Tetramethylfluoroformamidinium hexafluorophosphate (TFFH)/ benzyltriphenylphosphonium dihydrogen trifluoride (PTF): a unique reagent for the conversion of carboxylic acids to the corresponding alcohols as well as hydroxamic acids

The present work describes the utility of TFFH ( 1 ) for the conversion of carboxylic acids to the corresponding alcohols 4 as well as the hydroxamic acids 5 in the presence or absence of the fluoride additive PTF ( 3 ) . The addition of the fluoride additive 3 during the activation step improves the yield and purity of the products, due to the fast activation to the acid fluoride derivatives as observed from IR examination.


Introduction
Halouronium salts are frequently described as good reagents especially for coupling of sterically hindered N-substituted or N,N-disubstituted amino acids, which is not easily carried out under standard conditions. 1 Tetramethylfluoroformamidinium hexafluorophosphate 1 (TFFH), was introduced by Carpino and El-Faham 2 as a benign substitute for the corrosive cyanuric fluoride 2. Cyanuric fluoride 2 was reported as a mild reagent, suitable for the preparation of acyl fluorides even when unsaturated double bonds, hydroxyl groups, or aromatic rings are present. 3,4TFFH has been shown to act as a coupling reagent that proceeds via in situ conversion to an acid fluoride. 2,5Acyl fluorides, having a greater stability than the corresponding chlorides towards neutral oxygen nucleophiles such as water and methanol, appear to be of equal reactivity toward anionic nucleophiles and amines. 6Recently, Fmoc-, 7 Boc-, or Z-amino acid fluorides 8 have been found to be stable and fast acylating reagents for peptide bond formation.Moreover, TFFH (1) was reported as a convenient reagent for the preparation of isothiocyanates from the corresponding primary amines in the presence of carbon disulfide. 9In a recent paper, 10 we described TFFH as a useful reagent for the conversion of carboxylic acids into anilides, hydrazides as well as acyl azides.The present work extends the utility of TFFH (1) for eventual conversion of carboxylic acids to the corresponding alcohols and hydroxamic acids.Moreover, addition of the fluoride additive (PTF, 3) 11 during the activation step with 1, improves the yield and purity of the desired products.

Results and Discussion
Carboxylic acids 4a-h were converted into the corresponding fluorides by treatment with 1 in the presence of triethylamine or diisopropylethylamine as a base (Scheme 1).Acyl fluorides were then reduced in situ to the primary alcohols by sodium borohydride with dropwise addition of methanol at room temperature.A variety of acids, such as benzoic acid (4a), 2-nitrobenzoic acid (4b) phenylacetic acid (4c), and 9-fluorene carboxylic acid (4d), Boc-Phe-OH (4e), Z-Phe-OH (4f), Fmoc-Leu-OH (4g), Fmoc-Glu(OBn)-OH (4h), were converted into the corresponding alcohols 5a-h respectively in very good yields (Table 1).Addition of PFT (3) during the activation of the carboxylic acid with TFFH improves the yield of the products (Table 1).

Scheme 1
It can be observed from Table 1 that TFFH alone gave lower yields than the TFFH/PTF procedure in case of aryl carboxylic acids (4a-d).The deficiency was traced to inefficient conversion to the acid fluorides, which under the conditions used was accompanied by the formation of the corresponding symmetric anhydrides as observed from infrared examination during the activation step. 10On the other hand it is shown that if a fluoride additive PTF (3) is present during the activation step, the corresponding symmetric anhydrides are avoided and a maximum yield of acid fluoride is obtained.a The products 5a-h were identified by their physical constants, IR, 1 H NMR data and comparison with data reported in the literature.b Yields are of isolated and purified products c The present method (TFFH alone or TFFH/PTF) proceeds with retention of optical purity as indicated by comparison of the specific rotation values with those reported in the literature. 3Protected amino alcohols are important synthetic intermediates, particularly in the synthesis of peptides that are potent inhibitors of proteases, 12 and are also incorporated at the Cterminal of biological active peptides. 13The conversion of amino acids into alcohols by chemoselective reduction of their corresponding mixed anhydrides 14 and N-carboxyanhydrides 15 with sodium borohydride has also been reported.In the present work, a variety of N-protected amino acids 4e-h were converted rapidly into alcohols 5e-h by in situ reduction of their corresponding acid fluorides with sodium borohydride in high yield.There was not much difference between TFFH alone or the TFFH/PTF method (Table 1), because the symmetric anhydride was not observed during IR examination.
The present work also describes a useful method for the preparation of a variety of hydroxamic acids using TFFH (1) alone, or in the presence of the fluoride additive PTF (3).Carboxylic acids 6a-b as well as N-protected amino acids 6c-i were activated for 5 min with TFFH alone, or the TFFH/PTF mixture, in the presence of triethylamine (Et 3 N) or diisopropylethyl amine (DIEA) as a base in dichloromethane (DCM) followed by addition of ARKAT hydroxylamine.HCl at 0 o C. The reaction mixture was warmed to room temperature and then stirred at room temperature overnight.After workup, the products were obtained in high yields and purity (Table 2, Scheme 2).There was no difference in the yield and purity for urethane Nprotected amino acids with the use of TFFH alone or TFFH/PTF.5.4(c 1, DMF) *All compounds 7a-i gave a positive test for hydroxamic acids on treatment with iron (III) chloride solution. 16 IR and 1 H NMR spectra of compounds 7a-i were in accordance with their structure b Yields are of isolated and purified products

