Isothiocyanates, addition cyclization

From carbonohydrazide. Equimolar quantities of carbonohydrazide (71) and aroyl isothiocyanates undergo an addition-cyclization in dimethyl-formamide at 100 °C, with elimination of hydrazine, resulting in moderate yields of 2-aroylamido-5-hydroxy-l,3,4-thiadiazoles (73). The postulated intermediate mono-adducts (72) are not isolable, but stable addition... 

Isothiocyanate esters undergo an addition-cyclization with 3-amino-3-alkyl-l-butynes at 50 C to form 2-amino-A -thiazolines (Scheme 9) 3-alkyl-amino-3-alkyl-l-butynes produce the corresponding iminothiazolidines (212). ... 

Addition [of (213)] to the C=N bond of phenyl isothiocyanate and cyclization affords 5-arylidene-l-phenylrhodanines (216). The reaction of acrylic acids (213) with formaldehyde in acetic acid produces 4-arylidene-l,3-oxathiolan-5-ones (217), which are in their turn convertible by concentrated ammonia into 5-arylidenethiazolidin-4-ones (218). ... 

The formation of compounds 2-503 proceeds via the addition of a hydrazide 2-500 onto the central carbon of an isothiocyanate 2-499. Subsequent cyclization by attack of the hydrazide nitrogen in the formed 2-501 onto the nitrile moiety gives intermediate 2-502. A further attack of the newly formed amidine nitrogen onto the carbonyl group followed by extrusion of water affords the triazoloquinolines 2-503. 

The cyclization to the desired head-to-tail linked bis-benzimidazoles could also be performed utilizing aryl or alkyl isothiocyanates with N, N -dicyclohexylcarbodiimidc (DCC) [82]. Upon completion, the insoluble N,N -dicyclohexylthiourea formed had to be removed by filtration and the desired PEG-bound products were precipitated by the addition of diethyl ether. The results were essentially the same as those of the cyclizations with the above mentioned aldehydes. 

Addition of isothiocyanates to 2-amino-4H-pyran-3-carbonitriles with subsequent cyclization affords pyrano[2,3-d]pyrimidinethiones-2 290 (89JPR971, 08PS1145) (Scheme 121). 

Thioxo-1,2,4-dithiazolidines can be obtained from thioxo-l,2,4-thiadiazolidines by Dimroth rearrangement (Scheme 47) or reversibly by addition and elimination of acetone (Scheme 22). 1,2,4-Dithiazole type products are also obtained from thiocarbonyl isothiocyanates (154) by reaction with CI2 <84CHEC-I(6)897>, PhMgBr, Sj, or CS2. Other routes include reactions of carbonyl isothiocyanates and thiocarbonyl isocyanates with P4S10 or Sg <84Chec-I(6)897> and sulfonyl isocyanates with dialkyl thioketenes. Phenylisothiocyanate heated with N,C-disubstituted oxaziridines affords 3,5-diimino-l,2,4-dithiazolidines (226, 227). Other miscellaneous syntheses of 1,2,4-dithiazoline derivatives include cyclization of A7-thioacyl hexafluoroacetonimine to 5,5-bis(trifluoromethyl)-... 

An unusual reaction leading to the formation of 4-thioxopyrazolo[3,4-d]-pyrimidines has been reported. 1-Substituted 4-cyano-5-aminopyrazoles (103, R = H) react with phenyl isothiocyanate in dimethylformamide (DMF) saturated with hydrogen chloride to yield 1-substituted 4(5//)-pyrazolo[3,4-d]-pyrimidinethione (110). A proposed reaction sequence involved an initial nucleophilic addition of phenyl isothiocyanate to the protonated o-amino-nitrile to give an o-aminothioamide (108), followed by formylation by the dimethylformamide-hydrogen chloride mixture affording 109, which then cyclizes to the final product 110 (70MI1). 

Amidoximes (46) were first used as a source of 1,2,4-thiadiazoles in 1889 their condensation with carbon disulfide or with an excess of aryl isothiocyanate yields 3-aryl-5-mercapto- (47)6 -73 or 3-aryl-5-aryl-amino- 1,2,4-thiadiazoles (50),71,74,75 respectively. The latter reaction has been reexamined and discussed by Gheorgiu and Barbos76 who suggest that an initial addition of two moles of phenyl isothiocyanate to one of benzamidoxime is followed by cyclization of the intermediate (49), with elimination of phenylthiocarbamic acid (51). Decomposition of the latter gives rise to the by-products observed (cf. following scheme). 

Dihydro-1,3-oxazines or -thiazines bearing amino groups at the 2-position are available through the addition of 3-aminopropanols to isothiocyanates. The product thioureas readily cyclize to thiazines on treatment with base (1890CB87), but in order to form the analogous oxazines consecutive treatment with methyl iodide and base is required (Scheme 89) (74KGS354). In both cases the products are best formulated as imines rather than amines (see Section 2.27.2.2.1). 

