Cascade reactions of HDDA-benzynes with tethered cyclohexadienones: strain-driven events originating from ortho-annulated benzocyclobutenes.

Intramolecular net [2 + 2] cycloadditions between benzyne intermediates and an electron-deficient alkene to give benzocyclobutene intermediates are relatively rare. Benzynes are electrophilic and generally engage nucleophiles or electron-rich π-systems. We describe here reactions in which an alkene of a tethered enone traps thermally generated benzynes in a variety of interesting ways. The number of atoms that link the benzyne to C4 of a cyclohexa-2,5-dienone induces varying amounts of strain in the intermediates and products. This leads to a variety of different reaction outcomes by way of various strain-releasing events that are mechanistically intriguing. This work demonstrates an underappreciated class of strain that originates from the adjacent fusion of two rings to both C1-C2 and C2-C3 of a benzenoid ring - i.e. 'ortho-annulation strain'. DFT computations shed considerable light on the mechanistic diversions among various reaction pathways as well as allow more fundamental evaluation of the strain in a homologous series of ortho-annulated carbocycles.

Examples Showing the Utility of Doping Experiments in 1H NMR Analysis of Mixtures.

Here we provide examples that demonstrate the value of using properly designed and easily performed doping experiments to give insights about the nature of the analyte(s) present in a 1H NMR sample. Two mixtures, the first quite complex and the second far less so, have been chosen: (i) the crude pyrolysate from reaction of butyric acid in (supercritical) water at 600 °C and (ii) a mixture of two basic amines. In the former, 13 distinct carbonyl-containing compounds, ranging in relative concentration of nearly 2 orders of magnitude, were positively identified. The latter highlights the advantage of using a doping experiment as opposed to merely comparing the spectra from two separate samples containing the same analyte.

Trapping Reactions of Benzynes Initiated by Intramolecular Nucleophilic Addition of a Carbonyl Oxygen to the Electrophilic Aryne.

We describe here reactions in which a carbonyl oxygen atom initiates cascade reactions by nucleophilic attack on a covalently attached benzyne. The benzynes are produced by thermal cyclization of triynes via hexadehydro-Diels-Alder reaction. The initially produced oxocarbenium/aryl carbanionic zwitterion is protonated in situ by an external protic nucleophile (NuH) of appropriate acidity. The resulting ion pair (oxocarbenium+/Nu-) collapses through several different mechanistic manifolds, adding to the diversity of structural classes that can be generated.

ß-Methyl-δ-valerolactone-containing Thermoplastic Poly(ester-amide)s: Synthesis, Mechanical Properties, and Degradation Behavior.

Poly(ester-amide)s (PEAs) have been prepared from (glucose-derived) ß-methyl-δ-valerolactone (MVL) by reaction of MVL-derived diamidodiols with diacid chlorides in solution to form poly(ester-amide)s having alternating diester-diamide subunits. The PEAs formed by this method exhibit plastic properties and are of sufficiently high molecular weight to be tough, ductile materials (stress at break: 41-53 MPa, strain at break: 530-640%). The length of the methylene linker unit (n = 1,2,3) between amide groups of the diamidodiols affects the Young's modulus; longer linkers reduce the stiffness of the materials. This allows tuning of the properties by judicious choice of precursors. MVL was also converted to a diacid chloride that was then used to prepare a PEA that is 76 wt% MVL-derived. The degradation rates of suspensions of these new PEAs in basic aqueous media were benchmarked and their instability in aqueous acid was also observed. NMR studies were used to detect the hydrolytic degradation products of both these PEAs as well as a structurally simpler analog.

Coumarin (5,6-Benzo-2-pyrone) Trapping of an HDDA-Benzyne.

Although the parent 2-pyrone is known to react with simple o-benzynes to produce naphthalene derivatives, there appear to be no examples of the successful reaction of coumarin, a benzo-annulated 2-pyrone analogue, with an aryne. We report such a process here using benzynes generated by the hexadehydro-Diels-Alder reaction to produce phenanthrene derivatives (i.e., benzo-annulated naphthalenes). Density functional theory computations were used to help understand the difference in reactivity between 2-pyrone and the slower trapping agent, coumarin. Finally, the reaction of o-benzyne itself [from o-(trimethylsilyl)phenyl triflate and CsF] with coumarin was shown to be viable, although slow.

Acid catalysed rearrangement of isobenzofurans to angularly fused phthalides.

An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from isobenzofurans under transition metal free conditions has been reported. This process is very general for diverse gem-disubstituted isobenzofuran substrates. Control experiments supported the mechanism as the nucleophilic attack of the carboxylate onto the acid activated furan ring for the simultaneous ring closing-ring opening cascade followed by dehydration. This method serves as a greener alternative for the synthesis of angularly fused polycyclic phthalides.

Highly regioselective, electrophile induced cyclizations of 2-(prop-1-ynyl)benzamides.

We report an electrophile promoted, highly regioselective (∼100%) synthesis of 5-membered haloimidiates from 2-(1-alkynyl)benzamides under metal free conditions. The steric bulk in association with neighbouring group assistance at the propargylic carbon of an alkyne has been employed as the dictating factor to achieve the regioselectivity. A very broad structural diversity has been observed for propargylic alcohols and acetates, and for amide functional groups. Control experiments supported the role of the steric bulk as well as neighbouring group assistance from the oxygen atom of the substituent for the observed high regioselectivity.

Total synthesis of selaginpulvilins A and C.

An efficient formal total synthesis of two compounds from the selaginpulvilin family of natural products, selaginpulvilin A and C, has been successfully achieved. The tetradehydro Diels-Alder (TDDA) reaction between an enyne and alkyne has been utilized for the creation of the necessary fluorene skeleton. Attempts at the conversion of selaginpulvilin A to selaginpulvilin B, F and H were unsuccessful.

Formal total synthesis of selaginpulvilin D.

An efficient and mild synthetic strategy for the total synthesis of selaginpulvilin D has been reported. A highly chemoselective enyne-alkyne dehydro Diels-Alder reaction has been employed for the construction of the tricyclic fluorene framework present in the natural product selaginpulvilin D. An improved overall yield (10.5%) has been achieved for selaginpulvilin D, starting from commercially available m-anisaldehyde in 9 linear, operationally simple synthetic transformations.

Stereoselective, Cascade Synthesis of trans-Enynones through Coupling-Isomerization Reaction.

A mild, cascade methodology based on the modified Cadiot-Chodkiewicz reaction was developed for the stereoselective synthesis of trans-enynones. By this methodology, structurally divergent trans-enynones, which are embedded with sensitive functional groups, were synthesized. Control experiments suggested that the CuCl alone does not have a role in the isomerization step, whereas the CuCl-piperidine complex (formed during the cross coupling) may have a rate enhancing effect. Furthermore, additional sets of control experiments favor the involvement of unimolecular [1,2]-H shift rather than a homobimolecular proton abstraction during the isomerization step.