Sequential palladium-catalysed C- and N-arylation reactions as a practical and general protocol for the synthesis of the first series of oxcarbazepine analogues

Article abstract of DOI:10.1016/j.tet.2006.11.003

The first series of oxcarbazepine analogues, starting from readily-available materials and through a high-yielding five-step sequence based on palladium catalysis, is reported. The so-obtained compounds incorporate not only a variety of substituents in both of?the aryl rings comprising the framework of an oxcarbazepine, but also involve the more challenging palladium-catalysed coupling of a number of heteroaromatic substrates. The addition of small amounts of water in some of the metal-catalysed processes showed a beneficial effect, highly increasing the selectivity of such reactions.

Full text of DOI:10.1016/j.tet.2006.11.003

Tetrahedron 63 (2007) 690–702
Sequential palladium-catalysed C- and N-arylation reactions
as a practical and general protocol for the synthesis
of the first series of oxcarbazepine analogues
*
Monica Carril, Raul SanMartin, Esther Domınguez and Imanol Tellitu
*
ꢀ
ꢀ
Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea, PO Box 644, 48080 Bilbao, Spain
Received 11 September 2006; revised 31 October 2006; accepted 1 November 2006
Available online 28 November 2006
Abstract—The first series of oxcarbazepine analogues, starting from readily-available materials and through a high-yielding five-step
sequence based on palladium catalysis, is reported. The so-obtained compounds incorporate not only a variety of substituents in both of the
aryl rings comprising the framework of an oxcarbazepine, but also involve the more challenging palladium-catalysed coupling of a number of
heteroaromatic substrates. The addition of small amounts of water in some of the metal-catalysed processes showed a beneficial effect, highly
increasing the selectivity of such reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Most of them are based on transformations in the iminostil-
bene or iminodibenzyl rings obtained through a sequence
of drastic oxidation and reduction reactions from o-nitro-
toluene. Since these harsh reaction conditions may only be
achieved using specialised production equipment, they are
inadequate and economically disadvantageous for industrial
manufacturing purposes.6
Oxcarbazepine (TrileptalÒ) has become the most widely
prescribed drug for the treatment of epilepsy, due to its
anticonvulsant properties and improved side-effect profile
compared to the previously employed antiepileptic agent
carbamazepine (TegretolÒ) (Fig. 1).1 The efficacy of oxcarb-
azepine (OXC) in the treatment of psychosomatic diseases,2
trigeminal neuralgia,2 Parkinsonian syndromes3 and AIDS-
related neural disorders4 is, in addition to its analgesic
properties, well-established. More recently, OXC has
additionally proved effective in the treatment of refractory
bipolar and schizoaffective disorders.5
Thus, Novartis Pharma has recently designed two valuable
protocols that provide access to OXC, employing either re-
mote metallation7 or Friedel–Crafts acylation8 as key steps
in the construction of the tricyclic skeleton of OXC. Whereas
the scale-up process for the latter protocol has been success-
fully achieved,6,9 this is still limited for the former due to the
excess of LDA–TMEDA required.7 Nevertheless, none of
these synthetic routes to OXC has led to the formation of
analogues, presumably because of the scope of the reaction
conditions employed or the limited availability of the
required starting materials.
O
N
N
O
NH2
O
NH2
Oxcarbazepine
(Trileptal)®
In this context, we have recently reported a straightforward
and high-yielding synthesis of OXC through a sequence
of palladium-catalysed C- and N-arylation reactions,10 that
were performed in inter- and intramolecular fashions, respec-
tively, and starting from commercially available 20-amino-
acetophenone 1a and 1,2-dibromobenzene 3a (Scheme 1).11
Carbamazepine
(Tegretol)®
Figure 1.
Due to its aforementioned appealing properties, a number of
routes leading to OXC has been described in the literature.
Given that this approach employs simple protocols, afford-
able palladium-catalysts, standard carbonate and phos-
phate-type bases and water as a co-solvent, its application
to the synthesis of a range of OXC analogues was envisaged
(Scheme 2). Furthermore, the lack of a general and an
Keywords: Oxcarbazepine; Analogues; Palladium; Cross-coupling.
* Corresponding authors. Tel.: +34946015435; fax: +34946012748 (R.S.);
tel.: +34946012577; fax: +34946012748 (E.D.); e-mail addresses: raul.
sanmartin@ehu.es; esther.dominguez@ehu.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.003

M. Carril et al. / Tetrahedron 63 (2007) 690–702
691
O
O
O
R1
R1
Br
Br
S
(b)
1a R1 = H
+
R
1b R1 = OMe
N
H
NH2
NH2
1c
1a R = H
2a R = Ts
3a
(a)
3a X = CH; R2, R3, R4 = H
R2
R3
O
O
X
Br
Br
3b X = CH; R2, R3 = CH3, R4 = H
3c X = CH; R2, R3 = OCH3, R4 = H
3d X = CH; R2, R4 = F, R3 =H
3e X = N; R2, R3, R4 = H
O
(d), (e)
R4
N
R
Br
N
H
NH2
OXC
Br
4a R = Ts
5a R = H
X
R5
(c)
3g X = O; R5 = Br, R6 = H
3h X = S; R5 = Br, R6 = H
Br
3f
R6
Br
S
3i X = S; R5 = H, R6 = Br
Scheme 1. Synthesis of OXC. Reagents and conditions: (a) TsCl, Py,
CH2Cl2, rt; (b) Pd(OAc)2, Xantphos, Cs2CO3, PhMe, H2O; (c) H2SO4, rt;
(d) Pd(OAc)2, BINAP, K3PO4, PhMe, H2O and (e) ClSO2NCO.
Figure 2. Starting materials 1 and 3.
efficient entry to such analogues, that could potentially ex-
hibit therapeutic activity, was particularly attractive. Herein,
we present the synthesis of a series of OXC analogues ob-
tained by varying not only the substituents located on the
two aryl rings of the parent pharmaceutical, but also by in-
corporating suitably substituted heteroaryls into the tricyclic
skeleton of OXC, as depicted below (Scheme 2). Indeed, the
random modification of the structure of known drugs, for
instance by introducing different substitution patterns, is
a promising and respected strategy for the discovery of
new antiepileptic drugs, thus far more successful than the
rational-design of new molecules.1b
conditions previously reported for the palladium-catalysed
a-arylation reaction, or modified forms thereof (Table 1).
The proposed methodology proved to be suitable for the cou-
pling of phenyl derivatives 2a, 2b and 3a–d rendering the
corresponding deoxybenzoins 4a–h in good to excellent
yields (Table 1, entries 1–8). As it happened for the synthesis
of OXC, the addition of small amounts of water clearly im-
proved the selectivity of the reactions tested, diminishing the
impact of side-reactions.12
It should be mentioned that the coupling reaction between
sulfonamide 2a and the dimethoxylated dibromide 3c was
disfavoured, presumably because of the greater electron den-
sity present in the aryl ring of the electrophilic counterpart
(Table 1, entry 3). Further evidence for this postulate was ob-
tained by performing the coupling reaction with the elec-
tron-deficient, fluorinated dibromoarene 3d. In this case,
the product was furnished in 94% yield, as it could be pre-
dicted taking into account its more electrophilic nature com-
pared to the rest of the dibromoarenes 3a–c (Table 1, entry
4). Interestingly, when the reaction between the dibromo-
arenes 3b and 3c and the methoxy-substituted sulfonamide
2b was performed, an increase in the yield was observed
(relative to that in which the simple sulfonamide 2a was
used) (Table 1, entries 6 and 7). This suggests that the meth-
oxy substituents in the ketone coupling partner conversely
have a beneficial effect on the reaction outcome (4f 84%
vs 4b 68% or 4g 67% vs 4c 43%).
O
Ar
O
HetAr
Ar
HetAr
Ar
HetAr
Ar
HetAr
Br
N
H
NH2
6
5
O
Br
Br
Ar
HetAr
Ar
HetAr
+
NH2
1
3
Scheme 2. Retrosynthetic proposal.
2. Results and discussion
2.1. Synthesis of diarylethanones 4
Of the heteroarene substrates, thiophene derivative 2c ini-
tially failed to react with dibromoarenes 3a–e under the con-
ditions employed above and was especially challenging to
arylate. Furthermore, application of the experimental condi-
tions reported for the only similar C-arylation example
found in the literature resulted in no conversion of any of
the substrates.13 Fortunately, by means of slight modifica-
tions to our procedure14 the desired products 4i–l were ob-
tained in moderate to good yields (Table 1, entries 9–12),
apparently overcoming the tendency of the sulfur atom to
bind to the palladium and hinder the reaction progress.15
The first key step of the retrosynthetic route displayed above,
consists of a palladium-catalysed arylation reaction of an
aryl ketone enolate with an o-dibromoarene. In order to ob-
tain a family of OXC analogues, a range of commercially
available starting materials was chosen (Fig. 2), including
not only aryl derivatives 1a, 1b and 3a–d, but also the struc-
turally-diverse heteroarenes 1c and 3e–i.
In order to selectively achieve the desired C-arylation reac-
tion avoiding competitive N-arylation processes, substrates
1a–c were first transformed into the corresponding sulfon-
amide derivatives 2a–c. Each of these sulfonamides was
subsequently reacted with dibromoarenes 3a–d using our
Following with the use of heteroarene substrates, it was
observed that the 2,3-dibromopyridine 3e successfully

