Ru-Catalyzed Redox-Neutral Cleavage of the N-O Bond in Isoxazolidines: Isatogens to Pseudoindoxyls via a One-Pot [3 + 2]-Cycloaddition/N-O Cleavage

Article abstract of DOI:10.1021/acs.orglett.5b00837

A novel metal-catalyzed oxygen atom transfer reaction onto olefins is reported. By taking isatogens as substrates, a one-pot [3 + 2]-cycloaddition of nitrone with olefins followed by the Ru-catalyzed redox-neutral N-O bond cleavage of intermediate isoxazo

Full text of DOI:10.1021/acs.orglett.5b00837

Letter
pubs.acs.org/OrgLett
Ru-Catalyzed Redox-Neutral Cleavage of the N−O Bond in
Isoxazolidines: Isatogens to Pseudoindoxyls via a One-Pot [3 + 2]-
Cycloaddition/N−O Cleavage
Chepuri V. Suneel Kumar and Chepuri V. Ramana*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
S
* Supporting Information
ABSTRACT: A novel metal-catalyzed oxygen atom transfer
reaction onto olefins is reported. By taking isatogens as
substrates, a one-pot [3 + 2]-cycloaddition of nitrone with
olefins followed by the Ru-catalyzed redox-neutral N−O bond
cleavage of intermediate isoxazolidine has been executed as a
simple method for the synthesis of 2,2-disubstituted
pseudoindoxyls.
atalytic internal redox-neutral reactions are often
C
characterized by atom economy and reaction efficiency,1
and the metal-catalyzed internal reorganization of oxygen
atoms, employing nucleophilic oxygen atom donors such as
nitro, N-oxides, nitrone, sulfoxides, and epoxides; olefins and
alkynes as acceptors have been particularly well explored in the
context of the synthesis of various heterocyclic units and also in
target oriented synthesis.2 Oxygen-bearing directing groups
have also been employed to develop redox-neutral C−H
activation reactions, which, at the outset, make this “C−H
activation and functionalization protocol” even more green by
avoiding any external oxidants.3−8 While, the N−O bond, as a
part of nitro, nitrone, and N-oxides, is most frequently used in
such internal oxygen atom transfer processes, hydroxylamine
derivatives have been commonly employed as oxidizing
directing groups in redox-neutral C−H activation processes.
Isoxazolidines (derived from the classical [3 + 2]-cyclo-
addition of a nitrone with olefin) that bear such an oxidizing
N−O bond have particularly attracted our attention,9 for
reductive cleavage of the N−O bond leading to a β-
aminoalcohol substructural unit is commonly practiced. There
are a couple of processes for the conversion of isoxazolidines
directly to the β-aminoketones, which, in general, employ a
suitably positioned leaving group that departs after the
reductive N−O bond cleavage, leading to a β-aminoketone.10,11
Thus, the catalytic redox neutral N−O bond cleavage would be
an interesting proposal for the preparation of β-aminoketones,
yet, surprisingly, this has not yet been explored.12 We
hypothesized such a proposal could expedite our total synthesis
of pseudoindoxyl natural products employing the isatogens (a
cyclic nitrone) as key intermediates.13 The isatogens readily
undergo cycloaddition with olefins leading to tricyclic
oxazolidines.14 The catalytic redox neutral N−O bond cleavage
of these tricyclic oxazolidines should lead to 2,2-disubstituted
pseudoindoxyl derivatives (Figure 1).15 Apart from their
potential as valuable intermediates in the synthesis of natural
products such as austamide, hinckdentine, brevianimide, and
Figure 1. Selected examples on the internal oxygen transfer and redox-
neutral processes involving N−O bonds and proposed novel redox-
neutral N−O cleavage of isoxazolidine.
aristotelone, these pseudoindoxyl compounds display large
Stoke shifts.16,17 Thus, a protocol that combines both the
cycloaddition and redox neutral N−O bond cleavage in one pot
could provide a simple means for fluorescence labeling.
