Efficient syntheses of ω-trifluoromethyl substituted ω-amino acids

Article abstract of DOI:10.1055/s-2002-35636

Syntheses of N-protected β-trifluoromethyl-β-amino acids, γ-trifluoromethyl-γ-amino acids, δ-trifluoromethyl-δ-amino acids, and β-trifluoromethyl-β-amino-α-hydroxy acids (4,4,4-trifluoroisothreonine) starting from N-acyl-1-chloro-2,2,2-trifluoroethylamines are described.

Full text of DOI:10.1055/s-2002-35636

SPECIAL TOPIC
2579
Efficient Syntheses of -Trifluoromethyl Substituted -Amino Acids
Efficient
S
ynthese
a
s
of -Amin
t
oAcid
a
s
lia N. Sergeeva,a Alexander S. Golubev,b Lothar Hennig,a Klaus Burger*a
a
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: burger@organik.chemie.uni-leipzig.de
b
Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, GSP-1, V-334 RUS, 117813 Moscow, Russia
Received 5 June 2002
Dedicated to Prof. L. Yagupolskii on the occasion of his 80th birthday.
synthesis of fluorine-containing amino acids is an area of
current interest because of their high potential for peptide
modification, for drug synthesis and their application as
building blocks in organic synthesis.2a,17
Abstract: Syntheses of N-protected -trifluoromethyl- -amino ac-
ids, -trifluoromethyl- -amino acids, -trifluoromethyl- -amino
acids, and -trifluoromethyl- -amino- -hydroxy acids (4,4,4-tri-
fluoroisothreonine) starting from N-acyl-1-chloro-2,2,2-trifluoro-
ethylamines are described.
Most of the synthetic routes described so far for -fluoro-
alkyl substituted -amino acids are based on following
key reactions:
Key words: -amino acids, Grignard reactions, organometallic re-
agents, oxidations, ozonolysis
(1) [2+2]-Cycloaddition of fluoroalkylimines and ketene
imines.18
There is still a growing interest in the development of new
routes to non-proteinogenic amino acids1 ( -amino, -
amino and -amino acids included) although less abun-
dant than their -analogues. -Amino acids as constitu-
ents of natural products,2 are present in biological active
peptides,3 and many of them exhibit biological activities
on their own.4 -Amino- -hydroxy acids represent crucial
substructures of medicinally valuable molecules like
taxol5 and the anti-tumor agent bestatin.6 Furthermore, -
amino acids are synthetic precursors of -lactams,7 and
are monomers of a new class of promising biooligomers,
namely, -peptides.8
(2) Diastereoselective reduction of fluorine-containing -
hydroxy- -iminoesters.19
(3) Addition of silyl enol ethers to fluorosubstituted ace-
taldimines.20
(4) Asymmetric Michael addition of ammonia or amines
to fluoroalkyl substituted , -unsaturated esters.21,22
(5) Chemo- and stereoselective reduction of -fluoro-
alkyl- -enamino esters.23,24
(6) Stereoselective biomimetic transamination of
fluoroalkyl- -keto esters.25
-
The use of -amino acids in peptide design is a newly
emerging area of current research.9 This is mainly due to
the ability of these amino acids to modify the geometry of
the peptide backbone,10 providing proteolytic resistance to
bioactive peptide sequences. -Aminobutyric acid
(GABA), a neurotransmitter enzymatically produced in
the mammalian brain,11 has been used to design unusual
foldamers.9e Insertion of one or more extra carbon atoms
into the intramolecular hydrogen bonded, folded struc-
tures leads to the formation of unusual turns and novel he-
lical folds.12
Recently we reported a synthesis of , -bis(trifluorometh-
yl) -amino acids based on the Morita-Baylis-Hillman re-
action.26 Now, we disclose a new, efficient access to
-
trifluoromethyl -amino acids starting from N-acyl-1-
chloro-2,2,2-trifluoroethylamines (1).27 Compounds 1, in
contrast to the acylimines of fluoral, are relatively stabile
crystalline products, easy to handle and can be stored in a
fridge for months with exclusion of moisture, while the
acylimines of fluoral 2 exhibit a pronounced tendency to
polymerize, especially at elevated temperatures. There-
fore, we generated the acylimines 2 from 1 using the in
situ technique. The construction of the amino acid back-
bone was accomplished by reaction of Grignard
reagents28 of type CH2=CH–(CH2)nMgBr (n = 1 3) with
compounds 1. Since a large variety of linear and branched
bromoalkenes is available, the method provides a general
It has been shown that fluorinated analogues of naturally
occurring and of man-made biologically active com-
pounds often exhibit unique physiological activities.13,14
Therefore, there is an increasing interest in the incorpora-
tion of fluoroamino acids into peptides.15 Despite the bio-
medicinal benefits of hydrogen replacement by fluorine in
strategical positions of a molecule,13,14 not much is known
about the chemistry and biological activity of fluorine-
containing -amino acids, quite likely due to the lack of
general methods for their preparation.16 Nevertheless, the
access to an arsenal of -trifluoromethyl substituted
-
amino acids with a structurally variable backbone pattern.
