ethers 1 derived from readily available 1,2-amino alcohols
(Scheme 1). This approach has significant potential utility,
as the reactions should proceed with kinetic control of
stereochemistry and provide enantiomerically pure pro-
ducts with good levels of diastereoselectivity.7,8 However,
in order to accomplish this goal it was necessary to over-
come two key obstacles. The transformations were expected
to proceed via intramolecular syn-aminopalladation of
intermediate 2,7ꢀ9 but enol ethers (or similarly electron-
rich alkenes) have not previously been employed in Pd-
catalyzed carboaminations between unsaturated amines
and aryl/alkenyl halides.10 No studies have demonstrated
that such highly electron-rich alkenes can undergo syn-
migratory insertion into PdꢀN bonds of LnPd(R1)(NR2)
complexes.11 Moreover, mechanistic experiments by Stahl
indicate that the transition state for syn-aminopalladation
exhibits characteristics of a N-nucleophile/alkene electro-
phile combination,12 which suggests that insertions of
electron-rich alkenes could have relatively high barriers.13
In addition to the challenges associated with syn-amino-
palladation of an electron-rich alkene, the reductive elim-
ination of intermediate 3 was also expected to be difficult.
The two inductively electron-withdrawing heteroatoms on
the carbon beta to Pd will slow the rate of CꢀC bond
formation from 3.9a,b,14 Thus, competing β-hydride
elimination15 to generate 6 or β-alkoxide elimination11,16
to form 5 could be problematic.
In preliminary feasibility studies we elected to examine
the reactivity of bromobenzene with the simple, geometri-
cally constrained enol ether 7. Given the anticipated
challenges described above, we focused our catalyst opti-
mization studies on two classes of ligands: (a) bis-phos-
phine ligands withrelatively wide bite angles; and (b) bulky
monodentate phosphine ligands (Table 1). These classes of
ligands have been shown to promote rapid CꢀC bond-
forming reductive elimination,17 and prior studies sug-
gested they could also potentially facilitate the key amino-
palladation step.18 A preliminary survey of catalysts
composed of Pd2(dba)3 and a wide bite angle ligand
indicated that the yield of 8 increased with increasing
bite angle, and promising results were obtained with
Xantphos (58% yield).19 However, our experiments
with monodentate phosphines showed the monodentate
S-Phos ligand was superior to Xantphos,20 as the 1,
3-oxazolidine product 8 was isolated in 70% yield when
this phosphine was employed.
(7) For reviews on Pd-catalyzed carboamination reactions between
aryl/alkenyl halides and amines bearing pendant alkenes, see: (a) Wolfe,
J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P. Synlett 2008, 2913.
(8) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org. Chem. 2008,
73, 8851.
(9) For recent mechanistic studies on syn-aminopalladation reactions
of palladium(aryl)(amido) complexes, see: (a) Neukom, J. D.; Perch,
N. S.; Wolfe, J. P. Organometallics 2011, 30, 1269. (b) Neukom, J. D.;
Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 6276. (c) Hanley,
P. S.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 6302.
(10) For examples of oxidative coupling reactions between allylic
sulfonamides and butyl vinyl ether that afford 2-alkoxypyrrolidines, see:
Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251.
(11) Stahl has reported the Pd(II)-catalyzed transfer of vinyl groups
from enol ethers to nitrogen nucleophiles. These reactions proceed via
aminopalladation of a cationic Pd(II) alkene complex followed by β-
alkoxide elimination. See: (a) Brice, J. L.; Meerdink, J. E.; Stahl, S. S.
Org. Lett. 2004, 6, 1845. The stereochemistry of the aminopalladation
step in the vinyl exchange reactions is not entirely clear, but subsequent
studies suggest these reactions may occur through an outer-sphere anti-
aminopalladation pathway rather than an inner-sphere (migratory
insertion) syn-aminopalladation mechanism. See:(b) Maleckis, A.; Jaun-
zeme, I.; Jirgensons, A. Eur. J. Org. Chem. 2009, 36, 6407.
(12) Ye, X.; Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 76,
1031.
Table 1. Catalyst Optimization Studiesa
entry
ligand
dppb
yieldb
1
2
3
4
5
6
0%
Dpe-Phos
Xantphos
P(o-tol)3
Ru-Phos
S-Phos
13%
58%
0%
(13) The insertion of electron-poor alkenes, such as acrylonitrile, into
PtꢀN bonds of platinum amido complexes is much more facile than
analogous reactions of electron-neutral alkenes. See: Cowan, R. L.;
Trogler, W. C. Organometallics 1987, 6, 2451.
(14) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
(15) Competing β-hydride elimination from intermediate 3 could be
facilitated by the nonbonding electrons on the N- and O-atoms. For
further discussion, see: (a) Mueller, J. A.; Sigman, M. S. J. Am. Chem.
Soc. 2003, 125, 7005. (b) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005,
127, 16468.
20%
70%c
a Conditions: 1.0 equiv of 7, 2.0 equiv of PhBr, 2.0 equiv of NaOtBu,
2 mol % Pd2(dba)3, 2ꢀ4 mol % ligand, Toluene, 95 °C. b Yields were
determined by 1H NMR analysis of crude reaction mixtures using
phenanthrene as an internal standard. c Isolated yield (average of two
experiments).
(16) (a) Muzart, J. Tetrahedron 2005, 61, 4179. (b) Zhao, H.; Ariafard,
A.; Lin, Z. Organometallics 2006, 25, 812.
(17) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338. (b) Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Chem.
Soc. Rev. 2009, 38, 1099.
(18) Mechanistic studies suggest that the insertion of alkenes into
PdꢀN bonds occurs via intermediate palladium complexes that contain
a single bound phosphine. For further discussion, see ref 9.
(19) Enamide and ketene aminal side products with structures similar
to 5 and 6 were not isolated and could not be unambiguously identified
through 1H NMR analysis of crude reaction mixtures. However, these
side products may be prone to hydrolysis during workup.
(20) Ligand definitions: Dpe-Phos = bis(diphenylphosphinophenyl)
ether; dppb = 1,4-bis(diphenylphosphino)butane; Xantphos = 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene; Ru-Phos = 2-dicyclo-
hexylphosphino-20,60-di-isopropoxy-1,10-biphenyl, S-Phos = 2-dicyclo-
hexylphosphino-20,60-dimethoxy-1,10-biphenyl.
(6) Transformations that lead to CꢀC bond formation during ox-
azolidine generation typically involve 1,3-dipolar cycloaddition reac-
tions between carbonyl ylides and imines or between azomethine ylides
and aldehydes. For selected examples, see: (a) Bentabed-Ababsa, G.;
Derdour, A.; Roisnel, T.; Saez, J. A.; Perez, P.; Chamorro, E.; Domingo,
L. R.; Mongin, F. J. Org. Chem. 2009, 74, 2120. (b) Kim, N. S.; Kang,
S. Y.; Lee, S. H. Bull. Korean Chem. Soc. 2010, 31, 553. (c) Kielland, N.;
Catti, F.; Bello, D.; Isambert, N.; Soteras, I.; Luque, F. J.; Lavilla, R.
Chem.;Eur. J. 2010, 16, 7904. (d) Seashore-Ludlow, B.; Torssell, S.;
Somfai, P. Eur. J. Org. Chem. 2010, 3927. (e) Huo, C.; Wei, R.; Zhang,
W.; Yang, L.; Liu, Z.-L. Synlett 2005, 161.
Org. Lett., Vol. 13, No. 17, 2011
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