Reversible alkene insertion into the Pd-N bond of Pd(II)-sulfonamidates and implications for catalytic amidation reactions

Article abstract of DOI:10.1021/ja208560h

Alkene insertion into Pd-N bonds is a key step in Pd-catalyzed oxidative amidation of alkenes. A series of well-defined Pd(II)-sulfonamidate complexes have been prepared and shown to react via insertion of a tethered alkene. The Pd-amidate and resulting P

Full text of DOI:10.1021/ja208560h

COMMUNICATION
pubs.acs.org/JACS
Reversible Alkene Insertion into the PdꢀN Bond of Pd(II)-
Sulfonamidates and Implications for Catalytic Amidation Reactions
Paul B. White and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S Supporting Information
b
ABSTRACT: Alkene insertion into PdꢀN bonds is a key
step in Pd-catalyzed oxidative amidation of alkenes. A series
of well-defined Pd(II)-sulfonamidate complexes have been
prepared and shown to react via insertion of a tethered
alkene. The Pdꢀamidate and resulting Pdꢀalkyl species
have been crystallographically characterized. The alkene
insertion reaction is found to be reversible, but complete
conversion to oxidative amination products is observed in
the presence of O2. Electronic-effect studies reveal that
alkene insertion into the PdꢀN bond is favored kinetically
Figure 1. X-ray crystal structures of 3a (left) and 4a (right) with
thermal ellipsoids shown at the 40% and 50% probability level, respec-
tively. Most hydrogen atoms have been omitted for clarity.12
and thermodynamically with electron-rich amidates.
he discovery of PdII-catalyzed oxidative coupling of ethylene
T
and water (the Wacker Process) >50 years ago inspired
extensive efforts to develop methods for the oxidative amination
of alkenes (aza-Wacker reactions).1 Early studies showed that
many alkyl- and arylamine nucleophiles coordinate strongly to
PdII and inhibit catalytic turnover. Therefore, much of this
work focused on stoichiometric reactions of nitrogen nucleo-
philes with preformed PdIIꢀalkene complexes.2 In 1982, Hege-
dus and McKearin demonstrated that p-toluenesulfonamides
(tosylamides) could be used in catalytic intramolecular aza-Wacker
reactions, with benzoquinone as the oxidant.3 More recently, amide-
type nucleophiles have been used in aerobic oxidative amination
reactions,4 including enantioselective5 and intermolecular6 applica-
tions. Mechanistic studies suggest that these aza-Wacker reactions
often proceed via alkene insertion into the PdꢀN bond of the
amidate ligand, not attack of a nitrogen nucleophile onto a PdII-
coordinated alkene.7,8 The first fundamental studies of alkene
insertion into PdꢀN bonds were reported only recently by the
groups of Wolfe and Hartwig with PdIIꢀanilide complexes.9ꢀ11
Analogous reactions with Pd-amidates are unknown. Here, we
describe well-defined PdIIꢀsulfonamidate complexes that undergo
alkene insertion into the PdꢀN bond, and the reactions are shown
to be reversible. The presence of O2 influences the fate of the
resulting alkylꢀPdII species. These observations, elaborated below,
have important implications for catalytic reactions, including oxida-
tive and non-oxidative transformations.
Scheme 1. Amidopalladation of an Alkene
(tBu2bpy)PdCl2 (1, tBu2bpy = 4,40-di-tert-butyl-2,20-bipyridine)
to a suspension of sodium tosylamidate (2a) in CH2Cl2 at room
temperature. The air-stable Pdꢀamidate complex 3a was ob-
tained in good yield (eq 1) and was characterized by 1H and 13
C
NMR spectroscopy, mass spectrometry, and X-ray crystallogra-
phy (Figure 1, left).12 Initial attempts to observe alkene insertion
into the PdꢀN bond of 3a were carried out in benzene, THF, and
dichloromethane, but no reaction was observed (Scheme 1). In
chloroform, however, 3a reacted very slowly at room tempera-
ture, affording the alkylꢀPdII amidopalladation (AP) product 4a
in good yield (Figure 1, right). At higher temperatures, 4a
underwent further reaction via β-hydride elimination and could
not be obtained cleanly from the reaction mixture. The reaction
proved to be much more efficient in dimethyl sulfoxide (DMSO)
as the solvent, proceeding in 84% yield in 12 h.
