Oxime radical promoted dioxygenation, oxyamination, and diamination of alkenes: Synthesis of isoxazolines and cyclic nitrones

Article abstract of DOI:10.1002/anie.201203799

Up the tempo: The intramolecular addition of oxime radicals to C=C bonds was achieved by using DEAD and TEMPO to give 4,5-dihydroisoxazoles as a result of a C=O bond-forming, 5-exo-trig cyclization. γ,δ-Unsaturated ketoximes also reacted to afford cyclic nitrones through C-N bond formation. The reactions offer a metal-free approach for the vicinal difunctionalization of unactivated alkenes. Copyright

Full text of DOI:10.1002/anie.201203799

Angewandte
Chemie
DOI: 10.1002/anie.201203799
Cyclization
Oxime Radical Promoted Dioxygenation, Oxyamination, and
Diamination of Alkenes: Synthesis of Isoxazolines and Cyclic
Nitrones**
Bing Han,* Xiu-Long Yang, Ran Fang, Wei Yu, Chao Wang, Xiao-Yong Duan, and Shuai Liu
In memory of Jay K. Kochi
nation and oxyamination at the alkene moiety. In addition,
Oximes are fascinating molecules which are used widely in
both organic chemistry and biochemistry.[1] The cyclization of
when g,d-unsaturated ketoximes were subjected to the
reaction conditions, cyclic nitrones were generated as the
À
b,g-unsaturated oximes constitutes
a
general synthetic
result of the 5-exo-trig N C bond-forming cyclization pro-
moted by oxime radicals (Scheme 1).
approach toward isoxazolines which are structurally impor-
tant in organic synthesis. So far the strategies employed for
this purpose involve the activation of carbon–carbon double
bonds by running the reaction under ionic conditions in the
presence of strong electrophilic reagents[2] or using palladium
as the catalyst;[3] methods of initiating the reactions from the
oxime side have not been reported. The free radical cycliza-
tion reactions have found wide applications in the synthesis of
carbo- and heterocyclic compounds.[4] In this context, it is
reasonable to expect that the oxime radical (iminoxyl radical)
involved in the intramolecular addition to a carbon–carbon
double bond should provide a convenient method for the
synthesis of isoxazolines. However, to the best of our knowl-
edge the participation of an oxime radical in reactions has not
been reported so far. This situation is a little bit surprising
considering that oxime radicals have been known for a long
time, and their analogues, aminoxyl radicals such as TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy), have found wide ap-
plications in organic synthesis.[5]
Oxime radicals were first identified by Thomas using EPR
spectroscopy as early as 1964,[6] and Ingold et al. isolated and
studied the di-tert-butyliminoxyl radical in 1971.[7] The
physical properties such as structure, stability, and spectros-
copy of oxime radicals have been extensively studied since
then.[8] Given our continued interest in the aminoxyl radical
mediated reactions,[9] we report herein the first 5-exo-trig
cyclization of b,g-unsaturated oximes involving an oxime
radical, a reaction which was initiated by commercially
available TEMPO or DEAD (diethyl azodicarboxylate).
The reactions afforded 4,5-dihydroisoxazoles with dioxyge-
Scheme 1. Oxime radical 5-exo-trig cyclization. T=trap.
At the beginning of this study, we first chose TEMPO to
initiate the free radical cyclization of b,g-unsaturated oximes.
Previous studies indicate that the O H bond in an oxime has
À
a relatively low bond dissociation energy (BDE, an average of
about 83 kcalmolÀ1).[10] We anticipated that TEMPO might
convert oximes into oxime radicals by a hydrogen atom
abstraction (HAT) process. The formed oxime radicals would
then undergo a 5-exo-trig cyclization to give the correspond-
ing carbon-centered radicals which could be trapped imme-
diately by TEMPO to produce isoxazoline derivatives. With
this in mind, we set out by treating a mixture of the b,g-
unsaturated ketoxime 1a with TEMPO (3 equiv) in toluene at
808C under argon. As expected, the desired reaction took
place, thus generating the TEMPO-trapped 4,5-dihydroisox-
azole 2a in 71% yield (Scheme 2).
