A R T I C L E S
Liu and Stahl
Table 6. Sterochemical Outcome for the Oxidative Cyclization of the Deuterium-Labeled Substrate trans-3-d-20a
product ratiob
trans-AP 21/trans-2-d-22
entry
Pd catalysts
time (h)
yieldb (%)
cis-AP 3-d-21/3-d-22
1
2
3
4
5
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
Pd(IMes)(O2CCF3)2/Na2CO3 (F)
24
24
24
32
32
73
47
83
74
34
100:0
4:7
14:2
22:24
32:1
85:4
78:6
41:13
65:2
b
a All reactions performed at 80 °C; 5 mol % Pd; 33 µmol scale. NMR yield, the product ratio was determined by NMR.
The results of the oxidative cyclization of trans-3-d-20 are
more complex. Use of the Pd(OAc)2/DMSO catalyst system
results in exclusive formation of the trans-aminopalladation
product 21 (Table 6). With each of the other catalyst systems,
including the NHC-coordinated catalyst with both acid and
base additives, the oxidative cyclization of trans-3-d-20 yields
products arising from both cis- and trans-aminopalladation.
in the presence of acid (AcOH, BzOH, and TFA) (Figure 1);
the selectivity shifts toward trans-aminopalladation with in-
creasing acid strength. In contrast, use of stoichiometric base
in the reaction (NaOAc or Na2CO3) leads to exclusive cis-
aminopalladation of the alkene.
The precise origin of the preference for cis- or trans-
aminopalladation is not known; however, the following mecha-
nistic considerations provide the basis of ongoing investig-
ations. Trans-aminopalladation presumably arises from a mech-
anism resembling classical electrophile-promoted addition of
nucleophiles to alkenes (top pathway, Scheme 7; cf. eq 1):
coordination of the alkene to the electrophilic PdII center,
nucleophilic attack by the sufonamide nucleophile, and depro-
tonation of the zwitterionic intermediate 24. Cis-aminopalla-
dation probably arises from formation of a PdII-sulfonamidate
intermediate followed by alkene insertion into the Pd-N bond
(bottom pathway, Scheme 7).18,37 Formation of the Pd-amidate
species 25 liberates 1 equiv of HX and, therefore, should be
Analysis and Implications. In this study, we have probed
the Wacker-type oxidative cyclization of sulfonamide-substituted
aminoalkenes with several different Pd catalysts. The results
reveal that these reactions generally favor cis- rather than trans-
aminopalladation. This outcome is noteworthy because it
contradicts widespread assumptions concerning the stereochem-
ical course of such reactions. In recent studies, for example,
the term “Wacker-type reaction” has been used as a mechanistic
synonym for trans-heteropalladation of an alkene,17b,d,31 or trans-
heteropalladation of the alkene was simply assumed.32 Such
prevailing assumptions probably reflect the impact of elegant
early studies by Stille, Ba¨ckvall, Åckermark, Hegedus, and
others who reported definitive examples of trans-heteropalla-
dation of alkenes through isotopic labeling experiments and
fundamental reactivity studies of Pd-alkene complexes.33 These
results were countered by Henry, however, who argued that data
for the Wacker process itself were most consistent with cis-
hydroxypalladation of ethylene.34,35
(33) For leading references, see ref 15 and (a) Stille, J. K.; James, D. E. J.
Organomet. Chem. 1976, 108, 401-408. (b) James, D. E.; Hines, L. F.;
Stille, J. K. J. Am. Chem. Soc. 1976, 98, 1806-1809. (c) Ba¨ckvall, J. E.;
Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264-
265. (d) Stille, J. K.; Divakaruni. R. J. Am. Chem. Soc. 1978, 100, 1303-
1304. (e) Ba¨ckvall, J. E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411-2416. (f) Stille, J. K.; Divakaruni, R. J. Organomet.
Chem. 1979, 169, 239-248. (g) Kurosawa, H.; Majima, T.; Asada, N. J.
Am. Chem. Soc. 1980, 102, 6996-7003. (h) Andell, O. S.; Ba¨ckvall, J. E.
J. Organomet. Chem. 1983, 244, 401-407. (i) Ba¨ckvall, J. E.; Heumann,
A. J. Am. Chem. Soc. 1986, 108, 7107-7108. (j) Åkermark, B.; So¨derberg,
B. C.; Hall, S. S. Organometallics 1987, 6, 2608-2610.
Recent studies by several laboratories, including our own,
have provided increasing support for the viability of cis-
heteropalladation of alkenes, including both oxy-13c,19,21g,31 and
aminopalladation.16,17 The present study provides the first
systematic analysis of intramolecular Wacker-type oxidative
amination. Although cis-aminopalladation of the alkene is
generally favored in these reactions, trans-aminopalladation is
also possible and can predomimate, depending on the identity
of the substrate, the catalyst, and/or the reaction conditions.36
The energy barriers associated with cis- and trans-aminopalla-
dation appear to be especially finely balanced with the NHC-
Pd catalyst system (Figure 1). Products are observed from both
cis- and trans-aminopalladation in the absence of additives and
(34) For extensive analysis of the mechanistic pathway of the parent Wacker
process, see: Henry, P. M. Palladium Catalyzed Oxidation of Hydrocar-
bons; D. Reidel Publishing Co.: Boston, 1980.
(35) (a) Henry, P. M. J. Am. Chem. Soc. 1966, 88, 1595-1597. (b) Gragor,
N.; Henry, P. M.; J. Am. Chem. Soc. 1981, 103, 681-682. (c) Wan, W.
K.; Zaw, K. Henry, P. M. J. Mol. Catal. 1982, 16, 81-87. (d) Wan,
W. K.; Zaw, K.; Henry, P. M. Organometallics 1988, 7, 1677-1683.
(e) Zaw, K.; Henry, P. M. J. Org. Chem. 1990, 55, 1842-1847. (f)
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082-
7083. (g) Hamed, O.; Henry, P. M. Organometallics 1997, 16, 4903-
4909.
(36) The apparent discrepancy between our observations (which favor cis-
aminopalladation reactions) and the early studies of Pd-mediated alkene
amination (which favor trans-aminopalladation reactions; ref 15) undoubt-
edly reflects differences between the substrates (sulfonamides vs alky-
lamines) and/or reaction conditions (catalytic vs precomplexation of the
alkene at low temperature followed by addition of stoichiometric amine
nucleophile).
(37) Another mechanism that could account for cis-aminopalladation of an alkene
involves a six-membered electrocyclic transition state (see below). See ref
16a.
(31) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(b) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762-763.
(32) For example, see ref 4b and (a) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett.
2004, 45, 1785-1788. (b) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz,
K. J. Am. Chem. Soc. 2005, 127, 14586-14587.
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6334 J. AM. CHEM. SOC. VOL. 129, NO. 19, 2007