Metal-free oxidative amidation of aldehydes with aminopyridines employing aqueous hydrogen peroxide

Article abstract of DOI:10.1039/c6ob01454b

The first metal free report on the amidation of aldehydes with aminopyridines was accomplished using simple aqueous hydrogen peroxide (aq. H₂O₂) as the oxidant. No catalysts or additives were needed for this transformation and the reaction proceeded in water, an environmentally benign reaction medium. Green oxidant and reaction conditions, and the ability to construct diverse N-(pyridin-2-yl)benzamide by this elegant method render it a practical alternative for the synthesis of these amides.

Full text of DOI:10.1039/c6ob01454b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. D. E, A. A, T. A,
S. Nagarajan, V. Sridharan and U. M. C, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB01454B.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C6OB01454B
Journal Name
COMMUNICATION
Metal-free oxidative amidation of aldehydes with aminopyridines
employing aqueous hydrogen peroxide
E. Sankari Devi,a Anitha Alanthadka,a A. Tamilselvi,b Subbiah Nagarajan,a Vellaisamy Sridharana
Received 00th January 20xx,
Accepted 00th January 20xx
and C. Uma Maheswaria*
DOI: 10.1039/x0xx00000x
www.rsc.org/
First metal free report on the amidation of aldehydes with
aminopyridines was accomplished using simple aqueous hydrogen
reported NHC-catalysed oxidative amidation of aldehydes with
amines and are on the process of developing cleaner and
7c
peroxide (aq. H2O2) as the oxidant. No catalysts or additives were greener oxidative amidation protocol with inexpensive
oxidants. Aqueous hydrogen peroxide (aq. H2O2) proves to be
the oxidant of interest as it is economically cheap and greener
and it produces water as the by-product. Till date, there are only
two reports on the oxidative amidation of aldehydes employing
aq. H2O2 reported where aldehyde is coupled with cyclic
secondary amines to generate amides under normal
conditions10 and under continuous flow micro-reactor
systems.11
needed for this transformation and the reaction proceeded in
water, an environmentally benign reaction medium. Green oxidant
and reaction conditions, and the ability to construct diverse N-
(pyridin-2-yl)benzamide by this elegant method render it to be a
practical alternative for the synthesis of these amides.
Formation of amide bond is an important task in organic
synthesis as amide functionality is widespread in various natural
products and pharmaceuticals that exhibits several biological
activities.1 Conventional methods for the generation of amide
bond involve the reaction of activated carboxylic acid or its
derivatives with amines.2 Due to several drawbacks associated
with these methods, including generation of stoichiometric
amount of by products, various alternative strategies have been
devised. Carboxylic acid is usually obtained as the result of
oxidation of aldehydes or alcohols and application of aldehydes
as starting material appears to be economically viable route for
the synthesis of amide. Thus oxidative amidation of aldehydes
with amines in presence of transition metal catalysts and
stoichiometric amount of oxidant proves to be a convenient
synthetic strategy.3-6 Apart from the metal catalysed oxidative
amidation, organocatalytic amidation was also performed
employing N-heterocyclic carbene (NHC) catalysis.7 In addition,
catalyst-free oxidative amidation were also reported using tert-
butyl hydroperoxide (TBHP)8 or oxone9 as oxidants. In spite of
being advantageous over conventional methods, these
protocols have innate drawbacks like harsh reaction conditions,
stoichiometric use of base and expensive oxidant hence there is
scope for devising efficient strategies. We have recently
Scheme 1 . Synthesis of N-(Pyridin-2-yl)benzamide from aldehyde and 2-aminopyridine.
