Synthesis of partially fluorinated β-amino acids via Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1055/s-2001-10816

A convenient synthesis of fluorinated β-amino acids via Morita-Baylis-Hillman reaction is described. Hydrogenation of Morita-Baylis-Hillman adducts or cuprate addition to the double bond provides ready access to α-substituted β,β-bis(trifluoromethyl) β-am

Full text of DOI:10.1055/s-2001-10816

PAPER
281
Synthesis of Partially Fluorinated b-Amino Acids via Morita-Baylis-Hillman
Reaction
Natalia N. Sergeeva, Alexander S. Golubev, Klaus Burger*
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: burger@organik.chemie.uni-leipzig.de
Received 19 July 2000; revised 18 September 2000
Dedicated to Prof. Dr. Rolf Huisgen on the occasion of his 80th birthday
of the educt. A stoichiometric amount of DABCO resulted
Abstract: A convenient synthesis of fluorinated b-amino acids via
in an improved conversion. Nevertheless, under these
Morita-Baylis-Hillman reaction is described. Hydrogenation of
conditions, the reaction could not be brought to comple-
Morita-Baylis-Hillman adducts or cuprate addition to the double
tion. Noteworthy, DBU9 caused a fast decomposition of
bond provides ready access to a-substituted b,b-bis(trifluorometh-
yl) b-amino acids.
imine 1a.
Key words: a-substituted b-fluoroalkyl b-amino acids, Morita-
Baylis-Hillman reaction, cuprate addition reactions, 1,3-oxazin-6-
ones, peptides
During the last decade b-amino acids have attracted con-
siderable attention because of their numerous biochemical
and synthetic applications. b-Amino acids themselves are
present in nature, and are constituents of naturally occur-
ring biologically active peptides.1-3
Scheme 1
Fluorine-containing b-amino acids have also received a
great deal of attention. Useful synthetic approaches have
been developed for the synthesis of different classes of
fluorine-containing b-amino acids. a-Substituted b-fluo-
roalkyl b-amino acids were the persistent aim of many
synthetic efforts, primarily, due to their biological activi-
ties as enzyme inhibitors.4-7
Finally, we found that addition of CaH2 to the mixture of
imine 1a, methyl acrylate and stoichiometric amounts of
DABCO at room temperature in a clean reaction gave
product 2a in 65% yield within a reasonable reaction time
(Table 1). Benzyl acrylate reacted in the same manner.
The role of the additive CaH2 remains somewhat obscure,
although the transition metal hydride complex catalysis of
the MBH reaction is well-known.8 At this stage we rein-
vestigated the MBH reaction of hexafluoroacetone N-ben-
zoylimine 1b.10 We found, that catalysis of the MBH
reaction with DABCO is very capricious. We could not
obtain the stated yield even with stoichiometric amounts
of DABCO because of incomplete conversion and forma-
tion of by-products.
As an extension of our studies on the synthesis of fluorine-
containing amino acids as building blocks for peptide mi-
metics with enhanced lipophilicity and proteolytic stabil-
ity, we report on a new and efficient two-step approach to
a-alkyl b,b-bis(trifluoromethyl) b-amino acids. The key
step is a Morita-Baylis-Hillman reaction8 (MBH) of
hexafluoroacetone imines with acrylic esters followed by
functionalisation of the double bond by hydrogenation or
cuprate addition.
Again, under optimised conditions, the reaction gave the
products 2c-e in fair yields in acceptable reaction times.
A very striking example of the usefulness of CaH2 addi-
tion was the reaction of imine 1b with tert-butyl acrylate
to provide 2f. Indeed, this reaction does not take place
without CaH2 at room temperature, even under careful
Table 1 Products of MBH Reaction 2a−f
Among the hexafluoroacetone imines available, N-tert-
butyloxycarbonylimine 1a seems to be the best substrate
for a MBH reaction with respect to an orthogonal protec-
tion group strategy. The first attempts to obtain MBH
products on reaction of hexafluoroacetone N-tert-butyl-
oxycarbonylimine 1a and methyl acrylate using classical
MBH reaction conditions (10 mol%, DABCO, THF as
solvent) were disappointing because of a low conversion
Product
R1
R2
Time (days) Yield (%)
