In situ generated bulky palladium hydride complexes as catalysts for the efficient isomerization of olefins. Selective transformation of terminal alkenes to 2-alkenes

Article abstract of DOI:10.1021/ja9108424

Application of an in situ generated bulky palladium(II) hydride catalyst obtained from a 1:1:1 mixture of Pd(dba)₂, P(tBu)₃, and isobutyryl chloride provides an efficient protocol for the isomerization and migration of a variety of olefins. In addition to the isomerization of (Z)- to (E)-olefins, the conjugative migration of allylbenzenes, allyl ethers, and amines was effectively achieved in near-quantitative yields and with excellent functional group tolerance. Catalyst loadings in the range of 0.5-1.0 mol % were typically applied, but even loadings as low as 0.25 mol % could be achieved when the reactions were performed under neat conditions. More interestingly, the investigated catalyst proved to be selective for converting terminal alkenes to 2-alkenes. This one-carbon migration process for monosubstituted olefins provides an alternative catalyst, which bridges the gap between the allylation and propenylation/vinylation protocols. Several substrates, including homoallylic alcohols and amines, were selectively transformed into their corresponding 2-alkenes, and examples using enantiomerically enriched substrates provided products without epimerization at the allylic stereogenic carbon centers. Finally, some mechanistic investigations were undertaken to understand the nature of the active in situ generated Pd-H catalyst. These studies revealed that the catalytic system is highly dependent on the large steric demand of the P(tBu)₃ ligand. The use of an alternative ligand, cataCXium PinCy, also proved effective for generating an active catalyst, and it was demonstrated in some cases to display better selectivity for the one-carbon shifts of terminal olefins. A possible intermediate involved in the preparation of the active catalyst was characterized by its single-crystal X-ray structure, which revealed a monomeric tricoordinated palladium(II) acyl complex, bearing a chloride ligand.

Full text of DOI:10.1021/ja9108424

Published on Web 05/19/2010
In Situ Generated Bulky Palladium Hydride Complexes as
Catalysts for the Efficient Isomerization of Olefins. Selective
Transformation of Terminal Alkenes to 2-Alkenes
Delphine Gauthier, Anders T. Lindhardt,* Esben P. K. Olsen, Jacob Overgaard, and
Troels Skrydstrup*
The Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the
Interdisciplinary Nanoscience Center, Aarhus UniVersity, Langelandsgade 140,
8000 Aarhus, Denmark
Received December 31, 2009; E-mail: ts@chem.au.dk
Abstract: Application of an in situ generated bulky palladium(II) hydride catalyst obtained from a 1:1:1
mixture of Pd(dba)2, P(tBu)3, and isobutyryl chloride provides an efficient protocol for the isomerization
and migration of a variety of olefins. In addition to the isomerization of (Z)- to (E)-olefins, the conjugative
migration of allylbenzenes, allyl ethers, and amines was effectively achieved in near-quantitative yields
and with excellent functional group tolerance. Catalyst loadings in the range of 0.5-1.0 mol % were typically
applied, but even loadings as low as 0.25 mol % could be achieved when the reactions were performed
under neat conditions. More interestingly, the investigated catalyst proved to be selective for converting
terminal alkenes to 2-alkenes. This one-carbon migration process for monosubstituted olefins provides an
alternative catalyst, which bridges the gap between the allylation and propenylation/vinylation protocols.
Several substrates, including homoallylic alcohols and amines, were selectively transformed into their
corresponding 2-alkenes, and examples using enantiomerically enriched substrates provided products
without epimerization at the allylic stereogenic carbon centers. Finally, some mechanistic investigations
were undertaken to understand the nature of the active in situ generated Pd-H catalyst. These studies
revealed that the catalytic system is highly dependent on the large steric demand of the P(tBu)3 ligand.
The use of an alternative ligand, cataCXium PinCy, also proved effective for generating an active catalyst,
and it was demonstrated in some cases to display better selectivity for the one-carbon shifts of terminal
olefins. A possible intermediate involved in the preparation of the active catalyst was characterized by its
single-crystal X-ray structure, which revealed a monomeric tricoordinated palladium(II) acyl complex, bearing
a chloride ligand.
bonds.2,3 In addition to the direct application of olefins in organic
synthesis, they can also serve as protecting groups masking
Introduction
Olefins represent key structural features in a plethora of
naturally and non-naturally occurring compounds, as well as
being precursors for the industrial synthesis of polymers.1,2 This
unsaturation occupies an important position in organic synthesis,
since it can readily be transformed into a wide variety of other
functionalities, as well as being a substrate for the metathesis
reaction for the generation of new carbon-carbon double
heteroatom-containing functionalities such as acids, amides,
alcohols, amines, thiols, and others.4 Despite a large variety of
synthetic methods for the introduction of C-C double bonds
into a number of molecular structures, such transformations are
not always straightforward. An alternative way of positioning
an unsaturation is to transpose a pre-existing carbon-carbon
double bond with control of the stereochemistry. Consequently,
the transformation of alkenes involving either the interconver-
(3) (a) Larock, R. C. In ComprehensiVe Organic Transformations: A Guide
to Functional Group Preparations, 2nd ed.; VCH: New York, 1999;
and references cited therein. (b) Mackenzie, K. In The Chemistry of
Alkenes; Patai, S., Ed.; Wiley: New York, 1964. For a review on the
Wittig reaction, see: (c) Maryanoff, B. E.; Reitz, A. B. Chem. ReV.
1989, 89, 863. For a review on olefin metathesis, see: (d) Grubbs,
R. H. Tetrahedron 2004, 60, 7117. (e) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vols.
1-3.
(4) (a) Kocienski, P. J. In Protecting Groups, 3rd ed.; Thieme Verlag:
Stuttgart, Germany, 2005. (b) Wuts, P. G. M.; Greene, T. W. In
Green’s ProtectiVe Groups in Organic Synthesis, 4th ed.; Wiley-
Interscience: New York, 2006. (c) Guibe´, F. Tetrahedron 1998, 54,
2967. (d) Guibe´, F. Tetrahedron 1997, 53, 13509. (e) Escoubet, S.;
Gastaldi, S.; Bertrand, M. Eur. J. Org. Chem. 2005, 3855.
(1) Kricheldorf, H. R.; Nuyken, O.; Swift, G. In Handbook of Polymer
Synthesis, 2nd ed.; Marcel Dekker: New York, 2005.
(2) Selected examples: (a) Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman,
P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997,
36, 2744. (b) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. Am.
Chem. Soc. 2000, 122, 10033. (c) Ley, S. V.; Brown, D. S.; Clase,
J. A.; Fairbanks, A. J.; Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.;
Wadsworth, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2259. (d)
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet,
J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (e) Fleming,
I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063. (f) Nicolaou,
K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia,
F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997,
119, 7960.
9
7998 J. AM. CHEM. SOC. 2010, 132, 7998–8009
10.1021/ja9108424  2010 American Chemical Society

Palladium Hydride Complexes as Catalysts
A R T I C L E S
sion of (E)- and (Z)-alkenes or the controlled migration of this
functionality along a carbon chain is of high importance.5-10
Recently, the selective transformation of terminal alkenes into
2-alkenes has received increased attention, since such migrations
allow the conversion of products obtained from a C-C bond-
forming allylation to the corresponding adducts of vinylation
or propenylation. This one-carbon shift protocol was recently
highlighted by Donohoe and co-workers,11 stating: “Allyl groups
have the advantage that they can be installed readily in
procedures that are more convenient than the addition of a vinyl
group, for example, through a radical Keck-type allylation of
haloalkanes the allylation of an enolate, or the addition of an
allylic organometallic reagent to a carbonyl group. Subsequent
isomerization of the terminal olefin to the internal position
affords a propenyl group, which can be further functionalized.
