Selective synthesis of 5- or 6-aryl octahydrocyclopenta[b]pyrroles from a common precursor through control of competing pathways in a Pd-catalyzed reaction

Article abstract of DOI:10.1021/ja0430346

The Pd/phosphine-catalyzed reaction of 1 with aryl bromides leads to the selective synthesis of either 6-aryl octahydrocyclopenta[b]pyrroles (3), the corresponding 5-aryl isomers 5, diarylamine 2, or hexahydrocyclopenta[b]pyrrole 4 depending on the struct

Full text of DOI:10.1021/ja0430346

Published on Web 05/27/2005
Selective Synthesis of 5- or 6-Aryl
Octahydrocyclopenta[b]pyrroles from a Common Precursor
through Control of Competing Pathways in a Pd-Catalyzed
Reaction
Joshua E. Ney and John P. Wolfe*
Contribution from the Department of Chemistry, UniVersity of Michigan,
930 North UniVersity AVenue, Ann Arbor, Michigan, 48109-1055
Received November 18, 2004; E-mail: jpwolfe@umich.edu
Abstract: The Pd/phosphine-catalyzed reaction of 1 with aryl bromides leads to the selective synthesis of
either 6-aryl octahydrocyclopenta[b]pyrroles (3), the corresponding 5-aryl isomers 5, diarylamine 2, or
hexahydrocyclopenta[b]pyrrole 4 depending on the structure of the phosphine ligand. These transformations
are effective with a variety of different aryl bromides and provide 3-5 with excellent levels of diastereo-
selectivity (dr g 20:1). The changes in product distribution are believed to derive from the influence of
Pd-catalyst structure on the relative rates of reductive elimination, â-hydride elimination, alkene insertion,
and alkene displacement processes in a mechanistically complex reaction. The effect of phosphine ligand
structure on product distribution is described in detail, along with analysis of a proposed mechanism for
these transformations.
amino)alkenes with aryl bromides (eq 1).2-4 These transforma-
Introduction
tions lead to the formation of a C-C and a C-N bond along
A significant challenge in the development of metal-catalyzed
reactions is the suppression of competing mechanistic pathways
without inhibiting desired steps in a catalytic cycle. In recent
years, several remarkable transformations have been effected
through the use of palladium catalysts that minimize side
reactions (e.g., â-hydride elimination) while still allowing
reductive elimination or transmetalation processes to occur.1
Despite these achievements, the factors that affect the relative
rates of competing mechanistic pathways in catalytic reactions
(e.g., reductive elimination versus olefin insertion, or C-C
versus C-N bond-forming reductive elimination) are not well
understood. If these fundamental processes could be controlled,
the selective construction of a diverse array of products from
common starting materials could be achieved under similar
reaction conditions by varying catalyst structure.
with up to two stereocenters in a single process. During the
course of these studies, we noted that the Pd/P(o-tol)3-catalyzed
reaction of 1a with 4-bromobiphenyl provides an unexpected
mixture of four products (Scheme 1, 2-5). We suggested that
these products may derive from a common intermediate (6),
which undergoes reductive elimination to afford 2,5 or intra-
molecular alkene insertion into the Pd-N bond6-8 followed by
(1) For recent examples, see: (a) Kirchhoff, J. H.; Netherton, M. R.; Hills, I.
D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662-13663. (b) Torraca, K.
E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 10770-10771. (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 1473-1478. (d) Lee, C.-W.; Oh, K. S.; Kim, K. S.; Ahn, K. H.
Org. Lett. 2000, 2, 1213-1216. (e) Aggarwal, V. K.; Davies, P. W.; Moss,
W. O. J. Chem. Soc., Chem. Commun. 2002, 972-973. (f) Coperet, C.;
Negishi, E.-i. Org. Lett. 1999, 1, 165-168.
(2) A portion of this work has been previously communicated. See: Ney, J.
E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605-3608.
(3) For related transformations that provide indolines or tetrahydrofurans,
see: (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906-13907.
(b) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(c) Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099-
3107.
(4) For recent, complementary methods involving late transition metal-catalyzed
synthesis of pyrrolidines from γ-aminoalkenes, see: (a) Bender, C. F.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070-1071. (b) Manzoni,
M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R. Organometallics 2004, 23,
5618-5621.
(5) (a) Muci, A. R.; Buchwald, S. L Top. Curr. Chem. 2002, 219, 131-209.
(b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; p 107.
(6) (a) Boncella, J. M.; Villanueva, L. A. J. Organomet. Chem. 1994, 465,
297-304. (b) Villanueva, L. A.; Abboud, K. A.; Boncella, J. M.
Organometallics 1992, 11, 2963-2965. (c) Helaja, J.; Go¨ttlich, R. J. Chem.
Soc., Chem. Commun. 2002, 720-721. (d) Tsutsui, H.; Narasaka, K. Chem.
Lett. 1999, 45-46. (e) Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi,
N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869.
(7) For examples of alkene insertion into Pt-N bonds see: (a) Cowan, R. L.;
Trogler, W. C. Organometallics 1987, 6, 2451-2453. (b) Cowan, R. L.;
Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750-4761.
