Syntheses of Heterocycle-2,3-Fused Indoline and Azaindoline -Derivatives

Article abstract of DOI:10.1055/s-0037-1610771

We describe a practical method for synthesizing heterocycle-2,3-fused indoline or azaindoline derivatives through haloetherification and cyclization. We applied this method in syntheses of six- to eight-membered heterocycle-2,3-fused indoline and azaindoline derivatives. These derivatives, which contain sp 3 -hybridized carbons, might be useful as new scaffolds in medicinal chemistry.

Full text of DOI:10.1055/s-0037-1610771

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–E
letter
A
en
T. Nishi et al.
Letter
Synlett
Syntheses of Heterocycle-2,3-Fused Indoline and Azaindoline
Derivatives
R2
Takahide Nishi*
HN R2
Ag2O or K2CO3
H
Br
N
N
n
H
HO
R2
Naoki Mishima
Haruna Kato
Koji Yamada
n
n
R
R
O
N
R1
O
R
NBS
N
R1
N
R1
H
n = 1–3
Faculty of Pharmaceutical Sciences, Health Sciences University
of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
nishi-t@hoku-iryo-u.ac.jp
R2
R2
N
H
R2
H
R2
H
N
N
N
H
8
7
O
H
R
O
R
O
N
R
O
R
N
N
H
N
R1
N
R1
H
H
R1
TFeaMckauailChltoiyndrioersefhNsPip-ihsto@ahnrihmdoinakcgue-Auirutyitcoha-olurS.accie.jnpces, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
R1
2 examples
2 examples
6 examples
6 examples
Received: 12.03.2021
Accepted after revision: 27.03.2021
Published online: 20.04.2021
ring-fused indolines. Wang and co-workers reported a cop-
per-catalyzed [4+2]-cycloaddition of indoles with chlori-
nated hydrazones,9 and the Ji group reported a metal-free
dearomatization of indoles with -bromo hydrazones.10
Palacios and co-workers reported a [4+2]-cycloaddition be-
tween indoles and nitrosoalkenes,11 and the Larionov group
reported the first example of a copper-catalyzed asymmet-
ric [4+2]-cycloaddition of nitrosoalkenes.12 In 2020, the Favi
group developed a Zn(II)-catalyzed [4+2]-cycloaddition of
indoles with 1,2-diaza-1,3-dienes,13 and Li and co-workers
reported dearomative [4+2]-annulations of 3-nitroindoles
and enals.14 Although these methods for synthesizing six-
membered-ring-fused indolines are relatively well devel-
oped, the range of heterocyclic structures is often limited
by hypervalent iodine oxidation.15 However, in 2020, Lei
and co-workers reported an efficient electrooxidative
[4+2]-dearomatization/annulation of indoles with various
bisnucleophiles containing O-, N-, or S-nucleophilic groups
by an electrochemical method.16 This method can be ex-
tended to intermolecular [3+2]-, [5+2]-, and [6+2]-annula-
tions for the construction of seven- and eight-membered-
ring-fused 2,3-indolines, respectively.
DOI: 10.1055/s-0037-1610771; Art ID: st-2021-u0097-l
Abstract We describe a practical method for synthesizing heterocy-
cle-2,3-fused indoline or azaindoline derivatives through haloetherifica-
tion and cyclization. We applied this method in syntheses of six- to
eight-membered heterocycle-2,3-fused indoline and azaindoline deriv-
atives. These derivatives, which contain sp3-hybridized carbons, might
be useful as new scaffolds in medicinal chemistry.
Key words haloetherification, indolines, azaindolines, morpholines,
oxazepines, oxazocines
Indoles and indolines are important privileged struc-
tures present in several biologically active compounds of
both natural and synthetic-pharmaceutical origin. Of par-
ticular interest are heterocycle-fused indolines containing
sp3-hybridized carbons, which can open up new vectors for
exploring three-dimensional chemical spaces in terms of
druggability in pharmaceuticals.1,2 This fact has stimulated
worldwide efforts to develop new synthetic approaches for
preparing novel sp3-rich heterocyclic scaffolds.
