Palladium-catalyzed oxidative arylhalogenation of alkenes: Synthetic scope and mechanistic insights

Article abstract of DOI:10.1021/ja101851v

This article describes the development of a Pd-catalyzed reaction for the arylhalogenation (halogen = Cl or Br) of diverse α-olefins by oxidatively intercepting Mizoroki-Heck intermediates. These transformations afford synthetically useful 1,2- and 1,1-arylhalogenated products in good yields with good to excellent selectivities that can be modulated by changing the nature of the halogenating reagent and/or the reaction conditions. The selectivity of these reactions can be rationally tuned by (i) controlling the relative rates of oxidative functionalization versus β-hydride elimination from equilibrating Pd^II-alkyl species and (ii) stabilization of organometallic Pd^II intermediates through the formation of π-benzyl adducts. These arylhalogenations exhibit modest to excellent levels of stereoselectivity, and the key carbon-halogen bond-forming step proceeds with predominant retention of stereochemistry at carbon.

Full text of DOI:10.1021/ja101851v

Published on Web 06/01/2010
Palladium-Catalyzed Oxidative Arylhalogenation of Alkenes:
Synthetic Scope and Mechanistic Insights
Dipannita Kalyani, Andrew D. Satterfield, and Melanie S. Sanford*
UniVersity of Michigan, Department of Chemistry, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109
Received March 5, 2010; E-mail: mssanfor@umich.edu
Abstract: This article describes the development of a Pd-catalyzed reaction for the arylhalogenation (halogen
) Cl or Br) of diverse R-olefins by oxidatively intercepting Mizoroki-Heck intermediates. These transforma-
tions afford synthetically useful 1,2- and 1,1-arylhalogenated products in good yields with good to excellent
selectivities that can be modulated by changing the nature of the halogenating reagent and/or the reaction
conditions. The selectivity of these reactions can be rationally tuned by (i) controlling the relative rates of
oxidative functionalization versus ꢀ-hydride elimination from equilibrating PdII-alkyl species and (ii)
stabilization of organometallic PdII intermediates through the formation of π-benzyl adducts. These
arylhalogenations exhibit modest to excellent levels of stereoselectivity, and the key carbon-halogen bond-
forming step proceeds with predominant retention of stereochemistry at carbon.
Introduction
(eq 2). Such transformations would complement the traditional
Mizoroki-Heck reaction by providing access to products
The Mizoroki-Heck reaction involves the Pd-catalyzed
coupling of an alkene with an aryl halide or aryl metal species.1
This transformation is widely used in organic synthesis for the
construction of carbon-carbon bonds,2 and significant effort
has been devoted to both catalyst development1-3 and mecha-
nistic investigations.1-4 As shown in eq 1, the general mech-
anism involves formation of a σ-aryl Pd species followed by
olefin insertion to generate σ-alkyl Pd intermediate A and then
ꢀ-hydride elimination/olefin dissociation to release product B.
containing two additional bonds and one additional stereocenter
as compared to B. Some success has been realized in this area
by trapping intermediate A via alkene, alkyne, or CO insertion.5,6
However, the scope, generality, and range of products accessible
from these reactions remain limited, in large part because the
relative rate of ꢀ-hydride elimination to form B is often
competitive in these processes.
On the basis of our interest in high oxidation state palladium
chemistry, we thought that oxidation of A would provide an
attractive alternative route for intercepting this intermediate.
Indeed, very early studies by Heck demonstrated the feasibility
of this transformation. For example, in 1968, he reported the
Pd-catalyzed reaction of methylvinylketone with PhHgCl and
CuCl2 to afford 1,2-arylchlorination product 1 in 80% yield (eq
3).7 However, the overall synthetic utility of this transformation
was limited by a modest substrate scope, competing ꢀ-hydride
Methods for intercepting Mizoroki-Heck intermediate A via
other fundamental organometallic reactions would provide
attractive routes for the 1,2-arylfunctionalization of R-olefins
(1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320. (c)
The Mizoroki-Heck Reaction; Oestreich, M., Ed.; John Wiley & Sons
Ltd.: Chichester, U.K., 2009. (d) Cabri, W.; Candiani, I. Acc. Chem.
Res. 1995, 28, 2. (e) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV.
2000, 100, 3009.
(2) (a) Link, J. T. The Intramolecular Heck Reaction. In Organic
Reactions; Overman, L. E., Ed.; John Wiley & Sons, Inc.: Hoboken,
NJ, 2002; Vol. 60. (b) de Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379. (c) Brase, S.; de Meijere, A. Cross-
Coupling of Organyl Halides with Alkenes: the Heck Reaction. In
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany,
2004. (d) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(e) Majumdar, K. C.; Ansary, I.; Sinha, B.; Chattopadhyay, B.
Synthesis 2009, 3593.
(4) For examples, see: (a) Amatore, C.; Jutand, A. J. Organomet. Chem.
1999, 576, 254. (b) Knowles, J. P.; Whiting, A. Org. Biomol. Chem.
2007, 5, 31. (c) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 79.
(5) For examples of CO insertion, see: (a) Sugihara, T.; Coperet, C.;
Owczarczyk, Z.; Harring, L. S.; Negishi, E.-i. J. Am. Chem. Soc. 1994,
116, 7923. (b) Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5,
1523. For examples of alkyne and alkene instertion, see: (c) Schweizer,
S.; Song, Z.-Z.; Meyer, F. E.; Parsons, P. J.; de Meijere, A. Angew.
Chem., Int. Ed. 1999, 38, 1452. (d) Tietze, L. F.; Kahle, K.; Raschke,
T. Chem.sEur. J. 2002, 8, 401.
(3) For examples, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Focus on
Catalyst Development and Ligand Design. In The Mizoroki-Heck
Reaction; Oestreich, M., Ed.; Wiley: Chichester, U.K., 2009. (b) Yoo,
K. S.; O’Neill, J.; Sakaguchi, S.; Giles, R.; Lee, J. H.; Jung, K. W. J.
Org. Chem. 2010, 75, 95. (c) Lamblin, M.; Nassar-Hardy, L.; Hierso,
J.-C.; Fouquet, E.; Felpin, F.-X. AdV. Synth. Catal. 2010, 352, 33.
