A contribution from the Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, Saint Louis, Missouri 63130

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1 BENZOTETRAMISOLE (BTM): A REMARKABLY ENANTIOSELECTIVE ACYL TRANSFER CATALYST Vladimir B. Birman* and Ximin Li A contribution from the Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, Saint Louis, Missouri SUPPORTING INFORMATION: Experimental procedures (8 pages), 1 H NMR and 13 C NMR spectra (10 pages). EXPERIMENTAL PART. 1. General. All reagents were obtained commercially and used as received unless otherwise specified. Catalysts 1 6 and 2 5g were prepared as previously described. Substrate 6b was prepared according to a known procedure. 16 Substrate 7b 17 was prepared by addition of tert- BuMgCl to 2-naphthaldehyde. All other substrates were purchased or prepared as reported earlier. 6,5g A description of other general experimental details is given in Ref. 5g. 2. Preparation of Tetramisole Base. 25.2mg (0.105 mmol) (-)-Tetramisole hydrochloride (Sigma-Aldrich) was dissolved in 1 ml of water and treated with 2 ml of 33% aqueous NaOH. The solution was extracted with CH 2 Cl 2 several times. The extract was dried over Na 2 SO 4 and rotary evaporated to afford 20.2 mg (94% yield) of (S)-tetramisole base (4). 3. Preparation of (R)-Benzotetramisole (R)-N-(Thiazolyl-2)-2-hydroxy-1-phenylethylamine (15) S N Cl + H 2 N Ph OH i-pr 2 NEt 130±5 C S N NH Ph OH A 30-mL pressure tube charged with 2-chlorobenzothiazole (1.72 g, 10.1 mmol), (R)-(+)- phenylglycinol (1.42 g, 10.4 mmol), i-pr 2 NEt (2.7 ml, 15 mmol) and a stir bar was flushed with nitrogen several times, stoppered and heated at 130 ± 5 C for 19 hours. After cooling the tube to C, the viscous reaction mixture was treated with 5 ml of CH 2 Cl 2 and left at room temperature to dissolve (2-3 hours or overnight). The diluted reaction mixture was applied directly to a chromatographic column (silica gel, 2 in wide, 6 in long) and eluted with 4% isopropanol in CH 2 Cl 2 to afford 2.27 g of white solid (83% yield). 1 H NMR (300 MHz, CD 3 OD): d 7.55 (d, J = 8.0 Hz, 1H), (m, 7H), 7.03 (t, J = 7.1 Hz, 1H), 5.00 (dd, J 1 = 7.1 Hz, J 2 = 5.2 Hz, 1H), (m, 2H); 13 C NMR (75 MHz, CD 3 OD): d 169.2, 153.1, 141.2, 131.5, 129.7, 128.7, 128.2, 127.0, 122.8, 121.9, 119.2, 67.0, 62.4; IR (film, cm -1 ) (br), 1538, 1447; MS: HR-FAB calculated for C 15 H 14 N 2 OSLi (M+Li + ) m/z: , found: ; mp C; [a] D = (c 0.99, MeOH). S1

