Synthesis of dimedone-annelated heterocycles: Regioselective heterocyclization of 2-(Cyclohex-2′-enyl)-5,5-dimethyl-3-hydroxy cyclohex-2-enone

Article abstract of DOI:10.1081/SCC-120015824

2-(Cyclohex-2′-enyl)-5,5-dimethyl-3-hydroxycyclohex-2-enone undergoes regioselective heterocyclization to give bridged heterocycles 5a,b and 7 on treatment with pyridine hydrotribromide or hexamethylenetetramine hydrotribromide (1 h); or elemental bromine

Full text of DOI:10.1081/SCC-120015824

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Dimedone-Annelated Heterocycles:
Regioselective Heterocyclization of 2-(Cyclohex-2′-
enyl)-5,5-dimethyl-3-hydroxy cyclohex-2-enone
K. C. Majumdar , S. K. Samanta & P. K. Basu
To cite this article: K. C. Majumdar , S. K. Samanta & P. K. Basu (2003) Synthesis of
Dimedone-Annelated Heterocycles: Regioselective Heterocyclization of 2-(Cyclohex-2′-enyl)-5,5-
dimethyl-3-hydroxy cyclohex-2-enone, Synthetic Communications, 33:4, 679-686, DOI: 10.1081/
SCC-120015824
To link to this article: http://dx.doi.org/10.1081/SCC-120015824
Published online: 16 Aug 2006.
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 679–686, 2003
Synthesis of Dimedone-Annelated Heterocycles:
Regioselective Heterocyclization of
2-(Cyclohex-20-enyl)-5,5-dimethyl-3-hydroxy
cyclohex-2-enone
*
K. C. Majumdar, S. K. Samanta,and P. K. Basu
Department of Chemistry, University of Kalyani,
Kalyani, W.B., India
ABSTRACT
2-(Cyclohex-20-enyl)-5,5-dimethyl-3-hydroxycyclohex-2-enoneunder-
goes regioselective heterocyclization to give bridged heterocycles
5a,b and 7 on treatment with pyridine hydrotribromide or hexameth-
ylenetetramine hydrotribromide (1 h); or elemental bromine (7 h);
N-iodosuccinimide in acetonitrile at 0–5ꢀC (1 h) and conc. H2SO4
at 0–5ꢀC (2 h), respectively.
*Correspondence: K. C. Majumdar, Department of Chemistry, University of
Kalyani, Kalyani 741 235, W.B., India; Fax: þ0091-33-5828282; E-mail: kcm@
klyuniv.ernet.in.
679
DOI: 10.1081/SCC-120015824
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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Majumdar,Samanta,and Basu
INTRODUCTION
Claisen rearrengement[1] has long been used for the carbon–carbon
bond formation.[2–7] The importance of Claisen rearrangement is partly
[8]
due to its utility forthe synthesis of oxygen,
nitrogen[9] and sulfur[10]
heterocycles and partly because of the recent developments of different
variants[11–17] of its aliphatic counter part. We have recently utilized the
Claisen rearrangement for the dimedone annelated heterocycles.[18] Our
recent success on the regioselective cyclization of the products of Claisen
rearrangement of cyclohex-2-enyl phenyl ether, 1,3-dimethyl-5-cyclohex-
20-enyloxy uracil, etc., motivated us to study the heterocyclization of
2-(cyclohex-20-enyl)-5,5-dimethyl-3-hydroxycyclohex-2-enone (3) with
different reagents. Here we report the results.
RESULTS AND DISCUSSIONS
We directed our effort towards the synthesis of different heterocycles
derived from (2-cyclohex-20-enyl)-5,5-dimethyl-3-hydroxycyclohex-2-enone
3. Compound 3 was synthesized by the reaction of dimedone (1) with
3-bromocyclohexene (2) in dry acetone in the presence of K2CO3 at room
temperature for 8 h (Sch. 1).
We considered three different routes for the heterocyclizations. We
have recently reported the use of pyridine hydrotribromide[19–21] and
hexamethylenetetramine hydrotribromide[22] forthis type of heteor-
cyclization. So the substrate 3 was treated with 1 equivalent of pyridine
hydrotribromide and hexamethylenetetramine hydrotribromide sepa-
rately for 1 h to give a new product (79%). This new product was
characterized as the bridged bromo compound 5a from its elemental
analysis and spectral data.
We also reported the heterocyclization of 6-cyclohex-20-enyl-1,3-
dimethyl-5-hydroxy uracil by treatment with elemental bromine.[23]
Scheme 1.

