C2-Symmetric Bisamidines: Chiral Brønsted Bases Catalysing the Diels-Alder Reaction Of

Supporting Information

C2-symmetric bisamidines: Chiral Brønsted bases catalysing the Diels-Alder reaction of anthrones

Deniz Akalay, Gerd Dürner, Jan W. Bats and Michael W. Göbel*

Address: Johann Wolfgang Goethe University Frankfurt, Institute of Organic Chemistry and Chemical Biology, Max-von-Laue-Str. 7, D-60438 Frankfurt am Main, Germany.

Email: Michael W. Göbel* -

* Corresponding author

Table of Contents:

S2 Experimental Section

S2 General Methods

S2 Chiral Diamines 9

S3 C2-symmetric bisamidines 8

S6 Anthrone derivatives 1

S6 N-substituted maleimides 2

S8 General procedure for Diels-Alder reaction of 1 with 2.

S8 Diels-Alder adducts 3

S15 General procedure for kinetics of reaction 1a with 2a.

S16 Results for optimal reaction conditions

S17 Spectroscopic Data of Compounds

S44 Copies of chromatograms on chiral column

S59 X-Ray Data of 3k and 3m

S62 References

Experimental section

General Methods All NMR spectra were recorded on a 250 MHz, 300 MHz or 400 MHz spectrometer. 1H chemical shifts (δ) are quoted in parts per million downfield to tetramethylsilane, relative to CDCl3 (7.26 ppm) or DMSO (2.50 ppm) against an internal deuterium lock; multiplicities are indicated as s for singlet, d-doublet, dd-double doublet, t-triplet, sp-septet, m-multiplet, br s-broad singlet; J in Hz; 13C chemical shifts (δ) are reported with complete proton decoupling and are quoted in parts per million downfield to tetramethylsilane, relative to CDCl3 (t, 77.0 ppm) or DMSO (septet, 39.43 ppm) against an internal deuterium lock. FT-IR spectra were recorded as liquid films on NaCl plates or as KBr pellets (KBr); peaks are reported in cm-1, intensities are classified as strong (s), medium (m) and weak (w). Melting points are uncorrected. Analytical thin layer chromatography (TLC) with F254 indicator were used with visualization by UV light (254 nm).

Anhydrous dichloromethane and ethanol were stored over molecular sieves, anthrone (1a), maleimides 2a, 2d, 2e, and chiral diamine 9d*2HCl were purchased and used without further purification. CDCl3 was stored over molecular sieves and NaHCO3.

(2S,3S)-1,4-Bis(2-naphthylmethoxy)-2,3-diaminobutane (9b). The synthesis of 9b was carried out as in the reported procedure (32% over 9 steps) [1]. Colorless crystals; m.p. 110-111 °C (Lit. 100-102 °C) [1]; 1H NMR (250 MHz, CDCl3) δ 1.42 (br s, 4 H), 3.02-3.09 (m, 2 H), 3.46 (dd, J1 = 6.5 Hz, J2 = 9.3 Hz, 2 H), 3.55 (dd, J1 = 4.4 Hz, J2 = 9.1 Hz, 2 H), 4.66 (s, 4 H), 7.42-7.51 (m, 6 H), 7.75 (d, J = 0.5 Hz, 2H), 7.79-7.85 (m, 6 H); 13C NMR (63 MHz, CDCl3) δ 52.70, 73.39, 73.62, 125.68, 125.87, 126.11, 126.45, 127.67, 127.83, 128.20, 132.96, 133.21, 135.65; IR (KBr) 3367 (w), 3292 (w), 3049 (w), 2899 (m), 2855 (m), 1600 (w), 1506 (w), 1477 (w), 1439 (w), 1407 (w), 1347 (m), 1274 (w), 1246 (w), 1176 (w), 1119 (s), 1062 (w), 1042 (w), 1008 (w), 998 (w), 950 (w), 926 (w), 902 (m), 890 (w), 864 (s), 820 (s), 752 (s), 731 (w) cm-1; optical rotation: [α]D24 = +12.7 (c = 1.2 CHCl3, Lit. [α]D24 = -10.7* (c = 2.5 CHCl3) [1]); Anal. Calcd for C26H28N2O2: C, 77.97; H, 7.05; N, 6.99; Found: C, 77.95; H, 7.10; N, 6.82. *Note: The direction of the optical rotation deviates from reference [1]. However, the optical rotations of all intermediates leading from l-(+)-tartaric acid (R,R) to diamine 9b agree well with data given in [1].

