Oxidative amidation of aldehydes and alcohols with primary amines catalyzed by KI-TBHP

Article abstract of DOI:10.1002/ejoc.200800454

Oxidative amidation of aldehydes and alcohols with amines to afford the corresponding amides in excellent yields and ee values over 98% is achieved by using a catalytic amount of KI in combination with TBHP as the external oxidant. This method avoids the use of expensive and/or air-sensitive reagents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800454

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800454
Oxidative Amidation of Aldehydes and Alcohols with Primary Amines
Catalyzed by KI-TBHP
K. Rajender Reddy,*[a] C. Uma Maheswari,[a] M. Venkateshwar,[a] and
M. Lakshmi Kantam[a]
Keywords: Oxidative amidation / Aldehydes / Alcohols / Primary amines / Potassium iodide
Oxidative amidation of aldehydes and alcohols with amines
to afford the corresponding amides in excellent yields and ee
values over 98 % is achieved by using a catalytic amount of
KI in combination with TBHP as the external oxidant. This
method avoids the use of expensive and/or air-sensitive rea-
gents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
idation of aldehydes with secondary amines,[14] copper-cata-
lyzed oxidative amidation of aldehydes with hydrochloride
salts of primary amines in the presence of base and AgNO3
as an additive,[15] catalytic amidation of aldehydes with sec-
ondary amines by lanthanum complexes,[17] and a metal-
free oxidative amidation of aldehydes with secondary
amines achieved solely by an oxidant (TBHP).[16] Recently,
the Milstein group reported the amidation of alcohols and
amines via aldehyde intermediates by using Ru-PNN pincer
catalysts.[18] Despite the rapid progress made in catalytic
amidation reactions, there are still shortcomings in the
adaptability of these methodologies to scale-up. For exam-
ple, most of the catalysts reported are either expensive or
involve a multistep synthesis. Moreover, stoichiometric
amounts of bases and sensitive reagents are employed.
Molecular halogens and related reagents are well known
oxidizing agents with simple operation and low cost.
Among the several reagents reported in literature, molecu-
lar iodine is an attractive candidate as it is cheap, readily
available, and less toxic than molecular bromine or chlorine.
Several reports appeared recently on the use of iodine for
various organic transformations.[19] Furthermore, molecu-
lar iodine is efficiently utilized for the oxidation of alcohols
and aldehydes into their corresponding esters.[20] One of the
limitations of these procedures is the use of stoichiometric
amounts of iodine and a base, which could lead to the gen-
eration of excessive amounts of waste. We have recently ob-
served a simple and mild procedure for the facile oxidative
esterification of aldehydes and alcohols by using a catalytic
amount of KI in combination with TBHP as an external
oxidant [Equation (2)].[21]
Introduction
Simple and convenient methods for the construction of
amide (-CONH-) units are highly desirable in synthetic or-
ganic chemistry.[1] These motifs play a significant role in
biological systems as well as in important molecules in the
fields of pharmaceuticals, natural products, and polymers.[2]
Conventional methods for the synthesis of amides involve
reactions between carboxylic acids or their activated ana-
logues like acyl chlorides, anhydrides, azides, or an active
ester and amines.[3] Alternate methods include metal-cata-
lyzed aminocarbonylation,[4–6] modified Staudinger reac-
tion,[7] acid-promoted Schmidt reaction,[8] coupling of car-
boxylic acids with isocyanide,[9] and oxidation of imines to
amides via an oxaziridine.[10] Recently, Rovis’ and Bode’s
group reported amidation with N-heterocyclic carbene
(NHC) catalysts.[11] Another alternative approach, which is
quite attractive from the economical and green chemistry
points of view, is the oxidative amidation of aldehydes
[Equation (1)].
(1)
Few reports adapting the above strategy have appeared
in the literature.[12–17] Among them, the most recent exam-
ples are: ruthenium- and rhodium-catalyzed oxidative am-
[a] Inorganic and Physical Chemistry Division, Indian Institute of
Chemical Technology
Tarnaka, Hyderabad 500007, India
Fax: +91-40-27160921
E-mail: rajender@iict.res.in
rajenderkallu@yahoo.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
(2)
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K. R. Reddy, C. U. Maheswari, M. Venkateshwar, M. L. Kantam
SHORT COMMUNICATION
Table 2. KI-TBHP-catalyzed oxidative amidation of aldehydes with
amines.[a]
Results and Discussion
Encouraged by these results, we extended the methodol-
ogy for much more interesting and challenging oxidative
amidations of aldehydes with amines. The results are pre-
sented here.
