Access to Benzoxazepines and Fully Substituted Indoles via HDDA Coupling

Xiaojie Zheng, Baohua Liu, Feihu Yang, Qiong Hu, Liangliang Yao, and Yimin Hu*

Letter

Access to Benzoxazepines and Fully Substituted Indoles via HDDA

Coupling

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sı Supporting Information

ABSTRACT: The HDDA-derived benzyne intermediate was captured by

oxazolines based on the addition reaction of benzyne to the CN double

bond. Benzoxazepine derivatives, fused benzoxazepine derivatives, and fully

substituted indoles are synthesized in one step. The reaction does not require

any catalyst or additives. Possible reaction mechanisms are presented.

enzoxazepine, which is formed by fusing oxazepine with a

benzene ring, is generally considered biologically and

protocol for the synthesis of benzoheterocycles [1,4] by using

palladium-catalyzed Heck reactions to obtain vinylogous

carbonates/carbamates. Although these methods are useful

pharmaceutically active. Biological and drug molecules such

as amoxicilin, loxapine, (1,2,3,5-tetrahydro-4,1-benzoxaze-

pine-3-yl)pyrimidines and -purines (with anticancer activity in

and novel, most are limited by the requirement of metal

catalyst and long reaction routes. Indole is another useful

heterocyclic compound that is widely distributed in nature.

Many natural compounds which are closely related to life

activities contain an indole skeleton in their structure. Quite a

MCF-7 cells), bozepinib (a potent and selective anticancer

compound), and TAK 475 (squalene synthase inhibitor)

always contain these structural units (Figure 1 ). Given the

few indole-preparation methods have been reported, while

studies on the preparation of indole via benzyne are

uncommon to ﬁnd. Wang reported the synthesis of

substituted indoles from 2-azidoacrylates and o-silyl aryltri-

ﬂates. He reported the transition-metal-free synthesis of

multisubstituted N-arylindoles through the reaction of arynes

and α-amino ketones.

The hexadehydro-Diels−Alder (HDDA) reaction is a new

method to produce benzyne intermediates named by the Hoye

group in 2012. This reaction is catalyst and additive free, and

cyclization of three alkyne bonds in the molecules can directly

form benzyne intermediates. By intra- or intermolecular

capture, a series of aromatic ring compounds could be

obtained immediately. This approach is a good complement

for preparing benzyne intermediates compared to the tradi-

tional methods because it is compatible with base-sensitive

groups and products that cannot be stable under alkaline

Figure 1. Biological and drug molecules containing benzoxazepine

structures.

complicated structure of benzoxazepine, its synthesis is

relatively challenging. The Tanaka group reported the

formation of seven-membered nitrogen heterocycles through

the cyclization of bromoallenes bearing an oxygen nucleophilic

Received: December 16, 2019

functionality. The Basso group reported the synthesis of

triazolo-fused benzoxazepines and benzoxazepinones through

the Passerini reaction. The Anuradha group reported a

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

and a substrate ratio of 2.1:1 (Figure 3 ). The scope of tetrayne

Letter

conditions. The reaction between benzyne and oxazoline has

not yet been reported. The only example was that the Peng

research group reported the three-component reaction of

traditional benzyne, oxazoline, and chloroform to obtain a

optimized reaction conditions at 115 °C in toluene for 12 h

trichloromethylated oxazoline derivative. In the beginning,

we attempted to use tetrayne as an HDDA-derived benzyne

precursor with 2,4,4- trimethyl-2-oxazoline (2c) to synthesize

N,O heterocyclic compounds. Interestingly, a benzoxazepine

compound 3c containing an outer CC double bond was

obtained (Figure 2 ). The optimal yield could be obtained at

Figure 3. Preparation of fused benzoxazepines. Experimental details

are provided in the Supporting Information: 1i−1l (2.1 mmol, 2.1

equiv), 4,4-dimethyl-2-oxazoline (1.0 mmol, 1.0 equiv), 115 °C,

toluene 5 mL.

substrate was expanded to include X = dimethyl malonate (4i),

diethyl malonate (4j), dipropyl malonate (4k, 4l) and R =

phenyl (4i−k), p-methylphenyl (4l) and achieved excellent

yields (76%−86%) for the four compounds.