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M. Carril et al. / Tetrahedron 63 (2007) 690–702
Table 1. Synthesis of diarylethanones 4
O
Ar
O
HetAr
Br
Br
Ar
Ar
HetAr
Ar
HetAr
(b)
HetAr
+
Br
NH
R
NH
Ts
1 R = H
(a)
3
4
2 R = Ts
Entry
4a
Entry
4a
Entry
11d,e
4a
OMe
Br
Me
O
OMe
Me
O
O
MeO
S
1
6
Br
NH
Ts
Br
NH
Ts
MeO
NH
Ts
4a 86 (85)
4f 84
4k 31 (52)
F
OMe
Me
Me
OMe
O
O
O
MeO
MeO
12e,f
S
2
7
F
Br
Br
Br
NH
Ts
NH
Ts
NH
Ts
4b 68
4g 67
4l 61
F
OMe
OMe
O
N
O
O
13g
MeO
MeO
3
8
F
Br
NH2
Br
Br
NH
Ts
NH
Ts
5m 78
4c 43
4h 99
F
O
N
O
O
MeO
MeO
S
4
9c,d,e
14g
F
Br
Br
NH2
NH
Ts
Br
NH
Ts
4i 82 (82)
5n 71
4d 94
Me
O
Me
O
N
O
MeO
MeO
S
5b
10d,e
15c,d,e
S
Br
Br
NH
Br
NH
Ts
NH
Ts
Ts
4o 63 (28)
4e 87
4j 65
Reagents and conditions: (a) TsCl, Py, CH2Cl2, rt and (b) 1 equiv 2, 2.4 equiv 3, 4.4% Pd(OAc)2, 8.5% Xantphos, 1.4 equiv Cs2CO3, PhMe, H2O, 120 ꢀC,
47–72 h.
a
Isolated yields calculated on the basis of the percentage conversion (assumed to be 100% unless otherwise indicated in parentheses) of substrates 2.
[2b]:[3a]¼1:3.7.
b
c
[2c]:[3a]¼1:1.6.
d
[Pd]:[Xantphos]¼0.045:0.096.
e
K3PO4 (2.65 equiv) was used as base, 1,4-dioxane as solvent and the reaction was performed in a sealed tube for 4 days.
[2c]:[3d]:[Pd]:[Xantphos]¼1.5:1:0.04:0.083.
f
g
(i) 1.2 equiv 2, 1 equiv 3e, 4.3% Pd(OAc)2, 8% Xantphos, 2.3 equiv K3PO4, PhMe, 130 ꢀC, 24 h and (ii) H2SO4, 60 ꢀC, 25 min.
participated in the palladium-catalysed a-arylation reactions
of substrates 2a, 2b, although the purification of the so-
obtained diarylethanones 4m and ,4n was not easily ac-
complished. For this reason they were directly transformed
into the corresponding free amine derivatives 5m and 5n
in good overall yield (Table 1, entries 13 and 14). When ke-
tone 2c was employed instead, the interesting diheteroaryl
product 4o was obtained in 63% yield, together with a sub-
stantial amount of unreacted ketone 2c (Table 1, entry 15),
despite several unsuccessful attempts to increase the conver-
sion of the starting materials. Since such C-arylated product
4o could not be obtained in synthetically useful quantities it
was not considered for the subsequent steps in the scheduled
sequence.

M. Carril et al. / Tetrahedron 63 (2007) 690–702
693
However, when the original reaction conditions and modi-
fied ones were applied to the reactions in which ketone 2a
and the 1,2-dibromoheteroarenes 3f–i were involved, the re-
sults obtained were rather disappointing. For instance, the
furan derivative 3g systematically decomposed under every
set of reaction conditions tested, whereas the thiophene
derivative 3h remained largely unreacted,16 even though a
number of examples featuring palladium-catalysed arylation
reactions of 2-bromothiophene derivatives can be found in
the literature.17 However, when the benzothiophene 3f or
the 3,4-dibromothiophene 3i was used, the corresponding
diarylethanones bearing a second thiophene unit were
obtained in 25% yield or trace amounts, respectively.18
Unfortunately, all attempts to avoid these side-reactions
were unsuccessful.19
entries 13 and 14), although a range of different experimen-
tal conditions was tested on both substrates.21
By employing the methodology developed by our research
group for the synthesis of OXC, a range of 12 tricyclic com-
pounds was successfully prepared, each of which could, in
principle, be directly transformed into OXC analogues
through a simple carbamoylation reaction (Scheme 1). In-
deed, by applying the improved carbamoylation conditions
reported in the recently patented synthesis of OXC from aze-
pine 6a,22 it was possible to increase our previously reported
yield for this transformation up to 95%. Consequently, the
same carbamoylation procedure without further optimisa-
tion was applied to the selected substrates 6b, 6d and 6g–j
furnishing the corresponding OXC analogues 7b, 7d and
7g–j in modest to excellent yields. The pharmaceutical ac-
tivity of each of these analogues is currently being investi-
gated and will be reported elsewhere.
The protocol described thus far has proved to be a useful
tool, delivering a diverse array of up to 15 diarylethanones
4a–o, which may be regarded as potential precursors of
OXC analogues. In addition, this methodology, slightly
modified, has allowed us to perform several examples of
the palladium-catalysed a-arylation reaction employing
different heteroarene substrates, field much less explored
than other related palladium-catalysed arylation reac-
tions.20
3. Conclusion
In summary, we have shown that the methodology previ-
ously designed by our research group for the synthesis of
OXC may be conveniently applied (albeit with slight modi-
fications) to the synthesis of a number of azepinone deriva-
tives in good to excellent yields, several of which have been
subjected to simple carbamoylation to afford the first family
of analogues of this important pharmaceutical. The facile
and high-yielding procedures involving simple catalyst and
reagent systems, together with the readily-available starting
materials, not only lend this methodology to the synthesis of
a wide variety of OXC analogues, otherwise unattainable via
existing methodologies,23 but also presents a significant
contribution to the scope of palladium-catalysed C- and
N-arylation chemistry involving the more challenging hetero-
aromatic substrates, especially regarding the palladium-
catalysed a-arylation of ketone enolates.
2.2. Syntheses of dibenzoazepinones 6 and
OXC analogues 7
On the basis of our previous work depicted in Scheme 1,11
we first carried out the deprotection of the amine moiety in
substrates 4 in order to accomplish the second and final
key step of the sequence, i.e. the intramolecular palla-
dium-catalysed N-arylation reaction to render the target tri-
cyclic framework. The removal of the protective tosyl group
was performed by stirring intermediates 4 in concentrated
sulfuric acid for several minutes to afford, in almost quanti-
tative yield, the corresponding free amine derivatives 5a–n
(Table 2). Then, the reaction conditions previously em-
ployed for the palladium-catalysed cyclisation step in the
synthesis of azepinone 6a from amine 5a,11 were subse-
quently tested for the rest of primary amines 5b–n, as shown
in Table 2.
4. Experimental section
4.1. General remarks
In general, the non-heteroaromatic substrates 5a–h smoothly
underwent cyclisation to deliver the corresponding azepi-
none derivatives 6a–h in good to excellent yields (Table 2,
entries 1–8), although it was sometimes necessary to slightly
modify the original protocol to allow certain substrates to re-
act until complete conversion. Once again, the presence of
water played an important role, as for the synthesis of the
corresponding diarylethanones.12 Surprisingly, the elec-
tron-rich aryl bromide moiety of substrates 5c and 5g fav-
oured nucleophilic attack of the amine moiety (in contrast
to previously observed difficulties in the formation of the
corresponding deoxybenzoins 4c and 4g).
All reagents and solvents were purchased and used without
further purification. Redistilled water was employed for the
1
palladium-catalysed reactions when indicated. H and 13C
spectra were recorded in CDCl3 solution in a Bruker AC-
250, AC-300 and AC-500. Chemical shifts are reported in
parts per million downfield (d) from Me4Si. Coupling con-
stants(J)areexpressedinhertz(Hz). IRspectrawererecorded
on a Perkin–Elmer 1600 FT infrared spectrophotometer and
only noteworthy absorptions are listed. Melting points were
determined in a capillary tube and are uncorrected. TLC
was carried out on SiO2 (silica gel 60 F254, Merck), and the
spots were located with UV light. Flash chromatography
was carried out on SiO2 (silica gel 60, Merck, 230–400
mesh ASTM). Drying of organic extracts after work-up of
reactions was performed over anhydrous Na2SO4. Evapora-
In the case of the heteroaromatic substrates, the aforemen-
tioned procedure worked extremely well for the thiophene
substrates 5i–l (Table 2, entries 9–12), with the exception
of 5k (Table 2, entry 11), which cyclised to form target 6k
in a modest yield. In contrast, the pyridine derivatives 5m
and 5n, did not render the desired azepinones (Table 2,
€
tionof solvents was accomplished with a Buchi rotatory evap-
orator. HRMS were measured using a Waters GCT Mass
Spectrometer. Except for the protection and deprotection
steps, the rest of reactions were carried out under argon.

694
M. Carril et al. / Tetrahedron 63 (2007) 690–702
Table 2. Syntheses of azepinones 6 and OXC analogues 7
O
Ar
HetAr
O
b
Ar
HetAr
Ar
Ar
HetAr
N
R'
HetAr
NH
Br
R
4 R = Ts
5 R = H
6 R' = H
7 R' = CONH2
a
c
Entry
5
6/7a
Entry
5
6/7a
O
O
F
O
F
MeO
MeO
O
MeO
MeO
1
8
N
R
N
R
F
Br
NH2
Br
F
NH2
6h R = H
87
6a R = H
91
5a 95
5h 98
7h R = CONH2 50
OXC R = CONH2 95
O
O
Me
O
S
Me
S
Me
O
2
9e
10e
11e
12c
N
N
R
R
Me
81
Br
NH2
Br
NH2
6i R = H
85
5i 96
6b R = H
5b 97
7i R = CONH2 80 (80)
7b R = CONH2 80 (95)
O
OMe
O
Me
OMe
Me
S
O
Me
O
OMe
3b
4c,d
5
N
S
N
R
Me
71
H
OMe
Br
Br
NH2
O
NH2
6j R = H
6c 80
5j 97
7j R = CONH2 89 (94)
5c 93
O
F
OMe
O
OMe
F
O
S
OMe
OMe
S
N
R
F
N
H
Br
Br
F
NH2
6d R = H
77
NH2
O
6k 47
5k 97
5d 98
7d R = CONH2 65
F
O
O
O
S
MeO
MeO
MeO
MeO
F
S
F
N
H
N
H
Br
NH2
Br
5l 98
NH2
F
5e 98
6l 91
6e 84
Me
O
O
N
Me
O
MeO
MeO
Me
Me
MeO
6
7
13f
NR
NR
N
Br
NH2
H
Br
NH2
MeO
5m 78
6f 89
5f 95
O
OMe
O
N
OMe
O
MeO
MeO
OMe
MeO
MeO
14f
MeO
MeO
N
R
Br
5n 71
OMe
80
7g R = CONH2 83 (93)
NH2
Br
6g R = H
NH2
5g 99
Reagents and conditions: (a) H2SO4, rt; (b) 4.9% Pd(OAc)2, 7.9% BINAP, 2 equiv K3PO4, PhMe, H2O, 130 ꢀC, 4.5–6 h and (c) (i) ClSO2NCO, CH2Cl2, 0 ꢀC and
(ii) AcOH, H2O, 0 ꢀC/rt.
Isolated yields calculated on the basis of the percentage conversion (assumed to be 100% unless otherwise indicated in brackets).
a
b
Cyclisation performed over 24 h.
Cyclisation performed in a sealed tube, using 1,4-dioxane as solvent.
Cyclisation performed over 21 h.
H2O was not added as a co-solvent.
c
d
e
f
NR¼no reaction.

