Accepted Manuscript Title: Trifluoroacetic Acid: Uses and Recent Applications in Organic Synthesis Author: Sim´on E. L´opez Jos´e Salazar PII: DOI: Reference:
S0022-1139(13)00316-3 http://dx.doi.org/doi:10.1016/j.jfluchem.2013.09.004 FLUOR 8191
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Received date: Revised date: Accepted date:
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Please cite this article as: S.E. L´opez, J. Salazar, Trifluoroacetic Acid: Uses and Recent Applications in Organic Synthesis, Journal of Fluorine Chemistry (2013), http://dx.doi.org/10.1016/j.jfluchem.2013.09.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Trifluoroacetic Acid: Uses and Recent Applications in Organic Synthesis Simón E. López* and José Salazar
Ac ce
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an
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Laboratorio de Química Medicinal y Heterociclos, Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000. Venezuela
* Address correspondence: Laboratorio de Química Medicinal y Heterociclos, Universidad Simón Bolívar, Departamento de Química, Edificio de Química y Procesos, Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000, Venezuela. Tel: (+58-212)9063960; Fax: (+58-212)9063961; Email:
[email protected]
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Abstract: Trifluoroacetic acid (TFA), discovered at the early 20th century, has been widely used in organic synthesis as a solvent, catalyst and reagent. Many chemical transformations should be done with the aid of TFA, including rearrangements, functional group deprotections, oxidations, reductions,
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condensations, hydroarylations and trifluoromethylations. This review covers TFA synthetic applications, giving to the organic chemistry research community an opportunity to go in depth on
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the many diverse uses of this strong acid, water miscible and low boiling point reagent.
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Key Words: Organic synthesis, reagent, solvent, TFA, trifluoroacetic acid, trifluoromethyl group.
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Contents 1. Introduction 2. Solvent
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2.1.Solvent for atom transfer radical cyclization reactions
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2.2.Solvent for polymers and polymer processes
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3. Rearrangements 4. Protecting group removal
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4.1. Cleavage of acetal protecting groups
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4.2. Deprotection of O-triethyl silyl (O-TES; O-SiEt3) group 4.3. Deprotection of O-p-methoxyphenyl (O-PMB) group
ed
4.4. Deprotection of N-tert-butyloxycarbonyl (N-Boc) group
pt
4.5. Deprotection of N-MOM and N-MEM groups
Ac ce
4.6. Deprotection of N-benzyloxymethyl (N-BOM) group 4.7. Deprotection of t-butyl ether (O-tBu; O-Tr) group 4.8. Deprotection of N-2-Trimethylsylilethyl-carbamate (N-Teoc) group 4.9. Deprotection of O-tetrahydropyranyl (O-THP) group 5. Oxidations 6. Reductions 6.1. Reductions with silicon hydride reagents
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6.2. Reductions with boron reagents 6.2.1. Reductions with sodium borohydride 6.2.2. Reductions with sodium cyanoborohydride 6.2.3. Reductions with borane
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6.3. Other TFA-reducing agents
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6.3.1. Diisopropoxyaluminium trifluoroacetate 7. Condensations
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8. Reactions with organophosphorus reagents
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9. Hydroarylations
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10.Synthesis of trifluoromethyl building blocks and trifluoromethyl substituted compounds 11.Miscellaneous reactions
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11.1. Iodination
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11.2. Metal mediated reactions
11.3. Formylation of aromatic compounds with hexamethylenetetramine and trifluoroacetic acid.
Ac ce
The Duff reaction
12. Summary and conclusions Acknowledgements
References and notes
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1. Introduction
Trifluoroacetic acid 1 (TFA, d 1.480) is the simplest perfluoroorganic acid available, characterized by its strong acidity (pKa 0.23 at 25°C in H2O), high dielectric constant (= 42.1 at 25°C), miscibility with water and most organic solvents and relativity low boiling point (71.8°C) [1a-c]. It is perharps one of the most widely employed fine chemicals worldwide, with a production volume of more than 1-10 million pounds in 2002, only in the United States [1d]. Industrially, TFA is prepared by the electrochemical fluorination of acetyl chloride or acetic anhydride in anhydrous hydrogen fluoride using the Simons process, followed by hydrolysis of the resulting trifluoroacetyl fluoride in excellent
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yields (>90 %) [1e]. This reagent was discovered by Swarts in 1922 [2], and is widely employed in
organic synthesis as a solvent [3,6] or as an acid catalyst for different organic transformations such as solvolysis [162], rearrangements [7-18], functional group deprotections [19-39], oxidations [4044], reductions [45-96], condensations [97-104], hydroarylations [110] as well as in
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trifluoromethylation reactions [157-168]. Taking into account the importance of the CF3 substitution in organic compounds for many applications [1f], but particular in biological active
cr
molecules [1g-i] such as the marketed pharmaceuticals mefloquine (lariam®; antimalarial), fluoxetine (prozac®; anti-depressant), celecoxib (celebrex®; COX-2 inhibitor), tipranavir (aptivus®; HIV ®
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protease inhibitor) and efavirenz (sustiva ; HIV protease inhibitor) (Figure 1), as well as the usefulness of
trifluoroacetic acid as the starting material for the preparation of important trifluoroacetylating
an
agents (i.e. ethyl trifluoroacetate) [155], trifluoromethylated building blocks [106] or its key participation in trifluoromethylation procedures [157a], this review covers TFA synthetic
M
applications, evincing its versatility for organic chemistry reactions, including the introduction of a trifluoromethyl group into more complex molecules and the preparation of important intermediates
ed
for pharmaceutical and agrochemical targets.
O
F 3C
1
pt
Ac ce
CF3 N
H
CF3
H N
OH
H3C
O
OH
N N
CF3
H
NH
H 2NO2S Fluoxetine
Mefloquine
OH
O
CF3
H N
Celecoxib
SO2 Cl
O
CF3 Tripanavir
F3 C O N H
O
Efavirenz
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Figure 1. CF3 containing marketed pharmaceutical compounds. 2. Solvent The high dielectric contant, miscibility with water and most organic solvents of TFA has permited its use alone or mixed as a solvent for different purposes, such as in atom transfer cyclization
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reactions and polymer processes.
2.1. Solvent for atom transfer radical cyclization reactions
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Trifluoroacetic acid has served as a remarkable solvent in atom transfer radical cyclization reactions
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(Scheme 1) [3a,b]. Apart from raising the solubility of organic substrates when compared with water for the same type of reactions [3c,d], TFA played a possible role of acid catalyst, knowing
an
these atom transfer cyclization reactions are usually promoted by Lewis acids [4,5].
O 2
M
I
O
BEt3 (0.1 equiv.) TFA (0.03 M)
O
20°C
O
I 3
pt
ed
Scheme 1. TFA as a solvent for the radical cyclization of allyl iodoacetate2 to iodo-lactone 3
Ac ce
2.2. Solvent for polymers and polymer processes Several nanofiber products containing chitosan, a natural polysaccharide derived from chitin, have been produced by electrospinning. Recently, electrospun nanofibers based on chitosan have found potential applications in various areas [6a]. An electrospun nanofibrous material of pure chitosan was successfully prepared by Ohkawa et. al. [6b] using trifluoroacetic acid as electrospinning solvent. TFA is a suitable spinning solvent for chitosan because the amino groups of the chitosan can form salts with TFA [6c], capable to destroy effectively the intermolecular interactions between the chitosan molecules facilitating electrospinning. By other hand, cellulose triacetate (CTA) forms mesophases when dissolved in TFA at the proper concentration [6d,e], dichloroacetic acid, and mixtures of TFA and dichloromethane [6e] at room temperature. Patel and Gilbert demonstrated
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that such liquid-crystalline solutions are cholesteric and forms cholesteric mesophases in trifluoroacetic acetic acid and mixtures of TFA and dichloromethane, 1,2-dichloroethane and chloroform [6f]. Polymer-stabilized cholesteric liquid crystals (PSCLCs) have been used for the development of optoelectronic devices [6g-i].
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Trifloroacetic acid is also an efficient promoter for several polymerization reactions [6j-m]. The polymerization of isobutyl vinyl ether (IBVE) was effected by initiation with trifluoroacetic acid
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[6k] in 1,2-dichloroethane and in 1,2-dichloroethane/carbon tetrachloride mixtures [6k]. This reaction was studied over a temperature range between -2,5 °C to 35°C; a proposed mechanism
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involved trifluoroacetate esters as reactive intermediates solvated by a the monomer.
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3. Rearrangements
TFA is a common catalyst for most acid-catalyst rearrangements, having the advantage of easy
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elimination through evaporation during workup because of its low boiling point. Some of these reactions include a useful acid-catalysed epoxyde ring opening for the preparation of butenolides
ed
(Scheme 2) [7], pinacol rearrangements in spiroskeletal annelations (Scheme 3) [8] and biomimetic polyene ciclizations (Scheme 4) [9].
O
pt
O
OMe
TFA, CHCl3
O
70% 5
4
Ac ce
O
Scheme 2. TFA catalyzed epoxide ring opening
O
EtO OTMS
O 6
TFA, -78 oC to rt, 81-90%
O 7
Scheme 3. Pinacol rearragement for the preparation of spiro[4.5]decane-1,4-dione 7
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TMS 0.5% TFA, CH2Cl2
H H
-35°C, 1h
H
HO 8
Scheme 4. TFA promoted biomimetic polyene cyclization
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9
cr
Rearrangements such as the acid-catalyzed Cope rearrangement of 2-acyl-1,5-dienes (Scheme 5)
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[10] and Claisen rearrangement followed by cyclization from Baylis-Hillman adducts of acrylates (Scheme 6) [11] have also been done. Interestingly, similar compounds obtained from the acetyl
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derivatives of the Baylis–Hillman adduct of acrylonitrile on treatment with trifluoroacetic acid furnished 3-arylmethyl-2-amino-quinoline after isomerization in low to medium yields (Scheme 7).
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An effective Wagner-Meerwein type rearrangement of the natural triterpene betulin 16 to allobetulin 17 has been achieved by TFA in a dichloromethane solution (Scheme 8) [12].
ed
Trifluoroacetic acid considerably increases the allyl-aryl-ether Claisen rearrangement rate [13], although the resulting allylphenols generally undergo further transformations under the acidic conditions.
The
neolignan
aurein
18
rearranges
to
2-(2-allyl-4-hydroxy-3,5-
pt
reaction
dimethoxyphenyl)-1-(3,4,5-trimethoxy-phenyl)-propane 19 promoted by trifluoroacetic acid
Ac ce
(Scheme 9) [14a]. The reaction of crotyl-tolyl-ether 22 in trifluoroacetic acid afforded cumarane 23 as the major product, resulting from the cyclization of the [3,3] rearranged product 24 (Scheme 10) [14b]. An unusual [1,3] rearrangement of aryl 2-halocyclohexenylmethyl ethers 26 promoted by trifluoroacetic acid was reported (Scheme 11), where expected products due to Claisen rearrangement were not formed [15]. When lignan arboreol 28, a natural product isolated from Gmelina arborea, was treated with TFA in nitrobenzene it produced gmelanone 29a by an acidcatalysed pinacol-type rearrangement in 80% yield, but, when treated with H2SO4 in acetic acid (1:10), it gave the acetoxyfuranone 29b, which is an acetylated cleavage product of gmelanone (Scheme 12) [16]. A Curtius type rearrangement was observed during the reaction of 4-substituted aroyl azides 30a with NaBH4 and TFA (Scheme 13) [17]. When the para-substituent was an
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electron donating group, 4-substituted N,N-di(2,2,2-trifluoroethyl)aniline derivatives 31 were isolated in excellent yields instead of the expected aminomethyl compounds. 4-Substituted aryl isocyanates 30b were shown to provide identical products under similar reaction conditions [18].
O
O
ip t
TFA, CH 2Cl2 25°C, 90 min 11
cr
10
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Scheme 5. TFA catalyzed Cope rearrangement of 2-acyl-1,5-dienes
O
TFA, 60°C EWG
8-14 h 63-93 %
12 t
R1
13
R = Ar R 1 = H; 6-Cl; 6-Br; 6-F; 6-OMe; 6-Me; 8-Me; 5,6,7-(OMe)3
ed
EWG = CO2Et, CO2 Me, CO 2Bu
NH
M
R
R
an
R1 HN
pt
Scheme 6. Claisen rearrangement followed by cyclization of Baylis-Hillman acrylate adducts
R1
Ac ce
HN
CN
R
14
NH 2 TFA, reflux
R
N
24 h 28-53 %
R1 15 R = Ar R1 = H; 6-Cl
Scheme 7. TFA promoted Claisen rearrangement followed by cyclization and isomerization of Baylis-Hillman acrylonitrile adducts.
