intramolecular diels-alder chemistry of 4 … diels-alder chemistry of 4-vinylimidazoles ... 3,...

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


(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


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


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


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


(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


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


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


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


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


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


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


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


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


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


(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


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


(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


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


(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


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


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.


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)


N

NNBn

HPh O

H

SOO

NMeMe 62

Figure S2: X-ray structure of compound 62 (there are two molecules in the asymmetric unit)


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)


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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