An efficient synthesis of N-methylamino acids and some of their derivatives

Article abstract of DOI:10.1055/s-1998-1998

N-Methylamino acid derivatives are obtained in high yield by a stereoselective one-pot procedure from hexafluoroacetone protected amino acids via N-chloromethylation and treatment with triethylsilane/trifluoroacetic acid.

Full text of DOI:10.1055/s-1998-1998

January 1998
SYNTHESIS
67
An Efficient Synthesis of N-Methylamino Acids and Some of Their Derivatives
Jan Spengler, Klaus Burger*
Department of Organic Chemistry, University of Leipzig, Talstr. 35, D-04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: burger@organic.orgchem.uni-leipzig.de
Received 12 August 1997
N-Methylamino acid derivatives are obtained in high yield by a ste- fractional distillation under reduced pressure. In the case
reoselective one-pot procedure from hexafluoroacetone protected
amino acids via N-chloromethylation and treatment with triethyl-
silane/trifluoroacetic acid.
of the low boiling compound 4a diphenylmethylsilane in-
stead of triethylsilane was used for the transformation of
the N-chloromethylamino into the a-N-methylamino acid
derivatives. The 2,2-bis(trifluoromethyl)-3-methyl-1,3-
oxazolidin-5-ones 4 can be stored in the refrigerator with-
out decomposition over weeks.
a-N-Methylamino acids are constituents of various pep-
tides and depsipeptides isolated from plant strains, micro-
organisms and marine species. Some of these are
pseudopeptides like cyclosporine,1 dolastatin,2 didemnin3
etc. exhibiting highly interesting therapeutic profiles.4 In-
corporation of a-N-methylamino acids into strategic posi-
tions of peptides leads to an enhanced proteolytic
stability, to an increase in lipophilicity and to profound
conformational changes.5 Therefore, they are valuable
building blocks for the synthesis of peptidomimetics and
combinatorial chemistry. Furthermore, certain a-N-meth-
ylamino acids themselves have been found to be biologi-
cally active in their own right.6 Consequently, a number of
synthetic routes to optically pure a-N-methylamino acids
have been developed.4, 7, 8
Recently we have shown that hexafluoroacetone (HFA) is
Scheme 2
a useful reagent for the simultaneous protection of the
amino and the carboxylic group of a-amino acids.9 The
protected carboxylic group turned out to be stabile against
a wide range of electrophilic reagents, however, the
carboxylic group is activated towards nucleophiles.
Therefore, deprotection of the carboxylic group and the a-
amino group can be achieved simultaneously under mild
conditions. Nucleophilic ring opening reactions of the ox-
azolidinones are always coupled with the deprotection of
the a-amino group.
Since compounds 4 are carboxylic group activated species
they can be readily transformed into acid hydrochlorides,
ester hydrochlorides and hydroxamic acids, respectively.
a-Amino hydroxamic acid derivatives are a class of ami-
no acid analogs of current interest.11 To our knowledge a-
N-methylamino hydroxamic acids have not been de-
scribed so far.
Solvents were purified and dried prior to use. Reagents were used as
purchased. Melting points (uncorrected) were determined on a Boe-
tius hot plate. Optical rotations were measured on a Polartronic pola-
rimeter (Schmidt & Haensch) in a 5 cm cell. For C, H, N analyses a
CHNO-Rapid-Elemental-Analyser (Hereaus) was used. Mass spectra
were recorded on a VG 12-250 (Masslab) electron ionization spec-
trometer (EI = 70 eV) or by GC/MS on a HP5890 MSD spectrometer.
IR spectra were obtained using a Specord spectrometer (Carl Zeiss,
Scheme 1
1
Jena). H (200.041 or 300.075 MHz), 13C (50.305 or 75.462 MHz)
and 19F NMR (188.205 or 282.33 MHz) spectra were recorded on a
Varian Gemini 2000 or a Varian Gemini 300 spectrometer. TMS was
used as reference standard for 1H and 13C NMR spectra (internal) and
TFA for 19F NMR spectra (external).
We now report on a preparatively simple stereoconserva-
tive route to a-N-methylamino acid derivatives starting
from hexafluoroacetone protected a-amino acids 2. In a
three component condensation compound 2, paraformal-
dehyde and thionyl chloride react - without any solvent -
to give the a-N-chloromethyl compounds 3 in nearly
quantitative yield. The progress of the reaction can be
monitored by 19F NMR spectroscopy. Compounds 3 were
treated without further purification with triethylsilane/tri-
fluoroacetic acid.10 The transformation 3 ® 4 is an exo-
3-Chloromethyl-2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-ones 3;
General Procedure:
A mixture of 2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-ones12
2
(20 mmol) and paraformaldehyde (1.20 g, 40 mmol) was stirred in
SOCl2 (5 mL) at 60°C until gas evolution ceased (l-5 h). The progress
of the reaction was monitored by 19F NMR spectroscopy. After re-
moval of the excess of SOCl2, the residue was distilled in vacuo. The
reaction mixture of 3 can be used without any purification for N-me-
thermic process. Purification of 4 can be achieved by thylation to give 4 (Table 1).

