Synthesis of some C-4 hydroxybenzo[c]pyrans: A new approach

Article abstract of DOI:10.1080/00397910600592001

A new synthetic approach to the synthesis of some epimeric C-4-hydroxybenzo[c]pyrans is described. A key step in their formation is stereoisomerisation of a nonconjugated ortho alkenylphenylketone and -ester using palladium bisacetonitrile [bisacetonitril

Full text of DOI:10.1080/00397910600592001

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Synthesis of Some C‐4
Hydroxybenzo[c]pyrans: A New Approach
Victor I. Hugo a , Tebogo Masenya a & Ivan R. Green b
a Department of Interdisciplinary Mathematics and Science Studies , Cape
Peninsula University of Technology , Cape Town, Republic of South Africa
b Department of Chemistry , University of the Western Cape , Bellville,
Republic of South Africa
Published online: 21 Aug 2006.
To cite this article: Victor I. Hugo , Tebogo Masenya & Ivan R. Green (2006) Synthesis of Some C‐4
Hydroxybenzo[c]pyrans: A New Approach, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:11, 1631-1636
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Synthetic Communicationsw, 36: 1631–1636, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600592001
Synthesis of Some C-4
Hydroxybenzo[c]pyrans: A New Approach
Victor I. Hugo and Tebogo Masenya
Department of Interdisciplinary Mathematics and Science Studies,
Cape Peninsula University of Technology, Cape Town,
Republic of South Africa
Ivan R. Green
Department of Chemistry, University of the Western Cape,
Bellville, Republic of South Africa
Abstract: A new synthetic approach to the synthesis of some epimeric C-4-hydroxy-
benzo[c]pyrans is described. A key step in their formation is stereoisomerisation of a
nonconjugated ortho alkenylphenylketone and -ester using palladium bisacetonitrile
[bisacetonitriledichloropalladium(II)] to give the corresponding conjugated E stereo-
isomers which cyclize on treatment with meta-chloroperbenzoic acid (m-CPBA) to
afford the target compounds.
Keywords: C-4 hydroxybenzo[c]pyrans, hydroxy[c]pyrans, meta-chloroperbenzoic
acid, palladium bisacetonitrile
Some naturally occurring compounds contain a C-4 hydroxypyran ring (in
which the hydroxyl may occupy a pseudo-axial or pseudo-equatorial
position) as part of their structures. Two examples are the extended quinones,
protoaphins-fb and-sl.[1] We have previously developed novel syntheses that
afford such C-4 hydroxypyranquinones.[2–4] More recently, an oxidative
mercury-mediated ring closure of 2-(prop-10-enyl)phenylmethanol derivatives
was reported, which afforded diastereomeric isochroman-4-ols.[5]
Received in Poland November 22, 2004
Address correspondence to Victor I. Hugo, Department of Interdisciplinary
Mathematics and Science Studies, Cape Peninsula University of Technology,
PO Box 652, Cape Town, 8000, Republic of South Africa. E-mail: vhugo@cput.ac.za
1631

1632
V. I. Hugo, T. Masenya, and I. R. Green
We now have developed a convenient new synthetic approach by which
the diastereomeric hydroxypyran pairs 1 and 2, as well as 3 and 4, are
available in good overall yield (Scheme 1).
Ketone 5[4] was smoothly converted to the conjugated E olefin 6[4] (89%)
on treatment with a catalytic amount of palladium bis(acetonitrile)[6] in
1
dry dichloromethane. H NMR integration showed the presence of some
(less than 2%) of the corresponding Z-isomer. Our earlier work[2,3] in this
regard relied entirely on base-induced conjugations employing potassium
t-butoxide in THF.
Compound 6 gave alcohol 7[4] on treatment with lithium aluminium
hydride. This was followed by epoxidation of the olefinic bond of 7 using
m-CPBA to give the diastereomeric C-4 hydroxypyran 1[4] as the major
product (in which the OH is pseudo axial) as well as pyran 2[4] (in which
the OH is pseudo equatorial) as their racemates in yields of 46% and 36%,
respectively. The target hydroxypyrans presumably formed via cyclization
of the intermediate epoxide 8. We have found the same product distribution
in our earlier[4] oxidative cylization reactions employing cerium(IV)
ammonium nitrate–the product with the hydroxy in a pseudo-axial position
being the major diastereomer.
Compound 9[4] could also be converted to the E olefin 10[5] with
palladium bisacetonitrile in excellent yield (90%). This was treated as for
compound 6 to afford alcohol 11,[5] which, upon treatment with m-CPBA,
gave the epimeric C-4 hydroxypyrans 3 and 4[5] as their racemates in yields
of 58% and 23%, respectively (also probably via cyclization of the interme-
diate epoxide 12).
The 1H NMR spectroscopic data for pyrans 1, 2, 3, and 4 agreed entirely
with those published earlier.[4,5]
We envisage that this new synthetic approach to C-4 hydroxybenzo[c]-
pyrans could be employed as a model for the synthesis of naturally
occurring compounds containing the C-4 hydroxypyran ring system.

