Iron-catalyzed dehydration of aldoximes to nitriles requiring neither other reagents nor nitrile media

Article abstract of DOI:10.1002/asia.201600085

The dehydration of aldoximes is an environmentally benign reaction affording the desired nitrile and water as a by-product. However, most of the reported catalytic dehydration reactions of aldoximes require a solvent containing nitrile to synthesize the corresponding nitrile compounds. Inspired by recent reports on the enzymatic synthesis under nitrile-free conditions, we here describe that a simple iron salt catalyzes the dehydration of aldoximes requiring neither other reagents nor nitrile media. Our method can be applied to the one-pot synthesis of nitiriles from aldehydes. Dehydration causes: The dehydration of aldoximes is an environmentally benign reaction affording the desired nitrile and water as a by-product. However, most of the reported catalytic dehydration reactions of aldoximes require a solvent containing nitrile to synthesize the corresponding nitrile compounds. Inspired by recent reports on the enzymatic synthesis under nitrile-free conditions, here a simple iron salt-catalyzed dehydration of aldoximes requiring neither other reagents nor nitrile media is reported.

Full text of DOI:10.1002/asia.201600085

DOI: 10.1002/asia.201600085
Communication
Dehydration Reactions
Iron-Catalyzed Dehydration of Aldoximes to Nitriles Requiring
Neither Other Reagents Nor Nitrile Media
Kengo Hyodo,* Saki Kitagawa, Masayuki Yamazaki, and Kingo Uchida[a]
Abstract: The dehydration of aldoximes is an environmen-
tally benign reaction affording the desired nitrile and
water as a by-product. However, most of the reported cat-
alytic dehydration reactions of aldoximes require a solvent
containing nitrile to synthesize the corresponding nitrile
compounds. Inspired by recent reports on the enzymatic
Scheme 1. Proposed reaction mechanism of nitrile synthesis in CH3CN.[11b]
synthesis under nitrile-free conditions, we here describe
that a simple iron salt catalyzes the dehydration of aldox-
imes requiring neither other reagents nor nitrile media.
This indicates that CH3CN will be a good receptor for the
Our method can be applied to the one-pot synthesis of ni-
oxime hydroxyl group to generate the corresponding nitrile;
tiriles from aldehydes.
indeed, solvent containing the nitrile group was required to
synthesize nitrile from aldoxime.[17] However, this fact has not
been referred to in most reports in which Lewis acid-catalyzed
Nitriles are important compounds found in pharmaceuticals,
natural products, polymers and textiles.[1] The Sandmeyer reac-
tion is a powerful tool for synthesizing aromatic nitriles from
metal cyanide and diazo compounds[2] but requires more than
a stoichiometric amount of highly toxic metal cyanide. Recent-
ly, methodologies for synthesizing nitriles not requiring cya-
nide compounds have been developed, for example, for the
ammoxidation of methyl arene[3] and alcohol,[4] and the dehy-
dration of amide.[5] The dehydration of aldoximes to nitriles is
a particularly environmentally benign method, giving water as
the only by-product. Although this reaction cannot remove
water from aldoxime easily, stoichiometric dehydrating re-
agents such as Burgess reagent,[6] BOP/DBU,[7] PPh3/CCl4,[8]
Tf2O/pyridine,[9] and ynamine[10] allow the dehydration of aldox-
imes to proceed smoothly. However, water does not appear in
situ when these reagents are used, and remaining dehydrating
reagent reacts with the hydroxyl group of aldoxime to form a
by-product. In contrast, catalytic syntheses have been achieved
using Cu(OAc)2,[11] Ru,[12] Ga(OTf)3,[13] Pd(OAc)2,[14] Bi(OTf)3,[15] (3-
FC6H4Se)2/H2O2,[16] and InCl3.[17] Interestingly, most of these cata-
