An efficient entry to 1,2-benzisoxazoles via 1,3-dipolar cycloaddition of in situ generated nitrile oxides and benzyne

Article abstract of DOI:10.1039/b927235f

An efficient protocol for the synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reactants simultaneously. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b927235f

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Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 8 | Number 11 | 7 June 2010 | Pages 2481–2652
ISSN 1477-0520
FULL PAPER
John E. Moses et al.
EMERGING AREA
Y.-M. He and Q.-H. Fan
Efficient entry to 1,2-benzisoxazoles
via 1,3-dipolar cycloaddition of in situ
generated nitrile oxides and benzyne
Phosphine-free chiral metal catalysts
for highly effective asymmetric catalytic
hydrogenation
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An efficient entry to 1,2-benzisoxazoles via 1,3-dipolar cycloaddition of in situ
generated nitrile oxides and benzyne†
Christian Spiteri,a,b Christopher Mason,a Fengzhi Zhang,a Dougal J. Ritson,a Pallavi Sharma,a,b Steve Keelingb
and John E. Moses*a
Received 5th January 2010, Accepted 9th March 2010
First published as an Advance Article on the web 7th April 2010
DOI: 10.1039/b927235f
An efficient protocol for the synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar
cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation
of the reactive nitrile oxide and benzyne reactants simultaneously.
Introduction
1,2-Benzisoxazoles are a major class of five membered N–O
containing heterocycles with immediate application in the phar-
maceutical industry.1 Their isosteric relationship with the indole
core allows 1,2-benzisoxazoles to bind to important biological
enzymes in a mode that mimics the indole core.1g,1i Consequently,
numerous 1,2-benzisoxazoles have been found to possess potent
pharmacological properties.1 This high degree of bioactivity is
exemplified by Zonisamide 1,1b,1d a potent antiepileptic drug and
R
the blockbuster drug Risperidoneꢀ 2, approved by the United
States FDA in 1993 for the treatment of schizophrenia (Fig. 1).1a
Scheme 1 Synthetic approaches to 1,2-benzisoxazoles.
=
the 2-3 C N double bond (although this strategy has been
used with less frequency).5 However, these protocols are often
hindered by long reaction times, multiple-steps, and harsh reaction
conditions, favoring the formation of undesirable by-products. For
example, the basic conditions employed in (i) (Scheme 1) often
leads to Beckmann-type rearrangement of the starting material,
giving the undesired 1,3-benzisoxazoles.2 On the other hand,
3-unsubstituted, 3-acyl-, and 3-carboxyl-1,2-benzisoxazoles are
easily cleaved in the strongly basic environment used in (i) and
(ii), leading to the corresponding salicylonitriles or the salicylic
acid derivatives.2
An alternative strategy involves the simultaneous formation
of the 3-3a and 7a-1 bonds, via a Huisgen-type6 1,3-dipolar
cycloaddition of benzyne (3) with nitrile oxides (4) (Scheme 2).4b,7
Unfortunately, such reactions generally suffer from low yields,
mainly due to competing side-reaction pathways resulting from
the highly reactive intermediates.
Although most attractive in terms of convergence and step-
economy, there are limited examples of the syntheses of 1,2-
benzisoxazoles using this 1,3-dipolar cycloaddition strategy.4b,7
One of the earliest applications of this chemistry was reported
by Minisci and Quilico (1964) who reacted benzyne (3), generated
Fig. 1 Example of biologically active 1,2-benzisoxazoles.
