Iron-catalyzed efficient synthesis of amides from aldehydes and amine hydrochloride salts

Article abstract of DOI:10.1002/adsc.201200020

A practical and efficient method for the synthesis of amides has been developed by iron-catalysed oxidative amidation of aldehydes with amine hydrochloride salts. A wide range of amides have been obtained in good to excellent yields under mild conditions. The application of this novel amide formation reaction to the synthesis of pharmaceutical compounds has been successfully demonstrated. Copyright

Full text of DOI:10.1002/adsc.201200020

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DOI: 10.1002/adsc.201200020
Iron-Catalyzed Efficient Synthesis of Amides from Aldehydes
and Amine Hydrochloride Salts
Subhash Chandra Ghosh,a Joyce S. Y. Ngiam,a Christina L. L. Chai,a,b
Abdul M. Seayad,a Tuan Thanh Dang,a and Anqi Chena,*
a
Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, Neuros #07-01, Singapore 138665
Fax : (+65)-6464-2102; e-mail: chen_anqi@ices.a-star.edu.sg
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
b
Received: January 6, 2012; Revised: March 12, 2012; Published online: May 15, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200020.
Abstract: A practical and efficient method for the
synthesis of amides has been developed by iron-cat-
alysed oxidative amidation of aldehydes with amine
hydrochloride salts. A wide range of amides have
been obtained in good to excellent yields under
mild conditions. The application of this novel amide
formation reaction to the synthesis of pharmaceuti-
cal compounds has been successfully demonstrated.
have not been applied in industry due to drawbacks
such as the use of expensive transition metal catalysts,
limited substrate scope, harsh reaction conditions, etc.
Hence, the development of efficient and practical
amide formation reactions remains a great challenge.
Among the emerging amide formation methods, the
direct oxidative amidation of aldehydes with amine
salts[17d] (Scheme 1) is an attractive method with prac-
ticality and potential industrial applications. This is
because the reaction can be highly efficient and both
aldehydes and amine salts are widely available. A key
challenge to enable the industrial use of this reaction
is to develop inexpensive catalysts that could effec-
tively catalyse the reaction under practical and mild
conditions. Herein, we report the use of inexpensive
Keywords: aldehydes; amidation; amides; amine
salts; catalysis; iron(II) sulphate
The amide bond is one of the most abundant func- and easily accessible iron compounds as catalysts for
tional groups found in natural products, polymers and the oxidative amidation of aldehydes with amine hy-
pharmaceuticals.[1] A comprehensive survey revealed drochloride salts.
that more than 25% of known drugs contain an
Our investigation began with the identification of
amide group.[2] Conventionally, amides are prepared an inexpensive catalyst system using the reaction of
by the reaction of an amine with a carboxylic acid de- benzaldehyde and glycine methyl ester hydrochloride
rivative (acyl halide or anhydride) or by using a cou- to form methyl-2-benzamidoacetate as the test reac-
pling reagent.[3] However, these methods suffer from tion (Table 1). As iron salts are inexpensive, environ-
poor atom-efficiency and/or the use of highly hazard- mentally benign and have been shown to catalyse per-
ous reagents. Consequently one of the major challeng- oxide reagent-mediated oxidation reactions,[18] we
es in chemical synthesis is to develop alternative sought to screen commercially available iron salts as
methods of amide bond formation that circumvent catalysts for the reaction. The initial reaction per-
these problems.[4] This has led to the development of formed with FeCl3·6H2O as a catalyst, CaCO3 as
alternative methods for amide synthesis,[5] such as the a base, hydrogen peroxide (30% in water) as an oxi-
Staudinger reaction,[6] the Schmidt reaction,[7] the dant in acetonitrile at 608C was unsuccessful. GC
Beckmann rearrangement,[8] aminocarbonylation of analysis of the reaction mixture showed that <5% of
haloarenes,[9] iodonium-promoted a-halo nitroalkane the desired amide was formed (entry 1) together with
amine coupling,[10] direct amide synthesis from alco-
hols with amines or nitroarenes,[11] aminolysis of
esters,[12] coupling of nitriles with amines or alco-
hols,[13] hydroamidation of alkynes,[14] amidation of
thioacids with azides,[15] transamidation of primary
amides[16] and oxidative amidation of aldehydes.[17]
Scheme 1. Oxidative amidation of aldehydes with amine hy-
Despite this, most of the methods outlined above drochloride salts.
Adv. Synth. Catal. 2012, 354, 1407 – 1412
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Table 1. Optimisation of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
FeCl3·6H2O
FeCl3·6H2O
FeCl2·4H2O
FeCl2
H2O2
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
–
Na2CO3
K2CO3
NaHCO3
Cs2CO3
LiOH
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
<5
85
70
75
89
81
<5
0
5
10
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
–
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
T-Hydro
FeSO4·7H2O
Fe
N
Fe3O4
FeSO4·7H2O
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
21
<5
<5
<5
<5
7
60
19
<5
75[c]
68[d]
88[e]
dioxane
t-BuOH
toluene
CH3CN
CH3CN
CH3CN
[a]
Reactions were carried out with benzaldehyde (1.0 mmol), glycine methyl ester HCl salt (1.2 mmol), base (1.1 mmol), ox-
idant (1.1 mmol), Fe catalyst (5 mol% unless otherwise indicated), solvent (0.2 mL) at 608C for 16 h.
Yields were determined by quantitative GC analysis using dodecane as an internal standard.
2 mol% catalyst was used.
1 mol% catalyst was used.
Reaction time was 6 h.
[b]
[c]
[d]
[e]
~25% of benzoic acid formed via oxidation of the al- of the product was formed (entries 9 and 10). The
dehyde and large amounts of unreacted aldehyde. effect of bases was also examined and our study
Subsequently, a variety of oxidants including NaOCl, showed that replacement of CaCO3 with other bases
NaO2Cl, PhIACHTUNGTRENNUNG
(OAc)2, TEMPO, Oxoneꢁ and air was such as K2CO3, NaHCO3 drastically reduced the yield
screened but in all cases only 0–5% amide product of the amide product (entries 11–15) due to ester hy-
formation was observed (not shown in Table 1). drolysis under the reaction conditions (608C, 16 h)
When the inexpensive peroxide oxidant T-Hydro and imine formation.[19] The advantage of CaCO3
(70% aqueous tert-butyl hydroperoxide) was used as could be attributed to its weak basicity and insoluble
the oxidant, the yield of amide increased to 85% nature which enables the slow formation of amine
