Synthesis of α-keto-imides via oxidation of ynamides

Article abstract of DOI:10.1021/jo8015067

(Chemical Equation Presented) A de novo preparation of α-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO₂-NaIO₄ mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of α-keto-imides, the RuO₂-NaIO₄ protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO ₂-NaIO₄ protocol is not effective. These studies provide further support for the synthetic utility of ynamides.

Full text of DOI:10.1021/jo8015067

Synthesis of r-Keto-Imides via Oxidation of Ynamides
Ziyad F. Al-Rashid,*,† Whitney L. Johnson,† Richard P. Hsung,*,† Yonggang Wei,†
Pei-Yuan Yao,‡ Renhei Liu,‡ and Kang Zhao‡
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of Wisconsin, Madison,
Wisconsin 53705, and College of Pharmaceuticals and Biotechnology, Tianjin UniVersity,
Tianjin 300072, People’s Republic of China
zalrashid@alchemicalresearch.com; rhsung@wisc.edu
ReceiVed July 9, 2008
A de novo preparation of R-keto-imides via ynamide oxidation is described. With a number of alkyne
oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation
have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety
of R-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via
oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective
oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO2-NaIO4
protocol is not effective. These studies provide further support for the synthetic utility of ynamides.
Introduction
tion via copper mediated amidation of bromoalkynes2c-i along
with the recently reported amidations of terminal acetylenes2b
have tolerated a variety of amide types and alkyne func-
tionality,2e,g,3,12 providing access to a wide variety of ynamides.
Building on this versatile synthon, we pursued a highly efficient
In our efforts to explore the reactivity of ynamides and to
establish their utility as versatile synthons,1-4 we arrived at
R-keto-imides5 (see 1a in Scheme 1), a hitherto underrepresented
chemical entity. Literature precedents on the engagement of
R-keto-imides toward diastereoselective outcomes,6 as well as
a significant body of literature surrounding the structurally
related R-keto-amides (1b) and esters (1c),7-11 prompted us to
pursue an optimized entry to these molecules. Ynamide prepara-
(3) For recent references on the chemistry of ynamides, see: (a) Istrate, F. M.;
Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz, F. Org. Lett. 2008, 10,
925. (b) Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49, 1745. (c)
Mart´ınez-Espero´n, M. F.; Rodr´ıguez, D.; Castedo, L.; Saa´, C. Tetrahedron 2008,
64, 3674. (d) Yavari, I.; Sabbaghan, M.; Hosseini, N.; Hossaini, Z. Synlett 2007,
20, 3172. (e) Hashimi, A. S. K.; Salathe, R.; Frey, W. Synlett 2007, 1763. (f)
Rodr´ıguez, D.; Mart´ınez-Espero´n, M. F.; Castedo, L.; Saa´, C. Synlett 2007, 1963.
(g) Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819. (h) Tanaka, K.; Takeishi,
K. Synthesis 2007, 2920.
(4) For our recent work on ynamides, see: (a) Yao, P.-Y.; Zhang, Y.; Hsung,
R. P.; Zhao, K. Org. Lett. 2008, 10, 4275. (b) Zhang, X.; Hsung, R. P.; Li, H.;
Zhang, Y.; Johnson, W. L.; Figueroa, R. Org. Lett. 2008, 10, 3477. (c)
Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao, P.-Y.; Liu,
R.; Zhao, K. Org. Lett. 2007, 9, 2361. (d) Oppenheimer, J.; Hsung, R. P.;
Figueroa, R.; Johnson, W. L. Org. Lett. 2007, 9, 3969. (e) You, L.; Al-Rashid,
Z. F.; Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007,
1656. (f) Li, H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung, R. P.
Heterocycles 2007, 74, 553. (g) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun.
2007, 2420.
† University of Wisconsin.
‡ Tianjin University.
(1) For reviews on ynamides, see: (a) Katritzky, A. R.; Jiang, R.; Singh,
S. K. Heterocycles 2004, 63, 1455. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung,
R. P. Synlett 2003, 1379. (c) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575. (d) For a special
issue dedicated to the chemistry of ynamides, see: Tetrahedron-Symposium-In-
Print: “Chemistry of Electron-Deficient Ynamines and Ynamides.” Tetrahedron
2006, 62, Issue No.16.
