

B. Gangadasu et al. / Tetrahedron 62 (2006) 8398–8403
Table 1. Synthesis of substituted chloronicotinaldehydes
8399
which was acetylated to give enamide19 9. Serine and threo-
nine methyl ester hydrochlorides20 were prepared and then
S.No.
Enamides (1–11)
Chloronicotinaldehydes
(12–22)
Yieldsa
(%)
converted into the corresponding enamides21,22 10 and 11.
H3C
CHO
Cl
R2
H3C
C2H5
POCl3
(or)
R2
R1
CHO
Cl
1
94
N
Bz
O
+
Triphosgene
(or)
+
R1
N
O
DMF
N
N
R3
Diphosgene
C2H5
n-C3H7
i-C3H7
1
-
11
12-22
CHO
Cl
Chloronicotinaldehyde
Enamide
2
3
4
5
92
92
91
90
N
Bz
O
12: R1 = H; R2 = Me
1: R1 = H; R2 = Me; R3 = CH2-Ph
2: R1 = H; R2 = Et; R3 = CH2-Ph
3: R1 = H; R2 = n-Pr; R3 = CH2-Ph
4: R1 = H; R2 = i-Pr; R3 = CH2-Ph
5: R1 = H; R2 = Pent; R3 = CH2-Ph
6: R1 = H; R2 = Ph; R3 = H
N
13: R1 = H; R2 = Et
14: R1 = H; R2 = n-Pr
15: R1 = H; R2 = i-Pr
CHO
Cl
n-C3H7
i-C3H7
n-C5H11
16: R1 = H; R2 = Pent
17: R1 = H; R2 = Ph
N
Bz
O
18: R1 = H; R2 = p-(OCH3)C6H4
19: R1 = Ph; R2 = CH3
20: R1 = Ph; R2 = CO2Et
21: R1 = CO2Me; R2 = H
22: R1 = CO2Me; R2 = CH3
7: R1 = H; R2 = p-(OCH3)C6H4; R3 = H
8: R1 = Ph; R2 = Me; R3 = H
N
9: R1 = Ph; R2 = CO2Et; R3 = H
10: R1 = CO2Me; R2 = H; R3 = H
11: R1 = CO2Me; R2 = CH3; R3 = H
CHO
Cl
N
Bz
O
Scheme 1.
N
Scheme 1 illustrates the synthesis of various chloronicotin-
aldehydes (Table 1). A DMF solution of enamide was added
to the excess Vilsmeier reagent (7 equiv) initially prepared
from DMF and POCl3/diphosgene/triphosgene. The reaction
mixture was held at room temperature and then refluxed
atw75 ꢀC. The crude product was extracted and purified by
column chromatography (Table 1). Various chloronicotin-
aldehydes 12–22 were synthesized with very good yields by
using enamides 1–11 that are listed in Table 1.
n-C5H11
CHO
Cl
N
Bz
O
N
CHO
Cl
6
92
N
H
O
N
H3CO
H3CO
The results arranged in Table 2 show that the selectivity
toward the formation of chloronicotinaldehyde improved
upon increasing Vilsmeier reagent concentration. Enamide 1
was used for the studies as a representative example to
understand selectivity and yield improvements. Upon using
2.5 equiv of Vilsmeier reagent (entry 1; Table 2) the yield of
chloronicotinaldehyde 12 was less and 2-chloro-5-methyl-
pyridine 23 was the major product (Scheme 2). Using excess
of Vilsmeier reagent (7 equiv entry 5; Table 2), chloronico-
tinaldehyde 12 was obtained as the major product with a
trace amount of 2-chloro-5-methylpyridine 23 (Scheme 2).
Replacing POCl3 by triphosgene (entries 9 and 10; Table 2)
provided the same selectivity in the formation of chloronico-
tinaldehyde but with higher yields (Scheme 2). The diphos-
gene (liquid) or triphosgene (solid) are employed because
they are safe substitutes for the toxic phosgene gas, offer
mild reaction conditions, provide excellent yields, and avoid
the formation of inorganic phosphorus salts. The same pro-
cedure was extended to other enamides 2–11 and the corre-
sponding chloronicotinaldehydes 13–22 were synthesized in
higher yields (Table 1).
