Copper(I)-catalyzed intramolecular cyclization reaction of 2-(2'- chlorophenyl)ethanol to give 2,3-dihydrobenzofuran

Article abstract of DOI:10.1016/S0040-4039(00)00548-7

Functionalized 2,3-dihydrobenzofuran can be synthesized in good yield via an intramolecular cyclization of an aryl chloride and a primary alcohol under the catalysis of copper(I) chloride salt. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00548-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4011–4014
Copper(I)-catalyzed intramolecular cyclization reaction of
2-(20-chlorophenyl)ethanol to give 2,3-dihydrobenzofuran
Jingyang Zhu,∗ Benjamin A. Price, Shannon X. Zhao and Paul M. Skonezny
Process Development Labs, Bristol-Myers Squibb Company, PO Box 4755, Syracuse, NY 13221, USA
Received 16 March 2000; revised 31 March 2000; accepted 3 April 2000
Abstract
Functionalized 2,3-dihydrobenzofuran can be synthesized in good yield via an intramolecular cyclization of an
aryl chloride and a primary alcohol under the catalysis of copper(I) chloride salt. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: 2-(20-chlorophenyl)ethanol; intramolecular cyclization; catalysis; copper(I) chloride; 2,3-dihydrobenzofuran.
Several drug candidates in development contain a core structure of a substituted dihydrobenzofuran.1
A common intermediate in the synthesis of these drugs is 4-vinyl-2,3-dihydrobenzofuran. This compound
could be prepared from the 4-halo-2,3-dihydrobenzofuran by known chemistry, such as palladium-
catalyzed cross-coupling reactions of aryl halides, e.g. the ‘Stille’ reaction and the ‘Suzuki’ reaction,
or nickel-catalyzed Grignard cross-coupling reactions. However, there is no method readily available in
the literature to synthesize the necessary starting 4-halo-2,3-dihydrobenzofuran.
We reasoned that 20,60-dichlorophenylacetic acid, commercially available and inexpensive, should be
easily reduced to an alcohol, and the latter could be subjected to an intramolecular cyclization that would
give us the desired product. The Ullman reaction, a well-known method for synthesis of aryl ethers, has
been widely used in organic synthesis.2 In general, the Ullman reaction requires an activated aryl iodide
or bromide under the catalysis of a copper(I) salt under forcing conditions and in the presence of a large
excess of alkoxide.3 We found no reports on the intramolecular cyclization reaction between an alcohol
and aryl chloride. A palladium-catalyzed intramolecular cyclization reaction giving dihydrobenzofuran
derivatives has recently been reported.4 However, the substrates are also restricted to aryl bromides or
iodides and secondary or tertiary alcohols. In our case, cyclization of a poorly active aryl chloride and
a primary alcohol are required to produce the desired dihydrobenzofuran. Therefore, it was necessary
to examine the Ullman reaction for its ability to perform an intramolecular cyclization between an aryl
chloride and a primary alcohol. The general reaction is shown in Scheme 1.
2-(20,60-Dichlorophenyl)ethanol was prepared by reduction of 2-(20,60-dichlorophenyl)acetic acid
using a literature procedure.5 The intramolecular cyclization reaction of 2-(20,60-dichlorophenyl)ethanol
∗
Corresponding author. Tel: 1-315-432-9628; fax: 1-315-432-2330; e-mail: jingyang.zhu@bms.com (J. Zhu)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00548-7
tetl 16827

