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org/OrgLett Letter

Expeditious Synthesis of Spiroindoline Derivatives via Tandem

C(sp2)−H and C(sp3)−H Bond Functionalization of
N‑Methyl‑N‑nitrosoanilines
Kelin Wang, Yuqian Sun, Bin Li, Xinying Zhang,* and Xuesen Fan*
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ABSTRACT: Presented herein is a novel synthesis of pharmaceutically privileged spiroindoline derivatives via cascade reactions of
N-methyl-N-nitrosoanilines with diazo homophthalimides. A group of mechanistic studies disclosed that the formation of product
involves an unusual reaction mode of N-methyl-N-nitrosoaniline featuring an initial C(sp2)−H bond activation/alkylation followed
by a C(sp3)−H bond activation/spiroannulation. To our knowledge, this is the first example in which N-methyl-N-nitrosoaniline
acts as a C3N1 synthon to accomplish formal [4+1] spiroannulation with the participation of the N-methyl unit rather than the
previously reported C2N1 synthon to undergo formal [3+2] annulation without the participation of the N-methyl unit. In general,
this newly developed synthetic protocol features simple and readily accessible starting materials, valuable products, unique reaction
mechanism, high efficiency and atom-economy, excellent compatibility with diverse functional groups, and ready scalability.

S pirocyclic skeletons featuring high rigidity and unique

three-dimensional geometries are ideal probes to inter-
rogate protein targets. In many cases, incorporating a spiro unit
into organic molecules could substantially enhance the
feasibility of drug discovery.1 Moreover, by taking advantage
of their rigidity and three-dimensional structure, chemists have
developed spiro compounds as effective ligand and catalyst
motifs for asymmetric synthesis. Among various spiroheter-
ocyclic scaffolds, spiroindoline constitutes the essential
structural backbone of numerous pharmaceuticals and natural
alkaloids.2 Some representative examples in this context are
listed in Figure 1. In addition, spiroindolines possess versatile
reactivity and have thus been used as precursors for the
preparation of a wide variety of fine chemicals. Due to their Figure 1. Some biologically significant spiroindoline derivatives.
importance, reliable methods for the construction of spiroindo-
line scaffolds are urgently needed.
So far, the preparation of spiroindoline derivatives still
remains as a hot topic due to the fact that new spiroindoline
scaffolds are highly valuable for the organic synthesis and Received: February 24, 2024
medicinal chemistry.3 Through unremitting efforts, chemists Revised: March 18, 2024
have managed to develop some intramolecular and inter- Accepted: April 2, 2024
molecular reactions including cycloaddition, condensation/
cyclization, and dearomatization of specific indole or indoline
precursors to construct the spiroindole scaffolds. While these

