A-substituted isocyanates

Ketenes react with imines via [2+2]-cycloaddition to produce P-lactams.278 An example is the reaction of the acid chloride of phenylacetic acid with Proton Sponge to give ketene 340, which reacted with the tosyl imine shown and a quinuclidine catalyst to give a 65% yield of P-lactam 341, in 96% ee.229 A-Substituted isocyanates also undergo thermal [2+2]-cycloaddition reactions with alkenes, generating P-lactams.280... 

If the acid chloride prepared as in Schemes 10.35 and 10.36 is treated with hydroxylamine hydrochloride in pyridine solution, the corresponding hydroxamic acid is generated. When the hydroxamic acid (Scheme 10.37) is allowed to react with acetic anhydride, the O-acetate results and, on heating, the hydroxamic acid derivative undergoes decomposition (the Lessen rearrangement) to produce the same A -substituted isocyanate as previously seen. 

When the isocyanate contains a carbonyl, thiocarbonyl or an imidoyl group adjacent to the cumulative system, a different type of dimer is formed, resulting from addition of the cumulative C=N bond to the heterodiene system in the a-substituted isocyanate to form... 

Industrially, polyurethane flexible foam manufacturers combine a version of the carbamate-forming reaction and the amine—isocyanate reaction to provide both density reduction and elastic modulus increases. The overall scheme involves the reaction of one mole of water with one mole of isocyanate to produce a carbamic acid intermediate. The carbamic acid intermediate spontaneously loses carbon dioxide to yield a primary amine which reacts with a second mole of isocyanate to yield a substituted urea. 

Pyrolysis approaches can also be used to prepare substituted isocyanates which caimot be prepared using other methods. For example, A[,A[(A[ -trichlorocyanuric acid [87-90-1] thermally dissociates to yield chloroisocyanate [13858-09-8] and carbonyl diisocyanate [6498-10-8]. The carbonyl isocyanate is unstable and polymerizes (8,94). Table 3 Hsts specialty isocyanates. 

The use of an organic isocyanate instead of potassium isocyanate gives a A-substituted hydantoin. 

In most cases, the allophanate reaction is an undesirable side reaction that can cause problems, such as high-viscosity urethane prepolymers, lower pot lives of curing hot-melt adhesives, or poor shelf lives of certain urethane adhesives. The allophanate reaction may, however, produce some benefits in urethane structural adhesives, e.g., additional crosslinking, additional modulus, and resistance to creep. The same may be said about the biuret reaction, i.e., the reaction product of a substituted urea linkage with isocyanate. The allophanate and biuret linkages are not usually as thermally stable as urethane linkages [8]. 

In similar fashion, A-substituted-2(3fT)-oxazolones were prepared directly from the hydroxy-ketone by reaction with urethanes in the presence of pyridine and dimethylformamide or by using isocyanates. 

Salts of aliphatic or aromatic carboxylic acids can be converted to the corresponding nitriles by heating with BrCN or CICN. Despite appearances, this is not a substitution reaction. When R COO was used, the label appeared in the nitrile, not in the C02, and optical activity in R was retained. The acyl isocyanate... 

Diesters of phosphoramidic acid are converted to the corresponding isocyanates by phosgene but with A-substituted derivatives the phosphoramidic chlorides are formed. In a similar reaction oxalyl chloride... 

A number of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-l-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of an a-chlorobenzyl isocyanate with A-substituted aminocrotonates <06SL375>. 

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>. 

For this library, we chose to use three types of isocyanates (neutral, electron rich, and electron deficient) to demonstrate the broad utility of the urea-formation reactions. Employing the above strategy and using the split-and-pool approach, we synthesized a 27-membered urea library with purities ranging from 95 to 99%. All the compounds prepared were characterized by 1FI NMR and mass spectroscopy. Acetonitrile can also be used as a substitute for DCM, but lower yields and product purities are generally observed. Attempts to use other protic solvents, such as isopropyl and ethyl alcohol, were unsuccessful. The best results were achieved when a chlorinated solvent (DCM) was used. The structure identity of all products was confirmed by 1FI NMR and MS spectroscopy. Expected molecular ions (M + Na+) were observed for all the products, and in all cases as the base peak. The compounds and yields are listed in Appendix 3.1. 

Additions of lithiated alkoxyallenes to alkyl-substituted isocyanates and isothiocyanates as electrophiles were recently disclosed by Nedolya and co-workers [87-91]. A short route to N-[2(5H)-furanylidene]amines 133 consists in the addition of lithiated methoxyallene 42 to alkyl isocyanates 132 and silver acetate-mediated cydi-zation of the intermediate (Scheme 8.33) [87]. 

The similar addition of a mesityl-substituted isocyanate to 1-morpiiolino-cyclohexene gave the dihydrothiazinone 233, which is in ring-chain equilibrium with 234. In the attempted preparation of the rerr-butyl-substituted derivative, the tetrahydrobenzothiazinone 235 was formed by loss of morpholine (81CB549). 

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,... 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

A conceptually different approach to dihydropyrimidine analogues was developed by Kishi and co-workers (Scheme 4.8) [137, 138], The trimolecular room-temperature condensation of an enamine, acetaldehyde, and isocyanic acid provides the bicyclic dihydropyrimidine derivative 21. With some modification, this strategy was initially employed toward a stereospecific [138, 139] and later an enan-tioselective [140] synthesis of the natural product saxitoxin. Recent investigations by Elliott and coworkers have shown that substituted isocyanates can also be employed in this method [141-146], but a more general modification of this trimolecular condensation towards monocyclic dihydropyrimidine derivatives of the Bigi-nelli type has not yet been reported. 

Reactivities of isocyanates depend on their structure. Table 2.6 gives the main isocyanates used for polymer network synthesis. Conjugation with aromatic nuclei makes ArNCO particularly reactive. The reactivity of diisocyanates is well documented in the literature. For symmetric diisocyanates such as diphenylmethane 4,4 -diisocyanate (MDI) or para-phenylene 4,4 -diisocyanate (PPDI), both NCO groups have initially the same reactivity. But as the NCO group itself exhibits an activating effect on isocyanate reactivity, the fact that one NCO group has reacted introduces a substitution effect that usually decreases the reactivity of the second NCO group. 

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6) [24]. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 28] while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. 

Treatment of the imine (72 R = H) with phenyl isocyanate, acetic anhydride or an arenesulfonyl chloride ArS02Cl gives the corresponding A-substituted imines (72 R=CONHPh, Ac or S02Ar respectively) (70CHE141). 

Spontaneous reaction of iV-chlorosulfonyl isocyanate with a-substituted allylsilanes is valuable for the synthesis of 4-silyl-2-pyrrolidinones.179-181 The [3 + 2]-cycloaddition of crotylsilanes proceeds stereospecifically as does the... 

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