We recently described a new stereoselective synthesis of
N-aryl pyrrolidines via Pd-catalyzed reactions of γ-(N-aryl-
9
8644
J. AM. CHEM. SOC. 2005, 127, 8644-8651
10.1021/ja0430346 CCC: $30.25 © 2005 American Chemical Society

Synthesis of 5-, 6-Aryl Octahydrocyclopenta[b]pyrroles
A R T I C L E S
Scheme 1 a
Figure 1.
be minimized, the reaction may be directed toward product 4
provided that alkene insertion into the Pd-N bond is not
completely inhibited. The two main classes of phosphines that
are well-documented in their ability to decrease the rate of
reductive elimination reactions are small, electron-rich ligands
(e.g., PMe2Ph)12 and chelating ligands with small bite angles
(e.g., dppe).12,13 Therefore, these types of ligands seemed to be
potentially viable candidates for the selective formation of 4.14
The selective formation of products 3 and 5 was more difficult
to envision, as the formation of these products requires
conditions that minimize C-N bond-forming reductive elimina-
tion without completely suppressing C-C bond-forming reduc-
tive elimination. In the case of product 3, the rate of C-C bond-
forming reductive elimination of intermediate 7 would need to
be faster than competing â-hydride elimination (k3 > k4). We
reasoned that it might be feasible to achieve selectivity for 3
by employing chelating ligands with moderate to large bite
angles (e.g., dppf, BINAP, or dpe-phos) to minimize the rate
of â-hydride elimination15 (k4) while still allowing C-C bond-
forming reductive elimination16 of 7 to occur at a reasonable
rate (k3).17 If adequate control of the relative rates of C-N and
C-C bond-forming reductive elimination could not be achieved
through variation of phosphine ligand, we felt it should be
possible to decrease the rate of C-N bond-forming reductive
elimination by employing an electron-deficient N-aryl substituent
on the substrate 1.18
a Conditions: 1.0 equiv of 1a, 1.2 equiv of 4-Ph(C6H4)Br, 1.4 equiv of
NaOtBu, 1 mol % Pd2(dba)3, 4 mol % P(o-tol)3, toluene, 110 °C. Isolated
yield: 2 (19%), 3 (32%), 4 (5%), 5 (12%) for Ar ) 4-methoxyphenyl,
Ar1 ) 4-(phenyl)phenyl.
(a)reductive elimination to afford 3,9 (b) â-hydride elimination
and alkene displacement to afford 4, or (c) â-hydride elimina-
tion, reinsertion, and reductive elimination to afford 5 (Scheme
1).2 Despite the apparently complex mechanism of this reaction,
we felt that selective formation of 2-5 might be achieved by
altering the catalyst structure and/or the nitrogen nucleophilicity
to control the relative rates (k1-k7) of each possible step in the
catalytic cycle. This would provide access to a variety of
products with a 1-azabicyclo[3.3.0]octane core, which is found
in a number of biologically active molecules.10,11 In this article,
we present a detailed description of the effects of ligand
structure, nitrogen nucleophilicity, and aryl halide electronics
on the ratios of products observed in reactions of 1 with aryl
bromides. These studies have led to the selective synthesis of
products 2-5 in good yields from a single precursor via the
use of an appropriate catalyst for each transformation. The
experiments described herein also provide further evidence to
support the mechanistic hypothesis outlined in Scheme 1.
The selective synthesis of 5 would require a scenario in which
the rate of reversible â-hydride elimination19 from 7 to afford
8 is fast relative to the rate of reductive elimination from 7 (k4
> k3). In this scenario it seemed likely that the equilibrium
between alkylpalladium complex 7 and π-complex 8 would lie
far to the right, as examination of molecular models reveals a
severe steric interaction between the N-aryl substituent and the
metal fragment in 7 (Figure 1). In principle, 8 could undergo
Results
Effect of Ligand Structure on Product Distribution. Prior
to the start of our optimization studies, we sought to identify
catalyst properties that might be expected to provide some
degree of selectivity for each of the products 2-5. The
mechanistic proposal described above (Scheme 1) suggests that
if the rate of reductive elimination from 6 (k1) is fast relative to
all other steps, then 2 should be obtained in high yield. Thus,
we hypothesized that the selective synthesis of product 2 could
be achieved in a straightforward manner by employing pal-
ladium catalysts supported by bulky, electron-rich phosphine
ligands that are known to be highly effective at promoting C-N
bond-forming reductive elimination reactions.5
(12) (a) Gillie, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4933-4941. (b)
Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-8245.
(c) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-
7218.
(13) Dppe ) 1,2-bis(diphenylphosphino)ethane, dppp ) 1,3-bis(diphenylphos-
phino)propane, dppb ) 1,4-bis(diphenylphosphino)butane, dppm ) 1,1-
bis(diphenylphosphino)methane, dpp-benzene ) 1,2-bis(diphenylphosphino)-
benzene, dcpe ) 1,2-bis(dicyclohexylphosphino)ethane, BINAP ) (()-
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, dpe-phos ) bis(2-diphen-
ylphosphinophenyl)ether, dppf ) 1,1′-bis(diphenylphosphinoferrocene),
xantphos ) 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
(14) Our previous studies showed that use of certain electron-rich phosphines
(e.g., 2-dicyclohexylphosphinobiphenyl) provided acceptable yields in the
Pd-catalyzed carboamination reactions of γ-aminoalkenes. Thus, it seemed
possible that the alkene insertion into the Pd-N bond may also potentially
proceed with other electron-rich phosphines. See ref 2.
(15) (a) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S. Angew.
Chem., Int. Ed. 2003, 42, 3810-3813. (b) Steinhoff, B. A.; Stahl, S. S.
Org. Lett. 2002, 4, 4179-4181 and references therein.
(16) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398-3416 and
references therein.
(17) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P.
Chem. ReV. 2000, 100, 2741-2770.
(18) The rate of C-N bond-forming reductive elimination decreases as the
nitrogen becomes less nucleophilic. See: (a) Reference 12b. (b) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048. (c) Yamashita,
M.; Cuevas Vicario, J. V.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
16347-16360.
We reasoned that, if the rates of all possible C-N and C-C
bond-forming reductive elimination steps (k1, k3, and k7) could
(8) For an example of a catalytic reaction that likely proceeds via insertion of
norbornene into an Ir-N bond, see: Casalnuovo, A. L.; Calabrese, J. C.;
Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738-6744.
(9) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981-4991.
(10) (a) Schultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645-648. (b)
Borioni, A.; Del Guidice, M. R.; Mustazza, C.; Gatta, F. J. Heterocycl.
Chem. 2000, 37, 799-810.
