2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde as a new synthon for the synthesis of fused ring heterocycles via intramolecular 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1002/jhet.250

(Chemical Equation Presented) The title compound 2-butyl-5-chloro-3H- imidazole-4-carbaldehyde was transformed into tricyclic heterocycles by substituting the chlorine atom by an unsaturated thiolate or alkoxide and then converting aldehyde function into 1,3-dipole. Chloramine-T was used as an efficient reagent for the generation of 1,3-dipoles, which resulted the formation of fused ring heterocycles via intramolecular 1,3-dipolar cycloaddition reaction. The method is very useful for the construction of many biologically active fused heterocycles.

Full text of DOI:10.1002/jhet.250

May 2010
2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde as a New Synthon
for the Synthesis of Fused Ring Heterocycles via Intramolecular
1,3-Dipolar Cycloaddition Reactions
543
S. L. Gaonkar and K. M. Lokanatha Rai*
Department of Studies in Chemistry, University of Mysore, Manasagangotri,
Mysore 570 006, India
*E-mail: kmlrai@yahoo.com
Received April 20, 2009
DOI 10.1002/jhet.250
Published online 2 April 2010 in Wiley InterScience (www.interscience.wiley.com).
The title compound 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde was transformed into tricyclic het-
erocycles by substituting the chlorine atom by an unsaturated thiolate or alkoxide and then converting
aldehyde function into 1,3-dipole. Chloramine-T was used as an efficient reagent for the generation of
1,3-dipoles, which resulted the formation of fused ring heterocycles via intramolecular 1,3-dipolar
cycloaddition reaction. The method is very useful for the construction of many biologically active fused
heterocycles.
J. Heterocyclic Chem., 47, 543 (2010).
INTRODUCTION
chloro and formyl groups ortho to each other. The chlo-
rine atom can be easily substituted by nucleophiles 2
and the formyl function is suitable for conversion into
series of 1,3-dipoles. The final step is the intramolecular
cycloaddition of dipole and dipolarophile 3 to give the
fused ring system 4 (Scheme 1).
The intramolecular 1,3-dipolar cycloaddition is a
powerful method for the construction of fused ring het-
erocycles [1,2]. In particular intramolecular nitrile oxide
cycloaddition results dihydroisoxazole derivatives, which
are precursors for c-amino alcohols, b-hydroxy ketones
and derivatives, useful in the synthesis of natural prod-
ucts [3]. Similarly intramolecular nitrile imine cycload-
dition results 2-pyrazoline derivatives.
CHEMISTRY
The starting compound 2-butyl-5-chloro-3H-imidaz-
ole-4-carbaldehyde was synthesized by literature proce-
dure [9]. Substitution of chloro group with allyl thiols
furnished 2-butyl-5-(allylsulfanyl)imidazole-4-carbalde-
hyde. This compound could be transformed into the
tricyclic heterocycles by converting the aldehyde func-
tion into 1,3-dipoles (Scheme 2). Similarly, substitution
with allyl alcohol furnished the 2-butyl-5-(allyloxyl)imi-
dazole-4-carbaldehyde which could be transformed into
corresponding tricyclic heterocycles by converting the
aldehyde function into 1,3-dipoles (Scheme 3).
In our previous report, we have used chloramine-T
for the generation of nitrile oxide [4], nitrile imine [5],
nitroso alkene [6], and azoalkene [7] which are useful
intermediates for the synthesis of biologically active 2-
isoxazolines, 2-pyrazolines, 1,2-oxazines, and pyrida-
zines, respectively. 2-Butyl-5-chloro-3H-imidazole-4-
carbaldehyde 1, a key intermediate for the synthesis of
Losartan a nonpeptide angiotensin antagonist, which is
an orally active antihypertensive drug [8], and also
shows broad spectrum of activity [9–10]. Compounds of
these types are interesting starting materials for intramo-
lecular cycloaddition reaction due to the presence of
The aldehyde 5 was converted into the oxime and
then oxidized with chloramine-T to give nitrile oxide,
C
V
2010 HeteroCorporation

544
S. L. Gaonkar and K. M. Lokanatha Rai
Vol 47
Scheme 1
Scheme 3
and 131.9 due to vinylic CH2 and vinylic CH groups,
respectively. The aldehydic carbon was observed at d
184.2.
which undergoes intramolecular cycloaddition to form
dihydroisoxazole 6. The aldehyde 5 was converted to
phenyl hydrazone and then oxidized with chloramine-T
to give nitrile imine, which on intramolecular cycloaddi-
tion results pyrazole derivative 7. The aldehyde 5 was
prepared by substituting chloro group of aldehyde 1
with allyl thiol, generated by basic decomposition of the
allyl isothiourea salt. Similarly, compounds 9 and 10 are
synthesized to form aldehyde 1 by substituting chloro
group with allyl alcohol.
