Rapid and efficient microwave-assisted synthesis of aryl aminobenzophenones using Pd-catalyzed amination

Article abstract of DOI:10.1021/jo049572i

Substituted aryl aminobenzophenone p38 MAP kinase inhibitors were synthesized in good to excellent yields using palladium-catalyzed aryl amination under conditions of microwave irradiation. Various ligands have been screened, and the reaction conditions w

Full text of DOI:10.1021/jo049572i

Ra p id a n d Efficien t Micr ow a ve-Assisted Syn th esis of Ar yl
Am in oben zop h en on es Usin g P d -Ca ta lyzed Am in a tion
Thomas A. J ensen, Xifu Liang, David Tanner,† and Niels Skjaerbaek*
Department of Medicinal Chemistry, LEO Pharma, Industriparken 55, DK-2750 Ballerup, Denmark, and
Department of Chemistry, Building 201, Technical University of Denmark,
DK-2800 Kgs. Lyngby, Denmark
nskdk@leo-pharma.com
Received March 16, 2004
Substituted aryl aminobenzophenone p38 MAP kinase inhibitors were synthesized in good to
excellent yields using palladium-catalyzed aryl amination under conditions of microwave irradiation.
Various ligands have been screened, and the reaction conditions were optimized. These coupling
reactions are suitable for various anilines and aryl bromides that bear a variety of functional groups.
Some leaving groups (iodides, chlorides, triflates, and tosylates) other than bromides have also
been investigated. By this method, a large number of aryl aminobenzophenone p38 MAP kinase
inhibitors were prepared in short order.
In tr od u ction
Activation of the p38 MAP kinase cascade has been
implicated in the production of the proinflammatory
cytokines interleukin 1â (Il-1â) and tumor necrosis factor
R (TNF-R).1 In response to this discovery, structurally
diverse p38 MAP kinase inhibitors have been sought for
the treatment of a variety of inflammatory diseases such
as rheumatoid arthritis.2 Aryl aminobenzophenones rep-
resent a new class of p38 MAP kinase inhibitors (Figure
1).3 EO-1221 (1) was found to have a high affinity for
p38R MAP kinase isoform and displayed effective inhibi-
tion of TNF-R and Il-1â release from human peripheral
blood mononuclear cells stimulated by LPS.
In an ongoing project with the aim of preparing this
type of inhibitor, an efficient amination of aryl halides
was required (Scheme 1). Toward this end two methods
have been used, the simplest being direct nucleophilic
substitution of aryl halides with anilines in the presence
of base, giving aryl aminobenzophenones. However, aryl
F IGURE 1. Structure of EO-1221(1) and its biological data.
SCHEME 1
† Technical University of Denmark.
(1) (a) Lee, J . C.; Laydon, J . T.; McDonnell, P. C.; Gallagher, T. F.;
Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J .; Heys, J . R.;
Landvatter, S. W.; Strickler, J . E.; Mclaughlin, M. M.; Siemens, I. R.;
Fisher, S. M.; Livi, G. P.; White, J . R.; Adams, J . L.; Young, P. R. Nature
1994, 372, 739-746. (b) Gallagher, T. F.; Seibel, G. L.; Kassis, S.;
Laydon, J . T.; Blumenthal, M. J .; Lee, J . C.; Lee, D.; Boem, J . C.; Fier-
Thompson, S. M.; Abt, J . W.; Sorensen, M. E.; Smietana, J . M.; Hall,
R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.; Krog, A. J .;
Hofmann, G. A.; Sheldrake, P. L.; McDonnell, P. C.; Kumar, S.; Young,
P. R.; Adams, J . L. Bioorg. Med. Chem. 1997, 5, 49-64. (c) Adams, J .
L.; Badger, A. M.; Kumar, S.; Lee, J . C. Prog. Med. Chem. 2001, 38,
1-60.
(2) For recent reviews, see: (a) Kumar, S.; Boehm, J .; Lee, J . C.
Nat. Rev. Drug Discov. 2003, 717-726. (b) Pargellis, C.; Regan, J . Curr.
Opin. Invest. Drugs 2003, 4, 566-571. (c) Chakravarty, S.; Dugar, S.
Ann. Rep. Med. Chem. 2002, 37, 177-186. (d) J ackson, P. F.; Bulling-
ton, J . L. Curr. Top. Med. Chem. 2002, 2, 1011-1020. (e) Boehm, J .
C.; Adams, J . L. Expert Opin. Ther. Patents 2001, 10, 25-37.
(3) Ottosen, E. R.; Sørensen, M. D.; Bjo¨rkling, F.; Skak-Nielsen, T.;
Fjording, M. S.; Aaes, H.; Binderup, L. J . Med. Chem. 2003, 46, 5651-
5662.
fluorides are very inert to nucleophiles under normal
conditions, except in cases where there are sustituents
of -M type (e.g., nitro or nitrile) in the ortho or para
position with respect to the fluorine atom. A more general
method is transition-metal-catalyzed amination of aryl
halides with anilines.
In recent years, the Pd-catalyzed amination of aryl
halides (or their equivalents such as triflates and tosy-
lates), which was independently developed by the groups
of Buchwald and Hartwig, has emerged as a “power tool”
10.1021/jo049572i CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004
4936
J . Org. Chem. 2004, 69, 4936-4947

Synthesis of Aryl Aminobenzophenones
for the synthesis of substituted anilines.4 This methodol-
ogy is now widely used in synthetic chemistry programs
in both academic and industrial settings. However, in our
hands, these Pd-catalyzed aminations typically required
reaction times from several hours to several days. In a
high-throughput synthetic context, it would obviously be
more attractive to have reaction times in the order of
minutes. Recently, high-speed microwave-assisted syn-
thesis has been applied successfully in many fields of
synthetic organic chemistry,5 the hallmark of performing
reactions under microwave irradiation conditions being
the significant rate enhancements and the higher product
yields that are frequently observed. These features have
been particularly welcomed in medicinal chemistry re-
search.
Although several reports of microwave-assisted Pd-
catalyzed aryl amination have appeared,6 these examples
were limited to amination of simple aromatic systems
that bear just a limited number of functional groups.
Moreover, palladium-catalyzed amination of aryl triflates
and tosylates under microwave-irradiation has not been
described so far. Herein we report our efforts to system-
atically optimize microwave-assisted synthesis of aryl
aminobenzophenones and the use of this technique in the
preparation of some p38 MAP kinase inhibitors.
Resu lts a n d Discu ssion
To optimize conditions for preparation of aryl ami-
nobenzophenones, the amination of bromobenzene with
4-aminobenzophenone was initially selected as a model
reaction for investigating the effects of various ligands,
Pd sources, solvents, bases, and temperatures.
First, effects of phosphine ligands on the reactivity
were examined. In a typical experiment, a mixture of
4-aminobenzophenone (1 equiv) and bromobenzene (1.2
equiv) in 1,4-dioxane was heated by microwave irradia-
tion at 100 °C for 10 min in the presence of Cs2CO3 (1.4
equiv), Pd2(dba)3 (1 mol %), and phosphine ligand (4 mol
%). The results of ligand screening are summarized in
Figure 2, and it can be seen that the extent of the
amination was dependent on the ligand used. Of the six
ligands screened, the highest yield (18%) was achieved
by using ligand B (X-Phos), while the other ligands gave
much lower yields. Buchwald and co-workers reported
F IGURE 2. Ligand effects on palladium-catalyzed amination
reaction of bromobenzene with 4-aminobenzophenone. Bro-
mobenzene (1.2 equiv), 4-aminobenzophenone (1.0 equiv), Cs2-
CO3 (1.4 equiv), Pd2(dba)3 (1 mol %), ligand (4 mol %), 1,4-
dioxane, MW 150 W, 100 °C, 10 min.
that the catalyst system based on ligand B exhibits both
dramatically increased activity and stability relative to
those based on simpler biaryl phosphine ligands.7 Recent
studies suggest that the high activity of catalyst systems
based on bulky phosphines results from their ability to
promote the formation of monophosphine complexes
(L1Pd0).8 However, our best result was still only 18%
yield, so we proceeded to further optimize the reaction
by varying other parameters: Pd source, solvent system,
base, and temperature.
As the Pd source has been previously shown to affect
the amination,9 two different Pd sources were investi-
gated, and the results are listed in Table 1. All cases
successfully provided amination products, but the use of
Pd(OAc)2 gave 2a in 40% yield instead of only 27% yield
when using Pd2(dba)3 under the same reaction conditions
(Table 1, entries 1 and 2). As a result of the copious
precipitation of inorganic salts, the magnetic stir bar was
trapped during the reaction, which caused elongation of
(4) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131-209. (b) Hartwig, J . F. In Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2000; pp
195-262. (c) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999,
576, 125-146. (d) Wolfe, J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805-818. (e) Hartwig, J . F. Angew.
Chem., Int. Ed. 1998, 37, 2046-2067.
(5) For reviews, see: (a) Perreux, L.; Loupy, A.; Tetrahedron 2001,
57, 9199-9223. (b) Lidstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J .
Tetrahedron 2001, 57, 9225-9283. (c) Lew, A.; Krutzik, P. O.; Hart,
M. E.; Chamberlin, A. R. J . Comb. Chem. 2002, 4, 95-105. (d)
Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem. 2002, 9,
1251-1283. (e) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717-727.
(6) For examples of microwave-assisted Pd-catalyzed aryl amina-
tions, see: (a) Weigand, K.; Pelka, S. Mol. Diver. 2003, 7, 181-184.