(6) For complementary routes to the 1,2-arylfunctionalization of alkenes,
see: (a) Wolfe, J. P. Synlett 2008, 2913. (b) Chemler, S. R.; Fuller,
P. H. Chem. Soc. ReV. 2007, 36, 1153.
(7) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5538.
9
10.1021/ja101851v  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 8419–8427 8419

A R T I C L E S
Kalyani et al.
elimination/olefin dissociation (to form 2), and the requirement
for aryl mercury reagents.
to generate σ-alkyl Pd intermediates followed by oxidative
halogenation,18,19 amination,20 oxygenation,21 and arylation22 have
been developed to afford diverse organic products.
Sporadic subsequent reports have also suggested that Heck
intermediate A can be intercepted under oxidative conditions
to generate 1,1-difunctionalized products.8 For example,
Tamaru and co-workers demonstrated the palladium-catalyzed
1,1-phenylchlorination of 1-octene with PhSnBu3 in the
presence of CuCl2 (eq 4).9,10 However, the yield of this
transformation was not reported, and 1-octene was the only
substrate examined.11 More recently, a similar Pd-catalyzed
1,1-phenylchlorination product 4 was unexpectedly observed
in the reaction between 3, PhSnBu3, and CuCl2 (eq 5).12
Again, this was an isolated example, and the reaction was
not explored further.
We report herein the implementation of this strategy in the
development of general oxidative reactions for the 1,2- and 1,1-
arylhalogenation of alkenes.23 The full scope of both 1,2- and
1,1-arylchlorination and bromination reactions is described.
Additionally, investigations of the mechanism and the stereo-
selectivity of these transformations are discussed in detail.
Results
Reaction Design. To develop general and robust conditions
for alkene arylfunctionalization, we needed a working
mechanistic hypothesis for the formation of each of the
products. As shown in Scheme 1, the Heck product B is
known to be generated from σ-alkyl Pd intermediate A via
(16) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300. (b) Giri, R.; Liang, J.; Lei, J. Q.; Li, J. J.; Wang, D. H.;
Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J. Q. Angew.
Chem., Int. Ed. 2005, 44, 7420. (c) Desai, L. V.; Malik, H. A.; Sanford,
M. S. Org. Lett. 2006, 8, 1141. (d) Desai, L. V.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 9542. (e) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (f) Wang, D. H.; Hao,
X. S.; Wu, D. F.; Yu, J. Q. Org. Lett. 2006, 8, 3387. (g) Neufeldt,
S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532.
(17) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Reference 16e. (c) Giri, R.; Maugel, N.; Li,
J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am.
Chem. Soc. 2007, 129, 3510. (d) Wasa, M.; Engle, K. M.; Yu, J. Q.
J. Am. Chem. Soc. 2009, 131, 9886. (e) Deprez, N. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 11234. (f) Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2010, 132, 3965.
These prior studies suggested that it might be possible to develop
oxidative transformations for the predictable and selective conver-
sion of R-olefins into 1,2- or 1,1-arylfunctionalized products of
general structures C and D (eq 6). Recent work from our group
and others has shown that σ-alkyl Pd intermediates related to A
can be intercepted with a wide variety of oxidants to install diverse
functional groups, including C-Cl, C-Br, C-I, C-F, C-N,
C-O, and C-C bonds. This has been demonstrated in the context
of Pd-catalyzed ligand-directed C-H functionalization,13 where
sp3 C-H activation has been followed by oxidative halogenation,14
amination,15 oxygenation,16 and arylation.17 In addition, a variety
of sequences involving amino-, oxy-, or halopalladation of olefins
(18) For examples, see: (a) Helaja, J.; Gottlich, R. Chem. Commun. 2002,
720. (b) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785.
(c) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618. (d) Michael, F. E.; Sibbald, P. A.;
Cochran, B. M. Org. Lett. 2008, 10, 793. (e) Wu, T.; Yin, G.; Liu, G.
J. Am. Chem. Soc. 2009, 131, 16354. (f) Christie, S. D. R.; Warrington,
A. D.; Lunniss, C. J. Synthesis 2009, 148. (g) Doroski, T. A.; Cox,
M. R.; Morgan, J. B. Tetrahedron Lett. 2009, 50, 5162.
(19) For examples, see: (a) El-Qisairi, A.; Hamed, O.; Henry, P. M. J.
Org. Chem. 1998, 63, 2790, and references therein. (b) Hamed, O.;
Henry, P. M. Organometallics 1998, 17, 5184. (c) El-Qisairi, A. K.;
Qaseer, H. A.; Henry, P. M. J. Organomet. Chem. 2002, 656, 168.
(d) El-Qisairi, A. K.; Qaseer, H. A.; Katsigras, G.; Lorenzi, P.; Trivedi,
U.; Tracz, S.; Hartman, A.; Miller, J. A.; Henry, P. M. Org. Lett.
2003, 5, 439.
(8) For related Pd-catalyzed 1,1-diarylation reaction of terminal alkenes,
see: Urkalan, K. B.; Sigman, M. S. Angew. Chem., Int. Ed. 2009, 48,
3146.
(20) For examples, see: (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.;
Mun˜iz, K. J. Am. Chem. Soc. 2005, 127, 14586. (b) Mun˜iz, K. J. Am.
Chem. Soc. 2007, 129, 14542. (c) Mun˜iz, K.; Hovelmann, C. H.;
Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (d) Mun˜iz, K.; Streuff,
J.; Chavez, P.; Hovelmann, C. H. Chem. Asian J. 2008, 3, 1248. (e)
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147. (f) Qiu, S.;
Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 2856.
(21) For examples, see: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am.
Chem. Soc. 2005, 127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 7179. (c) Desai, L. V.; Sanford, M. S. Angew. Chem.,
Int. Ed. 2007, 46, 5737. (d) Li, Y.; Song, D.; Dong, V. M. J. Am.
Chem. Soc. 2008, 130, 2962. (e) Wang, A.; Jiang, H.; Chen, H. J. Am.
