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Intramolecular Diels-Alder Chemistry of 4-Vinylimidazoles
Yong He, Pasupathy Krishnamoorthy, Heather M. Lima, Yingzhong Chen, Haiyan Wu, Rasapalli Sivappa,‡ H.V. Rasika Dias,* and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
General Experimental:
All chemicals were purchased from commercial vendors and were used as received unless stated
otherwise. All reactions were conducted under an atmosphere of dry nitrogen or argon in oven-
dried glassware unless stated otherwise. Solvents were dried using a Pure-Solv 400 solvent
purification system (Innovative Technology, Inc.), except for DMF, which was dried over CaH2
and then distilled under vacuum. The 1H NMR spectra were acquired at 300 or 500 MHz in
CDCl3, unless indicated otherwise, using residual CHCl3 as reference. 13C NMR spectra were
obtained at 75 or 125 MHz in CDCl3, unless otherwise indicated, using solvent as internal
standard. Low resolution mass spectra were obtained in-house by electron impact or
electrospray methods (MS-EI or MS-ESI), high resolution mass spectra were obtained at the
University of Florida Mass Spectrometry Laboratory by electrospray ionization (HRMS-ESI).
The methyl esters and alcohols were prepared from urocanic acid by procedures described in the
literature.1-3
General Procedure A for alkylation (and some acylations) reactions (GP-A): A THF (5
mL) solution of alcohol 5 (183 mg, 0.50 mmol) was cooled in an ice bath for 20 min. NaH (34
mg, 60% suspension in mineral oil, ~0.85 mmol) was added to the flask in two portions, and
the flask was purged with nitrogen after the addition was completed. The solution was held in
the ice bath for 1 h. The neat alkyl halide (0.50 mmol) was added dropwise by syringe. The ice
bath was removed after 10 min and the reaction flask was allowed warm up to room
temperature.4 Tetrabutylammonium iodide (50 mg, 0.13 mmol) was added and stirring was
continued until the reaction was deemed complete by TLC analysis (12-36 h). Water (5 mL)
was added to quench the reaction with the flask in an ice bath. After the mixture was stirred for
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
20 min, the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layer
was washed with water (2 x 6 mL) then dried (MgSO4) and concentrated. The EtOAc solution
was concentrated and the residue was purified by flash column chromatography.
General Procedure B for N-acylation reactions with acid chlorides (GP-B): The appropriate
acyl chloride (1.05 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of the amine (1.00
mmol) and sodium bicarbonate (101 mg, 1.20 mmol) in CH2Cl2 (3 mL) at 0 ºC. After the
completion of addition, the reaction was allowed to warm up to room temperature and stirred for
several hours until completion (TLC). The reaction mixture was diluted with CH2Cl2 (5 mL),
washed with water (2x5 mL), brine, dried (Na2SO4) and concentrated. Purification of the crude
sample by chromatography gave the corresponding N-acylated product.
General Procedure C for EDCI coupling reactions (GP-C): The alcohol or amine (1.00
mmol), EDCI (287 mg, 1.50 mmol) and acid (1.50 mmol) were dissolved in anhydrous CH2Cl2
(10 mL). The solution was cooled to 0 ºC and DMAP (183 mg, 1.50 mmol) was added in one
portion. The solution was allowed to warm to room temperature and stirred overnight. On
completion of the reaction (TLC), the reaction mixture was diluted with CH2Cl2, washed with
water (3x5 mL), brine, dried (Na2SO4) and concentrated. The residue was purified by
chromatography to afford the pure ester or amide.
General Procedure D for DCC coupling reactions (GP-D): Allylic alcohol (2.0 mmol),
DMAP (10 mg) and acid (3.0 mmol) were dissolved in CH2Cl2 (3 mL). The solution was cooled
to -78 ºC and DCC (500 mg, 2.4 mmol) in CH2Cl2 (1.5 mL) was added by cannula. The solution
was allowed to warm to room temperature over a period of 3-4 h. On completion of the reaction
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
(TLC), the reaction mixture was filtered through Celite and washed with CH2Cl2. The combined
filtrates were evaporated under vacuum and the residue purified by chromatography to afford the
pure ester.
General procedure for thermal Diels-Alder reactions: The Diels-Alder substrate was
dissolved in the appropriate solvent (usually benzene) to prepare a ~0.1 M solution in a pressure
tube with a Teflon screw-cap. The solution was degassed by bubbling N2 or Ar gas through it for
a few minutes and then the tube was sealed. The mixture was heated at the indicated temperature
and the reaction was monitored by TLC or 1H NMR spectroscopy of the crude reaction mixture.
On completion of the reaction, the solvent was removed by rotary evaporation followed by
purification of the residue by chromatography to afford the cycloadducts.
E-3-(1-Triphenylmethylimidazol-4-yl)-2-propenyl 2-propenyl Ether (14a): Prepared
according to GP-A with allyl bromide (62 mg, 0.50 mmol), yield (122 mg,
60%). mp 135-137 C; 1H NMR: 7.40 (s, 1H), 7.36-7.31 (m, 9H), 7.15-7.11
(m, 6H), 6.75 (s, 1H), 6.46 (d, J = 15.7 Hz, 1H), 6.39 (dt, J = 15.7, 5.5 Hz, 1H), 5.92 (m, 1H),
5.27 (dd, J = 17.2, 1.4 Hz, 1H), 5.16 (dd, J = 10.3, 1.4 Hz, 1H), 4.15 (d, J = 5.5 Hz, 2H), 4.00
(dd, J = 5.5, 1.4 Hz, 2H); 13C NMR: 142.3, 135.0, 129.8, 129.7, 128.2, 119.4, 116.9, 75.2,
71.0, 70.6; IR (KBr, cm-1): 3082, 1107; Anal. Calcd For C28H26N2O: C, 82.73; H, 6.45; N, 6.89.
Found: C, 82.33; H, 6.60; N, 6.57.
E-3-Phenyl-2-propenyl E-3-(1-Triphenylmethylimidazol-4-yl)-2-propenyl
Ether (15a): Prepared according to GP-A with cinnamyl chloride (76 mg,
N
N
O
TrPh
N
N
O
Tr
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
0.50 mmol), yield (164 mg, 70%). mp 121-123 C; 1H NMR: 7.42 (s, 1H), 7.38-7.28 (m, 12H),
7.23-7.13 (m, 8H), 6.79 (s, 1H), 6.62 (d, J = 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 6.42 (dt, J
= 15.8, 6.0 Hz, 1H), 6.30 (dt, J = 15.8, 6.0 Hz, 1H), 4.18 (m, 4H); 13C NMR: 142.4, 139.3,
138.8, 137.0, 132.3, 129.9, 129.7, 128.6, 128.4, 128.2, 127.6, 126.6, 126.3, 124.7, 124.4, 119.5,
75.4, 70.7, 70.5; IR (KBr, cm-1): 3086, 3051, 2382, 1700, 1663, 1516, 1461, 1139, 1057, 986,
770. Despite extensive efforts we have been unable to obtain satisfactory elemental analysis or
high resolution mass spectra for this compound.
E-3-(1-Triphenylmethylimidazol-4-yl)-2-propenyl 2-propenoate (16a): Prepared according to
GP-A with acryloyl chloride (45 mg, 0.50 mmol), NaH (22 mg, 0.55 mmol),
yield (67 mg, 32%). mp 126–128 C; 1H NMR: 7.36-7.30 (m, 9H), 7.14-
7.12 (m, 6H), 6.78 (s, 1H), 6.51 (d, J = 15.8 Hz, 1H), 6.43 (dt, J = 15.8, 6.1 Hz, 1H), 6.41 (dd, J
= 17.3, 1.3 Hz, 1H), 6.12 (dd, J = 17.3, 10.4 Hz, 1H), 5.81 (dd, J = 10.4, 1.3 Hz, 1H), 4.77 (d, J
= 6.1 Hz, 2H); 13C NMR: 166.1, 142.2, 139.4, 138.1, 130.9, 129.8, 128.5, 128.2, 125.9, 121.7,
120.1; IR (KBr, cm-1): 3103, 3061, 1750, 1683, 1635, 1485, 1445, 1182, 1050, 771; Anal. Calcd
For C28H24N2O2: C, 79.98; H, 5.75; N, 6.66. Found: C, 79.54; H, 6.01; N, 6.52.