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Dimedone-Annelated Heterocycles
681
The heterocyclization of 6-cyclohex-20-enyl-1,3-dimethyl-5-N-methyl-
aminouracil[24] and 5-(cyclohex-20-enyl)-1,3-dimethyl-6-hydroxyuracil[25]
were also successful with elemental bromine. We, therefore, treated
substrate 3 with elemental bromine in chloroform wiꢀth constant stirring
at 0.5ꢀC for7 h to give a white solid (60%) m.p. 91 C. The compound
was characterized as the bridged bromo compound 5a from its elemental
analysis and spectroscopic data.
We have also recently studied the N-iodosuccinimide mediated cycli-
zation of ortho-cyclohex-2-enyl phenols.[26] As a logical consequence we
have treated substrate 3 with N-iodosuccinimide in dry acetonitrile at
0.5ꢀC for 1 h to give a viscous oil (85%). This was characterized as
bridged iodo compound 5b from its elemental analysis and spectral
data. The product 5b remains unaffected when treated with alcoholic
KOH at 25ꢀC for 2 h. The formation of product 5a,b from 3 may be
explained via the halonium ion intermediate 4 which may then undergo
‘‘6-endo’’ cyclization to give products 5a and 5b. The cyclization of
the proposed halonium ion intermediate 4 is facile undersuch mild
conditions, perhaps due to the favorable juxtaposition of the reacting
functionalities to give stable bridged cyclic products 5a and 5b. The
alternative mode of cyclization of the cyclic halonium ion intermediate
4 by a ‘‘5-exo’’ trig to give 6 is discarded (Sch. 2).
Scheme 2.

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682
Majumdar,Samanta,and Basu
Scheme 3.
Lastly, cold conc. H2SO4 has been widely used forthe cyclization of
ortho-allyl phenols. The substrate 3 was treated with cold conc. H2SO4 at
0–5ꢀC to give a white solid (84%), m.p. 102ꢀC. This was characterized as
the bridged product 7 from its elemental analysis and spectral data (Sch. 3).
Compound 7 resisted dehydrogenation when refluxed with palladized
charcoal in diphenyl ether indicating bridged nature of the product 7.
The heterocyclization of 2-(cyclohex-20-enyl)-5,5-dimethyl 3-hydroxy-
cyclohex-2-enone 3 is found to be regioselective with elemental bromine,
pyridinehydrotribromide or hexamethylenetetramine hydrotribromide,
N-iodosuccinimide and also with cold conc. H2SO4 to give 5a, 5b, and 7,
respectively.
EXPERIMENTAL
Melting points were determined in a sulphuric acid bath and are
uncorrected. UV absorption spectra were recorded in EtOH on a
Hitachi 200-20 spectrophotometer (ꢀmax in nm) and IR spectra in KBr
discs on a Perkin Elmer 1330 apparatus (ꢁmax in cmÀ1). 1H NMR spectra
were run in CDCl3 with TMS as internal standard on a Bruker 300 MHz
instrument at the Indian Institute of Chemical Biology, Kolkata and
Bruker 500 MHz instrument at the Bose Institute, Kolkata (chemical
shifts in ꢂ ppm). Elemental analyses and mass spectra were recorded by
RSIC (CDRI), Lucknow on a [JEOL D-300 (E1)] instrument. Silica gel

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Dimedone-Annelated Heterocycles
683
(60–120 mesh) was obtained from Spectrochem, India. Extracts were
dried over anhydrous sodium sulphate. Petroleum ether refers to the
fraction boiling between 60 and 80ꢀC.
Preparation of 2-(Cyclohex-20-enyl)-5,5-dimethyl-3-
hydroxycyclohex-2-enone (3,C 14H20O2)
A mixture of dimedone (1.40 g, 10 mmol), 3-bromocyclohexene
(1.6 g, 10 mmol) and anhydrous potassium carbonate (3 g) in dry acetone
(100 mL) was stirred for 8 h at room temperature. On completion of the
reaction (monitored by TLC) it was filtered and the solvent was removed
from the filtrate. The residue was extracted with CHCl3 (3 Â 25 mL), the
organic layer was separated, washed with water (2 Â 25 mL), dried
(Na2SO4) and the solvent was removed. Purification of the crude product
by column chromatography (benzene–petroleum ether 1:1) over silica gel
gave the title compound 3.
Compound 3: Yield 90%; White solid; m.p.: 118ꢀC; ꢀmax/nm 293;
ꢁ
max/cmÀ1 3200, 2920, 1610, 1380; (300 MHz) ꢂH: 1.04 (s, 3H, C-CH3),
1.07 (s, 3H, C-CH3), 1.37–2.12 (m, 6H), 2.23 (s, 2H, CH2CO), 2.28 (s, 2H,
¼CCH2), 3.66–3.73 (m, 1H), 5.83–5.86 (m, 1H) and 6.09–6.16 (m, 1H);
m/z 220 (Mþ); (Found: C, 76.34; H, 9.12. C14H20O2 requires C, 76.36;
H, 9.09%).
Pyridine Hydrotribromide or Hexamethylenetetramine
Hydrotribromide Mediated Cyclization of Compound 3
A solution of compound (3, 0.33 g, 1.5 mmol) in CHCl3 (100 mL) was
magnetically stirred with solid pyridine hydrotribromide (0.45 g,
1.5 mmol) at 0–5ꢀC for1 h. The CHCl solution was washed with 5%
3
Na2CO3 solution (2 Â 10 mL), then with water(2 Â 25 mL) and dried
(Na2SO4). Evaporation of CHCl3 left a gummy residue. This was purified
by column chromatography over silica gel using benzene–ethyl acetate
(9:1) as eluent to give product 5a.
Compound 5a: Yield 79% with PyHBr3 and 60% with elemental
bromine; white solid; m.p. 91ꢀC; ꢀmax/nm: 284, ꢁmax/cmÀ1 2960, 1630
and 1400; (500 MHz) ꢂH: 1.21 (s, 3H, C-CH3); 1.27 (s, 3H, C-CH3);
1.49–2.00 (m, 6H); 2.13 (s, 2H, CH2CO); 2.56 (s, 2H, ¼CCH2);
3.31–3.36 (m, Hc); 4.38–4.40 (brs, Ha); 4.86–4.91 (m, Hb); m/z 298, 300
(Mþ); (Found C, 56.22, H, 6.33. C14H19BrO2 requires C, 56.19;
H, 6.35%).

