Copper-catalyzed rearrangement of oximes into primary amides

Article abstract of DOI:10.1016/j.tetlet.2011.05.129

The atom-efficient and cost-effective rearrangement of oximes into primary amides is catalyzed by simple copper salts. The use of homogeneous Cu(OAc) ₂ (1-2 mol %) was found to be effective for this transformation at 80 °C. The reaction was successful with either conventional or microwave heating. CuO and CuO/ZnO on activated carbon provided a competent reuseable heterogeneous catalyst which could be used in a batch process or in flow. Copper salts are much cheaper than the precious metals previously used for this rearrangement, and the reaction conditions are milder than those reported.

Full text of DOI:10.1016/j.tetlet.2011.05.129

Tetrahedron Letters 52 (2011) 4252–4255
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed rearrangement of oximes into primary amides
Sumeet K. Sharma a,d, Simon D. Bishopp a, C. Liana Allen a, Ruth Lawrence a, Mark J. Bamford b,
Alexei A. Lapkin c, Pawel Plucinski d, Robert J. Watson b, Jonathan M. J. Williams a,
⇑
a Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage SG1 2NY, UK
c School of Engineering, University of Warwick, Coventry CV4 7AL, UK
d Department of Chemical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The atom-efficient and cost-effective rearrangement of oximes into primary amides is catalyzed by sim-
ple copper salts. The use of homogeneous Cu(OAc)2 (1–2 mol %) was found to be effective for this trans-
formation at 80 °C. The reaction was successful with either conventional or microwave heating. CuO and
CuO/ZnO on activated carbon provided a competent reuseable heterogeneous catalyst which could be
used in a batch process or in flow. Copper salts are much cheaper than the precious metals previously
used for this rearrangement, and the reaction conditions are milder than those reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 April 2011
Revised 17 May 2011
Accepted 27 May 2011
Available online 2 June 2011
Keywords:
Amide
Copper
Rearrangement
Sustainable chemistry
Synthetic methods
The rearrangement of oximes 1 into amides is usually associ-
ated with the Beckmann rearrangement (Scheme 1) where the R
group migrates to give the formamide 2.1 The metal-catalyzed
rearrangement of oximes provides an alternative synthetic out-
come with the formation of a primary amide 3.2 Recently, there
have been several reports of the use of precious metals for this
reaction, including Rh,3 Ir,4 Ru,5 Pd6 and Ag/Au7 catalysts. Given
the importance of amides, and the conventional approach requir-
ing the use of a stoichiometric coupling agent to activate carboxylic
acids,8 catalytic approaches to amide formation are highly desir-
able.9 The rearrangement of oximes provides an alternative cata-
lytic approach which is completely atom-efficient. We recently
reported that zinc salts could be used as cheaper alternatives to
precious metals as catalysts for this reaction, although catalyst
loadings of 10–15 mol % were required.10 We therefore wanted to
identify a catalyst which was cheap, effective at lower catalyst
loading and could be used under milder conditions than those pre-
viously reported. In this Letter, we report that simple copper salts
can fulfil these objectives.
90% conversion, respectively, whereas CuBrÁSMe2, CuSO4, CuCO3,
CuCl2, CuBr2 and Cu(OTf)2 did not work to any useful level. We fur-
ther investigated Cu(NO3)2, Cu(OAc)2 and Cu2O catalysts using the
p-tolyl substituted oxime 6 as the analysis of the 1H NMR spectrum
to distinguish starting material from product 7 was more straight-
forward. A series of optimization reactions was performed (Table
1) in order to reduce the catalyst loading and reaction temperature.
Pleasingly, with 5 mol % of catalyst, the conversion of oxime 6 into
amide 7 was still complete when the reaction was performed at
80 °C (Table 1, entries 1–3), which is the lowest temperature re-
ported for the metal-catalyzed rearrangement of oximes to amides.
In fact, reasonable activity was observed even at 50 °C (Table 1, en-
tries 4–6). We chose to investigate the use of Cu(OAc)2 further due
to the lower reactivity of Cu(NO3)2 and the higher effective loading
of Cu2O (5 mol % corresponds to 10 mol % in Cu). The use of addi-
tives was briefly investigated but found to offer no advantage
(Table 1, entries 7–9). Lower catalyst loadings were effective, espe-
cially when the reactions were run at higher concentration.
We applied the conditions shown in Table 1, entries 10 and 12
to the conversion of other oximes to give the corresponding amides
shown in Table 2.11 Oximes containing aryl groups with either
electron-withdrawing moieties (Table 2, entry 3), halides (Table
2, entries 4 and 5), or electron-rich groups (Table 2, entries 6 and
7) were all successful. The least reactive substrate when using
1 mol % Cu(OAc)2 was the aliphatic butyraldehyde oxime, although
at the higher catalyst loading, complete conversion into butyra-
mide was observed.
During the course of screening reactions for the conversion of
benzaldehyde oxime (4) into benzamide (5) (Scheme 2), we found
that some simple copper(I) and copper(II) salts were successful for
this transformation. Using 5 mol % of Cu(NO3)2, Cu(OAc)2 or Cu2O
all gave 100% conversion after 24 h. CuO and CuBr gave 80% and
⇑
Corresponding author.
E-mail address: j.m.j.williams@bath.ac.uk (J.M.J. Williams).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.129

