N -Heterocyclic carbene (NHC) catalyzed amidation of aldehydes with amines via the tandem N -hydroxysuccinimide ester formation

Article abstract of DOI:10.1039/d1nj00591j

A facile method for the amidation of aldehydes by a cascade approach was developed. This methodology, reported for the first time, uses a N-heterocyclic carbene (NHC) as the catalyst, and N-hydroxysuccinimide (NHS) mediated synthesis of amides utilising TBHP as the oxidant. Various substituted aldehydes reacted smoothly with NHS giving the corresponding active esters in moderate to good yields, which facilely converted into amides in one pot. In addition, the drug moclobemide was synthesized to represent the practical utility of the developed methodology. This journal is

Full text of DOI:10.1039/d1nj00591j

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N-Heterocyclic carbene (NHC) catalyzed
amidation of aldehydes with amines via the
tandem N-hydroxysuccinimide ester formation†
Cite this: New J. Chem., 2021,
45, 7486
Received 4th February 2021,
Accepted 22nd March 2021
Ashmita Singh and A. K. Narula
*
DOI: 10.1039/d1nj00591j
rsc.li/njc
A facile method for the amidation of aldehydes by a cascade a promising path breaking system.11 NHCs are actively used
approach was developed. This methodology, reported for the first as ligands in coordination with various transition metals to
time, uses a N-heterocyclic carbene (NHC) as the catalyst, and catalyze the amidation reaction of aldehydes or alcohols with
N-hydroxysuccinimide (NHS) mediated synthesis of amides utilising amines in the presence of an external oxidant. The said process
TBHP as the oxidant. Various substituted aldehydes reacted proceeds through the formation of a hemiaminal intermediate
smoothly with NHS giving the corresponding active esters in resulting from an aldehyde/alcohol and amine coupling
moderate to good yields, which facilely converted into amides in followed by its subsequent oxidation into amides.12
one pot. In addition, the drug moclobemide was synthesized to Ghosh et al. and other groups reported a series of Ru-13 and
represent the practical utility of the developed methodology.
Rh-14 NHC catalyzed syntheses of amides from various aldehydes
and amines. In 2019, Balaboina et al. published Ag-NHC
catalyzed amide synthesis from alcohol and amine coupling
via the formation of a hemiaminal intermediate.15 However,
the use of costly transition metal catalysts limits the use of the
above methodologies. Recently, the authors have reported a
cheaper Fe, Cu metal and NHC catalyzed amidation of aldehydes
with amines.16,17
Another elegant unconventional methodology includes the
catalytic transformation of functionalized aldehydes into active
esters in the presence of NHC and co-catalyst, which are then
reacted with amines to give amides. Armido Studer, in 2010,
reported the oxidative amidation of aldehydes through hexa-
fluoroisopropyl active ester formation.18 Despite good progress,
these methods suffer from drawbacks of limited substrate
scope, use of co-catalysts, and need for excess of starting
reagents.
In this report, using the ester formation approach, the
authors utilized N-hydroxysuccinimide (NHS) and aldehydes,
along with NHCs, which could smoothly afford NHS esters as
they are vital intermediates in amide (peptide) bond formation,
which can then be easily converted into amides in one pot. The
NHS ester mediated conversions, for amide formation, that
have been reported earlier use transition metal catalysts, such
as Cu,19 Co,20 and the hypervalent iodine/bromine21 catalysts,
that require longer reaction duration for the ester intermediate
formation.
Introduction
Amide functionality plays a pivotal role in organic and biological
chemistry. The existence of amides in numerous prevalent
pharmaceuticals, natural products, and agrochemicals makes
them an essential moiety in synthetic chemistry.1,2 The general
approach used for their synthesis involves the reaction of
activated carboxylic acid derivatives with amines.3 On the
contrary, a plethora of reports have also been published, in
which the activated amines (amines as their hydrochloride salts)
react with aldehydes or alcohols to give amides.4 Staudinger
reaction,5 Beckmann rearrangement,6 and Schmidt reaction7 are
also among the various alternative strategies developed for their
synthesis. However, most of the reactions reported experience
innate setbacks of providing equimolar hazardous by-products,
limited substrate scope, and lower product yields.8
Nowadays, emerging trends in the use of a phosphene free
catalytic system, i.e., the N-heterocyclic carbenes (NHCs) as
organocatalysts, have diversified the synthetic chemistry field
to a significant extent.9,10 In terms of the amide bond
formation also, the NHC catalyzed reactions have emerged as
University School Of Basic and Applied Sciences (USBAS), Guru Gobind Singh
Indraprastha University, Sector – 16 Dwarka, New Delhi, India.
