We report an enantioselective phase transfer α-chlorination of β-keto esters catalyzed by hybrid amide-based Cinchona derivatives. The chlorination process proceeds with proper quantitative yields (up to <99%) and high asymmetric induction (up to 97% ee). We show that the use of only 0.5 mol % hybrid catalyst based on a Cinchona core allows the chlorination reaction to be conducted in a highly enantioselective manner with various indanone and tetralone carboxylate esters.
We report an enantioselective phase transfer α-chlorination of β-keto esters catalyzed by hybrid amide-based Cinchona derivatives. The chlorination process proceeds with proper quantitative yields (up to <99%) and high asymmetric induction (up to 97% ee). We show that the use of only 0.5 mol % hybrid catalyst based on a Cinchona core allows the chlorination reaction to be conducted in a highly enantioselective manner with various indanone and tetralone carboxylate esters.
The
challenge of stereoselectively introducing a halogen atom into
organic compounds has become one of the forefront research issues
in organic chemistry in recent years.[1] The
diverse pharmaceutical activity of optically active halogen-containing
molecules, as well as their ability to undergo further stereoselective
modifications, plays a key role in modern organic synthesis and, consequently,
in the design of drug targets.[2,3] Halogenated molecules
often display distinct characteristics compared to their parent compounds,
owing to the unique hydrophobic, space-filling, and electronic properties
of the halogen atom.[4] It is therefore not
surprising that asymmetric construction of chlorine-containing molecules
has become a fascinating and intensely investigated research field.However, catalytic asymmetric installation of halogenated carbon
centers (especially quaternary ones) poses a great synthetic challenge;
hence, numerous approaches to this problem have been developed. Since
Hintermann and Togni[5] reported the first
example of α-halogenation of β-keto esters with a Ti(IV)/TADDOL
complexes, extensive studies have been undertaken. Most such procedures
are based on metal catalysis, including a Lewis acid transition metal
species accompanied by a chiral ligand.[6,7] Organocatalytic
approaches for asymmetric halogenation have also been developed, including
enamine catalysis,[8] diaminomethylenemalononitrile,[9]Cinchona-mediated
processes,[10] and indirect approaches using
halogenated substrates in enantioselective C–C bond forming
reactions.[11] There are also reports related
to chiral quaternary ammonium catalysts.[12]In 2013, the Luo group[13] reported
the
first catalytic enantioselective chlorination of β-keto esters
by employing this type of catalysis (Figure ).
Figure 1
Previously reported Cinchona PTC
catalysts in asymmetric chlorination.
Previously reported Cinchona PTC
catalysts in asymmetric chlorination.They found that only a bulky group at the bridgehead nitrogen of
adamantoyl-derivatized Cinchona alkaloids
was crucial for the expected stereoselectivity. It is worth mentioning
here that these catalysts were actually inefficient when the C9 hydroxyl
function was unprotected. The main decisive factor for successful
enantiodiscrimination using these catalysts is their ionic interactions.
However, such interactions leading to the formation of ionic pairs
do not provide a defined stereochemical course of these reactions.
A partial solution to such a dysfunction emerged with the introduction
of a new family of hybrid catalysts[14,15] having both
an ionic function and a hydrogen bond donor. This approach allows
for selective chlorination of β-keto esters with satisfactory
values of asymmetric induction.[16,17] Interestingly, the
abovementioned catalysts are rather rare examples of onium, showing
very good catalytic efficiency in α-halogenation reactions of
carbonyl compounds. Despite extensive work in the PTC field, there
are only a few cases in which the generation of a quaternary stereogenic
center that contains the chlorine atom has been accomplished, and
these exclusively involve the asymmetric α-chlorination reaction
of dicarbonyl compounds.Recently, our team has introduced a
new class of hybrid derivatives
of Cinchona alkaloids, which have been
thoroughly studied in alkylation reactions of the imino glycine t-butyl ester[14c] and epoxidation
of α,β-unsaturated ketones.[15c] The obtained results have demonstrated the effectiveness of the
amide derivatives, showing a beneficial effect of the hydrogen bond
donor in the catalyst structure. Given the satisfactory selectivities
obtained so far with our library of hybrid catalysts in alkylation,
we now targeted the use of these quaternary derivatives for a more
challenging reaction: α-chlorination of β-keto esters.
Results
and Discussion
At the beginning, a set of hybrid catalysts
from the amide-based
family of Cinchona derivatives were
prepared according to our synthetic procedure that was described earlier,[14c] as presented in Scheme .
Scheme 1
Synthesis of Selected Amide-Based Cinchona Alkaloids
To determine a suitable catalyst system for the enantioselective
chlorination of β-keto esters, we initially applied a reaction
of methyl ester indanone carboxylate13a with N-chlorosuccinimide (NCS) as the chlorine electrophilic
source. After optimization of conditions (see the Supporting Information), the reaction was carried out in toluene
at room temperature for 5 min in the presence of 0.5 mol % catalyst
(1–12) and potassium fluoride as
a weak base. As Table shows, all of the catalysts promoted the reaction with almost quantitative
yields, even when a 0.5 mol % catalyst was used; however, enantioselectivity
of the obtained product 14a strongly depended on the
amide function attached to the bridgehead nitrogen in the catalyst.
