Synthesis of tetracyclic DIBENZO[c,f]azepine and benzo[f]thieno[3,2-c]azepine derivatives via N-acyluminium ion cyclization

Article abstract of DOI:10.3987/com-01-9240

Tetracyclic dibenzo[c,f]-4-oxopyrrolo[1,2-c]azepine (2a), dibenzo[c,f]-5-oxopiperido[1,2-c]azepine (2b), benzo[f]-4-oxopyrrolo[1,2-a]thieno[3,2-c]azepine (2c), and benzo[f]-5-oxopiperido[1,2-a]thieno[3,2-c]azepine (2d) were prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams (3a-d) with aromatic or heteroaromatic rings such as benzene and thiophene as a π-nucleophile. In the case of furan ring, the hydroxylactams (3e, f) were completely decomposed under the acidic conditions (formic acid or methanesulfonic acid). Subsequent reduction of 2a-d with BF₃·O(C₂H₅)₂ and BH³·S(CH₃)₂ finally provided the tetracyclic dibenzo[c,f]pyrrolo[1,2-c]azepine (1a), dibenzo[c,f]piperido[1,2-c]azepine (1b), benzo[f]pyrrolo[1,2-a]thieno[3,2-c]azepine (1c), and benzo[f]piperido[1,2-a]thieno[3,2-c]azepine derivatives (1d) as analogues of mianserin.

Full text of DOI:10.3987/com-01-9240

HETEROCYCLES, Vol. 55, No. 8, pp. 1519 - 1526, Received, 7th May, 2001
SYNTHESIS OF TETRACYCLIC DIBENZO[c,f]AZEPINE AND
BENZO[f]THIENO[3,2-c]AZEPINE DERIVATIVES VIA N-ACYLIMINIUM
ION CYCLIZATION
Jae Yeol Leea*, Nam Jun Baek b, Sook Ja Leeb, Hokoon Parka, and Yong Sup Leea*
aDivision of Life Sciences, Korea Institute of Science & Technology,
P.O. Box 131, Cheongryang, Seoul 130-650, Korea
E-mail: ljy@kist.re.kr
bDepartment of Chemistry, Hankuk University of Foreign Studies,
Yong-in 449-791, Korea
Abstract- Tetracyclic dibenzo[c,f]-4-oxopyrrolo[1,2-c]azepine (2a), dibenzo[c,f]-5-
oxopiperido[1,2-c]azepine (2b), benzo[f]-4-oxopyrrolo[1,2-a]thieno[3,2-c]azepine
(2c), and benzo[f]-5-oxopiperido[1,2-a]thieno[3,2-c]azepine (2d) were prepared
through intramolecular N-acyliminium ion cyclization of hydroxylactams (3a-d) with
aromatic or heteroaromatic rings such as benzene and thiophene as a π-nucleophile.
In the case of furan ring, the hydroxylactams (3e, f) were completely decomposed
under the acidic conditions (formic acid or methanesulfonic acid). Subsequent
reduction of 2a-d with BF3·O(C2H5)2 and BH3·S(CH3)2 finally provided the
tetracyclic dibenzo[c,f]pyrrolo[1,2-c]azepine (1a), dibenzo[c,f]piperido[1,2-c]azepine
(1b), benzo[f]pyrrolo[1,2-a]thieno[3,2-c]azepine (1c), and benzo[f]piperido[1,2-
a]thieno[3,2-c]azepine derivatives (1d) as analogues of mianserin.
The benzoazepine unit is present in a large number of natural alkaloids, including lennoxamine,1

