Investigation of O-Sulfonylation-promoted Heterolytic N?O Bond Cleavage of Amidoximes and Ketoximes

Article abstract of DOI:10.1002/jccs.201700104

Two different reaction pathways were observed in the sulfonylation of N-phenylbenzamidoximes. The reaction with o-NsCl at a heating temperature gave N,N′-diphenylureas via Tiemann rearrangement, while the reaction with Ts₂O at a lower temperature formed 2-phenylbenzimidazoles via intramolecular electrophilic aromatic substitution. When the amide nitrogen was replaced with carbon substituents, oxime derivatives of benzoins and benzils underwent Beckmann fragmentation reactions upon sulfonylation, whereas sulfonylation of 2-phenylacetophenone oxime afforded exclusively the Beckmann rearrangement adduct.

Full text of DOI:10.1002/jccs.201700104

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Investigation of O-Sulfonylation-promoted Heterolytic N O Bond Cleavage
of Amidoximes and Ketoximes
Tsung-Han Hsieh, Pen-Yuan Liao, Yu-Ting Liu, Chien-Hong Wang, Chia-Chi Lin
*
and Tun-Cheng Chien
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
(Received: March 22, 2017; Accepted: May 11, 2017; DOI: 10.1002/jccs.201700104)
Two different reaction pathways were observed in the sulfonylation of N-phenylbenzamidoximes.
The reaction with o-NsCl at a heating temperature gave N,N0-diphenylureas via Tiemann rear-
rangement, while the reaction with Ts2O at a lower temperature formed 2-phenylbenzimidazoles
via intramolecular electrophilic aromatic substitution. When the amide nitrogen was replaced with
carbon substituents, oxime derivatives of benzoins and benzils underwent Beckmann fragmenta-
tion reactions upon sulfonylation, whereas sulfonylation of 2-phenylacetophenone oxime afforded
exclusively the Beckmann rearrangement adduct.
Keywords: Tiemann rearrangement; Beckmann rearrangement; Beckmann fragmentation;
Electrophilic aromatic substitution.
Tun-Cheng Chien received his B.S. degree in Chemistry from National Taiwan University, Taipei, Taiwan in
1991, M.S. degree in Pharmacy from National Defense Medical Center, Taipei, Taiwan in 1995, and Ph.D.
degree in Chemistry from The University of Michigan, Ann Arbor, MI, USA in 2004. He completed his post-
doctoral training at College of Pharmacy, The University of Texas, Austin, TX, USA and joined the faculty in
Department of Chemistry, National Taiwan Normal University (NTNU), Taipei, Taiwan in 2006. His
research interests focus on (1) organic, medicinal and biological chemistry of nucleosides and nucleotides;
(2) heterocyclic chemistry.
Sulfonylation of oxime derivatives can be dated
back to 1891 when Tiemann1 and Pinnow2 both reported
the reaction of benzamidoxime with PhSO2Cl to afford
phenylurea,3 which is known as Tiemann rearrangement.
In 1904, Werner reported that benzonitrile was obtained
simply by the dehydration of benzaldoxime with
PhSO2Cl,4 while Wege reported in 1891 that N-
phenylbenzamide was formed from the reaction of benzo-
phenone oxime with PhSO2Cl via Beckmann rearrange-
ment (Scheme 1).4,5 The above-mentioned reactions were
all initiated by O-sulfonylation of the oxime followed by
the heterolytic cleavage of the N O bond, but diverse
reaction outcomes were observed from different reaction
substrates. Except the reaction of aldoximes, sulfonyla-
tion of amidoximes and ketoximes triggered the
subsequent C C bond disconnections to furnish the rear-
ranged adducts.
Our previous investigation established that sulfo-
nylation of carboxamidoximes with TsCl or o-NsCl
under anhydrous condition afforded exclusively the N-
substituted cyanamides via Tiemann rearrangement.6
The proposed mechanism starts with O-sulfonylation of
carboxamidoximes followed by the N O bond cleavage
with the concomitant alkyl/aryl group migration over
the C N bond to furnish the N-substituted cyanamides
(Scheme 1(e)).7 The success also prompted us to explore
the reaction outcomes from the sulfonylation of other
oxime derivatives.