Two equivalents of the Grignard reagent are necessary to
obtain optimal yields of compounds 3a–f, because one
equivalent is consumed during the elimination process to
generate the acylimines (1 2) (Scheme 1).
In a second step, the C=C double bond was transformed
into a carboxy group by standard oxidation protocols29 to
Synthesis 2002, No. ´17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2579,2584,ftx,en;C04702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
give N-protected, i.e. Z-protected, -trifluoromethyl
-

2580
N. N. Sergeeva et al.
SPECIAL TOPIC
in the presence of BF3 Et2O to give compound 5
(Scheme 3). Therefore, 1 can be used as building block to
construct in a one step synthesis the backbone of -triflu-
oromethyl -amino acids with an option for introducing
additional functionalities into -position.31 Iminium salts
are probably the intermediates of this reaction.
Compound 5 on ozonolysis32 is transformed into methyl
3-(N-benzoyl)amino-4,4,4-trifluoro-2-oxo butanoate (6).
Reduction of the keto group with sodium borohydride in
methanol provides access to a diastereomeric mixture (ra-
tio 7:1) of methyl 3-(N-benzoyl)amino-4,4,4-trifluoro-2-
hydroxy butanoate (4,4,4-trifluoroisothreonine) 7a/b
(Scheme 4). L-4-Fluorothreonine represents one of the
rare examples of organofluorine compounds occurring in
nature, produced as secondary metabolite by Streptomy-
ces cattleya.33
Scheme 1
Table 1 Yields of Compound 3
3
a
b
c
d
e
f
R
Pg
Yield, %
CH2CH=CH2
PhCO
89
80
76
73
66
64
CH2CH=CH2
PhCH2OCO
PhCO
CH2CH2CH=CH2
CH2CH2CH=CH2
CH2CH2CH2CH=CH2
CH2CH2CH2CH=CH2
The assignment of the stereochemistry of compound 7a is
based on NOE experiments performed on a racemic mix-
ture of the five-membered ring system 8 obtained from the
main product 7a on reaction with triphosgene
(Scheme 5).19 Irradiation of H caused a strong NOE-ef-
fect of the signal for C-(4)-H at 5.69 ppm (m), likewise a
strong NOE-effect was observed for the signal of C(5)-H
at 5.25 ppm on irradiation of H . These results unequivo-
cally indicate cis-configuration for 8. Consequently, the
main product 7a is anti-configured.19
PhCH2OCO
PhCO
PhCH2OCO
amino, -trifluoromethyl -amino and -trifluoromethyl
-amino acids (4a–c), respectively (Scheme 2). Com-
pounds 4 and their derivatives are interesting building
blocks for fluoroorganic synthesis, for peptide modifica-
ton and in itself, since 4b is a GABA derivative.
Previously it was reported, that N-acyl-1-chloro-2,2,2-tri-
fluoroethylamines (1) are readily attacked by O-, S-, N-
and C-nucleophiles.34 We found that the nucleophilic ca-
pacity of silyl enol ethers is sufficient to undergo nucleo-
philic substitution reactions in the presence of catalysts.