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H H
CH 2OH
H HO
O
H TFA, CH 2Cl2
H
8 min, 22°C
H HO
H
H
16
ip t
17
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Scheme 8. Wagner-Meerwein type rearrangement of betulin 16 to allobetulin 17
OMe
OMe
OMe O
OH
OH
OMe
OMe
TFA
MeO
then water
an
OMe
MeO
MeO
+
MeO
OMe
MeO
OR
MeO OMe
M
OMe
19
R= H: 20 R= CF3CO: 21
ed
18
pt
Scheme 9. Claisen type rearrangement of neolignan aurein 18 promoted by TFA
Ac ce
O
Me OH
O Me
TFA
Me
OH
Me
+
+
rt, 14.5 h
Me 22
Me (69%)
Me (8%)
23
24
Me (8%) 25
Scheme 10. Claisen rearrangement of crotyl-tolyl-ether 22 in trifluoroacetic acid. X R3
R2
R3 O
TFA X
R1 26
R2
OH X +
CH 2Cl2, rt
R1
R2
OH X
R1 27a
27b
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Scheme 11. Unexpected [1,3] rearrangement of aryl2-halocyclohexenylmethyl ethers 26 promoted by trifluoroacetic acid.
O
O TFA
H Ar
Ar
OH Ar
H PhNO 2
O
Ar
29a
O
H 2SO 4
OH
AcOH
OAc
Ar
O 28
Ar
O H
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O
29b
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Ar= 3,4-methylenedioxyphenyl
R
Y 30 a,b
N
CF3
31 71-82%
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Y = CON 3: 30a, N=C=O : 30b R = Br, Cl, Me, MeO
CF3
R
an
NaBH4, TFA
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Scheme 12. TFA/nitrobenzene promoted pinacol type rearrengement of arboreol 28 to gmelanone 29a.
pt
ed
Scheme 13. Curtius type rearrangement during the reaction of 4-substituted aroyl-azides and isocyanates with NaBH4 and TFA.
4. Protecting group removal
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Trifluoroacetic acid has been used as the reagent of choice for the removal of nitrogen and oxygen protecting groups by solvolysis under aqueous or anhydrous conditions. Different methods for the cleavage of O- and N- protecting groups by TFA are given below.
4.1. Cleavage of acetal protecting groups A one-pot conversion of amino-acetals and acetals 32 to the corresponding homoallylic alcohols 33 has been successfully achieved by their treatment with TFA followed by tetra-allyltin (Scheme 14) [19a]. The method represents an interesting route for the efficient allylation of relative unstable aldehydes from their available and more stable acetal precursors.
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MeO
OMe
R
H
OH
a) TFA, MeOH b)
Sn
32
4
R 33 84-100%
R = Ph, PhCH 2, NH 2CH 2CH2, Boc-D-NHCHCH3
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Scheme 14. One-pot conversion of amino acetals and acetals to homoallylic alcohols
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The selective cleavage of the 2,3-O-isopropylidene group from alkyl 2,3-O-isopropylidene-5-O-
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methoxymethylfuranoside derivatives in the presence of MOM ethers using TFA has been effected [19b]. The above cleavage was selective for the 2,3-O-isopropylidene group, if oriented cis to
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the O-glycoside 34; otherwise with a trans-orientation 36, the cleavage of MOM was observed (Scheme 15).
O
O
O O
TFA, CH2Cl2
M
MOMO
MOMO
2h, rt
34
O
ed
O
35
TFA, CH2Cl2
O
pt
MOMO
OH OH O O
Ac ce
36
O
2h, rt
86% HO
OH OH O O 37 77%
Scheme 15. Selective cleavage of 2,3-O-isopropylidene group
Recently, the last step of a reported short synthesis of the commercial antiviral ganciclovir 39 was achieved by a concomitant deprotection of acetal and trityl functions of the synthetic precursor 38, using TFA in dichloromethane and subsequent reduction of the aldehyde derivative using NaBH 4 (Scheme 16) [19c].
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O
O
H 2N
1. TFA, CH 2Cl2 2. NABH4, MeOH
N
HN
EtO
N
N
OEt O
38
H 2N
73%
N
HN
N
N
OH O
39
OCPh3
OH
ip t
Scheme 16. Concommitant deprotection of ethyl-acetal and trityl groups by TFA
cr
4.2. Deprotection of O-triethyl silyl (O-TES; O-SiEt3) group
TFA has been used during the last step of scale-up semisynthesis of Paclitaxel 41 (Taxol) (Scheme
us
17) [20a]. An aqueous acetic acid soluction (AcOH-H2O; 3:1, v/v) of trifluoroacetic acid was found to be very effective for the removal of both the C-7-TES group and C-2methoxypropyl of precursor
an
40 without affecting the quality of the product. Despite 48% HF-pyridine procedure [20b] also gave
O OAc NH
Ph
O
O
OSiEt 3
2´
O
O OMe HO H BzO AcO
7
AcOH-H 2O 3:1 (v/v)
O
O
Ph Ph
OAc NH
O
O
OH
2´
O
7
OH HO H BzO AcO
O
41
pt
40
TFA
ed
Ph
M
excellent results, safety issues related to manufacturing scale precluded the latter.
Ac ce
Scheme 17. TFA for the deprotection of O-triethyl silyl group in a scale-up semisynthesis of Paclitaxel 39 (Taxol)
4.3. Deprotection of O-p-methoxyphenyl (O-PMB) group The p-methoxybenzyl ethers (R-O-PMB) have been used as acid-labile protecting groups in oligosaccharide synthesis [21a]. During the preparation of the C20-C46 segment of the macrolide phorboxazole B, precursor 42 was treated with 10% CF3CO2H in CH2Cl2, giving an easy removal of PMB protecting groups. The resultant triol cyclisized simultaneously to afford the lactone 43 (Scheme 18) [21b].
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OMe PMBO
OMe CO 2Et
HO
10% TFA/CH 2Cl2 HO
85% yield
OPMB
O
O
OH
42
43
ip t
Scheme 18. Deprotection of O-p-methoxyphenyl group by TFA
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4.4. Deprotection of N-tert-butyloxycarbonyl (N-Boc) group
The deprotection of N-Boc amines 44 was rapidly accomplished employing 5 equivalents of TFA in
us
methylene chloride using a focused microwave instrument with irradiation at 60°C for 30 min. The free base amines 45 were then obtained by scavenging the crude reaction mixture with the basic
an
ion-exchange resin Amberlyst A-21. This procedure is suitable for the parallel deprotection of
M
N-Boc amines (Scheme 19) [22].
O N H
1) 5 equiv TFA, mw, 60°C, 30 min Ot -Bu 2) 10 equiv Amberlyst A-21, 30 min
44
R NH2 45
ed
R
Scheme 19. TFA deprotection of N-Boc amines using microwave irradiation
pt
Amino ether 13 was then treated with
Addition of 5% H2O during the deprotection of the amino benzyl-ether 46 using TFA (TFA-
Ac ce
CH2Cl2-H2O) was found to be the key to prevent double bond isomerization that occurred under anhydrous acidic conditions (TFA-CH2C12) (Scheme 20) [23].
OBn
TFA, CH 2 Cl2, 5% H 2O
OBn
NHBoc 46
NH 2 47
Scheme 20. TFA deprotection N-Boc amino ethers
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TFA has been also used in the presence of thiophenol for an efficient deprotection of N-Boc groups during peptide synthesis (20°C, 1h, 100% yield) [24]. Thiophenol is used to scavenge the liberated t-butyl cations, thus preventing alkylation of methionine or tryptophan. Other scavengers such as anisole, thioanisole, cresol, and dimethyl sulfide have also been used [25]. TBDPS [26] and
ip t
TBDMS [27] groups are stable to TFA during Boc cleavage. A TFA deprotection of N-Boc has been used in a key step during the total synthesis of lyconadin A
cr
50 from (R)-5-methylcyclohex-2-enone 48 (Scheme 21) [28]. The deprotected amine was heated
us
under reflux in pyridine to induce ring expansion and formation of a C-N bond through a postulated allylic cation intermediate 49 in 96% yield.
H
Br Me
1) TFA, CH2 Cl2 , 0°C to rt.
H
2) Py, ref lux, 96%, (two steps)
H
Boc 48
H
N H
H
Br
H
H H
Me
M
N
Br
H
H
H H
an
Br H
H
Me H
N 50
ed
49
Scheme 21. TFA N-Boc deprotection during the total synthesis of lyconadin A
pt
Baldwin et al have recently described an ellegant biomimetic total synthesis of (+)-himbacine 51,
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an alkaloid isolated from the bark of Australian magnolias [29]. Treatment of butenolide intermediate 52 with trifluoroacetic acid for N-Boc deprotection, followed by an in situ condensation and iminium ion activated intramolecular Diels−Alder cycloaddition gave the (+)himbacine precursor 53 under reductive conditions (Scheme 22). Compound 53 was converted into (+)-himbacine in four additional synthetic steps. Me H
H
H
N
Me Me O
H
O 51
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Me O NH NHBoc Me Me
TFA, CH2Cl2
H
Me
H
then NaCNBH 4
O H
52
O 53
ip t
O
cr
Scheme 22. TFA N-Boc deprotection during the biomimetic total synthesis of (+)-himbacine 51
A TFA mediated N-Boc deprotection of the indolic ketone intermediate 54 followed by cyclodehydrative
us
dehydrogenation to the pyrazinone 55a (Scheme 23) was succesfully employed for unite two indole-
an
containing sectors in the total synthesis of the bis indole sponge alkaloid (±)-Dragmacinin E 55b [30].
H N
HN
NHBoc H N
O NH
O
HN
O NH
2) DDQ, 1,4-dioxane (65% yield after 2 steps) OBn
Br
N H 55a
pt
54
N
1) TFA, CH 2Cl2 ; then aq. NaHCO 3
ed
N OBn Boc
Br
H N
O
M
O
H N
Ac ce
Scheme 23. N-Boc deprotection followed by dehydrogenative cyclisation: a key step for the total synthesis of the bis indole sponge alkaloid (±)-Dragmacinin E. H N H2N
Br
N
HN
N O NH
N H
OH 55b
Perhaps the most popular use of TFA to achieve the N-Boc deprotection is that employed in peptide chemistry. High purity TFA is generally required for an efficient peptide sequencing process [31].
Page 17 of 69
Simple and effective protocols have been developed for manual and machine-assisted Boc chemistry solid phase peptide synthesis using polystyrene resins [32]. These protocols use in situ neutralization (10% DIEA in DMF), high concentrations (>0.2 M) of Boc-amino acid-OBt esters plus base for fast coupling, 100% TFA for rapid Boc group removal, and a single short (30 sec)
cr
ip t
DMF flow wash between deprotection/coupling and between coupling/deprotection of aminoacids.
4.5. Deprotection of N-MOM and N-MEM groups
us
N-MOM and N-MEM cyclic carbamates (2(3H)-benzoxazolones and 2(3H)-benzothiazolones) have
an
been efficiently deprotected using TFA under reflux (Scheme 24) [33]. To validate the usefulness of the developed methodology, it was applied for the synthesis of 6-benzoyl-2(3H)-benzothiazolone (Scheme
25), knowing that the introduction of tributyltin in the 6-position of the 2(3H)-benzothiazolone for the
M
subsequent Stille reaction could be performed only on N-methyl compounds and not on the free NH derivatives.
O
O N H
pt
N Pg
X
TFA, reflux, 4h
ed
X
Pg = MOM, X = O,S : 56 Pg = MEM, X = O,S : 57
From Pg = MOM, X = O (92%): 58 , S (96%): 59 From Pg = MEM, X = O (95%): 58, S (97%): 59
Br
Ac ce
Scheme 24. TFA removal of N-MOM and N-MEM protecting groups from cyclic carbamates
X
O
60
N H
(Bu 3Sn) 2,
MEM-Cl, K2CO3, Br
X
DMF
N MEM
O
Bu 3Sn
X O N MEM
Pd(PPh 3) 4, toluene 62
61
ClCOPh, PdCl2(PPH 3 )2, toluene O
TFA, reflux, 2h
X
O X
O 64
N H
63
O N MEM
Scheme 25. Synthesis of 6-benzoyl-2(3H)-benzothiazolone using TFA deprotection of N-MEM
Page 18 of 69
4.6. Deprotection of N-benzyloxymethyl (N-BOM) group The N1,N3-dibenzyloxymethyl derivatives of pyrimidines 65 and dihydropyrimidines 66 have been successfully deprotected by the use of trifluoroacetic acid [34]. These N-BOM derivatives can be
ip t
selectively removed from a variety of derivatives including nucleosides 67 and compounds which
O
O TFA, 72°C
N
O
N R BOM
30-45 min, 78-87% (R=CO 2Me, H)
65 TFA, 72°C
N
O
N R BOM 66 O
O
N
24 h, 100%
O
pt
AcOCH2
TFA, 25°C
N
OAc
Ac ce
AcO
N H 68 O
H
R
N
4-7 h, O 30-60% (R=CO 2Me, H, Me)
ed
BOM
O
N R H 69 O
M
BOM
N
an
O
H
us
BOM
cr
are sensitive to base and reducing conditions (Scheme 26).
