Synthesis of fluorinated α,β-diamino esters by ring opening of activated 3-trifluoromethyl-aziridine-2-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2006.01.142

The activation of trifluoromethyl aziridine-2-carboxylates resulted to be a suitable strategy for their ring opening under neutral conditions. Using amines as nucleophiles the reaction proceeded regio- and diastereoselectively, giving rise to α,β-diamino-

Full text of DOI:10.1016/j.tetlet.2006.01.142

Tetrahedron Letters 47 (2006) 2065–2068
Synthesis of fluorinated a,b-diamino esters by ring opening
of activated 3-trifluoromethyl-aziridine-2-carboxylates
a
a
Giuseppe Rinaudo,a Satoru Narizuka,a,b Neda Askari, Benoˆıt Crousse
´
a,
*
`
and Daniele Bonnet-Delpon
a
ˆ
CNRS Biocis UMR 8076, Faculte´ de Pharmacie, Universite´ Paris-Sud, 5, rue J.B. Cle´ment, Chatenay-Malabry 92296, France
bChemical Research Centre Central Glass Co. Ltd, 2805 Imafuku-Nakadai, Kawagoe, Saitama 350-1151, Japan
Received 5 December 2005; revised 30 January 2006; accepted 31 January 2006
Available online 14 Ferbruary 2006
Abstract—The activation of trifluoromethyl aziridine-2-carboxylates resulted to be a suitable strategy for their ring opening under
neutral conditions. Using amines as nucleophiles the reaction proceeded regio- and diastereoselectively, giving rise to a,b-diamino-b-
trifluoromethyl esters in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The ring opening of aziridine-2-carboxylates represents
a useful reaction to obtain a- and b-amino acids.1 Its
extension to fluorinated aziridines constitutes a promis-
ing route to fluorinated amino acids. The introduction
of fluorine atoms in organic molecules often results in
a deep modification of physical, chemical and thus, bio-
logical properties of the parent compounds.2 This ‘fluo-
rine approach’ has proved its viability and the synthesis
of fluorinated amino acids and nitrogen-containing
compounds finds increasing interest.3
In order to better exploit this stereoselective route to
new trifluoromethyl-a-substituted b-amino esters, we
were interested in developing different reaction condi-
tions. Our aim was in particular to have a good access
to fluorinated diamino acids. If several methodologies
have been developed for the preparation of fluorine-
substituted amino acids,3,6 only few examples of fluoro-
alkyl a,b-diamino acids are reported in the literature.7
We report here our investigations on the ring opening
of trifluoromethyl aziridine-2-carboxylates with amino-
containing nucleophiles.
A regio- and stereoselective synthesis of anti-a-function-
alized-b-amino trifluoromethyl esters was described
through the acid-catalyzed ring opening of non acti-
vated trans-ethyl 3-trifluoromethyl-aziridine-2-carboxyl-
ates.4 More recently, our research group developed a
stereoselective synthesis of non activated cis-ethyl 3-tri-
fluoromethyl-aziridine-2-carboxylates as an access to
syn-a-functionalized-b-amino trifluoromethyl esters.5
These trifluoromethyl aziridine ring opening reactions
require the in situ generation of an aziridinium ion
under very harsh acidic conditions. They are consequently
limited to only a few nucleophiles such as carboxylates,
thiols and halides.
In this study it was anticipated that non activated cis-
ethyl 3-trifluoromethyl-aziridine-2-carboxylates 1 and 2
(Fig. 1) would exhibit a low reactivity towards amines.
Aziridine-2-carboxylates are reported to undergo ring
opening with amines only when they are activated. Con-
cerning non activated CF3-substituted aziridines, there is
only one example in the literature: N-benzyl-2-trifluoro-
methylaziridine is inert towards BnNH2 even in Lewis
acid-catalyzed ring opening.7a The presence of CF3
R
N
F3C
COOEt
Keywords: Trifluoromethyl aziridine-2-carboxylates; Activated aziri-
dine; Ring opening; Trifluoromethyl a,b-diamino esters.
