Simple reaction conditions for the formation of ketonitrones from ketones and hydroxylamines

Article abstract of DOI:10.1021/jo901653d

(Chemical Equation Presented) The condensation of ketones and hydroxylamines to form ketonitrones was reinvestigated by using thermal conditions previously found to minimize hydroxylamine decomposition (t-BuOH, 110°C). This simple approach allows the formation of exocyclic, acyclic, and α,β-unsaturated ketonitrones with benzylic, linear, and branched nitrogen substituents in modest to excellent isolated yields.

Full text of DOI:10.1021/jo901653d

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hydroxylamines, or imines,3 (3) N-alkylation of oximes and
Simple Reaction Conditions for the Formation of
Ketonitrones from Ketones and Hydroxylamines
derivatives,4 and (4) Cope-type hydroamination5 of alkynes
or allenes with hydroxylamines.6 However, most of the
nitrone literature relates to aldonitrones, and reports on
the synthesis and reactivity of ketonitrones remain scarce
and mostly limited to specific substrates such as N-methyl or
N-benzyl substituted,7 or endocyclic ketonitrones (which can
be prepared by intramolecular reactions). With respect to the
condensation approach, aldonitrones are prepared simply by
mixing the aldehydes and N-alkylhydroxylamines, while
ketonitrones are usually prepared by using Exner’s two-step
ꢀ
Jennifer Y. Pfeiffer and Andre M. Beauchemin*
Centre for Catalysis Research and Innovation, Department of
Chemistry, University of Ottawa, 10 Marie Curie, Ottawa,
Ontario, Canada, K1N 6N5
andre.beauchemin@uottawa.ca
Received July 29, 2009
procedure (condensation of the ketone with RNHOH HCl
3
to afford the ketonitrone HCl adduct, followed by neutra-
3
lization with dry ammonia).7n,8 In recent work on the inter-
molecular Cope-type hydroamination5 reactivity of
hydroxylamines,9 we noted that the thermal stability of N-
alkylhydroxylamines is highly solvent and substitution de-
pendent, and that significant decomposition can occur upon
heating in various common organic solvents.10 However,
heating is typically required in the scarce reports of ketoni-
trone formation from ketones and hydroxylamines.2c,7n
Arguably, the scope of the direct condensation approach
to ketonitrones would likely be extended if reaction condi-
tions providing increased thermal stability for the hydro-
xylamines could be developed. Herein, we provide such
procedures that allow the formation of exocyclic, acyclic,
The condensation of ketones and hydroxylamines to form
ketonitrones was reinvestigated by using thermal condi-
tions previously found to minimize hydroxylamine de-
composition (t-BuOH, 110 °C). This simple approach
allows the formation of exocyclic, acyclic, and R,β-un-
saturated ketonitrones with benzylic, linear, and
branched nitrogen substituents in modest to excellent
isolated yields.
(5) Such reactions are also called reverse Cope cyclizations/eliminations.
For a review, see: Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
(6) [Alkynes]: (a) Padwa, A.; Wong, G. S. K. J. Org. Chem. 1986, 51,
3125. (b) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron
1996, 52, 11601 and references cited therein. See also: (c) Nguyen, T. B.; Martel,
A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10, 4493. [Allenes]: (d) Dumez, E.;
ꢁ
Dulcere, J.-P. Chem. Commun. 1998, 479. (e) Schade, W.; Reissig, H.-U. Synlett
Nitrones are valuable intermediates in synthetic organic
chemistry.1 Various methods have been developed for their
formation,2 including (1) condensation of a carbonyl
precursor and a hydroxylamine, (2) oxidation of amines,
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J. Org. Chem. 1989, 54, 2862.
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Chem. Pap. 2005, 59, 275. (b) Tomioka, Y.; Nagahiro, C.; Nomura, Y.;
Maruoka, H. J. Heterocycl. Chem. 2003, 40, 121. (c) Torrente, S.; Noya, B.;
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(1) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; John Wiley & Sons: New York, 1984; Vol. 2, Chapter 9. (b) Torssell, K. B. G.
In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; Feuer, H., Ed.;
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Hoboken, NJ, 2003; Chapter 1.
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A.; Hwu, J. R. J. Org. Chem. 1985, 50, 5913. (k) Cummins, C. H.; Coates, R.
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Eds.; Pergamon Press: New York, 1979; Vol. 2, Part 8. (d) Delpierre, G. R.;
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(8) A more recent, practical alternative has been reported by Merino et al.
for BnNHOH and several ketones using equimolar amounts of ZnCl2 and
MgSO4 in CH2Cl2. See ref 7f for details.
(9) (a) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Seguin, C.;
Dimitrijevic, E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008,
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and references cited therein. For related reactivity of oximes with π-bonds, see
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Tetrahedron 2000, 56, 10087. [Allenes]: (g) Shaw, R.; Lathbury, D.; Anderson,
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therein.
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17893. (c) Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-
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DOI: 10.1021/jo901653d
r
Published on Web 09/30/2009
J. Org. Chem. 2009, 74, 8381–8383 8381
2009 American Chemical Society

