Zhou and Snider
JOCArticle
to give 94 mg of a 3:1 mixture of benzisoxazolinone 21b and
methyl 2-amino-30,50-dimethoxy-[1,10-biphenyl]-3-carboxy-
late (22b) as a semisolid. The crude product was washed with
10 mL of 3:1 hexanes/EtOAc, which removed the amino ester
giving 56 mg (66%) of pure 21b: mp 124 °C (decomposition);
1H NMR (CDCl3) 8.53 (br s, 1, NH), 7.85 (d, 1, J=7.3), 7.75
(d, 1, J=7.3), 7.40 (dd, 1, J=7.3, 7.3), 6.77 (d, 2, J=2.0), 6.52 (t, 1,
J=2.0), 3.85 (s, 6); 13C NMR (CDCl3) 169.0, 161.5 (2 C), 153.0,
137.0, 134.0, 126.3, 125.4, 124.8, 113.1, 105.7 (2 C), 100.5, 55.5
(2 C); IR (neat) 1742, 1736, 1605, 1156; HRMS (ESIþ) calcd for
C15H14NO4 (MHþ) 272.0923, found 272.0919.
The mixture was cooled, diluted with Et2O, and filtered. The
filtrate was concentrated to give 400 mg of crude 26a. Flash
chromatography on silica gel (6:1 hexanes/EtOAc) gave 273 mg
(95%) of pure 26a: mp 109.5-111 °C; 1H NMR (CDCl3) 8.08
(d, 1, J=8.0), 7.62 (dd, 1, J=8.0, 8.0), 7.56 (d, 1, J=8.0), 7.56 (d, 1,
J=8.0), 7.46 (dd, 1, J=8.0, 8.0), 7.33 (dd, 1, J=8.0, 8.0), 7.14
(d, 1, J=8.0), 4.50 (dd, 1, J=12.8, 4.4), 4.41 (dd, 1, J=12.8, 7.6),
3.92 (s, 3), 1.79 (dd, 1, J=7.6, 4.4, OH); 13C NMR (CDCl3) 163.6,
149.8, 139.0, 135.5, 133.8, 133.4, 130.5, 129.7, 129.6, 129.4, 128.7,
127.7, 123.0, 63.0, 53.1; IR 1730, 1540, 1372, 1440; HRMS (ESIþ)
calcd for C15H13NO5Na (MNaþ) 310.0691, found 310.0703.
4H,7H-Isoxazolo[4,3,2-de]phenanthridin-4-one (12). A solu-
tion of 26a (73 mg, 0.26 mmol) in 5 mL of 2:2:1 MeOH/THF/
H2O was treated with activated Zn (80 mg) and NH4Cl (60 mg).
The resulting mixture was sonicated at 25 °C for 30 min. The
reaction was diluted with EtOAc and filtered. The filtrate was
washed with H2O and brine and dried (Na2SO4). Concentration
gave 64 mg of a 3:1 mixture of 7-(2-hydroxymethylphenyl)-2,
1-benzisoxazolin-3-one (27a) and methyl 2-amino-20-hydro-
xymethyl-[1,10-biphenyl]-3-carboxylate as a solid.
Flash chromatography of the 3:1 mixture of 21b and 22b on
silica gel (5:1 hexanes/EtOAc) resulted in the decomposition of
21b. Only 22b was isolated in 15-25% yield: 1H NMR (CDCl3)
7.89 (dd, 1, J=8.0, 1.8), 7.23 (dd, 1, J=8.0, 1.2), 6.68 (dd, 1, J=
8.0, 8.0), 6.55 (d, 2, J=2.0). 6.48 (t, 1, J=2.), 6.04 (br, 2, w1/2
=
19, NH2), 3. 88 (s, 3), 3.81 (s, 6); 13C NMR (CDCl3) 168.8, 161.2
(2 C), 147.8, 140.4, 134.6, 130.8, 128.6, 115.5, 110.5, 107.1 (2 C),
99.8, 55.4 (2 C), 51.6; HRMS (ESIþ) calcd for C16H18NO4
(MHþ) 288.1236, found 288.1222.
