Tetrahedron Letters
Atom-economical construction of tetracyclic [1,4]oxazepines
involving intramolecular arylation of a 2-imidazoline moiety
Kseniya Karamysheva a, Elena Reutskaya a, Alexander Sapegin a, Mikhail Dorogov a, Mikhail Krasavin b,
⇑
a The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russian Federation
b Institutes of Chemistry and Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel [1,4]oxazepines containing a fused imidazoline moiety were synthesized from 2-hydroxyphenyl
imidazolines and bis-electrophilic aromatic substrates in a reaction involving sequential nucleophilic
aromatic substitution steps and a Smiles rearrangement. A notable step was the remarkably facile,
metal-free intramolecular N-arylation of the imidazoline moiety with a fluoro-, nitro- or chloroaromatic
or heteroaromatic ring. The approach presented in this Letter not only details access to a new, medici-
nally relevant tetracyclic [1,4]oxazepine core but also extends the scope of imidazoline arylation
chemistry.
Received 13 July 2015
Revised 15 August 2015
Accepted 22 August 2015
Available online xxxx
Keywords:
Imidazoline arylation
Monoamine uptake inhibitors
Polycyclic aromatic scaffolds
Smiles rearrangement
Nucleophilic aromatic substitution
Regiospecificity
Ó 2015 Published by Elsevier Ltd.
N
N
K2CO3
Y
X
The base-promoted condensation of phenols containing poten-
tially nucleophilic functional groups (such as pyrazole1 or a sec-
ondary amide2), which can be activated by deprotonation, with
1,2-halonitro3 or 1,2-dihalo4 aromatic synthons has been recently
reported by our research group as an efficient, atom-economical
strategy to construct medicinally relevant polycyclic [1,4]
oxazepine scaffolds from readily available precursors (Scheme 1).
Our current efforts in this area have been focused on identifying
new N–H-acidic heterocyclic motifs that could be incorporated, as
substituents, on the structure of the phenolic synthon, thus
enabling new types of heterocycles to be fused to the [1,4]
oxazepine core. In light of its privileged character5 and also the
similarity of the resultant compounds to classical tricyclic antide-
pressants such as nitroxazepine, trianeptine, or imipramine,6 par-
ticular emphasis was given to the 2-imidazoline moiety. We
speculated that a 2-imidazoline derivative, such as compound 1,
could be considered as a mimetic of mirtazapine, a selective
norardernaline reuptake inhibitor.7,8 The reason for a lack of work
in this area could be the relative scarcity of methods for 2-imida-
zoline N-arylation. Indeed, prior to the development of metal-
catalyzed protocols by us9 and others,10,11 only a handful of Letters
had existed describing the direct substitution of either a halide12 or
N
O
+
(Het)Ar
N
H
(Het)Ar
DMF, Δ
2-36 h
OH
2a
3
4a-l
Scheme 1. Preparation of imidazolino-fused [1,4]oxazepines 4a–l via base-pro-
moted double nucleophilic aromatic substitution.
a methyl sulfonyl group13 on highly activated (electron-deficient)
halo(hetero)aromatics. Our strategy to construct compounds such
as 1 described herein, relied on the availability of imidazoline-
substituted phenols 2 and ultimately, on a more facile imidazoline
N-arylation reaction due to its intramolecular character (Fig. 1).
Indeed, as we have recently shown, the initial aromatic halide sub-
stitution facilitates subsequent intramolecular displacement of
otherwise poorly reactive halides.4
2-Hydroxyphenylimidazoline 2a, prepared as described in the
literature,14 was reacted with a range of 1,2-dihalo- or 1-halo-,
2-nitroaromatic and heteroaromatic substrates 3 in the presence
of anhydrous K2CO3 in DMF at elevated temperature (Scheme 1).
This reaction proceeded to completion within 2–36 h and the
respective tetracyclic products 4a–l were isolated in good yields
(Table 1). Their identity and purity were confirmed by 1H and 13C
NMR spectroscopy, as well as elemental analyses (see ESI).
⇑
Corresponding author. Tel.: +7 931 3617872; fax: +7 812 428 6939.
0040-4039/Ó 2015 Published by Elsevier Ltd.