(11) For recent synthetic approaches to the 1-azabicyclo[3.3.0]octane ring system,
see: (a) Aron, Z. D.; Overman, L. E. Org. Lett. 2005, 7, 913-916. (b)
Pecanha, E. P.; Verli, H.; Rodrigues, C. R.; Barreiro, E. J.; Fraga, C. A.
M. Tetrahedron Lett. 2002, 43, 1607-1611. (c) Gansauer, A.; Pierobon,
M.; Bluhm, H. Synthesis 2001, 2500-2520. (d) Denmark, S. E.; Senan-
ayake, C. B. W. Tetrahedron 1996, 52, 11579-11600. (e) Larock, R. C.;
Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172-
4178.
9
J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8645

A R T I C L E S
Ney and Wolfe
Table 1. Trialkylphosphine Ligand Effectsa
entry
ligand
cone angle
2
3a
4
5a
1b,c
2b,c
3
4
5
6
7
8
PMe3‚HBF4
11826a
13226a
16126b
16126b
17026a
17026a
17427
0
0
0
0
1
2
6
81
100
98
0
0
0
0
2
2
6
5
0
2
98
92
0
0
1
6
0
0
0
2
PEt3‚HBF4
8
100
100
96
90
88
14
0
P(t-Bu)2Me‚HBF4
Pd[PMe(t-Bu)2]2
Pd[PCy3]2
PCy3
Pd[P(t-Bu)Cy2]2
Pd[P(t-Bu)2Cy]2
Pd[P(t-Bu)3]2
P(t-Bu)3‚HBF4
17827
9
18226a
18226a
10b
0
0
a Conditions: 1.0 equiv of 1a, 2.0 equiv of 4-bromotoluene, 1.2 equiv
of NaOtBu, 1 mol % Pd2(dba)3, 4 mol % ligand, toluene (0.25 M), 110 °C.
The product ratios refer to GC ratios of products 2-5 that have been
corrected for GC response factor. All reactions proceed to completion unless
otherwise noted. b The reaction was conducted with 1.4 equiv of 4-bromo-
toluene. c The reaction proceeded to 80% conversion.
reversible reinsertion of the alkene into the Pd-H bond with
opposite regiochemistry19 to afford 9; the position of the
equilibrium between 8 and 9 is difficult to predict. However, if
equilibration is rapid and the rate of reductive elimination from
9 is faster than the rate of the alkene displacement from 8 (k7
> k5), then selective formation of 5 should occur. There was
not sufficient literature precedent to allow us to predict how
ligand variation would affect the relative rates of the required
olefin insertion processes versus reductive elimination reactions.
However, the effects of ligand steric and electronic properties
on the rates of reductive elimination reactions are well-
documented.20 Additionally, we expected that increasing the size
and electron-donor ability of the ligand should slow the rate of
alkene displacement from 8, which likely proceeds through an
associative mechanism involving attack of an external
nucleophile.19,21-23 Thus, it seemed feasible that the correct
combination of ligand steric and electronic properties could
potentially provide good selectivity for 5.
Table 2. Effect of Other Monodentate Phosphine Ligandsa
cone
entry
ligand
angle
2
3a
4
5a
1
2
t-Bu2P(o-biphenyl) (10)
2-(dicyclohexylphosphino)-2′-(N,N-
dimethylamino)biphenyl
Cy2P(o-biphenyl)
2-(diphenylphosphino)-2′-(N,N-
dimethylamino)biphenyl (11)
P(o-tol)3
P[C6H4(m-CF3)]3
P[C6H4(p-CF3)]3
PPh3
P[C6H4(p-OMe)]3
P(2-furyl)3
94
76 24
6
0
0
0
0
3
4
52 39
56 40
1
2
8
2
5
6
7
8
9
10
11
19426a 18 42
9
31
16526c
14526d
14526a
14526c
4
3
3
0
0
0
0
31 32 33
28 26 43
9
5
8
0
0
55 33
59 36
82 10
86 14
Ph2PMe
13626a
12226a
12b PhPMe2
92
8
To probe the hypotheses described above, we examined the
Pd-catalyzed reaction of 1a with 4-bromotoluene in the presence
of a variety of different phosphine ligands (eq 2). All reactions
examined proceeded to completion with a catalyst loading of 1
mol % of Pd2(dba)3 except reactions conducted with PMe3 and
PEt3, which both stopped at ca. 80% conversion. In all cases,
compounds 2-5 accounted for g95% of the products detected
by GC and/or 1H NMR analysis of the crude reaction mixtures,
and products derived from oxidation of 1a to the corresponding
N-aryl imine via â-hydride elimination of 65 were not observed
in most reactions.
As shown in Table 1, experiments with monodentate trialkyl-
phosphine ligands24 demonstrated that selectivity is highly
dependent on the steric bulk of the ligand and that excellent
selectivity for products 2, 4, and 5 can be achieved with the
appropriate ligand. In general, the very bulky ligands (cone angle
g 178°) favored N-arylation, the medium-sized ligands (cone
angle ) 160-174°) favored the formation of 5, and the very
small ligands (cone angle e 132°) favored the formation of 4.
a Conditions: 1.0 equiv of 1a, 2.0 equiv of 4-bromotoluene, 1.2 equiv
of NaOtBu, 1 mol % Pd2(dba)3, 4 mol % ligand, toluene (0.25 M), 110 C.
The product ratios refer to GC ratios of products 2-5 that have been
corrected for GC response factor. All reactions proceed to completion unless
otherwise noted. b The reaction was conducted with 1.4 equiv of 4-bromo-
toluene.
Use of preformed L2Pd complexes1a,25 gave results similar to
those obtained with Pd2(dba)3/phosphine mixtures.
The selectivities observed in Pd-catalyzed reactions conducted
with other monodentate phosphine ligands are shown in Table
2. In general, sterically bulky ligands favor the formation of 2
and/or 3, whereas smaller ligands provide 4 and/or 5 as the
major products. Of the ligands examined in this series, bulky,
electron-rich phosphines provided the highest selectivity for 2,
and the selectivity for 4 increased with decreasing ligand size.
