Iodine-Promoted Semmler–Wolff Reactions: Step-Economic Access to meta-Substituted Primary Anilines via Aromatization

Article abstract of DOI:10.1002/chem.201701712

An atom- and step-economic access to an array of unprotected meta-substituted primary anilines was disclosed using the Semmler–Wolff reaction, promoted by molecular iodine. Therein, noble metal catalysts and inert atmosphere are unnecessary while the forcing reaction conditions and the lengthy synthesis can be avoided. The synthetic utility of this approach is evident in the de novo syntheses of three bioactive molecules with good total yields.

Full text of DOI:10.1002/chem.201701712

A Journal of
Accepted Article
Title: Iodine-promoted Semmler-Wolff reactions: step economic access
to meta-substituted primary anilines via aromatization
Authors: Shi-Ke Wang, Xia You, Da-Yuan Zhao, Neng-Jie Mou, and
Qun-Li Luo
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To be cited as: Chem. Eur. J. 10.1002/chem.201701712
Link to VoR: http://dx.doi.org/10.1002/chem.201701712
Supported by

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COMMUNICATION
Iodine-promoted Semmler−Wolff reactions: step economic
access to meta-substituted primary anilines via aromatization
Shi-Ke Wang,[a] Xia You,[a] Da-Yuan Zhao,[a] Neng-Jie Mou[a] and Qun-Li Luo*[a]
Abstract: An atom and step economic access to an array of
unprotected meta-substituted primary anilines was disclosed via the
Semmler−Wolff reaction promoted by molecular iodine, in which
noble metal catalysts and inert atmosphere are unnecessary while
the forcing reaction conditions and the lengthy synthesis can be
avoided. The synthetic utility of this approach is evident in the de
novo syntheses of three bioactive molecules with good total yields.
catalysts and inert atmosphere were necessary for the
aromatization step (Scheme 1b).[9]
To date, almost all of the Semmler−Wolff reactions required
either strong Brønsted acids or transition metal as promoters,
and were conducted in two steps.[8, 9] In continuation of our work
on the iodine-mediated methodologies for organic synthesis,[10]
we unprecedentedly realized a dehydrative aromatization of
cyclohex-2-enone oximes through a metal-free one-step protocol
(Scheme 1c). This protocol provided a practical route from
inexpensive commercial chemicals to the unprotected meta-
substituted primary anilines.
Aromatic amines are prevalent in our society at scales ranging
from the laboratory bench to the industrial manufacture of fine
and bulk chemicals. They are widely used in various fields as
intermediates for the manufacture of numerous chemical
products such as pharmaceuticals, agrochemicals, dyes,
surfactants, polymers and flame retardants.[1] Metal-catalyzed
C−N cross-coupling with aryl halides, arylboronic acid
derivatives, or other substituted arenes provides reliable
methods for the synthesis of secondary and tertiary aryl
amines.[2] Primary aryl amines play a key role as intermediates
in chemical synthesis. However, direct introduction of the
unprotected amino functionality is recognized as a key challenge
through the strategies of C−N cross-coupling.[3] The general
approach to prepare ortho- and para-substituted primary anilines
normally relies on the reduction of nitro arenes,[4] but
regiospecific synthesis of meta-substituted counterparts through
such approach frequently suffered from tedious multistep
synthesis due to the regioselectivity in aromatic substitution
chemistry.[5] Accordingly, amination/aromatization of cyclohex-2-
enones has been appropriate for an alternative choice, enabling
good yields of variously substituted secondary and tertiary aryl
amines in concise routes.[6] Nevertheless, the advances on the
related methods to directly afford the primary amines are
frustrating.[7] The condensation of ketones with ammonia is not
as favored as that with a primary or secondary amine.[6b] The
oxidative aromatization of the imines derived from cyclohex-2-
enones with ammonia is expected to form the mixtures of phenol
and aniline products. It is unlikely that primary anilines could be
prepared by a similar approach.
Scheme 1. Semmler−Wolff reactions for the syntheses of meta-substituted
primary anilines.
