Rh(iii)-Catalyzed three-component cascade annulation to produce theN-oxopropyl chain of isoquinolone derivatives

Article abstract of DOI:10.1039/d0ob02389b

Developing powerful methods to introduce versatile functional groups at theN-substituents of isoquinolone scaffolds is still a great challenge. Herein, we report a novel three-component cascade annulation reaction to efficiently construct theN-oxopropyl chain of isoquinolone derivativesviarhodium(iii)-catalyzed C-H activation/cyclization/nucleophilic attack, with oxazoles used both as the directing group and potential functionalized reagents.

Full text of DOI:10.1039/d0ob02389b

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DOI: 10.1039/D0OB02389B
Journal Name
ARTICLE
Rh(III)-Catalyzed Three-Component Cascade Annulation to
Produce N-oxopropyl Chain of Isoquinolone Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Yuan He,a Xian-Zhang Liao,a Lin Dong a,* and Fen-Er Chen a,b,c
*
Developing powerful methods to introduce the versatile functional groups at the N-substituents of isoquinolone scaffolds
is still a great challenge. Herein, we report a novel three-component cascade annulation reaction to efficiently construct N-
oxopropyl chain of isoquinolone derivatives via rhodium(III)-catalyzed C−H activation/cyclization/nucleophile attack, with
oxazoles using both as the directing group and potential functionalized reagents.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Isoquinolones are an attractive class of structural units, and their activation/cyclization/nucleophile attack by using oxazoles as the
extensive prevalence in various biologically active compounds, directing group as well as potential functionalized reagents (eq 4).
alkaloids and natural products, such as dorianine, ruprechstyril,
At the outset of our studies, 5-methyl-2-phenyloxazole (1a) and
protoberberines and benzo[c]phenanthridines.1 Meanwhile, diphenylacetylene (2a) were chosen as model substrates to
isoquinolone derivatives as versatile intermediates have widely optimize the reaction conditions (Table 1). Initially, no desired
access to a large variety of chemical molecules and drug structures.2 product was observed when choosing AgOAc or Cu(acac)2 as the
Due to these properties, a large number of strategies have paved oxidant (entries 1 and 2). To our delight, the desired N-oxopropyl
the way to the formation of different isoquinolone derivatives.3
chain product 3aa could be isolated in 57% yield by using
In recent years, transition-metal-catalyzed C−H bond Cu(OAc)2·H2O as the oxidant (entries 3 and 4). Silver salt screening
functionalization has received increasing attention because of high showed that AgNTf2 gave the increased result (entries 4-8). Notably,
atom-economic, activity, selectivity together with great practical reaction efficiency was increased by adding trace amount of H2O
worth.4 Therefore, these highly efficient synthetic methods have (entry 9). The addition of pivalic acid can effectively promote the
been directed to construct the useful isoquinolone skeletons. Most reaction activity (entries 10-14). The solvent effect is still obvious in
strategies utilized various types of benzamide derivatives direct the cascade reaction (entries 15-20). Delightedly, decreasing the
working with coupling partners such as alkynes, diynes and diazo loading of catalyst resulted in a higher yield (entry 21). Further
compounds (Scheme 1, eq 1).5 Some other reports have appeared decreasing the loading of 2a, AgNTf2 and PivOH could facilitate the
on the establishment of the motifs from benzohydrazines, acyl cascade reaction (entry 22). Scaling up the reaction still led to good
azides and nitriles, etc.6 Despite these achievements, the further isolated yield (entry 23).
