Propargylic oxidations catalyzed by dirhodium caprolactamate in water: Efficient access to α,β-acetylenic ketones

Article abstract of DOI:10.1021/jo800382p

(Chemical Equation Presented) Dirhodium(II) caprolactamate (1, Rh ₂(cap)₄) with 70% w/w aqueous tert-butyl hydroperoxide (T-HYDRO) is a highly effective catalytic oxidation protocol for the selective C-H oxidation of alkynes to propargylic ketones. The oxidation occurs readily in aqueous solvent under mild conditions with an inexpensive and easily handled oxidant. α,β-Acetylenic carbonyl compounds are formed in up to 80% isolated yield.

Full text of DOI:10.1021/jo800382p

Early examples of alkyne oxidations used superstoichiometric
amounts of chromium(VI) complexes to afford low yields of
ynones.7 Muzart provided the first example of catalytic prop-
argylic oxidation by using a bis-tributyltin oxide dichromi-
um(VI) complex in conjunction with t-BuOOH.8 Recent pro-
pargylic oxidations have made use of N-hydroxyphthalimide
or t-BuOOH with transition metal catalysts [Cr (VI), Cu(II),
Fe(II) and Fe(IV)].9 However, few of these processes show
exceptional selectivity, efficiency, and sustainability.
Propargylic Oxidations Catalyzed by Dirhodium
Caprolactamate in Water: Efficient Access to
r,ꢀ-Acetylenic Ketones
Emily C. McLaughlin and Michael P. Doyle*
Department of Chemistry and Biochemistry, UniVersity of
Maryland, College Park, Maryland 20742
mdoyle3@umd.edu
The utility of R,ꢀ-acetylenic ketones (ynones) has been
reported in the synthesis of biologically relevant molecules such
as C-nucleosides,10 antitumor agents,11 and insect pheromones.12
Ynones are also versatile synthons in the preparation of chiral
propargylic alcohols,13 γ-acetylenic enones,14 Diels-Alder
adducts,15 and a variety of heterocyclic compounds.16 Tradition-
ally, they are prepared in two steps by terminal acetylide anion
addition to aldehydes, followed by oxidation of the resultant
alcohol.17 Ynones can also be prepared in a single step by
stoichiometric acylation of organometallic alkyne equivalents18
or catalytic metal-mediated coupling,19 although many of these
one-step methods are limited to only aryl-substituted substrates.
ReceiVed February 15, 2008
Dirhodium(II) caprolactamate (1, Rh2(cap)4) with 70% w/w
aqueous tert-butyl hydroperoxide (T-HYDRO) is a highly
effective catalytic oxidation protocol for the selective C-H
oxidation of alkynes to propargylic ketones. The oxidation
occurs readily in aqueous solvent under mild conditions with
an inexpensive and easily handled oxidant. R,ꢀ-Acetylenic
carbonyl compounds are formed in up to 80% isolated yield.
We have found that oxidation of 4-octyne (2) with 1.0 mol
% of 1 and T-HYDRO in a chlorinated hydrocarbon solvent
(1,2-dichloroethane, DCE) at 40 °C afforded ynone 3 in 86%
yield. However, the same oxidation in water furnished 3 more
rapidly and in higher yield (89%, Scheme 1).20 Moreover, water
acted as a heat sink for the exothermicity of dirhodium(II)-
(7) (a) Shaw, J. E.; Sherry, J. J. Tetrahedron Lett. 1971, 4379. (b) Sheats,
W. B.; Olli, L. K.; Stout, R.; Lundeen, J. T.; Justus, R.; Nigh, W. G. J. Org.
Chem. 1979, 44, 4075.
Mild and selective hydrocarbon oxidation methods are an
invaluable tool in synthetic organic chemistry. Installing oxygen
into a molecule (oxyfunctionalization) is an important form of
oxidation for which increasing degrees of selectivity, efficiency,
and sustainability are essential.1 For these reasons, transition-
metal-mediated oxyfunctionalization has been a long-standing
focus in both academic and industrial research.2
Recently, we have reported that dirhodium caprolactamate
1, Rh2(cap)4, with tert-BuOOH (TBHP) can effectively catalyze
allylic,3 benzylic,4 and amine oxidations.5 Initially we thought
anhydrous TBHP in decane was necessary to avoid hydrolysis
of ligands from the dirhodium catalysts such as 1. However,
we recently found that that Rh2(cap)4 is compatible with 70%
aqueous TBHP (T-HYDRO) in allylic oxidations.6 In efforts
to continue improvements in dirhodium oxidation technology,
we have found that water can replace organic solvent. Herein,
we report the oxidation of alkynes to R,ꢀ-acetylenic ketones
by T-HYDRO (70% w/w aqueous t-BuOOH), catalyzed by 1
with water as the reaction solvent.
