Barbier conditions for reformatsky and alkylation reactions on trifluoromethyl aldimines

Article abstract of DOI:10.1055/s-2007-1000864

β-Trifluoromethyl β-amino acids and α-trifluoromethyl α-alkyl amines can be easily prepared under Barbier conditions from trifluoromethyl aldimines in moderate to good yields. β-Trifluoromethyl β-amino acids were obtained in good enantioselectivity from t

Full text of DOI:10.1055/s-2007-1000864

LETTER
399
Barbier Conditions for Reformatsky and Alkylation Reactions on
Trifluoromethyl Aldimines
B
arbier Conditions on
i
Trifluo
c
romethyl
A
k
ldimines ael Dos Santos, Benoit Crousse,* Danièle Bonnet-Delpon
BioCIS-CNRS, Faculté de Pharmacie, Université Paris-Sud, 5 rue J. B. Clément, 92296 Châtenay-Malabry cedex, France
Fax 33(1)46835740; E-mail: benoit.crousse@u-psud.fr
Received 3 October 2007
65–70% conversion) (Table 1, entries 1 and 3). Large ex-
cess of ethyl bromoacetate (6 equiv) and of zinc (5 equiv)
were required to obtain a complete conversion in 4–5
hours. Only one product was obtained. Corresponding b-
amino esters 3 and 4 were isolated in high yields (Table 1,
entries 2 and 4).
Abstract: b-Trifluoromethyl b-amino acids and a-trifluoromethyl
a-alkyl amines can be easily prepared under Barbier conditions
from trifluoromethyl aldimines in moderate to good yields. b-Tri-
fluoromethyl b-amino acids were obtained in good enantioselectiv-
ity from the chiral trifluoromethyl aldimine starting material.
Key words: Barbier reaction, Reformatsky, fluoroalkyl amines,
amino acids
Since the addition of alkyl organometallic reagents on CF3
imine derivatives has been less studied than that of unsat-
urated ones (phenyl, allyl, vinyl),10 these easy Barbier
conditions have also been applied to the addition of sim-
ple alkyl halides to aldimines 1 and 2. We first investigat-
ed the addition of isopropyl iodide on the aldimine 1 in
DMF. With 2.5 equivalents of the alkyl iodide and 1.5
equivalents of Zn, the corresponding trifluoromethyl
amine 5a (Table 1, entry 5) was obtained in an excellent
yield (95%). The reaction was then generalized to other
alkyl halides. Under the same conditions, the reaction was
less efficient with primary alkyl halides, C5H11I or EtI,
which required longer reaction time, and provided poor
yields of amines. As for reaction with ethyl bromoacetate,
by using larger excesses of halides (6 equiv) and zinc (5
equiv), 5b and 5c could be obtained in 70% and 97%
yields, respectively (Table 1, entries 6 and 7). It is worth
noting that competitive reduction products, which are
generally obtained by the addition of alkyl Grignard re-
agents to nonfluorinated aldimines,11 were not detected
from 2 under these conditions.12
b-Amino acids have received great attention due to their
potential medicinal and synthetic applications.1 Consider-
ing the expected benefits of the fluorine substitution, b-