Previous work
introducing the versatile functional groups at the N-substituents of
O
O
R'
R
alkynes
diynes
diazos
R'
isoquinolone scaffolds during the C−H functionalization/cascade
reaction aroused our great interest. Very recently, Cui and Kapur
separately featured beautiful oxazoline-directed aromatic C−H
activation approaches to build N-(2-acetoxyalkyl)isoquinolones
from alkynes or diazo compounds (eq 2).7 Nevertheless, oxazoles
serving as a directing group are still very limited, and only one
example provided anthracene skeletons from 5-aryl-2-
phenyloxazole (eq 3).8 Therefore, we describe a novel three-
component cascade annulation reaction to generate N-oxopropyl
chain of isoquinolone derivatives via rhodium(III)-catalyzed C−H
[M]
1)
N
N
H
+
R
O
O
O
R'
O
R
R
R'
+
OAc
2)
[Rh/Ru]
-OAc
N
N
N
N2
or
R
R
R
R'
R
N
R'
O
O
R
R
R
[Rh]
3)
R
R
R
R
+
R
R
R
O
R'
This work
H2O
[Cp*RhCl2]2
O
R'
+
O
Cu(OAc)2 H2O
R
AgNTf2
PivOH, CH3OH
+
N
N
4)
R
100 oC, 12 h, air
R
aKey Laboratory of Drug Targeting and Drug Delivery System of Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041,
China; E-mail: dongl@scu.edu.cn
R
Scheme
1 Strategies to Form Isoquinolone Skeletons via C−H Bond
bEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of
Chemistry, Fudan University, Shanghai 200433, China
Functionalization
cShanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,
Shanghai 200433, China; E-mail: rfchen@fudan.edu.cn
With the optimized reaction conditions in hand, we explored the
substrate scope of 2-aryloxazolines. As revealed in Scheme 2, in
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-4 | 1
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Journal Name
general, 2-aryloxazolines bearing electron-donating substituents at high regioselectivity.
para-position of phenyl ring were well tolerated, affording the
View Article Online
DOI: 10.1039/D0OB02389B
Scheme 2 Substrate Scope of 2-Aryloxazolineaa
Table 1 Optimization of the Reaction Conditionsa
O
O
R'
O
R'
[Cp*RhCl2]2 (4 mol%)
Cu(OAc)2 H2O ( 2.1 equiv)
AgNTf2 (10 mol%)
O
O
O
Ph
catalyst, additive
N
N
Ph
Ph
+
+
R
N
oxidant, solvent
100 oC, 12 h, air
N
PivOH (0.5 equiv)
R
Ph
Ph
Ph
H O
100 oC, 12 h, air
CH3OH :
(10:1)
2
Ph
Ph
1
2a
R = Me, 75%,
2a
3aa
1a
3bab
3cac
O
O
O
Entry
Oxidant
Additive
Solvent
Yieldb
R
O
= OMe, 93%,
3dab, c
= OEt, 82%,
= i-Pr, 83%,
= t-Bu, 73%,
= CF3, 74%,
N
1
2
3
4
5
6
7
8
AgOAc
Cu(acac)2
Cu(OAc)2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgOTf
AgSO3CH3
AgBF4
AgSbF6
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
ND
ND
N
3eab, c
3fab, c
3ga
3ka
3la
ma
= F, 50%, 3
R = Me, 51%,
= Ph, 21%,
R
R
Ph
Ph
Trace
57%
14%
40%
51%
52%
65%
40%%
42%
65%
66%
74%
56%
41%
57%
Trace
42%
64%
53%
52%
80%
86%
64%
Ph
O
Ph
O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
3ha
= F, 35%,
= Cl, 41%,
= CN, 51%,
3ia
O
O
O
O
3ja
MeO
MeO
N
N
N
9
AgNTf2/H2O
Ph
Ph
Ph
10
11
12
13
AgNTf2/Na2CO3/H2O
AgNTf2/HOAc/H2O
AgNTf2/PhCOOH/H2O
AgNTf2/1-AdCOOH/H2O
3nab, c
Ph
R = Me, 84%,
Ph
Ph
3oa
