Br?nsted Base-Catalyzed Umpolung Intramolecular Cyclization of Alkynyl Imines

Article abstract of DOI:10.1002/chem.201800219

A novel “umpolung” intramolecular cyclization of alkynyl imines, in which the electrophilic imine sp²-carbon formally serves as a nucleophilic site, was developed under Br?nsted base catalysis. The reaction involves the unprecedented catalytic generation of α-aminoester enolates from α-iminoesters via the 1,2-addition of the anion of a secondary phosphite to an imine moiety followed by the [1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to nitrogen, which is a formal umpolung process, and the intramolecular addition to an alkyne. This is a rare example of a [1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to nitrogen to generate an α-amino carbanion and the first catalytic carbon–carbon bond forming reaction utilizing the resulting carbanion as a nucleophile.

Full text of DOI:10.1002/chem.201800219

A Journal of
Accepted Article
Title: Brønsted Base-Catalyzed Umpolung Intramolecular Cyclization of
Alkynyl Imines
Authors: Azusa Kondoh and Masahiro Terada
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To be cited as: Chem. Eur. J. 10.1002/chem.201800219
Link to VoR: http://dx.doi.org/10.1002/chem.201800219
Supported by

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Brønsted Base-Catalyzed Umpolung Intramolecular Cyclization of
Alkynyl Imines
[
b]
[a]
Azusa Kondoh, and Masahiro Terada*
Abstract: A novel “umpolung” intramolecular cyclization of alkynyl
formation, have never been developed, despite the fact that the
original oxygen version has been well-accomplished and utilized
in several catalytic carbon-carbon bond forming reactions under
2
imines, in which the electrophilic imine sp -carbon formally serves as
a nucleophilic site, was developed under Brønsted base catalysis.
The reaction involves the unprecedented catalytic generation of α-
aminoester enolates from α-iminoesters via the 1,2-addition of the
anion of a secondary phosphite to an imine moiety followed by the
[2,4]
Brønsted base catalysis.
Therefore, the establishment of an
efficient catalytic system for an unprecedented catalytic
“umpolung” generation of carbanions from imines is the key to
the development of subsequent catalytic carbon-carbon bond
forming reactions and hence presents a significant challenge.
As a target carbon-carbon forming reaction, we focused our
attention on the intramolecular cyclization of alkynyl-substituted
imines. In particular, we intended to develop the reaction of
imines possessing an alkyne moiety in the nitrogen substituent,
providing a nitrogen heterocyclic structure (Scheme 1). Catalytic
intramolecular cyclization of alkynyl-substituted imines with
[
1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to
nitrogen, which is formal umpolung process, and the
intramolecular addition to an alkyne. This is a rare example of a
1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to
a
[
nitrogen to generate an α-amino carbanion and the first catalytic
carbon-carbon bond forming reaction utilizing the resulting carbanion
as a nucleophile.
external nucleophiles is
a
powerful and atom-efficient
The [1,2]-phospha-Brook rearrangement involves the migration
methodology for the construction of nitrogen heterocyclic
of
a
dialkoxyphosphoryl moiety of an alkoxide of an α-
[6]
frameworks. In the general approach, the imine nitrogen
hydroxyphosphonate from carbon to oxygen to generate an α-
serves as the nucleophilic site of the cyclization, and thus
carbon-nitrogen bond formation occurs to construct a cyclic
framework with concomitant introduction of external nuclephiles
[
1]
oxygenated carbanion. This rearrangement enables the facile
generation of carbanions from easily accessible precursors.
Therefore, the generation of the carbanion by using the [1,2]-
2
on the imine sp -carbon, which is the “normal” reactivity
phospha-Brook rearrangement is potentially
a
useful
considering the polarity of the imine moiety (Scheme 1a and
methodology for developing new carbon-carbon bond forming
[7,8]
1b).
In contrast, our intended reaction can be regarded as a
[2]
reactions. We have been focusing on the [1,2]-phospha-Brook
rearrangement as a useful tool for the development of novel
catalytic “umpolung” intramolecular cyclization, in which the
2
electrophilic imine sp -carbon formally serves as the nucleophilic
[3]
synthetic reactions under Brønsted base catalysis. Recently,
we successfully established catalytic carbon-carbon bond
forming reactions involving the catalytic generation of
carbanions of less acidic compounds through the formal
[4a,b,e]
site for carbon-carbon bond formation (Scheme 1c).
