Selective N-arylation of aminobenzanilides under mild conditions using triarylbismuthanes

Article abstract of DOI:10.1021/jo000614m

Diarylamines are prepared selectively in good yields under mild conditions by treatment of aminobenzanilides with triarylbismuthanes in the presence of copper(II) acetate and triethylamine. Arylation under these conditions occurs preferentially at the amino- rather than the amide-nitrogen of the benzanilide. Thus, heating an aminobenzanilide in dichloromethane under reflux in the presence of 1 equiv each of a triarylbismuthane, triethylamine, and copper(II) acetate affords the diarylamine in good yields. This method thereby provides a mild and expeditious route to functionalized diarylamines.

Full text of DOI:10.1021/jo000614m

J . Org. Chem. 2000, 65, 7747-7749
7747
Selective N-Ar yla tion of Am in oben za n ilid es u n d er Mild Con d ition s
Usin g Tr ia r ylbism u th a n es
Roderick J . Sorenson
Department of Medicinal Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories,
Ann Arbor, Michigan 48105
Received April 21, 2000
Diarylamines are prepared selectively in good yields under mild conditions by treatment of
aminobenzanilides with triarylbismuthanes in the presence of copper(II) acetate and triethylamine.
Arylation under these conditions occurs preferentially at the amino- rather than the amide-nitrogen
of the benzanilide. Thus, heating an aminobenzanilide in dichloromethane under reflux in the
presence of 1 equiv each of a triarylbismuthane, triethylamine, and copper(II) acetate affords the
diarylamine in good yields. This method thereby provides a mild and expeditious route to
functionalized diarylamines.
In tr od u ction
extension of this approach in which the amino nitrogen
of a benzanilide is selectively arylated while the amide
functionality is preserved unchanged.
Diarylamines are of considerable importance as syn-
thetic intermediates and as potential therapeutic agents.1
Because anilines are widely available as precursors to
this class of compounds, a number of methods have been
developed for the arylation of aromatic amino groups.
Classical methods for this transformation, typified by the
Ullmann-Goldberg condensation,2 often require high
temperatures, long reaction times, or other harsh or
stringent conditions incompatible with many functional
groups. Accordingly, novel protocols have been developed
to address these limitations. The research groups of
Buchwald3 and Hartwig4 utilized palladium to catalyze
the amination of aryl halides. Barton and co-workers
introduced triarylbismuthanes5 and organolead deriva-
tives6 for the N-arylation of anilines. Chan and co-
workers subsequently demonstrated the use of organo-
bismuth(III) reagents for the N-arylation of amides and
amide-like moieties.7 Finet and Combes8 have continued
to exploit the reactivity of triarylbismuth(V) reagents for
arylation reactions. We have previously described a
method for the N-phenylation of anilines bearing a wide
variety of functional groups utilizing triphenylbismuth-
ane under very mild conditions.9 We herein report an
Resu lts a n d Discu ssion
Confronted with a need for the expedient preparation
of a series of diarylamines, and drawing upon previous
research in this area, we were prompted to explore the
reaction of organobismuth(III) reagents with functional-
ized aminobenzanilides. In the presence of a basic
promoter, arylation was observed to occur exclusively at
the amino nitrogen rather than the amide nitrogen of the
substrates, thus providing a novel route to the desired
class of compounds. This result is surprising in that Chan
et al.7 had originally developed this modification of the
Barton procedure expressly for the purpose of arylating
amide nitrogens. Even so, in most cases throughout our
investigation no evidence was found for the production
of any bis- or tris-adducts. Accordingly, a large number
of diarylamines were prepared using this procedure.
Representative examples are shown in Table 1. Both
electron-withdrawing and electron-donating groups were
tolerated in either the substrate or the triarylbismuth-
ane. In some examples small amounts of unidentified
byproducts were observed. These were easily removed by
recrystallization or column chromatography.
The required triarylbismuthanes were readily obtained
via a simple procedure in which the corresponding
Grignard or aryllithium reagents were allowed to react
with bismuth(III) halide.10 These reagents are usually
crystalline, easy to purify, and exhibit low reactivity
toward moisture and oxygen so that multigram quanti-
ties can be prepared and stored for prolonged periods.
