Synthesis of N-Fused Indolines via Copper (II)-Catalyzed Dearomatizing Cyclization of Indoles

Article abstract of DOI:10.1002/adsc.202100290

Herein, a copper(II)-catalyzed dearomative cyclization amination of N-(2-aminobenzoyl) indoles is presented. Under mild reaction conditions, the cyclization proceeds to afford tetracyclic indolines by forming a new C?N bond in good yields. The tetracyclic

Full text of DOI:10.1002/adsc.202100290

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DOI: 10.1002/adsc.202100290
Synthesis of N-Fused Indolines via Copper (II)-Catalyzed
Dearomatizing Cyclization of Indoles
Jingyu Zhang,a Wei Xia,a Saskia Huda,a Jas S. Ward,b Kari Rissanen,b and
Markus Albrechta,*
a
Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
Phone: +49 241 80 94678
Fax: +49 241 80 92385
E-mail: markus.albrecht@oc.rwth-aachen.de
University of Jyvaskyla, Department of Chemistry, Survontie 9 B, FIN-40014 Jyväskylä, Finland
b
Manuscript received: March 5, 2021; Revised manuscript received: March 24, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100290
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
antitumor activity),[4] and isatisine (4, antiviral activity)
Abstract: Herein, a copper(II)-catalyzed dearoma-
(Figure 1).[5]
tive cyclization amination of N-(2-aminobenzoyl)
indoles is presented. Under mild reaction conditions,
To date, some initial synthetic approaches for N-
fused indoline synthesis have already been
the cyclization proceeds to afford tetracyclic indo-
developed.[6] In past decades, methodologies for prepa-
lines by forming a new CÀ N bond in good yields.
ration of indolines has been a focus of attention,[2,7]
however, establishing an efficient protocol to construct
privileged skeletons with therapeutic potential remains
highly challenging in synthetic chemistry. The dear-
omatization of indoles has been recognized as an
efficient approach to obtain indolines. Recently, dear-
omatizing strategies have attracted increased attention,
with a myriad of methods to access indolines via
intramolecular[8] or intermolecular dearomatization[9]
having been developed.
The tetracyclic 5a,6-dihydroindolo[2,1-b]
quinazolin-12(5H)-ones are obtained in good to
excellent yields (up to 99% yield) by using
trifluoromethanesulfonic acid (TfOH) mediated
NÀ Ts bond cleavage. The obtained compounds
could be easily functionalized by simple synthetic
methods.
Keywords: Indoline; cyclization; dearomatization;
Up to this point, some cases involving N-tethered
indoles are used to synthesize indolines via dearoma-
tizing cyclization (Scheme 1).[10–13] These reactions
usually proceed in the presence of a catalyst, such as
palladium or nickel salts, or by visible-light photo-
catalysis. The dearomative cyclization proceeds with
CÀ C bond formation (Scheme 1, a).[10] On the other
indoles; copper catalyst
Introduction
Indole and its derivatives continue to inspire develop- hand, just recently, our group and others developed
ments in organic synthetic chemistry even after so protocols for the synthesis of fused indolines by
many years since their discovery. The specific scaffold dearomatizing cyclization of N-acylindoles.[11,12,13]
is a privileged structure and is ubiquitous in pharma- These reactions involve CÀ O bond formation in the
ceuticals and biologically active compounds.[1] Fused presence of a palladium catalyst, BBr3 or triflic acid,
indolines as indole derivatives are of particular interest and an FeCl3 catalyst (Scheme 1, b). Only one low
as they are often found in natural products and yield example involving CÀ N bond formation was
bioactives,[2] for example, strychnine and tryptanthrins reported in the previous work.[13] However, developing
(1, 2, alkaloids),[3] mitosanes and mitosenes (3, mild and effective reaction conditions to access novel
indoline structures is still highly desirable.
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Results and Discussion
The N-acylindole 3a (N-(2-(1H-indole-1-carbonyl)
phenyl)-4-methylbenzenesulfonamide) is easily avail-
able in three steps from commercially available indole
(see experimental section) and was selected as the
standard substrate for this study. Initially, we began the
investigation employing Fe2(SO4)3 (10 mol%) and H2O
°
(20 μL) in chloroform (0.1 mL) at 60 C for 48 hours
and obtained the cyclization product 4a in only 5%
yield. To our delight, the cyclization product was
obtained in 44% yield with FeCl3 ·6H2O. The yield
improved dramatically when FeCl2 ·4H2O and FeCl3
were used, giving 4a in 91% and 92%, respectively.
However, Y(OTf)3 and Ga(acac)3 did not yield any of
the cyclization product, while MnCl2 ·2H2O,
YbCl3 ·6H2O, Cu(OAc)2, CuCl2, and the “classical”
Lewis acid TiCl4 gave 4a in low yields. Several
additional Lewis acids were also screened. The best
yield (99%) of 4a was obtained by employing Cu-
(OTf)2 as the catalyst, with SnCl4 or Ga(OTf)3 also
yielding the desired product in good to excellent
yields. The use of TfOH (10 mol%) affords 4a in 21%
yield as well as 53% of 7aa. Hence, TfOH derived
from Cu(OTf)2 also catalyzes the dearomative cycliza-
tion. Nevertheless, the copper salt seems to be essential
to obtain excellent yields of the direct cyclization
product 4a.[14] The effects of the reaction solvent and
the reaction temperature were also subsequently
screened. However, the desired product yield decreased
dramatically by using CH3CN or THF as the solvent.