(b) McCarroll, A. J .; Sandham, D. A.; Titcomb, L. R.; Lewis, A. K. de
K; Cloke, F. G. N.; Davies, B. P.; de Santana, A. P.; Hiller, W.; Caddick,
S. Mol. Diversity 2003, 7, 115-123. (c) Maes, B. U. W.; Loones, K. T.
J .; Lemiere, G. L. F.; Dommisse, R. A. Synlett 2003, 1822-1825. (d)
Wang, T.; Magnin, D. R.; Hamann, L. G. Org. Lett. 2003, 5, 897-900.
(e) Wan, Y.; Alterman, M.; Hallberg, A. Synthesis 2002, 1597-1600.
(f) Sharifi, A.; Hosseinzadeh, R.; Mirzaei, M. Monatsh. Chem. 2002,
133, 329-332.
(7) Huang, X.; Anderson, K. W.; Zim, D.; J iang, L.; Klapars, A.;
Buchwald, S. L. J . Am. Chem. Soc. 2003, 125, 6653-6654.
(8) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J . Am. Chem.
Soc. 2003, 125, 13978-13980.
(9) Wolfe, J .; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144-1157.
J . Org. Chem, Vol. 69, No. 15, 2004 4937

J ensen et al.
TABLE 1. P d Sou r ce Effects on P a lla d iu m -Ca ta lyzed
Am in a tion Rea ction of Br om oben zen e w ith
4-Am in oben zop h en on ea
TABLE 4. Tem p er a tu r e Effects on P a lla d iu m -Ca ta lyzed
Am in a tion Rea ction of Br om oben zen e w ith
4-Am in oben zop h en on ea
entry
Pd source
temp (°C)
time (min)
yield (%)b
1
2
3
4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
100c
100c
140d
140d
20
20
25
25
27
40
68
84e
a
Reagents: bromobenzene (1.2 equiv), 4-aminobenzophenone
(1.0 equiv), Cs2CO3 (1.4 equiv), Pd(0) (1 mol %) or Pd(II) (2 mol
b
%), ligand B (4 mol %), 1,4-dioxane. Isolated yield based on
d
4-aminobenzophenone. c MW, 150 W. MW, 200 W. e The reaction
was performed in the presence of Celite [Cs2CO3/Celite 2/1
(w/w)].
entry temp (°C) time (min) PhBr (equiv) 2a :3 yield (%)b
TABLE 2. Solven t Effects on P a lla d iu m -Ca ta lyzed
Am in a tion Rea ction of Br om oben zen e w ith
4-Am in oben zop h en on ea
1
2
3
4
5
6
7
8
100
120
120
140
160
120
120
120
10
5
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.0
72:2c
73:20
67:25
nde
nd
nd
nd
nd
72d
73
67
64
62
88
89
81f
10
10
10
10
3
entry
solvent
yield (%)b
1
2
3
4
5
6
1,4-dioxane
toluene
t-butanol
toluene/tert-butyl alcohol 1:1
toluene/tert-butyl alcohol 5:1
toluene/tert-butyl alcohol 10:1
48
38
54
58
65
42
1
a
Reagents and conditions: bromobenzene, 4-aminobenzophe-
none (1.0 equiv), NaOt-Bu (1.4 equiv), Pd(OAc)2 (2 mol %), ligand
b
B (4 mol %), tert-butyl alcohol/toluene (1/5), MW 200 W. Isolated
a
Reagents and conditions: bromobenzene (1.2 equiv), 4-amino-
benzophenone (1.0 equiv), Cs2CO3 (1.4 equiv), Pd(OAc)2 (2 mol %),
yield for 2a based on 4-aminobenzophenone. c The ratio was
d
calculated on the basis of the isolated products. 22% of 4-
b
ligand B (4 mol %), MW 150 W, 100 °C, 20 min. Isolated yield
aminobenzophenone was isolated. e nd ) not determined. f The
based on 4-aminobenzophenone.
reaction was not complete according to TLC control.
TABLE 3. Ba se Effects on P a lla d iu m -Ca ta lyzed
Am in a tion Rea ction of Br om oben zen e w ith
4-Am in oben zop h en on ea
conditions (1.2 equiv of bromobenzene, 1.0 equiv of
4-aminobenzophenone, 1.4 equiv of NaOt-Bu, 2 mol % of
Pd(OAc)2, 4 mol % of ligand B, MW 200 W) at various
temperatures and reaction times. When run at 100 °C
for 10 min, the reaction was incomplete and the desired
product 2a was obtained in 72% yield together with 22%
of recovered 4-aminobenzophonone and 2 % of diarylation
byproduct 3 (Table 4, entry 1). However, raising the
temperature resulted in a significant amount of 3 and
decreased the yields of 2a (Table 4, entries 2-5). The low
yield of 2a was clearly caused by the presence of the
excess bromobenzene, and decreasing the ratio of 4-ami-
nobenzophenone and bromobenzene to 1:1 greatly af-
fected the ratio of 2a and 3. Use of a 1:1 ratio of coupling
partners led to 2a in 89% yield under optimized condi-
tions (1.0 equiv of bromobenzene, 1.0 equiv of 4-amino-
benzophenone, 1.4 equiv of NaOt-Bu, 2 mol % of
Pd(OAc)2, 4 mol % of ligand B, MW 200 W) after 3 min
(Table 4, entries 6 and 7). In the last entry of Table 4,
total conversion was not achieved after 1 min, giving
relatively lower yield (Table 4, entry 8).
entry
base
yield (%)b
1
2
3
4
K3PO4
K2CO3
Cs2CO3
NaOt-Bu
29
13
65
78
a
Reagents and conditions: bromobenzene (1.2 equiv), 4-amino-
benzophenone (1.0 equiv), base (1.4 equiv), Pd(OAc)2 (2 mol %),
ligand B (4 mol %), tert-butyl alcohol/toluene (1/5), MW 200 W,
b
100 °C, 20 min. Isolated yield based on 4-aminobenzophenone.
reaction time (Table 1, entry 3). To alleviate this situa-
tion, Celite was added and this indeed provided a better
yield in the same time period (Table 1, entry 4).
We also explored several solvent systems: 1,4-dioxane
and toluene are two common solvents used for the aryl
amination, while tert-butyl alcohol and tert-butyl alcohol/
toluene have been used for the amination of aryl sul-
fonates by Buchwald et al.8 Our results are summarized
in Table 2. It was found that tert-butyl alcohol was
superior to 1,4-dioxane and toluene (Table 2, entries
1-3). However, the combination of toluene/tert-butyl
alcohol was found to be even more effective, the best yield
(65%) being achieved when a 5:1 ratio of toluene/tert-
butyl alcohol was used (Table 2, entries 4-6).
The use of other bases, for example, K3PO4, K2CO3, and
NaOt-Bu, was then investigated, and the results are
presented in Table 3. Using K3PO4 and K2CO3, 2a was
obtained in 29% and 13% yield, respectively (Table 3,
entries 1 and 2), whereas using NaOt-Bu gave higher
yield (78%) than when using Cs2CO3 (65%) (Table 3,
entries 3 and 4).
Having now changed so many reaction parameters, we
wished to determine whether ligand B was still the best
for the model reaction, so we reinvestigated the effect of
ligands. Two more ligands were screened. The results are
outlined in Figure 3. The reactions were run for 3 min,
and all the ligands gave better yields than in the original
screening. Although ligand B was still found to perform
very efficiently, ligand C now proved to be equally
effective, giving 2a in 91% yield. The use of ligands A,
D, and F gave moderate to good yields, and ligands E, G
and H were found to be the least effective. Recently,
methods for direct amination of aryl halides and triflates
with amines and anilines under microwave irradiation
Finally, we explored the temperature effect (Table 4).
The reaction was carried out under the standard set of
4938 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of Aryl Aminobenzophenones
substrate, leading to catalyst deactivation.12 Aryl and
pyridyl chlorides can also be aminated in high yields
(Table 5, entries 11 and 12). For aryl bromides bearing
base-sensitive functional groups such as nitro and nitrile,
the reactions turned out to be less effective. Buchwald
et al. found out that by using Cs2CO3, the reaction
conditions are sufficiently mild to tolerate the presence
of nitrile and nitro groups, which are incompatible with
reaction conditions that employ NaOt-Bu as the stoichio-
metric base.13 We thus examined the amination of aryl
bromides bearing nitro and nitrile functional groups
using Cs2CO3 as base and found that higher yields could
indeed be achieved for the amination of 1-bromo-3-
nitrobenzene and 4-bromobenzonitrile, respectively (Table
5, entries 15 and 16). Amination of aryl triflates with
NaOt-Bu as base gave only low yields (Table 5, entry 14),
which is attributable to cleavage of the triflate by attack
of NaOt-Bu on sulfur, leading to the formation of sodium
phenoxide.11a,c However, the use of Cs2CO3 in place of
NaOt-Bu led to much higher yield (Table 5, entry 18).
Amination of aryl tosylates turned out to be more difficult
even if Cs2CO3 was used as base (Table 5, entries 13 and
17). First, even using Cs2CO3 might not effectively
prevent cleavage of the tosylate, and second excessive
precipitation caused incomplete (vide supra).