However, initial experiments were disappointing when
we tried to catalyze the addition reaction with TiCl4,
SnCl4, BF3 OEt2 or Bu2BOTf. The transformation result-
Furthermore, we found that ‘hydroalumination’, the nu-
cleophilic transfer of vinyl substructures from [ -(alkoxy-
carbonyl)vinyl]diisobutylaluminium to highly electro-
philic acylimines of hexafluoroacetone and trifluoropyru-
vate,30 can also be applied to N-acyl-1-chloro-2,2,2-tri-
fluoroethylamines (1). Compound 1 reacts readily and
cleanly with two equivalents of the vinyl transfer reagent
Scheme 2
Scheme 3
Scheme 4
Synthesis 2002, No. ´17, 2579–2584 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Syntheses of -Amino Acids
2581
Scheme 5
Scheme 6
ed in the formation of a N-acyl-1-hydroxy-2,2,2-trifluoro-
ethylamine dimer and only trace amounts of the target
compounds could be detected (Scheme 6). However,
Lewis acids like MgBr2 OEt2 strongly promote the de-
sired substitution reactions, providing good yields of com-
pounds 9.
4-(N-Benzoyl)amino-5,5,5-trifluoropent-1-ene (3a)
Yield: 89% (0.43 g); mp 125 °C.
1H NMR (300 MHz, CDCl3): = 2.51 (m, 1 H), 2.72 (m, 1 H), 5.01
(m, 1 H), 5.26 (m, 2 H), 5.84 (m, 1 H), 6.14 (m, 1 H), 7.43 (m, 3 H),
7.81 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 33.1, 50.0 (q, J = 30 Hz), 119.9,
125.2 (q, J = 280 Hz), 127.2, 128.8, 131.7, 132.4, 133.6, 167.4.
19F NMR (282 MHz, CDCl3): = 2.59 (d, J = 6 Hz, 3 F).
HRMS: m/z calcd for C12H12F3NO (M + H+), 244.09438; found,
Complete conversion was achieved only in the presence
of a twofold excess of the magnesium, aluminium or silyl
organic compound. A plausible explanation for this fact is
that one equivalent of the metal organic compound being
consumed during the in situ formation of the iminium
salts. -Amino- -trifluoromethyl ketones are highly valu-
able building blocks for synthetic organofluorine chemis-
try.20,35
244.09441.
4-(N-Benzyloxycarbonyl)amino-5,5,5-trifluoropent-1-ene (3b)
Yield: 80% (0.41 g); white solid; mp 74 °C.
1H NMR (300 MHz, CDCl3): = 2.34 (m, 1 H), 2.59 (m, 1 H), 4.44
(m, 1 H), 4.89 (m, 1 H), 5.23 (m, 2 H), 5.25 (m, 2 H), 5.78 (m, 1 H),
7.39 (m, 5 H).
Solvents were purified and dried prior to use. Reagents were used
as purchased. Mps were determined on a Boetius heating table. MS
were recorded on a VG-250 (Masslab) EI spectrometer (70 eV) or
by a VG ZAB-HSQ FAB spectrometer. 1H (200 MHz or 300 MHz),
13C (50 or 75 MHz) and 19F NMR spectra (188 or 282 MHz) were
recorded on a Varian Gemini 2000 or a Varian Gemini 300 spec-
trometer. TMS was used as reference standard for 1H and 13C NMR
spectra (internal), and TFA for 19F NMR spectra (external). Flash
chromatography was performed by using silica gel (32–63 m, ICN
Biomedicals) with solvent systems given in the text.
13C NMR (50 MHz, CDCl3): = 33.2, 52.4 (q, J = 30 Hz), 67.6,
119.8, 125.2 (q, J = 281 Hz), 128.2, 128.4, 128.7, 131.4, 136.1,
155.8.
19F NMR (282 MHz, CDCl3): = 1.73 (d, J = 6.0 Hz, 3 F).
HRMS: m/z calcd for C13H14F3NO2 (M + H+), 274.10494; found,
274.10481.
5-(N-Benzoyl)amino-6,6,6-trifluorohex-1-ene (3c)
Yield: 76% (0.39 g); white solid; mp 88 °C.
1H NMR (200 MHz, CDCl3): = 1.76 (m, 1 H), 2.01 (m, 1 H), 2.21
(m, 2 H), 4.88 (m, 1 H), 5.08 (m, 2 H), 5.79 (m, 1 H), 6.08 (m, 1 H),
7.41 (m, 3 H), 7.79 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 27.8, 29.5, 50.6 (q, J = 30 Hz),
116.6, 125.6 (q, J = 280 Hz), 127.4, 128.9, 132.4, 133.7, 136.6,
167.9.
