Novel oxidative nitrogen to carbon rearrangement found in the conversion of anilines to benzaldoximes by treating with HCHO/H2O2

Article abstract of DOI:10.1016/j.tetlet.2008.03.033

Novel rearrangement was found by reacting anilines with HCHO/H₂O₂ resulting in the synthesis of various benzaldoximes. The mechanism of the rearrangement is proposed and suggested that the rearrangement might proceed via unstable N-phenyloxazirane intermediate followed by the transfer of aryl moiety from nitrogen to carbon atom leading to the formation of benzaldoxime.

Full text of DOI:10.1016/j.tetlet.2008.03.033

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2886–2890
Novel oxidative nitrogen to carbon rearrangement found
in the conversion of anilines to benzaldoximes by
treating with HCHO/H2O2
Naval Kapuriya a, Kalpana Kapuriya a, Narsinh M. Dodia a, Yi-Wen Lin a,
Rajesh Kakadiya a, Chao-Ting Wu a, Ching-Huang Chen a, Yogesh Naliapara b,
Tsann-Long Su a,*
a Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
b Department of Chemistry, Saurashtra University, Rajkot, India
Received 1 February 2008; revised 3 March 2008; accepted 6 March 2008
Available online 10 March 2008
Abstract
Novel rearrangement was found by reacting anilines with HCHO/H2O2 resulting in the synthesis of various benzaldoximes.
The mechanism of the rearrangement is proposed and suggested that the rearrangement might proceed via unstable N-phenyloxazirane
intermediate followed by the transfer of aryl moiety from nitrogen to carbon atom leading to the formation of benzaldoxime.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Rearrangement; Amines; Oxidation; Peroxides; Benzaldoximes
1. Introduction
acetaldehyde and glyoxal), organic acids (formic, methoxy-
acetic, acetic, glycolic, glyoxylic and oxalic acids) and the
mono- and diformate ester of ethylene glycol.12 In view
of the structures of benzaldoximes (3) generated from ani-
lines, one can envisage that the formation of these com-
pounds requires a one-carbon source. Hence, it suggested
that formaldehyde generated from long stored 1,4-dioxane
might be a key one-carbon source involved in the reaction.
To mimic the transformation of anilines to benzaldoximes,
we have reacted anilines with ethylene glycol or glycerol in
the presence of hydrogen peroxide. The results showed that
benzaldoximes (3) were obtained under these reaction con-
ditions. Finally, we found that compound 3 can also be
prepared by reacting anilines with paraformaldehyde
followed by the treatment of the products 1,3,5-triphenyl-
hexahydro-s-triazines (2) with H2O2. From these studies,
we found a novel oxidative nitrogen-to-carbon rearrange-
ment of the N-aryl group in compounds having N–C–C
system (Scheme 1). The results of the new synthetic route
for benzaldoximes (3) are reported herein.
During the course of our research on the synthesis of
heterocyclic compounds, we surprisingly found that ani-
lines were converted into the corresponding benzaldoximes
when heated in over-aged 1,4-dioxane (purchased 12 years
ago). It prompted us to investigate the actual reactant(s)
involved in this novel transformation, although benzaldox-
imes can be easily synthesized by reacting benzaldehydes
with hydroxylamine hydrochloride as described previ-
ously.1–3
It is known that 1,4-dioxane can induce a chain radical
reactions under thermal,4 chemical oxidation (i.e., NaClO,
O3/H2O2),5,6 photochemical7–9 or sonolysis10,11 producing
several intermediates including aldehydes (formaldehyde,
*
Corresponding author. Tel.: +886 2 2789 9045; fax: +886 2 2782 5573.
E-mail address: tlsu@ibms.sinica.edu.tw (T.-L. Su).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.033