Use of ligands that were extremely bulky (e.g., tris[2,4,6-
trimethoxyphenyl]phosphine) and/or extremely electron-poor
(e.g., P[C6F5]3, P[o-C6H4CF3]3) resulted in low reactivity.28
(19) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056-2057.
(20) The rate of reductive elimination generally increases as ligand size increases
and decreases as ligand basicity increases. Steric effects can outweigh
electronic effects, as electron-rich ligands that are sterically bulky are known
to promote reductive elimination. For reviews, see: (a) Christmann, U.;
Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366-374. (b) Brown, J. M.;
Cooley, N. A. Chem. ReV. 1988, 88, 1031-1046.
(23) Increased back-bonding from the electron-rich metal to the alkene may
also play a role in decreasing the rate of alkene dissociation. For a discussion
of back-bonding in electron-rich Pd(II)-alkene complexes, see: Miki, K.;
Shiotani, O.; Kai, Y.; Kasai, N.; Kanatani, H.; Kurosawa, H. Organo-
metallics 1983, 2, 585-593.
(24) Most air-sensitive trialkylphosphine ligands were employed in the form of
their air-stable, crystalline tetrafluoroborate salts. See: Netherton, M. R.;
Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
(21) Ligand substitution reactions at d8-Pd(II) complexes generally occur via
an associative mechanism. See: (a) Shultz, L. H.; Tempel, D. J.; Brookhart,
M. J. Am. Chem. Soc. 2001, 123, 11539-11555 and references therein.
For rare exceptions, see: (b) Bartolome, C.; Espinet, P.; Martin-Alvarez,
J. M.; Villafane, F. Eur. J. Inorg. Chem. 2004, 2326-2337. (c) Louie, J.;
Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598-11599.
(25) Yoshida, T.; Otsuka, S. Inorg. Synth. 1990, 28, 113-119.
(26) (a) Tolman, C. A. Chem. ReV. 1977, 77, 313-348. (b) Lee, K. J.; Brown,
T. L. Inorg. Chem. 1992, 31, 289-294. (c) Rahman, M. M.; Liu, H. Y.;
Prock, A.; Giering, W. P. Organometallics 1987, 6, 650-658. (d) This
value was estimated based on the cone angle of the closely related ligands
PPh3 and P[C6H4(p-OMe)]3.
(22) Rates of associative ligand substitution should decrease as the electron
density on the metal center increases due to electron-electron repulsion
between the metal and the incoming nucleophile.
(27) Approximate value calculated using the method of Tolman. See: Tolman,
C. A.; Seidel, W. C.; Gosser, L. W. J. Am. Chem. Soc. 1974, 96, 53-60.
9
8646 J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005

Synthesis of 5-, 6-Aryl Octahydrocyclopenta[b]pyrroles
A R T I C L E S
Table 3. Effect of Chelating Phosphine Ligandsa
Table 4. Selective Synthesis of 3a
entry
ligand
bite angleb
2
3a
4
5a
1
dppm
dppe-p-CF3
dppe
dppe-p-OMe
dpp-benzene
dcpe
dppp
BINAP
dppb
7329a
86c
12
20
5
11
25
7
4
3
4
58
9
10
42
12
27
46
51
28
63
69
7
19
8
37
56
12
0
26
27
25
24
4
2
3f
4
8629a
86c
3
5
6
7
8
87d,29b
8729c
9129a
9329d
9429e
9929f
87
11
31
32
4
27
13
19
54
66
3
22
30
19
75
17
0
9f
10
11
12
13
dppf
dppf-i-Pr
dpe-phos
xantphos
10329g
104e,29h
108e,29h
37
0
a Conditions: 1.0 equiv of 1a, 2.0 equiv of 4-bromotoluene, 1.2 equiv
of NaOtBu, 1 mol % Pd2(dba)3, 2 mol % ligand, toluene (0.25 M), 110 °C.
The product ratios refer to GC ratios of products 2-5 that have been
corrected for GC response factor. All reactions proceed to completion unless
otherwise noted. b Bite angles were obtained from crystal structures of
bis(phosphine)PdCl2 complexes. c The bite angle was estimated based on
analogy to dppe. d The bite angle was obtained from a crystal structure of
the bis(phosphine)PdBr2 complex. e The bite angle was obtained from a
crystal structure of the bis(phosphine)Pd(1,1-dimethylallyl)tetrafluoroborate
complex. f Approximately 3% of an imine side product derived from
substrate oxidation was detected by GC and GC-MS analysis of the crude
reaction mixture.
To probe the effect of chelation and ligand bite angle on
product distribution, a number of bidentate ligands were
employed in the transformation shown in eq 2; the results are
described in Table 3. Systematic variation of ligand bite angle
did not result in clear trends of product distribution. However,
electronic effects similar to those described above for reactions
involving monodentate ligands were observed within series of
ligands that possess identical backbone structures. For example,
reactions catalyzed by mixtures of Pd2(dba)3 and 1,2-bis-
(phosphino)ethane derivatives (entries 2-4 and 6) afforded
increasing amounts of 4 and 5a (relative to 2 and 3a) as the
electron-donicity of the phosphines increased. Similarly, use of
1,2-bis(diphenylphosphino)ferrocene as ligand afforded pre-
dominantly 2 and 3a, whereas 1,2-bis(diisopropylphosphino)-
ferrocene provided 5a as the major product (entries 10 and 11).
