Metal-free synthesis of novel indolizines from chromones and pyridinium salts via 1,3-dipolar cycloaddition, ring-opening and aromatization

Article abstract of DOI:10.1016/j.tetlet.2019.04.056

A simple, efficient, and economical synthetic approach to construct a variety of stucturally novel indolizines bearing a phenolic hydroxy group has been developed through 1,3-dipolar cycloaddition of chromones and pyridinium salts. The methodology is tolerant of a wide range of functional groups and applicable to library synthesis.

Full text of DOI:10.1016/j.tetlet.2019.04.056

Accepted Manuscript
Metal-Free Synthesis of Novel Indolizines from Chromones and Pyridinium
Salts via 1,3-Dipolar Cycloaddition, Ring-opening and Aromatization
Kai-Kai Dong, Qiang Huang
PII:
S0040-4039(19)30417-4
https://doi.org/10.1016/j.tetlet.2019.04.056
TETL 50771
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 March 2019
10 April 2019
30 April 2019
Please cite this article as: Dong, K-K., Huang, Q., Metal-Free Synthesis of Novel Indolizines from Chromones and
Pyridinium Salts via 1,3-Dipolar Cycloaddition, Ring-opening and Aromatization, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.04.056
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Tetrahedron Letters
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Metal-Free Synthesis of Novel Indolizines from Chromones and Pyridinium Salts via
1,3-Dipolar Cycloaddition, Ring-opening and Aromatization
Kai-Kai Donga,b , Qiang Huanga,b,

a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b University of the Chinese Academy of Sciences, Beijing 100049, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: huangqiang65@sina.com
Article history:
Received
Received in revised form
Accepted
A simple, efficient, and economical synthetic approach to construct a variety of stucturally novel
indolizines bearing a phenolic hydroxy group has been developed through 1,3-dipolar
cycloaddition of chromones and pyridinium salts. The methodology is tolerant of a wide range
of functional groups and applicable to library synthesis
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Indolizines
Chromones
Pyridinium salts
1,3-Dipolar Cycloaddition
Base
1
2
The indolizine structural motif is a class of important nitrogen-containing heterocycles with diverse biological activities , such as
anti-cancer 3, anti-inflammatory 4, anti-convulsant 5 and inhibitors for phosphodiesterase 4 (PDE4) 6, topoisomerase I and HIV integrase
7
8
(Figure 1). Besides, indolizine skeleton has also been widely used in fluorescent materials . Therefore, the wide use of this
heterocyclic moiety as a preferred scaffold has prompted the exploration of efficient and novel protocols for the synthesis of
multisubstituted indolizine derivatives in organic chemistry and material science.
O
OMe
O
OH
O
NC
NH2
N
N
N
O
O
Ph
NH2
O
anti-cancer
anti-inflammatory activity
anti-convulsant
Cl
AcO
HO
N
O
Me
N
N
HN
O
O
Cl
O
N
H
MeO
CN
O
Cl
O
O
Me
N
NH2
AcO
OAc
O
OH
inhibitor of topoisomerase I
HIV integrase inhibitor
PDE4 inhibitors
SGLT1 antagonists
Figure 1. Bioactive indolizines
9
10
Generally, Scholtz and Tschitschibabin reactions have become the classical methodologies for the straightforward synthesis of
indolizines. Recently, several other synthetic approaches have also been reported 11, such as 1,3-dipolar cycloaddition of activated
alkynes or alkenes with pyridinium salts 11a, cyclization of pyridines with alkenyldiazoacetates 11d-e, metal-catalyzed C-H
functionalization 11g-h. Notably, Liu’s 12 and Shi’s 13 groups successively developed a series of gold(I)-catalyzed synthesis of indolizines
via hydroarylation. Among the above methods, the 1,3-dipolar cycloaddition of pyridinium ylides with 1,3-dipolarphiles, such as
electron-deficient alkenes and alkynes 14, has emerged as a powerful tool for the construction of indolizines with substituent groups at
positions C-1 or C-3 15. Despite some great achievements, the 1,3-dipolar cycloaddition of pyridinium ylides with structure-specific
alkenes, which could provide a method for the synthesis of indolizines with other types of substituents, remains to be explored.

