Practical method for transforming alkynes into α-diketones

Article abstract of DOI:10.1021/jo051793g

Oxidation of alkynes to α-dicarbonyl derivatives through a convenient one-pot procedure via a Bronsted acid-promoted "hydration" and a DMSO-based oxidation sequence has been achieved in high yields, The scope and limitations of the reaction have also been investigated.

Full text of DOI:10.1021/jo051793g

SCHEME 1. Possible Stepwise Oxidation of Alkynes to
r-Dicarbonyl Derivatives
Practical Method for Transforming Alkynes into
r-Diketones
Zhonghui Wan,* Chauncey D. Jones, David Mitchell,
John Y. Pu, and Tony Y. Zhang
Global Chemical Process Research and DeVelopment,
Eli Lilly and Company, Lilly Corporate Center,
Indianapolis, Indiana 46285
wanzh@lilly.com
require high temperature (usually >150 °C) and are thus
considered potentially hazardous, transition-metal-catalyzed
oxidations7 have their substrate limitations, and oxidation via
ozonolysis8 requires cryogenic reaction conditions. Obviously,
as a result of these drawbacks and limitations of the existing
methods, a practical and general method for oxidizing alkynes
to R-dicarbonyl derivatives is highly desirable. Such a method
should utilize mild reaction conditions and avoid the use of
stoichiometric inorganic oxidants as well as toxic transition-
metal catalysts.
ReceiVed August 25, 2005
Our approach is based on the consideration outlined in
Scheme 1. We envisioned that the difficulty associated with
the direct oxidation of an alkyne triple bond to the R-dicarbonyls
can be circumvented by a stepwise approach, such as the
possibility of first hydrating an alkyne 1 to the monoketone 3
and/or 4, followed by oxidizing 3 and/or 4 into the dicarbonyl
2.
In the literature, there are numerous reports of alkyne
hydration under either acid9 or transition-metal catalysis.10 In
our case, the most attractive result was reported by Shvo and
Menashe.11 They found that electron-rich alkynes 1 could be
“hydrated” to form monoketones 3 and/or 4 by pure formic acid
without any catalyst, while electron-poor alkynes needed
transition-metal catalysis. These results indicated the role of
formic acid serving as a formal and efficient “water donor” for
alkyne hydrations. There are also numerous methods12 to
transform the monoketones 3 and/or 4 to the dicarbonyls 2. We
were particularly intrigued by the DMSO-based oxidations
reported by Kornblum and co-workers13 and further developed
by Floyd and co-workers,14 which appear to fit the criteria set
forth for this method development effort and appear to be
compatible with the alkyne hydration conditions.
Oxidation of alkynes to R-dicarbonyl derivatives through a
convenient one-pot procedure via a Brønsted acid-promoted
“hydration” and a DMSO-based oxidation sequence has been
achieved in high yields. The scope and limitations of the
reaction have also been investigated.
R-Dicarbonyl derivatives are versatile building blocks capable
of undergoing a variety of chemical transformations,1 especially
for the synthesis of biologically active heterocyclic compounds.2
Several approaches3 have been reported to prepare the R-di-
carbonyl derivatives. The direct oxidation of properly substituted
alkynes, which are easily accessible via Sonogashira coupling,4
appears to be the most straightforward method to synthesize
the R-dicarbonyl derivatives. However, the frequently used
potassium permanganate oxidation5 is neither environmentally
benign nor operatively efficient, the DMSO-based oxidations6
(1) (a) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahadron
Lett. 1995, 40, 7305-7308 and references cited therein. (b) De Kimpe, N.;
Stanoeva, E.; Boeykens, M. Synthesis 1994, 427-431 and references cited
therein.
(2) (a) Barta, T. E.; Stealey, M. A.; Collins, P. W.; Weier, R. M. Bioorg.
Med. Chem. Lett. 1998, 8, 3443-3448. (b) Callahan, J. M.; Burgess, J. L.;
Fornwald, J. A.; Gaster, L. M.; Harling, J. D.; Harrington, F. P.; Heer, J.;
Kwon, C.; Lehr, R.; Mathur, A.; Olson, B. A.; Weinstock, J.; Laping, N. J.