(2S,3S)-1,4-Bis(tert-butyldiphenylsilyloxy)-2,3-diaminobutane (9c). The synthesis of 9c was carried out as in the reported procedure (29% over 9 steps) [1]. Colorless oil; 1H NMR (250 MHz, CDCl3) δ 1.05 (s, 18 H), 1.66 (br s, 4 H), 2.89-2.96 (m, 2 H), 3.55 (dd, J1 = 6.0 Hz, J2 = 10.0 Hz, 2 H), 3.63 (dd, J1 = 6.0 Hz, J2 = 10.0 Hz, 2 H), 7.31-7.45 (m, 12 H), 7.60-7.65 (m, 8 H); 13C NMR (63 MHz, CDCl3) δ 19.25, 26.90, 53.81, 66.72, 127.71, 129.71, 133.39, 133.41, 135.54; IR (Film) 3384 (w), 3071 (m), 3049 (m), 2958 (s), 2950 (s), 2891 (m), 2857 (s), 1589 (w), 1472 (m), 1428 (s), 1390(w), 1361 (w), 1261 (w), 1187 (w), 1112 (s), 1007 (w), 938 (w), 824 (m), 740 (m), 701 (s) cm-1; optical rotation: [α]D20 = +0.8 (c = 1.0 MeOH); ESI+ Mass Spectra m/z Calcd for C36H49N2O2Si2+: 597.3 (M+H+). Found: 597.5.

General Procedure for the synthesis of C2-symmetric bisamidines 8 as hydrochloride

After addition of 0.55 equiv malonodiimic acid diethyl ester dihydrochloride 10 [2] to a solution of diamine 9 in abs. ethanol (~ 0.1 M) the reaction mixture was stirred at 65 °C for 16 h. The crude reaction mixture was concentrated in vacuo, adsorbed on silica gel and purified by column chromatography (ethyl acetate/methanol eluent), which afforded bisamidine 8 as the hydrochloride salt.

The synthesis of 8a*HCl was carried out as in the reported procedure [2].

8b*HCl Yield 79%; yellowish foam; m.p. 63-66 °C; 1H NMR (250 MHz, DMSO) δ 3.51 (br s, 8 H), 3.88 (br s, 4 H), 4.10 (s, 1 H), 4.69 (br s, 8 H), 7.43-7.52 (m, 12 H), 7.80-8.06 (m, 20 H); IR (KBr) 3171 (m), 3050 (m), 2857 (m), 1589 (s), 1508 (m), 1368 (w), 1340 (w), 1271 (w), 1212 (w), 1171 (w), 1124 (m), 1102 (m), 952 (w), 894 (w), 856 (w), 816 (m), 751 (m) cm-1; optical rotation: [α]D20 = -15.9 (c = 1.0 MeOH); Anal. Calcd for C55H53ClN4O4: C, 75.97; H, 6.14; N, 6.44; Found: C, 75.77; H, 5.93; N, 6.66.

8c*HCl Yield 60%; yellowish foam; m.p. 68-71 °C; 1H NMR (250 MHz, DMSO) δ 0.95 (s, 36 H), 3.64 (br s, 8 H), 3.94 (br s, 4 H), 4.15 (s, 1 H), 7.35-7.48 (m, 24 H), 7.59-7.62 (m, 16 H), 7.83 (br s, 4 H); IR (KBr) 3178 (w), 3049 (w), 2929 (m), 2855 (m), 1588 (s), 1472 (w), 1427 (m), 1389 (w), 1362 (w), 1113 (s), 1007 (w), 937 (w), 883 (w), 823 (w), 739 (w), 701 (s) cm-1; optical rotation: [α]D20 = +22.3 (c = 1.2 MeOH); ESI Mass Spectra m/z Calcd for C75H93N4O4Si4+: 1225.6 (M-Cl-). Found: 1226.0.