2a
2b
2c
2d
2e
2f
t-BuOCO
t-BuOCO
PhCO
PhCO
PhCO
Me
CH2Ph
Me
CH2Ph
Et
t-Bu
3
3
2
1
2
7
65
55
52
65
45
27
PhCO
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282
N. N. Sergeeva et al.
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Scheme 2
Table 2 Products of Hydrogenation and Saponification 3a, c; 4a, b
Product R1
R2
Catalyst Time
(days)
Yield
(%)
3a
3c
4a
4b
4a
4b
t-BuOCO Me
Pd/C
Pd/C
Pd/C
Pd/C
–
3
3
2
2
2
2
92
90
88
PhCO
t-BuOCO
PhCO
Me
H
H
Scheme 3
90
t-BuOCO
PhCO
H
H
88a
89b
–
Having N-protected b-amino acid 4b in hand, we investi-
gated its application for the peptide coupling reaction with
the tert-butyl ester of L-phenylalanine. We used standard
peptide coupling conditions, namely, HOAt (1-hydroxy-
7-azabenzotriazole), DIC (1,3-diisopropylcarbodiimide),
a Obtained from 3a.
b Obtained from 3c.
exclusion of water. Therefore, the function of CaH2 in the and NMM (N-methylmorpholine) in DMF. The coupling
19
experiment described is far beyond that of a drying reaction was monitored by F NMR. We detected spec-
agent.10-12
troscopically, the formation of an intermediate immedi-
ately after starting the coupling reaction. This
intermediate was transformed slowly into the final prod-
uct. However, after work-up, the yield of dipeptide 6 was
below 30%.
Next, we investigated the reaction behaviour of 2a-d
(Scheme 2, Table 2). Hydrogenation of 2a, c in MeOH
provided esters of b-amino acids 3a, c, which were readily
saponificated by KOH in MeOH to give the correspond-
ing N-protected b-amino acids 4a, b. An alternative ap- We assumed the intermediate to be a cyclic adduct in anal-
proach to N-protected b-amino acids 4a, b was ogy to the known 1,3-oxazol-5-one formation in the case
hydrogenation of 2b, d, which included simultaneous hy- of a-amino acids. We isolated the intermediate by cyclisa-
drogenation of the double bond and deprotection of the tion of starting acid 4b using HOAt and DIC in DMF. Ac-
carboxy group.
cording to NMR and IR-spectroscopic data we ascribe this
compound the structure of a 1,3-oxazin-6-one 7. Forma-
tion of analogous 1,3-oxazin-6-ones is described in litera-
ture.15-17
We have considered the cuprate addition to the double
bond of the MBH product 2a to be a good tool for intro-
duction of various substituents into the a-position of
b-bis(trifluoromethyl) b-amino acids. Transfer of ligands We found that the cyclic product 7 cleanly reacted with
from R2CuLi to the double bond of a,b-unsaturated car- the tert-butyl ester of L-phenylalanine in DMF in the pres-
bonyl compounds is usually very efficient and highly tol- ence of NMM to give the dipeptide 6 in 63% yield. This
erant with respect to other functionalities present in the two-step procedure is more convenient than the one-step
substrate.13,14 We found the addition of cuprates to the procedure.
double bond of 2a to proceed quite smoothly in good
yields. Optimal conditions of the methyl transfer from
lithium di-methylcuprate were found with 3.5 equivalents
of cuprate. In the case of phenyl transfer from lithium
Noteworthy, compound 7 can be smoothly converted into
derivatives of N-protected b-amino acids with various
N-nucleophiles. For example, 7 reacts with (R)-(1-phe-
nyl)ethylamine in DMF to give the corresponding amide
8 in 70% yield.
diphenylcuprate, this ratio should be reduced to 2.5:1.
Scheme 4
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Synthesis of Partially Fluorinated b-Amino Acids
283
Methyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluoromethyl-
2-methylenbutanoate (2c)
White solid; yield: 0.92 mg (52%); mp: 79-80 ∞C (hexanes).
1H NMR (300 MHz, CDCl3): d = 3.70 (s, 3H), 6.35 (s, 1H), 6.54 (s,
1H), 6.80 (s, 1H), 7.47-7.57 (m, 3H), 7.74-7.77 (m, 2H).
19F NMR (CDCl3): d = 7.6 (s).
13C NMR (75 MHz, CDCl3): d = 52.26, 66.59 (septet, J = 29 Hz),
122.58 (q, J = 290 Hz), 127.28, 128.95, 129.73, 131.91, 132.59,
133.50, 163.97, 167.40.
