An easy access to the exocyclic lactams analogous of the central nervous system active tricyclic nitroxapine, mianserine and chlothiapine agents using N-acyliminium chemistry

Article abstract of DOI:10.3987/COM-08-S(N)97

The conformationally restrained dibenzothia(oxa)zepines and dibenzazepines 4-6 analogous to the antidepressant Sintamil were prepared easily by π-cationic cyclization of the N-acyliminium ions 9A-C precursors with neat trifluoroacetic acid in three step-sequence starting from available amines and anhydrides. The regioselectivity in the reduction of imides especially in the maleimide derivatives as well as in the cyclization step was also discussed.

Full text of DOI:10.3987/COM-08-S(N)97

HETEROCYCLES, Vol. 76, No. 2, 2008
1017
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1017 - 1022. © The Japan Institute of Heterocyclic Chemistry
Received, 30th March, 2008, Accepted, 19th May, 2008, Published online, 26th May, 2008. COM-08-S(N)97
AN EASY ACCESS TO THE EXOCYCLIC LACTAMS ANALOGOUS OF
THE CENTRAL NERVOUS SYSTEM ACTIVE TRICYCLIC
NITROXAPINE, MIANSERINE AND CHLOTHIAPINE AGENTS USING
N-ACYLIMINIUM CHEMISTRY
Abderrahmane Hadou,a,b Abdulkareem Hamid,a Hilarion Mathouet,a
Mohamed-Fadel Deïda,b and Adam Daïch a,*
a URCOM, EA 3221, UFR of Sciences & Techniques, University of Le Havre, BP
540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
b LCME, Faculty of Sciences & Techniques, University of Nouakchott, BP 5062,
Mauritania. E.mail : adam.daich@univ-lehavre.fr
Abstract – The conformationally restrained dibenzothia(oxa)zepines and dibenz-
azepines 4-6 analogous to the antidepressant Sintamil® were prepared easily by
π-cationic cyclization of the N-acyliminium ions 9A-C precursors with neat
trifluoroacetic acid in three step-sequence starting from available amines and
anhydrides. The regioselectivity in the reduction of imides especially in the
maleimide derivatives as well as in the cyclization step was also discussed.
INTRODUCTION
Dibenzothia(oxa)zepines are important and widely used scaffolds in medicinal chemistry. For example,
Methiapine (1a) and Clothiapine (1b) are reported as anti-psychoneurotics1 and their oxygenated
derivatives Defanyl® (2a),2 Sintamil® (2c)3 and Loxpine (2b)4 are also efficient as antidepressants and
antipsychotics, respectively. In addition, other analogous have also shown remarkable activities as a
non-nucleoside type inhibitors of wild type HIV-1 replication.5 The dibenzothiazepine Seroguel related to
products 1a,b, exerts and increasing 5-HT2 affinity relative to the so popular Clozapine and possibly a
lower potential for causing agranulocytosis,6 constitutes also another interesting example. Also,
dibenzodiazepines Perlapine (3a) and Mianserine (3b), as the carbon-analogous of the latter structures,
were used for their hypnotic and sedative properties and for the treatment of depressions associated or not
with the anxiety. As a consequence, new methods enabling the efficient preparation of libraries based on
these scaffolds should be useful for lead generation of various drug discovery programs.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Chart 1. Representative active dibenzothiazepines 1a,b, dibenzoxazepines 2a-c, dibenzazepines 3a,b
and our targets 4-6.
O
N
S
O
N
NO2
R1
Cl
N
N
O
N
N
N
N
N
N
H2N
.HCl
2c: Nitroxapine
(Sintamil®)
R2
3a: Perlapine
1a: R1=Me Methiapine
1b: R1=Cl Clothiapine
2a: R2=H Amoxapine
2b: R2=Me Loxapine
X
N
X
N
X
N
N
R3
R3
R3
N
X=S, O, CH2
R3=H, Cl
O
O
O
5: Our targets
4: Our targets
6: Our targets
3b: Mianserine
RESULTS AND DISCUSSION
In our group we are interested in the development of simple approaches towards aza-heterocyclic systems
containing benzo(thia and oxa)azepines moieties with promising pharmaceutical activities. Our objective
herein was to construct the conformationally restrained products 4-6 analogous to Sintamil® (2c) and the
use of N-acyliminium chemistry to provide these targets in an efficient and concise manner seemed to be
a valuable strategy. In fact, in association with our recent reports using N-acyliminium cyclization in
tandem with Grignard reaction7 and heterocyclization processes,8 we reasoned that a suitably substituted
N-acyliminium precursor of type I could allow a facile approach to the title targets 4-6 (Scheme 1).