J. Med. Chem. 2002, 45, 999-1001. (c) McKenna, J. M.; Halley, F.;
Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed,
I. J. Med. Chem. 2002, 45, 2173. (d) Singh, S. K.; Saibaba, V.; Ravikumar,
V.; Rudrawar, S. V.; Daga, P.; Rao, C. S.; Akhila, V.; Hegde, P.; Rao, Y.
K. Bioorg. Med. Chem. 2004, 12, 1881-1893.
(3) Katritzky, A. R.; Zhang, D.; Kirichenko, K. J. Org. Chem. 2005, 70,
3271-3274 and references therein.
(4) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis
1980, 8, 627-630.
(5) (a) Srinvasan, N. S.; Lee, D. G. J. Org. Chem. 1979, 44, 1574. (b)
Lee, D. G.; Chang, V. S.; Chandler, W. D. J. Org. Chem. 1985, 50, 4306.
(6) (a) Wolfe, S.; Pilgrim, W. R.; Garrad, T. F.; Chamberlain, P. Can. J.
Chem. 1971, 49, 1099-1015. (b) Yusubov, M. S.; Filimonov, V. D.;
Vasilyeva, V. P.; Chi, K. W. Synthesis 1995, 1234-1236.
(7) (a) Zhu, Z. L.; Espenson, J. H. J. Org. Chem. 1995, 60, 7728-7732.
(b) Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov, E.
V.; Knight, D. W. Tetrahedron 2002, 58, 1607-1610 and references therein.
(8) Favino, T. F.; Fronza, G.; Fuganti, C.; Fuganti, D.; Grasselli, P.; Mele,
A. J. Org. Chem. 1996, 61, 8975-8979.
(9) (a) Kozhevnikov, I. V. Chem. ReV. 1998, 98, 171. (b) Tsuchimoto,
T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Synlett 2000, 12, 1777-1778.
(10) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563-4565 and references therein.
(11) (a) Menashe, N.; Shvo, Y. J. Org. Chem. 1991, 56, 2912-2914.
(b) Menashe, N.; Shvo, Y. J. Org. Chem. 1993, 58, 7434-7439.
(12) (a) Rabjohn, N. Org. React. 1949, 5, 331. (b) Rabjohn, N. Org.
React. 1976, 24, 261. (c) Wentzel, B. B.; Donners, M. P. J.; Alsters, P. L.;
Feiters, M. C.; Nolte, R. J. M. Tetrahedron 2000, 56, 7797-7803. (d)
Tatsugi, J.; Izawa, Y. J. Chem. Res., Miniprint 1988, 11, 2747-2763. (e)
Bonadies, F.; Bonini, C. Synth. Commun. 1988, 18, 1573-1580.
(13) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson,
H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562.
(14) Floyd, M. B.; Du, M. T.; Fabio, P. F.; Jacob, L. A.; Johnson, B. D.
J. Org. Chem. 1985, 50, 5022-5027.
10.1021/jo051793g CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/22/2005
826
J. Org. Chem. 2006, 71, 826-828

TABLE 1. Acid-Promoter Screena
TABLE 2. Oxidation of Alkynes to r-Dicarbonyl Compoundsa
entry
acidb (equiv)
CF3SO3H
(CF3SO2)2NH
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
H2SO4
H2SO4
H2SO4
H3PO4
CF3CO2H
timec (h)
yield of 2ad (%)
1
2
3
4
5
6
7
8
9
0.50
0.50
0.25
0.50
1.00
2.00
0.25
0.50
1.00
0.50
0.50
10
10
15
15
15
10
15
15
10
15
15
84
82
71
75
82
60
78
75
69
50
63
10
11
a All reactions were run with different acid promoters under the same
conditions: 1.0 mmol of diphenylacetylene, 1.0 mL of 88% formic acid,
5.0 mmol of DMSO, and 0.10 mmol of 48% HBr. The reactions were heated
at ∼105 °C using a short path to distill off any volatiles. b Acid equivalent
to diphenylacetylene. c Actual time, not the optimal time. d Isolated yield.
