| 79% |
With N-ethyl-N,N-diisopropylamine; 1,2-dichloro-benzene; In toluene; at 195℃; for 24h;Dean-Stark; |
A 250 mL round-bottomed flask containing a stirrer bar was chargedwith (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), odichlorobenzene(34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5equiv), and <strong>[615-20-3]2-chlorobenzothiazole</strong> (1; 8.60 mL, 69.43 mmol, 1.0equiv). The resulting yellow suspension was stirred vigorously andheated to reflux at 195 C (DrySyn temperature), at which point thesuspended solid had dissolved to leave a yellow solution. After 24 h atreflux,24 the orange reaction mixture was allowed to cool to r.t. Oncecooled, the mixture was diluted with distilled H2O (100 mL) and toluene(75 mL) with vigorous stirring. A precipitate formed over the next15 min and stirring was maintained for a further 1 h. The reactionmixture was filtered through a 1.0 L sintered glass filter funnel (porosity3) under vacuum to leave the solid precipitate. The solid waswashed with toluene (2 × 100 mL) and dried on the sinter under vacuumfor 30 min until a free-flowing powder was obtained. The crudeproduct (typically 22-24 g) was transferred to a 500 mL round-bottomedflask containing a stirrer bar, followed by toluene (100 mL). A10 mL Dean-Stark trap filled with toluene and a reflux condenserwere fitted to the flask, and the suspension heated to reflux (180 CDrySyn temperature). Once at reflux, further 10 mL portions of toluenewere added down the condenser, waiting ~5 min between portions,until a clear solution was obtained (4-6 portions were typicallyneeded). The reflux was maintained until no further H2O was observedcondensing into the trap (typically 30 min were sufficient).The flask was removed from the heating block and allowed to coolslowly to r.t., over which time a precipitate formed. Once cooled, theflask was further cooled to -10 C in a NaCl/ice/water bath for 30 min.The solid precipitate was recovered by vacuum filtration on a 1.0 Lsintered glass filter funnel (porosity 3), and washed with further portionsof toluene (2 × 100 mL). The solid was dried on the sinter undervacuum for 30 min, then transferred to a 250 mL round-bottomedflask and dried in vacuo to constant weight. This gave title compound(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A secondrecrystallisation from toluene at reflux may be required if a powderis obtained from the first attempt. Typical mass loss on secondrecrystallisation was 99% ee.1H NMR (500 MHz, MeOH-d4): delta = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55(1 H, d, J = 7.8 Hz, ArH).13C{1H} NMR (126 MHz, MeOH-d4): delta = 62.2, 66.9, 119.0, 121.7, 122.7,126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,66.57; H, 5.31; N, 10.33.1H and 13C NMR data were consistent with literature values.1 |
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