Therefore, this sequence builds a bridge between the chemistry
of an allyl group and that of a vinyl group; this tactic is
particularly useful in synthesis.”
(5) For representative examples of E/Z interconversions, see the following.
Isomerizations based on acids: (a) Gibson, T. W.; Strassburger, P. J.
Org. Chem. 1976, 41, 791. Isomerizations based on halogens: (b)
Hepperle, S. S.; Li, Q.; East, A. L. L. J. Phys. Chem. A 2005, 109,
10975. (c) Kodomari, M.; Sakamoto, T.; Yoshitomi, S. Bull. Chem.
Soc. Jpn. 1989, 62, 4053. Isomerizations based on photochemistry: (d)
Sairre, M. I.; Arau´jo, L. F. N.; Silva, R.; Donate, P. M.; Silve´rio,
C. A.; Okano, L. T. J. Braz. Chem. Soc. 2008, 19, 194. (e) Dugave,
C.; Demange, L. Chem. ReV. 2003, 103, 2475. (f) Baag, M. M.; Kar,
A.; Argade, N. P. Tetrahedron 2003, 59, 6489. (g) Jacobsen, E. N.;
Deng, L.; Furukawa, Y.; Martine´z, L. E. Tetrahedron 1994, 15, 4323.
(h) Iranpoor, N.; Mottaghinejad, E. J. Organomet. Chem. 1992, 423,
399. Isomerizations based on radical processes: (i) Bosanac, T.; Yang,
J.; Wilcox, C. S. Angew. Chem., Int. Ed. 2001, 40, 1875. (j) Ali, M. A.;
Tsuada, Y. Chem. Pharm. Bull. 1992, 40, 2842.
One-carbon migrations of alkenes have in the past few years
been successfully performed, exploiting a ruthenium hydride
based complex derived from a Grubbs generation II metathesis
catalyst.9t-x,10i,11-14 Migration of the unsaturation does not
proceed further, despite the fact that additional isomerization
of the unsaturation would afford products of higher thermody-
namic stability (conjugation or increased substitution pattern
of the olefin). Impressive examples on the use of this Ru-based
catalyst have been reported in the literature with catalyst
loadings generally in the range of 5-10 mol % and sometimes
with the necessity for stoichiometric additives.12,14 These
catalysts are, however, not without some drawbacks, as they
also can promote unwanted side reactions such as reduction and
self-dimerization of the olefin.11,15 In the end, this leads to
depletion of the overall yield of the transformation in combina-
tion with potentially difficult purification steps.
(6) For representative examples of E/Z interconversions, using palladium,
see: (a) Canovese, L.; Santo, C.; Visentin, F. Organometallics 2008,
27, 3577. (b) Kim, I. S.; Dong, G. R.; Jung, Y. H. J. Org. Chem.
2007, 72, 5424. (c) Yu, J.; Gaunt, M.; Spencer, J. B. J. Org. Chem.
2002, 67, 4627.
(7) For representative examples of migrations in allyl groups, see
migrations based on bases: (a) Catozzi, N.; Edwards, M. G.; Raw,
S. A.; Wasnaire, P.; Taylor, R. J. K. J. Org. Chem. 2009, 74, 8343.
(b) Bo¨hrsch, V.; Blechert, S. Chem. Commun. 2006, 1968. (c) Sagoet,
O.; Monteux, D.; Langlois, Y.; Riche, C.; Chiaroni, A. Tetrahedron
Lett. 1996, 37, 7019.
(8) For reviews of migrations in O-allyl systems, see: (a) Kuz´nik, N.;
Krompiec, S. Coord. Chem. ReV. 2007, 251, 222. (b) Uma, R.; Cre´visy,
C.; Gre´e, R. Chem. ReV. 2003, 103, 27. (c) van der Drift, R. C.;
Bouwmann, E.; Drent, E. J. Organomet. Chem. 2002, 650, 1.
(9) For representative examples of migrations in allyl groups using
transition metals, see the following. For Fe: (a) Crivello, J. V.; Kong,
S. J. Org. Chem. 1998, 63, 6745. For Ir: (b) Baxendale, I. R.; Lee,
A.-L.; Ley, S. V. Synlett 2002, 3, 516. For Rh: (c) Boons, G.-J.; Burton,
A.; Isles, S. Chem. Commun. 1996, 141. (d) Corey, E. J.; Suggs, W.
J. Org. Chem. 1973, 38, 3224. (e) Galbe, K. P. Tetrahedron Lett. 1991,
32, 23. (f) Gent, P. A.; Gigg, R. J. Chem. Soc., Chem. Commun. 1974,
227. (g) Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1993, 115,
2027. (h) van Boeckel, C. A. A.; Oltvoort, J. J.; van Boom, J. H.
Tetrahedron 1981, 37, 3751. (i) Strohmeier, W.; Weigelt, L. J.
Organomet. Chem. 1975, 86, C17. (j) Kloosterman, M.; van Boom,
J. H.; Chatelard, P.; Boulanger, P.; Descotes, G. Tetrahedron Lett.
1985, 26, 5045. (k) Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett.
1998, 39, 2075. (l) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45,
2139. For Pd: (m) Golborn, P.; Scheinmann, F. AdV. Catal. 1969, 20,
291. (n) Stork, G.; Atwal, K. S. Tetrahedron Lett. 1982, 23, 2073. (o)
Carless, H. A. J.; Haywood, D. J. J. Chem. Soc., Chem. Commun.
1980, 980. (p) Boss, R.; Scheffold, R. Angew. Chem., Int. Ed. Engl.
1976, 15, 558. (q) Moreau, B.; Lavielle, S.; Marquet, A. Tetrahedron
Lett. 1977, 18, 2591. For Ni: (r) Taniguchi, T.; Ogasawara, K. Angew.
Chem., Int. Ed. 1998, 37, 1136. (s) Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 1998, 39, 4679. For Ru: (t) Donohoe, T. J.; Flore,
A.; Bataille, C. J. R.; Churruca, F. Angew. Chem., Int. Ed. 2009, 48,
6507. (u) Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahdron Lett. 2002, 43,
1839, and references cited therein. (v) Alcaide, B.; Almendros, P.;
Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3, 3781. (w) Wang, D.;
Chen, D.; Haberman, J. X.; Li, C.-J. Tetrahedron 1998, 54, 5129. (x)
Zoran, A.; Sasson, Y.; Blum, J. J. Org. Chem. 1981, 46, 255. For Zr:
(y) Gibson, T.; Tulich, L. J. Org. Chem. 1981, 46, 1821.
Just recently, the RajanBabu group reported the use of another
interesting class of catalysts for this valuable single-carbon
migration reaction derived from [(allyl)PdCl]2, a triarylphos-
phine, and silver triflate.16 Although the transformation of
terminal olefins to 2-alkenes was successfully achieved with
the few examples tested, the E:Z ratio of the newly formed
disubstituted olefin was moderate. Hence, the identification of
alternative catalysts which can not only promote this interesting
migration reaction but also provide products with control of
the CdC bond geometry could be of significant importance.
(11) Donohoe, T. J.; O’Riordan, T. J. C.; Rosa, C. P. Angew. Chem., Int.
Ed. 2009, 48, 1014.
(12) For reviews on double-bond isomerizations with Ru hydride catalysts,
see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067. (b) Naota, T.; Takaya, H.; Murahahsi, S.-I. Chem. ReV.
1998, 98, 2599.
(13) (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem.
2002, 114, 4926; Angew. Chem., Int. Ed. 2002, 41, 4732. (b) Arisawa,
M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. J. Org.
