Br?nsted Base-Catalyzed Reductive Cyclization of Alkynyl α-Iminoesters through Auto-Tandem Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02236

A novel reductive cyclization of alkynyl α-iminoesters was developed through auto-tandem catalysis with a Br?nsted base as the catalyst. The reaction system involves two mechanistically different elementary processes, both of which are efficiently catalyz

Full text of DOI:10.1021/acs.orglett.8b02236

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Base-Catalyzed Reductive Cyclization of Alkynyl
α‑Iminoesters through Auto-Tandem Catalysis
Azusa Kondoh‡ and Masahiro Terada*,†
†Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578,
Japan
S
* Supporting Information
ABSTRACT: A novel reductive cyclization of alkynyl α-iminoesters was
developed through auto-tandem catalysis with a Brønsted base as the
catalyst. The reaction system involves two mechanistically different
elementary processes, both of which are efficiently catalyzed by an
organosuperbase P2-tBu: the unprecedented reduction of α-iminoesters
with 1-dodecanethiol as the reductant to provide α-aminoesters and the
following intramolecular addition of ester enolates to an alkyne. The
operationally simple reaction under mild conditions provides new
efficient access to N-H indoline derivatives, demonstrating the high
potential of auto-tandem catalysis with a Brønsted base as a methodology
for organic synthesis.
Scheme 1. Brønsted Base-Catalyzed Reductive Cyclization
of Alkynyl α-Iminoesters 1 through Auto-Tandem Catalysis
(This Work)
rønsted base catalysis is fundamental and reliable catalysis
Bin organic chemistry, which enables the transformation of
small molecules as intended in a catalytic fashion.1 Trans-
formations based on Brønsted base catalysis are generally
initiated by the deprotonation of a substrate by a Brønsted
base catalyst to generate an anionic species. The resulting
anionic species then participates in an elementary process, such
as nucleophilic addition to an electrophile, rearrangement, or
isomerization, to form a different anionic intermediate that is
subsequently protonated by a conjugated acid of the Brønsted
base or the substrate to provide a product along with the
regeneration of the Brønsted base catalyst or the starting
anionic species. These conventional catalytic cycles have been
adopted in a tremendous amount of applications so far. One
efficient application to construct structurally complex mole-
cules is a multistep reaction through auto-tandem catalysis.
Auto-tandem catalysis is a process in which one catalyst
promotes more than two mechanistically distinct processes in a
single reactor.2 Whereas auto-tandem catalysis using a
Brønsted base as the catalyst is particularly attractive due to
its operational simplicity and the mildness of the reaction
conditions, most of the reactions reported to date consist of
two or more independent nucleophilic addition reactions that
limit the substrate design and thus the accessible structural
motifs.3 Therefore, the development of reactions involving
auto-tandem catalysis with a new combination of elementary
processes would provide new facile access to a range of
structurally complex molecules. In this context, we report
herein a novel reductive cyclization of alkynyl α-iminoesters to
construct a heterocyclic framework containing nitrogen under
auto-tandem catalysis with the Brønsted base as a catalyst
(Scheme 1). The first catalytic cycle involves an unprecedented
chemoselective reduction of the imine moiety of N-(2-
alkynylaryl)-α-iminoester 1 with 1-dodecanethiol (2a) as the
reductant under the influence of a Brønsted base catalyst to
provide α-aminoester 3. Then α-aminoester 3 undergoes
intramolecular cyclization in the second catalytic cycle, which
involves the formation of enolate A through deprotonation by
the Brønsted base catalyst and the following intramolecular
addition of the enolate to an alkyne moiety, providing N-H
indoline 5.4
The key feature of our strategy is a distinctive elementary
process under Brønsted base catalysis, that is, the catalytic
reduction. During the course of our study on the development
Received: July 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of a new methodology involving Brønsted base catalysis,5 we
serendipitously found that a Brønsted base catalyzed the
reduction of α-iminocarbonyl compounds (Scheme 2).
alkyne moiety on the substituent on the nitrogen atom was
chosen as the initial substrate. First, 1a and 2.0 equiv of 2a
were treated with 10 mol % P2-tBu (pKBH+ = 21.5 in DMSO)8
in DMF at room temperature. As a result, 1a was fully
consumed, and desired indoline 5a was obtained in 73% NMR
yield as the product along with disulfide 4a (Table 1, entry 1).
Scheme 2. Catalytic Reduction of α-Iminocarbonyl
a
Compounds 6a and 8a with 1-Dodecanethiol (2a)
a
Table 1. Screening of Reaction Conditions
b
b
entry
base
solvent
5a (%)
3a (%)
1
2
3
4
5
6
7
8
P2-tBu
P4-tBu
P1-tBu
TBD
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
73
76
<1
3
<1
<1
88
83
90
1
<1
<1
73
83
91
<1
<1
<1
80
a
Yields and amounts of products were determined by 1H NMR
DBU
<1
<1
c
analysis of crude mixture.
