A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan

Article abstract of DOI:10.1016/j.bmc.2006.05.070

A practical preparation of benzazepine derivatives using a series of radical and ionic reactions is reported. This approach was applied to the synthesis of tolvaptan, a very promising vasopressin V₂ receptor antagonist currently in clinical trials.

Full text of DOI:10.1016/j.bmc.2006.05.070

Bioorganic & Medicinal Chemistry 14 (2006) 6165–6173
A flexible approach for the preparation of substituted benzazepines:
Application to the synthesis of tolvaptanq
*
´
Alejandro Cordero-Vargas, Beatrice Quiclet-Sire and Samir Z. Zard
`
´
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Received 14 February 2006; revised 21 May 2006; accepted 31 May 2006
Available online 16 June 2006
Dedicated with respect to Professor Bernd Giese, recipient of last year’s Tetrahedron Prize.
Abstract—A practical preparation of benzazepine derivatives using a series of radical and ionic reactions is reported. This approach
was applied to the synthesis of tolvaptan, a very promising vasopressin V2 receptor antagonist currently in clinical trials.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
H
N
O
R1
Benzazepines and related compounds such as benzazepi-
nones and benzodiazepines constitute a wide class of
compounds with diverse and often important pharmaco-
logical properties. Paullones (1),1 for example (Fig. 1),
show important antitumor activity, while others behave
as inhibitors of angiotensin converting enzyme2 and as
analgesics.3 Recent studies revealed that N-substituted
benzazepines can act as powerful vasopressin V2 recep-
tor antagonists and thus have a potential for the treat-
ment of heart diseases.4 Some of the most promising
derivatives of this group are tolvaptan (2)5 and OPC-
31260 (3),6 currently undergoing clinical trials (Fig. 1).
1 Paullones
HN
R2
H
H
N
N
O
O
O
O
2
N
1
5
N
N
3
4
Cl
HO
2 Tolvaptan
3 OPC-31260
Figure 1. Some vasopressin V2 receptor antagonists.
Even though benzazepines are well known and studied
structures, difficulties arise in their preparation especial-
ly when a C5-substituent is required or if electron with-
drawing groups are present in the aromatic ring. The
preparation of tolvaptan, for example, required 11 line-
ar steps, some involving harsh conditions that limit the
generality of this approach (Scheme 1).5 Besides, even
if the final steps of this route seem trivial, the yields
are low, thus resulting in a very low overall yield
(<1%). In addition, the introduction of a C5-substituent
other than oxygen would require extra steps in order to
modify the ketone precursor. In other words, this route
lacks flexibility, and cannot be easily transposed to the
synthesis of analogues.
One practical method for the preparation of benzaze-
pines is by application of the Beckmann rearrangement
to tetralone ketoximes7 followed by amide reduction.
Although this transformation is very effective, the main
problem lies in the preparation of substituted tetralones.
A few years ago, we reported a new method for the
preparation of a-tetralones by means of a tin-free radi-
cal chemistry.8 This method allows the synthesis of a
wide variety of substituted a-tetralones under neutral,
mild conditions. More recently, this methodology was
Keywords: Xanthate; Benzazepines; Beckmann rearrangement;
Tolvaptan.
q
This work has been the subject of a patent. Cordero-Vargas, A.;
Quiclet-Sire, B.; Zard, S. Z. Proce´de´ utile pour la pre´paration de
´ ´ ´
benzazepines et derives de celles-ci. France. French patent.
FR-0450416. 02 March 2004.
Corresponding author. Tel.: +33 1693 34867; fax: +33 1693 33851;
e-mail: zard@poly.polytechnique.fr
*
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.05.070

6166
A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
Cl
CO2Me
Cl
Cl
CO2H
NO2
H
3 steps
N
H
Ts
N
N
O
H
O
Cl
Br
CO2Et
CO2Et
K2CO3
Cl
N
PGO
O
-BuOK
t
acylation
deprotection
CO2R
4
CO2Me
Cl
Cl
toluene
HO
reduction
N
Ts
94% Yield
N
Ts
Tolvaptan 2
OH
H
O
N
N
conc. HCl
AcOH
Beckmann
60% Yield
O
Cl
O
Cl
O
PGO
Cl
PPA
OPG
6
5
N
H
81% Yield
N
Ts
free radical
addition and
cyclization
O
32% Yield
Cl
S
OEt
O2N
O
NEt3
S
Cl
+
CH2Cl2
O
N
8
O
Cl
Cl
H2 / PtO2
HCl / AcOH
Cl
OPG
OPG
9
N
7
O
O
39% Yield
O
NH2
Scheme 2. Retrosynthetic analysis for tolvaptan.
NO2
Cl
Our synthesis starts with the preparation of the required
tetralones 11a–c as previously reported.9 Thus, xanthate
group transfer addition of xanthates 8a–c,12 using
dilauroyl peroxide (DLP) as radical initiator and 1,2-
dichloroethane (DCE) as the solvent, produces adducts
10a–c in excellent yield. The latter were then subjected
to the same free radical conditions in the presence of a
catalytic amount of camphorsulfonic acid (CSA)13 to
generate tetralones 11a–c by ring closure to the aromatic
ring. This step requires stoichiometric quantities of the
peroxide, which acts both as initiator for the radical
cyclisation and as oxidant for the intermediate cyclo-
hexadienyl radical (Scheme 3).
53% Yield
NEt3
CH2Cl2
HO
NaBH4
MeOH
O
Cl
Cl
N
O
30% Yield
N
O
O
O
N
H
N
H
Tolvaptan 2
Scheme 1. Reported synthesis of tolvaptan.
employed for the preparation of substituted naphtha-
lenes9 and C-arylglycosides10 as well as for the first total
synthesis of the natural product 10-norparvulenone.11
We have now found that this chemistry can be applied
in an efficient practical synthesis of tolvaptan. More
generally, it represents a flexible entry into benzazepines
with various substitution patterns hitherto not easily
accessible.
The preparation of the corresponding oximes 12a–c was
easily achieved by reaction of 11a–c with NH2OH–HCl
and sodium acetate in ethanol/water (Scheme 4). Having
obtained the required precursors for the Beckmann
rearrangement, we proceeded to prepare key intermedi-
ates 13a–c. Unfortunately, all standard conditions for
mediating the ring expansion failed. Our worries
concerning the lability of the benzylic ester as the main
stumbling block of the synthesis were thus well founded.
2. Results and discussion
The main general features of our route are outlined in
Scheme 2. Tolvaptan (2) could derive from benzazepine
4 by acylation and deprotection of the alcohol group.
The latter can be derived, in the crucial step of the syn-
thesis, by a Beckmann rearrangement and amide reduc-
tion from ketoxime 6. The protected alcohol group has
to resist the Beckmann rearrangement conditions. This
is not an easily fulfilled requirement since we had shown
that adducts 7 readily undergo aromatisation to naph-
thols upon exposure to acid.9 Furthermore, the lability
to acid increases as the lactam 5 stage is reached because
of the electron releasing effect of the nitrogen lone pair.
Finally, tetralone 7, the direct precursor of 6, would be
easily prepared in a convergent manner from an ace-
tophenone xanthate (8) and an appropriate olefin (9),
the latter serving as the radical trap.
OEt
OPiv
(DLP)
S
O
O
O
S
S
R
R
S
OEt
1,2 -DCE
reflux
O
8a, R = Cl
8b, R = F
10a, R = Cl, 97%
10b, R = F, 90%
10c, R = OMe, 86%
8c, R = OMe
O
DLP / CSA
11a, R = Cl, 84%
11b, R = F, 54%
11c, R = OMe, 30%
R
1,2 -DCE
reflux
O
O
Scheme 3. Radical sequence for the preparation of tetralones.