E-mail: aknarula@ipu.ac.in
Herein, for the first time, we report a metal-free and convenient,
NHC catalyzed tandem synthesis of amides via the NHS
ester formation by the reaction of aldehydes with
† Electronic supplementary information (ESI) available: [DETAILS]. See DOI:
10.1039/d1nj00591j
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Table 1 Optimization of the reaction conditionsa
Fig. 1 NHC precursors used in the study.
Entry NHC precursors Oxidant
Time (h) Solvent Yieldb (%)
1
2
3
4
5
6
7
8
1
1
1
—
1
2
3
4
5
6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
None
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
Oxone
Air
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
24
24
24
24
8
CH3CN
CH3CN
CH3CN
CH3CN
—
—
—
—
c
the same reaction with different NHC precursors (Fig. 1). NHC
precursors 4 and 5 gave slightly better yields, i.e., 62% and 66%,
respectively, when compared with precursors 2, 3, and 6 after 24 h
duration (Table 1, entries 6–10), and it was concluded that
precursor 1 was the ideal or the most suited precursor for this
reaction.
d
CH3CN 85(B85)e
CH3CN 34
CH3CN 28
CH3CN 62
CH3CN 66
CH3CN 20
24
24
24
24
24
24
24
24
24
24
24
24
24
24
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Next, the role of different readily available oxidants was
evaluated for the required oxidative process. No product
formation was realized when classical oxidizing agents such
as H2O2, oxone and air were used (Table 1, entries 11–13). So,
TBHP was chosen as the oxidant of choice for continuing our
study. However, the use of anhydrous TBHP did not alter the
rate of product formation (Table 1, entry 20). On screening
different solvents, such as THF, toluene, methanol, ethanol,
DMF, DMSO and acetonitrile, it was found that acetonitrile was
a good choice for the current oxidative reaction methodology
(Table 1, entries 14–19). Bases used other than NaH, such as
K2CO3, Cs2CO3, and tBuOK, resulted in lower product yields
(Table 1, entries 21–23). When optimisation was carried out
with lower NHC precursor loading (5 mol%), 80% of the
product yield was obtained (Table 1, entry 24). On increasing
the precursor loading to 20 mol%, no significant increase in
product formation was noticed, confirming that the catalyst
loading of 10 mol% was ideal (Table 1, entry 25).
CH3CN
CH3CN
CH3CN
CH3CN 72
THF 78
Toluene 53
Ethanol 58
DMF
—
—
—
33
42
DMSO
anhy. TBHP 24
CH3CN 85
CH3CN 51f
CH3CN 64g
CH3CN 73h
CH3CN 80i
CH3CN 85j
TBHP
TBHP
TBHP
TBHP
TBHP
24
24
24
24
24
a
Reaction conditions: reaction was carried out using 1 (2.5 mmol), 2
(2.5 mmol), oxidant (3 equiv.), NHC precursor 10 mol% and NaH
b
10 mol% in solvent (3 mL). Isolated yields after column chromato-
graphy. Reaction was carried out at room temperature. Instead of
c
d
e
f
NHS, HOAt was used. When carried for 24 h. Base Cs2CO3 was used.
g
h
i
Base tBuOK was used. Base K2CO3 was used. When 5 mol% of
j
NHC precursor was used. When 20 mol% NHC precursor was used.
After optimizing the conditions for NHS ester formation, the
feasibility of performing a one-pot conversion of aldehydes into
amides was tested. Thus, in the second step, when benzylamine
(2 mmol) was introduced in one portion to the reaction
mixture, the desired amide product was obtained in good yield
in 6 h–8 h (Fig. 2). In this process, the free amine was used
directly, alleviating the necessity of the preparation of an amine
salt as required in most of the previously reported methodologies.