iPr2NEt
tBuOK
KHMDS
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
72
71
13
2
Treatment of α-iminoester 6a with 1.1 equiv of 1-
dodecanethiol (2a) in the presence of 10 mol % of P2-tBu
in DMF provided α-aminoester 7a in 43% yield along with the
formation of didodecyl disulfide (4a). The use of 2.1 equiv of
thiol 2a increased the yield of 7a to 85%, and accordingly, the
production of 4a was also increased, clearly suggesting that
thiol 2a serves as the reductant in the reaction. The reduction
of α-iminoketone 8a also proceeded under identical reaction
conditions in a highly chemoselective manner; only the imine
moiety of 8a was reduced, and the corresponding α-
aminoketone 9a was obtained in 93% yield. Most importantly,
to the best of our knowledge, such reduction of imines under
Brønsted base catalysis has not been reported so far, indicating
that our finding should expand the repertoire of elementary
processes under Brønsted base catalysis. In addition, as a
distinctive feature of the process, the anionic species generated
by the deprotonation, that is, thiolate, is not introduced into
the product molecule, which is uncommon in the reactions
under Brønsted base catalysis. Therefore, 1-dodecanethiol
(2a), which is known as an odorless thiol,6 is potentially
recyclable by the reduction of disulfide 4a7 and thus would be
regarded as an environmentally benign reductant. Motivated
by this finding, we envisioned utilizing the newly found
reduction as an elementary process in a multistep reaction
under auto-tandem catalysis with a Brønsted base. The
reduction of α-iminoesters would generate an acidic proton
at the position α to the ester moiety, which would be further
transformable through a conventional elementary process, such
as nucleophilic addition to an electrophile, initiated by the
deprotonation by a Brønsted base catalyst. Thus, as an
immediate goal to provide proof of concept, we designed a
reductive cyclization of N-(2-alkynylaryl)-α-iminoester 1
(Scheme 1). Generally, a fundamental difficulty of auto-
tandem catalysis emerges from the likelihood that the optimal
conditions differ for the two catalytic processes. We
successfully managed to resolve this issue by using an
organosuperbase and describe herein a new efficient synthesis
to N-H indoline derivatives, which demonstrates the high
potential of auto-tandem catalysis with a Brønsted base as a
methodology for organic synthesis.
9
10
11
12
13
14
Et2O
toluene
CH2Cl2
DMSO
CH3CN
DMF
2
12
84
d
90 (82)
<1
e
f
15
a
Reaction conditions: 1a (Z/E > 95/5, 0.10 mmol), 2a (0.20 mmol),
b
base (0.010 mmol), solvent (1.0 mL), rt, 3 h. Yields are based on 1H
NMR measurement of the crude mixture. Isolated yield is in
parentheses. 74% of 1a was recovered. 80% of 1a was recovered. 4-
Methoxythiophenol (2b) was used instead of 2a. 10% of 1a was
recovered.
c
d
e
f
Then, the screening for catalysts was conducted (entries 2−8).
P4-tBu (pKBH+ = 30.3), which has higher basicity than P2-tBu,
provided 5a in comparable yield to that obtained with P2-tBu
(entry 2). In contrast, the use of weaker bases, such as P1-tBu
(pKBH+ = 15.7), TBD,9 and DBU (pKBH+ = 13.6), than P2-tBu
gave not 5a, but α-aminoester 3a in good yields (entries 3−5).
Hunig’s base, a weak organobase, provided neither 5a nor 3a,
and a significant amount of 1a was recovered (entry 6).
Inorganic bases having high basicity, such as tBuOK and
KHMDS, were also tested (entries 7 and 8). In these cases, 5a
was obtained in 72% and 71% yields, respectively. These
results indicate that the basicity of the Brønsted base catalysts
is the key to completing both catalytic cycles. In particular, the
second catalytic process, that is, the intramolecular cyclization
of alkynyl esters, requires the use of a catalyst having a rather
+
high basicity (pKBH > 20) because of the low acidity of
We began our investigation by evaluating the viability of the
designed reaction system. α-Iminoester 1a having a terminal
intermediate 3a.10 Next, the solvents were screened with P2-
tBu as the catalyst (entries 9−14). The solvent effect was also
B
DOI: 10.1021/acs.orglett.8b02236
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Organic Letters
Letter
significant in this reaction system. The use of ethereal solvents
and toluene dramatically retarded the intramolecular cycliza-
tion, and 3a was obtained as the major product (entries 9−11).
In contrast, dichloromethane was detrimental to the first
reduction step, whereas the second cyclization proceeded
smoothly (entry 12). Finally, aprotic polar solvents were
proven to be the solvent of choice (entries 1, 13, and 14), and
acetonitrile gave the best result (entry 14). For comparison, 4-
methoxythiophenol (2b) was used instead of 2a (entry 15). In
this case, only reduction proceeded to provide 3a in 80% yield.
It should be noted that the reaction on gram scale proceeded
without any problems (Scheme 3).
1h, derived from diethyl mesoxalate, was also applicable to this
reaction, and corresponding 5h was isolated in high yield,
although the intramolecular cyclization required a long
reaction time. Next, the aryl groups on the nitrogen atom
were investigated. 1i and 1j having a methoxy group and a
fluoro group provided 5i and 5j in good yields, respectively.
