Catalytic acylation of amines with aldehydes or aldoximes

Article abstract of DOI:10.1021/ol101978h

The simple nickel salt NiCl₂?6H₂O catalyzes the coupling of aldoximes with amines to give secondary or tertiary amide products. The aldoxime can be prepared in situ from the corresponding aldehyde. The use of ¹⁸O-labeled oximes has allowed insight into the mechanism of this reaction.

Full text of DOI:10.1021/ol101978h

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5096-5099
Catalytic Acylation of Amines with
Aldehydes or Aldoximes
C. Liana Allen, Simge Davulcu, and Jonathan M. J. Williams*
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath, U.K., BA2 7AY
j.m.j.williams@bath.ac.uk
Received August 21, 2010
ABSTRACT
The simple nickel salt NiCl2·6H2O catalyzes the coupling of aldoximes with amines to give secondary or tertiary amide products. The aldoxime
can be prepared in situ from the corresponding aldehyde. The use of 18O-labeled oximes has allowed insight into the mechanism of this
reaction.
The amide bond is one of the most important in contempo-
rary chemistry, with applications in pharmaceutical, agro-
chemical, and polymer synthesis.1,2 Currently, the most
popular methods of amide synthesis rely on activation of a
carboxylic acid with a coupling agent and reaction with an
amine. However, this methodology suffers from the inherent
drawback of producing a stoichiometric amount of waste
product.3 Enzymatic methods are also available, although
high isolation costs and somewhat limited substrate ranges
can be problematic.4 Increasing attention is now being
devoted to developing catalytic amide bond syntheses.5
Employing metal catalysis in amide syntheses also creates
the possibility to start from substrates other than carboxylic
acids.6 Several methods for oxidation of an aldehyde via an
aminol intermediate to the amide have been developed, all
using a stoichiometric amount of oxidant.7 More recently,
lanthanide catalysts have been shown to be active for the
amidation of aldehydes by amines.8
our research group9 and from others.10 The majority of
reports has used precious metal complexes to catalyze the
reaction, although our recent work has demonstrated that zinc
and indium salts are also effective. The involvement of a
nitrile intermediate in these reactions seems likely since for
reactions run in the presence of acetonitrile acetamide is
formed and the oxime is converted into a nitrile. There are
also reports of the metal-catalyzed coupling of nitriles with
(7) For examples, see; (a) Ishihara, K.; Yano, T. Org. Lett. 2004, 6,
1983–1986. (b) Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064–
13065. (c) Ekoue - Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429–3432. (d)
Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc. 2007, 129, 14106–
14107. (e) Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008,
49, 5732–5735. (f) Gao, J.; Wang, G. W. J. Org. Chem. 2008, 73, 2955–
2958. (g) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–
13799. (h) Tillack, A.; Rubloff, I.; Beller, M. Eur. J. Org. Chem. 2001,
523–528.
(8) (a) Seo, S.; Marks, T. J. Org. Lett. 2008, 10, 317–319. (b) Wang, J.;
Li, J.; Xu, F.; Shen, Q. AdV. Synth. Catal. 2009, 351, 1363–1370. (c) Li,
J.; Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575–2577. (d)
Qian, C.; Zhang, X.; Zhang, Y.; Shen, Q. J. Organomet. Chem. 2010, 695,
747–752.
There have been several recent reports of the metal-
catalyzed rearrangement of oximes into primary amides from
(9) (a) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007,
9, 73–75. (b) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.
2007, 9, 3599–3601. (c) Allen, C. L.; Burel, C.; Williams, J. M. J.
Tetrahedron Lett. 2010, 51, 2724–2726.
(1) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337–2347
(2) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Linderman, R. J.; Lorentz, K.; Manley, J.; Pearlman, B. A.;
.
(10) (a) Park, S.; Choi, Y.; Han, H.; Yang, S. H.; Chang, S. Chem.
Commun. 2003, 1936–1937. (b) Fujiwara, H.; Ogasawara, Y.; Yamaguchi,
K.; Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 5202–5205. (c) Fujiwara,
H.; Ogasawara, Y.; Kotani, M.; Yamaguchi, K.; Mizuno, N. Chem. Asian
J. 2008, 3, 1715–1721. (d) Gnanamgari, D.; Crabtree, R. H. Organometallics
2009, 28, 922–924. (e) Mishra, A.; Ali, A.; Upreti, S.; Gupta, R. Inorg.
Chem. 2008, 47, 154–161. (f) Ali, M. A.; Punniyamurthy, T. AdV. Synth.
Catal. 2010, 352, 288–292. (g) Ramon, R. S.; Bosson, J.; Diez-Gonzalez,
S.; Marion, N.; Nolan, S. P. J. Org. Chem. 2010, 75, 1197–1202.
Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411–420
.
(3) Valeur, E.; Bradley, M. Chem. Soc. ReV. 2009, 38, 606–631.
(4) Wang, M.-X. Top. Catal. 2005, 35, 117–130.
(5) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876–2879.
(6) Gunanathan, C.; Yehoshoa, B.-D.; Milstein, D. Science 2007, 317,
790–792.
10.1021/ol101978h  2010 American Chemical Society
Published on Web 10/14/2010