2 (R)-2, 3-dihydro-2-phenyl-imidazo[2,1-b]benzothiazole (Benzotetramisole, 16) S N 15 NH OH Ph MsCl, NEt 3 CH 2 Cl 2, 0 C; then reflux S N 16: BTM N Ph A solution of 1.35 g (5.0 mmol) of 15 in anhydrous CH 2 Cl 2 (50 ml) was cooled to 0 C under N 2 atmosphere and treated with NEt 3 (2.09 ml, 15.0 mmol) followed by MsCl (0.58 ml, 7.5 mmol). The mixture was stirred at 0 C for 1 h and then warmed up to room temperature. Methanol (0.3 ml) was then added to quench the excess MsCl. NEt 3 (7 ml) was added and the mixture was refluxed overnight. The cooled mixture was washed with a small amount of water, dried over Na 2 SO 4 and rotary evaporated. The crude product was purified by chromatography (5% i-proh, 1% NEt 3 /hexanes) to give 1.22 g of white solid (97% yield). The compound was recrystallized from Et 2 O/hexanes to produce g of the 1 st crop of the product (mp C), g of the 2 nd crop (mp C) and g of the 3 rd crop (mp C). The 1 st crop and the recrystallized 2 nd crop (mp C) were used in kinetic resolution experiments. 1 H NMR (300 MHz, CDCl 3 ): d (m, 6H), 7.19 (td, J 1 = 7.7 Hz, J 2 = 1.1 Hz, 1H), 6.98 (td, J 1 = 7.7 Hz, J 2 = 1.4 Hz, 1H), 6.67 (dd, J 1 = 8.0 Hz, J 2 = 0.8, Hz, 1H), 5.67 (dd, J 1 = 10.3 Hz, J 2 = 8.2 Hz, 1H), 4.29 (dd, J 1 = 10.3 Hz, J 2 = 8.8 Hz, 1H), 3.72 (dd, J 1 = 8.8 Hz, J 2 = 8.2 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): d 166.6, 143.0, 137.0, 128.7, 127.5, 127.2, , , 123.1, 121.4, 108.5, 75.3, 52.4; IR (film, cm -1 ) 1593, 1574, 1466; MS: HR-FAB calculated for C 15 H 12 N 2 S Li (M+Li + ) m/z: , found: ; mp C; [a] D = (c 1.00, MeOH). 4. Kinetic resolution experiments. Workup and HPLC analysis procedures have been described in earlier work. 5g,6a Experimental Conditions. Procedure A: The Enantioselectivity test. The procedure described earlier 6b was followed. The stock solution of each catalyst was prepared by dissolving mmol of the catalyst (1,2, 4 and 14) and 131 mg (0.75 mmol) of i-pr 2 NEt in CDCl 3 in a 1.00 ml volumetric test tube and bringing the volume to the mark. A one dram vial was charged with 68 mg (0.50 mmol) of (±)- phenylethyl carbinol and 0.50 ml of the stock solution of the catalyst. 48 ml (0.375 mmol) of propionic anhydride was added (at which point the timing was started), the contents was mixed and transferred into a 5 mm NMR tube. The reaction was monitored by 1 H NMR at room temperature by comparing integration values of peaks at d 4.5 ppm and d 5.6 ppm and stopped by pouring the contents into a vial with MeOH upon reaching conversion of 45-50%. The workup and HPLC analysis followed the standard procedure. S2

3 Table 1S. Entry Catalyst Time # ee E ee A C HPLC % % % s (S)-4 4 h (R)-16 1 h C AVG % s AVG Procedure B: Use of (S)-Tetramisole at 0 C. A one-dram vial was charged with 0.50 mmol of a racemic substrate, 0.50 ml of the stock catalyst solution (0.10 M of 4 and 0.75 M of i-pr 2 NEt in CDCl 3 ) and cooled in an ice bath for 15 minutes before adding 48 ml (0.375 mmol) of propionic anhydride. The mixture was swirled and left in the ice bath for a specified period of time, and then quenched with 0.5 ml of methanol, worked up and analyzed by HPLC. In all cases, the product was enriched in the S- enantiomer, and the recovered starting material, in the R-enantiomer. Table 2S. Entry Substrate Time # ee E ee A C HPLC % % % s 1 5b 6 h a 6 h a 3.75 h h C AVG % s AVG Procedure C1: Influence of Moisture and Drying Agents. Eight one-dram vials were each charged with 0.50 mmol of (±)-phenylethyl carbinol, 2.00 ml of the stock catalyst solution (0.010 M of 16 and M of i-pr 2 NEt in CDCl 3 ) and a stir bar and divided into four pairs. A droplet of water (20 ml) was added to each of the first pair of vials, 20 mg of 4Å molecular sieves to each of the second pair, and 100 mg of Na 2 SO 4 to each of the third pair. The fourth pair was left without any additives and used as a control. After stirring for 15 min at room temperature, 48 ml (0.375 mmol) of propionic anhydride was added to each of the vials. The reactions were monitored by periodically withdrawing aliquots and checking them by 1 H NMR. The reactions were stopped by quenching with methanol after reaching ca. 50% conversion or when no progress was observed for 1h. The workup and HPLC analysis followed the standard procedure. S3