Among the numerous methods available,3 the dearoma-
tive annulation of indoles through cycloaddition reactions
has emerged as a powerful tool for preparing heterocycle-
2,3-fused indolines. Cyclopropanation,4 1,3-dipole cycload-
dition,5 [2+2]-photocycloaddition,6 Diels–Alder,7 and cas-
cade electrophilic addition/annulation reactions8 are well-
documented methods for obtaining 2,3-five-membered-
ring-fused indolines. Compared with five-membered-ring-
fused indolines, for which several well-established methods
are available, biologically valuable indoles with rings of six
or more members are rarely accessed under thermal condi-
tions. In this regard, [4+2]-cycloaddition has been the most
frequently applied method for synthesizing six-membered-
R2
R2
H
N
N
H
7
O
R
R
O
N
N
R1
H
H
R1
1
2
R2
R2
H
N
N
H
8
O
R
N
O
R
N
R1
H
N
H
R1
3
4
Figure 1 Design of indoline and azaindoline scaffolds
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Nishi et al.
Letter
Synlett
Here, we report the design and syntheses of six- to
eight-membered heterocycle-2,3-fused indoline and azain-
doline derivatives 1–4 (Figure 1).
Table 1 Haloetherification of 5a–c
NHR2
HO
NHR2
Br
These novel six- to eight-membered heterocycle-2,3-
fused indoline and azaindoline derivatives containing sp3-
hybridized carbons might be useful as new scaffolds in me-
dicinal chemistry. For the preparation of compounds 1, we
considered the retrosynthetic route shown in Scheme 1. We
planned to apply our reported haloetherification methods
to 2,2-disubstituted morpholine analogues17 and 4-benzyl-
oxyindoles.18
(3 eq)
O
N
NBS (1.5 eq)
R1
N
R1
C6H5CF3 or CH3CN
5a (R1 = Ts)
6a (R1 = Ts, R2 = Boc)
6b (R1 = Ts, R2 = Ns)
6c (R1 = Ns, R2 = Boc)
6d (R1 = Ns, R2 = Ns)
5b (R1 = Ns)
Ns = 2-nitrobenzenesulfonyl
Entry
R1
Ts
Ts
Ns
Ns
R2
Solvent
C6H5CF3
CH3CN
C6H5CF3
CH3CN
Product
6a
Yield (%)
1
2
3
4
Boc
Nsa
Boc
Ns
80
38
57
51
R2
N
NHR2
Br
6b
H
R
6c
O
R
N
R1
O
R
N
6d
N
R1
H
R1
a Ns = SO2(2-O2NC6H4)
1
6
5
Scheme 1 Retrosynthesis of compounds 1
ports of N-methylations of carbamates and amides by using
MeI and silver oxide.19 We also recently reported a silver-
mediated intramolecular Friedel–Crafts-type cyclization of
2-benzyloxy-3-bromoindolines.20 Speculating that the ha-
logenophilicity of silver oxide toward C(sp3)–halogen bonds
might permit mild activation of the N-alkylation of 6a, we
carried out the reaction by using 6a and silver oxide (5
equiv) in EtOAc at 80 °C for two hours. The cyclization pro-
ceeded smoothly to afford the desired product 1a in 84%
yield, with 8a as a byproduct in 9% yield (entry 6). Several
solvents were examined for this reaction, among which
The haloetherification of 1-tosylindole (5a) with non-
protected 2-aminoethanol did not proceed in the presence
of N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS).
Initially, the reaction was carried out by using N-Boc-2-am-
inoethanol (3 equiv) and NBS (1.5 equiv) in (trifluorometh-
yl)benzene at room temperature. As expected, the reaction
proceeded smoothly to afford the desired compound 6a in
80% yield along with 3-bromo-1-tosylindole (7a) as a by-
product in 20% yield (Scheme 2). To improve the yield of 6a,
a large excess of N-Boc-2-aminoethanol (10 equiv) was
used, and a good conversion into 6a (91%) was observed.
Table 2 Reaction Conditions for the Synthesis of 1a
NHBoc
(3 eq)
NHBoc
Br
Br
HO
+
O
N
Ts
Boc
N
Ts
NBS (1.5 eq)
C6H5CF3, r.t.
N
N
H
Ts
6a (80%)
O
5a
7a (20%)
N
H
Scheme 2 Synthesis of compound 6a
Ts
NHBoc
Br
1a
Conditions
+
O
NHBoc
Table 1 shows examples of this reaction. Haloetherifica-
tions of 1-tosylindole (5a) and 1-(2-nitrobenzenesulfo-
nyl)indole (5b) as substrates were carried out with N-Boc-
or N-(2-nitrobenzenesulfonyl)-2-aminoethanol (N-Ns-2-
aminoethanol) in the same manner as shown in Scheme 2.
Because the solubility of N-Ns-2-aminoethanol in C6H5CF3
is poor, the solvent was changed to acetonitrile in this case
(Table 1, entries 2 and 4). In both cases, the reactions pro-
ceeded smoothly to afford the desired products in moderate
yields.
