Synthesis of Indolizines from Pyridinium Salts and Ethyl Bromodifluoroacetate

Xiaoya Hou, Sen Zhou, Yuli Li, Minjie Guo,* Wentao Zhao, Xiangyang Tang, and Guangwei Wang *

Letter

Synthesis of Indolizines from Pyridinium Salts and Ethyl

Bromodi ﬂ uoroacetate

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03540

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sı Supporting Information

ABSTRACT: Here we present a novel annulation of pyridinium

salts with BrCF CO Et to access the indolizine derivatives with high

eﬃciency. The α substitution of pyridine plays a key role in

determining the reaction pathways. Various types of indolizines can

be conveniently accessed from easily available pyridinium salts

under mild and simple reaction conditions.

N-Heterocycles are ubiquitous structural motifs in natural

products and synthetic pharmaceuticals. Among them,

Scheme 1. Synthesis of Indolizines Starting from Pyridines

indolizine is an important N-fused skeleton which possesses

a pyridine-type six-membered ring condensed with a pyrrole-

type ﬁve-membered ring. The indolizine derivatives are widely

spread in many bioactive and pharmaceutical compounds that

display remarkable biological activities. Generally, indolizines

can be accessed by the following methods: (1) Chichibabin

indolizine synthesis, which involves a base-mediated cycliza-

tion of 1-(2-oxoalkyl)-2-methylpyridinium salts for the syn-

thesis of 2-substituted indolizines (Scheme 1a); (2)

intermolecular cyclization which involves [3 + 2] cyclo-

additions of pyridiniums or C2-substituted pyridines with

various unsaturated substrates such as alkynes, alkenes, and

allenes (Scheme 1b); (3) intramolecular cyclization that

features transition metal catalyzed cycloisomerization reactions

of propargylic pyridines (Scheme 1c). Although there are

many eﬃcient and useful methods for synthesis of indolizines,

there are still some unsolved issues. For example, 2-alkyloxy

indolizines have only been sporadically reported with low

b,c

yields.

Therefore, development of novel and convenient

synthetic strategies toward various biologically active indoli-

zines derivatives is still in great demand.

Fluorine-containing organic compounds have received

widespread attention in recent years due to their speciﬁc

bioactivity and good biocompatibility compared with their

nonﬂuorinated analogues. Fluorine-containing indolizines

have been reported with ﬂuorine in ﬂuoroalkyl motifs or

directly docked on aromatic rings. However, 2-diﬂuorome-

thoxy indolizines have never been reported in previous

literature.

Received: October 23, 2020

Commercially available ethyl halodiﬂuoroacetate

(

XCF CO Et) has been widely used as a diﬂuoroalkylating

2 2

reagent to synthesize various ﬂuorinated compounds in

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

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Letter

medicinal chemistry. Generally, XCF CO Et can serve as a

following reaction parameters were chosen as the optimized

conditions: Cs CO as a base and CH CN as solvent with 5.0

precursor to the ethyl diﬂuoroacetate radical and diﬂuor-

ocarbene species. In addition, XCF CO Et can also serve as a

novel C1 source, the application of which has been explored by

the Song group since 2018. Our group has been devoted to

development of various types of tandem reactions initiated by

equiv of H O at 80 °C for 7 h.

With the optimized conditions in hand, the reaction

compatibility toward various substitutions on the pyridine

ring was explored, and the results were summarized in Scheme

2. Although the model substrate 1a gave a high isolated yield of

diﬂuoromethylation with BrCF CO Et and its derivatives.

Herein, we disclose a novel reaction of BrCF CO Et with

various N-pyridinium salts leading to a series of indolizines.

Depending on the substitution mode of pyridine at α-position,

highly regioselective 1,3-diester substituted indolizines (when

α-position is unsubstituted) or indolizines with a 2-

diﬂuoroalkoxy group (when α-position is substituted by

methyl group) can be obtained (Scheme 1d).

