2228 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
2-(3-(2-Th ien yl)isoxa zol-5-yl)eth a n ol (13). The procedure
described for 12 was employed to scale with the following
differences: 2-thiophenealdoxime (358 mg, 2.8 mmol), HCl (1.43
mL, 17 mmol), sodium nitrite (583 mg, 8.4 mmol), 3-butyn-1-ol
(493 mg, 7.0 mmol), and triethylamine (342 mg, 3.4 mmol) to
were used give 13 (286 mg, 52%). Mp 51-52 °C; IR 3369, 2936,
6 Hz, 2H), 2.95 (t, J ) 7.5 Hz, 2H), 2.08 (tt, J ) 7.5 and 6 Hz,
2H); 13C NMR δ 173.5, 170.4, 170.4, 163.2, 154.2, 154.2, 149.6,
148.7, 136.9, 136.8, 128.5, 128.1, 127.9, 124.3, 121.5, 101.4, 101.3,
100.0, 73.0, 69.8, 63.6, 62.5, 27.5, 23.4. Anal. Calcd for
C26H24N4O5: C, 66.09; H, 5.12; N, 11.86. Found: C, 66.24; H,
5.21; N, 11.84.
1598, 1050 cm-1
;
1H NMR δ 7.39 (dd, J ) 3.5 and 1 Hz, 1H),
5-[(Ben zyloxy)m et h yl]-5′-{[(3-(2-t h ien yl)isoxa zol-5-yl)-
m eth oxy]-m eth yl}-3,3′-d iisoxa zole (19). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: alcohol 12 (127 mg, 701 µmol), bromide 5 (245 mg, 701
µmol), NaH (18.5 mg, 771 µmol), and chromatography (35-50%
ethyl acetate in hexanes) were used to give 19 (255 mg, 81%).
7.38 (dd, J ) 5 and 1 Hz, 1H), 7.08 (dd, J ) 5 and 3.5 Hz, 1H),
6.36 (s, 1H), 3.92 (t, J ) 6 Hz, 2H), 3.4 (b, var., 1H), 2.48 (t, J )
6 Hz, 2H); 13C NMR δ 171.2, 157.4, 130.6, 127.4, 127.3, 126.6,
100.1, 59.6, 30.1.
(3-(2-F u r yl)isoxa zol-5-yl)m eth a n ol (14).34 The procedure
described for 12 was employed to scale with the following
differences: 2-furanaldoxime (945 mg, 8.5 mmol), HCl (4.29 mL,
52 mmol), sodium nitrite (1.76 g, 26 mmol), propargyl alcohol
(1.43 g, 26 mmol), and triethylamine (1.03 g, 10 mmol) were used
to give 14 (646 mg, 46%). Mp 83-84 °C; IR 3337, 3128, 2934,
1064, 1013 cm-1; 1H NMR δ 7.53 (d, J ) 1 Hz, 1H), 6.88 (d, J )
3.5 Hz, 1H), 6.51 (dd, J ) 3.5 and 1 Hz, 1H), 6.50 (s, 1H), 4.78
(s, 2H), 3.5 (b, var., 1H); 13C NMR δ 171.9, 157.0, 154.0, 144.0,
111.7, 110.5, 99.5, 56.2.
1
Mp 72-73 °C; IR 3122, 2927, 2867, 1096, 1069 cm-1; H NMR
δ 7.46 (dd, J ) 3.5 and 1 Hz, 1H), 7.43 (dd, J ) 5 and 1 Hz, 1H),
7.37 (m, 5H), 7.11 (dd, J ) 5 and 3.5 Hz, 1H), 6.85 (s, 1H), 6.80
(s, 1H), 6.57 (s, 1H), 4.78 (s, 2H), 4.75 (s, 2H), 4.69 (s, 2H), 4.64
(s, 2H); 13C NMR δ 170.6, 169.2, 168.5, 157.7, 154.3, 154.0, 136.9,
130.4, 128.5, 128.1, 127.9, 127.7, 127.6, 127.6, 102.0, 101.6, 101.4,
73.0, 63.4, 63.2, 62.5. Anal. Calcd for C23H19N3O5S: C, 61.46;
H, 4.26; N, 9.35. Found: C, 61.14; H, 4.32; N, 9.30.
5-[(Ben zyloxy)m et h yl]-5′-{[(3-(2-t h ien yl)isoxa zol-5-yl)-
eth oxy]-m eth yl}-3,3′-d iisoxa zole (20). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: alcohol 13 (105 mg, 539 µmol), bromide 5 (188 mg, 539
µmol), NaH (14.2 mg, 593 µmol), and chromatography (35-50%
ethyl acetate in hexanes) were used to give 20 (187 mg, 75%).
