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1,3-Dithianes, 1,3-Dithiolanes

T. W. Green, P. G. M. Wuts,
Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 329-344, 724-727.

 

Stability

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

General

1,3-Dithianes and 1,3-dithiolanes can easily be prepared from carbonyl compounds with 1,3-propanedithiol or 1,2-ethanedithiol in the presence of a Brönsted or a Lewis acid catalyst. Removal of a dithiane protection group often requires harsh conditions and is usually performed in the late synthetic stage.


Summary of the use of 1,3-dithianes in synthesis


Protection of Carbonyl Compounds


Carbonyl compounds have been successfully converted into their corresponding oxathiolane, dithiolane, and dithiane derivatives with 2-mercaptoethanol, 1,2-ethanedithiol, and 1,3-propanedithiol using catalytic amount of yttrium triflate. In addition, by using this catalyst, highly chemoselective protection of aldehydes has been achieved.
S. K. De, Tetrahedron Lett., 2004, 45, 2339-3241.


Tungstophosphoric acid (H3PW12O40) was found to be an effective and highly selective catalyst for the thioacetalization of aldehydes, ketones, acetals, acylals and O,S-acetals in excellent yields in the absence of solvent. Chemoselective conversions of α- or β-diketones and a β-keto ester are described. Sterically hindered carbonyl compounds were converted to the corresponding thioacetals in refluxing petroleum ether in good yields.
H. Firouzabadi, N. Iranpoor, K. Amani, Synthesis, 2002, 59-60.


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 and O,S-acetals and acylals.
H. Firouzabadi, N. Iranpoor, H. Hazarkhani, J. Org. Chem., 2001, 66, 7527-7529.


A new procedure for the protection of aldehydes and ketones as thioacetals promoted by catalytic amount of p-toluenesulfonic acid and silica gel has been developed. This procedure offers versatility, short reaction time, excellent yield, and is easy to carry out. A simple filtration followed by removal of solvent in most cases produces pure product.
M. H. Ali, M. G. Gomes, Synthesis, 2005, 1326-1332.


Perchloric acid adsorbed on silica gel (HClO4-SiO2) has been found to be an extremely efficient and reusable catalyst for 1,3-dithiolane and 1,3-dithiane formation under solvent-free conditions at room temperature.
S. Rudrawar, R. C. Besra, A. K. Chakraborti, Synthesis, 2006, 2767-2771.


Praseodymium triflate is an efficient and recyclable catalyst for chemoselective protection of aldehydes.
S. K. De, Synthesis, 2004, 2837-2840.


As a non-thiolic, odorless propane-1,3-dithiol equivalent, 3-(1,3-dithian-2-ylidene)pentane-2,4-dione has been investigated in acid-promoted thioacetalization under solvent-free conditions. A range of selected aldehydes and aliphatic ketones have been converted into the corresponding dithioacetals in high yields. The relatively slow reaction rate of aromatic ketones allows chemoselective protection.
Y. Ouyang, D. Dong, C. Zheng, H. Yu, Q. Liu, Z. Fu, Synthesis, 2006, 3801-3804.


3-(1,3-dithian-2-ylidene)pentane-2,4-dione has been used as a nonthiolic, odorless 1,3-propanedithiol equivalent in the p-dodecylbenzenesulfonic acid-catalyzed thioacetalization of various aldehydes and ketones in water.
D. Dong, Y. Ouyang, H. Yu, Q. Liu, J. Liu, M. Wang, J. Zhu, J. Org. Chem., 2005, 70, 4535-4537.


Other Syntheses of Dithianes


b
-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. These masked 1,3-dicarbonyl systems can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.
M. J. Gaunt, H. F. Sneddon, P. R. Hewitt, P. Orsini, D. F. Hook, S. V. Ley, Org. Biomol. Chem., 2003, 1, 15-16.


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.


Deprotection


An efficient and convenient procedure has been developed for the hydrolysis of thioacetals/thioketals to the corresponding carbonyl compounds in excellent yields with o-iodoxybenzoic acid (IBX) in presence of β-cyclodextrin (β-CD) in water under neutral conditions at room temperature.
N. S. Krishnaveni, K. Surendra, Y. V. D. Nageswar, K. R. Rao, Synthesis, 2003, 2295-2297.


