Convenient titanium(III)-catalyzed synthesis of cyclic aminoketones and pyrrolidinones - Development of a formal [4+1] cycloaddition

Article abstract of DOI:10.1002/anie.201302460

Have it both ways: α-Aminated ketones can be prepared by the titanium(III)-catalyzed reductive radical cyclization of iminonitriles. Depending on the position of the nitrile at the imine carbon or nitrogen, cyclic aminoketones or pyrrolidin-3-ones with a tetrasubstituted α-carbon can be formed in up to quantitative yield. In the latter case, the imine condensation and Ti^III catalysis correspond to a formal [4+1] cycloaddition. Copyright

Full text of DOI:10.1002/anie.201302460

Angewandte
Chemie
DOI: 10.1002/anie.201302460
Redox Umpolung
Convenient Titanium(III)-Catalyzed Synthesis of Cyclic Aminoketones
and Pyrrolidinones—Development of a Formal [4+1] Cycloaddition**
Georg Frey, Hieu-Trinh Luu, Plamen Bichovski, Markus Feurer, and Jan Streuff*
a-Aminated carbonyl compounds represent important build-
ing blocks for the synthesis of bioactive molecules.[1] There-
fore, a convenient access to cyclic a-aminated ketones and the
related pyrrolidin-3-one units, which are structural motifs in
many natural products and pharmaceutical drug candidates, is
highly desirable.[2] There are several established procedures
for synthesizing these compounds,[3,4] but when full substitu-
tion at the aminated a-carbon is required, the methods for
constructing these molecules are very limited.[5] To our
knowledge no straightforward method for the preparation
of such a-aminoketones or pyrrolidin-3-ones has been
published so far.
In 2006, Oltra, Cuerva, Gansꢀuer, and co-workers
reported
a titanocene-catalyzed reductive umpolung of
Scheme 1. Concept for the synthesis of aminoketones and pyrrolidi-
carbonyl compounds in a Michael-type addition.[6–8] In 2011
we established this principle for the cross-coupling of Michael
acceptors to yield 1,4- or 1,6-difunctionalized products.[9] This
led to the development of an enantioselective cross-coupling
between ketones and nitriles[10] and more recently a TiIII-
catalyzed umpolung of hemiaminals was published.[11] We
herein report the application of this titanium-catalyzed
reductive umpolung strategy in the synthesis of aminoketone
and pyrrolidinone building blocks through the direct con-
nones by the reductive umpolung of iminonitriles.
aqueous workup would then yield the desired aminoke-
tones.[14]
À
struction of the C C bond between the carbonyl carbon and
the a-aminated carbon (Scheme 1). In this way, both motifs
become available from the corresponding iminonitriles, which
can be easily accessed from either commercially available or
literature-known ketones by standard condensation proto-
cols. Importantly, the sequence of ketimine formation fol-
lowed by the reductive umpolung to the pyrrolidinone
product represents a formal [4+1] cycloaddition, for which
only few examples have been reported to date.[12,13]
This idea was supported by several literature reports on
reductive pinacol-type dimerizations of imines with a number
of catalysts including [Cp2TiCl2][7,15] and thus we started
investigations towards this reductive umpolung reaction.
After the first promising results, we optimized the reaction
conditions for each cyclization type using substrates 1a and
2a.[16] Starting from iminonitrile 1a, we found that 10 mol%
[Cp2TiCl2] and slightly elevated temperature (408C) were
optimal to achieve high yields of aminoketone 3a (Scheme 2).
With 2a the reaction already took place at room temperature
and under these mild conditions we achieved quantitative
conversion to pyrrolidinone 4a with 5 mol% of the catalyst.
With a catalyst loading of only 1 mol%, this pyrrolidinone
was still isolated in 90% yield after 3 days. While this
reductive cyclization already occurred in the presence of
only [Cp2TiCl2] and zinc, we noticed that the yields were
typically 15–20% higher when Et3N·HCl was added and that
TMSCl had a strong beneficial effect on the reaction rate and
yield.[17] Imines 1 were usually employed as isomeric mixtures
and both isomers were converted smoothly to the desired
product.
Our initial idea was that a TiIII catalyst (generated from
a TiIV precursor and zinc metal) could be capable of
promoting this transformation by a single-electron transfer
to an imine and subsequent attack of the aminomethyl radical
to the nitrile functionality [Eq. (1)]. Further reduction and
[*] G. Frey, H.-T. Luu, P. Bichovski, M. Feurer, Dr. J. Streuff
Institut fꢀr Organische Chemie und Biochemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
E-mail: jan.streuff@ocbc.uni-freiburg.de
Homepage: http://portal.uni-freiburg.de/streuff
[**] We thank Dr. Nils Trapp for the X-ray analysis and the Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft
(DFG) for financial support.
With the goal of developing a reliable methodology for
the synthesis of a-aminoketones with a tetrasubstituted a-
carbon, we tested the scope of the reaction for a variety of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302460.
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with arenes containing alkyl, alkoxy, or halogen groups (3e–j)
as well as a heterocycle such as a 2-thiophenyl unit (3k).
Importantly, the formation of 2-aminocyclohexanone 3l
proceeded smoothly in 79% yield and only for the cycliza-