cephalotaxine2 and chilenine.3 Dibenzo[b,f]azepine, in particular, forms the skeleton of tricyclic
antidepressant such as desipramine, imipramine and lofepramine.4 The mianserin, antidepressant agent as
a selective 5-HT2 receptor antagonist, also contains dibenzo[c,f]azepine annelated to piperazine ring
(Figure 1).5 In this regard, many synthetic efforts have been directed toward synthesis of benzoazepine
derivatives because of their unique structural features and potential biological activities.6 We have also
reported the synthesis of azepino[5,4,3-cd]indole derivatives in the course of searching the
pharmacologically active compound.7
O
O
O
Ar
N
OCH3
OCH3
N
N
N
( )n
N
CH3
N(CH3)2
Imipramine
1
Lennoxamine
Mianserin
Figure 1.
In connection with our interest in the synthesis of diverse polycyclic alkaloids, we wish to report herein
the synthesis of tetracyclic dibenzo[c,f]azepine and benzo[f]thieno[3,2-c]azepine derivatives (1) from 2-
arylmethylanilines (5) through N-acyliminium ion cyclization. Our synthesis is based on the
hydroxylactams (3) as key intermediates for N-acyliminium ion cyclization. These hydroxylactams (3)
would be obtained by reduction of imides (4), which would be prepared from the condensation reaction of
2-arylmethylaniline (5) with cyclic anhydride. The cyclization of hydroxylactams (3) having aromatic
rings as a π-nucleophile8 and subsequent reduction of tetracyclic lactams (2) should complete the
synthesis of the target tetracyclic dibenzo[c,f]azepine and benzo[f]thieno[3,2-c]azepine (1) respectively.
The 2-thienyl and 2-furylmethylanilines (5b, c) if not commercially available, could be readily prepared
by known procedures.9 The condensation of anilines (5a-c) with cyclic anhydrides [succinic anhydride
(n=1) or glutaric anhydide (n=2) ] followed by treatment with excess of AcCl in refluxing xylene gave the

Ar
N
Ar
N
Ar
NH2
O
OH
( )n
ii
iii
i
( )n
O
O
5a, Ar=phenyl
5b, Ar=2-thienyl
5c, Ar=2-furyl
4a, Ar=phenyl, n=1 (99%)
4b, Ar=phenyl, n=2 (68%)
4c, Ar=2-thienyl, n=1 (87%)
4d, Ar=2-thienyl, n=2 (70%)
4e, Ar=2-furyl, n=1 (70%)
4f, Ar=2-furyl, n=2 (53%)
3a, Ar=phenyl, n=1 (57%)
3b, Ar=phenyl, n=2 (46%)
3c, Ar=2-thienyl, n=1 (20%)
3d, Ar=2-thienyl, n=2 (43%)
3e, Ar=2-furyl, n=1 (48%)
3f, Ar=2-furyl, n=2 (58%)
iv
N
N
( )n
from 3a,b
from 3c,d
( )n
O
Ar
H
2a, n=1 (91%)
2b, n=2 (85%)
1a, n=1 (81%)
1b, n=2 (42%)
N+
( )n
S
O
S
N-Acyliminium ion, 6
iv
N
N
( )n
( )n
O
2c, n=1 (80%)
2d, n=2 (99%)
1c, n=1 (61%)
1d, n=2 (71%)
(i) succinic anhydride (n=1) or glutaric anhydride (n=2), xylene, reflux; then AcCl, reflux; (ii) DIBAL-H,
THF, -78 ℃ ~ rt; (iii) CH3SO3H, CH2Cl2, reflux; (iv) BF3·O(C2H5)2 and BH3·S(CH3)2, THF, reflux
Scheme 1.
cyclic imides (4a-f) in 53-99% yield (Scheme 1).10 In the case of reduction of imides (4a-f) for
hydroxyimides (3a-f), the use of NaBH4 as a reducing agent gave over-reduced compounds
(hydroxyamide) or imide ring-opened compounds (methyl ester) in the presence of 1M H2SO4/ MeOH.
This result was totally unexpected as many research groups and we have previously performed the exact
reduction of cyclic imides by using the same condition.11 Therefore, the intended hydroxylactams (3a-f),

