Synthesis of new N-aryl oxindoles as intermediates for pharmacologically active compounds

Article abstract of DOI:10.1016/j.tet.2004.09.064

Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active 2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.064

Tetrahedron 60 (2004) 11571–11586
Synthesis of new N-aryl oxindoles as intermediates for
pharmacologically active compounds
a
b
a
a
Murat Acemoglu,a, Thomas Allmendinger, John Calienni, Jacques Cercus, Olivier Loiseleur,
*
Gottfried H. Sedelmeiera and David Xub
aChemical and Analytical Development, Novartis Pharma AG, CH-4002 Basel, Switzerland
bChemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA
Received 26 January 2004; revised 26 August 2004; accepted 17 September 2004
Available online 12 October 2004
Abstract—Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active
2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core
structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic
acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
this paper, the synthesis of a number of new N-aryl
oxindoles will be described, using new methods developed
in our laboratories as well as utilizing known literature
methods mentioned above. The new methods will be
discussed in detail: (i) nitrile groups can be used as masked
methyl equivalents to activate aryl halides towards nucleo-
philic aromatic substitution and can subsequently be
converted to methyl groups, to afford 4-methyl-diaryl-
amines and (ii) the condensation of 2-oxo-cyclohexylidene
acetic acid derivatives with anilines affords dihydro-N-aryl-
oxindoles, which can be dehydrogenated to obtain the
corresponding N-aryl oxindoles.
Since the discovery of anti-inflammatory effects of salicylic
acid many decades ago, a number of much more powerful
non-steroidal anti-inflammatory drugs (NSAID’s) have
been discovered and commercialized. The structures of a
number of these drugs including Naproxenw, Ibuprofenw,
Diclofenacw, Celecoxibw, Rofecoxibw and Lumiracoxibw
are shown in Figure 1. Voltarenw (diclofenac)1 and
Prexigew (lumiracoxib)2 are prominent representatives of
the 2-(N-arylamino)-phenylacetic acids, a class of com-
pounds exhibiting anti-inflammatory properties. N-Aryl
oxindoles can be converted to the corresponding 2-(N-
arylamino)-phenylacetic acids in one hydrolysis step and
are thus useful intermediates for the preparation of these
compounds. N-Aryl oxindoles themselves can be prepared
from corresponding diarylamines by N-acetylation with
chloroacetyl-chloride followed by intramolecular Friedel–
Crafts alkylation (ring closure) to N-aryl oxindoles. This
route is of particular usefulness because of the availability
of various methods for the preparation of diarylamines, the
most frequently used methods being the Ullmann coupling3
and the Buchwald–Hartwig coupling4 of aryl halides with
aryl amines. The Smiles rearrangement5 is yet another
useful method utilizing phenols and N-chloroacetyl anilines
as starting materials for the synthesis of diaryl amines. In
2. Results and discussion
2.1. Diarylamines and N-chloroacetyl-diarylamines from
Buchwald-coupling
In a first set of experiments, 4-alkyl-substituted anilines
(1–2) and aryl bromides (3–4) were coupled with the ortho-
halogenated aryl bromides (5–6) and anilines (7–12)
respectively, utilising the Pd(0) catalyzed Buchwald–
Hartwig reaction (Scheme 1 and Table 1). Numerous
reports on the Pd(0)-catalyzed amination appeared in recent
years, indicating the subtle influence of the ligand to
reaction rate, conversion and yield.6 Therefore, Pd(dba)2
was used as Pd-source and the influence of ligands on the
reaction rate, conversion, and yield was investigated in
detail for the coupling of toluidine (1) with 2-chloro-6-
fluoro-bromobenzene (5) to diaryl-amine 13a. The results of
Keywords: Diarylamines; N-Aryl oxyindoles; 2-(N-Arylamino)-phenyl-
acetic acids; NSAID’s.
* Corresponding author. Tel.: C41 61 3245929; fax: C41 61 3249536;
e-mail: murat.acemoglu@pharma.novartis.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.064

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M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
Figure 1. A selection of marketed non-steroidal anti-inflammatory drugs (NSAID’s).
Scheme 1.

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
Table 1. Starting materials for the Buchwald–Hartwig coupling
11573
Compound
X1
X2
R1
R2
R3
R4
R5
R6
1
2
3
4
5
6
7
8
NH2
NH2
Br
Br
—
—
—
—
—
—
—
—
—
Br
Br
NH2
NH2
NH2
NH2
NH2
NH2
Me
Et
Me
Et
—
—
—
—
—
—
—
—
—
—
—
—
Cl
F
Cl
Cl
F
—
—
—
—
H
F
H
H
F
—
—
—
—
H
H
H
Cl
F
H
—
—
—
—
H
H
H
H
H
—
—
—
—
F
F
F
Me
F
F
9
10
11
12
—
—
—
F
Cl
Cl
F
H
H
F
H
H
F
H
Me
Me
Table 2. Ligand screening for the Buchwald-coupling of toluidine (1) with 2-chloro-6-fluoro-bromobenzene (5)
Ligand
I
II
III
IV
V
VI
VII
VIII
IX
Cat. (mol%)
Reaction time (h)
Conversion (%)
2
20
0
2
20
0
2
18
15
4
18
30
0.7
14
100
1.0
4
80
1.1
20
100
1.8
5
100
0.2
14
100
the ligand screening are summarized in Table 2. Catalysts
with simple triaryl-phosphines as ligands, such as triphenyl-
phosphine (I) and tri-(ortho-toluyl)phosphine (II) did not
show any catalytic activity for the coupling of 1 and 5 to
form 13a. Tricyclohexyl-phosphine (III) and 2-(2-diphenyl-
phosphanyl-phenyl)-4-isopropyl-4,5-dihydro-oxazole (IV)
showed low activity with 15 and 30% conversion,
respectively, after 18 h reaction time. The bidentate ligands
BINAP (V), DPE-Phos (VI) and DPPF (VII) gave good
conversions and yields. The best results were obtained with
tri-t-butyl-phosphine (TTBP, VIII) as ligand. TTBP was
also the ligand of choice for the inverse coupling strategy:
using Pd(dba)2 with TTBP (VIII) as ligand, p-bromo
toluene (3) and 4-ethyl-phenyl-bromide (4) were coupled
with the ortho-halogen substituted anilines 7–12 (Scheme 1
and Table 3), to obtain the corresponding diaryl amines
13a–g in good yields. Under optimal conditions, the catalyst
load could be reduced to 0.2 mol% with TTBP (VIII) as
ligand. Similar results were obtained with 2-(N,N-dimethyl-
amino)-20-(dicyclohexylphosphino)biphenyl7 (IX) as
monodentate ligand. When BINAP (V) was used as ligand,
a higher load of catalyst and longer reaction times were
necessary as compared to TTBP (VIII). Under the
optimized Buchwald–Hartwig coupling conditions with
Pd(dba)2/TTBP, excess aryl bromides reacted rapidly with
the products (diarylamines 13a–h) to form the correspond-
ing triarylamines as byproducts. Thus, the purity of the
crude products depended on the catalyst and on the excess
arylbromide used. On small scale (0.5–5 g), the diaryl-
amines could be separated from triarylamines and other
byproducts by simple Kugelrohr-distillation. On large scale
(5–100 g), short path distillation resulted in polymerization
with only low recovery of the products. Alternatively, the
products could be purified by chromatography on silica gel
with cyclohexane/toluene as eluent. However, when a 1:1
ratio of the arylamine and the arylbromide components were
used, only negligible amounts of the triarylamines were
formed and a purification at this stage was not necessary.
The crude products 13a–g were then acylated with 2-chloro-
acetyl-chloride to afford the mainly crystalline compounds
14a–g (Scheme 1 and Table 3).
2.2. Diarylamines and N-chloroacetyl-diarylamines from
Smiles rearrangement
The Buchwald-coupling is among the most useful methods
for the preparation of diarylamines using aryl halides and
anilines as starting materials. However, on a large scale and
for commercial production, the cost of palladium catalysts
and ligands may still account for a major part of the total
production costs. Thus, the Smiles rearrangement8 utilizing
phenols as starting materials is a complementary and
valuable alternative for the preparation of diarylamines.
Smiles rearrangement of substituted aryloxy-acetamides has
been reported for the synthesis of 2,6-dichoro-diphenyl-
amine, an intermediate of diclofenac, using KOH/toluene9
Table 3. Diaryl-amines (13) and N-(chloroacetyl)-diarylamines (14) from Buchwald–Hartwig coupling
Product
Aniline
Aryl-bromide
Yield (%)
Product
Yield (%)
13a
13a
13b
13c
13d
13e
13f
1
7
8
5
3
4
3
4
3
3
4
6
70
90
56
82
75
73
89
58
86
14a
14a
14b
14c
14d
14e
14f
82
82
92
92
70
60
78
88
9
10
11
12
12
2
13g
13h
14g

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M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
Scheme 2.
or MeONa/n-BuOH.10 The Smiles-rearrangement works
well only with sufficiently activated phenoxy components
bearing at least one halogen substituent. 2-Chloro- and
2,4-dichloro-phenolethers are less reactive and the cleavage
of the amide bond predominates under similar reaction
conditions.11 Smiles rearrangement of 2-chloro-6-fluoro-
and 2,6-difluoro-phenoxy-derivatives proceeds smoothly.
The rearrangement is usually accompanied by a major side
reaction, arising from intramolecular nucleophilic substi-
tution of the fluorine atom by nitrogen. This side reaction
can be minimized by the proper choice of the reaction
conditions, MeONa/i-PrOH being much better than KOH/
toluene. Thus, compounds 13a and 13h–k were synthesized
by this method using a simple one pot procedure: the
2-chloro(4-alkylphenyl)acetamides 15 and 16 (Scheme 2
and Table 4) were coupled with the 2,6-dihalogenated
phenols 17–20 (Table 4) in boiling 2-propanol in the
presence of potassium carbonate. The resulting phenol
ethers 21 were treated with methanolic sodium methylate
and heated to 85 8C to effect the rearrangement. Fast trans-
esterification of the N-(2-hydroxyacetyl)-diarylamine inter-
mediates 22 afforded the desired diarylamines 13a and
13h–k. The crude diarylamines were converted into the
corresponding N-(2-chloroacetyl)-diarylamines 14a and
14h–k by heating with pure, excess chloroacetyl chloride.
After work-up, the products 14a and 14h–k were isolated as
crystalline compounds (Table 5). The overall yields from
the corresponding phenols were: 14a (76% from 17), 14h
(45% from 18), 14i (66% from 19), 14j (78% from 17) and
14k (89% from 20).
Table 5. N-(Chloroacetyl)-diarylamines (14) from Smiles-rearrangement
Product
N-(Chloroacetyl)-aniline
Phenol
Yield (%)
14a
14h
14i
14j
14k
15
16
15
16
15
17
18
19
17
20
76
45
66
78
89
2.3. Diarylamines from nucleophilic aromatic
substitution
Yet another generally applicable method for the synthesis of
certain diarylamines is the utilization of an electron-
withdrawing group (EWG) for a nucleophilic aromatic
Table 4. Starting materials for the Smiles rearrangement
R1
R2
R3
R4
R5
R6
15
16
17
18
19
20
Me
Et
—
—
—
—
—
—
Cl
F
Cl
Cl
—
—
H
F
H
H
—
—
H
H
Me
H
—
—
H
H
H
—
—
F
F
Cl
Cl
H