An efficient, mild and chemoselective method for the deprotection of S,S-acetals to the corresponding carbonyl compounds using silicasulfuric acid/NaNO3 is reported.
A. R. Hajipour, A. Zarei, L. Khazdooz, A. E. Ruoho, Synthesis, 2006, 1480-1484.


Different new reactions of IBX with heteroatom-containing substrates were discovered and their utility was demonstrated. IBX was used for the generation of imines from secondary amines in notably high yields, for oxidative aromatization of nitrogen heterocycles and for cleavage of dithianes.
K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem., 2003, 115, 4211-4216.


A new and efficient method for the cleavage of the PMP, THP and 1,3-dithiane protecting groups with Selectfluor™ has been developed.
J. Liu, C.-H. Wong, Tetrahedron Lett., 2002, 43, 4037-4039.


Deprotection of several dithiane-containing alkaloids and a nonchromatic purification cleanly generates corresponding ketoamines. The described procedure is ideal for labile alkaloids.
F. F. Fleming, L. Funk, R. Altundas, Y. Tu, J. Org. Chem., 2001, 66, 6502 - 6504.


Conversion of Dithianes to Other Functional Groups


Different new reactions of IBX with heteroatom-containing substrates were discovered and their utility was demonstrated. IBX was used for generation of imines from secondary amines in notably high yields, for oxidative aromatization of nitrogen heterocycles and for cleavage of dithianes.
K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem., 2003, 115, 4211-4216.


Easily prepared 2-alkyl-1,3-dithiane derivatives were reacted with BrF3 to form the corresponding 1,1-difluoromethyl alkanes in good yield. The reaction proceeds well with primary alkyl halides. The limiting step for secondary alkyl halides is the relatively low yield of the dithiane preparation.
R. Sasson, A. Hagooly, S. Rozen, Org. Lett., 2003, 5, 3635-3641.


Dithianes in Multi-step Syntheses


Corey-Seebach Reaction


A linchpin coupling protocol is based on anion relay chemistry (ARC). The addition of an anion to an epoxide, bearing on a distal carbon a trialkyl silyl group and an anion stabilizing group furnishes upon epoxide ring opening an oxyanion. Addition of HMPA triggers a solvent controlled 1,4-Brook rearrangement leading to a new distal anion, which reacts with various electrophiles.
A. B. Smtih, III, M. Xiang, J. Am. Chem. Soc., 2006, 128, 66-67.


Arenesulfonates of primary alcohols react smoothly with lithio derivatives of 1,3-dithiane and 2-phenyl-1,3-dithiane at room temperature to give 2-alkyl derivatives in high yields.
D. Seebach, E.-M. Wilka, Synlett, 1976, 476-477.


While 3,4;5,6-di-O-isopropylidene-N-phthaloyl-D-glucosamine propane-1,3-diyl dithioacetal underwent fast β-elimination, the corresponding N-acetyl derivative was easily deprotonated with butyllithium to form the dilithiated intermediate. Stoichiometry and temperature were crucial factors for selective C-C coupling with various electrophiles.
Y.-L. Chen, R. Leguijt, H. Redlich, R. Fröhlich, Synthesis, 2006, 4212-4218.


Multicomponent Linchpin Coupling of Silyl Dithianes Employing an N-Ts Aziridine as the Second Electrophile: Synthesis of (-)-Indolizidine 223AB
A. B. Smith, D.-S. Kim, Org. Lett., 2004, 6, 1493-1495. DOI: 10.1021/jo035391p (free Supporting Information)


Total Synthesis of the Boron-Containing Ion Carrier Antibiotic Macrodiolide Tartrolon B
J. Mulzer, M. Berger, J. Org. Chem., 2004, 69, 891-898. DOI: 10.1021/jo035391p (free Supporting Information)


Reviews

The role of 1,3-dithianes in natural product synthesis
Miguel Yus, Carmen Nájera and Francisco Foubelo, Tetrahedron, 2003, 59, 6147-6212. DOI: 10.1016/S0040-4020(03)00955-4