E-3-(1-Triphenylmethylimidazol-4-yl)-2-propenyl E-3-phenyl-2-propenoate (17a): Prepared
according to GP-A with cinnamoyl chloride (85 mg, 0.50 mmol), yield (43
mg, 16%). mp 165-166 C. 1H NMR: 7.70 (d, J = 16.0 Hz, 1H), 7.52-7.50
(m, 2H), 7.46 (s, 1H), 7.40-7.29 (m, 13H), 7.15-7.11 (m, 6H), 6.80 (d, J = 1.6 Hz, 1H), 6.55 (d, J
= 15.8 Hz, 1H), 6.49 (dt, J = 15.8, 6.1 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 4.83 (d, J = 6.1 Hz,
2H); 13C NMR: 166.8, 144.9, 142.3, 139.4, 138.3, 134.5, 130.3, 129.8, 129.0, 128.5, 128.4,
N
N
O
Tr O
N
N
O
Tr OPh
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
128.2, 128.2, 126.1, 121.7, 120.1, 118.2, 77.4, 77.1, 76.9, 75.5, 65.2; IR (KBr, cm-1): 3137, 3061,
1702, 1675, 1630, 1491, 1443, 1274, 1202, 1105, 979, 758; Anal. Calcd For C34H38N2O2: C,
82.23; H, 5.68; N, 5.64. Found: C, 82.37; H, 5.41; N, 5.78.
E-3-(1-Triphenylmethylimidazol-4-yl)-2-propenyl 2-Propynyl Ether (18a): Prepared
according to GP-A with propargyl bromide (74 mg, 0.50 mmol), yield 131 mg,
65%. mp 121-123 C; 1H NMR: 7.47 (s, 1H), 7.35-7.32 (m, 9H), 7.14-7.11
(m, 6H), 6.76 (d, J = 1.0 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.42 (dt, J = 15.8, 6.2 Hz, 1H), 4.19
(d, J = 6.2 Hz, 2H), 4.16 (d, J = 2.4 Hz, 2H), 2.40 (t, J = 2.4 Hz, 1H); 13C NMR: 142.6, 139.7,
138.7, 129.9, 128.2, 125.8, 123.1, 120.3, 80.0, 75.8, 74.5, 69.8, 56.7; IR (KBr, cm-1): 3217, 3047,
3023, 2105, 1520, 1485, 1445, 1232, 1025, 747, 675; Anal. Calcd For C28H24N2O: C, 83.14; H,
5.98; N, 6.93. Found: C, 82.76; H, 5.73; N, 6.91.
(2E)-3-(1-Trityl-1H-imidazol-4-yl)prop-2-enyl propynoate (19a): Compound 19a was
prepared according GP-C procedure from 13a (1.19 g, 3.24 mmol). Flash
chromatography (30/70, EtOAc/hexane) afforded product 19a (796 mg,
59%) as colorless solid: mp: 200 C (dec.); 1H NMR: = 7.39 (s, 1H), 7.32
(m, 9H), 7.12 (m, 6H), 6.80 (s, 1H), 6.53 (d, J = 15.8 Hz, 1H), 6.38 (dt, J = 15.8, 6.6 Hz, 1H),
4.79 (d, J = 6.6 Hz, 2H), 2.86 (s, 1H); 13C NMR: = 152.6, 142.3, 139.6, 138.0, 129.8, 128.2,
128.1, 127.9, 127.5, 120.4, 120.0, 75.5, 74.8, 66.9; IR (KBr, cm-1): 3240, 3160, 3061, 2117,
1718, 1490, 1447, 1208, 973, 942, 748, 705; EIMS (m/z): 298 (100%), 243, 225, 183, 143,91;
Anal. Calcd for C28H22N2O2: C, 80.36; H, 5.30; N, 6.69. Found: C, 80.53; H, 5.64; N, 6.65.
N
N
O
Tr O
N
N
O
Tr
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
2,7,7a,8-Tetrahydro-4-triphenylmethylimidazo[4,5-e]benzo[c]furan (20a): Propargyl ether
18a (200 mg, 0.50 mmol) was heated in benzene at 145 C for 26 h. The mixture was separated
by flash chromatography (Et2O/hexane, 65:35) providing two cycloadducts, the oxidized adduct
(68 mg, 34%), and 20a (20 mg, 10%).
2,8-Dihydro-4-triphenylmethylimidazo[4,5-e]benzo[c]furan: Thick light yellow oil. 1H NMR:
7.86 (s, 1H), 7.57 (s, 1H), 7.32-7.30 (m, 9H), 7.18-7.16 (m, 6H), 6.28 (s, 1H),
5.11 (s, 2H), 4.86 (s, 2H); 13C NMR: 140.3, 136.0, 133.8, 129.9, 128.6,
128.0, 111.0, 108.1, 77.3, 77.1, 76.8, 73.0; IR (KBr, cm-1): 3058, 2919, 1689, 1490, 1056, 906,
701.
2,7,7a,8-Tetrahydro-4-triphenylmethylimidazo[4,5-e]benzo[c]furan (20a): White solid. mp
215-216.5 C. 1H NMR: 7.36 (s, 1H), 7.34-7.27 (m, 9H), 7.18-7.09 (m, 6H),
5.08 (dt, J = 2.8, 2.2 Hz, 1H), 4.26 (dd, J = 8.0 Hz, 1H), 4.21 (dt, J = 14.4, 2.2
Hz, 1H), 4.09 (dt, J = 14.4, 2.2 Hz, 1H), 3.48 (dd, J = 10.2, 8.6 Hz, 1H), 3.18 (m, 1H), 2.88 (dd,
J = 15.7, 8.6 Hz, 1H), 2.55 (dd, J = 15.7, 15.7 Hz, 1H); 13C NMR: 142.0, 139.4, 137.9, 137.9,
130.0, 129.7, 128.4, 128.3, 128.1, 128.0, 108.2, 74.9, 74.0, 69.3, 42.2, 25.8; IR (KBr, cm-1):
3039, 2848, 1716, 1540, 1489, 911, 750; Anal. Calcd For C28H24N2O: C, 83.14; H, 5.98; N, 6.93.
Found: C, 83.14; H, 5.98; N, 6.93; HRMS (ESI): calcd for C28H25N2O (M+H)+ 403.1805, found
403.1836; calcd for C56H49N4O2 (2M+H)+ 805.3537, found 805.3581.
3,7,7a,8-Tetrahydro-3-trityl-5H-furo[3,4-f]benzimidazol-5-one (21a): Compound 21a was
prepared by general procedure for Diels-Alder reaction from 19a (195 mg,
0.466 mmol) at 140 C overnight Flash chromatography (80/20,
EtOAc/hexane) afforded product 21a (57 mg, 30%) as colorless solid: mp: 193
C (dec.); 1H NMR: = 7.39 (s, 1H), 7.33 (m, 9H), 7.12 (m, 6H), 6.31 (d, J = 2.9 Hz, 1H), 4.66
N
NTr
O
O
N
N
Tr
O
N
N
Tr
O
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
(dd, J = 9.2, 8.8 Hz, 1H), 3.96 (dd, J = 9.2, 9.2 Hz, 1H), 3.41 (m, 1H), 3.08 (dd, J = 16.1, 9.2
Hz, 1H), 2.66 (dd, 1H, J = 17.2 16.1, Hz); 13C NMR: = 169.3, 143.9, 141.3, 141.0, 129.7,
128.9, 128.5, 124.1, 121.7, 75.7, 72.0, 36.4, 27.4; IR (KBr, cm-1): 1743, 1634, 1446, 1251, 1183,
1002, 752, 702; EIMS (m/z): 419 (M+ + 1), 243, 177, 167 (100%); Anal. Calcd for C28H22N2O2:
C, 80.36; H, 5.30; N, 6.69. Found: C, 80.01; H, 5.63; N, 6.58; HRMS (ESI): calcd for
C28H22N2O2 (M+H)+ 405.1961, found 405.1987; calcd for C56H43H4O4 (2M+H)+ 809.3850, found
809.3878.