precursors for N-acyliminium ion (6), were successfully obtained by the reduction of imides (4a-f) with
DIBAL-H in THF at -78 ℃ to room temperature without over-reduction.12
HCO2H
reflux
OH
N
N
O
O
2a (88%)
3a
HCO2H
reflux
OH
+
N
NH
N
O
O
H
O
3b
7 (15%)
8 (49%)
HCO2H
reflux, 39%
Scheme 2.
The hydroxylactams (3a-f) were subjected to the general N-acyliminium ion cyclization condition (formic
acid, reflux).13 The compound (3a) only was cyclized to afford the target compound (2a) in 88% yield. In
the case of six-membered hydroxylactam (3b), however, this same condition did not provide the cyclized
lactam (2a) but the enamide compound (7) (15%) resulting from the dehydration of hydroxylactam (3b)
1
and formamido compound (8) (49%), which was identified with NMR, MS, IR, and H-1H COSY. The
isolated enamide (7) was converted to formamido compound (8) (39%) under the reflux condition of
formic acid (Scheme 2). The thienyl compounds (3c, d) were not cyclized and the furyl compounds (3e, f)
were completely decomposed under this condition. However, the application of more acidic condition
(methanesulfonic acid, reflux) to hydroxylactams (3a-d) gave successfully tetracyclic lactam (2a-d) in 80-
99% yield,14 while furyl compounds (3e, f) were not cyclized but decomposed again in this condition due

to the cyclization difficulty of furan 2-to-3 closure.15 Finally, reduction of lactams (2a-d) with
BH3·S(CH3)2 in the presence of BF3·O(C2H5)2 afforded tetracyclic dibenzo[c,f]azepine (1a, b) and
benzo[f]thieno[3,2-c]azepine (1c, d) respectively in good yield (42-81%).16,17
In conclusion, we have accomplished the synthesis of tetracyclic dibenzo[c,f]azepine and
benzo[f]thieno[3,2-c]azepine derivatives (1a-d) annelated to pyrrolidine or piperidine moiety through N-
acyliminium ion cyclization by using aromatic rings such as benzene and thiophene as a π-nucleophile,
followed by subsequent reduction. In the N-acyliminium ion cyclization, the five-membered benzyl
compound (3a) was easily cyclized under both of formic acid and methanesulfonic acid. The six-
membered benzyl compound (3b) and thienyl compounds (3c, d) were cyclized only under the more
acidic condition (methanesulfonic acid), while the furyl compounds (3e, f) were completely decomposed
under both of acids.
ACKNOWLEDGEMENTS
This work was supported by grants from The Ministry of Health and Welfare (2M10170)
REFERENCES AND NOTES
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14. Typical procedure of cyclization: To a solution of 3a (695 mg, 2.60 mmol) in dry CH2Cl2 (20 mL)
was added methanesulfonic acid (2.02 mL, 31.2 mmol). The reaction mixture was heated under reflux
for 24 h, cooled to rt, and neutralized with 10% NaHCO3 solution. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4,
concentrated, and purified by flash column chromatography (EtOAc/hexane=3:2) to afford 2a (588
mg, 91%).
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Y. M. Choi, Synthesis, 1981, 996.

