Synthesis of Azepino[1,2-a]indole-10-amines via [6+1] Annulation of Ynenitriles with Reformatsky Reagent

Article abstract of DOI:10.1002/ejoc.202100021

Lewis acid-catalyzed [6+1] annulation reactions of 2-cyano-1-propargyl- and 2-alkynyl-1-cyanomethyl-indoles with Reformatsky reagent are described. 8-Aryl, 8-alkyl-, 8-hetaryl-, 9-aryl, and 9-alkyl-azepino[1,2-a]indole amines were obtained through a 7-endo-mode cyclization of the β-aminoacrylate intermediates. The antiproliferative activity of the azepino[1,2-a]indoles analogs against the HCT-116 cells were also examined.

Full text of DOI:10.1002/ejoc.202100021

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doi.org/10.1002/ejoc.202100021
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Synthesis of Azepino[1,2-a]indole-10-amines via [6+1]
Annulation of Ynenitriles with Reformatsky Reagent
Ryoya Iioka,[a] Kohei Yorozu,[a] Yoko Sakai,[a] Rika Kawai,[a] Noriyuki Hatae,[b]
Katsuki Takashima,[c] Genzoh Tanabe,[c] Hiroaki Wasada,[d] and Mitsuhiro Yoshimatsu*[a]
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analogs. Therefore, we explored the easy accessed to the
indoleamines. The present three methods for these analogs
(Scheme 1a, Scheme 1b and Scheme 1c)[10b,16e,19–21] are pio-
neering works and often difficult to access because of their
multi-step synthesis using pyridyl- and piperidyl-indoles and
some unsure reasons. Due to these difficulties, we have
planned to synthesize azepino[1,2-a]indole-10-amines using
a protocol for amino-annulation process, the Blaise reaction
using Reformatsky reagent and nitriles.[22] The 7-membered
ring construction at the N1À C2 face of indoles could be
achieved by involving the amine functionalization at the
10 positions on the azepino[1,2-a]indole rings (Scheme 1d).[23]
Here we report the convenient and regioselective synthesis
of azepino[1,2-a]indole-10-amines and their isomers from 2-
cyano-1-propargyl- and 2-alkynyl-1-cyanomethyl-indoles and
the screening results for their anti-proliferative activities.
Lewis acid-catalyzed [6+1] annulation reactions of 2-cyano-
1-propargyl- and 2-alkynyl-1-cyanomethyl-indoles with Refor-
matsky reagent are described. 8-Aryl, 8-alkyl-, 8-hetaryl-, 9-
aryl, and 9-alkyl-azepino[1,2-a]indole amines were obtained
through a 7-endo-mode cyclization of the β-aminoacrylate
intermediates. The antiproliferative activity of the azepino
[1,2-a]indoles analogs against the HCT-116 cells were also
examined.
Introduction
Azepino[1,2-a]indole-10-amine analogs have been useful
pharma cores in the human cancer cell lines due to their
huge potential as an antiproliferative agent against chol-
angiocarcinoma, hepatocellular carcinoma, lung carcinoma,
and lymphoblastic leukemia.[1,2] Furthermore, maxonine iso-
lated from Simira maxonii,[3] and arborescidine BÀ D isolated
from Pseudodistoma arborescens,[4] apogeissoschizine,[5]
akagerine,[6] and coreantine,[7] whose core structures are
azepino[1,2-a]indole-10-amines, could be the most promising
scaffold for drug development.[8]
Classically, the azepino[1,2-a]indoles are synthesized by
the flush vacuum pyrolysis of o-aziodiphenylmethanes at
[9]
°
°
350 C–700 C. Tricyclic carbolines are usually synthesized
by intramolecular cyclization under acidic conditions.[8d,10–12]
Recently, useful protocols of synthesis of azepino[1,2-a]
indoles were established by some excellent methods using
transition metal-catalyzed reactions of indoles,[13] like RCM
method using Grubbs II catalysts,[14] Pauson-Khand type
reactions,[15] one pot sequential processes from the haloalkyl
indoles with aryl halides,[16] the intermolecular [5+2],[17] and
[4+3] cyclization reactions.[18] However, most of the present
methods are not suitable for the synthesis of their amine
[a] R. Iioka, K. Yorozu, Y. Sakai, R. Kawai, Prof. Dr. M. Yoshimatsu
Department of Chemistry, Faculty of Education, Gifu University
Yanagido 1–1, 501-1193 Gifu, Japan
E-mail: yoshimae@gifu-u.ac.jp
[b] Prof. Dr. N. Hatae
Faculty of Pharmaceutical Sciences, Yokohama University of Pharmacy
601 Matano, Totsuka-ku, 245-0066 Yokohama, Kanagawa, Japan
[c] Dr. K. Takashima, Prof. Dr. G. Tanabe
Faculty of Pharmacy, Kinki University,
3-4-1 Kowakae, 577-8502 Higashi-osaka, Osaka, Japan
[d] Prof. Dr. H. Wasada
Department of Chemistry, Faculty of Regional Study, Gifu University,
Yanagido 1–1, 501-1193 Gifu, Japan
Scheme 1. Recent study for the synthesis of azepino[1,2-a]azepine-10-
amines.
