Reactive intermediates from DMDO oxidation of ynamides. Trapping of a de novo chiral push-pull carbene via cyclopropanation

Article abstract of DOI:10.1021/ol703083k

The reaction profile of DMDO oxidations of ynamides is described. This work illustrates the first examples of highly diastereoseiective intramolecular cyclopropanations of a push-pull carbene derived from alkyne oxidation. In addition, the ynamide oxidati

Full text of DOI:10.1021/ol703083k

ORGANIC
LETTERS
2008
Vol. 10, No. 4
661-663
Reactive Intermediates from DMDO
Oxidation of Ynamides. Trapping of a de
novo Chiral Push
−Pull Carbene via
Cyclopropanation
Ziyad F. Al-Rashid and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received December 21, 2007
ABSTRACT
The reaction profile of DMDO oxidations of ynamides is described. This work illustrates the first examples of highly diastereoselective
intramolecular cyclopropanations of a push pull carbene derived from alkyne oxidation. In addition, the ynamide oxidation provides facile
access to ketoimides and reveals mechanistic insights into the chemistry of electronically biased oxirenes.
−
Oxocarbene intermediates derived from epoxidations of
alkynes have been strongly suggested to arise from the
rearrangement of oxirenes.1 Subsequent transformations of
the oxocarbenes include Wolff rearrangement and further
reaction of the resultant ketene, C-H insertion, hydrogen
or alkyl migration, secondary oxidation, and formation of
stable metalla-keto carbene complexes.2 Despite unleashing
a remarkable array of transformations through a simple
π-bond oxidation, little has been reported on engaging this
potential toward precise ends.1 Ynamides,3 a class of
electron-rich and electronically biased alkynes, are uniquely
positioned for the tuning of such reactivity.
The postulated oxirenes 2 derived from an oxidation of
ynamides 14 could rearrange to amido-oxocarbene 3 or
push-pull carbene 4, the latter experiencing dual stabiliza-
tion5 (Scheme 1). While amido-oxocarbenes 3 have been
represented by related diazo compound decomposition reac-
tions,6 push-pull carbenes 4 represent a novel species that
is intriguing both in reactivity and in synthetic potential.7
(4) For oxidations of ynamines employing ozone and oxygen, see: (a)
Foote, C. S.; Lin, J. W.-P. Tetrahedron Lett. 1968, 9, 3267. (b) Schank,
K.; Beck, H.; Himbert, G. Synthesis 1998, 1718. (c) During our submission
of this work, an account on epoxidation of ynamides appeared. See: Couty,
S.; Meyer, C.; Cossy, J. Synlett 2007, 18, 2819 (received July 28, 2007).
(d) For our preliminary disclosure of this work, see: Al-Rashid, Z. F.;
Hsung, R. P.; Antoline, J. E.; Ko, C.; Wei, Y.; Yang, J. 40th ACS National
Organic Symposium, Durham, NC, June 3, 2007; Abstract No. A-11.
(5) For push-pull carbene stability and reactivity, see: (a) Buron, C.;
Gornitzka, H.; Romanenko, V.; Bertrand, G. Science 2000, 288, 834. (b)
Moss, R. A.; Zdrojewski, T.; Ho, G.-J. J. Chem. Soc., Chem. Commun.
1991, 946. For elegant work on donor-acceptor metal carbenoids, see: (c)
Hedley, S. J.; Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.; Davis, H.
M. L. J. Org. Chem. 2006, 71, 5349. (d) Davis, H. M. L.; Hedley, S. J.
Chem. Soc. ReV. 2007, 36, 1109.
(1) For reviews on oxirenes, see: (a) Zeller, K. P. Sci. Synth. 2002, 9,
19. (b) Lewars, E. G. Chem. ReV. 1983, 83, 519. (c) Torre, M.; Lown, E.
M.; Gunning, H. E.; Strauzz, O. P. Pure Appl. Chem. 1980, 52, 1623.
(2) For an example of metal keto carbenoid formation by DMDO
oxidation of alkynes, see: Sun, S.; Edwards, J. O.; Sweigart, D. A.;
D’Accolti, L.; Curci, R. Organometallics 1995, 14, 1545.
(3) For a review, see: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
10.1021/ol703083k CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/17/2008

