Synthesis of chiral N-trifluoroacetyl-methionine derivatives and applying them as acyl donors for Friedel-Crafts acylation

Article abstract of DOI:10.24820/ark.5550190.p010.815

A chiral N-protected -amino acid N-hydroxysuccinimide ester (OSu) is a common useful reagent for peptide bond formation. Recently, N-trifluoroacetyl (TFA) -amino acid OSu esters have been reported as acyl donors for Frieldel–Crafts reactions to synthesize

Full text of DOI:10.24820/ark.5550190.p010.815

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2019, part v, 0-0
Synthesis of chiral N-trifluoroacetyl-methionine derivatives and applying them as
acyl donors for Friedel-Crafts acylation
Natsumi Kurokawa, Yurika Tokoro, Zetryana Puteri Tachrim, Haruna Wakasa, Yasuko Sakihama,
Yasuyuki Hashidoko, and Makoto Hashimoto*
Division of Applied Science, Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
E-mail: hasimoto@abs.agr.hokudai.ac.jp
Received 11-16-2018
Accepted 12-20-2018
Published on line 01-20-2019
Abstract
A chiral N-protected -amino acid N-hydroxysuccinimide ester (OSu) is a common useful reagent for peptide
bond formation. Recently, N-trifluoroacetyl (TFA) -amino acid OSu esters have been reported as acyl donors
for Frieldel–Crafts reactions to synthesize chiral -amino phenyl ketones retaining the configurations of the
starting -amino acids. There are few reports for chiral TFA protected methionine, which has methylthioethyl
structure in the side-chain of the -amino acid. The detailed synthesis of chiral TFA-Met-OSu and its
application as an acyl donor for Friedel–Crafts acylation is reported.
Keywords: Trifluoroacetamide, -amino acid, N-hydroxysuccinimide ester, Friedel–Crafts acylation, -amino
phenyl ketone
DOI: https://doi.org/10.24820/ark.5550190.p010.815
Page 1
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
Introduction
Chiral N-protected α-amino aryl-ketones are often used as precursors in the synthesis of various biologically
active compounds.1,2 The most favourable strategy to synthesize α-amino aryl-ketone is by Friedel–Crafts
acylation3 of arenes, which is known as a reliable method that results in satisfactory product yields4 and can
utilize convenient optically pure α-amino acid derivatives as skeletons.5 N-Hydroxysuccinimide ester (OSu)
derivatives of α-amino acids have high storage stability6 and have sufficient reactivity with amines under
moderate conditions for peptide synthesis.7 This utility indicated that -amino acid OSu derivatives may act as
acyl donors for Friedel–Crafts reactions. Protecting groups for the N-terminal are one of the important factors
to achieve the reactions. The Boc protecting group, which is commonly used for peptide formation in the solid
phase, is unstable in the presence of a Lewis acid. Fmoc and Z protecting groups, which are stable under acidic
condition, react easily as acyl acceptors in the Friedel–Crafts acylation. Acetyl protecting group sometimes
promote racemization during the reaction. The trifluoroacetyl group, which is moderately stable in acid
conditions and easily deprotected under alkaline conditions, is one of the most suitable amine protecting
groups for Friedel–Crafts acylation.8 Methionine, which has methylthioethyl structure in the side-chain, would
afford very rare structures, chiral -amino -methylthioethyl phenyl ketones, from Friedel–Crafts acylation,
but only few examples of the synthesis of TFA protected methionine derivatives, including both L- and D-
isomers, have been reported. The detailed synthesis of TFA-Met derivatives and application of them for
Friedel–Crafts acylations are reported in this paper.
Results and Discussion
There are several methods for trifluoromethylation of chiral L-methionine L-1 by S-ethyl
trifluoroacetate/NaOH,9 methyl trifluoroacetate/1,1,3,3-tetramethylguanidine10 and trifluoroacetic
anhydride/trifluoroacetic acid.11 Ethyl trifluoroacetate is utilized commonly as a trifluoroacetylating reagent
with various bases, sodium methoxide, potassium methoxide12 and triethylamine.13 Triethylamine is an easier
base to handle than the metal methoxides, however the paper13 did not give details of the synthesis (chemical
yield, optical rotation, etc.). Furthermore, trifluoromethylation of D-methionine (D-1) has not been reported.