A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
6167
by the Otsuka chemists (Scheme 1). In their route, the
presence of the electron withdrawing ketone function
deactivates the nitrogen and lowers considerably the effi-
ciency of the acylation step. Reduction of the nitro
group of 14a–b with tin (II) chloride in ethanol/HCl
afforded anilines 15a–b. Finally, acylation of the latter
with 2-methyl benzoyl chloride and saponification of
the ester group under basic conditions allowed us to ob-
tain tolvaptan (2) and its 50-fluoro analogue (16) in
excellent yield.
OH
N
O
NH2OH.HCl
AcONa
12a, R = Cl, 96%
12b, R = F, 92%
12c, R = OMe, 92%
11a-c
R
EtOH / H2O
O
PCl5 / CH2Cl2
H
O
H
O
N
N
Cl
Zn
Cl
R
R
O
O
AcOH
O
O
Our method for the synthesis of a-tetralones is quite
flexible and several substituents can be introduced
into the molecule just by choosing the appropriate
radical trap. In order to show the scope and applica-
bility of this method, we prepared some analogues
possessing a hydrocarbon chain at C5 (Scheme 6).
Thus, reaction of xanthate 8b with a small amount
of DLP in the presence of allyl cyanide afforded ad-
duct 17 in 81% yield. Tetralone 18 was prepared
from 17 in 44% yield after the CSA catalyzed cyclisa-
tion step. The final three-step sequence was then ap-
plied to oxime 19, affording benzazepine 20 in good
overall yield.
BH3.THF
THF
H
N
13a, R = Cl, 40% (3 steps)
13b, R = F,61% (3 steps)
R
13c, R = OMe, 21% (3 steps)
O
O
Scheme 4. Beckmann rearrangement-reduction sequence.
Ultimately, after careful experimentation, we found that
treatment of oximes 12a–c with an excess of PCl5 in
CH2Cl2 produced an a,a-dichloro lactam,14 which was
then subjected to reduction with Zn powder in acetic
acid. The amide carbonyl could then be selectively re-
duced15 by BH3–THF complex to give key benzazepines
13a–c in good overall yields, except for the methoxy
substituted derivative. This is not surprising since the
presence of the electron donating group increases the
sensitivity of the pivalate group to the presence of acid
during the Beckmann rearrangement.
As seen in Scheme 6, the presence of the nitrile group in
20 is not arbitrary. This functional group is highly useful
because it could be used as a starting point to prepare a
series of other benzazepines possessing a primary amine
(21), an acid (22),4b or an oxathiadiazole oxide (23).17
The latter structure also exhibits interesting antihyper-
glycemic activity.15
While a-halo lactams have been reported as important
intermediates for the synthesis of C3-substituted
Completion of the synthesis of tolvaptan is shown in
Scheme 5. With the benzazepine precursor in place,
the next step toward tolvaptan was the acylation of
the secondary amine with 2-methyl-4-nitro benzoyl
chloride.16 The high efficiency of this seemingly trivial
step contrasts with the analogous acylation described
CN
O
(DLP)
1,2-DCE,reflux
S
OEt
O
S
S
F
S
OEt
81% Yield
NC
F
8b
17
NH2OH.HCl
AcONa
NO2
O
DLP / CSA
1,2-DCE
reflux
OH
O
N
Cl
O
EtOH / H2O
N
NO2
F
F
13a-b
44% Yield
78% Yield
R
NC
NC
NEt3 / DCM
rt
18
19
PivO
14a, R=Cl, 98%
14b, R=F, 97%
1) PCl5 / CH2Cl2
2) Zn / AcOH
3) BH3.THF / THF
H
N
SnCl2
EtOH / HCl
rt
5
F
39%Yield (3 steps)
CN
20
O
O
Cl
NH2
NH
1)
O
N
O
NEt3 / DCM
rt
H
N
H
H
N
N
N
2) NaOH / EtOH
50 ˚C
R
R
F
F
F
H
PivO
HO
N
O
S O
2, R = Cl, 85% (2 steps)
16, R = F, quantitative(2 steps)
HO
N
H2N
15a, R=Cl, 82%
15b, R=F, 78%
O
21
22
23
Scheme 5. Synthesis of tolvaptan and its fluoro analogue.
Scheme 6. Synthesis of further analogues.

6168
A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
Transform Spectrophotometer. Mass spectra were
Nu
recorded with a HP 5989B mass spectrometer. Melting
points were determined by Reichert microscope appara-
tus and were uncorrected.
HO
H
N
N
N
Nu
R2
R1
R1
R1 R2
R2
24
25
4.1.1. 2,2-Dimethyl-propionic acid 1-ethoxythiocar-
bonylsulfanyl-4-(4-methoxy-phenyl)-4-oxo-butyl ester (10c).
A solution of 8c (0.5 g, 1.85 mmol) and of 0.55 mL
(2.7 mmol) of vinyl pivalate in 1,2-dichloroethane
(2 mL) was refluxed for 15 min under argon. Lauroyl
peroxide (DLP) was then added (5 mol %) to the reflux-
ing solution, followed by additional portions (2 mol %
every 90 min). When starting material was totally con-
sumed (after addition of 7.5 mol % of DLP), the crude
mixture was cooled to room temperature, concentrated
under reduced pressure and purified by flash column
chromatography (silica gel, petroleum ether–ethyl ace-
Scheme 7. Trapping the intermediate in the Beckmann rearrangement.
OH
H
N
N
O
1) PCl5 / CH2Cl2
2) NaBH4 / EtOH
Cl
Cl
Cl
Cl
12a
Scheme 8. Synthesis of a dichlorobenzazepine.
48% Yield (2 steps)
O
O
O
26
1
tate, 95:5) to give 10c as a yellow oil (86% yield): H
benzazepinones,2 benzazepines bearing this substitution
pattern are rare. It is known7 that the intermediate of
the Beckmann reaction is an iminium ion (24) that can
be trapped by a nucleophile in order to generate the cor-
responding imines (25) (Scheme 7).
NMR (CDCl3, 400 MHz) d 7.92 (d, 2H, CH arom,
J = 8.8 Hz), 6.93 (d, 2H, CH arom, J = 8.8 Hz), 6.71
(t, 1H, CH–S, J = 8.0 Hz), 4.65–4.59 (m, 2H, O–CH2),
3.87 (s, 3H, OCH3), 3.08 (dq, 2H, CO–CH2, J = 7.2,
4.4 Hz), 2.42–2.35 (m, 2H, CH–CH2), 1.41 (t, 3H,
CH2–CH3, J = 6.0 Hz), 1.19 (s, 9H, (CH3)3); 13C NMR
(CDCl3, 100 MHz) d 210.3 (CS), 196.6 (CO), 176.9
(O–CO), 163.7 (C–OMe), 130.9 (C–CO), 130.4 (CH
arom), 113.9 (CH arom), 80.4 (CH–S), 70.4 (O–CH2),
55.6 (OCH3), 43.5 (C–(CH3)3), 33.9 (CO–CH2), 28.8
(CH–CH2), 27.1 (3C, (CH3)3), 13.8 (CH2–CH3); MS
(CI+NH3) m/z: 416 (MH++NH3), 399 (MH+), 297
(MH+–PivOH); IR (cmꢀ1, CCl4): 1738 (O–C@O), 1683
(C@O), 1229 (C@S).
We exploited this feature in order to prepare a novel
benzazepine derivative possessing a halide in the 3-posi-
tion, which would be difficult to access otherwise. When
oxime 12a was treated with an excess of PCl5 in CH2Cl2
and quenched with a suspension of NaBH4 in ethanol,
compound 26 was obtained in 48% overall yield
(Scheme 8). This molecule could, of course, be used as
starting material for the synthesis of yet another tolvap-
tan analogue.
