Ullmann condensation using copper or copper oxide as the reactant. Arylation of active hydrogen compounds (imides, amides, amines, phenol, benzoic acid, and phenylacetylene)

Abstract

Ullmann condensation using Cu or copper oxide as the reactant and using no base has been studied. Reactions of active N—H, O—H, and C—H compounds, RZH (imides, amides, amines, phenol, benzoic acid, and phenylacetylene), with mixtures of aryl halides and more than a stoichiometric amount of Cu or copper oxide (Cu2O or CuO) without addition of base lead to facile arylation of the active hydrogen compounds. In the arylation reaction Cu and copper oxides serve not only as the catalyst but also as the acceptor of halogen from aryl halide. The reactivity of phenyl halide, PhX, increases in the order PhCl < PhBr < Phl. Cu generally gives higher yields than Cu2O and CuO and, of the two copper oxides, Cu2O has the higher activity. The stronger the acidity of the active hydrogen compound (RZH), the more easily the compound is phenylated by the mixture of PhX and Cu; a roughly linear correlation between Ti, the temperature where the phenylation starts, and the pKa value of the active hydrogen compound has been observed. A mechanism involving initial formation of an RZ—Cu species by the reaction between RZH and Cu or copper oxide and ensuing attack of organic halide at the RZ—Cu species is proposed.

Synthesis and Structure-Activity Relationship of N-Arylrolipram Derivatives as Inhibitors of PDE4 Isozymes.

“…To illustrate our findings, we have arbitrarily chosen PDE4D activity for this correlation, however since none of our compounds shows significant isozyme selectivity, the results are similar for PDE4A and PDE4B (graph not shown). The correlation between the potencies of our compounds (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) at the two binding sites is surprisingly good, giving a regression coefficient of 0.88 (S.D. 0.26; pϹ 0.001).…”

“…As can be seen from Fig. 1, rolipram is the only compound which clearly stands out, while SB-207499 (3) is indistiguishable in its behaviour from the rolipram derivatives (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The data suggest that all of our compounds have a significantly improved l-PDE4/h-PDE4 ratio compared to rolipram and should therefore have a side effect profile similar to SB-207499.…”

“…The simple 3-benzyloxy ether (10) was about 5 fold less active than the corresponding benzoate (14), but the result was thought to be encouraging enough to warrant further investigation. As in the benzoate series the introduction of a pmethoxy group (17) lead to an improvement in the activity on all isozymes, however the most potent compound was found to be the 3-(3-methoxybenzyloxy)phenyl substituted rolipram (11).…”

“…This method pioneered by Yamamoto 17) proved to be very versatile for the synthesis of a wide range of N-arylrolipram derivatives in moderate to high yield. 18) In general aryl iodides were the preferred halides in these coupling reactions, whereas bromides only gave satisfactory results in the case of bromobenzene or when electron withdrawing groups were present (e.g.…”

“…The esters (14) and (15) were prepared in good yield by reacting 7 with the corresponding acyl halides in pyridine. The ether (17) was synthesized by alkylation of the sodium salt of 7 with 4-methoxybenzyl chloride in DMF. One of the key compounds in this series 4-(3-cyclopentyloxy-4-methoxyphenyl)-1-[3-(3-methoxybenzyloxy)phenyl]-pyrrolidin-2-one (11) could be prepared either by direct copper catalyzed coupling of 3-(3-methoxybenzyloxy)iodobenzene with rolipram (Table 1), or alternatively by reaction of 7 with 3-methoxybenzyl chloride in the presence of cesium carbonate (Table 2).…”