SYNLETT0936-52141437-2096
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 418–419
spotlight
Syn lett
418
Spotlight
M. D. Norris
Matthew D. Norris
School of Chemical and Physical Sciences, Flinders University, GPO Box 2100, SA 5001,
Adelaide, Australia
[email protected]
Published online: 23.01.2015
DOI: 10.1055/s-0034-1379995; Art ID: st-2014-v0507-v
Introduction
Trifluoroacetic acid (TFA, CAS: 76-05-1, Scheme 1) is a
simple fluorinated derivative of the most elementary organic building block, acetic acid. Characterised by its strong
acidity (pKa 0.23 at 25 °C in H2O), TFA is a colourless liquid
at standard temperature and pressure with a density of
1.480 g/mL and relatively low boiling point of 71.8 °C.1
O
F3C
R
trifluoroacetic acid (TFA)
R = OH
trifluoroacetate
R = O–
R = O2CCF3 trifluoroacetic anhydride (TFAA)
Scheme 1 The trifluoroacetyl group highlighted in red and its most
common forms as a synthetic reagent.
Matthew D. Norris was born in Bedford Park,
South Australia and studied organic chemistry
at Flinders University, receiving his B.Sc. (Hons)
in 2011. He was then awarded the MF & MH
Joyner Scholarship in Science and began doctoral work as a student of Associate Professor Michael V. Perkins. Matthew also received the Australian Fulbright Alumni (WG Walker) Postgraduate Scholarship and worked with Professor Erik
J. Sorensen at Princeton University in 2014. His
research has focused on chemical synthesis and
methodology with a strong emphasis on the total synthesis of natural products.
The trifluoroacetyl group has unique chemical properties that can facilitate a wide variety of transformations often with greater efficiency, selectivity and atom economy
than methods otherwise developed. It can act as an effective acid catalyst, activate substrates to chemical fragmentation and multi-bond forming processes and complement
transition-metal catalysis as a suitable counterion.1 Importantly, TFA is cheap and readily available; non-toxic; resistant to photochemical and environmental degradation, metabolism in plants, animals and microorganisms; is highly
soluble in organic and aqueous solvents and is easily removed from chemical processes as the non-hazardous acetate salt.2 TFA is prepared industrially by the electrofluorination of acetyl chloride or acetic anhydride in anhydrous
hydrofluoric acid, followed by hydrolysis of the resulting
acid fluoride.1
Table 1 Use of Trifluoroacetic Acid (TFA)
(A) Installation and removal of protecting groups:
TFA is widely used for the installation and removal of protecting
groups by acidic condensation and hydrolysis, respectively.1 It is
commonly employed for the condensation of mono- and di-alcohols
with trichloroacetimidates, carbonyls and acetals to yield ether and
acetal protecting groups. It is also used for the catalytic or stoichiometric removal of acetals, benzyl ethers, silyl ethers, tert-butoxycarbonate esters and tert-butyl ethers and esters. TFA is often applied
in the final stages of solid-phase peptide synthesis for the global removal of protecting groups and scission of peptide substrates from
solid supports.3 This can also activate and encourage folding of the
secondary and tertiary peptide structure. The trifluoroacetate ester
itself can be installed as a non-enolisable acetyl protecting group for
alcohols, amines and thiols.4 It is typically introduced by the condensation of trifluoroacetic anhydride (TFAA) or ethyl trifluoroacetate and removed by base hydrolysis or transesterification.
CO2t-Bu
H
N
O
O
N
H
protected peptide substrate
attached to solid support
O
H
N
H
N
N
H
O
Ot-Bu
P
O
O
1. TFA, TIS, m-cresol, H2O, 90 min
2. H2O, 18 h
O
Me2N
O
CO2H
NMe2
H
N
O
O
N
H
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 418–419
H
N
O
OPO3H2
O
N
H
OH
H
N
O
OH
O
liberated peptide structure
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Trifluoroacetic Acid (TFA)
419
Spotlight
M. D. Norris
(B) Cyclisation reactions and multi-bond forming processes:
A high level of acidity and solubility in both organic and aqueous
solvents makes TFA an ideal reagent to activate polarised functional
groups and promote the generation of organic cations in solution,
which can encourage cyclisation reactions, rearrangements and
multi-bond forming processes. One of the most notable examples of
this is the acid-catalysed π-cation cyclisation of polyenes in the synthesis of steroid ring systems.5 More recently, a total synthesis of the
non-opioid analgesic conolidine was realised in a tandem imine
condensation and intramolecular Mannich reaction catalysed by
TFA.6 In another example, the unsaturated furanylidene core structure of the polyketide metabolites gracilioether B, C and spongosoritin A was constructed in a biomimetic cyclisation–dehydration
cascade.7
(C) Dehydrating agent:
Due to the stability and non-nucleophilic character of trifluoroacetate, elimination of β-hydroxy carbonyls to α,β-unsaturated systems
is easily effected with TFAA under mildly basic or neutral conditions. Whitehead8 was able to access derivatives of the manzamenone polyketide metabolites in a biomimetic dehydrative
dimerisation of (±)-untenone A by the addition of TFAA followed by
a range of external nucleophiles.
