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The multicomponent reaction of ethyl 3-aminocrotonate ( 1 ), substituted phenylisothiocyanates ( 2a – i ) and acetic anhydride ( 7 ), afforded facile access to a series of substituted 1,3-thiazine-6-phenylimino-5-carboxylates under mild conditions in 15–65% yields. Limited tolerance for modification of the anhydride moiety was noted with a significant reduction in yield for propionic and trifluoroacetic anhydrides. The use of benzoic anhydride favoured a two-component coupling product.

There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.

Two series (VI) and (XI) of norcantharidin analogues are synthesized using continuous flow hydrogenation in key steps.

Several norcantharidin derivatives (IV) are synthesized by substitution of the hydroxy group as well as further modifications in the side chain.

Raney-Ni catalyzed flow hydrogenation of α,β-unsaturated nitriles in methanol provides the title compounds (II), whereas Pd-C in acetone allows the selective reduction of the olefin double bond to give the saturated nitrile (III).

Four-component Ugi—Knoevenagel reaction of o-aminophenyl ketones (I) with aromatic aldehydes, cyanoacetic acid and isonitriles provides access towards polyfunctionalized quinolinones, e.g. (V) and (IX).

The four component Ugi reaction of 2-furaldehyde, an alkenoic acid (three examples), an isonitrile (eight examples) and an amine (eight examples) affords rapid access to a family of acetylenic furan analogues, which on heating undergo an intramolecular Diels–Alder (IMDA) reaction yielding highly substituted tricyclic lactams (17 examples) in good to excellent yields (38–72% two-steps). This Ugi-IMDA reaction proved to be highly substituent tolerant across both the isonitriles and amines examined. In one instance, with N,N-dimethylaminopropylamine, a second equivalent of alkynoic acid was required to afford a good yield of the desired tricyclic lactam.

Replacement of organic volatile compounds by the ionic liquid results in significant acceleration of the reaction of anhydrides (I) with functionalized amines (16 h versus 20 min).

A highly efficient, atom-economic, and mild protocol for the synthesis of highly substituted members of the title series and is described.

Aldehydes 2a – e react with tetraallyltin (1,0.25 equiv.) in methanol or other polar solvent at room temperature (ca 30°C

Treatment of acetals ( 1 and 2 ) and amino acetals ( 3–5 ) with either trifluoroacetic acid (TFA) or silica gel followed by tetraallyltin gave excellent yields of the corresponding homoallylic alcohols (68 – 100%).

Methanol promotes the addition of allyltrimethylstannane (1a) to isobutyraldehyde (2a, 30 degrees C) yielding the corresponding homoallylic alcohol (3a), without the necessity for added catalyst. The corresponding reaction of aldehydes 2a-e or activated ketone 2f with tetraallyltin (1b, 0.25 equiv) is substantially faster and proceeds in high yield (81-98%) and with easy separation of the product from tin residues. Aliphatic ketones 2g and 2h also react, but require more forcing conditions, Competitive experiments involving equimolar mixtures of selected aldehydes and ketones with 1b indicates very high aldehyde chemoselectivity. The reaction of 1b with aldehydes proceeds slowly at first, followed by a rapid acceleration which may be attributable to a build up of partially soluble tin(TV) methoxide. The increased rate of carbonyl allylation by 1a and 1b in methanol, relative to dimethyl sulfoxide, suggests that the primary activating influence of the solvent is via hydrogen bonding to the carbonyl oxygen. There is no NMR spectroscopic evidence for a significant change in the ground state structure of these allylic stannanes in methanol, relative to other solvents.

Tethering the N 6 -substituents of N 6 -substituted adenosines to N1 has resulted in a series of conformationally restricted adenosine analogues. The resultant diimidazo[1,2- c :4′,5′- e ]pyrimidines were shown to be adenosine A 1 selective.

Photolysis of tetrachlorodiazocyclopentadiene (1) in oxygen-saturated hydrocarbon solvents results in the transient formation of tetrachlorocyclopentadienone O-oxide (3). This rapidly decomposes, giving rise to products derived from oxidation of the hydrocarbons. Cyclopentane, cyclopentene, cycloheptane, cycloheptene, cycloheptatriene, and indene have been studied. Cycloheptatriene and indene gave only low yields of tractable products, but the others gave the corresponding ketones and secondary alcohols as the major products. Although yields varied considerably, the ketone and alcohol products were always obtained, within experimental error, in a 1 : 1 molar ratio. This observed product ratio supports the disproportionation of cycloalkyldioxyl radicals as a crucial step.

