Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (+/-)-codeine proceeds via the previously unknown alpha-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.

The potential safety hazards associated with the Mizoroki–Heck cross-coupling of bromobenzenes with styrenes were evaluated. The heat output from the reaction in various solvents was comparable in a variety of solvents; however, the rate of reaction was significantly faster in the presence of water. Thermal stability evaluation of the postreaction mixtures in DMSO and 3:1 DMSO/water by differential scanning calorimetry indicated that the onset temperatures of thermal decomposition were significantly lower than that of neat DMSO. Evaluation of the substrate scope revealed that the substitution pattern on the bromobenzene did not affect the heat output. The reaction rate of electron-deficient bromobenzenes was slower than that of the electron-rich bromobenzenes. In general, substituted styrenes afforded similar magnitudes of exotherms; however, the reaction rate of bromobenzene with 2-methylstyrene was significantly slower than the other studied styrenes. The predicted heat of reaction using the density functional theory method, B3LYP, was in good agreement with the experimental data. Such excellent agreement suggests that this calculation method can be used as a preliminary tool to predict heat of reaction and avoid exothermic reaction conditions. In many of the studied cases, the maximum temperature of a synthesis reaction was considerably higher than the solvent boiling point and thermal decomposition onset temperatures when the reaction was performed in DMSO or 3:1 DMSO/water. It is crucial to understand the thermal stability of the reaction mixture to design the process accordingly and ensure the reaction temperature is maintained below the onset temperature of decomposition to avoid potential runaway reactions.

2006Carboxylic amides P 0320New Reagent for Convenient Access to the α,β-Unsaturated N-Methoxy-N-methyl-amide Functionality by a Synthesis Based on the Julia Olefination Protocol.-A readily available, crystalline reagent for the transformation of aldehydes into chain-elongated unsaturated Weinreb amides is presented. -(MANJUNATH, B. N.; SANE, N. P.; AIDHEN*, I. S.; Eur.

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A new reagent for the synthesis of the α,β-unsaturated Nmethoxy-N-methyl-amide structural unit has been developed. 2-(Benzo [d]thiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide, a crystalline solid with an indefinite shelf life that can be easily prepared in two convenient steps from 2-In contrast to the α,β-unsaturated ester structural unit which boasts a rich chemistry and has often been a common target in organic synthesis, the interest in the α,β-unsaturated N-methoxy-N-methyl-amide structural unit has found a significant surge only in recent times. This unit has served as a valuable functionality in many synthetic endeavours [1] because of the presence of a versatile N-methoxy-N-methyl-amide functionality, popularly known as Weinreb amide (WA).[2] WA has been an excellent carbonyl equivalent with large applications in organic synthesis exclusively because of its ease of preparation and its versatile reactivity, for example, in nucleophilic addition and selective reduction reactions to form aldehydes.[3] Among the many applications of the α,β-unsaturated N-methoxy-N-methylamide functionality, this structural unit has shown unique distinction on two occasions. In the light of the fact that α,β-unsaturated aldehydes and ketones have been poor substrates for the asymmetric dihydroxylation (AD) process, the facile and convenient AD process at the α,β-unsaturated Weinreb amide has brought to the surface their importance for indirect access to these functionalities.[4] A similar advantage has been observed during cyclopropanation of α,β-unsaturated N-methoxy-N-methyl-amide for indirect access to α,β-cyclopropyl ketones, particularly when well-documented direct cyclopropanation of α,β-unsaturated ketones failed. Currently, two approaches are available in the literature to obtain the α,β-unsaturated N-methoxy-N-methyl-amide structural unit. The first approach, based on Wittig carbonyl olefination, uses N-methoxy-N-methyl-2-(triphenylphosphoranylidene)acetamide [6] or its Horner-WadsworthEmmons (HWE) variant, [7] whereas the second approach makes use of N-methoxy-N-methyl-2-(phenylsulfinyl)acetamide [8] as a reagent for reaction with alkyl halides to furnish the same target. Although the former approach shows significant potential for general use, the latter has been severely restricted to nonfunctionalized and simple substrates. None of the approaches have been used to extend the chain on aldehydes from the carbohydrate domain. Our own Figure 1. Reaction of reagent 2 with various aldehydes to give α,β-unsaturated Weinreb amides.