Conversion of aldoximes into nitriles and amides under mild conditions

Article abstract of DOI:10.1039/c3ob27362h

A series of Pd(en)X₂ salts were used as catalysts for the conversion of aldoximes into nitriles and amides. Highlights of this protocol include the use of inexpensive polar solvents, including water, and moderate reaction temperatures. A high degree of selectivity in the reaction outcome was observed when using aliphatic vs. aromatic/conjugated aldoximes. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27362h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Conversion of aldoximes into nitriles and amides under
mild conditions†
Cite this: Org. Biomol. Chem., 2013, 11,
2466
Koujiro Tambaraa and G. Dan Pantoş*b
Received 6th December 2012,
Accepted 11th February 2013
A series of Pd(en)X2 salts were used as catalysts for the conversion of aldoximes into nitriles and amides.
Highlights of this protocol include the use of inexpensive polar solvents, including water, and moderate
reaction temperatures. A high degree of selectivity in the reaction outcome was observed when using
aliphatic vs. aromatic/conjugated aldoximes.
DOI: 10.1039/c3ob27362h
www.rsc.org/obc
rhodium8 catalysts. Nitriles, meanwhile, are important precur-
sors in drug molecules as well as being key starting materials
Introduction
We herein report a mild and general protocol for the palla- in the industrial synthesis of adhesives9 and rubbers.10 The
dium-catalysed conversion of aldoximes into nitriles and two currently dominant industrial processes for the prep-
amides, respectively. In the aldoxime–amide rearrangement aration of nitriles – ammoxidation and hydrocyanation – are
the catalyst displays a high selectivity for non-conjugated vs. both green regarding the by-products generated, but both have
conjugated substrates, while it is generally applicable in the drawbacks: the former suffers from atom-economy due to the
aldoxime to nitrile dehydration reaction. In the cases where multiple equivalents of water as the by-product, whilst the
the reactants are water-soluble, we demonstrate that the aldo- latter requires the use of the highly-toxic hydrogen cyanide as
xime–amide rearrangement can also be carried out in water, a starting material.
making this transformation more environmentally friendly
Our research efforts focussed on the development of cata-
and cost-effective.
lytic protocols using mild reaction conditions and, where
The development and discovery of transition metal catalysts possible, environmentally friendly and cost-effective solvent
has facilitated rapid progress in the interconversion of various systems such as water and, to a lesser extent, methanol. Our
functional groups, with particular attention being given to the first foray in this area used commercially available palladium
transformations of greater industrial or biological signifi- catalyst, Pd(en)(NO3)2, whose activity was studied in the
cance.1 Of these, metal-catalysed aldoxime to amide rearrange- conversion of aldoximes into other synthetically useful
ment reactions2 represent an atom-economical method for the functional groups (Fig. 1). We investigated also analogues of
synthesis of a biologically relevant, robust and industrially this Pd(en)(II) catalyst where the counteranion was systemati-
important functional group. These types of reactions have cally varied.
been shown previously3 to be viable as a one-pot procedure
A series of aldoximes was prepared using commercially
using the corresponding aldehyde, hydroxylamine hydrochlo- available aldehydes and hydroxylamine hydrochloride.11 In
ride and base to generate the aldoxime in situ, although high
boiling-point organic solvents and stringent reaction con-
ditions are typically required for obtaining the amide in high
yields.3,4 Aldoxime to primary amide conversions have been
previously reported for gold/silver,5 iridium,6 ruthenium7 and
aThe University Chemical Laboratory, University of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, United Kingdom. E-mail: kt287@cam.ac.uk;
Fax: +44 (0)1223 336362; Tel: +44 (0)2113 336300
bDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY,
United Kingdom. E-mail: g.d.pantos@bath.ac.uk; Fax: +44 (0)1225 386231;
Tel: +44 (0)1225 386444
†Electronic supplementary information (ESI) available: X-ray data, 1H and 13C
NMR data, synthetic protocols, oxime E/Z isomer kinetic studies. CCDC 896279.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27362h
Fig. 1 General reaction scheme for the conversion of oximes into their corres-
ponding primary amides.
2466 | Org. Biomol. Chem., 2013, 11, 2466–2472
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Fig. 2 Synthetic route for NDI dioxime C.