C-4 Hydroxybenzo[c]pyrans
1633
Scheme 1. (i) Palladium bis(acetonitrile)/CH2Cl2; (ii) LiAlH4/ether; (iii) m-CPBA/
CH2Cl2.
EXPERIMENTAL
1H NMR spectra were recorded using a Varian 200-MHz instrument at
ambient temperature in deuterochloroform. Infrared spectra were measured
as Nujol mulls on a Beckman Aculab spectrometer. High-resolution mass
spectra were recorded on a modified AEI-902 spectrometer. Melting points
were recorded on a Fischer-John apparatus and are uncorrected. Column

1634
V. I. Hugo, T. Masenya, and I. R. Green
chromatography was carried out on dry columns with Merck kieselgel (silica
gel) 60 (70–230 mesh) as adsorbent.
The phrase “residue obtained on workup” refers to the residue when the
organic layer was separated and dried (MgSO4), and the solvent evaporated
under reduced pressure.
Light petroleum refers to petroleum ether (bp 60–808C). Palladium bis-
acetonitrile refers to bisacetonitriledichloropalladium(II) and m-CPBA to
meta-chloroperbenzoic acid. All solvents and reagents were distilled before use.
2,5-Dimethoxy-6-(trans-10-propenyl)acetophenone (6)
Palladium bisacetonitrile (119 mg, 0.459 mmol) in dry dichloromethane
(5 ml) was added to a stirred solution of compound 5[4] (202 mg,
0.918 mmol) in dry dichloromethane (10 ml) under nitrogen. After 18 h, the
reaction mixture was thrown into water and extracted with dichloromethane.
The residue obtained on workup was chromatographed (eluant 30% ethyl
acetate in light petroleum) to afford product 6[4] (179 mg, 89%) as a light
yellow oil. (Found: Mþ, 220.1097. C13H16O3 requires 220.1099.) n
max 1700 cm21. d (CDCl3) 1.85 (3H, d, J 6.6 Hz, Ar-CH55CHCH3), 2.41
(3H, s, Ar-COCH3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 6.04
(1H, dq, J 16.2 and 6.6 Hz, Ar-CH55CHCH3), 6. 38 (1H, dq, J 16.2 and
1.8 Hz, Ar-CH55CHCH3), 6.72 (1H, d, J 9.0 Hz, Ar-H), 6.80 (1H, d, J
9.0 Hz, Ar-H).
1-(Hydroxyethyl)-2,5-dimethoxy-6-(trans-10-propenyl)benzene (7)
Ketone 6[4] (168 mg, 0.765 mmmol) in dry ether (10 ml) was added dropwise
to a stirred suspension of lithium aluminium hydride (145 mg, 3.827 mmol) in
dry ether (20 ml). After 20 min, saturated ammonium chloride (2 ml) was
added followed by anhydrous magnesium sulphate. Workup of the filtrate
gave a residue, which was chromatographed (eluant 30% ethyl acetate in
light petroleum) to afford product 7[4] (151 mg, 89%) as white crystals; m.p.
83–848C (from light petroleum) (lit.[4] 83–84.58C). (Found: Mþ: 222.1260.
C13H18O3 requires 222.1256.) nmax 3520 cm21; d (CDCl3) 1.55 (3H, d, J
6.6 Hz, Ar-CH3CHOH), 1.90 (3H, dd, J 6.6 and 2.0 Hz, CH55CHCH3), 3.75
(3H, s, OCH3), 3.86 (3H, s, OCH3), 5.22–5.36 (1H, br s, OH, D2O exchange-
able), 5.64–5.82 (1H, dq, J 16.0 and 6.6 Hz, CH55CHCH3), 6.35 (1H, dq, J
16.0 and 2.0 Hz, CH55CHCH3), 6.69 (1H, d, J 8.8 Hz, Ar-H) and 6.77 (1H,
d, J 8.8 Hz, Ar-H).
(+) (1R, 3R, 4R)-3,4-Dihydro-4-hydroxy-5,8-dimethoxy-1,3-
dimethyl-1H-benzo[2,3-c]pyran (1) and Its 4S-diastereomer (2)
The conjugated alcohol 7[4] (206 mg, 0.928 mmol) was dissolved in
dichloromethane (10 ml) and immersed in ice. m-CPBA (240 mg,

