The Ugi reaction with CF3-carbonyl compounds: effective synthesis of α-trifluoromethyl amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2008.10.004

The Ugi reaction with CF₃-carbonyl compounds is described in detail. The method is efficient for the multicomponent preparation of α-trifluoromethyl (Tfm) amino acids, α-Tfm containing dipeptides, and iminodicarboxylic acids. In addition, the first protected CF₃-opine derivative was prepared. The scope, limitations, and stereochemistry of the approach are discussed.

Full text of DOI:10.1016/j.tet.2008.10.004

Tetrahedron 64 (2008) 11706–11712
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The Ugi reaction with CF3-carbonyl compounds: effective synthesis of
a-trifluoromethyl amino acid derivatives
,
Anton V. Gulevich a, Nikolay E. Shevchenko a, Elisabeth S. Balenkova a, Gerd-Volker Ro¨schenthaler b
*
,
,
Valentine G. Nenajdenko a
*
a Department of Chemistry, Moscow State University 119991, Leninskije Gory, Moscow, Russia
b Institute of Inorganic and Physical Chemistry, University of Bremen, 28334 Leobener Str., Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The Ugi reaction with CF3-carbonyl compounds is described in detail. The method is efficient for the
multicomponent preparation of -trifluoromethyl (Tfm) amino acids, -Tfm containing dipeptides, and
iminodicarboxylic acids. In addition, the first protected CF3-opine derivative was prepared. The scope,
limitations, and stereochemistry of the approach are discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 10 July 2008
Received in revised form
16 September 2008
Accepted 2 October 2008
Available online 10 October 2008
a
a
Keywords:
Ugi Reaction
Fluoral
Dipeptides
Opine
Fluorine chemistry
1. Introduction
natural peptides or micromolecular inhibitors of some matrix
metalloproteinases.5 Also, the
a-Tfm group strongly effects the
The Ugi multicomponent reaction (U-MCR) has attracted con-
siderable interest owing to its exceptional synthetic efficiency and
extensive diversity-generating ability.1 The development of new
types of components can increase the synthetic potential of the
reaction. Herein we focus our attention on polyfluorocarbonyl
compounds possessing high carbonyl activity and other unique
properties.2 The fluorine-modified Ugi reaction can result in im-
portant fluorine-containing compounds, especially derivatives of
proteolytic stability of peptides and their interaction with enzyme
or receptor subsites.6
Usually, the preparation of polyfluorinated peptides is based on
the condensation of the corresponding amino acids.7 However, ef-
fective noncondensation-type synthesis of trifluoroalanine di-
peptides has also been developed.8 Isocyanide-based approaches to
a-Tfm peptides have been described. As an example, a-CF3-
substituted dipeptide building blocks can be obtained by a [4þ1]-
cycloaddition of hexafluoroacetone or trifluoropyruvate derived
N-acylimines and isocyanoacetic acid derivatives with subsequent
acidic hydrolysis of the cycloadducts.9 The Ugi reaction with CF3-
substituted isocyanides or CF3-carboxylic acid was also used for the
a-CF3 amino acids (a-Tfm Aas), which could become interesting
candidates for combinatorial chemistry to generate libraries of
trifluoromethyl peptides and peptide mimetics. Fluorinated amino
acids and their small peptides have found a wide range of appli-
cations in enzymology, pharmaceutical, medicinal, and agricul-
multicomponent preparation of a
-Tfm alanine peptides.10 One ex-
tural chemistry.3
a-Tfm Aas attract considerable interest in
ample of the Ugi reaction with trifluoroacetaldehyde was reported in
2007 but, in this paper, there was no isolated products, spectroscopic
data, or complete experimental procedures. The authors only
measured the anti-microbial activity but no evidence of the Ugi re-
action with CF3CHO was given.11 Therefore, the multicomponent Ugi
reaction involving CF3-carbonyl compounds or imines is still
unexplored.
It is well-known that polyfluorocarbonyl compounds differ
from non-fluorinated analogs in carbonyl activity and other prop-
erties.4 We supposed that CF3-carbonyl compounds could be
modern peptide chemistry due to the unique stereoelectronic
properties of the trifluoromethyl group.4 CF3-containig peptides
can be very effective peptidomimetics, for example, mimics of
* Corresponding authors. Tel.: þ49 (0)421 218 2493; fax: þ49 (0)421 218 4267
(G.-V.R.); tel.: þ7 495 939 2276; fax: þ7 495 932 8846 (V.G.N.).
E-mail addresses: gvr@chemie.uni-bremen.de (G.-V. Ro¨schenthaler), nen@
acylium.chem.msu.ru (V.G. Nenajdenko).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.004

A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
11707
R2
O
R2
N
O
Bn
N
OH
N
Ugi-3CC
R4
U-4CC
t-Bu
N
H
COR3
N
H
COCF3
F3C
O
F3C
R1
R1 CF3
CF3
max. 52%
COOEt
1
3
4 max. 89%
R3
NC
S
5
R4
O
R2
N
R2 R3
R5 CF3
EtOOC
N
H
COCF3
HOOC
N
H
COOH
MeOOC
N
CONHPG
HOOC
N
COOH
R1 CF3
H
COCF3
CF3-dipeptides
α,α-Iminodicarboxylic Acid
Methiopine
CF3-IDCAs
(IDCA)
B
8
6
A
Scheme 1. The Ugi reaction with CF3-carbonyl compounds.
Table 2
Synthesis of CF3-imines
interesting for the Ugi reaction. In this paper, we report the Ugi
reaction with polyfluorocarbonyl compounds as a new approach to
R2
a
-Tfm amino acids derivatives, dipeptides, and iminodicarboxylic
OH
O
R2NH2
-H2O
N
acids (Scheme 1).
or
R1
F3C
1a
O
F3C
1b-d
R1
F3C
3a-g
2. Results and discussions
Entry
R1
R2
Product 3
Yield (%)
Trifluoroacetaldehyde (fluoral) methylhemiacetal 1a is the most
convenient and commercially available form of gaseous tri-
fluoroacetaldehyde (bp ꢀ18.8 to ꢀ17.5 ꢁC). We have found that 1a
reacts directly in the Ugi four component condensation (U-4CC)
with benzylamine, CF3COOH, and tert-butyl isocyanide, but the
expected product 4a was formed in 21% yield only (Table 1). This
fact can be explained by the ability of trifluoroacetaldehyde to form
a stable hemiaminal 2a.12 tert-Butyl isocyanide is supposed to be
both the isocyanide component and dehydrating agent.13 Indeed,
using 2 and 3 equiv of isocyanide slightly increased the yield of 4a
up to 28 and 34% correspondingly.
1a
2a
3b
4b
5c
6d
7d
H
H
Bn
3a
3b
3c
3d
3e
3f
50
51
83
85
93
77
81
(S)-Me(Ph)CH
i-Pr
Bn
Bn
4-MeOC6H4
BnCH2
CH3
CH3
Ph
CF3
CF3
3g
a
PhMe/TsOH (cat), reflux.
TiCl4/NEt3/CH2Cl2.
C6H6/AcOH, reflux with Dean–Stark apparatus.