When the group at the 2-position of oxazoline was changed

to a phenyl, we selected 2,4-diphenyl-4,5-dihydrooxazole

(

2m−2x) as the reaction substrate and obtained the fully

substituted indole compound 5m−5x for good yields (72−

2%) unexpectedly (Figure 4). To further explore the principle

of this reaction, we reacted 2-phenyl-4,5-dihydrooxazole with

tetrayne substrate. However, it did not produce the expected

fully substituted indole compound. We speculated that the

phenyl at the 4-position of oxazoline may have a crucial eﬀect

on this reaction. The molecular structures of 3c, 4i, and 5n

were conﬁrmed by X-ray diﬀraction.

Based on the above reaction studies, taking the reaction of

tetrayne with 2,4,4-trimethyl-2-oxazoline as an example, we

Figure 2. Preparation of benzoxazepine. Experimental details are

provided in the Supporting Information : 1a−1h (1.0 mmol, 1.0

equiv), oxazolines (1.2 mmol, 1.2 equiv), 100 °C, toluene 5 mL.

speculated the mechanism of the reaction. First, tetrayne

substrate 1 undergoes HDDA reaction and self-cyclization by

free radicals to form the benzyne intermediate A. Combining

the results of our previous research, the β-carbon on the alkyne

bond is preferentially attacked by nucleophiles to take the

electron and steric eﬀects of the reaction substrate into

00 °C in toluene, and the ratio of tetrayne to oxazoline

substrate was 1:1.2; the reaction was carried out for 10 h. It is

worth noting that protic solvents are not compatible with this

reaction. We expanded the scope of tetrayne substrates

subsequently, including X = p-toluenesulfonamide (3a),

dimethyl malonate (3b−3f, 3h), diethyl malonate (3g), R =

n-butyl (3a, 3b), phenyl (3c, 3h), p-methylphenyl (3d, 3g), p-

chlorophenyl (3e), and p-ﬂuorophenyl (3f), and obtained

eight compounds for good yields (76−88%). Considering the

expansion of oxazoline compounds, we reacted tetrayne with

account. According to the molecular structures of 3c by X-

ray diﬀraction, we speculate that the possible explanation is

that nitrogen atom attacks β-carbon preferentially will increase

steric hindrance caused by an alkyl group at 2-position of the

oxazoline with an ortho R group of the α-carbon on an alkyne

bond. Thus, the nitrogen containing the lone pair of electrons

attacks preferentially at the α-carbon on the alkyne bond to

form intermediate B. The β-carbon on alkyne bond attacks the

carbon of the CN double bond to form a quaternary ring

intermediate C. The unstably quaternary ring is opened to

form the intermediate D, accompanied by resonance E via

electron delocalization. Intermediate E is relatively more stable

due to cations stabilized by oxygen with lone-pair electron.

Finally, deprotonation−protonation occurs directly, and

compound 2 is obtained (Scheme 1).

(

4s,5s)-(−)-4-methoxymethyl-2-methyl-5-phenyl-2-oxazoline

(2g), which produced the target compound 3g. It indicated

that the reaction was suitable for 4,5-substituted oxazoline

compounds. We reacted tetrayne with 2-ethyl-2-oxazoline (2h)

to obtain compound 3h. It indicated that the reaction can be

conducted when R containing active hydrogen and oxazoline

has no 4,5-substituent. In addition, we also reacted tetrayne

with 2-methylthiazoline, expecting to get N and S in the

product, but only the nucleophilic addition product of sulfur

atom to benzyne was obtained.