N-(Pyridin-2-yl)benzamide moiety is an important
pharmacophore found widely in many bioactive compounds,
identified as a luciferase inhibitor,12 found to be effective for the
treatment of osteoporosis,13 and as anti-ulcer agent.14 4-N-
pyridin-2-yl-benzamides based fluorescent para-aminobenzoic
acid (PABA) nanotubes was found to possess dual property, as
a delivery vehicle of therapeutic agents and acting as a
therapeutic agent by itself.15 N-(Pyridin-2-yl)benzamide was
a.Organic Synthesis group, Department of Chemistry, School of Chemical and
Biotechnology, SASTRA University, Thanjavur-613401, India. Fax: (+91)-4362-
264111 E-mail: umamaheswaric@scbt.sastra.edu; uma.cchem@gmail.com
b.Department of Chemistry, Thiagarajar College, Madurai-625009, India.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
previously synthesized via CuI catalysed dehydrogenative Butyl peroxybenzoate (TBPB) and Dicumyl PeroxidVeie(wDACrtPic)lefOanrleinde
reaction between aldehyde and aminopyridine (Scheme 1a).16 poorly under the present reaction conditiDoOnI:(e10n.t1r0i3e9s/C26-4O)B.0W14h5e4Bn
An alternate method employs Cu(OTf)2 as a catalyst in presence aq. H2O2 was taken as the oxidant, surprisingly the yield of the
of I2 as an oxidant under anionic micellar catalysis in aqueous desired product was increased to 91% (entry 5). In the absence
medium for the synthesis of aforementioned amides (Scheme of oxidant, the desired amide was not observed (entry 6). Once
1b).17 A heterogeneous approach for the synthesis N-(Pyridin-2- we fixed the suitable oxidant for this reaction, we diverted our
yl)benzamide was achieved by employing Cu2O and CuI attention to find out the suitable solvent for this oxidative
supported on multi-walled carbon nanotubes (MWCNTs).18 amidation. Polar solvents like H2O, DMF and CH3CN gave
However, to the best of our knowledge, metal-free oxidative comparatively good yields (entries 5, 7 and 8). In case of non-
amidation for the synthesis of N-(pyridin-2-yl)benzamide has polar solvents, other than toluene, the yields are marginal
never been explored. Herein, we present the first metal free (entries 9-13). Finally, we arrived at water as the reaction
oxidative amidation of aryl aldehydes with aminopyridines-a medium for this amidation strategy due to its environmentally
primary amine, in presence of aq. H2O2 as the terminal oxidant benign nature and other advantages (entry 5). When the
using water as the green and environmentally benign reaction reaction was performed at room temperature, the yield of the
medium (Scheme 1c).
desired product was decreased drastically (entry 14). Gradual
increase in the temperature increases the product yield and the
Results and discussion
o
yield was optimal at 80 C and further rise in the temperature
o
above 80 C doesn’t increase the product yield (entries 5, 15-
In order to arrive at the optimized reaction condition for the
synthesis of N‐(pyridin‐2‐yl)benzamides, benzaldehyde and 2-
aminopyridine were taken as the model substrates (Table 1).
Initially, when TBHP in water was taken as the oxidant for this
coupling in water at 80 oC, the yield was only 38% (entry 1). Then
variation of different oxidants were performed and it was
observed that oxidants like Di-t-Butyl Peroxide (DTBP), tert-
17). When the reaction was performed with 2 equiv. of oxidant,
Table 2. Scope of aldehydes for the oxidative amidation with 2-aminopyridine.a
Table 1. Optimization of reaction conditions for H2O2 mediated oxidative
amidation. a
Entry
1
2
Oxidant
TBHP
DTBP
TBPB
DCP
Solvent
H2O
H2O
Yield (%)b
38
32
<5
3
H2O
4
5
6
H2O
H2O
H2O
NR
91
NR
64
87
83
H2O2
--
7
8
9
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
DMF
CH3CN
Toluene
PhCl
Dioxane
EtOH
THF
10
11
12
13
14
15
16
17
18
19
20
37
21
23
13
48
56
[c]
H2O2
H2O2
H2O
H2O
[d]
[e]
H2O2
H2O
H2O
H2O
79
81
66
[f]
H2O2
[g]
H2O2
[h]
H2O2
H2O
H2O
77
74
[i]
H2O2
[a]Reaction Conditions: Aldehyde (1.0 mmol), 2-aminopyridine (1.0 mmol),
o
[a]Reaction Conditions: Aldehyde (1.0 mmol), aminopyridine (1 mmol), oxidant (3
equiv.), solvent (2 mL), 80 oC, 4 h. [b]I solated yield. [c] Reaction at rt. [d] Reaction
at 40 oC. [e] Reaction at 60 oC. [f] Reaction at 100 oC. [g] Reaction with 2 equiv. of
oxidant. [h] Reaction time 3 h. [i] Reaction time 5 h.
oxidant (3 equiv.), solvent (2 mL), 80 C, 4 h, Isolated yield.