POCl3/NEt3/CH2Cl2.
b
c
d
We have investigated several dehydrating agents for promotion
of the reaction, and MS 4 Å was found to be the most effective,
giving the target molecule 4a in 52% yield. Other CF3-carbonyl
compounds namely trifluoroacetone and trifluoroacetophenone
form the products in yields not exceeding 50% even with MS 4 Å
promotion.
To increase yields, pure imines were prepared according to the
14
modified literature procedures
(Table 2) and tested in the Ugi
reaction conditions. Using a model experiment (entry 1, Table 3;
Scheme 2), optimal conditions were found to be CH2Cl2, 0.1 M,
ꢀ20 ꢁC to rt, 12 h.
Only strong acids such as CH2ClCOOH (pKa 2.85), CHCl2COOH
(pKa 1.48), CCl3COOH (pKa 0.7), and CF3COOH (pKa 0.23) gave the
desired Ugi products. Weaker acids such as 4-NO2C6H4COOH (pKa
3.44), PhCOOH (pKa 4.2), and AcOH (pKa 4.75) reacted with no suc-
cess. This fact can be explained by the lower basicity of the imines
Table 1
The Ugi reaction with fluoral methylhemiacetal
O
Bn
N
OH
Ugi
N
H
COCF3
F3C
O
BnNH2
CF3COOH
t-BuNC
CF3
4a
1a
BnNH2
Bn
CF3COOH
Table 3
Synthesis of
tBuNC
a-Tfm amino acids derivatives via Scheme 2
Bn
N
HN
Entry Imine R1
R2
R3
R4
Product Yield (%)
t-BuNC
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3c
3c
3c
3d
3d
3e
3e
3f
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
CF3
t-Bu
4a
89
60
58
75
88
64
40
57
70
73
45
d
F3C
H
F3C
OH
-H2O
CH2Cl 4-MeOC6H4CH2 4b
CHCl2 4-MeOC6H4CH2 4c
3a
tBuNHCHO
2a
CCl3
CF3
CF3
CCl3
CF3
CF3
CF3
CF3
CF3
Bn
Bn
Bn
Bn
4-MeC6H4
Bn
t-Bu
Bn
t-Bu
Bn
Bn
4d
4e
4f
4g
4h
4i
CH3 i-Pr
CH3 i-Pr
CH3 i-Pr
CH3 Bn
CH3 Bn
Entry
Conditionsa
Yield (%)
1
2
3
4
5
6
CF3COOH (1 equiv), t-BuNC (1 equiv)
CF3COOH (1 equiv), t-BuNC (2 equiv)
CF3COOH (1 equiv), t-BuNC (3 equiv)
(CF3CO)2O (1 equiv), t-BuNC (2 equiv)
CF3COOH (1 equiv), t-BuNC (1 equiv), Ti(i-PrO)4
CF3COOH (1 equiv), t-BuNC (1 equiv), MS 4 Å
21
28
34
39
15
52
9
10
11
12
13
14
4j
Ph
Ph
Bn
Bn
4k
d
d
d
CF3 4-MeOC6H4 CF3
CF3 CH2CH2Ph CF3
d
a
3g
d
Compound 1a (1 equiv), BnNH2 (1 equiv), CH2Cl2, rt, 0.1 M.

11708
A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
Ugi-MCR.16 Usually no high stereoselectivity is observed in the Ugi
R2
R1
O
R2
N
R1
R3COOH
R4NC
N
R4
reaction (3CC or 4CC modification) with
a-methylbenzylamine
N
H
COR3
(max de is 60%).15
CH2Cl2, -20-r.t.
F3C
F3C
We have investigated the stereochemistry of the reaction using
chiral imine 3b and the bulky tert-butyl isocyanide (Scheme 4).
Under suitable conditions (temperature, solvents), the stereo-
selectivity of the fluoro-modified reaction is comparable with the
selectivity of the standard Ugi reaction without fluorinated sub-
strate. Trifluoroalanine derivative 4l was obtained in 67% yield with
de up to 53%. Further development in this direction is under
investigation.
3
4
Scheme 2. Synthesis of a-Tfm amino acids.
due to the strong electron withdrawing effect of the CF3 moiety.
Trifluoroaceticacidis the reagentofchoice for further investigations.
Imines of fluoral 3a and trifluoroacetones 3c,d reacted smoothly
(entries 1–10, Table 3). Trifluoroacetophenone imine 3e reacted
worse (entry 9), possibly, due to lower electrophilicity of the imine
group and its sterically hindered structure. Unfortunately, the most
bulky imines of hexafluoroacetone containing aryl 3f or alkyl 3g
substituents did not give Ugi products at all. In general, the struc-
ture of the isocyanide has no serious effect on the reaction, except
for the reaction of trifluoroacetone imine 3e with t-BuNC (Table 3,
entry 12). Aliphatic, aromatic, and sterically hindered isocyanides
react straightforwardly. Consequently, we have demonstrated that
imines 3 are more effective starting materials for the Ugi reaction
than CF3-carbonyl compounds. Imines 3a–e gave several de-
Ph
O
a
N
Ph
N
N
H
COCF3
tBuNC
CF3COOH
F3C
H
CF3
4l
3b
yield 67%
max d.e. 53%
Scheme 4. Diastereoselective modification of the reaction:(a) MeOH, 0.1 M, ꢀ20 ꢁC, 24 h.
rivatives of trifluoroalanine, a-Tfm alanine and a-Tfm phenylala-
nine in good yields using this very simple procedure.
Esters of
a-aminoacids can be conveniently used as chiral
In the case of isocyanoacetic acid derivatives 5 this method
opens a new multicomponent one-step route to orthogonally
protected semi-natural dipeptides containing natural amino acid
auxiliaries since they are available in both enantiomeric forms.
Moreover, in several synthetic applications in the field of peptido-
mimetics their structure may also be retained.1 However, di-
astereomeric excesses of the reaction are often only moderate and
strongly influenced by the structure of the side chain of the
residue and
is notable that the Ugi multicomponent reaction with CF3-imines is
a general approach to construct a broad variety of -Tfm dipeptides.
a-Tfm substituted amino acid fragments (Scheme 3). It
a
a
-amino acid.17
All compounds were isolated in good yields as a mixture of di-
The previously unknown imine of fluoral and aminoacid
astereomers (w1:1), this is usual for Ugi reaction. 15
(L
-valine18) 7a was synthesized and introduced in the Ugi reaction
Asymmetric multicomponent reactions (AMCRs) are a topical
field of modern stereoselective synthesis.15 Chiral amines (the most
with 4-methoxybenzylisocyanide (PMBNC). Unfortunately the
maximum de was only 20% (Scheme 5). Product 8a is a fluorinated
orthogonally protected analog of a,a-iminodicarboxylic acid (IDCA).
common is commercially available
a-methylbenzylamine) were
used to control the formation of a new stereogenic center in the
IDCAs and their derivatives can be isolated from several types of
poisonous mushrooms.19 IDCA is structural fragment of a series of
R2
R1
O
Bn
N
synthetic dipeptides, which have been demonstrated to be potent
pharmaceutically active ACE-inhibitors
CF3COOH
COOEt
N
a
20
and inhibitors of some
EtOOC
N
H
COCF3
other enzymes.21 IDCA is a framework of opines, specific markers of
crown gall tumors produced by the parasitic bacterium Agro-
bacterium tumefaciens.22 As an example, fluorinated orthogonally
protected methiopine analog 8b was prepared in good yield
(Scheme 5).