Scheme 1. Retrosynthetic scheme leading to the tetracyclic targets 4-6.
O
R=H,Me
X
N
X
N
X
X
O
R
+
O
R3
R3
N
+
NH2
8a-d
R3
9A-C
O
7A-C
O
O
R
R
O
R3
I
4-6
R
First, the synthesis of the required N-acyliminium ions precursors of type 10 was accomplished by a
two-step sequence as outlined in Scheme 2. The N-alkylated imides 9 as starting materials are not
commercially available but were prepared easily according to known procedures from anhydrides 7A-C
and amines 8a-d by thermal amino-anhydride condensation in refluxing acetic acid for 48 h (40-99%).
Reduction of imides 9Aa (X=O) and 9Ab (X=S) was performed with a large excess of NaBH4 (3-6
equiv.) in dry EtOH at 0 °C for a short time (1 h). Under these conditions, only the opened alcohol-amides
10A(a,b)U were isolated in excellent yields (Table 1). Interestingly, the reaction profile was inverted
giving the expected hydroxyl-lactams 10A(a,b)V when Zn(BH4)2 was used instead of NaBH4 under

HETEROCYCLES, Vol. 76, No. 2, 2008
1019
conditions ii (Scheme 2).9 The yields were however lower (61 and 66%, respectively) than those obtained
for 10A(a,b)U under conditions i. Further, all attempts of reduction of imides 9B(a,b) to access hydroxyl-
lactams 10B(a,b) by using conditions i but at 0-5 °C failed since only succinimide derivatives 9A(a,b)
were isolated in high yields average 90% in both cases. The regioselective reduction of one function of
the imides 9B(a-d) was ultimately accomplished under mild conditions with NaBH4 in MeOH at 0 °C for
1-2 h (monitored by TLC using a silica gel plate and cyclohexane/AcOEt as the eluting mixture) in the
presence of CeCl3.7H2O (40-99% yield).10 By using the same protocol, the imides 9C(a-d) provided only
α-hydroxy-lactams 10C(a-d) in yields ranging from 40 to 83%. In all cases no opened alcohol-amides
were detected in the crude reaction mixture but we observe the formation of two regioisomers in 9:1
(10CaU,V; 60% yield) and 8:2 (10CdU,V; 40% yield) ratios in favor of 10C(a,d)V in which the
hydroxyl function is near the methyl group at C4-position of the 1,5-dihydropyrrol-2-one nuclei. These
results are in accordance with those published by us11 and others12 for related structures.
Scheme 2. Scheme leading to α-hydroxy-lactams 10 precursors of the tetracyclic systems.
O
X
X
X
X
AcOH
O
+
R
O
O
O
reflux, 48 h
N
N
N
NH2
8a-d
R3
R3
R3
O
O
O
O
R3
(i) NaBH4
EtOH
9B(a-d)
7A-C
9A(a,b)
9C(a-d)
0 °C, 1 h
NaBH4, EtOH
0 - 5 °C
CeCl3.7H2O
NaBH4, 0 °C
MeOH, 1-2 h
(ii) Zn(BH4)2
7A: succinic anhydride
7B: maleic anhydride
7C: citraconic anhydride
EtOH, 0 °C, 2 h
X
X
X
X
N° X R3
OH
OH
OH
OH
a
b
c
O
S
H
H
Cl
H
N
N
N
O
NH
R3
R3
R3
R3
S
O
10A(a,b)V
O
O
d
CH2
10B(a-d)
10A(a,b)U
10C(a-d)U,V
Table 1. Imides 10 and corresponding α-hydroxy-lactams 10.
