[2346-00-1] · C4H7NS · 2-Methyl-2-thiazoline · (MW 101.19)
(lithiation produces an acetaldehyde enolate equivalent for synthesis of mono-, di-, and trisubstituted acetaldehydes,1,2 b-hydroxy aldehydes,3 homoallylic alcohols,3 and a,a-disubstituted b-ethylenic methyl ketones4)
Alternate Name: 4,5-dihydro-2-methylthiazole.
Physical Data: bp 144.5-145 °C; d 1.067 g cm-3.
Form Supplied in: commercially available.
Handling, Storage, and Precautions: no special precautions are warranted. Use in a fume hood.
2-Methyl-2-thiazoline functions as a latent acetaldehyde equivalent. Lithiation with n-Butyllithium occurs at -78 °C to produce the thiazoline anion, which can be alkylated with a variety of electrophiles. Reductive hydrolysis of the thiazoline ring then releases the free monoalkylated acetaldehyde (eq 1).2 Some examples of this methodology are given in Table 1.2,5 Neutral conditions are employed (Aluminum Amalgam/Mercury(II) Chloride) for the release of the substituted acetaldehyde. Sodium Cyanoborohydride in MeOH/TsOH has been utilized instead of Al(Hg) for the reduction of the thiazoline ring to the thiazolidine ring.6 A variety of methods have been used to convert the thiazolidines to aldehydes (e.g. I2, MeOH).7
If the initially alkylated thiazoline is again metalated and alkylated, dialkylated acetaldehydes are formed (eqs 2-4).2 Repeating this process (with Lithium Diisopropylamide as the base) results in trialkylated acetaldehydes (eq 5).2
Deuterated aldehydes are formed when the aluminum amalgam reduction is conducted in the presence of D2O (eq 6).2
Treatment of 2-aminoethanethiol with alkyl cyanides results in cyclization to the corresponding thiazolines, which can take part in the above outlined protocol. For example, enantiomerically pure (+)-(S)-3-methylpentanenitrile can be converted to the thiazoline in 60% yield (eq 7).8 Metalation and reaction with 2-iodomethyl-1,3-dioxolane affords the alkylated product in 68% yield. This differentially protected dialdehyde can be selectively deprotected.
Addition of the lithio salt of the title reagent to nitriles forms the corresponding enamino thiazoline which can, in principle, be hydrolyzed to b-keto aldehydes (eq 8).9
The lithio anion of 2-methyl-2-thiazoline undergoes 1,2-carbonyl addition to aldehydes and ketones.3 Aldehyde liberation from the thiazoline then results in the corresponding b-hydroxy aldehydes (eq 9).
Due to the instability of b-hydroxy aldehydes, in situ methoxymethylation with Chloromethyl Methyl Ether (MOMCl) is necessary immediately after nucleophilic addition to the carbonyl carbon (eq 10).3 The MOM group is resistant to the thiazoline cleavage conditions (i.e. Al(Hg) and HgCl2).
These protected b-hydroxy aldehydes can be conveniently transformed into homoallylic alcohols by treatment with a Wittig reagent and then subsequent alcohol deprotection.3 2-Methyl-2-thiazoline has also successfully formed adducts with electrophilic species such as a-oxo ketene dithioacetals,10 isotopically labeled alkyl halides,11 and hydroxamates.12
1,2-Addition of allylic Grignard reagents to the imine double bond of 2-methyl-2-thiazoline (and derivatives) occurs with transposition of the allylic double bond in good yields (eq 11).4 Thiazoline hydrolysis affords the two-carbon extended a,a-disubstituted b-ethylenic methyl ketones.
In addition to the title reagent, similar two-carbon extension synthons, such as 2-Methylbenzothiazole (1)13 and 4,5-dihydroimidazoles (e.g. 2),14,15 have been utilized in homologation procedures.
Todd D. Nelson & Albert I. Meyers
Colorado State University, Fort Collins, CO, USA