Trisyl azide

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

Triisopropylbenzenesulfonyl azide (trisyl azide), ArSCKN, (1), m. p. 41-43°. Preparation from trisyl chloride and NaN, (80% yield).1... 

Sulfonamide anions react with a variety of electrophiles, as was showcased in CHEC-II(1996). One example from the recent literature involves the reaction of bicyclic sulfonamide 142 with trisyl azide to afford approximately a 2 1 mixture of diastereomers 143 and 144 (Equation 20) <2003T7047>. 

Benzodiazepin-l,4-dione 22 was a key intermediate for synthesis of a series of peptidomimetic inhibitors <2004BML3535>. The preparation of 22 starts by the reaction of the enolate of diazepine 20 with trisyl azide giving azide 21. Reduction of 21 under heterogeneous hydrogenation conditions gives amine 22 (Scheme 4). 

The direct azidation of l,4-benzodiazepin-2-ones with trisyl azide provided access to 3-amino derivatives after reduction of the intermediate azide in a process that is compatible with a range of N-l and C-5 substituents (Scheme 15) <1996TL6685>. This protocol offers a convenient alternative to the reduction of a C-3 oxime, obtained by reaction of the l,4-benzodiazepin-2-one with isoamyl nitrite, which requires more vigorous conditions... 

Although some reactions of electrophilic animation of phosphorus-stabilized anions had already been reported in the literature [5a,d], the first example of such a stereoselective reaction opening access to optically active a-amino phosphonic acids was described in 1992 by Denmark and co-workers [45] and by Jommi and co-workers [46]. Both of these groups used chiral amino alcohols as auxiliaries for diastereo-selective induction in the animating process. Denmark and co-workers chose trisyl azide (2,4,6-triisopropylbenzenesulfonyl azide) as equivalent of NHJ , whereas Jommi and co-workers performed the reaction with DTBAD. 

The phosphorus-stabilized carbanion of 94 was generated at -100 °C with LDA (1.2 equiv.) in THF. Amination reactions were performed both with DTBAD and trisyl azide. Direct addition of a stoichiometric amount of DTBAD (1.1 equiv.) at -100 °C followed by acidic quench led to a mixture of hydrazino products 95 (major diastereomer indicated) in good yield and diastereoselectivity (Scheme 44). 

A mechanistic rationale for the observations is presented, although it is not really known why it is the potassium enolate, the trisyl azide and the acetic acid quench that lead to the high yield in the stereoselective azide transfer reactions2. The diastereomeric //-configurated carbox-imides were prepared via a bromination/azide substitution sequence, not detailed here2. 

K. enolate with KHMDS (1.1 equiv) in THF at — 78, C (30min) the Li enolate is similarly prepared with LDA. b TrisylN, = 2,4,6-triisopropylbenzenesulfonyl azide PNBSA = 4-nitroben-zenesulfonyl azide. c Recovered starting material. a Inverse addition of 1 to trisyl azide. e 2 equiv are used. 

The best results are obtained with trisyl azide, which again leads to high yields of the azide transfer product 2, especially if the enolate 1 is added to trisyl azide (see entries 1 and 2). Interestingly, the best chemoselectivity and, in addition, identical yields of azide (73%) result from the reaction of the lithium enolate with trisyl azide (entry 3). The reaction of the ester enolate 1 with trisyl azide is less sensitive to the nature of the enolate metal than is the corresponding imide enolate reaction (see Section 7.1.1.). Acetic acid quench, on the other hand, again proved to be useful. Unfortunately, bis-azidation to 3 and diazo transfer to 4 are also observed. 

The application of these observations to a stereoselective azide transfer is shown in the following example. Reaction of the dilithiuni compound 6, prepared from the racemic 3-hy-droxybutyrate 5 with trisyl azide and acetic acid quench, leads to the (3-hydroxy-a-azido ester 7 in 77% yield and a diastereoselection d.r. [(2R, >R )/(2R, 3S )] of 82 18 (determined by H NMR). 

The successful azide transfer with triisopropylbenzenesulfonyl azide (trisyl azide)2 (see Section 7.1.1.) is also the method of choice for the preparation of optically active a-aminophospho-nic acids from chiral, phosphorus-stabilized carbanions12. 

