Catalytic Ring Expansion of Activated Heteroarenes Enabled by Regioselective Dearomatization

Regioselective Dearomatization

Letter

Catalytic Ring Expansion of Activated Heteroarenes Enabled by

Jiyoung Kim and Eun Jeong Yoo *

Cite This: Org. Lett. 2021, 23, 4256 −4260

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sı Supporting Information

ABSTRACT: Catalytic ring expansion of activated heteroarenes through 1,4-

dearomative addition of diazoacetates was established for the construction of various

fused azepines by an elaborate control of the reaction kinetics at each step. The use

of a silver catalyst was essential to drive the overall reaction for generating the

desired seven-membered azepines. Because of the excellent substrate scope and

selectivity, the developed methodology presents an innovative approach for the

synthesis of multifused azepines, which are biologically relevant molecules.

even-membered heterocyclic compounds, especially aze-

and careful preliminary consideration was required before

initiating the investigation.

pines or diazepines, are privileged structures in natural

products and potent pharmacophores. In particular, azepine

frameworks fused with another heterocycle are frequently

responsible for outstanding biological activities in humans and

1,2-Dearomative ring expansion of a quinolinium zwitterion,

as reported previously (Scheme 1B, (b)), and the cyclo-

addition of quinolinium zwitterions and diazo compounds

were considered as the predominant pathways (Scheme 1B,

(c)). It was already observed that the nucleophilicity of

quinolinium zwitterions was suﬃcient to attack the pregen-

livestock. Hence, synthetic methods that provide easy access

to azepine derivatives or their precursors have received

signiﬁcant attention in ﬁelds such as organic synthesis,

pharmaceutical chemistry, and the animal feed industry.

To construct medium-sized azepine derivatives, ring

expansion via ring opening of fused cyclic systems is

considered an eﬀective approach. In particular, methods for

the introduction of cyclopropane-containing intermediates by

employing diazo compounds, which are thermodynamically

driven by releasing nitrogen gas, have received considerable

attention (Scheme 1A). In the early stages, unsafe diazo-

methane or its Grignard form was used as a source of C1 from

quinolinium salts to induce the formation of reactive

erated carbenoid species. Hence, it was crucial to establish

the reaction conditions that could regulate the kinetics of each

step. In other words, it was necessary to establish reaction

conditions, especially a catalyst, in the presence of which the

,4-dearomative addition of diazoacetates preceded the release

of nitrogen gas (r > r ).

Considering the plausible reaction pathways, we attempted

to develop a ring-expansion reaction via regioselective

dearomatization with a quinolinium zwitterion (1a) and

ethyl diazoacetate (2a) as the starting materials (Table 1).

First, rhodium(II), gold(I), and copper(I) catalysts were

cyclopropane intermediates, followed by ring expansion.

employed for the generation of a carbenoid species, a key

The use of TMS-diazomethane is eﬀective in synthesizing

intermediate, from the diazo compound (2a) (entries 1−3).

However, the desired product was not obtained, presumably

due to the extremely rapid generation of the corresponding

carbenoid. Interestingly, in the presence of silver catalysts,

azepines from quinoline derivatives; however, the developed

method could not be used to prepare diverse derivatives.

Although various other strategies such as the use of

diazoacetate have also been employed, all previous studies

hardly known to generate carbenoids of diazoacetates, the

essentially extend the 1,2-addition reaction of diazo com-

reaction produced azepine derivative 3a. The structure of the

obtained azepine (3a) was conﬁrmed by NMR and X-ray

pounds to imine compounds, i.e., ring expansion via 1,2-

dearomative addition. Herein, for the ﬁrst time, we describe

the regioselective 1,4-dearomative ring expansion of quinoli-

nium zwitterions which provides access to a variety of azepine

derivatives that are otherwise diﬃcult to synthesize (Scheme

analyses of its single-molecule crystal. AgPF , AgOTf, and

AgOBz catalyzed the reaction of the quinolinium zwitterion

Received: April 9, 2021

Published: May 24, 2021

B, (a)).