Corresponding author. Tel.: +33 146 835 738; fax: +33 146 835
740; e-mail: daniele.bonnet-delpon@cep.u-psud.fr
cis-1 R = Bn
cis-2 R = PMP
*
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.142

2066
G. Rinaudo et al. / Tetrahedron Letters 47 (2006) 2065–2068
disfavors the coordination of the nitrogen atom with the
Lewis acid. 1 and 2 combine the disadvantages of both
substituents. Effectively, when cis-1 and cis-2 were sub-
mitted to reaction with amines, in the presence of
Lewis acids (Yb(OTf)3 and Cu(OTf)2) at the reflux of
dichloroethane for 36 h, no ring opening occurred.
O
OBn
O
NHBn
CO2Et
BnNH2 (2 eq.)
N
N
F3C
cis-4a
Scheme 2.
CO2Et
solvent, T C
F3C
˚
24 h
cis-6
These unsuccessful experiments prompted us to activate
the aziridines by introducing an electron withdrawing
group on the nitrogen atom. Numerous ring opening
reactions of activated aziridines are described in the lit-
erature,8 but, to the best of our knowledge, only one
example is known for fluorinated aziridines.7b
Yb(OTf)311 or BF3ÆEt2O also failed to direct the reaction
towards the ring opening.
Nevertheless, the preparation of a,b-diamino-b-trifluo-
romethyl esters could be achieved from the N-tosyl and
N-nosyl trifluoromethyl aziridines 4b and 4c, under rather
mild reaction conditions, using amines or NaN3 as nucleo-
philes, without Lewis acid catalysis (Scheme 3). Opti-
mized conditions and yields are reported in Table 3.12
cis-N-Benzyl-trifluoromethylaziridine 1 was first reduced
into the aziridine cis-3, which was further easily con-
verted into cis-4a and cis-4b, in the presence of carbo-
benzyloxy chloride (CbzCl) or tosyl chloride (TsCl)
(Scheme 1 and Table 1).
It is noteworthy that the ring opening always occurred
at the C-2 carbon with a complete regioselectivity. This
is most often observed in nucleophilic reactions with
CF3-substituted rings (epoxides and cyclic sulfates),13
and can be easily explained by the steric hindrance
and electrostatic repulsion offered by trifluoromethyl
group towards the attacking nucleophiles.7a Further-
more, in our case, the CF3 substituent is less able than
COOEt to stabilize a p orbital on the Ca carbon in a
pure SN2 process, and/or to accommodate the develop-
ment of a positive charge in the dissociation of the Ca–N
bond.14 Concerning the stereoselectivity of these
reactions, we always observed the sole formation of
one diastereoisomer. The syn configuration for 7b was
determined by X-ray diffraction.15
When reacted with ortho-nosyl chloride (NsCl) in the
presence of pyridine, aziridine cis-3 provided amino
ester 5c, resulting from the ring opening of the N-nosyl
aziridine by the chloride present in the reaction mixture
(entry 3).9 This result clearly shows the more activating
effect of the nosyl group as compared to that of the tosyl
group. Several attempts were performed to selectively
obtain aziridine cis-4c by varying solvents, bases, tem-
peratures. The only successful result was obtained with
Na2CO3 as base, but the reaction time was very long,
even at reflux of dichloroethane (entry 4).
The reactivity of activated aziridines 4a–c was first
investigated towards benzylamine, in the presence or
not of a Lewis acid as catalyst. The reaction of aziridine
cis-4a with BnNH2 required reflux of dichloroethane
and was incomplete after 24 h (ꢀ 60% conversion). Fur-
thermore, the major reaction was the attack at the benz-
yloxycarbonyl group of Cbz instead of the ring
opening10a,b (Scheme 2 and Table 2). The use of
This highly stereoselective ring opening prompted us to
prepare the trans-N-tosyl trifluoromethyl aziridine in or-
der to obtain the anti-stereoisomers. The aziridine trans-
1,4 was reduced into the aziridine trans-3, which was
then used without purification. When tosylation was
H2 (1 atm)
R
R
N
Bn
N
H
N
Pd(OH)2/C
RCl
HN
CO2Et
Cl
+
CH2Cl2
base, solvent
F3C
F3C
CO2Et
F3C
CO2Et
F3C
CO2Et
T
C, time
3 days, 30 C
˚
˚
(90%)
cis-1
cis-3
cis-4a R = Cbz
cis-4b R = Ts
cis-4c R = Ns
5c R = Ns
Scheme 1.