4 Table 3S. Entry Additive Time # ee E ee A C HPLC % % % s 1 None 2.75 h H 2 O 2.25h Å molecular h sieves Na 2 SO h C AVG % s AVG Procedure C2: Variation of the solvent. Stock catalyst solutions in five different solvents containing M of 16 and M of i- Pr 2 NEt were prepared. Five pairs of vials, each charged with 0.25 mmol of (±)-phenylethyl carbinol, 100 mg of Na 2 SO 4, 1.00 ml of the respective stock catalyst solution and a stir bar, were stirred at room temperature. 24 ml (0.188 mmol) of propionic anhydride was added to each vial. The reactions were monitored by periodically withdrawing aliquots and checking them by 1 H NMR. The reactions were stopped by quenching with methanol after 24 h or after reaching ca. 50% conversion. The workup and HPLC analysis followed the standard procedure. In the case of reactions carried out in THF and Et 2 O, HPLC analyses were not performed due to the very low conversion levels. Table 4S. Entry Solvent Time # ee E ee A C HPLC % % % s 1 CH 2 Cl 2 7 h tert-amyl h alcohol PhMe 24 h THF 24 h 1 nd nd <1 a nd 2 nd nd <1 a nd 5 Et 2 O 24 h 1 nd nd 2 a nd 2 nd nd 2 a nd a ) estimated from 1 H NMR spectrum of the crude reaction mixture C AVG % s AVG nd 2 nd Procedure C3: Variation of the anhydride. Six one-dram vials, each charged with 0.25 mmol of (±)-phenylethyl carbinol, 100 mg of Na 2 SO 4, 1.00 ml of the stock catalyst solution (0.010 M of 16 and M of i-pr 2 NEt in CDCl 3 ) and a stir bar, were divided into three pairs and stirred at room temperature mmol of acetic, isobutyric and benzoic anhydrides were added, respectively, to each of the first, the second, and the third pairs of vials. The reactions were monitored by periodically withdrawing aliquots and checking them by 1 H NMR. The reactions were stopped by quenching with S4

5 methanol after 24 h or after reaching 45-50% conversion. The workup and HPLC analysis followed the standard procedure. Table 5S. Entry Anhydride Time # ee E ee A C HPLC % % % s 1 (MeCO) 2 O 4 h (i-prco) 2 O 18 h (PhCO) 2 O 24 h C AVG % s AVG Procedure D1: Use of BTM under anhydrous conditions. Propionic anhydride. Chloroform (OmniSolv), chloroform-d (Sigma-Aldrich) and N,N-diisopropylethylamine (Sigma- Aldrich) used for KR experiments were distilled from CaH 2. Propionic and isobutyric anhydrides were taken from recently opened bottles or distilled under reduced pressure if significant amounts of the carboxylic acids (>5%) were found by 1 H NMR analysis. Two or three one-dram vials were each charged with 0.25 mmol of a racemic substrate, 100 mg of Na 2 SO 4, 1.00 ml of the stock solution of the catalyst (0.010 M of 16 and M of i-pr 2 NEt in CHCl 3 ) and a stir bar, closed with a rubber septum and stirred in an ice bath for 15 minutes. Propionic anhydride (24 ml, mmol) was added via syringe through the septum. The reactions were monitored by periodically withdrawing aliquots and checking them by 1 H NMR. In the case of substrates 5d, 6b and 10, additional stock catalyst solution (40 ml, 0.25 M) was added after 12 h. The reactions were stopped by quenching with methanol after reaching ca. 50% conversion. The workup and HPLC analysis followed the standard procedure. Table 6S. Entry Substrate Time # ee E ee A C HPLC % % % s 1 5a 24 h b 33 h c 36 h a) 5d 48 h a 8.5 h a 10.5 h C AVG % s AVG S5

6 h 8 a) 6b 32 h 9 7b 32 h h 11 a) h a ) 4 mol% (R)-16 added after 12 h Procedure D2: Anhydrous conditions. Control experiment with catalysts 1, 2 and 4. Procedure D1 was followed exactly, except that catalysts 1 (0.010 M), 2 (0.010 M) or 4 (0.025 M) were used instead of BTM 16 and (±)-phenylethyl carbinol was used as the substrate in all experiments. Table 7S. Catalyst ee Entry Catalyst Time # E ee A C HPLC s loading % % % (R)-1 4 mol% 12 h (R)-2 4 mol% 3.5 h 3 (S)-4 10 mol% 10.5 h C AVG % s AVG Procedure D3: Use of BTM under anhydrous conditions. Isobutyric anhydride. Procedure D1 was followed exactly, except that isobutyric anhydride was used instead of propionic. Table 8S. Entry Substrate Time # ee E ee A C HPLC % % % s a 33 h b 36 h a 8.75 h a 10.5 h C AVG % s AVG S6

