N-heterocyclic carbene-catalyzed oxidative amidation of aldehydes with amines

Article abstract of DOI:10.1002/adsc.201400739

The N-heterocyclic carbene (NHC)-catalyzed oxidative amidation of aromatic aldehydes with amines in the presence of N-bromosuccinimide (NBS) as an oxidant has been developed for the synthesis of amides. This amidation strategy is tolerant to both the electronic and the steric nature of the aryl aldehydes employed. The present methodology was extended to chiral amino acid derivatives to generate the corresponding amides in good yields and excellent ee values (>98%).

Full text of DOI:10.1002/adsc.201400739

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DOI: 10.1002/adsc.201400739
N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of
Aldehydes with Amines
Anitha Alanthadkaa and C. Uma Maheswaria,*
a
Organic Synthesis Group, Department of Chemistry, School of Chemical and Biotechnology, SASTRA University,
Thanjavur – 613401, India
Fax : (+91)-4362-264-111; e-mail: umamaheswaric@scbt.sastra.edu
Received: July 28, 2014; Revised: January 21, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400739.
Abstract: The N-heterocyclic carbene (NHC)-cata-
lyzed oxidative amidation of aromatic aldehydes
with amines in the presence of N-bromosuccinimide
(NBS) as an oxidant has been developed for the
synthesis of amides. This amidation strategy is toler-
ant to both the electronic and the steric nature of
the aryl aldehydes employed. The present method-
ology was extended to chiral amino acid derivatives
to generate the corresponding amides in good
yields and excellent ee values (>98%).
Over the past few years, a large number of syntheti-
cally important transformations have been developed
in the presence of N-heterocyclic carbene (NHC)-
based organocatalysts.[7] Unlike phosphine ligands,
NHCs are found to be very stable under oxidative
conditions and can even act as a stabilising ligand in
Pd-catalyzed oxidation reactions.[8] A considerable
number of oxidative transformations have also been
developed in the presence of NHC-coordinated metal
complexes.[9] Similarly, oxidative NHC catalysis was
employed for several transformations: oxidation of al-
dehydes to esters,[10] amidation and azidation of alde-
hydes,[11] b-activation of saturated aldehydes,[12] a-
functionalization of simple aldehydes,[13] oxidative
cleavage of cyclic 1,2-diketones,[14] oxidation of aro-
matic aldehydes to aryl esters using boronic acids,[15]
oxidation of non-activated aldehydes to acids,[16]
Keywords: amides; N-heterocyclic carbenes; organ-
ic catalysis; oxidation; oxidative amidation
Amides are ubiquitous structural motifs found in vari- redox esterification of enals and ynals,[17] and oxo-
ous natural products that have immense importance acyl
AHCTUNGTRENNUNG
in the chemical as well as the pharmaceutical indus- In addition, a recent review on NHC catalysis under
try[1a] and exhibit a wide array of biological activi- oxidative conditions gives a detailed account of the
ties.[1b] Classical methods for the synthesis of amides application of NHCs as organocatalysts for various
include acylation of amines with carboxylic acid deriv- oxidative processes and their applications in cascade
atives including acid chlorides, anhydrides and acti- reaction, enantioselective transformations, and in nat-
vated esters.[2] However, these methods have the ural product synthesis.[19]
innate drawbacks of generating a stoichiometric
Amide bond formation of a-functionalized alde-
amount of by-product and employing hazardous re- hydes with amines catalyzed by NHC has been re-
agents. An alternative method for the synthesis of ported previously.[20] However, to the best of our
amides is oxidative amidation, which is quite attrac- knowledge, the NHC-catalyzed amidation of simple
tive from atom economy and green chemistry points aryl aldehydes with primary amines has not been ex-
of view. Here, an equivalent amount of aldehyde and plored. Herein, we present the oxidative amidation of
amine were coupled together. Up to date, oxidative aryl aldehydes with aliphatic primary/secondary
amidation was performed by employing homogene- amines catalyzed by an imidazolium-based NHC, in
ous/heterogeneous catalysis which uses expensive the presence of N-bromosuccinimide (NBS) as the
and/or toxic transition metal catalysts such as Mn, Al, terminal oxidant [Eq. (1)].
