Baylis-Hillman adducts between pyridine carboxaldehyde derivatives and cyclic enones

Article abstract of DOI:10.1016/j.tet.2005.10.032

Baylis-Hillman (BH) adducts were synthesized using pyridinecarboxaldehyde derivatives and cyclic enones. The Baylis-Hillman reaction was examined by employing various organic tertiary bases and solvents. It was observed that DBU in MeOH as well as imidazo

Full text of DOI:10.1016/j.tet.2005.10.032

Tetrahedron 62 (2006) 954–959
Baylis–Hillman adducts between pyridine carboxaldehyde
derivatives and cyclic enones*
P. Narender,a B. Gangadasu,a M. Ravinder,a U. Srinivas,a G. Y. S. K. Swamy,b
a,
K. Ravikumarb, and V. Jayathirtha Rao
*
*
aOrganic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
bLaboratory of Crystallography, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
Received 26 July 2005; revised 28 September 2005; accepted 13 October 2005
Available online 8 November 2005
Abstract—Baylis–Hillman (BH) adducts were synthesized using pyridinecarboxaldehyde derivatives and cyclic enones. The Baylis–
Hillman reaction was examined by employing various organic tertiary bases and solvents. It was observed that DBU in MeOH as well as
imidazole and N-methylimidazole in aqueous MeOH are very effective. These pyridinecarboxaldehydes were reactive and efficient towards
the Baylis–Hillman reaction and the resulting adducts are highly stable. The crystal structure for one of the BH adducts was determined.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
base effects including DMAP, tributylphosphines and
DBU,11 TiCl4 (Lewis acid) without the use of Lewis base
have all been applied to highly reactive aldehydes.12
Lithium phenylselenide (PhSeLi) catalyzed Baylis–Hillman
reaction with cyclic enones,13 DMAP in aqueous THF used
as a catalyst for the Baylis–Hillman reaction between
aldehydes (aromatic and aliphatic) and cyclic enones14 have
also been reported. The Baylis–Hillman reactions involving
cyclic enones and heterocyclic compounds are less
explored. Only Kim et al. reported with quinolinecarbox-
aldehyde14b and Batra et al. reported using 5-isoxazole-
carboxaldehyde.15 To the best of our knowledge there are no
other BH reactions involving heterocyclic compounds and
cyclic enones reported in the literature. The Baylis–Hillman
reaction between pyridine carboxaldehyde/furfuraldehyde
and cyclic enones are reported to produce unstable BH
adducts.16 In contrast to earlier reports, we have success-
fully synthesized Baylis–Hillman adducts between
pyridinecarboxaldehyde derivatives and cyclic enones
under a variety of conditions. Synthesized Baylis–Hillman
adducts containing a pyridine moiety are very stable and for
one of the BH adducts an X-ray structure was also
determined. The formation of these Baylis–Hillman adducts
is found to be very fast and with high yields compared to
earlier reports. Such Baylis–Hillman adducts have wide
applicability in organic synthesis in preparation of
quinolines, naphthyridines, and aza pyrazoles.
The Baylis–Hillman (BH) reaction is one that results in the
formation of a carbon–carbon bond between the a-position
of an activated alkene and carbon electrophile containing an
electron-deficient sp2 carbon atom under the influence of a
suitable catalyst. The Baylis–Hillman (BH) and related
processes have become increasingly important for synthetic
organic chemists because the resulting adducts are packed
with functional groups and stereochemistry, which can be
subjected to numerous transformations.1 Cyclic enones are
also activated alkenes but the Baylis–Hillman reaction of
2-cyclopenten-1-one or 2-cyclohexen-1-one is sluggish or
does not occur at all under traditional conditions.2 To make
the reaction more efficient, a variety of methods including
physical as well as chemical attempts have been explored.
Recently, various organic bases and methods for the
synthesis of the Baylis–Hillman adducts of cyclic enones
have been developed. Methoxide anion in MeOH solvent,3
imidazole in aqueous media,4 azoles in basic water
solution,5 imidazole in basic water solution,6 the combi-
nation of 2,6-diphenyl-4H-chalcogeno-4-ones and TiCl4 in
methylene chloride,7 the combination of LiClO4 and
DABCO in ether,8 the use of Et2AlI in CH2Cl2,9
tributylphosphine combined with 1,1-bi-naphthol,10 Lewis
* IICT communication no. 050919.
