An Economic and Practical Synthesis of the 2-Tetrahydrofuranyl Ether Protective Group

Abstract

Primary, secondary, and tertiary alcohols as well as phenols and carbohydrates are efficiently transformed into the corresponding 2-tetrahydrofuranyl ethers by a combination of Mn(0) powder and CCl₄ in tetrahydrofuran.

Despite its well-established reputation¹ as a versatile, orthogonal² protecting group, the 2-tetrahydrofuranyl (THF) ether is often disregarded in favor of its homologous relative, the tetrahydropyranyl (THP) ether. This is due, in large measure, to limitations in the extant procedures for its introduction, i.e., the required reagents not commercially available, corrosive, incompatible with sensitive functionality, and/or unstable.^2-11 To address these issues, we introduced a convenient protocol utilizing CrCl₂ and CCl₄ in tetrahydrofuran.¹² However, the high costs of CrCl₂, the need for a large excess of reagent, and chromium’s toxicity spurred us to seek a more economic and environmentally benign alternative.

Initially, a panel of readily available, eco-friendly metals was evaluated for their ability to promoted the 2-tetrahydrofuranylation of n-octanol (1) under a standard set of reaction conditions (0.4 M in THF, 65°C, 15 h, 1.5 equiv of CCl₄). Fe(0) and Zn(0) furnished only modest yields of 2¹³ (73% and 63%, respectively). Mg(0), with the largest reduction potential of all the metals tested, gave rise to a disappointing 5% of the desired THF ether. The most consistent results were obtained with Mn(0) powder.¹⁴ Just 1.5 equivalents of Mn(0) provided an excellent yield of 2 (Table 1, entry 1); fewer equivalents of Mn(0) led to portionately lower yields of 2.

Table 1.

preparation of THF ethers.

Entry	Alcohol	THF Ether	Time(h)	yield(%)
1			15	96
2			15	99a
3			7	85a
4			4	93
5			6	91
6			6	88a
7			14	90
8			6	99a,b
9			3	96
10			4	88b
11			13	85a
12			8	91a,b

^a∼1:1 diastereomeric mixture by NMR analysis.

^b2 equiv each of Mn(0) and ccl₄ were used.

Likewise, secondary¹² (entry 2), allylic¹⁵ (entry 3), and benzylic¹² (entry 4) THF ethers were easily obtained from alcohols 3, 5, and 7, respectively. Less reactive hydroxyls such as phenol (9) and the highly hindered dimethylphenylcarbinol 11 were transformed without complication into their THF derivatives 10¹² (entry 5) and 12¹² (entry 6), respectively. Importantly, a variety of common funtionality proved compatible with the standard reaction conditions. For instance, methylenedioxy (entry 7), acetonide (entry 8), and silyl (entry 9) groups were all well tolerated and led accordingly to THF ethers 14,¹² 16,¹⁵ and 18.¹⁵ The successful protection of labile 1,1,1-trichloride 19¹², acid sensitive epoxide 21, and α,β-unsaturated steroidal ketone 23, all in excellent yields, are especially notable.¹⁵

The mechanism of the tetrahydrofuranylation most like parallels that of the CrCl₂-mediated reaction,¹² i.e., single electron transfer from Mn(0)¹⁶ to CCl₄ during the initiation phase generates the well-known trichloromethyl radical (Scheme 1). This radical subsequently abstracts a hydrogen atom from the tetrahydrofuran methylene adjacent to oxygen in the first step of the propagation phase forming chloroform and a heteroatom stabilized radical that is chlorinated by a second molecule of CCl₄. The newly evolved trichloromethyl radical can either propagate the reaction via hydrogen atom abstraction from another equivalent of tetrahydrofuran or is further reduced and in the process consumes the HCl produced during the etherification step.

General Procedure: CCl₄ (0.145 mL, 1.5mmol, 1.5 equiv) was added via syringe to a stirring suspension of alcohol (1 mmol, 1.0 equiv) and Mn(0) powder¹⁴ (83 mg, 1.5 mmol, 1.5 equiv) in anhydrous THF (3 mL) under an argon atmosphere and then warmed to 65°C. A white precipitate of MnCl₂ accumulated during the course of the reaction. After the times indicated in Table 1, the reaction mixture was cooled to room temperature, diluted with ether (20 mL), filtered through a pad of silica gel, and the filter cake was washed with ether. In most cases, the residue after concentration in vacuo required no further purification, but if necessary, was passed over a SiO₂ column to give the corresponding THF ether in indicated yields (Table 1).

In summary, an operationally simple, inexpensive, and efficient method to make THF ethers has been developed. Its mild reaction conditions and general tolerance of most functional groups make it widely applicable in the synthesis of complex molecules.