It is also noteworthy that, in these conversions, the NHS used and
the excess of aldehyde could be collected unmodified.
With the optimized protocols in hand for NHS ester
formation and successive amide bond formation, the evaluation
of the substrate scope was focused. Firstly an array of substituted
aldehydes were subjected to standard optimized conditions for
NHS ester formation. The results are displayed in Table 2. The
reaction proceeded smoothly with various substituted aromatic
N-hydroxysuccinimide in the presence of an oxidant, tert-butyl
hydroperoxide (TBHP), to afford a wide variety of substituted
amides in good yields.
Results and discussion
To begin with, we initiated our study with the model substrate
reaction of anisaldehyde (1a) and N-hydroxysuccinimide (2) in
acetonitrile by employing different NHC precursors and
oxidant TBHP. The results are shown in Table 1. Firstly, in a
control experiment using NHC precursor 1 in the absence of an
oxidant, no product was obtained (Table 1, entry 1). Furthermore,
no product formation was observed when the same reaction was
carried out in the presence of oxidant TBHP at room temperature
(Table 1, entry 2). Moreover, the results were also discouraging
when no carbene precursor was used and when 1-hydroxy-7-
azabenzotriazole (HOAt) was used instead of NHS, for esterification
(Table 1, entry 3 and 4). On proceeding further, reaction at refluxing
temperature in the presence of precursor 1 and oxidant TBHP
yielded 85% of the desired product in 8 h duration (Table 1, entry 5).
On continuing the same reaction for 24 h, no significant improve-
ment in yield was noticed (Table 1, entry 5). We then carried out
Fig. 2 One-pot synthesis of amides.
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Table 2 Substrate scope of the NHS ester formationa,b
(Table 2, entries a–j). In ortho-substituted benzaldehydes the role
of electronic effect rather than steric effect was observed, as
o-tolualdehyde gave 82% yield and o-fluoro benzaldehyde gave
74% yield of the desired ester product. (Table 2, entry 3d and 3i).
Naphthaldehyde and alkyl aldehydes bearing long chain and steric
hindrance also reacted conveniently to give the desired ester in
good yields (Table 2, entries 3k–n and 3p). Heteroaryl aldehydes
such as thiophene-2-carbaldehyde and 1H-pyrolle-2-carbaldehyde
could smoothly afford the corresponding ester in good yields
(Table 2, entries 3o and 3q).
Next, on moving further, the substrate scope for the amidation
reaction was investigated. A wide variety of mono and di-
substituted amides were conveniently achieved using optimized
protocols in good yields (Table 3). Benzylamine underwent
the amidation reaction well with various substituted aromatic
aldehydes, alkyl aldehydes and heteroaryl aldehydes, yielding
amides in good yields (Table 3, entries 4a–4f and 4q–4t).
Secondary amines such as morpholine, piperidine, and pyrrolidine
also reacted smoothly with aldehydes giving good product yields
(Table 3, entries 4g–4j). Moreover, various substituted anilines
and alkyl amines were also well tolerated during the amidation
reaction producing the respective amides in satisfactory yields
(Table 3, entries 4k–4o). This procedure was also found suitable for
the preparation of the commercially available anti-depressant
MAO-inhibitor moclobemide drug in 87% yield (Table 3, entry 4p).
A possible reaction mechanism was also proposed in the
a
Reaction conditions. Reaction was carried out using 1 (2.5 mmol), 2
(2.5 mmol), TBHP (3 equiv.), NHC precursor 1 (10 mol%) and NaH
(10 mol%) in acetonitrile (3 mL). Isolated yields after column
b
chromatography.
aldehydes giving a moderate to good yield of the corresponding
NHS ester. Aldehydes having electron neutral and donating groups generalized form by observing the reaction outcomes and
gave better yields than those having electron-withdrawing groups reviewing previous literature reports (Fig. 3). The imidazolium
Table 3 Substrate scope of the amidation reaction.a,b
Reaction conditions. a Reaction was carried out in step 1 using 1 (2.5 mmol), NHS (2.5 mmol), TBHP (3 equiv.), NHC precursor 1 (10 mol%) and
b
NaH (10 mol%) in acetonitrile (3 mL); in step 2, amine (2 mmol). Isolated yields after column chromatography.
