CBr4 Mediated Oxidative C-N Bond Formation: Applied in the Synthesis of Imidazo[1,2-α]pyridines and Imidazo[1,2-α]pyrimidines

Article abstract of DOI:10.1021/acs.orglett.6b00137

The carbon tetrabromide mediated oxidative carbon-nitrogen bond formation of 2-aminopyridines or 2-aminopyrimidines with β-keto esters or 1,3-diones, leading to a variety of complex imidazo[1,2-α]pyridines or imidazo[1,2-α]pyrimidines, is reported. The re

Full text of DOI:10.1021/acs.orglett.6b00137

Letter
pubs.acs.org/OrgLett
CBr4 Mediated Oxidative C−N Bond Formation: Applied in the
Synthesis of Imidazo[1,2-α]pyridines and Imidazo[1,2-α]pyrimidines
Congde Huo,* Jing Tang, Haisheng Xie, Yajun Wang, and Jie Dong
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
S
* Supporting Information
ABSTRACT: The carbon tetrabromide mediated oxidative carbon−
nitrogen bond formation of 2-aminopyridines or 2-aminopyrimidines
with β-keto esters or 1,3-diones, leading to a variety of complex
imidazo[1,2-α]pyridines or imidazo[1,2-α]pyrimidines, is reported.
The reactions were realized under mild and metal-free conditions.
Scheme 1. Related Background
he formation of carbon−nitrogen bonds continues to be
Tan active and challenging field of heterocyclic chemistry.
Imidazo[1,2-a]pyridines (IPYs) are an important type of
heterocycles and have attracted much attention due to their
remarkable biological and pharmacological activities.1 Within
the IPY family, commercially available drugs have been derived,
including alpidem (anxiolytic),2 zolpidem (insomnia),3 necopi-
dem (anxiolytic),4 saripidem (anxiolytic),5 and zolimidine
(antiulcer)6 (Scheme 1, part A). In addition, molecules with
the IPY moiety are also broadly applied in organometallic
chemistry and material science because of their structural
characteristics.7 Not surprisingly, because of their applications
in a variety of fields, many synthetic methods have been
developed for IPYs. Although the preparation of these
compounds has been investigated for more than a century,
the past decade has witnessed a remarkable advancement in the
synthesis of IPYs.8 Among a variety of new synthetic
transformations, transition-metal-catalyzed reactions have
proven to be a powerful tool for the synthesis of IPY
derivatives.9 Very recently, TBAI/BF3Et2O/TBHP10 or Fe/I2/
11
O2 -catalyzed oxidative coupling of the C−N bond has been
developed for the construction of IPYs (Scheme 1, part B).
Although elegant processes have been reported, the develop-
ment of new routes is still highly desirable for the synthesis of
functionalized IPYs from readily available precursors without
the necessity for prefunctionalities under simple metal-free
conditions. Since 2015, carbon tetrabromide (CBr4) has been
found to show good reactivity in cross-dehydrogenative
coupling (CDC) reactions to construct carbon−carbon bonds
by us (Scheme 1, part C).12 Herein, we developed a new and
facile CBr4-promoted protocol to construct structurally
sophisticated IPY derivatives from readily accessible starting
materials in a single operation under mild conditions (Scheme
1, part D).
benzoylacetate 2a in the presence of 2 equiv of CBr4. To our
delight, as shown in Table 1, when the mixture was heated at 80
As part of our continuing interest in CBr4 assisted
transformation, we wanted to attempt the CBr4 mediated C−
N bond formation reaction. The study was initiated by
investigating the reaction of 2-aminopyridine 1a with ethyl 2-
Received: January 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00137
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Screening of Reaction Conditions
Scheme 2. CBr4 Mediated Syntheses of Imidazo[1,2-
α]pyridines and Imidazo[1,2-α]pyrimidines
a
b
entry
[Hal]
CBr4
loading
solvent
temp
yield [%]
1
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
1 equiv
0.5 equiv
3 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
60 °C
100 °C
rt
90
60
62
40
32
44
trace
0
2
NCS
3
NBS
4
NIS
5
DBDMH
Br2
6
7
CHBr3
CH2Br2
DBE
8
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
CuBr2
KBr/H2O2
CBr4
0
trace
83
43
89
42
26
17
77
53
87
88
50
CBr4
CBr4
CBr4
CBr4
CBr4
toluene
H2O
CBr4
CBr4
MeOH
MeCN
MeCN
MeCN
CBr4
CBr4
CBr4
a
Reaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), solvent (2 mL),
b
6 h. Yields of the isolated product. NCS = N-Chlorosuccinimide.
NBS = N-Bromosuccinimide. NIS = N-Iodosuccinimide. DBDMH =
1,3-dibromo-5,5-dimethylhydantoin. DBE = dibromoethane.
°C for 6 h, the desired product 3aa was isolated in excellent
yield (Table 1, entry 1). The use of other halogen analogues
such as NCS, NBS, NIS, DBDMH, and Br2, instead of CBr4,
was found to be less effective (Table 1, entries 2−6).
BrCH2CH2Br, CHBr3, CH2Br2, CuBr2, and KBr/H2O2 were
inactive for this transformation (Table 1, entries 7−11). The
