From Isocyanates or Isothiocyanates

1 By Catalytic Conversion. Symmetrically substituted carbodiimides are best obtained by the catalytic conversion of two equivalents of isocyanates into a carbodiimide and carbon dioxide. This is the most convenient method of synthesis of symmetrically substituted carbodiimides, because the byproduct is carbon dioxide gas, and the yields approach quantitative. A solvent is not necessary and numerous isocyanates are readily available as starting materials.  

Heating of isocyanates above 150 °C slowly produces carbodiimides. For example, heating of hexamethylene diisocyanate at 189-195 °C for 20 hr produced 4-6 % of oligomeric isocyanate terminated carbodiimides, but in addition 18-20 % of isocyanate terminated isocyanurates were formed. The reaction is facilitated if a slow stream of nitrogen is passed through the boiling isocyanate. The unsymmetrical isocyanate dimer 47 was proposed as an intermediate in this transformation. 

In 1962 Campbell and Monagle at Du Pont discovered that cyclic phosphine oxides are excellent catalysts for the conversion of isocyanates into carbodiimides. The most effective catalyst is 1,3-dimethylphospholine -1-oxide (48). However, the more readily available l-ethyl-3-methylphosphohne 1-oxide and l-phenyl-3-methylphospholine 

1-oxide effect this conversion equally well. Other cyclic phosphorous compounds, such as 1-phenylphospholene-l-oxide (49), phosphetane 4-oxides (50) and 1,3-diazaphos-pholidine oxides (51) also convert isocyanates into carbodiimides. The reaction occurs at room temperature, but is best conducted below 60 °C to avoid excessive formation of carbon dioxide. 

A study of the mechanism of this catalytic process revealed that the reaction proceeds by two [2-1-2] cycloaddition sequences via a phosphine imine (iminophosphorane) intermediate 

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Apart from the preceding processes, the hydroxy group in hydroxyalkyl-phosphonic or -phosphinic esters has been acylated straightforwardly or by carboxylic acids in the presence of dicyclohexylcarbodiimide " , a procedure also particularly useful for the N-acylation of aminoalkylphosphonic acids for the purpose of enantiomer analysis, phos-phitylated ", phosphorylated and replaced by halogen (Chapter 3, Section II.C. 1). Carbamates have been prepared from isocyanates or isothiocyanates " and hemiacetals formed in reactions with trichloroacetaldehyde the acetal 200 was prepared from ben-zaldehyde and the bis(a-hydroxybenzyl)phosphinic acid. Cyclic boron diesters have also been prepared. ... 

The free acids are not known although their formation from isocyanic or isothiocyanic acid and one mole of a hydrogen halide can be visualized. While the esters of isocyanic acid, the isocyanates III, add one mole of hydrogen halide to afford the corresponding carbamic acid chlorides (IV), methyl isothiocyanate (V) adds hydrogen bromide to form a mixture of two isomers, to which 1-bromothioformidic acid structures VI and VII have been assigned ( ). 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

Additional examples of 9-deazaxanthines can be obtained from pyrrole 218 by treatment with a group of isocyanates or isothiocyanates to give the corresponding compound 219 (Equation 77) <1994H1087>. Compounds 219b, 219e, and 219f were prepared in acetonitrile with KOH and water added. 

Compounds (46a) and (46b) lose formaldehyde and thioformaldehyde, respectively, before nitrogen extrusion from intermediate unsubstituted tetrazole (46c) the tetrazole then extrudes N2 to form cyanamide. For (49a,b) and (50b,c,e-h) the predominant reaction is 3 + 2-cycloreversion to azides and isocyanates or isothiocyanates, respectively. 

Symmetrically substituted carbodiimides are also obtained from iminophosphoranes and carbon dioxide or carbon disulfide, involving isocyanates or isothiocyanates as intermediates. Instead of the heterocumulenes di-t-butylcarbonate is also used in the reaction with iminophosphoranes. For example, bis(l-naphthyl)carbodiimide is obtained in 64 % yield using this procedure. 

Like other heterocyclic iV-oxides, imidazole 3-oxides 1063 react with AC2O to give the corresponding imidazolones 1064 and 1065 (Scheme 257). TMSCN transforms 1063 into imidazole 2-carbonitriles 1066, whereas alkyl thiones convert 1063 to 1067 <2000HCA728, 1998HCA1585, 2002AGE2290>. The 2-aminoimidazoles 1068, formed from the reactions with either isocyanate or isothiocyanate, react further with isocyanates to form ureas but are inert toward thiourea formation. In contrast to nonaromatic imidazole A -oxides (nitrones), oxides 1063 react with DMAD to form butanedioates 1069, rather than the (putative) [3-1-2] adduct <2000T5405>. 

