Pd-Catalyzed Amination of Aryl Chlorides and Bromides
capped vial. A small stirbar was added, and the vial was sealed
with a cap containing a PTFE septum before removing it from
the drybox. KOH (45 wt % in water, 150 µL, KOH 1.2 mmol,
H2O 4.57 mmol) or NaOH (50 wt % water solution, 96 µL,
NaOH 1.2 mmol, H2O 2.65 mmol) was added to the mixture
by syringe. The reaction mixture was then stirred vigorously
at 90 °C. The reaction was monitored by GC. After the reaction,
the mixture was absorbed onto the silica gel and purified by
flash column chromatography on silica gel to give the desired
arylamine in the yield shown.
P r oced u r e for th e Am in a tion of 1-Ch lor o-4-n itr oben -
zen e (Activa ted Ar yl Ch lor id e) w ith An ilin e w ith ou t th e
Use of a Dr ybox. Pd[P(t-Bu)3]2 (5.1 mg, 10 µmol), cetyltri-
methylammonium bromide (1.8 mg, 5.0 µmol), 1-chloro-4-
nitroaniline (159 mg, 1.01 mmol), KOH (84 mg, 1.50 mmol),
and a small stirbar were placed in a Schlenk-type flask (not
oven-dried) in air. The flask was sealed with a septum,
evacuated, backfilled with nitrogen, and charged with regent-
grade toluene (1.0 mL) that had been bubbled with nitrogen
for a few minutes. Aniline (98 mg, 1.05 mmol) and water (27
µL, 1.50 mmol) were added by syringe. The reaction mixture
was stirred vigorously at 90 °C for 1 h, at which time the
mixture was absorbed onto the silica gel and purified by flash
column chromatography on silica gel (20% EtOAc in hexanes)
to give 4-nitro-N-phenylaniline71 (205 mg, 95%) as an orange
solid. In another experiment, the title compound was obtained
in 91% yield: 1H NMR (400 MHz, CDCl3, TMS) δ 6.26 (br s,
1H), 6.94 (d, J ) 9.4 Hz, 2H), 7.17 (t, J ) 7.4 Hz, 1H), 7.21 (d,
J ) 7.2 Hz, 2H), 7.40 (t, J ) 7.8 Hz, 2H), 8.13 (d, J ) 9.4 Hz,
2H); 13C {1H} NMR (100 MHz, CDCl3) δ 113.6, 121.9, 124.6,
126.2, 129.7, 139.4, 139.7, 150.1.
transfer catalyst and concentrated aqueous NaOH or
KOH led to acceptable reaction rates and high yields for
the formation of arylamines. The new base system
performed as well as NaO-t-Bu in certain reactions.
However, reactions catalyzed by Pd[P(t-Bu)3]2 gave the
arylamine in higher yield than those conducted with
other catalysts tested. Other catalysts that are active for
aminations in the presence of NaO-t-Bu failed to give
high conversions of aryl chloride in the presence of
hydroxide as base. The hydroxide base was suitable for
reactions of substrates bearing reactive functionality such
as methyl esters, enolizable ketones, nitro groups, and
cyano groups. Aryl chlorides bearing nitro and tert-butyl
esters reacted with various amines in high yields. The
procedure developed is simple to conduct. The palladium
catalyst Pd[P(t-Bu)3]2 is commercially available, and a
batch of catalyst that had been stored in air at -30 °C
reacted similarly to a batch of catalyst that had been
stored in a nitrogen-filled drybox. Although removal of
oxygen from solvent was required, bubbling of nitrogen
through reagent grade toluene for a few minutes removed
enough oxygen from the solvent to obtain the product in
high yield. Most remarkable was the tolerance of the
system to added water. Phosphine-ligated palladium
hydroxides are known to generate phosphine oxide,68 and
one might expect the amido intermediates in the catalytic
process to be hydrolyzed. Yet, the reactions occurred in
high yield in the presence of excess water.
P r oced u r e for th e Am in a tion of p-Ch lor otolu en e (Un -
a ctiva ted Ar yl Ch lor id e) w ith Mor p h olin e w ith ou t th e
Use of a Dr ybox. Pd[P(t-Bu)3]2 (5.1 mg, 10 µmol), cetyltri-
methylammonium bromide (1.8 mg, 5.0 µmol), KOH (84 mg,
1.50 mmol), and a small stirbar were placed in a Schlenk-type
flask (not oven-dried) in air. The flask was sealed with a
septum, evacuated, backfilled with nitrogen, and charged with
toluene (1.0 mL) that had been distilled from sodium-ben-
zophenone ketyl. p-Chlorotoluene (124 mg, 0.98 mmol), mor-
pholine (91 mg, 1.04 mmol), and water (27 µL, 1.50 mmol) were
added by syringe. The reaction mixture was stirred vigorously
at 90 °C for 30 h, at which time the mixture was absorbed
onto the silica gel and purified by flash column chromatogra-
phy on silica gel (10% EtOAc in hexanes) to give N-(4-
methylphenyl)morpholine72 (153 mg, 88%) as a white solid. In
another experiment, the title compound was obtained in 81%
yield: 1H NMR (400 MHz, CDCl3, TMS) δ 2.28 (s, 3H), 3.10
(t, J ) 4.8 Hz, 4H), 3.86 (t, J ) 4.8 Hz, 4H), 6.83 (d, J ) 8.4
Hz, 2H), 7.09 (d, J ) 8.4 Hz, 2H); 13C {1H} NMR (100 MHz,
CDCl3) δ 20.4, 49.9, 67.0, 116.0, 129.6, 129.7, 149.2.