fluoroalkyl b-amino acid derivatives, when incorporated
into peptide sequences, are expected to modify properties
and enhance resistance toward proteolysis. In this context
they recently aroused great interest and numerous groups
have designed new synthetic methodologies, with the ob-
jective of obtaining pure stereomers.2 Among them, meth-
ods involving nucleophilic additions on trifluoromethyl
imines3 or related derivatives (oxazolidines,4a pyruvates,5
imidoyl chlorides,6 etc.) appeared to be powerful ap-
proaches. Most of the methods used to access the b-CF3 b-
amino acid derivatives involve addition of ester enolates,7
Mannich-type4 and Reformatsky4,8 reactions. This latter
reaction, performed on trifluoromethyl aldimine deriva-
tives,4,8a proceeds in moderate yield and provides, as main
products, corresponding azetidinones resulting from a cy-
clization of the intermediate metalloamine. Considering
that this is probably due to the reaction conditions (THF
reflux, reagent excess), we revisited the Reformatsky re-
action on trifluoromethyl aldimines under milder condi-
tions.
When performed onto the N-benzyl trifluoromethyl aldi-
mine 2, the addition of various alkyl iodides afforded the
corresponding amines 6 in moderate to low yields after 24
hours (Table 1, entries 9–11) or no reaction occurred at all
even with excess of reagents (Table 1, entries 10–12).
We have previously reported that allylation reactions on
trifluoromethyl aldimines proceeded smoothly in dimeth-
ylformamide at room temperature when performed under
Barbier conditions.9
These reactions were then investigated with the methyl
ether of the (R)-phenylglycinol trifluoromethyl aldimine
7, which provided excellent stereoselectivity in allylation
reactions under Barbier conditions.9
Similar conditions were evaluated for the Reformatsky re-
action performed on the N-(p-methoxyphenyl) aldimine 1
and the N-benzyl aldimine 2. The reaction was conducted
in DMF at room temperature with three equivalents of
ethyl bromoacetate in the presence of 1.5 equivalents of
granular zinc activated by a small amount of TMSCl.9 Re-
action times were long and the conversion incomplete (ca.
In DMF, the product 8 resulting from the addition of iso-
propyl iodide (3 equiv) in the presence of zinc (2.5 equiv)
was obtained in a 72% yield and a poor selectivity (de =
53%; Scheme 1). The configuration of 8 proved to be R,R
(see below).
Under the conditions presented in Table 1, the Refor-
matsky reaction performed between ethyl bromoacetate
(6 equiv) and 7 failed. Replacement of DMF by THF re-
sulted in a complete reaction and a good diastereoselectiv-
ity (de = 80%) but a longer reaction time (>20 h) was
SYNLETT 2008, No. 3, pp 0399–0401
x
x.
x
x.
2
0
0
8
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000864; Art ID: G30507ST
© Georg Thieme Verlag Stuttgart · New York

