Copper-catalyzed cyclization of Z-oximes into 3-methyl-1,2-benzisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2009.12.070

A practical and effective room temperature copper-catalyzed cyclization of Z-oximes is developed. 3-Methyl-1,2-benzisoxazoles are obtained in 58-79% yields. Also, the Z-selective synthesis of o-bromo acetophenone oximes is presented for the first time.

Full text of DOI:10.1016/j.tetlet.2009.12.070

Tetrahedron Letters 51 (2010) 1030–1033
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Tetrahedron Letters
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Copper-catalyzed cyclization of Z-oximes into 3-methyl-1,2-benzisoxazoles
Sandra Udd a, Reija Jokela a, Robert Franzén b, Jan Tois b,
*
a Faculty of Chemistry and Material Sciences, Department of Chemistry, Helsinki University of Technology, P.O. Box 6100, FIN-02015 TKK, Finland
b Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and effective room temperature copper-catalyzed cyclization of Z-oximes is developed. 3-
Methyl-1,2-benzisoxazoles are obtained in 58–79% yields. Also, the Z-selective synthesis of o-bromo ace-
tophenone oximes is presented for the first time.
Received 29 October 2009
Revised 30 November 2009
Accepted 11 December 2009
Available online 21 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Oximes
Copper
1,2-Benzisoxazoles are motifs present in a wide range of phar-
maceutically potent agents, including diuretics,1 acetylcholinester-
ase inhibitors,2 antileptics,3 and neuroleptics.4 As a result, several
approaches have been developed to obtain these heterocycles.5 De-
spite the diversity of existing methods only two are frequently
used to access 3-substituted-1,2-benzisoxazoles (Fig. 1).
Route A involves formation of the N–O bond via dehydration
while in route B a C–O bond is formed via nucleophilic aromatic
substitution (SNAr reaction).6 The aforementioned strategy re-
quires an ortho-hydroxy group relative to the oxime functionality
and transformation of the oximino hydroxy into a good leaving
group. To accomplish the dehydration, a variety of reagents have
been used.7 The latter method, route B, requires a good leaving
group ortho relative to the oxime functionality. The deprotonated
oximino hydroxy attacks the ortho-position and the leaving group
is subsequently eliminated. It is believed that an electron-with-
drawing ketoxime functionality at the ortho-position and the close
proximity of the leaving group are the factors needed for this cycli-
zation to occur.8
The effectiveness of fluoride as a leaving group in SNAr reactions
is known to be superior to other halogens and 1,2-benzisoxazole
formation is not an exception.9 Despite the higher reactivity of
fluorinated starting materials, chloride,10 bromide,11 and nitro12
have also been used as leaving groups. von Borsche and Schriba13
found that an electron-donating substituent para relative to the
leaving group diminished the reactivity when the oximes were re-
acted under harsh conditions. On the other hand, electron-with-
drawing substituents are known to enhance the reactivity. In
addition to these charge-stabilizing effects, the most limiting factor
is the need for the oxime to be in Z-configuration, in other words,
the hydroxy group needs to be cis to the aromatic ring.14
R
LG
Route A
N
R
R
OH
R
N
R
O
OH
Route B
N
R
LG
Figure 1. Synthetic routes to 1,2-benzisoxazoles.
O
O
hydroxylamine
hydrochloride
Br
Ref. 18
R
R
H2O/MeOH
RT,16 h
Br
Br
1a-f
2a-f
OH
HO
N
N
Br
NaBH4
R
R
MeCN/H2O
RT,1 h
Br
Br
3a-f
4a-f
* Corresponding author. Tel.: +358 3 31153693.
E-mail address: Jan.Tois@tut.fi (J. Tois).
Scheme 1. Z-Selective synthesis of oximes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.070

S. Udd et al. / Tetrahedron Letters 51 (2010) 1030–1033
1031
Table 1
Synthesized Z-oximesa
N
N
Entry
Product
Yieldb (%)
N
N
L2
L4
HO
L1
N
O
1
74
NH HN
4a
4b
4c
4d
H2N
OH
Br
HO
L3
N
Br
2
3
4
5
75
Figure 2. Structures of ligands L1–L4.
Br
HO
To avoid the forcing reaction conditions typically needed for
SNAr reactions, attempts to perform the transformation catalyti-
cally have been made.15 So far, these trials have been restricted
to the formation of 3-phenyl-1,2-benzisoxazoles, because the pre-
dominant isomer of the o-halogeno benzophenone oxime is in the
Z-configuration.16 According to our knowledge there are no cata-
lytic methods reported for the preparation of 3-alkyl-substituted
1,2-benzisoxazoles. In this Letter, we describe the first catalytic
cyclization leading to 3-methyl-1,2-benzisoxazoles.
N
O2N
MeO
83
89
95
91
Br
N
HO
HO
Br
N
Z-Configured o-bromo acetophenone oximes were prepared by
the seldom-utilized method, for unsubstituted acetophenone oxi-
mes, reported by Smith and Kaiser17 (Scheme 1).
MeO
MeO
The
a-bromination of o-bromoacetophenones 1a–f was per-
Br 4e
formed using CuBr2.18 Oximation was accomplished in the absence
of base according to the method of Chaudhuri and co-workers19
yielding a mixture of E- and Z-isomers. Finally, treatment of the
mixtures of 3a–f with sodium borohydride17 afforded the desired
Z-oximes 4a–f in acceptable overall yields (Table 1).
HO
N
O
O
6
4f
Br
With the Z-oximes in hand we next screened the copper-cata-
lyzed cyclization conditions (Table 2).
a
See Supplementary data for details.
Isolated yield after two steps (2a–f?4a–f).
b
At first, the reaction conditions of Maitra and co-workers15b
were explored. According to TLC, the reaction was complete in
Table 2
Screening of the copper-catalyzed cyclization conditionsa
HO
CuI (10 mol%)
base (200 mol%)
N
ligand (30 mol%)
N
solvent, conditions
O
Br
4a
5a
Entry
Base
Ligand
Solvent
Conditions temp (°C)/time (min)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12e
13f
14g
15g
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L3
L3
L3
L3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
THF
THF
THF
THF
110/40
110/40
110/40
23/90
60/90
80/90
23/90
23/90
23/20
23/5
23/60
23/200
23/200
23/200
67/60
45
43
—
—
—
17
24
35
57
58
32
26
34
—
d
THF
THF
THF
—
a
b
c
d
e
f
See Supplementary data for experimental conditions.
Isolated yield.
40 mol % Na,K-tartrate added together with the ligand.
All reagents added at once.
5 mol % of CuI.
20 mol % of ligand.
g
E-Oxime was used as the reactant.