Chiral methionine L-/D-1 were seaparetly subjected to trifluoroacetylation with ethyl trifluoroacetate (1.3 eq)
and triethylamine (1.5 eq) in methanol at rt to afford chiral TFA-Met-OH L- and D-2 in near quantitative yields.
The optical rotation of the L- and D-isomers of TFA-Met-OH was found to be +30.0 and -30.0 in CHCl3,
respectively. To date, an N-hydroxysuccinimide ester of chiral TFA-Met had not been reported. Chiral TFA-
Met-OH and N-hydroxysuccinimide (1.6 eq) were reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (WSCD HCl, 1 eq) at rt in CH2Cl2 to afford chiral TFA-Met-OSu L-/D-3 with good yields (Scheme 1).
Scheme 1. Synthesis of chiral TFA-Met-OSu (L- and D-3).
Page 2
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
It has been reported that chiral TFA--amino acid-OSu was subjected to Friedel–Crafts acylation with AlCl3
(3 eq) in benzene at 70 °C afforded TFA- -amino acid-Ph with moderate yield.8 The chirality of the amino acid
skeleton was retained during the reaction using four isoleucine isomers (L- and D-isoleucine and L- and D-allo-
isoleucine). Similarly, TFA-L-Met-OSu L-3 was treated under the identical conditions (AlCl3, 3 eq, 70 °C, 120
min) for Friedel–Crafts acylation to afford TFA-Met-Ph L-4 but in less than 10% yield (Table 1, Entry 1).
Improvement of chemical yield of L-4 was observed by increasing the amount of AlCl3 (Table 1 Entry 2). A
lower temperature (40 °C and rt) with six equivalents of AlCl3 also improved the chemical yield (Table 1,
Entries 3 and 4). Detailed analysis indicated that the reaction time can be shortened to 40 minutes at rt.
Changing the amount of acyl acceptor did not improve the selectivity (Table 1, entries 4, 5, 8 and 9). Increasing
the amount of AlCl3 at rt improved the chemical yield of Friedel–Crafts acylation. Finally, 48 equivalents of
AlCl3 afforded 84% of L-4 selectively at rt (Table 1, entry 10). The large excess of AlCl3 required for the Friedel–
Crafts acylation to give TFA-L-Met-Ph L-4 might be due to coordination of the AlCl3 to the lone pairs of the
starting material L-3. TFA-D-Met-OSu D-3 was also reacted in benzene with established condition to afford TFA-
D-Met-Ph D-4 in good yield.
Table 1. Friedel-Crafts acylation of TFA-Met-OSu L-3 with benzene
Temp
(°C)
AlCl3
(eq)
3
Time
(min)
120
120
120
40
benzene
(mL)
4.5
Yield
(%)
10
Entry
1
2
70
40
6
4.5
31
3
6
4.5
40
4
6
4.5
48
5
6
40
18
43
6
12
24
36
36
48
40
18
57
7
rt
40
18
71
8
40
4.5
72
9
40
18
74
10
40
18
84
In Table 2, Lewis acids were screened for Friedel–Crafts acylation utilizing TFA-L-Met-OSu L-4. In the
presence of 48 equivalents of Lewis acid, AlCl3 is superior for conducting the reaction compared with AlBr3,
GaCl3, GaBr3, TiCl3, TiBr4 and FeCl3. Other Lewis acids did not afford a Friedel–Crafts acylated product (Table 2).
Page 3
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
Table 2. Screening of Lewis acid for the Friedel-Crafts acylation of L-3 with benzene
Lewis
acid
L-4 Yield
Lewis
acid
L-4 Yield
(%)
84
65
57
16
17
19
(%)
0
AlCl3
AlBr3
GaCl3
GaBr3
TiCl4
TiBr4
SnCl4
ZnCl2
ZrCl4
InCl3
InBr3
FeCl3
0
9
0
0
14
Figure 2. Friedel-Crafts acylation of various aromatics with TFA-Met-OSu (L- or D-3).