(2) For synthesis of ynamides, see: (a) Tracey, M. R.; Hsung, R. P.; Antoline,
J. A.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In Science of Synthesis,
Houben-Weyl Methods of Molecular Transformations, Weinreb, S. M., Ed.; Georg
Thieme Verlag KG: Stuttgart, Germany, 2005; Chapter 21.4. (b) Hamada, T.;
Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (c) Sagamanova, I. K.;
Kurtz, K. C. M.; Hsung, R. P. Org. Synth. 2007, 84, 359. (d) Kohnen, A. L.;
Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88. (e) Zhang, X.; Zhang,
Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.;
Sagamanova, I. K.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170. (f) Riddell,
N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681. (g) Zhang, Y.; Hsung,
R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151. (h)
Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011. (i) Frederick, M. O.;
Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen,
L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368.
(5) For the communication relevant to this paper, see: Al-Rashid, Z. F.;
Hsung, R. P. Org. Lett. 2008, 10, 661.
(6) For preparations and reactions of R-keto-imides, see: (a) Kosior, M.;
Asztemborska, M.; Jurczak, J. Synthesis 2004, 1, 87. (b) Chen, J.-H.; Venkate-
sham, U.; Lee, L.-C.; Chen, K. Tetrahedron 2006, 62, 887. [also see ref 20]. (c)
Hsu, H.-L.; Wu, H.-L.; Venkatesham, U.; Chen, K.-M. J. Chin. Chem. Soc. 2006,
53, 449. (d) Raszplewicz, K.; Sikorska, L.; Kiegiel, K.; Jurczak, J. Pol. J. Chem.
2002, 76, 1595. (e) Kudyba, I.; Raczko, J.; Jurczak, J. Synthesis 2004, 8, 1147.
8780 J. Org. Chem. 2008, 73, 8780–8784
10.1021/jo8015067 CCC: $40.75 2008 American Chemical Society
Published on Web 10/21/2008

Synthesis of R-Keto-Imides
SCHEME 1. Ynamide-Derived r-Keto-Imides
SCHEME 2. r-Keto-Imide Formation RhCl(PPh3)3-AgBF4
SCHEME 3. DMDO Oxidation of Ynamides
oxidative protocol transforming a range of ynamide types to
access a structurally diverse array of R-keto-imides.
The limited literature involving R-keto-imides confirms their
utility as synthons with the potential of incorporating elements
of stereocontrol. Some examples are successes in hetero-
Diels-Alder reactions,6a an intriguing divergent diastereose-
lective allylation,6b diastereoselective cyanation,6c and Grignard
additions.6d In these reports, preparations of R-keto-imides were
accomplished by amidation of R-keto-acids, or by ozonolytic
or osmium mediated oxidative cleavage of acrylimides. Al-
though there is a compelling parallel between R-keto-imides
1a and the related R-keto-amides (1b) and esters (1c), the latter
has attracted much more synthetic interest as is evident from
an array of elegant solutions to their construction,8 including
seminal work on oxidations of ynamines7a-d that is related to
the efforts described herein, as well as advances in their ap-
plications as synthons,9 and a greater understanding of their role
as pharmacophores.10
The underlying reactivity of R-keto-amides (1b) and esters
(1c) stems from the enhanced electrophilicity of their respective
keto carbonyl group. Transformations of these compounds have
involved the addition of nucleophiles9a with particular interest
placed on attaining stereochemical control through a chirality-
inducing element substituted on the oxygen or nitrogen atom.
It is noteworthy that R-keto-amides 1b have also been engaged
in pinacol-type couplings9b as well as photocyclizations leading
to ꢀ-lactams.9c In the biological setting, this reactivity is
implicated in the engagement of key cysteine and lysine residues
important to protease,10a-d lipase,10e and histone deacetylase
activity.10f Facile hydrate formation of the R-keto carbonyl,
which serves as a transition state mimic of the tetrahedral
intermediates associated with amide and ester hydrolysis, has
also been associated with enzyme inhibitory activity.10b Given
the close analogy between R-keto-imides 1a and R-keto-amides
or esters (1b or 1c), access to R-keto-imides should prove to
be of significance in organic synthesis and medicinal chemistry.
