Synthesis of benz[c]benzothiopheno[2,3-e]azepines via Heck-type coupling and Pictet-Spengler reaction

Article abstract of DOI:10.1055/s-2006-947351

New benz[c]benzothiopheno[2,3-e]azepine derivatives 1 of potential biological properties were synthesised in four steps from bromobenzo[b] thiophene. The synthetic pathway is based on 'Heck-type' and Pictet-Spengler reactions. Georg Thieme Verlag Stuttgar

Full text of DOI:10.1055/s-2006-947351

2016
LETTER
Synthesis of Benz[c]benzothiopheno[2,3-e]azepines via Heck-Type Coupling
and Pictet–Spengler Reaction
S
ynthesisof Be
m
nz[
c
]benzothiophen
i
o[2,3-
e
l
]azepin
i
es e David, Claudine Rangheard, Stéphane Pellet-Rostaing, Marc Lemaire*
Université Claude Bernard Lyon 1, Laboratoire de Catalyse et Synthèse Organique, CPE Bât 308, UMR 5181, 43 Bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
Fax +33(4)72431408; E-mail: marc.lemaire@univ-lyon1.fr
Received 18 March 2006
R4
Abstract: New benz[c]benzothiopheno[2,3-e]azepine derivatives 1
of potential biological properties were synthesised in four steps
from bromobenzo[b]thiophene. The synthetic pathway is based on
‘Heck-type’ and Pictet–Spengler reactions.
H
N
R3
R2
Key words: azepine, benzo[b]thiophene, fused-ring systems, Heck
reaction, Pictet–Spengler reaction
S
R1
1
R4
N
E
N
Synthesis of azepine and benzazepine derivatives is of a
great interest due to their known biological properties. For
example, indolo[3,2-d]benzoazepinones (paullones), de-
scribed by Kunick1 and their heterocyclic analogues
represent a large class of cyclin dependent kinase inhibi-
tors. Dibenzodiazepine such as clozapine as well as di-
benzothiazepine and dibenzoxazepine analogues are
known for their antipsychotic activities.2 Several azepine
derivatives are also known as arginine vasopressin recep-
tor antagonists.3
R2
R1
N
X
R
R3
3
2
X = O, S
Figure 1 Benz[c]azepine rings annulated to different heterocycles
yields (Table 1). As previously described,7 couplings
were performed with a catalytic amount of Pd(OAc)2, an
excess of potassium carbonate as a base, a crown ether and
a slight excess of aryl bromide in DMF at 140 °C
(Scheme 2). Good isolated yields of 2-aryl-3-cyanoben-
zo[b]thiophenes 6a–g were obtained. Reduction of 6a–g
with BH3–THF complex afforded C-[2-(aryl)ben-
zo[b]thiophen-3-yl]methylamines 7a–g with moderate
isolated yields due to a dimerisation side reaction
(Scheme 2, Table 1).8
Nyerges et al. recently described the access to benz[c]in-
dolo[2,3-e]azepine derivatives 2 by 1,7-dipolar electrocy-
clisation of azomethine ylides derived from 2-aryl-indol-
3-carboxaldehydes.4 Furthermore, Grigg et al. proposed a
sequential combination of azomethine imine cycloaddi-
tion with palladium-catalysed cyclisation leading to 6–8
membered heterocycles such as benz[c]thiopheno and
furano[2,3-e]azepine derivatives 3.5 To the best of our
knowledge, the synthesis of benz[c]azepines fused with a
benzo[b]thiophene moiety such as benz[c]benzothiophe-
no[2,3-e]azepines 1 (Figure 1) has never been described.
Compounds 7a–g derivatives were then involved in a
Pictet–Spengler reaction to afford benz[c]benzothiophe-
no[2,3-e]azepines 8–14 (Scheme 3). Various para-substi-
tuted benzaldehyde derivatives (R4 = CN, Cl, H, OMe)
were condensed with 7a–g to give imine intermediates
We propose here a strategy for the synthesis of new
benz[c]benzothiopheno[2,3-e]azepine derivatives from 3-
1
with total conversions (followed by H NMR). The reac-
bromobenzo[b]thiophene.
The
formation
of
Br
CN
benz[c]azepine ring is based on a Heck-type coupling of
3-cyanobenzo[b]thiophene (5) with appropriate aryl
halides followed by a Pictet–Spengler cyclisation of the
corresponding C-(2-arylbenzo[b]thiophen-3-yl)methyl-
amine derivatives 7 (Scheme 1).
