Route optimization, coupling reaction

The Heck coupling reaction appeared to be a route of choice to achieve the synthesis of the modified-DIOP ligands. We previously studied the palladium-catalyzed coupling of acrolein and acrolein acetals with several polyaromatic and heteroaromatic bromides either in the presence of homogeneous or heterogeneous catalytic systems (6, 7). After optimization of the reaction conditions, high conversions and selectivities were achieved except with anthracenyl derivatives (8). Based on these results, we developed the synthesis of the desired ligands. The... 

With the desired aldehyde in hand, we next turned our attention to optimizing the thiazolium-catalyzed coupling reaction. E q)osing this aldehyde to a mixture of tosylamide 13, thiazolium catalyst and TEA in THE provided the desired ketoamide 20 in 94% yield. Cyclization widi iV-methylamine as previously described provided imidazole 12 in 94% yield. Removal of the Cbz group provided corq oimd 1. This route provides the desired conq)ound 1 in S steps and 56% overall yield from 2-chloro-4-cyanopyridine. 

It became apparent that the optimal route towards the desired con5>ound 1 would involve the thiazolium-catalyzed coupling reaction of aldehyde 19 with the tosyl amide 13. In order to optimize this desired transformation we decided to investigate the scope of this new reaction as well as understand its mechanistic underpinnings. The first parameter to investigate was the scope of reaction with respect to the aldehyde-coupling partner (Table 1.)... 

In 2009, Majumdar and coworkers developed a new efficient route for the synthesis of polycyclic sultones via ligand-free Pd-catalyzed intramolecular coupling reaction (Scheme 4.15) [22]. Using the optimized condition [Pd(PPh3)4/ TBAB/KOAc/DMF/100°C], benzenesulfonic acid 2-bromophenyl esters were successfully cyclized to afford the sultone in 90% yield. 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

The Merck process group in Rahway has developed two syntheses of rizatriptan (4) utilizing palladium catalyzed indolization reactions (Schemes 19 and 20). Both routes start from the iodoaniline 51, which was prepared by reaction of 47 with iodine monochloride in the presence of CaCOa. " Palladium catalyzed coupling of iodoaniline 51 with bis-triethylsilyl protected butynol in the presence of NaaCOa provided a mixture of indoles 52a and 52b. This mixture was desilylated with aqueous HCl in MeOH to furnish the tryptophol 53 in 75% yield from 51. Protection of the alkyne prevented coupling at the terminal carbon of the alkyne and tnethylsilyl (TES) was found to be optimal because it offered the correct balance between reactivity (rate of coupling) and... 

The solvent-free, microwave-assisted coupling of thienyl boronic acids and esters with thienyl bromides, using aluminum oxide as the solid support, served to rapidly check the reaction trends on changing times, temperature, catalyst, and base and easily optimize the experimental conditions to obtain the desired product in fair amounts. This procedure offers a novel, general, and very rapid route to the preparation of soluble thiophene oligomers. Quaterthiophene 265 was obtained in 6 min by reaction of 2-bromo-2,2 -bithiophene with bis(pinacolato)diborane(4) in 65% yield, whereas dithiophene 266 was obtained with 70% yield. The synthesis of new chiral 2,2 -bithiophenes also was reported. The detailed... 

It might be noted that it is possible to conduct the exchange between i-BuLi and a primary iodide at temperatures significantly higher than those commonly used in academic research laboratories. A study of the reactions of 1-iodooctane, a representative primary aUcyl iodide, with i-BuLi at 0°C in a variety of solvent systems composed of heptane and various ethers demonstrated that an optimal ether-heptane ratio, which varied for each of the ethers studied, was found to maximize the extent of lithium-iodine exchange and minimize side reactions such as coupling and elimina-tion.3 Numerous examples of the utility of this general route to primary alkyUithiums may be found elsewhere, " ° and a few additional examples are summarized in Scheme 12.7." ... 

There was, however, a niggling problem with such a rationalization, which is outlined in Scheme 7b. The stereochemical aspect of neighboring group participation, is (sometimes) twinned with the kinetic aspect termed anchimeric assistance 18). Thus, the reaction of 31 should proceed through a dioxolenium intermediate 32 en route to the trans product. This assistance should be optimal for a trans-1,2 donors such as 22 and 25, and should cause them to react faster than the armed counterparts 21 and 24. Self-coupling of 22 and 25 should therefore have been the principal reaction pathways ... 

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