F3C
CF3
R3
NC
6a, 58%
3
5
S
Ph
O
Bn
O
Bn
N
N
EtOOC
N
H
COCF3
COCF3
EtOOC
N
H
COCF3
CF3
CF3
R1
R1
OMe
OH
a
6c, 65%
6b, 61%
COOEt
-H2O
MeOOC
N
CF3
F3C
MeOOC
NH2
O
Bn
N
7a, R1=i-Pr, yield 50%
1a
HN
O
Bn
N
7b, R1=CH2CH2SMe, yield 47%
EtOOC
N
H
COCF3
COCF3
EtOOC
N
H
R1
R1 CF3
CF3
CF3
6e, 49%
b
6d, 68%
MeOOC
N
CF3
MeOOC
N
CONHPMB
CF3COOH
PMBNC
O
Bn
N
O
i-Pr
COCF3
EtOOC
N
H
8a, R1=i-Pr, d.e. 20%,yield 57%
N
7a, b
EtOOC
N
H
COCF3
CH3
CH3
8b, R1=CH2CH2SMe, d.e. 10%, yield 58%
F3C
F3C
S
6g, 56%
6f, 48%
COOEt
R2 R3
O
Bn
N
O
Bn
N
HOOC
N
COOH
HOOC
N
H
COOH
H
EtOOC
N
H
COCF3
EtOOC
N
H
COCF3
CH3
Ph
F3C
F3C
6i, 45%
Methiopine
a,a-Iminodicarboxylic Acid
IDCA
6h 55%
Scheme 5. Synthesis of IDCAs: (a) Toluene, reflux; (b) CH2Cl2: 0.1 M, ꢀ20 ꢁC, 24 h.
Scheme 3. Synthesis of
a
-Tfm dipeptides: (a) CH2Cl2, ꢀ20 ꢁC to rt.

A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
11709
3. Conclusion
162.1, 169.9. HRMS (EI): calculated for C20H20ClF3N2O3 428.1115;
found 428.1129.
In conclusion, the Ugi reaction with CF3-carbonyl compounds
was described. We have investigated the reaction of fluoral hemi-
acetal in U-4CC conditions and found that MS 4 Å can promote the
reaction. It was found that CF3-imines are more effective precursors
in comparison with CF3-carbonyl compounds. The method is
4.3.2. N2-Benzyl-N2-(dichloroacetyl)-3,3,3-trifluoro-N1-(4-
methoxybenzyl)alaninamide 4c
Yield 58% (268 mg), colorless oil. Rf (hexanes/ethyl acetate 2:1)
0.6; IR (Nujol, cmꢀ1) 2870, 1670; 1H NMR (CDCl3, 400 MHz): 3.77 (s,
3H), 4.30 (d, J 5.6 Hz, 1H), 4.48 (d, J 5.6 Hz, 1H), 4.94 (d, J 18.2 Hz),
5.23 (d, J 18.2 Hz), 5.96 (s,1H), 6.0 (m,1H), 6.80 (d, J 8.6 Hz), 7.13 (d, J
8.6 Hz, 2H), 7.27–7.40 (m, 5H), 7.5 (br s, 1H); 13C NMR (CDCl3,
50 MHz): 43.3, 44.2, 55.2, 57.1 (q, 32.2 Hz), 63.9, 66.3, 114.0, 122.9
(q, J 290.0 Hz), 125.3, 127.6, 129.2, 135.3, 136.7, 159.1, 161.7, 167.4.
HRMS (EI): calculated for C20H19Cl2F3N2O3 462.0725; found
462.0744.
simple and an efficient approach to
a-Tfm amino acids and or-
thogonally protected semi-natural CF3-containing dipeptides and
CF3-iminodicarboxylic acids. Also the first CF3-opine derivative was
prepared. We believe that our research can open a new frontier of
multicomponent chemistry, efficient for the synthesis of fluorine-
containing compounds.
4. Experimental section
4.3.3. N1,N2-Dibenzyl-3,3,3-trifluoro-N2-(trichloroacetyl)-
alaninamide 4d
4.1. General procedure for Ugi-4CC
Yield 75% (350 mg), white solid, mp 105–108 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.7; IR (Nujol, cmꢀ1) 3434, 1697, 1673; 1H NMR
(CDCl3, 200 MHz): 4.07–4.52 (m, 3H), 4.55–5.01 (m, 1H), 5.3 (br s,
1H), 6.1 (br s, 1H), 7.18–7.55 (m, 10H); 19F NMR (CDCl3, 188 MHz):
ꢀ65.1 (s, 3F). HRMS (EI): calculated for C19H16Cl3F3N2O2 466.0230;
found 466.0230.
Benzylamine (1 mmol) and trifluoroacetaldehyde methyl-
hemiacetal 1a were dissolved in CH2Cl2 (10 mL) and CF3COOH
(1 mmol) and tert-Butyl isocyanide was added at 20 ꢁC. The mixture
was stirred for 12 h and treated with a mixture of EtOH/HCl(aq)
(10:1, 0.5 mL) to remove isocyanide remains. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (hexanes/ethyl acetate 4:1).
4.3.4. N1,N2-Dibenzyl-3,3,3-trifluoro-N2-(trifluoroacetyl)-
alaninamide 4e
4.2. MS 4 Å promoted Ugi-4CC reaction
Yield 88% (368 mg), white solid, mp 86–88 ꢁC. Rf (hexanes/ethyl
acetate 3:1) 0.8; IR (Nujol, cmꢀ1) 3278, 1714, 1658; 1H NMR (CDCl3,
200 MHz): 3.98–4.15 (m, 1H), 4.22–4.37 (m, 1H), 4.75–4.90 (m, 1H),
5.02–5.16 (m, 2H), 6.3 (br s, 1H), 7.10–7.40 (m, 10H); 13C NMR
(CDCl3, 50 MHz): 43.9, 51.2, 59.0 (q, J 31.1 Hz), 116.2 (q, J 288.3 Hz,
CF3), 121.4 (q, J 284.6 Hz, CF3), 127.3, 127.7, 127.8, 128.4, 128.8, 128.9,
133.9, 136.5, 159 (q, J 38.2 Hz), 160.6; 19F NMR (CDCl3, 188 MHz,
20 ꢁC) ꢀ69.3 (s, 0.78ꢂ3F), ꢀ68.3 (s, 0.23ꢂ3F), ꢀ67.8 (s, 0.23ꢂ3F),
ꢀ67.1 (s, 0.78ꢂ3F); HRMS calculated for C19H16F6N2O2 418.1116;
found 418.1111.