2
Tetrahedron
Chromones are privileged scaffolds that can be converted into valuable functional groups for the purpose of constructing
compounds with pharmacological activity 16. Recent investigations in the C-H bond functionalization and cyclization of chromones
have attracted considerable attention 17. Especially, Yang et al developed a series of approaches to synthesize high-functionalized
molecules by chromones as starting materials 17b-f. Inspired by these remarkable works, here, we believe that chromones may react with
pyridinium ylides via 1,3-dipolar cycloaddition, which provided an alternative strategy for the synthesis of complex indolizines
derivatives. Herein, a base-promoted synthesis of indolizines from chromones and pyridinium salts was disclosed in this work.
We commenced our study by choosing chromone 1a and 1-(2-ethoxy-2-oxoethyl)pyridin-1-ium 2a as our model substrates to
examine the optimal reaction conditions (Table 1). To our delight, when the reaction was performed in DMF by using DBU as base, the
desired product 3aa was obtained in 52% yield, and the structure of 3aa was confirmed by single crystal XRD analysis (Table 1, entry
1). Solvent screening found that 1,4-dioxane was to be the best choice (Table 1, entries 1-5). Subsequently, various bases were
investigated. When other bases were added in the system, such as Et3N, DIPEA, K2CO3, DMAP, DBACO and TBD, the reaction
efficiency was not obviously improved (Table 1, entries 6-11). However, none of product was detected when the reaction was
performed in the absence of base, which indicated that the base plays a key role in the present transformation (Table 1, entry 12).
Further investigation for the amount of base and reaction temperature did not give improved yield of 3aa (Table 1, entries 13-16).
Table 1. Optimization of reaction conditionsa
O
OEt
O
O
Base
O
Br
N
+
N
OH
Solvent, Temp,12 h
O
EtO
3aa
1a
2a
Entry
Base
DBU
DBU
DBU
DBU
DBU
Et3N
Solvent
DMF
T (°C)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
Yields (%)b
1
52
72
78
76
81
70
76
56
38
30
NR
NR
49
76
70
74
2
DMSO
NMP
3
4
toluene
1,4-dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
5
6
7
DIPEA
K2CO3
8
9
DBACO
DMAP
TBD
-
10
11
12
13c
14d
15
16
DBU
DBU
DBU
DBU
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), , Base (1.0 mmol),
Solvent (3.0 mL), 12 h. NR = no reaction. b Isolated yields based on 1a;
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DBACO: 1,4-
diazabicyclo[2.2.2]octane; TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene. c 0.5
mmol DBU. d 1.25 mmol DBU. NR means no reaction.
With the best reaction conditions in hand, we began to study the substrate scope of the chromones 1. As illustrated in Table 2, both
electron-donating and electron-withdrawing substituted chromones at C-6, C-7 and C-8 position were smoothly transformed into the
desired products (3aa-3ta) in good yields. Notably, aryl and heteroaryl substituted chromones could also give the desired products in
60-83% yield (3ga-3ja and 3na-3qa). In addition, the steric hindrance of substituent had no detrimental effect on the synthesis of
indolizines (3ra-3ta). Importantly, the halogens such as fluoro-, chloro- or bromo- substitutions on the chromone rings were well
tolerated to give the corresponding indolizines in good yields (3da-3fa, 3ka-3ma and 3sa-3ta). Multi-substituted chromones were also
suitable for the reaction leading to more complex indolizines in 65-81% yield (3ua-3xa)
Table 2. The substrate scope of chromones a,b