© XXXX American Chemical Society https://doi.org/10.1021/acs.orglett.4c00703

A Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

literature methods are generally reliable, they more or less Scheme 1b to undergo a simple C−H arylation to furnish
suffer from limitations such as tedious preparation of the product B. Herein, we report the detailed results we obtained
starting materials, narrow substrate scopes, low efficiency, and in this regard.
atom-economy. Therefore, the development of novel synthetic Our study was commenced by treating 1a with 2a in the
protocols allowing more concise and sustainable synthesis of presence of [RhCp*Cl2]2 and AgOAc in HFIP at 80 °C under
spiroindoline derivatives from simple and readily accessible air for 0.5 h. From this reaction, to our surprise, neither
starting materials is currently highly desirable. product A nor product B as depicted in Scheme 1c was
In the past several decades, direct C−H bond activation obtained. Meanwhile, the totally unexpected spiroindoline
(CHA) reactions have been developed as a robust tool for derivative 3aa was formed in 40% yield (Table 1, entry 1).
streamlining organic synthesis owing to their efficient,
economical and sustainable nature.4 To date, CHA reactions Table 1. Optimization Study for the Formation of 3aaa
have significantly facilitated the synthesis of numerous natural
products, medicines, agrochemicals, and functional materials
by providing step- and atom-economical synthetic methods.
Meanwhile, it is worth noting herein that C−H bonds are
omnipresent in organic compounds and often located in
similar chemical and spatial environments. Therefore, differ- Yield
Entry Catalyst Additive(s) Solvent (%)b
entiation among the various C−H bonds in the same
substrates can be dauntingly challenging. In recent years, 1 [RhCp*Cl2]2 AgOAc HFIP 40
significant advances in overcoming this challenge have been 2 [RhCp*Cl2]2 AgOAc TFE ND
made by seeking the assistance of directing groups (DGs) to 3 [RhCp*Cl2]2 AgOAc MeOH ND
guarantee proximity-driven regioselectivity and chelation- 4 [RhCp*Cl2]2 AgOAc toluene ND
facilitated reactivity. In this regard, the nitroso group in N- 5 [RhCp*Cl2]2 AgOAc dioxane ND
nitrosoanilines has emerged as an outstanding DG for CHA 6 [RhCp*Cl2]2 CsOAc HFIP 43
reactions since it can not only be conveniently introduced and 7 [RhCp*Cl2]2 NaOAc HFIP 40
8 [RhCp*Cl2]2 Zn(OAc)2 HFIP 44
uninstalled but also readily coordinates with TM catalysts to
9 [RhCp*Cl2]2 AgSbF6 HFIP ND
assist the cleavage of the proximal C(sp2)−H bonds.5,6 In this
10 [RhCp*Cl2]2 Cu(OAc)2 HFIP 54
regard, Zhu et al. developed an effective method for the
11 [RhCp*Cl2]2 Cu(OAc)2/PivOH HFIP 40
preparation of functionalized indole derivatives by using N-
12 [RhCp*Cl2]2 Cu(OAc)2/HOAc HFIP 45
methyl-N-nitrosoaniline as a C2N1 synthon to undergo formal
13 [RhCp*Cl2]2 Cu(OAc)2/ HFIP 60
[3+2] annulation with α-diazo-β-keto compounds (Scheme TEMPO
1a).6d 14 [RhCp*Cl2]2 Cu(OAc)2/TBHP HFIP 36
15 CoCp*(CO)I2 Cu(OAc)2/ HFIP ND
Scheme 1. C−H Functionalization Reactions of N-Methyl- TEMPO
N-nitrosoaniline 16 [IrCp*Cl2]2 Cu(OAc)2/ HFIP ND
TEMPO
17 [Ru(p-cymene) Cu(OAc)2/ HFIP ND
Cl2]2 TEMPO
18c [RhCp*Cl2]2 Cu(OAc)2/ HFIP 72
TEMPO
19c,d [RhCp*Cl2]2 Cu(OAc)2/ HFIP 82
TEMPO
20c,d Cu(OAc)2/ HFIP ND
TEMPO
21c,d [RhCp*Cl2]2 TEMPO HFIP ND
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (5
mol %), additive 1 (0.4 mmol), additive 2 (0.2 mmol), solvent (2
mL), 80 °C, air, 0.5 h. bIsolated yields. cUnder O2. dTEMPO (0.1
mmol).
More recently, Yan et al. reported a regioselective ortho C−
H insertion of N-nitrosoanilines with naphthoquinone
carbenes to afford the corresponding arylation product Notwithstanding that our initially designed reactions were
(Scheme 1b).6g In this context, we have developed a unsuccessful, we realized that the formation of 3aa should be
condition-controlled selective synthesis of pyranone-tethered much more rewarding. As described above, the spiroindoline
indazoles or carbazole derivatives via the cascade reactions of scaffold is highly valuable for drug development, and the
N-nitrosoanilines with iodonium ylides.7a Inspired by these concise synthesis of such spirocyclic compounds from simple
pioneering studies and as a continuation of our interests in substrates is still rare. Based on its structure, we deduced that
CHA-initiated annulation and spiroannulation,7,8 we have the formation of 3aa should involve a novel reaction mode of
designed a reaction of N-methyl-N-nitrosoaniline with diazo N-methyl-N-nitrosoaniline featuring an initial C(sp2)−H bond
homophthalimide.9 We were curious whether diazo homo- activation/alkylation followed by C(sp3)−H bond activation/
phthalimide would follow the reaction pattern of a α-diazo-β- spiroannulation. To our knowledge, this is the first example in
keto compound as shown in Scheme 1a to undergo an which N-methyl-N-nitrosoaniline acts as a C3N1 synthon to
alkylation/annulation cascade reaction with N-methyl-N-nitro- accomplish formal [4+1] spiroannulation with the participa-
soaniline to give formal [3+2] annulation product A, or follow tion of the N-methyl unit rather than the previously reported
the reaction pattern of diazonaphthoquinone as shown in C2N1 synthon to undergo formal [3+2] annulation without
B https://doi.org/10.1021/acs.orglett.4c00703
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

