α-aminoxylation of ketones and β-chloro-α-aminoxylation of enones with tempo and chlorocatecholborane

Article abstract of DOI:10.1021/ol301979b

Oxidation of various cyclic and acyclic ketones under mild conditions with chlorocatecholborane, a bulky pyridine base, and TEMPO to the corresponding α-aminoxylated products in good to excellent yields (52-99%) is described. For enones as substrates, products of a β-chloro-α-aminoxylation are obtained (70-89%).

Full text of DOI:10.1021/ol301979b

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4474–4477
r‑Aminoxylation of Ketones and
β‑Chloro-r-aminoxylation of Enones with
TEMPO and Chlorocatecholborane
Yi Li,† Martin Pouliot,‡ Thomas Vogler,† Philippe Renaud,*,‡ and Armido Studer*,†
Institute of Organic Chemistry, University of Mu€nster, Corrensstrasse 40, 48149
€
Mu€nster, Germany, and Departement fu€r Chemie und Biochemie, Universitat Bern,
Freiestrasse 3, CH-3012 Bern, Switzerland
philippe.renaud@ioc.unibe.ch; studer@uni-muenster.de
Received July 17, 2012
ABSTRACT
Oxidation of various cyclic and acyclic ketones under mild conditions with chlorocatecholborane, a bulky pyridine base, and TEMPO to the
corresponding R-aminoxylated products in good to excellent yields (52ꢀ99%) is described. For enones as substrates, products of a β-chloro-R-
aminoxylation are obtained (70ꢀ89%).
The 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO)
has become a highly valuable reagent for organic syn-
thesis.1 It is well-known that ester and amide enolates are
not oxidized by TEMPO to the corresponding R-amino-
xylation products.2 However, N-oxoammonium salts
(TEMPOþXꢀ), whichcan be generatedinsituby oxidation
of TEMPO or be used as stoichiometric reagents, show far
higher reactivity and various metal enolates are readily
transformed to the corresponding alkoxyamines upon
reaction with TEMPOþXꢀ.3 Readily enolizable ketones
also react with TEMPO-derived oxoammonium salts to
provide R-diketones.4 R-Aminoxylation of enolates with
TEMPO can be achieved in the presence of an external
oxidant,5 and aldehydes are R-aminoxylated by TEMPO
using secondary amines in combination with an external
oxidant.6 Enolate oxidations have been intensively studied
in the past with various oxidants.7
We recently showed that catecholboronenolates are
readily oxidized with 2.5 equiv of TEMPO.8,9 In these
transformations, the first N-oxyl radical reacts at the
boron atom of the B-enolate thereby generating an
R-enoyl radical which in turn gets trapped by TEMPO to
form the corresponding R-aminoxylation product (Scheme 1).
The intermediate CatB-enolates can be generated either by
(6) (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124–
4125. (b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012–10014. (c)
Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Org. Lett. 2010, 12,
1804–1807. (d) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166–167. (e)
Bui, N.-N.; Ho, X.-H.; Mho, S.-i.; Jang, H.-Y. Eur. J. Org. Chem. 2009,
5309–5312. (f) Kano, T.; Mii, H.; Maruoka, K. Angew. Chem., Int. Ed.
2010, 49, 6638–6641. (g) Akagawa, K.; Kudo, K. Org. Lett. 2011, 13,
3498–3501. (h) Simonovich, S. P.; Van Humbeck, J. F.; MacMillan,
† University of M€unster.
‡
€
Universitat Bern.
(1) Reviews: (a) Vogler, T.; Studer, A. Synthesis 2008, 1979–1993. (b)
Tebben, L.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 5034–5068.
(2) For oxidation of highly electron-rich enols with TEMPO, see:
Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed.
2008, 47, 8727–8730.
ꢀ
D. W. C. Chem. Sci. 2012, 3, 58–61. (i) Dinca, E.; Hartmann, P.; Smrcek,
J.; Dix, I.; Jones, P. G.; Jahn, U. Eur. J. Org. Chem. 2012, 4461–4482.
(7) Reviews: (a) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E.
Org. React. 2003, 62, 1–356. (b) Davis, F. A., Chen, B. C. In Houben-
Weyl Methods in Organic Synthesis Stereoselective Synthesis, 4th ed.;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme:
Stuttgart, Germany, 1995; Vol. E21e, pp 4497ꢀ4518. (c) Davis, F. A.;
Chen, B. C. Chem. Rev. 1992, 92, 919–934.
€
€
(3) Schamann, M.; Schafer, H. J. Synlett 2004, 1601–1603.
(4) (a) Hunter, D. H.; Barton, D. H. R.; Motherwell, W. J. Tetra-
hedron Lett. 1984, 25, 603–606. (b) Weik, S.; Nicholson, G.; Jung, G.;
Rademann, J. Angew. Chem., Int. Ed. 2001, 40, 1436–1439.
(5) Jahn, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J. Org. Chem.
2001, 3333–3355.
(8) Pouliot, M.; Renaud, P.; Schenk, K.; Studer, A.; Vogler, T.
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r
10.1021/ol301979b
Published on Web 08/17/2012
2012 American Chemical Society

