Cyclic carbodiimides reactions

I became involved in carbodiimide chemistry in my research work on isocyanates at the former Donald S. Gilmore Research Laboratories of the Upjohn Company in North Haven, CT. Carbodiimides are readily synthesized from isocyanates using a phospholene oxide catalyst. This reaction can be conducted without a solvent, and the byproduct is carbon dioxide. We used this reaction in the manufacture of a liquid version of MDI (4,4 -diisocyanatodiphenylmethane), which today is sold in huge quantities worldwide. By reacting MDI with dicarboxylic acids in a vented extruder we manufactured a family of thermoplastic polyamide elastomers, which are sold today by the Dow Chemical Company. Also, N-sulfonylcarbodiimides were synthesized for the first time in our laboratories. They are the precursors of the antidiabetic sulfonamides, such as Upjohn s Tolbutamide (Orinase). Because of the close relationship of isocyanates with carbodiimides we studied many linear and cyclic carbodiimide reactions, especially their cycloaddition reactions. 

Extension of these studies to benzologues of tetrazolo[l,5- ]pyridine, that is, for tetrazolo[l,5- ]quinoline 21 and tetrazolo[5,l- ]isoquinoline 22, led to interesting results <2003JOC1470> as shown in Scheme 7. Both of these fused tetrazoles resulted in formation of a nitrene 23 and 24, respectively, which could be interconverted via formation of the fused cyclic carbodiimide derivative 25. Isoquinolylnitrene 24, furthermore, was found to undergo subsequent reactions ring opening afforded the vinylnitrene 26, which was transformed to o-cyanophe-nylacetonitrile 27 by a 1,2-H shift and to 4-cyanoindole 28 by an intramolecular cyclization in 40% and 25% yields, respectively. 

Fig. 4 Nucleic acid immobilization. Immobilization of 5 -amino-C6 modified probes onto (a) carboxylate modified latex beads (1 im) via carbodiimide reaction and (b) Cyanogen bromide (CNBr) activated Sepharose beads (100 un). (0 cyclic structure, e.g. dicyclo-hexylcarbodiimide)...

Carbodiimides have chiral structures similar to allenes, i.e., they can exist in optically active forms. Schloegl and Mechtler were the first to report a partial optical separation of N,N"-diferrocenylcarbodiimide into enantiomers by chromatography on acetylated cellulose, but other authors doubt the validity of these results. According to theoretical calculations a separation of carbodiimide enantiomers is not possible. N,N -diferrocenylcarbodiimide was also obtained in optically active form by kinetic resolution in the reaction with (-)-S-6,6"-dinitrodiphenic acid. Cervinka and coworkers isolated both enantiomers of (R,S)-N,N"-bis(o -phenylethyl)carbodiimide, and they found that they undergo racemization at room temperature. A recent study on the racemization mechanism of macrocyclic carbodiimides indicates that the open chain as well as the large ring carbodiimides racemize by nitrogen inversion or tra 5-rotation, while medium size cyclic carbodiimides racemize by cw-rotation. ... 

The cyclic thiourea 19, upon reaction with HgO affords the cyclic carbodiimide 20, but the compound has not been isolated in pure form. ... 

The reaction of bisaryliminophosphoranes with di-t-butylcarbonate(Boc)20 in the presence of 4-dimethylaminopyridine, or carbon dioxide results in the formation of an intermediate isocyanate, which reacts with the second -N=PPh3 group to form a cyclic carbodiimide or a cyclic dicarbodiimide. Reaction of the bisaryliminophosphorane with carbon disulfide generates a bis-isothiocyanate which undergoes reaction with the bisaryliminophosphorane to give the corresponding cyclic dicarbodiimide in high yield. Examples of these reactions are listed in Tables 11.1 and 11.2. 

Seven membered ring cyclic carbodiimides, such as 1,3-diazahepta-l,2-diene 37 and tetramethyl-l,3-diazahepta-l,2-diene are not stable in solution, but rapidly form dimers and oligomers. For example, from 37 the cyclodimer 38 formed by a [2+2] cycloaddition reaction and the cyclic trimer 39 are formed. ... 

Cyclic carbodiimides also undergo a facile [2+2] cycloaddition reaction with alkyl- and aryl isocyanates to give the cycloadducts 44. With aryl isocyanates the reaction is exothermic and is completed within several minutes. 

The reaction of cyclic carbodiimides 47 (n = 4,5), generated in situ, with carbon disulfide, results in the formation of the diisothiocyanates 48 in 23-28 % yield. ... 

Cyclic carbodiimides also undergo a rapid reaction with phosgene in methylenechloride to form the expected adducts 55, which on hydrolysis give cyclic allophanoyl chlorides 56.22... 

The reaction of cyclic carbodiimides with oxalyl chloride affords bicyclic para-banic acid derivatives 57 (when n = 11) or spiro(oxazolisine) derivatives 58 (when... 

