Short communication
Synthesis of 3-Phenyl-2,1-benzisoxazoles via Conversion of Diethyl a-(o-Nitroaryl)benzylphosphonates
Daniel Sulikowski and Mieczys l aw Mž^kosza
Institute of Organic Chemistry PAS, ul. Kasprzaka 44/52 01-224 Warszawa, Poland
* Corresponding author: E-mail: icho-s@icho.edu.pl Fax: 0048 22 632 66 81
Received: 24-10-2008
Dedicated to Professor Branko Stanovnik on the occasion of his 70'h birthday
Abstract
Diethyl a-(o-nitroaryl)benzylphosphonates readily available via ONSH reaction upon treatment with base undergo cyclization leading to 3-phenyl-2,1-benzisoxazole in high yields. Possible route for this transformation is discussed.
Keywords: Benzisoxazoles, cyclization, heterocycles, nitroarenes, phosphonates
1. Introduction
2,1-Benzisoxazoles (anthranils) form an important class of heterocyclic compounds having 10n-electron system. Due to multifacial reactivity, they are used as versatile intermediates in organic synthesis1and also as biologically active compounds acting as anti-inflammatory agents2 and glucohydrolase inhibitors.3 Their wide use in organic synthesis is a result of high susceptibility to reducing and oxidizing agents, thus they are intermediates in synthesis of o-amino- and o-nitrobenzophenones,4 the former are key educts in manufacturing benzodiazepines and other important heterocyclic systems.5 Furthermore, ant-hranils are susceptible to reaction with electrophiles6a and active in photochemical transformations to form azepine or acridanone derivatives.6b
Due to these properties of benzoxazoles, their synthesis has been of considerable interest. Perhaps, the simplest and the most efficient is method reported by Davis - reaction of arylacetonitriles with nitroarenes in the presence of KOH in aqueous alcohols.7 This method is however limited to nitroarenes bearing electron-withdrawing substituents in para-position. Wróbel has presented an alternative version of this reaction that is carried out in aprotic solvents in the presence of Lewis acid and DBU.8
Anthranils can be also produced via reduction o-ni-
trobenzoyl9a or o-nitrosobenzoyl9b compounds, dehydratation of o-nitrotoluenes9c and others.9d
2. Results and Discussion
In this communication we wish to present new efficient way for synthesis of 3-phenyl-2,1-benzisoxazoles from diethyl a-(o-nitroaryl)benzylphosphonates 1a-g.
During our studies on oxidative nucleophilic substitution of hydrogen (ONSH) in nitroarenes with carba-nions,10 we have recently developed an efficient synthesis of series a-(o- and p-nitroaryl)benzylphosphonates of via ONSH in nitroarenes with carbanion of diethyl benzylp-hopshonate (Scheme 1).
Scheme 1. Synthesis of a-(o- and p-nitroaryl)benzylphopshonates.
Using appropriate conditions we can direct this reaction selectively ortho to the nitro group, thus produce convenient starting material for synthesis of anthranils.11 Treatment of a solution of appropriate phosphonate 1a-g with 1.1 equiv. of t-BuOK in THF at -30 °C resulted in formation of dark-coloured mixture, indicating formation of the nitrobenzylic anion. Reaction must be kept under protective atmosphere of argon, otherwise some amounts of o-nitrobenzophenone derivative is formed. Bubbling air through solution of anion of 1f gave 5-met-hoxy-2-nitrobenzophenone in nearly quantitative yield. The mixture was allowed to reach slowly RT and kept at this temp., till the reaction was complete. Disappearing of the deep colour indicates completing of the reaction. It should be mentioned, that rate of the reaction is strongly affected by nature of substituents in the nitroaromatic ring, reaction of 2b or 2f is completed within 1 h, while the reaction of 2c needs about 7 d. After standard work-up products may be isolated by column chromatography or simple recrystallization (Scheme 2). Results of the reaction with other phosphonates are presented in Table 1. Majority of benzisoxazoles produced in this work were reported earlier. Their physicochemical data are identical with those reported.
Table 1.
Substrates				Products		
Z		Z		Yields	m.p.	Lit. m.p.
				[%]	[°C]	[°C]
H	1a	H	2a	79	51-52	53-558
3-Cl	1b	7-Cl	2b	71	89-90	-
4-N02	1c	6-N02	2c	43	173-174	174-17512
5-F	1d	5-F	2d	80	94-95	96-9713
5-Cl	1e	5-Cl	2e	85	114-115	116-1178
5-OMe	1f	5-OMe	2f	80	80-81	-
4-CN	1g	6-CN	2g	82	171-172	173-1748
Scheme 3. Hypothetical way of formation of 2,1-benzisoxazole system.
On Scheme 3 we present hypothetical way of transformations of a-(o-nitroaryl)-benzylphosphonates into 3-phenyl-2,1-benzisoxazoles. We suppose, that in the first step, stabilized ylide attacks nitrogen atom of the nitro group producing an intermediate analogous to that involved in the Horner-Wadsworth-Emmons reaction, which after elimination of diethyl phosphorane anion gives 3-phenyl-
Scheme 2. Cyclization of carbanions of a-(o-nitroaryl)-benzylphopshonates to 2,1-benzoxazole ring and oxidation of anions to o-nitrobenzophenones.
benzo[b]azete oxide (4). The later rearranges to benzisoxa-zole ring. Intermediacy 4 of has already been postulated on the way of pyrolytic transformation of 4-phenyl-1,2,3-ben-zotriazine 3-oxide in 2,1-benzisoxazoles.14
solvent was evaporated, and the residue was chromato-graphed on silica gel (hexane/ethyl acetate) giving 5-met-hoxy-2-nitrobenzophenone as an yellow, solidifying oil, 234 mg, 92% yield.
