C O M M U N I C A T I O N S
Table 1. Yields and Enantiomer Ratios (er) in Room-Temperature
Heck Cyclizations of Axially Chiral o-Iodoacrylanilides
yield % chirality
entry
R
precursor
er 4
product
er 5
%
transfer
1
2
3
4
Me (M)-(-)-4a 99.5/0.5 (R)-(+)-5a 85.5/14.5 95
Me (P)-(+)-4a 98.5/1.5 (S)-(-)-5a 86.5/13.5 92
86
88
89
91
Figure 2. Dynamic kinetic resolution (dkr) model for Heck reactions of
Pd complexes with chiral ligands (L*).
Br (M)-(-)-4b 99.5/0.5 (R)-(+)-5b 89/11
Br (P)-(+)-4b 97.5/2.5 (S)-(-)-5b 89/11
77
69
trolling step in asymmetric Heck reactions is a dynamic kinetic
resolution (oxidative addition to the C-I) bond and not a face
selective reaction (complexation or insertion to the alkene). This
knowledge should help advance such reactions by aiding catalyst
design and by guiding the selection of appropriate substrates and
reaction conditions. Indeed, in asymmetric Heck reactions, the use
of substrates with high N-Ar rotation barriers and low reaction
temperatures may actually be undesirable because the dynamic
kinetic resolution is spoiled if the Heck process becomes faster
than precursor racemization.
Acknowledgment. We thank the National Science Foundation
for funding of this work.
Note Added after ASAP Publication. After ASAP publication on
December 29, 2006, a compound number was corrected in Table 1.
The corrected version was published ASAP on January 4, 2007.
Supporting Information Available: Details of experiments and
characterization. This material is available free of charge via the Internet
Figure 1. Model for transfer of axial chirality in room-temperature Heck
reactions of 4.
reaction occurs. Accordingly, we propose that the axial chirality
of the acryloyl group of 4 is not important because this group exists
in two (or more) low energy conformers that rapidly interconvert
because of the low-rotation barrier of bond a.
Instead, the geometric requirements of the alkene/palladium
complex 7 dictate which face of alkene 6 reacts; complexation on
the re-face of the alkene can occur without undue strain to give 7,
which in turn suffers C-Pd bond insertion and â-hydride elimina-
tion to provide (R)-5 via 8. Complexation on the si-face of 6 and
onward reaction cannot occur directly because the palladium atom
is not positioned over the alkene π-orbitals. To establish this
positioning would impose an energy penalty associated with
significant distortion of the amide.
Implications of this work for asymmetric Heck reactions of
o-iodoacrylamides are summarized in Figure 2. In such reactions,
there is typically no other ortho substituent besides the iodine, so
the racemic (not achiral) precursors 9/ent-9 will be in rapid
equilibration under typical high-temperature Heck conditions.3f,g
Insertion of the chiral palladium catalyst into the carbon-iodine
bond 9 to give 10 is a dynamic kinetic resolution step that dictates
both the sense and magnitude of the asymmetric induction of the
overall transformation.7 Subsequent face-selective insertion of 10
to provide 11 is now more rapid than N-Ar bond rotation of 10
(not shown).8 The insertion is important because it relays the
configuration to 13, but this relay is inherent in the axial chirality
of 10 and the chiral ligands on palladium are not required.
In short, low-temperature Heck reactions of chiral o-iodoacryl-
anilides with achiral palladium catalysts occur with efficient transfer
of chirality from the chiral axis of the precursor to the new
stereocenter of the product. The results suggest that the stereocon-
References
(1) (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453-3516.
(b) Shibasaki, M.; Vogl, E. M.; Ohshima, T. AdV. Synth. Catal. 2004,
346, 1533-1552. (c) Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8,
781-794. (d) Shibasaki, M.; Miyazaki, F. In Handbook of Organopal-
ladium Chemistry for Organic Synthesis; Negishi, E.-I., de Meijere, A.,
Eds.; Wiley; New York, 2002; Vol. 1, p 1283-1315. (e) Dounay, A. B.;
Overman, L. E. Chem. ReV. 2003, 103, 2945-2963. (f) Shibasaki, M.;
Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371-7395.
(2) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477-6487. (b) Ashimori, A.; Bachand, B.; Calter, M.
A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998,
120, 6488-6499. (c) Cyclizations under “cationic conditions” with silver
additives often provide very different results.
(3) (a) Horne, S.; Taylor, N.; Collins, S.; Rodrigo, R. J. Chem. Soc., Perkin
Trans. 1 1991, 3047-3051. Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog,
A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G.
Tetrahedron: Asymmetry 1997, 8, 3955-3975. (b) Curran, D. P.; Geib,
S.; DeMello, N. Tetrahedron 1999, 55, 5681-5704. (c) Curran, D. P.;
Liu, W. D.; Chen, C. H.-T. J. Am. Chem. Soc. 1999, 121, 11012-11013.
(d) Curran, D. P.; Chen, C. H. T.; Geib, S. J.; Lapierre, A. J. B.
Tetrahedron 2004, 60, 4413-4424. (e) Petit, M.; Geib, S. J.; Curran, D.
P. Tetrahedron 2004, 60, 7543-7552. (f) Adler, T.; Bonjoch, J.; Clayden,
J.; Font-Bardia, M.; Pickworth, M.; Solans, X.; Sole, D.; Vallverdu, L.
Org. Biomol. Chem. 2005, 3, 3173-3183. (g) Petit, M.; Lapierre, A. J.
B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994-14995.
(4) McDermott, M. C.; Stephenson, G. R.; Hughes, D. L.; Walkington, A. J.
Org. Lett. 2006, 8, 2917-2920.
(5) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 2677-2678.
(6) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585-4595.
(7) The figures illustrate the insertion occurring before formation of the
π-complex; however, it is also possible that the π-complex reversibly
forms first, or that the two steps occur together.
(8) Evidence suggests that related (albeit cationic) insertion reactions are fast
relative to N-Ar rotation of anilides bearing bulky o-substituents (ref
3b). See (a) Brown, J. M.; Pe´rez-Torrente, J. J.; Alcock, N. W.; Clase, H.
J. Organometallics 1995, 14, 207-213. (b) Brown, J. M.; Hii, K. K.
Angew. Chem., Int. Ed. 1996, 35, 657-659. Alternatively, if N-Ar rotation
of 10 is faster than insertion, then axial chirality dictates product
configuration in a dynamic thermodynamic resolution.
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