Additional Nucleophile-Free FeCl₃-Catalyzed Green Deprotection of 2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids

Abstract

The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtration.

The protection/deprotection method is important and the deprotection under mild conditions associated with perfect tolerance of the non-target functional groups can be a powerful tool to effectively construct the target molecules in organic reactions.¹⁾ The 4-methoxyphenylmethyl (MPM) group and its derivatives are widely utilized as the protecting group of alcohols, and the various deprotection methods have been developed.^1–21) 4-MPM ethers are generally deprotected by the use of a stoichiometric amount of oxidants [2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)^2,3) and ceric ammonium nitrate (CAN)^4,5)], Pd/C-catalyzed hydrogenation under atmospheric hydrogen gas¹⁾ or the combination of a stoichiometric amount of nucleophiles and the catalytic or stoichiometric Lewis acids^6–17) [Chart 1, (a)–(d)]. However, the stoichiometric byproducts derived from 4-MPM protective groups (e.g., anisaldehydes, and toluene derivatives) and the acidic residues derived from reagents when using DDQ and CAN should be removed from the reaction mixture by the purification process using silica-gel column chromatography. In addition, a stoichiometric amount of Ph₃C·BF₄^18,19) and the chlorosulfonyl isocyanate (CSI)–NaOH combination²⁰⁾ has also been used for the deprotection of the 4-MPM ether. Although a catalytic method using ZrCl₄ in CH₃CN has been developed for the deprotection of the 4-MPM ether, silica-gel column chromatography purification is necessary to remove the undefined side-products.²¹⁾ We have found that the widely used iron(III) chloride (FeCl₃) could effectively activate the benzylic position and achieved various reactions accompanied by the cleavage of the benzylic C–O bond to construct unique skeletons.^22–29) Furthermore, we have recently developed the FeCl₃-catalyzed self-cleaving deprotection method of various types of MPM ethers without the addition of nucleophiles³⁰⁾ [Chart 1, (e)]. We now report the extensive results of the FeCl₃-catalyzed deprotection method of 2,4-dimethylphenylmethyl (DMPM)-protected alcohols without purification using silica-gel column chromatography together with a novel application for the deprotection of 2,4-DMPM-protected carboxylic acids. Because 2,4-DMPM-protected alcohols were found to be preferentially deprotected in comparison with 4-MPM-protected alcohols in the reported methods (DDQ,^1,31) the combination of CeCl₃ and NaI¹⁰⁾ or Ph₃C·BF₄¹⁹⁾), the synthetic route via the 2,4-DMPM-protected alcohol could be adapted in the efficient synthesis of target molecules (e.g., total syntheses of natural products).^19,31,32) However, the problems of side-products derived from 2,4-DMPM group, which should be separated by silica-gel column chromatography, have been unsolved.

Chart 1. General and Novel Deprotection Methods of MPM Type-Protected Alcohols

The 4-MPM-protected 1-decanol (1a) effectively underwent deprotection in the presence of 5 mol% of FeCl₃ without any additional nucleophile in CH₂Cl₂ at room temperature to produce the mother alcohol (2a) and many side-products derived from the 4-MPM moiety, which should be separated by silica-gel column chromatography (Eq. 1). Since benzyl (Bn) ether was tolerant under the FeCl₃-catalyzed conditions, the chemoselective deprotection of the 4-MPM protective group of 1b could be accomplished (Eq. 2). Meanwhile, the deprotection of 3,4-DMPM also efficiently proceeded to form the corresponding deprotected alcohol (2a) and an inseparable mixture of the corresponding cyclic trimer, tetramer, pentamer and hexamer (m/z; 478.1934, 623.2623, 773.3293, 923.3951 [M+Na]⁺)^33–35) of the 3,4-DMPM protective group, which were detected and determined by an electrospray ionization (ESI)/MS spectral analysis (Eq. 3, the chart is in the Supplementary Materials). It is noteworthy that the FeCl₃-catalyzed deprotection of the 2,4-DMPM ether (1d) was completed within 5 min and only the sufficiently-pure 1-decanol (2a) was isolated without the purification process using silica-gel column chromatography (Eq. 4, Chart 2, middle ¹H-NMR spectrum). Peaks derived from the 2,4-DMPM group of the substrate (1d, Chart 2, top) were never observed after the filtration and subsequent extraction of the reaction mixture of the deprotection reaction of 1d (Chart 2, middle ¹H-NMR spectrum), and sufficiently-pure 1-decanol (2a) could be obtained in comparison to the spectrum of the commercially available 1-decanol as a standard sample (2a, Chart 2, bottom). During the deprotection of 1d, the resorcinarene derivative (3d) was produced as a hardly-soluble precipitate, which was slightly soluble in CH₂Cl₂, but hardly dissolved in Et₂O. Therefore, the residual mixture containing the deprotected 2a and 3d was treated with Et₂O after removal of CH₂Cl₂ as the solvent under reduced pressure, and the insoluble 3d was simply removed by filtration. The subsequent extraction (Et₂O washing) of the filtrate gave the sufficiently-pure 1-decanol (2a). In a similar fashion, the FeCl₃-catalyzed deprotection of 2,4-dibutoxyphenylmethyl ether (1e) also efficiently proceeded to produce lipophilic resorcin[4]arene octabutyl ether (3e: m/z; 959.6376 [M+Na]⁺ see Supplementary Materials) together with the deprotected 2a (Eq. 5), which strongly supported that the hardly-soluble tetramer of 2,4-DMPM was obtained as nearly the only side-product from the deprotection of 1d (Eq. 4).

