Expeditious synthesis of multisubstituted indoles: Via multiple hydrogen transfers

Article abstract of DOI:10.1039/c8cc07009a

Described herein is the expeditious construction of multi-substituted indole skeletons via multiple hydrogen transfers. When ortho-amino ketoesters were treated with a catalytic amount of TiCl₄ in the presence of 1.0 equivalent of dehydrating reagent, three types of hydrogen transfer processes ([1,5]-hydride shift, proton transfer, and [1,2]-hydride shift) occurred to give various 3-alkoxycarbonylindoles. Further study revealed that a [1,2]-alkyl shift instead of a [1,2]-hydride shift proceeded to afford 3-alkylindoles from the substrates with an amino group having tertiary carbons adjacent to a nitrogen atom.

Full text of DOI:10.1039/c8cc07009a

Volume 54 Number 90 21 November 2018 Pages 12661–12776
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Chemical Communications
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COMMUNICATION
Taira Yoshida and Keiji Mori
Expeditious synthesis of multisubstituted indoles via multiple
hydrogen transfers

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Expeditious synthesis of multisubstituted indoles
via multiple hydrogen transfers†
Cite this: Chem. Commun., 2018,
54, 12686
Taira Yoshida and Keiji Mori
*
Received 29th August 2018,
Accepted 2nd October 2018
DOI: 10.1039/c8cc07009a
rsc.li/chemcomm
Described herein is the expeditious construction of multi-substituted
indole skeletons via multiple hydrogen transfers. When ortho-amino
ketoesters were treated with a catalytic amount of TiCl4 in the presence
of 1.0 equivalent of dehydrating reagent, three types of hydrogen
transfer processes ([1,5]-hydride shift, proton transfer, and
[1,2]-hydride shift) occurred to give various 3-alkoxycarbonylindoles.
Further study revealed that a [1,2]-alkyl shift instead of a [1,2]-hydride
shift proceeded to afford 3-alkylindoles from the substrates with an
amino group having tertiary carbons adjacent to a nitrogen atom.
Scheme 1 C(sp3)–H functionalization by an internal redox process.
Direct transformation of inert C–H bonds has attracted much
attention because it offers novel and efficient strategies for the
synthesis of complex organic molecules.1 Recently, hydride shift
triggered C(sp3)–H bond functionalization, namely the ‘‘internal
redox process’’ has attracted much attention (Scheme 1).2 The key
feature of this transformation is the [1,5]-hydride shift of the
C(sp3)–H bond a to a heteroatom. Subsequent 6-endo cyclization
to a cationic species A affords fused heterocycle 2.3–7
Scheme 2 Multiple hydrogen transfer strategy.
Recent efforts by us3,4 and other groups5–7 elucidated the multiple hydrogen transfer strategy that uses a substrate having a
great potential of this methodology as a synthetic tool; various highly electrophilic ketone moiety as the hydride acceptor would be
synthetically important polyheterocycles, such as isoquino- effective to overcome this limitation (Scheme 2, bottom). The key
lines,3e,g benzopyrans,3b,6f tetralins,3c,d,h and spirooxindoles3i,6j,7g point is the proton transfer after the [1,n]-hydride shift, which
could be constructed based on this method. This reaction system would be induced by the strong electrophilic character of the EWG
was not limited to 6-membered ring construction by a [1,5]-hydride group. The subsequent C–C bond formation followed by dehydra-
shift. The construction of 5- and 7-membered rings by a [1,4]- or tion would afford n-membered ring adducts.
[1,6]-hydride shift was also achievable,8,9 which broadens the
diversity and library of compounds synthesized by the internal the formation of multisubstituted indoles (n = 5, Scheme 3).
redox process. This reaction consists of three hydrogen transfer processes:
Herein, we want to report the realization of this strategy for
In the conventional internal redox process, the size of the ring (1) [1,5]-hydride shift, (2) proton transfer, and (3) [1,2]-hydride
system is dependent on the hydride shift mode, that is, the reaction shift. When ortho-amino ketoesters (R1 = H and R2 a H) were
involving a [1,n]-hydride shift would result in the formation of treated with a catalytic amount of TiCl4 in the presence of
(n + 1)-membered rings (Scheme 2, top). We envisioned that the 1.0 equivalent of dehydrating reagent, DMC (2-chloro-1,3-
dimethylimidazolium chloride), three hydrogen transfer events
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University
occurred to give various 3-alkoxycarbonylindoles. Further study
