An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters

Abstract

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ∼4 s at -78 °C.

Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench

“…This result indicates that the rotation of the Boc group is slow at -78 °C, but fast at -50 °C, in line with previous work. 4,7 The n-BuLi coordinates to the carbonyl oxygen atom of the Boc group (sometimes referred to as a 'complex induced proximity effect'), 6 so for benzylic lithiation to occur in high yield the Boc group must rotate under the conditions of the reaction. Please do not adjust margins Please do not adjust margins …”

Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary α‐Oxy‐ and α‐Thio‐Substituted Organolithium Species

“…We speculated that as low electrophilic quench might have resulted in partial racemization of Li-4 and therefore monitored the reaction by in situ IR spectroscopy (Scheme 9). [22,23] With the test electrophile ClCO 2 Me,w here high e.r. values were observed, the in situ IR studies revealed that both lithiation of 4a and subsequent electrophilic quenching were extremely rapid at À78 8 8C.…”

Diastereoselective synthesis of α,α,α′-trisubstituted pyrrolidines and piperidines by directed sequential lithiation/alkylation

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In 1989, Beak disclosed that unsubstituted Boc-protected azaheterocycles may be effectively functionalized at the a-position through a lithiation/alkylation sequence. 19 Several researchers, [20][21][22][23][24][25][26] including one of us, 27,16 have since extended the Beak methodology to include sequential a-functionalizations en route to access a,a-and a,a 0 -disubstituted N-heterocycles, in both racemic and enantioenriched forms. It has been shown that the lithiation of phenyl pyrrolidine S-1 (Fig.…”

“…20 Mechanistic studies conducted by Coldham and O'Brien have since revealed that the minor rotamer of 1 rotates extremely slowly at low temperatures (the half-life for rotation of the Boc-group was determined to be $10 h at À80°C). 21 It is thus likely that the modest yields obtained by Beak, 24 Campos, 28 and O'Brien 20 in the a 0 -lithiation/alkylation of 1 were due to the restricted mobility of the minor rotamer under their reaction conditions as well as due to competitive benzylic lithiation.…”

“…27,21,38 Figure 1 illustrates several of the enantioenriched pyrrolidines and piperidines that have been prepared by this route (see [5][6][7][8][9]. As part of a program aimed at synthesizing cyclic amine derivatives through the intermediacy of functionalized organolithiums, and with a few a,a-disubstituted pyrrolidines and piperidines in hand, we sought to investigate the possibility of a third lithiation/alkylation sequence.…”