Oxidation of catecholboron enolates with tempo

Full text of DOI:10.1002/anie.200902242

Angewandte
Chemie
DOI: 10.1002/anie.200902242
Synthetic Methods
Oxidation of Catecholboron Enolates with TEMPO**
Martin Pouliot, Philippe Renaud,* Kurt Schenk, Armido Studer,* and Thomas Vogler
The persistent nitroxide radical 2,2,6,6-tetramethylpiperi-
dine-N-oxyl (TEMPO) has found widespread application in
organic synthesis. Along with its use as a catalyst for the
oxidation of alcohols, TEMPO has been shown to oxidize
À
various organometallic compounds leading to efficient C H
arylation and homocoupling reactions.[1–4] However, alkyl
organometallic species of Li, Mg, Zn, Cu, Sm, and Ti do not
provide the corresponding homocoupling products upon
exposure to TEMPO.[5] In these processes, one equivalent of
Scheme 1. Reaction of B-alkylcatecholboranes with TEMPO.
the nitroxide is used to oxidize the organometallic species to
the corresponding C-centered radical, which is then trapped
by a second equivalent of TEMPO to give the alkoxyamine.
Along these lines, we have shown that B-alkylcatecholbor-
anes 1 react similarly: formal homolytic substitution at boron
in 1 with TEMPO leads to the boric ester 2 and the
corresponding C-centered radical, which is irreversibly trap-
ped by TEMPO (Scheme 1).[6]
methods for the formation of catecholboron enolates and
report on regio- and stereoselective transformations.
We envisaged that a formal homolytic substitution at
boron in catecholboron ketone enolate 3 with TEMPO
should liberate the stabilized enolyl radical 4, which upon
trapping with TEMPO should give the corresponding a-
aminoxylated ketone 5 (Scheme 2).
B-alkylcatecholboranes, easily prepared by hydroboration
of alkenes with catecholborane, constitute a highly effective
source of alkyl radicals. Based on this property, a wide range
of synthetic applications including conjugate addition, allyla-
tion, and chalcogenation have been recently developed.[7]
However, so far all reactions involving B-alkylcatecholbor-
anes concern exclusively the generation of non-functionalized
alkyl and benzyl radicals. Herein we report the first examples
of the generation of resonance-stabilized a-carbonyl radicals
(enolyl radicals) from ketone-derived catecholboron enolates
by reaction with TEMPO and their further trapping with
TEMPO to form the corresponding a-aminoxylated
ketones.[8,9] In addition, we introduce two simple and general
Scheme 2. Generation of a-carbonyl radicals from catecholboron eno-
lates.
[*] Dr. M. Pouliot,[+] Prof. Dr. P. Renaud
Universitꢀt Bern, Departement fꢁr Chemie und Biochemie
Freiestrasse 3, 3000 Bern 9 (Switzerland)
Fax: (+41)31-631-3426
We were surprised to find that catecholboron ketone
enolates have not been well investigated to date. These
enolates have been generated either by reduction of a-halo
ketones with catecholborane[10] or from the corresponding
enones by conjugate reduction with catecholborane.[11] Our
initial studies were performed on a boron enolate readily
generated in situ from chlorochalcone 6. Enolate formation
and TEMPO trapping could be conducted under mild
conditions as a one-pot process. The best result was achieved
in CH2Cl2 by using a slight excess of borane (1.1 equiv) and
TEMPO (2.5 equiv) to afford 7 in 87% yield and 8 in 11%
yield (Scheme 3). In THF as a solvent under otherwise
identical conditions 7 was isolated in 81% yield along with 8
in 10% yield.[12] Our attempts to convert the corresponding
pinacol- or dibutylboron enolate to the a-aminoxylated
ketone 7 were not successful. We attribute this to unproduc-
tive homolytic bond cleavage of these enolates.
E-mail: philippe.renaud@ioc.unibe.ch
Prof. Dr. A. Studer, Dr. T. Vogler[+]
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax: (+49)251-83-36523
E-mail: studer@uni-muenster.de
Dr. K. Schenk
ꢂcole Polytechnique Fꢃdꢃrale de Lausanne
Laboratoire de Cristallographie, Le Cubotron—Dorigny
1015 Lausanne (Switzerland)
[+] T.V. and M.P. have contributed equally to this research.