Fig. 3 (Above) Single crystal X-ray structure of NDI dialdehyde B in its hemi-
acetal form. (Below) The packing arrangement for B, showing the π-stacking
mode and the interdigitation of the alkyl chains (atom colours: C: grey, N: blue,
O: red, H: white).
this study, the aldehyde was simply stirred at room temp-
erature overnight with one equivalent of hydroxylamine hydro-
chloride and sodium carbonate; anhydrous magnesium sulfate
was also added to the reaction mixture to shift the equilibrium
towards oxime formation. A simple workup yielded in most
cases the desired aldoxime in high yield and purity (see ESI†).
The naphthalenediimide (NDI) dialdoxime – envisaged as a
useful reactant for testing the retention of chirality at the
α-carbon – was prepared by a straightforward three-step syn-
thesis, which involved the reaction12 of the corresponding
anhydride with isoleucinol, followed by the oxidation of the
NDI diol to the corresponding dialdehyde using the Dess–
Martin reagent (Fig. 2).13 The NDI dialdehyde structure was
confirmed by X-ray analysis of single crystals of the corres-
ponding hemiacetal obtained by slow evaporation of an etha-
nolic solution of the NDI dialdehyde B (Fig. 3).
conversion rates (determined by 1H NMR spectroscopy) were
obtained for the catalyst (44–95%), with only entry 13 under-
going below 50% conversion.
This was attributed to conjugation of the oxime functionality
with an electron-rich indole ring, making it more thermodyna-
mically stable and thus more inert towards nitrile conversion.
Isolation of the products was achieved either by a straight-
forward work-up or through column chromatography (see
ESI†); isolated yields for 6 selected entries in Table 1 ranged
from 23–82% (see ESI†), although it must be noted that only
entry 10 gave below 50% yield due to solubility problems of
the product during work-up and subsequent column chro-
matographic purification.
Reactivity in methanol
General protocol for the reaction with
palladium catalyst
In methanol, a first inspection of the results indicated that
whilst aliphatic, non-conjugated aldoximes (entries 1–7,
Table 1) undergo oxime–amide rearrangement in reasonable
conversion rates (Table 2), their conjugated counterparts
remained unreacted under identical reaction conditions. This
type of aromatic/conjugated vs. aliphatic oxime selectivity has
been previously reported16 and it is hypothesised that the con-
jugation prevents the nitrile N lone pair from coordinating to
For all reactions, the oximes – unseparated with respect to E/Z
isomers – were heated overnight at 60 °C under nitrogen in the
selected solvent with 10 mol% loading of the Pd(en)(NO3)2
catalyst.14
Reactivity in acetonitrile
In acetonitrile (Table 1), all reactions yielded the correspond- the metal centre, and thus stopping the conversion at this
ing nitrile species as the major product by the dehydration of stage. This is supported by the fact that we observed one
the oxime starting material. In addition, one equivalent of equiv. of acetamide per aldoxime used when acetonitrile was
acetamide (relative to the nitrile product) was observed in each used as a sacrificial reagent or solvent.
case. A wide range of aldoximes was screened, including
In an effort to perform the rearrangement in a cheap and
those biased towards pharmaceutically attractive ‘lead-like’ environmentally friendly fashion, we investigated the possi-
space,15 (entries 13-16) and the catalyst was shown to tolerate a bility of using water as a solvent for this transformation. Of
wide range of functional groups for this transformation. Good the substrates described in Table 2, entries 1 and 2 are
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2466–2472 | 2467

View Article Online
Paper
Organic & Biomolecular Chemistry
chiral centres remained unaffected during the reactions (entries
5 and 7, Table 2; see ESI†).
Table 1 Conversion rates of the reactions carried out in acetonitrile
Isolation of the compounds was achieved through
a
straightforward work-up process without the need for further
purification (see ESI†); isolated yields for four selected entries
in methanol from Table 2 ranged from 58–71%.
Entry
Reactant
Product
Conversion (%)
Kinetic studies for the NDI dioxime, in which the three EE,
EZ, and ZZ isomers could be separated, showed the E isomer
undergoing conversion at a faster rate than for its Z counter-
part (Fig. 4). The quasi-quantitative conversions can be
explained by the isomerisation of the Z isomer into the
E isomer prior the addition to the Pd centre.
