A facile chemoselective deprotection of aryl silyl ethers using sodium hydride/DMF and in situ protection of phenol with various groups

Abstract

An efficient method for the selective removal of aryl silyl protection using NaH in DMF solvent is developed. The method is rapid, operationally simple and can be carried out at room temperature. Excellent chemoselectivity and high yields of phenol products are other advantages of this method. A one-pot desilylation and reprotection as aryl alkyl ethers and esters has also been demonstrated.

---

Introduction

The development of new synthetic methodologies and further refinement through modifications is an unending quest in organic synthesis and method development. A developed method is validated for its synthetic potential, general applicability and usefulness. In the target oriented synthesis of complex molecules especially multi-steps total synthesis, the use of protecting groups becomes inevitable.¹ When multiple protecting groups (PGs) are involved, the selective deprotection is most important and often becomes unpredictable even in the most reliable cases due to substrate specificity.¹ It is more difficult when two same groups are involved at different loci. A subtle difference in the surrounding of the PG or electronic factors can be exploited for a chemoselective deprotection. Of the several known protecting groups, the silyl ether protection for hydroxyl group is very common.¹ This is mainly due to simpler reaction conditions available in protection and deprotection and also that the silyl ether group is stable under basic and mild acidic conditions.^1,2 Tetrabutylammonium fluoride (TBAF) is a very common reagent for the deprotection of silyl ethers. In literature a number of methods are reported for the cleavage of aryl silyl ethers such as fluoride source (TBAF,^2,3a KF/18-C-6,^3b KF/Al₂O₃ ^3c,d and KF/tetraethylene glycol^3e), acids (HF^4a,b and CSA^4c), strong bases (alkali hydroxides^5a–d and carbonates^5e–g), organic bases (TMG^6a,b) and tetraethyl amine N-oxide^6c), LiOAc⁷ and phosphate.⁸ The catalytic use of LiOAc for selective aryl silyl deprotection is noteworthy. They proposed Lewis acid–Lewis base bifunctional catalyst model to rationalize the efficiency and selectivity.⁷ The electronic nature of alkyl and aryl groups revealed that the aryl silyl ethers are more liable to base hydrolysis than alkyl silyl ethers. Although this approach works well for deprotection of silyl ether with above reagents, there are some limitations to use them in multi-steps synthesis such as long reaction time, harsh reaction conditions and low selectivity. Herein we report a simple, efficient and highly chemoselective method for the deprotection of different aryl silyl ethers by using sodium hydride in DMF in a very short reaction time (few minutes) and with excellent yields. In addition, the in situ protection of resulting phenolate with other protecting groups like allyl, methyl, isopropyl, MOM, benzyl and acyl is also developed.

Results and discussion

In our recent total synthesis of astropaquinones B and C, the compound 1 on treatment with NaH/MeI delivered compound 2 (Scheme 1).⁹ The aryl silyl ether was cleaved and subsequently both phenolic hydroxyl groups were methylated, while the aliphatic silyl ether was intact. In another reaction, the addition of NaH to compound 1 in DMF gave compound 3 through chemoselective deprotection of aryl silyl ether. We planned to optimize this reaction as literature search revealed that NaH has not been used for selective deprotection of aryl silyl ether. The optimization study is shown in Table 1.

Scheme 1 Chemoselective deprotection of aryl silyl ether.

Table 1 Optimization of desilylation of silyl ether 4a using NaH

Entry	Solvent	NaH (equiv.)	Temp. (°C)	Time	Yield^a (%)
a Isolated yields.
1	DMF	2	rt	5 min	100
2	DMF	2	0 °C	8 min	95
3	DMF	1.5	rt	9 min	99
4	DMF	1	rt	40 min	95
5	THF	2	rt	6 h	90
6	Benzene	2	rt	6 h	—
7	Benzene	2	60 °C	12 h	—
8	Toluene	2	60 °C	12 h	—
9	Et2O	2	rt	12 h	—
10	1,4-Dioxane	2	rt	20 h	74
11	1,4-Dioxane	2	60 °C	6 h	80
12	DMSO	2	rt	8 min	85

