Metal-Free Regioselective Alkylation of Imidazo[1,2- a ]pyridines with N -Hydroxyphthalimide Esters under Organic Photoredox Catalysis

Article abstract of DOI:10.1055/s-0039-1691567

A visible-light-induced direct C-H alkylation of imidazo[1,2- a ]pyridines has been developed. It proceeds at room temperature by employing inexpensive Eosin Y as a photocatalyst and alkyl N -hydroxyphthalimide (NHP) esters as alkylation reagents. A varie

Full text of DOI:10.1055/s-0039-1691567

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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
Synlett
B. Sun et al.
Letter
Metal-Free Regioselective Alkylation of Imidazo[1,2-a]pyridines
with N-Hydroxyphthalimide Esters under Organic Photoredox
Catalysis
Bin Suna,c
Tengwei Xub,c
Liang Zhangb,c
Rui Zhub,c
O
Eosin Y (1 mol%)
TfOH (50 mol%)
R2
N
N
R1
R1
+
N
O
O
N
N
DMSO, N2, r.t.
blue LEDs
R
R2
O
H
R
Jin Yangb,c
Min Xua,c
Can Jin*a,b,c
1
2
R , R = EDG, EWG
mild reaction conditions
oxidant- and metal-free
R = 1°, 2°, and 3° alkyl
30 examples
38–86% yield
a
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
College of Pharmaceutical Sciences, Zhejiang University of Technology,
b
Hangzhou 310014, P. R. of China
jincan@zjut.edu.cn
c
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
jincan@zjut.edu.cn
Received: 14.11.2019
Accepted after revision: 29.12.2019
Published online: 14.01.2020
sition of imidazo[1,2-a]pyridines has already been exten-
sively explored, the modification of imidazo[1,2-a]pyri-
dines at C-5 position has still rarely been investigated.
There were only two studies describing the direct C–H
functionalization of imidazo[1,2-a]pyridines at C-5 posi-
tion.12 As pioneering works in this regard, Yan’s group first-
ly developed an effective DTBP-promoted hydroxyalkyla-
DOI: 10.1055/s-0039-1691567; Art ID: st-2019-r0617-l
Abstract A visible-light-induced direct C–H alkylation of imidazo[1,2-
a]pyridines has been developed. It proceeds at room temperature by
employing inexpensive Eosin Y as a photocatalyst and alkyl N-hydroxy-
phthalimide (NHP) esters as alkylation reagents. A variety of NHP esters
derived from aliphatic carboxylic acids (primary, secondary, and tertia-
ry) were tolerated in this protocol, giving the corresponding C-5-al-
kylated products in moderate to excellent yields. Mechanistic studies in-
dicate that a radical decarboxylative coupling pathway was involved in
this process.
tion of imidazo[1,2-a]pyridines at C-5 position with alco-
12a
hols.
Very recently, Hajra and coworkers reported a
Mn(II)-catalyzed regioselective C–H alkylation of imid-
azo[1,2-a]pyridines under reflux, which employed aliphatic
aldehydes or alkanes as alkylating agents.1 To the best of
our knowledge, there is lack of effective methods to realise
the regioselective C-5 functionalization of imidazo[1,2-
a]pyridines at room temperature without assistance of
chemical oxidants. Therefore, developing greener and more
convenient synthetic approaches to C-5-functionalized im-
idazo[1,2-a]pyridines is still of great interest.