At the start of the investigation, the model reaction of
cyclohex-2-enone oxime 1a was explored to optimize the
reaction conditions (Table S1).[11] The reaction in DMSO at 60 oC
led to the decomposition of substrate, accompanied by the 3,5-
diaryl phenol in low yield. No intended product in toluene was
obtained albeit the decomposition became slow. When
increasing the reaction temperature to 100 oC, the desired
aniline (2a) was isolated in low yield. The reaction became
complicated when the temperature was elevated to reflux in
toluene or to 120 oC in DMF. We then screened some polar
solvents of boiling point ranging from 60 to 110 oC (Table 1,
entries 1–4). The results were better in ether solvents than that
in others at the temperature higher than 80 oC, and the best
solvent was DME. The outcome under acidic conditions was
slightly inferior to that under neutral conditions, whereas the
reaction did not occur in the presence of base. By the use of 1.5
equivalents of iodine, the reaction became more efficient as
demonstrated by thin-layer chromatography (TLC) and the yield
slightly increased (entry 5). The experiments on halogen source
screening showed that NIS was less efficient than molecular
iodine, whereas NCS, NBS and iodides were unworkable. Based
on an overall consideration of the investigated parameters, we
established optimized conditions. The aromatization was
accomplished under refluxing for 24 h in DME using 1.5
equivalents of molecular iodine.
The Semmler−Wolff reaction is a classic method for the
synthesis of protected primary aryl amines in which
hydroxylamine is conveniently used as the ammonia surrogate,
but it is rarely utilized, particularly in relation to the harsh
reaction conditions and low yields (Scheme 1a).[8] In order to
avoid the use of strong Brønsted acids, the variant methods
underwent the indirect protocols by the conversion of oximes to
O-acyl oximes in advance, but trialkyl phosphine-coordinated Pd
[a]
S.-K. Wang, X. You, D.-Y. Zhao, N.-J. Mou, Prof. Dr. Q.-L. Luo
Key Laboratory of Applied Chemistry of Chongqing Municipality,
College of Chemistry and Chemical Engineering, Southwest
University,
Chongqing 400715 (P. R. China)
E-mail: qlluo@swu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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reported. The present protocol provides a facile route to meta-
substituted 3-aminobenzoic acids and their derivatives.
Table 1. Optimization of the reaction conditions [a]
Table 2. Substrate scope of iodine-promoted Semmler−Wolff reaction[a]
entry
I2 (equiv.)
1.2
solvent
MeCN
DME
T (oC)[b]
82
Yield (%)
entry
R1
4-CH3OC6H4-
Ph-
R2
Ph-
1/2
Yield (%)
65
1
2
3
4
5
55
60
0
1
2
3
4
5
6
7
8
1a/2a
1b/2b
1c/2c
1d/2d
1e/2e
1f/2f
1.2
85
Ph-
67
1.2
THF
66
4-CH3C6H4-
4-ClC6H4-
2-naphthalenyl
2-furanyl
Ph-
Ph-
63
1.2
1,4-dioxane
DME
101
85
53
65
Ph-
64
1.5
Ph-
61[b]
60[b]
58
[a] Reaction conditions: 1a (0.2 mmol), solvent (1 mL) under ambient air.
Isolated yields are given. [b] The boiling point of the corresponding solvent.
Ph-
4-CH3OC6H4-
4-CH3C6H4-
1a’/2a
1c’/2c
1g/2g
Ph-
60
We then applied the optimized conditions to a series of
oximes (1) and were pleased to successfully achieve a diverse
array of meta-substituted primary anilines (Table 2). In general,
3,5-diaryl-substituted cyclohex-2-enone oximes performed
effectively in the transformation (entries 1–13). For the 3,5-
diaryl-substituted substrates, the electronic (entries 2 vs 1, 3–4)
and steric (entries 5 vs 6) effects of R1 had few influences on the
reactions, whereas an electron-withdrawing R2 was slightly
superior to an electron-donating one (entries 10 vs 7–9). An
alkyl substituent at the 2- or 6-position of substrates hardly
impacted the yields of aromatization (entries 12 vs 1, entries 13
vs 2, respectively).
Following the protocol, two bioactive m-terphenyl amines with
sulfur-containing substituents were straightforward obtained
(entries 14–15). Compounds 2l and 2m were identified as
selective inhibitors of COX-1.[12] The previous syntheses of 2l
and 2m included steps of the deprotection of amino and the
remove of cyano that were carried out at the temperature as
high as 220 oC under high pressure in strong alkaline
solutions.[5a] Luckily, we de novo synthesized the two
compounds with widely available and inexpensive reagents in
concise routes. In each step, the reaction conditions were
relatively mild, heavy metal reagents were not used, and it was
unnecessary to protect any functional groups.