---

We studied the solvent dependence and equivalents of NaH along with temperature effects in the selective desilylation reaction. The desilylation of model compound 4a with NaH (2.0 equiv.) in DMF occurred within 5 minutes at room temperature giving 5a in quantitative yield (Table 1, entry 1). The same reaction at 0 °C required 8 min for completion giving 5a in 95% yield (Table 1, entry 2). Lowering of NaH concentration to 1.5 equiv. and at room temperature the reaction was equally rapid giving 5a in 99% yield in 9 min (Table 1, entry 3). Further lowering of NaH to 1 equiv., the reaction was comparably slow and produced 5a in 95% yield after 40 min (entry 4). The desilylation of 4a in dry THF at room temperature gave 5a in excellent yield (90%), but the reaction took 6 h to complete (entry 5). The same reaction in other aprotic solvents like benzene (room temperature and 60 °C), toluene and diethyl ether failed to desilylate 4a (entries 6–9) and resulted in recovery of unreacted 4a showing a solvent dependence. In case of reaction in 1,4-dioxane solvent at room temperature and at 60 °C, it gave 5a in 74% and 80% yields respectively (entries 10 and 11). The reaction in DMSO solvent was also rapid (8 min, entry 12) but provided 5a in lower yield (85%). With the optimized conditions which include the use of NaH (1.5 equiv.) in DMF at room temperature we evaluated the scope and limitations of this method (we chose a lower concentration of NaH, i.e. 1.5 vs. 2.0 equivalents as the reaction time was comparable, 9 vs. 5 min, entry 3 vs. entry 1).

Various aryl silyl ethers were subjected to desilylation using NaH (1.5 equiv.) in DMF solvent at room temperature. The results are shown in Table 2. Thus, compounds 4a–c with 4-bromo-3-alkoxy group (i-Pr, Me and Bn) gave the corresponding phenols 5a–c in excellent yields in just 9 to 12 minutes of reaction time (Table 2, entries 1–3). Similarly compounds with electron rich aryl ring 4d–g produced the corresponding phenols 5d–g in good to excellent yields (entries 4–7). Compounds with electron withdrawing groups (CHO, NO₂ or OAc), 4h–l also reacted effectively producing the phenols 5h–l in good to quantitative yields (entries 8–12). Other functional groups like MOM (4m) or ester (4n and 4o) were also tolerated (entries 13–15). Bis-silylated compound 4p with NaH (3 equiv.) gave resorcinol 5p in a 10 minute reaction in quantitative yield (entry 16).

Table 2 Desilylation of aryl silyl ethers with NaH/DMF

Entry	Substrate	Product	Time (min)	Yield^a (%)
a Isolated yields.b NaH (3.0 equiv.) was used.
1		5a	9	100
2		5b	10	93
3		5c	12	92
4		5d	12	91
5		5e	9	83
6		5f	9	88
7		5g	9	85
8		5h	9	97
9		5i	8	93
10		5j	9	91
11		5k	3	100
12		5l	3	75
13		5m	3	100
14		5n	3	97
15		5o	2	98
16^b		5p	10	100

---

The desilylation method was further explored for chemoselective deprotection of aryl silyl ethers against the alkyl silyl ethers. There are limited literature methods available for chemoselective deprotection, for example using K₂CO₃/EtOH,^5e LiOH/DMF,^5a Cs₂CO₃/DMF/H₂O^5f or using acid/base conditions.¹⁰ We observed the present method showed excellent chemoselectivity and gave high yields towards mono desilylation of aryl silyl groups producing exclusive phenol products as shown in Table 3. The method was quite rapid and the reactions were completed in a few minutes. Thus various bis-silylated compounds 6a–f underwent a rapid desilylation of aryl silyl group producing the corresponding phenols 7a–f (Table 3, entries 1–6) in high yields and exclusive chemoselectivity. The naphthalene compounds 6g and 6h also reacted well giving 7g and 7h respectively in good yields. The compound 6i with two aryl OTBS groups was desilylated in 60 min to give 7i in 93% yield. The bis-desilylation was slow in the latter case probably that the first formed phenolate retards the second desilylation.