3
OEt
O
O
O
DBU
1,4-dioxane
O
Br
R1
N
O
R1
N
+
80 °C,12 h
OH
O
EtO
3
1
2a
O
O
R1
N
N
N
R1
OH
OH
OH
O
O
O
R1
EtO
, R1 = F, 72%
, R1 = Cl, 74%
, R1 = Br, 76%
, R1 = Ph, 81%
EtO
1 = Me, 80%
1 = Cl, 70%
1 = Br, 72%
O
EtO
3ra,
3sa
3ta,
R
, R1 = H, 81%,
, R1 = Me, 82%
, R1 = Et, 80%
, R1 = F, 75%
, R1 = Cl, 76%
1 = Br, 78%
, R1 = Ph, 83%
, R1 = 4-MeOC6H4, 82%
3aa
3ka
3la
R
3ba
3ca
3da
3ea
3fa,
3ga
3ha
3ia
R
3ma
3na
3oa
, R1 = 4-MeOC6H4, 80%
3pa,
3qa
R
R
1 = 4-CO2EtC6H4, 69%
N
, R1 = thiophen-2-yl, 60%
OH
O
, R1 = 4-CO2EtC6H4, 70%
, R1 = thiophen-2-yl, 66%
EtO
3ua,
81%
3ja
O
O
O
O
O
Cl
N
N
N
OH
OH
OH
O
O
O
Cl
EtO
EtO
EtO
75%
3va,
3xa,
78%
3wa,
65%
a Reagents and reaction conditions: chromone derivatives 1 (0.5 mmol), 2a (0.55 mmol), DBU (1.0 mmol), 1,4-dioxane (3.0 mL), 80 °C, 12 h. b isolated yields.
Next, we further investigated the scope of various pyridinium salts under the standard conditions. As illustrated in Table 3, various
pyridinium salts 2 could generate the corresponding products smoothly in moderate yields (3ab-3ao). Compared with the electron-
donating substituted pyridinium salts, electron-withdrawing substituted pyridinium salts showed lower reaction activity in the system
(3ab and 3ac). Notably, other types of aza-aromatic rings could afford the target indolizines in moderate to good yields (3ad-3ag). To
our delight, pyridinium salts derived from α-halo aryl ketones reacted well with 1a, generating the more complex products in moderate
to good yields (3ah-3ao). These results indicated that this method could be very suitable for constructing structural diversity molecules
base on chromones motif.
Table 3. The substrate scope of pyridinium salts a
R2
N
R3
O
O
O
DBU
1,4-dioxane
O
Br
X
X
N
+
OH
80 °C,12 h
O
R3
R2
1a
2
3
O
O
O
Br
N
N
N
OH
OH
OH
O
O
O
EtO
EtO
EtO
3ab
3ac
3ad
, 60%
, 71%
, 50%
O
O
O
N
N
N
N
N
OH
MeO
OH
O
O
OH
O
EtO
EtO
, 50%
3ag
, 72%
3ae
, 55%
3af
O
O
N
N
OH
O
OH
O
R
R
3ah
, R = H, 68%
3am
, R = OMe, 52%
, R = Cl, 50%
, R = Br, 51%
3ai
3aj
, R = Me, 61%
3an
3ao
, R = OMe, 58%
3ak
, R = Cl, 52%
3al
, R = Br, 56%
a Reagents and reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), DBU (1.0 mmol), 1,4-dioxane (3.0 mL), 80 °C, 12 h, isolated yields.