Imide 9A Alcool- Hydroxy- Imide 9B Hydroxy- Imide 9C
Hydroxy-lactams
amide
lactam
lactam
10CUc,d and 10CVc,d
Product
10AUb
10AVb
10B
Yield (%) Yield (%) Yield (%) Yield (%) Yield (%) Yield (%)
Yield (%), Ratio
a (X=O)
b (X=S)
93
95
89 (0)
93 (0)
0 (61)
0 (66)
61
64
58
65
81
69
47
74
93
90
40
99
68
47
83
40
(80/20)
(100/0)
(100/0)
(90/10)
a
a
a
c (X=S)
-
-
-
a
a
a
d (X=CH2)
-
-
-
a The reaction was not performed in this case. b Conditions i lead only to alcohol-amides 10A(a,b)U while
conditions ii provided exclusively α-hydroxy-lactams 10A(a,b)V. c The ratio of products was determined
by 1H NMR spectroscopy. d Yields of the reaction are in % and the ratios are given in parentheses.

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Having established earlier the capacity of trifluoroacetic acid to promote the capture of an N-acyliminium
ion in an intramolecular manner with an array of nucleophiles,7,8 o-phenyoxy(thio)-N-phenylamidals and
o-benzyl-N-phenylamidals of type 10 (Scheme 3) were subjected to this general π-cyclization protocol
(neat TFA, room temperature).13 Under these conditions, α-hydroxy-lactams 10A,B provided a cyclized
lactams 4a,b14 and 5a-d15 with the intermediacy of species I (Scheme 1). In the tetracyclic system 5a-d,
the double bond of the dihydropyrrole ring is in conjugation with the benzene ring in accordance with our
own earlier observations.11 Interestingly, under same conditions a mixture of 10C(a-d)U and 10C(a-d)V
led to the expected products 6U and 6V in moderate to very good yields (Table 2). These products, which
in case of 6(a,b)U16 and 6(a,b)V were separable easily by flush chromatography on silica gel column,
were obtained in yields ranging from 46 to 84% (Table 2). The structure of these products as well as all
13
reported in this paper was supported by NMR (1H, C, Dept) spectroscopic analysis. In fact, the NMR
studies demonstrate that lactams 6(a,c,d)U appeared in less conjugated form (proved by the presence of
an angular proton in the 1H NMR spectra) except in the case of 6bU (form L) while lactams 6(a,b)V exist
only in the more conjugated form as mentioned above for the corresponding lactams 5a-d.
Scheme 3. π-Cyclization of α-hydroxy-lactams 10 into the tetracyclic systems 4-6.
S
X
X
X
X
OH
OH
OH
+
O
N
N
N
N
N
R3
R3
R3
R3
O
O
O
HO
O
10A(a,b)V
10B(a-d)
6bU form K
10C(a-d)U
10C(a-d)V
TFA, ta
12 h
TFA, ta
12 h
TFA, ta
12 h
45-66%
46-84%
84%,87%
X
N
X
X
N
X
N
S
R3
R3
N
R3
R3
N
O
O
O
O
O
4a,b
6(a,c,d)U
5a-d
6(a,b)V
6bU form L
Table 2. Yields and melting points of the tetracyclic systems 4-6.
Cyclic product 4 Cyclic product 5 Cyclic product 6U Cyclic product 6V
Product
index
a (X=O)
Yield (%), mp (°C) Yield (%), mp (°C) Yield (%), mp (°C) Yield (%), mp (°C)
84 , 127
64 , 115
57 , 207
66 , 172
45 , 181
65b , 159
84c , 207
71 , 129
46 , 155
65b , 172
84c , 170
b (X=S)
c (X=S)
87 , 144
a
d
-
-
a
d
d (X=CH2)
-
-
a No reaction was performed in this case. b The separable regioisomers were obtained in 9/1 ratio in favor
of 6aU. c The separable regioisomers were obtained in 8/2 ratio in favor of 6bU. d Products not obtained.

