Ruthenium-Catalyzed Oxidative Cleavage of Alkynes to Carboxylic Acids

Article abstract of DOI:10.1021/jo0357925

We describe an efficient method for the oxidative cleavage of alkynes to carboxylic acids using a combination of RuO₂/Oxone/NaHCO₃ in a CH₃CN/H₂O/EtOAc solvent system. Both internal and terminal alkynes, regardless of their electron density, can be oxidized to carboxylic acids in excellent yield (up to 99%). ¹H NMR spectroscopy and ESI-MS experiments provided evidence for α-diketones and anhydrides as possible intermediates in these oxidation reactions.

Full text of DOI:10.1021/jo0357925

SCHEME 1
Ru th en iu m -Ca ta lyzed Oxid a tive Clea va ge
of Alk yn es to Ca r boxylic Acid s
Dan Yang,*,†,‡ Fei Chen,† Ze-Min Dong,† and
Dan-Wei Zhang‡
TABLE 1. Oxid a tive Clea va ge of Va r iou s Alk yn esa
Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong, China, and Department of
Chemistry, Fudan University, Shanghai 200433, China
yangdan@hku.hk
Received December 7, 2003
Abstr a ct: We describe an efficient method for the oxidative
cleavage of alkynes to carboxylic acids using a combination
of RuO2/Oxone/NaHCO3 in a CH3CN/H2O/EtOAc solvent
system. Both internal and terminal alkynes, regardless of
their electron density, can be oxidized to carboxylic acids in
1
excellent yield (up to 99%). H NMR spectroscopy and ESI-
MS experiments provided evidence for R-diketones and
anhydrides as possible intermediates in these oxidation
reactions.
The oxidative cleavage of alkynes to carboxylic acids
is a fundamental class of reactions in organic chemistry.
Available methods employ oxidants such as ozone,1
potassium permanganate,2 ruthenium tetraoxide,3 Mo
and W polyoxometalates,4 methylrhenium trioxide,5 al-
kaline hydrogen peroxide,6 and [bis(trifluoroacetoxy)iodo]-
benzene.7 However, most of these methods are not
efficient enough to be utilized for synthetic purposes. For
example, ozonolysis is used commonly for the cleavage
of both terminal and internal alkynes, but a special
apparatus is needed to prevent any possible explosion,
and potentially unwanted esters are obtained as side
products when the reaction is conducted in alcohol
solutions.1b Other oxidation methods usually form R-dike-
tones as the main side products, and their further
cleavage to carboxylic acids is difficult to achieve under
the oxidation conditions described above. Lewis acids2c
and ultrasound2b can promote the oxidative cleavage of
alkynes by potassium permanganate, but successful
examples of the use of this approach are limited. Griffith
a
† The University of Hong Kong.
Unless otherwise indicated, the reaction was carried out with
‡ Fudan University.
1 mmol of alkyne, 0.03 equiv of RuO2, and a 3:1 ratio of NaHCO3
and Oxone, in 15 mL of acetonitrile, 10 mL of water, and 3 mL of
(1) (a) Long, L. Chem. Rev. 1940, 27, 437. (b) Bailey, P. S.; Chang,
V. S.; Kwie W. W. L. J . Org. Chem. 1962, 27, 1198. (c) Yang, N. C. C.;
Libman, J . J . Org. Chem. 1974, 39, 1782. (d) Ando, W.; Miyazaki, H.;
Ito, K.; Auchi, D. Tetrahedron Lett. 1982, 23, 555. (e) Silbert, L. S.;
Foglia, T. A. Anal. Chem. 1985, 57, 1404.
(2) (a) Lee, D. G.; Chang, V. S. J . Org. Chem. 1979, 44, 2726. (b)
Lie Ken J ie, M. S. F.; Kalluri, P. Lipids 1996, 31, 1299. (c) Lai, S.;
Lee, D. G. Tetrahedron 2002, 58, 9879.
(3) (a) Gopal, H.; Gordon, A. J . Tetrahedron Lett. 1971, 12, 2941.
(b) Mukai, C.; Miyakawa, M.; Hanaoka, M. Synlett 1994, 165. (c)
Griffith, W. P.; Shoair, A. G.; Suriaatmaja, M. Synth. Commun. 2000,
30, 3091. (d) Cornely, J .; Ham, L. M. S.; Meade, D. E.; Dragojlovic, V.
Green Chem. 2003, 5, 34.
(4) Ballistreri, F. P.; Failla, S.; Spina, E.; Tomaselli, G. A. J . Org.
Chem. 1989, 54, 947.
b
ethyl acetate at room temperature for 1 h. Yield of isolated
product. c Acetone instead of acetonitrile. THF instead of aceto-
d
nitrile. e Yield determined by NMR spectroscopy. f RuCl3 instead
g
h
of RuO2. 0.04 equiv of RuO2. Yield determined by GC.
et al.3c have found that periodic acid can oxidize terminal
alkynes to carboxylic acids in the presence of a catalytic
amount of RuCl3 in a H2O/CCl4/CH3CN solvent system,
but no examples were reported in which internal alkynes
were applied as substrates. We found that internal
alkynes were tricky to be oxidized to carboxylic acids in
such a system because the R-diketone intermediates were
difficult to cleave. Therefore, there is high demand for a
general and efficient method for the oxidative cleavage
of alkynes to carboxylic acids.
(5) Zhu, Z. L.; Espenson, J . H. J . Org. Chem. 1995, 60, 7728.
(6) Sawaki, Y.; Inoue, H.; Ogata, Y. Bull. Chem. Soc. J pn. 1983, 56,
1133.
(7) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.; Prakash, I. J .
Org. Chem. 1988, 53, 6124.
10.1021/jo0357925 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004
J . Org. Chem. 2004, 69, 2221-2223
2221