= Cl, 49%,
3pa
66%,
3qa
50%,
O
O
O
O
R
O
O
14
15
16
17
18
19
20
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
AgNTf2/PivOH/H2O
CH3OH
THF
DCE
CH3CN
Toluene
N
3ra
R= H, 62%,
= 4-Me, 29%,
= 4-OMe, 42%,
= 3-Me, 20%,
N
N
3sa
Ph
Ph
3xad
Ph
3wa
3ta
3ua
3va
Ph
Ph
Ph
60%,
Ph
O
= 3-OMe, 27%,
26%,
1,4-Dioxane
EtOH
O
O
O
O
O
21c
22d
21e
22f
23g
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
N
N
N
Ph
Ph
Ph
Ph
Ph
3za
Ph
3ya
Ph
trace,
48%,
3Aa
47%,
aUnless otherwise stated, reaction conditions are as follows: 1a (0.05 mmol),
2a (2 equiv), [Cp*RhCl2]2 (5 mol%), oxidant (2.1 equiv), silver salt (20 mol%),
acid (1 equiv), solvent (0.5 mL), H2O (50 L), 100 C, 12 h, under air. b Isolated
aReaction conditions: 1 (0.05 mmol), 2a (1.5 equiv), [Cp*RhCl2]2 (4 mol%),
Cu(OAc)2·H2O ( 2.1 equiv), AgNTf2 (10 mol%), PivOH (0.5 equiv), CH3OH (0.5
mL), H2O (50 L), 100 C, 12 h, under air, isolated yield. b2a (1.2 equiv). c10 h.
d (E)-5-methyl-2-styryloxazole was used.
c
f
yield. 80 oC. d120 oC. e[Cp*RhCl2]2 (4 mol%). 2a (1.5 equiv), [Cp*RhCl2]2 (4
mol%), AgNTf2 (10 mol%), PivOH (0.5 equiv). g1a (1 mmol).
Scheme 3 Substrate Scope of Alkynesa
corresponding products (3ba-3fa) in higher yields than electron-
poor ones (3ha-3ja), except 3ga, probably because trifluoromethyl
groups are more stable than other electron-absorbing groups in
catalytic system. Due to the influence of steric hindrance, ortho
substituted substrates were sluggish in the catalytic system, giving
the products (3ka-3ma) ranging from 21% to 51% yields. Excellent
regioselectivity was isolated because of steric reasons, when meta-
substituted substrates (3na and 3oa) were used under the
conditions. Naphthalene ring and dimethoxy substituted substrates
were also compatible, affording 3pa and 3qa in 66% and 50% yields,
respectively. Aryl group substituted oxazole proceeded successfully,
providing N-acetophenone chain products in acceptable yields (3ra-
3va). Tertiary butyl group substituted oxazole also gave 3wa in
useful yield. In particular, Csp2-H still showed good reactivity,
affording triphenylpyridin (3xa-3za) in modest yields, while dialkyl
substituted olefin 1A nullified reactivity.
O
[Cp*RhCl2]2 (4 mol%)
Cu(OAc)2 H2O ( 2.1 equiv)
AgNTf2 (10 mol%)
O
O
N
R1
R2
+
N
PivOH (0.5 equiv)
R2
H O
CH3OH :
(10:1)
R1
2
100 oC, 12 h, air
2
1a
3
O
O
O
O
3ab
3ac
R = Me, 75%
N
N
= i-Pr, 63%
R
3adb
3aeb, c
3afb
= OMe, 76%,
= F, 71%,
= Cl, 58%,
= Br, 62%,
3aib, c
3ab, c
3akb
R
R = Me, 75%,
= OMe, 78%,
R
3ag
= Cl, 37%,
3ah
= CF3, 39%,
R
O
O
O
O
O
O
O
O
N
N
N
N
S
S
3amd
Subsequently, diverse alkynes coupling with 5-methyl-2-
phenyloxazole 1a were explored, and the results were showed in
Scheme 3. Pleasingly, moderate to good yields from symmetrical
diarylacetylenes (3ab-3ak) were obtained, whether the substituent
was electron-rich or -poor. Dialkyl alkynes were excellent coupling
partners in the reaction (3al and 3am). Dithiophene alkyne could
also react with 1a to give the heteroaryl product 3an in 52% yield.