Several synthetic methodologies have been developed to access
1,2-benzisoxazoles, driven in part by the desirable biological
properties these compounds possess. The most common synthetic
routes are illustrated in Scheme 1;2 (i) formation of the 1-2
bond by an intramolecular cyclization of o-hydroxybenzyloxime
sulfonates or acetates;3 (ii) a base-induced intramolecular cy-
clization of o-halo benzoyl derivatives for the formation of the
1-7a bond;4 (iii) intramolecular oximation for the assembly of
aSchool of Chemistry, University of Nottingham, University Park, Notting-
ham, NG7 2RD, UK. E-mail: john.moses@nottingham.ac.uk; Fax: + 44
(0)115 951 3533; Tel: + 44 (0)115 951 3533; Web: www.moseslabs.com
bGlaxoSmithKline, Research Medicines Centre, Stevenage, UK
† Electronic supplementary information (ESI) available: Experimental
data and NMR spectra. See DOI: 10.1039/b927235f
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is limited by the availability of starting materials. Anthranilic
acids, on the other hand, are widely available with diverse
functionality. The 1,3-dipolar nitrile oxides (4) are available from
their corresponding hydroximoyl chlorides, which upon exposure
to a suitable base undergo rapid dehydrodehalogenation.17
Herein, we describe an efficient approach to 1,2-benzisoxazoles
using a microwave enhanced one-pot protocol, beginning with
anthranilic acid (5) as a benzyne precursor and hydroximoyl
chlorides as a starting point for nitrile oxides (4). We believe
that this improved method represents a major step forward in
the syntheses of 1,2-benzisoxazoles.
Results and discussion
Preliminary studies using anthranilic acid (5) as benzyne precursor
We recently employed anthranilic acid (5) as a suitable benzyne
precursor in the synthesis of several benzotriazoles. Simply heating
5 in a [1 : 1] ratio with a suitable alkyl nitrite reagent, in the presence
of an organic azide, led to the target benzotriazoles in excellent
yields.14 Beginning with these optimised conditions, preliminary
investigations were conducted with nitrile oxide precursor, electron
rich, p-methoxyphenyl hydroximoyl chloride (11).
In the initial screening stage the conditions for the formation
of benzyne (3) were kept constant, while the formation of
the nitrile oxide (4) was investigated by sampling a range of
inorganic and organic bases in polar media. Unfortunately, most
conditions did not afford any of the target products,18 except for
the reaction performed on 11 using K2CO3 in refluxing MeCN
(Scheme 3). These conditions furnished 3-(4-methoxyphenyl)-1,2-
benzisoxazole (12) in 15% yield. The disappointing results were
assumed to be a consequence of an imbalance in the rate of
formation of the benzyne (3) and nitrile oxide (4) intermediates,
thus leading to undesirable self-reaction pathways. Indeed, the
corresponding furoxan 13 was detected as the main by-product in
most instances.19
Scheme 2 Reaction pathways of nitrile oxides 4.
from anthranilic acid (5), with benzonitrile oxide to give 3-phenyl-
1,2-benzisoxazole (6) in 53% yield.7a Since these pioneering studies
little advance has been made towards a general and reliable method
for 1,2-benzisoxazole synthesis using cycloaddition chemistry.8
In general, the reactive nitrile oxide species (4) are first generated
separately, then quickly added to a mixture of benzyne precursor
(e.g. anthranilic acid (5) and an alkyl nitrite). It is not surprising
then that side reactions are commonplace, and perhaps this has
been a major factor in the limited use of this methodology.
Benzyne (3) is an extremely short lived intermediate with an
estimated life-time of 400 ps,9c undergoing rapid dimerisation via
a stepwise [2+2] cycloaddition to yield diphenylene.9a,b On the
other hand, aliphatic and aromatic nitrile oxides dimerize in dilute
solutions, even at low temperature (0 ◦C), within seconds or,
at best, minutes to the corresponding furoxans 7 (Scheme 2).10
The only known stable nitrile oxides are those possessing a
+
-
highly hindered C N –O group.11 Furthermore, nitrile oxides are
known to isomerize into isocyanates (8) at elevated temperatures,12
while in the presence of pyridine in ethanol or excess BF3 in
benzene, they dimerize furnishing 1,4,2,5-dioxadiazines (9).12 The
formation of 1,2,4-oxadiazole-4-oxides (10) in the presence of
Et3N or BF3 is less significant.13
≡
Taking into consideration all the available information, it
became evident that a substantial improvement of the efficiency of
1,2-benzisoxazole synthesis would only be possible if the relative
rates of formation of benzyne (3) and nitrile oxide (4) were
matched. Building upon our recent success in benzyne chemistry,
and our emerging interest in developing new protocols for the
construction of heterocycles,14 we were keen to modernise the
related nitrile oxide-aryne chemistry.
