Synthesis of 2-anilinotropones via palladium-catalyzed amination of 2-triflatotropone

Article abstract of DOI:10.1021/ol991310t

(matrix presented) 9 examples, 36 - 90% yield A series of 2-anilinotropones were synthesized via the palladium-catalyzed cross coupling of 2-triflatotropone and a wide variety of anilines, sterically hindered as well as electron-poor ones.

Full text of DOI:10.1021/ol991310t

ORGANIC
LETTERS
2000
Vol. 2, No. 2
219-221
Synthesis of 2-Anilinotropones via
Palladium-Catalyzed Amination of
2-Triflatotropone
Frederick A. Hicks and Maurice Brookhart*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, 27599
mbrookhart@unc.edu
Received December 6, 1999
ABSTRACT
A series of 2-anilinotropones were synthesized via the palladium-catalyzed cross coupling of 2-triflatotropone and a wide variety of anilines,
sterically hindered as well as electron-poor ones.
The chemistry of tropone derivatives has been a rich field
of research for half a century due to inherent interest in their
homoaromatic character and their presence in a number of
biologically active natural compounds such as colchicine.1
In particular, extensive investigations into the nucleophilic
substitution chemistry of tropone derivatives have revealed
complex reactivity patterns. For instance, tropones with a
leaving group X in the 2-position, 1, may produce com-
pounds arising from attack at the 1-, 2-, 3-, 6-, or 7-position
or admixtures thereof.2 The site of attack is often difficult
utilizing the nucleophilic substitution of tropone derivatives
in a synthetic sequence is an uncertain endeavor.
As part of a program focusing on the development of new
ligands for transition metal chemistry, we attempted to
synthesize a series of 2-anilinotropones 2 via nucleophilic
substitution of the corresponding 2-tosyloxytropone. How-
ever, we were only able to obtain a trace of the desired
product, 2, using sterically hindered 2,6-diisopropylaniline
(eq 1). Instead we isolated predominantly the benzenoid
(1)
to predict and is dependent on the nature of the leaving group
X, the nucleophile, and the nature and position of other
substituents on the tropone ring. While this diversity of
chemistry is interesting from a mechanistic perspective,
rearrangement product, 3,3 derived from attack of the aniline
at the 3-position.4 On the basis of the work of Buchwald5
(3) Chang, S.; Jones, L., II; Wang, C.; Henling, L. M.; Grubbs, R. H.
Organometallics 1998, 17, 3460.
(4) Mukai, T. Bull. Chem. Soc. Jpn. 1959, 32, 272.
(5) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125.
(1) Pietra, F. Chem. ReV. 1973, 73, 293.
(2) (a) Ito, S.; Tsunetsugu, J.; Kanno, T.; Sugiyama, H.; Takeshita, H.
Tetrahedron Lett. 1965, 3659. (b) Biggi, G.; Cima, F. D.; Pietra, F. J. Am.
Chem. Soc. 1973, 95, 7101. (c) Biggi, G.; de Hoog, A. J.; Cima, F. D.;
Pietra, F. J. Am. Chem. Soc. 1973, 95, 7108.
10.1021/ol991310t CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/23/1999

