Construction of isoxazolone-fused phenanthridinesviaRh-catalyzed cascade C-H activation/cyclization of 3-arylisoxazolones with cyclic 2-diazo-1,3-diketones

Article abstract of DOI:10.1039/d0ob02310h

A Rh(iii)-catalyzed cascade C-H activation/intramolecular cyclization of 3-aryl-5-isoxazolones with cyclic 2-diazo-1,3-diketones was described, leading to the formation of isoxazolo[2,3-f]phenanthridine skeletons. The protocol features the simultaneous one-pot formation of two new C-C/C-N bonds and one heterocycle in moderate-to-good yields with good functional group compatibility. It is amenable to large-scale synthesis and further transformation.

Full text of DOI:10.1039/d0ob02310h

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DOI: 10.1039/D0OB02310H
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Construction of isoxazolone-fused phenanthridines via Rh-
catalyzed cascade C-H activation/cyclization of 3-arylisoxazolones
with cyclic 2-diazo-1,3-diketones
Received 00th January 20xx,
Accepted 00th January 20xx
Wangcheng Hu, Xinwei He,* Tongtong Zhou, Youpeng Zuo, Shiwen Zhang, Tingting Yang, Yongjia
Shang*
DOI: 10.1039/x0xx00000x
A
Rh(III)-catalyzed cascade C-H activation/intramolecular removal of the DGs after transformations.11 Recently, isoxazol-
cyclization of 3-aryl-5-isoxazolones with cyclic 2-diazo-1,3- 5(4H)-ones have attracted chemists’ attention used as DGs
diketones was described, leading to the formation of mainly because their nitrogen atom could serve as a strong
isoxazolo[2,3-f]phenanthridine skeleton. The protocol features the donor atom and undergo cyclometalation at the adjacent
simultaneous one-pot formation of two new C-C/C-N bonds and position, followed by a subsequent reaction with various
one heterocycle in moderate-to-good yields with good functional partners.12 Thus 3-aryl-5-isoxazolone could be considered as a
group compatibility. It is amenable to large-scale synthesis and novel and facile coupling partner to synthesize diverse
further transformation.
isoquinolines through simple C−H bond activation followed by
intramolecular annulation.12b, 13 In continuation of our efforts
to enrich transition-metal catalyzed cascade C-H
Nitrogen-containing heterocyclic compounds are frequently
found as fundamental units in biologically active natural and
non-natural products,1 and designing novel heterocyclic motifs
has become an increasingly urgent mission for chemists and
biologists.2 Among them, phenanthridine scaffolds are very
important core structural units and possess a wide spectrum of
biological activities, such as antitumor,3 anti-HIV,4 and
antileukemic.5 In addition, isoxazolones represent an
interesting class of heterocycles that display inhibitory
activities against Escherichia coli and Yersinia pestis CDP-ME
kinases6 and as well demonstrate antagonistic antiandrogen
activity on human prostate tumor LNCaP cells.7 Moreover, the
N-functionalized isoxazolones have been found as core
structures in many natural products and pharmaceutical
molecules.8 From a synthetic point of view, to date, methods
for obtaining isoxazolone-fused phenanthridine derivatives are
still limited.
activation/intramolecular
cyclization
for
heterocycle
synthesis,14 We herein disclosed a simple and efficient strategy
for the synthesis of isoxazolo[2,3-f]phenanthridines via the
Rh(III)-catalyzed cascade C-H bond activation and sequential
intramolecular annulation of 3-aryl-5-isoxazolones and cyclic 2-
diazo-1,3-diketones (Scheme 1). Remarkably, one C−C bond
and one C−N bond were formed simultaneously with releasing
by-products of H2O and N2 in the reaction make the process
environmentally benign.
O
O
O
O
N
N2
R1
O
n R3
R2
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 8 h
+
N
R1
O
R3
R2
O
(n = 0, 1)
H
Scheme 1 Synthesis of isoxazolo[2,3-f]phenanthridines via Rh(III)-catalyzed cascade
Transition-metal-catalyzed direct selective conversion of
unactivated C−H bonds has emerged as an attractive and
arguably ideal new strategy to synthesize heterocyclic
molecules,9 which generally require directing groups (DGs) to
resolve the regioselectivity.10 The heteroatom as a directing
group participated in the annulation reaction to avoid the
reaction of 3-aryl-5-isoxazolones with cyclic 2-diazo-1,3-diketones.
The study was initiated to establish the optimal conditions
with 3-phenylisoxazol-5(4H)-one (1a) and 2-diazo-5,5-
dimethylcyclohexane-1,3-dione (2a) as the starting materials.
