Herein, we have developed a new approach
for the synthesis of 11
to 21-membered macrolactones via intramolecular dehydrogenative coupling
of primary alcohols by using Ru-MACHO as a catalyst and Cs2CO3 as a base. This protocol generated 11–21-ring-sized macrocycles (26 derivatives),
free from an external oxidant or an additive, eliminating stoichiometric
reagents and producing only hydrogen as a byproduct.
A base-free
and acceptorless Ru-catalyzed dehydrogenative approach
has been developed for the synthesis of N-heterocycles
by using 1,3-dicarbonyls and amino alcohols through a domino sequential
enamine formation and intramolecular oxidative cyclization strategy.
This unified approach is also applicable for the synthesis of O-heterocycles
involving 2-hydroxybenzyl alcohol as a coupling reactant via consecutive
C-alkylation and intramolecular cyclization steps. The present protocol
is general for the synthesis of varieties of biologically important
scaffolds, such as tetrahydro-4H-indol-4-one, 3,4-dihydroacridin-1(2H)-one, and tetrahydro-1H-xanthen-1-ones
derivatives using a single catalytic system, viz. RuH2CO(PPh3)3. Environmentally benign H2O and H2 are the only byproducts in this domino process. Moreover,
RuH2CO(PPh3)3-catalyzed C3-alkylation
of tetrahydro-4H-indol-4-one using alcohol as a alkylating
partner is also described in this report. For the first time, a solvent-free
gram-scale reaction for the acceptorless dehydrogenative annulation
has been demonstrated. A plausible mechanism for the Ru-catalyzed
base-free and acceptorless dehydrogenative annulation of amino alcohols
or 2-hydroxybenzyl alcohols has been provided with several experimental
investigations and spectroscopic evidence.
Herein
we describe a new approach for end-to-end cyclization to
construct macrocycles through the inter/intramolecular dehydrogenative
coupling of alcohols and ketones in the presence of a Ru-MACHO catalyst.
This method is highly atom economical and sustainable and can be used
for many substrates. Additionally, this method results in the generation
of only water as the byproduct. Moreover, in this approach, high dilution
of the reactants is crucial for cyclization and high-yield macrocycle
synthesis.
An efficient continuous flow process
for the macrolactonization
of seco acids and diacids using diols in the presence of Mukaiyama
reagent (N-methyl-2-chloropyridinium iodide) has
been developed for medium to large sized macrocyclic lactones. In
comparison with other methods, the continuous flow process provided
good to high yield in a short reaction time. By using this methodology,
a wide range of macrocyclic lactones (11 compounds), dilactones (15
compounds), and tetralactone derivatives (2 compounds) with various
ring sizes (12–26 atoms in the core) were synthesized in just
35 min of residence time. Advantageously, macrolactonization under
the flow process is very elegant to handle the high dilution of reactants
with a defined perfluoroalkoxy alkanes (PFA) tube reactor volume (7
mL).
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