FeIII-catalyzed synthesis of primary amides from aldehydes

Article abstract of DOI:10.1002/ejoc.201001738

A direct synthetic route for the transformation of aldehydes into primary amides in the presence of catalytic amounts of FeCl₃ in water is described. A direct synthetic route for the transformation of aldehydes into primary amides in the presence of catalytic amounts of FeCl₃ in water is described. Copyright

Full text of DOI:10.1002/ejoc.201001738

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001738
FeIII-Catalyzed Synthesis of Primary Amides from Aldehydes
Ravikumar R. Gowda[a] and Debashis Chakraborty*[a]
Keywords: Aldehydes / Amides / Aldoximes / Iron / Rearrangement
A direct synthetic route for the transformation of aldehydes into primary amides in the presence of catalytic amounts of FeCl3
in water is described.
prompted us to investigate the direct catalytic transforma-
Introduction
tion of aldehydes into primary amides by reaction with hy-
Metal-mediated organic transformations are a current fo-
droxylamine hydrochloride.
cus for synthetic chemists.[1] In this regard, the development
of suitable methodologies for the synthesis of amides has
been in the limelight because of the importance of amides
Results and Discussion
in plastics, lubricants, and detergent manufacturing, and
they also serve as important intermediates in organic syn-
Ammonia has been described previously as a nitrogen
thesis.[2] In recent years, a number of papers and reviews
source.[10] A variety of aromatic, aliphatic, and conjugated
have appeared that describe the catalytic chemistry of
aldehydes were converted directly into the amide with stoi-
iron.[3] Iron salts have been employed for a large number of
chiometric amounts of hydroxylamine hydrochloride in the
different reactions, namely, aldol condensation, hydro-
presence of Cs2CO3 and catalytic quantities of FeCl3. This
silylation, oxidative esterification of aldehydes, synthesis of
method possesses a wide range of capabilities, does not in-
sulfonylimines from aldehydes, and addition to arylboronic
volve cumbersome workup, and exhibits chemoselectivity.
acids.[4] The synthesis of primary amides from aldoximes is
The resulting products are obtained in good yields within
especially challenging and involves the use of reactive rea-
reasonable time period.
gents in stoichiometric to over stoichiometric quantities.[5]
Initial attempts to optimize the reaction conditions were
The selectivity towards the formation of the desired product
carried out with benzaldehyde as a suitable substrate in the
is often very low because nitriles and carboxylic acids may
presence of a stoichiometric amount of hydroxylamine hy-
be produced as undesirable side products.[6] These side reac-
drochloride and an inorganic base along with catalytic
tions become exceedingly important when the reactions are
quantities (5 mol-%) of different iron salts in several sol-
scaled up. To overcome these drawbacks, recent research
vents. The reaction proceeds in two steps, the first being the
has focused on new catalytic processes. To the best of our
direct reaction of the aldehyde with hydroxylamine hydro-
knowledge, there are very few metal-mediated methodolo-
chloride, resulting in the formation of the aldoxime, which
gies known for the conversion of aldehydes into primary
proceeds even in the absence of any metal salt. The second
amides in the presence of hydroxylamine.[7] These depend
step involves iron-catalyzed rearrangement, which is essen-
upon expensive metals such as rhodium, ruthenium, irid-
tially the hydrolysis of the resulting aldoxime. This reaction
ium, and palladium, with a few reports involving the use of
does not occur in the absence of base or an iron catalyst.
nickel, indium, and zinc.[7] Research involving the discovery
Among the different polar solvents used for standardization
and development of environmentally and technologically
of the protocol, the best results were realized in water. We
desirable catalytic processes shall always remain an attract-
have studied this transformation in the presences of dif-
ive avenue in this area.[8] Our recent research into new
ferent inorganic bases and found that Cs2CO3 yielded the
methodologies for environmentally benign processes[9]
best results. Among the different FeIII and FeII salts used
in our studies, FeCl3 was found to be the best catalyst. It is
important to note that at room temperature, the reaction is
[a] Department of Chemistry, Indian Institute of Technology
sluggish and complete conversion occurred at 100 °C within
Madras
a reasonable time.
Chennai-600 036, India
Fax: +91-44-2257-4202
Having realized the correct conditions for oxidation, we
continued our quest with a variety of aromatic (Table 1)
and aliphatic substrates (Table 2).
E-mail: dchakraborty@iitm.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001738.
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FeIII-Catalyzed Synthesis of Primary Amides from Aldehydes
Table 1. FeCl3-catalyzed conversion of aryl aldehydes into
amides.[a]
Table 2. FeCl3-catalyzed conversion of allyl and alkyl aldehydes
into amides.[a]
[a] Reactions performed in H2O with FeCl3 (5 mol-%) and Cs2CO3
(1 equiv.) at 100 °C. [b] Monitored with TLC. [c] Isolated yield after
column chromatography of the crude material.
ably (Table 1, Entries 11–13). Our catalytic system is mild
and shows sufficient selectivity in carrying out the expected
