Thioamides acylation

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Next the product is acylated with bromoacetyl chloride and the glycine equivalent is constructed in place by a Gabriel amine synthesis (phthalamide anion followed by hydrazine) subsequent to which cyclization to benzodiazepine occurs. The synthesis of the tranquilizer quazepam (88) is finished by thioamide conversion with phosphorus pentasulfide. ... 

N-Substituted amides can be prepared by direct attack of isocyanates on aromatic rings.The R group may be alkyl or aryl, but if the latter, dimers and trimers are also obtained. Isothiocyanates similarly give thioamides. The reaction has been carried out intramolecularly both with aralkyl isothiocyanates and acyl isothiocyanates.In the latter case, the product is easily hydrolyzable to a dicarboxylic acid this is a way of putting a carboxyl group on a ring ortho to one already there (34 is... 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

Acyl thioamides react with lithium diisopropylamide (LDA) to give p-thiolactams (Scheme 30).57... 

The 5-alkylthioethaniminium salt (10 mmol) (see 4.1.11) and the appropriate acyl halide (10 mol) in PhH (50 ml) are stirred at room temperature with TBA-Br (97 mg, 0.3 mmol) in aqueous NaOH (30%, 50 ml) for 15 min. The organic phase is separated, washed with H20 (3 x 50 ml), dried (Na2S04), and fractionally distilled under reduced pressure to give the thioamidate. 

C, and then three molecular equivalents of acetyl chloride and triethy-lamine were added. Three types of acetylated materials, 11, 12, and 13, were isolated accompanied by a small amount of thioketone 7 and thioamide 9 (Scheme 8 and Table 6). All of the acetylated materials showed optical activity. For the reaction of 6a, 84% ee of 2-(acetylthio)aziridine 11a, 50% ee of 4-(acetyl-thio)oxazoline 12a, and 20% ee of 4-(acetylthio)oxazolidin-2-one 13a were obtained in 39,10, and 16% yields, respectively. In the reaction of 6b,c, the corresponding optically active materials 11-13 were obtained as shown in Table 9. The formation of oxazoline 12 involves the rearrangement ofAT-acyl aziridines, which occurs by intramolecular attack of the carbonyl oxygen at the ring carbon to cause rupture of the system. 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

C-Terminal activation of peptides containing a terminal thioamide group results in thiazo-lone formation this leads to epimerization at the marked chiral centers (see Scheme 35) the thiazolone is only a weak acylating agent 500 The coupling yield may still be satisfactory, if achiral C-terminal amino acids are employed 488,503 ... 

An alternate step-wise cyclization strategy to form 3-carboline 22 is shown in Scheme 7. Acylation of D-tryptophan (21) with piperonyloyl chloride afforded amide 25, which was converted to thioamide 26 with Lawesson s reagent. Thioamide 26 was treated with methyl iodide in refluxing CH2CI2 to give a a-thiomethylimmonium ion, which was trapped by the intramolecular addition of indole. The thiomethyl group was... 

Thioamides are suitable intermediates for the preparation of amidines, thiazoles, and thiophenes. Thioamides have mainly been prepared on insoluble supports by C-acylation of enamines or C,H-acidic compounds with isothiocyanates (Entries 1-3,... 

Table 13.21) or from amides by treatment with Lawesson s reagent. Thioamides can also be prepared on cross-linked polystyrene by the addition of H2S to nitriles (Entry 5, Table 13.21), by thiocarbamoylation of resin-bound organolithium compounds (Entry 6), or by the acylation of amines with reactive thio acid derivatives (Entry 7, Table 13.21). 

Keywords acyl chloride, 77-alkyl piperazine, Lawesson s reagent, microwave irradiation, thioamide... 

The diamine 2 was added to an etherial solution of an acyl chloride 1 in a Teflon-capped vial. Salt precipitaion was instant. The solvent was removed by filtration, where the Teflon cap served as the filter. Lawesson s reagent (1.0-1.5 equiv.) was added to the salt 3 and the resulting mixture of solids was mixed thoroughly and thereafter irradiated for 8 min in a domestic microwave oven (900 W, Whirlpool M401). Solid-phase extraction afforded the thioamides 4 in adequate purities and yields. 

Acylation reactions can be carried out by the action of acid anhydrides [66, 67], chloroanhydrides [47, 61], isocyanates [68], isothiocyanates [68, 69] and thioamides [70]. It was shown that the reaction of aziridinyl ketone 49 with chloroacetyl chloride 50 in the presence of Et3N [61] leads to the formation of A-acyl derivative 51, whereas the alkylation product was not isolated. 

In the next section the formation of acyl anion equivalents by nucleophilic addition to thiocarbonyl compounds is discussed. A direct and non-classical route to thiocarbonyl anions has been achieved [141]. Treatment of a thiocarbamoyl chloride by lithium powder, in the presence of both naphthalene and the carbonyl compound to which the intermediate will be added, led to a-hydroxy thioamides. 

The same intermediate was also formed by direct deprotonation of N,N-dimethylthioformamide with LDA, and was used to prepare a-oxo thioami-des by acylation with carboxylic esters [141]. Deprotonation of the formed thioamides laterally takes place on the AT-methyl group and intramolecular addition of the anion to the carbonyl group provides a new entry to /1-thio-lactam rings. 

Other results with unsaturated thioamides include a nice reversal [233] of the endo selectivity in favour of the exo adduct by adjustment (Table 4, entry 9) of the thermal conditions (-30 °C vs 80 °C). Unexpected dimerisa-tions of enethioamides (entries 10 and 11) were observed [234, 235]. Thiocarbonyl chemistry has already been used in fullerene chemistry Acyl thio-acrylamides react [236] with [60]fullerene to yield hetero-Diels-Adler products (Table 4, entry 12). 

Pyrroles 779 and 781 were regioselectively acylated with ethoxycarbonyl isothiocyanate, affording acylated thioamides 780 and 782, respectively, as intermediates in the synthesis of pyrroloamidines, guanidine bioisostere analogs (Equations 184 and 185) <2001JME1217>. 

The compound Ar2Bi(0)0Me, which was prepared via the reaction of ArsBi and 4-MeC6H4S02NClNa, has been reported to acylate amides, thioamides, ureas, and thioureas. The first step of the process is believed to be reaction of the Ar2Bi(0)0Me compound with acetic acid to replace the methoxide with acetate. ... 

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