Expeditious Synthesis of Isoquinolone Derivatives by Rhodium(I)-Catalyzed Annulation Reaction through C-C Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.8b03653

A Rh(I)-catalyzed intermolecular cyclization between isocyanates and benzocyclobutenols leading to isoquinolin-1(2H)-ones through selective cleavage of a C-C bond has been realized. Exploiting the same strategy, we developed a Rh(I)-catalyzed three-component reaction of benzocyclobutenols, isonitriles, and sulfonyl azides to access isoquinolin-1(2H)-imines. These procedures provide unique and expeditious access to isoquinolone derivatives which are otherwise difficult to prepare in satisfactory yields with excellent functional-group tolerance under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.8b03653

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Expeditious Synthesis of Isoquinolone Derivatives by Rhodium(I)-
Catalyzed Annulation Reaction through C−C Bond Cleavage
Yiyi He,† Chengsha Yuan,† Zeqi Jiang, Li Shuai, and Qing Xiao*
College of Pharmacy, Third Military Medical University, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: A Rh(I)-catalyzed intermolecular cyclization between isocyanates and benzocyclobutenols leading to
isoquinolin-1(2H)-ones through selective cleavage of a C−C bond has been realized. Exploiting the same strategy, we
developed a Rh(I)-catalyzed three-component reaction of benzocyclobutenols, isonitriles, and sulfonyl azides to access
isoquinolin-1(2H)-imines. These procedures provide unique and expeditious access to isoquinolone derivatives which are
otherwise difficult to prepare in satisfactory yields with excellent functional-group tolerance under mild reaction conditions.
nitrogen atoms of products are restricted because of the
limitation of amides as directing groups in the transformation.
The regioselectivity of alkynes is not good in most cases. Thus, it
is still in demand to develop innovative methods to obtain
isoquinolone derivatives via distinctive catalytic pathways.
Transition-metal-catalyzed “cut and sew”12a transformation
through selective C−C single bond cleavage12 and subsequent
functionalization has recently emerged as a novel and valuable
strategy for the synthesis of complex molecular structures.
Mechanistically, most C−C bond cleavage processes are
initiated by oxidative addition or β-carbon elimination.12c Due
to the release of ring strain via site-selective β-carbon
elimination, benzocyclobutenols (BCBs)13−16 have been
employed as privileged synthons in the “cut and sew”
transformation under mild conditions. In this context,
Murakami et al. and He et al. reported the rhodium-catalyzed
cyclization of BCBs with alkynes,13a vinyl ketones,13b and
allenes.13c A wide array of useful dihydro- or tetrahydronaph-
thalene derivatives were achieved in high yields with excellent
diastereoselectivity. Along this line, Zhu et al. developed an
iridium-catalyzed annulation of ring-fused BCBs with alkynes to
efficiently prepare polycyclic aromatic hydrocarbons
(PAHs).13d These reactions can be considered as formal two-
carbon insertion into a C−C bond. Merging the “cut and sew”
transformation and carbene chemistry, Wang et al. disclosed a
rhodium-catalyzed annulation of BCBs with diazo esters to
produce indanol derivatives.14a This reaction can be regarded as
a formal carbene (one carbon) insertion into a C−C bond.14
Encouraged by these remarkable findings, we expected to exploit
this strategy in the field of heterocyclic synthetic chemistry and
s structural motifs widely found in diverse natural
1
Aproducts, isoquinolones play important roles in pharma-
ceutical chemistry. Compounds containing the isoquinolone
skeleton are famous for their antitumor, antiallergic, and
antipsychotic activities.2 Consequently, great efforts of synthetic
chemists have been devoted to establishing some efficient
procedures for the preparation of isoquinolone derivatives in
recent years.3−11 Among these, the most amazing and popular
strategy is the transition-metal-catalyzed oxidative annulation of
benzamide derivatives with alkynes through C−H/N−H dual
activation.4,5 Several hypervalent transition-metal catalysts, such
as RhIII,6 RuII,7 CoIII,8 PdII,9 and FeIII,10 can be employed in this
transformation (Figure 1).11 Despite considerable advantages,
these reactions usually require stoichiometric amounts of
external or internal oxidants, and substituent groups on the
Received: November 15, 2018
Figure 1. Strategies to synthesize isoquinolone derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03653
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
expand the range of molecular fragments inserting into the C−C
bond. Herein, we report our preliminary results: rhodium(I)-
catalyzed annulation of BCBs with isocyanates and a three-
component reaction of BCBs, isonitriles, and sulfonyl azides
(Figure 1). Both reactions can be considered as a formal CN
fragment insertion into a C−C bond. These procedures afford
complementary methodologies for the rapid construction of
isoquinolone scaffolds in good yields with excellent functional-
group tolerance.
Our initial attempts were aimed at studying the model
reaction of 8-MeO BCB 1a and aryl isocyanate 2a (Table 1).
a
Table 1. Effect of Reaction Parameters
isolated yield (%)
entry
variation of standard conditions I
none
without CF3CO2H
1a
3a
4
.
