Direct experimental evidence for the epimerization of diastereoisomers in the enantioselective organocatalyzed michael addition of acetoacetates to nitroolefins

Article abstract of DOI:10.1055/s-0030-1261139

The evolution of the addition of acetoacetates to nitrostyrene catalyzed by a bifunctional thiourea has been followed by ¹⁹F NMR. The results show for the first time that the diastereoselectivity varies along the reaction time and that both the

Full text of DOI:10.1055/s-0030-1261139

LETTER
2203
Direct Experimental Evidence for the Epimerization of Diastereoisomers in
the Enantioselective Organocatalyzed Michael Addition of Acetoacetates to
Nitroolefins
19
R
F
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MR
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of
A
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oolefins Manzano, José M. Andrés, Rafael Pedrosa*
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/n, 47011 Valladolid, Spain
Fax +34(983)423013; E-mail: pedrosa@qo.uva.es
Received 17 June 2011
were also obtained in the construction of two adjacent ste-
Abstract: The evolution of the addition of acetoacetates to nitrosty-
rene catalyzed by a bifunctional thiourea has been followed by 19
NMR. The results show for the first time that the diastereoselectiv-
ity varies along the reaction time and that both the major and minor
diastereoisomers epimerize in the presence of the catalyst.
reocenters by the same methodology but, in that case, the
diastereoselectivity was dependent on the prostereogenic
nature of the methylene or methine groups acting as nu-
cleophiles. For instance, good to excellent dr was obtained
in the addition of unsymmetrical4 and cyclic ketones,8 or
cyclic ketoesters5a,9 but only moderate stereoselection was
observed in the addition of acyclic 2-substituted b-keto
esters to nitrostyrene.9d,10 In contrast, excellent enantiose-
lectivity, but low or no diastereoselection was reported for
the reaction of the same olefin with unsubstituted b-keto
esters.5a,11 These differences have been explained on the
basis of the stereochemical lability of the tertiary stereo-
center owing to the acidity of the hydrogen attached to a
carbon bearing two different electron-withdrawing groups
but, to the best of our knowledge, there are no data sup-
porting that fact.
F
Key words: asymmetric synthesis, epimerization, Michael addi-
tion, organocatalysis, thioureas
The conjugate addition of nucleophiles to electron-poor
olefins is one of the most powerful reactions in organic
synthesis because, in addition to the formation of carbon–
carbon or carbon–heteroatom bonds, it allows the creation
of up to three contiguous stereocenters.1 Enantioselective
organocatalytic transformations have been shown in the
last decade as a useful tool to get enantioenriched addition
products,2 and one of the most studied reactions is the con-
jugated addition of carbonyl derivatives to b-substituted
nitroolefins promoted by bifunctional thioureas. In that re-
action it is possible to create one3 or two contiguous stereo-
centers, depending on the prochirality of the carbonyl
derivative.
Now we report here our results on the stereoselective
Michael addition of ethyl acetoacetate and methyl aceto-
acetate to trans nitrostyrene and trans 4-fluoro nitrosty-
rene respectively by using valine-derived thiourea 1 as
bifunctional organocatalyst.5e,9d The reaction of a 0.5 M
solution of nitrostyrene (2) in toluene with two equiva-
lents of ethyl acetoacetate (3), for four hours at –20 °C in
the presence of 10 mol% of 1, yielded 99% of the addition
products as a mixture 54:46 of diastereoisomers (2S,3S)-4
and (2R,3S)-4.12 Under these conditions, the diastereose-
In general, good to excellent enantioselectivities are ob-
tained in the formation of a single stereocenter for addi-
tion of methyl ketones,4 malonates,5 2-substituted
malonates,5a,6 and acetylacetone7 to nitroalkenes promot-
ed by chiral thioureas or guanidines. Very high ee values
1
H
COMe
H
EtO2C
Ph
EtO2C
CO2Et
COMe
toluene, –20 °C
2
NO2
+
3
Ph
NO2
NO2
COMe
Ph
H
4
H
NMe2
S
3
2
(2R,3S)-
4
(2S,3S)-
4
HN
HN
CF3
COMe
H
H
EtO2C
EtO2C
1
COMe
NO2
CO2Me
COMe
6
F3C
NO2
NO2
+
toluene, –20 °C
F
H
H
F
F
5
(2S,3S)-
7
(2R,3S)-7
Scheme 1 Addition of acetoacetates to nitrostyrenes catalyzed by thiourea 1
SYNLETT 2011, No. 15, pp 2203–2205
x
x
.x
x
.2
0
1
1
Advanced online publication: 31.08.2011
DOI: 10.1055/s-0030-1261139; Art ID: B11211ST
© Georg Thieme Verlag Stuttgart · New York

