Cu-Catalyzed Synthesis of 3-Formyl Imidazo[1,2-a]pyridines and Imidazo[1,2-a]pyrimidines by Employing Ethyl Tertiary Amines as Carbon Sources

Article abstract of DOI:10.1021/acs.orglett.7b02015

A highly efficient synthesis of 3-formyl imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine, under Cu-catalyzed aerobic oxidative conditions and by utilizing ethyl tertiary amines as carbon sources, is disclosed. A novel activation mode of ethyl tertiary amines in which simultaneous selective cleavage of C-C bond and C-N bond of ethyl group with molecular oxygen as terminal oxidant in this one-pot protocol is reported for the first time. This reaction features broad substrate scope, good functional group tolerance, as well as diversified and valuable products.

Full text of DOI:10.1021/acs.orglett.7b02015

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Synthesis of 3‑Formyl Imidazo[1,2‑a]pyridines and
Imidazo[1,2‑a]pyrimidines by Employing Ethyl Tertiary Amines as
Carbon Sources
Changqing Rao, Shaoyu Mai, and Qiuling Song*
The Institute of Next Generation Matter Transformation, College of Chemical Engineering & College of Material Sciences
Engineering, Huaqiao University, 668 Jimei Blvd., Xiamen, Fujian 361021, PR China
S
* Supporting Information
ABSTRACT: A highly efficient synthesis of 3-formyl imidazo[1,2-
a]pyridine and imidazo[1,2-a]pyrimidine, under Cu-catalyzed aerobic
oxidative conditions and by utilizing ethyl tertiary amines as carbon
sources, is disclosed. A novel activation mode of ethyl tertiary amines in
which simultaneous selective cleavage of C−C bond and C−N bond of
ethyl group with molecular oxygen as terminal oxidant in this one-pot
protocol is reported for the first time. This reaction features broad substrate scope, good functional group tolerance, as well as
diversified and valuable products.
used heterocyclic compounds constitute one of the
privileged core structural motifs in pharmaceuticals and
both carbon source and formylation reagent. At the same time,
we present access to diverse imidazo[1,2-a]pyrimidines from 2-
aminobenzimidazoles and ethyl tertiary amines. Due to the high
C−N bond dissociation energy and the stability of unactivated
N-containing compounds, C−N bond activation has emerged as
a great challenge in organic chemistry.11 As one of most stable
nitrogen-containing compounds, the application of ethyl tertiary
amines as amino sources via C−N bond activation has aroused
much attention in recent years. In 2011, Huang’s group
established a Cu-catalyzed oxidative amination of benzoxazoles
via C−N bond activation of Et3N (Scheme 1a).12 In 2013, Bao
and co-workers developed the first selective aminolysis of aryl
esters using inert tertiary amines as nitrogen sources (Scheme
1b).13 Later on, an effective supported gold nanoparticle-
catalyzed aminolysis of esters using tertiary amines as amino
donors was also reported by Bao et al. (Scheme 1c).14 In 2016,
Sun’s group demonstrated a Cu-catalyzed coupling reaction of
sulfonyl chlorides with tertiary amines via oxidative C−N bond
cleavage of Et3N (Scheme 1d).15 Recently, selective synthesis of
β-arylsulfonyl enamines from sodium sulfinates via C−H
activation of tertiary amines has been achieved by Yuan and
co-workers (Scheme 1e).16 Although ethyl tertiary amines have
been widely used as nitrogen sources via C−N bond activation,
their usage as carbon sources via C−C bond activation has rarely
been explored. In addition, simultaneous cleavage of C−C bond
and C−N bond of ethyl group in ethyl tertiary amines followed
by the formation of acrolein which was involved in the
subsequent transformation has not been reported before. Herein,
we report the synthesis of imidazo[1,2-a]pyridine and imidazo-
[1,2-a]pyrimidine by utilizing ethyl tertiary amines as carbon
sources via both C−C bond and C−N bond activation in one-pot
protocol (Scheme 1f).
