Synthesis of bridged benzazocines and benzoxocines by a titanium-catalyzed double-reductive umpolung strategy

Article abstract of DOI:10.1002/chem.201405852

A sequence of two titanium(III)-catalyzed reductive umpolung reactions is reported that allows the rapid construction of benzazo- and benzoxozine building blocks. The first step is a reductive cross-coupling of quinolones or chromones with Michael acceptors. This reaction proceeds with complete syn-selectivity for the quinolone functionalization while the anti-diastereomers are obtained as the major products from chromones. With different 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 provided and the product configurations were unambiguously verified by X-ray analyses and 2D NMR spectroscopic experiments.

Full text of DOI:10.1002/chem.201405852

DOI: 10.1002/chem.201405852
Communication
&
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
E-mail: jan.streuff@ocbc.uni-freiburg.de
[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.
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Table 1. Reductive cross-coupling of quinolones and chromones with Mi-
chael acceptors.
Figure 1. X-ray analysis of compound 10 and possible rationale for the ob-
served syn-diastereoselectivity tetrahydroquinolinone products 9–16. Ther-
mal ellipsoids were drawn at the 50% probability level.
The relative configuration at C2/C3 was exclusively syn in all
products obtained from quinolones, which was confirmed by
X-ray analysis of 10 (Figure 1). Compounds 9 and 11–16 were
1
assigned in analogy by their H NMR coupling constants and
by NOE experiments.[14,15] The reaction was also carried out
using chromones, which were smoothly converted into the
corresponding products 17–19 (Table 1). Here, the products
were isolated in a diastereomeric mixture, with the anti-diaste-
reomer as the major product. This was confirmed by NOE-ex-
periments as well.[15] With ipriflavone as a commercial precur-
sor, the reaction resulted in 82% isolated yield of 19 as a 1.7:1
diastereomeric mixture. C3-Unsubstituted chromones including
the sterically demanding flavone could be employed too, re-
sulting in moderate yields (20, 21). In addition, the methodolo-
gy was successfully expanded to coumarin derivatives (Table 1,
products 22, 23).
The syn-selectivity observed for the tetrahydroquinolin-4-
one products could be explained by a steric repulsion between
the cyanoalkyl chain and the nitrogen substituent (Figure 1).
The cyanoalkyl chain was thus located in a pseudo-axial posi-
tion during the enolate protonation and the syn-diastereomers
were received. In the case of the 4-chromanone products, this
steric repulsion was absent, which led to the formation of the
anti-diastereomers. Based on this observation, we reasoned
that the syn-chromanone products could be accessible as well
by quenching the silyl enol ether under kinetically controlled
conditions. Indeed, by changing the workup procedure of the
cyanoalkylation, the corresponding syn-chromanones 24–26
became the favored products (Figure 2).
[a] 48 h reaction time. [b] 2.5 mmol scale. [c] Workup with tetrabutylam-
monium fluoride (TBAF). [d] Combined yield. The ratio was calculated
from the individual yields of the separated diastereomers after flash chro-
matography. [e] Mn was used instead of Zn. [f] 1.0 mmol scale. Cp=cyclo-
pentadienyl.
tron-donating phenyl and methyl groups but also a thiophenyl
or phenylacetylene group still allowed the reaction to proceed
in moderate yields (3–8). Substitution at the 3-position of the
quinolone led to a significant improvement in the isolated
yields (9–12, 72–91%). Importantly, the reaction worked equal-
ly well with methacrylonitrile and gave product 13 in 90%
combined yield as a mixture of diastereomers having the op-
posite configuration at the nitrile a-carbon atom (1.4:1 d.r.). In
addition, the acrylonitrile could be replaced by ethyl or phenyl
acrylate and the corresponding products 14 and 15 were ob-
tained in 47 and 51% yield. With mesityl acrylate that had
been a superior coupling partner in SmII-catalyzed reductive
umpolung reactions,[13] the yield was further improved (16,
81%).