1
2
3
4
5
6
7
0
0
0
0
0
0
45
84
22
65
32
64
35
34
0
0
0
16
0
0
56
0
0
0
HCl instead of CF3CO2H
[RhCl(cod)]2 instead of [RhOH(cod)]2
[IrOMe(cod)]2 instead of [RhOH(cod)]2
PhMe instead of DCE
55
17
0
0
room temperature instead of 50 °C
a
With 0.2 mmol 1a and 0.24 mmol 2a in 1 mL of DCE.
After a series of experiments, we found the optimal conditions
for the reaction: 2 mol % of [RhOH(cod)]2 catalyzed the
process at 50 °C in DCE for 5 h, and subsequent dehydration
reaction with TFA furnished isoquinolone 3a in 84% isolated
yield (entry 1). Control experiments established the importance
of [RhOH(cod)]2 and TFA for efficient formation of target
molecule 3a (entries 2−5). Without the acid-promoted
dehydration process, only 22% 3a and 56% 5 could be obtained
(entry 2). Other low valence state metal catalysts, such as
[RhCl(cod)]2 and [IrOMe(cod)]2, also enabled the reaction, in
low yields (entries 4 and 5) with poor chemoselectivity (entry
4). Replacing DCE with toluene, ring-opening product 4
became the main product of the reaction (entry 6). In addition,
transformation required being heated at 50 °C to avoid
generation of byproduct 4 (entry 7).
We studied the scope of the substrates (Figure 2). Substituent
phenyl isocyanates with either an electron-donating or electron-
withdrawing group on the benzene ring were able to undergo
annulation with BCB 1b to generate corresponding products in
good to excellent yields (3b−3l). Reaction conditions were
compatible with alkyl, bromide, chloride, fluoride, methoxy,
ester, and trifluoromethyl groups on the ortho-, meta-, and para-
position of the benzene ring. Alkyl, benzyl, and naphthyl
isocyanates were also proven to be useful starting materials for
efficient construction of isoquinolones 3m−3p. Further
exploration demonstrated that the reaction proceeded success-
fully with a variety of combinations of BCBs and isocyanates.
Diverse substituents on the phenyl ring of BCB showed
essentially no effect on the reaction (3q−3ac). Remarkably,
the presence of the Cl, Br, and I in 3e, 3j, 3l, 3t−3w, 3ab, and 3ac
Figure 2. Effect of reaction parameters. All reactions were carried out
with 0.2 mmol 1 and 0.24 mmol 2 in 1 mL of DCE.
provides an opportunity for later functionalization of the
molecule through cross-coupling reactions. Except for a methyl
group, BCBs bearing an ethyl, isopropyl, phenyl, or benzyl group
adjacent to the α-carbon of the tertiary alcohol can participate in
this reaction smoothly (3w, 3ad−3ah). As analogues of BCB,
naphthocyclobutenol and phenanthocyclobutenol can also be
effectively used in this reaction (3ai, 3aj, 3ao). Inspired by Zhu’s
recent report, we realized the reaction using ring-fused BCBs as
substrates to construct isoquinolone[c]-fused cyclic compounds
(3ak−3ao). Satisfactory results indicate the value of our method
because these products are otherwise difficult to prepare. To
produce isoquinolone dimers, we investigated double annula-
tion between BCBs and commercially available diisocyanates.
The desired products can be easily generated under the standard
conditions in moderate yields (3ap, 3aq).
In addition, isoquinolones produced by this method can be
further functionalized with no trouble (Figure 3). For instance, a
C8-selective arylation (a)17a and a C4-selective alkynylation
(b)17b were successfully achieved using hypervalent iodine
reagents through C−H activation enabled by iridium and gold
catalysts, respectively. A bromo group which is important for
many organic transformations was accurately introduced onto
B
DOI: 10.1021/acs.orglett.8b03653
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Organic Letters
Letter
reaction temperature (Figure 5, 12a). A series of isoquinolin-
1(2H)-imines which are difficult to prepare by other means were
Figure 3. Derivative reactions of the isoquinolone products. Reagents,
conditions, and isolated yields: (a) 0.15 mmol 3d, 0.18 mmol Ph2IPF6,
5 mol % of [IrCp*Cl2]2, 20 mol % of AgSbF6, 0.15 mL of AcOH, 100
°C, 24 h, 71%; (b) 0.15 mmol 3o, 0.18 mmol 1-[(triisopropylsilyl)-
ethynyl]-1,2-benziodoxol-3(1H)-one, 10 mol % of AuCl, 2 mL of
MeCN (dry), 50 °C, 24 h, 67%; (c) 0.2 mmol 3d, 0.2 mmol NBS, 1 mol
% of AuCl3, 2 mL of DCE, 25 °C, 5 h, 95%; (d) 0.2 mmol 3ao, 0.6 mmol
DDQ, 2 mL of DCM, 25 °C, 6 h, 95%.