amines leading to secondary and tertiary amides.11 We
therefore reasoned that by performing the oxime to amide
rearrangement in the presence of an amine that it may be
possible to form secondary and tertiary amides. By generating
the oxime in situ from the aldehyde, this would lead to a
one-pot conversion of aldehydes into amides (Scheme 1).
Table 1. Range of Amine Substratesa
isolated
yield (%)
entry
amine
conversionb (%)
Scheme 1. Proposed Scheme for Amide Formation
1
2
3
4
4-chlorobenzylamine
piperonylamine
5-methylfurfurylamine
n-butylamine
100
100
100
100
100
67
100
68
100
100
81
83
89
90
96
79
-
91
-
5
6
allylamine
tryptamine
aniline
4-fluoroaniline
N-methylbenzylamine
morpholine
pyrrolidine
(R)-1-methylbenzylamine
7c
8c
9
89
83
70
10
11
12
100
91 (>95% ee)
Initially, we focused on identifying a suitable catalyst for
the conversion of an oxime into a secondary amide, and we
used the coupling of butyraldehyde oxime with benzylamine
as a model reaction. The use of indium nitrate or Ru(PPh3)4H2
led mainly to the formation of undesired primary amide. Zinc
triflate was more successful, giving the secondary amide as
the major product, although further reactions to improve the
selectivity were unsuccessful. However, NiCl2·6H2O gave a
very high conversion to the secondary amide, and further
optimization studies allowed us to reduce the catalyst loading
and reaction time to 5 mol % and 18 h with a small excess
of oxime when the reaction was run at a temperature of 155
°C, although reasonable reactivity was also observed at 110
°C. The use of a 1:1 ratio of oxime to amine gave marginally
lower yields in some cases. We then examined the reaction
for a range of amines with butyraldehyde oxime and a range
of oximes with benzylamine, which are presented in Tables
1 and 2.
Most substrates gave a very high conversion into amide,
indicating that the reaction tolerates a wide range of
functional groups on either substrate, including halogens,
alkenes, and heterocycles, as well as some secondary and
R-branched amines. Although the amine in entry 9 was used
successfully, more hindered secondary amines were poor
substrates (see Supporting Information). Enantiopurity was
completely preserved when an amine containing a chiral
center was used in the reaction (Table 1, entry 12). Using
particularly sterically hindered amines resulted in lowered
conversions into the secondary amide, as did using less
nucleophilic amines. The presence of a second nucleophilic
nitrogen atom in the molecule also lowered conversions,
possibly due to coordination of this nitrogen to the catalyst.
As has been found with other metal-catalyzed rearrangements
of oximes, ketoximes and oxime ethers were unreactive in
these reaction conditions.
a Additional examples in Supporting Information. b Determined by NMR.
c Run with 1.2 equiv of oxime.
Table 2. Range of Oxime Substratesa
isolated
entry
oxime
acetaldoxime
conversionb (%) yield (%)
1
100
100
100
70
100
36
71
100
92
88
89
90
62
83
-
66
76
76
2
heptaldoxime
3
3-phenylpropaldoxime
benzaldoxime
4-fluorobenzaldoxime
4-methoxybenzaldoxime
3-chlorobenzaldoxime
piperonaldoxime
4c
5c
6
7
8
9
2-naphthaldoxime
a Additional examples in Supporting Information. b Determined by NMR.
c Run with 1.2 equiv of oxime.
We decided to develop a one-pot conversion of aldehydes
into secondary and tertiary amides by forming the aldoxime
in situ. This required the addition of hydroxylamine hydro-
chloride (and a base; see Supporting Information) to the
reaction mixture of an aldehyde, an amine, and the nickel
catalyst. A range of different aldehydes and amines were
coupled to form the respective amides using these reaction
conditions (Table 3).
A broad range of amides were successfully synthesized
with good isolated yields using this new methodology. As
with the reaction using the preformed oxime, several
functional groups have been shown to be tolerated.
During the course of our studies on the rearrangement of
oximes and our expansion of this reaction to allow formation
(11) (a) Murahashi, S. I.; Naota, T.; Saito, E. J. Am. Chem. Soc. 1986,
108, 7846–7847. (b) Cobley, C. J.; van den Heuvel, M.; Addabi, A.; de
Vries, J. G. Tetrahedron Lett. 2000, 41, 2467–2470. (c) Allen, C. L.; Lapkin,
A. A.; Williams, J. M. J. Tetrahedron Lett. 2009, 50, 4262–4264.
Org. Lett., Vol. 12, No. 22, 2010
5097