4.1.2. Dithiocarbonic acid [1-cyanomethyl-4-(4-fluoro-
phenyl)-4-oxo-butyl] ester ethyl ester (17). A solution
of 8b (2.0 g, 7.74 mmol) and of 1.25 mL (1.03 g,
15.48 mmol) of allyl cyanide in 1,2-dichloroethane
(8 mL) was refluxed for 15 min under argon. Lauroyl
peroxide (DLP) was then added (5 mol %) to the
refluxing solution, followed by additional portions
(2 mol % every 90 min). When starting material was
totally consumed (after addition of 15 mol % of
DLP), the crude mixture was cooled to room temper-
ature, concentrated under reduced pressure and puri-
fied by flash column chromatography (silica gel,
petroleum ether–ethyl acetate, 9:1) to give 17 as a yel-
low oil (81% yield): 1H NMR (CDCl3, 400 MHz) d
7.98 (dd, 2H, CH arom, J = 8.4, 5.2 Hz), 7.14 (t,
2H, CH arom, J = 8.4 Hz), 4.63 (m, 2H, O–CH2),
4.01 (dddd, 1H, CH–S, J = 15.2, 5.3, 5.3, 5.3 Hz),
3.19 (t, 2H, CO–CH2, J = 7.2 Hz), 2.96 (t, 2H, CH2–
CN), 2.39 (ddt, 1H, CO–CH2–CH2, J = 10.9, 7.2,
4.3 Hz), 2.15 (dddd, 1H, CO–CH2–CH2, J = 18.0,
7.2, 6.8, 6.8 Hz), 1.42 (t, 3H, CH2–CH3, J = 7.0 Hz);
13C NMR (CDCl3, 100 MHz) d 212.0 (CS), 196.5
3. Conclusion
In summary, we have illustrated a useful application of
the xanthate methodology. The mild conditions of this
protocol allow the preparation of a great diversity of
functionalized benzazepines tedious to obtain by more
traditional routes. The efficiency of our approach to tol-
vaptan (2) is indicated by the good overall yield (21%),
which contrasts with the low overall yield reported for
the original route (<1%). In addition, the synthesis of
the 50-fluoro derivative 16 (20.6% overall yield) as well
as the preparation of analogues 20 and 26 underscores
its flexibility.
4. Experimental
4.1. General considerations
All reactions were carried out under an inert atmo-
sphere. Commercial reagents were used as received with-
out further purification. All products were purified by
using silica gel SDS 60 C.C. 40–63 or by crystallisation.
NMR spectra were recorded in CDCl3 with TMS as an
internal standard at room temperature on a Bruker
1
(CO), 165.9 (d, 1C, C–F, JC–F = 255.2 Hz), 132.9
(C–CO), 130.7 (d, 2C, CH arom, JC–F = 13.0 Hz),
2
3
117.1 (C„N), 115.9 (d, 2C, CH arom, JC–F
=
22.0 Hz), 70.7 (O–CH2), 46.2 (CH–S), 35.4 (CO–
CH2), 26.7 (CH2–CN), 24.5 (CO–CH2–CH2), 13.8
(CH2–CH3); MS (CI+NH3) m/z: 343 (MH++NH3),
326 (MH+), 205 (MH+–SC(S)OEt); IR (cmꢀ1, CCl4):
2250 (C„N), 1741 (C@O), 1236 (C@S).
1
AMX400 operating at 400 MHz for H and 100 MHz
for 13C. Infrared Absorption spectra were recorded as
a solution in CCl4 with a Perkin-Elmer 1600 Fourier

A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
6169
4.1.3. 2,2-Dimethyl-propionic acid 7-methoxy-4-oxo-
1,2,3,4-tetrahydro-naphthalen-1-yl ester (11c). A solution
of 10c (3.0 g, 7.50 mmol) in 1,2-dichloroethane (75 mL)
was refluxed for 15 min under argon. Lauroyl peroxide
(DLP) was then added portionwise (20 mol % per hour)
to the refluxing solution. When starting material was
totally consumed (after addition of 1.2 equiv DLP),
the crude mixture was cooled to room temperature, con-
centrated under reduced pressure and purified by flash
column chromatography (silica gel, petroleum ether–
AcOEt, 9:1 to 8:2) and recrystallised with ethanol to give
tetralone 11c (30% yield) as white crystals (mp 80 °C):
1H NMR (CDCl3, 400 MHz) d 8.06 (d, 1H, CH arom,
J = 8.0 Hz), 6.96 (dd, 1H, CH arom, J = 8.0, 4.0 Hz),
6.89 (d, 1H, CH arom, J = 4.0 Hz), 6.08 (dd, 1H, CH–
OPiv, J = 8.0, 4.0 Hz), 3.89 (s, 3H, OCH3), 2.87 (ddd,
1H, CO–CH2, J = 18.0, 9.0, 6.0 Hz), 2.66 (ddd, 1H,
CO–CH2, J = 16.0, 8.0, 4,0 Hz), 2.45–2.37 (m, 1H,
CO–CH2–CH2), 2.29–2.21 (m, 1H, CO–CH2–CH2),
1.26 (s, 9H, (CH3)3); 13C NMR (CDCl3, 100, 5 MHz)
d 195.8 (CO), 177.9 (O–CO), 164.0 (C–OMe), 143.7
(C–CO), 129.8 (CH arom), 125.5 (C–C–CO), 114.9
(CH arom), 111.9 (CH arom), 69.1 (CH–OPiv), 55.6
(OCH3), 39.1 (C–(CH3)3), 34.6 (CO–CH2), 28.8 (CO–
CH2–CH2), 27.18 (3C, (CH3)3); MS (CI+NH3) m/z:
294 (MH++NH3), 277 (MH+), 176 (MH+–PivOH); IR
(cmꢀ1, CCl4): 1731 (O–C@O), 1687 (C@O), 1146 (O–
C@O); Anal. calcd. for C16H20O4: C, 69.54; H, 7.3.
Found: C, 69.07; H, 7.27.
hydroxylamine hydrochloride (1.3 mmol) and anhyd
sodium acetate (1.2 mmol) in 0.3 mL of water. The
resulting mixture was then refluxed for 2 h. After con-
sumption of all the starting material, ethanol was evap-
orated and the resulting mixture was diluted with water,
extracted with ethyl acetate, dried over Na2SO4 and con-
centrated. The residue was purified by crystallisation to
afford the desired oximes.
4.1.6. 2,2-Dimethyl-propionic acid 4-[(E)-hydroxyimino]-
7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl ester (12a).
According to the general procedure, a solution of 1.99 g
(7.11 mmol) of tetralone 11a in 5.3 mL of ethanol is treat-
ed with a solution of NH2OH Æ HCl (0.6 g, 9.24 mmol)
and anhyd sodium acetate (1.16 g, 8.53 mmol) in water
(2.1 mL) to furnish oxime 12a as a yellow solid (96%),
mp 110–112 °C (petroleum ether): 1H NMR (CDCl3,
400 MHz) d 9.19 (br, 1H, OH), 7.86 (d, 1H, CH arom,
J = 8.0 Hz), 7.35 (d, 1H, CH arom, J = 4.0 Hz), 7.29
(dd, 1H, CH arom, J = 8.0, 4.0 Hz), 5.89 (t, 1H, CH–
OPiv, J = 4.0 Hz), 2.93 (t, 2H, C(NOH)–CH2,
J = 6.0 Hz), 2.07 (m, 2H, CH–CH2), 1.22 (s, 9H,
(CH3)3); 13C NMR (CDCl3, 100 MHz) d 178.0 (O–CO),
153.3 (C–NOH), 138.3 (C–C(NOH)), 135.6 (C–Cl),
129.0 (CH arom), 128.9 (C–CH), 128.0 (CH arom),
125.7 (CH arom), 69.0 (CH–OPiv), 39.1 (C–(CH3)3),
27.2 (3C, (CH3)3), 26.3 (C(NOH)–CH2), 19.3 (CH–CH2).
4.1.7. 2,2-Dimethyl-propionic acid 4-[(E)-hydroxyimino]-
7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl ester (12b).