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11575
Scheme 3.
substitution and subsequent conversion of the EWG to a
given substituent. For this purpose, nitrile groups12 and
hindered carboxylic ester groups13 can serve as EWG. This
strategy was successfully applied for the synthesis of
compound 13a by using a nitrile substituent as a masked
methyl equivalent (Scheme 3). The reaction of 2-chloro-4-
fluoro-aniline (7) with 4-chloro-benzonitrile (23) in DMF or
DMPU as solvent and NaH as base afforded 24 in 91%
yield. Excess base (2 equiv) had to be applied in this case,
since the product 24 was more acidic than the aniline 7 and
was readily deprotonated by the anilide-salt. Attempts to
achieve a direct catalytic hydrogenation of the nitrile
function into a methyl group failed due to de-chlorination
side reaction in all cases. Different Ni- and Pd-catalysts
were tested for this purpose without success. Therefore, the
nitrile function was converted into the imido-ester hydro-
chloride intermediate 25, which on treatment with H2SO4 in
EtOH/H2O afforded the ethyl ester derivative 26 in 80%
yield over two steps. The imido-ester intermediate 25 was
very sensitive to heat and humidity and the corresponding
amide was formed as by-product at temperatures O40 8C.
Heating the wet crystalline product 25 to 90 8C resulted in
complete conversion to the amide within a few minutes.
Finally, the ethyl ester function in 26 could be reduced to the
desired methyl substituent with Red-Al in toluene to obtain
compound 13a in 83% yield. Reductive de-fluorination to
the corresponding 2-chloro-diarylamine was a significant
side reaction (ca. 5–10%), as could be detected by GC/MS.
In addition, dimeric condensation products (from 26 with
13a) were also formed in smaller quantities. Other reducing
agents like NaBH4 and LiAlH4 in the presence or absence of
AlCl3 in different solvents were unsuccessful for the
reduction of the ethyl ester, even in refluxing toluene. In
many cases, the ester was completely inert to reduction and
de-fluorination occurred. This unusual inertness of the ethyl
ester function towards reduction might reflect its structural
feature as a vinylogous aromatic carbamate. Finally, the
diaryl-amine 13a was converted into its 2-chloro-acetyl
derivative 14a in 92% yield (55.6% overall yield from
2-chloro-6-fluoro-aniline (7)).
2.4. Synthesis of N-aryl oxindoles and phenylacetic acid
derivatives
A selection of N-chloroacetyl-diarylamines (compounds
14a, 14e–k) were subjected to Friedel–Crafts alkylation
conditions to obtain the corresponding N-aryl oxindoles
27a, and 27e–k (Scheme 4, see also Table 6). The
cyclizations were performed by heating with AlCl3 at
150–170 8C without solvent or in chlorobenzene at reflux. A
major side reaction was the migration of the p-alkyl
substituent to the meta position. The amount of the meta
isomer was ca. 3–5% in case of the methyl-substituent and
10–20% in case of the ethyl-substituent. The migration of
the alkyl substituents is a known14 side reaction. It is
catalyzed by AlCl3 and HCl, which is formed during the
Friedel–Crafts alkylation.
Finally, the N-aryl oxindoles 27a, 27f, 27g and 27i were
hydrolysed with NaOH in EtOH/H2O to obtain the

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M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
Table 6. Substitution pattern of the product series 13, 14, 27 and 28
R1
R2
R3
R4
R5
R6
a
b
c
d
e
f
g
h
i
Me
Et
Me
Et
Me
Me
Et
Et
Me
Et
Cl
Cl
F
H
H
F
H
Cl
F
H
F
H
H
H
Me
H
H
H
H
F
H
H
H
H
H
H
H
F
Me
F
F
F
F
Cl
Cl
Cl
F
Cl
Cl
Cl
H
H
H
F
H
H
H
Me
Me
Me
F
Cl
F
j
k
Me
H
Cl
physiologically active phenylacetic acid derivatives 28a
(lumiracoxib),2 28f, 28g and 28i, respectively (Scheme 4).
The substitution pattern of all products is summarized in
Table 6. The sequence 13a, 14a, 27a and 28a corresponds to
a total synthesis of lumiracoxib, a new NSAID.
(35) and morpholine (30) gave the enamine 36, which was
condensed with glyoxylic acid ethyl ester to obtain
compound 37 (25% yield over both steps). Hydrolysis of
crude 37 to 38 and condensation of 38 with 2-chloro-6-
fluoro-aniline (7) gave the nicely crystalline dehydro-N-aryl
oxindole 39 in 57.8% yield over two steps. Finally, the
oxidation of 39 was accomplished with I2 in the presence of
DBU in refluxing xylene, to obtain the N-aryl oxindole 27a
in 76% yield. The overall yields from 4-methylcyclohexa-
none varied from 11% for 27a to 1.2% for 27g. However,
the overall yields were significantly higher with regard to
the more expensive anilines: 58% for 27a from 2-chloro-6-
fluoroaniline (7) and 5.4% for 27g from 2-chloro-6-methyl-
aniline (12).
During our search for new synthetic routes to N-Aryl-
oxindoles, the condensation of anilines with 2-oxo-cyclo-
hexylidene-acetic acid derivatives was found to be a viable
method for the preparation of dehydro-N-aryl-oxindoles:
2-ethyl-cyclohexanone (29) was condensed (Scheme 5)
with morpholine (30) to obtain enamine 31. Condensation15
of crude 31 with gyloxylic acid ethyl ester gave 32 in 25%
yield over two steps. Compound 32 was stable and could be
distilled and fully characterized. Subsequent hydrolysis of
32 afforded the 2-oxo-cyclohexylidene acetic acid deriva-
tive 33, which was condensed with compound 12 to obtain
the dihydro-N-aryl-oxindole 34 (22.8% over two steps). The
conversion of 34 to 27g was performed by dehydrogenation
on Pd/C. The dehydrogenation on Pd/C proved to be a clean
but very slow reaction and gave only 21% yield of 27g after
72 h reaction time in refluxing xylene. The analogous
reaction sequence starting from 4-methyl-cyclohexanone
3. Conclusions
N-Aryl oxindoles are useful intermediates for the synthesis
of pharmacologically active phenylacetic acid derivatives.
Their diarylamine core structures can be synthesized by
different methods, including Buchwald–Hartwig arylamina-
tion, Smiles-rearrangement and coupling of anilines with
Scheme 4.

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11577
4-chloro-benzonitrile derivatives. Whilst the Buchwald–
Hartwig arylamination is generally applicable for the
synthesis of diarylamines, the applicability of the Smiles-
rearrangement is limited to ortho-halogene substituted
phenols as starting materials. Nitrile groups can be used as
masked methyl equivalents to activate aryl halides towards
nucleophilic aromatic substitution and can subsequently be
converted to methyl groups, to afford 4-methyl-diaryl-
amines. It is obvious that only ortho- and/or para-methyl
substituted diarylamines can be prepared by this method.
The condensation of 2-oxo-cyclohexylidene acetic acid
derivatives with anilines and subsequent oxidation of the
formed tetrahydroindol-2-ones represent another, novel
route for the synthesis of N-aryl oxindoles. Lumiracoxib
(28a) can be synthesized by any of the methods described
above.
spectra were measured on a Fisons VG Quattro II (ESI) or
Finnigan TSQ 7000 (ApCI) or Finnigan 8430 (EI)
instrument. High Resolution Mass Spectra were measured
on a Bruker Daltonics, 9.4T APEX-III FT-MS instrument.
NMR spectra were recorded on a BRUKER DPX300 or
BRUKER AMX 400 or BRUKER DRX500 spectrometer at
the indicated temperature in the given solvent.
4.2. Diarylamines from Buchwald–Hartwig coupling
Typical procedure A. A mixture of the aniline (27.5 mmol),
arylbromide
(27.5 mmol),
sodium
tert-butylate
(49.4 mmol), and toluene (55 mL) was stirred at 25 8C
under nitrogen for 30 min. To this mixture, a solution of
palladium-bis-(dibenzylidenacetone) (55 mmol) and tri-tert-
Scheme 5.
4. Experimental
4.1. General
butylphosphine (82 mmol) in toluene (5 mL) was added
and the resulting suspension was stirred at 110 8C for 14 h.
The mixture was then cooled to 30 8C. Water (30 mL),
concentrated hydrochloric acid (10 mL), charcoal and
cellite (1 g each) were added and stirring was continued
for 1 h. The mixture was filtered to obtain two clear phases.
The organic phase was separated, washed with water (3!
10 mL) and the solvent was evaporated under reduced
pressure to obtain the crude diaryl-amine 13. The crude
product was purified by Kugelrohr-distillation or was used
directly for the next step without purification.
Reagents and solvents were obtained from commercial
sources and were used as received. All reactions were
carried out under an atmosphere of nitrogen unless
otherwise stated. Temperatures are internally measured
unless otherwise stated. Chromatography was performed
using silica gel (E. Merck, Grade 60, particle size 0.040–
0.063 mm, 230–400 mesh ASTM) with the eluent indicated.
Melting points were determined on a Leitz Kofler hot-stage
apparatus and are uncorrected. IR spectra were measured
on a BRUKER IFS66 or BRUKER IFS88 instrument. Mass
Typical procedure B. A mixture of the aniline (0.153 mol),
arylbromide (0.153 mol), sodium tert.butylat (0.286 mol),