Ru, Rh, Pd, Cu, Fe, Au and Ag salts.[3–6] A modified
approach involving the use of an organocatalyst was
also found to be effective to carry out this transforma-
tion.
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Anitha Alanthadka and C. Uma Maheswari
Table 1. Optimization of the reaction conditions for the
NHC-catalyzed oxidative amidation of aldehydes.[a]
Entry NHC pre- Base
catalyst
Oxidant Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
A
B
C
D
E
F
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
Cs2CO3
NaH
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
H2O2
TBHP
BQ[d]
AQ[e]
NQ[f]
NCS
NBS
NBS
NBS
CH3CN 63
CH3CN 75
CH3CN 53
CH3CN 51
CH3CN 45
CH3CN 42
CH3CN 38
CH3CN 56[c]
CH3CN 26
G
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH3CN
CH3CN
CH3CN
<5
–
–
Figure 1. Structures of different NHCs employed for the oxi-
dative amidation.
CH3CN 32
CH3CN 43
CH3CN
CH3CN
–
–
on changing the oxidant from NBS to its halogen
counterpart NCS (entries 2 and 14). Then, variation
of bases for this oxidative amidation was performed
(entries 15–19). With inorganic bases like K2CO3 and
Cs2CO3, the reaction does not yield the desired prod-
uct, but on employing a strong base like NaH, a 48%
yield of the desired amide was observed (entries 15–
17). It was observed that organic bases gave better re-
sults than inorganic bases (entries 2 and 19). Even
though Et3N and diethyl azodicarboxylate (DEAD)
gave comparable yields, Et3N was used for further
studies due to its wide availability and cost effective-
ness. Different solvents were screened for this oxida-
tive amidation and acetonitrile proved to be the best
solvent (entries 2, 20–23).
CH3CN 48
CH3CN 52
CH3CN 73
t-BuOK NBS
DEAD
Et3N
Et3N
Et3N
NBS
NBS
NBS
NBS
NBS
MeOH
DCM
toluene
DMF
61
<5
<5
<5
Et3N
[a]
Reaction conditions: benzaldehyde (1 mmol), n-butyl-
ACHTUNGTRENNUNGamine (1.2 mmol), NHC pre-catalyst (10 mol%), base
(10 mol%), oxidant (3 mmol) in CH3CN (3 mL) at 258C
for 18 h.
Isolated yield.
B (5 mol%), Et3N (5 mol%) for 24 h.
BQ=benzoquinone.
[b]
[c]
[d]
[e]
[f]
AQ =anthraquinone.
NQ=naphthaquinone.
To demonstrate the synthetic utility of this amida-
tion process, various aldehydes and amines were
tested under the optimized reaction conditions
(Scheme 1). The reaction was tolerant to the electron-
For our initial optimization studies, benzaldehyde ic nature of the aryl aldehydes as both electron-with-
and n-butylamine were taken as model substrates for drawing and electron-donating substituted aldehydes
the oxidative amidation (Table 1). By varying differ- worked well to deliver the corresponding products in
ent NHC-salts from
A to G as pre-catalysts moderate to good yields (3a–3f). Generally, when
(Figure 1), we found out that both A and B gave electron-withdrawing substituents are present in the
better results than the other pre-catalysts, and the benzene ring, the yields are better compared to their
yield was optimal with B (entries 1–7). When the re- electron-donating counterparts. The steric factors had
action was performed with 5 mol% of B, the yield of minimal effect on this transformation, as 2-substituted
the desired product decreased significantly from 75% aryl aldehydes gave their corresponding products in
to 56% (entry 8). Once the pre-catalyst was fixed, we good yields, for example, 2-bromo- and 2-cyanoben-
tested different oxidants for this transformation (en- zaldehydes gave 78% and 68% yields of the corre-
tries 9–14). The yield obtained was found to be low sponding amides, respectively (3g and 3h). Moreover,
with H2O2 and TBHP as terminal oxidant (entries 9 the heteroaromatic thiophene-2-carboxaldehyde gave
and 10). When quinones were used as oxidants, the corresponding amide in a good yield of 82% (3i).
except for naphthaquinone, the reaction failed miser- Then variation of the primary amines was performed
ably (entries 11–13). The yield decreased considerably and the yields obtained are comparable with those of
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N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of Aldehydes
Scheme 1. Scope of the oxidative amidation via NHC catalysis. Reaction conditions: aldehyde (1 mmol), amine (1.2 mmol.),
NHC pre-catalyst B (10 mol%), base (10 mol%), NBS (3 mmol) in CH3CN (3 mL), 258C, 18 h. Isolated yields reported.
n-butylamine, when tert-butylamine and cyclohexyl-
ACHTUNGTRENNUNGamine were taken as coupling partners (3j and 3k).