To our delight, the unsymmetrical alkynes could work smoothly
with 1a to give the products 3ao-3ar in good yields together with
3aoc, e
alb, c
O
91%, (9:1)
O
95%,
81%, 3
3an
52%,
O
O
O
O
N
N
N
CHO
OH
3apb, e, f
3aqb, e
64%, (6:1)
60%, (13.6:1)
3arb, e
88%, (12.8:1)
aReaction conditions: 1a (0.05 mmol), 2 (1.5 equiv), [Cp*RhCl2]2 (4 mol%),
Cu(OAc)2·H2O ( 2.1 equiv), AgNTf2 (10 mol%), PivOH (0.5 equiv), CH3OH (0.5
mL), 50 L H2O, 100 C, 12 h, under air, isolated yield. 2 (1.2 equiv). 10 h.
o
b
c
2 | J. Name., 2012, 00, 1-4
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d2o (2.0 equiv), Cu(OAc)2·H2O (3.0 equiv). eratio determined by 1H NMR of Scheme 4 Study on Characteristics and Mechanism
View Article Online
the crude reaction mixture, only the major isomer was shown. f(3,3-
The transformations of the products werDeOuIn: d10e.r1t0a3k9e/Dn0inOBS0c2h3e8m9Be
5. Compound 3aa could build the product 4 in 95% yield via second
C−H functionalization with methyl acrylate (eq 7). Additionally,
condensation of carbonyl functionalized long chain with formamide
precursor generated the key ethenamine 5 in 68% yield, which
could be further subjected cyclization to give pyrazole derivative 6
(eq 8).9 Moreover, phenylhydrazone compound 7 introducing from
N-carbonyl chain of 3aa, converted to novel heterocyclic compound
8 using Vilsmeier–Haack reagent (DMF-POCl3) in 86% yield (eq 9).10
diethoxyprop-1-yn-1-yl)benzene was used.
The intermolecular competition reaction between the F- and Me-
substituent on the para-position of aryl ring with 2a under standard
conditions indicated that the electron-donating substituent
exhibited a little bit better reaction activity in the one-pot
competition reaction (Scheme 4, eq 1). While the yield of 3ga was
higher than 3ba, which indicate that the special strong electron-
poor substituent CF3 exhibited better reaction activity in the one-
pot competition reaction (eq 2). Furthermore, 3ab and 3ae were
obtained in a ratio of 1:1.1, which implied that there was no
obvious reactivity difference in this reaction system (eq 3).
Subsequently, some deuterium-labeling experiments were carried
out to further investigate the catalytic mechanism. 90% deuterium
was observed at both ortho-positions when the reaction was
performed in the absence of 2a using CH3OD as the solvent,
showing that the possibility of the reaction pathway via ortho-C−H
bond activation (eq 4). In addition, a kinetic isotope effect (KIE) was
determined to be 1.3, indicating that the cleavage of the ortho C–H
bond might be not involved in the rate-determining step (eq 5).
Then the reaction was performed in the presence of H2O18 (eq 6),
which unambiguously proving the nucleophilic attack of water step
and suggesting that the carbonyl oxygen on the oxopropyl chain of
the isoquinolone derivative comes from the water used in the
reaction conditions.
