2,3-Dimethoxyindolines: a latent electrophile for SNAr reactions triggered by indium catalysts

Article abstract of DOI:10.1039/d0cc01210f

2,3-Dimethoxyindolines (DiMeOINs) have emerged as a latent electrophile in indium-catalyzed S_NAr reactions. They are easily obtained from commercially available indoles and allowed access to 3-substituted indoles. The reaction proceedsviaS_NAr reactions ofin situgenerated 3-methoxyindoles. Formation of C2-substituted indoles was also possible utilizing the C2-nucleophilicity of DIMeOIN. Our protocol is user friendly as DiMeOIN is a bench-stable easy-to-handle crystalline reagent.

Full text of DOI:10.1039/d0cc01210f

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2,3-Dimethoxyindolines: A Latent Electrophile for SNAr Reactions
Received 00th January 20xx,
Triggered by Indium-Catalyst†
Seiya Hirao,† Toshiki Yamashiro,† Kyouka Kohira, Naoki Mishima, and Takumi Abe*a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
2,3-Dimethoxyindolines (DiMeOIN) have emerged as a latent are often problematic. Taking inspiration from Tsuchimoto’s
electrophile in indium-catalyzed SNAr reactions. They are easily pioneering studies, we became interested in further developing
obtained from commercially available indoles and allowed the the untapped reactivity of 3-methoxyindoles.8
access to 3-substituted indoles. The reaction proceeds via SNAr
3-Oxigenated indoles are unstable against Lewis acid or
reactions of in situ-generated 3-methoxyindoles. Formation of C2- metals and this may be one of a reason for them being an
substituted indoles was also possible utilizing the C2- untapped substrate to date. To investigate the reactivity of 3-
nucleophilicity of DIMeOIN. Our protocol is user friendly as alkoxyindoles, there still remains a significant methodological
DiMeOIN is a bench-stbale easy-to-handle crystalline reagent.
gap. Thus, the development of a more suitable indole enol ether
surrogate combining high reactivity with enhanced stability is
highly needed.
Methoxyarenes are versatile building blocks in which the C–O
bond could be involved in a various transformation through the
cleavage of C–O bonds (Scheme 1a).1 For example, in 1979,1a
the Wenkert laboratory developed the nickel-catalyzed
Kumada–Tamao–Corriu-type cross-coupling of methoxyarenes
with Grignard reagents, which involved the activation of an
inert C–O bond.2b Over the past decade, the scope of the
transformations of methoxyarenes has expanded considerably
to various conditions, including Ni,1 Ru,2 In,3 TfOH,4 NaH,5
organic superbases6, and photoredox catalysts.7
Scheme 1 Previous works on methoxyarenes
Transformation of 3-methoxyindoles offers an alternative to
3-bromoindoles and indole-3-boronic acids, but the
development of such protocols has proven challenging due to
their instability, and no approaches have been reported to date
(Scheme 1a). In 2011, Tsuchimoto and co-workers made
In light of our previous research on development of electrophilic
indole reagents,9 we planned to develop alternative readily
accessible indole enol ether surrogates. Particularly, we were
interested in investigating the effect of methyl enol ether in place of
enol acetate hoping to find enhanced stability. A simple and easily
available 2,3-dimethoxyindolines10 would be a superior precursor of
3-methoxyindole (Scheme 2a). We reasoned that the 3-
methoxyindoles should be generated in situ from the 2,3-
dimethoxyindolines upon regioselective elimination of MeOH
assisted by Lewis acid. Furthermore, the 3-methoxyindole is
electrophilic at the C3 position, but the C2 position is nucleophilic.
Ideally, 2,3-dimethoxyindolines can be used as a precursor of 3-
methoxyindole, which possess both C3 electrophilic and C2
nucleophilic characters. Herein, we report an indium-catalyzed C3-
functionalization of 2,3-dimethoxyindolines to directly access 3-
substituted indoles. Compared with the previous works,3, 11, 12 the
indium-catalyzed C3-functionalization of 2,3-dimethoxyindolines
completely showed C3-selectivity (Scheme 1b vs Scheme 2b); this
transformation is a challenge because indoles usually gave 2,3’-
landmark
progress
on
SNAr
reactions
of
alkoxyarenes/acyloxyarenes by using 3-acetoxyindole instead
of 3-methoxyindoles under indium catalyst (Scheme 1b).3
Despite effecting one-pot SNAr reactions of heteroarylarenes,
this protocol has not seen broad adoption, likely because of the
use of unfamiliar indoxyl as a substrate and the mixed
regioisomers at the 2- and 3-positions (C2/C3 = 76/24), which
a. Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-tobetsu, Hokkaido 0610293, Japan. E-mail: abe-t@hoku-iryo-u.ac.jp
† S.H. and T.Y. contributed equally.