Nevertheless, in toluene the desired 4a was obtained in
95% yield. When the reaction temperature was
Figure 1. Natural products and bioactives bearing the N-fused
indoline core.
°
decreased to 40 C or even to room temperature almost
no 4a was formed. The concentration of the substrates
as well as the presence of water was also found to
influence the reaction (Table 1).
To evaluate the generality of this novel trans-
formation, the reaction was conducted by employing
10 mol% Cu(OTf)2 with H2O (20 μL) in chloroform
Scheme 1. Dearomatization cyclization reactions at indole skel-
eton.
°
(0.1 mL) at 60 C for 48 hours under an atmosphere of
air (standard conditions). The scope of the reaction is
shown in Scheme 2. Initially, the substituent effect at
Our recent discovery of an iron catalyzed dearomati- the terminal amine was tested, and generally, the
zation cyclization of phenol-substituted acylindoles dearomative cyclization products can be obtained in
opened the door to exploring potential protocols for the moderate yields. Notably, it was found that the
preparation of new indoline structures. In a first attempt electron-donating methyl group at different positions
the cyclization proceeds by tosylamides forming the of the benzene ring showed different reactivity. Only
CÀ N bonds in modest yield.[13] Encouraged by these 4% of the product 4c was obtained when the methyl
results and following our continuous effort of polycyclic group was located at the ortho position. Shifting this
framework synthesis, we now report a copper(II) group to the meta- or para-positions, products 4d or
trifluoromethanesulfonate catalyzed dearomatizing cyc- 4a were obtained in moderate or excellent yields.
lization of N-acylindoles by forming a new CÀ N bond, When no substituent was present at the phenyl ring, a
yielding N-fused indolines in moderate to good yields. moderate yield of 4b was found. Inspired by these
Selective NÀ Ts bond cleavage in the presence of TfOH results, other substituents were investigated at the
affords tetracyclic 5a,6-dihydroindolo[2,1-b]quinazolin- para-position of the phenyl ring. It was found that the
12(5H)-ones in good to excellent yields (Scheme 1, c).
substrates with electron-donating groups, halogens,
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Table 1. Effects of reaction parameters.[a]
°
Entry
Cat. (0.1 eq.)
Solvent
T ( C)
4a (%)[b]
1
2
3
4
5
6
7
8
Fe2(SO4)3
FeCl3 ·6H2O
FeCl2 ·4H2O
FeCl3
Y(OTf)3
YbCl3 ·6H2O
TiCl4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
rt
5
44
91
92
0
trace
13
71
trace
0
94
trace
5
99 (94)
trace
0
95
trace
0
51
55
SnCl4
9
MnCl2 ·2H2O
Ga(acac)3
Ga(OTf)3
Cu(OAc)2
CuCl2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
11
12
13
14
15
16
17
18
19
20[c]
21[d]
22[e]
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
60
60
60
83
[a] Standard conditions: 1a (0.2 mmol), Cu(OTf)2 (10 mol%),
°
CHCl3 (0.1 mL), H2O (20 μL), 60 C, air, 48 hrs.
[b] Yield are determined by 1H NMR with 1,3,5-trimeth-
oxybenzene as the internal standard; Isolated yields are
shown in brackets.
[c] CHCl3 (0.2 mL).
[d] CHCl3 (0.4 mL).
Scheme 2. Scope of substrates bearing terminal aryl amine.
[e] without H2O.
6b, 6c–6d, and 6g) were compatible with the reaction.
and electron-withdrawing groups at the para-position However, rather moderate yields of the cyclization
of the aromatic ring were compatible with the reaction products were formed when strong electron-donating
conditions, with the desired products formed in or withdrawing groups at the C5-position (6b–6d)
moderate to good yields (4e–4m). Notably, only 7% were introduced. Chloro substituents at the C5- or C6-
of 4k was obtained with two chloro substituents. position of the indole has a positive effect compared
Moreover, phenyl groups and additional rings at the with a bromine atom at the C5-position (6e–6f, and
phenyl moiety can also yield the desired products in 6h). The methyl substituent at the C2-position of
moderate yields (4n–4o). Unfortunately, when benzoyl indole resulted in a moderate cyclization yield, while
and substituted benzoyl groups were used instead of the phenyl at the C2-position only afforded a low yield
the aryl sulfonyl groups at the nitrogen atom, no (3%) of the product (6j). Notably, there are still large
desired products (4p–4q) were obtained. Compounds amounts of unreacted starting substrates in the test
4g, 4h, 4j, 4l were confirmed by X-ray crystallo- reactions. The structures of 6b and 6i were confirmed
graphic analysis (Scheme 2).
by X-ray crystallographic analysis (Scheme 3).