19F NMR (188 MHz, CDCl3): = 0.51 (d, J = 7.5 Hz, 3 F).
HRMS: m/z calcd for C13H14F3NO (2M + Na+), 537.19472; found,
Addition of Grignard Reagents to 1; General Procedure
To a soln of the Grignard reagent, prepared from the corresponding
bromoolefin (5.0 mmol) and magnesium (5.3 mmol) in THF (50
mL), a soln of 1 (2.0 mmol) in THF (2 mL) was added at –78 °C.
The reaction mixture was stirred at –78 °C for 40 h (in the case of
3c–d the mixture was stirred overnight at –30 °C to 10 °C). Then the
mixture was allowed to warm up slowly to r.t., quenched with sat.
aq soln of NH4Cl (15 mL) and extracted with CH2Cl2 (3 10 mL).
The combined organic layer was dried with MgSO4. The solvents
were removed in vacuo and the residue was purified by column
chromatography (hexanes EtOAc, 5:1).
537.19461.
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N. N. Sergeeva et al.
SPECIAL TOPIC
5-(N-Benzyloxycarbonyl)amino-6,6,6-trifluorohex-1-ene (3d)
4-(N-Benzyloxycarbonyl)amino-5,5,5-trifluoropentanoic Acid
Yield: 73% (0.42 g); white solid; mp 66 °C.
(4b)
Yield: 67% (0.31 g); white solid; mp 115 °C.
1H NMR (300 MHz, CDCl3): = 1.58 (m, 1 H), 1.89 (m, 1 H), 2.17
(m, 2 H), 4.31 (m, 1 H), 4.81 (m, 1 H), 5.06 (m, 2 H), 5.14 (s, 2 H),
5.77 (m, 1 H), 7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 27.8, 29.4, 52.6 (q, J = 30 Hz),
67.7, 116.7, 125.3 (q, J = 281 Hz), 128.2, 128.4, 128.7, 135.9,
137.6, 156.1.
19F NMR (282 MHz, CDCl3): = 1.01 (d, J = 6.2 Hz, 3 F).
HRMS: m/z calcd for C14H16F3NO2 (2 M + Na+), 597.21585; found,
1H NMR (300 MHz, Acetone-d6): = 1.92 (m, 1 H), 2.18 (m, 1 H),
2.53 (m, 2 H), 4.81 (m, 1 H), 5.17 (s, 2 H), 6.97 (m, 1 H), 7.41 (m,
5 H), 10.81 (br, 1 H).
13C NMR (50 MHz, Acetone-d6): = 23.8, 29.6, 53.0, (q, J = 30
Hz), 67.3, 126.7 (q, J = 280 Hz), 128.6, 128.8, 129.2, 137.8, 157.2,
173.7.
19F NMR (282 MHz, Acetone-d6): = 1.48 (d, J = 9 Hz, 3 F).
HRMS: m/z calcd for C13H14F3NO4 (2M + H+), 633.16420; found,
597.21590.
633.16421.
6-(N-Benzoyl)amino-7,7,7-trifluorohept-1-ene (3e)
Yield: 66% (0.36 g); white solid; mp 75 °C.
5-(N-Benzyloxycarbonyl)amino-6,6,6-trifluorohexanoic Acid
(4c)
1H NMR (200 MHz, CDCl3): = 1.58 (m, 3 H), 1.90 (m, 1 H), 2.11
(m, 2 H), 4.83 (m, 1 H), 4.93 (m, 2 H), 5.73 (m, 1 H), 6.15 (m, 1 H),
7.48 (m, 3 H), 7.77 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 24.6, 27.9, 33.1, 50.9 (q, J = 30
Hz), 115.6, 125.5 (q, J = 280 Hz), 127.2, 128.8, 132.2, 133.7, 137.6,
167.7.
19F NMR (188 MHz, CDCl3): = 0.45 (d, J = 6.0 Hz, 3 F).
HRMS: m/z calcd for C14H16F3NO2 (2M + Na+), 565.22602; found,
Yield: 61% (0.29 g); white solid; mp 135 °C.