†
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and spectra data for all compounds, including scanned images of 1H
and 13 NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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bisindoles due to both C3-nucleophilicity and C2-electrophilicity,11 in Similar results were obtained when InCl3•4H2O, Cu(OTf)2, and
which 2,3-dimethoxyindolines functioned as 3-methoxyindoles and Bi(OTf) were used (entries 12, 14, and 16). MeanwhilVei,ewatAtreticmlepOtnslitnoe
DOI: 10.1039/D0CC01210F
3
acted as novel C3 electrophilic indole surrogates.13 In the umpoled use other catalysts proved unfruitful, leading to bisindoles in lower
transformation, an in situ generated 3-methoxyindole was detected yield (entries 8-10, 13, 15, and 17). Decreasing the loading of In(OTf)3
as a key intermediate.
let to a decrease of yield (entries 18–19). Further screenings with 10
mol% TfOH in MeCN was unsuccessful, demonstrating that use of
metal triflate was important (entry 20). This result implied that “dual
- and -activation” ability of In(OTf)3, not the protonation ability,
were important for the success of our transformation.4
(a) This work: SNAr reaction using 3-methoxyindoles generated in situ under Lewis acid as a catalyst
R
OMe
OMe
Nu
R
R
R
NuH
OMe
SNAr
LA
LA
OMe
LA
PG
N
OMe
N
N
N
MeOH
PG
PG
DiMeOIN
PG
3-MeO-indoles
MeOH
Table 1 Optimization of reaction conditionsa
3-substituted indoles
(b) Unprecedented selectivity on the indium-catalyzed SNAr reactions
OMe
3
3
2
OMe
N
NH
N
NH
N
Ts
2
Me
2,3’-biindole
Ts
Me
3,3'-biindole
Ts
DiMeOIN
C2 : C3 = 0 : 100
Scheme 2 SNAr Reaction of 2,3-Dimethoxyindolines
NBS
OMe
OMe
Br
entry
Lewis acids
Solvents
C2/C3
(5aa/6aa)b
---
Yield of
R1
R1
(1.1 equiv) R1
MeOH
reflux
6aa (%)c
(X mol %)
OMe
N
R2
MeOH
rt
N
R2
N
R2
1
---
1,4-dioxane
1,4-dioxane
toluene
ClPh
0
1
trans
2
trans
3
2
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(acac)3 (10)
InF•3H2O (10)
InBr3 (10)
<1/20
1/20
1/20
1/9
30–91
86
OMe
OMe
OMe
3b (R2 = Bz): 31%
3
3c (R2 = Boc):11% (2 steps)b
3d (R2 = Ac): 29%
4
88
OMe
N
N
R2
3e (R2 = 2-Ns): 13%
Ts
5
CHCl3
74
3a: 58% (8.74 g)
6
DCE
1/20
<1/20
---
93
Cl
R1
7
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
94
OMe
OMe
OMe
OMe
OMe
OMe
3f (R1 = MeO): 72%
3g (R1 = Cl): 15%
3h (R1 = Br): 12% (27%, brsm)
8
0
Cl
N
N
N
Ts
9
---
trace
73
Ts
Ts
10
11
12
13
14
15
16
17
18
19
20
<1/20
<1/20
<1/20
<1/20
<1/20
1/20
<1/20
<1/20
<1/20
<1/20
---
3i: 32% (65%, brsm)
3j: 69%
Scheme 3 Substrate scopea,b
:
Yields of 3 based on 2 shown here. Further
a
InCl3 (10)
84
details on the reaction conditions for each reaction are given in the Supporting
InCl3•4H2O (10)
Zn(OTf)2 (10)
Cu(OTf)2 (10)
Yb(OTf)2 (10)
Bi(OTf)3 (10)
AgOTf (10)
In(OTf)3 (5)
In(OTf)3 (3)
TfOH (10)
88
Information. b Yields of 3c based on 1c shown here.
