Ammonia surrogates

Pronucleophiles Serving as Ammonia Surrogates N,N-Diacylamines, Trifluoroacetamide and N-Sulfonylamines... 

Aromatic C-N Bond Formation with Non-Amine Substrates and Ammonia Surrogates... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

An intermolecular version of the arylation of carbamates has been recently published by Hartwig et al. (Eq. (21)) [132]. His group showed that reactions catalyzed by a combination of Pd(OAc)2 and P( -Bu)3 formed /V-aryl carbamates from aryl bromides or chlorides and f-butylcarbamate as substrate. Again, the reaction conditions were not as mild as those for amination, but were similar to those of the intramolecular reactions. For the intermolecular reactions, the use of sodium phenox-ide as base was crucial. Reactions using Cs2C03 showed low conversions. Those involving NaO-r-Bu as base rapidly formed a gel, presumably from the deproto-nated carbamate, and also showed little or no conversion. The products of these reactions serve as conveniently protected anilines, and r-butylcarbamate can be considered one type of ammonia surrogate. In addition, the products of these reactions are suitable for subsequent directed metalation procedures [100]. 

Benzophenone imine is commercially available and serves as an ammonia surrogate that reacts with aryl halides in high yields under standard palladium-catalyzed conditions. Catalysts based on both DPPF- and BINAP-ligated palladium gave essentially quantitative yields for reactions of aryl bromides. These reactions can be conducted with either Cs2C03 or NaO-/-Bu as base [137,138]. The products are readily isolated by chromatographic techniques or by crystallization. They can be cleaved to the parent aniline by using hydroxylamine, acid, or Pd/C [138]. 

Recently, Fu and coworkers reported an alternative method for assembly of primary aryl amines [17]. In their reaction amidine hydrochlorides were used as the ammonia surrogates (Scheme 9.3). The ligand was also L-proUne (LI) and heating (110°C) was required for good yields. 

So far no arylation of ammonia has been reported, and it is difficult to prepare aniline derivatives directly by the Pd-catalyzed reaction of aryl halides with ammonia. Aniline derivatives are prepared indirectly by the reaction of ammonia surrogates (ammonia equivalents). The reaction of the ammonia surrogates with aryl halides, followed by deprotection affords aniline derivatives. As one of them, LiN(TMS)2 (61) reacts with aryl bromides and chlorides. P(t-Bu)3 is the best ligand, and the coupled products are converted easily to anilines by treatment with aq. HCl. 

Synthesis of 62 from 60 is an example [51], Use of LiN(TMS)2 as the ammonia surrogate is problematic for aryl bromides containing an amide group, but the reaction of p-bromoacetanilide (63) proceeds smoothly using 2.2 equivalents of 61 [29],... 

No smooth reaction of LiN(TMS)2 was observed with sterically congested ortho-substituted aryl halides. In such a case, Ph3SiNH2 can be used as an ammonia surrogate and the coupled product 64 was converted to 65 [52]. 

Benzophenone imine (66) is another ammonia surrogate. Arylation of the imine 66 is carried out using BINAP and CS2CO3. Hydrolysis of the arylated imine 67 affords the aniline derivative 68 [53]. 

Allylation of ammonia gives a mixture of products, and it is difficult to prepare primary amines from ammonia, and several ammonia surrogates are used. Allylation of sodium diformylamide (219) with the allyl acetate 218 proceeded smoothly by using DPPF as a ligand to afford 220, which was hydrolyzed to provide the primary allylamine 221. The reaction was sluggish when PPhs was used. The primary allylamine 224 with high ee (95.5 %) was obtained from 94 via 223 by the use of (5)-BINAP [81]. 

Azide is a reactive nucleophile and is used as an ammonia surrogate. Desym-metrization of the dicarbonate 229 occurred by the reaction with TMS azide to afford azide 230 in 82 % yield with higher than 95 % ee. The reaction is a key step in the asymmetric total synthesis of (+)-pancratistatin [83]. 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

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