11578
M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
(C)-BINAP [2,20-bis-(diphenylphosphino)-1,10-binaphtha-
lin, (1.1 mmol, 0.7 mol%) and toluene (250 mL) was stirred
under nitrogen for about 30 min. After the addition of
palladium-bis-(dibenzylideneaceton) (0.8 g, 1 mmol), the
mixture was heated to 110 8C (slight reflux) for 14–20 h.
The mixture was then cooled to 30 8C, water (60 mL),
concentrated hydrochloric acid (60 mL) as well as charcoal
and cellite (5 g each) were added and stirring was continued
for 1 h. The mixture was filtered to obtain two clear phases.
The organic phase was washed with water (3!70 mL) and
the solvent was evaporated under reduced pressure to obtain
the crude diaryl-amine 13. The crude product was purified
by Kugelrohr-distillation or by chromatography. Alterna-
tively, the crude product was used directly for the next step.
4.2.3. N-(20,30,40,60-Tetrafluorophenyl)-4-methylanilin
(13c). In analogy to typical procedure A, 2,3,4,6-tetra-
fluoroaniline (9) (1 equiv), 4-bromotoluene (3) (0.8 g,
4.7 mmol), sodium tert-butoxide (1.9 equiv), tri-tert-butyl-
phosphin (0.14 equiv) and bis-dibenzylideneacetone-palla-
dium(0) (0.04 equiv) in toluene (70 mL/g 9) were allowed
to react at 85 8C for 3 h. Aqueous workup and chroma-
tography (silica gel, heptane/toluene 2:1) afforded 13c as
a solid, mp 64–65 8C. Yield: 82%. HRMS: 254.05971
(MKH)K, C13H9F4N requires 254.05984 (MKH)K. 1H
NMR (400 MHz, DMSO-d6 300 K): d 2.20 (s, 3H, CH3–
C(4)), 6.63 (d, JZ8.2 Hz, 2H, H–C(2)), 6.99 (d, JZ8.2 Hz,
3
4
2H, H–C(3)), 7.56 (tdd, JHFZ10.9 Hz, JHFZ7.3 Hz,
5JHFZ2.4 Hz, 1H, H–C(50)), 7.84 (s, 1H, NH). N,N-Bis-p-
tolyl-2,3,4,6-tetrafluoroaniline was isolated as a byproduct,
mp: 94–96 8C.
4.2.1. N-(2-Chloro-6-fluoro-phenyl)-4-methylaniline
(13a). Synthesis from aryl bromide 3 and aniline 7
according to typical procedure A (14 h reaction time at
110 8C, 90% yield) or from aryl bromide 5 and aniline 1
according to procedure B (70% yield). 1H NMR (DMSO-d6,
500 MHz, 300 K) d 2.17 (s, 3H, H3C), 6.53 (dd, JZ8.5 Hz,
JH–FZ1.5 Hz, 2H, H–C(2) and H–C(6)), 6.94 (d, JZ8.0 Hz,
2H, H–C(3) and H–C(5)), 7.16 (ddd, JZ8.0, 6.0 Hz, 1H,
H–C(40)), 7.25 (ddd, JZ8.0, 1.5 Hz, JH–FZ8.0 Hz, 1H,
H–C(50)), 7.34 (ddd, JZ8.0, 1.5 Hz, JH–FZ1.5 Hz, 1H,
H–C(30)), 7.63 (s, 1H, NH). 13C NMR (DMSO-d6,
125 MHz, 300 K) 20.6 (s, 1C, CH3), 114.9 (s, 2C,
C(2,6)), 115.7 (d, JC–FZ20.7 Hz, 1C, C(50)), 125.35 (d,
JC–FZ9 Hz, 1C, C(40)), 126.2 (s, 1C, C(30)), 127.8 (s, 1C,
C(4)), 128.4 (d, JC–FZ14.6 Hz, 1C, C(10)), 129.0 (s, 2C,
C(3,5)), 130.8 (d, JC–FZ3.7 Hz, 1C, C(20)), 142.6 (s, 1C,
C(1)), 158 (d, JC–FZ248 Hz, 1C, C(60)).
4.2.4. N-(20,30,50,60-Tetrafluorophenyl)-4-ethylanilin
(13d). In analogy to typical procedure A, 2,3,5,6-tetra-
fluoroaniline (10) (1 equiv), 4-ethylbromobenzene (4)
(0.99 equiv), sodium tert-butoxide (1.76 equiv), tri-tert-
butylphosphin (0.039 equiv) and bis-dibenzylideneacetone-
palladium(0) (0.016 equiv) were stirred in toluene at 85 8C
for 15.5 h. Aqueous workup and chromatography (silica gel,
hexane/toluene 9:1 to 3:1) afforded 13d as a liquid. Yield:
75%. HRMS: 268.07534 (MKH)K, C14H11F4N requires
268.07549 (MKH)K. 1H NMR (400 MHz, CDCl3, 300 K) d
1.26 (t, JZ7.5 Hz, 3H, CH3–C–C(4)), 2.65 (q, JZ7.5 Hz,
3
2H, Me–CH2–C(4)), 5.65 (br s, 1H, NH), 6.73 (tt, JHF
Z
4
10 Hz, JHFZ7 Hz, 1H, H–C(40)), 6.88 (d, JZ7.8 Hz, 2H,
H–C(2,6)), 7.15 (d, JZ7.8 Hz, 2H, H–C(3,5)); MS(EI) m/z
268 (MKH), 248 (MKHF).
4.2.2. N-(20,40Dichloro-60-methylphenyl)-4-ethylaniline
(13b). In analogy to typical procedure B, 2,4-dichloro-6-
methylaniline (8) (1 equiv), 4-ethyl bromobenzene (4)
(1.06 equiv), sodium tert-butoxide (1.86 equiv), racemic
BINAP (0.02 equiv) and bis-dibenzylideneacetone-palla-
dium(0) (0.02 equiv) were heated at reflux in toluene for
22 h to afford pure 13b after aqueous workup and
chromatography (silica gel, toluene as eluent). Yield:
56%. HRMS: 280.0655 (MCCH); C15H15Cl2N requires
280.0654 (MCCH). 1H NMR (DMSO-d6, 500 MHz,
300 K) d 1.11 (t, JZ7.6 Hz, 3H, H3C–CH2–), 2.15 (s, 3H,
H3C–C(60)), 2.46 (q, JZ7.6 Hz, 2H, CH2–CH3), 6.40 (d,
JZ8.4 Hz, 2H, H–C(2,6)), 6.94 (d, JZ8.4 Hz, 2H, H–
C(3,5)), 7.36 (d, JZ2.1 Hz, 1H, H–C(30)), 7.43 (s, 1H, NH),
7.50 (d, JZ2.1 Hz, 1H, H–C(50)).
4.2.5. N-(20-Chloro-40-fluoro-60-methylphenyl)-4-methyl-
aniline (13e). 2-Chloro-4-fluoro-6-methyl-aniline (11)
(prepared from N-acetyl-4-fluoro-2-methylaniline by chlori-
nation followed by hydrolysis) was coupled with 4-bromo-
toluene (3) according to the typical procedure A. Reaction
time was 40 min at 90 8C. Aqueous workup and chroma-
tography afforded 13e as an oil, yield: 73%. HRMS:
250.07945 (MCCH); C14H13ClFN requires 250.07933
(MCCH). 1H NMR (400 MHz, DMSO-d6): d 2.13 and
2.16 (each s, each 3H, CH3–C(4) and CH3–C(60)), 6.32 (d,
JZ8 Hz, 2H, H–C(2,6)), 6.88 (d, JZ8 Hz, 2H, H–C(3,5)),
3
4
7.16 (dd, JHFZ9.25 Hz, JHHZ2.4 Hz, 1H, H–C(50)),
3
4
7.28 (s, 1H, NH), 7.31 (dd, JHFZ8.4 Hz, JHHZ3 Hz,
1H, H–C(30)).
The reaction proceeded much faster even at 85 8C when
BINAP was replaced by tri-tert-butylphosphin; however,
N,N-di-(4-ethylphenyl)-20,40-dichloro-60-methylaniline was
formed as a byproduct in considerable amounts when excess
of 4-ethyl bromobenzene was used. This byproduct can be
isolated as a solid, mp: 74–75 8C. HRMS: 384.12801 (MCC
4.2.6. N-(20-Chloro-60-methylphenyl)-4-methylaniline
(13f). 2-Chloro-6-methylaniline (12) and 4-bromotoluene
(3) were coupled according to typical procedure A. Reaction
time: 20 min at 90 8C and 16 h at 60 8C. Aqueous workup
and chromatography (silica gel, heptan/toluene 4:1)
afforded pure 13f as an oil, yield: 89%. HRMS: 232.0889
(MCCH), C14H14ClN requires 232.0888 (MCCH). 01H
NMR (400 MHz, CDCl3, 300 K): d 2.21 (s, 3H, CH3–C(6 )),
2.29 (s, 3H, CH3–C(4)), 5.61 (br s, 1H, NH), 6.57 (d, JZ
8.4 Hz, 2H, H–C(2,6)), 7.04 (d, JZ8.4 Hz, 2H, H–C(3,5)),
7.07 (t, JZ8.0 Hz, 1H, H–C(40)), 7.16 (d, JZ8.0 Hz, 1H,
H–C(50)), 7.33 (d, JZ8.0 Hz, 1H, H–C(30)). MS (EI): m/z
232 (80%, MCH), 197 (100%, MCHKCl), 140 (55%,
MKC7H7).
1
H); C23H23Cl2N requires 384.12803 (MCCH). H NMR
(400 MHz, CDCl3, 300 K): d 1.24 (t, JZ7.5 Hz, 6H, CH3–
C–C(4)), 2.09 (s, 3H, CH3–C(60)), 2.61 (q, JZ7.5 Hz, 4H,
Me–CH2–C(4)), 6.89 (d, JZ8.5 Hz, 4H, H–C(2,6)), 7.06 (d,
JZ8.5 Hz, 4H, H–C(3,5)), 7.20 (s, 1H, H–C(50)), 7.36 (s, 1H,
H–C(30)); MS (EI): m/z 387 (12%, MC, 35Cl, 37Cl), 385
(70%, MC, 35Cl, 37Cl), 383 (100%, MC, 35Cl, 35Cl), 368/370
(50/30%, MKCH3), 354 (6%, MKCH2CH3).

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11579
4.2.7. N-(20-Chloro-60-methylphenyl)-N-4-ethylaniline
(13g). In analogy to typical procedure A, 2-chloro-6-
methylaniline (12), 4-etyhl-bromobenzene (4), sodium
tert-butoxide, tri-tert-butylphosphin and bis-dibenzyl-
ideneacetone-palladium(0) (1.4 mol%) were heated in
toluene (90 8C, 3 h) followed by aqueous workup and
chromatography (silica gel, n-heptane) to afford 13g as an
oil. Yield: 58%. HRMS: 246.1044 (MCCH), C14H14ClN
356.0370 (MCCH). 1H NMR (DMSO-d6, 400 MHz,
393 K) d 1.20 (t, JZ7.5 Hz, 3H, H3C–C–C(4)), 2.23 (br s,
3H, H3C–C(60)), 2.62 (q, JZ7.5 Hz, 2H, H2C–C(4)), 4.17
(br s, 2H, H2C–C(O)), 7.21 (m, 4H, H–C(2,3,5,6)), 7.40 (m,
1H, H–C(30)), 7.54 (m, 1H, H–C(50)).
4.3.3. 2-Chloro-N-(2,3,4,6-tetrafluoro-phenyl)-N-p-tolyl-
acetamide (14c). Preparation from 13c according to
acetylation procedure B. Yield: 92%. Viscous oil. 1H
NMR (400 MHz, DMSO-d6, 300 K): spectrum comprised
signals of several rotamers. d 2.33 (br s, 3H, H3C), 4.30–
4.42 (m, 2H, H2C), 7.10–7.60 (m, 4H, arom. H), 7.70 (m,
1H, arom. H). HRMS: 332.04601 (MCCH); C15H10ClF4-
NO requires 332.04598 (MCCH).
1
requires 246.1044 (MCCH). H NMR (300 MHz, CDCl3,
300 K): d 1.10 (t, JZ7.5 Hz, 3H, CH3–C–C(4)); 2.10 (s,
3H, CH3–C(60)), 2.50 (q, JZ7.5 Hz, 2H, Me–CH2–C(4)),
5.54 (br s, 1H, NH), 6.48 (d, JZ8.3 Hz, 2H, H–C(2,6)), 7.93
(t, JZ8.0 Hz, 1H, H–C(40)), 7.95 (d, JZ8.3 Hz, 2H,
H–C(3,5)), 7.05 (d, JZ8.0 Hz, 1H, H–C(50)), 7.22 (d, JZ
8.0 Hz, 1H, H–C(30)).
4.2.8. N-(203060-Trifluorophenyl)-4-ethylanilin (13h). In
analogy to typical procedure B, 4-ethylaniline (2) (2 equiv),
2,3,6-trifluoro-bromobenzene (6) (1 equiv), sodium tert-
butoxide, BINAP and bis-dibenzylideneaceton-palladium
(10 mol%) were allowed to react in refluxing toluene for
6 h. Aqueous workup and chromatography (silica gel,
toluene) afforded pure 13h as an oil. Yield: 86%. HRMS:
250.08465 (MKH)K, C14H12F3N requires 250.08491
(MKH)K. 1H NMR (400 MHz, CDCl3, 300 K): d 1.14
(t, JZ7.7 Hz, 3H, CH3–C–C(4)); 2.53 (q, JZ7.7 Hz, 2H,
Me–CH2–C(4)); 5.29 (br s, 1H, NH); 6.7–6.81 (m, 2H,
H–C(40,50)); 6.75 (d, JZ8.5 Hz, 2H, H–C(2,6)); 7.02
(d, JZ8.5 Hz, 2H, H–C(3,5)).
4.3.4. 2-Chloro-N-(2,3,5,6-tetrafluoro-phenyl)-N-p-ethyl-
phenyl-acetamide (14d). Preparation from 13d according
to acetylation procedure B. Crystallization from n-heptane.
Yield 70%. Mp 72 8C. HRMS: 346.06148 (MCCH);
C16H12ClF4NO requires 346.06163 (MCCH). 1H NMR
(400 MHz, DMF-d7, 413 K): d 1.25 (t, JZ7.5 Hz, 3H,
CH3); 2.70 (q, JZ7.5 Hz, 2H, CH2); 4.28 (s, 2H, CH2–CO);
7.35 (d, JZ8.1 Hz, 2H, H–C(3,5)); 7.43 (d, JZ8.1 Hz, 2H,
H–C(2,6)); 7.65 (tt, JHFZ10.5 Hz, JHFZ7.6 Hz, 1H,
H–C(40)). Anal. Calcd for C16H12ClF4NO: C, 55.59; H,
3.50; Cl, 10.25; F, 21.98; N, 4.05%. Found: C, 55.42; H,
3.58; Cl, 10.24; F, 22.35; N, 4.07%.
3
4
4.3.5. 2-Chloro-N-(2-chloro-4-fluoro-6-methyl-phenyl)-
N-p-tolyl-acetamide (14e). Preparation from 13e according
to acetylation procedure B. Crystallization from n-heptane/
2-propanol 9:1). Yield 60%. Mp 96–97 8C. 1H NMR
(400 MHz, DMSO-d6, 394 K): d 2.24 (s, 3H, H3C), 2.29
(s, 3H, H3C), 4.15 (br s, 2H, H2C), 7.10–7.24 (m, 5H, arom.
H), 730–7.40 (m, 1H, arom. H). Anal. Calcd for C16H14-
Cl2FNO: C, 58.91; H, 4.33; N, 4.29; Cl, 21.74; F, 5.82.
Found: C, 58.82; H, 4.27; N, 4.37; Cl, 21.84; F, 5.85%.
4.3. N-(2-Chloroacetyl)-derivatives 14a–g of from
Buchwald coupling-products 13a–g
Typical acetylation procedure A. Diarylamine 13
(350 mmol) was heated to about 80 8C and 2-chloroacetyl-
chloride (425 mmol) was added within 45–90 min during
which time the temperature of the exothermic reaction was
maintained below 90 8C (caution: gaseous HCl is being
formed). After the addition was complete, the mixture was
stirred for an additional hour at 80–85 8C and then 145 mL
of 2-propanol was added within 30 min at a 70–80 8C. The
mixture was then cooled to 35 8C and seeded with
crystalline product. After cooling to 0–5 8C, the product
was isolated by filtration, washed with cold 2-propanol and
dried under reduced pressure to obtain product 14.
4.3.6. 2-Chloro-N-(2-chloro-6-methyl-phenyl)-N-p-tolyl-
acetamide (14f). Preparation from 13f according to
acetylation procedure B. Crystallization from n-heptane.
1
Yield 78%. Mp 113–114 8C. H NMR (400 MHz, DMSO-
d6, 394 K): spectrum comprised signals of two rotameres.
Main rotamer: d 2.20 (s, 3H, H3C), 2.29 (s, 3H, H3C), 4.12
(m, 2H, H2C), 7.08–7.25 (m, 4H, arom. H), 7.25–7.37 (m,
2H, arom. H), 7.40–7.46 (m, 1H, arom. H). Anal. Calcd. for
C16H15Cl2NO: C, 62.35; H, 4.91; N, 4.54; Cl, 23.01%.
Found: C, 62.61; H, 5.03; N, 4.43; Cl, 22.97%.
Typical acetylation procedure B. Reaction in analogy to
typical acetylation procedure A. For workup, the reaction
mixture was diluted with toluene and extracted with
aqueous sodium-bicarbonate. After evaporation of the
solvent, the crude product was purified by column
chromatography on silicagel (toluene as eluent) and
crystallized to afford product 14.
4.3.7. 2-Chloro-N-(2-chloro-6-methyl-phenyl)-N-p-ethyl-
phenyl-acetamide (14g). Preparation from 13g according
to acetylation procedure B. Yield 88%. Viscous liquid.
HRMS 322.0760 (MCCH), 344.0580 (MCCNa),
360.0319 (MCCK), C17H17Cl2NO requires 322.0760
4.3.1. 2-Chloro-N-(2-chloro-6-fluoro-phenyl)-N-p-tolyl-
acetamide (14a). Preparation from 13a according to
acetylation procedure A. Yield 82%, mp 80–82 8C.
Analytical data see Section 4.4.
1
(MCCH), 344.0579 (MCCNa), 360.0319 (MCCK). H
NMR (400 MHz, DMF-d7, 413 K): d 1.22 (t, JZ7.5 Hz, 3H,
CH3–C–C(4)), 2.32 (s, 3H, CH3–C(60)), 2.65 (q, JZ7.5 Hz,
2H, Me–CH2–C(4)), 4.15 (m, 2H, CH2–Cl), 7.22 (d, JZ
8.5 Hz, 2H, H–C(2,6)), 07.31 (d, JZ8.5 Hz, 2H, H–C(3,5)),
7.3–7.4 (m, 2H, H–C(4 ,50)), 7.47 (dd, JZ6.8, 2.4 Hz, 1H,
H–C(30)).
4.3.2. 2-Chloro-N-(2,4-dichloro-6-methyl-phenyl)-N-p-
ethylphenyl-acetamide (14b). Preparation from 13b
according to acetylation procedure B. Yield 92%, mp 83–
84 8C. HRMS: 356.0369 (MCCH); C17H16Cl3NO requires