The anilines were either commercially available or
readily synthesized using standard methods. 3-Amino-
4-fluoro-N-(3,4-difluorophenyl)benzamide (Table 1, entry
(1) (a) Buchwald, S. L.; Harris, M. C.; Geis, O. J . Org. Chem. 1999,
64, 6019-6022. (b) Sawyer, J . S.; Schmittling, E. A. J . Org. Chem.
1993, 58, 3229-3230, and references therein.
(2) (a) Lindley, J . Tetrahedron 1984, 40, 1433-1456. (b) Kalten-
bronn, J . S.; Scherrer, R. A.; Short, F. W.; J ones, E. M.; Beatty, H. R.;
Saka, M. M.; Winder, C. V.; Wax, J .; Williamson, W. R. N. Arzneim.-
Forsch. 1983, 33, 621-627. (c) Hebky, J .; Radek, O.; Kejha, J . Collect.
Czech. Chem. Commun. 1958, 3988-39. (d) Galy, J .-P.; Hanoun, J .-
P.; Tenaglia, A. Synth. Commun. 1995, 25, 2443-2448. (e) Pellon, R.
F.; Carrasco, R.; Rodes, L. Synth. Commun. 1996, 26, 3869-3876.
(3) (a) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. (b) Old, D. W.; Wolfe, J . P.; Buchwald,
S. L. J . Am. Chem. Soc. 1998, 120, 9722-9723.
(4) (a) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.
(b) Hartwig, J . F.; Dawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-5580.
(5) Barton, D. H. R.; Finet, J .-P.; Khamsi, J . Tetrahedron Lett. 1987,
28, 887-890. For a review of organobismuth applications, see: (a)
Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249-267. (b) Finet,
J . P. Chem. Rev. 1989, 89, 1487-1501. (c) Abramovitch, R. A.; Barton,
D. H. R.; Finet, J . P. Tetrahedron 1988, 44, 3039-3071.
(6) Barton, D. H. R.; Yadav-Bhatnagar, N.; Finet, J .-P.; Khamsi, J .
Tetrahedron Lett. 1987, 28, 3111-3114.
(7) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016.
(8) Finet, J .-P.; Combes, S. Tetrahedron 1998, 54, 4313-4318.
(9) Sorenson, R. J . N-Arylations with triphenylbismuthane. Book
of Abstracts; 218th ACS National Meeting, New Orleans, LA, Aug 22-
26, 1999; American Chemical Society: Washington, D.C.; ORGN-523.
(10) (a) Banfi, A.; Bartoletti, M.; Bellora, E.; Bignotti, M.; Turconi,
M. Synthesis 1994, 775-776. (b) Klaveness, J .; Berg, A.; Almen, T.;
Golman, K.; Droege, M.; Yu, S. WO96/ 22994, Issued: August 1, 1996.
(c) For a review see Freedman, L. D.; Doak, G. O. Chem. Rev. 1982,
82, 15-57.
10.1021/jo000614m CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

7748 J . Org. Chem., Vol. 65, No. 23, 2000
Sorenson
Ta ble 2. N-Ar yla tion of Am in oben za m id esa ,b
Ta ble 1. Selective N-Ar yla tion of 3-Am in oben za n ilid esa ,b
entry
R1
R2
R3
compd isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
H
H
1
2
2
3
4
5
6
7
8
94
74
4-OMe
4-OMe
4-OMe 2-OMe
4-OMe 3,4-di-F
4-OMe
4-OMe
4-OMe
4-F
4-Cl
2-F
4-SMe
4-OCF3 4-F
0c
85
81
81
82
51
74
77
90
46
48
90
3-OBn
2-OMe
3-Cl
3,5-di-Me
3-CF3
H
3-CF3
3-CF3
3-CF3
H
H
H
3,4-di-F
H
H
H
9
10
11
12
13
4-OMe 4-CO2Me 3-CF3
a
Satisfactory 1H NMR, CIMS, and microanalyses were obtained
b
for all substrates and products. 1.0 equiv of substrate, 1.05 equiv
each of Ar3Bi, Cu(OAc)2, TEA in CH2Cl2; reflux; 3-20 h. cNo TEA
added.