reaction without affecting other functionalities such as-
phenol and amine (Table 1, Entries 7 and 8). Oxidation of
α,β-unsaturated derivatives (Table 2, Entries 1 and 2) re-
sulted in the formation of the expected amide in very good
yield. We tested our methodology on a few key substrates.
The results are depicted in Table 3.
We were able to synthesize the corresponding diamide
(Table 3, Entry 1) in good yield. This type of compound has
antithrombotic activity, which especially inhibits the blood
coagulation factor.[11] This exploratory work demonstrates
the feasibility of the synthesis of unprotected α-amino
amides from the corresponding aldehydes (Table 3, En-
tries 2 and 3). This method provides efficiently access to β-
d-ribofuranose derivatives (Table 3, Entries 4 and 5).[12]
This class of compounds is useful for the formation of syn-
thetic intermediates of the pharmaceutical nucleic acid
series. These products were subjected to HPLC analysis. We
were pleased to observe no racemization of the various chi-
ral centers in these products. These results imply that our
methodology is sufficiently mild.
It is pertinent to note that the reaction does not proceed
beyond the aldoxime stage when performed without FeCl3.
With benzaldehyde, hydroxylamine hydrochloride in anhy-
drous FeCl3, DMSO, and activated molecular sieves, benzo-
nitrile is produced in a quantitative manner.
[a] Reactions performed in H2O with FeCl3 (5 mol-%) and Cs2CO3
(1 equiv.) at 100 °C. [b] Monitored with TLC. [c] Isolated yield after
column chromatography of the crude material.
The scope of our catalytic system is large, as it is appli-
The presence of water is mandatory for the subsequent
cable to a wide range of aromatic, conjugated, and aliphatic step of this reaction. The addition of water to this reaction
substrates. These aldehydes were converted into the corre- mixture results in the formation of the amide product. The
sponding amides in good isolated yields in reasonable times. kinetic studies of the conversion of aldehydes into primary
Substitutions at different positions on the phenyl ring do amides were studied with benzaldehyde, 4-nitrobenzalde-
not hinder the reaction, although the reaction time is affec- hyde, and furan-2-carboxaldehyde. HPLC was used to de-
ted. The reaction is much faster with substrates containing termine the various starting materials and products present
electron-donating substituents in the aromatic ring (Table 1, as a function of time. The concentration of the aldehyde
Entries 1–8 vs. 9–13). Substitution of a strong electron- decreases steadily while that of the amide increases. We have
withdrawing group like NO2 retards the reaction consider- calculated the rate of such reactions. As an example, con-
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R. R. Gowda, D. Chakraborty
SHORT COMMUNICATION
Table 3. FeCl3-catalyzed conversion of various aldehydes into Figure 1, it is clear that this reaction proceeds with second-
amides.[a]
order kinetics (n = 2.03) and the rate constant k =
7.5497 Lmol–1 h–1. For the other substrates, namely, 4-ni-
trobenzaldehyde and furan-2-carboxaldehyde, the order of
the reaction n ≈ 2 with k = 4.9505 and 14.4847 Lmol–1 h–1,
respectively.
A few interesting reports have appeared in the literature
regarding the role of contaminants in catalysts, for example,
Cu2O in iron salts.[13] We used 99.99% FeCl3 (Aldrich, cata-
logue no 451649) and 99.90% Cs2CO3 (Aldrich, catalogue
no 202126). To remain sure that our reaction is not cata-
lyzed by contaminants, these salts were subjected to ICP-
MS analysis. The results indicate that the catalysis is not as
a result of contaminants. To ascertain that these reactions
are not Brønsted catalyzed,[14] we performed trials in the
presence of 2,6-di-tert-butylpyridine.
Conclusions
In summary, we have developed a simple, efficient,
chemoselective, and inexpensive catalytic method for the
conversion of aldehydes into primary amides with a table-
top reagent such as FeCl3. It is noteworthy to mention that
this method does not use ligands or other additives.
[a] Reactions performed in H2O with FeCl3 (5 mol-%) and Cs2CO3
(1 equiv.) at 100 °C. [b] Monitored with TLC. [c] Isolated yield after
column chromatography of the crude material.
Experimental Section
General Procedure: To
a stirred solution of FeCl3 (8.0 mg,
sider the conversion of benzaldehyde into benzamide. The
van’t Hoff differential method was used to determine the
order and rate constant (Figure 1).
0.05 mmol) and aldehyde (1 mmol) in water (4 mL) was added
NH2OH·HCl (1 mmol) and Cs2CO3 (1 mmol). The reaction mix-
ture was heated to reflux. The reaction was monitored by using
TLC periodically. The reaction mixture was extracted repeatedly
with ethyl acetate. All the volatile organics were removed under
reduced pressure. The crude product was purified by flash
chromatography.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, copies of the NMR spectra, HPLC
data, kinetics data, ICP-MS analysis data, concentration vs. time
plots, and van’t Hoff differential plots.
Acknowledgments
This work was supported by the Department of Science and Tech-
nology, New Delhi. The authors are grateful to the referees for their
suggestions.
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Received: December 29, 2010
Published Online: March 9, 2011
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