A Facile Synthesis of N -Alkoxyacylimidoyl Halides from α-Nitro Ketones and Alkyl Halides in the Presence of NaHSO4/SiO2

Article abstract of DOI:10.1055/s-0036-1588914

A novel method was developed for the synthesis of N-alkoxyacylimidoyl halide by the reaction of α-nitro ketone and alkyl halides in the presence of NaHSO₄/SiO₂. Nitrile oxides that are generated from α-nitro ketones by silica gel sup

Full text of DOI:10.1055/s-0036-1588914

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
T. Aoyama et al.
Letter
Synlett
A Facile Synthesis of N-Alkoxyacylimidoyl Halides from α-Nitro
Ketones and Alkyl Halides in the Presence of NaHSO4/SiO2
Tadashi Aoyama*a
Ken-ichi Itohb
Yuri Furukawaa
Mamiko Hayakawaa
Shigeru Shimadac
Akihiko Ouchia
O
O
NaHSO4/SiO2
N
R2
R1 = aryl, thienyl, alkyl
X
+
NO2
R1
OR2
R1
toluene (10 mL)
80 °C, 8 h
X
up to 88% yield
17 novel compounds
R
2 = tert-alkyl, diphenylmethyl
a Department of Materials and Applied Chemistry, College of Science
and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku,
Tokyo 101-8308, Japan
aoyama.tadashi@nihon-u.ac.jp
b Department of Liberal Arts and Science, College of Science and
Technology, Nihon University, 7-24-1, Narashinodai, Funabashi-shi,
Chiba 274-8501, Japan
c National Institute of Advanced Industrial Science and Technology
(AIST), Tsukuba, Ibaraki 305-8565, Japan
Received: 05.09.2016
Accepted after revision: 23.10.2016
Published online: 21.11.2016
alkylation of amidoxime was carried out in order to obtain
O-methyl-α-methoxyphenyl acetamidoxime; (3) the latter
was then converted into the hydroximoyl chloride by nitro-
sative deamination in the presence of chloride ion; (4) the
final step was the transformation of the α-methoxy group
into a ketone functional group by reaction of the hydroxi-
moyl chloride with N-bromosuccinimide (NBS) in the pres-
ence of a small amount of concentrated hydrobromic acid.10
In this report, 3 was considered as a potential precursor
for the preparation of heterocyclic compounds because it
contains two functional groups that can react with nucleo-
philes at the same time. Applicability of this useful synthet-
ic precursor, 3, will be extended if more simple synthetic
methods for 3 are developed.
DOI: 10.1055/s-0036-1588914; Art ID: st-2016-u0585-l
Abstract A novel method was developed for the synthesis of N-alkoxy-
acylimidoyl halide by the reaction of α-nitro ketone and alkyl halides in
the presence of NaHSO4/SiO2. Nitrile oxides that are generated from α-
nitro ketones by silica gel supported acid catalysts are the possible in-
termediate, which react with alkyl halides to form N-alkoxyacylimidoyl
halides. Novel 17 N-alkoxyacylimidoyl halides were synthesized by this
procedure.
Key words alkoxyacylimidoyl halide, nitrile oxide, solid acid, one pot,
stereoselective
N-Alkoxyimidoyl halides (3′) are very useful synthetic
intermediate because they can be transformed into various
functional groups1 and heterocycles,2 and they are also em-
ployed for the C–C bond formations.3 Generally 3′ are syn-
thesized by the halogenation of O-alkyl benzaldoximes by
using N-halosuccinimide, in which O-alkyl benzaldoximes
were prepared by the alkylation of benzaldehyde oxime1f,4
or by the reaction of benzaldehyde with O-alkyl hydroxyl-
amine5 (Scheme 1, a, method A).6 N-Alkoxyimidoyl halides
(3′) are also synthesized by the reaction of hydroxamates
using phosphorus pentachloride,7 or phosphorus tribro-
mide/bromine,8 or triphenylphosphine/tetrahalomethane9
(Scheme 1, a, method B). Although several methods for the
synthesis of N-alkoxyimidoyl halides have been reported,
only one report describes the preparation of N-alkoxya-
cylimidoyl halide (3); 3 (X = Cl) was prepared from α-me-
thoxyphenylacetonitrile in four steps (Scheme 1, b), name-
ly, (1) amidoxime was prepared from the reaction of α-me-
thoxyphenyl acetonitrile with hydroxylamine; (2)
Solid acid catalysts have many advantages such as easy
handling, easy isolation of the products and separation of
the catalysts. Recently, we have reported various organic
transformations, such as alkylation of β-dicarbonyls11 and
aromatics,12 cross-coupling of alcohols,13 Ritter reactions,14
C–C bond cleavage15 and construction of heterocycles,16 by
using silica gel supported sodium hydrogensulfate (NaHSO4/
SiO2) as solid acid catalyst. We herein report, for the first
time, a simple one-pot synthesis of 3 from α-nitro ketones
and alkyl halides using NaHSO4/SiO2 (Scheme 2).