The introduction of chloro groups slightly diminished the
yields of 5k and 5l. In these cases, the formation of a small
amount of unidentified byproducts was observed. On the other
hand, the reaction of 1m having a bromo group proceeded
without any problem to afford 5m in good yield. Finally,
substrates having an internal alkyne moiety were investigated.
As a result, the substrates possessing a phenyl group and an
electron-deficient aryl group, such as 4-chloro- or 2-
chlorophenyl group, at the alkyne terminus underwent the
reaction smoothly to provide the corresponding N-H indolines
in high yields although the Z/E selectivities were markedly
dependent on the substituents. In contrast, the substrates
having an electron-rich aryl group and an alkyl substituent
were not applicable to the reaction. In these cases, the second
cyclization did not proceed and corresponding α-aminoesters 3
were obtained. As an application of the newly developed
reaction, imine 10 derived from oxindole was subjected to the
reaction conditions (Scheme 5). As a result, the reductive
cyclization proceeded to furnish desired product 11 having a
spirocyclic-oxindole scaffold in high yield.
Scheme 3. Gram-Scale Reaction
With the optimized reaction conditions in hand, the scope of
substrates was investigated (Scheme 4). First, the substituents
on the imine carbon were examined. Substrates having a
variety of aryl groups (1b−f) were applicable to the reaction to
provide the corresponding products (5b−f) in high yields. A
heteroaryl group, such as the 2-thienyl group, was compatible
under the reaction conditions to afford 5g in good yield. Imine
Scheme 5. Reaction of Imine 10 Derived from Oxindole
a
Scheme 4. Substrate Scope
The mechanism of the unprecedented catalytic reduction of
α-iminoesters is not clear at this stage. Nonetheless, we show a
plausible mechanism in Scheme 6. First, 1-dodecanethiol (2a)
is deprotonated by P2-tBu to form the ion pair of the thiolate
and the conjugated acid of P2-tBu. Then, proton-coupled
electron transfer (PCET)11 occurs between the ion pair and α-
iminoester 1 to generate two radical species concomitantly
Scheme 6. Plausible Mechanism of Reduction of α-
Iminoester 1 with 2a Catalyzed by P2-tBu
a
Conditions: 1 (Z/E > 92/8, 0.10 mmol), 2a (0.20 mmol), P2-tBu
(0.010 mmol), CH3CN (1.0 mL), rt, 3 h. Yields are isolated yields.
b
The reaction was performed for 16 h.
C
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Organic Letters
Letter
with the regeneration of P2-tBu.12 One is α-amino carbon
radical A, which is highly stabilized by the captodative effect,
and the other is thiyl radical B. Finally, carbon radical A
abstracts a hydrogen from thiol 2a to provide α-aminoester 3
along with thiyl radical B. Didodecyl disulfide 4a, which was
obtained as a byproduct, would be formed through the
homocoupling of thiyl radicals thus generated. In this proposed
mechanism, the cross-coupling between radicals A and B,
which provides an undetected N,S-acetal, might be conceiv-
able. In that case, the N,S-acetal would be immediately
decomposed into starting α-iminoester 1 and thiol 2a (or
thiolate) through the deprotonation of N-H proton followed
by the elimination of thiolate under the influence of P2-tBu.
The subsequent cyclization would proceed through the
generation of enolate by deprotonation of 3 followed by
addition to the alkyne. Indeed, treatment of the isolated 3a
with P2-tBu provided 5a in high yield (Scheme 7).
on the development of new transformations as well as the
mechanistic study of the unprecedented reduction process.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02236.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mterada@m.tohoku.ac.jp.
ORCID
Azusa Kondoh: 0000-0001-7227-8579
Masahiro Terada: 0000-0002-0554-8652
Scheme 7. Control Experiment
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Hybrid Catalysis for Enabling
Molecular Synthesis on Demand” (JP17H06447) from MEXT
(Japan) and a Grant-in-Aid for Scientific Research (C)
(JP16K05680) from the JSPS.
Finally, the transformation of N-H indoline 5a was explored.
The N-H indoline skeleton was convertible to the 3-H indole
skeleton through the rearrangement of the ester moiety
(Scheme 8). Thus, treatment of 5a with p-toluenesulfonic
Scheme 8. Transformation of 5a into 3-H Indoles 12 and 13
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In conclusion, we have developed a novel reductive
cyclization of alkynyl α-iminoesters under auto-tandem
catalysis with a Brønsted base as the catalyst. The reaction
system involves two mechanistically different elementary
processes: the unprecedented reduction of α-iminoesters
with 1-dodecanethiol as the reductant to provide α-amino-
esters and the following intramolecular addition of ester
enolates to an alkyne. The organosuperbase P2-tBu efficiently
catalyzed both of the elementary processes owing to its high
basicity. The operationally simple reaction under mild
conditions provides new efficient access to N-H indoline
derivatives, demonstrating the high potential of auto-tandem
catalysis with a Brønsted base as a methodology for organic
synthesis. Further investigations of the newly established auto-
tandem catalysis with a Brønsted base are in progress, focusing
D
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Letter
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E
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