3
the optimized reaction conditions in hand i.e. 1 equiv. aldehyde,
1.2 equiv. amine, 1.1 equiv. of 70% aq. TBHP, 10 mol% of
TBAB and 10 mol% of FeCl2.4H2O in CH3CN at 40 °C (Table
1, Entry 29), we further examined the substrate scope of this
protocol. For this various electronically and structurally diverse
aldehydes and amines were subjected to optimized reaction
conditions and the results from these studies are shown in Table
2. While performing these studies, it was observed that at 40 °C
the reactions with secondary amines gave very low yields of the
corresponding amides. This can be attributed to the generally
higher basic nature of secondary amines compared to primary
amines, as a result the carbamates formed from secondary amines
are more stable and require higher temperature for CO2
desorption. Thus, the reactions were carried out at 40 °C and 60
°C for primary and secondary amines, respectively for optimal
CO2 desorption.
The amidation was also compatible with a variety of electron-
rich and electron-poor aryl aldehydes as shown in Table 2.
Notably, the hydroxyl group of 3-hydroxybenzaldehyde was not
affected under these oxidative conditions and the reaction with n-
butyl amine afforded the corresponding amide (3l) in 61% yield
(Table 2). The halide substituted aromatic aldehydes, such as 2-
Cl (3o, 3p), 4-Cl (3q), 4-Br (3r) and 4-I-benzaldehyde (3s) are
well tolerated under these reaction conditions and hence gave the
potential for further functionalization of aryl ring (Table 2).
When aliphatic and hetero-aromatic aldehydes were utilized as a
reactants, the desired amides 3u and 3v were obtained in 37%
and 72% yields, respectively. (Table 2).
Based on literature17, 19, 20 and control experiments, a plausible
mechanism is shown in Figure 2. Initially, in the presence of
CO2, the amine (I) is converted to carbamate (II), that slowly
releases free amine (I) on application of heat. Amine (I) reacts
with aldehyde (III) to form hemi-aminal intermediate (IV). The
FeCl2.4H2O catalyst in the presence of TBAB as co-catalyst
along with TBHP as oxidant further catalyses the oxidation of
hemi-aminal (IV) to amide (V) via a free radical mechanism. The
free-radical nature of this protocol is confirmed by inhibitory
effect placed by 1.0 equiv. of the radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) on this reaction.
Table 2: Iron-catalyzed oxidative amidation of aldehydes
under neutral reaction conditions.
Figure 2: Plausible mechanism of iron-catalysed oxidative amidation of
aldehyde.
Conclusions
In conclusion, we have developed an iron-catalysed mild and
efficient protocol for the oxidative amidation of aldehydes with
amines. This protocol allowed clean and easy synthesis of
various structurally diverse secondary and tertiary amides in
moderate to good yields. The reaction involves in situ sequential
protection of amines by carbon dioxide as ammonium carbamate
salts, followed by slow deprotection of amines on application of
heat. CO2 is found to be ideal protecting group for amines that
can be easily put on or put off without generating any waste by-
products. Compared to existing methods the reaction medium is
neutral and does not employ acid-base protection and
deprotection sequence resulting in advantages like high
functional group tolerance, high atom economy and clean
reaction with low waste generation.
Acknowledgments
TB and VSR thank the University Grant Commission (UGC),
New Delhi for the award of a Research Fellowship.
a
Reaction conditions: aldehyde (1.0 mmol), amine (1.2
mmol), 70% aq. TBHP (1.1 mmol), FeCl2·4H2O (10 mol %) and
TBAB (10 mol%) in CH3CN (2 mL) at 40 °C (for primary
amines) and 60 °C (for secondary amines) under an inert
atmosphere.
References and notes
1. (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Greenberg, A.; Breneman, C. M.; Liebman, J. F. In The
Amide Linkage: Structural Significance in Chemistry,
Biochemistry and Materials Science, John Wiley & Sons: New
York, NY, 2000; (c) Deopura, B. L.; Gupta, B.; Joshi, M.;
Alagirusami, R. In Polyesters and Polyamides, CRC: Boca Raton,
2008; (d) Johansson, I. Kirk-Othmer Encyclopedia of Chemical
Technology, John Wiley & Sons: New York, NY, 2004; Vol. 2, pp
442; (e) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
2. Sogani, S. K.; Dandiya, P. C. J. Med. Chem. 1965, 8, 139.
3. Yang, X. D.; Zeng, X. H.; Zhao, Y. H.; Wang, X. Q.; Pan, Z. Q.;
Li, L.; Zhang, H. B. J. Comb. Chem. 2010, 12, 307.
b Isolated Yields.
As we can see from Table 2, the reaction proceeds smoothly
with various aldehydes and amines to afford the corresponding
amides (3b-3u) in moderate to good yields. Steric effects of
amines may play a role, since among the acyclic amines as
expected the reaction rate is found to depend on the bulkiness of
the alkyl groups in the order dimethylamine > diethylamine >
dibutylamine (Table 2, entries 3d, 3e, 3f). Consequently,
diisopropylamine reacts very slowly under the optimized reaction
conditions and no 3g was formed (Table 2). At the same time 2-
chloro benzaldehyde afforded amide 3p in low yield (Table 2).
4. Khan, K. M.; Khan, M. Z.; Taha, M.; Maharvi, G. M.; Saify, Z. S.;
Parveen S.; Choudhary, M. I. Nat. Prod. Res. 2009, 23, 479.