The reaction of α-nitroacetophenone (1a, 1 equiv) with
tert-butyl bromide (2a, 6 equiv) was carried out in the pres-
ence of NaHSO4/SiO2 (1 equiv; Table 1). The desired product
3aa was obtained in 86% yield in cyclohexane at 80 °C for
eight hours (Table 1, entry 1). To optimize the reaction con-
dition, several solvents were tested; namely, 1,2-dichlo-
roethane, mono- and dichlorobenzenes and toluene. All sol-
vents tested gave 3aa in moderate to good yield (Table 1,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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T. Aoyama et al.
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Table 1 Optimization of the Reaction Conditions for the Synthesis of 3
a) General method for the synthesis of N-alkoxyimidoyl halide
O
O
Method A
acid
Br
2a (6 mmol)
N
+
NO2
Ph
O
Ph
N
Ph
1a (1 mmol)
solvent (10 mL)
80 °C, 8 h
OH
Br
3aa
H
Ph
N
Ph
N
NXS
OR
OR
Entry Acid
Amount
Solvent
Yield
(%)a
X
X = Cl, Br
H
O
3'
1
2
NaHSO4/SiO2
1 mmol
cyclohexane
86
55
88
69
87
30
62
20
49
69
NR
20d
0e
Ph
H
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
NaHSO4/SiO2
H2SO4
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
0.1 g
1,2-dichloroethane
monochlorobenzene
o-dichlorobenzene
toluene
Method B
O
3
R1
N
4
PPh3/CX4
X = Cl, Br
OMe
N
OMe
R1
N
H
5
X
3'
6
toluene
R1
N
R1
7
TsOH·H2O
toluene
PCl5 or Br2, PBr3
NaI
OMe
OMe
b
8
PPA/SiO2
toluene
Br
3' (X = Br)
I
c
9
SA/SiO2
1 mmol
0.2 g
toluene
3' (X = I)
10
11
12
13
14
Amberlyst 15®
NaHSO4·H2O
SiO2
toluene
b) A method for the synthesis of N-alkoxyacylimidoyl halide
1 mmol
0.5 g
toluene
toluene
OMe
N
OMe
OMe
CN
H2NOH
NaOH
N
ZnCl2/SiO2
none
1 mmol
–
toluene
(Me)2SO4
Ph
OMe
Ph
OH
Ph
toluene
NR
NH2
NH2
a Yields were determined by GLC.
HCl
NaNO2
b Silica gel supported polyphosphoric acid was employed.
c Silica gel supported sulfamic acid was employed.
d No reaction took place.
O
OMe
NBS
HBr, H2O
N
e Reaction time was 16 min.
N
Ph
OMe
Ph
OMe
Cl
Cl
3
6 and 7) and heterogeneous (Table 1, entries 8–10) condi-
tions but the reaction using a grained NaHSO4·H2O (Table 1,
entry 11) was not effective. Silica gel also catalyzed the re-
action to afford 3aa in 20% yield (Table 1, entry 12). Howev-
er, when silica gel supported zinc chloride (ZnCl2/SiO2) was
used, tert-butyl toluene was formed by a Friedel–Crafts re-
action instead of the expected product (Table 1, entry 13).
In the reactions of tert-butyl halides (Table 2), the use of
c) This work
O
O
NaHSO4/SiO2
N
R2
X
R1
OR2
NO2
+
R1
X
1
2
3
Scheme 1 The synthetic methods for N-alkoxyimidoyl halide
a)
O
O
O
O
O
NaHSO4/SiO2
N
Ph
Ph
R2
X
R1
OR2
NO2
+
R1
Ph
O
+
+
1a
+
+
2b
2c
3ab
X
3
8 h
1
2
N
N
N
O
7%
O
O
5
4
38%
Scheme 2 Synthesis of N-alkoxyacylimidoyl halides from 1 and 2
21%
b)
O
N
O
entries 2–5). Although a high yield was obtained with cy-
clohexane, it was not an ideal solvent because of the poor
solubility of 1a and 2a.