N. Kapuriya et al. / Tetrahedron Letters 49 (2008) 2886–2890
2887
version of anilines to benzaldoximes required one carbon
source, such as formaldehyde. Many studies have been
reported concerning the production of formaldehyde from
polyhydroxy compounds. For example, polyhydroxylated
alcohols (i.e., glycerol) and vicinal diols (i.e., ethylene
glycol) were oxidized by microsomes isolated from rat liver
to formaldehyde together with an aldehyde with less
carbon atoms. The reaction was catalyzed in the presence
of H2O2 and iron.13–15 These studies demonstrated that
H2O2 play an important role in the overall pathway for oxi-
dizing ethylene glycol or glycerol to formaldehyde. To
mimic the generation of formaldehyde in a biological sys-
tem, we treated anisidines (1b,c,d) and toluidines (1e–g)
with ethylene glycol or glycerol with 30% H2O2 in the
freshly distillated 1,4-dioxane. We were able to isolate ben-
zaldoximes (3b–g) in moderate yields from these experi-
ments (Table 1). In general, the amount of benzaldoximes
(3) generated from the reaction of ethylene glycol or glyc-
erol/H2O2 has no significant difference. It demonstrates
that both agents can liberate formaldehyde upon treatment
with H2O2. To understand that 1,4-dioxane is not involved
in the reaction under the applied reaction conditions, we
used toluene as the solvent instead of 1,4-dioxane, similar
results were observed. It should be noted that the
known benzaldoximes (3) were isolated as mixture of E/Z
diastereomers, which were determined by 1H NMR
spectrophotometric analysis. It revealed that the E/Z ratio
of benzaldoximes (3b–g) synthesized by all three methods
were almost identical (Table 2).
over-aged 1,4-dioxane,
ethylene glycol, glycerol
[O]
R
HCHO
R
H
º
80
C
NH2
1a-g
N
OH
3a,b,c,d,e,f,g,
HCHO/ Dioxane/Reflux
30% H2O2/
Dioxane/Reflux
R
N
N
N
R
R
2b,c,d,e,f,g
Scheme 1. a: R = H; b: 2-OMe; c: 3-OMe; d: 4-OMe; e: 2-Me; f: 3-Me; g:
4-Me.
2. Results and discussion
A mixture of an appropriate aniline (1a,d) in over-aged
1,4-dioxane was heated at 80 °C. The reaction discontinued
after 12 h, but can be re-ignited by adding more 1,4-diox-
ane. After the removal of solvent, the residue was
chromatographed on a silica gel column to give benzaldox-
imes (3a,d) as the major products (Scheme 1). However,
when the same reactions carried out in the freshly distil-
lated 1,4-dioxane (pretreated with KOH), no reaction
was observed even in the presence H2O2. This indicated
that the reactants (formaldehyde or peroxides) appeared
in the over-aged 1,4-dioxane were removed during the
pretreatment with KOH and/or distillation processes.
To find a way to reproduce benzaldoximes (3) directly
from anilines was necessary since we have limited amount
of over-aged 1,4-dioxane. One can anticipate that the con-
The reaction of anilines with formaldehyde is of greater
interest. Giumanini and Verardo16,17 reported that reacting
anilines with paraformaldehyde afforded 1,3,5-triphenyl-
perhydro-s-triazines (2, Scheme 1) in toluene under reflux.
Triazines 2 may be the key intermediate for constructing
benzaldoximes (3). To study the conversion of anilines to
benzaldoximes in a stepwise manner, we prepared triazines
by reacting anilines (1a–g) with paraformaldehyde
Table 1
Reaction of anilines (1b–g) with ethylene glycol or glycerol/H2O2 in freshly distillated 1,4-dioxane, reaction conditions and yields of compound 3
Reactant-1a Reactant-2b Solvent (mL) dioxane 30% H2O2 (mL) Reaction time (days) Product (yield, %) E/Z ratio mp (°C)/Reference
Compound 3
1b
1c
1d
1e
1f
Ac
Bd
A
B
A
B
A
B
A
B
100
100
100
100
20
20
60
60
20
10
10
10
10
2
2
10
6
4
6
4
6
3
4
2
4
1
3
3
3
2
3
1
1
3b (9.2)
3b (6.6)
3c (33)
100:18
100:18
100:40
100:40
100:29
100:29
100:40
100:40
100:38
100:38
100:33
100:33
3b (83–84)26
3c (43–44)27
3d (73–75)28
3e (52–54)29
3f (oil)30
3c (29)
3d (27.8)
3d (31.2)
3e (25.1)
3e (27.6)
3f (16.3)
3f (19.9)
3g (31.1)
3g (43.9)
60
20
60
1g
A
B
3g (50–51)31
a
b
c
Reactant-1 (1 equiv).
Reactant-2 (4 equiv).
A = Ethylene glycol.
B = Glycerol.
d

