Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N-O bond-forming cyclization of 2-azidobenzoic acids

Article abstract of DOI:10.3762/bjoc.12.86

The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.

Full text of DOI:10.3762/bjoc.12.86

Synthesis of 2,1-benzisoxazole-3(1H)-ones by
base-mediated photochemical N–O bond-forming
cyclization of 2-azidobenzoic acids
Daria Yu. Dzhons and Andrei V. Budruev*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 874–881.
Chemistry Department, Lobachevsky State University of Nizhny
Novgorod, Gagarina pr. 23, Building 5, 603950, Nizhny Novgorod,
Russian Federation
doi:10.3762/bjoc.12.86
Received: 18 December 2015
Accepted: 18 April 2016
Published: 04 May 2016
Email:
Andrei V. Budruev* - budruev@gmail.com
Associate Editor: T. P. Yoon
* Corresponding author
© 2016 Dzhons and Budruev; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aryl azides; azepinones; 2,1-benzisoxazolones; 1,5-electrocyclization;
nitrenes; photochemical cyclization
Abstract
The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is re-
ported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of
2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.
Introduction
Substituted 2,1-benzisoxazoles display diverse biological activi- However, the presence of electron-withdrawing substituents in
ty [1-6] (Figure 1) and are widely used as starting materials for the 3-, 5- and 7-position of the benzisoxazole dramatically
the synthesis of important heterocyclic pharmacophores, such as reduces the thermal stability of these compounds. Indeed, these
acridines [7,8], quinolines [9-13] and quinazolines [14-16]. compounds are the most labile representatives of several
Therefore, the search for new methods leading to 2,1-benzisox- isomeric oxazoles [32], and they begin to decompose at temper-
azoles is of great interest.
atures slightly above 30 °C, which limits the number of
methods for their preparation. Thus the search for new methods
For the preparative synthesis of 2,1-benzisoxazoles, in addition for the synthesis of substituted 2,1-benzisoxazoles under mild
to the traditional method based on the reductive heterocycliza- reaction conditions is required.
tion of ortho-substituted nitro compounds [17-21], two other
routes are available: the annulation of nitroso compounds Previously, in the investigation of the photochemical cycliza-
[22,23] and the thermal [24], catalytic [25-27] or photochemi- tion of 2-azidobenzoic acid (1a) using aqueous organic solvent
cal cyclization of aryl azides [28-31].
mixtures (Scheme 1), the formation of the cyclization products
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Beilstein J. Org. Chem. 2016, 12, 874–881.
Figure 1: Selected examples of biologically active, fused 2,1-isoxazole derivatives.
Scheme 1: Photochemical cyclization of substituted 2-azidobenzoic acids and possible reaction mechanism [34-59].
such as 2,1-benzisoxazole-3(1H)-one (2a) and 2-oxo-3- of 20% and 50%, respectively, at a water content of 50%. Under
carboxy-3H-azepine (3a) has been reported [30]. The structure these conditions, no formation of the primary amine 4 (a prod-
of benzisoxazole 2a was determined by IR, 1H and 13C NMR uct of the typical triplet nitrene reaction (Scheme 1, intermedi-
spectroscopy and by comparison of its mass spectrum with the ate D)) was detected. The replacement of the aprotic solvent
corresponding spectrum from the NIST library (NIST: 37717). dioxane with acetonitrile or THF did not affect the yield of the
In addition, the structure was confirmed by the alternative syn- cyclization products. The photolysis of 1a (Scheme 1, interme-
thesis of 2a through the heterocyclization of 2-nitrobenzoic acid diate A) resulted in low yields of 2a because of the competitive
[28,29] and X-ray structure analysis [33].
formation of reaction products.