Scheme 5
Mps (uncorrected) were determined on a Boetius heating table. 1H
NMR spectra were recorded at Varian Gemini 2000 (200 MHz) and
300 (300 MHz). Chemical shifts are reported in ppm relative to
TMS in CDCl3, CD3OD and acetone-d6; J values are given in Hz.
13C NMR spectroscopy was performed at 50 MHz and 75 MHz.
19F NMR spectra were recorded at 188 MHz with trifluoroacetic
acid (TFA) as an external standard. For flash chromatography, silica
gel (32-63 mm) was used with solvent systems given in the text. Or-
ganic solvents were dried and distilled prior to use. 10% Pd/C was
purchased from Aldrich. Imines 1a, b were synthesised according
to W. Steglich et al.18
Anal. Calcd for C14H11F6NO3: C, 47.34; H, 3.12; N, 3.94. Found: C,
47.20; H, 3.01; N, 3.59.
Benzyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluoromethyl-
2-methylenbutanoate (2d)
Colourless oil; yield: 1.40 mg (65%); bp: 180∞C (1 mbar).
1H NMR (200 MHz, CDCl3): d = 5.13 (s, 2H), 6.36 (s, 1H), 6.50 (s,
1H), 6.85 (s, 1H), 7.30-7.69 (m, 10H).
19F NMR (CDCl3): d = 7.8 (s).
13C NMR (50 MHz, CDCl3): d = 66.66 (septet, J = 29 Hz), 67.51,
122.64 (q, J = 289 Hz), 127.29, 128.37, 128.45, 128.58, 128.92,
129.86, 132.16, 132.53, 133.41, 135.39, 163.41, 167.26.
Morita-Baylis-Hillman Adducts (2a-g); General Procedure
To a stirred mixture of acrylic ester (5.05 mmol), DABCO (5 mmol,
560 mg) and CaH2 (150 mg) in dry THF (10 mL), imine 1a (or 1b)
(5 mmol) was added at r.t. The mixture was stirred for 1-3 days (see
Table 1) (19F NMR-analysis). Volatiles were removed under re-
duced pressure and the residue was re-dissolved in CH2Cl2 (20 mL).
The solution was washed with 1% HCl (2 ¥ 10 mL) and brine (2 ¥
10 mL) and dried (MgSO4). The solvent was removed under re-
duced pressure. Products were isolated either by crystallisation or
by distillation.
Ethyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluoromethyl-2-
methylenbutanoate (2e)
White solid; yield: 0.83 g (45%).
Spectroscopic and physical data of 2e were in a full accordance with
those given in ref. 10.
tert-Butyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluorometh-
yl-2-methylenbutanoate (2f)
White solid; yield: 0.54 g (27%); mp: 107 ∞C (hexanes).
1H NMR (200 MHz, CDCl3): d = 1.42 (s, 9H), 6.23 (s, 1H), 6.55 (s,
Methyl 3-(N-tert-Butoxycarbonyl)amino-4,4,4-trifluoro-3-tri-
fluoromethyl-2-methylenbutanoate (2a)
White solid; yield: 1.14 g (65%); mp: 64-65 ∞C (hexanes).
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9H), 3.76 (s, 3H), 5.25 (s,
1H), 6.29 (s, 1H), 6.71 (s, 1H).
1H), 6.70 (s, 1H), 7.47-7.57 (m, 3H), 7.76-7.78 (m, 2H).
19F NMR (CDCl3): d = 7.95 (s).
13C NMR (50 MHz, CDCl3): d = 27.8, 66.82 (septet, J = 29 Hz),
82.28, 122.70 (q, J = 290 Hz), 127.28, 128.97, 130.71, 131.4,
132.59, 133.46, 162.67, 166.80.
19F NMR (CDCl3): d = 7.0 (s).
13C NMR (75 MHz, CDCl3): d = 27.91, 52.40, 66.05 (septet, J = 29
Hz), 82.06, 122.40 (q, J = 289 Hz), 130.21, 131.73 (t, J = 1.5 Hz),
153.14, 163.94.
Anal. Calcd for C17H17F6NO3: C, 51.39; H, 4.31; N, 3.53. Found: C,
51.30; H, 4.11; N, 3.23.
Hydrogenation of Morita-Baylis-Hillman Adducts 2a-d; Typi-
cal Procedure
Anal. Calcd for C12H15F6NO4: C, 41.03; H, 4.30; N, 3.99. Found: C,
40.80; H, 4.32; N, 3.78.
A mixture of ester 2a (1.5 mmol, 527 mg) and Pd/C (70 mg) in an-
hyd MeOH (20 mL) was stirred for 2-3 days under H2. The catalyst
was removed by filtration. MeOH was removed under reduced pres-
sure to give 487 mg (92%) of 3a.
Benzyl 3-(N-tert-Butoxycarbonyl)amino-4,4,4-trifluoro-3-tri-
fluoromethyl-2-methylenbutanoate (2b)
Colourless oil; yield: 1.17 g (55%); bp: 120 ∞C (1mbar).
1H NMR (200 MHz, CDCl3): d = 1.34 (s, 9H), 5.13 (s, 2H), 5.31(s,
1H), 6.24 (s, 1H), 6.71 (s, 1H), 7.3 (m, 5H).
Methyl 3-(N-tert-Butoxycarbonyl)amino-4,4,4-trifluoro-3-tri-
fluoromethyl-2-methylbutanoate (3a)
White solid; mp: 72 ∞C.
19F NMR (CDCl3): d = 5.82 (s).
13C NMR (50 MHz, CDCl3): d = 28.08, 66.31 (septet, J = 29 Hz),
67.41, 82.21, 122.58 (q, J = 289 Hz), 128.33, 128.43, 128.68,
130.26, 132.29 (m), 135.55, 153.23, 163.39.
1H NMR (200 MHz, CDCl3): d = 1.38 (d, 3H, J = 6.8 Hz), 1.45 (s,
9H), 3.31 (q, 1H, J = 6.8 Hz), 3.74 (s, 3H), 6.70 (s, 1H).
19F NMR (CDCl3): d = 13.52 (br s), 4.48 (q, J = 6.2 Hz).
Scheme 6
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284
N. N. Sergeeva et al.
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13C NMR (50 MHz, CDCl3): d = 13.94, 28.51, 38.94, 53.35, 66.53
(septet, J = 29 Hz), 81.80, 122.63 (q, J = 289 Hz), 123.99 (q,
J = 291 Hz), 153.28, 174.19.
organic layer was separated, washed with H2O and dried (MgSO4).
The solvent was evaporated under reduced pressure to give 230 mg
(73%) of 5a as a white solid; mp: 94 ∞C.
Anal. Calcd for C12H17F6NO4: C, 40.08; H, 4.85; N, 3.97. Found: C,
40.80; H, 4.75; N, 3.89.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, 3H, J = 5.0 Hz), 1.46 (s,
9H), 1.85 (m, 2H), 3.12 (t, 1H, J = 5.0 Hz), 3.77 (s, 3H), 6.60 (s,
1H).
19F NMR (CDCl3): d = 14.01 (br s), 5.31 (q, J = 6.7 Hz).
13C NMR (75 MHz, CDCl3): d = 11.41, 20.10 (d, J = 2.2 Hz), 28.05,
45.82, 52.55, 66.24 (septet, J = 29 Hz), 81.31, 122.21 (q, J = 289
Hz), 123.41 (q, J = 291 Hz), 152.65, 173.28.
Methyl 3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluoromethyl-
2-methylbutanoate (3c)
Obtained by the same procedure from 2c in 90% (482 mg) yield; co-
lourless oil.
1H NMR (300 MHz, CDCl3): d = 1.47 (d, 3H, J = 7.2 Hz), 3.37 (q,
1H, J = 7.2 Hz), 3.83 (s, 3H), 7.45-7.58 (m, 3H), 7.91-7.96 (m, 2H).
19F NMR (CDCl3): d = 14.82 (q, J = 9 Hz), 5.00 (q, J = 9 Hz).
Anal. Calcd for C13H19F6NO4: C, 42.51; H, 5.21; N, 3.81. Found: C,
42.40; H, 5.12; N, 3.73.
13C NMR (75 MHz, CDCl3): d = 14.26 (m), 38.92, 53.74, 66.73
(septet, J = 29 Hz), 122.53 (q, J = 290 Hz), 124.01 (q, J = 290 Hz),
127.77, 129.34, 132.88, 133.89, 166.20, 175.73.
