Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2823
and the reaction was quenched with saturated NaHCO3. The
organic layer, washed with saturated NaHCO3 and water, was
dried and vacuum-concentrated. The resulting crude oil was
loaded onto a plug of silica and washed with CH2Cl2 before
elution with 9:1 CH2Cl2/MeOH afforded 95 mg (79%) of 16 as
an off-white solid: mp 85-86 °C; IR (CHCl3) 3290 (br), 1651
δ 7.73 (1 H, d, J ) 8.5), 7.68 (1 H, d, J ) 8.5), 7.55 (2H,
overlapping t), 7.30 (2H, complex), 5.33 (1 H, broad), 4.96 (1
H, broad), 3.56 (1 H, q, J ) 7.3), 1.72 (3 H, s), 1.52 (3 H, d, J
) 7.4); MS (EI) of the mixture, m/e (relative intensity) 225.1
(9), 182.1 (10), 181.1 (100), 166.1 (21), 165.1 (50); MS (CI) of
the mixture, 228.1 (3), 227.1 (15), 226.1 (100), 181.1 (1), 89.1
(3), 74.1 (4); HRMS (EI) calcd for C15H15NO 225.1154, found
225.1153.
Meth od B. P r ep a r a tion of P u r e 17t by Selective Hy-
d r olysis of a Mixtu r e of 8t a n d 8c. Catalytic hydrogenation
of 1.0 g (4.9 mmol) of nitrile 8 under the standard conditions
described below provided 1.0 g of a mixture of 8t (80%) and
8c (20%). Hydrolysis of this with KOH in (CH2OH)2, as
described above for 15, yielded a CH2Cl2-soluble neutral
fraction that was washed, dried, vacuum-concentrated, and
flash-chromatographed on silica gel. Elution with 9:1 CH2Cl2/
acetone afforded 300 mg (30%) of pure 17t: mp 109-111 °C;
1H NMR was essentially identical to that of the major
component of the 17t /17c mixture produced by Method A
above; 13C NMR (100 MHz) δ 175.92, 147.66, 147.14, 131.54,
128.67 (2C), 128.28, 124.23, 123.19, 119.46, 119.13, 58.95,
51.34, 24.82, 15.21.
cm-1 1H NMR (400 MHz) δ 8.15 (1 H, broad), 7.76 (2 H,
;
complex), 7.59 (3 H, complex), 7.45 (1H, d, J ) 8.5), 5.98 (1 H,
s), 5.63 (1 H, s), 1.82 (3 H, s); MS (EI), m/e (relative intensity)
239.3 (39), 221.2 (88), 178.2 (100), 165.2 (58), 152.2 (50), 44.0
(48); HRMS (EI) calcd for C15H13NO2 239.0946, found 239.0941.
tr a n s-1,2-Dim eth yla cen a p h th en e-1-h yd r oxa m ic Acid
(16t). Treatment of 100 mg (0.44 mmol) of a mixture of acids
15t (81%) and 15c (19%) with 800 µL (9.2 mmol) of (COCl)2,
as described above for 16, provided the crude acid chloride,
which was then treated with 500 µL (3.6 mmol) of Et3N and
200 mg (2.88 mmol) of NH2OH‚HCl in anhydrous DMF to
afford 16 mg (15%) of a mixture of 16t (82%) and 16c (18%)
as a white solid: mp 90-92 °C; IR of the mixture (CH2Cl2)
3378, 3210 (br), 1660, 1603 cm-1 1H NMR of the major
;
component (400 MHz) δ 8.36 (1 H, broad), 7.76 (1 H, d, J )
8.5), 7.70 (1 H, d, J ) 7.7), 7.55 (2 H, overlapping t, J ) 7.2,
6.7), 7.33 (1 H, d, J ) 7.1), 7.28 (1 H, d, J ) 6.8), 3.56 (1 H, q,
J ) 7.4), 1.73 (3 H, s), 1.45 (3 H, d, J ) 7.5); 13C NMR of the
mixture (100 MHz) δ 171.21, 128.9, 128.18, 124.82, 123.31,
119.68, 119.39, 57.11, 51.75, 25.01, 24.82; MS (EI) of the
mixture, m/e (relative intensity) 241.1 (9), 182.1 (10), 181.1
(100), 180.1 (48), 179.1 (10), 166.1 (26), 165.1 (78), 164.1 (11),
152.1 (9), 86.1 (17), 85.0 (33), 84.1 (25), 83.1 (51), 82.1 (23);
MS (CI) of the mixture 242.1 (100), 226.1 (14), 181.0 (38), 180.1
(24); HRMS (EI) calcd for C15H15NO2 241.1103, found 241.1108.
cis-1,2-Dim eth ylacen aph th en e-1-h ydr oxam ic Acid (16c).