67
H
N
O AcOCH2
AcO
N O
OAc 70
Scheme 26. Deprotection of N-BOM pyrimidines and dihydropyrimidines by TFA
4.7. Deprotection of t-butyl ether (O-tBu; O-Tr) group The t-butyl ether (trityl-ether) functionality is stable to most reagents except strong acids, such as trifluoroacetic acid. The O-trityl group could be removed by anhydrous TFA at 0-20°C in good yields (80-90%) [35,36]. Nicolaou et.al. employed a TFA O-t-butyl ether deprotection during the synthesis of the BCDE ring system of brevetoxin A (Scheme 27) [37].
Page 19 of 69
Me H TBDPSO
OH
PivO
Me H OAc
Me H O
H
H
O
OH
PivO
Me H OAc
Me H O
H TBDPSO
96%
OTr
H
Me
TFA, CH 2Cl2-MeOH (25:1)
H
H
O
OH
H
72
71
cr
ip t
Scheme 27. TFA O-t-butyl ether deprotection during the synthesis of the BCDE ring system of brevetoxin A.
4.8. Deprotection of N-2-Trimethylsilylethyl-carbamate (N-Teoc) group
us
The deprotection of the N-Teoc group could be achieved either using a 20% or 50% solution of
O B
Ph
CO(aa)3 NHR O
O
HN
NH
NHTeoc
O O
CH 2Cl2 90%
NHZ
O
CO(aa)3NHR O
O
HN
NH
NH 2
O
MeO 2CHN
NHZ
O O 74
ed
73
O B
Ph
M
MeO2 CHN
20% TFA,
an
TFA in dichloromethane (Schemes 28 and 29) [38].
50% TFA, CH2Cl2, Ph O°C to rt, 45 min
Ac ce
O
pt
Scheme 28. TFA N-Teoc deprotection during the synthesis of macrocylic transition state analogue inhibitors of α-Chymotrypsin.
NHTeoc 75
O
Ph Na 2HPO4, D2O, 1 min
NH 3+ CF3CO 276
Ph N 77
Scheme 29. TFA N-Teoc deprotection for the preparation of cyclic imine 77.
4.9. Deprotection of O-tetrahydropyranyl (O-THP) group TFA has been sucessfully employed for both the protection and deprotection of alcohols 78 and phenols bearing a tetrahydropyranyl group 79 (Scheme 30) [39]. The key factor for deprotection was to change the solvent from dichloromethane to methanol. The method was useful for substrates having other functionalities such as ester, nitro, aldehyde, amide and olefinic bonds.
Page 20 of 69
Dihydropyran, TFA (20% mol) CH2Cl2, rt, 45 min-3 h ROH
R
O
O
TFA (20% mol), MeOH, rt, 15--30 min
78
79
ip t
Scheme 30. TFA catalyzed protection of alcohols and phenols and deprotection of THP derivatives.
cr
5. Oxidations
Sodium percarbonate combined with TFA have been used as a replacement for trifluoroperacetic
us
acid (TFPAA) [40] in the Baeyer–Villiger reaction (Scheme 31) [41a]. Yields vary between good to excellent. The procedure is not applicable to aliphatic ketones, as TFA esters are produced from
O
an
transesterification with the solvent.
O
M
Na 2CO4, TFA 0°C, 40 min 25°C, 14h 76%
80
O
81
ed
Scheme 31. Baeyer-Villinger oxidation of benzophenone 80 using sodium percarbonate/TFA
pt
The use of household sodium percarbonate and TFA to perfom a Baeyer-Villinger oxidation of
Ac ce
cyclopentanone 82 to -valerolactone 83 has been reported (Scheme 32) [41b]. The above procedure was performed for educational purposes and TFA employed as solvent. Attempted cutting down on the quantity of TFA even by dilution with acetic acid was unsatisfactory.
O
O
+ CF3CO2H + Na 2CO3 + Na 2CO3 . 1.5 H2 O2
82
O 50% 83
Scheme 32. Sodium percarbonate/TFA for Baeyer-Villinger oxidation of cyclopentanone. Also, trifluoroacetic acid catalyzed the action of m-chloroperbenzoic acid (mcpba) in the BaeyerVillinger oxidation of cyclic and acyclic ketones (Scheme 33) [42a]. The treatment of the methyl-
Page 21 of 69
ketone 88 with mcpba-TFA underwent concurrent Baeyer-Villinger oxidation and peracid mediated acetal oxidation to give (-)-(S)-4-benzyl-2-furanone 89 (Scheme 34) [42b].
mcpba (2.6 equiv.), CH 2Cl2 TFA (1 equiv.) 0°C, 1h
O
O O
84
ip t
88% 85 mcpba (2.6 equiv.), CH 2Cl2 TFA (1 equiv.) 0°C, 8h
O
cr
O
O
75% 86
us
87
O
H
O
88
mcpba (2.6 equiv.) Ph TFA (1 equiv.), CH 2Cl2, 0°C, 10-20 min
H
H
Ph
O
O
H
O
M
H Ph
an
Scheme 33. TFA catalyzed Baeyer-Villinger oxidation of cyclic and acyclic ketones with mcpba
H+
H
H O
mcpba Ph
+ O
O
Ph
O O
O
ed
Ph O
89
Ac ce
pt
Scheme 34. Concurrent Baeyer-Villinger oxidation and peracid mediated acetal oxidation of the methyl-ketone 88. Fluorous [bis(trifluoroacetoxy)-iodo]perfluoroalkanes 91 have been prepared by the oxidation of the corresponding perfluoroalkyl iodides 90 with oxone in trifluoroacetic acid at room temperature (Scheme
35)
[43].
Trifluoroacetates
91,
were
transformed
into
their
corresponding
[hydroxy(tosyloxy)iodo]perfluoroalkanes 92, which are stable for storage at room temperature and not sensitive to light and moisture. The methodology was extended for the preparation of various [bis(trifluoroacetoxy)iodo]arenes 94, which are important hypervalent iodine reagents widely used in organic synthesis [44].
Page 22 of 69
OCOCF3 I OCOCF3
R
C nF2n+1
TFA, rt
90
R
93
0°C to rt
C nF2n+1 92
91
n = 4,6,8,10,12
ArI
TsOH H 2O, MeCN
Oxone , TFA CHCl3, rt, 1.2-4 h
OH I OTs
86-100%
OCOCF3 Ar I OCOCF3
(13 examples, up to 97 % yield)
ip t
C nF2n+1 I
Oxone
94
us
cr
Scheme 35. Preparation of Fluorous [bis(trifluoroacetoxy)-iodo]perfluoroalkanes and [bis(trifluoroacetoxy)iodo]arenes with oxone in TFA.
6. Reductions
an
Reductions with silicon [45] and boron [46] hydride reagents in trifluoroacetic acid have been
followed by delivery of a hydride.
M
performed and extensively used. Generally, the reaction involves initial protonation of the substrate
6.1. Reductions with silicon hydride reagents
ed
Tetravalent organosilicon species such as triethylsilane hydride (Et3SiH) have a very low intrinsic nucleophilicity [47], this is the reason why they react mostly with substantially electron deficient
pt
species, for example carbocations and ,-unsaturated double bonds. The combination of
Ac ce
triethylsilane hydride and trifluoroacetic acid (Et3SiH-TFA) as the reducing agent is versatile and the most common because of its application to a broad number or substrates as described below. Tertiary alcohols are easily reduced by Et3SiH-TFA, many examples should be found in the literature, such as the reduction of the tertiary alcohol intermediate 95 in 86% during the preparation of natural phosphodiesterase II (PDE-II) inhibitors analogues (Scheme 36) [48]. A large scale Et3SiH-TFA reduction of a tertiary alcohol piperidine intermediate has been employed in the parallel development of Neurokinin (NK) antagonists (Scheme 37) [49]. The alcohol is first activated as its trifluoroacetate ester and then displaced by the hydride from Et3SiH, some elimination byproduct was also observed.
Page 23 of 69
HO
N
N
EtO2 C O
HN
Et3SiH, TFA
O N
EtO2C O O N
HN
86%
CH3 95
ip t
CH3 96
OMe
us
OMe
SMe Et3 SiH, TFA
HO
cr
Scheme 36. Reduction of a tertiary alcohol intermediate during the synthesis of PDE-II inhibitors
SMe
an
78%
N CBz 98
M
N CBz 97
ed
Scheme 37. Large scale reduction of a tertiary alcohol piperidine intermediate in the parallel development of Neurokinin (NK) antagonists. Reduction of sterically congested aryl-diadamantylmethanols 99 to atropisomeric diastereomeric
pt
mixtures of the corresponding aryl-diadamantylmethanes 100-101 has been achieved with
Ac ce
Et3SiH/TFA (Scheme 38) [50]. Et
Ad Ad
Et
Et
Et
Et3 SiH, TFA, CH 2 Cl2
O
OH
99
-10°C, rt, 16 h
O 100
Et
H + Ad Ad
Ad Ad
Et O
H
101
(-) 1:1
Scheme 38. Reduction of sterically congested aryl-diadamantylmethanols.
By other hand, with the exception of benzyl alcohol itself [51], most benzylic alcohols are efficiently reduced by the combination of an acid and organosilicon hydrides [47]. Treatment of 2,4,6-tri-tert-butylbenzyl alcohol 102 with Et3SiH-TFA generates 2,4,6-tri-tertbutyltoluene 103 in 90% yield (Scheme 39) [52]. A similar reduction protocol has shown to be effective for the
Page 24 of 69
quantitative reduction
of 2-(hydroxymethyl)-1,4,6,8-tetramethylazulene
104 to 1,2,4,6,8-
pentamethylazulene 105 in 19 hours (Scheme 40) [53]. OH tBu
Et3SiH, TFA
tBu
tBu
tBu
CH 2 Cl2, 1 h 90%
tBu
102
ip t
tBu
103
Et3SiH HO
TFA, 60°C, 19 h 100%
an
104
us
cr
Scheme 39. Reduction of 2,4,6-tri-tert-butylbenzyl alcohol with Et3SiH-TFA
105
M
Scheme 40. Quantitative reduction of 2-(hydroxymethyl)-1,4,6,8-tetramethylazulene 104 to 1,2,4,6,8-pentamethylazulene 105. The stereochemistry and rate of reduction vs. elimination using a combination of different
ed
organosilane-hydrides and TFA have been described for the cis 106 and trans 107 isomers of 4-tertbutyl-1-phenylcyclohexanol (Scheme 41) [51]. Treatment of exo or endo isomers of 2-phenyl-2-
pt
norbornanol with trifluoroacetic acid and triethylsilane, triphenylsilane, or phenylsilane in
Ac ce
dichloromethane gives endo-2-phenylnorbornane 114 quantitatively (Scheme 42) [54]. Ph
OH
tBu
Ph R 3 SiH
CH 2Cl2, TFA
Ph H
tBu
+
tBu
cis 106
R = Et
108 ; 59%
109 ; 41%
t rans 107
R = Et
110 ; 78%
111 ; 22%
Scheme 41. Reduction vs elimination rate of of 4-tert-butyl-1-phenylcyclohexanol.
Page 25 of 69
Ph R3 SiH OH
0%
113
CH 2Cl2, TFA
Ph 112
100%
R = Et, Ph
ip t
Ph 114
cr
Scheme 42. Reduction of 2-phenyl-2-norbornanol with trifluoroacetic acid and tetravalent organosilicon hydrides.
us
Benzylic alcohol reduction with Et3SiH-TFA has now become a common procedure in organic chemistry, it is found in many recently examples of pharmaceutical and agrochemical important
an
intermediates preparation [55-57] and natural products synthesis [58]. Dehydroxylation of 115 using refluxing Et3SiH and TFA gave intermediate 116 in 22% yield, useful for the preparation of
ed
M
the phenyl pyridal scaffold of helical peptide mimetics (Scheme 43) [55]. Reduction of the
Et3 SiH, TFA, reflux 22%
pt
N
OH
N
OH
116
Ac ce
115
OH
Scheme 43. Dehydroxylation of a peptidemimetic synthesis intermediate using Et3SiH-TFA. benzylic alcohol 117 with TFA/Et3SiH (1:4) at 25°C gave in 69% the designed 1H-pyrazolo[3,4b]pyridine 118 as an inhibitor of cyclin-dependent kinases (Scheme 44) [56]. The positive allosteric modulator (PAM) of the metabotropic glutamate receptor 2 120 has been prepared by the reduction of the alcohol intermediate 119 in 79 % yield (Scheme 45) [57].
Page 26 of 69
OH
OnBu
OnBu
TFA/Et3SiH (1:4)
Ph
Ph
N N
N
25°C, 69%
N H
N H
N
117
118
F
O
N Cl
F N
Et 3SiH, TFA, rt, 1h
cr
O
ip t
Scheme 44. TFA/Et3SiH promoted benzylic alcohol reduction in the preparation of 1H-pyrazolo[3,4-b]pyridine derivatives.
