Tetrahedron Letters
Annulation chemistry based on tandem Michael addition-enamine
formation – An improved method for the preparation of 1-substituted-
2,3,5,6,7,8-hexahydroquinolin-4(1H)-ones
⇑
Andrew Glass, Tyler Higgins, David A. Hunt
Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, NJ 08628, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2-(but-2-enoyl)cyclohexan-1-one
2 with primary amines affords 1-substituted-
Received 7 August 2019
Revised 7 September 2019
Accepted 15 September 2019
Available online xxxx
2,3,5,6,7,8-hexahydroquinolin-4(1H)-ones through a tandem Michael addition/enamine formation reac-
tion sequence at room temperature in high yields. Reaction times are greatly reduced (4–24 h vs. 1–2 h;
reflux versus room temperature) when powdered 4 Å sieves are used.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Annulation
Michael addition
Enamine formation
Tandem reaction
Introduction and discussion
observed (3.5 h). No screening of other amines was reported. We
reasoned that since an enamine condensation was a key mechanis-
The first reported tandem reaction sequence adopted for the syn-
thesis of tropinone was reported by Robinson in 1917 [1]. However,
only recently has the adaptation of tandem reaction methodology
witnessed enormous growth due in no small part to the atom eco-
nomic nature of the process [2]. While our lab has been keenly inter-
ested in the utility of the Michael reaction as one of the featured
steps in tandem reaction methodology using b-nitrostyrenes as
the Michael acceptor [3], we have also investigated other Michael
acceptors [4]. Recently, our attention has been drawn to the use of
tic step (Scheme 2), we could reduce reaction time and utilize
milder conditions if a dehydration agent which might also function
as an acid catalyst was incorporated. Indeed, when we used molec-
ular sieve powder, we found that the reaction was typically com-
pleted within an hour at room temperature. A total of eight
derivatives were prepared using eight different primary amines
[6]. Although yields and conversion times varied, every reaction
saw successful conversion (as determined by GC/MS) to the enam-
ine product without significant byproduct formation.
Both toluene and dichloromethane were suitable solvents for
this reaction. The decreased nucleophilicity of the aromatic amines
led to both longer reaction times and the need for more forcing
reaction conditions. Aniline saw 64% conversion by GC after stir-
ring at room temperature, but the reaction had to run for 48 h.
3-Bromoaniline was far less reactive, and only provided 23% con-
version to the desired product after an overnight reflux in toluene.
Depending on the stoichiometry of the reactants and the nature
of the reaction, some reactions could be purified with a simple
aqueous acid workup to remove excess amine. The reactions are
easily purified via flash chromatography. The results of each reac-
tion are summarized in Table 1.
2-(but-2-enoyl)cyclohexan-1-one 2 as a Michael acceptor (Fig. 1).
During our work in this area, we sought to prepare substantial
quantities of the derivative 4 as a test substrate. While we were
able to prepare 4 via enamine chemistry, yields were very poor
(<10% isolated); however, employing crotonyl chloride quenching
of the
a-anion of cyclohexanone generated via LDA afforded the
derivative 2 yields ranging from 65 to 72%. Comparable attempts
to prepare 4 via LDA-mediated chemistry failed. (Scheme 1) [5].
A single reaction of n-butylamine with 2 has been reported [5].
The reaction was conducted in a 1:1 THF/water mixture employing
TsOH as the catalyst under reflux until the disappearance of 2 was
⇑
Corresponding author.
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Glass, T. Higgins and D. A. Hunt, Annulation chemistry based on tandem Michael addition-enamine formation – An improved
Glass, Andrew
