A highly efficient preparative method of α-ylidene-β-diketones via AuIII-catalyzed acyl migration of propargylic esters

Article abstract of DOI:10.1021/ja062777j

A highly efficient synthesis of α-alkylidene or benzylidene-β-diketones from readily available propargylic esters has been developed. The proposed key transformation is a novel intramolecular acyl migration to nucleophilic Au^III-C(sp²

Full text of DOI:10.1021/ja062777j

Published on Web 06/09/2006
A Highly Efficient Preparative Method of r-Ylidene-â-Diketones via
AuIII-Catalyzed Acyl Migration of Propargylic Esters
Shaozhong Wang and Liming Zhang*
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received April 21, 2006; E-mail: lzhang@chem.unr.edu
Table 1. Optimizing Reaction Conditions for Au-Catalyzed
Formation of 2 from Propargylic Acetate 1
Au salts are powerful soft Lewis acids and readily activate
alkynes and allenes toward attacks by a variety of nucleophiles.1
While these reactions typically result in the formation of Au-C
bond-containing intermediates, the nucleophilicity of these orga-
noaurates2 has rarely been exploited3 except simple protonation or
elimination. Reactions of these Au-C bonds, especially those
leading to the formation of C-C bonds, could result in sequential
functionalization of alkynes/allenes in a cascade process, substan-
tially enriching Au chemistry.
R-Alkylidene- or benzylidene-â-diketones are versatile synthetic
intermediates and, in general, can be prepared through the Kno-
evenagel condensation of aldehydes/ketones and â-diketones.4
However, this condensation is often plagued by the formation of
Michael adducts and by the isomerization to â,γ-unsaturated
products. Furthermore, the double bond geometry of the adduct is
mainly governed by steric effects, leading to a mixture of double
bond isomers.5
time
(h)
yield of
entry
catalyst
conditions
2 (%)a
E:Z
1
2
3
4
5
6
7
8
9
5 mol % of AuCl3
5 mol % of AuCl3
1 mol % of AuCl3
5 mol % of PyAuCl3
toluene, 80 °C
MeNO2, 80 °C
toluene, 80 °C
toluene, 80 °C
toluene, 80 °C
toluene, 80 °C
ClCH2CH2Cl, 80 °C
0.25 >99
0.25 94
0.25 >99
1:1.6
1:2
1:1.6
1:2
12
1.5
3.5
8
84
b
5 mol % of LAuCl2
1 mol % of LAuCl2
>99c 7:1
b
>99c 4:1
d
5 mol % of L′AuNTf2
5 mol % of PtCl2
5 mol % of HNTf2
26
e
1:2
ClCH2CH2Cl, 80 °C 12
ClCH2CH2Cl, 80 °C
6
e
a Estimated by 1H NMR using diethyl phthalate as internal standard.
b L ) pyridine-2-carboxylato. c Isolated yield. d L′ ) 2-(dicyclohexylphos-
phino)biphenyl. e Mostly starting material.
Table 2. Au-Catalyzed Efficient Formation of
3-Alkylidene-2,4-Diketones
Herein, we report our investigation into the nucleophilicity of
Au-C bonds following Au activation of alkynes/allenes. A highly
efficient and general synthetic method of R-alkylidene or ben-
zylidene-â-diketones is developed, featuring a novel intramolecular
acyl migration to nucleophilic AuIII-C(sp2) bonds.
On the outset, we treated oct-3-yn-2-yl acetate (1) with AuCl3
(5 mol %) in refluxing ClCH2CH2Cl. Surprisingly, a clean conver-
sion to an isomeric mixture of 3-ethylidene-2,4-octadiones (2) was
observed (eq 1). These geometric isomers of 2 were readily
separated by flash column chromatography, and their structures were
assigned based on spectroscopic studies, including 1D NOESY.
This efficient transformation of a simple substrate, such as 1, into
synthetically versatile alkylidene diketones is remarkable and
prompted us to optimize the reaction conditions and study its scope.
We first examined the influence of solvents on the reaction.
Interestingly, this reaction showed remarkable insensitivity to
solvent polarity with 5 mol % of AuCl3 as compound 2 was formed
in excellent yields both in nonpolar toluene (entry 1, Table 1) and
in polar nitromethane (entry 2), while the E/Z ratio remained largely
unchanged. Further experiments proved that toluene was the best
solvent, and a quantitative conversion of 1 to 2 was observed with
1 mol % of AuCl3 (entry 3). Attempts to improve the stereoselec-
tivity of this reaction was initially unsuccessful with complex
PyAuCl3 (entry 4); however, complex dichloro(pyridine-2-carboxyl-
ato)gold(III) (3)6 appeared to be an excellent catalyst/precatalyst7
as the stereoselectivities were improved significantly (entries 5 and
6). Although the reaction in the presence of complex 3 took
substantially longer time to complete than in the cases of AuCl3,
its ease of handling and the improved stereoselectivity led us to
choose conditions in entries 5 and 6 for studying the reaction scope.
1
a Isolated yield. b Estimated by H NMR.
Other catalysts, such as cationic Au(I) complexes (e.g., entry 7),
PtCl2 (entry 8), and HNTf2 (entry 9), proved to be largely
ineffective.
With the optimal reaction conditions (catalyst 3, toluene, 80 °C),
the scope of this reaction was promptly studied. Table 2 shows the
results with various propargylic acetates (4). What is immediately
apparent is the high efficiency of this reaction as the isolated yields
of all the entries are g90%. Various substituents at the propargyl
