Copper-catalyzed highly efficient oxidative amidation of aldehydes with 2-aminopyridines in an aqueous micellar system

Article abstract of DOI:10.1039/c5gc00628g

An environmentally benign protocol for the synthesis of N-(pyridine-2-yl)amides from aldehydes and 2-aminopyridines has been developed under mild reaction conditions. This approach requires Cu(OTf)₂ as a catalyst, and inexpensive molecular iodi

Full text of DOI:10.1039/c5gc00628g

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ARTICLE TYPE
Copper-catalyzed highly efficient oxidative amidation of aldehydes with
2-aminopyridines in aqueous micellar system
Om P. S. Patel,‡a Devireddy Anand,‡a Rahul K. Maurya,a Prem P. Yadav*a
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
solubility of reagents, thereby accelerating the reaction rate due to
the aggregation of reactants in unique micellar environment.12b,13
Recently, Huang et al.14 reported the synthesis of N-(pyridine-
2-yl)amides using CuI (10 mol %) in DMF at 80 ºC for 24 h
(Scheme 1a). Luo et al.15 also reported the Rh(III) catalyzed
synthesis of N-pyridinamides in acetone at 100 ºC for 12 h
(Scheme 1b). However, these methodologies suffer from several
55 drawbacks, such as harsh reaction conditions, long reaction time,
and use of hazardous solvents. In addition, these approaches were
limited only to aryl aldehydes.
An environmentally benign protocol for the synthesis of N-
(pyridine-2-yl)amides from aldehydes and 2-aminopyridines
has been developed under mild reaction conditions. This
10 approach requires Cu(OTf)2 as a catalyst, inexpensive
molecular iodine as an oxidant under anionic micellar
catalysis in aqueous medium at room temperature.
50
The amide linkage is a key chemical connection in synthetic
organic chemistry, natural polymers (peptides and proteins) and
15 pharmaceuticals.1 Amides are widely applicable intermediates for
the synthesis of a diverse range of medicinally important
molecules.2 Conventionally, amides are accessed by treating
amines with activated carboxylic acids and are limited to harsh
reaction conditions, use of hazardous reagents, and generation of
20 excess amount of by-products.3 Recently, several innovative
strategies, including the Staudinger reaction4 and hydrative
coupling reaction of alkynes with azides,5 have emerged.
Additionally, several direct oxidative amidation methods have
been reported in recent past from the reaction of aldehydes,6,7
25 alcohols,8 alkynes,1c,9 esters,10 and anhydrides11 with amines to
furnish amides. Among all, oxidative amidation of aldehydes
with amines are of great interest in synthetic organic chemistry
because of atom economy and easy availability of substrates.
However, these reactions usually need harsh reaction conditions,
30 inert atmosphere, and anhydrous organic solvents. Thus, an eco-
friendly protocol for amide synthesis in aqueous media would be
highly desirable.
Previous work
R2
Ref. 14
O
a)
CuI (10 mol %)
R1
DMF, 80 °C
24 hr
NH2
N
R1 = Aromatic, Heteroaromatic only.
Ref. 15
b)
O
R2
NH2
R2
[RhCp*(MeCN)3] (SbF6) (4.5 mol %)
O
R1
Ag2CO3, Acetone
100 °C, 12 hr
R1 NH
N
R1= Aryl, R2= Pyridyl
c) This work
. Water as solvent
Cu(OTf)2 (5 mol %)
I2 (50 mol %)
. At room temperature
. Short reaction time
. Low catalyst loading
R2
O
H2O, SDS (5 mol %)
RT,15 - 35 min
R1
NH2
N
R1 = Alkyl, Aromatic, Heteroaromatic.