Arynes are accessible via numerous protocols.15 Until recently,
the most widely used involved the diazotization of anthranilic
acid derivatives to benzenediazonium-2-carboxylates, which de-
compose to benzyne (3) upon elimination of nitrogen and carbon
dioxide.9a,9b More recently, arynes have been obtained under
milder conditions from o-(trimethylsilyl)aryl triflates, via fluoride-
promoted elimination of the trimethylsilyl group and the o-triflate
group.16 In this regard, we have recently reported a one pot pro-
tocol to access 1,2-benzisoxazoles utilising o-(trimethylsilyl)aryl
triflates as the benzyne precursor.8 However, although preferable
in terms of safety and efficiency, this method of benzyne generation
Scheme 3 Successful formation of 1,2-benzisoxazole 12.
During our previous work on benzotriazoles,14 we found that
microwave irradiation dramatically improved the yield and rate of
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Table 1 Optimization
Table 2 Scope of the reaction
Entrya
1
Product R =
14
Yield [%]b
80
Entrya
K2CO3 (equiv.)
Solvent
T (◦C)
t (min)
Yield [%]b
1
2
3
4
5
6
7
8
1.5
1.5
1.5
0
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOEt
1,2-DCE
Toluene
THF
120
120
120
120
120
120
40
5
10
20
10
10
10
10
10
10
10
10
10
10
10
10
10
81
85
74
2
3
15
96
67
c
—
74
73
78
83
81
63
43
35
49
3
16
80
9
160
120
120
120
120
120
120
120
10
11
12
13
14
15
16
4
17
76
MeOH
DMSO
H2O
5
6
18
71
70
12
27
a Reaction performed on 0.54 mmol. b Isolated yield. c The purification of
12 from by-products was not possible because of similar Rf values.
19
7
8
20
21
55
90
◦
reaction. Thus when 11 was irradiated at 120 C in the presence
of 5 (2.0 equiv.), t-BuONO (2.0 equiv.) and K2CO3 (1.5 equiv.)
in MeCN for 10 min 12 was obtained in 85% yield. Keen to
build upon this outcome, we endeavoured to optimize the reaction
conditions with substrate 11 using K2CO3 as base (Table 1).
Surprisingly, we could not improve upon the initial conditions.
Firstly, the duration of microwave irradiation was varied, heating
the reaction mixture at 120 ◦C for 5, 10 and 20 min (Table 1,
entries 1-3). This did not offer any beneficial effect on the yield of
12, with longer reaction times showing an erosion of the yield, sug-
gesting degradation of the product under the conditions (Table 1,
entry 3).
9
22
71
10
11
12
6
80
39
51
23
24
Next, the number of equivalents of base was investigated by
varying the molar ratio of K2CO3 (with respect to 11) from 0 to
2. The formation of 12 was observed (TLC) even in the absence
of base, suggesting that 4-methoxyphenylnitrile oxide was being
generated under the given conditions (Table 1, entry 4). In fact,
subjecting a solution of 11 in MeCN to microwave conditions
(120 ◦C, 10 min) in the absence of any other reagent, resulted in its
consumption (1H NMR and TLC). Unfortunately, in the absence
of K2CO3 the reaction gave numerous by-products which proved
difficult to purify by conventional chromatographic techniques.
Furthermore, using either 1.0 or 2.0 equivalents of K2CO3 afforded
12 in 74% and 73% isolated yield, respectively (Table 1, entries
5 and 6). Optimal results were obtained using 1.5 equivalents
of K2CO3 (Table 1, entry 2). Varying the temperature relative to
120 ◦C resulted in lower yields of 12 (Table 1, entries 7-9), whereas
changing the solvent from MeCN did not offer any benefit (Table 1,
entries 10-16).