14
Our investigation started with the synthesis of 2,3-
dimethoxyindoles 3 from N-protected indoles 1 (Scheme 3). After
several attempts to obtain a crystalline material, we noticed that
reported protocols10 showed low reproducibility; it formed an oily
mixture of cis- and trans-isomer under the reaction conditions.
Therefore, to obtain a crystalline substrate, the cis-isomer must be
isomerized. It was found that the stepwise protocol by a reaction of
N-tosyl indole (1a) with NBS in methanol and then reflux in methanol
was essential to afford trans-2,3-dimethoxyindoline (3a, DiMeOIN)
as a colorless crystal in good yield. This protocol could also be
applicable to synthesis of 3b-g, in which the unreacted
bromomethoxyindolines 2 could be recovered in high purity.
90
70
92
76
86
69
trace
a
b
c
3a (0.1 mmol), 4a (0.15 mmol), solvent (2 mL). Determined by 1H-NMR analysis.
Isolated yields.
With the optimized conditions in hand (Table 1, entry 7), we first
investigated a range of diverse 2,3-dimethoxyindolines (Scheme 4).
Reactions of N-substituted 2,3-dimethoxyindolines with 4a occurred
to form 3,3’-bisindoles 6aa–6ca, 6ea in useful yields. 2,3-
Dimethoxyindolines with electron-donating and -withdrawing
groups on the benzene ring of indole were suitable substrates,
affording 3,3’-bisindoles in good yields as a single diastereomer
(6ba–6ja). Notably, the methoxy group remained intact (6fa).
With bench-stable precursors in hand, we next examined the
reaction of 3a with 2-methylindole (4a) using Lewis acid in dioxane
at 100 °C over the course of 16 h (Table 1, run 1). No product was
observed in the absence of catalyst (entry 1). Notably, DiMeOIN do
not itself undergo reaction with nucleophile. Consequently, we
found that addition of a catalytic amount of In(OTf)3 afforded the
desired product 6aa in 91% yield as a single diastereomer (entry 2).
In this case, we were surprised to observe exclusive formation of
3,3’-bisindole (Scheme 1b vs Table 1, entry 2).3a This is an important
advantage of 3-methoxyindoles in comparison to indoxyl acetate
that showed C2-selectivity in the indium chemistry.14 Encouraged by
this initial result, solvents were also examined (entries 3–7). Among
them, replacement of 1,4-dioxane with MeCN turned out to be most
efficient (entries 3-6 vs 7). From the view point of practical use, it is
important to emphasize that MeCN is comparable to 1,4-dioxane in
reproducibility. Next, we investigated other catalysts (entries 8–17).
Next, we examined the various indoles as a nucleophile using 3a
as the starting material (Scheme 5). DiMeOIN reacts with simple
indole and N-protected indoles to afford 3,3’-bisindoles (6ab, 90%;
6ac, 28%; 6ad, 0% [6ab, 32%]). In the case of indoles having electron-
donating groups at C5 position, our reaction proceeded in good
conversion to give the corresponding 3,3’-bisindoles (6ae, 88%; 6af,
84%). Lower yields were observed for the reactions using indoles
having electron-withdrawing groups at the C5 position (6ag, 65%;
2 | J. Name., 2012, 00, 1-3
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6ah, 54%). We were pleased to see that C4-, C6, and C7-substituted
indoles reacted under optimized conditions to deliver 3,3’-bisindoles
6ai–m in good yields (57–87%). To highlight the efficiency of this
transformation, a gram-scale synthesis (3a: 1.67 g) was undertaken,
and 2.05 g of 6am was obtained (83% yield).
View Article Online
DOI: 10.1039/D0CC01210F
Scheme 7 Control experiments. a Without using In(OTf)3.
Scheme 4 Scope of 2,3-dimethoxyindolinesa,b
;
a 3a (0.5 mmol), 4a (0.75
mmol), In(OTf)3 (0.05 mmol), MeCN (10 mL). b Isolated yields.