In summary, the best selectivity for 2 was obtained with the
bulky, monodentate, electron-rich ligands P(t-Bu)3 and t-Bu2P-
(o-biphenyl) (10). Use of the small, monodentate electron-rich
ligands PMe3, PEt3, and PhPMe2 provided the best selectivity
for 4, whereas the medium-sized, electron-rich ligands P(t-Bu)2-
Me and PCy3 provided the highest selectivity for 5a. None of
the ligands examined provided excellent selectivity for 3a;
however, dppp provided modest selectivity for 3a, with 2 formed
as the major side product. The xantphos, Cy2P(o-biphenyl), and
2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl (11)
ligands also provided close to 1:1 ratios of 2/3a, with only small
amounts of 4 and 5a generated. Although the selectivity for 3a
was not ideal, we reasoned that we could further improve the
ratio of 3/2 by employing substrates bearing electron-withdraw-
ing N-aryl substituents, which would slow the rate of competing
C-N bond-forming reductive elimination (see below).5
a Conditions: 1.0 equiv of amine, 1.4 equiv of Ar2Br, 1.2 equiv of NaOt-
Bu, 1 mol % Pd2(dba)3, 2 mol % 11, toluene (0.25 M), 110 °C. b 11 )
2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl. c 1a:
Ar
)
p-(MeO)C6H4; 1b: Ar ) p-(Cl)C6H4; 1c: Ar ) p-(NC)C6H4; 1d: Ar )
p-(t-BuO2C)C6H4. d Ligand ) dppp. e This material contained 7% of 4c as
an inseparable impurity.
aryl bromides; the results are summarized below. As shown in
Table 4, the reaction of 4-bromotoluene with 1a afforded a
modest 44% isolated yield of 3a in the presence of the Pd2-
(dba)3/dppp catalyst system (entry 1). Analysis of the crude
reaction mixture showed that the four products (2, 3a, 4, and
5a) were formed in a 25:65:10:0 ratio; the Pd2(dba)3/11 catalyst
provided a 48:48:2:2 ratio of 2/3a/4/5a (entry 2). As expected,
significantly higher yields of isomer 3 were obtained with
substrates bearing electron-deficient N-aryl substituents (entries
3-5 and 7). For example, the reaction of substrate 1d bearing
a N-para-carbo-tert-butoxyphenyl group with 4-bromotoluene
afforded a 75% yield of 3e (entry 7). Use of 11 as ligand
provided superior results in reactions of substrates 1c and 1d,
which failed to react in the presence of the Pd2(dba)3/dppp
catalyst system. Aryl halide electronics also had a significant
effect on the selectivity with which products 3a-g were formed.
As noted above, the reaction of electron-deficient substrate 1d
with 4-bromotoluene afforded 3e in 75% isolated yield as the
sole detectable product (entry 7), whereas the reaction of 1d
with the electron-rich 4-bromoanisole afforded a separable 9:1
Selective Synthesis of 6-Aryl Octahydrocyclopenta[b]-
pyrroles (3): Effect of Aryl Bromide Structure and N-Aryl
Substituent. With optimized conditions in hand, we examined
the reaction of several derivatives of 1 with a number of different
(28) Use of trimesitylphosphine provided a very complex mixture of unidentified
products.
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8647

A R T I C L E S
Ney and Wolfe
Table 5. Selective Synthesis of 5a
product 4 was achieved in 60% yield as shown in eq 3; the
best results were obtained with PMe3 as ligand. Although 4 is
the sole product formed under these conditions, the reaction
did not proceed beyond 80% consumption of starting material;
use of 2 mol % Pd2(dba)3 led to only modest improvements in
conversion and yield. Reactions in which PMePh2, PMe2Ph, or
P(2-furyl)3 were employed as ligands all provided similar
isolated yields (44-54%) despite differences in selectivity due
to the difficult chromatographic separation of 4 from 5.31
The N-arylated product 2 was obtained in 88% yield using
the Pd2(dba)3/t-Bu2P(o-biphenyl) (10) catalyst system (eq 4).
The scope of this transformation was not explored due to the
large body of existing literature on the effect of aryl bromide
substitution on Pd-catalyzed N-arylation reactions.5
Discussion
Synthetic Scope and Limitations. The palladium-catalyzed
reaction of N-aryl-2-(cyclopent-2-enyl)ethylamines 1 with aryl
bromides provides 5- or 6-aryloctahydrocylopenta[b]pyrroles in
moderate to good yields with excellent diastereoselectivity
(g20:1 dr). The 5-aryl regioisomers 5a-g are selectively formed
in reactions that employ the medium-sized electron-rich phos-
phine P(t-Bu)2Me as a ligand for palladium, whereas use of
catalysts composed of Pd2(dba)3 and either dppp or 11 leads to
selective formation of the 6-aryl products 3a-g. The yields
obtained in reactions that afford predominantly 5-aryl products
are not greatly affected by the electronics of either the amine
N-aryl substituent or the aryl bromide. In contrast, reactions
that afford 6-aryl products provide the highest yields when
substrates bearing electron-poor N-aryl substituents are em-
ployed in combination with electron-neutral or slightly electron-
a Conditions: 1.0 equiv of amine, 1.4 equiv of Ar2Br, 1.2 equiv of NaOt-
Bu, 1 mol % Pd2(dba)3, 2 mol % P(t-Bu)2Me‚HBF4, toluene (0.25 M), 110
°C. b 1a: Ar ) p-(MeO)C6H4; 1b: Ar ) p-(Cl)C6H4; 1c: Ar ) p-(NC)C6H4;
1d: Ar ) p-(t-BuO2C)C6H4; 1e Ar ) Ph. c This material contained 7% of
isomer 3 as an inseparable impurity.
mixture of 3f/4d (entry 8), and the reaction of 1d with an aryl
bromide bearing an electron-withdrawing substituent led to the
formation of significant amounts of N-arylated side products
(entry 9). In all cases examined, the 1-azabicyclo[3.3.0]octane
derivatives 3a-g were obtained with diastereomeric ratios of
g20:1.