400
M. Dos Santos et al.
LETTER
Table 1 Reformatsky and Alkylation Reactions under Barbier Con- achieved in 80% yield in a three-step procedure involving
the reaction with BBr3,14 Pb(OAc)4 and HCl (6 N)
ditions
hydrolysis4a (Scheme 2). The R-configuration of the b-tri-
F3C
HN
3–6
R2
R1
F3C
R2X, Zn
fluoromethyl-b-amino acid 10 obtained was assigned by
N
R1
DMF, r.t.
comparison of its data with the data and the optical rota-
21
tion reported in the literature {[a]D +25 (c = 0.5, 6 N
1 R1 = PMP
2 R1 = Bn
HCl), [a]D25 +26.6 (c = 0.5, 6 N HCl)4a}.
Entry Imine (R1) R2X (equiv)
Zn
(equiv) (h)
Time Prod. Yield
F3C
1) BBr3
F3C
CO2Et
CO2H
NH2·HCl
(%)
69a
80
2) Pb(OAc)4
3) 6 N HCl
(R)
HN
OMe
1
2
1
1
2
2
1
1
1
1
2
2
2
2
PMP EtOCOCH2Br (3) 1.5
PMP EtOCOCH2Br (6)
10
4
3
Ph
5
3
9
(R)-(+) 10
3
Bn
Bn
EtOCOCH2Br (3) 1.5
24
5
4
66a
86
Scheme 2
4
EtOCOCH2Br (6)
5
4
In conclusion, we have described an easy method to intro-
duce an alkyl group directly on trifluoromethylated aldi-
mines under Barbier conditions and to perform an
efficient Reformatsky reaction with an improved
chemoselectivity and a good stereoselectivity. This pro-
vided a concise access to enantiopure b-trifluoromethyl b-
amino acids.
5
PMP i-PrI (2.5)
PMP C5H11I (6)
PMP EtI (6)
1.5
5
2
5a
5b
5c
5d
6a
6b
6c
6d
95
6
7
70
7
5
10
3
97
8
PMP t-BuI (2.5)
1.5
2.5
5
72
9
Bn
Bn
Bn
Bn
i-PrI (3)
C5H11I (6)
EtI (6)
24
24
24
24
59
10
11
12
trace
33
Acknowledgment
5
M.D.S. thanks MENRT for a fellowship. The authors thank Central
Glass Co., Ltd for a kind gift of fluoral, and the DSM Company for
the donation of (R)-phenylglycine.
t-BuI (6)
5
trace
a The starting material was also obtained.
References and Notes
(1) (a) Kukhar, V. P.; Soloshonok, V. A. Fluorine-Containing
Amino Acids: Synthesis and Properties; Wiley: New York,
1995. (b) Bégué, J. P.; Bonnet-Delpon, D. Chimie
Bioorganique et Médicinale du Fluor; EDP-Sciences/CNRS
Editions: Paris, 2006.
i-PrI (3 equiv),
Zn (2.5 equiv)
F3C
HN
(R)
DMF, 10 h, r.t., 72%
OMe
F3C
Ph
(R)
8
53% de
N
(2) (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004,
60, 6711; and references cited therein. (b) Fustero, S.;
Salavert, E.; Pina, B.; Ramirez de Arellano, C.; Fuentes, A.
S.; Asensio, A. Tetrahedron 2001, 57, 6475. (c) Davoli, P.;
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G.; Fokina, N. A.; Shishkina, I. P.; Galushko, S. V.; Kukhar,
V. P.; Svedas, V. K.; Kozlova, E. V. Tetrahedron:
Asymmetry 1994, 5, 1119.
OMe
Ph
7
F3C
CO2Et
BrCH2CO2Et (5 equiv)
Zn (3.5 equiv)
(R)
HN
OMe
THF, reflux, 3 h, 80%
Ph
9
81% de
Scheme 1
required. Surprisingly an increased reaction rate (3 h) was
obtained in refluxing THF without changing the course of
the reaction. The only products formed were b-amino es-
ters 9 obtained in 80% yield and with a good diastereose-
lectivity (de = 81%, determined by 19F NMR of the crude;
Scheme 1). Each diastereomer could be easily separated
by flash chromatography to afford 69% isolated yield of
the major isomer and 10% isolated yield of the minor
one.13 These results suggest that neither high temperature
nor excess of Zn are responsible of the conversion of b-
amino esters into azetidinones. The major isomer was ob-
tained in the free form after deprotection of the chiral aux-
iliary and the hydrolysis of the ester function. This was
(3) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J.
Chem. Soc. Rev. 2005, 34, 562.
(4) (a) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159.
(b) Takaya, J.; Kagoshima, H.; Akiyama, T. Org. Lett. 2000,
2, 1577. (c) Blond, G.; Billard, T.; Langlois, B. R. J. Org.
Chem. 2001, 66, 4826. (d) Xu, Y.; Dolbier, W. R. J. Org.
Chem. 2000, 65, 2134. (e) Xu, Y.; Dolbier, W. R.
Tetrahedron Lett. 1998, 39, 9151. (f) Sergeeva, N. N.;
Golubev, A. S.; Hennig, L.; Burger, K. Synthesis 2002,
2579.
Synlett 2008, No. 3, 399–401 © Thieme Stuttgart · New York

