Synthesis of 3-acetoxyacetanilide derivatives by means of semmler-wolff-type aromatization reaction of cyclohexane-1,3-dione monooximes

Article abstract of DOI:10.1246/cl.2008.1066

A novel method for synthesizing 3-acetoxyaniline derivatives from substituted cyclohexane-l, 3-diones is described. This synthetic process includes regioselective formation of cyclohexane-l, 3-dione monooximes 2 and their Semmler-Wolff-type aromatization under very simple reaction conditions. Copyright

Full text of DOI:10.1246/cl.2008.1066

1066
Chemistry Letters Vol.37, No.10 (2008)
Synthesis of 3-Acetoxyacetanilide Derivatives by means of Semmler–Wolff-type
Aromatization Reaction of Cyclohexane-1,3-dione Monooximes
Teruhiko Ishikawa,ꢀ1;2 Masaki Arai,1 Hironori Nishiuchi,2 Hiroshi Ishiguro,2 and Seiki Saitoꢀ1
1Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology,
Okayama University, Tsushima, Okayama 700-8530
2Graduate School of Education, Okayama University, Tsushima, Okayama 700-8530
(Received July 22, 2008; CL-080710; E-mail: teruhiko@cc.okayama-u.ac.jp)
A novel method for synthesizing 3-acetoxyaniline deriva-
tives from substituted cyclohexane-1,3-diones is described.
This synthetic process includes regioselective formation of
cyclohexane-1,3-dione monooximes 2 and their Semmler–
Wolff-type aromatization under very simple reaction conditions.
Table 1. Results for 3-acetoxyacetanilide synthesis from cyclo-
hexane-1,3-dionesa
Yield of
oxime 2/%b
Product
Yield of
3/%b,c
Entry X of
dione 1
OAc
1
2
H
72
75
3a
3b
48
50
Aniline derivatives are very significant synthetic intermedi-
ates for pharmaceuticals and agrochemicals, and development of
new methods for aniline synthesis is still important in organic
synthesis, particularly in industrial disciplines because of their
broad applicability. In general, substituted anilines have been
synthesized by the reduction of nitroarenes given through the
nitration of aromatic rings.1 Although this method has been used
most commonly, there emerge some problems when applied to
selective organic synthesis: the regioselectivity of nitration of
substituted benzenes is not so high, and the desired introduction
of a nitro group is sometimes deteriorated owing to unwanted
orientation dictated by the nature of ring substituents.1 The
Friedel–Crafts acylation or alkylation of simple anilines is also
a method for synthesizing substituted anilines, which, however,
often suffers from disadvantage that Lewis acid catalysts are
deactivated by their coordination to an amino group.1
The Semmler–Wolff aromatization reaction (SWAR)2,3 has
also been known for anilines synthesis, which involves the iso-
merization reaction of ꢀ; ꢁ-unsaturated cyclohexanone oximes
to aromatic amines under acidic conditions. This method was
previously improved by Kita et al.,3b,3c and partially utilized as
a key step in natural product synthesis.4 However, SWAR has
not been established as a versatile and standard method for
aniline synthesis because of small availability of substituted
cyclohexenones and their oxime derivatives.
NHAc
OAc
5-Me
NHAc
OAc
3
4
5
5-Ph
4-Me
78
70
74
3c
65
50
65
Ph
NHAc
OAc
3d
NHAc
OAc
C5H11
4-pentyl
3e
NHAc
OAc
6
4-i-Pr
72
3f
51
NHAc
OAc
4-Et
During the course of our studies on the synthetic potential of
cyclohexane-1,3-diones,5 we have discovered a novel method
for synthesizing aniline derivatives via direct aromatization of
cyclohexane-1,3-dione oximes, which is outlined in Scheme 1,
in which extremely simple reagents and conditions are used.
For instance, cyclohexane-1,3-diones 1 are commercially avail-
7
8
73
71
3g
31
71
5-CO2Et
EtO2C
C5H11
NHAc
OAc
4-pentyl
5-CO2Me
3h
MeO2C
NHAc
aConditions: NH2OH–HCl (1.5 equiv), NaHCO3 (1.5
equiv), THF–H2O (5:1), rt, 12 h for 1 ! 2; MeSO3H (3
equiv), Ac2O, 50 ꢁC, 12 h for 2 ! 3. bFor product isolat-
NH2OH−HCl
(1.5 equiv)
NaHCO3
(1.5 equiv)
MeSO3H
(3 equiv)
O
O
OAc
c
ed by SiO2 column chromatography. Yield for 2 ! 3.
X
X
X
Ac2O
50 °C, 12 h
THF−H2O (5:1)
rt, 12 h
O
NOH
NHAc
able or easily synthesized by the chemoselective Michael–
Claisen cascade reaction of simple ketones and ꢀ; ꢁ-unsaturated
esters.5a The diones can be converted to mono-oximes 2 in a
conventional way (NH2OH–HCl, NaHCO3/THF, rt). Treating
3
1
2
Scheme 1. Synthesis of 3-acetoxyacetanilides from cyclohex-
ane-1,3-dione via its monooxime.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.10 (2008)
1067
OAc
OAc
OAc
OAc
H11C5
MeSO3H
a
a
− H+
H11C5
NO2
+
3e
2
X
X
OAc
OAc
Ac2O
NHAc
N
H
N
H
NHAc
NO2
H
4e (39%)
4e' (22%)
2-1
2-2
H+
CO2Me
CO2H
OAc
C5H11
OAc
HO
3h
aromatization
N-acetylation
− HOAc
H
H+
NH
3
X
AcHN
OAc
X
O
X
O
H
N
H
R
NHAc
influenza neuraminidase
inhibitors
2-4
2-3
4h: R= NO2 (54 %)
5: R= NHAc (91 %)
b
Scheme 2. Plausible reaction mechanism.
X = NH2 or guanidyl
Scheme 3. Nitrations of acetoxyacetanilide 3: (a) NH4NO3,