The reaction was performed by [Cp*RhCl2]2 as catalyst in DCE
at 90 ºC, affording the desired product 3aa in 39% yield (Table
1, entry 1). However, the replacement of [Cp*RhCl2]2 with
other Rh- or Ru-catalysts failed to produce the desired product
(Table 1, entries 2-6). Increasing or decreasing the loading of
catalyst gave inferior outcomes (Table 1, entries 7,8). Next,
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui
Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal University, Wuhu
241000, P.R. China. E-mail: xinweihe@mail.ahnu.edu.cn, shyj@mail.ahnu.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental procedures, when the solvent was changed to tetrahydrofuran (THF),
analytical data, and copies of NMR spectra. CCDC 2045428. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
ethanol, and acetonitrile, no improvements could be achieved
(Table 1, entries, 9, 10, 12). Importantly, higher yield was
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obtained when toluene was used as solvent (Table, entry 11). investigated under the standard conditions. Both VHie,waAlrktiyclle(Oen.lgin.e,
2
DOI: 10.1039/D0OB02310H
Furthermore, the yield was improved to 72% when the methyl) and aryl (e.g., phenyl) R groups were well-tolerated
amount of diazo compound 2a was increased to 2 equivalents affording the corresponding products 3ab-3ad in 63%, 58%,
as well as the reaction mixture was heated to 110 °C (Table 1, and
54%
yields,
respectively.
Additionally,
2-
entry 15). Afterward, further optimization of the additive, diazocyclopentane-1,3-dione was also found to undergo this
including AgSbF6, CsOAc, and PivOH, as more competent for transformation, generating the corresponding product 3ae in
this reaction protocol, the product 3aa was delivered with no 46% yield. However, the protocol is not suitable for noncyclic
remarkable improve in terms of yield (Table 1, entries 17-19).
diazo substrates, such as 3-diazopentane-2,4-dione and ethyl
2-diazo-3-oxobutanoate.
Table 1 Optimization of the Reaction Conditions.a
Table 2. Substrate scope.a,b
O
O
O
O
N2
O
O
catalyst (2 mol%)
solvent, 90 oC, 8 h
N
N
Me
Me
+
O
O
O
O
N
H
2a
O
N2
R1
Me
Me
n R3
R2
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 8 h
1a
N
+
3aa
R1
O
R3
R2
H
Entry
1
2
catalyst
solvent
DCE
DCE
yield(%)b
39
O
(n = 0, 1)
[Cp*RhCl2]2
[Cp*IrCl2]2
O
O
nd
3
4
5
Ru(Ph3P)2Cl2
Rh(PPh3)Cl
Rh2(OAc)4
DCE
DCE
DCE
nd
nr
nr
O
O
N
N
R1
R1
6
[(p-cym)RuCl2]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
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
DCE
DCE
DCE
THF
nr
27
21
13
nr
48
nr
58
65
72
68
trace
33
Me
Me
Me
Me
O
O
7c
: R1 = Me, 76%
: R1 = Et, 73%
: R1 = H, 72%
: R1 = F, 53%
: R1 = Cl, 57%
: R1 = Br, 78%
O
3ea
3aa
8d
9
3aa
X-ray structure of
3fa
3ba
3ca
3da
: R1 = iPr, 71%
: R1 = tBu, 83%
(CCDC 2045428)
3ga
3ha
10
11
12
13e
14e,f
15e,g
16e,h
17e,i
18e,j
19e,k
EtOH
toluene
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
O
O
R1
R1
O
N
O
O
N
N
R1
Me
O
Me
O
Me
O
Me
Me
Me
3ia: R1 = OMe, 82%
: R1 = Cl, 52%
: R1 = F, 68%
3ka
3oa
3pa
3ja
: R1 = Br, 54%
: R1 = CF3, 73%
: R1 = Me, 72%
3la
45
: R1 = Me, 74%
3ma
a
Reaction conditions: 3-phenylisoxazol-5(4H)-one (1a) (0.25
mmol), 2-diazo-5,5-dimethylcyclohexane-1,3-dione (2a) (0.25
: R1 = OMe, 70%
3na
O
O
O
mmol), and catalyst (2 mol%) in solvent (4 mL) at 90 °C for 8 h
c
d
i
R1
under air atmosphere. b Isolated yields. 1 mol% of catalyst.
4
8
O
N
O
O
N
e
f
g
h
N
mol% of catalyst. 1a:2a = 1:2. 100 °C. 110 °C. 120 °C.
mol% of AgSbF6 as additive. j 20 mol% of CsOAc as additive. k 20
mol% of PivOH as additive. nd = not detected. nr = no reaction.