Benzylamine (1 mmol) and trifluoroacetaldehyde methyl-
hemiacetal 1a were dissolved in CH2Cl2 (10 mL). MS 4 Å (400 mg),
CF3COOH (1 mmol), and tert-Butyl isocyanide were added at 20 ꢁC.
The mixture was stirred for 12 h and treated with a mixture of
EtOH/HCl(aq) (10:1, 0.5 mL) to remove isocyanide remains. The
solvents were removed in vacuo and the residue was purified by
column chromatography (hexanes/ethyl acetate 4:1).
4.2.1. N2-Benzyl-N1-(tert-butyl)-3,3,3-trifluoro-N2-
(trifluoroacetyl)alaninamide 4a
It was found that 19F NMR spectra of trifluoroalanine derivatives
4a–c and 6a–e have interesting multipets, which supposed to be
signals of rotamers. We have demonstrated that multiplets disap-
pear if the spectrum measured at 60 ꢁC and, consequently, certain
signals correspond to rotamers (See Supplementary data).
Substituted derivatives 4f,h and 6f,h,i were obtained in hydrate
form. In 13C NMR of these compounds the signal of COCF3
(q, w158 ppm) group transform to the signal of C(OH)2CF3 group
(q, w98 ppm).
Yield 89% (342 mg), white solid, mp 71–73 ꢁC. Rf (hexanes/ethyl
acetate 3:1) 0.7; IR (Nujol, cmꢀ1) 3351 (NH), 1703 (CONH), 1673
(COCF3); 1H NMR (CDCl3, 200 MHz): 1.19 (s, 9H), 4.70–5.13 (m, 3H),
5.7 (br s, 1H), 7.32–7.50 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ69.4
(s, 0.73ꢂ3F), ꢀ68.4 (s, 0.27ꢂ3F), ꢀ67.7 (s, 3F); 13C NMR (CDCl3,
50 MHz): 28.0, 50.7, 52.4, 59.0 (q, J 31.1 Hz), 116.1 (q, J 288.3 Hz,
CF3), 123.5 (q, J 285.4 Hz, CF3), 127.0, 128.2, 128.9, 134.6, 159.0 (q, J
36.7 Hz), 159.5; HRMS (EI) calculated for C16H18F6N2O2 384.1273;
found 384.1264.
4.3.5. N-Benzyl-3,3,3-trifluoro-2-[isopropyl(trifluoroacetyl)amino]-
2-methylpropanamide$H2O 4f
4.3. General procedure for Ugi-3CC
Yield 64% (246 mg), white solid, mp 161–163 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.8; IR (Nujol, cmꢀ1) 3375, 1717, 1673; 1H NMR
(CD3OD, 400 MHz): 1.30 (d, J 6.8 Hz, 3H), 1.33 (d, J 6.8 Hz, 3H), 1.60
(9s, 3H), 3.85 (sept., J 6.9 Hz, 1H), 4.46 (d, J 16.2 Hz, 1H), 4.72 (d, J
16.2 Hz,1H), 7.15–7.30 (m, 5H); 19F NMR (CDCl3,188 MHz): ꢀ74.0 (s,
3F), ꢀ71.0 (s, 3F); 13C NMR (CD3OD, 100 MHz): 18.9, 23.5, 23.7, 45.4,
48.2, 67.6 (q, J 29.3 Hz), 97.9 (q, J 33.7 Hz), 123.3 (q, J 289.3 Hz, CF3),
125.9 (q, J 287.0 Hz, CF3), 127.7, 128.0, 129.3, 137.6, 170.9. HRMS (EI):
calculated for C16H18F6N2O2 384.1273; found 384.1273.
Imine 3 or 7 (1 mmol) was dissolved in CH2Cl2 (10 mL) and
carboxylic acid (1 mmol) and isocyanide was added at ꢀ20 ꢁC. The
mixture was allowed to warm up to ambient temperature and
stirred for 12 h and treated with a mixture of EtOH/HCl(aq) (10:1,
0.2 mL) to remove isocyanide remains. The solvents were removed
in vacuo and the residue was purified by column chromatography.
4.3.1. N2-Benzyl-N2-(chloroacetyl)-3,3,3-trifluoro-N1-(4-
methoxybenzyl)alaninamide 4b
4.3.6. N-Benzyl-3,3,3-trifluoro-2-[isopropyl(trichloroacetyl)-
amino]-2-methylpropanamide 4g
Yield 60% (257 mg), colorless oil. Rf (hexanes/ethyl acetate 2:1)
0.7; IR (film, cmꢀ1) 2870, 1660; 1H NMR (CDCl3, 400 MHz): 3.76 (s,
3H), 3.80–3.85 (m, 1H), 4.10–4.23 (m, 1H), 4.25–4.30 (m, 2H), 4.83
(d, J 17.9 Hz, 1H), 5.18 (d, J 17.9 Hz, 1H), 6.13 (q, J 7.6 Hz, 1H), 6.77–
6.86 (m, 3H), 7.10–7.15 (m, 4H), 7.27–7.32 (m, 2H), 7.8 (br s, 1H); 13C
NMR (CDCl3, 50 MHz): 41.9, 43.2, 49.1, 55.2, 56.3 (q, J 30.7 Hz),114.0,
123.0 (q, J 283.2 Hz), 125.4, 127.7, 128.7, 128.9, 129.2, 136.0, 159.0,
Yield 50% (216 mg), white solid, mp 126–128 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.7; IR (Nujol, cmꢀ1) 3429, 1697, 1673; 1H NMR
(CDCl3, 400 MHz): 1.51 (d, J 6.3 Hz, 3H), 1.62 (d, J 6.3 Hz, 3H), 1.98 (s,
3H), 4.38–4.43 (m, 1H), 4.58–4.64 (m, 1H), 5.11 (sept., J 6.3 Hz, 1H),
5.9 (br s, 1H), 7.23–7.37 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ68.6
(s, 3F); 13C NMR (CD3OD, 100 MHz): 19.8, 21.9, 44.4, 52.1, 71.3 (q, J

11710
A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
27.8 Hz), 94.3, 125.1 (q, J 288.1 Hz), 127.7, 127.8, 128.8, 137.6, 162.1,
167.0. HRMS (CI, NH3): calculated for C16H18Cl3F3N2O2 432.0386;
found 432.0384.
J 27.6 Hz, 0.76ꢂ3F); 13C NMR (CDCl3, 50 MHz): 14.0, 17.4, 17.98, 48.5,
48.7, 51.05, 51.42, 58.9 (q, J 31.1 Hz), 61.8, 116.0 (q, J 288.3 Hz, CF3),
128.6 (q, J 284.0 Hz, CF3), 127.3, 127.7, 128.5, 128.9, 133.6, 134.0,
160.0, 160.1, 164.8 (m), 171.9, 172.0. Several peaks in 13C NMR
spectrum are duplicated. HRMS (EI): calculated for C17H18F6N2O4
428.1171; found 428.1152.