As a part of our ongoing study on the regiodivergent

reactions of N-aromatic compounds, we focused on the ring

expansions of quinolinium derivatives via a 1,4-dearomative

reaction, which has not been investigated to date. However,

undesired but plausible reaction pathways were anticipated,

2021 American Chemical Society

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Org. Lett. 2021, 23, 4256−4260

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Letter

Scheme 1. Strategies to Synthesize Azepines

Fortunately, silver catalysts with a counteranion of a

benzoate derivative bearing an electron-withdrawing group

(

e.g., F, Cl, or NO ) signiﬁcantly improved the reaction

eﬃciency and aﬀorded product 3a in high yields. When 5 mol

of silver 3,5-dinitrobenzoate was added to the THF solution

of the quinolinium zwitterion and ethyl diazoacetate, product

a was obtained in 83% yield (entry 9). The reaction did not

proceed in the presence of an inorganic base (entry 10) or

organic base (entry 11). Hence, it was already evident that

silver played a crucial role in this reaction.

With the optimized reaction conditions in hand, we explored

the scope of both reactants for synthesizing the azepine

derivatives (Scheme 2). First, electronic and steric variations

(

R ) were introduced on the quinolinium moiety of the

zwitterion to understand their eﬀect on silver catalysis. The 5-

bromoquinolinium zwitterion, which could be used for further

transformations, participated in this catalytic reaction to give

the desired product (3b) in 58% yield. The 6-methoxyquino-

linium zwitterion smoothly reacted with ethyl diazoacetate to

aﬀord the corresponding product (3c) in 62% yield. In

contrast to an electron-rich substituent, the quinolinium

zwitterion bearing the electron-deﬁcient ﬂuoro group on an

identical position required 10 mol % of silver catalyst and 4.0

equiv of the reacting partner (2a) to aﬀord a similar yield of

product 3d. The 8-methoxyquinolinium zwitterion also

aﬀorded the desired product 3e in a satisfying yield, although

the product was too unstable to be isolated by silica gel column

chromatography. Addition of 1.5 equiv of K CO after the

completion of catalysis aﬀorded the detosylated compound

(

3e′) in 46% yield. It was also noteworthy that the zwitterion

derived from 1,7-phenanthroline transformed into the fused

seven-membered azepine derivative 3f in 66% yield, albeit

requiring a higher amount of the catalyst. Compounds with

Table 1. Optimization of the Ring-Expansion Reaction

modiﬁcation (R ) on the enamine moiety of the zwitterions

were also tolerated. Para-tert-butylphenyl- and para-triﬂuor-

omethylphenyl groups on R of the zwitterions did not

inﬂuence the eﬃciency of this silver-catalyzed reaction, and the

desired products 3g and 3h were obtained in 65% and 73%

yields, respectively. Comparing products 3i and 3j, it was

observed that the electronic feature of the meta-substituted

entry

catalyst

additive

yield (%)

phenyl group on R slightly aﬀected product yields, and the

zwitterion with the electron-deﬁcient ﬂuoro substituent was

readily converted into the desired product 3j in 83% yield. In

addition, ortho-ﬂuoro and 3,5-diﬂuoro substituents were well

tolerated under the optimized reaction conditions. Conversely,

electronic variations of the sulfonyl group on the quinolinium

zwitterions dramatically inﬂuenced the overall yield. Con-

sequently, products (3m and 3n) with neutral- or electron-rich

sulfonyl groups on the nitrogen atom were obtained in

acceptable yields.

Evidently, the scope of the diazoacetates in this reaction is

quite broad. Primary, secondary, and even tertiary alkyl

diazoacetates could be employed as substrates for the ring-

expansion reaction to aﬀord the desired products (3p−3t) in

high yields under the optimized reaction conditions. The

compatibility of the diazo compounds is an outstanding feature

of this reaction and is distinct from previously reported

strategies. Further, para-methoxyphenyl diazoacetate was

reacted with the quinolinium zwitterion (1a) to furnish the

desired product (3u) in 50% yield under slightly modiﬁed

reaction conditions.