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W. Schilling, J. Kollmann and S. Das, ACS Catal., 2018, 8,
6659–6664; (c) Y. Zhang, D. Reimer, W. Schilling,
J. Kollmann and S. Das, Nat. Protoc., 2020, 15, 822–839;
(d) W. Schilling and S. Das, et al., Chem. – Eur. J., 2020, 26,
390–395; (e) Y. Zhang and S. D. Schilling, et al., Chem-
SusChem, 2019, 12, 2898–2910.
3 (a) S. Y. Han and Y. A. Kim, Tetrahedron, 2004, 60,
2447–2468; (b) C. A. G. N. Montalbetti and V. Falque, Tetra-
hedron, 2005, 61, 10827–10852; (c) E. Valeur and M. Bradley,
Chem. Soc. Rev., 2009, 38, 606–631; (d) R. C. Larock, Com-
prehensive Organic Transformations, VCH, New York, 1999;
(e) J. R. Dunetz, J. Magano and G. A. Weisenburger, Org.
Process Res. Dev., 2016, 20, 140–177.
4 (a) R. Cadoni, A. Porcheddu, G. Giacomelli and L. D. Luca,
Org. Lett., 2012, 14, 5014–5017; (b) T. N. Reddy and
A. Beatriz, et al., Chem. – Asian J., 2019, 3, 344–388;
(c) R. M. de Figueiredo, J. S. Suppo and J. M. Campagne,
Chem. Rev., 2016, 116, 12029–12122.
Fig. 3 The proposed mechanism for the synthesis of amides.
carbene generated reacts with an aldehyde to form a Breslow
intermediate A, which subsequently gets oxidized to intermediate
B by the action of TBHP. In the next step, NHS attacks
intermediate B to give the corresponding NHS ester C and
imidazolium carbene, thus reviving the catalytic cycle. The NHS
ester formed reacts with the amine to produce the desired
amide D.
5 (a) E. Saxon and C. R. Bertozzi, Science, 2000, 287,
2007–2010; (b) F. Damkaci and P. De Shong, J. Am. Chem.
Soc., 2003, 125, 4408–4409; (c) Y. G. Gololobov and
L. F. Kasukhin, Tetrahedron, 1992, 48, 1353–1406.
6 (a) N. A. Owston, A. J. Parker and J. M. J. Williams, Org. Lett.,
2007, 9, 3599–3601; (b) M. Hashimoto, Y. Obora,
S. Sakaguchi and Y. Ishii, J. Org. Chem., 2008, 73, 2894–2897.
7 (a) T. Ribelin, C. E. Katz, D. G. English, S. Smith,
A. K. Manukyan, V. W. Day, B. Neuenswander,
J. L. Poutsma and J. Aube, Angew. Chem., Int. Ed., 2008,
47, 6233–6331; (b) S. Lang and J. A. Murphy, Chem. Soc. Rev.,
2006, 35, 146–156.
Conclusion
In conclusion, a novel and efficient methodology was developed
for the construction of various mono and di-substituted amides
in good yields by a cascade approach of the NHS ester
formation via aldehydes. This methodology is unique because
it utilizes readily available, non-hazardous, and cheaper starting
reagents and simple imidazolium-based N-heterocyclic carbenes.
Further attempts to explore the scope, limitation, and
mechanism of this reaction are underway in our laboratory.
8 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. L. Leazer, Jr., R. J. Linderman, K. Lorenz, J. Manley,
B. A. Pearlman, A. Wells, A. Zaksh and T. Y. Zhang, Green
Chem., 2007, 9, 411–420.
9 (a) K. Ofele, J. Organomet. Chem., 1968, 12, 42–45;
¨
(b) H. W. Wanzlick and H. J. Schonherr, Angew. Chem., Int.
Ed. Engl., 1968, 7, 141–142; (c) A. J. Arduengo, R. L. Harlow
and M. Kline, J. Am. Chem. Soc., 1991, 113, 361–363;
(d) D. Ragno and A. Brandolese, et al., Chem. – Eur. J.,
2021, 27, 1839–1848; (e) C. Richter, M. Schedler and
F. Glorious, Nature, 2014, 510, 485–496.
Conflicts of interest
There are no conflicts of interest.