Table 1. Preparation of activated trifluoromethyl aziridine-2-carboxylates
Entry
RCl (equiv)
Base (equiv)
Solvent
T (°C)
Time
Yield (%)a
1
2
3
4
CbzCl (1.2)
TsCl (2)
NsCl (2)
NsCl (4)
NaHCO3 (1.5)
Pyridine (3)
Pyridine (3)
Na2CO3 (9)
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
0
0
3 h
1 h
24 h
8 days
cis-4a (92)
cis-4b (80)
5c (65)b,c
0–4
Reflux
cis-4c (60)
a Isolated yield.
b cis-4c was present as 12% of the crude mixture after work-up (calculated by 19F NMR).
c Only one diastereoisomer of 5c was present in the crude mixture (determined by 19F NMR).

G. Rinaudo et al. / Tetrahedron Letters 47 (2006) 2065–2068
Table 2. Attack of benzyl amine at benzyloxycarbonyl of N-Cbz activated aziridine
2067
Entry
Lewis acid (equiv)
Solvent
T (°C)
Product
Yield (%)a
1
2
3
—
ClCH2CH2Cl
THF
Et2O
Reflux
Reflux
Reflux
cis-6
cis-6
cis-6
25
52
67
Yb(OTf)3 (0.2)
BF3ÆEt2O (1 equiv)
a Isolated yield.
R
HN
Ts
R
N
Ts
N
NuX
CO2Et
Cl
CO2Et
Nu
HN
KHMDS
F3C
F3C
solvent
THF
-60 C
F3C
CO2Et
F3C
CO2Et
r.t.
T C, time
˚
˚
4b
5b (17/83)
48h
cis-4b R = Ts
cis-4c R = Ns
syn-7 Nu = NHBn
syn-8 Nu =
cis/trans = 13/87
N
O
yield of trans-4b = 40%
syn-9 Nu = N3
Scheme 5.
Scheme 3.
The diastereoselective formation of syn and anti diamino
esters, from respectively, cis and trans aziridines, con-
firms the supposed SN2 mechanism for this reaction.
No isomerization of products in the reaction medium
was observed.
performed at 0 °C in CH2Cl2, only 20% conversion
occurred after 4 h, giving rise to the ring opening prod-
uct 5b, as already observed from the cis-N-nosyl aziri-
dine 4c (Scheme 4).
H2 (1 atm)
Pd(OH)2 /C
Bn
N
H
N
Ts
Ts
N
TsCl
HN
CO2Et
Cl
Py
F3C
F3C
CO2Et
F3C
CO2Et
r.t.
F3C
CO2Et
trans-4b
CH2Cl2
5b
trans-1
trans-3
4h, 0 C:
conversion = 20%
˚
27h, reflux:
yield related to trans-1 = 41%
diastereomeric ratio = 17/83
Scheme 4.
For a complete conversion of trans-3 into 5b a 1 day
reaction at reflux was required, but a partial isomeriza-
tion occurred, producing a 17/83 mixture of both diaste-
reoisomers (ratio determined by 19F NMR) (Scheme 4).
This mixture was used for preparing the trans-N-
tosyl trifluoromethyl aziridine by ring closure using
NaHMDS.9 After purification and separation, the aziri-
dine trans-4b could be obtained in 40% yield (Scheme 5).
Preliminary experiments were performed to evaluate the
usefulness of these new ring opening conditions. The
reaction of aziridine cis-4b with potassium ethyl xan-
thate was thus investigated. The reaction proceeded at
room temperature in CH3CN/H2O as solvent, produc-
ing a 66% yield of 10 as a (58/42) mixture of both diaste-
reoisomers (Scheme 7).
The lack of diastereoselectivity is probably the result of
an isomerization due to the higher acidity of Ha, vicinal
to the carboxylate and xanthate functions. The use of
this new synthon 10 for further radical reactions16 is
under investigation.
