A convenient trifluoroacetylation reagent: N- (trifluoroacetyl)succinimide

Article abstract of DOI:10.1055/s-1999-3667

N-(Trifluoroacetyl)succinimide, easily prepared from trifluoroacetic anhydride and succinimide forms a novel, convenient trifluoroacetylating reagent. It trifluoroacetylates alcohols, phenols and mines, to generate trifluoroacetate esters, and trifluoroacetamides in excellent yields with very efficient work up procedures.

Full text of DOI:10.1055/s-1999-3667

SHORT PAPER
55
A Convenient Trifluoroacetylation Reagent: N-(Trifluoroacetyl)succinimide
Alan R. Katritzky,* Baozhen Yang, Guofang Qiu, Zhongxing Zhang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax: +1(352)3929199; E-mail: Katritzky@chem.uß.edu
Received 3 April 1998; revised 21 May 1998
sis. Attempts to obtain pure N-(trifluoroacetyl)-
succinimide by adding excess trifluoroacetic anhydride to
the reaction mixture or by recrystallization were unsuc-
cessful. The crude crystalline product can be stored in a
sealed bottle for several weeks at 5¡C without decompo-
sition and used directly for trifluoroacetylations.
Abstract: N-(Trifluoroacetyl)succinimide, easily prepared from
trifluoroacetic anhydride and succinimide forms a novel, conve-
nient trifluoroacetylating reagent. It trifluoroacetylates alcohols,
phenols and amines, to generate trifluoroacetate esters, and trifluo-
roacetamides in excellent yields with very efficient work up proce-
dures.
Key words: N-(trifluoroacetyl)succinimide, trifluoroacetylating re-
agent, trifluoroacetate esters, trifluoroacetamides
Trifluoroacetylation of alcohols or phenols with N-(triflu-
oroacetyl)succinimide (1) was carried out at reflux in tet-
rahydrofuran or toluene. After the reaction was finished,
the precipitated byproduct (succinimide) was filtered off,
and solvent was then removed to give the trifluoroacetate
esters 2aÐf in excellent yields. The trace of succinimide
Trifluoroacetylation has many uses in the protection and
1
activation of functional groups. Recently, we have re- present in the products 2 can be removed by extracting
ported trifluoroacetylbenzotriazole as a convenient novel with dry diethyl ether and evaporating the filtrate after re-
2
trifluoroacetylation reagent for amines and alcohols.
Continuing our research work on this area, we found that
N-(trifluoroacetyl)succinimide is an easily prepared, crys-
talline solid trifluoroacetylating reagent with a unique ad-
vantage: the byproduct of the reaction, succinimide is a
solid sparingly soluble in most organic solvents and there-
fore easily removed from the reaction mixture.
moval of undissolved succinimide. The results are sum-
marized in Scheme 2 and Table 1.
The only previous literature report of N-(trifluoro-
3
acetyl)succinimide is its formation by oxidation of N-(tri-
Scheme 2
fluoroacetyl)pyrrolidine with ruthenium tetroxide. To the
best of our knowledge, no one has prepared N-(trifluoro-
acetyl)succinimide by the simple reaction of succinimide
and trifluoroacetic anhydride, and no one has used it as tri- Compound
fluoroacetylating reagent. Bergeron et al. protected
primary amines using N-(trifluoroacetoxy)succinimide
Table 1 Synthesis of Trifluoroacetates 2
R
Solvent
Time (h) Yield
%)
(
2
2
2
a
b
c
n-C H
37
menthyl
(1S)-endo-(–)-bornyl THF
THF
THF
5
10
10
12
5
95
86
95
92
99
96
18
which is prepared from N-hydroxysuccinimide and triflu-
oroacetic anhydride; this reagent needs to be stored in
4
benzene solution in a freezer. We now report a simple 2d
3-pentadecylphenyl
1-naphthyl
4-nitrophenyl
THF
toluene
toluene
procedure for N-(trifluoroacetyl)succinimide and its abil- 2e
2f
10
ity to trifluoroacetylate alcohols, phenols and amines.