Keywords: Baylis–Hillman reaction; Substituted 2-chloropyridine-3-
carboxaldehydes; Cyclic enones; Organic tertiary bases; Solvents;
Baylis–Hillman adducts; X-ray crystal structure.
2. Results and discussions
*
Corresponding authors. Tel./fax: C91 40 27193118 (K.R.) Tel.: C91 40
27160123; fax: C91 40 27160757 (V.J.R.); e-mail addresses:
jrao@iict.res.in; ravikumar_iict@yahoo.co.in
The Baylis–Hillman (BH) reaction was conducted using
various substituted 2-chloro-pyridine-3-carboxaldehydes17
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.032

P. Narender et al. / Tetrahedron 62 (2006) 954–959
955
OH
Cl
O
O
R2
R1
R2
CHO
Cl
1 eq. imidazole
+
n
aq MeOH
20-30 min.
R1
N
N
n
85-98%
2a-2n
n = 1
n = 2
1a-1g
1a: R1 = H, R2 = CH3
2a: R1 = H, R2 = CH3, n = 1;
2b: R1 = H, R2 = C2H5, n = 1;
2c: R1 = H, R2 = Ph, n = 1;
2h: n = 2
2i: n = 2
2j: n = 2
1b: R1 = H, R2 = C2H5
1c: R1 = H, R2 = Ph
1d: R1 = H, R2 = 4-OMe-C6H4
1e: R1 = Ph, R2 = CH3
1f: R1 = COOMe, R2 = H
1g: R1 = Ph, R2 = COOEt
2d: R1 = H, R2 = 4-OMe-C6H4, n = 1; 2k: n = 2
2e: R1 = Ph, R2 = CH3, n = 1;
2f: R1 = COOMe, R2 = H, n = 1;
2g: R1 = Ph, R2 = COOEt, n = 1;
2l: n = 2
2m: n = 2
2n: n = 2
Scheme 1.
Table 1. The Baylis–Hillman reaction between substituted pyridinecarboxaldehyde (1a–1g) and cyclic enones in the presence of imidazolea,b
Entry
Aldehyde (1a–1g)
Cyclic enone
Product (2a–2n)
Time (min)
Yield (%)c
98
1
20
2
3
20
25
98
96
4
5
6
7
20
25
15
20
90
90
85
82
8
25
25
30
90
92
96
9
10
11
12
13
14
25
30
22
25
95
92
80
78
a The reactions were conducted in MeOH–H2O, (1/1, v/v) system at room temperature and the reaction was monitored by TLC.
b Mole ratio of aldehyde/cycloalkenone/imidazoleZ1:1.2:1.
c Isolated yields.

956
P. Narender et al. / Tetrahedron 62 (2006) 954–959
(1a–g) and cyclic enones (2-cyclopenten-1-one; 2-cyclo-
hexen-1-one) in the presence of 1 equiv imidazole as an
organic base in aqueous methanol solvent system at room
temperature (Scheme 1). The BH adducts (2a–n) were
readily formed (within 15–30 min) in high yields (80–98%).
A slight excess of cyclic enone (1.2 equiv) was found to
give higher yields in these reactions. The results of these
studies are shown in Table 1. The reaction time indicated in
Table 1 represents the reactivity and efficiency of the
aldehydes towards BH reaction. The yields are somewhat
lower for entries 6, 7, 13 and 14 in Table 1 and this may be
due to the presence of the ester functionality, which can lead
to other products, which were not analyzed. All the BH
adducts were found to be stable and we determined an X-ray
crystal structure for 2a.
a variety of organic bases in MeOH:H2O (1:1) and MeOH
was carried out to understand the role of the organic tertiary
base (Table 2). The three bases imidazole,
N-methylimidazole and DMAP readily gave Baylis–Hill-
man adducts in MeOH–H2O (1/1) in excellent yields
(entries 1–3; Table 2). DABCO, DBU, trimethylamine and
triethylamine (entries 4–7; Table 2) gave Baylis–Hillman
adduct (2a) in MeOH–H2O (1/1) with lower yields along
with Aldol-type product (2o) (Scheme 2). The reaction was
found to be complete within 45 min for all these above-
mentioned bases. Other bases such as 1,2,3-triazole, 1,2,4-
triazole and pyridine in MeOH–H2O (1/1) were found to be
non-effective in the formation of BH adducts (entries 8–10;
Table 2) even after 5 h. To know the role of water, the
reaction was conducted in pure MeOH using DBU and
DMAP. The DBU base in MeOH gave the BH adduct in
excellent yield (entry 11; Table 2) without any Aldol-type
product formation, whereas DMAP gave the BH adduct
albeit in lower yield, but without formation of the Aldol-
type product. These observations show that the polar nature
of the medium used and as well as the water present are
important. To probe further the role of water, we conducted
reactions in various solvents with and without water using
2-chloro-5-methylpyridine-3-carboxaldehyde, cyclopent-2-
enone and imidazole as an organic base (Table 3). The
Baylis–Hillman adduct formation is facile in all the pure
solvents selected (Table 3), but the reaction time differs.
