Catalysis by lithium perchlorate enables double-conjugate addition of electron-deficient maleimides to 2-aminopyridines and 2-aminothiazoles

Article abstract of DOI:10.1080/00397911.2011.580883

Lithium perchlorate has been found to catalyze the conjugate addition of maleimides with 2-aminopyridines and 2-aminothiazoles. The reaction proceeds under mild conditions leading to the corresponding double adducts in good yields. A plausible mechanism of this reaction has been proposed. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.580883

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Catalysis by Lithium Perchlorate
Enables Double-Conjugate Addition of
Electron-Deficient Maleimides to 2-
Aminopyridines and 2-Aminothiazoles
Tetiana Matviiuk a , Marian Gorichko a , Andriy Kysil a , Svitlana
Shishkina b , Oleg Shishkin b c & Zoia Voitenko a
a Department of Chemistry, Kiev National Taras Shevchenko
University, Kiev, Ukraine
b Division of Functional Materials Chemistry, State Scientific
Institution “Institute for Single Crystals” of National Academy of
Science of Ukraine, Kharkiv, Ukraine
c Department of Inorganic Chemistry, V. N. Karazin Kharkiv National
University, Kharkiv, Ukraine
Accepted author version posted online: 12 Jan 2012.Version of
record first published: 18 Jul 2012.
To cite this article: Tetiana Matviiuk , Marian Gorichko , Andriy Kysil , Svitlana Shishkina , Oleg
Shishkin & Zoia Voitenko (2012): Catalysis by Lithium Perchlorate Enables Double-Conjugate
Addition of Electron-Deficient Maleimides to 2-Aminopyridines and 2-Aminothiazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:22, 3304-3310
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Synthetic Communications1, 42: 3304–3310, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580883
CATALYSIS BY LITHIUM PERCHLORATE ENABLES
DOUBLE-CONJUGATE ADDITION OF
ELECTRON-DEFICIENT MALEIMIDES TO
2-AMINOPYRIDINES AND 2-AMINOTHIAZOLES
Tetiana Matviiuk,1 Marian Gorichko,1 Andriy Kysil,1
Svitlana Shishkina,2 Oleg Shishkin,2,3 and Zoia Voitenko1
1Department of Chemistry, Kiev National Taras Shevchenko University,
Kiev, Ukraine
2Division of Functional Materials Chemistry, State Scientific Institution
‘‘Institute for Single Crystals’’ of National Academy of Science of Ukraine,
Kharkiv, Ukraine
3Department of Inorganic Chemistry, V. N. Karazin Kharkiv National
University, Kharkiv, Ukraine
GRAPHICAL ABSTRACT
Abstract Lithium perchlorate has been found to catalyze the conjugate addition of
maleimides with 2-aminopyridines and 2-aminothiazoles. The reaction proceeds under mild
conditions leading to the corresponding double adducts in good yields. A plausible mech-
anism of this reaction has been proposed.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Synthetic Communications1 to view the free supplemental file.
Keywords Bis-adducts; conjugate addition; lithium perchlorate; maleimides
Received April 4, 2011.
Address correspondence to Tetiana Matviiuk, Department of Chemistry, Kiev National Taras
Shevchenko University, 64 str. Volodymyrska, Kiev, 01033, Ukraine. E-mail: tatyana.matviyuk@
iflab.kiev.ua
3304

CATALYTIC DOUBLE-CONJUGATE ADDITION
3305
INTRODUCTION
Michael and conjugate addition reactions offer efficient methods for the con-
struction of carbon–carbon and carbon–heteroatom bonds with wide applications
in organic synthesis.[1–4] These approaches have been used already in the synthesis
of pharmaceutical intermediates, peptide analogs, antibiotics, and other drugs.[5–7]
Such transformations are often performed without use of catalysts. On the other
hand, the search for new and efficient catalysts for various organic transformations
is a relevant area of research. Traditionally, conjugate additions are performed under
the influence of strong bases, but this approach often leads to the formation of unde-
sirable side products by polymerization, self-condensation, and other reactions. Vari-
ous alternative catalysts, such as phase-transfer catalysts, transition-metal complexes,
lanthanides, alumina,[8] and others have been proposed.[1,9] However, many of the cat-
alysts reported suffer from significant drawbacks, such as the use of expensive or non-
commercial reagents, coupled with long reaction times and poor yields. Thus,
development of new methods using cheap, commercially available, nontoxic catalysts
capable of generating products in good yields is of paramount importance.
Perchlorate salts have attracted attention as a simple yet efficient catalyst over
the past few years. It was discovered that metal perchlorates are powerful and selec-
tive catalysts that can usually be employed under mild reaction conditions, at rela-
tively low temperatures, with good tolerance to several spectator functional
groups.[10,11] In this respect, lithium perchlorate is of particular interest as a mild
and efficient Lewis acid catalyst because of low cost, ease of handling, and low tox-
icity. Yet, efficacy of lithium perchlorate as a catalyst was discovered only recently—
the first example of use of lithium perchlorate as an activator of carbonyl group was
reported in 2002 by Bartoli and Bosco[12] We hereby report our recent results on use
of LiClO4 as an efficient catalyst for series of conjugate addition reactions.[13,14] Our
current interest focused on maleimides because of the large number of biologically
active molecules containing the pyrolidine-2,5-dione motif.[15,16]
It is well known that molecules containing succinimide as a structural fragment
have been employed numerous times in drug design. For example, such drugs can be
effective anticonvulsant agents, capable of preventing the spread of the seizure within
the brain and, thus, offering protection against possible excitotoxic effects that may
culminate in the lethal brain damage.[17a–d] Some of succimide derivatives have shown
antiepileptogenic effects in animal models of epilepsy. That is, they either prevent the
expected development of epilepsy or can halt or reverse the progression of epilepsy.[18]
We present results of our study of the conjugate addition of 2-aminopyridines 3
and 2-aminothiazoles 6 to maleimides using catalytic amounts of LiClO4 as a Lewis
acid catalyst. This reaction proceeded under mild conditions to afford the double-
conjugate addition products (5a–e, 7a and 7b).
It was previously reported[19] that the reaction of 2-aminopyridine with maleic
anhydride gave tricarboxylic acid 1 (Scheme 1). Initially, the product 1 was obtained
in acetic acid in poor yield (8%). The carboxylic acid 2 was detected as an intermedi-
ate in this reaction.
In our research we have used N-aryl maleimides as electron-deficient reactants
in conjugate addition with 2-aminopyridines and 2-aminothiazoles. The reactions,
in general, proceed smoothly at room temperature, and the products (5a–e, 7a, 7b)