HN
N
TFA, (CH2O)n
H
MeCN, 80 °C
PMBO
OH
O
O
1. DDQ, CH2Cl2
H2O, 20 °C, 3 h
O
OMe
O
2. TFA, CH2Cl2
20 °C, 48 h
OMe
O
furanylidene core structure
(85%, 2 steps)
protected biomimetic
precursor
O
MeO2C
O
1. TFAA, CDCl3
r.t., 24 h
MeO
2
HO
+ ent
C16H33
O
H33C16
C16H33
H
CO2Me
+ ent
H
2. RH, r.t., 24 h
O
(±)-untenone A
(D) Fragmentation:
Detrifluoroacetylative fragmentation, similar to the decarboxylation
of β-keto acids, facilitates the formation of fluorinated enolate nucleophiles, which can participate in aldol reactions and α-halogenation under exceptionally mild conditions.9 Aldol reactions assisted
by pendant trifluoroacetate groups have also been developed to effect olefination yielding α,β-unsaturated carbonyl systems.10
O
R
(±)-manzamenone derivatives (10–63%)
1. LHMDS, THF
0 °C to r.t., 30 min
O
OH
CF3
2. TFAA, r.t., 20 min
K2CO3, (CH2O)n
18-crown-6, benzene
80–90 °C, 6 h
O
O
– CF3CO2–
(88%, 2 steps)
(E) Transition-metal catalysis and oxidation reactions:
Trifluoroacetate is used extensively as a counterion in transitionmetal catalysis and is often used for stoichiometric activation of
DMSO in Swern–Moffat oxidations. Recently, palladium(II) trifluoroacetate effected a Wacker–Heck cascade to establish the chroman
framework of vitamin E;11 an effective procedure for the oxidative
coupling of indoles with thallium(III) trifluoroacetate was developed;12 and a novel DMSO-mediated oxidation of isonitriles to isocyanates was demonstrated with catalytic TFAA.13
N
H + ent
(±)-conolidine (90%)
N
H
O
N
C
DMSO, TFAA (5 mol%)
O–
CF3
O
N
C
O
+
CH2Cl2, –60 °C to r.t., 5 min
94%
References and Notes
(1) For a recent and comprehensive review on synthetic applications of TFA, see: López, S. E.; Salazar, J. J. Fluorine Chem. 2013,
156, 73.
(2) Han, C.; Kim, E. H.; Colby, D. A. Synlett 2012, 23, 1559.
(3) Eberhard, H.; Seitz, O. Org. Biol. Chem. 2008, 6, 1349.
(4) López, S. E.; Restrepo, J.; Salazar, J. Curr. Org. Synth. 2010, 7, 414.
(5) (a) Johnson, W. S.; Semmelhack, M. F.; Sultanbawa, M. U. S.;
Dolak, L. A. J. Am. Chem. Soc. 1968, 90, 2994. (b) Johnson, W. S.;
Gravestock, M. B.; McCarry, B. E. J. Am. Chem. Soc. 1971, 93,
4332.
(6) Tarselli, M. A.; Raehal, K. M.; Brasher, A. K.; Streicher, J. M.;
Groer, C. E.; Cameron, M. D.; Bohn, L. M.; Micalizio, G. C. Nat.
Chem. 2011, 3, 449.
(7) Norris, M. D.; Perkins, M. V. Tetrahedron 2013, 69, 9813.
(8) Doncaster, J. R.; Etchells, L. L.; Kershaw, N. M.; Nakamura, R.;
Ryan, H.; Takeuchi, R.; Sakaguchi, K.; Sardarian, A.; Whitehead,
R. C. Bioorg. Med. Chem. Lett. 2006, 16, 2877.
(9) (a) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133,
5802. (b) John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163.
(10) Riofski, M. V.; John, J. P.; Zheng, M. M.; Kirshner, J.; Colby, D. A. J.
Org. Chem. 2011, 76, 3676.
(11) Tietze, L. F.; Stecker, F.; Zinngrebe, J.; Sommer, K. M. Chem. Eur. J.
2006, 12, 8770.
(12) Keller, P. A.; Yepuri, N. R.; Kelso, M. J.; Mariani, M.; Skelton, B.
W.; White, A. H. Tetrahedron 2008, 64, 7787.
(13) Le, H. V.; Ganem, B. Org. Lett. 2011, 13, 2584.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 418–419
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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