A Simple Synthesis of (S)-α,α-Diaryl-2-pyrrolidinemethanols
481
and the rest of SOCl2 were removed under reduced pressure to give l-proline methyl ester
hydrochloride 1 as light yellow slurry. The product was used in the next step without further
purification. Yield: 164.2 g (99%), [α]25 = −30.6◦ (c = 1.0, in H2O, lit.2 = [α]25
=
D
D
−31.0◦).
Preparation of N-Benzyl-L-Proline Methyl Ester (2)
To a 500 mL of methanol solution of 1 (82.5 g, 0.5 mol) added anhydrous K2CO3 (207.3
g, 1.5 mol) and the suspension was stirred at 0◦C for 1.5 h. Then, the reaction mixture
was heated to reflux, and benzyl chloride (BnCl, 58.0 mL, 0.5 mol) was added dropwise
at this temperature over a period of 2.0 h under nitrogen atmosphere. After the end of
addition of BnCl, the reaction mixture was stirred and refluxed for 12 h. The reaction
was monitored by TLC (methylene chloride/ethyl acetate 1:1 v/v). When the reaction was
complete, the suspension was filtered and the cake was washed twice with methanol. The
filtrate was evaporated under reduced pressure to give crude product 2 as yellow oil. This
oil was dissolved in 500 mL of ethyl acetate, and the solution was washed with water and
brine, and it was dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure to give N-benzyl-l-proline methyl ester 2 (95.3 g, 87%) as light yellow oil. [α]25
D
= +73.4◦ (c = 2.15, in CHCl3, lit.22 [α]25 = +73.8◦); H NMR (300 MHz, CDCl3): δ
1
D
1.69–2.28 (m, 4H), 2.42 (m, 1H,) 3.10 (m, 1H), 3.22 (m, 1H), 3.60 (s, 2 H, PhCH2), 3.66
(s, 3H, OCH3), 7.32–7.38 (m, 5H, ArH); Rf = 0.30 (CH2Cl2 / EtOAc 1:1 v/v).
Preparation of N-Benzyl-(S)-α,α-Diaryl-2-Pyrrolidinemethanols (3a and 3b)
To a solution of phenylmagnesium bromide in anhydrous THF (300 ml, 0.3 mol) was added
dropwise N-benzyl-l-proline methyl ester 2 (22.0 g, 0.1 mol) in anhydrous THF (100 ml)
over a period of 45 min with ice-water cooling. The reaction mixture was stirred for 1.5 h
at 0◦C and allowed warm to stir overnight at r.t., and the reaction mixture was refluxed for
30 min. The reaction was monitored by TLC (n-hexane/ethyl acetate 1:1 v/v). The reaction
was carefully quenched at 0◦C by addition of 30 mL of sat. NH4Cl (200 g NH4Cl in 100
mL). The solvent was evaporated under reduced pressure to give yellow foam, which was
dissolved in EtOAc (300 ml). After filtration, the filtrate was washed with water and brine
and dried over anhydrous Na2SO4. The solvent was evaporated to furnish a residue as light
yellow foam, which was purified by recrystallization from ether and n-hexane to yield
N-benzyl-α,α-diphenyl-l-prolinol 3a as colorless crystals. 3b was prepared by the same
procedure as 3a using 1-naphthylmagnesium bromide as Grignard reagent.
N-Benzyl-(S)-α,α-diphenyl-2-pyrrolidinemethanol (3a), Rf = 0.45, (n-hexane/ethyl
acetate 1:1 v/v), Yield: 27.1 g (79%), as colorless blocks, mp. 112–114◦C; [α]25 = +99◦
D
(c = 1.0, in CHCl3, lit.23 mp. 115–116◦C, [α]25 = +95◦); 1H NMR (500 MHz, CDCl3):
D
δ 1.53–1.56 (m, 2H, PhCH2), 1.65–1.69 (m, 1H), 1.83–1.91 (m, 1H), 2.24–2.29 (m, 1H),
2.81–2.84 (m, 1H), 2.93–2.95 (d, 1H, J = 12.5 Hz), 3.13–3.16 (d, 1H, J = 12.5 Hz),
3.87–3.90 (q, 1H, J = 4.5 Hz), 4.85 (s, 1H, OH), 6.95–7.22 (m, 11H, ArH), 7.49 (d, 2H,
J = 8.0 Hz, ArH),7.64 (d, 2H, J = 8.0 Hz, ArH); HRMS (ESI): m/z [M+H]+ calcd for
C24H26NO: 344.2009, Found: 344.2013.
N-Benzyl-(S)-α,α-di(1-naphthyl)-2-pyrrolidinemethanol (3b), Rf = 0.40, (n-hexane/
ethyl acetate 1:1 v/v), Yield: 23.9 g (54%), as colorless blocks, mp. 170.5-172.0◦C; [α]25
=
D