Syntheses of α-pyrones using gold-catalyzed coupling reactions

Article abstract of DOI:10.1021/ol200794w

Sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts yields compounds having α-pyrone skeletons. Novel cascade reactions involving propiolic acids are reported that give rise to α-pyrones with different substitution patterns.

Full text of DOI:10.1021/ol200794w

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2834–2836
Syntheses of r-Pyrones Using Gold-
Catalyzed Coupling Reactions
Tuoping Luo,†,‡ Mingji Dai,†,‡ Shao-Liang Zheng,‡ and Stuart L. Schreiber*,†,‡
Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, 7 Cambridge
Center, Cambridge, Massachusetts 02142, United States, and Department of Chemistry
and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United
States
stuart_schreiber@harvard.edu
Received March 25, 2011
ABSTRACT
Sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts yields compounds having R-pyrone skeletons.
Novel cascade reactions involving propiolic acids are reported that give rise to R-pyrones with different substitution patterns.
In efforts to synthesize compounds having properties
that facilitate small-molecule probe and drug discovery,1
we have developed multicomponent coupling reactions
that use gold(I) catalysts and yield, among others, complex
R-pyrones.2 Activation of the electron-deficient alkyne in
propargyl propiolate 1 by a cationic gold(I) catalyst results
in allenyl propiolate 2, which undergoes a 6-endo-dig
cyclization3 to oxocarbenium intermediate A (Figure 1).
In order to generate diverse and previously inaccessible
R-pyrones,4 we investigated the possibility of generating
the vinyl propiolate 5. We imagined this intermediate
undergoing a similar 6-endo cyclization to afford oxocar-
benium intermediate B and then R-pyrone 6 after depro-
tonation and proto-demetalation. Intermediate 5 would
result from an intermolecular coupling of propiolic acid 3
and alkyne 4 catalyzed by the same gold(I) catalyst.5
Herein, we describe a new gold(I)-catalyzed cascade reac-
tion based on the concept of sequential alkyne activation,2,6
synthesizing substituted R-pyrones in one step from readily
available propiolic acids.
We initiated our investigation using commercially avail-
able propiolic acid 3a and terminal alkyne 4a. The counter-
ion of the cationic gold(I) catalyst was determined to have
† Broad Institute of Harvard and MIT.
‡ Harvard University.
(1) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47,
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8250–8253. (b) Luo, T.; Schreiber, S. L. J. Am. Chem. Soc. 2009, 131,
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(3) For the application of gold-catalyzed 6-endo-dig cyclization, see:
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ꢀ
ꢀ
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Raaij, M. J.; Abrahams, J. P.; Leslie, A. G.; Walker, J. E. Proc. Natl.
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Figure 1. Syntheses of R-pyrones via gold(I)-catalyzed cascade
reactions.
r
10.1021/ol200794w
Published on Web 05/02/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditions for the Synthesis
of 6a
Figure 2. Cyclization of vinyl propiolate 5a into R-pyrone 6a.
yield%b
entry
catalyst
conditionsa
6a
43
7a
(entries 9 and 10). The best result was obtained by increas-
ing the amount of alkyne 4a to 5 equiv and using the
catalyst [(Ph3P)AuCl]/AgOTf in dichloromethane, which
gave rise to 6a in 83% yield (entry 11). Unexpectedly,
increasing the amount of alkyne 4a and using the catalyst
[(Ph3P)AuCl]/AgPF6 in toluene (entry 12) resulted in the
isolation of the vinyl propiolate 5a, which was further
subjected to the optimized reaction conditions to give 6a in
excellent yield (Figure 2).
1
[(Ph3P)AuCl]/AgOTf
[(Ph3P)AuCl]/AgPF6
[(Ph3P)AuCl]/AgSbF6
[(Ph3P)AuCl]/AgNTf2
[(Ph3P)AuCl]/AgPF6
[(Ph3P)AuCl]/AgOTf
[(Cy3P)AuCl]/AgOTf
toluene, rt
toluene, rt
toluene, rt
toluene, rt
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
<5
<5
84
60
<5c
<5
<5
<5
2
52
<5
20
12
74
75
68
3
4
5
6
7
8
[(p-CF3C6H4)3P]AuCl/AgOTf CH2Cl2, rt
9
AuCl
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
toluene, rt
N.R.
N.R.
10
11
12
AgOTf
[(Ph3P)AuCl]/AgOTf
[(Ph3P)AuCl]/AgPF6
83d
35d
<5
<5e
a [3a] = 0.2 M, 1.5 equiv of 4a. b Isolated yields after column
chromatography. c 39% of 3a was recovered. d 5 equiv of 4a were
employed. e 5a was isolated in 29% yield.
a significant effect on the product distribution (Table 1,
entries 1À4). When AgOTf or AgPF6 was used, we isolated
R-pyrone 6a in modest yields (entries 1 and 2), presumably
via the vinyl propiolate 5a resulting from the gold-cata-
lyzed Markovnikov addition of the carboxylic acid to the
terminal alkyne.5 However, AgSbF6 led to R-pyrone 7a as
the predominant product (entry 3; structure determined by
X-ray crystallography),7 whereas AgNTf2 gave both
R-pyrones (entry 4). The reaction was also sensitive to
the identity of the solvent. With [(Ph3P)AuCl]/AgPF6 as
the catalyst, switching the solvent from toluene to dichlor-
omethane significantly lowered the yield of 6a with sub-
stantial starting material recovery (Table 1, entry 5). In
contrast, with [(Ph3P)AuCl]/AgOTf as the catalyst, di-
chloromethane afforded 6a in higher yield than that
afforded by toluene (entry 6). The more electron-donating
ligand tricyclohexylphosphine and less electron-donating
ligand tris(para-trifluoromethylphenyl)phosphine had
minimal effects on the reaction (entries 7 and 8). AuCl or
AgOTf alone failed to catalyze the cascade reaction
Figure 3. Dimerization of propiolic acid leading to 4-hydroxy R-
pyrone.
While we do not understand why different counterions
provide different product distributions (6a vs 7a), a
proposed mechanism of the serendipitously discovered
propiolic acid dimerization is offered in Figure 3. The
addition of the carboxylic acid to the β-position of the
propiolic acid yields vinyl ester D. Further activation of D
by cationic gold(I) generates oxocarbenium E, where the
acyl group is transferred to the CÀAu bond with con-
comitant regeneration of the gold(I) catalyst.8 The
6-endo-dig cyclization of carboxylic acid G onto the
activated alkyne followed by enolization affords 4-hydro-
xy R-pyrone 7 as the final product.
(5) (a) Roembke, P.; Schmidbaur, H.; Cronje, S.; Raubenheimer, H.
J. Mol. Catal. A 2004, 212, 35–42. (b) Cui, D.-M.; Meng, Q.; Zheng,
J.-Z.; Zhang, C. Chem. Commun. 2009, 1577–1579. (c) Chary, B. C.;
Kim, S. J. Org. Chem. 2010, 75, 7928–7931. (d) Lee, P. H.; Kim, S.; Park,
A.; Chary, B. C.; Kim, S. Angew. Chem., Int. Ed. 2010, 49, 6806–6809.
(6) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285–2288. (b) Zhao, J.; Hughes, C. O.;
Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436–7437. (c) Liu, X.-Y.;
Che, C.-M. Angew. Chem., Int. Ed. 2008, 47, 3805–3810. (d) Sperger, C.;
Fiksdahl, A. Org. Lett. 2009, 11, 2449–2452. (e) Sperger, C. A.; Fiksdahl,
A. J. Org. Chem. 2010, 75, 4542–4553.
(7) Crystallographic Information Files (CIFs) for 7a and 6p are
available at the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif. See Supporting Information for
further details.
(8) For an example of a related acyl transfer involving a gold(III)
intermediate, see: Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128,
8414–8415.
Org. Lett., Vol. 13, No. 11, 2011
2835

