Angewandte
Chemie
DOI: 10.1002/anie.201107561
Homogeneous Catalysis
Rapid Access to Chroman-3-ones through Gold-Catalyzed Oxidation
of Propargyl Aryl Ethers**
Yanzhao Wang, Kegong Ji, Sylvester Lan, and Liming Zhang*
Chroman-3-one is an important structural motif and its
derivatives have served as key intermediates in the total
synthesis of natural products such as miroestrol,[1] (+)-myr-
istinin A,[2] and afzelechin,[3] as well as in accessing a range of
bioactive chromans for managing various diseases including
hypertension,[4] HIV,[3] sexual dysfunction,[5] and melanoma.[6]
In their 1991 review,[7] Danan and Kirkiacharian concluded
that there was a lack of efficient synthetic methods for this
structure. Since then, little progress[8] has been made. To date,
the 20 year old statement still remains largely true. Invariably,
these compounds are prepared through multistep routes[7,9]
from basic chemicals. For example, a typical route starts from
basic condensation of salicylaldehyde with acrylonitrile to
form 2H-chromene-3-carbonitrile under refluxing conditions
with subsequent basic hydrolysis, acidification, formation of
acyl azide, Curtius rearrangement, and acidic hydrolysis of the
resulting vinyl isocyanate.[1,9–10] While the overall yield could
be as high as 60%,[1] the step[11] and atom[12] economy is low.
An alternative approach using toxic a-diazo-a’-phenoxy
acetones still requires four steps starting from phenols
(Scheme 1),[13] and no application of this method has been
reported in the literature because of its limited scope[14] and
the clear drawback associated with using dangerous diazo-
methane. Herein, we report an efficient synthesis of chroman-
3-ones through gold-catalyzed oxidation of propargyl aryl
ethers, which in turn can be easily prepared in one step from
readily available phenols.
We have in the past two years developed several gold-
catalyzed intermolecular oxidations of alkynes using pyridine/
quinoline N-oxides as oxidants.[15] The common intermediates
generated in these reactions were most likely a-oxo gold
carbenes, which appeared to be highly reactive and under-
[15b,c]
[15a]
[15d]
À
À
N H,
À
went facile O H,
or 1,2 C H insertions
or
reaction with nitriles en route to oxazoles.[15e] Several recent
reports from other research groups also corroborated the
intermediacy of gold carbenes.[16] Since metal carbenes in
general can be generated through dediazotization,[17] this
strategy permits replacement of the toxic, potentially explo-
sive, and sometimes difficult-to-access a-diazo ketones with
benign and readily available alkynes in gold carbene chemis-
try.[18] In the context of chroman-3-one synthesis, we envi-
sioned that this strategy would allow replacement of a-diazo-
a’-phenoxy acetones with readily available propargyl aryl
ethers (Scheme 1), thereby establishing a succinct, safe, and
potentially highly efficient route to this class of heterocycles.
At the outset, 4-tert-butylphenyl propargyl ether (1a) was
chosen as the substrate for optimization of the reaction
conditions. Some of the results are listed in Table 1.
[19]
When either Ph3PAuNTf2
(entry 1) or the more
[20]
electrophilic phosphite-coordinated L1AuNTf2 [L1 =
tris(2,4-di-tert-butylphenyl)phosphite; entry 2] was
employed as the catalyst and 2,6-dibromopyridine N-
oxide as the oxidant, both reactions were sluggish, and
the desired chroman-3-one 2a was formed in less than
10% yield.
In our previous work on azetidine-3-one synthe-
sis,[15a] we noticed that gold catalysts based on biphenyl-
phosphine ligands[21] were increasingly effective as the
biphenyl moiety became bulkier and BrettPhosAuNTf2
was the optimal catalyst. To our delight, the same trend
was observed with this reaction (compare entries 3–5,
Table 1), and the chroman-3-one 2a was formed in 65%
yield (NMR) in only 0.5 hours with BrettPhosAuNTf2 as
the catalyst (entry 5). In seeking to additionally improve this
reaction, we tried Me4tBuXPhosAuNTf2.[22] To our delight,
the yield was improved to 78% (entry 6). Single-crystal X-ray
diffraction studies established the structure of this effective
catalyst (Figure 1). In comparison with BrettPhosAuNTf2
(Figure 1),[15a] the Au1-P1-C2 angle is smaller by 5.528, and
the distance between Au1 and C1’ is shorter by 0.265 ꢀ, thus
suggesting that Me4tBuXPhos presses the Au center more
towards the shielding 2,4,6-triisopropylphenyl group[23] and
thereby increases the steric crowding of the metal center. This
Scheme 1. Access to chroman-3-ones via metal carbene intermediates?
[*] Y. Wang, Dr. K. Ji, S. Lan, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California, Santa Barbara, CA 93106 (USA)
E-mail: zhang@chem.ucsb.edu
[**] We thank the NIGMS (R01 GM084254) and UCSB for generous
financial support, and Dr. Guang Wu for helping with X-ray
crystallography.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1915 –1918
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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