R1
Me
Me
: R1 = Me, 53%
: R1 = OMe, 48%
O
Me
O
O
O
Me
Me
3ab
: 63%
3sa
: 63%
3qa
3ra
After establishing the optimal reaction conditions (Table 1,
entry 15), the substrate scope was examined for the
preparation of various functionalized isoxazolo[2,3-
f]phenanthridine derivatives (Table 2). In general, the reaction
proceeded smoothly with a broad spectrum of 3-arylisoxazol-
5(4H)-ones. Electron–deficient (e.g., -F, -Cl, -Br, and –CF3), –
neutral (e.g., -Me, -Et, -iPr, and -tBu), and –rich (e.g., -OMe)
groups at the para-position of beneze ring in substrate 1 were
well-tolerated, affording the corresponding products 3aa-3ja
in 53-83% yields. In addition, changing the substituents to
meta- and orth-position of beneze ring in the starting material
1 could also generated the desired products 3ka-3pa in 52-
74% yields. Moreover, the disubstituted 3-arylisoxazol-5(4H)-
ones were found to react with diazo-5,5-dimethylcyclohexane-
1,3-dione 2a yielding the corresponding products 3qa, 3ra in
53% and 48% yields, respectively. Furthermore, it was found
that the aryl framework could be extended to naphthalene,
affording the desired product 3sa with a percentage yield of
63%. Next, the suitability of cyclic diazo compounds was
O
O
O
N
O
N
O
N
O
O
Ph
O
3ae
3ad
: 54%
3ac
: 58%
: 46%
O
O
O
O
N
N
Me
Me
O
O
Me
OEt
: 0%
3af
: 0%
3ag
a Reaction conditions: 3-arylisoxazol-5(4H)-one 1 (0.25 mmol), cyclic 2-
diazo-1,3-diketones 2 (0.5 mmol), and [Cp*RhCl2]2 (2 mol%) in toluene
(4 mL) at 110 °C for 8 h under air atmosphere. b Isolated yields.
To further study the applicability of this strategy by
preparation of compound 3aa on a scale-up synthesis (3 mmol
of 1a with 6 mmol of 2a) under the standard conditions as
2 | Org. Biomol. Chem., 2020, 00, 1-3
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described above (Scheme 2a). The large-scale synthesis
proceeded smoothly to give the desired product 3aa in 66%
yield (557 mg). In addition, derivatization of 3aa was
performed by reacting with pyridinium tribromide in the
presence of K2CO3 in DCM (dichloromethane) at room
temperature for 5 h, affording the bromo-substituted product
4 in 78% yield (Scheme 2b).
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DOI: 10.1039/D0OB02310H
1a
(a) H/D exchange experiment with substrate
O
O
D/H
D/H
0%
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 2 h
O
N
N
D2O (0.3 mL)
H/D 23%
H
1a
(3 mmol)
3aa
(b) H/D exchange experiment with product
O
D
O
O
O
O
N2
standard conditions
D2O (0.3 mL)
N
(a) Scale-up synthesis
N
+
Me
Me
O
O
O
O
H
1a
2a
Me
Me
(64%)
O
N2
O
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 8 h
N
Me
Me
(c) compectitive experiment
O
+
N
3aa-d
O
O
O
O
H
2a
(6 mmol)
Me
Me
(66%, 557 mg)
O
N2
O
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 8 h
1a
(3 mmol)
N
N
Me
Me
+
3aa
MeO/F3C
MeO/F3C
1i 1j
H
2a
(b) Further transformation
O
Me
Me
O
/
= 1:1
Br
O
3ia 3ja
/
= 1.8:1
O
N
O
(d) KIE experiment (parallel reactions)
N
Pyridinium tribromide (1 equiv.)
K2CO3 (5 equiv.), DCM, rt, 5 h
O
O
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 2 h
kH/kD = 1.5
O
O
N2
Me
Me
(1 mmol)
Me
Me
(78%)
O
N
N
+
O
H4/D4
Me
Me
H5/D5
3aa
O
4
2a
1a 1a-d
or
Me
Me
3aa/3aa-d4
5
O
Scheme 2. Scale-up synthesis and further synthetic transformation.
(e) KIE experiment (competitive reaction)
In order to gain insight into the reaction mechanism, we
initially performed the H/D exchange experiment in deuterium
oxide under the standard conditions (Scheme 3a). The
deuteration reaction of 1a mainly occurs at the C(sp2)-H bond
(D, 23%) on the benzene ring, while no deuterated product
was detected at the C(sp3)-H on the isoxazol-5(4H)-one ring.
This result showed that the activation process of the C(sp2)-H
bond is favorable and fast and no alkenylation occurred on the
isoxazol-5(4H)-one ring at the initial stage of the reaction. As
we expect, more than 99% of product 3aa-d was deuterated at
the α-H of carbonyl group on the isoxazol-5(4H)-one ring when
the reaction of substrates 1a with 2a in the presence of
deuterium oxide under the standard conditions (Scheme 3b).