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N. Kapuriya et al. / Tetrahedron Letters 49 (2008) 2886–2890
Table 2
Reaction of anilines (1b–g) (1 equiv), with paraformaldehyde (1.2 equiv)/
H2O2 in freshly distillated 1,4-dioxane: reaction conditions and yields of
compound 3
H
R
R
R
R
2
N
H
N
H
N
H
NH2
1
Anilines Solvent (mL) 30% H2O2 Reaction
Product
(yield %)
E/Z
ratio
O
HO
dioxane
(mL)
time (h)
H
H
H
6
5
4
1b
1c
1d
1e
1f
70
60
50
60
60
60
2
2
2
2
2
2
3
3
2.5
2.5
3
3b (35.3)
3c (21)
3d (55.1)
3e (46)
3f (28)
3g (61.2)
100:18
100:40
100:29
100:40
100:38
100:33
R
-H
R
R
1g
2.5
H
H
H
H
N
O
N
O
N
H
H
OH
3
(1.2 equiv) by following the method described previ-
ously.16,17 In some cases, we were able to isolate the tri-
azine derivatives (2a,d,g) as crystal form, which were
further treated with H2O2 in the freshly distillated 1,4-diox-
ane to give benzaldoximes (3a,d,g). The overall yields of
3a,d,g were better when the intermediate triazines (2a,d,g)
were not isolated and directly treated with H2O2. Thus,
the desired benzaldoximes (3b–g) were prepared in better
yields in comparison with what were obtained from other
synthetic routes by treating anilines (1b–g) with parafor-
maldehyde, followed by direct reacting with H2O2 (Table
2).
The Stieglitz rearrangement has been widely studied.
Compounds involved in this carbon-to-nitrogen rearrange-
ment usually consist of an ‘Ar-C–N’ skeleton. Hoffmann
et al. reported that the Stieglitz rearrangement of tritylam-
ines, benzhydrylamines and benzyl amines can be induced
by p-nitrobenzensulfonyl peroxide or N-(arylsulfon-
oxy)amine.18,19 They postulated a mechanism for the rear-
rangement and demonstrated that the aryl migration from
carbon to nitrogen atom is concerted with the loss of the
arylsulfonate leaving group to form arylenamines.
As previously described, benzaldoximes (3) can be pre-
pared by heating anilines in old-aged 1,4-dioxane, formal-
dehyde or with triazines 2 in the presence of H2O2 possibly
via an aryl migration. Early reports by Emmons20 and
others showed that triazines 2 were unstable and can be
thematically convert into Schiff base 4 bearing an ‘Ar-N–C’
back bone. Thus, a plausible reaction mechanism for the
synthesis of compounds 3 is proposed as shown in Scheme
2. The initiate intermediate of the reaction would be the
Schiff bases (4), which may be delivered from triazines 2
upon heating. Early studies showed that Schiff base can
be oxidized by peracetic acid to oxazirane (5) in a similar
manner as of oxidation of alkenes to epoxides.19,20 The tri-
azine or Schiff base is possibly transformed into oxaziranes
(5) upon treatment with hydrogen peroxide. Since the com-
mercially available hydrogen peroxide (30%) is acidic in
nature, under such reaction conditions, oxaziranes (5) are
subsequently converted into the unstable intermediates 6,
which lead to the formation of the transition state 7. This
proposed structure illustrates that the N-aryl moiety prefer-
entially migrates to the positively charged primary carbon,
leading to the formation of intermediates 8, which are
further converted into benzaldoximes (3).
7
8
Scheme 2. The proposed mechanism for the rearrangement of aryl group
in phenyloxaziranes.
3. Conclusion
In the current study, we surprisingly found an alternative
synthetic route for benzaldoximes (3) by the reaction of ani-
lines with paraformaldehyde/H2O2 or triazine/H2O2. These
were obtained in moderate yields in a mixture of diastereo-
meric E/Z isomers with a ratio of about 100:30 in most
cases. It indicated that the method lacks stereo-selectivity
for the formation of E/Z isomers. However, we found a
novel oxidative nitrogen-to-carbon rearrangement in oxa-
ziranes (5), from which benzaldoximes (3) were prepared.
4. Experimental
Melting points were determined on a Fargo melting
point apparatus and are uncorrected. Column chromato-
graphy was carried out on Silica Gel G60 (70–230 mesh,
ASTM; Merck and 230–400 mesh, Silicycle Inc.). Thin-
layer chromatography was performed on Silica Gel G60
254 (Merck) with short-wavelength UV light for visualiza-
tion. Elemental analyses were done on a Heraeus CHN–O
Rapid instrument. H NMR spectra were recorded on a
F
1
600 MHz, Brucker AVANCE 600 DRX and 400 MHz,
Brucker Top-Spin spectrometers. The chemical shifts were
reported in ppm (d) relative to TMS.
4.1. Reaction of anilines (1a,d) with over-aged 1,4-dioxane
A mixture of aniline (1a, 10 mmol) in over-aged 1,4-
dioxane (50 mL) was heated at 80 °C for 5 days. After all
aniline was consumed, the reaction mixture was evaporated
in vacuo to dryness and the residue was chromatographed
on a silica gel column using hexane/EtOAc (100:30 v/v) as
the eluent to give known benzaldoxime (3a): yield 0.427 g
(35%) as an oil.24,25
4.2. 4-Methoxybenzaldoxime (3d)
Compound 3d was prepared from 4-anisidine (1d,
10 mmol) in over-aged 1,4-dioxane (50 mL) by following