While this result verified our initial hypothesis, the yield
of 2a was unsatisfactory to us. To improve the yield, we turned
our attention to dialkyl azodicarboxylates such as DEAD and
DIAD (diisopropyl azodicarboxylate), which are known to
react with NHPI (N-hydroxyphthalimide) and TEMPOH to
afford the PINO (phthalimido-N-oxyl) radical and TEMPO,
respectively.[11] Very recently, Alexanian et al. reported that
DIAD could be used to generate hydroxamic acid radicals
from hydroxamic acids which are analogues of NHPI.[12] To
our delight, when DEAD (1 equiv) was used as the oxime
radical initiator, and TEMPO (2 equiv) was used as the
carbon radical trapping agent, the same product 2a was
obtained in 93% yield along with a tiny amount of the
DEAD-trapped by-product isoxazoline 3a (Scheme 3, con-
[*] Prof. Dr. B. Han, X.-L. Yang, Dr. R. Fang, Prof. Dr. W. Yu, C. Wang,
X.-Y. Duan, S. Liu
State Key Laboratory of Applied Organic Chemistry College of
Chemistry and Chemical Engineering Lanzhou University
Lanzhou 730000 (P.R. China)
E-mail: hanb@lzu.edu.cn
[**] We are grateful for financial support from the NSFC (Nos. 20902040
and J1103307), the Program for Changjiang Scholars and Innovative
Research Team in University (No. IRT1138), the 111 Project, and the
Fundamental Research Funds for the Central Universities (lzujbky-
2012-61).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203799.
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Table 1: Oxime radical promoted dioxygenation and oxyamination of
alkenes to synthesis of isoxazolines.[a]
Entry Substrate
Condi- Product
tions[b]
t
Yield
[h] [%][c]
A
B
20 90[d]
1
20 88[d]
A
B
15 96
15 88
2
3
Scheme 2. TEMPO-initiated oxime radical 5-exo-trig cyclization.
A
B
15 90
15 86
4
5
A
A
15 93
24 77
Scheme 3. DEAD-initiated oxime radical 5-exo-trig cyclization.
ditions A). In contrast, when DEAD (3 equiv) was used in the
absence of TEMPO under the same reaction conditions, the
compound 3a was obtained in 91% yield (Scheme 3, con-
ditions B). This result demonstrates clearly that DEAD could
serve as an oxime radical initiator as well as carbon radical
trapping agent in the reaction.[13]
6
7
8
A
A
A
24 90
80
48
59:41[e]
Besides the importance of the isoxazoline structure motif,
the formation of compounds 2a and 3a involves dioxygena-
tion and oxyamination, respectively, of unactivated alkenes,
and these are two types of reactions which are of synthetic
significance.[14] To examine the scope of the present protocols,
a variety of b,g-unsaturated ketoximes were subjected to the
reaction conditions as shown in Scheme 3. The results are
summarized in Table 1. Compounds 1b–j reacted very well
under both sets of reaction conditions, thus giving rise to the
corresponding dioxygenation and oxyamination products 2
and 3, respectively, in good to excellent yields. Both aromatic-
and aliphatic-substituted ketoximes were tolerated (Table 1,
entries 1–5). Indole-containing ketoxime 1g was also trans-
formed into the desired product in excellent yield (Table 1,
entry 6). When compound 1h was used as the substrate, the
product was formed as a mixture of diastereoisomers
(Table 1, entry 7). When the alkene moiety was incorporated
into a ring, as in the cases of 1i and 1j, the reaction afforded
the trans dioxygenation and oxyamination products with high
stereoselectivity. Apparently, the trapping of the cyclization-
derived carbon radicals was more favored from the less
hindered exo direction (Table 1, entries 8 and 9). Notably, the
reaction could also be easily carried out in a gram scale
without difficulty, thereby delivering 2b and 3b in excellent
yield.
