Metal-free TBHP-mediated oxidative ring openings of 2-arylimidazopyridines via regioselective cleavage of C-C and C-N bonds

Article abstract of DOI:10.1039/c5ra17740e

A highly regioselective TBHP-mediated ring opening of imidazopyridines via cleavage of C-C and C-N bonds has been achieved for the first time to afford N-(pyridin-2-yl)benzamides. Preliminary mechanistic investigations revealed that the present metal-free

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Metal-Free TBHP-Mediated Oxidative Ring Openings of 2-
Arylimidazopyridines Via Regioselective Cleavage of C−C and C−N
Bonds
Received 00th January 20xx,
Accepted 00th January 20xx
Kelu Yan, Daoshan Yang,* Wei Wei, Guoqing Li, Mingyang Sun, Qingyun Zhang, Laijin Tian, and
Hua Wang*
DOI: 10.1039/x0xx00000x
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approaches to cleave C–C and C-N bonds. Futhermore, cleavage of
both C-C and C-N bonds in a single organic transformation is an
A
highly regioselective TBHP-mediated ring openings of
imidazopyridines via cleavage of C-C and C-N bonds has been
achieved for the first time to afford N-(pyridin-2-yl)benzamides. undoubtedly attractive but challenging objective. Nevertheless,
Preliminary mechanistic investigations revealed that the present
metal-free transformation involved a radical pathway, and the
oxygen atom incorporated in the end products might derive from
TBHP.
until now, very few strategies for the cleavage of C-C and C-N bonds
have been successfully developed in one molecule under one set of
conditions.15 In 2014, Laha and co-workers developed an elegant
tandem
oxidative
conversion
of
10,11-dihydro-5H-
dibenzo[b,e][1,4]diazepines to phenazines via C-C and C-N bond
cleavage under metal-free condtions.15b Especially, the direct
transformation of relatively stable five-membered heterocyclics
through C-C and C-N bonds cleavage in one step is still far from
being addressed. Herein, for the first time, we describe a novel
transition-metal-free oxidative C-C and C-N bonds cleavage of
imidazopyridines leading to N-(pyridin-2-yl)benzamides using TBHP
(tert-butyl hydroperoxide) as the oxidizing agent (Scheme 1).
Carbon-carbon bonds are the most basic chemical bonds in organic
molecules. The selective catalytic cleavage of C-C bonds for
chemical transformations is a prime topic in synthetic organic
chemistry and has become one of the most attractive and
challenging tasks faced by researchers.[1] Traditionally, C-C bonds
cleavage have been accomplished by β-carbon elimination,2
decarbonylation reactions,3 and oxidative addition reactions4 etc.
Recently, transition-metal-catalyzed selective C-C bonds cleavage
has attracted considerable attention, and lots of excellent research
achievements have been reported.5 For example, copper-catalyzed
aerobic selective C(CO)-C(alkyl) bond cleavage has been successfully
achieved by Jiao,6 Bi7 and other groups.8 On the other hand, the C-N
bonds are omnipresent in organic compounds. Seeking mild and
selective approaches for the cleavage of C-N bonds has become the
hot topic of intensive studies.9 Classical methods for C-N bond
cleavage include the deprotection of N-protecting groups,10 and the
transformations of ammonium salts,11 imidazoles,12 triazenes,13
diazonium salts9b and others.14
Scheme 1 Synthesis of N-(pyridin-2-yl)benzamides via C-C and
C-N bond cleavage
Although great advances of these C-C and C-N bonds cleavage
transformations have been achieved, there are still certain
limitations including harsh reaction conditions, and toxic and
expensive metal salts in combination with oxidants which make it
highly desirable to develop facile, efficient and transition-metal-free
As shown in Table 1, we firstly chose 2-phenylimidazo[1,2-
a]pyridine (1a) as the model substrate to explore the optimal
reaction conditions. At the outset, when 1a (0.4 mmol) and 4.0
equiv of TBHP were heated at 90 oC using toluene as the solvent
under air atmosphene, the ring-open product 2a could be obtained
in 69% yield. Other oxidants such as DTBP, H2O2, and K2S2O8 were
surveyed at 90°C in 2 mL toluene, and TBHP was found to be the
most effective oxidant (entries 1-5). Furthermore, the solvents,
including DMF, H2O, 1,4-dioxane, CH3CN and DCE were tested using
TBHP as the oxidant at 90 °C, and DCE provided the highest yield
(73%) (entries 1, 6-10). Different reaction temperatures were also
The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and
Chemical Engineering
,
Qufu Normal University, Qufu 273165, Shandong, P. R.
China. E-mail: yangdaoshan@tsinghua.org.cn; huawang_qfnu@126.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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investigated (entries 10-12), showing that the best yield was investigations to explore more powerful catalyst and oxidant was
obtained when the reaction was conducted at 80 oC (entry 11, Table required. Some functional groups could be compatible in the
1). Additionally, different amounts of TBHP were attempted, and present reactions, including methyl, methoxy, nitro, and
4.0 equiv of TBHP was more suitable for the present transforamtion trifluoromethyl.
(compare entries 11, 13 and 14). Thus, the optimized reaction
Table 2 TBHP-mediated oxidative ring openings of imidazopyridines
(1) leading to N-(pyridin-2-yl)benzamides (2) a,b
conditions for this ring-open conversation was: 1a (0.4mmol), TBHP
(4 equiv), in DCE at 90 oC under an air atmosphere for 18h.