1
2
3
95
95
95
4
95
The role of the counteranion in Pd(en)X2 catalyst systems
5
6
95
95
The role of the counteranion was also investigated by a sys-
tematic variation of the anion from the original Pd(en)(NO3)2
−
salt (Table 3). In addition to the weakly-coordinating NO3
anion, Pd(en)2+ salts with BF4−, ClO4− and OTf− counteranions
were synthesised, whilst the Cl− salt was purchased from a
7
95
95
95
93
95
commercial source. OTf− and BF4 anions were chosen with
−
the aim of increasing the solubility of the catalyst in apolar
media but, in both cases, it remained insoluble in TCE (con-
firmed by the absence of signals in 19F NMR even at 100 °C).
The data presented in Table 3 reveals that the catalyst
requires a weakly coordinating anion in order to be active in
the oxime–nitrile dehydration or oxime–amide rearrangement
reactions. This is not surprising as the labile anion presum-
ably dissociates in solution thus allowing the metal centre to
interact with the oxime substrates.
8
9
10
11
12
95
Mechanistic insights
Based on this counterion-, solvent- and substrate-dependent
behaviour, a catalytic cycle similar to the one proposed by
Williams et al.17 can be used to explain the outcome of these
reactions (Fig. 5). The key steps in the cycle are as follows:
(1) generation of the active catalytic species through solvation-
induced dissociation of the counteranion; (2) coordination of
an oxime molecule onto one of the two available Pd(II) coordi-
nation sites via the N-lone pair following a ligand exchange
process, presumably due to the fact that it is a better ligand
for Pd2+ than either MeOH or H2O; (3) dehydration of the
oxime to generate the nitrile intermediate; (4) coordination of
a second oxime molecule onto the Pd(II) metal centre; (5) an
intramolecular reaction in which the O lone pair of the bound
oxime attacks the bound nitrile; (6) collapse of the adduct,
resulting in the release of the amide product.
13
14
44
95
15
16
74
91
In the first step, the counteranion (represented as X in
Fig. 5) must be labile in the chosen solvent; this allows their
dissociation from the metal centre in exchange for solvent
molecules, thereby forming a dicationic, catalytically active
Pd(II) species. This is supported by the lack of catalytic activity
of the Pd(en)Cl2 salt in either MeOH or water, solvents in
which the Pd–Cl bond is known to be kinetically inert owing to
the strong soft metal-borderline ligand interaction. Following
the formation of the active species, an oxime molecule coordi-
nates to one of the two available coordination sites on the
water-soluble molecules, whilst entry 3 showed partial solubility
that could be enhanced to useful concentrations by the addition
of 10% methanol (v/v). We were pleased to find that, although
the reactions required slightly higher temperatures (80 °C), con-
version rates comparable to those carried out in pure methanol
were obtained. The conversion of non-conjugated aldoximes
into the respective primary amides proceeded with good yields
1
(84–95%, determined by H NMR spectroscopy). Furthermore,
2468 | Org. Biomol. Chem., 2013, 11, 2466–2472
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Conversion rates of the oximes screened, determined by 1H NMR integration
Entry
1
Reactant
Product
Solvent
Conversion (%)
H2O
MeOH
95
78
2
3
4
H2O
MeOH
70
95
H2Oa
MeOH
80
95
MeOH
78
5
6
MeOH
MeOH
93
95
7
MeOHb
84
a10% MeOH (v/v) and b10% acetone (v/v) added to solvent to aid solubility of reactant.
Fig. 4 The different reactivity of the E/Z isomers of aldoximes. The NDI-diald-
oxime (C) was used for this study.
Fig. 5 Proposed catalytic cycle for reactions in protic solvents.
Table 3 The effect of the counteranion on the catalytic activity
centre for the softer N donor as opposed to the O donor. The
reactant subsequently undergoes dehydration to the nitrile
species, which remains coordinated to the metal centre via its
nitrogen lone pair. A second oxime molecule then coordinates
to the second coordination site of the palladium centre. The
subsequent steps leading to hydration of the nitrile into the
amide product were elucidated by conducting the reaction
X
NO3
80
BF4
95
OTf
95
ClO4
95
Cl
0
Conversion (%)
metal centre. Its mode of coordination is thought to be via the with the NDI dioxime in methanol doped with 3% (v/v)
18O-labelled water. No 18O incorporation was observed into the
final product, as judged by mass spectrometric analysis,
nitrogen lone pair of the oxime, as shown in the literature,18
presumably driven by the preference of the soft Pd(II) metal
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2466–2472 | 2469

View Article Online
Paper
Organic & Biomolecular Chemistry
Conclusions
We have reported a high-yielding, mild and general protocol
for the conversion of aliphatic aldoximes into primary amides
in water and methanol. In acetonitrile, the reaction stops at
the oxime dehydration step, yielding the corresponding nitrile
along with one equivalent of acetamide. The respective roles of
solvent and counteranion were investigated systematically
allowing us to propose a catalytic mechanism.
