Efficient and highly enantioselective construction of trifluoromethylated quaternary stereogenic centers via high-pressure mediated organocatalytic conjugate addition of nitromethane to β,β-disubstituted enones

Article abstract of DOI:10.1021/ol502941d

A very effective high-pressure-induced acceleration of asymmetric organocatalytic conjugate addition of nitromethane to sterically congested β,β-disubstituted β-CF₃ enones has been developed. A combination of pressure (8-10 kbar) and noncovalent catalysis with low-loading of chiral tertiary amine-thioureas (0.5-3 mol %) is shown to provide very efficient access to a wide range of γ-nitroketones containing trifluoromethylated all-carbon quaternary stereogenic centers in the β-position (80-97%, 92-98% ee).

Full text of DOI:10.1021/ol502941d

Letter
pubs.acs.org/OrgLett
Efficient and Highly Enantioselective Construction of
Trifluoromethylated Quaternary Stereogenic Centers via High-
Pressure Mediated Organocatalytic Conjugate Addition of
Nitromethane to β,β-Disubstituted Enones
Piotr Kwiatkowski,* Agnieszka Cholewiak, and Adrian Kasztelan
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
S
* Supporting Information
ABSTRACT: A very effective high-pressure-induced acceleration of
asymmetric organocatalytic conjugate addition of nitromethane to
sterically congested β,β-disubstituted β-CF3 enones has been
developed. A combination of pressure (8−10 kbar) and noncovalent
catalysis with low-loading of chiral tertiary amine-thioureas (0.5−3
mol %) is shown to provide very efficient access to a wide range of
γ‑nitroketones containing trifluoromethylated all-carbon quaternary stereogenic centers in the β-position (80−97%, 92−98% ee).
Scheme 1. Construction of Quaternary Stereocenters
Containing CF3 Group via 1,4-Conjugate Addition
he growing role of organofluorine compounds in medicinal
agrochemistry,2 and material sciences3 is
stimulating the development of new synthetic methods, with
particular attention to strategies providing access to novel types
of fluorinated molecules. In recent years, there has been
increasing interest in the asymmetric synthesis of compounds
containing the trifluoromethyl group at secondary and tertiary
carbon stereogenic centers.4 Methods yielding enantiomerically
enriched compounds with all-carbon quaternary stereogenic
centers5 containing the CF3 group are still rare and very
challenging for organic synthetic chemists.6,7
1
Tchemistry,
Scheme 2. Addition of Nitromethane to β-CF3-β-R Enones
This goal can be achieved by utilizing sterically congested
prochiral β,β-disubstituted β-CF3 alkenes of type I as Michael
acceptors (Scheme 1). In 2010, Shibata8 demonstrated, for the
first time, the application of enones representing this group (I) in
asymmetric 1,4-addition. The reaction of hydroxylamine with
β‑CF3-chalcones catalyzed by Cinchona-based ammonium salts
resulted in the formation of trifluoromethyl-substituted 2‑iso-
xazolines with 80−99% yield and 82−94% ee. Since this work,
only a few examples of asymmetric catalytic conjugate additions
of C-nucleophiles (e.g., cyanide, nitromethane, indoles)7 and
heteronucleophiles (e.g., methylhydrazine, H2O2 and thioles)9 to
enones or nitroalkenes of type I have been reported.
Here, we demonstrate the remarkable effect of hydrostatic
pressure10 on the asymmetric organocatalytic 1,4-conjugate
addition11 of nitromethane12 to sterically congested β,β‑disub-
stituted β-CF3 enones 1 (Scheme 2) in the presence of easily
available bifunctional tertiary amine-thiourea catalysts (Figure 1)
in a homogeneous system. This reaction opens access to
interesting γ-nitroketones 2 with trifluoromethylated all-carbon
quaternary stereogenic centers, as well as to trifluoromethylated
diarylpyrrolines, their N-oxides,7c and β-CF3-GABA analogs.7f,13
In the first stage, we tested well-defined bifunctional tertiary
amine−thiourea catalysts14 (Figure 1) in the model reaction of
nitromethane and (E)-4,4,4-trifluoro-1,3-diphenylbut-2-en-1-
Figure 1. Organocatalysts examined in the model reaction.