Our investigation began with a stepwise sequence by first
screening commonly used strong Brønsted acids (see Table 1)
in either a catalytic or a stoichimetric amount for the “hydration”
of diphenylacetylene 1a to form 1,2-diphenylethanone 3a, using
commercially available 88% formic acid as both “water donor”
and solvent. After the “hydration” of diphenylacetylene 1a to
form 1,2-diphenylethanone 3a was completed, DMSO and a
catalytic amount of HBr were added to oxidize 3a to form the
desired dibenzyl 2a.
To our delight, a variety of strong Brønsted acids promoted
the “hydration” of diphenylacetylene 1a to form 1,2-diphenyl-
ethanone 3a in 88% formic acid, and the ensuing hydrobromic
acid-catalyzed DMSO oxidation afforded the desired dicarbonyl
2a in high yields.
More conveniently, we found that even though the reaction
is stepwise in nature, all the reagents could be added at the
same time at the beginning. Typically, heating a mixture of
diphenylacetylene 1a (1.0 equiv), 88% formic acid (∼5.0-10
vol), DMSO (∼5.0-10 equiv), aqueous 48% HBr (∼0.10-0.15
equiv), and a variety of strong Brønsted acids (0.25-1.0 equiv)
at about 105 °C using a short path to distill off the volatiles,
which contains the reaction-generated dimethyl sulfide and some
solvent, afforded the desired dicarbonyl 2a in high yields.15 The
best results (Table 1) were obtained from reactions using
trifluoromethanesulfonic acid (entry 1), trifluoromethane sul-
fonimide (entry 2), methanesulfonic acid (entry 5), and sulfuric
acid (entry 7) as promoters. When the cost, the effectiveness,
and the operational convenience of these acids are considered,
methanesulfonic acid appeared to be the Brønsted acid promoter
choice.
a All reactions were under the same conditions: 2.0 mmol of the
substituted acetylene, 2.0 mL of 88% formic acid, 10.0 mmol of DMSO,
and 0.20 mmol of 48% HBr. The reactions were heated at ∼105 °C until
complete conversion. b Isolated yields. c Stoichiometric amount of HBr was
used.
n) all underwent a smooth transformation to form the corre-
sponding R-dicarbonyl derivatives in good to excellent yields.
An aryl terminal alkyne (entry o) formed the corresponding
glyoxal derivative. It is surprising to notice the different
reactivities of the substrates with tertial alkyl substituents (entries
d and e). The reaction of 1d stopped at the R-bromoketone stage
as the isolated product (entry d), while the corresponding
trifluoromethyl analogue, 1e, gave the R-dione product, 2e, with
good yield (entry e). We assume that the relative electron-rich
property of 1d contributed to the lower reactivity of the
intermediate R-bromoketone. R-Unbranched alkyl-substituted
alkynes are not valid substrates for this oxidation reaction as a
result of the continuous R-oxidation to form multiple carbonyl
derivatives, which are not stable under the reaction conditions.
We briefly studied the alkyne oxidation reaction mechanism
by detecting the off gas with headspace GC-MS and the reaction
intermediates with liquid chromatography mass spectrometry
(LC-MS). We found that CO and Me2S evolved from the
Encouraged by the diphenylacetylene oxidation results, we
then attempted to oxidize alkynes bearing a variety of substit-
uents with the general structure 1 to the dicarbonyls 2 (Table
2). Alkynes with electron-rich (entries a-c) or electron-poor
(entries f-i) diaryl substituents, heteroaryls (entries j-l), an aryl
with an unprotected free amine (entry m), or a free acid (entry
(15) The efficient removal of the generated dimethyl sulfide by distillation
from the reaction system is crucial for reaction completion. See Supporting
Information.