We then explored the more challenging coupling of aryl
bromides with 4-amino-2-chloro-2′-methylbenzophenone;3
the results are outlined in Table 6. Two byproducts (5a
and 6a ) were observed (Table 6, entry 1), 6a arising from
amination of 4-amino-2-chloro-2′-methylbenzophenone by
another molecule of 4-amino-2-chloro-2′-methylbenzophe-
none. This gave two problems: (i) to form one molecule
of 6a , two molecules of 4-amino-2-chloro-2′-methylben-
zophenone are required, thus lowering the yield (71%)
of the desired product (Table 6, entry 1); (ii) as a result
of the similar polarities of 4a and 6a , it was difficult to
separate the desired product by chromatography. To
suppress the undesired reaction, the amount of aryl
bromide was increased, and when 1.5 equiv of aryl
bromide was used, a higher yield of the desired product
(79%) was achieved (Table 6, entry 2). Under these
conditions, some aryl bromides bearing various functional
groups were chosen for the amination reaction (Table 6,
entries 3-11). All of the reactions were complete within
3 min, with good yields. Amination of 4-iodotoluene
expectedly turned out to be a fast reaction as well, giving
4k in 75% yield (Table 6, entry 12). Considering the issue
of compatibility of functional groups, the base was again
switched from NaOt-Bu to Cs2CO3 for amination of aryl
bromides bearing nitro and nitrile groups (Table 6,
entries 14 and 15). As expected, longer reaction times
were needed, but the yields are comparable. Entry 15 of
Table 6 shows a more complicated situation: besides the
two above-mentioned byproducts 5 and 6, a third byprod-
uct, trione 7, was observed (Scheme 2). The structure of
7 was deduced from 1H and 13C NMR spectroscopy in
combination with HRMS. Clearly, trione 7 was formed
by further amination of 6k with 4-amino-2-chloro-2′-
methylbenzophenone, implying that the aryl triflate
substrate is not as reactive as the corresponding aryl
iodide or bromide.
F IGURE 3. Ligand effects on palladium-catalyzed amination
reaction of bromobenzene with 4-aminobenzophenone.
without a transition-metal catalyst have been reported.10
To rule out this possible mechanism shift, the amination
reaction was carried out in the absence of Pd catalyst
and ligand B under otherwise identical conditions. No
reaction occurred, thus demonstrating that the catalyst
was indeed necessary. The same reaction using ligand
B was also carried out using an oil bath to heat the
reaction mixture under the same conditions as for the
microwave-assisted reaction. As expected, a much longer
reaction time (70 min) was needed for the same degree
of conversion.
The above systematic investigations suggested that
ligands B and C are highly effective for the amination of
bromobenzene with 4-aminobenzophenone in the pres-
ence of NaOt-Bu. With optimized conditions in hand, we
subsequently explored the substrate scope of the reaction
with various aryl bromides, chlorides, triflates,11 and
tosylates.7,12 Considering its high activity in all cases,
ligand B was our choice for further experimentation, and
the results (summarized in Table 5) show that a variety
of aryl bromides can be coupled to differently substituted
anilines. Both electron-neutral and electron-rich aryl
bromides reacted efficiently under the optimized condi-
tions, giving the desired arylamines in high isolated
yields (Table 5, entries 1-6). When electron-rich aryl
bromides were aminated, higher temperature was needed
(Table 5, entries 7 and 8). Selective substitution of Br
over Cl can be achieved in the coupling of 2-bromo-1-
chlorobenzene with 4-aminobenzophenone (Table 5, entry
9). Amination of 3-bromopyridine turned out to be a slow
reaction even at higher temperature (Table 5, entry 10).
The reason is probably that nonchelating triarylphos-
phines can be displaced from the metal by the pyridine
(10) For microwave-assisted direct amination of halides and triflate,
see: (a) Shi, L.; Wang, M.; Fan, C.; Zhang F.; Tu, Y. Org. Lett. 2003,
5, 3515. (b) Brown, G. R.; Foubister, A. J .; Roberts, C. A.; Wells, S. L.;
Wood, R. Tetrahedron Lett. 2001, 42, 3917. (c) Xu, G.; Wang, Y. Org.
Lett. 2004, 6, 985-987.
(11) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1264-
1267. (b) Louie, L.; Driver, M. S.; Hamann, B. C.; Hartwig, J . F. J .
Org. Chem. 1997, 62, 1268-1273. (c) Åhman, J .; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6363-6366.
(12) (a) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120,
7369-7370. (b) Bolm, C.; Hildebrand, J . P.; Rudolph, J . Synthesis 2000,
911-913.
(13) (a) Wolfe, J . P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6359-6362. (b) Ali, M. H.; Buchwald, S. L. J . Org. Chem. 2001, 66,
2560-2565.
J . Org. Chem, Vol. 69, No. 15, 2004 4939

J ensen et al.
TABLE 5. Rea ction s of Ar yl Br om id es, Ar yl Ch lor id es, Ar yl Tosyla te, a n d Ar yl Tr ifla te w ith Am in oben zop h en on e
a
Reagents: bromobenzene (1.0 equiv), 4-aminobenzophenone (1.0 equiv), base (1.4 equiv), Pd(OAc)2 (2 mol %), ligand B (4 mol %),
tert-butyl alcohol/toluene (1/5). Isolated yield based on 4-aminobenzophenone. c The reaction was performed in the presence of Celite.
b
4940 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of Aryl Aminobenzophenones
TABLE 6. Rea ction of Ar yl Br om id es, Ar yl Iod id e, a n d Ar yl Tr ifla te w ith 4-Am in o-2-ch lor o-2′-m eth ylben zop h en on ea
a
Reagents and conditions: bromobenzene (1.0 equiv), 4-aminobenzophenone (1.0 equiv), base (1.4 equiv), Pd(OAc)2 (2 mol %), ligand
B (4 mol %), tert-butyl alcohol/toluene (1/5), MW 250 W, 150 °C. Isolated yield based on 4-aminobenzophenone. c The reaction was
b
performed in the presence of Celite.
We were also interested in performing the aryl ami-
nation in an alternative mode, because of the large
number of readily available anilines. Therefore, we
examined the coupling of substituted 4-bromobenzo-
phenones with various anilines, the starting material (9)
being readily prepared in three steps (Scheme 3). Ac-
J . Org. Chem, Vol. 69, No. 15, 2004 4941

J ensen et al.
TABLE 7. Am in a tion of 9 w ith Va r iou s An ilin esa
SCHEME 2 a
a
Reagents and conditions: see reagents and conditions for
Table 6, entry 15.
SCHEME 3 a
a
Reagents and conditions: (a) isopropylmagnesiumchloride,
THF, -60 °C, 2 h; (b) 2-methylbenzaldehyde, THF, rt, 2 h (92%
over two steps); (c) Dess-Martin periodinane, CH2Cl2, rt, 30 min
(94%).
cording to Knochel’s protocol,14,15 a functionalized aryl
iodide was reacted with i-PrMgCl in THF at -60 °C for
2 h, leading to halogen-metal exchange. Reaction of the
newly formed Grignard reagent with 2-methylbenzalde-
hyde at room temperature for 2 h then furnished alcohol
8 in 92% yield. Finally, oxidation of 8 with the Dess-
Martin periodinane provided benzophenone 9 in 94%
yield.
Substrate 9 was then subjected to amination with
several different anilines; the results are presented in
Table 7. The reaction was first carried out by using
NaOt-Bu as base, which led to a complicated product
distribution and isolation of only 24% of the desired
product 4a (Table 7, entry 1). Fortunately, replacement
of NaOt-Bu by Cs2CO3 led to a much higher yield (79%),
although a longer reaction time was required (Table 7,
entry 2). Coupling of other anilines also gave good yields
under the same conditions (Table 7, entries 3-7).
In summary, we have developed a convenient protocol
for the rapid and efficient preparation of aryl aminoben-
zophenones from the corresponding anilines and aryl
halogens (or triflates). Amination of an electronically
diverse array of aryl halides with a variety of anilines
was realized with good to excellent yields, and it was not
a
Reagents and conditions: 9 (1.0 equiv), aniline (1.0 equiv),
base (1.4 equiv), Pd(OAc)2 (2 mol %), ligand B (4 mol %), tert-butyl
b
alcohol/toluene (1/5), MW 250 W, 150 °C. Isolated yield based
on (4-bromo-2-chlorophenyl)(2-methyl)methanone. c The reaction
was performed in the presence of Celite.
necessary to work under an inert atmosphere. Unfortu-
nately, coupling of aryl tosylates under conditions of
microwave irradiation turned out to be sluggish, and in
some cases the chemoselectivity of the process was not
satisfactory. However, in general, the procedure is suit-
able for the preparation of a large number of aryl
aminobenzophenones and also for automated library
production. High-throughput medicinal chemistry efforts
are currently under way using this technique.
Exp er im en ta l Section
{4-[(4-F lu or op h e n yl)a m in o]p h e n yl}(p h e n yl)m e t h -
a n on e (2b). General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 2-bromo-4-
fluorobenzene (175.0 mg, 1.00 mmol), using ligand B (17.1 mg,
0.04 mmol). The reaction was conducted under microwave
irradiation (200 W) at 120 °C for 12 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to yield 264.1 mg (91%) of the title
compound as a yellow solid: mp 155-157 °C; 1H NMR (CDCl3,
300 MHz) δ 7.77-7.72 (m, 4H), 7.54-7.51 (ddt, J ) 1.1, 5.7,
7.1 Hz, 1H) 7.47-7.45 (m, 2H), 7.19-7.14 (m, 2H), 7.07-7-
01 (m, 2H), 6.92-6.88 (dt, J ) 2.7, 7.1 Hz, 2H), 6.14 (s, 1H);
(14) Varchi, G.; Ricci, G.; Gahiez, G.; Knochel, P. Tetrahedron 2000,
56, 2727-2731.
(15) For a review, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem., Int. Ed. 2003, 42, 4302-4320.
4942 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of Aryl Aminobenzophenones
13C NMR (CDCl3, 75.4 MHz) δ 195.2, 159.3 148.9, 138.7, 136.5,
132.8, 131.6, 129.6, 128.4, 128.1, 123.6, 116.3, 113.7; HRMS
(EI) (M+) calcd for C20H17NO 291.1059, found 291.1053.