Treatment of 100 mg (0.44 mmol) of a mixture of acids 15c
(87%) and 15t (13%) with 400 µL (4.6 mmol) of (COCl)2 and
subsequent reaction with NH2OH, as described above for 16,
yielded 40 mg (38%) of a mixture of 16c (82%) and 16t (18%)
as a white solid: mp 141-144 °C; IR (CH2Cl2) 3227 (br), 1628,
cis-1,2-Dim et h yla cen a p h t h en e-1-ca r b oxa m id e (17c).
Portionwise treatment of 300 mg (1.33 mmol) of a mixture of
acids 15c (87%) and 17t (13%) with a total of 500 mg (3.1
mmol) of 1,1′-carbonyldiimidazole, followed by 0.6 mL of
concentrated NH4OH, as described above for 17, afforded 300
mg (100%) of a mixture of 17c (81%) and 17t (19%) as a
colorless oil: IR of the mixture (CH2Cl2) 3473, 1668, 1600,
1
cm-1; H NMR of the major component (400 MHz) δ 7.73 (1
H, d, J ) 8.1), 7.68 (1 H, d, J ) 8.3), 7.55 (2 H, overlapping t),
7.36 (1 H, d, J ) 6.9), 7.30 (1 H, d, J ) 6.7), 5.42 (1 H, broad),
5.32 (1H, broad), 3.97 (1 H, q, J ) 7.5), 1.54 (3 H, s), 1.49 (3
H, d, J ) 7.4); MS (EI) of the mixture, m/e (relative intensity)
225 (14), 182 (15), 181 (100), 166 (25), 165 (53); MS (CI) of the
mixture 228.1 (3), 227.1 (15), 226.1 (100), 181.1 (1), 89.1 (3),
74.1 (4); HRMS (EI) calcd for C15H15NO 225.1154, found
225.1150.
1
1600 cm-1; H NMR (400 MHz) δ 8.0 (1 H, d, broad), 7.76 (1
H, d, J ) 8.5), 7.69 (1 H, d, J ) 8.3), 7.55 (2 H, overlapping t,
J ) 6.9), 7.35 (1 H, d, J ) 6.9), 7.29 (1 H, d, J ) 6.8), 3.91 (1
H, q, J ) 7.3), 1.58 (3 H, s), 1.48 (3 H, d, J ) 7.5); MS (EI) of
the mixture, (relative intensity) 241.1 (96), 182.1 (10), 181.1
(100), 180.1 (19), 179.1 (12), 166.1 (27), 165.1 (98), 152.1 (9),
89.0 (5), 83.1 (6), 76.1 (5), 69.1 (8), 57.1 (15), 55.1 (9); MS (CI)
242 (100), 226 (77), 182 (12), 181 (91); HRMS (EI) calcd for
1-H y d r o x y m e t h y l-1-m e t h y l-2-m e t h y le n e a c e n a p h -
th en e (22). Meth od A. To a stirred -78 °C solution of 2.1 g
(8.82 mmol) of methyl ester 18 in 53 mL of dry THF under Ar
was added 40 mL (40 mmol) of DIBAL-H (1 M in THF)
dropwise. The mixture was warmed to 25 °C over 1.5 h, and
then the reaction was quenched at -78 °C by slowly adding
90 mL of 2 N HCl. Vacuum-concentration and CH2Cl2-
extraction led to a crude product that was flash-chromato-
graphed from silica gel with 7:3 CH2Cl2/hexane to afford 1.75
g (94%) of 22 as a colorless oil: IR (CHCl3) 3550-3000 (br)
C
15H15NO2 241.1103, found 241.1100.