SNAr
S
S
1) ‘Heck’
4
5
2) reduction
R4
Previously obtained by aromatic nucleophilic substitution
of the commercially available 3-bromobenzo[b]thiophene
(4), 3-cyanobenzo[b]thiophene6 (5) was involved in a
one-step Heck-type coupling with various aryl bromides
to afford 2-aryl-3-cyanobenzo[b]thiophenes 6a–g in good
H
N
R3
CH2NH2
R3
R2
Pictet–
Spengler
R2
S
S
R1
7
R1
8–10
SYNLETT 2006, No. 13, pp 2016–2020
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7
.0
8
.2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-947351; Art ID: G09706ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthetic approach to benz[c]benzothiopheno[2,3-e]aze-
pines.

LETTER
Synthesis of Benz[c]benzothiopheno[2,3-e]azepines
2017
R3
Br
as the cyclisation worked rapidly at room temperature
with electron-poor benzaldehydes (Table 2, entries 1, 2).
When the amine 7b was condensed with p-cyano-
benzaldehyde (Table 2, entry 5), the cyclisation failed,
even after 2 days in refluxing TFA. This result could be
explained by the insufficient electronic enrichment of the
aryl moiety.
CN
CN
(i)
R2
+
S
S
R1
R3
R1
6a–g
R2
5
6a: R1 = R2 = R3 = OMe
6b: R1 = R2 = R3 = H
(ii)
6c: R2 = OMe, R1 = R3 = H
6d: R1 = OMe, R2 = R3 = H
6e: R1 = Oi-Pr, R2 = R3 = H
6f: R1 = NMe2, R2 = R3 = H
6g: R1 = Cl, R2 = R3 = H
R3
NH2
R4
R2
R4
N
R3
NH2
R3
R2
S
(i)
R1
7a–g
R2
+
S
S
Scheme 2 Reagents and conditions: (i) 5% Pd(OAc)2, 3 equiv
K2CO3, 1 equiv DCH-18-C-6, DMF, 140 °C; (ii) 2 equiv BH3 (1 M in
THF), THF, reflux.
R1
R1
(ii)
CHO
7a–g
7a: R1 = R2 = R3 = OMe
7b: R1 = R2 = R3 = H
7c: R2 = OMe, R1 = R3 = H
R4
tion time was very short with electron-poor benzaldehyde
derivatives (R4 = CN, Cl) at room temperature in dichlo-
romethane whereas the use of benzaldehyde or electron-
rich benzaldehydes (R4 = 0Me) required refluxing tolu-
ene.
H
N
R3
R2
S
R1
8–10
The Pictet–Spengler cyclisation of imines was then
realised using TFA according to Ohwada’s conditions.11
Stoichiometric amount or little excess of TFA was not
sufficient to have total conversion of the starting materi-
als. When the Pictet–Spengler cyclisation was realised in
pure TFA, total conversions were obtained but yields
rarely exceeded 50% (Table 2 and Table 3). We assumed
that products were not stable in this strong acidic medium.
As we can see (Table 2, entries 1–4), the presence of elec-
tron-donating groups on the aryl moiety is required.
Whatever the nature of the benzaldehyde derivative is, the
cyclisation occurred. However, the reaction time is
dependent of the electrophilic character of the imine inter-
mediate. Refluxing TFA was necessary with benzalde-
hyde (Table 2, entry 3) or electron-rich benzaldehydes
such as p-methoxybenzaldehyde (Table 2, entry 4) where-
Scheme 3 Reagents and conditions: (i) 1.05 equiv p-R4PhCHO,
CH2Cl2 at r.t. (R4 = CN, Cl) or refluxing toluene (R4 = H, OMe); (ii)
refluxing TFA.
With the mono-methoxy-substituted aryl moiety, the
position of the electron-donating group is primordial for
the azepine ring formation. In the case of 7c with a p-
methoxy-substituted aryl moiety (Table 2, entry 6), the
reaction with the p-cyanobenzaldehyde failed even with a
stronger acid than TFA such as TFSA. Only amine 7d
derived from m-methoxy aryl bromide afforded desired
benz[c]benzothiopheno[2,3-e]azepines 11a–d (Scheme 4).
In this case, two regioisomers can be obtained.
R4
Table 1 Isolated Yields for Arylation9 and Reduction10 steps
R4
N
NH2
Aryl bromide
Isolated yield Isolated yield
(i)
of 6 (%)a
of 7 (%)b
+
R1
S
S
R1
R2
OMe
H
R3
OMe
H
6d–g
R1
CHO
OMe
H
70
63
64
78
82
71
80
59
62
43
46
49
73
32
7d: R1 = OMe
7e: R1 = Oi-Pr
7f: R1 = NMe2
7g: R1 = Cl
(ii)
R4
R4
H
OMe
H
H
H
H
N
N
OMe
Oi-Pr
NMe2
Cl
H
R1
H
H
+
S
S
H
H
R1
B
A
H
H
11–14
a Performed with 5% Pd(OAc)2, 3 equiv of K2CO3, 1 equiv of DCH-
18-C-6, and 1.1 equiv of aryl bromide in DMF at 140 °C.