lytic reactions were performed in CH3CN, and both Kim and
Hell et al. proposed similar reaction mechanisms where aceto-
nitrile reacted with aldoxime to give the corresponding nitrile
and acetamide from acetonitrile (Scheme 1).[11b,14a]
dehydration of aldoxime in CH3CN was performed. To our
knowledge, there are only two examples in which a dehydra-
tion reaction of aldoximes was achieved using only catalyst in
non-acetonitrile media without loading stoichiometric re-
agents.[18] In 2002, Yamamoto and Ishihara et al. reported the
first dehydration reaction of aldoximes to nitriles by rheniumVII
oxo complexes in toluene.[18a] Later, Mizuno and co-workers
performed this reaction with a heterogeneous W-Sn hydroxide
catalyst in o-xylene.[18b]
Meanwhile, Rhodococcus sp. YH3-3 was isolated from soil by
Asano et al., and the enzyme aldoxime dehydratase can syn-
thesize nitrile by the dehydration of aldoximes under nitrile-
free conditions.[19] The crystal structure of this enzyme revealed
the following dehydration mechanism: the FeII heme in the
active site and the surrounding amino acid residues cooperate
to remove one water molecule from aldoxime.[20] Inspired by
this natural system, we speculated that iron would also exhibit
a high catalytic activity for the non-enzymatic dehydration of
aldoximes. Therefore, we aimed at mimicking the environmen-
tal reaction to synthesize nitriles by using an iron catalyst as
well as aldoxime dehydratase under mild conditions. In this
work, as the initial step, we attempted simple iron salt-cata-
lyzed reactions by satisfying the following two conditions:
1) absence of stoichiometric amounts of reagents and 2) ab-
sence of a nitrile-containing solvent such as CH3CN to achieve
nitrile-free conditions (Figure 1).[21]
[a] Dr. K. Hyodo, S. Kitagawa, M. Yamazaki, Prof. Dr. K. Uchida
Department of Material Chemistry
Faculty of Science and Technology
Ryukoku University
(E)-2-Naphthaldoxime 1a[22] was dehydrated using several
iron salts (10 mol%) in toluene under reflux (Table 1). No reac-
tion occurred in the absence of catalyst (entry 1), and a very
small amount of nitrile was observed when FeO and Fe(O)OH
were used (entries 2, 3). In contrast, FeBr3, Fe(OAc)2, Fe(O-
H)(OAc)2, Fe(acac)3, Fe(ClO4)2·6H2O, FeSO4·7H2O and Fe(OTf)2
Seta, Otsu, Shiga 520-2194 (Japan)
E-mail: hyodo@rins.ryukoku.ac.jp
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600085.
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Communication
ic aldoxime possessing an electron-donating group or halogen
gave the desired products in high yield (entries 3–8) whereas
aldoximes with an electron-withdrawing group were less reac-
tive, with unreacted aldoxime remaining (entry 9). Bulky aro-
matic aldoximes were converted to the desired nitrile in good
yield (entries 10–13), and aliphatic aldoxime also smoothly un-
derwent dehydration in this reaction system (entries 14, 15).
Next, we attempted one-pot synthesis of nitrile 2 catalyzed
by Fe(OTf)3 catalyst through dehydrated condensation reac-
tions of aldehydes with hydroxylamine (Table 3).[25] In the pres-
ence of Fe(OTf)3 (10 mol%), the reaction of 2-naphthaldehyde
3a and hydroxylamine sulfate gave the corresponding nitrile
2a in good yield (entry 1); by contrast , the reaction proceeded
insignificantly in the absence of Fe(OTf)3, affording aldoxime
1a in a low yield of 5% (entry 2). As a result, we found that
Fe(OTf)3 also promoted the formation of aldoximes from alde-
hyde and hydroxylamine. Aromatic aldehydes having an elec-
tron-donating group or halogen gave the desired products in
good yield (entries 3, 4). Bulky aromatic and aliphatic alde-
hydes were also converted into corresponding nitriles with
good yield (entries 5, 6).
Figure 1. Methods for the dehydration of aldoximes.