Chem. Soc. 2009, 131, 3846. (f) Wang, W.; Wang, F.; Shi, M.
Organometallics 2010, 29, 928.
(9) (a) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 735. (b) Tamaru, Y.; Hojo, M.; Kawamura,
S.; Yoshida, Z. J. Org. Chem. 1986, 51, 4089.
(10) For a related Pd-catalyzed 1,1-acetoxyarylation of R,ꢀ-unsaturated olefins,
see: Rodriguez, A.; Moran, W. J. Eur. J. Org. Chem. 2009, 1313.
(11) For synthesis of heterocycles via 1,1-arylfunctionalization reactions,
see ref 9.
(12) Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W. J. Org. Chem.
2002, 67, 7127.
(13) For a review on ligand directed C-H functionalization, see: Lyons,
T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147.
(14) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483. (c) Giri, R.; Wasa, M.; Breazzano, S. P.;
Yu, J.-Q. Org. Lett. 2006, 8, 5685. (d) Hull, K. L.; Anani, W. Q.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
(22) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 15945.
(23) For a preliminary account of this work, see: Kalyani, D.; Sanford,
M. S. J. Am. Chem. Soc. 2008, 130, 2150.
(15) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048.
9
8420 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010

Pd-Catalyzed Oxidative Arylhalogenation of Alkenes
A R T I C L E S
Scheme 1. Working Mechanistic Hypothesis for Formation of B-D
enhancement in both selectivity for and yield of 6a (entry 8).
The yield was improved further by increasing the amount of
PhSnBu3 from 1.3 to 2.6 equiv (entry 9). Ultimately, optimal
conditions were found to be as follows: 10 mol % of
PdCl2(PhCN)2, 2 equiv of PhICl2, 2.6 equiv of PhSnBu3 in
CH2Cl2 (0.064 M) starting at -78 °C with gradual warming
over 5 h to 25 °C. This afforded a quantitative yield of 6 as a
10:1 mixture of isomer 6a:6b (entry 9).
These conditions proved general for the 1,2-arylchlorina-
tion of numerous R-olefins (Table 2). The reactions were
tolerant of a wide variety of common functional groups,
including esters, aromatic and alkyl halides, benzylic hydro-
gens, amides, and silyl ethers. Additionally, both electron-
rich and electron-deficient arylstannanes were effective
coupling partners. The products were obtained in good to
excellent yields and with good selectivity for the 1,2-isomer.
In general, the mass balance in these reactions consisted of
small amounts of the 2,1-phenylchlorination, dichlorination,
and/or ꢀ-hydride elimination products.
Table 1. Optimization of the 1,2-Arylchlorination Reaction
1,1-Arylchlorination Reactions. We next sought conditions
that would selectively provide 1,1-arylchlorinated products.
The solvent screen in Table 1 showed that the reaction of 5
with PhICl2 significantly favored formation of the 1,1-product
6b in ethereal solvents. We reasoned that the use of a less
reactive chlorinating reagent would further slow competing
1,2 functionalization and thus provide higher selectivity for
6b. Gratifyingly, the use of NCS or CuCl2 under otherwise
identical conditions resulted in >20:1 selectivity for 6b in a
variety of solvents (Table 3). While the yields were modest
at room temperature (ranging from 10-58%), they could be
significantly improved by conducting the reactions at -78
°C. Under optimal conditions (10 mol % of PdCl2(PhCN)2,
4 equiv of CuCl2, 1.3 equiv of PhSnBu3 in Et2O (0.032 M)
starting at -78 °C with gradual warming over 5 h to 25 °C),
6b was obtained in 82% yield and with >20:1 selectivity as
Entry
Solvent
Temperature
Concentration
Yielda
6a:6ba
1
2
3
4
5
6
7
8
9b
Dioxane
THF
Et2O
25 °C
25 °C
0.032 M
0.032 M
0.032 M
0.032 M
0.032 M
0.032 M
0.032 M
0.064 M
0.064 M
77%
53%
64%
55%
46%
55%
56%
82%
100%
1:6.7
1:9.6
1:9.7
1:8.9
1:1.3
1.9:1
8:1
25 °C
C6H6
25 °C
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25 °C
0 °C to 25 °C
-78 °C to 25 °C
-78 °C to 25 °C
-78 °C to 25 °C
10:1
10:1
a Yield and ratio of isomers determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. b 2.6 equiv of PhSnBu3.
ꢀ-hydride elimination/olefin dissociation. The 1,2-arylfunc-
tionalization product C could be formed by direct oxidative
functionalization of A. Finally, the isomeric 1,1-product D
could derive from A via a sequence involving ꢀ-hydride
elimination, olefin insertion with opposite regiochemistry, and
finally oxidative functionalization of the resulting Pd-benzyl
complex (E) (Scheme 1). This mechanistic proposal suggests
that the ratio of products B, C, and D should be tunable by
modifying the relative rates of four fundamental organome-
tallic transformations: oxidative functionalization, ꢀ-hydride
elimination, olefin dissociation, and olefin insertion.
1
determined by H NMR spectroscopy (entry 8).
The substrate scope of 1,1-arylchlorination with CuCl2 was
similar to that of the PhICl2 reactions. Aryl stannanes and
R-olefins containing diverse functional groups were effective
coupling partners, and the 1,1-isomer was consistently
obtained in >20:1 selectivity (Table 2). In all cases, <10%
of alkene products derived from ꢀ-hydride elimination/alkene
dissociation were observed by 1H NMR spectroscopic
analysis of the crude mixtures.25
1,2- and 1,1-Arylbromination Reactions. We next pursued
analogous palladium-catalyzed arylbromination reactions
using CuBr2 and NBS as electrophilic brominating reagents
(PhIBr2 is not readily available).26,27 As shown in Table 4,
NBS was poorly effective for this transformation. In contrast,
CuBr2 efficiently promoted the formation of both 1,1-
arylbromination product 28b and 1,2-arylbromination product
28a. The isomer ratio in these CuBr2-mediated reactions could
be tuned by simply changing the solvent. For example, 1,1-
1,2-Arylchlorination Reactions. We reasoned that use of the
highly reactive electrophilic chlorinating reagent PhICl2 should
increase the rate of oxidative functionalization of A relative to
that of ꢀ-hydride elimination, thereby promoting formation of
1,2-product C. Thus, we first studied the Pd-catalyzed reaction
24
between alkene 5, PhICl2, and PhSnBu3 in a variety of
common solvents. Unexpectedly, the 1,1-product (6b) was the
major isomer observed at room temperature in all solvents
examined (Table 1, entries 1-5). The most promising initial
lead was in CH2Cl2, which showed formation of significant
quantities of 6a (1:1.3 ratio of 6a:6b, 46% overall yield, entry
5). Lowering the temperature to -78 °C and increasing the
reaction concentration to 0.064 M in CH2Cl2 led to a significant
(25) The 1,1-arylchlorination products typically underwent some decom-
position during isolation/chromatographic purification (as reflected in
the discrepancy between the isolated yield and the yield determined
from analysis of the crude reaction mixtures).
