TEMPO-mediated aliphatic C-H Oxidation with Oximes and hydrazones

Article abstract of DOI:10.1021/ol4014969

A method for aliphatic C-H bond oxidation of oximes and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) has been developed, which enables the concise assembly of substituted isoxazole and pyrazole skeletons.

Full text of DOI:10.1021/ol4014969

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
TEMPO-Mediated Aliphatic CꢀH
Oxidation with Oximes and Hydrazones
Xu Zhu, Yi-Feng Wang, Wei Ren, Feng-Lian Zhang, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received April 17, 2013
ABSTRACT
A method for aliphatic CꢀH bond oxidation of oximes and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) has been
developed, which enables the concise assembly of substituted isoxazole and pyrazole skeletons.
The sp3-hybridized carbonꢀhydrogen bonds (aliphatic
CꢀH bonds) are ubiquitous in organic molecules, while
most of them especially without activation by the adjacent
functional groups (e.g., carbonyl groups) are inert even
under harsh reaction conditions. As direct functionalization
of such nonreactive aliphatic CꢀH bonds can potentially
result in the atom- and step-economical assembly of
functionalized chemical structures, development of chemo-
and regioselective CꢀH oxidation strategies is one of the
most challenging topics in synthetic chemistry.1
especially in CꢀH oxygenation2 and CꢀH amination,3
which have actually revolutionized the retrosynthetic tac-
tics of biologically active complex molecules.4 On the other
hand, our reaction design for the CꢀH oxidation was
motivated by the potential of free radical reactions that
could be operated under transition-metal-free conditions.
A representative example of aliphatic CꢀH oxidation with
€
the free-radical strategy is the HofmannꢀLofflerꢀFreytag
reaction (Scheme 1A).5 The process is initiated by thermal
or photochemical decomposition of protonated N-halo-
amines to afford nitrogen-centered radicals (N-radicals),
which immediately induce a 1,5-H radical shift to provide
carbon-centered radicals (C-radicals). Further chlorina-
tion of the C-radicals followed by a base-mediated intra-
molecular substitution reaction results in the CꢀN bond.
Transition-metal catalysts have played a significant role
in state-of-the-art aliphatic CꢀH oxidation processes,
(1) For recent reviews on CꢀH oxidation, see: (a) White, M. C.
Science 2012, 335, 807. (b) Davies, H. M. L.; Du Bois, J.; Yu, J.-Q. Chem.
Soc. Rev. 2011, 40, 1855. (c) Newhouse, T.; Baran, P. S. Angew. Chem.,
Int. Ed. 2011, 50, 3362. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147 and references therein.
€
However, the HofmannꢀLofflerꢀFreytag reaction tends
to afford poor product yields while being difficult to
control, mainly due to the instability of the radical pre-
cursors (N-haloamines) and inherent high chemical reac-
tivity of the resulting aminyl radicals. Moreover, several
steps (i.e., preparation of N-haloamines, radical CꢀH
halogenation, and base-mediated substitution reaction
for the CꢀN bond construction) are required to obtain
CꢀH amination products. Based on these backgrounds,
(2) For recent selected reports on CꢀH oxygenation, see: (a) Wang,
Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 11980.
(b) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70. (c) McNeill, E.;
Du Bois, J. Chem. Sci. 2012, 3, 1810. (d) Zhang, S.-Y.; He, G.; Zhao, Y.;
Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313.
€
(e) Prat, I.; Mathieson, J. S.; Guell, M.; Ribas, X.; Luis, J. M.; Cronin,
L.; Costas, M. Nat. Chem. 2011, 3, 788. (f) Bigi, M. A.; Reed, S. A.;
White, M. C. Nat. Chem. 2011, 3, 216. (g) Gormisky, P. E.; White, M. C.
J. Am. Chem. Soc. 2011, 133, 12584. (h) Chen, M. S.; White, M. C.
Science 2010, 327, 566. (i) McNeil, E.; Du Bois, J. J. Am. Chem. Soc.
2010, 132, 10202. (j) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 14654.
