Reactions, with phenylisocyanate

Urethanes. The reaction with phenylisocyanate should be used for crystalline derivative formation (see below), and not as a general reaction for alcohols. 

After treatment with an excess of trimethyl orthoformate, the hydrazino-isoborneol derivatives 412, via the corresponding dipoles, and reaction with phenylisocyanate, furnish stereoselectively oxazolo[3,2-A [l,2,4]triazoles 50 (Equation 85) <2002TL607, 2000PAC1721, 1995JOC1720>. 

Guanidines have been prepared by the reaction between an amine, or an amine salt, and a host of other reagents, such as a thiourea in the presence of lead or mercuric oxide [83, 157, 158], carbodi-imides [140, 174, 175],calcium cyanamide [176, 177], isonitrile dichlorides [178—180], chloroformamidines [181], dialkyl imidocarbonates [182], orthocarbonate esters [183], trichloro-methanesulphenyl chloride [184], and nitro- or nitroso-guanidines [185-188]. Substituted ureas can furnish guanidines, either by treatment with amines and phosphorus oxychloride [189], or by reaction with phenylisocyanate [190] or phosgene [191]. 

Two main pathways for the formation of the rearranged sulphamide 434 can be considered (equation 144). Path B involves an intramolecular path for the formation of the sulphamide 434. However, when the reaction was carried out in the presence of phenyl isocyanate, the urea (441) was isolated from the reaction mixture. This provided evidence for the existence of free 2,2,4,4-tetramethylpyrrolidine (440), which was considered to arise from the tert-octyl nitrene (438) by y-hydrogen insertion. Later work401, however, showed that when the rearranged sulphamide is heated in the presence of phenylisocyanate under identical conditions to those for its formation, pyrrolidinylurea (441) is formed in 60% yield. Thus the formation of 441 is not evidence of the existence of free 440, because 434 once formed is capable of dissociation and reaction with phenylisocyanate to give 441. In addition, attempts to independently generate tert-oc y nitrene failed to produce any... 

Aliphatic nitrile oxides can also be prepared by the dehydration of primary nitro compounds with phenylisocyanate in the presence of a catalytic amount of a tertiary base such as triethylamine. Phenylcarbamate generated in situ on reaction with phenylisocyanate is subsequently converted into urea derivative (Scheme 5.37). 

Subsequently, N-arylated pyrazoles can undergo deprotonation by n-butyllithium and reaction with phenylisocyanate to generate moderately substituted pyrazoles as Factor Xa inhibitors. The aniline portion of the Factor Xa inhibitor can also be formed by using aryltrimethoxysiloxane as organometaUoid (Scheme 5.17) [35]. 

Alkylation of benzotriazole yields mixtures of 1- and 2-alkylbenzotriazoles. However, acylation and sulfonylation give only 1-substitution products, as well as reaction with phenylisocyanate leading to (1-phenylcarbamoyl)benzotriazole (2) ... 

The reaction of isocyanates with enamines disubstituted at the -carbon gives -amino- -lactams (107,108). Thus the enamine (16) reacted exothermally with phenylisocyanate to give (33) dimethyl-l-phenyl-4-dimethylamino-2-acetidinone (157), which was converted by acid hydrolysis to 2-formyl-2-methyl propionanilide (158). 

Thus unsubstituted (R=H) and substituted (R = alkyl) non-stabilized diyiides 1 react with phenylisocyanate and dicyclohexylcarbodiimide (R NCX), leading to the formation of new monoylide type intermediates. These last ones react in situ with carbonyl compounds through a Wittig type reaction leading respectively to a,)8-unsaturated amides 2 and amidines 3, with a high E stereoselectivity, the double bond being di- or tri-substituted [48,49]. By a similar reactional pathway, diyiides also react with carbonic acid derivatives, with the synthesis as final products of -a,/l-unsaturated esters 4 and acids 5 [50]. 

Reactions of the hydrido(hydroxo) complex 2 with several substrates were examined (Scheme 6-14) [6]. The reactions are fairly complicated and several different types of reachons are observed depending on the substrate. Methyl acrylate and small Lewis bases such as CO, P(OMe)3, BuNC coordinate to the five-coordinated complex 2 affording the corresponding six-coordinate complexes. In reactions with the unsaturated bonds in dimethylacetylenedicarboxylate, carbon dioxide, phenylisocyanate indications for the addition across the O-H bond but not across the Os-OH bond were obtained. In reactions with olefins such as methyl vinyl ketone or allyl alcohol, elimination of a water molecule was observed to afford a hydrido metalla-cyclic compound or a hydrido (ethyl) complex. No OH insertion product was obtained. 

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

An aza-Wittig reaction-cycloaddition reaction sequence was utilized for the synthesis of pyridotriazines 94. Treatment of iminophosphorane 92 with phenylisocyanate leads to the formation of the corresponding carbodiimide intermediate, which with another molecule of isocyanate affords 94 in [4+2] heterocycloaddition reactions (Equation 13) <1997T16061>. 