Chiral TFA-Met-OSu L- and D-3 were used for Friedel–Crafts acylation of several aromatics. Reaction with
toluene (5) afforded an acyl product mainly at the p-position (9) with respect to the methyl group. Main
products from xylenes (6-8) are based on the orientations of methyl substitutions. There is no big difference
for the reactivity between chiral centers. Other isomers 9, 10 and 11 were detected less than 5% by NMR
analysis.
Conclusions
Synthetic details of chiral trifluoroacetyl protected methionine and their N-hydroxysuccinimide derivatives are
reported. These derivatives are utilized as acyl donor for Friedel–Crafts acylation to form -trifluoroacatamide
-methylthioethyl phenyl ketone derivatives in good yields. Excess amounts of Lewis acid are needed to
perform Friedel–Crafts acylation due to coordination between the Lewis acid and the lone pairs of TFA-
methionine derivatives. These derivatives of methionine will be utilized not only for peptide and protein
chemistry but also for other thioether chemistry in further work.
Page 4
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
Experimental Section
General. All reagents used were analytical grade. FTIR spectra were recorded on a FT-IR 4100 spectrometer
(JASCO, Tokyo, Japan). NMR spectra were measured by a EX 270 spectrometer (JEOL, Tokyo, Japan). Optical
rotations were measured at 23 °C on a JASCO DIP370 polarimeter (JASCO, Tokyo, Japan). HRMS-ESI spectra
were obtained with a Waters UPLC ESI-TOF mass spectrometer (Waters, Milford, CT, USA).
(S)-6-(Methylthio)-2-(2,2,2-trifluoroacetamido) hexanoic acid (L-2). To L-methionine L-1 (500 mg, 3.35 mmol)
in dry MeOH (1.68 mL), Et3N (508 mg, 5.03 mmol) was added at rt. After the reaction mixture was stirred for
15 min at rt, ethyl trifluoroacetate (619 mg, 4.36 mmol) was slowly added at same temperature. The reaction
mixture was stirred overnight at rt. After H2O (100 mL) and 12 M HCl (4 mL) were added, the reaction mixture
was stirred 15 min at rt. The reaction mixture was partitioned between water and EtOAc. The organic layer
was washed with brine, dried over MgSO4, filtered and concentrated. The residue was precipitated by
1
petroleum ether to give a colorless solid (791 mg, 79 %). H-NMR (270 MHz, CDCl3) δ: 4.81 (1H, dd, J 12.5, 7.3
Hz), 2.60 (2H, m), 2.28 (2H, m), 2.13 (3H, s). 13C-NMR (67.8 MHz, CDCl3) δ: 174.9, 157.4 (q, 2JCF 38.2 Hz), 115.5
1
(q, JCF 289.4 Hz), 51.9, 30.0, 29.7, 15.2. [α]D +30.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for
C7H11F3NO3S+ 246.0406, found 246.0415.
1
Compound D-2 was obtained from D-methionine D-1 in the same manner as L-2 (97 %). H-NMR (270 MHz,
CDCl3) δ: 4.81 (1H, dd, J 12.4, 7.1 Hz), 2.59 (2H, m), 2.28 (2H, m), 2.11 (3H, s). 13C-NMR (CDCl3) δ: 174.8, 157.8
(q, 2JCF 37.6 Hz), 115.9 (q, 1JCF 287.3 Hz), 52.4, 30.4, 30.1, 15.5. [α]D -30.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+H]+
calcd for C7H11F3NO3S+ 246.0406, found 246.0392.
2,5-Dioxopyrrolidin-1-yl (S)-6-(methylthio)-2-(2,2,2-trifluoroacetamido)hexanoate (L-3). To TFA-L-methionine
L-2 (200 mg, 0.816 mmol) and N-hydroxysuccinimide (156.4 mg, 1.36 mmol) in dry CH2Cl2 (8.2 ml), 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSCD･HCl, 156.4 mg, 0.816 mmol) in dry CH2Cl2 (8.2
ml) was added on ice. The reaction mixture was stirred 2 at rt and partitioned between water and CH2Cl2. The
organic layer was washed with brine, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The
1
residue was precipitated by petroleum ether to give colorless solid (242 mg, 87 %). H-NMR (270 MHz, CDCl3)
13
δ: 7.56 (1H, br s), 5.18 (1H, dd, J 13.2, 6.9 Hz), 2.84 (4H, s), 2.68 (2H, m), 2.30 (2H, m), 2.11 (3H, s). C-NMR
(67.8 MHz, CDCl3) 168.8, 166.3, 157.0 (q, 2JCF 38.0 Hz), 115.4 (q, 1JCF 288.3 Hz), 50.3, 30.4, 29.4, 25.5, 15.1. [α]D
-13.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+Na]+ calcd for C11H13F3N2NaO5S+ 365.0389, found 365.0381.
