Syntheses of Tetrahydrobenzoazepinoindoles and Dihydrobenzodiazepinoindoles via Ring-Opening Cyclization of Activated Aziridines with 2-(2-Bromophenyl)-1H-indoles

Article abstract of DOI:10.1021/acs.orglett.7b01397

Two efficient, modular, step- and pot-economic strategies to access various 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indoles and 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[1,7-a]indoles are disclosed that advance via S_N2-type regioselective ring opening of enantiopure aziridines with 2-(2-bromophenyl)-1H-indoles at their C3 and indolyl N centers, respectively, followed by Cu-mediated C-N cyclization which furnishes the products in excellent yields with outstanding enantiomeric excesses (up to >99%).

Full text of DOI:10.1021/acs.orglett.7b01397

Letter
pubs.acs.org/OrgLett
Syntheses of Tetrahydrobenzoazepinoindoles and
Dihydrobenzodiazepinoindoles via Ring-Opening Cyclization of
Activated Aziridines with 2‑(2-Bromophenyl)‑1H‑indoles
Sajan Pradhan, Chandan Kumar Shahi, Aditya Bhattacharyya, Navya Chauhan, and Manas K. Ghorai*
Indian Institute of Technology Kanpur, 208016, Kanpur, Uttar Pradesh India
S
* Supporting Information
ABSTRACT: Two efficient, modular, step- and pot-economic
strategies to access various 5,6,7,12-tetrahydrobenzo[2,3]-
azepino[4,5-b]indoles and 6,7-dihydro-5H-benzo[5,6][1,4]-
diazepino[1,7-a]indoles are disclosed that advance via SN2-
type regioselective ring opening of enantiopure aziridines with
2-(2-bromophenyl)-1H-indoles at their C3 and indolyl N
centers, respectively, followed by Cu-mediated C−N cycliza-
tion which furnishes the products in excellent yields with
outstanding enantiomeric excesses (up to >99%).
5,6,7,12-Tetrahydrobenzo[2,3]azepino[4,5-b]indoles are an im-
portant class of indoloazepine often found in naturally occurring
compounds with intriguing bioactivities (Figure 1). A few
tion,1 Cu-catalyzed [4 + 2] cyclization of 2-vinylindoles,11
fragmentation of an indole diazabicyclo[3.2.2]nonedione de-
rivative,12 Au-catalyzed intramolecular cyclization of indolylcy-
clopropenes,13 Pd-catalyzed intramolecular oxidative C−H
coupling of N-alkylated indoles,14 etc. A number of existing
strategies typically rely onmultistep syntheses. To circumventthe
shortcomings of the existing methodologies, we sought an
expedient access to both of these indoloazepine skeleta with
extensivescopeforstructural andfunctional diversification. Based
on our longstanding interest in SN2-type ring openingof activated
aziridines15 followed by cyclization strategies with functionalized
nucleophilestoconstructchiralaza-heterocyclesandothertargets
of contemporary interest,16 we recognized the prospect of
procuring THB-[2,3]azepino[4,5-b]indoles and DHB-[5,6]-
[1,4]diazepino[1,7-a]indoles through the ring opening of
activated aziridines with 2-(2-bromophenyl)-1H-indoles by
exploiting their C3 and N centers as nucleophilic sites,
respectively, followed by metal-assisted C−N bond-forming
cyclization. Herein, we wish to report our results as a Letter.
Our study commenced with the SN2-type ring opening of 2-
phenyl-N-tosylaziridine (1a) with 2-(2-bromophenyl)-1H-
indole(2a)17 through its C3 site in the presence of 10 mol %
LiClO4 as the Lewis acid (LA) in acetonitrile at 80 °C,16e,f and the
corresponding ring-opened product formed as a single
regioisomer in 89% yield (Scheme 1).18 Next, 3a was subjected
to an intramolecular C−N cyclization in the presence of 10 mol %
copper(I) iodide, 20 mol % L-proline as the ligand, and 2.5 equiv
of sodium hydride in DMF at 120 °C19 to afford the
corresponding THB-[2,3]azepino[4,5-b]indole 4a in moderate
yield (42%, Scheme 2). The structure of 4a was confirmed by
single crystal X-ray analysis.18
Figure 1. Representative examples of natural products containing
azepino- and diazepinoindoles.
