Mild Debenzylation of Aryl Benzyl Ether with BCl₃ in the Presence of Pentamethylbenzene as a Non-Lewis-Basic Cation Scavenger

Abstract

Scope and limitations of the debenzylation conditions for aryl benzyl ether, which was developed during our synthetic studies on yatakemycin, were investigated. The chemoselective debenzyl­ation proceeds at low temperature with a combination of BCl₃ and pentamethylbenzene as a cation scavenger in the presence of various functional groups.

Key words

protecting groups - total synthesis - phenols - debenzyl­ation - aryl benzyl ethers

References and Notes

• 1a Kocienski PJ. Protecting Groups   Thieme; New York: 1994. 
• 1b Wuts PGM. Greene TW. Protective Groups in Organic Synthesis   4th ed.:  Wiley-Interscience; New York: 2006. 
• 2a Okano K. Tokuyama H. Fukuyama T. J. Am. Chem. Soc.  2006,  128:  7136 
• 2b Okano K. Tokuyama H. Fukuyama T. Chem. Asian J.  2008,  3:  296 
• 3 Chong R. Gray RW. King RR. Whalley WB. J. Chem. Soc. D  1970,  101 
• 4a Kiso Y. Isawa H. Kitagawa K. Akita T. Chem. Pharm. Bull.  1978,  26:  2562 ; treatment of O-benzyltyrosine with TFA yielded tyrosine and undesired 3-benzyltyrosine in the ratio of 57:43
• 4b Kiso Y. Ukawa K. Nakamura S. Ito K. Akita T. Chem. Pharm. Bull.  1980,  28:  673 ; a combination of thioanisole with TFA was effective to debenzylation of O-benzyltyrosine without formation of 3-benzyltyrosine
• 5a Various cation scavengers on debenzylation of O-benzyltyrosine in TFA were investigated. It was reported that pentamethylbenzene increased the rate of deprotection most efficiently among other scavengers such as thioanisole, anisole, 1,3-dimethoxybenzene, 1,2,3-dimethoxybenzene, m-xylene, 1,2,3-trimethylbenzene, and 1,2,3,4-tetramethylbenzene. Isolation and characterization of benzylpentamethylbenzene generated by trapping of benzyl cation were also reported. See: Yoshino H. Tsuchiya Y. Saito I. Tsujii M. Chem. Pharm. Bull.  1987,  35:  3438 
• 5b Yoshino H. Tsujii M. Kodama M. Komeda K. Niikawa N. Tanase T. Asakawa N. Nose K. Yamatsu K. Chem. Pharm. Bull.  1990,  38:  1735 
• 6 Tummatorn J. Khorphueng P. Petsom A. Muangsin N. Chaichit N. Roengsumran S. Tetrahedron  2007,  63:  11878 

7

Physical and Spectroscopic Data for 2-Benzyl-4,5-dimethoxyphenol (5) Colorless oil; R _f  = 0.43 (hexanes-EtOAc, 1:1). ^¹H NMR (600 MHz, CDCl₃): δ = 7.32-7.26 (m, 2 H), 7.25-7.17 (m, 3 H), 6.66 (s, 1 H), 6.45 (s, 1 H), 4.37 (s, 1 H), 3.93 (s, 2 H), 3.83 (s, 3 H), 3.80 (s, 3 H). ^¹³C NMR (151 MHz, CDCl₃):
δ = 148.5, 147.7, 143.1, 140.0, 128.7, 128.4, 126.4, 117.6, 114.5, 101.3, 56.6, 55.9, 36.0. IR (neat): 3445, 2932, 1614, 1520, 1452, 1416, 1205, 1109, 997, 669 cm^-¹. HRMS (EI⁺): m/z calcd for C₁₅H₁₆O₃ [M⁺]: 244.1099; found: 244.1089.

8

Boron trichloride (1.0 M in CH₂Cl₂) was purchased from Aldrich Chemical Company and was used as supplied. Pentamethylbenzene was purchased from Tokyo Chemical Industry Co., Ltd. and was used as supplied.
Typical Procedure (Table 3, Entry 20)
To a stirred solution of N-[3-(benzyloxy)phenyl]-2,2,2-trifluoroethanamide (1.61 g, 5.44 mmol, 1.0 equiv) and pentamethylbenzene (2.42 g, 16.3 mmol, 3.0 equiv) in dry CH₂Cl₂ (27.0 mL) was added BCl₃ (1.0 M in CH₂Cl₂, 10.9 mL, 2.0 equiv) dropwise over 10 min via syringe at -78 ˚C. After 15 min, TLC indicated complete consumption of the starting material. The reaction was quenched with CHCl₃-MeOH (10:1, 20 mL) at -78 ˚C, and the resulting mixture was warmed to r.t. The excess organic solvents were removed under reduced pressure. The residue was purified by column chromatography on SiO₂ (eluent: hexanes to hexanes-EtOAc = 1:1, gradient) to provide 2,2,2-trifluoro-N-(3-hydroxyphenyl)ethanamide (1.10 g, 5.36 mmol, 99%).
Physical and Spectroscopic Data for 2,2,2-trifluoro- N -(3-hydroxyphenyl)ethanamide
Colorless crystals; R _f  = 0.54 (hexanes-EtOAc, 1:1); mp 128.4-129.6 ˚C (hexanes-EtOAc). ^¹H NMR (600 MHz, CDCl₃): δ = 7.81 (br s, 1 H), 7.37-7.34 (m, 1 H), 7.25 (dd, 1 H, J = 7.8, 7.8 Hz), 6.95 (dd, 1 H, J = 7.8, 1.2 Hz), 6.74 (dd, 1 H, J = 7.8, 2.4 Hz), 5.22 (s, 1 H). ^¹³C NMR (100 MHz, CD₃OD): δ = 158.9, 156.5 (q, ^² J _C-F = 37 Hz), 138.5, 130.6, 117.3 (q, ^¹ J _C-F = 285 Hz), 113.8, 113.1, 109.2. IR (neat): 3312, 1715, 1614, 1566, 1495, 1456, 1188 cm^-¹. HRMS (FAB⁺): m/z calcd for C₈H₇NO₂F₃ [M + H⁺]: 206.0429; found: 206.0427.