Palladium-catalyzed tandem N-arylation/carboamination reactions for the stereoselective synthesis of N-aryl-2-benzyl pyrrolidines

Article abstract of DOI:10.1021/ol050647u

(Chemical Equation Presented) The tandem N-arylation/carboamination of γ-amino alkenes with two different aryl bromides provides rapid entry to differentially arylated N-aryl-2-benzyl pyrrolidine derivatives in good yields with good to excellent levels of diastereoselectivity. The selective diarylation is achieved in a one-pot process by an in situ modification of the palladium catalyst via phosphine ligand exchange.

Full text of DOI:10.1021/ol050647u

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2575-2578
Palladium-Catalyzed Tandem
N-Arylation/Carboamination Reactions
for the Stereoselective Synthesis of
N-Aryl-2-benzyl Pyrrolidines
Qifei Yang, Joshua E. Ney, and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan,
930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
jpwolfe@umich.edu
Received March 25, 2005
ABSTRACT
The tandem N-arylation/carboamination of
γ-amino alkenes with two different aryl bromides provides rapid entry to differentially arylated
N-aryl-2-benzyl pyrrolidine derivatives in good yields with good to excellent levels of diastereoselectivity. The selective diarylation is achieved
in a one-pot process by an in situ modification of the palladium catalyst via phosphine ligand exchange.
In recent years much effort has been devoted to the
development of tandem or sequential reactions that effect
the formation of several different bonds, stereocenters, and/
or rings in one-pot transformations.1 These types of reactions
lead to the conversion of simple starting materials to
relatively complex molecules in a rapid and efficient manner,
and have considerable potential utility for the construction
of diverse libraries of compounds. Transition metal catalysis
has played a central role in the development of many of these
processes.1,2
challenging, as the efficiency and selectivity of many metal-
catalyzed reactions is highly dependent on catalyst structure.
We have recently described a new method for the
stereoselective synthesis of N-aryl-2-benzylpyrrolidines via
Pd-catalyzed reactions of γ-(N-arylamino)alkenes with aryl
bromides (Scheme 1, eq 1).4-6 In our initial studies, several
of the substrates for these transformations were prepared by
Pd-catalyzed N-arylation of primary amines.7 Since both the
carboamination and the N-arylation reactions were effected
using palladium/phosphine catalysts, we reasoned that a
Transformations effected through tandem metal-catalyzed
reactions can be broadly grouped into two categories:
(1) sequences that involve multiple iterations of the same
reaction2 and (2) sequences that involve two or more
fundamentally different reactions.3 The latter tend to be more
(3) For recent examples, see: (a) Ajamian, A.; Gleason, J. L. Angew.
Chem., Int. Ed. 2004, 43, 3754. (b) Yamamoto, Y.; Nakagai, Y.; Itoh, K.
Chem.sEur. J. 2004, 10, 231. (c) Cossy, J.; Bargiggia, F.; BouzBouz, S.
Org. Lett. 2003, 5, 459. (d) Thadani, A. N.; Rawal, V. H. Org. Lett. 2002,
4, 4317. (e) Son, S. U.; Park, K. H.; Chung, Y. K. J. Am. Chem. Soc. 2002,
124, 6838. (f) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312. (g) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc.
2001, 123, 4609.
(1) (a) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
(b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96,
195. (d) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(2) (a) Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289.
(b) Malacria, M. Chem. ReV. 1996, 96, 289.
(4) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(5) For related syntheses of N-acyl- and N-boc-2-benzylpyrrolidines,
see: Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, in press.
(6) For related syntheses of tetrahydrofurans, see: (a) Wolfe, J. P.; Rossi,
M. A. J. Am. Chem. Soc. 2004, 126, 1620. (b) Hay, M. B.; Hardin, A. R.;
Wolfe, J. P. J. Org. Chem. 2005, 70, 3099.
10.1021/ol050647u CCC: $30.25
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as we felt that chelating ligand 2 would be more difficult to
replace with a different phosphine prior to the second step
of the sequence. The chelating ligand dppe9 was employed
for the second reaction of the sequence, as we have found
this ligand to be effective in a broad range of carboamination
processes.4
Scheme 1
In a representative experiment, a 0.25 M toluene solution
of 4-pentenylamine (1) and 1 equiv of bromobenzene were
added to a dry, argon-filled Schlenk tube containing catalytic
amounts of Pd2(dba)3 (1 mol %) and 3 (2 mol %), and 2.4
equiv of NaOtBu. The reaction mixture was heated to
60 °C with stirring and monitored periodically by GC
analysis. When the bromobenzene had been completely
consumed (c.a. 30-90 min), a 0.005 M toluene solution of
dppe (2 mol %) was added and the reaction mixture was
heated to 110 °C for 15 min to allow the exchange process
to occur. 4-Bromoanisole (1.2 equiv) was then added, and
heating was continued until the intermediate N-aryl alkyl-
amine was completely consumed. Upon aqueous workup and
