β-hydrogen-containing sodium alkoxides as suitable bases in palladium- catalyzed aminations of aryl halides

Full text of DOI:10.1021/jo991949a

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J . Org. Chem. 2000, 65, 2612-2614
the corresponding tert-butylcarbamate (III, 9%) and
dimeric urea (IV, 11%) byproducts were also isolated.
Thus, sodium tert-butoxide was not compatible with the
methylcarbamate functionality. Reactions were also not
clean or were incomplete with other bases, e.g., cesium
carbonate and tripotassium phosphate. This prompted
us to investigate this reaction with sodium methoxide,
even though palladium-catalyzed reduction of aromatic
halides with sodium methoxide had been identified.7-9
Sodium methoxide not only would eliminate the tert-
butylcarbamate byproduct (III) but also would minimize
the urea dimer (IV), as it is less basic than sodium tert-
butoxide. We rationalized that sodium methoxide could
be a suitable base, because these amination reactions do
not necessarily require a palladium-aryl-alkoxide com-
plex as an intermediate, which might undergo reduction
in the case of sodium methoxide. This supposition was
based on the fact that cesium carbonate and tripotassium
phosphate are also suitable bases, and amination reaction
using these bases may involve a pentacoordinated inter-
mediate, as proposed by Buchwald, which simply requires
a deprotonation of the coordinated amine with the base
to generate a palladium-amido-aryl complex.10 Even if
the reaction involved a palladium-aryl-alkoxide com-
plex, as proposed by Hartwig,8 the differences in the
reaction rates of the displacement of the â-hydrogen-
containing alkoxide in this complex with an amine to
generate a palladium-amido-aryl complex and of the
reduction to a palladium-aryl-hydride complex would
determine the outcome. Such a study with â-hydrogen-
containing sodium alkoxides, e.g., sodium methoxide, was
not reported. Treatment of our substrate (I) with ben-
zophenone imine in the presence of sodium methoxide
using Pd2(dba)3 and (()-BINAP at 80 °C yielded the
desired product (II) in 80% yield with <3% of the dimeric
urea (IV, Scheme 1). No reduction product could be
detected, even at 105 °C.
To test the general synthetic utility of sodium meth-
oxide as a base in palladium-catalyzed aminations,
several aryl halides were reacted with benzophenone
imine. Hydrolysis of the resulting imine adduct with HCl
in THF under known conditions6 yielded anilines in
excellent yields (Table 1). Similar results were also
obtained using sodium isopropoxide as the base. The
yields were comparable to those reported with sodium
tert-butoxide.6 The synthetic utility of sodium methoxide
and sodium isopropoxide was further demonstrated dur-
ing amination of several aromatic halides (electronically
neutral, with an electron-withdrawing or electron-donat-
ing group) with primary amines, secondary amines, and
anilines. The results are listed in Table 2. In all cases,
yields were good to excellent and were comparable to
those reported with sodium tert-butoxide.10,11
â-Hyd r ogen -Con ta in in g Sod iu m Alk oxid es
a s Su ita ble Ba ses in P a lla d iu m -Ca ta lyzed
Am in a tion s of Ar yl Ha lid es
Mahavir Prashad,* Bin Hu, Yansong Lu,
Robert Draper,1 Denis Har, Oljan Repicˇ, and
Thomas J . Blacklock
Process Research & Development, Chemical & Analytical
Development, Novartis Institute for Biomedical Research,
59 Route 10, East Hanover, New J ersey 07936
Received December 20, 1999
The synthesis of N-unsubstituted anilines generally
requires nitration of an aromatic compound followed by
reduction of the nitro group. This route is not desirable
on a large scale because of the unsafe nature of the
nitration reaction. Palladium- and nickel-catalyzed ami-
nations of aromatic halides and triflates, pioneered by
Buchwald2,3 and Hartwig,4,5 provide not only an efficient
route to substituted anilines but also a safer route to
N-unsubstituted anilines when using benzophenone imi-
ne as an ammonia equivalent.6 Commonly used bases in
palladium-catalyzed aminations are sodium tert-butoxide,
cesium carbonate, and tripotassium phosphate. The use
of â-hydrogen-containing sodium alkoxide bases, e.g.,
sodium methoxide or sodium isopropoxide, has not been
reported in these amination reactions because of their
known ability6 to reduce palladium-aryl-alkoxide com-
plexes to palladium-aryl-hydride complexes, which
results in the reduction of aryl halide to arene, as was
observed during palladium-catalyzed etherification of
aromatic halides with sodium methoxide.7,8 A method for
the palladium-catalyzed reduction of aromatic halides by
sodium methoxide has also been reported.9 In this paper,
we report that sodium methoxide and sodium isopro-
poxide, both of which contain a â-hydrogen, are suitable
bases for palladium-catalyzed aminations of aromatic
halides.
Nitrations have been successfully eliminated in a
number of projects in our laboratories using palladium-
catalyzed aminations of aryl halides with benzophenone
imine as an ammonia equivalent. In one of our projects,
amination of a highly substituted aromatic halide (I,
Scheme 1), which also contained a methylcarbamate
moiety, with benzophenone imine (1.2 equiv) using
sodium tert-butoxide (1.4 equiv) as a base in the presence
of Pd2(dba)3 (0.5 mol %) and (()-BINAP (1.5 mol %) at
105 or 80 °C yielded a complicated mixture. In addition
to the desired product (II, 55%), substantial amounts of
(1) Undergraduate summer intern (1999) from Princeton University.
(2) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999, 576,
125-146.
In summary, the â-hydrogen-containing alkoxides so-
dium methoxide and sodium isopropoxide are suitable
bases in palladium-catalyzed amination reactions of
aromatic halides. These results suggest that either the
reaction mechanism with â-hydrogen-containing alkoxide
bases does not involve a palladium-aryl-alkoxide com-
plex as an intermediate or that the displacement of the
(3) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818.
(4) Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-
2067.
(5) Hartwig, J . F. Synlett 1997, 327-340.
(6) Wolfe, J . P.; Ahman, J .; Sadighi, J . P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367-6370.
(7) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 3395-3396.
(8) Mann, G.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 13109-
13110.
(9) Zask, A.; Helquist, P. J . Org. Chem. 1978, 43, 1619-1620.
(10) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215-7216.
10.1021/jo991949a CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/29/2000