60 Scheme 1. Different methods to synthesize N-(pyridine-2-yl)amides.
O
In view of green chemistry, water is the most abundant, cost
effective, and environmentally benign solvent, used in organic
35 synthesis.12 Aqueous reactions demonstrate unique selectivity and
reactivity when compared to organic solvents.12c However, these
reactions have limitations due to poor solubility and sensitivity of
organic reagents in water. Micellar system can improve the
H
O
N
N
F
N
F3C
H
O
N
COOH
F
O
N
N
H
O
N
N
O
O
COOH
O
II. PF-04991532
O
I. GKA-50
F
COOH
III. GKA-60
O
S
N
O
O
N
H
O
N
N
N
Cl
N
N
N
H
H
O
O
N
N
IV
O
40 aMedicinal and Process Chemistry Division; CSIR-Central Drug
Research Institute, Lucknow-226031, India
CF3
O
VI
O
V. Piragliatin
O
F
O
E-mail: pp_yadav@cdri.res.in; ppy_cdri@yahoo.co.in Fax: +91-522-
2771942/2771970; Tel: + 91-522-2772450, Ext. 4761.
†Electronic Supplementary Information (ESI) available: [Experimental
45 procedures and spectroscopic data 1H NMR, 13C NMR and HRMS (ESI)
spectra of all the compounds]. See DOI: 10.1039/b000000x/
‡ O. P. S. P. and D. A. Contributed equally to this work.
Figure 1. Selected antidiabetic agents that have progressed into clinical
trials.
65
In continuation of our research on the development of eco-
friendly protocols,16 herein, we report a copper-catalyzed mild
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DOI: 10.1039/C5GC00628G
Green Chemistry
Page 2 of 6
and rapid dehydrogenative cross-coupling approach for the
presence of Cu(OTf)2 (10 mol %) and I2 (1.0 equiv.) in water at
synthesis of N-(pyridine-2-yl)amides via coupling of aldehydes 30 room temperature furnished desired product 3aa in 30% yield
with 2-aminopyridines using sodium dodecyl sulfate (SDS) in
water. SDS is an important amphiphilic surfactant, which forms
micelles in aqueous media13a and catalyzes various organic
reactions.12c,13b,17
(Table 1, entry 1). To our delight, when we used SDS (30 mol %)
in the reaction, an enhancement in product yield was observed
(Table 1, entry 2). In light of these results, a series of metal salts,
namely Cu(OTf)2, FeCl3, CuBr2, CuI and CuBr, were investigated
5
It is important to note that N-(pyridine-2-yl)amides can act as 35 (entries 2-6). Among all, Cu(OTf)2 displayed the highest catalytic
small molecule glucokinase activators (Figure 1).18 GKAs
activate the glucokinase enzyme to convert glucose into glucose-
activity (entry 2).
10 6-phosphate selectively in the liver and pancreas to confirm its
potential role in the treatment of type-2-diabetes.18a Many
pharmaceutical companies are currently working to develop
potential and safe glucokinase activators.18a,19
Table 2. Synthesis of N-(pyridine-2-yl)amides under the
optimum reaction conditions.a, b
R2
Cu(OTf)2 (5 mol %)
I2 (50 mol %)
R2
O
O
R1
N
N
R1
H
H2N
N
H2O, SDS (5 mol %)
RT, 15 - 35 min
H
2
1
15 Table 1. Optimization of reaction conditions.a,i
3
40
R
Cl
R
O
O
O
O
Catalyst,
O
Oxidant (X)
N
N
H
N
N
N
H
N
H
H
H2N
N
Surfactant (Y)
Solvent (Z)
RT, 20 min
N
N
1a
3aa
H
2a
3ba,
R = Br, 64%, 30 min
3ca, R = Cl, 73%, 30 min
3ab, R = Me, 78%, 20 min
3ad,
Yieldb
(%)
3ac,
66%, 30 min
O
R = F, 63%, 25 min
3da,
R = NO2, 71%, 35 min
Entry
Catalyst
(10 mol %)
X
Y
Z
CH3
N
(1 equiv)
(30 mol %)
O
O
1
2
3
4
Cu(OTf)2
Cu(OTf)2
FeCl3
I2
I2
I2
I2
-
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
PF 127
Tween 80
TBAB
TBAI
SLS
SDSf
SDSg
SDSh
SDSg
SDSg
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DCM
