Stereoselective Construction of Methylenecyclobutane-Fused Indolines through Photosensitized [2+2] Cycloaddition of Allene-Tethered Indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00309

Irradiation of 1-(hexa-4,5-dienoyl)indole derivatives in the presence of an aromatic ketone by a high-pressure mercury lamp through Pyrex glass gave the corresponding cyclized products stereoselectively in high yields. The major part of the products was an all-cis-fused methylenecyclobutane-type compound produced through [2+2] cycloaddition, accompanied by small amounts of alkynes via 1,5-hydrogen transfer of a biradical intermediate. Among a range of aromatic ketones, 3′,4′-dimethoxyacetophenone was found to sensitize the substrate quite effectively.

Full text of DOI:10.1021/acs.orglett.9b00309

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereoselective Construction of Methylenecyclobutane-Fused
Indolines through Photosensitized [2+2] Cycloaddition of Allene-
Tethered Indole Derivatives
,
†
,†,‡
Noriyoshi Arai* and Takeshi Ohkuma*
†
Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
‡
*
S Supporting Information
ABSTRACT: Irradiation of 1-(hexa-4,5-dienoyl)indole derivatives in the presence of an aromatic ketone by a high-pressure
mercury lamp through Pyrex glass gave the corresponding cyclized products stereoselectively in high yields. The major part of
the products was an all-cis-fused methylenecyclobutane-type compound produced through [2+2] cycloaddition, accompanied
by small amounts of alkynes via 1,5-hydrogen transfer of a biradical intermediate. Among a range of aromatic ketones, 3′,4′-
dimethoxyacetophenone was found to sensitize the substrate quite effectively.
yclobutanes are versatile synthetic building blocks that
offer a balance between the inherent rigidity of a small-
reactions with 1-aroylindoles can be performed without the
13
C
sensitizer. However, the reactions required large excesses of
alkenes to obtain acceptable yields of the products in many
cases, and the regioselectivity, namely, head-to-head or head-
to-tail selectivity, depended on the electronic properties of the
ring compound and a greater stability toward ring-opening
1
reactions compared with cyclopropanes. Recently, cyclo-
butanes have also attracted attention in drug discovery due
to the growing demand for lipophilic conformationally
restricted analogues of known scaffolds rather than bulky
14,15
alkenes employed.
To overcome this problem, intra-
molecular cycloadditions were investigated by tethering the
alkene to the acyl substituent of the indoles. This strategy gave
the [2+2] adducts regio- and stereoselectively, while the
resulting cyclobutane ring did not have any functional groups
2
−6
aromatic compounds.
The photochemical [2+2] cyclo-
addition reaction is one of the most popular and facile methods
of constructing four-membered cyclic compounds represented
7
,8
18
by cyclobutanes.
that were useful for further molecular transformation.
Indoline-fused cyclic compounds form an important core of
bioactive natural products, and they are also typical structural
In the course of our investigation of the photochemistry of
19
five-membered heteroaromatic compounds, we envisaged
that reactions between 1-acylindoles and allenes would give
methylenecyclobutane-fused indolines that are readily func-
tionalized by transforming the methylene moiety. To the best
of our knowledge, such photochemical transformation has
9
motifs in several useful pharmaceuticals. Novel fused cyclic
indoline frameworks are of interest in bioactive screening for
10
new pharmaceutical candidates. To meet the demand for
such frameworks, new methods of synthesizing diverse
indoline derivatives are needed. To date, a number of synthetic
methods have been reported for this important class of
compounds, whereas there has been much less exploration of
2
0
never been reported in the literature. After extensive
screening of photosensitizers, we found that 3′,4′-dimethox-
yacetophenone sensitizes the intramolecular [2+2] cyclo-
addition between indoles and allenes quite effectively. We
report herein the photocyclization of 1-(hexa-4,5-dienoyl)-
indole derivatives with this particular sensitizer, which yielded
tetracyclic cyclobutane-fused indoline derivatives in a highly
stereoselective manner.
11,12
cyclobutane-fused indolines.
The [2+2] photocycloaddi-
tion using 1-acylindoles as components is an exception. It has
been extensively examined to access the cyclobutane-fused
1
3−17
compounds.