S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 4252–4255
4253
H
N
OH
H
Beckmann
rearrangement
O
N
4
H
Cu catalyst
R
toluene, 110 °C
Ph
NH2
NH2
Ph
2
O
OH
H
5
N
O
R
OH
H
O
1
N
6
Cu catalyst
Metal-catalyzed
rearrangement
R
NH2
3
toluene, 50-80 °C
24 h (see Table 1)
p-Tol
p-Tol
7
Scheme 1. Rearrangement of oximes to amides.
Scheme 2. Use of copper catalysts for the rearrangement of oximes into amides.
Table 1
Optimization of the catalyst and conditionsa
Table 2
a
Conversion of oximes into amides with Cu(OAc)2
Entry Catalyst
Loading
(mol %)
Temp
(°C)
Additive
(5 mol %)
Conversion
(%)
OH
O
N
Cu(OAc)2 (1-2 mol%)
toluene, 80 °C, 24 h
1
2
3
Cu(NO3)2
Cu(OAc)2
Cu2O
5
5
5
5
5
5
5
5
5
2
2
1
1
—
80
80
80
50
50
50
50
50
50
80
80
80
80
110
—
—
—
—
—
—
AcOH
K2CO3
Bipy
—
100
100
100
10
37
40
40
25
17
R
NH2
R
H
1
3
4
5
6
Cu(NO3)2
Cu(OAc)2
Cu2O
Entry Amide product
Catalyst loading
(mol %)
Conversionb
(%)
7
8
9
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
None
O
1
2
100 (82)
100 (81)
100 (67)
100 (76)
100 (75)
100 (65)
Ph
NH2
100b
100
100b
64
O
—
—
—
—
2
3
4
5
6
2
2
2
2
2
NH2
NH2
4-MeC6H4
4-O2NC6H4
<1
O
a
Reactions were performed on oxime 6 (2 mmol) in toluene (3 mL) with additive
(2.4 mmol) and copper catalyst for 24 h at the temperature indicated.
b
O
Reactions performed under more concentrated conditions, toluene (0.5 mL).
NH2
4-ClC6H4
4-FC6H4
O
As expected for a metal-catalyzed oxime rearrangement, the
ketoxime derived from acetophenone was inert to reaction under
these conditions, perhaps due to the mechanism of reaction in
the case of aldoximes, which can proceed via dehydration of the
oxime to give a nitrile intermediate followed by further reaction
to give the amide product.10
NH2
O
NH2
4-Et2NC6H4
O
We found that the rearrangement reactions could conveniently
be performed using microwave irradiation. Thus, benzaldehyde
oxime (4) and butyraldehyde oxime (8) were converted into the
corresponding amides 5 and 9 after 1 h at 80 °C using microwave
conditions (Scheme 3). Using a lower catalyst loading of 4 mol %,
complete conversion of oxime 8 into amide 9 was achieved after
2 h at 80 °C under microwave conditions. The reaction was per-
formed on other substrates under microwave conditions (Table 3).
We were pleased to find that shorter reaction times could also
be used when using conventional heating, at least for the conver-
sion of oxime 6 into amide 7. Performing the reaction at 110 °C
with 2 mol % Cu(OAc)2, 17% conversion was observed after
10 min, but complete conversion was obtained after 30 min. Per-
forming the reaction at 80 °C, 85% conversion was observed after
60 min.
O
O
NH2
NH2
7
1
90 (84)
O
8
9
2
1
88 (78)
90 (58)
O
NH2
NH2
S
O
10
11
2
2
100 (91)
100 (82)
O
NH2
Having established good reaction conditions for the homoge-
neous isomerization of oximes into amides, we wanted to explore
the development of a heterogeneous variant of this process. Given
the success with homogeneous copper and zinc catalysts we chose
to investigate the use of CuO on activated carbon, ZnO on activated
carbon and CuO/ZnO on activated carbon.12 We were pleased to
find that these heterogeneous catalysts were also active for the
rearrangement reaction for the conversion of benzaldehyde oxime
(4) into benzamide (5) (Scheme 4). In all of these cases, small
amounts of benzonitrile (10) and other unidentified by-products
were detected by GC analysis of the crude reaction mixtures.
Based on these results we undertook an optimization study for
the rearrangement of oxime 4 using CuO/ZnO on activated carbon,
O
12
3
79 (70)
NH2
a
Reactions were performed on oxime (3 mmol) in toluene (0.75 mL) with
Cu(OAc)2 (1–3 mol %) for 24 h at 80 °C.
b
Values in parentheses are isolated yields.
varying the time, temperature and catalyst loading, as detailed in
Table 4. We chose to use a catalyst loading of 60 mg for reactions
performed on a 5.5 mmol scale, which approximates to 2 mol %