7.08 (m, 2H), 6.86-6.79 (m, 4H), 2.94 (s, 6H); 13C NMR
(CD3OD, 75.4 MHz) δ 197.4, 153.3, 149.6, 140.5, 134.2, 132.6,
132.1, 130.4, 129.3, 126.9, 125.2, 115.4, 113.5, 41.6; HRMS (EI)
(M+) calcd for C21H20N2O 316.1576, found 316.1566.
[4-(2-Me t h y lp h e n y la m in o )p h e n y l](p h e n y l)m e t h -
a n on e (2c). General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 2-bromotoluene
(171.0 mg, 1.00 mmol), using ligand B (17.1 mg, 0.04 mmol).
The reaction was conducted under microwave irradiation (200
W) at 120 °C for 6 min. The crude material was purified by
flash column chromatography (ethyl acetate/petroleum ether
1:8), to yield 274.4 mg (96%) of the title compound as a yellow
{4-[(2-Met h oxyp h en yl)a m in o]p h en yl}(p h en yl)m et h -
a n on e (2h ).18 General Procedure 6 was used to couple
4-aminobenzophenone (197.2 mg, 1.00 mmol) with 2-bro-
moanisole (187.0 mg, 1.00 mmol), using ligand B (17.1 mg,
0.04 mmol). The reaction was conducted under microwave
irradiation (300 W) at 160 °C for 10 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to yield 275.4 mg (91%) of the title
compound as a yellow solid: mp 93-95 °C (lit.18 mp 130 °C);
1H NMR (DMSO, 300 MHz) δ 8.27 (s, 1H), 7.67-7.52 (m, 7H),
7.33-7.30 (m, 1H), 7.11-7.09 (m, 2H), 6.97-6.94 (m, 3H), 3.81
(s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 193.5, 151.9, 149.7,
138.6, 132.0, 131.3, 129.1, 128.9, 128.2, 126.0, 124.3, 122.3,
1
solid: mp 133-134 °C; H NMR (CDCl3, 300 MHz) δ 7.77-
7.72 (m, 4H), 7.56-7.50 (tt, J ) 1.5, 7.3 Hz, 1H), 7.47-7.42
(m, 2H), 7.31-7.21 (m, 3H), 7.12-7.09 (dt, J ) 1.2, 7.3 Hz,
1H), 6.83-6.80 (dt, J ) 1.9, 8.9 Hz, 2H), 5.85 (s, 1H), 2.26 (s,
3H); 13C NMR (CDCl3, 75.4 MHz) δ 195.2, 149.4, 138.8, 138.7,
132.8, 132.0, 131.4, 131.3, 129.5, 128.1, 128.0 127.0, 124.9,
123.3, 113.8, 17.9; HRMS (EI) (M+) calcd for C20H17NO
287.1310, found 287.1324.
120.5, 113.3, 112.0, 55.4; HRMS (EI) (M+) calcd for C20H17
NO2 303.1259, found 303.1247.
-
[4-(2-C h lo r o p h e n y la m in o )p h e n y l](p h e n y l)m e t h -
a n on e (2i). General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 2-chloro-bro-
mobenzene (191.5 mg, 1.00 mmol), using ligand B (17.1 mg,
0.04 mmol). The reaction was conducted under microwave
irradiation (200 W) at 160 °C for 15 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to yield 252.1 mg (82%) of the title
compound as a yellow solid: mp 123-125 °C; 1H NMR (CDCl3,
300 MHz) δ 7.82-7.75 (m, 4H), 7.56 (dt, J ) 1.5, 7.3 Hz, 1H),
7.50-7.40 (m, 4H), 7.25 (m, 1H), 7.14 (t, J ) 2.3 Hz, 1H), 7.11
(t, J ) 1.9 Hz, 1H), 6.97-6.96 (dt, J ) 1.5, 8.0 Hz, 1H), 6.34
(s, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 195.2, 146.6, 138.4,
137.9, 132.5, 131.8, 130.1, 130.1 129.7, 128.2, 127.5, 124.2,
123.0, 119.1, 116.0; HRMS (EI) (M+) calcd for C19H14ClNO
307.0769, found 307.0779.
(4-{[3-(Tr iflu or om eth yl)ph en yl]am in o}ph en yl)(ph en yl)-
m eth a n on e (2d ). General Procedure 6 was used to couple
4-aminobenzophenone (197.2 mg, 1.00 mmol) with 3-bromo-
trifluoromethylbenzene (225.1 mg, 1.00 mmol), using ligand
B (17.1 mg, 0.04 mmol). The reaction was conducted under
microwave irradiation (200 W) at 120 °C for 9 min. The crude
material was purified by flash column chromatography (ethyl
acetate/petroleum ether 1:8), to give 282.2 mg (84%) of the title
compound as a yellow solid: mp 169-171 °C; 1H NMR (DMSO,
300 MHz) δ 9.19 (s, 1H), 7.76-7.52 (m, 9H), 7.45 (s, 1H), 7.30-
7.29 (m, 1H), 7.21 (d, J ) 8.8 Hz, 2H); 13C NMR (DMSO, 75.4
MHz) δ 193.8, 147.3, 142.3, 138.2, 132.2, 131.7, 130.5, 130.1
129.0, 128.3, 128.0, 124.1, 121.8, 117.6 114.9, 114.6; HRMS
(EI) (M+) calcd for C20H14F3NO 341.1027, found 341.1013.
[4-(2,4-Diflu or op h en yla m in o)p h en yl](p h en yl)m et h -
a n on e (2e). General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 2,4-difluorobro-
mobenzene (193.0 mg, 1.00 mmol), using ligand B (17.1 mg,
0.04 mmol). The reaction was conducted under microwave
irradiation (200 W) at 120 °C for 10 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to yield 272.5 mg (88%) of the title
compound as a yellow solid: mp 147-149 °C; 1H NMR (DMSO,
300 MHz) δ 8.63 (s, 1H), 7.67-7.33 (m, 9H), 7.14-7.07 (m,
1H), 6.89 (s, 1H), 6.86 (s, 1H); 13C NMR (DMSO, 75.4 MHz) δ
193.7, 160.1, 157.1, 154.0, 149.4, 138.4, 132.1, 131.5, 128.6,
126.7, 126.1, 124.8, 113.1, 111.8, 104.9; HRMS (EI) (M+) calcd
for C19H13F2NO 309.0965, found 309.0951.
{4-[3-(1,3-Dioxolan -2-yl)ph en ylam in o]ph en yl}(ph en yl)-
m eth a n on e (2f). General Procedure 6 was used to couple
4-aminobenzophenone (197.2 mg, 1.00 mmol) with 2-(3-bro-
mophenyl)-1,3-dioxolane (229.1 mg, 1.00 mmol), using ligand
B (17.1 mg, 0.04 mmol). The reaction was conducted under
microwave irradiation (200 W) at 120 °C for 6 min. The crude
material was purified by flash column chromatography (ethyl
acetate/CH2Cl2 1:20), to yield 290.8 mg (84%) of the title
compound as a yellow solid: mp 147-149 °C; 1H NMR (DMSO,
300 MHz) δ 8.96 (s, 1H), 7.70-7.51 (m, 7H), 7.35 (t, J ) 7.7
Hz, 1H), 7.26-7.23 (m, 2H), 7.12-7.05 (m, 3H), 5.73 (s, 1H),
4.07-3.90 (m, 4H); 13C NMR (DMSO, 75.4 MHz) δ 194.5, 149.3,
142.0, 140.4, 139.3, 133.2, 132.4, 130.1, 129.8, 129.2, 127.8,
121.1, 120.7, 118.3, 114.8, 103.4, 65.6; HRMS (EI) (M+) calcd
for C22H19NO3 345.1365, found 345.1370.
[4-(P yr id in -3-yla m in o)p h en yl](p h en yl)m eth a n on e (2j).
General Procedure 6 was used to couple 4-aminobenzophenone
(197.2 mg, 1.00 mmol) with 3-bromopyridine (158.0 mg, 1.00
mmol), using ligand B (17.1 mg, 0.04 mmol). The reaction was
conducted under microwave irradiation (300 W) at 160 °C for
20 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:1), to yield
250.3 mg (91%) of the title compound as a yellow solid: mp
1
108-110 °C; H NMR (CD3OD, 300 MHz) δ 8.41 (d, J ) 2.7
Hz, 1H), 8.15 (dd, J ) 1.5, 4.9 Hz, 1H), 7.75-7.67 (m, 5H),
7.59 (dt, J ) 1.5, 7.3 Hz, 1H), 7.51 (m, 2H), 7.35 (dd, J ) 4.9,
8.4 Hz, 1H), 7.14 (t, J ) 2.3 Hz, 1H), 7.11 (t, J ) 2.3 Hz, 1H);
13C NMR (CD3OD, 75.4 MHz) δ 197.3, 149.4, 143.2, 141.9,
140.4, 139.8, 133.8, 133.1, 130.6, 130.0 129.4, 127.7, 125.6,
115.8; HRMS (EI) (M+) calcd for C18H14N2O 274.1106, found
274.1103.
2j. General Procedure 6 was used to couple 4-aminoben-
zophenone (197.2 mg, 1.00 mmol) with 3-chloropyridine (113.6
mg, 1.00 mmol, using ligand B (17.1 mg, 0.04 mmol). The
reaction was conducted under microwave irradiation (300 W)
at 160 °C for 20 min. The crude material was purified by flash
column chromatography (ethyl acetate/petroleum ether 1:1),
to give 250.3 mg (91%) of the title compound as a yellow solid.