reduction of enones with catecholborane (CatBH) or by
transmetalation of silyl enol ethers or zinc enolates with
chlorocatecholborane (CatBCl).8 We report herein that
R-aminoxylation can be achieved directly from ketones upon
reaction with a bulky amine base, TEMPO, and CatBCl.
Moreover, we disclose the first results on an unprecedented
β-chloro-R-aminoxylation of enones by using CatBCl and
TEMPO and provide some mechanistic studies.
yields are presented in Figure 1. The ring size of cyclic
ketones heavily influences the reaction outcome. Whereas
transformation of cyclopentanone delivered a complex
mixture in which the targeted product was not identified,
cycloheptanone provided alkoxyamine 1c in quantitative
yield. Open chain aliphatic ketones, as shown for acetone
used in large excess, can also be oxidized with this method
(see 1d). Alkyl aryl ketones are good substrates for this
reaction. R-Aminoxylation of acetophenone provided 1e
in 56% isolated yield. In this transformation, overoxida-
tion to the corresponding gem-diaminoxylated compound
was also observed (5% yield, see Supporting Information
(SI)). Overoxidation is fully suppressed when an alkyl
group is present at the R-position.
Scheme 1. Generation of Catecholboronenolates and
TEMPO-Mediated R-Oxidation
We first studied the R-aminoxylation of cyclohexanone
and found that the reaction is best conducted in dichloro-
methane with 1.1 equiv of CatBCl and 2,6-di-tert-butyl-
pyridine (1.1 equiv) as the base in the presence of TEMPO
(2.8 equiv). TEMPO, the base, and then CatBCl were
added at 0 °C, and the reaction mixture was allowed to
warm to room temperature over 3 h, resulting in alkoxy-
amine 1a being isolated in 83% yield (Scheme 2). It is
important to note that B-enolization in the presence of
TEMPO afforded the optimal results. If TEMPO is added
after enolization, the yield dropped to 20%. The yield also
decreased in the absence of the pyridine base (67%).
Double oxidation was achieved upon increasing the
amount of base (2.2 equiv), CatBCl (2.2 equiv), and
TEMPO (5.5 equiv), and bisalkoxyamine 1b was obtained
in 76% yield with complete trans-selectivity along with
12% of the monooxidation product 1a.
Figure 1. Various alkoxyamines prepared via mild R-aminoxy-
lation of ketones.
The scope of the monoaminoxylation was studied next
under optimized reaction conditions. The products and
Hence, ethyl phenyl ketone and propyl phenyl ketone
were quantitatively oxidized to 1f and 1i, respectively.
p-Methoxy and p-chloro substituents on the aryl group
are well tolerated, and the corresponding R-aminoxylation
products 1g and 1h formed in quantitative yields. Cyclic
alkyl aryl ketones also worked well (see 1j and 1k), and
even formation of a quaternary C-center by oxidation of
phenyl propyl ketone was possible (see 1l). β-Ketoesters
lacking acidic R-protons are also substrates for the
Scheme 2. R-Aminoxylation of Cyclohexanone
(9) Reviews on the use of boron in radical chemistry: (a) Olivier, C.;
Renaud, P. Chem. Rev. 2001, 101, 3415–3434. (b) Darmency, V.;
Reanud, P. Top. Curr. Chem. 2006, 263, 71–106. (c) Renaud, P.
In Encyclopedia of Radicals in Chemistry, Biology and Materials;
Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons Ltd.: Chichester,
U.K., 2012; Vol. 2, pp 601ꢀ628.
Org. Lett., Vol. 14, No. 17, 2012
4475