Furthermore, an intermolecular competition experiment was
conducted to examine the electron-rich substrate 1i and its
electron-deficient counterpart 1j (Scheme 3c). The higher yield
for 1i than 1j highlights the fact that electron-rich substrates
are inherently more reactive, implying that stronger
coordination ability of the N-atom in these substrates with the
Rh(III) catalyst, which in turn facilitates the following C-H
activation step. Furthermore, we determined the kinetic
isotope effect (KIE) of this cascade C-H activation/cyclization. A
KIE value of 1.5 was determined from two parallel reactions
(Scheme 3d), and a KIE value of 2.2 was determined from a
competition reaction (Scheme 3e). These results suggested
that C(sp2)−H bond cleavage might be the limiting step.
O
O
O
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 2 h
kH/kD = 2.2
O
O
N2
N
N
+
H4/D4
Me
Me
H5/D5
1a
O
2a
1a-d
and
Me
Me
5
O
3aa/3aa-d4
Scheme 3. Mechanistic studies.
On the basis of the above control experiment results and
literature reports,15 a plausible mechanism is proposed for the
formation of product 3aa (Scheme 4). Initially, the reaction of
the Rh-catalyst with the substrate 1a leads to the five-
membered rhodacycle intermediate A by deprotonation.
Subsequently, the cyclic 2-diazo-1,3-diketone 2a coordinates
with intermediate A to form the intermediate B by releasing
N2. Then, migratory insertion of carbine into Rh-C bond
completes the C-C coupling and affords the six-membered
intermediate C, which can be protonated with hydrochloric
acid to generate intermediate D and release the Rh(III)-
catalyst. In the next stage of this cascade process, an
alkenylation occurs with the in situ generated intermediate E
via 1,3-H shift. Finally, the desired product 3aa was formed
through an intramolecular nucleophilic addition of the amino
group to carbonyl in intermediate E to form intermediate F,
followed by water elimination.
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2
3
A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor,
O
View Article Online
O
Comprehensive Heterocyclic Chemistry III; Pergamon Press:
DOI: 10.1039/D0OB02310H
O
N
O
N
O
O
O
Oxford, 2008.
H
1,3-H shift
O
(a) D. Bellocchi, A. Macchiarulo, G. Costantino and R.
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O
O
N
E
D
H
1a
[Cp*RhCl2]2
O
s
i
s
HCl
y
C-H
metalation
l
o
n
O
o
t
4
5
6
7
8
S. Patil, S. Kamath, T. Sanchez, N. Neamati, R. F. Schinazi and
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HCl
o
N
r
O
p
HO
O
O
N
O
O
F
Rh
N
Cl
Cp*
O
A
Cl
Rh
Cp*
O
O
e
n
H2O
e
n
o
O
O
b
N2
m
i
r
3aa
T. Ishioka, A. Tanatani, K. Nagasawa and Y. Hashimoto,
Bioorg. Med. Chem. Lett., 2003, 13, 2655.
t
i
a
g
a
i
r
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h
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a
s
m
t
e
r
o
o
r
r
O
R
t
y
f
C
i
o
2a
N
n
N2, Cl-
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Cp*
Rh
Cl-
O
O
B
Scheme 4. A plausible mechanism.
Conclusions
In summary, we have developed rhodium-catalyzed cascade C-
H activation/intramolecular cyclization of 3-aryl-5-isoxazolones
with cyclic 2-diazo-1,3-diketones. Under the reaction
conditions, structurally diverse isoxazolo[2,3-f]phenanthridine
scaffolds could be produced in moderate-to-good yields. The
advantages of the current strategy include additive-free
conditions, good functional tolerance, and broad substrate
scope. Particularly noteworthy is that the by-products of N2
and H2O in the reaction make the process environmentally
benign. In addition, a large-scale synthesis and further
transformation are also presented to show the practicality and
potential of the current reaction.
9
Conflicts of interest
10 Selected literatures, see: (a) H. Wang, H. Xu, B. Li and B.
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There are no conflicts to declare.
Acknowledgement
The work was partially supported by the National Natural
Science Foundation of China (No. 21772001), the Anhui
Provincial Natural Science Foundation (No. 1808085MB41),
and Cultivation Project for University Outstanding Talents of
Anhui Province (2019).
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DOI: 10.1039/D0OB02310H
Table of Contents
O
O
O
O
O
N2
R1
N
n R3
[Cp*RhCl2]2 (2 mol%)
toluene, 110 oC, 8 h
+
N
R2
R1
O
R3
R2
O
(n = 0, 1)
H
mild conditions, scalability & practicality
N2 & H2O as the only by-products
two new bonds and one heterocycle formation in one-pot
good functional group tolerance, e.g. -F, -Cl, -Br, -CF3, -OMe, alkyl.....
A Rh(III)-catalyzed cascade C-H activation/intramolecular cyclization of 3-aryl-5-isoxazolones
with cyclic 2-diazo-1,3-diketones was described, leading to functional isoxazolone-fused
phenanthridine derivatives in moderate to good yields.