9), for example, was prepared from 3-nitro-4-fluoroben-
zoic acid by formation of the acid chloride, reaction with
3,4-difluoroaniline, and subsequent catalytic reduction
of the nitro group.11
This method is remarkable for the mild conditions
required. Many of the arylations proceeded readily at
room temperature, though the time required to attain
completion was considerably shortened by heating under
reflux in dichloromethane. Tetrahydrofuran is also a
suitable solvent for the reaction, but in some experiments
its use resulted in a small amount of bis-arylation.
Palladium-catalyzed methodologies developed for the
amination of aryl halides,12 even when performed at room
temperature, often require the use a strong base that may
not be compatible with sensitive substrates. In contrast,
the method described here utilizes only triethylamine as
a promoter. Barton et al.5 were able to achieve the
formation of diarylamines without a promoter, but in a
control experiment in which triethylamine was omitted
(Table 1, entry 3) we were unable to push the chemose-
lective reaction to completion, despite prolonged heating
under reflux.
a
Satisfactory 1H NMR, CIMS, and microanalyses were obtained
b
for all substrates and products. 1.0 equiv of substrate, 1.05 equiv
each of Ar3Bi, Cu(OAc)2, TEA in CH2Cl2; room temp; 20 h. c See
ref 13.
1 equiv of the bismuth reagent was added. When an inert
atmosphere was maintained, it was in some cases neces-
sary to add a small additional amount of copper(II)
acetate after several hours to obtain full conversion of
the starting material. The effect of oxygen on the reaction
has been previously described.5
Table 2 illustrates the generalization of this method
to a broader array of substrates, including those in which
the relationship of the substituents is less favorable, as
in entries 1 and 2. Chemoselectivity is realized even when
the amino group of the benzanilide is part of a vinylogous
amide.
A limitation was encountered when a primary amide
was selected as the substrate, as shown in entry 3. In
this case a complex mixture of products was obtained,
from which previously characterized benzanilide 2 (6%
yield) was the only product isolated. This limitation was
not attributable to the selectivity being specific to N-
arylbenzamides, however, as N-cyclopropyl and N-methyl
analogues 20 and 22 were the only detectable products
of the arylation reaction shown in entries 4 and 5.
A minor drawback to this method is that only one of
the aryl groups of the bismuth reagent is transferred to
An inert atmosphere was not required during the
reaction: protection from atmospheric moisture was
sufficient. An experiment in which 1 equiv of water was
deliberately introduced to the reaction mixture resulted
in consumption of the organobismuth reagent without
concomitant appearance of product, even after another
(11) Connor, D. T.; Roark, W. H.; Sexton, K.; Sorenson, R. J . WO
9932433, 1999.
(12) (a) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
6054-6058. (b) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38,
4807-4810. (c) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 1998, 39, 617-620. (d) Yamamoto, T.; Nishiyama, M.; Koie, Y.
Tetrahedron Lett. 1998, 39, 2367-2370. (e) Hamann, B. C.; Hartwig,
J . F. J . Am. Chem. Soc. 1998, 120, 7369-7370.
(13) Legrand, L.; Lozac’h, N. Bull. Soc. Chim. Fr. 1973, (Part 2),
1665-1667.

Selective N-Arylation of Aminobenzanilides
J . Org. Chem., Vol. 65, No. 23, 2000 7749
oxy-phenyl)bismuthane were obtained similarly (see Supporting
Information, compounds 23 and 24). Tris(2-methoxyphenyl)-
bismuthane is commercially available from Aldrich Chemical
Co. Solvents were used without prior drying.
the substrate, and this may be a disadvantage in the case
of more elaborate aryl groups. Another consideration is
that the copper salt is required in stoichiometric amounts,
and its disposal may become a concern as the scale of
the reaction is increased. Since arylations using bismuth-
(V) reagents are known to be catalytic in copper,5 we are
currently investigating the selectivity of these conditions.