ent-8d*HCl Yield 75%; yellowish foam; m.p. 248-250 °C (decomp.); 1H NMR (400 MHz, DMSO) δ 4.73 (s, 1 H), 5.80 (s, 4 H), 7.23 (t, J = 7.6 Hz, 4 H), 7.46 (t, J = 7.6 Hz, 4 H) 7.53 (d, J = 8.4 Hz, 4 H), 7.66 (t, J = 7.6 Hz, 4 H), 7.81 (t, J = 6.0 Hz, 4 H), 7.99 (t, J = 7.6 Hz, 8 H), 8.70 (br s, 4 H); IR (KBr) 3404 (w), 3133 (w), 3047 (m), 1584 (s), 1511 (m), 1490 (w), 1396 (w), 1383 (w), 1362 (w), 1320 (w), 1306 (w), 1260 (w), 1212 (w), 1166 (w), 1102 (m), 800 (m), 798 (m), 775 (s), 735 (w) cm-1; optical rotation: [α]D20 = +227.2 (c = 0.5 MeOH); Anal. Calcd for C47H37ClN4: C, 81.43; H, 5.38; N, 8.08; Found: C, 81.22; H, 5.52; N, 8.04.

General Procedure for the deprotonation of 8*HCl

A two-phase mixture of 8*HCl in CH2Cl2 (~ 0.05 M) and saturated Na2CO3 aqueous solution (1:1) was stirred for 30 minutes. The separated aqueous phase was extracted with dichloromethane. The combined organic phase was dried over MgSO4 and concentrated in vacuo to give neutral bisamidine 8.

The synthesis of 8a was carried out as in the reported procedure [2].

8b Yield 93%; yellowish foam; m.p. 127-128 °C; 1H NMR (250 MHz, CDCl3) δ 1.68 (br s, 2 H), 3.24 (s, 2 H), 3.45 (br s, 8 H), 3.82 (br s, 4 H), 4.60 (br s, 4 H), 7.36-7.48 (m, 12 H), 7.68-7.82 (m, 16 H); IR (KBr) 3050 (w), 2919 (s), 2850 (s), 1579 (s), 1560 (m), 1508 (w), 1450 (m), 1124 (s), 1095 (s), 1018 (s), 854 (w), 817 (w), 749 (w) cm-1; optical rotation: [α]D20 = +93.2 (c = 1.0 MeOH); Anal. Calcd for C55H52N4O4: C, 79.30; H, 6.29; N, 6.73; Found: C, 79.24; H, 6.34; N, 6.59.

8c Yield 95%; yellowish foam; m.p. 48-51 °C; 1H NMR (250 MHz, CDCl3) δ 0.44 (br s, 2 H), 0.99 (s, 36 H), 3.11 (s, 2 H), 3.59-3.94 (m, 12 H), 7.27-7.41 (m, 24 H), 7.60-7.65 (m, 16 H); IR (KBr) 3070 (w), 3048 (w), 2929 (m), 2856 (m), 1618 (w), 1472 (w), 1427 (m), 1389 (w), 1362 (w), 1113 (s), 998 (w), 823 (w), 739 (w), 700(s) cm-1; optical rotation: [α]D20 = +50.0 (c = 1.0 MeOH); Anal. Calcd for C75H92N4O4Si4: C, 73.48; H, 7.56; N, 4.57; Found: C, 73.22; H, 7.65; N, 4.41.

ent-8d Yield 100%; yellowish foam; m.p. 138-140 °C; 1H NMR (250 MHz, CDCl3) δ 3.85 (br s, 2 H), 4.44 (br s, 2 H), 5.65 (s, 4 H), 7.05-7.10 (m, 4 H), 7.32-7.47 (m, 12 H), 7.60-7.63 (m, 4 H), 7.75-7.82 (m, 12 H); IR (KBr) 3396 (w), 3046 (m), 2930 (w), 1617 (s), 1596 (s), 1510 (m), 1458 (m), 1396 (m), 1383 (w), 1356 (w), 1312 (w), 1257 (w), 1216 (w), 1165 (w), 1082 (w), 1002 (w), 858 (w) cm-1; optical rotation: [α]D20 = +134.0 (c = 0.25 MeOH); ESI Mass Spectra m/z Calcd for C47H36N4+: 657.3 (M+H+). Found: 657.4. Calcd for ([M+2H+]/2): 329.2, Found: 329.3. Calcd for ([M+2H+-CH2]/2): 322.1, Found: 323.0.

The synthesis of 1b and 1c was carried out as in the reported procedure [3,4].