illustrative examples include the iboga alkaloids viz. ibogamine
(I) and ibogaine (II) that can attenuate addiction of major drugs
ofabuse,1 catharanthine(III)thatdemonstratespotentinhibition
to TRPM8 activity,2 and the paullones (IV−VI) that are cyclin-
dependent and glycogen synthase kinase inhibitors.3,4 Another
structural variant of indoloazepines, the 6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[1,7-a]indole VII, acts as an HCV NS5B-
polymerase inhibitor.5
Despite the immense pharmacological significance of THB-
[2,3]azepino[4,5-b]indoles and DHB-[5,6][1,4]diazepino[1,7-
a]indoles, only a few reports are known for their syntheses that
include Au-catalyzed intramolecular hydroarylation of alkynyl
indoles,6−9 Ir-catalyzed allylic dearomatization/retro-Mannich/
hydrolysis cascade reaction,10 Ni-catalyzed C−H functionaliza-
Received: May 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01397
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Organic Letters
Letter
Scheme 1. LiClO4-Catalyzed Ring Opening of 2-Phenyl-N-
tosylaziridine (1a) with 2-(2-Bromophenyl)-1H-indole (2a)
Table 1. Optimization Studies for One-Pot Synthesis of THB-
[2,3]azepino[4,5-b]indole 4a via Ring-Opening-Cyclization
of 2-Phenyl-N-tosylaziridine (1a) with 2-(2-Bromophenyl)-
1H-indole (2a)
Scheme 2. Synthesis of THB-[2,3]azepino[4,5-b]indole 4a via
Intramolecular Cyclization of 3a through Cu(I)-Catalyzed C−
N Coupling
entry
metal, ligand, base, solvent, temp
t (h)
yield (%)
1
2
3
4
5
6
7
8
CuI, L-proline, NaH, DMF, 120 °C
CuI, L-proline, K2CO3, DMF, 120 °C
CuI, glycine, NaH, DMF, 120 °C
CuBr, L-proline, NaH, DMF, 120 °C
Cu powder, DMF, 120 °C
Cu powder, toluene, 110 °C
Cu powder, DMSO, 120 °C
Cu powder, NMP, 120 °C
8
36
10
9
trace
25
9
28
6
81
10
8
35
70
10
65
a
The reaction was carried out in the presence of 10 mol % metal
To improve the efficiency of the transformation, a one-pot
(stepwise) protocol for the synthesis of 4a through the ring
opening of 1a with 2a followed by Cu-catalyzed cyclization was
explored, and the desired THB-[2,3]azepino[4,5-b]indole 4a was
obtained in 36% overall yield (Scheme 3). It is noteworthy that
the developed strategy does not require protection of the indolyl
nitrogen,20 thus furnishing the desired products with free N−H
groups.
b
source, 20 mol % ligand, and 2.5 equiv of base. The reaction was
carried out in the presence of 1.0 equiv of the metal source.
Table 2. One-Pot Synthesis of THB-[2,3]azepino[4,5-
b]indoles (4) via Ring-Opening Cyclization of 2-Aryl-N-
tosylaziridine with 2-(2-Bromophenyl)-1H-indole (2a)
Scheme 3. Synthesis of THB-[2,3]azepino[4,5-b]indole 4a via
One-Pot Ring-Opening Cyclization of 2-Phenyl-N-
tosylaziridine with 2-(2-Bromophenyl)-1H-indole (2a)
entry
aziridine (Ar, 1)
indole (2)
4
time (h)
yield (%)
1
2
3
4
5
Ph, 1a
2a
2a
2a
2a
2a
4a
4b
4c
4d
4e
6
81
82
83
85
77
4-FC6H4, 1b
4-ClC6H4, 1c
3-ClC6H4, 1d
2-naphthyl, 1e
6
6.5
6
6
To optimize the reaction conditions with respect to the yield of
the isolated product (4a), various metal sources, ligands, and
bases in different solvents were screened. The best result was
obtained under Cu-powder-mediated C−N bond forming
reaction conditions16d to furnish 4a in 81% overall yield (entry
5). Altering the solvent from DMF to toluene (entry 6), DMSO
(entry 7), or NMP (entry 8) failed to enhance the yield of 4a
further. The results of the complete optimization study are
detailed in Table 1.
To investigate the substrate tolerance of our approach, a range
ofracemic2-aryl-N-tosylaziridines1a−ewerestudiedfortheone-
pot ring-opening cyclization cascade with 2-(2-bromophenyl)-
1H-indole (2a), and in all the cases the corresponding THB-
[2,3]azepino[4,5-b]indoles 1a−e formed in high yield. The
results are described in detail in Table 2.
The strategy was further generalized by engaging a range of
substituted 2-(2-bromophenyl)-1H-indoles as the nucleophiles.