revealed that a [1,2]-alkyl shift instead of a [1,2]-hydride shift
proceeded to afford 3-alkylindoles from the substrates with an
of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan.
E-mail: k_mori@cc.tuat.ac.jp; Fax: +81 42 388 7034; Tel: +81 42 388 7034
† Electronic supplementary information (ESI) available. CCDC 1860895. For ESI
amino group having the tertiary carbons adjacent to the nitrogen
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc07009a
atom (R1 = alkyl, R2 a H, without DMC).10,11
12686 | Chem. Commun., 2018, 54, 12686--12689
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Although diethyl azodicarboxylate (DEAD) led to negative
results, N,N0-dicyclohexylcarbodiimide (DCC) and DMC12 were
effective for realizing the catalytic reaction, and the latter
turned out to be the best. The desired indole 4a was obtained
in 77% yield without 5a formation. The exposure of 5a to the
optimized reaction conditions (entry 11, Table 1) afforded 4a in
excellent chemical yield (91%), which clearly indicates that the
internal redox process is an initial event in this reaction.
Importantly, the use of ketoester 3a was the key to achieving
indole formation, and the reaction from trifluoromethyl ketone
and benzophenone derivatives resulted in the exclusive formation
of N,O-acetal (not shown).
Scheme 3 Concise construction of the indole skeleton via multiple
hydrogen transfers.
With the optimum reaction conditions in hand, we next
examined the substrate scope of this reaction (Fig. 1). The ester
portion was not limited to methyl ester, and good chemical
yields were also achieved for the substrates 3b and 3c with ethyl
ester and isopropyl ester moieties (64% and 67%, respectively).
Indoles 4a–g with not only cyclic amines (pyrrolidine and
piperidine units), but also acyclic amines such as N,N-dibenzyl,
N,N-diethyl and N,N-dimethyl amines were obtained in moderate
to good chemical yields (49–77%). In the case of the substrate 4g
having an N,N-dimethylamine moiety, a stoichiometric amount
of TiCl4 (1.0 equiv.) was required for the completion of the
reaction (49%). This low reactivity is ascribed to the weak cation
stabilization ability of the methyl group, which is an important
factor for inducing the [1,5]-H shift.3d This reaction was applic-
able to the substrates 3h–k with various substituents on the
aromatic ring (Me, OMe, and Cl) and the naphthyl-type substrate
3l, and the corresponding adducts 4h–l were obtained in
moderate to good chemical yields (57–73%) with 30 mol% TiCl4.
To obtain further insight into the scope of the reactions,
some chemoselective reactions were examined (Scheme 4).
Ketoester 3a having an ortho-pyrrolidine moiety was selected
as the suitable substrate because of the strong electron-
withdrawing character of the ester moiety and its easy prepara-
tion (Table 1). When a solution of 3a in ClCH2CH2Cl was
treated with 30 mol% of Sc(OTf)3, which exhibited excellent
catalytic performance in the internal redox reaction with a
CF3-ketone moiety that we recently developed,3j the starting
material was consumed. Only N,O-acetal 5a was generated in
78% yield and the desired indole 4a was not obtained (entry 1).
Yb(OTf)3 and Gd(OTf)3 also resulted in the exclusive formation
of 5a (entries 2 and 3). Various Lewis acids, such as SnCl4 and
BF3ꢀOEt2, afforded only 5a in moderate to good chemical yields
(50% and 63%, entries 4 and 5, respectively). The same result
was noted for the strong Brønsted acid catalyst TfOH (5a: 73%,
entry 6). Gratifyingly, in the case of TiCl4, the desired indole 4a
was obtained in 22% yield, together with 5a in 35% yield
(entry 7). Even the titanium reagent, Cp2TiCl2 did not promote
the reaction (entry 8). In this reaction, a stoichiometric amount
of H2O, which was generated after the product formation,
might have a detrimental effect on catalytic species. Based on
this consideration, various dehydrating reagents were added to
the reaction mixture with TiCl4 as the catalyst (entries 9–11).
Table 1 Screening for reaction conditionsa
Yieldb [%]
Additive
Entry
Catalyst
(1.0 equiv.)
4a
5a
Fig. 1 Substrate scope.
1
2
3
4
5
6
7
8
Sc(OTf)3
Yb(OTf)3
Gd(OTf)3
SnCl4
None
None
None
None
None
None
None
None
DEAD
DCC
0
0
0
0
0
0
22
78
70
58
50
63
73
35
BF3ꢀOEt2
TfOH
TiCl4
Cp2TiCl2
TiCl4
TiCl4
TiCl4
No reaction
9
10
11
23
46
77
14
0
0
DMC
a
Unless otherwise noted, all reactions were conducted with 0.10 mmol
of 3a in the presence of an acid catalyst (30 mol%) in ClCH2CH2Cl