yields dropped to 83% and 43% when the CBr4 loading was
reduced to 1 and 0.5 equiv, respectively (Table 1, entries 12,
13). Increasing the amount of CBr4 from 2 to 3 equiv resulted
in no appreciable differences (Table 1, entry 14). Furthermore,
the use of other solvents such as DCM (42%), THF (26%),
toluene (17%), water (77%), and MeOH (53%) was found to
be less productive than MeCN (Table 1, entries 15−19). Both
increasing and decreasing the temperature resulted in lower
yields (Table 1, entries 20−22). Thus, it was determined that
CBr4 (2 equiv) at 80 °C in acetonitrile were the optimal
reaction conditions (90%, Table 1, entry 1).
With the optimized conditions in hand, we applied this
strategy to the oxidative C−N bond formation of various 2-
aminopyridines 1 with different β-keto esters or 1,3-diones
substrates 2. As shown in Scheme 2, the reactivity of 2-
aminopyridine 1 was remarkably dependent on the electronic
properties of the substituents from the pyridine ring. 2-
Aminopyridines without a substituent group or with an
electron-donating group such as Me provided higher yields of
IPYs, but 2-aminopyridines with an electron-withdrawing group
such as Cl gave lower yields. Intriguingly, 2-aminopyrimidine
(1i, a guanidine surrogate) smoothly underwent this trans-
formation generating the desired products 3ia−3ih in moderate
a
Reaction conditions: 1 (1.5 mmol), 2 (0.5 mmol), MeCN (2 mL), 80
b
°C, 3−36 h. Yield of the isolated product.
to good yields. The structure of 3ig was confirmed by single
crystal X-ray diffraction as shown in Scheme 2.13 It is
noteworthy that these imidazo[1,2-α]pyrimidine products
were also widely applied in the synthesis of biologically active
heterocycles.14
To examine the scalability of the present methodology, a
reaction of 2-aminopyridine 1a and ethyl 2-benzoylacetate 2a
was performed at the 10 g scale. The corresponding 3aa was
B
DOI: 10.1021/acs.orglett.6b00137
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Letter
obtained in 81% isolated yield as shown in Scheme 3. That is to
say, here we present a practical and scalable synthetic entry to
the highly functionalized IPY derivatives.
Scheme 5. Proposed Mechanism
Scheme 3. Scalability of the Reaction to the Multigram Scale
Control experiments were carried out in order to have a
better understanding of this transformation. Intermediate A was
isolated from the reaction mixture of 1a and 2a under the
standard reaction conditions by stopping the reaction after a
short time (0.5 h) [Scheme 4, eq 1]. Furthermore, we proved
Scheme 4. Control Experiments
In summary, we have developed an efficient CBr4-mediated
oxidative C−N bond formation reaction of 2-aminopyridines or
2-aminopyrimidines with β-keto esters or 1,3-diones to
construct complex imidazo[1,2-α]pyridines and imidazo[1,2-
α]pyrimidines. The starting materials and the promoter are
commercially available. The reactions were performed under
simple and mild reaction conditions. Further studies on the
mechanistic details and synthetic applications of this method
are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00137.
Experimental details, compound characterization, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: huocongde1978@hotmail.com.
Notes
The authors declare no competing financial interest.
that the reaction of intermediate A and 1a gave the same
product 3aa in high yield even without CBr4 as the promoter
[eq 2].15 These results indicate that A is the intermediate of this
CBr4 induced transformation. Tetramethylpiperidin-1-oxyl
(TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) were
employed in the standard reaction as a radical scavenger, and
no obvious inhibition was observed [eqs 3 and 4]. These results
suggested that no radical process was involved in the present
CBr4 induced reaction.
According to these results, we were able to propose the
tentative mechanism of the reactions, as shown in Scheme 5.
Taking the reaction of 2-aminopyridine 1a and ethyl 2-
benzoylacetate 2a for example, in the synthesis of IPY 3aa, 1a is
first brominated with CBr4 to give intermediate A. The
nucleophilic substitution of 2-aminopyridine (2a) with
intermediate A affords intermediate B. Subsequent intra-
molecular nucleophilic addition of B provides intermediate C.
Finally, the proton transfer and the subsequent dehydration and
dehydrogenation produced IPY 3aa. Alternatively (path b),
condensation of A with 2a affords imine intermediate E.
Intramolecular nucleophilic substitution of E also provides 3aa.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21262029, 21562037) and the Natural Science Foundation of
Gansu Province (1506RJZA122) for financially supporting this
work.
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