1H NMR (300 MHz, Acetone-d6): = 1.82 (m, 4 H), 2.41 (m, 2 H),
4.36 (m, 1 H), 5.17 (s, 2 H), 7.01 (m, 1 H), 7.41 (m, 5 H), 9.71 (br,
1 H).
13C NMR (50 MHz, Acetone-d6): = 21.4, 27.7, 33.3, 53.5 (q,
J = 30 Hz), 67.3, 126.7 (q, J = 280 Hz), 128.6, 128.7, 129.2, 137.8,
157.2, 174.2.
19F NMR (282 MHz, Acetone-d6): = 1.56 (br, 3 F).
HRMS: m/z calcd for C14H16F3NO4 (M + H+), 320.11042; found,
565.22586.
6-(N-Benzyloxycarbonyl)amino-7,7,7-trifluorohept-1-ene (3f)
320.11038.
Yield: 64% (0.39 g); white solid; mp 47 °C.
Methyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-2-methylene But-
anoate (5)
1H NMR (200 MHz, CDCl3): = 1.42 (m, 3 H), 1.77 (m, 1 H), 2.05
(m, 2 H), 4.27 (m, 1 H), 4.79 (m, 1 H), 5.01 (m, 2 H), 5.13 (s, 2 H),
5.72 (m, 1 H), 7.35 (m, 5 H).
13C NMR (50 MHz, CDCl3): = 24.4, 27.8, 33.1, 52.8 (q, J = 30
Hz), 67.6, 115.6, 125.5 (q, J = 280 Hz), 128.2, 128.4, 128.7, 135.9,
137.6, 156.0.
19F NMR (188 MHz, CDCl3): = 0.98 (d, J = 5.9 Hz, 3 F).
HRMS: m/z calcd for C15H18F3NO2 (M + H+), 302.13624; found,
To a stirred soln of HMPTA (932 mg, 5.2 mmol) in THF (50 mL),
1 M DIBAL-H (2.6 mmol, 2.6 mL) in hexane was added at 0 °C. Af-
ter stirring the reaction mixture for 0.5 h at 0 °C methyl propiolate
(219 mg, 2.6 mmol) was added. The reaction mixture was stirred
until the color changed to yellow (ca. 1 h). Then BF3 Et2O (301 mg,
2.1 mmol) and N-acyl-1-chloro-2,2,2-trifluoroethylamine (507 mg,
2 mmol), dissolved in anhyd THF (2 mL), were added at 78 °C.
The reaction mixture was allowed to warm up to r.t. and stirring was
continued overnight. The mixture was quenched with sat. aq soln of
NH4Cl (25 mL) at 0 °C, and extracted with CH2Cl2 (3 15 mL). The
combined organic layer was dried with MgSO4. The solvents were
removed in vacuo and the residue was purified by column chroma-
tography (hexanes EtOAc, 4:1) to give 5.
302.13619.
Amino Acid Synthesis via Oxidation of the CC Double Bond of
Compounds 3; General Procedure
To an aq soln of NaIO4 (2.95 g, 13.8 mmol, 150 mL) and KMnO4
(80 mg, 0.5 mmol), 3 (1.5 mmol) dissolved in acetone (5 mL) was
added at r.t. with stirring. Stirring was continued until the color of
the reaction mixture turned from violet to red. The soln was extract-
ed with CH2Cl2 (6 15 mL) and the combined organic layer was
dried with MgSO4. After evaporation of the solvent in vacuo, the
residue was purified by recrystallization (hexanes Et2O, 2:1) to
give compounds 4a–c.
Yield: 65% (0.36 g); white solid; mp 105 °C.
1H NMR (300 MHz, CDCl3): = 3.85 (s, 3 H), 5.72 (m, 1 H), 6.13
(s, 1 H), 6.58 (s, 1 H), 7.51 (m, 3 H), 7.83 (m, 2 H), 7.98 (d, 1 H,
J = 8 Hz).
13C NMR (75 MHz, CDCl3): = 52.7, 53.8 (q, J = 32.5 Hz), 124.1
(q, J = 280 Hz), 127.1, 128.9, 131.4, 132.4, 133.2, 133.9, 166.0,
166.6.