Chart 2. Comparison of ¹H-NMR Spectra of 1d and 2a

(Top) substrate 1d; (Middle) deprotection product; (Bottom) standard sample 2a.

The present deprotection of 2,4-DMPM ether (1d) should proceed via the FeCl₃-catalyzed self-assembling mechanism (Chart 3). The electron-rich aromatic ring of 1d attacked the benzylic position of another substrate (1d) activated by FeCl₃ to give the deprotected alcohol (2a) and a corresponding dimer (4). The repeated similar intermolecular nucleophilic attacks continue until the formation of the tetramer (5), which undergoes the intramolecular annulation to give the hardly-soluble 3d accompanied by the complete deprotection. Alternatively, the homo-coupling of the dimer (4) can also directly produce the tetramer (5).

Chart 3. Proposed Reaction Mechanism of Deprotection of 2,4-DMPM Ether

The green and self-cleaving deprotection method of the 2,4-DMPM ether (1d) without the silica-gel column chromatography purification could be accomplished using other Lewis acids (e.g., AuCl₃,^36–38) trimethylsilyl trifluoromethanesulfonate (TMSOTf), BF₃·Et₂O) instead of FeCl₃ in CH₂Cl₂ to produce the deprotected 1-decanol (2a) in high yields within 5 min (Table 1, entries 1–4). On the other hand, Brønsted acids, such as trifluoroacetic acid (TFA) and AcOH, were insufficient and most of the starting material (1d) remained unchanged. CH₂Cl₂ or CH₃CN was found to be an adequate solvent (Table 1, entries 1, 10), while the use of n-hexane, THF or toluene gave the desired deprotected alcohol (2a) in a relatively low yield (entries 7–9).

Table 1. Catalyst and Solvent Efficiencies of Deprotection of 2,4-DMPM-Protected Alcohol (1d)

Entry	Catalyst	Solvent	Time	Yield (%)
1	FeCl3	CH2Cl2	5 min	99
2	AuCl3	CH2Cl2	5 min	99
3	TMSOTf	CH2Cl2	5 min	99
4	BF3·Et2O	CH2Cl2	5 min	97
5	TFA	CH2Cl2	3 h	11 (70)a)
6	AcOH	CH2Cl2	3 h	0 (100)a)
7	FeCl3	n-Hexane	3 h	38 (59)a)
8	FeCl3	THF	3 h	25 (55)a)
9	FeCl3	Toluene	30 min	75
10	FeCl3	CH3CN	5 min	92

a) The yield in parenthesis indicates the recovered starting material (1d).

Furthermore, the deprotection reactions using 2,4-dibutoxyphenylmethyl ether (1e) as a protected alcohol produced the resorcin[4]arene octabutyl ether (3e) as nearly the only tetramer side-product even when using AuCl₃, FeBr₃ and ZnCl₂ as the Lewis acid catalysts instead of FeCl₃ (Eq. 6).

MPM-type protecting groups are also utilized for the protection of carboxylic acids.^1,39,40) Similarly, DDQ or the nucleophile in the presence of a catalytic Lewis acid is used for the deprotection of MPM-protected carboxylic acids. The 2,4-DMPM-protected palmitic acid (6a) was also effectively deprotected using FeCl₃ and AuCl₃ in a short time to give the corresponding deprotected carboxylic acid (7a) in excellent yields (Table 2, entries 1, 2). Although TMSOTf and BF₃·Et₂O were also effective (entries 3, 4), Brønsted acids, such as TFA and AcOH, were insufficient (entries 5, 6). While the FeCl₃-catalyzed deprotection could smoothly proceed in CH₂Cl₂, toluene and CH₃CN as the solvent, n-hexane and THF were found to be inadequate solvents (entries 1, 9, 10 vs. 7, 8). From the viewpoint of cost performance and reaction efficiency, the use of a catalytic amount (5 mol%) of FeCl₃ in CH₂Cl₂ was chosen as the optimum reaction conditions for the deprotection of the 2,4-DMPM-protected carboxylic acids.