aminoxylation, and 1m was isolated in 52% yield.
R-Aminoxylation of 4-methylcyclohexanone occurred
with complete diastereoselectivity (see 1n, >98:2, 1,3-
stereoinduction).10 The preparation of 1o and 1p pro-
ceeded also with good stereoselectivities.
During investigations on the R-aminoxylation of 2-
cyclohexenone we observed stereoselective formation of
trans-3-chloro-2-TEMPO-cyclohexan-1-one 2a as a major
product. Upon treatment of 2-cyclohexenone with CatBCl
and TEMPO at room temperature in CH2Cl2 in the
absence of base, 2a was formed in 79% yield. However,
we faced difficulties in reproducing that result. Yields of 2a
varied from 50 to 70%, and the alkoxyamine derived from
R-aminoxylation of 2-cyclohexenone (not shown) was
obtained in 15ꢀ20% yield as a side product.
Scheme 3. Oxidation of 2-Cyclohexenone
Figure 2. β-Chloro-R-aminoxylation of various enones.
TEMPOþClꢀ is known to act as an oxidant for alcohol
oxidations. To prove its formation, we reacted p-methoxy-
benzylalcohol with TEMPO and CatBCl in CH2Cl2 and
indeed obtained p-methoxybenzaldehyde in 70% isolated
yield. This experiment gives strong support to the fact that
TEMPOþClꢀ can be generated from TEMPO and CatBCl.
Moreover, since that reaction is very fast, we currently
assume that all R-aminoxylations occur with TEMPOþClꢀ
as the oxidant.
The lackof reproducibility of the reaction wasattributed
to small variations of the mixing time of CatBCl and
TEMPO. In order to obtain reproducible results, CatBCl
was added to a solution of TEMPO and 2-cyclohexenone
at rt. While this procedure allowed the formation of 2a
with a reproducible yield (61%), the overoxidized bisalk-
oxyamine 3 was also obtained in 17% yield (Scheme 3).
Formation of 3 could be suppressed by running the reac-
tion at 0 °C (reaction worked even at ꢀ78 °C), and 2a was
obtained with complete regio- and diastereoselectivity in
76% isolated yield. Under optimized conditions, various
enones were tested in the β-chloro-R-aminoxylation reac-
tion (Figure 2). 2-Cycloheptenone provided alkoxyamine
2b with complete stereoselectivity in 84% isolated yield.
Similar results were achieved with methyl vinyl ketone and
phenyl vinyl ketone (see products 2c and 2d). However,
β,β-doubly substituted enones such as 4-methylpent-3-en-
2-one and isophorone were unreactive and the targeted
products were not detected. Chiral 2-cyclohexenones bear-
ing additional substituents at position 4 or 5 reacted with
complete stereoselectivity, and products 2f and 2g were
isolated in good yields. The relative configuration was
assigned by NMR spectroscopy (see SI).
Scheme 4. Control Experiments and Suggested Mechanisms
In order to elucidate the mechanism of these transfor-
mations we performed additional control experiments. We
noted a fast reaction of TEMPO upon addition of CatBCl
in CH2Cl2 in the absence of ketone as judged by the
immediate color change. Based on this observation, we
assumed that TEMPO dismutates in the presence of CatBCl
to produce TEMPOþClꢀ and TEMPOBCat (Scheme 4).
1
(10) In the H NMR spectrum the other isomer was not identified.
The relative configuration was assigned by NMR analysis.
4476
Org. Lett., Vol. 14, No. 17, 2012

Hence, deprotonation of the ketone, which is probably
activated by interaction with the Lewis acidic TEMPOB-
Cat formed as a byproduct during oxoammonium salt
formation, provides a B-enolate that undergoes ionic
reaction with TEMPOþClꢀ to afford the R-aminoxylated
ketone 1. β-Chlorination likely occurs via activation of the
enone with a B-Lewis acid and subsequent conjugate ionic
chloride addition. The B-enolate is subsequently trapped
with TEMPO to eventually give the β-chloro-R-aminoxy-
lation product 2. We ran an additional control experi-
ment to support that mechanism. TEMPO was first re-
acted with CatBCl at 0 °C (formation of TEMPOþClꢀ and
TEMPOBCat). Then 2-cyclohexenone was added to the
reaction mixture at that temperature, and after workup
and purification, 2a was isolated in 71% yield. This yield
compares well with the yield obtained using the standard
protocol (76%; see Scheme 3).
TEMPO, and 2,6-di-tert-butylpyridine under mild conditions.
The substrate scope is broad, and products are obtained
with good to excellent yields. For enones as substrates
in the absence of the pyridine base, an unprecedented
β-chloro-R-aminoxylation reaction is obtained. For cyclic
enones, this vicinal difunctionalization occurs with com-
plete trans-diastereoselectivity. Reactions are easy to con-
duct, and all reagents used are commercially available.
Acknowledgment. We thank the Alexander von Humboldt
Foundation (stipend to Y.L.) and the Swiss National
Science Foundation (Grant 200020_135087 to P.R.) for
€
supporting our work. Dr. Klaus Bergander (WWU Munster)
is acknowledged for conducting the NMR experiments.
Supporting Information Available. Experimental details,
characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we presented the high yielding R-aminoxy-
lation of various ketones with chlorocatecholborane,
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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