DMF
CH3CN
Toluene
30
85
10
80
50
57
18
10
NR
NR
NR
93
60
40
55
10
NR
88
92
93
70
75
40
27
20
62
30
N
N
N
N
N
H
H
H
R
3ea,
3fa,
3ga,
3ha,
O
R
R = CN, 75%, 25 min
R = Cl, 83%, 20 min
R = F, 78%, 25 min
R = Me, 88%, 20 min
O
3ia,
3fe,
R = Cl, 80%, 20 min
CuBr2
89%, 15 min
O
3he, R = Me, 80%, 18 min
R
5
6
7
8
CuI
CuBr
I2
I2
O
O
O
N
N
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2S2O8
TBHP
PIFA
DDQ
O2
H
O
O
N
N
N
N
O
H
H
O
9
O
O
3la,
89%, 20 min
CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3ja,
95%, 15 min
O
3ka,
R = H, 91%, 15 min
3ke, R = Me, 90%, 18 min
CH3
I2 (0.5 eq)
I2(0.2 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2(0.5 eq)
I2(0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
I2 (0.5 eq)
O
O
N
H
N
N
N
N
H
N
H
O
3ma,
3oe,
66%, 20 min
74%, 20 min
O
O
3nb,
84%, 20 min
O
O
R
Ph
R
O
N
H
N
N
N
N
N
N
H
N
c
H
S
3pa,
Cu(OTf)2
3ra,
R = H, 58%, 30 min
3rc, R = F, 55%, 35 min
Ph
3qa,
R = H, 64%, 25 min
3pc, R = 5-F, 58%, 25 min
3pd, R = 4-Cl, 55%, 25 min
c
Cu(OTf)2
61%, 25 min
O
c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CH3
O
CH3
d
e
O
N
H
N
N
N
c
H
N
N
3tb,
56%, 28 min
O
3ua,
68%, 30 min
c
H
-
-
-
R
3se,
3va,
61%, 30 min
O
c
c
N
N
Cu(OTf)2
H
N
N
a Reaction conditions: 1a (0.93 mmol), 2a (1.39 mmol), catalyst (10 mol
%), X (1 equiv.) and Y (30 mol %) at RT, 20 min., under air. b Isolated
yields based on 1a. c 5 mol %, d 3 mol %, e 1 mol % Cu(OTf)2. f Y 10 mol
H
3wa,
R = H, 64%, 35 min
3wc, R = F, 60%, 35 min
57%, 30 min
a
Reaction conditions: 1 (0.93 mmol), 2 (1.39 mmol), Cu(OTf)2 (5 mol
g
h
i
20 %, 5 mol %, 1 mol %. NR = No Reaction. Abbreviations used in
table: SDS = Sodium dodecyl sulfate; PF 127 = Pluronic F 127; Tween 80
= Polyoxyethylene(20)sorbitanmonooleate (Polysorbate 80); TBAB =
Tetra-n-butyl ammonium bromide; TBAI = Tetra-n-butyl ammonium
iodide; SLS = Sodium lauryl sulfate.
%), I2 (50 mol %) and SDS (5 mol %) in 4.0 mL of water at room
temperature. b Isolated yields based on 1.
45
Next, a variety of oxidants, namely K2S2O8, TBHP, PIFA, DDQ,
and O2, were screened in the reaction. However, none of them
were found to be more efficient than I2 (Table 1, entries 7-11 vs.
2). Further optimization of I2 loading revealed that 50 mol % of
25
Initially, we commenced our studies with commercially
available benzaldehyde (1a) and 2-aminopyridine (2a) as the
model substrates to optimize the reaction conditions. In the
50 iodine produced the best yield of the desired product (entries 2,
2
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Green Chemistry
12-13). Next, the effect of surfactants on the reaction was
formation of desired products in high yields. The results are
summarized in Table 2. Unfortunately, no desired products were
observed when different anilines (4-chloroaniline and 4-
methylaniline), 3-aminopyridine, 4-aminopyridine, piperidine, 2-
examined and only anionic surfactant (SDS) was found to be
most suitable for this transformation whereas neutral and cationic
surfactants failed to improve the yield of product (entries 14-17
5
vs. entry 12). This might be due to the stabilization of copper 55 aminobenzimidazole, 2-aminopyrimidine, cyclohexylamine, and
catalyst with anionic dodecyl sulfate by the formation of a
Cu(DS)2 complex.20 Interestingly, optimization of surfactant
loading revealed that 5 mol % of SDS is enough to this reaction
(entries 19-21).
n-butylamine were used under optimized reaction conditions.
