Tetrahedron Letters,Vol.29,No.37,pp 4687-4690,1988 0040-4039/88 $3.00 + .OO Printed in Great Britain Pergamon Press plc

SYNTHESIS OF BENZOFURANS VIA PALLADIUM-PROMOTED CYCLIZATION OF ORTHO-SUBSTITUTED ARYL ALLYL ETHERS

Richard C. Larock* and Dean E. Stinn Department of Chemistry, Iowa State University,

Summary. o-Iodo- or (chloromercurio)aryl ally1 ethers undergo

cyclization to benzofurans.

Ames, Iowa 50011

facile palladium-promoted

Transition metal reagents have proven highly valuable for the cyclization of nitrogen-

containing ortho-haloaryl alkenes to heterocycles. Nickel and palladium catalysts are the

most useful for such cyclizations.' We recently reported that catalytic amounts of Pd(OAc)2

in the presence of @u4NCl, DMF and an appropriate base (Na2C03, NaOAc or Et3N) cyclize such

o-iodoaryl alkenes to indoles, indolines, oxindoles, quinolines, isoquinolines and

isoquinolones in short reaction times, under mild temperatures, and in high yield (eq. 1). 1

,R

While the palladium-promoted cyclization of o-allylic2 or vinylic3 phenols to 2- and 3-

substituted benzofurans respectively (eqs. 2 and 3) has proven quite successful, the

Pd(OAc), CH3

PdClz

Ph Ph

(2)

(3)

cyclization of g-iodoaryl ally1 ethers to benzofurans (eq. 4) is much more problematical as a

(4)

CH3

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4688

route to benzofurans in view of the known ability of palladium(O) to react with aryl ally1

ethers to form n-allylpalladium compounds (eq. 5).4

H,C=CHCH,OAr + Pd - H - C3H,PdOAr (5)

After considerable experimentation, we have found reaction conditions which allow us to

effect the cyclization described in equation 4 under mild conditions and in reasonably good

isolated yields. Our results are summarized in Table I. Optimum reaction conditions are

essentially those reported earlier by us for the cyclization of the analogous nitrogen-

containing compounds,I except for the addition of one equivalent of NaO$H which has been

found to improve the overall yield of benzofuran. It may be that the formate is reducing any

n-allylpalladium intermediates formed by carbon-oxygen insertation (eq. 5) and is thus keeping

the palladium(O) catalyst active. Consistent with the idea that Pd(0) insertion into the

carbon-oxygen bond is the major side reaction is the observation that the less hindered the

double bond (Table I, entry 1) or the better the aryl leaving group (Table I, entry 8), the

lower the yield of benzofuran.

Mechanistically, we believe that these reactions proceed as indicated in Scheme I.

(Note: additional ligands on palladium have been omitted for clarity.)

Scheme I -~--.

+ Pd -

To improve the yields of benzofuran from those systems that do not work well in this

palladium-catalyzed process, we have also examined the palladium(II)-proinoted cyclization of

the analogous arylmercurials. The requisite arylmercurials were readily prepared by Mitsunobu

coupling5 of o-(chloromercurio)phenol 6 and the appropriate allylic alcohol (eq. 6).

OH + HOCH,CH=CH, EtO,CN=NCO,Et O+N (6)

HgCl PPh3

HgCl

Cyclization using one equivalent of Li2PdClq occurred readily in a matter of minutes at room

temperature to afford high yields of the corresponding benzofuran (Table II). The only

difficulty encountered here is the apparent side chain elimination of palladium hydride noted

in entry 3 of Tabie II. An attempt to make thfs process catalytic in palladium chloride by

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Table I. Synthesis of Benzofurans via Q-Iodoaryl Ally1 Ethersa

Entry Substrate Benzofuranb Isolated Yield (%)

Ph

Ph

47

83

45d, 81e

76

52

4of

42g

aAll reactions were stirred in a l-dram vial at 80°C for 2 days using 5%

Pd(OAc), (0.015 mmol), Na&Oa (0.75 mmol), NaO$H (0.3 mmol), the substrate

(0.3 mmol), DMF (0.6 ml), and ~-Bu~Ncl (0.33 mmol) . b All products gave

appropriate 'H and 13C NMR, IR, and mass spectral data. 'Substrate was a

60:40 E/Z mixture. d Contained 45% unreacted substrate. eWith 10%

PdC12(MeCN),, 81% of the benzofuran product and 9% of the substrate were

obtained. f This result has proven to be irreproduceable. 'Reaction was

run for 1 day.

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addition of CuC12 and 02 gave back mostly starting atylmercurial even after 5 days of reaction

at room temperature.

Table II. Synthesis of Benzofurans via Organomercurialsa

Entry Organomercurial Time Benzofuran(s) b

Isolated

(min) Yield (%)

2 60 Ph

65'

98

12 28

aAll reactions were stirred at ambient temperature using LiZPdC14 (0.30

mmol), b Et3N (0.6 mmol), the substrate (0.3 mmol), THF (6 ml) and DMF (1.2

ml) . All products gave appropriate 'H and r3C NMR, IR, and mass spectral

data. 'HMPA was used instead of DMF.

Acknowledgment. Financial support of this research by the National Institutes of Health (GM

24254) and generous loans of palladium acetate and palladium chloride by Johnson Matthey, Inc.

and Kawaken Fine Chemicals Co., Ltd. are gratefully acknowledged.

1.

2.

R. C. Larock and S. Babu Tetrahedron Lett. 28, 5291 (1987) and references therein.

(a) T. Hosokawa, K. Maeda, K. Koga and I. Moritani Tetrahedron Lett. 739 (1973); (b) T. Hosokawa, H. Ohkata and I. Moritani Bull. Chem. Sot. Japan 48, 1533 (1975); (c) T. Hosokawa, S. Yamashita, S. Murahashi and A. Sonoda Bull. Chem. Sot. Japan 49, 3662 (1976); (d) T. Hosokawa, S. Miyagi, S. Murahashi and A. Sonoda J. Chem. Sot., Chem. Commun. 687 (1978); and (e) T. Hosokawa, T. Uno, S. Inui and S. Murahashi J. Am. Chem. Sot. 103, 2318 (1981).

3. (a) B. Cardillo, M. Cornia and L. Merlini Gazz. Chim. Ital. 105, 1151 (1975); and (b) G. Casiraghi, G. Casnati, G. Puglia, G. Sartori and C. Terenghi Synthesis 122 (1977).

4.

5.

J. Tsuji, Y. Kobayashi, H. Kataoka and T. Takahashi Tetrahedron Lett. 21, 1475 (1980).

(a) S. Bittner and Y. Assaf Chem. Ind. (London) 281 (1975); (b) M. S. Manhas, W. H. Hoffman, B. La1 and A. K. Bose J. Chem. Sot Perkin Trans. I 461 (1975); and ___tL.-.- (c) 0. Mitsunobu Synthesis 1 (1981).

6. F. C. Whitmore and E. R. Hanson Org. Syn. Coll. Vol. 1, 161 (1941).

REFERENCES

(Received in USA 22 June 1988)