F
material sciences. Among them, imidazo[1,2-a]pyridines and
imidazo[1,2-a]pyrimidines show prominent biological applica-
tions in pharmaceutical agents and natural products.1 These two
important frameworks have emerged in a variety of drugs, such as
zolpidem (A),2 alpidem (B),3 olprinone (C),4 p38 kinase
inhibitor (D),5 Fasiplon (E)6 and Divaplon (F)7 (Figure 1).
Figure 1. Biologically active or potent imidazo[1,2-a]pyrimidines and
imidazo[1,2-a]pyridines.
Therefore, continued effort has been devoted to the develop-
ment of new and efficient synthetic strategies for the preparation
of 3-formyl imidazo[1,2-a]pyridine and imidazo-[1,2-a]-
pyrimidine backbones. In 2011, Zhu’s group developed a Cu-
catalyzed intramolecular dehydrogenative aminooxygenation to
produce various imidazo[1,2-a]pyridine-3-carbaldehydes from
readily available N-allyl-2-aminopyridines.8 In 2012, an aqueous
synthesis of 3-formyl imidazo[1,2-a]pyridines via silver-catalyzed
aminooxygenation was also achieved by Adimurthy.9 In 2014,
Cao and co-workers demonstrated a novel Cu-catalyzed selective
formylation of imidazo[1,2-a]pyridines by using DMSO as the
formylation reagent.10 Herein, we report a Cu-catalyzed
synthesis of 3-formyl imidazo[1,2-a]pyridines from commer-
cially available 2-aminopyridines by using ethyl tertiary amines as
Received: July 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02015
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Organic Letters
Letter
reaction was performed at 100 °C rendering the best yield of
3a (Table 1, entries 3−5). The effect of ligands was further
explored in this transformation (Table 1, entries 6−9). To our
delight, the yield of desired product 3a was slightly increased to
66% by using TMEDA as ligand (Table 1, entry 9). Of note, only
marginal improvements were obtained when we changed the
amount of catalyst and the loading of ligand (Table 1, entries 10−
14).
Scheme 1. Application of Tertiary Amines as Material to
Synthesis of N-Containing Compounds
Inspired by the C−N activation of Et3N to construct
imidazo[1,2-a]pyridine-3-carbaldehyde, other variety of ethyl
amines were further employed under the standard conditions to
react with 2-aminopyridine 1a (Scheme 2). To our delight,
a
Scheme 2. Scope of Tertiary Amines
We began our investigation by treatment of 2-aminopyridine
1a in the presence of 20 mol % CuI and 40 mol % DMEDA in
DMSO using O2 as the oxidant at 130 °C,17 which delivered the
product imidazo[1,2-a]pyridine-3-carbaldehyde (3a) in 20%
yield along with 10% yield of N-(pyridin-2-yl)formamide (Table
1, entry 1). The results inspired us and indicated the feasibility of
the envisioned strategy by employing ethyl tertiary amines as
carbon sources albeit the low yield. Subsequently, when other
metals such as CuBr, Pd(OAc)2 or Cu(OAc)2 were used instead
of CuI, stagnant reactions were observed (see Supporting
Information). Among the temperatures tested, the model
a
Reaction conditions: la (0.5 mmol), 2 (2.5 equiv), Cul (20 mol %),
TMEDA (40 mol %), DMSO (1 mL), at 100 °C, under O2, 24 h. The
isolated yield of 3a was based on 1a.
Table 1. Optimization of the Reaction Conditions for the
Reaction
a
various ethyl-containing tertiary amines (2a−2i) were suitable
for this transformation, delivering the desired product 3a in
moderate to good yields. In addition to tertiary amines,
secondary amine 2j was also amenable to this reaction albeit
with a low yield of 3a (36% yield). No product 3a was detected
when 2k or 2l was submitted to the standard conditions, which
indicated that the ethyl group installed on the amines was a
prerequisite for this transformation.