Methyl 3-(N-tert-butoxycarbonyl)amino-4,4,4-trifluoro-3-tri-
fluoromethyl-2-benzylbutanoate (5b)
To a solution of Ph2CuLi, prepared from PhLi (6.38 mmol, 3.5 mL
of 1.8 M solution in cyclohexane/Et2O, 70:30) and CuI (3.19 mmol,
608 mg) in Et2O (15 mL), at -78∞C was added a solution of 2a (1.54
mmol, 540 mg) in Et2O (10 mL). The mixture was stirred for 90 min
at -78 ∞C, for 2 h at -30 ∞C and for 90 min at -10 to -5 ∞C. Aqueous
NH3 (pH 9) was added to the reaction mixture at r.t., and stirring
was continued for 2-3 h. The organic layer was separated, washed
with H2O, and dried (MgSO4). The solvent was evaporated under
reduced pressure. Flash chromatography (hexanes/EtOAc, 15:1)
gave 430 mg (65%) of 5b as a white solid; mp: 91 ∞C.
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 9H), 3.35 (m, 2H), 3.63
(s, 3H), 3.78 (m, 1H) 6.97 (s, 1H), 7.41-7.43 (m, 2H), 7.52-7.55 (m,
3H).
19F NMR (CDCl3): d = 13.97 (br s), 5.65 (q, J = 6.6 Hz).
3-(N-tert-Butoxycarbonyl)amino-4,4,4-trifluoro-3-trifluorome-
thyl-2-methylbutanoic Acid (4a)
Obtained by the same procedure from 2b in 88% (447 mg) yield;
white solid; mp: 129 ∞C.
1H NMR (300 MHz, acetone-d6): d = 1.41 (d, 3H, J = 7.3 Hz), 1.45
(s, 9H), 3.44 (m, 1H), 7.30 (s, 1H).
19F NMR (acetone-d6): d = 12.65 (m), 7.89 (m).
13C NMR (75 MHz, CD3OD): d = 14.01, 28.39, 39.41, 67.53 (sep-
tet, J = 29 Hz), 82.23, 123.75 (q, J = 289 Hz), 125.03 (q, J = 291
Hz), 154.72, 176.03.
Anal. Calcd for C11H15F6NO4: C, 38.95; H, 4.46; N, 4.13. Found: C,
38.60; H, 4.32; N, 3.79.
3-(N-Benzoyl)amino-4,4,4-trifluoro-3-trifluoromethyl-2-meth-
ylbutanoic Acid (4b)
Obtained by the same procedure from 2d in 90% (461 mg) yield;
white solid; mp: 158 ∞C.
1H NMR (300 MHz, CD3OD): d = 1.48 (d, 3H, J = 6.9 Hz), 3.40 (q,
1H, J = 6.9 Hz), 7.51-7.61 (m, 3H), 7.81-7.84 (m, 2H).
13C NMR (75 MHz, CDCl3): d = 28.21, 34.05, 46.81, 52.43, 66.38
(septet, J = 29 Hz), 81.69, 122.46 (q, J = 290 Hz), 123.48 (q,
J = 291 Hz), 127.44, 128.88, 129.26, 136.22, 152.79, 172.43.
Anal. Calcd for C18H21F6NO4: C, 50.36; H, 4.93; N, 3.26. Found: C,
50.30; H, 4.86; N, 3.24.
19F NMR (CD3OD): d = 13.36 (q, J = 9.2 Hz), 4.22 (q, J = 9.2 Hz).
13C NMR (75 MHz, CD3OD): d = 14.43 (m), 39.44, 67.81 (septet,
J = 27 Hz), 123.58 (q, J = 290 Hz), 125.11 (q, J = 289 Hz), 128.22,
129.99, 133.67, 134.74, 168.16, 177.42.
tert-Butyl [3-(N-benzoyl)amino-4,4,4-trifluoro-3-trifluorometh-
yl-ambo-2-methylbutanoyl]-S-phenylalaninate (6)
A solution of NMM (0.51 mmol, 51 mg) in CH2Cl2 (0.2 mL) was
added to a mixture of 7 (0.35 mmol, 114 mg) and tert-butyl ester of
(S)-phenylalanine (0.53 mmol, 136 mg) in DMF (10 mL). The reac-
tion was stirred at r.t. until compound 7 disappeared (19F NMR).
The mixture was diluted with Et2O (20 mL), washed with H2O (4 ¥
10 mL), aqueous 10% citric acid, and brine, and dried (MgSO4).
The solvent was removed under reduced pressure. Flash chromatog-
raphy (hexanes/EtOAc/CHCl3, 6:1:2) gave 116 mg (63%) of 6 (a
mixture of two diastereoisomers) as an oil.
1H NMR (200 MHz, CDCl3): d = 1.16-1.56 (m, 24H), 2.86-3.02 (m,
4H), 3.16-3.26 (m, 2H), 4.78-4.82 (m, 2H), 6.21-6.25 (m, 2H), 7.15-
7.21 (m, 4H), 7.26-7.32 (m, 6H), 7.45-7.56 (m, 6H), 7.95-8.01 (m,
4H), 9.72 (s, 1H), 9.76 (s, 1H).
Anal. Calcd for C13H11F6NO3: C, 45.49; H, 3.23; N, 4.08. Found: C,
45.80; H, 3.23; N, 3.93.
Saponification of 3a, 3c
A solution of 3a (1.5 mmol, 527 mg) in a mixture of MeOH (10 mL)
and 4 N KOH (5 mL) was stirred at 20 ∞C for 2 days. MeOH was
removed under reduced pressure. The residue was dissolved in Et2O
(10 mL) and treated with 2 N HCl (20 mL). The organic layer was
separated, washed with H2O and dried (MgSO4). The solvent was
removed under reduced pressure to give 446 mg (88%) of 4a, with
spectroscopic and physical data in full accordance with a sample of
4a, obtained from 2b.
19F NMR (CDCl3): d = 15.08 (q, J = 9.1 Hz), 5.71 (q, J = 9.1 Hz).
13C NMR (50 MHz, CDCl3): d = 15.26, 15.30, 28.39, 28.46, 38.32,
38.37, 39.75, 54.09, 54.15, 67.34 (septet, J = 29 Hz), 83.49, 83.57,
122.66 (q, J = 288 Hz), 124.34 (q, J = 291 Hz), 127.74, 127.79,
128.03, 129.06, 129.14, 129.28, 129.84, 129.93, 132,71, 134.14,
136.14 (m), 136.34, 166.47, 170.45, 170.54, 172.64, 173.73.
Compound 4b was obtained by the same procedure by saponifica-
tion of 3c in 89% (457 mg) yield. The spectroscopic and physical
data were in full accordance with a sample of 4b, obtained from 2d.
Methyl 3-(N-tert-butoxycarbonyl)amino-4,4,4-trifluoro-3-tri-
fluoromethyl-2-ethylbutanoate (5a)
To a stirred solution of Me2CuLi, prepared from MeLi (6.28 mmol,
3.6 mL of 1.6 M solution in hexane) and CuI (3.14 mmol, 598 mg)
in Et2O (15 mL), at -78 ∞C was added a solution of 2a (0.86 mmol,
300 mg) in Et2O (10 mL). The reaction was stirred for 90 min at
-78 ∞C, for 2 h at -30 ∞C, and for 90 min at -5 °C to 0 ∞C. Aqueous
NH3 was added at 0 ∞C, and stirring was continued for 1 h at r.t. The
2-Phenyl-4,4-bis(trifluoromethyl)-5-methyl-1,3-oxazin-6-one
(7)
A solution of DIC (0.88 mmol, 110.4 mg) in CH2Cl2 (0.3 mL)
was added to a mixture of 4b (0.73 mmol, 250 mg) and HOAt
(0.88 mmol, 119.1 mg) in DMF (10 mL). The reaction mixture was
stirred at r.t. until the starting material 4b disappeared (19F NMR).
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PAPER
Synthesis of Partially Fluorinated b-Amino Acids
285
The mixture was diluted with Et2O (20 mL), washed with H2O
(4 ¥ 10 mL), aqueous 10% citric acid, and brine, and dried
(MgSO4). Et2O was removed under reduced pressure. Flash chro-
matography (hexanes/EtOAc, 5:1) gave 204 mg (86%) of 7 as a
white solid; mp: 51 °C.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Innovationskolleg), Stiftung Volkswagenwerk, and the Fonds der
Chemischen Industrie.
IR (KBr): n = 1673, 1806 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.61 (d, 3H, J = 7.2 Hz), 3.26 (q,
1H, J = 7.2 Hz), 7.46-7.51 (m, 2H), 7.59-7.64 (m, 1H), 8.11-8.14
(m, 2H).
