Iron(III) trifluoroacetate [Fe(O 2 CCF 3 ) 3 ] catalyzed epoxide opening with amines

Non-hygroscopic, non-toxic, and readily available iron(III) trifluoroacetate [Fe(O 2 CCF 3 ) 3 ] was found to be a highly regioselective catalyst for the ring opening of a wide variety of epoxides with diverse amines under solvent-free conditions. The stereospecific ring opening of ( R )-styrene oxide ( 4 ) with p -anisidine ( 2b ) in the presence of 1 mol% of Fe(O 2 CCF 3 ) 3 gave 2-( p - methoxyphenyl-amino)-2-phenylethanol ( 5b ) in enantiopure form (>99 % ee ) within 60 minutes.


Introduction
The 1,2-amino alcohol functionality is found in many naturally occurring molecules (such as alkaloids) and bioactive synthetic molecules exhibiting diverse biological activities 1 (such as βblocking activity, 2a-c cytotoxicity 2d etc.).The β-amino alcohols have been also extensively used as chiral auxiliars and chiral ligands in asymmetric synthesis. 3The most frequently used method for the generation of 1,2-amino functionality is the ring opening of epoxides with amines.Per the usual method for the preparation of 1,2-amino alcohols, an epoxide and the excess of the amine are heated together in a protic solvent. 4However, this method has several limitations, such as moderate chemo-and regio-selectivity, low yields, no toleration of certain functional groups, etc.Therefore, a number of catalytic methods for the ring opening of epoxides with stoichiometric amount of amines have been developed in the literature.Certain metal salts were employed as Lewis acids for this purpose. 5Several novel concepts have also been described by means of heterogenous catalytic systems, 6a-h organic molecules (hexafluoro-2-propanol [HFIP] 6i and tributylphosphine [Bu 3 P] 6j ), water, 6k and ionic liquids (ILs).6l The majority of the existing methods for the aminolytic opening of epoxides suffer from some drawbacks, such as the need for expensive or toxic catalysts, high catalyst loading, long reaction times, low yields, narrow substrate scope, chemo-and regio-selectivity etc.On the other hand, the use of non-toxic, inexpensive, recyclable, and readily available catalysts is indispensable for the sustainable chemical industry.
In respecting the above mentioned considerations, we decided to develop a green method 7 for the synthesis of 1,2-amino alcohols through the epoxide opening with amines.Iron is the most abundant transition metal on earth and its inexpensive salts are non-toxic.Herein, we report the aminolytic epoxide opening catalyzed by iron(III) trifluoroacetate [Fe(O 2 CCF 3 ) 3 ] as a non-toxic, non-hygroscopic, and environmentally friendly catalyst. 8In contrast to other iron(III) salts (e.g.FeCl 3 ), iron(III) trifluoroacetate is remarkably non-hygroscopic and bench-stable for long periods (e.g.longer than 6 months during our studies).
Table 2. Fe(O 2 CCF 3 ) 3 catalyzed ring opening of racemic styrene oxide (rac-4) with aromatic and aliphatic amines under solvent-free conditions a

