Synthesis of aminoisoquinolines via Rh-catalyzed [4 + 2] annulation of benzamidamides with vinylene carbonate

Article abstract of DOI:10.1016/j.cclet.2021.04.058

A new strategy is developed for the synthesis of 1-aminoisoquinoline derivatives. This Rh(III)-catalyzed [4 + 2] annulation reaction employs benzamidines as efficient directing groups and the vinylene carbonate as an acetylene surrogate. Additionally, the reaction features broad substrate scopes and good yields, only producing carbonate anion as byproduct.

Full text of DOI:10.1016/j.cclet.2021.04.058

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis of aminoisoquinolines via Rh-catalyzed [4 + 2] annulation
of benzamidamides with vinylene carbonate
Xin Huang, Yingying Xu, Jianglian Li, Ruizhi Lai, Yi Luo, Qiantao Wang, Zhongzhen Yang∗,
Yong Wu∗
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan
Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy is developed for the synthesis of 1-aminoisoquinoline derivatives. This Rh(III)-catalyzed
[4 + 2] annulation reaction employs benzamidines as efficient directing groups and the vinylene carbon-
ate as an acetylene surrogate. Additionally, the reaction features broad substrate scopes and good yields,
only producing carbonate anion as byproduct.
Received 4 March 2021
Revised 22 April 2021
Accepted 30 April 2021
Available online xxx
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Keywords:
Benzamidamide
Aminoisoquinolines
Vinylene carbonate
C−H Activation
Rh-catalyzed
During the past decades, transition-metal catalyzed cascade C-
H activation/annulation reaction has clearly served as an efficient
method in synthetic chemistry [1–6] to construct diverse heterocy-
cles such as isoquinolines [7], quinazolines [8], naphthalenone [9],
naphthols [10] and others [11–24]. And this method has been well
explored by numerous chemists because of its simple operation,
fewer synthetic steps, high atom economy and high regioselectiv-
ity.
[61,62]. However, all of these transformations only provided the
aminoisquinolines with R2 or R3 (phenyl or alkyl), and the
construction of nonsubstituted aminoisquinoline skeletons (R2,
R3 = H) were seldom disclosed through C-H activation.
Recently, vinylene carbonate, featuring higher operational secu-
rity and commercial availability as acetylene surrogate, has been
involved in the transition-metal-catalyzed C(sp2)-H activation re-
actions [63–66] by extruding a carbonate anion (Scheme 1b). In
these cases, heterocyclic structures such as isoquinolinones and
isocoumarins, have been successfully and efficiently synthesized
utilizing vinylene carbonate as a new C2 synthon under Co(III)
or Rh(III) catalysis with N-methoxybenzamide [67] or benzoic acid
[68]. In this regard, we herein demonstrate a facile method to gen-
erate nonsubstituted aminoisoquinolines derivatives by a Rh(III)-
catalyzed cascade C-H activation/annulation reaction using benz-
imidamides with vinylene carbonate (Scheme 1c).
On the other hand, 1-aminoisoquinolines are frequently found
in many drug molecules (Fig. 1) and exhibit
a wide range
of biological and pharmaceutical activities [25–31]. Therefore,
straightforward strategy to access 1-aminoisoquinolines has inten-
sively intrigued the scientists. According literatures, many meth-
ods have been reported including the coupling reaction of 1-
aminoisoquinoline with phenylboronic acid [32], the transforma-
tion of 1-chloroisoquinoline with amine [33–35], and the amina-
tion between isoquinoline-N-oxide with amines [36–42], phenyl
isothiocyanate [43]. Besides, benzamidines are efficient direct-
ing groups [44–53], which have been widely employed for the
construction of 1-aminoisoquinolines derivatives via C-H acti-
vation/annulation adopting different C2 synthons, such as α-
OMs/OTs acetophenone [54], diazo compounds [55–57], allyl car-
bonates [58], alkynes [59,60] and sulfoxonium ylides (Scheme 1a)
We commenced the reaction of Rh(III)-catalyzed [4+2] annula-
tion reaction with N-(tert-butyl)benzimidamide (1a) and vinylene
carbonate (2a) as model substrates. To our delight, we obtained
the expected aminoisoquinolines products in 20% yields by em-
ploying [Cp∗RhCl2]2 (5 mol%) and AgSbF6 (20 mol%) as catalytic
system in 1,2-dichloroethane at 100°C for 24 h under argon at-
mosphere (Table 1, entry 1). Initially, the yields of aminoisoquino-
lines did not increase when replacing the Rh catalyst with other
metal catalysts (entries 2 and 3). Then several sliver salts were
investigated, among which AgOTf gave the superior result com-
pared with AgSbF6, AgBF4 and AgOTs (entries 4–6). In order to
∗
Corresponding authors.
E-mail addresses: zhongzhenyang1991@163.com (Z. Yang), wyong@scu.edu.cn (Y.
Wu).
https://doi.org/10.1016/j.cclet.2021.04.058
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: X. Huang, Y. Xu, J. Li et al., Synthesis of aminoisoquinolines via Rh-catalyzed [4 + 2] annulation of benzami-
damides with vinylene carbonate, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.04.058