(4) For recent reviews, see: (a) Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (b) Chen, D. Y.-K.;
Youn, S. W. Chem.;Eur. J. 2012, 18, 9452.
(3) For recent reviews on CꢀH amination, see: (a) Roizen, J. L.;
Harvey, M. E.; Du Bois, J. Acc. Chem. Rec. 2012, 45, 911. (b) Du Bois, J.
Org. Process Res. Dev. 2011, 15, 758. (c) Collet, F.; Lescot, C.; Dauban,
P. Chem. Soc. Rev. 2011, 40, 1926. (d) Zalatan, D. N.; Du Bois, J. Top.
Curr. Chem. 2010, 292, 347. (e) Collet, F.; Dodd, R. H.; Dauban, P.
(5) (a) Titouania, S. L.; Lavergne, J.-P.; Viallefonta, P.; Jacquierb, E.
Tetrahedron 1980, 36, 2961. (b) Corey, E. J.; Hertler, W. R. J. Am. Chem.
ꢀ
€
Chem. Commun. 2009, 5061. (f) Dıaz-Requejo, M. M.; Perez, P. J. Chem.
Soc. 1960, 82, 1657. (c) Loffler, K.; Freytag, C. Ber. 1909, 42, 3427. (d)
Rev. 2008, 108, 3379.
Hofmann, A. W. Ber. 1883, 16, 558.
r
10.1021/ol4014969
XXXX American Chemical Society

we have designed the intramolecular setting for remote
CꢀH functionalization6 using stabilized heteroatom-centered
(O- or N-) radicals derived from oxime7 or hydrazone8
derivatives. It could be envisioned that these heteroatom
radicals from oximes or hydrazones undergo 1,5-H-radical
abstraction9 to generate C-radicals at the β-position, where
the concentration of the C-radicals could be kept lower due to
the weaker reactivity of the oxime or hydrazone radicals that
can potentially result in the highly selective oxidative trans-
formation of the C-radicals (Scheme 1B). Herein, we report
the realization of this concept as TEMPO-mediated oxidative
aliphatic sp3 CꢀH oxygenation with oximes as well as sp3
CꢀH amination with hydrazones.
while a polar protic one (t-BuOH, entry 8) made the reac-
tion sluggish. A higher reaction temperature (140 °C) in
DMF and DMA resulted in the best yields of 2a (86% and
84%, respectively), with full conversion and acceleration
of the reaction rate (entries 9 and 10). The reaction with
a sterically less hindered nitroxyl radical, AZADO10
(2-adamantan-N-oxyl), afforded a lower yield of 2a
(entry 11). Although the reaction with DIAD11 (diisopropyl
azodicarboxylate) consumed 1a rapidly (for 3 h), the yield of
2a was moderate along with the formation of unidentified
complex mixtures (entry 12).
Table 1. Optimization of Reaction Conditionsa
Scheme 1. CꢀH Oxidation with Radical Strategies
oxidants additives
temp time yield of
entry (3 equiv) (2 equiv) solvents
(°C)
(h)
2a (%)b
1
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
AZADO
DIAD
ꢀ
toluene
toluene
toluene
toluene
DMSO
DMF
120
120
120
120
120
120
120
120
140
140
140
140
24
48
48
48
48
48
48
48
17
17
23
3
30 (30)c
68 (10)c
57 (25)c
56 (30)c
78 (14)c
83 (9)c
78 (6)c
21 (47)c
86
2
K2CO3
K3PO4
NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
3
4
5
6
7
DMA
8
t-BuOH
DMF
9
10
11
12
DMA
84
DMF
58
We commenced our investigation with the reaction
of ketoxime 1a to oxidize its tertiary CꢀH bond at the
β-position of the oxime moiety (marked in red) using various
nonmetal oxidants for generation of the corresponding
iminoxyl radical under an inert (N2) atmosphere (Table 1).
When 1a was treated with TEMPO (2,2,6,6-tetramethyl-
piperidin-1-oxyl, 3 equiv) in toluene,7a the reaction proceeded
at 120 °CtoaffordanintramolecularCꢀH oxygenation prod-
uct, dihydroisoxazole 2a, in 30% yield along with 30% re-
covery of 1a and some unidentified complex mixtures (entry 1).