To demonstrate the generality of the present approach, we
performed the reaction of trans-cinnamaldehyde (1x) with 2-
aminopyridine (2a) under identical reaction conditions and only
10
Subsequently, the effect of solvents was examined and the 60 trace amount of amide product (3xa) was formed. Interestingly,
water was found to be a superior solvent over other organic
solvents (Table 1, entries 20 vs. 24-27). To our surprise,
decreasing the catalyst loading to 5 mol % led to the formation of
the amide product in 93% yield (entry 20). Further decreasing the
when we carried out the reaction at 60 ºC for 24 h, 2-
phenylimidazo[1,2-a]pyridine-3-carbaldehyde (4xa) was isolated
as a major product and N-(pyridine-2-yl)cinnamamide as a minor
product (Scheme 2).
15 amount of catalyst to 3 mol % and 1 mol % afforded declined
yields 75% and 40%, respectively (entries 22-23).
With the optimal conditions (Table 1, entry 20) in hand, we
next probe the scope and generality of this oxidative amidation
approach to a variety of aldehydes and 2-aminopyridines.
20 Initially, a set of aldehydes, including aromatic and aliphatic 70 precursor to synthesize anxiolytic drug necopidem.22
65
Imidazo[1,2-a]pyridine and its derivatives exhibit a broad
range of biological activities and are considered to be key
structural scaffolds in variety of natural products and drugs such
as zolpidem, alpidem, necopidem, zolimidine, saripidem and
olprinone.21 Notably, formyl group of 4xa is an important
aldehydes, were employed in the reaction and the results are
summarized in Table 2. The reaction was compatible with a
O
O
TEMPO (2 equiv.)
(1)
N
H
3aa
N
H
H
H2N
N
Optimal condition
15 min
variety of substituents (CH3, OCH3, F, Cl, Br, CN and NO2) on
the aryl aldehyde moiety and furnished the products in moderate
25 to excellent yields (3ba-3la). It is worth noting that halogens, CN
and NO2 groups are very important substituents for post-
diversification in medicinal chemistry. The aldehydes bearing
electron-donating groups provided better yields than electron-
withdrawing groups (3ia-3la vs. 3ba-3ga & 3fe). Sterically
30 hindered substituent such as Br at the ortho-position of
benzaldehyde gave the lower yield of product 3ba. Following the
aryl aldehydes, various heterocyclic aldehydes were well
tolerated and furnished the corresponding products in moderate to
good yields under optimal reaction conditions (3oe-3qa).
1a
2a
85%
O
O
O
I2 (50 mol %)
(2)
(3)
N
H
N
N
H2N
H2N
N
2a
SDS (5 mol %)
H2O, RT, 1 h
3aa
1a
0%
O
Cu(OTf)2 (5 mol %)
H
N
H
3aa
N
2a
SDS (5 mol %)
H2O, RT, 1 h
1a
0%
Scheme 3. Control experiments.
75
Furthermore, in order to investigate the reaction mechanism,
some control experiments were performed (Scheme 3). The
reaction of benzaldehyde with 2-aminopyridine, in the presence
35 Subsequently,
a variety of aliphatic aldehydes such as
acetaldehyde, propionaldehyde, butyraldehyde, heptaldehyde,
isobutyraldehyde and cyclohexanal were also tested in this
reaction and delivered the corresponding products in good yields
(3ra-3wc). The lower yields in case of aliphatic aldehydes when
40 compared to aromatic aldehydes, may be due to the side reactions
such as aldol condensation and oxidation to the corresponding
carboxylic acids.
of
a
radical inhibitor such as TEMPO (2,2,6,6-
tetramethylpiperidine 1-oxy) had no significant effect on the yield
80 of the desired product (Scheme 3, eq 1), indicating the absence of
a radical mechanism. When the reaction was performed without
Cu(OTf)2, the reaction failed to deliver the desired product
(Scheme 3, eq 2). The amide product was also not formed in the
absence of I2 (Scheme 3, eq 3). These results collectively
85 indicated the importance of metal catalyst and oxidant in this
reaction.
