Amides, Sulfonamides, Carbamates, and Ureas

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

---

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

This reaction allows aryl carbon-heteroatom bond formation via an oxidative coupling of arylboronic acids, stannanes or siloxanes with N-H or O-H containing compounds in air. Substrates include phenols, amines, anilines, amides, imides, ureas, carbamates, and sulfonamides. The reaction is induced by a stoichiometric amount of copper(II) or a catalytic amount of copper catalyst which is reoxidized by atmospheric oxygen. 

A variety of N-H containing compounds are A-arylated by Ar3Bi in the presence of a stoichiometric amount of Cu(OAc)2, 155-161 which plays dual important roles it oxidizes Ar3Bi to Ar3Bi(OAc)2 and mediates the arylation via transmetallation (Equation (94)). In the presence of Et3N or pyridine, the Cu(OAc)2-promoted A-arylation of amides, sulfonamides, ureas, carbamates, and anilines with Ar3Bi occurs much more efficiently than the reaction without a... 

The indole linker 1.11 (68), easily prepared from aminomethyl PS resin and N-carboxyalkylated indole-3-carboxaldehyde, was used to support amines and to transform them on SP, obtaining, by release with TFA-DCM 1/1 in 30 min, a variety of compounds, including amides, sulfonamides, guanidines, ureas, and carbamates. 

Hydroamination of olefins is also possible with gold catalysts. In this reaction, the attack comes Ifom a nitrogen nucleophile as a carbamate,a urea, an amide, or a sulfonamide. In the latter case, the reaction can be carried out intermolecularly. While the carbamates, ureas, and amides give only products of intramolecular anunations, the sulfonamides can perform the intermolecular addition. Only the addition of ureas (equation 146) takes place at room temperature, and in the rest of the additions heating is required. The catalysts of choice in all these reactions are cationic gold(I)-species stabilized by phosphines or NHC ligands. The reaction times have been reduced by the use of microwave irradiation. The mechanism of the hydroamination reaction has been studied in detail theoretically. ... 

The conversion of secondary azetidines into amides, carbamates, sulfonamides and ureas is accomplished without difficulty by the usual procedures a number of these derivatives are listed in Tables 1, 2 and 3. An extensive survey of these reactions has been csxried out -with 3-phenylazetidine. T -Nitroso derivatives ore obtuned -with nitrous acid, and. y-mirofiO -S-phenylaeetidine has been reduced with lithium... 

N-Arylaminophthalimides, hydrazines, hydrazones, and N-H containing heterocycles are N-arylated by combined use of Ar3Bi and Cu(OAc)2 (Scheme 14.134) [281] in which Cu(OAc)2 oxidizes Ar.l i to Ar jl i(OAc)2 and catalyzes the arylation via transmetalation (Section 14.3.4.2). The Cu(OAc)2-promoted N-arylation of amides, sulfonamides, ureas, carbamates, and anilines with ArsBi proceeds efficiently in the presence of EtsN or pyridine (Scheme 14.135) [282]. N-Arylation occurs selectively on the primary amino group of aminobenzanilides (Scheme 14.136) [283]. A variety of amines are N-alkylated in moderate yields by use of alkylbismuthanes assisted by Cu(OAc)2 [284]. 

A number of amides, imides, ureas, carbamates and sulfonamides have also been efficiently arylated by the triphenylbismuthane-copper diacetate system, when a tertiary amine promoter, such as triethylamine or pyridine, was added. 104... 

It appears also that, for the synthesis of large libraries, there are few reactions that fulfil these prerequisites. Among the reactions that proved to have wide applicability, amide bond formations and peptide-like protecting group strategies can be found. In a general way all amine functionalization reactions are usually effective and lead to stable structures (i.e. sulfonamide, carbamate, urea, thiourea formation, reductive amination and nucleophilic substitution). Moreover, for any of these reactions the suitable linker can be easily selected from various literature sources. 

In addition to amines, some derivatives of amines can be arylated. Weakly basic amides are arylated, and intermolecular reactions between aryl bromides and tri-flates 48 with benzamide can be carried out. Combined uses of xantphos (IX-IO) and CS2CO3 in THF or dioxane gave the most successful results. The cyclic urea 49 was diarylated [40]. Sulfonamides are also arylated [41]. Intramolecular reaction of the secondary amides such as 50 or carbamates offers convenient synthetic methods for five-, six-, and seven-membered lactams like 51. As ligands, MOP (VI-12), DPEphos (IX-9), xantphos (IX-IO), and BINAP are used depending on the size of the rings. As an example, ligand IX-9 is the most suitable for the preparation of the five-membered A-carbobenzyloxy derivative 52a from 52, but BINAP was not effective. 

Reports by the groups of Chan, Evans, and Lam in 1998 revealed an alternative method to conduct copper-mediated couplings that form C(aryl)-0 and C(aryl)-N bonds. In this process, arylboronic acids react with compounds containing N-H or 0-H bonds in the presence of a Cu(II) reagent or catalyst. TTiese reactions were initially conducted with stoichiometric amounts of copper reagents. " Amines, anilines, amides, ureas, carbamates, and sulfonamides underwent N-arylation in moderate to excellent yields by this process (Equation 19.124). The commercial availability of boronic acids and the ability to conduct these arylations in air under mild conditions has caused this method to be adopted quickly for synthetic applications on a small scale. 

However, when electron-rich aryl halides were used in amidations, by-products arising from the exchange of the phenyl group ofXantPhos (11) with the aryl group of the product were observed [123]. Not only amides and enolizable amides, but also urethanes, urea derivatives, and primary and secondary sulfonamides were successfully arylated. The coupling of carbamic acid tert-butyl ester was reported by Hartwig et a. [46] in 1999 and provided N-Boc-protected anilines in one synthetic step (Scheme 13.74). 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

To populate our monomer collection with enabled monomers, we focused initially on the amino group because amines are involved in many library transformations such as amidation, sulfonamidation, reductive amination and SfjAr reactions. The process began with the selection of a readily available and diverse set of mono-Boc diamines, and then a virtual library (VL) was built via capping of the free amine (for example, this can be done through amidation, reductive amination, SNAr, sulfonylation, urea formation or carbamate formation) (Figure 18.12). 

---