Addition of inorganic bases (2 equiv) rendered the reac-
tions more efficient (entries 2ꢀ4). Further screening of the
solvents revealed that the polar aprotic solvents (DMSO,
DMF, and DMA) gave good yields of 2a (entries 5ꢀ7),
(6) The recent reports on sp3 CꢀH oxidation (oxygenation and
desaturation) by Baran’s group have shown the great potential of the
radical strategy via remote H-radical abstraction as a key step; see: (a)
Voica, A.-F.; Mendoza, A.; Gutekunst, W. R.; Fraga, J. O.; Baran, P. S.
Nat. Chem. 2012, 4, 629. (b) Chen, K.; Baran, P. S. Nature 2009, 459, 824. (c)
Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247.
(7) For application of iminoxyl radicals to organic synthesis, see: (a)
Han, B.; Yang, X.-L.; Fang, R.; Yu, W.; Wang, C.; Duan, X.-Y.; Liu, S.
Angew. Chem., Int. Ed. 2012, 51, 8816. (b) Ngo, M.; Larson, K. R.;
Mendenhall, G. D. J. Org. Chem. 1986, 51, 5390. (c) Cornejo, J. J.;
Larson, K. R.; Mendenhall, G. D. J. Org. Chem. 1985, 50, 5382.
(8) For application of hydrazonyl radicals to organic synthesis, see:
(a) Zhu, M.-Z.; Chen, Y.-C.; Loh, T.-P. Chem.;Eur. J. 2013, in press
(DOI: 10.1002/chem.201203832). (b) Harej, M.; Dolenc J. Org. Chem.
2007, 72, 7214 and references therein.
DMF
33
a The reactions were carried out using 0.25 mmol of 1a in solvents
(0.1 M). b Isolated yields. c Recovery yield of 1a.
We next examined the generality of this TEMPO-
mediated CꢀH oxygenation of oximes 1 for the synthesis
of isoxazole derivatives 2 under the optimized reaction
conditions (Table 1, entry 9). By varying the substituent
R1, various aromatic rings including both electron-rich
and -deficient benzene rings as well as a thienyl unit could
be installed (Scheme 2, for 2bꢀ2g).12 The reaction of oxime
1h bearing an ethyl moiety as R1 also proceeded, while the
yield of 2h was moderate (in 40% yield). Oxygenation of
diaryl methine moieties bearing various aromatic rings
proceeded smoothly to give the corresponding 5,5-diaryl-
4,5-dihydroisoxazoles in good yields (for 2iꢀ2k). The
reaction of oxime 1l (R2 = Me; R3 = Ph) afforded
(10) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
Chem. Soc. 2006, 128, 8412.
(11) For the use of DIAD as a radical initiator, see: (a) Shan, A.;
George, M. V. Tetrahedron 1971, 27, 1291. (b) Huisgen, R.; Pohl, H.
Chem. Ber. 1960, 93, 527.
(12) Oximes 1g, 1h, and 1o were obtained as
a mixture of
E/Z-isomers. No difference was observed in the yields of 2g between
treatment of E/Z mixture of 1g and that of pure E-isomer 1g, which
suggested that isomerization of the NꢀO bond in the oxime E/Z isomers
could readily occur under the present reaction conditions. See the SI for
more details.
(9) For reviews, see: (a) Cekovic, Z. Tetrahedron 2003, 59, 8073. (b)
Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095.