In summary, we have developed a practical and
versatile method for the selective N-arylation of amino
groups in functionalized aminobenzanilides that proceeds
under mild conditions using readily available, easily
handled reagents.
Rep r esen ta tive P r oced u r e for th e Ar yla tion Rea ction .
(3-(3-Ch lor op h en yla m in o)-4-m et h oxy-N-p h en ylb en za -
m id e (6). Copper(II) acetate (1.16 g, 6.4 mmol) was added to
a stirred mixture of 3-amino-4-methoxy-N-phenylbenzamide
(1.5 g, 6.2 mmol), tris(3-chlorophenyl)bismuthane (3.5 g, 6.4
mmol), and triethylamine (0.65 g, 6.4 mmol) in dichloro-
methane (120 mL), and the mixture was heated to reflux. After
4 h, heating was discontinued and the mixture diluted with
additional dichloromethane (150 mL) and stirred into 2 N
hydrochloric acid (200 mL). After 2 h, the layers were
separated, and the organic phase was washed successively
with 2 N HCl, water, 0.5 M aqueous potassium carbonate,
water, and saturated aqueous sodium chloride and then dried
over MgSO4. The solution was filtered and then stripped of
solvent under reduced pressure. The residue was chromato-
graphed on a column of silica gel in chloroform/ethyl acetate
(99:1) to afford the product (1.8 g, 82% yield): mp 163-165
°C. A sample was recrystallized from ethanol to give pure 6
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. The 1H
NMR spectra were recorded at 400 MHz in DMSO-d6. Chemi-
cal shifts are reported in ppm (δ) and referenced to the residual
proton signal for DMSO-d6 (2.49 ppm). The coupling constants
(J ) are reported in hertz. Elemental analyses were performed
by Quantitative Technologies Inc. and were within 0.4% of
theory. Reagents were obtained from commercial sources and
used without additional purification. Reaction progress was
monitored using EM Science precoated silica gel 60 F254 thin-
layer chromatography plates, eluting with CHCl3/EtOAc 9:1.
Biotage prepacked silica gel columns were used for chromato-
graphic purifications.
Ma ter ia ls. Substrates for Table 1, entries 1-3, 6-8, 10,
and Table 2, entries 1 and 2, were obtained from Apin
Chemicals Ltd. Benzamide 18 was obtained from Pfaltz &
Bauer, Inc. Substrates for Table 1, entries 5, 11, 12, and 13
were prepared according to published procedures.11 Substrates
for Table 1, entries 4 and 14 were prepared analogously to
that for Table 1, entry 8 (see Supporting Information for data).
Triphenylbismuthane was obtained from Alfa Aesar. The
preparation of tris(3-chlorophenyl)bismuthane and tris(3-
trifluoromethylphenyl)bismuthane is described in the litera-
ture.10 Tris(3,5-dimethylphenyl)bismuthane and tris(3-benzyl-
as glittering white scales: mp 168-170 °C; IR (KBr, cm-1
)
1
3395, 3322, 1647, 1589, 1519, 1245, 758; H NMR (DMSO) δ
10.02 (s, 1H), 7.80 (d, J ) 8.8 Hz, 2H), 7.68 (d, J ) 7.6 Hz,
2H), 7.62 (d, J ) 8.5 Hz, 1H), 7.27 (dd, J ) 7.9 Hz, 2H), 7.13
(m, 2H), 7.02 (t, J ) 7.3 Hz, 1H), 6.94 (m, 2H), 6.75 (d, J ) 7.8
Hz, 1H), 3.84 (s, 3H); MS (APCI), m/z 353.0, 355.0 (M+ + 1).
Anal. Calcd for C20H17ClN2O2: C, 68.09; H, 4.86; N, 7.94.
Found: C, 67.91; H, 4.71; N, 7.80.
Ack n ow led gm en t. The author is indebted to Drs.
David T. Connor and J ie J ack Li for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR for all
substrates, triarylbismuthanes, and products; microanalyses
and melting points for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O000614M