the participation of the N-methyl unit. Therefore, this reaction Scheme 2. Substrate Scope of Diazo Homophthalimides for
deserves a systematic study from the perspective of both the the Synthesis of 3a,b
reaction mechanism and synthetic application.
To develop this reaction into a reliable synthetic protocol,
various conditions were evaluated, and the results thus
obtained were summarized in Table 1. First, TFE, methanol,
toluene, and 1,4-dioxane were tested as the reaction medium.
Unfortunately, they were found to be ineffective for this
cascade reaction (entries 2−5). Second, the effect of CsOAc,
NaOAc, Zn(OAc)2, AgSbF6, or Cu(OAc)2 as an additive was
examined (entries 6−10). In the presence of Cu(OAc)2, the
yield of 3aa increased to 54% (entry 10). In the following
study, PivOH, HOAc, 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO), or tert-butylhydroperoxide (TBHP) was used as
an auxiliary additive (entries 11−14). We were pleased to find
that when TEMPO was used together with Cu(OAc)2, the
yield of 3aa increased to 60% (entry 13). Third, CoCp*-
(CO)I2, [IrCp*Cl2]2, as well as [Ru(p-cymene)Cl2]2 were
tried as a catalyst in place of [RhCp*Cl2]2 (entries 15−17).
However, they were found to be ineffective for the formation
of compound 3aa. On the other hand, when this reaction was
run under oxygen instead of air, the reaction efficiency
increased to 72% (entry 18). Next, the amount of TEMPO was
reduced from 1 to 0.5 equiv under O2. In this case, 3aa was
obtained in an 82% yield (entry 19). Finally, control
experiments showed that in the absence of either [RhCp*Cl2]2
or Cu(OAc)2, the formation of 3aa was not detected (entries
20 and 21). a
With the establishment of the optimal reaction conditions, Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2
the substrate generality of this reaction was investigated. First, (5 mol %), Cu(OAc)2 (0.4 mmol), TEMPO (0.1 mmol), HFIP (2
mL), 80 °C, O2, 0.5 h. bIsolated yields. c2 h.
a group of diversely substituted N-methyl-N-nitrosoanilines 1
was tested using 2a as a model coupling partner. The results
included in Scheme 2 showed that 1 attached with either an and 3va were obtained in reasonably good yields. On the other
electron-donating group (EDG) such as methyl, ethyl, iso- hand, when the methyl group attached on the amino moiety of
propyl, tert-butyl, benzyl, and acetate, or an electron-with- 1 was replaced by an ethyl, propyl, butyl, or benzyl unit, the
drawing group (EWG) such as fluoro, chloro, bromo, iodo, reaction produced a complex mixture, from which the
trifluoromethyl, trifluoromethoxy, and ester on the para-site of spiroindoline product was not obtained.
the phenyl ring of the aniline moiety took part in this reaction After the scope of substrate 1 had been identified, the
smoothly to afford products 3ba−3na in generally good yields. generality of coupling partner 2 for this reaction was
The good tolerance of alkoxy, halide, and ester groups investigated by using 1a as a model substrate. It was thus
manifested the mild nature of this reaction and provided found that 2 tethered with various alkyl units such as ethyl,
possible reaction sites for structural derivation of the products. propyl, isopropyl, or benzyl on their N-1 site (as R2) reacted
Generally speaking, this reaction showed some electronic effect with 1a smoothly to give the corresponding products 3ab, 3ac,
in that substrates 1 bearing EDGs furnished the corresponding 3ad, and 3ae in moderate yields (Scheme 3). Subsequent
products in higher yields than those bearing EWGs. For 1 studies showed that, in addition to alkyl groups, diazo