N-(Trifluoroacetyl)succinimide (1) was obtained by reac-
tion of trifluoroacetic anhydride with succinimide in dry N-(Trifluoroacetyl)succinimide also reacts with amines to
tetrahydrofuran at room temperature overnight (Scheme generate trifluoroacetamides 3 in excellent yields as
1
). The succinimide gradually dissolved as the reaction shown in Scheme 3 and Table 2. The workup procedure is
took place. After the removal of the solvent and byproduct again very simple: direct filtration of the succinimide
trifluoroacetic acid, a white solid was obtained which con- byproduct and removal of the solvent.
tains 10% succinimide as determined by H NMR analy-
1
Scheme 1
Scheme 3
Synthesis 1999, No. 1, 55Ð57 ISSN 0039-7881 © Thieme Stuttgart · New York

5
6
A. R. Katritzky et al.
SHORT PAPER
Table 2 Synthesis of Trifluoroacetamides 3
Trifluoroacetylation of Alcohols or Phenols; General Proce-
dure
Compound
R
R'
Time (h) Yield
%)
A solution of alcohol or phenol (5 mmol) and N-(trifluoro-
acetyl)succinimide (8 mmol) in anhyd THF or toluene (20 mL) was
(
stirred under reflux for several hours under N . After cooled down,
2
3
3
3
3
3
3
3
3
a
b
c
d
e
f
2-phenylethyl
4-methylbenzyl
benzyl
H
H
benzyl
10
12
12
12
12
12
12
12
88
83
83
87
91
92
91
86
the solid precipitated and was filtered off. Then, the solvent was re-
moved, the product, trifluoroacetate ester 2 was obtained.
1-piperidinyl
Octadecyl Trißuoroacetate (2a)
t-Bu
phenyl
phenyl
4-nitrophenyl
H
ethyl
H
Colorless oil; yield: 1.74 g (95%).
1
H NMR: δ = 0.88 (t, J = 6.9 Hz, 3H), 1.15Ð1.40 (m, 30H), 1.69Ð
g
h
1
.78 (m, 2H), 4.34 (t, J = 6.3 Hz, 2H).
H
13C NMR: δ = 14.0, 22.7, 25.5, 28.2, 29.1, 29.2, 29.4, 29.5, 29.7,
2.0, 68.3, 114.6 (q, J = 283.9 Hz), 157.6 (q, J = 41.7 Hz).
3
We have already pointed out that N-(trifluoroacetyl)ben-
C
20
H
37
O
2
F
3
calcd
C
65.52
65.16
H
10.18
10.16
zotriazole has significant advantages over previously (366.5)
found
available trifluoroacetylation reagents. N-(Trifluoro-
acetyl)succinimide (1) as a trifluoroacetylation reagent Menthyl Trifluoroacetate (2b)
shares many of these advantages: (i) ease of preparation, Colorless oil; yield: 1.08 g (86%).
1
H NMR: δ = 0.79 (d, J = 6.8 Hz, 3H), 0.92Ð0.95 (m, 6H), 1.04Ð
as described above, reagent 1 can easily be prepared from
succinimide and trifluoroacetic anhydride at room tem-
perature; (ii) ease of handling, as solid 1 can be stored in
a covered bottle for several weeks and weighted out in air;
1
1
.21 (m, 2H), 1.49Ð1.58 (m, 2H), 1.70Ð1.77 (m, 2H), 1.80Ð1.88 (m,
H), 2.02Ð2.08 (m, 1H), 4.88 (dt, J = 11.0 and 4.5 Hz, 1H).
13C NMR: δ = 16.1, 20.4, 21.7, 23.5, 26.3, 31.4, 33.9, 40.1, 46.8,
9.3, 114.2 (q, J = 284.1 Hz), 157.1 (q, J = 41.3 Hz).
7
(iii) ease of workup, as the only byproduct, succinimide is
C H O F
2 3
calcd
C
57.11
56.55
H
7.59
7.66
1
2
19
precipitated and can be filtered off due to its low solubility
in most of solvents; (iv) safe and unambiguous reaction:
the only byproduct formed is unreactive; (v) when N-(tri-
fluoroacetyl)benzotriazole is used for trifluoroacetylation,
the byproduct benzotriazole is most conveniently re-
moved by washing with aqueous sodium hydroxide. Our
new reagent 1 is advantageous for the preparation of tri-
fluoroacetate esters which are easily hydrolyzed in aque-
ous solution.
(
252.1)
found
(
1S)-endo-(Ð)-Bornyl Trifluoroacetate (2c)
Colorless oil; yield: 1.19 g (95%).
1
H NMR: δ = 0.88 (s, 3H), 0.91 (s, 3H), 0.93 (s, 3H), 1.12 (dd, J =
1
4.0 and 3.2 Hz, 1H), 1.24Ð1.44 (m, 2H), 1.72Ð1.96 (m, 3H), 2.38Ð
.50 (m, 1H), 5.10 (dd, J = 9.6 and 2.3 Hz, 1H).
2
13C NMR: δ = 13.2, 18.7, 19.6, 26.8, 27.8, 36.2, 44.8, 48.1, 49.2,
4.9, 114.6 (q, J = 285.9 Hz), 157.8 (q, J = 42.0 Hz).
8
In a conclusion, N-(trifluoroacetyl)succinimide (1) is a
convenient, practical, and useful trifluoroacetylation re- 250.1183.
agent due to its ease of preparation, handling and workup.