90
36
95:5[e,f]
90
A
B
36
36
95:5[e,f]
9
88
95:5[e,f]
[a] All reactions run at 0.5m toluene using oxime 1 (0.5 mmol) under Ar
at 508C. [b] Conditions A: DEAD (0.5 mmol) and TEMPO (1.0 mmol);
Conditions B: DEAD (1.5 mmol). [c] Yield of isolated product. [d] On
a gram scale 5 mmol oxime was used. [e] Diastereomeric ratios
determined by 1H NMR spectroscopy of crude reaction mixtures. [f] The
configuration of diastereomer was confirmed by NOE and coupling
constants from 1H NMR spectroscopy.
ketones. Following the reported procedure,[14d,15] the dioxyge-
nation product 2b can be reduced to the synthetically useful
compounds, the b,g-diol 4, in good yield. Compound 3b was
reduced in the same way to give b-hydroxy-g-diethyl hydra-
zine-1,2-dicarboxylate ketone (5) in excellent yield
(Scheme 4).
The reductive cleavage of 4,5-dihydroisoxazoles consti-
tutes a highly effective method for the synthesis of b-hydroxy
Having successfully achieved the 5-exo-trig radical cycli-
zation of b,g-unsaturated ketoximes, we moved on to extend
2
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resonance structures A and B (Fig-
ure 1).[6,8a–e] Later computational stud-
ies showed that the single-electron
spin densities are located on the
O atom (0.54–0.58) and on the
N atom (0.45–0.47) in oxime radi-
cals.[10] Our own computational study
also gave the similar spin densities on
O and N atoms in the ketoxime radical
C. It means that oxime radicals can
behave as nitrogen-centered radicals
as well as oxygen-centered radicals in the reaction. This result
also proves that oxime radicals are s radicals rather than
p radicals.[10]
Theoretical calculations on the energy profile for the
cyclization processes of C indicates that the C N bond-
Figure 1. Resonance
structures A and B
exist for oxime radi-
cals.
Scheme 4. Reductive cleavage of 4,5-dihydroisoxazoles.
the protocol to g,d-unsaturated ketoximes to see if the latter
compounds could undergo 6-exo-trig cyclization to form 5,6-
dihydro-4H-1,2-oxazines. However, when 6a was used as the
substrate, the expected 6-exo-trig cyclization product was not
formed. Instead, we obtained the cyclic nitrones 7a and 8a as
the products under reaction conditions A and B, respectively
À
À
(Table 2, entry 1). Apparently, 5-exo-trig C N bond-forming
forming 5-exo-trig cyclization via TS1 is more favored than
À
cyclization of the oxime radical is more favored than the 6-
the C O bond-forming 6-exo-trig cyclization via TS2 by
À
exo-trig C O bond-forming cyclization for compound 6a.
3.8 kcalmolÀ1 in terms of free energy of activation
(Figure 2).[16] Such an energy difference explains why the
reaction of compound 6a failed to deliver the 6-exo-trig
cyclization products. In fact, numerous studies have shown
that the 5-exo-trig cyclization of nitrogen- or oxygen-centered
radicals is generally a facile process, but the 6-exo-trig
cyclization is seldom reported.[4a,b]
Although this result seemed surprising at first, that is, the
DIAD-promoted cyclization of g,d-unsaturated hydroxamic
À
acids proceeding in the 6-exo-trig C O bond-forming fash-
ion,[12] it is consistent with the pattern of single-electron
distribution in oxime radicals. The previous EPR studies
revealed that oxime radicals should be represented by
The same product, 7a, was also obtained in 70% yield
when TEMPO (3 equiv) was used as the radical initiator in
the absence of DEAD, thus demonstrating that the formation
of the cyclic nitrone 7a from 6a is unambiguously a free
radical process (Scheme 5).