M. Carril et al. / Tetrahedron 63 (2007) 690–702
695
4.2. Typical procedure for the synthesis of substrates
2a–c
1H NMR (CDCl3) d 2.22 (3H, s), 2.25 (3H, s), 2.36 (3H,
s), 4.34 (2H, s), 6.94 (1H, s), 7.10 (1H, t, J¼7.53), 7.21
(2H, d, J¼8.33), 7.38 (1H, s), 7.48 (1H, t, J¼7.53), 7.74
(1H, d, J¼8.32), 7.98 (1H, d, J¼7.93, Harom), 11.36 (1H,
s); 13C NMR (CDCl3) d 19.1, 19.2, 21.5 (CH3), 46.1
(CH2), 118.9 (CH), 121.5, 121.6 (C), 122.6, 127.2, 129.6,
131.0, 132.7, 133.4, 135.0 (CH), 136.2, 136.5, 137.9,
140.3, 143.7, 200.8 (C); IR (film, cmꢁ1) 3119.9, 2920.1,
1655.0; EIMS (m/z, %) 274 (13), 111 (18), 97 (31), 85
(39), 83 (32), 57 (100); HRMS calcd for C23H22BrNO3S,
471.0504; found, 471.0507.
4.2.1. 1-[2-N-(4-Methylbenzenesulfonamido)phenyl]-
ethanone (2a).11 Typical procedure: A solution of 20-amino-
acetophenone 1a (3 g, 21.75 mmol), p-toluenesulfonyl
chloride (12 g, 61.77 mmol) and pyridine (8 ml,
98.12 mmol) in CH2Cl2 (200 ml) was stirred overnight.
The reaction mixture was washed twice with a saturated
aqueous solution of CuSO4 and once with water. The organic
layer was dried and concentrated in vacuo and the resulting
residue was purified by crystallisation from ethyl acetate to
yield sulfonamide 2a (6.03 g, 96%).
4.3.3. 2-(2-Bromo-4,5-dimethoxyphenyl)-1-[2-N-(4-
methylbenzenesulfonamido)phenyl]ethanone (4c). The
typical procedure was followed employing 2a (401 mg,
1.39 mmol) and 3c (1005 mg, 3.33 mmol) to afford com-
pound 4c (301.9 mg, 43%) as a brown solid, mp 165–
166 ꢀC (Et2O). 1H NMR (CDCl3) d 2.34 (3H, s), 3.84 (3H,
s), 3.87 (3H, s), 4.33 (2H, s), 6.69 (1H, s), 7.05 (1H, s),
7.09 (1H, dd, J¼1.18, 7.93), 7.19 (2H, d, J¼7.92), 7.46
(1H, dt, J¼1.19, 7.14), 7.72 (2H, d, J¼8.33), 7.97 (1H, dd,
J¼1.19, 7.92), 11.35 (1H, s); 13C NMR (CDCl3) d 21.4
(CH3), 46.2 (CH2), 56.0, 56.1 (CH3), 114.0 (CH), 114.9
(C), 115.4, 118.8 (CH), 121.4 (C), 122.5 (CH), 125.9 (C),
127.2, 129.6, 131.1, 135.0 (CH), 136.5, 140.3, 143.8,
148.4, 148.9, 200.7 (C); IR (film, cmꢁ1) 3123.5, 2943.6,
2850.5, 1655.0; EIMS (m/z, %) 505 (M+2, 3), 503 (M, 4),
319 (18), 317 (19), 274 (100), 209 (23), 119 (24), 91 (43);
HRMS calcd for C23H22BrNO5S, 503.0402; found,
503.0407.
4.2.2. 1-[4,5-Dimethoxy-2-N-(4-methylbenzenesulfon-
amido)phenyl]ethanone (2b). The typical procedure was
followed employing 1b (500 mg, 2.51 mmol) to afford com-
pound 2b (804.7 mg, 92%) as a yellow solid, mp 158–
1
159 ꢀC (ethyl acetate). H NMR (CDCl3) d 2.33 (3H, s),
2.46 (3H, s), 3.82 (3H, s), 3.89 (3H, s), 7.10 (1H, s), 7.17
(2H, d, J¼7.92), 7.25 (1H, s), 7.64 (2H, d, J¼8.32), 11.53
(1H, s); 13C NMR (CDCl3) d 21.4, 27.9, 56.1 (CH3),
102.5, 113.2, 115.1, 127.1, 129.5 (CH), 136.0, 136.2,
143.8, 144.1, 154.2, 200.4 (C); IR (film, cmꢁ1) 2955.3,
2850.5, 1637.4; EIMS (m/z, %) 349 (M, 5), 194 (22), 166
(100); HRMS calcd for C17H19NO5S, 349.0984; found,
349.0988.
4.2.3. 1-[3-N-(4-Methylbenzenesulfonamido)-2-thienyl]-
ethanone (2c). The typical procedure was followed employ-
ing 1c (402.4 mg, 2.76 mmol) to afford compound 2c
(812.3 mg, 99%) as a white solid, mp 144–146 ꢀC (ethyl
4.3.4. 2-(2-Bromo-4,6-difluorophenyl)-1-[2-N-(4-methyl-
benzenesulfonamido)phenyl]ethanone (4d). The typical
procedure was followed employing 2a (152 mg, 0.53 mmol)
and 3d (359.3 mg, 1.33 mmol) to afford compound 4d
(238.2 mg, 94%) as a white solid, mp 147–149 ꢀC (Et2O).
1H NMR (CDCl3) d 2.37 (3H, s), 4.41 (2H, s), 6.72–6.77
(1H, m), 6.89 (1H, td, J¼2.77, 8.32), 7.12 (1H, t, J¼7.53),
7.22 (2H, d, J¼7.93), 7.51 (1H, td, J¼1.58, 7.13), 7.69–
7.78 (3H, m), 7.92 (1H, dd, J¼1.19, 8.32), 11.14 (1H, s);
13C NMR (CDCl3) d 21.5 (CH3), 46.3 (CH2), 104.1 (t,
J¼25.47, CH), 106.9 (d, J¼16.15, C), 114.3 (dd, J¼3.59,
23.3), 119.5 (CH), 121.4 (C), 122.8, 127.3, 129.7, 130.9,
135.5 (CH), 136.5, 137.7 (d, J¼8.97), 140.5, 143.9, 159.4
(dd, J¼12.56, 247.73), 161.6 (dd, J¼10.77, 249.52), 199.0
(C); IR (film, cmꢁ1) 3083.8, 1654.6; EIMS (m/z, %) 481
(M+2, 4), 479 (M, 3), 274 (100), 210 (88), 182 (12);
HRMS calcd for C21H16BrF2NO3S, 479.0002; found,
479.0006.
1
acetate). H NMR (CDCl3) d 2.34 (3H, s), 2.37 (3H, s),
7.22 (2H, d, J¼7.93), 7.37 (1H, d, J¼5.55), 7.40 (1H, d,
J¼5.55), 7.72 (2H, d, J¼8.32), 10.68 (1H, s); 13C NMR
(CDCl3) d 21.4, 28.5 (CH3), 119.2 (C), 120.4, 126.8,
129.7, 132.2 (CH), 136.3, 143.3, 144.1, 192.8 (C); IR
(film, cmꢁ1) 3108.1, 2920.1, 1625.8; EIMS (m/z, %) 295
(M, 63), 155 (60), 140 (82), 126 (92), 112 (92), 98 (53),
91 (100), 83 (32); HRMS calcd for C13H13NO3S2,
295.0337; found, 295.0337.
4.3. Typical procedure for the synthesis of 1,2-diaryl-
ethanones 4a–h
4.3.1. 2-(2-Bromophenyl)-1-[2-N-(4-methylbenzenesulfon-
amido)phenyl]ethanone (4a).11 A solution of sulfonamide
2a (150 mg, 0.52 mmol), 1,2-dibromobenzene 3a (0.15 ml,
1.25 mmol), Pd(OAc)2 (5.3 mg, 0.023 mmol), Xantphos
(26.5 mg, 0.044 mmol), Cs2CO3 (243.6 mg, 0.74 mmol),
toluene (2.6 ml) and water (0.5 ml) was heated at 120 ꢀC.
After 48 h the reaction mixture was partitioned between wa-
ter and dichloromethane. The organic layer was dried and
concentrated in vacuo. The crude product was then purified
by flash chromatography (CH2Cl2) to give starting material
2a (22.1 mg) and deoxybenzoin 4a (167.8 mg, 86%) as
translucent prisms.
4.3.5. 2-(2-Bromophenyl)-1-[4,5-dimethoxy-2-N-(4-
methylbenzenesulfonamido)phenyl]ethanone (4e). The
typical procedure was followed employing 2b (249.8 mg,
0.72 mmol) and 3a (0.33 ml, 2.65 mmol) to afford com-
pound 4e (314.8 mg, 87%) as a pale yellow solid, mp 147–
149 ꢀC (Et2O). 1H NMR (CDCl3) d 2.34 (3H, s), 3.81 (3H,
s), 3.89 (3H, s), 4.28 (2H, s), 7.05 (1H, d, J¼7.14), 7.09–
7.25 (5H, m), 7.30 (1H, s), 7.55 (1H, d, J¼7.53), 7.63 (1H,
d, J¼7.93), 11.43 (1H, s); 13C NMR (CDCl3) d 21.4
(CH3), 46.6 (CH2), 56.0, 56.1 (CH3), 102.7, 112.4 (CH),
114.3, 124.6 (C), 124.6, 127.0, 127.5, 128.8, 129.5, 131.2,
132.6 (CH), 134.5, 136.2, 136.4, 143.7, 144.1, 154.3,
198.7 (C); IR (film, cmꢁ1) 3085.3, 2943.6, 2850.5, 1637.5;
4.3.2. 2-(2-Bromo-4,5-dimethylphenyl)-1-[2-N-(4-methyl-
benzenesulfonamido)phenyl]ethanone (4b). The typical
procedure was followed employing 2a (310 mg, 1.08 mmol)
and 3b (702 mg, 2.58 mmol) to afford compound 4b
(346.6 mg, 68%) as a white solid, mp 182–184 ꢀC (Et2O).

