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Reactions >> Protecting Groups >> Stability

1,3-Dioxanes, 1,3-Dioxolanes

T. W. Green, P. G. M. Wuts,
Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 308-322, 724-727.



H2O: pH < 1, 100°C pH = 1, RT pH = 4, RT pH = 9, RT pH = 12, RT pH > 12, 100°C
Bases: LDA NEt3, Py t-BuOK Others: DCC SOCl2
Nucleophiles: RLi RMgX RCuLi Enolates NH3, RNH2 NaOCH3
Electrophiles: RCOCl RCHO CH3I Others: :CCl2 Bu3SnH
Reduction: H2 / Ni H2 / Rh Zn / HCl Na / NH3 LiAlH4 NaBH4
Oxidation: KMnO4 OsO4 CrO3 / Py RCOOOH I2, Br2, Cl2 MnO2 / CH2Cl2


1,3-Dioxanes and 1,3-dioxolanes can easily be prepared from carbonyl compounds with 1,3-propanediol or 1,2-ethanediol in the presence of a Brönsted or a Lewis acid catalyst. 1,3-Diols give more stable compounds. A standard procedure for protection employs toluenesulfonic acid as catalyst in refluxing toluene, which allows the continuous removal of water from the reaction mixture using a Dean-Stark apparatus. A mixture of orthoesters or molecular sieves can also provide effective water removal through chemical reaction or physical sequestration.

Cyclic acetals offer stability against all types of nucleophiles and bases.

Deprotection is often performed by acid catalyzed transacetalization in acetone or hydrolysis in wet solvents or in aqueous acid. Some strong oxidation agents may cleave acetals such as HClO4 in CH2Cl2. Cyclic ketals and acetals as a rule are stable to mild high-valent chromium reagents (PCC, PDC, Jones, etc.), but strongly acidic reagents will oxidize them to the lactone, or related cleavage products. Addition of strong Lewis acids enhances the sensitivity towards oxidants such as KMnO4, and MCPBA.

Protection of Carbonyl Compounds

Acyclic and cyclic acetals of various carbonyl compounds were obtained in excellent yields in the presence of trialkyl orthoformate and a catalytic amount of tetrabutylammonium tribromide in absolute alcohol. This convenient, mild, chemoselective method allows acetalization of an aldehyde in the presence of ketone, unsymmetrical acetal formation, and tolerates acid-sensitive protecting groups.
R. Gopinath, Sk. J. Haque, B. K. Patel, J. Org. Chem., 2002, 67, 5842-5845.

Zirconium tetrachloride (ZrCl4) is a highly efficient and chemoselective catalyst for the acetalization, and in situ transacetalization of carbonyl compounds under mild reaction conditions.
H. Firouzabadi, N. Iranpoor, B. Karimi, Synlett, 1999, 321-323.

Carbonyl compounds were converted to the corresponding 1,3-dioxanes in the presence of ethyl orthoformate, 1,3-propanediol, and a catalytic amount of NBS via an in situ acetal exchange process. The reaction tolerates acid-sensitive groups such as THP ethers and TBDMS ethers.
B. Karimi, G. R. Ebrahimian, H. Seradj, Org. Lett., 1999, 1, 1737-1739.

Various types of carbonyl compounds are efficiently converted to their 1,3-dioxanes by the use of 1,3-bis(trimethylsiloxy)propane (BTSP) and a catalytic amount of iodine under essentially neutral aprotic condition.
B. Karimi, B. Golshani, Synthesis, 2002, 784-788.

Using a photochemical method for acetalization of aldehydes under low-energy visible light irradiation, a broad range of aromatic, heteroaromatic, and aliphatic aldehydes have been protected under neutral conditions in good to excellent yields using a catalytic amount of Eosin Y as the photocatalyst. Even challenging acid-sensitive aldehydes and sterically hindered aldehydes can be converted, while ketones remain intact.
H. Yi, L. Niu, S. Wang, T. Liu, A. K. Singh, A. Lei, Org. Lett., 2017, 19, 122-125.

Various types of hydroxyacetophenones are efficiently converted into the corresponding cyclic acetals in the presence of a diol, triisopropyl orthoformate, and a catalytic amount of cerium(III) trifluoromethanesulfonate under mild reaction conditions.
F. Ono, H. Takenaka, T. Fujikawa, M. Mori, T. Sato, Synthesis, 2009, 1318-1322.

Aliphatic and aromatic ketones can be directly converted into their corresponding α-chloroketone acetals in very good yields using iodobenzene dichloride in ethylene glycol in the presence of 4 Å molecular sieves at room temperature.
J. Yu, C. Zhang, Synthesis, 2009, 2324-2328.

Other Syntheses of Cyclic Acetals

ReOCl3(PPh3)2 catalyzes a rapid oxidation of secondary alcohols by DMSO in the presence of ethylene glycol and refluxing toluene to provide the corresponding ketals in very good yields. Methyl sulfide and water as byproducts of the reaction are easily removed.
J. B. Arterburn, M. C. Perry, Org. Lett., 1999, 1, 769-771.

