Notes
J . Org. Chem., Vol. 62, No. 3, 1997 727
Ta ble 1. P r ep a r a tion of Tr iflu or oa ceta m id es 2
compd
R1
R2
reaction time (h)
solvent
temp (°C)
isolated yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
H
H
H
H
H
2-phenylethyl
4-methylbenzyl
2-methylbutyl
tert-butyl
1-(hydroxymethyl)benzyl
2-naphthyl
p-nitrophenyl
2-isopropylphenyl
4-(phenylamino)phenyl
-(CH2)5-a
4
4
3
3
5
3
3
4
5
6
6
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O
rt
rt
rt
rt
rt
rt
rt
rt
rt
39
39
100
92
97
95
90
93
90
92
92
89
85
2j
2k
Et
phenyl
a
Piperidyl.
Ta ble 2. P r ep a r a tion of Tr iflu or oa ceta te Ester s 3
crude product was obtained. Recrystallization or column chro-
matography of the crude compound gave pure product.
a
compd
R
time (h)
isolated yield (%)
N -[(R )-(+)-r-P h e n y le t h y l]-2,2,2-t r iflu o r o a c e t a m id e
(2a ): beige solid; mp 95-97 °C [lit.14 mp 97-98 °C]; 1H NMR
(CDCl3) δ 1.55 (d, 3 H, J ) 7.0 Hz), 5.06-5.16 (m, 1 H), 6.88 (br
s, 1 H), 7.29-7.39 (m, 5 H); 1H NMR (C6D6 + Eu) δ 1.02 (d, 3 H,
J ) 6.9 Hz), 5.20-5.40 (m, 1 H), 6.48 (br s, 1 H), 6.96-7.10 (m,
3a
3b
3c
3d
3e
3f
benzyl
4-methylbenzyl
cyclohexyl
3
3
3
4
3
95
92
80 (100)b
54 (100)b
79 (100)b
94
pentyl
1
5 H); 13C NMR (CDCl3) δ 20.9, 49.8, 115.8 (q, J C-F ) 286.2 Hz,
2,2-dimethylpropyl
4-chlorophenyl
4-nitrophenyl
6
16
CF3), 126.1, 128.0, 128.9, 141.0, 156.3 (q, 2J C-F ) 37.1 Hz, CdO).
N-[(RS)-r-P h en yleth yl]-2,2,2-tr iflu or oacetam ide (2a′): 1H
NMR (C6D6 + Eu) δ 1.07 (d, 3 H, J ) 6.9 Hz), 1.08 (d, 3 H, J )
6.9 Hz), 5.20-5.40 (m, 1 H), 6.48 (br s, 1 H), 6.96-7.10 (m, 5
H).
3g
60c
All reactions carried out in boiling THF. GC yield. c NMR
a
b
yield.
N-(4-Meth ylben zyl)-2,2,2-tr iflu or oa ceta m id e (2b): white
solid; mp 100-102 °C; 1H NMR (CDCl3) δ 2.33 (s, 3 H), 4.40 (s,
1 H), 4.42 (s, 1 H), 7.02 (br s, 1 H), 7.10-7.19 (m, 4 H); 13C NMR
dride forms trifluoroacetic acid as a byproduct which can
initiate several side reactions.3 (4) Good selectivity:
when a compound contains both amino and hydroxy
groups, the reagent selectively trifluoroacetylated at the
amino group. In a molecule with both primary amino
and secondary amino groups, trifluoroacetylation only
occurred at the primary amino group.
In a conclusion, (trifluoroacetyl)benzotriazole is a
convenient trifluoroacetylation reagent due to its facile
preparation, easy handling, and stability. We believe this
novel trifluoroacetylation reagent will be widely applied
in protection and activation of functional groups in
organic and bioorganic synthesis.
1
(CDCl3) δ 21.0, 43.6, 115.9 (q, J C-F ) 285.8 Hz, CF3), 127.9,
129.6, 132.9, 138.0, 157.2 (q, 2J C-F ) 36.8 Hz, CdO). Anal. Calcd
for C10H10F3NO: C, 55.30; H, 4.64; N, 6.45. Found: C, 55.35;
H, 4.59; N, 6.41.
N-(2-Meth ylbu tyl)-2,2,2-tr iflu or oa ceta m id e (2c): yellow
1
oil [lit.15 bp 115 °C/11 mmHg]; H NMR (CDCl3) δ 0.93 (d, 3 H,
J ) 6.9 Hz), 0.94 (t, 3 H, J ) 7.2 Hz), 1.14-1.29 (m, 1 H), 1.38-
1.49 (m, 1 H), 1.65-1.73 (m, 1 H), 3.13-3.20 (m, 1 H), 3.26-
3.32 (m, 1 H), 8.02 (br s, 1 H); 13C NMR (CDCl3) δ 10.6, 16.4,
26.6, 34.3, 45.5, 116.0 (q, 1J C-F ) 285.5 Hz, CF3), 157.8 (q, 2J C-F
) 36.5 Hz, CdO).
N-ter t-Bu tyl-2,2,2-tr iflu or oa ceta m id e (2d ): yellow solid;
mp 44 °C [lit.16 mp 44-45 °C]; 1H NMR (CDCl3) δ 1.33 (s, 9 H);
13C NMR (CDCl3) δ 27.8, 52.7, 115.6 (q, 1J C-F ) 287.3 Hz, CF3),
2
Exp er im en ta l Section
156.2 (q, J C-F ) 35.6 Hz, CdO).