Rh (OPiv)

IPrAuCl

CuCl

AgPF₆

AgOTf

AgOBz

Ag[O C(4-FC H )]

Ag[O C(4-NO C H )]

Ag[O C(3,5-(NO ) C H )]

NaOBz

DBU

Reaction conditions: 1a (0.2 mmol), 2a (3.0 equiv), catalyst (5 mol

), additive (1.3 equiv), and THF (4 mL) at 35 °C for 12 h. Isolated

yields.

(

1a) with ethyl diazoacetate (2a) to aﬀord the desired product

3a) in ∼50% yield; slight diﬀerences in the yields were

observed with these catalysts (entries 4−6). To improve the

yield of the desired product (3a), several silver salts derived

from silver benzoate were synthesized and employed in the

reaction (entries 7−9).

To verify further synthetic utility of the developed

methodology, general transformations were examined. As

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Org. Lett. 2021, 23, 4256−4260

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Letter

Scheme 2. Silver-Catalyzed Ring-Expansion Reactions of N-

Aromatic Zwitterions and Diazoacetates

Scheme 3. Synthetic Applications

a,b

When treated with DIBAL-H, the ester group of compound 4

was reduced to an alcohol (6) in high yield. Moreover, the

alcohol functional group of compound 6 was converted into

alkyl chloride (7) in appreciable yield under Appel reaction

condtions.

Next, we investigated the detailed mechanism of the

developed ring-expansion reaction. As shown in Scheme 4, a

series of isotope-labeling experiments were conducted. Under

the optimized reaction conditions, the deuterium-labeled

quinolinium zwitterion (1a-D) reacted with ethyl diazoacetate

(

2a) to give the seven-membered product 3a -D, in which

deuterium was quantitatively incorporated in the identiﬁed

position. In contrast, the reaction between the quinolinium

zwitterion (1a) and ethyl diazoacetate labeled with deuterium

(

2a-D) did not result in deuterium incorporation in the

product (3a) under identical reaction conditions. Interestingly,

when unlabeled reactants were stirred with the silver catalyst in

a THF−D O (40:1) mixture, the product (3a -D) with

deuterium incorporated at the 3-position was aﬀorded.

Applying our previously reported method, cyclopropane-

fused heterocyclic compound 8 was successfully synthesized to

examine the ring-opening reaction. However, compound 8 was

too stable to be converted to the desired compound under the

standard reaction conditions. In fact, we recovered compound

8, which did not react even when treated with stronger bases.

Thus, the reaction pathway in which both cyclopropane and

imidazole were formed ﬁrst, followed by ring expansion, was

tentatively ruled out. Other diazo compounds, referred to as

acceptor−donor or acceptor−acceptor substituted, did not

react with the quinolinium zwitterion (1a) under the

Reaction conditions: 1 (0.2 mmol), 2 (3.0 equiv), silver catalyst (5

mol %), and THF (4 mL) at 35 °C for 12 h. Isolated yields. 4.0

equiv of 2 and 10 mol % of silver catalyst were used. H NMR yield

based on the dibromomethane internal standard.

shown in Scheme 3, the gram-scale reaction conducted with 1a

as the starting material proceeded smoothly to give the desired

product (3a), without any signiﬁcant loss of yield. As

mentioned before, deprotection of the sulfonyl group of the

obtained product (3a) was quantitatively achieved by adding

optimized reaction conditions; only diazoacetates were

compatible in this catalysis. In addition, we observed that the

diazoacetate anion was formed when diazoacetate was stirred

with a stoichiometric amount of silver salt regardless of the

.5 equiv of K CO to give compound 4, which was stable

2 3

enough to easily transform into other functionalized products.

