Nucleophilic SN2 displacements on (pivaloyloxy)methyl 6.alpha.-[(fluorosulfonyl)oxy]penicillanate

Abstract

SrCI4/CH2CI2 or CHClj RN3 + (CH3 )3SiX Ns VR1.R2.R3 * H 2-R|-CH3; Rg.Rs-H 3*R1.R2*CH3:R3*H 4*Ri,R2, R3 * CK3 6 7 ff Q"' 8solvent to provide the corresponding azides. However, the reaction does not proceed with unactivated alkyl halides. We have found now in our studies that polycyclic adamantyl,20 diamantyl related halides and cyclic cyclohexyl and cyclopentyl halides react with trimethylsilyl azides under stannic chloride catalysis to give the corresponding azides in moderate to excellent yields (Table I).The reaction works well with both tertiary bridgehead as well as with secondary halides. This is significant, since secondary hydroxy compounds do not give the secondary azides directly using the NaN3/H2S04 method.1 23 4The presently developed procedure to prepare polycyclic and cyclic azides using readily available trimethylsilyl azide is superior to other existing methods for its convenience, good yields, and general applicability to both secondary and tertiary systems. Experimental SectionTo a stirred solution of the polycyclic or cyclic halide and trimethylsilyl azide23® (relative ratios in Table I) in 50 mL of dry dichloromethane or chloroform under nitrogen at 0 °C is added stannic chloride233 catalyst (see table for the exact amount). After the addition, the mixture was brought to room temperature followed by prolonged stirring or reflux for the stipulated period of time (Table I). After the reaction was complete the mixture was quenched with ice-water (100 mL) followed by methylene chloride or chloroform extraction (2 X 100 mL). The organic layer was dried over anhydrous MgS04 and evaporated to obtain the crude azide. The crude azide was further purified, when necessary, on a silica gel column using hexane-dichloromethane eluent (20:1) or fractional distillation. The purity of the product azide was confirmed by 13C NMR (Table I), IR, and melting point measurement.Acknowledgment. Support of our work by the National Institutes of Health is gratefully acknowledged.

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

“…The former reactivity pattern includes the conversion of carboxylic acids and primary alcohols to acyl [118] and aliphatic fluorides, respectively, using SO 2 F 2 in the presence of base. [119] Secondary fluorosulfates can be made and isolated when the carbinol center is embedded in the molecule between electron-withdrawing substituents that make both S N 1 and S N 2 substitution difficult, as is the case with a C6-fluorosulfated penicillin analogue tested as a covalent inhibitor of porcine pancretic elastase. [120] In addition, certain perfluorinated aliphatic fluorosulfates can be isolated and were shown to form stable sulfate and sulfamate connections.…”

Synthesis and Chemical Transformations of Fluorosulfates

“…Setti and Mascaretti synthesized (pivaloyloxy)methyl 6α‐((fluorosulfonyl)oxy)penicillanate ( 26 ) from the reaction of (pivaloy1oxy)methyl 6β‐aminopenicillanate ( 25 ) with fluorosulfonic acid and tert ‐butyl nitrite in CH 2 Cl 2 at 0 °C for 30 min (Scheme ) …”

“…Setti and Mascaretti reported a S N 2 nucleophilic displacement reaction on 6α‐((fluorosulfonyl)oxy)penicillanate 26 to give 6β‐halopenicillanates 157 in good yields upon reaction with tetrabutylammonium halide in THF (Scheme ) . The pom 6β‐chloro‐ and 6β‐iodopenicillanates were more stable than the corresponding 6β‐bromopenicillanate.…”

Schwefel(VI)‐fluorid‐Austausch (SuFEx): Eine weitere gute Anwendung für die Click‐Chemie

“…In ersterem Fall gelingen Umsetzungen mit Carbonsäuren und primären Alkoholen zu acylischen [118] oder aliphatischen Fluoriden, wenn SO 2 F 2 in Gegenwart einer Base eingesetzt wird. [119] Sekundäre Fluorsulfate kçnnen hergestellt und isoliert werden, wenn das Carbinolzentrum im Molekül zwischen elektronenziehenden Substituenten eingebettet ist, die sowohl S N 1-als auch S N 2-Substitutionen erschweren, wie es bei dem an C6 fluorsulfatierten Penicillinanalogon der Fall ist, welches als kovalenter Inhibitor der Elastase aus boviner Bauchspeicheldrüse getestet wurde. [120] Auch perfluorierte aliphatische Fluorsulfate wurden isoliert, für die gezeigt wurde, dass sie stabile Sulfat-und Sulfamatbindungen bilden.…”