C-4 Hydroxybenzo[c]pyrans
1635
1.391 mmol) in dichloromethane (10 ml) was added dropwise to the stirred
alcohol solution. After 2 h, the reaction was thrown into a sodium hydroxide
solution (0.1 mol dm23). The organic components were extracted into dichlor-
omethane. The residue obtained upon workup was chromotographed on a
short column (eluant 30% ethyl acetate in petroleum ether) to afford first
compound 2[4] (74 mg, 36%) as an oil; nmax (film) 3480–3100 cm21(br).
(Found: Mþ, 238.1182. Calc. for C13H18O4: M, 238.1205.) This was
followed by compound 1[4] (94 mg, 46%) as white crystals; mp 113–1148C
(from hexane) (lit.[4] mp 113–1158C).
Allyl-3,6-dimethoxy-2-(trans-10-propenyl)benzoate (10)
Ester 9[4] (209 mg, 0.798 mmol) in dry dichloromethane (10 ml) was
treated with palladium bisacetonitrile (166 mg, 0.638 mmol), as for the prep-
aration of compound 6. Workup and chromatography (eluant 30% ethyl
acetate in light petroleum) gave 10[5] (188 mg, 90%) as a yellow oil. nmax
1845 and 1700 cm21. (Found: Mþ, 262.1207. C15H18O4 requires 262.1205).
d (CDCl3) 1.85 (3H, dd, J 6.6 and 1.8 Hz, Ar-CH55CHCH3, 3.32 (2H, dt, J
5.8 and 1.4 Hz, Ar-CO2CH2CH55CH2), 3.77 and 3.79 (3H each, s,
2 ꢀ OCH3), 4.75–4.82 (2H, m, Ar-CO2CH2CH55CH2), 5.32–5.48 (1H, m,
J
16.0 and 6.7 Hz, Ar-CH55CHCH3), 5.80–6.25 (1H, m, Ar-
CO2CH2CH55CH2), 6.42 (1H, dq, J 16.0 and 1.8 Hz, Ar-CH55CHCH3),
6.76 (1H, d, J 9.0 Hz, 5-H), 6.82 (1H, d, J 9.0 Hz, 6-H).
[3,6-Dimethoxy-2-trans-(10-propenyl)phenyl]methanol (11)
Ester 10[5] (104 mg, 0.397 mmol) was reduced with lithium aluminium
hydride (75 mg, 1.98 mmol) as for the synthesis of compound 7. Similar
workup and chromatography afforded alcohol 11[5] (73 mg, 89%) as an oil.
nmax 3400, 1640, and 1600 cm21 and d (CDCl3) 1.94 (3H, dd, J 6.6 and
1.8 Hz, Ar-CH55CHCH3), 2.28 (1H, br s, OH, D2O exchangable), 3.78 (3H,
s, 6-OCH3), 3.83 (3H, s, OCH3), 4.77 (2H, s, Ar-CH2OH), 5.89–6.07 (1H
dq, J 16.0 and 6.7 Hz, Ar-CH55CHCH3), 6.48 (1H, dq, J 16.0 and 1.8 Hz,
Ar-CH55CHCH3), and 6.74 (2H, s, 4- and 5-H).
(+)(3R, 4R)-3,4-Dihydro-4-hydroxy-5,8-dimethoxy-3-methyl-1H-
benzo[c]pyran (3) and Its 4S Diastereomer (4)
Alcohol 11[4] (152 mg, 0.729 mmol) was cyclized using a solution of m-CPBA
(188.7 mg, 1.0933 mmol) as in the preparation of compounds 1 and 2. Similar
workup and chromatography gave pyran 4[5] (35 mg, 23%); mp 61–628C
(from hexane) (lit.[5] 60–618C); (Found: Mþ 224.1038. Calc. for C12H16O4:

1636
V. I. Hugo, T. Masenya, and I. R. Green
M, 224.1049.) This was followed by pyran 3[5] (88 mg, 58%); mp 69–708C
(from hexane) (lit.[5] 68–708C). (Found: Mþ 224.1039. Calc. for C12H16O4:
M, 224.1049.)
ACKNOWLEDGMENTS
We thank the Councils of the Cape Peninsula University of Technology,
University of the Western Cape, and the National Research Foundation
for financial support and Philip Boshoff of the Cape Peninsula University of
Technology for providing high-resolution mass spectra.
REFERENCES
1. Thompson, R. H. In Naturally Occurring Quinones; 2nd Ed.; Academic Press:
London and New York, 1971; p. 597.
2. Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.; Yorke, S. C. Naphtho-
pyrans by ring-closure of substituted naphthalenes using potassium-t-butoxide in
dimethylformamide. J. Chem. Soc. Perkin Trans. 1 1983, 2309–2313.
3. Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.; Yorke, S. C.
Naphtho[2,3-c]pyran-5,10-quinones: Synthesis of the racemates of quinone A,
quinone A0 and deoxyquinone A dimethyl ethers of 7-methoxyeleutherin, and of
isoeleutherin. J. Chem. Soc. Perkin Trans. 1 1984, 2383–2388.
4. Green, I. R.; Hugo, V. I.; Oosthuizen, F. J.; van Eeden, N.; Giles, R. G. F.
Convenient synthetic routes to antimicrobial benzo[c]pyranquinones. S. Afr. J.
Chem. 1995, 48, 15–12.
5. de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J. R. The Synthesis of
isochroman-4-ols and isochroman-3-ols: models for naturally occurring benzo[g]
isochromanols. Tetrahedron 2001, 57, 9623–9634.
6. Giles, R. G. F.; Green, I. R.; Taylor, C. P. Isochromenes and their quinones through
cyclisations with bisacetonitriledichloropalladium(II). Tetrahedron Lett. 1999, 40,
4871–4872.