30.3.1.3 Acyclic S,S-Acetals (Update 2016)

A. Tsubouchi

General Introduction

Previously published information regarding acyclic S,S-acetals can be found in Section 30.3.1. This update presents complementary information with respect to new developments and transformations. It also contains important extensions to the coverage of the previous contribution.

30.3.1.3.1 Method 1: Thioacetalization of Carbonyl Compounds

30.3.1.3.1.1 Variation 1: With Metal Salt Based Lewis Acid Catalysts

See also Section 30.3.1.1.1.2.

The S,S-acetals 1 are synthesized by copper salt catalyzed thioacetalization of carbonyl compounds with thiols (▶ Scheme 1).^[1,2] Copper(I) bromide in acetonitrile is an efficient catalyst for the thioacetalization of aromatic and aliphatic aldehydes, whereas copper(I) iodide is less effective for this transformation.^[1] Copper(I) chloride can be employed for the thioacetalization, although yields are slightly decreased in comparison with copper(I) bromide. Anhydrous copper(II) sulfate promotes the thioacetalization of benzaldehydes and pentanal in dichloromethane at room temperature.^[2] Chloroform, benzene, acetonitrile, and hexane can also be used as solvents for this reaction. Under solvent-free conditions,S,S-acetals 1 are prepared in yields similar to those obtained in dichloromethane by heating at 40–50 °C for less than 5 minutes. The reaction with ethanethiol and phenylmethanethiol is complete within 5 minutes, whereas a longer reaction time is required for the thioacetalization with benzenethiol.

Scheme 1 Copper Salt Catalyzed Thioacetalization of Aldehydes^[1,2]

Thioacetalization of aldehydes and ketones with thiols is catalyzed by lanthanide salts (▶ Scheme 2).^[3,4] Various functionalized benzaldehydes, thiophene-2-carbaldehyde, and 6-(tert-butyldimethylsiloxy)hexanal are transformed into S,S-acetals 2 (R³ = Et) by thioacetalization with ethanethiol in the presence of lanthanum(III) nitrate hexahydrate as the catalyst.^[3] Aldehydes having an acid labile group, such as a tert-butyldimethylsilyl group, are applicable to this transformation, and the catalytic system does not require special care to be taken to exclude moisture. A catalytic amount of cerium(III) trifluoromethanesulfonate can be used as a water-tolerant and recyclable Lewis acid for the thioacetalization of aldehydes and ketones under solvent-free conditions, with wide-ranging functional group compatibility.^[4] The catalyst is similarly effective for the reaction in 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) and acetonitrile, although longer reaction times are needed. Complete chemoselectivity for aldehydes over ketones is observed in the competitive thioacetalization of an equimolar mixture of acetophenone and various benzaldehydes with benzenethiol.

Scheme 2 Lanthanide Salt Catalyzed Thioacetalization of Aldehydes and Ketones^[3,4]

Hafnium(IV) trifluoromethanesulfonate (0.1 mol%) catalyzes the transformation of a wide range of aliphatic and aromatic aldehydes and ketones into S,S-acetals 3 (▶ Scheme 3).^[5] This thioacetalization tolerates various functional groups and protecting groups, and no racemization takes place when α-amino aldehydes are employed. Aromatic aldehydes are chemoselectively converted into the corresponding S,S-acetals in preference to aliphatic aldehydes and ketones.

Scheme 3 Hafnium(IV) Trifluoromethanesulfonate Catalyzed Thioacetalization of Aldehydes and Ketones^[5]

R1	R2	Time (min)	Yield (%)	Ref
H	Ph	5	99	[5]
H	4-O2NC6H4	5	99	[5]
H	4-NCC6H4	5	99	[5]
H	4-ClC6H4	5	99	[5]
H	4-BrC6H4	5	99	[5]
H	3-BrC6H4	5	99	[5]
H	2-BrC6H4	8	98	[5]
H	4-MeOC6H4	5	99	[5]
H	4-Me2NC6H4	5	97	[5]
H	2,4-(MeO)2C6H3	10	98	[5]
H	2,4,6-(MeO)3C6H2	15	97	[5]
H	2,3,4-(MeO)3C6H2	10	98	[5]
H	2-naphthyl	5	99	[5]
H	4-HOC6H4	5	99	[5]
H	3-MeO-4-TBDMSOC6H3	5	98	[5]
H	Bn	20	99	[5]
H	CH2OBn	20	99	[5]
H		240	92	[5]
H		240	93	[5]
H		240	94	[5]
Me	Ph	30	98	[5]
Me	(CH2)2Ph	120	98	[5]

S,S-Acetals 1; General Procedure Using Copper(II) Sulfate under Solvent-Free Conditions:^[2]

The thiol (5–6 mmol) and anhyd CuSO₄ (3.5 mmol) were added to a soln of the aldehyde (2.5 mmol) in Et₂O (5 mL). The solvent was removed under reduced pressure and the residue was heated at 40–50 °C for 5–20 min until completion of the reaction (as monitored by TLC). CH₂Cl₂ (20 mL) was added, the catalyst was removed by filtration, and the solvent was removed under reduced pressure to give a crude product. While this product was sufficiently pure in general, further purified material was obtained by crystallization (petroleum ether) or preparative TLC.