A benzotriazole reagent derived from 2-ethoxydioxolane and benzotriazole can be used as a remarkably stable and versatile electrophilic formylating reagent in reactions with Grignard reagents and organozinc reagents. The procedure is mild, efficient, and tolerable to multifunctional organic molecules, which makes it suitable for multistep syntheses.
A. R. Katritzky, H. H. Odens, M. V. Voronkov, J. Org. Chem., 2000, 65, 1886-1888.

Ammonium salts that can act as hydrogen-bond donors exert a remarkable acceleration on the rates of the regioselective arylation of electron-rich olefins by aryl halides in ionic liquids and common solvents.
J. Mo, J. Xiao, Angew. Chem. Int. Ed., 2006, 45, 4152-4157.

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf)3 provides a broad range of functionalized protected aldol compounds. A Swern oxidation-CBS reduction sequence enables the preparation of chiral protected aldol products.
P. Quinio, L. Kohout, D. S. Roman, J. Gaar, K. Karahiosoff, P. Knochel, Synlett, 2016, 27, 1715-1719.

A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a radical chain process enables a metal-free and redox-neutral conversion of inexpensive materials to a broad range of protected α-amino aldehydes in very good yields using only a catalytic amount of radical precursor. Both the thiol and a small amount of oxygen from air are indispensable to the success of this reaction.
H. Zeng, S. Yang, H. Li, D. Lu, Y. Gong, J.-T. Zhu, J. Org. Chem., 2018, 83, 5256-5266.

A new palladium(0)-catalyzed three-component reaction of salicylic aldehyde triflates, ethylene glycol vinyl ether, and various secondary nucleophilic amines involving an initial internal Heck arylation, iminium ion formation, and subsequent tandem cyclization gives tertiary 3-aminoindan acetals.
A. Arefalk, M. Larhed, A. Hallberg, J. Org. Chem., 2005, 70, 938-942.


Acetals and ketals are readily deprotected under neutral conditions in the presence of acetone and indium(III) trifluoromethanesulfonate as catalyst at room temperature or mild microwave heating conditions to give the corresponding aldehydes and ketones in good to excellent yields.
B. T. Gregg, K. C. Golden, J. F. Quinn, J. Org. Chem., 2007, 72, 5890-5893.

Er(OTf)3 is a very gentle Lewis acid catalyst in the chemoselective cleavage of alkyl and cyclic acetals and ketals at room temperature in wet nitromethane.
R. Dalpozzo, A. De Nino, L. Maiuolo, M. Nardi, A. Procopio, A. Tagarelli, Synthesis, 2004, 496-498.

A chemoselective method for the cleavage of acetals and ketals at room temperature in wet nitromethane by using catalytic cerium(III) triflate at almost neutral pH is presented. High yields and selectivity make this procedure particularly attractive for multistep synthesis.
R. Dalpozzo, A. De Nino, L. Maiuolo, A. Procopio, A. Tagarelli, G. Sindona, G. Bartoli, J. Org. Chem., 2002, 67, 9093-9095.

A convenient deprotection of acyclic and cyclic O,O-acetals and O,O-ketals is achieved in excellent yields within minutes under neutral conditions in the presence of a catalytic amount of iodine. Double bonds, hydroxyl groups, acetate groups, and highly acid-sensitive groups such as furyl, tert-butyl ethers, and ketoximes are tolerated.
J. Sun, Y. Dong, L. Cao, X. Wang, S. Wang, Y. Hu, J. Org. Chem., 2004, 69, 8932-8934.

Deprotection of acetals and ketals can be achieved by using a catalytic amount of sodium tetrakis(3,5-trifluoromethylphenyl)borate (NaBArF4) in water at 30 °C. For example, a quantitative conversion of 2-phenyl-1,3-dioxolane into benzaldehyde was accomplished within five minutes.
C.-C. Chang, B.-S. Liao, S.-T. Liu, Synlett, 2007, 283-287.

The combination of R3SiOTf/2,4,6-collidine promotes a highly discriminative and chemoselective transformation of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals.
R. Ohta, N. Matsumoto, Y. Ueyama, Y. Kuboki, H. Aoyama, K. Murai, M. Arisawa, T. Maegawa, H. Fujioka, J. Org. Chem., 2018, 83, 6432-6443.

Conversion of Cyclic Acetals and Ketals to Other Functional Groups

Aldehydes and ketones were protected as their thioacetals in the presence of a catalytic amount of iodine. These mild reaction conditions were also applied in the transthioacetalization of O,O-acetals, O,O-ketals, O,S-acetals, and acylals.
H. Firouzabadi, N. Iranpoor, H. Hazarkhani, J. Org. Chem., 2001, 66, 7527-7529.

An efficient oxidation of various acetals, including open-chain acetals, 1,3-dioxanes and 1,3-dioxalanes, with molecular oxygen in the presence of catalytic amounts of N-hydroxy­phthalimide (NHPI) and Co(OAc)2 as co-catalyst gave esters.
B. Karimi, J. Rajabi, Synthesis, 2003, 2373-2377.

An efficient oxidation of cyclic acetals provided hydroxy alkyl esters in good yields in the presence of MCPBA.
J. Y. Kim, H. Rhee, M. Kim, J. Korean Chem. Soc., 2002, 46, 479-483.