4254
S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 4252–4255
98% conversion was achieved with much higher selectivity for
OH
H
O
N
Cu(OAc)2 (10 mol%)
the amide (Table 4, entry 4). This implies that benzonitrile is an
intermediate in the reaction pathway.13 At 100 °C (Table 4, entries
5–8) and 130 °C (entries 9–12), higher conversions were observed,
although selectivity was not improved. We chose to use the condi-
tions of 100 °C for 4 h for subsequent experiments. In the absence
of catalyst there was very little conversion (Table 4, entry 13) with
the majority of the product being the nitrile. Higher catalyst load-
ings did help to drive the reaction to completion and the selectivity
was also improved when a catalyst loading of 200 mg was used
(entry 17).
toluene, 80 °C, 1 h
microwaves
Ph
NH2
Ph
4
5
95% conversion
81% isolated yield
OH
H
O
N
Cu(OAc)2 (10 mol%)
nPr
NH2
nPr
toluene, 80 °C, 1 h
microwaves
8
9
100% conversion
93% isolated yield
It was possible to re-use the supported catalyst, which was
recovered by the addition of ethanol to cool the reaction mixture
followed by filtration to isolate the catalyst. The solids were then
washed with acetone followed by ethanol to remove adsorbed
reactant or products. The washed catalyst was first dried at 80 °C
for 4 h then at 250 °C for 8 h in a flow of nitrogen. The dried cata-
lyst was used for the rearrangement of benzaldehyde oxime (4) un-
der reaction conditions similar to that of fresh catalyst. Fresh
catalyst gave 98% conversion with 93% selectivity (Table 4, entry
7), and the first re-use led to essentially identical results (98% con-
version, 92% selectivity). Subsequent runs afforded 93% conversion
with 89% selectivity and then 80% conversion with 85% selectivity
on the fourth run.
Using the optimized conditions, we employed the CuO/ZnO
supported catalyst for the rearrangement of other oximes into
amides, as shown in Table 5. This catalyst was found to be effective
for the transformation of a range of substituted aryl oximes,
although the presence of electron-withdrawing substituents led
to somewhat lower conversions (Table 5, entries 2 and 3). Alkenyl
(Table 5, entry 10) and alkyl (Table 5, entries 11 and 12) oximes
underwent the rearrangement successfully, although the conver-
sions and selectivities were lower than those observed for aryl
oximes.
Scheme 3. Oxime rearrangement using microwave irradiation.
Table 3
a
Conversion of oximes into amides with Cu(OAc)2
OH
O
N
Cu(OAc)2 (4 mol%)
toluene, 80 °C, 2 h
microwaves
R
NH2
R
H
1
3
Entry
1
Amide product
Conversionb (%)
95 (81)
O
Ph
NH2
O
2
3
97 (90)
86
NH2
O
4-ClC6H4
NH2
4-Et2NC6H4
O
4
93 (80)
NH2
The activity of the CuO–ZnO/C catalyst for rearrangement of
benzaldehyde oxime (4) in batch encouraged us to perform the
same reaction in a flow reactor (X-Cube, ThaleNano, Hungary).
Complete conversion of 4 with 88% selectivity for benzamide was
observed in the flow reactor using a 4.86 mol/L concentration of
benzaldehyde oxime at 150 °C.
In conclusion, effective homogeneous and heterogeneous cata-
lysts have been identified for the rearrangement of oximes into
amides. The reaction is atom-efficient and uses relatively mild
O
5
6
7
100 (74)
100 (93)
93 (85)
NH2
S
O
nPr
NH2
O
NH2
a
Reactions were performed on oxime (2 mmol) in toluene (0.75 mL) with
Cu(OAc)2 (4 mol %) for 2 h at 80 °C.
b
Table 4
Values in parentheses are isolated yields.
Conversion of oxime 4 into products 5 and 10 using CuO/ZnO on C
Entry Time
(h)
Loading
(mg)
Temp
(°C)
Conversion
(%)
Selectivitya
5:10:other
OH
O
N
Supported catalyst (60 mg)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
2
4
6
1
2
4
6
1
2
4
6
4
4
4
4
4
60
60
60
60
60
60
60
60
60
60
60
60
0
80
80
80
30
58
88
98
39
67
98
>99
75
97
>99
100
5
47:44:9
74:19:7
91:4:6
94:4.5:1.5
53:36:11
80:12:8
93:5:2
Ph
CN
toluene (1.1 mL)
100 °C, 4 h
Ph
NH2
Ph
H
4
5
10
80
670 mg
100
100
100
100
130
130
130
130
100
100
100
100
100
5
10
: other
:
89% conv.
87% conv.
98% conv.
8% conv.
90 : 7 : 3
91 : 6 : 3
93 : 5 : 2
0 : 75 : 25
CuO on activated C
ZnO on activated C
CuO/ZnO on activated C
activated C only
93:5:2
73:13:14
83:6:11
89:3:8
87:3:10
2:97:1
71:22:7
87:8:5
93:5:2
Scheme 4. Oxime rearrangement with heterogeneous catalysts.
7.5
30
100
200
52
93
99
100
catalyst loading as used in the homogeneous reactions. After 1 h at
80 °C, the products were formed in only 30% conversion and con-
tained almost equal amounts of benzamide (5) and benzonitrile
(10) (Table 4, entry 1), but as the reaction times increased, up to
96:3:1
a
Selectivity and conversion were determined by GC.