(entry 2). With T-Hydro being identified as an appro- and thus avoids the hydrolysis of the ester and imine
priate oxidant, a wide range of commercially available formation. Screening of solvents was also carried out
iron salts was screened with varying success (en- and it was found that acetonitrile was the best solvent
tries 3–7). FeSO4·7H2O performed better as com- among several others screened (entries 16–19). A cat-
pared to other iron catalysts and as it is also non-cor- alyst loading of 5 mol% was found to be optimal as
rosive and less expensive, this catalyst was selected decreasing catalyst loading to 2 mol% or 1 mol% re-
for further optimissation. Control experiments re- duced the yield to 75% and 68%, respectively (en-
vealed that all three components, that is, iron catalyst, tries 20 and 21). Optimisation of the reaction times
base and oxidant, are essential for this transformation. showed that the reaction was completed within 6 h at
In the absence of tert-butyl hydroperoxide (TBHP), 608C (entry 22) as comparable yields were obtained
no amide formation was observed (entry 8) whereas when the reaction was carried out for 16 h at the
without the iron catalyst and/or the base, only <10% same temperature (entry 5).
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Iron-Catalyzed Efficient Synthesis of Amides from Aldehydes and Amine Hydrochloride Salts
Table 2. Oxidative amidation of aldehydes with primary amine hydrochloride salts.[a,b]
[a]
Reactions were carried out with an aldehyde (1.0 mmol), primary amine hydrochloride salt
(1.2 mmol), calcium carbonate (1.1 mmol), TBHP (70 wt% in water, 1.1 mmol) in acetonitrile
(0.2 mL) at 608C under an inert atmosphere.
Isolated yields.
Reaction was carried out by in-situ HCl salt formation.
4-Methoxybenzoic acid (20%) was isolated as a by-product.
[b]
[c]
[d]
With the optimised conditions in hand, the sub- ride salts, providing tertiary amides in good to excel-
strate scope of this reaction was explored with various lent yields (Table 3).
aldehydes and primary amine hydrochloride salts
Similar to the case of primary amine salts, the reac-
(Table 2). In general, secondary amides were obtained tion with secondary amine salts is not sensitive to
in good to excellent yields for aldehydes with both electronic influence as both electron-rich and elec-
electron-donating and electron-withdrawing substitu- tron-deficient aldehydes gave good to excellent yields
ents. The reaction is compatible with various function- of the desired amides. The reaction is well tolerated
al groups such as ester (3c–3e and 3i–3p), alkyl chlo- with various functional groups, again indicating the
ride (3f) and alcohol (3g). However, the reaction is broad applicability of this reaction. Surprisingly, ali-
sensitive to steric hindrance as the reaction with tert- phatic aldehydes and heterocyclic aldehydes gave
butylamine hydrochloride salt afforded the corre- much improved yields of the desired amides than in
sponding amide in moderate yield (3h). Aliphatic or the case of secondary amides (4m–4o). Weinreb
heteroaromatic aldehydes were converted into their amides, which are important synthetic intermediates,
corresponding amides in moderate to good yields can also be prepared by this amidation method in
(3n–3p).
moderate yield (4l) under our current conditions.
With the promising results for secondary amide for-
Particularly noteworthy for this reaction is that hy-
mation, we further explored the possibility of extend- drochloride salts derived from amino acids such as
ing the reaction to the more challenging tertiary phenylalanine, valine (3d, 3e) and proline (4c) under-
amides which were not accessible under CuI-AgIO3- went amidation to provide the corresponding amides
catalysed conditions.[17d] Gratifyingly, the reaction in high yields and without detectable racemisation
worked well with various secondary amine hydrochlo- (see the Supporting Information). This could provide
Adv. Synth. Catal. 2012, 354, 1407 – 1412
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Subhash Chandra Ghosh et al.
Table 3. Oxidative amidation of aldehydes with secondary amine hydrochloride salts.[a,b]
COMMUNICATIONS
[a]
Reactions were carried out with an aldehyde (1.0 mmol), a secondary amine hydrochlo-
ride salt (1.2 mmol), calcium carbonate (1.1 mmol), TBHP (70 wt% in water, 1.1 mmol)
in acetonitrile (0.2 mL) at 608C for the time indicated under an inert atmosphere.
Isolated yields.
[b]
[c]
Reaction was carried out by in-situ HCl salt formation.
an alternative and economical method for peptide those using commercial amine salts. This strategy was
synthesis without using expensive, high molecular further applied to the synthesis of antiarrhythmic
weight coupling reagents.[3]
drug N-acetylprocainamide (8) in which 2-diethylami-
It is known[20] that amines undergo N-oxidative de- noethylamine (5) was converted to its bis-hydrochlo-
composition or imine formation (for primary amines) ride salt by the addition of 2.05 equivalents of concen-
in the presence of TBHP. Our present work and that trated hydrochloric acid, followed by the usual amide
reported by Li et al.[17d] showed that the use of amine formation procedures (see the Supporting Informa-
salts is crucial for this oxidative amidation because it tion). The desired product (8) was isolated in 76%
is less prone to oxidation by TBHP. The use of insolu- yield (Scheme 2). This one-step synthesis of 8 is much
ble CaCO3 as the base could also be beneficial to the more efficient than a three-step patented route in
reaction as it enables slow formation of the amine 16% overall yield.[21] This example demonstrates the
hence minimises the undesired amine oxidation reac- potential industrial application of our iron-catalysed
tions. However, numerous amines are commercially oxidative amidation.
supplied in the free form, which are not suitable for
The mechanism of this iron-catalysed oxidative
this TBHP-mediated oxidative amidation, we thus amidation was investigated briefly. Initially, in the
sought to expand the substrate scope by in-situ forma- presence of CaCO3, the amine salt is converted to the
tion of amine salts from free amines. This strategy free amine which then reacts with the aldehyde. The
was successfully demonstrated in the case of benzyl- amidation step could theoretically proceed via a hemi-
ACHTUNGTRENNUNG
amine (3b) and morpholine (4d) and the correspond- aminal,[5,17d] an imine[11g] or less likely a carboxylic
ing amides were obtained in yields comparable to acid intermediate under the reaction conditions. How-
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Adv. Synth. Catal. 2012, 354, 1407 – 1412