The
ee values were determined by
HPLC analysis using a chiral column Chiralcel OD-H.
Molar ratio: 13a (0.2
mmol), NCS (0.21 mmol), catalyst 1−12 (0.5 mol %), and KF (0.4 mmol).Isolated yields.The
ee values were determined by
HPLC analysis using a chiral column Chiralcel OD-H.Comparison of the catalysts based
on cinchonidine showed that the
introduction of an electron-withdrawing or -donating substituent attached
to the aromatic ring reduces selectivity and enantiomeric excess in
all cases is moderate (≤50% ee). The best result—71%
ee—was obtained for catalyst 4 with the sterically
demanding substituent 2-Ph, which can be related to the inhibition
of substituent rotation. Given such a favorable result at room temperature,
we decided to examine catalyst 5, based on a quinine
scaffold, for which the enantiomeric induction increased to 76% ee.
Thus, we also examined catalyst 6 (diastereoisomer of 5 based on quinidine), thereby obtaining product 14a with almost complete inversion of the configuration (−75%
ee). Interestingly, there has been no report regarding the possibility
of using two diastereoisomers of Cinchona alkaloids to generate both enantiomers of the chlorination product
or especially maintaining complete inversion of configuration on the
quaternary carbon atom. Finally, considering such a fast reaction
(only 5 min) and almost quantitative yield, we decided to examine
the impact of the temperature on enantioselectivity using the best
catalyst 5. In Table , we presented results for different temperatures under
the reaction conditions described in Table .
Table 2
Optimization of the
Temperature under
the Reaction Conditions Described in Table a
The ee values were
determined by
HPLC analysis using a chiral column Chiralcel OD-H.
Molar ratio: 13a (0.2
mmol), NCS (0.21 mmol), KF (0.4 mmol), and catalyst 5 (0.5 mol %).Isolated
yields.The ee values were
determined by
HPLC analysis using a chiral column Chiralcel OD-H.As might be expected, lowering of
the temperature to values below
0 °C highly increased the enantioselectivity (to 93% ee at −50
°C). Notably, the reaction proceeded very well and the yield
of the isolated product was excellent despite such rigorous conditions.Next, we examined how the type of ester group in the substrate
can affect the enantiomeric excess of the obtained products. To this
end, we used the set of nine β-keto esters13a–13i in Scheme .
Scheme 2
Study of the Ester Group
For example, compound 14a was obtained using 13a (1.0 mmol), NCS (1.05
mmol),
KF (2 mmol), and catalyst 5 (0.5 mol%) in toluene (5
mL) for 30 min at −50 °C.
Study of the Ester Group
For example, compound 14a was obtained using 13a (1.0 mmol), NCS (1.05
mmol),
KF (2 mmol), and catalyst 5 (0.5 mol%) in toluene (5
mL) for 30 min at −50 °C.The
reaction with simple methyl and ethylesters of indanone carboxylates
with NCS provided the corresponding products 14a, 14a′, and 14b in excellent yields and
with very good enantioselectivities (up to 93% ee). To our knowledge,
only Miura group’s presented organocatalytic synthesis of these
products with moderate enentioselectivities (78% for methyl ester).[9] Likewise, the use of bulky esters such as i-propyl, t-butyl, or adamanthyl in the
chlorination reaction gave chlorinated products 14c–14e and 14e′ with very high enantiomeric excess
(up to 97%). For 14g–14i derivatives based on
tetralone, a decrease in the asymmetric induction is observed; however,
it is still a satisfactory value (up to 86% ee), which is not always
achievable with the use of known organocatalysts.Based on the
best results for catalyst 5, we proposed
a plausible transition state model depicted in Figure .
Figure 2
Proposed transition state model for catalyst 5 and
substrate 13a.
Proposed transition state model for catalyst 5 and
substrate 13a.As can be seen, the negatively charged enolate is stabilized by
the hydrogen bonds from the amide function. A key element determining
the high enantioselective manner is the phenyl ring which blocks the si-face of the enolate. In addition, the hydroxyl group
of the catalyst directs the electrophile from the re-face of the enolate, further increasing the selectivity of the underlying
nucleophile attack, which is agreement with the obtained results.
This hypothesis can be supported by reaction with the use of an N-methylated analogue of catalyst 5 which generated
nearly racemic product 14a.With the reaction conditions
optimized, we attempted to explore
the substrate scope (Scheme ).
Scheme 3
Study of β-Keto Derivative Scope
(a)Molar ratio: NCS
(1.05 equiv), catalyst 5 (0.005 equiv), and KF (2 equiv). (b) Isolated yields. (c) The ee values were determined
by HPLC analysis using a chiral column Chiralcel OD-H.