Ph
Entry Amine Fe(O 2 CCF 3 ) 3 (mol%) To extend the generality and selectivity of Fe(O 2 CCF 3 ) 3 catalyzed aminolytic epoxide opening further, we allowed various epoxides to react with aniline (2a) in the presence of 1 mol% of Fe(O 2 CCF 3 ) 3 (Table 3).The treatment of cyclopentene oxide (7) with an equimolar amount of aniline (2a) at room temperature for 3 h in the presence of 1 mol% of Fe(O 2 CCF 3 ) 3 gave trans-2-(phenylamino)cyclopentanol (rac-8) in good yield (79% y; Table 3, entry 1).The reaction of epichlorohydrin (rac-9) with aniline (2a) at room temperature for 1 h in the presence of 1 mol% of Fe(O 2 CCF 3 ) 3 afforded the amino alcohol rac-10 as the sole regioisomer formed by the nucleophilic attack of aniline (2a) at the less hindered carbon atom of the epoxide ring (82% y; entry 2).The reaction of phenoxymethyl oxirane (rac-11) with aniline (2a) in turn furnished the corresponding amino alcohol rac-12 as only one regioisomeric product in good yield (78% y; entry 3).While the reaction of epichlorohydrin (rac-9) and phenoxymethyl oxirane (rac-11) gave the corresponding amino alcohols rac-10 and rac-12 in good yields under full-regioselectivity, in the reaction between 1-hexene oxide (rac-13) and aniline (2a) a moderate yield (58% y) and somewhat diminished regioselectivity (rac-14/rac-15 = 84:16; entry 4) were observed.It was also observed that the reaction between rac-13 and 2a was rather exothermic and 2a was not fully consumed at the end of the reaction (TLC).Additionally, another (side) product was observed on the TLC plate which was then isolated by column chromatography.The isolated side product (one spot on the TLC plate) was a mixture of two dimerization products formed from the reaction of two equivalents of 1-hexene oxide (rac-13) and one equivalent of aniline (2a) (GCMS, NMR).We isolated the mixture of the side products in a 25% yield.According to the NMR and GC spectra of the side products, the dimerization of 1-hexene oxide (rac-13) with aniline (2a) catalyzed by Fe(O 2 CCF 3 ) 3 proceeded via the ring opening of the second 1-hexene oxide molecule (rac-13) by the nucleophilic attack of the oxygen atom of the amino alcohols rac-14 and rac-15, and not the nitrogen atom.
In order to elucidate the stereospecificity of the Fe(O 2 CCF 3 ) 3 catalyzed aminolytic epoxide opening, the reaction of enantiomerically pure (R)-styrene oxide (4, >99% ee) with p-anisidine (2b) was performed (Scheme 1).We are pleased to report that the corresponding amino alcohol 5b was obtained in enantiopure form in high yield and under high regioselectivity from enantiopure (R)-styrene oxide (4) and p-anisidine (2b) in the presence of 1 mol% of Fe(O 2 CCF 3 ) 3 (93% y, 5b/6b = 98:02, >99% ee for 5b).To the best of our knowledge, this is the first report on the synthesis of 5b in enantiopure form. 9Since enantiomerically pure epoxides are currently available by the hydrolytic kinetic resolution (HKR) of epoxides, this method could be rather useful for the synthesis of enantiopure 1,2-amino alcohols from enantiopure epoxides and amines. 10 In summary, we have shown that a very low amount of Fe(O 2 CCF 3 ) 3 (down to 1 mol%) can catalyze the ring opening reactions of a wide variety of epoxides with aromatic and aliphatic amines to give corresponding 1,2-amino alcohols under solvent-free conditions.High yields, high regioselectivities, and short reaction times were the general features of this catalytic system.Furthermore, stereospecific ring opening of (R)-styrene oxide (4) with p-anisidine (2b) could be conducted without loss of enantiopurity.The non-toxicity, ready availability of Fe(O 2 CCF 3 ) 3 along with the great abundance of iron in nature could make this catalytic system rather attractive for the large scale applications in the chemical industry.

Experimental Section
General Procedures.All of the reactions were carried out in oven-dried Schlenk tubes under a positive pressure of argon.Epoxides were purchased from Aldrich or Fluka, and were used as received.Iron(III) trifluoroacetate [Fe(O 2 CCF 3 ) 3 ] was prepared according to the usual procedure described in the literature.8a Thin layer chromatography (TLC) was conducted on aluminum sheets that were pre-coated with silica gel SIL G/UV 254 from MN GmbH & Co., in which the spots were visualized in UV-light (λ = 254 nm) and/or by staining with 5% of a phosphomolybdic acid solution in ethanol.Chromatographic separations were performed using silica gel (MN-silicagel 60, 230-400 mesh).The melting points were measured in open glass capillary using a Gallenkamp melting point apparatus and were uncorrected.NMR spectra were recorded on Bruker DPX400 NMR spectrometer.Chemical shifts δ are reported in parts per million (ppm) relative to the residual protons in the NMR solvent (CHCl 3 : δ 7.24) and carbon resonance of the solvent (CDCl 3 : δ 77.0).Mass spectra were recorded on a gas chromatography with mass sensitive detector from ThermoQuest Finnigan Multi Mass (EI, 70 eV Sucromat Digital Automatic Saccharimeter using 10 mL cell with a 1 dm path length and the sample concentration is given in g/100 mL unit.All the products are known in the literature and were characterized by NMR and GC-MS.NMR spectra were found to be consistent with those reported in the literature (rac-3a 5a , rac-3b 5a , rac-3c 5a , rac-3d 5a , rac-5a 5a , rac-5b 5a , rac-5c 5u , rac-6c 5g , rac-5d 11 , rac-6d 11 , rac-8 5a , rac-10 5a , rac-12 5a , rac-14 12 ).Selected spectral data were given below.Although heat evolution took place in the ring opening of epoxides with aromatic amines there was no safety problem in all reactions.

a
Reactions were carried out by employing equimolar amounts of epoxide 1 and amines 2a-d on a 2.5 or 5.0 mmol scale.b Yield of isolated product after column chromatography.c Determined by NMR.

Table 1 .
Fe(O 2 CCF 3 ) 3 catalyzed ring opening of cyclohexene oxide (1) with aromatic and aliphatic amines under solvent-free conditions a