(26) ArIBr2 generally lacks stability and cannot be isolated. It is typically
generated in situ from PhI(OAc)2 and a bromide source. (a) Macdonald,
T. L.; Narasimhan, N. J. Org. Chem. 1985, 50, 5000. (b) Stang, P. J.;
Zhdankin, V. V. Chem. ReV. 1996, 96, 1123. (c) Braddock, D. C.;
Cansell, G.; Hermitage, S. A. Synlett. 2004, 461. (d) Karade, N. N.;
Shirodkar, S. G.; Dhoot, B. M.; Waghmare, P. B. J. Chem. Res. 2005,
274.
(24) PhSnBu3 was chosen as the arylating reagent because it undergoes
facile transmetallation with palladium(II) under mild conditions in the
absence of strong bases or other additives. Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508.
9
J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010 8421

A R T I C L E S
Kalyani et al.
Table 2. Substrate Scope for Arylchlorination
a 1,2-Arylchlorination conditions: 10 mol % of PdCl2(PhCN)2, 2-4 equiv of PhICl2, 2.6 equiv of ArSnBu3, CH2Cl2. b 1,1-Arylchorination conditions:
10 mol % of PdCl2(PhCN)2, 4 equiv of CuCl2, 1.3 equiv of ArSnBu3, Et2O. c Isolated yields and selectivities (crude yields, where determined, are in
parentheses). In some of the 1,2-arylchlorinations, the isolated material contained minor impurities (typically 2,1-phenylchlorination or dichlorination
products). See Supporting Information for details. The 1,1 and 1,2-isomers were generally not separable by column chromatography, but could be
isolated in pure form using HPLC. The variation in 1,2:1,1 selectivity as a function of substrate may be due to differing interactions of polar functional
groups within the substrate with the Pd catalyst.
Table 3. Optimization of 1,1-Arylchlorination Reactionc
selectivity to afford 28a as the major product (28a:28b )
3:1), albeit in modest (49%) yield (Table 4, entry 8). This is
in notable contrast to the trend observed for arylchlorination,
where the use of CuCl2 in THF favored 1,1-products.
Subsequent optimization revealed that increasing the con-
centration to 0.128 M resulted in 80% yield of a 10:1 mixture
of 28a:28b (entry 10). Under these conditions, the mass
Yield
CuCl2a
Yield
NCSa
Entry
Solvent
Temperature
balance consisted of 29 (20% yield), which is the product of
1,2-addition of Ph and ring opened THF to the alkene.28
As shown in Table 5, the optimal conditions for formation
of the 1,1- and 1,2-arylbrominated products were general for
numerous R-olefins. These transformations exhibited a scope
and functional group tolerance similar to the arylchlorination
reactions. Notably, THF-addition products analogous to 29 were
formed as a significant byproduct (5-20% yield as determined
by 1H NMR spectroscopic analysis of the crude reaction
mixtures) in the 1,2-arylbrominations.29
1
2
3
4
5
6
7
8
Dioxane
C6H6
AcOH
CH2Cl2
THF
THF
Et2O
Et2O
25 °C
25 °C
13%
28%
10%
32%
58%
75%
29%
82%
34%
48%
46%
36%
39%
ndb
25 °C
25 °C
25 °C
-78 °C to 25 °C
25 °C
-78 °C to 25 °C
36%
44%
a Yield and ratio of isomers determined by 1H NMR spectroscopic
analysis of crude reaction mixture. b nd ) not determined. c The ratio of
6b:6a was uniformly >20:1.
(27) NIS, CuI, and I2 did not produce appreciable yields of 1,2- or 1,1-
aryliodinated products under any conditions examined.
(28) The catalyst PdCl2(MeCN)2 afforded slightly better yields than
PdCl2(PhCN)2 for arylbromination.
product 28b was formed in high (82%) yield and with >20:1
selectivity in Et2O (entry 6). However, moving from Et2O
to THF under similar conditions resulted in a reversal of
9
8422 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010

Pd-Catalyzed Oxidative Arylhalogenation of Alkenes
A R T I C L E S
Table 4. Optimization of Arylbromination Reactiond
Mechanistic Investigations: General Goals. We next turned
our efforts to investigating the mechanism of these transfor-
mations. In particular, we sought to (i) interrogate the
proposed reaction pathways for formation of the 1,2- and
the 1,1-products, (ii) understand the role of oxidant and
solvent in imparting 1,2- versus 1,1-selectivity, (iii) gain
mechanistic insights into the high selectivity for benzylic
functionalization with CuCl2 and CuBr2 in Et2O, and (iv)
probe the stereochemical course of the key carbon-halogen
bond-forming step of these transformations. The results of
these mechanistic studies are detailed below, and their
implications are discussed later in the manuscript.
Deuterium Labeling. Deuterium labeled 1-octene-(1,1-d2) was
utilized as a substrate for both the 1,2- and 1,1-phenylhaloge-
nations. Reaction with PhICl2 or with CuBr2/THF afforded 40a-
Cl/Br as the sole 1,2-phenylhalogenated products (eq 7). Less
than 5% deuterium incorporation was observed at any other site
along the alkyl chain.