(1.0 mL) at refluxing temperature. Isolated yield.
b
Scheme 4 Chemoselective reactions.
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Fig. 2 Substrate scope of the reaction involving an alkyl shift.
Scheme 5 Clarification of the reaction pathway to intermediate B.
Excellent site-selective reactions in benzyl and ethyl groups over
methyl groups were observed. These results strongly indicate
that the difference of the stability of carbocation species after the
hydride shift (secondary carbocation vs. primary carbocation)
is the key to controlling the position of the hydride shift as
observed in our previous studies.3d,l This assumption implies
that the reaction of the substrate 3o with the 2-methyl pyrroli-
dine moiety would lead to the selective formation of N,O-acetal
5o via a tertiary carbocation. In contrast to our assumption,
however, indole 4o was the only detectable product (75%), and
the expected 5o was not obtained.
The formation of 4o in the above reaction indicates that
the iminium cation B shown in Scheme 5 was produced as the
key intermediate. There are two possible pathways for the
formation of B: (1) a hydride shift from the methylene position
(path I), and (2) a hydride shift of the methine hydrogen
followed by isomerization (path II). To elucidate the reaction
mechanism, a D-labeling experiment was conducted. The
absence of a D-atom adjacent to the methoxycarbonyl group
(H/D = 95/5) indicates a selective hydride shift from the
methylene moiety over the methine moiety.
Scheme 7 Transformation to a biologically active molecule.
afforded 8a in almost the same chemical yield as cis-6a (27%). The
reaction mechanism for the formation of 8a is shown in Scheme 6.
The outline of the mechanism resembles that of 3-alkoxycarbonyl-
indole formation (see, Scheme 3). The major difference between
the two is the absence of the a-hydrogen of the nitrogen atom in
the key intermediate F (cf. F0). Thus, a [1,2]-methyl shift instead of a
[1,2]-hydride shift occurred to give a tertiary cation intermediate G.
The subsequent Krapcho-type decarbonylation resulted in the
formation of 8a.
This reaction involving an alkyl shift was applicable to
various substrates (Fig. 2). 3-Methylindoles 8b–d with various
substituents on the aromatic ring and 8e with a piperidine unit
were obtained in moderate chemical yields (30–38%, respectively).
A [1,2]-ethyl shift was also attainable, and the corresponding
3-ethylindole 8d was obtained in 42% yield. In addition, this
reaction system could be extended to ring expansion reactions:
the reaction of the substrate 6e with the N,N-cyclopentyl methyl
amine moiety afforded the carbazole derivative 8e in 25%.
The indoles thus obtained are important intermediates for
the synthesis of some biologically active molecules (Scheme 7).
Hydrolysis of the methoxycarbonyl group in 4d, transformed
into acid chloride 9 with (COCl)2 followed by coupling with
alcohol 10, afforded 11, which works as a 5-HT4 receptor
antagonist, in 74% yield (3 steps from 4d).13
In summary, we have developed a concise synthetic route
to multisubstituted indoles via multiple hydrogen transfers.
In this reaction, three types of hydrogen transfer events ([1,5]-
hydride shift, proton transfer, and [1,2]-hydride shift) occurred
to give various 3-alkoxycarbonylindoles 4 in good chemical
yields. Another interesting feature of this reaction was that an
alkyl shift was also a viable process when the substrates with
the amino group having the tertiary carbon adjacent to the nitrogen
atom were employed. Further investigations to develop a new
synthetic transformation based on the multiple hydrogen transfer
strategy are underway in our laboratory.
These results stimulated our interest in the reactions of the
substrate 6a with a 2,5-dimethyl pyrrolidine unit, which only
accepts a hydride shift from the methine moiety (Scheme 6).
When cis-6a was subjected to slightly modified optimized
reaction conditions (1.0 equiv. of TiCl4 in refluxing ClCH2CH2Cl),
cis-6a was consumed after 14 h. The resulting product was not the
expected N,O-acetal 7, but the 3-methylindole 8a (31%). The relative
stereochemistry of 6a was irrelevant to the results, and trans-6a
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion
of Science, and by grant from The Naito Foundation.
Scheme 6 Finding of a reaction involving an alkyl shift.
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Conflicts of interest
There are no conflicts of interest.
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