[**] We thank the Fonds der Chemischen Industrie (stipend to T.V.),
Novartis Pharma AG (Young Investigator Award to A.S.), the DFG
(A.S.), and the Swiss National Science Foundation (P.R.) for
financial support. Ciba Specialty Chemicals and BASF Corporation
are acknowledged for the donation of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902242.
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Scheme 3. Generation of catecholboron enolate and subsequent
TEMPO oxidation.
Scheme 4. Thermal isomerization of alkoxyamines.
Under optimized conditions a series of readily available
enones (see the Supporting Information) were transformed to
the corresponding alkoxyamines 9–13 (Figure 1). Aryl alkenyl
ketones gave the desired oxidation products 9 and 10 in high
such as acetophenone. Therefore, we tried to access catechol-
boron enolates by transmetalation of the corresponding
ketone enolates. Unfortunately, all attempts to obtain these
by ketone deprotonation with Li amide bases (several tested)
or amines followed by treatment with bromo- or chloroca-
techolborane failed.
However, we succeeded in generating these boron eno-
lates in situ from readily available trimethylsilyl enol ethers
(see the Supporting Information) upon treatment with
chlorocatecholborane. To the best of our knowledge, this
approach to catecholboron enolates is unprecedented.[15]
Importantly, boron enolate formation and TEMPO trapping
could be performed as a one-pot process. Hence, treatment of
a trimethylsilyl enol ether with chlorocatecholborane and
TEMPO in CH2Cl2 at low temperature afforded the corre-
sponding a-oxidation products 18–23 in good to excellent
yields (66–97%, Scheme 5). Although we currently favor the
boron enolate 16 as an intermediate, the reaction might also
Figure 1. Preparation of TEMPO-derived alkoxyamines 9–13.
À
proceed via the B C-bound species 17. This novel method
allowed a-aminoxylation of cyclic ketones as shown for
alkoxyamines 20–23, which were not accessible via the
corresponding cyclic a,b-unsaturated ketones. As expected
for a radical reaction, trans-22 and trans-23 were obtained as
yields. Alkoxyamines 11 and 12 derived from heteroaryl-
substituted enones were obtained in slightly lower yields. It is
important to note that hydroboration and hence oxidation
occurred with excellent regioselectivity. Products arising from
oxidation of the terminal double bond were not identified.
Furthermore, no cyclization products were observed in these
reactions because of the highly efficient TEMPO trapping of
the a-carbonyl radicals generated in situ. Pleasingly, this
strategy also worked for alkyl alkenyl ketones as shown for
regioselective transformation of b-ionone to give alkoxy-
amine 13 (81%).
TEMPO-derived alkoxyamines bearing a double bond at
an appropriate position can serve as substrates for tin-free
radical isomerization reactions, as we have previously
shown.[13] Heating of alkoxyamine 9 in tBuOH at 1308C in a
sealed tube for 20 h provided products 14a (42%) and 14b
(28%) by radical 5-exo and 6-endo cyclizations, respectively.
By analogy, alkoxyamine 12 was readily isomerized to give
15a and 15b. The 5-exo cyclizations afforded trans products,
whereas the 6-endo products were obtained as mixtures of
diastereomers (Scheme 4).[14]
Unfortunately, enolate formation followed by TEMPO
oxidation could not be used for a-aminoxylation of cyclic a,b-
unsaturated ketones. The desired boron enolates cannot be
formed by application of the established conjugate reduction
protocol, as presented above, since these undergo slow 1,2-
reduction.[11a] Moreover, this procedure inherently precludes
the a-aminoxylation of the methyl residue of methyl ketones
Scheme 5. Aminoxylation of silyl enol ethers.
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Angewandte
Chemie
the major diastereomers from the kinetically favored trapping
of the corresponding cyclohexyl radicals.[16] The relative
configuration of 22 and 23 was secured by X-ray crystallog-
raphy (see the Supporting Information).[17]
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Cadot, P. I. Dalko, J. Cossy, C. Ollivier, R. Chuard, P. Renaud, J.
Org. Chem. 2002, 67, 7193.