The authors observed that the yields of both 2a and 3a in- In the past, research has been focused on the formation of
creased with increasing amount of water as nucleophilic sol- 2-substituted 3H-azepines 3 as products of the photolysis or
vent in the reaction mixture [30] and obtained a maximum yield thermolysis of aromatic azides [34,35]. The proposed mecha-
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Beilstein J. Org. Chem. 2016, 12, 874–881.
nism for their formation was confirmed by identification of the atom abstraction [58], secondary amines, 1,2-arylhydrazides
reaction intermediates using low-temperature and time-resolved and azo compounds 5, which are obtained by recombination of
spectroscopy [36-43]. It is currently believed that azepines are radicals [59]. Moreover, it was shown that yields of primary
formed through the singlet nitrogen pathway of the reaction amines increased in the photolysis reactions of aryl azides
(Scheme 1, path: 1 → A → B → C → 3) [44-49].
without participating ortho-substituents in hydrocarbons as the
solvents [39].
These nitrenes form benzazirines [19] (Scheme 1, intermediate
B) that rearrange into cyclic ketenimines – 1,2-didehydro- In the present research it is demonstrated that using ethanol as
azepines (Scheme 1, intermediate C) [50]. According to quan- the solvent for the photolysis reaction leads to benzisoxazole 2a
tum-chemical calculations, the energy barrier of this rearrange- with an increased yield of 35% and the yield can be further im-
ment is approximately 40 kJ mol−1 [51], with the limiting step proved to 40% by the addition of a base. Thus, the optimization
being the formation of B. Therefore, the direction of this reac- of the reaction conditions of the base-mediated photochemical
tion solely depends on the conversion of A and formation of C. synthesis of substituted 2,1-benzisoxazole-3(1H)-ones 2 has
been performed.
Dyall et al. [52,53] have proposed a pericyclic mechanism for
the formation of heterocyclic compounds in the pyrolysis of Results and Discussion
aryl azides with unsaturated ortho-substituents. A possible reac- For optimizing the reaction conditions for the synthesis of 2a by
tion mechanism for the photochemical formation of 2 photolysis of 1a, the reaction was performed in different sol-
(Scheme 1, path: 1 → A → 2) based on the report by Platz et al. vents in the absence or presence of a base. As solvents, alco-
[54] includes the benzofuroxan formation by photolysis of hols and aqueous organic solvent mixtures were tested and
2-azidonitrobenzene through the intermediate singlet nitrene A alkali metal hydroxides, carbonates or acetates were screened as
(Scheme 1) without the formation of other intermediates.
the base. All reactions were carried out by irradiating the base
suspended in the solution of 1a with a mercury low-pressure
The formation of substituted 2,1-benzisoxazoles from aryl quartz lamp (254 nm) in a quartz reactor with intensive stirring.
azides was reported for the first time by Smith et al. [24] in the
synthesis of 3-phenyl-2,1-benzisoxazole (3-phenylanthranil) by It was found that the yields of 2a after photolysis of 1a substan-
thermolysis of 2-azidobenzophenone. In another work [55], the tially increased in the presence of a base. No dependency on the
photochemical formation of 3-amino-6-nitro-2,1-benzisoxazole nature of the base could be observed and the yield did not
starting from 2-azido-4-nitrobenzamide was observed. The improve further when more than 1 equivalent of the base was
authors subsequently investigated the multiplicity of the used (Table 1). Without irradiation, the reaction did not proceed
involved nitrene by repeating the reaction in the presence of at all. Replacing EtOH as the solvent with iPrOH did not
isoprene as a triplet nitrene quencher. The addition of isoprene change the yield of 2a. A chromatographic separation of the
lead to a significantly increased yield of 3-amino-6-nitro-2,1- reaction mixture obtained by photolysis of 1a in alcohols
benzisoxazole and an insignificant decrease of the primary showed that 2a had formed as the sole product. In this case,
amine yield. Thus it was demonstrated that the formation of neither the formation of 3a nor the corresponding 2-ethoxy- or
3-amino-6-nitro-2,1-benzisoxazole goes through an intermedi- 2-isopropoxy-substituted azepines could be detected.
ate singlet nitrene.