1H NMR of isoxazoline 6 showed multiplet at d
2.92–2.98 for one proton due to CH group. A multiplet
at d 3.15–3.23 is due to CH2S group and a multiplet at
d 3.92–4.01 is due to CH2 group of isoxazoline ring.
13C NMR showed doublet at d 33.3 due to CH group. A
triplet at d 44.4 may be due to carbon of CH2S group
and triplet at d 63.3 is due to CH2 group of isoxazoline
ring. All other substituents are observed in the expected
region. The moderate yield of 67% is obtained starting
from aldehyde 5 because the intermediate impure oxime
was taken directly for next step without purification.
The yield of isoxazoline 6 can be improved by purifying
the oxime.
RESULTS AND DISCUSSION
1H NMR, 13C NMR, IR, and elemental analyses char-
acterized all the synthesized compounds. 1H NMR of
aldehyde 5 showed a doublet at d 3.89 for two protons
due to CH2S group and two multiplets at d 4.9–5.02 and
5.62–5.71 are due to vinylic CH2 and vinylic CH
groups, respectively. Aldehydic proton was observed at
d 9.63 and a broad singlet at d 11.7 is due to NH group
of imidazole ring. 13C NMR showed peak at d 116.2
1H NMR of pyrazoline 7 showed multiplet at d 2.85–
2.92 for one proton due to CH group. A doublet was
observed at d 3.10 is due to CH2S group and a multiplet
at d 3.86–3.92 is due to CH2 group of pyrazolines ring.
The aromatic protons are observed in the region d 6.85–
7.12. In 13C NMR a triplet at d 32.5 may be due to car-
bon of CH2S group and a triplet at d 56.1 may be due
to CH2 group of isoxazoline ring. A doublet at d 46.9
indicates the presence of CH group. All other substitu-
ents are observed in the expected region. The moderate
yield of 65% is obtained starting from aldehyde 5. The
yield of pyrazoline 7 can be improved by purifying the
intermediate phenyl hydrazone.
Scheme 2
1H NMR of aldehyde 8 showed a doublet at d 4.79
for two protons due to CH2O group and two multiplets
at d 5.22–5.31 and 5.60–5.69 are due to vinylic CH2
and vinylic CH groups, respectively. Aldehydic proton
was observed at d 9.89 and a broad singlet at d 11.59 is
due to NH group of imidazole ring. 13C NMR showed
peak at d 117.0 and 134.9 due to vinylic CH2 and
vinylic CH groups, respectively. The aldehydic carbon
was observed at d 182.1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde as a New Synthon for the Synthesis
of Fused Ring Heterocycles via Intramolecular 1,3-Dipolar Cycloaddition Reactions
545
1H NMR of isoxazoline 9 showed multiplet at d
2.96–3.0 for one proton due to CH group. A doublet d
4.16 is due to CH2O group and a multiplet at d 3.96–
4.04 is due to CH2 group of isoxazoline ring. 13C NMR
showed doublet at d 44.3 due to CH group. A triplet at
d 73.3 may be due to carbon of CH2O group and triplet
at d 62.1 is due to CH2 group of isoxazoline ring. All
other substituents are observed in the expected region.
1H NMR of pyrazoline 10 showed multiplet at d
2.80–2.86 for one proton due to CH group. A multiplet
at d 3.76–3.83 is due to CH2 group of pyrazolines ring.
A doublet was observed at d 4.22, which is due to
OCH2 group. The aromatic protons are observed in the
region d 6.85–7.12. 13C NMR showed doublet at d 44.2
due to CH group. A triplet at d 52.1 may be due to CH2
group of isoxazoline ring and a triplet at d 71.3 is due
to OCH2 group. All other substituents are observed in
the expected region.