Chem. 2006, 71, 4255. (c) Terada, Y.; Arisawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2004, 43, 4063. (d) Louie, J.; Grubbs, R. H.
Organometallics 2002, 21, 2153. (e) Lee, H. M.; Smith, D. C., Jr.;
He, Z.; Stevens, E. D.; Yi, C. S.; Nolan, S. P. Organometallics 2001,
20, 794. (f) Dharmasena, U. L.; Foucault, H. M.; dos Santos, E. N.;
Fogg, D. E.; Nolan, S. P. Organometallics 2005, 24, 1056. (g) Trnka,
T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl, M.;
Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 2546. (h) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2004, 126, 7414.
(10) For representative examples of migrations applying transition metals,
see the following. For Mo: (a) Joe, D.; Overmann, L. E. Tetrahedron
Lett. 1997, 38, 8635. For Cr: (b) Sodeoka, M.; Yamada, H.; Shibasaki,
M. J. Am. Chem. Soc. 1990, 112, 4906. For Rh: (c) Matsuda, I.; Kato,
T.; Sato, S.; Izumi, Y. Tetrahedron Lett. 1986, 27, 5747. For Pd: (d)
Sen, A.; Lai, T. W. Inorg. Chem. 1984, 23, 3257. (e) Sen, A.; Lai,
T. W. Inorg. Chem. 1981, 20, 4036. For Ni: (f) Lochow, C. F.; Miller,
R. G. J. Org. Chem. 1976, 41, 3020. For Ru: (g) Grotjahn, D. B.;
Larsen, C. R.; Gustafson, J. L.; Nair, R.; Sharma, A. J. Am. Chem.
Soc. 2007, 129, 9592. (h) Yue, C. J.; Liu, Y.; He, R. J. Mol. Catal. A:
Chem. 2006, 259, 17. (i) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
(j) Wakamatsu, H.; Nishida, M.; Adachi, N.; Mori, M. J. Org. Chem.
2000, 65, 3966. (k) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz,
H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204.
(14) (a) Alcaide, B.; Almendros, P.; Luna, A. Chem. ReV. 2009, 109, 3817,
and references therein. (b) Dinger, M. B.; Mol, J. C. Organometallics
2003, 22, 1089. (c) Dinger, M. B.; Mol, J. C. Eur. J. Inorg. Chem.
2003, 2827. (d) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006,
8, 5481. (e) Donohoe, T. J.; Rosa, C. P. Org. Lett. 2007, 9, 5509. (f)
Donohoe, T. J.; Chiu, J. Y. K.; Thomas, R. E. Org. Lett. 2007, 9,
421.
(15) Hong, S. H.; Snaders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160.
(16) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74,
4565.
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 7999

A R T I C L E S
Gauthier et al.
Figure 1. Direct intermolecular ene-yne coupling and its catalytic cycle.
Figure 2. Isomerization/migration of C-C double bonds catalyzed by Pd-H complexes.
Previously, we reported the direct intermolecular coupling
of alkynes to alkenes via a proposed palladium(II) hydride
catalyzed Mizoroki-Heck (MH) type mechanism (Figure 1).17,18
We proposed that the complex 1 was formed in situ from a
mixture of Pd(dba)2, P(tBu)3, and isobutyryl chloride, and in
all steps of the catalytic cycle, palladium was retained in the
oxidation state II (Figure 1). Hills and Fu have previously
isolated this complex and suggested it to be a potential MH-
coupling resting state strongly dependent on the choice of base.19
The increased stability of 1 compared to that of other Pd-H
complexes is explained by the large steric bulk of the two
coordinating P(tBu)3 ligands, forcing them to be placed trans
to each other in the square-planar structure of the Pd(II)
complex, thereby retarding decomposition via reductive elimina-
tion.19 Furthermore, it is a well-known problem in MH couplings
that a palladium hydride resting state can initiate double-bond
isomerizations by a repeated olefin addition/ꢀ-hydride elimina-
tion mechanism, leading to the undesired formation of byprod-
ucts (Figure 2).20 With the apparent stability of palladium
hydride complexes such as 1 and with a protocol leading to the
possible in situ formation of such complexes, we sought to
investigate their application in alkene isomerization/migration
processes.
P(tBu)3, and isobutyryl chloride for the isomerization of double
bonds with excellent functional group tolerance. Not only does
this catalyst perform simple and selective Z to E isomerizations
of 1,2-disubstituted olefins in almost quantitative yields but it
can efficiently catalyze the migration of a variety of terminal
olefins such as heteroatom-substituted allylic systems and
allylbenzenes to their corresponding 1-propenyl derivatives
under mild reaction conditions,21 in which for the latter a high
selectivity for the E isomer was achieved. Furthermore, we
demonstrate that the combination of these three reagents
generates a catalyst, which can successfully migrate various
terminal olefins by one carbon to 2-alkenes, even though further
migration would lead to products of higher thermodynamic
stability through conjugation with other functional groups. This
method represents thereby a viable alternative to the Ru-based
catalysts. A detailed study on the factors which govern the activity
of this catalyst revealed that an alternative phosphine, cataCXium
PinCy, proved in some cases to be superior to P(tBu)3. Finally,
studies were undertaken to provide information about the mech-
anism of formation and structure of the active catalyst.
Results and Discussion
Cis-Trans Isomerizations. Initial screenings revealed that
direct transfer of the catalytic system applied to the intermo-
lecular ene-yne coupling using Pd(dba)2 (5 mol %), P(tBu)3 (10
mol %), and isobutyryl chloride (10 mol %) in toluene at 50
°C overnight afforded full isomerization of (Z)-stilbene (2) and
Herein, we wish to report on the application of a highly
effective catalytic system composed of a 1:1:1 ratio of Pd(dba)2,
(17) Lindhardt, A. T.; Mantel, M. L. H.; Skrydstrup, T. Angew. Chem.,
Int. Ed. 2008, 47, 2668.
(18) For a review on palladium hydride complexes, see: (a) Grushin, V. V.
Chem. ReV. 1996, 96, 2011. (b) Hii, K. K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.;
Wiley-Interscience: New York, 2002; Chapter II.2.5.
(21) For examples of the relevance of propenylbenzenes, see: (a) Bauer,
K.; Garbe, D.; Surberg, H.; In Ullmann’s Encyclopedia of Industrial
Chemistry, 6th ed.; Wiley: New York, 2002. (b) Luu, T. X. T.; Lam,
T. T.; Le, T. N.; Duus, F. Molecules 2009, 14, 3411. (c) Sharma,
S. K.; Srivastava, V. K.; Pandya, P. H.; Jasra, R. V. Catal. Commun.
2005, 6, 205. (d) Sharma, S. K.; Srivastava, V. K.; Jasra, R. V. J.
Mol. Catal. A: Chem. 2006, 245, 200.
(19) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178.
(20) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience: New
York, 2002, Chapter IV.2.
9
8000 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Palladium Hydride Complexes as Catalysts
A R T I C L E S
Table 1. Catalyst Optimization
accomplished in a 96% isolated yield under the standard
conditions described above. On the other hand, performing the
reaction under neat conditions using 0.25 mol% catalyst on a
27.8 mmol scale (4.5 g of safrole) resulted in quantitative
isolation of the migrated product with the same high stereose-
lectivity favoring the trans isomer 15. Conjugative migration
of the electron-deficient allylpentafluorobenzene again per-
formed well under neat conditions, furnishing 16 in an 84%
isolated yield.22
Allylic ethers and amines were also susceptible to the
migration protocol at hand, and the results are depicted in
Scheme 2. In order for the double-bond migration to reach
completion, the catalyst loading was increased to 1.0 mol %.
