Thiourea cascades

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

Most of the now synthetically used quantitative cascade reactions involve an initial substitution step. That is quite clear for the reactions of acyl hahdes with thioureas to give 2-aminothiazoliiun salts. The 3-cascade consists of substitution to form the thiuronium salt, specific cychzation with the more nucleophihc of the amino groups, and elimination of water. In all reported cases, the water of reaction is taken up by the product crystal and it can be removed by heating to about 80 °C in a vacuiun. For example, if the thioureas 162 and phenacyl bromide 217 are stoichiometrically ball-milled at room temperature for 30 min, quantitative yields of the pure products 428 are obtained in all cases after drying at 0.01 bar at 80 °C [ 10] (Scheme 67). The free bases 429 can be obtained by trituration of 428 with NaHCOj solution. Furthermore, the thioureido-acet-amides 275 react correspondingly with 217 to give quantitative yields of the salts 430 from which the free bases can be obtained by NaHCOj trituration [96]. 

Later on, the same group developed a highly stereoselective Michael-Michael cascade process catalyzed by the quinine-based thiourea 81b [29b]. In the presence of a low catalyst loading (2 mol%), the reaction of trans-3-(2-mercaptophenyl)-2-prope-noic acid ethyl ester (106) with a wide range of nitroalkenes (107) afforded thio-chromanes (108) having three new stereocenters with high stereoselectivity (dr >30 1, up to 99% ee, Scheme 9.36). 

Keywords solid-solid reaction, cascade reaction, anilines, 1,2-diisothiocyanato benzene, thioureas, quantitative... 

Bunce and coworkers explored the tandem SN2/Michael addition cascade of 6- and 7-halo-2-alkenoate esters using both primary amines and thiourea to form... 

Thioamides and thioureas also undergo the silyl-mediated cascade reaction. For example, compound 503 gave 504 in 67% yield, while structural variants generally afforded related cyclized products in 50-87% yield. Thiourea 505 provided 506 in 64% yield, although a related substrate whose alkyne tether was conformationally more flexible failed to produce any cyclized product. 

Kaupp et al. employed ball-milling technique to transform thioureas 79 by reaction with phenacyl bromide to 2-amino-4-phenyl-thiazole-hydrobromides 80 in quantitative yields from stoichiometric mixtures of the reagents at room temperature (Scheme 4.21) [14]. In soUd-state conditions, base catalyst was not needed. The water formed in the reaction does not hydrolyze phenacyl bromide under applied mild conditions and was removed by heating at 80°C in vacuo. When the same reaction was performed in a melt at 110°C, partial hydrolysis occurred, which diminishes yield, while yields obtained in solntion were lower (80-90%). This Hantzsch thiazole synthesis starts with nucleophilic snbstitution on snlfur and formation of the carbon-sulfur bond (S-alkylation), followed by further reaction cascade which results in heterocychc ring. 

On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

Scheme 7.71 One example of a cascade sulfa-Michael/aldol reaction catalyzed by a chiral thiourea.

Xu and Dixon and co-workers also described a trimolecular cascade process, also involving a nitro-olefln. In this case, however, the nucleophile was a 1,3-dicarbonyl compound 183 whose 1,4-addition into the nitro-olefln 185 was facilitated by bifunctional thiourea catalyst 186. However, a secondary amine... 

The possibilities of enantioselective sulfa-Michael additions using amino derivatives of Cinchona alkaloids are also demonstrated through tandem (cascade, domino) reactions, thus allowing the formation of multiple stereocentres with up to 99% ee. In comparison to Cfnc/zona-thiourea derivatives, natural Cinchona alkaloids or their ethers gave lower... 

In 2010, Zhong and co-workers [32] tried a similar approach using nitrotyrenes and cyclic ketoesters. The reaction occurs through a Michael-Henry cascade reaction catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids. The reaction furnished the desired bicyclic products 43 in good yields and excellent stereoselectivities (Scheme 10.14). 

SCHEME 14.10. Enantioselective synthesis of thiochromanes by a sulfa-Michael-Michael cascade process promoted by quinine derived thiourea 12. 

