Aza-Michael Addition of Nosyloxycarbamates to 2-(Trifluoromethyl)acrylates

Article abstract of DOI:10.1021/ol0361554

(Matrix presented) The amination of 2-(trifluoromethyl)acrylates, performed by nosyloxycarbamates, gives two different aminated products, the derivatives of α-trifluoromethyl β-amino esters or the aziridines, in high yields by changing the reaction conditions. The aza-Michael addition product was isolated for the first time in this kind of reaction. This finding confirms the aza-MIRC mechanism we previously proposed. Asymmetric induction was also pursued.

Full text of DOI:10.1021/ol0361554

ORGANIC
LETTERS
2004
Vol. 6, No. 2
197-200
Aza-Michael Addition of
Nosyloxycarbamates to
2-(Trifluoromethyl)acrylates†
Daniele Colantoni, Stefania Fioravanti,* Lucio Pellacani,* and Paolo A. Tardella*
Dipartimento di Chimica dell’UniVersita` degli Studi di Roma La Sapienza,
Piazzale Aldo Moro 2, I-00185 Roma, Italy
lucio.pellacani@uniroma1.it
Received November 4, 2003
ABSTRACT
The amination of 2-(trifluoromethyl)acrylates, performed by nosyloxycarbamates, gives two different aminated products, the derivatives of
r-trifluoromethyl â-amino esters or the aziridines, in high yields by changing the reaction conditions. The aza-Michael addition product was
isolated for the first time in this kind of reaction. This finding confirms the aza-MIRC mechanism we previously proposed. Asymmetric induction
was also pursued.
The presence of fluorine in organic compounds such as
trifluoromethyl derivatives can influence their chemical,
physical, and physiological properties.1 Therefore these
compounds have great interest in pharmaceutical and indus-
trial fields.2 Moreover, a high biological activity was found
in fluorinated analogues of natural R- or â-amino acids,
compounds with a wide range of potential applications either
as is or as building blocks.
We have previously reported that olefins bearing two
geminal EWG groups may be successfully aziridinated with
ethyl nosyloxycarbamate (NsONHCO2Et) in the presence of
inorganic bases.3
Considering the synthetic relevance of CF3-substituted
compounds, we attempted direct amination reactions on
2-(trifluoromethyl)acrylates.
(2) (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan,
S., Eds.; John Wiley & Sons: New York, 1991. (b) Kitatsume, T.; Ito, K.
Jpn. Kokai Tokkyo Koho JP02167252, 1990; Chem. Abstr. 1991, 114,
62757. (c) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Kobayashi, Y., Yagulpolskii, Y. L.,
Eds.; Elsevier: Amsterdam, The Netherlands, 1993. (d) Organofluorine
Chemistry: Principles and Commercial Applications; Banks, R. E., Smart,
B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994. (e) Sani, M.;
Bruche´, L.; Chiva, G.; Fustero, S.; Piera, J.; Volonterio, A.; Zanda, M.
Angew. Chem., Int. Ed. 2003, 42, 2060-2063.
† Presented in part at the 13th European Symposium on Organic
Chemistry (ESOC 13), September 10-15, 2003, Cavtat-Dubrovnik, Croatia;
Abstracts, p 144.
(1) (a) Welch, J. T. Tetrahedron 1987, 43, 3123-3197. (b) Fluoroorganic
Chemistry: Synthetic Challenges and Biomedicinal Rewards; Resnati, G.,
Soloshonok, V. A., Eds.; Tetrahedron Symposia in Print No. 58: Tetra-
hedron 1996, 52, 233-304. (c) Gross, U.; Ru¨diger, S. In Houben-Weyl:
Methods of Organic Chemistry; Baasner, B., Hagemann, H., Tatlow, J. C.,
Eds.; Georg Thieme Verlag: Stuttgart, Germany, 1999; Vol. E10a, pp 18-
26.
(3) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Synthesis
2001, 1975-1978.
10.1021/ol0361554 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003

