Fragmentation of carbonyl oxides by N-oxides: An improved approach to alkene ozonolysis

Article abstract of DOI:10.1021/ol061001k

Ozonolysis of alkenes in the presence of amine N-oxides results in the direct formation of aldehydes. This reaction, which appears to involve an unprecedented trapping and fragmentation of the short-lived carbonyl oxide intermediates, avoids the hazards associated with generation and isolation of ozonides or other peroxide products.

Full text of DOI:10.1021/ol061001k

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3199-3201
Fragmentation of Carbonyl Oxides by
N-Oxides: An Improved Approach to
Alkene Ozonolysis
Chris Schwartz, Joseph Raible, Kyle Mott, and Patrick H. Dussault*
Department of Chemistry, UniVersity of NebraskasLincoln,
Lincoln, Nebraska 68588-0304
pdussault1@unl.edu
Received April 26, 2006
ABSTRACT
Ozonolysis of alkenes in the presence of amine N-oxides results in the direct formation of aldehydes. This reaction, which appears to involve
an unprecedented trapping and fragmentation of the short-lived carbonyl oxide intermediates, avoids the hazards associated with generation
and isolation of ozonides or other peroxide products.
Although ozonolysis of alkenes to produce carbonyl com-
pounds is a traditional and powerful synthetic transforma-
tion,1,2 its utility is often limited by safety concerns.3 The
1,2,4-trioxolane (ozonide) products are typically capable of
spontaneous and exothermic decomposition, yet are often
reduced slowly by mild reducing agents;4 their persistence
following incomplete reduction has resulted in explosions.5
We sought a new approach to alkene ozonolysis that would
avoid generation or accumulation of peroxide products.6 We
now report a “reductive ozonolysis” based upon capture and
directed fragmentation of carbonyl oxides by amine N-oxides.
Cycloaddition of ozone with an alkene furnishes a 1,2,3-
trioxolane (primary ozonide), which undergoes low-temper-
ature cycloreversion to carbonyl oxide and carbonyl frag-
ments. Carbonyl oxides are reactive intermediates able to
enter into a number of reaction pathways,7-9 including
cycloaddition with an aldehyde or ketone to form 1,2,4-
trioxolanes (ozonides), addition of unhindered protic nu-
cleophiles, or oligomerization. Our goal was the discovery
of reagents capable of intercepting and reducing carbonyl
oxides during a typical ozonolysis reaction (Scheme 1,
illlustrated for aprotic conditions).
(1) Lee, D. G.; Chen, T. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 7, p 544.
(2) Bailey, P. S. Ozonation in Organic Chemistry; Academic Press: New
York, 1978; Vol. 1.
(3) Kula, J. Chem. Health Safety 1999, 6, 21; Gordon, P. M. Chem. Eng.
News 1990, 68, 2.
(4) See, for example: Chen, L.; Wiemer, D. F. J. Org. Chem. 2002, 67,
7561. The use of more effective reducing agents such as PPh3 (Griesbaum,
K.; Kiesel, G. Chem. Ber. 1989, 122, 145. Clive, D. L. J.; Postema, M. H.
D. J. Chem. Soc., Chem. Commun. 1994, 235), BH3 (Flippin, L. A.;
Gallagher, D. W.; Jalali-Araghi, K. J. Org. Chem. 1989, 54, 1430), LiAlH4
(Greenwood, F. L. J. Org. Chem. 1955, 20, 803), NaBH4 (Witkop, B.;
Patrick, J. B. J. Am. Chem. Soc. 1952, 74, 3855), and Mg/MeOH or Zn/
HOAc (Dai, P.; Dussault, P. H.; Trullinger, T. K. J. Org. Chem. 2004, 69,
2851) can lead to problems with separation of byproducts or functional
group compatibility. For an overview of ozonide reduction, see: Kropf, H.
In Houben-Weyl Methoden Der Organische Chemie; Kropf, H., Ed.; Georg
Thieme Verlag: Stuttgart, 1988; Volume E13/2, pp 1111-1114.
(5) Lavalle´e, P.; Bouthillier, G. J. Org. Chem. 1986, 51, 1362, footnote
27.
Scheme 1. Overview of Alkene Ozonolysis
A report describing the production of adipaldehyde upon
ozonolysis of cyclohexene in the presence of Et3N drew our
attention to the potential of tertiary amines as reductants.10
(6) Ozonolysis of electron-poor alkenes in methanolic base results in
the direct formation of methyl esters: Marshall, J. A.; Garofalo, A. W.;
Sedrani, R. C. Synlett 1992, 643.
10.1021/ol061001k CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/21/2006

