Palladium-catalyzed amination of aryl bromides with hindered N-alkyl-substituted anilines using a palladium(I) Tri-tert-butylphosphine bromide dimer

Article abstract of DOI:10.1021/jo020609d

An efficient palladium-catalyzed amination of aromatic bromides with hindered N-alkyl-substituted anilines is described, either using the combination of Pd(OAc)₂ and P(t-Bu)₃ or a palladium(I) tri-tert-butylphosphine bromide dimer, [Pd(μ-Br)(t-Bu₃P)]₂, a new, commercially available, and easily handled catalyst.

Full text of DOI:10.1021/jo020609d

SCHEME 1
P a lla d iu m -Ca ta lyzed Am in a tion of Ar yl
Br om id es w ith Hin d er ed
N-Alk yl-Su bstitu ted An ilin es Usin g a
P a lla d iu m (I) Tr i-ter t-bu tylp h osp h in e
Br om id e Dim er
Mahavir Prashad,* Xiao Yin Mak,1 Yugang Liu, and
Oljan Repicˇ
TABLE 1. Effect of Liga n d s a n d Tem p er a tu r e on th e
Am in a tion of Br om oben zen e (2a ) w ith
N-Cycloh exyla n ilin e (1a )a
Process Research and Development,
Chemical and Analytical Development,
Novartis Institute for Biomedical Research,
One Health Plaza, East Hanover, New J ersey 07936
isolated
% conversionb
entry Pd(OAc)2 (mol %) (°C) 1 h 3 h 6 h 21 h
mol %
ligand temp
yield of
3a (%)
1
2
0.5
1.0
0.5
0.5
0.5
0.1
0.1
1.0
1.0
binap
(0.5)
binap
(2.0)
110 30
40.1 41
27
14
11
mahavir.prashad@pharma.novartis.com
Received September 17, 2002
110 17.7 19.3
3
xantphos 110 7.9 9.5 11
(0.5)
DPEphos 110 0.8 1.2
(0.5)
P(t-Bu)3
(0.5)
P(t-Bu)3
(0.3)
P(t-Bu)3
(1.0)
P(t-Bu)3
(1.0)
P(t-Bu)3
(1.0)
13.7
Abst r a ct : An efficient palladium-catalyzed amination of
aromatic bromides with hindered N-alkyl-substituted anilines
is described, either using the combination of Pd(OAc)2 and
P(t-Bu)3 or a palladium(I) tri-tert-butylphosphine bromide
dimer, [Pd(µ-Br)(t-Bu3P)]2, a new, commercially available,
and easily handled catalyst.
4
2.3 not isolated
86
5
110 100
6
110 41.3 64.8 76.1 88.5
110 100
70
7
87
We required a practical method for the preparation of
hindered N-alkyl-substituted diarylamines, such as N-
cyclohexyldiphenylamine and N-isopropyldiphenylamine.
Their synthesis by a high-temperature and high-pressure
reductive alkylation of diphenylamine with cyclohex-
anone and acetone, respectively, had previously been
reported in the patent literature to give poor yields.2 We
envisioned that the most straightforward route to this
class of compounds would be a palladium-catalyzed ami-
nation, pioneered by Buchwald3-5 and Hartwig,6-9 of
aromatic halides with N-cyclohexylaniline or N-isoprop-
ylaniline. The palladium-catalyzed amination of aromatic
halides with hindered N-alkyl-substituted anilines was
reported10 by Buchwald et al. using xantphos or 2-(di-
phenylphosphino)-2′-(N,N-dimethylamino)biphenyl as
ligands. In this paper, we describe an efficient synthesis
of hindered N-alkyl-substituted diarylamines by an ami-
nation of aromatic bromides with hindered N-alkyl-
substituted anilines utilizing either a combination of
Pd(OAc)2 and P(t-Bu)3 or the new, commercially avail-