Aminocyclopropanes were easily acylated by acid chlorides, isocyanates or isothiocyanates (e.g. Refs 3, 24, 27, 36, 71, 80, 82, 125, 178, 179, 184, 224). Polyureas, polyurethanes or polyamides have been prepared from 1,2-diaminocyclopropane Reduction of the carbonyl group in 423 by lithium aluminum hydride worked quite well for tertiary amides 5,473.495. longer reaction times effected a ring-opening in the case of a secondary amide (423, R = H) (LiAlH4 reduction of secondary... 

The 3-carbazoyl group of pyrimido[l,2-a]azepine 462 was acylated at N-2 with benzoyl chloride, or reacted with aldehydes, isocyanates, or isothiocyanates (77MI1). 3-Bromohexahydropyrimido[l,2-fl]azepin-4-one was obtained from the 3-carboxylic acid 415 (R = = H, R = COOH) in the... 

Nucleophilic carbenoids (also called ylides by some authors) react with heterocumulenes, such as isocyanates and isothiocyanates, to yield hy-dantoins, 2-thiohydantoins, and 2,4-dithiohydantoins via dipolar intermediates. Thus dimethoxycarbene adds to aryl isocyanates and isothiocyanates to form 5,5-dimethoxyhydantoins and dithiohydantoins.107 Thiazolium ylides (61) (resulting from thiazolium salts and NEt3 in DMF) give dipolar 1 1 adducts (62) or l 2-cycloadducts (63) with isocyanates or isothiocyanates.108-110 Other substrates are imidazolidine111 or 2-imidazoline derivatives.112... 

Reductions of ketones, sulfones, and sulfoxides with triphenyltin hydride have been shown to give hexaphenylditin as the tin-containing product 232, 237). Isocyanates or isothiocyanates 233, 239) as well as benzoyl peroxide 239a) also produce the same product from triphenyltin hydride. In contrast, however, alkyltin hydrides undergo addition to carbonyl groups to form alkyltin alkoxides 239b). 

The interaction of enamines with sulphur in conjunction with carbon disulphide, isocyanates, or isothiocyanates results in the production of sulphur-containing heterocyclics. Cyanamide has now been shown to participate in this reaction. Treatment of enamines of type (24) with sulphur and cyanamide at room temperature in ethanol produces a range of 2-aminothiazoles (27) in 30—70% yield no catalyst is required. Initial formation of the thiolated intermediate (25) is probably followed by addition of cyanamide, yielding (26) elimination of amine finally produces the observed thiazoles (27). Since AW-dialkylcyanamides do not undergo this reaction, cyanamide may react as the tautomeric carbodi-imide. An actual example of the reaction employing the enamine derived from cyclohexanone and morpholine is also shown [(28) - (29)]. ... 

The silylene 79 abstracts oxygen or sulfur from isocyanates and isothiocyanates. Cyclic sUoxanes are the products with isocyanates (equation 129) these probably arise by polymerization of the silanone, Ar2Si=0 (83). 

Homoleptic lithium complexes [Li NNE 2]Cl (E = 0, S), containing Juc-coordinating NNE-donor hgands prepared from bis(3,5-dimethylpyrazol-l-yl)methanewith BuLi and alkyl- or aryl-containing isocyanates or isothiocyanates, have been used to synthesize a series of scandium and yttrium complexes. ... 

Carhamyl- and thiocarhamyl-keteneacetals from keteneacetals and isocyanates or isothiocyanates respectively s. 14, 723... 

The enol betaines derived from 1-phenacylpyridiniimi salts undergo analogous reactions. Characteristic examples are the formation of (32) and (33) from phenacylpyridinium enol betaine and phenyl isocyanate or isothiocyanate s and benzoyl chloride or benzoic anhydride, respectively. In a related casei54e reaction with carbon disulphide gives (34). 

Other functional groups that are easily differentiated are cyanide (5c =110-120) from isocyanide (5c = 135- 150), thiocyanate (5c =110-120) from isothiocyanate (5c = 125 - 140), cyanate (5c = 105- 120) from isocyanate (5c = 120- 135) and aliphatic C atoms which are bonded to different heteroatoms or substituents (Table 2.2). Thus ether-methoxy generally appears between 5c = 55 and 62, ester-methoxy at 5c = 52 N-methyl generally lies between 5c = 30 and 45 and. S-methyl at about 5c = 25. However, methyl signals at 5c = 20 may also arise from methyl groups attached to C=X or C=C double bonds, e.g. as in acetyl, C//j-CO-. 

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