PhI(OAc)2-mediated oxidative C[sbnd]H sulfoximination of imidazopyridines under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2019.151362

A facile protocol for direct oxidative C[sbnd]N bond coupling of unactivated imidazo[1,2-a]pyridines with NH-sulfoximines was disclosed using sulfoximines as the nitrogen sources in the presence of (diacetoxy)iodobenzene (PhI(OAc)₂). The reacti

Full text of DOI:10.1016/j.tetlet.2019.151362

Journal Pre-proofs
PhI(OAc)2-Mediated Oxidative C-H Sulfoximination of Imidazopyridines un-
der Mild Conditions
Nannan Luan, Zhenwei Liu, Shuaijun Han, Linhua Shen, Jingya Li, Dapeng
Zou, Yangjie Wu, Yusheng Wu
PII:
S0040-4039(19)31153-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151362
TETL 151362
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 September 2019
30 October 2019
2 November 2019
Please cite this article as: Luan, N., Liu, Z., Han, S., Shen, L., Li, J., Zou, D., Wu, Y., Wu, Y., PhI(OAc)2-Mediated
Oxidative C-H Sulfoximination of Imidazopyridines under Mild Conditions, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151362
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PhI(OAc)2-Mediated Oxidative C-H
Sulfoximination of Imidazopyridines under
Mild Conditions
Leave this area blank for abstract info.
Nannan Luan, Zhenwei Liu, Shuaijun Han, Linhua Shen, Jingya Li, Dapeng Zou, Yusheng Wu, Yangjie Wu
N
metal-free
O
N
PhI(OAc)2 (1.2 equiv)
 operational simplicity
 broad substrate scopes
 mild conditions
N
R1
S
NH
R
+
N
R
DMSO, 30C, air, 3h
N
R2
R2
H
S
O
R1
27 examples
up to 91% yeild

1
Tetrahedron Letters
journal homepage: www.elsevier.com
PhI(OAc)2-Mediated Oxidative C-H Sulfoximination of Imidazopyridines under Mild
Conditions
Nannan Luana, Zhenwei Liua, Shuaijun Hana, Linhua Shena, Jingya Lib, Dapeng Zoua,, Yangjie Wua, and
Yusheng Wua,b,c,
aThe College of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
bTetranov Biopharm, LLC. And Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, PR China
cTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
Highlights
•The sulfoximination of imidazopyridines at C3 position was firstly achieved
•PhI(OAc)2 was used as oxidant
•The reaction proceeds under air without metal catalyst
•This method features mild conditions and good substrate tolerance
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile protocol for direct oxidative C-N bond coupling of unactivated imidazo[1,2-a]pyridines
with NH-sulfoximines was disclosed using sulfoximines as the nitrogen sources in the presence
of (diacetoxy)iodobenzene (PhI(OAc)2). The reaction proceeded smoothly under air without any
metal catalyst to give a series of C-3 sulfoximidoyl-functionalized imidazo[1,2-a]pyridines
products regioselectively.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Imidazopyridines
C-H functionalization
C-N bond formation
Oxidant sulfoximination
———
* Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, wyj@zzu.edu.cn,
zdp@zzu.edu.cn

2
Introduction
sulfoximines. In the continuation of our previous work on direct
C-H functionalization,12 we herein report the metal-free,
regioselective sulfoximination of imidazo[1,2-a]pyridines and
other imidazoheterocycles with PhI(OAc)2 as oxidant under mild
conditions. This method provides an convenient access to a new
type of compounds, C-3 sulfoximidoyl-functionalized
imidazo[1,2-a]pyridines, which might have potential value in
organic chemistry and drug discovery.
