bromide was observed by the end of the reaction time, and
the reduced (H for Br) arene accounted for the vast
predominance of the mass balance of starting aryl bromide.
Scheme 1. Amination of Naphthyl and Quinolinyl Bromides
In our efforts to find literature precedence for Pd-catalyzed
aryl amination of substituted quinolines, we observed that
no reports describing application of this methodology for 5-
or 8-bromoquinolines existed. As observed with the naphthyl
substrates, a marked rate acceleration was observed under
the microwave conditions relative to standard heating (Table
1, entries 6-11). In addition, yields for microwave conditions
were reproducibly enhanced in all cases under the microwave-
assisted conditions (the magnitude of this effect ranged from
15-75% improvement).
Certain substrates failed to provide the desired amination
products under conventional heating, even after prolonged
reaction times. In our hands, under the standard conditions
employed previously, we did not observe any appreciable
reaction with 5-bromo-8-methoxyquinoline and piperidine
or with the strongly electron-deficient 5-bromo-8-cyano-
quinoline with any of the primary or secondary amines tested.
Unlike the previous examples where reduced arene byprod-
ucts predominated, recovery of aryl bromide was high (65-
90%), indicating failure of Pd insertion for these substrates.
However, under microwave-assisted conditions, these reac-
tions proceeded reproducibly without event in the usual 10
min reaction time in yields ranging from 50-90% (Table 1,
entries 12-16). To rule out a possible shift in mechanism,
specifically for the 5-bromo-8-cyanoquinoline substrate due
to the perceived potential for microwave-assisted nucleophilic
aromatic substitution para to the electron-withdrawing cyano
group, an additional investigation was initiated. Thus, the
microwave-promoted aryl amination was carried out under
identical conditions in the absence of Pd catalyst and PPFA
ligand with piperidine as the amine component. As previously
observed, these conditions provided solely the recovered
starting aryl bromide, demonstrating the requirement for Pd
in the reaction and ruling out involvement of a potentially
competing mechanism under these conditions.
In the course of our research, we sought to prepare a series
of naphthyl or quinolinylamines where the amino substitution
was located at either the 1 or 4 (5 or 8) position. Additionally,
we desired a convergent route that would allow both
maximum flexibility for variation of the amine moiety as
well as the aryl scaffold. Our strategy focused on Pd-
catalyzed aryl amination of naphthyl and quinolinyl bromide
substrates, using simple primary or secondary aliphatic
amines (Scheme 1). Because of the known propensity for
interfering Pd chelation from pyridyl or quinolinyl sub-
strates,8 more powerful chelating ligands were chosen for
these studies. Results from preliminary experimentation with
several different ligands for the Pd catalyst showed satisfac-
tory conversion to products using either BINAP9 or (S)-(R)-
PPFA.10 However, as chromatographic elution times of the
BINAP ligands frequently coincided with those of naphthyl
and quinolinylamine reaction products under most standard
solvent systems, the latter ligand was routinely employed.
Not unexpectedly, comparable yields of desired amination
products were obtained under microwave or sealed tube
reaction conditions in initial experiments with 4-substituted-
1-bromonaphthalenes (Table 1, entries 1-5), though a
marked rate acceleration was observed in the microwave
reactions.11 Typically, reactions performed under conven-
tional heating conditions were still progressing after 16 h
and were essentially complete by 24 h, whereas the micro-
wave reactions appeared to be complete after 10 min of
reaction time. In most cases, complete consumption of aryl
(8) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240-7241.
(9) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157.
(10) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. W. J. Org. Chem. 1997,
62, 1568-1569.
Because the conditions employed in our studies with both
conventional and microwave-assisted reactions were other-
wise identical (temperature, concentration, pressure, reaction
vessel), these results suggest an opportunity to consider
historically debated potential nonthermal effects of micro-
wave reactions.12 One possible factor contributing to en-
hanced yields for non-cyano-(5- or 8-)-bromoquinoline
substrates relates to the potential for catalyst degradation over
the extended reaction times required for conventional
methods, which are obviated under the rapid microwave
protocol. This is consistent with the observed findings where
reduced arenes comprise the majority of the remainder of
the mass balance of product, though contribution from other
microwave-specific effects cannot be definitively ruled out.
(11) Typical procedure. All aryl amination reactions were conducted in
Personal Chemistry 2 mL Smith Process thick-walled borosilicate glass
conical vials that were degassed, filled with argon, and sealed with a cap
containing a PTFE septum. Aryl bromides were either obtained com-
mercially or prepared by known methods. Pd2(dba)3, (S)-(R)-PPFA, NaOt-
Bu, aniline, benzylamine, N-methylaniline, and piperidine were obtained
from Aldrich Chemical Co. and were used as received. Anhydrous toluene
was purchased from VWR. Yields reported are for isolated compounds of
greater than 98% purity as determined by HPLC. All reactions were run at
an approximately 0.25 M aryl bromide concentration. Standard conditions
combined 2 mol % Pd2(dba)3 with 6 mol % PPFA in 0.50 mL of toluene
under argon with addition of aryl bromide (1.0 equiv) and then amine (1.2
equiv), followed by NaOt-Bu (1.5 equiv). The system was degassed and
back-filled with argon. In the conventional method, the reaction mixture
was stirred in an oil bath at 120 °C for a maximum time of 24 h, and most
reactions proceeded to completion (consumption of aryl bromide) in this
period. Microwave reactions were carried out in a Personal Chemistry Emrys
Optimizer model microwave reactor. Typical reactions were run using 150
W of power for the initial 250-400 s until the temperature reached 120 °C
as measured with an IR probe, and this temperature was then maintained
using approximately 100 W of power until the final experiment time reached
900 sec. In each method, after completion of the reaction time, the mixture
was diluted with EtOAc and filtered. The volatiles were removed by rotary
evaporation, and the resulting residue was purified using standard silica
gel flash chromatography with hexanes/EtOAc as eluents.
(12) (a) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863-1866. (b)
Strauss, C. R. Angew. Chem., Int. Ed. 2002, 41, 3589-3590. (c) Perreux,
L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223. (d) Strauss, R.; Trainor,
R. W. Aust. J. Chem. 1995, 48, 1665. (e) Raner, K. D.; Strauss, C. R.;
Vyskoc, F.; Mokbel, L. J. Org. Chem. 1993, 58, 950-953. (f) Pagnotta,
M.; Pooley, C. L. F.; Gurland, B.; Choi, M. J. Phys. Org. Chem. 1993, 6,
407-411.
898
Org. Lett., Vol. 5, No. 6, 2003
Wang, Tammy