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°
Results and Discussion
d5 (Figure 1).[23,24] When the temperature was raised to 80 C,
the spectral data clearly exhibited each peak on azepine ring.
In particular, the 6-methylene protons, which could not be
observed in CDCl3, appeared at δ 4.50 ppm, accompanied by
the methylene protons at δ 4.28 ppm and ethoxy groups at
9-position of azepino[1,2-a]indoles in pyridine-d5, because of
the acceleration of interconversion of some conformers. The
typical structure was supported by their spectral data and
elemental analysis.
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We first examined a [6+1] annulation reaction of the parent
substrate, 2-cyano-1-propargylindole 1a with Reformatsky
reagent, generated from ethyl bromoacetate and activated
zinc, in the presence of hafnium triflate as a standard
condition of [6+1] annulation reaction of N-tethered
ynenitriles.[23] Both azepino[1,2-a]indole 2a and pyridoindole
3a were respectively obtained via either a 7-endo-mode or a
6-exo-mode annulation of the β-aminoacrylate intermediates.
We were pleased to see the preliminary results and further
examined the Lewis acid screening to lower the formation of
6-exo-mode cyclization products (Table 1). The reaction with-
out Lewis acids gave 2a (49%) and 3a (38%), respectively.
The most suitable reaction condition of the monocyclic
azepines using hafnium triflate gave an unsatisfactory result
(entry 2). Both the reactions using either indium triflate or
ytterbium triflate resulted in low yields of products; however,
the scandium triflate-catalyzed reaction exclusively under-
went a [6+1] annulation reaction to give 2a in 99% yield.
The product, 10-amino-6H-azepino[1,2-a]indole-9-carbox-
ylate (2a), did not give a complete set of proton signals in
the 1H NMR spectrum. For instance, we cannot clearly see
some protons of both the 6-methylene protons and/or the
methylene protons of ethoxy carbonyl group on the azepine
Under the optimized reaction conditions in hand, we next
researched the scope of the [6+1] annulation reactions of 2-
cyano-1-propargylindoles with some Reformatsky reagents
and the results are summarized in Table 2. The reaction of 2-
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cyano-1-(phenylpropargyl)indole 1b with
a Reformatsky
reagent (BrZnCH2CO2Et) succeeded to give the azepine 2b in
75% yield. Interestingly, the methyl signal of 9-ethoxy
carbonyl group of 2b was significantly upfield-shifted at δ
0.63 ppm in the 1H NMR spectrum due to the anisotropic
effect of 8-phenyl group. The upfield shift of the signal due
to methyl group of esters was also observed in the other 8-
phenylated azepino indole derivatives. We next performed
the reactions of both 1a and 1b with methyl ester
(BrZnCH2CO2Me) afforded methyl 10-amino-8-phenyl-5b and
methyl 10-amino-8-ethyl-6H-azepino[1,2-a]indole-8-carboxy-
late (5a), respectively. In order to investigate the substituent
effect on the indole ring, we prepared a wide variety of
substrates by almost the same method (the results are
summarized in the SI). The Reformatsky reaction of 5-meth-
oxyindole gave the azepino[1,2-a]indole 2d, accompanied by
the pyrido[1,2-a]indole 3d; however, the reaction with meth-
yl ester selectively afforded the azepine analog 2f in 78%
yield. The reaction of 1e with the bulky t-butyl ester resulted
in the low yield of 7e. The reactions of 5,6-dimethoxyindoles
1f and 1 g exclusively afforded two kinds of azepines 2f and
2g, respectively; however, the reactions of 5-fluoro-, 4,6-
difluoro-, and 4,6-dichloroindoles 1h–j with a Reformatsky
reagent, obtained a significant amount of pyrido[1,2-a]
indoles in each case. We also investigated the substituent
effect of these annulation reactions using 2-cyano-1-prop-
argylindoles 1k–1q bearing some substituents at the alkyne
terminus. We selected indole 1r as a tentative substrate for a
large–scale scandium-catalyzed [6+1] annulation reaction.
The reaction of 1r was tolerated at 0.30 g scale (1.00 mmol
scale) and afforded 2r in 72% yield. The 1 g scale reaction of
1x successfully afforded 0.5 g of 2 x, however, a half amount
of complex mixture was obtained. The scalability of this
annulation needs further optimization processes.