4.3.7. 3,3,3-Trifluoro-2-[isopropyl(trifluoroacetyl)amino]-2-methyl-
N-(4-methylphenyl)propanamide$H2O 4h
Yield 57% (219 mg), white solid, mp 143–145 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.8; IR (Nujol, cmꢀ1) 3347, 1702; 1H NMR (DMSO-
d6, 400 MHz): 1.30 (d, J 6.8 Hz, 6H), 1.73 (s, 3H), 2.32 (s, 3H), 3.86
(sept., J 6.8 Hz, 1H), 7.17 (d, J 8.1 Hz, 2H), 7.26 (d, J 8.1 Hz, 2H), 8.18 (s,
1H); 19F NMR (CDCl3, 188 MHz): ꢀ63.4 (s, 3F), ꢀ70.7 (s, 3F); 13C
NMR (DMSO-d6, 100 MHz): 18.5, 20.6, 22.9, 23.3, 46.3, 65.7 (q, J
27.8 Hz), 97.4 (q, J 32.9 Hz), 121.8 (q, J 290.6 Hz), 124.5 (q, J
288.8 Hz), 128.5, 129.4, 131.0, 138.2, 167.0. HRMS (EI): calculated for
C16H18F6N2O2 384.1272; found 384.1254.
4.3.13. Ethyl N-benzyl-3,3,3-trifluoro-N-(trifluoroacetyl)-
alanylphenylalaninate 6b (mixture of diastereomers, w1:1)
Yield 61% (307 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.7; IR (film, cmꢀ1) 3342, 1749, 1685; 1H NMR (CDCl3, 200 MHz):
1.25 (t, J 7.0 Hz, 3H), 2.95–3.20 (m, 2H), 4.17 (q, J 7.0 Hz, 2H), 4.42–
5.15 (m, 4H), 6.15–6.50 (m, 1H), 6.95–7.52 (m,10H); 19F NMR (CDCl3,
188 MHz): ꢀ69.3 (d, J 22.4 Hz, 0.76ꢂ3F), ꢀ68.5–68.0 (m, 0.35ꢂ3F),
ꢀ67.9 (s, 0.12ꢂ3F), ꢀ67.0 (dd, J 75.9 Hz, 0.76ꢂ3F); 13C NMR (CDCl3,
50 MHz): 37.3, 37.4, 51.5 (m), 53.4, 53.6, 59.3 (m), 61.8, 116.0 (q, J
288.5 Hz, CF3), 129.3 (q, J 288.5 Hz, CF3), 127.1, 127.3, 127.4, 128.4,
128.6, 128.8, 129.1, 129.2, 133.4, 133.6, 135.1, 135.3, 160.0, 160.3,
170.4, 170.5, 171.5 (q, J 7.2 Hz). Several peaks in 13C NMR spectrum
are duplicated. HRMS (EI): calculated for C23H22F6N2O4 504.1484;
found 504.1489.
4.3.8. N-Benzyl-2-[benzyl(trifluoroacetyl)amino]-3,3,3-trifluoro-2-
methylpropanamide 4i
Yield 70% (302 mg), white solid, mp 125–127 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.8; IR (Nujol, cmꢀ1) 3372, 1714, 1673; 1H NMR
(CDCl3, 200 MHz): 1.62 (s, 3H), 4.90 (d, J 4.9 Hz, 2H), 4.90 (AB-system,
J 19.1 Hz, 2H), 6.0 (br s, 1H), 7.20–7.55 (m, 10H); 19F NMR (CDCl3,
188 MHz): ꢀ71.3 (3F, s), ꢀ69.3 (3F, s); 13C NMR (CDCl3, 50 MHz): 19.1,
44.3, 48.6, 68.1 (q, J 26.9 Hz),116.0(q, J 288.3 Hz),125.4 (q,J289.7 Hz),
125.6,127.7,127.8,128.8,136.9,137.1,158.4 (q, J 36.7 Hz),165.6. HRMS
(EI): calculated for C20H18F6N2O2 432.1272; found 432.1283.
4.3.14. Ethyl N-benzyl-3,3,3-trifluoro-N-(trifluoroacetyl)-
alanylmethioninate 6c (mixture of diastereomers, w1:1)
Yield 65% (320 mg), yellow oil. Rf (hexanes/ethyl acetate 3:1)
0.7; IR (film, cmꢀ1) 3345, 1687; 1H NMR (CDCl3, 200 MHz): 1.19–
1.34 (m, 3H), 1.79–2.20 (m, 5H), 2.26–2.47 (m, 2H), 4.20 (d, J 7.3 Hz,
2H), 4.30–4.55 (m, 1H), 4.60–5.15 (m, 3H), 6.40–6.90 (m, 1H), 7.15–
7.50 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ68.7 (d, J 7.0 Hz,
0.79ꢂ3F), ꢀ67.7–67.3 (m, 0.31ꢂ3F), ꢀ67.2 (s, 0.12ꢂ3F), ꢀ66.2 (dd, J
43.1 Hz, 0.79ꢂ3F); 13C NMR (CDCl3, 50 MHz): 14.0, 15.3, 29.3, 29.6,
30.7, 31.09, 50.1, 51.8, 52.1, 59.3 (m), 62.0, 116.0 (q, J 288.3 Hz, CF3),
122.9 (q, J 285.6 Hz, CF3), 127.6, 127.9, 128.8, 129.0, 129.1, 133.4, 157.7
(q, J 28.2 Hz), 160.3, 160.5, 170.8, 171.0. Several peaks in 13C NMR
spectrum are duplicated. HRMS (EI): calculated for C19H22F6N2O4S
488.1204; found 488.1211.
4.3.9. 2-[Benzyl(trifluoroacetyl)amino]-N-(tert-butyl)-3,3,3-
trifluoro-2-methylpropanamide 4j
Yield 73% (290 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.8; IR (film, cmꢀ1) 3480, 1716, 1697; 1H NMR (CDCl3, 200 MHz):
1.35 (s, 9H), 1.52 (s, 3H), 4.60 (d, J 19.1 Hz, 1H), 5.03 (d, J 19.1 Hz, 1H),
5.5 (br s, 1H), 7.21–7.53 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ70.8
(s, 3F), ꢀ68.8 (s, 3F); 13C NMR (CDCl3, 50 MHz): 19.1, 28.4, 48.6, 52.2,
68.5 (q, J 26.85 Hz), 116.1 (q, J 288.3 Hz, CF3), 125.6 (q, J 288.3 Hz,
CF3), 125.7, 127.6, 128.9, 137.1, 158.3 (q, J 36.7 Hz), 164.2. HRMS (EI):
calculated for C17H20F6N2O2 398.1429; found 398.1428.
