Direct aminoalkylation of arenes and hetarenes via Ni-catalyzed negishi cross-coupling reactions

Article abstract of DOI:10.1021/ol702499h

A direct room-temperature Ni-catalyzed cross-coupling of aminoalkylzinc halides, readily available from the corresponding aminoalkyl chlorides via Grignard reagents, with aryl and hetaryl electrophiles, allows a convenient one-step preparation of aminoalk

Full text of DOI:10.1021/ol702499h

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5529-5532
Direct Aminoalkylation of Arenes and
Hetarenes via Ni-Catalyzed Negishi
Cross-Coupling Reactions
Laurin Melzig, Andrey Gavryushin, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received October 12, 2007
ABSTRACT
A direct room-temperature Ni-catalyzed cross-coupling of aminoalkylzinc halides, readily available from the corresponding aminoalkyl chlorides
via Grignard reagents, with aryl and hetaryl electrophiles, allows a convenient one-step preparation of aminoalkyl (het)arenes, bearing a basic
tertiary nitrogen in the side chain, including piperidine and tropane derivatives. Such aminoalkylarene scaffolds are widely present in various
biologically active molecules.
The aminoalkyl moiety is one of the most frequently
occurring functionalities in biologically active molecules.1
Basic trialkylamine groups are one of the most important
pharmacophores.2 Of great interest would be a method
allowing a simple and direct introduction of an amino-
alkyl moiety into a molecule.3 For aryl and hetaryl com-
pounds this task can be accomplished by using cross-coupling
chemistry. While many reports dealing with cross-coupling
of alkylmetal derivatives bearing an amide or sulfonamide
nitrogen have been published,4 no coupling reaction of
an aminoalkyl organometallic species (except boron) pos-
sessing a basic nitrogen is known so far. Very recently,
Molander described a direct coupling of aminoalkyl groups
to arenes and hetarenes by a Pd-catalyzed cross-coupling
reaction of potassium aminoalkyltrifluoroborates. He dem-
onstrated the high potential of this method for the synthesis
of biologically active molecules.5 Those reagents, however,
often require a multistep preparation, and the reaction is so
far limited to primary alkylamines. Herein, we report a
novel aminoalkylation protocol, based on a Ni-catalyzed
cross-coupling reaction between aminoalkylzinc compounds
(1) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug
Synthesis; Wiley: New York, 1997; Vol. 7.
(2) Muegge, I.; Britelli, D.; Held, S. L. J. Med. Chem. 2001, 44, 1841.
(3) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1999, 42, 5095.
(4) Amidoalkylzinc coupling: (a) Duddu, R.; Eckhardt, M.; Furlong, M.;
Knoess, H. P.; Berger, S.; Knochel, P. Tetrahedron, 1994, 50, 2415. (b)
Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J.
Org. Chem. 1992, 57, 3397. (c) Hunter, C.; Jackson, R. F. W.; Rami, H. K.
J. Chem. Soc., Perkin Trans. 1, 2000, 219. (d) Corley, E. G.; Conrad, K.;
Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org. Chem. 2004, 69,
5120. (e) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538. Alkyllithium coupling: (f)
Barluenga, J.; Montserrat, J. M.; Flo´rez, J. J. Org. Chem. 1993, 58, 5976.
Boron coupling: (g) Kamatani, A.; Overman, L. J. Org. Chem. 1999, 64,
8793. Tin coupling: (h) Jensen M. S.; Yang, C.; Hsiao, Y.; Rivera, N.;
Wells, K. M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. Org.
Lett. 2000, 2, 1081.
(5) (a) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203. (b) Molander,
G. A.; Sandrock, D. Org. Lett. 2007, 9, 1597.
(6) For the beneficial effect of LiCl in the preparation of organ-
omagnesium and organozinc compounds, see: (a) Krasovskiy, A.;
Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2005, 45,
159. (b) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 497. (c) Krasovskiy, A.; Malakhov, V.; Gavryushin,
A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 6040. See also ref
14b.
10.1021/ol702499h CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