2b
Key words photocatalysis, C–H alkylation, NHP esters, regioselectivi-
ty, metal-free reactions
Among nitrogen-containing fused heterocycles, imid-
azo[1,2-a]pyridine and its derivatives have attracted much
attention. They are of special interest in medicinal chemis-
try and synthetic organic chemistry in terms of their
unique structures and diverse pharmacological activities,
including antimicrobial, anti-inflammatory, antiviral, anti-
tuberculosis, anti-tumor, antipyretic, analgesic, and anti-
In recent years, visible-light-mediated photoredox ca-
talysis has emerged as an efficient and environmentally
compatible synthetic strategy for elusive bond construction
and challenging chemical transformations.13 Meanwhile, al-
kyl NHP esters exhibit specific photochemical properties
because they can be reduced under photocatalytic condi-
tions, delivering a variety of alkyl radicals by elimination of
1
depressant. In addition, a variety of imidazo[1,2-a]pyri-
dine moieties exist in several marketed drugs or bioactive
molecules. Hence, a significant effort has been dedicated to
the synthesis of substituted imidazo[1,2-a]pyridine deriva-
14
CO and phthalimide. It could be reasonably hypothesized
2
2
tives. To date, the direct C–H functionalization has served
that the regioselective alkylation of imidazo[1,2-a]pyri-
dines could be accomplished through the decarboxylative
coupling reaction with alkyl NHP esters. With our ongoing
exploration on developing green and efficient methods for
as a powerful strategy for the synthesis of imidazo[1,2-
a]pyridine derivatives, and many successful examples in-
3
4
5
cluding C–H acylation, dicarbonylation, alkylation, thio-
6
7
8
15
lation, sulfonylation, difluoroalkylation, difluorophos-
direct C–H functionalization, herein we describe a visible-
9
10
phate, amination at C-3 position have been reported
light-induced alkylation of imidazo[1,2-a]pyridines with al-
kyl NHP esters, which firstly employed a photocatalytic sys-
(
Scheme 1).11 Though the C–H functionalization at C-3 po-
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
B. Sun et al.
Letter
Table 1 Optimization of the Reaction Conditionsa
Previous works:
N
N
C-3 functionalization
O
R
Ar
R
Ar
1)
N
photocatalyst,
additive
N
Cl
Ref. 3–11
N
Cl
N
FG
+
N
O
O
N
solvent,
visible light
FG = COR', alkyl, NR'R'', SR',
SO2R', CF3, CF2COR, etc.
N
O
2
)
C-5 functionalization
1
a
2a
3aa
N
R2
R2
R3
R1
N
N
DTBP, HCl
Ref. 12a
N
R1
R4
+
H
Yield (%)b
Entry
Photocatalyst
Additive
Solvent
OH
HO
R4
R3
1
2
3
4
5
6
7
8
9
fac-Ir(ppy)
3
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
acetone
MeCN
31
N
R2
N
N
R2
R-CHO
II
R1
Mn , DTBP
Ref. 12b
R1
Eosin Y
–
32
+
or
R-H
N
R
Rose Bengal
Methylene Blue
Rhodamine 6G
Eosin Y
–
n.d.
n.d.
n.d.
71
–
This work:
–
O
Eosin Y (1 mol%)
TfOH (50 mol%)
N
N
R1
R1
TFA
TfOH
AcOH
N
O
O
+
N
N
DMSO, N2, r.t.
blue LEDs
R
R2
R2
Eosin Y
82
O
H
R
Eosin Y
54
Scheme 1 Strategies for the synthesis of substituted imidazo[1,2-
a]pyridine derivatives
Eosin Y
Et N
3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
trace
77
10
11
12
13
14
Eosin Y
DIPEA
Eosin Y
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
tem in the C-5 functionalization of imidazo[1,2-a]pyridine.
This strategy is metal- and oxidant-free, and shows wide
substrate scope, good functional group tolerance, and ex-
cellent regioselectivity.
Eosin Y
Eosin Y
2 2
CH Cl
Eosin Y
DCE
THF
DMF
To begin our study, we chose 7-chloro-2-phenylimid-
azo[1,2-a]pyridine 1a and tert-butyl NHP ester 2a as model
substrates to explore and optimize the reaction conditions.
The transformation was initially carried out in the presence
15
16
Eosin Y
Eosin Y
7c
1
1
1
2
Eosin Y
DMSO
DMSO
DMSO
DMSO
DMSO
8d
9e
0
Eosin Y
72
of fac-Ir(ppy) in DMSO with the irradiation of blue LEDs
3
Eosin Y
n.d.
n.d.
trace
under N atmosphere at room temperature for 48 hours.
2
–
To our delight, the desired product 3aa was obtained in
a yield of 31%. Encouraged by this result, a variety of other
photosensitizers such as Eosin Y, Rose Bengal, Methylene
Blue, and Rhodamine 6G were also screened. Only Eosin Y
exhibited a similar catalytic reactivity compared to that of
21f
Eosin Y
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), photocatalyst (0.005
mmol), additive (0.25 mmol), solvent (2.0 mL), N
2
, blue LEDs, r.t., 48 h.
b
Isolated yields; n.d. = not determined.
White LEDs.
Green LEDs.
Without light.
Under air atmosphere.
c
d
e
f
fac-Ir(ppy) , while no desired product was detected when
3
other photocatalysts were employed (Table 1, entries 2–5).