With this proposition in mind, an examination of various
metal complexes commonly employed in redox-neutral C−H
activation reactions has revealed a widespread use of ruthenium
complexes in this domain, which provided a starting point for
our exploration. Table 1 saliently describes the exploratory
experiments that were conducted in this context. In general, the
reactions were carried out in a sealed tube employing 1 equiv of
Received: March 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00837
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a
Table 1. Optimization of Catalysts and Additives
Scheme 1. Olefins Scope in One-Pot Cycloaddition and Ru-
Catalyzed Redox-Neutral N−O Cleavage
b
yield (%)
entry
catalyst
additive
base
3
4
1
2
3
4
5
6
7
8
9
RuCl2(PPh3)3
AdCO2H
AdCO2H
AdCO2H
AdCO2H
−
K2CO3
K2CO3
K2CO3
K2CO3
−
62
0
12
74
58
0
[RuCl2(p-cymene)]2
Ru3(CO)12
0
derivatives, with styrene 2c and 4-methylstyrene 2d, the
reactions provided the corresponding β-aminoketone products
4ac and 4ad in 60% and 62% yield, respectively. Additionally,
the reaction with cyclohexene 2e produced a neat conversion
and 4ae was obtained in good yield. However, with allylated
benzylether 2f, the corresponding 4af was obtained in 49%
yield along with several unidentified products.
−
82
0
c
c
c
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
63
66
54
69
67
AdCO2H
−
0
−
K2CO3
K2CO3
NaHCO3
14
0
CH3CO2H
AdCO2H
0
a
Reaction conditions: 1 (1 equiv), 2 (5 equiv), toluene (3 mL),
[RuCl2(p-cymene)]2 (5 mol %), AdCO2H (30 mol %) and K2CO3 (2
equiv), 120 °C, 12 h in a sealed tube. Isolated yields. 48 h.
During this survey, the reaction with vinylpyrrolidone 2g
proved interesting (Scheme 2). Instead of the expected redox
b
c
Scheme 2. A One-Pot Cycloaddition and Ru-Catalyzed N−O
Bond Cleavage with N-Vinyl Pyrrolidone
isatogen and 5 equiv of olefin in toluene at 120 °C in the
presence of 5 mol % of catalyst along with 30 mol % of
adamantane carboxylic acid (AdCO2H) and 2 equiv of
K2CO3.5c Under these conditions, when RuCl2(PPh3)3 was
employed as a catalyst, the cycloaddition product 3aa (62%)
was obtained as the major product along with substantial
amounts of the expected β-amino ketone 4aa (12% yield). This
early result was promising and suggested that the proposed N−
O bond cleavage with a concomitant C−O bond oxidation was
possible. Gratifyingly, when [RuCl2(p-cymene)]2 was employed
as a catalyst, the keto compound 4aa was obtained exclusively in
74% yield. Even the reaction with the Ru3(CO)12 complex
delivered 4aa as the only product, although the yield was not
comparable and thus the reaction also required prolonged
heating. As expected, the cycloaddition product 3aa was
obtained exclusively when AdCO2H and K2CO3 were
employed without using the catalyst. Control experiments
revealed that the thermal cycloaddition of 1a and 2a proceeds
at 110 °C within 8 h providing 3aa in 78% yield [see
Supporting Information for complete details]. Interestingly,
only when complex A ([RuCl2(p-cymene)]2) alone was
present, the reaction seemed to be facile even in the absence
of both a base and an additive. However, it required more than
2 days for the complete consumption of the intermediate
cycloaddition product and a nominal decrease in the isolated
yield was noticed. A similar result was obtained when the
reaction was carried out in the absence of a base. However,
when conducted in the absence of an additive, the N−O
cleavage reaction was incomplete even after 2 days and
substantial amounts of an intermediate cycloaddition product
were isolated. A preliminary screening of other additives
revealed that AdCO2H was superior. When other bases were
examined, such as NaHCO3, there was not much improvement
in yield, when compared to K2CO3.
product; the intermediate N−O cleavage product underwent
dehydration, resulting in 5ag with a net C2-alkenylation of
starting isatogen. This apparent regioselective sp2 C−H
activation and functionalization of vinylpyrrolidone involving
an oxidizing-directing group was remarkable and opens up new
possibilities and queries, especially in C−H activation protocols
employing pyridine-/quinolone-N-oxides.18
After examining the various facets of the current protocol, we
next proceeded to generalize this one-pot reaction, employing a
broad range of isatogens with selected alkenes. Diverse
isatogens having different C2-substituents (aryl or alkyl) and
different substituents on both the aromatic rings were
employed in this context. As summarized in Scheme 3, the 2-
hexylisatogen 1b, on reaction with ethylvinyl ether 2b and
styrene 2c, underwent the [3 + 2]-cycloaddition with a redox
neutral cascade, providing the C2-alkylated pseudoindoxyl 4bb
and 4bc in 66% and 60% yields. Control experiments with 1b
revealed that its cycloaddition with styrene 2c proceeds at 80
°C, whereas the key N−O cleavage required heating at 100 °C.