Table 2. Catalyst Efficiencies of Deprotection of 2,4-DMPM-Protected Carboxylic Acid (6a)

Entry	Catalyst	Solvent	Time	Yield (%)
1	FeCl3	CH2Cl2	5 min	99
2	AuCl3	CH2Cl2	20 min	96
3	TMSOTf	CH2Cl2	5 min	88
4	BF3·Et2O	CH2Cl2	5 min	86
5	TFA	CH2Cl2	3 h	34 (46)a)
6	AcOH	CH2Cl2	3 h	0 (99)a)
7	FeCl3	n-Hexane	3 h	75 (25)a)
8	FeCl3	THF	3 h	46 (50)a)
9	FeCl3	Toluene	45 min	98
10	FeCl3	CH3CN	5 min	96

a) The yield in parenthesis indicates the recovered starting material (6a).

For the FeCl₃-catalyzed deprotection of 2,4-DMPM-protected carboxylic acid, the rigorous purification process to remove the side-products derived from the 2,4-DMPM protective group was also unnecessary (Chart 4). After the filtration of the resulting precipitate derived from 2,4-DMPM using a small amount of a silica-gel pad, the ¹H-NMR peaks resulting from 2,4-DMPM moiety were hardly observed (top vs. middle) and the sufficiently-pure palmitic acid (7a) was obtained (middle vs. bottom). Due to the highly polar property of the deprotective carboxylic acid (7), the use of water should be avoided during work-up to avoid any undesired loss. Therefore, the reaction mixtures including the deprotected carboxylic acid (7) and the hardly-soluble resorcinarene derivative (3d) were directly filtered with a small amount of a siliga-gel pad. Alternatively, the use of the celite pad for the filtration could also produce the highly pure carboxylic acid (7a). Since resorcin[4]arene octabutyl ether (3e) was also obtained in 95% yield as a tetramer side-product by the FeCl₃-catalyzed deprotection of the 2,4-dibutoxyphenylmethyl ester (6b) (Eq. 7), the formation and structure of the hardly-soluble 3d was equally probable.

Chart 4. Comparison of ¹H-NMR Spectra of 6a and 7a

(Top) substrate 1d; (middle) deprotection product; (Bottom) standard sample 2a.

The versatility of the substrate applicability was next investigated regarding the FeCl₃-catalyzed deprotection of 2,4-DMPM-protected alcohols and carboxylic acids (Table 3). The 2,4-DMPM ethers prepared from primary and secondary alcohols were effectively deprotected into the corresponding mother alcohols within 5 min in nearly quantitative yields without purification by the silica-gel column chromatography (entries 1, 2). Because benzyl ether was stable under the FeCl₃-catalyzed conditions, benzyl 2,4-DMPM ether was perfectly converted into the corresponding benzyl alcohol by the chemoselective cleavage at the electron-rich benzylic position (entry 3) and the 2,4-DMPM ether coexisting benzyl ether within the same molecule was selectively deprotected without the deprotection of the benzyl ether moiety (entry 4). The tert-butyldimethylsilyl (TBS) ether and acetoxy (AcO) group could be tolerant under the present deprotection conditions (entries 5, 6), while the ketal as a protective group of the ketone was partially deprotected along with the complete deprotection of the 2,4-DMPM ether protective group to form a mixture of the ketal and ketone (entry 7). The acidic proton on the hydroxyl group never influenced the deprotection (entry 8) and the 2,4-DMPM-protected phenol was also efficiently deprotected into mother phenol (entry 9).

Table 3. Scope and Limitation^a)

Entry	Substrate	Product	Time	Yield (%)
1			5 min	99
2			5 min	99
3			5 min	92
4			5 min	99
5			5 min	Quant
6			5 min	Quant
7			5 min	69
				31
8			15 min	99
9			5 min	80b)
10			5 min	96
11			5 min	78c)
12			6 h	No reaction
13			5 min	96
14			5 min	99
15			5 min	94
16			5 min	96
17			5 min	75
18			5 min	84
19			5 min	99
20			5 min	87
21			5 min	86

a) The reactions were carried out according to the general procedures shown in Experimental unless otherwise noted. Spectral data without the rigorous purification process are shown in the Supplementary Materials. b) The product was purified by silica-gel column chromatography due to the contamination of unidentified byproducts. c) The yield after the purification using silica-gel column chromatography.