Table 2: Oxime radical promoted oxyamination and diamination of
alkenes to synthesis of cyclic nitrones.[a]
Entry
Substrate
Condi-
tions[b]
Product
t
Yield
[%][c]
[h]
A
B
72
72
80[d]
75[d]
1
90
A
B
48
48
90:10[e]
2
3
71
64:36[e]
83
A
48
50:50[e]
75
A
B
30
48
>99:1[e,f]
4
Figure 2. a) Energy profiles for the 6-exo-trig cyclization (O atom) and
5-exo-trig cyclization (N atom) of the ketoxime radical C; the relative
energies are given in kcalmolÀ1. b) The calculated Mulliken spin
density values for the O and N atoms and the spin density map of the
ketoxime radical C. Gridline indicates regions of positive spin density.
68
>99:1[e,f]
[a]–[f] See Table 1.
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In conclusion, we have demonstrated that the reactions
involving an oxime radical could be of great synthetic value.
Oxime radicals can be conveniently prepared from ketoximes
by using commercially available TEMPO or DEAD as the
radical initiator. By using this protocol, simple methods were
developed for the synthesis of 4,5-dihydroisoxazoles and
cyclic nitrones from b,g-unsaturated and g,d-unsaturated
Scheme 5. TEMPO-initiated oxime radical N-atom 5-exo-trig cycliza-
tion.
À
À
ketoximes, respectively, through C O bond-forming and C
N bond-forming 5-exo-trig cyclizations. TEMPO and DEAD
act as carbon radical scavengers as well in the reactions, and
consequently, the dioxygenation, oxyamination, and diami-
nation of unactivated alkenes can be realized. Furthermore,
this work gives direct evidence for the notion that single-
electron spin densities are delocalized on both the O atom
and N atom in the oxime radicals. Further studies on the
oxime radical promoted reaction are in progress in our
laboratory.
The procedures were then applied to several other g,d-
unsaturated ketoximes. As shown in Table 2, in all these cases,
cyclic nitrones were obtained in good yields. Compound 6b
was transformed under reaction conditions A into 7b and its
diastereoisomer 7b’, in a combined yield of 90% (Table 2,
entry 2). The ratio of 7b to 7b’ was 90:10. The structure of
compound 7b was confirmed by a single-crystal X-ray
diffraction study.[17] The observed stereoselectivity can be
explained with the model shown in Figure 3. In this model, the
carbon radical generated from 6b reacts with TEMPO
Received: May 17, 2012
Published online: && &&, &&&&
Keywords: alkenes · cyclization · heterocycles · radicals ·
.
synthetic methods
[1] a) K. Narasaka, M. Kitamura, Eur. J. Org. Chem. 2005, 4505;
b) J. Kassa, K. Kuca, L. Bartosova, G. Kunesova, Curr. Org.
Chem. 2007, 11, 267.
[2] a) M. Tiecco, L. Testaferri, L. Bagnoli, V. Purgatorio, A.
Temperini, F. Marini, C. Santi, Tetrahedron: Asymmetry 2001,
12, 3297; b) H. A. Dondas, R. Grigg, M. Hadjisoteriou, J.
Markandu, P. Kennewell, M. Thornton-Pett, Tetrahedron 2001,
57, 1119; c) V. Karapetyan, S. Mkrtchyan, T. T. Dang, A.
Villinger, H. Reinke, P. Langer, Tetrahedron 2008, 64, 8010;
d) M. D. Mosher, A. L. Norman, K. A. Shurrush, Tetrahedron
Lett. 2009, 50, 5647.
[3] a) M.-K. Zhu, J.-F. Zhao, T.-P. Loh, J. Am. Chem. Soc. 2010, 132,
6284; b) D. Jiang, J. Peng, Y. Chen, Org. Lett. 2008, 10, 1695.
