Amine ammonia equivalents

Dibromobenzothiadiazole 89 can also undergo asymmetric stepwise Buchwald amination with various anilines (Scheme 12) <2002TL9009, 2005JOC2754>, and 4-bromo-7-methylbenzothiadiazole 91 can be aminated using benzophe-none imine as an ammonia equivalent via a two-step palladium-catalyzed amination route (Scheme 13) <2003JHC713>. 

Protected primary allylic amines were generated from allylic carbonates and ammonia equivalents. Iridium-catalyzed allylic substitution has now been reported with sulfonamides [90, 91], imides [89, 91-93], and trifluoroacetamide [89] to form branched, protected, primary allylic amines (Table 5). When tested, yields and selectivities were highest from reactions catalyzed by complexes derived from L2. Reactions of potassium trifluoroacetamide and lithium di-tert-butyhminodi-carboxylate were conducted with catalysts derived from the simplified ligand L7. Reactions of nosylamide and trifluoroacetamide form singly-protected amine products. The other ammonia equivalents lead to the formation of doubly protected allylic amine products, but one protecting group can be removed selectively, except when the product is derived from phthalimide. 

Catalyst activation became a necessity when reactions with bulky aliphatic amines and arylamines (cf Section 9.4.2) as nucleophiles were probed. It was also required for intramolecular aminations [8,18]. Thus, with Ph2CHNH2, an ammonia equivalent, conversion was only 11% upon application of procedure (a) (Table 9.2, entry 11), while the reaction promoted by the activated catalyst proceeded with high selectivity and yield. Catalyst activation is faster with ligand L2 than LI, and accordingly in situ activation occurs more readily for the former (cf entries 10 and 12). Examples presented in entries 16-20 further demonstrate the advantages of catalyst activation [53] (note that excellent results can be achieved with the simpH-fied ligand L5a). 

Surprisingly though, the rather weakly nucleophilic (diphenylmethylene) amine (DPMA-H) and its cyclopropyl analog (cyclopropylphenylmethylene) amine (CPMA-H) 93 [8, 9, 10 c, 21b, 22b, 58-601 which can also serve as ammonia equivalents, add to 1-R and 2-R cleanly and in most cases quantitatively in a 1,4-fashion (Scheme 29). 

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

Note that in the preparation of the above, Rink resin acts as an immobilized ammonia equivalent (RNH2 = Rink amine) and generally gives higher purity products than its solution-phase ammonia counterpart [58]. The cinnamic acid is originally masked as a t-butyl ester in the condensation, only to be subsequently released after TFA treatment. 

Other nucleophiles have been used in this reaction. For example, BINAP was shown to be the best ligand for the enantioselective allylic amination of 19 with sodium diformylamide, a protected ammonia equivalent, furnishing the desired product in good yield and excellent enantioselectivity [96]. Also, a P,N-ligand has been developed for the allylic sulfonylation with good ee but moderate yield [97]. 

Benzophenone inline or allylamine can be used as ammonia equivalents in the CN coupling reactions of halopyr-idines <1996JOC7240,1998TL1313>. Primary S-aminopyrimidines can also be prepared using benzophenone imine as the amine source, as demonstrated by the synthesis of 970 from 968 via 969 <20060PD70>. Aromatic amines also efficiently aminate S-bromopyrimidine (Scheme 115) <2005OL3965>. 

In a related context, 2-(/Koiuenesulfonyl)ethy]amine was used as an ammonia equivalent in an aza-ene reaction by which aldehyde 92.1 was converted to the bicycle 912 [Scheme 8.92].223 After N-acetylation and Pd(0)-catalysed hydro-stannylation, the alkenylstannane 914 dintensed under copper(II) nitrate catalysis. The 2-(p-toiuenesulfonyl)ethyl group was then discharged by p-elimination with potassium rm-butoxide. 

Several groups have utilized benzophenone imine as an ammonia equivalent in the palladium-catalyzed cross coupling. For example, Mullen and co-workers prepared a new thermotropic dye via the BINAP/Pd-coupling of the corresponding bromide, Eq. (130) [110]. Similarly, Basu reported the amination of a mixture of bromopyrene derivatives [111]. 

Lee described a strategy where benzylamine could be used as an ammonia equivalent as well [90]. The double reaction of the ditriflate below, followed by hydrogenolysis, furnished the desired ligand precursor in 69% yield over two steps, Eq. (135). The diamine product was also produced by double amination of the corresponding dibromide. 

A fluorous imine reagent (3), also commercially available, was introduced by Herr as an ammonia equivalent in the Buchwald-Hartwig amination of aryl bromides, iodides, and triflates (Reaction Scheme 9)3 In this case, the problem of introducing a primary amine was solved by the use of (3) as a synthon for ammonia. 

