Imidazoline-2-thiones reactions

An adaptation of this reaction is the transformation of 3-substituted l-amino-4-oxo-imidazoline-2-thiones (282) into 2-alkylimino-5-aryl-3,6-dihydro-2//-l,3,4-thiadiazine-3-acetic esters, involving ring-scission of an imidazo[l,2-6]thiadiazine intermediate (283), occurs on treating the imidazoline thiones with a phenacyl bromide in hot alcohol solution <89S518>. The free bases (284) are liberated on heating the hydrobromides under reflux with triethylamine in ethanol. The thiadiazines (284) can also be synthesized independently from the A-(alkoxycarbonylmethyl) semicarbazides (R NHCSN(NH2)CH2C02Et) and phenacyl bromide. 

Chiral imidazoUdin-2-thione or 2-one were prepared from o-glucoseamine by reaction with o,o -disubstituted arylisothiocyanates to give 39 which can be cycHzed to 40 [76]. Thus, a variety of derivatives were prepared carrying different aryl groups and as a consequence of hindered rotation, some of them exist as stable rotamers (Fig. 7). Treatment of 39 with acetic anhydride in pyridine at low temperature gave the respective per-O-acetyl derivative imidazolidine thione, which upon elimination of acetic acid gave the imidazoline thion 41 as a mixture of atropisomers [76]. 

Imidazoline-2-thione, 4,5-diphenyl-oxidation, 5, 405, 445 Imidazoline-2-thione, 4-methyl-Mannich reaction, S, 405 oxidation, 5, 445... 

S-group removal from, S, 445 oxidation, S, 445 reactions, S, 443-445 reactivity, 5, 375-376 synthesis, S, 493 Imidazoline-2-thiones Mannich reaction, 5, 405 reactions, 5, 102, 443-444 with alkynes, 5, 444 synthesis, S, 493... 

Unsaturated five membered 2-chalcogenons with two heteroatoms at 1,3-positions (6) will show versatile reactivities with acceptors, since E in 6 must be very electron rich with the formation of a stable cyclic 671 electron system (6A).27,28 A saturated ring system 7 is expected to show similar trend due to the stabilization by the allylic X-C-Y framework with 471 electrons (7A). Arduengo reported the TBP formation of 1,3-dimethyl-4-imidazoline-2-thione (8), a typical example of 6 (X = Y = NMe and E = S), with bromine (8 Br2), together with the reactions.36... 

Numereous derivatives of benzimidazole, naphthoimidazoles and other condensed imidazole systems can be very effectively thiated with elemental sulfur on heating without solvent at 230-260°C. The product of this reaction is the corresponding imidazolin-2-thione formed in excellent yield (67ZOR1518, 95IZV2231). For example, imidazo[4,5-cjpyridines (329, R =H, Aik, Ar, C6H5CH2) gave 1,3-dihydro-2//-imidazo[4,5-c]pyridine-2-thiones (330). 

When the imidazoline-4-thione (347) was treated with hydrazine the 1,2,4,5-tetrazine (348) was obtained, probably via the intermediate thiohydrazide (349) (72LA(76l)95). Reaction of the alkynic thioacetate (350) with hydrazine affords 3,6-dipentyl- 1,4-dihydro-1,2,4,5-tetrazine (351), the formation of which can be rationalized by the intermediate formation of (352) (67RTC907). 

Asinger s studies demonstrated that product formation is sensitive to the ratio of sulfur to ketone (1), the structure of the ketone, the replacement of ammonia by amines, the temperature and the medium. Room temperature (20-25 °C) reactions in which the ratio of sulfur to ketones is 0.5 favors the formation of 3-thiazoline, 2, as shown in Figure 1. The formation of 5-alkylidene-3-thiazolines, 3, sometimes competes with the formation of 3-thiazolines such is the case when aryl ketones such as l-phenylpropan-2-one and l-phenylbutan-2-one are employed (4). Also the additional presence of hydrogen sulfide promotes the generation of 1,2,4-trithiolanes and 1,2,4,5-tetrathiolanes from ketones ana aldehydes at the expense of 3-thiazoline formation (11-12). Increasing the S/ketone ratio to 8 favors the formation of the 3-imidazoline-5-thione (5), a product which has a greater tendency to result from aryl methyl ketones (3). 

Retro-Hantzsch, mechanism of, 84, 85, 102 Rhodanine, alkylation of, 419 ambident reactivity of. 419 reaction with aryldiazonium salts, 419 reaction with halogenothiazoles, 79 Rice cultures, 135, 136, 137 Ring-chain tautomerism, 113 Ring opening, of A-2-thiazoline-5-one, 433 Ring transformation, 5 amino-A-4-thiazo-line-2-thione to 4-mercapto-imidazoline-2-thione, 399 5,5-diphenyl-2,4-thiazolidinedithione, to 4,5-diphenyl-A-4-thiazoline-2-thione, 37 3... 