The [2+2] photocycloaddition between 1-acylindoles and
substituted ethenes is known to proceed under the
sensitization of acetophenone with Pyrex-filtered irradiation
Received: January 24, 2019
(
>300 nm) to yield cyclobutane-fused indolines, though
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00309
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
We first attempted a reaction of 1-(hexa-4,5-dienoyl)indole
1a) sensitized by acetophenone in a range of solvents under
Table 2. Screen of Photosensitizers
2
1
(
irradiation by a high-pressure mercury lamp through Pyrex
glass (Table 1). The solvents were thoroughly degassed by
a
Table 1. Solvent Screen
E
conversion
2a
(%)
3a
(%)
T
b
c
c
c
entry
sensitizer
(kcal/mol)
(%)
d
1
2
3
4
5
6
7
8
9
AP
none
benzophenone
xanthone
4′-Cl-AP
4′-F-AP
4′-MeO-AP
3′,4′-(OCH O)-AP
3′,4′-(MeO) -AP
3′,4′,5′-(MeO) -AP
73.6
90
37
100
100
91
71
86
88
100
98
62
12
10
trace
trace
trace
10
7
d
e
e
68.5
41
30
61
46
58
64
80
18
35
78
0
d
74.2
f
71.7
g
72.8
f
70.1
9
h
65.8
10
12
9
6
12
0
b
b
b
2
entry
solvent
conversion (%)
2a (%)
3a (%)
f
67.3
2
1
2
3
4
5
6
benzene
AcOEt
MTBE
84
90
80
57
74
53
54
62
50
28
42
32
10
10
10
5
5
5
10
11
12
3
2′,6′-(MeO) -AP
2′,4′-(MeO) -AP
2-acetonaphthone
60
100
11
2
2
2
CH Cl2
13
59.3
d
MeCN
MeOH
a
All reactions were carried out in a Pyrex test tube by external
irradiation with a high-pressure Hg lamp at a concentration of 10 mM.
AP, acetophenone. Determined by the H NMR integral ratio using
d e
a
b
c
1
All reactions were carried out in a Pyrex test tube by external
irradiation with a high-pressure Hg lamp at a concentration of 10 mM.
Determined by the H NMR integral ratio using 1,1,2,2-tetrachloro-
1,1,2,2-tetrachloroethane as an internal standard. From ref 23. 1,3,5-
b
1
f
Trimethoxybenzene was used as an internal standard. From ref 24.
g
h
ethane as an internal standard.
From ref 25. From ref 26.
freeze−thaw cycles before use. The reaction was conducted at
room temperature and discontinued in 1 h irrespective of the
conversion of 1a. The reaction proceeded well in aromatic or
medium polar solvents, giving methylenecyclobutane-type
product 2a in moderate yield, unexpectedly accompanied by
terminal alkyne 3a (entries 1−3). The reaction pathway
forming 3a is discussed in detail in the following section. When
isolated 2a was irradiated under the reaction conditions, it was
recovered unchanged almost quantitatively. The reactions in a
halogenated solvent (entry 4) and highly polar solvents
dimethoxyacetophenone (4) was the sensitizer of choice for
this reaction, affording the cyclized products 2a and 3a in a
92% combined yield (entry 9). The 2′,6′-isomer was not as
effective as 4 (entry 11). Though the 2′,4′-isomer was equally
effective (entry 12), for budgetary reasons we chose the 3′,4′-
isomer for further investigations. The amounts of the sensitizer
were reduced to 30 mol %, with little sacrifice of the product
yield (Table S1). The triplet energy (E ) of 1a is not known,
T
but those of 1-benzoylindole and 1-methylindole are reported
15f,22
as 68 and 69.3 kcal/mol, respectively, in the literature.
(
entries 5 and 6) gave inferior results. We chose ethyl acetate
While ketones that have an E of nearly 70 kcal/mol sensitized
T
as the best solvent because it gave the highest yield of 2a and
the cleanest reaction, although benzene was the most
frequently employed solvent in the previous studies.
1a well, 2-acetonaphthone that has a much smaller E (59
T
kcal/mol) did not give the product (2a or 3a) at all (entry 13).
The small conversion might be attributed to side reaction(s)
via slight absorption by 1a itself. These results are consistent
with the triplet sensitization mechanism described below.