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684
Majumdar,Samanta,and Basu
Cyclization of Compound 3 by Elemental Bromine
Elemental bromine (0.25 g, 1.5 mmol) in chloroform (25 mL) was
added slowly to a well-stirred solution of compound 3 (0.33 g,
1.5 mmol) in chloroform (10 mL) at 0–5ꢀC. Stirring was continued for
an additional period of 7 h at 0–5ꢀC. Afterthe eraction was over(as
monitored by TLC) it was extracted with chloroform. The CHCl3 layer
was washed with 5% Na2CO3 solution (2 Â 10 mL), then with water
(2 Â 25 mL) and dried (Na2SO4). Evaporation of CHCl3 left a gummy
residue. This was purified by column chromatography over silica gel
using benzene–ethyl acetate (9:1) as eluent. From comparision of TLC,
m.p. mixed m.p. and superimposable IR this product was found to be
identical with product 5a obtained from the reaction of compound 3 with
PyHBr3 orC H12N4HBr3.
6
N-Iodosuccinimide Mediated Cyclization of Compound 3
N-Iodosuccinimide (0.225 g, 1 mmol) was added to acetonitrile
solution of the compound 3 (0.22 g, 1 mmol) at 0–5ꢀC. The reaction
mixture was then stirred for 1 h on a magnetic stirrer at 0–5ꢀC. It was
stirred for an additional period of 30–45 min at room temperature. On
completion of the reaction (monitored by TLC) acetonitrile solution was
removed from the reaction mixture under reduced pressure. The residual
mass was extracted with chloroform and washed with 5% NaHSO3
solution (3 Â 25 mL), water(3 Â 25 mL) and dried (Na2SO4). The residual
mass after removal of the solvent was subjected to column chromatog-
raphy over silica gel using benzene–ethyl acetate (9:1) as eluent to give
product 5b.
Compound 5b: Yield 85%; Viscous oil; ꢀmax/nm 264; ꢁmax/cmÀ1 2960,
1650 and 1400; (500 MHz) ꢂH: 1.08 (s, 6H, 2 C-CH3), 1.38–2.13 (m, 6H),
2.22 (s, 2H, CH2CO), 2.34 (s, 2H, ¼CCH2), 3.12 (brs, Hc), 4.50 (brs, Ha),
4.56 (brs, Hb); m/z 346 (Mþ); (Found: C, 48.58, H, 5.50. C14H19IO2
requires C, 48.55, H, 5.49%).
Sulphuric Acid Mediated Cyclization of Compound 3
Compound 3 (0.33 g, 1.5 mmol) was added in portions to conc.
H2SO4 (2 mL) at 0.5ꢀC and the mixture was magnetically stirred for 2 h
at this temperature. The reaction mixture was then poured into crushed
ice and was extracted with CHCl3 (3 Â 25 mL). The CHCl3 layerwas

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Dimedone-Annelated Heterocycles
685
washed with 5% Na2CO3 Solution (3 Â 10 mL), water(3 Â 25 mL) and
dried (Na2SO4). Evaporation of CHCl3 gave a gummy mass. This was
purified by column chromatography over silica gel using benzene–ethyl
acetate (9:1) as eluent to give product 7. This was recrystallized from
chloroform–petroleum ether.
Compound 7: Yield 84%; White solid; m.p. 102ꢀC; ꢀmax/nm 264;
ꢁ
max/cmÀ1 2940, 1610 and 1400; (300 MHz) ꢂH: 1.07 (s, 3H, C-CH3);
1.08 (s, 3H, C-CH3); 1.49–2.03 (m, 8H), 2.22 (s, 2H, CH2CO), 2.32
(s, 2H, ¼CCH2), 3.02 (brs, Hb), 4.57 (brs, Ha); m/z: 220 (Mþ); (Found:
C, 76.39; H, 9.07. C14H20O2 requires C, 76.36; H, 9.09%).
ACKNOWLEDGMENTS
We thank the CSIR (New Delhi) forfinancial assistance. P. K. B. is
thankful to UGC (New Delhi) fora JuniorReseacrh Fellowship and
S. K. S. is grateful to CSIR (New Delhi) for a fellowship.
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Received in the Netherlands February 24, 2002