Compound D-3 was obtained from D-2 in the same manner as L-3 (86 %). 1H-NMR (270 MHz, CDCl3) δ: 7.65 (1H,
13
br s), 5.12 (1H, dd, J 12.9, 7.3 Hz), 2.79 (4H, s), 2.63 (2H, m), 2.26 (2H, m), 2.07 (3H, s). C-NMR (67.8 MHz,
CDCl3) δ: 168.6, 166.4, 157.0 (q, 2JCF 38.0 Hz), 115.5 (q, 1JCF 288.8 Hz), 50.3, 30.5, 29.4, 25.5, 15.2. [α]D +13.0 (c
1.0, CHCl3). HRMS-ESI (m/z) [M+Na]+ calcd for C11H13F3N2NaO5S+ 365.0389, found 365.0387.
(S)-2,2,2-Trifluoro-N-(6-(methylthio)-1-oxo-1-phenylhexan-2-yl) acetamide (L-4). To TFA-L-methionine-OSu L-
3 (57.5 mg, 0.168 mmol) in benzene (4.5 ml, 1.01 mmol), AlCl3 (1.07 g, 8.02 mmol) was added at rt. The
reaction mixture was stirred 40 min at rt and partitioned between water and EtOAc. The organic layer was
washed with H2O, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was purified
1
by column chromatography (EtOAc: n-hexane, 1:1) to give colorless solid (43.2 mg, 84 %). H-NMR (270 MHz,
CDCl3) δ: 7.94 (2H, d, J 7.6 Hz), 7.57 (2H, t, J 7.6 Hz), 7.44 (2H, t, J 7.6 Hz), 5.72 (1H, td, J 7.6, 4.0 Hz), 2.43 (2H,
2
m), 2.21 (1H, m), 1.94 (3H, s), 1.87 (1H, m). 13C-NMR (67.8 MHz, CDCl3) δ: 196.3, 156.9 (q, JCF 36.9 Hz), 134.5,
133.3, 129.0, 128.7, 115.7 (q, J 288.8 Hz), 53.6, 32.4, 29.8, 15.40. [α]D +27.0 (c 1.0, CHCl3). HRMS-ESI (m/z)
[M+Na]+ calcd for C13H14F3NNaO2S+ 328.0590, found 328.0604.
Page 5
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
Compound D-4 was obtained from D-3 in the same manner as L-4 (83 %). 1H-NMR (270 MHz, CDCl3) δ: 7.94 (2H,
d, J 7.4 Hz), 7.57 (1H, t, J 7.4 Hz), 7.44 (2H, t, J 7.4 Hz), 5.72 (1H, td, J 7.7, 3.8 Hz), 2.43 (2H, m), 2.23 (1H, m),
13
2
1.94 (3H, s), 1.87 (1H, m). C-NMR (67.8 MHz, CDCl3) δ: 196.3, 156.9 (q, JCF 37.6 Hz), 134.5, 133.3, 129.0,
128.7, 115.7 (q, JCF 287.8 Hz), 53.6, 32.4, 29.8, 15.3. [α]D -27.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+Na]+ calcd
for C13H14F3NNaO2S+ 328.0590, found 328.0583.