Selective Synthesis of 5-Aryl Octahydrocyclopenta[b]-
pyrroles (5): Effect of Aryl Bromide Structure and Nitrogen
Electronics. As shown in Table 5, the selective synthesis of
isomer 5 was achieved for a variety of different substrate
combinations using the Pd2(dba)3/P(t-Bu)2Me‚HBF4 catalyst
system. Good to excellent selectivities and yields were obtained
in transformations of substrates bearing electron-rich, -neutral,
or -poor N-substituents. The reactions also proceeded in good
yield with aryl bromides of varying electronic properties,
although the ratios of 5/3 decreased when certain electron-
deficient or o-substituted aryl bromides were employed as
coupling partners (entries 3, 4, and 6). Products 2 and 4 were
not observed except in the reaction of 1c with 3-bromopyridine
(entry 5). In all cases, the products 5a-g were obtained with
g20:1 dr.
(29) (a) Steffen, W. L.; Palenik, G. J. Inorg. Chem. 1976, 15, 2432-2439. (b)
Estevan, F.; Garcia-Bernabe, A.; Lahuerta, P.; Sanau, M.; Ubeda, M. A.;
Galan-Mascaros, J. R. J. Organomet. Chem. 2000, 596, 248-251. (c)
Ganguly, S.; Mague, J. T.; Roundhill, D. M. Acta Crystallogr., Sect. C.
1994, C50, 217-219. (d) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi,
T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics 1993, 12,
4188-4196. (e) Makhaev, V. D.; Dzhabieva, Z. M.; Konovalikhin, S. V.;
D’yachenko, O. A.; Belov, G. P. Russ. J. Coord. Chem. 1996, 22, 563-
567. (f) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163. (g) Boyes, A. L.; Butler,
I. R.; Quayle, S. C. Tetrahedron Lett. 1998, 39, 7763-7766. (h) van Haaren,
R. J.; Goubitz, K.; Fraanje, J.; van Strijdonck, G. P. F.; Oevering, H.;
Coussens, B.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Inorg. Chem. 2001, 40, 3363-3372.
(30) For other examples of Pd-catalyzed oxidative amination reactions of olefins,
see: (a) Reference 6e. (b) Hegedus, L. S. Tetrahedron 1984, 40, 2415-
2434. (c) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002,
41, 164-166. (d) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (e) Larock, R. C.;
Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61,
3584-3585.
Selective Synthesis of Oxidative Amination Product 4 and
N-Arylated Product 2. The synthesis of oxidative amination30
(31) The use of PMe2Ph, PMePh2, or P(2-furyl)3 as ligands afforded isolated
yields of 54, 44, and 53%, respectively.
9
8648 J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005

Synthesis of 5-, 6-Aryl Octahydrocyclopenta[b]pyrroles
A R T I C L E S
Scheme 2
rich aryl bromides. Functional groups such as nonenolizable
nitriles, ketones, and esters are tolerated in these transformations,
and the synthesis of 5-aryl products bearing o-substituents or
heterocylic groups is also feasible. The reaction of 1a with
4-bromotoluene in the presence of a catalytic amount of Pd2-
(dba)3/10 leads to clean N-arylation of the substrate to afford
2, whereas use of the Pd2(dba)3/PMe3 catalyst system provides
oxidative amination product 4 in moderate yield.
from intermolecular carbopalladation of 1a followed by C-N
bond-forming reductive elimination (Scheme 2, path A). How-
ever, this pathway is unlikely due to the high stereoselectivity
for formation of products in which the aryl group is installed
syn to the C-3 methylene. If the reactions were to occur via
intermolecular carbopalladation without chelation of the amino
group or formation of an amido complex it is likely that steric
repulsion between the Pd(Ar)(X) complex and the alkyl chain
would favor formation of the anti-diastereomer 12 (or at least
would likely provide mixtures of diastereomers).34 The forma-
tion of 3 via Wacker-type aminopalladation (Path B) can be
ruled out, as this pathway would result in anti-addition of the
heteroatom and the metal across the carbon-carbon double bond
to provide 12 rather than the observed products 3a-g.35 The
reductive Heck arylation of 4 (path C) can also be discounted
as a possible mechanism for the generation of 3a and/or 5a, as
the transformation of 4 to 3a and/or 5a is not observed under
the conditions employed for the conversion of 1a to 3a or 5a.36
The data described above also argue against insertion of the
alkene into the Pd-C bond of 6 or a related mechanism
involving amino chelate-directed carbopalladation from inter-
mediate 6′. As shown below (Scheme 3), alkene insertion into
the Pd-C bond of 6 or 6′ would afford 13 or 13′. In principle,
13 or 13′ could be converted to 3a via sp3C-N bond-forming
reductive elimination. However, C-C bond-forming alkene
insertions are generally irreversible,37 and this pathway could
not provide either 4 or 5a from intermediates 13 or 13′. In
addition, ligands that are known to slow the rate of C-C and
sp2C-N bond-forming reductive elimination (e.g., dppe or
PMe3)12 would also be likely to slow the rate of sp3C-N bond-
forming reductive elimination. If the reductive elimination from
13 or 13′ were slowed, it is likely that â-hydride elimination of
13 or 13′ would afford product 14. However, use of dppe or
PMe3 in the catalytic reactions leads instead to the formation
The results described above (Table 4, entry 1; Table 5, entry
1; and eqs 3 and 4) demonstrate that a single starting material
can be converted to four different products (2-5) in moderate
to excellent yield by changing only the nature of the metal
catalyst employed in the reaction. For example, in separate
experiments 1a was treated with 4-bromotoluene and an
appropriate palladium catalyst to afford either 2 (88% yield),
3a (44% yield), 4 (60% yield), or 5a (74% yield). Although
the selectivity for formation of 3a was modest (a 65:35 ratio of
3a/(2 + 4 + 5a) was obtained under optimal conditions),32
products 2, 4, and 5a were each obtained with excellent
selectivity (g94:6). High selectivity for isomer 3 was achieved
by changing the substrate’s N-aryl substituent to an electron-
withdrawing p-C6H4CO2t-Bu group. The reaction of this modi-
fied substrate (1d) with 4-bromotoluene and the Pd2(dba)3/11
catalyst afforded 3e in 75% yield with 100:0 selectivity (Table
4, entry 7).