696
M. Carril et al. / Tetrahedron 63 (2007) 690–702
EIMS (m/z, %) 505 (M+2, 3), 503 (M, 4), 334 (100), 269
(12); HRMS calcd for C23H22BrNO5S, 503.0402; found,
503.0387.
(0.1 ml, 0.8 mmol), Pd(OAc)2 (5.3 mg, 0.023 mmol), Xant-
phos (29.5 mg, 0.049 mmol), K3PO4 (298 mg, 1.36 mmol)
and 1,4-dioxane (2.5 ml) was heated at 130 ꢀC in a sealed
tube. After 4 days the reaction mixture was partitioned be-
tween water and dichloromethane. The organic layer was
dried and concentrated in vacuo. The crude product was
then purified by flash chromatography (CH2Cl2) to give
starting material 2c (26.5 mg) and compound 4i (156.3 mg,
4.3.6. 2-(2-Bromo-4,5-dimethylphenyl)-1-[4,5-dimeth-
oxy-2-N-(4-methylbenzenesulfonamido)phenyl]ethanone
(4f). The typical procedure was followed employing 2b
(149.5 mg, 0.43 mmol) and 3b (285 mg, 1.03 mmol) to af-
ford compound 4f (191.1 mg, 84%) as a pale yellow solid,
1
82%) as a yellow solid, mp 124–126 ꢀC (Et2O). H NMR
1
mp 144–146 ꢀC (Et2O). H NMR (CDCl3) d 2.16 (3H, s),
(CDCl3) d 2.38 (3H, s), 4.18 (2H, s), 7.15–7.33 (5H, m),
7.46 (2H, s), 7.58 (1H, d, J¼8.32), 7.73 (1H, d, J¼7.93),
10.62 (1H, s); 13C NMR (CDCl3) d 21.5 (CH3), 47.8
(CH2), 118.6 (C), 120.7 (CH), 125.1 (C), 127.0, 127.6,
129.2, 129.8, 131.8, 132.5, 132.8 (CH), 133.9, 136.5,
144.1, 144.4, 191.6 (C); IR (film, cmꢁ1) 3108.1, 2920.1,
1631.5; EIMS (m/z, %) 451 (M+2, 82), 449 (M, 81), 370
(33), 280 (99), 215 (100), 186 (94), 171 (60), 169 (65),
125 (94), 97 (50); HRMS calcd for C19H16BrNO3S2,
448.9755; found, 448.9756.
2.21 (3H, s), 2.35 (3H, s), 3.82 (3H, s), 3.91 (3H, s), 4.22
(3H, s), 6.89 (1H, s), 7.18 (2H, d, J¼8.32), 7.23 (1H, s),
7.32 (1H, s), 7.34 (1H, s), 7.66 (2H, d, J¼8.32), 11.51
(1H, s); 13C NMR (CDCl3) d 19.1, 19.2, 21.5 (CH3), 46.1
(CH2), 56.1, 56.2 (CH3), 102.5, 112.6 (CH), 114.3, 121.2
(C), 127.1, 129.5 (CH), 131.4 (C), 132.2, 133.3 (CH),
136.3, 136.3, 136.6, 137.9, 143.7, 144.1, 154.3, 199.1 (C);
IR (film, cmꢁ1) 3010.1, 2931.0, 2850.5, 1637.0; EIMS
(m/z, %) 533 (M+2, 1), 531 (M, 1), 334 (100); HRMS
calcd for C25H26BrNO5S, 531.0715; found, 531.0719.
4.4.2. 2-(2-Bromo-4,5-dimethylphenyl)-1-[3-N-(4-
methylbenzenesulfonamido)-2-thienyl]ethanone (4j).
The typical procedure was followed employing 2c (175.2 mg,
0.59 mmol) and 3b (388 mg, 1.43 mmol) to afford com-
pound 4j (184.5 mg, 65%) as a white solid, mp 191–
192 ꢀC (Et2O). 1H NMR (CDCl3) d 2.19 (3H, s), 2.22 (3H,
s), 2.38 (3H, s), 4.10 (2H, s), 6.98 (1H, s), 7.23 (2H, d,
J¼8.32), 7.34 (1H, s), 7.44 (2H, s), 7.73 (2H, d, J¼8.32),
10.67 (1H, s); 13C NMR (CDCl3) d 19.1, 19.2, 21.5 (CH3),
47.3 (CH2), 118.6 (C), 120.6 (CH), 121.5 (C), 126.9, 129.7
(CH), 130.7 (C), 132.5, 132.7, 133.3 (CH), 136.1, 136.4,
138.0, 144.1, 144.2, 192.0 (C); IR (film, cmꢁ1) 3108.1,
2908.3, 1625.6; EIMS (m/z, %) 479 (M+2, 6), 477 (M, 5),
398 (88), 280 (100), 215 (98), 199 (28), 125 (58), 91 (93);
HRMS calcd for C21H20BrNO3S2, 477.0068; found,
477.0070.
4.3.7. 2-(2-Bromo-4,5-dimethoxyphenyl)-1-[4,5-dimeth-
oxy-2-N-(4-methylbenzenesulfonamido)phenyl]ethanone
(4g). The typical procedure was followed employing 2b
(249.4 mg, 0.72 mmol) and 3c (518 mg, 1.72 mmol) to af-
ford compound 4g (270 mg, 67%) as a pale yellow solid,
1
mp 180–181 ꢀC (Et2O). H NMR (CDCl3) d 2.35 (3H, s),
3.81 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.91 (3H, s), 4.23
(2H, s), 6.69 (1H, s), 7.03 (1H, s), 7.18 (2H, d, J¼7.93),
7.25 (1H, s), 7.31 (1H, s), 7.67 (2H, d, J¼8.33), 11.52
(1H, s); 13C NMR (CDCl3) d 21.5 (CH3), 46.2 (CH2),
56.0, 56.1, 56.2, 56.3 (CH3), 102.3, 112.6, 113.4, 114.1
(CH), 114.6 (C), 115.3 (CH), 126.2 (C), 127.2, 129.6
(CH), 136.5, 136.8, 143.8, 144.1, 148.5, 148.8, 154.5,
199.0 (C); IR (film, cmꢁ1) 3010.1, 2931.0, 2850.5, 1637.0;
EIMS (m/z, %) 334 (100); HRMS calcd for C25H26BrNO7S,
563.0613; found, 563.0614.
4.4.3. 2-(2-Bromo-4,5-dimethoxyphenyl)-1-[3-N-(4-
methylbenzenesulfonamido)-2-thienyl]ethanone (4k).
The typical procedure was followed employing 2c
(269.7 mg, 0.91 mmol) and 3c (666.5 mg, 2.19 mmol) to af-
ford starting material 2c (129 mg) and compound 4k (75 mg,
4.3.8. 2-(2-Bromo-4,6-difluorophenyl)-1-[4,5-dimethoxy-
2-N-(4-methylbenzenesulfonamido)phenyl]ethanone
(4h). The typical procedure was followed employing 2b
(252.6 mg, 0.72 mmol) and 3d (462 mg, 1.72 mmol) to af-
ford compound 4h (388.7 mg, 99%) as a yellow solid, mp
1
31%) as a pale yellow solid, mp 154–155 ꢀC (Et2O). H
1
163–164 ꢀC (Et2O). H NMR (CDCl3) d 2.35 (3H, s), 3.84
NMR (CDCl3) d 2.38 (3H, s), 3.84 (3H, s), 3.87 (3H, s),
4.11 (2H, s), 6.74 (1H, s), 7.04 (1H, s), 7.24 (2H, d,
J¼8.71), 7.45 (1H, s), 7.74 (2H, d, J¼7.93), 10.67 (1H, s);
13C NMR (CDCl3) d 21.5 (CH3), 47.5 (CH2), 56.0, 56.1
(CH3), 114.1, 115.4 (CH), 118.4 (C), 120.6 (CH), 125.6
(C), 127.0, 127.3, 129.8 (CH), 132.6, 136.5, 144.1, 144.5,
148.4, 148.9, 191.9 (C); IR (film, cmꢁ1) 3302.5, 2920.1,
2850.5, 1625.6; EIMS (m/z, %) 511 (M+2, 4), 509 (M, 4),
430 (57), 280 (100), 275 (96), 231 (21), 215 (80), 91 (77);
HRMS calcd for C21H20BrNO5S2, 508.9966; found,
508.9963.
(3H, s), 3.91 (3H, s), 4.31 (2H, s), 6.67–6.71 (1H, m), 6.84
(1H, dt, J¼2.77, 8.33), 7.17–7.19 (3H, m), 7.32 (1H, s),
7.62 (2H, d, J¼7.93), 11.28 (1H, s); 13C NMR (CDCl3)
d 21.4 (CH3), 46.1 (CH2), 56.2, 56.3 (CH3), 102.8, 103.9
(t, J¼26.03, CH), 106.7 (dd, J¼3.59, 21.54, C), 112.2,
113.9 (dd, J¼3.59, 23.34, CH), 114.1 (C), 127.1, 129.6
(CH), 136.2, 136.7, 138.0 (d, J¼10.77), 143.9, 144.4,
154.8, 159.3 (dd, J¼12.57, 247.73), 161.5 (dd, J¼12.57,
249.37), 197.3 (C); IR (film, cmꢁ1) 3084.6, 2955.3,
2850.5, 1608.0; EIMS (m/z, %) 541 (M+2, 17), 539 (M,
19), 334 (100), 269 (15); HRMS calcd for C23H20BrF2NO5S,
539.0214; found, 539.0216.
4.4.4. 2-(2-Bromo-4,6-difluorophenyl)-1-[3-N-(4-methyl-
benzenesulfonamido)-2-thienyl]ethanone (4l). The typical
procedure was followed employing 2c (150.5 mg,
0.51 mmol) and 3d (95 mg, 0.35 mmol) to afford compound
4l (102.6 mg, 61%) as a yellow solid, mp 144–146 ꢀC
4.4. Typical procedure for the synthesis of 1-thiophene-
2-arylethanones 4i–l,o
1
4.4.1. 2-(2-Bromophenyl)-1-[3-N-(4-methylbenzenesulfon-
amido)-2-thienyl]ethanone (4i). A solution of sulfon-
amide 2c (151.3 mg, 0.51 mmol), 1,2-dibromobenzene 3a
(Et2O). H NMR (CDCl3) d 2.38 (3H, s), 4.19 (2H, s),
6.79–6.91 (2H, m), 7.25 (2H, d, J¼8.33), 7.46 (1H, d,
J¼5.55), 7.49 (1H, d, J¼5.55), 7.73 (2H, d, J¼8.32),