Among
numerous
nitrogen-containing
heterocycles,
imidazo[1,2-a]pyridine has been considered as a privileged
structural unit found in many natural products and
pharmaceuticals.1 Their derivatives shows highly biological
activity, such as antiviral, antitumor, antifungal activities, etc.2 In
particular, amido-substituted imidazo[1,2-a]pyridine is the core
structure of several commercially available drugs such as alpidem,
zolpidem, saripidem, GSK812397, etc.1a,3 Therefore, the synthesis
methods of amido-substituted imidazopyridines has gained
considerable interest of synthetic chemists.4a-k In this respect, a
direct dehydrogenative C-N coupling between C-H and N-H
partners would be the most efficient strategy. In 2017, a radical-
type oxidative amination of imidazo[1,2-a]pyridines in the
presence of (diacetoxy)iodobenzene was reported by Hajra
(Scheme 1a).4a Subsequently, Sun group reported a visible-light-
induced C(sp2)-H amidation of imidazopyridines using
Ir(ppy)2(dtbbpy)PF6 as photocatalyst (Scheme 1b).4b Later, Sun
and co-workers demonstrated a Cu-catalyzed direct C-N bond
formation on the C-3 position of imidazo[1,2-a]pyridines using
saccharin as an amino source (Scheme 1c).4c Recently, Lei
reported an electrochemical oxidative C-H/N-H cross-coupling to
give C-3 aminated imidazo[1,2-a]pyridines (Scheme 1d).4d
Despite the above achievements, the diversity of nitrogen sources
Results and Discussion
The optimization of reaction conditions was started by taking
2-phenylimidazo[1,2-a]pyridine (1a) and diphenyl sulfoximine
(2a) as model substrates. Initially, the reaction was carried out
using PhI(OAc)2 as oxidant in acetonitrile (Table 1, entry 1). The
target
product
C-3
sulfoximidoyl-functionalized
2-
phenylimidazo[1,2-a]pyridine (3aa) was obtained in 29% yield.
Then, the effect of different solvents were checked (Table 1,
entries 2-10), and DMSO was the most effective one for the
reaction, affording 48% of the desired product (Table 1, entry 8).
Subsequent oxidants screening indicated that PhI(OAc)2 was the
best one. (Table 1, entries 8 vs 11-13). To our delight, when 1.5
equiv of 1a was used, the yield of desired product was increased
to 77% (Table 1, entry 14). Increasing the amount of PhI(OAc)2 to
1.2 equiv, the yield was improved to 82% (Table 1, entries 15).
Then, the effect of gaseous environment was also investigated
(Table 1, entries 15, 17-18). When the reaction was performed
under O2 atmosphere, almost same results were obtained.
Whereas, the yield of the target product decreased dramatically
under Ar atmosphere. In the absence of the oxidant, no desired
product was observed (Table 1, entry 19). Thus, the optimized
reaction conditions were determined as the combination of 2-
phenylimidazo [1,2-a]pyridine 1a (1.5 equiv), diphenyl
sulfoximine 2a (1.0 equiv), PhI(OAc)2 (1.2 equiv) in DMSO at 30
°C for 3 h. The structure of product 3aa was further confirmed by
single-crystal X-ray diffraction analysis (CCDC 1942822).
remains limited.
a) Metal-free oxidative amination of imidazo[1,2-a]pyridines
N
Ar
H
N
PIDA
N
N
1,4-dioxiane
rt, 10-30 min
+
Ar
N
N
O
O
b) Visible-light-induced amidation of imidazopyridines
H
N
R2
O
R2
S
R1
Ir(ppy)2(dtbbpy)PF6
O
N
N
N
R1
R2
S
R1
+
N
R2
1.4-dioxane
5W white LEDs
N
O
R1
O
Table 1. Optimization of the reaction conditionsa
N
c) Cu-catalyzed amidation of imidazopyridines
O
Ph
N
O
N
Oxidant
N
+
Ph
N
Ph
S
NH
[Cu], Selectflour
N
S
R2
R1
R2
Ph
N
R1
N
+
NH
O
Solvent, 30C, 3h
Ph
N
DCE, 120C, 12h
Ph
S
NSacc
O
O
1a
2a
3aa
d) electrochemical oxidative amination of imidazo[1,2-a]pyridines
Entry
1
Oxidant (equiv)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(TFA)2 (1.0)
TBHP (1.0)
Solvent
CH3CN
CH2Cl2
1,4-dioxane
EtOAc
CH3Ph
THF
Yieldb (%)
29
N
R1
HN
R2
N
Ar
R2
C
Ni
Ar
+
N
N
N
2
14
R1
3
26
Scheme 1. Methods for direct dehydrogenative C-N coupling
of imidazo[1,2-a]pyridines.