Next, treatment of the 2-phenylisatogen having an electron-
withdrawing substituent (e.g., chloro) at the para-position to
the carbonyl group was investigated, with 1-dodecene 2a,
ethylvinyl ether 2b, and styrene 2c. All proceeded smoothly,
giving the corresponding C2-alkylated products 4ca, 4cb, and
4cc in very good yields. A similar trend was observed with the
isatogen 1d having an electron-donating substituent (e.g.,
methoxy), indicating that the electronic influence on the keto
does not alter the reaction outcome. Subsequently, the reaction
of the isatogen 1e having the electron-withdrawing −NO2
group at the para-position of the C2-aryl of the nitrone unit
Next, the compatibility of different alkenes in this one-pot
protocol was scrutinized. Scheme 1 summarizes the results.
Treatment of 1a with ethylvinyl ether 2b provided the
corresponding C2-(ethyl acetate) pseudoindoxyl derivative
4ab in 69% yield. Regarding the reactions with vinylbenzene
B
DOI: 10.1021/acs.orglett.5b00837
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Organic Letters
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synthesis of natural products and applications in inorganic
materials chemistry.
Scheme 3. Scope of One-Pot Cycloaddition/Ru-Catalyzed
Redox-Neutral N−O Cleavage
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
the new compounds are provided in the Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vr.chepuri@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank CSIR (India) for funding this project under 12FYP
CSIR-NCL-IGIB Joint research program (BSC0124) and a
research fellowship to C.V.S.
REFERENCES
■
(1) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259−281.
(b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695−705. (c) Newhouse,
T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010−
3021.
(2) Selected reviews for atom transfer processes: (a) Xiao, J.; Li, X.
W. Angew. Chem., Int. Ed. 2011, 50, 7226−7236. (b) Yeom, H. S.;
Shin, S. Acc. Chem. Res. 2014, 47, 966−977. (c) Zhang, L. M. Acc.
Chem. Res. 2014, 47, 877−888. For oxygen atom transfer from NO2:
(d) Asao, N.; Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2003, 44,
5675−5677. (e) Ramana, C. V.; Patel, P.; Vanka, K.; Miao, B. C.;
Degterev, A. Eur. J. Org. Chem. 2010, 5955−5966.
was examined. The reaction worked magnificently with the
alkenes 1-dodecene 2a and ethylvinyl ether 2b, providing the
corresponding alkylation products 4ea and 4eb in fairly good
yields. A similar trend was noticed in the case of the isatogen 1f,
where the −NO2 group was replaced with the electron-
donating −OMe group. Again, 4fa and 4fb were isolated in
excellent yields. Gratifyingly, even the reactions of the isatogen
1g (where the −CF3 group is present at the same para-
position) with 1-dodecene and with the ethylvinyl ether
delivered 4ga and 4gb in good yields. Furthermore, the effect
of steric hindrance was examined by performing the reaction of
2-(o-MeOPh) isatogen 1h with 1-dodecene under the standard
conditions. This procured the C2-alkylated pseudoindoxyl 4ha
in 60% yield. Also, the reaction with the isatogen 1i proceeded
smoothly with 1-dodecene and ethyl vinyl ether, thus revealing
the compatibility of the N-Boc group under the present
reaction conditions. Compound 1i delivered the corresponding
β-aminoketo and ester compounds 4ia, 4ib in 66% and 62%
yields, respectively.
