Syntheses of Hexahydro-1H-pyrrolo[1,2-a]imidazoles
J . Org. Chem., Vol. 65, No. 12, 2000 3687
for C15H18N2: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.95; H,
8.25; N, 12.77.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-P h en yl-
5-(b en zot r ia zol-1-yl)h exa h yd r o-1H -p yr r olo[1,2-a ]im id -
a zole (18). A mixture of 2,5-dimethoxytetrahydrofuran (1.3
mL, 10 mmol) and 0.1 M HCl aqueous solution (40 mL) was
refluxed under N2 for 1 h and then cooled to room temperature.
A solution of benzotriazole (1.19 g, 10 mmol) and N-phenyl-
ethylenediamine (1.36 g, 10 mmol) in CH2Cl2 (100 mL) was
added and the mixture stirred overnight. The reaction mixture
was washed with 2 M NaOH solution and H2O. The organic
layer was dried over anhyd Na2SO4. After removal of the
solvent in vacuo, the residue was purified by column chroma-
tography (silica gel) with hexane/EtOAc (10:1) as eluent to
give 1-phenyl-5-(benzotriazol-1-yl)hexahydro-1H-pyrrolo[1,2-a]-
imidazole (18) and N-[2-(1H-pyrrol-1-yl)ethyl]aniline (19).
1-P h en yl-5-(ben zotr ia zol-1-yl)h exa h yd r o-1H-p yr r olo-
[1,2-a ]im id a zole (18): colorless crystal; mp 98.0-99.0 °C; 1H
NMR δ 2.10-2.22 (m, 1H), 2.42-2.70 (m, 3H), 3.12-3.40 (m,
3H), 3.68-3.81 (m, 1H), 4.97-5.03 (m, 1H), 5.98 (t, J ) 6.3
Hz, 1H), 6.63 (d, J ) 8.0 Hz, 2H), 6.78 (t, J ) 7.1 Hz, 1H),
7.27 (t, J ) 7.7 Hz, 2H), 7.36 (t, J ) 7.8 Hz, 1H), 7.47 (t, J )
7.8 Hz, 1H), 7.86 (d, J ) 8.2 Hz, 1H), 8.07 (d, J ) 8.2 Hz, 1H);
13C NMR δ 29.7, 31.0, 46.8, 49.2, 79.6, 81.0, 111.5, 113.2, 117.2,
119.8, 123.9, 126.9, 129.1, 131.5, 145.8, 146.8. Anal. Calcd for
1-P h e n yl-5-vin ylh e xa h yd r o-1H -p yr r olo[1,2-a ]im id -
a zole (20d ): colorless oil; 1H NMR δ 1.70-1.88 (m, 2H), 1.94-
2.06 (m, 1H), 2.30-2.43 (m, 1H), 3.04-3.32 (m, 4H), 3.57-
3.68 (m, 1H), 4.78 (dd, J ) 5.8, 2.2 Hz, 1H), 5.13 (d, J ) 10.1
Hz, 1H), 5.23 (d, J ) 17.0 Hz, 1H), 5.72-5.87 (m, 1H), 6.53 (d,
J ) 8.0 Hz, 2H), 6.70 (t, J ) 7.4 Hz, 1H), 7.22 (t, J ) 7.7 Hz,
2H); 13C NMR δ 31.1, 32.6, 45.7, 47.8, 66.7, 80.4, 112.8, 116.3,
116.5, 129.1, 140.5, 146.0. Anal. Calcd for C14H18N2: C, 78.46;
H, 8.47; N, 13.07. Found: C, 78.25; H, 8.72; N, 13.06.