Table 1 Optimization of the Conditions a
Entry
1
Oxidant
TBHP
DTBP
TBPB
H2O2
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Temp [oC] Yieldb[%]
90
90
90
90
90
90
90
90
90
90
80
70
80
80
69
Trace
15
2
3
4
18
5
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Trace
26
6
7
H2O
44
8
1,4-Dioxane
CH3CN
DCE
31
9
65
10
11
12
13
14
73
DCE
73
DCE
62
DCE
71c
56d
DCE
a
Reaction conditions: 1a (0.4mmol), TBHP (tert-butyl
hydroperoxide 70 wt % in water.), solvent (2 ml) and reaction time
b
c
d
(18 h). Isolated yield. In the presence of TBHP (5 equiv). In the
presence of TBHP (3 equiv).
With the optimized reaction conditions in hand, we next turned
our attention toward the scope and limitation of the ring-open
transformation, with the results summarized in Table 2. It was
found that substrates bearing either electron-donating or electron-
withdrawing groups on any aryl ring of the imidazopyridines could
be applied to afford the corresponding products 2a-2z in moderate
to good yields. Strong electron-withdrawing substitutes such as -
NO2 and -CF3 showed no obvious affect of the oxidative ring-open
reaction (2m, 2w and 2x). This transformation displayed a
satisfactory tolerance of halogen atom (2f, 2g, 2j, 2k, 2l, 2p and 2s),
which could be used for further transformations through transition-
metal-catalyzed cross-coupling reactions. Additionally, a naphthyl
group could also participate participated in this transformation with
a
Reaction conditions: 1a (0.4mmol), TBHP (tert-butyl
a
high reactivity (2q). Notably, when 2-furan imidazo[1,2-
hydroperoxide 70 wt % in water.), solvent (2 ml), and reaction time
(18 h). b Isolated yield.
a]pyridines were used, the desired products of 2y and 2z were
obtained in 52% and 54% isolated yields, respectively. Although this
transformation was efficient, unfortunately, not all the
imidazopyridines were compatible. For example, if 2-
methylimidazo[1,2-a]pyridine 1aa and 2-tert-butylimidazo[1,2-
a]pyridine 1ab were used as the substrates under the optimal
reaction conditions, only a trace of product was obtained (2aa and
2ab). The reason might be the electronic effect of the substrates
influenced the stability of the transition state. Thus, further
In order to gain an insight into the reaction mechanism, several
control experiments were performed with the results shown in
Scheme 2. The reaction was suppressed remarkably when 2 equiv
of BHT (2,6-di-tert-butyl-4-methylphenol), a well known radical-
trapping reagent, was added into the present reaction system,
which implied that the reaction might proceed via a free radical
process (eq 1, Scheme 2). When the model reaction was performed
under strictly moistureless conditions, the ring-opening products 2a
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was obtained in 72% yield (eq 2, Scheme 2). Futhermore, the Reaction of A with t-BuO· lead to an unstable four-membered
reaction can also proceed under a nitrogen atmosphere (eq 3, peroxide intermediate B, which was possibly converted to C.
Scheme 2). Additionally, no 18O2-2a was detected when H218O was Subsequently, a tert-butyl formate16 was released from the
introduced into in the reaction system (see Figure 1 in the intermediate C leading to D that could proceed the isomerization so
Supporting Information) (eq 4, Scheme 2). These preliminary results as to afford the desired product 2a. Further investigations on the
indicated that the incorporated oxygen of the products might come more detailed mechanism are underway in our laboratory.
from TBHP. Moreover, the reaction mixture was examined by HRMS
In conclusion, we have realized an unusual metal-free TBHP-
after reation of 1a with TBHP for a time, and peroxide intermediate
mediated simultaneous cleavage of C-C and C-N bonds in 2-
(B) or (Z)-N-(1-formylpyridin-2(1H)-ylidene)benzamide (C) were
arylimidazopyridines. Preliminary mechanistic studies disclosed that
found (see Figure 2 in the Supporting Information) (eq 5, Scheme 2).
the reactions might proceed via a radical pathway, and the oxygen
atoms incorporated in the ring-opening products might derive from
OH
H
N
N
TBHP. The present protocol introduces a new model of C-C and C-N
bonds cleavge in organic chemistry, although the detailed
mechanism for the cleavage of C−C and C−N bonds remains unclear,
of which further invetigations are ongoing in our laboratory.
TBHP, DCE, 80o
C
(1)
BHT:
N
N
O
BHT (2 equiv)
2a
trace
1a
H
N
N
TBHP ( 4 equiv)
(2)
DCE (dry), 80oC, 4 A MS
N
N
O
This work was supported by the National Natural Science
Foundation of China (Nos. 21302110, 21302109 and 21375075), the
Natural Science Foundation of Shandong Province (ZR2013BQ017
and ZR2013M007), the Taishan Scholar Foundation of Shandong
Province, the Project of Shandong Province Higher Educational
Science and Technology Program (J13LD14). We thank Pengfei Sun
in this group for reproducing the results of 2a and 2t.
2a
72%
1a
TBHP: 5-6M in decane
H
N
TBHP, DCE, 80o
N2
C
N
(3)
N
O
N
2b
1a
74%
H
H
N
N
N
TBHP, H218O
(4)
O18 CH3
N
N
O
CH3
DCE, 80o
C
N
1b H3
C
2b
73%
Not observed
TBHP:H2O18 (v1/v2) = 7:3
Notes and references
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+ ...... (5)
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A highly regioselective TBHP-mediated ring openings of imidazopyridines via
cleavage of C-C and C-N bonds has been realized for the first time to afford useful
N-(pyridin-2-yl)benzamides under mild conditions.