Rhodium-Catalyzed C?H Activation/Annulation Cascade of Aryl Oximes and Propargyl Alcohols to Isoquinoline N-Oxides

Article abstract of DOI:10.1002/adsc.202100239

A β-hydroxy elimination instead of common oxidization to carbonyl group in secondary propargyl alcohols was successfully developed to form 2-benzyl substituted isoquinoline N-oxides by a Rhodium-catalyzed C?H activation and annulation cascade, in which moderate to excellent yields (up to 92%) could be obtained under mild reaction conditions, along with good regioselectivity, broad generality and applicability. (Figure presented.).

Full text of DOI:10.1002/adsc.202100239

RESEARCH ARTICLE
DOI: 10.1002/adsc.202100239
Rhodium-Catalyzed CÀ H Activation/Annulation Cascade of Aryl
Oximes and Propargyl Alcohols to Isoquinoline N-Oxides
Yuan Li,a, b Feifei Fang,b Jianhui Zhou,b Jiyuan Li,b Run Wang,b Hong Liu,b, c,*
and Yu Zhoub, c,*
a
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, People’s Republic of
China
b
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
201203, People’s Republic of China
and
University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
E-mail: hliu@simm.ac.cn; zhouyu@simm.ac.cn
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of
c
Sciences, Hangzhou 310024, People’s Republic of China
Manuscript received: February 23, 2021; Revised manuscript received: April 29, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100239
Abstract: A β-hydroxy elimination instead of common oxidization to carbonyl group in secondary propargyl
alcohols was successfully developed to form 2-benzyl substituted isoquinoline N-oxides by a Rhodium-
catalyzed CÀ H activation and annulation cascade, in which moderate to excellent yields (up to 92%) could be
obtained under mild reaction conditions, along with good regioselectivity, broad generality and applicability.
Keywords: Isoquinoline N-oxides; β-hydroxy elimination; Rhodium; Secondary propargyl alcohols
Introduction
The N-oxides of isoquinoline and pyridine are impor-
tant structural units widely embedded in various
natural products,[1] pharmaceutical agents,[2] and chiral
ligands (Figure 1).[3] Meanwhile, they are also widely
used as powerful directing groups in the CÀ H
functionalization of isoquinolines, pyridines and other
natural product scaffolds.[4] However, the traditional
synthesis of these N-oxides mainly involves the direct
oxidation of parent heterocycles with a stoichiometric
amount of peroxides or peracids, such as m-CPBA,
H2O2, CF3CO3H, and MeReO3/H2O2.[4d,5] The major
limitations of them are that the parent heterocycles
need to be prepared in advance and probably suffer
from the overoxidation.[5] Over the past decades,
Figure 1. Representative compounds containing isoquinoline
and pyridine N-oxides.
transition-metal-catalyzed heteroatom-directed CÀ H
functionalization and cycloaddition cascade reactions
have become a powerful approach for the synthesis of
these N-oxides.[5–6] Among them, oxime exhibits to be
a facile precursor and can couple with alkynes,[6f] diazo Shin group reported a pioneering silver(I)-catalyzed
compounds,[5–6] and other coupling partners[6c] to build direct route to isoquinoline N-oixides via an intra-
intriguing isoquinoline or pyridine N-oxides. Such as, molecular annulation from o-alkynylarylaldoximes
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(Scheme 1a).[6h] After that, some similar strategies and annulation cascade with moderate to excellent yields
were also reported.[6d,e,g] Interestingly, Huang and co- (up to 92%) under mild reaction conditions, along with
workers in 2013 fulfilled a novel oxime directed CÀ H regioselectivity, broad generality and versatile applicabil-
activation cascade with diaryl alkynes to efficiently ity.
build
multisubstituted
isoquinoline
N-oxides
(Scheme 1b).[6f] Besides, Glorious’s group and Ram-
Results and Discussion
ana’s group independently achieved a N-oxide directed
CÀ H activation of aryl oxime and further annulation The explorations were firstly employed by the treat-
with diazo compound by the Rh(III) or Ir(III) catalytic ment of acetophenone oxime 1a (0.4 mmol, 1 equiv.)