The photolysis in a mixture of 1,4-dioxane/water led to a de-
Possibly, similar to the benzofuroxan and 3-amino-6-nitro-2,1- creased yield of 2a with a simultaneous increase in the yield of
benzisoxazole formation, the carboxylate group of A (Lewis 3a. In our opinion, this effect of the solvent or base on the yield
base) donates an electron lone pair to the electron-deficient of 2a may be explained by the formation of 2a through a hetero-
singlet nitrene fragment of A (Lewis acid) with formation of the cyclization of 2-azidobenzoate anions. Therefore, the role of the
N–O bond in 2 through a 1,5-electrocyclization reaction base in the reaction is the in situ generation of the 2-azidoben-
[56,57].
zoate anion and the solvent efficiently supports this formation.
Nonreacted singlet nitrenes A may undergo intersystem The best yield of 2a was obtained by photolysis of 1a in ethanol
crossing (ISC) into the less reactive triplet state (Scheme 1, in the presence of sodium acetate (Table 1, entry 14).
intermediate D). Although a multiplicity change is a spin-
forbidden transition, it can be partially allowed in some cases. With the optimal conditions at hand, we next investigated the
According to another report [39], the major products formed scope of the cyclization using differently substituted 2-azido-
from triplet nitrenes are primary amines 4 through hydrogen- benzoic acids (Table 2). The desired products 2b–f were isolat-
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Beilstein J. Org. Chem. 2016, 12, 874–881.
Table 1: Optimization of conditions for the synthesis of substituted 2,1-benzisoxazole-3(1H)-ones.a
Entry
Base (equiv)
Solvent
Yield (2a)b
Yield (3a)b
t, minc
1
–
1,4-dioxane
–
–
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
2
–
EtOH
38%
63%
75%
75%
43%
75%
65%
73%
70%
70%
60%
30%
75%
63%
1%
–
3
K2CO3 (0.5)
K2CO3 (1)
K2CO3 (1)
K2CO3 (5)
K2CO3 (3)
Na2CO3 (0.5)
Na2CO3 (1)
NaHCO3 (0.5)
NaHCO3 (1)
KOH (1)
EtOH
4
EtOH
–
5
iPrOH
–
6
1,4-dioxane/water 1:1 (v/v)
8%
–
7
EtOH
8
EtOH
–
9
EtOH
–
10
11
12
13
14
15
EtOH
–
EtOH
–
EtOH
–
NaOH (1)
NaOAc (1)
NaOAc (1)
Water
12%
–
EtOH
1,4-dioxane/water 1:1 (v/v)
20%
aReaction conditions: 1a (0.78 mmol), solvent (15.0 mL); UV light (2 × 15 W Hg low-pressure lamp (254 nm), UV intensity was approximately
7 mW/cm2). bYields were determined by HPLC analysis using an external standard. cIrradiation time: the degree of conversion of 1a was 100%.
The thermal stability of the products of 2 decreases in the
Table 2: Substrate scope for the heterocyclization of 2-azidobenzoic
acid.a
series: 2f > 2a > 2e > 2d > 2c > 2b. Halogen-substituted com-
pounds 2b–e decompose at room temperature within about
5–30 min and the products 2a,f are stable for a couple of hours.
In general, azides with electron-withdrawing groups tend to
give higher yields than those substituted with electron-donating
groups (2b−e vs 2f, Table 2, entries 2–5 vs entry 6). However,
the yield of 2 decreased in the series Cl → Br → I (2b–e,
Table 2, entries 2–5), which was probably a manifestation of the
internal photochemical heavy-atom effect [60]. The presence of
bromo- or iodo-substituents in the substrates 1c–e increases the
probability of intersystem crossing for the initially formed
singlet nitrenes (Scheme 1, intermediate A) to the triplet state
(Scheme 1, intermediate D), thus resulting in decreased yields
of the cyclization products 2c–e. In these cases, the formation of
the triplet nitrene D should lead to increased yields of primary
amines. However, as can be seen from Table 1, the formation of
the latter was not observed when ethanol was used as the sol-
vent. To further test the solvent effect on the outcome of the
reaction, we repeated the photolysis of azides 1a–f under the
optimized conditions but in aqueous dioxane instead of ethanol.
