Tetrahedron report number 728
Recent advances in ether dealkylationIntroduction
The O-dealkylation of ethers, or ether cleavage, remains an integral functional group transformation, primarily as a deprotection step to unmask a hydroxyl group. The utility of this reaction extends to both academic and commercial pursuits including natural product, pharmaceutical and fine chemical syntheses.
This topic has most recently been reviewed in 1983 by Bhatt and Kulkarni1 and in 1996 by Ranu and Bhar.2 The former review attempted to cover all reagents of synthetic value through 1981 while the latter focused primarily on developments since the prior review. A review in 1997 by Guibé3 on allylic protecting groups included a subsection on removal of this specific group. This review will cover the recent developments in the field from 1995 through the end of 2004, focusing on those reagents that are of practical, synthetic value and display some level of generality. Subject overlap with the prior reviews was kept to a minimum. The ethers covered are those in which the oxygen-bearing carbon atom being removed is only attached to other carbon or hydrogen atoms. Thus, such species as acetals, ketals, silyl ethers and tetrahydropyranyl ethers are excluded, as are methods that further functionalize the deprotected alcohols (acylation, silylation, oxidation for example). The extent to which these excluded groups are affected (or not) by the reagents cited in the review, will be mentioned. In addition, in a few cases, we have included well-known reagents that have been utilized in large-scale syntheses. For the more practical methodologies, examples where the reagent was subsequently used in the synthesis of complex molecules has been included periodically. Whenever applicable, the reagent selectivity relative to other types of hydroxyl protecting groups will be highlighted, as this remains a key factor in the choice of reagent, especially in poly-functional molecules. The review has been organized by functional group then by reagent type. The groups are: (1) aryl and alkyl ethers (including propargylic), (2) allyl ethers (including isoprenyl), (3) benzylic ethers (including trityl), and (4) cyclic ethers. In some Figures, an arrow has been placed to denote the dealkylation site, indicative of regio- or chemo-selectivity.
Section snippets
Lewis acids
A Pfizer group4 demonstrated the utility of BCl3 as a dealkylating reagent can be greatly enhanced by the addition of tetrabutylammonium iodide. The reactions are run with 2.5equiv of each reagent in DCM. This reagent combination displays enhanced reactivity over BBr3 as shown in the bis demethylation of 3,5-dimethoxyfluorobenzene (1) (Scheme 1). Methyl and ethyl aryl ethers are readily cleaved, but an isopropyl group is not.
The removal of a benzyl group was achieved in the presence of a methyl
Allyl and related ethers
The protection of alcohols with allyl and related (prenyl, methyallyl, cinnamyl, homoallyl) groups is predominantly confined to carbohydrate synthesis due to their stability under the conditions required for glycoside formation. These groups are moderately stable to acids and bases, and offer the potential for selective dealkylation of differentially protected sites. Initially, the deprotection schemes involved a metal- or base-induced (potassium tert-butoxide in DMSO) isomerization to the
Lewis acids
Yamamoto87 reported a novel debenzylation of aryl ethers such as 43 using catalytic amounts (1–3mol%) of rare earth metals including scandium(III) triflyl methide Sc(CTf3)3 (Fig. 20). Reactions are run in anisole over 0.5–2.5h at 100°C and the product obtained in 87–97% yield. Cleavage of secondary benzyl ethers resulted in poor yields due to competitive dehydroxylation and/or debenzyloxylation, however activated benzyl ether 44 gave a near quantitative yield of the corresponding sec-alcohol
Cyclic ethers
The ring-opening reactions of cyclic ethers differs dramatically from the dealkylation of alkyl ethers. Whereas the former is mainly intended to further functionalize the substrate, the latter is primarily utilized to deprotect an alcohol. The emerging trend in cleavage of cyclic ethers is the asymmetric ring opening of epoxides. This topic has just recently been reviewed (>100 references).151 Accordingly, only a few examples will be covered herein, representing the ‘best in class’ for a
Acknowledgements
The authors thank Professors François Guibé and Phillip Kocienski for their insight feedback on the manuscript.
Steven A. Weissman, a native of Marblehead, MA, received his BA degree in Chemistry from the University of Vermont in 1983 and PhD from Tufts University working under the guidance of Professor Stephen G. Baxter in the field of organophosphorus chemistry. He then accepted a postdoctoral appointment at Purdue University with Professor Herbert C. Brown before joining Merck in 1990. In 1997, he joined the Merck Process group where he is a Senior Research Fellow and is responsible for developing
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Citation Excerpt :
Neither route was successful, and this was attributed to the steric hindrance around the ether group in L2. The deprotection of L3 proved similarly challenging, even though there are a number of methodologies for the removal of benzyl protecting groups [54]. Catalytic hydrogenolysis could not be successfully employed as both N-benzylic and O-benzylic moieties are present, even though conditions similar to those reported for cleaving a benzyl group used to protect 2,4-di-tert-butyl phenol linked to an aromatic amine by an amide bond were employed [56].
Side-bridged cyclam transition metal complexes (M = Ni(II), Cu(II) and Zn(II)) bearing a phenolic ether or phenolate pendent arm have been synthesised. For [NiL1]+ and [CuL1]+, evidence for a phenoxyl radical was obtained (quasi reversible peak at +0.74 V and +0.48 V respectively), as well as oxidation of OH, due to protonation of the phenolate, at ∼+1.24 V. The phenoxyl radical in [Ni(L1)]2+ is harder to oxidise by 0.26 V compared with the corresponding Cu(II) complex. UV–Vis data for [Ni(L1)]2+ suggests that the Ni(II) ion may be 4 or 6 coordinate whereas the Cu(II) ion in [Cu(L1)]2+ is five coordinate. The Ni(II) ion in the crystal structure of [Ni(L2)][(ClO4)2] possesses a distorted square-planar geometry in which the phenolic ether pendent arm is not involved in the coordination sphere. The cyclam ligand in this complex adopts a trans-II configuration.
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Steven A. Weissman, a native of Marblehead, MA, received his BA degree in Chemistry from the University of Vermont in 1983 and PhD from Tufts University working under the guidance of Professor Stephen G. Baxter in the field of organophosphorus chemistry. He then accepted a postdoctoral appointment at Purdue University with Professor Herbert C. Brown before joining Merck in 1990. In 1997, he joined the Merck Process group where he is a Senior Research Fellow and is responsible for developing practical syntheses of pre-clinical candidates.
Daniel Zewge was born in Asebe Teferi (Ethiopia) and received his BA degree in Chemistry from Addis Ababa University in 1987. After working as a chemist at the Ethiopian Health Research Institute, he immigrated to the USA in 1991. He then received his MS degree in Chemistry from Rutgers University in 1998, while teaching chemistry at the Chad Science Academy. After a one year stay at Avon Cosmetics, he joined the Merck Process Research group in 1999, where he is a Research Chemist. His research interest is focused on synthesis of pharmacologically active compounds.
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