When aziridines 1a, 1d, and 1fwere subjected tothe one-pot ring-
opening cyclization with 2-(2-bromophenyl)-5-fluoro-1H-indole
(2b) under the optimized reaction conditions, the corresponding
THB-[2,3]azepino[4,5-b]indoles 4f−h were obtained in ex-
cellent overall yield (up to 84%, entries 1−3). Likewise, the
reaction of 5-chloro- and 5-fluoroindole derivatives 2c and 2d,
respectively, with aziridines 1aand 1daffordedthe corresponding
THB-[2,3]azepino[4,5-b]indoles 4i−l single regioisomers in
excellent yield (up to 84%, entries 4−7). It is pertinent to note
here that the halogen groups appended around the synthesized
THB-[2,3]azepino[4,5-b]indoles could naturally allow further
synthetic elaboration to other heterocyclic frameworks. All the
results are detailed in Table 3.
The efficiency of the developed methodology was further
examined by using substituted indole nucleophiles with varying
electronic nature. To enhance the nucleophilicity of the C3
center, amethyl group was installed at the NH moiety.21 When 1a
was reacted with 2e, the corresponding THB-[2,3]azepino[4,5-
b]indole derivative 4m was obtained in 75% yield (Scheme 4).
To extend the scope of the methodology further by
accommodating additional functionality in the products, 2-
vinyl-N-tosylaziridine (1g) was employed as the substrate. When
1g was treated with 2a under the optimized reaction conditions,
the corresponding vinyl-substituted THB-[2,3]azepino[4,5-b]-
indole derivative 4n formed as a single regioisomer in 75% yield
(Scheme 5).
To synthesize enantioenriched THB-[2,3]azepino[4,5-b]-
indoles, enantiopure aziridines were employed as the substrates.
When enantiopure (R)-2-phenyl-N-tosylaziridine (R)-1a (ee
>99%) and (S)-2-vinyl-N-tosylaziridine (S)-1g (ee 98%) were
reacted with 2a−e, the corresponding THB-[2,3]azepino[4,5-
B
DOI: 10.1021/acs.orglett.7b01397
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
try,22,23 we attempted the deprotection of the tosyl group. As a
representative example, detosylation of 4a was accomplished in
the presence of sodium naphthalenide in THF at −78 °C and the
corresponding THB-[2,3]azepino[4,5-b]indole derivative 5a
with a free NH group was obtained in excellent yield (88%,
Scheme 7).
Table 3. One-Pot Synthesis of
Tetrahydrobenzoazepinoindoles (4) via Ring-Opening
Cyclization Cascade of 2-Aryl-N-tosylaziridine with 2-(2-
Bromophenyl)-1H-indoles (2)
Scheme 7. Detosylation of THB-[2,3]azepino[4,5-b]indole
with Sodium-Naphthalenide
entry
1 (Ar)
1a (Ph)
2 (R)
4
time (h)
yield (%)
1
2
3
4
5
6
7
2b (F)
2b (F)
2b (F)
2c (Cl)
2c (Cl)
2d (Br)
2d (Br)
4f
4g
4h
4i
6
84
80
79
84
80
81
79
1d (3-ClC6H4)
1f (3-BrC6H4)
1a (Ph)
6.5
6.5
6
Encouraged by our successful results for the synthesis of THB-
[2,3]azepino[4,5-b]indoles, we next directed our efforts to
synthesize another important yet rarely accessed class of
heterocycles viz. DHB-[5,6][1,4]diazepino[1,7-a]indoles by
altering the reactivity of the nucleophile under appropriate
reaction conditions.
To perform the initial ring-opening reaction of 2-phenyl-N-
tosylaziridine1awiththeNsiteoftheindole, 2awastreatedwitha
strong base (1.1 equiv of sodium hydride) in DMF and 1a was
added at rt.16h After complete consumption of 1a in 3 h, 3.0 equiv
of Cu powder were added to the reaction mixture in DMF
portionwise and the temperature of the reaction was elevated to
125 °C. The reaction completed in 5 h, and the desired DHB-
[5,6][1,4]diazepino[1,7-a]indoles 6a was obtained in 73% yield
as the only product (Scheme 8). It is worth noting that the ring
1d (3-ClC6H4)
1a (Ph)
4j
6.5
6.5
7
4k
4l
1d (3-ClC6H4)
Scheme 4. Synthesis of THB-[2,3]azepino[4,5-b]indoles via
One-Pot Ring-Opening Cyclization of 2-Phenyl-N-
tosylaziridine (1a) with 2-(2-Bromophenyl)-1-methyl-1H-
indole (2e)
Scheme 8. Synthesis of DHB-[5,6][1,4]diazepino[1,7-
a]indole 6a via One-Pot Ring-Opening Cyclization of N-
Tosylaziridines (1a) with 2-(2-Bromophenyl)-1H-indole (2a)
Scheme 5. Synthesis of THB-[2,3]azepino[4,5-b]indoles via
One-Pot Ring-Opening Cyclization of 2-Vinyl-N-
tosylaziridine (1g) with 2-(2-Bromophenyl)-1H-indole (2a)
opening primarily took place from the less hindered site of the
aziridine1a. Thestructureof6awasconfirmedbysinglecrystalX-
ray analysis.18
The methodology was generalized by studying a wide range of
structurally different activated aziridines with 2-(2-bromophen-
yl)-1H-indoles under the above-described basic reaction
conditions. Unsubstituted N-tosylaziridine (1h)smoothly under-
went the transformation to furnish the corresponding DHB-
[5,6][1,4]diazepino[1,7-a]indoles 6b in 82% yield (entry 2).