S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 4252–4255
4255
Table 5
previously been reported for this reaction. In addition, the reac-
tions are performed at lower temperatures than previously
reported.
Conversion of oximes into amides with CuO/ZnO
OH
O
N
CuO/ZnO (10 wt%)
Acknowledgements
toluene, 100
°
C, 4 h
R
NH2
R
H
1
3
We thank the EPSRC for funding through the Doctoral Training
Centre in Sustainable Chemical Technology and through grant EP/
G028141/1 and GlaxoSmithKline for additional support. We are
also grateful to Mast Carbon Technology Ltd for the donation of
supported catalysts.
Entry Amide product
Conversion (%) Selectivity 3:nitrile:othera
O
1
98
86
89
98
98
97
99
99
93:5:2
91:8:1
88:10:2
89:8:3
91:8:1
89:9:2
91:8:1
90:7:3
Ph
NH2
O
2
3
4
5
6
7
8
Supplementary data
NH2
4-O2NC6H4
4-NCC6H4
4-MeC6H4
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.129.
NH2
O
References and notes
NH2
1. Gawley, R. E. Org. React. 1988, 35, 1–420.
O
2. (a) Field, L.; Barnet, P.; Shumaker, S. H.; Marshall, W. S. J. Am. Chem. Soc. 1961,
83, 1983–1987; (b) Leusink, A. J.; Meerbeek, T. G.; Noltes, J. G. Recl. Trav. Chim.
1976, 123–125.
NH2
4-MeOC6H4
O
3. (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.,
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(b) Gnanamgari, D.; Crabtree, R. H. Organometallics 2009, 28, 922–924; (c) Hull,
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2010, 75, 1197–1202.
NH2
4-F3COC6H4
O
NH2
4-ClC6H4
O
NH2
3-ClC6H4
O
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9
99
88
86:12:2
77:20:3
NH2
9. (a) Carey, J. S.; Laffan, D.; Thompson, C.; Williams, M. T. Org. Biomol. Chem.
2006, 4, 2337–2347; (b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey,
G. R.; Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells,
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11. Representative experimental procedure; benzaldehyde oxime (4) and
Cu(OAc)2ÁH2O (12.0 mg, 3 mol %) were dissolved in toluene (0.5 mL) in an
oven-dried Schlenk tube and heated at 80 °C for 24 h. After cooling, the solvent
was removed under vacuum and the product isolated by column
chromatography (silica, EtOAc/hexane, 3:1) to give benzamide (5) (298 mg,
82%) as a colourless solid. Products were analyzed by comparison of their 1H
and 13C NMR spectra with authentic samples. Further experimental details are
provided in the Supplementary data.
O
10
Ph
NH2
NH2
O
11
12
75
75
78:14:8
Ph
O
60:18:22
NH2
C6H13
12. Kindly donated by Mast Carbon Technology Ltd, Henley Park, Normandy,
Guildford, Surrey, GU3 2AF, UK.
a
Selectivity and conversion were determined by GC.
13. Based on the mechanism with other catalysts, it seems likely that the
intermediate nitrile is converted into the amide by oxygen transfer from
another oxime molecule: Allen, C. L.; Davulcu, S.; Williams, J. M. J. Org. Lett.
2010, 12, 5096–5099.
reaction conditions and catalyst loading. Copper salts are signifi-
cantly cheaper than the precious metal complexes which have