1 h. Ethanolic NaOH solution (3.2 g, 50 mL) was then added
and the reaction mass was refluxed for 1 h. The aldehyde 1
(5.0 g, 26.9 mmol) was added to the mixture, which was then
refluxed for 2 h. Ethanol was removed under vacuum and the
residue was extracted with diethyl ether (2 ꢁ 50 mL), washed
with water, dried (Na2SO4), and the solvent was removed to
give crude oil which was purified by column chromatography
(chloroform:ethyl acetate, 7:3) to give 5 as a pale yellow oil
1
(4.10 g, 68%). H NMR CDCl3: d 0.94 (t, 3H, CH3), 1.33 (m,
2H, CH2), 1.64 (m, 2H, CH2), 2.60 (t, 2H, CH2), 3.89 (d, 2H,
CH2S), 4.9–5.02 (m, 2H, vinylic CH2), 5.62 (m, 1H,vinylic
CH), 9.63 (s, 1H, CHO), 11.70 (bs, 1H, NH). 13C NMR
CDCl3: d 13.4 (q), 23.0 (t), 28.4 (t), 32.1 (t), 39.2 (t), 118.2
(t), 131.9 (d), 139.8 (s), 147.2 (s), 157.8 (s), 181.2 (d). IR
(KBr pellets cmꢀ1) m 3410, 2949, 2816, 1669, 1461. Anal.
Calcd. for C11H16N2OS: C, 58.90; H, 7.19; N, 12.49%. Found:
C, 58.96; H, 7.10; N, 12.44%.
7-Butyl-3a,4-dihydro-3H,8H-2-oxa-5-thia-1,6,8-triaza-as-
indacene 6. A solution of aldehyde 5 (2.0 g, 8.92 mmol) in
ethanol (20 mL) was warmed with aqueous NH2OH.HCl (0.92
g 13.33 mmol) and CH3COONa (1.10 g, 13.40 mmol) for 1 h.
Ethanol was removed under vacuum and the residue was
extracted with ethyl acetate (2 ꢁ 25 mL), washed with water,
dried (Na2SO4), and the solvent was removed. The resultant
residue was dissolved in ethanol (20 mL), chloramine-T (3.0
g, 10.67 mmol) was added, and the mixture was warmed under
vigorous stirring for 2–3 h. Ethanol was removed under vac-
uum and the residue was extracted with diethyl ether (2 ꢁ 25
mL), washed with 1N NaOH (2 ꢁ 25 mL), washed with water,
dried (Na2SO4), and the solvent was removed. The residue left
behind was purified by column chromatography (chlorofor-
m:ethyl acetate, 7:3) to give 6 as a pale yellow oil (1.41 g,
67%). 1H NMR CDCl3: d 0.92 (t, 3H, CH3), 1.32 (m, 2H,
CH2), 1.64 (m, 2H, CH2), 2.61 (t, 2H, CH2), 2.92–2.98 (m,
1H, CH), 3.15–3.23 (m, 2H, CH2), 3.92–4.01 (m, 2H, CH2),
11.79 (bs, 1H, NH). 13C NMR CDCl3: d 13.0 (q), 23.4 (t),
28.4 (t), 32.5 (t), 33.3 (d), 44.4 (t), 69.3 (t), 111.3 (s), 136.2
(s), 148.8 (s), 156.1 (s). IR (KBr pellets cmꢀ1) m 3416, 2981,
1590, 1421, 1220, 1151. Anal. Calcd. for C11H15N3OS: C,
55.67; H, 6.37; N, 17.71%. Found: C, 55.59; H, 6.41; N,
17.78%.
7-Butyl-2-phenyl-2,3a,4,8-tetrahydro-3H-5-thia-1,2, 6,8-
tetraaza-as-indacene 7. A solution of aldehyde 5 (2.0 g, 8.92
mmol) in ethanol (20 mL) was warmed with aqueous phenyl
hydrazine hydrochloride (1.93 g, 13.40 mmol) and
CH3COONa (1.10 g, 13.41 mmol) for 1 h. The reaction mass
was cooled and the solid formed was filtered. The solid was
dissolved in ethanol (20 mL), chloramine-T (3.0 g, 10.67
mmol) was added, and the mixture was warmed under vigor-
ous stirring for 2–3 h. Ethanol was removed under vacuum
and the residue was extracted with diethyl ether (2 ꢁ 25 mL),
washed with 1N NaOH (2 ꢁ 25 mL), washed with water, dried
(Na2SO4), and the solvent was removed. The residue left
behind was purified by column chromatography (chlorofor-
m:ethyl acetate, 8:2) to give 7 as a yellow oil (1.81 g, 65%).