4-[(1E)-3-(Allyloxy)prop-1-enyl]-1-benzyl-1H-imidazole (14b): Compound 14b was prepared
by GP-A method from 13b3 (214 mg, 1.00 mmol) and allyl bromide. Flash
chromatography (EtOAc) provided 13b (136 mg, 53%) as colorless liquid: 1H
NMR: = 7.37 (s, 1H), 7.24 (m, 3H), 7.04 (m, 2H), 6.73 (s, 1H), 6.41 (d, J =
15.8 Hz, 1H), 6.32 (dt, J = 15.8, 5.9 Hz, 1H), 5.84 (ddt, J = 17.2, 10.6, 5.5 Hz, 1H), 5.21 (d, J =
17.2 Hz, 1H), 5.08 (d, J = 10.6 Hz, 1H), 4.93 (s, 2H), 4.03 (d, J = 5.9 Hz, 2H), 3.93 (d, J = 5.5
Hz, 2H); 13C NMR: = 140.4, 137.7, 136.2, 135.0, 129.0, 128.3, 127.3, 124.39, 124.33, 117.1,
116.8, 70.8, 70.6, 50.8; IR (CHCl3, cm-1): 3031, 2849, 1666, 1497, 1455, 1356, 1237, 1106, 969,
711, 632; EIMS (m/z): 254 (M+), 213 (100%), 185, 135, 106, 91, 79, 65; Anal. Calcd for
C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C, 75.58; H, 7.20; N, 11.01.
1-Benzyl-4-((1E)-3-{[(2E)-3-phenylprop-2-enyl]oxy}-prop-1-enyl)-1H-imidazole (15b):
Compound 15b was prepared by GP-A from 13b3 (214 mg, 1.00 mmol) and
cinnamyl chloride. Flash chromatography (EtOAc) of the crude product
afforded 15b (137 mg, 42%) as a colorless solid: mp: 53-54 C; 1H NMR: =
7.50 (s, 1H), 7.10-7.40 (m, 10H), 6.82 (s, 1H), 6.61 (d, J = 16.1 Hz, 1H), 6.51 (d, J = 15.4 Hz,
1H), 6.41 (dt, J = 15.4, 5.9 Hz, 1H), 6.29 (dt, 1H, J = 16.1, 5.9 Hz), 5.04 (s, 2H), 4.17 (d, J = 5.9
N
N
O
Bn
N
N
O
BnPh
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H); 13C NMR: = 140.4, 137.7, 136.9, 136.0, 132.3, 129.1, 128.6,
128.4, 127.7, 127.4, 126.6, 126.4, 124.6, 124.4, 117.1, 70.7, 70.5, 51.0; IR (CHCl3, cm-1): 3028,
2845, 1663, 1540, 1496, 1453, 1357, 1235, 1113, 968, 820, 745, 632; EIMS (m/z): 330 (M+),
213, 185, 117, 91 (100%); Anal. Calcd for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C,
79.95; H, 7.02; N, 8.74.
(2E)-3-(1-Benzyl-1H-imidazol-4-yl)prop-2-enyl propenoate (16b): Compound 16b was
prepared by the GP-A from 13b3 (214 mg, 1.00 mmol) and acryloyl
chloride. It is very sensitive to column chromatography, so flash
chromatography (EtOAc) only afforded 218 (12 mg, 5%) in low yield as a
colorless solid: mp: 69.5 – 70.5 C; 1H NMR: = 7.59 (s, 1H), 7.12-7.38 (m, 5H), 6.86 (s, 1H),
6.53 (d, J = 15.8 Hz, 1H), 6.44 (dt, J = 15.8, 6.2 Hz, 1H), 6.41 (dd, J = 17.2, 1.5 Hz, 1H), 6.12
(dd, J = 17.2, 10.6 Hz, 1H), 5.80 (dd, J = 10.6, 1.5 Hz, 1H), 5.08 (s, 2H), 4.77 (d, J = 6.2 Hz,
2H); 13C NMR: = 166.1, 137.7, 135.7, 130.9, 129.1, 128.57, 128.55, 127.5, 125.4, 122.1,
117.6, 65.1, 51.2; IR (KBr, cm-1): 3032, 2943, 1719, 1497, 1269, 1190, 1045, 969, 811, 711, 632;
EIMS (m/z): 268 (M+), 254, 213, 197, 184, 163, 91 (100%), 80, 65; Anal. Calcd for C16H16N2O2:
C, 71.62; H, 6.01; N, 10.44. Found: C, 71.32; H, 6.17; N, 10.71.
(2E)-3-(1-Benzyl-1H-imidazol-4-yl)prop-2-enyl (2E)-3-phenylpropenoate (17b): Compound
17b was prepared by GP-A from 13b3 (214 mg, 1.00 mmol) and cinnamoyl
chloride. Flash chromatography (EtOAc/hexane, 4:1) of the crude product
afforded 17b (201 mg, 58%) as colorless solid: mp: 90-91 C. 1H NMR: =
7.69 (d, J = 16.1 Hz, 1H), 7.53 (s, 1H), 7.12-7.51 (m, 10H), 6.86 (s, 1H), 6.58 (d, J = 15.8 Hz,
1H), 6.45 (dt, J = 15.8, 6.2 Hz, 1H), 6.44 (d, J = 16.1 Hz, 1H), 5.06 (s, 2H), 4.82 (d, J = 6.2 Hz,
2H); 13C NMR: = 166.8, 144.9, 139.9, 137.9, 135.9, 134.5, 130.3, 129.1, 129.0, 128.5, 128.2,
N
N
O
Bn O
N
N
O
Bn OPh
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
127.4, 125.9, 121.9, 118.2, 117.7, 65.2, 51.1; IR (KBr, cm-1): 3060, 2929, 1707, 1638, 1489,
1308, 1171, 975, 961, 769, 705; EIMS (m/z): 344 (M+), 254, 213, 184, 107, 91 (100%), 80, 65;
Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C, 76.71; H, 6.21; N, 8.01.
1-Benzyl-4-[(1E)-3-(prop-2-ynyloxy)prop-1-enyl]-1H-imidazole (18b): Compound 18b was
prepared by GP-A from 13b3 (429 mg, 2.00 mmol) and propargyl bromide.
Flash chromatography (EtOAc/hexane, 9:1) afforded 18b (219 mg, 43%) as a
colorless liquid: 1H NMR: = 7.45 (s, 1H) 7.30 (m, 3H), 7.12 (m, 2H), 6.81
(s, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.33 (dt, J = 15.8, 6.2 Hz, 1H,), 5.03 (s, 2H), 4.17 (d, J = 6.2
Hz, 2H), 4.14 (d, J = 2.4 Hz, 2H), 2.39 (t, J = 2.4 Hz, 1H); 13C NMR: = 140.3, 137.7, 136.1,
129.0, 128.4, 127.3, 125.4, 123.3, 117.3, 80.0, 74.4, 70.0, 56.7, 50.9; IR (CHCl3, cm-1): 3287,
3031, 2851, 2113, 1664, 1541, 1497, 1455, 1356, 1237, 1077, 970, 834, 711, 633, 460; EIMS
(m/z): 253 (M+ + 1), 252 (M+), 222, 213, 197 (100%), 187, 136, 91; Anal. Calcd for C16H16N2O:
C, 76.16; H, 6.39; N, 11.10. Found: C, 76.45; H, 6.23; N, 10.85.
(2E)-3-(1-Benzyl-1H-imidazol-4-yl)prop-2-enyl propynoate (19b): Compound 19 was
prepared by GP-C from 13b3 (468 mg, 2.18 mmol) and propiolic acid.
Crude 19b (499 mg, 86%) was obtained, but it was very sensitive to column
chromatography. Attempted chromatographic purification led to
decomposition (EtOAc/Et3N, 99:1), only 1H NMR data of the crude product was obtained: 1H
NMR: = 7.40 (s, 1H) 7.00-7.30 (m, 5H), 6.80 (s, 1H), 6.45 (d, 1H, J = 15.6 Hz), 6.28 (dt, 1H, J
= 15.6, 6.7 Hz), 4.97 (s, 2H), 4.68 (d, 2H, J = 6.7 Hz), 2.93 (s, 1H).
