5646 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
mmol in 180 mL of water) at 80 °C over a period of 1 h. The
mixture was heated under reflux for an additional 50 h. After
acidification of the reaction mixture with aqueous HCl to pH 3,
the resulting precipitate was collected and recrystallized from
hexane to afford 5.9 g (82%) of 5 as pale yellow needles: mp
2.92 (1 H, sept, J ) 7 Hz), 2.59 (2 H, sept, J ) 7 Hz), 1.27 (6 H,
d, J ) 7 Hz), 1.14 (6 H, d, J ) 7 Hz), 1.03 (6 H, d, J ) 7 Hz); IR
(KBr) 3500 (OH), 2960, 1650 (ketone CdO), 1605, 1460, 1285,
1260, 950 cm-1; MS (EI) m/e (rel intensity) 338 (16, M+), 320
(79), 307 (100), 231 (9); HRMS calcd for C23H30O2 338.2246, found
338.2231.
1
221-223 °C; H NMR (CDCl3, 200 MHz) δ 8.17 and 7.91 (4 H,
AB, J ) 8 Hz), 7.06 (2 H, s), 2.93 (1 H, sept, J ) 7 Hz), 2.55 (2
H, sept, J ) 7 Hz), 1.28 (6 H, d, J ) 7 Hz), 1.10 (12 H, broad d,
J ) 7 Hz); IR (KBr) 3500-2500 (OH), 2970, 1690 (acid CdO),
1675 (ketone CdO), 1280, 1245, 735 cm-1; MS (EI) m/e (rel
intensity) 352 (44, M+), 307 (100), 231 (20). Anal. calcd for
C23H28O3: C, 78.38; H, 8.01. Found: C, 78.50; H, 7.85.
p-(2,4,6-Tr iisop r op ylben zoyl)ben zyl (R)-2-P h en ylp r op i-
on a te ((R)-1b). Into a solution containing 210 mg (1.40 mmol)
of (R)-(-)-2-phenylpropionic acid and 16 mg (0.13 mmol) of
4-(dimethylamino)pyridine in dry CH2Cl2 (5 mL) was added 288
mg (1.40 mmol) of DCC in dry CH2Cl2 (2 mL), then 450 mg (1.33
mmol) of 6 in dry CH2Cl2 (3 mL). The solution was stirred at
room temperature for 60 h. The reaction mixture was filtered,
and the filtrate was washed successively with water, 5% aqueous
AcOH, and water. After drying over MgSO4, the solvent was
removed by rotary-evaporation and the residue was separated
by preparative TLC (Merck Kieselgel 60 F254, 5:1 hexane/AcOEt).
Recrystallization from hexane afforded 250 mg (40%) of (R)-1b
as white crystals: mp 70 °C; 1H NMR (CDCl3, 200 MHz) δ 7.75
(2 H, d, J ) 8.5 Hz), 7.33-7.19 (7 H, m), 7.04 (2 H, s), 5.15 (2 H,
s), 3.78 (1 H, q, J ) 7 Hz), 2.92 (1 H, sept, J ) 7 Hz), 2.56 (2 H,
sept, J ) 7 Hz), 1.51 (3 H, d, J ) 7 Hz), 1.27 (6 H, d, J ) 7 Hz),
1.14 (6 H, d, J ) 7 Hz), 1.02 (6 H, d, J ) 7 Hz); IR (KBr) 2952,
1726 (ester CdO), 1666 (ketone CdO), 1607, 1454, 1285, 1254,
1229, 1153, 1065, 760, 726, 698 cm-1; MS (EI) m/e (rel intensity)
470 (0.4, M+), 320 (100), 305 (11). Anal. calcd for C32H38O3: C,
81.66; H, 8.14. Found: C, 81.40; H, 8.38.