Once again, the catalytic system proved effective in the presence
of a range of sensitive functional groups, including aromatic
aldehydes and aliphatic alcohols as for compounds 17 and 18,
respectively, and all migrated compounds could be isolated in
yields ranging from 92% to quantitative yield, although with a
drop in the E:Z selectivity in most cases. The loss of stereo-
selectivity observed in these systems was not considered
problematic, since a typical procedure would involve one-pot
migration followed by acidic treatment in order to remove the
resulting vinyl ether protecting group.22,23 The double migration
of 1-allyl-2-(allyloxy)benzene afforded 20 in a 99% isolated
yield using the same catalyst loading of 1 mol %.
Three different O-allylic glycosides of protected glucosamine,
21-23, were also tested.23c Addition of dioxane as a cosolvent
proved helpful in order to ensure a homogeneous solution of
the glycosides, and all products were isolated in yields ranging
from 95% to 97%. Finally, a few N-allylated compounds were
screened, and again all proved to be successful substrates for
these isomerization conditions. This led to the formation of the
products 24-27, which included both a simple and a function-
alized indole,9v the latter of which was isolated in a 99% yield
with an overall 90:10 E:Z stereoselectivity. At this point, it
should be mentioned that basic allylamines proved detrimental
for the catalyst, with full recovery of the starting material. This
observation will be addressed in further detail in Mechanistic
Considerations.
During the study on the allylic ethers, another allyl derivative
was tested, which led to an interesting observation. Protecting
eugenol with 3-chloro-2-methyl-1-propene and a base afforded
the O-alkylated derivative 28 (Scheme 3). When 28 was
subjected to our isomerization conditions, migration was
predominantly observed for the simple allyl functionality rather
than for the 1,1-disubstituted olefin, leading to a 95:5 mixture
of 29 and 30 in a 92% isolated yield. This result was also noted
for the doubly functionalized 1,7-naphthalenediol 31, in which
selective shift of the C-C double bond of the allylic ether took
place, providing exclusively the vinyl ether 32 in a 96% yield.
One-Carbon Migrations of Terminal Olefins. Interestingly,
when N-Boc-N-tosyl-4-pentenamine (33) was subjected to the
catalytic conditions at 50 °C in toluene, isomerization to the
3-pentenyl amine isomer 34 was the only product observed for
this reaction instead of complete migration with the formation
of the vinyl amide derivative (Scheme 4). Inspired by these
a Conversion determined by 1H NMR analysis of the crude product
mixture. b Isolated yield after chromatography.
(Z)-dimethyl maleate (3) to their corresponding E isomers 4
and 5 (Table 1, entry 1). Control experiments proved that the
palladium source, the phosphine, or the acid chloride individu-
ally or in combinations of two could not catalyze the cis-trans
double-bond isomerization. Apart from DMF, other solvents
such as EtOAc, dioxane, and THF did not seem to affect the
catalytic activity (see the Supporting Information), and hence
toluene was therefore chosen as a representative solvent for
further screening. Lowering of the catalyst loading to Pd(dba)2
(1 mol %), P(tBu)3 (2 mol %), and isobutyryl chloride (2 mol
%) afforded the same high conversion (entry 2). Changing the
catalyst composition to a 1:1:1 ratio of the Pd(dba)2:P(tBu)3:
isobutyryl chloride mixture (1 mol % of each) provided the same
activity, and even an amount as low as 0.5 mol % allowed the
reaction to be completed within 24 h with almost quantitative
yields of the isolated products (entries 3 and 4). Applying a 0.1
mol % catalyst loading promoted the quantitative isomerization
of (Z)-dimethyl maleate, but only an 87% conversion was
detected for (Z)-stilbene after 24 h (entry 5). When methyl (Z)-
3-(2-methoxyphenyl)-2-propenoate was tested with the same
catalyst loading, a 99% isolated yield of the E isomer 6 with a
>95:5 E:Z ratio was obtained (eq 1).
Migration of Allylic Alcohols and Amines and Allyl-
benzenes. With these conditions in hand, we decided to
investigate the catalyst’s reactivity on terminal olefins in
examples where migration to internal alkenes is possible.
Initially, the allylbenzenes were subjected to conditions operat-
ing with a 0.5 mol % catalyst loading in toluene. When the
temperature was increased from 50 to 80 °C, we were pleased
to find that all the allylbenzenes tested underwent isomerization,
affording the more stable conjugated trans isomer in high
isolated yields ranging from 84 to 99% (Scheme 1). Several
functionalities proved compatible to the catalytic conditions,
including tosylates (9), phenols (10, 11, 13 and 14), heteroaro-
matic cores (13), and even a free aromatic carboxylic acid (14).
The presence of a free alcohol positioned ortho to the allylic
chain resulted in a lower E:Z ratio, but this effect was remedied
upon functionalization of the alcohol as its benzylic ether instead
(11 and 12). Isomerization of safrole to isosafrole (15) was
(22) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 2002, 1850.
(23) (a) Wille, A.; Tomm, S.; Frauenrath, H. Synthesis 1998, 305. (b)
Davies, S. G. In Organotransition Metal Chemistry: Applications To
Organic Synthesis; Pergamon: Oxford, U.K., 1982. (c) Christensen,
H.; Christiansen, M. S.; Petersen, J.; Jensen, H. H. Org. Biomol. Chem.
2008, 6, 3276.
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 8001

A R T I C L E S
Gauthier et al.
Scheme 1. Conjugative Migrations of Allylbenzenes
Scheme 2. Conjugative Migrations of Allylic Ethers, Amines, and Indoles
Scheme 3. Examples of Regioselective C-C Double-Bond Migration
findings, we decided to screen more substrates, including
homoallylic amines and alcohols, the results of which are
presented in Table 2. This same one-carbon migration was
observed in these similar systems, even though further migration
in general would lead to products of higher stability.
Applying the catalytic system directly to the nonprotected
homoallylic alcohol 35 at 80 °C afforded an approximately 90%
conversion to 43 with an isolated yield of 73% and a E:Z ratio
of 90:10.24 In contrast to that observed for the pentenyl amine
33, attempted migration at 50 °C only led to lower conversions.
9
8002 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Palladium Hydride Complexes as Catalysts
A R T I C L E S
Scheme 4. Olefin Migration Studies with
N-Boc-N-tosyl-4-pentenamine
versions (52, 53 and 55, 56 respectively) was attempted in order
to establish the role of the alcohol or oxygen atom’s position
for the selective isomerization (Table 3). In contrast to the
examples shown in Table 2, these homologues provided a
mixture of products resulting from one- and two-carbon
migration of the double bond. Nevertheless, it is interesting to
note that again no ketone or aldehyde products were identified
in the product mixtures from 51 and 54. Protection of the alcohol
functionality as the benzyl ether (52 and 55) or TIPS ether (53
and 56) did, however, reveal some perplexing results. Whereas,
the amount of two-carbon migrated products doubled for the
protected versions of 51 (entries 2 and 3) the opposite was
observed for 55 and 56 (entries 5 and 6). One explanation for
this decrease in two-carbon migration with 55 and 56 could be
that protection of the alcohol retards the coordinating ability of
the oxygen atom allowing the steric interaction with the 2-methyl
side chain to influence the overall selectivity (entries 5 and 6).
Silylation or benzylation of the free hydroxyl group had a
significant effect on the conversion efficiency. For example, in
the case of the benzyl ether 37, selective migration of the
terminal olefin led to an improved level of conversion and the
alcohol derivative 45 could be secured in an excellent 92% yield.