1-Benzyl-4,4a,5,7-tetrahydro-1H-furo[3,4-f]benzimidazole (20b): Compound 20b was
obtained from the Diels-Alder reaction of compound 18b (215 mg, 0.85
N
N
O
Bn
N
N
O
Bn O
N
N
Bn
O
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
mmol) in benzene. Flash chromatography (EtOAc/Et3N, 99:1) afforded product 20b (163 mg,
76%) as colorless solid: mp: 132.5-133.0 C; 1H NMR: = 7.10-7.35 (m, 6H), 5.94 (s, 1H), 5.07
(d, J = 16.1 Hz, 1H), 5.02 (d, J = 16.1 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 4.36 (d, J = 15.2 Hz,
1H), 4.32 (dd, J = 8.5, 7.4 Hz, 1H), 3.54 (dd, J = 10.3, 8.5 Hz, 1H), 3.25 (m, 1H), 2.91 (dd, J =
16.1, 8.8 Hz, 1H), 2.54 (dd, J = 16.1, 16.1 Hz, 1H); 13C NMR: = 141.5, 137.1, 136.2, 135.9,
129.1, 128.2, 128.0, 126.9, 104.5, 74.0, 69.3, 48.9, 42.7, 25.7; IR (KBr, cm-1): 2846, 1496, 1435,
1360, 1244, 1187, 1077, 1033, 910, 746, 709; EIMS (m/z): 253 (M++1), 252 (M+),179, 125, 111,
97, 65 (100%), 59; Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.32; H,
6.51; N, 10.97.
4-[(1E)-3-(Allyloxy)prop-1-enyl]-1-dimethylsulfamoyl-1H-imidazole (14c): This compound
14c5 was prepared by GP-A from 13c (231 mg, 1.00 mmol) and allyl
bromide. Flash chromatography (EtOAc/hexane, 3:2) afforded 14c (87 mg,
32%) as colorless solid: mp: 47-48 C; 1H NMR: = 7.80 (s, 1H), 7.10 (s,
1H), 6.52 (dt, J = 15.8, 4.4 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 5.91 (ddt, J
= 17.2, 10.3, 5.9 Hz, 1H), 5.28 (ddt, J = 17.2, 1.8, 1.5, Hz, 1H), 5.17 (ddt, J = 10.3, 1.8, 1.5 Hz,
1H), 4.12 (d, J = 4.4 Hz, 2H), 4.01 (ddd, J = 5.9, 1.5, 1.5 Hz, 2H), 2.82 (s, 6H); 13C NMR: =
141.2, 136.9, 134.8, 128.1, 122.0, 117.1, 114.2, 71.3, 70.1, 38.3; IR (KBr, cm-1): 3126, 2852,
1479, 1419, 1393, 1263, 1176, 1077, 966, 842, 729, 603, 514; EIMS (m/z): 271 (M+), 230, 214,
163 (100%), 108, 94; Anal. Calcd for C11H17N3O3S: C, 48.69; H, 6.32; N, 15.49. Found: C,
48.65; H, 6.50; N, 15.74.
1-Dimethylsulfamoyl-4-((1E)-3-{[(2E)-3-phenylprop-2-enyl]oxy}prop-
1-enyl)-1H-imidazole (15c): Compound 15c was prepared by GP-A from
13c5 (231 mg, 1.00 mmol) and cinnamyl chloride. Flash chromatography
(EtOAc/hexane, 4:1) afforded 15c (113 mg, 34%) as colorless solid: mp: 86-87 C; 1H NMR: =
N
N
O
SOO
NMeMe
N
N
O
SPhO
ONMe
Me
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
7.84 (s, 1H), 7.22-7.40 (m, 5H), 7.12 (s, 1H), 6.63 (d, J = 16.1 Hz, 1H), 6.56 (dt, J = 5.1, 15.8
Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H), 6.31 (dt, J = 16.1, 5.9 Hz, 1H), 4.20 (m, 2H), 4.19 (m, 2H),
2.84 (s, 6H); 13C NMR: = 141.2, 136.9, 136.8, 132.6, 128.6, 128.1, 127.8, 126.6, 126.1, 122.1,
114.2, 70.9, 70.1, 38.3; IR (KBr, cm-1): 3149, 3126, 3030, 2841, 2786, 1478, 1386, 1262, 1169,
1127, 1083, 1037, 959, 734, 688, 605; EIMS (m/z): 348 (M+ + 1), 347 (M+), 254, 213, 142, 117,
91 (100%); Anal. Calcd for C17H21N3O3S: C, 58.77; H, 6.09; N, 12.09. Found: C, 59.06; H, 6.48;
N, 11.80.
(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)prop-2-enyl propenoate (16c): Compound
16c was prepared by GP-A 13c5 (463 mg, 2.00 mmol) and acryloyl chloride. Flash
chromatography (EtOAc) afforded 16c (208 mg, 37%) as a colorless
solid: mp: 72-73 C; 1H NMR: = 7.81 (s, 1H), 7.12 (s, 1H), 6.46-6.54
(m, 2H), 6.40 (d, J = 17.2 Hz, 1H), 6.11 (dd, J = 17.2, 10.6 Hz, 1H), 5.81
(d, J = 10.6 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 2.81 (s, 6H); 13C NMR:
= 165.9, 140.6, 137.0, 131.1, 128.4, 125.0, 123.8, 114.8, 64.5, 38.2; IR (KBr, cm-1): 3156, 3138,
2963, 1717, 1628, 1482, 1409, 1379, 1298, 1198, 1080, 965, 813, 730, 608, 513; EIMS (m/z):
285 (M+), 230, 214, 177, 123 (100%), 108; Anal. Calcd for C11H15N3O4S: C, 46.30; H, 5.30; N,
14.73. Found: C, 46.13; H, 5.30; N, 14.64.
(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)prop-2-enyl (2E)-3-phenylpropenoate (17c):
Compound 17c was prepared by GP-A from 13c5 (463 mg, 2.00 mmol)
and cinnamoyl chloride. Flash chromatography (EtOAc) afforded 17c
(245 mg, 34%) as colorless solid: mp: 111-112 C. 1H NMR: = 7.85 (s,
1H), 7.71 (d, J = 15.8 Hz, 1H), 7.34-7.54 (m, 5H), 7.15 (s, 1H), 6.60 (dt, J = 15.8, 4.8 Hz, 1H),
6.54 (d, J = 15.8 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 4.86 (d, J = 4.8 Hz, 2H), 2.85 (s, 6H); 13C
N
N
O
S OOO
NMeMe
N
N
O
S OOO
NMeMe
Ph
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NMR: = 166.7, 145.3, 140.7, 137.1, 134.4, 130.5, 129.0, 128.2, 125.3, 123.7, 117.9, 114.8,
64.6, 38.3; IR (KBr, cm-1): 3142, 3128, 2938, 1727, 1638, 1480, 1451, 1381, 1312, 1166, 1091,
954, 757, 617, 604; EIMS (m/z): 362 (M+ + 1), 361 (M+), 253, 230, 213, 148 (100%),131, 102,
91, 64; Anal. Calcd for C17H19N3O4S: C, 56.49; H, 5.30; N, 11.63. Found: C, 56.88; H, 5.68; N,
11.33.
(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)propenoic acid: Ester 12c (500 mg, 1.93
mmol) was dissolved in THF (4.6 mL) and LiOH (1N in water, 5.5 mL)
and stirred at room temperature for 4 h. The basic solution was
neutralized to pH = 6-7 with 1 N HCl. The resulting white precipitate was
collected and washed with a small amount of cold water. After drying
under vacuo, the corresponding acid (399 mg, 84%) was obtained as a colorless solid which was
used in the next step without further purification. mp: 176-176.5 ºC. 1H NMR (DMSO-d6): =
12.38 (brs, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.46 (d, J = 15.6 Hz, 1H), 6.46 (d, J = 15.6 Hz, 1H),
2.84 (s, 6H); 13C NMR (DMSO-d6): = 168.0, 138.85, 138.81, 135.5, 120.9, 119.4, 38.4; IR
(KBr, cm-1): 3140, 2945, 2809, 1698, 1389, 1264, 1171, 1086, 970; EI-MS (m/z): 244.4 (M+,
30%), 200.2 (100%), 106.8 (60%). Anal. Calcd for C8H11N3O4S: C, 39.18; H, 4.52; N, 17.13.
Found: C, 39.22; H, 4.16; N, 16.86.