alkyne terminus, such as cyclopropyl (entry 1), phenyl (entry 2),
and sterically demanding cyclohexyl (entry 4), were all tolerated,
and the reactions were completed in an hour with 5 mol % of
catalyst 3. Phenyl substituents at both ends of the propargyl moiety
were allowed, and benzylidene derivative 5c was formed efficiently
(entry 3). An isopropyl group R to the propargylic position led to
9
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10.1021/ja062777j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Au-Catalyzed Highly Stereoselective Formation of Dienyl
Diketones
GC-MS, and ES-MS. Although the allene intermediate B has never
been observed during the reaction, the treatment of carboxyallene
8 indeed yielded 5d with excellent yield and an E/Z ratio identical
to that in entry 4, Table 1 (eq 2).
The scope of this reaction can be further expanded to include
benzoates (e.g., eq 3) and carbonates (e.g., eq 4). Particularly
noteworthy is that the Boc group survived the reaction conditions
and the tert-butyl ester was isolated in excellent yield based on
recovered starting material, testifying to the mild nature of this
transformation.
1
a Isolated yield. b Estimated by H NMR.
Scheme 1. Proposed Reaction Mechanism
In conclusion, a highly efficient synthesis of R-alkylidene or
benzylidene-â-diketones from readily available propargylic esters
is developed. The proposed key transformation is a novel intramo-
lecular acyl migration to nucleophilic AuIII-C(sp2) bonds. Note-
worthy features of this method are the excellent yields and the
stereoselectivity. High to excellent stereoselectivities were observed
in the cases of dienyl â-diketones.
Acknowledgment. This research was supported by the Uni-
versity of Nevada, Reno. We thank Myoung-Geun Song for
preparing some of the starting materials.
slower reaction, and 10 mol % of catalyst 3 was required to
complete the reaction in order to offset its decomposition (entry
5). Although mixtures of E/Z isomers of 5a-e were obtained, the
E isomers were always the predominant products. Pronounced
selectivities were observed in entries 4 and 5. Remarkably, acetate
4f derived from a tertiary propargylic alcohol worked equally well,
leading to tetrasubstituted alkene 5f in 94% yield (entry 6).
This general synthetic method of R-ylidene-â-diketones can be
applied to highly stereoselective synthesis of versatile dienyl dike-
tones. As shown in Table 3, acryloyl groups with various substit-
uents, including alkyl, phenyl, and silyl groups, were allowed, and
dienyl â-diketones (7) were obtained in close to quantitative yields.
Moreover, these reactions exhibited remarkably high to excellent
Z selectivity. Interestingly, the erosion of Z/E selectivity was ob-
served with elongated reaction times, accompanied by appreciable
decomposition of catalyst 3. For example, a 1.4:1 mixture of Z
and E isomers of 7e was isolated after heating 6e with 1 mol % of
3 for 40 min.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(2) The nucleophilicity of organoaurates generated via Au activation of C-H
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The proposed mechanism of this reaction is shown in Scheme
1. Hence, propargylic ester A undergoes an initial Au-catalyzed
3,3-rearrangement to form carboxyallene B, which can be further
activated by the same AuIII catalyst in situ.3b,8 The resulting
intermediate C9,10 has been shown to react efficiently with nucleo-
philes at the oxocarbenium moiety;3b however, in the absence of
suitable nucleophiles, an acyl group migration ensues as the
nucleophilic AuIII-C(sp2) attacks the acyl carbonyl group intramo-
lecularly, generating a tetrahedral intermediate (D). The collapse
of D results in R-ylidene-â-diketone E with concomitant regenera-
tion of the Au catalyst. The formation of the double bond isomer
of E is most likely due to isomerization catalyzed by either AuIII
or H+ formed due to the decomposition of 3.4b,11 An alternative
route for the acyl migration via intermolecular reaction between a
gold allenolate and an acylium is not supported by a cross reaction
(5) One exception we are aware of: Tanikaga, R.; Konya, N.; Hamamura,
K.; Kaji, A. Bull. Chem. Soc. Jpn. 1988, 61, 3211-3216.
(6) For its preparation, see: Dar, A.; Moss, K.; Cottrill, S. M.; Parish, R. V.;
McAuliffe, C. A.; Pritchard, R. G.; Beagley, B.; Sandbank, J. J. Chem.
Soc., Dalton Trans. 1992, 1907-1913.
(7) For a previous study of its role as precatalyst, see: Hashmi, A. S. K.;
Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E. Angew. Chem., Int. Ed.
2004, 43, 6545-6547.
(8) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442-1443.
(9) Alternatively, intermediate C can be formed directly from A without the
intermediacy of carboxyallene B.
(10) The selective formation of C with R2 cis to AuIII has been implied in our
previous work (see ref 3b) as well as in our unpublished results.
(11) Inokuchi, T.; Kawafuchi, H. J. Org. Chem. 2006, 71, 947-953.
1
of esters 4d and 6b. No cross product was observed by H NMR,
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