This
“
umpolung” approach is attractive because it enables the
construction of heterocyclic frameworks that are difficult to
access by conventional approaches. Therefore, development of
new reactions based on this approach potentially will provide
new avenues to heterocyclic compounds.
“
umpolung” process from the corresponding carbonyl
compounds, i.e., the addition of a secondary phosphite to a keto
moiety followed by the [1,2]-phospha-Brook rearrangement
[4]
under the influence of a Brønsted base catalyst. As the next
stage of our research, we envisioned the development of
catalytic carbon-carbon bond forming reactions involving
“
umpolung” generation of α-amino carbanions from imines. In
contrast to the original [1,2]-phospha-Brook rearrangement,
namely the [1,2]-rearrangement from carbon to oxygen, the
[
1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon
to nitrogen is very rare and has been observed only in very
[5]
specific cases. Furthermore, catalytic reactions involving the
generation of α-amino carbanions via rearrangement and
subsequent transformation, such as carbon-carbon bond
[
[
a]
b]
Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Dr. A. Kondoh
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Scheme 1. Catalytic intramolecular cyclization of alkynyl-substituted imines
with external nucleophiles.
Supporting information for this article is given via a link at the end of
the document.
Specifically, we designed an intramolecular cyclization of N-(2-
alkynylaryl)-α-iminoester 1 as an immediate goal (Scheme 2).
First, deprotonation of phosphite 2 followed by the addition of
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the resulting anion of 2 to the imine moiety of 1 provides amide
A. Subsequently, the key [1,2]-rearrangement of the
dialkoxyphosphoryl moiety from carbon to nitrogen would
proceed to generate enolate B. We expected that the
introduction of an electron-withdrawing ester moiety on the imine
carbon would provide a driving force for the rearrangement by
enhancing the stability of the resulting carbanion. Finally, the
intramolecular addition of B to the alkyne moiety in 5-exo
fashion followed by protonation affords indoline 3 along with
regeneration of the Brønsted base or the anion of 2. Based on
this concept and reaction design, we report herein a novel
catalytic “umpolung” intramolecular cyclization of alkynyl imines
under Brønsted base catalysis.
from protonation of the enolate generated by the [1,2]-
rearrangement, were not observed at all in the crude reaction
mixture. The effect of secondary phosphites was then examined
3
using P2-tBu as the catalyst in CH CN (Scheme 3). As a result,
other dialkyl phosphites, such as dimethyl phosphite (2b) and
diisopropyl phosphite (2c) provided results similar to that of
diethyl phosphite (2a). In contrast, the use of diphenyl phosphite
(2d) resulted in no reaction probably due to the low
nucleophilicity of the anion of 2d.
[
a]
Table 1. Screening of reaction conditions.
[
b]
yield [%]
entry
base
solvent
3aa (Z/E)
4aa
1a
1
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
<1 (-)
<1 (-)
<1 (-)
5
86
50
61
<1
<1
<1
<1
<1
14
68
64
2
TBD
45
36
<1
<1
<1
<1
<1
80
27
32
3
P1-tBu
P2-tBu
P4-tBu
tBuOK
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
4
99 (40/60)
99 (46/54)
99 (43/57)
90 (42/58)
5
Scheme 2. Reaction design.
6
7
To ascertain the viability of our proposed catalytic reaction
system, our investigation began with screening of reaction
conditions using α-iminoester 1a having a phenylethynyl group
as the primary substrate. First, a number of Brønsted bases
were tested in DMF at room temperature for the reaction of 1a
with diethyl phosphite (2a) (Table 1, entries 1-6). The use of
[
c]
8
CH
THF
CH Cl
toluene
3
CN
97 (92/8)
9
<5 (-)
10
11
2
2
<1 (-)
+
[9]
[10]
+
<1 (-)
DBU (pKBH = 13.6 in DMSO), TBD
and P1-tBu (pKBH =
1
5.7) resulted in low to moderate conversion of 1a, and only 1,2-
[
(
a] Reaction conditions: 1a (Z/E = 94/6, 0.10 mmol), 2a (0.11 mmol), base
1
adduct 4aa was obtained as the product (entries 1-3). In contrast,
0.010 mmol), solvent (1.0 mL), 10 h. [b] Yields are based on H NMR
the use of stronger Brønsted bases dramatically changed the
reaction outcome. P2-tBu (pKBH = 21.5) afforded desired
measurement of the crude mixture unless otherwise noted. Dibenzyl ether
was used as the internal standard. [c] Isolated yield.