Because of its non-toxicity and easy commercial availabili-
ty, Eosin Y was chosen as the photocatalyst for further opti-
mization. In order to further enhance the yield of 3aa, vari-
ous additives such as trifluoroacetic acid (TFA), TfOH, AcOH,
entries 17–18). A contrast experiment indicated that both
visible light and a photocatalyst were essential for this de-
carboxylative coupling reaction, and of note, only a trace
amount of the desired product was detected when this
transformation was carried out under air atmosphere (Ta-
ble 1, entries 19–21). On the basis of the screening of the
reaction conditions, it could be concluded that this decar-
boxylative coupling reaction should be performed at room
temperature in the presence of Eosin Y and TfOH in DMSO
Et N, and N,N-diisopropylethylamine (DIPEA) were also
3
studied. Screening revealed that acidic additives had a posi-
tive influence on this reaction. The desired product was ob-
tained in yields of 82, 71 and 54% when TfOH, TFA, and
AcOH were employed, respectively (Table 1, entries 6–8).
However, no desired product was observed when basic ad-
ditives were added (Table 1, entries 9–10).
Futher investigation of the solvents indicated that ex-
cept for DMSO, other screened solvents such as acetone,
MeCN, CH Cl , DCE, THF, and DMF were all not suitable for
this transformation (Table 1, entries 11–16). We then em-
ployed 3 W white or green LEDs as a light source and the
results revealed that no improvement was obtained (Table 1,
with irradiation of blue LEDs under a N atmosphere for 48
hours.
Having the optimized reaction conditions in hand, we
next turned our attention to probing the scope and general-
ity of these two coupling partners. As summarized in
Scheme 2, a broad range of imidazo[1,2-a]pyridines 1 with
2
2
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
Synlett
B. Sun et al.
Letter
O
R2
1i, leading to the desired product 3ia in 72% yield. Further
investigation was carried out with respect to the substitu-
ents on the C-2 benzene ring, and starting materials with
variation of substituents at the ortho, meta, and para posi-
tions of benzenes were well compatible to give the corre-
sponding products 3ja–sa in moderate to good yields. For
example, substrates bearing electron-withdrawing groups
such as fluoro, chloro, bromo, trifluoromethyl, and cyano at
the para position of the benzene ring showed good toler-
ance for this reaction, and provided the corresponding
products 3ja–na in 64 to 80% yield. Moreover, the electron-
donating groups at the para position of the benzene ring
such as methyl and methoxy, also displayed excellent toler-
ance for this transformation, and the alkylated products
N
N
R2
+
Eosin Y, TfOH R1
R1
N
N
O
O
N
DMSO, N2, r.t.
blue LEDs
H
O
1
2a
3
N
R
Ph
N
3aa, R = 7-Cl, 82%
ba, R = 7-Br, 86%
ca, R = 7-CF3, 81%
da, R = 7-CN, 75%
3
3
3
3
ea, R = 7-OMe, 70%
fa, R = 7-Me, 51%
ga, R = 8-Cl, 60%
ha, R= 8-Me, 66%
3
3
3
N
N
N
F
Cl
N
N
N
3
ia, 72%
3ja, 68%
3ka, 75%
N
N
N
Br
CF3
CN
N
N
N
3
oa and 3pa were obtained in 51 and 55% yield, respective-
3
la, 80%
3ma, 67%
3na, 64%
ly. Meanwhile, imidazo[1,2-a]pyridines bearing substitu-
ents at the ortho and meta positions of the benzene ring
were also evaluated. Similarly, the corresponding products
N
N
MeO
N
OMe
N
N
N
3qa–sa were obtained in moderate yields whether the ben-
zene ring contained electron-donating or electron-with-
drawing groups.
3
oa, 51%
3pa, 55%
3qa, 44%
OMe
Cl
N
N
Furthermore, the scope of the alkyl NHP esters was
evaluated through the decarboxylative alkylation with 7-
chloro-2-phenylimidazo[1,2-a]pyridine (1a) under the op-
timized reaction conditions (Scheme 3). Different types of
precursors including primary, secondary, and tertiary alkyl
NHP esters were all suitable for this reaction and gave the
desired coupling products 3ab–al in 38 to 75% yield. Initial-
ly, the primary alkyl NHP esters containing n-propyl and n-
octyl exhibited good tolerance for this protocol and afford-
ed the desired products 3ab and 3ac in 54 and 38% yield,
respectively. Notably, the primary alkyl NHP esters contain-
ing additional functional groups, such as halogen, phenyl,
and ester on the aliphatic chain were also well compatible
with this transformation, providing the primary alkylated
products 3ad–af in fair yields. Subsequently, we explored
whether the secondary alkyl NHP esters could adapt to this
reaction. The experimental results indicate that the second-
ary alkyl NHP esters bearing isopropyl or cyclohexyl also
showed good reactivity in this process and produced the
desired products 3ag and 3ah in satisfactory yields under
the optimal conditions. Furthermore, a secondary alkyl
NHP ester containing a nitrogen atom on the aliphatic ring
also performed well to provide the product 3ai in good
yield. It is worth noting that the derived alkyl NHP esters of
natural amino acids were also suitable substrates for this
transformation. For example, NHP esters of valine and phe-
nylalanine derivatives were used as radical precursors to
deliver the aminoalkylated products 3aj and 3ak in syn-
thetically useful yields. Apart from the tert-butyl, another
tertiary alkyl species, such as adamantyl NHP ester, was
also employed in the reaction, and we were pleased to find
that this substrate also worked well and gave the desired
product 3al in 48% yield.