13
25
55
a Reaction performed on 0.54 mmol of 11; b Isolated yield.
nitrile oxides (Table 2, entries 3, 5, 6 and 8) and/or those having a
+
-
≡
sterically hindered C N –O group (Table 2, entries 1 and 2). On
the other hand, moderate yields were recorded for electron-poor
nitrile oxides (Table 2, entries 4, 9 and 13). Pleasingly, 3-phenyl-
1,2-benzisoxazole (6) was obtained in 80% yield (Table 2, entry
10), almost 30% higher than in the method described by Minisci
and Quilico (53%).7a This method was found to be amenable
to substrates bearing more than one hydroximoyl chloride, as
exemplified by 23 (Table 2, entry 11). Gratifyingly, even highly
unstable aliphatic nitrile oxides could be used, as demonstrated by
24 (Table 2, entry 12).
To explore the scope of this protocol, a variety of hydroximoyl
chloride derivatives were examined (Table 2, entries 1-13). In
general, good to excellent yields were observed with electron-rich
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Preliminary mechanistic studies
using Merck silica gel 60 (230-400 mesh). All solvents and reagents
were used as received from commercial suppliers.
A plausible explanation for the successful results obtained under
microwave irradiation was attributed to a possible cycloreversion
of an in situ generated furoxan to the nitrile oxide (4), hence a pool
of the reactive intermediate would be stored as the stable furoxan
which could be consumed at the rate of benzyne formation. This
process is known to occur at elevated temperatures.20 To test this
hypothesis, substrate 11 was subjected to 10 min of microwave
irradiation at 120 ◦C in the presence of K2CO3 (1.5 equiv.) in
General procedure for the synthesis of 1,2-benzisoxazoles using
anthranilic acid 5 as benzyne precursor under microwave condi-
tions—synthesis of 3-(4-methoxyphenyl)-1,2-benzisoxazole (12)
A heterogeneous mixture of 4-methoxyphenylhydroximoyl chlo-
ride 11 (100 mg, 0.54 mmol), anthranilic acid 5 (2.0 equiv.),
and K2CO3 (1.5 equiv.) was stirred in MeCN (2.0 mL) at room
temperature for 5 min followed by the addition of t-BuONO
(2.0 equiv.) in a single portion. The mixture was stirred for an
additional 30 s and then heated in a microwave reactor at 120 ◦C
for 10 min. The volatile components were then removed under
reduced pressure on a rotatory evaporator at 40 ◦C. The crude
mixture was purified by flash column chromatography on silica
gel using 1% ethyl acetate in petroleum ether 40-60 ◦C as the
eluting solvent, giving 3-(4-methoxyphenyl)-1,2-benzisoxazole 12
as a white solid (104 mg, 0.46 mmol, 85%).
1
MeCN-d3 to generate the corresponding furoxan (13). H NMR
of the resulting mixture indicated incomplete consumption of
11, in addition to numerous other products which we were not
able to characterise unequivocally as dimerized material. After
allowing the mixture to cool to room temperature, t-BuONO and
anthranilic acid (5) were added, and the heterogeneous mixture
was subjected to microwave irradiation at 120 ◦C for 10 min.
The yield, which was under 20%, contradicted the involvement
of a dimerized furoxan as the source of the nitrile oxide under
our optimised conditions for the synthesis of benzisoxazoles. It
was evident that under the microwave “enhanced” conditions, the
rate of benzyne (3) and nitrile oxide (4) formation were tuned
to an extent to favour the formation of benzisoxazoles over all
other possible side reactions. Interestingly, when a heterogeneous
mixture of 11, 5 (2 equiv.), t-BuONO (2 equiv.) and K2CO3
(1.5 equiv.) in MeCN were heated at 120 ◦C in a pressure tube
using an oil bath, the corresponding 1,2-benzisoxazole 12 was
obtained in 83%. This was comparable to the yield obtained in the
microwave reactor, thus excluding any microwave enhancement
effect and suggesting the likely involvement of a pressure effect.
However, a thorough survey of the reactions, using conventional
heating and a sealed tube, was not carried out as the microwave
method was more convenient.