N. Kapuriya et al. / Tetrahedron Letters 49 (2008) 2886–2890
2889
the same procedure as that for 3a. Yield 0.805 g (53.3%),
mp 73–75 °C (Lit.28 mp 73–74 °C).
was again heated to reflux for 2–3 h. After completion of
reaction, the reaction mixture was evaporated to dryness
under reduced pressure and the residue was chromato-
graphed on a silica gel column (solvent: CHCl3/MeOH,
100:1 v/v). The fractions containing the main product were
combined and evaporated to dryness to yield the corre-
sponding benzaldoximes (3b–g). The yields of each product
are shown in Table 2.
4.3. General procedure for the synthesis of benzaldoximes
(3b–g) by the reaction of anilines (1b–g) with ethylene
glycol or glycerol/H2O2
A mixture of an appropriate anilines (1b–g, 1 equiv),
ethylene glycol (4 equiv) or glycerol (4 equiv) and 30%
H2O2(0.5 mL/1 mmol of aniline) in freshly distillated 1,4-
dioxane was heated at reflux for an appropriate time as
indicated in Table 1. After the reaction is completed, the
reaction mixture was evaporated to dryness and the desired
product was isolated by column chromatography (SiO2,
hexane/EtOAc, 100:30 v/v). The yields of 3b–g are shown
in Table 1.
Acknowledgements
This work was supported by the National Science Coun-
cil, Taiwan (Grant No. NSC 95-2320-B-001-025-MY3).
The NMR spectra of the synthesized compounds were
obtained at High-Field Biomacromolecular NMR Core
Facility supported by the National Research Program for
Genomic Medicine (Taiwan). We would also like to thank
Dr. Shu-Chuan Jao in the Institute of Biological Chemistry
at Academia Sinica for providing the NMR service. In
addition, we are grateful to the National Center for
High-performance computing for computer time and
facilities.
4.4. General procedure for the synthesis of benzaldoximes
(3a,d,g) by reacting 1,3,5-triphenylperhydro-s-triazines
(2a,d,g) with H2O2
To a solution of known 1,3,5-triphenylperhydro-s-tri-
azine (2a, 0.945 g, 3 mmol)21 in freshly distillated or newly
purchased 1,4-dioxane (50 mL) was added dropwise 30%
H2O2 (1 mL) at room temperature. The mixture was then
heated at reflux temperature until all starting material
was consumed (2–3 h). The reaction mixture was evapo-
rated to dryness under reduced pressure and the residue
was chromatographed on a silica gel column (solvent:
CHCl3/MeOH, 100:1 v/v). The fractions containing the
main product were combined and evaporated to dryness
to yield the corresponding benzaldoximes (3a), 0.197 g
(54.3%), which is identical with one previously synthesized.
By following the same procedure as that for 3a, the
following compounds were prepared.
Supplementary data
Characterization data, a copy of 1H and 13C NMR
spectrum of each compound and copy of HMBC spectrum
of compound 3a,d. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.03.033.
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