The spectroscopic data are identical with those described above
for 2j.
{4-[(4-Me t h ylp h e n yl)a m in o]p h e n yl}(p h e n yl)m e t h -
a n on e (2k ).19 General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 4-chlorotoluene
(126.6 mg, 1.00 mmol), using ligand B (17.1 mg, 0.04 mmol).
(4-{[4-(Dim eth ylam in o)ph en yl]am in o}ph en yl)(ph en yl)-
m et h a n on e (2g). General Procedure 6 was used to couple
4-aminobenzophenone (197.2 mg, 1.00 mmol) with 4-bromo-
N,N-dimethylaniline (200.1 mg, 1.00 mmol), using ligand B
(17.1 mg, 0.04 mmol). The reaction was conducted under
microwave irradiation (300 W) at 160 °C for 15 min. The crude
material was purified by flash column chromatography (ethyl
acetate/CH2Cl2 1:20), to yield 269.8 mg (85%) of the title
(16) Kamikawa, K.; Sugimoto, S.; Uemura, M. J . Org. Chem. 1998,
63, 8407-8410.
(17) Staskun, B. J . Org. Chem. 1968, 33, 3031-3036.
(18) Bhavsar, M. D.; Saraiya, P. N. Man-Made Text. India 1986,
29, 224-230. In this literature the compound 2h was not fully
characterized. Only IR data and melting point for 2h were found.
(19) Birchall, J . M.; Clark, M. T. J . Chem. Soc., Perkin. Trans. 1
1973, 1259-1263.
1
compound as a yellow solid: mp 129-131 °C; H NMR (CD3-
OD, 300 MHz) δ 7.67-7.63 (m, 4H), 7.56-7.45 (m, 3H), 7.11-
J . Org. Chem, Vol. 69, No. 15, 2004 4943

J ensen et al.
The reaction was conducted under microwave irradiation (300
W) at 160 °C for 10 min. The crude material was purified by
flash column chromatography (ethyl acetate/petroleum ether
1:8), to give 260.6 mg (91%) of the title compound as a yellow
solid: mp 128-130 °C (lit.19 mp 126-127 °C); 1H NMR (CDCl3,
300 MHz) δ 7.77-7.72 (m, 4H), 7.53 (dt, J ) 1.5, 7.3 Hz, 1H),
7.47-7.41 (m, 2H), 7.17-7.08 (m, 4H), 6.95 (t, J ) 2.3 Hz, 1H),
6.92 (t, J ) 1.5 Hz, 1H), 6.11 (s, 1H), 2.33 (s, 3H); 13C NMR
(CDCl3, 75.4 MHz) δ 195.1, 149.0, 138.8, 137.9, 133.4, 132.8,
131.5, 130.1, 129.6, 128.2, 128.1, 121.6, 113.8, 60.4; HRMS (EI)
(M+) calcd calcd for C20H17NO 287.1310, found 287.1305.
2k . General Procedure 6 was used to couple 4-aminoben-
zophenone (197.2 mg, 1.00 mmol) with 4-tolyl 4-toluene-
sulfonate (262.3 mg, 1.00 mmol), using ligand B (17.1 mg, 0.04
mmol). The reaction was conducted under microwave irradia-
tion (300 W) at 160 °C for 30 min. The crude material was
purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to give 62.8 mg (22%) of the title
compound as a yellow solid. The spectroscopic data are
identical with those described above for 2k .
2k . General Procedure 6 was used to couple 4-aminoben-
zophenone (197.2 mg, 1.00 mmol) with 4-tolyl triflate (240.2
mg, 1.00 mmol), using ligand B (17.1 mg, 0.04 mmol). The
reaction was conducted under microwave irradiation (300 W)
at 160 °C for 30 min. The crude was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to give
129.9 mg (45%) of the title compound as a yellow solid. The
spectroscopic data are identical with those described above for
2k .
instead of NaOt-Bu, Cs2CO3 as base. The reaction was
conducted under microwave irradiation (300 W) at 160 °C for
15 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum 1:8), to give 261.1
mg (91%) of the title compound as a yellow solid. The
spectroscopic data are identical with those described before
for 2k .
{2-Ch lor o-4-(p h en yla m in o)p h en yl}(2-m et h ylp h en yl)-
m eth a n on e (4a ),3 [2-Ch lor o-4-(d ip h en yla m in o)p h en yl](2-
m eth ylp h en yl)m eth a n on e (5a ), a n d [(2-{[2-Ch lor o-4-(2-
m eth ylben zoyl)]ph en ylam in o}-4-ph en ylam in o)ph en yl](2-
m eth ylp h en yl)m eth a n on e (6a ). General Procedure 7 was
used to couple (4-amino-2-chlorophenyl)(2-methylphenyl)-
methanone (245.7 mg, 1.00 mmol) with bromobenzene (235.5
mg, 1.50 mmol), using NaOt-Bu (134.5 mg, 1.40 mmol). The
reaction was conducted under microwave irradiation (250 W)
at 150 °C for 3 min. The ratio of the crude products was
determined by 1H NMR spectroscopy. The crude material was
purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4a (252.8 mg, 79%) as a yellow
solid, 5a (40.1 mg) as a yellow solid and 6a (10.1 mg) as a
yellow syrup. 4a : mp 93-95 °C (lit.3 mp 79-82 °C). 5a : 1H
NMR (CDCl3, 300 MHz) δ 7.37-7.13 (m, 15H), 6.97 (d, J )
2.3 Hz, 1H), 6.85(dd, J ) 2.3, 8.8 Hz,1H), 2.47 (s, 3H); 13C NMR
(CDCl3, 75.4 MHz) δ 196.5, 151.3, 146.1, 138.9, 138.2, 134.3,
132.6, 131.4, 131.0, 130.3, 129.9, 129.8, 126.1, 125.4, 125.0,
121.3, 117.7, 20.5. 6a : 1H NMR (DMSO, 300 MHz) δ 10.94 (s,
1H), 9.05 (s, 1H), 7.53-7.02 (m, 18H), 6.50 (dd, J ) 1.9, 8.8
Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO, 75.4 MHz)
δ 197.7, 195.6, 150.4, 147.0, 144.4, 140.3, 137.9, 137.4, 137.0,
134.3, 132.5, 132.3, 131.5, 131.4, 131.3, 130.3, 129.7, 129.2,
129.0, 126.8, 125.7, 125.3, 122.8, 120.7, 120.6, 118.4, 112.7,
106.9, 98.0, 20.1, 19.0; HRMS (EI) (M+) calcd for C34H27ClN2O2
530.1761, found 530.1749.
{4-[(3-N it r o p h e n y l)a m in o ]p h e n y l}(p h e n y l)m e t h -
a n on e (2l). General Procedure 6 was used to couple 4-ami-
nobenzophenone (197.2 mg, 1.00 mmol) with 3-bromonitroben-
zene (202.0 mg, 1.00 mmol), using ligand B (17.1 mg, 0.04
mmol) and instead of NaOt-Bu, Cs2CO3 as base. The reaction
was conducted under microwave irradiation (300 W) at 160
°C for 20 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to give
255.1 mg (80%) of the title compound as a yellow solid: mp
{2-Ch lor o-4-[(3-ch lor op h en yl)a m in o]p h en yl}(2-m eth -
ylp h en yl)m et h a n on e (4b ),20 (2-Ch lor o-4-{[d i(3-ch lor o-
ph en yl)]am in o}ph en yl)(2-m eth ylph en yl)m eth an on e (5b),
a n d [(2-{[2-Ch lor o-4-(2-m eth ylben zoyl)]p h en yla m in o}-4-
[(3-ch lor op h en yl)a m in o])p h en yl](2-m eth ylp h en yl)m eth -
a n on e (6b). General Procedure 7 was used to couple (4-amino-
2-chlorophenyl)(2-methylphenyl)methanone (245.7 mg, 1.00
mmol) with 3-chloro-bromobenzene (287.2 mg, 1.50 mmol),
using NaOt-Bu (134.5 mg, 1.40 mmol). The reaction was
conducted under microwave irradiation (250 W) at 150 °C for
1
173-175 °C; H NMR (DMSO, 300 MHz) δ 9.34 (s, 1H), 7.97
(t, J ) 1.9 Hz, 1H), 7.79-7.53 (m, 7H), 7.58 (d, J ) 1.9 Hz,
1H), 7.56 (d, J ) 1.5 Hz, 1H), 7.53 (t, J ) 1.5 Hz, 1H), 7.26 (s,
1H), 7.23 (s, 1H); 13C NMR (DMSO, 75.4 MHz) δ 193.8, 148.6,
146.7, 142.9, 138.0, 132.1, 131.7, 130.6, 129.0, 128.5, 128.3,
124.0, 115.4, 115.3, 111.8; HRMS (EI) (M+) calcd for C19H14N2O3
318.1004, found 318.1016.
1
3 min. The ratio of the crude products was determined by H
4-[(4-Ben zoyl)p h en yla m in o]ben zon itr ile (2m ). General
Procedure 6 was used to couple 4-aminobenzophenone (197.2
mg, 1.00 mmol) with 4-bromobenzonitrile (182.0 mg, 1.00
mmol), using ligand B (17.1 mg, 0.04 mmol) and instead of
NaOt-Bu, Cs2CO3 as base. The reaction was conducted under
microwave irradiation (300 W) at 160 °C for 20 min. The crude
material was purified by flash column chromatography (ethyl
acetate/CH2Cl2 1:20), to give 251.3 mg (84%) of the title
compound as a yellow solid: mp 185-187 °C; 1H NMR (DMSO,
300 MHz) δ 9.44 (s, 1H), 7.79-7.67 (m, 4H), 7.66 (t, J ) 2.3
Hz, 1H), 7.63 (t, J ) 1.5 Hz, 1H), 7.58 (s, 1H), 7.56 (d, J ) 1.2
Hz, 1H), 7.53 (t, J ) 1.5 Hz, 1H), 7.31-7.29 (m, 4H); 13C NMR
(DMSO, 75.4 MHz) δ 193.9, 146.2, 145.8, 137.9, 133.7, 132.0,
131.8, 129.2, 129.1, 128.3, 119.5, 116.9, 116.7, 101.5; HRMS
(EI) (M+) calcd for C20H14N2O 298.1106, found 298.1104.