M. Carril et al. / Tetrahedron 63 (2007) 690–702
697
10.51 (1H, s); 13C NMR (CDCl3) d 21.5 (CH3), 47.2 (CH2),
104.1 (t, J¼26.92, CH), 106.9 (dd, J¼3.59, 21.54, C), 114.4
(dd, J¼3.59, 23.33, CH), 118.3 (C), 120.9, 126.9, 129.8,
132.9 (CH), 136.4, 137.2 (d, J¼8.98), 144.3, 144.7, 159.3
(dd, J¼12.56, 249.52), 161.5 (dd, J¼12.56, 249.52), 190.2
(C); IR (film, cmꢁ1) 3302.5, 2920.1, 1625.6; EIMS (m/z,
%) 487 (M+2, 33), 485 (M, 33), 280 (100), 251 (27), 222
(33), 215 (92), 125 (71), 91 (90); HRMS calcd for
C19H14BrF2NO3S2, 484.9567; found, 484.9552.
56.4 (CH3), 98.9 (CH), 109.1 (C), 112.5 (CH), 122.1 (C),
123.0 (CH), 139.7 (C), 139.9, 147.6 (CH), 148.1, 155.2,
155.4, 194.8 (C); IR (film, cmꢁ1) 3448.9, 3331.4, 2931.8,
2850.5, 1631.5; EIMS (m/z, %) 352 (M+2, 87), 350 (M,
91), 336 (21), 334 (21), 271 (90), 180 (100), 152 (90), 94
(57); HRMS calcd for C15H15BrN2O3, 350.0266; found,
350.0276.
4.6. Typical procedure for the synthesis of substrates
5a–l
4.4.5. 2-(3-Bromo-2-pyridinyl)-1-[3-N-(4-methylbenz-
enesulfonamido)-2-thienyl]ethanone (4o). The typical pro-
cedure was followed employing 2c (52.9 mg, 0.18 mmol)
and 3e (67.7 mg, 0.43 mmol) to afford starting material 2c
(76.7 mg) and compound 4o (14 mg, 63%) as a yellow solid,
mp 68–70 ꢀC (Et2O). 1H NMR (CDCl3) d 2.39 (3H, s), 4.45
(2H, s), 7.13 (1H, dd, J¼4.77, 7.95), 7.24 (2H, d, J¼8.35),
7.45 (1H, d, J¼5.56), 7.46 (1H, d, J¼5.55), 7.73 (2H, d,
J¼8.35), 7.89 (1H, dd, J¼1.19, 8.15), 8.50 (1H, dd,
J¼1.19, 4.57), 10.60 (1H, s); 13C NMR (CDCl3) d 21.6
(CH3), 49.6 (CH2), 119.9 (C), 120.7, 123.8 (CH), 124.9 (C),
127.0, 129.8, 132.7 (CH), 136.5 (C), 140.4 (CH), 144.2,
4.6.1. 1-(2-Aminophenyl)-2-(2-bromophenyl)ethanone
(5a).11 A solution of deoxybenzoin 4a (1.19 g, 2.68 mmol)
in 20 ml of concentrated sulfuric acid was stirred at room
temperature in an open vessel for 10 min (until complete so-
lution of the substrate is visually observed). The reaction
mixture was then poured onto an ice-water mixture. The re-
sulting solution was allowed to reach room temperature and
then was extracted with dichloromethane. The organic layer
was dried and the solvent was removed in vacuo to give
amine 5a (736 mg, 95%).
144.4 (C), 147.9 (CH), 153.6, 190.6 (C); IR (film, cmꢁ1
)
4.6.2. 1-(2-Aminophenyl)-2-(2-bromo-4,5-dimethylphe-
nyl)ethanone (5b). The typical procedure was followed em-
ploying 4b (178.9 mg, 0.38 mmol) to afford compound 5b
(116.8 mg, 97%) as a yellow solid, mp 100–101 ꢀC
3300.5, 2920.1, 1625.6; EIMS (m/z, %) 452 (M+2, 3), 450
(M, 3), 297 (56), 295 (56), 269 (45), 267 (46), 216 (100),
187 (84), 91 (66); HRMS calcd for C18H15N2O3S2Br,
449.9712; found, 449.9707.
1
(Et2O). H NMR (CDCl3) d 2.21 (3H, s), 2.24 (3H, s),
4.38 (2H, s), 6.11 (2H, br s), 6.65–6.73 (2H, m), 7.01 (1H,
s), 7.29 (1H, t, J¼7.14), 7.39 (1H, s), 7.89 (1H, d,
J¼7.93); 13C NMR (CDCl3) d 19.0, 19.2 (CH3), 45.6
(CH2), 115.7, 117.3 (CH), 121.7 (C), 131.0, 132.4, 132.6
(CH), 133.2 (C), 134.4 (CH), 135.9, 137.3, 150.5, 198.7
(C); IR (film, cmꢁ1) 3460.7, 3343.2, 2920.0, 1649.1;
EIMS (m/z, %) 319 (M+2, 44), 317 (M, 49), 238 (98), 121
(100), 92 (99); HRMS calcd for C16H16BrNO, 317.0415;
found, 317.0412.
4.5. Typical procedure for the synthesis of 1,2-diaryl-
ethanones 5m and 5n
4.5.1. 1-(2-Aminophenyl)-2-(3-bromo-2-pyridinyl)etha-
none (5m). A solution of sulfonamide 2a (251 mg,
0.87 mmol), 2,3-dibromopyridine 3e (166 mg, 0.7 mmol),
Pd(OAc)2 (7 mg, 0.03 mmol), Xantphos (33.4 mg,
0.056 mmol), K3PO4 (350 mg, 1.61 mmol) and toluene
(3.8 ml) was heated at 130 ꢀC. After 24 h the reaction mix-
ture was partitioned between water and dichloromethane.
The organic layer was dried and concentrated in vacuo.
The crude product was partially purified by flash chroma-
tography (4% Et2O/CH2Cl2) and then treated with concen-
trated sulfuric acid (5 ml) at 60 ꢀC for 25 min to afford
compound 5m (159 mg, 78% over two steps) as a yellow
4.6.3. 1-(2-Aminophenyl)-2-(2-bromo-4,5-dimethoxy-
phenyl)ethanone (5c). The typical procedure was followed
employing 4c (301.9 mg, 0.59 mmol) to afford compound 5c
(194.2 mg, 93%) as a yellow solid, mp 120–122 ꢀC (Et2O).
1H NMR (CDCl3) d 3.82 (3H, s), 3.86 (3H, s), 4.36 (2H, s),
6.28 (2H, br s), 6.64–6.70 (2H, m), 6.73 (1H, s), 7.06 (1H, s),
7.28 (1H, dt, J¼1.19, 7.53), 7.86 (1H, d, J¼7.93); 13C NMR
(CDCl3) d 5.8 (CH2), 55.9, 56.0 (CH3), 113.9 (CH), 115.0
(C), 115.3, 115.7, 117.3 (CH), 127.3 (C), 130.9, 134.5
1
solid, mp 124–126 ꢀC (Et2O). H NMR (CDCl3) d 4.71
(2H, s), 6.26 (2H, br s), 6.64–6.70 (2H, m), 7.07–7.12
(1H, m), 7.25–7.31 (1H, m), 7.80–7.90 (2H, m), 8.52
(1H, d, J¼4.76); 13C NMR (CDCl3) d 48.4 (CH2), 115.8,
117.3 (CH), 122.5 (C), 123.2, 131.1, 134.5, 140.1, 147.9
(CH), 148.2, 148.4, 150.5, 198.6 (C); IR (film, cmꢁ1
)
3460.7, 3343.2, 2931.8, 2850.5, 1608.0; EIMS (m/z, %)
351 (M+2, 23), 349 (M, 26), 270 (99), 229 (21), 121
(100), 92 (97); HRMS calcd for C16H16BrNO3, 349.0314;
found, 349.0324.
(CH), 150.6 (C), 155.5, 197.6 (C); IR (film, cmꢁ1
)
3459.8, 3342.3, 3048.5, 1642.8; EIMS (m/z, %) 292
(M+2, 20), 290 (M, 22), 211 (72), 120 (100), 92 (77);
HRMS calcd for C13H11BrN2O, 290.0055; found,
290.0065.
4.6.4. 1-(2-Aminophenyl)-2-(2-bromo-4,6-difluorophenyl)-
ethanone (5d). The typical procedure was followed employ-
ing 4d (360.3 mg, 0.75 mmol) to afford compound 5d
(240.2 mg, 98%) as an orange solid, mp 130–132 ꢀC
4.5.2. 1-(2-Amino-4,5-dimethoxyphenyl)-2-(3-bromo-
2-pyridinyl)ethanone (5n). The typical procedure was
followed employing 2b (304 mg, 0.86 mmol) and 3e
(168.8 mg, 0.71 mmol) to afford compound 5n (176.9 mg,
71% over two steps) as a brown solid, mp 111–112 ꢀC
1
(Et2O). H NMR (CDCl3) d 4.46 (2H, s), 6.17 (2H, br s),
6.65–6.73 (2H, m), 6.82–6.89 (2H, m), 7.31 (1H, dt,
J¼1.19, 8.32), 7.81 (1H, d, J¼7.53); 13C NMR (CDCl3)
d 45.7 (CH2), 55.8, 56.7 (CH3), 99.2, 103.5 (t, J¼25.13,
CH), 106.8 (dd, J¼3.59, 21.54), 109.1 (C), 112.4, 114.0
(dd, J¼3.59, 23.34, CH), 139.4 (d, J¼8.98), 140.3, 148.4,
155.8, 159.2 (dd, J¼12.57, 247.73), 161.5 (dd, J¼12.57,
1
(Et2O). H NMR (CDCl3) d 3.74 (3H, s), 3.75 (3H, s),
4.54 (2H, s), 6.04 (1H, s), 6.30 (1H, br s), 7.00 (1H, dd,
J¼4.76, 7.92), 7.10 (1H, s), 7.79 (1H, d, J¼7.92), 8.42
(1H, d, J¼3.56); 13C NMR (CDCl3) d 48.2 (CH2), 55.5,