Scheme 8 Plausible reaction mechanism
To demarcate the capabilities of DiMeOINs 3a, further C–N, C–O,
and C–C bonds forming reactions were performed (Scheme 6). To our
delight, 3-aminated indole 7 was obtained in 81% yield as a single
regioisomer. When 2- aminoacetophenone was used as nucleophile
and subjected to react with 3a, it generated indolo[3,2-b]quinpline 8
in 61% yield. This result suggests that 3-methoxyindole are
“chameleonic” species, which possess both C3-electrophilicity and
C2-nucleophilicity. Furthermore, methoxy-alkoxy exchange reaction
was also achieved with complete regioselectivity (9, 46%).3,15
Surprisingly, DiMeOIN 3a reacts with in situ generated Michael
acceptor to give C2-alkylated indolin-3-one 10 in 43% yield. This
result opens up for future work aimed at favoring formation of C2-
alkylated indolin-3-ones. Given that the straightforward synthesis of
C2-alkylated indolin-3-ones is scarce,16 the present protocol using 3a
as an C2 nucleophile is synthetically useful.
Scheme 5 Scope of indoles a,b a 3a (0.5 mmol), 4 (0.75 mmol), In(OTf)3 (0.05
;
mmol), MeCN (10 mL). bIsolated yields. cInstead of 6ad, 6ab was obtained in 32% yield.
d3a (5 mmol), 4m (7.5 mmol), In(OTf)3 (0.5 mmol), MeCN (80 mL).
To probe the mechanism of our transformation, some
experiments were carried out (Scheme 7). The 3-methoxyindole 11
could be isolated from the mixture treated by 2 equivalent of In(OTf)3
(Scheme 7, eq 1). When 11 was subjected to the standard reaction
conditions using 2-methylindole as a nucleophile, 3,3’-bisindole 6aa
was formed in high yield with complete regioselectivity (eq 2). These
results strongly suggested that the 3-methoxyindole should be the
intermediate of the reaction. According to the results mentioned
14, 17
above and the previous literatures,3,
our proposed reaction
mechanism is shown in Scheme 8. The DiMeOIN 3a is converted to
3-methoxyindole 11 from intermediate A with release of MeOH by
indium catalyst through -activation.17 One way is to form
intermediate D via -activation by indium catalyst, which could
endure SNAr reaction to form 2,3’-bisindole 5aa.3a While the other
way is to form intermediate B via -activation or C via -activation,
they undergoes SNAr reaction to form 3,3’-bisindole 6aa.3b,c Because
2,3’-bisindole 5aa was not obtained in our transformation using
In(OTf)3, the intermediate D could be excluded. In the formation of
products containing ethers (6fa, 6ae, 6af, 6ai, 6ak, and 6am), the
ether moieties were intact in all cases. Therefore, the intermediate B
may be formed in our transformations, thus showing notable chemo-
Scheme 6 Synthetic versatility of 3a
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and regioselectivities through “dual - and -activation”.18 At
present, we could not exclude the possibility of intermediate C. The
details are not clear and under investigation.
M. Ohmura, M. Taniguchi and K. Yamada, Org. Lett., 2019, 21
,
3367; (f) T. Yamashiro, K. Yamada, H. YDoOshI:id10a.,10Y3V.9iTe/woDm0ArCtiiscClae0k1Oa2n1,li0nTFe.
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10 For the synthesis of 2,3-dialkoxyindolines, see: (a) S. Kwon and
In summary, we have demonstrated the first example of 2,3-
dimethoxyindolines (DiMeOIN, 3) as a latent C3-electrophile and
outlined their reactivity in regioselective SNAr reactions. A broad
range of 3-substituted indoles could be synthesized. The
unprecedented “chameleonic” reactivity of 2,3-dimethoxyindolines
could be also shown as both C3-electrophile and C2-nucleophile. It is
noteworthy that the previous reports deal with C2-selective
indolization under indium catalyst. However, we achieved the first
C3-selective indolization through SNAr reaction. We believe that the
bench-stable 2,3-dialkoxyindoline are highly useful in synthetic
chemistry. Further investigations directed at the development of
new umpoled indole reagents and enantioselective construction of
five-five axially chiral biaryl skeletons19 are currently underway in our
laboratory.
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This work was financially supported by JSPS (KAKENHI Grant
Number 16K18849 for T.A.) as a Grant-in-Aid for Young Scientists (B).
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