Synthesis of α-diketones from alkylaryl- and diarylalkynes using mercuric salts

Article abstract of DOI:10.1021/ol500592m

Both alkylarylalkynes and diarylalkynes 1 are converted into the α-diketones 2 in good yield by the use of mercuric salts, e.g., mercuric nitrate hydrate or mercuric triflate, in the presence of water. Other mercuric salts, e.g., sulfate, chloride, acetate, or trifluoroacetate, do not provide the diketone product. A possible mechanism is proposed.

Full text of DOI:10.1021/ol500592m

Letter
pubs.acs.org/OrgLett
Synthesis of α‑Diketones from Alkylaryl- and Diarylalkynes Using
Mercuric Salts
Michael E. Jung* and Gang Deng
Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Avenue, Los Angeles, California
90095, United States
S
* Supporting Information
ABSTRACT: Both alkylarylalkynes and diarylalkynes 1 are converted into
the α-diketones 2 in good yield by the use of mercuric salts, e.g., mercuric
nitrate hydrate or mercuric triflate, in the presence of water. Other mercuric
salts, e.g., sulfate, chloride, acetate, or trifluoroacetate, do not provide the
diketone product. A possible mechanism is proposed.
nitrate hydrate at 22 °C in aqueous THF for 12 h gave the
expected α-diketone, benzil 2a, in 52% yield (Scheme 2). We
he oxidation of alkylarylalkynes and diarylalkynes 1 to
Tfurnish the corresponding α-diketones 2 is well-known in
organic chemistry. A very large number of oxidants have been
used for this process. For example, KMnO4 has been employed
often for this transformation1 as has RuO4 (often generated in
situ or immobilized).2 There are also several reports of the use
of various DMSO-based oxidations, usually with an added
electrophile3 or in the presence of a palladium catalyst4 for the
formation of 2 from 1. Finally, a large variety of other metal-
based5 and nonmetal-based6 oxidations have been reported. For
a project involving the synthesis of androgen receptor
antagonists, we had need of a good method for converting
alkylarylalkynes into α-diketones. We report here that method-
ology and its application to the conversion of several
disubstituted alkynes 1 to the corresponding α-diketones 2.
We hoped if it might be possible to intercept the well-known
mechanism7 for mercuric-catalyzed hydration of an alkyne
(Scheme 1) by reaction of the α-mercurioketone intermediate
D with another equivalent of the mercuric salt.
Scheme 2. Oxidation of 1a To Give 2a
carried out several experiments on this test reaction to find the
best set of conditions. Carrying out the reaction under air or
under argon gave the same results, so oxygen is not required for
the process. The use of anhydrous THF with an added
equivalent of water afforded good yields. Other solvents worked
well, e.g., methanol, DME, dioxane, acetonitrile, acetone, acetic
acid, DMSO, and especially DMF. The best yields were
obtained in methanol with 1 equiv of added water (22 °C, 20
min, 84%) and in DMF (22 °C, 24 h, 90%). The use of other
mercuric salts, e.g., sulfate, chloride, acetate, and trifluoroace-
tate, did not give any 2a. However, the use of mercuric triflate,
Hg(OTf)2, also produced good yields of the α-diketone 2a.
We then applied this method to the synthesis of a wide
variety of α-diketones using the following set of conditions,
namely treatment of the alkyne 1 with 2 equiv of mercuric
nitrate hydrate in DMF in air at 22 °C. The results are shown in
Table 1. Arylalkynes generally gave good yields of the expected
α-diketone products, e.g., 2b,d−f,m,n, with yields ranging from
47 to 82%. In addition, most of the diarylacetylenes gave quite
good yields of product. The presence of halogens (1c,i,j,n) did
not hinder the oxidation nor did the more oxidizable or labile
functionalities, such as phenols (1l and 1m), esters (1k and
1o), amines (1e, 1p, and 1q), or nitriles (1f), all of which gave
reasonable yields of the desired products 2. Substrates with
electron-donating substituents (methoxy, 2g, or methyl, 2h)
gave good yields, while the substrate having a 4-trifluoromethyl
We examined this process using 1,2-diphenylacetylene 1a as
the substrate. Thus treatment of 1a with 2 equiv of mercuric
Scheme 1. Mercuric Nitrate Catalyzed Hydration of an
Alkyne
Received: February 26, 2014
Published: April 1, 2014
© 2014 American Chemical Society
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Letter
Table 1. Oxidation of Alkynes with Mercuric Nitrate Hydrate
group 1d gave the lowest yield among the successful substrates,
