Regioselective heterocyclization of 3-(cyclohex-2′-enyl)-4-hydroxy-6-methylpyran-2-one

Article abstract of DOI:10.1007/s007060200109

Regioselective heterocyclization of 3-(cyclohex-2′-enyl)-4-hydroxy-6-methyl pyran-2-one with various reagents afforded different heterocycles. With N-iodosuccinimide in acetonitrile at 0-5°C it gave 6-methyl-9′-iodo-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-

Full text of DOI:10.1007/s007060200109

Monatshefte fur Chemie 133, 1317±1323 ꢀ2002)
Regioselective Heterocyclization
of 3-ꢀCyclohex-29-enyl)-4-hydroxy-6-
methylpyran-2-one
Ã
Krishna C.Majumdar and Subhojit Ghosh
Department of Chemistry, University of Kalyani, Kalyani-741235, India
Summary. Regioselective heterocyclization of 3-ꢀcyclohex-20-enyl)-4-hydroxy-6-methyl pyran-2-
one with various reagents afforded different heterocycles. With N-iodosuccinimide in acetonitrile at
0±5ꢀC it gave 6-methyl-90-iodo-20-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one, with C5H5NHBr3 or
0
C6H12N4HBr3 in CHCl3 at 0±5ꢀC it furnished 6-methyl-9 -bromo-20-oxabicyclo[3.3.1]nonano[3,2-
c]pyran-2-one. Cold concentrated H2SO4 lead to 6-methyl-20-oxabicyclo[3.3.1]nonano[3,2-c]pyran-
2-one, whereas PdCl2ꢀPhCN)2 in C6H6 at 80ꢀC afforded 9-methyl benzofuro[3,2-c]pyran-2-one.
Keywords. Pyridine hydrotribromide; N-Iodosuccinimide; Palladium chloride bisbenzonitrile;
Heterocycles; Cyclization.
Introduction
4-Hydroxy-6-methylpyran-2-one ꢀ1) is a natural product of polyketide origin [1].
Many natural products containing the fundamental skeleton of 4-hydroxy- or 4-
methoxy-6-methyl-2-pyrone have been isolated, some of them carrying biogeneti-
cally plausible groups at C-3 or C-5 or both. Elasnin, isolated from Streptomyces, is
a speci®c inhibitor of human leucocyte elastase [2]. As a logical extension, many
pyrones structurally related to elasnin have been synthesized, and their biological
activity has been tested [3]. In continuation of our work on the synthesis of bioac-
tive heterocycles [4] by application of [3,3]-sigmatropic rearrangements [5] we
became interested in the synthesis of heterocycles derived from 1 [6, 7]. Presently,
we report our results on the regioselective cyclization of 3-ꢀcyclohex-20-enyl)-4-
hydroxy-6-methylpyran-2-one ꢀ4) with a variety of reagents.
Results and Discussion
The starting material for this investigation ꢀ4) was obtained by thermal [3,3]-sigma-
tropic rearrangement of 4-ꢀcyclohex-20-enyloxy)-6-methylpyran-2-one ꢀ3) in re¯ux-
ing xylene as an extension of our study of Claisen rearrangements. 3 in turn was
prepared by the reaction of 1 with 3-bromocyclohexene ꢀ2) in re¯uxing acetone in
Ã
Corresponding author. E-mail: kcm@klyuniv.ernet.in