The ring opening of trans-4b with benzyl amine pro-
ceeded under the same reaction conditions as for cis-
4b to provide the anti-isomer 7b as the only product
(74% yield) (Scheme 6).
Table 3. Ring opening of N-sulfonyl activated aziridines with amino containing nucleophiles
Entry
Substrate
NuX (equiv)
Solvent
T (°C)
Time
Product
Yield (%)a
1
2
3
4
5
cis-4b
cis-4c
cis-4b
cis-4c
cis-4c
BnNH2 (2.5)
BnNH2 (1.2)
Morpholine (2.5)
Morpholine (1.2)
NaN3 (3)
CH2Cl2
Reflux
Reflux
Reflux
Reflux
rt
24 h
8 h
22 h
3 h
syn-7b
syn-7c
syn-8b
syn-8c
syn-9c
78
75
90
74
90
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
DMF
1 h
a Isolated yield.

2068
G. Rinaudo et al. / Tetrahedron Letters 47 (2006) 2065–2068
572; (c) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron
Ts
Ts
N
BnNH2 (2 eq)
2004, 60, 6711–6745.
HN
CO2Et
4. Davoli, P.; Forni, A.; Franciosi, C.; Moretti, I.; Prati, F.
Tetrahedron: Asymmetry 1999, 10, 2361–2371.
F3C
NBn
CH2Cl2
reflux, 24 h
(74%)
F3C
CO2Et
H
´
´
5. Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Begue, J.-P
Synlett 2001, 679–681.
trans-4b
Scheme 6.
anti-7b
6. Asymmetric Fluoroorganic Chemistry: Synthesis, Applica-
tions, and Future Directions; Ramachandran, P. V., Ed.;
ACS Books, American Chemical Society: Washington,
DC, 2000.
7. (a) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.;
Uneyama, K. J. Org. Chem. 1999, 64, 7323–7329; (b)
Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K.
Tetrahedron 2003, 59, 9839–9847; (c) Soloshonok, V. A.;
Avilov, D. V.; Kukhar, V. P.; Van Meervelt, L.; Mis-
chenko, N. Tetrahedron Lett. 1997, 38, 4671–4674.
8. For a recent review see: Hu, X. E. Tetrahedron 2004, 60,
2701–2743.
S
Ts
Ts
CO2Et
Hα
HN
F3C
S-K+
EtO
(1.2 eq)
N
S
OEt
CH3CN/H2O
r.t., 8 h
F3C
CO2Et
S
(66%)
10 (58/42)
9. Hanessian, S.; Moitessier, N.; Cantin, L.-D. Tetrahedron
2001, 57, 6885–6900.
Scheme 7.
10. For competitive attack of nucleophiles at carbonyl versus
ring carbon see: (a) Hassner, A.; Kascheres, A. Tetra-
hedron Lett. 1970, 11, 4623–4626; (b) Dauban, P.; Dubois,
L.; Tran Huu Dau, M. E.; Dodd, R. H. J. Org. Chem.
1995, 60, 2035–2043.
In this study of ring opening of trifluoromethyl aziridine
carboxylates, we have found conditions to circumvent
their low reactivity towards nucleophiles. We could
demonstrate that after their activation by a sulfonyl
N-substituent, trifluoromethyl aziridine carboxylates
could undergo a nucleophilic ring opening without any
Lewis acid catalysis. The ring opening reaction with
amino-containing nucleophiles proceeded in good yield
and with a total regio- and diastereoselectivity to pro-
vide the corresponding trifluoromethyl-containing
diamino esters. This is a good alternative to the harsh
conditions hitherto required, which could be suitable
to a wider range of nucleophiles.
11. Meguro, M.; Yamamoto, Y. Heterocycles 1996, 43, 2473–
2482.
12. Typical procedure for the synthesis of syn-ethyl 2-benz-
ylamino-4,4,4-trifluoro-3-(4-methylphenyl)sulfonylamino-
butanoate (syn-7b): To a stirred solution of the aziridine
(167 mg, 0.5 mmol) in CH2Cl2 (2 mL), BnNH2 (0.11 mL,
1.0 mmol) was added at rt. The reaction mixture was then
stirred at reflux of CH2Cl2 for 24 h. After dilution with
CH2Cl2 (100 mL), the mixture was washed with water
(50 mL) and brine (50 mL) and then dried on MgSO4.