COOMe
COOMe
O
[Cp*RhCl2]2 (5 mol%)
Cu(OAc)2 H2O ( 2.1 equiv)
AgSbF6 (20 mol%)
O
(7)
N
PivOH (2 equiv)
CH3OH
130 oC, 16 h, air
Ph
Ph
95%
4,
N
MeO
MeO
O
N
N
N
O
N
Ph
(8)
O
O
O
N
NHNH2
EtOH
N
toluene,
110 oC, 24 h
Ph
Ph
Ph
Ph
Ph
Ph
5,
68%
6,
54%
3aa
NNHPh
O
CHO
O
NHNH2
POCl3
DMF
N
N
(9)
N
EtOH
N
Ph
Ph
Ph
110 o
C
Ph
Ph
80%
overnight
7,
8,
86%
Scheme 5 Synthetic Applications
(a) Intermolecular competition experiments
A plausible mechanism for the reaction were proposed in Scheme
6. First, a coordination of nitrogen of 1a by rhodium and C−H bond
O
N
O
N
O
O
O
2a
3 equiv
O
(1)
N
N
+
activation occurred to afford
a rhodacyclic intermediate I.
standard
Me
PhF
Ph
conditions
F
Me
Subsequently, coordination of diphenylacetylene 2a to rhodacyclic
intermediate I was followed by insertion of the C-Rh bond to give
complex III, which underwent reductive elimination to generate
oxazolinium salt IV. Then the reduced rhodium(I) was oxidized to
regenerate rhodium(III) participating in the next catalytic cycle.
Finally, H2O as a nucleophile attacked oxazolinium salt IV and living
cationic ring-opening to afford the final product 3aa.
Ph
, 28%
Ph
, 9%
1b
1h
3ba
3ha
1 equiv
1 equiv
O
N
O
O
O
O
2a
3 equiv
O
(2)
N
N
N
+
standard
F3C
Ph
Ph
Me
conditions
F3C
Me
Ph
, 41%
Ph
3ba
1b
1g
3ga
, 24%
1 equiv
1 equiv
F
Me
O
O
O
O
N
N
CuI
1a
1a
2 equiv
(3)
[RhIIICp*X2]
CuII
standard
H+
conditions
Me
F
O
[RhICp*]
H2O
3aa
Me
F
2e
1.5 equiv
N
2b
Me
3ab
F
1.5 equiv
3ae, 34%
, 31%
Ph
O
(b) Deuterium-labeling and 18O-labeling experiments
Ph
IV
O
90%
[Cp*RhCl2]2 (4 mol%)
N
O
H
O
D
N
RhIII
Cp*
RhIII
Cu(OAc)2 ( 2.1 equiv)
AgNTf2 (10 mol%)
Cp*
N
N
X
(4)
(5)
I
CH3OD
100 oC, 12 h, air
Ph
D
H
O
Ph
90%
O
N
III
2a
1a
[D2]-1a
O
N
H/D
O
D
O
H
RhIII
Cp*
2a
N
N
Ph
standard conditions
4 h
Ph
D
Ph
, 51%
H
O
II
Ph
[H/D]-3aa
kH/kD = 1.3
Scheme 6 Plausible Mechanism
1a
[D2]-1a
18O
O
[Cp*RhCl2]2 (4 mol%)
Cu(OAc)2 ( 2.1 equiv)
AgNTf2 (10 mol%)
Ph
N
N
+
Conclusions
(6)
H O18
Ph
73%
anhydrous CH3OH,
100 oC, 16 h, Ar
2
Ph
Ph
3aa'
In summary, we highly efficiently synthesized isoquinolone
derivatives bearing functional N-oxopropyl chain via chelation
assistance of oxazoline ring. Novel three-component cascade
1a
2a
Exact Mass [ M+Na]+: 378.1356
Found [ M+Na]+: 378.1355
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Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
We highly appreciate the financial support from Key
Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, Sichuan Research Center for Drug
Precision Industrial Technology, 111 Project B18035 and “the
Fundamental Research Funds for the Central Universities”.
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DOI: 10.1039/D0OB02389B
Rh(III)-Catalyzed Three-Component Cascade Annulation to
Produce N-oxopropyl Chain of Isoquinolone Derivatives
Yuan He, Xian-Zhang Liao, Lin Dong* and Fen-Er Chen*
R'
O
R'
H2O
O
R
+
O
RhIII
R
N
+
N
R
R
Functionalized chain
Wide substrate scope