Scheme 4 Reagents and conditions: (i) 1.05 equiv p-R4PhCHO,
CH2Cl2 at r.t. (R4 = CN, Cl) or refluxing toluene (R4 = H, OMe); (ii)
refluxing TFA.
b Performed with 2 equiv of BH3 (1 M in THF) in refluxing THF.
Synlett 2006, No. 13, 2016–2020 © Thieme Stuttgart · New York

2018
E. David et al.
LETTER
Table 2 Pictet–Spengler Cyclisation with Amines 7a–c12
Entry
Amine
Product
Time (h)
Isolated yield (%)a
R4
NH2
OMe
OMe
OMe
1
2
3
4
8a
8b
8c
8d
CN
Cl
H
1
2
12
72
54b
57b
45
S
OMe
40
7a
7b
7c
NH2
5
6
9a
CN
CN
48
48
–
S
S
NH2
a,c
10a
–
OMe
a 1 M in refluxing TFA.
b 1 M in TFA at r.t.
c 1 M in refluxing TFSA.
Refluxing TFA was required with all benzaldehyde deriv- Then, we compared the steric hindrance of various elec-
atives to afford a regioisomer mixture with about 50% tron-donating groups R1 (Scheme 4). With p-cyanoben-
yields (Table 3, entries 1–3). Regioisomers were not sep- zaldehyde, the large isopropoxy group (Table 3, entry 5)
1
arated and proportions were determined by H NMR. gave better regioselectivity than the methoxy group
Comparing the electron-withdrawing effect of R4 clearly (Table 3, entry 1). With the bulky dimethylamino group
suggests that highly electron-withdrawing groups gave (Table 3, entries 6–8), the reaction is totally regioselective
better regioselectivity in shorter reaction times. In contrast with all benzaldehyde derivatives tested in 40–50%
with previous results (Table 2, entry 4), the reaction did yields. Thus, the larger R1, the better the regioselectivity.
not work with the enriched p-methoxybenzaldehyde
Eventually, a substituent with both a para-directing and
(Table 3, entry 4), even with a Yb(OTf)3 catalytic
an electron-withdrawing inductive effects such as chlo-
system13 or an N-acylium intermediate.14 This result could
rine (Table 3, entry 9), does not allow azepine formation,
be explained by the lower electronic density of the mono-
probably because of the strong deactivated inductive
substituted aryl moiety.
effect.
Table 3 Pictet–Spengler Cyclisation with Mono-Substituted Aryl Moiety12
Entry
Product
Time (h)
Isolated yield (%)a
A:Bb
R1
R4
1
2
3
4
11a
11b
11c
11d
OMe
CN
Cl
H
2
5
20
24
50
48
52
94:6
88:12
80:20
–
a,c,d
OMe
–
5
12a
Oi-Pr
CN
1
38
97:3
6
7
8
13a
13b
13c
NMe2
CN
Cl
H
2
2
4
40
44
70
100:0
100:0
100:0
9
14a
Cl
CN
72
–
–
a 1 M in refluxing TFA.
b Determined by 1H NMR.
c Yb(OTf)3, TMSCl, CH2Cl2–THF, reflux.
d AcCl, 2,6-lutidine, CH2Cl2.
Synlett 2006, No. 13, 2016–2020 © Thieme Stuttgart · New York

LETTER
Synthesis of Benz[c]benzothiopheno[2,3-e]azepines
2019
Analytical Data of 3-Cyano-2-(3¢,4¢,5¢-trimethoxy-
phenyl)benzo[b]thiophene (6a).
Off-white solid obtained in 70% yield after flash
chromatography (heptane–CH2Cl2 = 7:3) of the crude
In summary, Heck-type coupling and Pictet–Spengler
methodology allowed the synthesis of new and various
benz[c]benzothiopheno[2,3-e]azepine derivatives in four
steps with good yields. This pathway can be applied to
other heterocycles such as indole, pyrrole and thiophene
for the synthesis of fused heterocycles. Further studies are
under investigation to use these new benz[c]ben-
zothiopheno[2,3-e]azepine derivatives as template for the
synthesis of new benzazepines.