When tetrayne reacted with 4,4-dimethyl-2-oxazoline (2i),

novel fused benzoxazepine derivative 4i was obtained using the

When the 2-substituent of oxazoline is hydrogen, the

nitrogen atom as a nucleophile still attacks the β-carbon

preferentially as normal. In the intermediate F, the electron-

rich benzene ring attacked the carbon cation and the aromatic

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

nucleophilic addition reaction with the product 3 to obtain the

product 4 in ﬁnal form (Scheme 2).

Scheme 2. Proposed Mechanism for the Preparation of

Fused Benzoxazepines (4i−4l)

When the 2,4-disubstituents of oxazoline are phenyl, the

intermediate I is formed through a [2 + 2] cycloaddition

process similar to the case of an alkyl group. Since the negative

charge on nitrogen atom is unstable, deprotonation−

protonation occurred to form the intermediate J. It is

contributed to a conjugate eﬀect for carbanion caused by the

benzene ring at the 4-position, dispersing the negative charges

and stabilizing the structure. The carbanion will combine with

carbocation to form the intermediate K. The unstable ring

opening of the intermediate K will eventually remove a

molecule of HCHO to obtain the fully substituted indole

derivative 5 (Scheme 3).

Scheme 3. Proposed Mechanism for the Preparation of

Fully Substituted Indoles (5m−5x)

In conclusion, we obtained benzoxazepines, fused benzox-

azepine, and fully substituted indoles by using HDDA-derived

benzyne intermediates trapped by substituted oxazoline

compounds when the substituent at the 2-position of oxazoline

is an alkyl, hydrogen, or phenyl group. The reaction displayed

novel features of the representative transformations based on

the insertion reaction of benzyne into the CN double bond

and conducted without any catalyst or additive. Benzoxazepine

derivatives obtained containing an external CC double bond

and seven-membered ring skeleton containing N and O led to

new ideas for the synthesis of complex heterocyclic molecules.

Our team will continue to explore possible applications and

transformation pathways for products.

Figure 4. Preparation of fully substituted indoles. Experimental details

are provided in the Supporting Information: 1m−1x (1.0 mmol, 1.0

equiv), 2,4-diphenyl-4,5 dihydrooxazole (1.2 mmol, 1.2 equiv), 110

°C, toluene 5 mL.

Scheme 1. Proposed Mechanism for the Preparation of

Benzoxazepines (3a−3h)

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.9b04499.

Experimental procedures for all reactions; spectroscopic

characterization data for all new compounds; details of

computational methods; copies of H and C NMR

spectra (PDF)

Accession Codes

CCDC 1939365, 1939371, and 1946590 contain 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.

C−H bond was activated. Deprotonation−protonation oc-

curred subsequently, and fused benzoxazepine derivative 3 was

formed. Another molecular benzyne immediately underwent a

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

ega, A.; Gallo, M.; Espinosa, A.;

Letter

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AUTHOR INFORMATION

■

Corresponding Author

Yimin Hu − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, State Laboratory Cultivation Base, College of

Chemistry and Materials Science, Anhui Normal University,

Wuhu 241002, China; orcid.org/0000-0002-1638-5393;

Email: yiminhu@ahnu.edu.cn

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Baohua Liu − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, State Laboratory Cultivation Base, College of

Chemistry and Materials Science, Anhui Normal University,

Wuhu 241002, China

Feihu Yang − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

Materials, State Laboratory Cultivation Base, College of

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Qiong Hu − Key Laboratory of Functional Molecular Solids,

Ministry of Education, Anhui Laboratory of Molecule-Based

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Liangliang Yao − Key Laboratory of Functional Molecular

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.9b04499

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Notes

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The authors declare no competing ﬁnancial interest.

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ACKNOWLEDGMENTS

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This work was ﬁnancially supported by National Natural

Science Foundation of China (21572002, 21272005) and

Department of Human Resources of Anhui Province.

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Multicomponent Coupling Reaction Induced by Insertion of Arynes

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