As a model system, we selected ozonolysis of decene.11
Terminal alkenes are common ozonolysis substrates; more-
over, the rapid cycloaddition of the derived aldehyde
O-oxide/formaldehyde pair provides a realistic benchmark
against which to measure the efficacy of a reductant.12
Ozonolysis of decene in the presence of triethylamine,
N-methylmorpholine, or other tertiary amines did in fact
produce nonanal as the major product but invariably con-
taminated with 10-30% of residual ozonide.
Several observations led us to question whether the amines
were the actual reducing agents. First, in contrast to a typical
alkene ozonolysis, reactions were accompanied by intense
fuming persisting for a period proportional to the amount of
added amine; during this interval, we observed little forma-
tion of ozonide or aldehyde (TLC or NMR of quenched
aliquots). Second, ozonolysis of solutions of amines resulted
in similar fuming. Third, addition of decene to a solution of
ozone-treated amine, followed by resumption of ozonolysis,
afforded nonanal as the major product. Amines are known
to react efficiently with ozone, and we began to suspect that
the active reagents might be amine oxides generated in situ.13
We therefore reinvestigated ozonolysis of 1-decene in the
presence of stoichiometric N-methylmorpholine N-oxide
(NMMO). The reaction proceeded without fuming to furnish,
after concentration and chromatography, a high yield of
nonanal and no detectable ozonide (Table 1).
Table 1. Ozonolysis in the Presence of N-Oxides (eq 1)
aldehyde
(yield, %)a
ozonide
(yield, %)a
substrate
N-oxide (equiv)
none
NMMO (1.0)
NMMO (3.0)
1
1
1
1
1
1
2
trace
1c (90)
1a (88)
1a (94)
1a (94)
1a (78)
1a (79)
1a (74)
2b (96)
NMMO (5.0)
pyridine N-oxide (5.0)
DABCO N-oxide (5.0)
NMMO (1.0)
a Isolated yields.
The formation of aldehydes could in theory result from
reaction of the amine oxides with the primary ozonide, the
carbonyl oxide, or the ozonide. However, the product
distributions obtained for ozonolysis of decene, decene and
methanol, or decene and methanol and NMMO, suggest a
competition for the carbonyl oxide (Table 2). Methoxy-
The use of excess NMMO resulted in a slightly improved
yield of aldehyde. Reduction was also achieved using
pyridine N-oxide or DABCO N-oxide.14,15 The method was
also effective for ozonolysis of methyl oleate, a 1,2-
disubstituted alkene.
Table 2. Competition Reactions (eq 2)
(7) Bunnelle, W. H. Chem. ReV. 1991, 91, 335.
(8) Kuczkowski, R. L. Chem. Soc. ReV. 1992, 21, 79.
(9) Barton, M.; Ebdon, J. R.; Foster, A. B.; Rimmer, S. J. Org. Chem.
2004, 69, 6967.
(10) Pokrovskaya, I. E.; Ryzhankova, A. K.; Menyailo, A. T.; Mishina,
L. S. Neftekhimiya 1971, 11, 873-8 (CAN 76: 71953).
additive(s)
none
MeOH (1 equiv)
MeOH (1 equiv) +
NMMO (1 equiv)
1a (%)
1d (%)
1c (%)
90-95
10
trace
(11) Any work involving peroxides should follow standard precautions:
Medard, L. A. Accidental Explosions: Types of ExplosiVe Substances; Ellis
Horwood Ltd.: Chichester, 1989; Vol. 2. Patnaik, P. A ComprehensiVe
Guide to the Hazardous Properties of Chemical Substances; Van Nostrand
Reinhold: New York, 1992. Shanley, E. S. In Organic Peroxides; Swern,
D., Ed.; Wiley-Interscience: New York, 1970; Vol. 3, p 341.
(12) The rate of ozonide formation varies with the carbonyl oxide/
carbonyl pair. For ozonolysis of terminal alkenes (aldehyde O-oxides and
formaldehyde), 1,1-disubstituted alkenes (ketone O-oxides and formalde-
hyde), and 1,2-disubstituted alkenes (aldehyde O-oxides and aldehydes),
cycloaddition is rapid and ozonides are the predominant products under
aprotic conditions. See ref 7 for more details.
trace
70
66
20
decene, which undergoes ozonolysis via the same nonanal
O-oxide intermediate but cannot easily form an ozonide,7
also furnishes mainly nonanal upon reaction in the presence
of NMMO (not shown).
(13) Bailey, P. S. Ozonation in Organic Chemistry; Academic Press:
New York, 1978; Vol. 2, pp 155-201. Maggiolo, A.; Niegowski, S. J. In
Ozone Chemistry and Technology; American Chemical Society: Washing-
ton, DC, 1959; pp 202-204.
NMMO does promote a slower base-promoted fragmenta-
tion of decene ozonide to furnish a 1:1 mixture of nonanal
and formate; an analogous reaction is known for amines.16
This fragmentation is a minor contributor to the formation
of aldehyde during ozonolysis in the presence of amine
oxides, as the crude reaction mixtures consistently featured
ratios of aldehyde/formate > 4:1. However, the base-
promoted process may serve to scavenge traces of residual
ozonide. For example, if the crude reaction mixture from
ozonolysis of decene and NMMO is washed with pH 6 buffer
prior to concentration and purification, a small amount (up
(14) Typical Procedure. To a dry 100 mL round-bottom flask was added
3.0 mmol of decene, 20 mL of methylene chloride, and 9.0 mmol of
N-methylmorpholine N-oxide. The stirred solution was cooled to 0 °C, and
a solution of 2% O3/O2 (nominal output of 1 mmol O3/min) was introduced
directly above the solution via a glass pipet for 6.6 min (nominally 2.2
equiv ozone relative to alkene). This mode of ozone addition furnished the
most consistent results. The solution was then sparged with O2 for 2 min
and warmed to room temperature. Following confirmation of the absence
of ozonide (TLC), the solution was concentrated and the residue was purified
by flash chromatography using 5% diethyl ether/pentane. Alternatively, the
crude reaction was quenched into pH 6 phosphate buffer and extracted with
ether prior to chromatography.
(15) NMMO and pyridine N-oxide were used as received. DABCO
N-oxide was generated in situ by ozonolysis of the amine prior to the
addition of alkene.
(16) Hon, Y. S.; Lin, S.-W.; Lu, L.; Chen, Y.-J. Tetrahedron 1995, 51,
5019.
3200
Org. Lett., Vol. 8, No. 15, 2006