system to give the intriguing polysubstituted isoquino- and secondary propargyl alcohol 2a (0.8 mmol,
line and pyridine N-oxides (Scheme 1c).[5–6]
2 equiv.) under the catalyst system consists of [Cp*Rh-
Despite these progress, other readily available syn- (CH3CN)][SbF6]2 (8 mol%), Ag2CO3(100 mol%) and
thons still were highly desired. Propargyl alcohols have PivOH (0.8 mmol, 2 equiv.) in methanol (MeOH) at
°
been applied widely as important building blocks in 90 C for 12 h. As expected, the hydroxyl group in
transition-metal-catalyzed intermolecular annulations.[7] secondary propargyl alcohol was oxidized to carbonyl
In our continuous efforts on the development of transition group and further reserved in the formation of hetero-
metal-catalyzed CÀ H functionalization strategies to con- cycle (4aa) with 45% yield (Table 1, entry 1). How-
struct diverse drug-like heterocycles,[4e,7o,q,8] we serendip- ever, we surprisingly detected a new product 2-benzyl
itously found an unusual aspect of secondary propargyl substituted isoquinoline N-oxide 3aa which was
alcohols that could smoothly couple with aryl oximes to suspected to undergo an unprecedented β-hydroxy
form 2-benzyl substituted isoquinoline N-oxides via a elimination instead of oxidization when we changed
Rh(III)-catalyzed CÀ H activation and unusual β-hydroxy this metal catalyst into [Cp*RhCl2]2 (Table 1, entry 2).
elimination cascade (Scheme 1d). To the best of our The structures of 3aa and 4aa were unambiguously
1
knowledge, the hydroxyl group in secondary propargyl confirmed by their H and 13C NMR spectra, mass
alcohols was usually oxidized to carbonyl group, or spectrometry data, and X-ray crystallographic analysis,
directly
reserved
into
the
formed
target respectively.[10] The new finding inspired our interest to
heterocycles,[7g,l,m,o–u] still no related reports involved a β- further screen the catalysts, and the results indicated
hydroxy elimination in Rh(III)-catalyzed CÀ H activation that [Ru(p-cymene)Cl2]2 and [Cp*IrCl2]2 could not
and annulation cascade between oxime and secondary catalyze this new transformation (Table 1, entries 3 and
propargyl alcohol.[7d,h,j,u,9] Herein, we report this new 4). Subsequently, we screened different additives, such
finding that the secondary propargyl alcohols underwent as Ag2CO3, PivOH, AcOH, benzoic acid, phenylacetic
an unprecedented β-hydroxy elimination instead of acid, propanedioic acid, succinic acid and citric acid,
common oxidization to form 2-benzyl substituted iso- and the results revealed that succinic acid was superior
quinoline N-oxides via Rh(III)-catalyzed CÀ H activation to other additives (Table 1, entries 5–12), providing the
product 3aa with 82% yield. Therefore, succinic acid
was chose as the additive in subsequent experiments.
Further investigations of different solvents indicated
that MeOH was the best choice for this transformation
(Table 1, entries 13–18). Besides, we also investigated
the influences of reaction time and temperature to this
reaction (Table 1, entries 19–23), the results demon-
strated that this transformation could proceed smoothly
°
with the yield of 85% at 90 C for 24 h. Meanwhile,
we could obtaine product 3aa with the yield of 54% in
a low [Cp*RhCl2]2 loading (Table 1, entry 24). Mean-
while, the molar ratios of substrates 1a and 2a were
investigated (Table 1, entries 25–26). Besides, the
controlled reaction experiment showed that the target
product 3aa could not be obtained in the absence of
[Cp*RhCl2]2 or succinic acid (Table 1, entries 27 and
28). Briefly, the optimum result could be obtained
when aryl oxime (0.4 mmol, 1a) and secondary
propargyl alcohol (0.8 mmol, 2a) were treated in
MeOH under the presence of [Cp*RhCl2]2 (8 mol%)
as catalyst and succinic acid (2.0 equiv.) as additive at
Scheme 1. Transition-metal-catalyzed Synthesis of N-oxides of
Isoquinoline.