Exchange of the homoallylic side chain from an alkyl to a phenyl
group proved also equally rewarding, providing selectively 46
in a satisfactory 91% yield, even though the driving force for
conjugation would be greater for this substrate. In addition to
the homoallylic alcohols, a few enantiomerically pure homoal-
lylic amines were tested. Again, the same high selectivity for
the one-carbon migration was observed, and in both examples
examined, 47 and 48 were obtained in good yields. Importantly,
chiral HPLC analysis of the products revealed that no epimer-
ization of the nitrogen-bearing stereogenic carbon centers had
occurred.
Upon application of 57, the nontosylated version of 33 in
Scheme 4, a one-carbon shift of the double bond was primarily
observed with only minor amounts of the two-carbon migrated
product (eq 2). Notably, when dibenzylated cis-2-butene-1,4-
diol (60; eq 3) was examined, under our conditions only the Z
to E isomerization was observed, with no trace of products
resulting from migration to the conjugated vinyl ether. When
all these results are compared with the conjugative migrations
in Table 2, it becomes clear that it is difficult to provide a
concise model predicting the regioselectivity of this migration
depending on the position or mode of protection on the
heteroatom (oxygen or nitrogen) in these systems. However, it
appears that the migration toward conjugation is impeded due
to the presence of a secondary allylic heteroatom.
Finally, subjecting substrates derived from either the stereo-
selective allylation of glutamate or Evans N-acyl oxazolidinone
to our conditions provided the desired 1,2-disubstituted olefins
49 and 50 in good yields without sign of products derived from
conjugation of the C-C double bond. Again, epimerization of
the stereogenic carbon centers was not observed.
Whereas the conversions were high in all cases, for some
substrates the reaction ceased after approximately 90% conver-
sion.25 Whether this was the result of catalyst decomposition
or the attainment of an equilibrium between reactant and product
was examined with the pure E isomer of the allylic alcohol 43.
Subjecting this substrate to the same reaction conditions led to
an identical 9:1 product distribution of the internal and terminal
alkenes, exactly as observed for the migration reaction of 35,
suggesting that indeed the aforementioned migrations had
reached thermodynamic equilibrium. Nevertheless, as illustrated
with 37, benzylation of the homoallylic alcohol can influence
this equilibrium in favor of the allylic alcohol formation.
The selective one-carbon migration observed for the substrates
in Scheme 4 and Table 2 also matches with the observations
made for compounds 28 and 31 in Scheme 3. Here selective
migration of the simple allyl functionality over the 1,1-
disubstituted olefin occurred. This reactivity discrepancy may
originate in the energy differences between the intermediate
alkyl-palladium complexes obtained after the hydropalladation
step. It would be expected that a tertiary alkyl-palladium
species carrying a bulky P(tBu)3 ligand is higher in energy
compared to a secondary alkyl-palladium species, hence
accounting for the observed selectivity.
Influence of the Catalyst Composition. With these substrate
effects in mind, it was therefore decided to further investigate
the factors which influenced the catalytic system, including the
palladium and hydride source, as well as to what extent P(tBu)3
was unique as the ligand. The silylated homoallylic alcohol 62
was chosen as the test substrate, and the results of this study
are depicted in Table 4. Applying Pd(PPh3)4 as the palladium
precursor only affected the yield and the product distribution
marginally, despite the presence of extra triphenylphosphine in
the catalyst mixture (entry 2). The importance of the structure
of the dba ligand in Pd(dba)2 was also investigated. Modified
dba ligands represented by their corresponding 4,4′-MeO and
4,4′-fluoro derivatives on the aromatic rings were prepared as
the Pd2(dba-OMe)3 and Pd2(dba-F)3 complexes according to
Firmansjah and Fu.26 Again, little difference was observed with
these Pd(0) variations on the aptitude for migration, although
the fluorine substitution showed a small drop in conversion
Application of this catalytic system to the substrates 51 and
54, in which the length between the olefin and the alcohol
functionality has been extended by one methylene group, as
well as to their corresponding benzyl- and TIPS-protected
(24) Compound 43 could not be separated from the starting material 35
by column chromatography. See the Supporting Information.
(25) Subjecting 6-methyl-1-hepten-4-ol to another in situ generated Pd-
H catalyst provided mainly the fully migrated ketone product or inferior
conversion rates and yields; see: (a) Balraju, V.; Dev, R. V.; Reddy,
D. S.; Iqbal, J. Tetrahedron Lett. 2006, 47, 3569. (b) Trost, B. M.; Li,
Y. J. Am. Chem. Soc. 1996, 118, 6625. (c) Trost, B. M.; Lee, D. C.;
Rise, F. Tetrahedron Lett. 1989, 30, 651.
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 8003

A R T I C L E S
Gauthier et al.
Table 2. Terminal Olefins Which Undergo a One-Carbon Migration
b
a Isolated yield after chromatography. Ratio of isomers determined by H NMR analysis of the crude product.
1
Table 3. Studying the Effect of the Alcohol or Ether Functionality
a Isolated yield after chromatography. b Ratio of isomers determined by 1H NMR analysis of the crude product. c Formation of one unidentified
product in minor proportion.
(entries 3 and 4). Once again the choice of solvent did not
interfere with the catalytic system and all solvents tested,
including EtOAc, dioxane, MeCN, THF, and dichloroethane,
provided product mixtures nearly identical with that of toluene
(Table 4, entry 1; see the Supporting Information).
(26) (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(b) Fairlamb, I. J. S.; Lee, A. F. Organometallics 2007, 26, 4087. (c)
Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.;
Weissburger, F.; de Vries, A. H. M.; Schmieder-van de Vondervoort,
L. Chem. Eur. J. 2006, 12, 8750. (d) Fairlamb, I. J. S.; Kapdi, A. R.;
Lee, A. F. Org. Lett. 2004, 6, 4435. For an overview of the role of
dba in palladium-catalyzed coupling reactions, see: (e) Amatore, C.;
Jutand, A. Coord. Chem. ReV. 1998, 178, 511.
Substituting iPrCOCl with an acetyl bromide or an acid
fluoride did lead in both cases to the generation of an active
catalyst, though with somewhat lower conversion for the acetyl
bromide (Table 5, entries 2 and 3).27 To avoid the possible
removal of the TIPS group in our test substrate 62 under the
acid fluoride conditions, the benzylated 4-penten-2-ol 65 was
9
8004 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Palladium Hydride Complexes as Catalysts
A R T I C L E S
Table 4. Effect of the Palladium Source on the One-Carbon
Migration
Table 6. Ligand Screening Studies in the Olefin Migration of
4-Penten-2-ol
Entry
Pd Source
Total yield (%)a
62:63:64 (%)b
Yield (%)
1
2
3
4
Pd(dba)2
Pd(PPh3)4
Pd2(dba-OMe)3
Pd2(dba-F)3
92
93
91
93
9:80:11
13:78:9
9:80:11
14:76:10
Entry
Ligand
66
67 (E:Z)
68a
1
P(tBu)3
9
21
47
63
18
21
6
12
13
4
15
4
4
12
4
61 (91:9)
67 (88:12)
26 (69:31)
37 (66:33)
76 (80:20)
64 (81:19)
50 (88:12)
88 (89:11)
57 (95:5)
96 (91:9)
80 (85:15)
73 (88:12)
61 (97:3)
78 (90:10)
81 (94:6)
30
2
nBuP(Adm)2
PCy3
P(2-furyl)3
PPh3
12
27
trace
6
15
44
3b
4
a Isolated yield after chromatography. b Ratio of isomers determined
by H NMR analysis of crude product.
1
5
6
P(o-Tol)3
7b
8
cataCXium PtB
cataCXium PCy
cataCXium PintB
cataCXium PinCy
S-Phos
9
30
10
11
12
13b
14
15
5
Table 5. Investigation of Different Hydride Sources
X-Phos
23
35
10
15
JohnPhos
Cyclohexyl JohnPhos
MePhos
a Ratios 66:67(E:Z):68 determined by 1H NMR analysis of the crude
reaction mixture. b Formation of several unidentified byproducts.