2204
R. Manzano et al.
LETTER
lection was very poor but the enantioselection was excel-
lent because both diastereoisomers were obtained in 96:4
enantiomeric ratio. The reaction was scaled up to 4 mmol
by using only 2 mol% of catalyst 1 obtaining the same re-
sults but at the expense of increasing the reaction time to
48 hours.
Interestingly, the temperature plays an important role in
both the reaction rate and the diastereoselectivity. At
room temperature the reaction led to a mixture (1.4:1) of
diastereoisomers in 62% yield after stirring for 70 min-
utes. The same yield but an increase of the diastereoselec-
tivity to 2.8:1 was obtained if the reaction was carried out
at –20 °C for 130 minutes. The comparison of the last data
with those obtained after four hours of reaction indicates
that the diastereoselectivity also decreases with the time,
pointing to the epimerization of the addition products un-
der the reaction conditions.
Figure 2 19F NMR traces of the reaction mixture of trans-4-fluoro-
b-nitrostyrene with methyl acetoacetate catalyzed by thiourea 1
diastereoselection diminished over time, and only a 2.1:1
mixture of epimers was obtained after consumption of the
nitroolefin (about 600 min, trace 8). Interestingly, if the
reaction mixture was left standing for a long period of
time (1500 min) practically total epimerization occurred
and the diastereoisomers were obtained in near equimolar
ratio (trace 9). Interestingly, an equimolar mixture of
epimers was obtained when the pure minor diastereoiso-
mer (2R,3S)-4 was dissolved in chloroform and stirred in
the presence of a catalytic amount of 1, but remained un-
changed after six days in chloroform solution in the ab-
sence of the catalyst. An additional important fact is that
the enantioselectivity of the reaction did not change along
the reaction, because chiral HPLC analysis of the reaction
mixtures at different times showed that the enantiomeric
ratio in all cases varied from 95:5 to 96:4 for both diaste-
reoisomers.13
To test that fact, we decided to study the evolution of the
reaction mixture by 19F NMR spectroscopy because the
1H NMR spectra were too complex to determine the dia-
stereomeric ratios in the mixtures accurately. The reaction
of trans-4-fluoronitrostyrene (5) with two equivalents of
methyl acetoacetate (6) was chosen as the model reaction
(Equation 2 in Scheme 1), and we first tested whether the
fluoro nitroolefin behaves in a similar way as nitrostyrene,
because under the same conditions (0.5 M toluene solu-
tion, –20 °C, 4 h) a mixture (58:42) of diastereoisomers
(2S,3S)-7 and (2R,3S)-7 was formed in 98% yield in ex-
cellent 96:4 enantiomeric ratio for both of them. To study
the evolution of the reaction, 0.15 mmol of 4, 0.30 mmol
of 5 and 0.015 mmol of thiourea 1 was dissolved in 0.6
mL of toluene-d8 (0.25 M solution with respect to the ni-
troolefin) and CFCl3 as internal standard in an NMR tube,
and monitored by 19F NMR at 253 K (Figure 1).13
Although diastereoisomers 4 had been previously de-
scribed,5a,14 only the absolute configuration at C-3 was un-
equivocally determined, and no information about the
configuration at C-2 had been provided. It was necessary
to know the geometry of both diastereoisomers, and fortu-
nately we have now been able to obtain the relative ste-
reochemistry by X-ray diffraction analysis13 of the
racemate and assigned the absolute configuration as
(2R,3S)-4 for the minor diastereoisomer. Then, the stereo-
chemistry of diastereoisomers 7 was assigned by exten-
sion of that of compounds 4.
The reaction has been previously well studied from both
the chemical5a and computational11b,15 points of view, and
the generally accepted mechanism supposes a dual activa-
tion of the reagents by the catalyst leading to a ternary
complex (Scheme 2). In our case, the stereochemistry of
the addition products could be explained by accepting
that, after deprotonation of the acetylacetonate by the
amine group, the nitrostyrene derivative is coordinated by
the protonated amino group while the anion is stabilized
by the hydrogen donors of the thiourea moiety. The major
diastereoisomer (2S,3S)-4 will be formed from the ternary
complex A, whereas complex B, less stable by steric inter-
actions, will be the responsible of the formation of the mi-
nor (2R,3S)-4 isomer. Once formed, the mixture of
diastereoisomers equilibrates in the presence of the cata-
lyst through the enolate C. That enolization, in both a-po-
Figure 1 Evolution of the conversion (a) and dr (b) of the reaction
of trans-4-fluoro-b-nitrostyrene with methyl acetoacetate catalyzed
by thiourea 1
Figure 2 shows part of some representative 19F NMR trac-
es that indicate the evolution of the reaction mixture along
the time. In these spectra, the signal at d = –106.8 ppm
corresponds to trans-4-fluoro-b-nitrostyrene, whereas the
signals at d = –113.3 and –113.5 ppm correspond to
(2S,3S)-7 and (2R,3S)-7, respectively.
In fact, after 60 minutes of reaction, a 3.0:1 mixture of dia-
stereoisomers was formed in 37% yield (trace 1), but the
Synlett 2011, No. 15, 2203–2205 © Thieme Stuttgart · New York