HETEROCYCLES, Vol. 76, No. 2, 2008
1021
In summary, we have developed efficient and versatile method for the synthesis of conformationally
constrained 4-6 analogous to the antidepressant Sintamil® in three step-sequence starting from easily
available substrates. The key step of this sequence was the trifluoroacetic acid-catalyzed intramolecular
π-cationic cyclization and significant structural variation via the heteroelement (X=O, S, CH2) as an
N-acyliminium source was also realized.
ACKNOWLEDGEMENTS
The authors are grateful to the AUF (Agence Universitaire de la Francophonie) Graduate Fellowship
(2005/2006) attributed to one of us, A. Hadou and the University of Le Havre for supporting this work.
REFERENCES AND NOTES
1. K. Yamamoto, J. Koyanagi, I. Horie, M. Ogawa, K. Sakuma, and A. Tanaka, Chem. Pharm. Bull.,
1995, 43, 2064; M. Ogawa, J. Koyanagi, K. Sakuma, A. Tanaka, and K. Yamamoto, J. Heterocycl.
Chem., 1999, 36, 819.
2. N. Cailleux, I. Marie, C. Noblet, N. D. Moore, L. Verdure, H. Lévesque, and H. Courtois, La Revue
de Médecine Interne, 1998, 19, 139.
3. K. Nagarajan, A. Venkateswarlu, C. L. Kulkarni, G. A. Nagana, and R. K. Shah, Indian J. Chem.,
1974, 12, 236; K. Nagarajan, J. Indian Chem. Soc., 1997, 74, 931; K. Nagarajan, J. David, Y. S.
Kulkarni, S. B. Hendi, S. J. Shenoy, and P. Upadhyaya, Eur. J. Med. Chem., 1986, 21, 21.
4. Y. Liao, B. J. Venhuis, N. Rodenhuis, W. Timmerman, and H. Wikström, J. Med. Chem., 1999, 42,
2235.
5. For example, see: P. Storck, A.-M. Aubertin, and D. S. Grierson, Tetrahedron Lett., 2005, 46, 2919.
6. Drug treatment of schizophrenia has advanced significantly with the discovery of Clozapine but
unfortunately causes agranulocytosis. For this end, see: J. A. Lowe, Curr. Med. Chem., 1994, 1, 50.
7. A. Chihab-Eddine, A. Daïch, A. Jilale, and B. Decroix, Heterocycles, 2002, 58, 449; T. Bousquet,
J.-F. Fleury, A. Daïch, and P. Netchitaïlo, Tetrahedron, 2006, 62, 706 and references therein.
8. A. Mamouni, A. Daïch, Š. Marchalín, and B. Decroix, Heterocycles, 2001, 54, 275; J. Sikoraiová, Š.
Marchalín, A. Daïch, and B. Decroix, Tetrahedron Lett., 2002, 43, 4747; N. Hucher, A. Pesquet, P.
Netchitaïlo, and A. Daïch, Eur. J. Org. Chem., 2005, 2758 and references therein.
9. For the preparation of Mg(BH4)2, see: M. Fieser, and L. Fieser, Reagents Org. Synth., 1972, 3, 337.
10. A. L. J. Beckwith, and D. R. Boate, J. Org. Chem., 1988, 53, 4339; N. Mase, T. Nishi, M. Hiyoshi, K.
Ichihara, J. Bessho, H. Yoda, and K. Takabe, J. Chem. Soc., Perkin Trans. 1, 2002, 707.
11. F. Pin, S. Comesse, B. Garrigues, Š. Marchalín, and A. Daïch, J. Org. Chem., 2007, 72, 1181.
12. For recent paper in this area, see: W. Zhang, L. Huang, and J. Wang, Synthesis, 2006, 2053.

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13. General procedure for cyclization of hydroxy-lactams 10. Neat TFA (10 mL) was added to a stirred
solution of the hydroxyl-lactam (10, 10 mmol), obtained by standard borohydride reduction of the
imide 9 as indicated above in the text. After 4–12 h of reaction at rt whilst stirring, the reaction
mixture was diluted with water (45 mL) and neutralized on cooling with 5% NaOH aqueous solution.