Experimental
General
All solvents used were of reagent quality and purchased com-
mercially. All purchased starting materials were used without
further purification; the aldehyde starting materials for entries
12–16 in Table 1 were supplied by GlaxoSmithKline, and used
without further purification. 1H NMR spectra were recorded on
400 MHz instruments, 13C NMR on 100 MHz instruments, and
referenced to the solvent. Liquid Chromatography-Mass Spec-
troscopy (LC-MS) was used to monitor the reaction progress in
some cases. All spectra were recorded at 298 K. 1H NMR
spectra data are reported as follows: chemical shift in ppm on
the δ scale, integration, multiplicity, coupling constants (Hz)
and assignments. For 13C NMR spectra data, their chemical
shifts in ppm are reported. All spectra were referenced to their
respective solvent residual peaks.19
Fig. 6 The proposed catalytic mechanism in acetonitrile.
Table 1, entry
7
(reactant): S-3,7-dimethyloct-6-enal
suggesting that the water molecule required to hydrate the
intermediate nitrile does not originate from the solvent.
Instead, it is thought that the O lone pair of the bound oxime
– due to the higher effective molarity and nucleophilicity com-
pared to bulk water – attacks the Pd-bound nitrile to generate
an unstable adduct which spontaneously collapses and results
in the release of the amide product.
In acetonitrile, it is hypothesised that competition in
binding between the nitrile intermediate and solvent occurs
following the dehydration of the oxime to the nitrile (Fig. 6), as
both possess the nitrile functionality capable of coordinating
to the Pd(II) centre. Due to the large excess of solvent over the
substrate, nitrile exchange occurs between the reaction inter-
mediate nitrile and the solvent, causing premature release of
the substrate midway through the cycle.
As a result, the observed major product in acetonitrile is the
nitrile formed from the dehydration of the oxime starting
material. One equivalent of acetamide by-product is formed
through the subsequent hydration of the Lewis acid-activated
acetonitrile molecule bound to the Pd(II) centre. In contrast,
water or methanol, being a weaker ligand for the soft Pd(II)
centre, is thought to be unable to substitute the nitrile formed
via the oxime dehydration as in the case of acetonitrile. As a
result, the oxime substrate and nitrile intermediate stay coordi-
nated to the Pd(II) throughout the cycle, resulting in the for-
mation of the amide.
oxime. S-(−)-Citronellal (426 mg, 500 μl, 2.759 mmol) was dis-
solved in methanol. To this, hydroxylamine hydrochloride
(192 mg, 2.759 mmol) and sodium carbonate (292 mg,
2.759 mmol) was added. The reaction progress was monitored
by LC-MS. The methanol was removed under reduced pressure,
and the residue redissolved in dichloromethane. The organic
phase was washed with water, and dried with anhydrous mag-
nesium sulfate. Concentrating and drying in vacuo yielded the
product as a colourless oil (374 mg, 80%).
1H NMR (400 MHz, CDCl3) δ(ppm): 0.94 (3H, t, J = 7.3 Hz),
1.16–1.28 (1H, m), 1.32–1.41 (1H, m), 1.59 (3H, s), 1.67 (3H, s),
1.93–2.08 (2H, m), 2.17–2.40 (2H, m), 5.06–5.10 (1H, m), 6.74
and 7.42 (1H, CHvNOH, E and Z isomers, t, JE = 5.4 Hz, JZ =
6.6 Hz), 8.85 and 9.22 (1H, CHvNOH, E and Z isomers, br s).
13C NMR (100 MHz, CDCl3) δ(ppm): 17.8, 25.4, 25.6, 30.6, 30.9,
32.0, 36.6, 124.4, 131.7, 151.6, 152.0. HRMS (EI) calcd for
C10H19NO [M]+ (m/z): 169.1461, found: 169.1464.
