Exploring Cyclopropane-Heterocumulene [3+2] Intramolecular Cycloadditions on ortho- Benzylidene Scaffolds

We herein report on a new class of intramolecular [3+2] cycloaddition reactions potentially occurring in Naryl heterocumulenes ortho-substituted by a cyclopropylidenemethyl unit. The required isothiocyanates, ketenimines and carbodiimides were prepared following aza-Wittig processes of common phosphazene intermediates. To date, only carbodiimides seem to behave as suitable substrates for the desired cyclization. keywords: [3+2] cycloaddition reactions, heterocumulenes, cyclopropanes, carbodiimides

For an easy access to the starting materials, we planned to link the cyclopropane ring to the ortho position of the benzene ring through a methylidene unit, since abundant and simple synthetic methodologies for forming double C=C bonds are available.

Preparation of ortho-azidobenzylidenecyclopropane 9
To a stirred suspension of sodium hydride (60% in oil, 6 mmol) in anhydrous tetrahydrofuran (20 mL) cyclopropyltriphenylphosphonium bromide (6 mmol) was added, and the reaction mixture was heated at 60 ºC for 10 h. Next, a solution of 2-azidobenzaldehyde 7 (5 mmol) and tris [2-(2-methoxyethoxy)ethyl]amine (TDA-1) (0.5 mmol) in anhydrous tetrahydrofuran (15 mL) were added and the stirring was continued at the same temperature for 4 h. After that, the reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3 x 50 mL). The organic layers were combined, washed with brine (30 mL) and dried over anhydrous MgSO 4 . The solvent was removed under reduced pressure and the crude product so obtained was purified by silica gel column chromatography using hexanes as eluent.

Preparation of the phosphazene 10
To a solution of 1-azido-2-(cyclopropylidenemethyl)benzene 9 (6 mmol) in anhydrous dichloromethane (15 mL) triphenylphosphine (6 mmol) was added. The resulting mixture was stirred at reflux temperature under nitrogen for 4 h. Then, the solvent was removed under reduced pressure and the crude phosphazene was precipitated with diethyl ether and isolated by filtration.

3.-RESULTS AND DISCUSSION
The experimental study started with the selection of the phosphazene 10 as the optimal starting material for opening the access to a variety of heterocumulenic functions, such as ketenimine, carbodiimide and isothiocyanate, via aza-Wittig reactions. The synthetic way to compound 10 started with 2-aminobenzyl alcohol 5, which was treated with sodium nitrite and aqueous sulphuric acid, cooled at 0 ºC for 30 min, an aqueous sodium azide solution added with stirring at room temperature, and the mixture further stirred for 16 h, yielding 2-azidobenzyl alcohol 6. [3] In the next step, 2-azidobenzaldehyde 7 was obtained by the oxidation of the benzylic alcohol 6 with pyridinium chlorocromate (PCC) in dichloromethane (DCM) solution at room temperature for 2 h. [4] Next, a Wittig reaction served to install the cyclopropane ring.
Thus, cyclopropyltriphenylphosphonium bromide was added to a suspension of sodium hydride in anhydrous tetrahydrofuran (THF), at room temperature, and the mixture was heated at 60 ºC for 10 h, giving rise to a solution of the non-isolated cyclopropylidenephosphorane 8. was obtained by reaction of phosphazene 10 with 4-methoxyphenylisocyanate in anhydrous toluene solution at room temperature (Scheme 4). bond of the benzene ring and the C=C double bond of the benzylidene unit. [5,6]  With the aim of shedding light into which of these two reaction paths is the energetically most favourable one for the conversion of 11c into 4c we planned to carry out a DFT computational study, which is now underway. We are also currently studying in our laboratories the range of application of the above synthetic methodology for accessing to tricycles 4, attempting to increase the number of successful transformations of the 11 to 4 type.

4.-CONCLUSIONS
In this communication we have disclosed the successful preparation of two cyclopropane-heterocumulenes (isothiocyanate and carbodiimide) and the results obtained in our attempts of thermally inducing their respective intramolecular [3+2] cycloaddition reactions.
Only in the case of the carbodiimide 11c the expected cycloaddition occurred as planned yielding the corresponding pyrrolo [2,3-b]quinoline 4c. A dichotomy of mechanistic routes to explain that transformation has been proposed, which is now under scrutiny by DFT calculations.