The solution was extracted twice with CH2Cl2 (25 mL) and separated. The organic layer was washed
with water, brine, separated, dried with MgSO4, and the solvents evaporated in vacuo. The resulting
crude residue was purified by chromatography [SiO2, AcOEt/cyclohexane (4:1)] and recrystallized
from the indicated solvents to give the expected tricyclic product.
14. Selected data for 1,2,3,13b-tetrahydropyrrolo[1,2-d]dibenzo[b,f][1,4]oxazepin-3-one (4a). This
compound was isolated as a white solid in 84% yield after recrystallization from Et2O and melted at
127 °C; IR (KBr) ν 1711 cm-1; 1H-NMR (CDCl3) δ 2.22-2.44 (m, 1H, Hpyrrolidine), 2.47-2.71 (m, 3H,
Hpyrrolidine), 5.28-5.39 (m, 1H, CH), 7.07-7.28 (m, 7H, Haromatic), 7.72 (d, 1H, J=8.3 Hz, Haromatic);
13C-NMR (CDCl3) δ 27.1 (CH2), 31.3 (CH2), 60.4 (CH), 121.8 (CH), 125.0 (CH), 125.1 (CH), 125.2
(CH), 126.6 (CH), 127.0 (CH), 127.6 (CH), 129.5 (CH), 130.4 (Cq), 130.9 (Cq), 151.6 (Cq), 155.7
(Cq), 174.1 (CO); MS (EI, 70 ev) m/z: 251 (M+); Anal. Calcd for C16H13NO2 (251.28): C, 76.48; H,
5.21; N, 5.57. Found: C, 76.31; H, 5.09; N, 5.48.
15. Selected data for 1,2-dihydropyrrolo[1,2-d]dibenzo[b,f][1,4]oxazepin-3-one (5a). This product was
isolated as a white solid in 64% yield after recrystallization from Et2O/cyclohexane and melted at
115 °C; IR (KBr) ν 1712 cm-1; 1H-NMR (CDCl3) δ 3.40 (s, 2H, CH2-C=), 5.60 (s, 1H, CH=C),
7.13-7.42 (m, 6H, Haromatic), 7.52 (d, 1H, J=7.6 Hz, Haromatic), 7.87 (d, 1H, J=7.6 Hz, Haromatic);
13C-NMR (CDCl3) δ 37.5 (CH2), 102.3 (CH=), 121.0 (CH), 121.8 (CH), 125.5 (CH), 125.6 (CH),
125.7 (CH), 127.0 (Cq), 127.3 (CH), 128.6 (CH), 129.0 (Cq), 131.2 (CH), 142.5 (Cq), 151.5 (Cq),
156.6 (Cq), 176.1 (CO); MS (EI, 70 ev) m/z: 249 (M+); Anal. Calcd for C16H11NO2 (249.27): C
77.10; H 4.45; N 5.62. Found: C 76.92; H 4.30; N 5.48.
16. Selected data for 1-methyl-3,13b-dihydropyrrolo[1,2-d]dibenzo[b,f][1,4]oxazepin-3-one (6Ua). This
product was isolated as a white solid in 65% yield after recrystallization from Et2O/hexane and
melted at 159 °C; IR (KBr) ν 1687 cm-1; 1H-NMR (CDCl3) δ 2.07 (d, 3H, J=1.3 Hz, CH3(CH)), 6.11
(q, 1H, J=1.3 Hz, CH(CH3)), 6.96-7.17 (q, 4H, Haromatic+CH=C), 7.20-7.35 (m, 4H, Haromatic), 8.85 (d,
1H, J=7.6 Hz, Haromatic); 13C-NMR (CDCl3) δ 11.6 (CH3), 60.7 (CH), 120.7 (CH), 121.3 (CH), 122.0
(CH), 125.0 (CH), 125.2 (CH), 125.3 (CH), 126.8 (CH), 129.5 (Cq), 130.6 (CH), 131.2 (Cq), 137.5
(CH), 137.7 (Cq), 146.1 (Cq), 156.6 (Cq), 169.9 (CO); MS (EI, 70 ev) m/z: 263 (M+); Anal. Calcd
for C17H13NO2 (263.29): C 77.55; H 4.98; N 5.32. Found: C 77.33; H 4.76; N 5.16.