The asymmetric reduction of imidazolinones with trichlorosilane

Article abstract of DOI:10.1039/c7cc01561e

It is shown how imidazolinones are reduced by trichlorosilane in a highly enantioselective fashion when treated with a novel Lewis base organocatalyst that is based on a 2,2′-bispyrrolidine core. Under mild reaction conditions and with low catalyst loading the hydrosilylation reaction provides a broad range of chiral imidazolidinones with various structural motifs including sterically demanding substituents, alkyls and aryls.

Full text of DOI:10.1039/c7cc01561e

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The asymmetric reduction of imidazolinones with
trichlorosilane†
Cite this:DOI: 10.1039/c7cc01561e
Christian Wagner, Andreas F. Kotthaus and Stefan F. Kirsch
*
Received 28th February 2017,
Accepted 30th March 2017
DOI: 10.1039/c7cc01561e
rsc.li/chemcomm
It is shown how imidazolinones are reduced by trichlorosilane in
a highly enantioselective fashion when treated with a novel Lewis
base organocatalyst that is based on a 2,20-bispyrrolidine core.
Under mild reaction conditions and with low catalyst loading the
hydrosilylation reaction provides a broad range of chiral imidazolidinones
with various structural motifs including sterically demanding sub-
stituents, alkyls and aryls.
Scheme 1 The reduction of imidazolinones.
Chiral a-amino acids are fundamentally important structural
motifs.1 A great range of synthesis methods have been developed was of no avail. We then began our studies on the catalytic
over the last decades with the goal not only to grant de novo access asymmetric reduction of imidazolinones by employing several
to naturally occurring a-amino acids and their enantiomers, but catalyzed hydrogenation conditions, i.e. transition metal-catalyzed
particularly to provide access to unnatural amino acid derivatives.2 with Ru-13 and Rh-complexes14 and Brønsted acid-catalyzed
Important catalytic strategies for the asymmetric synthesis of transfer hydrogenation.15 While all of those early attempts led
a-amino acids are, amongst others,2b,3 the hydrogenation of to unusable conversions or shockingly low enantioselectivities,
dehydroamino acids,4 the Strecker reaction5 and the electrophilic the results with trichlorosilane and Lewis base catalysts were,
alkylation of glycine derivatives with chiral phase-transfer at least, promising.
catalysts.6
Trichlorosilane (HSiCl3) is a remarkable, and still somewhat
We became interested in the de novo synthesis of functio- underused reducing agent: it is a truly cheap reagent prepared
nalized a-amino acids when studying small peptide catalysts with in the silicon industry that requires activation through coordi-
artificial amino acids for their use in site-selective reactions.7 nation with a Lewis base to generate the actual reducing
At the beginning of our studies in the field, we felt that the species.16 Despite the fact that the trichlorosilane reduction
enantioselective reduction of the imidazolinone core 1 would methods produce some quantities of halogen waste, the Lewis
provide a straightforward entry into chiral a-amino acids: the base-catalyzed conditions benefit from being metal-free and
imidazolinone substrates 1 can be easily generated with all mild. Trichlorosilane has been extensively used for the reduction
variants regarding the substituent R,8 and the imidazolidinone of CQN bonds17 and, to some lower extend, for the reduction of
products 2 can be certainly hydrolyzed to the desired a-amino CQO bonds18 and heterocycles.19 In combination with chiral
acids (Scheme 1).9 Moreover, the chiral imidazolidinones are Lewis base organocatalysts, a number of asymmetric reductions
widely appreciated heterocycles due to their value as chiral were reported; the catalyst design is typically comprised of either
organocatalysts10 and their use as building blocks for the N-formyl amino acid derived carboxamides or picolinamides,16c
synthesis of pharmaceuticals.11
and chiral sulfonamides have attracted recent interest too.20
We now show that trichlorosilane is ideally suited for the challen-
To our surprise, the reduction of imidazolinones was hardly
attempted,12 and our literature search on stereocontrolled variants ging reduction of imidazolinones. We also present a new organo-
catalyst that allows for the asymmetric reduction of the imidazolinone
¨
Organic Chemistry, Bergische Universitat Wuppertal, Gaußstr. 20,
core at low catalyst loading: a broad range of chiral imidazolidinones
can be easily formed with excellent enantioselectivities.
Our studies on the trichlorosilane reduction of imidazolinones
began with a preliminary screening for enantioselectivity: several
42119 Wuppertal, Germany. E-mail: sfkirsch@uni-wuppertal.de
† Electronic supplementary information (ESI) available: Experimental procedures,
analytical data and copies of 1H, 13C NMR-spectra and HPLC traces. See DOI:
10.1039/c7cc01561e
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Scheme 3 Influence of the catalyst loading.
observed (Scheme 3). Nevertheless, a high enantiopurity was
observed even with 1 mol% of catalyst E, and the formation of
undesired by-products was hardly detected under any conditions
1
(by H NMR).
With useful conditions in hand, we explored the scope of the
Lewis base-catalyzed hydrosylilation of imidazolinones. On a
0.1 mmol scale, a range of heterocyclic substrates 1 bearing
aromatic substituents (R = aryl) were treated with trichloro-
silane (2.5 equiv.) and acetic acid (2.0 equiv.) in chloroform
(0.1 M) at room temperature. In general, 2 mol% of catalyst E
were employed, and the reactions were run for 24 h to ensure
complete conversion of the starting substrates. As summarized
in Scheme 4, para- and meta-methylated phenyl substrates 1b
and 1c afforded the products in excellent yields with good
enantioselectivities. However, ortho substitution of the phenyl