and various aryl and heteroaryl bromides, chlorides, and
triflates. This method allows a direct introduction of both
primary and secondary aminoalkyl groups possessing a basic
nitrogen.
Table 1. Ligand Screening in the Cross-Coupling Reaction of
3-Dimethylaminopropylzinc Halide with 3-Bromoanisole
Treatment of commercial 3-dimethylaminopropyl chloride
hydrochloride with an excess of LiH in THF followed by
filtration gave a dry solution of the corresponding base,
suitable for the preparation of a Grignard reagent. The
insertion of magnesium metal in the presence of LiCl6 (2
equiv) and DIBAL-H7 (3 mol %) in THF afforded the
corresponding organomagnesium compound in 82% yield,
as was determined by the iodometric titration.8 A transmeta-
lation using ZnBr2 (2.0 M ZnBr2 in THF-NMP)9 gave
3-dimethylaminopropylzinc halide 1a (Scheme 1).
ratio Ni to
ligand
yield of 2
(%)
entry
ligand
1
2
3
4
5
6
7
dppp
1:1
1:1
1:2
1:3
1:3
1:4
1:3
33
17
50
73
79
87
88
IPr-HCl
n-BuPAd2
P(Oi-Pr)3
Ph3P
p-Tol3P
8
9
10
t-Bu3P
DPE-Phos
DPE-Phos
1:2
1:1
1:2
12
93
97
Scheme 1. Preparation of 3-Dimethylaminopropylzinc Halide
protocol, aminoalkylzinc reagents 1a-1d were prepared
starting from commercially available hydrochlorides (for 1b-
1d), and from tropanol (for 1e). Noteworthy, the solutions
of the corresponding aminoalkylmagnesium chlorides in THF
are relatively stable and can be stored at 0 °C (titration after
6 months revealed loss of the active magnesium species less
than 20%).
Initial attempts to employ Pd-catalysts, previously used
to perform sp3-sp2 Negishi cross-couplings,10-13 were not
very promising. Only traces of the cross-coupling product
were detected using Pd(dba)2 (3 mol %) and PPh3, o-Tol3P,10
t-Bu3P,11 or tri-(2-furyl)phosphine12 in the model reaction
of the zinc reagent 1a with m-bromoanisole (2a), while Pd-
(dppf)Cl213 gave 3a in 37% yield at 25 °C after 16 h. Bearing
in mind the high activity of Ni-catalysts in the Negishi cross-
coupling,9,14 we have screened several common phosphine
ligands in the presence of Ni(acac)2 (2.5 mol %). Among
the ligands screened, bis-(2-diphenylphosphinophenyl)ether
(DPE-Phos) gave the best results, affording the cross-
coupling product 3a in almost quantitative yield (Table 1).
Further optimization revealed that the optimal ratio of the
ligand to nickel was 2:1, and the optimal amount of ZnBr2
was 2 mol per mol of the Grignard reagent. Having
established the optimized conditions for the cross-coupling
reaction, we investigated the behavior of other primary and
secondary aminoalkylzinc reagents. Following the same
Cross-coupling of the prepared aminoalkylzinc derivatives
under the optimized conditions proceeded smoothly with a
broad range of aryl and heteroaryl bromides, chlorides, and
triflates. In most cases, the reaction was completed within
1-3 h at 25 °C, giving the products of type 3 in 78-98%
yield (Table 2). The isolation of the aminoalkyl arenes is
very facile and usually consists of an acid-base extraction
with ether, affording pure compounds by NMR and GC-
MS analysis. To our delight, the reaction with secondary
aminoalkyl zinc species proceeded equally well and furnished
only slightly lower yields (Table 2, entries 12-17). Note-
worthy, triflates are also suitable substrates for this coupling
reaction (entries 14 and 17), making possible the transforma-
tion of a phenol function into an aminoalkyl group. The
reaction conditions tolerate various functionalities such as
an ester, a nitrile, and a keto group. Interestingly, the cross-
coupling of 8-methyl-8-azabicyclo[3.2.1]octylzinc species
gives exclusively exo-3-aryltropanes, as was confirmed by
NOESY experiments15 (Scheme 2, Table 2, entries 15-17).
(7) Tistam, U.; Weinmann, H. Org. Proc. Res. DeV. 2002, 6, 906.
(8) Krasovskiy, A.; Knochel, P. Synthesis 2006, 5, 890.
(9) (a) Gavryushin, A.; Kofink, C.; Manolikakes, G.; Knochel, P. Org.
Lett. 2005, 7, 4871. (b) Gavryushin, A.; Kofink, C.; Manolikakes, G.;
Knochel, P. Tetrahedron 2006, 62, 7521.
(10) Boudier, A.; Knochel, P. Tetrahedron Lett. 1999, 40, 687.
(11) Dai, C.; Fu, G. J. Am. Chem. Soc. 2001, 123, 2719.
(12) (a) Rottla¨nder, M.; Knochel, P. Synlett, 1997, 1084. (b) Dohle, W.;
Staubitz, A.; Knochel, P. Chem. Eur. J. 2003, 5323.
(13) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
Scheme 2. One-Step Synthesis of exo-3-Aryltropanes
(14) (a) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999, 121,
5819. (b) Lipshutz, B. H.; Blomgren, P. A.; Kim, S.-K. Tetrahedron Lett.
1999, 40, 197.
(15) Mu, L.; Drandarov, K.; Bisson, W. H.; Schibig, A.; Wirz, C.;
Schubiger, P. A.; Westera, G. Eur. J. Med. Chem. 2006, 41, 640.
(16) For a recent discussion on the configurational stability of Grignard
reagents during their preparation and reactions, see: Beckmann, J.;
Dakternieks, D.; Draeger, M.; Duthie, A. Angew. Chem., Int. Ed. 2006, 45,
6509. Secondary alkylzinc compounds are known to undergo cross-coupling
with retention of configuration: Boudier, A.; Knochel, P. Tetrahedron Lett.
1999, 40, 687.
This selectivity originates from the stereospecific formation
of the corresponding Grignard reagent, as the cross-coupling
reaction proceeds with retention of configuration.16
5530
Org. Lett., Vol. 9, No. 26, 2007