3306
T. MATVIIUK ET AL.
Scheme 1. Synthesis of 2-[3-(carboxymethyl)-2-oxo-2,3-dihydroimidazo [1,2-a]pyridine-3-yl]succinic
acid (1).
are obtained in good yields (Scheme 2, Table 1). Importantly, the reactions of
2-aminothiazoles with maleic anhydride reported earlier[20–22] yield simple amides
or N-thiazolyl-2-maleinimides via acylation of the exocyclic amino group under
much harsher conditions. Catalysis by lithium perchlorate is crucial for the success
of the synthesis. Indeed, in the absence of a suitable catalyst, the double-conjugate
addition of 2-aminothiazoles or 2-aminopyridines with maleimides simply fails.
The few examples of at least some reactivity in the absence of a catalyst between
[23]
the classes of compounds studied by us were reported by Augustin and Jeschke,
Scheme 2. Interaction of substituted 2-aminopyridines (3) and 2-amionothiazoles (6) with N-aryl
maleimides (4a–c).

CATALYTIC DOUBLE-CONJUGATE ADDITION
3307
Table 1. Bis-Michael adducts 5a–e, 7a and 7b produced via Scheme 2
Procuct
R
R0
Yield (%)a
5a
5b
5c
5d
5e
7a
7b
CH3
CH3
CH3
Cl
C6H5
73
68
62
50
56
80
43
4-CH3O-C6H4
4-CH3-C6H4
4-CH3O-C6H4
C6H5
Cl
H
C6H5
4-CH3O-C6H4
4-CH3O-C6H4
aFor all products, the yields are given after recrystallization.
and in that case, again, reaction occurred at the exocyclic amino group. In stark con-
trast to the catalytically enabled reactivity reported here, Diels–Alder reactions
between 2-aminohiazole and maleimide reported earlier yielded Diels–Alder adducts
only after reflux for 200 h.[24]
The structures of the products were confirmed by infrared (IR), (1H, 13C)
NMR, and mass spectroscopy. Apparently, this reaction has the same mechanism
as in the formation of 1 (Scheme 3).
First, 2-aminopyridine and 2-aminothiazole react with maleimide at the
endocyclic nitrogen atom (compound 8). Subsequent recyclization of the substituted
succinimide leads to formation of intermediate compound 10 (analog of 2). Alterna-
tively, this reaction can proceed another way when maleimide first reacts with amino
Scheme 3. Possible mechanism of the formation of 5 and 7.

3308
T. MATVIIUK ET AL.
Figure 1. Correlations in NOESY spectrum for compound 5a.
group of the heterocycle to afford adduct 11; however, nuclear Overhauser effect
spectroscopy (NOESY) experiments (Fig. 1 for 5a) showed strong correlations
between the proton in the a-position of the pyridine ring with the proton of methyl-
ene group in the side chain. Intermediate 10, being a relatively strong CH acid, reacts
with the second molecule of the maleimideto afford 5 and 7.
Finally, x-ray diffraction study of compound 7a confirms the structure of adducts
(Fig. 2). Vicinal arrangement of two bulky substituents at the C4 atom probably causes
[25]
˚
the elongation of the C4–C5 bond up to 1.565(2) A as compared with its mean value,
˚
1.522 A. The carbamide fragment is located in –sc conformation relative to the N2–C4
bond and it is turned with respect to the C4–C6 bond (the N2–C4–C6–C7 and C4–
C6–C7–O2 torsion angles are ꢀ44.8(2)ꢁ and ꢀ63.0(2)ꢁ, respectively). Such localization
of the carbamide fragment causes the intramolecular nonbonded p–p interaction
between the C7¼O2 carbonyl group and p system of the bicycle (the shortened intramol-
[26]
˚
˚
ecular contact O2 . . . C5 2.87A as compared with van der Waals radii sum 3.00 A).
In conclusion, we have demonstrated that lithium perchlorate is an efficient
Lewis acid catalyst for the Michael addition of maleimides to 2-aminopyridines
Figure 2. Molecular structure of the compound 7a with atom’s numeration used in structural analysis
(Supplementary Material).

CATALYTIC DOUBLE-CONJUGATE ADDITION
3309
and 2-aminothiazoles under mild conditions. Also, the developed procedure repre-
sents an atom-economical formation of 2-oxo-2,3-dihydroimidazo[1,2-a]pyridin-3-yl
and 2-oxo-2,3-dihydroimidazo[1,2-a]thiazol-4-yl derivatives (5, 7). The advantages
of this approach such as mild reaction conditions, simple experimental procedure,
and low toxicity of the catalyst can make this method useful in synthesis, and the
products could have some interesting biological activity.
ACKNOWLEDGMENTS
We are grateful to Olexandr V. Turov, Magdalina D. Tsapko, and Olexandr
Petin for help with NMR studies.
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