Aldehydes sulfenylation

Williams and Rastetter also accomplished an elegant synthesis of ( )-hyalodendrin (83) in 1980 [39]. Beginning with the sarcosine anhydride-derived enolic aldehyde 78, silyl protection of the enal enabled alkylation of the glycine center with benzyl bromide and thiolation using LDA and monoclinic sulfur a la Schmidt. After protection of the thiol with methylsulfenyl chloride and deprotection of the silyl ether, the enol was sulfenylated with triphenylmethyl chlorodisulfide to afford bis(disulfide) 82 as a 2 1 mixture of diastereomers favoring the anti isomer. Reduction of the disulfides with sodium borohydride and oxidation with KI3 in pyridine afforded ( )-hyalodendrin (83) in 29 % yield (Scheme 9.4). 

In 2007, Hiemstra et al. established a catalytic asymmetric Pictet-Spengler reaction that proceeds via (V-sulfenyliminium ions (Scheme 15) [27], Treatment of iV-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f (5 mol%, R = 3,5-(CF3)2-CgH3) afforded tetrahydro-P-carbohnes. After completion of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot... 

Chloroallyl) thiocarbamate sulfoxides (. ., 5-2) un-.doubtedly rearrange in an analogous manner but in tbis case tbe sulfenate quickly undergoes an additional 1,2-elimination reaction (7 ). Tbe resulting products are tbe IJ, -dialkylcarbamoyl-sulfenyl chloride (M) and tbe carbonyl compound, aldehydes... 

Based on the previous findings by Koomen [21], the Hiemstra group subsequently reported the Pictet-Spengler reaction of N-tritylsulfenyl tryptamines and various aliphatic and aromatic aldehydes by 11 (Scheme 5.11) [22]. Notably, the authors found that stabilization of the N-sulfenyliminium ion by the sulfenyl substituent facilitated preferential cyclization over enamine formation. 

The introduction of a-heteroatom functionalization into an aldehyde or ketone is a very useful class of transformation. Performing it directly and asymmetrically, using organocatalysts, has been reviewed for reactions such as amination, oxygenation, halo- genation, and sulfenylation (44 references).260... 

Protected sulfenylation reagents (Lg-S-Pg) a-sulfenylate aldehydes, using steri- cally encumbered chiral pyrrolidines as enantioselective organocatalysts.298... 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

In the following sections we will describe recent developments and applications in the organocatalytic a-heteroatom functionalization of aldehydes and ketones catalyzed by chiral amines [1]. Notably, the C-H to C-Het transformations associated with amination, oxygenation, halogenation (fluorination, chlorination, bro-mination), and sulfenylation will be outlined (Scheme 2.24). 

It should be noted that the more sterically demanding a,a-disubstituted aldehydes could be efficiently sulfenylated when the same catalyst was used, even if with lower enantiomeric excess (61% ee). 

Sulfenyl halides with an aldehyde function ortho to the sulfur react with ammonia with the formation of 1,2-benzisothiazoles0 [Eq. (1)]. 

Dicarbonyl compounds. The adducts (2) of the anion (1) of meth-oxy(phenylthio)methane and aldehydes (12, 316) are converted into a-sulfenyl aldehydes (3) on treatment with methanesulfonyl chloride and triethylamine (1 1). Reaction of 3 with a Wittig or Wittig-Horner reagent followed by isomerization... 

Addition of aldehydes, acetals, or phenylsulfenyl chloride at this stage gives the respective aldol and sulfenylated products. 

Because of their tendency to undergo aldol reactions, various conditions have been investigated to develop methods for the sulfenylation of aldehydes. Indirect methods involving metallation of the corresponding imines (10 Scheme 11 ) offer a preferred alternative to the low temperature direct sulfenylation described above, but better methods are still required. One possibility may Ite to exploit the rapid room temperature enolization of aldehydes observed on treatment with potassium hydride in THF. ... 

Potassium enolates of aldehydes, Enolates of aldehydes are somewhat difficult to generate because of competing polymerization by base. They have been obtained recently in high yield by use of potassium hydride in THF at 0° and successfully alkylated, sulfenylated with diphenyl disulfide, and converted into o-iodo aldehydes by iodine. The last two reactions have not been observed previously. Sulfenylation of aldehydes has previously used indirectly generated lithium enolates and a reactive sulfenyl chloride. All three reactions are useful, however, for aldehydes with only one a-proton. Otherwise yields of monosubstituted aldehydes are low and largely by-products are obtained. 

The alkylation of SAMP/RAMP hydrazones with heteroelectrophiles leads to enantiomerically pure a-silyl aldehydes and ketones (eq 15), a-sulfenyl aldehydes and ketones (eq 16), and a-hydroxy aldehydes and ketones (eq 17). ... 

A noteworthy improvement comes from the use of ligand systems which are themselves optically active." This is die case of the complex (150), shown in Scheme 21, that is prepared from a sulfenylated norephedrine (149). The results reported for the in situ reactions of (150) with various aldehydes (Scheme 21) are summarized in Table 14." Nothing is reported concerning the mechanism of the en-antioselecdve addition, since the absolute configuration of the asymmetrically substituted Ti atom is not known. 

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