DOI: 10.1002/chem.201405852
Communication
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Catalysis
Synthesis of Bridged Benzazocines and Benzoxocines by
a Titanium-Catalyzed Double-Reductive Umpolung Strategy
Plamen Bichovski,[a] Thomas M. Haas,[a] Daniel Kratzert,[b] and Jan Streuff*[a]
Abstract: A sequence of two titanium(III)-catalyzed reduc-
tive umpolung reactions is reported that allows the rapid
construction of benzazo- and benzoxozine building
blocks. The first step is a reductive cross-coupling of qui-
nolones or chromones with Michael acceptors. This reac-
tion proceeds with complete syn-selectivity for the quino-
lone functionalization while the anti-diastereomers are ob-
tained as the major products from chromones. With differ-
ent reaction conditions, the stereochemical outcome can
be altered to afford the syn-chromanone products as well.
A subsequent reductive ketyl radical cyclization forges the
tricyclic title compounds in good yields. A stereochemical
model explaining the observed stereoselectivities is pro-
vided and the product configurations were unambiguous-
ly verified by X-ray analyses and 2D NMR spectroscopic
experiments.
Bridged benzazocines and benzoxocines are structural motifs
of several natural products, for example, aspernomine, sespe-
nine, strychnochromine, iso-tetrahydrocannabinol (iso-THC),
Scheme 1. Concept of the titanium(III)-catalyzed double-reductive umpolung
sequence.
and several murraya alkaloids (Scheme 1).[1] The known syn-
thetic routes to these frameworks usually proceed by cationic
cyclization reactions that often require harsh conditions.[2]
Hence, a mild approach for the rapid construction of bridged
benzazocine and benzoxocine structures would represent a sig-
nificant advancement.
tacks the acrylonitrile forming the new carbon–carbon bond.
The products obtained from this cross-coupling are tetrahydro-
quinolin-4-ones and 4-chromanones, which are the core struc-
tures of a number of compounds with anticancer, antitumor,
antibacterial, and other important biological properties.[9,10]
The second step consists of a titanium(III)-catalyzed reductive
ketonitrile cyclization.[11] Here, the catalyst likely initiates a ketyl
radical attack to the nitrile, which leads to the formation of the
methylene-bridged eight-membered ring.[12]
To this end, we herein report a double-reductive umpolung
approach that allows the rapid assembly of such tricyclic skele-
tons from readily available quinolone and chromone precur-
sors.[3] The reaction sequence consists of two titanium(III)-cata-
lyzed reactions:[4,5] Step one is a catalytic C2-functionalization
in the form of a reductive cross-coupling with a Michael ac-
ceptor, such as acrylonitrile.[6–8] The in situ generated titani-
um(III) catalyst likely generates an allylic radical which then at-
The investigation of the first step was started using 4-quino-
lones and acrylonitrile as coupling partners. It was found that
a mixture of titanocene dichloride (10 mol%), zinc dust, trie-
thylamine hydrochloride, and chlorotrimethylsilane gave good
results after 24 h reaction time (Table 1). Thus, the coupling of
N-methylquinolone with acrylonitrile at 358C provided 77%
yield of the desired cyanoethylation product 1 after aqueous,
acidic workup (1m aq. HCl). An excess of the inexpensive acryl-
onitrile (5 equiv) was employed to achieve exclusive and fast
formation of the desired product. The N-benzylated 4-quino-
lone was reacted in a similar fashion giving 78% yield of 2. Var-
iations at the aromatic backbone were then investigated. Elec-
[a] P. Bichovski, T. M. Haas, Dr. J. Streuff
Institut fꢀr Organische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstraße 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8715
[b] Dr. D. Kratzert
Institut fꢀr Anorganische und Analytische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstraße 21, 79104 Freiburg (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405852.
Chem. Eur. J. 2014, 20, 1 – 5
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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