4,5-dichloro-10H-anthracen-9-one (1b). Yield: 53%; yellow crystals; m.p. 197-198 °C (acetone, Lit. 194 °C) [3]; 1H NMR (250 MHz, CDCl3) δ 4.26 (s, 2 H), 7.47 (t, J = 7.9Hz, 2 H), 7.71 (dd, J1 = 1.4 Hz, J2 = 7.9Hz, 2 H), 8.30 (dd, J1 = 1.4 Hz, J2 = 7.9Hz, 2 H); 13C NMR (63 MHz, CDCl3) δ 29.45, 126.36, 128.07, 132.83, 133.70, 134.16, 137.30, 182.69; IR (KBr) 3081 (w), 1659 (s), 1591 (s), 1560 (w), 1458 (w), 1442 (w), 1391 (m), 1339 (w), 1312 (s), 1284 (w), 1168 (w), 1135 (s), 1071 (w), 961 (w), 915 (w), 871(m), 820 (m), 786 (w), 743 (s) cm-1; Calcd for C14H8Cl2O: C, 63.91; H, 3.06; Found: C, 63.65; H, 3.11.

1,8-dichloro-10H-anthracen-9-one (1c). Yield 20%; yellow crystals; m.p. 166-168 °C (dichloromethane/n-hexane, Lit. 167-168 °C) [4]; 1H NMR (250 MHz, CDCl3) δ 4.20 (s, 2 H), 7.29-7.46 (m, 6 H); 13C NMR (63 MHz, CDCl3) δ 33.86, 126.25, 130.23, 131.78, 132.01, 133.51, 140.80, 183.45; IR (KBr) 3069 (w), 2861 (w), 1676 (s), 1592 (s), 1560 (w), 1508 (w), 1454 (w), 1437 (m), 1406 (w), 1334 (w), 1296 (w), 1255 (m), 1190 (w), 1162 (w), 1140 (w), 944 (w), 916 (w), 882 (w), 769 (s), 753 (s), 692 (w), 681 (m) cm-1; Anal. Calcd for C14H8Cl2O: C, 63.91; H, 3.06; Found: C, 64.00; H, 3.08.

N-substituted maleimides 2. The synthesis of 2 was carried out as in the reported procedure [5-7].

2b Yield 67%; colorless oil; 1H NMR (250 MHz, CDCl3) δ 1.38 (d, J = 6.8 Hz, 6 H), 4.32 (sp, J = 6.9 Hz, 1H), 6.61 (s, 2 H); 13C NMR (63 MHz, CDCl3) δ 20.11, 42.96, 133.93, 170.80; IR (film) 3456 (m), 3102 (m), 2978 (m), 2940 (m), 2882 (m), 1765 (m), 1702 (s), 1596 (w), 1459 (m), 1407 (s), 1385 (s), 1367 (s), 1294 (w), 1207 (m), 1182 (w), 1117 (m), 1021 (m), 988 (m), 879 (w), 829 (s) cm-1. Mass spectra m/z calcd for C7H10NO2+: 140.1 (M+H+). Found: 140.1, m/z calcd for C7H9NO2+: 139.1 (M+). Found: 139.1, m/z calcd for C6H6NO2+: 124.0 (M+-CH3). Found: 124.1, m/z calcd for C4H4NO2+: 98.0 (Maleimide+H+). Found: 98.0, m/z calcd for C4H2NO2+: 96.0 (M+-iPr). Found: 96.1.

2c Yield 14%; colorless oil; 1H NMR (250 MHz, CDCl3) δ 1.58 (s, 9 H), 6.51 (s, 2 H); 13C NMR (63 MHz, CDCl3) δ 28.87, 57.37, 133.89, 172.15; IR (film) 3454 (w), 3104 (w), 2977 (m), 1707 (s), 1603 (w), 1459 (m), 1390 (w), 1351 (s), 1260 (w), 1211 (m), 1140 (s), 1079 (w), 1003 (w), 984 (m), 829 (m), 692 (s) cm-1; Anal. Calcd for C8H11NO2: C, 62.73; H, 7.24; N, 9.14; Found: C, 62.53; H, 7.42; N, 9.09.