11580
M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
4.4. N-(2-Chloroacetyl)-diaryl amines (14a and 14h–k)
from Smiles-rearrangement
413 K, 400 MHz) d 1.24 (t, JZ7.55 Hz, 3H, CH3), 2.70 (q,
JZ7.61 Hz, 2H, CH2–CH3), 4.25 (s, 2H, CH2–Cl), 7.20 (m,
1H, HC(50)), 7.34 (d, JZ8.17 Hz, 2H, HC(3) and HC(5)),
7.42 (d, JZ8.30 Hz, 2H, HC(2) and HC(6)), 7.46 (m, 1H,
HC(40)). IR (film): characteristical absorbtions: 1699, 1504,
815 cmK1. Anal. Calcd for C16H13ClF3NO: C, 58.64; H,
4.00; N, 4.27; Cl, 10.82; F, 17.39. Found: C, 58.60; H, 3.84;
N, 4.07; Cl, 10.91; F, 17.45%.
General procedure for the preparation of diaryl-amines
13 by Smiles-rearrangement and subsequent acylation to
N-(2-chloroacetyl)-diaryl amines 14.
Potassium carbonate (10.5 g, 76 mmol) and the anilide 15
or 16 (70 mmol) were added to a solution of the phenol-
component (67 mmol) in 2-propanol (25 mL) and the
mixture was heated for 4 h at reflux, until the formation of
intermediate 21 was completed. Then a solution of sodium
methylate (30% m/m in methanol, 13.2 g, 73.3 mmol) was
added over 30 min at 70 8C and the temperature was
increased to about 85 8C by distilling 25 mL of the solvent.
The mixture was stirred for additional 2 h at this
temperature to complete the rearrangement. For work-up,
water (25 mL) was added at 70 8C and the mixture was
stirred for 5 min. The organic layer was separated, diluted
with heptanes (20 mL), washed with water (2!25 mL) and
the solvent was evaporated under reduced pressure to obtain
the corresponding diaryl-amine 13 as an oil. The crude
diaryl-amine 13 was heated to 90 8C and treated slowly with
chloroacetyl chloride (9.2 g, 81 mmol). The reaction
mixture was stirred for an additional hour at this
temperature and cooled to 70 8C. Isopropanol (40 mL) was
added at 70 8C, the formed solution was cooled to 40 8C and
seeded. Crystallization occurred. The suspension was
cooled to 0–5 8C, diluted with heptanes (20 mL) at 0 8C,
stirred for an additional hour at this temperature and the
crystals were collected by filtration to obtain the crystalline
product 14.
4.4.3. 2-Chloro-N-(20,60-dichloro-40-methyl-phenyl)-N-p-
tolyl-acetamide (14i). Preparation from 2-chloro-N-(4-
methylphenyl)acetamide (15) and 2,6-dichloro-4-methyl-
phenol (19). Yield 66% from 19. Mp 140–141 8C. MS
(APCI) 342 (MHC). 1H NMR (DMF-d7, 413 K, 400 MHz) d
2.33 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.18 (s, 2H, CH2), 7.22
(d, JZ8.29 Hz, 2H, HC(5) and HC(3)), 7.38 (d, JZ8.40 Hz,
2H, HC(2) and HC(6)), 7.42 (s, 2H, HC(30)and HC(50)). IR
(film): characteristical absorbtions: 1694, 1509, 1469,
811 cmK1. Anal. Calcd for C16H14Cl3NO: C, 56.08; H,
4.12; N, 4.09; Cl, 31.04. Found: C, 56.02; H, 3.93; N, 3.84;
Cl, 30.93%.
4.4.4. 2-Chloro-N-(20-chloro-60-fluoro-phenyl)-N-(4-
ethyl-phenyl)-acetamide (14j). Same procedure starting
from 2-chloro-N-(4-ethylphenyl)acetamide (16) and
2-chloro-6-fluorophenol (17). Yield 78% from 17. Mp
67–68 8C. MS (APCI) 326 (MHC). 1H NMR (DMF-d7,
413 K, 400 MHz) d 1.23 (t, JZ7.55 Hz, 3H, CH3), 2.68 (q,
JZ7.53 Hz, 2H, CH2–CH3), 4.20 (s, 2H, CH2–Cl), 7.29 (d,
2H, HC(3) and HC(5)), 7.31 (m, 3H, HC(5), HC(3) and
HC(50)), 7.47 (m, 4H, HC(2), HC(6), HC(30) and HC(40)).
IR (film): characteristical absorbtions: 1701, 1506, 1469,
1451, 783 cmK1. Anal. Calcd for C16H14Cl2FNO: C, 58.91;
H, 4.33; N, 4.29; Cl, 21.74; F, 5.82. Found: C, 58.82; H,
4.12; N, 4.03; Cl, 21.90; F, 5.77%.
4.4.1. 2-Chloro-N-(20-chloro-60-fluoro-phenyl)-N-p-tolyl-
acetamide (14a). Same procedure starting from 2-chloro-N-
(4-methylphenyl)acetamide (15) and 2-chloro-6-fluoro-
phenol (17). Yield 76% from 17. Mp 80–82 8C. MS
(APCI) 312 (MHC). 1H NMR (DMF-d7, 393 K,
400 MHz) d 2.4 (s, 3H, CH3), 4.3 (s, 2H, CH2), 7.35 (d,
JZ8.0 Hz, 2H, HC(3) and HC(5)), 7.43 (ddd, JZ8.0,
2.0 Hz, JH–FZ8.0 Hz, 1H, HC(50)), 7.48 (d, JZ8.0 Hz, 2H,
HC(2) and HC(6)), 7.55 (d, JZ8.0 Hz, 1H, HC(30)), 7.6
(ddd, JZ8.0 Hz, JH–FZ5.5 Hz, 1H, HC(40)). 13C NMR
(DMF-d7, 100 MHz, 300 K) d 15.4 (s, 1C, CH3), 37.1 (s, 2C,
4.4.5. 2-Chloro-N-(20,60-dichloro-phenyl)-N-p-tolyl-acet-
amide (14k). Same procedure starting from 2-chloro-N-(4-
methylphenyl)acetamide (15) and 2,6-dichlorophenol (20).
At the end of the chloroacetylation the reaction mixture was
diluted with a small amount of toluene (0.2 part) to prevent
solidification before dilution with isopropanol. Yield 89%
from 20. Mp 129–130 8C. MS (APCI) 328 (MHC). 1H
NMR(DMF-d7, 393 K, 400 MHz) d 2.40 (s, 3H, CH3), 4.28
(s, 2H, CH2–Cl), 7.30 (d, JZ7.43 Hz, 2H, HC(3) and
HC(5)), 7.46 (d, JZ7.63 Hz, 2H, HC(2) and HC(6)), 7.54
(d, JZ7.63 Hz, 1H, HC(40)), 7.67 (d, JZ7.63 Hz, 2H,
HC(30) and HC(50)). IR (film): characteristical absorbtions:
CH2), 111.0 (d, JC–FZ21 Hz, C(50)), 121.7 (d, 1C, JC–F
Z
3.5 Hz, C(30)), 122 (s, 2C, C(2,6)), 124 (d, 1C, JC–FZ16 Hz,
C(10)), 125.3 (s, 2C, C(3,5)), 126.1 (d, 1C, JC–FZ9 Hz,
C(40)), 129.6 (s, 1C, C(20)), 133.3 (s, 1C, C(4)), 133.6 (s, 1C,
C(1)), 154.9 (d, 1C, JC–FZ251 Hz, C(60)), 161.2 (s, 1C,
carbonyl C). IR (film): characteristical absorbtions: 1699,
1512, 1470, 1452, 782 cmK1. Anal. Calcd for C15H12Cl2-
FNO: C, 57.71; H, 3.87; N, 4.49; Cl, 22.71; F, 6.09. Found:
C, 57.73; H, 3.70; N, 4.15; Cl, 22.59; F, 6.13%.
1704, 1509, 1440, 793 cmK1
.
Anal. Calcd for
C15H12Cl3NO: C, 54.82; H, 3.68; N, 4.26; Cl, 32.36.
Found: C, 54.90; H, 3.54; N, 4.14; Cl, 32.28%.
4.5. Synthesis of diaryl-amine 13a from 2-chloro-6-fluoro
aniline (7) and 4-chloro-benzonitrile (23)
4.4.2. 2-Chloro-N-(4-ethyl-phenyl)-N-(20,30,60-trifluoro-
phenyl)-acetamide (14h). Same procedure starting from
2-chloro-N-(4-ethylphenyl)acetamide (16) and 2,3,6-tri-
fluorophenol (18). The crude intermediate N-(2,3,6-tri-
fluorophenyl)-4-ethylaniline was filtered on silicagel using
toluene as eluent before chloroacetylation. Yield 45%
from 18.
4.5.1. Synthesis of 4-(2-chloro-6-fluoro-phenylamino)-
benzonitrile (24). DMF (190 mL) was placed in a dry
4-necked, round bottomed flask equipped with a mechanical
stirrer, thermometer, and argon inlet/outlet and was cooled
to 0–4 8C. NaH (12.09 g, ca. 60% m/m, corresponding to ca.
7.254 g 100% pure NaH, 302 mmol) was added at 0–4 8C,
followed by slow addition of a solution of 2-chloro-6-
fluoro-aniline (20 g, 137.4 mmol) in DMF (114 mL) at this
Mp 49–50 8C. MS (APCI) 328 (MHC). 1H NMR (DMF-d7,