We wish to report here highly efficient oxidative transformations
of ynamides to novel R-keto-imides.
been correlated with the use of contaminated/decomposed
samples of Wilkinson’s catalyst containing triphenylphosphine
oxide.
A more consistent entry to R-keto-imides from ynamides
became apparent during our exploration of the dimethyldioxirane
(DMDO) oxidation of ynamides 4 (Scheme 3).5 We were
interested in probing the possibility of arriving at push-pull
carbenes 5 derived from the oxidation of 1 through the
rearrangement of presumed oxirenes A. This event was con-
firmed by the isolation of push-pull carbene-derived cyclo-
propanes 6. The formation of R-keto-imides 7 was often a
competing outcome of these reactions, presumably resulting
from a second oxidation of the carbenes 5, although oxidation
of oxirenes A to 1,3-dioxabicyclobutanes 8 followed by rear-
rangement to R-keto-imides 7 cannot be ruled out.
Persuing the purposeful preparation of R-keto-imides, we
examining a number of alkyne oxidation conditions of ynamide
9 (Table 1). In addition to DMDO oxidation,5,13 R-keto-imide
10 formation could be achieved by the action of ozone,7b-d
m-CPBA,14 and RuO4 generated in situ from either RuO2 or
RuCl3.7a,15 We also examined the action of I2 in DMSO,16 as
well as CuCl2 in DMSO17 at elevated temperatures (150 °C);
however, no evidence of R-keto-imide 10 was found, with
(7) For accounts on R-keto-amide formation from RuO4 oxidation of
ynamines, see: (a) Mu¨ller, P.; Godoy, J. Tetrahedron Lett. 1982, 23, 3661. For
oxidations of ynamines or push-pull ynamines employing ozone and oxygen,
see: (b) Schank, K.; Beck, H.; Werner, F. HelV. Chim. Acta 2000, 83, 1611 (this
reference includes detailed mechanistic consideration). (c) Schank, K.; Beck,
H.; Himbert, G. Synthesis 1998, 1718. (d) Foote, C. S.; Lin, J. W.-P. Tetrahedron
Lett. 1968, 29, 3267. For leading accounts on R-keto-ester formation from
oxidation of ynol-ethers, see: (e) Tatlock, J. H. J. Org. Chem. 1995, 60, 6221.
(f) Bassignani, L.; Brandt, A.; Caciagli, V.; Re, L. J. Org. Chem. 1978, 43,
4245.
(8) For other elegant strategies on R-keto-amide and ester formation, see:
(a) Chen, J.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509. (b) Hua, R.; Takeda,
H.-A.; Abe, Y.; Tanaka, M. J. Org. Chem. 2004, 69, 974. (c) Chen, J. J.;
Deshpande, S. V. Tetrahedron Lett. 2003, 44, 8873. (d) Bolm, C.; Kasyan, A.;
Heider, P.; Saladin, S.; Drauz, K.; Gu¨nther, K.; Wagner, C. Org. Lett. 2002, 4,
2265. (e) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org.
Lett. 2002, 4, 1103. (f) Uozumi, Y.; Arii, T.; Watanabe, T. J. Org. Chem. 2001,
66, 5272. (g) Wong, M.-K.; Yu, C.-W.; Yuen, W.-H.; Yang, D. J. Org. Chem.
2001, 66, 3606. (h) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59,
4364.
(9) For reactions of R-keto-amides and esters, see: (a) Young, S. W.; Kim,
Y. H.; Hwang, J.-W.; Do, Y. Chem. Commun. 2001, 996. (b) Kim, S. M.; Byun,
I. S.; Kim, Y. H. Angew. Chem., Int. Ed. 2000, 39, 728. (c) Hashizume, D.;
Kogo, H.; Sekine, A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem. Soc., Perkin
Trans. 2 1995, 61. (d) Corey, E. J.; McCaully, R. J.; Sachdev, H. S. J. Am.
Chem. Soc. 1970, 92, 2476.
Results and Discussion
Our first experiences with R-keto-imides arose from studies
aimed at the preparation of benzofurans via a Rh(I)-catalyzed
demethylation-cyclization of o-anisole-substituted ynamides
such as 2 (Scheme 2).4c While not highly reproducible, R-keto-
imide 35 could be obtained in 45% yield by exposure of ynamide
2 to the action of Wilkinson’s catalyst and AgBF4, and an X-ray
structure of R-keto-imide 35 was also attained (see the Sup-
porting Information). Although we have not identified the
stoichiometric oxidant involved, R-keto-imide formation has
J. Org. Chem. Vol. 73, No. 22, 2008 8781

Al-Rashid et al.