The presence of water in all these solvents accelerates the
formation of the BH adduct with a given selected organic
base. Particularly striking are the THF and dioxane solvents,
where the reaction time for BH adduct formation is reduced
by 6–7 times by the presence of water (entries 3–6; Table 3).
The solvents like sulfolane and DMSO have comparable
reaction times leading towards formation of BH adducts
(Table 3). It has been reported that protic solvents or polar
solvents with water accelerate BH adduct formation,
through either stabilization of enolate by hydrogen bonding
or by activation of the aldehyde through hydrogen
On crystallization, compound 2a led to crystals suitable for
single-crystal X-ray diffraction studies.19 The molecular
configuration of 2a is shown in Figure 1. Although the
molecule contains a chirotopic stereogenic atom, C6, the
crystal belongs to a centro-symmetric space group and thus
represents a racemate. The dihedral angle formed by the
plane of the pyridine ring and the cyclopent-2-enone
plane is 78.1(1)8. The hydroxyl oxygen is tilted towards
the cyclopent-2-enone due to steric interactions between the
hydroxyl group and the Cl atom as the C4–C6–O1
[111.7(1)8] bond angle is distinctly larger than that of the
C7–C6–O1 [106.6(2)8]. The C6–H6/Cl intra-molecular
interaction closes the five-membered pseudo-ring
Cl–C5–C4–C6–H6 according to the S(5) pattern.20 Similar
interactions were noted in the literature.21 The crystal
structure of (2a) is stabilized by O–H/O intermolecular
interactions forming hydrogen-bonded dimmers.22
The Baylis–Hillman reaction between 2-chloro-5-methyl-
pyridine-3-carboxaldehyde and cyclopent-2-enone using
Table 2. Effect of base on Baylis–Hillman reactiona
Entry Base
Time
(min)
Yield (%)b
Baylis–Hillman Aldol type
adduct (2o)
adduct (2a)
1
2
3
Imidazole
30
45
40
98
95
90
None
None
None
N-Methylimidazole
4-Dimethylamino-
pyridine (DMAP)
Diazabicyclooctane
(DABCO)
4
35
55
40
5
6
7
8
DBU
Me3N/H2O
Et3N
30
25
25
300
300
300
20
38
45
35
25
40
38
None
None
None
None
None
1,2,3-Triazole
1,2,4-Triazole
Pyridine
Nonec
Nonec
15c
98
9
10
11
12
DBU (in MeOH)d
DMAP (in MeOH)d
120
35
a The reaction was conducted between 2-chloro-5-methyl-3-pyridine-
carboxaldehyde (1a; 1 equiv) and cyclopent-2-enone (1.2 equiv) in the
presence of 1 equiv of base in MeOH–H2O (1/1, v/v) solvent system at
room temperature and the reaction was monitored by TLC.
b Isolated yields.
c Aldehyde was recovered.
d Pure MeOH as medium.
Figure 1. A view of product 2a with the atomic numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level.

P. Narender et al. / Tetrahedron 62 (2006) 954–959
957
OH
O
OH
Cl
O
O
H3C
H3C
CHO
Cl
H3C
base
+
+
solvent
N
Cl
N
N
2a
2o
Aldol type
product
Baylis-Hillman
adduct
Scheme 2.
Table 3. Effects of medium on the BH reactiona
reaction mixture was added cyclic enone (1.2 mmol) at
room temperature and the reaction progress was monitored by
TLC. Upon completion of the reaction, the reaction mixture
was acidified with aqueous HCl (5 mL) and extracted with
CHCl3 (3!20 mL). Combined organic layers were washed
with brine solution (2!10 mL). The organic layer was
concentrated and column chromatography of the crude
product on silica gel, using 30% ethyl acetate in hexane as
eluent, gave pure Baylis–Hillman adduct (2a–2n).