When cyclic secondary amines like piperidine, mor-
pholine and pyrrolidine were taken, the desired prod-
ucts were observed in good yields of 79%, 77%, and
81%, respectively (3l–3n). When an acylic secondary
amine such as dibenzylamine was used for the amida-
tion process along with the expected amide (3o,
54%), N-benzylbenzamide (3o’, 33%) was obtained as
À
a side product, due to benzylic C H oxidation [Eq.
(2)].
Scheme 2. Oxidative amidation of benzaldehyde with chiral
amino acid derivatives.[21]
The scope of this oxidative amidation was extended
to chiral amino acid derivatives. When the reaction of yields with excellent enantioselectivities (Scheme 2).
benzaldehyde with l-valine methyl ester hydrochlo- The reaction of benzaldehyde with l-phenylglycine
ride was performed under the optimized conditions, methyl ester hydrochloride resulted in a poor yield of
the corresponding amide was obtained in 77% yield the corresponding amide (34%) with partial racemiza-
with >98% enantioselectivity.
tion (92% ee).
Similarly, reactions with other amino acid deriva-
To probe the reaction mechanism, several back-
tives like l-leucine and l-alanine methyl ester hydro- ground reactions were performed. The reaction of
chlorides gave the corresponding amides in moderate benzaldehyde with n-butylamine resulted in the for-
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Anitha Alanthadka and C. Uma Maheswari
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mation of imine which could be observed by H NMR
of the crude reaction mixture. With this imine, when
NHC pre-catalyst B was added along with base fol-
lowed by the addition of NBS, we could not observe
the formation of the desired amide. Similarly, when
benzoic acid was used as coupling partner, instead of
aldehyde, the corresponding amide was not detected.
These two test reactions suggest that neither imine
nor acid can be the reaction intermediate. Reaction in
the absence of either NHC or oxidant did not yield
the desired product. This shows that the presence of
both NHC and NBS is essential for this oxidative
transformation. To arrive at the possible reaction
pathway, trans-4-aminocyclohexanol was coupled with
benzaldehyde under the optimized reaction condi-
tions. Grimme and Studer et al. reported the regiose-
lective formation of esters with the same substrates
employing N,N’-dimethylimidazolium iodide as an
NHC precursor for oxidative esterification.[22] They
proposed that the reaction proceeds via an acylazoli-
um ion intermediate. But under the present reaction
conditions, we observed the regioselective formation
of the amide [Eq. (3)]. The N-bromination of amines
employing NBS has been reported previously.[23]
Based on these reports, we anticipate that the bromi-
nation of amine employing NBS might have occurred
under the reaction conditions, resulting in the forma-
tion of an N-bromoamine which may act as the key
intermediate for this oxidative amidation.
Scheme 3. Plausible mechanism for the oxidative amidation
of aldehydes with amines.
aldehydes and chiral amino acid derivatives, which
are important intermediates in pharmaceuticals and
synthetic organic chemistry.
Based on these reactions, we propose a plausible
mechanism as shown in Scheme 3. The initial step is
the generation of free carbene a from imidazolium
salt precursor B on treatment with base. The carbene
reacts with the aldehyde to generate intermediate
b,[24] which rearranges to generate the Breslow inter-
mediate c.[25] The amine reacts with NBS to give an
N-bromoamine which further reacts with Breslow in-
termediate c to generate the aminal intermediate d.[26]
Intermediate d undergoes further oxidation to yield
the desired amide along with regeneration of the free
carbene, thus making this reaction catalytic.