2-(3-(2-F u r yl)isoxa zol-5-yl)eth a n ol (15). The procedure
described for 12 was employed to scale with the following
differences: 2-furanaldoxime (1.40 g, 13 mmol), HCl (6.35 mL,
77 mmol), sodium nitrite (2.61 g, 38 mmol), 3-butyn-1-ol (2.65
g, 38 mmol), and triethylamine (1.53 g, 15 mmol) were used to
give 15 (903 mg, 40%). Mp 99-100 °C; IR 3358, 3127, 2954, 1052,
Mp 132-133 °C; IR 3136, 3060, 2911, 1092 cm-1 1H NMR δ
;
1
1014 cm-1; H NMR δ 7.52 (d, J ) 1 Hz, 1H), 6.85 (d, J ) 3.5
7.42 (dd, J ) 3.5 and 1 Hz, 1H), 7.34 (m, 6H), 7.07 (dd, J ) 5
and 3.5 Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.33 (s, 1H), 4.67 (s,
2H), 4.66 (s, 2H), 4.61 (s, 2H), 3.87 (t, J ) 6.5 Hz, 2H), 3.08 (t,
J ) 6.5 Hz, 2H); 13C NMR δ 170.5, 170.4, 169.9, 157.6, 154.2,
154.0, 136.8, 130.8, 128.5, 128.0, 127.8, 127.5, 127.3, 127.3, 101.5,
101.3, 100.1, 72.9, 68.0, 63.5, 62.4, 27.5. Anal. Calcd for
C24H21N3O5S: C, 62.19; H, 4.57; N, 9.07. Found: C, 62.04; H,
4.55; N, 8.96.
Hz, 1H), 6.50 (dd, J ) 3.5 and 1 Hz, 1H), 6.36 (s, 1H), 3.97 (t, J
) 6 Hz, 2H), 3.03 (t, J ) 6 Hz, 2H), 2.8 (b, var., 1H); 13C NMR
δ 170.9, 154.7, 144.2, 143.7, 111.6, 110.1, 99.6, 59.8, 30.2. Anal.
Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.51;
H, 5.05; N, 7.87.
5-[(Ben zyloxy)m et h yl]-5′-{[(3-(2-p yr id yl)isoxa zol-5-yl)-
m eth oxy]-m eth yl}-3,3′-d iisoxa zole (16). Alcohol 9 (205 mg,
1.2 mmol) and bromide 5 (407 mg, 1.2 mmol) were dissolved in
THF (2 mL) and added to a slurry of NaH (30.8 mg, 1.3 mmol)
in THF (8 mL) at 0 °C via cannulation. The solution was allowed
to stir for 30 min, at which time it was warmed to room
temperature with stirring for 3 h. The reaction was quenched
with water and extracted with ethyl acetate, and the combined
organic layers were dried with sodium sulfate and the filtrate
was concentrated to give a crude solid. Purification by column
chromatography (50-75% ethyl acetate in hexanes) gave 16 as
a white powder (437 mg, 84%). Mp 99-100.5 °C; IR 3125, 2889,
1099, 1065 cm-1; 1H NMR δ 8.68 (d, J ) 5 Hz, 1H), 8.07 (d, J )
8 Hz, 1H), 7.80 (td, J ) 8 and 2 Hz, 1H), 7.35 (m, 6H), 6.98 (s,
1H), 6.85 (s, 1H), 6.80 (s, 1H), 4.79 (s, 2H), 4.79 (s, 2H), 4.69 (s,
2H), 4.64 (s, 2H); 13C NMR δ 170.4, 169.2, 168.4, 163.2, 154.2,
154.0, 149.8, 149.7, 148.1, 136.8, 128.5, 128.0, 127.8, 124.5, 121.6,
102.6, 101.8, 101.3, 72.9, 63.2, 63.0, 62.4. Anal. Calcd for
C24H20N4O5: C, 64.86; H, 4.54; N, 12.61. Found: C, 64.85; H,
4.61; N, 12.48.
5-[(Ben zyloxy)m et h yl]-5′-{[(3-(2-p yr id yl)isoxa zol-5-yl)-
eth oxy]-m eth yl}-3,3′-d iisoxa zole (17). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: alcohol 10 (156 mg, 818 µmol), bromide 5 (286 mg, 818
µmol), and NaH (21.6 mg, 899 µmol) were used to give 17 (274
mg, 73%). Mp 116-117 °C; IR 3125, 2889, 1106, 1064 cm-1; 1H
NMR δ 8.56 (dd, J ) 3 and 1 Hz, 1H), 7.94 (dd, J ) 8 and 1 Hz,
1H), 7.67 (td, J ) 8 and 2 Hz, 1H), 7.26 (m, 6H), 6.69 (s, 1H),
6.67 (s, 1H), 6.65 (s, 1H), 4.60 (s, 2H), 4.58 (s, 2H), 4.53 (s, 2H),
3.82 (t, J ) 6.5 Hz, 2H), 3.05 (t, J ) 6.5 Hz, 2H); 13C NMR δ
170.6, 170.4, 170.0, 163.4, 154.2, 154.1, 149.6, 148.5, 136.9, 136.7,
128.5, 128.1, 127.8, 124.3, 121.5, 101.5, 101.4, 100.8, 72.9, 68.1,
63.6, 62.4, 27.6. Anal. Calcd for C25H22N4O5: C, 65.49; H, 4.84;
N, 12.22. Found: C, 65.43; H, 4.86; N, 12.20.