N
N
3
ra, 59%
3sa, 63%
Scheme 2 Substrate scope of imidazo[1,2-a]pyridines. Reagents and
conditions: 1 (0.5 mmol), 2a (1.0 mmol), Eosin Y (0.005 mmol), and
TfOH (0.25 mmol) in DMSO (2.0 mL) at room temperature with irradia-
tion by blue LEDs under a N atmosphere for 48 h.
2
diverse substituents on the arene moiety or the pyridine
ring were examined with tert-butyl NHP ester 2a under the
optimized conditions. Expectedly, this transformation was
applicable to a variety of imidazo[1,2-a]pyridine deriva-
tives 1a–s, which were all able to undergo this decarboxyl-
ative coupling reaction smoothly to give the desired prod-
ucts 3aa–sa in 44 to 86% yield. For example, the imid-
azo[1,2-a]pyridines possessing various halogens, such as
chloro and bromo at the C-7 position of the pyridine rings,
were well compatible and gave the desired products 3aa
and 3ba in 82 and 86% yield, respectively.
Remarkably, the cyano and trifluoromethyl substitu-
ents, which were considered as strong electron-withdraw-
ing groups, also survived well and afforded the coupling
products 3ca and 3da in 81 and 75% yield, respectively. Im-
idazo[1,2-a]pyridine containing a methyl or methoxy group
at the C-7 position was also well tolerated, furnishing the
desired products 3ea and 3fa in 70 and 51% yield, respec-
tively. In addition, imidazo[1,2-a]pyridines containing
chloro as an electron-withdrawing group or methyl as an
electron-donating group at the C-8 position of the pyridine
ring also underwent this decarboxylative coupling smooth-
ly with 2a to give the corresponding alkylated products 3ga
and 3ha in yields of 60 and 66%, respectively. The reaction
also tolerated the substituent-free imidazo[1,2-a]pyridine
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
Synlett
B. Sun et al.
Letter
O
model reaction, this decarboxylative coupling process was
completely suppressed. Subsequently, a similar result was
observed when another radical scavenger BHT (butylated
hydroxytoluene) was employed in same reaction system,
and the corresponding radical-trapping product (4) was de-
tected by HRMS.
Cl
Cl
Eosin Y, TfOH
N
N
+
N
O
O
N
N
DMSO, N2, r.t.
blue LEDs
R
O
R
H
1
a
2
3
Cl
Cl
N
Cl
N
N
N
N
N
O
standard Cl
Cl
N
N
conditions
+
N
O
O
N
TEMPO
2.0 equiv)
N
(
3
ab, 54%
3ac, 38%
3ad, 46%
O
3aa
not detected
Br
1a
2a
Cl
Cl
N
N
N
N
Cl
N
O
N
Cl
standard
conditions
N
tBu
tBu
+
N
O
3aa
+
O
O
N
BHT
(2.0 equiv)
O
not
detected
tBu
3ae, 52%
3af, 41%
3ag, 51%
O
O
1a
2a
4
Cl
Cl
Cl
detected by HRMS (ESI)
N
N
N
N
N
N
O
O
O
NBoc
Boc
N
standard
N
H
Cl
N
conditions
+
3ai
+
N
N
O
1,1-diphenylethylene trace
(2.0 equiv)
NBoc
3ah, 54%
Boc 3ai, 75%
3aj, 50%
2i
1a
Cl
Cl
N
N
N
5, 57% yield
N
Scheme 5 Control experiments
NH
Boc
These results indicate that the reaction might involve a
radical pathway. The hypothesis was further confirmed by
the addition of another milder radical scavenger, 1,1-di-
phenylethylene, and the radical adduct 5 of alkyl with di-
phenylethylene was isolated in 57% yield. In addition,
Stern–Volmer experiments (for details, see Supporting In-
formation) revealed that the excited state of Eosin Y could
be quenched by alkyl NHP esters, suggesting that the reac-
tion might proceed through an oxidative quenching path-
way.