4.3.15. Diethyl N-benzyl-3,3,3-trifluoro-N-(trifluoroacetyl)-
alanylglutamate 6d (mixture of diastereomers, w1:1)
4.3.10. N1,N2-Dibenzyl-3,3,3-trifluoro-2-phenyl-N2-
(trifluoroacetyl)alaninamide 4k
Yield 68% (350 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.6; IR (film, cmꢀ1) 3351, 1629, 1693; 1H NMR (CDCl3, 200 MHz):
1.15–1.33 (m, 6H), 1.82–2.43 (m, 4H), 4.05–4.40 (m, 5H), 4.65–5.17
(m, 3H), 6.60–7.10 (m, 1H), 7.15–7.45 (m, 5H); 19F NMR (CDCl3,
188 MHz): ꢀ69.3 (s, 0.74ꢂ3F), ꢀ68.5–67.5 (m, 0.31ꢂ3F), ꢀ67.2 (s,
0.53ꢂ3F), ꢀ67.0 (dd, J 51.7 Hz, 0.74ꢂ3F); 13C NMR (CDCl3, 50 MHz):
14.0, 26.2, 26.8, 29.7, 30.0, 51.5, 52.0, 52.4, 59.4 (m), 60.7, 60.9, 61.8,
61.9, 116.0 (q, J 288.6 Hz, CF3), 122.7 (q, J 284.3 Hz, CF3), 127.5, 127.6,
128.5, 128.9, 133.6, 133.7, 158.5 (m), 160.5, 160.7, 170.6, 170.8, 172.7,
173.1. Several peaks in 13C NMR spectrum are duplicated. HRMS
(EI): calculated for C21H24F6N2O6 514.1539; found 514.1529.
Yield 40% (200 mg), white solid, mp 124–126 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.8; IR (Nujol, cmꢀ1) 3347, 1744, 1698; 1H NMR
(CDCl3, 200 MHz): 3.87 (d, J 16.1 Hz,1H), 4.39–4.62 (m, 3H), 4.98 (d, J
15.1 Hz, 1H), 7.02–7.48 (m, 15H); 19F NMR (CDCl3, 188 MHz): ꢀ76.3
(3F, s), ꢀ67.5 (3F, s); 13C NMR (CDCl3, 50 MHz): 44.9, 47.9, 72.5, 97.3
(q, J 32.9 Hz),124.5 (q, J 290.6 Hz, CF3),124.9 (q, J292.1 Hz, CF3),127.4,
128.0, 128.1, 128.2, 128.3, 128.5, 128.7, 129.1, 132.1, 136.1, 136.4, 167.2.
HRMS (EI): calculated for C25H20F6N2O2 494.1429; found 494.1425.
4.3.11. N1-(tert-Butyl)-3,3,3-trifluoro-N2-[(1S)-1-phenylethyl]-N2-
(trifluoroacetyl)alaninamide 4l (mixture of diastereomers, w3.35:1)
Yield 67% (270 mg), colorless oil. Rf (hexanes/ethyl acetate 4:1)
0.6; IR (film, cmꢀ1) 3465, 1739, 1720; 1H NMR (CDCl3, 400 MHz):
1.06 (s, 0.23ꢂ9H), 1.33 (s, 0.77ꢂ9H), 1.60–1.75 (m, 3H), 3.90–4.10
(m, 1H), 5.40–5.50 (m, 1H), 6.3 (br s, 1H), 7.28–7.45 (m, 5H); 19F
NMR (CDCl3, 188 MHz): ꢀ68.2, ꢀ68.1 (ds, 3F), ꢀ61.8 (s, 0.77ꢂ3F),
ꢀ61.7 (s, 0.23ꢂ9F). HRMS (EI): calculated for C17H20F6N2O2
398.1429; found, 398.1421.
4.3.16. Ethyl N-benzyl-3,3,3-trifluoro-N-(trifluoroacetyl)-
alanyltryptophanate 6e (mixture of diastereomers, w1:1)
Yield 49% (266 mg), yellow oil. Rf (hexanes/ethyl acetate 3:1)
0.6; IR (film, cmꢀ1) 3382, 1687; 1H NMR (CDCl3, 200 MHz): 1.10–
1.30 (m, 3H), 3.15–3.35 (m, 2H), 4.00–4.20 (m, 2H), 4.40–4.55 (m,
4H), 6.22–6.47 (m, 1H), 6.90–7.55 (m, 10H), 8.00–8.20 (m, 1H); 19F
NMR (CDCl3, 188 MHz, 20 ꢁC): ꢀ68.6 (d, J 20.7 Hz, 0.74ꢂ3F), ꢀ68.0–
67.3 (m, 0.51ꢂ3F), ꢀ66.2 (dd, J 87.9 Hz, 0.74ꢂ3F); 19F NMR (CDCl3,
188 MHz, 60 ꢁC): ꢀ68.6 (s, 3F), ꢀ66.4 (s, 3F); 13C NMR (CDCl3,
50 MHz): 13.8, 13.9, 27.0, 51.7, 53.2, 53.4, 59.6 (m), 61.8, 109.0, 109.1,
111.3, 111.4, 116.0 (q, J 288.3 Hz, CF3), 118.2, 118.3, 119.5, 122.0, 122.3,
122.8 (q, J 284.1 Hz, CF3), 123.0, 127.2, 127.4, 127.6, 128.5, 128.8,
128.9, 133.3, 136.0, 136.1, 158.3 (m), 160.1, 160.6, 170.8, 170.9. Several
peaks in 13C NMR spectrum are duplicated. HRMS (EI): calculated
for C25H23F6N3O4 543.1593; found 543.1598.
4.3.12. Ethyl N-benzyl-3,3,3-trifluoro-N-(trifluoroacetyl)-
alanylalaninate 6a (mixture of diastereomers, w1:1)
Yield 58% (250 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.7; IR (film, cmꢀ1) 3450, 1729, 1700; 1H NMR (CDCl3, 200 MHz):
1.15–1.48 (m, 6H), 4.07–4.52 (m, 3H), 4.67–5.21 (m, 3H), 6.5 (br s,
1H), 7.12–7.60 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ69.4 (d, J
13.8 Hz, 0.76ꢂ3F), ꢀ68.3 (s, 0.33ꢂ3F), ꢀ67.9 (s, 0.12ꢂ3F), ꢀ67.5 (dd,

A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
11711
4.3.17. Ethyl N-{3,3,3-trifluoro-2-[isopropyl(trifluoroacetyl)-
amino]-2-methylpropanoyl}glycinate$H2O 6f
(d, J 6.8 Hz, 3H), 2.34 (sept., J 6.8 Hz,1H), 3.73–3.77 (m, 4H), 7.63 (q, J
3.3 Hz, 1H); 19F NMR (CDCl3, 188 MHz): ꢀ71.5; 13C NMR (CDCl3,
100 MHz): 18.0, 19.1, 31.5, 52.2, 77.8, 118.3 (q, J 275.2 Hz, CF3), 151.7
(q, J 38.8 Hz, CF3), 170.2. Anal. Calcd for C8H12F3NO2: C, 45.50; H,
5.73; N, 6.63. Found C, 50.41; H, 5.61; N, 6.82.
