Rh(III)-Catalyzed Synthesis of 3-Amino-4-arylisoquinolinones from 4-Diazoisochroman-3-imines and N-Methoxybenzamides

Article abstract of DOI:10.1021/acs.orglett.9b00290

A Rh(III)-catalyzed reaction of N-methoxybenzamides and 4-diazoisochroman-3-imines is described. This method offers a rapid entry to 3-amino-4-arylisoquinolinone architectures from readily available starting materials under mild reaction conditions. A one

Full text of DOI:10.1021/acs.orglett.9b00290

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Synthesis of 3‑Amino-4-arylisoquinolinones from
4
‑Diazoisochroman-3-imines and N‑Methoxybenzamides
Zhenmin Li, Li Wu, Ben Chang, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. China
*
S Supporting Information
ABSTRACT: A Rh(III)-catalyzed reaction of N-methoxybenzamides and 4-diazoisochroman-3-imines is described. This
method offers a rapid entry to 3-amino-4-arylisoquinolinone architectures from readily available starting materials under mild
reaction conditions. A one-pot cascade C−H bond activation/formal [4 + 2] cycloaddition mechanism is proposed. The
synthesized 3-amino-4-arylisoquinolinones can be conveniently converted into dibenzo[c,f ][1,8]naphthyridines.
3
-Amino-4-arylisoquinolinones are privileged structures in
construction of five-, six-, and seven-membered heterocycles,
respectively (Scheme 1). Among these heterocycles, isoquino-
linones are extremely important in pharmaceutics and were
alternatively prepared through Rh(III)-catalyzed C−H activa-
tion/functionalization of N-methoxybenzamides with alkyne
1
medicinal science (Figure 1). For instance, compound I is
Scheme 1. Rh(III)-Catalyzed Preparation of
Isoquinolinones
Figure 1. Bioactive molecules containing a 3-amino-4-arylisoquino-
linone core.
one of the cholesterol acyltransferase inhibitors that present
excellent activity inhibiting cholesterol acyltransferase, control-
ling absorption of cholesterol from the intestinal tract, and
suppressing precipitation of cholesterol at the arterial wall.
Therefore, it is useful for the protection of cardiovascular
system. For more practical examples, compound II is a JNK
inhibitor, while compound III is an antibacterial agent.
Consequently, much attention has been made for construction
2
of this important class of heterocyclic compounds.
Diazo compounds have been reported to be a class of special
components for the investigation of the transition-metal-
3
,4
catalyzed ortho C−H bond activation/functionalization. On
the basis of the strategy of the metal−carbene migratory
insertion, reactions between benzamides and diazo compounds
5
6
could form isoindolinones, isoquinolinones, isoquinolinedio-
7
,6c
8
nes,
benzo[c]azepinones via C−C/C−N bond formation,
9
and isochromenones via C−C/C−O bond formation. In
these cases, diazo components exhibited unique advantages
and could serve as one-, two-, and three-carbon partners in the
Received: January 23, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00290
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Organic Letters
Letter
1
0
using N−O bond as an internal oxidant in 2010. Following
(DCM), 1,4-dioxane, or acetone was used as solvent (Table
1, entries 2−7). Relatively higher yield was observed when
acetonitrile was used as the solvent (Table 1, entry 8). Thus,
the optimal solvent was determined to be acetonitrile. The
reaction did not occur in the absence of the rhodium catalyst
(Table 1, entry 9) or in the absence of potassium acetate
this step, 4-amino-3-arylisoquinolinones could be regioselec-
1
1
tively obtained.
On the other hand, we recently reported a new family of
diazo compounds, 4-diazoisochroman-3-imines, which could
be easily prepared by a copper-catalyzed alkyne−azide
cycloaddition. These diazo compounds had been demon-
strated to be effective to form rhodium carbenes in the
presence of Rh(II) and brought out a series of Rh(II)-
catalyzed reactions, such as cyclopropanation as well as formal
3 + 2] and [3 + 4] cycloadditions. Herein, we examine a
new reaction type of these diazo compounds using Rh(III)
catalyst.