3-(N-Benzyloxycarbonyl)amino-4,4,4-trifluorobutyric Acid
(4a)
19F NMR (282 MHz, CDCl3): = 3.5 (d, J = 8 Hz, 3 F).
Yield: 70% (0.31 g); white solid; mp 150 °C.
HRMS: m/z calcd for C13H12F3NO3 (M + Na+), 310.06615; found,
310.06611.
The ozonolysis of 5 was performed according to literature.32
1H NMR (300 MHz, Acetone-d6): = 2.79 (dd, J = 9.6 Hz, J = 16.7
Hz, 1 H), 2.94 (dd, J = 4.5 Hz, 16.7 Hz, 1 H), 4.88 (m, 1 H), 5.16 (s,
2 H), 7.15 (m, 1 H), 7.41 (m, 5 H), 11.24 (br, 1 H).
13C NMR (50 MHz, Acetone-d6): = 34.2, 51.6 (q, J = 31 Hz),
67.9, 126.9 (q, J = 281 Hz), 129.4, 129.5, 129.8, 138.3, 157.2,
171.1.
Methyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-2-oxo Butanoate (6)
Yield: 71% (710 mg); mp 122 °C.
1H NMR (200 MHz, CDCl3): = 3.96 (s, 3 H), 6.31 (m, 1 H), 7.06
(m, 1 H), 7.53 (m, 3 H), 7.83 (m, 2 H).
19F NMR (282 MHz, Acetone-d6): = 1.42 (d, J = 5.9 Hz, 3 F).
HRMS: m/z calcd for C12H12F3NO4 (M + Na+), 314.06106; found,
314.06112.
13C NMR (50 MHz, CDCl3): = 54.1, 55.8 (q, J = 31 Hz), 122.4 (q,
J = 282 Hz), 127.6, 128.9, 129.1, 132.9, 160.3, 167.3, 184.5.
19F NMR (188 MHz, CDCl3): = 7.25 (d, J = 7.7 Hz, 3 F).
Synthesis 2002, No. ´17, 2579–2584 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Syntheses of -Amino Acids
2583
HRMS: m/z calcd for C12H10F3NO4 (M + H+), 290.06347; found,
290.06336.
3-(N-Benzyloxycarbonyl)amino-4,4,4-trifluoro-1-phenylbutan-
1-one (9b)
Yield: 66% (0.26 g); white solid; mp 110 °C.
Methyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-2-hydroxy But-
anoate (anti-4,4,4-Trifluoroiso-threonine Methyl Ester) (7a)
To a soln of 6 (290 mg, 1.00 mmol) in MeOH (150 mL), NaBH4 (38
mg, 1.00 mmol) was added at 0 °C. The reaction mixture was stirred
for 1.5 h. The mixture was quenched with sat. aq NH4Cl (20 mL)
soln. The aq layer was extracted with CH2Cl2 (3 15 mL) and the
combined organic phase was dried with MgSO4. After the solvent
was removed in vacuo, the crude product was purified by column
chromatography (hexanes EtOAc, 1:1) to give 7a.
1H NMR (300 MHz, CDCl3): = 3.38 (m, 2 H), 5.02 (m, 1 H), 5.14
(s, 2 H), 5.45 (m, 1 H), 7.46 (m, 8 H), 7.93 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 36.9, 50.0 (q, J = 32 Hz), 67.7,
125.3 (q, J = 280 Hz), 128.1, 128.3, 128.4, 128.7, 129.0, 133.9,
136.1, 136.3, 155.6, 194.9.
19F NMR (282 MHz, CDCl3): = 2.91 (d, J = 9.3 Hz, 3 F).
HRMS: m/z calcd for C18H16F3NO3 (M + H+), 352.11550; found,
352.11550.
Yield: 65% (199 mg); mp 125 °C.
1H NMR (300 MHz, CDCl3): = 3.30 (m, 1 H), 3.93 (s, 3 H), 4.51
(m, 1 H), 5.41 (m, 1 H), 6.93 (m, 1 H), 7.53–7.64 (m, 3 H), 7.87–
7.90 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 52.2 (q, J = 31 Hz), 54.0, 67.9,
124.2 (q, J = 280 Hz), 127.4, 128.9, 132.6, 132.8, 167.2, 172.1.