B
Org. Lett., Vol. XX, No. XX, XXXX

5-methyl-3,5-diphenyl-4,5-dihydroisoxazole (2l) in 55%
yield, while that of oxime 1m (R2 and R3 = Me) resulted
in a moderate yield (34%) of 5,5-dimethyldihydroisoxazole
2m. However, R-cyclopropyl- and R-cyclohexyloximes 1n
and 1o were not converted into the desired dihydroisoxa-
zoles at all. Oxime 1p having a more reactive dibenzylic
methine CꢀH bond at the 6-position (marked in green) to
the oxime oxygen underwent cyclization onto the 5-position
(markedinred) togive2p albeit in low yield. Oxygenation of
a benzylic methylene moiety of 1q and 1r could also be
achieved to give the corresponding aromatized isoxazoles 2q
and 2r, respectively, by the reaction of oximes with TEMPO
and subsequent treatment of the reaction mixture under an
air atmosphere for completion of the aromatization.
both an ionic and radical 5-endo manner.15 The presence
of C-radical B could be speculated by the reactions of
oxime 1s bearing an R-quaternary carbon with a cycpropyl
unit. While the reaction of 1s with 4 equiv of TEMPO was
very sluggish, isoxazole 2s bearing a 2-aminoxyethyl part
was formed via radical ring opening of the cyclopropane16
followed by trapping of the resulting primary C-radical
(on the carbon marked in green) with TEMPO (see the
Supporting Information (SI) for the detailed reaction
mechanism). It was found that the combined use of TEMPO
and DIAD (3 equiv in each) could accelerate the reaction and
improve the yield of 2s to 56% yield. It is noted that the re-
actions of other types of R-quaternary oximes (2,2-dimethyl
1t, cyclohexyl 1u, and benzene tethered 1v; see the SI) gave no
desired CꢀH oxgenation products.
Scheme 2. TEMPO-Mediated CꢀH Oxygenation of Oximes 1aꢀc
Scheme 3. A Proposed Reaction Mechanism and Reactions
of 1s
a Unless otherwise noted, the reactions were carried out using
0.25 mmol of oximes 1 under a N2 atmosphere at 140 °C for 6ꢀ31 h
(see the Supporting Information for more details). b Oximes 1 except for
1g, 1h, and 1r were obtained as a pure E-isomer. Oximes 1g, 1h, and 1r
were used as an E/Z mixture for the reaction (see ref 12 and the SI for
more details). c Isolated yields were recorded above. d Recovery yield of
oxime 1. e Upon heating under a N2 atmosphere for 23 h, the reaction
mixture was exposed to air for 3 h.
Stimulated by the structural analogy of hydrazones 3
with oximes 1, we next examined the TEMPO-mediated
reactions of hydrazones 3for sp3 CꢀH amination (Scheme 4).
As expected, treatment of both N-phenyl and N-benzoyl
hydrazones 3a and 3b with TEMPO (3 equiv) delivered the
corresponding β-CꢀH amination products, dihydropyra-
zoles 4a and 4b, respectively in good yields.17 Various 5,5-
diaryl-4,5-dihydropyrazoles could be constructed in good
yields (for 4cꢀ4g). Amination of methine CꢀH bonds
bearing only one phenyl group (3h: R2 = Me, R3 = Ph)
Based on these results, a proposed mechanism of this
TEMPO-mediated CꢀH oxygenation of oximes 1is depicted
in Scheme 3. TEMPO induces generation of iminoxyl radical
A that undergoes a rate-determining 1,5-H radical shift to
give C-radical intermediate B. Another TEMPO traps the
resulting C-radical B to generate β-aminoxyl oxime C, and
successive elimination of 1-hydroxy-2,2,6,6-tetramethyl-
piperidine (TEMPO-H)13 affords R,β-unsaturated oxime D,14
which cyclizes to give dihydroisoxazole 2 probably via
(15) To investigate the mechanism of the cyclization, we have pre-
pared R,β-unsaturated oxime 1q0 (the model of intermediate D for the
reaction of 1q to 2q) and examined several reactions of 1q0. See: Shotter,
R. G.; Sesardic, D.; Wright, P. H. Tetrahedron 1975, 31, 3069.
(16) (a) Newcomb, M. Tetrahedron 1993, 49, 1151. (b) Griller, D.;
Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(17) The formation of N-benzoyl dihydropyrazole 4b needed 39 h to
complete the reaction. It was found that quenching the reaction of 3b for
4 h provided R,β-unsaturated hydrazone 4b0 in 39% yield along with the
formation of dihydropyrazole 4b in 26% yield and recovery of 3b in 26%
yield. The isolation of R,β-unsaturated hydrazone 4b0 supported the
reaction mechanism of the present CꢀH oxidation depicted in Scheme 2.
