Nitrosobenzene-mediated C-C bond cleavage reactions and spectral observation of an oxazetidin-4-one ring system

Article abstract of DOI:10.1021/ja804325f

While bond formation processes have traditionally garnered the attention of the chemical community, methods facilitating bond breaking remain relatively undeveloped. We report a novel, transition-metal-free oxidative C-C bond cleavage process for a broad range of ester and dicarbonyl compounds involving carbanion addition to nitrosobenzene. ReactIR experiments on the nitrosobenzene-mediated oxidative decarboxylation of esters indicate the reaction proceeds via fragmentation of a previously unobserved oxazetidin-4-one heterocycle, characterized by an intense IR stretching frequency at 1846 cm^-1. These mechanistic studies have allowed further expansion of this protocol to ketone cleavage reactions of a diverse array of β-ketoester and 1,3-diketone substrates. The conceptual and mechanistic insights offered by this study are likely to provide a platform for further development of bond-breaking methodologies. Copyright

Full text of DOI:10.1021/ja804325f

Published on Web 08/23/2008
Nitrosobenzene-Mediated C-C Bond Cleavage Reactions and Spectral
Observation of an Oxazetidin-4-one Ring System
Joshua N. Payette and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received June 16, 2008; E-mail: yamamoto@uchicago.edu
Scheme 1. Preliminary Data on Oxidative Decarboxylation
Synthetic organic chemistry is concerned with the assembly of
complex chemical structures from relatively simple starting materi-
als. Not surprisingly, processes facilitating the formation of new
chemical bonds encompass a preponderance of the literature.1
However, the inverse process of C-C bond cleavage, while
synthetically desirable in many cases, poses a great challenge due
to the inherent strength of the C-C bond.2,3 Accordingly, relatively
few procedures have been reported for this transformation, and those
that have usually rely on transition metal catalysis.4 In the present
work, we describe a powerful, one-step oxidative C-C bond
cleavage methodology for a broad range of ester and dicarbonyl
substrates utilizing nitrosobenzene as an oxidant. Moreover,
mechanistic studies using ReactIR spectrometry have allowed the
first spectral observation of the oxazetidin-4-one ring system. This
methodology marks a breakthrough over related multistep and
metal-mediated procedures, providing a highly robust oxidative
C-C bond cleavage protocol for a diverse array of carbonyl
compounds.5,6
Scheme 2. Plausible Pathways for Oxidative Decarboxylation
Given our long standing work in Diels-Alder chemistry, we
became interested in C-C bond cleavage methodology in the
context of developing a highly versatile asymmetric ketene equiva-
lent.7 In preliminary studies toward an asymmetric route to
bicyclo[2.2.1]hept-5-ene-2-one derivatives it was found that treat-
ment of N-hydroxy methyl ester 2 with LiOH provided bicyclic
ketone 4 in 75% yield over two steps (after acidic hydrolysis of
the imines).8,9 Interestingly, under identical conditions N-hydroxy
ethyl ester 5 gave the corresponding product 6 in only 16% yield.
By increasing the lability of the ester it was found that direct
addition of nitrosobenzene to the lithium enolate of phenyl ester 7
at -78 °C provided the corresponding N-phenyl imines 6, ac-
companied by evolution of CO2, within 5 min in 91% yield in one
step (Scheme 1).
gave only a complex mixture of decomposition products. To verify
if Pathway 2 was indeed correct, spectroscopic observation of the
oxazetidin-4-one functionality of 11 was required. However, due
to the slow rate of conversion of 2 to 3, the low concentration as
well as the expected short lifetime of 11 would make detection
difficult. The observation that phenyl esters are directly cleaved to
yield the corresponding imine products by addition of nitrosoben-
zene at -78 °C suggested that under these conditions observation
of the oxazetidin-4-one intermediate was feasible.
In situ ReactIR technology was employed to monitor the
conversion of phenyl ester 7 to the corresponding N-phenyl imines
6. As can been seen in Figure 1B (3D and 2D plots), less than 1
min after addition of nitrosobenzene to the lithium enolate of 7, a
new, sharp peak appears at 1846 cm-1. The intensity of this peak
gradually decreases as the cooling bath is warmed to -20 °C.
Importantly, the disappearance of the 1846 cm-1 band is marked
by the appearance of two bands at 1695 and 1679 cm-1 corre-
sponding to N-phenyl imines 6. We believe the new IR absorption
at 1846 cm-1 is attributable to the existence of spiro-oxazetidin-
4-one intermediate 14. IR data of similar cyclic compounds reveal
that a stretch of 1846 cm-1 is highly characteristic of this type of
four-membered, spiro ring system.15 Thus, we can now conclude
that the conversion of 7 to 6 follows a mechanistic course analogous
The markedly contrasting results obtained between the related
ethyl, methyl, and phenyl bicyclo[2.2.1]hept-5-ene-2-carboxylates
prompted us to undertake detailed mechanistic studies. As a starting
point, the conversion of N-hydroxy methyl ester 2 to N-phenyl
imines 3 was examined. Two conceivable reaction pathways may
exist for this transformation. Initial hydrolysis of the methyl ester
of 2 would afford carboxylate intermediate 9. Subsequent loss of
CO2 and elimination of a hydroxide ion would furnish imines 3.10