(2E)-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)allyl (2E)-3-(1-
Dimethylsulfamoyl-1H-imidazol-4-yl)propenoate (22): According to
GP-D, alcohol 13c (600 mg, 2.59 mmol) and acid above (954 mg, 3.89
N
N
S
OH
OO
NMeMe
O
N
N
S
O
O
N
N
OO
NMeMe
S
N
OO
MeMe
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
mmol) afforded ester 22 (1.02 g, 86%) after chromatography (EtOAc/MeOH 95:5) as a colorless
solid. mp: 138-139 ºC. 1H NMR: = 7.89 (d, J = 1.2 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.54 (d,
J = 15.6 Hz, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 1.2 Hz, 1H), 6.70 (d, J = 15.6 Hz, 1H),
6.58 (dt, J = 15.8, 5.3 Hz, 1H), 6.53 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 5.3 Hz, 2H), 2.89 (s, 6H),
2.85 (s, 6H); 13C NMR: = 166.6, 140.8, 139.4, 137.7, 137.0, 134.7, 125.3, 123.5, 119.3, 118.7,
114.8, 64.5, 38.3 (DMAS methyl groups are coincident); IR (KBr, cm-1): 3161, 3126, 2981,
2927, 1713, 1651, 1480, 1392, 1269, 1171, 1078, 968, 839, 731, 606, 513; ESI-MS (m/z),
positive mode: 481 (M+Na+, 100%), 459 (M+H+, 3%), 437 (17%); negative mode: 539 (100%),
493 (M+Clֿ, 68%), 457 ([M-H]ֿ, 22%), 350 (3%). Anal. Calcd for C16H22N6O6S2: C, 41.91; H,
4.84; N, 18.33. Found: C, 41.78; H, 4.85; N, 18.07.
Ethyl (2E)-3-(1-benzyl-1H-imidazol-4-yl)-2-propenyl (2E)-2-Butenedioate (27b): To the allyl
alcohol 13b (1.00 g, 2.33 mmol) and triethylamine (378 mg, 3.73 mmol) in
dry CH2Cl2 (50 mL) at 0 ºC was added ethyl fumaryl chloride6 (569 mg, 3.50
mmol) dropwise and stirred at room temperature overnight, after which water
was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2
and the combined organic layers were washed with aqueous saturated NaHCO3 solution. Organic
layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
solution was concentrated and the residue was purified by flash chromatography (hexane/EtOAc,
2:3), yielding the product as a white solid (850 mg, 54%). mp: 96-98 °C; 1H NMR (300 MHz):
= 7.45 (s, 1H), 7.34-7.25 (m, 2H), 7.12-7.09 (m, 2H), 6.82-6.81 (m, 3H), 6.52 (d, J = 15.6 MHz,
1H), 6.36 (dt, J = 15.6, 6.0 Hz, 1H), 5.02 (s, 2H), 4.77 (d, J = MHz, 2H), 4.20 (q, J = 7.2 Hz,
2H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz): = 165.0, 164.8, 139.7, 137.9, 135.9, 133.8,
N
NO
Bn O
OEt
O
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
133.5, 129.0, 128.4, 127.3, 126.6, 120.6, 117.8, 65.9, 61.3, 50.9, 14.1. IR (neat, cm-1) = 2982,
1717, 1645, 1540, 1497, 1454. HRMS (ESI): calcd for C19H21N2O4 (M+H)+ 341.1496, found
341.1516.
Ethyl (4aS*,7aR*,8S*)-1-Benzyl-7-oxo-4,4a,7a,8-tetrahydro-1H-furo[3,4-f]benz-imidazole-
8-carboxylate (29b): Compound 29b was prepared by the general Diels-Alder reaction
procedure from 27b (200 mg, 0.587 mmol) in benzene at 145 C for 3 days.
Chromatography (CHCl3/MeOH, 19:1) provided 33b (140 mg, 70%) as a
white solid. mp: 123-125 C; 1H NMR (300 MHz): = 7.39 (s, 1H), 7.32-
7.25 (m, 3H), 6.97 (m, 2H), 5.02 (ABq, J = 16.2 Hz, 2H), 4.48 (dd, J = 8.7, 6.9 Hz, 1H), 4.05
(dd, J = 10.5, 9.0 Hz, 1H), 3.96 (m, 2H), 3.65 (d, J = 10.2 Hz, 1H), 3.03 (dd, J = 13.5, 10.8 Hz,
1H), 2.86 (dd, J = 14.4, 4.5 Hz, 1H), 2.67 (ddd, J = 14.4, 10.8, 2.4 Hz, 1H), 2.60-2.49 (m, 1H);
13C NMR (75 MHz): = 174.6, 170.8, 138.9, 138.6, 135.7, 129.0, 128.2, 126.6, 122.7, 71.5,
62.0, 48.9, 46.4, 40.4, 39.6, 27.4, 14.0; IR (neat, cm-1): = 2982, 1778, 1732, 1497, 1454; HRMS
(ESI): calcd for C19H21N2O4 (M+H)+ 341.1496, found 341.1513.
(2E)-3-(1-benzyl-1H-imidazol-4-yl)-2-propenyl (E)-3-acetylpropenoate (30b): To a solution
of (E)-3-acetylpropenoic acid (750 mg, 6.5 mmol) and alcohol 13b (1.00 g,
4.66 mmol) in CH2Cl2 (40 mL), DCC (1.40 g, 6.80 mmol) followed by
DMAP (55 mg) was added and stirred for 30 h at room temperature. The
precipitated N,N-dicyclohexylurea was removed by filtration and the filtrate was washed with
EtOAc. The organic solution was concentrated and to the resulting residue was added EtOAc (50
mL), whereupon additional N,N-dicyclohexylurea precipitated from the mixture and was
N
NO
Bn OO
N
NO
OBnOEtOH
H
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removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 solution (10 mL),
dried (Na2SO4), filtered, and concentrated. Column chromatography (EtOAc/hexane, 1:1)
afforded 34b as a thick oil (1.00 g, 70 %). 1H NMR (300 MHz): δ = 7.48 (s, 1H), 7.33-7.31 (m,
3H), 7.13 (m, 2H), 6.99 (d, J = 15.9 Hz, 1H), 6.84 (s, 1H), 6.62 (d, J = 16.2 Hz, 1H), 6.53 (d, J =
15.9 Hz, 1H), 6.38 (dt, J = 15.9, 6.6 Hz, 1H), 5.05 (s, 2H), 4.79 (d, J = 6.3 Hz, 2H), 2.31 (s, 3H).
13C NMR (75 MHz): δ = 197.7, 165.3, 140.1, 139.7, 138.0, 136.1, 131.5, 129.1, 128.4, 127.4,
126.8, 120.6, 118.0, 66.1, 50.9, 28.2. IR (neat, cm-1): = 2358, 1774, 1715, 1539. HRMS (ESI):
calcd for C18H19N2O3 (M+H)+ 311.1390, found 311.1394.
(4aS*,7aR*,8S*)-8-Acetyl-1-benzyl-7-oxo-4,4a,7a,8-tetrahydro-1H-furo[3,4-f]benz-
imidazole (31b): Compound 31b was prepared by the general Diels-Alder reaction procedure
from 30b (300 mg, 0.960 mmol) at 145 C for 44 h in benzene.
Chromatography (EtOAc/MeOH, 19:1) 31b (176 mg, 59%) as a white solid.
mp: 153-155 °C; 1H NMR (300 MHz): = 7.70 (s, 1H), 7.65-7.58 (m, 3H),
7.25 (m, 2H), 5.32 (d, J = 16.2 Hz, 1H), 4.96 (d, J = 16.5 Hz, 1H), 4.78 (dd, J = 8.7, 6.3 Hz, 1H),
4.33 (t, J = 8.7 Hz, 1H), 4.00 (m, 1H), 3.15 (m, 1H), 2.91–2.90 (m, 3H), 2.58 (s, 3H); 13C NMR
(75 MHz): = 208.9, 175.1, 139.5, 139.2, 135.3, 129.5, 128.8, 127.0, 124.1, 71.8, 49.9, 47.5,
47.0, 40.7, 31.8, 27.5; IR (neat, cm-1): = 2907, 1771, 1712, 1496, 1454; HRMS (ESI): calcd for
C18H19N2O3 (M+H)+ 311.1390, found 311.1381.