Entry Solvent
Temperature
Yield CuBr2a 28a:28ba Yield NBSa 28a:28ba
1
2
3
4
5
6
7
Dioxane
C6H6
AcOH
CH2Cl2
Et2O
25 °C
25 °C
25 °C
25 °C
25 °C
29%
24%
16%
27%
46%
1:>20
1:13
19%
8%
0%
6%
8%
ndb
11%
ndb
ndb
ndb
1:>20
1:>20
ndb
1:>20
1:>20
ndb
1:>20
1:>20
1:>20
1:>20
1:>20
3:1
Et2O
THF
-78 °C to 25 °C 82%
25 °C 25%
-78 °C to 25 °C 49% (17%)
-78 °C to 25 °C 50% (5%)
-78 °C to 25 °C 80% (20%)
1:>20
8c THF
9c THF
10c THF
ndb
10:1
10:1
ndb
ndb
a Yield and ratio of isomers determined by 1H NMR spectroscopic
analysis of crude reaction mixture. The yield of 29 is shown in
parentheses where applicable. b nd ) not determined. c 1.9 equiv of
PhSnBu3. d Concentration of reactions was 0.032 M for entries 1-8,
0.064 M for entry 9 and 0.128 M for entry 10.
The reaction of 1-octene-(1,1-d2) was also examined with
CuCl2 and CuBr2/Et2O. In both cases, 40b-Cl/Br was the only
1,1-phenylhalogenated product formed (eq 8). Again, less than
5% of other isomers were observed, indicating clean migration
of the deuterium from the 1- to the 2-position.8
Table 5. Substrate Scope for Arylbromination
a 1,2-Arylbromination conditions: 10 mol % of PdCl2(MeCN)2, 4 equiv of CuBr2, 1.3-2.0 equiv of PhSnBu3, THF. b 1,1-Arylbromination conditions:
10 mol % of PdCl2(MeCN)2, 4 equiv of CuBr2, 1.3 equiv of PhSnBu3, Et2O. c Isolated yields and selectivities (crude values are in parentheses). In the
1,2 arylbromination reactions, between 5 and 20% of THF-addition products analogous to 29 was observed by crude 1H NMR spectroscopic analysis
with all substrates. The 1,1 and 1,2-isomers were generally not separable by column chromatography, but could be isolated in pure form using HPLC.
The variation in 1,2:1,1 selectivity as a function of substrate may be due to differing interactions of polar functional groups within the substrate with the
Pd catalyst. d Approximately 10% of the Heck byproduct was observed by crude NMR. e Isolated ratio reflects 1,2 product to a mixture of 1,1 and
1,4-products.
9
J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010 8423

A R T I C L E S
Kalyani et al.
Table 6. Reactions of Styrene Substrates
4-(4-Chlorophenyl)-1-butene. The reactivity of 4-(4-chlo-
rophenyl)-1-butene (33) was examined under both 1,2- and 1,1-
arylhalogenation conditions. With CuCl2 and CuBr2/Et2O,
mixtures of two isomeric products were formed (eq 9). In both
cases, the major isomer was the expected 1,1-product 41-Cl/
Br. However, a minor amount of a second benzylic halogenation
product 42-Cl/Br was also observed. The ratio of 41-Cl:42-Cl
was 4:1 in the chlorination reaction and the ratio of 41-Br:42-
Br was 7:1 under the bromination conditions as determined by
1H NMR spectroscopic analysis of the crude reaction mixtures.
Entry
Oxidant/Solvent
X
Y
Z
Yield
Ratio 1,2:1,1
1
PhICl2/CH2Cl2
CuCl2/Et2O
CuBr2/THF
CuBr2/Et2O
PhICl2/CH2Cl2
CuCl2/Et2O
CuBr2/THF
CuBr2/Et2O
Cl
Cl
Br
Br
Cl
Cl
Br
Br
F
F
F
F
H
H
H
H
H
H
H
H
F
F
F
F
50%a
48%b
45%b
69%b
79%a
50%b
30%b
50%b
>20:1a
1.4:1b
>20:1b
9:1b
2
3c
4d
5
>20:1a
2.2:1b
>20:1b
24:1b
6
7c
8d
a Yield and selectivity determined based on isolated material. b Yield
and selectivity determined by 1H NMR spectroscopic analysis of crude
reaction mixture. c Reaction conditions were optimized to -78 to 25 °C
with 2 equiv of organostannane to increase the yield - there was no
difference in selectivity compared to the reaction at 0 °C. d Pd(acac)2
used as [Pd].
Table 7. Reactions of Vinylnaphthalene
The use of PhICl2 or CuBr2/THF as the oxidant produced
1,2-arylhalogenated products 43-Cl/Br in 62/81% crude yield
(eq 10). The analogous 1,1-products were also formed (17/4%
crude yield) along with traces (2/2%) of the 1,4-arylfunction-
alized compounds 42-Cl/Br (eq 10). Notably, isomers derived
from chlorination/bromination at other sites in the middle of
the alkyl chain were not detected in these transformations.
Entry
Oxidant/Solvent
X
Yielda
Ratio 1,2:1,1a
1
PhICl2/CH2Cl2
CuCl2/Et2O
CuBr2/THF
CuBr2/Et2O
Cl
Cl
Br
Br
60%b
76%
>50:1
>50:1
>50:1
>50:1
2
3c
4c
12%d
48%d
a
1
Yield and selectivity determined by H NMR spectroscopic analysis
of crude reaction mixture. b Mass balance in 1,2-chlorination is
accounted for by formation of 25% of the 1,2-dichloro product.
c Pd(acac)2 used as [Pd]. d Mass balance in arylbromination reactions is
predominantly accounted for by incomplete conversion (15% conversion
of vinylnaphthalene in entry 3 and 70% conversion of vinylnaphthylene
in entry 4).
and (p-FC6H4)SnBu3, and again, 1,2-arylhalogenated products
predominated in all four cases (Table 6, entries 5-8).