1-Met h yl-2-m et h ylen ea cen a p h t h en e-1-ca r b oxa m id e
(17). To a stirred 25 °C solution of 896 mg (4.0 mmol) of acid
15 in 12 mL of anhydrous DMF under Ar was added 988 mg
(6.1 mmol) of 1,1′-carbonyldiimidazole in portions. The solution
was stirred for 30 min at 25 °C, heated for 30 min at 40 °C,
treated with 1.3 mL of concentrated NH4OH dissolved in 2.7
mL of DMF and heated for 30 min at 80 °C. The mixture was
cooled to 4 °C, and the reaction was quenched by slow addition
of 15 mL of 2 N HCl. The crude product provided by CH2Cl2
extraction and vacuum-concentration was flash-chromato-
graphed from 50 g of silica gel with 9:1 CH2Cl2/MeOH to afford
697 mg (78%) of 17 as an off-white solid: mp 122-123 °C; IR
1
cm-1; H NMR (400 MHz) δ 7.74 (1 H, d, J ) 7.7), 7.69 (1 H,
d, J ) 8.5), 7.62 (1 H, d, J ) 6.8), 7.55 (2 H, overlapping t),
7.32 (1 H, d, J ) 6.8), 5.93 (1 H, s), 5.34 (1 H, s), 3.79 (2 H, m),
1.52 (3 H, s), 1.48 (1 H, t, J ) 6.8); 13C NMR (100 MHz) δ
153.77, 146.88, 139.55, 137.81, 131.30, 128.18, 128.16, 124.95,
123.53, 117.76, 116.45, 105.58, 70.71, 53.19, 22.90; MS(EI),
m/e (relative intensity) 210.0 (70), 179.0 (100), 165.0 (10), 152.0
(11); HRMS (EI) calcd for C15H14O 210.1045, found 210.1044.
Meth od B. To a stirred 25 °C solution of 1.16 g (5.2 mmol)
of acid 15 in 16 mL of anhydrous DMF under Ar was added
1.2 g (7.4 mmol) of 1,1′-carbonyldiimidazole in portions. After
stirring for 30 min at 25 °C and then 30 min at 40 °C, the
warm solution was treated with 388 mg (10.3 mmol) of NaBH4
in portions. The cooled mixture was quenched by slow addition
of H2O and then vacuum-concentrated. The residue in CH2Cl2
was washed with 1 N HCl and brine, dried, and vacuum-
concentrated at 50 °C for 2 h to afford a yellowish oil. Flash
chromatography on silica gel and elution with 1:1 CH2Cl2/
hexane afforded 1.02 g (92%) of 22 as a colorless oil with 1H
NMR essentially identical to that described for Method A
above.
1
(CHCl3) 3522, 3407, 1682, 1580 cm-1; H NMR (400 MHz) δ
7.78 (1 H, d, J ) 8.5), 7.74 (1 H, d, J ) 7.7), 7.66 (1 H, d, J )
6.8), 7.58 (2 H, complex), 7.44 (1 H, d, J ) 6.8), 5.99 (1 H, s),
5.60 (1H, s), 5.30 (2 H, broad), 1.76 (3 H, s); 13C NMR (100
MHz) δ 175.86, 153.03, 145.48, 138.52, 137.47, 131.42, 128.46
(2C), 125.22, 124.12, 118.92, 116.93, 107.87, 58.12, 24.94; MS
(FAB+), m/e (relative intensity) 447.3 (60), 224 (52), 181.1
(100), 165.1 (26), 154.0 (32), 136.0 (22); HRMS (EI) calcd for
C
15H13NO 223.0997, found 223.1000.
tr a n s-1,2-Dim eth yla cen a p h th en e-1-ca r boxa m id e (17t).
Meth od A. Portionwise treatment of 900 mg (4.0 mmol) of a
mixture of acids 15t (81%) and 15c (19%) in 3:1 DMF/CH2Cl2
with a total of 1.5 g (9.3 mmol) of 1,1′-carbonyldiimidazole,
followed by 2.7 mL of concentrated NH4OH, as described above
for 17, afforded 550 mg (61%) of a mixture of 17t (84%) and
17c (16%) as a colorless oil: IR of the mixture (CH2Cl2) 3475,
1673, 1600 cm-1; 1H NMR of the major component (400 MHz)
1-Hydr oxym eth yl-tr a n s-1,2-dim eth ylacenaphth en e (22t).
Treatment of 120 mg (0.5 mmol) of a mixture of methyl esters
18t (70%) and 18c (30%) in 6:5 THF/CHCl3 with 5.0 mL (5.0
mmol) of DIBAL-H (1 M in toluene), as described above for
22, afforded 67 mg (63%) of a mixture of 22t (69%) and 22c
(31%) as a colorless oil: IR of the mixture (CH2Cl2) 3600-