+
indoline 3aa in almost quantitative yield with a 40:60 Z/E ratio
+
(
entry 4). Other strong Brønsted bases, such as P4-tBu (pKBH
=
30.3 in DMSO) and tBuOK, also provided 3aa as the sole
product in high yields (entries 5 and 6). Next, the solvents were
screened with P2-tBu as the catalyst. The solvent effect was
significant in this reaction, and aprotic polar solvents, such as
DMF, DMSO, and CH
and 8). CH CN was the best solvent by consideration of the
Z/E ratio (entry 8).
3
CN, were found to be effective (entries 4,
7
3
[
11]
The reaction in other solvents provided
only a trace amount of desired 3aa even with a strong Brønsted
base as a catalyst, and 1,2-adduct 4aa was obtained as the
major product along with recovered starting 1a (entries 9-11). It
should be noted that, in this initial screening, 1,2-adduct 4aa
was the only byproduct, and other potential byproducts, such as
indole 5aa formed through C-N bond formation based on
[12]
“
normal” reactivity
and uncyclized α-aminoester 6aa formed
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proceeded with lower selectivity than those of 1a and 1b to
provide 3ca in a 85/15 Z/E ratio. Furthermore, the selectivity of
the reaction of 1d with a chloro group at the ortho position was
much lower, and 3da was obtained in a 40/60 Z/E ratio. The
substrate having an alkyl group was also applicable to the
reaction. In this case, DMF was the more suitable solvent and
corresponding product 3ea was obtained in high yield with
perfect Z selectivity. The substrate having a terminal alkyne
moiety underwent the reaction without any problem to provide
Scheme 3. Effect of phosphites.
3fa in good yield. Next, the aryl groups on the nitrogen atom
were investigated. 1g and 1h having a methoxy group and a
fluoro group provided 3ga and 3ha in high yields, respectively.
The introduction of chloro and bromo groups slightly diminished
the yields of desired products 3 because of the formation of a
small amount of unidentified byproduct. Nonetheless, 3ia, 3ja,
and 3ka were still obtained in good yields. Finally, substituents
on the imine carbon were examined. Substrates having a variety
of aryl groups were applicable to the reaction to provide the
corresponding products in high yields. A hetero aryl group, such
as the 2-thienyl group, was compatible under the reaction
conditions. Furthermore, the reaction of trifluoromethyl-
substituted 1r, which involved the generation of an enolate
having a trifluoromethyl group at the α-position, proceeded to
afford 3ra in good yield without suffering the elimination of
fluoride prior to the addition of the enolate to the alkyne moiety.
It is worth noting that this reaction was sufficiently reliable to
perform on the gram-scale, and 3fa was obtained in good yields
With the optimized reaction conditions in hand, the scope of
substrates was investigated (Scheme 4). First, the substituents
on the alkyne terminus were examined. The substrates
possessing aryl groups underwent the reaction smoothly to
provide the corresponding products in high yields regardless of
the substituents on the aryl group. However, the Z/E selectivities
were highly dependent on the substituents. For instance, the
reaction of 1b with an electron-donating methoxy group at the
para position proceeded in a highly selective manner to provide
only the Z isomer of 3ba. In contrast, the reaction of 1c with an
electron-withdrawing chloro group at the para position
(
Scheme 5).
Scheme 5. Gram-scale reaction.
Finally, in order to clarify whether the generation of the enolate
involved the [1,2]-rearrangement of the dialkoxyphosphoryl
moiety from carbon to nitrogen as we intended, control
experiments were carried out (Scheme 6). The other possibility
for the generation of the enolate is the direct attack of the anion
of the phosphite to the nitrogen of the α-iminoester. Such
reactivity of an α-iminoester is often observed in the addition of
organometallic reagents, such as Grignard reagents and lithium
[
13]
reagents.
4fa, which is the 1,2-adduct of diethyl phosphite
(
2a) to 1f, was treated with 10 mol% P2-tBu in the presence of
an equivalent molar amount of 1n (Scheme 6a). As a result, 3fa
was obtained in 96% yield along with a small amount of 3na
derived from 1n. 3na would be formed through the elimination of
the anion of 2a from 4fa followed by reaction with 1n. On the
other hand, treatment of the 1:1:1 mixture of 1f, 1n and 2a with
20 mol% P2-tBu provided a mixture of 3fa and 3na in a 21:79
ratio, which indicates that the anion of 2a preferentially reacts
[
a]
Scheme 4. Substrate scope. [a] Conditions: 1 (Z/E > 92/8, 0.10 mmol), 2a
0.11 mmol), P2-tBu (0.010 mmol), CH CN or DMF (1.0 mL), rt, 10 h. Yields
are isolated yields unless otherwise noted. [b] NMR yield.
