Catalytic synthesis of isoquinolines via intramolecular migration of n-aryl sulfonyl groups on 1,5-yne-imines

Article abstract of DOI:10.1246/BCSJ.20190301

Isoquinolines are ubiquitous structural motifs in a variety of bioactive compounds, including medicinal agents and natural products. The development of novel strategies for the preparation of isoquinolines using non-toxic organocatalysts is thus worthwhile. Herein, we report a simple amine-catalyzed protocol for the synthesis of isoquinolines from 1,5-yne-imines via the intramoleular migration of an N-aryl sulfonyl group to the carbon atom of the alkyne moiety.

Full text of DOI:10.1246/BCSJ.20190301

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Catalytic Synthesis of Isoquinolines via Intramolecular Migration of N-Aryl Sulfonyl
Groups on 1,5-Yne-Imines
Yoichi Hoshimoto, Chika Nishimura, Yukari Sasaoka, Ravindra Kumar, and Sensuke Ogoshi*
Advance Publication on the web November 29, 2019
doi:10.1246/bcsj.20190301
© 2019 The Chemical Society of Japan
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Publication manuscripts.

Catalytic Synthesis of Isoquinolines via Intramolecular Migration of N-Aryl Sulfonyl
Groups on 1,5-Yne-Imines
Yoichi Hoshimoto,1 Chika Nishimura,1 Yukari Sasaoka,1 Ravindra Kumar,2,3 and Sensuke Ogoshi*1
1Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
2Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow 226031, India
3 Academy of Scientific and Innovative Research, New Delhi, India
E-mail: <ogoshi@chem.eng.osaka-u.ac.jp>
Sensuke Ogoshi
Sensuke Ogoshi received his Ph.D. from Osaka University in 1993 (advisor: Prof. Shinji Murai). During his Ph.D. study, he
also worked with Prof. Lanny S. Liebeskind at Emory University (1991). In that year he joined the faculty at Osaka University
as an assistant professor (Prof. Hideo Kurosawa’s group). He was promoted to an associate professor in 1999, and is a full
professor since 2007. In the meantime, he pursued his academic career also at the University of Alberta during 1996-1997,
where he joined the research group of Professor Jeffrey M. Stryker (JSPS Fellowships for Research Abroad). He received CSJ
Award for Young Chemists (1999), and The Japan Chemical Society Award for Creative Work (2013).
Abstract
Isoquinolines are ubiquitous structural motifs in a variety
of bioactive compounds, including medicinal agents and natural
products. The development of novel strategies for the
preparation of isoquinolines using non-toxic organocatalysts is
thus worthwhile. Herein, we report a simple amine-catalyzed
protocol for the synthesis of isoquinolines from 1,5-yne-imines
via the intramoleular migration of an N-aryl sulfonyl group to
the carbon atom of the alkyne moiety.
Keywords: Isoquinoline, Organocatalysis, Sulfonyl
migration
1. Introduction
Isoquinoline derivatives form one of the largest groups
of natural alkaloids and exhibit a variety of bioactive
properties derived from their unique structures.1
Scheme 1. Simplified schemes for previously reported synthetic routes
Isoquinolines have been employed as building blocks for
to isoquinolines by (A) transition-metal-mediated C-H functionalization,
the synthesis of chemotherapeutics,2,3 and as ligands for
and (B) Lewis-acid/metal-mediated cyclization. (C) This work.
transition-metal-based catalysts.4,5 Remarkable advances
have been accomplished in the synthesis of isoquinolines,6
including classical methods such as the Bischler-
3. Results and Discussion
Napieralski, Pomeranz-Fritsch, and Pictet-Spengler
We have previously contributed to the development of
reactions.7 Recently, transition-metal-catalyzed protocols
nickel-catalyzed molecular transformations that proceed via
the oxidative cyclization of two  components on nickel(0)
have enabled the rapid construction of isoquinoline
structures; most of these protocols have been proposed to
complexes.10,11 A recent example involved the nickel-
proceed via chelation-assisted CAr‒H functionalization with
catalyzed
intermolecular
[2+2+1]
carbonylative
alkynes or in-situ-generated azides, followed by cyclization
(Scheme 1A).8 Isoquinolines are also accessible from 1,4-
yne-imines via the pre-activation of the alkyne moieties by
I2 or Lewis-acidic transition metals followed by endo-
cyclization (Scheme 1B).9 However, despite these
achievements, novel strategies for the generation of
isoquinolines remain in high demand, especially those
involving reactions catalyzed by readily available and non-
toxic organic compounds. Herein, we report a simple
amine-catalyzed synthesis of isoquinolines that proceeds
via the formal exo-cyclization of a 1,5-yne-imine, followed
by the intramolecular migration of an N-aryl sulfonyl group
to the carbon center of the alkyne moiety (Scheme 1C). The
results of mechanistic studies using a crossover experiment
and DFT calculations are also reported.
cycloaddition between imines and alkynes, in which CO
was generated in situ by treatment with phenyl formate and
NEt3.11a Given the versatility of the produced -lactams, we
thought about expanding this carbonylation method to
intramolecular reactions, e.g., the synthesis of a tricyclic -
lactam from 1,5-yne-imine 1a; however, isoquinoline 2a
was obtained as the major product, and the targeted -lactam
was not produced.12,13 Subsequently, we confirmed the role
of NEt3 in the formation of the isoquinoline by treating 1a
in C6D6 at 80 °C with NEt3 (2.0 equiv.), which afforded 2a
in 58% yield (Figure 1). The molecular structure of 2a was
unambiguously confirmed by
a single-crystal X-ray
diffraction analysis, which confirmed the migration of the
N-tosyl (Ts) group. To the best of our knowledge, this is the
first example of a synthetic route to isoquinolines that