Finally, we tried to combine our novel a-aminoxylation
À
with a stereoselective C C bond-forming reaction. The
asymmetric reaction should deliver an intermediate that can
be readily transformed to the corresponding catecholboron
enolate. The intensively investigated copper-catalyzed 1,4-
addition of diethyl zinc to cyclohexenone was chosen as the
test reaction.[18] Initially, we tried to convert the zinc enolate
formed in situ to the corresponding silyl enol ether (by
addition of TMSOTf)[19] followed by a-aminoxylation. This
route provided the desired alkoxyamine (À)-22 in only 20%
yield. However, we found that direct treatment of the zinc
enolate intermediate 24 with chlorocatecholborane and
subsequent TEMPO trapping gave alkoxyamine (À)-22 in
61% overall yield (Scheme 6). TEMPO trapping occurred
[7] For review articles see: a) C. Ollivier, P. Renaud, Chem. Rev.
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[9] For a-aminoxylated esters see: a) K. Matyjaszewski, B. E.
Woodworth, X. Zhuand, S. G. Gaynor, Z. Metzner, Macro-
molecules 1998, 31, 5955; b) U. Jahn, M. Mꢁller, S. Aussieker, J.
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Scheme 6. One-pot enantioselective 1,4-addition/a-aminoxylation.
[10] T. Mukaiyama, T. Takuwa, K. Yamane, S. Imachi, Bull. Chem.
Soc. Jpn. 2003, 76, 813.
[11] a) D. A. Evans, G. C. Fu, J. Org. Chem. 1990, 55, 5678; b) Y.
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[12] Currently we do not understand the mechanism for the
formation of the undesired side product 8. Hydrolysis of the
boron enolate seems unlikely since careful drying of the solvent
or addition of 3 ꢄ molecular sieves to the reaction mixture did
not suppress its formation. Transenolization between the initially
formed boron enolate and the more acidic a-alkoxyaminoketone
cannot be excluded.
[13] a) A. Studer, Angew. Chem. 2000, 112, 1157; Angew. Chem. Int.
Ed. 2000, 39, 1108; b) C. Wetter, K. Jantos, K. Woithe, A. Studer,
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with very good trans diastereoselectivity (91:9). This cascade
reaction clearly showed that the zinc enolate was efficiently
converted to the corresponding catecholboron enolate upon
treatment with chlorocatecholborane. Ketone 22 was
obtained with excellent enantioselectivity (96% ee).[20]
In summary, we have developed a novel method for the
generation of a-carbonyl radicals from catecholboron ketone
enolates by reaction with TEMPO. The boron enolates were
readily obtained by reduction of linear enones with catechol-
borane or by transmetalation of silyl enol ethers and zinc
enolates with chlorocatecholborane. In situ trapping of the a-
carbonyl radicals with TEMPO provided the corresponding
alkoxyamines in high yields. An enantiomerically enriched
chiral boron enolate generated in situ reacted with TEMPO
with very good diastereoselectivity.
[14] The trans relative configuration of the 5-exo cyclization products
14a and 15a presumably results from an epimerization process
(see Ref. [13a]).
[15] For related Si-to-B transmetalation see: a) J. L. Duffy, T. P.
Yoon, D. A. Evans, Tetrahedron Lett. 1995, 36, 9245; b) Y. Mori,
K. Manabe, S. Kobayashi, Angew. Chem. 2001, 113, 2897; Angew.
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[16] D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1995; P. Renaud in Radicals in
Received: April 27, 2009
Published online: July 7, 2009
Keywords: alkoxyamines · boron enolates · enolyl radicals ·
.
nitroxides · oxidation
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Communications
Organic Synthesis, Vol. 1 (Eds.: P. Renaud, M. P. Sibi), Wiley-
VCH, Weinheim, 2001, p. 400.
Engl. 1997, 36, 2620; b) B. L. Feringa, Acc. Chem. Res. 2000, 33,
346.
[17] CCDC 732856 (23) and 732857 (22) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[19] O. Knopff, A. Alexakis, Org. Lett. 2002, 4, 3835.
[20] The enantiomeric excess was measured for 3-ethylcyclohexa-
none, which was obtained by hydrolysis of the zinc enolate 24
(see Ref. [18a] and the Supporting Information).
[18] a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M.
de Vries, Angew. Chem. 1997, 109, 2733; Angew. Chem. Int. Ed.
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