3-(4-Methoxyphenyl)-1,2-benzisoxazole (12)
◦
◦
White solid; mp = 100–102 C (lit.21 100–101 C); IR (n[cm-1])
3011, 1613; NMR: dH (400 MHz, CDCl3) 7.95-7.91 (m, 3H), 7.65-
7.56 (m, 2 H), 7.37 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.11-7.09
(m, 1H), 7.08-7.06 (m, 1H), 3.89 (s, 3H); dC (100 MHz, CDCl3)
163.7, 161.2, 156.7, 129.6, 129.3 (2C), 123.6, 122.2, 121.1, 120.5,
114.5 (2C), 110.1, 55.3; HRMS (ESI) (m/z): [M+H]+ calcd for
C14H12NO2, 226.0863; found 226.0863.
3-(2,6-Dimethylphenyl)-1,2-benzisoxazole (14)
◦
◦
Yellow solid; mp = 85–86 C (lit.5 83–84 C); IR (n[cm-1]) 3011,
1610; NMR: dH (400 MHz, CDCl3) d 7.70 (td, J = 8.5, 0.8 Hz,
1H), 7.61 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.41 (brd, J = 7.7 Hz,
1H), 7.35-7.29 (m, 2H), 7.20 (brd, J = 7.5 Hz, 2H), 2.15 (s, 6H); dC
(100 MHz, CDCl3) 163.1, 157.7, 137.7, 129.8, 129.4, 127.6 (2C),
127.1, 123.6, 121.9 (2C), 121.8, 110.0, 20.1 (2C); HRMS (ESI)
(m/z): [M+H]+ calcd for C15H14NO, 224.1070; found 224.1075.
Conclusion
In summary, the present protocol describes an expedient one-
pot access to 1,2-benzisoxazoles in good to excellent yields from
readily accessible starting materials. The reaction was accelerated
by using microwave irradiation or heating in a sealed tube, which
lead to improved yields compared to previous methods of 1,2-
benzisoxazoles synthesis starting from anthranilic acid 5.
3-(2-Ethylphenyl)-1,2-benzisoxazole (15)
Brown oil; IR (n[cm-1]) 2972, 1609; NMR: dH (400 MHz, CDCl3)
7.68-7.66 (m, 1H), 7.62-7.59 (m, 2H), 7.52-7.45 (m, 3H), 7.40-7.33
(m, 2H), 2.78 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H); dC
(100 MHz, CDCl3) 163.0, 158.0, 143.9, 130.2, 130.0, 129.7, 129.4,
127.1, 126.0, 123.7, 122.2 (2C), 109.9, 26.6, 15.8; HRMS (ESI)
(m/z): [M+H]+ calcd for C15H14NO, 224.1070; found 224.1069.
Experimental
General information
Melting points were recorded using a Stuart Scientific SMP3
melting point apparatus and are uncorrected. High Resolution
Mass Spectra were recorded on VG micron Autospec or Bruker
microTOF. Fourier Transform Infrared Spectroscopy (FT-IR)
spectra were obtained on Perkin Elmer 1600 series or Bruker
3-(2-Methoxyphenyl)-1,2-benzisoxazole (16)
Tensor 27 spectrometer as a solution in chloroform. H and 13C
Yellow brown oil; IR (n[cm-1]) 3011, 1610; NMR: dH (400 MHz,
CDCl3) 7.70 (brd, J = 8.0 Hz, 1H), 7.67 (dd, J = 7.5, 1.7 Hz, 1H),
7.63 (brd, J = 8.4 Hz, 1H), 7.58-7.50 (m, 2H), 7.33-7.29 (m, 1H),
7.14-7.09 (m, 2H), 3.86 (s, 3H); dC (100 MHz, CDCl3) 163.2, 157.4,
156.4, 131.6, 131.3, 129.4, 123.5, 123.1, 121.9, 120.9, 117.6, 111.4,
109.7, 55.5; HRMS (ESI) (m/z): [M+H]+ calcd for C14H12NO2,
226.0823; found 226.0864.