For the subsequent step of morpholine-ring formation
from 6a, cyclization reactions were first attempted under
various basic conditions, as shown in Table 2. However, the
cyclization did not proceed smoothly, resulting in recovery
of the starting material (Table 2, entries 1 and 2) or the for-
mation of decomposition products (entries 3–5). We then
focused our attention on silver oxide as there have been re-
N
Ts
O
6a
N
Ts
8a
Entry
Conditions
Yield (%)
a
1
2
3
4
5
6
7
8
Et3N (1.5 equiv), EtOAc, r.t., overnight
Cs2CO3 (1.5 equiv), EtOAc, r.t.
–
a
–
b
K2CO3 (1.5 equiv), CH3CN, 50 °C, 30 min
t-BuOK (1.5 equiv), THF, r.t., 30 min
NaH (1.5 equiv), DMF, r.t., 2 h
–
b
–
b
–
Ag2O (5 equiv), EtOAc, 80 °C, 2 h
Ag2O (5 equiv), CH3NO2, 80 °C, 2 h
84
85
6a (5.0 g), Ag2O (5 equiv), EtOAc, 80 °C, 4 h 80
a Starting material recovered.
b Undesired products.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

C
T. Nishi et al.
Letter
Synlett
and 7). On the other hand, the (2-nitrobenzene)sulfonyl
(Ns) group developed by Kan and Fukuyama is well known
as an effective protecting group for the alkylation of
amines.21 By applying this method, the cyclization of 6b
and 6d with potassium carbonate in acetonitrile at 50 °C
cleanly gave the desired compounds 1b and 1d in quantita-
tive yields (entries 4 and 8). For the construction of the Ns-
protected morpholine ring, better results were obtained by
using Conditions B.
By following a procedure similar to that used for the
preparation of compound 1a, compounds 1e–h were also
synthesized in moderate yields from 5- or 6-substituted 1-
tosylindole derivatives (Scheme 3).
Next, we applied this method to the construction of sev-
en- and eight-membered rings (Scheme 4). To the best of
our knowledge, there are only a few examples of the prepa-
rations of seven- and eight-membered heterocycle-2,3-
fused indolines,16b and this is the first example of the
preparation of 1,4-oxazepine and 1,4-oxazocine ring-2,3-
fused indoline-like compounds 2 and 3. By following a pro-
cedure similar to that used for the preparation of 6a, ha-
loetherification of 1-tosylindole (5a) or 1-(2-nitrobenzene-
sulfonyl)indole (5b) with N-Boc-3-aminopropan-1-ol or N-
Boc-4-aminobutan-1-ol proceeded smoothly to afford the
desired compounds 9 and 11 in good yields. Next, the cy-
clization reactions of 9 and 11 were carried out by using sil-
ver oxide in EtOAc at 80 °C. As shown in Scheme 4, com-
pared with the six-membered ring cyclization, the yields of
the desired products were considerably reduced because
Table 3 Reaction Conditions for the Synthesis of 1a–d
R2
NHR2
Br
Conditions
A or B
N
H
O
O
N
N
H
R1
A: Ag2O (5.0 eq), EtOAc, 80 °C
B: K2CO3 (1.5 eq), CH3CN, 50 °C
R1
1a–d
6a–d
En-
try
Starting Mate-
rial
R1
R2
Condi-
tions
Prod-
Yield (%)
uct
1a
1a
1b
1b
1c
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6c
6c
6d
6d
Ts
Ts
Ts
Ts
Ns
Ns
Ns
Ns
Boc
Boc
Nsa
Ns
A
B
A
B
A
B
A
B
84
0
64
100
53
0
Boc
Boc
Ns
1c
1d
1d
38
98
Ns
EtOAc and CH3NO2 gave the best results. To investigate the
applicability in large-scale reactions, we conducted a reac-
tion at a scale of 5.0 g (9.8 mmol), and we obtained the de-
sired product in 80% yield (Entry 8).
The structure of 1a was determined by 1H, 13C, and two-
dimensional NMR analyses (HMQC, HMBC) in CDCl3 and
DMSO-d6. The 1H and 13C NMR investigations of 1a suggest-
ed the presence of rotamers due to the Boc protecting
groups, but equilibrating species were most often distin-
guished by variable-temperature NMR. The cis-configura-
tion was confirmed by comparison with the HC(2)–HC(3) cou-
pling constant and from the results of an NOE experiment.
