Organic Letters
Letter
Scheme 4. Enantioselective Cycloisomerization
REFERENCES
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chiral phosphoric acid (R)-19 in combination with RuH2(CO)-
PPh3 (SI) gave rise to benzoxazine 3a with encouraging levels of
enantioselectivity (81:19 er). Interestingly, this phosphoric acid
also allowed the reaction to be performed under reduced
temperature (40 °C) with full conversion and selectivity.21 This
positive result paves the way for an asymmetric method to
synthesize 1,3-oxazaheterocycles and represents the first example
of an enantioselective tandem Ru−H/chiral Brønsted acid
catalyzed process in which an N-homoallyl amide is used.
In summary, we have reported a novel catalytic procedure for
the synthesis of six- and seven-membered 1,3-oxazaheterocycles
through a simple, redox-economical dual Ru−H/Brønsted acid
catalyzed cycloisomerization of 2-hydroxy(alkyl) substituted N-
alkenyl aniline and benzylamine derivatives. The use of the
commercially available RuH2(CO)(PPh3)3 complex enables an
efficient long-distance chain-walking process, thus allowing a
wide range of 2-alkylsubstituted 1,3-oxazaheterocycles to be
obtained in very good yields. We have found that the hydroxyl
unit, besides its nucleophilic function, plays also an important
role in the stabilization of the Ru catalyst. In addition, preliminary
studies show that 1,3-oxazaheterocycles can be obtained in an
enantioselective fashion by using a chiral phosphoric acid, which
provides space for further study of this asymmetric variant.
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(b) Larionov, E.; Lin, L.; Guenee, L.; Mazet, C. J. Am. Chem. Soc.
́ ́
2014, 136, 16882. (c) Mei, T.-S.; Patel, H. H.; Sigman, M. S. Nature
2014, 508, 340.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
Experimental procedures, spectral data of all products
(14) Carboxybenzyl (Cbz) and acetyl (Ac) protected amides and failed
to give the corresponding cyclization products.
(15) Starting with 1c, isomerization of the N-4-penten-1-yl to N-[(E)-
3-penten-1-yl] isomer was observed when using nonhydride ruthenium
catalysts (only one “step-walk”). See ref 4.
AUTHOR INFORMATION
Corresponding Author
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(16) No cycloisomerization occurred when a substrate containing a N-
(3-methyl-3-butenyl) chain was used.
Notes
(17) For a related stabilization, see: Perdriau, S.; Chang, M.-C.; Otten,
E.; Heeres, H. J.; de Vries, J. G. Chem. - Eur. J. 2014, 20, 15434.
(18) For other catalytic combinations using lower amounts of a
Brønsted acid, incomplete cycloisomerizations were found (see SI).
(19) For a review on the use of chiral Brønsted acids in asymmetric
transformations, see: Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
Chem. Rev. 2014, 114, 9047.
(20) For examples on enantioselective tandem ruthenium-hydride/
chiral Brønsted acid catalyzed cycloisomerizations of N-allyl derivatives,
see refs 8a, 8b, 9b, and 9c.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by MINECO (Spain) (Projects
CTQ2011-28258 and CTQ2014-59015R), Xunta de Galicia
(Project GRC2014/032), and the European Regional Develop-
ment Fund (Projects CTQ2014-59015R and GRC2014/032).
R.B. thanks MEC for a predoctoral FPU fellowship, and J.S.
thanks XUGA for a postdoctoral contract. M.F.-M. thanks
(21) Heating the enantiomeric mixture of 3a under the reaction
conditions for 24 h gave no epimerization (see SI).
́
MINECO for a “Ramon y Cajal” contract.
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