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11581
temperature. Evolution of hydrogen gas started immedi-
ately. The reaction mixture is stirred for additional 1 h at
0–4 8C, until the gas evolution was ceased and a dark brown
suspension was formed. A solution of 4-chlorobenzonitrile
(19.49 g, 141.7 mmol) in DMF (100 mL) was added during
5 min at 0–4 8C and the reaction mixture was heated to
50–55 8C for 20 h. For work-up, the suspension was cooled
to 0–4 8C and was diluted with ethyl acetate (400 mL) and
water (300 mL). After intense stirring for additional 5 min,
the layers were separated and the aqueous layer was
extracted with ethyl acetate (2!250 mL). The combined
organic layers were washed with brine (2!350 mL), dried
over anhydrous sodium sulfate (20 g) and the solvent was
evaporated at reduced pressure. The residue was dissolved
in ethanol (100 mL) and the solvent was evaporated. The
residue was re-dissolved in ethanol (100 mL) and the
solution was heated to 55–60 8C. Water (100 mL) was
added at this temperature over a time period of 1.5 h, during
which time crystallization occurred. The suspension was
stirred at rt over night and for another 2 h at 0 8C and the
product was collected by filtration. The product was dried in
vacuo at 50 8C to obtain 30.87 g (91%) of 4-(2-chloro-6-
fluoro-phenylamino)-benzonitrile (24) as red-brown solid,
mp 135.5–139 8C. MS (EI): m/z 246 (MC, 100%), 226
(MKHF), 211 (MKHCl). IR (KBr): strong absorbtions at
3342 (NH), 2217 (CN), 1613, 1599, 1576, 1523, 1480, 1467,
1447, 1414, 1331 (Ar–N), 1288, 1249, 1175, 906, 877, 827,
occurred during evaporation. The crude precipitate was
isolated by filtration and the wet product was used directly
for the next step. An analytical sample was dried in vacuo at
room temperature and was characterized as following: MS
(EI): m/z 292 (MC), 264 (MKC2H4), 248 (100%), 211, 185.
IR (KBr): 3397 (NH), 2982 (NHC), 1679 (C]N), 1612,
1594, 1529, 1499, 1470, 1437, 1386, 1335, 1291, 1257,
1229, 1195, 1156, 1138, 1119, 1064, 1002, 905, 881, 842,
1
771, 749 cmK1. H NMR (DMSO-d6, 500 MHz, 300 K): d
1.44 (t, JZ7 Hz, 3H, H3C), 4.54 (q, JZ7 Hz, 2H, H2C),
6.72 (d, JZ8.4 Hz, 2H, H–C(2,6)), 7.39 (m, 2H, H–
C(40,50)), 7.48 (m, 1H, H–C(30)), 7.95 (d, JZ9 Hz, 2H,
H–C(3,5)), 9.07 (s, 1H, NH), 11.01 (br s, 2H, H2NC). 13C
NMR (DMSO-d6, 125 MHz, 300 K): d 13.6 (s, 1C, CH3),
68.4 (s, 1C, CH2), 113.0 (s, 2C, C(2,6)), 113.8 (s, 1C, C(4)),
115.7 (d, JC–FZ20.7 Hz, 1C, C(50)), 125.1 (d, JC–F
15.2 Hz, 1C, C(10)), 126.2 (s, 1C, C(30)), 128.1 (d, JC–F
9.2 Hz, 1C, C(40)), 131.1 (s, 2C, C(3,5)), 132.2 (d, JC–F
2.5 Hz, 1H, C(20)), 151.6 (s, 1C, C(1)), 158.4 (d, JC–F
Z
Z
Z
Z
249 Hz, 1C, C(60)), 169.6 (s, 1C, O–C]N). Assignments
according to diaryl-amine numbering is given in Scheme 5.
4.5.3. Synthesis of 4-(2-chloro-6-fluoro-phenylamino)-
benzoic acid ethyl ester (26). The crude product 24 from
the previous step was suspended in ethanol (77 mL). Water
(38.5 mL) and concd H2SO4 (3.85 mL) were added and the
suspension was heated to 66–70 8C to obtain a clear
solution. The reaction mixture was stirred at this tempera-
ture for 4 h until the conversion was completed according to
HPLC. The reaction mixture was then cooled down to 60 8C
and water (4.8 mL) was added at this temperature. The
cloudy solution was allowed to cool down slowly to room
temperature. Crystallization occurred. The suspension was
stirred for 16 h at room temperature and the product was
isolated by filtration. The filter cake was washed with ice
cold water/ethanol (9:1) and dried in vacuo at 55 8C to
obtain 9.5 g (80%) of 4-(2-chloro-6-fluoro-phenylamino)-
benzoic acid ethyl ester (26), mp 113–115.5 8C. MS (EI):
m/z 293 (MC), 265, 250, 248 (100%), 221, 185. IR (KBr):
strong absorbtions at 3353 (NH), 2958, 1684 (CO), 1610,
1594, 1522, 1500, 1476, 1450, 1366, 1339 (Ar–N), 1311,
1279 (CO), 1251, 1175, 1130, 1211, 1108, 1025, 905, 880,
1
774, 749 cmK1. H NMR (DMSO-d6, 500 MHz, 300 K):
d 6.66 (d, JZ8.7 Hz, 2H, H–C(2,6)), 7.34 (m, 2H,
H–C(40,50)), 7.45 (m, 1H, H–C(30), 7.55 (d, JZ8.7 Hz,
2H, H–C(3,5)), 8.68 (s, 1H, NH). 13C NMR (DMSO-d6,
125 MHz, 300 K): d 99.6 (s, 1C,0C(4)), 114.1 (s, 2C, C(2,6)),
116 (d, JC–FZ20.6 Hz, 1C, C(5 )), 120.3 (s, 1C, CN), 125.9
(d, JC–FZ15.1 Hz, 1C, C(10)), 126.5 (d, JC–FZ2.8 Hz, 1C,
C(30)), 128.2 (d, JC–FZ9.2 Hz, 1C, C(40)), 132.6 (s, 1C,
C(20)), 133.9 (s, 2C, C(3,5)), 149.5 (s, 1C, C(1)), 158.8 (d,
JC–FZ248.9 Hz, 1C, C(60)). Assignments according to
diarylamine numbering given in Scheme 5. Anal. Calcd
for C13H8ClFN2: C, 63.30; H, 3.27; N, 11.36; Cl, 14.37, F,
7.70. Found: C, 63.39; H, 3.32; N, 11.34; Cl, 14.20; F, 7.67.
4.5.2. Synthesis of 4-(2-chloro-6-fluoro-phenylamino)-
benzimidic acid ethyl ester hydrochloride (25). 4-(2-
Chloro-6-fluoro-phenylamino)-benzonitrile (24) (10 g,
40.54 mmol) was dissolved in EtOH (100 mL) and ethyl
acetate (100 mL). The solution was cooled down to K5 8C
and HCl-gas (135 g) was bubbled into the solution during
1.5 h. The reaction mixture was stirred for 1 h at 0 to K5 8C
and water (5 mL) was added, maintaining the temperature at
0 8C. The mixture was allowed to warm up to room
temperature and stirring was continued at room temperature.
Water (5 mL) was added after 10 and 26 h reaction time,
maintaining the temperature at 20–25 8C. HPLC analysis
after 36 h reaction time indicated the disappearance of
compound 24 and the formation of the imino-ester 25 as
main product. The reaction mixture was poured onto ice-
water (300 g) and stirred for 30 min. Then, ethyl acetate
(650 mL) was added, followed by the addition of water
(500 mL) to obtain two clear phases. The organic layer was
separated and was extracted twice with aq HCl (250 mL of a
2 M solution). The aqueous phases were combined and the
solvent was evaporated at T!40 8C under reduced pressure
to a final volume of 500 mL. Precipitation/crystallization
844, 783, 770 cmK1 1H NMR (DMSO-d6, 500 MHz,
.
300 K): d 1.262 (t, JZ7.0 Hz, 3H, CH3), 4.222 (q, JZ
7.0 Hz, 2H, CH2), 6.638 (d, JZ8.5 Hz, 2H, H–C(2,6)), 7.32
(m, 2H, H–C(40,50)), 7.43 (m, 1H, H–C(30)), 7.75 (d, 2H,
JZ8.5 Hz, H–C(3,5)), 8.51 (s, 1H, NH). 13C NMR (DMSO-
d6, 125 MHz, 300 K): d 14.7 (s, 1C, H3C), 60.3 (s, 1C, H2C),
113.4 (s, 2C, C(2,6)), 115.9 (d, JC–FZ20.7 Hz, 1C, C(50)),
119.7 (s, 1C, C(4)), 126.5 (m, 2C, C(10,30)), 127.7 (d, JC–F
9.2 Hz, 1C, C(40)), 131.2 (s, 2C, C(3,5)), 132.4 (d, JC–F
2.6 Hz, 1C, C(20)), 149.8 (s, 1C, C(1)), 158.8 (d, JC–F
248.8 Hz, 1C, C(60)), 166.0 (s, 1C, COOEt). Assignments
according to diaryl-amine numbering given in Scheme 5.
Anal. Calcd for C15H13ClFNO2: C, 61.34; H, 4.46; N, 4.77;
Cl, 12.07; F, 6.47. Found: C, 61.37; H, 4.60; N, 4.55; Cl,
11.77; F, 6.29.
Z
Z
Z
4.5.4. Reduction of 4-(2-chloro-6-fluoro-phenylamino)-
benzoic acid ethyl ester (26) to diaryl-amine 13a. Red-Al
(14.75 g of a 70% (w/w) solution in toluene, 10.325 g 100%,
51.07 mmol) was dissolved in toluene (25 mL) and the
solution was heated to 60–62 8C. A solution of the ester 26

11582
M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
(5 g, 17.02 mmol)) in toluene (50 mL) was added during 1 h
and the reaction mixture was stirred for additional 1.5 h at
this temperature. The reaction mixture is then cooled down
to 30–40 8C and was poured onto a stirred mixture of ethyl
acetate (100 mL) and sulfuric acid (150 mL of a 20%
aqueous solution) at 0–4 8C. The two-phases mixture was
stirred for 30 min at 0–4 8C, the layers were separated and
the aqueous layer was extracted with ethyl acetate
(100 mL). The organic layers were combined, washed
with aq sodium bicarbonate (150 mL), water (150 mL) and
the solvent was evaporated under reduced pressure to afford
4.0 g of crude product as an oil. The crude product was
purified by column chromatography on silica gel with
hexanes/ethyl acetate (8:2) as eluent to obtain 3.35 g (83%)
of 13a as an oil. The product was converted into its N-(2-
chloroacetyl) derivative 14a according to acetylation
procedure A (see Section 4.3). Analytical data of the
products 13a and 14a were identical with those described
above.
C(2)). IR (film): characteristical absorbtions: 1726, 1497,
1477, 1457, 780 cmK1. Anal. Calcd for C15H11ClFNO: C,
65.35; H, 4.02; N, 5.08; Cl, 12.86; F, 6.89. Found: C, 65.51;
H, 3.90; N, 4.96; Cl, 12.92; F, 6.90%.
4.6.2. N-(20-Chloro-40-fluoro-60-methylphenyl)-5-methyl-
oxindole (27e). Preparation according to Friedel–Crafts
procedure B. The crude product was purified by column
chromatography on silicagel (toluene/ethylacetate 19:1 to
4:1) and crystallized from n-hexane. Yield 11%. Mp 111–
112 8C. 1H NMR (DMSO-d6, 500 MHz) d 2.10 (s, 3H,
CH3), 2.28 (s, 3H, CH3), 3.80 (m, 2H, HC(3)), 6.23 (d, JZ
7.9 Hz, 1H, HC(7)), 6.99 (d, JZ7.9 Hz, 1H, HC(0 6)), 7.19 (s,
1H, HC(4)), 7.38 (dd, JZ9.3, 2.6 Hz, 1H, HC(5 )), 7.56 (dd,
JZ8.4, 2.7 Hz, 1H, HC(30). Anal. Calcd for C16H13ClFNO:
C, 66.33; H, 4.52; N, 4.83; Cl, 12.24; F, 6.56. Found: C,
66.16; H, 4.57; N, 4.72; Cl, 12.28; F, 6.43%.
4.6.3. N-(20-Chloro-60-methylphenyl)-5-methyloxindole
(27f). Preparation according to Friedel–Crafts procedure
B. Crystallization from 2-propanol/hexane. Yield 47%. Mp
158–159 8C. 1H NMR (DMSO-d6, 500 MHz) d 2.10 (s, 3H,
CH3), 2.28 (s, 3H, CH3), 3.80 (m, JZ7.3 Hz, 2H, HC(3)),
6.18 (d, JZ7.9 Hz, 1H, HC(7)), 6.98 (d, JZ7.9 Hz, 1H,
HC(6)), 7.19 (s, 0 1H, HC(4)), 7.44 (m, JZ7.2 Hz, 2H,
HC(30) and HC(4 )), 7.53 (dd, 1H, HC(50)).
4.6. Synthesis of N-aryl oxindoles (27) from
N-(2-chloroacetyl)-diaryl amines (14)
General procedures for the Friedel–Crafts cyclisation of
N-(2-chloroacetyl)-diaryl-amines 14 to N-aryl-oxindoles 27.
Friedel–Crafts procedure A. A mixture of the N-(chloro-
acetyl)-diarylamine (14) (20 mmol) and aluminium tri-
chloride (26 mmol) was heated slowly to 170 8C and was
stirred at this temperature for 3 h. During this time, nitrogen
was continuously bubbled into the melt. The mixture was
cooled to 100–110 8C, diluted with toluene (20 mL) and was
poured onto warm water (20 mL). The organic layer was
separated, washed with water and evaporated. The residue
was crystallized from 2-propanol (20 mL) to obtain the
crystalline N-aryl-oxindole 27.
Anal. Calcd for C16H14ClNO: C, 70.72; H, 5.19; N, 5.15; Cl,
13.05. Found: C, 70.64; H, 5.23; N, 4.97; Cl, 12.99%.
4.6.4. N-(20-Chloro-60-methylphenyl)-5-ethyloxindole
(27g). Preparation according to Friedel–Crafts procedure
A. The crude product was purified by column chromato-
graphy on silicagel (toluene/ethylacetate 19:1 to 4:1) and
crystallized from n-hexane to afford 27g. Yield: 59%, Mp:
1
99–101 8C. H NMR (DMSO-d6, 500 MHz) d 1.17 (t, JZ
7.6 Hz, 3H, CH3), 2.10 (s, 3H, CH3), 2.58 (q, JZ7.6 Hz, 2H,
CH2), 3.81 (m, 2H, HC(3)), 6.20 (d, JZ7.9 Hz, 1H, HC(7)),
7.01 (d, JZ7.9 Hz, 1H, HC(6)), 7.23 (s, 1H, HC(4)), 7.44
(m, 2H, HC(40) and HC(50)), 7.53 (m, 1H, HC(30)). Anal.
Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90; Cl,
12.41. Found: C, 71.34; H, 5.72; N, 4.79; Cl, 12.41%.
Friedel–Crafts procedure B. A mixture of the N-(chloro-
acetyl)-diarylamine (14) (2 mmol) and aluminium tri-
chloride (2.6 mmol) in chlorobenzene (2 mL) was heated
at 155 8C (oil bath temperature) for 5 h. The reaction
mixture was diluted with toluene (30 mL) and water
(20 mL) and the phases were separated. The organic layer
was washed with aq 2 N HCl and water. Evaporation of
the solvent and crystallization afforded the corresponding
N-aryl oxindole.
4.6.5. N-(20,30,60-Trifluorophenyl)-5-ethyloxindole (27h).
Preparation according to Friedel–Crafts procedure A. After
4 h reaction time, 10% more aluminium trichloride was
added and the mixture was stirred for another 2 h. Yield
from 14h: 48% after two re-crystallizations.
4.6.1. N-(20-Chloro-60-fluorophenyl)-5-methyloxindole
(27a). Preparation according to Friedel–Crafts procedure
A. Yield 80% from 14a. Mp 137–138 8C. MS (APCI) 276
Mp 171–172 8C. MS (APCI) 292 (MHC). 1H NMR
(DMSO-d6, 400 MHz, 300 K) d 1.18 (t, JZ7.63 Hz, 3H,
CH3), 2.60 (q, JZ7.63 Hz, 2H, CH2–CH3), 3.89 (s, 2H,
CH2–CO), 6.62 (d, JZ8.02 Hz, 1H, HC(7)), 7.09 (d, JZ
8.02 Hz, 1H, HC(6)), 7.25 (s, 1H, HC(4)), 7.46 (m, 1H,
HC(50)), 7.76 (m, 1H, HC(40)). 13C NMR (CDCl3,
125 MHz, 300 K) d 16.4 (s, 1C, CH3), 28.3 (s, 1C, CH2),
35.5 (s, 1C, C(3)), 0109 (s, 1C, C(7)), 112,07 (m, 1C, C(50)),
113.2 (m, 1C, C(1 )), 118.7 (m, 1C, C(4 )), 124.9 (s, 1C,
C(4)), 125.2 (s, 1C, C(3a)), 127.3 (s, 1C, C(6)),0139.3 (s, 1C,
C(5)), 1041.0 (s, 1C, C(7a)), 146.1 (m, 1C, C(2 )), 148.1 (m,
1C, C(3 )), 154.5 (d, JC–FZ249 Hz, 1C, C(60)), 173.8 (s, 1C,
C(2)). IR (film): characteristical absorptions: 1729, 1503,
1485, 822 cmK1. Anal. Calcd for C16H12F3NO: C, 65.98; H,
1
(MHC). H NMR (DMSO-d6, 500 MHz, 300 K) d 2.27 (s,
3H, CH3), 3.83 (s, 2H, CH2); 6.35 (d, JZ8.0 Hz, 1H,
HC(7)), 7.01 (d, JZ8.0 Hz, 1H, HC(6)), 7.19 (s, 1H,
HC(4)), 7.52 (ddd, JZ8.5, 2.0 Hz, JH–FZ10.0 Hz, 1H,
HC(50)), 7.60 (ddd, JZ8.5, 2.0 Hz, JH–FZ1.5 Hz, 1H,
HC(30)), 7.63 (ddd, JZ8.5 Hz, JH–FZ1.5 Hz, 1H, HC(40)).
13C NMR (DMSO-d6, 125 MHz, 300 K) d 21.0 (s, 1C, CH3),
35.5 (s, 1C, CH2), 108.8 (s, 1C, C(7)), 116.3 (d, JC–F
Z
20.2 Hz, 1C, C(50)), 121 (d, JC–FZ16.1 Hz, 1C, C(10)), 125
(s, 1C, C(3a)) 126 (s, 1C, C(4)), 126.7 (d, JC–FZ2.2 Hz, 1C,
C(30)), 128.4 (s, 1C, C(6)), 132.2 (d, JC–FZ9.3 Hz, 1C,
C(40)), 132.4 (s, 1C, C(5)), 134.2 (s, 1C, C(20)), 141.2 (s, 1C,
C(7a)), 159.4 (d, JC–FZ252.3 Hz, 1C, C(60)), 173.9 (s, 1C,