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
MeOH
90
30
360
50
95
98
65
90
75
82
65
90
80
75
MeOH/H2O
THF
THF/H2O
4
5
6
7
8
9
10
Dioxane
300
45
360
120
100
110
Dioxane/H2O
Dimethylformamide (DMF)
DMF/H2O
Sulpholane
DMSO
4.3. Characterization data
a The reaction was conducted using 2-chloro-5-methyl-3-pyridine-
carboxaldehyde (1a; 1 mmol) and cyclopent-2-enone (1.2 mmol) in the
presence of 1 mmol of imidazole at room temperature and the reaction
was monitored by TLC.
4.3.1. 2-[(2-Chloro-5-methylpyridine-3-yl)(hydroxy)
methyl]cyclopent-2-en-1-one (2a). White Solid; Mp
120–123 8C; H NMR (200 MHz, CDCl3): d 8.16 (d, JZ
2.3 Hz, 1H), 7.82 (d, JZ2.3 Hz, 1H), 7.14 (t, JZ3.4 Hz, 1H),
5.78 (s, 1H), 4.18 (s, 1H), 2.65 (m, 2H), 2.52 (m, 2H), 2.4 (s,
3H); 13C NMR: (50 MHz, CDCl3): d 209.6, 160.5, 148.7,
146.1, 145.0, 137.6, 134.9, 132.8, 65.6, 35.1, 26.7, 17.7; MS
EI (m/z): 237 (MC), 202, 156, 117, 92, 39; IR (KBr): 3436,
2983, 1683 cmK1. Anal. Calcd for C12H12ClNO2: C, 60.61;
H, 5.13; N, 5.89%; Found: C, 60.80; H, 5.23; N, 5.98%.
1
b Isolated yields.
bonding.18 All these observations show that it is important
to choose the correct organic base and solvent for a given
aldehyde in conducting the Baylis–Hillman reaction.
3. Summary
4.3.2. 2-[(2-Chloro-5-ethylpyridine-3-yl)(hydroxy)-
methyl]cyclopent-2-en-1-one (2b). White Solid; Mp
107–110 8C; H NMR (200 MHz, CDCl3): d 8.08 (d, JZ
2-Chloropyridine-3-carboxaldehyde derivatives were inves-
tigated as highly reactive substrates toward Baylis–Hillman
reaction with cyclic enones. The influence of organic
tertiary base and reaction media was significant. This may
be the fastest Baylis–Hillman reaction with cyclic enones
observed with respect to aldehyde substrates. The Baylis–
Hillman adducts involving pyridine heterocycle are found to
be stable and an X-ray structure for one of the Baylis–
Hillman adducts was solved.
1
2.3 Hz, 1H), 7.78 (d, JZ2.3 Hz, 1H), 7.07 (t, JZ3.7 Hz,
1H), 5.70 (s, 1H), 4.42 (br, 1H), 2.66 (q, JZ7.4 Hz, 2H),
2.54 (m, 2H), 2.4 (m, 2H), 1.20 (t, JZ7.4 Hz, 3H); 13C
NMR: (50 MHz, CDCl3): d 209.3, 160.6, 147.6, 145.9,
145.0, 138.8, 136.4, 135.1, 65.1, 34.8, 26.5, 25.2, 14.8; MS
EI (m/z): 251 (MC), 216, 170, 131, 104, 53; IR (KBr): 3462,
2921, 1662 cmK1. Anal. Calcd for C13H14ClNO2: C, 62.03;
H, 5.61; N, 5.56%; Found: C, 62.44; H, 5.98; N, 5.74%.
4. Experimental
4.3.3. 2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy)-
methyl]cyclopent-2-en-1-one (2c). White solid; Mp 112–
114 8C; 1H NMR (200 MHz, CDCl3): d 8.53 (d, JZ3.0 Hz,
1H), 8.21 (d, JZ3.0 Hz, 1H), 7.36–7.59 (m, 5H), 7.16 (t,
JZ3.2 Hz, 1H), 5.83 (s, 1H), 4.34 (s 1H), 2.46–2.72 (m,
4H); 13C NMR: (50 MHz, CDCl3): d 209.0, 160.1, 147.1,
146.1, 144.4, 135.8, 135.7, 135.5, 135.0, 128.6, 128.0,
126.6, 126.5, 65.1, 34.6, 26.1; MS (EI) m/z: 299 (MC), 264,
236, 153, 77; IR (KBr): 3432, 2989, 1643 cmK1. Anal.