Experimental Section
General Procedure for the Synthesis of Amides from
Aldehyde and Amine
A mixture of NHC (10 mol%) and base (10 mol%) in 3 mL
of CH3CN was stirred at 258C for 30 min. To this mixture,
aldehyde (1.0 mmol) and amine (1.2 mmol) were added fol-
lowed by NBS (3 mmol), and stirring was continued at 258C
for 18 h. After the completion of the reaction, the solvent
was evaporated to dryness. Then the reaction mixture was
washed with Na2S2O3 solution and extracted with ethyl ace-
tate and dried over anhydrous Na2SO4. Removal of the sol-
vent under vacuum afforded the crude product, which was
In conclusion, a simple and straightforward method
for the synthesis of the amides by oxidative coupling
between aldehydes and amines was achieved using
oxidative NHC catalysis. The scope of the reaction in-
purified by column chromatography using hexane/ethyl ace-
cludes heterocyclic, sterically hindered 2-substituted tate mixtures and was analyzed by H NMR and 13C NMR.
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N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of Aldehydes
O. H. Winkelmann, J. Otten, D. A. Vicic, O. Navarro,
Chem. Eur. J. 2010, 16, 6857–6860.
Acknowledgements
[10] For the NHC-catalyzed conversion of aldehydes to
esters, see: a) S. D. Sarkar, S. Grimme, A. Studer, J.
Am. Chem. Soc. 2010, 132, 1190–1191; b) X. Chen, S.
Yang, B.-A. Song, Y. R. Chi, Angew. Chem. 2013, 125,
11340–11343; Angew. Chem. Int. Ed. 2013, 52, 11134–
11137; c) S. Iwahana, H. Iida, E. Yashima, Chem. Eur.
J. 2011, 17, 8009–8013; d) M. T. Berry, D. Castrejon,
J. E. Hein, Org. Lett. 2014, 16, 3676–3679; e) E. G.
Delany, C. L. Fagan, S. Gundala, A. Mari, T. Broja, K.
Zeitler, S. J. Connon, Chem. Commun. 2013, 49, 6510–
6512; f) E. G. Delany, C. L. Fagan, S. Gundala, K. Zei-
tler, S. J. Connon, Chem. Commun. 2013, 49, 6513–
6515; g) C. Noonan, L. Baragwanath, S. J. Connon, Tet-
rahedron Lett. 2008, 49, 4003–4006.
C.U. thanks DST, SERB, New Delhi for the award of a re-
search grant for young scientist (no. SB/FT/CS-108/2012),
and SASTRA University for the facilitating infrastructure and
for NMR analysis. A.A. and C.U. thank the reviewers for
their valuable suggestions. C.U. thanks Dr. V. Sridharan and
Dr. S. Nagarajan for their valuable inputs in revising the
manuscript.
References
[1] a) N. Sewald, H. D. Jakubke, in: Peptides: Chemistry
and Biology, Wiley-VCH, Weinheim, 2002; b) I. Jo-
hansson, Kirk-Othmer Encyclopedia of Chemical Tech-
nology: Amides, Fatty Acids, (Ed.: J. I. Kroschwitz), 5th
edn., Wiley, Hoboken, New Jersey, 2004, Vol. 2,
pp 442–463.
[2] E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606–
631.
[3] K. I. Shimizu, K. Ohshima, A. Satsuma, Chem. Eur. J.
2009, 15, 9977–9980.
[11] S. D. Sarkar, A. Studer, Org. Lett. 2010, 12, 1992–1995.
[12] J. Mo, L. Shen, Y. R. Chi, Angew. Chem. 2013, 125,
8750–8753; Angew. Chem. Int. Ed. 2013, 52, 8588–8591.
[13] J. Mo, R. Yang, X. Chen, B. Tiwari, Y. R. Chi, Org.
Lett. 2013, 15, 50–53.
[14] S. Gundala, C. L. Fagan, E. G. Delany, S. J. Connon,
Synlett 2013, 24, 1225–1228.
[15] P. Arde, B. T. Ramanjaneyulu, V. Reddy, A. Saxena,
R. V. Anand, Org. Biomol. Chem. 2012, 10, 848–851.
[16] L. Mohlmann, S. Ludwig, S. Blechert, Beilstein J. Org.
Chem. 2013, 9, 602–607.
[17] a) S. S. Sohn, J. W. Bode, Org. Lett. 2005, 7, 3873–3876;
b) K. Zeitler, Org. Lett. 2006, 8, 637–640.