and Hartwig6 on the palladium-catalyzed cross coupling of
amines with aryl halides and triflates, we considered the
possibility of a palladium-catalyzed cross coupling of the
aniline and a 2-halo- or triflatotropone. While the synthetic
utility of transition metal-catalyzed cross couplings employ-
ing halo- and triflatotropones to form carbon-carbon bonds
has been demonstrated in recent years7 no reports of related
carbon-heteroatom bond formation have yet appeared.8 We
considered this approach an appealing alternative to the lack
of control often associated with the nucleophilic substitution
reactions of tropones and report its successful implementation
herein.
Table 1. Synthesis of 2-Anilinotropones
It was found that 2-triflatotropone7g could be cleanly
coupled with a variety of anilines under conditions similar
to those employed with aryl triflates (eq 2).9-11 This method
(2)
is applicable to the synthesis of sterically hindered derivatives
substituted in the 2,6-position of the aniline as indicated in
entries 1 and 2 of Table 1. To test the limitations of this
methodology with respect to steric influences, the coupling
of a series of increasingly hindered anilines was investigated.
While 2-tert-butylaniline (entry 3) could be utilized without
incident, attempts to effect cross couplings with the more
hindered 2-tert-butyl-6-methylaniline and 2,6-diphenylaniline
(entries 4 and 5) led to product formation in noticeably
decreased yield. These anilines seem to represent the upper
(6) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Hartwig,
J. F. Acc. Chem. Res. 1998, 31, 852.
(7) Heck coupling: (a) Horino, H.; Inoue, N.; Asao, T. Tetrahedron Lett.
1981, 22, 741. (b) Horino, H.; Inoue, N.; Asao, T. Bull. Chem. Soc. Jpn.
1991, 64, 183. Suzuki coupling: (c) Nair, V.; Powell, D. W.; Suri, S. C.
Synth. Commun. 1987, 17, 1897. (d) Suri, S. C.; Nair, V. Synthesis 1990,
695. Stille coupling: (e) Banwell, M. G.; Collis, M. P.; Crisp, G. T.;
Lambert, J. N.; Reum, M. E.; Scoble, J. A. J. Chem. Soc., Chem. Commun.
1989, 616. (f) Banwell, M. G.; Cameron, J. M.; Collis, M. P.; Crisp, G. T.;
Gable, R. W.; Hamel, E.; Lambert, J. N.; Mackay, M. F.; Reum, M. E.;
Scoble, J. A. Aust. J. Chem. 1991, 44, 705. Carbonylative coupling: (g)
Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110, 1557. Aryl
zinc coupling: (h) Keenan, R. M.; Kruse, L. I. Synth. Commun. 1989, 19,
793. (i) Iyoda, M.; Sato, K.; Oda, M. Tetrahedron Lett. 1987, 28, 625.
(8) One example involving the use of a catalytic amount of Cu(OAc)2
to promote phenolic substitution with 3-bromotropolone (yield increased
from 49% uncatalyzed to 90%) has been reported. Takase, K. Bull. Chem.
Soc. Jpn. 1964, 37, 1288.
(9) A° hman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(10) Control reactions were conducted involving the cross coupling
conditions in the absence of palladium. For 2-tosyloxytropone, only the
rearranged product 3 was observed. For 2-triflatotropone, only unreacted
aniline could be isolated at the end of the reaction.
limit with regard to steric hindrance as attempts to couple
2,4,6-tri-tert-butylaniline failed with this catalyst system. The
ability to employ 2,6-dihaloanilines (entries 6 and 7)
represents a particularly impressive result as these anilines
are both sterically hindered and electron deficient, making
them particularly poor candidates as nucleophiles. Addition-
ally, the presence of halogens on the aniline, which could
lead to potential cross coupling side products, was not a
significant problem. It is interesting to note that the reaction
involving 2,6-dibromoaniline is the only one which proceeds
in substantially higher yield (69% vs 32%) when 5 rather
than 1 mol % of catalyst is employed. Finally, extremely
(11) Representative Procedure. A Schlenk tube, flame-dried in vacuo,
was placed under an Ar atmosphere on a vacuum line. The tube was charged
with Pd2(dba)3 (5 mg, 0.005 mmol), rac-BINAP (7 mg, 0.01 mmol), Cs2-
CO3 (456 mg, 1.4 mmol), and 2-triflatotropone (254 mg, 1.0 mmol). Toluene
(2 mL) was added followed by 2,6-dimethylaniline (148 µL, 1.2 mmol).
The Schlenk tube was sealed and heated to 80 °C for 12 h. The reaction
mixture was allowed to cool to room temperature, filtered through a pad of
silica gel with the aid of ether (100 mL), and concentrated to afford the
crude product. Purification via flash column chromatography on silica gel
(eluants 3:2 hexane:ether) afforded 200 mg (89% yield) of an orange solid.
1
Mp: 76-78 °C. H NMR (250 MHz, CDCl3): δ 8.40 (bs, 1 H); 7.32 (m,
2 H); 7.18 (m, 3 H); 7.08 (t, J ) 10.5 Hz, 1 H); 6.73 (m, 1 H); 6.22 (d, J
) 10.5 Hz, 1 H); 2.15 (s, 6 H).
220
Org. Lett., Vol. 2, No. 2, 2000

electron-poor anilines (entries 8 and 9) were also successfully
coupled using this protocol.
formation for regioselective tropone synthesis, and this
general approach should find application with respect to more
highly substituted tropones and other nucleophiles.
In summary, a variety of 2-anilinotropones, which are
inaccessible using traditional nucleophilic displacement ap-
proaches, can be readily synthesized via the palladium-
catalyzed amination of 2-triflatotropone. The methodology
shows a tolerance for anilines possessing a high degree of
steric encumbrance and for highly electron deficient, poorly
nucleophilic anilines. This work highlights the potential
power of transition metal-catalyzed carbon-heteroatom bond
Acknowledgment. This research was funded by Dupont.
Supporting Information Available: The preparation and
characterization of all compounds in Table 1. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL991310T
Org. Lett., Vol. 2, No. 2, 2000
221