the yield of the desired product decreased suggesting that 3
equiv. of oxidant is needed to carry out the reaction (entry 18).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
benzaldehyde as shown in table 3. Irrespective of the electronic
DOI: 10.1039/C6OB01454B
nature of the substituents in 2-aminopyridine, the yield ranges from
good to excellent (3s-3x). When a strong electron-withdrawing nitro
The product yield decreased when the reaction was carried out
for 3 h and if it is prolonged for 5 h, the yield decreased
marginally due to the formation of acid under the reaction
condition (entries 19 and 20). Thus we arrived at the optimized
reaction condition: aq. H2O2 (3 equiv.) in H2O at 80 oC for 4 h.
To explore the scope of this metal-free process, various
aldehydes were coupled with 2-aminopyridine under the
optimized reaction condition (table 2). The reaction was
tolerant to the electronic nature of aryl aldehydes as both
electron-donating and withdrawing substituted aldehydes
worked well to deliver the corresponding products in good to
excellent yields (3a-3g). Strongly electron-withdrawing
substituents like –NO2 and –CN had a negative impact on the
reaction, as the yield of the corresponding products decreased
significantly, irrespective of the position of the substituents (3h-
3j). The steric factor has negligible effect on this transformation,
as 2-substituted aryl aldehydes gave their corresponding
products in good yields. For instance, 2-F, 2-Cl, 2-Br
benzaldehydes gave 78%, 80% and 81% of the corresponding
amides respectively (3k-3m). In addition, hetero-aromatic
aldehydes such as thiophene-2-carboxaldehyde, furan-2-
carbaldehyde and pyridine-2-carboxaldehyde gave the
corresponding amides in excellent yields (3n-3p). Gratifyingly,
when the reaction was performed with aliphatic aldehydes like
cyclohexanecarbaldehyde and n-butyraldehyde the reaction
proceeded to give products with 76% and 42% yields
respectively (Entries 3q-3r).
View Article Online
group is present in the 5th position, the yield of the product
decreased drastically to 55% (3y). Even dichloro substituent in 2-
aminopyridine gave the corresponding amide in excellent yield of
82% (entry 3z). Interestingly, when 3-aminopyridine and 4-
aminopyridine were taken as the coupling partners, respective
amides were obtained in good yields of 78% and 79% respectively
(3aa, 3ab). When 2-aminopyrazine was taken as the amine
counterpart, the corresponding amide was obtained in a moderate
yield of 62% (3ac).
Scheme 2. Control experiments for oxidative amidation
Table 3. Scope of aminopyridines for the oxidative amidation with benzaldehyde.a
Scheme 3. Plausible mechanism for the oxidative amidation
In order to arrive at the plausible reaction mechanism, we have
done several background experiments. The reaction did not proceed
when benzoic acid was taken as the starting material, instead of
benzaldehyde along with 2-aminopyridine under the optimized
reaction conditions (Scheme 2). This reaction confirms that acid
cannot be the reaction intermediate. When benzaldehyde was
treated with 2-aminopyridine, we could observe imine by TLC. To this
imine, when oxidant was added, the desired amide was obtained in
good yields. Moreover, when the reaction was carried out in absence
of oxidant, the reaction failed indicating that the oxidant is essential
for this amidation process. Based on the above observations, we
propose the mechanism as shown in scheme 3. Addition of amine
across the carbonyl group is a well-established process both in
[a]Reaction Conditions: Benzaldehyde (1.0 mmol), aminopyridine (1.0 mmol),
oxidant (3 equiv.), solvent (2 mL), 80 oC, 4 h, Isolated yield.
Next, we explored the scope and limitations of this oxidative
amidation process for various substituted aminopyridines with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
solution19a and vapour phase.19b-d This is similar to the one proposed
by Wolf et al. where amidation of aldehydes with secondary amines
were performed in presence of TBHP as the oxidant.8 The
hemiaminal intermediate I1 water to generate the imine I2 followed
by the addition of H2O2 to the imine giving the hydroperoxide I3.11
Removal of water from the hydroperoxide I3 afforded the required
amide.
14 a) A. Robert and L. L. Skaletzky, U. S. Patent 3,418,325, 1968;
View Article Online
b) R. B. Moffett, A. Robert and L. L. SkDalOeIt:z1k0y.1,0J3.9M/Ce6dO.BC0h14e5m4B.,
1971, 14, 963.