[4] Y. Wang, D. Zhu, L. Tang, S. Wang, Z. Wang, Angew.
Chem. 2011, 123, 9079–9083; Angew. Chem. Int. Ed.
2011, 50, 8917–8921.
[5] S. D. Gonzꢁlez, N. Marion, S. P. Nolan, Chem. Rev.
2009, 109, 3612–3676.
[6] E. A. Kantchev, C. J. OꢂBrien, M. G. Organ, Angew.
Chem. 2007, 119, 2824–2870; Angew. Chem. Int. Ed.
2007, 46, 2768–2813.
[7] For a review on NHCs as organocatalysts, see: D.
Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007,
107, 5606–5655.
[18] R. N. Reddi, P. V. Malekar, A. Sudalai, Org. Biomol.
Chem. 2013, 11, 6477–6482.
[19] S. D. Sarkar, A. Biswas, R. C. Samanta, A. Studer,
Chem. Eur. J. 2013, 19, 4664–4678.
[20] a) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2007, 129,
13796–13797; b) J. W. Bode, S. S. Sohn, J. Am. Chem.
Soc. 2007, 129, 13798–13799; c) K. B. Ling, A. D. Smith,
Chem. Commun. 2011, 47, 373–375.
[21] K. Nadia, B. Malika, K. Nawel, B. M. Yazid, R. Zine,
N. E. Aouf, J. Heterocycl. Chem. 2004, 41, 57–60.
[22] R. C. Samanta, S. D. Sarkar, R. Frohlich, S. Grimme,
A. Studer, Chem. Sci. 2013, 4, 2177–2184.
[23] a) Y. Wei, F. Liang, X. Zhang, Org. Lett. 2013, 15,
5186–5189; b) L. Zhou, J. Chen, J. Zhou, Y.-Y. Yeung,
Org. Lett. 2011, 13, 5804–5807; c) Z. Wang, Y. Zhang,
H. Fu, Y. Jiang, Y. Zhao, Synlett 2008, 2667–2670.
[24] C. J. Collett, R. S. Massey, O. R. Maguire, A. S. Batsa-
nov, A. C. OꢂDonoghue, A. D. Smith, Chem. Sci. 2013,
4, 1514–1522.
[25] a) R. Breslow, J. Am. Chem. Soc. 1957, 79, 1762–1763;
b) R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719–3726.
[26] B. Shen, D. M. Makley, J. N. Johnston, Nature 2010,
465, 1027–1033.
[8] a) S. S. Stahl, J. L. Thorman, R. C. Nelson, M. A.
Kozee, J. Am. Chem. Soc. 2001, 123, 7188–7189;
b) M. M. Konnick, I. A. Guzei, S. S. Stahl, J. Am.
Chem. Soc. 2004, 126, 10212–10213; c) M. Yamashita,
K. Goto, T. Kawashima, J. Am. Chem. Soc. 2005, 127,
7294–7295.
[9] a) F. Hanasaka, K.-I. Fujita, R. Yamaguchi, Organome-
tallics 2004, 23, 1490–1492; b) M. J. Schultz, S. S. Hamil-
ton, D. R. Jensen, M. S. Sigman, J. Org. Chem. 2005,
70, 3343–3352; c) K. MuÇiz, Adv. Synth. Catal. 2004,
346, 1425–1428; d) M. Poyatos, J. A. Mata, E. Falomir,
R. H. Crabtree, E. Peris, Organometallics 2003, 22,
1110–1114; e) M. Muehlhofer, T. Strassner, W. A. Her-
mann, Angew. Chem. 2002, 114, 1817–1819; Angew.
Chem. Int. Ed. 2002, 41, 1745–1747; f) X. Liu, Q. Xia,
Y. Zhang, C. Chen, W. Chen, J. Org. Chem. 2013, 78,
8531–8536; g) C. Berini, D. F. Brayton, C. Mocka, O.
Navarro, Org. Lett. 2009, 11, 4244–4247; h) C. Berini,
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6 N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of
Aldehydes with Amines
Adv. Synth. Catal. 2015, 357, 1 – 6
Anitha Alanthadka, C. Uma Maheswari*
6
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