Sulfonylation of N-aryl carboxamidoximes was
brought to our attention as an extension of our previous
*Corresponding author. Email: tcchien@ntnu.edu.tw
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Article
Hsieh et al.
rearrangement adducts were not observed from their
reported reactions.
Previously, we had found that tosylation of N-
phenyl-4-methoxybenzamidoxime (1ac) with TsCl gave
a complicated result, while the reaction of N-phenyl-4-
nitrobenzamidoxime (1ae) under the same condition
gave only 2-(4-nitrophenyl)benzimidazole (2ae) in 20%
yield (TsCl (1.05 equiv), DIPEA (1.05 equiv), CH2Cl2
(0.1 M); 0ꢀC– rt; 3 h).6 The rearranged adducts, either
carbodiimides or ureas, were not observed in both reac-
tions. Since we devoted our initial effort to pursuing
the Tiemann rearrangement, o-NsCl was employed
instead of TsCl with a higher temperature to facilitate
the rearrangement. The designated condition allowed
Tiemann rearrangement of N-phenyl carboxamidox-
imes (1aa–ae) to proceed, and the corresponding N,N0-
disubstituted ureas (3aa–ae), presumably hydrolyzed
from the corresponding carbodiimides, were obtained
in good yields.6
Accordingly, we observed two different reaction
outcomes, Tiemann rearrangement and 2-substituted
benzimidazole formation, from sulfonylation of N-
aryl carboxamidoximes. Both reactions can be ratio-
nalized as starting with the O-sulfonylation of the
carboxamidoximes. Subsequently, heterolytic cleavage
of the N O bond to form the putative nitrene inter-
mediate immediately followed by two different modes
of reaction. A direct intramolecular electrophilic aro-
matic substitution between the nitrene species and
the N-aryl ring carbon would give the 2-substituted
benzimidazoles, whereas the Tiemann rearrangement
would lead to the formation of ureas/carbodiimides.
In our continuous effort to explore the sulfonylation
of oxime derivatives, we further examined the O-
sulfonylation reaction of N-aryl carboxamidoximes in
order to chemoselectively alter the reaction pathway
toward the formation of 2-substituted benzimidazoles.
The reactions of N-phenyl-4-nitrobenzamidoxime
(1ae) with a series of sulfonylating reagents under var-
ious conditions, including different bases, solvents,
and reaction concentrations, were screened to optimize
the electrophilic ring-closure reaction. N-Phenyl-4-
methylbenzamidoxime (1ab) was also subjected to opti-
mization to fine-tune the reaction condition (part of the
results is summarized in Table 1). The optimum condition
was to carry out the reaction with 1.2 equiv of Ts2O and
2.5 equiv of Et3N in THF from −20ꢀC to room
Scheme 1. Sulfonylation of amidoximes, aldoximes,
and ketoximes. (a) Tiemann1 and Pinnow1;
(b) Werner4; (c) Wege5 and Werner4;
(d) Partridge8 and Yamamoto9; (e) Partridge8
and Chien6.
study on carboxamidoximes (Scheme 2).6 By analogy to
the Tiemann rearrangement of carboxamidoximes, car-
bodiimides or N,N0-disubstituted ureas would be antici-
pated as the products from sulfonylation of N-aryl
carboxamidoxime derivatives. However, Partridge
reported that sulfonylation of N-phenylbenzamidoxime
with PhSO2Cl gave 2-phenylbenzimidazole in 88%
yield.8 Yamamoto further demonstrated that sulfonyla-
tion of N-aryl carboxamidoximes with p-toluenesulfonic
anhydride (Ts2O) afforded solely 2-substituted benzimi-
dazoles (Scheme 1(d)).9 It is noteworthy that the
Scheme 2. Tiemann rearrangement of N-phenylbenza-
midoximes (1)6.