the C4 position of the isoquinolone scaffold in the presence of
N-bromosuccinimide (c).17c Isoquinolone[c]-fused cyclic com-
pound 3ao was almost quantitatively oxidized to a N-containing
PAH under mild conditions (d).13d
To further demonstrate the synthetic utility of this “cut and
sew” transformation, we applied this method to the synthesis of a
biologically interesting 2,3-diaryl isoquinolinone derivative 9,
which exhibits significant antiproliferative and antiangiogenesis
activities against human breast cancer cells.1 Through the Rh(I)-
catalyzed annulation reaction and Pd-catalyzed C−O coupling
reaction, the ERα binding reagent and VEGFR-2 inhibitor 8
were prepared. The most potential dual inhibitor 9 can be
produced from 8 in one step via a literature procedure (Figure
4).1
Figure 5. Three-component reaction with BCBs, isonitriles, and
sulfonyl azides. All reactions were carried out with 0.2 mmol 1, 0.3
mmol 10, and 0.3 mmol 11 in 4 mL of PhMe.
efficiently produced in satisfactory yields with excellent
regioselectivity from the combinations of various isonitriles,
BCBs, and sulfonyl azides (12a−12l). Furthermore, the
structure of 12e (CCDC1866730) is confirmed by X-ray
crystallography. Although other azides including acyl, aryl, and
alkyl ones have not been smoothly applied in this reaction, it
provides a facile method to formally insert an amidino motif
[−(CNR′)−NR−] into the C−C bond for construction of
N,N′-disubstituted cyclic amidine compounds.
Finally, we investigated the mechanism of our reaction
(Scheme 1). The observation of byproduct 4 (Table 1, entries 4,
6, and 7) indicated that an aryl−rhodium species might be
generated through a β-carbon elimination mechanism. The
deuterium labeling experiment A further proved this process in
the Rh(I) catalytic cycle (Scheme 1I, I → II).20 Deuterium
labeling experiments B and C ruled out another possible route to
the aryl−rhodium species from byproduct 4 via C−H activation.
Experiment D indicated that cyclization product 5 could be
partially converted to isoquinolone 3a in the absence of acid. It
was in accordance with the experiment result of the model
reaction of 1a and 2a (Table 1, entry 2). Unexpectedly, the
annulation reaction of 1a and prepared carbodiimide 1319d
failed under standard conditions II (Scheme 1E). In other
words, the three-component reaction cannot be described as an
intermolecular cyclization of BCBs with carbodiimides
generated in situ. The results of experiments F and G revealed
that the isoquinolin-1(2H)-imines cannot be obtained through a
tandem reaction of BCBs with azides and then with isonitriles.
Experiment H might be explained by the insertion of isonitrile
10a into the aryl−rhodium(I) bond of intermediate II being a
fast and reversible process (Scheme 1I). Moreover, to our
Figure 4. Synthesis of antibreast cancer agents.
Through the annulation of BCBs with isocyanates, an amide
motif (−CONR−) can be inserted into a C−C bond efficiently.
Encouraged by this finding, we searched for other nitrogenous
molecular motifs that can be introduced into the corresponding
heterocyclic products by exploiting the same “cut and sew”
strategy.12a Unfortunately, the analogues of isocyanates, such as
thioisocyanates and carbodiimides, cannot be used driectly in
this transformation after multiple attempts. In consideration of
the fact that the inserted molecular segment is derived from not
only one reactant but also several substrates, the main emphasis
of our research shifted to developing mutilcomponent reactions
in this field. As we know, carbodiimide intermediates, especially
some unstable ones, which were recently used in coupling
reactions, can be conveniently generated from transition-metal-
catalyzed nitrene transformation of azides with isonitriles.18,19
Hence, we investigated the three-component reaction of BCB
1a, 1,3-dimethylphenyl isonitrile 10a, and tosyl azide 11a. The
reaction was performed successfully by the same Rh(I) catalysis,
but replacing the DCE solvent with toluene and increasing the
C
DOI: 10.1021/acs.orglett.8b03653
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Mechanistic Studies and Discussion
Detailed experimental procedures, characterization data,
1
and copies of H and 13C NMR spectra for all new
products (PDF)
Accession Codes
CCDC 1866730 (12e) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiaoqing@tmmu.edu.cn.
ORCID
Qing Xiao: 0000-0002-9019-937X
Author Contributions
†Y.H. and C.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by The National Key
Research and Development Program of China (Grant No.
2018YFA0507900), the Scientific Research Foundation for
High-Level Talent Introduction Plan (Grant No. XZ215429),
and the Foundation for Transformation of Sci-tech Achieve-
ments (Grant No. 2016XZH02) of Third Military Medical
University.
knowledge, because of the relative electron deficiency of the
metal center, intermediate V is more reactive to decompose
azide 11a for nitrene formation than intermediate II.21 Based on
these facts, we preferred a stepwise catalytic pathway to
illuminate the generation of intermediate VII (Scheme 1I, II
→ V → VI → VII). In addition, the confirmed structure of 12e
and the excellent regioselectivity of the reaction might be
rationalized by the [1,3]-migration22 and the follow-up insertion
from intermediate VII to intermediate IX (Scheme 1I).
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03653.
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DOI: 10.1021/acs.orglett.8b03653
Org. Lett. XXXX, XXX, XXX−XXX