CHO
7
8
92
90
88
N
H
O
N
Cl
H3C
O
H3C
O
CHO
N
H
O
O
N
N
Cl
CHO
Cl
EtO
EtO
9
N
H
CHO
Cl
10
90
90
MeO2C
H3C
N
MeO2C
H3C
N
O
H
CHO
Cl
11
MeO2C
N
H
O
MeO2C
N
a
Isolated yields using diphosgene/triphosgene.
A mechanism is proposed to explain the formation of chloro-
nicotinaldehydes with selectivity (Scheme 3). The enamide
initially reacts with Vilsmeier reagent to form bis-enamine
havingachloro group (Scheme 3). The netresultis the forma-
tion of a more nucleophilic bis-enamine. The bis-enamine
undergoes formylation to produce two possible mono-formyl-
ated bis-enamines. The mono-formylated bis-enamine can
undergo cyclization to give 2-chloro-5-methyl pyridine23
(23) or the mono-formylated bis-enamine can undergo sec-
ond formylation before undergoing cyclization. The second
formylation process is quite possible at higher concentrations
of Vilsmeier reagent and the same was observed (Table 2;
Scheme 2). The di-formylated bis-enamine undergoes cycli-
zation to give the substituted chloronicotinaldehyde (pyri-
dine-3-carboxaldehyde), which is the main product. The
products isolated were substituted chloronicotinaldehyde
and benzyl chloride (in the case of enamides 1–5). The di-
methylamine remains in aqueous phase as amine hydrochlo-
ride after work up. These observations clearly indicate that
under modified Vilsmeier reaction conditions (i.e., at higher
Vilsmeier reagent concentrations) the enamide undergoes

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B. Gangadasu et al. / Tetrahedron 62 (2006) 8398–8403
Me
Me
OHC
Cl
Me
DMF
POCl3
2.5 eq.
+
+
+
+
2.5 eq.
Cl
Cl
N
O
N
N
12
<10%
23
45%
Ph
Enamide
1 eq.
OHC
Cl
Me
DMF
7 eq.
POCl3
7 eq.
+
+
N
O
N
N
12
64%
23
<1%
Ph
Enamide
1 eq.
OHC
Cl
Me
Cl-CO-OCCl3
(diphosgene)
OR
DMF
7 eq.
+
+
O
N
N
Cl3CO-CO-OCCl3
(triphosgene)
7 eq.
12
90%
Ph
Enamide
1 eq.
Scheme 2.
Mechanism
+
N
R
R
R
R
R
V.R
+
Cl
N
O
N
Cl
N
Cl
N
Cl
N
Imine
Ph
Ph
Ph
Ph
2-Chloro-5-alkyl
Mono-formylated
Bis-enamine
-pyridine (23)
Bis-enamine
+
+
+
+
N
N
N
N
R
R
R
R
OHC
R
H2O
Cl
N
Cl
N
Cl
N
Cl
N
Cl
N
Ph
Ph
2-Chloro-5-alkyl
-pyridine
2-Chloro-5-alkylpyridine
-3-carboxaldehyde
Mono-formylated
Di-formylated
Bis-enamine
Bis-enamine
Scheme 3.
di-formylation before undergoing cyclization to give selec-
tively chloronicotinaldehyde.
Table 2. Studies to improve the formation of chloronicotinaldehydes
3. Conclusions
No. DMF
POCl3/DP/TP Temperature Time Yield (%)
(ꢀC)
(mol equiv) (mol equiv)
(h)
12
23
Various enamides were prepared to synthesize substituted
chloronicotinaldehydes. The selectivity toward the forma-
tion of chloronicotinaldehydes was achieved at higher Vils-
meier reagent concentration. The replacement of POCl3 by
diphosgene/triphosgene provides higher yields and avoids
formation of inorganic phosphorus salts. A mechanism is
proposed to explain the selectivity.