According to the general procedure, a solution of
1.14 g (4.31 mmol) of tetralone 11b in 3.2 mL of ethanol
is treated with a solution of NH2OH Æ HCl (0.36 g,
5.6 mmol) and anhyd sodium acetate (0.43 g,
5.17 mmol) in water (1.3 mL) to furnish oxime 12b as
a yellow solid (92%), mp 125–128 °C (petroleum
ether): 1H NMR (CDCl3, 400 MHz) d 9.10 (br, 1H,
OH), 7.92 (dd, 1H, CH arom, J = 8.8, 6.0 Hz), 7.05
(dt, 1H, CH arom, J = 8.5, 2.5 Hz), 7.02 (dd, 1H, CH
arom, J = 8.2, 3.0 Hz), 5.89 (dd, 1H, CH–OPiv,
J = 7.0, 3.8 Hz), 2.94 (m, 2H, C(NOH)–CH2), 2.07 (m,
2H, CH–CH2), 1.23 (s, 9H, CH3); 13C NMR (CDCl3,
100 MHz) d 178.0 (O–CO), 164.7 (C–NOH), 163.5 (d,
4.1.4. 7-Fluoro-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-
yl)-acetonitrile (18). A solution of 17 (2.0 g, 6.14 mmol)
and of CSA (0.14 g, 0.61 mmol) in 1,2-dichloroethane
(61 mL) was refluxed for 15 min under argon. Lauroyl
peroxide (DLP) was then added portionwise (20 mol %
per hour) to the refluxing solution. When starting mate-
rial was totally consumed (after addition of 1.2 equiv
DLP), the crude mixture was cooled to room tempera-
ture, concentrated under reduced pressure and purified
by flash column chromatography (silica gel, petroleum
ether–AcOEt, 8:2) and recrystallised with petroleum
ether to give tetralone 18 (44% yield) as a yellow solid
1
(mp 126–128 °C): H NMR (CDCl3, 400 MHz) d 8.12
1
(dd, 1H, CH arom, J = 9.0, 5.8 Hz), 7.1 (dt, 1H, CH
arom, J = 8.2, 2.4 Hz), 7.05 (d, 1H, CH arom,
J = 9.6 Hz), 3.38 (tt, 1H, CH, J = 11.6, 6.1 Hz), 2.75–
2.83 (m, 3H, CO–CH2 and CH2–CN), 2.68 (ddd, 1H,
CH2–CN, J = 18.0, 7.4, 5.0 Hz), 2.45 (ddd, 1H, CO–
CH2–CH2, J = 19.0, 9.4, 4.6 Hz), 2.20–2.28 (m, 1H,
CO–CH2–CH2); 13C NMR (CDCl3, 100 MHz) d 194.9
1C, C–F, JC–F = 250 Hz 153.3 (C–C–(NOH)), 139.2
3
(d, 1C, CH arom, JC–2F = 8.0 Hz), 126.5 (C–CH),
116.2 (d, 1C, CH arom, JC–F = 22 Hz), 114.3 (d, 1C,
2
CH arom, JC–F = 23 Hz), 69.1 (CH–OPiv), 39.1
(C–(CH3)3), 27.2 (3C, (CH3)3), 26.4 (C(NOH)–CH2),
19.5 (CH–CH2); MS (CI+NH3) m/z: 297 (MH++NH3),
280 (MH+), 179 (MH+–OPiv); IR (cmꢀ1, CCl4): 3593
(N–OH), 1730 (O–C@O), 1279 (O–C@O).
1
(CO), 166.06 (d, 1C, C–F, JC–F = 256 Hz), 146.1
3
(C–CO), 131.3 (d, 1C, CH arom, JC–F = 10.9 Hz),
122.0 (C„ N), 117.6 (C–CCO), 115.9 (d, 1C, CH arom,
4.1.8. 2,2-Dimethyl-propionic acid 4-[(E)-hydroxyimino]-
7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl ester (12c).
According to the general procedure, a solution of 2.2 g
(0.78 mmol) of tetralone 11c in 0.6 mL of ethanol is
treated with a solution of NH2OH Æ HCl (0.07 g,
1.0 mmol) and anhyd sodium acetate (1.13 g,
0.93 mmol) in water (0.2 mL) to furnish oxime 12c as a
yellow solid (92%), mp 114–115 °C (petroleum ether):
1H NMR (CDCl3, 400 MHz) d 9.34 (br, 1H, OH), 7.86
(d, 1H, CH arom, J = 8.0 Hz), 6.90 (d, 1H, CH arom,
J = 2.0 Hz), 6.87 (dd, 1H, CH arom, J = 7.8, 2.2 Hz),
2
2JC–F = 23 Hz), 114.2 (d, 1C, CH arom, JC–F = 22 Hz),
35.1 (CH), 34.9 (CO–CH2), 27.6 (CH2–CN), 22.9 (CO–
CH2–CH2); MS (CI+NH3) m/z: 221 (MH++NH3), 204
(MH+); IR (cmꢀ1, CCl4): 2254 (C„N), 1693 (C@O),
1250 (C–F); Anal. calcd. for C12H10NOF: C, 70.93; H,
4.96; N, 6.44. Found: C, 70.53 ; H, 5.03 ; N, 6.56.
4.1.5. General procedure for the preparation of oximes.
To a stirred solution of the corresponding tetralone
(1 mmol) in ethanol (0.75 mL) was added a solution of

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A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
5.91 (dd, 1H, CH–OPiv, J = 6.0, 4.0 Hz), 3.82 (s, 3H,
OCH3), 2.93 (t, 2H, C(NOH)–CH2, J = 6.8 Hz), 2.04–
2.11 (m, 2H, CH–CH2), 1.22 (s, 9H, (CH3)3);
13C NMR (CDCl3, 100 MHz) d 178.13 (O–CO), 160.7
(C–OMe), 153.8 (C–NOH), 138.4 (C–C(NOH)), 125.8
(CH arom), 123.0 (C–CH), 115.4 (CH arom), 112.2
(CH arom), 69.6 (CH–OPiv), 55.4 (OCH3), 39.1 (C–
(CH3)3), 27.2 (3C, (CH3)3), 26.6 (C(NOH)–CH2), 19.4
(CH–CH2); MS (CI+NH3) m/z: 292 (MH+), 191
(MH+–OPiv); IR (cmꢀ1, CCl4): 3596 (N–OH), 1727
(O–C@O), 1604 (C@N–OH), 1272 (O–C@O).
oxime 12a as a white solid (40% over 3 steps), mp
65–66 °C (petroleum ether): 1H NMR (CDCl3,
400 MHz) d 7.27 (d, 1H, CH arom, J = 2.4 Hz), 7.02
(dd, 1H, CH arom, J = 8.4, 2.4 Hz), 6.64 (d, 1H, CH
arom, J = 8.8 Hz), 5.84 (d, 1H, CH–OPiv, J = 8.0 Hz),
3.83 (br, 1H, NH), 3.25 (dt, 1H, NH–CH2, J = 13.2,
4.2 Hz), 2.93 (ddd, 1H, NH–CH2, J = 13.2, 9.6,
3.2 Hz), 1.80–2.0 (m, 4H, CH–CH2 and NH–CH2–
CH2), 1.27 (s, 9H, (CH3)3); 13C NMR (CDCl3,
100 MHz) d 177.3 (O–CO), 147.5 (C–NH), 131.5
(C–Cl), 128.1 (CH arom), 127.7 (CH arom), 125.2
(C–CH), 120.8 (CH arom), 73.7 (CH–OPiv), 47.5
(NH–CH2), 41.7 (C–(CH3)3), 31.3 (CH–CH2), 27.3
(3C, (CH3)3), 27.0 (NH–CH2–CH2); MS (CI+NH3)
m/z: 284 (MH+), 282 (MH+), 184 (MH+–PivOH) 181
(MH+–PivOH); IR (cmꢀ1, CCl4): 3386 (NH), 1729
(O–C@O), 1151 (O–C@O); Anal. calcd. C15H20NO2Cl:
C, 63.94; H, 7.15. Found: C, 63.75; H, 7.15.