secondary amide. These reactions supported the formation
of a nitrile intermediate in the reaction but also implied that
hydration to the primary amide and addition of the amine to
give an amidine intermediate were not significant mechanism
pathways.
Table 3. Use of Aldehyde Substrates
We then performed a series of experiments using 18O
labels.15 The rearrangement of unlabeled butyraldehyde
oxime was performed in the presence of 18OH2, which
afforded the primary amide without incorporation of the 18
O
label (Scheme 2, reaction A). When butyraldehyde oxime
Scheme 2.
Reactions Using 18O-Labeled Substratesa
a Determined by NMR.
of secondary and tertiary amides, we have performed several
experiments to gain further insight into the mechanisms
which might be operating.
From previously reported work by Kopylovich et al., we
could assume that the oxime binds to the nickel through the
nitrogen.12 Loss of water from the nickel-oxime complex
would generate a nitrile.13 We investigated isolating the
nitrile intermediate by running the reaction of 2-phenylac-
etaldoxime in a 10-fold excess butyronitrile. This did allow
the reaction to be intercepted at the nitrile stage, and the
products isolated from this reaction were 2-phenylacetonitrile
and butyramide.
After generation of a nitrile intermediate, one possible
reaction pathway is hydration of the nitrile to the primary
amide and subsequent transamidation or N-alkylation to give
a secondary or tertiary amide. We found there was no
reaction of butyramide with benzylamine under the reaction
conditions, implying that the mechanism does not proceed
via the primary amide. Alternatively, addition of the amine
to the nitrile would generate an amidine intermediate, which
could subsequently be hydrolyzed by water liberated in an
earlier step.14 However, we also found the reaction of
benzylamine with propionitrile under these reaction condi-
tions to be very slow and gave very low conversion into a
a 92% isotopic enrichment in starting oxime.
was reacted with benzylamine in the presence of 18OH2, we
again saw no incorporation of the 18O label (Scheme 2,
reaction B). These experiments suggest that loss of water
from the oxime or addition to the nitrile is not occurring to
any significant extent during the reaction, as it was expected
that 16OH2 exchange with 18OH2 would have been facile and
rapid, leading to incorporation of the 18O into the amide
product, at least to some extent. The possibility of an
(12) Makarycheva-Mikhailova, A. V.; Gushchin, P. V.; Kopylovich,
M. N.; Ganebnykh, I. N.; Charushin, V. N.; Haukka, M.; Pombeiro, A. J. L.;
Kukushkin, V. Y. Inorg. Chem. Commun. 2006, 9, 869–871.
(13) (a) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209–4211. (b)
Sarvari, M. H. Synthesis 2005, 5, 787–790.
(14) (a) Rousselet, G.; Capdevielle, P.; Maumy, M. Tetrahedron Lett.
1993, 34, 6395–6398. (b) Wang, J.; Xu, F.; Cai, T.; Shen, Q. Org. Lett.
2008, 10, 445–448.
(15) Rajendran, G.; Van Etten, R. L. Inorg. Chem. 1986, 25, 876–878.
5098
Org. Lett., Vol. 12, No. 22, 2010