Calcd for C17H14ClNO2: C, 68.18; H, 4.70; N, 4.67%;
Found: C, 68.24; H, 4.83; N, 4.87%.
4.1. General methods
All activated alkenes and tertiary amines were obtained
commercially. The melting points were determined on a
Mel-Temp apparatus and are uncorrected. IR was recorded
with a Perkin-Elmer model 1600 series FTIR spectrometer
using KBr optics. All 1H NMR and 13C NMR spectra were
recorded on a 200 and 50 MHz, respectively. EIMS were
detected on VG Micromass 7070H (70 eV). Aldehydes
were synthesized according to the earlier published work by
us.17
4.3.4. 2-[(2-Chloro-5-(4-methoxyphenyl)pyridine-3-l)-
(hydroxy)methyl]cyclopent-2-en-1-one (2d). White solid;
1
Mp 110–114 8C; H NMR (200 MHz, CDCl3): d 8.43 (d,
4.2. Typical experimental procedure
JZ2.3 Hz, 1H), 8.13 (d, JZ2.3 Hz, 1H), 7.49 (m, 2H), 7.17
(t, JZ3.9 Hz, 1H), 6.92 (m, 2H), 5.8 (s, 1H), 3.81 (s, 3H),
2.53 (m, 2H), 2.45 (m, 2H); MS (EI) m/z: 329 (MC), 294,
The clear solution of aldehyde (1a–1g) (1 mmol) and
imidazole (1 equiv) in 5 mL of MeOH was slowly charged
with 5 mL of deionized water. To a stirred homogeneous
276, 251, 107, 65; IR (KBr): 3487, 2993, 1674, 1323 cmK1
.

958
P. Narender et al. / Tetrahedron 62 (2006) 954–959
Anal. Calcd for C18H16ClNO3: C, 65.56; H, 4.89; N, 4.25%;
Found: C, 65.87; H, 5.12; N, 4.45%.
4.3.10. 2-[(2-Chloro-5-phenylpyridine-3-yl)(hydroxy)-
methyl]cyclohex-2-en-1-one (2j). White solid; Mp
116–118 8C; H NMR (200 MHz, CDCl3): d 8.51 (d, JZ
1
2.6 Hz, 1H), 8.19 (d, JZ2.6 Hz, 1H), 7.34–7.64 (m, 5H),
6.54 (t, JZ4.3 Hz, 1H), 5.8 (s, 1H), 3.88 (br, 1H), 2.35–2.6
(m, 4H), 2.05 (m, 2H); 13C NMR: (50 MHz, CDCl3): d
200.3, 148.5, 148.0, 146.4, 138.6, 136.4, 136.0, 135.8,
135.4, 129.0, 128.4, 127.0, 68.5, 38.3, 25.8, 22.3; MS (EI)
m/z: 313 (MC), 278, 260, 217, 71, 57; IR (KBr): 3424,
2924, 1685 cmK1. Anal. Calcd for C18H16ClNO2: C, 68.90;
H, 5.14; N, 4.46%; Found: C, 69.12; H, 5.27; N, 4.48%.
4.3.5. 2-[(2-Chloro-5-methyl-6-phenylpyridine-3-yl)-
(hydroxy)methyl]cyclopent-2-en-1-one (2e). White solid;
1
Mp 138–142 8C; H NMR (200 MHz, CDCl3): d 7.85 (s,
1H), 7.35–7.55 (m, 5H), 7.23 (t, JZ3.0 Hz, 1H), 5.81 (s,
1H), 4.09 (s, 1H), 2.62–2.68 (m, 2H), 2.48–2.55 (m, 2H), 2.4
(s, 3H); 13C NMR: (50 MHz, CDCl3): d 210.0, 160.4, 157.9,
145.5, 144.7, 139.4, 138.8, 133.3, 130.4, 129.0, 128.4,
128.2, 66.2, 35.1, 26.7, 19.4; MS (EI) m/z: 313 (MC), 278,
50, 235, 193, 115, 77; IR (KBr): 3402, 2981, 1663 cmK1
.
