Highly enantioselective addition of ketones to nitroolefins catalyzed by new thiourea-amine bifunctional organocatalysts

Article abstract of DOI:10.1039/b517937h

A new and effective organocatalytic system: primary amine derived chiral thiourea catalyst 4a and AcOH-H₂O additive, which converts different ketones to γ-nitroketones in high yields (82-99%) and enantioselectivities (90-99%) has been described

Full text of DOI:10.1039/b517937h

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Highly enantioselective addition of ketones to nitroolefins catalyzed by
new thiourea–amine bifunctional organocatalysts{
Svetlana B. Tsogoeva* and Shengwei Wei
Received (in Cambridge, UK) 16th December 2005, Accepted 30th January 2006
First published as an Advance Article on the web 23rd February 2006
DOI: 10.1039/b517937h
anticipated.15 Furthermore, the neighbouring thiourea was
A new and effective organocatalytic system: primary amine
expected to interact, via hydrogen-bonding, with a nitro group
of the nitroolefins and enhance their electrophilicity.13g–j,16
In addition, the chiral arylethyl moiety adjacent to a thiourea
was expected to shield one side of the activated nitroolefin.
Here we present a successful application of the new chiral
bifunctional organic catalysts 1–3 and 4a–b (Fig. 2) to the
asymmetric Michael additions of different ketones to nitroolefins.
To evaluate the catalytic efficiency of the chiral thioureas the
addition of acetone to b-nitrostyrene was first performed in non-
polar toluene in the presence of each of these catalysts (Table 1,
entries 1, 3, 5, 7). Initial screening studies identified toluene as the
optimal solvent for the reaction.
derived chiral thiourea catalyst 4a and AcOH–H2O additive,
which converts different ketones to c-nitroketones in high yields
(82–99%) and enantioselectivities (90–99%) has been described.
Michael reaction of ketones with nitroolefins represent without
question a convenient access to c-nitroketones which are valuable
building blocks in organic synthesis.1 Barbas,2 List3 and Enders4
with co-workers independently reported the first organocatalytic
addition of acetone to trans-b-nitrostyrene using L-proline as the
catalyst. However, only poor enantioselectivity was obtained with
this natural catalyst.2–4 As a result, considerable effort has been
directed towards the development of an organocatalytic asym-
metric version of the Michael addition of ketones to nitroolefins
over recent years and many improvements to this reaction have
been made using pyrrolidine-based catalytic systems.5–10 Highly
enantio- and diastereoselective pyrrolidine–pyridine-catalyzed
nitro-Michael reactions, recently reported by Kotsuki and co-
workers, have focused on the use of cyclohexanone and
tetrahydrothiopyran-4-one as ketones.10 Poor to moderate enan-
tioselectivities still resulted when acetone (12–42% ee)4–9 or
methylethylketone (10–51% ee (syn))3,6 was used as a substrate.
The use of chiral bifunctional catalysts for the synthesis of
optically active compounds has become a new and exciting area of
contemporary synthetic organic chemistry.11,12
The use of proline based chiral thioureas 1 and 2 gave the
product only in racemic form and in low yields (up to 36% yield,
Table 1, entries 1, 3). Notably, much higher catalytic activity were
displayed by catalysts 3 (74%, 82% ee, entry 5) and 4a (75%, 87%
ee, entry 7, Table 1), which contain just a primary amino group in
place of proline moiety.
In the pioneering investigations of the role of acid in the
formation of enamine, carried out by Hine,17 it was shown that, in
water, protonated primary amines formed imines from the
corresponding carbonyl compounds at a rate that was 15 times
faster than that achieved by amines alone. This fact has motivated
us for the further experiments.
Chiral bifunctional thiourea derivatives have recently emerged
as enantioselective catalysts for different organic transforma-
tions.13 More recently, we reported14 on a new bifunctional
organocatalyst, bearing both a thiourea moiety and an imidazole
group on a chiral scaffold, as a more effective catalyst in the
addition of acetone to trans-b-nitrostyrene. We showed that this
bifunctional organocatalyst outperformed recently reported pyr-
rolidine-based catalytic systems,5–10 in the context of enantioselec-
tivity. Although a remarkable improvement in the ee value (87% ee)
has been achieved, the yield was moderate (55%).
With an interest in developing an efficient chiral organocatalytic
system to achieve high levels of yield and enantioselectivity in
Michael additions of different ketones to nitroolefins, we have
designed new chiral bifunctional organic catalysts that possess
both a thiourea moiety and an amine group as a base (Fig. 1).