7 h 6 a ) 5d 48 h 7 a ) 6b 48 h a ) 4 mol% (R)-16 added after 12 h Procedure E: Use of isobutyric anhydride with CF 3 -PIP. The previously published set of conditions 6a was followed exactly, except that isobutyric anhydride was used instead of propionic. Two one-dram vials were each charged with 0.50 mmol of (±)-phenylethyl carbinol and 0.50 ml of the stock catalyst solution (0.020 M of 1 and 0.75 M of i-pr 2 NEt in CHCl 3 ) and cooled in an ice bath. After 15 minutes, mmol of isobutyric anhydride was added to each vial. The vials were swirled and left in the ice bath for 8 h, whereupon the reaction mixtures were quenched by rapid addition of 0.5 ml of methanol, allowed to warm slowly and left for one more hour at room temperature. The workup and HPLC analysis followed the standard procedure. Table 9S. Expt ee E ee A C HPLC # % % % s C AVG % s AVG Table 10S. HPLC separation and properties of alcohol substrates. Substrate OH Bu t 6b OH Bu t 7b OH Me Me 8 Retention time (min) HPLC conditions (R)-ent (S)-ent 5% IPA/hexane OD-H 5% IPA/hexane OD-H 2% IPA/hexane AD-H Unreacted alcohol Sign of rotation Absolute Configuration ( ) S ( ) S ( ) S 19 S7

8 Me Me 9 OH Me Me 2% IPA/hexane AD-H ( ) S 20 HPLC separation of enantiomers was achieved by eluting free alcohols on CHIRALPAK AD and CHIRALCEL OD-H analytical columns (4.6x250 mm, Chiral Technologies, Inc.) with isopropanol/hexane eluent of the concentration indicated at 1 ml/min flow rate. Spectral data for previously unreported compounds. Propionate of 6b: 1 H NMR (300 MHz, CDCl 3 ): d 8.52 (d, J = 7.4 Hz, 1H), (m, 2H), (m, 4H), 6.53 (broad s, 1H), (m, 2H), 1.16 (t, J = 7.7 Hz, 3H), 1.01 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ): d 173.8, 135.5, 133.6, 132.2, 128.9, 128.3, 126.1, 125.5, 124.9, 124.0, 76.8 (broad), 36.5, 28.1, 26.7, 9.3; IR (film, cm -1 ) 2972, 1737, 1180; MS: HR-FAB calculated for C 18 H 22 O 2 Li (M+Li + ) m/z: , found: Isobutyrate of 6b: 1 H NMR (300 MHz, CDCl 3 ): d 8.26 (d, J = 8.2 Hz, 1H), (m, 2H), (m, 4H), 6.51 (broad s, 1H), 2.64 (m, J = 7.0 Hz, 1H), 1.23 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.02 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ): d 176.2, 135.6, 133.6, 132.2, 129.0, 128.3, 126.2, 125.5, 125.3, 124.9, 124.0, 76.7 (broad), 36.6, 34.5, 26.7, 19.2, 19.1; IR (film, cm -1 ) 2971, 1734, 1191, 1153; MS: HR-FAB calculated for C 19 H 24 O 2 Li (M+Li + ) m/z: , found: Propionate of 7b: 1 H NMR (300 MHz, CDCl 3 ): d (m, 4H), (m, 3H), 5.69 (s, 1H), (m, 2H), 1.19 (t, J = 7.6 Hz, 1H), 1.00 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ): d 173.7, 163.4, 133.1, 133.0, 128.2, 127.8, 127.3, 126.9, 126.2, 126.0, 82.9, 35.6, 28.1, 26.4, 9.4; IR (film, cm -1 ) 2972, 1738, 1181; MS: HR-FAB calculated for C 18 H 22 O 2 Li (M+Li + ) m/z: , found: ; mp (racemic compound) C. ADDITIONAL REFERENCES 16 Pomares, M.; Grabuleda, X.; Jaime, C.; Virgili, A.; Alvarez-Larena, A; Piniella, J. F. Magn. Reson. Chem. 1999, 37, Jeong, K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-J.; Kim, K. S. Chem. Lett. 2002, The absolute configuration was assigned by Mosher ester analysis: Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003, 125, Corey, E. J.; Cheng, X.-M.; Cimprich, K.A.; Sarshar, S. Tetrahedron Lett. 1991, 32, S8

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