Anal. Calcd for C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46%;
Found: C, 69.12; H, 5.43; N, 4.76%.
4.3.11. 2-[(2-Chloro-5-(4-methoxyphenyl) pyridine-3-yl)-
(hydroxy)methyl]cyclohex-2-en-1-one (2k). Pale yellow;
1
Mp 110–113 8C; H NMR (200 MHz, CDCl3): d 8.45 (d,
JZ2.1 Hz, 1H), 8.12 (d, JZ2.1 Hz, 1H), 7.5 (m, 2H), 6.95
(m, 2H), 6.55 (t, JZ4.3 Hz, 1H), 5.78 (s, 1H), 3.82 (s, 3H),
2.3–2.6 (m, 4H), 2.02 (m, 2H); 13C NMR: (50 MHz,
CDCl3): d 200.5, 160.1, 148.5, 147.4, 146.1, 138.7, 135.7,
135.3, 135.2, 128.8, 128.2, 114.6, 68.8, 55.4, 38.4, 25.8,
22.4, 19.1; MS (EI) m/z: 343 (MC), 308, 290, 247, 107, 65.
Anal. Calcd for C19H18ClNO3: C, 66.38; H, 5.28; N, 4.07%;
Found: C, 66.97; H, 5.56; N, 4.34%.
4.3.6. Methyl-6-chloro-5-[hydroxy(5-oxo-cyclopent-1-
en-1-yl)methyl]pyridine-2-carboxylate (2f). Pale yellow
solid; Mp 76–79 8C; 1H NMR (200 MHz, CDCl3): d 8.22 (d,
JZ7.7 Hz, 1H), 8.13 (d, JZ7.7 Hz, 1H), 7.17 (t, JZ2.2 Hz,
1H), 5.89 (s, 1H), 4.01 (s, 3H), 2.65 (m, 2H), 2.5 (m, 2H);
13C NMR: (50 MHz, CDCl3): d 209.3, 164.2, 160.7, 148.8,
146.9, 144.2, 139.8, 137.9, 124.1, 65.7, 52.9, 34.9, 26.7; MS
(EI) m/z: 281 (MC), 246, 218, 202, 188, 122, 69; IR (KBr):
3414, 2954, 1723, 1689, 1315 cmK1. Anal. Calcd for
C13H12ClNO4: C, 55.43; H, 4.29; N, 4.97%; Found: C,
55.67; H, 4.67; N, 5.14%.
4.3.12. 2-[(2-Chloro-5-methyl-6-phenylpyridine-3-yl)-
(hydroxy)methyl]cyclohex-2-en-1-one (2l). White solid;
1
Mp 134–136 8C; H NMR (200 MHz, CDCl3): d 7.87 (s,
1H), 7.35–7.55 (m, 5H), 6.65 (t, JZ3.9 Hz, 1H), 5.80 (s,
1H), 3.86 (br, 1H), 2.5 (m, 2H), 2.41 (m, 2H), 2.4 (s, 3H),
2.0 (m, 2H); 13C NMR: (50 MHz, CDCl3): d 200.6, 157.7,
148.5, 146.0, 139.9, 138.9, 138.7, 133.4, 130.2, 129.0,
128.4, 128.2, 68.7, 38.4, 25.8, 22.4, 19.4; MS (EI) m/z: 327
(MC), 311, 291, 273, 249, 218, 117; IR (KBr): 3405, 2912,
1612 cmK1. Anal. Calcd for C19H18ClNO2: C, 69.62; H,
5.53; N, 4.27%; Found: C, 70.07; H, 5.74; N, 4.56%.
4.3.7. Ethyl 6-chloro-5-[hydroxy(5-oxo-1-cyclopentenyl)-
methyl]-2-phenyl nicotinate (2g). Pale yellow; Mp
1
123–126 8C; H NMR (200 Hz, CDCl3): d 8.87 (s, 1H),
7.6 (m, 2H), 7.42 (m, 3H), 7.22 (t, JZ3.7 Hz, 1H), 5.92 (s,
1H), 4.2 (q, JZ6.8 Hz, 2H), 2.65 (m, 2H), 2.5 (m, 2H), 1.1
(t, JZ6.7 Hz, 3H). 13C NMR: (50 MHz, CDCl3): d 209.6,
165.6, 161.2, 149.1, 148.1, 145.8, 139.2, 136.4, 134.4,
132.7, 129.1, 128.4, 124.7, 65.5, 54.2, 36.0, 25.2, 14.3; MS
(EI) m/z: 371 (MC), 336, 318, 275, 263, 178, 77; IR (KBr):
3423, 2967, 1733, 1646, 1328 cmK1. Anal. Calcd for
C20H18ClNO4: C, 64.61; H, 4.88; N, 3.77%; Found: C,
64.92; H, 5.09; N, 3.78%.