1
2
(Table 1, entry 10). Without AgSbF , the reaction still
6
occurred to give 3a in 72% yield (Table 1, entry 11). Altering
KOAc to sodium or cesium acetates led to a lower yield of 3a
(Table 1, entries 12 and 13). When potassium carbonate was
used, 3a was isolated in 23% yield (Table 1, entry 14). No
reaction occurred when potassium formate was applied (Table
12b
[
1
, entry 15). Steadily raising the reaction temperature led to a
decrease in the yield (Table 1, entries 16 and 17), whereas a
slightly higher yield (73%) was obtained when the reaction was
conducted at room temperature (Table 1, entry 18). Increasing
the amount of base did not improve the reaction, whereas
decreasing the amount of base led to a decrease in the yield
Initially, we tested the reaction between N-methoxybenza-
mide (1a) and 4-diazoisochroman-3-imine 2a using
[
Cp*RhCl ] as catalyst. The reaction was carried out in the
2 2
presence of AgSbF and KOAc in tetrahydrofuran (THF) at 40
6
°
C for 12 h under N2 atmosphere, and 3-amino-4-
(
Table 1, entries 19−22). When the reaction was carried out in
air, a significantly decreased yield (44%) was observed (Table
, entry 23). Cobalt catalysts such as [Cp*Co(CO)I ] were
arylisoquinolinone 3a was isolated in 68% yield (Table 1,
entry 1). Based on this finding, we screened the reaction
conditions. Several other solvents were screened first, and a
lower or comparable yield was obtained when toluene, ethyl
acetate (EA), dichloroethane (DCE), dichloromethane
1
2
also examined, but no reaction occurred (Table 1, entries 24
and 25).
With the optimized reaction conditions in hand (Table 1,
entry 18), we next tested the substrate scope (Scheme 2). First,
the tolerance of the substituents on 4-diazoisochroman-3-
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of 4-Diazoisochroman-3-imines 2
b
entry additive
base (mol %)
solvent
THF
toluene
EA
DCE
DCM
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
60
80
rt
68
46
51
52
66
67
67
71
NR
NR
72
58
62
23
trace
68
51
73
1,4-dioxane
acetone
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
KOAc (20)
NaOAc (20)
CsOAc (20)
K CO (20)
2
3
HCO K (20)
2
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (50)
KOAc (30)
KOAc (10)
KOAc (5)
KOAc (20)
KOAc (20)
KOAc (20)
rt
rt
rt
71
73
18
rt
9
d
e
rt
rt
rt
44
NR
NR
AgSbF6
e
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
2.5 mol %), additive (10 mol %), base (x mol %), solvent (2 mL),
(
b
c
d
N , 12 h. Isolated yield. Without [Cp*RhCl ] . Under air
2
2 2
e
atmosphere. [Cp*Co(CO)I ] (5 mol %).
2
B
DOI: 10.1021/acs.orglett.9b00290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
imines 2 which were prepared from sulfonyl azides and (2-
ethynylphenyl)methanols were examined. The sulfonyl groups
could be toluenesulfonyl, p-methoxybenzenesulfonyl, benzene-
sulfonyl, 2-naphthalenesulfonyl, p-fluorobenzenesulfonyl, and
p-chlorobenzenesulfonyl. Thus, products 3a−f were obtained
in moderate to good yields. Among these sulfonyls, p-
fluorobenzenesulfonyl provided the highest yield when the
reaction was carried out at 40 °C (3e, 80%). The substituent
on (2-ethynylphenyl)methanols could be either electron-
donating group (MeO) or electron-withdrawing groups (F,
2a. In these cases, the desired products 3v and 3w were
isolated in 51% and 67% yields, respectively. Benzamide, N-
methylbenzamide, and N-hydroxybenzamide did not work for
this reaction with the recovery of both starting materials.
