Journal of the American Chemical Society
Communication
pentafluorobenzoate as the leaving group.2,7f In these processes
the equivalent of acid generated via the β-hydride elimination
step triggers protodecarboxylation of the pentafluorobenzoate
leaving group, thereby maintaining access to a cationic cycle.7f
Cationic Heck-like manifolds accommodate bidentate chiral
ligands, and this renders them ideal for enantioselective
reaction development.21 By contrast, optimal efficiencies are
achieved in the current processes with only a 1:1.2 ratio of Pd/
PR3 (see Table 1). This observation is consistent with
cyclization occurring via a neutral pathway, where the sulfonate
leaving group is ligated to the Pd-center during alkene aza-
palladation.22 In this scenario, the increased enantioselectivity
observed in the cyclizations of 3qd vs 3q can be attributed to
an electronic effect (see Table 2). This interpretation must be
treated with caution, and alternative rationalizations cannot be
discounted on the basis of available data.
In summary, we show that Pd(0)-systems modified with
SPINOL-derived phosphoramidate ligands promote highly
enantioselective 5- and 6-exo aza-Heck cyclizations of alkenyl
N-(tosyloxy)carbamates. The substrates are easily accessed by
Mitsunobu alkylation of bifunctional amino reagent
BocNHOTs (2a) or CbzNHOTs (2b), and this underpins a
direct route to enantioenriched pyrrolidines and piperidines
that are challenging or inaccessible using conventional
approaches. In particular, this new aza-Heck method is
complementary to related oxidative aza-Wacker cyclizations
(see Scheme 1C); highly enantioselective variants of the latter
are rare and, to our knowledge, have not been achieved for
carbamate-based nucleophiles.10,11 Ultimately, the aza-Heck
method described here is able to provide high enantioselec-
tivity because external oxidants are avoided, and this allows the
use of highly tunable chiral P-based ligands. These
considerations are one of several key benefits of the aza-
Heck approach,6a and the continued development of this
manifold is ongoing in our laboratory.
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
Experimental details and characterization data (PDF)
Crystallographic data for a derivative of 4a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the Royal Society for a URF (J.F.B.) and the
European Research Council for financial support via the EU’s
Horizon 2020 Programme (ERC Grant 639594 CatHet).
I.R.H. thanks AstraZeneca and EPSRC (EP/M506473/1) for a
PhD studentship. We thank the University of Bristol, School of
Chemistry X-ray crystallography service and Fiona Bell
(AstraZeneca) for analysis.
́
Ryden-Landergren, M.; Sparkes, H. A.; Bower, J. F. Enantioselective
Narasaka−Heck Cyclizations: Synthesis of Tetrasubstituted Nitrogen-
Bearing Stereocenters. Chem. Sci. 2017, 8, 1981. (b) Bao, X.; Wang,
Q.; Zhu, J. Palladium Catalyzed Enantioselective Narasaka−Heck
Reaction/Direct C−H Alkylation of Arenes: Iminoarylation of
Alkenes. Angew. Chem., Int. Ed. 2017, 56, 9577.
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