1-P h en yl-5-(4-m et h ylp h en yl)h exa h yd r o-1H -p yr r olo-
[1,2-a ]im id a zole (20e): pale yellow plate; mp 74.0-75.0 °C;
1H NMR δ 1.80-1.97 (m, 2H), 2.01-2.24 (m, 1H), 2.35 (s, 3H),
2.38-2.48 (m, 1H), 3.00-3.11 (m, 2H), 3.21-3.30 (m, 1H),
3.63-3.73 (m, 1H), 3.87 (dd, J ) 9.9, 4.2 Hz, 1H), 4.89 (dd, J
) 5.5, 3.5 Hz, 1H), 6.57 (d, J ) 8.2 Hz, 2H), 6.72 (t, J ) 7.2
Hz, 1H), 7.16 (d, J ) 7.8 Hz, 2H), 7.24 (t, J ) 8.0 Hz, 2H),
7.32 (d, J ) 7.9 Hz, 2H); 13C NMR δ 21.1, 31.5, 35.9, 45.9,
48.4, 67.3, 80.6, 112.9, 116.3, 127.2, 129.1, 129.2, 136.8, 139.9,
146.1. Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06.
Found: C, 81.59; H, 8.29; N, 9.87.
1-P h en yl-5-(4-flu or o-3-m et h ylp h en yl)h exa h yd r o-1H -
p yr r olo[1,2-a ]im id a zole (20f): colorless oil; 1H NMR δ 1.80-
1.94 (m, 2H), 2.10-2.20 (m, 1H), 2.28 (s, 3H), 2.37-2.48 (m,
1H), 2.96-3.14 (m, 2H), 3.21-3.30 (m, 1H), 3.60-3.72 (m, 1H),
3.82 (dd, J ) 8.8, 3.4 Hz, 1H), 4.87 (dd, J ) 5.8, 3.3 Hz, 1H),
6.55 (d, J ) 8.3 Hz, 2H), 6.71 (t, J ) 7.1 Hz, 1H), 6.95 (t, J )
8.8 Hz, 1H), 7.14-7.30 (m, 4H); 13C NMR δ 14.6 (d, J ) 3.4
Hz), 31.5, 35.9, 45.8, 48.3, 66.9, 80.5, 112.9, 114.7 (d, J ) 22.4
Hz), 116.3, 124.6 (d, J ) 17.3 Hz), 126.0 (d, J ) 7.8 Hz), 129.1,
130.0 (d, J ) 5.1 Hz), 138.3 (d, J ) 3.3 Hz), 146.1, 160.5 (d, J
) 242.0 Hz). Anal. Calcd for C19H21FN2: C, 77.00; H, 7.14; N,
9.45. Found: C, 76.55; H, 7.52; N, 9.36.
C
18H19N5: C, 70.79; H, 6.27; N, 22.93. Found: C, 70.61; H,
6.40; N, 22.90.
N-[2-(1H-P yr r ol-1-yl)eth yl]a n ilin e (19): light yellow oil;
1H NMR δ 3.45 (t, J ) 5.9 Hz, 2H), 3.50-3.75 (brs, 1H), 4.04
(t, J ) 6.0 Hz, 2H), 6.14-6.20 (m, 2H), 6.57 (d, J ) 8.0 Hz,
2H), 6.60-6.68 (m, 2H), 6.73 (t, J ) 7.4 Hz, 1H), 7.17 (t, J )
8.0 Hz, 2H); 13C NMR δ 44.9, 48.4, 108.6, 113.1, 117.9, 120.7,
129.3, 147.1. Anal. Calcd for C12H14N2: C, 77.38; H, 7.58.
Found: C, 77.16; H, 7.89.
Gen er a l P r oced u r e for th e Nu cleop h ilic Su bstitu tion
of 18 w ith Gr ign a r d Rea gen ts. To a solution of 18 (0.3 g, 1
mmol) in dry THF (10 mL) under N2 at -78 °C was added
dropwise a solution of an appropriate Grignard reagent (1
mmol) in diethyl ether. The reaction mixture was allowed to
warm to room temperature and stirred overnight. Then, the
mixture was successively washed with 2 M NaOH and water.