product; Rf = 0.5 (CH2Cl2); mp 148–150 °C. 1H NMR (300
MHz, CDCl3): d = 3.93 (s, 3 H), 3.96 (s, 6 H), 7.13 (s, 2 H),
7.42–7.55 (m, 2 H), 7.83 (d, 1 H, J = 7.9 Hz), 7.96 (d, 1 H,
J = 7.9 Hz). 13C NMR (75 MHz, CDCl3): d = 56.5 (2 CH3),
61.2 (CH3), 101.8 (C), 105.7 (2 CH), 115.5 (C), 122.4 (CH),
122.6 (CH), 126.2 (CH), 126.3 (CH), 126.9 (C), 137.2 (C),
139.3 (C), 140.2 (C), 153.8 (2 C), 155.2 (C). Anal. Calcd for
C18H15NO3S: C, 66.44; H, 4.65; N, 4.30; S, 9.85. Found: C,
66.64; H, 4.63; N, 4.31; S, 9.20. MS (EI+): m/z = 325 [M+].
(10) General Procedure for the Preparation of Compounds 7.
To a 0.3 M stirred solution of 2-aryl-3-cyanobenzo[b]thio-
phene (6) in anhyd THF was added dropwise at 0 °C under
inert atmosphere a 1 M borane solution in THF (2 equiv).
The resulting mixture was allowed to warm at r.t. and then
stirred at reflux until completion of the reaction. The
reaction mixture was cooled to 0 °C, hydrolysed with a 6 M
HCl aq solution, neutralised with a 2 M NaOH aq solution
and then extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over MgSO4, filtered
and solvents were removed under reduced pressure. The
crude product was purified by flash chromatography.
Analytical Data of C-[2-(3,4,5-Trimethoxyphen-
Acknowledgment
The authors thank the ‘Ministère de la Recherche et de l’Enseigne-
ment Supérieur’ for the grant to E.D.’s PhD.
References and Notes
(1) (a) Kunick, C. Arch. Pharm. 1992, 325, 297. (b) 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) (a) Chakrabarti, J. K.; Hotten, T. M.; Pullar, I. A.; Steggles,
D. J. J. Med. Chem. 1989, 32, 2375. (b) Press, J. B.;
Hofmann, C. M.; Eudy, N. H.; Day, I. P.; Greenblatt, E. N.;
Safir, S. R. J. Med. Chem. 1981, 24, 154. (c) Liao, Y.;
Venhuis, B. J.; Rodenhuis, N.; Timmerman, W.; Wikstroem,
H.; Meier, E.; Bartoszyk, G. D.; Boettcher, H.; Seyfried, C.
A.; Sundell, S. J. Med. Chem. 1999, 42, 2235. (d) Liegeois,
J. F. F.; Rogister, F. A.; Bruhwyler, J.; Damas, J.; Nguyen,
T. P.; Inarejos, M. O.; Chleide, E. M. G.; Mercier, M. G. A.;
Delarge, J. E. J. Med. Chem. 1994, 37, 519.
(3) (a) Ogawa, H.; Yamashita, H.; Kondo, K.; Yamamura, Y.;
Miyamoto, H.; Kan, K.; Kitano, K.; Tanaka, M.; Nakaya, K.;
Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y. J.
Med. Chem. 1996, 39, 3547. (b) Aranapakam, V.; Albright,
J. D.; Grosu, G. T.; Chan, P. S.; Coupet, J.; Saunders, T.; Ru,
X.; Mazandarani, H. Bioorg. Med. Chem. Lett. 1999, 9,
1733. (c) Cho, H.; Murakami, K.; Nakanishi, H.; Fujisawa,
A.; Isoshima, H.; Niwa, M.; Kayakaw, K.; Yasunori, H.;
Uchida, I.; Watanabe, H.; Wakitani, K.; Aisaka, K. J. Med.
Chem. 2004, 47, 101.
yl)benzo[b]thiophen-3-yl]methylamine (7a).
Pale yellow oil obtained in 63% yield after flash
chromatography (CH2Cl2–MeOH = 98:2) of the crude
product; Rf = 0.2 (CH2Cl2–MeOH = 98:2). 1H NMR (300
MHz, CDCl3): d = 1.49 (br s, 2 H), 3.89 (s, 6 H), 3.91 (s, 3
H), 4.11 (s, 2 H), 6.88 (s, 2 H), 7.30–7.42 (m, 2 H), 7.80–7.83
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 37.8 (CH2), 56.2
(2 CH3), 60.9 (CH3), 121.2 (2 CH), 122.3 (CH), 124.4 (CH),
124.5 (CH), 129.5 (2 C), 138.1 (C), 139.0 (C), 139.9 (C),
140.5 (C), 153.2 (2 C). Anal. Calcd for C18H19NO3S: C,
65.63; H, 5.81; N, 4.25; S, 9.73. Found: C, 65.39; H, 5.89;
N, 4.13; S, 10.00. MS (EI+): m/z = 329 [M+].
