Synthesis of 2H-1-benzopyrans by Pd-catalyzed cyclization of o-allylic phenols

Full text of DOI:10.1055/s-1998-1709

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LETTERS
SYNLETT
Synthesis of 2H-1-Benzopyrans by Pd-Catalyzed Cyclization of o-Allylic Phenols
Richard C. Larock,* Lulin Wei and Timothy R. Hightower
Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
Fax: (515) 294-4660; e-mail: larock@iastate.edu
Received 25 November 1997
13
14
Derivatives of 2H-1-benzopyran (1), also known as chromenes, are
prominent natural products of many genera of the Asteraceae
possessing a wide range of valuable physiological activities. They are
We and others have previously shown that catalytic amounts of
palladium acetate in the presence of oxygen and DMSO provides an
excellent Pd(II) catalyst for the cyclization of functionalized alkenes
and the conversion of enol silanes to enones. While this catalyst system
proved unsatisfactory for the synthesis of 2H-1-benzopyrans, further
optimization has afforded reaction conditions which provide exclusively
the 6-membered ring ethers in high yields. Optimal conditions for the
cyclization of o-allylic phenols (0.5 mmol) require heating 5 mol %
1
also useful intermediates in the synthesis of complex natural products,
2
such as pterocarpans.
Pd(dba) (dba = dibenzylideneacetone) and KHCO (0.55 mmol) in 9:1
2
3
DMSO/water (10 ml) for 3 days at 60 °C in the presence of air.
The choice of Pd catalyst, base and solvent system are critical to the
clean formation of the 6-membered ring ether in high yields. The
reaction of o-allylphenol and PdCl gave exclusively 5-membered ring
2
3
The synthesis of 2H-1-benzopyrans is of considerable current interest.
Most pertinent to the present research are synthetic methods involving
2-methylbenzofuran, while Pd(OAc)
and Pd(dba)
afforded
2
2
(1) the palladium-catalyzed coupling of o-iodophenols and tertiary
allylic alcohols, (2) the iodoetherification or selenoetherification of
exclusively 2H-1-benzopyran. While Pd(dba) has usually been
2
4
5
6
employed as the catalyst, Pd(OAc) provided faster and cleaner
2
o-allylic phenols and subsequent elimination, and (3) the direct
reactions for electron-deficient phenols (see entries 9 and 10 in Table 1).
Carbonate bases afforded only the 6-membered ring ether, while acetate
7
oxidation of o-allylic phenols by DDQ or potassium dichromate-
7u
Adogen 464. While all of these methods afford good yields of 2,2-
disubstituted 2H-1-benzopyrans and iodoetherification or direct
oxidation afford 2-aryl-2H-1-benzopyrans as well, none of these
methods has been reported to work on phenols possessing a wide variety
of substitution patterns in the allylic side chain.
The cyclization of o-allylic phenols by palladium(II) salts has been
reported to produce a variety of cyclic ethers. Phenols bearing a simple
allyl, 2-butenyl or cinnamyl group react with NaOMe and
stoichiometric amounts of PdCl (PhCN) , stoichiometric Pd(OAc) , or
2
2
2
catalytic Pd(OAc) plus Cu(OAc) •H O to afford exclusively 5-
2
2
2
8
membered ring products. However, 2-(2-butenyl)phenol has been
reported to react directly with PdCl in methanol to produce a mixture
2
of 5- and 6-membered ring ethers in low yield. While the yields are
improved using Pd(OAc) , only 5-membered ring products are
2
8
obtained. Analogous reactions on 2-(3-methyl-2-butenyl)phenol afford
predominantly 6-membered ring ethers using PdCl and a mixture of 5-
2
and 6-membered ring ethers when PdCl plus NaOAc or Pd(OAc)
alone are employed. A mixture of 5-membered ring double bond
2
2
9
isomers has been observed in the reaction of 2-(2-cycloalkenyl)phenols
10
and Pd(OAc) . The latter process could be made catalytic if run under
2
1 atm of O . Finally, early attempts to effect the enantioselective
2
cyclization of 2-(2-butenyl)phenol using chiral π-allylpalladium
catalysts in the presence of O and Cu(OAc) afforded mixtures of 5-
2
2
11
membered ring ethers with low enantioselectivities, but recently 2-
(2,3-dimethyl-2-butenyl)phenol and 2-(3,4-dimethyl-3-pentenyl)phenol
have been cyclized to the corresponding 5- and 6-membered ring ethers
respectively with high enantioselectivities using 10 mol
%
12
Pd(O CCF ) , a chiral ligand and benzoquinone.
2
3 2
We have observed that the use of an appropriate Pd catalyst under the
right reaction conditions will very cleanly produce high yields of 2H-1-
benzopyrans from a wide variety of o-allylic phenols and that air can be
employed as the sole reoxidant for palladium (eq 1).

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SYNLETT
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(entry 14). This is quite surprising, since the corresponding phenol
(entry 4) affords solely the 2H-1-benzopyran. No more than traces of 5-
membered ring ethers were observed in any of the other reactions. This
methodology has also proven useful for the synthesis of precocene-II
15
(6,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran, entry 11)
and 6-
cyano-2,2-dimethyl-2H-1-benzopyran (entry 10), an important
intermediate for the synthesis of benzopyran potassium channel
16
openers, as well as flav-3-enes (entry 5) and neoflav-3-enes (entry 6).
The mechanism of this cyclization is not presently known. Two options
appear reasonable. The allylic phenol may be directly converted to an
aryl-substituted π-allylpalladium intermediate, which then undergoes Pd
substitution at the remote end of the allylic system to afford the
observed 6-membered ring products and Pd(0). Subsequent oxidation of
palladium regenerates the requisite Pd(II) catalyst. The formation of π-
allylpalladium intermediates directly from alkenes and nucleophilic
17
substitution of such compounds are both well known processes.
Alternatively, these reactions may be proceeding via oxypalladation,
subsequent palladium hydride beta elimination, and Pd(0) reoxidation;
17a-c
again all are well known processes.
Both mechanisms have been
suggested by us previously to explain the products of the Pd(II)-
13c
catalyzed cyclization of o-allylic tosylanilides.
In summary, a wide variety of 2H-1-benzopyrans can now be prepared
by the Pd-catalyzed cyclization of o-allylic phenols. The process is
highly regioselective, accommodates a variety of substitution patterns in
the aryl ring and allylic moiety, proceeds in good to excellent yields and
utilizes air as the sole reoxidant for palladium. The mechanism of this
process appears to involve either direct π-allylpalladium formation or
oxypalladation.
Acknowledgment. We gratefully acknowledge the U.S. Department of
Education for a GAANN Fellowship (LW). In addition, we thank the
donors of the Petroleum Research Fund, administered by the America
Chemical Society, for partial support of this research. Thanks are also
extended to Johnson Matthey, Inc. and Kawaken Fine Chemicals Co.,
Ltd. for donating palladium acetate.
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2
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10
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