F IGURE 1. 1H NMR spectra of the crude products obtained after the ruthenium-catalyzed oxidation of 3 with (a) 1 equiv of
Oxone and (b) 1.8 equiv of Oxone.
F IGURE 2. ESI-MS spectrum of the crude product obtained after oxidation of 3 with 1.8 equiv of Oxone.
It is known that peroxomonosulfuric acid oxidizes
R-diketones to carboxylic acids8 and that R-diketones are
generated from the oxidation of alkynes by using a
catalytic amount of RuO2 together with a co-oxidant.3a
We envisioned that a combination of RuO2 and Oxone
(2KHSO5‚KHSO4‚K2SO4) could be used to oxidize alkynes
to carboxylic acids under mild and neutral conditions.
Previously, we reported that alkenes can be oxidized to
aldehydes by Oxone in a reaction catalyzed by RuCl3 in
a NaHCO3-buffered CH3CN/H2O solvent system.9 Here,
we report that a modified reaction system can be applied
to oxidize both terminal and internal alkynes to carbox-
ylic acids in excellent yield (Scheme 1).
The new protocol, exemplified in Scheme 1, involves
the use of acetonitrile, water, and ethyl acetate (volume
ratio 15:10:3) as the solvent system, ruthenium dioxide
as the catalyst, Oxone as the terminal oxidant, and
sodium bicarbonate as the buffer that maintains the
neutral conditions. Ethyl acetate was present to improve
the solubility of the substrates, and from solvent screen-
ing, we found that acetonitrile was superior as the
cosolvent to either acetone or THF (Table 1, entries 1-3).
Another ruthenium source, RuCl3, also performed well
as a catalyst in the oxidative cleavage of 1 (99% yield of
2, Table 1, entry 4).
Next we investigated the oxidative cleavage of alkynes
possessing different substituents: alkyl (3-5), aromatic
ring (6-8), ester (9), ether (10 and 11), silyl ether (12),
ketone (13), and chloride (14) units (entries 5-16). In
most cases, we achieved clean reactions (except for 8 and
11) and excellent yields, and no column purifications were
needed after workup since almost no side products could
be detected in the NMR spectra of the crude products.
The aromatic rings of 6-8, the ester group of 9, the
simple ether group of 10, and the TBDPS group of 12
were all stable in this system. The benzyl ether (11) was
further oxidized at the benzylic position to afford the
benzoic ester as a side product in 14% yield. We attribute
the relatively low yield of entry 10 to the stability of
benzil, which was detected in the crude NMR spectrum
and could be removed by a modified workup.10 The
(8) Panda, R.; Panigrahi, A. K.; Patnaik, C.; Sahu, S. K.; Mahapatra,
S. K. Bull. Chem. Soc. J pn. 1988, 61, 1363.
(9) Yang, D.; Zhang, C. J . Org. Chem. 2001, 66, 4814.
2222 J . Org. Chem., Vol. 69, No. 6, 2004