1
NMR spectra were recorded on a Bruker AV(III) 400, Bruker
AV 400, Bruker DPX 400 (400 MHz (1H) and 101 MHz (13C))
spectrometers. Coupling constants are given in hertz (Hz) and the
following notations indicate the multiplicity of the signals: s (sin-
glet), d (doublet), brd (broad doublet), t (triplet), q (quartet), sept
(septet), m (multiplet). Column chromatography was performed
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3-(2-Nitrophenyl)-1,2-benzisoxazole (17)
3-(Phenyl)-1,2-benzisoxazole (6)25
◦
◦
◦
Yellow solid; mp = 105–108 C; IR (n[cm-1]) 1610, 1532, 1351,
Off-white solid; mp = 80–83 C (lit.26 80–82 C); IR (n[cm-1])
1613; NMR: dH (400 MHz, CDCl3) 8.04-7.97 (m, 2H), 7.94 (d,
J = 8.0 Hz, 1H), 7.66-7.52 (m, 5H), 7.39 (t, J = 7.5 Hz, 1H); dC
(100 MHz, CDCl3) 163.7, 157.2, 130.1, 129.7, 129.1 (2C), 128.8,
127.9 (2C), 123.8, 122.1, 120.4, 110.0; HRMS (ESI) (m/z): [M+H]+
calcd for C13H10NO, 196.0757; found 196.0762.
852; NMR: dH (400 MHz, CDCl3) 8.22-8.19 (m, 1H), 7.84-7.72 (m,
3H), 7.69-7.67 (m, 1H), 7.64-7.60 (m, 1H), 7.47 (bs, J = 8.0 Hz,
1H), 7.36-7.32 (m, 1H); dC (100 MHz, CDCl3) 163.0, 155.7, 148.7,
133.5, 132.2, 131.1, 130.1, 125.0, 124.1, 123.5, 120.9 (2C), 110.15;
HRMS (ESI) (m/z): [M+Na]+ calcd for C13H8N2NaO3, 263.0427;
found 263.0422.
1,4-Bis-(1,2-benzisoxazole)benzene (23)
3-(1-Naphthalen)-1,2-benzisoxazole (18)22
Yellow solid; IR (n[cm-1]) 1611; NMR dH (400 MHz, CDCl3)
8.22 (s, 4H), 8.05-8.01 (m, 2H), 7.75-7.71 (m, 2H), 7.69-7.64 (m,
2H), 7.49-7.44 (m, 2H); dC (100 MHz, CDCl3) 164.0 (2C), 156.6
(2C), 130.8 (2C), 130.0 (2C), 128.8 (4C), 124.2 (2C), 122.0 (2C),
120.3 (2C), 110.3 (2C); HRMS (ESI) (m/z): [M+H]+ calcd for
C20H13N2O2 313.0972, found 313.0978.
Orange brown oil; IR (n[cm-1]) 1610; NMR: dH (400 MHz, CDCl3)
8.18 (d, J = 8.4 Hz, 1H), 8.06 (brd, J = 8.3 Hz, 1H), 7.98 (brd, J =
7.6 Hz, 1H), 7.82 (dd, J = 7.1, 1.2 Hz, 1H), 7.74 (brd, J = 8.5 Hz,
1H), 7.66-7.51 (m, 5H), 7.35-7.31 (m, 1H); dC (100 MHz, CDCl3)
163.3, 157.5, 133.9, 131.3, 130.4, 129.9, 128.4, 128.3, 127.0, 126.4,
125.7, 125.5, 125.2, 123.7, 122.4, 122.3, 110.0; HRMS (ESI) (m/z):
[M+H]+ calcd for C17H12NO, 246.0913; found 246.0907.
3-(1-Phenyl-ethyl)-1,2-benzisoxazole (24)
Colourless oil; IR (n[cm-1]) 2982, 2932, 2855, 1612; NMR: dH
(400 MHz, CDCl3) 7.47-7.44 (m, 1H), 7.38 (ddd, J = 8.2, 7.0,
1.2 Hz, 1H), 7.28-7.22 (m, 4H), 7.20-7.14 (m, 2H), 7.05 (ddd, J =
8.0, 7.0, 0.9 Hz, 1H), 4.46 (q, J = 7.2 Hz, 1H), 1.78 (d, J = 7.2 Hz,
3H); dC (100 MHz, CDCl3) 163.2, 161.0, 142.3, 129.5, 128.8 (2C),
127.5 (2C), 127.0, 123.0, 121.9, 121.0, 109.8, 38.0, 20.0; HRMS
(ESI) (m/z): [M+Na]+ calcd for C15H13NNaO, 246.0889; found
246.0912.