Vinylnaphthalene Substrate. The Pd-catalyzed reaction
between vinylnaphthalene and (p-FC6H4)SnBu3 was also
explored, and the 1,2-arylhalogenation product 46-Cl/Br was
the major isomer observed under all four sets of conditions
(Table 7).30 The regioselectivity with CuCl2 and CuBr2/Et2O
increased significantly in comparison to that observed in the
corresponding reactions of styrene. For example, upon
Styrene Substrates. The Pd-catalyzed reaction of 4-fluorosty-
rene with PhSnBu3 under 1,2-arylhalogenation conditions af-
forded the expected 1,2-isomer (44-Cl/Br) with >20:1 selectivity
(Table 6, entries 1 and 3). Intriguingly, the 1,2-product 44-Cl/
Br was also favored in this transformation with CuCl2 or CuBr2/
Et2O as the oxidant (selectivity ) 1.4:1 in the chlorination and
9:1 in the bromination reaction) (Table 6, entries 2 and 4). This
experiment was repeated with styrene as the alkene substrate
(29) The 1,2- and 1,1-arylbromination products typically underwent some
decomposition during isolation/chromatographic purification (as re-
flected in the discrepancy between the isolated yield and the yield
determined from analysis of the crude reaction mixtures).
(30) For analogous reactions between substituted stannanes and vinylnaph-
thalene/styrene, see Table S5.
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Pd-Catalyzed Oxidative Arylhalogenation of Alkenes
A R T I C L E S
Table 8. Effect of Substituted THF-Derivatives on 1,2- versus
1,1-Phenylbromination with CuBr2
Table 10. Arylhalogenation of cis-48 and trans-48a
Yieldb,c
Ratio 49:50b
Entry
Solvent
Yielda
Ratio 1,2:1,1a
Entry
Substrate
Oxidant
Solvent
1
2
3
THF
80%
37%
57%
15:1
1.5:1
1.8:1
1
2
3
4
5
6
cis-48
cis-48
cis-48
trans-48
trans-48
trans-48
PhICl2
CuCl2
CuBr2
PhICl2
CuCl2
CuBr2
CH2Cl2
Et2O
Et2O
CH2Cl2
Et2O
Et2O
40%
51%
41%
21%
45%
9%
12:1
>30:1
5:1
1:1.6
1:8
MeTHFb
Me2-THFc
a
1
Yield and selectivity determined by H NMR spectroscopic analysis
of crude reaction mixture. b Me-THF
) 2-methyltetrahydrofuran.
1:8
c Me2-THF ) 2,5-dimethyltetrahydrofuran.
a Conditions: 2 equiv of PhSnBu3, 10 mol % PdCl2(PhCN)2, 0.032
b
1
Table 9. Effect of Aprotic Solvents on 1,2 versus 1,1
Arylbromination with CuBr2
M, -78 f 23 °C, 36 h. Yield and selectivity determined by H NMR
spectroscopic analysis of crude reaction mixture. c The mass balance in
these reactions is accounted for by recovered starting material as well as
the corresponding Mizoroki-Heck product. See Supporting Information
for full details.
a
was significantly diminished, particularly with PhICl2 (Table
10, entries 4-6).32 However, in all cases, the major product
was diastereomer 50-Cl/Br, which is again the product of syn
Ph/X addition.
Entry
Solvent
ε
Yieldb
Ratio 1,2:1,1b
1
2
3
4
5
6
7
8
9
THF
7.58
7.2
49%c
14%
63%
45%
82%
23%d
76%
56%
30%
3.4:1
>20:1
1:8
1:>20
1:24
1:>20
1:5.9
1:>20
1:20
1,2-Dimethoxyethane
EtOAc
Discussion
6.02
4.81
4.33
4.33
3.9
1,2-Arylhalogenation Reactions. All of the mechanistic ex-
periments presented above are consistent with the mechanism
proposed in Scheme 1. In this scenario, 1,2-arylhalogenation
products are generated via oxidative halogenation of Mizoroki-
Heck intermediate A. The deuterium labeling studies in eq 7
are in line with this proposal, as they show clean formation of
40-Cl/Br without accompanying migration of the deuterium
label.
The 1,2-arylbrominations are particularly intriguing because
simply moving from THF to Et2O reverses product selectivity.
We were thus very interested to understand the role of solvent
in these transformations. As shown in Table 8, changing the
solvent from THF to Me-THF or Me2-THF resulted in a steep
drop in selectivity for the 1,2-product 28a. Me-THF and Me2-
THF are expected to have very similar polarity but significantly
poorer coordinating capabilities than THF.33 Thus, this result
suggests that THF coordination (to either Pd34 or Cu35) may
play a key role in switching the selectivity in this system. The
results in Table 9 suggest that solvent polarity may also be an
important factor for selectivity, with more polar solvents
favoring the 1,2-product. Polar coordinating solvents are likely
to enhance the solubility of CuBr2, which should increase the
rate of oxidative bromination relative to that of ꢀ-hydride
elimination, thereby providing improved selectivity for 1,2-
product 28a.
CHCl3
Et2O
Anisole
iPr2O
MTBE
2.6
2.25
Dioxane
a These reactions were performed at 0.032 M to maximize solubility
and improve reproducibility across this broad range of solvents.
b Determined by 1H NMR spectroscopy. c 1.9 equiv of PhSnBu3 used.
d 0 °C f 25 °C.
changing from styrene to vinylnaphthalene, the 1,2:1,1
selectivity changed from 2.2:1 to >50:1 for chlorination with
CuCl2 and from 24:1 to >50:1 for bromination with CuBr2/
Et2O.
Solvent Effects in Arylbromination. To explore the role of
solvent in the 1,1- versus 1,2-arylbrominations with CuBr2/
THF, the reactions were examined in 2-methyltetrahydrofuran
(Me-THF) and 2,5-dimethyltetrahydrofuran (Me2-THF). As
shown in Table 8, changing the solvent resulted in a dramatic
decrease in selectivity for the 1,2-product. With Me-THF, a
1.5:1 ratio of 28a:28b was obtained, with similar results (28a:
28b ) 1.8:1) in Me2-THF.
These reactions were also examined in a series of aprotic
solvents with dielectric constants (ε) ranging from 7.58 to 2.25.
As shown in Table 9, there is a rough correlation between
product ratio and ε, with more of 1,2-product 28a generally
formed in higher dielectric solvents.