Cl
us
79% HO OMe
OMe
120
an
119
M
Scheme 45. Reduction of an alcohol intermediate for the preparation of 1,5-disubstituted pyridone 120, a positive allosteric modulator (PAMs) of the metabotropic glutamate receptor 2. The Et3SiH-TFA reduction protocol has been succesfully employed in diverse natural product
ed
synthetic procedures, for example in the development of the Leucetta-derived group of alkaloids [58]. The above mentioned reduction was applied for the removal of the benzylic alcohol function
pt
of intermediate 121 at room temperature in the total syntheses of marine alkaloids preclathridine A 123 and clathridine A 124 (Scheme 46) [58b]. A similar approach was applied for the synthesis of
Ac ce
alkaloids naamidine G 127 (Scheme 47) [58c], isonaamine C 130 and isonaamidine E 131 (Scheme 48) [58d].
OH
N
O
N
O
Me
121
N
Et3 SiH, TFA CH 2Cl2, rt 72%
O
N
O
Me 122 O Me N
N
NH
O
H2N
N O
N
N
O
Me
O O
Me 123
124
Scheme 46. Removal of the benzylic alcohol function of intermediate 121.
Page 27 of 69
OMe OH
O
N
N
Et3 SiH, TFA
N
N
OMe CH Cl rt 2 2, 81%
Me
Me N
NH N
OMe O
Me
N
OMe
Me OMe
127
125
ip t
OMe 126
us
cr
Scheme 47. Key reduction step for the synthesis of the alkaloid naamidine G.
OH Et3 SiH, TFA
N
OMe
ed
128
OMe
OMe 129 OMe OMe
O Me N
N N
OMe
Ac ce
N
pt
N H2N
N
M
OMe CH Cl rt 2 2, 86%
N
an
N
O
HN N
OMe
130
OMe 131
Scheme 48. Dehydroxylation strategy during the synthesis of isonaamine C and isonaamidine E.
The chemoselective dehydroxylation at the benzylic position by Et3SiH-TFA has been shown by the reduction of the optically active diol 132 to the desired (+)-methyl lactate 133 (75% yield; >99% ee) (Scheme 49), a key intermediate for the convergent total synthesis of the anti-HIV natural product lithospermic acid 136 (Scheme 50) [59].
Page 28 of 69
OH O R
MeO
OMe
OH
MeO 132
O
Et3 SiH TFA
R
MeO
OMe
OH
CH 2Cl2, 0°C MeO 75%
133
O
+
COOMe
O
EDCI
O COOMe
DMAP HOBt
O
OMe O
OMe
OMe
O OMe
HO
OH
cr
O
MeO
OMe
us
133 HO
HO
MeO
OH
MeO
O
O
OMe
OMe
an
R
MeO
ip t
Scheme 49. Reduction of the optically active diol 132 to the (+)-methyl lactate 133.
135 OMe 134
O
COOH OH
O OH
OH 136
M
Scheme 50. Convergent synthesis of the anti-HIV natural product lithospermic acid 136.
ed
Examples on the reduction of hemiacetals to the corresponding ether functions have been reported. The hydroxyl acid intermediate 141 was obtained from the lactol natural product Enfumafungin 137
pt
by its reduction using Et3SiH and TFA in toluene, followed by deglycosylation in methanol under
Ac ce
the presence of sulfuric acid (Scheme 51) [60]. The Et3SiH-TFA combination reduces easily hemiacetals in the presence of a quinone moiety (Scheme 52), as shown in the synthesis of antibiotics demethoxyeleutherin 144 and nanaomycin A 145 [61].
Alkene reductions by the combination of silicon based hydrides and trifluoroacetic acid have also been performed. Most of those reductions use excess trifluoroacetic acid and triethylsilane either neat [62, 63] or in an inert solvent such as 2-nitropropane [64] or dichloromethane [54, 65], in temperatures ranging from -78°C to over 100°C, although ambient or ice-bath temperatures are
Page 29 of 69
O O
OH
O
Glu
15-28°C
H
H
O
Et3 SiH, TFA
O
OH
OH
O H
O O
HO HO
O
MeOH, H 2SO 4
O O
reflux
H
137
138
O
OH
O
OH
O H
H +
O HO
HO
H
H 139
us
140 O
OH
an
H
MeO
85% overall
O
cr
O
ip t
OH
OH
O HO H
M
141
ed
Scheme 51. Et3SiH-TFA reduction of the lactol natural product Enfumafungin.
OMe O HO
Et3SiH, TFA, CH 2Cl2
pt
O
CO 2Et
Ac ce
O 142
OMe O O
-78° to 0° C 95%
CO 2Et O 143
Scheme 52. Et3SiH-TFA reduction of hemiacetals in the presence of a quinone moiety.
O
OH
O
O
O CO 2H
O 144
O 145
Page 30 of 69
more commonly used. The combination of triethylsilane and trifluoroacetic acid with ammonium fluoride is a variant for the reduction of olefins to alkanes [66]. These reductions range from poor to excellent yields depending largely on the ability of the alkene to form carbocations upon protonation. The more substituted olefins are reduced in better yields and styrene double bonds are reduced in high yields [65, 67-69]. Reductions of olefin conjugated double bonds have also been effected [69,70], an example was
ip t
given by the treatment of progesterone 146 (Scheme 53) with triethylsilane and trifluoroacetic acid in dichloromethane followed by the saponification of the trifluoroacetate ester and Jones oxidation to yield 5--
cr
pregnanedione 147 in 65% [70]. O 1. TFA, Et3SiH, CH 2Cl2 2. H 2O, -OH H
an
3. CrO 3, acetone
us
O
O
H
O
146
147
M
Scheme 53. Reduction of progesterone to 5--pregnanedione by Et3SiH-TFA.
ed
Aminals (Scheme 54) [71] and hemiaminals (Scheme 55) [72] as well as enamines (Scheme 56) [73-75] are also reduced with Et3SiH-TFA in good yields.
pt
CO2Me N
Ac ce
N Me H HO
CO2Me
Et3SiH, TFA rt, 4 h, 79%
148
N Me H H
N
149
Scheme 54. Reduction of aminal 148 to the tertiary amine 149 by Et3SiH-TFA.
O
O
Et3SiH, TFA
MeO2C N OH 150
CHCl3, rt, 20 h, 63 %
MeO2C N Me 151
Scheme 55. Reduction of hemiaminal 150 to the tertiary amine 151 by Et3SiH-TFA.
Page 31 of 69
Cl
Cl
Me
N (CH 2) 10 CH 3 Boc
Cl
Cl
Et3SiH-TFA, -42°C
+
+
79 %
Me
152
N (CH 2) 10 CH 3 Me Boc
N (CH 2) 10 CH 3 Me Boc
N (CH 2) 10 CH 3 Boc
153
154
155
(Ratio: 153: 154: 155 = 75: 10:15)
ip t
Scheme 56. Stereoselective reduction of dihydropyridine 152 during the synthesis of alkaloid (+/-)-solenopsin A. Recently, effective reductive amination reactions were performed using polymethylhydrosiloxane (PMHS)
cr
and trifluoroacetic acid [76]. Several (het)arylprimary amines 157 were successfully alkylated by
benzaldehyde 156 using PMHS/TFA in dichloromethane giving their corresponding secondary
us
amines 158 in moderate to excellent yields (28-87%) (Scheme 57). The reaction was successful even with fully deactivated anilines such as 4-nitroaniline 159, which was alkylated with different
an
aldehydes, ketones, and a representative acetal (Scheme 58).
1) TFA, CH 2Cl2, rt, 12h
M
CHO + RNH2
2) PMHS, rt, 8-10 h 157
156
HN R 158
ed
Scheme 57. Reductive amination of (het)arylprimary amines with benzaldehyde by PMHS/TFA. O
R1 NH 2
+
2) PMHS, rt, 8-10 h
OMe
Ac ce
159
1) TFA, CH 2 Cl2, rt, 12h
or
pt
O2N
R2
Ph
40-92 %
O2 N
NH R2 160
R1
OMe
Scheme 58. Reductive amination of 4-nitroaniline with different aldehydes, ketones and (dimethoxymethyl)benzene by PMHS/TFA.
The reductive N-alkylation of primary amides, thioamides, carbamates and ureas with a variety of aromatic and aliphatic aldehydes was performed using Et3SiH-TFA (Scheme 59) [77]. The reaction was also applied to the synthesis of a primary amine from the corresponding aldehyde via the carbamate intermediate followed by deprotection.
Page 32 of 69
X
X
R´CHO
R
NH2 161
TFA, Et3 SiH 63-97%
R
N H 162
R´
X = O, S R = aryl, alkyl, RNH, RO R´= aryl, alkyl
ip t
Scheme 59. Reductive N-alkylation of primary amides, thioamides, carbamates and ureas using Et3SiH-TFA
cr
2-Aryl-1-N-carboalkoxyenamines 163 were selectively reduced to 2-arylethylamine carbamates 164 by Et3SiH-TFA in high yields (Scheme 60) [78]. The reduction proceeds through a hydride addition
R
OEt O
163
H N
Et3SiH, TFA -10°C, 92-99%
an
H N
us
at C-1 followed by a proton transfer from the TFA, which is the rate-limiting step.
R
OEt
O 164
M
Scheme 60. Reduction of 2-aryl-1-N-carboalkoxyenamines by Et3SiH-TFA.
ed
6.2. Reductions with boron reagents
6.2.1. Reductions with sodium borohydride
pt
The combination of sodium borohydride with trifluoroacetic acid provides an efficient method for the reduction of di- and triarylcarbinols to di- and triarylmethanes (Scheme 61) [79]. The method
Ac ce
could be considered as general for those alcohols whose derived carbocation is highly stabilized. Diarylketones are also reduced to diarylmethanes with NaBH4-TFA (Scheme 62) [80]. A wide range of functional groups tolerates the reaction conditions and only in the case of strong electronwithdrawing groups (e.g., p-NO2) the reaction resulted incomplete. The reaction was extended to the reduction of 1,3-azole and 1,3-benzazole carbinols provided with an additional aryl or pi-excessive heteroaryl (thienyl, benzo[b]thienyl, furyl, or benzo[b]furyl) substituent [81] and to pyridyl carbinols possessing two additional aromatic or heteroaromatic ligands for sufficient stabilization of the carbocation intermediate [82].
Page 33 of 69
OH NaBH4 CF 3CO2 H 15-20 °C 93%
COH
166a
NaBH4 CF 3CO2 H 15-20 °C 94%
3 165b
cr
166b
ip t
165a
us
Scheme 61. Reduction of di- and triarylcarbinols to di- and triarylmethanes by NaBH4-TFA.
NaBH 4
167
92 89 88 90 82 94
pt
H Me OMe OH F Br
% yield
R
CN NMe 2 NHPh CO2H CO2Me NO2
ed
R
R
M
CF3CO 2H 15-20 °C
R
an
O
168
% yield 90 82 93 73 93 43 (+57% alcohol)
Ac ce
Scheme 62. Reduction of diarylketones to diarylmethanes with NaBH4-TFA.
The reduction of amides and lactams to their corresponding amines has been performed using NaBH4-TFA (Scheme 63) [83,84], where sultams and carbamates are not affected under the employed conditions. This reaction has been applied for the reduction of indole-amide to indoleamine (Scheme 64), particularly the indole double bond is not reduced [85].
Page 34 of 69
BocHN
THF 20°C 65%
169
170
O
H N O
H N
NaBH4
N H
N H
TFA, THF 73%
171 H N O O
O
172 H N
NaBH4
OH TFA, dioxane HO 100°C, 73% HO
O
NaBH 4-TFA
Ph
O2S
dioxane 82%
Ph
176
M
175
H N
an
O2S
OH
174
173 H N
NHBoc
ip t
O
H N
us
BocHN
NaBH 4-TFA
NHBoc
cr
H N
Scheme 63. Reduction of amides and lactams to their corresponding amines using NaBH4-TFA.
ed
O N
H N
TFA, dioxane, heat 90%
N
pt
N
NaBH 4
178
177
Ac ce
Scheme 64. Reduction of indole-amide 177 by NaBH4-TFA.
The reduction of nitriles to primary amines can be accomplished with NaBH4-TFA, an example is given by the reduction of the functionalized benzonitrile 179 in the presence of both a nitro group and a carbamate (Scheme 65) [86]. The reduction of aliphatic carboxylic acids to the corresponding
O2 N
CN
TFA, THF 73%
HN EtO O
179
O2N
NaBH4
NH 2
HN EtO O
180
Scheme 65. Reduction of nitriles employing NaBH4-TFA.
Page 35 of 69
aliphatic primary alcohols has been also achieved using NaBH4-TFA (Scheme 66) [87]. The reaction gave poor yields for aromatic systems such as benzoic acid (30%).