Therefore, we have used toluene as the standard sol-
vent. Several acids were also tested. Brønsted acids promot-
ed this reaction under both homogeneous (Table 1, entries
1a
+
Ph
Ph
24 h
N
I
O
3ac
27%
4
>8%
Scheme 3 Reaction using 2b and 2c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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O
O
NaHSO4/SiO2
N
+
NO2
R
O
Br
toluene (10 mL)
80 °C, 8 h
R
Br
1b–m
2a
3ba–ma
O
O
O
O
N
N
N
N
O
O
O
O
Br
Br
Br
Br
MeO
Br
O2N
3ba: 79%
3ca: 82%
3da: 79%
3ea: 86%
O
O
O
O
N
N
N
N
S
S
S
O
O
O
O
Br
Br
Br
Br
Br
3fa: 83%
3ga: 85%
3ha: 88%
3ia: 86%
O
O
O
O
N
N
N
N
O
O
O
O
3
7
Br
Br
3ka: 39%
Br
3la: 61% (24 h)
Br
3ma: 53% (24 h)
3ja: 66%
Scheme 4 Synthesis of 3 using various α-nitro ketones
tert-butyl chloride (2b) in place of 2a gave the correspond-
ing 3ab in 7% yield along with 38% yield of 3-benzoyl-5,5-
dimethylisoxazoline (4) and 21% yield of 3,4-dibenzoyl-
1,2,5-oxadiazole 2-oxide (5; Scheme 3, a). Compound 5 was
formed by a dimerization of benzoylmethyl nitrile oxide
(6),17 which was confirmed by a selective formation of 5 by
carrying out the reaction in the absence of 2. In the reaction
using tert-butyl iodide (2c), only a trace amount of 3ac was
formed, but many unidentified by-products were formed.
The low yield of 3ac was rationalized by secondary re-
actions of labile 3ac with a large excess of 2c. Therefore, we
carried out this reaction by using 1.2 equivalents of 2c
against 1a and obtained 27% yield of 3ac along with >8% of
4 (Scheme 3, b). When 2-bromo-2-methylbutane (2d) was
used, 3ad was formed in 67% yield. On the other hand, sec-
ondary and primary alkyl bromides, 3-bromopentane (2e)
and n-bromopentane (2f), did not give the corresponding
3ae and 3af but 5 was formed in these reactions. When
bromodiphenylmethane (2g) was used for the reaction, p-
diphenylmethyl toluene was formed by a reaction with the
solvent in place of the expected 3ag. However when 1,2-di-
chloroethane was used in place of toluene to avoid the reac-
tion with the solvent, 3ag was formed in 33% yield. The re-
actions using benzyl bromide (2h) were carried out in tolu-
ene or in 1,2-dichloroethane, but the expected 3ah or
alkylated toluene was not detected. In this reaction, 5 was
formed as a major product. The scope of the reaction was
investigated using various α-nitroketones with 2a (Scheme
4). 1-Aryl-2-nitroethanones and 2-nitro-1-(2-thienyl)etha-
nones were converted into the corresponding N-tert-bu-
toxyacylimidoyl bromides in good yields (3ba–ia). Reac-
tions using 1-alkyl-2-nitroethanones also gave the corre-
sponding products but with lower yields than those of 1a–j.
In the reactions of 1l and 1m, which have longer alkyl
chains, longer reaction time was required for the complete
consumption of the starting materials.
1H NMR spectra showed that all products consisted of a
single stereoisomer in regard to the C=N double bond. X-ray
crystal structure analyses of 3ag, 3fa and 3ja revealed that
the products were Z-isomers (Figure 1). Scheme 5 shows a
plausible reaction pathway for the reaction of 1a with 2a.