Pleasingly, a 5-aryl substituted 3-aminobenzoic acid and its
derivatives were prepared successfully (entries 16–19). Esters
could tolerate the reaction conditions (entry 17) despite of the
fact that a compound containing ester functionality is labile to
aminolysis under the conditions of heating.[10c] 3-Amino-5-
arylbenzoic acids and their derivatives are prevalent as
structural motifs and intermediates in drug discovery. Their
preparations were mainly available in the patent literature in
which frequent transformations of functional group were
involved.[13] A straightforward access to them has not been
Ph-
57
9
10
11
Ph-
4-nitrophenyl
4-ClC6H4-
1h/2h
1i/2i
69[c]
70[b]
2-thiopheneyl
12
13
1j/2j
66[c]
1k/2k
67[b]
Ph-
Ph-
14
15
1l/2l
52[b]
54[b]
1m/2m
16
17
18
19
20
21
22
23
24
Ph-
-CO2H
-CO2Et
1n/2n
1o/2o
1p/2p
1q/2q
1r/2r
63
65
Ph-
Ph-
-CONHPh
-CONHBn
Ph-
57
Ph-
Me-
53
35[b]
35[b]
34[b]
41[b]
48[b]
Me-
4-BrC6H4-
4-CH3OC6H4-
Ph-
1s/2s
1t/2t
Me-
H-
1u/2u
1v/2v
4-CH3OC6H4-
H-
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14]
radical or other iodine species causes iodo imine C1,[10d,
[a] Reaction conditions: 1 (0.2 mmol), I2 (0.3 mmol), DME (1 mL), under
ambient air for 24 h unless otherwise stated. R3 = 4-MeOC6H4-. Isolated
yields are given. [b] For 36 h. [c] For 48 h.
which subsequently generates imine D via the elimination of HI.
The two paths can not be ruled out at the current stage.[18, 19]
Remarkably, the conjugated effect of substituents at the 3-
and 5-positions of the cyclohexene ring highly impacted on the
reactions. The yields significantly decreased when either R1 or
R2 was a nonconjugated substituent, i.e., a hydrogen atom or an
alkyl (entries 20–24 vs 1–19). Improving the yields of 2r–2v was
unsuccessful despite several attempts under various reaction
conditions.
Compared with the traditional Semmler−Wolff reaction, our
method required neither the harsh conditions of strong Brønsted
acids in the aromatization step, nor the extra step of acid/base
hydrolysis for the cleavage of acyl protected group(s). Unlike
Stahl’s variant, the present transformations did not require strict
atmospheric controls, extra derivations of substrates, and Pd
catalyst systems sensitive to air. The reaction installation was as
simple as in a common reaction tube with a condenser. After
oximes 1 were completely consumed as monitored by TLC, the
mixtures were quenched with aqueous sodium thiosulfate and
subjected to the conventional aqueous work-up and purification
with column chromatography on silica gel. Such procedure
represents an example in which the experiment process is facile
to operate and the reaction results are well repeatable. Overall,
our protocol ranks among the most benign method suggested
for the Semmler−Wolff reaction.
Scheme 2. Proposed mechanism.
The
control
experiments
indicated
that
2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) totally inhibited the
transformation (Equation 1), but butylated hydroxytoluene (BHT)
hardly affected the yield of the reaction (Equation 2).
Scheme 3 De novo synthesis of anticancer agent 6. Reaction conditions: (a)
NaOH, EtOH, r.t., 6 h. (b) acetone, NaOMe, Ar, 50 oC, 4 h. (c) (i) NH2OH∙HCl,
Lei and co-workers proved that the conjugated radical
intermediates were possibly produced from ketone oxime
derivatives under heating.[14] The trap of a radical by TEMPO will
lead to the quench of radicals (Scheme 2a).[15] However, the
reaction of BHT with a radical will form BHT radical that is able
to abstract a hydrogen atom from a certain radical (via radical
disproportionation) or molecule (via radical relay), as shown in
Scheme 2b.[16] Therefore, our observations are preliminarily in
agreement with a radical mechanism (Scheme 2c). The I2-
mediated homolysis of N-O bond in oxime A gives imine radical
B,[17] which may quickly isomerize to -carbon radical C via 1,3-
H shift.[14, 17] Radical C undergoes two possible paths. In path a,
the abstract of one hydrogen atom on C by a radical (e.g., iodine
radical) leads to imine D that tautomerizes to the final product E.
Such path is similar to the disproportionation of free radicals in
Scheme 2b.[16] In path b, the -iodination of radical C by iodine
AcONa, MeOH, reflux,
4 h; (ii) I2 (150 mol%), DME, reflux, 24 h. (d)
CHCl2CO2H, I2, P(OMe)3, NEt3, DCM, 0 oC to r.t., 3 h.