Conclusions
The TFFH/PTF procedure provides a general, rapid, and convenient method for the conversion of carboxylic acids in the presence of NaBH 4 into alcohols as well as to hydroxamic acids.The present method proceeds also with retention of optical purity as indicated by comparison of the specific rotation values with those reported in the literature.

Experimental Section
General Procedures.Melting points was obtained in open capillary tubes using a melting heating apparatus and are uncorrected.NMR spectra were recorded using a Bruker 300 MHz or a Jeol 500 MHz instrument with TMS as internal standard.Infrared spectra were obtained using a Shimadzu 8300 series Fourier Transform instrument.Optical rotations were measured at 25 o C. All asymmetric amino acids derivatives were of the L-configuration and were purchased from Fluka Chemical Co.All solvents and chemical were of reagent grade and used without further purification.Silica gel 60 (70-230 mesh, Merck) was used for column chromatography.General Procedure for the Preparation of Alcohols (5a-h): TFFH or TFFH/PTF (2 mmol, 0.528 g/0.824 g respectively) was added to a stirred solution of the acid 4a-d (2 mmol) and Et 3 N (4 mmol, 0.404 g) or N-protected amino acid 4e-h (2 mmol) and diisopropylamine (DIEA, 4 mmol, 0.516 g) in CH 2 Cl 2 (5 mL), and kept under a N 2 atmosphere at 0 o C.After the mixture was stirred at 0 o C for about 1 h, ice-cold water (10 mL) was added along with CH 2 Cl 2 (20 mL).The organic layer was separated, and the aqueous layer was extracted once with CH 2 Cl 2 (10 mL).The combined organic layer was washed with ice-cold water (10 mL), dried (MgSO 4 ), and concentrated under reduced pressure to a small volume (2 mL).NaBH 4 (76 mg, 2 mmol) was added in one portion, and MeOH (2 mL) was then added dropwise over a period of 15-20 min at rt.The reaction mixture was neutralized with 1N H 2 SO 4 , and the organic solvents were evaporated under pressure.The residue was treated with EtOAc (10 mL) and H 2 O (5 mL); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL).The combined organic layers were washed consecutively with 1N H 2 SO 4 (5 mL) and H 2 O (2 x 10 mL) and dried (MgSO 4 ), the solvent was evaporated under reduced pressure.The residue was purified by distillation or column chromatography using EtOAc/hexane (1:1) as an eluent.General Procedure for the Preparation of Hydroxamic Acids (7a-i): TFFH or TFFH/PTF (2 mmol, 0.528 g/0.824 g respectively) was added to a stirred solution of the acid 6a-b (2 mmol) and Et 3 N (4 mmol, 0.404 g) or N-protected amino acid 6c-i (2 mmol) and diisopropylamine (DIEA, 4 mmol, 0.516 g) in CH 2 Cl 2 (10mL) and was activated for 5-10 min at 0 o C. Hydroxylamine hydrochloride (140 mg, 2 mmol) and Et 3 N or diisopropylamine (2 mmol) were added to the reaction mixture at 0 o C.After the addition, the reaction mixture was warmed to Scheme 2 11

Table 1 .
Reduction of carboxylic acids and N-protected amino acids to alcohols

Table 2 .
Preparation of aryl hydroxamic acids and N-protected amino hydroxamic acids using TFFH or TFFH/PTF*