1
2
3
4
5
6
7
8
9
2.5
4.0
5.0
6.0
7.0
8.0
8.0
8.0
2.5
2.5
4.0
5.0
6.0
7.0
8.0
8.0
8.0
2.5
7.0
75
75
75
75
75
75
90
90
75
75
5
5
5
5
5
5
5
8
5
5
<10
24
36
54
64 <1
64 <1
64 <1
64 <1
10 45
90 <1
45
25
12
6
4. Experimental
10 7.0
DP ¼ diphosgene; TP ¼ triphosgene. Enamide used is 1; isolated yields;
addition of enamide to Vilsmeier reagent (DMF–POCl3/DP/TP) was carried
out atw0 ꢀC; mol equiv with respect to enamide.
For entries 1–8 POCl3 was used and for 9 and 10 diphosgene/triphosgene
was used.
4.1. General procedure for the preparation of aldimines
Inthesynthesisofenamides1–5,thealdimineswereprepared
by condensation of appropriate aldehyde and benzylamine.16

B. Gangadasu et al. / Tetrahedron 62 (2006) 8398–8403
8401
Benzylamine (5 g, 46 mmol) was added to a 50 mL round
bottom flask fitted with magnetic stirrer and dropping funnel.
Propionaldehyde (2.71 g, 46 mmol) was added gradually
over a period of 1 h at 0 ꢀC, with constant stirring. Potassium
hydroxide flakes (1.3 g, 23 mmol) were added to the reaction
mixture at 0 ꢀC and the mixture was allowed to stand until
separation into two layers appeared complete at 0 ꢀC. The
organic layer was then removed and allowed to stand over
potassium hydroxide pellets in the refrigerator for over night.
The same procedure was adopted for making other aldimines
(Schiff bases).
To a solution of 3-amino-2-alkenoate in THF (12 mL) were
added pyridine (2 mL) and acetic anhydride (6 mL). The
reaction mixture was then heated under reflux for 24 h. Re-
action mixture was rotary evaporated to remove solvent and
triethylamine. The residue was dissolved in EtOAc (20 mL)
and the solution was washed with water (10 mL), 1 N HCl
(10 mL), 1 M KH2PO4 (10 mL), NaHCO3 (saturated,
10 mL), and brine (15 mL). After the solution was dried over
sodium sulfate, the solvent was evaporated under reduced
pressure. Chromatography of the residue on silica gel with
a solvent gradient of EtOAc in hexane (15–70%) as eluant
gave compound 9.
4.2. Preparation of various enamides
4.2.5. Preparation of methyl 2-(acetylamino)acrylate (10)
and methyl (E)-2-(acetylamino)-2-butenoate (11).20,21
Triethylamine (30 mL) was added to methyl ester of L-serine
hydrochloride (5 g, 27.9 mmol) at 0 ꢀC. After 10 min stir-
ring acetic anhydride (7.0 g, 70 mmol) was added drop
wise. The reaction mixture was allowed to stir at room tem-
perature over night. The reaction mixture was washed
with 10% sodium bicarbonate solution and extracted with
dichloromethane solvent. The obtained methyl 2-(acetyl-
4.2.1. General procedure for the preparationof N-alkenyl-
N-benzyl acetamides (1–5).17 Acetic anhydride (4.163 g,
40 mmol) was added to a stirred solution of N-benzyl pro-
pionaldimine (6 g, 40 mmol) and triethylamine (4.12 g,
40 mmol) at 0–5 ꢀC for about 30 min. The reaction mixture
was allowed to reach room temperature. Distillation under
reduced pressure yields N-benzyl-N-[(1E)-prop-1-en-1-yl]-
acetamide (1) in 88% yield. The same procedure was adopted
in making other enamides (2–5).
1
amino)acrylate (10) was characterized with H NMR and
Mass spectroscopies. The same procedure using methyl ester
of L-threonine afforded methyl (E)-2-(acetylamino)-2-bute-
noate (11).
4.2.2. Preparation of N1-[(E)-2-phenyl-1-ethenyl]acet-
amide (6) and N1-[(E)-2-(4-methoxyphenyl)-1-ethenyl]-
acetamide (7).11 Phosphorus pentachloride (3.1 g, 15 mmol)
was added to 4-phenyl-3-butene-2-one-oxime (5.0 g, 30
mmol) in dry THF (50 mL) at 0 ꢀC, and the mixture was
shaken for 30 min. The mixture was then poured slowly into
a vigorously stirred mixture of crushed ice (50 g) and 40%
aqueous potassium carbonate (50 mL), the pH being main-
tained at 7 (pH paper) by the addition of solid potassium car-
bonate. The THF layer was then removed and the resultant
solid was collected by filtration, and washed twice with light
petroleum. TLC (7:3 light petroleum–ethyl acetate) showed
the presence of E (Rf 0.40) and Z (Rf 0.52) isomers of
N1-[2-phenyl-1-ethenyl]acetamide (6) and these two com-
pounds were characterized by 1H NMR.