2
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Sulfonylation of Oxime Derivatives
Table 1. Optimization for 2-substituted benzimidazole formation
Entry
R
ArSO2X (1.2 equiv)a
Base (2.5 equiv)
Solvent (M)b
Yield (%)c
1
2
3
4
5
6
7
8
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
Me
Me
Me
Me
Me
Me
Me
TsCl
TsCl
TsCl
TsCl
PhSO2Cl
p-NsCl
o-NsCl
4-MeOPhSO2Cl
Ts2O
MsCl
TIPSCl
Ts2O
MsCl
TIPSCl
Ts2O
Ts2O
Ts2O
DIPEA
DIPEA
DIPEA
CH2Cl2 (0.4)
THF (0.4)
CH3CN (0.4)
Pyridine (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.1)
THF (0.1)
CH2Cl2 (0.1)
CH2Cl2 (0.1)
68
75
42
29
74
74
63
68
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
9
85 (75)d
0 (70)d,e
77 (65)d
46
10
11
12
13
14
15
16
17
18
0 (60)d,f
40
72d
DIPEA
Et3N
DIPEA
50d
40d
Ts2O
31d
a ArSO2X: TsCl = p-toluenesulfonyl chloride; o- or p-NsCl = o- or p-nitrobenzenesulfonyl chloride; Ts2O = p-toluenesulfonic
anhydride; MsCl = methanesulfonyl chloride; TIPSCl = 2,4,6-triisopropylbenzenesulfonyl chloride.
b Reaction concentration (M).
c Unless specified otherwise, the yields were determined by 1H NMR analysis of the crude products using 1,3,5-
trimethoxybenzene as an internal standard.
d Isolated yield.
e O-mesyl-N-phenyl-4-nitrobenzamidoxime was obtained.
f N-(4-methylphenyl)-N0-phenylurea was obtained.
temperature in 4 h (entry 15, Table 1), which was a modi-
fied condition from Yamamoto’s protocol.9 Ts2O was
found to be superior to all the other tested sulfonyl
chloride reagents, which suggested that the non-
nucleophilic counter-anion existing in the reaction mixture
is beneficial to the electrophilic ring-closure pathway.
The optimized condition was then applied to a
series of N-aryl bezamidoximes in order to survey the
scope and generality of the reaction (Scheme 3). The
results indicated that the reaction yields were dependent
on the electronic nature of the substituents on benzami-
doximes (R1), which was consistent with our previous
observation
that
electron-withdrawing
arene-
carboxamidoximes disfavored the rearrangement reac-
tion and, therefore, can be readily directed to the benzi-
midazole formation pathway.
Originally, we expected that increase of the
π-electron density on the N-aryl ring carbon would
Scheme 3. Formation of 2-phenylbenzimidazoles (3).
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Article
Hsieh et al.
facilitate the electrophilic ring-closure reaction. In a direct
comparison between N-aryl 4-nitrobenzamidoximes 1ae
and 1be, we found that increasing the π-electron density
on the N-aryl substituent (R2) did not enhance the ring-
closure reaction. Furthermore, the reaction of N-(4-meth-
oxyphenyl)-4-methoxybenzamidoxime (1bc) under the
same condition did not proceed to the formation of benzi-
midazole, but underwent Tiemann rearrangement to give
exclusively N,N0-di-(4-methoxyphenyl)urea (3bc) (Scheme
3). The result further illustrated that the electron-donating
property on the amide nitrogen side of carboxamidox-
imes also has a stronger tendency to undergo Tiemann
rearrangement and, thus, disfavored the ring-closure
pathway.
In an effort to investigate the role of the amide
nitrogen in the ring-closure reaction of N-aryl car-
boxamidoximes, the amide nitrogen was replaced
with carbon substituents and, thus, a series of ketox-
imes (4,5a,6a), derived from 2-phenylacetophenone,
benzoin, and benzil, were subjected to the same con-
dition to explore the reaction outcomes. The reaction
of 2-phenylacetophenone oxime (4) under our stand-
ard condition afforded exclusively the Beckmann
rearrangement adduct N-phenyl-2-phenylacetamide
(9) in a good yield. Meanwhile, the reaction of ben-
zoin oxime (5a) underwent Beckmann fragmenta-
tion4,10 to form benzonitrile (10a) and benzaldehyde
(11a) as the products, while the reaction of benzil
oxime (6a) under the same condition gave a compli-
cated result. None of the above reactions afforded the
intramolecular electrophilic ring-closure adducts
(Scheme 4).