O
H
Cu(OTf)2 (5 mol %)
N
CHO
I2 (50 mol %)
N
65% (4xa)
H2N
N
H2O, SDS (5 mol %)
60 °C, 24 h
1x
2a
O
N
N
H
25% (3xa)
45 Scheme 2. Synthesis of 2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde.
Next, we investigated the substrate scope of various 2-
aminopyridines under the standard reaction conditions. The 2-
aminopyridines containing a variety of substituents (H, CH3, Cl
50 and F) were well tolerated to this transformation and led to the
Scheme 4. Proposed reaction mechanism.
According to the control experiments described above and
90 previous literature reports,6g,14,23 a proposed mechanistic pathway
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C5GC00628G
Green Chemistry
Page 4 of 6
60
65
70
R. R. Kale, B. B. Mishra, D. Kumar, V. K. Tiwari, Org. Lett., 2012,
14, 2936-2939; (d) C. L. Allen, S. Davulcu, J. M. J. Williams, Org.
Lett., 2010, 12, 5096-5099; (e) J. Liang, J. Lv, Z. –C. Shang,
Tetrahedron, 2011, 67, 8532-8535.
is depicted in Scheme 4. Initially, the reaction commences with
the nucleophilic addition of 2-aminopyridine (2) to aldehyde (1),
leading to the formation of hemiaminal intermediate (A), which
upon oxidation in presence of I2, delivers the desired amide
product (3).
In summary, we devised an eco-friendly and mild protocol for
the synthesis of N-(pyridine-2-yl)amides from aldehydes with 2-
aminopyridines by using Cu(OTf)2 as a catalyst and I2 as an
oxidant under micellar system in water. The present work offers
10 several practical advantages such as the use of mild reaction
conditions, short reaction time, absence of base and ligand, under
air, and easy workup procedure. In addition to previously
reported methods,14,15 we demonstrated that aliphatic aldehydes
were well tolerated under optimal reaction conditions. Further
15 synthesis of a library of new diversified N-(pyridine-2-yl)amides
are under progress to evaluate their biological potential.
8
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Watson, R. J. Wakeham, A. C. Maxwell, J. M. J. Williams,
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David, D. Milstein, Science, 2007, 317, 790-792; (g) A. J. A.
Watson, A. C. Maxwell, J. M. J. Williams, 2009, 11, 2667-2670.
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5
9
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1682-1685; (b) R. Arora, S. Paul, R. Gupta, Can. J. Chem., 2005,
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Acknowledgements
80
16, 2018-2021.
11 Y. Li, L. Ma, F. Jia, Z. Li, J. Org. Chem., 2013, 78, 5638-5646.
12 (a) A. Chanda, V. V. Fokin, Chem. Rev., 2009, 109, 725-748; (b) R.
D. Shukla, A. Kumar, Green. Chem., 2015, 17, 848-851; (c) K.
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20
O. P. S. P. is thankful to UGC-New Delhi, D. A. and R. K. M.
to CSIR, New Delhi for financial assistance. We are also thankful
to Mr. Anoop K. Srivastava for technical support and SAIF-
CDRI, Lucknow, India for providing spectral and analytical data.
This work was supported by CSIR network project “THUNDER”
85
25 Towards holistic understanding of complex diseases: Unraveling
the threads of complex disease (BSC0102). This is CDRI
communication No. 8980.
90
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|Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C5GC00628G
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DOI: 10.1039/C5GC00628G
Copper-catalyzed highly efficient oxidative amidation of
aldehydes with 2-aminopyridines in aqueous micellar system
Om P. S. Patel,‡a Devireddy Anand,‡a Rahul K. Maurya,a Prem P. Yadav*a
R2
O
Cu(OTf)2 (5 mol %)
2 (50 mol %)
R2
I
O
R1
N
N
H
R1
H
H2O, SDS (5 mol %)
RT
15 - 35 min
H2N
N
34 examples
Yields 25 - 95%
R1= Alkyl, Aryl, Heteroaryl etc.
R2= H, CH3, Cl, F, etc.
* Water as solvent
* Under mild conditions
* Ligand & base free protocol
* Short reaction time
* Under air
An environmentally benign protocol for the synthesis of N-(pyridine-2-yl)amides from aldehydes and 2-aminopyridines has
been developed under mild conditions.