Table 1. Compounds 2–4 Prepared
Pro-
R1
R2
NR
Yield
(%)
bp
(°C)/Torr
[a]D25
(c, CHCl3)
IR (film) 1H NMR (CDCl3/TMS)
13C NMR (CDCl3/TMS), d
19F NMR (CDCl3),
ducta
n C=O
d, J (Hz)
db
(cm–1)
NR
H-4
NR
C-4
C-2
C-5
CF3
2a
2b
CH3
(CH3)2CH
H
H
H
H
98
98
54/12
74/13
+14.4 (1.3) 1823
–2.22 (4.1) 1823
3.00 (br s)
2.95 (br s)
4.01 (m)
3.86 (t, J=4.8)
–
–
50.9
60.1
88.8 (m) 172.8
88.4 (m) 170.8
–2.97 (br s)
–2.71 (q, J=8.3)
–2.38 (q, J=8.3)
–2.82 (br s)
2c
2d
(CH3)2CHCH2
H
H
Ph
H
H
95
95
85/15
72/0.3
–3.81 (4.2) 1818
–68.3 (2.4) 1825
2.98 (d, J=7.0)
3.42 (d, J=6.0)
3.87 (m)
4.99 (d, J=6.4)
–
–
53.0
58.7
88.5 (m) 172.1
88.4 (m) 170.0
–2.55 (q, J=8.0)
–2.36 (q, J=8.0)
–0.65 (q, J=8.7)
3.23 (q, J=8.7)
0.74 (q, J=7.7)
3.46 (q, J=7.7)
–0.33 (q, J=9.0)
3.48 (q, J=9.0)
0.54 (q, J=9.0)
3.46 (q, J=9.0)
–1.29 (q, J=8.0)
4.24 (q, J=8.0)
–0,68 (q, J=7.7)
4.38 (q, J=7.7)
–1.02 (q, J=8.0)
4.37 (q. J=8.0)
–0.50 (q, J=7.6)
4.25 (q, J=7.6)
3a
3b
3c
3d
4a
4b
4c
4d
CH3
H
CH2C1 83
CH2C1 87
CH2C1 87
CH2C1 91
65/11
+30.9 (1.1) 1844
5.22 (d, J=12.2) 4.22 (q, J=6.4)
5.39 (d, J=12.2)
5.18 (d, J=12.2) 4.10 (d, J=3.2)
5.38 (d, J=12.2)
5.20 (d, J=12.4) 4.18 (m)
5.37 (d, J=12.4)
4.87 (d, J=12.1) 5.15 (s)
5.35 (d, J=12.1)
58.1
58.5
58.6
57.9
32.5
32.3
33.2
33.3
51.0
59.6
53.3
59.6
56.3
64.3
59.3
65.5
88.5 (m) 169.1
87.4 (m) 167.4
87.7 (m) 169.0
87.5 (m) 166.6
89.9 (m) 170.8
88.9 (m) 167.7
90.0 (m) 170.6
89.9 (m) 167.7
(CH3)2CH
(CH3)2CHCH2
H
H
88–90/8
42/0.36
+35 (1.0)
1841
1844
1848
H
+105 (1.7)
Ph
H
65–67/0.01 –209 (1.5)
CH3
CH3
CH3
CH3
CH3
67
75
85
83
53/12
+32 (1.02) 1843
+36 (1.06) 1837
2.72 (q, J=1.6)
3.59 (d, J=6.6)
3.45 (d, J=2.0)
3.55 (t, J=4.8)
4.54 (s)
(CH3)2CH
(CH3)2CHCH2
H
H
87/23
2.70 (m)
H
89–90/21
44–46/0.05
+44 (2.3)
120 (1.1)
1840
1847
2.70 (q, J=2.2)
2.68 (q, J=2.3)
Ph
a Satisfactory microanalyses obtained: C+ 0.46, H ± 0.43, N ± 0.35,
b CF3CO2H was used as the external standard.