4.3.13. Methyl-6-chloro-5-[hydroxy(6-oxo-cyclohex-1-
en-1-yl)methyl]pyridine-2-carboxylate (2m). Pale yellow;
1
Mp 67–70 8C; H NMR (200 MHz, CDCl3): d 8.18 (d, JZ
7.5 Hz, 2H), 8.12 (d, JZ7.5 Hz, 1H), 6.56 (t, JZ3.8 Hz,
1H), 5.85 (s, 1H), 4.00 (s, 3H), 2.5 (m, 2H), 2.4 (m, 2H),
2.05 (m, 2H); 13C NMR: (50 MHz, CDCl3): d 199.9, 164.3,
149.2, 148.7, 146.8, 139.9, 138.3, 123.9, 68.5, 52.9, 38.2,
25.7, 22.2; MS (EI) m/z: 295 (MC), 260, 232, 229,
201, 160, 112, 59; IR (KBr): 3494, 2953, 1727, 1651,
1315 cmK1. Anal. Calcd for C14H14ClNO4: C, 56.86; H,
4.77; N, 4.74%; Found: C, 57.12; H, 4.98; N, 4.98%.
4.3.8. 2-[(2-Chloro-5-methylpyridine-3-yl)(hydroxy)-
methyl]cyclohex-2-en-1-one (2h). White solid; Mp
105–107 8C; H NMR (200 MHz, CDCl3): d 8.11 (d, JZ
1
2.3 Hz, 1H), 7.78 (d, JZ2.3 Hz, 1H), 6.47 (t, JZ4.1 Hz,
1H), 5.72 (s, 1H), 2.5 (m, 2H), 2.38 (s, 3H), 2.38 (m, 2H),
2.03 (m, 2H); 13C NMR: (50 MHz, CDCl3): d 200.2, 148.5,
148.2, 138.7, 137.9, 134.7, 132.5, 68.4, 38.3, 25.7, 22.3,
17.7; MS EI (m/z): 251 (MC), 216, 198, 116, 84, 65, 48; IR
(KBr): 3425, 2957, 1673 cmK1
. Anal. Calcd for
4.3.14. Ethyl 6-chloro-5-[hydroxy(5-oxo-1-cyclohexe-
nyl)methyl]-2-phenyl nicotinate (2n). Pale yellow; Mp
C13H14ClNO2: C, 62.01; H, 5.64; N, 5.56%; Found: C,
62.24; H, 5.74; N, 5.68%.
1
112–115 8C; H NMR (200 MHz, CDCl3): d 8.87 (s, 1H),
7.6 (m, 2H), 7.4 (m, 3H), 6.60 (t, JZ4.4 Hz, 1H), 5.95 (s,
1H), 4.2 (q, JZ7.5 Hz, 2H), 2.38–2.57 (m, 4H), 2.02 (m,
2H), 1.1 (t, JZ7.5 Hz, 3H); MS (EI) m/z: 385 (MC), 350,
332, 321, 278, 165, 73; IR (KBr): 3421, 2949, 1746, 1678,
1347 cmK1. Anal. Calcd for C21H20ClNO4: C, 65.37; H,
5.22; N, 3.63%; Found: C, 65.78; H, 5.67; N, 3.78%.
4.3.9. 2-[(2-Chloro-5-ethyl pyridine-3-yl)(hydroxy)-
methyl]cyclohex-2-ene-1-one (2i). Pale yellow; Mp
98–102 8C; H NMR (200 MHz, CDCl3): d 8.06 (d, JZ
1
2.4 Hz, 1H), 7.76 (d, JZ2.4 Hz, 1H), 6.5 (t, JZ4.0 Hz, 1H),
5.72 (s, 1H), 4.22 (br, 1H), 2.64 (q, JZ8.0 Hz, 2H), 2.5 (m,
2H), 2.38 (m, 2H), 1.99 (m, 2H), 1.28 (t, JZ8.0 Hz, 3H);
13C NMR: (50 MHz, CDCl3): d 200.2, 149.4, 148.9, 139.1,
138.8, 135.3, 134.2, 128.1, 67.7, 38.0, 25.9, 25.8, 22.3, 14.9;
MS EI (m/z): 265 (MC), 230, 212, 130, 98, 79, 62. Anal.