1H NMR CDCl3: d 0.95 (t, J ¼ 7.5 Hz, 3H, CH3), 1.35 (m,
2H, CH2), 1.69 (m, 2H, CH2), 2.65 (t, J ¼ 7.5 Hz, 2H, CH2),
2.85–2.92 (m, 1H, CH), 3.10–3.15 (d, 2H, CH2), 3.86–3.92,
(m, 2H, CH2), 6.85–6.95 (m, 3H, ArH), 7.12 (t, 2H, ArH),
CONCLUSIONS
In conclusion, we have demonstrated that 2-butyl-5-
chloro-3H-imidazole-4-carbaldehyde can be used for
intramolecular 1,3-dipolar cycloaddition by substituting
chloro group with unsaturated nucleophiles and convert-
ing the aldehyde function into 1,3-dipole. Chloramine-T
is found to be an efficient reagent for the generation of
1,3-dipole. Other compounds possessing a halogen and
aldehyde group at ortho position are also potential can-
didates for carrying out similar reactions.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM 300 MHz
spectrometer using CDCl3 as solvent and tetramethylsilane as
internal standard. 13C NMR spectra were measured on Jeol
400 (100 MHz) instrument. The chemical shifts are expressed
in d and following abbreviations were used, s ¼ singlet, d ¼
doublet, t ¼ triplet, and m ¼ multiplet. Infrared (IR) spectra
were recorded on Shimadzu 8300 IR spectrometer. Elemental
analyses were obtained on a Vario-EL instrument. Thin layer
chromatography (TLC) was done with precoated silica gel G
plates.
2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde 1 [7]. The
aldehyde 1 was synthesized by literature procedure [9]. 1H
NMR CDCl3: d 0.92 (t, J ¼ 7.5 Hz, 3H, CH3), 1.32 (m, 2H,
CH2), 1.64 (m, 2H, CH2), 2.61 (t, J ¼ 7.5 Hz, 2H, CH2), 9.32
(s, 1H, CHO), 11.89 (bs, 1H, NH). 13C NMR CDCl3: d 13.2
(q), 23.2 (t), 28.1 (t), 30.1 (t), 128.2 (s), 144.1 (s), 158.8 (s),
179.2 (d). IR (KBr pellets cmꢀ1) m 3409, 3070, 2969, 2827,
1672, 1459. Anal. Calcd for C8H11ClN2O: C, 51.48; H, 5.94;
N, 15.01%. Found: C, 51.38; H, 5.98; N, 15.10%.
5-Allylsulfanyl-2-butyl-3H-imidazole-4-carbaldehyde
5. A solution of allyl bromide (4.87 g, 40.24 mmol) and thiou-
rea (3.08 g, 40.52 mmol) in ethanol (50 mL) were refluxed for
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S. L. Gaonkar and K. M. Lokanatha Rai
Vol 47
11.77 (bs, 1H, NH). 13C NMR CDCl3: d 13.1 (q), 23.6 (t),
28.9 (t), 30.7 (t), 32.5 (t), 46.9 (d), 56.1 (t), 110.3 (s), 112.9
(d), 118.1 (d), 119.9(s), 129.8 (d), 134.1 (s), 144.8 (s), 151.1
(s), 153.6 (s). IR (KBr pellets cmꢀ1) m 3411, 3012, 2956,
1643, 1319, 1014. Anal. Calcd. for C17H20N4S: C, 65.35; H,
6.45; N, 17.93%. Found: C, 65.45; H, 6.40; N, 17.90%.
hydrazine hydrochloride (1.03 g, 7.15 mmol) and CH3COONa
(0.60 g, 7.31 mmol) for 1 h. The reaction mass was cooled
and the solid formed was filtered. The solid was dissolved in
ethanol (10 mL), chloramine-T (1.62 g, 5.76 mmol) was
added, and the mixture was warmed under vigorous stirring
for 2–3 h. Ethanol was removed under vacuum and the residue
was extracted with diethyl ether (2 ꢁ 20 mL), washed with 1N
NaOH (2 ꢁ 25 mL), washed with water, dried (Na2SO4), and
the solvent was removed. The residue left behind was purified
by column chromatography (chloroform:ethyl acetate, 8:2) to
5-Allyoxy-2-butyl-3H-imidazole-4-carbaldehyde 8. A mix-
ture of aldehyde 1 (5 g, 26.9 mmol), allyl alcohol (2.34 g, 40.3
mmol), and potassium tert-butoxide (3.61 g, 32.23 mmol) in tet-
rahydrofuran (50 mL) were stirred at room temperature for 4 h.