Table 3 Chemoselective desilylation of aryl silyl ethers in presence of alkyl silyl ethers

Entry	Substrate	Product	Time (min)	Yield^a (%)
a Isolated yields.b NaH (3.0 equiv.) was used.
1			8	95
2			9	92
3			10	97
4			9	100
5			9	91
6			9	100
7			10	92
8			15	85
9^b			60	93

---

We also investigated a chemoselective deprotection of aryl silyl ethers with NaH (1.5 equiv.) and in situ reprotection with various groups giving aryl ethers and esters. Remarkably the one-pot desilylation and etherification or esterification proceeds in a short reaction time with good yields (Table 4). When we subjected the aryl OTBS compound 4c for one-pot TBS deprotection with NaH in DMF and then etherification with different groups (viz. Me, Bn, MOM) and acylation, it delivered the corresponding ethers 8a–c and ester 8d in 30 to 35 min in good yields (Table 4, entries 1–4). The chemoselective removal of only aryl silyl ether in 6f followed by one-pot etherification or esterification of phenol afforded the corresponding ethers 8e–i and ester 8j in excellent yields (entries 5–10). Similarly, the naphthalene compound 6g delivered the ethers 8k and 8l in good yields (entries 11 and 12). Compounds 6j and 1 on one pot methylation produced 8k and 2 in 68 and 70% yields respectively (entries 13 and 14). The bis-OTBS aryl compound 6i reacted efficiently in 35 min to give 8m in 82% yield (entry 15). The reaction time here was shorter than only desilylation (Table 3, entry 9, 60 min). Here the first formed phenolate probably gets immediately methylated. This favours the second desilylation and methylation.

Table 4 One-pot chemoselective deprotection/etherification or acylation with NaH

Entry	Substrate	Product	Time (min)	Yield^a (%)
a Isolated yields.b NaH (3.0 equiv.) was used.
1	4c	8a, R = Me	30	91
2	4c	8b, R = Bn	35	72
3	4c	8c, R = MOM	35	80
4	4c	8d, R = Ac	30	83
5	6f	8e, R = Me	40	81
6	6f	8f, R = MOM	15	89
7	6f	8g, R = i-Pr	35	85
8	6f	8h, R = Bn	15	94
9	6f	8i, R = allyl	15	94
10	6f	8j, R = Ac	30	92
11	6g	8k, R = Me	20	90
12	6g	8l, R = Bn	40	70
13^b			30	68
14^b			30	70
15^b			35	82

---

The scope of this method was explored for other silyl groups like TES and TBDPS. In literature there are very few reports for selective deprotection of aryl TES and TBDPS ethers.^1c When we subjected the bis-TES ether compound 9a for chemoselective deprotection of aryl TES it produced the corresponding phenol 10a in excellent yield of 96% in just 8 minutes of reaction time (Table 5, entry 1). The one-pot deprotection of aryl TES ether and subsequent allyl ether protection also worked well on 9a giving 10b in 91% yield (entry 2). Similarly the aryl TBDPS ether in 9b was also selectively cleaved in 45 min giving 10c in 88% yield (entry 3). The one-pot desilylation/methylation of 9b delivered 10d in 85% yield (entry 4).

Table 5 Chemoselective deprotection/etherification of TES and TBDPS ethers with NaH

Entry	Substrate	Product	Time (min)	Yield^a (%)
a Isolated yields.
1			8	96
2	9a		10	91
3			45	88
4	9b		60	85

---

An intermolecular selectivity experiment with equimolar mixture of 4b and 11 treated with NaH (1.5 equiv.) in DMF, gave 5b (88%) and with complete recovery of 11 (Scheme 2). A cross-over experiment to check silyl migration¹¹ with 6b and 12 mixture (1 : 3) treated with NaH (2.0 equiv.) in DMF produced only 7b (90%) and compound 12 was recovered unreacted, while formation of 11 was not detected. A selective protection experiment with compound 13 treated with NaH (1.0 equiv.) and TBSCl (1.0 equiv.) produced 14 (59%) and 7c (30%) in 2 : 1 ratio showing moderate selectivity for protection of phenolic OH group. Thus the method was chemoselective for deprotection of only aryl silyl ether. The probable reason could be attributed to the activated aryl silyl ether and the stabilized phenolate formation.

Scheme 2 Intermolecular selectivity experiments and selective protection of phenol.

Conclusion

In conclusion, we have developed an efficient method for the selective removal of aryl silyl protection using NaH in DMF solvent. The method is rapid, operationally simple and can be carried out at room temperature. High yields of phenol products and excellent chemoselectivity are other advantages of this method. A one-pot desilylation and reprotection also worked well.

Experimental

General procedure: aryl silyl ether deprotection

To a stirred solution of aryl silyl ether (0.1 mmol, 1.0 equiv.) in dry DMF (3 mL) was added sodium hydride (0.15 mmol, 1.5 equiv.) at room temperature and stirred for specified time. After completion of reaction (monitored by TLC) it was quenched with water (1 mL) and diluted with EtOAc (10 mL). The organic layer was separated, washed with water (3 × 5 mL), dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc as eluent to give the phenol.