1,1-Arylhalogenation Reactions. These mechanistic studies
provide evidence that the 1,1-products are derived from the
Stereochemistry. Finally, we examined the stereochemical
outcome of these transformations with alkenes cis-48 and trans-
48. With cis-48, all of the reactions produced arylfunctional-
ization product 49-Cl/Br as the major diastereomer with modest
to excellent levels of selectivity (Table 10, entries 1-3).31
Compound 49-Cl/Br is the result of net syn addition of Ph and
X across the alkene.31,32 With trans 48, the stereoselectivity
(31) The stereochemistry of 49-Cl/Br and 50-Cl/Br was determined by
1H NMR spectroscopy (based on chemical shift and coupling constant
analysis) by analogy to several related products that were characterized
by X-ray crystallography. See Supporting Information for complete
details.
(32) Analogous results are not reported for CuBr2/THF because this reaction
was extremely poor yielding under these conditions.
(33) Wax, M. J.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 7028.
9
J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010 8425

A R T I C L E S
Kalyani et al.
PdII-naphthyl intermediate G-σ/π (eq 12). Thus, the increase
in 1,2-product with vinylnaphthalene suggests that kox/kꢀ-H
(where kox ) rate constant for direct oxidative functional-
ization and kꢀ-H ) rate constant for ꢀ-hydride elimination)
is significantly larger for intermediate G than for F.
Importantly, this is consistent with literature precedent, which
has shown that π-naphthyl complexes are more kinetically
reactive toward nucleophilic functionalization than their
π-benzyl counterparts.36
Scheme 2. Two Possible Mechanisms for Formation of
1,1-Products
ꢀ-hydride elimination/reinsertion/oxidation mechanism shown
in Scheme 1 and in Scheme 2, path 1. The migration of
deuterium from the 1- to the 2-position to generate 40b-Cl/Br
(eq 8) is fully consistent with this mechanism. In addition, the
formation of 1,4-addition product 42-Cl/Br from the reactions
of 4-(4-chlorophenyl)-1-butene with CuX2/ether (eq 9) provides
strong evidence for equilibrating ꢀ-hydride elimination/reinser-
tion steps prior to oxidative cleavage.
A possible alternative pathway involving a standard
Mizoroki-Heck mechanism followed by hydrohalogenation of
the resulting alkene (Scheme 2, path 2) can be ruled out based
on the data in Table 6. In path 2, the reaction of styrene/(p-
FC6H4)SnBu3 should produce the same alkene product as that
of 4-fluorostyrene/PhSnBu3. Accordingly, the mechanism in path
2 should afford identical mixtures of 44 to 45 for both reactions.
However, as shown in Table 6, the ratio of 44:45 changed
depending on the alkene/stannane used (entries 2 versus 6 and
4 versus 8).
Selective 1,1-arylfunctionalization with CuX2/ether appears
to derive from a preference for oxidative functionalization
of PdII-benzyl intermediates (like E) versus PdII-alkyl inter-
mediates (like A) (Scheme 2). This preference is reflected
in the sole formation of 42 and 41 (as opposed to isomers
resulting from halogenation at other sites along the alkyl
chain) in reactions of 4-(4-chlorophenyl)-1-butene with CuX2/
ether (eq 9). Additionally, the observation that 1,2-products
predominate in the functionalization of styrene derivatives
with CuX2/ether (Table 6) is consistent with fast oxidative
functionalization of an initially formed PdII-benzyl species
in these systems.
We hypothesize that the selectivity for Pd-benzyl func-
tionalization under equilibrating conditions derives from a
π-benzyl interaction (F-π, eq 11). This proposal is supported
by the experiments in Tables 6 and 7, which compare CuX2/
ether reactions of styrene to those of vinylnaphthalene. With
both CuCl2 and CuBr2, the selectivity for 1,2-functionalization
increases significantly upon moving from styrene to vinyl-
naphthalene (from 2.2:1 to >50:1 with CuCl2 and from 24:1
to >50:1 with CuBr2). In both cases, initial alkene insertion
should generate a PdII-benzyl intermediate F-σ/π (eq 11) or
Stereochemistry. The stereochemical course of oxidatively
induced sp3-carbon-halogen bond formation is of interest from
a fundamental mechanistic perspective. Additionally, the future
development of asymmetric arylfunctionalization reactions
hinges upon the ability to achieve clean retention or inversion
of stereochemistry at carbon during C-X coupling. Without
high stereochemical fidelity in this step, the new stereocenter
will be eroded over the course of the reaction.
As summarized in Table 10, the arylfunctionalization of cis-
48 and trans-48 favors products of syn addition. The insertion
of alkenes into Pd-Ph bonds is well-known to occur with high
syn-selectivity.37 Thus, this result indicates that C-X bond
formation occurs primarily with retention of configuration at
carbon (eq 13).
(34) For examples of PdII(THF) complexes, see: (a) Uson, R.; Fornies, J.;
Tomas, M.; Menjon, B. Organometallics 1985, 4, 1912. (b) Sperrle,
M.; Gramlich, V.; Consiglio, G. Organometallics 1996, 15, 5196. (c)
Yagyu, T.; Hamada, M.; Osakada, K.; Yamamoto, T. Organometallics
2001, 20, 1087. (d) Clegg, W.; Eastham, G. R.; Elsegood, M. R. J.;
Heaton, B. T.; Iggo, J. A.; Tooze, R. P.; Whyman, R.; Zacchini, S.
Organometallics 2002, 21, 1832. (e) Kim, Y.; Verkade, J. G. J.
Organomet. Chem. 2003, 669, 32.