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Table 1
Optimization of reaction conditions.a
Entry
Catalyst
Additive
Base
Solvent
Yield (%)b
1
[Cp∗RhCl2]2
[Rh(cod)Cl]2
[Ir(cod)Cl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
[Cp∗RhCl2]2
AgSbF6
AgSbF6
AgSbF6
AgBF4
AgOTs
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
-
DCE
20
10
Trace
15
17
30
40
45
10
50
60
74
79
2
-
DCE
3
-
DCE
4
-
DCE
5
-
DCE
6
-
DCE
7
NaOAc
KPF6
K2CO3
KOPiv
KOPiv
KOPiv
KOPiv
DCE
8
DCE
9
DCE
10
11
12
13
DCE
DMF
Cyclohexane
Toluene
Fig. 1. Selected examples of bioactive aminoisoquinolines.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol%), ad-
ditive (20 mol%), base (20 mol%), solvent (1.5 mL), under Ar, 100 °C, 24 h.
b
Isolated yields.
Scheme 2. Substrate scope of benzamidines. Reaction conditions: 1 (0.2 mmol),
2a (0.4 mmol), [Cp∗RhCl2]2 (5 mol%), AgOTf (20 mol%), KOPiv (20 mol%), Toluene
(1.5 mL), Ar, 100 °C, 24 h.
With the optimized conditions in hand, we started to inves-
tigate the scope and generality of benzamidines derivatives for
the [4 + 2] annulation reactions. Generally, benzamidines bear-
ing electron-donating (Me, OMe, t-Bu) and electron-withdrawing
groups (F, Cl, Br) on the benzene ring could generate aminoiso-
quinolines derivatives (Scheme 2, 3aa-3ha) smoothly by reacting
with vinylene carbonate in moderate to good yields. As shown in
Scheme 2, it was obvious that the yields of the transformation de-
creased dramatically to 33%–42% for ortho-substituent substrates
(3na-3pa), which indicated that the transformation was tremen-
dously influenced by steric hindrance effect. Besides, it was in-
teresting to note that the substrates with diverse groups at the
meta position demonstrated higher efficiencies than that at the
para position on the whole. In addition, meta-methyl-, meta-cholro-
and meta-bromo-substituted benzamidines preferred the site with
less hindrance (3ia-3ka), while meta-methoxyl- and meta-fluoro-
Scheme 1. Synthesis of aminoisoquinolines and other heterocycles via C-H activa-
tion/annulation.
further increase the yield, different bases were screened includ-
ing NaOAc, KPF6, K2CO3, KOPiv, and the results revealed that KOPiv
was the best base for this reaction (entries 7–10). Finally, the use
of toluene significantly increased the yield to 79%, which revealed
solvents have a significant impact on the conversion (entries 11–
13). In conclusion, the optimal conditions are shown as follows:
the reaction proceeded in 79% yield under [Cp∗RhCl2]2 (5 mol%)
and AgOTf (20 mol%), using KOPiv (20 mol%) as additives in Tol
(2.0 mL) at 100 °C for 24 h under Ar.
2