[4] For reviews, see: a) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603;
b) J. Hartung, Eur. J. Org. Chem. 2001, 619; c) C. P. Jasperse,
D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. For selected
examples, see: d) L. Song, K. Liu, C. Li, Org. Lett. 2011, 13, 3434;
e) F. Liu, K. Liu, X. Yuan, C. Li, J. Org. Chem. 2007, 72, 10231.
[5] For reviews, see: a) L. Tebben, A. Studer, Angew. Chem. 2011,
123, 5138; Angew. Chem. Int. Ed. 2011, 50, 5034; b) C. Galli, P.
Gentili, O. Lanzalunga, Angew. Chem. 2008, 120, 4868; Angew.
Chem. Int. Ed. 2008, 47, 4790; c) R. A. Sheldon, I. W. C. E.
Arends, G.-J. Brink, A. Dijksman, Acc. Chem. Res. 2002, 35, 774;
d) T. Vogler, A. Studer, Synthesis 2008, 1979; e) A. Studer,
Chem. Soc. Rev. 2004, 33, 267.
Figure 3. Rationalization of the high selectivity for the formation of 7b.
through either conformer F or conformer G, with G being
lower in energy than F. TEMPO is expected to attack the
carbon radical from the direction away from the nitrone ring
to avoid the steric repulsion. The formation of 7b, which
resulted from the trapping of conformer G by TEMPO, is
preferred according to the Curtin–Hammett principle.[18] In
contrast, the stereoselectivity is much lower for the reaction
of 6b under reaction conditions B, probably because DEAD
is not as sterically demanding as TEMPO. The reactions of
compound 6d afforded either 7d or 8d in good yield and
excellent stereoselectivity, similar to the reactions of 1i and 1j
as mentioned previously (Table 2, entry 4).
Cyclic nitrones have attracted great attention because of
their multiple uses in pharmaceuticals[19] and as spin-trapping
reagents.[20] In addition, the [3+2] cycloaddition of nitrones
with dipolarophiles are important transformations in organic
synthesis.[21] In this context, 7a reacted with methyl propiolate
through a [3+2] cycloaddition to form the product 9 in
excellent yield (Scheme 6).
[6] J. R. Thomas, J. Am. Chem. Soc. 1964, 86, 1446.
[7] J. L. Brokenshire, G. D. Mendenhall, K. U. Ingold, J. Am. Chem.
Soc. 1971, 93, 5278.
[8] a) H. Lemaire, A. Rassat, Tetrahedron Lett. 1964, 5, 2245;
b) M. C. R. Symons, J. Chem. Soc. 1965, 2276; c) W. M. Fox,
M. C. R. Symons, J. Chem. Soc. A 1966, 1503; d) B. C. Gilbert,
R. O. C. Norman, J. Chem. Soc. B 1966, 86; e) A. Mackor, J. Org.
Chem. 1978, 43, 3241; f) T. S. Dobashi, D. R. Parker, E. J.
Grubbs, J. Am. Chem. Soc. 1977, 99, 5382; g) G. D. Mendenhall,
K. U. Ingold, J. Am. Chem. Soc. 1973, 95, 627; h) M. Lucarini,
G. F. Pedulli, A. Alberti, J. Org. Chem. 1994, 59, 1980; i) B. M.
Eisenhauer, M. Wang, H. Labaziewicz, M. Ngo, G. D. Menden-
hall, J. Org. Chem. 1997, 62, 2050.
Scheme 6. The [3+2] cycloaddition of cyclic nitrone with methyl
propiolate.
4
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Chemie
[9] a) Y.-X. Chen, L.-F. Qian, W. Zhang, B. Han, Angew. Chem.
2008, 120, 9470; Angew. Chem. Int. Ed. 2008, 47, 9330; b) B. Han,
C. Wang, R.-F. Han, W. Yu, X.-Y. Duan, R. Fang, X.-L. Yang,
Chem. Commun. 2011, 47, 7818; c) B. Han, X.-L. Yang, C. Wang,
Y.-W. Bai, T.-C. Pan, X. Chen, W. Yu, J. Org. Chem. 2012, 77,
1136; d) B. Han, R.-F. Han, Y.-W. Ren, X.-Y. Duan, Y.-C. Xu, W.