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2613
Ta ble 1. P a lla d iu m -Ca ta lyzed Am in a tion of Ar yl Br om id esa
a
In all cases, 0.25 mol % of Pd2(dba)3 and 0.75 mol % of BINAP were used. The imine adduct was hydrolyzed with 2.0 M HCl in THF
b
in each case (see ref 6). For reported yields with sodium tert-butoxide, see ref 6.
Ta ble 2. P a lla d iu m -Ca ta lyzed Am in a tion of Ar yl Br om id esa
a
In all cases, 0.25 mol % Pd2(dba)3 and 0.75 mol % BINAP were used, except for 7 and 10, for which 0.5 mol % Pd2(dba)3 and 1.5 mol
b
% BINAP were used, and 11, for which 1.0 mol % Pd2(dba)3 and 3.0 mol % BINAP were used. For reported yields with sodium tert-
butoxide, see ref 10 for examples 4-6, 11, and 12 and ref 11 for example 8.

2614 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
Sch em e 1
1
Sp ectr a l Da ta of Selected Com p ou n d s. 7: H NMR (300
MHz, CDCl3) δ 2.17 (s, 3H), 2.23 (s, 3H), 2.43 (s, 3H), 3.88 (s,
2H), 6.67 (d, 1H, J ) 7.5 Hz), 6.77 (s, 1H), 6.95 (d, 1H, J ) 7.5
Hz), 7.13-7.28 (m, 5H); 13C NMR (300 MHz, CDCl3) δ 17.96,
21.18, 40.75, 60.82, 120.7, 123.63, 126.9, 128.24, 129.52, 130.92,
135.93, 139.22, 152.3.
alkoxide in this complex with an amine to form a
palladium-amido-aryl complex is much faster than its
reduction to the palladium-aryl-hydride complex.
Exp er im en ta l Section
9: 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 3H), 5.96 (bs, 1H),
6.56-6.61 (m, 3H), 7.9 (dd, 1H, J ) 8.07 and 8.06 Hz), 7.43 (m,
Gen er a l P r oced u r e. A dry three-neck flask, equipped with
a magnetic stirrer bar, septum, and a condenser with a nitrogen
inlet-outlet, was charged with the aromatic halide (5.0 mmol),
the imine or amine (6.0 mmol), Pd2(dba)3 (0.0125 mmol), (()-
BINAP (0.0375 mmol), and the base (7.0 mmol). The flask was
evacuated and flushed with nitrogen. Dry and de-aerated toluene
(10 mL) was added. The mixture was heated to 80-110 °C, and
the reaction was allowed to continue for the specified time
(Tables 1 and 2). The reaction mixture was cooled to room
temperature. Water (10 mL) and ethyl acetate (20 mL) were
added sequentially. The organic layer was separated, washed
with water (10 mL), dried over anhydrous sodium sulfate, and
concentrated. The crude material was purified by silica gel
chromatography in cases 4-12 or hydrolyzed with HCl in cases
1-3.6 All of the compounds gave satisfactory spectroscopic data
(1-3;6 4-6, 11, and 12;10 8;11 and 1012).
2H), 7.51 (m, 2H), 7.61 (m, 1H), 7.88 (m, 1H), 8.06 (m, 1H); 13
C
NMR (300 MHz, CDCl3) δ 55.11, 102.87, 105.52, 109.73, 116.74,
121.87, 123.25, 125.67, 125.96, 126.08, 127.97, 128.45, 130.05,
134.63, 138.37, 146.29, 160.67.
Ack n ow led gm en t. We thank Prof. S. L. Buchwald
(Massachusetts Institute of Technology, Cambridge,
MA) for a helpful discussion.
Su p p or tin g In for m a tion Ava ila ble: Spectra of com-
pounds 7 and 9. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991949A
(11) Sadighi, J . P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett.
1998, 39, 5327-5330.
(12) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936.