(8) (a) Muzart, J. New J. Chem. 1989, 13, 9. (b) Muzart, J. Synth. Commun.
1989, 19, 2061. (c) Muzart, J.; Piva, O. Tetrahedron Lett. 1988, 29, 2321.
(9) For all other methods of propargylic oxidation, see: (a) Ajjou, A. N.;
Ferguson, G. Tetrahedron Lett. 2006, 47, 3719. (b) Ryu, J. Y.; Heo, S.; Park,
P.; Nam, W.; Kim, J. Inorg. Chem. Commun. 2004, 7, 534. (c) Ferguson, G.;
Ajjou, A. N. Tetrahedron Lett. 2003, 44, 9139. (d) Perollier, C. P.; Sorokin,
A. B. Chem. Commun. 2002, 1548. (e) Li, P.; Fong, W. M.; Chao, L. C. F.;
Fung, S. H. C.; Williams, I. D. J. Org. Chem. 2001, 66, 4087. (f) Sakaguchi, S.;
Takase, T.; Iwahama, T.; Ishii, Y. Chem. Commun. 1998, 2037.
(10) Adlington, R. M.; Baldwin, J. E.; Pritchard, G. J.; Spencer, K. C.
Tetrahedron Lett. 2000, 41, 575.
(11) Kundu, N. G.; Mahanty, J. S.; Spears, C. P. Bioorg. Med. Chem. Lett.
1996, 6, 1497.
(12) Clennan, E. L.; Heah, P. C. J. Org. Chem. 1981, 46, 4107.
(13) For recent examples, see: (a) Baker, J. R.; Thominet, O.; Britton, H.;
Caddick, S. Org. Lett. 2007, 9, 45. (b) Lou, S.; Moquist, P. N.; Schaus, S. E.
J. Am. Chem. Soc. 2006, 128, 12660.
(14) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am.
Chem. Soc. 1997, 119, 698.
(15) For representative examples of Diels-Alder reactions with ynones, see:
(a) Winkler, J. D.; Holland, J. M.; Peters, D. A. J. Org. Chem. 1996, 61, 9074.
(b) Feng, X. Q.; Olsen, R. K. J. Org. Chem. 1992, 57, 5811. (c) Kraus, G. A.;
Taschner, M. J J. Am. Chem. Soc. 1980, 102, 1974.
(16) For examples, see: (a) Korivi, R. P.; Cheng, C. H. J. Org. Chem. 2006,
71, 7079. (b) Xiong, X.; Bagley, M. C.; Chapaneri, K. Tetrahedron Lett. 2004,
45, 6121. (c) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.;
Tang, L. T. J. Chem. Soc., Perkin Trans. 1 2000, 2311. (d) Hwu, J. R.; Patel,
H. V.; Lin, R. J.; Gray, M. O. J. Org. Chem. 1994, 59, 1577.
(17) For recent examples, see: (a) Waddell, M. K.; Bekele, T.; Lipton, M. A.
J. Org. Chem. 2006, 71, 8372. (b) Wang, C.; Forsyth, C. J. Org. Lett. 2006, 8,
2997. (c) Zhang, X. X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
(18) Yamaguchi, M.; Shibato, K.; Fujiwara, S.; Hirao, I. Synthesis 1986, 421.
(19) For examples, see: (a) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. J.
Org. Chem. 2004, 69, 1615. (b) Chowdhury, C.; Kundu, N. G. Tetrahedron
1999, 55, 7011.
(1) (a) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977. (b) Li,
C.-J. Chen, L. Chem. Soc. ReV. 2006, 5, 68.
(2) For metal-mediated oxidations, see: Modern Oxidation Methods; Ba¨ckvall,
J.-E., Ed.; Wiley: Weinheim, 2004.
(3) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
126, 13622.
(4) Catino, A. J.; Nichols, J. M.; Choi, H. J.; Gottipamula, S.; Doyle, M. P.
Org. Lett. 2005, 7, 5167.
(5) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745.
(6) Choi, H.; Doyle, M. P. Org. Lett. 2007, 9, 5349.