2f Yield 28%; colorless crystals; m.p. 144-146 °C (MeOH, Lit. 139-141 °C) [8]; 1H NMR (250 MHz, CDCl3) δ 6.51 (s, 1 H), 6.71 (s, 2 H), 7.27-7.38 (m, 10 H); 13C NMR (63 MHz, CDCl3) δ 57.61, 127.74, 128.40, 128.52, 134.16, 138.05, 170.30; IR (KBr) 3096 (m), 3026 (m), 1698 (s), 1598 (w), 1491 (m), 1448 (w), 1399 (s), 1362 (s), 1314 (w), 1260(w), 1203 (w), 1150 (s), 1112 (w), 1082 (w), 1026 (m), 918 (w), 868 (m), 832 (s), 796 (m), 752 (m), 731 (m), 699 (s) cm-1; Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32; Found: C, 77.43; H, 5.14; N, 5.21.

2g Yield 55%; yellow crystals; m.p. 122-124 °C (2-propanol, Lit. 118-120 °C) [9]; 1H NMR (250 MHz, CDCl3) δ 6.86 (s, 2 H), 7.23-7.29 (m, 2 H), 7.56-7.62 (m, 2H); 13C NMR (63 MHz, CDCl3) δ 121.57, 127.33, 130.26, 132.27, 134.28, 169.03; IR (KBr) 1708 (s), 1560 (w), 1490 (s), 1389 (m), 1212 (w), 1153 (m), 1065 (w), 1013 (w), 950 (w), 827 (m), 733 (w), 712 (m), 687 (m) cm-1; Anal. Calcd for C10H6BrNO2: C, 47.65; H, 2.40; N, 5.56; Found: C, 47.74; H, 2.47; N, 5.48.

2h Yield 35%; yellow crystals; m.p. 146-148 °C (EtOH, Lit. 148 °C) [10]; 1H NMR (250 MHz, CDCl3) δ 3.83 (s, 3 H), 6.83 (s, 2 H), 6.95-7.01 (m, 2 H), 7.20-7.26 (m, 2 H); 13C NMR (63 MHz, CDCl3) δ 55.47, 114.46, 123.73, 127.55, 134.10, 159.14, 169.78; IR (KBr) 3109 (w), 2966 (w), 2836 (w), 1707 (s), 1607 (w), 1587 (w), 1510 (s), 1450 (w), 1441 (w), 1414 (m), 1400 (m), 1304 (m), 1249 (s), 1180 (w), 1166 (m), 1159 (m), 1106 (w), 1055 (w), 1029 (m), 962 (w), 955 (w), 940 (w), 838 (m), 828 (m), 800 (w), 722 (w), 687 (w) cm-1; Anal. Calcd for C11H9NO3: C, 65.02; H, 4.46; N, 6.89; Found: C, 64.90; H, 4.55; N, 6.78.

2i Yield 53%; yellow crystals; m.p. 114-116 °C (n-hexane, Lit. 111-114 °C) [7]; 1H NMR (250 MHz, CDCl3) δ 1.16 (d, J = 7.0 Hz, 12 H), 2.62 (sp, J = 6.9 Hz, 2 H), 6.88 (s, 2 H), 7.24-7.27 (m, 2 H), 7.40-7.46 (m, 1 H); 13C NMR (63 MHz, CDCl3) δ 23.91, 29.29, 123.97, 126.17, 130.21, 134.26, 147.46, 170.50; IR (KBr) 3468 (w), 3091 (w), 2967 (m), 2930 (w), 2872 (w), 1710 (s), 1459 (m), 1391 (m), 1375 (m), 1250 (w), 1157 (w), 1157 (m), 1056 (w), 1033 (w), 950 (w), 937 (w), 834 (m), 802 (m), 755 (w), 690 (m) cm-1; Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.54; H, 7.24; N, 5.26.

General procedure for the Diels-Alder reaction of anthrone derivatives 1 with N-substituted maleimides 2. 0.1 mmol of maleimide 2, 1.1 equiv of corresponding anthrone 1 and catalyst 8 were cooled to the indicated temperature. After addition of temperated CH2Cl2 (abs., 1 mL) the solution was stirred as described in table 4. The crude reaction mixture was purified by column chromatography (ethyl acetate/n-hexane eluent) to afford 3 as colorless crystalline solid. The racemic compound was prepared with triethylamine (10 μl) instead of bisamidine. After 30 minutes the crude product was also purified by flash column chromatography.