5-[(Be n zyloxy)-m e t h yl]-5′-{[(3-(2-fu r yl)isoxa zol-5-yl)-
m eth oxy]-m eth yl}-3,3′-d iisoxa zole (21). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: alcohol 14 (54.1 mg, 327 µmol), bromide 5 (114 mg, 327
µmol), NaH (8.6 mg, 360 µmol), and chromatography (40-60%
ethyl acetate in hexanes) were used to give 21 (112 mg, 79%).
Mp 110-111 °C; IR 3124, 2913, 1106, 1067 cm-1 1H NMR δ
;
7.56 (d, J ) 1.5 Hz, 1H), 7.37 (m, 5H), 6.92 (d, J ) 3.5 Hz, 1H),
6.85 (s, 1H), 6.80 (s, 1H), 6.59 (s, 1H), 6.53 (dd, J ) 3.5 and 1.5
Hz, 1H) 4.78 (s, 2H), 4.76 (s, 2H), 4.69 (s, 2H), 4.64 (s, 2H); 13
C
NMR δ 170.6, 169.2, 168.2, 154.9, 154.4, 154.1, 144.0, 143.9,
136.9, 128.6, 128.1, 127., 111.8, 110.5, 102.0, 101.4, 101.2, 73.0,
63.3, 63.2, 62.5. Anal. Calcd for C23H19N3O6: C, 63.74; H, 4.42;
N, 9.70. Found: C, 63.55; H, 4.37; N, 9.48.
5-[(Be n zyloxy)m e t h yl]-5′-{[(3-(2-fu r yl)isoxa zol-5-yl)-
et h oxy]m et h yl}-3,3′-d iisoxa zole (22). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: diheterocyclic alcohol 15 (227 mg, 1.27 mmol), bromide
5 (442 mg, 1.27 mmol), NaH (33.5 mg, 1.4 mmol), and chroma-
tography (40% to 60% ethyl acetate in hexanes) were used to
give 22 (409 mg, 72%). Mp 81-82 °C; IR 3124, 3065, 2909, 1108
cm-1; 1H NMR δ 7.52 (d, J ) 2 Hz, 1H), 7.36 (m, 5H), 6.86 (d, J
) 3.5 Hz, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 6.49 (dd, J ) 3.5 and 2
Hz, 1H) 6.35 (s, 1H), 4.69 (s, 2H), 4.68 (s, 2H), 4.63 (s, 2H), 3.89
(t, J ) 6.5 Hz, 2H), 3.10 (t, J ) 6.5 Hz, 2H); 13C NMR δ 170.5,
170.1, 170.0, 154.9, 154.2, 154.1, 144.3, 143.7, 136.5, 128.5, 128.1,
127.8, 111.6, 110.0, 101.5, 101.4, 99.6, 73.0, 68.0, 63.6, 62.5, 27.5.
Anal. Calcd for C24H21N3O6: C, 64.42; H, 4.73; N, 9.39. Found:
C, 64.64; H, 4.82; N, 9.33.
Ack n ow led gm en t. We thank the National Science
Foundation and the Department of Energy for their
financial support of this research.
5-[(Ben zyloxy)m et h yl]-5′-{[(3-(2-p yr id yl)isoxa zol-5-yl)-
p r op oxy]-m eth yl}-3,3′-d iisoxa zole (18). The procedure de-
scribed for 16 was employed to scale with the following differ-
ences: alcohol 11 (148 mg, 723 µmol), bromide 5 (252 mg, 723
µmol), and NaH (19.1 mg, 795 µmol) to give 18 (304 mg, 89%).
Mp 107-108 °C; IR 3111, 3032, 2887, 1117, 1068 cm-1; 1H NMR
δ 8.66 (dd, J ) 6.5 and 1 Hz, 1H), 8.04 (d, J ) 8 Hz, 1H), 7.77
(td, J ) 8 and 2 Hz, 1H), 7.36 (m, 6H), 6.79 (s, 1H), 6.78 (s, 1H),
6.65 (s, 1H), 4.68 (s, 2H), 4.67 (s, 2H), 4.64 (s, 2H), 3.64 (t, J )
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 12 and 13. This material is
J O991551E
(34) Yoshioka, T.; Sasaki, T. J pn. Patent 32,782, 1969.