The reaction mass was diluted with diethyl ether (25 mL) and
the solid was filtered. The filtrate was evaporated and the resi-
due was purified by column chromatography (chloroform:ethyl
1
give 10 as a yellow oil (0.90 g, 63%). H NMR CDCl3: d 0.93
(t, J ¼ 7.5 Hz, 3H, CH3), 1.33 (m, 2H, CH2), 1.66 (m, 2H,
CH2), 2.64 (t, J ¼ 7.5 Hz, 2H, CH2), 2.88–2.93 (m, 1H, CH),
3.86–3.92 (m, 2H, CH2), 4.08–4.15, (m, 2H, CH2), 6.90–7.05
(m, 3H, ArH), 7.24 (t, 2H, ArH), 11.75 (bs, 1H, NH). 13C
NMR CDCl3: d 13.2 (q), 23.8 (t), 29.2 (t), 30.9 (t), 44.2 (d),
52.4 (d), 71.3 (t), 114.3 (s), 112.0 (d), 117.4 (d), 129.2 (d),
1
acetate, 7:3) to give 8 as a pale yellow oil (4.02 g, 72%). H
NMR CDCl3: d 0.92 (t, J ¼ 7.5 Hz, 3H, CH3), 1.30 (m, 2H,
CH2), 1.65 (m, 2H, CH2), 2.65 (t, J ¼ 7.5 Hz, 2H, CH2), 4.79
(d, J ¼ 7.0 Hz, 2H, CH2S), 5.22–5.41 (m, 2H, vinylic CH2),
5.60–5.69 (m, 1H, vinylic CH), 9.89 (s, 1H, CHO), 11.59 (bs,
1H, NH). 13C NMR CDCl3: d 13.8 (q), 23.0 (t), 28.4 (t), 32.1
(t), 76.2 (t), 118.2 (t), 122.2 (s), 134.9 (d), 149.8 (s), 155.8 (s),
182.1 (d). IR (KBr pellets cmꢀ1) m 3422, 2959, 2856, 1669,
1641, 1215. Anal. Calcd. for C11H16N2O: C, 63.44; H, 7.74; N,
13.45%. Found: C, 63.49; H, 7.70; N, 13.40%.
132.1 (s), 144.8 (s), 149 (s), 153.1 (s). IR (KBr pellets cmꢀ1
)
m 3396, 3026, 2990, 1635, 1235. Anal. Calcd. for C17H20N4O:
C, 68.90; H, 6.80; N, 18.90%. Found: C, 68.99; H, 6.71; N,
18.84%.
Acknowledgment. S. L. Gaonkar is grateful to the University of
Mysore, Mysore for providing laboratory facility to carry out the
research work.
7-Butyl-3a,4-dihydro-3H,8H-2,5-dioxa-1,6,8-triaza-as-
indacene 9. A solution of aldehyde 8 (1.0 g, 4.80 mmol) in
ethanol (10 mL) was warmed with aqueous NH2OH.HCl (0.50
g 7.24 mmol) and CH3COONa (0.60 g, 7.30 mmol) for 1 h.
Ethanol was removed under vacuum and the residue was
extracted with ethyl acetate (2 ꢁ 10 mL), washed with water,
dried (Na2SO4), and the solvent was removed. The resultant
residue was dissolved in ethanol (10 mL), chloramine-T (1.62
g, 5.76 mmol) was added, and the mixture was warmed under
vigorous stirring for 2–3 h. Ethanol was removed under vac-
uum and the residue was extracted with diethyl ether (2 ꢁ 20
mL), washed with 1N NaOH (2 ꢁ 25 mL), washed with water,
dried (Na2SO4), and the solvent was removed. The residue left
behind was purified by column chromatography (chlorofor-
m:ethyl acetate, 7:3) to give 9 as a pale yellow oil (0.65 g,
61%). 1H NMR CDCl3: d 0.92 (t, 3H, CH3), 1.32 (m, 2H,
CH2), 1.64 (m, 2H, CH2), 2.61 (t, 2H, CH2), 2.96–3.0 (m, 1H,
CH), 3.92–4.04 (m, 2H, CH2), 4.16 (d, 2H, CH2), 11.80 (bs,
1H, NH). 13C NMR CDCl3: d 13.0 (q), 23.4 (t), 29.4 (t), 31.5
(t), 44.3 (d), 58.4 (t), 73.3 (t), 109.3 (s), 136.2 (s), 149.8 (s),
157.1 (s). IR (KBr pellets cmꢀ1) m 3410, 2952, 1638, 1598,
1220, 1100. Anal. Calcd. for C11H15N3O2: C, 59.71; H, 6.83;
N, 18.99%. Found: C, 59.61; H, 6.89; N, 19.04%.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet