α-Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping

Abstract

A general and straightforward procedure for the lithiation trapping of cyclic sulfides such as tetrahydrothiophene, tetrahydrothiopyran and a thiomorpholine is described. Trapping with a wide range of electrophiles is demonstrated, leading to more than 50 diverse α-substituted saturated sulfur heterocycles. The methodology provides access to a range of α-substituted cyclic sulfides that are not easily synthesised by the currently available methods.

Keywords: Cyclic Sulfides; Organolithium; α-Functionalization.

Figure 1

Natural products, chiral catalysts and potential pharmaceuticals containing α‐substituted saturated sulfur heterocycles. CXCR=Chemokine receptor.

Scheme 1

Strategies for the synthesis of α‐substituted sulfur heterocycles from the corresponding cyclic sulfides. Strategy A: Radical intermediate. Strategy B: Pummerer Rearrangement. Strategy C: α‐metalation. Azobisisobutyronitrile (AIBN); transition metal (TM); cross‐dehydrogenative coupling (CDC); N,N,N′,N′‐tetramethylethylene‐diamine (TMEDA).

Scheme 2

Functionalisation of tetrahydrothiophene 4, tetrahydrothiopyran 5 and N‐methyl morpholine 6. A: Tetrahydrothiophene. B: Tetrahydrothiopyran. C: Thiomorpholine. D: Tetrahydrothiophene Scope. E: Tetrahydrothiopyran Scope. F: Thiomorpholine Scope. N,N,N′,N′‐tetramethylethylene‐diamine (TMEDA); benzyl (Bn); tert‐butyldimethylsilyl (TBS); pinacolate (pin). ^[a] PhCHO as electrophile for entries 3 and 4. ^[b] Yield after chromatography. ^[c] 0.3 eq. TMEDA used. ^[d] Eq. of s‐BuLi/TMEDA. ^[e] Reaction carried out at −10 °C. ^[f] % yield of 7 i ⋅ HCl over 2 steps; corresponding Ellman's t‐butyl sulfinamide used followed by deprotection with HCl_(aq). ^[g] Transmetalation to Cu using CuCN ⋅ 2LiCl prior to addition of Ph₂IPF₆. ^[h] 1.3 eq. s‐BuLi/TMEDA, hexane, 0 °C, 2 h then Electrophile, 0 °C, 1 h. ^[i] Single unidentified diastereomer. ^[j] 2.5 eq. of 5. ^[k] Lithiation conditions: 1.3 eq. s‐BuLi, 0.3 eq. TMEDA, hexane, −10 °C, 3 h. ^[l] Lithiation conditions: 1.3 eq. s‐BuLi, 1.3 eq. TMEDA, hexane, −10 °C, 2 h.

Scheme 3

Diastereoselective functionalisation of 4‐substituted tetrahydrothiopyrans 10. tri‐iso‐propylsilyl (TIPS); N,N,N′,N′‐tetramethylethylenediamine (TMEDA); benzyl (Bn).

Scheme 4

A: Preparation of a key intermediate in the synthesis of CXCR antagonist 2. B and C: Further functionalisation of α‐substituted tetrahydrothiophenes and tetrahydrothiopyrans. N,N,N′,N′‐tetramethylethylene‐diamine (TMEDA); 9‐borabicyclo[3.3.1]nonane (9‐BBN); pinacolate (pin) N‐bromosuccinimide (NBS); tris(2‐(4‐fluorophenyl)pyridine (Ir(p‐F‐ppy)₃); dimethylsulfoxide (DMSO); Compact fluorescent light (CFL).