2k . General Procedure 6 was used to couple 4-aminoben-
zophenone (197.2 mg, 1.00 mmol) with 4-tolyl 4-toluene-
sulfonate (262.3 mg, 1.00 mmol), using ligand B (17.1 mg, 0.04
mmol) and instead of NaOt-Bu, Cs2CO3 as base. The reaction
was conducted under microwave irradiation (300 W) at 160
°C for 30 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum 1:8), to give 78.8 mg
(27%) of the title compound as a yellow solid. The spectroscopic
data are identical with those described before for 2k .
NMR spectroscopy. The crude material was purified by flash
column chromatography (ethyl acetate/petroleum ether 1:8),
to provide 4b (280.6 mg, 79%) as a yellow solid, 5b (31.8 mg)
as a yellow solid and 6b (8.0 mg) as a yellow syrup. 4b: mp
104-106 °C; 1H NMR (DMSO, 300 MHz) δ 9.08 (s, 1H), 7.42-
7.27 (m, 6H), 7.21-7.03 (m, 5H), 2.35 (s, 3H); 13C NMR (DMSO,
75.4 MHz) δ 195.3, 147.2, 142.5, 138.8, 136.7, 133.7, 133.3,
133.2, 131.1, 131.0, 130.9, 129.1, 128.2, 125.6, 121.7, 118.5,
117.4, 116.4, 113.2, 19.9; HRMS (EI) (M+) calcd for C20H15Cl2-
NO 355.0531, found 355.0547. 5b: 1H NMR (DMSO, 300 MHz)
δ 7.46-7.15 (m, 13H), 6.94 (d, J ) 2.3 Hz, 1H), 6.90 (t, J )
1.9 Hz, 1H), 2.41 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 195.5,
149.7, 146.6, 137.7, 137.5, 134.1, 132.4, 132.3, 131.6, 131.5,
131.4, 131.3, 129.9, 125.7, 125.7, 125.3, 124.3, 121.5, 119.0,
20.1; HRMS (EI) (M+) calcd for C26H18Cl3NO 465.0454, found
465.0457. 6b: 1H NMR (DMSO, 300 MHz) δ 10.84 (s, 1H), 9.16
(s, 1H), 7.51-7.03 (m, 17H), 6.54 (dd, J ) 2.3, 8.8 Hz, 1H),
2.39 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 197.9,
195.6, 149.3, 146.9, 144.4, 142.2, 140.1, 137.9, 137.3, 136.9,
134.4, 133.6, 132.6, 132.3, 131.5, 131.4, 131.3, 130.8, 130.4,
129.7, 129.1, 126.9, 125.7, 125.4, 122.0, 121.0, 119.3, 118.3,
118.1, 113.6, 107.4, 99.1, 20.1, 19.1; HRMS (EI) (M+) calcd for
C
34H26Cl2N2O2 564.1371, found 564.1382.
{2-Ch lor o-4-[(2-m eth ylp h en yl)a m in o]p h en yl}(2-m eth -
2k . General Procedure 6 was used to couple 4-aminoben-
zophenone (197.2 mg, 1.00 mmol) with 4-tolyl triflate (240.2
mg, 1.00 mmol), using ligand B (17.1 mg, 0.04 mmol) and
ylp h en yl)m eth a n on e (4c).3 General Procedure 7 was used
to couple (4-amino-2-chlorophenyl)(2-methylphenyl)methanone
(245.7 mg, 1.00 mmol) with 2-bromotoluene (256.6 mg, 1.50
4944 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of Aryl Aminobenzophenones
mmol), using NaOt-Bu (134.5 mg, 1.40 mmol). The reaction
was conducted under microwave irradiation (250 W) at 150
°C for 3 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to provide
4c (262.5 mg, 78%) as a yellow solid: mp 100-102 °C (lit.3
mp 98-99 °C).
{2-Ch lor o-4-[(4-flu or o-2-m eth ylp h en yl)a m in o]p h en yl}-
(2-m eth ylp h en yl)m eth a n on e (4d ).3 General Procedure 7
was used to couple (4-amino-2-chlorophenyl)(2-methylphenyl)-
methanone (245.7 mg, 1.00 mmol) with 2-bromo-5-fluorotolu-
ene (283.5 mg, 1.50 mmol), using NaOt-Bu (134.5 mg, 1.40
mmol). The reaction was conducted under microwave irradia-
tion (250 W) at 150 °C for 3 min. The crude material was
purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4d (283.4 mg, 80%) as a yellow
solid: mp 153-155 °C (lit.3 mp 151-152 °C).
{2-Ch lor o-4-[(3,5-d iflu or op h en yl)a m in o]p h en yl}(2-m e-
th ylp h en yl)m eth a n on e (4e).20 General Procedure 7 was
used to couple (4-amino-2-chlorophenyl)(2-methylphenyl)-
methanone (245.7 mg, 1.00 mmol) with 1-bromo-3,5-difluo-
robenzene (289.5 mg, 1.50 mmol), using NaOt-Bu (134.5 mg,
1.40 mmol). The reaction was conducted under microwave
irradiation (250 W) at 150 °C for 3 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4e (275.2 mg, 77%) as a yellow
solid: mp 86-88 °C; 1H NMR (DMSO, 300 MHz) δ 9.24 (s,
1H), 7.46-7.14 (m, 5H) 7.17-7.14 (m, 2H), 6.85-6.76 (m, 3H),
2.36 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 195.4, 163.1, 146.0,
144.1, 133.0, 132.9, 131.2, 131.1, 129.3, 129.3, 101.1, 100.9,
100.8, 100.7, 96.8, 96.5, 96.1, 19.9; HRMS (EI) (M+) calcd for
3 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to provide
4h (320.3 mg, 76%) as a yellow solid: mp 94-96 °C; 1H NMR
(DMSO, 300 MHz) δ 8.44 (s, 1H), 7.45-7.19 (m, 8H), 6.83 (d,
J ) 1,9 Hz, 1H), 6.77 (dd, J ) 1.9, 8.4 Hz, 1H), 2.31 (s, 3H),
2.23 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 195.2, 149.5, 144.6,
139.2, 137.8, 136.4, 134.6, 133.6, 133.5, 131.0, 130.6, 128.8,
126.5, 125.6, 124.8, 123.5, 119.3, 118.4, 115.0, 111.8, 19.7, 17.6;
HRMS (EI) (M+) calcd for C22H17ClF3NO2 419.0900, found
419.0897.
{2-C h lo r o -4-[(4-m e t h o x y -2-m e t h y lp h e n y l)a m in o ]-
p h en yl}(2-m eth ylp h en yl)m eth a n on e (4i). General Proce-
dure 7 was used to couple (4-amino-2-chlorophenyl)(2-meth-
ylphenyl)methanone (245.7 mg, 1.00 mmol) with 2-bromo-5-
methoxytoluene (301.6 mg, 1.50 mmol), using NaOt-Bu (134.5
mg, 1.40 mmol). The reaction was conducted under microwave
irradiation (250 W) at 150 °C for 3 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4i (268.1 mg, 73%) as a yellow
solid: mp 137-139 °C; 1H NMR (DMSO, 300 MHz) δ 8.33 (s,
1H), 7.34-7.23 (m, 5H), 7.14 (d, J ) 8.8 Hz, 1H), 6.91 (d, J )
3.1 Hz, 1H), 6.83 (dd, J ) 3.1 Hz, J ) 8.8 Hz, 1H), 6.59 (d, J
) 1.9 Hz, 1H), 6.55 (dd, J ) 2.3, 8.4 Hz, 1H), 3.76 (s, 3H), 2.28
(s, 3H), 2.16 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 194.4,
157.0, 151.5, 139.6, 136.1, 135.5, 134.0, 130.8, 130.7, 130.3,
128.4, 127.2, 125.5, 124.8, 116.1, 113.5, 112.1, 110.6, 55.1, 19.6,
17.8; HRMS (EI) (M+) calcd for C22H20ClNO2 365.1183, found
365.1148.
(4-{[2-Ch lor o-3-(1,3-d ioxola n -2-yl)]p h en yla m in o}p h en -
yl)(2-m eth ylp h en yl)m eth a n on e (4j). General Procedure 7
was used to couple (4-amino-2-chlorophenyl)(2-methylphenyl)-
methanone (245.7 mg, 1.00 mmol) with 2-(3-bromophenyl)-1,3-
dioxolan (343.6 mg, 1.50 mmol), using NaOt-Bu (134.5 mg, 1.40
mmol). The reaction was conducted under microwave irradia-
tion (250 W) at 150 °C for 3 min. The crude material was
purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4j (312.3 mg, 79%) as a yellow
solid: mp 81-83 °C; 1H NMR (DMSO, 300 MHz) δ 9.01 (s,
1H), 7.43-7.22 (m, 8H), 7.12 (d, J ) 7.3 Hz, 1H), 7.05 (d, J )
1.9 Hz, 1H), 7.02 (dd, J ) 1.9, 8.4 Hz, 1H), 5.74 (s, 1H), 4.07
(m, 4H), 2.33 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 195.2,
148.1, 140.6, 139.6, 139.1, 136.5, 133.5, 133.4, 131.0, 130.7,
129.3, 128.9, 127.2, 125.6, 120.7, 120.2, 117.7, 115.5, 112.4,
102.4, 64.7, 19.8; HRMS (EI) (M+) calcd for C23H20ClNO3
393.1132, found 393.1138.