4.1.9. {7-Fluoro-4-[(E)-hydroxyimino]-1,2,3,4-tetrahydro-
naphthalen-1-yl}-acetonitrile (19). According to the
general procedure, a solution of 0.4 g (1.96 mmol) of
tetralone 18 in 0.9 mL of ethanol is treated with a solu-
tion of NH2OH Æ HCl (0.16 g, 2.55 mmol) and anhyd
sodium acetate (0.32 g, 2.36 mmol) in water (0.4 mL)
to furnish oxime 19 as a yellow solid (78%), mp 167–
168 °C (ethyl acetate/petroleum ether): 1H NMR
(CDCl3/DMSO–d6, 400 MHz) d 9,94 (br, 1H, OH),
7.97 (dd, 1H, CH arom, J = 8.8, 6.0 Hz), 6.93–7.0 (m,
2H, CH arom), 3.16–3.22 (m, 1H, CH), 2.96 (dt, 1H,
C(NOH)–CH2, J = 18.8, 5.2 Hz), 2.73 (m, 1H,
C(NOH)–CH2), 2.58–2.66 (m, 1H, CH2–CN), 2.05–
2.12 (m, 2H, CH–CH2); 13C NMR (CDCl3, 100 MHz)
4.1.12. 2,2-Dimethyl-propionic acid 7-fluoro-2,3,4,5-tet-
rahydro-1H-benzo[b]azepin-5-yl ester (13b). Following
the general method, this compound was obtained from
oxime 12b as a white solid (61% over 3 steps), mp 58–
1
60 °C (petroleum ether): H NMR (CDCl3, 400 MHz)
d 7.05 (dd, 1H, CH arom, J = 9.4, 3.0 Hz), 6.78 (td,
1H, CH arom, J = 8.3, 3.1 Hz), 6.68 (dd, 1H, CH arom,
J = 8.4, 4.8 Hz), 5.84 (d, 1H, CH–OPiv, J = 10.0 Hz),
3.58 (br, 1H, NH), 3.26 (dt, 1H, NH–CH2, J = 13.2,
4.2 Hz), 2.79 (td, 1H, NH–CH2, J = 11.7, 2.8 Hz),
1.7–2.0 (m, 4H, CH–CH2 and NH–CH2–CH2), 1.26 (s,
9H, (CH3)3); 13C NMR (CDCl3, 100 MHz) d 177.2
1
d 162.3 (d, 1C, C–F, JC–F = 250 Hz), 150.7 (C@NOH),
140.0 (C–C@NOH), 126.8 (C„N), 126.2 (d, 1C, CH
arom, JC–F = 7.7 Hz), 117.8 (C–CH), 114.4 (d, 1C,
3
2
CH arom, JC–F = 15.0 Hz), 113.6 (d, 1C, CH arom,
2JC–F = 23 Hz), 34.7 (CH), 24.8 (C(NOH)–CH2), 21.9
(CH2–CN), 19.1 (CH–CH2); MS (CI+NH3) m/z: 236
(MH++NH3), 219 (MH+); IR (cmꢀ1, CCl4): 3591
(N–OH), 1741 (C@N–OH), 1239 (O–C@O).
1
(O–CO), 157.7 (d, 1C, C–F, JC–F = 236 Hz), 144.4
(C–NH), 133.2 (C–CH), 120.9 (d, 1C, CH arom,
=
2
2JC–F = 7.0 Hz), 114.1 (d, 1C, CH arom, JC–F
3
7.0 Hz), 113.7 (d, 1C, CH arom, JC–F = 24 Hz), 73.6
(CH–OPiv), 47.6 (NH–CH2), 39.0 (C–(CH3)3), 32.0
(NH–CH2–CH2), 27.5 (CH–CH2), 27.3 (3C, (CH3)3);
MS (CI+NH3) m/z: 266 (MH+), 165 (MH+–OPiv);
IR (cmꢀ1, CCl4): 3385 (NH), 1729 (O–C@O), 1152
(O–C@O); Anal. calcd. for C15H20NO2F: C, 67.9; H,
7.6. Found: C, 67.93; H, 7.62.
4.1.10. General procedure for the preparation of benzaze-
pines. To a stirred suspension of PCl5 (4 mmol) in dry
CH2Cl2 (10 mL) at 0 °C was slowly added a solution
of the corresponding oxime (1 mmol) in 10 mL of dry
CH2Cl2. The mixture was stirred at room temperature
for 2 h, neutralised with saturated aqueous NaHCO3,
extracted with CH2Cl2, dried over NaSO4 and concen-
trated under reduced pressure. The residue was then dis-
solved in 10 mL of acetic acid and heated to reflux.
Then, powdered Zn (6 mmol) was slowly added to the
reaction mixture. The resulting mixture was then re-
fluxed for further 30 min. When starting material was
totally consumed, the crude mixture was diluted with
ethyl acetate, filtered through Celite, washed with satu-
rated aqueous NaHCO3 and concentrated in vacuo.
The residue was then dissolved in THF (1.5 mL) and
added dropwise to a solution of BH3 Æ THF (2 mmol)
in THF (1.5 mL) at 0°C. The resulting solution was then
refluxed for 30 min, acidified with saturated aqueous cit-
ric acid and the solvent was evaporated under reduced
pressure. The residue was then basified with saturated
aqueous Na2CO3, extracted with CH2Cl2, dried over
Na2SO4 and concentrated under reduced pressure. The
title compound is purified by flash chromatography.
4.1.13. 2,2-Dimethyl-propionic acid 7-methoxy-2,3,4,5-
tetrahydro-1H-benzo[b]azepin-5-yl ester (13c). According
to the general method, this compound was obtained
1
from oxime 12c as a yellow oil (21% over 3 steps): H
NMR (CDCl3, 400 MHz) d 6.93 (d, 1H, CH arom,
J = 2.4 Hz), 6.66–6.7 (m, 2H, CH arom), 5.87 (d, 1H,
CH–OPiv, J = 9.2 Hz), 3.76 (s, 3H, OCH3), 3.24 (dt,
1H, NH–CH2, J = 12.8 et 4.2 Hz), 2.78 (td, 1H, NH–
CH2, J = 11.7, 2.8 Hz), 1.75–2.0 (m, 4H, CH–CH2 and
NH–CH2–CH2), 1.28 (s, 9H, (CH3)3); 13C NMR (CDCl3,
100 MHz) d 189.1 (O–CO), 141.9 (C–OMe), 134.0 (C-
NH), 130.2 (C–CH), 121.0 (CH arom), 112.9 (CH arom),
112.5 (CH arom), 74.1 (CH–OPiv), 55.6 (OCH3), 48.2
(NH–CH2), 39.1 (C–(CH3)3), 32.3 (NH–CH2–CH2),
27.7 (CH–CH2), 27.4 (3C, (CH3)3); MS (CI+NH3) m/z:
278 (MH+), 177 (MH+–PivOH); IR (cmꢀ1, CCl4): 3450
(NH), 1727 (O–C@O), 1156 (O–C@O).