4.3. Synthesis of substituted chloronicotinaldehydes
4.3.1. General procedure for the synthesis of substituted
2-chloronicotinaldehydes (substituted 2-chloro-pyridine-
3-carboxaldehydes) using POCl3 (12–22). N,N-Dimethyl-
formamide (13.5 g, 185 mmol) was added to a well stirred
and cooled solution of phosphorus oxychloride (28.3 g,
185 mmol) at 0 ꢀC for 30 min and followed by N-benzyl-
N-[(1E)-prop-1-en-1-yl]acetamide (1) (5 g, 26 mmol) at
the same temperature. The ice bath was removed and the
mixture was further stirred for 2 h at room temperature.
The reaction mixture was heated to 75 ꢀC for 5 h. The
orange-yellow colored organic mass was poured into
crushed ice (200 g) with stirring. The mass was extracted
with methylene chloride (2ꢁ200 mL) and the layers were
separated. The organic layer was dried over sodium sulfate
and the solvent was removed under reduced pressure. Thus
obtained residue was subjected to column chromatography
purification on silica gel to give 2-chloro-5-methylnicotin-
aldehyde (2-chloro-5-methylpyridine-3-carboxaldehyde) (12)
in 64% yield. The same procedure was adopted in making
other chloronicotinaldehydes (13–22).
The same is carried out for the synthesis of N1-[2-(4-meth-
oxyphenyl)-1-ethenyl]acetamide (7) byusing4-[(p-methoxy)-
phenyl]-3-butene-2-one-oxime.
4.2.3. Preparation of N1-[(E)-1-phenyl-1-propenyl]acet-
amide (8).18 1-Phenyl-1-propanone oxime (5 g, 33 mmol)
was heated in acetic anhydride (3.3 g, 33 mmol) and acetic
acid (10 mL, 3 mol equiv) in the presence of iron powder
(1 g)for4 hat100 ꢀC.Themixturewasthenfiltered,extracted
with dichloromethane, and the organic layer was washed with
water and aqueous K2CO3, dried, and evaporated.
4.3.2. General procedure for the synthesis of substituted
2-chloronicotinaldehydes (substituted 2-chloro-pyridine-
3-carboxaldehydes) using triphosgene or diphosgene
(12–22). N,N-Dimethylformamide (13.5 g, 185 mmol) was
added to a cooled solution of triphosgene (28.3 g,
185 mmol), in the case of diphosgene (36.6 g, 185 mmol)
at 0–10 ꢀC for 30 min and followed by N-benzyl-N-[(1E)-
prop-1-en-1-yl]acetamide (1) (5 g, 26 mmol) at the same
temperature. The ice bath was removed and the mixture was
further stirred for 2 h at room temperature. The reaction mix-
ture was heated to 75 ꢀC for 5 h. The orange-yellow colored
organic mass was poured into ice cold water (200 g) with
stirring. The mass was extracted with methylene chloride
4.2.4. Preparation of ethyl (E)-3-(acetylamino)-3-phenyl-
2-propenoate (9).19 A solution of b-keto ester, ethyl
benzoylacetate (2.3 g, 12 mmol), and NH4OAc (4.6 g,
60 mmol) in MeOH (15 mL) was stirred at room tempera-
ture for 3 days. After the solvent was evaporated under
reduced pressure, the residue was diluted with CHCl3
(30 mL). The resulting solid was filtered off and washed
with CHCl3 (2ꢁ30 mL). The combined filtrate was washed
with water and brine, and dried over sodium sulfate. Evapo-
ration of the solvent gave 3-amino-2-alkenoate, which was
used for the next step without purification.