(2E)-3-(1-Benzyl-1H-imidazol-4-yl)prop-2-enyl 3-phenylpropynoate
(32b): The allylic alcohol (3.52 g, 16.3 mmol), phenyl propiolic acid (2.00 g,
13.7 mmol), DMAP (0.17 g, 1.39 mmol) and camphorsulfonic acid (0.20 g,
N
N
O
Bn OPh
N
NO
OBn
O
H
H
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0.86 mmol) were dissolved in CH2Cl2 (50 mL) and the mixture was cooled to -78 °C under N2.
A solution of DCC (4.24 g, 20.6 mmol) in CH2Cl2 (10 mL) was added dropwise. The solution
was allowed to warm to room temperature and stir overnight. The solids were filtered through
Celite and washed with CH2Cl2. The filtrate was concentrated under reduced pressure and
purified by column chromatography (EtOAc/hexane, 4:1) to afford 36b (2.81 g, 60%) as an off-
white solid. mp: 57-61 °C; 1H NMR (300 MHz): δ = 7.11-7.53 (m, 11H), 6.34 (s, 1H), 6.36-6.59
(m, 2H), 5.02 (s, 2H), 4.81 (d, J = 6.3 Hz, 2H); 13C NMR (75 MHz): δ = 153.9, 139.8, 138.0,
136.0, 133.1, 130.7, 129.1, 128.7, 128.4, 127.4, 127.3, 120.3, 119.7, 118.0, 86.4, 80.7, 66.7,
50.9; IR (NaCl disk, cm-1): 3068, 2936, 2219, 1705, 1491, 1444, 1285, 1186, 1170, 966, 759,
690; HRMS (ESI): calcd for C22H19N2O2 (M+H)+ 343.1441, found 343.1453; calcd for
C44H36N4O2Na (2M+Na)+ 707.2629, found 707.2639.
3-Benzyl-3,7,7a,8-tetrahydro-4-phenyl-5H-furo[3,4-f]benzimidazol-5-one (33b): The
substrate 32b (1.50 g, 4.38 mmol) was dissolved in benzene (200 mL) and
heated to 130 °C for 24 h. The solvent was removed under reduced pressure
and the resulting solid was purified by column chromatography
(MeOH/CHCl3, 5:95) to afford 33b (1.27 g, 85%) as an off-white solid. mp: 228-231 °C; 1H
NMR (DMSO-d6, 300 MHz): δ = 7.80 (s, 1H), 7.14-7.34 (m, 8H), 6.50-6.52 (m, 2H), 4.88 (d, J =
16.2 Hz, 1H), 4.58 (t, J = 9.0 Hz, 1H), 4.16 (d, J = 15.9 Hz, 1H), 3.97 (t, J = 8.7 Hz, 1H), 3.52-
3.61 (m, 1H), 2.91, (dd, J = 15.9, 15.6, Hz, 1H), 2.66 (dd, J = 17.4, 15.9 Hz, 1H); 13C NMR
(DMSO-d6, 75 MHz): δ = 167.9, 144.7, 142.6, 139.1, 137.3, 132.6, 129.2, 128.9, 128.8, 128.3,
128.0, 127.6, 126.4, 117.6, 70.7, 49.4, 37.9, 27.5,; IR (KBr, cm-1): 3048, 2936, 1734, 1609, 1525,
1350, 1255, 1214, 1188, 1098, 1074, 1018, 752, 719,697; HRMS (ESI) calcd for C22H19N2O2
(M+H)+ 343.1441, found 343.1439.
N
NBn
O
OPh
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(E,E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)-N-[3-(1-dimethylsulfamoyl-1H-imidazol-
4-yl)-2-propenyl]-2-propenamide: Following GP-D using allyl amine 47 (150 mg, 0.65 mmol),
acid (240 mg, 0.98 mmol), EDCI (187 mg, 0.98 mmol) and DMAP 119 mg, 0.98 mmol) in
CH2Cl2 (5 mL) and DMF (1.5 mL) provided the the title compound (264
mg, 89%) as a colorless solid after chromatography (EtOAc,MeOH,
4:0.35). mp: 118-120 ºC. 1H NMR: = 7.88 (s, 1H), 7.83 (s, 1H), 7.49
(d, J = 15.1 Hz, 1H), 7.32 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 1.2 Hz, 1H),
6.69 (d, J = 15.1 Hz, 1H), 6.48 (dt, J = 15.6, 5.7 Hz, 1H), 6.41 (d, J =
15.6 Hz, 1H), 5.86 (t, J = 5.5 Hz, 1H), 4.16 (dd, J = 5.7, 5.5 Hz, 2H), 2.88 (s, 6H), 2.85 (s, 6H).
13C NMR: = 165.6, 141.0, 139.7, 137.5, 137.0, 131.1, 127.3, 122.2, 121.8, 118.2, 114.3, 41.1,
38.32, 38.29. IR (KBr, cm-1): 3280, 3140, 2922, 1666, 1629, 1548, 1480, 1419, 1174, 1077, 966,
727, 596; ESI-MS (m/z), positive mode: 496 (M+K+, 1%), 480 (M+Na+, 100%), 458 (M+H+,
20%). Anal. Calcd for C16H23N7O5S2: C, 42.00; H, 5.07; N, 21.43. Found: C, 41.87; H, 4.97; N,
21.19.
(E,E)-N-t-Butoxycarbonyl-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-N-[3-(1-
dimethylsulfamoyl-1H-imidazol-4-yl)-2-propenyl]-2-propenamide
(49): A mixture of the amide (194 mg, 0.42 mmol), DMAP (26 mg,
0.21 mmol), NEt3 (0.06 mL, 0.43 mmol) and (Boc)2O (224 mg, 1.03
mmol) in CH2Cl2 (2 mL) was stirred overnight at room temperature
Then the reaction mixture was diluted with CH2Cl2, washed with H2O (2x), brine, dried
(Na2SO4) and concentrated. The crude oil was purified by chromatography (hexane/EtOAc, 1:3)
N
NNH
O
N
NS
S
N
N
MeMe
MeMe
OO
OO
N
N
S
N
O
N
N
BOC
OO
NMeMe
S
N
OO
MeMe
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to provide pure 49 (197 mg, 84%) as a colorless solid. mp: 83-85 ºC. 1H NMR: = 7.86 (s, 1H),
7.79 (s, 1H), 7.64 (d, J = 15.1 Hz, 1H), 7.46 (d, J = 15.1 Hz, 1H), 7.34 (d, J = 0.9 Hz, 1H), 7.07
(d, J = 0.9 Hz, 1H), 6.45 (dt, J = 15.6, 6.0 Hz, 1H), 6.37 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 6.0 Hz,
1H), 2.85 (s, 6H), 2.82 (s, 6H), 1.51 (s, 9H); 13C NMR: = 168.4, 153.0, 141.1, 140.1, 137.5,
136.9, 132.5, 116.7, 123.0, 122.5, 118.3, 114.2, 83.6, 46.2, 38.29, 38.27, 28.1; IR (KBr, cm-1):
3129, 2979, 2934, 1727, 1671, 1625, 1480, 1392, 1262, 1175, 1149, 1007, 968, 851, 728, 598;
ESI-MS (m/z), positive mode: 596 (M+K+, 4%), 580 (M+Na+, 70%), 558 (M+H+, 62%), 480
(45%), 458 (100%); negative mode: 638 (100%), 592 (M+Clֿ, 80%), 556 ([M-H]ֿ, 36%). Anal.
Calcd for C21H31N7O7S2: C, 45.23; H, 5.60; N, 17.58. Found: C, 45.22; H, 5.33; N, 17.44.
N-Benzhydryl-N-((2E)-3-(1-benzyl-1H-imidazol-4-yl)-2-propenyl)amine (53b): Following
Method B for the synthesis of 44b, aldehyde 50b3 (210 mg, 0.99 mmol),
diphenylmethylamine (0.19 mL, 1.10 mmol), molecular sieves (494 mg)
and NaBH4 (94 mg, 2.5 mmol) in MeOH (5 mL) provided the pure
product 53b (338 mg, 90%) as a colorless semi-solid after trituration with ether. 1H NMR: =
7.48 (s, 1H), 7.43-7.41 (m, 4H), 7.35-7.26 (m, 7H), 7.21-7.14 (m, 4H), 6.78 (s, 1H), 6.46-6.40
(m, 2H), 5.04 (s, 2H), 4.94 (s, 1H), 3.33 (d, J = 5.1 Hz, 2H), 1.94 (brs, 1H); 13C NMR: = 144.0,
140.8, 137.4, 136.0, 128.9, 128.4, 128.2, 127.3, 127.2, 126.9, 126.8, 123.0, 116.3, 66.1, 50.8,
49.3; IR (KBr, cm-1): 3060, 3026, 2924, 1493, 1453, 968, 746, 704; ESI-MS (m/z), positive
mode: 402 (M+Na+, 12%), 380 (M+H+, 15%), 197 (100%). HRMS (ESI): calcd for C26H26N3
(M+H)+ 380.2121, found 380.2117.