°
90 C for 12 h or 24 h.
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Table 1. Optimization of Reaction Conditions.[a]
Table 2. Substrate Scope of (Hetero)Aryl Oximes.[a]
Entry Catalyst
Additive
Yield[b]
3aa(4aa)
1
[Cp*Rh (CH3CN)] [SbF6]2 Ag2CO3/PivOH ND (45)
2
3
4
[Cp*RhCl2]2
[RuCl2(p-cymene)]2
[Cp*IrCl2]2
Ag2CO3/PivOH 23 (24)
Ag2CO3/PivOH ND
Ag2CO3/PivOH ND
5
6
7
8
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Ag2CO3
PivOH
AcOH
Benzoic acid
Phenylacetic acid 53
Propandioic acid 70
25
45
67
56
9
10
11
12
Succinic acid
Citric acid
82
81
[a] Reaction conditions: 1 (0.4 mmol), 2 a (0.8 mmol),
[Cp*RhCl2]2 (8 mol%), Succinic acid (2.0 equiv) in MeOH
13[c] [Cp*RhCl2]2
14[d] [Cp*RhCl2]2
15[e] [Cp*RhCl2]2
16[f] [Cp*RhCl2]2
17[g] [Cp*RhCl2]2
18[h] [Cp*RhCl2]2
19[i] [Cp*RhCl2]2
20[j] [Cp*RhCl2]2
21[k] [Cp*RhCl2]2
22[l] [Cp*RhCl2]2
23[m] [Cp*RhCl2]2
24[n] [Cp*RhCl2]2
25[o] [Cp*RhCl2]2
26[p] [Cp*RhCl2]2
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
Succinic acid
–
20
ND
ND
10
ND
ND
35
64
44
63
85
54
56
69
ND
ND
°
(4 mL) at 90 C for 12 h.
[b] 24 h.
also could afford the target compounds with good
yields when the reaction time was prolonged to 24 h
(3ia, 3ja and 3ka). Surprisingly, we found an
interesting regioselectivity when the electron-with-
drawing groups (À F and À CN) and electron-donating
group (À CH3) were independently introduced into the
meta position of the benzene ring of aryl oxime 1a.
The introduction of m-F and m-CN gave the 2-position
CÀ H activation products 3la and 3na. In contrast, the
CÀ H activation of m-CH3 substrate took place solely at
6-position of aryl oxime to give product 3ma. This
regioselectivity is probably attributed to the CÀ H bond
acidity or the RhÀ C bond stability in the cyclo-
rhenation step.[11] The structures of 3la, 3ma and 3na
were also unambiguously confirmed by an X-ray
crystallographic analysis.[12] Besides, fused ring (1o)
was integrated into aryl oximes, and the resulting
substrate could also provide the corresponding N-oxide
3oa in a moderate yield. Notably, other functionalized
27
28
–
[Cp*RhCl2]2
[a]
Reaction conditions: 1 a (0.4 mmol), 2a (0.8 mmol),
[Cp*RhCl2]2 (8 mol%), Succinic acid (2.0 equiv.) in MeOH
(4.0 mL) at 90 C under air for 12 h. [b] Isolated yield.
°
[c–h]
Solvent: EtOH: ethanol, DCE: dichloroethane,
(CH3)2CO: acetone, ACN: acetonitrile, THF: tetrahydrofur-
an, PhMe: toluene. At 60 C. At 100 C. [k] 2 h. [l] 6 h.
[m] 24 h. [n] [Cp*RhCl2]2 (5 mol%). [o] 1a/2a=1/1. [p] 1a/
2a=1/1.5.
[i]
[j]
°
°
With the optimized reaction conditions in hand, we aryl oximes were compatible with the standard reaction
firstly examined the scope of differently substituted conditions to form the corresponding target products
aryl oximes (1b–1q) in the catalytic system above (3pa and 3qa) with good yields.
with propargyl alcohol 2a (Table 2). In general,
Based on the above results, we next explored the
introducing an electron-donating or electron-withdraw- scope of propargyl alcohols (2b-2l, Table 3). As we
ing group into the para position of aryl oximes could expected, coupling oxime 1a with propargyl alcohols
smoothly couple with propargyl alcohol 2a to afford equipping various substitutions at R1 position (2b–2i)
the target compounds (3ba–3ha) in good yields. It all gave the desired products in good to excellent
seemed that the electron-donating groups were signifi- yields (3ab–3ai). The thienyl substituted propargyl
cantly superior to the electron-withdrawing groups alcohol was also tolerant and gave product 3aj with
especially trifluoromethyl group (3ha, 25%) with a the yield of 40%. Subsequently, we explored the
lower yield. Introduction of halide substituents (À F, influences of other bulkier R2 groups, such as cyclo-
À Cl and À Br) to the para position of the benzene ring propyl and n-butyl groups, and the results displayed
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Table 3. Scope of Propargyl Alcohols.[a]
regioselectivity of the C1-methyl of 5, which may be
further used for structural modification in drug discov-
ery (Scheme 2b).
