The Au(I)-catalyzed intramolecular hydroarylation of terminal alkynes under mild conditions: Application to the synthesis of 2H-chromenes, coumarins, benzofurans, and dihydroquinolines

Article abstract of DOI:10.1021/jo902032p

(Chemical Equation Presented) Operationally simple Au(I)-catalyzed intramolecular hydroarylation (IMHA) reactions of terminal alkynes that proceed in high yield and under very mild conditions are described. These processes involve low catalyst loadings, mild reaction temperatures, and short reaction times, require no cocatalysts or additives, and allow for the generation of a number of important heterocyclic motifs from readily accessible starting materials.

Full text of DOI:10.1021/jo902032p

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complexes can be particularly effective in selectively activat-
The Au(I)-Catalyzed Intramolecular Hydroarylation
of Terminal Alkynes Under Mild Conditions:
Application to the Synthesis of 2H-Chromenes,
Coumarins, Benzofurans, and Dihydroquinolines
ing alkynes toward nucleophilic addition and numerous
reactions employing this strategy have been disclosed
recently.2 The majority of such processes require a cocata-
lyst, usually in the form of a silver salt, to activate the Au(I)
species that is used. However, these silver salts are often
hygroscopic, difficult to weigh accurately, and frequently
result in an acidic reaction medium. Furthermore, the pre-
sence of a silver cocatalyst can promote unwanted side
reactions.3 Accordingly, a single-component Au(I) species
that can activate alkynes toward nucleophilic attack offers
numerous advantages over the conventional Au-Ag coca-
talyst systems.
Rajeev S. Menon, Alison D. Findlay, Alex C. Bissember, and
Martin G. Banwell*
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200,
Australia
mgb@rsc.anu.edu.au
Recently, Echavarren and co-workers reported the synthesis
of the stable Au(I) complex 1 possessing a weakly coordinating
acetonitrile ligand that can, in the absence of silver and upon
addition of a suitable substrate, be replaced by alkyne func-
tionalities.4 As a result this complex, which is able to be
handled under standard benchtop conditions, has proven
effective in catalyzing the cyclization of both enynes2g,5a and
indole-tethered alkynes.5b
Received September 21, 2009
Operationally simple Au(I)-catalyzed intramolecular
hydroarylation (IMHA) reactions of terminal alkynes
that proceed in high yield and under very mild conditions
are described. These processes involve low catalyst load-
ings, mild reaction temperatures, and short reaction
times, require no cocatalysts or additives, and allow for
the generation of a number of important heterocyclic
motifs from readily accessible starting materials.
Our recent discovery of a highly efficient cascade reaction6
that is catalyzed by complex 1 prompted us to investigate the
capacity of this species to effect the intramolecular hydro-
arylation (IMHA) of alkynes. The latter process involves the
formal addition of an arene unit and a hydrogen across the
sp-hybridized carbons of a tethered alkyne.7 While metals
such as Pd,8 Ru,9 Ga,10 Pt,11 and Hg12 as well as Tf2NH13 are
(3) (a) Nevado, C.; Echavarren, A. M. Chem. Eur. J. 2005, 11, 3155.
(b) Curtis, N. R.; Prodger, J. C.; Rassias, G.; Walker, A. J. Tetrahedron Lett.
2008, 49, 6279.
Cationic gold complexes are rapidly emerging as excellent
catalysts for facilitating the assembly of a variety of car-
bon-carbon and carbon-heteroatom bonds with the result
that powerful new methodologies based upon such processes
are now being reported with increasing frequency.1 Such
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DOI: 10.1021/jo902032p
r
Published on Web 10/22/2009
J. Org. Chem. 2009, 74, 8901–8903 8901
2009 American Chemical Society

Menon et al.
JOCNote
known to promote the IMHA reactions of alkynes, AuCl3 is
not effective11d in this regard. Among the isolated examples
of Au(I)-catalyzed IMHA reactions of alkynes that have
been reported, almost all require the use of a cocatalyst such
as a Ag(I) salt or HBF4.3 We speculated that the now
commercially available catalyst 1 would be ideal for effecting
the IMHA reactions of a broad range of alkynes under mild
conditions. As revealed herein, this has proved to be the case
and allowed us to establish particularly convenient methods
for the preparation of various 2H-chromenes, coumarins,
benzofurans, and dihydroquinolines.
TABLE 1. Outcomes of Au(I)-Catalyzed IMHA Reactions of Certain
Aryl Propargyl Ethers, Aryl Propargylates, and Aryl Propargyl Amine
Derivatives
In a preliminary experiment designed to test our hypoth-
esis, a dichloromethane solution of readily available phenyl
propargyl ether (2a) maintained at ambient temperatures
was treated with 1 mol % of complex 1. Pleasingly, after 1 h
the expected product, 2H-chromene (3a), was generated in
62% yield (Scheme 1).14 Accordingly, we immediately sought
SCHEME 1. Au(I)-Catalyzed IMHA Reaction of Phenyl Pro-
pargyl Ether (2a)
to establish the scope and generality of this type of process. To
that end a range of readily accessible aryl propargyl ethers was
prepared and then subjected to the same reaction conditions.
The outcomes of such studies are shown in Table 1, which
reveals that the IMHA reactions effected by catalytic
quantities of complex 1 are both broad in scope and highly
efficient, even in instances where the arene ring incorporates
electron-withdrawing groups (entries 3, 5, and 6). In cases
involving nonsymmetrically substituted arene rings (entries 4
and 8) the cyclization reactions proceed regioselectively.
Furthermore, when the ether tether was replaced with an ester
linkage, as in the case of substrates 2k and 2l (entries 10
and 11, respectively), the corresponding coumarin-derived
products 3k and 3l were obtained in good yield.
Benzofurans (4) were generated as coproducts (or as the
only product) in a number of instances (entries 4, 5, 6, 8, and
9). Prior to the present study, the formation of benzofurans
(4) from aryl propargyl ethers (3) had only been observed
under much more forcing conditions (>200 °C, refluxing
diethylaniline).15 The formation of such coproducts in the
present work may well involve fragmentation of the aury-
lated species 5, a likely late-stage intermediate associated
with the formation of the 2H-chromenes 3, to give the allene
6 (Scheme 2), which engages in a 5-exo-dig cyclization
reaction to give the observed product 4.16 This proposal is
SCHEME 2. Possible Pathway for the Formation of Benzofur-
ans 4 from Substrates 3
aThe substrates were readily prepared by conventional methods (see
the SI). bConditions used for effecting the IMHA reactions shown are
given in the Experimental Section and/or the SI. cAll yields cited are of
isolated and chromatographically purified materials.
(12) Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T.
Org. Lett. 2003, 5, 4563.
(13) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204.
(14) See the Supporting Information for experimental details.
8902 J. Org. Chem. Vol. 74, No. 22, 2009

