Cyclization with Isocyanate

A novel route to synthesize phthahmide derivatives through ruthenium-catalyzed C-H bond functionalization of aromatic amides was developed by Ackermann and coworkers (Eq. (7.57)) [66]. This method is applicable to generate a potent COX-2 enzyme inhibitor in step-economical way. The reaction features by the insertion of a cycloruthenated species into a C—Het multiple bond of isocyanate and cleavage of pyrrolidinyl group. Electron-rich amides were found to favor the reaction, and an initial reversible C-H bond metalation step was also observed. 

Ruthenium-catalyzed heterocycle synthesis through C-H bond activation and cyclization has received an increasing interest in the past few years. In this chapter the oxidative cyclization reactions with a series of unsaturated small molecules under ruthenium catalysis have been summarized. Among these reactions, the formations of heterocycles were realized by several synthetic pathways after initial C-H bond activation, which involved formation of intramolecular C-C bond, intramolecular C-N bond, intermolecular C-C/C-O bonds, and intermolecular C-C/C-N bonds. On the other hand, many challenges still need to overcome, such as heterocycle synthesis via ruthenium-catalyzed C(sp )-H activation. On the basis of the solid and exciting progress, no doubt that more reactive 

The Chemistry of Heterocycles, Wiley-VCH Verlag GmbH, Weinheim (c) Katrizky, A.R. and Pozharskii, A.E (eds) (2000) Handbook of Heterocyclic Chemistry, 2nd edn, Pergamon Press, Amsterdam. 

Activation, Topics in Current Chemistry, vol. 292, Springer, Berlin. 

Selective reviews for carbon—carbon bond formation, see (a) Bugaut, X. and Glorius, E. (2011) Angew. Chem. 

---

Norton et al. investigated cyclization of zirconocene and imine to form several types of zirconaaziridine 1-16. The rich reaction chemistiy of 1-16 includes cyclization with alkene or alkyne to afford azazirconacyclopentene 1-17 and cyclization with isocyanate or aldehyde to form azaoxazirconacycle 1-18 and 1-19. These functionalized zirconacycles could be further transformed into zirco-naoxazolidione, aUylic amine, and a-amino amide (Scheme 1.12) [43, 44]. 

In a related reaction the isocyanate from azide (109) cyclized with aminopyridine esters via a ureido intermediate to give (110) (80JHC733). 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

Chiral 4,7-disubstituted perhydropyrazino[l,2-f]pyrimidine-l,6,8-triones 170 were synthesized from [4+2] atom fragments by reacting separately, the four diastereomers of 169 with isocyanates in a base-catalyzed cyclization (Scheme 23) <2002TL4899>. 

A library of l,3,7-substituted-perhydropyrazino[l,2-f]pyrimidine-2,6,8-triones was built by preparation of functionalized ketopiperazines on the solid phase, followed by N-acylation with 2-bromoacetic acid, reaction with isocyanate and with concomitant cyclization using trifluoroacetic acid (TFA) <2003W02003/013740>. 

Addition of phosphinomethyl spirophosphorane 260 to isocyanates and azides presumaby generates anionic nitrogen intermediates that cyclize with the phosphorane to give spirophosphoranides 96, 97, and 261 (Scheme 35) <1996PS493>. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

Allenes react with isocyanates to give the a-alkylidene-/Mactams. The highly reactive chlorosulfonyl isocyanate (CSI) is often used. Initial nucleophilic attack of the central allenic carbon atom to the central isocyano carbon atom produces an allylic cation intermediate, which cyclizes to the /i-lactam. 

When simple substituted benzimidazoles such as 2-azidomethyl benzimidazole are employed, their iminophosphoranes (148) react with isocyanate to give carbodiimide 149. The free NH group of the imidazole can intercept the carbodiimide intermolecularly. Thus, upon addition of a second equivalent of isocyanate, cyclization affords 2,3-dihydro-l//-imidazo[l,5-a]benzimidazole 150 (Scheme 59) (89T1823 94S1197). 

Oxadiazoles are obtained by reaction of aromatic isocyanates or CS2 with N-acylaminoiminophosphoranes (151), as shown in Scheme 60. Upon treatment with isocyanate, an unstable carbodiimide 152 is generated, which cyclizes spontaneously in 80-84% yield. With CS2 as reagent, the corresponding isocyanate cyclizes without isolation of any intermediates to 2-mercapto-l,3,4-oxadiazole 154 in 72-90% yield [91PS(57)11]. 

Some recent work has made several heterocondensed furo[3,2-c]pyri-dines accessible. Starting compounds are the aldehydes of furo[3,2-c]pyri-dines, which are converted into the azides 203 (Scheme 75). Reaction with triphenylphosphane furnishes the iminophosphoranes 204, which are finally cyclized with phenyl isocyanate to afford the substituted pyrrolo[2, 3 4,5]-furo[3,2-c]pyridines 205 (92M807 94H1695). 

In a one-pot reaction (Scheme 126) the iminophosphorane of 6-aminoura-cil (346) (92AHC129) is transformed with isocyanate in the presence of pyridine into a nonisolable carbodiimide. Spontaneous addition of pyridine follows to give a 1,6-dipolar pyridinium ylide (347), which cyclizes to the... 

Amidoximes (96) react at the hydroxy group with isocyanates or carbamoyl chlorides. The resulting urethanes (105) can be cyclized in boiling acetic anhydride (Scheme 43). A,A-Disubstituted urethanes (106) as well as the A-carbamoyl compounds (108), give oxadiazolinones (107) (Schemes 43 and 44) <63HCA1073>. 

A -Aminopyrimidinones and quinazolinones can be acylated and sulfonylated to give amide and sulfonamide derivatives, and also reacted with isocyanates to give ureas, and with aldehydes and ketones to give imines. They can also participate in cyclization reactions to form fused pyrimidine heterocycles. 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

Reaction of ethyl 5-aminopyrazole-4-carboxylates (123) with isocyanates or isothiocyanates gives intermediate 124, which cyclizes readily into 125 (59GEP1104964 59GEP1106329 61AG15 72CPB391). 

Diones are normally synthesized from /3-hydroxy acids in two steps first, conversion into carbamates by reaction with sodium cyanate, and then cyclization with thionyl chloride (Scheme 103) (54JCS839). Alternative preparations utilize oxetanes, which may be combined either with isocyanates in the presence of boron trifluoride (68JAP6808278) or with S-alkylthioureas (Scheme 104) (69ZOR1844). In the last example the initial products are imines (224) which may readily be hydrolyzed to the required diones. Similar methods can be applied to the synthesis of tetrahydro-l,3-thiazine-2,4-diones, and, for instance, the 4-oxo-2-thioxo derivative (225) is obtained from /3-propiolactone and dithiocarbamic acid (Scheme 105) (48JA1001). 

Bond formation between oxygen and sulfur occurs when the AM2-hydroxyethyl)thiourea (155) is oxidatively cyclized with bromine to give the 1,2,4-oxathiazine (3) (77TL4245), and when the intermediate (183), from reaction of ketones with fluorosulfonyl isocyanate (FSI), is cyclized with base to give (184) <80AG(E)13l). 

---