The beneficial effect of a polar solvent (DMSO) suggested
that the reaction proceeds via an ionic intermediate. At least two
reasonable ionic mechanisms can be considered: (1) dissociation
of the amidate, followed by alkene coordination and nucleophilic
attack of the pendant amidate on the alkene (trans-AP), or (2)
chloride dissociation, followed by alkene coordination and
A well-defined PdIIꢀsulfonamidate complex, suitable for
fundamental investigation, was prepared by adding a solution of
Received: September 10, 2011
Published: October 18, 2011
r
2011 American Chemical Society
18594
dx.doi.org/10.1021/ja208560h J. Am. Chem. Soc. 2011, 133, 18594–18597
|

Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Proposed Mechanism for the Parallel Formation
of 8 and 9 under Anaerobic Conditions
Figure 2. Chloride inhibition on amidopalladation for 3a.
Scheme 2. Isotopic Labeling Study Demonstrating that CꢀN
Bond Formation Proceeds via cis-Amidopalladation
performed under anaerobic conditions: the β-hydride elimination
products 8aꢀ8a00 were obtained in 50% yield, together with a 40%
yield of 4-pentenyl tosylamide 9 (eq 3).
The formation of 9 in eq 3 was unexpected, but this result can
be rationalized if alkene insertion into the PdꢀN bond is
reversible (i.e., 4a / 3a). According to the mechanism in
Scheme 3, β-hydride elimination from 4a forms the enamide
products 8aꢀ8a00 together with a PdIIꢀhydride species 10. In the
absence of O2,15 HCl can form via reductive elimination from 10
and react with 3a to afford the alkenyl tosylamide 9. This
proposal implies that HCl reacts much more rapidly with 3a
than with 4a. In order to test this hypothesis, excess HCl (∼60
equiv) was added to a DMSO-d6 solution of 4a at room
temperature. Rapid and quantitative formation of 9 was ob-
served in this reaction, together with (tBu2bpy)PdCl2 (1, eq 4);
pyrrolidine 11, the product of protonolysis of the PdꢀC bond of
4a, was not observed.
insertion into the PdꢀN bond (cis-AP), and reassociation of the
chloride ligand to the PdII center. Two experimental observa-
tions support the latter, cis-AP pathway. Addition of chloride
to the reaction mixture strongly inhibits the reaction (Figure 2),
consistent with a mechanism involving pre-equilibrium dissocia-
tion of chloride prior to the AP step. In addition, we prepared a
Pdꢀsulfonamidate complex with a stereochemically defined,
deuterium-labeled substrate probe (5, Scheme 2).13 The reaction
of this complex under an atmosphere of O2 led to products 6 and
7, which arise from cis-AP of the alkene, followed by β-hydride
elimination. No products arising from competing trans-AP of the
alkene were observed.
As expected from the reaction illustrated in Scheme 2, the
alkylꢀPdII complex 4a is susceptible to β-hydride elimination.