NaBH 4-TFA 93%
CH 3(CH 2) 7CH 2OH 182
181 CH 3(CH 2) 8COOH
NaBH 4 -TFA 95%
CH 3(CH 2) 8CH 2OH
183
184 NaBH 4-TFA
HOH2 C(CH 2) 8CH 2OH
65%
186
185 NaBH 4-TFA 78%
187
H3COOC(CH2 )8 CH 2OH
us
H3COOC(CH2)8COOH
cr
HOOC(CH 2 )8 COOH
ip t
CH 3(CH 2) 7COOH
188
an
Scheme 66. Reduction of aliphatic carboxylic acids by NaBH4-TFA.
M
The reduction with NaBH4-TFA has been successfully employed during the last cyclization step in the synthesis of tetrahydroquinoline alkaloids (R)-(+) 190 and (S)-(-)-salsolidine 192 (Scheme 67)
ed
[88], and (S)-(-)-methylbharatamine 194 (Scheme 68) [89].
EtO
OEt
MeO
NH
pt
MeO
a) 6M HCl (aq) b) NaBH 4/TFA
CH 3
58% yield, 95.5% ee
MeO NH
MeO
CH 3 190
Ac ce
189
EtO
(R)-(+)-salsolidine OEt
MeO MeO
191
NH CH 3
a) 6M HCl (aq) b) NaBH 4/TFA
MeO
98% ee
MeO
NH
CH 3 192 (S)-(-)-salsolidine
Scheme 67. Cyclization step in the synthesis of tetrahydroquinoline alkaloids (R)-(+) and (S)-(-)-salsolidine.
Page 36 of 69
MeO OMe MeO
a) 5M HCl (aq) b) NaBH 4/TFA
N
MeO
MeO N
MeO
88% ee
H
H 194 (S)-(-)-methylbharatamine
ip t
193
Scheme 68. Cyclization step in the synthesis of (S)-(-)-methylbharatamine.
cr
The reduction of cobalt-complexed secondary-alkynic alcohols with sodium borohydride and trifluoroacetic acid has been achieved (Scheme 69) [90]. Oxidative decomposition of the resulting
us
cobalt complex produces secondary alkynes in good to moderate yields. A common intermediate
OH
an
made by protonation and dehydration, followed by stereoselective hydride addition was postulated.
a) Co2(CO)8 b) TFA, NaBH 4
OH
a) Co2 (CO)8 b) TFA, NaBH 4 c) Fe(NO3)3
M
c) Fe(NO3)3
197
195
196
ed
Scheme 69. Reduction of cobalt-complexed secondary-alkynic alcohols with NaBH4-TFA. 6.2.2. Reductions with sodium cyanoborohydride
pt
The first conversion of the antifungal lipopeptide echinocandin B 198 to echinocandin C 199 was
Ac ce
accomplished in a one single step using sodium cyanoborohydride in TFA (Scheme 70) [91]. The selective reduction of the homotyrosine C4-hydroxyl group was made in just 2 minutes. HO
O
HO
5
NH
H 3C
N
H
OH orn H N linoleoyl
O
HO O htyr HO 4
HN H NH O NH H N
H OH O
HO 198
HO O
HO
NH
H3 C
O
5
N
H
OH orn H N linoleoyl
O OH
NaCNBH3 -TFA HO 2 min, 42%
O htyr H 4
OH HO
O
HN H NH O NH H N H OH O
OH
OH
199
Scheme 70. Conversion of echinocandin B to echinocandin using NaCNBH3-TFA.
Page 37 of 69
The unsaturated tosamide 200 was effectively reduced by its treatment with 1 equivalent of trifluoroacetic acid followed by sodium cyanoborohydride (Scheme 71) [92]. The reaction is thought to occur by protonation at the 3 position followed by a hydride nucleophilic attack at the 2 position. NaCNBH3 -TFA 78%
N H Ts 201
cr
N Ts 200
CH 3
ip t
CH 3
us
Scheme 71. Reduction of a cyclic unsaturated tosamide by NaCNBH3-TFA.
The indole ester 202 was reduced by sodium cyanoborohydride in TFA giving the corresponding
an
dihydroindole esters 203 and 204 in a combined yield of 79% (Scheme 72) [93]. The same reduction with trimethylamine–borane complex was inefficient. The reduction was unselective and
M
the isomers were obtained in a 1:1 ratio (estimated by NMR) and couldn´t be separated by column chromatography.
CO2Et
79%
H
H +
N H 203
CO2Et
N H 204
CO2Et
pt
N H 202
ed
NaCNBH3 -TFA
Ac ce
Scheme 72. Reduction of an indole ester by NaCNBH3-TFA. Ketcha´s group reported a tandem reduction of both the carbonyl group and the indole double bond of 2- and 3-acyl-l-(phenylsulfonyl)indoles to the corresponding alkyl-1-(phenylsulfonyl)indolines (Scheme 73) [94]. A similar reduction occurred for 2- and 3-acyl-l-(phenylsulfonyl)pyrroles, which underwent tandem reduction of the carbonyl group and the pyrrole ring to provide the appropriately substituted alkyl-l-(phenylsulfonyl)-3-pyrrolines in good yield and without acid-catalyzed rearrangement of substituents (Scheme 74) [95].
Page 38 of 69
R2
R4
X
X R1 N SO2 Ph
NaCNBH3-TFA
R3 N SO2Ph
75-98%
X=H, Br R 1=H, COMe, COEt, Me R 2=COMe, COEt, H, Me, Et
X=H, Br R 3=H, Et, Pr, Me R 2=Et, Pr, H, Me, Et
205
ip t
206
R3 NaCNBH3 -TFA
R2 N SO2Ph
R 2=H, Et, Pr R 3=H, Et, CH2 Ph
an
R 68-97% N SO2 Ph R=H, COMe, COEt, Et R 1=H, COMe, COPh.
us
R1
cr
Scheme 73. Reduction of the carbonyl group and the indole double bond of 2- and 3-acyl-l-(phenylsulfonyl)indoles.
207
208
6.2.3. Reductions with borane
(BH3-THF)
in
trifluoroacetic
acid
produces
acid-stable
pt
Borane-tetrahydrofuran
ed
M
Scheme 74. Reduction of the carbonyl group and the pyrrole ring of 2- and 3-acyl-l-(phenylsulfonyl)pyrroles.
BH[OC(O)CF3]2.THF. The above combination was developed as a high-yield method for the
Ac ce
selective reduction of indoles 209 to indolines 210 in the presence of other functional groups (Scheme 75) [86]. The same reaction gave low yields of the corresponding indoline 210a using NaBH4-TFA (35%) but good yields for NaCNBH3-TFA (80%).
Page 39 of 69
NH
N
H
BH 3-THF, TFA
209a
NH
N
N2 , 0°C, 80%
210a H
N2, 0°C, 90%
209b
H
N H 210b
NH 2 BH 3-THF, TFA N2, 0°C, 86%
209c
N H
us
N H
cr
NH 2
ip t
BH 3-THF, TFA N H
Me
an
210c
BH 3-THF, TFA
N H
N2 , 0°C, 88%
M
209d
Me
N H
210d
ed
BH 3-THF, TFA N
N2, 0°C, 73%
CN
CN 210e
pt
209e
N
Ac ce
NHBz
N H
NHBz
BH 3-THF, TFA N2 , 0°C, 80%
209f
N H 210g
Scheme 75. Selective reduction of indoles 209 to indolines 210 using borane-tetrahydrofuran in TFA.
6.3. Other TFA-reducing agents 6.3.1. Diisopropoxyaluminium trifluoroacetate The reducing agent diisopropoxyaluminium trifluoroacetate 212 has been prepared by reacting aluminium isopropoxide with trifluoroacetic acid in dichloromethane (Scheme 76). It is a white solid and stable when stored under dry conditions. Using this reagent various aldehydes and ketones
Page 40 of 69
have been reduced to the corresponding alcohols in moderate to quantitative yields, at room temperature in short time (Scheme 77) [96]. O F3 C
O
OH + Al(i-PrO) 3 211 1
CH 2Cl2
O-Al+(i-PrO) 2
F3 C
rt
212
ip t
Scheme 76. Preparation of diisopropoxyaluminium trifluoroacetate 212. O O -Al+(i-PrO)2
R
CH 2Cl2, rt, 15 min 213a (R=H) 213b (R= NO2)
quant. yield
CH 2OH
cr
F3C
R
214 (R=H) 215 (R=NO2)
us
CHO
an
Scheme 77. Reduction of benzaldehyde to benzylic alcohol by diisopropoxyaluminium trifluoroacetate. 7. Condensations
M
Trifluoroacetic acid has result an excellent catalyst for different condensation reactions. These reactions include the Biginelli cyclocondensation of oxaloacetic acid 216 with diverse aldehydes
ed
217 to give 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones 218 (Scheme 78) [97], the Biginellitype synthesis of 3,4-dihydropyrimidin-2(1H)-ones (-thiones) 222 via one-pot three-component
pt
condensation of β-dicarbonyls 219, arylaldehydes 220, urea or thiourea 221 (Scheme 79) [98], a multicomponent synthesis of 1,2,4,5-tetrasubstituted imidazoles 227 under microwave-assisted,
Ac ce
solvent-free conditions (Scheme 80) [99] and the room temperature chemoselective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazole derivatives 230 in aqueous media via the condensation reaction of o-phenylenediamines 228 and aromatic aldehydes (Scheme 81) [100].
O
HO
O RCHO 217, urea OH
O
TFA
O
H N
HN
R H
216 HO
O 218
Scheme 78. Biginelli cyclocondensation of oxaloacetic acid 216 with diverse aldehydes 217 to give 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones 218 promoted by TFA.
Page 41 of 69
Ar
O
X CO2Et +
EtO2C
EtO2C
ArCHO + H2 N
220
219
TFA (4% mol) NH2
CH 3CN, 70°C
NH
EtO 2C
N H 222
X= O,S 221
X
Ph Ph
O O
+ ArCHO + RNH2 + NH 4OAc 224
225
226
TFA (20% mol) solvent f ree
Ph
mw, 150 W, 4 min, 79-94%
N
Ar
N R
cr
223
Ph
ip t
Scheme 79. Biginelli-type synthesis of 3,4-dihydropyrimidin-2(1H)-ones (-thiones).
227
R
NH 2
TFA +
R
NH 2
R
ArCHO H 2O/EtOH 1:2 rt
229
N
Ar
R
N
M
228
an
us
Scheme 80. Multicomponent synthesis of 1,2,4,5-tetrasubstituted imidazoles
230
95-100%
Ar
R
N
R
N H
Ar
+ 231 0-5%
ed
Scheme 81. Synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazole
pt
Apart from its catalytic effect in condensation reactions, several research groups have employed trifluoroacetic acid directly as a reagent source for trifluoroacetylations. A microwave-promoted
Ac ce
procedure has been reported for the direct preparation of trifluoroacetanilides 233 from anilines in high yields (Scheme 82) [101]. The reaction was carried out without solvent and was simple and clean. Searching for a more scalable procedure, Kikugawa et. al. developed an interesting, economic and environmentally friendly methodology for the trifluoroacetylation of anilines using trifluoroacetic acid as the acetylating reagent in xylene (Scheme 83) [102]. The addition of an equimolar amount of pyridine to that of the trifluoroacetic acid present in the reaction mixture facilitates the trifluoroacetylation of rather basic arylamines. The trifluoroacetylation of arylamines using trifluoroacetic acid and poly-phosphoric acid trimethylsilylester (PPSE) as the condensation agent was also reported (Scheme 84) [103].
Page 42 of 69
NH 2
NHCOCF3 TFA, mw
R
R
80-95%
233
232
R = H, 2-Cl, 2-OMe, 3-Cl, 3-OMe, 4-Cl, 4-Br, 4-F, 4-OMe, 4-Me
NHCOCF3
cr
NH2 TFA (2-4 equiv.) R
R
us
Xylene, 150°C 65-94%
234
ip t
Scheme 82. Microwave promoted trifluoroacetylation of anilines by TFA
235
an
Scheme 83. Thermal trifluoroacetylation of anilines by TFA in xylene.
M
P2O5 + (Me 3Si) 2O
NH 2
NHCOCF3
PPSE
+ 236
CF3CO2 H
R
ed
R
CH 2Cl2 62-93%
237
An
Ac ce
pt
Scheme 84. Trifluoroacetylation of arylamines using trifluoroacetic acid and PPSE
interesting methodology was developed
for the
trifluoroacetylation
followed by
cyclocondensation of several 2-aminomethyl substituted anilines with TFA and HCl as a catalyst (Scheme 85) [104]. The resulting 1-methyl-2-trifluoromethyl-benzimidazoles 239 showed to be very active against various human protozoan parasites.
ArO
NH 2
R
NHCH3 238
TFA, HCl cat heat
ArO
N CF3
R 239
N CH3
Scheme 85. Trifluoroacetylation and cyclocondensation using TFA for the preparation of 2-trifluoromethyl-benzimidazoles.