(11) (a) Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem.
1999, 64, 611. (b) Nakamura, S.; Tanaka, M.; Taniguchi, T.;
Uchiyama, M.; Ohwada, T. Org. Lett. 2003, 5, 2087.
(12) General Procedure for Preparation of Compounds 8–14.
To a 0.2 M stirred solution of compound 7 in anhyd toluene
was added the para-substituted benzaldehyde derivative
(1.05 equiv). The reaction mixture was heated at reflux until
total conversion of the amine into the imine intermediary
(followed by 1H NMR). The reaction mixture was
(4) Nyerges, M.; Pinter, A.; Viranyi, A.; Bitter, I.; Toke, L.
Tetrahedron Lett. 2005, 46, 377.
(5) Fishwick, C. W. G.; Grigg, R.; Sridharan, V.; Virica, J.
Tetrahedron 2003, 59, 4451.
(6) Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire, M.
Tetrahedron 2004, 60, 3221.
(7) Fournier Dit Chabert, J.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 2002, 43, 1829.
concentrated in vacuo and the resulting crude product was
dissolved in TFA to have a 1 M solution. The resulting
reaction mixture was heated at r.t. until completion of the
reaction. Residual TFA was neutralised with an aq sat.
Na2CO3 solution. The reaction mixture was extracted with
CH2Cl2. The combined organic layers were successively
washed with H2O and brine, dried over MgSO4, filtered and
solvents were removed under reduced pressure. The crude
product was purified by flash chromatography.
(8) Caddick, S.; Haynes, A. K. D. K.; Judd, D. B.; Williams, M.
R. V. Tetrahedron Lett. 2000, 41, 3513.
(9) General Procedure for Preparation of Compounds 6.
In a 1 M solution of 3-cyanobenzo[b]thiophene(5) in anhyd
DMF were successively added under inert atmosphere
DCH-18-C-6 (1 equiv), K2CO3 (3 equiv), 3-cyano-
benzo[b]thiophene (5) and aryl bromide (1.1 equiv). The
mixture was heated at 100 °C for 5 min and Pd(OAc)2 (0.05
equiv) was added. The resulting mixture was then heated at
130 °C overnight. After cooling to r.t., the mixture was
filtered over Celite®, which was rinsed with CH2Cl2. The
combined organic layers were successively washed with
H2O and brine, dried over MgSO4, filtered and solvents were
removed under reduced pressure. The crude product was
purified by flash chromatography.
Analytical Data of 5-(p-Chlorophenyl)-2,3,4-trimethoxy-
5,6,7-trihydrobenz[c]benzothiopheno[2,3-e]azepine (8b).
Pale yellow solid obtained in 57% yield after flash
chromatography (CH2Cl2–MeOH = 99.5:0.5) of the crude
product; Rf = 0.2 (CH2Cl2–MeOH = 99:1). 1H NMR (300
MHz, CDCl3): d = 3.68 (s, 3 H), 3.92 (s, 3 H), 3.97 (d, 1 H,
J = 17.3 Hz), 4.00 (s, 3 H), 4.25 (d, 1 H, J = 17.3 Hz), 6.05
(s, 1 H), 7.07–7.14 (m, 4 H), 7.24 (s, 1 H), 7.27–7.31 (m, 2
H), 7.42 (m, 1 H), 7.74 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 44.0 (CH2), 56.2 (CH3 + CH), 61.0 (CH3), 61.6
(CH3), 109.3 (CH), 121.5 (CH), 121.8 (CH), 124.3 (CH),
Synlett 2006, No. 13, 2016–2020 © Thieme Stuttgart · New York

2020
E. David et al.
LETTER
(13) Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron:
Asymmetry 2003, 14, 177.
(14) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
125.0 (CH), 128.5 (2 CH), 129.1 (C), 129.5 (C), 129.8 (2
CH), 132.6 (C), 133.7 (C), 137.5 (C), 137.9 (C), 138.6 (C),
139.8 (C), 141.8 (C), 151.4 (C), 152.5 (C). Anal. Calcd for
C25H22ClNO3S: C, 66.44; H, 4.91; Cl, 7.84; N, 3.10; S, 7.09.
Found: C, 66.55; H, 5.06; Cl, 7.61; N, 2.92; S, 7.24. MS
(ESI+): m/z = 452 [MH+].
10558.
Synlett 2006, No. 13, 2016–2020 © Thieme Stuttgart · New York