Figure 2. The syn-4-chromanones were accessible by protonation of the silyl
enol ether at low temperature. [a] Combined yield of the individually isolat-
ed diastereomers after flash chromatography.
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We previously established the reductive coupling of ketones
with nitriles as a powerful approach for the synthesis of a-hy-
droxyketones in an intra- and intermolecular fashion.[11a,b] This
concept was now advanced towards the challenging titani-
um(III)-catalyzed ketonitrile cyclization forming the desired
methylene-bridged tricyclic building blocks (Table 2).[12] The
Table 2. Titanium(III)-catalyzed cyclization to bridged tricyclic building
blocks. The structure of product 27 was confirmed by X-ray analysis.
Thermal ellipsoids were drawn at the 50% probability level.
Scheme 2. Cyclization of anti-chromanones 17–19 to products 35–37. The
X-ray analysis of product 36 confirmed the tricyclic structure and the relative
configuration of the three stereocenters. Thermal ellipsoids were drawn at
the 50% probability level.
lated yield (respective to 17). This allowed a more convenient
chromatographical separation of the final product.
In conclusion, we have developed a titanium(III)-catalyzed
cross-coupling of quinolones and chromones with Michael ac-
ceptors. By combination with a second titanium(III)-catalyzed
ketonitrile cyclization, this was advanced into a two-step ap-
proach to oxygenated benzazocines and benzoxocines. We fur-
ther demonstrated that the diastereoselectivity of the first step
could be controlled towards the syn- or anti-product by the
choice of the workup procedure. A full account on the devel-
opment and further application of this strategy will be report-
ed in due course.
[a] 72 h reaction time.
Acknowledgements
polyfunctionalized tetrahydroquinolinone derivatives 1–8 were
submitted to reductive umpolung conditions using 10 mol%
of titanocene dichloride, zinc and slightly increased amounts
of triethylamine hydrochloride and chlorotrimethylsilane. The
room-temperature reaction gave the desired products 27–34
in good yields and the various functional groups that were
present in the precursors were tolerated very well. Product 28
was isolated in 82% yield, which corresponded to 64% yield
for the two-step sequence. In addition, the ketonitrile cycliza-
tion was attempted with the a-substituted anti-chromanones
17–19. The reaction proceeded smoothly and the tricyclic
products were isolated in good yields of 58–81% (Scheme 2).
The structure of the final product 36 was verified by X-ray
analysis.[14] From our cyclization attempts of syn-chromanones
24–26 a complex product mixture was received that contained
unreacted starting material, pinacol coupling products, and
only trace amounts of the cyclization product. This can be ra-
tionalized by an unfavorable axial position of the methyl or
phenyl substituent in the newly formed cyclohexanone ring.
We therefore employed the diastereomeric mixture obtained
from the cyanoalkylation of 3-methylchromone directly in the
cyclization reaction and product 35 was obtained in 55% iso-
The Fonds der Chemischen Industrie (Liebig Fellowship to J.S.)
and the Deutsche Forschungsgemeinschaft (DFG, Grant Nr. STR
1150/3-1) are acknowledged for financial support.
Keywords: catalysis · cyclization · electron transfer · titanium ·
umpolung
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[15] See the Supporting Information.
Received: October 28, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Catalysis
P. Bichovski, T. M. Haas, D. Kratzert,
J. Streuff*
&& – &&
Titanium for two: A sequence of two ti-
tanium(III)-catalyzed reductive umpo-
lung reactions is reported that allows
the rapid construction of fused benza-
zo- and benzoxozine building blocks. It
consists of a reductive cross-coupling of
quinolones and chromones with Mi-
chael acceptors followed by a reductive
ketonitrile cyclization (see scheme).
Synthesis of Bridged Benzazocines
and Benzoxocines by a Titanium-
Catalyzed Double-Reductive
Umpolung Strategy
Chem. Eur. J. 2014, 20, 1 – 5
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These are not the final page numbers! ÞÞ