able, air-stable, and easily handled solid palladium(I) tri-
tert-butylphosphine bromide dimer, [Pd(µ-Br)(t-Bu3P)]2,
as the catalyst.11 We had previously demonstrated the
practical utility of the palladium-catalyzed amination
reactions on a multikilogram scale.12,13
8
25
70
0
0
0
not isolated
93
9
66
10
[Pd(µ-Br)(t-Bu3P)]2 110 100
(0.25)
a
Conditions: N-cyclohexylaniline (11.4 mmol), 2a (13.7 mmol),
b
sodium tert-butoxide (17.1 mmol), and toluene (20.0 mL). Moni-
tored by GC using an HP-5 column (30 m × 0.32 mm).
The palladium-catalyzed amination of bromobenzene
(2a ) with N-cyclohexylaniline (1a ) to N-cyclohexyldiphen-
ylamine (3a ) was selected as the representative example
to develop suitable reaction conditions (Scheme 1). The
results with different commercially available ligands are
summarized in Table 1. Amination of 2a with 1a in the
presence of palladium acetate (0.5 mol %), 2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl14 (binap; 0.5 mol %),
and sodium tert-butoxide in refluxing toluene afforded
only a 27% yield (entry 1) of the desired 3a . An increase
in the amounts of the catalyst and the ligand did not
improve the yield (entry 2). Almost no reaction was
observed using DPEphos15 as the ligand (entry 4). Xant-
phos,16 which was reported as an effective ligand for such
an amination,10 afforded only an 11% yield (entry 3) of
3a . In all cases, the reaction was monitored by GC, and
the poor yield was due to the poor conversion. We next
investigated P(t-Bu)3, which has been reported17-19 as a
very effective ligand in the amination of aromatic halides
(1) Undergraduate Summer Intern (2002) from the University of
Rochester, Rochester, NY.
(2) Malz, R. E.; Greenfield, H.; Wheeler, E. L. Eur. Patent 0014998,
1980; Chem. Abstr. 1981, 94, 121069.
(3) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-
209.
(11) [Pd(µ-Br)(t-Bu3P)]2 is available from J ohnson Matthey, 2001
Nolte Drive, West Deptford, NJ 08066.
(4) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999, 576,
125-146.
(12) Prashad, M.; Hu, B.; Har, D.; Repicˇ, O.; Blacklock, T. J .;
Acemoglu, M. Adv. Synth. Catal. 2001, 343, 461-472.
(13) Prashad, M.; Hu, B.; Lu, Y.; Draper, R.; Har, D.; Repicˇ, O.;
Blacklock, T. J . J . Org. Chem. 2000, 65, 2612-2614.
(14) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144-
1157.
(15) Sadighi, J . P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett.
1998, 39, 5327-5330.
(16) Yin, J .; Buchwald, S. L. J . Am. Chem. Soc. 2002, 124, 6043-
6048.
(5) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818.
(6) Hartwig, J . F. Pure Appl. Chem. 1999, 71, 1417-1423.
(7) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-2067.
(8) Hartwig, J . F. Acc. Chem. Res. 1998, 31, 852-860.
(9) Hartwig, J . F. Synlett 1997, 327-340.
(10) Harris, M. C.; Geis, O.; Buchwald, S. L. J . Org. Chem. 1999,
64, 6019-6022.
10.1021/jo020609d CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/07/2003
J . Org. Chem. 2003, 68, 1163-1164
1163