tions to 3i, 3j, and 3l did we have to extend the reaction time
to 48 h. In addition, in 9 of 12 cases our optimized protocol
provided the pure products without the need for chromatog-
raphy.
Afterwards, we turned our attention to the synthesis of
pyrrolidinones 4 (Scheme 4). As already mentioned, these
Scheme 2. First results after optimization and structural confirmation
of aminoketone 3a by X-ray analysis (thermal ellipsoids at the 50%
probability level).[18]
Scheme 4. Titanium-catalyzed reductive synthesis of pyrrolidinones.
Formal [4+1] cycloaddition sequence. Yield of isolated product; yield
of the imine formation is shown in brackets. [a] No chromatography
was necessary. [b] 1 mol% catalyst, 3 d reaction time, no Et3N·HCl
added. [c] 10 mol% catalyst. [d] 48 h reaction time.
cyclizations proceeded under milder conditions, often with
lower catalyst loading and quantitative yield. Together with
the imine-formation step, this formal [4+1] sequence turned
out to be a convenient and straightforward approach to the
pyrrolidin-3-one fragment. Again, a number of substituents
could be installed at the tetrasubstituted a-carbon, including
various alkyl and aryl groups, with good to high yields. The
fluorophenylated product 4c was obtained in 99% yield in the
presence of 5 mol% catalyst. The 4-chlorophenyl- and 4-
bromophenyl-substituted products 4d,e as well as the more
electron-rich arylated products 4 f–h were obtained in good
yields (62–83%) in the presence of 10 mol% titanium
catalyst. Reaction with the 4-dimethylamino- and 3-methyl-
phenyl-substituted substrates proceeded with full conversion
and 97–99% yield in the presence of 5 mol% [Cp2TiCl2].
Scheme 3. Titanium-catalyzed reductive synthesis of aminoketones.
Yield of isolated product; yield of the imine formation is shown in
brackets. [a] No chromatography was necessary. [b] 48 h reaction time.
imines (Scheme 3). These compounds were synthesized by
condensation of the corresponding ketone with the respective
amine, which usually proceeded with full conversion.[16] The
reductive umpolung to form a-aminoketones 3 was then
found to tolerate several substituents at the imine nitrogen.
N-arylated, -benzylated, or -alkylated imines were cyclized in
good to excellent yields and N-benzylketimine 1b reacted
quantitatively (99%). Hence, we continued exploring further
variations using this group. The a-carbon could be substituted
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Even the challenging cyclization to the spirocyclic product 4k
took place, resulting in quantitative yield with 10 mol%
catalyst. In summary, for both reaction types good to excellent
yields were observed and simple acid–base extraction sufficed
for convenient isolation of many products. It should be noted
that an aryl substituent on the imine carbon was required to
achieve good results.
Then, we attempted the enantioselective reductive imine–
nitrile coupling. After several experiments we obtained
a maximum enantiomeric excess of 19% with Vollhardtꢁs 8-
phenylmenthol-derived titanocene catalyst 5 and substrate
1a, which was used as a 3.3:1 mixture of E/Z isomers
[Eq. (2)].[16,19] An experiment using stoichiometric amounts of
ing,[21] which is proposed to be similar to the activation of
carbonyls by a TiIII catalyst in Barbier-type allylations and
related reactions.[22]
The fact that the cyclization of 1a results in a lower yield
with bulkier catalyst 5 could point further in that direction,
because coordination of a second titanocene to the substrate
would be significantly hampered in this case. We assume that
the title reaction is titanium(III)-catalyzed because the initial
species formed in the reduction with zinc is the well-known
lime-green [Cp2TiCl] dimer. Nevertheless, it should be noted
that a titanium(II) isopropoxide alkene complex was found to
promote the coupling of N-propylbenzaldimine with propio-
nitrile in stoichiometric experiments.[14]
In conclusion, a convenient reductive imine–nitrile cou-
pling was developed that provides direct access to a-aminated
ketones and pyrrolidin-3-ones with tetrasubstituted a-car-
bons. In the latter case, the sequence of imine formation and
reductive umpolung cyclization represents a formal [4+1]
cycloaddition. We are now developing new catalysts for the
asymmetric reaction and expanding this methodology to
further substrate classes.
Received: March 24, 2013
Published online: June 5, 2013
complex 5 gave similar results.[16] Other common chiral
titanocene catalysts were inferior. Product 3b arising from
the corresponding benzylimine (1:1 E/Z ratio) was racemic
when the same catalytic conditions were applied. Thus, one
could argue that the imine configuration plays a crucial role in
the asymmetric induction. But the stereoinformation is lost
during the electron transfer that forms the aminomethyl
radical, which we assume to take place before the enantio-
discriminating step [Eq. (1)]. We also attempted the asym-
metric cyclization of 2a, which was available exclusively as
the E isomer. In this case, only racemic material could be
obtained from these experiments. Therefore, it is likely that
high enantioselectivities cannot be achieved with the conven-
tional titanocenes and that new catalysts will have to be
designed.
Keywords: catalysis · radical reactions · reduction · titanium ·
.
umpolung
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