ACS Catalysis
Research Article
(10) For a metal-free protocol for oxidation of secondary amines to
nitrones see: Gella, C.; Ferrer, E.; Alibes, R.; Busque, F.; de March, P.;
Figueredo, M.; Font, J. J. Org. Chem. 2009, 74, 6365−6367 and
references cited therein. See also ref 6c.
important compounds containing CN bonds is currently
being investigated in our lab.13
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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(11) (a) Andrade, M. M.; Barros, M. T.; Pinto, R. C. Tetrahedron
2008, 64, 10521−10530. (b) Valizadeh, H. Heteroat. Chem. 2010, 21,
78−83. (c) Samadi, A.; Soriano, E.; Revuelta, J.; Valderas, C.; Chioua,
S
́ ́
M.; Garrido, I.; Bartolome, B.; Tomassolli, I.; Ismaili, L.; Gonzalez-
Lafuente, L.; Villarroya, M.; García, A. G.; Oset-Gasque, M. J.; Marco-
Contelles, J. Bioorg. Med. Chem. 2011, 19, 951−960.
Additional optimization studies, the comparison of
conditions previously reported for the prepared com-
(12) Reimann, J. E.; Jencks, W. P. J. Am. Chem. Soc. 1966, 88, 3973−
3982.
1
pounds, the H NMR experiments, spectroscopy data of
each compound, and computational details (PDF)
(13) Nigst, T. A.; Antipova, A.; Mayr, H. J. Org. Chem. 2012, 77,
8142−8155.
AUTHOR INFORMATION
Corresponding Authors
(14) Morales, S.; Guijarro, F. G.; García Ruano, J. L.; Cid, M. B. J.
Am. Chem. Soc. 2014, 136, 1082−1089.
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(15) Appel, R.; Chelli, S.; Tokuyasu, T.; Troshin, K.; Mayr, H. J. Am.
Chem. Soc. 2013, 135, 6579−6587.
(16) See SI for more details.
Notes
(17) Intramolecular proton transfer through a five-membered
transition states have also been proposed in the literature to be
involved in nitrone formation, see Zhao, J.; Sun, C.; Sun, N.; Meng, L.;
Chen, D. Int. J. Quantum Chem. 2013, 113, 2457−2463. However, the
participation of other molecules as a proton relay could also be
possible. This approach had been proposed in related processes such
us enamine formation, see: Patil, M. P.; Sunoj, R. B. J. Org. Chem.
2007, 72, 8202−8215. In our case, when a molecule of methanol was
included in transition states, despite unfavorable entropic factors, both
free energy barriers as well as the difference between them decreased
(see SI for more details).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the Spanish Government (CTQ-2012-35957) for
financial support. S.M. thanks the Spanish Ministry of Economy
and Competitiveness for a predoctoral fellowship (FPI). We
́
́
Cientifica (UAM) for
also thank the Centro de Computacion
generous allocation of computer time and Dr. Pablo Mauleon
and Dr. Jose Luis Acena for useful discussions.
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̃
(18) This reaction is slower in methanol (it needs 48 h to be
completed) affording 3aa in 71% along with azoxybenzene as side
product. It is described that azoxybenzene can be formed in basic
media; see: Bigelow, H. E. Chem. Rev. 1931, 9, 117−167. In fact, the
use of proline instead of pyrrolidine as catalyst avoided the formation
of the azoxybenzene and provided an almost quantitative yield of 3aa
in 16 h. Nevertheless, the formation of the azoxybenzene was not
observed using catalytic pyrrolidine in dichloromethane as solvent.
(19) Under pyrrolidine catalysis, the complete conversion of 3aa was
obtained in 3 h in 94% yield, whereas it required 7.5 h in the absence
of catalyst.
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1
(24) We could confirm by H NMR the effective liberation of 2b·
HCl and the formation of pyrrolidinium chloride when 1 equiv of
pyrrolidine was used in DMSO-d6 (see SI).
(25) We demonstrated that substoichiometric amounts of pyrrolidine
allowed the formation of nitrone, probing the catalytic effect of
pyrrolidine (63% conversion with 0.5 equiv after 3 days). Nevertheless,
at least 1 equiv of pyrrolidine is mandatory to completely liberate
hydroxylamine hydrochloride. Other reaction conditions were
investigated, including the use of other bases to liberate the
hydrochloride along with pyrrolidine, but the results were less
significant than those indicated in Table 1 (see SI).
(26) The magnitude of the catalytic effect of the pyrrolidine with
respect to Et3N in MeOH is lower than that in CH2Cl2, but quite
significant yet, as it was established following the evolution of the
reactions by NMR using both reagents in MeOH-d4 (see SI).
(27) In some cases, only one of the conditions has been used,
because the generality of the method has been demonstrated in
comparable compounds.
(9) A recent umpolung approach toward N-aryl nitrones starts from
1,2-dicarbonyl compounds and nitroso electrophiles, see:
Chavannavar, A. P.; Oliver, A. G.; Ashfeld, B. L. Chem. Commun.
2014, 50, 10853−10856.
(28) The higher reactivity of the orto-hydroxybenzaldehydes and the
2-pyridylcarboxaldehyde was detected by Kool in the formation of
90
ACS Catal. 2016, 6, 84−91