15 J. S Yadav, M. P Lavanya, P. P Das, I. Bag, A. Krishnan, B.
Jagannadh, R. Leary, A. Bagchi, D. K Mohapatra, M. P. Bhadra
and U. Bhadra, Nanotechnology, 2010, 21, 155102.
16 S. Yang, H. Yan, X. Ren, X. Shi, J. Li, Y. Wang and G. Huang,
Tetrahedron, 2013, 69, 6431.
17 O. P. S. Patel, D. Anand, R. K. Maurya and P. P. Yadav, Green
Chem., 2015, 17, 3728
18 H. N. Hareesh, K. U. Minchitha, N. Nagaraju and N. Kathyayini,
Chin. J. Catal., 2015, 36, 1825.
Conclusions
19 a) T. Iwasawa, R. J. Hooley and J. Rebek, Science, 2007, 317
,
In conclusion, aqueous H2O2, a green oxidant, without any
additive or metal catalyst in environmentally benign water
medium, has been utilized for the efficient synthesis of N-
(pyridinyl)benzamide from aldehydes and aminopyridines. The
scope of the reaction includes heterocyclic aldehydes and
sterically hindered 2-substituted aldehydes. Apart from 2-
aminopyridine and it’s derivatives, the reaction proceeded with
3-aminopyridine and 4-aminopyridine also as coupling partners.
493; b) B. J. Xu, L. Zhou, R. J. Madix and C. M. Friend, Angew.
Chem., Int. Ed., 2010, 49, 394; c) L. Zhou, C. G. Freyschlag, B.
J. Xu, C. M. Friend and R. J. Madix, Chem. Commun., 2010, 46
,
704.
Acknowledgements
Financial support from the Department of Science and
Technology, DST, New Delhi for the award of a research grant
for young scientist (no. SB/FT/CS-108/2012) is gratefully
acknowledged.
Notes and references
1
a) N. Sewald and H. D. Jakubke, in: Peptides: Chemistry and
Biology, Wiley-VCH, Weinheim, 2002; b) I. Johansson and Kirk-
Othmer, Encyclopedia of Chemical Technology: Amides, Fatty
Acids, (Ed.: J. I. Kroschwitz), 5th edn., Wiley, Hoboken, New
Jersey, 2004, Vol. 2, pp 442–463.
a) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606
and references cited therein; b) A. T. Londregan, G. Storer, C.
2
Wooten, X. Yang and J. Warmus, Tetrahedron Lett., 2009, 50
1986.
,
3
4
5
6
7
K. I. Shimizu, K. Ohshima and A. Satsuma, Chem. Eur. J., 2009,
15, 9977.
Y. Wang, D. Zhu, L. Tang, S. Wang and Z. Wang, Angew. Chem.
Int. Ed., 2011, 123, 9079.
S. D. González, N. Marion and S. P. Nolan, Chem. Rev., 2009,
109, 3612.
E. A. B. Kantchev, C. J. O’Brien and M. G. Organ, Angew. Chem.
Int. Ed., 2007, 46, 2768.
a) J. W. Bode and S. S. Sohn, J. Am. Chem. Soc., 2007, 129
,
13798; b) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007,
129, 13796; c) A. Alanthadka and C. U. Maheswari, Adv. Synth.
Catal., 2015, 357, 1199.
8
9
K. Ekoue-Kovi and C. Wolf, Org. Lett., 2007,
9, 3429.
J. Gao and G. W. Wang, J. Org. Chem., 2008, 73, 2955.
10 R. Tank, U. Pathak, M. Vimal, S. Bhattacharyya and L. K.
Pandey, Green Chem., 2011, 13, 3350.
11 X. Liu and K. F. Jensen, Green Chem., 2012, 14, 1471.
12 L. H. Heitman, J. D. Veldhoven, A. Zweemer, K. Ye, J. Brussee
and A. P. IJzerman, J. Med. Chem., 2008, 51, 4724.
13 a) C. Petrie, M. W. Orme, N. Baindur, K. G. Robbins, S. M.
Harris, M. Kontoyianni, L. H. Hurley, S. M. Kerwin and G. R.
Mundy, WO 9715308, 1997; b) M. W. Orme, N. Baindur and
K. G. Robbins, WO 9817267, 1998.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins