N-Heterocyclic Carbene/Cobalt Cooperative Catalysis for the Chemo- and Regioselective C?N Bond Formation between Aldehyde and Amines/Amides

Article abstract of DOI:10.1002/cctc.202000156

A novel methodology for the construction of various secondary (4 examples), tertiary amides (31 examples), and imides (16 examples) by a Cobalt(II) catalyzed oxidative amide coupling in aqueous media. The Co(III)-TMC was reacted with N-Heteroatom Carbene to form active catalyst Co(II)NHC-TMC in situ which involves in the coordination with Breslow's intermediate and SET for the activation of aldehyde and amides. The mechanism for activation of amide and amine differs on the basis of SET based nucleophilic addition and ligand exchange respectively. The regeneration of the catalyst was achieved using Fe(III)(EDTA)-H₂O₂ as oxidant. The use of Co(II)TMC-O₂ was also found equally efficient in the process. The method is found regioselective for N?H activation in the presence of equally susceptible ortho-C?H bond activation. And amines were found more susceptible then the corresponding amide for the reaction.

Full text of DOI:10.1002/cctc.202000156

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: N-Heterocyclic Carbene/Cobalt Cooperative Catalysis for
the chemo-and regioselective C–N Bond formation between
aldehyde and amines/amides
Authors: Imran Ahmd Khan, Mohd. Samim, Anam Khalid, Asher M
Siddiqui, Chandra S Azad, and Arif Khan
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To be cited as: ChemCatChem 10.1002/cctc.202000156
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01/2020

10.1002/cctc.202000156
ChemCatChem
COMMUNICATION
N-Heterocyclic Carbene/Cobalt Cooperative Catalysis for the
chemo-and regioselective C–N Bond formation between aldehyde
and amines/amides
Asher M. Siddiqui[a], Anam Khalid[a], Arif Khan[a], Chandra S. Azad[b], Mohd. Samim[a]* and Imran A. Khan[a]*
[a]
Dr. Asher M. Siddiqui, Ms. Anam Khalid, Mr. Arif Khan, Dr. Mohd. Samim, and Dr. Imran A. Khan
Department of Chemistry
School of Chemical and Life Sciences, Jamia Hamdard,
New Delhi-110062, INDIA
E-mail: imranakhan@jamiahamdard.ac.in, mshamim@jamiahamdard.ac.in
Dr. Chandra S. Azad
[b]
School of Pharmaceutical Science and Technology
Tianjin University,
Tianjin- 300072, CHINA
E-mail:csazad@gmail.com
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Dedication ((optional))
Abstract: A novel methodology for the construction of various
secondary (4 examples), tertiary amides (31 examples), and imides
(16 examples) by a Cobalt(II) catalyzed oxidative amide coupling in
aqueous media. The Co(III)-TMC was reacted with N-Heteroatom
Carebene (NHC) to form active catalyst Co(II)NHC-TMC in situ which
involves in the coordination with Breslow’s intermediate and SET for
the activation of aldehyde and amides. The mechanism for activation
of amide and amine differs on the basis of SET based nucleophilic
addition and ligand exchange respectively. The regeneration of the
catalyst was achieved using Fe(III)(EDTA)-H2O2 as oxidant. The use
of Co(II)TMC-O2 was also found equally efficient in the process. The
method is found regioselective for N-H activation in the presence of
equally susceptible ortho-C–H bond activation. And amines were
found more susceptible then the corresponding amide for the reaction.
Further, the above methods are mostly for the formation of
amides but not for imides which need still higher activation of N-
H bond present in the amide (-CONH). Additionally, Cobalt has
[11]
shown a crucial role in hydroformylation reactions, Nicholas
[12]
and Pauson-Khand reaction,
cyclization reactions, homo and
[13]
cross-coupling reaction of Grignard reagent,
dimerization, [14] radical cyclization, [15], Heck-type
radical
[16]
and C-H
[17-18]
activation reactions
as co-catalyst and as activator when
coupled with SET reagents like NBS, NCS, NIS and AIBN/I2 using
peroxo-metal complexes as an oxidant in a stoichiometric amount
in the presence various organic and inorganic bases in aqueous
media (in the presence of ~10% of DMPU in DMF). Although
transition-metals such as Pd, Pt, Ni, Cu, etc. can catalyze an
oxidative amidation and esterification of aldehydes, the
corresponding
Co-catalyzed
oxidative
amidation
and
esterification have rarely reported, only very recently a Co-
catalyzed oxidative esterification of aldehyde appeared.[19a]
Among these oxidative derivatizations, the examples of the
corresponding imidation between aldehydes and amides were
rather fewer, and the Co-catalyzed such imidation has not been
documented.[19b-d] Cobalt catalysis usually demonstrates high
activity and efficiency in the ortho C-H activation of
benzamides.[20] In the present amidation and imidation, the
selectivity between N-H and ortho C-H of benzamides formed in
the amidation of Ar-CHO or the substrates of imidation thus
presents a big challenge.[20b, 21] The reported protocols usually
proceeded under heated conditions and in anhydrous solvents,
the present reactions could proceed in aqueous solution at room
temperature.
In view of above and in continuation of our recent
endeavours in metal-based catalysis protocols [22] effective in the
formation of the desired target molecules of importance in
pharmaceutical, diagnostic (fluorescent probes) and material
(OLED devices) sciences, the present investigation of exploring
Co-based complexes as catalysts for N-H activation mediated
amide bond formation was undertaken and results are reported in
this paper.
Amide and imides are important functional groups present in
various biomolecules, privileged pharmacophores and
compounds of pharmaceutical importance. [1] In addition, Imide-
functionalized π-conjugated polymer has received a great deal of
interest owing to their unique physicochemical properties. The
release of H2O in conventional amide bond-forming procedures is
the only byproduct [2] during the condensation of an amine with a
carboxylic acid in the presence of a coupling reagent. However,
the addition of an extra step for the activation of the carboxylic
acid through the coupling reagents is not favored by the organic
chemists as it leads to the formation of additional byproducts.
Therefore, the development of newer alternative synthetic
strategies to this ubiquitous functional group has attracted
[3-13]
attention over the years.
Different reactions have been
[4]
investigated including Schmidt reaction, Staudinger ligation,
Beckmann rearrangement of oximes,
alkenes, haloarenes and alkynes,
aldehydes and alcohols [7] hydrative amide synthesis with alkynes,
[5]
aminocarbonylation of
oxidative amidation of
[6]
[8]
[9]
and amidation of thioacids and ketones with azides/amines
including the recent high atom economic systems: transition-
metal-catalyzed oxidative amidation of aldehyde with primary
amines using Fe, Cu, Ru, Rh, Pd, lanthanide and Ag-based
catalysts. [10] These synthetic methods require heated reaction
conditions and prolonged time, and the substrate scope is limited.
In the first model reaction, the benzamide (1a) and
benzaldehyde (2a) were used in direct cross-dehydrogenative
coupling reaction conditions. Various single electron transfer
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10.1002/cctc.202000156
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(SET) oxidants (11 examples) were screened with various
transition metal complexes (16 examples) in combination with five
N-heteroatom carbene (Table 1). During the standardization of
the reaction condition, it was found that the use of both thiazolium
and imidazolium precatalysts (in 20:20 mol% ratio) for the
respective half of the reaction offered better reaction yield and
rate than
the
cases
where
either
thiazolium
or
triazolium/imidazolium salts were used.
A
Scheme 1. (A) Schematic representation of plausible mechanism for the optimised reaction. (B)The energy profile of the reaction after combination of BH5 (A
and/or B) with SH3 (C and /or D)
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Table 1. Standardization of the reaction condition for the synthesis of imides and ortho-substituted amides.
b)
Entry a)
NHC1
M(X)n
NHC2
Oxidant
Time c)
Yield d, e)
1
NHC1a, NHC1b
CoCl2.2H2O
NHC2c
NHC2c
NHC2c
UHP
Fe(III)-EDTA-H2O2
Co(EDTA)-H2O2
15h
54, 35
28, 15
26, 21
2
NHC1a
CoBr
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NCS+Ag2O
BzOOH
H2O2
TBHP
UHP
12h
15
14
31
42
32
48
35
Fe(III)-EDTA-H2O2
Co(EDTA)-H2O2
3
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
NHC1a
PdCl2 + EDTA
Pd(OAc)2 + EDTA
FeBr2
NHC2b,
NHC2c
Fe(EDTA)-H2O2
Fe(EDTA)-H2O2
12h
24h
32h
22h
12h
12h
12h
12h
12h
24h
12h
12h
32,
42
4
NHC2b,
NHC2c
41,
56
5
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
NHC2c
UHP
Fe(EDTA)-H2O2
28
22
6
Co(acac)3
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
42
64
7
Co(bpym)Cl2
Co(bibim-2)
Co(bibim-3)
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
62
68
8
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
71
76
9
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
60
69
[18e]
10
11
12
13
14
(iPrPDI)CoCl2
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
71
85
Co(trop2DAD)Br2
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
74
89
(PPh3)3CoCl
Co(II)-EDTA-H2O2
Fe(III)-EDTA-H2O2
45
54
[Co(12-TMC)(ACN)](ClO4)2
[Co(13-TMC)(ACN)](ClO4)2
[Co(12-TMC)(O2)](ClO4) [18f]
Fe(III)-EDTA-H2O2
86
96
[Co(12-TMC)(O2)](ClO4) [18f]
Fe(III)-EDTA-H2O2
88
96
15
16
NHC1a
NHC2c
[Co(12-TMC)(ACN)](ClO4)2
[Co(12-TMC)(ACN)](ClO4)2
NHC1a
NHC2c
Fe(III)-EDTA-H2O2
Fe(III)-EDTA-H2O2
12h
12h
<5
32
a) All the reaction were carried out using DMPU:H2O as solvent system and K2CO3 + KHCO3 as base (0.6:0.6 mol)
b) These complexes were prepared using the method reported in the literature. The catalyst was used in 20 mol%.
c) in hrs;
d) Isolated yield in percentage (%).
e) In entry 1 the conversion of reactant was quantitative therefore the crude yield (3 and 4) was found to be in approximately 100-Yield%.
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Catalytic effects of various transition metal salts on the
thiazolium mediated Breslow and SET halves respectively which
justifies the observed better yield in entry 16 than entry 15 (table
1) since a larger proportion of the thiazolium would get engage
formation of Breslow's intermediates. Thus, after carrying out
both possibilities, it is found that the amide forms SH1, SH2 and
SH3 intermediate with ΔΔG values of -2.4, -17.7 and -6.9 kJ/mol
via coordination through NH and CO thus are more stable than
the amine. Also, we can clearly say the formation of BH5 as
endoergic with 5.3 and 14.9kJ/mol for NHC1 and NHC2
respectively.
cross-coupling of benzamide (1a) with benzaldehyde (2a) were
firstly evaluated in the presence of Fe(III)-EDTA-H2O2
[23]
as
oxidant. The best result was obtained in DMPU using slightly
excess stoichiometry of oxidant in both Fe and Co-based
catalysis (Entry 2-4, Table 1). The oxidants having the same
central atoms though the stability of these peroxo-metal
complexes limits further exploration of [Co(12-TMC)(O2)](ClO4)
and [Co(13-TMC)(O2)] (ClO4) as oxidant through their high
propensity worth noting for future consideration.
The possible mechanism of the reaction is depicted in
scheme 1, which closely very related NHC-catalyzed oxidative
coupling with TEMPO various exogenous alcohols, water, and
benzyl mercaptan reacted with aldehydes to afford esters,
cinnamic acid, and thioesters.[20] The anticipated reactivity
difference between the thiazolium and imidazolium salt with
aldehyde separated the path into respective two halves where
the imidazolium (BH1) goes for Breslow's intermediate formation
with the aldehyde and thiazolium catalyst (SH1) proceeds for the
SET based activation of amide or amine in cooperativity of Co-
cat. The DFT calculations using Qchem5.2 [24] were carried out
at B3LYP/6-31g(d) level and LanL2Dz level for C, H, O, N and
S and Co respectively to rationalize that thiazoline based
catalyst are upright for activating amide whereas aldehyde is
activated through imidazolium-based catalyst. As the energy
change during the aldehyde to Breslow intermediate was found
to be -35.9kJ/mol for thiazolium based catalyst (NHC1) and
imidazolium (NHC2) afforded -25.9kJ/mol. The conversion of
BH2 to BH4 accomplished with ΔG of 0.76 and -5.59kJ/mol for
thiazolium and imidazolium catalyst. The activation of amide
before the formation of intermediate II via I afforded at an
expense of -24.7kJ/mol and -25.3kJ/mol for imidazolium and
The reaction with both amine and amide as the starting
material resulted in the formation of imine in larger excess than
the corresponding amide which supports the proposed
mechanism, due to the more stability of the Co(12TMC)-amide
complex SH3 than the complex with the amine. The combination
of SH3 and BH5 resulted in the formation of I which found to be
twice endoergic for B-D and C-D (when NHC2 as aldehyde
activating) than B-A and C-A (NHC1 as aldehyde activating).
Followed by conversion of I to II via Nucleophilic addition of
activated amide on the Breslow half (I, Figure 1A). The ΔGBD
II), ΔGBD (I II), showing that the I to II conversion is free energy
favored step than their respective counterparts. The conversion
of II to III due to N to O hydrogen transfer to form Co-chelated
aminal complex followed by conversion of III to IV via
deprotonation mediated oxidation of aminal to imide is a highly
exoergic process for B-D combination (approximately ~3 time of
C-D, C-A and ~30 time of B-A combination reaction pathway for
the former step and 39.5kJ/mol for the latter step which is lower
than the C-D combination reaction pathway but favorable than
C-A and B-A) the favoring the reaction towards the formation of
our desired product.
→
(I
→
Figure 2. Substrate scope for N-Alkoxylation and Aroylation of secondary
amines
All the common metal complexes were prepared through
reported protocols and screened, where Co-based paramagnetic
complexes were found more effective (84%) than their commonly
available precursors like Co(acac)2 (59%), CoCl2·6H2O (48%)
and CoBr (62%). Other transition metal catalysts such as
Pd(OAc)2, FeBr2 and NiCl2·6H2O (Table 1) showed significant
Figure 1. Substrate scope for N-Aroylation of amine to amide
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10.1002/cctc.202000156
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catalytic activities for the formation of the product (3) but along
with the undesired ortho C-H activated acylation product (4) in
considerable amount. This led to the insight towards the
regioselectivity in the Metal catalyzed methodology for the
construction of the N-H activation mediated functionalization and
C-H activation mediated functionalization having unequal
propensity of formation under conditions either differing in terms
of catalysts or base used in the reaction. In order, to decide
regioselectivity of [Co(13-TMC)(ACN)](ClO4) screening of
different base was performed and found that the use of CsCO3
resulted in the formation of C-H activation based substitution
product (ortho-arylation, 4) in major amounts which are beyond
the scope of this work, whereas K2CO3/ KHCO3 was found to give
N-H activation mediated desired product in major amount (3,
Table 1), the reaction afforded quantitative conversion thus the
obtained two product was in the cases where both aldehyde and
N-partners are aromatic whereas the cases where aromatic
amides or amines coupled with alkyl aldehyde the ortho-alkylation
product was not obtained but traceable respective carboxylic acid
were obtained (Figure 2 and 3). The reaction showed no
indication of product formation when only Co-catalyst and NHC
were used even after 48hrs at room temperature conditions thus
we recovered our starting materials with some trace of the
respective carboxylic acid of aldehyde due to Arial oxidation
under the optimized reactions conditions.
Figure 3. Substrate scope for the formation of imides.
After screening a series of peroxides and other oxidants, [25]
the Fe(III)-EDTA-H2O2 was found to offer the best results (Table
1, entries 2 and 14–19). The use of the [Co(13-TMC)(O2)](ClO4)
as oxidant offered an almost similar result. The other oxidants like
UHP, TBHP, H2O2, Ag2O offered lesser yields while CoBr was
used as catalyst (Entry 1, Table 1). The higher temperature was
not beneficial for this reaction (Table S2†, entry 23), meanwhile,
yields were slowly decreasing with the lowering of the reaction
temperature (Table S1†). It was worth noting that the cross-
coupling reaction also took place at room temperature giving the
coupling product in a moderate yield (Table S1†). Although a high
coupling yield could be obtained in just 6-7 hours (68% Table S1†),
but for assuring quantitative yields all the reactions were executed
for 12h to assure higher yields.