Entry
R1
R2
Yield (2)b t, minc
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)d
6 (1f)
H
H
75% (2a) 60
92% (2b) 60
68% (2c) 60
62% (2d) 60
51% (2e) 60
Cl
Br
Br
I
Cl
H
Br
H
Tre
H
39% (2f)
60
aReaction conditions: 1 (0.78 mmol), NaOAc (1 equiv), EtOH 96%
(15.0 mL); UV light (2 × 15 W Hg low-pressure lamp (254 nm), UV in-
tensity was approximately 7 mW/cm2). bYield of the isolated product.
cIrradiation time: the degree of conversion of 1a–f was 100%. dFor the
optimal conditions for synthesis of 2e see Table 4, entry 10. eTr – tri-
phenylmethyl group (trityl group).
ed in moderate to high yields (Table 2). Both electron-with- As can be seen in Table 3, the photolysis of 1c,d in a 1,4-
drawing groups (Cl, Br, I) and the electron-donating group (tri- dioxane/water mixture under these conditions lead to decreased
phenylmethyl) were well-tolerated.
yields of 2c,d and to the formation of azepine 3c and primary
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Beilstein J. Org. Chem. 2016, 12, 874–881.
Table 3: Scope for photo-induced heterocyclization of 2-azidobenzoic acids in 1,4-dioxane/water mixture in the presence of potassium carbonate.a
Entry
R1
R2
Yield (2)b
Yield (3)b
Yield (4)b
t, minc
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)
6 (1f)
H
H
25% (2a)
92% (2b)
34% (2c)
62% (2d)
5% (2e)
20% (3a)
– (3b)
– (4a)
90
Cl
Br
Br
I
Cl
H
– (4b)
60
18% (3c)
– (3d)
10% (4c)
4% (4d)
– (4e)
180
60
Br
H
– (3e)
120
60
Tr
H
40 % (2f)
– (3f)
– (4f)
aReaction conditions: 1 (0.78 mmol), K2CO3 (1 equiv), 1,4-dioxane/water 1:1 (v/v) (15.0 mL); UV light (2 × 15 W Hg low-pressure lamp (254 nm), UV
intensity was approximately 7 mW/cm2). bYields determined by HPLC analysis using an external standard. cIrradiation time: the degree of conversion
of 1a–f was 100%.
amines 4c,d with significant yields. An explanation for the de- HPLC monitoring) was found to be 100% and azepine 3c was
creased yields observed for isoxazoles 2c,d may be the photo- isolated after preparative column chromatography in 50% yield
induced breaking of the C–Br bond that completely changed the (see Supporting Information File 1).
way of the reaction. However, this possibility does not explain
the formation of primary amines 4c,d.
As is also shown in Table 3, the high photochemical sensitivity
of both the C–I bond and the azide group present in 1e, unlike
It should be noted that the photolysis of double ortho-substi- the others, complicates the synthesis of benzisoxazolone 2e.
tuted azides (Table 3, entries 2, 4, R2 ≠ H) did not lead to the The photolysis of 1e under these conditions resulted in the for-
formation of azepines 3. This confirms the suggestions of mation of several products in low yields. Therefore, the synthe-
previous reports [61,62] about the impossibility of ring expan- sis towards benzisoxazolone 2e was reoptimized (Table 4). It
sion of such aryl azides.
was found that increasing the amount and strength of the base
resulted in an increased selectivity and reaction rate. Indeed,
Interestingly, under these conditions (Table 3), the yields for using 10 equiv of sodium hydroxide as the base in the reaction
3H-azepine 3a and 3c were determined as 20 and 18%, respec- resulted in a 51% yield of benzisoxazole 2e at complete photol-
tively. We wondered if the yields of these compounds could be ysis of 1e (Table 4, entry 10). Under these conditions, in addi-
improved to allow a preparative synthesis of 3a and 3c. For this tion to compound 2e, the formation of 2a together with some
reason, the reaction conditions were optimized towards azepines other unidentified products was observed (albeit in low yields).