Cyclic carbodiimides. Bis(iminophosphoranes) behave as nucleophiles toward BocjO. After an isocyanate is formed, a Wittig reaction follows. Either an intramolecular or intermolecular process predominates according to the influence of ring strain. 

The synthesis of larger rings has also been accomplished including the fully unsaturated azolo-fused 1,3-diazepines (222) from bis(iminophosphoranes) (221) and novel cyclic carbodiimides (e.g. 223). Iminophosphoranes are also intermediates in the synthesis of macrolactams (e.g. 225) from the reaction of co-azido acid anhydrides (e.g. 224) with tributylphosphine. The synthesis of iminophosphorane-containing cryptands and a spherand-type structure have been reported. 

For example, 2-quinolylnitrene rearranges thermally to 1-isoquinolyl-nitrene, from which the products 166a-c arise (Scheme 33) 221,222,222a cyclic carbodiimide 165 (R = H) was isolable at - 196°C and directly observable by IR spectroscopy (2000 cm following flash vacuum pyrolysis of either tetrazolo[ 1,5-a] quinoline or tetrazolo [5,1-a] isoquinoline at 490°C. Compound 165 dimerized on warming to — 55°C. This intermediate had originally been postulated as the mesomeric form 165a (Scheme 33). The bicyclic azirines 167 and 168 (Scheme 33) can be written as intermediates or transition states en route to 165, but they are not expected to be stable intermediates under these reaction conditions, and no evidence for their formation has been obtained. 

Cyclic carbodiimides 38 react with carbon disulfide to give aliphatic diisothiocyanates 39. This reaction involves an initial [2-1-2] cycloaddition across one of the C=N groups of the carbodiimide . 

Mixed dimers derived from macrocyclic carbodiimides and diphenylcarbodiimide are also reported. For example, the unstable 1,3-diazahepta-l,2-diene 15 (n = 4) was trapped with diphenylcarbodiimide to give the [2-1-2] cycloadduct 16 (n = 4). The larger ring cyclic carbodiimides also afford the [2-1-2] cycloadducts 16. These reactions proceed in quantitative yield... 

A full development of the rate law for the bimolecular reaction of MDI to yield carbodiimide and CO indicates that the reaction should truly be 2nd-order in MDI. This would be observed experimentally under conditions in which MDI is at limiting concentrations. This is not the case for these experimements MDI is present in considerable excess (usually 5.5-6 g of MDI (4.7-5.1 ml) are used in an 8.8 ml vessel). So at least at the early stages of reaction, the carbon dioxide evolution would be expected to display pseudo-zero order kinetics. As the amount of MDI is depleted, then 2nd-order kinetics should be observed. In fact, the asymptotic portion of the 225 C Isotherm can be fitted to a 2nd-order rate law. This kinetic analysis is consistent with a more detailed mechanism for the decomposition, in which 2 molecules of MDI form a cyclic intermediate through a thermally allowed [2+2] cycloaddition, which is formed at steady state concentrations and may then decompose to carbodiimide and carbon dioxide. Isocyanates and other related compounds have been reported to participate in [2 + 2] and [4 + 2] cycloaddition reactions (8.91. 

Amidines and cyclic amidines are also converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, imino-sulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur. Ureas, thioureas, guanidines, carbodiimides, and cyanimides react with chlorocarbonylsulfenyl chloride to produce 1,2,4-thiadiazol-5-one derivatives in another example of a type B synthesis <1996CHEC-II(4)307>. 

A number of annelated 1,3,4,6-thiatriazepines (613) have been prepared by the reactions of the sodium salts of cyclic thioureas with dichlorodiazabutadienes (612). Acyclic thioureas take an alternative reaction path via the elimination of a carbodiimide to give only 2,5-diphenyl-l,3,4-thiadiazole (80CC156). An X-ray structure determination on (613 n = 2) shows that the seven-membered ring has the expected boat conformation and that ring fusion does not appear to strain the five-membered ring <81AX(B)486>. 

However, the reaction of the binuclear rj2-thioaldehyde titanocene complexes 112 (see Scheme 26) with valeronitrile, benzonitrile, and methyl thiocyanate proceeded in a similar fashion (Scheme 39).69 Related metalla-cyclic compounds were also obtained from the reactions of 112 with benzo-phenone (Scheme 39), various imines, phenyl isothiocyanate, or dicyclohexyl carbodiimide via insertion of the C = 0 and C = N bond, respectively, into the Ti-C bond.69,70... 

Williams, A., and Ibrahim, I. A. (1981) A mechanism involving cyclic tautomers for the reaction with nucleophiles of the water-soluble peptide coupling reagent l-ethyl-3-(3-dimethyla-minopropyl) carbodiimide (EDC). J. Am. Chem. Soc. 103, 7090—7095. 

In a similar fashion, cycloaddition reaction of 2-vinylpyrrolidines with carbodiimides in the presence of Pd(OAc)2 and l,5-bis(diphenylphosphino)pentane affords the seven-membered ring cyclic arylguanidines in acceptable yields and conversions (Equation 16) <2004T73>. 

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]. 

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