4
43
5
11
Sulfoximine derivatives are of great significance as their
applications in organic synthesis5 and medicinal chemistry.6 In
drug discovery, they have been used as important pharmacophores
to improve specificity7a-b or reduce undesired toxicity.7c-e In
addition, due to the fact that some sulfoximine derivatives showed
anticancer activity,8 the synthesis of N-(hetero)arylsulfoximines
has attracted the interest of chemists.9
6
9
7
DMF
trace
48
8
DMSO
EtOH
9
21
10
11
12
13
14c
15c
16c
i-propanol
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
35
However, since the nucleophilic properties of nitrogen in
sulfoximine are lower than that in amines and imines, development
of a new C-N bond formation of sulfoximines remains a challenge.
In recent years, iodine(III)-mediated oxidative amination of
C(sp2)-H bond has become an important strategy.10 Several
examples of amination of (hetero)arenes using hypervalent iodine
have been reported,11 which prompted us to investigate the
feasibility of an iodine(III) reagent in C-N bond construction of
trace
nd
Na2S2O8 (1.0)
nd
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.5)
77
82
81

3
N
17c,d
18c,e
19c
PhI(OAc)2 (1.2)
DMSO
DMSO
DMSO
83
14
nd
R2
O
N
N
PhI(OAc)2 (1.2 equiv)
R1
Ph
S
NH
R2
+
N
N
DMSO, 30C, 3h
R1
PhI(OAc)2 (1.2)
-
Ph
Ph
S
O
Ph
1
2a
3
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), PhI(OAc)2 (1.0 equiv),
N
N
N
solvent (1.0 mL) at 30 ºC for 3 h, sealed tube, nd = not detected.
tBu
N
N
N
N
N
S
N
S
bHPLC yield.
Ph
Ph
Ph
S
Ph
3aa
Ph
Ph
O
O
O
c1a (0.3 mmol), 2a (0.2 mmol).
dunder O2 atmosphere.
eunder argon atmosphere.
,76%
3ba
, 81%
3ca
, 65%
O
N
N
N
N
N
CN
O
NO2
N
N
N
N
N
S
O
N
S
N
Ph
Ph
Ph
Ph
S
S
O
Ph
Ph
3ga
N
Ph
Ph
O
O
Under the optimized conditions, imidazo[1,2-a]pyridines (1)
were reacted with diphenyl sulfoximine (2a) to give the desired
products in moderate to good yields (Table 2, 3aa-3ta). Initially,
the effect of substituents on the benzene ring of imidazo[1,2-
a]pyridines was explored. Imidazo[1,2-a]pyridines with electron-
withdrawing groups on the benzene ring worked comparatively
well than the substrates possessing electron-donating groups (3fa-
3ha vs 3ba-3ea). The halogen groups containing substrates were
tolerated in the reaction to give the corresponding products in good
yields (3ja-3la). When the substrate bearing phenyl group at the
2-phenyl moiety was checked, the desired 3ma was obtained in
63% yield. The effect of various groups on the pyridyl ring was
also investigated. The substrates with halogen groups proceeded
well (3qa-3ra), whereas, alkyl substituents reduced the yields
(3na-3pa). When 2-phenyl moiety was switched to methyl or
hydrogen, the yields of the target product dramatically decreased
(3sa-3ta). Other imidazoheterocycles, such as 2-(p-tolyl)
imidazo[1,2-a]pyrimidine and 2-phenylbenzo[d]imidazo[2,1-
b]thiazole were also compatible to this catalytic system, giving the
desired 3ua, 3va in 67% and 63% yield, respectively.