one (1a, Table 1). The application of organocatalysts 3a−3f,
effective in an analogous reaction with simple chalcones,15 failed
in the model reaction of 1a under classical conditions. With 2 mol
% of catalysts 3a−h at rt, traces of product 2a were usually
observed after 2 weeks (Table 1) and the best result was obtained
Received: October 5, 2014
Published: November 12, 2014
© 2014 American Chemical Society
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a
a
Table 1. Catalyst Screening in the Model Reaction
Table 2. Model Reaction Optimization Studies
bc
,
d
entry catalyst (mol %)
pressure
time
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
3a (2%)
3a (2%)
3a (2%)
3a (2%)
3a (1%)
3a (0.5%)
3a (2%)
3a (2%)
3d (1%)
3d (0.5%)
3d (1%)
3d (2%)
3d (2%)
3d (1%)
6 kbar
20 h
20 h
20 h
20 h
20 h
20 h
5 h
60
87
97
8 kbar
96
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
6 kbar
97 (92)
96
95.5 (S)
86
1 bar
e
f
(14 days)
8 kbar (20 h)
10 kbar (20 h)
84 (80)
90
95.5
94
catalyst
yield GC
yield
b
ee
(%)
yield
b
ee
(%)
b
c
c
entry
(2 mol %)
(%)
(%)
(%)
86
95.5
96
1
2
3
3a
3b
3c
3d
3e
3f
∼0.5
1.5
4
75
68
85
93
46
81
0
95
95
97
96
98
99
80
99
0
94
94
2 h
58
d
d
20 h
20 h
5 h
97 (91)
81 (78)
83
96.5 (R)
96
96
96
93
93
−
95
95
90
90
−
f
e
d
d
10
11
12
13
14
4
9
97.5
97.5
98
5
6
7
8
1
2 h
72
2
g
20 h
20 h
81
3g
0
d
d
8 kbar
89
97.5
3h
∼0.5
33
50
56
45
a
a
Conditions: 1a (E/Z 99:1, c = 1.0 mol/L), 3a or 3d, MeNO2 (3−4
Reaction conditions: 1a (E/Z ∼98:2, 0.25 mmol, c = 0.5 mol/L),
nitromethane (0.75 mmol, 3 equiv), and catalyst 3 (0.005 mmol, 2 mol
%) in toluene (ca. 0.75 mL), 20−25 °C. Determined by GC analysis
using biphenyl as the internal standard. Determined by HPLC
b
equiv) in toluene at 20−25 °C. Determined by GC analysis using
c
b
biphenyl as the internal standard. Numbers in parentheses refer to
d
c
isolated yield of 2a. Determined by HPLC analysis using Chiralpak
IC column. 1a, E/Z ratio 94:6. Reaction carried out at 50 °C.
e
f
d
analysis using the Chiralpak IC column. Product 2a with opposite
e
absolute configuration, (R). ee = 96.5 (∼0.5% yield after 1 day).
f
g
Experiment at 4 kbar (20 h): 24% yield, ee = 97.5%. Also with
kbar indicate that quinine derived thioureas 3c and 3d are slightly
more active in comparison to thioureas 3a and 3b derived from
quinidine and cinchonine, offering the opposite enantiomer of
2a. Also, the Takemoto catalyst 3f23 turned out to be very active
under high-pressureconditions, however, the enantioselectivity is
lower (ee = 90%, entry 6).