bearing a meta-methyl substituted phenyl unit, its reaction with homophthalimides 2 attached with a phenyl, 4-methylphenyl,
2a occurred on the less sterically hindered site to generate 4-ethylphenyl, 4-tert-butyl phenyl, 4-fluorophenyl, 4-chloro-
product 3oa in comparable efficiency. On the other hand, 1 phenyl, 4-bromophenyl, or 4-trifluoromethylphenyl group on
bearing a meta-fluoro, meta-chloro, or 3-fluoro-4-methyl- their N-1 site could also react with 1a to furnish products 3af−
substituted phenyl moiety chose to react with 2a on the 3am in good yields. Moreover, 2 bearing a methyl group on
more crowed ortho-position to afford 3pa, 3qa, and 3ra, most the 6-position of the isoquinolinedione skeleton participated in
likely due to the auxiliary directing effect of the strongly the reaction smoothly to give product 3an. Interestingly, when
electronegative fluorine or chlorine atom. Interestingly, diazopyrazolones were used as the diazo coupling partners to
substrates 1 derived from naphthalene and dibenzo[b,d]- react with 1a, the desired spiroindoline products 3ao and 3ap
thiophene were also competent for this reaction to furnish were successfully generated, albeit in lower yields. Notably,
products 3sa and 3ta. In addition, it is acknowledged that methyl phenyldiazoacetate, diazoacetoacetone, methyl diazo-
natural products and known pharmaceutical molecular frame- acetoacetate, and dimethyl diazomalonate have also been tried
works are highly valuable for drug development. Recently, the to react with 1a under standard conditions. In these cases, part
inclusion of these chemotypes in the creation of novel lead of the substrates remained intact and complex mixtures were
compounds has been revitalizing strong interest. To provide generated, from which the desired indoline products were not
more opportunities for drug discovery, the structural derivation obtained.
of thymol and menthol was explored by using this novel To probe the reaction mechanism, a group of mechanistic
spiroannulation strategy. As a result, hybrid compounds 3ua studies were carried out. First, 1a was subjected to the standard
C https://doi.org/10.1021/acs.orglett.4c00703
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 3. Substrate Scope of Nitrosoanilines for the exchange at the unreacted ortho-site of the phenyl moiety of
Synthesis of 3a,b 3aa was observed (Scheme 4b), suggesting that the C−H bond
alkylation step should proceed much faster than the C−H
bond cleavage. Third, a mixture of 1a/1a-d8 or 1a/1a-d3 was
treated with 2a under standard reaction conditions (Schemes
4c and 4d). From these competing reactions, kH/kD values of
5.7 and 2.2 were observed, respectively. These results reveal
that both the Csp2−H bond cleavage and the Csp3−H bond
cleavage might have been involved in the rate-limiting steps in
the formation of 3aa. Fourth, competition experiments with
regard to the electronic effect showed that 4-Me-substituted
substrate 1b reacted with 2a five times faster than its 4-CF3-
substituted analogue 1l (Scheme 4e). In other words, the
presence of an electron-donating group on the phenyl ring
accelerates the reaction substantially. It is thus deduced that an
electrophilic aromatic substitution pathway might have been
involved for the CHA process.
In another set of mechanistic studies, a five-membered
rhodacycle species A was prepared from the reaction of 1j with
[RhCp*Cl2]2.10 A was then used as a catalyst for the reaction
of 1j with 2a. From this reaction, product 3ja was obtained in
60% yield (Scheme 5).