Entry
Acid-X
Total yield (%)a
62:63:64 (%)b
1
2
3
4
5
iPrCOCl
92
94
9:80:11
23:70:7
7:80:13
nd
AcBr
RFc d
88
,
Ac2O
TsOH ·H2O
nde
nde
nd
a Isolated yield after chromatography. b Ratio of isomers determined
by 1H NMR analysis of crude product. c 4-(1,3-Dioxoiso-
indolin-2-yl)butanoyl fluoride used as acid fluoride. d 65 was used
instead of 62; see the Supporting Information. e Formation of a complex
mixture.
used instead (entry 3).28 Also, acetic anhydride and p-toluene-
1
sulfonic acid were tested, but in both cases H NMR analysis
of the crude reaction mixtures were complex, with formation
of several unidentifiable products (entries 4 and 5).
7, 9, 12, 13, and 15). Smaller cone angles of the ligands also
had an influence on the reactivity of the system, providing lower
conversion rates (entries 3-6). Only ligands with properties
similar to those of P(tBu)3 showed promising results. Especially,
PCy and PinCy of the cataCXium series performed well with
good E:Z ratios and reasonable conversion rates, but importantly,
only the desired one-carbon migration was observed (entries 8
and 10).30,31 Especially the cataCXium PinCy ligand proved to
be an excellent alternative, as shown in Scheme 5.
Apart from the alternative activators of entries 4 and 5 in
Table 5, the catalytic system proved to be adaptable to changes
in all but one component of the catalyst mixture: namely, the
ligand. To examine the effect of the ligand, it was decided to
alter the screening protocol from the original TIPS-protected
4-penten-2-ol (62) to 4-penten-2-ol (66).29 This modification
was made in order to perform the study on a homoallylic alcohol
with a minimum of steric hindrance adjacent to the hydroxy
group, to ensure that any changes observed were the result of
the phosphine ligand and were not due to the bulk of the
substrate. Furthermore, the catalyst loading was increased to 5
mol % of all components. A selection of results from this ligand
screening is depicted in Table 6.
When both the protected 4-pentenol and 4-pentenamine were
subjected to a catalyst generated from the cataCXium ligand at
(30) For representative references of CataCXium ligands, see: (a) Rataboul,
F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.;
Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983. (b) Zapf,
A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann,
C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun. 2004,
38. (c) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem. 2000, 112,
4315; Angew. Chem., Int. Ed. 2000, 39, 4153. (d) Ehrentraut, A.; Zapf,
A.; Beller, M. AdV. Synth. Catal. 2002, 344, 209. (e) Stambuli, J. P.;
Stauffer, S. R.; Shaugnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 2677. (f) Ko¨llhofer, A.; Pullmann, T.; Plenio, H. Angew.
Chem., Int. Ed. 2003, 42, 1056.
Once again the effect of the substrate became evident, since
applying P(tBu)3 as the ligand provided the ketone product 68
in 30% yield as a result of a two-carbon migration (entry 1).
Significant formation of 68 was also observed for several other
ligands, but no general trend could be determined (entries 1, 3,
(31) P(tBu3), CataCXium PinCy,30 and the Phos series of Buchwald’s
ligands are known to provide monodentate phosphine complexes. For
P(tBu)3: (a) Stambuli, J. P.; Incarvito, C. D.; Bu¨hl, M.; Hartwig, J. F.
J. Am. Chem. Soc. 2004, 126, 1184. (b) Hansen, A. L.; Ebran, J.-P.;
Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem., Int. Ed.
2006, 45, 3349. Buchwald’s Phos ligands: (c) Martin, R.; Buchwald,
S. L. Acc. Chem. Res. 2008, 1461.
(27) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J. Am.
Chem. Soc. 1990, 112, 9651.
(28) Applying 4-(1,3-dioxoisoindolin-2-yl)butanoyl chloride as the acid
halide precursor afforded a product mixture comparable to that of
iPrCOCl.
(29) 4-Penten-2-ol is commercially available.
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 8005

A R T I C L E S
Gauthier et al.
Scheme 5. Selective One-Carbon Migrations using cataCXium
PinCy as the Ligand
Scheme 6. Migration Experiments with Allylbenzenes Possessing
an Iodide or Triflate Substituent
Figure 3. ORTEP diagram of acylpalladium complex 76.
species revealed the tricoordinated Pd(II) complex 76 formed
by the oxidative addition of iPrCOCl to PdP(tBu)3 (Figure 3).
Compound 76 represents an example of a monomeric
tricoordinated acylpalladium(II) complex carrying a chloride
ligand. It is interesting to compare this structure with the crystal
structures of related Pd(II) complexes bearing a P(tBu)3 ligand,
such as those described by Hartwig34 and Beller.35 The Hartwig
group has earlier observed that oxidative addition of an aryl
chloride to the Pd-P(tBu)3 complex leads to the formation of
a dimeric Pd(II) complex,34 rather than a monomeric structure,
as in our observations using an acid chloride. On the other hand,
Beller and co-workers reported the structure of the monomeric
acylpalladium complex [Pd(Br)(p-CF3C6H4CO)(PtBu3)], bearing
a bromide ligand.35 As with the complex 76, the acyl group is
oriented trans to the empty site of the metal nucleus. The reason
for this particular configuration, according to Beller et al., is
presumably not due to steric effects, since the bulky phosphine
ligand is placed cis to the acyl moiety and not cis to the smaller
chlorine atom.35 Instead, a strong trans effect of the acyl moiety
has been suggested for this particular configuration, placing this
group opposite to the empty site on the palladium center.
Although the formation of 1 and 76 occurred rapidly, the
80 °C, the products 69 and 34 from the one-carbon migration
could be isolated in good yields. Even more gratifyingly, the
single-carbon shift of the double bond in the 10-undecenamine
derivative 70 also proved possible, affording the desired
disubstituted alkene 71 in a 74% yield. Repeating this experi-
ment with P(tBu)3 as the ligand provided product contaminated
with significant amounts of products from further migration of
the olefin unit at this reaction temperature, revealing the much
higher selectivity of the cataCXium PinCy ligand.32
Mechanistic Considerations. Throughout this work on the
migration of double bonds, some classes of substrates were of
particular interest, as the results of the migration provided
information toward a better understanding of the structure of
the active catalyst. As mentioned previously, basic allylic amines
failed to undergo isomerization, which is in accordance with
the base-induced reductive elimination of the MH coupling
depleting the catalytic palladium(II) hydride species.20,33 Elec-
trophiles such as the aryl iodide 72 and the activated aryl triflate
74 did not interfere with the catalytic isomerization, indicative
of the mildness of the catalytic system and the fact that the
catalytic cycle is devoid of Pd(0) intermediates (Scheme 6).
The 31P NMR spectrum of the catalyst mixture obtained only
a few minutes after its preparation at room temperature in THF
indicated the formation of the known Pd(II)-H complex 1
residing at 83.1 ppm.19 In THF, a minor species was also
detected at 77.5 ppm in a 1:4 relation with 1 as the major
species, along with free P(tBu)3 ligand (63.4 ppm). The complex
at 77.5 ppm was obtained selectively by reacting the com-
mercially available complex Pd[P(tBu)3]2 with 3 equiv of
isobutyryl chloride in THF at room temperature. This reaction
released 1 equiv of free P(tBu)3 (δ 63.4 ppm), measured by the
integration of the two signals formed in the 31P NMR spec-
trum.19 The single-crystal X-ray structure of this unknown
1
stability of the catalyst mixture was inadequate for further H
NMR and 31P NMR studies, with formation of new unidentified
phosphorus-containing species within 10-15 min in combina-
tion with palladium precipitation.36 Changing the solvent to
safrole seemingly increased the stability of the catalyst, and the
formation of both 1 and 76 could be followed by 31P NMR, as
shown in Figure 4. 1 and 76 were formed almost exclusively
after 30 min in safrole at room temperature from a 1:1:1 mixture
of Pd(dba)2, P(tBu)3, and iPrCOCl using a 25% aqueous solution
of H3PO4 as the external reference. Although 76 is rapidly
formed in safrole (5 min by 31P NMR; Figure 1) compared to
THF as the solvent, there is a continuous buildup of this species
until all P(tBu)3 is consumed (see the Supporting Information).