2,2-Dip h e n yl-1-[4-(t r iflu or om e t h yl)p h e n yl]-1-e t h a -
n on e (5). In a drybox, phenyl bromide (378 mg, 2.41 mmol)
was added to a mixture of 4′-(trifluoromethyl)acetophenone
(193 mg, 1.03 mmol), NaO-t-Bu (231 mg, 2.4 mmol), Pd(OAc)2
(4.4 mg, 20 µmol), and P(t-Bu)3 (4.9 mg, 20 µmol) in THF (2.0
mL) in a screw-capped vial. A small stirbar was added, and
the vial was sealed with a cap containing a PTFE septum and
removed from the drybox. The reaction mixture was stirred
at room temperature for 1 h, and then at 60 °C for 2 h. The
mixture was diluted with H2O and was extracted with EtOAc.
The organic layer was washed with 2 N aqueous HCl, dried
with MgSO4, and then evaporated. The residue was purified
by flash column chromatography on silica gel (1% EtOAc in
hexanes) to give 5 (294 mg, 84%) as a white solid: mp 139-
140 °C; 1H NMR (400 MHz, CDCl3, TMS) δ 6.00 (s, 1H), 7.23-
7.29 (m, 6H), 7.31-7.37 (m, 4H), 7.66 (d, J ) 8.0 Hz, 2H), 8.80
(d, J ) 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 59.9, 123.5
Exp er im en ta l Section
Gen er a l Meth od s. Toluene was distilled from sodium-
benzophenone ketyl under nitrogen. Aryl halides except tert-
butyl p-chlorobenzoate were purchased from commercial sources
and were used without further purification. tert-Butyl p-
chlorobenzoate was prepared according to the literature.69,70
Amines were purchased from commercial sources and were
distilled from CaH2 under nitrogen before use with the
exception of diphenylamine, which was used without further
purification. KOH powder was made from KOH pellets with
a pestle and mortar in a nitrogen-filled drybox, and the powder
was stored in the drybox. Cetyltrimethylammonium bromide
(1), 45 wt % aqueous KOH, and 50 wt % aqueous NaOH were
purchased from Aldrich Chemicals. Pd[P(t-Bu)3]2 was pur-
chased from Strem Chemicals.
Gen er a l P r oced u r e for Am in a tion s of Liqu id Ar yl
Ha lid es w ith KOH p ow d er . In a drybox, aryl halide (1.0
mmol) and amine (1.05 mmol) were added to a suspension of
Pd[P(t-Bu)3]2 (5.1 mg, 10.0 µmol), cetyltrimethylammonium
bromide (1.8 mg, 5.0 µmol), and KOH powder (84 mg, 1.5
mmol) in toluene (1.0 mL) in a screw-capped vial. A small
stirbar was added, and the vial was sealed with
a cap
containing a PTFE septum and removed from the drybox.
Water (27 µL, 1.5 mmol) was added to the mixture by syringe.
The reaction mixture was then stirred vigorously at 90 °C. The
reaction was monitored by GC. After the reaction, the mixture
was absorbed onto the silica gel and purified by flash column
chromatography on silica gel to give the desired arylamine in
the yield shown. Procedures for the reactions of solid materials
are described in the Supporting Information.
Gen er a l P r oced u r e for Am in a tion s of Ar yl Ch lor id es
w ith Aqu eou s Hyd r oxid e. In a drybox, aryl chloride (0.8
mmol) and amine (0.84 mmol) were added to a suspension of
Pd[P(t-Bu)3]2 (4.1 mg, 8.0 µmol) and cetyltrimethylammonium
bromide (1.5 mg, 4.0 µmol) in toluene (0.8 mL) in a screw-
(68) Grushin, V. V.; Alper, H. Organometallics 1993, 12, 1890-1901.
(69) Altschul, R. J . Am. Chem. Soc. 1948, 70, 2569-2572.
(70) Altschul, R. J . Am. Chem. Soc. 1946, 68, 2605-2609.
(71) Goldberg, I. Ber. 1907, 40, 4541-4546.
(72) Tsuji, Y.; Huh, K. T.; Ohsugi, Y.; Watanabe, Y. J . Org. Chem.
1985, 50, 1365-1370.
J . Org. Chem, Vol. 67, No. 18, 2002 6485