°
ring at 25 C due to the broadening in the spectral data in
CDCl3. In order to solve this inconveniency, we performed the
temperature variable NMR measurements of 2a in pyridine-
Table 1. Optimization of the [6+1] cycloaddition.[a]
Entry
Lewis acids
Reaction time (h)
Yield of 2a[b]
Yield of 3a
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2.5
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–
Hf(OTf)4
In(OTf)3
Yb(OTf)3
Sc(OTf)3
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0.5
99
[a] Reaction condition: 1a (0.19 mmol), zinc (0.19 mmol), ethyl bromoace-
tate (0.95 mmol) and catalyst (0.027 mmol) in 1,4-dioxane (1.00 mL).
[b] Yields of isolated products. [c] 1a was recovered in 50% yield.
The annulations of 2-cyanoindoles bearing hetaryl groups
at the alkyne terminus afforded 8-(thiophen-2-yl)- and 8-
(indolyl-3-yl)-azepines 2α and 2β; however, the reaction of
pyridine-substituted indole 1γ did not give azepino[1,2-a]
indole 2γ, but pyrido[1,2-a]indole 3γ in good yield.
In light of these encouraged results, the [6+1] annulation
reactions of different types of substrates, 2-alkynyl-1-
cyanomethyl indoles 8 with similar Reformatsky reagent were
performed and the results are shown in Table 3. After few
screenings of Lewis acids, we chose hafnium triflate as suitable
Figure 1. Temperature variable NMR measurements of 2a in pyridine-d5.
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Table 2. Substrate scope of [6+1] annulation reaction of 2-cyano-1-
Table 3. [6+1] Annulation reaction of 2-alkynyl-1-cyanomethylindoles.[a]
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propargylindoles with Reformatsky reagents.[a,b]
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[a] Yields of isolated products. [b] β-Enaminoester 10 was isolated.
tions. Thienopyrroles are privileged scaffolds in medicinal
chemistry (Scheme 2).[25] Therefore, we next selected the
azepine-fused thienopyrroles as the target material. Using a
similar synthetic procedure for 2-cyano-5,6-dimeth-
oxyindoles, we prepared thieno[3,2-b]pyrrole-5-carbonitrile
13 from methyl thiophene-2-carbonitrile (11) by sequential
process: (i) reduction of esters, (ii) oxidation with PCC,
(iii) cyanomethylation, and (iv) base-promoted cyclization.
Propargylation and successive annulation reaction afforded
ethyl
9-amino-7-phenyl-5H-thieno[2’,3’:4,5]pyrrolo[1,2-a]
azepine-8-carboxylate (15) in high yields. In the 1H NMR
spectrum of 15, one of singlet protons due to methyl group
of ethyl ester moiety was detected at δH 0.64 ppm, suggest-
ing that methyl protons were also located immediately above
the π plane of 7-phenyl ring. Finally, the structure of 15 was
confirmed by X-ray crystallographic analysis, in which the
methyl carbon was revealed to be distant from the π plane of
phenyl ring with a distance of ca. 3.9 Å, which is sufficient
distance for intramolecular CH/π interaction (Figure 2).
The mechanism for selective formation of azepines are
proposed in Scheme 3.[23] Nucleophilic addition of Reformat-
sky reagent with nitrile gives the key intermediate, β-amino-
acrylate, whose intramolecular 7-endo-mode cyclization gives
azepines, otherwise 6-exo-mode cyclization gives pyrido
indoles. As shown in eq 1 of Scheme 3, the calculated
[a] Reaction conditions: most of substrates were used 0.10–0.19 mmol.
Substrates 1b–1g, 10 equiv. of zinc and 7.0 equiv. of alkyl bromoacetates
were refluxed for 0.5–4 h in 1,4-dioxane (1.0–1.5 mL). [b] Yields of isolated
products. [c] yield of 2r from 1r (1.00 mmol); yield of 2x from 1x (1.00 g)
and scandium triflate (0.05 equiv). [d] copper acetate was used as a
catalyst.
Lewis acids in the reactions of 2-alkynyl-1-cyanomethylindoles.
Most of reactions exclusively proceeded to give azepines;
however, the system seems to be difficult to undergo intra-
molecular annulation of acrylate intermediates by comparing
with that of 2-cyano-1-propargylindoles.
We next turn our attention to the synthesis of hetero-
cycle–fused indole derivatives using [6+1] annulation reac-
Scheme 2. [6+1] Annulation reaction of 4-(3-phenylprop-2-yn-1-yl)-4H-thie-
no[3,2-b]pyrrole-5-carbonitrile.