1-Hydroxymethyl-7-phenyl-2,1-benzisoxazolin-3-one (13). A
solution of 21a (50 mg, 0.23 mmol) in 8 mL of 1:1 THF/H2O
was treated with Na2CO3 (60 mg) and 37% aqueous CH2O
(0.7 mL). The reaction was stirred at 25 °C for 2.5 h. The solu-
tion was then diluted with EtOAc, washed with water and brine,
and dried (Na2SO4). Concentration gave 44 mg of crude 13 as
a white solid, which was washed with 10:1 hexanes/EtOAc to give
34 mg (61%) of pure 13: mp 119 °C (decomposition); 1H NMR
(CDCl3) 7.82 (d, 1, J=8.0), 7.64 (d, 1, J=8.0), 7.59 (d, 2, J=7.2),
7.50 (dd, 2, J=7.2, 7.2), 7.44 (t, 1, J=7.2), 7.42 (dd, 1, J=8.0, 8.0),
4.81 (s, 2), 3.14 (br s, 1, w1/2=21.6, OH); 13C NMR (CDCl3) 168.6,
152.1, 136.1, 136.0, 129.2 (2 C), 128.8, 128.2 (2 C), 128.1, 126.0,
124.7, 116.3, 74.1; IR 1764 1739; HRMS (ESIþ) calcd for
C14H11NO3Na (MNaþ) 264.0637, found 264.0636.
7-(3,5-Dimethoxyphenyl)-1-hydroxymethyl-2,1-benzisoxazolin-
3-one (23b). A solution of 21b (51 mg, 0.21 mmol) in 8 mL of 1:1
THF/H2O was treated with Na2CO3 (60 mg) and 37% aqueous
CH2O (0.7 mL). The reaction was stirred at 25 °C for 12 h. The
solution was then diluted with EtOAc, washed with water and
brine, and dried (Na2SO4). Concentration gave 48 mg of white
solid crude 23b, which was washed with 5:1 hexanes/EtOAc
to give 43 mg (76%) of pure 23b: mp 136 °C (decomposition);
1H NMR (CDCl3) 7.80 (d, 1, J=8.0), 7.64 (d, 1, J=8.0), 7.39
(dd, 1, J = 8.0, 8.0), 6.71-6.76 (m, 2), 6.51-6.55 (m, 1), 4.89
(d, 2, J = 8.0), 3.83 (s, 6), 3.50 (t, 1, J = 8.0, OH); 13C NMR
(CDCl3) 168.7, 161.2 (2 C), 152.0, 137.9, 135.7, 128.0, 125.8,
124.8, 116.2, 106.2 (2 C), 100.6, 74.3, 55.5(2 C); IR(neat) 3413,
1767, 1746, 1602, 1157; HRMS (ESIþ) calcd for C16H15NO5Na
(MNaþ) 324.0848, found 324.0842.
8,10-Dimethoxy-4H,7H-isoxazolo[4,3,2-de]phenanthridin-4-one
(24b). A solution of 23b (24 mg, 0.08 mmol) in CH2Cl2 (3 mL)
was treated with TFA (0.3 mL) in one portion at 0 °C. The
reaction was slowly warmed to 25 °C and stirred for 30 min.
Concentration and flash chromatography of the residue on
silica gel (6:2:1 hexanes/EtOAc/CH2Cl2) gave 6 mg (27%) of
pure 24b: mp 222 °C (decomposition); 1H NMR (CDCl3) 7.76
(d, 1, J=7.3), 7.70 (d, 1, J=8.0), 7.26 (dd, 1, J=8.0, 7.3), 6.90
(d, 1, J=1.8), 6.49 (d, 1, J=1.8), 4.63 (s, 2), 3.90 (s, 3), 3.87 (s, 3);
13C NMR (CDCl3) 168.0, 161.1, 157.8, 156.5, 130.7, 127.1,
124.9, 124.5, 121.6, 112.2, 110.7, 99.3, 99.0, 55.7, 55.6, 48.7;
IR (neat) 1762; HRMS (ESIþ) calcd for C16H14NO4 (MHþ)
284.0923, found 284.0920.
Methyl 20-Hydroxymethyl-2-nitro-[1,10-biphenyl]-3-carboxylate
(26a). A mixture of methyl 3-chloro-2-nitrobenzoate (18) (220 mg,
1.0 mmol), 2-(hydroxymethyl)phenylboronic acid (25a) (228 mg,
1.5 mmol, 1.5 equiv), Pd(OAc)2 (7 mg, 0.03 equiv), SPhos (13 mg,
0.03 equiv), and K3PO4 (636 mg, 3.0 mmol, 3 equiv) in THF (1 mL)
and H2O (10 μL) was heated at 40 °C under N2 for 4 h.