4.1.11. 2,2-Dimethyl-propionic acid 7-chloro-2,3,4,5-tet-
rahydro-1H-benzo[b]azepin-5-yl ester (13a). Following
the general method, this compound was obtained from
4.1.14. (7-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-
yl)-acetonitrile (20). According to the general procedure,
thiscompoundwasobtainedfromoxime19asawhitesolid

A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
6171
1
(39% over 3 steps), mp 74–75 °C (petroleum ether): H
NMR (CDCl3, 400 MHz) d6.84 (dd, 1H, CH arom,
J = 9.2, 2.4 Hz), 6.78 (td, 1H, CH arom, J = 8.2, 3.0 Hz),
6.67 (dd, 1H, CH arom, J = 8.4, 4.8 Hz), 3.59 (sl, 1H,
NH), 3.19–3.29 (m, 2H, CH and NH–CH2), 3.0 (dd, 1H,
CH2–CN, J = 16.6, 8.6 Hz), 2.81 (dd, 1H, CH2–CN,
J = 16.6, 7.4 Hz), 2.72 (ddd, 1H, NH–CH2, J = 12.6,
10.8, 2.0 Hz), 2.05–2.1 (m, 1H, NH–CH2–CH2), 1.84–
1.95 (m, 1H, NH–CH2–CH2), 1.71–1.79 (m, 2H, CH–
CH2); 13C NMR (CDCl3, 100 MHz) d 157.8 (d, 1C, C–F,
1JC–F = 241 Hz), 145.7 (C–NH), 134.4 (d, 1C, CH arom,
3JC–F = 6.0 Hz), 121.8 (C„N), 119.2 (C–CH), 116.7
(silica gel, petroleum ether–AcOEt, 9:1) and recrystal-
lised with petroleum ether to give benzazepine 20 (98%
yield) as a white solid (mp 58–60 °C): 1H NMR (CDCl3,
400 MHz) d 7.92 (d,1H, CH arom, J = 2.0 Hz), 7.77 (dd,
1H, CH arom, J = 8.2, 2.2 Hz), 7.15 (d, 1H, CH arom,
J = 8.4 Hz), 7.14 (s, 1H, CH arom), 6.85 (dd, 1H, CH
arom, J = 8.0, 2.4 Hz), 6.51 (d, 1H, CH arom,
J = 8.4 Hz), 5.95 (dd, 1H, CH–OPiv, J = 5.6, 2.6 Hz),
4.74 (dt, 1H, N–CH2, J = 14.0, 4.1 Hz), 2.81 (ddd, 1H,
N–CH2, J = 12.0, 10.1, 2.1 Hz), 2.49 (s, 3H, Ar–CH3),
2.09–2.19 (m, 2H, N–CH2–CH2), 1.67–1.82 (m, 2H,
CH–CH2), 1.29 (s, 9H, CH3); 13C NMR (CDCl3,
100 MHz) d 177.2 (O–CO), 167.9 (N–CO), 147.7 (C–
NO2), 141.8 (C–N), 140.2 (C–CO), 137.6 (C–Cl), 137.4
(C–CH), 134.28 (C–CH3), 128.9 (CH arom), 128.0
(CH arom), 127.6 (CH arom), 125.3 (CH arom), 124.6
(CH arom), 121.0 (CH arom), 71.8 (CH–OPiv), 46.6
(N–CH2), 39.14 (C–(CH3)3), 32.0 (N–CH2–CH2), 27.3
(3C, (CH3)3), 25.4 (CH–CH2), 20.2 (Ar–CH3); MS
(CI+NH3) m/z: 465 (MH++NH3), 463 (MH++NH3),
447 (MH+), 445 (MH+), 346 (MH+–PivOH), 344
(MH+–PivOH); IR (cmꢀ1, CCl4): 1735 (O–C@O), 1659
(N–C@O), 1529 (NO2), 1139 (O–C@O).
2
(d, 1C, CH arom, JC–F = 22.1 Hz), 114.2 (d, 1C, CH
arom, 2JC–F = 19.1 Hz), 48.9 (NH–CH2), 42.5 (CH), 29.9
(CH2–CN), 26.1 (NH–CH2–CH2), 19.1 (CH–CH2); MS
(CI+NH3) m/z: 205 (MH+); IR (cmꢀ1, CCl4): 3384 (NH),
2246 (C„N), 1253 (O–C@O); Anal. calcd. for C12H13
N2F: C, 70.57; H, 6.42. Found: C, 70.42 ; H, 6.55.
4.1.15. 2,2-Dimethyl-propionic acid 3,3,7-trichloro-
2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester (26). To
a stirred suspension of PCl5 (0.28 g, 1.35 mmol) in dry
CH2Cl2 (1,5 mL) at 0 °C was slowly added a solution
of oxime 12a (0.1 g, 0.34 mmol) in 1.5 mL of dry
CH2Cl2. The mixture was stirred at room temperature
for 2 h. The solution was then cooled at 0 °C and a sus-
pension of NaBH4 (0.13 g, 3.38 mmol) in ethanol
(0.3 mL) was added dropwise. When starting material
was completely consumed, water was added and the
reaction mixture was extracted with CH2Cl2, dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography
(silica gel, petroleum ether–AcOEt, 95:5) and recrystal-
lised with petroleum ether to give benzazepine 20 (48%
yield over 2 steps) as a white solid (mp 103–104 °C):
1H NMR (CDCl3, 400 MHz) d 7.21 (d, 1H, CH arom,
J = 2.0 Hz), 7.10 (dd, 1H, CH arom, J = 8.8, 2.4 Hz),
6.72 (d, 1H, CH arom, J = 8.4 Hz), 6.03 (t, 1H, CH–
OPiv, J = 5.6 Hz), 4.22 (br, 1H, NH), 3.75 (dd, 1H,
CH–CH2, J = 14.8, 6.8 Hz), 3.57 (d, 1H, CH–CH2,
J = 14.0 Hz), 3.86 (d, 2H, NH–CH2, J = 4.0 Hz), 1.29
(s, 9H, (CH3)3); 13C NMR (CDCl3, 100 MHz) d 177.0
(O–CO), 145.2 (C–NH), 142.3 (C–Cl), 128.5 (CH
arom), 128.2 (CH arom), 126.6 (C–CH), 121.0 (CH
arom), 88.4 (CCl2), 69.2 (CH–OPiv), 61.6 (NH–CH2),
50.1 (CH–CH2), 39.0 (C–(CH3)3), 27.3 (3C, (CH3)3);
MS (CI+NH3) m/z: 352 (MH+), 350 (MH+), 250
(MH+–PivOH), 248 (MH+–PivOH); IR (cmꢀ1, CCl4):
3446 (NH), 1735 (O–C@O), 1139 (O–C@O); Anal.
calcd. for C15H18NO2Cl3:C, 51.38; H, 5.17. Found: C,
51.31; H, 5.16.
4.1.17. 2,2-Dimethyl-propionic acid 7-fluoro-1-(2-methyl-
4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-
yl ester (14b). Using the same procedure as 14a, benzaze-
pine 14b (97%) was obtained from 13b (0.05 g,
0.18 mmol) as
a
yellow oil: 1H NMR (CDCl3,
400 MHz) d 7.98 (d, 1H, CH arom, J = 2.4 Hz), 7.82
(dd, 1H, CH arom, J = 8.6, 2.6 Hz), 7.22 (d, 1H, CH
arom, J = 8.8 Hz), 6.94 (d, 1H, CH arom, J = 8.8 Hz),
6.63 (d, 1H, CH arom, J = 5.2 Hz), 6.63 (s, 1H, CH
arom), 6.03 (dd, 1H, CH–OPiv, J = 11.4, 3.0 Hz), 4.81
(dt, 1H, N–CH2, J = 13.6, 4.2 Hz), 2.88 (td, 1H, N–
CH2, J = 12.1, 2.0 Hz), 2.56 (s, 3H, Ar–CH3), 2.16–
2.25 (m, 2H, N–CH2–CH2), 1.75–1.9 (m, 2H,
CH–CH2), 1.36 (s, 9H, CH3); 13C NMR (CDCl3,
100 MHz) d 177.2 (O–CO), 168.04 (N–CO), 162.04 (d,
1
1C, C–F, JC–F = 248 Hz), 147.7 (C–NO2), 142.0 (C–
N), 137.6 (C–CO), 134.8 (C–CH), 129.4 (d, 1C, CH
2
arom, JC–F = 10.5 Hz), 127.5 (CH arom), 125.2 (d,
2
1C, CH arom, JC–F = 4.2 Hz), 120.9 (CH arom),
120.2 (CH arom), 114.8 (C–CH3), 111.6 (d, 1C, CH
arom, JC–F = 28.0 Hz), 72.0 (CH–OPiv), 46.6 (N–
3
CH2), 39.1 (C–(CH3)3), 32.1 (N–CH2–CH2), 27.3 (3C,
(CH3)3), 25.5 (CH–CH2), 19.9 (Ar–CH3); MS (CI+NH3)
m/z: 446 (MH++NH3), 429 (MH+), 326 (MH+–PivOH);
IR (cmꢀ1, CCl4): 1735 (O–C@O), 1659 (N–C@O), 1529
(NO2), 1346 (NO2), 1139 (O–C@O).