Yield 48% (150 mg), colorless oil.; Rf (hexanes/ethyl acetate 3:1)
0.6; IR (film, cmꢀ1) 3471, 1239, 1720; 1H NMR (CDCl3, 400 MHz):
1.20–1.29 (m, 6H), 1.33 (d, J 7.1 Hz, 3H), 1.60 (s, 3H), 3.92 (sept., J
7.1 Hz, 1H), 4.03 (d, J 17.9 Hz, 1H), 4.20 (q, J 7.1 Hz, 2H), 4.42 (d,
J 17.9 Hz, 1H), 4.5 (br s, 1H); 19F NMR (CDCl3, 188 MHz): ꢀ79.2 (q, J
6.9 Hz, 0.32ꢂ3F), ꢀ78.0 (s, 0.69ꢂ3F), ꢀ75.6 (q, J 6.9 Hz, 0.32ꢂ3F),
ꢀ74.48 (s, 0.69ꢂ3F); 13C NMR (CDCl3, 100 MHz): 13.8, 18.4, 21.3,
23.1, 42.2, 46.3, 62.5, 65.7 (q, J 27.8 Hz), 96.0 (q, J 33.7 Hz), 122.4 (q, J
292.0 Hz, CF3), 124.3 (q, J 289.1 Hz, CF3), 168.2, 169.7. HRMS (EI):
calculated for C13H18F6N2O4 365.0936 (MꢀCH3), 311.1219 (MꢀCF3);
found 365.0947 (MꢀCH3), 311.1225 (MꢀCF3).
4.3.22. Methyl N-(2,2,2-trifluoroethylidene)-L-methioninate 7b
Compound 7b was prepared according to the procedure for 7a,
yield 47%, colorless liquid, bp 70 ꢁC/8 Torr. Rf (hexanes/ethyl acetate
25
4:1) 0.8; [
a
]
ꢀ73.3 (c 0.0481, CH2Cl2); IR (film, cmꢀ1) 2923, 1741;
D
1H NMR (CDCl3, 400 MHz): 2.03 (s, 3H), 2.08–2.38 (m, 3H), 2.50–
2.58 (m, 1H), 3.71 (s, 3H), 4.22–4.29 (m, 1H), 7.7 (q, J 3.3 Hz); 19F
NMR (CDCl3, 188 MHz): ꢀ72.5; 13C NMR (CDCl3, 100 MHz): 14.9,
29.6, 30.8, 52.5, 68.9, 118.3 (q, J 275.2 Hz, CF3), 152.8 (q, J 38.1 Hz,
CF3), 170.0. Anal. Calcd for C8H12F3NO2S: C, 39.5; H, 4.97; N, 5.76.
Found C, 39.60; H, 4.90; N, 5.81.
4.3.18. Ethyl 2-({2-[benzyl(trifluoroacetyl)amino]-3,3,3-
trifluoro-2-methylpropanoyl}amino)propanoate 6g
(mixture of diastereomers, w1:1)
Yield 56% (250 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.6; IR (film, cmꢀ1) 3322, 1727, 1708; 1H NMR (CDCl3, 200 MHz):
1.28 (t, J 7.1 Hz, 3H), 1.46 (t, J 8.5 Hz, 3H), 1.57 (s, 3H), 4.70–4.37 (m,
2H), 4.45–4.73 (m, 2H), 5.07 (d, J 19.1 Hz, 1H), 6.35–6.67 (m, 1H),
7.22–7.52 (m, 5H); 19F NMR (CDCl3, 188 MHz): ꢀ71.7, ꢀ73.7(ds, 3F),
ꢀ69.4, ꢀ69.3 (ds, 3F); 13C NMR (CDCl3, 50 MHz): 13.9, 17.8, 18.0,
18.9, 48.6, 48.9, 61.7, 61.8, 68.0 (q, J 26.9), 115.9 (q, J 288.3 Hz, CF3),
125.3 (dq, J 288.4 Hz, CF3), 125.6, 127.6, 127.7, 128.8, 128.9, 136.8,
136.9, 158.4 (q, J 36.8 Hz), 164.7, 164.8, 172.4, 172.5. Several peaks in
13C NMR spectrum are duplicated. HRMS (CI, NH3): calculated for
C18H20F6N2O4 442.1327; found 442.1320.
4.3.23. Methyl N-(trifluoroacetyl)-N-(2,2,2-trifluoro-1-{[(4-
methoxybenzyl)amino]carbonyl}ethyl)-D-valinate 8a (mixture of
diastereomers, w1:1.5, according to GC–MS)
Yield 57% (270 mg), white solid, mp 117–122 ꢁC. Rf (hexanes/
ethyl acetate 4:1) 0.7; IR (Nujol, cmꢀ1) 3311, 1747, 1710, 1658; 1H
NMR (CDCl3, 400 MHz): 0.64–0.72 (m, 0.043ꢂ6H), 0.90–1.08 (m,
0.84ꢂ6H), 1.17–1.25 (m, 0.12ꢂ6H), 1.95–2.25 (m, 0.77ꢂ1H), 2.55–
2.70 (m, 0.23ꢂ1H), 3.60–3.80 (m, 6H), 4.12–4.27 (m, 1H), 4.30–4.47
(m, 2H), 4.60–4.70 (m, 0.16ꢂ1H), 4.75–4.85 (m, 0.14ꢂ1H), 5.05–5.13
(q, J 7.8 Hz, 0.33ꢂ1H), 5.18–5.26 (q, J 7.8 Hz, 0.39ꢂ1H), 6.0 (br s,
0.41ꢂ1H), 6.4 (br s, 0.13ꢂ1H), 6.83–6.90 (m, 2H), 6.9 (br
s, 0.43ꢂ1H), 7.15–7.23 (m, 2H); 19F NMR (CDCl3, 188 MHz): ꢀ69.3 (s,
0.043ꢂ6F), ꢀ68.41 (s, 0.068ꢂ6F), ꢀ67.5–66.7 (m, 0.52ꢂ6F), ꢀ62.0
(s, 0.2ꢂ6F), ꢀ60.2 (s, 0.17ꢂ6F); 13C NMR (CDCl3, 100 MHz): 169.2,
169.1, 161.4, 159.9, 159.2, 158.2 (m), 129.3, 129.1, 128.9, 122.7 (dq, J
284.7 Hz), 115.8 (q, J 286.2 Hz), 114.2, 60.1, 65.9, 65.6, 63.5 (q, J
32.2 Hz), 60.8 (q, J 32.2 Hz), 62.2, 52.7, 52.6, 43.8, 43.7, 29.1, 29.5,
29.1, 29.0, 19.7, 18.8, 18.5. Several peaks in 13C NMR spectrum are
duplicated. Anal. Calcd for C19H22F6N2O5: C, 48.31; H, 4.69; N, 5.93.
Found C, 48.31; H, 4.61; N, 5.82. HRMS (EI): calculated for
C19H22F6N2O5 472.1433; found, 472.1427.