cyclopentene out competed the ynamide for DMDO. While
not informative concerning the parent carbenes, amidoglyoxal
8 and ketoimides 9-12 could be obtained in good yields
and represent potentially useful synthons.11
Scheme 1
To continue probing for the proposed oxocarbenes, we
examined intramolecular systems. As shown in Scheme 3,
Scheme 3
Were such a carbene to arise, one may expect promiscuity
with respect to the reactive partners it may choose (electron-
rich versus electron-deficient).5b We report here the first
epoxidation of ynamides 1 and trapping of novel chiral
push-pull carbenes 4 via intramolecular cyclopropanations.8
Our efforts commenced with dimethyldioxirane (DMDO)
oxidation of terminally unsubstituted ynamide 7 (Scheme 2).
Scheme 2
oxidation of ynamide 13 provided amido-cyclopropane 14
in a 3:1 isomeric ratio with 14-major being confirmed by
X-ray crystal analysis. Ketoimide 15 was also obtained, but
its formation appears to decrease at elevated temperatures.
The competing intermolecular DMDO oxidation of the
proposed oxocarbenes was further suppressed by dilution.
Oxidation of 4,5-diphenyl oxazolidinone-substituted ynamide
16 provided amido-cyclopropane 17 as a single diastereomer.
The respective ketoimide 18, free auxiliary 19, and ketoacid
20 were also identified. The formations of 19 and 20 are
likely mutually related.
To account for all the observed products, a comprehensive
reaction profile for the oxidation of ynamides is shown in
Figure 1. Amido-cyclopropanes 14 and 17 unambiguously
confirm the presence of push-pull carbenes 4. The major
stereoisomer is likely derived from cyclopropanations of
oxocarbenes 4 assuming a conformation that accommodates
both the nitrogen electron pair donation (pink) to the carbene
empty p-orbital (red) and delocalization of the carbene
electron pair into the keto carbonyl group (green), while the
oxazolidinone carbonyl is anti to the carbene lone pair.
Ketoimide formation can be rationalized through a second
DMDO oxidation of oxocarbene intermediates 4 (or 3),10a
although a pathway involving dioxabicyclobutane 21 cannot
be ruled out. The stability of ketoimides 15 in acetone/water
suggests ketoacids 20 do not arise simply by hydrolysis.
While initial reaction analysis was complicated by partition-
ing of the resulting amidoglyoxal 89 with its hydrate
(confirmed by X-ray), it became clear that (1) ynamide
oxidation could be achieved and is relatively faster than
reported alkyne oxidations;10 (2) oxidation of the proposed
oxocarbenes proceeded at a faster rate than cyclopropanation
of cyclohexenone, even when DMDO concentrations were
limited by syringe pump addition; (3) electron-rich olefin
(6) (a) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse, R. A.
J. Org. Chem. 1985, 50, 1663. (b) Doyle, M. P.; Kalinin, A. V. Synlett
1995, 1075. (c) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.; Wang, J. J.
Org. Chem. 2003, 68, 893.
(7) For some examples of related R-azacarbenoids, see: (a) Scho¨llkopf,
U.; Hauptreif, M.; Dippel, J.; Nieger, M.; Egert, E. Angew. Chem., Int. Ed.
Engl. 1986, 25, 192. (b) Rigby, J. H.; Cavezza, A.; Heeg, M. J. Tetrahedron
Lett. 1999, 40, 2473. (c) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004,
69, 1262. (d) Be´gis, G.; Sheppard, T. D.; Cladingboel, D. E.; Motherwell,
W. B.; Tocher, D. A. Synthesis 2005 3186. For elegant examples of
R-azametallo-carbenoids, see: (e) Hegedus, L. S. Tetrahedron 1997, 53,
4105. (f) Hegedus, L. S.; Lastra, E.; Narukawa, Y.; Snustad, D. C. J. Am.
Chem. Soc. 1992, 114, 2991. (g) Powers, T. S.; Wulff, W. D.; Quinn, J.;
Shi, Y.; Jiang, W. Q.; Hsung, R. P.; Parisi, M.; Rahm, A.; Jiang, X. W.;
Yap, G. A.; Rheingold, A. L. J. Organomet. Chem. 2001, 617, 182.
(8) For leading reviews, see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (b) Gnad, F.; Reiser, O.
Chem. ReV. 2003, 103, 1603.
(10) For DMDO oxidation of alkynes, see: (a) Zeller, K.-P.; Kowallik,
M.; Haiss, P. Org. Biomol. Chem. 2005, 3, 2310. (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.
(11) For some examples, see: (a) Kim, S. M.; Byun, I. S.; Kim, Y. H.
Angew. Chem., Int. Ed. 2000, 39, 728. (b) Corey, E. J.; McCaully, R. J.;
Sachdev, H. S. J. Am. Chem. Soc. 1970, 92, 2476.
(9) See Supporting Information.
662
Org. Lett., Vol. 10, No. 4, 2008