1318
K. C. Majumdar and S. Ghosh
Scheme 1
the presence of anhydrous potassium carbonate ꢀScheme 1). Manas et al. have
reported [8] the preparation of 4 from 1 and cyclohex-2-enyl acetate in the presence
of Pdꢀacac)2 and Ph3P exploiting thermodynamically controlled conditions.
Compound 3 was characterized from by elemental analysis and spectroscopic
1
data; compound 4 had an identical H NMR spectroscopic pattern and melting
point to those of the compound prepared by Manas et al. [8].
The present investigation involves heterocyclization of 4 to the construction of
the pyran or furan ring in the resulting heterocycles. To achieve this goal, four
different approaches were considered: ꢀi) reaction of 4 with N-iodosuccinimide,
ꢀii) reaction of 4 with pyridine hydrotribromide and hexamine hydrotribromide,
ꢀiii) acid-catalyzed cyclization of 4, and ꢀiv) PdCl2ꢀPhCN)2 mediated intramolec-
ular oxidative cyclization of 4.
4 was treated with N-iodosuccinimide in acetonitrile at 0±5ꢀC for 1 h to furnish
6a in 80% yield ꢀScheme 2). 6a was characterized by elemental analysis and spec-
troscopic data. The 1H NMR spectrum of 6 showed three protons ꢀ3.43±3.50 ppm,
Hc; 4.25±4.33 ppm, Ha; 5.05±5.10 ppm, Hb). Ha appeared as an eight-line multiplet
ꢀddd, J ˆ 10, 6.9, and 4.5 Hz), Hb as a triplet which upon expansion revealed a
doublet of doublets with J values of 6.9 and 6.7 Hz, and Hc as a doublet of triplets
with J values of 6.8 and 6.7 Hz. The proton assignments were deduced from a COSY
spectrum and proton decoupling experiments. A Dreiding model of 6a could be
constructed by 1,3-fusion of the pyran ring in the half-chair conformation with
the cyclohexane ring in the chair conformation ꢀdistorted) as shown in Fig. 1. How-
ever, the coupling constant of 10 Hz found for Ha cannot be explained if 6a attains
this conformation. An alternative model can be constructed by 1,3-fusion of the
pyran ring in the half-chair form with the cyclohexane ring in the boat ꢀdistorted)
form ꢀFig. 2) which is in accordance with the above coupling information. It may be
noted that bicyclo[3.3.1]nonane is known to prevail in the chair-boat conformation
[9]. The bicyclic nature of 6a is re¯ected in its reluctance to undergo any change in
re¯uxing diphenyl ether containing palladium on charcoal as well as in re¯uxing
xylene in the presence of DDQ. Treatment of 4 with pyridinium hydrotribromide
[10] in chloroform at 0±5ꢀC for 1 h afforded 6b which was characterized by its
elemental analysis and spectroscopic data. It was assigned the structure shown in
Scheme 2 by reasoning similar to that followed for 6a. The use of hexamine hydro-
tribromide [11] instead of pyridinium hydrotribromide gave the same result.
Acid catalysis has been used to generate pyran and furan rings from 2-allyl
enols [12, 13]. Treatment of 4 with cold concentrated sulfuric acid gave the bicy-
1
clic compound 6c in 66% yield ꢀScheme 2). Its H NMR spectrum displayed two
broad singlets at 3.26 and 4.84 ppm due to the ring juncture protons; the residual

Heterocyclization of a Substituted Pyranone
1319
Scheme 2
Fig.1. Chair conformation of 6a
six protons of the cyclohexane ring appeared at 1.40±1.47 ꢀ1H), 1.59±1.65 ꢀ3H),
2.11±2.13 ꢀ1H), and 1.84 ꢀ3H) ppm as three multiplets and one broad singlet,
respectively. Compound 6c resisted dehydrogenation in re¯uxing diphenyl ether
containing palladium on charcoal or in re¯uxing xylene containing DDQ.
Palladium chloride bisbenzonitrile ꢀPdCl2ꢀPhCN)2) and palladium chloride
bisacetonitrile ꢀPdCl2ꢀMeCN)2) have been successfully employed in the synthesis
of benzofurans [14] and indoles [15] from the sodium salts of 2-allyl phenols and
2-allylanilines. Recently, our group has reported a facile synthesis of a linearly

1320
K. C. Majumdar and S. Ghosh
Fig.2. Boat conformation of 6a
Scheme 3
fused pyrimidine-annealated heterocycle from 6-ꢀcyclohex-20-enyl)-5-hydroxy-1,3-
dimethyluracil by treatment with the above reagent [16]. These results prompted us
to treat a suspension of 4 in thiophene-free dry benzene with PdCl2ꢀPhCN)2 at
room temperature in the presence of NaOCH3, followed by re¯uxing the reaction
mixture for 6 h. The isolated product ꢀ9) may result from dehydrogenation of the in-
cipient intermediate 8 ꢀnot isolated) by the initially deposited palladium ꢀScheme 3).
Recently there has been interest in the intramolecular epoxidation of suitably
substituted alkenes in the context of the synthesis of various furo [17] and pyrano
[18] compounds. The cyclization of 4 was therefore also attempted with m-chloro-
peroxybenzoic acid in dry thiophene-free benzene; however, no tractable products
were obtained.
In conclusion, 4 was regioselectively cyclized under different conditions to
achieve different polyheterocycles in appreciable yields. Only in one case a furo
derivative was obtained by a 5-exo cyclization; in the other cases, bicyclic pyran
derivatives were produced by 6-endo cyclization.
Experimental
Melting points were measured on a H2SO4 bath and are uncorrected. UV spectra ꢀEtOH) were recorded
on a Hitachi 200±20 spectrophotometer. IR spectra were run on KBr disks on a Perkin-Elmer 1330
apparatus. 1H NMR spectra were determined for solutions in CDCl3 with TMS as internal standard on
Bruker AC-250 ꢀ300MHz) and Bruker DRX-500 ꢀ500 MHz) NMR spectrometers. Elemental analyses
in accordance with the calculated values. Mass spectra were carried out by RSIC ꢀCDRI) Lucknow on
a JEOL D-300 ꢀEl) instrument. Silica gel ꢀ60±120 mesh, Spectrochem, India) was used for chromato-
graphic separation. Petroleum ether refers to the fraction boiling between 60 and 80ꢀC.

