a new method for the generation of isobenzofurans: a simple entry to substituted naphthalenes
TRANSCRIPT
P*trm Letters Vol. 21, pp 3663 - 3666 @‘Peremon Press Ltd. 19% Printed in Great Britain
A NEW IElTioD FOR 'RIE &NERATION OF ISORDNZDPURANS:
A SXMPLR ENTRY TO SUBSTITUTED NAPHTUIERES.
B.A. Keay, D.K.N. Lee aad R. Rodrigo*
Guelpb-Waterloo Centre fox Graduate Work in Chemistry
Department of rBemistry, Uuiveristy of Waterloo, Waterloo, Ontario, Canada
Abstract - 5,6-Dimethoxy isooonzofurau is generated in situ from the dimuthylocetal of 6-hydroxy-
methyl vsratraldehyde and intercepted by a variety of dienophiles to produce the expected ox&en-
bridged adducts in good yield. ~lmy of the latter ale easily aromatised to naphthalenes.
me outstanding properties of isobenzofurans as dienes in the Dlels-Alder rorction are well
documented.' They have generally been obtained by the thermolysis of bridged polycyclic systems in
reverse Dielt-Alder processes and their widespnad application to the construction of naturally
occurring aromatic tmd hydroaromatic polyoyclic systems haa been limited onSy by the difficulty of
preparing suitebly substituted bicyclic precursors. Da13 noteworthy exception is the isobenxoAvan
approach to anthtacyclinone synthesis. * In recent years new preparations of isobenzofurans (not
involviag Diels-Alder reversions] have been developed. 3,4,5 Overall versatility is again limited i
3‘5 these procedures either by nature of the precursor ox by conditions of isobenzofuran generation4
which preclude the isolation of non-aronatised products.
Wo now report a afnple, efficient method for the generation of isobenzdurms which is both
nild end versatile, permitting in principle the elaboration of most desired substitution patterns
and the isolation of bridged adducts after reaction with various dienophiles. To avoid regiochemic
problems at the present time we have chosen to illustrate our procedure with 5,6-dimethoxyisobenso-
furen but our oxporionce to date confi.rns the generality of the method with other non-symuetric var
i-ants. Thus 6-bromoveratraldehyde L was quantitatively converted6 to its dimethyl acetal s, lithi-
atcd with n butyl lithium (halogen-sotal ox&awga) and rcaotod with dry formaldehyde to provide
6-hydroxymethyl vefatraldehyde dimethyl acetal zin virtually quantitative yield. The latter wes a
heavy oil which could not be distilled without decomposition end resisted crystallisation. Its
structure was apparent however from the accrued spectroscopic data (M+ = 242; S(CnC13) 3.01(t,I)
(exchanges with D,o), 3.35 @.a), 5.85 (s,d), 4.59 (d,Z) (collapses to singlet with D20), 5.41 (s,l
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6.82 (s,l), 7,OO (s,l); IRyneat = 3430 broad). Treatment of this compound with glecial acetic OH
acid in’s suitable refluxing solvent and in the presence of various dienophiles resulted in oxyge
bridged adducts (of the type 9 in an average yield of 70%. The outcolne of this reaction can on1
be attributed to the formation and interception of the isobenzafuran 2 by the process shown in
Scheme 1.
scheme 1
1 R1 = CHO, R2 = Br
1. Rl = CWW2, R2
J Rl = CWCW2, R2
No direct evidence
tically expected in view
for the existence of 2 has been obtained, nor can such evidence be realis
of the well-known instability of simple isobenzofurans, ’ but brief treaty
of fwith acetic acid did produce the acetal 9 (6 (CDC13) 3.38 (s,3), 3.86 (s,3), 3.87 (s,3), 4.91
(d,l,J = 12.0 Hz], 5.16 (dd,l, J = 12.0, 2.2 Hz), 6.12 (d,l, J = 2.2 Hz), 6.75 (s.l), 6.88 (s,l)).
The table suxmzazises our results with various dienophiles. It is noteworthy that even acid
sensitive materials like butenolide and methyl vinyl ketone can be succesSfully used.
Table
1. dimethylacetylensdicarboxylate
2. benzoquinone
3 naphthaquinone
4. methylvinyl ketone
5. 2-butenolide
6. acryloni Wile
7. u-cbloroacrylonitrile
8. maleic anhydride
9. methyl acrylate
Dienophi 1s Isolated Yield 01
99
60
86
80
72
64
70
60
50
a “a Solvent (Time)
none L20 min)
CH2C12 (15 h)
cHc13 (1 h)
cc14 (6 hl cm3 145 h)
CHCl3 (4 hl
CH2C12 (15 h]
CH2CI2 (24 h)
cHC13 (10 hl
Endo/Exo
by (p.n.r.1
-c
7:3
3:l
3:2
1:2*
9:l 1
3.7
7:3
3:2
t based on individually isolated isolllers.
Endo/exo mixtures can usually be readily detected wd estimated by inspection of the p.m.r.
spectra. Bridgehead protons appear as singlets in the exe-adducts but are doublets (J = 4.5-5.1 Hz)
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in the endo- adduots. Separations have been achieved in certain instances by a combination of colum
chromatography and fractional crystallisation (entries 4 and 5). In other cases the endo isomers
have been isolated from the mixtures
dimethyl f-rate produced the tram
compound swas obtained in two steps
of 82%. (Scheme 21
Scheme 2
as crystalline solids (entries 3,6,9). The reaction with
diester in a disappointing yield of E. 5%. Howevex, the some
from the acetylene dicarbowlate adduct L in an overall yield
7 8 9
Naphthalenes g, 11, E and G were obtained from the corresponding oxygen-bridged compounds
by brief acid treatmmt~'the synthesis of substituted naphthalenes has recently attracted sonm atten-
tion. ' Quinone 14 was prepared by sintilar aromstisatiun (&duct of entry 3J .8 -
10 I$ = OH, 5 = R3 = ccy40 - E- 11 Rl - H, R2 = R3 = C02Ms
12 Rl = Rz = H, Rg q CN
Is Rl 0 R2 = H, R3 = COMe
these results co&ined with our recent. directed lithiation procedure’ for aromatic acetals
provides a method of great potential for the synthesis of msny natural products. It has already
been exploited10 in a short synthesis af som arylnaphthalide lignans. A further interesting
aspect now being actively investigated is the generation of furopyridines 11 and other heterocyclic
analogues.
Acknowledgements - We thank the Natural Sciences and Engineering Research Comcil of Canada for
support.
References
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tent with their structures. Mixtures of exo-endo isomers if not separable were analysed as
such.
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