Study of β-Keto Derivative Scope
(a)Molar ratio: NCS
(1.05 equiv), catalyst 5 (0.005 equiv), and KF (2 equiv). (b) Isolated yields. (c) The ee values were determined
by HPLC analysis using a chiral column Chiralcel OD-H.As shown in Scheme , variously substituted cyclic β-keto esters 13(j–p), including both electron-withdrawing
and electron-donating substituents in the phenyl ring, were succesfully
chlorinated with excellent yields (99%) and high enantiopurity (up
to 93% ee) within 30 min. Substrates with the halogen-containing substituent
in the phenyl ring gave similar results.
Conclusions
In
conclusion, we successfully carried out the highly enantioselective
α-chlorination of a wide range of β-keto esters using
cheap and readily available hybrid amide-based catalysts. Significantly,
only 0.5 mol % Cinchona catalyst is
enough to give excellent yields (up to 99%) and very high enantiomeric
excess (ee up to 97%), even when methyl ester of indanone carboxylate
was used as a substrate. In addition, we have also shown the possibility
of obtaining both enantiomers of the chlorination product, while maintaining
a high asymmetric induction value. Further investigation involving
such substrates and a wide range of various electrophiles is currently
underway at our laboratory.
Experimental Section
Materials
and Methods
Chemicals and solvents were purchased
from commercial suppliers and used without further purification. Column
chromatography was carried out using Merck Kieselgel 60 (63–100
μm mesh size), and TLC was carried out on Merck Kieselgel F254
plates. Melting points were determined using a Boëtius M HMK
hot-stage apparatus and were uncorrected. The NMR spectra were recorded
on a Bruker Mercury 400 instrument. Chemical shifts are reported in
ppm and are set to the solvent residue peak. The splitting pattern
of multiplets is described by abbreviations (s—singlet, d—doublet,
t—triplet, q—quartet, dd—doublet of doublets,
m—multiplet, c—covered signal, and b—broad peak). J coupling constants values are reported in Hz. Mass spectral
analyses were performed with the ESI-TOF technique on a Mariner mass
spectrometer from PerSeptive Biosystem. Specific rotations were measured
using a JASCO P-2000 polarimeter. [α]D values are
given in units of 10–1 deg cm2 g–1. The enantiomeric excesses of products were determined
by chiral HPLC analysis.Initially, β-keto esters were
synthesized according to the literature procedures.[18] Amide-based Cinchona catalysts 1–12 were prepared according to our previous
paper.[14c] Catalysts 5 and 6 have not been previously reported. Chlorination products 13(a–p) are known from the
literature, and their analytical data (NMR spectra and MS) fully matched
those reported previously in the literature.[13,17,19−21]
General Procedure for the Asymmetric Chlorination of β-Keto
Esters 13(a–p)
A mixture of substrate 13(a–p) (0.2 mmol), the catalyst (0.001 mmol), and solid KF (2
equiv) was stirred in toluene (1 mL) at room temperature for 20 min.
Then, the mixture was cooled to appropriate temperature, and N-chlorosuccinimide (0.21 mmol) was added in one portion.
The reaction was conducted for 5–80 min at this temperature
and quenched with saturated ammonium chloride solution. The product 14(a–p) was extracted with
ethyl acetate (2 × 10 mL), dried over Na2SO4, and evaporated to dryness. The purification process was carried
out using flash chromatography (SiO2, ethyl acetate/hexane
= 2:8) to afford the pure product in the reported yields and enantiopurities.
Methyl (2R)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (14a) and Methyl (2S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(14a′)
Following the general procedure
and using 13a (38 mg, 0.2 mmol), the products 14a and 14a′ (45 mg, 0.2 mmol, 99%) were obtained
as colorless oils after flash chromatography (SiO2, ethyl
acetate/hexane = 2:8). For the reaction using 1 mmol of 13a (190 mg), the product 14a was obtained in an amount
of 225 mg (1.0 mmol, 99%). [α]D20 = −46.3 (c = 1.0,
CHCl3, 93% ee) (R-enantiomer) and [α]D20 = +11.7 (c = 0.25, CHCl3, 90% ee) (S-enantiomer). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.1 Hz, 1H),
7.51–7.45 (m, 2H), 4.11 (d, J = 17.6 Hz, 1H),
3.82 (s, 3H), 3.57 (d, J = 17.8 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 194.3,
167.6, 150.5, 136.5, 132.4, 128.6, 126.3, 126.0, 67.9, 54.1, 43.4.
HPLC-separation conditions: Chiralcel OD-H, 20 °C, 254 nm, 80/20
hexane/i-PrOH, 1.0 mL/min; t1 = 6.71 min, t2 = 7.55 min. Absolute
configuration was determined by comparison of the retention times
and the [α]D value with reported data.[20]
Figure 1
Scheme 1
Scheme 2
Figure 2
Scheme 3