chromatographic purification, the desired N-phenyl-2-(4-
methoxybenzyl)pyrrolidine product (9) was obtained in 67%
yield (Table 1, entry 1, method A).
As shown in Table 1, this method is effective for the
conversion of a variety of γ-aminoalkenes to N-aryl-2-
benzylpyrrolidine derivatives.11 In general, the best results
are obtained when electron-neutral or -deficient aryl bromides
are employed in the first step of the tandem transformation.
Use of electron-rich aryl halides such as 4-bromoanisole as
the first coupling partner often resulted in slow reactions and
provided only modest yields of the desired, differentially
arylated products due to the formation of N,N-diarylamine
side products (entry 5), or N-aryl-2-benzylpyrrolidine side
products that had incorporated 2 equiv of the electron-rich
arene (entry 6). However, the reaction of substrate 4, which
bears a phenyl substituent at the 1-position, proceeded in
good yield when 4-bromoanisole was employed as the first
coupling partner (entry 7). Electron-neutral or -rich aryl
bromides provide the best yields in the second step of the
sequence; use of electron-deficient halides as the second
coupling partner often led to the formation of substantial
amounts of N,N-diarylated side products.
modular synthesis of N-aryl-2-benzylpyrrolidines might be
achieved in a one-pot, Pd-catalyzed process via sequential
treatment of a 4-pentenylamine derivative with two different
aryl bromides (Scheme 1, eq 2). A transformation of this
type would lead to the formation of two C-N bonds, one
C-C bond, one ring, and one stereocenter in a single
operation. Additionally, this protocol could potentially be
employed in the conversion of readily available starting
materials into pyrrolidine libraries in which two groups on
the heterocycle could be easily varied.8 Our preliminary
studies on the development of this one-pot reaction sequence
are described herein.
Both palladium-catalyzed N-arylations of amines and
Pd-catalyzed carboamination reactions are known to be very
sensitive to catalyst structure.4,7 A search of the literature
revealed that relatively few ligands are highly effective and
selective for the Pd-catalyzed monoarylation of primary
aliphatic amines; (rac)-BINAP (2)9 and 2-di-tert-butylphos-
phinobiphenyl (3) appeared to be the most general with
respect to substrate scope.7 Our previous studies indicated
that 2 was only marginally effective for the conversion of
γ-(N-arylamino)alkenes to N-aryl-2-benzylpyrrolidines,
whereas 3 provided low yields in all reactions examined.4,10
Thus, we felt that it would be necessary to carry out the
desired sequential transformation by modifying the palladium
catalyst following the N-arylation reaction. This would allow
for maximum efficiency of each reaction in the sequence
and could be achieved via an in situ ligand exchange that
would not require the use of additional palladium or workup/
purification between steps. We chose to employ the mono-
dentate ligand 3 for the first step of the reaction sequence,
The tandem transformations of substrates 4-7, which bear
substituents at the 1- or 3-position, proceeded with good to
excellent levels of diastereoselectivity.12 Reactions of 1-sub-
stituted aminoalkenes 4 and 5 afforded 2,5-cis-disubstituted
pyrrolidines with >20:1 dr (entries 7-10). Transformations
of 3-phenyl-substituted amine 6 (entries 11-13) also pro-
ceeded with excellent stereocontrol (>20:1 dr), and the
analogous 3-methyl-substituted substrate 7 was transformed
with good (ca. 10:1) diastereoselectivity for the formation
of 2,3-trans-disubstituted products (entries 14 and 15). In
contrast, the reactions of 8 proceeded with low stereoselec-
(7) For recent reviews on Pd-catalyzed N-arylation reactions, see:
(a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(b) Hartwig, J. F. In Modern Arene Chemistry; Didier, A., Ed.; Wiley-
VCH: Weinheim, 2002, p 107. (c) Schlummer, B.; Scholz, U. AdV. Synth.
Catal. 2004, 346, 1599.
(8) For related transformations of 2-allylanilines to N-aryl-2-benzylin-
dolines, see: Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906.
(9) BINAP ) 2,2′-diphenylphosphino-1,1′-binaphthyl, dppe ) 1,2-bis-
(diphenylphosphino)ethane, dpe-phos ) bis(2-diphenylphosphinophenyl)-
ether.
(10) Pd2(dba)3/3-catalyzed reaction of N-(4-pentenyl)aniline with 2-bromo-
naphthalene afforded <5% yield of the desired pyrrolidine; use of 2 in
place of 3 provided a 65% GC yield of the pyrrolidine product. However,
the Pd2(dba)3/2-catalyzed reaction of 5-(N-phenylamino)-1,8-nonadiene with
2-bromonaphthalene afforded only 41% isolated yield of the desired
2,5-disubstituted pyrrolidine.
(11) Small amounts (ca. 5-10%) of 2-methyl-3-arylpyrrolidine deriva-
tives were also formed in some of these transformations. See Supporting
Information for further details.
(12) Diastereomeric ratios were determined by 1H NMR and/or GC
analysis. The relative stereochemistry of the products was assigned on the
basis of the results of 1H NMR NOE experiments or by comparison of
spectra to related compounds of known configuration. See Supporting
Information for further details.
2576
Org. Lett., Vol. 7, No. 13, 2005