Table 1, entry 4 (product). 3-Phenylpropionaldoxime (5 mg,
0.034 mmol) and Pd(en)(NO3)2 (0.97 mg, 0.0034 mmol) were
dissolved in an NMR tube in d3-acetonitrile (1 ml) under nitro-
gen. The reaction mixture was then heated for 16 hours at
60 °C.
1H NMR (400 MHz, d3-MeCN) δ(ppm): 2.49 (2H, t, J =
7.8 Hz), 2.9 (2H, t, J = 7.8 Hz), 7.17 (1H, tt, J1 = 1.6 Hz, J2
=
7.1 Hz), 7.22 (2H, d, J = 7.1 Hz), 7.26 (2H, t, J = 7.1 Hz).
13C NMR (100 MHz, d3-MeCN) δ(ppm): 32.8, 38.4, 127.2, 129.3,
2470 | Org. Biomol. Chem., 2013, 11, 2466–2472
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
129.5, 142.2, 178.2. HRMS (ESI+) calcd for C9H10N1 [M + H]+
(m/z): 132.0808, found: 132.0807.
1H NMR (400 MHz, d4-MeOD) δ(ppm): 0.96 (3H, t, J = 7.4
Hz), 1.64 (2H, m, J = 7.4 Hz), 2.18 (2H, t, J = 7.4 Hz); 13C NMR
Table 1, entry 5 (product). C (8.48 mg, 0.017 mmol) and (100 MHz, d4-MeOD) δ(ppm): 14.0, 20.4, 38.4, 179.2. HRMS
Pd(en)(NO3)2 (0.5 mg, 0.0017 mmol) were dissolved in an NMR (ESI+) calcd for C4H10NO [M + H]+ (m/z): 88.0756, found:
tube in d3-acetonitrile (1 ml) under nitrogen. The reaction 88.0757. Elemental Analysis for 11C4H9NO·1MeOH, calcd:
mixture was then heated for 16 hours at 60 °C.
The experiment was repeated on a larger scale of C N 15.93%.
(100 mg, 0.203 mmol) and Pd(en)(NO3)2 (6 mg, 0.0203 mmol). Table 2, entry
C 54.57%, H 10.48%, N 15.56%, found: C 54.35%, H 10.29%,
6
(product). tert-Butyl((4-hydroxyimino)-
The starting materials were dissolved in acetonitrile and methyl)piperidine-1-carboxylate (7.86 mg, 0.034 mmol) and
heated for 16 hours at 60 °C. The acetonitrile was removed Pd(en)(NO3)2 (1 mg, 0.0034 mmol) were dissolved in an NMR
under reduced pressure, and the residue was redissolved in tube in d4-methanol (1 ml) under nitrogen. The reaction
dichloromethane. All solids were filtered off, and the solvent mixture was then heated for 16 hours at 60 °C.
removed under reduced pressure without heating to yield the
product as a brown powder (63 mg, 68%).
The experiment was repeated on a larger scale of 6 (100 mg,
0.438 mmol) and Pd(en)(NO3)2 (13 mg, 0.0438 mmol). The
1H NMR (400 MHz, d3-MeCN) δ(ppm): 1.00 (6H, d, J = starting materials were dissolved in methanol and heated for
6.6 Hz), 1.03 (6H, d, J = 6.6 Hz), 1.79 (2H, septet, J = 6.6 Hz), 16 hours at 60 °C. The methanol was removed under reduced
4.63 (2H, br s), 5.53 (2H, br s), 6.10 (2H, J1 = 7.0 Hz, J2
=
pressure, and the residue was redissolved in dichloromethane.
8.4 Hz), 8.76 (4H, s). 13C NMR (100 MHz, d3-MeCN) δ(ppm): All solids were filtered off, and the solvent removed under
21.9, 22.5, 25.9, 40.1, 41.0, 117.8, 127.6, 127.7, 131.9, 163.0. reduced pressure to yield the product as an off-white powder
HRMS (ESI+) calcd for C26H25N4O4 [M + H]+ (m/z): 457.1870, (61 mg, 61%).
found: 457.1870.