(
3
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Keywords: Brønsted base catalysis • umpolung • intramolecular
cyclization • rearrangement • organocatalyst
[
1]
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[
2]
1
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with 1n over 1f (Scheme 6b). These results clearly suggest that
the formation of 3fa from 4fa in Scheme 6a involves the
generation of the enolate via the intramolecular process, i.e., the
[
3]
a) A. Kondoh, M. Terada, Org. Lett. 2013, 15, 4568-4571; b) A. Kondoh,
M. Terada, Org. Chem. Front. 2015, 2, 801-805; c) A. Kondoh, S.
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d) A. Kondoh, K. Koda, Y. Kamata, M. Terada, Chem. Lett. 2017, 46,
[
1,2]-rearrangement of the dialkoxyphosphoryl moiety from
carbon to nitrogen, and hence our proposed reaction
mechanism in Scheme 2, which includes the rearrangement of
the dialkoxyphosphoryl moiety, is plausible.
1020-1023.
[4]
a) A. Kondoh, T. Aoki, M. Terada, Org. Lett. 2014, 16, 3528-3531; b) A.
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7277-7281.
In conclusion, we have developed a novel catalytic “umpolung”
intramolecular cyclization of alkynyl imines under Brønsted base
catalysis. The reaction involves the unprecedented catalytic
generation of an α-aminoester enolate from an α-iminoester via
the 1,2-addition of the anion of a phosphite to an imine moiety
followed by the [1,2]-rearrangement of a dialkoxyphosphoryl
moiety from carbon to nitrogen, which is a formal umpolung
process, and the intramolecular addition to an alkyne. This is a
rare example of a [1,2]-rearrangement of a dialkoxyphosphoryl
moiety from carbon to nitrogen to generate an α-amino
carbanion. Furthermore, the resulting carbanion was, for the first
time, utilized as a nucleophile in a catalytic carbon-carbon bond
forming reaction. Further investigation utilizing this newly-
developed methodology is in progress.
[
[
5]
6]
a) Y. V. Rassukana, P. P. Onys’ko, A. G. Grecjilja, A. D. Sinitsa, Eur. J.
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The reaction of 1a with diethyl phosphite (2a) is representative (Table 1,
entry 8). To a solution of 1a (35 mg, 0.10 mmol) and diethyl phosphite (3,
14 μL, 0.11 mmol) in acetonitrile (1.0 mL) was added a solution of P2-tBu
in THF (2.0 M, 5.0 µL, 0.010 mmol) at room temperature. The resulting
mixture was stirred at that temperature for 10 h. The reaction was then
quenched with sat. aq. NH
The combined organic layer was dried over Na
purification of the crude mixture by column chromatography
hexane/AcOEt = 3:2) provided 3aa (Z/E = 92/8, 48 mg, 0.097 mmol,
7%) as a white solid.
4
Cl, and the product was extracted with AcOEt.
2
SO and evaporated. The
4
(
9
[9]
Y. Kondo, M. Ueno, Y. Tanaka, Y. J. Synth. Org. Chem. Jpn. 2005, 63,
453-463.
[
10] The basicity of TBD seems to lie between those of DBU and P1-tBu in
Acknowledgements
+
DMSO. The pKBH values of those bases in CH
3
CN are 24.34 (DBU),
2
6.03 (TBD), and 26.98 (P1-tBu), respectively. See ref. 9.
[11] The Z configuration of an alkene moiety of the major stereoisomer of
aa was confirmed by single-crystal X-ray diffraction analysis (CCDC
No.1581236). See the supporting information for details.
This research was supported by a Grant-in-Aid for Scientific
Research from the JSPS.
3
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[
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Azusa Kondoh, Masahiro Terada*
Page No. – Page No.
Brønsted Base-Catalyzed Umpolung
Intramolecular Cyclization of Alkynyl
Imines
A novel “umpolung” intramolecular cyclization of alkynyl imines, in which the
2
electrophilic imine sp -carbon formally serves as a nucleophilic site, was developed
under Brønsted base catalysis. This is a rare example of a [1,2]-rearrangement of a
dialkoxyphosphoryl moiety from carbon to nitrogen to generate an α-amino
carbanion and the first catalytic carbon-carbon bond forming reaction utilizing the
resulting carbanion as a nucleophile.
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