3
ak, 53%
3al, 48%
Scheme 3 Substrate scope of alkyl NHP esters. Reagents and condi-
tions: 1a (0.5 mmol), 2 (1.0 mmol), Eosin Y (0.005 mmol), and TfOH
0.25 mmol) in DMSO (2.0 mL) at room temperature with irradiation by
(
blue LEDs under a N atmosphere for 48 h.
2
To evaluate the potential synthetic utility of this decar-
boxylative coupling strategy, a gram-scale reaction was car-
ried out between 7-chloro-2-phenylimidazo[1,2-a]pyridine
(
1a) and tert-butyl NHP ester 2a under the optimized con-
According to the above experimental results and previ-
ous literature reports,1
4i,16
a plausible mechanism for this
ditions, and the desired product 3aa was finally isolated in
a yield of 68% (Scheme 4).
decarboxylative coupling reaction is proposed in Scheme 6.
Initially, the organic dye Eosin Y was irradiated to its excited
state (Eosin Y*), which underwent a single electron transfer
(SET) process with 2a' that was generated by protonation of
substrate 2a to afford a radical intermediate I and a radical
O
Cl
Cl
Eosin Y (1 mol%)
TfOH (50 mol%)
N
N
N
+
N
O
O
N
DMSO, N2, r.t.
blue LEDs
H
O
•+
1a, 5 mmol, 1.14 g
2a, 10 mmol, 2.47 g
3aa, 68%, 0.97 g
cation (Eosin Y ). The radical I was then converted into tert-
butyl radical II after the elimination of CO and phthalim-
2
Scheme 4 Gram-scale synthetic experiment
ide. Subsequently, the radical II regioselectively attacked at
the C-5 position of 1a to produce radical III, which could be
further oxidized by Eosin Y• to give the corresponding cat-
ion intermediate and regenerate the photocatalyst. After
deprotonation, IV was finally transformed into the desired
product 3aa.
+
In order to gain a deeper insight into the reaction mech-
anism, several control experiments were carried out as
shown in Scheme 5. When the radical scavenger TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) was added to the
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
Synlett
B. Sun et al.
Letter
O
Cl
N
References and Notes
Cl
N
Eosin Y, TfOH
N
N
O
O
+
(1) (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888. (b) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali,
E.; Rugarli, P.; Biancotti, A.; Gamba, A.; Murmann, W. J. Med.
Chem. 1965, 8, 305. (c) Dymińska, L. Bioorg. Med. Chem. 2015,
N
DMSO, blue LEDs
N2, r.t.
O
H
1
a
3aa
2a
CF3SO3–
23, 6087. (d) Deep, A.; Bhatia, R. K.; Kaur, R.; Kumar, S.; Jain, U.
CF3SO3H
K.; Singh, H.; Batra, S.; Kaushik, D.; Deb, P. K. Curr. Top. Med.
Chem. 2017, 17, 238.
Eosin Y
Cl
+
N
N
O
N
O
O
hn
N
H
(2) (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun.
2015, 51, 1555. (b) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem.
Commun. 2011, 47, 11333. (c) Gao, Y.; Yin, M.; Wu, W.; Huang,
H.; Jiang, H. Adv. Synth. Catal. 2013, 355, 2263. (d) Zeng, J.; Tan,
Y. J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2012, 14, 4386. (e) Huang,
H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.; Jiang, H. Org. Lett. 2013, 15,
IV
O
Eosin Y*
SET
CF3SO3H
Cl
CF3SO3–
Eosin Y
N
H
SET
6
254. (f) Palani, T.; Park, K.; Kumar, M. R.; Jung, H. M.; Lee, S.
O
O
O
III
Eur. J. Org. Chem. 2012, 5038.
N
(3) (a) Cao, H.; Lei, S.; Li, N.; Chen, L.; Liu, J.; Cai, H.; Qiu, S.; Tan, J.
Chem. Commun. 2015, 51, 1823. (b) Nitha, P. R.; Joseph, M. M.;
Gopalan, G.; Maiti, K. K.; Radhakrishnan, K. V.; Das, P. Org.
Biomol. Chem. 2018, 16, 6430.