LETTER
Barbier Conditions on Trifluoromethyl Aldimines
401
(5) Bravo, P.; Fustero, S.; Guidetti, M.; Volonterio, A.; Zanda,
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(6) (a) Ohkura, H.; Handa, M.; Katagiri, T.; Uneyama, K.
J. Org. Chem. 2000, 67, 2692. (b) Fustero, S.; Pina, B.;
Garcia de la Torre, M.; Navarro, A.; Ramirez de Arellano,
C.; Simon, A. Org. Lett. 1999, 1, 977.
(7) (a) Lazzaro, F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.;
Malpezzi, L.; Volonterio, A.; Zanda, M. Tetrahedron:
Asymmetry 2004, 15, 889. (b) Gong, Y.; Kato, K.
J. Fluorine Chem. 2004, 125, 767.
(8) (a) Gong, Y.; Kato, K. J. Fluorine Chem. 2001, 111, 77.
(b) Costerousse, G.; Teutsch, G. Tetrahedron 1986, 42,
2685.
(9) Legros, J.; Meyer, F.; Coliboeuf, M.; Crousse, B.; Bonnet-
Delpon, D.; Bégué, J. P. J. Org. Chem. 2003, 68, 6444.
(10) (a) Nguyen Thi Ngoc, T.; Magueur, G.; Ourévitch, M.;
Crousse, B.; Bégué, J. P.; Bonnet-Delpon, D. J. Org. Chem.
2005, 70, 699. (b) Gosselin, F.; Roy, A.; O’Shea, P. D.;
Chen, C.-Y.; Volante, R. P. Org. Lett. 2004, 6, 641.
(c) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T.
Tetrahedron Lett. 2002, 43, 2827. (d) Magueur, G.;
Crousse, B.; Bonnet-Delpon, D. Tetrahedron Lett. 2005, 46,
2219.
(11) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Hatano, M.;
Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.
(12) Addition of EtMgBr (1.3 equiv, 1 N THF) to CF3 aldimine 2
led to a mixture of products [CF3CH(Et)NHBn: 42%;
CF3CH2NHBn: 13%; 2: 33%, side products: 13%].
(13) Typical Procedure for the Synthesis of 4,4,4-Trifluoro-3-
(2-methoxy-1-phenylethylamino)butyric Acid Ethyl
Ester (9): The methyl ether of the (R)-phenylglycinol
trifluoromethyl aldimine 7 (1 mmol, 231 mg) was dissolved
in THF (5 mL) and kept under argon. Ethyl bromoacetate (6
equiv, 6 mmol, 1 g) and granular zinc (5 equiv, 5 mmol, 327
mg) were then introduced, followed by a few drops of
TMSCl. After being stirred at reflux for 3 h, the reaction
mixture was quenched with a sat. NH4Cl solution (15 mL)
and extracted with Et2O (3 × 5 mL). The organic layers were
washed with brine (15 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel (cyclohexane–
Et2O, 80:20) to afford a mixture of two diastereomers of 9
(80%, 255 mg).
Major Diastereomer: yellow oil; yield: 69%; [a]D22 –25.0
(c = 0.20, CHCl3). 1H NMR (200 MHz, CDCl3): d = 1.28 (t,
J = 7.1 Hz, 3 H), 2.10 (br s, 1 H), 2.56 (dd, J = 6.5, 15.7 Hz,
1 H), 2.72 (dd, J = 4.3, 15.8 Hz, 1 H), 3.38 (s, 3 H), 3.40 (dd,
J = 5.3, 7.9 Hz, 1 H), 3.52 (m, 1 H), 4.11 (dd, J = 5.5, 7.8 Hz,
2 H), 4.18 (q, J = 7.0 Hz, 2 H), 7.36 (m, 5 H). 13C NMR (50
MHz, CDCl3): d = 14.1, 34.6, 54.2 (q, JCF = 29 Hz, CHCF3),
58.7, 60.0, 61.0, 77.8, 125.8 (q, JCF = 281 Hz, CF3), 127.8,
128.0, 128.5, 139.4, 170.1. 19F NMR (188 MHz, CDCl3):
d = –76.30 (d, J = 7.6 Hz, CF3). IR: 2984, 1735 cm–1.
Minor Diastereomer: yellow oil; yield: 10%; [a]D22 +12.5
(c = 0.16, CHCl3). 1H NMR (200 MHz, CDCl3): d = 1.19 (t,
J = 7.0 Hz, 3 H), 2.87 (dd, J = 2.6, 15.0 Hz, 1 H), 3.05 (dd,
J = 5.6, 14.9 Hz, 1 H), 3.31 (s, 3 H), 3.53 (dd, J = 4.9, 9.8 Hz,
1 H), 3.85 (m, 1 H), 4.03 (t, J = 9.9 Hz, 1 H), 4.14 (q, J = 7.1
Hz, 2 H), 4.53 (dd, J = 5.3, 9.9 Hz, 1 H), 7.27 (m, 5 H). 13
C
NMR (50 MHz, CDCl3): d = 13.8, 49.5, 51.5 (q, JCF =35 Hz,
CHCF3), 58.7, 60.0, 61.4, 72.2, 124.1 (q, JCF = 278.8 Hz,
CF3), 127.7, 128.0, 128.6, 135.8, 165.5. 19F NMR (188 MHz,
CDCl3): d = –76.0 (d, J = 5.9 Hz, CF3). IR: 2932, 1768 cm–1.
(14) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
Synlett 2008, No. 3, 399–401 © Thieme Stuttgart · New York

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