1032
S. Udd et al. / Tetrahedron Letters 51 (2010) 1030–1033
40 min and 5a was isolated in 45% yield after chromatography (en-
try 1). The reaction was repeated in the absence of Na,K-tartrate to
afford a similar result (entry 2).20 When the reagents were added
simultaneously to the flask followed by the solvent, a complex
mixture was obtained. 1H NMR analysis of the crude reaction mix-
ture indicated that formation of 5a had not occurred. When the
reaction was repeated at room temperature (entry 4) or at 60 °C
(entry 5) only starting material was detected by TLC. When the
reaction temperature was 80 °C (entry 6) the desired compound
5a was obtained after purification in 17% yield. During the experi-
ment there was a color change from colorless to yellow after the
addition of base, which is probably due to deprotonation. This indi-
cates that the oxime hydroxy group needs to be deprotonated be-
fore addition of the ligand and catalyst. We decided to use a
stronger base, t-BuONa, and to our delight the reaction took place
at room temperature (entry 7). However, the reaction did not pro-
ceed toward completion, but there was no formation of side prod-
ucts either. We concluded that the poor solubility of 4a in toluene
at room temperature might explain the incomplete reaction. Tolu-
ene was replaced by THF and 5a was isolated in 35% yield (entry 8).
In this case also the reaction never went to completion. Next, we
decided to screen several readily available ligands (Fig. 2) which
have been utilized in copper-catalyzed C–O bond-forming
reactions.21
work-up, compound 5a was obtained in 57% yield (entry 9). When
TMEDA was replaced by DMEDA (L3), the reaction was even faster
and the target molecule was formed in five minutes in comparable
yield (entry 10). Also in this case, there was no need for chromato-
graphic purification. The N,O-chelating ligand (L4) was not as
effective and side products were observed (entry 11).
Decreasing the amount of copper or ligand led to incomplete
reactions, thus indicating that 10 mol % of CuI and 30 mol % of li-
gand were needed for successful cyclizations (entries 12 and 13).
When an E-configured oxime was subjected to the optimized con-
ditions only a mixture of side products was obtained (entries 14
and 15). Under these conditions no isomerization22 (E?Z) was ob-
served and the side reactions became dominant. To confirm that
the reaction proceeded catalytically and not via a SNAr mechanism,
a control reaction was performed. The Z-oxime 4a was stirred with
t-BuONa in THF and the reaction was monitored by TLC. After 90
min no formation of 5a was detected. Ligand L3 was added and
the reaction was further stirred for 60 min without formation of
5a. When CuI was added, the cyclization occurred immediately,
clearly demonstrating that the reaction is catalytic. To explore
the scope of the reaction, Z-oximes 4b–f were subjected to the
reaction conditions and the results are shown in Table 3.
When an electron-donating methoxy group was present para to
the bromo-substituent, the reaction time was 60 min (entry 4). As
expected, the electron-withdrawing NO2-substituent activated the
system to such an extent that 4c cyclized without addition of the
ligand and catalyst via a SNAr mechanism (entry 3).
When L2 was utilized as the ligand, the reaction was complete
in 20 min at room temperature according to TLC. After aqueous
In summary, we have developed an efficient copper-catalyzed
method for the preparation of 3-methyl-1,2-benzisoxazoles. The
catalytic reaction is rapid, selective, and no heating is required.
The obtained products are pure and therefore chromatographic
purification can be omitted. For cyclization to occur under the cat-
alytic conditions employed here, it is vital that the acetophenone
oxime is of Z-configuration and thus a synthetic pathway for o-bro-
mo acetophenones was developed. Further investigations to ex-
tend this strategy to other alkyl substituents and to utilize this
method for more complex molecules are currently underway in
our laboratory.
Table 3
Products, yields, and reaction times for the cyclization of Z-oximes
HO
CuI (10 mol%)
L3 (30 mol%)
t-BuONa (200 mol%)
N
N
R
R
THF, RT
O
Br
5a-f
4a-f
Entry
1
Product
Timea (min)
Yieldb (%)
58
N
5
Acknowledgments
O
5a
We thank Orionpharma Corporation for financial support, and
Mrs. Mia Malmström and Dr. Marko Ahlmark for valuable assis-
tance with NMR spectrometry.
Br
N
2
3
4
5
6
5
66
63
79
68
70
O
5b
Supplementary data
O2N
5c
N
Supplementary data (experimental procedures and data for
compounds 4a–f and 5b–f) associated with this Letter can be
found, in the online version, at doi:10.1016/j.tetlet.2009.12.070.
O
5c
MeO
N
N
References and notes
60
35
45
O
5d
5e
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