1H NMR (400 MHz, d4-MeOD) δ(ppm): 1.46 (9H, s),
Table 1, entry 12 (product). Anthracene-9-carbaldehyde 1.51–1.58 (2H, m), 1.77 (2H, d, J = 13.4 Hz), 2.41 (1H, tt, J1 =
oxime (7.62 mg, 0.034 mmol) and Pd(en)(NO3)2 (1 mg, 3.8 Hz, J2 = 11.7 Hz), 2.77 (2H, br s), 4.10 (2H, d, J = 13.4 Hz);
0.0034 mmol) were dissolved in an NMR tube in d3-acetonitrile 13C NMR (100 MHz, d4-MeOD) δ(ppm): 27.2, 28.7, 29.7, 43.5,
(1 ml) under nitrogen. The reaction mixture was then heated 81.1, 156.4, 180.3. HRMS (ESI+) calcd for C11H21N2O3 [M + H]+
for 16 hours at 60 °C.
(m/z): 229.1547, found: 229.1538. Elemental Analysis for
The experiment was repeated on a larger scale of anthra- C11H20N2O3, calcd: C 57.87%, H 8.83%, N 12.27%, found:
cene-9-carbaldehyde oxime (200 mg, 0.904 mmol) and Pd(en)- C 57.81%, H 8.83%, N 12.10%.
(NO3)2 (27 mg, 0.0904 mmol). The starting materials were dis-
solved in acetonitrile and heated for 16 hours at 60 °C. The
acetonitrile was removed under reduced pressure without
heating, and the residue was redissolved in dichloromethane.
Acknowledgements
All solids were filtered off, and the solvent removed under We thank Prof. Jeremy K. M. Sanders for his support and
reduced pressure. The product was purified by flash column helpful suggestions, Prof. Jonathan M. J. Williams for helpful
chromatography (eluent: DCM, product Rf = 0.67) to yield the discussions and suggestions, and Dr Naoki Ousaka for his
product as a bright yellow powder (151 mg, 82%).
advice. We thank the EPSRC (K. T.) and the University of Bath
1H NMR (400 MHz, d3-MeCN) δ(ppm): 7.62–7.66 (2H, m), (G. D. P.) for financial support, and Dr J. E. Davies for the X-ray
7.75–7.79 (2H, m), 8.17 (2H, d, J = 8.6 Hz), 8.33 (2H, dq, J1 = crystal structure of B. We thank GlaxoSmithKline for supplying
0.9 Hz, J2 = 8.7 Hz), 8.83 (1H, s). 13C NMR (100 MHz, d3-MeCN) the aldehyde starting materials for entries 11 & 13–16 in
δ(ppm): 105.9, 117.9, 125.7, 127.5, 130.2, 130.4, 131.6, 134.1, Table 1.
134.3. HRMS (EI) calcd for C15H10N [M+] (m/z): 204.0730,
found: 203.0726. Elemental Analysis for 5C15H9N·1H2O, calcd:
C 87.10%, H 4.58%, N 6.77%, found: C 87.31%, H 4.68%,
N 6.75%.
Notes and references
Table 2, entry
3
(product). Butyraldoxime (3.00 mg,
1 (a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams,
Org. Biomol. Chem., 2006, 4, 2337–2347; (b) N. Sewald and
H. D. Jakubke, Peptides: Chemistry and Biology, Wiley-VCH,
Weinheim, 1996; (c) A. Greenberg, C. M. Breneman and
J. F. Liebman, The Amide Linkage: Selected Structural Aspects
in Chemistry, Biochemistry and Materials Science, Wiley-Inter-
science, New York, 2000.
2 (a) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011,
40, 3405–3415; (b) M. Kim, J. Lee, H.-Y. Lee and S. Chang,
Adv. Synth. Catal., 2009, 351, 1807–1812; (c) J. Lee, M. Kim,
S. Chang and H.-Y. Lee, Org. Lett., 2009, 11, 5598–5601;
(d) S. K. Sharma, S. D. Bishopp, C. L. Allen, R. Lawrence,
0.034 mmol) and Pd(en)(NO3)2 (1 mg, 0.0034 mmol) were dis-
solved in an NMR tube in d4-methanol (1 ml) under nitrogen.
The reaction mixture was then heated for 16 hours at 60 °C.
The experiment was repeated on a larger scale of butyral-
doxime (200 μl, 185 mg, 2.123 mmol) and Pd(en)(NO3)2
(62 mg, 0.212 mmol). The starting materials were dissolved in
methanol and heated for 16 hours at 60 °C. The methanol was
removed under reduced pressure, and the residue was redis-
solved in dichloromethane. All solids were filtered off, and the
solvent removed under reduced pressure to yield the product
as a white powder (131 mg, 71%).