N-(p -(2,4,6-Tr iisop r op ylb en zoyl)b en zoyl)-L-p h en yla la -
n in e Meth yl Ester ((S)-p -1a ). A solution containing L-phe-
nylalanine methyl ester hydrochloride (351 mg, 1.63 mmol) and
triethylamine (165 mg, 1.63 mmol) in dry methylene chloride
(16 mL) was stirred at room temperature for 30 min. Into this
solution was added 571 mg (1.62 mmol) of 5 and subsequently
was added dropwise 337 mg (1.63 mmol) of 1,3-dicyclohexylcar-
bodiimide (DCC) in methylene chloride (8 mL) under cooling with
ice/water. The mixture was stirred at 0 °C for 1 h and then for
an additional 24 h at room temperature. After the resulting
precipitate was filtered off, the filtrate was rotary-evaporated
to give the crude desired product. This was purified with column
chromatography on silica gel (Wakogel C-200) by using hexane
and AcOEt as eluent. Recrystallization from methanol afforded
507 mg (61%) of (S)-p-1a as colorless plates: mp 213-214 °C;
1H NMR (CDCl3, 200 MHz) δ 7.86 and 7.74 (4 H, AB, J ) 8.5
Hz), 7.29-7.23 (3 H, m), 7.13-7.08 (2 H, m), 7.05 (2 H, s), 6.56
(1 H, d, J ) 8 Hz, NH), 5.06 (1 H, d of t, J ) 8 and 6 Hz, CHCH2),
3.76 (3 H, s, CO2CH3), 3.27 and 3.23 (2 H, d of AB, J ) 6 and 14
Hz, CHCH2), 2.92 (1 H, sept, J ) 7 Hz), 2.53 (2 H, sept, J ) 7
Hz), 1.27 (6 H, d, J ) 7 Hz), 1.14 (6 H, broad d, J ) 7 Hz), 1.03
(6 H, broad d, J ) 7 Hz); IR (KBr) 3280 (NH), 2960, 1740 (ester
CdO), 1675 (ketone CdO), 1635 (amide CdO), 1545, 1280, 1245,
1020, 710 cm-1; MS (EI) m/e (rel intensity) 513 (8, M+), 351 (18),
(R)-s-Bu tyl p-(2,4,6-Tr iisop r op ylben zoyl)ben zoa te ((R)-
1c). A solution containing 435 mg (1.17 mmol) of 3 and 200 mg
(2.70 mmol) of (R)-(-)-2-butanol in dry pyridine (15 mL) was
kept at room temperature for 24 h with stirring. After the
reaction, the reaction mixture was evaporated under reduced
pressure and the residue was separated by preparative TLC
(Merck Kieselgel 60 F254, CHCl3) to afford 99 mg (21%) of (R)-
1c as a yellow oil, which crystallized on standing in a refrigerator
as pale yellow needles: mp 77-78 °C; 1H NMR (CDCl3, 200
MHz) δ 8.10 and 7.88 (4 H, AB, J ) 8.5 Hz), 7.06 (2 H, s), 5.09
(1 H, sext, J ) 6 Hz), 2.92 (1 H, sept, J ) 7 Hz), 2.56 (2 H, sept,
J ) 7 Hz), 1.71 and 1.66 (2 H, quint of AB, J ) 7 and 14 Hz,
CH2), 1.31 (3 H, d, J ) 6 Hz), 1.27 (6 H, d, J ) 7 Hz), 1.14 (6 H,
broad d, J ) 6 Hz), 1.03 (6 H, broad d, J ) 6 Hz), 0.94 (3 H, t,
J ) 7 Hz); IR (KBr) 2960, 1720 (ester CdO), 1670 (ketone Cd
O), 1280, 1100, 730 cm-1; MS (EI) m/e (rel intensity) 408 (22,
M+), 351 (67), 307 (100); HRMS calcd for C27H36O3 408.2664,
found 408.2672.
335 (33), 334 (34), 306 (100); HRMS calcd for
513.2879, found 513.2859.
C33H39NO4
m -(2,4,6-Tr iisop r op ylben zoyl)ben zoic Acid (8). Similarly
to the hydrolysis of 3 to 5, hydrolysis of 3.7 g (10 mmol) of 7
with NaOH(aq) gave 2.4 g (69%) of 8 as white crystals: mp 185-
1
186 °C; H NMR (CDCl3, 200 MHz) δ 8.56 (1 H, t, J ) 1.5 Hz),
8.29 (1 H, d of t, J ) 8 and 1.5 Hz), 8.05 (1 H, d of t, J ) 8 and
1.5 Hz), 7.56 (1 H, t, J ) 8 Hz), 7.06 (2 H, s), 2.93 (1 H, sept, J
) 7 Hz), 2.56 (2 H, sept, J ) 7 Hz), 1.29 (6 H, d, J ) 7 Hz), 1.16
(6 H, broad d, J ) 7 Hz), 1.04 (6 H, broad d, J ) 7 Hz); IR (KBr)
3500-2500 (OH), 2954, 1692 (acid CdO), 1676 (ketone CdO),
1282, 1248, 735 cm-1; MS (EI) m/e (rel intensity) 352 (100, M+),
307 (56), 231 (55).
