Synthesis and cycloadditions of 9H-furo[3,4-b][1]benzo(thio)pyran-9-ones: Furan ring formation by a novel hydrolytically induced cycloreversion

Article abstract of DOI:10.1016/S0040-4039(02)00820-1

C-2 lithiation of acetals 2 followed by trapping with aldehydes gives 3. Subsequent unmasking of the acetal function provides furobenzo(thio)pyrans 4, cycloadditions of which have been investigated.

Full text of DOI:10.1016/S0040-4039(02)00820-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4507–4510
Synthesis and cycloadditions of
9H-furo[3,4-b][1]benzo(thio)pyran-9-ones: furan ring formation
by a novel hydrolytically induced cycloreversion
G. Elena Daia,a Christopher D. Gabbutt,a,* John D. Hepworth,b B. Mark Heron,c David E. Hibbsd
and Michael B. Hursthousee
aDepartment of Chemistry, University of Hull, Hull HU6 7RX, UK
bJames Robinson Ltd, PO Box B3, Hillhouse Lane, Huddersfield HD1 6BU, UK
cDepartment of Colour Chemistry, University of Leeds, Leeds LS2 9JT, UK
dSchool of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
eDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 7 March 2002; revised 15 April 2002; accepted 25 April 2002
Abstract—C-2 lithiation of acetals 2 followed by trapping with aldehydes gives 3. Subsequent unmasking of the acetal function
provides furobenzo(thio)pyrans 4, cycloadditions of which have been investigated. © 2002 Elsevier Science Ltd. All rights
reserved.
Cycloadditions to 2,3-dimethylidenechroman-4-ones 1
(X, Y=H or substituent) would offer an entry to
2,3-disubstituted 9H-xanthen-9-ones and linear fused
derivatives. The intermediacy of 1 (X=NH-NMe2, Y=
H) is evident in the cycloaddition of 3-(dimethyl-
hydrazonomethyl)-2-methylchromone with N-methyl-
maleimide (NMM),1 and 1 (X=OH, Y=H) has been
Scheme 1. Reagents and conditions: (i) LTMP, THF, −78°C; (ii) RCHO; (iii) TsOH (cat.), PhMe, ca. 50°C; (iv) NaBH4 1 equiv.,
MeOH.
* Corresponding author. Present address: Department of Colour Chemistry, University of Leeds, Leeds LS2 9JT, UK; e-mail: c.d.gabbutt@
leeds.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00820-1

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G. E. Daia et al. / Tetrahedron Letters 43 (2002) 4507–4510
invoked in the base-catalysed deacylative dimerisation of
3-acetylchromone.2 A more versatile approach to deriva-
tives of 1 would permit access to a wide range
of xanthone-containing systems, for which few cyclo-
addition strategies exist. We sought, therefore, to
investigate stable synthetic equivalents of 1 and focussed
on derivatives of furo[3,4-b][1]benzopyran-9-one. Very
few of these compounds are known, and their chemistry
remains unexplored.3 The cycloaddition chemistry of
furans and their iso-condensed derivatives represents an
area of significant current interest.4
furyl)propane has been reported.9 The syn orientation of
6 can be considered as the outcome of ‘double ortho’
regiocontrol. Evidently electronic factors are sufficient to
over-ride unfavourable interactions arising between the
Me groups in the addition of 4a to the 1:1 adduct.10 The
stereochemistry of 6 is in accord with both observations
and semi-empirical calculations4,11 that indicate, under
kinetic conditions, pincer Diels–Alder reactions of furans
lead to exo–endo adducts preferentially. We were unable
to observe the 1:1 adduct from 4a and MP; the reaction
gave 6 directly. Furan 4c failed to react with MP,
presumably steric factors account for its diminished
reactivity.
We now report an expedient and versatile synthesis of
furo[3,4-b][1]benzopyran-9-ones and some of their
cycloaddition chemistry. We have shown that the readily
available acetal 2 (Z=O) can be metallated with lithium
2,2,6,6-tetramethylpiperidide (LTMP), and the C-2 lithio
derivative intercepted with electrophiles.5 Extension of
this chemistry provided 3a–d in useful yields (40–56%).6
Unmasking of the acetal function proceeded rapidly with
a trace of TsOH in warm toluene, with concomitant
cyclisation and elimination of propanediol, presumably
via the dioxyallyl cation 3A (Z=O), to give the furoben-
zopyrans 4a–d (45–67%) (Scheme 1). Attempts to obtain
3e via anhydrous HCHO failed. However, reduction of
55 proceeded chemospecifically to give 3e (77%, mp
126–127°C), unfortunately, treatment with TsOH failed
to give an identifiable product, even in the presence of
a dienophile.
Reaction of 4a with DMAD gave the 1:1 adduct 7a as
the only characterisable product. However, under the
same conditions 4c gave two compounds the least polar
(TLC) of which was 7c (52%, mp 149.0–149.6°C). The
polar compound exhibited very simple 1H and 13C NMR
spectra consistent with a highly symmetrical structure
whilst CI-HRMS exhibited [MH]+ at m/z 695.1912
corresponding to C42H30O10. This data is only compat-
ible with the C2 symmetric, anti exo–exo adduct 812 (24%,
mp 225–226°C). Formation of 8 parallels the behaviour
of 2-methylfuran towards symmetrical acetylenes.9 Sur-
prisingly, we did not observe any of the analogous 2:1
adduct from the cycloaddition of 4f with DMAD, the
only product being 9 (45%, mp 176–177°C). Although 4d
reacted with DMAD it provided a highly complex
mixture that we failed to resolve.
The thiochromone 2 (Z=S) was converted to 4f (62.5%
overall, mp 183.5–184.5°C) by an identical protocol
(Scheme 1), in this case the lithiation proceeded more
efficiently than 2 (Z=O). Cycloadditions of 4a–d and the
furobenzothiopyran 4f have been investigated. When 4a
was treated with methyl propiolate (MP) (PhMe, rt, 48
h) flash chromatography provided a new compound
(43%, mp 228–229°C). Both NMR and HRMS indicated
this was a 2:1 adduct of 4a with MP (Scheme 2). The 1H
and 13C NMR spectra were consistent with the syn
exo–endo adduct 6, which was proved unequivocally by
X-ray crystallography7 (Fig. 1). The octacycle 6 is
remarkable since it represents the first example of a
pincer adduct from cycloaddition of an unsymmetrically
substituted furan with a propiolic ester,8 although an
intramolecular pincer addition of MP to 1,3-bis(2-
Scheme 2. Reagents and conditions: (i) HCꢀCCO2Me, PhMe, rt, 48 h; (ii) MeO2CCꢀCCO2Me, PhMe, D, 2 h.