4
Tetrahedron
To demonstrate the potential application of the method, a gram-scale reaction was carried out under the standard conditions. As
seen from Scheme 1, to our delight, the reaction proceeded smoothly and afforded the desired product 3aa in 83% yield (Scheme 1a).
Moreover, the valuable functionalization of the product 3aa was further investigation. For instance, the ketone group could be reduced
to alcohol to generate 4 easily. Hydrolysis of the ester moiety in 3aa generated 5 with free carboxyl group. Importantly, the phenolic
group could be modified with acryloyl chloride and methanesulfonyl chloride (MsCl) to deliver potential biologically valuable acrylate
6 and sulfonate 7 (Scheme 1b).
Scheme 1. Gram-scale reaction and synthetic applications
a) Gram-scale reaction
O
O
DBU
1,4-dioxane
N
N
Br
80
, 12 h
°C
O
OH
EtO
O
O
OEt
, 8.22 mmol
1a,
2a
3aa
, 1.75 g, yield: 83%
6.85 mmol
b) Synthetic application
OH
O
O
O
N
N
OH
a
c
O
O
O
EtO
EtO
4
6
, yield: 61%
, yield: 72%
N
O
O
O
OH
O
H3C
S
O
EtO
N
3aa
O
N
b
d
OH
O
O
EtO
HO
5
7
, yield: 82%
, yield: 85%
Reagents and conditions: a. NaBH4, CeCl3, MeOH, 0 °C - RT, 5 h; b. 2N NaOH solution, VTHF :VMeOH = 2 : 1, 0 °C - RT, 16 h; c. Acryloyl Chloride, Et3N, DCM,
0 °C - RT, 1.5 h; d. MsCl, Et3N, DCM, 0 °C - RT, 4 h.
In order to illustrate the reaction pathway, a series of control experiments were conducted. When the free radical scavenger 2,2,6,6-
tetramethyl-piperidinyloxyl (TEMPO) was added in the model reaction, the reaction did not be inhibited obviously (Scheme 2a), which
precluded the free radical process involved in the reaction. Next, the reaction was carried out under N2 or O2. It was observed that the
reaction efficiency kept almost consistent (Scheme 2b and c). The result showed that O2 was not involved in the process of the reaction.
However, no reaction occurred in the absence of DBU (Table 1, entry 12), indicating DBU as base played a key role in the dehydrogen
process. HRMS experiment was performed to detect the possible intermediate, a Michael addition intermediate was found by LC-
HRMS analysis (Scheme 2d).
Scheme 2 control experiments
O
OEt
O
TEMPO (2.0 equiv.)
Standard conditions
O
N
N
(a)
+
Br
N
OH
EtO
O
O
1a
1a
2a
3aa
, 79%
O
OEt
O
O
O
N2
Br
(b)
+
N
Standard conditions
OH
O
EtO
2a
3aa
, 78%
O
OEt
O
O
O
O2
N
Br
(c)
+
N
Standard conditions
OH
O
EtO
1a
2a
OEt
3aa
, 77%
O
O
O
O
1 h
Br
(d)
+
N
N
Standard conditions
OH
OEt
O
1a
2a
[M+H]+ calcd, 312.1236
found, 312.1245
Basing on the above results and previous reports 18, a proposed mechanism was illustrated in Scheme 3. First, the pyridinum salt 2a
was converted to the corresponding ylide 2a' in the presence of DBU via the hydrogen-transfer reaction. Subsequently, the
regioselective 1,3-dipolar cycloaddition occurred between the electron-deficient C=C bond of 1a and 2a', forming a Michael addition
intermediate D. Unstable D readily was converted into intermediate E via the ring-open isomerization. Finally, the desired product 3aa
was produced by dehydroaromatization in the presence of DBU 19
.

5
Scheme 3. Plausible reaction mechanism
O
O
O
O
O
O
1a
DBU
-H+
N
N
N
OEt
OEt
O
C
OEt
2a
2a'
O
O
O
O
H
ring-open
DBU
dehydroaromatization
N
N
OH
N
isomerization
OH
OEt
OEt
O
O
O
OEt
3aa
E
D
In conclusion, we have developed a novel method for the synthesis of complex indolizines bearing a phenolic hydroxyl group from
various chromones and halogenated pyridinium salts via 1,3-dioplar cycloaddition under the mild conditions. This protocol is
compatible with a wide range of functional groups and represents a simple, efficient, and economical method of producing biologically
active indolizines derivatives with moderate to good yields. Moreover, the obtained products could be easily functionalized under the
suitable conditions.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No.21572217).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.****
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6
Tetrahedron
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Metal-Free Synthesis of Novel Indolizines
from Chromones and Pyridinium Salts via
1,3-Dipolar Cycloaddition, Ring-opening and
Aromatization
Leave this area blank for abstract info.
Kai-Kai Dong, Qiang Huang
R
R2
O
O
Metal-free
1,4-dioxane
O
Br
R1
N
R1
N
Base, 80 oC
O
H
O
O
R2
3
1
2
R
High-functionalization


Metal-free


Wide substrate scope
42 examples, up to 83%
1. Metal- free synthesis
2. Wide substrate scope
3. Novel substitution pattern
4. High-functionaliztion