ynamide 24d only to find ketoimide 27d as the sole product.13
A tether dependence reported in enyne cycloisomerizations14
prompted our investigation of the oxidation of nitrogen-
tethered ynamide 24e. In this case, amido-cyclopropane 26e
was isolated in 41% along with ketoimide 27e with no traces
of bicyclo[3.1.0]hexane 25.
While amido-oxocarbenes 3 cannot be ruled out, these
experiments further demonstrated the tendency for ynamide
oxidation to yield cyclopropane products exclusively arising
from push-pull carbenes 4, thereby suggesting either a
strong bias in the rearrangement of oxirenes 2 or a pathway
that does not involve an oxirene. Electrophilic substitution
of ynamides 28 could occur preferentially at the â-position,3a
as is conveyed by the electronic distribution in resonance
structure 29 (Figure 2). This in turn could lead to the
Figure 1. A mechanistic overview.
Instead, a sequence of Wolff rearrangement of 4 (or 3) follow
by oxidation of the resulting ketene 2212a has been proposed
as the major pathway en route to 20 via R-lactones 23.10a
In the context of ynamides 13 and 16, the involvement of
amido-oxocarbenes 3 in cyclopropanation is less likely given
the concomitant cyclobutane formation. To probe for 3, we
examined oxidations of homologous ynamides 24a-e (Scheme
4) because cyclopropanations of the respective olefin in
Figure 2. An alternative pathway to push-pull carbenes 4.
oxyketene iminium ion 30 giving rise to push-pull carbenes
4.
Scheme 4
We have described here a mechanistic profile of DMDO
oxidation of ynamides that led to the first examples of
stereoselective intramolecular cyclopropanations of a chiral
push-pull carbene derived from alkyne oxidation, a facile
access to ketoimides, and insights in the chemistry of
electronically biased oxirenes. Further investigations into
reactivities and applications are underway.
Acknowledgment. We thank NIH (GM066055) for
funding. We thank Dr. Vic Young and Ben Kucera at
University of Minnesota for solving X-ray structures.
24a-e through the amido-oxocarbene intermediate 3 would
lead to bicyclo[3.1.0]hexanes 25. To our surprise, the
epoxidation of the acrylate containing ynamide 24a gave
neither cyclopropanes 25 nor 26a but only ketoimide 27a.
This outcome was unaltered by inclusion of a buttressing
moiety in the tether (see 24b).13
Reasoning that the respective amido-oxocarbene 3 could
prefer electron-rich olefins, we prepared ynamide 24c.
Although the olefin of 24c was not entirely stable to
oxidation conditions,12b a single isomer of amido-cyclopro-
pane 26c was obtained, thereby confirming the promiscuity
of push-pull carbenes 4. Attempting to again enhance the
cyclopropanation pathway, we examined the oxidation of
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectral and characterizations
are available for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL703083K
(13) We attributed this observation as a result of the complexation of
the ester carbonyl oxygen with carbene intermediates derived from 24a
and 24b (or 24d), leading to carbonyl ylides vi and vii, respectively, with
an enhanced nucleophilicity favoring the second electrophilic addition of
DMDO over cyclopropanation. Related discussions were reported (ref 10a)
where the solvent acetone (see viii) was observed to facilitate the double
oxidation.
(12) (a) Attempts at trapping this ketene afforded ketoaminal iii ac-
companied by free auxiliary. The formation of iii suggests the interception
of oxocarbene iv. (b) Ketoimide v was isolated in 8% yield.
(14) (a) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000,
122, 6785. (b) Nieto-Oberhuber, C.; Lo´pez, S.; Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem.sEur. J. 2006, 12, 5916.
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