Next, to widen the scope of the strategy we engaged 2-alkyl
substituted aziridines as the substrates. When 2-methyl-N-
tosylaziridine (1i) and 2-n-octyl-N-tosylaziridine (1j) with a
long hydrophobic tail were reacted with 2a, the corresponding
DHB-[5,6][1,4]diazepino[1,7-a]indoles 6c and 6d were ob-
tained in very good yields (entries 3 and 4). Interestingly, the
strategy works well with cyclopentane- and cyclohexane-fused
bicyclic aziridines as well. When 1k and 1l were reacted with 2a
and 2c, respectively, thecorresponding products wereobtained in
high yields (entries 5 and 6). All the results are shown in Table 4.
To synthesize enantioenriched DHB-[5,6][1,4]diazepino[1,7-
a]indoles, enantiopure (R)-1a was reacted with 2a under the
optimized reaction conditions and the corresponding product
b]indole derivatives were obtained in very high yields with
excellent enantiomeric excesses (ee up to 98%, Scheme 6).
To enhance the potential and applicability of the THB-
[2,3]azepino[4,5-b]indole derivatives in medicinal chemis-
Scheme 6. Stereospecific Synthesis of THB-[2,3]azepino[4,5-
b]indoles via One-Pot Ring-Opening Cyclization of (R)-2-
Aryl/Vinyl-N-tosylaziridines with 2-(2-Bromophenyl)-1H-
a
indole (2a)
a
(R)-1a: >99% ee; (S)-1g: 98% ee; R1, R2, R3: Ph, H, H, (S)-4a, 96%
ee; Ph, F, H, (S)-4f, 96% ee; Ph, Cl, H, (S)-4i, 94% ee; Ph, Br, H, (S)-
4k, 97% ee; Ph, H, Me, (S)-4m, 98% ee; vinyl, H, H (S)-4n, 98% ee
C
DOI: 10.1021/acs.orglett.7b01397
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Organic Letters
Letter
Notes
Table 4. Synthesis of DHB-[5,6][1,4]diazepino[1,7-a]indoles
via One-Pot Ring-Opening Cyclization of N-Tosylaziridines
(1) with 2-(2-Bromophenyl)-1H-indoles (2)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.K.G. is grateful to IIT Kanpur and CSIR, India. S.P. and A.B.
thank CSIR, India for research fellowships. C.K.S. and N.C. thank
UGC, India for research fellowships.
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1 (R1, R2)
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1
2
3
4
5
6
1a (Ph, H)
2a (H)
2a (H)
2a (H)
2a (H)
2c (Cl)
2a (H)
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Based on our experimental observations we reasoned that the
reactions proceed via an SN2-type ring opening of aziridines with
indoles followed by a rearomatization process to generate the
corresponding ring-opened products that further undergo a well-
documented Cu-powder mediated C−N cyclization16d to furnish
the final products.18
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routes to THB-[2,3]azepino[4,5-b]indoles and DHB-[5,6][1,4]-
diazepino[1,7-a]indoles via one-pot ring-opening cyclization of
activated aziridines with 2-(2-bromophenyl)-1H-indoles utilizing
both C3 and N nucleophilic centers of the indoles. This simple,
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ASSOCIATED CONTENT
* Supporting Information
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HPLC chromatograms, and crystallographic data (PDF)
X-ray data for compound 4a (CCDC 1530701) (CIF)
X-ray data for compound 6a (CCDC 1530700) (CIF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mkghorai@iitk.ac.in.
ORCID
Aditya Bhattacharyya: 0000-0001-7011-2102
Manas K. Ghorai: 0000-0002-0472-4757
D
DOI: 10.1021/acs.orglett.7b01397
Org. Lett. XXXX, XXX, XXX−XXX