Scheme 2. Scope with Various Pyridinium Salts

We initially treated 1-(2-ethoxy-2-oxoethyl)pyridin-1-ium

bromide (1a) with BrCF CO Et in the presence of Cs CO

and water in acetonitrile (CH CN) at 80 °C for 7 h (Table 1,

Table 1. Optimization of Reaction Conditions

entry

variation from the “standard” conditions

2a (%)

3a (%)

none

without H O

THF, instead of CH CN

94 (91)

CH Cl , instead of CH CN

Tol, instead of CH CN

DMSO, instead of CH CN

NaOH, instead of Cs CO

K PO , instead of Cs CO

K CO , instead of Cs CO

90 (87)

TMEDA, instead of Cs CO

Reaction conditions: 1a (0.5 mmol), BrCF CO Et (0.7 equiv), base

(

1.5 equiv), H O (5.0 equiv) in solvent (2.0 mL) for 7 h under argon

atmosphere. Yields were determined by GC analysis with mesitylene

as an internal standard. The numbers in parentheses are isolated

yields.

entry 1). To our delight, 2a was obtained with a 94% yield.

Water is essential to the reaction since in the absence of water

a low yield of 2a resulted together with 3a as byproduct (Table

Reaction conditions: Unless otherwise noted, all reactions were

, entry 2). Then, various reaction parameters were screened

performed with 1 (1.0 mmol), BrCF CO Et (0.7 equiv), H O (5.0

equiv), Cs CO (1.5 equiv) in CH CN (4 mL) at 80 °C under Ar for

for reaction optimization with 1a and BrCF CO Et as

substrates, and the results were summarized in Table 1.

Other solvents such as tetrahydrofuran (THF), dichloro-

methane (CH Cl ), toluene (Tol), and dimethyl sulfoxide

h. Isolated yields. 90% yield in a 5.0 mmol scale.

(

DMSO) were also tested, but no better results resulted

entries 3−6). Afterward, various bases had been evaluated

91%, the yields drastically decreased to 55% and 44% when 1-

(2-ethoxy-2-oxoethyl)-4-methylpyridin-1-ium bromide (1b)

and 1-(2-ethoxy-2-oxoethyl)-3,5-dimethylpyridin-1-ium bro-

mide (1d) were used as substrates. When the pyridine ring

was substituted at the C3-position, 2c was obtained with a

yield of 83%, which indicates that the C2-position is more

reactive. When the C3-position was substituted with other

groups such as amino, amide, and alkoxy groups, moderate to

good yields resulted for 2e−2k (49−78%) with excellent

regioselectivities. When the pyridine was halogenated at the

C3-position, the reaction still occurred at the C2-position to

aﬀord the corresponding products (2l−2m, 49−52% yields)

with excellent regioselectivities. When the C3-position was

with CH CN as solvent in the presence of 5.0 equiv of water.

NaOH and K PO led to lower yields in this reaction (entries

−8). When K CO was used as a base, product 2a was

obtained with 90% yield, which is similar to that of Cs CO

(

entry 9). When organic base tetramethylethylenediamine

TMEDA) was used, no reaction occurred (entry 10). When

the reaction time was shortened to 5 h, the yield decreased to

0%, and when the reaction time was extended to 16 h, the

yield was 95% with trace byproduct 3a (see Table S1 in the

Supporting Information (SI) for details of reaction conditions

optimization). Based on the above screening results, the

Org. Lett. XXXX, XXX, XXX−XXX

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Letter

substituted by an electron-withdrawing group (e.g., m-COMe,

Scheme 3. Scope with Various 2-Methylpyridinium Salts

m-COPh, m-CO Me), the reaction selectively occurred at the

C6-position with a low yield (2n−2p, 17−25%). Substrates

with other electron-withdrawing groups on the pyridine ring

(

e.g., m-CONH , CONHBn, m-CHO, m-F, p-CN) or other

substituents on nitrogen (e.g., N-cyanomethyl salt, N-2-oxo-2-

phenylethyl salt) have also been subjected to the current

conditions; however, the reactions are messy and no desired

products can be isolated. A detailed discussion on

regioselectivity of m-substituted pyridinium salts and reaction

of more substrates is included in the SI (see Schemes S1 −S3).