+
HRMS (EI): m/z calcd for C H O F : 250.1181 (M ). Found:
12
17
2 3
Especially for the preparation of high molecular weight 3-Pentadecylphenyl Trifluoroacetate (2d)
Colorless oil; yield: 1.84 g (92%).
trifluoroacetate esters, N-(trifluoroacetyl)succinimide has
1
H NMR: δ = 0.88 (t, J = 6.9 Hz, 3H), 1.15Ð1.40 (m, 24H), 1.55Ð
.68 (m, 2H), 2.63 (t, J = 7.7 Hz, 2H), 7.00Ð7.05 (m, 2H), 7.13 (d,
unique advantages and should be widely applied in organ-
ic and bioorganic synthesis.
1
J = 7.5 Hz, 1H), 7.30Ð7.38 (m, 1H).
13C NMR: δ = 14.0, 22.7, 29.2, 29.4, 29.5, 29.6, 29.7, 31.1, 31.3,
32.0, 35.7, 35.9, 114.6 (q, J = 283.8 Hz), 117.6, 120.3, 127.3, 129.5,
145.4, 149.5, 155.8 (q, J = 42.7 Hz).
Mps were measured with a Koefler hot stage apparatus without cor-
1
13
rection. The H NMR and C NMR spectra were recorded on a
Varian Gemini (300 MHz and 75 MHz respectively) spectrometer
C H O F
2 3
calcd
C
68.96
69.29
H
8.81
8.95
23
35
1
in CDCl or DMSO-d with TMS as the internal standard for H and
3
6
1
3
(400.5)
found
solvent as the internal standard for C. Elemental analyses were
performed using a Carlo Erba 1106 elemental analyzer. HRMS was
measured on an AEI-30 mass spectrometer.
1
-Naphthyl Trifluoroacetate (2e)
Colorless oil; yield: 1.20 g (99%).
1
H NMR: δ = 7.31Ð7.36 (m, 1H), 7.37Ð7.44 (m, 1H), 7.48Ð7.54 (m,
Preparation of N-(Trifluoroacetyl)succinimide (1)
To a solution of succinimide (9.8 g, 0.1 mol) in anhyd THF
2
H), 7.72Ð7.78 (m, 1H), 7.79Ð7.87 (m, 2H).
13C NMR: δ = 114.9 (q, J = 284.0 Hz), 117.2, 120.1, 125.1, 125.5,
127.0, 127.3, 127.4, 128.1, 134.7, 145.0, 155.9 (q, J = 43.1 Hz).
(100 mL) was added slowly trifluoroacetic anhydride (30.5 g, 0.15
mol) at rt under N . The mixture was stirred overnight until no solid
2
was in the solution. After removal of the solvent, excess of anhy-
dride and byproduct TFA, a white solid was obtained, which con-
tained 10% succinimide as determined by H NMR.
C H O F
2 3
calcd
C
59.99
59.82
H
2.94
3.41
12
7
1
(240.0)
found
1H NMR: δ = 2.95 (s, 4 H).
4
-Nitrophenyl Trifluoroacetate (2f)
13C NMR: δ = 172.3, 158.0 (q, J = 43.0 Hz), 114.0 (q, J = 285.3 Hz),
2
Colorless oil; yield: 1.13 g (96%).
1
2
8.7.
H NMR: δ = 7.48 (d, J = 9.1 Hz, 2H), 8.35 (d, J = 9.1Hz, 2H).
13C NMR: δ = 114.3 (q, J = 283.6 Hz), 121.7, 125.5, 146.4, 153.3,
1
54.9 (q, J = 44.5 Hz).
Synthesis 1999, No. 1, 55Ð57 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient Trifluoroacetylation Reagent
57
+
1H NMR: δ = 1.38 (s, 9H), 6.25 (br s, 1H).
HRMS (EI): m/z calcd for C H NO F : 235.0092 (M ). Found:
8
4
4 3
2
35.0085.
13C NMR: δ = 27.8 [27.1], 53.4 [54.0], 115.6 (q, J = 286.4 Hz)
[115.5 (q, J = 286.3 Hz)], 160.1 (q, J = 39.8 Hz) [157.1 (q, J =
Trifluoroacetylation of Amines; General Procedure
3
6.1 Hz)].
A solution of amine (5 mmol) and N-(trifluoroacetyl)succinimide
(
8 mmol) in anhyd THF (20 mL) was stirred at reflux for 12 h under
N-Ethyl-N-phenyltrifluoroacetamide (3f)
Oil; yield: 1.00 g (92%) (Lit. bp 120¡C/11 Torr).
N . After cooled down, the solid was precipitated and filtered off.
