Bertrand et al.
SCHEME 3. Formation of 31 and 33
SCHEME 4. Formation of 42
Two key pieces of evidence support this mechanistic hy-
pothesis, along with the notion that the mechanism for pyrro-
lidine formation is not dependent on the nature of the base.31
First of all, the transformations proceed with suprafacial addition
across both terminal and internal alkenes, as illustrated by the
examples shown in Table 4, eqs 2, 6, and 10, and Scheme 1.
The suprafacial addition is observed when either NaOtBu or
Cs2CO3 is employed as base, and is consistent with the
conversion of 71 to 72 via syn-aminopalladation.
The formation of 2-ethylpyrrolidine derivatives 31 and 33
(Table 4, entries 2 and 3) and 2-(1-phenylethyl)pyrrolidine 42
(eq 3) is also consistent with the mechanism shown above, and
cannot satisfactorily be explained by alternative mechanisms
that involve carbopalladation rather than aminopalladation.32 As
shown above (Scheme 3), products 31 and 33 are most likely
generated through syn-ꢀ-hydride elimination from intermediate
72 (via transition state 73) to give 74. Reinsertion of the alkene
into the Pd-H bond of 74 with the opposite regioselectivity
would yield 75, which can undergo a second series of ꢀ-hydride
elimination/reinsertion processes to provide 77. Reductive
elimination from 77 could then afford isomers arylated at the
3-position, whereas additional ꢀ-hydride elimination/reinsertion
steps could ultimately generate isomers arylated at the 4- or
5-position.
bromides (Table 4, entries 2-3). The absence of these side-
products in most reactions of N-Boc and N-acyl-protected
substrates may be due to decreased rates of ꢀ-hydride elimina-
tion from intermediate 72 relative to the analogous N-aryl
derivative. This may be due to stabilization of 72 through
chelation of the metal to the carbonyl of the amide or
carbamate,33 or through inductive effects induced by the amide/
carbamate protecting groups. These electron-withdrawing groups
likely destabilize the developing positive charge on C2 in the
transition state for ꢀ-hydride elimination (73).34 The fact that a
similar regioisomer was not generated when the electron-neutral
2-bromonaphthalene was coupled with 25 may be due to the
decreased electrophilicity of the arylpalladium complex (72, Ar
) 2-naphthyl), which could slow the rate of ꢀ-hydride elimina-
tion. However, the reasons for formation of only trace amounts
(ca. 1-5%) of regioisomers in transformations of Cbz-protected
substrate 27 are unclear.
The pathway by which 42 is generated is likely similar to
the mechanism for the formation of 31 and 33, but with initial
ꢀ-elimination of a hydride from the methyl group of 72a
(Scheme 4) rather than from C2 (Scheme 3). The formation of
regioisomers analogous to 42 was not observed with p- or
m-substituted aryl bromides. This suggests the steric bulk of
2-bromochlorobenzene may increase the rate of ꢀ-hydride
elimination from the less hindered methyl group relative to the
more hindered C2 position, or slow the rate of reductive
elimination from 72a or 77 relative to 79.35
Interestingly, the formation of regioisomers similar to 31 and
33 was not observed in reactions of N-Boc-protected (Z)-alkene
substrate 28. This may be due to severe developing allylic strain
interactions in the transition state for ꢀ-hydride elimination, from
steric destabilization of the resulting (Ar)Pd(H)(alkene) complex,
or both. As shown in Scheme 5, alkene insertion from 71 would
yield 72, which could undergo ꢀ-hydride elimination from
transition state 73 to provide 74. This intermediate could then
be converted to the observed regioisomers as described above.
A similar sequence of transformations from (Z)-alkene-derived
intermediate 71a could lead to the analogous intermediate 74a.
However, the eclipsing interaction between the methyl group
and the carbamate protecting group in transition state 73a would
result in developing allylic strain similar to that in an S-cis-
The formation of 3-arylpyrrolidine side products is commonly
observed in Pd-catalyzed carboamination reactions of γ-(N-
arylamino) alkenes bearing relatively electron-rich N-aryl groups
(e.g., Ph or PMP).5a In contrast, the formation of mixtures of
regioisomers is usually not observed in reactions of N-Boc-,
N-acyl-, or N-Cbz-protected substrates, except for couplings of
(E)-disubstituted alkenes 25 and 27 with electron-poor aryl
(28) For examples of syn-alkene insertion into Pt-N bonds, see: (a) Cowan,
R. L.; Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750–4761. (b) Cowan,
R. L.; Trogler, W. C. Organometallics 1987, 6, 2451–2453. For examples of
syn-alkene insertion into Ni-N bonds, see: (c) VanderLende, D. D.; Abboud,
K. A.; Boncella, J. M. Inorg. Chem. 1995, 34, 5319–5326. For examples of
syn-alkene insertion into Ir-N bonds, see: (d) Casalnuovo, A. L.; Calabrese, J. C.;
Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738–6744. For examples of syn-
alkene insertion into Rh-N bonds, see: (e) Zhao, P.; Krug, C.; Hartwig, J. F.
J. Am. Chem. Soc. 2005, 127, 12066–12073. For examples of syn-insertion of
dimethyl acetylenedicarboxylate into Pd-N bonds, see: (f) Villanueva, L. A.;
Abboud, K. A.; Boncella, J. M. Organometallics 1992, 11, 2963–2965. For a
review on alkene aminopalladation (syn- and anti-), see: (g) Minatti, A.; Muniz,
K. Chem. Soc. ReV. 2007, 36, 1142–1152.
(29) For other Pd-catalyzed reactions that likely proceed via alkene syn-
aminopalladation, see: (a) Helaja, J.; Gottlich, R. J. Chem. Soc., Chem. Commun.
2002, 720–721. (b) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45–46. (c) Brice,
J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem.
Soc. 2005, 127, 2868–2869.
(30) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981–4991.
(31) The formation of benzocyclobutene 44 from the Pd-catalyzed reaction
of 43 with 4-bromobiphenyl when Cs2CO3 is used as a base appears to arise
from a divergence in mechanism prior to formation of intermediate palladium
amido complex 71. For further discussion, see ref 19.
(33) (a) Zhang, L.; Zetterberg, K. Organometallics 1991, 10, 3806–3813.
(b) Lee, C.-W.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org. Lett. 2000, 2, 1213–
1216. (c) Oestreich, M.; Dennison, P. R.; Kodanko, J. J.; Overman, L. E. Angew.
Chem., Int. Ed. 2001, 40, 1439–1442. (d) Clique, B.; Fabritius, C -H.; Couturier,
C.; Monteiro, N.; Balme, G. Chem. Commun. 2003, 272–273.
(34) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005–
7013.
(35) It is also possible that the o-chloro substituent facilitates ꢀ-hydride
elimination by effecting dissociation of one arm of the chelating phosphine ligand.
For a discussion of the effect of o-halo groups on ligand substitution processes,
see: Kuniyasu, H.; Yamashita, F.; Terao, J.; Kambe, N. Angew. Chem., Int. Ed.
2007, 46, 5929–5933.
(32) For a detailed discussion of all mechanistic possibilities in Pd-catalyzed
reactions of unsaturated amines or alcohols that generate heterocyclic products,
see ref 4b.
8858 J. Org. Chem. Vol. 73, No. 22, 2008