Single-crystal analysis of 3u further confirmed the structure of
3-amino-4-arylisoquinolinone.
It is noteworthy that this reaction could be run on a gram
scale. When 1a (0.605 g, 4 mmol) and 2a (1.308 g, 4 mmol)
were mixed and reacted under the optimized reaction
conditions, 1.368 g (76% yield) of 3a was obtained by the
recrystallization from the mixed solvents of DCM/EA/n-
hexane.
Cl, CF ). Thus, products 3g−k were obtained in 51−84%
3
yields.
Various substituents on N-methoxybenzamides tolerated the
reaction conditions and provided the corresponding products
The prepared 3-amino-4-arylisoquinolinones 3 could be
used to construct the skeleton of dibenzo[c,f ][1,8]-
naphthyridines (Scheme 4). For instance, 3a reacted with
3l−w in moderate to good yields (Scheme 3). Thus, the
Scheme 3. Scope of N-Methoxybenzamides 1
Scheme 4. Preparation of 4 and 5
thionyl chloride to provide dichlorinated compound 4a in 70%
yield. Further treatment of 4a with triethylamine derived the
dechlorinated product 5a in 95% yield, which owned the
skeleton of dibenzo[c,f ][1,8]naphthyridine with four contin-
uously fused ring. The structures of 4a and 5a were confirmed
by single-crystal analysis. Similar treatment of 3l and 3i
provided 4b (69% yield) and 4c (65% yield) and subsequently
furnished 5b and 5c in yields of 85% and 92%, respectively.
To probe the reaction mechanism for the formation of 3,
deuterium-labeling experiments were performed. When the
reaction of 1a was conducted with the addition of 1 equiv of
D O under the standard conditions in the absence of diazo
2
compound, a deuterium-incorporated product was obtained.
This result indicates that the C−H activation is irreversible
(
Scheme 5, eq 1). Kinetic isotope effect (KIE) was carried out
in parallel experiments (Scheme 5, eq 2). By treatment of 1a or
a-d under standard reaction conditions for 20 min, KIE of
1
5
substituent at the 4-position of N-methoxybenzamides could
be either an electron-donating group (Me, Ph, MeO) or an
the reaction was determined to be 2.0. This value indicated
that the C−H activation might be the rate-determining step.
On the basis of these results and the previously reported
electron-withdrawing group (Cl, CF ). The highest yield (3l,
3
5
a,6a,8,13
7
5%) was observed in the case where N-methoxy-4-
references,
a possible mechanism is proposed in
methylbenzamide reacted with 2a. The methyl group or
chloro could be altered from the 4-position (3l or 3o) of N-
methoxybenzamide to the 3-position (3q or 3r) and 2-position
Scheme 6. In the presence KOAc, rhodium catalyst is initially
activated via ligand exchange to form the rhodium species A.
Assisted by the N-methoxyamido group, the ortho C−H bond
of N-methoxybenzamide 1a is activated to generate Rh(III)
complex intermediate B. B is active toward diazo partner 2a,
(
3s or 3t) as well. N-Methoxy-1-naphthamide and N-
ethoxybenzamide were also examined for their reaction with
C
DOI: 10.1021/acs.orglett.9b00290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Mechanistic Experiments
Accession Codes
CCDC 1881378−1881379 and 1881381−1881382 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: pinglu@zju.edu.cn.
E-mail: orgwyg@zju.edu.cn.
*
ORCID
Scheme 6. Possible Mechanism for the Formation of 3a
Ping Lu: 0000-0002-3221-3647
Yanguang Wang: 0000-0002-5096-7450
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the National Natural
Science Foundation of China (Nos. 21632003, 21772169).
■
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preparation of 3-amino-4-arylisoquinolinones from readily
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(
(
3
(
(
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DOI: 10.1021/acs.orglett.9b00290
Org. Lett. XXXX, XXX, XXX−XXX