Then, the solvent was removed and the product, trifluoroacetamide
3
2
2
1H NMR: δ = 1.18 (t, 3H, J = 7.1 Hz), 3.80 (q, 2H, J = 7.2 Hz), 7.20Ð
was obtained.
7
.23 (m, 2H), 7.42Ð7.44 (m, 3H).
13C NMR: δ = 11.7, 47.3, 116.3 (q, J = 285.6 Hz), 128.1, 129.2,
129.4, 138.3, 157.8 (q, J = 37.0 Hz)
N-(2-Phenylethyl)trifluoroacetamide (3a)
Solid; yield: 0.96 g (88%); mp 57Ð58¡C.
1H NMR: δ = 2.87 (t, J = 7.0 Hz, 2H), 3.57 (q, J = 6.8 Hz, 2H), 6.81
N-Phenyltrifluoroacetamide (3g)
Solid; yield: 0.86 g (91%); mp 87Ð88¡C (Lit. mp 88Ð89¡C).
(
br s, 1H), 7.18 (d, J = 6.9 Hz, 2H), 7.21Ð7.36 (m, 3H).
13C NMR: δ = 34.8, 41.0, 115.7 (q, J = 286.0 Hz), 126.7, 128.6,
28.8, 137.6, 157.3 (q, J = 37.7 Hz)
6
1H NMR: δ = 7.23 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.56
1
(
d, J = 7.9 Hz, 2H).
13C NMR: δ = 115.7 (q, J = 287.0 Hz), 120.6, 126.4, 129.3, 135.1,
55.0 (q, J = 37.0 Hz).
C H NOF calcd
C
55.28
54.99
H
4.64
4.74
N
6.45
6.11
10
10
3
(217.2)
found
1
N-(4-Methylbenzyl)trifluoroacetamide (3b)
White solid; yield: 0.96 g (83%); mp 99Ð100¡C (Lit. mp 100Ð
N-(4-Nitrophenyl)trifluoroacetamide (3h)
Yellow solid; yield: 1.01 g (86%); mp 150Ð151¡C (Lit. mp 151Ð
2
2
1
02¡C).
1H NMR: δ = 2.36 (s, 3H), 4.49 (d, J = 5.8 Hz, 2H), 6.51 (br s, 1H),
.19 (s, 4H).
13C NMR: δ = 21.0, 43.6, 115.8 (q, J = 285.8 Hz), 127.9, 129.6,
32.9, 138.0, 157.2 (q, J = 34.6 Hz).
1
52¡C).
1
H NMR (DMSO-d ): δ = 7.97 (d, J = 9.3 Hz, 2H), 8.31 (d, J =
6
7
9
.3 Hz, 2H), 11.8 (s, 1H).
1
3
C NMR (DMSO-d ): δ = 115.5 (q, J = 286.7 Hz), 121.0, 124.8,
6
1
1
42.4, 144.0, 155.0 (q, J = 37.8 Hz).
N,N-Dibenzyltrifluoroacetamide (3c)
5
Oil; yield: 1.22 g (83%) (Lit. bp 140Ð142¡C/0.4 Torr).
Acknowledgement
1H NMR: δ = 4.52 (s, 4H), 7.15Ð7.23 (m, 4H), 7.32Ð7.42 (m, 6H).
13C NMR: δ = 48.3, 49.6, 116.7 (q, J = 286.7 Hz), 127.3, 128.0,
We thank Dr. Delphine Semenzin for helpful discussion.
1
28.2, 128.3, 128.8, 129.0, 133.9, 134.5, 157.9 (q, J = 36.3 Hz).
References
1
-(Trifluoroacetyl)piperidine (3d)
(
1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
2
Oil; yield: 0.79 g (87%) (Lit. bp 77¡C/15 Torr).
Synthesis; Wiley & Sons: New York, 1991; p 353.
1H NMR: δ = 1.60Ð1.78 (m, 6H), 3.56Ð3.62 (m, 4H).
13C NMR: δ = 23.8, 25.2, 26.2, 45.2, 47.2, 116.5 (q, J = 285.3 Hz),
(2) Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem. 1997,
2, 726.
6
(3) Sheehan, J. C.; Tulis, R. W. J. Org. Chem. 1974, 39, 2264.
(4) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1988, 53, 3108.
(5) Landini, D.; Penso, M. Synth. Commun. 1988, 18, 791.
(6) Svirskaya, P. I.; Leznoff, C. C. J. Org. Chem. 1987, 52, 1362.
1
56.0 (q, J = 35.3 Hz).
N-tert-Butyltrifluoroacetamide (3e)
Yellow solid; yield: 0.77 g (91%); mp 45Ð47¡C (Lit. mp 44¡C); a
mixture of two isomers.
2
Synthesis 1999, No. 1, 55Ð57 ISSN 0039-7881 © Thieme Stuttgart · New York