17. Selected data for: dibenzo[c,f]pyrrolo[1,2-a]azepine (1a): mp 104 ℃(EtOAc-hexane); MS m/z: 235
1
(M+); IR (KBr) 2964, 1596, 1498, 746 cm-1; H NMR (300 MHz, CDCl3) δ 7.21-7.16 (m, 4H, Ph),
7.04-6.97 (m, 2H, Ph), 6.55 (t, J=7.3 Hz, 1H, Ph), 6.45 (d, J=8.0 Hz, 1H, Ph), 5.35 (t, J=6.6 Hz, 1H,
N-CH-Ph), 4.80 and 3.58 (ABq, J=14.8 Hz, 2H, Ph-CH2-Ph), 3.34-3.29 (m, 2H, N-CH2-CH2-), 2.41
(m, 1H, N-CH2-CH-), 2.26 (m, 1H, N-CH2-CH-), 2.10-2.01 (m, 2H, N-CH2-CH2-CH2-); 13C NMR (75
MHz, CDCl3) δ 146.7, 140.4, 138.7, 130.1, 128.4, 128.1, 128.0, 127.1, 124.3, 117.2, 114.2, 60.2,
50.7, 41.2, 30.8, 23.8; HRMS (EI) Calcd for C17H17N (M+) m/z 235.1361, Found 235.1351. Anal.
Calcd for C17H17N: C, 86.77; H, 7.28; N, 5.95. Found: C, 86.74; H, 7.27; N, 5.86.
dibenzo[c,f]piperido[1,2-a]azepine (1b): mp 245-248 ℃ (EtOAc-hexane); MS m/z: 249 (M+); IR
1
(KBr) 3220, 1452, 1048, 610 cm-1; H NMR (300 MHz, CDCl3) δ 7.57-6.87 (m, 8H, Ph), 4.85 and
3.32 (ABq, J=12.4 Hz, 2H, Ph-CH2-Ph), 3.88 (dd, J=10.5, 2.1 Hz, 1H, N-CH-Ph), 3.43 (m 1H, N-CH-
CH2-), 3.30 (m, 1H, N-CH-CH2-), 2.00-1.66 (m, 6H, -CH2-CH2-CH2-); 13C NMR (75 MHz, CDCl3) δ
141.3, 140.7, 139.5, 129.6, 128.2, 127.5, 126.8, 126.6, 122.1, 119.6, 69.1, 53.6, 39.2, 39.0, 27.29,
26.4; HRMS (EI) Calcd for C18H19N (M+) m/z 249.1517, Found 249.1516. benzo[f]pyrrolo[1,2-
a]thieno[3,2-c]azepine (1c): mp 148 ℃ (EtOAc-hexane, decomp); MS m/z: 241(M+); IR (KBr)
3420, 1450, 1084, 745 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.12-7.02 (m, 2H, Ph), 6.96 (d, J=7.8 Hz,
1H, Ph), 6.82 (d, 1H, J=5.2 Hz, thienyl-H5), 6.77 (t, J=7.8 Hz, 1H, Ph), 6.58 (d, 1H, J=5.2 Hz, thienyl-
H4), 4.30 and 3.65 (ABq, J=15.2 Hz, 2H, Ar-CH2-thienyl), 3.92 (dd, J= 8.1, 7.2 Hz, 1H, N-CH-Ph),
3.24-3.10 (m, 2H, N-CH2-), 2.29 (m, 1H, N-CH-CH-), 1.93-1.78 (m, 3H, N-CH-CH- and N-CH2-CH2-
13
CH2-); C NMR (75 MHz, CDCl3) δ 148.6, 138.4, 134.1, 133.8, 128.9, 128.1, 127.9, 122.2, 121.6,
118.2, 63.9, 51.3, 33.9, 33.6, 22.3; HRMS (EI) Calcd for C15H15NS (M+) m/z 241.0925, Found
241.0922. Anal. Calcd for C15H15NS: C, 74.65; H, 6.26; N, 5.80. Found: C, 74.64; H, 6.33; N, 5.73.
benzo[f]piperido[1,2-a]thieno[3,2-c]azepine (1d): mp 178 ℃ (EtOAc-hexane, decomp); MS m/z:
255(M+); IR (KBr) 3424, 3126, 1458, 1084, 750 cm-1; 1H NMR (300 MHz, pyridine-d5 and CDCl3) δ
7.32-7.25 (m, 3H, Ph), 7.20 (d, 1H, J= 5.2 Hz, thienyl-H5), 7.18 (m, 1H, Ph), 6.95 (m, 1H, Ph), 6.91(d,
1H, J= 5.2 Hz, thienyl-H4), 4.77 and 3.44 (ABq, 2H, J= 15.7 Hz, Ph-CH2-thienyl), 3.87(dd, 1H,

J=10.5, 2.0 Hz, N-CH-thieny-), 3.31 (m, 1H, N-CH-CH2-), 3.15 (m, 1H, N-CH-CH2-), 1.99-1.54 (m,
13
6H, N-CH2-CH2-CH2-); C NMR (75 MHz, pyridine-d5 and CDCl3) δ 151.3, 141.1, 139.2, 135.7,
128.8, 127.9, 126.7, 122.7, 121.0, 65.5, 53.9, 37.8, 32.2, 27.2, 25.7 (one of aromatic carbons was
overlapped with solvent peaks); HRMS (EI) Calcd for C16H17NS (M+) m/z 255.1082, Found 255.1089.