Bz
Bz
N+
N
O–
O
5
acid
Bz
NO2
Bz
C
N
O
6
1a
Bz
N
Ot-Bu
Br
Z-isomer
Scheme 5 Proposed reaction pathway for the synthesis of 3
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Table 2 Synthesis of 3 Using Several Alkyl Halides
O
O
NaHSO4/SiO2
NO2
N
R
X
+
Ph
Ph
OR
toluene (10 mL)
80 °C, 8 h
1a
2a–h
X
3aa–ah
Entry
1
2 (mmol)
Time (h) Yield (%)a
Br
Cl
I
2a
2b
2c
2c
2d
6.0
6.0
6.0
1.2
6.0
8
8
3aa
3ab
3ac
3ac
3ad
81
7
2
3
4
5
8
trace
27
67
I
24
8
Br
Br
6
7
2e
2f
6.0
6.0
8
8
3ae
3af
NDb
NDb
Br
Br
8
9
2g
2h
1.2
1.2
8
8
3ag
3ah
0 (33)c
Ph
Ph
Ph
Br
Figure 1 ORTEP drawings (50% probability ellipsoids) of 3ag, 3fa and
3ja
NDb
a Isolated yield.
b The product was not detected.
c 1,2-Dichloroethane was used as a solvent.
the first time.22 Seventeen novel compounds were easily
synthesized by this procedure in good yields, and the prod-
ucts had Z-stereochemistry in regard to the C=N double
bond. Further investigations about a detailed reaction path-
way and application for heterocycle synthesis are now in
progress.
First, nitrile oxide (6) is formed from 1a by dehydration
with acid. In the absence of 2a or in the presence of less re-
active primary or secondary alkyl bromides, 6 is easily di-
merized to 5. On the other hand, in the presence of 2a, the
Z-isomer of 3aa is formed. The formation of 6 is supported
by our previous report; that is a synthesis of isoxazoles
from 1a and alkynes occurred in the presence of an acid, in
which 6 was generated in situ and trapped an alkyne in or-
der to obtain isoxazoles.18 Until today, 6 were mainly stud-
ied on 1,3-dipolar addition with unsaturated compounds,
such as olefins, acetylenes, carbonyl compounds, and Schiff
bases.19 As for the reactions of 6 with nucleophiles, some
reactions with hydrogen halides,17 amines,20 acid anhy-
dride20 and thiols21 have been reported. However, to the
best of our knowledge, our present report is the first exam-
ple of the reaction of 6 with alkyl halides. The detailed
pathway for the formation of the Z-isomer is now under in-
vestigation.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588914.
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References and Notes
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In conclusion, we have developed a simple one-pot syn-
thesis of N-alkoxyacylimidoyl halides (3) from α-nitro ke-
tones and alkyl halides in the presence of NaHSO4/SiO2 for
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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(22) Typical Procedure for the Synthesis of N-Alkoxyacylimidoyl
Halide: A mixture of α-nitro ketone 1 (1 mmol), alkyl halide 2
(6 mmol) and NaHSO4/SiO2 (2.1 mmol/g, 0.5 g) in toluene (10
mL) was stirred at 80 °C for 8 h, and then the used supported
reagent was removed by filtration. The filtrate was evaporated
to leave the crude product, which was purified by column chro-
matography (hexane–EtOAc) to obtain N-alkoxyacylimidoyl
halide 3 (see Supporting Information).
Typical Data for Representative Compound; N-Diphenyl-
methyloxy(benzoylformimidoyl Bromide) (3ag): white solid;
1
mp 71–72 °C (n-hexane). H NMR (400 MHz, CDCl3): δ = 7.62–
(10) Johnson, J. E.; Maia, J. A.; Tan, K.; Ghafouripour, A.; de Meester,
P.; Chu, S. S. C. J. Heterocycl. Chem. 1986, 23, 1861.
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68, 7077.
7.64 (m, 2 H), 7.49–7.53 (m, 1 H), 7.34–7.42 (m, 10 H), 7.24–
7.28 (m, 2 H), 6.46 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ =
183.6, 139.6, 134.2, 133.5, 131.1, 130.9, 128.6, 128.3, 128.1,
127.5, 89.2. IR (neat): 1665, 1559 cm–1. HRMS (ESI, MeOH): m/z
[M + Na] calcd for C21H16NO2NaBr: 416.0262; found: 416.0264.
Anal. Calcd for C21H16NO2Br: C, 63.97; H, 4.09; N, 3.55. Found: C,
64.06; H, 3.95; N, 3.53.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E