A transient activation of ketone donors through formation of
an enamine on the primary or secondary amino group was
Fig. 1 Design of bifunctional organocatalysts for the Michael addition
of acetone to trans-b-nitrostyrene.
Institut fu¨r Organische und Biomolekulare Chemie der Georg-August-
Universita¨t Go¨ttingen, Tammannstrasse 2, 37077 Go¨ttingen, Germany.
E-mail: stsogoe@gwdg.de; Fax: +49-0551-39-9660;
Tel: +49-0551-39-3285
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b517937h
Fig. 2 Screened chiral thiourea based bifunctional organocatalysts.
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Table 1 Screening of new chiral thiourea catalysts 1–3 and 4a–b for
asymmetric addition of acetone (6) to trans-b-nitrostyrene (5)
Table 2 Catalytic asymmetric Michael addition of ketones to
nitroolefins under optimised conditions
Entry
Catalyst
Additive
t/h
Yield (%)b
ee (%)c
Entry t/h Product
Yield (%)a drb (syn : anti) ee (%)c (syn)
1
2
3
4
5
6
7
8
9
a
1
1
2
2
3
3
4a
4a
4b
—
AcOH, H2Oa
—
72
72
72
72
72
48
72
48
72
20
50
36
55
74
97
75
98
79
0
3
0
1
48
98
—
91
AcOH, H2Oa
—
3
82
84
87
91
77
b
AcOH, H2Oa
—
2
40
99
—
90
AcOH, H2Oa
AcOH, H2Oa
0.15 equiv. of AcOH and 2 equiv. of H2O were used. Yield of
isolated product after column chromatography on SiO2.
Enantioselectivities were determined by chiral HPLC analysis
c
3
4
50
61
98
84
—
—
90
91
(Daicel Chiralpak AS) in comparison with authentic racemic
material.
The Michael reaction of acetone with b-nitrostyrene was next
examined with thioureas 1–3 and 4a in the presence of AcOH and
H2O as additives.18 Water, it is known, plays a significant role in
the enamine catalytic reaction, including in regeneration of the
catalyst.15
5
6
72
72
82
89
80 : 20
96
98
To our delight, the addition of 0.15 equiv. of AcOH and 2 equiv.
of H2O significantly improved the reaction yield as well as slightly
improving the enantioselectivity relative to that with the catalysts
in the absence of additives (Table 1, entries 2, 4, 6, 8 versus entries
1, 3, 5, 7). The acid additive, thus, functioned ‘‘cooperatively’’ as
part of the catalysis and the catalytic system 4a–AcOH–H2O
provided Michael product 7 in excellent yield (98%) and with
91% ee (Table 1, entry 8 versus entry 7).
83 : 17
Encouraged by the excellent results obtained with bifunctional
thiourea (S,S,R)-4a in the presence of AcOH–H2O additive, we
next explored the effectiveness of its stereoisomer (S,S,S)-4b for the
same Michael addition. It is noteworthy that both catalysts
(S,S,R)-4a and (S,S,S)-4b provide the R enantiomer of the adduct
7. However, lower yield and enantioselectivity were afforded by
catalyst (S,S,S)-4b vs. those by (S,S,R)-4a (Table 1, entry 8 versus
entry 9). These results demonstrated that the original thiourea
(S,S,R)-4a was the best choice as a chiral organocatalyst.
With optimal catalyst and reaction conditions established, a
variety of aromatic nitroolefins were then evaluated as substrates
and the results are summarized in Table 2. Nitroolefins underwent
clean reactions with acetone as the simplest ketone affording the
desired product in high yields (98–99%), with the sole exception of
the slightly reduced yield (84%) achieved with aromatic nitroolefine
bearing an electron-donating substituent (Table 2, entries 1–3
versus entry 4). At the same time, the substituents of the nitroolefin
appear to have very little effect on the enantioselectivities of the
reaction, which range from 90% to 91% for catalyst 4a (Table 2,
entries 1–4).
7
72
88
14 : 86
.99d
a
b
Yield of isolated product after column chromatography on SiO2.
Determined by 1H NMR spectroscopy. Enantioselectivities were
c
determined by chiral HPLC analysis (Daicel Chiralpak AS) in
comparison with authentic racemic material.
diastereomer.
d
Ee % of anti
Surprisingly, the addition of a nonsymmetrical ketone such as
methylethylketone to b-nitrostyrene under the same conditions as
above, led to the opposite diastereomer (syn : anti 14 : 86) with very
high enantiocontrol (>99% ee). This selectivity is the reverse of that
normally found for this example in literature.3,6 To our delight,
remarkably high yields and enantioselectivities were achieved for
all investigated ketones and aromatic nitroolefins with the new
primary amine derived chiral thiourea catalyst 4a.