Based on catalyst screening at 8 and 10 kbar (Table 1) for
further optimization studies we selected cinchona thiourea 3a, as
well as catalyst 3d offering the opposite product enantiomer
(Table 2). A higher concentration of enone 1a (1.0 M in Table 2
vs 0.5 M in Table 1) improved the yield from 75% to 87% at 8
kbar with 2 mol % of 3a. Experiments at lower pressure, e.g. 6
kbar, resulted in a decreased reaction rate (60% yield) (Table 2,
entry 1). Based on these results further optimization studies were
performed with 3a for a more concentrated reaction mixture (1.0
M) at the 8−10 kbar pressure range (Table 2).
The E/Z ratio of enone 1a used in the reaction has a very
important influence on the enantioselectivity. Application of 1a
as a 94:6 E/Z mixture decreased the enantiomeric purity of the
product to 86% (Table 2, entry 4). The model reaction is effective
under 10 kbar even with 1 mol % of 3a at rt or 0.5 mol % at 50 °C
after 20 h (Table 2, entries 5 and 6). With 2 mol % of the catalyst
satisfactory results were obtained also after shorter reaction times
(5 and 2 h, Table 2, entries 7 and 8). To obtain optically pure
product 2a with opposite absolute configuration (R), more active
catalyst 3d (1−0.5 mol %) derived from quinine was applied
(Table 2, entries 9−14). In this case good yield and very high
enantioselectivity (81%, 98% ee) were observed even at 6 kbar
after 20 h (Table 2, entry 13). We also demonstrated that this
methodology is applicable with 1 mol % of 3a and 0.5 mol % of 3d
for multigram scale synthesis (5−12 mmol) with good isolated
yields (78−92%, Table 2, entries 3, 5, 9, and 10) and high
enantioselectivity (ee = 94−97%). For comparison, the reaction
with 10 mol % of 3d under atmospheric pressure at 50 °C gives
product 2a with up to a 28% yield after 7 days.16
additive of PhCO2H (2 mol %).
for 3d (9% yield and 96% ee, Table 1, entry 4). A higher loading of
3d (10 mol %), an excess of nitromethane (≥5 equiv), and
elevated temperature (50 °C) improved the yield after 1 week to
ca. 15−28%.16 A similar observation in this reaction has been
reported by Shibata7c with 10 mol % of catalyst 3c (14% yield, ee
= 93% ee; 50 °C for 7 days). This group finally succeeded in
performing the reaction under phase-transfer catalysis conditions
with 10−30 mol % of ammonium salt of cupreidinium n-butyl
ether.7c Using this method, diarylated products of type 2 were
obtained after 1.5−3 days with 80−99% yields and 90−93% ee’s.
Our preliminary experiments with well-known organocatalysts
3a−f confirmed their very low activity (Table 1) in the model
reaction under atmospheric pressure. Inspired by the pioneering
work of Matsumoto17 in the high-pressure activation of a
cinchona alkaloid-catalyzed Michael reaction and our recent
discoveries in high-pressure conjugate additions with primary
amine catalysis,12c,18 we decided to investigate the influence of
hydrostatic pressure in this case as well. High-pressure method-
ology in liquid systems has been quite well recognized as a
powerful tool in organic synthesis,10 but the influence of pressure
on asymmetric organocatalytic reactions still remains a very
poorly explored area of catalysis.19,20
In 2011, our group demonstrated that a combination of
pressure and catalysis with primary amines of type 3g remarkably
accelerate the enantioselective addition of nitroalkanes to
congested β-substituted cyclic enones.12c This class of organo-
catalysts failed in the reaction of β-CF3-chalcone (1a) with
MeNO2 (Table 1, entry 7). Theuse of quinidine (3h)17 improved
the yield under high-pressure conditions, although the
enantioselectivity was moderate (entry 8).
