Intramolecular didehydro-Diels-Alder reaction and its impact on the structure-function properties of environmentally sensitive fluorophores.

Reaction discovery plays a vital role in accessing new chemical entities and materials possessing important function.1 In this Account, we delineate our reaction discovery program regarding the [4 + 2] cycloaddition reaction of styrene-ynes. In particular, we highlight our studies that lead to the realization of the diverging reaction mechanisms of the intramolecular didehydro-Diels-Alder (IMDDA) reaction to afford dihydronaphthalene and naphthalene products.

Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-Ynes.

The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate.

Cyclopenta[b]naphthalene cyanoacrylate dyes: synthesis and evaluation as fluorescent molecular rotors.

We describe the design, synthesis and fluorescent profile of a family of environment-sensitive dyes in which a dimethylamino (donor) group is conjugated to a cyanoacrylate (acceptor) unit via a cyclopenta[b]naphthalene ring system. This assembly satisfies the typical D-π-A motif of a fluorescent molecular rotor and exhibits solvatochromic and viscosity-sensitive fluorescence emission. The central naphthalene ring system of these dyes was synthesized via a novel intramolecular dehydrogenative dehydro-Diels-Alder (IDDDA) reaction that permits incorporation of the donor and acceptor groups in variable positions around the aromatic core.

Intramolecular dehydro-Diels-Alder reaction affords selective entry to arylnaphthalene or aryldihydronaphthalene lignans.

Intramolecular dehydro-Diels-Alder (DDA) reactions are performed affording arylnaphthalene or aryldihydronaphthalene lactones selectively as determined by choice of reaction solvent. This constitutes the first report of an entirely selective formation of arylnaphthalene lactones utilizing DDA reactions of styrene-ynes. The synthetic utility of the DDA reaction is demonstrated by the synthesis of taiwanin C, retrohelioxanthin, justicidin B, isojusticidin B, and their dihydronaphthalene derivatives.

Attachable solvatochromic fluorophores and bioconjugation studies.

The synthesis and utility of attachable cyclopenta[b]naphthalene solvatochromic fluorophores related to Prodan are described. Two fluorophores were selected for functionalization and bioconjugation studies. The skeletons were chemically modified to include reactive functional groups and showed minimal alteration of the optical properties when compared to the parent dyes.

Microwave-assisted intramolecular dehydrogenative Diels-Alder reactions for the synthesis of functionalized naphthalenes/solvatochromic dyes.

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to the preparation of new organic dyes. Although numerous strategies have been reported to access naphthalene scaffolds, many procedures still present limitations in terms of incorporating functionality, which in turn narrows the range of available substrates. The development of versatile methods for direct access to substituted naphthalenes is therefore highly desirable.

A thermal dehydrogenative Diels-Alder reaction of styrenes for the concise synthesis of functionalized naphthalenes.

Functionalized naphthalenes are valuable building blocks in many important areas. A microwave-assisted, intramolecular dehydrogenative Diels-Alder reaction of styrenyl derivatives to provide cyclopenta[b]naphthalene substructures not previously accessible using existing synthetic methods is described. The synthetic utility of these uniquely functionalized naphthalenes was demonstrated by a single-step conversion of one of these cycloadducts to a fluorophore bearing a structural resemblance to Prodan.

Synthesis and photophysical properties of a series of cyclopenta[b]naphthalene solvatochromic fluorophores.

The synthesis and photophysical properties of a series of naphthalene-containing solvatochromic fluorophores are described within. These novel fluorophores are prepared using a microwave-assisted dehydrogenative Diels-Alder reaction of styrene, followed by a palladium-catalyzed cross coupling reaction to install an electron donating amine group. The new fluorophores are structurally related to Prodan.

2,4-Diaminopyrimidine inhibitors of c-Met kinase bearing benzoxazepine anilines.

Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model.