TABLE 2. Am in a tion w ith Hin d er ed An ilin esa
(2d ). While 6a was obtained in moderate yield (52%) from
the amination of 2d with 1a , the reaction of 2d with 1b
and 1c afforded 6b and 6c in poor yield, even with 2.0
equiv of 2d and 2.0 equiv of base.
One of the drawbacks with P(t-Bu)3 is the handling of
this air-sensitive and pyrophoric reagent on a large scale.
We now report that this problem can be circumvented
by using 0.25 mol % (0.5 mol % Pd) of the new, com-
mercially available,11 and easily handled solid [Pd(µ-Br)-
(t-Bu3P)]2 catalyst. Amination of 2a with 1a in the
presence of 0.25 mol % of [Pd(µ-Br)(t-Bu3P)]2 afforded 3a
in a 93% yield (Table 1, entry 10). Excellent yields were
also obtained from the amination of aromatic bromides
2a -c with anilines 1a -c (Table 2) and were comparable
to or better than those of the Pd(OAc)2/P(t-Bu)3 combina-
tion. In fact, the palladium(I) tri-tert-butylphosphine
bromide dimer catalyst gave higher yields of 6a -c (60,
51, and 61%, respectively) from the amination of 2d with
1a -c, compared to the Pd(OAc)2/P(t-Bu)3 combination
(52, 25, and 12%, respectively).
In summary, an efficient palladium-catalyzed amina-
tion of aromatic bromides with hindered N-alkyl-substi-
tuted anilines is described, using either the combination
of Pd(OAc)2 and P(t-Bu)3 or [Pd(µ-Br)(t-Bu3P)]2, a new,
commercially available, and easily handled catalyst.
Exp er im a n ta l Section
Gen er a l P r oced u r e for th e Am in a tion Usin g a Com bi-
n a tion of P d (OAc)2 a n d P (t-Bu )3. A dry three-necked flask,
equipped with a magnetic stirring bar, septum, and condenser
with an argon inlet-outlet was charged with palladium acetate
(12.8 mg, 0.057 mmol), sodium tert-butoxide (1.64 g, 17.1 mmol),
a hindered aniline (1a -c, 11.4 mmol), and aryl bromide (13.7
mmol). The flask was flushed with argon, and dry, deaerated
toluene (20 mL) was added. The mixture was stirred at room
temperature for 15 min, and P(t-Bu)3 (11.5 mg, 0.057 mmol) was
added as a solution in toluene (11.5 mg) using a syringe. The
syringe was washed with toluene (1 mL), and the wash was
added to the reaction mixture. The reaction mixture was heated
to 108-110 °C and stirred with gentle reflux for the specified
time (Tables 1 and 2). The reaction mixture was cooled to room
temperature, and water (10 mL) was added. The organic layer
was separated, washed with water (5 mL), and concentrated.
The crude material was purified by silica gel chromatography.
All of the compounds gave satisfactory spectroscopic data.
Gen er a l P r oced u r e for th e Am in a tion Usin g a P a lla -
d iu m (I) Tr i-ter t-bu tylp h osp h in e Br om id e Dim er . A dry
three-necked flask, equipped with a magnetic stirring bar,
septum, and condenser with an argon inlet-outlet was charged
a
b
All the compounds gave satisfactory spectral data. 2.0 equiv
of aromatic halide and 2.0 equiv of base were used. (A) With
Pd(OAc)2 and P(t-Bu)3 and (B) with
butylphosphoine bromide dimer.
a palladium(I) tri-tert-
with various amines and anilines but not with hindered
N-alkyl-substituted anilines such as 1a . The amination
of 2a with 1a was complete in 1 h using P(t-Bu)3 (0.5
mol %) and palladium acetate (0.5 mol %) in refluxing
toluene (entry 5), affording 3a in an 86% yield. A decrease
in the amount of the palladium catalyst to 0.1 mol % and
an increase in the palladium-to-ligand ratio to 1:3 led to
a slower reaction (entry 6). However, with 0.1 mol %
palladium acetate using a 1:10 palladium-to-ligand ratio,
the reaction was complete in 1 h, affording 3a in an
87% yield (entry 7). The amination of aromatic bromides
with N-methylaniline and diphenylamine has been re-
ported at room temperature using palladium acetate and
P(t-Bu)3.18 However, in our case with 1a , no reaction was
observed at room temperature (entry 8), further confirm-
ing the steric demands of the cyclohexyl group in 1a . Only
a 66% conversion was observed when the reaction was
carried out at 70 °C for 21 h (entry 9).
11
with [Pd(µ-Br)(t-Bu3P)]2 (22 mg, 0.0285 mmol), sodium tert-
butoxide (1.64 g, 17.1 mmol), a hindered aniline (1a -c, 11.4
mmol), and aryl bromide (13.7 mmol). Dry, deaerated toluene
(20 mL) was added. The mixture was stirred at room temper-
ature for 15 min. The reaction mixture was heated to 108-110
°C and stirred with gentle reflux for the specified time (Tables
1 and 2). The reaction mixture was cooled to room temperature,
and water (10 mL) was added. The organic layer was separated,
washed with water (5 mL), and concentrated. The crude material
was purified by silica gel chromatography.
We selected the P(t-Bu)3 (0.5 mol %) and palladium
acetate (0.5 mol %) catalytic system (entry 5) in refluxing
toluene to study the amination of various aromatic
bromides (2a -d ) with several hindered N-alkyl-substi-
tuted anilines (1a -c). The results are listed in Table 2.
In all cases the yields were excellent, except with the
aromatic bromide containing an o-methyl substituent
Ack n ow led gm en t. We thank Dr. Thomas J . Black-
lock for all his support and Mr. Yansong Lu for a helpful
discussion.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and MS for compounds 3c, 4a -c, 5a -c, and 6a -c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998,
39, 2367-2370.
(18) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.
H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-5580.
(19) Lee, M.; J orgensen, J .; Hartwig, J . F. Org. Lett. 2001, 3, 2729-
2732.
J O020609D
1164 J . Org. Chem., Vol. 68, No. 3, 2003