Because the yield of 3a was higher when DIPEA was used
instead of Et3N (Scheme 2), DIPEA was then employed as
carbon sources for further assessment of the scope of 2-
aminopyridine derivatives. As shown in Scheme 3, a variety of 2-
aminopyridine derivatives bearing different substituents on the
pyridine ring were well tolerated, giving the desired imidazo[1,2-
a]pyridine-3-carbaldehydes in moderate to good yields (Scheme
3, 3a−3j), among them, 3a could be obtained in 60% yield in a 2
mmol-scale reaction. Interestingly, quinolin-2-amine 1k was also
amenable to this transformation, delivering the product 3k in
moderate yield. To our delight, 3-amino pyridazine (1l) could
produce the corresponding imidazo[1,2-b]pyridazine-3-carbal-
dehyde (3l) as well, albeit with a relative low yield.
entry
catalyst
Cul
temp (°C) ligand yield (%) of 3a yield (%) of 3a″
1
2
3
4
5
6
7
8
9
130
130
80
L1
L1
L1
L1
L1
L1
L2
L3
L4
L4
−
20
10
N.D.
49
33
10
22
20
trace
23
32
20
25
12
9
Pd(OAc)2
Cul
N.D.
25
Cul
100
120
100
100
100
100
100
100
100
100
100
41
Cul
32
b
Cul
63
Cul
48
10
Cul
b
Cul
66
c
b
10
Cul
58
d
11
Cul
44
56
47
16
e
12
Cul
L4
L4
L4
f
13
Cul
g
14
Cul
a
Reaction conditions: 1a (0.5 mmol), 2a (2.5 equiv), catalyst (20 mol
Next, the copper-catalyzed annulation reaction of the 2-
aminobenzo[d]imidazole compounds 4 with DIPEA to provide
imidazo[1,2-a]pyrimidines 5 was further performed with
CH3CN as the solvent (Scheme 4) after condition optimization
(see SI for details). Among them, a variety of symmetrical bis-
substituted 2-aminobenzo[d]imidazoles were first tested under
%), ligand (40 mol %), DMSO (1 mL), under O2, 24 h, GC yield.
b
c
d
e
Isolated yield. Cul 40 mol %. no TMEDA. TMEDA 20 mol %.
f
g
TMEDA 60 mol %. TMEDA 100.
B
DOI: 10.1021/acs.orglett.7b02015
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Letter
Scheme 3. Scope of 2-Aminopyridines toward C-3 Formyl-
imidazo[1,2-a]pyridines
Scheme 5. Control Experiments to Elucidate the Reaction
Pathway
a
a
Reaction conditions: 1 (0.5 mmol), 2b (2.5 equiv), Cul (20 mol %),
b
TMEDA (40 mol %), DMSO (1 mL), at 100 °C, under O2, 24 h. 2
mmol scale.
Scheme 4. Scope of 2-Aminobenzo[d]imidazoles toward
a
Imidazo[1,2-a]pyrimidines
confirmed by the reaction between 1a and acrolein, since 3a was
afforded in 80% yield (Scheme 5c). When the reaction was
performed in DMSO-d6 under the optimized conditions, 3a-d
was not detected by 1H NMR (Scheme 5d), which indicated that
the aldehyde group of 3a did not originate from DMSO. In order
to exclude the source of formaldehyde from TMEDA, the
reaction was run without TMEDA and the target product was
obtained in 61% isolated yield (Scheme 5e). Remarkably, when
trimethylamine (2a) was employed with 1a under the standard
conditions, 3a was obtained in 66% yield along with the
formation of N,N-diethyl formamide (detected by GCMS). This
is strong evi- dence that the C−C bond of the ethyl group in
trimethylamine was cleaved under the standard conditions and
formaldehyde was generated during this process (Scheme 5f). In
order to understand the origin of oxygen in aldehyde, H2O18 was
added to the system in anhydrous DMSO, and 3a was obtained in
70% yield with 3:7 ratio of 3a and 3a-O18 (detected by GCMS)
(Scheme 5g). This result infers that water is involved in the
transformation and most likely is involved in the formation of
acetaldehyde (see Scheme 5 for details). Noteworthily, when the
reaction was performed under 18O2 in anhydrous DMSO, 3a was
afforded in 71% yield with 1:1 ratio of 3a and 3a-O18 (detected
by GCMS) (Scheme 5h). This result was also expected since one
equivalent of H2O18 was generated in situ when N−CH2 bond of
iPr2NEt was oxidized into NC bond in the presence of CuI and
18O2; the H2O18 eventually could be introduced into final
product by hydrolysis of NC bond to release CH3CHO.