Application of 2 mol % of cinchona alkaloid-thiourea catalysts
3a−d15a,21 or the corresponding squaramide 3e15c,22 under 8 and
10 kbar of pressure remarkably accelerated the reaction rate
(Table 1, entries 1−5). From traces of product 2a observed at
atmospheric pressure (after 2 weeks), the yield dramatically
increased to 68−93% at 8 kbar and >95% at 10 kbar (after 20 h)
with very high enantioselectivity (ee = 94−96%). Results at 8
Having established the optimal conditions for the model
reaction, we extended our investigations to reactions of other
enones with nitromethane. All experiments were carried out
under 9−10 kbar of pressure in the presence of 3a (usually 2−3
mol %).24 The reaction tolerates different heteroaromatic
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Organic Letters
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Scheme 3. Products 2b−2f Modified in the Aryl-Ketone Part
Figure 2. Products with CF2Cl and CF2CF2CF3 groups.
Scheme 5. Synthesis of β-CF3−GABA Analog
Scheme 4. β-CF3 Products 2g−2r Modified in β-Position
Nitroketones with CF2R type groups (e.g., CF2Cl and
CF2CF2CF3) are also attainable using the high-pressure
approach, and promising preliminary results are presented in
Figure 2. The synthesis of 2t with a perfluoro-n-propyl group is
much more demanding and requires a higher catalyst loading (5−
10 mol %)24 compared to the model reaction of 1a. Use of a
2‑thiazole analog improved the yield but unfortunately reduced
the enantioselectivity (see product 2u).
The high-pressure approach has several advantages over the
method under phase transfer catalysis conditions with Cinchona-
based ammonium salts:7c a considerably lower loading of very
well-defined and commercially available thiourea-organocatalysts
(0.5−3 mol %), shorter reaction time (5−20 h), and slightly
higher enantioselectivity (ee = 93−98% vs 90−93%). Moreover,
the high-pressure method offers a much broader reaction scope,
including products with heteroaromatic substituents as well as
alkyl groups in the β-position.
Trifluoromethylated γ-nitroketones 2 are very interesting
precursors for further applications. Shibata7c utilized them to
synthesize trifluoromethyl diarylpyrrolines and their N-oxides.
We demonstrate the synthesis of β-CF3-β-aryl functionalized
γ‑aminobutyric acid 6 (Scheme 5) from nitroketone 2b.
Analogous β-monosubstituted-γ-aminobutyric acids (e.g., baclo-
fen, pregabalin) are very important molecules in medicine and
psychopharmacology.27 Baeyer−Villiger oxidation of (S)-2b
under optimized conditions followed by reduction with Raney
nickel provide (S)-β-trifluoromethyl-β-phenyl-butyrolactam 5.
Finally, hydrolysis of the lactam afforded β-trifluoromethylated
γ‑amino acid hydrochloride 6, the analog of phenibut (Scheme
5).
In summary, we have found that a combination of pressure (8−
10 kbar) and cinchona alkaloid-thioureas 3a and 3d (0.5−3 mol
%) can remarkably accelerate the reaction rate of nitromethane
addition to sterically congested β-trifluoromethyl enones.28 This
approach allows for a very efficient asymmetric synthesis of
γ‑nitroketones containing all-carbon quaternary stereogenic
centers bearing a trifluoromethyl group with very high
enantioselectivity (ee = 92−98%). This work has also
demonstrated the first example of a highly enantioselective
(>90% ee) organocatalytic reaction proceeding via a noncovalent
activation under high-pressure conditions (8−10 kbar).
substituents neighboring the carbonyl group in enone (e.g.,
2‑pirydyl, 2-furyl, and 2-thienyl, Scheme 3). Except for 2f (with a
2‑thiazole), very high yields and enantioselectivity (92−96.5%),
comparable to those of the model reaction, were observed.
We focused more attention on reactions of various
β‑trifluoromethylated enones with different aryl, heteroaryl,
and alkyl substituents in the β-position. The structures of
synthesized products 2g−2r are presented in Scheme 4. The
reaction tolerates different para- and meta-substituted phenyl
groups in the β-position (see examples 2g−i) including 2-naphtyl
(2j).25 Moreover, we extended the reaction scope to enones with
different heteroaryl (products 2k−2n) and alkyl (2o−2r)
substituents in the β-position. As shown in Schemes 3 and 4,
this reaction works very well for a broad range of β-CF3 enones,
affording good to very good yields and high enantioselectivity (ee
= 92−98%) with a low loading of 3a (2−3 mol %).24,26 In all
cases, control experiments under atmospheric pressure were
performed and only traces of products were detected.