After filtration and evaporation of the solvent, the crude
product was purified by flash chromatography on silica gel
(petroleum ether/AcOEt = 2/1) to give a colourless solid
(78% yield): mp: 77 °C. IR (neat) 3330, 3263, 1739 cmÀ1
.
3
1H NMR (CDCl3) d 1.30 (t, 3H, J = 7.2 Hz), 2.4 (br s,
3
Acknowledgements
1H), 2.42 (s, 3H), 3.62 (d, 1H, J = 2.1 Hz), 3.77 (d, 1H,
3J = 14.0 Hz), 3.78 (d, 1H, 3J = 14.0 Hz), 4.16 (dq, 1H,
2J = 10.7 Hz, 3J = 7.2 Hz), 4.17 (dq, 1H, 2J = 10.7 Hz,
3J = 7.2 Hz), 4.37 (m, 1H), 5.8 (br s, 1H), 7.23–7.37 (m,
7H), 7.70–7.76 (m, 2H). 13C NMR (CDCl3) d 13.8, 21.3,
`
We gratefully thank Michele Ourevitch (CNRS Biocis
UMR 8076, Univ. Paris-Sud) for 2D NMR experiments
and Patrick Herson (Laboratoire de Chimie Inorga-
nique et Materiaux Moleculaires, UMR CNRS 7071,
2
52.6, 55.8 (q, JCF = 31 Hz), 58.0, 62.5, 123.3 (q,
1JCF = 275 Hz), 126.9, 127.3, 128.1, 128.4, 129.4, 137.5,
138.6, 143.6, 170.4. 19F NMR (CDCl3) d À73.6 (d,
3JFH = 7 Hz). Anal. Calcd for C20H23F3N2O4S: C,
54.05%; H, 5.22%; N, 6.30%. Found: C, 54.02%; H,
5.27%; N, 6.24%.
´
Universite Pierre et Marie Curie) for X-ray crystallo-
graphic experiments. We also thank the European Com-
munity for the financial support (RTN Contract No.:
HPRN-CT-2002-00181) and research fellowship (G.R.).
´
´
13. (a) Avenoza, A.; Busto, J. H.; Jimenez-Oses, G.; Pere-
grina, J. M. J. Org. Chem. 2005, 70, 5721–5724; (b) Jiang,
Z.-X.; Qing, F.-L. J. Org. Chem. 2004, 69, 5486–5489; (c)
References and notes
´
´
Begue, J.-P.; Benayoud, F.; Bonnet-Delpon, D. J. Org.
Chem. 1995, 60, 5029–5036.
1. For a general review on aziridine chemistry see: (a)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–
619; (b) McCoull, W.; Davis, F. A. Synthesis 2000, 10,
1347–1365.
14. (a) Allen, A. D.; Tidwell, T. T. In Advances in Carbocation
Chemistry; Creary, X., Ed.; JAI Press: Greewich, Con-
necticut, 1989; pp 1–44; (b) Creary, X. Chem. Rev. 1991,
91, 1625–1678.
15. Crystallographic data (excluding structure factors) for
compound syn-7b have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication number CCDC 291307. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
16. For a review on xanthate chemistry see: Zard, S. Z.
Angew. Chem., Int. Ed. 1997, 36, 672–685.
´
´
2. (a) Begue, J. P.; Bonnet-Delpon, D. Chimie Bioorganique
et Me´dicinale du Fluor; EDP Sciences/CNRS Editions:
Paris, 2005; (b) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS
Books, American Chemical Society: Washington, DC,
1996.
3. (a) Fluorine-containing Amino Acids: Synthesis and Prop-
erties; Kukhar, V. P., Soloshonok, V. A., Eds.; John Wiley
´
´
& Sons: Chichester, 1995; (b) Begue, J. P.; Bonnet-Delpon,
D.; Crousse, B.; Legros, J. Chem. Soc. Rev. 2005, 34, 562–