{2-Ch lor o-4-[(4-m eth ylp h en yl)a m in o]p h en yl}(2-m eth -
ylp h en yl)m eth a n on e (4k ). General Procedure 7 was used
to couple (4-amino-2-chlorophenyl)(2-methylphenyl)methanone
(245.7 mg, 1.00 mmol) with 4-iodotoluene (327.1 mg, 1.50
mmol), using NaOt-Bu (134.5 mg, 1.40 mmol). The reaction
was conducted under microwave irradiation (250 W) at 150
°C for 3 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to provide
4k (250.7 mg, 75%) as a yellow solid: mp 140-142 °C; 1H NMR
(DMSO, 300 MHz) δ 8.83 (s, 1H), 7.45-7.08 (m, 9H), 6.97 (d,
J ) 2.3 Hz, 1H), 6.93 (dd, J ) 2.3, 8.4 Hz, 1H), 2.31 (s, 3H),
2.28 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 195.1, 149.0, 139.3,
137.7, 136.3, 133.7, 133.6, 132.1, 130.9, 130.5, 129.8, 128.7,
126.2, 125.5, 120.7, 114.8, 111.7, 20.3, 19.7; HRMS (EI) (M+)
calcd for C21H18ClNO 335.1077, found 335.1061.
C
20H14ClF2NO 357.0732, found 357.0747.
{2-Ch lor o-4-[(2,4-d iflu or op h en yl)a m in o]p h en yl}(2-m e-
th ylp h en yl)m eth a n on e (4f). General Procedure 7 was used
to couple (4-amino-2-chlorophenyl)(2-methylphenyl)methanone
(245.7 mg, 1.00 mmol) with 2,4-difluorobromobenzene (289.5
mg, 1.50 mmol), using NaOt-Bu (134.5 mg, 1.40 mmol). The
reaction was conducted under microwave irradiation (250 W)
at 150 °C for 3 min. The crude material was purified by flash
column chromatography (ethyl acetate/petroleum ether 1:8),
to provide 4f (279.3 mg, 78%) as a yellow solid: mp 140-142
1
°C; H NMR (DMSO, 300 MHz) δ 8.70 (s, 1H), 7.45-7.30 (m,
6H), 7.27 (d, J ) 3.8 Hz, 1H), 7.15-7.08 (m, 1H), 6.83 (d, J )
1.5 HZ, 1H), 6.79 (dd, J ) 1.5, 8.8 Hz, 1H), 2.32 (s, 3H); 13C
NMR (DMSO, 75.4 MHz) δ 195.3, 158.8, 155.6, 149.1, 139.0,
136.5, 133.4, 133.3, 131.0, 130.7, 128.9, 127.0, 126.3, 125.6,
124.3, 114.8, 112.1, 111.8, 105.0, 19.8; HRMS (EI) (M+) calcd
for C20H14ClF2NO 357.0732, found 357.0728.
{2-Ch lor o-4-[4-(d im eth yla m in o)p h en yla m in o]p h en yl}-
(2-m eth ylp h en yl)m eth a n on e (4g). General Procedure 7 was
used to couple (4-amino-2-chlorophenyl)(2-methylphenyl)-
methanone (245.7 mg, 1.00 mmol) with 4-bromo-N,N-dimethy-
laniline (300.1 mg, 1.50 mmol), using NaOt-Bu (134.5 mg, 1.40
mmol). The reaction was conducted under microwave irradia-
tion (250 W) at 150 °C for 3 min. The crude product was
separated by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4g (274.0 mg, 75%) as a yellow
solid: mp 155-157 °C; 1H NMR (DMSO, 300 MHz) δ 8.58 (s,
1H), 7.42-7.24 (m, 5H), 7.07 (s, 1H), 7.04 (s, 1H), 6.78-6.71
(m, 4H), 2.88 (s, 6H), 2.28 (s, 3H); 13C NMR (DMSO, 75.4 MHz)
δ 194.8, 150.7, 147.6, 139.7, 136.0, 134.0, 130.8, 130.3, 128.9,
128.4, 125.5, 124.8, 123.9, 113.6, 113.2, 110.8, 40.3, 19.6;
HRMS (EI) (M+) calcd for C22H21ClN2O 364.1342, found
364.1345.
{2-Ch lor o-4-[2-m eth yl-4-(tr iflu or om eth oxy)p h en yla m i-
n o]ph en yl}(2-m eth ylph en yl)m eth an on e (4h ). General Pro-
cedure 7 was used to couple (4-amino-2-chlorophenyl)(2-
methylphenyl)methanone (245.7 mg, 1.00 mmol) with 2-methyl-
4-(trifluoromethoxy)bromobenzene (382.6 mg, 1.50 mmol),
using NaOt-Bu (134.5 mg, 1.40 mmol). The reaction was
conducted under microwave irradiation (250 W) at 150 °C for
4-{[3-Ch lor o-4-(2-m eth ylben zoyl)p h en yl]a m in o}-3-m e-
th ylben zon itr ile (4l).20 General Procedure 7 was used to
couple (4-amino-2-chlorophenyl)(2-methylphenyl)methanone
(245.7 mg, 1.00 mmol) with 4-bromo-3-methylbenzonitrile
(294.1 mg, 1.50 mmol), using Cs2CO3 (456.1 mg, 1.40 mmol)
and Celite (228 mg). The reaction was conducted under
microwave irradiation (250 W) at 150 °C for 15 min. The crude
material was purified by flash column chromatography (ethyl
acetate/petroleum ether 1:8), to provide 4l (267.4 mg, 74%) as
a yellow solid: mp 153-155 °C; 1H NMR (DMSO, 300 MHz) δ
8.53 (s, 1H), 7.70 (d, J ) 1.2 Hz, 1H), 7.61 (dd, J ) 1.9, 8.4
Hz, 1H), 7.45-7.25 (m, 6H), 7.15 (d, J ) 2.3 Hz, 1H), 7.09 (dd,
(20) Ottosen, E. R. WO 0142189, 2001.
J . Org. Chem, Vol. 69, No. 15, 2004 4945

J ensen et al.
J ) 1.9, 8.4 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H); 13C NMR
(DMSO, 75.4 MHz) δ 196.3, 147.5, 145.0, 139.4, 137.8, 135.5,
133.8, 133.7, 132.1, 132.0, 131.9, 130.9, 130.2, 130.0, 126.6,
120.1, 119.9, 118.9, 115.6, 104.8, 20.8, 18.4; HRMS (EI) (M+)
calcd for C21H18ClNO 360.1029, found 360.1023.
warm to room temperature. A saturated aqueous solution of
NH4Cl was then added, and the mixture was extracted three
times with diethyl ether. The combined organic phases were
washed with a saturated aqueous solution of NaCl, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (EtOAc/petroleum ether
1:10), giving 9.0293 g (92%) of the title compound as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 7.52 (d, J ) 1.9 Hz, 1H),
7.40 (dd, J ) 1.9, 8.4 Hz, 1H), 7.24-7.14 (m, 6H), 6.24 (s, 1H),
2.30 (s, 3H); 13C NMR (CDCl3, 75.4 MHz) δ 139.5, 139.4, 135.9,
133.9, 132.1, 130.6, 130.2, 129.8, 128.0, 126.3, 126.2, 121.7,
69.5, 19.0; HRMS (EI) (M+) calcd for C14H12BrClO 309.9760,
found 309.9778.
{2-Ch lor o-4-[(3-n it r op h en yl)a m in o]p h en yl}(2-m et h -
ylp h en yl)m eth a n on e (4m ). General Procedure 7 was used
to couple (4-amino-2-chlorophenyl)(2-methylphenyl)methanone
(245.7 mg, 1.00 mmol) with 3-bromo-nitrobenzene (303.02 mg,
1.50 mmol), using Cs2CO3 (456.1 mg, 1.40 mmol) and Celite
(228 mg). The reaction was conducted under microwave
irradiation (250 W) at 150 °C for 15 min. The crude material
was purified by flash column chromatography (ethyl acetate/
petroleum ether 1:8), to provide 4m (275.7 mg, 75%) as a
(4-Br om o-2-ch lor op h e n yl)(2-m e t h ylp h e n yl)m e t h a -
n on e (9). To a solution of 8 (8.9293 g, 28.7 mmol) in CH2Cl2
(200 mL) was added Dess-Martin periodinane (12.1542 g, 28.7
mmol) at room temperature. The obtained mixture was stirred
at the same temperature for 30 min. The mixture was then
concentrated in vacuo together with silica gel and purified by
flash column chromatography (ethyl acetate/petroleum ether
1:20), giving 8.3273 g (94%) of the title compound as white
1
yellow solid: mp 138-140 °C; H NMR (DMSO, 300 MHz) δ
9.35 (s, 1H), 7.94 (t, J ) 1.9 HZ, 1H), 7.82 (dt, J ) 1.9, 7.3 Hz,
1H), 7.65-7.57 (m, 2H), 7.47-7.28 (m, 5H), 7.18 (d, J ) 1.9
Hz, 1H), 7.14 (d, J ) 2.3 Hz, 1H), 2.36 (s, 3H); 13C NMR
(DMSO, 75.4 MHz) δ 195.4, 148.6, 146.4, 142.5, 138.5, 136.9,
133.1, 131.2, 131.1, 130.7, 129.3, 129.1, 128.8, 125.7, 124.3,
116.9, 115.9, 113.9, 112.3, 19.9; HRMS (EI) (M+) calcd for
1
C
20H15ClN2O3 366.0771, found 366.0756.
solid: mp 76-78 °C; H NMR (CDCl3, 300 MHz) δ 7.61 (d, J
) 1.9 Hz, 1H), 7.50 (dd, J ) 1.5, 8.0 Hz, 1H), 7.45(dt, J ) 1.5,
7.3 Hz, 1H), 7.32-7.17 (m, 4H), 2.56 (s, 3H); 13C NMR (CDCl3,
75.4 MHz) δ 196.3, 139.6, 138.4, 136.6, 133.0, 132.3, 132.0,
131.6, 131.2, 131.1, 130.1, 125.6, 125.0, 21.2; HRMS (EI) (M+)
calcd for C14H10BrClO 307.9604, found 307.9620.