Iron-Catalyzed Efficient Synthesis of Amides from Aldehydes and Amine Hydrochloride Salts
the reaction. This practical method should find wide
applications in amide synthesis.
Experimental Section
General Procedure for the Oxidative Amidation of
Aldehydes with Amine Hydrochloride Salts
To
a
mixture of FeSO4·7H2O (13.9 mg, 0.05 mmol,
5.0 mol%), amine hydrochloride salt (1.2 mmol, 1.2 equiv.)
and CaCO3 (110 mg, 1.1 mmol, 1.1 equiv.) in acetonitrile
(0.2 mL) was added aldehyde (1 mmol, 1 equiv.) and TBHP
(70 wt% in H2O, 0.16 mL, 1.1 mmol, 1.1 equiv.) under argon
atmosphere at room temperature. The reaction vessel was
capped and the mixture allowed to stir for 6–24 h at 608C.
All the volatiles were removed under reduced pressure and
the crude product was purified by flash chromatography on
silica gel to obtain the amide product.
Scheme 2. Synthesis of N-acetylprocainamide by the in-situ
formation of a bis-amine HCl salt.
Acknowledgements
This work was supported by GlaxoSmithKline (GSK), Singa-
pore Economic Development Board (EDB) and the Agency
for Science, Technology and Research (A*STAR), Singapore.
Scheme 3. Proposed mechanism of iron sulphate-catalysed
oxidative amidation.
ever, the reaction of benzylamine with benzoic acid
and the pre-formed N-benzylimine of benzaldehyde
did not yield a significant amount of amides, this
ruled out the possible involvement of an imine or
a carboxylic acid. Hence a hemiaminal intermediate is
most likely to be involved as has been proposed pre-
viously.[5,17d] Since the oxidation reactions with TBHP
in the presence of an iron compound are known to
proceed via a free radical process,[22] it is likely that
this iron-catalysed oxidative amidation reaction could
also involve a radical mechanism. This hypothesis was
confirmed by the addition of a free radical scavenger,
2,6-di-tert-butyl-4-methylphenol (1 equiv.), and this re-
sulted in complete inhibition of amide formation. This
supports the mechanism outlined in Scheme 3 where
this amidation reaction is likely to proceed through
the slow formation of free amine from the amine salt
with insoluble CaCO3, followed by reaction with alde-
hydes to form a hemiaminal intermediate which is
subsequently oxidised to the amide by TBHP in the
presence of the iron catalyst.
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