G. E. Daia et al. / Tetrahedron Letters 43 (2002) 4507–4510
4509
Figure 1. Perspective view and X-ray crystal structure of cycloadduct 6.
4-hydroxycoumarin (77%). This unique and unprece-
dented pathway formally represents a hydrolytic retro
Compound 4b and NMM (PhMe, rt, 6 h) gave both
exo 10a and endo 10b adducts (79% overall, ratio
2.75:1) from which only the former could be obtained
pure (mp 257–259°C) by chromatography. In contrast
4b reacted slowly with 1,4-naphthoquinone and gave
the endo adduct 11 exclusively.
Diels–Alder (RDA) reaction of
a
7-oxabicy-
clo[2.2.1]heptadiene ring. Cleavage of 7c is triggered by
protonation of the chromone carbonyl group that pro-
motes conjugate addition of water to C-4a (Scheme 3);
collapse of the intermediate hemiacetal ensues. The
hemiacetal may be regarded as the [4+2] adduct of 13
and 2-hydroxychromone, a minor tautomer of 4-
hydroxycoumarin. The differing reactivity of 7c and 9
stems from higher basicity of the carbonyl group in the
chromone than in the thiochromone system, due to
diminished heteroatom p–p conjugation in the latter. In
accord with this, a study of electrostatic potentials
predicted that C-2 in chromones is more electrophilic
than C-4, and that replacement of ring O by S pro-
motes a reversal in reactivity.14 The reaction 7c“13 is
noteworthy since it generates a furan with a new substi-
tution pattern. Other acid promoted RDA reactions of
7-oxabicycloheptadienes are known, but these merely
furnish the addends.15
Dramatically differing behaviour was exhibited in the
acid-catalysed aromatisation (aq. HCl, MeOH, D) of 7c
and 9 (Scheme 3). Whilst the latter gave the expected
hydroxythioxanthone 12 [red needles, 82%, mp 218–
220°C, l(CDCl3) 16.65, OH] the former provided,
remarkably, the furan diester 1313 (68%) together with
Acknowledgements
We thank the CVCP for an ORSAS award to G.E.D.,
Dr. D. F. Ewing (Hull) for helpful discussions, the
EPSRC for provision of the mass spectrometry service
at the University of Wales, Swansea and access to the
X-ray crystallography service at the University of
Southampton.
Scheme 3.

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G. E. Daia et al. / Tetrahedron Letters 43 (2002) 4507–4510
8. Thermal cycloaddition of furan and 2,5-dimethylfuran
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,
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