While the sufficiently-pure deprotected carboxylic acid could be obtained after a simple filtration of the 2,4-DMPM deprotection mixture through a small amount of a silica-gel pad (entry 10), the deprotection of the 4-MPM ester required the normal silica-gel column chromatography process to obtain the pure carboxylic acid (entry 11). Meanwhile, the benzyl ester was never deprotected under the FeCl₃-catalyzed conditions (entry 12). The 2,4-DMPM esters derived from branched aliphatic carboxylic acids were also effectively deprotected into the corresponding carboxylic acids in nearly quantitative yields (entries 13, 14). The alkene, alkyne, ketone, tetrahydropyranyl (THP) ether and TBS ether were all tolerable under the deprotection conditions and only the deprotection of 2,4-DMPM could be achieved (entries 15–19). The 2,4-DMPM-protected benzoic acid derivatives were also adaptable to the present deprotection (entries 20, 21).

In conclusion, the 2,4-DMPM ethers and esters were effectively deprotected under inexpensive iron(III) chloride-catalyzed conditions without any additional nucleophile. The deprotections proceeded via the self-assembling mechanism by the nucleophilic attack of the 2,4-DMPM protective group itself to produce the hardly-soluble resorcinarene derivative as a precipitate, which was easily removed by adequate filtration. The present deprotection method generating less residues is useful and environmentally friendly in process chemistry.

Experimental

Deprotection of 2,4-DMPM-Protected Ether (1)

To a solution of the 2,4-DMPM ether (0.2 mmol) in CH₂Cl₂ (1 mL) was added FeCl₃ (0.01 mmol), then stirred at room temperature under argon. After being stirred until the reaction was completed, the reaction mixture was quenched with water (3 mL) and the organic layer (CH₂Cl₂) was evaporated in vacuo. Et₂O was added to the aqueous residue and the resulting precipitate was filtered using a Celite pad and washed with Et₂O. The combined organic layers were dried over Na₂SO₄, and concentrated in vacuo to give the sufficiently-pure alcohol.

Deprotection of 2,4-DMPM-Protected Ester (6)

To a solution of the 2,4-DMPM ester (0.2 mmol) in CH₂Cl₂ (1 mL) was added FeCl₃ (0.01 mmol), then stirred at room temperature under argon. After being stirred until the reaction was completed, the reaction mixture was directly filtrated through a small amount of a silica-gel pad and washed with Et₂O. The filtrate was concentrated in vacuo to give the sufficiently-pure carboxylic acid. When some peaks derived from undetermined side-products were observed in the ¹H-NMR spectra, the analytically-pure deprotected carboxylic acid was obtained after the normal silica-gel column chromatography (Table 3).