Table 1. Optimization of base
Figure 1. NEt3-mediated synthesis of 2a. The molecular structure for
2a is also shown with ellipsoids set at 30% probability. C, black; N,
blue; O, red; S, yellow; H, white.
proceeds via the migration of an N-aryl sulfonyl group to
the carbon center.
The development of a catalytic variant of the
aforementioned NEt3-mediated isoquinoline synthesis was
explored using fluorine-substituted 1b as a model substrate.
In the presence of 20 mol% NEt3, the transformation of 1b
afforded 2b in 14% yield after 3 h at 60 °C (56% after 40 h),
as confirmed by 19F NMR spectroscopy (Table 1, run 1).
Subsequently, a variety of amines were examined (runs 2-
6), and quinuclidine was found to work well under the
applied conditions (run 2). Phosphines (runs 7-10), a
phosphite (run 11), and inorganic bases (runs 12-15) were
ineffective. Although 1b did not react when DMAP, PtBu3,
P(OMe)3, or CaH2 were used, almost complete consumption
of 1b was observed when the other bases were employed.
Further optimizations of the reaction conditions with
respect to the solvent, reaction temperature, and
concentration of 1b were conducted in the presence of 20
mol% quinuclidine (Table S1).14 Based on these results, we
determined the optimal conditions to include: THF, 80 °C,
General conditions: 1b (0.1 M) and base (20 mol%) were mixed in
THF/C6D6 (v/v = 4/1), followed by heating at 60 °C. Yield was
determined using 19F NMR using benzotrifluoride as an internal
standard. a Reaction was conducted with 1b (0.05 M) and 5 mol%
quinuclidine in THF at 80 °C for 12 h. 80 °C. Reaction was
conducted in THF (0.05 M) at 80 °C for 24 h (NaHMDS, LiHMDS) or
3 h (CaH2). n.r. means no reaction.
b
c
isoquinolines 2g and 2f in 79% (4 h) and 71% (30 h) yield,
respectively, again demonstrating the impact of the acidity
of the benzylic proton on the reaction rate. The
benzo[f]isoquinoline derivative 2h was prepared in 74%
yield under the optimized reaction conditions.
and [1]0 = 0.05 M. Under the optimized conditions, an
amount of quinuclidine could be reduced to 5 mol%, and 2b
Subsequently, we explored the scope of the N-
substituent
(R3)
(Table
2B).
When
N-4-
was obtained in 72% yield after 12 h (shown in Table 1, run
2).
nitrobenzenesulfonyl (Nos)-substituted 1i was employed,
the formation of 2i was confirmed, and 1i was completely
consumed over 20 h; however, the yield of 2i remained low
(35% isolated yield). In the case of 1j, which contains an N-
diphenylphosphinoyl substituent, the protonated product 2j′
was obtained in 43% yield via the protonation of the N-
The quinuclidine-catalyzed transformation of
1
afforded a variety of isoquinolines via the migration of the
2
N-Ts group to the carbon atom in the alkyne moiety (Table
2A). Under the optimized conditions, 2a was isolated in
69% yield, and a reaction time of 30 h was required for the
complete consumption of 1a. The introduction of a meta-
fluorine or para-chlorine substituents with respect to the
propargyl group accelerated the reaction to furnish 2b and
2c in 86% and 75% yield, respectively, after 4 h. The
reaction of 1d, which contained a para-methoxy substituent
relative to the propargyl moiety furnished a complex
mixture that included 2d in 26% yield after 96 h. The use of
DBU in the reaction with 1d resulted in the formation of a
complex mixture. These results indicate that the acidity of
the benzylic proton of the propargyl is probably important
diphenylphosphinoyl moiety in the presence of
a
stoichiometric amount of quinuclidine. The source of this
proton is unclear at present, but we cannot completely
exclude the possibility that the system contained trace
contaminations of H2O. The use of 1k resulted in the
formation of a complex mixture that did not include the
targeted isoquinoline, and a significant amount of 1k
remained unreacted even after 48 h (conversion of 1k
=
22%).
To gain insight into the reaction mechanism, a
crossover experiment was conducted using 1f and 1l, which
produced 2f and 2l in 63% and 54% yield, respectively, as
confirmed by the 1H NMR analysis (Scheme 2). The
crossover products were not obtained. Thus, under the
reaction conditions, N-tosyl migration seems to occur
exclusively via an intramolecular pathway.
for the formation of 2. When 1e, in which a terminal TMS
group was located on the alkyne moiety, was subjected to
the optimized conditions, the in-situ generation of 2e in 65%
yield was observed; the product was eventually isolated as
2e′ (68%) due to a moisture-induced protodesilylation
during the isolation. This protonation process was
independently confirmed by treating the in-situ-generated
Based on the aforementioned results and some
previous reports,15 a plausible reaction mechanism for the
2e with methanol-d4, which afforded 2e′-d1
the reaction of 1g (R2 = Ph) proceeded more quickly than
that of 1f (R2 nC5H11) to afford the corresponding
.
14 As expected,
=