More interestingly, the N-hydroxyl group could first be deprotonated
to give 10. Intramolecular attack of the methyl ester by the oxy-
anion would give the highly energetic, spiro-oxazetidin-4-one
intermediate 11.11 This strained species should spontaneously
fragment, expelling CO2, to give imines 3 (Scheme 2).12,13
To ascertain if the reaction proceeded through Pathway 1 (viz.
intermediate 9), carboxylic acid 1214 (for preparation, see Sup-
porting Information) was subjected to the identical conditions for
which imines 3 had been obtained from N-hydroxy methyl ester 2
(Figure 1A). However, under these same reaction parameters 12
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2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Nitrosobenzene-Mediated Oxidative Decarboxylationa
Figure 1. Control and ReactIR experiments were conducted to determine
the mechanistic course of the nitrosobenzene-mediated oxidative decar-
boxylation reaction. (A) Control experiment showing that conversion of 2
to 3 does not follow Pathway 1. (B) 3D and 2D plots of ReactIR experiment
showing Pathway 2 is correct with the first spectral observation of an
oxazetidin-4-one heterocycle 14. Immediately after addition of nitrosoben-
zene to the lithium enolate of 7 at -78 °C, oxazetidin-4-one 14, having an
IR stretch at 1846 cm-1, is observed. As the cooling bath is gradually
warmed, the disappearance of 14 is marked by the appearance of N-phenyl
imines 6. Note: The intensity of the line plot of 6 is reflective of only one
isomer of 6.
a Products in entries 4-10 were hydrolytically stable to SiO2. See
Supporting Information for additional details. b Base ) LDA (lithium
diisopropylamide) or NaHMDS (sodium bis(trimethysilyl)amide). c Iso-
lated yield. d Determined by 1H NMR with MeNO2 as internal standard.
to Pathway 2. While oxazetidin-4-ones have been postulated as
reaction intermediates in only a handful of synthetic and theoretical
papers,12,13,16 direct evidence for the existence of this functional
group has hitherto been unreported.17
Scheme 3. Initial Results for Cleavage of ꢀ-Ketoesters
The reaction scope of this novel process was subsequently
examined. Table 1 summarizes these results. The present method
tolerates a range of bicyclic, cyclic, sp2-sp3, and sp2-sp2 R,R′-
disubstituted phenyl esters to provide either ketone or imine
products in generally excellent yields. In general, ketimines
containing at least one sp2 R-subsitutent were stable to silica gel
while those having only sp3 R-subsitutents (entries 1-3) were
immediately hydrolyzed. Further, malonic ester derivatives could
also be applied to provide the corresponding R-imino phenyl esters
in uniformly high yields as well.
Unexpectedly, when ꢀ-keto phenyl ester 15 was subjected to
the standard reaction conditions, an ∼1:1 mixture of R-imino-
ester 16 and R-keto-imine 17 was obtained, presumably from
attack of the aminooxy anion at either the ketone or ester
functionalities (Scheme 3). Guided by our previous findings, use
of the corresponding less labile ꢀ-keto methyl ester 18 resulted
in exclusive cleavage of the ketone moiety furnishing R-imino-
methyl ester 19 in 93% yield. Gratifyingly, this process could
be applied to ring-opening cleavage reactions of a diverse array
of mono- and bicyclic ꢀ-ketoesters to afford highly functional-
ized dioxo- (acidic workup) or oxo-imino acids (workup under
buffered conditions) in quantitative yields (Table 2, entries 1-9).
Further, a simple extension of this ketone cleavage methodology
to symmetric 1,3-diketone substrates allows for a regioselective
route to R-ketoimines (Table 2, entries 11-13). It should be
noted that in both oxidative decarboxylation and ketone cleavage
reactions spectroscopically pure compounds can be obtained after
simple aqueous workup procedures obviating the need for
chromatographic purification.
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C O M M U N I C A T I O N S
Table 2. Nitrosobenzene-Mediated Ketone Cleavagea
alized products in excellent yields and in short reaction times.
Current work in our laboratory is aimed at expanding the full scope
and applications of this new C-C bond cleavage methodology.
We believe the findings from the present study will provide impetus
for further research into alternative, metal-free bond fission
methodologies.
Acknowledgment. This work was supported by NIH Grant
GM068433-01. We are grateful to Dr. Will Kowalchyk and Mettler
Toledo for assistance with ReactIR experiments. We also thank
Dr. Ian Steele of The University of Chicago for X-ray crystal-
lographic analyses.
Supporting Information Available: Experimental procedures, X-ray
crystallographic data, and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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In summary, we have developed an efficient single step oxidative
decarboxylation reaction of esters involving nitrosobenzene addition
to the corresponding enolate. A series of control and spectroscopic
experiments have elucidated the mechanism of this novel cleavage
process, providing the first spectral evidence for the existence of
an oxazetidin-4-one ring system. Based on these findings, this
methodology could be generalized to cleavage reactions involving
a wide scope of dicarbonyl compounds affording highly function-
JA804325F
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