After transformation of commercially available 2-(trifluo-
romethyl)acrylic acid into the corresponding chloride,4 the
compounds 1a-d (Scheme 1) were synthesized in high
yields by using different alcohols in the presence of pyridine.
Scheme 2. Direct Amination Reaction of 1a-d
Scheme 1. 2-(Trifluoromethyl)acrylates
The direct amination reaction, involving the intermediate
aza-anion (NsON-CO2Et) as the very likely reactive species,
showed a new interesting outcome depending on reaction
conditions.
Of special interest is the use of calcium oxide promoted
aza-Michael 1,4-addition5 giving N,N′-disubstituted R-trif-
luoromethyl â-amino esters in high yields (Table 1).
Table 1. Different Conditions for Amination Reactions
yield (%)b
molar
1
base
solvent
ratiosa
time (h)
2
3
a
a
a
b
CaO
LiOH
CaO
CaO
CH2Cl2
CH2Cl2
THF
1:3:1.2
1:2:2
1:3:1.2
1:4:2
4
4
4
7
>95c
>95c
79
experimental evidence7 for the aziridination of electron-poor
alkenes. The presence of a CF3- group probably affects the
basicity/nucleophilicity of the intermediate carbanion A,
leading to the â-amino esters by immediate protonation. The
carbanion A did not undergo ring closure under these
conditions.
Accordingly, the use of a different inorganic base such as
sodium hydride in THF on 2 promotes an R-deprotonation,
followed by intramolecular ring closure to quantitatively give
the corresponding aziridines 3 (Scheme 2). With NaH the
absence of a protonated base might favor the ring closure
reaction.
Moreover, the N-O bond reductive cleavage of 2 by Zn/
CH3COOH quantitatively gave the corresponding N-ethoxy-
carbonyl R-trifluoromethyl â-amino esters 4. Thus, starting
from 2 it is possible to obtain two different aminated
precursors of a variety of important molecules.8
The synthesis of optically active trifluoromethyl amino
derivatives is very important both in organic chemistry and
in the biological and pharmacological fields.
CH2Cl2
90
a
b
NaH
NaH
THF
THF
1:4:1.2
1:4:1.2
4
2
86
90
a Substrate:base:NsONHCO2Et. b Isolated product by flash chromatog-
raphy. c By H NMR on the crude mixture.
I
Otherwise by using sodium hydride in THF at 0 °C an
aza-MIRC (Michael-initiated ring closure) reaction6 yielded
directly aziridines 3a,b (Scheme 2) in agreement with our
previous findings.
The isolation of 2 for the first time in this kind of reaction
supports the pathway proposed by us on the basis of first
(4) Yamazaki, T.; Ichige, T.; Takei, S.; Kawashita, S.; Kitazume, T.;
Kubota, T. Org. Lett. 2001, 3, 2915-2918.
(5) (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4,
1319-1322. (b) Sharma, G. V. M.; Reddy, V. G.; Chander, A. S.; Reddy,
K. R. Tetrahedron: Asymmetry 2002, 13, 21-24. (c) Cardillo G.; Fabbroni,
S.; Gentilucci, L.; Gianotti, M.; Perciaccante, S.; Tolomelli, A. Tetrahedron:
Asymmetry 2002, 13, 1407-1410. (d) Molteni, M.; Volonterio, A.; Zanda,
M. Org. Lett. 2003, 5, 3887-3890. (e) Enders, D.; Wallert, S.; Runsink, J.
Synthesis 2003, 1856-1868. (f) Waibnitz, T. C.; Spencer, J. B. Org. Lett.
2003, 5, 2141-2144. (g) Xu, L. W.; Xia, C. G.; Hu, X. X. Chem. Commun.
2003, 2570-2571.
(7) (a) Fioravanti, S.; Pellacani, L.; Stabile, S.; Tardella, P. A.; Ballini,R.
Tetrahedron 1998, 54, 6169-6176. (b) Fioravanti, S.; Pellacani, L.;
Tabanella, S.; Tardella, P. A. Tetrahedron 1998, 54, 14105-14112. (c)
Fioravanti, S.; Marchetti, F.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Org. Lett. 2003, 5, 1019-1021. (d) A similar mechanistic sequence was
hypothesized without isolating any aza-Michael addition product: Zeifman,
Yu. V.; Rokhlin, E. M.; Utebaev, V.; Knunyants, I. L. Dokl. Akad. Nauk.
SSSR 1976, 226, 1337-1340.
(6) (a) Little, R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609-
2612. (b) Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De
Kimpe, N.; Verhe, R. Synlett 2002, 1089-1092. (c) Kozhushkov, S. I.;
Leonov, A.; de Meijere, A. Synthesis 2003, 956-958.
198
Org. Lett., Vol. 6, No. 2, 2004