1
(S)-2,2,2-Trifluoro-N-(4-(methylthio)-1-oxo-1-(p-tolyl)butan-2-yl)acetamide (L-9). To TFA-L-methionine-OSu L-
3 (57.5 mg, 0.168 mmol) in toluene (5, 5.4 ml, 1.01mmol), AlCl3 (1.07 g, 8.02 mmol) was added at rt. The
reaction mixture was stirred 40 min at rt and partitioned between water and EtOAc. The organic layer was
washed with H2O, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was purified
by column chromatography (EtOAc: hexane = 1: 3) to give pale yellow solid (L)-9 (40.1 mg, 75 %). 1H-NMR (270
MHz, CDCl3) δ: 7.93 (2H, d, J 8.2 Hz), 7.71 (1H, br s), 7.33 (2H, d, J 8.2 Hz), 5.78 (1H, td, J 7.7, 3.7 Hz), 2.60-2.47
(2H, m), 2.44 (3H, s), 2.29 (1H, m), 2.04 (4H, s), 1.95 (1H, m). 13C-NMR (67.8 MHz, CDCl3) δ: 195.8, 156.9 (q, 2JCF
1
37.8 Hz), 145.8, 130.7, 129.7, 128.8, 115.7 (q, JCF 287.5 Hz), 53.5, 32.6, 29.8, 21.7, 15.4. [α]D +28.0 (c 1.0,
CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for C14H17F3NO2S+ 320.0927, found 320.0925.
Compound D-9 was obtained from D-3 in the same manner as L-9 (71 %). 1H-NMR (270 MHz, CDCl3) δ: 7.92 (2H,
d, J 8.2 Hz), 7.58 (1H, br s), 7.34 (2H, d, J 8.2 Hz), 5.75 (1H, td, J 7.5, 4.1 Hz), 2.54 (2H, m), 2.45 (5H, s), 2.35-2.26
13
2
(1H, m), 2.04 (3H, s), 1.97 (1H, dd, J 13.8, 5.9 Hz). C-NMR (67.8 MHz, CDCl3) δ: 195.8, 157.0 (q, JCF 37.4 Hz),
145.9, 130.7, 129.9, 128.9, 115.7 (q, 1JCF 288.3 Hz), 53.5, 32.8, 29.8, 21.8, 15.5. [α]D -28.0 (c 1.0, CHCl3). HRMS-
ESI (m/z) [M+H]+ calcd for C14H17F3NO2S+ 320.0927, found 320.0922.
(S)-N-(1-(3,4-Dimethylphenyl)-4-(methylthio)-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide (L-10). To TFA-L-
methionine-OSu L-3 (57.5 mg, 0.168 mmol) in o-xylene (6, 6.1 ml, 1.01mmol), AlCl3 (1.07 g, 8.02 mmol) was
added on rt. The reaction mixture was stirred 40 min at rt and partitioned between water and EtOAc. The
organic layer was washed with H2O, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The
residue was purified by column chromatography (EtOAc: hexane = 1: 3) to give light yellow solid L-10 (41.1 mg,
74 %). 1H-NMR (270 MHz, CDCl3) δ: 7.79 (1H, s), 7.75 (1H, d, J 7.9 Hz), 7.55 (1H, br s), 7.28 (1H, d, J 7.9 Hz), 5.75
13
(1H, td, J 7.5, 4.1 Hz), 2.48 (2H, m), 2.34 (6H, s),2.30 (1H, m), 2.04 (3H, s), 1.96 (1H, m). C-NMR (67.8 MHz,
2
1
CDCl3) δ: 196.0, 156.9 (q, JCF 37.6 Hz), 144.6, 137.6, 131.1, 130.3, 129.8, 126.5, 115.7 (q, JCF 288.1 Hz), 53.5,
32.3, 29.8, 20.1, 19.7, 15.40. [α]D +21.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+
334.1083, found 334.1057.
1
Compound D-10 was obtained from D-3 in the same manner as L-10 (73 %). H-NMR (270 MHz, CDCl3) δ: 7.79
(1H, s), 7.75 (1H, d, J 8.2 Hz), 7.56 (1H, br s), 7.28 (1H, d, J 8.2Hz), 5.75 (1H, td, J 7.5, 4.1 Hz), 2.48 (2H, m), 2.34
13
2
(6H, s), 2.04 (3H, s), 1.96 (1H, m). C-NMR (67.8 MHz, CDCl3) δ: 196.0, 157.0 (q, JCF 38.5 Hz), 144.6, 137.7,
1
131.2, 130.3, 129.8, 126.5, 115.7 (q, JCF 290.0 Hz), 53.5, 32.8, 29.8, 20.1, 19.7, 15.4. [α]D -22.0 (c 1.0, CHCl3).