698
M. Carril et al. / Tetrahedron 63 (2007) 690–702
247.73), 194.7 (C); IR (film, cmꢁ1) 3472.4, 3343.2, 3084.0,
1649.1; EIMS (m/z, %) 327 (M+2, 6), 325 (M, 6), 214 (12),
120 (100), 92 (27); HRMS calcd for C16H14BrF2NO3,
324.9914; found, 324.9923.
(100), 152 (80), 125 (38), 94 (45); HRMS calcd for
C16H14BrF2NO3, 385.0125; found, 385.0118.
4.6.9. 1-(3-Amino-2-thienyl)-2-(2-bromophenyl)etha-
none (5i). The typical procedure was followed employing
4i (259.3 mg, 0.58 mmol) to afford compound 5i
(162.9 mg, 96%) as an orange solid, mp 146–148 ꢀC
4.6.5. 1-(2-Amino-4,5-dimethoxyphenyl)-2-(2-bromo-
phenyl)ethanone (5e). The typical procedure was followed
employing 4e (208.8 mg, 0.41 mmol) to afford compound 5e
(141.8 mg, 98%) as a brown solid, mp 109–110 ꢀC (Et2O).
1H NMR (CDCl3) d 3.81 (3H, s), 3.82 (3H, s), 4.33 (2H,
s), 7.07–7.13 (1H, m), 7.16 (1H, s), 7.23 (1H, s), 7.24 (1H,
d, J¼7.53), 7.57 (1H, d, J¼7.53); 13C NMR (CDCl3)
d 46.2 (CH2), 55.6, 56.5 (CH3), 99.1 (CH), 109.3 (C),
112.6 (CH), 124.8 (C), 127.4, 128.4, 131.3, 132.5 (CH),
1
(Et2O). H NMR (CDCl3) d 4.18 (2H, s), 5.82 (2H, br s),
6.54 (1H, d, J¼5.15), 7.11–7.17 (1H, m), 7.28–7.32 (3H,
m), 7.58 (1H, d, J¼7.93); 13C NMR (CDCl3) d 47.4 (CH2),
110.7 (C), 119.9 (CH), 125.2 (C), 127.4, 128.6, 131.8,
132.2, 132.6 (CH), 135.2, 154.9, 189.7 (C); IR (film, cmꢁ1
)
3425.4, 3307.9, 3096.4, 1602.1; EIMS (m/z, %) 297 (M+2,
24), 295 (M, 25), 216 (79), 126 (100), 89 (22); HRMS calcd
for C12H10BrNOS, 294.9666; found, 294.9682.
135.8, 139.9, 148.1, 155.3, 196.1 (C); IR (film, cmꢁ1
)
3448.9, 3331.4, 2931.8, 2850.0, 1631.5; EIMS (m/z, %)
351 (M+2, 96), 349 (M, 98), 180 (100), 152 (96), 137
(13), 125 (25), 94 (46); HRMS calcd for C16H16BrNO3,
349.0314; found, 349.0311.
4.6.10. 1-(3-Amino-2-thienyl)-2-(2-bromo-4,5-dimethyl-
phenyl)ethanone (5j). The typical procedure was followed
employing 4j (317.1 mg, 0.66 mmol) to afford compound
5j (209 mg, 97%) as a brown solid, mp 113–114 ꢀC (Et2O).
1H NMR (CDCl3) d 2.18 (3H, s), 2.21 (3H, s), 4.09 (2H, s),
6.18 (2H, br s), 6.54 (1H, d, J¼4.36), 7.05 (1H, s), 7.29
(1H, d, J¼5.15), 7.34 (1H, s); 13C NMR (CDCl3) d 19.0,
19.1 (CH3), 46.8 (CH2), 111.2 (C), 120.0 (CH), 121.6,
132.0, 132.1, 132.7, 133.2 (CH), 135.9, 137.4, 154.3, 190.1
(C); IR (film, cmꢁ1) 3437.2, 3319.7, 2920.1, 1596.3; EIMS
(m/z, %) 322 (30), 244 (79), 126 (100), 98 (19); HRMS calcd
for C14H14BrNOS, 322.9979; found, 322.9992.
4.6.6. 1-(2-Amino-4,5-dimethoxyphenyl)-2-(2-bromo-
4,5-dimethylphenyl)ethanone (5f). The typical procedure
was followed employing 4f (177.8 mg, 0.33 mmol) to afford
compound 5f (120 mg, 95%) as a pale yellow solid, mp 146–
148 ꢀC (Et2O). 1H NMR (CDCl3) d 2.15 (3H, s), 2.18 (3H, s),
3.82 (3H, s), 3.83 (3H, s), 4.26 (2H, s), 6.05 (2H, br s), 6.10
(1H, s), 7.00 (1H, s), 7.18 (1H, s), 7.34 (1H, s); 13C NMR
(CDCl3) d 18.9, 19.1 (CH3), 45.7 (CH2), 55.6, 56.6 (CH3),
99.2 (CH), 109.5 (C), 112.7 (CH), 121.3 (C), 132.2 (CH),
132.6 (C), 133.1 (CH), 136.0, 137.2, 139.9, 147.8, 155.2,
196.6 (C); IR (film, cmꢁ1) 3448.9, 3319.7, 2931.0, 2850.5,
1631.5; EIMS (m/z, %) 379 (M+2, 88), 377 (M, 93), 180
(100), 152 (84), 125 (28), 94 (31); HRMS calcd for
C18H20BrNO3, 377.0627; found, 377.0619.
4.6.11. 1-(3-Amino-2-thienyl)-2-(2-bromo-4,5-dimethoxy-
phenyl)ethanone (5k). The typical procedure was followed
employing 4k (74.2 mg, 0.15 mmol) to afford compound
5k (50.4 mg, 97%) as a brown solid, mp 126–128 ꢀC
(Et2O). 1H NMR (CDCl3) d 3.84 (3H, s), 3.85 (3H, s), 4.09
(2H, s), 6.12 (2H, br s), 6.53 (1H, d, J¼5.55), 6.80 (1H, s),
7.04 (1H, s), 7.30 (1H, d, J¼5.16); 13C NMR (CDCl3)
d 46.9 (CH2), 55.9, 56.0 (CH3), 110.6 (C), 114.1, 115.3,
119.8 (CH), 126.9, 129.8 (C), 132.3 (CH), 148.2, 148.5,
155.0, 190.0 (C); IR (film, cmꢁ1) 3448.1, 3330.5, 2919.2,
2850.3, 1595.8; EIMS (m/z, %) 276 (77), 219 (28), 126
(100); HRMS calcd for C14H14BrNO3S, 354.9878; found,
354.9861.
4.6.7. 1-(2-Amino-4,5-dimethoxyphenyl)-2-(2-bromo-
4,5-dimethoxyphenyl)ethanone (5g). The typical pro-
cedure was followed employing 4g (268 mg, 0.48 mmol)
to afford compound 5g (193 mg, 99%) as a brown solid,
1
mp 170–171 ꢀC (Et2O). H NMR (CDCl3) d 3.79 (3H, s),
3.82 (9H, s), 4.25 (2H, s), 6.08 (1H, s), 6.29 (2H, s), 6.75
(1H, s), 7.03 (1H, s), 7.18 (1H, s); 13C NMR (CDCl3)
d 45.8 (CH2), 55.7, 55.8, 56.0, 56.6 (CH3), 99.1 (CH),
109.3 (C), 112.6, 113.5 (CH), 114.6 (C), 115.2 (CH),
127.6, 140.0, 148.2, 148.3, 148.4, 155.4, 196.5 (C); IR
(film, cmꢁ1) 3448.9, 3319.7, 2931.8, 2850.5, 1631.5;
EIMS (m/z, %) 411 (M+2, 50), 409 (M, 50), 330 (45), 180
(100), 152 (71), 125 (39), 111 (15), 97 (32); HRMS calcd
for C18H20BrNO5, 409.0525; found, 409.0521.
4.6.12. 1-(3-Amino-2-thienyl)-2-(2-bromo-4,6-difluoro-
phenyl)ethanone (5l). The typical procedure was followed
employing 4l (78.1 mg, 0.16 mmol) to afford compound 5l
(52 mg, 98%) as an orange solid, mp 103–104 ꢀC (Et2O).
1H NMR (CDCl3) d 4.18 (2H, s), 6.21 (2H, br s), 6.56
(1H, d, J¼5.15), 6.80–6.92 (2H, m), 7.34 (1H, d, J¼5.16);
13C NMR (CDCl3) d 46.8 (CH2), 103.6 (t, J¼26.03, CH),
106.9 (dd, J¼3.59, 21.54), 110.4 (C), 114.3 (dd, J¼3.59,
23.34), 119.9, 132.7 (CH), 138.7 (d, J¼8.97), 155.3, 159.3
(dd, J¼12.57, 247.73), 161.5 (dd, J¼12.57, 247.73), 188.3
(C); IR (film, cmꢁ1) 3448.9, 3331.4, 3084.6, 2920.1,
1590.4; EIMS (m/z, %) 322 (25), 126 (39), 83 (100);
HRMS calcd for C12H8BrF2NOS, 330.9478; found,
330.9471.
4.6.8. 1-(2-Amino-4,5-dimethoxyphenyl)-2-(2-bromo-
4,6-difluorophenyl)ethanone (5h). The typical procedure
was followed employing 4h (209.2 mg, 0.39 mmol) to afford
compound 5h (146.8 mg, 98%) as a yellow solid, mp 155–
157 ꢀC (Et2O). 1H NMR (CDCl3) d 3.83 (3H, s), 3.86 (3H,
s), 4.35 (2H, s), 6.10 (1H, s), 6.20 (2H, br s), 6.78–6.87
(2H, m), 7.11 (1H, s); 13C NMR (CDCl3) d 45.7 (CH2),
55.8, 56.7 (CH3), 99.2, 103.5 (t, J¼25.13, CH), 106.8 (dd,
J¼3.59, 21.54), 109.1 (C), 112.4, 114.0 (dd, J¼3.59,
23.34, CH), 139.4 (d, J¼8.98), 140.3, 148.4, 155.8, 159.2
(dd, J¼12.57, 247.73), 161.5 (dd, J¼12.57, 247.73), 194.7
(C); IR (film, cmꢁ1) 3448.9, 3331.4, 2931.8, 2850.5,
1631.0; EIMS (m/z, %) 387 (M+2, 68), 385 (M, 74), 180
4.7. Typical procedure for the synthesis of dibenzo-
azepinones 6a–h
4.7.1. 10,11-Dihydro-5H-dibenz[b,f]azepin-10-one (6a).11
A solution of amine 5a (100.6 mg, 0.35 mmol), Pd(OAc)2