General procedure for one pot chemoselective aryl silyl deprotection/reprotection with other protecting groups

To a stirred solution of aryl silyl ether (0.1 mmol, 1.0 equiv.) in dry DMF (3 mL) was added sodium hydride (0.15 mmol, 1.5 equiv.) at room temperature and subsequently the alkyl halide or acetyl chloride (0.1 mmol, 1.0 equiv.) was added. After completion of reaction (monitored by TLC) it was quenched with water (1 mL) and diluted with EtOAc (10 mL). The organic layer was separated, washed with water (3 × 5 mL), dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc as eluent to give differently protected product.

Acknowledgements

This work was financially supported by Department of Science and Technology, New Delhi (Grant no. SR/S1/OC-25/2008). S. P. G. and S. V .M. thank University Grants Commission and Council of Scientific and Industrial Research, New Delhi for research fellowships respectively.

Notes and references

1. (a) P. G. M. Wuts and T. W. Greene, Green's Protective Groups in Organic Synthesis, 4^th edn, John Wiley & Sons, Hoboken, NJ, 2007; (b) P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; (c) R. D. Crouch, Tetrahedron, 2004, 60, 5833–5871; (d) R. D. Crouch, Tetrahedron, 2013, 69, 2383–2417.
2. E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94, 6190–6191.
3. (a) E. W. Collington, H. Finch and I. J. Smith, Tetrahedron Lett., 1985, 26, 681–684; (b) G. Just and R. Zamboni, Can. J. Chem., 1978, 56, 2725–2730; (c) B. E. Blass, C. L. Harris and D. E. Portlock, Tetrahedron Lett., 2001, 42, 1611–1613; (d) E. A. Schmittling and J. S. Sawyer, Tetrahedron Lett., 1991, 32, 7207–7210; (e) H. Yan, J.-S. Oh and C. E. Song, Org. Biomol. Chem., 2011, 9, 8119–8121.
4. (a) P. M. Kendall, J. V. Johnson and C. E. Cook, J. Org. Chem., 1979, 44, 1421–1424; (b) A. K. Sinhababu, M. Kawase and R. T. Borchardt, Synthesis, 1988, 710–712; (c) S. R. Angle and T. Wada, Tetrahedron Lett., 1997, 38, 7955–7958.
5. (a) S. V. Ankala and G. Fenteany, Tetrahedron Lett., 2002, 43, 4729–4732; (b) R. D. Crouch, M. Stieff, J. L. Frie, A. B. Cadwallader and D. C. Bevis, Tetrahedron Lett., 1999, 40, 3133–3136; (c) Z.-Y. Jiang and Y.-G. Wang, Chem. Lett., 2003, 32, 568–569; (d) S. V. Ankala and G. Fenteany, Synlett, 2003, 825–828; (e) N. S. Wilson and B. A. Keay, Tetrahedron Lett., 1997, 38, 187–190; (f) Z.-Y. Jiang and Y.-G. Wang, Tetrahedron Lett., 2003, 44, 3859–3861; (g) C. Prakash, S. Saleh and I. A. Blair, Tetrahedron Lett., 1994, 35, 7565–7568.
6. (a) D. J. Trader and E. E. Carlson, J. Org. Chem., 2013, 78, 7349–7355; (b) K.-I. Oyama and T. Kondo, Org. Lett., 2003, 5, 209–212; (c) P. K. Zubaidha, S. V. Bhosale and A. M. Hashmi, Tetrahedron Lett., 2002, 43, 7277–7279.
7. B. Wang, H.-X. Sun and Z.-H. Sun, J. Org. Chem., 2009, 74, 1781–1784.
8. L. Yan, F. Zhao, Y. Gan, J. Zhao and Z. Jiang, Synth. Commun., 2012, 42, 285–291.
9. R. A. Fernandes and S. V. Mulay, Tetrahedron: Asymmetry, 2013, 24, 1281–1285.
10. J. S. Davies, C. L. Higginbotham, E. J. Tremeer, C. Brown and R. C. Treadgold, J. Chem. Soc., Perkin Trans. 1, 1992, 3043–3048.
11. Y.-Y. Ku, T. Grieme, P. Raje, P. Sharma, S. A. King and H. E. Morton, J. Am. Chem. Soc., 2002, 124, 4282–4286.

---

Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all the compounds. See DOI: 10.1039/c4ra00842a

---