Figure 4. Substrate scope for the formation of cyclic imides.
In conclusion, a novel methodology for the regioselective
construction of amide and imides using a Co-catalysed N-H
activation based functionalization methodology has been
developed which is capable of amide formation in a highly
effective manner with appreciable temperature-controlled kinetics
With a highly efficient cobalt catalyst in hand, we tested its
versatility in the direct N-aroylation of various aromatic amines
(Figure 1). Thus, both electron-rich amines and electron-deficient
aldehydes (Figure 1 and 2) and vice-versa were successfully
employed for the formation of the amides. Even the case where
electron-rich and electron-deficient amines and aldehyde were
also employed to obtain the amides in moderate to good yields.
However, in the cases where the steric bulk was high (like 3Bg4
and 3Bh4 where X = tert butyl) the yields were lower may be due
to the destabilized Breslow’s intermediate formation. (Figure 2).
After the achievement of the N-H bond activation mediated
coupling based amide/imide formation using in-situ generated
benzaldehyde derived Breslow intermediates as aroylating agent
with various amines and amides, the scope of various aldehydes
as the N-acylating and aroylating agents using amides as starting
materials were further explored. (Figure 3) The good to excellent
yields were obtained in almost all the cases and the steric effect
seemed to play a predominant role in lowering the yields in cases
where bulkier substituents were present proximal to the carbonyl
group resulting destabilization of the Breslow intermediates
(Scheme 1, BH2). In addition, we also have screened our
optimized reaction condition in the synthesis of cyclic imides.
(Figure 4)
Experimental Section
General Procedure: To a solution of [Co(13-TMC)(ACN)](ClO4)2 (65.6 mg,
0.2 mmol) was added NHC2c (55.5 mg, 0.15 mmol) in DMPU (0.5 mL) and
stirred the reaction for 1.5 h at r.t. the colour change from brown to dirty
green was observed which considered as an indicator of the formation of
Co(NHC)L after such, Fe(III)-EDTA-H2O2 complex (~382 mg, 1.0 mmol,
1.0 equiv.) and [Co(13-TMC)(NHC)](ClO4)2 (49.2 mg, 0.15 mmol) were
added to a stirred solution of specified aldehyde (1 mmol) in DMPU (1.5
mL) then NHC1c (60 mg, 0.2 mmol) and amine/amide (1.1 mmol) was
added to the solution and diluted the reaction mixture with TDW (8 mL)
followed by the addition of KHCO3:K2CO3 (0.6: 0.6 mmol) to the resulting
reaction mixture, the completion of amide formation was (6 to 14 h) was
checked by TLC or GC/MS. After a few hours (2-10 h), the mixture was
quenched carefully with aq. NH4Cl (10 mol %, 10 mL) and extracted with
Et2O or EtOAc (3 x 20 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
purification was carried out by running the resulting mixture through
Celite:SiO2 bed column.
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Acknowledgements
We thankfully acknowledge the technical and analytical support
by Mrs Anjum Baig, DIF-Jamia Hamdard, and CIF-Jamia
Hamdard. One of us (I.A.K.) is thankful to UGC, New Delhi, for
the award of Startup grant and Department of Chemistry, Jamia
Hamdard for providing facility, space, and infrastructure for
concluding part of the project. One of us (AK) is thankful to
Hamdard foundation for the award of Hamdard National
fellowship.
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Keywords: Breslow’s Intermediate, SET oxidant, N-heteroatom
carbene.
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Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
A novel methodology for the
construction of various secondary
(4 examples), tertiary amides (31
examples) and imides (16
Asher M. Siddiqui[a], Anam Khalid[a],
Arif Khan[a], Chandra S. Azad[b],
Mohd. Samim[a]* and Imran A.
Khan[a]*
examples) by a metal catalyzed
oxidative amide coupling in
Page No. – Page No.
aqueous media, has been devised
using insitu generated
N-Heterocyclic Carbene/Cobalt
Cooperative Catalysis for the
chemo-and regioselective C–N
Bond formation between aldehyde
and amines/amides
Co(II)(L)(NHC) based catalytic
system and Fe(III)(EDTA)-H2O2 as
oxidizing agent. The method is
regioselective for N-H activation in
presence of equally susceptible
ortho-C–H bond activation.
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