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11583
4.15; N, 4.81; F, 19.57. Found: C, 65.99; H, 4.20; N, 4.59; F,
19.67%.
4.7. Synthesis of phenylacetic acid derivatives 28 from
N-aryl oxindoles 27
General procedure for the hydrolysis of N-aryl-oxindoles
(27) to phenylacetic acid derivatives 28.
4.6.6. N-(20,60-Dichloro-40-methylphenyl)-5-methyl-oxin-
dole (27i). Preparation according to Friedel–Crafts pro-
cedure A. Yield: 55% from 14i. Mp 153–154 8C. MS
(APCI) 306 (MHC). 1H NMR (DMSO-d6, 400 MHz,
300 K) d 2.29 (s, 3H, CH3–C(5)), 2.41 (s, 3H, CH3–
C(40)), 3.81 (s, 2H, CH2), 6.27 (d, JZ8.02 Hz, 1H, HC(7)),
7.00 (d, JZ7.83 Hz, 1H, HC(6)), 7.19 (s, 1H, HC(4)), 7.58
(s, 2H, HC(30) and HC(50)). 13C NMR (CDCl3, 125 MHz,
300 K) d 20.8 (s, 1C, CH3), 21.1 (s, 1C, CH3), 35.5 (s, 1C,
C(3)), 108.6 (s, 1C, C(7)), 125.0 (s, 1C, C(3a)), 126,1 (s, 1C,
C(4)), 0127.7 (s, 1C, C(10)), 128.4 (s, 1C, C(6)), 130.1 (s, 2C,
C(30,5 )), 132.2 (s, 1C, C(5)), 134.3 (s, 2C, C(20,60)), 141.2
(s, 1C, C(7a)), 142.9 (s, 1C, C(40)); 173.7 (s, 1C, C(2)). IR
(film): characteristical absorptions: 1734, 1497, 816,
801 cmK1. Anal. Calcd for C16H13Cl2NO: C, 62.76; H,
4.28; N, 4.57; Cl, 23.16. Found: C, 62.61; H, 4.33; N, 4.26;
Cl, 22.89%.
A solution of the N-aryl-oxindole 27 (4.9 mmol), in ethanol
(18 mL) and water (1 mL) was heated to reflux. Sodium
hydroxide solution (1.9 g of a 30%, w/w solution) was
slowly added and reflux was continued for 4–5 h. The
solution was cooled to about 40 8C and treated slowly with a
solution of concentrated hydrochloric acid (1.5 g) in water
(12 mL) up to a pH of 3–4. The obtained suspension was
cooled to 20 8C. The crystals were collected by filtration,
washed with water and dried to obtain the phenylacetic acid
derivative 28.
4.7.1. 5-Methyl-2-(20-chloro-60-fluoroanilino)phenyl-
acetic acid (28a). Yield from 27a: 90%. Mp 152–154 8C.
MS(EI) m/z 293 (MC), 275, 240, 212 (100%). 1H
NMR(DMSO-d6, 500 MHz, 300 K) d 2.21 (s, 3H, CH3),
3.64 (s, 2H, CH2), 6.42 (dd, JZ8.0 Hz, JH–FZ3.0 Hz, 1H,
HC(3)), 6.90 (dd, JZ8.0, 2.0 Hz, 1H, HC(4)), 7.01 (d, JZ
2.0 Hz, 1H, HC(6)), 7.09 (s, 1H, NH), 7.09 (ddd, JZ8.5 Hz,
JH–FZ5.5 Hz, 1H, HC(40)), 7.23 (ddd, JZ8.5, 1.5 Hz,
JH–FZ11 Hz, 1H, HC(50)), 7.34 (ddd, JZ8.5, 1.5 Hz,
JH–FZ1.5 Hz, 1H, HC(30)), 12.67 (s, 1H, COOH). 13C
NMR (DMSO-d6, 125 MHz, 300 K) d 20.55 (s, 1C, CH3),
38.2 (s, 1C, CH2), 115.7 (d, JC–FZ20 Hz, 1C, C(50)), 117.2
(s, 1C, C(3)), 123.75 (d, JC–FZ8 Hz, 1C, C(40)), 124.8 (s,
1C, C(1)), 126.1 (s, 1C, C(30)), 127.7 (d, JC–FZ4 Hz, 1C,
C(20)), 128.3 (s, 1C, C(4)), 129.5 (d, JC–FZ14 Hz, 1C,
C(10)), 130.4 (s, 1C, C(5)), 131.7 (s, 1C, C(6)), 140.3 (s, 1C,
C(2)), 156 (d, JC–FZ247 Hz, 1C, C(60)), 173.9 (s, 1C,
CO2H). IR (film): characteristical absorbtions: 3359, 1672,
1511, 1479, 1255 cmK1. Anal. Calcd for C15H13ClFNO2: C,
61.34; H, 4.46; N, 4.77; Cl, 12.07; F, 6.47. Found: C, 61.38;
H, 4.54; N, 4.65; Cl, 12.12; F, 6.54%.
4.6.7. N-(20-Chloro-60-fluorophenyl)-5-ethyloxindole
(27j). Preparation according to Friedel–Crafts procedure
A. After 4 h reaction time, 10% more aluminium trichloride
was added and the mixture was stirred for another 2 h. Yield
from 14j: 38% after two recrystallizations. Mp 129–130 8C.
MS (APCI) 290 (MHC). 1H NMR (DMSO-d6, 300 K,
400 MHz) d 1.18 (t, JZ7.43 Hz, 3H, CH3), 2.59 (q, JZ
7.43 Hz, 2H, CH2–CH3), 3.86 (s, 2H, CH2–CO), 6.39 (d,
JZ8.02 Hz, 1H, HC(7)), 7.05 (d, JZ8.220 Hz, 1H, HC(6)),
7.24 (s, 1H, HC(4)), 7.53 (m, 1H, HC(5 )), 7.64 (m, 2H,
HC(30) and HC(40)). 13C NMR (CDCl3, 125 MHz, 300 K) d
116.4 (s, 1C, CH3), 28.3 (s, 1C, CH2), 35.6 (s, 1C, C(3)),
108.8 (s, 1C, C(7)), 116.3 (d, JC–FZ19.7 Hz, 1C, C(50)), 121
(d, JC–FZ16.2 Hz, 1C, C(10)), 124.9 (s, 1C, C(4)), 125.1 (s,
1C, C(3a)), 126.7 (s, 1C, C(30)), 127.3 (s, 1C, C0(6)), 132.2
(d, JC–FZ8.5 Hz, 1C, C(40)), 134.2 (s, 1C, C(2 )), 139 (s,
1C, C(5)), 141.8 (s, 1C, C(7a)), 159.4 (d, JC–FZ253 Hz, 1C,
C(60)), 173.9 (s, 1C, C(2)). IR (film): characteristical
absorbtions: 1727, 1499, 1477, 1456, 783 cmK1. Anal.
Calcd for C16H13ClFNO: C, 66.33; H, 4.52; N, 4.83; Cl,
12.24; F, 6.56. Found: C, 66.42; H, 4.57; N, 4.69; Cl, 12.31;
F, 6.65%.
4.7.2. 5-Methyl-2-(20-chloro-60-methylanilino)0-phenyl-
acetic acid (28f). Hydrolysis of N-(20-chloro-6 -methyl-
phenyl)-5-methyloxindole 27f in refluxing aqueous ethanol
in the presence of at least 2 equiv of sodium hydroxide
followed by precipitation by adding hydrochloric acid gave
28f. Mp 116–120 8C. 1H NMR (DMSO-d6, 500 MHz) d 2.02
(s, 3H, CH3), 2.19 (s, 3H, CH3), 3.67 (s, 2H, CH2), 6.07 (d,
JZ8.1 Hz, 1H, HC(3)), 6.78 (s, 1H, HN), 6.83 (dd, JZ8.2,
1.4 Hz, 1H, HC(5)), 6.99 (d, JZ1.5 Hz, 1H, HC(6)), 7.070(t,
JZ7.8 Hz, 1H, HC(40)); 7.21 (0d, JZ7.5 Hz, 1H, HC(5 )),
7.35 (d, JZ7.5 Hz, 1H, HC(3 )), 12.59 (s, 1H, COOH).
Anal. Calcd for C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83;
Cl, 12.24. Found: C, 66.50; H, 5.53; N, 4.69; Cl, 12.22%.
4.6.8. N-(20,60-Dichlorophenyl)-5-methyloxindole (27k).
Preparation according to Friedel–Crafts procedure A. Yield
from 14k: 70%.
Mp 152–153 8C. MS (EI) m/z 291 (MHC), 256, 228 (100%),
193. 1H NMR (DMSO-d6, 400 MHz, 300 K) d 2.30 (s, 3H,
CH3), 3.85 (s, 2H, CH2), 6.29 (d, JZ8.02 Hz, 1H, HC(7)),
7.02 (d, JZ8.02 Hz, 1H, HC0(6)), 7.22 (s, 1H, HC(4)), 7.62
(dd, JZ8.02 Hz, 1H, HC(4 )), 7.76 (d, JZ8.20 Hz, 2H,
HC(30) and HC(50)). 13C NMR (CDCl3, 125 MHz, 300 K) d
21.1 (s, 1C, CH3), 35.6 (s, 1C, C(3)), 108.7 (s, 1C, C(7)),
125.0 (s, 1C, C(3a0), 126.1 (s, 1C, C(4)), 128.4 (s, 1C, C(6)),
129.8 (s, 2C, C(3 ,50)), 130.5 (s, 1C, C(10)), 1032.2 (s, 1C,
C(40)), 132.3 (s, 1C, C(5)), 134.9 (s, 2C, C(20,6 )), 141.0 (s,
1C, C(7a)), 173.6 (s, 1C, C(2)). IR (film): characteristical
absorbtions: 1731, 1493, 1463, 819, 783 cmK1. Anal. Calcd
for C15H11Cl2NO: C, 61.67; H, 3.79; N, 4.79; Cl, 24.27.
Found: C, 61.70; H, 3.91; N, 4.61; Cl, 24.21%.
4.7.3. 5-Ethyl-2-(20-chloro-60-methylanilino)-phenyl-
acetic acid (28g). A mixture of 0.89 g of N-(20-chloro-60-
methylphenyl)-5-ethyloxindole (27g), 11 g of ethanol and
3 g of water was degassed with nitrogen under vigorous
stirring for 15 min. The mixture was then treated with 1.8 g
of 30% aqueous sodium hydroxide and heated to reflux for
36 h. After adding 1 N hydrochloric acid (about 10 g to
reach a pH of 4), the mixture was cooled to room
temperature and extracted with dichloromethane. The
organic phase was washed with water and evaporated to