4.1.18. 2,2-Dimethyl-propionic acid 1-(4-amino-2-methyl-
benzoyl)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-
5-yl ester (15a). To a solution of 14a (0.15 g, 0.34 mmol)
and HCl (0.2 mL) in ethanol (6 mL) at reflux was added
SnCl2 (0.32 g, 1.68 mmol). The mixture was refluxed for
2 h, cooled at room temperature, basified with saturated
aqueous Na2CO3, extracted with ethyl acetate, dried
over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatogra-
phy (silica gel, petroleum ether–AcOEt, 4:1) and recrys-
tallised with petroleum ether to give compound 15a
(82% yield) as a white solid (mp 185–186 °C): 1H
4.1.16. 2,2-Dimethyl-propionic acid 7-chloro-1-(2-methyl-
4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-
yl ester (14a). A solution of 2-methyl-4-nitrobenzoyl
chloride (0.21 g, 1.06 mmol) in CH2Cl2 (2 mL) was add-
ed dropwise to an ice-cooled solution of benzazepine 13a
(0.1 g, 0.35 mmol) and triethylamine (2 mL, 0.14 g,
1.41 mmol) in CH2Cl2. The mixture was stirred at room
temperature for 1 h, neutralised with saturated aqueous
Na2CO3, extracted with ethyl acetate, dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography

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A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
NMR (CDCl3, 400 MHz) d 7.22 (s, 1H, CH arom), 6.93
(d, 1H, CH arom, J = 8.0 Hz), 6.73 (d, 1H, CH arom,
J = 8.0 Hz), 6.56 (d, 1H, CH arom, J = 8.0 Hz), 6.4–
6.46 (m, 2H, CH arom), 6.22 (d, 1H, CH arom,
J = 8.0 Hz), 6.02 (d, 1H, CH–OPiv, J = 7.4 Hz), 4.84
(d, 1H, N–CH2, J = 8.4 Hz), 3.7 (br, 2H, NH), 3.78 (t,
1H, N–CH2, J = 12.0 Hz), 2.37 (s, 3H, Ar–CH3), 2.05–
2.21 (m, 2H, N–CH2–CH2), 1.68–1.77 (m, 2H, CH–
CH2), 1.35 (s, 9H, CH3); 13C NMR (CDCl3, 100 MHz)
d 177.1 (O–CO), 170.4 (N–CO), 147.1 (C–NCO), 139.3
(C–NH2), 137.7 (C–CO), 132.6 (C–Cl), 129.6 (CH
arom), 128.7 (CH arom), 127.7 (CH arom), 125.6
(C–CH), 124.2 (CH arom), 116.6 (CH arom), 114.3
(C–CH3), 111.9 (CH arom), 72.1 (CH–OPiv), 46.2 (N–
CH2), 39.0 (C–(CH3)3), 32.0 (N–CH2–CH2), 27.3 (3C,
(CH3)3), 25.6 (CH–CH2), 20.1 (Ar–CH3); MS (CI+NH3)
m/z: 433 (MH++NH3), 432 (MH++NH3), 416 (MH+),
414 (MH+), 315 (MH+–PivOH), 313 (MH+–PivOH);
IR (cmꢀ1, CCl4): 3400 (NH2), 1734 (O–C@O), 1651
(N–C@O), 1142 (O–C@O).
225.9 °C) whose spectroscopic and analytical data were
identical to those reported in the literature.
4.1.21. Fluoro-Tolvaptan (16). Using the same procedure
as 2, compound 16 (quantitative yield) was obtained
from 15b (0.04 g, 0.10 mmol) as a white solid (mp
1
196–198 °C): H NMR (CDCl3, 400 MHz) d 10.4 (br,
1H, NH), 7.70 (s,1H, CH arom), 7.4–7.63 (m, 6H, CH
arom), 6.91–7.0 (m, 3H, CH arom), 5.92 (br, 1H, OH),
5.88 (d, 1H, CH–OH, J = 4.0 Hz), 5.06 (d, 1H, N–
0
CH2, J = 10.0 Hz), 4.81 (d, 1H, N–CH2 , J = 13.2 Hz),
2.83 (t, 1H, N–CH2–CH2, J = 12.0 Hz), 2.53–2.56 (m,
1H, N–CH2–CH2), 2.50 (s, 6H, Ar–CH3), 2.25–2.26
(m, 1H, CH–CH2), 1.90–1.92 (m, 1H, CH–CH2 ); 13C
0
NMR (CDCl3, 100 MHz) d 167.8 (N–CO), 167.3
(N–CO), 160.8 (d, 1C, C–F, JC–F = 243 Hz), 145.6
1
(C–NCO), 139.2 (C–NCO), 136.9 (C–C(O)N), 136.0
(C–C(O)N), 135.8 (C–CH), 135.2 (C–CH3), 131.5
(C–CH3), 130.4 (CH arom), 129.5 (d, 1C, CH arom,
3JC–F = 13.0 Hz), 128.2 (CH arom), 127.1 (CH arom),
126.3 (CH arom), 125.6 (CH arom), 120.8 (CH arom),
=
2
115.8 (CH arom), 113.3 (d, 1C, CH arom, JC–F
4.1.19. 2,2-Dimethyl-propionic acid 1-(4-amino-2-methyl-
benzoyl)-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl
ester (15b). Using the same procedure as 15a, compound
15b (78%) was obtained from 14b (0.05 g, 0.13 mmol)
2
23.1 Hz), 111.7 (d, 1C, CH arom, JC–F = 26.1 Hz),
69.5 (CH–OH), 45.8 (N–CH2), 35.4 (N–CH2–CH2),
25.8 (CH–CH2), 19.6 (Ar–CH3), 19.2 (Ar–CH3); MS
(CI+NH3) m/z: 433 (MH+); IR (cmꢀ1, CCl4): 3490
(OH), 1640 (N–C@O), 1623 (N–C@O).
1
as a colourless oil: H NMR (CDCl3, 400 MHz) d 6.95
(d, 1H, CH arom, J = 9.6 Hz), 6.73 (d, 1H, CH arom,
J = 8.0 Hz), 6.56–6.66 (m, 2H, CH arom), 6.39 (s, 1H,
CH arom), 6.20 (d, 1H, CH arom, J = 8.4 Hz), 6.03
(d, 1H, CH–OPiv, J = 10.4 Hz), 4.84 (d, 1H, N–CH2,
J = 13.6 Hz), 3.71 (br, 2H, NH2), 2.77 (t, 1H, N–CH2,
J = 12.2 Hz), 2.36 (s, 3H, Ar–CH3), 2.13–2.15 (m, 2H,
N–CH2–CH2), 1.69–1.84 (m, 2H, CH–CH2), 1.34 (s,
Acknowledgments
We thank CONACYT (Mexico) and CNRS (France)
for its generous financial support to A.C.-V.