Menon et al.
JOCNote
consistent with that of Echavarren,5b who has invoked
related processes to account for the formation of 2-allenyl
indoles from certain N-propargyl tryptophans in the pre-
sence of complex 1.5b
can thus be formed expeditiously from readily accessible
starting materials.
Experimental Section
When aryl propargyl amines are used as substrates for the
IMHA reactions, the third group attached to nitrogen has a
significant impact on the nature of the observed product.
Thus, subjection of the N-Boc protected compound 2m
(entry 12) to the same reaction conditions as used earlier
afforded oxazolidinone 3m17 in 71% yield and as the ex-
clusive product of reaction. In contrast, replacement of the
Boc group on nitrogen with a tosyl residue provided sub-
strates that readily cyclized to the corresponding dihydro-
quinolines (see entries 13 and 14). Substrate 2p, possessing an
electron-withdrawing chloro-substituent on the aromatic
ring, cyclized as expected to afford the corresponding di-
hydroquinoline derivative 3p in 52% yield (entry 15). Com-
pound 2q, bearing a more easliy removed 2-nitrobenzene-
sulfonyl (Ns) nitrogen protecting group,18 also reacted in the
presence of complex 1 to give the corresponding dihydro-
quinoline derivative 3q in good yield (75%, entry 16).
The protocols reported here provide an operationally sim-
ple method for effecting IMHA reactions that proceed under
exceptionally mild conditions and in a time-efficient manner.
A number of important heterocyclic motifs including 2H-
chromenes, coumarins, benzofurans, and dihydroquinolines
Compound 3a. A magnetically stirred solution of aryl pro-
pargyl ether (2a)19 (40 mg, 0.30 mmol) in CH2Cl2 (4 mL)
maintained at 18 °C was treated with (acetonitrile)[(2-biphenyl)-
di-tert-butylphosphine]gold(I) hexafluoroantimonate(1) (2.4 mg,
1 mol %). The resulting solution was stirred at 18 °C for 1 h
then concentrated under reduced pressure and the ensuing
yellow oil was subjected to flash column chromatography20
(silica gel, hexane) to give, after concentration of the appro-
priate fractions (Rf 0.3 in 1:49 v/v ethyl acetate/hexane),
chromene 3a21 (25 mg, 62%) as a clear, colorless oil. 1H
NMR (300 MHz) δ 7.13-7.08 (1H, m), 6.96-6.95 (1H, d,
J = 7.2 Hz), 6.89-6.84 (1H, m), 6.78 (1H, d, J = 7.8 Hz), 6.43
(1H, d, J = 9.9 Hz), 5.80-5.74 (1H, m), 4.83 (2H, broad s); 13
C
NMR (75 MHz) δ 154.0, 129.1, 126.5, 124.5, 122.3, 121.9,
121.3, 115.7, 65.5; IR νmax (NaCl) 1640, 1608, 1488, 1458, 1229,
1201, 1117, 1043, 941, 756 cm-1; MS (EI, 70 eV) m/z 132
(Mþ•, 96%), 131 (100), 103 (56), 77 (61), 51 (78); HRMS m/z
calcd for C9H8O Mþ• 132.0575, found 132.0572.
Acknowledgment. We thank the Institute of Advanced Stu-
dies at The Australian National University and the Australian
Research Council (ARC) for generous financial support.
R.S.M. is the grateful recipient of an ARC Australian Post-
doctoral Fellowship.
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(16) We thank a referee for useful suggestions regarding the reaction
pathway proposed in Scheme 2.
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Tetrahedron Lett. 1997, 38, 5831. (b) Kurosawa, W.; Kan, T.; Fukuyama, T.
Org. Synth. 2002, 79, 186.
Supporting Information Available: Detailed procedures and
C
NMR spectra for compounds 2g, 2p, 2q, 3a-i, 3k-q, 4e-g, 4i,
and 4j. This material is available free of charge via the Internet at
http://pubs.acs.org.
full characterization data for all new compounds and 1H and 13
(20) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
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(19) Pal, M.; Parasuraman, K.; Yeleswarapu, K. R. Org. Lett. 2003, 5,
349.
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