Page 43 of 69
8. Reactions with organophosphorus reagents
Trifluoroacetimidoyl chlorides 240 are versatile intermediates easily prepared in high yields by heating a mixture of trifluoroacetic acid and a primary amine in carbon tetrachloride in the presence of triphenylphospine and triethylamine (Scheme 86) [105]. The corresponding bromides can be
ip t
obtained using carbon tetrabromide instead of carbon tetrachloride. It is also possible to use PPh3Cl2 instead of carbon tetrachloride due to the restrictions of its use [106]. Imidoyl iodides 240b could
cr
also be prepared almost quantitatively by displacement of the chloro group of 240a with iodine
Ar
O F3 C
us
using NaI/acetone.
OH
+
N
CCl4 + PPh 3 + Et3N
ArNH 2
F3 C
reflux, 85-95%
Cl
N
quant.
F3 C
an
1
Ar
NaI / acetone
240a
I 240b
M
Scheme 86. One-pot preparation of trifluoroacetimidoyl chlorides using TFA. The one pot synthesis of fluorinated β-carbolines 242 was achieved from tryptophan methyl esters
ed
and amides hydrochlorides using TFA, CCl4 and triphenyl phosphine (Scheme 87) [105b]. The
pt
reaction is thought to pass through an imidoyl chloride intermediate generated in situ.
O
O R
Ac ce
R
NH2
N
TFA, CCl4, PPh3
N H
241 R = O-alkyl or N-alkyl (HCl salts)
60-78%
N H
CF3
242
Scheme 87. One pot synthesis of trifluorometyl β-carbolines.
The trifluoroacetylation of primary amines with trifluoroacetic acid has been achieved using a combination of trichloroacetonitrile and triphenylphosphine [107]. The method was applied successfully to amines with stereogenic centers (Scheme 88). In the case of (R)-2-amino-2-
Page 44 of 69
phenylethanol 245, which has both amino and hydroxyl groups, only the amino group was trifluoroacetylated selectively (Scheme 89). NH 2
NHCOCF3 TFA, CCl3CN / PPh 3 Et 3N, MeCN, rt, 2h 92%
244
ip t
243
cr
Scheme 88. Trifluoroacetylation of primary amines with trifluoroacetic acid and CCl3CN/PPh3
NHCH2 OCF3
us
NH2 OH TFA, CCl3CN / PPh3
OH
Et3 N, MeCN, rt, 2h
246
an
90%
245
M
Scheme 89. Trifluoroacetylation of (R)-2-amino-2-phenylethanol 245.
The reagent 2,2,2-trifluoroethyldiphenylphosphine oxide 248, was easily prepared either treating
ed
chlorodiphenylphosphine 247 with trifluoroacetic acid and water (Scheme 90) [108]. The treatment of the above phosphine oxide with aromatic aldehydes in the presence of TBAF at room
pt
temperature afforded the corresponding 3,3,3-trifluoropropenyl 249 derivatives in good yields
Ac ce
(Scheme 91).
Ph2 PCl + CF3 CO2H 247
1
H 2O
rt, 30 min, then 90-100°C, 2 h 76%
Ph2 P(O)CH 2 CF3 248
Scheme 90. Preparation of 2,2,2-trifluoroethyldiphenylphosphine oxide using chlorodiphenylphosphine with TFA. Ph 2P(O)CH2 CF3 248 ArCHO TBAF, THF, rt
CF3
Ar 249
Scheme 91. Synthesis of 3,3,3-trifluoropropenyl compounds from aromatic aldehydes by the TBAF-mediated Horner reaction.
Page 45 of 69
The reaction of an equimolecular mixture of triphenylphosphine, N-bromosuccinimide and trfluoroacetic acid provides an excellent and chemoselective acyloxy-triphenylphosphonium reagent 250 for the selective trifluoroacetylation of primary or secondary amines, even at the presence of hydroxy groups from phenols (Scheme 92) [109].
ip t
NH2
NHCOCF3 O NBS
+ Ph 3P O
TFA, CH 2Cl2
CF3
OH
Br -
Py, CH2 Cl2
250
cr
Ph 3P
OH 251
us
81%
an
Scheme 92. Selective trifluoroacetylation of primary amines using a trifluoroacetyloxiphosphonium reagent. 9. Hydroarylations
The trifluoroacetic acid promoted hydroarylation of alkenes to afford dihydrocoumarins has been
M
achieved (Scheme 93) [110a]. The analogous dihydroquinolones could also be prepared in good yields by coupling anilines with cinnamic acids prior to hydroarylation (Scheme 94). Cinnamanilide
ed
256 reacted smoothly in TFA to provide dihydroquinolone 257, while the intermolecular hydroarylation of alkenes 259 with unprotected anilines 258 failed due the favorable protonation of
pt
the amino group prior to cyclisation, decreasing the nucleophilicity of the arene ring. Recently, the
Ac ce
FeCl3/AgOTf catalytic hydroarylation of alkynes with arenes in TFA has been reported [110b]. O
O
O
O
Method A
R
TFA / CH2Cl2 R1
252
253
Method B
HO + 254
R1
O
OH R
R
TFA / CH2 Cl2 255
R1
Scheme 93. Hydroarylation of cinnamoyl-esters and cinnamoyl acids promoted by TFA.
Page 46 of 69
H N
H N
O TFA, CH 2Cl2
t
Bu
t
23 h, rt 82%
Ar
O Ar = p-C 6H 4OMe
Bu Ar 257
256
ip t
O
NH 2 + HO
259
258
Ar
cr
t Bu
us
Scheme 94. Hydroarylation of cinnamoyl-anilides promoted by TFA.
10. Synthesis of trifluoromethyl building blocks and trifluoromethyl substituted compounds
an
CF3-containing synthetic blocks are relatively scarce in commercial large scale despite some should be purchased from different catalogs in gram quantitites, therefore it is very important to develop
M
more sophisticated CF3-building blocks for industry and research [106,111]. They should be synthesized in high yields from easily available starting materials and contain, if it is possible, other
ed
potential functional groups usable for further molecular modification [106]. Previously described trifluoroacetimidoyl halides 240 are valuable CF3-containing synthetic building blocks which offer
pt
the following advantages: a) easy one-step synthesis from the really available trifluoroacetic acid in excellent yields, b) relatively stable to be stored, and c) containing highly potential functional
Ac ce
groups such as CF3,imino C=N double bond and halogen (Figure 2) [106]. alkylation or hydrogenation
def luorinative functionalization
NR F3 C
X
oxidative addition to low valent metals or metal-halogen exchange
240 X= Cl, I, Br
Figure 2.Trifluoroacetimidoyl halides as CF3-containing synthetic building blocks. Imidoyl halides 240 have been used widely in organic synthesis, via carbocation 260, carbanion 261 and radical 262 species (Figure 3). For example, the chloride 240a (X=Cl) can be used for
Page 47 of 69
nucleophilic substitution reactions with nucleophiles (Schemes 95-97) [112-114] or acid-catalyzed Friedel-Crafts reactions (Scheme 98) [115] to convert chlorine to other functional groups. NR +
CF3
ip t
260
X
cr
NR CF3
240
us
NR
X= Cl, Br, I, SePh, N=NC(Ph)3, Pd, Rh, Si, Zn, Mg, Li
NR
.
CF3 262
an
.. CF3 261
F3 C
PMP
HOCH 2CO2R, Et3N
N
benzene, 50°C, 5h
Cl 263
i-PrOH-THF
HN F3 C
O
264
PMP
LiTMP
N
PMP CO 2R
DME-THF CO2R -105 -70°C F3 C 81-89%
OH 265
CO 2R
pt
NaBH4, ZnCl2
F3 C
PMP
ed
N
M
Figure 3. Chemical reactive intermediates from trifluoroacetimidoyl halides.
OH
Ac ce
266
Scheme 95. Reaction of trifluoroacetimidoyl chlorides with oxygen nucleophiles: an example for the preparation of fluorinated β-aminoacids.
OMe
OMe
N
F3 C
DMF-H 2 O
Cl 267
OMe
t-BuOCl/CH 2Cl2
(Me2 C=N)NH2 HN F3 C
.70°C N
268
N
N
rt F3 C
N
N
269
Scheme 96. Reaction of trifluoroacetimidoyl chlorides with nitrogen nucleophiles: an example for the preparation of trifluorometyl 1,3,4-benzotriazines.
Page 48 of 69
R O
O X
X
NaH / THF,
Y
then
Cl
Y
X
K2CO3, DMF
CF3
100°C
Cl
R
270
O
HN
Y
N
272
CF3 R
N from TFA Cl
273
ip t
F3C
271
I Pd(OAc)2 (5 mol %) PPh 3 (10% mol)
F3 C
AlCl3 /CH2 Cl2 rt
Cl
KOAc (200 mol %) DMF, 140°C, 30 min
I
Cl
Ac ce
I
N
F3 C
KOAc (200 mol %) DMF, 140°C, 15 min
pt
274
AlCl3/CH2Cl2 rt
ed
F3 C
Pd(OAc)2 (5 mol %) PPh 3 (10% mol)
N H
Cl
274
N R
AlCl3 /CH2 Cl2 rt
CF 3
275
M
274
N
N
an
N
us
cr
Scheme 97. Reaction of trifluoroacetimidoyl chlorides with carbon nucleophiles: an example for the preparation of 2-trifluorometyl 4(1H)-quinolones.
CF3 N
N
276 (68%)
F3C N
Pd(OAc)2 (5 mol %) PPh 3 (10% mol) KOAc (200 mol %) DMF, 140°C, 15 min
N R 277 (R=H, 78%) 278 (R=Me, 83%)
Scheme 98. Reaction of trifluoroacetimidoyl chlorides with carbon nucleophiles: examples for the preparation of different trifluoromethyl-heterocycles through acid-catalyzed FriedelCrafts reactions followed by palladium catalyzed C-H activation. Iodo, seleno and azo-imidoyl compounds produce radical species 262 by photochemical and thermal reactions, which form new carbon-carbon bonds with alkenes, alkynes and aromatic compounds (Schemes 99, 100) [116,117]. Imidoyl halide 240b can be converted to the
Page 49 of 69
corresponding imidoyl metals by the oxidative addition to low valent transition metals or the halogen-metal exchange reaction, which can also form new carbon-carbon bonds by electrophilic reactions with different electrophiles (Scheme 101) or the transition metal-catalyzed cross-coupling reactions [118-119]. The stability of the imidoyl metal depends on the type of metal used, for
ip t
example, lithium species have to be kept at temperatures lower than -60 °C, although they are most reactive as carbanions. At above -60 °C, unstable lithium species 283 dimerizes through a carbene
cr
intermediate 285 (Scheme 102) [120]. The more stable zinc species are generated with Zn-Al in DMF at room temperature, which reacts smoothly with electrophiles such as benzaldehyde (Scheme
us
103) [121]. Imidoyl metals derived from magnesium [122], silicon [123], palladium [124] and
NAr + PhC CH I 240b
MeO
N
CF 3
Ph
MeO
+
M
F3 C
MeCN, h
an
rhodium [125] have been also prepared and employed in organic synthesis.
N
Ph
CF 3
280
279
ed
Scheme 99. α-Trifluoroacetimidoyl radicals for the synthesis of 2-trifluoromethyl quinolines.
O
R
R
h
I CF3
.
acetone-H 2O
Ac ce
N
pt
R
N
CF3
53-69 % N H
CF3
281
282
Scheme 100. α-Trifluoroacetimidoyl radicals for the synthesis of indole derivatives.
NAr
F3 C
I 240b
nBuLi/ether -78°C
NAr F3 C
Li 283
electrophiles 26-89%
NAr F3 C
E 284
electrophiles: PhCHO, DMF, PhCOCl, PhCOMe, ClCO 2Et
Scheme 101. Reaction of trifluoroacetimidoyl-litium species with electrophiles.
Page 50 of 69
NAr F 3C
NH2Ar
above -60°C
Li
F 3C
283
285
Zn-Al / HMPA-DMF rt / 0.5 h
NAr + F3C
PhCHO
I
NAr
21-94%
Ph
F3C
OH
cr
240b
ip t
Scheme 102. Trifluoroacetimidoyl-litium decomposition to carbenes.
286
us
Scheme 103. More stable zinc species, generated with Zn-Al, react with benzaldehydes. The reaction of imidoyl chlorides 240a with azide anion produces 1-subtituted-5-trifluoromethyl
an
tetrazoles 288 through an imidoyl-azide intermediate 287 (Scheme 104) [126]. These types of tetrazoles are of particular interest in drug development. For example, the neurokinin-1-receptor
M
antagonist 292 (GR205171), a potent orally antiemetic compound developed by Glaxo Wellcome, was synthesized trough a trifluoromethyl-tetrazole moety prepared from the corresponding
N 3-
N
F 3C
Cl
CH3 CN or DMF
R N
N
F 3C
N3
50-94%
F3 C
N N N 288
287
Ac ce
240a
R
pt
R
ed
trifluoroacetimidoyl chloride (Scheme 105) [127].