Acknowledgment

This work was supported by Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

• 1) Wuts P. G. M., Greene T. W., “Greene’s Protective Groups in Organic Synthesis,” 5th ed., Wiley, Hoboken, 2007.
• 2) Oikawa Y., Yoshioka T., Yonemitsu O., Tetrahedron Lett., 23, 885–888 (1982).
• 3) Horita K., Yoshioka T., Tanaka T., Oikawa Y., Yonemitsu O., Tetrahedron, 42, 3021–3028 (1986).
• 4) Classon B., Garegg P. J., Samuelsson B., Lawesson S.-O., Norin T., Acta Chem. Scand. Ber. B, 38b, 419–422 (1984).
• 5) Johansson R., Samuelsson B., J. Chem. Soc., Perkin Trans. 1, 1984, 2371–2374 (1984).
• 6) Akiyama T., Shima H., Ozaki S., Synlett, 1992, 415–416 (1992).
• 7) Hébert N., Beck A., Lennox R. B., Just G., J. Org. Chem., 57, 1777–1783 (1992).
• 8) Srikrishna A., Viswajanani R., Sattigeri J. A., Vijaykumar D., J. Org. Chem., 60, 5961–5962 (1995).
• 9) Bouzide A., Sauvé G., Synlett, 1997, 1153–1154 (1997).
• 10) Cappa A., Marcantoni E., Torregiani E., Bartoli G., Bellucci M. C., Bosco M., Sambri L., J. Org. Chem., 64, 5696–5699 (1999).
• 11) Yu W., Su M., Gao X., Yang Z., Jin Z., Tetrahedron Lett., 41, 4015–4017 (2000).
• 12) Falck J. R., Barma D. K., Baati R., Mioskowski C., Angew. Chem. Int. Ed., 40, 1281–1283 (2001).
• 13) Falck J. R., Barma D. K., Venkataraman S. K., Baati R., Mioskowski C., Tetrahedron Lett., 43, 963–966 (2002).
• 14) Bikard Y., Mezaache R., Weibel J. M., Benkouider A., Sirlin C., Pale P., Tetrahedron, 64, 10224–10232 (2008).
• 15) Mezaache R., Dembelé Y. A., Bikard Y., Weibel J. M., Blanc A., Pale P., Tetrahedron Lett., 50, 7322–7326 (2009).
• 16) Wang B., Yin Z., Li Y., Yang T. X., Meng X. B., Li Z. J., J. Org. Chem., 76, 9531–9535 (2011).
• 17) Kern N., Dombray T., Blanc A., Weibel J. M., Pale P., J. Org. Chem., 77, 9227–9235 (2012).
• 18) Barton D. H. R., Magnus P. D., Streckert G., Zurr D., J. Chem. Soc., Chem. Commun., 1971, 1109–1110 (1971).
• 19) Fujioka H., Sawama Y., Kotoku N., Ohnaka T., Okitsu T., Murata N., Kubo O., Li R., Kita Y., Chem. Eur. J., 13, 10225–10238 (2007).
• 20) Kim J. D., Han G., Zee O. P., Jung Y. H., Tetrahedron Lett., 44, 733–735 (2003).
• 21) Sharma G. V. M., Reddy C. G., Krishna P. R., J. Org. Chem., 68, 4574–4575 (2003).
• 22) Sawama Y., Nagata S., Yabe Y., Morita K., Monguchi Y., Sajiki H., Chem. Eur. J., 18, 16608–16611 (2012).
• 23) Sawama Y., Shibata K., Sawama Y., Takubo M., Monguchi Y., Krause N., Sajiki H., Org. Lett., 15, 5282–5285 (2013).
• 24) Sawama Y., Shishido Y., Yanase T., Kawamoto K., Goto R., Monguchi Y., Kita Y., Sajiki H., Angew. Chem. Int. Ed., 52, 1515–1519 (2013).
• 25) Sawama Y., Ogata Y., Kawamoto K., Satake H., Shibata K., Monguchi Y., Sajiki H., Kita Y., Adv. Synth. Catal., 355, 517–528 (2013).
• 26) Sawama Y., Shishido Y., Kawajiri T., Goto R., Monguchi Y., Sajiki H., Chem. Eur. J., 20, 510–516 (2014).
• 27) Sawama Y., Goto R., Nagata S., Shishido Y., Monguchi Y., Sajiki H., Chem. Eur. J., 20, 2631–2636 (2014).
• 28) Sawama Y., Asai S., Kawajiri T., Monguchi Y., Sajiki H., Chem. Eur. J., 21, 2222–2229 (2015).
• 29) Asai S., Yabe Y., Goto R., Nagata S., Monguchi Y., Kita Y., Sajiki H., Sawama Y., Chem. Pharm. Bull., 63, 757–761 (2015).
• 30) Sawama Y., Masuda M., Asai S., Goto R., Nagata S., Nishimura S., Monguchi Y., Sajiki H., Org. Lett., 17, 434–437 (2015).
• 31) Smith A. B. III, Safonov I. G., Corbett R. M., J. Am. Chem. Soc., 123, 12426–12427 (2001).
• 32) Imagawa H., Saijo H., Kurisaki T., Yamamoto H., Kubo M., Fukuyama Y., Nishizawa M., Org. Lett., 11, 1253–1255 (2009).
• 33) Wanda S., Cezary K., “Calixarenes and Resorecinarenes,” WILEY-VCH, London, 2009.
• 34) Recent review; Agrawal Y. K., Pancholi J. P., Vyas J. M., J. Sci. Ind. Res., 68, 745–768 (2009).
• 35) Ogoshi T., Kitajima K., Umeda K., Hiramitsu S., Kanai S., Fujinami S., Yamagishi T., Nakamoto Y., Tetrahedron, 65, 10644–10649 (2009).
• 36) AuCl₃ also effectively catalyzed the cleavage of the benzylic C–O bonds.
• 37) Sawama Y., Sawama Y., Krause N., Org. Lett., 11, 5034–5037 (2009).
• 38) Sawama Y., Kawamoto K., Satake H., Krause N., Kita Y., Synlett, 2151–2155 (2010).
• 39) Kim C. U., Misco P. F., Tetrahedron Lett., 26, 2027–2030 (1985).
• 40) Kern N., Dombray T., Blanc A., Weibel J., Pale P., J. Org. Chem., 77, 9227–9235 (2012).