3-(2-Naphthalen)-1,2-benzisoxazole (19)
Orange brown oil; IR (n[cm-1]) 1611; NMR: dH (400 MHz, CDCl3)
8.48 (s, 1H), 8.12-7.93 (m, 5H), 7.71-7.69 (m, 1H), 7.65-7.58 (m,
3H), 7.45-7.41 (m, 1H); dC (100 MHz, CDCl3) 163.9, 157.2, 134.0,
133.2, 129.8, 129.0, 128.5, 127.9 (2C), 127.2, 126.8, 126.4, 125.0,
123.9, 122.3, 120.6, 110.2; HRMS (ESI) (m/z): [M+H]+ calcd for
C17H12NO, 246.0913; found 246.0913.
3-(4-Nitrophenyl)-1,2-benzisoxazole (25)
3-(4-Isopropylphenyl)-1,2-benzisoxazole (20)
◦
Pale yellow solid; mp = 213–214 C; IR (n[cm-1]) 1607, 1527,
◦
Amorphous colourless solid; mp = 78–81 C; IR (n[cm-1]) 3011,
1349, 853; NMR: dH (400 MHz, CDCl3) 8.48-8.43 (m, 2H), 8.22-
8.18 (m, 2H), 7.98-7.94 (m, 1H), 7.76-7.66 (m, 2H), 7.51-7.46 (m,
1H); dC (100 MHz, CDCl3) 164.2, 155.5, 148.8, 135.2, 130.3, 128.9
(2C), 124.6, 124.4 (2C), 121.6, 119.9, 110.5; HRMS (ESI) (m/z):
[M+H]+ calcd for C13H9N2O3 241.0608, found 241.0618.
2966, 1611; NMR: dH (400 MHz, CDCl3) 7.96 (td, J = 8.0, 0.9 Hz,
1H), 7.92 (brd, J = 8.3 Hz, 2H), 7.67-7.65 (m, 1H), 7.62-7.58 (m,
1H), 7.44 (brd, J = 8.0 Hz, 2H), 7.38 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H),
3.02 (sept, J = 7.0 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H); dC (100 MHz,
CDCl3) 163.8, 157.2, 151.3, 129.7, 128.1 (2C), 127.2 (2C), 126.4,
123.7, 122.3, 120.6, 110.1, 34.1, 23.9 (2C); HRMS (ESI) (m/z):
[M+H]+ calcd for C16H16NO, 238.1226; found 238.1230.
Acknowledgements
We thank The EPSRC, GlaxoSmithKline, Association for
International Cancer Research (AICR) and The University of
Nottingham for financial support.
3-(4-Biphenyl)-1,2-benzisoxazole (21)
◦
◦
Yellow solid; mp = 116–119 C (lit.23 119–120 C); IR (n[cm-1])
1613; NMR: dH (400 MHz, CDCl3) 8.09-8.06 (m, 2H), 8.00 (td,
J = 8.0, 0.9 Hz, 1H), 7.83-7.80 (m, 2H), 7.70-7.68 (m, 3H),
7.65-7.61 (m, 1H), 7.53-7.48 (m, 2H), 7.44-7.40 (m, 2H); dC
(100 MHz, CDCl3) 163.8, 156.8, 142.9, 140.1, 129.7, 128.9 (2C),
128.4 (2C), 127.8, 127.7 (3C), 127.1 (2C), 123.8, 122.1, 120.4, 110.1;
HRMS (ESI) (m/z): [M+H]+ calcd for C19H14NO, 272.1070; found
272.1077.
Notes and references
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Pale yellow solid; mp = 86–89 C (lit.24 93–94 C); IR (n[cm-1])
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