group decreased the degree of enantioselection dramatically,
and a lower conversion was observed after 24 h. Electron-
donating and electron-withdrawing substituents were suitable,
albeit with slightly lower enantioselection in the case of cyano-
substituted substrate 1h. A limitation was only found with
dimethylamino-substituted substrate 1i where product formation
was slow even at 45 1C with 10 mol% of the catalyst, although an
acceptable enantioselectivity (i.e., 86% ee) was reached in this
Scheme 2 Initial screening for enantioselectivity.
organocatalysts, most of which were previously reported in the
literature for reductions with trichlorosilane, were tested in the
reaction of phenyl-substituted imidazolinone 1a in CHCl3 at room
temperature. An excerpt of those results is shown in Scheme 2
demonstrating that the widely used N-formyl derivative A21 and
oxazoline derivative D22 results in poor enantioselectivity while
the known picolinamides B23 and C24 lead to imidazolidinone 2a
formation with good enantioselectivities. We also found that the
new picolinamide E (and its congener F) based on a chiral
bispyrrolidine core gave the desired product with similar enantio-
selectivity after 18 h.25,26 A typical side product of the reaction was
the acyclic amino acid derivative 3.
We then decided to optimize the reaction with newly developed
catalyst E. It was found that only chlorinated solvents (i.e., CH2Cl2,
CHCl3) were suited with CHCl3 being slightly superior in terms
of yield; other solvents led to unsatisfactory enantioselectivities
(e.g. toluene, THF, MeCN, n-heptane, MeOH). The reaction
temperature influenced the enantioselectivity only in a minor
way; the conversion at below 0 1C, however, was at an imprac-
tically low rate. For convenience, we therefore decided to run
the reductions at room temperature. In the course of our
optimization study, we found that the addition of acid additives
was of utmost importance with respect to the reproducibility of
the reaction, in particular regarding to the ratio 2a/3: we used a
standard procedure where 2.0 equivalents of acetic acid are
added to the reaction mixture. Under these conditions, the
formation of side product 3 was never observed. However, the
addition of acid additives led to a decrease of enantioselectivity
with catalyst C (89% ee) while the new catalysts E exhibited an
even higher efficacy (96% ee). We also note that pretty low
catalyst loadings were feasible without shrinkage of the enantio-
selection. At 10 mol% and 5 mol%, the smooth reaction resulted
in almost quantitative product formation in 495% ee while at
a lower catalyst loading, a decrease in conversion was naturally
Scheme 4 Scope with arylated substrates.
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D-valine was obtained from 2m27 without detectable loss of the
enantiomeric excess. As known from various reports,3a,12 aryl-
glycines are somewhat more difficult to access in enantiopure
form since they are prone to racemization due to the high
acidity of the a-aryl proton.2b,28 Accordingly, the harsh acidic
conditions used for the liberation of D-valine (4) led to an
erosion of enantiopurity when applied to the generation of
D-phenylglycine from 2a: 78% ee were achieved in this case.
However, we were able to generate the D-phenylglycine methyl
amide in moderate yield through the cleavage of the N,O-acetal
under milder conditions using diluted hydrochloric acid (1 M,
aqueous) for only 1 h at 100 1C. Of importance, no loss of
enantiopurity was observed for the conversion of 2a into 5.
In summary, we have shown the first asymmetric reduction
of imidazolinones using trichlorosilane as the hydride source
and a new Lewis base organocatalyst. The catalyst, easily derived
from a chiral 2,20-bispyrrolidine core, promoted the hydrosilylation
of a broad range of substrates, and the imidazolidinone
products were obtained in high yields and excellent ee-values
under mild conditions. Further investigations devoted to
the application scope of the catalyst are part of our current
research.
Scheme 5 Scope with alkylated substrates.
case, too. It was assumed that the Lewis base nature of the
dimethylamino substituent was competitive with the catalyst
with regard to the coordination of the trichlorosilane reagent.
We also demonstrated that the method is suitable for the
preparation of larger scale quantities of chiral imidazolidinones.
For example, 1.0 mmol of imidazolinone 1a were smoothly
transformed with 2.5 equiv. of HSiCl3, 2.0 equiv. of HOAc,
0.02 equiv. of E at room temperature in CHCl3, providing 2a
in 99% isolated yield and with 94% ee (Scheme 4).
The authors wish to thank Prof. Dr H.-J. Altenbach for
helpful discussions.
When attempting the asymmetric reduction of alkyl-substituted
imidazolinones (R = alkyl), we realized that the uncatalyzed
hydrosilylation became an important factor that led to lowered
enantioselectivities. We then decided to react the alkyl-substituted
substrates at a 10-fold lower concentration (i.e., 0.01 M instead of
0.1 M), where the background reaction was found to be almost
completely suppressed, a precaution that was not necessary with
the aryl-substituted substrates that showed no conversion in the
absence of Lewis base catalysts. We also found that catalyst F
possessing a naphthol core had a slightly better performance than
catalyst E with the phenol core under the reaction conditions.
Its use (10 mol%) together with HSiCl3 (2.5 equiv.) and HOAc
(2.0 equiv.) in CHCl3 (0.01 M) at room temperature gave access to
several chiral imidazolidinones having alkyl groups (Scheme 5).
For example, imidazolidinone 2j with R = n-hexyl was obtained in
99% isolated yield and 93% ee. Substrates with sterically more
demanding alkyl groups (e.g., i-Pr, 1m; Cy, 1n) also afforded the
desired products in good yields and with high ee values.
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