Initial optimization studies were carried out by treating
benzaldehyde with butylamine under different conditions.
The results are tabulated in Table 1. The blank reaction
with KI and without an oxidant provided imine as the sole
product, whereas the reaction with TBHP resulted in 15%
of the required amide. Under the similar conditions 5 mol-
% KI and TBHP provided 75% of amide. Organic solvents
like acetonitrile provided lower conversions.
Table 1. Optimization of oxidative amidation for the synthesis of
amide 1a.[a]
Entry Catalyst
[mmol]
Oxidant
[mmol]
Solvent
Yield [%][b]
[c]
1
2
3
4
5
6
7
KI [0.05]
–
–
H2O
H2O
H2O
H2O
H2O
CH3CN
CH3CN
–
TBHP [2.2]
TBHP [2.2]
TBHP [1.5]
H2O2 [2.2]
TBHP [2.2]
TBHP [2.2]
15
75
55
KI [0.05]
KI [0.05]
KI [0.05]
KI [0.05]
–
[c]
–
45
11
[a] Reaction conditions: benzaldehyde (1 mmol), butylamine
(1.2 mmol), solvent (3 mL), 80 °C, 15 h. [b] Isolated yield. [c] The
imine is the main product.
To explore the generality and scope of the reaction, the
oxidative amidation reaction was carried out with various
aldehydes and amines under the optimized reaction condi-
tions. The results are shown in Table 2. All the aromatic
aldehydes exhibited good reactivity. In general, aromatic al-
dehydes with electron-donating groups showed higher ac-
tivity than their electron-withdrawing counterparts
(Table 2, entries 1–10). Moderate to good yields were also
observed for different amine sources (Table 2, entries 11–
16). In case of aliphatic aldehydes, the reaction between oc-
tanal and n-butylamine was not straightforward, and the
required amide was obtained in a lower quantity (Ͻ20%)
[a] Reaction conditions: Aldehyde (1 mmol), primary amine
(1.2 mmol), TBHP (2.2 mmol), KI (0.05 mmol) in H2O (3 mL),
80 °C, 15 h. [b] Isolated yield. [c] Yields based on GC. [d] 30% of
the amide corresponding to benzaldehyde was also observed by
GC.
(Table 2, entry 17). Whereas a moderate yield (49%) was shows only 8% of product. However, changing the solvent
observed for the reaction between cyclohexanecarbaldehyde from water to acetonitrile improved product formation sig-
and n-butylamine (Table 2, entry 18). The reaction between nificantly (54%). Furthermore, increasing the catalyst load-
phenylacetaldehyde and n-butylamine led to a mixture ing to 20 mol-% yielded 81% of the coupled product with
of N-butylbenzamide and N-butyl-2-phenylacetamide Ͼ98% enantioselectivity. Similarly, reactions with -leucine,
(Table 2, entry 19). Our attempts with the reactions between -alanine methyl ester hydrochlorides and (S)-leucinol pro-
aromatic aldehydes and benzylamine derivatives were not vided the coupled products in reasonable yields with excel-
successful and usually led to mixtures of products.[22]
To widen the scope of oxidative amidation to chiral sys-
lent enantioselectivities (Scheme 1).
We have further investigated the applicability of the pres-
tems, benzaldehyde was treated with -valine methyl ester ent catalytic system to benzyl alcohol derivatives. The re-
hydrochloride under the optimized conditions (Table 1, en- sults are shown in Table 3. Moderate yields were observed
try 3). 1H NMR analysis of the crude reaction mixture with benzyl alcohol and p-methoxybenzyl alcohol, whereas
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Oxidative Amidation of Aldehydes and Alcohols with Primary Amines
product in 70% yield. These two experiments clearly prove
that iodine and TBHP are necessary for amide formation.