We carried out 1H NMR spectroscopy and ESI-MS
experiments to identify the reaction intermediates. When
an insufficient amount (e.g., 1-1.8 equiv) of Oxone was
used,11 4,5-octanedione (23) and butyric acid anhydride
(24) were observed in the 1H NMR spectrum after
4-octyne 3 was oxidized for 20 min (Figure 1). The signals
of 23 decreased significantly when the amount of Oxone
was increased from 1 to 1.8 equiv, and it disappeared in
the end when 3.3 equiv of Oxone was used (Table 1, entry
5). After the oxidation of 3 by 1.8 equiv of Oxone for 20
min, the reaction mixture was diluted with methanol/
water and subjected to ESI-MS analysis. We detected
three peaks at m/z 165.1, 181.1, and 197.0, which
correspond to the ions 23‚Na+, 23‚K+/24‚Na+, and 24‚
K+, respectively (Figure 2).
SCHEME 2. P r op osed Mech a n ism for th e
Oxid a tion of Alk yn es to Ca r boxylic Acid s
In conclusion, we have developed an efficient RuO2-
Oxone-NaHCO3 oxidation system, in CH3CN/H2O/
EtOAc, that can transform both terminal and internal
alkynes to the corresponding carboxylic acids in excellent
yields. Further research to apply this reaction to the
construction of chiral carboxylic acids and their deriva-
tives is in progress.
formation of the lactone in entry 16 resulted from an
intramolecular SN2 substitution reaction of the chloride
by the carboxylate anion generated at neutral pH. The
good solubility of 15 and 22 in water resulted in some
loss of these products during aqueous workup (entries 5
and 16). Even though the electron-withdrawing carbonyl
group deactivates the carbon-carbon triple bond of 13,
its alkyne cleavage proceeded smoothly upon the addition
of 6 equiv of Oxone (entry 15).
To highlight the utility of this reaction, the oxidative
cleavage of 1 was carried out successfully on a 20 mmol
(4 g) scale. Although 10% heptanoic acid anhydride
remained after 2 h, further hydrolysis for 1 h under acidic
conditions afforded product 2 cleanly (99% yield). We also
found that 6.5 equiv of NaIO4, rather than Oxone/
NaHCO3, could be used as a co-oxidant in our reaction
system to cleave some alkynes, such as 3 and 9, to their
corresponding carboxylic acids in good yields (>80%)
within 3 h. For the oxidation of 1, however, more than
40% of tetradecane-7,8-dione was present after 4 h
because of its slow cleavage by NaIO4.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Oxid a tion of Alk yn es to
Ca r boxylic Acid s by Ru O2/Oxon e. Sodium bicarbonate (9.9
mmol) and Oxone (3.3 mmol) were added to a stirred solution
of alkyne (1 mmol) in CH3CN/H2O/EtOAc (15:10:3 mL). Ruthe-
nium dioxide (0.03 mmol) was added 3 min later. After being
stirred for 1 h, the reaction was quenched with 10% sodium
bisulfite solution, acidified with 2 N HCl solution to pH < 2,
and extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo
to give the crude products.
Ack n ow led gm en t. This work was supported by The
University of Hong Kong, the Hong Kong Research
Grants Council, and the National Natural Science
Foundation of China (Project No. 20202001). We thank
Yu-Hui Zhang for help in ESI-MS analysis. D.Y. ac-
knowledges the Bristol-Myers Squibb Foundation for an
Unrestricted Grant in Synthetic Organic Chemistry and
the Croucher Foundation for a Croucher Senior Re-
search Fellowship Award.
The oxidative cleavage of alkynes to carboxylic acids
using the Oxone/RuO2 system is likely to proceed in two
steps (Scheme 2). First, alkyne 3 is oxidized to the
R-diketone 23 by the RuO4 generated in situ by the
reaction of RuO2 with Oxone, and then 23 undergoes a
Baeyer-Villiger-type oxidation by peroxymonosulfate to
form acid anhydride 24, which, upon aqueous hydrolysis,
generates the product, acid 15.
Su p p or tin g In for m a tion Ava ila ble: Synthetic schemes
and characterization data of compounds 10 and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) The reaction was quenched with 10% NaHSO3 solution. The
mixture was washed four times with saturated NaHCO3. The combined
aqueous layers was acidified using 5 N HCl solution to pH < 2,
saturated with NaCl, and then extracted with EtOAc. The combined
EtOAc extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo to give the product.
J O0357925
(11) Unless otherwise indicated, a 3:1 ratio of NaHCO3 and Oxone
was employed for the oxidative cleavage reactions.
J . Org. Chem, Vol. 69, No. 6, 2004 2223