19F NMR (CDCl3): d = 8.34 (q, J = 6.6 Hz), 4.23 (q, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3): d = 10.75, 35.21, 68.36 (septet, J = 28
Hz), 122.76 (q, J = 288 Hz), 123.04 (q, J = 286 Hz), 128.74, 128.83,
129.18, 133.71, 157.77, 164.58.
References
(1) Cole, D. C. Tetrahedron 1994, 50, 9517.
(2) Gelman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) Juaristi, E., Ed.; Synthesis of b-AminoAcids, Wiley-VCH:
New York, 1997.
(4) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas,
V. K. J. Org. Chem. 1998, 63, 1878.
(5) Uneyama, K; Hao, J.; Amii, H. Tetrahedron Lett. 1998, 39,
4079.
(6) Fustero, S.; Pina, B.; Garcia de la Torre, M.; Navarro, A.;
Ramirez de Arellano, C.; Simon, A. Org. Lett. 1999, 1, 977.
(7) Abouabdellah, A. J.; Begue, J. -P.; Bonnet-Delpon, D.; Thanh
Nga, T. T. J. Org. Chem. 1997, 62, 8826.
Anal. Calcd for C13H9F6NO2: C, 48.01; H, 2.79; N, 4.31. Found: C,
48.10; H, 2.54; N, 3.95.
(R)-(1-Phenyl)ethylamide of 3-(N-Benzoyl)amino-4,4,4-trifluo-
ro-3-trifluoromethyl-2-methylbutanoic Acid (8)
A solution of (R)-(1-phenyl)ethylamine (0.32 mmol, 38.6 mg) in
CH2Cl2 (5 mL) was added to a solution of 7 (0.23 mmol, 74 mg) in
DMF (10 mL). The mixture was stirred at r.t. until the starting ma-
terial 7 disappeared (19F NMR). The reaction procedure and purifi-
cation as for 7 gave 68 mg (68%) of 8 as a mixture of
diastereoisomers. Repeated flash chromatography (hexanes/
EtOAc/CHCl3, 6:1:2) gave one of the diastereoisomers 8a 30 mg
(60%) as a white solid; mp: 170 °C, Rf 0.26.
1H NMR (200 MHz, CDCl3): d = 1.51-1.55 (m, 6H), 2.98 (q, 1H,
J = 6.6 Hz), 5.15 (m, 1H), 6.65 (d, 1H, J = 8.1 Hz), 7.31-7.34 (m,
5H), 7.43-7.53 (m, 3H), 7.91-7.94 (m, 2H), 9.94 (s, 1H).
(8) Ciganek, E. Org. React. 1997, 51, 201.
(9) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 22, 2311.
(10) Cyrener, J.; Burger, K. Monatsh. Chem. 1994, 125, 1279.
(11) Encyclopedia of Reagents for Organic Synthesis, Vol. 2;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 964-965.
(12) Wang, Z. -M.; Zhou, W. -S.; Lin, G. -Q. Tetrahedron Lett.
1985, 26, 6221.
(13) Encyclopedia of Reagents for Organic Synthesis, Vol. 5;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 3107-3114.
(14) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(15) Zeifman,Yu. V.; Gambaryan, N. P.; Simonyan, L. A.;
Minasyan, R. B.; Knunyants, I. L. Zh. Obshch. Khim. 1967,
37, 2476; Chem. Abstr. 1968, 69, 285.
19F NMR (CDCl3): d = 14.94 (q, J = 6.1 Hz), 5.52 (q, J = 6.1 Hz).
13C NMR (50 MHz, CDCl3): d = 15.15, 21.07, 39.45, 49.36, 68.36
(septet, J = 28 Hz), 122.76 (q, J = 288 Hz), 123.04 (q, J = 286 Hz),
126.42, 127.61, 127.95, 128.91, 132.31, 133.68, 141.65, 166.28,
172.85.
(16) Drey, C. N. C.; Ridge, R. J.; Mtetwa, E. J. Chem. Soc., Perkin
Trans 1 1980, 378.
(17) Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 471.
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1974, 107, 1488.
Anal. Calcd for C21H20F6N2O2: C, 56.50; H, 4.52; N, 6.28. Found:
C, 56.50; H, 4.51; N, 6.13.
Article Identifier:
1437-210X,E;2001,0,02,0281,0285,ftx,en;T00500SS.pdf
Synthesis 2001, No. 2, 281–285 ISSN 0039-7881 © Thieme Stuttgart · New York