Table 1. Dehydration of (E)-2-naphthaldoxime catalyzed by various iron
catalysts.[a]
The effect of protecting groups on the aldoxime hydroxyl
group was also investigated (Scheme 2). We chose two kinds
of protecting groups for oxime 1a: the acetyl group as an
Entry
Catalyst
Conv. [%][b]
Select. [%]
1
–
0
–
2
FeO
1
0
3
4
5
6
7
8
9
10
11
12
13
14[d]
15[e]
Fe(O)OH
FePC[c]
FeCl3
6
53
59
76
78
92
74
80
88
75
> 99
> 99
> 99
50
34
25
51
51
48
50
41
31
57
70
80
92
FeBr3
Fe(OAc)2
Fe(OH)(OAc)2
Fe(acac)3
Fe(ClO4)2·6H2O
FeSO4·7H2O
Fe(OTf)2
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Scheme 2. Effect of protecting groups of aldoximes.
electron-withdrawing group and the methyl group as an elec-
tron-donating group. Protection with an acetyl group allowed
the reaction to proceed very quickly, whereas methyl oxime
ether gave a low yield of product after 24 h.[26] These results in-
dicate that electron density on the oxygen atom plays an im-
portant role in removing water, acetic acid or methanol from
the aldoxime to produce the corresponding nitrile. Based on
these results, we assumed that Fe(OTf)3 would probably work
as a Lewis acid[27] and coordinated the oxygen atom of aldox-
ime to promote the dehydration reaction. This proposed cata-
lytic system would be much different from that of aldoxime
dehydratase, which prefers a ferrous-ion-coordinated nitrogen
atom to the ferric-ion-coordinated oxygen atom on the aldox-
ime observed in the current investigation.[19a,28]
[a] Reaction conditions: 1a (0.29 mmol), iron catalyst (10 mol%) in tolu-
ene (0.40m, 0.73 mL) under reflux (oil bath temp.: 1258C) for 24 h.
[b] Conversion was determined by 1H NMR spectroscopy from unreacted
aldoximes. [c] PC: phthalocyanine. [d] Performed in 0.20m toluene.
[e] Performed in 0.05m toluene.
provided over 70% conversion, but the selectivity was low as
evidenced by the generation of by-products such as amide
and aldehyde derived from oxime (entries 6–12). However,
when Fe(OTf)3 was used as a catalyst, good conversion and
moderate selectivity were observed (entry 13). The best con-
version and selectivity were obtained when the reaction con-
centration of aldoxime 1a was decreased from 0.40m to
0.05m (entry 15).[23]
We investigated the possibility of the intermolecular reaction
between aldoxime 1a and nitrile 2a at higher concentrations
of 2a as well as the dehydration reaction of aldoximes in
CH3CN shown in Scheme 1. To confirm these reactions, nitrile
2a was added to a mixture of aldoxime 1a and Fe(OTf)3 in tol-
uene (0.40m) beforehand, and the dehydration of aldoxime
was conducted under reflux for 24 h (Table 4). Contrary to our
We next examined the scope and limitation of substrates
1a–1o (Table 2) in the presence of Fe(OTf)3 catalyst.[24] Aromat-
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Table 2. Scope of various (E)-aldoximes in the dehydration reaction cata-
lyzed by Fe(OTf)3.[a]
Table 2. (Continued)
Entry
15[f]
Substrate 1
Product 2
t [h] Yield [%][b]
Entry
1
Substrate 1
Product 2
t [h] Yield [%][b]
nC11H23CH=NOH
1o
nC11H23CN
2o
24
92
24
24
24
92 (85)[c]
[a] Reaction conditions: 1 (0.15 mmol), Fe(OTf)3 (10 mol%) in toluene
(0.05m, 2.9 mL) under reflux (oil bath temp.: 1258C). [b] Yield was deter-
mined by 1H NMR spectroscopy using an internal standard. [c] Isolated
yield is shown in parentheses. [d] E/Z ratio of 1e was 98:2. [e] E/Z ratio of
1n was 56:44. [f] E/Z ratio of 1o was 99:1.