The combined aqueous phase was extracted with EtOAc. The
combined organic layers were dried over anhyd Na2SO4. After
removal of the solvent in vacuo, the residue was purified by
column chromatography (silica gel) with hexane/EtOAc (10:1)
as eluent to afford 20a -f.
Gen er a l P r oced u r e for th e Rea ction of 18 w ith Allyl-
sila n e a n d Silyl Eth er s. To a solution of 18 (0.30 g, 1 mmol)
and (2-methylpropenyl)trimethylsilane (21) or silyl ether 23a ,b
(1 mmol) in dry CH2Cl2 (10 mL) under N2 was added BF3‚Et2O
(0.12 mL, 1 mmol) at 0 °C and the mixture stirred for 3 h.
The mixture was warmed to room temperature and stirred for
another 3 h. The mixture was washed with 5% NaHCO3 and
H2O, and the combined aqueous phase was extracted with
EtOAc. The combined organic layers were dried over anhyd
Na2SO4. After removal of the solvent in vacuo, the residue was
purified by column chromatography (silica gel) with hexane/
EtOAc (5:1) as eluent to afford 22 or 24a ,b.
1-P h en yl-5-b en zylh exa h yd r o-1H -p yr r olo[1,2-a ]im id -
a zole (20a ): light yellow oil; H NMR δ 1.60-1.80 (m, 2H),
1-P h en yl-5-(2-m et h yl-2-p r op en yl)h exa h yd r o-1H -p yr -
r olo[1,2-a ]im id a zole (22): light yellow oil; 1H NMR δ 1.52-
1.68 (m, 1H), 1.77 (s, 3H), 1.70-1.86 (m, 1H), 1.96-2.04 (m,
1H), 2.04-2.14 (m, 1H), 2.26-2.37 (m, 1H), 2.42 (dd, J ) 12.2,
2.4 Hz, 1H), 2.96-3.07 (m, 1H), 1.13-3.31 (m, 3H), 3.58-3.68
(m, 1H), 4.72-4.82 (m, 3H), 6.55 (d, J ) 8.3 Hz, 2H), 6.71 (t,
J ) 7.1 Hz, 1H), 7.23 (t, J ) 8.2 Hz, 2H); 13C NMR δ 22.9,
30.7, 31.5, 44.5, 46.2, 49.2, 62.0, 80.9, 112.1, 112.9, 116.3, 129.0,
143.3, 146.1. Anal. Calcd for C16H22N2: C, 79.29; H, 9.15; N,
11.56. Found: C, 79.12; H, 9.59; N, 11.47.
1
1.82-1.93 (m, 1H), 2.23-2.37 (m, 1H), 2.65 (dd, J ) 12.9, 8.0
Hz, 1H), 2.94-3.18 (m, 4H), 3.19-3.28 (m, 1H), 3.52-3.63 (m,
1H), 4.77 (dd, J ) 5.5, 2.6 Hz, 1H), 6.53 (d, J ) 8.0 Hz, 2H),
6.69 (t, J ) 7.2 Hz, 1H), 7.13-7.38 (m, 7H); 13C NMR δ 30.8,
31.6, 42.6, 46.2, 49.4, 65.6, 81.1, 112.9, 116.4, 126.1, 128.3,
129.0, 129.1, 139.5, 146.1. Anal. Calcd for C19H22N2: C, 81.97;
H, 7.97; N, 10.06. Found: C, 81.82; H, 8.33; N, 10.28.