Regioselective reduction reactions of compound 4 were also

accomplished. In the presence of a Pd/C catalyst and hydrogen

gas (1 atm), the conjugated carbon−carbon double bond of

compound 4 was selectively reduced to a single bond (5).

presence of the zwitterion. While exploring the substrate

scope, we were pleased to isolate side-product 9 with a

carbon−carbon double bond at the C4-position of the

quinoline moiety. These results strongly suggest that the

anion generated from the diazoacetate attacked the C4-

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Org. Lett. 2021, 23, 4256−4260

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The Supporting Information is available free of charge at

Letter

Scheme 4. Investigation of the Plausible Mechanism

(2′). However, this possibility was carefully excluded based on

the results of the mechanistic investigations, particularly the

results of the reaction employing disubstituted diazo

compounds. Following this, the reaction of a silver catalyst

accompanied by N release to generate silver-carbenoid Int II

is proposed (at this point, Int I or Int II can be converted into

a separable side product). Int II can then be readily

transformed into Int III through intramolecular cyclopropa-

nation via iminium formation. Afterward, ring expansion

proceeds via the neutralization of iminium-type Int III along

with regeneration of the silver catalyst for another cycle. It is

noteworthy that this route is consistent with the good yields

obtained using the zwitterions substituted with electron-poor

R . Finally, Int IV undergoes intramolecular hydroamination to

aﬀord the ﬁnal product (3).

In conclusion, a regioselective silver(I)-catalyzed reaction for

easy access to 4-substituted azepine derivatives has been

developed. Mechanistic studies revealed that the entire

catalytic reaction was driven by the ability of the diazoacetate

species to regioselectively undergo 1,4-dearomative addition,

which has been witnessed here for the ﬁrst time. This

methodology demonstrates that N-aromatic zwitterions allow

access not only to fused six-membered cyclic compounds via

simple dearomative strategies but also to their seven-

membered analogues via successive ring expansion. Further

related studies utilizing N-aromatic zwitterions and their

skeletal restructuring are currently underway in our laboratory.

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01173 .

Experimental procedures and analytical data (PDF)

position of the quinolinium zwitterion to aﬀord regioselective

Accession Codes

,4-dearomatization.

Based on the experimental results and reported literature,

CCDC 2060953 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

catalytic mechanism is proposed (Scheme 5). First, diazo-

acetate (2) is converted into the anionic form (2′) under the

reaction conditions, which regioselectively attacks the N-

aromatic zwitterion (1) to generate Int I possessing the diazo

functional group. We also considered the possibility that

diazoacetate could act as a 1,2-dipole to directly attack the N-

aromatic zwitterions without converting to the anionic form

AUTHOR INFORMATION

Corresponding Author

■

Scheme 5. Proposed Mechanism

Eun Jeong Yoo − Department of Applied Chemistry, Kyung

Hee University, Yongin 17104, Republic of Korea;

orcid.org/0000-0003-4027-2441; Email: ejyoo@

khu.ac.kr

Author

Jiyoung Kim − Department of Applied Chemistry, Kyung Hee

University, Yongin 17104, Republic of Korea

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01173

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

This research was supported by the National Research

Foundation of Korea (NRF) (grant nos. NRF-

■

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Org. Lett. 2021, 23, 4256−4260

Organic Letters

Zhang, T.; Zhong, K.; Xiong, Q.; Shen, B.; Liu, S.; Lan, Y.; Bai, R.

Letter

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Nucleophilicity versus Brønsted Basicity Controlled Chemoselectiv-

ity: Mechanistic Insight into Silver- or Scandium-Catalyzed Diazo

Functionalization. ACS Catal. 2020, 10, 1256. For silver(I)-catalyzed

reactions of ethyl diazoacetate, see: (d) Dias, H. V. R.; Browning, R.

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Alkyl Halides via a Silver-Catalyzed Carbene Insertion Process. J. Am.

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by the Korean government. This work was also supported by

the GRRC program of Gyeonggi Province (GRRCKyun-

gHee2017-A01).

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