The shaded squares in Figure 4, labeled a-d, depict 31P NMR
spectra of the individual species 1, 76, [P(tBu)3]2Pd, and P(tBu)3
(34) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 8141.
(35) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2008,
130, 15549.
(32) Work regarding the optimization of the one-carbon migration using
cataCXium PinCy as ligand is currently ongoing in our laboratories
and will be reported in due time.
(33) Whitcombe, N. J.; Hii, K. K. M.; Gibson, S. E. Tetrahedron 2001,
57, 7449.
(36) (a) Clark, H. C.; Goel, A. B.; Goel, S. Inorg. Chem. 1979, 18, 2803.
(b) Goel, R. G.; Ogini, W. O. Organometallics 1982, 1, 654. (c) Du`ra-
vila`, V.; Mingos, D. M. P.; Vilar, R.; White, A. J. P.; Williams, D. J.
J. Organomet. Chem. 2000, 198.
9
8006 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Palladium Hydride Complexes as Catalysts
A R T I C L E S
Figure 4. 31P NMR spectra of the catalyst mixture in safrole and its evolution over time.
Scheme 7. Plausible Pathway Leading to 1, 76, and 77
in safrole. This example serves to show the rapid formation of
1 and 76, although the individual ratios of the final catalytic
mixture should not be compared with reactions performed in
other solvents such as THF, toluene, and dioxane.
Slow decomposition of pure 76 into the Pd-H complex 1
was detected after 24 h at room temperature in THF.37 This
decomposition could potentially occur via two possible path-
ways, due to the T-shaped nature of the tricoordinated complex.
First, this Pd complex must isomerize, placing the acyl group
cis to the vacant coordination site. Subsequent formation of a
palladium hydride species could be envisaged to take place either
by ꢀ-elimination of the acyl R-hydrogen, forming the corre-
sponding ketene, or by decarbonylation followed by a ꢀ-hydride
elimination releasing carbon monoxide and propene, with the
eventual formation of 1 upon coordination of one extra P(tBu)3.
An indication of this decomposition pathway leading from 76
to 1 was observed by heating a solution of 76 in benzene-d6 at
50 °C. After 2 h, the specific 1H NMR shifts for the hydride of
1 were observed in combination with the shifts for propene
residing at 5.67 ppm (ddq, 1H, J ) 16.8, 10.0, 6.8 Hz), 4.96
ppm (ddq, 1H, J ) 16.8, 2.4, 1.6 Hz), and 4.90 ppm (ddq, 1H,
J ) 10.0, 2.4, 1.2 Hz) (see the Supporting Information).
However, complex 1 is formed rapidly upon mixing of Pd(dba)2,
P(tBu)3, and isobutyryl chloride at room temperature, suggesting
that an alternative pathway leading to 1 is operating.
are observable by 31P NMR, this implies that palladium(0) is
still left in the mixture without phosphine coordination. The
remainder of the added palladium is likely to participate in
equilibrium with several Pd species only stabilized by dba as
the ligand. Oxidative addition of iPrCOCl to Pd(dba)n followed
by dba dissociation, if required, would lead to an acyl tricoor-
dinated palladium(II) complex (78).38,39 This complex also
contains a vacant coordination site on the palladium and an
elimination pathway similar to those suggested above, leading
to a hydride species, could be envisaged. Replacement of the
dba ligand(s) by P(tBu)3 would then provide the stable and
detectable Pd-H complex 1.40
The active catalyst which promotes these isomerizations could
be represented by the Pd(II) hydride complex 77 depicted in
Scheme 7, carrying one phosphine ligand and a free site for the
coordination of the olefinic moiety prior to isomerization.
Scheme 7 illustrates possible pathways leading to the formation
of all the discussed complexes.
Neither of the two suggested pathways for the hydride
formation from 78, being either direct ꢀ-hydride elimination
Since Pd(dba)2 and P(tBu)3 are mixed in a 1:1 ratio and only
the bis-coordinated species Pd[P(tBu)3]2, 1, 76, and free ligand
(38) Personal correspondence with Anny Jutand (Ecole Normale Supe´rieure,
De´partement de Chimie, URA CNRS 1679, 24 rue Lhomond, 75231
Paris, Cedex 05, France).
(39) The presence of dba might not be essential, since Pd(PPh3)4 also
provided an active catalyst (Table 4, entry 2).
(37) It should be noted that heating a solution of complex 76 in safrole at
80 °C effectively promotes the migration to isosafrole, as observed
for the mixture Pd(dba)2:P(tBu)3:iPrCOCl.
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 8007

A R T I C L E S
Gauthier et al.
Scheme 8. Isomerization of Safrole Catalyzed by [P(tBu)3]2PdHCl
(1)
this mixture to safrole slowed the rate of reaction. This effect
was also noted previously, since the formation of 1 occurs at
room temperature from the 1:1:1 Pd(dba)2:P(tBu)3:iPrCOCl
catalyst mixture but does not initiate the double-bond isomer-
ization before heating. Only in the case with direct application
of 1 as in Scheme 8 did the reaction occur without the need for
external warming.
Conclusion
In conclusion, a highly efficient catalytic protocol for the
isomerization of olefins was presented using a catalyst generated
from the premixing of Pd(dba)2, P(tBu)3, and iPrCOCl. Apart
from simple Z to E isomerization, the conjugative migration of
allylbenzenes and heteroatom-substituted allyl groups was
performed with excellent functional group tolerance and the
products were furnished in high isolated yields. Furthermore,
the in situ formed bulky palladium(II) hydride catalyst was able
to catalyze a highly selective one-carbon migration of a variety
of substrates, including homoallylic alcohols and amines,
without epimerization at adjacent stereogenic centers. Finally,
the factors controlling these double-bond shifts were investigated
and revealed that the presence of bulky monodentate phosphine
ligands capable of forming tricoordinated complexes was
necessary for high catalytic activity. An alternative phosphine
ligand, cataCXium PinCy, proved in certain cases to be superior
to P(tBu)3, and further work with this ligand is currently under
investigation in our laboratories. Finally, some mechanistic
studies were undertaken, during which a novel monomeric
tricoordinated acylpalladium(II) complex was isolated and
characterized by X-ray crystallographic analysis. Additional
investigations are ongoing in order to obtain better conversion
levels for the selective one-carbon migration of terminal olefins,
as well as to obtain an in-depth understanding regarding the
formation of the palladium(II) hydride catalyst.
forming the ketene or decarbonylation followed by ꢀ-hydride
elimination releasing propene and CO, can be excluded at the
present time, since both acetyl chloride and pivaloyl chloride
afforded 1. Importantly, substituting isobutyryl chloride with
benzoyl chloride, an acid chloride devoid of hydrogens for
ꢀ-hydride elimination, only led to a phosphorus species residing
at 72.2 ppm in benzene-d6, presumably the benzoyl derivative
of 76, with no formation of 1 even after 14 h at room
temperature (see the Supporting Information).41
Furthermore, attempts to isolate products from these processes
with high-molecular-weight acid chlorides have so far been
unrewarding. Since the reaction of isobutyryl chloride with
Pd[P(tBu)3]2 only leads to 76, the formation of 1 does not
originate from trace water present in the reaction medium,
leading to HCl by reaction with the acid chloride.19 The Hartwig
group has previously described the formation of a palladium
hydride by ꢀ-hydride elimination of a Mizoroki-Heck (MH)
intermediate formed upon carbopalladation of an arylpalladium
halide complex to dba.34 Similar products obtained by MH
reactions with dba could not be observed or isolated from our
catalyst mixtures, and hence this pathway to 1 does not seem
plausible in the case of an acylpalladium(II) complex. Further-
more, the transformations of 76 to 1 in THF at room temperature
with or without added dba occur at similar rates (results not
shown).