In another variation on a type C synthesis which yields 5-substituted-3-oxo-l,2,4-thiadiazolines, the reaction of arylthioamides with phenylisocyanate affords the arenethiocarboxamide 89, which can then be transformed into product 90 by direct oxidation with bromine (Equation 26) <1996CHEC-II(4)307>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

The reaction of arylthioamides (248) with phenylisocyanate affords the arenethiocarboxamide (249), which can be benzylated to give (250) and then converted into 5-aryl-3-oxo-2-phenyl-1,2,4-thiadiazoline (251) on treatment with bromine in chloroform. Alternatively, (249) can be transformed into (251) by direct oxidation with bromine (Scheme 56) <85IJC(B)977>. 

A related cycloaddition/elimination reaction occurs when 5-imino-1,2,4-dithiazolidin-3-ones (300) or -3-thiones (306) are treated with phenylisocyanate to afford 2-phenyl-5-imino-1,2,4-thia-diazolidin-3-ones (307) (Equation (45)) <92JPR685>. 

In all cases, the initial addition to generate 520 was diastereospecific, that is, the isocyanate always adds to 519 from the face opposite to the 4-ethyl substituent of the oxazoline. In the cases wherein 521 was isolated (Entries 17-20 from Table 8.33), the stereochemistry of the two additional chiral centers from the secondary [2 + 2] cycloaddition was controlled by the chiral center formed during the initial reaction, that is, the isocyanate reacts with 520 from the opposite face of the neighboring Ri group. For Ri = H, R2 = Me, 519 reacted with an arylisocyanate (R3 = Ar) to give tricyclic adducts 521a and 521b as a 1.7 1 mixture of diaster-eomers (Entries 18-20). For Rj = Ph, R2 = Me, 519 reacted with phenylisocyanate... 

It has been recently described [55d) that aliphatic nitrile oxides can be formed in solution by treating an aliphatic a-nitro-hydrocarbon with phenylisocyanate in the presence of a catalytic amount of tri-ethylamine. Dehydration of the nitro compounds occurs with the con-committant formation of benzoylurea. From nitroethane, the reaction is formulated as follows ... 

Benzoylation of benzoylmethylene triphenylarsorane (20) with benzoyl bromide gave a kinetically controlled acylated product, which on treatment with sodium acetate in chloroform afforded thermodynamically controlled dibenzoylmethylene triphenylarsorane (21) (56). Acylation with carbonic acid anhydride (32, 56), phenylisocyanate (32), or chloroformic ester (32) gave in no case O-acylated product. Similarly, reaction with acetic anhydride afforded l,3-dioxo-l-phenyl-butylidene-(2)-triphenylar-sorane (56). 

The regioisomers of 3,3,4-trisubstituted l,2,4-dioxazolidine-3-ones 149 were obtained by the [3+2] reactions of carbonyl oxides 144 with phenylisocyanate, where the latter was used as a solvent. Initial carbonyl oxides 144 were generated by photooxygenation of furan derivatives 147 through peroxide intermediate 148 (Scheme 42) <1994J(P1)3295>. 

Reaction of the heteroannular diol (30) with phenylisocyanate or p-methoxyphenylisocyanate at room temperature gave the expected urethans, but use of these isocyanates at elevated temperature or use of p-nitrophenylisocyanate at room or elevated temperature gave the bridged amine (31 R = H, OCHs, and N02)18 The NMR spectrum of 31 shows a triplet for the ferrocene ring protons.19 This triplet is attributed to the direct inductive influence on the a-ring proton of the bridge nitrogen atom. 

The dicyanomethylene derivatives (362 X = O, S) react with phenylisothiocyanate yielding the products (363 X = O) (70% yield) and (363 X = S) (76% yield) <87KGS989>. These reactions are examples of transformations of the general type (300) - (290). With phenylisocyanate the reaction takes a different course and products (364) are obtained (Scheme 3). 

Cellulose reacts with isocyanates in anhydrous pyridine or with urea and substituted ureas at relatively high temperature to yield carbamates. The optimum carbamation reaction of microcrystalline cellulose with urea in a dry solid mixture has been studied [51]. In addition, a preferentially C6-modified cellulose carbamate derivative has been obtained [52]. Heating of cellulose with thiourea at 180°C yielded cellulose thiocarbamate [53]. Heat treatment of cellulose isocyanate products has been utilized for the production of urethanes [54]. When ceUuIose was treated with phenylisocyanate at 100 C in DMF in the presence of dibutyltin dilaurate and triethylenediamine, celiuiose bisphenylcarbamate was formed [55]. Treatment of cellulose with urea at temperatures at or above the latter s melting point (where urea decomposes into isocyanic acid and ammonia) has been employed for the production of cellulose carbamates fibers [56]. The advantages and disadvantages of using urea as an intermediate for production of fiber have been discussed [57]. 

Alkene-functionalized 1,3-diene complexes undergo regio-and stereoselechve 1,3-dipolar cycloaddition reactions with nitrile A-oxides. Related cycloaddihons of nitroalkanes in the presence of triethyl amine and phenylisocyanate afford dihydroisoxazoles. This type of cycloaddition was used in a synthesis toward macrolactin A (Scheme 163). 

Acylation with potassium cyanate, phenylisocyanate and similar reagents gives ureides <8lHC(37)l. p. 102). According to experimental conditions, cyanogen affords the carboxamide (87). The anomalous reaction with o-anisylisocyanate results in the isourea (88). 

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