Analogously, Bognar and coworkers45-46 prepared the same thiourea derivative 33, and synthesized some other N-glycosyl heterocyclic derivatives, such as thiazole 36, 1,3,4-thiadiazole 38, and 1,2,3,4-thiatriazole 39, using as the starting material isothiocyanate 2, or its ureido (34) or semicar-bazide (37) analogs. It is noteworthy that treatment of semicarbazide 37 with a nitroso acid at 0° afforded the 1,2,3,4-thiatriazole derivative 39 by addition and cyclization. The same 1,2,3,4-thiatriazole derivative 39 was obtained by treatment of isothiocyanate 2 with hydrazoic acid. 

The first route described to nonfused selenazepanes 67 from the aryl isoselenocyanates 65 and the chloro amine 66 by a stepwise amine addition-ring cyclization strategy (Equation 15) <2005TL6723> also has potential for application to the 1,3-thiazepane and 1,3-oxazepane analogues from the corresponding aryl isothiocyanates and aryl isocyanates. 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

Dithiocarbazic acids (CCXV) cyclize with isothiocyanates on simple warming to 5-imino-1,3,4-thiadiazolidine-2-thiones (CXVb) 70). Addition of alkali, however, causes the cyclization to follow a different path, or rather to give the classical transfer of an exocyclic nitrogen atom to a heterocyclic one or of a heterocyclic sulfur atom to an exocyclic thioxo group. This results in the formation of l,2,4-triazolidine-3,5-dithiones (CCXXXV) (Table 41). 

DihydroquinazoHnes have been synthesized by aza-Wittig coupling to form the carbodiimide and subsequent addition of a secondary amine to induce an intramolecular Michael addition of 157 [202], Elements of diversity are therefore added upon treating the iminophosphoranes with isocyanates or thioisocyanates, and upon the subsequent reaction of the carbodiimide with an excess of a secondary amine. 1,4-DihydroquinazoHnes have been prepared using a tetrafunctional scaffold cyclized with aryl isothiocyanates on Rink resin [204],... 

Addition reactions of 2-chloro-3-pyridylcarbonyl isothiocyanate with primary amines yield acylated thioureas 1. Because of the ambident character of the thiocarbamoyl group, in the following cyclization step the 2-chloro substituent of the pyridine may react either with the sulfur or the nitrogen center, depending on the reaction conditions. In the example below, heating under reflux in toluene yields 2-aminopyrido[3,2-e][l,3]thiazin-4-ones, whereas the anion prepared by metalation with lithium hydride in dimethylformamide at room temperature leads to 2-thioxo-l,2-dihydropyrido[2,3-c/]pyrimidin-4(3//)-ones 2.6... 

Radicals are also produced by manipulation of the a-carboxy and amino groups. The former usually results in decarboxylation, with the products no longer being a-amino acids [61]. Aminyl radicals have been generated from sulfenamide precursors and exploited in cyclization reactions, as illustrated in Scheme 11 [62]. Radical additions to imines [63], oximes [64], isothiocyanates [65] and isocyanides [66] of a-... 

Some of the syntheses of pyrimidines and quinazolines were automated so that combinatorial libraries of compounds could be generated. For instance, 2-thioxo-4-dihydropyrimidinones were prepared in this fashion by reductive alkylation of p-amino acids with aldehydes, addition of isothiocyanates, and then cyclization <97JOC9358>. The use of highly fluorinated substrates in the Ugi and Biginelli multicomponent reactions led to a combinatorially-suitable preparation of dihydropyrimidines 15 <97JOC2917>, and efficient solid phase syntheses of chiral quinazoline-... 

Gas-phase synthesis of 3,4-dihydro-2,4-dioxo-277-l,3,5-oxadiazinium ions (16 X = Y = O) via cyclization of acylium (17 X = O) and thioacylium ions (17 X = S) with isocyanates (18 Y = O) and isothiocyanates (18 Y = S) has been investigated using tandem-in-space pentaquadrupole mass spectrometry (MS) <2005JAM1602>. The formation of single (19) and double (20) addition products in these reactions was observed to occur concurrently with proton transfer. The products of double addition have been observed to be favored in reactions with ethyl isocyanate, whereas the reactions with ethyl isothiocyanate formed preferentially either the single-addition product or proton-transfer products, or both. Furthermore, ab initio calculations at the Becke3LYP//6-311- -G(dp) level indicate that cyclization of the double addition products is favored and 3,4-dihydro-2,4-dioxo-277-l,3,5-oxadiazinium ions (16 X = Y = 0) are formed (Scheme 2) <2005JAM1602>. 

With the help of a combination of selective dissolution and chromatographic separation, several of the cyclic ethers have been separated and isolated <2003OL3745>. Though not of synthetic value, gas-phase cyclization reactions of acylium ions with nitriles, forming 1,3,5-oxadiazinium ions 375 by double nitrile addition followed by cyclization, have been reported (Scheme 75) <2001MI445>. Similarly, the gas-phase reactions of acylium and thioacylium ions with isocyanates (18 Y = 0) and isothiocyanates (18 Y = S) have been reported to result in oxadiazinium (16 X = 0) and thiadiazinium (16 X = S) salts, respectively (see Scheme 2) <2005JAM1602>. 

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