a new method for the generation of isobenzofurans: a simple entry to substituted naphthalenes

4
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 GraduateWork 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 varietyof dienophiles to produce the expectedox&en- bridged adductsin good yield. ~lmy of the latterale easily aromatised to naphthalenes. me outstanding propertiesof isobenzofurans as dienesin the Dlels-Alder rorctionare well documented.' They have generally been obtainedby the thermolysis of bridged polycyclicsystemsin reverseDielt-Alder processesand their widespnad application to the construction of naturally occurringaromatictmd hydroaromatic polyoyclic systemshaa been limitedonSy by the difficulty of preparingsuiteblysubstituted bicyclicprecursors. Da13 noteworthy exceptionis the isobenxoAvan approachto anthtacyclinone synthesis. * In recentyears new preparations of isobenzofurans (not involviagDiels-Alder reversions] have been developed. 3,4,5 Overall versatility is again limitedi 3‘5 these procedureseither by nature of the precursor ox by conditions of isobenzofuran generation4 which preclude the isolationof non-aronatised products. Wo now report a afnple,efficientmethod for the generation of isobenzdurms which is both nild end versatile, permitting in principlethe elaboration of most desiredsubstitution patterns and the isolation of bridged adducts after reaction with various dienophiles. To avoid regiochemic problemsat the present time we have chosen to illustrate our procedurewith 5,6-dimethoxyisobenso- furen but our oxporionceto 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 acetals, lithi- atcd with n butyl lithium(halogen-sotal ox&awga) and rcaotodwith dry formaldehyde to provide 6-hydroxymethyl vefatraldehyde dimethylacetal zin virtually quantitative yield. The latterwes a heavy oil which could not be distilled without decomposition end resistedcrystallisation.Its structure was apparenthowever from the accruedspectroscopic 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 singletwith D20), 5.41 (s,l

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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

3664

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)

3665

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

1. M.E. Wiersum and N.J. Wijs, Chem. Comm. 347 C1972); B. Chacko, D.J. Sardella and J. Bornstsin,

Tetrahedron Lett., 2507 (1976).

2. A.S. Kende, D.P. Curran, Y. Tsay and J.E. Mills, Tetrahedron Lett., 3537 (1977).

5. J.G. Smith and R.T. Wikman, J. Org. Chem. 2, 3648 (1974).

4. R. Farragher and T.L. Gilchrist, J. Chem. Sot., ferkin 5, 336 [1976).

5. L. Contreras, C.E. Slemon and D.B. MacLean, Tetrahedron L&t., 4237 (1978).

6. M.E. Evans, Carbohydrate Res. 2l_* 473 (1972).

7. F.M. Hauser and R. RBee, J. Org. Chem. 43, 178 (1978); N.J.P. Broom and P.G. Sammes, Chem.

comm. 162 (1978).

8. Compounds 2 and 4 were unstable oils which could not be purified without decomposition. All

other new compounds prepared in this study had analytical and spectroscopic properties consis-

tent with their structures. Mixtures of exo-endo isomers if not separable were analysed as

such.

9. H.P. Plaumann, B.A. Xeay and R. Bodrigo, Tetrahedron Lett.. 4921 {1979).

LO. H.P. Plaumann, J.G. Smith and R. Rodrigo, Chem. Comm., 354 [1980).

Il. M.E. Wiersum, C.D. Eldred, P. Vrijhof end H.C. van der Plas, Tetrahedron Lett., 1741 (1977).

12. Refluxing in toluene for 3 h. with a catalytic quantity of F-toluene sulfonic acid,

followed by chromatography (silica).