Heating a DMSO solution of 4a to 60 °C under aerobic conditions
led to a mixture of isomeric products 8a, 8a0, and 8a00 (eq 2).14 A
different outcome was observed, however, when the reaction was
Additional, more-direct evidence for reversible amidopallada-
tion of the alkene was obtained in the investigation of a series of
substituted PdIIꢀsulfonamidate complexes (Figure 3). The
reactions of four different para-substituted benzenesulfonami-
date complexes [X = Me (3a), OMe (3b), Cl (3c), and NO2
1
(3d)] were monitored by H NMR spectroscopy at 30 °C in
DMSO-d6 under aerobic conditions (Figure 3a). Each of the Pd
complexes underwent clean amidopalladation of the alkene to
afford an equilibrium mixture of complexes 3aꢀd and the
corresponding alkylꢀPdII species 4aꢀd (Figure 3b), together
with slower concomitant formation of heterocycles 8ꢀ800aꢀd
via β-hydride elimination from 4aꢀd. The data were fit to a
simplified kinetic model, 3 / 4 f 8ꢀ800, that enabled quanti-
tative comparison of kinetic and thermodynamic constants
associated with the two observable steps (Figure 3c). Electronic
effects on these parameters were probed via Hammett analysis
(Figure 3d).16
Alkene insertion into the PdꢀN bond (i.e., cis-AP, k1) is
favored for electron-rich amidates. This trend is similar to
that observed previously for irreversible alkene insertion into
Pdꢀanilides, and it is consistent with an alkene insertion
mechanism that formally corresponds to intramolecular nucleo-
philic attack of the amidate ligand onto the coordinated alkene.9
18595
dx.doi.org/10.1021/ja208560h |J. Am. Chem. Soc. 2011, 133, 18594–18597

Journal of the American Chemical Society
COMMUNICATION
to reflect the lack of “resonance” electronic effects in the amidate
elimination step kꢀ1; the Hammett correlation for kꢀ1 is best fit
with the “inductive” Hammett parameter σI, rather than σp,
which incorporates both resonance and inductive effects. The k2
values estimated from these fits show that β-hydride elimination
is favored with more-electron-rich derivatives, consistent with a
formal “hydride”-transfer mechanism in which electron-donating
groups stabilize the buildup of positive charge on the adjacent
carbon atom in the transition state. The combined electronic
effects, K1 k2, reveal that the p-Me (tosylamidate) derivative 3a
3
is the most reactive complex toward formation of the oxidative
amidation products 8ꢀ800.
Overall, these observations have important implications for
catalysis. For example, the development of enantioselective
Wacker-type oxidation reactions has been a long-standing chal-
lenge in the field of asymmetric catalysis.17 Alkene insertion into
the PdꢀN bond of 3a results in formation of a new stereogenic
center (Scheme 1), and such steps provide the basis for en-
antioselective oxidative amination reactions (e.g., eq 5).5c Recent
work has highlighted the importance of controlling the stereo-
chemical course of the nucleopalladation step in enantioselective
reactions (i.e., cis- vs trans-nucleopalladation).1f The results
reported here reveal that nucleopalladation could be reversible,
in which case β-hydride elimination or another termination step
will be the stereochemistry-determining step of the reaction. To
our knowledge, this possibility has not been considered pre-
viously in Wacker-type reactions.
Reversible CꢀN bond formation has been observed in reac-
tions involving trans-AP of an alkene,18 but reversible insertion of
an alkene into a PdꢀN bond has not been observed previously.
The latter observation, combined with the significantly more-
facile protonolysis of PdꢀN bonds relative to PdꢀC bonds
(cf. eq 4), represents a key challenge for the development of
Pd-catalyzed hydroamination reactions that proceed via cis-AP
pathways.
In summary, this study has led to key insights into reactions of
PdII-sulfonamidates with alkenes, perhaps most notably demon-
strating that alkene insertion into the PdꢀN bonds of such
species is facile and reversible. This work provides an impor-
tant foundation for more-thorough characterization of cis-
amidopalladation reactions relevant to important catalytic
transformations.
Figure 3. Kinetic studies of alkene insertion/β-hydride elimination
reactions of four PdIIꢀsulfonamidate complexes. Conditions: 3.68 mM
3, 3.8 atm of O2, DMSO, 30 °C, 7ꢀ12 h. Note: Every fifth data point is
shown to enhance clarity.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, kinetic data, and X-ray crystallographic data
(CIF) for compounds 3a and 4a. This material is available free of
charge via the Internet at http://pubs.acs.org.
The reverse reaction, β-amidate elimination, (kꢀ1) is favored for
electron-deficient amidates (Figure 3c and 3d). Together, these
trends cause the equilibrium constant to be largest for the p-Me
derivatives 3/4a (K1 ≈ 10) and smallest for the electron-
deficient p-NO2 derivative 3/4d (K1 ≈ 1) (Figure 3c). That
K1 is largest for the p-Me, and not the p-OMe derivative, appears
’ AUTHOR INFORMATION
Corresponding Author
stahl@chem.wisc.edu
18596
dx.doi.org/10.1021/ja208560h |J. Am. Chem. Soc. 2011, 133, 18594–18597

Journal of the American Chemical Society
COMMUNICATION
’ ACKNOWLEDGMENT
(9) (a) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc.