Table 2. Ni-Catalyzed Cross-coupling Reaction of Aminoalkylzinc Reagents (1) with Aryl and Heteroaryl Electrophiles (2)
a Reagents and conditions: 2a-k (1.0 mmol), 1a-e (1.2 equiv), ZnBr2 (2.0 M in THF, 2 equiv), Ni(acac)2 (2.5 mol %), DPE-Phos (5 mol %), THF-
NMP (9:1), 25 °C, followed by the acid-base extractive workup. The yields are given for the isolated compounds of >97% purity by NMR and GC. b For
the preparation of aminoalkylzinc halides, see Supporting Information. c Yield after a chromatographical purification. d Only exo-product isolated.
Org. Lett., Vol. 9, No. 26, 2007
5531

In summary, we have developed a general method for the
one-pot installation of aminoalkyl groups, including cyclic
derivatives like piperidine and tropane, into an arene or
hetarene, using a Ni-catalyzed Negishi cross-coupling reac-
tion of aminoalkylzinc reagents, which are easily available
from the corresponding aminoalkyl chlorides. This approach
allows a fast and convenient construction of “drug-like”
molecules, possessing an aromatic system and a basic tertiary
nitrogen, using a simple one-pot protocol. Further develop-
ment of this method is currently underway in our laboratories.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFG, and Merck Research Laboratories (MSD)
for financial support. We also thank Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for the generous
gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and characterization of the compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702499H
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Org. Lett., Vol. 9, No. 26, 2007