Dicyclohexylcarbodiimide 4+2 cycloaddition reactions

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

An illustration of a cycloaddition reaction resulting in the formation of the N—C2 and C3—C4 bonds is the reaction of 2-chlorophenylketene (29) with dicyclohexylcarbodiimide, to give 3-chloro-l-cyclohexyl-4-cyclohexylimino-3-phenylazetidin-2-one (25) (Expt 8.10).17 The ketene is generated in situ from 2-chloro-2-phenylacetyl chloride by the action of triethylamine (cf. Expt 7.25). 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

Z + Z] Cycloaddition reactions are important in the construction of 1,3-thiazetidine rings . Isothiocyanates add carbodiimides across the carbonsulfur bond < 1975J(P2) 1475 >. For example, the reaction of the 2-thioxo-l,3-thiazepan-4-one derivative 208 with A,A-dicyclohexylcarbodiimide affords the 1,3-thiazetidine system 209 (Scheme 100) <1999JHC1167>. 

Likewise, l,3-diaza-2-azoniaallene salts 181 undergo the [3+2] cycloaddition reaction with diisopropyl and dicyclohexylcarbodiimide to give 1,3,4,5-tetrasubstituted 4,5-dihydro-tetrazolium salts 182 (see also Chapter 7, Section 7.2) ". ... 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Keywords dicyclohexylcarbodiimide, [2+2]-cycloaddition, catalysis, waste-free, gas-solid reaction... 

Anhydro-5-hydroxyoxazolium hydroxides lacking substituents at C(4) dimerize spontaneously by a process in which one molecule acts as an electrophile and the other as a nucleophile (Scheme 21). This accounts for the fact that dimeric products of this type are obtained by the action of dicyclohexylcarbodiimide on acylamino acids of the general formula R1C0NR2CH2C02H. Substituents at position 4 stabilize the mesoionic system the first compounds to be prepared were the acetyl derivatives (220) (B-49MI41800) and (221) (58Cl(L)46l) and much of the more recent work has been carried out with the relatively stable methyldiphenyl compound (222). This miinchnone decomposes above 115 °C to yield the allene (225) with loss of carbon dioxide. The mechanism proposed for this remarkable reaction (Scheme 22) involves valence isomerization to the ketene (223), which undergoes a 1,3-dipolar cycloaddition with the miinchnone. The product loses carbon dioxide to form a new betaine (224), which collapses to the allene as shown. 

Possible competitive reactions (e.g., cycloadditions on the double bond) proceed only very slowly with diazotoluene dibenzyl ether is produced by the reaction with water so that strictly anhydrous conditions are not necessary. Similarly, the presence of traces of water does not interfere with the esterification with the aid of N,N -dicyclohexyl-0-benzylisourea, which reacts with water with the production of benzyl alcohol. The reagent is synthesized from dicyclohexylcarbodiimide and benzyl alcohol with copper(I) chloride as the catalyst. The esterification proceeds according to Scheme 5.16. 

N-Alkyl- and N-aryl-ketenimines are poor electrophilic partners and do not react with benzylidene-aniline or dicyclohexylcarbodiimide." The introduction of an electron-withdrawing substituent (tosyl or cyano ) on the nitrogen atom enhances the electrophilic character of the cumulene and cycloadditions to imines occur under very mild conditions (Scheme 42). In most cases, the reactions are trans stereoselective. 

N// -Dicyclohexylcarbodiimide (DCC) also mediates the Lossen reaction of hydroxamic acids under neutral conditions.In the conversion of the hydroxamic acid (209) to the tricyclic compound (210), the Lossen rearrangement is accompanied by an intramolecular cycloaddition (equation 54). 

The formation of 111 (Scheme 32) has been rationalized as a [2-1-2] cycloaddition of one of the two carbon-nitrogen double bonds of the dicyclohexylcarbodiimide to the Cp-C. double bond of the allenylidene of 43 to give the intermediate 113, which rapidly evolves into 114, by an Alder-ene reaction, where the C -Cp double bond of 113 acts as an enophile. The presence... 

The reaction of hydroxy-substituted carbene complexes with the dehydrating agent dicyclohexylcarbodiimide (DCC) gives the adduct XVI (Weiss et al., 1974). The reaction is thought to proceed via dehydration to give a vinylidene-carbene complex which then undergoes a [2 -I- 2] cycloaddition with DCC. 

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