S,S-Acetals 2; General Procedure Using Lanthanum(III) Nitrate Hexahydrate:^[3]

Finely powdered La(NO₃)₃·6H₂O (0.05 mmol) was added to a mixture of the aldehyde (1 mmol) and the thiol (2.2 mmol), and the resulting mixture was stirred at rt for 60–90 min. H₂O (10 mL) was added to the mixture and the product was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel).

4-(tert-Butyldimethylsiloxy)-3-methoxybenzaldehyde S,S-Diethyl Dithioacetal (3, R¹ = H; R² = 3-MeO-4-TBDMSOC₆H₃); Typical Procedure:^[5]

A mixture of 4-(tert-butyldimethylsiloxy)-3-methoxybenzaldehyde (266.4 mg, 1.0 mmol), EtSH (0.15 mL, 2.1 mmol), and Hf(OTf)₄ (0.8 mg, 0.001 mmol) in CH₂Cl₂ (2 mL) was stirred at rt for 5 min. The resulting mixture was filtered through a short pad of Celite and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to chromatography (silica gel) to give a colorless oil; yield: 365.2 mg (98%).

30.3.1.3.1.2 Variation 2: With Non-Metal Lewis Acid Catalysts

See also Section 30.3.1.1.1.3.

Various functionalized benzaldehydes and furan-2-carbaldehyde (furfural) are transformed into S,S-acetals 4 on reaction with benzenethiol. This thioacetalization is catalyzed by iodine, which is itself generated in situ using a catalytic amount of iron(III) nitrate nonahydrate and sodium iodide (▶ Scheme 4).^[6] The reaction thus proceeds in dichloromethane at room temperature without using toxic and corrosive molecular iodine.

Scheme 4 Thioacetalization of Aromatic Aldehydes Using Iron(III) Nitrate and Sodium Iodide as a Molecular Iodine Precursor^[6]

1,1,3-Tris(alkylsulfanyl)- and 1,1,3-tris(arylsulfanyl)cyclohexanes are prepared from cyclohexenones by thioacetalization with various thiols in dichloromethane under reflux conditions in the presence of benzeneselenenyl bromide as a Lewis acid catalyst (▶ Scheme 5).^[7] The reaction proceeds through Michael addition of the thiol to the cyclohexenone, followed by thioacetalization of the resulting 3-(alkylsulfanyl)- or 3-(arylsulfanyl)cyclohexanone intermediate. Reaction with sterically hindered thiols, such as 2-methylpropane-2-thiol and 2-chlorobenzenethiol, does not give the desired S,S-acetals. Furthermore, when the reaction is carried out at –20 °C, the 3-(alkylsulfanyl)- and 3-(arylsulfanyl)cyclohexanones are obtained predominantly.

Scheme 5 Synthesis of 1,1,3-Tris(alkylsulfanyl)- and 1,1,3-Tris(arylsulfanyl)cyclohexanes Catalyzed by Benzeneselenenyl Bromide^[7]

R1	R2	Yield (%)	Ref
H	Ph	81	[7]
H	4-MeOC6H4	86	[7]
H	Pr	83	[7]
H	CH(Me)Et	60	[7]
H	(CH2)11Me	88	[7]
H	Bn	95	[7]
H		82	[7]
Me	4-MeOC6H4	92	[7]
Me	Pr	78	[7]
Me	Bn	89	[7]
Me		76	[7]

Propylphosphonic anhydride catalyzes the chemoselective thioacetalization of the aldehyde group of 4-formylacetophenone with propane- and benzenethiol to furnish the corresponding 4-[bis(propylsulfanyl)methyl]- and 4-[bis(phenylsulfanyl)methyl]acetophenones (▶ Scheme 6).^[8]

Scheme 6 Chemoselective Thioacetalization Catalyzed by Propylphosphonic Anhydride^[8]

S,S-Diphenyl Dithioacetals 4; General Procedure:^[6]

The aldehyde (1 mmol) and PhSH (4 mmol) were added to a mixture of Fe(NO₃)₃·9H₂O (10 mol%) and NaI (20 mol%) in CH₂Cl₂ (5 mL). The mixture was stirred at rt for 5–22 h, any insoluble materials were removed by filtration and washed with CH₂Cl₂ (5 mL), and Na₂S₂O₃ (2 g) was added to the filtrate portionwise. The resulting mixture was stirred for 5 min and then filtered, and the organic layer was washed with H₂O (25 mL) and brine (25 mL) and then dried (Na₂SO₄). The solvent was removed under reduced pressure and the residue was passed through a short column (silica gel, hexane) to give the pure product on removal of the solvent.

30.3.1.3.1.3 Variation 3: With Solid-Supported Lewis Acid Catalysts

Thioacetalization of aldehydes and ketones with thiols can be catalyzed by solid-supported Lewis acids, which are safe, easy to handle, and stable heterogeneous catalysts. The reaction proceeds at room temperature under solvent-free conditions and goes to completion immediately. The catalysts can be separated from the reaction mixture simply by filtration and are reusable several times without loss of activity. For example, in the presence of silica-supported phosphorus pentoxide (P₂O₅/SiO₂),^[9] at a loading of 0.5 mmol·g–1,^[10] a wide variety of aldehydes and ketones are transformed into S,S-acetals 5 on reaction with ethane- and phenylmethanethiol (▶ Scheme 7).^[9]

Scheme 7 Synthesis of S, S-Acetals Catalyzed by Silica-Supported Phosphorus Pentoxide^[9]

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