When we used the collidine-derived salt (4a) instead of 1a,

the product 5a was obtained in 70% isolated yield. The

reaction conditions were optimized, and the yield can be

improved to 99% in the absence of water at 50 °C (see Table

S2 in the Supporting Information for details of reaction

conditions optimization). Next, the substrate scope of this

reaction was explored, and the results were summarized in

Scheme 3. First, the eﬀect of the methyl position on pyridine

was investigated. When the methyl groups were present at both

C2- and C6-positions of pyridiniums, the yields were excellent

(

5a, 99% and 5b, 97%). However, when there was no methyl

group at the C6-position of pyridiniums, the yields decreased

to moderate levels (5c, 61% and 5d, 45%). Quinolinium salts

were also investigated, and 1-(2-ethoxy-2-oxoethyl)-2-methyl-

quinolin-1-ium bromide (4e) and 1-(2-ethoxy-2-oxoethyl)-

,6,7,8-tetrahydroquinolin-1-ium bromide (4f) under these

reaction conditions led to the desired products 5e and 5f in

4% and 99% yield, respectively. Therefore, the substitutions

on the C2- and C6-positions of pyridinium salts were beneﬁcial

to this reaction. A series of pyridinium salts substituted with

methyl groups at both C2- and C6-positions were prepared

(

4g−4p) and subjected to the optimized conditions. Gratify-

ingly, diﬀerent ether substitutions (such as alkyl, propargyl,

allyl, benzyl, and ester groups) on the C4-position of 2,6-

dimethylpyridinium salts could be well tolerated with the

target products being obtained in moderate yields ranging from

2% to 74% (5g−5n). However, when the bromine atom was

attached to the alkyloxy group, the yields slightly decreased to

7−57% (5o−5p). When 2-(2-methoxy-2-oxoethyl)-1-meth-

ylisoquinolin-2-ium bromide was subjected to the same

Reaction conditions: Unless otherwise noted, all reactions were

conditions, the desired product 2-(diﬂuoromethoxy)pyrrolo-

performed with 4 (1.0 mmol), BrCF CO Et (1.1 equiv), Cs CO (1.5

[2,1-a]isoquinoline was obtained together with ester group

equiv) in CH CN (4 mL) at 50 °C under Ar for 7 h. Isolated yields.

substituted byproducts (see Scheme S4 in the Supporting

Information for the reaction details).

92% yield in a 4.0 mmol scale.

To clarify the reaction mechanism of these transformations,

a series of control experiments were carried out. For the

reaction of 1a, three additional carbons were installed, which

might come from another molecule of pyridinium salt, or

BrCF CO Et, or both. When we treated compound 1a under

Scheme 4. Control Experiments for Mechanistic Studies

the optimized conditions in the absence of BrCF CO Et, no 2a

resulted. This implied that BrCF CO Et was essential to

formation of 2a, and at least one carbon was derived from

BrCF CO Et. In order to prove the origin of the esters in

product 2a, 1a-Me with methyl ester was synthesized and

subjected to the optimized conditions except in the absence of

water (Scheme 4a). Two products were obtained with the yield

of 2a-Me being 19% and the yield of 3a-Me being 12%. The

ethyl ester of indolizine at C2 implies that the C2 originates

from BrCF CO Et while the other two methyl esters originate

from pyridinium salt 1a-Me. Besides, GC analysis of the

reaction indicates that pyridine was formed, which suggested

that the reaction involved the participation of another

Yield and ratio were determined by GC analysis with mesitylene as

an internal standard. Isolated yields.

Org. Lett. XXXX, XXX, XXX−XXX

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the Supporting Information .

Letter

molecule of pyridinium salt 1a with the release of a pyridine

molecule. For a detailed discussion, see Scheme S5 in the

Supporting Information.

the presence of base will lead to diester 2. In the absence of

water, 3a can be aﬀorded which indicates that the reaction

might proceed through other pathways.

For compounds 4 with α-substitution, the α-deprotonation

become preferred. It is possible that compound 4 can undergo

base catalyzed intramolecular cyclization to aﬀord 8, which can

capture diﬂuorocarbene from BrCF CO Et to aﬀord 5.

