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DOI: 10.1002/cctc.201300140
Tandem Synthesis of N-Alkylated Amides from Aldoximes
and Alcohols by Using a Ru/Ir Dual-Catalyst System
Feng Li,* Panpan Qu, Juan Ma, Xiaoyuan Zou, and Chunlou Sun[a]
N-alkylated amides constitute
an important class of nitrogen-
containing compounds that are
widely utilized in fine chemicals,
natural products, pharmaceuti-
cals, peptides, and polymers.[1]
Traditionally, N-alkylated amides
are synthesized by the coupling
of carboxylic acids or their de-
rivatives (e.g., acid chlorides, an-
hydrides, and esters) with N-al-
Scheme 1. Strategy for the synthesis of N-alkylated amides from amines and alcohols.
kylated amines.[2] In addition, the Beckmann rearrangement,[3]
the Schmidt rearrangement,[4] Staudinger ligation,[5] the amino-
carbonylation of aryl halides,[6] and the oxidative amidation of
aldehydes[7] have been employed for the preparation of N-alky-
lated amides. However, these procedures typically require stoi-
chiometric amounts of hazardous and/or expensive reagents
and they suffer from the generation of at least stoichiometric
amounts of harmful waste byproducts.
mental points of view, the development of an alternative con-
trol strategy for the preparation of N-alkylated amides from al-
cohols would be of significant importance.
In recent years, tandem catalysis, which is capable of pro-
moting multiple mechanistically distinct reactions in a single
reactor, has becoming increasingly important as an alternative
to traditional multistep synthetic procedures, owing to it mini-
mizing the use of chemicals, energy, and waste production.[15]
Transition-metal complexes, such as rhodium,[16] ruthenium,[17]
and iridium complexes,[18] have been utilized as efficient cata-
lysts for the rearrangement of aldoximes into amides. On the
other hand, the N-alkylation of various amines with alcohols as
alkylating agents was developed, based on “hydrogen auto-
transfer” (or “hydrogen-borrowing”) processes,[19] by using iridi-
um,[20] ruthenium,[21] or other transition-metal catalysts.[22] Very
recently, we reported transition-metal-catalyzed direct N-alkyla-
tion reactions with alcohols for the preparation of 2-(N-alkyla-
mino)azoles,[23a–d] 2-(N-alkylamino)quinazolines,[23e] N,N’-alkylary-
lureas, and N,N’-dialkylureas,[23f] thus exhibiting the potential of
alcohols (rather than alkyl halides) as electrophiles in regiose-
lective reactions. As part of our continuing interest in exploring
CÀN bond-forming reactions, herein, we report the first exam-
ple of the direct synthesis of N-alkylated amides from aldox-
imes and alcohols through tandem rearrangement/N-alkylation
reactions. The proposed mechanism is outlined in Scheme 2. In
the presence of a catalyst(s), aldoximes first rearrange into
amides, followed by alkylation of the resulting amides with al-
cohols to afford N-alkylated amides.
In 2007, Milstein and co-workers reported a strategy for the
synthesis of N-alkylated amides from amines and primary alco-
hols catalyzed by a PNN-type ruthenium complex.[8] Presuma-
bly, the alcohols are first dehydrogenated to form their corre-
sponding aldehydes, which are condensed with amines to
afford hemiaminal intermediates; finally, the hemiaminals are
hydrogenated to give N-alkylated amides (Scheme 1). This pro-
cedure is attractive because alcohols are readily accessible and
inexpensive starting materials and because hydrogen gas is li-
berated as a byproduct. Following this pioneering work, sever-
al groups have developed this transformation by using other
transition-metal catalysts, such as the combination of a N-het-
erocyclic carbene (NHC) precursor with [{Ru(cod)Cl}2],[9] [{Ru(p-
cymene)Cl2}2], [[Ru(benzene)Cl2}2],[10] or [RuH2(PPh3)4] sys-
tems,[11] N-heterocyclic-carbene-based ruthenium complexes,[12]
ruthenium-diphosphine-diamine complexes,[13] and g-alumina-
supported silver clusters.[14] Despite these significant advances,
controlling the last step of the reaction mechanism is still ex-
tremely challenging because the resulting hemiaminal inter-
mediates may also eliminate water to form imines, which can
undergo hydrogenation with the liberated hydrogen gas to
generate amines (Scheme 1). From both synthetic and environ-
Initially, a range of commercially available ruthenium, rhodi-
um, and iridium complexes, including [{Ru(p-cymene)Cl2}2],
[(Cp*RhCl2)2]
(Cp*=pentamethylcyclopentadienyl),
[{Rh-
(cod)Cl}2] (cod=1,5-cyclooctadienyl), [(Cp*IrCl2)2], and [{Ir-
(cod)Cl}2] were assayed for their ability to catalyze the rear-
rangement of benzaldoxime (1a) into benzamide (3a) and the
N-alkylation of compound 3a with benzyl alcohol (2a) to
afford N-alkylated compound 4aa. As outlined in Equations (1)
and (2), various complexes exhibited catalytic activity for both
the rearrangement and N-alkylation reactions, although the
[a] Dr. F. Li, P. Qu, J. Ma, X. Zou, C. Sun
School of Chemical Engineering
Nanjing University of Science and Technology
Nanjing 210094 (P. R. China)
Fax: (+86)25-84431939
Supporting information for this article is available on the WWW under
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ChemCatChem 2013, 5, 2178 – 2182 2178