In order to gain an insight into the preliminary
mechanism, we carried out several mechanistic experi-
ments. Firstly, an H/D exchange experiment of aryl
oxime 1a was performed to probe the reversibility of
the CÀ H activation. A notable deuterium scrambling
was observed when the reaction was performed under
standard reaction conditions in CD3OD for 12 h
(Scheme 3a). The C(sp2)À H activation of the benzene
ring was reversible process with approximately 36.5%
deuteration at the ortho positions of the aryl oxime,
and 46.7% deuteration at the methyl of the aryl oxime
which may be a result of the isomerization of imine
and enamine. Next, the kinetic isotope effect (KIE)
experiments were carried out and the results indicated
that CÀ H cleavage may not be the rate-limiting step, as
evidenced by the values of kH/kD =1.86 (measured
from the competition experiment) and kH/kD =1.92
(measured from parallel reactions) as shown in
Scheme 3b. Meanwhile, the competition experiment
[a]
Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol),
[Cp*RhCl2]2 (8 mol%), Succinic acid (2.0 equiv) in MeOH
°
(4.0 mL) at 90 C for 12 h.
that the two substrates provided the corresponding between the electron-donating substituted 1b and
products in excellent yields (3ak and 3al). Similarly,
4-tert-butylaryl oxime (1e) and 4-fluoroaryl oxime
(1i) were further studied with differently substituted
secondary propargyl alcohols, and both could be
successfully converted into target products with good
yields (3eb–3ig).
To further assess the efficiency and potential
applications of this transformation, we firstly per-
formed a gramscale preparation, and obtained the
target product 3aa with 62% isolated yield (Sche-
me 2a). In view of the potential biological value of
isoquinoline core,[13] we have attempted to switch these
intriguing isoquinoline N-oxides into isoquinoline
cores. After explorations, the N-oxide 3aa was easily
reduced to isoquinoline product 5 by Zn/NH4Cl
catalytic system with a good yield (Scheme 2b). Addi-
tionally, we successfully achieved alkylation and
hydroxylation reaction between two different C(sp3)À H
bonds, indolin-2-ones and 5, to get product 6 through
an oxidative cross coupling reaction, and achieved
Scheme 2. Gram-scale Preparation and Conversion of 3aa.
Scheme 3. Preliminary Mechanism Studies.
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electron-withdrawing substituted 1h revealed that the to form 2-benzyl substituted isoquinoline N-oxides
transformation favored the electron-rich aryl oxime with mild reaction conditions and good function group
with ratio of 4/1 (Scheme 3c). Likewise, the competi- tolerance.
tion experiment was also conducted between different
propargyl alcohols 2e and 2g, and the result indicated
that the electron-withdrawing group on the benzene
Experimental Section
A pressure tube was charged with aryl oxime (1a, 55 mg,
0.4 mmol) and propargyl alcohol (2a, 119 mg, 0.8 mmol),
[Cp*RhCl2]2 (20 mg, 8 mol%), succinic acid (96 mg, 0.8 mmol)
ring of propargyl alcohol had a slightly better impact
than the electron-donating group (Scheme 3d). Be-
sides, we conducted the experiment of propargyl
alcohol alone under standard conditions (Scheme 3e),
and the results showed that propargyl alcohol may be
not esterified with stoichiometric succinic acid under
standard conditions.
On the basis of the preliminary mechanistic experi-
ments and precedent literature reports,[5,7d,14] we pro-
posed a possible mechanism (Scheme 4). Firstly, the
catalyst is generated through anion exchange and
further coordinates with aryl oxime 1a to form the
five-membered rhodacyclic intermediate I by reversi-
ble CÀ H bond activation. The metal species was
subsequently coordinated with propargylic alcohol 2a
to afford the intermediate II, followed by regioselec-
tive insertion into RhÀ C to give carbometalated
intermediate III, and then β-hydroxy elimination
affords the allene intermediate IV, which undergoes a
6π electrocyclization to afford the target compound
3aa.
°
and MeOH (4 mL). The reaction mixture was stirred at 90 C
for 12 h. After the reaction completed, dichloromethane (DCM)
10 mL was added and the mixture was filtered through a pad of
celite which was subsequently washed with DCM. Then the
solvent was removed under reduced pressure and the residue
was purified by silica gel chromatography using PE/EA (5:1–
1:1) to afford the product 3aa.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21977106, 21632008 and 81620108027), Shanghai
Science and Technology Development Funds (19431901000 and
19431901200), Science and Technology Commission of Shang-
hai Municipality (18JC1411304), Youth Innovation Promotion
Association CAS for financial support.
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RESEARCH ARTICLE
Rhodium-Catalyzed CÀ H Activation/Annulation Cascade of
Aryl Oximes and Propargyl Alcohols to Isoquinoline N-
Oxides
Adv. Synth. Catal. 2021, 363, 1–7
Y. Li, F. Fang, J. Zhou, J. Li, R. Wang, H. Liu*, Y. Zhou*