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B. Gangadasu et al. / Tetrahedron 62 (2006) 8398–8403
(2ꢁ200 mL). The organic layer was dried over sodium sul-
fate and the solvent was removed under reduced pressure.
Thus obtained residue was subjected to column chromato-
graphy purification on silica gel to give 2-chloro-5-methyl-
nicotinaldehyde (12) in 92% yield. The same procedure
was adopted for the preparation of other chloronicotinalde-
hydes (13–22).
4.3.2.6. 2-Chloro-5-(ethoxyacetate)-6-phenylnicotin-
aldehyde (20). Light yellow solid. Mp 72–73 ꢀC; dH
(200 MHz, CDCl3) 1.12 (t, 3H, J 7.26 Hz, Me), 4.20 (q,
2H, J 7.26 Hz, OCH2), 7.25–7.35 (m, 5H, aromatic), 9.05
(s, 1H, hetero aromatic), 10.55 (s, 1H, CHO); dC (50 MHz,
CDCl3) 188, 165, 144, 143, 138, 131, 129, 128, 123, 122,
116, 57, 14; EIMS (m/z) 289 (M+) (14), 260 (100), 244
(34), 216 (13), 153 (14), 126 (12), 77 (7); IR (KBr)
4.3.2.1. 2-Chloro-5-ethylnicotinaldehyde (13). White
solid. Mp 67–69 ꢀC; dH (200 MHz, CDCl3) 1.35 (t, 3H,
J 7.56 Hz, Me), 2.75 (m, 2H, CH2), 8.02 (s, 1H, hetero aro-
matic), 8.42 (s, 1H, hetero aromatic), 10.4 (s, 1H, CHO); dC
(50 MHz, CDCl3) 188.6, 153.2, 150.2, 138.8, 136.3, 127.6,
24.6, 14.2; EIMS (m/z) 169 (M+) (100), 153 (55), 140
(27), 132 (56), 105 (31), 90 (22), 77 (50), 63 (30), 51 (43);
IR (KBr) n 2362, 1696, 1559, 1426, 1374, 1275, 1220,
1058, 746 cmꢂ1; HRMS (EI+), exact mass calcd for
C8H8NOCl: 169.0292. Found: 169.0292.
n 1736, 1560, 1450, 1369, 1310, 1261, 1189, 735 cmꢂ1
.
Anal. Calcd for C15H12ClNO3: C, 62.18; H, 4.17; N, 4.83.
Found: C, 62.21; H, 4.21; N, 4.88.
4.3.2.7. Methyl 6-chloro-5-formyl-2-pyridincarboxy-
late (21). White solid. Mp 70–72 ꢀC; dH (200 MHz,
CDCl3) 4.0 (s, 3H, OCH3), 8.2 (d, J 3.2 Hz, 1H, hetero aro-
matic), 8.4 (d, J 3.2 Hz, 1H, hetero aromatic), 10.5 (s, 1H,
CHO); dC (50 MHz, CDCl3) 188, 163, 153, 151, 139, 131,
124, 53; EIMS (m/z) 199 (M+) (6), 169 (23), 141 (100),
112 (23), 76 (50), 59 (29); IR (KBr) n 3433, 1730, 1554,
1445, 1359, 1314, 1251, 1199, 1137, 1063, 956, 874, 813,
735 cmꢂ1. Anal. Calcd for C8H6ClNO3: C, 48.14; H, 3.02;
N, 7.01. Found: C, 48.21; H, 3.21; N, 7.08.
4.3.2.2. 2-Chloro-5-propylnicotinaldehyde (14). White
solid. Mp 34–36 ꢀC; dH (200 MHz, CDCl3) 0.9 (t, 3H,
J 7.56 Hz, Me), 1.7 (m, 2H, CH2), 2.64 (t, 2H, J 7.52 Hz,
CH2), 8.0 (s, 1H, hetero aromatic), 8.38 (s, 1H, hetero aro-
matic), 10.4 (s, 1H, CHO); dC (50 MHz, CDCl3) 189.2,
154.0, 150.7, 137.7, 137.2, 127.9, 33.7, 23.6, 13.2; EIMS
(m/z) 183 (M+) (57), 154 (100), 147 (15), 99 (15), 90 (20),
40 (36); IR (KBr) n 3376, 2960, 2871, 2364, 1695, 1587,
1432, 1378, 768 cmꢂ1; HRMS (EI+), exact mass calcd for
C9H10NOCl: 183.0450. Found: 183.0467.