This is further confirmed by the reaction between benzalde-
hyde and butylamine with 2.5 mol-% of iodine and
2.2 mmol TBHP, which resulted in 70% of the amide prod-
uct.[28] Similarly, the role of base is more pronounced in the
oxidative amidation of aldehydes with amine hydrochloride
salts. For example, the reaction between benzaldehyde and
(-valine methyl ester)·HCl in the presence of iodine and
TBHP provided only 11% of the coupled product, whereas
the same reaction in the presence of a combination of KI
and TBHP provided 54% of the amide product. The latter
result shows the role of the in situ generated base in activa-
ting the amine hydrochloride salt, which is similar to the
observations made by Li and co-workers during the oxidat-
ive amidation of aldehydes with amine hydrochloride salts
by using copper catalysts.[15]
Scheme 1. Reaction between benzaldehyde and amino acid deriva-
tives.
a low yield (10%) was obtained with p-nitrobenzyl alcohol.
The direct coupling of benzyl alcohol with (-valine methyl
ester)·HCl resulted in 46% of the amide product.
Scheme 2. Confirmation of the role of iodine, TBHP, and base in
oxidative amidation.
Table 3. KI-TBHP-catalyzed amidation of benzyl alcohols with pri-
mary amines.[a]
On the basis of the above results, we tentatively propose
the mechanism as shown in Scheme 3. In the first step,
TBHP oxidizes the potassium iodide to generate molecular
iodine and potassium hydroxide. The reaction between al-
dehyde and primary amine may probably proceed via a
hemiaminal intermediate, similar to the hemiacetal path in
the case of oxidative esterification. In the case of direct am-
idation of benzyl alcohols, the reaction was expected to go
through an aldehyde intermediate. Under the present condi-
tions, it is believed that the iodide salt is re-oxidized to io-
dine by TBHP, which makes the reaction catalytic. The re-
action between benzoic acid and butylamine under the pres-
ent reaction conditions provided only 15% of the amide
[a] Reaction conditions: alcohol (1 mmol), primary amine
(1.2 mmol), TBHP (3.0 mmol), KI (0.20 mmol), H2O (3 mL),
80 °C, 15 h. [b] Isolated yield. [c] 15% of aldehyde was observed.
Molecular iodine under alkaline conditions oxidizes
alcohols and aldehydes to their corresponding esters via
hemiacetal intermediates.[20,27] During our investigation on
oxidative esterification of aldehydes with the KI-TBHP sys-
tem, we observed that in situ generated iodine and KOH
are the main catalytic species.[21] To probe the role of in situ
generated iodine and KOH in the present oxidative amid-
ation reactions, the following experiments shown in
Scheme 2 were carried out. Reaction with iodine under al-
kaline conditions resulted only in the imine, whereas cata-
Scheme 3. Proposed mechanism for the oxidative amidation of al-
lytic amounts of iodine and TBHP provided the amide dehydes with amines.
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K. R. Reddy, C. U. Maheswari, M. Venkateshwar, M. L. Kantam
SHORT COMMUNICATION
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Experimental Section
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[11]
General Procedure for the Synthesis of Amides from Amines: To a
solution of aldehyde (1.0 mmol), potassium iodide (0.05 mmol),
and amine (1.2 mmol) in water (3 mL) was added a solution of
70% aqueous TBHP (2.2 mmol) dropwise over a period of 30 min
and while stirring at 80 °C. Progress of the reaction was monitored
by TLC, and after completion of the reaction the mixture was
quenched with saturated aqueous Na2S2O3, washed with brine, ex-
tracted with ethyl acetate, and dried with anhydrous Na2SO4. Re-
moval of the solvent under vacuum afforded the crude product,
which was purified by column chromatography by using a hexane/
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1
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[20]
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Preliminary results have been communicated for publication in
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Supporting Information (see footnote on the first page of this arti-
1
cle): General information, experimental conditions, H NMR and
mass spectral data of all compounds.
[22]
Acknowledgments
C. U. M. and M. V. thank the Council of Scientific Industrial Re-
search (CSIR) and Department of Biotechnology (DBT) India,
respectively, for their fellowship.
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Oxidative amidation of primary amines with catalytic amounts
of iodine (2.5 mol-%) and TBHP for various aldehydes have
provided the coupled product in good yield, and the results will
be communicated in due course.
Received: May 2, 2008
Published Online: June 18, 2008
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