The encouraging results obtained in the preparation of
1a prompted us to apply these cyclization conditions to the
preparation of compounds 1a–d (Table 3). In general, the
silver oxide-mediated cyclization (Conditions A) proceeded
smoothly with moderate yields regardless of the combina-
tion of protecting groups on 6a–d (Table 3, entries 1, 3, 5,
BocHN
HO
NHBoc
Br
(3 eq)
N
R1
O
NBS (1.5 eq)
C6H5CF3 or CH3CN
N
R1
5a (R1 = Ts)
5b (R1 = Ns)
9a (69%)
9b (71%)
BocHN
Boc
N
H
Ag2O (5 eq)
7
+
O
H
O
EtOAc, 80 °C
N
R1
N
R1
2a (22%)
2b (31%)
10a (28%)
10b (34%)
NHBoc
Br
NHBoc
HO
BocHN
Br
(3 eq)
R
NHBoc
R
O
HO
N
Ts
NBS (1.5 eq)
C6H5CF3
N
Ts
(3 eq)
5a,b
O
N
R1
11a (60%)
11b (69%)
NBS (1.5 eq)
C6H5CF3 or CH3CN
5e: R = 5-Cl
5f: R = 5-Br
5g: R = 5-OMe
5h: R = 6-Cl
6e (54%)
6f (73%)
6g (55%)
6h (67%)
Boc
N
H
BocHN
Boc
Ag2O (5 eq)
N
H
O
R
8
Ag2O (5 eq)
EtOAc, 80 °C
N
Ts
1e (59%)
1f (60%)
1g (65%)
1h (66%)
+
H
O
N
R1
12a (44%)
12b (59%)
O
H
EtOAc, 80 °C
N
R1
3a (6%)
3b (7%)
Scheme 4 Syntheses of 2a,b and 3a,b
Scheme 3 Syntheses of 1e–h
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

D
T. Nishi et al.
Letter
Synlett
Table 4 Syntheses of Azaindolines 4a–f
were prepared from 5-, 6-, or 7-halo-substituted 1-to-
sylazaindoles, as shown in Table 4. Because the reactivities
of azaindoles 13a–f were inferior to that of indole, heating
to 50 °C was required for haloetherification, and the chemi-
cal yields tended to be lower. Subsequent cyclization of
14a–f by using K2CO3 at 50 °C proceeded smoothly to give
the desired products 4a–f in good yields. In the case of
azaindolines, cyclization with Ag2O failed to proceed.
In conclusion, a potentially useful and versatile synthet-
ic method for the preparation of six- to eight-membered
heterocycle-2,3-fused indoline and azaindoline derivatives
through haloetherification and cyclization has been devel-
oped.23 It is possible to apply this method in the prepara-
tion of novel heterocycle-2,3-fused indoline and azaindo-
line scaffolds for pharmaceuticals. Further work in this area
is now in progress.
NHNs
HO
NHNs
Br
(3 eq)
N
R
O
N
R
N
Ts
NBS (1.5 eq)
CH3CN, 50 °C
N
Ts
Step A
13
14
Ns
N
H
K2CO3 (1.5 eq)
CH3CN, 50 °C
O
N
R
N
H
Ts
Step B
4
Ns
Ns
Ns
N
N
N
H
H
H
N
N
N
O
O
H
Ts
O
N
H
Ts
N
Ts
N
H
Br
Cl
Br
Br
Conflict of Interest
4a
Ns
4b
4c
Ns
N
Ns
N
The authors declare no conflict of interest.
N
H
H
H
O
O
H
Ts
O
N
N
Ts
H
N
N
Supporting Information
H
Ts
Cl
N
N
Cl
Supporting information for this article is available online at
4d
4e
4f
https://doi.org/10.1055/s-0037-1610771.
S
u
p
p
orti
n
gInformatio
n
Su
p
p
orti
n
gInformatio
n
Entry
Product
4a
Yield (%) from Step A
Yield (%) from Step B
References and Notes
1
2
3
4
5
6
30
43
39
21
71
45
80
83
92
83
85
62
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4b
4c
4d
4e
4f
byproducts 10 and 14 were preferentially obtained. Where-
as the desired products could not be obtained under basic
conditions from the Ns-protected derivatives, the cycliza-
tion using Ag2O was suitable for the construction of seven-
and eight-membered-ring-fused 2,3-indolines, albeit in low
yields.