4.3.2.8. Methyl 6-chloro-5-formyl-3-methyl-2-pyri-
dincarboxylate (22). White solid. Mp 43–45 ꢀC; dH
(200 MHz, CDCl3) 2.60 (s, 3H, Me), 4.0 (s, 3H, OCH3),
8.1 (s, 1H, hetero aromatic), 10.45 (s, 1H, CHO); dC
(50 MHz, CDCl3) 188, 164, 152, 148, 142, 135, 129, 53,
18; EIMS (m/z) 213 (M+) (44), 181 (54), 155 (52), 149
(75), 97 (29), 71 (56), 43 (100); IR (KBr) n 1730, 1559,
1440, 1359, 1319, 1069, 966, 874, 755 cmꢂ1. Anal. Calcd
for C9H8ClNO3: C, 50.60; H, 3.77; N, 6.55. Found: C,
50.62; H, 3.81; N, 6.58.
4.3.2.3. 2-Chloro-5-isopropylnicotinaldehyde (15).
White solid. Mp 38–39 ꢀC; dH (200 MHz, CDCl3) 1.2–1.4
(m, 6H, 2Me), 3.0 (m, 1H, CH), 8.04 (s, 1H, hetero aro-
matic), 8.44 (s, 1H, hetero aromatic), 10.4 (s, 1H, CHO);
dC (50 MHz, CDCl3) 189.1, 152.7, 150.7, 143.7, 135.3,
128.1, 30.9, 23.1; EIMS (m/z) 183 (M+) (44), 168 (100),
104 (40), 77 (40), 51 (24); IR (KBr) n 2966, 2873, 2361,
Acknowledgements
1695, 1586, 1432, 1378, 1281, 1090, 959, 771, 607 cmꢂ1
;
We thank the Director, Dr. J. S. Yadav and Dr. M. Hari Babu,
Head, Organic Division II for their interest in this work. B.G.
thanks UGC. P.N., S.B.K., and M.R. thank CSIR New Delhi
for a fellowship. IICT Communication No.: 060529.
HRMS (EI+), exact mass calcd for C9H10NOCl: 183.0450.
Found: 183.0448.
4.3.2.4. 2-Chloro-5-pentylnicotinaldehyde (16). White
solid. Mp 44–46 ꢀC; dH (200 MHz, CDCl3) 0.9 (t, 3H,
J 7.56 Hz, Me), 1.38 (m, 4H, 2CH2), 1.70 (m, 2H, CH2),
2.7 (t, 2H, J 7.52 Hz, CH2), 8.0 (s, 1H, hetero aromatic),
8.44 (s, 1H, hetero aromatic), 10.4 (s, 1H, CHO); dC
(50 MHz, CDCl3) 189.2, 153.9, 150.7, 138.0, 137.2, 128.0,
31.8, 30.9, 30.2, 22.1, 13.7; EIMS (m/z) 211 (M+) (40),
168 (75), 155 (100), 141 (27), 126 (8), 119 (15), 103 (21),
91 (47); IR (KBr) n 2930, 2864, 1696, 1588, 1431, 1337,
1281, 1154, 1071 cmꢂ1; HRMS (EI+), exact mass calcd
for C11H14NOCl: 211.0763. Found: 211.0767.
References and notes
1. Jones, G. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 5, p 167.
2. Balasubramanian, M.; Keay, J. G. Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon: Oxford, 1996; Vol. 5, p 245.
3. (a) Gavin, D. H. Tetrahedron 2004, 60, 6043; (b) Bailey, T. D.;
Goe, G. L.; Scriven, E. F. V. Chem. Heterocycl. Compd. 1984,
14, 1; (c) Thummel, R. P. Chem. Heterocycl. Compd. 1984, 14,
253; (d) Kumar, R.; Chandra, R. Adv. Heterocycl. Chem. 2001,
78, 269; (e) Hanket, T.; Brunne, R. M.; Miller, H.; Reichel, F.
Angew. Chem., Int. Ed. 1999, 38, 643.