The diastereoselective substrate-controlled aminations were
performed on the substrates 1c,d (Table 2) derived from two
different chiral auxiliaries.
Table 2. Amination of Chiral Substrates
yield (%)
molar
1
basea
ratiosb
time (h)
t (°C)
2
3
de (%)c
c
d
CaO
CaO
1:5:4
1:2:2
24
3
25
25
70
81
12
70
c
c
d
d
d
NaH
NaH
NaH
NaH
NaH
1:4:1.5
1:5:2
1:4:1.2
1:4:1.2
1:5:1.2
2
12
2
10
12
25
-78
25
-40
-78
93
90
85
94
96
18
19
68
70
72
a CH2Cl2 and THF were used as solvent with CaO and NaH, respectively.
Figure 1. 19F NMR spectra of diastereomeric mixtures of 2d and
3d (chemical shifts relative to CFCl3).
b Substrate:base:NsONHCO2Et. c By 1H and 19F NMR on the crude mixture.
In both cases good yields of aziridines were observed.
While the use of (-)-8-phenylmenthol9,10 induced a low
diastereoselectivity, more satisfactory results were obtained
by using the bulkier Helmchen’s auxiliary.10,11 Lower tem-
peratures did not allow any increase of the de values.
In all cases the diastereomeric aziridines were easily
separated by HPLC and isolated as optically pure com-
pounds.
one aziridine (6) was obtained with complete stereoselectivity
(Scheme 3), as shown by 19F NMR spectra (Figure 2).
Scheme 3. Stereoselective Ring Closure As Determined by
19F NMR Spectra
It is interesting to note that the diastereoselective induction
seems only to depend on the choice of the chiral auxiliary.
Indeed de values do not vary to a significant extent when
different reaction conditions are chosen to synthesize 3.
Starting from known mixtures of diastereomers 2c or 2d the
intramolecular cyclization showed a highly stereospecific
outcome, as demonstrated by 19F NMR (Figure 1). Probably
the stereochemistry was mostly controlled by the aza-anion
addition step.
In summary, the aziridination reaction of 2-(trifluoro-
methyl)acrylates with nosyloxycarbamates proceeds in a
stepwise manner, and simply by slightly changing the
Diastereoselective reagent-controlled aminations were also
attempted by using the chiral carbamate derived from the
Helmchen’s auxiliary (NsONHCO2R*).12
The amination of 1b with NsONHCO2R*, performed in
THF with NaH at -40 °C, after 12 h gives the aza-Michael
addition products 5 in high yields but in low diastereomeric
excesses and only traces of the corresponding aziridines were
formed. The different reactivity could be due to the steric
hindrance on the nitrogen atom that likely disfavors the
nucleophilic ring closure. However, by treating the separated
major diastereomer 5 with NaH at room temperature only
(8) (a) Fluorine-Containing Amino Acids Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; John Wiley & Sons: New York,
1995. (b) Enantiocontrolled Synthesis of Fluoro-Organic Compounds:
Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A.,
Ed.; Wiley: Chichester, UK, 1999. (c) Davoli, P.; Forni, A.; Franciosi, C.;
Moretti, I.; Prati F. Tetrahedron: Asymmetry 1999, 10, 2361-2371.
(9) Kotsuki, H.; Arimura, K.; Ohishi T.; Maruzasa, R. J. Org. Chem.
1999, 64, 3770-3773.
(10) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. J. Org.
Chem. 2002, 67, 4972-4974.
(11) Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985, 26, 6051-6054.
(12) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Tetra-
hedron Lett. 2003, 44, 3031-3034.
Figure 2. 19F NMR spectra of 5 and 6 (chemical shifts relative to
CFCl3).
Org. Lett., Vol. 6, No. 2, 2004
199

reaction conditions we have been able to isolate for the first
time the aza-Michael addition product, as well as the
aziridination product, always in high yield. The stereochem-
ical features of these reactions also have been studied and
will be further investigated.
Given the mild conditions required, the reported reactions
would provide valuable intermediates for synthetic applica-
tions.
(MIUR) and the Universita` degli Studi di Roma La Sapienza
(National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni”) for financial support.
Supporting Information Available: General procedures
and details of the spectroscopic characterization of repre-
sentative compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We would like to thank the Italian
Ministero dell’Istruzione, dell’Universita` e della Ricerca
OL0361554
200
Org. Lett., Vol. 6, No. 2, 2004