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Figure 3. Antiproliferative activity of Azepino[1,2-a]indoles against HCT-116
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cells. HCT-116 cells were treated with 10 (filled column) or 100 (open
column) μM of azepinoindoles, and the cell viabilities were assessed with
MTT method. Data are shown as mean�SEM values.
Figure 2. ORTEP Drawing of 15.
of 6-exo-mode-cyclized products, like indolo[1,2-a]pyridines.
In the reaction of pyridin-3-yl derivative 1γ, the used Lewis
acid acts on the nitrogen atom of pyridine so that the
scandium–alkyne complex does not form. Therefore, the
reaction of 1γ with Reformatsky reagent did not give the
azepine 2γ, but a complex mixture. After screening of metals
for the pyridinyl derivative, we found to afford the product
using copper catalysts; however, the product was only pyrido
[1,2-a]indole 2 g via a 6-exo-mode cyclization of β-amino-
acrylate intermediate. The reacions of 2-alkynyl-1-cyanometh-
ylindoles with Reformatsky reagent exclusively gave the
indolo[1,2-a]azepines via a 7-endo-mode cyclization reac-
tions. The selectivity would be explained as follows. Since the
nucleophilicity of C3 of indole ring is very high,[27] the rigid
metal-π-complex would be formed (eq 3). Therefore, the rigid
slippage-like complex on the alkyne would accelerate their
positive charge at the α-position of R group.
Some of the azepino[1,2-a]indole derivatives have been
reported to be biological compounds with hepatitis C virus
NS5B inhibition,[28] but without antiproliferative activity.
Synthesized azepino[1,2-a]indoles were assessed for their
antiproliferative activity against human colon tumor cell-
derived HCT-116 cells (Figure 3). All the analogs indicated
higher cell viability values on 100 μM treatments compared
with 10 μM treatments. Treatments with 10 μM of anlogs 2g,
2n, 2o, and 2p, were shown to have cell viability values
below 40%, and the dimethoxy moiety on indoles rings could
lead to increase in the antiproliferative activity against HCT-
116 cells. The IC50 value for analog 2f was indicated as 19.5�
3.6 μM (data not shown), although the values for analogs 2g,
2n, 2o, and 2p were not analyzable. The reason IC50 values
were not analizable maybe due to their low bio-availability
and solubility.
Scheme 3. DFT calculations on the [6+1] annulation reactions.
Mulliken charge of monocyclic intermediate shows a positive
charge at the exo carbon of the alkyne bearing the ethyl
group. The intramolecular cyclization would occur at the α-
carbon of the ethyl group to exclusively give the azepines.
This is true in the [6+1] annulation reactions of indole
system. We calculated the Mulliken charge of scandium metal
coordinated indole-2-yl aminoacrylate intermediates and the
result is shown in eq 2 of Scheme 3. However, the results of
calculations did not agree well with the experimental results
as follows. The Mulliken charges of both C2 and C3 of 7-endo-
mode-transition state (TS) were almost the same as that of 6-
exo-mode cyclization. Noteworthy is the significant differ-
ence between the relative energy levels between 7-endo-TS
and 6-exo-TS. The difference of energy level (ΔETS7endo-TS6-exo
of 5,6-(MeO)2-indolyl-TS is 2.31 kcal/mol. Whereas, ΔETS7endo-
)
Conclusion
of 5-fluoroindolyl-TS is 1.11 kcal/mol. The relatively
In conclusion, a scandium-catalyzed [6+1] annulation reac-
tion of cyano indoles with the Reformatsky reagents was
developed. Most of reactions proceeded to give the azepino
[1,2-a]indoles via intramolecular 7-endo-mode cyclization
reaction of β-aminoacrylate intermediates. The unique aze-
TS6-exo
large energy level of 5,6-(MeO)2indolyl-TS selectively under-
goes 7-endo-mode cyclization exclusively to give indolo[1,2-
a]azepines in good yields. The low difference energy level of
ΔETS7endo-TS6-exo of 5-fluoroindolyl-TS gives rise to the increase
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[8] a) X. Wang, D. Xia, W. Qin, R. Zhou, X. Zhou, Q. Zhou, W. Liu, X. Dai, H.
pine-fused thienopyrroles have been synthesized using the
simple 4-step procedure from methyl 3-((4-methylphenyl)
sulfonamido)-thiophene-2-carboxylate. The high selectivity of
annulation reactions could be supported by the DFT-calcu-
lation of transition states. Additional exploration of the
antiproliferative activity of azepino[1,2-a]indoles was also
described.
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Conflict of Interest
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The authors declare no conflict of interest.
Keywords: Annulation · Antitumor agents · Scandium · Zinc
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Manuscript received: January 7, 2021
Revised manuscript received: January 25, 2021
Accepted manuscript online: February 3, 2021
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