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M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
dryness to afford crude 5-ethyl-2-(20-chloro-60-methyl-
anilino)-phenylacetic acid (28) as a 92:8 mixture with the
meta-ethyl isomer. The crude product was purified by
chromatography on silica gel with toluene/ethylacetate 9:1
as eluent and crystallized from hexanes. Mp 108–110 8C. 1H
NMR (DMSO-d6, 500 MHz) d 1.13 (t, JZ7.6 Hz, 3H, CH3),
2.03 (s, 3H, CH3), 2.49 (q, JZ7.6 Hz, 2H, CH2(CH3)), 3.68
(s, 2H, CH2(COOH)), 6.09 (d, JZ8.2 Hz, 1H, HC(3)), 6.79
(s, 1H, NH), 6.86 (dd, JZ8.1, 1.8 Hz, 1H, HC(4)), 7.02 0(d,
JZ1.8 Hz, 1H, HC(6)), 7.07 (t, JZ7.7 Hz, 1H, HC(4 )),
7.21 (d, JZ7.5 Hz, 1H, HC(50)), 7.36 (d, JZ7.9 Hz, 1H,
HC(30)), 12.59 (s, 1H, COOH). Anal. Calcd for
C17H18ClNO2: C, 67.21; H, 5.97; N, 4.61; Cl, 11.67.
Found: C, 67.10; H, 5.98; N, 4.41; Cl, 11.62%.
MS (EI): m/z 279 (MC), 250 (MKC2H5)C, 234, 206 (MK
CO2C2H5)C, 176, 164, 135, 84.
4.7.6. Synthesis of (5-ethyl-2-oxo-cyclohexylidene)-acetic
acid ethyl ester (33). [5-Ethyl-2-morpholin-4-yl-cyclohex-
2-enylidene]-acetic acid ethyl ester (10 g, 35.79 mmol) was
dissolved in toluene (20 mL). HCl (12 mL of a 6 M
solution) was added dropwise under rigorous stirring and
the reaction mixture was stirred for additional 60 min at
22 8C. The organic layer was separated and was washed
with water (2!25 mL). The water layers were combined
and were extracted with toluene (25 mL). The toluene layers
were combined, dried over anhydrous sodium sulfate and
the solvent was evaporated under reduced pressure to yield
6.72 g (89%) of [5-ethyl-2-oxo-cyclohexylidene]-acetic
acid ethyl ester as an oil. HRMS: 211.13287 (MCCH);
C12H18O3 requires 211.13287 (MCCH). 1H NMR (CDCl3,
500 MHz, 277 K) d 0.935 (t, JZ7 Hz, 3H, H3C(12)), 1.259
(t, JZ7 Hz, 3H, H3C(10)), 1.31–1.45 (m, 2H, H2C(11)),
1.46–1.55 (m, 1H, H–C(5)), 1.59–1.69 (m, 1H, H–C(4)),
1.97–2.04 (m, 1H, H–C(5)), 2.296 (ddd, JZ17, 11, 3 Hz,
1H, H–C(3)), 2.383 (m, 1H, H–C(6)), 2.615 (dt, JZ17,
4 Hz, 1H, H–C(6)), 3.57 (dm, JZ17 Hz, 1H, H–C(3)), 4.17
(q, JZ7 Hz, 2H, H2C(9)), 6.42 (m, 1H, H–C(7)). Assign-
ments according to numbers given in the formula. 13C NMR
(DMSO-d6, 100 MHz, 300 K) d 11.41, 14.05, 27.99 (2C),
33.75, 35.54, 38.98, 60.12, 120.43, 150.34, 164.88,
199.93 ppm. IR (film): strong absorptions at 1719,
1698 and 1200 cmK1. MS (EI): m/z 210 (MC), 164
(MKC2H5OH)C, 135.
4.7.4. 5-Methyl-2-(20,60-dichloro-40-methylanilino)-
phenylacetic acid (28i). Yield from 27i: 82%. Mp 179–
1
182 8C. MS (EI) m/z 323 (MC), 305, 270, 242 (100%). H
NMR (DMSO-d6, 300 K, 400 MHz) d 2.22 (s, 3H, CH3–
C(5)), 2.32 (s, 3H, CH3–C(40)), 3.67 (s, 2H, CH2), 6.18 (d,
JZ8.40 Hz, 1H, HC(3)), 6.87 (dd, JZ8.40, 1.50 Hz, 1H,
HC(4)), 6.97 (s, 1H, NH), 7.02 (s, 1H, HC(6)), 7.36 (s, 2H,
HC(30) and HC(50)), 12.68 (br s, 1H, COOH). 13C NMR
(CDCl3, 125 MHz, 300 K) d 20.3 (s, 1C, CH3), 20.5 (s, 1C,
CH3), 38.2 (s, 1C, CH2), 116.3 (s, 1C, C(3)), 124.2 (s, 1C,
C(1)), 0128.3 (s, 1C, C(4)), 129.8 (s,1C, C(5)), 129.9 (s, 2C,
C(30,5 )), 130.1 (s, 2C, C(20, 60)), 131.8 (s, 1C, C(6)), 135.2
(s, 1C, C(10)), 135.9 (s, 1C, C(40)), 141 (s, 1C, C(2)), 173.8
(s, 1C, CO2H). IR (film): characteristical absorptions:
3336, 1696, 1510, 1486, 1305 cmK1. Anal. Calcd for
C16H15Cl2NO2: C, 59.28; H, 4.66; N, 4.32; Cl, 21.87.
Found: C, 59.11; H, 4.92; N, 4.30; Cl, 21.71%.
4.7.7. Synthesis of 1-(2-chloro-6-methyl-phenyl)-5-ethyl-
1,4,5,6-tetrahydro-indol-2-one (34). 2-Chloro-6-methyl-
aniline (3.45 g, 23.9 mmol) was dissolved in toluene
(26 mL). p-Toluene-sulfonic acid mono hydrate (0.227 g,
1.2 mmol) was added and the mixture was heated to reflux.
A solution of (5-ethyl-2-oxo-cyclohexylidene)-acetic acid
ethyl ester (33) (5.0 g, 23.9 mmol) in toluene (13 mL) was
added dropwise during 75 min and the water formed was
collected by the means of a water separator. The reaction
mixture was stirred under reflux for 15 h, during which time
the solvent was frequently removed and was replaced with
fresh toluene. For work-up, the mixture was cooled to 22 8C
and was treated with saturated aq sodium hydrogen
carbonate solution (70 mL) under rigorous stirring. The
layers were separated and the toluene phase was washed
with a 5% aqueous solution of citric acid and finally with a
10% solution of sodium chloride in water. The aqueous
phases were extracted with toluene (70 mL) and the toluene
phases were combined. The solvent was evaporated under
reduced pressure to yield 7.1 g of a highly viscose liquid as
crude product. The crude product was purified by chroma-
tography on silica gel with toluene/ethyl acetate (9:1) as
eluent to yield 1.76 g (25.6%) of pure 1-(2-chloro-6-methyl-
4.7.5. Synthesis of [5-ethyl-2-morpholin-4-yl-cyclohex-2-
en-(E/Z)-ylidene]-acetic acid ethyl ester (32). 4-Ethyl-
cyclohexanone (88.85 g, 704 mmol), morpholine (73.6 g,
845 mmol) and p-toluene-sulfonic acid monohydrate (2 g,
21 mmol) were dissolved in toluene (400 mL). The mixture
was heated to reflux and the water formed was removed by
a water separator. After 24 h reaction time, the reaction
mixture was cooled to 100 8C and p-toluene-sulfonic acid
mono hydrate (2 g, 21 mmol) was added, followed by the
addition of glyoxylic acid ethyl ester (78.61 g, 770 mmol)
during 30 min. The mixture was heated again to reflux for
5 h and allowed to cool down to 22 8C. The solvent was
evaporated under reduced pressure and the crude product
was distilled at 140–150 8C/9.5K2 mbar to obtain [5-ethyl-
2-morpholin-4-yl-cyclohex-2-en-(E/Z)-ylidene]-acetic acid
ethyl ester (32) as an oil. Yield: 48.3 g (25%). HRMS:
280.19076 (MCCH); C16H25NO3 requires 280.19072
1
(MCCH). H NMR(CDCl3, 500 MHz, 277 K) d 0.896 (t,
JZ7 Hz, 3H, H3C(17)), 1.277 (t, JZ7 Hz, 3H, H3C(10)),
1.20–1.45 (m, 2H, H2C(16)), 1.50–1.62 (m, 1H, H–C(4)),
1.876 (ddd, J1Z18 Hz, J2Z9 Hz, J3Z3 Hz, 1H, H–C(3)),
2.13 (m, 1H, H–C(5)), 2.35 (dt, J1Z17 Hz, J2Z5 Hz, 1H,
H–C(3)), 2.55–2.65 (m, 2H, H–C(12) and H–C(15)), 2.72–
2.80 (m, 2H, H–C(12) and H–C(15)), 3.55 (dm, JZ15 Hz,
1H, H–C(5)), 3.74 (m, 4H, H2C(13) and H2C(14)), 4.152 (q,
JZ7 Hz, 2H, H2C(9)), 5.46 (dd, J1Z5 Hz, J2Z3 Hz, 1H,
H–C(2)), 6.17 (br s, 1H, H–C(7)). Assignments according to
numbers given in the formula. IR (film): strong absorptions
phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one
(34).
HRMS: 288.11506 (MCCH); C17H18ClNO requires
288.11497 (MCCH). 1H NMR (DMSO-d6, 400 MHz,
300 K) d 0.894 ppm (t, JZ7 Hz, 3H, H3C(11)), 1.34–1.43
(m, 2H, H2C(10)), 1.70–1.82 (m, 1H, H–C(5)), 1.90–2.02
(m, 1H, H–C(6)), 2.038 (s, 3H, H3C(60)), 2.28–2.40 (m, 2H,
H–C(4) and H–C(6)), 2.87 (dd, J1Z17 Hz, J2Z4 Hz, 1H,
H–C(4)), 5.14 (m, 1H, 0H–C(7)),0 5.96 (br 0s, 1H, H–C(3)),
7.3–7.5 (m, 3H, H–C(3 ), H–C(4 ), H–C(5 )). Assignments
at 2960, 1710, 1624, 1609, 1191, 1156 and 1120 cmK1
.

M. Acemoglu et al. / Tetrahedron 60 (2004) 11571–11586
11585
according to the numbers given in the formula. 13C NMR
(DMSO-d6, 125 MHz, 300 K) d 11.3, 17.6, 27.6, 29.7, 37.2,
54.9, 110.1, 115.3, 127.5, 129.4, 130.0, 131.2, 133.4, 138.2,
140.0, 149.0, 168.3 ppm. IR (film): strong absorptions at
1703, 1660 and 1476 cmK1. MS (EI): m/z 287 (MC), 272
(MKCH3)C, 258 (MKC2H5)C, 252 (MKCl)C.
200 mL of a mixture of hexane/toluene (10:1) for crystal-
lization. The slurry was stirred at 0 8C for several hours, the
product was isolated by filtration and washed with hexane to
yield 111.45 g (76.0%) of 1-(2-chloro-6-fluoro-phenyl)-5-
methyl-1,4,5,6-tetrahydro-indol-2-one (39) as beige crys-
tals, mp 103–105 8C. 1H NMR (CDCl3, 400 MHz, 300 K): d
1.10 (d, JZ6.5 Hz, 3H), 1.98–2.18 (br m, 2H), 2.30–2.44
(br m, 2H), 2.86 (d, JZ16 Hz, 1H), 5.28 (br m, 1H), 5.93 (br
s, 1H), 7.11–7.18 (br m, 1H), 7.31–7.38 (br m, 2H). 13C
NMR (DMSO-d6, 125 MHz, 300 K) d 20.6, 30.4, 31.7,
110.8, 115.1, 115.6, 120.8, 126.0, 131.3, 134.4, 138.0,
150.0, 159.4 (d, JC–FZ252 Hz), 168.2. Anal. Calcd for
C15H13ClFNO: C, 64.87; H, 4.72; N, 5.04; Cl, 12.77; F,
6.84. Found: C, 64.83; H, 4.97; N, 5.04; Cl, 12.78; F, 6.87%.
4.7.8. Synthesis of N-(2-chloro-6-methyl-phenyl)-5-ethyl-
oxindole (27g). A mixture of 1-(2-chloro-6-methyl-phe-
nyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one (34) (1 g,
3.5 mmol) and 10% palladium on charcoal (0.1 g) in xylene
(20 mL) was heated under reflux for 72 h. The palladium-
catalyst was removed by filtration and the solvent was
evaporated. The product was purified by column chroma-
tography on silica gel (toluene/ethylacetate 19:1 to 4:1) and
the product was crystallized from n-hexane to obtain 0.21 g
(21%) of 27g. Analytical data see Section 4.6.
4.7.12. Oxidation of 39 to N-(20-chloro-60-fluorophenyl)-
5-methyloxindole (27a). Compound 39 (2.77 g, 10 mmol),
iodine (0.254 g, 1 mmol) and DBU (1.52 g, 10 mmol) were
dissolved in 35 mL of xylenes and heated under reflux at an
external temperature of 155 8C for 36 h. After almost
complete conversion the reaction mixture was worked up by
extraction with 2 N HCl and an aqueous solution of sodium
thiosulfate to remove DBU and iodine. The solvent was
evaporated under reduced pressure to obtain a crude
crystalline product (2.8 g). Re-crystallization of the crude
product from toluene/hexane afforded 2.1 g (76.0%) of
almost pure product 27a which contained traces of starting
material and an isomeric analogue of the starting material.
An analytically pure sample was obtained by re-crystal-
lization from ethyl acetate/hexane. Analytical data see
Section 4.6.
4.7.9. Synthesis of [5-methyl-2-morpholin-4-yl-cyclohex-
2-en-(E/Z)-ylidene]-acetic acid ethyl ester (37). Com-
pound 37 was prepared from sequential condensations
of 4-methyl-cyclohexanone (35), morpholine (30) and
glyoxylic acid ethyl ester according to the procedures
given above for the preparation of compound 32. Crude
37 was directly used for the preparation of compound 38.
4.7.10. Synthesis of (5-methyl-2-oxo-cyclohexylidene)-
acetic acid ethyl ester (38). Compound 37 was hydrolyzed
using the same procedure as described above for the
preparation of compound 32. The product 38 was purified
either by chromatography on silica gel or by distillation.
The yield after chromatography was higher (76%) as
compared to the yield from purification by distillation
(68.5%), presumably due to decomposition of the product
during distillation. Bp 80–85 8C at 8.0–9.0!10K2 bar.
HRMS: 197.11716 (MCCH); C11H16O3 requires
197.11722 (MCCH). 1H NMR (CDCl3, 400 MHz,
300 K): d (ppm) 1.10 (d, 3H), 1.30 (t, 3H), 1.52–1.68 (br
m, 1H), 1.87–2.02 (br m, 2H), 2.24–2.33 (ddd, 1H), 2.38–
2.50 (m, 1H), 2.61–2.70 (m, 1H), 3.62 (d, 1H), 4.22 (q, 2H),
6.45 (m, 1H).
Acknowledgements
Skillful technical assistance by Mrs. N. Braendlin and
Mrs. T. Ingold, G. Petignat, R. Schreiber, K. Schreiner
and H. Stettler is gratefully acknowledged. We thank the
Analytical Departments of Novartis Pharma AG for
analytical support.
4.7.11. Synthesis of 1-(2-chloro-6-fluoro-phenyl)-5-
methyl-1,4,5,6-tetrahydro-indol-2-one (39). 2-Chloro-6-
fluoroaniline (76.84 g, 0.528 mol) was dissolved in toluene
(400 mL). p-Toluene-sulfonic acid mono hydrate (5.02 g,
260 mmol) was added and the mixture was heated to reflux.
A solution of (5-methyl-2-oxo-cyclohexylidene)-acetic acid
ethyl ester (38) (103.6 g, 528 mmol) in toluene (200 mL)
was added dropwise during 4 h and the water formed was
collected by the means of a water separator. The reaction
mixture was heated to reflux for 18 h, during which time the
condensing solvent was frequently removed and was
replaced with fresh toluene. For work-up, the mixture was
cooled to 22 8C and was treated with saturated aq sodium
hydrogen carbonate solution (250 mL) under rigorous
stirring. The layers were separated and the toluene phase
was washed with 5% aqueous solution of citric acid
(250 mL) and finally with water (250 mL). The aqueous
phases were extracted with toluene (250 mL) and the
toluene phases were combined. The solvent was evaporated
under reduced pressure to yield 175 g of a highly viscose
liquid as crude product. The crude product was treated with
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