6o), ester (6i and 6j), halide (6k), and alkyne (6m, 6n, and
6o) functional groups are compatible with the reaction
conditions. The structure of R-pyrone 6p was verified by
X-ray analysis.7 Notably, R-pyrone 6t is a natural
product with antibiotic and antifungal activity,9 which
recently has been synthesized using a gold(I)-catalyzed
cycloisomerization of β-alkynylpropiolactone.10 Using
the new method reported here, 6t was synthesized in
one step from the commercially available propiolic acid
and 1-heptyne. Pyrone 6u was synthesized in 77% yield
from 3-bromopropiolic acid. The bromide functional-
ity provides a handle to introduce other groups at the
C-4 position via transition-metal-catalyzed cross-cou-
pling reactions. Gratifyingly, in separate reactions
using 0.5 g of phenylpropiolic acid, pyrones 6c and 6l
were obtained in good yields. Unfortunately, neither
phenylacetylene nor the internal alkyne 2-butyne reacts
at room temperature in CH2Cl2. Only a low yield of the
corresponding R-pyrone was obtained using elevated
reaction conditions (6v and 6w). When 4-methoxy-
4-oxobut-2-ynoic acid was used, only a 1,2-addition
of the acid to 3-phenyl-1-propyne took place, yielding
5b in 59% yield. A higher reaction temperature (50 °C)
gave a similar result, presumably because the capacity
of the triple bond of 4-methoxy-4-oxobut-2-ynoic acid
to coordinate gold is diminished by the existing ester
group.
Scheme 1. Gold(I)-Catalyzed Syntheses of R-Pyrones from
Propiolic Acids and Alkynesa
The method described herein provides an efficient and
simple route to multiply substituted R-pyrones. The gen-
erality observed thus far suggests that it will find many
future applications.
a Reaction conditions: propiolic acid (0.2À0.7 mmol, 0.2 M), alkyne
(5À6 equiv), [(Ph3P)AuCl]/AgOTf (5 mol %), CH2Cl2, rt, 12 h; bphe-
nylpropiolic acid (3.4 mmol), alkyne (5 equiv), [(Ph3P)AuCl]/AgOTf
(5 mol %), CH2Cl2, rt, 24 h; cCH2Cl2, 50 °C, 12 h; d3-(naphthalene-2-
yl)propiolic acid (0.1 M); ephenylacetylene (6 equiv), toluene, 60 °C, slow
addition of acid (over 2 h), 12 h; f2-butyne (10 equiv), toluene, 60 °C, 12 h.
Acknowledgment. The NIGMS-sponsored Center of
Excellence in Chemical Methodology and Library Devel-
opment (P50-GM069721) sponsored this research. S.L.S.
is an investigator with the Howard Hughes Medical
Institute.
The scope of the cascade reaction was explored with a
variety of propiolic acids and alkynes (Scheme 1). Gen-
erally, moderate to excellent yields were obtained with
different terminal alkynes and propiolic acids. More steri-
cally hinderedalkynes gavelower yields (6g). Ether (6h and
Supporting Information Available. Experimental proce-
dures and full spectroscopic data for all new compounds
and CIFs for 7a and 6p. The material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Dombray, T.; Blanc, A.; Weibel, J.-M.; Pale, P. Org. Lett. 2010,
12, 5362–5365.
(9) Evidente, A.; Cabras, A.; Maddau, L.; Serra, S.; Andolfi, A.;
Motta, A. J. Agric. Food Chem. 2003, 51, 6957–6960.
2836
Org. Lett., Vol. 13, No. 11, 2011