4.3.19. Diethyl N-{2-[benzyl(trifluoroacetyl)amino]-3,3,3-
trifluoro-2-methylpropanoyl}glutamate$H2O 6h
(mixture of diastereomers, w1:1)
Yield 55% (290 mg), colorless oil. Rf (hexanes/ethyl acetate 3:1)
0.6; IR (film, cmꢀ1) 3351, 1729, 1693; 1H NMR (CDCl3, 200 MHz):
1.10–1.40 (m, 6H), 1.56 (s, 3H), 1.30–2.91 (m, 4H), 3.95–4.48 (m, 6H),
4.70, 4.62 (ds, 1H), 5.3 (br s, 0.5H), 7.0 (br s, 0.5H), 7.13–7.50 (m, 5H);
19F NMR (CDCl3, 188 MHz): ꢀ81.1 (s, 0.5ꢂ3F), ꢀ80.2 (s, 0.5ꢂ3F),
ꢀ77.1 (s, 0.5ꢂ3F), ꢀ76.7 (s, 0.5ꢂ3F); 13C NMR (CDCl3, 100 MHz):
13.5, 13.8, 13.9, 14.0, 15.9, 16.1, 23.2, 24.7, 29.8, 31.3, 46.4, 46.5, 55.0,
56.6, 60.6, 61.9, 62.1, 63.7, 66.0 (m), 97.6 (m), 121.6 (dq, J 286.2 Hz,
CF3),123.7 (dq, J 286.3 Hz, CF3),127.0,127.5,127.8,128.0,128.1,138.1,
137.9, 168.0, 168.4, 172.6, 173.2, 177.0. Several peaks in 13C NMR
spectrum are duplicated. HRMS (EI): calculated for C22H26F6N2O6
528.1695; found 528.1694.
4.3.24. Methyl N-(trifluoroacetyl)-N-(2,2,2-trifluoro-1-{[(4-
methoxybenzyl)amino]carbonyl}ethyl)-D-methioninate 8b
(mixture of diastereomers, w1:1.1, according to GC–MS)
Yield 58% (290 mg), white solid, mp 122–125 ꢁC. Rf (hexanes/
ethyl acetate 4:1) 0.7; IR (Nujol, cmꢀ1) 3286, 1745, 1712, 1658;
1H NMR (CDCl3, 400 MHz): 1.80–1.90 (m, 0.66ꢂ1H), 2.03–2.11
(m, 3H), 2.17–2.30 (m, 0.4ꢂ3H), 2.43–2.85 (m, 3H), 3.63 (s,
0.21ꢂ6H), 3.72 (s, 0.18ꢂ6H), 3.75–3.83 (m, 0.62ꢂ6H), 3.98–4.07
(m, 0.22ꢂ2H), 4.29–4.52 (m, 2H), 4.66–5.03 (m, 0.78ꢂ2H), 6.3
(br s, 0.42ꢂ1H), 6.80–6.92 (m, 2H), 7.12–7.25 (m, 2H), 7.7 (br s,
0.38ꢂ1H); 19F NMR (CDCl3, 188 MHz): ꢀ76.7 (s, 0.077ꢂ6F),
ꢀ69.8–69.1 (m, 0.27ꢂ6F), ꢀ68.9 (s, 0.22ꢂ6F), ꢀ68.3 (s, 0.17ꢂ6F),
ꢀ67.7 (s, 0.21ꢂ6F), ꢀ63.0 (br s, 0.055ꢂ6F); 13C NMR (CDCl3,
100 MHz): 170.6, 169.8, 168.9, 160.6, 160.0, 159.2, 159.2, 157.3
(m), 129.1, 129.0, 128.7, 128.3, 122 (dq, J 283.4 Hz), 115.3 (dq, J
288.3 Hz), 114.1, 144.0, 60.5 (q, J 32.2 Hz), 60.0, 58.9, 58.8, 55.1,
53.2, 52.8, 52.4, 51.9, 43.6, 43.3, 43.6, 31.8, 31.4, 30.6, 30.3, 30.0,
29.5, 15.1, 15.0. Several peaks in 13C NMR spectrum are dupli-
cated. Anal. Calcd for C19H22F6N2O5S: C, 45.24; H, 4.40; N, 5.55.
Found C, 45.18; H, 4.49; N, 5.48. HRMS (EI): calculated for
C19H22F6N2O5S 504.1154; found, 504.1157.
4.3.20. Ethyl N-benzyl-3,3,3-trifluoro-2-phenyl-N-(trifluoroacetyl)-
alanylglycinate$H2O 6i
Yield 45% (220 mg), white solid, mp 112–115 ꢁC. Rf (hexanes/
ethyl acetate 3:1) 0.7; IR (Nujol, cmꢀ1) 3328, 1756, 1737, 1724;
1H NMR (CDCl3, 400 MHz): 1.33 (3H, t, J 7.1 Hz), 3.98 (1H, d, J
16.2 Hz), 4.20 (1H, d, J 17.7 Hz), 4.29 (2H, q, J 7.1 Hz), 4.46–4.65
(3H, m), 7.10–7.40 (10H, m); 19F NMR (CDCl3, 188 MHz): 77.0 (s,
3F), 67.2 (s, 3F); 13C NMR (CDCl3, 100 MHz): 14.0, 42.6, 47.9, 62.8,
72.6 (q, J 27.1 Hz), 96.7 (q, J 32.9 Hz), 122.1 (q, J 291.3 Hz), 124.2
(q, J 289.4 Hz), 127.3, 128.1, 128.2, 128.2, 128.4, 129.1, 132.1, 136.6,
167.5, 169.5. HRMS (EI): calculated for C22H20F6N2O4 490.1327;
found, 490.1336.
4.3.21. Methyl N-(2,2,2-trifluoroethylidene)-L-valinate 7a
A solution of fluoral monomethylacetale 1a (6.5 g, 50 mmol),
-valine methyl ether (6.55 g, 50 mmol) and TsOH$H2O (0.1 g) in
L
toluene was stirred at reflux with Dean–Stark trap for 2 h. The
solvent was removed in vacuo and the residue was distilled, Yield
Acknowledgements
50% (5.2 g), colorless liquid, bp 75–78 ꢁC/20 Torr. Rf (hexanes/ethyl
The authors thank the Deutsche Forschungsgemeinschaft (436
RUS 113/812/0-1) and Russian Science Support Foundaition for
financial support of this work.
20
acetate 4:1) 0.8; [
a]
ꢀ67.43 (c 0.0476, CH2Cl2); IR (film, cmꢀ1
)
D
2925, 1745; 1H NMR (CDCl3, 400 MHz): 0.91 (d, J 6.8 Hz, 3H), 0.92

11712
A.V. Gulevich et al. / Tetrahedron 64 (2008) 11706–11712
9. Koksch, B.; Mu¨tze, K.; Osipov, S. N.; Golubev, A. S.; Burger, K. Tetrahedron Lett.
Supplementary data
2000, 41, 3825–3828.
10. (a) Burger, K.; Hollweck, W.; Koksch, B. Tetrahedron 1998, 54, 5915–5928; (b)
Sewald, N.; Hollweck, W.; Mu¨ tze, K.; Schierlinger, C.; Seymour, L. C.; Gaa, K.;
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12. See for example: Gong, Y.; Kato, K. J. Fluorine Chem. 2001, 108, 83–86.
13. We have found the traces of the imine 3c and t-BuNHCHO in the reaction
mixture.
General information, synthesis of imines 1a–e and copies of all
1H, 13C, and 19F spectra. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.10.004.
14. See for example: (a) Fluoral imines: Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J. Org.
Chem. 1996, 61, 6563–6569; (b) Trifluoroacetone imines: Barten, J. A.; Lork, E.;
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Ojemaye, I. D.; Soloshonok, V. A. J. Fluorine Chem. 2004, 125, 603–607 Tri-
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Supplementary data.
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