intramolecular oxygen transfer was also deemed to be
unlikely, as the reaction involving 18O-labeled butyraldehyde
oxime and nonlabeled 3-phenylpropanaldoxime led to scram-
bling of the label in the amide products (Scheme 2, reactions
C and D).
On the basis of the results of these experiments, we now
propose the following bimolecular reaction mechanism
(Scheme 3). Intramolecular attack on the nitrile by a
that the reaction can be described by two consecutive
pseudofirst-order rate constants.
Chang and co-workers have reported their investigation
into the mechanism of rearrangement of an aldoxime into a
primary amide using a rhodium catalyst.18 They also suggest
a bimolecular process, whereby a coordinated nitrile is
attacked by the hydroxy group of a molecule of oxime, which
itself is associated with the metal center through the nitrogen
atom. Their mechanism is supported by the significant rate
increase seen when a catalytic amount of nitrile is added to
the reaction.
Scheme 3. Proposed Mechanism of Oxime Rearrangement
Although we have seen evidence to support our proposed
mechanism, other possible pathways cannot be completely
excluded at this stage. In the reaction involving one labeled
and one unlabeled oxime (Scheme 2, reaction C), the label
was not completely scrambled, leaving the butyramide
product with a higher proportion of 18O than the other amide.
This leads to questioning whether an intramolecular mech-
anism is also operating alongside our proposed intermolecular
one, as a minor reaction pathway. Additionally, in the course
of their work on novel ligand syntheses, Kukushkin et al.
have shown when platinum-nitrile complexes are treated
with an oxime, addition of the hydroxy group across the
carbon-nitrogen triple bond proceeds with the nitrile
remaining coordinated to the metal and the oxime uncoor-
dinated.19 It should be noted however that the platinum-nitrile
complexes were preformed before addition of the oxime.
Nonetheless, this observation indicates the possibility of
another reaction pathway in which a coordinated nitrile is
attacked by a free oxime in the reaction.
Herein, we have reported a novel synthesis of secondary
and tertiary amides from the coupling of an oxime (which
can be generated in situ from an aldehyde and hydroxylamine
hydrochloride) and an amine. This current method shows
clear advantages over other amide syntheses due to its low
cost, readily available catalyst, and simple experimental
procedure. We have also reported our efforts to elucidate
the mechanism of this reaction via a labeling study. Work
to improve the catalyst efficiency and expand the substrate
range as well as further experiments to investigate the
mechanism of this reaction are now in progress in our
laboratory.
coordinated oxime16 leads to a five-membered cyclic inter-
mediate. Decomposition of this intermediate gives the
primary amide product and another coordinated nitrile to
continue the catalytic cycle. In the presence of an amine,
the same cyclic intermediate could be intercepted, and
decomposition would then give a secondary or tertiary amide
product (Scheme 4).
Scheme 4. Proposed Interception of the Cyclic Intermediate
Acknowledgment. We thank the EPSRC for the award
of a studentship (to C.L.A.) administered through the
Doctoral Training Account.
Supporting Information Available: Experimental pro-
1
cedures, characterization of amides, and copies of H and
Evidence of a bimolecular mechanism operating in the
metal-catalyzed rearrangement of aldoximes into primary
amides has been reported by Johnson and Miller17 who found
13C NMR spectra are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101978H
(16) Kim, E. S.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 2009, 50,
2973–2975.
(18) Kim, M.; Lee, J.; Lee, H. Y.; Chang, S. AdV. Synth. Catal. 2009,
351, 1807–1812.
(17) (a) Johnson, A. K.; Miller, J. D. Inorg. Chim. Acta 1976, 16, 181–
184. (b) Leusink, A. J.; Meerbeek, T. G.; Noltes, J. G. Recl. TraV. Chim.
Pays-Bas 1976, 5, 123–125.
(19) Garnovskii, D. A.; Pombeiro, A. J. L.; Haukka, M.; Sobota, P.;
Kukushkin, V. Y. Dalton Trans. 2004, 1097–1103.
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