Access to 5,5'-diaryl substituted 4,5,4',5'-tetrahydro[3,3']bi-isoxazolyl 2,2'-dioxides, 4,5,4',5'-tetrahydro[3,3']bi-isoxazolyls and [3,3']bi-isoxazolyls via an initial ring-opening of 3,4-dinitrothiophene 1

By means of an iodide-catalyzed nitrocyclopropane to 4,5-dihydroisoxazoline 2-oxide isomerization, the 1,1 ′ -dinitro-[1,1 ′ ]bi(cyclopropyl)s 5 , deriving from an initial ring-opening of 3,4-dinitrothiophene 1 , can be stereospecifically converted into the bisnitronates 6 . From these, successive N -oxide reduction [P(OMe) 3 /dioxane] and aromatization (DDQ/toluene) provide convenient access to the interesting 4,5,4 ′ 5 ′ -tetrahydro[3,3 ′ ]bi-isoxazolyls 7, and [3,3 ′ ]bi-isoxazolyls 8 , respectively.


Introduction
As part of a long-standing research project on the synthetic exploitability of the highly functionalized building blocks deriving from the ring-opening of nitrothiophenes, 2 we have recently reported on the cyclopropanation of the 1,4-diaryl-2,3-dinitro-1,3-butadienes 3 (Scheme 1, steps c and c′ ) .2b Thus, the employment of defective or excess diazomethane allows one to isolate the (nitrovinyl)-nitrocyclopropanes, 4, and the 1,1′-dinitro [1,1′]bi(cyclopropyl)s, 5, respectively: the latter being formed essentially as mixtures of a racemic pair [ (d,l)-5] and an optically inactive form (meso-5), whose relative amounts depend on the nature of Ar. 2b On the grounds of the well-known nitrocyclopropane-to five-membered cyclic nitronate isomerization (Scheme 2, step d), 3 compounds 4 and 5 represent promising precursors of isoxazoline-(step e) and/or isoxazole-derivatives (steps f 4 or e + f′ ) .In particular, the possible access to the [3,3′]-bi(heterocycle)s 6, 7 or 8 from 5 is surely appealing, given the limited number of reports on the preparation of such systems 5 as compared to the large number of papers and reviews devoted to the five-membered 1,2-oxaza ring itself. 6  The interest is surely well justified by the observation that, besides playing a pivotal role in numerous molecules of, e.g., medicinal or agricultural interest, 8a,9 such a heterocycle is a building block for a variety of polyfunctionalized cyclic or acyclic targets through ring modification and cleavage, 7c-e,8a -d,10 respectively: in the latter case, γ-amino alcohols, 1,3-diols, α,β-unsaturated ketones, and β-hydroxy ketones are significant examples.

8
We report here some interesting results on the transformation of compounds 5 into 6 and 7 and eventually into 8, which significantly expand the range of applicability of the ring opening of nitrothiophenes to the synthesis of heterocycles and, in particular, add to previous syntheses of isoxazoles via an overall ring-opening / ring-closure route.2a,11

Isomerization of the nitrocyclopropane moieties of 5: Synthesis of the bisnitronates 6
As anticipated in the Introduction, the literature offers a few brief reports 3 on the nitrocyclopropane-to isoxazoline N-oxide isomerization, which represents only a secondary, and rather occasional route to such interesting intermediates as the five-member cyclic nitronates. 5esides thermal activation, 3a both electrophilic (BF 3 .Et 2 O) 3a -or nucleophilic (NaI) 3b,c -catalysis have been employed, in every case ringexpansion reportedly occurring via the selective breakage of the more substituted bond of the cyclopropane ring (cf.Scheme 2).
The thermal isomerization of compounds 5 reported here was found to be excessively slow, leading to complex final mixtures, accompanied by more-or less extensive decomposition.The use of NaI in DMSO at 70 °C (Scheme 3) was found to be most convenient for driving the reaction to completion within reasonable times, and minimizing undesired processes.Furthermore, we have judged it useful to carry out the reaction separately on the (d,l)-and mesoisomers, in order to gain mechanistic insight into the process from its stereochemical outcome.In this regard, we should remark that, to our knowledge, the literature 3  On the other hand, the conservation in compounds 6 of two of the four original stereocenters of 5 enables easy monitoring of the stereochemical course of the isomerization, which is precluded in similar processes on single nitrocyclopropane moieties.
Entries 1 and 2 of Table 1 refer to the p-tolyl derivatives (d,l)-5a and meso-5a, which have been found to lead stereospecifically to (d,l)-6a and meso-6a, respectively.The stereochemistry of the two reaction products, characterized by remarkably different physical properties (such as m.p. or solubility in DMSO), but having practically indistinguishable 1 H-and 13 C-NMR spectra (see Experimental), has been ascertained by means of stereoselective HPLC analysis on chiral columns (equipped with UV-and CD detectors) (Figures 1 and 2).A similar stereospecificity has been confirmed by chiral chromatography in the case of the 1naphthyl derivatives (5b to 6b isomerization; entries 3 and 4); consistently, the isomerization of a mixture of the two stereoisomeric 2-thienyl bicyclopropyls 5c, for which any separation of practical significance is precluded, 2b leads to the isolation of two diastereomeric products, with stereochemistry again being assigned (Entry 5) on the grounds of chiral-chromatography results.
The low isomerization yield for meso-5c can be mainly attributed to the instability observed, in particular, for this stereoisomer.
The observed stereochemical outcome, (a), is undoubtedly of the outmost importance in the perspective, e.g., of a stereoselective synthesis of acyclic polyfunctionalized targets via ring opening of 6 or of the isoxazolines 7 therefrom (see below) and, (b), imposes severe restrictions on the reaction mechanism.Thus, the iodide-assisted process, which can be hypothesized (Scheme 4) to occur via double S N 2 nucleophilic displacement at the benzylic chiral carbon atoms (and hence double inversion, with eventual retention of configuration at the two surviving stereocenters of 6), requires that cyclization of the nitronate oxygen onto the postulated intermediate iodonitronate anion A − be faster than iodine exchange, which would lead instead, starting from either (d,l)-5 or meso-5, to a mixture of (d,l)-6 and meso-6.For the iodide-assisted ring-opening step, alternative mechanisms could be hypothesized which would justify nucleophilic attack onto the more sterically crowded benzylic carbon; anyway, the one advanced here could be rationalized in terms of a S N 2 transition state in which the reacting carbon center bears a residual positive charge. 12Ar