M. Carril et al. / Tetrahedron 63 (2007) 690–702
699
(4 mg, 0.017 mmol), BINAP (17.4 mg, 0.027 mmol), previ-
ously ground K3PO4 (150 mg, 0.68 mmol), toluene (3.5 ml)
and water (1.5 ml) was heated at 130 ꢀC. After 5 h the reac-
tion mixture was partitioned between water and dichloro-
methane. The organic layer was dried and concentrated in
vacuo. The crude product was then purified by flash chroma-
tography (5% Et2O/CH2Cl2) to give compound 6a (66 mg,
91%) as yellow needles.
(C), 118.7 (CH), 123.9 (C), 124.5, 127.3, 129.5 (CH),
141.9, 142.9, 143.3, 154.0, 188.9 (C); IR (film, cmꢁ1
3296.2, 2815.0, 1608.0; EIMS (m/z, %) 269 (M, 49), 254
(62), 226 (100), 198 (45); HRMS calcd for C16H15NO3,
269.1052; found, 269.1052.
)
4.7.6. 10,11-Dihydro-5H-2,3-dimethyl-7,8-dimethoxydi-
benzo[b,f]azepin-10-one (6f). The typical procedure was
followed starting from 5f (91.5 mg, 0.24 mmol) to afford
compound 6f (64.1 mg, 89%) as a yellow solid, mp 166–
168 ꢀC (Et2O). 1H NMR (CDCl3) d 2.16 (6H, s), 3.72
(2H, s), 3.79 (3H, s), 3.82 (3H, s), 6.51 (1H, s), 6.84 (1H,
s), 6.96 (1H, s), 6.99 (1H, s), 7.48 (1H, s); 13C NMR
(CDCl3) d 18.8, 19.4 (CH3), 48.5 (CH2), 55.8, 55.9
(CH3), 101.3, 110.5 (CH), 116.2 (C), 119.7 (CH), 121.2
(C), 130.3 (CH), 132.9, 135.7, 139.7, 142.8, 143.5, 153.9,
189.2 (C); IR (film, cmꢁ1) 3319.7, 2943.6, 2820.0,
1608.0; EIMS (m/z, %) 297 (M, 100), 282 (96), 252 (15),
211 (14), 97 (15); HRMS calcd for C18H19NO3,
297.1365; found, 297.1354.
4.7.2. 10,11-Dihydro-5H-2,3-dimethyldibenzo[b,f]aze-
pin-10-one (6b). The typical procedure was followed start-
ing from 5b (95 mg, 0.29 mmol) to afford compound 6b
(57.1 mg, 81%) as a yellow solid, mp 180–182 ꢀC (Et2O).
1H NMR (CDCl3) d 2.21 (6H, s), 3.75 (2H, s), 6.75 (1H,
br s), 6.84 (1H, s), 6.90 (1H, dt, J¼0.79, 7.13), 7.01 (1H,
d, J¼8.32), 7.04 (1H, s), 7.38 (1H, dt, J¼1.58, 7.54), 8.02
(1H, dd, J¼1.58, 8.32); 13C NMR (CDCl3) d 18.9, 19.4
(CH3), 48.7 (CH2), 118.8, 119.0, 119.9 (CH), 121.1, 123.9,
130.4 (C), 130.5, 133.3 (CH), 135.9, 139.1, 146.7, 189.9
(C); IR (film, cmꢁ1) 3307.9, 1643.3; EIMS (m/z, %) 237
(99), 222 (100), 208 (44), 194 (47); HRMS calcd for
C16H15NO, 237.1154; found, 237.1156.
4.7.7. 10,11-Dihydro-5H-2,3,7,8-tetramethoxydibenzo-
[b,f]azepin-10-one (6g). The typical procedure was fol-
lowed starting from 5g (184.7 mg, 0.45 mmol) to afford
compound 6g (118 mg, 80%) as a yellow solid, mp
4.7.3. 10,11-Dihydro-5H-2,3-dimethoxydibenzo[b,f]aze-
pin-10-one (6c). The typical procedure was followed start-
ing from 5c (165 mg, 0.47 mmol) to afford compound 6c
(101.6 mg, 80%) as an orange solid, mp 172–174 ꢀC
1
>300 ꢀC (Et2O). H NMR (CDCl3) d 3.68 (2H, s), 3.76
(3H, s), 3.82 (6H, s), 3.86 (3H, s), 6.47 (1H, s), 6.59 (1H,
s), 6.72 (1H, s), 6.74 (1H, s), 7.46 (1H, s); 13C NMR
(CDCl3) d 48.3 (CH2), 55.9, 56.0, 56.1 (CH3), 101.2,
102.9, 110.6, 111.8 (CH), 115.8, 116.1, 135.4, 142.9,
1
(Et2O). H NMR (CDCl3) d 3.70 (2H, s), 3.74 (3H, s),
3.81 (3H, s), 6.61 (1H, s), 6.74 (1H, s), 6.88 (1H, t,
J¼8.01), 6.98 (1H, s), 7.04 (1H, d, J¼8.22), 7.37 (1H, t,
J¼7.61), 8.00 (1H, d, J¼8.01); 13C NMR (CDCl3) d 48.5
(CH2), 55.8, 56.1 (CH3), 102.9, 111.8 (CH), 115.4 (C),
118.8, 118.9 (CH), 123.6 (C), 130.3, 133.2 (CH), 134.8,
146.7, 146.8, 148.1, 189.3 (C); IR (film, cmꢁ1) 3331.4,
2815.3, 1649.1; EIMS (m/z, %) 269 (M, 13), 254 (63), 226
(100); HRMS calcd for C16H15NO3, 269.1052; found,
269.1052.
143.3, 146.7, 147.9, 153.9, 188.5 (C); IR (film, cmꢁ1
)
3343.2, 2943.6, 2815.3, 1608.0; EIMS (m/z, %) 329 (97),
314 (100), 286 (21), 97 (16); HRMS calcd for C18H19NO5,
329.1263; found, 329.1259.
4.7.8. 10,11-Dihydro-5H-1,3-difluoro-7,8-dimethoxydi-
benzo[b,f]azepin-10-one (6h). The typical procedure was
followed starting from 5h (98.5 mg, 0.26 mmol) to afford
compound 6h (67.6 mg, 87%) as a yellow solid, mp>300 ꢀC
(Et2O). 1H NMR (CDCl3) d 3.83 (3H, s), 3.87 (3H, s), 3.96
(2H, s), 6.50 (1H, s), 6.77–6.84 (2H, m), 7.48 (1H, s); 13C
NMR (CDCl3/CD3OD) d 48.4 (CH2), 55.7 (CH3), 101.7,
101.9 (dd, J¼2.75, 23.83), 110.1, 110.6 (dd, J¼3.67,
22.91, CH), 116.1, 126.8 (dd, J¼3.67, 11.91), 127.8 (d,
J¼8.25), 143.2, 143.3, 152.8 (dd, J¼11.91, 245.60), 154.4,
4.7.4. 10,11-Dihydro-5H-1,3-difluorodibenzo[b,f]azepin-
10-one (6d). The typical procedure was followed starting
from 5d (64.3 mg, 0.19 mmol), but by using 1,4-dioxane in-
stead of toluene and the reaction was performed in a sealed
tube to afford compound 6d (34.6 mg, 77%) as a yellow
1
solid, mp 166–167 ꢀC (Et2O). H NMR (CDCl3) d 3.86
(2H, s), 6.65 (1H, br s), 6.78–6.86 (2H, m), 6.98 (1H, t,
J¼7.53), 7.09 (1H, d, J¼8.32), 7.45 (1H, dt, J¼1.59,
8.72), 8.03 (1H, dd, J¼1.19, 7.93); 13C NMR (CDCl3)
d 49.1 (CH2), 102.4 (dd, J¼26.81, 26.86), 111.4 (dd,
J¼3.81, 22.69), 119.6, 120.2 (CH), 124.5, 126.6 (dd,
J¼3.38, 12.10), 127.5 (d, J¼11.40, C), 130.6, 133.9
(CH), 145.9, 152.8 (dd, J¼12.68, 245.19), 158.9 (dd,
J¼11.92, 245.89), 188.3 (C); IR (film, cmꢁ1) 3307.9,
1655.0; EIMS (m/z, %) 245 (M, 95), 216 (100), 196 (17),
169 (18); HRMS calcd for C14H9F2NO, 245.0652; found,
245.0654.
158.6 (dd, J¼11.92, 245.61), 188.0 (C); IR (film, cmꢁ1
)
3331.4, 2955.3, 2815.0, 1608.0; EIMS (m/z, %) 305 (M,
97), 290 (100), 262 (36), 234 (19), 219 (24), 214 (18), 203
(21), 190 (42); HRMS calcd for C16H13F2NO3, 305.0863;
found, 305.0857.
4.7.9. 9,10-Dihydro-4H-thieno[3,2,b][f]benzazepin-10-
one (6i). The typical procedure was followed without the
addition of water starting from 5i (41.5 mg, 0.14 mmol) to
afford compound 6i (25.7 mg, 85%) as a brown solid, mp
181–182 ꢀC (Et2O) (lit.23 195 ꢀC). 1H NMR (CDCl3)
d 3.76 (2H, s), 6.84 (1H, d, J¼5.15), 7.05 (1H, d, J¼7.53),
7.12–7.29 (3H, m), 7.35 (1H, br s), 7.49 (1H, d, J¼5.16);
13C NMR (CDCl3) d 48.5 (CH2), 118.6, 121.4 (CH), 122.5
(C), 124.8, 127.5, 130.9, 133.3 (CH), 141.3, 149.6, 185.3
(C); IR (film, cmꢁ1) 3284.4, 3084.6, 1602.1; EIMS (m/z,
%) 215 (M, 62), 187 (23), 186 (100), 115 (23); HRMS calcd
for C12H9NOS, 215.0405; found, 215.0396.
4.7.5. 10,11-Dihydro-5H-7,8-dimethoxydibenzo[b,f]aze-
pin-10-one (6e). The typical procedure was followed start-
ing from 5e (101.6 mg, 0.29 mmol) to afford compound 6e
(65.7 mg, 84%) as a yellow solid, mp 188–190 ꢀC (Et2O).
1H NMR (CDCl3) d 3.78 (2H, s), 3.79 (6H, s), 6.55 (1H,
s), 7.06–7.23 (5H, m), 7.48 (1H, s); 13C NMR (CDCl3)
d 48.9 (CH2), 55.8, 55.9 (CH3), 101.5, 110.4 (CH), 116.3