(20) Product formation was monitored by gas chromatography.
10.1021/jo800382p CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4317–4319 4317

TABLE 1. Propargylic Oxidation Catalyzed by Rh2(cap)4 (1)a
SCHEME 1
mediated decomposition of TBHP, allowing oxidation on a
larger scale than was allowable in organic solvents.21
Upon closer inspection of the oxidation in water, we observed
that the reaction medium was biphasic in that the organic
substrate was insoluble in the water layer. Additionally, the
oxidized form of Rh2(cap)4 (Rh25+), identified by its a charac-
teristic deep red color, was almost completely dissolved in the
water. Analysis of the aqueous layer by UV-visible spectros-
copy revealed the characteristic signature of Rh25+ with λmax at
505 and 971 nm.22
Reaction optimization was attempted by performing a screen-
ing of inorganic salts based previous reports of the use of
additives in allylic and benzylic oxidations.4 Several salts were
detrimental to the reaction (Na2CO3, NaHSO4, Cs2CO3, and
K2CO3), and all others gave yields comparable to the that of
the oxidation without additive (NaCl, NaHCO3, H2KPO4,
HK2PO4 ·H2O).23 Overall, we found no significant improvement
to the original oxidation of 2 using base additives in water or
in organic solvent.
Given the effectiveness of the oxidation of 2 in water (Scheme
1), we employed the same conditions in a survey of other
propargylic substrates (Table 1). Entries 1-6 summarize the
results obtained with varying substitution on the acetylenic
terminus. When the alkyne is substituted with phenyl, tert-butyl,
trimethylsilyl, and n-propyl groups, the oxidation affords good
isolated yields of the resulting ynones (entries 1-4). In the
oxidation of 2-tridecyne (entry 5), the internal methylene is
selectively oxidized over the competing methyl group. Oxidation
of the terminal alkyne in entry 6 afforded the corresponding
ynone in only moderate yield, yet it was comparable to the yield
of this product in previously reported oxidations.8b,c,9d–f
The remaining entries in Table 1 showcase a sampling of
functionality tolerated under aqueous oxidation conditions. We
found that a pendant primary alcohol (entry 7) was compliant
to our conditions in only modest yield. When the same alcohol
was protected as a tert-butyldimethylsilyl (TBS) ether, the
protecting group was cleaved as a result of the slightly acidic
(pH 4-5) reaction medium, and a small amount of alcohol
oxidation products was observed.24 Using a more acid-tolerant
a Reactions were performed by addition of T-HYDRO (5.0 equiv) to a
vigorously stirred mixture of 1 (1.0 mol %) and the alkyne (1.0 equiv,
0.54 M) in water followed by heating to 40 °C. b Isolated yields after
column chromatography. c GC yield, as determined by internal standard.
d This oxidation was stirred at ambient temperature (25 °C).
protecting group to mask the alcohol (entry 8), the desired ynone
was cleanly furnished in much higher yield. Finally, the
Rh2(cap)4-catalyzed propargylic oxidation conditions were
amenable to both the pendant carboxylic acid in entry 10 and
the methyl ester in entry 11 (Table 1),25 whereas a previously
reported propargylic oxidation by TBHP was ineffective in the
presence of carboxylic acid functionality.9e
The biphasic nature of these oxidations allowed us to reuse
or “recycle” the catalyst by extraction of the Rh5+-containing
aqueous layer from one reaction for use in the next (Scheme
2). In this series of oxidations, 4 was treated under standard
conditions (1.0 mol % of 1, 5.0 equiv T-HYDRO, in water) to
afford 5 in 70% yield. Following extraction of 5 with ether, the
aqueous layer from the first reaction was drained into a vessel
containing 6 and an additional 5.0 equiv of the oxidant was
added to initiate the second oxidation. The product, 7, was
(21) Under the same aqueous conditions, we were able to scale the oxidation
by a factor of 8 (1 mmol of 4-octyne gave 79% isolated yield and 8 mmol of
4-octyne gave 75% isolated yield of 4-octyn-3-one).
(22) Catino, A. J.; Nichols, J. M.; Forslund, R. E.; Doyle, M. P. Org. Lett.
2005, 7, 2787.
(23) The experiment was performed with 4-octyne (2), 0.54 M in water, with
1 mol % Rh2(cap)4 (1) and 5 equiv of T-HYDRO. To each separate reaction
was added 1 equiv of the respective salt, and the mixture was then heated to
40°C for 1 h.