J. Org. Chem, Vol. 71, No. 2, 2006 827

SCHEME 2. Possible Reaction Pathway
SCHEME 3. Dimethyl Sulfide Involved Nonproductive
Pathway
reaction media, and the amount of CO and Me2S evolution is
proportional to the conversion. We also detected reaction
intermediates, such as the monoketone 3 and the bromoketone
7, by LC-MS (Scheme 2). The results indicated the reaction
does indeed proceed through the sequence of a formic acid
addition to an alkyne to form the vinyl formate 5, which
decomposes to form the monoketone 3 by liberating CO, as
reported by Shvo and Menashe;11 the ensuing DMSO-based
oxidation of 3 using HBr/Br2 as a catalyst affords the expected
dicarbonyl 2 by liberating Me2S gas via either the Kornblum et
al.13 alkoxydimethyl sulfonium salt 8 or the Floyd et al.14
R-dibromoketone 9. It is also plausible that enol formate 5
undergoes bromination directly to afford the bromoketone 7,
which would readily undergo the DMSO oxidation.
yielding and also has circumvented the use of stoichiometric
inorganic oxidants and toxic transition-metal catalysts.
Experimental Section
General Procedure for the Oxidation of Alkynes to r-Dike-
tones. Typical experimental procedures for the oxidation of alkynes
to R-diketones, as exemplified by the formation of 1-(4-fluorophen-
yl)-2-(4-trifluoromethylphenyl)-ethane-1,2-dione (2i) are as fol-
lows: (4-Fluorophenyl)-ethynyl-4-trifluoromethylbenzene (530 mg,
2.0 mmol) was mixed with 2.0 mL of 88% formic acid, 2.0 mmol
of methanesulfonic acid, 12.0 mmol of DMSO, and 0.20 mmol of
48% HBr in a 10 mL flask. The reactions were heated to ∼105-
110 °C using a short path to distill off the volatiles (mostly dimethyl
sulfide generated from the reaction and some solvents) for 15 h
until complete conversion. The reaction was cooled to room
temperature. The crude product was extracted into ethyl acetate
after an aqueous workup. Flash chromatography on silica gel using
15% ethyl acetate in hexanes as the eluent afforded the title
We also found bromomethane and dimethyl disulfide in the
off gas and methyl methanesulfonate in the reaction mixture,
and the higher the concentrations of these byproducts, the lower
the dione product yields. A rationale for this phenomenon is
illustrated in Scheme 3. If too much dimethyl sulfide remains
in the reaction system, it will deplete both the reaction catalyst
bromine and the reaction reagent DMSO by reacting with the
in situ generated bromine catalyst to form dimethyl bromosul-
fonium bromide16 first, which is then converted to the byprod-
ucts, bromomethane, methyl methane sufonate, and dimethyl
disulfide, through a nonproductive pathway. It is clear that
efficient removal of dimethyl sulfide out of the reaction system
is important for achieving fast, complete, and high yielding
reactions.
1
compound (552 mg, 93% yield). H NMR (500 MHz, CDCl3): δ
7.22 (m, 2H), 7.80 (d, J ) 7.5 Hz, 2H), 8.04 (m, 2H), 8.10 (d, J )
7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 116.5 (d), 126.1,
130.3, 132.8, 132.9, 135.5, 166.0, 168.0, 191.5, 192.5. HRMS (M
+ H)+ calcd for C15H9F4O2, 297.0539; found, 297.0547. IR (KBr,
cm-1): 1670, 1664, 1598.
Acknowledgment. We would like to thank Professors
Marvin Miller, Peter Wipf, and William Roush for helpful
discussions. We are also grateful to the Lilly Physical Chemistry
Group for analytical data.
In conclusion, we have developed a practical and convenient
method for oxidizing aryl alkynes to R-dicarbonyl derivatives
using inexpensive 88% formic acid as both the reagent and the
solvent, hydrobromic acid as the catalyst, and DMSO as the
stoichiometric oxidant. The new procedure is efficient and high-
Supporting Information Available: Experimental details and
the characterization of dicarbonyl products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Chow, Y. L.; Bakker, B. H. Can. J. Chem. 1982, 60, 2268-2273.
JO051793G
828 J. Org. Chem., Vol. 71, No. 2, 2006