9H, CH3); 13C NMR (CDCl3, 100 MHz) d 177.1 (O–
1
CO), 170.5 (N–CO), 161.3 (d, 1C, C–F, JC–F
=
247 Hz), 150.3 (C–NCO), 147.0 (CH arom), 140.1
(C–NH2), 137.6 (C–CO), 129.9 (C–CH), 128.5 (CH
arom), 116.5 (d, 1C, CH arom, JC–F = 12.6 Hz), 114.4
References and notes
2
1. Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.;
Gussio, R.; Sausville, E. A.; Meijer, L.; Kunick, C. J. Med.
Chem. 1999, 42, 2909.
2
(d, 1C, CH arom, JC–F = 6.0 Hz), 112.2 (C–CH),
=
3
111.1 (C–CH3), 110.7 (d, 1C, CH arom, JC–F
26 Hz), 72.2 (CH–OPiv), 46.2 (N–CH2), 39.0 (C–
(CH3)3), 32.2 (N–CH2–CH2), 27.3 (3C, (CH3)3), 25.7
(CH–CH2), 19.3 (Ar–CH3); MS (CI+NH3) m/z: 399
(MH+), 298 (MH+–PivOH); IR (cmꢀ1, CCl4): 3399
(NH2), 1734 (O–C@O), 1649 (N–C@O), 1148 (O–C@O).
2. (a) Watthey, J. W. H.; Gavin, T.; Desai, M. J. Med. Chem.
1984, 27, 816; (b) Watthey, J. W.; Stanton, J. L.; Desai,
M.; Babiarz, J. E.; Finn, B. J. Med. Chem. 1985, 28, 1511.
3. (a) Hori, M.; Fujimura, H.; Masuda, T.; Sawa, Y.
Yakugaku Zasshi 1975, 95, 131; (b) Sawa, Y.; Kato, T.;
Morimoto, T.; Hori, M.; Fujimura, H. Yakugaku Zasshi
1975, 95, 261; (c) Sawa, Y.; Kato, T.; Masuda, T.; Hori,
M.; Fujimura, H. Chem. Pharm. Bull. 1975, 23, 1917.
4. (a) Albright, J. D.; Reich, M. F.; Delos Santos, E. G.;
Dusza, J. P.; Sum, F.-K.; Venkatesan, A. M.; Coupet, J.;
Chan, P. S.; Ru, X.; Mazandarani, H.; Bailey, T. J. Med.
Chem. 1998, 41, 2442; (b) Kondo, K.; Ogawa, H.;
Shinohara, T.; Kimura, M.; Tanada, Y.; Kan, K.;
Yamashita, H.; Nakamura, S.; Hirano, T.; Yamamura,
Y.; Mori, T.; Tominaga, M.; Itai, A. J. Med. Chem. 2000,
43, 4388; (c) Matsubara, J.; Kitano, K.; Otsubo, K.;
Kawano, Y.; Ohtani, T.; Bando, M.; Kido, M.; Uchida,
M.; Tabusa, F. Tetrahedron 2000, 56, 4667; (d) Kondo, K.;
Kan, K.; Tanada, Y.; Bando, M.; Shinohara, T.; Kurim-
ura, M.; Ogawa, H.; Nakamura, S.; Hirano, T.; Yamam-
ura, Y.; Kido, M.; Mori, T.; Tominaga, M. J. Med. Chem.
2002, 45, 3805.
4.1.20. Tolvaptan (2). A solution of 2-methylbenzoyl
chloride (0.05 g, 0.30 mmol) in CH2Cl2 (1 mL) was added
dropwise to an ice-cooled solution of benzazepine 15a
(0.05 g, 0.12 mmol) and triethylamine (0.07 mL, 0.05 g,
0.48 mmol) in CH2Cl2 (1 mL). The mixture was stirred
at room temperature for 1 h, neutralised with saturated
aqueous Na2CO3, extracted with ethyl acetate, dried over
Na2SO4 and concentrated under reduced pressure. The
crude mixture was then dissolved in ethanol (1.5 mL)
and 2 mL of a 2 N NaOH aqueous solution was added
to the solution. The resulting solution was then heated
at 50 °C for 2 h and cooled to room temperature. Water
was then added to the reaction mixture and the insoluble
material was removed by filtration. The solid thus ob-
tained was washed with cold water and recrystallised
from methanol/diethyl ether to furnish compound 1
(85% over 2 steps) as a white solid: mp 220–221 °C (lit.
5. (a) Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.;
Tanaka, M.; Nayaka, K.; Kitano, K.; Yamamura, Y.;
Nakamura, S.; Onogawa, T.; Mori, T.; Tominaga, M.

A. Cordero-Vargas et al. / Bioorg. Med. Chem. 14 (2006) 6165–6173
6173
´
Bioorg. Med. Chem. 1999, 7, 1743; (b) Matsubara, J.;
Morita, S.; Yamashita, H.; Otsubo, K.; Kitano, K.;
Ohtani, T.; Kawano, Y.; Bando, M.; Kido, M.; Uchida,
M.; Tabusa, F. Heterocycles 2001, 54, 131; (c) Yamashita,
H.; Ohtani, T.; Morita, S.; Otsubo, K.; Kan, K.; Matsu-
bara, J.; Kitano, K.; Kawano, Y.; Uchida, M.; Tabusa, F.
Heterocycles 2002, 56, 123; (d) Sorbera, L. A.; Castan˜er,
9. Cordero-Vargas, A.; Perez-Martin, I.; Quiclet-Sire, B.;
Zard, S. Z. Org. Biomol. Chem. 2004, 2, 3018.
10. Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Tetra-
hedron Lett. 2004, 45, 7335.
11. Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Org.
Lett. 2003, 20, 3717.
12. (a) Zard, S. Z. Angew. Chem. Int. Ed. Engl. 1997, 36, 672;
(b) Zard, S. Z. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M., Eds.; Wiley, VCH: Weinheim, 2001; pp
90–108.
13. Gagosz, F.; Zard, S. Z. Org. Lett. 2002, 4, 4345.
14. (a) Francis, W. C. et al. J. Am. Chem. Soc. 1958, 80, 6238;
(b) Sugg, E. E. et al. J. Org. Chem. 1985, 50, 5032.
15. Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912.
16. Bhat, A.; Chang, H.-M.; Wallace, L. J.; Weinstein, D. M.;
Shams, G.; Garris, C. C.; Hill, R. A. Bioorg. Med. Chem.
1998, 6, 271.
17. (a) Hattori, K.; Matsumura, Y.; Miyazaki, T.; Maruoka,
K.; Yamamoto, H. J. Am. Chem. Soc. 1981, 103, 7368; (b)
Sasatani, S.; Miyazaki, T.; Maruoka, K.; Yamamoto, H.
Tetrahedron Lett. 1983, 24, 4711.
´
J.; Bayes, M.; Silvestre, J. Drugs Fut. 2002, 27, 350.
6. Ogawa, H.; Yamashita, H.; Kondo, K.; Yamamura, Y.;
Miyamoto, H.; Kan, K.; Kitano, K.; Tanaka, M.;
Nayaka, K.; Nakamura, S.; Mori, T.; Tominaga, M.;
Yabuuchi, Y. J. Med. Chem. 1996, 39, 3547.
7. (a) Meyers, A. I.; Hutchings, R. H. Tetrahedron 1993, 34,
1807; (b) Nicholls, I. A.; Alewood, P. F. Bioorg. Chem.
1994, 22, 300; (c) Lowe, J. A.; Hageman, D. L.; Drozda, S.
E.; McLean, S.; Bryce, D. K.; Crawford, R. T.; Zorn, S.;
Morrone, J.; Bordner, J. J. Med. Chem. 1994, 37, 3789;
For a review on the Beckmann reaction, see: (d) Gawley,
R. E. Org. React. 1988, 35, 1.
8. Liard, A.; Quiclet-Sire, B.; Saicic, R.; Zard, S. Z.
Tetrahedron Lett. 1997, 38, 1759.