4) (a) Samanta, S.; Mondal, S.; Santra, S.; Kibriya, G.; Hajra, A.
J. Org. Chem. 2016, 81, 10088. (b) Shakoor, S. M. A.; Agarwal, D.
S.; Kumar, A.; Sakhuja, R. Tetrahedron 2016, 72, 645.
O
O
O
1a
+OH
a'
N
2
II
I
OH
CO2
NPhthH
(
Scheme 6 Proposed mechanism
(
5) (a) Naresh, G.; Lakkaniga, N. R.; Kharbanda, A.; Yan, W.; Frett, B.;
Li, H. Eur. J. Org. Chem. 2019, 770. (b) Patel, O. P. S.; Nandwana,
N. K.; Sah, A. K.; Kumar, A. Org. Biomol. Chem. 2018, 16, 8620.
In summary, we have successfully developed a green
2
3
and efficient method for the C(sp )–C(sp ) bond formation
through the decarboxylative coupling process between im-
idazo[1,2-a]pyridines and alkyl NHP esters under visible-
light irradiation at room temperature.17 This protocol ex-
hibits a broad substrate scope with respect to both the two
coupling partners, and a series of C-5-alkylated imid-
azo[1,2-a]pyridine derivatives were obtained in moderate
to good yields. Employing the commercially available and
low cost Eosin Y as the photocatalyst made this protocol en-
vironmentally friendly and practical. The advantages of this
reaction involve the avoidance of transition-metal and stoi-
chiometric oxidants, easy availability of substrates, and
mild conditions.
(c) Mondal, S.; Samanta, S.; Singsardar, M.; Hajra, A. Org. Lett.
2
017, 19, 3751. (d) Kibriya, G.; Bagdi, A. K.; Hajra, A. J. Org. Chem.
2018, 83, 10619. (e) Zhu, M.; Han, X.; Fu, W.; Wang, Z.; Ji, B.;
Hao, X.-Q.; Song, M.-P.; Xu, C. J. Org. Chem. 2016, 81, 7282.
(f) Su, H.; Wang, L.; Rao, H.; Xu, H. Org. Lett. 2017, 19, 2226.
(g) Kim, H.; Byeon, M.; Jeong, E.; Baek, Y.; Jeong, S. J.; Um, K.;
Han, S. H.; Han, G. U.; Ko, G. H.; Maeng, C.; Son, J.-Y.; Kim, D.;
Kim, S. H.; Lee, K.; Lee, P. H. Adv. Synth. Catal. 2019, 361, 1.
(h) Yang, Q.; Li, S.; Wang, J. Org. Chem. Front. 2018, 5, 577. (i) Lu,
S.; Zhu, X.; Li, K.; Guo, Y.-J.; Wang, M.-D.; Zhao, X.-M.; Hao, X.-
Q.; Song, M.-P. J. Org. Chem. 2016, 81, 8370.
(6) (a) Yuan, Y.; Cao, Y.; Qiao, J.; Lin, Y.; Jiang, X.; Weng, Y.; Tang, S.;
Lei, A. Chin. J. Chem. 2019, 37, 49. (b) Gao, Y.-C.; Huang, Z.-B.; Xu,
L.; Li, Z.-D.; Lai, Z.-S.; Tang, R.-Y. Org. Biomol. Chem. 2019, 17,
2
279. (c) Zhang, J.-R.; Zhan, L.-Z.; Wei, L.; Ning, Y.-Y.; Zhong, X.-
L.; Lai, J.-X.; Xu, L.; Tang, R.-Y. Adv. Synth. Catal. 2018, 360, 533.
d) Zhang, J.-R.; Liao, Y.-Y.; Deng, J.-C.; Feng, K.-Y.; Zhang, M.;
Ning, Y.-Y.; Lin, Z.-W.; Tang, R.-Y. Chem. Commun. 2017, 53,
784.
(
Funding Information
7
This work was supported by the National Natural Science Foundation
of China (21606202) and Natural Science Foundation of Zhejiang
Province (LY15B060007). We are also grateful to the College of Phar-
maceutical Sciences, Zhejiang University of Technology and Collabo-
rative Innovation Center of Yangtze River Delta Region Green
(
7) Guo, Y.-J.; Lu, S.; Tian, L.-L.; Huang, E.-L.; Hao, X.-Q.; Zhu, X.;
Shao, T.; Song, M.-P. J. Org. Chem. 2018, 83, 338.
8) Yin, G.; Zhu, M.; Fu, W. J. Fluorine Chem. 2017, 199, 14.