With the optimized conditions in hand, we explored the
reaction using a variety of indole derivatives (Table 3). The
reactions listed in Table 3 were carried out in a photochemical
reaction vessel for internal irradiation. The reactions were
discontinued as soon as possible after consumption of the
starting materials. The result of the reaction with 1a was
comparable to that with external irradiation, with 2a and 3a
being isolated with an only slight loss (entry 1). The
substituents at the benzene ring of indole had a strong
influence on the reaction. The reactions of 1b (5-Me), 1c (5-
F), and 1d (6-Cl) gave comparable yields of the cyclized
products (entries 2−4, respectively), while a somewhat lower
yield was obtained in the case of 5-Br-substituted 1e (entry 5).
It should be noted that ring junctures were created with perfect
diastereoselectivity, suggesting the high potential of this
reaction for the stereoselective synthesis of indolines with
fused rings. In entry 5, small amounts of debrominated
products (namely, 2a and 3a) were detected but could not be
Next, we screened photosensitizers (Table 2). Acetophe-
none nicely sensitized the reaction, as shown in the previous
table, whereas the reaction was substantially slowed in the
absence of the sensitizer, resulting in a much lower yield of the
photoadducts with unidentified messy byproducts (entries 1
and 2). Benzophenone and xanthone, which like acetophenone
are typical triplet sensitizers, gave inferior yields, though the
starting material 1a was completely consumed in 1 h (entries 3
and 4, respectively). This difference between acetophenone
and benzophenone (or xanthone) is difficult to explain.
Though generation of different triplet states by each sensitizer
or participation of electron-transfer sensitization might be
possible, details should be elucidated via further investigation.
These results prompted us to carry out the reaction by using a
range of substituted acetophenones, to gain information about
the electronic effect on the reaction. Neither the electron-
withdrawing nor the electron-donating groups improve the
yield of 2a, but the reaction with 4′-methoxyacetophenone
reduced the amounts of byproducts (entries 5−7). We then
conducted a reaction with di- or trialkoxy-substituted
acetophenones (entries 8−10). This revealed that 3′,4′-
isolated. Introduction of the 5-MeO or 5-CO Me group
2
B
DOI: 10.1021/acs.orglett.9b00309
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrate Screen
Scheme 1. Reaction of a Substrate with Disubstituted Allene
time
2
3
(%)
entry substrate R1
R2
R3
R4
(min) (%)
b
b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
Me
H
H
Me
F
H
Br
MeO
CO Me
H
H
H
H
H
Cl
H
H
H
H
H
40
40
40
40
60
120
120
40
71
69
72
69
58
26
46
71
14
11
13
14
14
15
5
d
13
2
Scheme 2. Reaction of a Substrate with Trisubstituted
Allene
c
2
180
a
All reactions were carried out in a Pyrex reaction vessel for
Scheme 3. Reaction of a Dideuterated Substrate
photochemical reaction by internal irradiation with a high-pressure
b
Hg lamp at a concentration of 10 mM. Yields of the isolated product.
c
In this case, separation of the products was too difficult and, as a
result, pure 3e was not obtained. The yield was calculated by a
1
proportional distribution based on the integrals of H NMR of the
d
mixture. This product had an estimated yield of <5%, but it could
not be separated from the unidentified byproducts.
reduced the reaction rate, giving the products in moderate
yields (entry 6 or 7, respectively). These results turned out to
be caused by undesirable side reactions, such as deacylation
and acyl migration of the indole substrates (photo-Fries
rearrangement), which are common pathways in the
photochemical reaction of 1-acylated indoles. Irradiation of
2
7
the down side of position 3 comes from the terminus of the
allene moiety.
Though the detailed mechanism is not clear at this stage, we
presume that the reaction pathway is as shown in Scheme 4
3
-Me-substituted substrate 1h afforded the [2+2] adduct with
a quaternary carbon 2h accompanied by stereoselective
formation of alkyne 3h (entry 8). The reaction with 1i
became complex, giving the cycloadducts only in low yields
Scheme 4. Plausible Reaction Pathway
(
entry 9). A deacylated compound, 2-phenylindole, was the
27
main product (22%) in this reaction.
This reaction worked well when the allene terminus was
substituted with a methyl group. When the internal allenyl
acylindole 1j was irradiated under the typical conditions, the
cycloaddition products (Z)-2j, (E)-2j, and 3j were obtained in
8
7% combined yield in a 66:23:11 ratio (Scheme 1).