2-[1-(N-Benzoyl)amino-2,2,2-trifluoroethyl]cyclohexanone (9c)
Yield: 40% (0.14 g); white solid; mp 137 °C.
1H NMR (300 MHz, CDCl3): = 1.86 (m, 4 H), 2.49 (m, 2 H), 2.51
(m, 2 H), 3.08 (m, 1 H), 4.89 (m, 1 H), 7.55 (m, 3 H), 7.88 (m, 2 H),
8.09 (m, 1 H).
13C (50 MHz, CDCl3): = 25.3, 28.6, 33.9, 43.5, 48.6, 52.3 (q,
J = 31 Hz), 124.7 (q, J = 280 Hz), 127.3, 128.8, 132.3, 133.1, 167.1,
194.3.
19F NMR (282 MHz, CDCl3): = 7.11 (d, J = 6.1 Hz, 3 F).
HRMS: m/z calcd for C12H12F3NO4 (M + H+), 292.07912; found,
292.07908.
19F NMR (282 MHz, CDCl3): = 4.74 (d, J = 5.3 Hz, 3 F).
HRMS: m/z calcd for C15H16F3NO2 (M + H+), 300.12059; found,
300.12054.
Methyl 3-Benzoyl-2-oxo-4-trifluoromethyloxazolidine-5-car-
boxylate (8)
To a soln of 7a (180 mg, 0.62 mmol) and i-Pr2NEt (239 mg, 1.85
mmol) in CH2Cl2 (30 mL), triphosgene (98 mg, 0.31 mmol) in
CH2Cl2 (1 mL) was added. The mixture was stirred overnight at 40 Acknowledgment
°C. The solvent was removed under vacuum and residue was puri-
fied by column chromatography (hexanes–EtOAc, 2:1) to give 8.
We are grateful to the Volkswagen Stiftung, Hanover and the Fonds
der Chemischen Industrie for financial support.
Yield: 50% (98 mg); white solid; mp 132 °C.
1H NMR (200 MHz, CDCl3): = 3.92 (s, 3 H), 5.25 (d, 1 H, J = 8.4
Hz), 5.69 (m, 1 H), 7.39 (m, 2 H), 7.62 (m, 1 H), 7.75 (m, 2 H).
References
19F NMR (188 MHz, CDCl3): = 3.82 (d, J = 6.2 Hz, 3 F).
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Reaction of 1 with Enol Ethers; General Procedure
To a suspension of MgBr2 Et2O (869 mg, 3.364 mmol) in CH2Cl2
(15 mL), was added the silyl enol ether (2.24 mmol). After 5 min, a
soln of 1 (1.12 mmol) in anhyd CH2Cl2 was added at –60 °C. After
stirring for 1 h at –60 °C, the reaction mixture was warmed up to r.t.,
and stirring was continued overnight (in the case with cyclohex-
anone the mixture was stirred for 2 d at r.t.). Then sat. aq soln of
NH4Cl (15 mL) was added. Finally, the reaction mixture was ex-
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by chromatography (hexanes–EtOAc, 3:1) to give compounds 9.
3-(N-Benzoyl)amino-4,4,4-trifluoro-1-phenylbutan-1-one (9a)
Yield: 74% (0.27 g); white solid; mp 155 °C.
1H NMR (200 MHz, CDCl3): = 3.34 (dd, J = 5.2 Hz, 22.7 Hz, 1
H), 3.66 (dd, J = 5.4 Hz, 22.7 Hz, 1 H), 5.43 (m, 1 H), 7.41 (m, 7
H), 7.81–7.94 (m, 2 H), 7.98 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 36.1, 48.4 (q, J = 32 Hz), 125.3 (q,
J = 280 Hz), 127.5, 128.5, 129.1, 132.4, 133.5, 134.4, 134.7, 136.3,
167.2, 196.8.
19F NMR (188 MHz, CDCl3): = 2.01 (d, J = 7.5 Hz, 3 F).
HRMS: m/z calcd for C17H14F3NO2 (M + H+), 322.10494; found,
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Synthesis 2002, No. ´17, 2579–2584 ISSN 0039-7881 © Thieme Stuttgart · New York