LETTER
19F NMR Studies of Addition of Acetoacetates to Nitroolefins
2205
O
O
O
O
H
H
N
N
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Me
H
H
N
O
N
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Ar
Ar
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(2S,3S-4)
(2R,3S-4)
C
Scheme 2 Models for the formation of diastereoisomers and epimerization in the presence of catalyst 1
(5) (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (b) McCooey, S. H.;
Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367.
(c) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org.
Chem. 2006, 71, 7494. (d) Ye, J.; Dixon, D. J.; Hynes, P. S.
Chem. Commun. 2005, 4481. (e) Andrés, J. M.; Manzano,
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(6) Terada, H.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006,
128, 1454.
(7) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett.
2005, 7, 4713.
sitions of the carbonyl and the nitro groups, has been
previously observed by us in some related reactions.16
Alternatively, although adducts 4 and 7 are very prone to
be deprotonated and form enolates, an enol-mediated
epimerization pathway might also be suggested, which
would involve the activation of the enol of the corre-
sponding adduct by both the amino group and the thiourea
moiety of the catalyst, as previously proposed for differ-
ent reactions.17
(8) (a) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett.
2006, 8, 2901. (b) Cao, Y.-J.; Lu, H.-H.; Lai, Y.-Y.; Lu, L.-
Q.; Xiao, W.-J. Synthesis 2006, 3795. (c) Ban, S.; Du, D.-
M.; Liu, H.; Yang, W. Eur. J. Org. Chem. 2010, 5160.
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R. Adv. Synth. Catal. 2010, 352, 3364.
In summary, the described results showed that the diaste-
reoselection in the addition of prochiral dicarbonyl com-
pounds to nitroolefins is dependent on a series of
experimental parameters, especially on the reaction time.
Only a careful control of the reaction evolution could get
acceptable diastereomeric ratios.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(10) (a) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Chem.
Commun. 2009, 2136. (b) Oh, Y.; Kim, S. M.; Kim, D. Y.
Tetrahedron Lett. 2009, 50, 4674.
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Zhang, J.; Wang, R. J. Org. Chem. 2009, 74, 5562.
(b) Almasi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera,
C. J. Org. Chem. 2009, 74, 6163.
Acknowledgment
We thank the Spanish MICINN for funding (Project CTQ2008-
03960/BQU). R.M. also thanks Spanish MEC for a pre-doctoral fel-
lowship (FPU).
(12) (3S)-Ethyl 2-Acetyl-4-nitro-3-phenylbutanoate (4): To a
stirred solution of trans-b-nitrostyrene (2; 0.30 mmol, 45.6
mg) and catalyst 1 (0.03 mmol, 12.0 mg) in toluene (0.6 mL)
was added ethyl acetoacetate (3; 0.60 mmol, 0.08 mL) at
–18 °C. The reaction mixture was stirred until disappearance
of the nitroolefin (observed by TLC). The solvent was removed
in vacuo and the residue was purified by flash chromatog-
raphy (hexane–EtOAc, 20:1 to 15:1 as eluent) to afford the
desired product 4 (0.30 mmol, 83 mg, 99% yield, 54:46 dr,
96:4 er).
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