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Scheme 5. Mechanistic studies.
Scheme 3. Substrate scope of N-phenylbenzimidamides.
Scheme 4. Ten-fold-scale synthesis of aminoisoquinolines.
substituted reactants gave the two regioselective products (3la-
3ma). Delightfully, the product was isolated in 90% yields when
reactant with a thiophene ring was used. Moreover, substituent
with naphthalene was also suitable for the reaction, albeit in a
58% yield. Furthermore, when tert-butyl is replaced by other alkyl
groups such as benzyl, isopropyl and n-butyl, this cascade pro-
cedure could also convert to generate corresponding products in
42%–46% yields (3sa-3ua). However, the reaction failed to work
when N-phenylbenzimidamide was added.
Scheme 6. Plausible reaction mechanism.
transforms into a rhodacyclic intermediate A by C-H activation.
Subsequently, the insertion of 2a with intermediate A results in the
formation of seven-member intermediate B. Then, intermediate B
undergoes reductive elimination to generate intermediate C releas-
ing the Cp∗Rh (I). The rhodium complexe D is obtained from oxida-
tive addition of intermediate C and Cp∗Rh (I). Finally, the rhodium
complexe D generates aminoisoquinoline with the formation of the
carbonate anion through β-oxygen elimination.
Due to the inert reactivity of N-phenylbenzimidamide, a se-
ries of reaction conditions were examined for realization of the
conversion by employing vinylene carbonate (see Supporting in-
formation for details). Fortunately, we obtained the expected N-
phenylisoquinolin-1-amine successfully and confirmed the opti-
mal conditions that the reaction proceeded in 60% yield with
[Cp∗RhCl2]2 (5 mol%), AgOAc (20 mol%) and ZnSO4·7H2O (20 mol%)
as catalytic system in chlorobenzene (2.0 mL) at 140°C for
24 h under Ar (Scheme 3). The electron-donating and electron-
withdrawing groups were all compatible in 45%–66% yields with-
out obvious electrical effect. Unfortunately, when the benzene ring
was replaced by thiophene ring or naphthalene, we did not ob-
serve obvious products.
In conclusion, we developed
a novel method to construct
aminoisoquinolines derivatives via Rh(III)-catalyzed C-H activa-
tion/annulation by coupling benzamidines with vinylene carbonate
as an acetylene surrogate. In this work, we realized the transfor-
mations of phenyl and alkyl-substituted benzamidines in good to
moderate yields under different conditions, which was applied for
larger scale.
In order to explore whether the strategy could be applied for
large scale, we enlarged the amount of 1a (2 mmol) and 2a
(4 mmol) under the optimized conditions (Scheme 4). The result
disclosed the transformation was less efficient in the yield of 55%.
To further explore the experimental mechanism, we completed
some mechanistic experiments. The H/D exchange experiment was
carried out by using 1b with CD3OD at 100 °C for 2 h, which
showed that 42% deuterium incorporation was estimated at ortho-
position by 1H NMR indicating C-H bond cleavage of the transfor-
mation was reversible (Scheme 5a). When equimolar amounts of
1b and 1e were added in intermolecular competition experiment,
the 3ba and 3ea were obtained in a ratio of 1.5:1, which indicated
that electron-donating group was more effective (Scheme 5b).
Based on the above experiments and related literature, a plau-
sible mechanism is presented in the Scheme 6. First, benzamidine
Declaration of competing interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper .
Acknowledgment
We are grateful for the support from the National Natural
Science Foundation of China (NSFC, Nos. 81602954, 81573286,
81373259 and 81773577).
3

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