9) Singsardar, M.; Mondal, S.; Laru, S.; Hajra, A. Org. Lett. 2019, 21,
(
(
5
606.
10) (a) Mondal, S.; Samanta, S.; Jana, S.; Hajra, A. J. Org. Chem. 2017,
2, 4504. (b) Yu, Y.; Yuan, Y.; Liu, H.; He, M.; Yang, M.; Liu, P.; Yu,
Pharmaceuticals for the financial help.
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5
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0
6
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(
8
B.; Dong, X.; Lei, A. Chem. Commun. 2019, 55, 1809.
Supporting Information
(
11) (a) Liu, P.; Gao, Y.; Gu, W.; Shen, Z.; Sun, P. J. Org. Chem. 2015,
80, 11559. (b) Fu, H. Y.; Chen, L.; Doucet, H. J. Org. Chem. 2012,
77, 4473. (c) Xue, C.; Han, J.; Zhao, M.; Wang, L. Org. Lett. 2019,
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691567.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
21, 4402. (d) Rafique, J.; Saba, S.; Rosário, A. R.; Braga, A. L.
Chem. Eur. J. 2016, 22, 11854. (e) Ren, Y.; Xu, B.; Zhong, Z.;
Pittman, C. U.; Zhou, A. Org. Chem. Front. 2019, 6, 2023. (f) Kim,
Y. J.; Kim, D. Y. Tetrahedron Lett. 2019, 60, 739.
(12) (a) Jin, S.; Xie, B.; Lin, S.; Min, C.; Deng, R.; Yan, Z. Org. Lett. 2019,
21, 3436. (b) Samanta, S.; Hajra, A. J. Org. Chem. 2019, 84, 4363.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
Synlett
B. Sun et al.
Letter
(
13) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
Lett. 2019, 21, 2064. (e) Sun, B.; Deng, J.; Li, D.; Jin, C.; Su, W. Tet-
rahedron Lett. 2018, 59, 4364. (f) Jin, C.; Zhuang, X.; Sun, B.; Li,
D.; Zhu, R. Asian J. Org. Chem. 2019, 8, 1490. (g) Jin, C.; Zhang, X.;
Sun, B.; Yan, Z.; Xu, T. Synlett 2019, 30, 1585. (h) Yan, Z.; Sun, B.;
Zhang, X.; Zhuang, X.; Yang, J.; Su, W.; Jin, C. Chem. Asian J. 2019,
14, 3344. (i) Wang, J.; Sun, B.; Zhang, L.; Xu, T.; Xie, Y.; Jin, C.
Asian J. Org. Chem. 2019, 8, 1942. (j) Sun, B.; Yang, J.; Zhang, L.;
Shi, R.; Zhang, X.; Xu, T.; Zhuang, X.; Zhu, R.; Yu, C.; Jin, C. Asian
J. Org. Chem. 2019, 8, 2058.
40, 102. (b) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Soc.
Rev. 2016, 45, 2044. (c) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-
J. Acc. Chem. Res. 2016, 49, 1911. (d) Marzo, L.; Pagire, S. K.;
Reiser, O.; König, B. Angew. Chem. Int. Ed. 2018, 57, 10034.
(e) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (f) Romero, N. A.; Nicewicz, D. A. Chem. Rev.
2016, 116, 10075. (g) Shi, L.; Xia, W. J. Chem. Soc. Rev. 2012, 41,
7687. (h) Zhao, Y.; Xia, W. J. Chem. Soc. Rev. 2018, 47, 2591.
(
5
2
i) Wang, J.; Huang, B.; Yang, C.; Xia, W. J. Chem. Commun. 2019,
5, 11103. (j) Cai, S.; Xiao, Z.; Shi, Y.; Gao, S. H. Chem. Eur. J.
014, 20, 8677. (k) Xiao, Z.; Cai, S.; Shi, Y.; Yang, B.; Gao, S. H.
(16) (a) Pirenne, V.; Kurtay, G.; Voci, S.; Bouffier, L.; Sojic, N.; Robert,
F.; Bassani, D. M.; Landais, Y. Org. Lett. 2018, 20, 4521. (b) Wang,
H.; Zhang, D.; Bolm, C. Chem. Eur. J. 2018, 24, 14942. (c) Tiwari,
D. P.; Dabral, S.; Wen, J.; Wiesenthal, J.; Terhorst, S.; Bolm, C.
Org. Lett. 2017, 19, 4295. (d) Sun, D.; Yin, K.; Zhang, R. Chem.
Commun. 2018, 54, 1335.