HRMS-ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+ 334.1083, found 334.1074.
(S)-N-(1-(2,4-Dimethylphenyl)-4-(methylthio)-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide (L-11). To TFA-L-
methionine-OSu L-3 (57.5 mg, 0.168 mmol) in m-xylene (7, 6.1 ml, 1.01mmol), AlCl3 (1.07 g, 8.02 mmol) was
added on rt. The reaction mixture was stirred 40 min at rt and partitioned between water and EtOAc. The
organic layer was washed with H2O, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The
residue was purified by column chromatography (EtOAc: hexane = 1: 3) to give dark green liquid L-11 (43.5 mg,
78 %). 1H-NMR (270 MHz, CDCl3) δ: 7.69 (1H, d, J 8.2 Hz), 7.58 (1H, s), 7.16-7.12 (2H, m), 5.65 (1H, td, J 7.6, 4.3
Hz), 2.52 (3H, s), 2.46 (3H, t, J 7.7 Hz), 2.39 (4H, s), 2.28-2.16 (2H, m), 1.99 (3H, s), 1.92 (2H, dd, J 14.2, 6.3 Hz).
2
1
13C-NMR (CDCl3) δ: 199.0, 157.8 (q, JCF 38.0 Hz), 144.9, 141.4, 134.4, 131.2, 130.3, 127.7, 116.6 (q, JCF 288.8
Hz), 55.8, 33.0, 30.5, 22.4, 22.3, 16.3. [α]D +11.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+
334.1083, found 334.1055.
Page 6
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
1
Compound D-11 was obtained from D-3 in the same manner as L-11 (72 %). H-NMR (270 MHz, CDCl3) δ: 7.69
(1H, d, J 8.2Hz), 7.60 (1H, br s), 7.14 (2H, m), 5.66 (1H, td, J 7.5, 4.4 Hz), 2.51 (3H, s), 2.45 (2H, m), 2.39 (3H, s),
13
2.24 (1H, m), 1.99 (3H, s), 1.92 (1H, m). C-NMR(CDCl3) δ:198.2, 157.0 (q, 2JCF 37.2 Hz) 144.1, 140.6, 133.6,
1
130.4, 129.5, 126.8, 115.8 (q, JCF 286.0 Hz), 55.0, 32.2, 29.7, 21.5, 21.5, 15.4. [α]D -11.0 (c 1.0, CHCl3). HRMS-
ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+ 334.1083, found 334.1064.
(S)-N-(1-(2,5-Dimethylphenyl)-4-(methylthio)-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide (L-12). To TFA-L-
methionine-OSu L-3 (57.5 mg, 0.168 mmol) in p-Xylene (8, 6.1 ml, 1.01mmol), AlCl3 (1.07 g, 8.02 mmol) was
added on rt. The reaction mixture was stirred 40 min at rt and partitioned between water and EtOAc. The
organic layer was washed with H2O, NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The
residue was purified by column chromatography (EtOAc: hexane = 1: 3) to give colorless solid L-12 (42.3 mg, 76
1
%). H-NMR (270 MHz, CDCl3) δ: 7.65 (1H, br s), 7.57 (1H, s), 7.28 (1H, d, J 7.2 Hz), 7.20 (1H, d, J 7.2 Hz), 5.68
13
(1H, td, J 7.5, 4.1 Hz), 2.48 (2H, m), 2.46 (3H, s), 2.38 (3H, s), 2.21 (1H, s), 1.98 (3H, s), 1.92 (1H, m). C-NMR
2
1
(CDCl3) δ: 199.1, 157.0 (q, JCF 37.6 Hz), 136.8, 135.8, 133.7, 133.3, 132.4, 129.5, 115.8 (q, JCF 287.5 Hz), 55.3,
31.7, 29.8, 20.8, 15.3. [α]D +6.0 (c 1.0, CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+ 334.1083, found
334.1086.
