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Catalytic Chan – Lam coupling using a ‘ tube-in-tube ’ reactor to deliver molecular oxygen as an oxidant

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ABSTRACT

A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

No MeSH data available.


Scope of the catalytic Chan–Lam reaction in continuous flow.
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C2: Scope of the catalytic Chan–Lam reaction in continuous flow.

Mentions: Using the optimised conditions determined for the synthesis of compound 19, a small library was prepared to demonstrate the scope of the reaction conditions. Excellent isolated yields were obtained when anilines were used as the nucleophilic partner with both 4-methoxyphenylboronic acid (90% yield of 21) and phenylboronic acid (92% yield of 22) as the aryl donors (Scheme 2). Phenylboronic acid also gave a moderate isolated yield when coupled with 3-amino-5-bromopyridine as the nucleophile (50% yield of 23, Scheme 2) and a good isolated yield with the electron withdrawing 4-chloroaniline (71% yield of 24, Scheme 2). Using L-tyrosine methyl ester as the nucleophile with phenylboronic acid, unfortunately, gave a poor isolated yield of 26% and also underwent some epimerisation (25, 53% ee determined by chiral HPLC, Scheme 2). Additionally, a small amount of the product (25) reacted further with phenylboronic acid through the phenol to give 26 in 3% isolated yield. In the case of L-leucine methyl ester an isolated yield of 60% was realised, but this substrate also underwent partial epimerisation (27, 71% ee determined by chiral HPLC, Scheme 2).


Catalytic Chan – Lam coupling using a ‘ tube-in-tube ’ reactor to deliver molecular oxygen as an oxidant
Scope of the catalytic Chan–Lam reaction in continuous flow.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4979635&req=5

C2: Scope of the catalytic Chan–Lam reaction in continuous flow.
Mentions: Using the optimised conditions determined for the synthesis of compound 19, a small library was prepared to demonstrate the scope of the reaction conditions. Excellent isolated yields were obtained when anilines were used as the nucleophilic partner with both 4-methoxyphenylboronic acid (90% yield of 21) and phenylboronic acid (92% yield of 22) as the aryl donors (Scheme 2). Phenylboronic acid also gave a moderate isolated yield when coupled with 3-amino-5-bromopyridine as the nucleophile (50% yield of 23, Scheme 2) and a good isolated yield with the electron withdrawing 4-chloroaniline (71% yield of 24, Scheme 2). Using L-tyrosine methyl ester as the nucleophile with phenylboronic acid, unfortunately, gave a poor isolated yield of 26% and also underwent some epimerisation (25, 53% ee determined by chiral HPLC, Scheme 2). Additionally, a small amount of the product (25) reacted further with phenylboronic acid through the phenol to give 26 in 3% isolated yield. In the case of L-leucine methyl ester an isolated yield of 60% was realised, but this substrate also underwent partial epimerisation (27, 71% ee determined by chiral HPLC, Scheme 2).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

No MeSH data available.