TABLE 1. Conditions for r-Keto-Imide Formation
TABLE 2. RuO2-NaIO4 Mediated Oxidation
entry
conditions
DMDO, acetone, rt, 2.5 h
(1) O3, CH2Cl2, -78 °C to rt, 2 h; (2) DMS
m-CPBA, CH2Cl2, rt, 2.5 h
RuO2 ·H2O, NalO4, CH2Cl2, CH3CN, H2O, rt, 4 h
RuCl3 ·H2O, NalO4, CH2Cl2, CH3CN, H2O, rt, 4 h
I2, DMSO, 150 °C, 1 h
yield [%]a
1
2
3
4
5
6
7
86%
70%
trace
96%
99%
ndb
CuCl2, DMSO, 150 °C, 24 h
nd
a Isolated yields. b Not detected.
complete consumption of the starting ynamide 9 (entries 6 and
7). Oxidation by DMDO18 provided the R-keto-imide in 86%
isolated yield (entry 1) with ∼5% yield of what appears to be
the corresponding R-keto-carboxylic acid accompanied by the
free Evans’ oxazolidinone auxiliary. The stability of R-keto-
imides in wet acetone suggests that the formation of R-keto-
carboxylic acid does not occur by a simple event of hydrolyzing
the respective imide motif.5 We are currently still investigating
this mechanistic issue. m-CPBA oxidation provided only trace
amounts of 10 (entry 3).19 The RuO4 mediated oxidation quickly
became the method of choice, yielding 10 in quantitative yields
(entries 4 and 5).
We proceeded to examine the scope of RuO2-NaIO4 medi-
ated oxidation varying ynamide electronic properties (Table 2).
The ynamides examined varied in the nature of the electron
withdrawing group on nitrogen, as well as the electron
withdrawing or donating ability of the alkyne substituent (entries
4-6). All oxidations proceeded in moderate to high yield, and
the resulting R-keto-imides tolerated routine laboratory handling
such as purification and storage. In addition to facile preparation
of a variety of R-keto-imides, this method provides ready access
a 5 mol % of RuO2 ·H2O, 3 equiv of NaIO4, CH2Cl2/CH3CN/H2O, rt,
4 h. b Isolated yields.
to the vicinal tricarbonyl motif as in 20 and 21 (entries 4 and
5) with long standing chemical and biological intrigue,20 and
these preparations also showcase the synthetic utility of so-called
push-pull ynamides 14 and 15. Imido acylsilanes such as 22
(entry 6) should be poised for umpolung chemistry elegantly
demonstrated by Johnson’s tandem alkylation-aldolizations of
silylglyoxylates.11
We then examined the preparation of R-keto-imides from
ynamides with varied alkyne substitution and compared DMDO
and RuO2-NaIO4 conditions (Table 3). Throughout this series,
the RuO2-NaIO4 mediated oxidation provided higher yields
of the doubly oxidized products. Increasing steric bulk sur-
rounding the alkyne (from entries 1-4) was well tolerated by
both methods, and is accompanied by increased yields under
DMDO oxidation conditions (remainder of the material is
(10) For accounts examining the biological activity of R-keto-amides see:
(a) Angelastro, M. R.; Mehdi, S.; Burkhart, J. P.; Peet, N. P.; Bey, P. J. Med.
Chem. 1990, 33, 11. (b) Ocain, T. D.; Rich, D. H. J. Med. Chem. 1992, 35, 451.
(c) Li, Z.; Patil, G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J. E.;
Eveleth, D. D.; Bartus, R. T.; Powers, J. C. J. Med. Chem. 1993, 36, 3472. (d)
Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Smith, S. A.; Petrillo,
E. W., Jr. J. Med. Chem. 1993, 36, 2431. (e) Chiou, A.; Markidis, T.;
Constantinou-Kokotou, V.; Verger, R.; Kokotos, G. Org. Lett. 2000, 2, 347. (f)
Wada, C. K.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Garland, R. B.; Holms, J. H.; Li,
J.; Pease, L. J.; Guo, J.; Glaser, K. B.; Marcotte, P. A.; Richardson, P. L.; Murphy,
S. S.; Bouska, J. J.; Tapang, P.; Magoc, T. J.; Albert, D. H.; Davidsen, S. K.;
Michaelides, M. R. Bioorg. Med. Chem. Lett. 2003, 13, 3331.