3. Conclusions
We have reported a new approach to the synthesis of 3-phenyl-2,1-benzisoxazoles staring from diethyl a-(o-ni-troaryl)-benzylphosphonates that can be easily obtained via ONSH in nitroarenes with carbanion of diethyl benzylphosphonate. Our method provides easy access to 3-phenyl-2,1-benzisoxazoles that can contain substituents in any position of the ring. We proposed also a hypotethi-cal route of transformation leading from phosphonate 1a-g to 3-phenyl-2,1-benzisoxazoles, postulating formation of benzo[&]azete oxide as an intermediate.
4. Experimental 4. 1. General remarks
Melting points are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Varian 400 MHz using CDCl3 as a solvent. Chemical shits are given in ppm relative to TMS as an internal standard, coupling constant J are given in Hertz. Electron impact mass spectra were recorded with an AMD 604 Inectra GmbH at 70 eV, Electron-spray mass spectra were recorded with MarinerTM. THF was distilled over potassium benzophenone ketyl. Silica gel Merck 60 (230-400 mesh) was used for column chromatography.
4. 2. General procedure for the synthesis of 2a-f
To a stirred solution of appropriate phosphonate (2a-f) (1.0 mmol) in THF (10 mL) cooled to -30 °C under argon atmosphere, 1.0 M solution of potassium tert-butoxide in THF (1.1 mL, 1.1 mmol) was added dropwise. Resulted dark solution was then allowed to reach RT. Progress of the reaction was monitored by TLC. After the reaction was finished, the reaction mixture was quenched with water, extracted with ethyl acetate, organic phase was dried with anhydrous magnesium sulfate and concentrated in vacuo. Solid residue was purified by column chromato-graphy and recrystallized from methanol.
4. 3. Oxidation of carbanion 1f with air
To the stirred solution on 1f (379 mg, 1 mmol) in THF (10 mL) cooled to -30 °C, 1.0 M solution of tert-BuOK in THF (1.5 mL. 1.5 mmol) was added. Dry air was passed through the reaction mixture that was allowed to reach RT. After about 20 min, when deep blue colour disappeared,
4. 4. Selected analytical data
7-chloro-2,1-benzisoxazole (2b). Yield 71%, mp 89-90 (MeOH). 1H NMR (400 HMz, CDCl3): 5d 8.02 ( 2H, dt, J = 6.8, 1.7), 7.74 (1H, dd, J = 8.8, 0.6), 7.60-7.52 (3H, m), 7.37 (1H, dd, J = 7.0, 0.6), 7.02 (1H, dd, J = 8.8, 7.0). 13C NMR (100 MHz, CDCl3): 5 165.3, 155.1, 130.8, 129.8,
129.4,	127.7, 126.8, 126.1, 124.8, 119.5, 115.5; EI (m/z, %) : 229 (100), 194 (90), 166 (59), 164 (12), 140 (10), 139 (12), 77 (33).
5-methoxy-2,1-benzisoxazole (2f). Yield 80%, mp 80-81 (MeOH). 1H NMR (400 MHz, CDCl3): 5 7.95 (2H, dd, J = 8.4, 1.3), 7.57-7.51 (3H, m), 7.47-7.43 (1H, m), 7.05 (1H, dd, J = 9.5, 2.2), 6.86 (1H, d, J = 1.8), 3.88 (3H, s). 13C NMR (100 MHz, CDCl3): 5 162.1, 156.7, 156.0,
129.5,	129.2, 128.8, 127.7, 126.1, 117.0, 114.3, 94.1, 55.4. ESI(+): 226 [MH]+ . Anal. Calcd. for C14H11NO2: C 74.65, H 4.95, N 6.33, N 6.22. Found: C 74.60, H 4.99
5-methoxy-2-nitrobenzophenone (3).15 1H NMR (500 HMz, CDCl3): 5 8.25 (1H, d, J = 9.2), 7.77-7.74 (2H, m), 7.60-7.56 (1H, m), 7.47-7.42 (2H, m), 7.08 (1H, dd, J = 9.2, 2.8), 3.92 (3H, s). 13C NMR (125 HMz, CDCl3): 5 193.1, 164.2, 139.5, 138.9, 135.9, 133.7, 129.1, 1^8.8, 127.0, 115.3, 113.4, 56.3. EI (m/z, %): 257 (12), 211 (17), 164 (90), 139 (13), 134 (11), 106 (16), 105 (100), 77 (45). HRMS-EI (m/z): [M]+ calcd for C14H11NO4, 257.07313; found, 257.06881.
5. References
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Povzetek
Dietil a-(o-nitroaril)benzilfosfonati so sintezno dostopni iz o-nitroarenov in dietil benzilfosfonata z oksidativno nukleo-filno substitucijo vodika (ONSH). Opisane so ciklizacije omenjenih fosfonatov v prisotnosti baze, ki vodijo do do 3-fe-nil-2,1-benzizoksazolov.