Experimental Section
General Methods. Solvents were dried according to standard
procedures. Flash chromatography was performed on silica gel 60
(230-400 mesh). The chemical shifts of the NMR spectra are
reported in ppm relative to the solvent residual peak.42 MS spectra
were recorded on a LC TOF (ES) apparatus. All isomerizations/
migrations were carried out in 7.0 mL sample vials with a Teflon
sealed screwcap in a glovebox under an argon atmosphere. All
purchased chemicals were used as received without further
purification.
To test the hypothesis of 1 being a precursor for the active
catalyst, this metal hydride complex was prepared according to
the protocol of Fu and co-workers.19 Applying this catalyst to
safrole under neat conditions gratifyingly provided a highly
active catalyst with TON’s of 1000 to 10 000 in 15-160 min
at room temperature (Scheme 8).
If 77 represents the catalytically active species, then the
addition of excess P(tBu)3 to the reaction mixture should slow
the migration reactions by shifting the equilibrium between 1
and 77 illustrated in Scheme 7 in favor of the tetracoordinated
Pd complex 1. To test this hypothesis, the isomerization of
(E)-7-(1-Propenyl)-8-quinolinol (13) (Scheme 1).43 General
Procedure for the Conjugative Migration. 7-Allyl-8-quinolinol
(185.2 mg, 1.0 mmol) dissolved in toluene (2.5 mL), Pd(dba)2 from
a 0.01 mg µL-1 stock solution in toluene (288.0 µL, 5.0 µmol),
P(tBu)3 from a 0.02 mg µL-1 stock solution in toluene (50.6 µL,
5.0 µmol), and isobutyryl chloride from a 0.01 mg µL-1 stock
solution in toluene (53.3 µL, 5.0 µmol) were reacted for 21 h at 80
°C. The crude product was purified by flash chromatography on
silica gel using CH2Cl2 as eluent. This afforded 164.2 mg of (E)-
7-(1-propenyl)-8-quinolinol (13) (89% yield, E/Z > 95:5) as a pale
1
safrole to isosafrole (15) was followed by H NMR at 65 °C
using a premixed 1:1:1 Pd(dba)2:P(tBu)3:iPrCOCl catalyst
mixture followed by the addition of P(tBu)3 (Figure 5).
Ligand addition significantly reduced the reaction rate, even
after the addition of only 1 equiv of P(tBu)3. A similar
experiment catalyzed by the addition of the isolated Pd-H
complex 1 proved even more sensitive to the phosphine addition,
as performing the isomerization at room temperature in the
presence of an extra 1 equiv of P(tBu)3 completely quenched
the reaction. Furthermore, premixing 1 with dba and adding
1
yellow solid. H NMR (400 MHz, C6D6): δ 9.06 (bs, 1H), 8.35
(dd, 1H, J ) 4.4, 1.6 Hz), 7.45 (d, 1H, J ) 8.8 Hz), 7.42 (dd, 1H,
J ) 8.0, 1.6 Hz), 7.17 (dq, 1H, J ) 16.0, 1.6 Hz), 6.91 (d, 1H, J
) 8.8 Hz), 6.64 (dd, 1H, J ) 8.4, 4.4 Hz), 6.31 (dq, 1H, 16.0, 6.8
Hz), 1.73 (dd, 3H, J ) 6.8, 1.6 Hz). 13C NMR (100 MHz, C6D6):
δ 148.8, 147.9, 139.1, 135.6, 127.4, 126.9, 126.0, 125.8, 120.9,
(40) A 1/1 mixture of Pd(dba)2 and isobutyryl chloride does not provide
an active catalyst in control experiments, suggesting that the catalyti-
cally active species carries at least one phosphine ligand.
(41) Fujihara, T.; Katafuchi, Y.; Iwai, T.; Terao, J.; Tsjui, Y. J. Am. Chem.
Soc. 2010, 132, 2094.
(42) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512.
(43) Bahloul, A.; Sebban, A.; Dardari, Z.; Boudouma, M.; Kitane, S.;
Belghiti, T.; Joly, J.-P. J. Heterocycl. Chem. 2003, 40, 243.
9
8008 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Palladium Hydride Complexes as Catalysts
A R T I C L E S
Figure 5. Influence of additional equivalents of P(tBu)3 on the conversion of safrole to isosafrole (15).
120.4, 117.5, 18.9. HRMS (m/z): C12H11NO [M + Na+], 208.0738;
found, 208.0730.
27.9, 21.6, 18.0. GCMS for C17H25NO4S (m/z (relative intensity)):
239 (0.5), 184 (84, CH3(CH)2(CH2)2NBoc•), 155 (100, Ts•), 91 (70),
65 (12).
(E)-tert-Butyl Pent-3-enyl(tosyl)carbamate (34) (Scheme
4).10 General Procedure for the One-Carbon Migration. tert-
Butyl pent-4-enyl(tosyl)carbamate (33) (135.0 mg, 0.4 mmol)
dissolved in toluene (1.0 mL), Pd(dba)2 from a 0.01 mg µL-1 stock
solution in toluene (230.4 µL, 4.0 µmol), P(tBu)3 from a 0.02 mg
µL-1 stock solution in toluene (40.5 µL, 4.0 µmol), and isobutyryl
chloride from a 0.01 mg µL-1 stock solution in toluene (42.8 µL,
4.0 µmol) were reacted for 24 h at 80 °C. The crude reaction was
concentrated in vacuo and purified by flash chromatography on
silica gel using pentane/Et2O (7:3) as eluent. This afforded 135.0
mg of tert-butyl pent-3-enyl(tosyl)carbamate (34) (99% yield, E/Z
> 95:5) as a white solid. Mp: 67 °C. 1H NMR (400 MHz, CDCl3):
δ 7.77 (d, 2H, J ) 8.2 Hz), 7.27 (d, 2H, J ) 8.2 Hz), 5.52 (dqt,
1H, J ) 15.3, 6.3, 1.2 Hz), 5.38 (dqt, 1H, J ) 15.3, 6.9, 1.4 Hz),
3.83-3.80 (m, 2H), 2.43-2.37 (m, 2H), 2.41 (s, 3H), 1.64 (dd,
3H, J ) 6.3, 1.4 Hz), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 151.0, 144.1, 137.6, 129.2, 128.1, 127.9, 126.9, 84.0, 46.9, 33.5,
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
The Danish Natural Science Research Council, the Carlsberg
Foundation, and the University of Aarhus. We gratefully appreciate
the donation of ligands and catalysts from Solvias. We also thank
Henrik H. Jensen, Martin J. Pedersen, and Jonas Krag for supplying
us with the glucosamine derivatives.
Supporting Information Available: Text, figures, and tables
giving experimental details and copies of 1H NMR and 13C NMR
spectra for all new compounds and a CIF file giving crystal-
lographic data for compound 76. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA9108424
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 8009