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2466–2472 | 2471

View Article Online
Paper
Organic & Biomolecular Chemistry
M. J. Bamford, A. A. Lapkin, P. Plucinski, R. J. Watson and
J. M. J. Williams, Tetrahedron. Lett., 2011, 52, 4252–4255;
D. Tian, H. Li and C. Lu, J. Appl. Polym. Sci., 2012, 126,
1351–1358.
(e) C. L. Allen, S. Davulcu and J. M. J. Williams, Org. Lett., 11 G. D. Vilela, R. R. da Rosa, P. H. Schneider, I. H. Bechtold,
2010, 12, 5059–5099.
3 M. A. Ali and T. Punniyamurthy, Adv. Synth. Catal., 2010,
352, 288–292.
J. Eccher and A. A. Merlo, Tetrahedron. Lett., 2011, 52,
6569–6572.
12 K. Tambara, N. Ponnuswamy, G. Hennrich and
G. D. Pantoş, J. Org. Chem., 2011, 76, 3338–3347.
4 (a) J. F. Hull, S. T. Hilton and R. H. Crabtree, Inorg. Chim.
Acta, 2010, 363, 1243–1245; (b) C. L. Allen, C. Burel and 13 I. Paterson, P. Maltas, S. M. Dalby, J. H. Lim and
J. M. J. Williams, Tetrahedron Lett., 2010, 51, 2724–2726. E. A. Anderson, Angew. Chem., Int. Ed., 2012, 51, 2749–2753.
5 R. S. Ramón, J. Bosson, S. Díez-González, N. Marion and 14 When lower catalyst loading at 1 mol% was attempted, no
S. P. Nolan, J. Org. Chem., 2010, 75, 1197–1202.
6 N. A. Owston, A. J. Parker and J. M. J. Williams, Org. Lett.,
2007, 9, 73–75.
conversion was observed under identical reaction con-
ditions. At 5 mol% catalyst loading, the reaction took
40 hours for completion under otherwise identical reaction
conditions.
7 (a) D. Gnanamgari and R. H. Crabtree, Organometallics,
2009, 28, 922–924; (b) R. García-Álvarez, A. E. Díaz-Álvarez, 15 A. Nadin, C. Hattotuwagama and I. Churcher, Angew.
J. Borge, P. Crochet and V. Cadierno, Organometallics, 2012,
31, 6482–6490.
8 (a) H. Fujiwara, Y. Ogasawara, K. Yamaguchi and
Chem., Int. Ed., 2012, 51, 1114–1122.
16 C. L. Allen, C. Burel and J. M. J. Williams, Tetrahedron Lett.,
2010, 51, 2724–2726.
N. Mizuno, Angew. Chem., Int. Ed., 2007, 46, 5202–5205; 17 C. L. Allen, R. Lawrence, L. Emmett and J. M. J. Williams,
(b) H. Fujiwara, Y. Ogasawara, M. Kotani, K. Yamaguchi Adv. Synth. Catal., 2011, 353, 3262–3268.
and N. Mizuno, Chem.–Asian J., 2008, 3, 1715–1721; 18 (a) J. Vicente, M.-T. Chicote, A. Abellán-López and
(c) S. Park, Y. Choi, H. Han, S. H. Yang and S. Chang,
Chem. Commun., 2003, 1936–1937.
9 P. Sasidharan Achary, C. Gouri and R. Ramaswamy, J. Appl.
Polym. Sci., 2001, 81, 2597–2608.
D. Bautista, Dalton Trans., 2012, 41, 752–762; (b) M. Kim
and F. P. Gabbaï, Dalton Trans., 2004, 3403–3407;
(c) N. V. Kaminskaia and N. M. Kostić, J. Chem. Soc., Dalton
Trans., 2001, 1083–1086.
10 (a) V. S. Vinod, S. Varghese and B. Kuriakose, J. Appl. 19 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem.,
Polym. Sci., 2004, 91, 3156–3161; (b) Z. Lu, X. Zhang,
1997, 62, 7512–7515.
2472 | Org. Biomol. Chem., 2013, 11, 2466–2472
This journal is © The Royal Society of Chemistry 2013