(11) For reactions of silylglyoxylates see: (a) Nicewicz, D. A.; Johnson, J. S.
J. Am. Chem. Soc. 2005, 127, 6170, also see the Supporting Information. (b)
Linghu, X.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128, 9302.
(12) (a) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.
(b) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A.
Org. Lett. 2005, 7, 1047.
(16) For an account of I2/DMSO mediated alkyne double oxidation, see:
Yusybov, M. S.-O.; Filimonov, V. D. Synthesis 1991, 131.
(17) We attempted these conditions because of an intriguing observation:
During the preparation of ynamide 13, an extended reaction time of 24 h (rather
than 4 h) employing Stahl’s amidation conditions [see ref 2b] with stoichiometric
CuCl2 in DMSO under O2 led to the isolation of ∼7% yield of a mixture of
ynamide 13 and R-keto-imide 19 with a ratio of 1.4:1 [see Table 2 for struc-
tures].
(13) For DMDO-oxidation of alkynes, see: (a) Zeller, K.-P.; Kowallik, M.;
Haiss, P. Org. Biomol. Chem. 2005, 3, 2310 (this reference includes detailed
mechanistic consideration). (b) Murray, R. W.; Singh, M. J. Org. Chem. 1993,
58, 5076. (c) Curci, R.; Fiorentino, M.; Fusco, C.; Mello, R.; Ballistreri, F. P.;
Failla, S.; Tommaselli, G. A. Tetrahedron Lett. 1992, 33, 7929.
(14) For accounts of peroxyacid oxidation of acetylenes, see: (a) Stille, J. K.;
Whitehurst, D. D. J. Am. Chem. Soc. 1964, 86, 4871. (b) McDonald, R. N.;
Schwab, P. A. J. Am. Chem. Soc. 1964, 86, 4866.
(18) DMDO/acetone solutions were prepared following the procedure reported
in: (a) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J. Am. Chem.
Soc. 2001, 123, 7174. Also see: (b) Murray, R. W.; Singh, M.; Marron, T. G.;
Pfeifer, L. A.; Roush, W. R. Org. Synth. 1997, 74, 91.
(19) Further Baeyer-Villiger type oxidation of 1,2-dicarbonyls is known to
occur under ozone and peroxyacid oxidation conditions [see refs 7b-d and 14].
Although inconclusive, the presence of byproduct benzoyl and phenyl ester-
type aromatic proton resonances in the crude 1H NMR spectra resulting from
the oxidation of ynamide 9 under these conditions suggests this course of action.
(20) For an excellent review on the chemistry of vicinal tricarbonyls and
related systems, see: Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687.
(15) For lead references on ruthenium mediated alkyne oxidation, see: (a)
Zibuck, R.; Seebach, D. HelV. Chim. Acta 1988, 71, 237. (b) Pattenden, G.;
Tankard, M.; Cherry, P. C. Tetrahedron Lett. 1993, 34, 2677. For recent
applications see: (c) Semmelhack, M. F.; Campagna, S. R.; Federle, M. J.;
Bassler, B. L. Org. Lett. 2005, 7, 569. (d) Herrera, A. J.; Rondo´n, M.; Sua´rez,
E. J. Org. Chem. 2008, 73, 3384. For a recent review, see: (e) Plietker, B.
Synthesis 2005, 15, 2453 (this review presents the suggested mechanism for
RuO4 mediated alkyne oxidation).
8782 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of R-Keto-Imides
TABLE 3. RuO2-NaIO4 versus DMDO Oxidation
TABLE 4. Chemoselectivity in Oxidatively Sensitive Ynamides
a 4 equiv of DMDO, acetone, rt, 2.5 h. b Isolated yields. c Also
isolated ∼33% yield of the epoxidized R-keto-imide.