Table 1. Palladium-Catalyzed Stereoselective Synthesis of N-Aryl-2-benzylpyrrolidine Derivatives
a Method A: 1.0 equiv of amine, 1.0 equiv of ArBr, 2.4 equiv of NaOtBu, 1 mol % Pd2(dba)3, 2 mol % 3, toluene (0.125 M), 60 °C, then 2 mol % dppe,
1.2 equiv of Ar1Br, 110 °C. Method B: 1.0 equiv of amine, 1.0 equiv of ArBr, 2.4 equiv of NaOtBu, 1 mol % Pd2(dba)3, 2 mol % (rac)-BINAP (2), toluene
(0.125 M), 80 °C, then 1.2 equiv of Ar1Br, 80 °C. bYields represent average isolated yields from two or more experiments. cThis product contained a small
amount (ca. 5-10%) of an inseparable regioisomer.
tivity (entries 16 and 17). The stereochemical outcome of
these reactions parallels that observed in previously described
reactions of γ-(N-arylamino)alkenes with aryl bromides.4
The use of BINAP as a ligand for both steps of the tandem
transformation was briefly examined and was found to be
effective in some reactions of the unsubstituted 4-pentenyl-
amine (1) (Table 1, entries 2 and 4). However, these
conditions were not effective for reactions of the more
substituted amines 4-8.13
In summary, the Pd-catalyzed tandem N-arylation/carbo-
amination of primary aliphatic amines proceeds in moderate
to good yield to afford differentially arylated N-aryl-2-
benzylpyrrolidine derivatives. Although each of the indi-
vidual catalytic reactions requires a different phosphine
ligand to achieve optimal yields, the two reactions can be
(13) Use of BINAP in the second step of the tandem reaction led to the
formation of increased amounts of N,N-diarylamino alkenes bearing two
different N-aryl substituents.
Org. Lett., Vol. 7, No. 13, 2005
2577

conducted sequentially in one-pot via an in situ ligand
exchange protocol that allows modification of the catalyst
structure after the first arylation. Further studies on the use
of in situ ligand exchange in sequential one-pot catalytic
processes and efforts to extend the scope of this transforma-
tion to allow for the synthesis of six- and seven-membered
nitrogen heterocycles are currently underway.
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 support was provided by Amgen, Eli Lilly, and
3M.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds
reported in the text. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank the University of
Michigan and the NIH-NIGMS (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
OL050647U
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Org. Lett., Vol. 7, No. 13, 2005