N-(2-P h en ylet h a n -1-ol)-2,2,2-t r iflu or oa cet a m id e (2e):
white solid; mp 128-130 °C; H NMR (DMSO-d6) δ 4.10-4.15
(m, 2 H), 5.36-5.38 (m, 1 H), 5.53 (br s, 1 H), 7.71-7.78 (m, 5
H), 10.23 (br s, 1 H); 13C NMR (DMSO-d6) δ 56.5, 63.8, 116.1 (q,
1J C-F ) 286.2 Hz, CF3), 126.9, 127.5, 128.4, 139.2, 156.3 (q, 2J C-F
) 35.6 Hz, CdO). Anal. Calcd for C10H10F3NO2: C, 51.50; H,
4.32; N, 6.01. Found: C, 51.56; H, 4.28; N, 6.72.
Melting points were measured on
a Bristoline hotstage
1
microscope and are uncorrected. 1H NMR spectra were recorded
at 300 MHz with tetramethylsilane (TMS) as an internal
reference. 13C NMR spectra were recorded at 75 MHz with the
solvent peak (CDCl3, δ ) 77.0 or DMSO, δ ) 39.5) as a reference.
19F NMR spectra were recorded at 282 MHz with R,R,R-
trifluorotoluene (δ ) -63.00) as an internal reference. THF was
distilled from sodium benzophenone prior to use.
N-(2-Naph th yl)-2,2,2-tr iflu or oacetam ide (2f): mauve solid;
mp 146 °C [lit.17 mp 146-148 °C]; 1H NMR (CDCl3) δ 7.43-
7.52 (m, 3 H), 7.74-7.85 (m, 3 H), 8.18 (br s, 1 H), 8.16-8.28
P r ep a r a tion of (Tr iflu or oa cetyl)ben zotr ia zole. To a
solution of benzotriazole (11.9 g, 0.1 mol) in THF (dried, 100
mL) was added slowly trifluoroacetic anhydride (30.5 g, 0.15 mol)
at room temperature under nitrogen. The formed mixture was
stirred at rt for 0.5 h. After removal of the solvent, excess of
anhydride, and byproduct trifluoroacetic acid, a white solid was
obtained in quantitative yield.
1
(m, 1 H); 13C NMR (CDCl3) δ 115.8 (q, J C-F ) 287.0 Hz, CF3),
118.3, 119.5, 126.1, 127.0, 127.7, 127.9, 129.3, 131.5, 132.4, 133.4,
2
155.0 (q, J C-F ) 36.3 Hz, CdO).
N-(4-Nitr op h en yl)-2,2,2-tr iflu or oa ceta m id e (2g): yellow
1
solid; mp 152 °C [lit.7 mp 151-152 °C]; H NMR (DMSO-d6) δ
7.91-7.95 (m, 2 H), 8.23-8.26 (m, 2 H), 11.74 (br s, 1 H); 13C
NMR (DMSO-d6) δ 115.5 (q, 1J C-F ) 286.7 Hz, CF3), 121.0, 124.7,
1-(Tr iflu or oa cetyl)ben zotr ia zole (1): white solid, mp 89-
1
91 °C; H NMR (CDCl3) δ 6.99-7.07 (m, 1 H), 7.09-7.17 (m, 1
2
142.4, 144.0, 155.0 (q, J C-F ) 37.6 Hz, CdO).
H), 7.46-7.49 (m, 2 H); 13C NMR (CDCl3) δ 113.6, 115.0 (q, 1J C-F
) 285.3 Hz, CF3), 120.5, 127.5, 130.6, 131.5, 145.2, 154.2 (q, 2J C-F
) 43.0 Hz, CdO). 19F NMR (CDCl3) δ 70.07. Anal. Calcd for
C8H4F3N3O: C, 44.66; H, 1.87; N, 19.53. Found: C, 43.75; H,
2.37; N, 19.12.
N-(2-Isop r op ylp h en yl)-2,2,2-t r iflu or oa cet a m id e (2h ):
brown solid; mp 84-86 °C; 1H NMR (CDCl3) δ 1.17 (d, 6 H, J )
6.9 Hz), 2.95 (heptet, 1 H, J ) 6.9 Hz), 7.12-7.41 (m, 4 H), 8.23
(br s, 1 H); 13C NMR (CDCl3) δ 22.8, 28.1, 116.0 (q, 1J C-F ) 280.0
Hz, CF3), 125.2, 126.1, 126.5, 127.9, 131.1, 142.1, 155.8 (q, 2J C-F
Gen er a l P r oced u r e for Tr iflu or oa cetyla tion of Am in es.
A solution of amine (5 mmol) and (trifluoroacetyl)benzotriazole
(5.5 mmol, 1.18 g) in THF (dried, 20 mL) was stirred at room
temperature for several hours (2j and 2k were refluxed in dried
ethyl ether). Then the mixture was washed with aqueous 2 N
sodium hydroxide solution (2 × 15 mL) and extracted with ethyl
acetate (2 × 20 mL). The combined organic layers were dried
over sodium sulfate. After the removal of organic solvent, the
(14) Skulski, L.; Palmer, G. C.; Calvin, M. Roczniki Chem. 1964,
38, 789; Chem. Abstr. 1964, 61, 10568c.
(15) Pailer, M.; Hubsch, W. J . Monatsh. Chem. 1966, 97, 1541.
(16) Svirskaya, P. I.; Leznoff, C. C.; Steinman, M. J . Org. Chem.
1987, 52, 1362.
(17) Bourne, E. J .; Henry, S. H.; Tatlow, C. E. M.; Tatlow, J . C. J .
Chem. Soc. 1952, 4014.