1
Compound D-12 was obtained from D-3 in the same manner as L-12 (72 %). H-NMR (270 MHz, CDCl3) δ: 7.56
(1H, s), 7.29 (1H, d, J 7.6 Hz), 7.21 (1H, d, J 7.6 Hz), 5.66 (1H, td, J 7.3, 4.3 Hz), 2.48 (2H, m), 2.47 (3H, s), 2.39
13
2
(3H, s), 2.20 (1H, m), 1.99 (3H, s), 1.91 (1H, m). C-NMR (67.8 MHz, CDCl3) δ: 199.0, 157.0 (q, JCF 37.4 Hz),
1
136.8, 135.8, 133.7, 133.2, 132.4, 129.4, 115.7 (q, JCF 288.6 Hz), 55.2, 31.7, 29.7, 20.8, 15.3. [α]D -6.0 (c 1.0,
CHCl3). HRMS-ESI (m/z) [M+H]+ calcd for C15H19F3NO2S+ 334.1083, found 334.1081.
Acknowledgements
Zetryana Puteri Tachrim thanks LPDP (Indonesia Endowment Fund for Education) for financial support. This
research was partially supported by the Ministry of Education, Science, Sports, and Culture Grant-in-Aid for
Scientific Research (C), (17K0194007 to Makoto Hashimoto). Part of this work was performed under the
Cooperative Research Program of “Network Joint Research Center for Materials and Devices”.
Supplementary Material
Nuclear magnetic resonance (1H and 13C NMR) figures for all synthetic compounds are available online.
References
1. Di Gioia, M. L.; Leggio, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G. J. Org. Chem. 2001, 66, 7002.
https://pubs.acs.org/doi/abs/10.1021/jo010414q
2. Nordlander, J. E.; Payne, M. J.; Njoroge, F. G.; Balk, M. A.; Laikos, G. D.; Vishwanath, V. M. J. Org. Chem.
1984, 49, 4107.
https://pubs.acs.org/doi/abs/10.1021/jo00196a001
3. Olah, G. A. Friedel-Crafts and Related Reactions, Volume 1; Interscience Publishers-John Wiley & Sons,
Inc.: London and Beccles, UK, 1963.
Page 7
©ARKAT USA, Inc

Arkivoc 2019, v, 0-0
Kurokawa, N. et al.
4. Tachrim, Z. P.; Wang, L.; Murai, Y.; Yoshida, T.; Kurokawa, N.; Ohashi, F.; Hashidoko, Y.; Hashimoto, M.
Catalysts 2017, 7, 40.
https://doi.org/10.3390/catal7020040
5. Wang, L.; Murai, Y.; Yoshida, T.; Okamoto, M.; Tachrim, Z. P.; Hashidoko, Y.; Hashimoto, M. Molecules
2014, 19, 6349.
https://doi.org/10.3390/molecules19056349
6. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am. Chem. Soc. 1964, 86, 1839.
https://pubs.acs.org/doi/abs/10.1021/ja01063a037
7. Joullie, M. M.; Lassen, K. M. Arkivoc 2010, (8), 189.
http://dx.doi.org/10.3998/ark.5550190.0011.816
8. Tachrim, Z. P. ; Oida, K.; Ikemoto, H.; Ohashi, F.; Kurokawa, N.; Hayashi, K.; Shikanai, M.; Sakihama, Y.;
Hashidoko, Y.; Hashimoto, M. Molecules 2017, 22, 1748.
https://doi.org/10.3390/molecules22101748
9. Wuensch, E.; Drees, F.; Jentsch, J.; Volk, A., Chem. Ber. 1965, 98, 803.
https://doi.org/10.1002/cber.19650980317
10. Steglich, W.; Hinze, S. Synthesis 1976, 6, 399.
https://doi.org/10.1055/s-1976-24057
11. Weygand, F.; Geiger, R. Chem. Ber. 1956, 89, 647.
https://doi.org/10.1002/cber.19560890312
12. Jass, P. A.; Rosso, V. W.; Racha, S.; Soundararajan, N.; Venit, J. J.; Rusowicz, A.; Swaminathan, S.; Livshitz,
J.; Delaney, E. J. Tetrahedron 2003, 59, 9019.
https://doi.org/10.1016/j.tet.2003.02.002
13. Wang, K.; Lu, Y.; Ishihara, K. Chem. Commun. 2018, 54, 5410.
https://doi.org/10.1039/C8CC02558D
Page 8
©ARKAT USA, Inc