N-sulfonyl-substituted ynamides 31 and 32 also did not yield
the respective R-keto-imides 4123 and 42.22
a Isolated yields. b 4 equiv of DMDO, acetone, rt, 2.5 h. c 5 mol % of
RuO2 ·H2O, 3 equiv of NaIO4, CH2Cl2/CH3CN/H2O, rt, 4 h. d See ref 5.
e
1
The last class of ynamides examined were those containing
a tethered olefin (Table 4). Ynamide oxidation employing
RuO2-NaIO4 led to the formation of a large number of higher
polarity products (SiO2 TLC analysis), attributed to alkene
dihydroxylation and further cleavage reactions,24 as well as the
potential for ketal and hemiketalization of the resulting dihy-
droxy-keto-imides. In these cases, DMDO oxidation proceeded
with chemoselective oxidation of the ynamide moeity. All the
olefinic motifs in these substrates were stable to DMDO
oxidation except for the relatively more electron rich styryl
group in 45 (entry 3), which suffered from competitive
epoxidation. In addition, for entries 1-4 and 6, we observed a
noticeable amount of the free oxazolidinone auxiliary, thereyby
Not detected by TLC or H NMR.
hydrolyzed). Both the TBS-silyl ether and THP acetal protect-
ing groups, as well as the N-tosyl group, are tolerated under
reaction conditions (see 27f37 and 28f38 in respective entries
5 and 6). The yield of R-keto-imide 38 suffers from elimination
of the O-THP group (entry 6).21 High yields of triethylsilyl
imido acylsilanes 39 and 40 were obtained employing the
RuO2-NaIO4 conditions (entries 7 and 8). The preparation of
these less hindered silanes (relative to triisopropylsilane 22 in
Table 2) was pursued due to their added susceptibility toward
engagement of the acylsilane.11 In contrast, the DMDO oxida-
tion of silylated ynamides 29 and 30 did not provide any trace
of imido acylsilanes 39 and 40.22 DMDO oxidation of both
(22) Silicon d-orbital overlap with the carbene may result a silyl-push-pull
carbene [see 5 in Scheme 3 with R ) SiR3] that is susceptible to undergo Wolff
rearrangement and subsequent transformations through the resulting silyl ketene
intermediate. Further studies are underway.
(23) We observed loss of the N-sulfonyl group during DMDO oxidations
of N-sulfonyl-substituted ynamides such as 31 [also observed for 11 shown
in Table 2].
(21) Minor amounts of the corresponding enone i apparent by 1H NMR.
(24) For a lead reference on ruthenium mediated alkene oxidation see: (a)
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem.
1981, 46, 3936. For a recent application see: (b) Neisius, N. M.; Plietker, B. J.
Org. Chem. 2008, 73, 3218.
J. Org. Chem. Vol. 73, No. 22, 2008 8783

Al-Rashid et al.
967 m; mass spectrum (APCI) m/e (% rel intensity) 258 (10) (M
+ 1)+, 202 (90), 172 (100), and 128 (25); HRMS (ESI) m/e calcd
for C11H20NO4Si+ (M + H+) 258.1156, found 258.1146.
suggesting the formation of the corresponding R-keto-carboxylic
acid.5 Intramolecular cyclopropanation through intermediate
push-pull carbenes 55 (Scheme 3) was not oberved in any of
these reactions.
General Procedure for DMDO Oxidation of Ynamides. To a
solution of ynamide 49 (45.4 mg, 0.167 mmol) in acetone (12 mL)
was added DMDO (6.0 mL, 0.11 M in acetone, 4 equiv)18,25 at rt.
The resulting reaction mixture was stirred for 2.5 h before it was
filtered through Celite, rinsed with CH2Cl2, and concentrated in
vacuo. The crude residue was purified by silica gel flash column
chromatography [gradient elution: 17-67% EtOAc in hexanes] to
provide R-keto-imide 56 as a yellow crystalline solid (44.6 mg,
88% yield). Rf 0.33 [67% EtOAc in hexanes]; mp 152.0-153.0
Conclusion
We have described here efficient preparations of R-keto-
imides through oxidations of ynamides. Both RuO2-NaIO4 and
DMDO oxidations tolerate a wide range of ynamide types and
substituents. In addition to facile preparation of a variety of
R-keto-imides, the RuO2-NaIO4 mediated oxidation provides
ready access to the vicinal tricarbonyl motif via the oxidation
of push-pull ynamides as well as imido acylsilanes via the
oxidation of silylated ynamides. The RuO2-NaIO4 protocol
does, however, lead to complex mixtures during the oxidation
of olefin containing ynamides. In these cases, the chemoselective
oxidation of such ynamides can be achieved by employing
DMDO. We believe these protocols provide practical access to
a class of building blocks that will be significant in synthesis.