to 7%) of ozonide is isolated. In the presence of three or
more equivalents of NMMO, no ozonide is observed
regardless of workup procedure, suggesting that capture of
the carbonyl oxide is complete at the higher reagent
concentration.
initial results with trialkylamines as well as the superiority
of the amine oxides as reagents.
Finally, the in situ reduction holds obvious potential for
tandem reaction sequences; an unoptimized example is
illustrated in eq 3.
To our knowledge, there is no precedent for the observed
fragmentation. The most likely mechanism involves nucleo-
philic addition of the amine oxide to the carbonyl oxide to
generate an unstable zwitterion, which fragments to liberate
aldehyde, dioxygen, and amine (Scheme 2). In the presence
In summary, we have demonstrated a protocol for “reduc-
tive“ ozonolysis in the presence of amine oxides. This
reaction, the first example of a new class of transformations
harnessing the reactivity of carbonyl oxides, offers a safer
approach to alkene ozonolysis. Further investigations into
the scope, mechanism, and synthetic utility of this transfor-
mation are in progress.
Scheme 2. Proposed Mechanism for Fragmentation
Acknowledgment. This work was supported by the
donors of the Petroleum Research Fund, administered by the
American Chemical Society.
1
of ozone, the liberated amine undergoes oxidation to
regenerate both amine oxide as well as cleavage products
derived from side-chain oxidation,13,17 accounting for our
Supporting Information Available: H NMR spectra for
1a,c,d, 2b, DABCO, DABCO N-oxide, and 3-undecanol.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Bailey, P. S.; Lerdal, D. A.; Carter, T. P., Jr. J. Org. Chem. 1978,
43, 2662.
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