Mechanistically it is believed that, under the conditions
employed, reduction of the initial Ru(II) to Ru(0) does not
occur. Hence, we assume that the reaction starts with oxidative
insertion of the ruthenium into the N−O bond followed by
formation of a Ru(IV)−H after the β-hydride elimination. A
final reductive elimination of Ru(II) positions the H on the
nitrogen.19
In conclusion, the catalytic redox neutral N−O bond
cleavage of isoxazolidines has been installed as a novel tool in
the armory of organic synthesis. Its compatibility with the
preceding cycloaddition has been developed as a simple
protocol for the synthesis of 2,2-disubstituted pseudoindoxyl
scaffolds having proven potential as intermediates in the total
(3) Selected papers for the redox-neutral C−H activation using Pd:
(a) Kitamura, M.; Zaman, S.; Narasaka, K. Synlett 2001, 974−976.
(b) Wu, J. L.; Cui, X. L.; Chen, L. M.; Jiang, G. J.; Wu, Y. J. J. Am.
Chem. Soc. 2009, 131, 13888−13889. (c) Tan, Y.; Hartwig, J. F. J. Am.
Chem. Soc. 2010, 132, 3676−3677. (d) Jithunsa, M.; Ueda, M.; Aoi,
N.; Sugita, S.; Miyoshi, T.; Miyata, O. Synlett 2013, 24, 475−478.
(4) Rh: (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org.
Lett. 2008, 10, 325−328. (b) Guimond, N.; Gouliaras, C.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 6908−6909. (c) Too, P. C.; Wang, Y.-F.;
Chiba, S. Org. Lett. 2010, 12, 5688−5691. (d) Rakshit, S.; Grohmann,
C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350−2353.
(e) Wang, F.; Song, G. Y.; Du, Z. Y.; Li, X. W. J. Org. Chem. 2011, 76,
2926−2932. (f) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem.
Soc. 2011, 133, 6449−6457. (g) Willwacher, J.; Rakshit, S.; Glorius, F.
Org. Biomol. Chem. 2011, 9, 4736−4740. (h) Zhang, X. Y.; Qi, Z. S.; Li,
X. W. Angew. Chem., Int. Ed. 2014, 53, 10794−10798. (i) Dateer, R. B.;
Chang, S. J. Am. Chem. Soc. 2015 (DOI: 10.1021/jacs.5b01065).
(5) Ru: (a) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.Eur. J. 2011,
17, 12573−12577. (b) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13,
6548−6551. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew.
Chem., Int. Ed. 2011, 50, 6379−6382. (d) Kornhaass, C.; Li, J.;
Ackermann, L. J. Org. Chem. 2012, 77, 9190−9198. (e) Yang, F.;
Ackermann, L. J. Org. Chem. 2014, 79, 12070−12082.
(6) Ir: Patel, P.; Chang, S. Org. Lett. 2014, 16, 3328−3331.
(7) Fe: Deb, I.; Yoshikai, N. Org. Lett. 2013, 15, 4254−4257.
(8) Cu: Zhao, M.-N.; Liang, H.; Ren, Z.-H.; Guan, Z.-H. Synthesis
2012, 44, 1501−1506.
(9) Selected reviews on intermolecular nitrone-cycloadditions:
(a) Martin, J. N.; Jones, R. C. F. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; Wiley: Hoboken, NJ, 2003;
pp 1−81. (b) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565−598.
C
DOI: 10.1021/acs.orglett.5b00837
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(c) Pellissier, H. Tetrahedron 2007, 63, 3235−3285. (d) Gothelf, K. V.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 863−909.
(10) For direct conversion of spirocyclopropane isoxazolidines to β-
aminoketone derivatives, see: (a) Estieu, K.; Paugam, R.; Ollivier, J.;
Salaun, J.; Cordero, F. M.; Goti, A.; Brandi, A. J. Org. Chem. 1997, 62,
8276−8277. (b) Ferrara, M.; Cordero, F. M.; Goti, A.; Brandi, A.;
Estieu, K.; Paugam, R.; Ollivier, J.; Salaun, J. Eur. J. Org. Chem. 1999,
2725−2739. (c) Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.;
Salaun, J.; Brandi, A. J. Am. Chem. Soc. 2000, 122, 8075−8076.
(d) Cordero, F. M.; Vurchio, C.; Brandi, A.; Gandolfi, R. Eur. J. Org.
Chem. 2011, 5608−5616.
