DOI: 10.1002/asia.201901647
Full Paper
KOtBu-Catalyzed Michael Addition Reactions Under Mild and
Solvent-Free Conditions
Dedicated to Prof. Amitava Das on the occasion of his 60th birthday
Abstract: Designed transition metal complexes predomi-
nantly catalyze Michael addition reactions. Inorganic and or-
ganic base-catalyzed Michael addition reactions have been
reported. However, known base-catalyzed reactions suffer
from the requirement of solvents, additives, high pressure
and also side-reactions. Herein, we demonstrate a mild and
environmentally friendly strategy of readily available KOtBu-
catalyzed Michael addition reactions. This simple inorganic
base efficiently catalyzes the Michael addition of underex-
plored acrylonitriles, esters and amides with (oxa-, aza-, and
thia-) heteroatom nucleophiles. This catalytic process pro-
ceeds under solvent-free conditions and at room tempera-
ture. Notably, this protocol offers an easy operational proce-
dure, broad substrate scope with excellent selectivity, reac-
tion scalability and excellent TON (>9900). Preliminary
mechanistic studies revealed that the reaction follows an
ionic mechanism. Formal synthesis of promazine is demon-
strated using this catalytic protocol.
Introduction
CÀC bond employing carbon nucleophiles are very well devel-
oped.[13] In contrast, Michael additions based on heteroatom
nucleophiles are less explored, which can be attributed to the
lower nucleophilicity. Often such heteroatom-Michael additions
also suffer from reversibility of the addition step. Thus, various
stoichiometric bases are used to deprotonate the heteroatom
nucleophiles so that reaction can proceed with anionic nucleo-
philes. Development of efficient catalytic protocol for the oxa-
and aza-Michael additions is highly desirable as alcohols and
amines are cheap industrial feedstock chemicals that can pro-
duce valuable products in chemical synthesis. Thus, a variety
of organic and inorganic bases were reported, which catalyzed
the Michael addition reactions with limited success and often
suffer from the requirement of solvents, additives, and high
pressure conditions.[14–29]
The development of a mild, atom-economical, and simple cata-
lytic process that can selectively and rapidly increase molecular
complexity starting from readily available compounds, espe-
cially from green renewable feedstock (e.g., alcohols, esters,
amines and alkanes) is an important objective for both aca-
demia and industry. In this direction, the Michael addition reac-
tion is one of the fundamental and efficient method for the
construction of CÀC and CÀX (X=O, N, P, Si, etc.) bonds.[1,2]
Arthur Michael discovered this reaction in 1887. Owing to the
complete atom economy, the addition of H-Nu (Nu=CR3, OH,
NR2, SR, etc.) to carbon-carbon multiple bonds is one of the
most desired and extensively studied synthetic transformations
in organic synthesis. The advantages of using abundant and in-
expensive starting materials are explored in several industrial
processes. Despite these tremendous progresses made in Mi-
chael addition reactions, method still operated using stoichio-
metric amount of strong bases, often reactions are not com-
patible with various functional groups and involve deleterious
side reactions.
The ability of transition metal complexes for the X-H (X=C,
N, O, S, etc.) bond activation is very well established over the
past decades. Thus far, various transition metal catalysts were
employed in Michael addition reactions and notable such cata-
lysts I–IX are summarized in Scheme 1.[30–38] Ru and Cu cata-
lyzed oxa-and aza-Michael addition reactions were report-
ed.[30–32,35] Nickel pincer complexes were found to catalyze aza-
Michael addition reactions.[33,37] Recently, Re and Mn pincer
complexes were revealed to catalyze the Michael addition of
alkyl cyanide derivatives to a,b-unsaturated esters and carbon-
yls.[34,38] Notably, Michael acceptors of a,b-unsaturated nitriles
have not received much attention as that of corresponding
carbonyl acceptors. This discrimination is attributed to lower
reactivity of acrylonitriles towards conventional nucleophiles.
Recently, the groups of de Vries and Otten have reported the
oxa-Michael addition reaction of alcohols to unsaturated ni-
triles utilizing Milstein PNN pincer ruthenium catalyst.[36] Very
recently, Milstein group have reported manganese pincer com-
plex catalyzed oxa-and aza-Michael addition reactions with un-
saturated nitriles.[39] Despite these advances, the addition of
Oxa-,[3–5] aza-,[6–8] thia-,[9–11] and phospha-[12] Michael addition
reactions are the conceptual extension to heteroatom-centered
anions. Utility of the Michael additions for the construction of
[a] S. Thiyagarajan, Dr. V. Krishnakumar, Prof. C. Gunanathan
School of Chemical Sciences
National Institute of Science Education and Research (NISER)
HBNI, Bhubaneswar-752050 (India)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
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tional Conference on Organometallics and Catalysis (ICOC-2020). Click here
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