Heterocyclization of a Substituted Pyranone
1321
4-ꢀCyclohex-20-enyloxy)-6-methyl-2-one ꢀ3; C12H14O3)
A mixture of 1.26g 4-hydroxy-6-methylpyran-2-one ꢀ10 mmol), 1.6 g 3-bromocycloxene ꢀ10 mmol),
and 3 g anhydrous K2CO3 was re¯uxed in 100 cm3 dry acetone for 5 h. The reaction mixture was
cooled and ®ltered. The solvent was distilled off, and the residual mass was chromatographed over
silica gel. Elution of the column with benzene:ethyl acetate ˆ 9:1 gave compound 3 as a transparent
sticky liquid.
1
Yield: 1.1 g ꢀ55%); H NMR ꢀCDCl3, ꢀ, 300 MHz): 1.43±2.28 ꢀm, 6H), 2.21 ꢀs, 3H, C-6-CH3),
4.74±4.78 ꢀm, 1H, C1-H), 5.47 ꢀs, 1H, C3-H), 5.76 ꢀs, 1H, C5-H), 5.81±6.26 ꢀm, 2H, C2-H, C3-H) ppm;
IR ꢀKBr): ꢁ ˆ 1700, 1540, 1480, 1230 cmÀ 1; UV=Vis ꢀEtOH): ꢂmax ˆ 216, 277 nm; MS: m=z ˆ 206
‡
ꢀM ).
3-ꢀCyclohex-20-enyl)-4-hydroxy-6-methylpyran-2-one ꢀ4)
A solution of 1 g ꢀ5 mmol) 3 in 3 cm3 xylene was re¯uxed for 17h. A solid was obtained after cooling
the reaction mixture; this was separated by ®ltration and puri®ed by recrystallization from an ace-
tone=petroleum ether mixture ꢀyield: 65%). The obtained compound was shown to be 4 by comparison
of its physical data with those of an authentic sample [8].
6-Methyl-90-iodo-20-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one ꢀ6a; C12H13IO3)
A solution of 0.2 g ꢀ1mmol) 4 in 50cm3 dry CH3CN was stirred at 0±5ꢀC with 0.23 g ꢀ1mmol) solid
N-iodosuccinimide for 1 h. The solvent was distilled off, and the residual mass was dissolved in 50cm3
CHCl3. The organic phase was washed with 20cm3 saturated Na2SO3 solution, twice with 20 cm3 H2O,
and dried ꢀNa2SO4). Removal of CHCl3 gave a gummy residue which was puri®ed by column
chromatography over silica gel. Elution of the column with benzene:ethyl acetateˆ 9:1 gave raw 6a
which was recrystallized from a CHCl3=petroleum ether mixture.
Yield: 0.25 g ꢀ80%); white solid; m.p.: 129±130ꢀC; 1H NMR ꢀCDCl3, ꢀ, 300MHz): 1.45±1.69 ꢀm,
Hg, Hi), 1.92±2.06 ꢀm, Hd, He, Hf), 2.10±2.20 ꢀm, Hh), 2.26 ꢀs, 3H, C6-CH3), 3.43±3.50 ꢀdt, J ˆ 6.8 and
6.7 Hz, Hc), 4.25±4.33 ꢀddd, J ˆ 10, 6.9, and 4.5 Hz, Ha), 5.05±5.10 ꢀdd, J ˆ 6.9 and 6.7 Hz, Hb), 5.97
ꢀs, 1H) ppm; IR ꢀKBr): ꢁ ˆ 1100, 1200, 1240, 1400, 1560, 1690 cmÀ 1; UV=Vis ꢀEtOH): ꢂmax ˆ 211,
‡
297 nm; MS: m=z ˆ 332 ꢀM ).
6-Methyl-90-bromo-20-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one ꢀ6b; C12H13BrO3)
A solution of 0.2 g ꢀ1mmol) 4 in 100 cm3 CHCl3 was stirred with 0.32g ꢀ1mmol) solid pyridinium
hydrotribromide [19] or 0.38g ꢀ1mmol) hexamine hydrotribromide [20] at 0±5ꢀC for 1 h or 40min,
respectively. The CHCl3 solution was washed twice with 10cm3 5% Na2CO3 solution, twice with
25cm3 H2O, and dried ꢀNa2SO4). Evaporation of CHCl3 left a gummy residue which was puri®ed by
column chromatography over silica gel. Compound 9 was obtained when the column was eluted with
benzene:ethyl-acetateˆ 4:1. The material was then recrystallized from a CHCl3=petroleum ether
mixture.
1
Yield: 0.2 g ꢀ72%); white solid; m.p.: 88±89ꢀC; H NMR ꢀCDCl3, ꢀ, 500 MHz): 1.53±1.60 ꢀm,
Hg), 1.70±1.75 ꢀm, Hi), 1.87±1.94 ꢀm, He), 1.99±2.03 ꢀq, J ˆ 6.5 Hz, Hd, Hf), 2.14±2.20 ꢀm, Hh), 2.25
ꢀs, 3H, C6-CH3), 3.60±3.64 ꢀdt, J ˆ 6.6 and 6.4Hz, Hc), 4.26±4.30 ꢀddd, J ˆ 10, 6.7, and 4.5 Hz, Ha),
4.96±4.99 ꢀdd, J ˆ 6.7 and 6.4 Hz, Hb), 5.96 ꢀs, 1H) ppm; IR ꢀKBr): ꢁ ˆ 1110, 1270, 1430, 1580,
‡
1670 cmÀ 1; UV=Vis ꢀEtOH): ꢂmax ˆ 211, 281 nm; MS: m=z ˆ 284, 286 ꢀM ).
6-Methyl-20-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one ꢀ6c; C12H14O3)
Compound 4 ꢀ0.1g, 0.5 mmol) was added in portions to 2 cm3 concentrated H2SO4 at 0±5ꢀC, and the
mixture was stirred for 2 h at this temperature. The solution was then poured into crushed ice and