2
84
3
82
Table 3. One-pot synthesis of nitrile 2 catalyzed by Fe(OTf)3.[a]
4
24
24
24
48
48
48
6
85 (74)
94
5[d]
Entry
1
Substrate
Product
t [h]
Yield [%][b]
80 (82)
10
6
84
2[c]
24
24
3
7
92
3
72 (72)
8
85 (71)[c]
4
24
76 (75)
9
47
5
6
24
24
96 (85)
90 (68)
10
88 (75)
nC9H19CHO
3n
nC9H19CN
2n
[a] Reaction conditions:
Fe(OTf)3 (10 mol%) in toluene (0.05m, 3.2 mL) under reflux (oil bath
temp.: 1258C). [b] Yields were determined by H NMR spectroscopy using
an internal standard and isolated yields are shown in parentheses.
[c] Without Fe(OTf)3.
3 (0.16 mmol), (NH2OH)2·H2SO4 (0.16 mmol),
11
12
48
24
92 (77)
1
90 (77)[c]
prediction, the production of amide 5a did not increase; the
conversion decreased as the amount of nitrile 2a was in-
creased and some aldoxime 1a remained unreacted after 24 h
(entries 2, 3). These results suggest that a high concentration
of nitrile 2a inhibits the catalytic activity by coordinating with
Fe(OTf)3; therefore, a lower concentration of 2a would be re-
quired in order to avoid coordination between 2a and
Fe(OTf)3.[29,30]
13
48
24
86 (69)[c]
nC9H19CH=NOH
1n
nC9H19CN
2n
14[e]
82
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Table 4. Investigation of intermolecular reaction between aldoxime and
nitrile.[a]
Keywords: aldehydes
catalyst · nitrile synthesis
· aldoximes · dehydration · iron
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0.5
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>99
86
73
70
75
72
8
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General Procedure for the Synthesis of Nitriles 2: To a flame-
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1
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Acknowledgements
This work was financially supported by Ryukoku University and
the Science and Technology Fund and by the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan (MEXT)
as a Supported Program for the Strategic Research Foundation
at Private Universities (S1311040). We are grateful to Prof. S.
Nakamura (Nagoya Institute of Technology) for giving an op-
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[22] Isomerization between (E)-1a and (Z)-1a using the current reaction
conditions was observed by TLC even if only (E)-1a or (Z)-1a was used
as the starting material. Thus, mixtures of isomers could be used with-
out problem. However, it is unknown whether isomer E or Z is suitable
for this reaction (see the Supporting Information).
AcOH (1.0 equiv), Fe(OTf)3 (10 mol%) in toluene under reflux; however,
the yield decreased to 74% (92% without AcOH).
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TfOH generated from the hydrolysis of Fe(OTf)3) we directly monitored
the reaction mixtures by 19F NMR spectroscopy in [D8]toluene. The fact
that we could observe a peak of Fe(OTf)3 provides weak evidence of
Fe(OTf)3 as catalytic species (see the Supporting Information).
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[23] See the Supporting Information about ligands and solvent effects as
well as scale-up.
[24] Under these reaction conditions, most of aldoximes were completely
consumed, and therefore the selectivity was equal to the yield of corre-
sponding nitriles except for 1i (selectivity: 58%). A trace amount of 3,5-
disubstituted-1,2,4-oxadiazole was observed as a by-product in this re-
action, which makes it difficult to purify crude mixtures to isolate nitrile
by silica gel column chromatography.
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[26] AcOH, which is generated as a by-product through the dehydration of
4a, is also known to promote the dehydration of aldoximes as a cata-
lyst, see ref. [21a]. Therefore, we attempted the reaction with 1a and
[30] When CH3CN was used instead of toluene as solvent, the yield of nitrile
2a was decreased and amide 5a was not observed (see the Supporting
Information).
Manuscript received: January 22, 2016
Accepted Article published: February 22, 2016
Final Article published: March 30, 2016
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