Carbon-halogen formation most likely occurs via initial 1
or 2 e- oxidation of PdII-alkyl species A with PhICl2 or CuX2
to form a PdIV or PdIII intermediate.38-40 The observed retention
of configuration is consistent with direct C-X bond-forming
reductive elimination from this high oxidation state Pd center
(eq 14, path 1)41 or with a phenyl group assistance mechanism
involving double inversion (eq 14, path 2).41b Both of these
(35) For examples of CuII(THF) complexes, see: (a) Breeze, S. R.; Wang,
S. Inorg. Chem. 1993, 32, 5981. (b) Amel’chenkova, E. V.; Denisova,
T. O.; Nefedov, S. E. Russ. J. Inorg. Chem. 2006, 51, 1218.
9
8426 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010

Pd-Catalyzed Oxidative Arylhalogenation of Alkenes
A R T I C L E S
pathways have been proposed in the literature for related
transformations.41
would most likely affect reactions of cis-48 and trans-48 to
similar degrees and thereby provide similar levels of stereo-
chemical erosion with both the cis and trans substrates. Thus,
this explanation does not readily account for the dramatically
different results for cis-48/PhICl2 (12:1 isomer ratio) versus
trans-48/PhICl2 (1:1.6 isomer ratio).
A second possible explanation for formation of mixtures of
diastereomers would be competing isomerization of the alkene
starting material under the reaction conditions. This scenario
would lead to an “apparent” erosion of stereoselectivity even if
C-X coupling proceeded with clean retention. Olefin isomer-
ization is likely to be particularly problematic with trans-48,
since it undergoes arylfunctionalization at a slower rate than
cis-48.44 Thus, the observation of lower diastereoselectivities
in reactions of trans-48 is consistent with a contribution from
1
this pathway. In addition, H NMR spectroscopic analysis of
the reaction between trans-48/PhSnBu3 and PhICl2 at 50%
conversion revealed the presence of detectable quantities (2%)
of cis-48. Furthermore, reaction of cis-48 at 23 °C with 2 equiv
of PhICl2 and 2 equiv of PhSnBu3 resulted in 18% yield and an
8:1 ratio of 49-Cl:50-Cl) along with 17% recovery of trans-
48. These results clearly indicate that alkene isomerization can
occur to a significant extent under the PhICl2/CH2Cl2 reaction
conditions. While this side reaction undoubtedly needs to be
addressed, the observation of good levels of stereoselectivity
with the cis substrates provides impetus for moving forward in
the development of asymmetric versions of these transformations.
While syn addition predominated in every case, modest levels
of stereoselectivity were observed in some reactions, particularly
with trans-48 and PhICl2 (Table 10, entry 4). There are several
potential explanations for these observations. First, selectivity
would be eroded if oxidative functionalization occurred with
competing retention and inversion of configuration at carbon.
Literature studies of related oxidatively induced carbon-
heteroatom coupling reactions at Pd suggest that both retention41
and inversion42 are possible. Further, small modifications of the
reaction conditions can sometimes lead to large changes in the
stereochemical outcome.43 However, such competing pathways
Summary
In summary, we have developed Pd-catalyzed reactions for
the arylchlorination and arylbromination of R-olefins by oxi-
datively intercepting Mizoroki-Heck intermediate A (Scheme
1). The selectivity of these reactions can be rationally tuned by
controlling the relative rates of oxidative functionalization versus
ꢀ-hydride elimination from equilibrating PdII-alkyl species and
by π-benzyl stabilization of PdII intermediates. This work
provides a mechanistic basis for the future development of
synthetically useful aryloxygenation, arylamination, arylhalo-
genation, and diarylation reactions using a variety of oxidants
and transmetalating reagents. Additionally, the insights gained
from these studies will be valuable for the design of enanti-
oselective versions of these transformations. Work in all of these
areas is ongoing in our laboratory and will be reported in due
course.
(36) (a) Becker, Y.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 845. (b)
Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 1828. (c) Johns, A. M.; Tye, J. W.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 16010. (d) Reference 8.
(37) Heck, R. F. J. Am. Chem. Soc. 1969, 91, 6707.
(38) For the oxidation of PdII starting materials to PdIV with PhICl2, see:
(a) Lagunas, M.-C.; Gossage, R. A.; Spek, A. L.; van Koten, G.
Organometallics 1998, 17, 731. (b) Whitfield, S. R.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 15142.
(39) For the oxidation of PdII starting materials to PdIII dimers with PhICl2,
see: Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
(40) For generation of high oxidation state Pd intermediates by oxidation
of PdII starting materials with 1 e- oxidants, see: Lanci, M. P.; Remy,
M. S.; Kaminsky, W.; Mayer, J. M.; Sanford, M. S. J. Am. Chem.
Soc. 2009, 131, 15618.
(41) For examples of oxidatively induced carbon-heteroatom bond-forming
reactions at Pd with retention of stereochemistry, see ref 21c and: (a)
Coulson, D. R. J. Am. Chem. Soc. 1969, 91, 200. (b) Backvall, J. E.;
Nordberg, R. E. J. Am. Chem. Soc. 1980, 102, 393. (c) Zhu, G.; Ma,
S.; Lu, X.; Huang, Q. J. Chem. Soc., Chem. Commun. 1995, 271. (d)
Zhu, G.; Lu, X. J. Organomet. Chem. 1996, 508, 83. (e) Yin, G.; Liu,
G. Angew. Chem., Int. Ed. 2008, 47, 5442.
Acknowledgment. This work was supported by NIH NIGMS
(R01GM073836). We also gratefully acknowledge Boehringer
Ingelheim and Bristol Myers Squibb for unrestricted funding. D.K.
thanks Bristol Myers Squibb for a graduate fellowship. We thank
Dr. Jeff Kampf for performing all of the X-ray crystallographic
studies.
(42) For examples of oxidatively induced carbon-heteroatom bond-forming
reactions at Pd with inversion of stereochemistry, see refs 20c, 21b,
and: (a) Backvall, J. E. Tetrahedron Lett. 1977, 467. (b) Backvall,
J. E. Tetrahedron Lett. 1978, 163. (c) Backvall, J. E.; Bjorkman, E. E.
J. Org. Chem. 1980, 45, 2893. (d) Tong, X.; Beller, M.; Tse, M. K.
J. Am. Chem. Soc. 2007, 129, 4906. (e) Lyons, T. W.; Sanford, M. S.
Tetrahedron 2009, 65, 3211.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(43) For an example of different stereochemical outcomes as a function of
reaction conditions, see: Wong, P. K.; Stille, J. K. J. Organomet. Chem.
1974, 70, 121.
(44) See Supporting Information (Table S3) for details.
JA101851V
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