An Au-Catalyzed Cyclialkylation of Electron-Rich Arenes with Epoxides to Prepare 3-Chromanols

Article abstract of DOI:10.1021/ja031953a

A gold-catalyzed cyclialkylation of electron-rich arenes with tethered epoxides afforded 3-chromanols stereospecifically. Copyright

Full text of DOI:10.1021/ja031953a

Published on Web 04/22/2004
An Au-Catalyzed Cyclialkylation of Electron-Rich Arenes with Epoxides To
Prepare 3-Chromanols
Zhangjie Shi and Chuan He*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received December 25, 2003; E-mail: chuanhe@uchicago.edu
3-Chromanol is a structural motif found in many natural products
and pharmaceutical agents (Figure 1A). For example, this group is
the core structure of catechin, epicatechin, and tupichinols, which
all bear electron-rich substituents on the phenyl ring.1 Methods to
efficiently construct this core structure in a regio- and stereocon-
trolled manner are limited. We have discovered a unique gold(III)-
catalyzed process that can access this core structure through direct
cyclialkylation of electron-rich arenes with the tethered epoxides
(Figure 1B). The endo addition products were obtained exclusively,
and the reaction is stereospecific.
Figure 1. (A) 3-Chromanol core structure. (B) Strategy for preparing
3-chromanol via a cyclialkylation reaction.
Table 1. Gold(III)-Catalyzed Intramolecular Cyclialkylationa
Reacting anhydrous gold(III) chloride with aromatic groups to
form arylgold(III) complexes regiospecifically at room temperature
has been demonstrated a long time ago.2 Recently, it was found
that AuCl3 can catalyze a 1,4-addition of electron-rich aromatic
rings to methyl vinyl ketone in acetonitrile.3 It was proposed that
the gold(III) species may be engaged in a direct C-H functional-
ization to form arylgold(III) species in this reaction. This species
then attacks methyl vinyl ketone in a manner like a Michael
addition. Hydroarylation of electron-deficient alkynes was also
discovered.4 However, a different mechanism with gold(III) merely
working as a Lewis acid that activates the alkyne groups was
proposed. None of these two mechanisms have been confirmed
through mechanistic studies. At the beginning of initiating this
program, we hypothesized that if an arylgold(III) intermediate could
form from an auration step, this species might be able to add to
other functional groups such as epoxides in an SN2 manner.
We tested this idea with (phenoxymethyl)oxiranes, materials that
are either commercially available or can be readily synthesized.5
To our delight, we discovered that treating these substrates with
AuCl3/3AgOTf (2.5 mol % based on gold) in dichloroethane yielded
endo addition product 3-chromanols (Table 1). The observation of
this endo addition cyclization is unique. Previously, metalation of
o-bromo-substituted (phenoxymethyl)oxiranes with butyllithium or
activated copper species at low temperature via bromine-metal
exchange was reported. Subsequent cyclization of the tethered
epoxide gave mostly exo addition five-membered ring products.6
The reaction catalyzed by the gold described here does not require
a bromo group at the ortho-position,6a,b nor does it need a directing
group for metalation.6c It produces the endo addition product
exclusively, which represents an excellent method for preparation
of various 3-chromanol-type structures efficiently.
The reactions were completed in 4 h at 50 °C for electron-rich
arene substrates. For less electron-rich substrates, higher temperature
and longer reaction time were required (entries 1, 3, and 9 in Table
1). The reaction also tolerated halide substituents on the electron-
rich ring, which is useful for further functionalization of the ring
(entry 9 in Table 1). Gold(III) catalyst was absolutely required for
the reaction. AuCl3 alone gave low yields of products (10-20%).
The yields increased dramatically in the presence of 3 equiv (based
on gold) of AgOTf. The exact role of the silver salt is not clear. It
might help to remove the chloride anion from AuCl3 to generate
a Reactions were typically conducted with 0.5 mmol of (phenoxymeth-
yl)oxiranes and 2.5 mol % of AuCl3/3AgOTf in 3 mL of dichloroethane.
The isolated yields are reported here. Reactions were typically run for 4 h.
b An increased catalyst loading of 5 mol % of AuCl3/3AgOTf was used,
and the reaction was run for 48 h (a portion of starting material was
recovered, and the reaction completion percentage is reported in the
parentheses). c The reaction was run for 48 h. d Exclusive trans product was
obtained.
more electrophilic gold(III) species. AgOTf alone did not catalyze
these reactions under the same conditions.
9
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J. AM. CHEM. SOC. 2004, 126, 5964-5965
10.1021/ja031953a CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Figure 3. Intermolecular addition of trimethoxybenzene to propylene oxide
afforded 1-(2,4,6-trimethoxyphenyl)-2-propanol.
epoxide primary carbon atom, which seems to be a unique feature
associated with the catalytic system described here and suggests
that the reaction goes through an SN2 type mechanism.
In summary, we report a gold(III)-catalyzed cyclialkylation of
electron-rich arenes with tethered epoxides. This reaction is
stereospecific and can be used to synthesize 3-chromanol-type
structures efficiently. The reaction could go through two different
types of mechanisms: (i) an auration step followed by an attack of
the arylgold(III) to the tethered epoxide in an SN2 manner; or (ii)
a concerted Lewis acid mechanism with gold(III) purely activating
the epoxides group. Efforts to understand the reaction mechanism
and explore synthetic utilities of the reactions reported here are in
progress in our laboratory.
Figure 2. (A) Gold-catalyzed cyclization of 1 to form 2 stereospecifically.
(B) ORTEP diagram of 2 showing the 40% probability thermal ellipsoids
for all non-hydrogen atoms.
Previously, cyclialkylation of arylalkyl epoxides was investi-
gated.7 Among Lewis acids that were tested, it was found that 2
equiv of SnCl4 can induce the cyclization of arylalkyl epoxides in
CH2Cl2. It was proposed that this reaction goes through a Friedel-
Crafts-type mechanism. We tested the same conditions with a
(phenoxymethyl)oxirane substrate (entry 7 in Table 1). Only a small
amount of the cyclized product was obtained. With longer reaction
time (refluxing for 24 h), ∼30% of the product could be obtained
with ∼30% of starting material recovered. A large excess amount
of toxic tin reagents was used for this reaction. Other Lewis acids
such as 20% BF3‚Et2O and triflic acid (15% and 30%) were also
tested under various conditions. No desired cyclized product was
obtained in all cases. These controls showed the unique activity of
gold catalyst in mediating this reaction.
Acknowledgment. This research was supported by the Uni-
versity of Chicago. We thank Dr. Ian M. Steele for helping with
the X-ray crystallography and C. Jin for helping with mass
spectrometry.
Supporting Information Available: Experimental details (PDF);
X-ray file (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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The reaction showed high diastereoselectivity with trans products
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