When R is CH , the anion I’ resulted which undergoes

intramolecular cyclization to result in intermediate J. Then

tautomerization of J followed by capture of diﬂuorocarbene

would result in 5 as a stable product. The formation of 6 in

Scheme 4b can be explained by the reaction of I’ with acetic

anhydride. A detailed mechanism for formation of 6 and other

possible mechanisms for 3 and 5 are included in Scheme S9 in

The role of water remains unclear in the above trans-

formations. As shown in Scheme 2, water can improve the

regioselectivity toward the diester 2. However, for the

formation of 2-diﬂuoroalkoxy indolizines 5, the reaction

proceeds more smoothly without water. This duality is due

to the diﬀerent reaction mechanisms involved. For selective

synthesis of 2, the water might serve as a proton mediator that

promotes the proton transfer from B to C, thus improving the

However, when 4d was treated under the optimized conditions

in the absence of BrCF CO Et, no 8 was aﬀorded. Considering

the lability of 8 reported in the literature, we attempted to

capture 8 with acetic anhydride. However, we only got 6 with

4% yield instead of the Chichibabin-like cyclization product

. When the reaction temperature rose to 80 °C, both

compounds 6 and 7 can be isolated in 30% and 51% yields,

respectively. With BrCF PO(OEt)^a^s^t^h^e^C^F2 carbene

precursor instead of BrCF CO Et, Chichibabin-like cyclization

product 5a can be isolated in 45% yield, which is lower than

that of BrCF CO Et. Then carbene trap experiments were

attempted, which indicated that diﬂuoromethyl carbene is

involved in the process of generating compounds 2a and 5a

regioselectivity and yield of 2. When D O was used instead of

for a detailed discussion, see Schemes S7 and S8 in the

H O, deuterated product 2a-D can be obtained (see Scheme

Supporting Information ).

S6 in the Supporting Information for details). For the

formation of 5, the key step is intramolecular cyclization of

highly active and moisture-sensitive I′ to form intermediate J.

Therefore, the anhydrous condition is more favorable under

this situation.

Based on the above experimental observations and previous

,13

reports,

a plausible reaction mechanism for the synthesis of

indolizines was proposed in Scheme 5. First, in the presence of

Scheme 5. Proposed Reaction Mechanism

In summary, we have developed an eﬃcient method for

synthesis of indolizines by the annulation of pyridinium salts

with BrCF CO Et as a key reagent. Through the regulation of

the α substitution of pyridine, highly regioselective 1,3-

disubstituted indolizines and C2-diﬂuoromethoxylation indo-

lizines derivatives can be aﬀorded, thus enriching the indolizine

compound library. The current transformations not only

provide a new synthetic strategy toward biologically active

indolizine derivatives but also enrich the chemistry of

BrCF CO Et as a versatile precursor. Further studies to

elucidate the mechanistic details of the transformation and

apply it to the synthesis of bioactive compounds is in progress

in our laboratory.

ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03540.

Experimental procedures, spectral and analytical data,

copies of H, F, and C NMR spectra for new

compounds (PDF )

AUTHOR INFORMATION

■

Corresponding Authors

Guangwei Wang − Tianjin Key Laboratory of Molecular

Optoelectronic Science, Department of Chemistry, School of

Science, Tianjin University, Tianjin 300072, P. R. China;

orcid.org/0000-0003-4466-9809; Email: wanggw@

tju.edu.cn

Minjie Guo − Institute for Molecular Design and Synthesis,

School of Pharmaceutical Science and Technology, Tianjin

University, Tianjin 300072, P. R. China; Email: gmj2016@

tju.edu.cn

Cs CO , the pyridinium salt would be deprotonated to aﬀord

ylide A which could capture the diﬂuorocarbene to aﬀord B.

Then intermediate B will undergo proton exchange and

−

elimination of F to aﬀord D, which would undergo

nucleophilic addition by another molecule of A. Elimination

−

of F followed by deprotonation results in G, which would

undergo intramolecular nucleophilic addition to furnish

intermediate H. Finally, removal of a molecule of pyridine in

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Authors

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Xiaoya Hou − Tianjin Key Laboratory of Molecular

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Sen Zhou − Tianjin Key Laboratory of Molecular

Optoelectronic Science, Department of Chemistry, School of

Science, Tianjin University, Tianjin 300072, P. R. China

Yuli Li − Tianjin Key Laboratory of Molecular Optoelectronic

Science, Department of Chemistry, School of Science, Tianjin

University, Tianjin 300072, P. R. China

Wentao Zhao − Tianjin Key Laboratory of Molecular

Optoelectronic Science, Department of Chemistry, School of

Science, Tianjin University, Tianjin 300072, P. R. China

Xiangyang Tang − Tianjin Key Laboratory of Molecular

Optoelectronic Science, Department of Chemistry, School of

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c03540

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The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

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(g) Dong, K.-K.; Huang, Q. Metal-Free Synthesis of Novel Indolizines

The authors are grateful for the ﬁnancial support from Major

National Science and Technology Projects of water pollution

control and treatment (2017ZX07402003). We also thank the

Natural Science Foundation of Tianjin (No. 19JCYBJC20200)

and Tianjin Chempharmatech Co., Ltd. for support of this

research.

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Ring-Opening and Aromatization. Tetrahedron Lett. 2019, 60, 1871 −

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Applications of Pyridinium Ylides toward Heterocyclic Synthesis.

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