Thioamides, halo

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

In contrast to thiomiinchnones, thioisomiinchnones (5) (l,3-thiazolium-4-olates) have received considerable attention over the past three decades, and a rich array of 1,3-dipolar cycloaddition chemistry is described in Section 10.2.5. These heterocycles were initially constructed by Potts (1,53,57) from thioamides and a-halo acid chlorides, an example of which is shown in Scheme 10.17 (58). 

Replacement of the a-halo ketone by a cyano analogue can lead to amino derivatives. The benzenesulfonyl ester of mandelonitrile (168) with a primary thioamide, RCSNH2 gives the 4-aminothiazole (169). 

Peptide-Based Thiazoles via the Condensation of 5-Halo- -oxo Esters with Thioamides A Modified Hantzsch Synthesis... 

Most reported solid-phase thiazole syntheses have been based on the cyclocondensation of thioamides or thioureas with a-halo ketones (Table 15.18). These reactions generally proceed smoothly under basic or acidic conditions, and are compatible with most common linkers. 

But the more heteroatoms, the more alternatives. We could disconnect the enamine first 27a and the C-S bond second 31. This suggests a reasonable a-halo-ketone 33 and an unstable-looking imine 32. Fortunately this is just a tautomer of the thioamide 34. Though thioketones are unstable, thio-amides are stable thanks to extra conjugation. 

Mono- and 2,5-di-substituted thiazoles are obtained in a similar way by the cyclization of higher a-halo aldehydes with thioformamide or higher thioamides (Scheme 161). The yields usually decrease with the size of the R2 chain of the thioamide. 

The mechanism of the Hantzsch synthesis has been established and is shown in Scheme 165. Substitution of the halogen atom of the a-halo ketone by the sulfur atom of the thioamide occurs first to give an open-chain a-thioketone (232), which under transprotonation proceeds to give a 4-hydroxy-A2-thiazoline (233) in aprotic solvents, or a thiazole (234) by acid-catalyzed dehydration of the intermediate thiazoline in protic solvents. 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

Halo ketones 218 react with amides (100 C, no solvent), thioamides (reflux in EtOH), and amidines to give oxazoles, thiazoles, and imidazoles (219 220 Z = O, S, NH), respectively (Scheme 108). Intermediates of type 221 can sometimes be isolated. This is the most important thiazole synthesis, and both the thioamide and the halo ketone components can be varied widely . 

Six-membered ring cyclic thioamides react with -halo ketones to give the thiazolo[3,2- ]pyridinium system, e.g., 58 (Scheme 36). A similar reaction of 59 affords the thioisomnchnone 60 (Scheme 37) <2001J(P1)2055, CHEC-III (11.10.8.2)487>. 

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an N—C(=S)— structural entity. Reaction of the a-bromoketone (65) with the primary thioamide (66) in hot benzene gave the intermediate hydroxy compound (67), which could be isolated in certain instances but in most cases underwent dehydration to form the thiazole (68). The diversity in the substituents capable of being introduced into the resultant thiazole by this procedure is illustrated in Chapter 4.19. Especially noteworthy in this respect is the reaction of the bromopyruvaldehyde oxime (69) with thiourea in methanol at room temperature. Neutralization with sodium carbonate resulted in the isolation of the 2-aminothiazole-4-carbaIdehyde oxime (70) in 39% yield (73JOC806). 

Thiazole and its derivatives are useful compounds in medicinal and agricultural chemistry. The thiazolium ring is present in vitamin B1 and its coenzyme form is important for the decarboxylation of a-keto acids [74]. This heterocyclic system has broad application in drug development for the treatment of inflammation [75] and bacterial [76] and HIV infections [77]. Hence the thiazole nucleus has been much studied in organic and medicinal chemistry. Originally it was synthesized by the Hantzsch reaction (a-halo ketones with thioamides or thioureas) (Equation 4.38) [78]. 

For most examples, addition of both a base and a thiophile is necessary for sulfide contraction to occur. However, the process can proceed in the absence of either reagent when a thioamide is alkylated with an active methylene species such as an a-halo malonate (equation 6) or another 1,3-dicai1x>nyl compound that exists primarily in the enolized form. In some cases, heat was needed to initiate sulfide contraction alkylation of monothiouracil (equation 7) with bromoacetophenone yielded an intermediate... 

Reaction of 6-halo-5-ketofuranose derivatives such as 612 (75HCA1507) or 6-diazo-5-ketohexofuranoses (76JOC4074) with thioamides gave products (613) that belong to this type of C-nucleosides (Scheme 160). 

Aldonic acid thioamide acetates (619) condensed with various a-halo-ketones to afford the 2-(alditol-l-yl)lhiazoles 620 [54AQ(B)609, 54CB78 69ACH(62)179, 69T3413 87H947 95TL3781] (Scheme 163). 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

The Hantzsch reaction, discovered in 1889, remains one of the most reliable routes to thiazoles. The reaction involves a [3 + 2] atom cyclization between thioamide 1, and an a-halo carbonyl compound 2 and is one of the most direct routes to thiazoles. The reaction can also be carried out with thioureas, thiosemicarbazides and other compounds containing the —N-0=S structural unit. " ... 

Although many phenylacetamides were successfully alkylated with 2-bromo-pyridine, the corresponding thioamides were not. The pyrrolidone XI-14was employed as the active methylene compound in a condensation with 2-bromopyridines. ° Treatment of quaternary salts of halo- or alkoxy-pyridines... 

Iminium salts, generated in situ from the amides and lactams, react with 1 to produce the corresponding thioamides and thio-lactams, respectively, in good yields (eq T)P- The advantages of this methodology are the easy work-up and chemoselectively amides are thionated in the presence of ketones, aldehydes, and esters (eq 8). ra-Halo acid chlorides react with 1 and the corresponding thiolactones are obtained in moderate yields under mild reaction conditions (eq 9). This reaction works well for the synthesis of small and medium ring thiolactones, but is not useful for the synthesis of macrocyclic thiolactones. ... 

Reactive functional groups withstand reactions with LR if proper conditions are chosen. The thionation of 7V (< -haloalkyl) amides with 0.5 equiv of LR yields the corresponding thioamides without attack at the halo substituent. Optically pure cj-thio-amides of Fmoc-asparagic and -glutamic acid (68) have heen prepared with another LR analog, 0,0-bis(tert-hutyldimethylsilyl)-4-methoxyhenzenephosphonothioate [p-MeO-C6H4-P(S)(OTB DMS)2]. The protected polyamine thioamide (69) is related to the spider toxin FTX. ... 

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