Chem. Commun. 2014, 50, 5254. (l) Cai, S.; Xiao, Z.; Ou, J.; Shi, Y.;
Gao, S. H. Org. Chem. Front. 2016, 3, 354.
(
14) (a) Cheng, W.-M.; Shang, R.; Fu, M.-C.; Fu, Y. Chem. Eur. J. 2017,
2
8
3, 2537. (b) Wang, G.-Z.; Shang, R.; Fu, Y. Org. Lett. 2018, 20,
88. (c) Wang, C.; Guo, M.; Qi, R.; Shang, Q.; Liu, Q.; Wang, S.;
(17) 5-(tert-Butyl)-7-chloro-2-phenylimidazo[1,2-a]pyridine (3aa);
Typical Procedure
Zhao, L.; Wang, R.; Xu, Z. Angew. Chem. Int. Ed. 2018, 57, 15841.
d) Yao, S.; Zhang, K.; Zhou, Q.-Q.; Zhao, Y.; Shi, D.-Q.; Xiao, W.-J.
Chem. Commun. 2018, 54, 8096. (e) Ouyang, X.-H.; Li, Y.; Song,
R.-J.; Li, J.-H. Org. Lett. 2018, 20, 6659. (f) Yu, L.; Tang, M.-L.; Si,
C.-M.; Meng, Z.; Liang, Y.; Han, J.; Sun, X. Org. Lett. 2018, 20,
A 10 mL Schlenk-tube was charged with 7-chloro-2-phenylim-
idazo[1,2-a]pyridine (1a) (114 mg, 0.5 mmol), tert-butyl NHP
ester 2a (247 mg, 1.0 mmol), Eosin Y (3 mg, 0.005 mmol), DMSO
(2 mL), and TfOH (37 mg, 0.25 mmol). The tube was evacuated
(
and backfilled with N (3×). The mixture was then irradiated by
2
4579. (g) Xia, Z.-H.; Zhang, C.-L.; Gao, Z.-H.; Ye, S. Org. Lett.
3 W blue LEDs at r.t. for 48 h. The reaction mixture was then
2018, 20, 3496. (h) Ren, L.; Cong, H. Org. Lett. 2018, 20, 3225.
quenched with 1 M NaOH aq (15 mL) and extracted with CH Cl2
2
(i) Yang, J.-C.; Zhang, J.-Y.; Zhang, J.-J.; Duan, X.-H.; Guo, L.-N.
(3 × 10 mL). The organic layer was dried with anhydrous Na SO4
2
J. Org. Chem. 2018, 83, 1598. (j) Zhao, Y.; Chen, J.-R.; Xiao, W.-J.
Org. Lett. 2018, 20, 224. (k) Hu, D.; Wang, L.; Li, P. Org. Lett.
and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (EtOAc/PE,
2
017, 19, 2770. (l) Liu, L.; Pan, N.; Sheng, W.; Su, L.; Liu, L.; Dong,
1:20) to afford 3aa as a white solid. Yield: 116 mg (82%); mp
1
J.; Zhou, Y.; Yin, S.-F. Adv. Synth. Catal. 2019, 361, 4126. (m) Lyu,
X-L.; Huang, S.-S.; Song, H.-J.; Liu, Y.-X.; Wang, Q.-M. Org. Lett.
141.6–142.4 °C. H NMR (400 MHz, CDCl ):  = 8.07 (s, 1 H),
3
7.96 (d, J = 7.2 Hz, 2 H), 7.58 (s, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.35
13
2
019, 21, 5728.
15) (a) Sun, B.; Wang, Y.; Li, D.; Jin, C.; Su, W. Org. Biomol. Chem.
018, 16, 2902. (b) Sun, B.; Yin, S.; Zhuang, X.; Jin, C.; Su, W. Org.
(t, J = 7.2 Hz, 1 H), 6.71 (s, 1 H), 1.57 (s, 9 H). C NMR (100 MHz,
(
CDCl ):  = 147.1, 146.5, 145.7, 133.6, 131.5, 128.8, 128.2, 126.2,
3
+
2
114.3, 110.7, 108.9, 35.6, 27.6. HRMS (ESI): m/z [M + H] calcd
Biomol. Chem. 2018, 16, 6017. (c) Sun, B.; Yan, Z.; Jin, C.; Su, W.
Synlett 2018, 29, 2432. (d) Jin, C.; Yan, Z.; Sun, B.; Yang, J. Org.
for C17H18ClN : 285.1153; found: 285.1163.
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F