NH
Ph
Ph
N
N
Bn
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(E)-N-Benzyl-N-[3-(1-benzyl-1H-imidazol-4-yl)-2-propenyl]-propenamide (56): To the allyl
amine 53a3 (300 mg, 0.99 mmol) and triethylamine (134 mg, 1.48 mmol) in
dry CH2Cl2 at 0 ºC was added acryloyl chloride (180 mg, 1.78 mmol)
dropwise and stirred at room temperature for 3 h, after which water was added and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic
layer were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
solution was concentrated and the residue was purified by flash chromatography
(EtOAc/methanol, 9:1), yielding the product as a colorless oil (28% yield, 100 mg). 1H NMR
(300 MHz) of 65:35 mixture of rotamers: δ = 7.56 (s, 1H), 7.37-7.27 (m, 8H), 7.31-7.26 (m, 5H),
7.23-7.16 (m, 3H), 6.81, 6.80 (s, total 1H), 6.56 (ddd, J = 16.5, 15.9, 10.2 Hz, 1H), 6.42, 6.40
(dd, J = 16.5 and 2.1 Hz, 16.5 and 1.8 Hz, total 1 H), 5.07 (s, 2H), 4.67, 4.60 (s, total 2H), 4.17,
4.01 (d, J = 5.4 Hz, s, total 2 H); 13C NMR (75 MHz): δ = 166.9, 166.7, 139.5, 137.7, 137.5,
137.3, 136.8, 135.6, 129.2, 128.9, 128.7, 128.6, 7, 128.61, 128.4, 127.8, 127.6, 127.4, 126.5,
51.1, 48.6, 48.3, 47.3; IR (neat, cm-1) = 3028, 2359, 1647, 1611, 1495, 1441; HRMS (ESI): calcd
for C23H24N3O (M+H)+ 358.1916, found 358.1914.
(E,E)-N-Benzhydryl-3-(1-benzyl-1H-imidazol-4-yl)-N-[3-(1-benzyl-1H-imidazol-4-yl)-2-
propenyl]-2-propenamide (58): Following procedure GP-C, amine 57b3
(750 mg, 1.98 mmol) and acid (677 mg, 2.96 mmol) provided amide 62
(924 mg, 80%) as a beige semi-solid after chromatography
(EtOAc/MeOH, 4:0.5). 1H NMR of a 75:25 mixture of two rotamers: =
7.63 (d, J = 14.9 Hz, 1H), 7.48 (s, 1H), 7.36-7.18 (m, 16.7H), 7.14-7.08
(m, 6H), 7.01, 6.97 (s, total 1H), 6.63 (d, J = 4.6 Hz, 0.3 H), 6.52 (s, 1H), 6.87-6.76 (m, 2H),
N
NNBn
OBn
N
N
Bn
N
O
N
N
Bn
Ph
Ph
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
5.05 (s, 2H), 4.97 (s, 2H), 4.22, 4.10 (brs, total 2H); 13C NMR of a 75:25 mixture of two
rotamers: = 167.9, 167.8, 140.3, 139.7, 139.6, 138.5, 137.3, 137.2, 136.1, 135.7, 135.0, 134.6,
129.21, 129.18, 128.4, 127.9, 127.4, 127.3, 123.8, 123.3, 121.4, 116.7, 116.3, 115.8, 65.0, 61.7,
51.1, 50.8, 47.3, 47.0, 31.7, 22.7, 14.2; IR (KBr, cm-1): 3110, 30331, 2932, 1650, 1602, 1496,
1454, 1410, 1182, 978, 732, 702, 630, 600; HRMS (ESI) calcd for C39H36N5O (M+H)+
590.2914, found 590.2940; calcd for C39H35N5ONa (M+Na)+ 612.2734, found 612.2752.
(4aR*/S*,7aS*)-3,6-Dibenzyl-4a,5,6,7,7a,8-hexahydro-5-oxo-5H-imidazo[4,5-f]isoindole
(70): Title compound was prepared by the general Diels-Alder reaction
procedure from 56 (700 mg, 1.96 mmol) at 145 C in toluene for 4 days.
The solution was concentrated and the residue was purified by flash
chromatography (EtOAc/methanol, 9:1), yielding the inseparable mixture of cis and trans
isomers (ratio = 7:2) as a white solid (500 mg, 71%). mp: 147 – 149 °C. 1H NMR: δ = 7.47, 7.42
(s, total 1H), 7.36-7.29 (m, 6H), 7.23, 7.21 (d, J = 7.4 Hz, 7.8 Hz, total 2H), 7.12, 7.09 (d, J = 7.5
Hz, 7.4 Hz, total 2H), 5.08, 5.00, 5.03 (d, ABq, J = 15.6 Hz, 15.6 Hz, total 2H), 4.57, 4.37, 4.49
(d, s, J = 14.7 Hz, total 2H), 3.42, 3.36 (dd, J = 9.7, 5.1 Hz and 9.2, 6.9 Hz, total 1H), 3.11 (t, J =
10.1 Hz, 1H), 2.91 (dd, J = 14.2, 4.1 Hz, 1H), 2.84 (dd, J = 15.2, 5.5 Hz, 1H), 2.60, 2.54 (m,
1H), 2.43 (m, 2H), 2.25 (m, 1H); 13C NMR (75 MHz): δ = 174.5, 137.4, 136.9, 136.6, 136.1,
129.2, 128.9, 128.4, 128.2, 127.8, 127.2, 127.0, 125.5, 51.8, 50.4, 48.9, 46.8, 45.4, 38.8, 31.4,
28.1, 21.5; IR (neat, cm-1): = 2923, 1686, 1495, 1441; HRMS (ESI): calcd for C23H24N3O
(M+H)+ 358.1914, found 358.1907.