Pfeiffer and Beauchemin
JOCNote
TABLE 1. Scope of Improved Conditions for Ketonitrone Formationa
Recently, we reported that ketonitrones can directly be
accessed from allenes and N-alkylhydroxylamines upon
heating in tert-butanol at 90-140 °C.9d Remarkably, these
conditions were even appropriate for linear N-alkylhydroxyl-
amines and provided in general modest to good yields,
suggesting that little hydroxylamine and/or ketonitrone
decomposition occurred under the reaction conditions. En-
couragingly, initial condensation attempts with 2-octanone
(1a) and N-cyclohexylhydroxylamine (2a) under similar
reaction conditions provided the ketonitrone 3a in 81%
isolated yield. Reaction of 2-octanone (1a) with the more
labile n-hexylhydroxylamine (2b) also provided the desired
ketonitrone 3b effectively (70% yield), which prompted the
determination of the substrate scope (Table 1).
Overall, the reaction conditions allow ketonitrone forma-
tion with various ketones and hydroxylamines. Both acyclic
(entries 1-7) and cyclic (entries 8-15) ketones yield the
desired adducts under the reaction conditions.11 The con-
densation is most efficient for cyclic and acyclic methyl
ketones (entries 8-13, 15, and 1-4, respectively), and shows
some sensitivity to substitution R to the carbonyl (entries
5-7 and 14). Interestingly, R,β-unsaturated ketones react to
form exclusively the condensation products over the possi-
ble12 1,4-addition products (entries 16-21). Various primary
hydroxylamines are also compatible with the reaction con-
ditions (entries 9-13 and 19), and the reactivity appears to be
minimally affected by the nature of the ketones as surveyed
with three representative hydroxylamines (entries 1-3 vs.
9-10, 12 vs. 16-18). In general, most ketonitrones could be
purified by chromatography, with some nitrones being
somewhat labile.
In contrast, acetophenone (1k) did not yield any product
under the reaction conditions (eq 1). Speculating that this
observation was due to unfavorable reaction thermody-
namics, various dessicants were surveyed and a modest
30% yield of the desired aromatic ketonitrone 3u could be
obtained with MgSO4.13 In contrast, indanone (1l) reacted
(11) To provide calibration on the importance of using t-BuOH as solvent
to minimize hydroxylamine decomposition, the condensation shown in entry
6 with 3-pentanone and BnNHOH (which is typically moderately sensistive
to thermolysis) was explored in other solvents, under identical reaction
conditions and scale. Ketonitrone 3f was formed in 12%, 12%, and 18%
NMR yields in toluene, dioxane, and CHCl3, respectively.
aConditions: Ketone (2 equiv), R3NHOH (1 equiv), t-BuOH (0.5 M),
110 °C, 18 h, under Ar. bTypically E/Z mixtures of ketonitrone isomers
were isolated with unsymmetrical ketones. See the Supporting Informa-
tion for ratios and stereochemical assignment. cPerformed with 5 equiv
of ketone.
(12) (a) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999, 121, 2456. See also:
ꢀ
ꢀ
(b) Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena, A .; Moltrasio,
~
G. Y.; Branchadell, V.; Ortuno, R. M. J. Org. Chem. 2002, 67, 2402.
(13) See the Supporting Information for details.
(14) A solution of ketonitrone 3u was heated under the usual reaction
conditions (t-BuOH [1.0 M], 110 °C, 18 h, under Ar) in the presence of 10
equiv of H2O. TLC and 1H NMR analysis of the unpurified reaction mixture
with an internal standard showed that partial hydrolysis of the ketonitrone
had occurred. See the Supporting Information for details.
and R,β-unsaturated ketonitrones bearing various nitrogen
substituents.
8382 J. Org. Chem. Vol. 74, No. 21, 2009

Pfeiffer and Beauchemin
JOCNote
under the standard reaction conditions to afford the desired
ketonitrone 3v, and no improvement was observed in the
presence of MgSO4 (eq 2). The fact that ketonitrone 3u was
partially hydrolyzed by water under similar reaction condi-
tions14 suggests that the condensation to form ketonitrones
is close to thermoneutrality, and that the position of the
equilibrium depends on the stability of the ketone used and
on the extent of steric destabilization of the ketonitrone
product (dependent on the size of the hydroxylamine).15
In summary, various primary hydroxylamines and ketones
are efficiently condensed simply upon heating in t-BuOH at 110 °C.
These conditions are compatible with linear, benzylic, and cyclic
hydroxylamines, as well as cyclic, acyclic, and R,β-unsaturated
ketones, thus providing a general route to ketonitrones.
tert-butanol (2.6 mL, 0.5 M to hydroxylamine), and ketone
(2.6 mmol, 2.0 equiv). The vial was sealed with a septum and
purged with argon and outlet for 5 min while stirring. The
vial was sealed by using a cap with a resealable septum and
was then heated while stirring in an oil bath at 110 °C for
18 h. The tube was cooled to ambient temperature, concen-
trated under reduced pressure, and analyzed by 1H NMR
(CDCl3) with 1,4-dimethoxybenzene as an internal stan-
dard, then again concentrated under reduced pressure
and purified by silica gel chromatography to give the
corresponding nitrone.
Acknowledgment. We thank the University of Ottawa, the
Canadian Foundation for Innovation, the Ontario Ministry
of Research and Innovation, and NSERC for their support.
A postgraduate scholarship to J.Y.P. (FQRNT) is also
acknowledged. Joseph Moran is also thanked for helpful
discussions.
Experimental Section
Procedure for the Condensation of N-Alkylhydroxylamines
with Ketones. A flame-dried 2 mL sealed vial was charged
with a stir bar, N-alkylhydroxylamine (1.3 mmol, 1.0 equiv),
Supporting Information Available: Complete experimental
procedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(15) A known strategy to overcome this issue involves the use of dialkylk-
etals, as their reaction is entropically more favorable: see ref 7n.
J. Org. Chem. Vol. 74, No. 21, 2009 8383