Whereas ammonia is an unsuitable nucleophile towards 7r-allylpalladium complexes, primary amines often participate well. Benzylamine and 4,4 -dimethoxybenzhydrylamine are especially useful, since subsequent removal of the benzylic substituents permits their use as ammonia equivalents. Such a deblocking procedure was used in a short synthesis of the enzyme inhibitor gabaculine from amino ester 1118. An allyl carbonate can be successfully employed as a substrate for palladium(0)-catalyzed animation to give 1219,20, but experimental difficulties have been experienced with a structurally similar carbonate9. As shown by the formation of 1016 and by the partial production of 13 prior to basic hydrolysis16, additional attack on an ester function may occur. Amino alcohols 13, formed with complete regioselectivity due to steric reasons, have been efficiently converted into isoquinuclidines16. 

An additional application of the observed trans diastereoselectivity in Michael reactions is demonstrated by performing this reaction with a c/5-4,5-diphenyloxazolidin-2-one as a chiral ammonia equivalent for the introduction of an amine functionality. This sequence, when carried out with enantiomerically pure (/ ,5)-4,5-diphenyloxazolidin-2-one, yielded diastereomerically and enantiomerially pure addition compounds which were separated by chromatography. ... 

Auxiliary methods can hold current value when the auxiliary is inexpensive, available in both enantiomeric forms, and, for amine synthesis, can be incorporated with concomitant generation of the new stereogenic a chiral amine center. Reductive amination with chiral ammonia equivalents not only holds this potential but is now a proven and established method that allows chiral primary amine synthesis in two reaction steps (reductive amination and hydrogenolysis) from prochiral ketones. The approach is of interest because of its overall reaction step efficiency. 

S) phenylethylamine (also referred to as a methylbenzylamine) and (R) and (S) tert butylsulfinylamide have gained widespread acceptance as useful chiral ammonia equivalents. The strategy is therefore to use these chiral amines to induce a new chiral amine stereogenic center on a ketone substrate. An alternative approach is to use a chiral ketone with an achiral source of nitrogen, for example, benzylamine. This latter approach is less often employed, but nonetheless equally important and discussed first. 

Triphenylsilylamine has been used as a protected ammonia equivalent for displacement of aryl halides to prepare anilines. For a more thorough discussion of silylat-ing reagents the section on alcohol protection should be consulted since many of the reagents described there will also silylate amines. 

D. G. Putnam described di- or mono-allylamine as a masked ammonia equivalent.92 The amination proceeds well with aryl bromides or halopyridines using either (DPPF)PdCl2 or [(o-tol)3P]2PdCl2. Deprotection was accomplished using standard Pd/C hydrogenolysis conditions. 

Nitrogen gas may serve as an ammonia equivalent by first capturing nitrogen with TiXVLi/TMSCl, which gives a LnTi-N(SiMe3)2 complex 50.93 (DPPF)Pd or (BINAP)Pd catalyze the amination of aryl bromides and triflates with this titanium amide complex in low yields after an acidic workup. Di-arylation is the major byproduct. 

Hartwig was able to show that LiHMDS could serve as both an ammonia equivalent and as the stoichiometric base for the amination reaction catalyzed by Pd(f-Bu)3P.94 The reaction conditions tolerate many aryl bromides and chlorides, but due to the size of LiHMDS, or/Ao-substituted haloarenes are not acceptable. As before, acidic workup reveals the aniline by cleavage of the N-Si bond. 

The four-component Ugi reaction has received renewed attention because of the large number of diverse substituents that can be arrayed over a series of scaffolds. Although the four-component (4CC) acylaminoamide synthesis proceeds readily for many aliphatic and aromatic amines, ammonia does not readily afford a 4CC product. A solution to this problem involves use of the RAM resin 7c as an ammonia equivalent [307-309] with products being cleaved from the resin using TFA. 

Electrophilic amination can be achieved using hydroxylamine-based ammonia equivalents. The preferred conditions for this transformation utilize sodium hydride in dioxane. Addition of the anion to 0-(p-nitrobenzoyl)hydroxylamine (NbzONH2) generates theiV-amino-2-oxazolidinone (eq 44). Although the amino compound can be isolated, typically the product is converted to the more stable hydrazone. 

More recently, Hartwig reported on the use of a zinc variant of LHM DS, namely Zn(HMDS)2, as a mild ammonia equivalent in combination with LiCl or R,NX as additives and P(t-Bu)3 as ligand [173]. This protocol has the advantage of extended functional group tolerance, allowing the use of substrates with, for example, eno-Hzable groups. Hence, when (S)-naproxen methyl ester was deliberately added to the amination reactions no racemization occurred, yet addition of the stronger base LHMDS led to almost complete racemization. 

Reduction of amides with LiAlHi adds two equivalents of hydride to afford amine products. Reaction of an acid chloride with an amine (ammonia NH3, primary RNH2, or secondary R2NH) generates the desired amide product. 

A Masked Ammonia Equivalent. Weinreb and co-workers described the utility of 3 as an ammonia synthon. TSE-NH2 (3) was reductively alkylated with benzaldehyde in the presence of NaBHj to afford secondary amine 4, which was subsequently 7V-acylated or A-sulfonylated to generate TSE amido compounds such as 5 (eq 2). Removal of the TSE group from 5 was achieved via a /3-elimination using potassium f-butoxide to afford 6 and vinyl sulfone (7), which polymerizes under these conditions. 

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