Table 2. Quinuclidine-catalyzed synthesis of isoquinoline derivatives 2 from 1
Conditions: 1 (0.05 M) and quinuclidine (20 mol%) were dissolved in THF and stirred at 80 °C. Isolated yields are shown and yields determined using 19
NMR spectroscopy with benzotrifluoride as the internal standard are given in parentheses. a C6D6 was used. n.d. means not detected.
F
Scheme 2. A crossover experiment between 1f and 1l, monitored by
NMR analyses. Yield of products was determined by 1H NMR using
1,3,5-trimethoxybenzene as an internal standard.
transformation of 1a into 2a is depicted in Scheme 3A. The
reaction is initiated by amine-mediated 1,3-proton
migration, forming allene intermediates such as
Spontaneous cyclization via attack of the imine nitrogen on
the electrophilic carbon on A′ affords intermediate . Lastly,
A .
and A′ 16
B
1,3-tosyl migration occurs in an intramolecular fashion to
yield isoquinoline 2a. To evaluate the steps after the
formation of the allene intermediates, DFT calculations
were carried out at the B97X-D/6-311+G(d,p) level of
theory. The optimized molecular structures of A′
and TS2 are shown in Scheme 3B‒E. In the cyclization step
from A′ to via TS1, the distance between N and the
, TS1, B,
B
central allenic carbon atom C1 continuously decreases from
2.98 to 1.44 Å; the activation energy barrier for this step is
estimated to be 19.1 kcal mol‒1 (23.1 kcal mol‒1 from
A
).
is clearly higher than
B in this system would be
As the thermodynamic stability of
that of , the formation of
B
A
favorable. In addition, the subsequent Ts-migration exhibits
a relatively high energy barrier (G‡ = 31.2 kcal mol‒1),
which should be included in the rate-determining event.
Nevertheless, this energy barrier could be overcome under
the applied reaction conditions, driven by the significantly
Scheme 3. (A) A plausible mechanism for the transformation of 1a to
2a. The relative Gibbs free energies (kcal mol‒1) with respect to 1a
were calculated at the B97X-D/6-311+G(d,p) level of theory and are
shown in parenthesis. The optimized molecular structures for (B) A′,
(C) TS1, (D) B, and (E) TS2 are shown.
exoergic, irreversible formation of 2a
.
4. Conclusion
In conclusion, we have demonstrated a novel strategy
for the synthesis of isoquinolines from 1,5-yne-imines via
the intramolecular migration of the N-aryl sulfonyl
substituent to the carbon center. Initial mechanistic studies
support the formation of an allene intermediate from the
alkyne unit via an amine-mediated 1,3-proton transfer,
followed by spontaneous cyclization and aryl sulfonyl
migration. The presented reaction uses readily available,
non-toxic amines such as NEt3 and quinuclidine and
exhibits excellent atom efficiency, demonstrating
potentially high utility for the preparation of a variety of
isoquinoline derivatives.

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Acknowledgement
This work was supported by Grant-in-Aid for
Scientific Research from Japan (JSPS KAKENHI Grant
Number; 15H05803 and 18K14219).
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