1322
K. C. Majumdar and S. Ghosh
extracted with CHCl3. The CHCl3 layer was washed with 3Â10 cm3 5% Na2CO3 solution, then with
3 Â 20cm3 H2O, and dried ꢀNa2SO4). Evaporation of CHCl3 gave a gummy residue which was puri®ed
by column chromatography over silica gel. Elution with benzene:ethyl acetateˆ 3:1 gave 6c which
was recrystallized from a CHCl3=petroleum ether mixture.
1
Yield: 0.066 g ꢀ66%); white solid; m.p.: 104±105ꢀC; H NMR ꢀCDCl3, ꢀ, 500 MHz): 1.40±1.47
ꢀm, 1H), 1.59±1.65 ꢀm, 3H), 1.84 ꢀbr s, 3H), 2.11±2.13 ꢀm, 1H), 2.23 ꢀs, 3H, C6-CH3), 3.26 ꢀbr s, 1H),
4.84 ꢀbr s, 1H), 5.98 ꢀs, 1H) ppm; IR ꢀKBr): ꢁ ˆ 1140, 1230, 1570, 1670 cmÀ 1; UV=Vis ꢀEtOH):
‡
ꢂmax ˆ 210, 260 nm; MS: m=z ˆ 206 ꢀM ).
9-Methyl-benzofuro[3,2-c]pyran-2-one ꢀ9; C12H8O3)
A suspension of 0.2g ꢀ1mmol) 4 in 50cm3 dry thiophene-free benzene was treated with 0.38g
ꢀ1mmol) PdCl2ꢀPhCN)2 in presence of 0.055 g ꢀ1mmol) NaOCH3 at room temperature. The mixture
was then re¯uxed for 6 h. Benzene was distilled off, and the residual mass was extracted with 50cm3
acetone. Evaporation of acetone left a white solid which was puri®ed by column chromatography over
silica gel using benzene:ethyl acetate ˆ 3:1 as eluent.
1
Yield: 0.11g ꢀ58%); white solid; m.p.: 226±228ꢀC; H NMR ꢀCDCl3, ꢀ, 300 MHz): 2.27 ꢀs, 3H,
C9-CH3), 5.99 ꢀs, 1H, C8-H), 7.36±7.50 ꢀm, 4H) ppm; IR ꢀKBr): ꢁ ˆ 1180, 1350, 1400, 1580,
‡
1650 cmÀ 1; UV=Vis ꢀEtOH): ꢂmax ˆ 211, 299 nm; MS: m=z ˆ 200 ꢀM ).
Attempted aromatization of 6a±c
0.068 g ꢀ0.2mmol) 6a, 0.062 g ꢀ0.3mmol) 6b, or 0.060 g ꢀ0.2mmol) 6c were re¯uxed with 0.020 g Pd±
C in 2 cm3 diphenyl ether or with 0.020 g DDQ in 5 cm3 xylene for 2 h. The isolated products were
shown to be identical with the starting compounds in each case.
Acknowledgements
We thank the CSIR ꢀNew Delhi) for ®nancial assistance and the University of Kalyani for providing
laboratory facilities.
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Received December 27, 2001. Accepted ꢀrevised)March 1, 2002