(11) Synthesis of β-aminoketone derivative from bicyclic isoxazoli-
dine, see: (a) Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem.
1991, 56, 2154−2161. (b) McAuley, B. J.; Nieuwenhuyzen, M.;
Sheldrake, G. N. Org. Lett. 2000, 2, 1457−1459. (c) Wilson, M. S.;
Padwa, A. J. Org. Chem. 2008, 73, 9601−9609. (d) Flick, A. C.; Arevalo
Caballero, M. J.; Padwa, A. Tetrahedron 2010, 66, 3643−3650.
(12) Yao, C.-Z.; Xiao, Z.-F.; Liu, J.; Ning, X.-S.; Kang, Y.-B. Org. Lett.
2014, 16, 2498−2501.
(13) (a) Kumar, C. V. S.; Puranik, V. G.; Ramana, C. V. Chem.Eur.
J. 2012, 18, 9601−9611. (b) Reddy, B. N.; Ramana, C. V. Chem.
Commun. 2013, 49, 9767−9769. (c) Patel, P.; Ramana, C. V. J. Org.
Chem. 2012, 77, 10509−10515.
(14) (a) Greci, L.; Tommasi, G.; Bruni, P.; Sgarabotto, P.; Righi, L.
Eur. J. Org. Chem. 2001, 3147−3153. (b) Astolfi, P.; Bruni, P.; Greci,
L.; Stipa, P.; Righi, L.; Rizzoli, C. Eur. J. Org. Chem. 2003, 2626−2634.
(15) (a) Kumar, C. V. S.; Ramana, C. V. Org. Lett. 2014, 16, 4766−
4769. (b) Marien, N.; Brigou, B.; Pinter, B.; Proft, F. D.; Verniest, G.
Org. Lett. 2015, 17, 270−273.
(16) (a) Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 3871−
3877. (b) Bhakuni, D. S.; Silva, M.; Matlin, S. A.; Sammes, P. G.
Phytochemistry 1976, 15, 574−575. (c) Hutchison, A. J.; Kishi, Y. J.
Am. Chem. Soc. 1979, 101, 6786−6788. (d) Williams, R. M.; Glinka,
T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am. Chem. Soc. 1990, 112,
808−821. (e) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
7904−7905. (f) Liu, Y. H.; McWhorter, W. W. J. Am. Chem. Soc. 2003,
125, 4240−4252. (g) Adams, L. A.; Valente, M. W. N.; Williams, R. M.
Tetrahedron 2006, 62, 5195−5200. (h) Higuchi, K.; Sato, Y.;
Tsuchimochi, M.; Sugiura, K.; Hatori, M.; Kawasaki, T. Org. Lett.
2009, 11, 197−199.
(17) For recent papers on the use of 2,2-disubstituted pseudoindox-
yls in bioimaging: (a) Matsumoto, S.; Samata, D.; Akazome, M.;
Ogura, K. Tetrahedron Lett. 2009, 50, 111−114. (b) Lee, J. H.; So, J.-
H.; Jeon, J. H.; Choi, E. B.; Lee, Y.-R.; Chang, Y.-T.; Kim, C.-H.; Bae,
M. A.; Ahn, J. H. Chem. Commun. 2011, 47, 7500−7502. (c) Chun, H.-
S.; Jeon, J. H.; Pagire, H. S.; Lee, J. H.; Chung, H.-C.; Park, M. J.; So,
J.-H.; Ryu, J.-H.; Kim, C.-H.; Ahn, J. H.; Bae, M. A. Mol. BioSyst. 2013,
9, 630−633. (d) Pagire, H. S.; Chun, H.-S.; Bae, M. A.; Ahn, J. H.
Tetrahedron 2013, 69, 3039−3044. (e) Goriya, Y.; Ramana, C. V.
Chem. Commun. 2013, 49, 6376−6378.
(18) Preciado, S.; Vicente-Garcia, E.; Llabres, S.; Luque, F. J.; Lavilla,
R. Angew. Chem., Int. Ed. 2012, 51, 6874−6877.
(19) (a) Backvall, J. E. J. Organomet. Chem. 2002, 652, 105−111.
(b) Simon, M. O.; Ung, G.; Darses, S. Adv. Synth. Catal. 2011, 353,
1045−1048.
D
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