3da
, 76%
3ea
3fa,
, 58%
91%
, 82%
N
N
N
CF3
F
Cl
Br
N
N
N
N
N
N
S
O
N
S
N
S
Ph
Ph
Ph
Ph
b
S
Ph
Ph
Ph
Ph
O
O
O
3ha
, 86%
F
3ia
3ja
3ka
, 81%
, 80%
, 70%
N
N
N
N
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
S
Ph
Ph
S
S
Ph
Ph
S
O
Ph
Ph
Ph
3la
O
O
O
c
3oa
, 57%
, 63%
3ma
, 68%
3na
, 65%
Ph
N
N
N
N
Ph
Ph
Ph
N
N
N
N
F
I
N
N
S
O
N
S
N
S
O
, 69%
Ph
Ph
S
Ph
Ph
Ph
Ph
3sa
Ph
O
O
3pa
3qa
, 73%
, 34%
3ra
, 83%
S
N
N
N
N
Ph
Ph
N
N
N
N
S
N
S
O
N
S
O
Ph
Ph
Ph
Ph
3va
Ph
3ta,
O
, 63%
3ua
, 67%
35%
To establish the scope of the protocol, several NH-sulfoximines
(2) were then examined under the optimized reaction conditions
(Table 3). It was found that most alkyl aryl sulfoximines reacted
smoothly with 1a under the optimum conditions (3ab-3af).
Sulfoximine bearing halogen (Br), electron-donating substituent
(OMe) or a strong electron-withdrawing group (NO2) on the
phenyl ring all worked well to give 3ac, 3ad and 3ae in good
yields. It is noteworthy that cycloalkyl sulfoximine, S,S-
tetramethylenesulfoximine also afforded the corresponding
product 3af in reasonable yield of 62%.
aReaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), PhI(OAc)2 (1.2 equiv),
DMSO (1.0 mL) at 30 °C for 3 h. Sealed tube. Isolated yields.
bDMSO (3.0 mL).
cDMSO (4.0 mL).
Table 3. Substrate Scope of sulfoximinesa,b
N
O
N
N
PhI(OAc)2 (1.2 equiv)
+
R1
S
NH
N
S
N
DMSO, 30C, 3h
R2
Ph
R2
R1
O
2
1a
3
N
N
N
Ph
Ph
Ph
N
N
N
N
S
N
S
N
S
Ph
Ph
O
O
O
, 73%
N
Br
3ac
3aa
, 79%
N
, 76%
N
3ab
Table 2. Substrate Scope of Imidazo[1,2-a]pyridinesa
Ph
Ph
Ph
N
N
N
N
N
N
O
S
S
S
O
O
O2N
O
3ae
, 78%
3ad
3af
, 65%
, 62%
aReaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), PhI(OAc)2 (1.2 equiv),
DMSO (1.0 mL) at 30 °C for 3 h. Sealed tube.
bIsolated yields.
Several control experiments were carried out to provide further
insights into the mechanism of this reaction (Scheme 2). When a
radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
was added under the optimized reaction conditions, only trace
amount of product was detected. In the presence of 2,6-di-tert-
butyl-4-methyl phenol (BHT), the reaction was also suppressed

4
Biancotti, A.; Gamba, A.; Murmann, W. J. Med. Chem. 1965, 8,
305-312.
obviously, together with the formation of the compound 4 and 5
detected by HRMS. These observations suggest that the reaction
probably proceeds through a radical pathway.
3.
4.
(a) Du, B.; Shan, A.; Zhong, X.; Zhang, Y.; Chen, D.; Cai, K. Am.
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Dev. 2009, 13, 781-785.
Scheme 2. Control Experiments.
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82, 4504-4510. (b) Gao, Y.; Chen, S.; Lu, W.; Gu, W.; Liu, P.; Sun,
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M.; Liu, P.; Yu, B.; Dong, X.; Lei, A. Chem. Commun. 2019, 55,
1809-1812. (e) Singsardar, M.; Mondal, S.; Sarkar, R.; Hajra, A.