Besides heterocycle-2,3-fused indolines, we also applied
this method to a synthesis of azaindoline derivatives. The
azaindole framework exhibits significant biological activi-
ties, such as inhibiting kinases.22 Although the design of
novel azaindoline scaffolds (sp3-rich) is valuable for medici-
nal chemistry, no synthetic examples of morpholine-ring
2,3-fused azaindolines have been reported. We applied our
method to the synthesis of halo-substituted 2,3-fused
azaindoline derivatives. These halo substituents are ex-
tremely useful for expanding the diversity and derivatiza-
tion of the products through Suzuki couplings, Buchwald–
Hartwig aminations, etc. By following a procedure similar
to that described for the preparation of 1b, compounds 4a–f
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© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

E
T. Nishi et al.
Letter
Synlett
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8.91 g, 55.3 mmol) in C6H5CF3 (100 mL), and the mixture was
stirred at r.t. for 4 h. The mixture was then diluted with brine
and extracted with EtOAc. The organic layer was dried (MgSO4)
and concentrated in vacuo, and the residue was purified by
flash column chromatography [silica gel, hexane–EtOAc (8:1 to
3:1)] to give a white solid; yield: 7.34 g (78%); mp 118–120 °C.
1H NMR (500 MHz, CDCl3):  = 7.66 (t, J = 8.6 Hz, 2 H), 7.33 (m, 1
H), 7.27 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.11 (m, 1 H),
5.66 (s, 1 H), 4.95 (s, 1 H), 4.76 (br s, 1 H), 3.99 (m, 1 H), 3.82 (m,
1 H), 3.39 (m, 1 H), 3.31 (m, 1 H), 2.33 (s, 3 H), 1.44 (s, 9 H). 13
C
NMR (125 MHz, CDCl3):  = 155.9, 144.7, 140.6, 135.1, 131.3,
130.7, 129.6, 127.7, 126.3, 125.5, 117.0, 98.8, 79.5, 67.9, 47.3,
40.2, 28.5, 21.6. HRMS (ESI): m/z [M + Na]+ calcd for C22H27Br-
N2NaO5S: 533.0722 and 535.0701; found: 533.0703 and
535.0686.
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He, X.-H.; Li, J.-L. Org. Chem. Front. 2020, 7, 3862.
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Abe, T. Synlett 2019, 30, 2247.
tert-Butyl (4aR*,9bR*)-5-Tosyl-2,3,5,9b-tetrahydro[1,4]oxaz-
ino[2,3-b]indole-1(4aH)-carboxylate (1a): Typical Procedure
Compound 6a (5.00 g, 9.78 mmol) was treated with Ag2O (11.32
g, 48.8 mmol) in EtOAc (150 mL) at 80 °C for 4 h. The mixture
was then cooled to r.t. and filtered through a Celite pad. The
solvent was removed in vacuo, and the residue was purified by
flash column chromatography [silica gel, hexane–EtOAc (8:1 to
3:1)] to give a white solid; yield: 3.37 g (80%); mp 197–199 °C.
Byproduct 8a was also obtained as a white solid; yield: 406 mg
(10%).
1H NMR (500 MHz, DMSO-d6):  = 7.83 (m, 2 H), 7.35 (d, J = 8.6
Hz, 2 H), 7.24 (br s, 2 H), 6.93–7.06 (m, 2 H), 5.89 + 5.80 (both d,
J = 5.2 Hz, total 1 H), 5.36 + 5.21 (both d, J = 5.2 Hz, total 1 H),
3.37–3.65 (m, 2 H), 3.48 + 3.38 (both m, total 1 H), 2.80 + 2.63
(both m, total 1 H), 2.47 + 2.32 (both s, total 3 H), 1.44 + 1.38
(both s, total 9 H). 13C NMR (125 MHz, DMSO-d6, 100 °C):  =
155.0, 144.8, 140.8, 136.8, 130.3, 130.1, 129.5, 127.8, 124.6,
124.6, 114.2, 87.1, 80.8, 60.9, 54.2, 41.0, 28.6, 21.4. HRMS (ESI):
m/z [M + Na]+ calcd for C22H26N2NaO5S: 453.1460; found:
453.1451.
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(22) Mérour, J.-Y.; Buron, F.; Plé, K.; Bonnet, P.; Routier, S. Molecules
2014, 19, 19935.
(23) tert-Butyl
[2-({3-Bromo-1-tosyl-2,3-dihydro-1H-indol-2-
yl}oxy)ethyl]carbamate (6a): Typical Procedure
NBS (4.92 g, 27.6 mmol) was added to a solution of 1-tosylin-
dole (5a; 5.00 g, 18.4 mmol) and N-Boc-2-aminoethanol (1;
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E