The quinine derived thiourea 12 was found to be the most efficient catalyst, in terms of conversion and enantioselectivity, in the Michael-Michael cascade process between tra y-3-(2-mercaptoaryl)-2-propenoic acid esters and /ra 5-nitroalkenes [39]. The thiochromanes, containing three new stereocenters, were obtained with excellent enantio- and diastereoselectivity irrespective of the electronic namre and substitution pattern of the aromatic ring in the nitroalkene and in the thiol. Although the first sulfa-Michael step of the process was poorly enantioselective, it was also reversible, so that the enantiomeric mixture of the adducts underwent an efficient dynamic kinetic resolution due to a retro-Michael-Michael-Michael sequence (Scheme 14.10). 

The stereoselective vinylogous Michael addition-cyclization cascade of alkylidene malononitriles and 3-alkylideneoxindoles was effectively catalyzed by rosin-derived thiourea 36 to give spirocyclic oxindoles with excellent stereoselectivity (Scheme 35) [61]. Although simple thiourea 20 (see Scheme 16) provided low stereoselectivity (dr = 3 1, 29% ee), introduction of the rosin unit into the thiourea core significantly improved the diastereoselectivity to >20 1 the pyrrolidine structure was essential for high enantioselectivity. The effect of the chirality of the rosin component on the absolute stereocontrol was negligible and, thus, the major proposed role of this structural unit was to increase the steric hindrance of the catalyst. One of the salient features of this protocol is the... 

An unprecedented enantio-selective Michael/hemiketalization/retro-Henry cascade sequence catalysed by a simple bifunctional indane amine-thiourea organocatalyst (7)... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Later, the same group [35] disclosed the synthesis of various potential bioactive chiral functionalized chromanes 222 with high levels of enantio- and diastereoselectivity (up to 76% ee and >20 1 dr) via the rosin-derived tertiary amine-thiourea 221 catalyzed enantioselective FC alkylation/cyclization cascade of 1-naphthol 217 with a variety of p,y-unsaturated a-ketoesters 209 (Scheme 2.32). 

Wang elegantly demonstrated the potentiality of chiral diarylprolinol ether 54 in the synthesis of chromanes 56 via enantioselective Michael-type Friedel-Crafts alkylation/cychzation cascade synthetic sequence between 5a and a,p-unsaturated aldehydes 37a [30a]. Under optimal conditions, moderate diastereoselectivity and high enantioselectivity were obtained. Differently, phenol was found unreactive (Scheme 5.17a). The same team years later documented also the activity of a rosin-derived tertiary amine-thiourea 55 in similar process involving 1- and 2-naphthols and P,y-unsaturated a-ketoesters 25 (Scheme 5.17b) [30b]. A proposed model of the enantiodiscrimi-nating step of the reaction is also provided by the authors (58). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

Wang and coworkers made a similar approach using isocyanoesters [25]. The reaction was catalyzed by bifunctional tertiary amine-thiourea catalysts and afforded the pyrrolidinyl spirooxindoles in good yields and excellent enantioselectivities but low diastereoselectivities. Later, Yan and coworkers developed a similar reaction involving the three-component cascade reaction of isatin, isocyanoesters, and malononitrile [26]. First, the Knoevenagel reaction between isatin and malononitrile afforded the... 

Du W, Curran D (2003) Synthesis of carbocycUc and heterocyclic fused quinoUnes by cascade radical annulations of unsaturated JV-aryl thiocarbamates, thioamides, and thioureas. Oig Lett 5 1765-1768... 

In addition to the chemistry described previously, a variety of enantioselective thia-Michael reactions have been developed [5]. An example of one of these approaches involved the addition of allyhc thiols to highly activated ketones using a thiourea organocatalyst (Scheme 5.5) [6]. This thia-Michael addition was carried out in a cascade process with another Michael addition to generate trisubstituted tetrahydrothiophenes under mild conditions. The reaction was highly enantioselective and high yielding. In related work. 

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