Imidazoline-2-thiones and imidazolidine-2-thiones react with 1,2-dibromoethane in the presence of aqueous sodium hydroxide and a charge transfer catalyst (CTC), or with a-cyanobenzyl benzenesulfonate, to give the corresponding imidazo[3,l-f>]thiazoles (equation 10) (80JHC393, 61JOC2715). In an analogous reaction, the condensation of 5,5-diphenyl-2-thiohydantoin with ethylene dibromide yielded two isomeric products, (99 major) and (100 minor) (8lJCS(P2)789). 

The reaction of methylketones with sulfur and ammonia produces A 3-imidazoline-5-thiones (37) (especially in the presence of pyridine).157 The initial stage of the reaction is formation of a phenylglyoxylic thionamide (38), followed by ring closure, and thus the reaction... 

The treatment of vinyl anions with elemental selenium also leads to seleno-carbonyl compounds via eneselenolate anions (Eqs. 4-6). Deprotonation of l,3-selenothio-2-thione with EDA followed by the reaction with elemental selenium proceeds accompanied with the rearrangement of vinylic skeleton to form l,3-dithio-2-selone derivatives (Eq. 4) [38]. The vinyl anions from oxa-zolines and imidazoles were treated with elemental selenium to give the oxazo-line selone and imidazoline selone after the aqueous workup (Eq. 5) [39]. The reaction of vinyl magnesium halides with elemental selenium and allyl bromide gives allyl vinyl selenides that undergo a seleno-Claisen rearrangement to generate y,6-unsaturated selenoaldehydes (Eq. 6) [40]. 

The related Mannich reaction is not common. Under the usual acidic reaction conditions TV-substitution occurs, but this is a reversible reaction in the presence of base. Therefore, in basic medium, C- substituted products accumulate, and all positions can be substituted. 2-Methylimidazole gives 1,4,5-tri, 4,5-di- and 4-mono-substituted products. The observation that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain activating substituents they are not very susceptible to reaction with aldehydes (except HCHO) and ketones. An exception appears to be the product (99) of interaction between imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-thione gives the 5-dimethylamino compound (100) imidazoline-2-thione gave only the (V-hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a free 5-position readily form benzylidene derivatives (B-76MI40701). 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

When urea (or thiourea) reacts with a-hydroxy ketones or a-diketones the products are imidazolin-2-ones (or -thiones) (70AHC(12)103,66RCR122). The reaction is limited to the preparation of 4,5-alkyl(or aryl)- or l,4,5-trialkyl(or triaryl)-imidazoles since an oxygen or sulfur function appears at C-2. Benzoin condenses with iV-phenylthiourea in hexanol in the presence of catalytic quantities of HCl to give l,4,5-triphenylimidazoline-2-thione (131) in 50-60% yield (Scheme 69). While 1-methylurea can also take part in the reaction. 

In the reaction of ammonia, sulfur and o-hydroxyacetophenone the methyl group of the ketone is so functionalized that the 2//-imidazoline-5-thione (149) is formed. The reaction proceeds best in the presence of pyridine, and involves formation of a phenylglyoxylic thioamide (148) in the first instance (Scheme 84). The ring closure of (148) resembles similar reactions discussed earlier (Section 4.08.1.2.2(1)). 

The two general methods for preparation of 4-imidazoline-2-thiones are the reaction of acyloins with thioureas and the acid hydrolysis of alkyl- or arylthiureidoacetals. The above reactions have been summarized in a review by Hofmann. Aren and Bite recently reported that the 2-phenyl-2-thiureido-l,3-indanediones (17) undergo rearrangement in strong acid to produce in high yield a series of 4-imidazoline-2-thiones (18). 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

Unlike an A, A -disubstituted imidazoline-2-thione, the reaction of imidazolidine-2-thione 665 itself with 2-phenyloxirane in the presence of BF3 leads to the formation of l,3-bis[(i4)-2-phenylethen-l-yl]im>dazolidine-2-thione 666 (Scheme 161) <2005HCA3253>. This unusual mode of reaction is presumably due to a Lewis-acid-catalyzed rearrangement of oxirane to aldehyde followed by an ene-like reaction with the iminothiol. 

Reduction of imidazole thiones 940 with Na/K in THF leads to carbenes 941 (Scheme 228) <2003AGE5243>. Under similar conditions, imidazoline 943 is formed from 942 <1999CEJ1931>. The carbene 944 can be obtained if the reaction is conducted in toluene. The intermediacy of a carbene has been proposed for the reaction of 4,4,5,5-tetramethylimidazolidine-2-thione and ( )-valine in the presence of Cso fullerene that leads to the formation of an open [5,6] adduct <1997TL6613>. 

Functionalization of the a-position of an aryl ketone is achieved by sulfur in the reaction between ammonia, sulfur, and o-hydroxyacetophenone. The product is a 2//-imidazoline-5-thione (5) as shown in Eq. (3). The rearrangement of cyclohexane-1,2-dione monophenylhydrazone in the presence of ammonium acetate in acetic acid gives an imidazole. ... 

---