4012
Scheme 1.
was first attempted using sodium hydride (1.0–1.25 equiv.) and CuI (0.5 equiv.) in collidine at ∼120°C for
2–4 h. After work-up, the crude product isolated was checked by 1H NMR, which indicated only ∼50%
conversion. Prolonging the reaction or increasing the amount of catalyst to 1.0 equiv. did not improve
the conversion. Increasing the amount of sodium hydride to 1.5–2.0 equiv. gave significant impurities,
including unknown polyaromatic impurities. Isolation of the product from such a reaction mixture proved
to be difficult.
Nevertheless, encouraged by the result that the cyclization reaction occurred to give the desired
product, we decided to optimize this novel intramolecular cyclization reaction under the catalysis of a
Cu(I) salt. To our knowledge, the choice of copper catalyst for normal Ullman reaction was not critical.2b
We preferred to use CuCl due to its lower cost. We found that the reaction could be carried out in a wide
range of solvents, such as pyridine, collidine, dioxane, toluene and toluene/ethyl acetate,6 but essentially
failed in lutidine. We have also found that the success of this intramolecular cyclization reaction was
dependent on the amount of catalyst and base used, as well as the solvent, as can be seen from the data
summarized in Table 1.
Table 1
Copper(I)-catalyzed intramolecular cyclization reaction of 2-(2,6-dichlorophenyl)ethanol
It was found that CuCl worked as well as CuI. It is interesting to note that when the amount of catalyst
was reduced, the yield increased (entries 4–8). The optimal amount of the catalyst was found to be
∼5 mol%. It can be seen from Table 1 (entries 7 and 14) that the reaction carried out in pyridine or
toluene (with 5 mol% ethyl acetate) gave the highest conversion (91–92%). It is also worth noting that

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no intermolecular Ullman reaction occurred when sodium methoxide was used as a base (entry 16),
indicating that intramolecular cyclization is much more favorable than intermolecular reaction.
Although a high yield was achieved by using 5 mol% CuCl in pyridine, two major impurities (1–4.5%)
were identified after analyzing the product profile by 1H NMR, 13C NMR and GC/MS. These were 2,6-
dichlorostyrene and 2,6-dichlorotoluene (Scheme 2). 2,6-Dichlorotoluene was at a relatively low level
and was easy to remove by distillation. However, the 2,6-dichlorostyrene was difficult to separate from
the product by simple distillation and thus had to be held to as low a level as possible.7
Scheme 2.
Only a few substrates were available for a study of the generality of this intramolecular cyclization
reaction. It was found that reaction can not only proceed with dichloro substitution on the benzene-ring,
but also with monochloro substitution. The results are summarized in Table 2.
Table 2
Copper(I) chloride-catalyzed intramolecular cyclization reaction8
It can be seen from Table 2 that toluene with 5 mol% ethyl acetate is clearly the preferred solvent to
use. Although the reaction is faster in pyridine, the selectivity of forming the desired product is poorer.
For example, the reaction of 2-(20,40-dichlorophenyl)ethanol in pyridine (entry 3) gave a reasonable
conversion, but 2,4-dichlorostyrene 3b, a byproduct, became rather significant with ∼22% selectivity.
In toluene/ethyl acetate, the product selectivity increased to ∼93% with the formation of only a small
amount of impurities. A similar phenomenon was also observed with other substrates. It can be concluded
that toluene/ethyl acetate gives a slower reaction, but higher selectivity for the formation of the desired
product. In addition, from a manufacturing point of view, the use of toluene is more attractive than
pyridine in view of its lower toxicity, lower cost and ease of recovery.
To demonstrate the practical utilization of 4-chloro-2,3-dihydrobenzofuran in our synthesis, the
substrate was subjected to the palladium-catalyzed ‘Stille’ cross-coupling reaction, which was recently
developed by Fu and Littke,9 with tributylvinyltin in the presence of 2 equiv. CsF and this gave 4-vinyl-
2,3-dihydrobenzofuran in a yield of ∼58%. The latter can then be converted into useful melatonergic
agents via a multiple-step synthesis (Scheme 3).1
In conclusion, we have developed an efficient method for the synthesis of 2,3-dihydrobenzofuran
derivatives via a novel intramolecular cyclization of a poorly active aryl chloride and a primary

4014
Scheme 3.
alcohol under the catalysis of copper(I) chloride. We believe that recent advancements made in ac-
tivating aryl chlorides under transition-metal catalysis can provide a useful tool to further elaborate
chlorodihydrobenzofurans.10
Acknowledgements
The authors are grateful to Mr. Douglas G. Weaver for his NMR analytical service and the Analytical
R&D group for GC/MS analytical service.
References
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was dried with anhydrous sodium sulfate before being concentrated under reduced pressure to give ∼0.7 g product, yield
88%.
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