Symmetrical carbodiimides

Figure 3.10 The symmetrical carbodiimide DIC reacts with carboxylates to form active-ester intermediates able to couple with amine-containing compounds to form amide bond linkages.

Symmetrical carbodiimides, i.e., molecules with the same substituent on both nitrogen atoms, are best prepared from alkyl or aryl isocyanates in the presence of a phospholene oxide catalyst, the byproduct being carbon dioxide gas. No solvent is required for this reaction. Unsymmetrical carbodiimides or alkylarylcarbodiimides are also obtained from isocyanates, either by reaction with amines and subsequent dehydration of the intermediate... 

Iminophosphoranes can also be used to synthesize symmetrical carbodiimides. In this case they are reacted with carbon dioxide, thereby mimicking the synthesis of carbodiimides from amines and carbon dioxide. Another useful synthesis of unsymmetrical carbodiimides, not requiring the use of carbonyl chloride, is the reaction of carbonimidoyl dihalides with amines. The synthesis and chemistry of carbonimidoyl halides was reviewed in 1968. ... 

In a similar manner, the aryliminophosphorane 84 is converted with carbon disulfide into the symmetrical carbodiimide 85. ... 

Imido zwitterionic titanium complexes, Ti=NAr[CH3B(C6F5)3], undergo reaction with carbon dioxide to give isocyanates and symmetrical carbodiimides via a ligand metathesis... 

In recent years, the metathesis reactions of carbodiimides, catalyzed by metal imido complexes, have been investigated. These reactions are useful to convert symmetrical carbodiimides into carbodiimides with different substituents (see Section 2.4.2.1). 

Another related zirconium complex 32 containing redox active tridentate NNN pincer ligand catalyzes nitrene transfer reactions from organic azides to f rf-butyl isocyanide to form non-symmetrical carbodiimides where the metal maintains the Zr(IV)... 

Corresponding arguments apply to pentatetraenes. In all these Z>2rf-systems the chemically interesting (outermost) orbitals have no nodal planes. Then, of course, in isoelectronic l,3-di ubstituted carbodiimides the situation is comparable with that in 1,3-disubstituted allenes and corresponding reasonings apply and similar findings are expected. From pe spectra it has been shown recently (99) that, indeed, the outermost a and b orbitals in symmetric carbodiimides are degenerate. 

The synthesis of symmetric 1-aryl 5-arylaminotetrazoles 230 was initially performed by reacting symmetrical diarylthioureas 229 with sodium azide in the presence of lead carbonate or lead oxide. The reaction proceeds via the transitional formation of a diarylcarbodiimide that readily reacts with the azide ion to give the l-aryl-5-arylaminotetrazole 230 (Scheme 44A) [166-168]. Percival and co-workers extended this method to the synthesis of a group of symmetrical l-alkyl-5-alkylaminotetrazoles 233 that were prepared from the appropriate symmetric carbodiimides 232 in benzene or toluene with hydrazoic acid (Scheme 44B) [156]. The carbodiimides 232 were generated in a previous step from symmetrical dialkylthioureas 231 in the presence of mercuric oxide. 

Scheme 46 Synthesis of 5-aminotetrazoles 242 starting from symmetrical or non-symmetrical carbodiimides 239 and TMSA (146) [111]...

Infrared Spectroscopy. Infrared spectra were recorded at room temperature using a Fourier transform Avatar 360 ESP spectrometer (Nicolet) in the range 4000—400 cm. To do so, the samples were dispersed in strictly anhydrous KBr and pressed into pellets (0 1.3 cm). The spectra were corrected for the presence of KBr. The obtained spectra showed the nonsym-metric stretch (Pas) 1988 cm and the deformation vibrations at 676 and 663 cm thereby corroborating the symmetric carbodiimide structural motif with two C=N double bonds between carbon and nitrogen. ... 

Reaction of isocyanides with primary amines in the presence of selenium and DBU, followed by the introduction of molecular oxygen in refluxing THF, affords unsymmetrical and symmetrical carbodiimides in isolated yields of 58-87% [1282] (see also Section 4.5.3.5, Table 4.48). The oxidation reaction is mediated by selenium with the assistance of base DBU. 

In the quest for an efficient route for the generation of quinazolin-4(3 0-ilnines 10 (Scheme 3.9), Pu and Wu developed a three-component methodology based on a palladium-catalyzed isocyanide insertion involving a A -(2-bromoaryl) carbodiimide, isocyanide, and a nucleophile (amine or alcohol) [20], When phosphites are used as nucleophiles, 4-imino-3,4-dihydroquinazolin-2-ylphosphonates are obtained [21], The same authors extended the procedure to include a second cyclization by employing symmetric carbodiimides containing two aryl iodide moieties [22],... 

Also, switterionic titanium-imide complexes mediate the reaction of carbon dioxide with primary amines to give the corresponding isocyanates and symmetrical carbodiimides via a ligand metathesis reaction . 

Carbodiimides (cyanamides) —N=C=N— 2140-2125 (s) 2150-2100 (vs) 1460 1150-1140 (vs) Asymmetric stretching of aliphatics Asymmetric stretching of aromatics two bands Symmetrical stretching of aliphatics Symmetric stretching of aryls... 

Anhydride Formation. The carboxyl group ia A/-protected amino acids is converted iato the symmetrical anhydride on treatment with the carbodiimide (84). 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

FIGURE 1.16 Purified symmetrical anhydrides of iV-alkoxycarbonylamino acids obtained using a soluble carbodiimide.15 The reagent ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride,14 also known as WSCD (water-soluble carbodiimide), the NW -dialkylurea, and the iV-acyl-iV,iV -dialkylurea are soluble in water and thus can be removed from a reaction mixture by washing it with water. 

FIGURE 1.18 2-AI koxy-5(4/7)-oxazol ones as intermediates in reactions of IV-alkoxycarbo-nylamino acids.22 After removal of the symmetrical anhydride from a reaction mixture containing Boc-valine and ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride, the filtrate contained a novel activated form of Boc-valine (20% yield) that was established to be the 2-alkoxy-5(4H)-oxazolone. Slow addition of Boc-valine to ethyl-(3-dimethylamino-propyl)-carbodiimide hydrochloride in dilute solution gave a 55% yield. Petrol = petroleum ether, bp 40-60°. 

The symmetrical anhydride is less reactive and consequently more selective in its reactions than the O-acylisourea. Although the latter can acylate both N- and O-nucleophiles, the symmetrical anhydride will only acylate V-nuclcophilcs. This means that the hydroxyl groups of the side chains of serine, threonine, and tyrosine that have not been deprotonated are not acceptors of the acyl group of the symmetrical anhydride. An additional feature of this approach to carbodiimide-mediated reactions is that it avoids a possible side reaction between the carbodiimide and the iV-nucleophilc, which gives a trisubstituted guanidine [(C6HuN)2C=N-CHR5CO-... 

The symmetrical anhydride is prepared using dicyclohexylcarbodiimide in dichloromethane, the urea and solvent are removed, and the anhydride is dissolved in dimethylformamide and added to the peptide-resin (see Section 2.5). The anhydride is a more selective acylating agent than the 0-acylisourea and, thus, gives cleaner reactions than do carbodiimides, but twice as much amino-acid derivative is required, so the method is wasteful. It avoids the acid-catalyzed cyclization of terminal glutaminyl to the pyroglutamate (see Section 6.16) and is particularly effective for acylating secondary amines (see Section 8.15). 

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