Zhang, Tetrahedron 2011, 67, 5615.
[10] a) D. A. Pratt, J. A. Blake, P. Mulder, J. C. Walton, H.-G. Korth,
K. U. Ingold, J. Am. Chem. Soc. 2004, 126, 10667, and references
therein; b) S.-S. Chong, Y. Fu, L. Liu, Q.-X. Guo, J. Phys. Chem.
A 2007, 111, 13112.
3846; c) Y. Zhang, M. S. Sigman, J. Am. Chem. Soc. 2007, 129,
3076; d) P. H. Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem.
Soc. 2008, 130, 17638; e) K. S. Williamson, T. P. Yoon, J. Am.
Chem. Soc. 2010, 132, 4570; f) H. Du, B. Zhao, Y. Shi, J. Am.
Chem. Soc. 2008, 130, 8590.
[15] D. Jiang, Y. Chen, J. Org. Chem. 2008, 73, 9181.
[16] See the Supporting Information for details of the theoretical
study.
[17] CCDC 880616 (7b) contains 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.
[11] a) E. Grochowski, T. Boleslawska, J. Jurczak, Synthesis 1977,
718; b) M. Hayashi, M. Shibuya, Y. Iwabuchi, J. Org. Chem.
2012, 77, 3005.
[18] a) J. I. Seeman, Chem. Rev. 1983, 83, 83; b) J. I. Seeman, J. Chem.
Educ. 1986, 63, 42.
[12] V. A. Schmidt, E. J. Alexanian, J. Am. Chem. Soc. 2011, 133,
11402.
[13] For azodicarboxylates serve as the carbon radical trapping agent,
see: a) A. Shah, M. V. George, Tetrahedron 1971, 27, 1291; b) J.
Waser, B. Gaspar, H. Nambu, E. M. Carreira, J. Am. Chem. Soc.
2006, 128, 11693.
[14] For transition metal catalyzed vicinal dioxygenation, oxyamina-
tion, and diamination of olefins, see: a) H. C. Kolb, M. S.
VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483;
b) A. Wang, H. Jiang, H. Chen, J. Am. Chem. Soc. 2009, 131,
[19] R. A. Floyd, R. D. Kopke, C.-H. Choi, S. B. Foster, S. Doblas,
R. A. Towner, Free Radical Biol. Med. 2008, 45, 1361.
[20] Y. Han, B. Tuccio, R. Lauricella, F. A. Villamena, J. Org. Chem.
2008, 73, 7108.
[21] a) J. Revuelta, S. Cicchi, A. Goti, A. Brandi, Synthesis 2007, 485,
and references therein; b) F. M. Cordero, M. Salvati, C. Vurchio,
A. de Meijere, A. Brandi, J. Org. Chem. 2009, 74, 4225; c) S.
Stecko, A. Mames, B. Furman, M. Chmielewski, J. Org. Chem.
2008, 73, 7402.
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Communications
Cyclization
B. Han,* X.-L. Yang, R. Fang, W. Yu,
C. Wang, X.-Y. Duan,
S. Liu
&&&& — &&&&
Oxime Radical Promoted Dioxygenation,
Oxyamination, and Diamination of
Alkenes: Synthesis of Isoxazolines and
Cyclic Nitrones
Up the tempo: The intramolecular addi-
also reacted to afford cyclic nitrones
=
À
tion of oxime radicals to C C bonds was
through C N bond formation. The reac-
achieved by using diethyl DEAD and
TEMPO to give 4,5-dihydroisoxazoles as
a result of a C O bond-forming, 5-exo-trig
cyclization. g,d-Unsaturated ketoximes
tions offer a metal-free approach for the
vicinal difunctionalization of unactivated
alkenes.
À
6
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