have been used to overcome this issue. Thus, allylamine,5
benzophenone imine,6,7 tert-butyl carbamate8 Li[N(SiMe3)2],9
and Zn[N(SiMe3)2]10 have been found as suitable masked forms
of ammonia in cross-coupling amination reactions.
Solid-supported ammonia surrogates have also been used in
Pd(0)-catalyzed amination reactions showing the advantage of
an easy separation of the primary aniline precursors from the
reaction byproducts. The final arylamines were obtained after
the cleavage step with high purities and reasonable yields.11
Very recently a fluoroalkyl benzophenone imine reagent f-BPI
has been used as an ammonia source (Scheme 1).12,13
Fluorous-Tagged Carbamates for the
Pd-Catalyzed Amination of Aryl Halides
Andre´s A. Trabanco,* Juan A. Vega, and
M. Alejandro Ferna´ndez
Johnson and Johnson Pharmaceutical Research and
DeVelopment, Research and Early DeVelopment Europe,
CNS-Psychiatry, DiVision of Janssen-Cilag, Medicinal
Chemistry Department, Jarama 75, 45007 Toledo, Spain
SCHEME 1. Synthesis of Primary Anilines Using f-BPI as
an Ammonia Surrogate
ReceiVed July 19, 2007
A novel fluorous-tagged ammonia surrogate has been
synthesized and its application to the synthesis of anilines
by Buchwald-Hartwig palladium-catalyzed amidation-hy-
drolysis protocol is described. Primary anilines were obtained
in moderate to good yields after a sequence of two reaction
steps involving fluorous separation techniques for their
purification. Preliminary results indicate that N-substituted
anilines can also be obtained using just N-substituted-FBoc
carbamates as the nitrogen source.
The use of this fluorous-tagged ammonia equivalent allowed
the purification of both N-arylimine intermediates A and the
final primary anilines B by fluorous solid-phase extraction (F-
SPE).14 To the best of our knowledge, this is the only reported
example of Pd(0)-catalyzed amination reactions using fluorous-
tagged amines.15
The synthesis of fluorous Boc (FBoc) carbamates has been
recently described by Curran et al., and it has been applied to
the library production of amides, benzimidazoles, and quinox-
alinones.16
Anilines are valuable building blocks that are used as
intermediates or additives for the production of dyes, pigments,
and agrochemical or pharmaceutical products.1 Their synthesis
has always been a topic of interest in organic chemistry, and
although many methods are available, the discovery of new and
improved methodology is still of interest. Among others, the
Buchwald-Hartwig palladium-catalyzed amination of aryl
halides/triflates has emerged in the last decades as a powerful
tool for the synthesis of arylamines.2 While a large variety of
amines and nitrogen nucleophiles undergo this reaction, the use
of ammonia as the coupling partner does not afford the
corresponding primary anilines.3,4 Several ammonia surrogates
With these precedents in mind, and with the aim of finding
a fluorous tag that would allow a more general amination
(4) For an alternative using Cu-catalyzed amination, see: Lang, F.;
Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42, 3251.
(5) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.
Tetrahedron Lett. 1998, 39, 1313.
(6) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett. 1997, 38, 6367.
(7) For the use of aldimines, see: Barluenga, J.; Aznar, F.; Valdes, C.
Angew. Chem., Int. Ed. 2004, 43, 343.
(8) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (b) Yin, J.; Buchwald,
S. L. Org. Lett. 2000, 2, 1101.
* Corresponding author. Fax: +34 925 23 57 71.
(9) (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(b) Huang, X. H.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
(10) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(11) (a) Weigand, K.; Pelka, S. Org. Lett. 2002, 4, 4689. (b) Weigand,
K.; Pelka, S. Mol. DiVersity 2003, 7, 181.
(12) Cioffi, C. L.; Berlin, M. L.; Herr, J. Synlett 2004, 5, 841.
(13) For recent reviews on fluorous chemistry, see: (a) Zhang, W.
Tetrahedron 2003, 59, 4475. (b) Curran, D. P. In The Handbook of Fluorous
Chemistry; Gladysz, J. A., Curran, D. P., Horwath, I. T., Eds.; Wiley-VCH,
Weinheim, 2004.
(14) For a recent review on fluorous solid-phase extraction, see: Zhang,
W.; Curran, D. P. Tetrahedron 2006, 62, 11837 and references cited therein.
(15) For an example of cross-coupling reactions of aryl perfluorooc-
tanesulfonates with amines, see: Zhang, W.; Nagashima, T. J. Fluorine
Chem. 2006, 127, 588.
(16) (a) Luo, Z.; Williams, J.; Read, R. W.; Curran, D. P. J. Org. Chem.
2001, 66, 4261. (b) Zhang, W.; Tempest, P. Tetrahedron Lett. 2004, 45,
6757.
(1) (a) Weissermel, K.; Arpe, H. J. Industrial Organic Chemistry; Wiley-
VCH: Weinheim, Germany, 1997. (b) Lawrence, S. A. Amines: Synthesis,
Properties and Application; Cambridge University Press: Cambridge, 2004.
(c) Suwanprasop, S.; Nhujak, T.; Roengsumran, S.; Petsom, A. Ind. Eng.
Chem. Res. 2004, 43, 4973.
(2) For recent reviews on palladium-catalyzed aryl amination, see: (a)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Hartwig, J. F. In
Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000;
p 195. (c) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E. I., Ed.; Wiley-Interscience: New York, 2002;
p 1051. (d) Mucci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (e) Hartwig, J. F. Synlett 2006, 1238.
(3) (a) Park, S.; Rheingold, A. L.; Roundhill, D. M. Organometallics
1991, 10, 615. (b) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995,
14, 3030. (c) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996,
15, 2755. (d) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028.
(e) Willis, M. C. Angew. Chem., Int. Ed. 2007, early view.
10.1021/jo701573w CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/18/2007
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J. Org. Chem. 2007, 72, 8146-8148