Mechanism and Ligand Effects. In addition to the hypoth-
esis outlined in Scheme 1, a number of other mechanistic
pathways could potentially lead to the formation of products
3-5 (Scheme 2).33 The ligand effects, stereoselectivity, and
product stereochemistry described above can be used to evaluate
the viability of the various possible mechanisms for this
transformation. For example, product 3 could potentially derive
(32) The 65:35 ratio of products was determined by 1H NMR analysis of the
crude reaction mixture and differs slightly from the 58:42 ratio measured
by GC analysis of the crude reaction mixture (Table 3, entry 7). Similarly,
small differences were observed for the product ratios described in Table
2, entry 4 (measured by GC) as compared to that for Table 4, entry 2
(measured by 1H NMR). The small differences in the product ratios for
these are likely due to experimental error associated with the measurement
techniques.
(33) The mechanism for Pd-catalyzed N-arylation reactions of amines is well-
documented and is believed to proceed via intermediate palladium(aryl)-
(amido) complexes such as 6. For lead references, see: (a) Reference 5.
(b) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
12905-12906. (c) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14104-14114. (d) Guari,
Y.; van Strijdonck, G. P. F.; Boele, M. D. K.; Reek, J. N. H.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M. Chem.-Eur. J. 2001, 7, 475-482. (e)
Hartwig, J. F. Synlett 1997, 329-340.
(34) Intermolecular Heck arylations of substituted cyclic, bicyclic, or heterocyclic
alkenes generally provide products resulting from arylation on the less
hindered face of the double bond. See: (a) Tietze, L. F.; Petersen, S. Eur.
J. Org. Chem. 2000, 1827-1830. (b) Haberli, A.; Leumann, C. J. Org.
Lett. 2001, 3, 489-492. (c) Desmazeau, P.; Legros, J.-Y.; Fiaud, J.-C.
Tetrahedron Lett. 1998, 39, 6707-6710. (d) Oliveira, D. F.; Severino, E.
A.; Correia, C. R. D. Tetrahedron Lett. 1999, 40, 2083-2086.
(35) (a) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785-1788. (b)
Ba¨ckvall, J. E.; Bjo¨rkman, E. E. J. Org. Chem. 1980, 45, 2893-2898. (c)
Akermark, B.; Ba¨ckvall, J. E.; Siirala-Hansen, K.; Sjoberg, K.; Zetterberg,
K. Tetrahedron Lett. 1974, 15, 1363-1366.
(36) Treatment of 4 with 4-bromotoluene in the presence of NaOtBu and a
catalytic amount of Pd2(dba)3 and either P(t-Bu)2Me‚HBF4 or dppp at 110
°C in toluene did not result in any detectable reaction.
(37) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-3066.
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8649

A R T I C L E S
Scheme 3
Ney and Wolfe
of 4 as the major product. Thus, a mechanistic pathway
involving intermediate 13 or 13′ cannot account for all products
that are obtained and is also not consistent with the observed
ligand effects.
palladium atoms.39 However, ligands that are known to decrease
the rate of reductive elimination (e.g., dppe)12 disfavor the
formation of 2 and 3, which is consistent with our mechanistic
hypothesis shown in Scheme 1. In addition, the electronic
effects20 observed within a structurally similar series of ligands
are also consistent with the hypothesis described above. For
example, use of the electron-poor dppe-p-CF3 ligand resulted
in the increased formation of 2 and 3 relative to dppe and use
of the electron-rich dppe-p-OMe led to a slight increase in the
formation of 4.
In contrast, the data described above in Tables 1-5 can be
explained using the mechanistic model outlined in Scheme 1.
For example, the trends observed with trialkylphosphines show
that, as the steric bulk of the ligand is decreased, the product
ratio shifts from predominantly 2 (P[t-Bu]2Cy, P[t-Bu]3) to 5
(PMe[t-Bu]2, PCy3, P[t-Bu]Cy2) to 4 (PMe3, PEt3). The decrease
in ligand size would be expected to slow the rate of reductive
elimination from 6 f 2,5,20 which may lead to the formation of
7. When medium-sized electron-rich ligands are employed, it
appears that â-hydride elimination from 7 f 8 occurs more
rapidly than reductive elimination from 7, but the conversion
of 8 f 9 f 5 is fast relative to the rate of alkene displacement
from 8. This is presumably due to a combination of ligand steric
and electronic properties that slow the associative ligand
substitution process required to covert 8 f 4.19,21 In contrast,
with the smaller ligands the metal becomes more sterically
accessible for attack by an external nucleophile, and the rate of
associative alkene displacement from 8 to afford 4 likely
becomes fast relative to the rate of olefin reinsertion and
reductive elimination. These arguments could also be used to
explain similar trends observed in reactions that involve other
monodentate ligands; the smaller ligands favor the formation
of 4 (Table 2, entries 10-12), and larger ligands favor the
formation of 2 and/or 3 (Table 2, entries 1-5). A comparison
of reactions involving isosteric triphenylphosphine derivatives
(Table 2, entries 7-9) reveals that increased amounts of products
2 and 3 are generated as phosphine basicity is decreased. This
trend is also consistent with the mechanism described in Scheme
1, as ligands that increase the rate of C-N and/or C-C bond-
forming reductive elimination20 should favor the formation of
2 and 3 over products 4 and 5, which are proposed to derive
from â-hydride elimination processes.
