Jean et al.
tions, and its tolerance for a wide range of functional
groups. Although less studied, nickel-catalyzed arylami-
nations have received increasing attention over the past
years and can offer an alternative to the use of costly
palladium derivatives. Different nickel-based catalysts
have been developed: Ni(COD)2 (COD ) cyclooctadiene)
associated with 1,1′-bis(diphenylphosphino)ferrocene
(DPPF) or 1, 10-phenanthroline,27 Ni(0)/C-DPPF,28 N-
heterocyclic carbenes,29 or Ni(0)-2,2′-bipyridine.30 This
latter was shown to be efficient for selective monoami-
nation of aryl di- and trichlorides31 and for sequential
arylation of piperazines.32 Copper-catalyzed aminations
of aryl halides is another attractive method due to the
low cost of copper salts. Recent works have shown that
copper (I) iodide is the preferred catalyst to prepare
enantiopure amino acid derivatives from amino acids and
aryl halides.33,34 In conjunction with potassium phosphate
and glycol, it allowed the coupling of alkylamines and
aryl iodides35 whereas copper(I) oxide in a glycol solution
of ammonia was more suitable for the amination of
bromopyridines.36
The coupling of aryl halides with 3-aminopyrrolidines
or 3-aminopiperidines has been only scarcely docu-
mented. To the best of our knowledge, the only described
example concerns the synthesis of ligands 4 and 5 of
gastrin and cholestokinin receptors (Figure 1).5 The
arylation of N-Boc-3-aminopyrrolidine 8 or N-Boc-3-
aminopiperidine 10, using the combination Pd(OAc)2/
BINAP/Cs2CO3/toluene, afforded the desired compounds
in low yields (11% and 2.5% after removal of the Boc
protection). 3-Aminopyrrolidines 6-8 or 3-aminopip-
eridines 9-10 (Figure 2) being easily available on a large
scale,37 we have envisaged the use of a cross-coupling
methodology to access rapidly to 3-(N-arylamino)pyrro-
lidines 11-13 and piperidines 14 and 15 (Scheme 1 and
Figure 3). In this paper, we report that arylation of the
secondary cyclic amine of unprotected 3-aminopyrrolidine
1 and 3-aminopiperidine 2 is highly selective whatever
FIGURE 1. 3-Aminopiperidine and pyrrolidine and related
complexes or compounds.
new chiral bases for asymmetric reactions,17 we have
undertaken a search for a reliable synthesis of 3-(N-
arylamino)pyrrolidines and 3-(N-arylamino)piperidines.
Numerous procedures have been reported for the prepa-
ration of these compounds including cyclization of amino
acids18 or cyclization of triols and related compounds,19
reductive amination of pyrrolidinones or piperidi-
nones,1b,9,10,20 nucleophilic substitution of halides21 or
sulfonates,3,22 Mitsunobu reaction,1a and SNAr reac-
tions.5d,7,23 Each synthesis has some limitations: (a)
reductive amination requires either a costly ketone or a
reactive amine, (b) nucleophilic substitution suffers from
low yields or harsh reaction conditions, and (c) SNAr
reactions are only possible with electron-poor arenes
bearing a good leaving group (i.e., fluorine).
Migita and co-workers,24 then Buchwald and Hartwig
independently25,26 have demonstrated the scope of the
palladium-catalyzed arylation of amines, its mild condi-
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