10 (a) A. J. Arduengo, M. Kline, J. C. Calabrese and F. Davidson,
J. Am. Chem. Soc., 1991, 113, 9704–9705; (b) L. Cavallo,
A. Correa, C. Costabile and H. Jacobsen, J. Organomet.
Chem., 2005, 690, 5407–5413; (c) R. S. Menon, A. T. Biju
and V. Nair, Chem. Soc. Rev., 2015, 44, 5040–5052;
(d) S. D. Sarkar, A. Biswas, R. C. Samanta and A. Studer,
Chem. – Eur. J., 2013, 19, 4664–4678.
11 (a) V. Kumar and S. J. Connon, Chem. Commun., 2017, 53,
10212–10215; (b) S. Premlatha, A. Ghosh and A. T. Biju,
et al., Chem. Commun., 2017, 53, 1478–1481; (c) R. A. Green,
D. Pletcher, S. G. Leach and R. C. D. Brown, Org. Lett., 2016,
18, 1198–1201; (d) P. Nagaraaj and V. Vijayakumar, Org.
Chem. Front., 2019, 6, 2570–2599.
Acknowledgements
The authors acknowledge the funding received from the Guru
Gobind Singh Indraprastha University for carrying out the
research experiments.
References
1 (a) T. Cupido, J. Tulla-Puche, J. Spengler and F. Albericio,
Curr. Opin. Drug Discovery Dev., 2007, 10, 768–783;
(b) J. W. Bode, Curr. Opin. Drug Discovery Dev., 2006, 9,
765–778; (c) J. M. Humphrey and A. R. Chamberlin, Chem.
Rev., 1997, 97, 2243–2266.
12 (a) C. E. I. Knappke, A. Imami and A. Jacobi von Wangelin,
ChemCatChem, 2012, 4, 937–940; (b) H. U. Vora and T. Rovis,
2 (a) A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski,
J. Comb. Chem., 1999, 1, 55–68; (b) Y. Zhang, D. Reimer,
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 7486–7490
| 7489

View Article Online
NJC
Communication
J. Am. Chem. Soc., 2007, 129, 13796–13978; (c) For the NHC- 15 (a) R. Balaboina, N. S. Thirukovela, R. Vadde and
catalyzed amidation of unactivated esters with amino alco-
hols, see: M. Movassaghi and M. A. Schmidt, Org. Lett.,
2005, 7, 2453–2455.
C. S. Vasam, Tetrahedron Lett., 2019, 60, 847–851;
(b) K. Singh, N. K. Pal, C. Guha and J. K. Bera,
J. Organomet. Chem., 2019, 886, 1–8.
13 (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 16 A. Singh, C. S. Azad and A. K. Narula, ChemistrySelect, 2020,
317, 790–792; (b) L. U. Nordstrøm, H. Vogt and R. Madsen, 5, 9417–9423.
J. Am. Chem. Soc., 2008, 130, 17672–17673; (c) A. J. A. Watson, 17 A. Singh and A. K. Narula, Synlett, 2021, 32, 718–722.
A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009, 11, 18 S. De Sarkar and A. Studer, Org. Lett., 2010, 12, 1992–1995.
2667–2670; (d) S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Xu and 19 S. Gaspa, A. Porcheddu and L. D. Luca, Org. Biomol. Chem.,
S. H. Hong, Adv. Synth. Catal., 2009, 351, 2643–2649.
2013, 11, 3803–3807.
14 (a) K. I. Fujita, Y. Takahashi, M. Owaki, K. Y. Yamamoto and 20 H. Yao and K. Yamamoto, Chem. – Asian J., 2012, 7, 1542.
R. Yamaguchi, Org. Lett., 2004, 6, 2785–2788; (b) T. Zweifel, 21 (a) H. Yao and K. Yamamoto, Tetrahedron Lett., 2012,
J. V. Naubron and H. Gru¨tzmacher, Angew. Chem., Int. Ed.,
2009, 48, 559–563.
53, 5094; (b) B. Tan, N. Toda and C. F. Barbas III, Angew.
Chem., Int. Ed., 2012, 51, 12538–12541.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
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