Unfortunately, the separation was quite difficult, but 3j was
separated from a geometrical mixture of 2j by repeated thin-
layer chromatography.
Irradiation of a substrate with two terminal methyl groups
k gave the [2+2] adduct 2k as a sole product in high yield
1
(Scheme 2). This result strongly suggested that the alkyne 3
mentioned above was produced through internal transposition
of hydrogen at the allene terminal to position 3 of indole.
To elucidate the mechanism underlying the formation of
alkyne 3, a substrate that was dideuterated at the allene
based on the results presented above and information from the
15
literature. Triplet 1a, which is generated by sensitizations
with the triplet 4, makes an internal carbon−carbon bond
between position 2 of indole and the allene moiety to form the
tricyclic biradical intermediate A. The mechanism underlying
this type of radical bond formation has been well established in
terminal was prepared (1a-d ) and then irradiated under the
2
typical conditions (Scheme 3). The reaction gave [2+2]
adduct 2a-d and alkyne 3a-d in which a deuterium was
2
2
15f
introduced at position 3 of indole from the same side as the
alkynyl moiety. This result clearly shows that the hydrogen on
the photoreaction between indoles and alkenes. When the
intermediate A undergoes ring closure accompanied by
C
DOI: 10.1021/acs.orglett.9b00309
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
intersystem crossing (ISC), the [2+2] adduct 2a is produced.
On the other hand, alkyne 3a is formed via the competitive
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In conclusion, we have developed an unprecedented [2+2]
photochemical cycloaddition reaction of 1-(hexa-4,5-dienoyl)-
indole derivatives. 3′,4′-Dimethylacetophenone acts as a quite
effective photosensitizer in this reaction. With appropriate
substrates, the reaction proceeds cleanly in <1 h to afford
synthetically valuable methylenecyclobutane-fused indolines
and alkynyl compounds in high yield. The perfect diaster-
eoselection in this reaction is noteworthy. A plausible reaction
pathway is proposed on the basis of some mechanistic
experiments.
(
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ASSOCIATED CONTENT
Supporting Information
■
(c) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175−191.
(10) (a) Blanco-Ania, D.; Gawade, S. A.; Zwinkels, L. J. L.;
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Org. Process Res. Dev. 2016, 20, 409−413. (b) Mo, Y.; Zhao, J.; Chen,
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*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00309.
Table S1, experimental procedures, and spectral data
(PDF)
1
(
2
2
2
2
5573−15578.
11) (a) Wang, Y.; Xie, F.; Lin, B.; Cheng, M.; Liu, Y. Chem. - Eur. J.
018, 24, 14302−14315. (b) Zi, W.; Zuo, Z.; Ma, D. Acc. Chem. Res.
AUTHOR INFORMATION
Corresponding Authors
■
015, 48, 702−711. (c) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res.
011, 44, 447−457. (d) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem.
010, 2010, 3975−3984.
*
E-mail: n-arai@eng.hokudai.ac.jp.
E-mail: ohkuma@eng.hokudai.ac.jp.
*
(
12) Formation of cyclobut[b]indolines: (a) Ogawa, N.; Yamaoka,
ORCID
Y.; Takikawa, H.; Tsubaki, K.; Takasu, K. J. Org. Chem. 2018, 83,
7994−8002. (b) Nandi, R. K.; Guillot, R.; Kouklovsky, C.; Vincent,
G. Org. Lett. 2016, 18, 1716−1719. (c) Miyoshi, T.; Aoki, Y.; Uno, Y.;
Araki, M.; Kamatani, T.; Fujii, D.; Fujita, Y.; Takeda, N.; Ueda, M.;
Kitagawa, H.; Emoto, N.; Mukai, T.; Tanaka, M.; Miyata, O. J. Org.
Chem. 2013, 78, 11433−11443. (d) Walter, H.; Sauter, H.; Schneider,
J. Helv. Chim. Acta 1993, 76, 11433−11443.
Noriyoshi Arai: 0000-0003-0964-223X
Notes
The authors declare no competing financial interest.
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́
̃
(
(
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(
6
(
(
2
(
1
(
(
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E
DOI: 10.1021/acs.orglett.9b00309
Org. Lett. XXXX, XXX, XXX−XXX