See the Supporting Information for mode details.
(13) For the elimination of TEMPO-H from C, several possible
pathways could be considered such as ionic anti-elimination with base,
ionic syn-elimination where the N atom of the aminoxyl group works as
an internal base, and radical elimination with CꢀO bond homolysis. For
a report on ionic syn-elimination, see: Ananchenko, G. S.; Fischer, H.
J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 3604. For a report on
radical elimination, see: Maity, S.; Manna, S.; Rana, S.; Naveen, T.;
Mallick, A.; Maiti, D. J. Am. Chem. Soc. 2013, 135, 3355.
(14) While we could not observe the presence of R,β-unsaturated
oxime D in the reaction of oximes 1 even by further lowering the reaction
temperature, the corresponding R,β-unsaturated hydrazone could be
isolated and characterized; see ref 17.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. TEMPO-Mediated Reactions of Hydrazones 3aꢀc
Scheme 5. Reactions of R-Cycloalkyl Hydrazones 3kꢀm
a Unless otherwise noted, the reactions were carried out using
0.25 mmol of hydrazones 3 under a N2 atmosphere at 130 °C for
b
12ꢀ60 h (see the SI for more details). Hydrazones 3 except for 3a
and 3e were obtained as a pure E-isomer. Hydrazones 3a and 3e were
used as an E/Z mixture for the reaction (see the SI for more details). c
Isolated yields. Upon heating under a N2 atmosphere for 28 h, the
d
reaction mixture was exposed to air for 3 h. e The reaction was run with
4.5 equiv of TEMPO for 28 h.
In summary, we have developed an operationally simple
TEMPO-mediated aliphatic CꢀH oxidation with oximes
and hydrazones, which enables the concise assembly of
substituted isoxazole and pyrazole skeletons under transi-
tion-metal-free conditions. The reaction mechanism in the
present processes includes a 1,5-H radical shift of iminoxyl
and hydrazonyl radicals generated from oxime and hydra-
zone derivatives, respectively, with TEMPO. We are cur-
rently engaged in further synthetic applications of this
radical mediated tactic for other types of aliphatic CꢀH
oxidation.
and even with a dimethyl motif (3i: R2 and R3 = Me)
proceeded smoothly to give 4h and 4i, respectively, in good
yields, which indicated that the N-radical species derived
from hydrazones 3 could possess higher reactivity toward
the targeted CꢀH bonds than that of the O-radicals from
oximes 1 (by comparison with the formation of 2l and 2m
in Scheme 2). Synthesis of 1,3,4,5-tetraphenylpyrazole (4j)
could be realized in excellent yield by methylene CꢀH
amination followed by further aromatization by air or
excess amounts of TEMPO.
The reaction of R-cyclopropyl hydrazone 3k with TEM-
PO (6 equiv) delivered aromatized pyrazoles 4k and 4k0
(Scheme 5a). In this case, the present β-CꢀH amination
generates the corresponding dihydropyrazole I, which
might undergo radical ring opening of the cyclopropane
moiety driven by aromatization to form C-radical inter-
mediate II. Subsequent trapping of the C-radical II with
TEMPO affords 4k, which could undergo further elimina-
tion of TEMPO-H to afford 4k0. It is worth noting that this
aromatization-driven radical ring opening could be ob-
served even for stable cyclopentane and -hexane rings of
hydrazones 3l and 3m, affording the corresponding pyr-
azoles 4l and 4m, respectively, although the yields were
moderate (Scheme 5b).
Acknowledgment. This work was supported by funding
from Nanyang Technological University and the Singapore
Ministry of Education (Academic Research Fund Tier 2:
MOE2012-T2- 1-014). Y.-F.W. is thankful for the Lee
Kuan Yew postdoctoral fellowship (the LKY PDF). We
acknowledge a generous gift of AZADO from Nissan
Chemical Industries, Ltd. We appreciate the valuable sug-
gestions from the referees to this work.
Supporting Information Available. Experimental proce-
dures, characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX