Palladium-catalyzed synthesis of N-aryl pyrrolidines from γ-(N-arylamino) alkenes: Evidence for chemoselective alkene insertion into Pd-N bonds

Article abstract of DOI:10.1002/anie.200460060

The formation of a C-C and a C-N bond in a reaction between γ-(N-arylamino) alkenes and aryl bromides results in the stereoselective synthesis of substituted pyrrolidine derivatives (see scheme). Preliminary studies suggest these reactions proceed by intramolecular alkene insertion into the Pd-N bond of intermediate [Pd(Ar)(amido)] complexes. dba = dibenzylideneacetone, dppb = 1,3-bis(diphenylphosphanyl) butane.

Full text of DOI:10.1002/anie.200460060

Angewandte
Chemie
Heterocycle Synthesis
Palladium-Catalyzed Synthesis of N-Aryl
Pyrrolidines from g-(N-Arylamino) Alkenes:
Evidence for Chemoselective Alkene Insertion
À
into Pd N Bonds**
Joshua E. Ney and John P. Wolfe*
In recent years, palladium(aryl)(amido) complexes have been
shown to serve as key intermediates in the synthesis of aniline
derivatives.[1] Although the propensity of these intermediates
À
to undergo C N bond-formingreductive elimination has
been well established,[1] small molecule (alkene) insertion
reactions of these complexes have been largely unexplored
and have not been exploited in catalytic processes.[2] In fact,
only a single example of the stoichiometric insertion of an
activated alkyne into an isolated [Pd(Ar)(NR2)] complex has
been reported,[2b] and insertions of alkenes have not been
demonstrated. Herein we describe a new, stereoselective,
palladium-catalyzed synthesis of pyrrolidines from g-(N-
arylamino) alkenes and aryl bromides, and present mecha-
nistic evidence that suggests the transformation proceeds by a
chemoselective intramolecular insertion of an unactivated
À
alkene into the Pd N bond of an intermediate
[Pd(Ar)(NRR’)] complex.[3] This reaction allows convergent
access to substituted pyrrolidines, which are found in a variety
of natural products.[4] In contrast to most methods available
for the synthesis of substituted pyrrolidines,[5] this reaction
À
effects intramolecular C N bond formation with concomitant
[6]
À
intermolecular formation of a C1’ C bond.
In preliminary studies we employed g-aminoalkene sub-
strates with N-aryl substituents because of their ease of
preparation and handling. After optimization of the reaction
conditions we found that the reaction of N-phenyl-4-pente-
nylamine (1a) with 2-bromonaphthalene in the presence of
NaOtBu and
a catalytic amount of [Pd2(dba)3]/dppb
(1 mol%; dppb = 1,4-bis(diphenylphosphanyl)butane) at
608C in toluene afforded the desired N-aryl 2-(b-naphthyl-
methyl)pyrrolidine 2a and regioisomeric product 3a in 94%
yield and a 25:1 ratio [Eq. (1)].
As shown in Table 1, the reactions of electron-rich,
electron-neutral, and electron-deficient N-aryl amine deriv-
atives with a variety of aryl bromide couplingpartners
proceeded in good yield. A number of functional groups are
[*] J. E. Ney, Prof. J. P. Wolfe
University of Michigan
Department of Chemistry
Ann Arbor, MI 48109-1055 (USA)
Fax: (+1)734-763-2307
E-mail: jpwolfe@umich.edu
[**] This research was supported by the University of Michigan. J.P.W.
thanks The Dreyfus Foundation for a New Faculty Award and
Research Corporation for an Innovation Award. J.E.N. thanks the
University of Michigan for a Regents Fellowship. Additional
unrestricted support was provided by Eli Lilly, 3M, and Amgen.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3605 –3608
DOI: 10.1002/anie.200460060
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3605

Communications
tolerated, includingnitriles, nonenolizable ketones, and
acetals. The main side products in these reactions are arenes
that result from reduction of the aryl bromide[7] and N,N-
diaryl amines that presumably form through Pd-catalyzed N-
arylation of the substrate.[1] Side products resultingfrom Heck
arylation of the alkene are generally not observed. These
results contrast with those of previously described Pd-
catalyzed reactions of g-(N-benzylamino)al-
kenes with aryl iodides, which have been
reported to afford exclusively products
Table 1: Palladium-catalyzed synthesis of pyrrolidines.[a]
resultingfrom Heck arylation of the
Entry
Amine
Aryl bromide
Product
2/3
Yield [%]
alkene.[8]
In most cases examined the cyclizations
proceed with good levels of diastereoselec-
1
16:1
73
tivity. The 3-substituted alkenyl amine 1g
underwent cyclization with > 20:1 diaster-
eoselectivity to provide the trans-2,3-disub-
stituted product 2l (Table 1, entry 11),[9] and
reactions of the 1-substituted alkenyl
amines 1d and 1e gave the cis-2,5-disubsti-
tuted pyrrolidines 2i and 2j with d.r. > 20:1
(Table 1, entries 8–9). In contrast, the C2-
substituted amine 1 f reacted with only
modest (2:1) cis stereoselectivity for the
2,4-disubstituted product 2k (Table 1,
entry 10).
2
3
1a
1a
17:1
81[b]
100:1
45
4
5
14:1
35:1
67
75
The ratio of the regioisomeric products
2/3 of the cyclization reactions typically
ranged from 10:1 to 25:1 for substrates with
terminal alkenes, although in some instan-
ces selectivities of up to > 100:1 were
observed.[10] However, reactions of sub-
strates with internal alkenes provided com-
plex mixtures of regioisomeric products.
Interestingly, the reaction of 4 with 4-
bromobiphenyl in the presence of catalytic
[Pd2(dba)3]/P(o-tol)3 afforded a mixture of
four products [Eq. (2)].[11] The desired 6-
aryl pyrrolizidine product 6 was formed as
1b
6
100:1
78
86
7
1c
>100:1
10:1
the major regioisomer.
A
substantial
66[c]
(d.r.>20:1)
amount of the 5-aryl regioisomer 7 was
also isolated, alongwith a small amount of
the unsaturated pyrrolizidine 8. The use of
dppb or dppe as a ligand led to the
formation of increased amounts of 8 relative
to the other products.[11,12]
8
72[c]
(d.r.>20:1)
9
10:1
Although the yield of the desired
regioisomer 6 is modest, these results pro-
vide important information about the mech-
anism of the cyclization reaction. This trans-
formation presumably occurs through initial
oxidative addition of the aryl bromide to
Pd0 followed by reaction of the resulting
complex with the substrate and base to
afford 9 (Scheme 1).[1] A syn insertion of the
88[c]
(d.r. 2:1)
10
8:1
68[c,d]
(d.r.>20:1)
11
10:1
[a] Conditions: amine (1.0 equiv), ArBr (1.1–1.3 equiv), NaOtBu (1.1–1.3 equiv), [Pd2(dba)3] (1 mol%),
dppb (2 mol%), toluene (0.25m), 608C. [b] This material contained a second, unidentified regioisomer
in approximately 3% yield. [c] Reaction conducted at 1008C; dppe used in place of dppb. [d] This
material contained N-(PMP)-2-(3-methoxybenzyl)-3-phenylpyrrole in approximately 8% yield. dppe=
1,4-bis(diphenylphosphanyl)ethane, PMP=4-methoxyphenyl.
À
alkene into the Pd C bond of 9 would
provide 10. However, products 7 and 8 can
À
not derive from 10; C C bond-forming
alkene-insertion reactions are generally
3606
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 3605 –3608

Angewandte
Chemie
4 with 4-bromobiphenyl provides the first probe
of the chemoselectivity of insertion under
catalytic conditions; the most plausible pathway
for the conversion of 4 into 7 and 8 involves
À
olefin insertion into a Pd N bond. Further
studies on the scope, limitations, applications,
and mechanism of these reactions are currently
underway.
Received: March 19, 2004 [Z460060]
Keywords: alkene insertion · aryl halides · diastereoselectivity ·
.
nitrogen heterocycles · palladium
À
[1] For reviews on aryl C N bond-formingreactions that involve
Pd(Ar)(NR2) intermediates, see: a) A. R. Muci, S. L. Buchwald,
Top. Curr. Chem. 2002, 291, 131 – 209; b) J. F. Hartwig, Pure
Appl. Chem. 1999, 71, 1417 – 1423.
[2] a) J. M. Boncella, L. A. Villanueva, J. Organomet. Chem. 1994,
465, 297 – 304; b) L. A. Villanueva, K. A. Abboud, J. M. Bon-
cella, Organometallics 1992, 11, 2963 – 2965.
Scheme 1. Proposed mechanism.
[3] For related studies on the synthesis of tetrahydrofurans, see: J. P.
Wolfe, M. A. Rossi, J. Am. Chem. Soc. 2004, 126, 1620 – 1621.
[4] a) D. OꢀHagan, Nat. Prod. Rep. 2000, 17, 435 – 446; b) J. R.
Lewis, Nat. Prod. Rep. 2001, 18, 95 – 128.
[5] a) A. Mitchinson, A. Nadin, J. Chem. Soc. Perkin Trans. 1 2000,
2862 – 2892; b) M. Pichon, B. Figadere, Tetrahedron: Asymmetry
1996, 7, 927 – 964.
not reversible.[13] Furthermore, if the alkene underwent
insertion into the metal–carbon bond to give 10, the use of
ligands that decrease the rate of reductive elimination, such as
dppe,[12] would not provide increased amounts of 8 as is
observed. A syn b-hydride elimination[13] of the intermediate
10 would instead afford the arylated imine 11, which is not
detected.[11]
À
[6] For pyrrolidine syntheses that involve intramolecular C N bond
À
formation and intermolecular C C bond formation, see: a) Y.
Tamaru, M. Kimura, Synlett 1997, 749 – 757; b) Y. Tamaru, M.
Hojo, Z.-i. Yoshida, J. Org. Chem. 1988, 53, 5731 – 5741; c) H.
Yorimitsu, K. Wakabayashi, H. Shinokubo, K. Oshima, Bull.
Chem. Soc. Jpn. 2001, 74, 1963 – 1970; d) R. C. Larock, H. Yang,
S. M. Weinreb, R. J. Herr, J. Org. Chem. 1994, 59, 4172 – 4178.
[7] Imine side products presumably formed through b-hydride
elimination of an intermediate [Pd(Ar)(NR2)] complex are
occasionally observed; see reference [1].
A more reasonable pathway, which would account for all
products formed in the reaction, involves syn insertion of the
[2]
À
alkene into the Pd N bond in 9 to afford 12 (Scheme 1).
À
Complex 12 could either undergo C C bond-formingreduc-
tive elimination with retention of configuration to afford the
desired product 6,[14] or could undergo reversible b-hydride
elimination to give the alkene complex 13.[13] Reinsertion of
[8] G. Fournet, G. Balme, J. Gore, Tetrahedron 1990, 46, 7763 – 7774.
[9] Diastereomeric ratios were determined by 1H NMR spectros-
copy and/or GC analysis of the crude reaction mixture. The
stereochemistry of the products was assigned on the basis of
1H NMR NOE experiments and/or by analogy with related
compounds of known configuration.
[10] The reaction of 2-bromonaphthalene with N-(4-methoxy-
phenyl)-3-pentenylamine under the standard reaction conditions
afforded only the product of N-arylation; no cyclized products
were observed. This result suggests that the regioisomeric
products are not formed through initial isomerization of the
alkene substrate followed by 5-endocyclization.
À
the alkene into the Pd H bond with reversal of regiochem-
istry would afford 14,[15] which would yield the regioisomeric
side product 7 followingreductive elimination. Dissociation
of the alkene complex 13 before reinsertion would provide 8.
À
The N-arylated product 5 is presumably formed through C N
bond-formingreductive elimination of 9.[1] This mechanistic
pathway is also consistent with observed ligand effects:
ligands that decrease the rate of reductive elimination
afford increased amounts of products derived from the
proposed intermediate 13.
[11] 1H NMR spectroscopic analysis of the reaction mixture showed
that the products 5, 6, 7, and 8 were formed in a ratio of 6:7:2:1.
The use of dppe as a ligand led to a 2:1:2:4 ratio of 5/6/7/8, and
the use of dppb as a ligand afforded a 2:2:2:1 mixture of 5/6/7/8.
[12] The ligands dppe and dppb have been shown to decrease the rate
Examples of the insertion of alkenes into palladium–
nitrogen bonds are rare,[2,16] and only two catalytic reactions
that proceed by alkene insertion into a Pd(NRR’)X complex
(X = Cl,[16a] OC(O)C6F5[16b]) have been described.[17–19] The
insertion of unactivated alkenes into [Pd(Ar)(NR2)] com-
plexes has not been reported.
In conclusion, we have developed a new, stereoselective
synthesis of pyrrolidines from g-(N-arylamino) alkenes. The
transformations described herein are the first examples of
catalytic reactions that most likely proceed by the chemo-
selective intramolecular insertion of an alkene into a
[Pd(Ar)(NRR’)] intermediate. Furthermore, the reaction of
À
À
of C C and C N bond-formingreductive elimination and
increase the formation of side products by competing b-hydride
elimination; see: a) A. Gillie, J. K. Stille, J. Am. Chem. Soc. 1980,
102, 4933 – 4941; b) M. S. Driver, J. F. Hartwig, J. Am. Chem.
Soc. 1997, 119, 8232 – 8245; c) J. P. Wolfe, S. L. Buchwald, J. Org.
Chem. 2000, 65, 1144 – 1157.
[13] I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009 –
3066.
[14] D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4981 – 4991.
Angew. Chem. Int. Ed. 2004, 43, 3605 –3608
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3607

Communications
[15] H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125, 2056 –
[18] For examples of insertion reactions of activated alkenes into
platinum–nitrogen bonds, see: a) R. L. Cowan, W. C. Trogler,
Organometallics 1987, 6, 2451 – 2453; b) R. L. Cowan, W. C.
Trogler, J. Am. Chem. Soc. 1989, 111, 4750 – 4761.
[19] For an example of a catalytic reaction that proceeds through the
insertion of norbornene into an iridium–nitrogen bond, see:
A. L. Casalnuovo, J. C. Calabrese, D. Milstein, J. Am. Chem. Soc.
1988, 110, 6738 – 6744.
2057.
[16] a) J. Helaja, R. Gꢁttlich, Chem. Commun. 2002, 720 – 721; b) H.
Tsutsui, K. Narasaka, Chem. Lett. 1999, 45 – 46
[17] The treatment of trans-[PdH(NHPh)(P(C6H11)3)2] with ethylene
or acrylonitrile led to reductive elimination of aniline rather than
alkene insertion: A. L. Seligson, R. L. Cowan, W. C. Trogler,
Inorg. Chem. 1991, 30, 3371 – 3381.
3608
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 3605 –3608