Scheme 5. Beckmann fragmentation of benzoin
oximes (5).
unidentified products.11 We adopted our previous
approach of using electron-withdrawing benzenesulfo-
nyl chlorides for the electron-deficient α-oxo-ketoximes
with increasing temperature for the reaction. As a
result, sulfonylation of benzil oximes 6a,d with p-NsCl
in CH2Cl2 afforded presumably the O-(p-nitrobenzene-
sulfonyl) adducts (13) in the reaction. The solvent was
changed to CH3CN and the reaction mixture was
heated at 70ꢀC to undergo the subsequent fragmenta-
tion reaction4,12 to give benzonitriles 10 in good yields
(Scheme 6).
In summary, we demonstrated five different reaction
types derived from the sulfonylation of oxime derivatives
(Figure 1). Our investigation showed that, upon sulfonyla-
tion of the oximes, only N-aryl carboxamidoximes (1) can
undergo the intramolecular electrophilic aromatic substi-
tution reaction to form the corresponding C N bond. In
the absence of the amide nitrogen and the lack of a strong
base in the reaction,13,14 heterolytic N O bond cleavage
of ketoximes 4–6 predominantly triggered the subsequent
C C bond dissociation between the oxime carbon and
the neighborintg carbons to undergo Beckmann rear-
rangement or fragmentation reactions. We postulated that
the amide nitrogen provided a resonance stabilization for
the putative nitrene species formed after the heterolytic
cleavage of the N O bond and allowed the electrophilic
The reaction condition for Beckmann fragmenta-
tion of benzoin oxime (5a) was slightly modified and
applied to benzoin oximes4,10 5a,d to afford the corre-
sponding benzonitriles 10 and benzaldehydes 11 in
good yields (Scheme 5). A quick screening for various
sulfonylations of benzil oxime (6a) showed that the O-
sulfonylated adducts were formed, accompanied by
Scheme 6. Beckmann fragmentation of benzil
Scheme 4. Sulfonylation of 2-phenylacetophenone
oximes (6).
oximes (4–6).
4
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Sulfonylation of Oxime Derivatives
General procedure for Beckmann fragmentation of benzil
oxime (6)
To the mixture of benzil oxime (6) and Et3N (2.5
equiv) in CH2Cl2 (0.1 M) at 0ꢀC was added p-NsCl (1.2
equiv). The mixture was stirred for 7 h under nitrogen
while the temperature was allowed to rise to room tem-
perature. The solvent was concentrated under reduced
pressure and the residue was dissolved in CH3CN
(0.1 M). To the above solution was added Et3N (1.2
equiv) at room temperature. The resulting solution was
stirred at 70ꢀC for 4 h. After cooling to room tempera-
ture, the yields of volatile products were determined by
HPLC. The reaction mixture was concentrated under
reduced pressure and the residue was purified by flash
column chromatography.
Fig. 1. Reaction types derived from sulfonylation of
oxime derivatives.
nitrogen to be captured by the N-aryl ring carbon. Further
application of this electrophilic ring-closure approach
would be useful for the synthesis of a variety of 2-
substituted benzimidazole derivatives.
ACKNOWLEDGMENT
EXPERIMENTAL
General procedure for the preparation of N,N0-diarylurea
(3) from N-aryl benzamidoxime (1)6
This work was supported by Research Grants
MOST 105-2113-M-003-003- and MOST 104-2113-M-
003-001- from Ministry of Science and Technology,
Taiwan.
To the mixture of N-aryl benzamidoxime (1) and
DIPEA (1.2 equiv) in CH3CN (0.1 M) at 0ꢀC was
added o-NsCl (1.20 eq). The mixture was stirred at 0ꢀC
for 10 min and then at 65ꢀC for 3 h under nitrogen.
After cooling to room temperature, the reaction mix-
ture was concentrated under reduced pressure and the
residue was purified by flash column chromatography.
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Article
Hsieh et al.
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Neber
rearrangement
of
2-
phenylacetophenone oximes: (a) T. Li, F. Xu, X. Li,
6
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