N
NNBn
OBn H
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
(4S*,4aR*,7aS*)-6-Benzyl-3-benzyl-4-(1-benzyl-1H-imidazol-4-yl)-4a,5,6,7,7a,8-hexahydro-
5H-imidazo[4,5-f]isoindole (77): The amide 57 (100 mg, 0.20 mmol) was dissolved in benzene
(2 mL) and then degassed by bubbling nitrogen through it for 10 min. The
resulting solution was heated at 130-135 C for 36 h. After cooling to
room temperature, the reaction mixture was concentrated and the crude
product was purified by chromatography (EtOAc/MeOH, 4:12:10:1) providing the
cycloadduct (66 mg, 66%) as a 5:4 mixture of diastereomers. This material was repurified by
prep TLC resulting in a slight enrichment of one diastereomer (2:1). 1H NMR: 7.51 (br s, 1H),
7.45 (br s, 0.6H), 7.40-7.35 (m, H), 7.32-7.22 (m, H), 7.21-7.11 (m, H), 6.80 (s, 1H), 6.66 (app d,
J = 6.6 Hz, 1.2H), 6.55 (app d, J = 7.9 Hz, 2H), 6.41 (s, 0.6 Hz), 5.11 (d, J = 14.7 Hz, 1H), 5.01
(d, J = 14.7 Hz, 1H), 4.98 (d, J = 14.7 Hz, 0.6H), 4.90 (d, J = 14.7 Hz, 0.6H), 4.78 (d, J = 16.0
Hz, 1H), 4.74 (d, J = 17.9 Hz, 0.6H), 4.53 (d, J = 15.1 Hz, 0.6H), 4.39 (ABq, J = 14.5 Hz, 2H),
4.33 (dd, J = 16.1, 7.3 Hz, 1.2H), 4.17 (d, J = 16.1 Hz, 1H), 3.79 (d, J = 10.6 Hz, 1H), 3.60 (d, J
= 10.5 Hz, 0.6H), 3.26 (dd, J = 9.2, 6.9 Hz, 1H), 3.16 (dd, J = 15.1, 4.1 Hz, 0.6H), 3.08-2.98 (m,
2.2H), 2.89-2.81 (m, 2.2H), 2.80-2.68 (m, 1.2H), 2.56-2.41 (m, 1.2H), 2.39-2.28 (m, 1.2H); IR
(neat, cm-1): = 2358, 1686, 1496. LiAlH4 was added to the mixture of lactams 71 and 72 (134
mg, 2.60 mmol, 5:4 mixture of regioisomers) in dry THF (5 mL) at 0 °C (158 mg, 4.17 mmol)
and stirred at 50 °C for 22 h. Upon cooling to 0 °C, the reaction mixture was quenched with
water (1 mL), filtered and extracted with EtOAc. The solution was concentrated and the residue
was purified by flash chromatography (chloroform/methanol, 7:3), yielding 77 as a colorless
thick oil (82% yield, 107 mg). 1H NMR: δ = 7.42 (s, 1H), 7.35 (m, 3H), 7.29-7.25 (m, 5H),
7.22-7.14 (m, 4H), 7.11 (m, 2H), 6.65 (m, 2H), 6.38 (s, 1H), 4.98 (d, J = 15.0 Hz, 1H), 4.88 (d, J
= 15.0 Hz, 1H), 4.73 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.74 (d, J = 13.0 Hz, 1H),
N
NNBn
H
NN
Bn
Bn
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
3.64 (d, J = 13.0 Hz, 1H), 3.50 (d, J = 10.5 Hz, 1H), 3.02 (m, 1H), 2.83 (dd, J = 15.0, 5.0 Hz,
1H), 2.66-2.52 (m, 4H), 2.38 (m, 1H), 2.24 (m, 1H); 13C NMR (75 MHz): δ = 143.0, 139.6,
139.0, 137.4, 137.0, 136.8, 136.2, 129.1, 128.7, 128.55, 128.52, 128.30, 127.54, 127.49, 126.88,
126.57, 116.2, 61.4, 58.7, 56.7, 50.9, 50.2, 49.0, 42.3, 38.4, 28.8; IR (neat, cm-1): = 3030, 1495,
1447; HRMS (ESI): calcd for C33H34N5 (M+H)+ 500.2809, found 500.2806.
(4S*,4aR*,7aS*)-6-Benzhydryl-3-benzyl-4-(1-benzyl-1H-imidazol-4-yl)-4a,5,6,7,7a,8-
hexahydro-5H-imidazo[4,5-f]isoindole (78): Compounds 73 and 74 were prepared by the
general Diels-Alder reaction procedure from 58 (600 mg, 1.02 mmol) at
95 ºC for 30 h. Chromatography (EtOAc/MeOH, 4:0.5) afforded a 1:1
mixture of 73 and 74 (total: 540 mg, 90%) as a colorless solid. 1H NMR
of the mixture: = 7.44 (s, 1H), 7.40 (s, 1H), 7.36-7.26 (m, 7H), 7.25-7.15 (m, 13H), 7.12-7.02
(m, 14H), 6.99 (appr d, J = 7.0 Hz, 2H), 6.72 (s, 1H), 6.55 (s, 1H), 6.53 (appr d, J = 8.7 Hz, 2H),
6.46 (appr d, J = 7.8 Hz, 2H), 6.41 (s, 1H), 6.33 (s, 1H), 5.02 (d, J = 15.1 Hz, 1H), 4.93 (d, J =
15.1 Hz, 1H), 4.91 (d, J = 15.1 Hz, 1H), 4.83 (d, J = 15.1 Hz, 1H), 4.70 (d, J = 16.0 Hz, 1H),
4.67 (d, J = 15.6 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 3.77 (d, J = 10.5
Hz, 1H), 3.46 (d, J = 8.7 Hz, 1H), 3.26 (dd, J = 9.5, 6.9 Hz, 1H), 3.12-3.04 (m, 2H), 2.85-2.70
(m, 5H), 2.66-2.62 (m, 1H), 2.50-2.46 (m, 2H), 2.37-2.32 (m, 1H); 13C NMR: = 141.4, 140.7,
139.0, 138.78, 138.76, 138.5, 138.2, 138.0, 137.9, 137.5, 137.1, 136.6, 136.56, 136.52, 136.50,
136.0, 129.3, 129.2, 129.0, 128.71, 128.66, 128.61, 128.59, 128.50, 127.9, 127.84, 127.79,
127.53, 127.50, 126.82, 126.79, 126.50, 126.46, 118.6, 116.51, 116.46, 60.5, 58.3, 58.2, 51.2,
51.1, 50.3, 49.2, 49.1, 47.4, 46.8, 46.1, 45.6, 39.3, 37.8, 34.3, 31.7, 28.1, 25.7, 22.7, 21.2, 14.3,
14.2. To a mixture of DA adducts 73 and 74 (100 mg, 0.17 mmol) in anhydrous THF (2 mL)
N
NN
Ph
PhH
NN
Bn
Bn
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was added LiAlH4 (1 M solution in THF, 1.6 mL, 1.6 mmol) at 0 °C, which was allowed to
warm to room temperature and stirred for 4 h. It was then quenched with H2O, NaOH (2N),
Rochelle’s salt. The aqueous layer was extracted with CH2Cl2 (3x). Combined organic solutions
were dried and concentrates. The crude product was triturated with Et2O to provide the pure
product 78 (73 mg, 75%) as a light-brown semi-solid. 1H NMR: = 7.40-7.07 (m, 20H), 6.61
(appr d, J = 6.4 Hz, 2H), 6.34 (s, 1H), 4.95 (d, J = 15.1 Hz, 1H), 4.86 (d, J = 15.1 Hz, 1H), 4.72
(d, J = 16.0 Hz, 1H), 4.47 (s, 1H), 4.25 (d, J = 16.0 Hz, 1H), 3.45 (d, J = 9.6 Hz, 1H), 2.88 (m,
1H), 2.78 (dd, J = 15.0, 4.1 Hz, 1H), 2.57-2.40 (m, 5H), 2.25 (m, 1H), 2.58 (m, 1H), 2.21 (s, 6H),
2.09 (ddd, J = 12.3, 12.0, 5.0 Hz, 1H), 1.99 (s, 6H); 13C NMR: = 144.6, 144.2, 142.8, 139.0,
137.5, 137.1, 136.9, 136.2, 129.1, 128.6, 128.4, 127.9, 127.53, 127.49, 126.9, 126.7, 126.5,
116.3, 76.7, 58.4, 56.4, 50.9, 49.9, 48.9, 42.2, 38.5, 28.8. IR (KBr, cm-1): 3062, 3030, 2922,
2797, 1659, 1599, 1496, 1453, 1278, 1146, 1076, 1029, 736, 705, 639; ESI-MS (m/z), positive
mode: 576 (M+H+, 100%), 486 (5%); negative mode: 610 (M+Clֿ, 21%), 574 ([M-H]ֿ, 28%),
563 (60%), 485 (100%). HR-MS (m/z): calcd for (M+H)+ C39H38N5 576.3122, found 576.3121.
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
Thermal ellipsoid plots for X-ray structures for compounds 20a, 62 and 68 showing the atoms in the asymmetric unit, the key molecule (Dias26A, Dias184s, and RD251A) are illustrated below
N
NO
20a
PhPhPh
Figure S1: X-ray structure of compound 20a (compound crystallizes with a molecule of benzene)
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
N
NNBn
HPh O
H
SOO
NMeMe 62
Figure S2: X-ray structure of compound 62 (there are two molecules in the asymmetric unit)
Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011
N
NN
H
NN
Ph
Ph
H
S
S
OO
O
O
NMeMe
NMe
Me
O
68
Figure S3: X-ray structure of compound 68 (compound crystallizes with a molecule of dichloromethane)
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References: 1. Sellier, C.; Buschauer, A.; Elz, S.; Schunack, W. Liebigs Ann. Chem. 1992, 317-323. 2. Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229-2230. 3. Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari, M. K.; He, Y.; Dias, H. V. R. J. Org. Chem.
2007, 72, 3741. 4. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989-993. 5. Greig, I. R.; Tozer, M. J.; Wright, P. T. Org. Lett. 2001, 3, 369-371. 6. Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595-4597.
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