4a . General Procedure 8 was used to couple aniline (93.1
mg, 1.0 mmol) with 9 (309.6 mg, 1.00 mmol) using NaOt-Bu
(134.5 mg, 1.40 mmol). The reaction was conducted under
microwave irradiation (250 W) at 150 °C for 6 min. The crude
material was purified by flash column chromatography (ethyl
acetate/petroleum ether 1:8) to provide 4a (78.3 mg, 24%) as
a yellow solid. The spectroscopic and other physical data are
identical with those described above.
4a . General Procedure 8 was used to couple aniline (93.1
mg, 1.0 mmol) with 9 (309.6 mg, 1.00 mmol) using Cs2CO3
(456.1 mg, 1.40 mmol) and Celite (228 mg). The reaction was
conducted under microwave irradiation (250 W) at 150 °C for
20 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8) to provide
4a (253.1 mg, 79%) as a yellow solid. The spectroscopic data
are identical with those described above.
4c. General Procedure 8 was used to couple 2-methyl-aniline
(107.2 mg, 1.00 mmol) with 9 (309.6 mg, 1.00 mmol) using Cs2-
CO3 (456.1 mg, 1.40 mmol) and Celite (228 mg). The reaction
was conducted under microwave irradiation (250 W) at 150
°C for 20 min. The crude material was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:8) to provide
4c (263.5 mg, 78%) as a yellow solid. The spectroscopic data
are identical with those described above.
4d . General Procedure 8 was used to couple 4-fluoro-2-
methylaniline (125.2 mg, 1.00 mmol) with 9 (309.6 mg, 1.00
mmol) using Cs2CO3 (456.1 mg, 1.40 mmol) and Celite (228
mg). The reaction was conducted under microwave irradiation
(250 W) at 150 °C for 20 min. The crude material was purified
by flash column chromatography (ethyl acetate/petroleum
ether 1:8) to provide 4d (280.3 mg, 79%) as a yellow solid. The
spectroscopic data are identical with those described above.
4e. General Procedure 8 was used to couple 3,5-difluoro-
aniline (129.1 mg, 1.00 mmol) with 9 (309.6 mg, 1.00 mmol)
using Cs2CO3 (456.1 mg, 1.40 mmol) and Celite (228 mg). The
reaction was conducted under microwave irradiation (250 W)
at 150 °C for 20 min. The crude product was purified by flash
column chromatography (ethyl acetate/petroleum ether 1:8) to
provide 4e (254.9 mg, 71%) as a yellow solid. The spectroscopic
data are identical with those described above.
4k , (2-Ch lor o-4-{[d i(4-m eth ylp h en yl)]a m in o}p h en yl)-
(2-m eth ylp h en yl)m eth a n on e (5k ), (2-{[2-Ch lor o-4-(2-m e-
th ylben zoyl)p h en yl]a m in o}-4-[(4-m eth ylp h en yl)a m in o]-
p h en yl)(2-m eth ylp h en yl)m eth a n on e (6k ), a n d Tr ion e 7.
General Procedure 7 was used to couple (4-amino-2-chloro-
phenyl)(2-methylphenyl)methanone (245.7 mg, 1.00 mmol)
with 4-tolyl triflate (360.3 mg, 1.50 mmol), using Cs2CO3 (456.1
mg, 1.40 mmol) and Celite (228 mg). The reaction was
conducted under microwave irradiation (250 W) at 150 °C for
15 min. The crude material was separated by flash column
chromatography (ethyl acetate/petroleum ether 1:8), to provide
4k (171.0 mg, 51%) as a yellow solid, 5k (11.0 mg) as a yellow
solid, 6k (52.2 mg) as a yellow syrup, and 7 (26.2 mg) as a
yellow syrup.
4k : The spectroscopic data are identical with those de-
scribed above.
5k : mp 80-82 °C; 1H NMR (DMSO, 300 MHz) δ 7.46-7.21
(m, 10H), 7.12 (s, 2H), 7.10 (s, 1H), 6.72 (d, J ) 2.3 Hz, 1H),
6.69 (dd, J ) 2.3, 8.8 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 6H); 13C
NMR (DMSO, 75.4 MHz) δ 195.3, 151.3, 142.5, 138.6, 136.8,
135.0, 132.9, 132.8, 131.1, 131.0, 130.5, 129.1, 128.0, 126.3,
125.6, 118.0, 115.4, 20.4, 19.9; HRMS (EI) (M+) calcd for
C
28H24ClNO 425.1546, found 425.1546.
6k : 1H NMR (DMSO, 300 MHz) δ 10.99 (s, 1H), 8.97 (s,
1H), 7.52-7.22 (m, 11H), 7.16-6.97 (m, 6H), 6.44 (dd, J ) 1.9,
9.2 Hz, 1H), 2.40 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H); 13C NMR
(DMSO, 75.4 MHz) δ 197.6, 195.6, 150.9, 147.0, 144.5, 140.3,
138.0, 137.5, 137.3, 137.0, 134.3, 132.6, 132.3, 132.2, 132.0,
131.4, 131.2, 130.3, 129.7, 129.0, 126.8, 125.7, 125.3, 121.1,
120.6, 120.4, 118.3, 112.4, 106.6, 97.6, 20.4, 20.1, 19.0; HRMS
(EI) (M+) calcd for C35H29ClN2O2 544.1918, found 544.1924.
7: 1H NMR (DMSO, 300 MHz) δ 10.80 (s, 1H), 10.73 (s, 1H),
8.89 (s, 1H), 7.49-6.96 (m, 23H), 6.81 (dd, J ) 1.9, 8.8 Hz,
1H), 6.45 (dd, J ) 1.9, 8.8 Hz, 1H), 2.37 (s, 3H), 2.25 (s, 3H),
2.23 (s, 3H), 2.20 (s, 3H); 13C NMR (DMSO, 75.4 MHz) δ 198.4,
197.5, 195.5, 150.6, 147.3, 146.2, 146.2, 144.4, 140.2, 139.8,
139.6, 137.9, 137.5, 137.3, 136.8, 136.5, 134.6, 134.4, 132.7,
132.2, 132.0, 131.4, 131.3, 131.3, 130.5, 130.3, 129.7, 129.6,
129.5, 129.1, 127.1, 126.9, 125.7, 125.4, 125.3, 120.9, 120.7,
118.5, 117.2, 115.9, 113.3, 111.1, 107.0, 103.8, 99.3, 20.3, 20.1,
19.1, 19.0; HRMS (EI) (M+) calcd for C49H40ClN3O3 753.2758,
found 753.2753.
(4-Br om o-2-ch lor op h en yl)(2-m eth ylp h en yl)m eth a n ol
(8). 4-Bromo-2-chloro-iodobenzene (10.0 g, 31.511 mmol) was
dissolved in dry THF (100 mL) under an argon atmosphere.
Isopropylmagnesiumchloride (2 M solution in THF, 16.5 mL,
33.09 mmol) was added at -60 °C. The solution was then
stirred at -60 °C for 2 h, and then 2-methylbenzaldehyde
(3.786 g, 31.51 mmol) was added. The reaction solution was
stirred at the same temperature for 1 h and then allowed to
4k . General Procedure 8 was used to couple 4-methylaniline
(107.16 mg, 1.00 mmol) with 9 (309.6 mg, 1.00 mmol) using
Cs2CO3 (456.1 mg, 1.40 mmol) and Celite (228 mg). The
reaction was conducted under microwave irradiation (250 W)
at 150 °C for 20 min. The crude product was purified by flash
4946 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of Aryl Aminobenzophenones
column chromatography (ethyl acetate/petroleum ether 1:8) to
provide 4k (244.1 mg, 73%) as a yellow solid. The spectroscopic
data are identical with those described above.
in characterization of the compounds prepared herein.
We thank Ms. Nina Nørager Christensen and Ms. Helle
J ørgensen for their technical assistance.
4f. General Procedure 8 was used to couple 2,4-difluoro-
aniline (129.1 mg, 1.00 mmol) with 9 (309.6 mg, 1.00 mmol)
using Cs2CO3 (456.1 mg, 1.40 mmol) and Celite (228 mg). The
reaction was conducted under microwave irradiation (250 W)
at 150 °C for 20 min. The crude material was purified by flash
column chromatography (ethyl acetate/petroleum ether 1:8) to
provide 4f (249.5 mg, 70%) as a yellow solid. The spectroscopic
data are identical with those described above.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal procedures and H and 13C NMR spectra of the compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. The Department of Spectroscopy
at LEO Pharma is acknowledged for their assistance
J O049572I
J . Org. Chem, Vol. 69, No. 15, 2004 4947