January 1998
SYNTHESIS
69
Scheme 3
Table 2. Compounds 5 Prepared
Pro-
duct
Yield mp (°C)
(%)
[a]D
1H NMR (D2O/TMS), d, J (Hz)
13C NMR (D2O/TMS), d
found
reported
found reported
NCH3
H-2
NCH3
C-2
CO2H
5a
5b
5c
5d
84
70
95
81
146–152 165.5–16613 +5.9a +5.7713
2.59 (s)
2.59 (s)
2.58 (s)
2.47 (s)
3.82 (m)
3.63 (m)
3.76 (m)
4.78 (s)
31.1
2.9
34.5
31.2
56.8
67.4
62.6
64.6
172.5
171.1
174.6
170.7
143–145 14914
+29b
+25.514
139–142
–
+20.5c +21.68
–108d –8715
209–211 24115
a c=6, H2O.
c c=9, H2O.
b c=2, EtOH. d c=1.49, 1 N HCl.
Table 3. Compounds 6 Prepared
Pro- Yield mp (°C)
duct (%)
[a]D
1H NMR (CDCl3/TMS), d, J (Hz)
13C NMR (CDCl3/TMS), d
found
reported
8216
found
reported
NCH3
OCH3
H-2
NCH3 OCH3 C-2 C=O
6a
6b
6c
6d
71
72
75
87
82–83
+1a
–316
+3018
+31.420
–
2.61 (s)
3.70 (s)
3.97 (m)b
3.60 (m)
3.74 (m)
4.95 (m)
31.2 54.1 56.7 171.1b
33.2 53.3 67.6 167.8
34.4 56.5 62.5 173.4
31.0 53.1 64.4 168.5
139–141 140–14117
+35c
+34d
–132e
2.77 (t, J=5.4) 3.85 (s)
2.68 (s) 3.78 (s)
2.61 (t, J=5.2) 3.77 (s)
131
127–12819
169–173 155–15621
a c=2, EtOH.
d c=1, EtOH.
b Recorded in D2O.
e c=1, 1 N HCl.
c c=1, EtOH.
Table 4. Compounds 7 Prepared
Pro-
duct (%)
Yield mp (°C)
[a]D25
1H NMR, d, J (Hz)
13C NMR, d
IR (KBr)
MS (m/z)
n C=O (cm–1) M+
NCH3
H-2
NCH3
C-2
C=O
7a
7b
7c
7d
85
91
79
72
149–l52
172–173
186–187
179
–20d
+30e
+40f
–140g
2.33 (s)
2.51 (s)
2.15 (s)
2.17 (s)
3.27 (m)b
3.16 (m)b
2.76 (m)c
3.89 (s)c
33.8
34.9
34.0
34.9
56.5
68.9
59.4
66.1
170.7c
168.2b
170.7c
169.7c
1645
1620
1619
1623
118
146
160
180
a Satisfactory microanalyses obtained: C ± 0.11, H ± 0.39, N ± 0.24. e c=1, 1 N HCl.
b Recorded in D2O.
c Recorded in DMSO-d6.
d c=1, H2O.
f c=1, 3 N HCl.
g c=1, 1 N HCl.
2,2-Bis(trifluoromethyl)-3,4-dimethyl-1,3-oxazolidin-5-one (4a):
To a mixture of 3a (5.7 g, 20 mmol) and diphenylmethylsilane (4.8
g, 24 mmol), was added CF3CO2H (4 mL) with stirring. An exother-
mal reaction started immediately! The mixture was stirred until gas
evolution ceased (0.5 h). Then the volat1le compounds were distilled
off (0.05 Torr/25 °C) and collected in a trap at –196°C. The distillate
was dissolved in CH2Cl2 (50 mL), treated with ice / water mixture (2 ´
25 mL) and satd NaHCO3 solution until the organic phase was neu-
tral. After drying (MgSO4) and evaporation of the solvent the residue
was distilled in vacuo (Table 1).

70
Papers
SYNTHESIS
2,2-Bis(trifluoromethyl)-3-methyl-1,3-oxazolidin-5-ones 4b–4d;
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To a mixture of 3 (20 mmol) and Et3SiH (2.8 g, 24 mmol) was added
CF3CO2H (4 mL) with stirring. An exothermic reaction started imme-
diately! The mixture was stirred until gas evolution ceased (0.5 h) and
distilled in vacuo (Table 1).
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