R= Aryl, -methylbenzyl, phenylethyl
Scheme 104. Synthesis of 5-substituted 1-trifluoromethyl-tetrazoles.
Ph
Ph
O
PPh3, CCl4
NH
O 289
Ph NaN 3, AcOH
O
93%
CF3
N Cl 290
69% CF3
O
MeO H N
CF3 N N N N 291
N H
Ph
CF3 N N N N 292
Could be prepared from the substituted aniline and TFA, see ref erences 99-101, 105
Scheme 105. Synthesis of the neurokinin-1-receptor antagonist 292 (GR205171) using an imidoyl chloride as a building block.
Page 51 of 69
Trifluoromethylated alkynyl imines 295 have been recently prepared by the Cu(I) catalyzed of fluorinated imidoyl halides with terminal alkynes (Scheme 106) [128]. The reaction is though to procede through an addition-elimination mechanism and has the advantage to avoid a palladium complex Alkynyl imines are versatile and useful intermediates for the synthesis of many different
ip t
kinds of heterocycles, such as pyridines [129-131], pyrroles [132,133], quinolines [134,135], among others [136-139], so it opens a possibility to obtain those type of heterocyclic systems incorporating
R1
R CuI (10% mol)
N F 3C
+
R2
I
294
F 3C
R=OCH 3; NO 2; H R 1=H; CF 3; CH 3 R 2=nBu; Ph; CO2 CH3, CH2 OCOCH3
R2
an
293
K 3PO 4/CH 3CN 50°C 62-94%
N
R
us
R1
cr
a CF3 group.
295
M
Scheme 106. Cu(I) catalyzed reaction of trifluoroacetimidoyl halides with terminal alkynes for the synthesis of trifluoromethylated alkynyl imines. 6-(Trifluoromethyl)phenanthridines were prepared in moderate to excellent yields from N-(2-
ed
bromophenyl)-trifluoroacetimidoyl chlorides through a palladium-catalyzed tandem Suzuki/C−H arylation reaction with arylboronic acids (Scheme 107) [140]. Phenanthridines are important
pt
heteroaromatic compounds which are frecuently encountered in natural products [141-143],
Ac ce
optoelectronic materials [144-146] and biologically active molecules [147-149]. The process could be used for the synthesis of trifluoromethyl-containing building blocks from simple starting materials, such as 2-bromoanilines. It also provided a new route for the construction of phenanthridine rings.
N
R Br 296
CF3
Cl
B(OH) 2
H
R1
+ 297
10% mol Pd(PPh3 )4 20% mol PCy3
N
CF3
R Ag2 CO3, K2CO3 toluene, 120°C 42-93 %
R1 298
Scheme 107. Palladium-catalyzed tandem Suzuki/C−H arylation reaction of N-(2-bromophenyl)trifluoroacetimidoyl chlorides with arylboronic acids for the synthesis of 6(trifluoromethyl)phenanthridines.
Page 52 of 69
The ethyl ester of trifluoroacetic acid, ethyl trifluoroacetate 299, is an affordable and commercially available reagent employed for the incorporation of a trifluoroacetyl group into important pharmaceutical [1h,150-152] and agrochemical intermediates [153,154]. This reagent is easily
ip t
synthesized through a Fischer esterification from trifluoroacetic acid and ethanol using sulphuric acid as a catalyzer (Scheme 108) [155]. Penthiopyrad 302, a farming used fungicide, is synthesized
cr
employing ethyl trifluoroacetate as the starting material [153,154]. Ethyl trifluoroacetate is reacted with ethyl cyanoacrylate to obtain an enol-ester 300 that allows the formation of a key
O OH
+
EtOH
O
F 3C
OEt 299
an
F 3C
H 2SO4 cat
us
trifluoromethyl substituted pyrazol 301 in the presence of N-methylhydrazine (Scheme 109).
1
M
Scheme 108. Synthesis of ethyl trifluoroacetate from trifluoroacetic acid.
F3 C
F3 C
OEt
Na/EtOH
F3 C
MeNNH 2
CN
HO
CO2Et 300
CO 2Et
N N Me
F3 C
NH2 301
N N Me
N H NH2 302
pt
299
CNCH2 CO 2Et
ed
O
S
O
Ac ce
Scheme 109. Synthesis of penthiopyrad from ethyl trifluoroacetate. Direct trifluoromethylation methods have emerged as important tools in organic synthesis [156]. Recently, the Pd(II) catalyzed C-H trifluoromethylation of diverse 2-aryl-pyridine derivatives 303 was reported (Scheme 110) [157a]. TFA resulted to be crucial for the success of this Ar-CF3 bond-forming protocol; other acids such as such as AcOH, TsOH, and TfOH were not effective. The above TFA promoted reaction was also effective for the preparation of trifluoromethylated important heterocycles very commonly used in medicinal chemistry, such as substituted pyrimidine, imidazol and thiazol (Scheme 111). A similar reaction was recently applied to the orthotrifluoromethylation of N-arylbenzamides using DMF as a promoter [157b].
Page 53 of 69
R1
R1
Pd(OAc)2 (10% mol) Cu(OAc)2 (1.0. equiv.) N
R
N
R
CF3
H +
BF 4-
S CF3 (1.5 equiv.)
303
304 R = H, Me-OMe, Cl, -CH-CH=CH-CHR1 = H, Me
ip t
DCE / TFA (10 equiv.), 110°C, 48 h 55-88%
N
N
R
Me
CF3
N
CF3
305
Het
from
R
CF3
306
62-88 %
S
us
MeN
R1
H
an
N
cr
Scheme 110. Pd(II) catalyzed C-H trifluoromethylation of pyridine derivatives
307
53%
74%
M
Scheme 111. C-H Trifluoromethylation using diverse heterocyclic directing groups
ed
The available reagent xenon difluoride 308 [158] reacts with trifluoroacetic acid to produce an intermediate, xenon(II) trifluoroacetate, which undergoes decomposition to yield carbon dioxide and hexafluoroethane (formed by in situ generated trifluoromethyl radicals) [159-160]. The direct
pt
trifluoromethylation of electron-poor aromatic and heterocyclic has been achieved by treatment
Ac ce
with TFA and xenon difluoride [161]. The yields of fluorinated products vary from moderate to good, but the reaction permits the preparation of structures that would otherwise be difficult to synthesize. 5-(Trifluoromethyl)-2´-deoxyuridine 311, a known antiviral agent, has been prepared using this reaction in the synthesis of a previous intermediate (Scheme 112).
XeF2 308
Page 54 of 69
O HN O
O
AcO
O HN
TFA, XeF2 N
25°C, 33%
O CF3
O
O
N
AcO
O
rt, 82%
AcO
O
N
HO
AcO
HO
310
311
ip t
309
CF3
HN
NH 3, MeOH
cr
Scheme 112. Use of XeF2-TFA during the preparation of the antiviral agent 5-(trifluoromethyl)-2´-deoxyuridine.
The condensation of mercury (II) oxide with trifluoroacetic acid (2 mol equivalents) produces
us
mercury (II) trifluoroacetate 312, which decomposes thermally by decarboxylation in the presence of carbonate followed by sublimation to yield bis(trifluoromethyl)mercury 313 (Scheme 113) [162]. of
bis(trifluoromethyl)mercury
with
313
Cu0
in
an
Treatment
N-methylpirrolidone
or
dimethylacetamide produces a stable trifluoromethylcopper reagent 314 (Scheme 114), very useful
M
for the introduction of a trifluoromethyl group into aromatic compounds [163,164]. Bromoarenes are less reactive by trifluoromethylcopper than iodoarenes and the chloro analogs are almost
ed
completely inert (Scheme 115) [165-166].
K2 CO 3
Hg(CF3COO)2
120-180°C
Hg(CF3)2 + CO 2
312
pt
313
Ac ce
Scheme 113. Preparation of bis(trifluoromethyl)mercury from mercury (II) trifluoroacetate.
NMP or DMA
Hg(CF3)2 + Cu 0
140°C
313
CF3 Cu + Hg0 314
Scheme 114. Preparation of trifluoromethyl copper from mercury (II) trifluoroacetate. I
CF3 150°C, 3h
CF3Cu +
88%
314 NO2 315
NO2 316
Scheme 115. Reaction of trifluoromethylcopper with iodoarenes.
Page 55 of 69
Trifluoromethyl ketones could be synthesized directly by the reaction of Grignard reagents with trifluoroacetic acid in refluxing ether [167]. The reaction is quite useful for the preparation of trifluoromethyl-alkynyl ketones in moderate yields (Scheme 116) [168]. Et2 O MgBr + CF3 CO2H
reflux, 2h 44%
1
317
O nC6 H13 318
CF3
ip t
nC6H13
cr
Scheme 116. Synthesis of trifluoromethyl-alkynyl ketones using Grignard reagents and TFA.
us
11. Miscellaneous reactions 11.1. Iodination:
an
Trifluoroacetic acid promotes the activation of N-iodosuccinimide 319 as an iodinating reagent (Scheme 117) [169]. A variety of aromatics compounds substituted with electron rich groups (i.e.
M
methoxy, methyl) were regioselectively iodinated with N-iodosuccinimide and catalytic trifluoroacetic acid with excellent yields under mild conditions and short reaction times (Scheme
ed
118).
+O H
N I + CF3 CO 2H 1
N I
+ N I
O
O
320
321
Ac ce
O 319
O H
pt
O
O
ArH CF3 CO 2-
N H + CF3 CO 2H Ar-I
O
1
322
Scheme 117. Activation of NIS by catalytic TFA.
R
323 R= Me, OMe
NIS (1.1 equiv.) CF3CO 2H (0.3 equiv.) rt-80°C, 0.5-4.5 h 81-99%
R
I 324 Monoiodinated products
Scheme 118. Iodination of electron rich aromatic compounds by NIS and catalytic TFA.
Page 56 of 69
11.2. Metal mediated reactions: Several zinc reagents have been generated in situ from the reaction between Et2Zn with CH2I2 and TFA [170]. The carbenoid compound CF3CO2ZnCH2I is effective for the cyclopropanation of a wide range of aryl and alkyl olefins (Scheme 119) and the diastereoselective cyclopropanation of
ip t
acyclic allylic silyl ethers (Scheme 120) [171]. The cyclopropanation of unfunctionalized olefins using chiral (iodomethyl)zinc species gave a reasonable level of enantioselectivity, providing a
cr
valuable improvement for the Simmons-Smith cyclopropanation reaction [172].
CF3CO2ZnCH 2I (2 equiv) OH
CH2Cl2, , rt, 40 min 80% yield
325
Ph
OH
us
Ph
326
an
Scheme 119. Cyclopropanation of alkenes by CF3CO2ZnCH2I.
OTES
OTES
M
CF3 CO 2ZnCH 2I (2 equiv)
Ph
CH 2Cl2,, 0°C, 30 min 87% yield
328 >99:1 ant i:syn
ed
327
Ph
pt
Scheme 120. Diasteroselective cyclopropanation of alkenes by CF3CO2ZnCH2I.
Ac ce
The nucleophilic ring-opening reaction of cyclo-1,3-diene monoepoxides using organozinc reagents generated by the treatment of organozinc species (Et2Zn, Ph2Zn) in the presence of TFA was reported [173], obtaining the cis-addition products exclusively when the reaction was performed with CF3CO2ZnEt (Scheme 121). This methodology was successfully applied in the synthesis of α-C-
glycosides using similar organozinc species (Scheme 122).
O
n
329
OH
Et2Zn, CF3CO2 H CH2Cl2,, 0°C, 2h 52-66% yield
n
330
n = 0,1,2,3
Scheme 121. Ring opening of cyclo-1,3-diene monoepoxides using organozinc reagents and TFA.
Page 57 of 69
From R 2 Zn + TFA O
BnO
CF3COOZnR
O
53-82%
BnO OBn
O
BnO
R
BnO
OH OBn
R= alkyl, aryl
332
331
ip t
Scheme 122. Zinc-mediated synthesis of α-C-glycosides from 1,2-anhydroglycosides
cr
Palladium complexes with bidentate phosphine ligands such as Pd(dppe)(OAc) 2 and
us
Pd(dppm)(OAc)2, were found to be effective catalysts for the hydroarylation of arenes with ethyl propiolate 334, affording arylbutadiene 335 derivatives with a high degree of regio- and
an
stereoselectively (Scheme 123) [174]. TFA demonstrated to play a key role to increase the rate of this reaction by its participation as a ligand, particularly in those cases were the arenes were less
Pd(dppe) (OAc) 2 or Pd(dppm)(OAc) 2
H R
M
reactive.