2010, 132, 6276–6277. (b) Hanley, P. S.; Markoviꢀc, D.; Hartwig, J. F.
J. Am. Chem. Soc. 2010, 132, 6302–6303. (c) Neukom, J. D.; Perch, N. S.;
Wolfe, J. P. Organometallics 2011, 30, 1269–1277. (d) Hanley, P. S.;
Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 15661–15673.
(10) Prior to fundamental studies of alkene insertion, Wolfe and co-
workers provided stereochemical evidence for a cis-amidopalladation step:
(a) Wolfe, J. P.; Ney, J. E. Angew. Chem., Int. Ed. 2004, 43, 3605–3608.
(b) Wolfe, J. P.; Ney, J. E. J. Am. Chem. Soc. 2005, 127, 8644–8651.
(c) Wolfe, J. P.; Nakhla, J. S.; Kampf, J. W. J. Am. Chem. Soc. 2006,
128, 2893–2901.
We thank Dr. Ilia Guzei for performing X-ray structure
determinations and Drs. Charlie Fry and Monika Ivancic for
training and experimental assistance in the acquisition of NMR
spectroscopic data. We are grateful for financial support from the
NIH (R01 GM67163). Instrumentation was partially funded by
the NSF (CHE-9974839, CHE-9629688, CHE-9629688, and
CHE-8813550) and the NIH (1 S10 RR13866-010).
(11) For leading references to fundamental studies of alkene reac-
tivity with other transition-metal amido complexes, see: (a) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673–686. (b) M€uller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795–3892. (c) Zhao, P.; Krug, C.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 12066–12073. (d) Hoover, J. M.; DiPasquale, A.; Mayer,
J. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132, 5043–5053. (e) Leitch,
D. C.; Platel, R. H.; Schafer, L. L. J. Am. Chem. Soc. 2011, 133,
15453–15463.
’ REFERENCES
(1) For reviews, see: (a) B€ackvall, J.-E. Acc. Chem. Res. 1983,
16, 335–342. (b) Hegedus, L. S. Tetrahedron 1984, 40, 2415–2434.
(c) Larock, R. C.; Zeni, G. Chem. Rev. 2004, 104, 2285–2309. (d)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev.
2007, 107, 5318–5365. (e) Minatti, A.; Mu~niz, K. Chem. Soc. Rev. 2007,
36, 1142–1152. (f) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011,
111, 2981–3019.
(2) See refs 1a, 1b and the follow representative primary references:
(a) Cope, A. C.; Kliegman, J. M.; Friedrich, E. C. J. Am. Chem. Soc. 1967,
89, 287–291. (b) Åkermark, B.; B€ackvall, J.-E.; Hegedus, L. S.; Zetterberg,
K; Siiralah-Hansꢀen, K.; Sj€oberg, K. J. Organomet. Chem. 1974, 72,
127–138. (c) B€ackvall, J.-E. Tetrahedron Lett. 1978, 163–166. (d)
Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem.
Soc. 1978, 100, 5800–5807. (e) Pugin, B.; Venanzi, L. M. J. Organomet.
Chem. 1981, 214, 125–133. (f) Åkermark, B.; Zetterberg, K. J. Am. Chem.
Soc. 1984, 106, 5560–5561. (g) Hegedus, L. S.; Åkermark, B.; Zetterberg,
K.; Olsson, L. F. J. Am. Chem. Soc. 1984, 106, 7122–7126.
(12) See Supporting Information for further details.
(13) For the synthesis and previous application of this substrate
probe, see ref 7d.
(14) This reaction was carried out in an NMR tube. Because
gasꢀliquid mixing is slow in an NMR tube, an elevated pressure of O2
was used to ensure at least 1 equiv of O2 was dissolved in solution.
(15) The reaction of O2 with (NꢀN)Pd(H)Cl complexes was the
focus of a recent study: Decharin, N.; Popp, B. V.; Stahl, S. S. J. Am.