ACS Omega 2018, 3, 12505-12512. (f) Lu, S.; Tian, L.; Cui, T.;
Zhu, Y.; Zhu, X.; Hao, X.; Song, M.; J. Org. Chem. 2018, 83,
13991-14000. (g) Samanta, S.; Ravi, C.; Rao, S.; Joshi, A.;
Adimurthy, S. Org. Biomol. Chem. 2017, 15, 9590-9594. (h) Chen,
H.; Yi, H.; Tang, Z.; Bian, C.; Zhang, H.; Lei, A. Adv. Synth. Catal.
2018, 360, 3220-3227. (i) Samanta, S.; Mondal, S.; Ghosh, D.;
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2004, 43, 5984-5987. (d) Sedelmeier, J.; Hammerer, T.; Bolm, C.
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R. K.; Sahoo, A. K. Chem. Eur. J. 2012, 18, 5541-5545.
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1319-1324.
(a) Griffith, O. W.; Meister, A. J. Biol. Chem. 1979, 254, 7558-
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220.
N
Ph
N
O
N
TEMPO
(2.0 equiv)
+
N
S
Ph
Ph
S
NH
N
Ph
standard conditions
Ph
Ph
O
3aa
, trace
1a
2a
OH
Ph
N
HO
Ph
N
O
N
BHT
(2.0 equiv)
+
N
S
O
Ph
Ph
S
NH
N
Ph
standard conditions
Ph
Ph
N
S
N
Ph
O
1a
2a
3aa
, 51%
N
Ph
5
4
detected by HR-MS
Based on the above results as well as previous reports,4a,4e,12a,13
a possible mechanism for this direct C-H sulfoximination of
imidazopyridines is proposed in Scheme 3. At first, NH-
sulfoximine (2a) produces N-iodoamino species A in the presence
of PhI(OAc)2, which subsequently generates the corresponding N-
5.
centered radical species
B
and acetoxy radical. The
imidazopyridine radical cation (C) is obtained from 2-
phenylimidazo[1,2-a]pyridine (1a) through a single electron
transfer process in the presence of acetoxy radical. Then, the N-
centered radical B coupled with the imidazopyridine radical cation
(C) regioselectively to produce the intermediate D. The
intermediate D consequently affords the product (3aa) through
further deprotonation by the acetate anion, together with the
elimination of AcOH.
6.
7.
Scheme 3. Plausible Mechanism.
Ph
PhI
I
O
O
O
AcO
OAc
OAc
Ph
N
Ph
S
N
I
Ph
S
NH
Ph
S
N
N
AcO
Ph
Ph
Ph
Ph
Ph
2a
Ph
N
S
D
N
AcOH
H
A
B
AcO
N
N
Ph
S
O
N
Ph
N
AcOH
Ph
O
Ph
Ph
N
N
3aa
8.
9.
(a) Lücking, U..; Siemeister, G.; Jautelat, R WO Patent WO
2006/099974, A1 2006. (b) Shetty, S. J.; Patel, G. D.; Lohray, B.
B.; Lohray, V. B.; Chakrabarti, G.; Chatterjee, A.; Jain, M. R.;
Patel, P. R. WO Patent WO 2007/077574, A2 2006.
AcO
C
1a
Conclusion
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In summary, an efficient method for PhI(OAc)2-mediated
regioselective sulfoximination of imidazopyridines via C(sp2)-H
bond functionalization has been developed. The reaction
proceeded smoothly with a wide range of substrates and provided
the coupling products in moderate to good yield. Other
imidazoheterocycles, such as 2-phenylbenzo[d]imidazo[2,1-
b]thiazole and 2-(p-tolyl) imidazo[1,2-a]pyrimidine were also
compatible to this system. Broad substrate scopes, operational
simplicity and mild conditions are the prominent advantages of
this methodology. We believe this strategy possesses great
potential in organic chemistry and pharmaceutical research.
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