Cyclohexanone and tetrahydrothiopyran-4-one were also
reacted with b-nitrostyrene in high yield and enantioselectivity
(up to 89%, and 99% ee), and good diastereoselectivity (syn : anti
up to 83 : 17) in the presence of catalyst 4a (Table 2, entries 5, 6).
Notably, a new interesting study by Xu and Co´rdova on the
enantioselective nitro-Michael addition using primary amino acid
derivatives as catalysts appeared during the preparation of this
manuscript.19 The authors demonstrated that amino acid derived
1452 | Chem. Commun., 2006, 1451–1453
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4 D. Enders and A. Seki, Synlett, 2002, 26.
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Fig. 3 ESI-MS experiment of the enamine intermediate 4a9 and
proposed transition states for the Michael reaction of symmetrical (A)
and nonsymmetrical ketones (B) with trans-b-nitrostyrene.
10 T. Ishii, S. Fujioka, Y. Sekiguchi and H. Kotsuki, J. Am. Chem. Soc.,
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catalysts with a primary amine residue can successfully catalyze the
asymmetric addition of ketones to nitroolefins. However, low to
moderate enantioselectivities resulted when hydroxyacetone
(27% ee) or methylethylketone (67% ee) were used as a substrate.19
To confirm the importance of the thiourea moiety of 4a for the
catalysis, (1S,2S)-(2)-1,2-diphenylethylenediamine alone as well as
with additive was next tested as catalyst. Intriguingly, whereas the
combination of (1S,2S)-(2)-1,2-diphenylethylenediamine and
AcOH–H2O in toluene (72 h) gives the R Michael product in
26% yield and with 60% ee, the (1S,2S)-(2)-1,2-diphenylethylene-
diamine alone produces the S product, in 10% yield and with
11% ee. These experiments show that the primary amine even in
the presence of acid additive is not able to facilitate the nitro-
Michael addition with good yield, and thus the prerequisite for
very good yield and enantioselectivity is that the catalyst possesses
both thiourea and amine functionalities, directly adjacent to the
neighbouring stereogenic carbon centers of the chiral linker.
The formation of enamine intermediate 4a9 from acetone and
primary amine group of catalyst 4a was confirmed using the ESI-
MS method (Fig. 3).
12 For reviews of bifunctional organic catalysts, see: (a) P. I. Dalko and
L. Moisan, Angew. Chem., 2004, 116, 5248, Angew. Chem., Int. Ed.,
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Organocatalysis: From Biomimetic Concepts to Applications in
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13 For chiral urea- and thiourea-catalyzed reactions, see: (a) M. S. Sigman
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From these results, we propose the plausible transition-state
model (A), which reasonably explains the relative (syn) and
absolute configuration of the Michael adducts 11 and 12 (Fig. 3).
Finally, to explain the inversion of diastereoselectivity with
methylethylketone as a substrate, we assumed the formation of the
Z enamine intermediate B (Fig. 3).
In summary, we have demonstrated for the first time that
primary amine derived chiral thioureas can catalyze the asym-
metric nitro-Michael addition, giving high yields (82–99%),
enantioselectivities (90–99% ee) and good diastereoselectivities for
a wide range of ketones and aromatic nitroolefines.
14 S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker and
K. Huthmacher, Eur. J. Org. Chem., 2005, 4995.
15 For example see: A. Co´rdova, W. Zou, I. Ibrahem, E. Reyes,
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A. Wittkopp and P. R. Schreiner, Chem.–Eur. J., 2003, 9, 407; (c)
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The authors gratefully acknowledge the Deutsche
Forschungsgemeinschaft
(Schwerpunktprogramm
1179
‘‘Organokatalyse’’) for generous financial support.
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Notes and references
1 For a review of asymmetric Michael addition to nitroolefins, see:
O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002,
1877.
2 K. Sakthivel, W. Notz, T. Bui and C. F. Barbas, III, J. Am. Chem. Soc.,
2001, 123, 5260.
3 B. List, P. Pojarliev and H. J. Martin, Org. Lett., 2001, 3, 2423.
18 We found that the combination of AcOH (0.15 equiv.) and H2O
(2 equiv.) is optimal among the set of tested additives (H2O; H2O–
AcOH; H2O–NH4Cl;8a PhCOOH;8a L-Asp; (R)-(2)-2-phenylpropionic
acid; (S)-(+)-2-phenylpropionic acid) for the addition of acetone to trans-
b-nitrostyrene.
19 Y. Xu and A. Co´rdova, Chem. Commun., 2006, 460.
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