3a and 3c. According to previously published reports A similar observation has been previously reported by Platz et
[30,63,64], the yields of the corresponding 3Н-azepines could al. [65].
be increased by increasing the amount of the nucleophile
(water) present in the reaction mixture. Thus, we attempted the Based on the results mentioned above and described in the
preparative synthesis of 3a based on our technique described related reports (Scheme 1), a possible reaction mechanism for
earlier [30]. After irradiating a solution of azide 1a in aceto- the formation of 2 was proposed (Scheme 2). At first, 1 pro-
nitrile/water (3:7, v/v) for 24 h in a quartz reactor, a complete duced a salt of 2-azidobenzoic acid 1 (Scheme 2, 1-anion) by
conversion of starting compound 1a according to HPLC moni- neutralization of a base. Next, the salt was decomposed by irra-
toring was observed. Following work-up and preparative diation and the singlet nitrene A (Scheme 2, intermediate A)
column chromatography azepine 3a could be isolated in was formed. Finally, the electron pair of the carboxylic group
50% yield. For the preparative synthesis of 3c the method had (Scheme 2, intermediate A) was joined by 1,5-electrocycliza-
to be slightly modified: In this case the reaction was performed tion to the electron-deficient singlet nitrene A with formation of
in 1,4-dioxane/water (1:10, v/v) solution and irradiated for 1.5 h 2-anion (see Scheme 2), which was neutralized by water (path
in a quartz reactor. After this, the conversion of 1c (according to I). Thus, the first path of cyclization of 1 was realized.
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Beilstein J. Org. Chem. 2016, 12, 874–881.
Table 4: Optimization of conditions for the synthesis of 5-iodo-2,1-benzisoxazole-3(1H)-one (2e).a
Entry
Base (equiv)
Solvent
Yield (2e)b
t, minc
1
–
1,4-dioxane/water 1:1 (v/v)
6%
60
2
–
EtOH
12%
16%
10%
5%
140
60
3
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1.4)
NaOAc (1.2)
KOH (2.8)
KOH (2.8)
KOH (10)
KOH (10)
EtOH
4
EtOH
160
60
5
1,4-dioxane/water 1:1 (v/v)
6
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
14%
13%
30%
18%
51%
34%
60
7
90
8
90
9
110
60
10
11
90
aReaction conditions: 1e (0.78 mmol), solvent (15.0 mL); UV light (2 ×15 W Hg low-pressure lamp (254 nm), UV intensity was approximately
7 mW/cm2). bYields determined by HPLC analysis using an external standard. cIrradiation time: the degree of conversion of 1e was 100%.
Scheme 2: Proposed reaction mechanism of the base-mediated photochemical cyclization of 2-azidobenzoic acids.
Meanwhile a molecular form of 1 produced azepine 3 (path II) Conclusion
by irradiation. The detailed mechanism of the formation of 3 is In summary, we have developed an effective photochemical
shown in Scheme 2.
cyclization strategy for the synthesis of functionalized 2,1-
benzisoxazole-3(1H)-ones. The present work offers a method to
Thus, in the photochemical reaction both ionic and molecular access 2,1-benzisoxazole-3(1H)-ones in good yields by using
forms of 1 can be used. To increase the yield of 2, it is neces- mild reaction conditions at room temperature. The proposed
sary to shift the equilibrium towards the ionic form 1 (in situ photochemical strategy permits the synthesis the high thermo-
salt formation).
labile compounds from the class of 2,1-benzisoxazole-3(1H)-
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Beilstein J. Org. Chem. 2016, 12, 874–881.
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Supporting Information File 1
Experimental procedures, characterization and spectral data
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