At the outset of these studies we hoped to be able to facilitate
the selective formation of 3 by employing chelating ligands to
minimize â-hydride elimination of 7. Although we found several
ligands (e.g., dppp, dppf, xantphos, and dpp-benzene) that
afforded high ratios of (2 + 3a)/(4 + 5a), which suggests that
chelation does affect the relative rates of reductive elimination
versus â-hydride elimination from 6 and 7, we were unable to
completely control the selectivity for formation of 3 over 2 by
varying phosphine ligand structure. However, substitution of
the nitrogen with an electron-deficient aryl group resulted in
good to excellent selectivities for 3c-3g with the pseudo-
chelating ligand 11,40 which is consistent with an expected
decrease in the rate of reductive elimination from 6 when the
nitrogen nucleophilicity is decreased.18
The observed effects of aryl bromide substitution on product
distribution are also consistent with the mechanistic hypothesis
outlined in Scheme 1. The rates of stoichiometric C-N and
C-C bond-forming reductive elimination reactions from LnPd-
(Ar)(NR2) and LnPd(Ar)(R) complexes are known to decrease
with increasing electron density on the aryl group.18a,41 When
1d is treated with the electron-deficient tert-butyl-4-bromo-
benzoate under conditions that favor formation of 3g, increased
amounts of N-arylated products 2 are formed compared to the
amounts generated by reaction of 1d with 4-bromotoluene
(Table 4, entries 7 and 9). This presumably derives from an
increase in the rate of reductive elimination of intermediate 6.
In contrast, reaction of 1d with the electron-rich 4-bromoanisole
leads to increased formation of 4d (Table 4, entry 8), which is
consistent with a decrease in the rate of reductive elimination
from intermediates 6, 7, and 9. Similarly, reactions of 1b or 1e
with aryl bromides bearing para-carbonyl functionality under
Examination of the data shown in Table 3 does not reveal a
clear relationship between bite angle of chelating ligands and
product distribution. This may be due in part to the fact that
the coordination chemistry of many of these ligands is com-
plicated, and it is difficult to say whether some of the ligands
are coordinated solely in a cis-bidentate fashion. For example,
trans-chelated Pd complexes of xantphos have been described,18b,38
and dppb is known to form bridging complexes with two
(39) Sanger, A. R. J. Chem. Soc., Dalton Trans. 1977, 1971-1976.
(40) Ligand 11 is believed to act as a bidentate ligand via complexation of the
aromatic ring bearing the dimethylamino group. See: Yin, J.; Rainka, M.
P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162-
1163 and references therein.
(41) Ozawa, F.; Kurihara, K.; Fujimori, M.; Hidaka, T.; Toyoshima, T.;
Yamamoto, A. Organometallics 1989, 8, 180-188.
(38) Zuideveld, M. A.; Swennenhuis, B. H. G.; Boele, M. D. K.; Guari, Y.; van
Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.; Goubitz, K.; Fraanje,
J.; Lutz, M.; Spek, A. L.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton
Trans. 2002, 2308-2317.
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Synthesis of 5-, 6-Aryl Octahydrocyclopenta[b]pyrroles
A R T I C L E S
conditions that favor formation of 5 also provided small amounts
of regioisomeric side product 3, which may derive from an
increase in the rate of reductive elimination from 7 (Table 5,
entries 3 and 6). This effect was not observed in the reaction of
1e with of 4-bromobenzonitrile, which provided 5g with
essentially complete selectivity. Although this latter result is
somewhat surprising, previous studies have shown that the rates
of reductive elimination reactions often do not follow simple
linear free energy relationships with the σ-values of arene
substituents.18a,41
4. However, as the size of the ligand decreases, a near complete
reversal in selectivity is observed such that the formation of 4
is favored over 5 (Table 1, entries 1-7).
Conclusion
In conclusion, we have demonstrated that the selective
conversion of 1 to four different products can be achieved by
using ligand effects to control the relative rates of C-N and
C-C bond-forming reductive elimination, â-hydride elimination,
alkene insertion, and alkene displacement in a mechanistically
complex process. These transformations allow for synthesis of
a variety of 5- or 6-aryl octahydrocyclopenta[b]pyrroles (5 and
3, respectively) in good yield with high regioselectivity and
diastereoselectivity. The observed effects of ligand structure on
product ratio provide further evidence to support our mechanistic
hypothesis and suggest that palladium(aryl)amido complex 6
is a plausible common intermediate in the conversion of 1 to 2,
3, 4, and 5.
In addition to providing further support for our mechanistic
hypothesis shown in Scheme 1, the results described above
illustrate several important concepts that are potentially relevant
to the future development of other new Pd-catalyzed reactions.
First of all, these results demonstrate that the rate of both C-N
and C-C bond-forming reductive elimination can be minimized
without completely suppressing alkene insertion processes,
which are required to transform 1 into 3-5. Furthermore, since
C-N bond-forming reductive elimination reactions require
larger ligands than are needed to effect C-C bond-forming
reductive elimination,5 it is possible to minimize the rate of C-N
bond-forming reductive elimination without completely sup-
pressing C-C bond-forming reductive elimination. This allows
for the selective synthesis of 3 and 5. These results also reaffirm
the notion that phosphines have a large impact on the relative
rates of reductive elimination and â-hydride elimination, and
that the appropriate choice of ligand can be used to favor either
transformation over the other. Finally, our data also suggest that
steric and electronic properties of phosphine ligands may have
a large impact on the rate of alkene displacement from Pd(II)
complexes. Medium-sized electron-rich ligands appear to slow
the rate of alkene displacement from a Pd(II)-alkene complex
to a greater degree than they decrease the rate of C-C bond-
forming reductive elimination, which facilitates the selective
preparation of 5 and minimizes the formation of side product
Acknowledgment. We thank the University of Michigan and
the National Institutes of Health-National Institute of General
Medical Sciences (GM-071650) for financial support of this
work. J.P.W. thanks the Camille and Henry Dreyfus Foundation
for a new faculty award and Research Corporation for an
innovation award. J.E.N. acknowledges the University of
Michigan for a Regents Fellowship and Pfizer for a Graduate
Research Fellowship. Additional unrestricted funding was
provided by 3M, Amgen, and Eli Lilly.
Supporting Information Available: Characterization data for
all new compounds in Tables 4, 5, and eqs 3 and 4, descriptions
of stereochemical assignments, and a table of ligand effects
organized in order of product formed. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0430346
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