(25) The oxidation of an electron-deficient alkyne, 2-octynoic acid methyl
ester, was sluggish, proceeding in only 50% conversion and furnishing 30%
isolated yield of 3-oxo-2-octynoic acid methyl ester.
(24) The aldehyde and carboxylic acid were observed by 1H NMR.
4318 J. Org. Chem. Vol. 73, No. 11, 2008

SCHEME 2
SCHEME 3
pot, three-component transformation using ynone 12, ammonium
acetate, and tert-butyl acetoacetate was accomplished with
complete regiocontrol and in good yield.
In summary, we have developed an efficient oxidation of
alkynes to ynones employing a mild, inexpensive oxidant in
water. As a solvent, water not only is beneficial in terms of
sustainability but also has a positive effect on the reaction rate
in this oxidation. Additionally, using this method, the catalyst,
Rh2(cap)4 (1), is readily recycled for use in additional oxidations.
isolated in similar reaction time and in comparable yield.
Subsequently, we found that the resultant aqueous layer from
the formation of 7 was able to catalyze yet another oxidation.
However, in the oxidation of 2 a color change could be observed
in the aqueous layer, and the yield of 3 was diminished,
indicating the loss of the active dirhodium species, but only
after 1.0 mol % of 1 successfully catalyzed three different C-H
oxidations.
The aqueous propargylic oxidation was directly compared
to allylic3 and benzylic4 oxidations catalyzed by 1. From the
analysis of the initial rates of consumption of 9 and 10, the
reactivity of the propargylic substrate 9 was found to be
comparable to that for the benzylic substrate 10 under aqueous
oxidation conditions. In the comparison of 8 and 9, the
consumption of allylic substrate 8 proved to be considerably
faster than the consumption of 9 (Figure 1).
Experimental Section
General Procedure for Propargylic Oxidations Catalyzed
by Dirhodium(II) Caprolactamate in Water. The alkyne was
stirred vigorously in water (0.54 M with respect to the alkyne) at
room temperature in a screwcap vial. Rh2(cap)4 (1.0 mol %) was
added to the vial followed by dropwise (2 drops/s) addition of 5.0
equiv of T-HYDRO. The reaction was slightly exothermic, and the
mixture bubbled and became dark purple-red in color. The vial was
loosely capped and stirred at room temperature or heated to 40 °C
while being monitored by TLC and gas chromatography. Upon
consumption of the starting alkyne, the reaction was extracted twice
into diethyl ether. The organic extracts were combined, dried over
anhydrous MgSO4, filtered, and then concentrated under reduced
pressure to a crude oil, which was purified via silica gel chroma-
tography (hexanes/ethyl acetate) to afford the desired product.
Sample Characterization for 1-Phenyl-1-octyn-3-one (7). Rf
1
0.55 (10% ethyl acetate/hexanes); H NMR (400 MHz, CDCl3) δ
7.57 (comp, 2 H), 7.43 (comp, 1 H), 7.37 (comp, 2 H), 2.66 (dd,
J ) 7.6 7.6 Hz, 2 H), 1.75 (dq, J ) 7.6 Hz, 2 H), 1.37-1.33 (comp,
4 H), 0.92 (dd, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
188.3, 133.0, 130.6, 128.6, 120.0, 90.5, 87.8, 45.5, 31.1, 23.8, 22.4,
13.9; FTIR (thin film) 2960, 2928, 2199, 1669, 1488, 1280, 1132,
1072 cm-1. Exact mass calculated for C14H16O (EI) 200.1201, found
200.1201.
FIGURE 1. Relative initial reactivitya of C-H oxidation in allylic,
benzylic, and propargylic oxidation.b
Supporting Information Available: Procedures and full
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
With an assortment of R,ꢀ-acetylenic ketones in hand, we
demonstrated the utility of these compounds in the preparation
of two polysubstituted heterocycles (Scheme 3). In the first
example, ynone 7 was treated with sodium azide in DMF to
effect a rapid [3 + 2] cycloaddition to form the 4,5-disubstituted
acyl triazole 11 in moderate yield. We were also able to prepare
a 2,6-disubstituted nicotinic acid derivative 13 in one step using
a procedure adapted from Bagley and co-workers.16b This one-
Acknowledgment. We are grateful for financial support for
this research from the National Institutes of Health (GM 46503)
and the National Science Foundation.
JO800382P
J. Org. Chem. Vol. 73, No. 11, 2008 4319