On the basis of earlier reports as well as our own experimental
observation, a plausible mechanism for the formation of 3a and
5a is depicted in Scheme 6.17,18 Formation of the immonium salt
from tertiary amine oxidations is the first step of this cascade
process under the standard condition. The immonium salt can go
through two different pathways and render acetaldehyde as well
as formaldehyde. The immonium salt is readily hydrolyzed to
a
Reaction conditions: 4a (0.5 mmol), 2b (2.5 equiv), Cul (20 mol %),
TMEDA (40 mol %), CH3CN (1 mL), at 100 °C, under O2, 24 h.
b
Mixture ratio.
the optimized conditions (Scheme 4, 5a−5e). Different 2-
aminobenzo[d]imidazole compounds which bear Cl, Br, F,
phenyl group on the benzene ring participated smoothly in this
annulation process to render the corresponding imidazo[1,2-
a]pyrimidines in good yields. Annulation reaction of the
monosubstituted 2-amine-benzo[d]imidazol-2-amine can also
provide corresponding imidazo[1,2-a]pyrimidines (5f−5h) in
the mixture of C7 and C8 position. The ratio of C7 and C8
products were determined by 1H NMR spectroscopy.
To gain further insight into the mechanism of this Cu(I)-
catalyzed annulation reaction, a series of control reactions were
carried out. First, radical inhibitor TEMPO was added to the
reaction and it turned out that the reaction was completely
inhibited (Scheme 5a) which inferred that this might be a radical-
involved reaction. Then, to test the source of the three carbon
units, we employed formaldehyde (concentration of 40% in
water) and acetaldehyde aqueous solution (concentration of
40%) to take the place of DIPEA and the desired product 3a was
obtained in 75% isolated yield (Scheme 5b). This reaction
suggested that the combination of formaldehyde and acetalde-
hyde play the same role as DIPEA. Given the fact that acrolein
could be made from formaldehyde and acetaldehyde, we have
reasons to believe that acrolein was generated in situ and became
the key intermediate for this transformation, which was further
C
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Organic Letters
Letter
ates’ Innovative Ability in Scientific Research of Huaqiao
University (for C. Rao) are gratefully acknowledged. We also
thank the Instrumental Analysis Center of Huaqiao University
for analysis support.
Scheme 6. A Plausible Mechanism for the Formation of
Desired Products 3 and 5
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02015.
Experimental procedure, characterization of all of the
products (PDF)
(20) Ghosh, T.; Das, A.; Konig, B. Org. Biomol. Chem. 2017, 15, 2536.
AUTHOR INFORMATION
Corresponding Author
■
*Fax: 86-592-6162990. E-mail: qsong@hqu.edu.cn.
ORCID
Qiuling Song: 0000-0002-9836-8860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Recruitment Program of Global
Experts (1000 Talents Plan), the Natural Science Foundation of
Fujian Province (2016J01064), Fujian Hundred Talents Plan,
Program of Innovative Research Team of Huaqiao University
(Z14X0047) and Subsidized Project for Cultivating Postgradu-
D
DOI: 10.1021/acs.orglett.7b02015
Org. Lett. XXXX, XXX, XXX−XXX