1
°C; H NMR (500 MHz, CDCl3) δ 2.17 (m, 2H), 2.52 (br s, 2H),
3.83 (t, 2H, J ) 7.5 Hz), 3.85 (s, 3H), 4.49 (ddd, 2H, J ) 6.0, 1.0,
1.0 Hz), 5.33 (ddt, 1H, J ) 10.5, 1.0, 1.0 Hz), 5.39 (ddt, 1H, J )
17.5, 1.5, 1.5 Hz), 5.96 (ddt, 1H, J ) 17.5, 10.5, 6.0 Hz), 6.39 (d,
1H, J ) 2.0 Hz), 6.63 (dd, 1H, J ) 9.0, 2.5 Hz), and 8.04 (d, 1H,
J ) 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 18.5, 32.1, 43.6, 55.9,
70.1, 99.2, 107.1, 116.4, 119.7, 132.3, 132.8, 161.1, 166.5, 168.1,
175.7, and 186.1; IR (film) cm-1 3079 w, 2938 w, 2899 w, 2852 w,
1738 m, 1673 m, 1656 m, 1595 s, 1575 m, 1504 m, 1447 m,
1421 m, 1363 s, 1286 m, 1251 s, 1231 s, 1204 s, 1175 m, 1115 m,
993 s, 909 m, and 837 m; mass spectrum (APCI) m/e (% rel
intensity) 304 (65) (M + 1)+ and 191 (100); HRMS (MALDI) m/e
calcd for C16H17NO5Na+ (M + Na+) 326.0999, found 326.0998.
Experimental Section
General Procedure for RuO2-NaIO4 Mediated Oxidation
of Ynamides. To a solution of ynamide 29 (377.0 mg, 1.670 mmol,
1 equiv) in CH2Cl2 (5 mL) and CH3CN (5 mL) was added NaIO4
(1.07 g, 5.02 mmol, 3 equiv) in H2O (7.5 mL), and then RuO2 ·H2O
(11.2 mg, 0.0840 mmol, 5 mol %). The reaction mixture was stirred
vigorously at rt, and the reaction progress was followed by thin
layer chromatography. The sides of the reaction flask were rinsed
with CH3CN (∼1 mL) at 2 h, and the reaction was stirred for
another 2 h. The reaction mixture was then filtered through a plug
of SiO2 rinsing with CH2Cl2. Further purification was accomplished
by silica gel flash column chromatography [gradient elution:
17-50% EtOAc in hexanes] to afford R-keto-imide 39 as a bright
yellow oil (386.0 mg, 90% yield). Rf 0.41 [50% EtOAc in hexanes];
1H NMR (500 MHz, CDCl3) δ 0.83 (q, 6H, J ) 8.0 Hz), 1.03 (t,
9H, J ) 8.0 Hz), 4.02 (m, 2H), and 4.59 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 2.3, 7.1, 41.1, 64.7, 154.2, 171.5, and 232.8; IR
(neat) cm-1 2958 w, 2914 w, 2879 w, 1780 s, 1681 s, 1642 m,
1478 w, 1390 s, 1361 m, 1335 m, 1226 s, 1117 m, 1028 m, and
Acknowledgment. The authors thank the NIH [GM066055]
and University of Wisconsin for support. We thank Dr. Haibing
Song at Nankai University for solving single-crystal X-ray
structure.
Supporting Information Available: Experimental proce-
1
dures, characterization data for all new compounds, H NMR,
13C NMR spectra, and X-ray structural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8015067
(25) DMDO/acetone concentration determined by 1H NMR analysis of the
crude residue resulting from the reaction (1 h, rt) of a known volume of DMDO/
acetone with an excess of thioanisole in Et2O (0.2 M), comparing the integration
values corresponding to the proton peaks belonging to the remaining thioanisole
and the resulting methyl phenyl sulfoxide.
8784 J. Org. Chem. Vol. 73, No. 22, 2008