The crude mixture of 27a and the amino ester was dissolved in
anhydrous CH2Cl2 (5 mL) and cooled to 0 °C. NEt3 (0.1 mL,
0.75 mmol) and MsCl (40 μL, 0.5 mmol) were added, and the
resulting reaction was stirred at 0 °C for 15 min. The reaction
was diluted with Et2O and washed with water and brine. The
organic layer was dried (Na2SO4) and concentrated to give
102 mg of crude 7-(2-methanesulfonyloxymethylphenyl)-2,
1-benzisoxazolin-3-one.
The crude mesylate was dissolved in 4 mL of 1:1 THF/H2O,
and Na2CO3 (80 mg) was added at 25 °C. The resulting mixture
was stirred at 25 °C for 40 min. The reaction was diluted with
Et2O and washed with brine. The organic layer was dried
(Na2SO4) and concentrated to give 62 mg of crude 12. Flash
chromatography (7:1 hexanes/EtOAc) gave 21 mg (37% from
26a) of pure 12: mp 137-138 °C; 1H NMR (CDCl3) 7.83 (d, 1,
J=8.0), 7.81 (d, 1, J=8.0), 7.71 (d, 1, J=8.0), 7.46 dd, 1, J=8.0,
8.0), 7.37 (dd, 1, J=8.0, 8.0), 7.32 (d, 1, J=8.0), 7.31 (dd, 1, J=
8.0, 8.0), 4.65 (s, 2); 13C NMR (CDCl3) 167.9, 156.4, 131.1,
129.35, 129.29, 129.2, 128.4, 127.0, 125.4, 124.4, 123.2, 121.7,
111.1, 55.3; IR 1766; HRMS (EI) calcd for C14H9NO2 (Mþ)
223.0633, found 223.0636.
Methyl 20-Hydroxymethyl-40,60-dimethoxy-2-nitro-[1,10-biphenyl]-
3-carboxylate (26b). Boronic acid 25b was prepared from 886 mg
(2.68 mmol) of the THP ether of 2-bromo-3,5-dimethoxybenzyl
alcohol by the literature procedure,12 except that the recrystalli-
zation step was not carried out. The entire batch of crude
25b was used directly in the Suzuki coupling.
Freshly distilled THF (1 mL) was added to a mixture of
Pd(OAc)2 (11.5 mg, 0.07 equiv) and SPhos (64 mg, 0.21 equiv).
The resulting solution was stirred at 25 °C under N2 for 30 min
to form a Pd stock solution. A mixture of methyl 3-chloro-2-
nitrobenzoate (18) (160 mg, 0.74 mmol), crude boronic acid 25b
(900 mg, 3 equiv), and K3PO4 (530 mg, 2.5 mmol, 3.4 equiv) was
mixed in a flask. The flask was purged with N2 three times.
Freshly distilled toluene (3 mL) and the Pd stock solution were
then added. The resulting mixture was refluxed for 90 min. The
mixture was cooled, diluted with Et2O, and filtered through a
pad of Celite. The filtrate was concentrated to give 946 mg of
crude 26b. Flash chromatography (hexanes/EtOAc 3:1 to 2:1)
1
gave 213 mg (83%) of pure 26b: mp 129-131 °C; H NMR
(CDCl3) 8.03 (d, 1, J=8.0), 7.60 (dd, 1, J=8.0, 7.3), 7.47 (d, 1,
J=7.3), 6.72 (d, 1, J=1.8), 6.42 (d, 1, J=1.8), 4.38 (dd, 1, J=
12.8, 3.6), 4.29 (dd, 1, J=12.8, 7.3), 3.90 (s, 3), 3.85 (s, 3), 3.66
(s, 3), 1.90 (dd, 1, J=7.3, 3.6, OH); 13C NMR (CDCl3) 164.0,
161.5, 158.0, 150.6, 141.7, 136.7, 130.6, 130.2, 130.0, 123.3,
114.7, 104.2, 98.0, 62.9, 55.8, 55.4, 53.0; IR 1730, 1540, 1370,
1155; HRMS (EI) calcd for C17H17NO7 (Mþ) 347.1005, found
347.1006.
8230 J. Org. Chem. Vol. 75, No. 23, 2010