Scheme 4
As far as the structure of the final products 6a-c is concerned, the position of the Ar group on the isoxazole ring (i.e., at C-5) is guaranteed throughout by the low-field resonance of the methine proton which is, in compounds 6, adjacent to the heterocyclic oxygen.Thus, breakage of the more substituted bond of the cyclopropane rings of 5 is occurring here, in keeping with the literature reports. 3It should also be noted that the spatial distance between the two stereocenters of 6 (which are five bonds away, and therefore not expected appreciably to influence each other) is in agreement with the observed peculiar almost perfect superimposition of the 1 H-and 13 C-NMR spectra of the d,l-and meso-isomers for both 6a and 6c, with only minimal chemical-shift differences for 6b (see Experimental).

Reduction of compounds 6 to the 5,5'-diaryl-4,5,4',5'-tetrahydro[3,3']bi-isoxazolyls 7
The reduction of compounds 6 to the corresponding 4,5,4',5'-tetrahydro[3,3']bi-isoxazolyls 7 has been performed quite efficiently with P(OMe) 3 in dioxane at reflux (Scheme 5).The excellent results are collected in Table 2.As expected for a process which should not involve configurational changes at C-5, (d,l)-6 gives a single diastereoisomer, (d,l)-7, and meso-6 gives meso-7.This has been confirmed by a stereoselective HPLC analysis (Figures 3 and 4, relating to the p-tolyl derivatives 7a).Based on previously reported procedures 11,13 the aromatization of compounds 7 was performed with excess 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dry toluene at reflux (Scheme 6): different methodologies were less efficient in preliminary tests.Under the conditions employed, prolonged reaction times were required, with some time-depending decomposition of DDQ.Further addition of reactant (see Experimental) was found to be necessary to achieve disappearance (TLC) of substrate: interestingly, in each case, chromatographic separation of the final mixture allowed isolation (Table 3) of a secondary product, identified as the monoaromatization derivative, 9.While the effectiveness of the process clearly rests on the excellent overall balance, compounds 9 themselves are interesting "asymmetrized" building blocks for further manipulation.

Conclusions
The reactions of Schemes 3, 5, and 6 represent a novel access to compounds 6, 7, and 8, respectively, characterized by the interesting [3,3']bi-isoxazolyl building block, coupling easy procedures with satisfactory-to excellent yields.The 5 -6 transformation has furthermore allowed us, on stereochemical grounds, to advance a mechanism for the iodide-catalyzed nitrocyclopropane-to five-membered cyclic nitronate isomerization.Finally, the results of Table 3 show that the aromatization of 7 could also be exploited, thanks to its stepwise nature, for the synthesis of the partially aromatized compounds 9, which in turn represent appealing intermediates.

Experimental Section
General Procedures.Melting points were determined on a Büchi 535 apparatus and are uncorrected. 1 Column-or preparative-plate chromatographies were performed on silica gel using petroleum ether (b.p. 40-60 °C) and gradients (or appropriate mixtures) with CH 2 Cl 2 , Et 2 O, or EtOAc as eluents, the solvents being distilled before use.

Isomerization of 1,1'-dinitro-2,2'-diaryl[1,1']bi(cyclopropyl)s (5) to 5,5'-diaryl-4,5,4',5'tetrahydro[3,3']bi-isoxazolyl 2,2'-dioxides (6)
In a flask equipped with an argon inlet and a magnetic stirring bar, a solution of 5 (1 mmol) and dry NaI (2 mmol) in anhydrous DMSO (22 ml) was heated at 70 °C.At the end of the reaction (as judged by TLC analysis) the mixture was cooled to room temperature and diluted with brine.The precipitated product was then collected by filtration.In the case of the 2-thienyl derivative 5c, as the instability of the (d,l)-and meso-diastereomers does not allow a practical separation, 2b the reaction was performed on the crude final mixture from the bicyclopropanation; in this case the work-up of the isomerization required extraction with diethyl ether, the extracts then being washed with water and dried over Na 2 SO 4 .After removal of the solvent under reduced pressure a flash-chromatography on silica gel with gradients of petroleum ether (b.p. 40-60 °C) and ethyl acetate provided (d,l)-6c and meso-6c as pure samples.
H NMR and13C NMR spectra were recorded using CDCl 3 solutions at 200 and 50 MHz, respectively, with a Varian Gemini 200 spectrometer; TMS was used as internal standard and chemical shifts are reported as δ values (ppm).Analytical chromatography was performed on a HPLC system comprising a Waters model 510 pump, a Rheodyne model 7725i 20 µl injector, and a Jasco model CD 995 UV/CD detector.Chromatographic data were collected and processed using Millennium 2010 Chromatography Manager software (Waters Chromatography).