CO2Et
TFA, 30°C, 5h 66-82%
Ar
CO2Et
ed
+
CO 2Et
334
333
335
pt
Scheme 123. Pd-catalyzed hydroarylation of ethyl propiolate with arenes. Palladium acetate has been used to catalyze the 1,4-acetoxy-trifluoroacetoxylation and 1,4-alkoxy-
Ac ce
trifluoroacetoxylations of cyclic 1,3-dienes (Scheme 124), where TFA was employed as an exchangeable nucleophile [175]. Reactions performed with 1,3-cyclohexadiene 336 provide the trans-product 337 predominantly while 1,3-cycloheptadiene favors the cis-diastereomer. O 5% Pd(OAc) 2
O
CF3
CF3COOH, CF3COOLi ROH, p-benzoquinone 336
MnO 2, CH 2Cl2, 14 h, rt 55-68% yield R = alkyl, cycloalkyl, Bn
OR 337 92-93% t rans
Scheme 124. Palladium-catalyzed 1,4-acetoxy-trifluoroacetoxylation and 1,4-alkoxy-trifluoroacetoxylation of cyclic 1,3-dienes.
Page 58 of 69
11.3. Formylation of aromatic compounds with hexamethylenetetramine and trifluoroacetic acid. The Duff reaction: The Duff reaction for the synthesis of salicylaldehydes consist in the direct formylation of phenols with hexamethylenetetramine (HMTA) in glycerol under the presence of glyceroboric acid followed by an aqueous workup [176]. The original method gave salicylaldehydes in low yield (20% or
ip t
lower). The reaction could also be applied to other aromatic systems but usually requires strongly electron donating substituents on the aromatic ring such as in a phenol. Formylation occurs
cr
preferably ortho to the electron donating substituent, unless the ortho positions are blocked, in
us
which case the formylation occurs para [177]. The natural product syringaldehyde 339 (3,5-di-tertbutylsalicylaldehyde) has been prepared using the Duff reaction in 32% yield (Scheme 125) [178].
OMe
N
1) glycerol, boric acid, 150°C 2) H2 SO4, H 2O
M
MeO
N N
an
N OH
338
32%
OH
MeO
OMe
CHO 339
ed
Scheme 125. Synthesis of syringaldehyde by the Duff reaction
Smith modified the original Duff conditions using HTMA in conjunction with trifluoroacetic acid
pt
[179]. A variety of aromatic compounds, including simple hydrocarbons, could be converted to
Ac ce
imine products, which were transformed to the corresponding aryl aldehydes upon hydrolysis (Scheme 126). The required conditions are mild, and good yields of pure products could be easily isolated, giving a high order of para regioselectivity. The reaction was also extended by Suzuki et. al [180] to phenols having electronwithdrawing groups and permited latter an improved preparation of 3,5-difluorosalicylaldehyde and 3,5-difluorosalicylic acid [181]. The Duff TFA-promoted protocol has been applied for the double formylation of substituted heterocyclic phenols, such as 8-hydroxyquinoline N-oxide 342 (Scheme 127), 5-hydroxy-2,3-diphenylbenzofuran, 2-hexyl-3hydroxy-6H-benzo[c]chromen-6-one and ethyl 3-hydroxypyrido[1,2-a]indole-10-carboxylate [182]. Chavan and Lansokar [183] have recently reported the one-pot migration–formylation of benzyl aryl ethers 344 under Duff reaction conditions (Scheme 128). The postulated mechanism (Scheme
Page 59 of 69
129) involves the protonation of the benzyloxy group by TFA to form a free phenol plus a benzyl cation. The benzyl cation thus generated is captured by the phenol in a Friedel–Crafts fashion to form 2-benzylphenol 345. Addition of the phenol to the corresponding imine, generated from TFA and HTMA in situ on the ortho-position of the –OH group followed by hydrolysis, gave the
O
Ar=
O
tBu
N
PhO
ArCHO 341
Me
tBu
HO
Me
an
340 1) TFA, 125-150°C 2) H2 O 29-93%
us
ArH
N N
cr
N
ip t
resulting aldehyde 346.
tBu
MeO
Me
Me
M
HO Me
ed
Scheme 126. Synthesis of diverse aromatic aldehydes by the TFA promoted Duff reaction CHO
pt
1. HTMA, TFA 2. HCl aq.
Ac ce
OH
N O
59%
OHC OH
342
N O
343
Scheme 127. Bis-fomilation of 8-hydroxy-quinoline N-oxide by the TFA-Duff protocol R1 O
O
HMTA, TFA
OHC
R2 R3
80°C, 3-6 h 52-74 %
R 344
R= Br, CHO, tBu, CH 2CO2 CH 3
R 346 R 1= H, Br R 2= H R 3= H, Br, OMe, NO 2
Scheme 128. One-pot migration–formylation of benzyl aryl ethers under Duff reaction conditions
Page 60 of 69
H O
O
H + O
TFA
+
OHC
+ R
R
1. HTMA, TFA 2. H 3O+
OHC
R
R
346
us
345
cr
OH
OH
ip t
R
344
an
Scheme 129. Postulated mechanism for the migration-formylation of benzyl aryl ethers under TFA promoted Duff reaction.
12. Summary and conclusions
M
Trifluoroacetic acid has a tremendous impact in organic synthesis by its versatility and wide applicability in many diverse organic transformations. Its low cost, high acidity, easy elimination
ed
and high solubility in water and organic solvents has marked its used as the catalyst of choice for a variety number of reactions such as rearrangements, functional group deprotectios, oxidations,
pt
reductions, condensations, hydroarylations and trifluoromethylations. TFA has been also
Ac ce
demonstrated to serve as the starting reagent for the preparation of important CF3 building blocks employed in the construction of useful intermediates and heterocyclic compounds. Recent applications in metal mediated reactions have proved its efficacy as a good ligand in organometallic chemistry.
Acknowledgements
Authors thank Decanato de Investigación y Desarrollo (DID-USB) for its continuous financial support and Programa de Estímulo a la Investigación e Innovación (PEII-Venezuela) for a fellowship.
Page 61 of 69
References and notes
Ac ce
pt
ed
M
an
us
cr
ip t
[1] (a) A.J. Elliott, Fluorinated acetic acids, in Kirk-Othmer Encyclopedia of Chemical Technology, Wiley: New York, 2000, pp. 1-6; (b) K.F. Eidman, P.J. Nichols, in Encyclopedia of Reagents for Organic Synthesis. L. Paquette. Ed., Wiley: New York, 2004; (c) J. H. Simons and K. E. Lorentzen, J. Am. Chem. Soc. 72 (1950), 1426-1427; (d) US EPA; Non-confidential production volume information submitted by companies for chemicals under the 1986-2002 Inventory Update Rule (IUR). Acetic acid, trifluoro- (76-05-1). Available from: http://www.epa.gov/cdr/tools/data/2002-vol.html (downloaded on August 25th 2013); (e) G. Siegemund, W. Schwertfeger, A. Feiring, B. Smart, F. Behr, H. Vogel, B. McKusick. Fluorine Compounds, Organic, Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, Germany, Vol 15, 2005, p. 470; (f) N. Shibata, A. Matsnev, D. Cahard, Beilstein J. Org. Chem. 6 (2010) doi:10.3762/bjoc.6.65; (g) S.E. López, Curr. Org. Synth. 7 (2010) 402; (h) S.E. López, J. Restrepo, J. Salazar, Curr. Org. Synth. 7 (2010) 414-432; (i) D. O’Hagan, J. Fluorine Chem. 131 (2010) 1071-1081. [2] F. Swarts, Bull. Soc. Chim. Belg. 8 (1922) 343-370. [3] (a) T. Wu, H. Yu, C. Li, ARKIVOC ix (2004) 60-65; (b) P.E. Peterson, C. Casey, E.V.P. Tao, A. Agtarap, G. Thompson, J. Am. Chem. Soc. 87 (1965) 5163-5169; (c) P.E. Peterson, R.J. Bopp, D.M. Chevli, E.L. Curran, D.E. Dillard, R.J. Kamat, J. Am. Chem. Soc. 89 (1967) 59025911; (d) H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, K. Omoto, H. Fujimoto, J. Am. Chem. Soc. 122 (2000) 11041-11047. [4] For a review article, see: P. Renaud, M. Gerster, Angew. Chem., Int. Ed. 37 (1998) 2562-2579. [5] X. Fang, H. Xia, H. Yu, X. Dong, M. Chen, Q. Wang, F. Tao, C. Li, J. Org. Chem. 67 (2002) 8481-8488. [6] (a) K. Sun, Z. H. Li, eXPRESS Polym. Lett. 5 (2011) 342-361; (b) K. Ohkawa, D. Cha, H. Kim, A. Nishida, H. Yamamoto, Macromol. Rap. Commun. 25 (2004) 1600-1605; (c) M. Hasegawa, A. Isogai, F. Onabe, M. Usuda, J. Appl. Polym. Sci. 45 (1992) 1857-1863; (d) M. Panar, O.B. Wilcox, German Patent (1977) 2705382; (e) D.L. Patel, R.D. Gilbert, J. Polym. Sci. Polym. Phys. Ed., 19 (1981) 1231-1236; (f) D.L. Patel, R.D. Gilbert, J. Polym. Sci. Polym. Phys. Ed., 21 (1983) 1079-1090; (g) D. K. Yang, L. C. Chien, J. W. Doane, Appl. Phys. Lett. 60 (1992) 31023104; (h) H. Ren, S. T. Wu, J. Appl. Phys. 92 (2002) 797-800; (i) H. Yang, K. Mishima, K. Matsuyama, K. I. Hayashi, H. Kikuchi, T. Kajiyama, Appl. Phys. Lett. 82 (2003) 2407-2409; (j) J.J. Throssell, S.P. Sood, M. Szwarc, V. Stannett, J. Am. Chem. Soc. 78 (1956) 1122-1125; (k) M. Sawmoto, T. Masuda, T. Higashimura, S. Kobayashi, T. Saegusa, Makromol. Chem. 178 (1977) 389-399; (l) F. Bolza, F. E. Treioar, Makromol. Chem. 181 (1980) 839-855; (m) R. González, R. Martínez, P. Ortiz, Makromol. Chem. 193 (1992) 1-9. [7] R.M. Cory, B.M. Ritchie, A.M. Shrier, Tetrahedron Lett. 31 (1990) 6789-6792. [8] E. Nakamura, I. Iwajima, Org. Synth. 65 (1987) 17-25. [9] (a) R. Schmid, P.L. Huesmann, W.S. Johnson, J. Am. Chem. Soc. 102 (1980) 5122-5123; (b) J. Amupitan, J.K. Sutherland, J. Chem. Soc., Chem. Commun. (1980) 398; (c) W.S. Johnson, S.D. Lindell, J. Steele, J. Am. Chem. Soc. 109 (1987) 5852-5853. [10] W.G. Dauben, A. Chollet, Tetrahedron Lett. 22 (1981) 1583-1586. [11] R. Pathak, S. Madapa, S. Batra, Tetrahedron 63 (2007) 451-460. [12] N.I. Medvedeva, O.B. Flekhter, O.S. Kukovinets, F.Z. Galin, G.A. Tolstikov, I. Baglin, C. Cavé, Russ. Chem. Bull. 56 (2007) 835-837. [13] (a) R.P. Lutz, Chem. Rev. 84 (1984) 205-247; (h) A.M. Martin-Castro, Chem. Rev. 104 (2004) 2939-3002. [14] (a) J.R. Velandia, M.G. de Carvalho, R. Braz-Filho, J. Braz. Chem. Soc. 7 (1996) 275-286; (b) U. Widmer, H.-J. Hansen, H. Schmid, Helv. Chim. Acta 56 (1973) 2644. [15] N. Geetha, K.K. Balasubramanian, Tetrahedron Lett. 39 (1998) 1417-1420. [16] R. Venkateswarlu, C. Kamakshi, P.V. Subhash, S.G.A. Moinuddin, M.P. Gowri, R.S. Ward, A. Pelter, M.B. Hursthouse, S.J. Coles, M.E. Light, Tetrahedron 61 (2005) 8956-8961. [17] D.M. Krein, P.J. Sullivan, K. Turnbull, Tetrahedron Lett. 37 (1996) 7213-7216. [18] K. Turnbull, D.M. Krein, Synthesis (1999) 391-392.
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Ac ce
pt
ed
M
an
us
cr
ip t
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Trifluoroacetic Acid: Uses and Recent Applications in Organic Synthesis Simón E. López* and José Salazar Rearrangements Protecting group removal
Trifluoromethylations O CF3 building blocks F3C
Trifluoroacetic acid Reductions
Reactions with organophosphorus reagents
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Hydroarylations
Oxidations
OH
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Condensations
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Many chemical transformations should be done with the aid of TFA. Trifluoroacetic acid has important properties for its use in organic synthesis, such as low boiling point, high dielectric constant and strong acidity.
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A number of pharmaceutical intermediates and agrochemicals should be prepared using TFA as a reagent or its derivatives during their synthesis.
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