700
M. Carril et al. / Tetrahedron 63 (2007) 690–702
4.7.10. 9,10-Dihydro-4H-6,7-dimethylthieno[3,2,b][f]-
benzazepin-10-one (6j). The typical procedure was fol-
lowed without the addition of water starting from 5j
(209 mg, 0.65 mmol) to afford compound 6j (111 mg,
71%) as a yellow solid, mp>300 ꢀC (Et2O). 1H NMR
(CDCl3) d 2.22 (6H, s), 3.68 (2H, s), 6.79 (1H, d, J¼5.15),
6.82 (1H, s), 7.02 (1H, s), 7.13 (1H, br s), 7.46 (1H, d,
J¼5.15); 13C NMR (CDCl3) d 18.9, 19.4 (CH3), 47.9
(CH2), 119.6 (CH), 119.8, 120.3 (C), 121.2, 131.7, 133.0
(CH), 133.3, 135.9, 139.0, 149.6, 185.5 (C); IR (film,
cmꢁ1) 3260.9, 2955.3, 1602.1; EIMS (m/z, %) 243 (M,
100), 228 (88), 214 (44), 199 (18); HRMS calcd for
C14H13NOS, 243.0718; found, 243.0712.
4.8.2. 10,11-Dihydro-5-aminocarbonyl-5H-1,3-difluoro-
dibenzo[b,f]azepin-10-one (7d). The same procedure was
followed starting from 6d (36 mg, 0.15 mmol) to give com-
pound 7d (25.2 mg, 65%) as a pale yellow solid, mp 194–
196 ꢀC (acetone). 1H NMR (CDCl3) d 3.86 (1H, d,
J¼14.58), 4.43 (1H, d, J¼14.58), 4.95 (2H, br s), 6.84
(1H, dt, J¼2.43, 8.79), 6.90 (1H, d, J¼7.67), 7.42 (1H, t,
J¼7.57), 7.62–7.68 (2H, m), 8.12 (1H, dd, J¼0.93, 7.95);
13C NMR (CDCl3) d 49.0 (CH2), 104.0 (t, J¼23.83), 112.3
(dd, J¼2.75, 22.91, CH), 125.3 (dd, J¼3.66, 14.00, C),
128.2 (CH), 128.6 (C), 130.1, 131.2, 134.6 (CH), 137.6 (d,
J¼9.17), 142.2, 154.9, 158.7 (dd, J¼13.29, 255.69), 162.1
(dd, J¼11.50, 252.93), 190.8 (C); IR (film, cmꢁ1) 3459.8,
3331.4, 2920.1, 1678.5, 1596.3; EIMS (m/z, %) 288 (M,
5), 245 (55), 216 (100), 196 (21), 169 (16); HRMS calcd
for C15H10F2N2O2, 288.0710; found, 288.0711.
4.7.11. 9,10-Dihydro-4H-6,7-dimethoxythieno[3,2,b]-
[f]benzazepin-10-one (6k). The typical procedure was
followed without the addition of water starting from 5k
(31.9 mg, 0.09 mmol) to afford compound 6k (11.5 mg,
4.8.3. 10,11-Dihydro-5-aminocarbonyl-5H-2,3,7,8-tetra-
methoxydibenzo[b,f]azepin-10-one (7g). The same proce-
dure was followed starting from 6g (64.2 mg, 0.19 mmol)
to give unreacted starting material 6g (4.7 mg) and com-
pound 7g (55.5 mg, 83%) as an orange solid, mp 214–
216 ꢀC (acetone). 1H NMR (CDCl3) d 3.67 (1H, d,
J¼14.21), 3.85 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 3.97
(3H, s), 4.33 (1H, d, J¼14.02), 5.06 (2H, br s), 6.83 (1H,
s), 6.96 (1H, s), 7.08 (1H, s), 7.52 (1H, s); 13C NMR
(CDCl3) d 48.2 (CH2), 56.1, 56.2, 56.3, 56.32 (CH3),
110.6, 111.1, 111.2, 112.2 (CH), 122.9, 126.6, 134.1,
138.3, 148.0, 148.5, 149.4, 153.2, 156.3, 191.1 (C); IR
(film, cmꢁ1) 3452.6, 3332.6, 1660.9, 1596.3; EIMS (m/z,
%) 372 (M, 18), 328 (53), 314 (53), 286 (100), 227 (21);
HRMS calcd for C19H20N2O6, 372.1321; found, 372.1320.
1
47%) as an orange solid, mp 190–191 ꢀC (Et2O). H NMR
(CDCl3) d 3.65 (2H, s), 3.84 (3H, s), 3.85 (3H, s), 6.57
(1H, s), 6.74 (1H, s), 6.80 (1H, d, J¼5.16), 7.12 (1H, br s),
7.47 (1H, d, J¼5.15); 13C NMR (CDCl3) d 47.8 (CH2),
56.0, 56.2 (CH3), 102.7, 113.0 (CH), 114.2 (C), 121.0
(CH), 133.0, 134.6, 146.7, 148.1, 149.6, 185.1 (C); IR
(film, cmꢁ1) 3272.6, 2920.1, 2815.0, 1602.1; EIMS (m/z,
%) 275 (M, 100), 260 (90), 232 (34), 189 (13), 83 (21);
HRMS calcd for C14H13NO3S, 275.0616; found, 275.0630.
4.7.12. 9,10-Dihydro-4H-6,8-difluorothieno[3,2,b][f]benz-
azepin-10-one (6l). The typical procedure was followed
but without the addition of water, using 1,4-dioxane instead
of toluene and the reaction was performed in a sealed tube
starting from 5l (29.1 mg, 0.09 mmol) to afford compound
6l (19.9 mg, 91%) as an orange solid, mp 220–221 ꢀC
4.8.4. 10,11-Dihydro-5-aminocarbonyl-5H-1,3-difluoro-
7,8-dimethoxydibenzo[b,f]azepin-10-one (7h). The same
procedure was followed starting from 6h (57.5 mg,
0.19 mmol) to give compound 7h (33 mg, 50%) as a pale
1
(Et2O). H NMR (CDCl3) d 3.78 (2H, s), 6.81–6.87 (3H,
m), 7.16 (1H, br s), 7.54 (1H, d, J¼5.15); 13C NMR
(CDCl3) d 48.3 (CH2), 100.0 (C), 102.3 (dd, J¼26.86,
26.90), 112.4 (dd, J¼3.72, 22.65), 121.5 (CH), 126.1 (d,
J¼11.12), 126.5 (dd, J¼3.48, 12.09, C), 133.8 (CH),
148.7, 152.4 (dd, J¼12.64, 244.51), 158.8 (dd, J¼12.08,
245.87), 183.6 (C); IR (film, cmꢁ1) 3249.1, 2908.3,
1619.8; EIMS (m/z, %) 251 (M, 92), 222 (100), 202 (52),
158 (47); HRMS calcd for C12H7F2NOS, 251.0216; found,
251.0213.
1
yellow solid, mp 228–230 ꢀC (Et2O). H NMR (CDCl3)
d 3.79 (1H, d, J¼14.51), 3.89 (3H, s), 3.98 (3H, s), 4.36
(1H, d, J¼14.51), 5.23 (2H, br s), 6.79–6.83 (1H, m), 6.88
(1H, d, J¼7.55); 13C NMR (CDCl3) d 40.8 (CH2), 56.2,
56.5 (CH3), 103.7 (dd, J¼23.83, 25.66), 110.7, 111.5,
112.2 (d, J¼23.82, CH), 123.0, 125.5 (d, J¼11.92), 137.1,
138.2 (d, J¼4.58), 148.7, 153.8, 155.2, 158.5 (dd,
J¼12.05, 256.60), 161.9 (dd, J¼11.91, 252.03), 189.9 (C);
IR (film, cmꢁ1) 3460.4, 3332.9, 2920.1, 1666.8, 1596.3;
EIMS (m/z, %) 348 (M, 15), 305 (82), 290 (100), 262 (67),
234 (50), 214 (43); HRMS calcd for C17H14F2N2O4,
348.0922; found, 348.0922.
4.8. Experimental data for oxcarbazepine analogues 7
4.8.1. 10,11-Dihydro-5-aminocarbonyl-5H-2,3-dimethyl-
dibenzo[b,f]azepin-10-one (7b). The patented procedure
for the carbamoylation22 was followed starting from 6b
(66.8 mg, 0.28 mmol) to give unreacted starting material
6b (3.5 mg) and compound 7b (60.1 mg, 80%) as an orange
4.8.5. 9,10-Dihydro-4-aminocarbonyl-4H-thieno[3,2,b]-
[f]benzazepin-10-one (7i). The same procedure was
followed starting from 6i (61.2 mg, 0.28 mmol) to give un-
reacted starting material 6i (12.4 mg) and compound 7i
(46.9 mg, 80%) as a pale yellow solid, mp 224–225 ꢀC (ace-
tone). 1H NMR (CDCl3) d 3.78 (1H, d, J¼13.71), 4.28 (1H,
d, J¼13.71), 4.99 (2H, br s), 7.34–7.35 (2H, m), 7.40–7.42
(1H, m), 7.48 (1H, d, J¼5.16), 7.49–7.51 (1H, m), 7.58
(1H, d, J¼5.37); 13C NMR (CDCl3) d 48.1 (CH2), 127.5,
127.8, 128.3, 129.2, 130.8 (CH), 131.6 (C), 131.9 (CH),
1
solid, mp 216–218 ꢀC (acetone). H NMR (CDCl3) d 2.26
(6H, s), 3.78 (1H, d, J¼14.11), 4.39 (1H, d, J¼13.84),
5.08 (2H, br s), 7.17 (1H, s), 7.27 (1H, s), 7.34 (1H, dt,
J¼0.59, 7.35), 7.57 (1H, dt, J¼1.59, 8.15), 7.66 (1H, d,
J¼7.95), 8.10 (1H, dd, J¼1.20, 7.95); 13C NMR (CDCl3)
d 19.4, 19.5 (CH3), 48.5 (CH2), 127.1, 128.4, 128.9 (CH),
129.9 (C), 130.6 (CH), 130.9 (C), 131.2, 133.8 (CH),
137.2, 138.1, 138.9, 140.0, 156.0, 192.1 (C); IR (film,
cmꢁ1) 3489.1, 3350.2, 2920.1, 1672.6, 1590.4; EIMS (m/z,
%) 280 (M, 33), 237 (76), 222 (100), 208 (81), 194 (36);
HRMS calcd for C17H16N2O2, 280.1212; found, 280.1210.
133.9, 140.8, 145.6, 154.7, 186.5 (C); IR (film, cmꢁ1
)
3478.3, 3354.9, 1655.0, 1597.5; EIMS (m/z, %) 258 (M,
81), 216 (100), 186 (91), 182 (27), 169 (19), 154 (47), 128

M. Carril et al. / Tetrahedron 63 (2007) 690–702
701
10. For some reviews on palladium N- and C-arylation reactions,
see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131; (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046; (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 211.
(55), 115 (54); HRMS calcd for C13H10N2O2S, 258.0463;
found, 258.0468.
4.8.6. 9,10-Dihydro-4-aminocarbonyl-4H-6,7-dimethyl-
thieno[3,2,b][f]benzazepin-10-one (7j). The same proce-
dure was followed starting from 6j (58.9 mg, 0.24 mmol)
to give unreacted starting material 6j (3.5 mg) and com-
pound 7j (58 mg, 89%) as a brown solid, mp 246–247 ꢀC
ꢀ
11. Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.; Domınguez,
E. Org. Lett. 2005, 7, 4787.
12. After the optimisation of the synthetic route to OXC, we found
in the literature an interesting study on the effect of the addition
of small amounts of water in the palladium-catalysed amida-
tion reactions. As in our case, the role of water was especially
determining when the base was cesium carbonate and the sol-
vents were either toluene or 1,4-dioxane. See: Dallas, A. S.;
Gothelf, K. V. J. Org. Chem. 2005, 70, 3321.
13. The only related example reported in the literature was
developed by Hartwig’s research group and involves the
palladium-catalysed a-arylation of 2-acetylthiophene with
bromobenzene, rendering the corresponding product in 68%
yield. See: Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382.
1
(acetone). H NMR (CDCl3) d 2.25 (6H, s), 3.68 (1H, d,
J¼13.51), 4.21 (1H, d, J¼13.51), 4.97 (2H, br s), 7.15 (1H,
s), 7.26 (1H, s), 7.46 (1H, d, J¼5.36), 7.55 (1H, d, J¼5.16);
13C NMR (CDCl3) d 19.3, 19.5 (CH3), 47.6 (CH2), 127.8,
128.1 (CH), 130.9 (C), 131.6, 131.7 (CH), 136.9, 138.0,
138.5, 145.9, 154.8, 186.9 (C); IR (film, cmꢁ1) 3459.8,
3320.1, 2920.0, 1655.0, 1596.7; EIMS (m/z, %) 286 (21),
243 (95), 228 (100), 214 (45), 199 (24); HRMS calcd for
C15H14N2O2S, 286.0776; found, 286.0773.
Acknowledgements
14. For a selection of the reaction conditions employed in the op-
timisation of this step, see the Supplementary data of this paper.
15. The tendency of the sulfur atom to strongly coordinate with
palladium is well-established. It is anticipated that poisoning
the catalyst in this manner will inhibit the reaction progress
and therefore account for the long reaction times required for
these transformations. See: (a) Mowery, D. L.; Graboski,
M. S.; Ohno, T. R.; McCormick, R. L. Appl. Catal., B 1999,
21, 157; (b) Luo, T.; Vohs, J. M.; Gorte, R. J. J. Catal. 2002,
210, 397.
This research was supported by the University of the Basque
Country (Project UPV 41.310-13656) and the Spanish Min-
istry of Education and Science (MEC CTQ2004-03706/
BQU). M.C. also thanks the Ministry of Education and Sci-
ence (MEC) for a predoctoral scholarship.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.11.003.
16. For additional information on the reaction conditions em-
ployed, see the Supplementary data of this paper.
17. For an excellent review on the use of polyhalogenated hetero-
cycles in different cross-couplings reactions, and a rational ex-
planation of the electronic behaviour of each of the carbons
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702
M. Carril et al. / Tetrahedron 63 (2007) 690–702
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ꢀ ꢀ
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