4. Marson, C. M. Tetrahedron 1992, 48, 3659.
5. Meth-Cohn, O. Heterocycles 1993, 35, 539.
6. Guzman, A.; Ronero, M.; Maddox, M. L.; Machowski, J. M.
J. Org. Chem. 1990, 55, 5793.
7. Sreenivasulu, M.; Krishna Rao, G. S. Indian J. Chem., Sect. B
1989, 28, 584.
4.3.2.5. 2-Chloro-5-methyl-6-phenylnicotinaldehyde
(19). Light yellow solid. Mp 67–69 ꢀC; dH (200 MHz,
CDCl3) 2.42 (s, 3H, Me), 7.39–7.61 (m, 5H), 8.04 (s, 1H,
hetero aromatic), 10.42 (s, 1H, CHO); dC (50 MHz,
CDCl3) 189.2, 163.1, 149.9, 140.1, 137.8, 130.8, 129.1,
128.8, 128.1, 126.6, 19.2; EIMS (m/z) 231 (M+) (50), 230
(100), 166 (20), 139 (12), 115 (10), 77 (9); IR (KBr)
n 2442, 1690, 1540, 1420, 1370, 1265, 1224, 1048,
746 cmꢂ1. Anal. Calcd for C13H10ClNO: C, 67.39; H,
4.35; N, 6.05. Found: C, 67.46; H, 4.50; N, 6.11.

B. Gangadasu et al. / Tetrahedron 62 (2006) 8398–8403
8403
8. Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2003, 68, 3966.
Rao, V. Indian J. Chem., Sect. B 2006, 45, 1259; (e) Narender,
P.; Gangadasu, B.; China Raju, B.; Jayathirtha Rao, V. Synth.
Commun. 2004, 34, 1097; (f) Srinivas, K.; Srinivas, U.;
Jayathirtha Rao, V.; Bhanu prakash, K.; Hara Kishore, B.;
Murthy, U. S. N. Bioorg. Med. Chem. Lett. 2005, 15, 1121.
16. Cambell, K. N.; Sommers, A. H.; Cambell, B. K. J. Am. Chem.
Soc. 1944, 66, 82.
9. Chupp, J. P.; Metz, S. J. Heterocycl. Chem. 1979, 16, 65.
10. Katrtizky, A. R.; Arend, M. J. Org. Chem. 1998, 63, 9989.
11. Amaresh, R. R.; Perumal, P. T. Synth. Commun. 2000, 30, 2269.
12. Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc., Perkin Trans. 1
1984, 1173.
13. Gigou, A.; Beaucourt, J. P.; Lellouche, J. P.; Gree, R.
Tetrahedron Lett. 1991, 32, 635.
14. Caijo, F.; Mosset, P.; Gree, R.; Bouchez, V. A.; Boutin, J.;
Renard, P.; Caignard, D. H.; Dacquet, C. Bioorg. Med. Chem.
Lett. 2005, 4421.
15. (a) China Raju, B.; Jayathirtha Rao, V. U.S. Patent 6,565,528,
2003; (b) Gangadasu, B.; Palaniappan, S.; Jayathirtha Rao, V.
Synlett 2004, 1285; (c) Gangadasu, B.; Narender, P.; China
Raju, B.; Jayathirtha Rao, V. J. Chem. Res. 2004, 7, 480; (d)
Gangadasu, B.; Narender, P.; China Raju, B.; Jayathirtha
17. Breederveld, H. Recl. Trav. Chim. Pays-Bas 1960, 79, 401.
18. Burk, M. J.; Casy, G.;Johnson, N. B. J. Org. Chem. 1998,63, 6084.
19. Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907.
20. (a) Vogel’s Textbook of Practical Organic Chemistry, 4th ed.;
London: Longman, 1978; p 501; (b) Hardy, P. J.; Kerrin,
S. L.; Manatt, S. L. J. Org. Chem. 1973, 38, 4196.
21. Kolar, A. J.; Olsen, R. K. Synthesis 1977, 457.
22. Srinivasan, A.; Stephenson, R. W.; Olsen, R. K. J. Org. Chem.
1977, 42, 2256.
23. Reihard, L. W. U.S. Patent 5,304,651, 1994.