perhaps due to lower electron density in the alkyne. The 1,4-
di(propynyl)benzene 1r afforded the bis(α-diketone) 2r in
good yield. A few substrates did not work well in this reaction,
giving mixtures of products. Thus, the 2-nitrophenyl substrate
1s gave the expected α-diketone 2s in 33% yield along with the
expected 3-benzoylanthranil 3s in 54% yield. The analogous 2-
nitrophenyl substrate with a propyl group on the end of the
alkyne, 1t, gave none of the α-diketone and only the anthranil
3t in 61% yield. This cyclization of a 1-(2-nitrophenyl)alkynes
such as 1s and 1t is well-known8 and is usually carried out by
treatment with either transition metals or Lewis acids. We also
attempted the oxidation on two different heterocyclic alkyne
substrates. Thus, the protected 4-pentynyl imidazole 1u gave a
relatively good yield of the desired α-diketone 2u (69%)
accompanied by the simple hydration product 3u in 20% yield.
The 3-pentynylpyridine 1v likewise gave the desired α-diketone
2v as the major product (49%) along with the opposite
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hydration product 3v in 38% yield.9 Finally the symmetrical (2-
nitrophenyl)acetylene 1w did not give any of the desired α-
diketone product 2w but rather the two byproducts, the simple
hydration product 3w in 32% yield and the anthranil 3w′ in
37% yield.10
H′. Elimination of trifluoromethanesulfinate from H′ would
then give the α-diketone 2. This last step, the elimination of
sulfinates to give ketones, is well precedented in the literature.13
In summary, we have developed a new method for the
oxidation of alkylarylalkynes and diarylalkynes 1 to give α-
diketones 2 with mercuric salts. The reaction is limited to salts
that can undergo facile subsequent elimination, namely nitrates
and triflates. The use of this process in synthesis is underway
and will be reported in due course.
We believe that the mechanism involves the steps shown in
Scheme 3, namely attack of the alkyne 1 on the mercuric nitrate
Scheme 3. Proposed Mechanism of Oxidation with Mercuric
Nitrate
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and proton and carbon NMR for all
new compounds and those prepared by routes different from
those in the literature. This material is free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jung@chem.ucla.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health for support of this
research. We also acknowledge a SPORE grant in Prostate
Cancer for support. This material is based upon work
supported by the National Science Foundation under equip-
ment grant no. CHE-1048804. The LC−MS used in this
project was supported by grant no. S10RR025631 from the
National Center for Research Resources. The content is solely
the responsibility of the authors and does not necessarily
represent the official views of the National Center for Research
Resources or the National Institutes of Health. The NMR
spectrometers were supported by the National Science
Foundation under equipment grant no. CHE-1048804.
to give the cyclic mercuronium ion A, which is then attacked by
water to give B, which loses a proton to give the α-mercurio
enol C. Tautomerization would then give the α-mercurio
ketone D. Up to this point, this is the same mechanism as for
the simple hydration of the alkyne (as shown in Scheme 1).
The key step is the attack of nitrate on the α-mercurio ketone
D, with activation by the second equivalent of mercuric nitrate,
to generate the α-nitrato ketone H and mercurous nitrate. The
final step is the reductive elimination of nitrous acid from H to
give the observed α-diketone product 2.
Perhaps the most unusual step in this proposed mechanism is
the conversion of the α-mercurio ketone D to the α-nitrato
ketone H, but this step has precedent in the literature since a
similar conversion of 2-methoxy-1,2-diphenylethyl mercuric
nitrate to the 2-methoxy-1,2-diphenylethyl nitrate is known.11
There is also good precedent for the final step, since the
conversion of α-nitrato ketones to α-diketones is well-known.12
This oxidation also proceeds, although less well, with 2 equiv
of anhydrous mercuric triflate and 2 equiv of water in THF. We
propose a very similar mechanism for the formation of the α-
diketone 2 in this reaction (Scheme 4), namely the attack of
triflate ion on the corresponding α-mercurio ketone D′
activated by mercuric triflate to give the α-sulfonyloxy ketone
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