Chem. Soc. 2011, 133, 13268–13271.
(16) Data acquisition focused on the alkene insertion/deinsertion
steps (K1). Thus, the reliability of the k2 data is constrained by the
limited data obtained for the β-hydride elimination step.
(3) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104,
2444–2451.
(4) For example, see: (a) van Benthem, R. A. T. M.; Hiemstra, H.;
Longarela, G. R.; Speckamp, W. N. Tetrahedron Lett. 1994,
35, 9281–9284. (b) R€onn, M.; B€ackvall, J.-E.; Andersson, P. G. Tetra-
hedron Lett. 1995, 36, 7749–7752. (c) Larock, R. C.; Hightower, T. R.;
Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585. (d)
Stahl, S. S.; Fix, S. R.; Brice, J. L. Angew. Chem., Int. Ed. 2002,
41, 164–166. (d) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2003, 42, 2892–2895.
(5) (a) Scarborough, C. C.; Bergant, A.; Sazama, G. T.; Guzei, I. A.;
Spencer, L. C.; Stahl, S. S. Tetrahedron 2009, 65, 5084–5092. (b) He, W.;
Yip, K. T.; Zhu, N. Y.; Yang, D. Org. Lett. 2009, 11, 5626–5628. (c) Jiang,
F.; Wu, Z. X.; Zhang, W. B. Tetrahedron Lett. 2010, 51, 5124–5126. (d)
McDonald, R. I.; White, P. B.; Weinstein, A. B.; Tam, C. P.; Stahl, S. S.
Org. Lett. 2011, 13, 2830–2833.
(17) For recent progress in this area, see refs 1f, 4d, 5, and the
following additional leading references: (a) Uozumi, Y.; Kyota, H.; Kato,
K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620–1625. (b)
Sasai, H.; Arai, M. A.; Kuraishi, M.; Arai, T. J. Am. Chem. Soc. 2001,
123, 2907–2908.
(18) See, for example, ref 8a and the following: (a) Vitagliano, A.;
Hahn, C.; Morvillo, P. Eur. J. Inorg. Chem. 2001, 419–429. (b) Michael,
F. E.; Cochran, B. M. J. Am. Chem. Soc. 2008, 130, 2786–2792. (c)
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888–17893.
(6) (a) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S. I.
Tetrahedron Lett. 1992, 33, 6643–6646. (b) Stahl, S. S.; Timokhin, V. I.;
Anastasi, N. R. J. Am. Chem. Soc. 2003, 125, 12996–12997. (c) Brice,
J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am.
Chem. Soc. 2005, 127, 2868–2869. (d) Kim, S. K.; Lee, J. M.; Ahn, D. S.;
Jung, D. Y.; Lee, J.; Do, Y.; Chang, S. K. J. Am. Chem. Soc. 2006,
128, 12954–12962. (e) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl,
S. S. Org. Lett. 2007, 9, 4331–4334. (f) Obora, Y.; Shimizu, Y.; Ishii, Y.
Org Lett. 2009, 11, 5058–5061. (g) Liu, X.; Hii, K. K. Eur. J. Org. Chem.
2010, 2010, 5181–5189.
(7) See ref 1a and the following: (a) Isomura, K.; Okada, N.;
Saruwatari, M.; Yamasaki, H.; Taniguchi, H. Chem. Lett. 1985,
385–388. (b) Liu, G. S.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128,
7179–7181. (c) Mu~niz, K.; H€ovelmann, C. H.; Streuff, J. J. Am. Chem.
Soc. 2008, 130, 763–773. (d) Liu, G. S.; Stahl, S. S. J. Am. Chem. Soc.
2007, 129, 6328–6335.
(8) For recent catalytic and fundamental studies of alkene amidation
reactions with carbamate and carboxamide nucleophiles that proceed via
trans-amidopalladation, see the following: (a) Michael, F. E.; Cochran,
B. M. J. Am. Chem. Soc. 2008, 130, 2786–2792. (b) Sibbald, P. A.;
Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 15945–15951.
18597
dx.doi.org/10.1021/ja208560h |J. Am. Chem. Soc. 2011, 133, 18594–18597