In light of these results, we found that a tosyl group
Subsequently, a facile and selective NÀ Ts bond
at the terminal amine was the most favoured substitu- cleavage approach to access novel tetracyclic indolines
ent for the dearomative cyclization reaction. Following was carried out by employing one equivalent trifluor-
this, the influence of the substituents at the indole ring omethanesulfonic acid (TfOH) in the presence of water
were tested. Both electron-donating and withdrawing (Scheme 4). Without water the yield drops signifi-
groups at the C5- and C6-position of the indole (6a– cantly. The substrates bearing electron-donating
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and chloro (7e and 7h) were all tolerated well.
Moreover, when the steric bulk of the methyl group
was introduced at the C2-position, a good yield of the
desired product 7i was observed, and its structure
confirmed by X-ray crystallographic analysis. Notably,
without a substituent at the indole ring, a near
quantitative yield of 7aa was obtained.
Finally, facile and selective derivatizations at the
tetracyclic
5a,6-dihydroindolo[2,1-b]quinazolin-
12(5H)-one (7aa) were carried out in Scheme 5.
Herein, benzoylation of 7aa provides an easy approach
to access 4p, which was not possible following the
protocol in Scheme 2. Moreover, 7aa can be oxidized
to obtain alkaloid tryptanthrin (8aa). Its antiviral
activities have been studied recently.[15] The carbonyl
group and CÀ N bond of 7aa can be selectively reduced
by employing B(C6F5)3 and NH3-BH3 to generate the
indoline product 9aa.
Conclusion
In conclusion, a versatile copper(II)-catalyzed dearo-
mative cyclization of indoles with terminal amine has
been developed. Various tetracyclic indolines were
obtained by forming a new CÀ N bond in moderate to
good yields. The TfOH mediated selective NÀ Ts bond
cleavage gives access to N-fused indolines in good to
excellent yields. In subsequent reaction steps, the
Scheme 3. Scope of substrates with substituents on indole.
tetracyclic
5a,6-dihydroindolo[2,1-b]quinazolin-
12(5H)-one can be easily functionalized by simple
procedures.
Experimental Section
General procedure I: The dearomatizing cyclization of N-
acylindoles. A solution of 3 or 5 (0.2 mmol), Cu(OTf)2 (7.2 mg,
10 mol%), H2O (20 μL) in CHCl3 (0.1 mL) were stirred under
°
an atmosphere of air at 60 C for 48–96 h. The reaction mixture
was washed with water and extracted with CH2Cl2 for three
times. The combined organic layers were dried with Na2SO4.
Scheme 4. Selective cleavage NÀ Ts bond to access novel
tetracyclic indolines.
groups, electron-withdrawing groups, and chloro sub-
stituents at the C5 or C6-position were suitable for this
reaction to afford the desired tetracyclic indolines in
good to excellent yields (7a–7h). Many kinds of
functional groups, such as methoxy (7b), cyano (7d),
Scheme 5. Derivatization
of
5a,6-dihydroindolo[2,1-b]
quinazolin-12(5H)-one (7aa): (i) N-acylation of the product 7aa.
(ii) oxidation of 7aa synthesis of tryptanthrin. (iii) reduction of
(C=O) and (CÀ N) bonds by B(C6F5)3 and NH3-BH3.
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The solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography over silica gel
with n-pentane/ethyl acetate to afford the pure products 4 and 6.
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General procedure II: Cleavage of the N-tosyl group. A
solution
of
5-tosyl-5a,6-dihydroindolo[2,1-b]quinazolin-
12(5H)-one 4 or 6 (0.1 mmol), trifluoromethanesulfonic acid
(TfOH) (8.8 μL, 0.1 mmol), H2O (20 μL) in CHCl3 (0.1 mL)
°
were stirred in a flask under an atmosphere of air at 60 C for
24 h. The reaction mixture was washed with water and extracted
with CH2Cl2 for three times. The combined organic layers were
dried with Na2SO4. The solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel with n-pentane/ethyl acetate to afford the pure
products 7.
CCDC-2067943 (4g), CCDC-2067944 (4h), CCDC-2067945
(4j), CCDC-2067946 (4l), CCDC-2067947 (6b), CCDC-
2067948 (6i), and CCDC-2067949 (7i) contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The supporting information contains further crystal structure
1
information, compound characterization and copies of H and
13C{1H} NMR spectra.
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Acknowledgements
Jingyu Zhang gratefully acknowledges support by the Chinese
Scholarship Council (CSC), Jas S. Ward the Finnish Cultural
Foundation Central Fund (grant number 00201148) and Kari
Rissanen the Alexander von Humboldt Foundation. (AvH
research award) Open access funding enabled and organized by
Projekt DEAL.
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Synthesis of N-Fused Indolines via Copper (II)-Catalyzed
Dearomatizing Cyclization of Indoles
Adv. Synth. Catal. 2021, 363, 1–7
J. Zhang, W. Xia, S. Huda, J. S. Ward, K. Rissanen, M.
Albrecht*