· (MW 175.09)
(reagent for diazo or trifluoromethanesulfonylamino transfer)
Alternate Name: triflyl azide, TfN3.
Physical Data: colorless liquid with a pungent odor, bp 80-81 °C,7 52.3 °C (444 mm Hg),1 45 °C (350 mm Hg),3 nD20 1.3474,7 d420 1.5400.7
Solubility: soluble in most organic solvents, e.g. hexane, decalin, dichloromethane, THF, dioxane, acetone, MeCN, DMF, DMSO, MeOH.
Form Supplied in: not commercially available.
Analysis of Reagent Purity: IR,1-6 Raman,6 19F-NMR,2 MS,3 UV;1,7 other analysis: gas electron diffraction.8
Preparative Methods: from Tf2O and NaN3 in H2O/CH2Cl2,2,5 Tf2O and NaN3 in H2O/catalyst Bu4NHSO4/hexane,4 TfF and NaN3 in MeOH,7 or TfCl and NaN3 in MeCN.3
Purification: distillation at reduced pressure1,3 (CAUTION!).
Handling, Storage, and Precautions: prepared in situ as a solution in dichloromethane,5 hexane,4 MeCN,3 or ClCH2CH2Cl.9 Solutions in dichloromethane are stable at -14 °C for several weeks;10 solutions in hexane are stable at 4 °C for several days.4 Neat TfN3 is stable up to 100 °C.7
CAUTION: Preparation of TfN3 in the absence of an organic solvent should be avoided as it may lead to an explosion.2 Reactions involving neat TfN3 should always be handled behind a safety shield.
TfN3 acts both as diazo- and as triflylamino-transfer reagent. Unlike other sulfonyl azides, it does not act as azido-transfer reagent, but readily undergoes cycloaddition to electron-rich alkenes at room temperature.
Transformation of Primary Amines into Azides
Azido groups are equivalents of temporarily protected primary amino groups. TfN3 transforms primary amines into azides in a single step (1). The reaction has been applied to alkylamines,2 aminodeoxyhexoses,5,11 amino acids, and peptides.12 The reaction is base catalysed. The reaction conditions are strongly influenced by the polarity of the amines. Lutidine in dichloromethane has been used for the azidation of lipophilic amines, DMAP in MeCN/CH2Cl2 or in MeOH/CH2Cl2, or NaOH (pH = 9.5) in H2O/CH2Cl2 for hydrophilic amines. Yields vary from 19% to 93%.
Imination of Phosphites and Phenylphosphonous Dihalides
TfN3 reacts with (PhO)3P and (C6H13O)3P quantitatively to N-triflyl-phosphorimidates13 (2). Similarly, PhPX2 (X = F, Cl, or Br) afford the corresponding phosphonimidic dihalides, whereas phosphorous trihalides do not react.
1,3-Dipolar Cycloaddition to Electron-rich Alkenes
At temperatures less than 30 °C, TfN3 adds to enolates,10 enol ethers,4,14 and enamines9,15,16 to form thermally unstable 1,2,3-triazolines which ring open to give unstable diazonium-triflylamide zwitterions (3). Depending on the nature of R1 to R3 and X, these zwitterions form a variety of products.
The aryldiazoacetate obtained via path A from ethyl indan-1-one-2-carboxylate is stable enough to be isolated (4), whereas the diazo group of the benzyldiazoacetate derived from the isomeric ethyl indan-2-one-1-carboxylate reacts in situ with the N-triflylamido group to yield bicyclic products.10 Acyclic b-keto esters react with TfN3 via path B to give diazo esters (5). Ethyl a-tetralone-2-carboxylate and benzosuberone-2-carboxylate yield the ring-contracted N-triflylamides via path C (6), whereas ethyl b-tetralone-1-carboxylate is transformed via path D to a N-triflylamine without ring contraction (7).
2,3-Dihydrofuran and 3,4-dihydro-2H-pyran react with TfN3 to afford N-triflylimino ethers (i.e. lactone N-triflylimines)4 (8), whereas cyclohex-1-enol TMS ether is transformed into a triflylamide14 (9). These reactions occur via path C, in the former case by a hydride shift and in the latter case by an alkyl shift leading to ring contraction. Open-chain silyl enol ethers, however, react via path D to N-triflyl a-amino ketones14 (10). The yield drops to 28% upon replacement of the tert-butyl by a phenyl group.
The reaction of TfN3 with 1-methyl-1,2-dihydropyridine gave the triflylaziridine via path D15 (11). In situ generated 1,2-dihydro-1-methyl-2-alkylidenequinolines react with TfN3 to N-triflylamidines, either via path C by alkenyl migration and ring enlargement, or via path B by fragmentation16 (12). Partial hydrolysis of the quinoline derivative led to the corresponding d-lactam (<15%). The relative extent of the fragmentation increases with increasing stability of RCHN2 (Me < t-Bu < Ph).
The decomposition of the 1,2,3-triazoline intermediate via path B is also favored by the presence of a keto group, and leads to an a-diazo ketone. a-Diazo ketones are thus available from a-methylene ketones in two steps [1. (MeO)2CHNMe2; 2. TfN3, 60 °C] and under mild conditions9 (the key step is shown in 13).
1,3-Dipolar Cycloaddition to Nitroso Compounds
The addition of TfN3 to 2-nitroso-2-methyl-propane leads to a thermally unstable oxatetrazolidine which loses N2O to afford TfN = N-t-Bu17 (14). This cycloaddition has not been used for synthetic purposes, although TfN = N-t-Bu homolytically decomposes to CF3 and tert-butyl radicals.
Triflyl Nitrene Addition to Pyridine and Benzenes
At higher temperature (> ca. 80 °C), TfN3 slowly decomposes to triflyl nitrene which adds to pyridine to form pyridinium N-triflylaminide18 (15). Triflyl nitrene also adds to benzene to form N-triflylaniline, and to monosubstituted benzenes to form mostly ortho/para monosubstituted N-triflylanilines in ratios between 1:1 and 2:1)3 (16).
XC2F4OC2F4SO2N3 (X = H, Cl, I);
FSO2N3, MsN3, PhSO2N3, TsN3;
ClC6H4 SO2N3, MeOC6H4SO2N3;
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Bruno Bernet & Andrea Vasella
ETH-Zurich, ETH-Hoenggerberg, Zurich, Switzerland
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