Ionic liquids based on the 1-butyl-3-methylimidazolium cation have been used as solvents for the preparation in good yield of homoallylic alcohols from tetraallylstannane and a range of aldehydes.

Thiazoles, including 2,7-dimethylthiazolo[4,5-d]pyradazine-4-(5H)-thione (4b) and the corresponding 5-phenylthiazolo[4,5-d]pyradazine-4-methylthiol (5a), were synthesized as part of an ongoing investigation into corticotrophin-releasing hormone (CRH) type 1 receptor activity. Subsequent screening indicated the successful discovery of receptor agonists. Assay results indicated a 52 and 3% increase in β-endorphin release after the administration of 100 M (4b) and (5a), respectively. It is believed that this represents the first evidence of this class of compounds displaying CRH type 1 receptor agonist activity.

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.

High pressure Diels-Alder reactions of furan and dimethylmaleate, and thiophene and maleimide resulted in two cantharidin analogues, 3 and 6 possessing PP1 selectivity (>40- and >30-fold selectivity) over PP2A. Both compounds exhibited moderate PP1 activity, 3 IC 50 50 μM and 6 IC 50 12.5 μM. Interestingly, the corresponding mono-ester derivatives of 3 showed no such selectivity.

We report a comparative study of the Knoevenagel condensation with a variety of substituted benzaldehydes (17 examples) and cyanoamides (3 examples), using three different methodologies: (a) traditional ethanol reflux; (b) water reflux; and (c) solvent free conditions. Almost without exception these reactions proceeded faster, more cleanly and in higher yields when the reactions were conducted in a solvent-free fashion. Additionally, our solvent free approach allowed the use of nitrobenzaldehydes, which failed to yield the desired products under traditional and water based approaches.

We have demonstrated the use of the room temperature ionic liquid, 1-butyl-3-methylimidazoliumhexafluorophosphate ([bmim]PF6), as an environmentally benign solvent for the preparation of isoquinoline derivatives through Bischler–Napieralski cyclization under mild conditions with excellent purity and yields. The role of HF as a catalyst in the reaction was also investigated.

Our group is currently developing in-field detection systems alongside the Australian Federal Police Forensic Services utilising molecularly imprinted polymers as the recognition elements. This review looks at MIP synthesis and our perceptions of future directions from an Australian and forensic perspective.

Opening of epoxides can be an effective means by which a variety of functional groups can be incorporated. In this letter, we outline how variation of conditions, in particular, that of solvent and concentration, give rise to different products using the Lewis acid catalyst BiCl3. (c) 2005 Elsevier Ltd. All rights reserved.

The reaction of 3-substituted indoles with 2-cyclohexenone under Lewis acid mediated conditions with Bi(NO3)3·5H2O has been investigated. We have demonstrated that electrophilic substitution of 3-substituted indoles with 2-cyclohexenone will readily occur at the nitrogen. Furthermore, the extent of regioselectivity is dependent on reaction solvent and the C3-substituent. Excellent conversion is obtained with good to excellent isolated yields of N- and C2-adducts. In general, more polar, aprotic solvents (CH3CN) give greater N-selectivity whereas with polar protic solvents (CH3OH) an increase in the C2-adduct is observed.

The reaction of α,β-unsaturated aldehydes with tetra-allystannane (1, 0.25 equivalents) results in regioselective 1,2-addition to generate the corresponding allylic-vinylic alcohols in good to excellent yields (> 90%). Reactions with the equivalent ketones also proceed well (15-91%j although requiring more forcing conditions. Under these conditions, a second reaction pathway was evident for ketones that were less substituted at C3, namely that of methanolysis at C3. In all instances these reactions are elegant in their simplicity and show high levels of atom efficiency not typically found in similar methodologies for the synthesis of allylic-vinylic alcohols.

We have explored the addition of tetraallylstannane ( 7 ) to a variety of N -protected Weinreb amides ( N -phthalimido and N -benzyl). Reactions were conducted in methanol and the ionic liquid, butylmethylimidazole tetrafluoroborate (bmim[BF 4 ]), yields of the corresponding N -protected allylketones were moderate to good. Allylation of the corresponding aminoaldehydes gave excellent yields of homoallylic alcohols (68–94%) and moderate to good diastereoselectivities (50–86%).