(CF3CO)2O/CHCl3; (b) Zn–6 M HCl/THF then Ac2O and
NaHCO3.
thus-obtained oximes 2 with acetylating reagent such as acetic
anhydride in the presence of methanesulfonic acid (3.0 equiv)
led to 3-acetoxyacetanilides 3 in an acceptable yield and purity.
Successful results for the synthesis of 3 from 1 are summarized
in Table 1.
acetylation because of the structure similarity of 5 to anilines
derivatives of biological interest such as a potent influenza
neuraminidase inhibitor and its analogue.7
The regioselective formation of monooxime from dissym-
metrical diones was effected under the given reaction conditions
to afford the one of sterically less congested carbonyl group
(Entries 4–8). Subsequent SWAR-type reactions smoothly pro-
ceeded to obtain substituted 3-acetoxyacetanilides 3 in an ac-
ceptable yield.6 Only two steps were required for the conversion
of 1 to 3. For every entry, seven-membered lactam expected via
possible Beckmann rearrangement was not detected at all. While
previous SWAR of cyclohexenone oximes generally required
high temperature (over 100 ꢁC) in the presence of excessive
strong acid such as hydrogen chloride, concd hydrochloric acid,
polyphosphoric acid (PPA), concd sulfuric acid, and so forth,2
the present aromatization reaction proceeds under much milder
conditions (50 ꢁC) by using acetic anhydride and methanesulfon-
ic acid. In addition, the present synthesis of 3-acetoxyacetani-
lides should be highly profitable to organic synthesis because
meta-oriented introduction of a nitro group to phenols or a
hydroxy group to anilines are well known to be energetically
highly unfavorable reaction pathway.
Plausible route from 1 to 3 can be described by modifying
previous SWAR mechanism as shown in Scheme 2.3d Both enol
and oxime functions of 2 could be acetylated under the em-
ployed reaction conditions to afford 3-acetoxycyclohexanone
oxime acetate such as 2-1, which could lead to enamine inter-
mediate 2-2. On protonation of N-acetoxy group (2-3), an acetic
acid unit would depart via 1,4-elimination to end up with the
formation of iminodiene 2-4.5b The final aromatization process
from 2-4 may be triggered by N-protonation and thus-generated
amino group would be acetylated by acetic anhydride to afford
the acetoanilide 3 although direct acetylation of imine cannot
be ruled out.
In conclusion, we have developed the novel chemical
process for converting cyclohexan-1,3-dione-based mono-ox-
imes 2 to 3-acetoxyaniline derivatives 3 by the Semmler–
Wolff-type aromatization protocol operated under mild condi-
tions.9 Since we can easily prepare diverse cyclohexane-1,3-di-
ones relying on Michael–Claisen cascade reactions,5 the present
synthesis would become highly attractive in diversity-oriented
organic synthesis.8
References and Notes
1
2
3
For example, see: J. March, in Advanced Organic Chemistry,
3rd ed., Wiley-Interscience Publication, 1985, Chap. 11.
a) F. W. Semmler, Ber. 1892, 25, 3352. b) L. Wolff, Ann.
1902, 322, 351.
a) M. I. El-Sheikh, J. M. Cook, J. Org. Chem. 1980, 45, 2585.
b) Y. Tamura, Y. Yoshimoto, K. Sakai, Y. Kita, Synthesis
1980, 483. c) Y. Tamura, Y. Yoshimoto, K. Sakai, J. Haruta,
Y. Kita, Synthesis 1980, 887. d) L. Bauer, R. E. Hewitson,
J. Org. Chem. 1962, 27, 3982.
4
5
For example, see: a) J. P. Davidson, E. J. Corey, J. Am.
Chem. Soc. 2003, 125, 13486. b) J. Haseltine, M. Visnick,
A. B. Smith, III, J. Org. Chem. 1988, 53, 6160.
a) T. Ishikawa, R. Kadoya, M. Arai, H. Takahashi, Y. Kaisi,
T. Mizuta, K. Yoshikai, S. Saito, J. Org. Chem. 2001, 66,
8000. b) T. Ishikawa, T. Miyahara, M. Asakura, S. Higuchi,
Y. Miyauchi, S. Saito, Org. Lett. 2005, 7, 1211.
Only a trace amount of 3 was detected for the reactions of
monooximes prepared from 2-methylcyclohexane-1,3-dione
and 4,6-dimethylcyclohexane-1,3-dione under the reaction
conditions.
6
7
In Scheme 3 is outlined the further aromatic ring functional-
izations of 3-acetoxyacetanilide such as 3e or 3h obtained by the
present method. For example, nitration of 3e with ammonium
nitrate in the presence of trifluoroacetic anhydride afforded the
separable mixture of 4e and 4e0 in moderate yield. On the
other hand, highly regioselective nitration of aromatic ring for
3h was effected to obtain 4h in moderate yield (54%), which
was converted to 5 sequentially through reduction followed by
V. R. Atigadda, W. J. Brouillette, F. Duarte, Y. S. Babu, S.
Bantia, P. Chand, N. Chu, J. A. Montgomery, D. A. Walsh,
E. Sudbeck, J. Finley, G. M. Air, M. Luo, G. W. Laver,
Bioorg. Med. Chem. 1999, 7, 2487.
8
9
S. L. Schreiber, Science 2000, 287, 1964.
Supporting Information is also available electronically on
the CSJ-Journal Web site, http://www.csj.jp/journals/chem-
lett/index.html.
Published on the web (Advance View) September 13, 2008; doi:10.1246/cl.2008.1066