The utility of our methodology was further exemplified in the
synthesis of terphenyl-derived bioactive molecules (Scheme 3).
2,2-Dichloroacetanilides that the phenyl was substituted at both
the 3- and 5-positions, especially compound 6, showed efficient
anticancer activity.[20] The previous route involved the Pd-
catalyzed Suzuki coupling of substituted phenylboronic acids
with N-haloaryl amides. However, the coupling was very
inefficient due to the low activity of the haloarenes. The isolated
yield of the coupling step for 6 was as low as 36% even by the
use of an iodoarene.[20] Meanwhile, the haloarenes required to
be synthesized in multiple steps due to their commercial
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In conclusion, an iodine-promoted protocol for the
Semmler−Wolff reaction is developed, which is particularly
efficient for the concise preparation of unprotected meta-
[11] See the Supporting Information.
substituted primary anilines under mild conditions. As
a
[12] J. D. Baue, M. S. Foster, J. D. Hugdahl, K. L. Burns, S. W. May, S. H.
Pollock, H. G. Cutler, S. J. Cutler, Med. Chem. Res. 2007, 16, 119–129.
[13] For the examples of patents involving the preparations of 3-amino-5-
arylbenzoic acid derivatives, see: a) F. J. Lopez-Tapia, D. Nitzan, C.
O'Yang, WO 2002070500 A1; b) M. Hoener, J. Wichmann, WO
2016169902 A1.
consequence, several bio-interesting molecules or intermediates
were de novo synthesized in good total yields. The high atom
and step economy, benign reaction conditions, wide availability
of reagents, low cost of chemicals, structural diversity of
products, and no requirements of heavy metal catalysts make
the method a green[22] and favorable alternative to prepare
primary aryl amines that contain functionalities or substituents at
the meta-positions of amino.
[14] J. Ke, Y. Tang, H. Yi, Y. Li, Y. Cheng, C. Liu, A. Lei, Angew. Chem. Int.
Ed. 2015, 54, 6604–6607; Angew. Chem. 2015, 127, 6704–6707.
[15] W.-T. Li, W.-H. Nan, Q.-L. Luo, RSC Adv. 2014, 4, 34774–34779.
[16] For the disproportionation of butylated hydroxytoluene radical, see: M. G.
Willcockson, M. M. Toteva, V. J. Stella, J. Pharm. Sci. 2013, 102, 3579–
3585.
Acknowledgements
[17] Imine radical B could be formed in the presence of molecular iodine, see:
H. Huang, J. Cai, L. Tang, Z. Wang, F. Li, G.-J. Deng, J. Org. Chem. 2016,
81, 1499–1505.
The authors thank the financial support from the National
Natural Science Foundation of China (20971105), the Science
Foundation of Chongqing Science & Technology Commission
(cstc2017jcyjAX0423), and the Experimental Technology
Foundation of Southwest University (SYJ2016019)
[18] a) The experiments on halogen source screening showed that molecular
iodine was much more efficient than NBS and NCS (Table S1, entries 12–
16). These results could be explained with the persistent radical effect.
Compared with bromine and chlorine radicals, iodine radical is relatively
stable (persistent radical), and can be reversibly produced from molecular
iodine via heating. The abstract of one hydrogen atom on radical C
(transient radical)[14] by iodine radical may result in imine D (path a). Such
transformation is similar to the radical disproportionation.[16] On the other
hand, path b that the coupling of radical C (transient radical) with iodine
radical (persistent radical) lead to iodo imine C1 is also possible, which is
similar to the radical/radical cross-coupling pathway reported by Lei et al.[14]
b) For reviews of persistent radical effect, see: H. Fischer, Chem. Rev.
2001, 101, 3581–3610.
Keywords: amines • aromatization • enones • iodine • synthetic
methods
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Entry for the Table of Contents
COMMUNICATION
I2 worked: An atom and step
Shi-Ke Wang, Xia You, Da-Yuan Zhao,
Neng-Jie Mou, Qun-Li Luo*
economic access to an array of
unprotected meta-substituted primary
anilines was developed via the iodine-
promoted Semmler−Wolff reaction.
The synthetic utility of this approach is
evident in the de novo syntheses of
three bioactive molecules with good
total yields.
Page No. – Page No.
Iodine-promoted Semmler−Wolff
reactions: step economic access to
meta-substituted primary anilines via
aromatization
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