1-P h en yl-5-p en t ylh exa h yd r o-1H -p yr r olo[1,2-a ]im id -
a zole (20b): colorless oil; 1H NMR δ 0.90 (t, J ) 6.1 Hz, 3H),
1.24-1.41 (m, 7H), 1.45-1.58 (m, 1H), 1.62-1.72 (m, 1H),
1.74-1.84 (m, 1H), 1.97-2.10 (m, 1H), 2.25-2.36 (m, 1H),
2.71-2.83 (m, 1H), 3.13-3.22 (m, 2H), 3.22-3.30 (m, 1H),
3.55-3.64 (m, 1H), 4.74 (dd, J ) 5.5, 3.3 Hz, 1H), 6.55 (d, J )
8.3 Hz, 2H), 6.70 (t, J ) 7.1 Hz, 1H), 7.22 (t, J ) 8.0 Hz, 2H);
13C NMR δ 14.0, 22.6, 26.5, 31.0, 31.6, 32.2, 36.1, 46.2,
49.3, 64.1, 81.0, 112.9, 116.3, 129.1, 146.2. Anal. Calcd for
1-P h en yl-2-(1-ph en ylh exah ydr o-1H-pyr r olo[1,2-a ]im id-
a zol-5-yl)-1-et h a n on e (24a ): colorless needles; mp 101.0-
1
102.0 °C; H NMR δ 1.53-1.68 (m, 1H), 1.81-1.94 (m, 1H),
2.17-2.39 (m, 2H), 3.03-3.41 (m, 5H), 3.47-3.58 (m, 1H),
3.58-3.68 (m, 1H), 4.77 (dd, J ) 5.2, 3.3 Hz, 1H), 6.56 (d, J )
8.2 Hz, 2H), 6.71 (t, J ) 7.1 Hz, 1H), 7.23 (t, J ) 8.0 Hz, 2H),
7.47 (t, J ) 7.4 Hz, 2H), 7.57 (t, J ) 7.1 Hz, 1H), 7.99 (d, J )
7.6 Hz, 2H); 13C NMR δ 31.0, 31.9, 45.3, 46.5, 49.8, 60.3, 80.7,
112.9, 116.4, 128.1, 128.6, 129.1, 133.1, 137.1, 146.1, 199.2.
Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found:
C, 78.36; H, 7.55; N, 9.14.
C
17H26N2: C, 79.00; H, 10.16; N, 10.84. Found: C, 78.60; H,
10.47; N, 11.09.
1-P h en yl-5-(p r op -1-yn yl)h exa h yd r o-1H-p yr r olo[1,2-a ]-
im id a zole (20c): pale yellow needles; mp 53.0-54.0 °C; 1H
NMR δ 1.75-1.88 (m, 1H), 1.86 (s, 3H), 1.91-2.09 (m, 1H),
2.09-2.21 (m, 1H), 2.32-2.44 (m, 1H), 3.18-3.32 (m, 2H),
3.33-3.42 (m, 1H), 3.53-3.67 (m, 2H), 4.76 (dd, J ) 5.3, 2.3
Hz, 1H), 6.51 (d, J ) 8.2 Hz, 2H), 6.71 (t, J ) 7.2 Hz, 1H),
7.22 (t, J ) 7.5 Hz, 2H); 13C NMR δ 3.6, 31.0, 32.9, 45.8, 48.7,
54.3, 78.4, 79.3, 79.8, 112.9, 116.5, 129.1, 145.9. Anal. Calcd
Met h yl 2-m et h yl-2-(1-p h en ylh exa h yd r o-1H -p yr r olo-
[1,2-a ]im id a zol-5-yl)p r op a n oa te (24b): colorless oil; 1H
NMR δ 1.15 (s, 3H), 1.22 (s, 3H), 1.63-1.74 (m, 1H), 1.84-
2.00 (m, 2H), 2.01-2.12 (m, 1H), 3.02-3.11 (m, 1H), 3.12-
3.31 (m, 3H), 3.44-3.58 (m, 1H), 3.69 (s, 3H), 4.64 (dd, J )
5.3, 3.2 Hz, 1H), 6.58 (d, J ) 8.2 Hz, 2H), 6.70 (t, J ) 7.4 Hz,
1H), 7.22 (t, J ) 7.9 Hz, 2H); 13C NMR δ 21.2, 21.4, 26.6, 31.4,