Calcd for C14H16ClNO2: C, 63.28; H, 6.07; N, 5.27%;
Found: C, 63.54; H, 6.42; N, 5.44%.
Acknowledgements
We thank Director, IICT and Head of the Division Organic
II for the continued encouragement. P.N. and M.RV. thanks

P. Narender et al. / Tetrahedron 62 (2006) 954–959
959
13. Jauch, J. J. Org. Chem. 2001, 66, 609.
CSIR-New Delhi, B.GD. and U.S. thanks UGC-New Delhi
for the fellowships.
14. (a) Rezgui, F.; EI Gaied, M. M. Tetrahedron Lett. 1998, 39,
5965. (b) Lee, K. Y.; Gong, J. H.; Kim, J. N. Bull. Korean.
Chem. Soc. 2002, 23, 659.
15. Patra, A.; Batra, S.; Joshi, B. S.; Roy, R.; Kundu, B.; Bhaduri,
A. J. Org. Chem. 2002, 67, 5783.
References and notes
16. Luo, S.; Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng, J.-P.
Tetrahedron Lett. 2002, 43, 7369.
1. (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2,155,113,
1972; Chem. Abstr. 1972, 77, 34174q. (b) Drewes, S. E.; Roos,
G. H. P. Tetrahedron 1988, 44, 4653. (c) Basavaiah, D.;
Dharma Rao, P.; Suguna, Hy. Tetrahedron 1996, 52, 8001. (d)
Ciganek, E. Org. React. 1997, 51, 201. (e) Basavaiah, D.;
Jaganmohan Rao, A.; Satyanarayana, T. Chem. Rev. 2003,
103, 811.
17. Gangadasu, B.; Chinaraju. B.; Jayathirtha Rao. V., U.S. Patent
6,479,664, 2002; Chem.Abstr. 2002, 137, 352892.
18. Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org.
Chem. 2002, 67, 510.
19. A colorless cube crystal of compound 1 was obtained from
chloroform. The crystal belongs to the triclinic crystal system,
space group P-1 with aZ7.6654 (7), bZ7.8985 (7), cZ
2. (a) Shi, M.; Li, C.-Q.; Jiang, J.-K. Chem. Commun. 2001, 833.
(b) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049.
3. Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J.-P. J. Org.
Chem. 2004, 69, 8413.
˚
10.6559 (9) A, aZ79.675(1)8, bZ77.282(1)8, gZ62.600(1)8;
3
˚
˚
VZ556.47(8) A , ZZ2, lZ0.71073 A, m(Mo Ka)Z
0.326 mmK1
, F000Z246, TZ273(2) K. Data collection
4. Gatri, R.; EI Gaied, M. M. Tetrahedron Lett. 2002, 43, 7835.
5. Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J.-P. Tetrahedron
Lett. 2004, 45, 5171.
yielded 4029 reflections resulting in 1955 unique (IO2sI), q
range: 1.97–25.08. Full matrix least-squares refinement led to a
final RZ0.0364, wRZ0.0960 and GOFZ1.042. Intensity data
were measured on Bruker Smart Apex [Bruker, 2001, SAINT
(version 6.28a) and SMART (version 5.625) Bruker AXS inc.,
Madison, Wisconsin, USA.] with CCD area-detector.
Crystallographic data for the structure of 2a have been
deposited with the Cambridge Crystallographic Data Center
as supplementary publication number CCDC 275627.
20. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555.
6. Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555.
7. Iwama, T.; Kinoshita, H.; Kataoka, T. Tetahedron Lett. 1999,
40, 3741.
8. Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40,
1539.
9. Zhu, Y.-H.; Vogel, P. Synlett 2001, 79.
10. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41,
2165.
11. Shi, M.; Xu, Y.-M. Chem. Commun. 2001, 1876.
12. Li, G.; Wei, H.-X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett.
2000, 41, 1.
21. Palinko, I. Acta Crystallogr., sect. B 1999, 55, 216.
22. Etter, M. C. Acc. Chem. Res. 1990, 23, 120.