a
Scheme 5. Mechanistic Studies (II)
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), [RhCp*Cl2]2
(5 mol %), Cu(OAc)2 (0.4 mmol), TEMPO (0.1 mmol), HFIP (2
mL), 80 °C, O2, 0.5 h. bIsolated yields. c12 h.

conditions in the presence of CD3OD for 10 min, from which

10% deuterium incorporation onto the ortho-positions of the
phenyl ring of 1a was observed (Scheme 4a), indicating that
C−H bond metalation should have taken place, and it is
somewhat reversible. Second, the reaction of 1a with 2a was
carried out in the presence of CD3OD. In this case, no H/D Based on the results obtained herein and those reported
previously,5 a plausible pathway accounting for the formation
Scheme 4. Mechanistic Studies (I) of 3aa was proposed in Scheme 6. Initially, Rh(III)-catalyzed

Scheme 6. Proposed Mechanism for the Formation of 3aa

and nitroso-group-assisted ortho-C−H bond metalation occurs

with 1a to furnish five-membered rhodacycle species I. Next,
the coordination of Rh(III) in I with 2a furnishes carbene
species II through an extrusion of N2. Then, insertion of the
carbene moiety into the C−Rh bond gives intermediate III.
Proto-demetalation of III furnishes intermediate IV, and
releases the Rh(III) catalyst for the next catalytic circle.
Under the reaction conditions, intermediate IV is oxidized into
an iminium intermediate V through Csp3−H bond cleavage.11
D https://doi.org/10.1021/acs.orglett.4c00703
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
The electron-deficient nature of the resultant iminium cation
allows the electron-rich enol to undergo an intramolecular
nucleophilic addition to give product 3aa.11 It is also noted
that the generation of side products through the oxidation
process prior to the ortho-C−H functionalization step was not
observed.
To showcase the synthetic utility of the products thus
obtained, structural elaborations of 3aa were explored. For
CHA reactions, the removal and implementation of the
directing group remaining in the products are very useful.
Thus, 3aa was first treated with SnCl2·2H2O.6e From this
reaction, the denitrosation product 4 was obtained in 75%
yield (Scheme 7a). Notably, the reduction-susceptible carbonyl
Scheme 7. Product Derivations and Gram-Scale Preparation
group embedded therein was intact. Second, 3aa was treated
with thiourea dioxide (TDO) to give nitroso reduction
product 5 (Scheme 7b).12 Finally, the preparation of product
3aa was tried in a scale of 3 mmol. To our delight, the reaction
proceeded effectively to afford 3aa in 72% yield (Scheme 7c),
showing that this method is suitable for a scale-up synthetic
scenario.
In summary, we developed an effective synthesis of
spiroindoline derivatives from the cascade reactions of N-
methyl-N-nitrosoanilines with diazo homophthalimides. This
method is based on an unprecedented reaction mode of N-
methyl-N-nitrosoaniline featuring an initial C(sp2)−H bond
activation/alkylation followed by C(sp3)−H bond activation/
spiroannulation. Compared with literature protocols for the
synthesis of spiroindoline derivatives, this newly developed
method has advantages such as simple and easily accessible
starting materials, unique reaction pathway, mild reaction
conditions, good efficiency, excellent compatibility with diverse
functional groups, and high atom-economy. Studies of more
applications of N-nitrosoanilines as substrates for C−H
activation reactions are currently underway in our laboratory.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its online Supporting Information.
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Experimental procedures, mechanism studies, data, and
copies of the NMR spectra of all products (PDF)
Accession Codes
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data for this paper. These data can be obtained free of charge
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■ AUTHOR INFORMATION
Corresponding Authors
Xinying Zhang − State Key Laboratory of Antiviral Drugs,
Pingyuan Laboratory, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China; orcid.org/0000-0002-3416-
4623; Email: xinyingzhang@htu.cn
Xuesen Fan − State Key Laboratory of Antiviral Drugs,
Pingyuan Laboratory, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China; orcid.org/0000-0002-2040-
6919; Email: xuesen.fan@htu.cn
Authors
Kelin Wang − State Key Laboratory of Antiviral Drugs,
Pingyuan Laboratory, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Yuqian Sun − State Key Laboratory of Antiviral Drugs,
Pingyuan Laboratory, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
Bin Li − State Key Laboratory of Antiviral Drugs, Pingyuan
Laboratory, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Collaborative Innovation
Center of Henan Province for Green Manufacturing of Fine
Chemicals, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.4c00703
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (22101075, U2004189), Postdoctoral Research Grant in
Henan Province (202103085), NMPA Key Laboratory for
Research and Evaluation of Innovative Drug, Henan Key
Laboratory of Organic Functional Molecules and Drug
Innovation, and 111 Project (D17007) for financial support.
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