The structure and absolute configuration of products 2f and 2l
was confirmed by X-ray crystallographic analysis.24 The use of
catalyst 3a afforded enantiomerically enriched products (S)-2f
and (S)-2l. Application of the more active pseudoenantiomeric
catalyst 3d leads to the opposite enantiomer.
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Synthesis at High Pressure; Wiley: New York, 1991. (c) Jurczak, J.;
Baranowski, B., Eds. High Pressure Chemical Synthesis; Elsevier:
Amsterdam, 1989.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data, including NMR
spectra, crystallographic data, and HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) For reviews on asymmetric organocatalytic conjugate additions,
see: (a) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42. (b) Vicario,
J.; Badía, D.; Carillo, L.; Reyes, E. Organocatalytic Enantioselective
Conjugate Addition Reactions. A Powerful Tool for the Stereocontrolled
Synthesis of Complex Molecules; RSC Publishing: Cambridge, 2010.
(c) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.;
Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561.
AUTHOR INFORMATION
■
Corresponding Author
(12) For examples of asymmetric organocatalytic 1,4-conjugate
addition of nitromethane to β,β-disubstituted enones and enals, see:
(a) Mitchell, C. E. T; Brenner, S. E.; Ley, S. V. Chem. Commun. 2005,
5346. (b) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302.
*E-mail: pkwiat@chem.uw.edu.pl.
Notes
The authors declare no competing financial interest.
(c) Kwiatkowski, P.; Dudzinski, K.; Łyzwa, D. Org. Lett. 2011, 13, 3624.
́
̇
(d) Akagawa, K.; Kudo, K. Angew. Chem., Int. Ed. 2012, 51, 12786.
(e) Hayashi, Y.; Kawamoto, Y.; Honda, M.; Okamura, D.; Umemiya, S.;
Noguchi, Y.; Mukaiyama, T.; Sato, I. Chem.Eur. J. 2014, 20, 12072.
(f) Mukaiyama, T.; Ogata, K.; Sato, I.; Hayashi, Y. Chem.Eur. J. 2014,
20, 13583 and ref 7a, 7c.
(13) By analogy to the synthesis of (R)-baclofen: Corey, E. J.; Zhang,
F.-Y. Org. Lett. 2000, 2, 4257.
(14) For selected reviews on bifunctional amine−thiourea catalysis,
see: (a) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298.
(b) Connon, S. J. Chem. Commun. 2008, 2499.
ACKNOWLEDGMENTS
■
This work was financially supported by the Polish National
Science Centre (Grant No. N N204 145740). Many thanks to
Professor Janusz Jurczak for his help and valuable discussion.
Dedicated to Professor Mieczysław Makosza on the occasion of
his 80th birthday.
̨
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substituted phenyls or 1-naphtyl in β-position. Shibata (ref 7c) also
presented only products with para- and meta- substituted β-aryls.
(26) For less reactive enone 1k, 4 mol % of 3a was added. Only for
product 2k is the enantioselectivity lower (86% ee), because a difficult-
to-separate E/Z-mixture (∼9:1) of enone 1k was used.
(27) Gajcy, K.; Lochyn
2338.
́
ski, S.; Librowski, T. Curr. Med. Chem. 2010, 17,
(10) (a) Van Eldik, R., Klaerner, F. G., Eds. High Pressure Chemistry:
Synthetic Mechanistic and Supercritical Applications; Wiley-VCH:
Weinheim, 2002. (b) Matsumoto, K.; Acheson, R. M., Eds. Organic
(28) Preliminary results were presented by P.K. at the 18th European
Symposium on Organic Chemistry in Marseille, 7−12 July, 2013.
5933
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