Thus, benzenediazonium tetrafluoroborate is not the electrophilic aminating reagent of choice, although the diastereoselection in the formation of the new C-N bond is very good. The yields, however, cannot compete with the results obtainable by the use of trisyl azide and di-Ze/7-butyl azodicarboxylate aminations, as shown in the preceding sections. It is possible that some other modified aryldiazonium tetrafluoroborates will prove to be more successful in electrophilic amination reactions. 

The stereoselective total synthesis of tt)-campherenone was accomplished by T. Uyehara and co-workers based on a photochemical Wolff rearrangement. The bicyclic ketone was treated with 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) under homogeneous basic conditions and the a-diazo ketone was obtained in excellent yield. The photochemical rearrangement of the diazo ketone was conducted in a THF-water mixture using a high-pressure 100 W mercury lamp. The ring-contracted acid was isolated as a 4 1 mixture of endo and exo products. 

Several methyl 2-cyclopropylacetate derivatives were converted to the corresponding methyl 2-azido-2-cyclopropylacetates by treating the starting material with lithium or potassium hexa-methyldisilazanide, followed by 2,4,6-triisopropylbenzenesulfonyl (trisyl) azide and acetic acid. F or example, formation of 1. It is noteworthy that treatment of the methyl 2-azido-2-cyclopropylacetates with lithium methoxide afforded the corresponding 2-iminoacetates in good yield. " ... 

Azidations of certain phosphorus-stabilized anions with 2,4,6-triisopropylben-zenesulfonyl azide ( trisyl azide, 41a) may be reversible.317... 

The most widely used application of sulfonyl azides is in the azidation of enolates and other stabilized carbanions. The main challenge here is the avoidance of the diazo transfer reaction, which leads to diazo compounds and thus makes a diastereoselective animation impossible. Addition of the enolates to the sulfonyl azide proceeds rapidly at low temperatures (—78° or lower) to give the mesomeric ion 42 (Eq. 30).318 Reagents 41, the counter ion M+, the solvent, and the quenching reagent all influence the subsequent partition between azide and diazo compound. For enolates of esters (39) and N-acyloxazolidinoncs (40) the preferred reagent is trisyl azide (41a) 4-nitrobenzenesulfonyl azide (41c) promotes diazo transfer, and tosyl azide (41b) usually leads to mixtures of the two types of products. For ester enolates 39, either lithium or potassium as the... 

Reaction of ester enolates with trisyl azide and short reaction times at —78° gives the a-azido esters in 50-70% yields 318,413,414 with 4-nitrobenzenesulfonyl azide, the diazo esters are formed almost exclusively.318 Azidomethyl phenyl sulfide and ester enolates give a-amino amides274,275 (Eq. 114),274 but the scope of this reaction has not been determined. 

Reaction of the lithium enolate of ethyl (3-hydroxybutyrate with trisyl azide furnishes the azide in 77% yield but with only 64% anti diastereomeric excess the diazo ester (10%) and the diazide (1%) are also formed.318... 

Other (i-substituents also promote anti selectivity with both azo esters and trisyl azide. Examples are given in Eqs. 118,425 and 119.426 Use of trisyl azide in the latter reaction gives the two diastereomeric azides as a 1 1 mixture in 90% yield.426 More remote substituents, however, may reverse the trend (Eq. 120) 427... 

A few problems have been reported. Cleavage of the (V-acyloxazolidinone occurs to a considerable extent in the reaction of Eq. 130.445,446 A bromine atom at a distance of five carbons from the carbonyl group causes the enolate to cyclize under normal procedures (product 64, Eq. 131) azide 63 (n = 3) is obtained in 40% yield only by adding an excess of trisyl azide early in the enolization step.443 The a,ft-unsaturated N-acyloxazolidinonc 65 does not undergo animation under conditions where its isomer 66 does (Eq. 132)453 However, product 67 epimerized on attempted removal of the auxiliary. 

Diphenylphosphinoyl)hydroxylamine (Eq. 137),143 azo esters (Eq. 138),460 and arenesulfonyl azides (Eq. 139)339 have been used to aminate lactam enolates. In the azidation of the lactam 70,461 the diazo compound 73 predominates over azide 72 even though trisyl azide is used as the animating agent amination with di(ferf-butyl) azodicarboxylate was unsuccessful. The closely related lactam 71462 reacts normally with trisyl azide (Eq. 140). 

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