Solu tion P h otolyses. A 10-mL solution containing 10-2
M
chiral 2,4,6-triisopropylbenzophenone (S)-p-1a , (S)-m-1a , (R)-1b,
or (R)-1c in benzene was placed in a Pyrex tube and was
irradiated at 10 °C with a 400-W high-pressure mercury lamp
under bubbling of N2 for 4 or 5 h. The corresponding 4,6-
diisopropyl-2,2-dimethyl-1-(4′- or 3′-substituted phenyl)-1,2-di-
hydrobenzocyclobuten-1-ols p-2a , m-2a , 2b, and 2c were pro-
duced almost quantitatively (NMR and TLC). They were
isolated by preparative TLC (Merck Kieselgel 60 F254, hexane/
AcOEt, CHCl3/ether or CHCl3/acetone).
Solid -Sta te P h otolyses. The crystals of a chiral 2,4,6-
triisopropylbenzophenone (S)-p-1a , (S)-m-1a , (R)-1b, or (R)-1c
(50-100 mg) were lightly crushed and spread between two Pyrex
plates, and then irradiated with a 400-W high-pressure mercury
lamp for several hours under a nitrogen stream. During the
irradiation, the photolysis vessel was cooled from the outside
by circulation of cold water (4 °C). The benzocyclobutenol was
produced almost quantitatively in each case (NMR and TLC)
and was isolated by preparative TLC.
N-(m -(2,4,6-Tr iisop r op ylben zoyl)ben zoyl)-L-p h en yla la -
n in e Meth yl Ester ((S)-m -1a ). This was prepared by conden-
sation of 8 with L-phenylalanine methyl ester in the same
manner as described for the para isomer (S)-p-1a . Thus, from
757 mg (2.15 mmol) of 8, 572 mg (52%) of (S)-m-1a was obtained
as white plates: mp 116-118 °C; 1H NMR (CDCl3, 200 MHz) δ
8.25 (1 H, s), 7.93 (1 H, d, J ) 8 Hz), 7.84 (1 H, d, J ) 8 Hz),
7.48 (1 H, t, J ) 8 Hz), 7.3-7.2 (3 H, m), 7.13-7.08 (2 H, m),
7.05 (2 H, s), 6.59 (1 H, d, J ) 7 Hz, NH), 5.06 (1 H, d of t, J )
7 and 6 Hz, CHCH2), 3.76 (3 H, s, CO2CH3), 3.26 and 3.20 (2 H,
d of AB, J ) 6 and 14 Hz, CHCH2), 2.92 (1 H, sept, J ) 7 Hz),
2.54 (2 H, broad sept, J ) 7 Hz), 1.27 (6 H, d, J ) 7 Hz), 1.15 (6
H, broad d, J ) 6 Hz), 1.03 (6 H, broad t, J ) 6 Hz); IR (KBr)
3327 (NH), 2961, 1743 (ester CdO), 1670 (ketone CdO), 1649
(amide CdO), 1539, 1250, 731, 701 cm-1; MS (EI) m/e (rel
intensity) 513 (5, M+), 351 (13), 335 (33), 334 (35), 306 (100);
HRMS calcd for C33H39NO4 513.2879, found 513.2872.
4-Hyd r oxym eth yl-2′,4′,6′-tr iisop r op ylben zop h en on e (6).
A solution containing 5.50 g (14.8 mmol) of 3 and 4.80 g (127
mmol) of NaBH4 in dioxane (50 mL) was heated with stirring
at 90-100 °C for 5 days. The reaction mixture was poured onto
water and was extracted with ether. The ethereal layer was
washed with brine, dried over MgSO4, and evaporated. The
residue was separated with column chromatography on silica
gel (Wakogel C-200, hexane/AcOEt), followed by recrystallization
with hexane/benzene (trace), to give 1.1 g (22%) of 6 as white
needles: mp 85-86 °C; 1H NMR (CDCl3, 200 MHz) δ 7.82 (2 H,
d, J ) 8 Hz), 7.42 (2 H, d, J ) 8 Hz), 7.04 (2 H, s), 4.76 (2 H, s),
Diastereomer ratios of benzocyclobutenols p-2a , m-2a , 2b, and
2c were determined by 1H NMR. Ytterbium tris[3-(heptafluo-
ropropylhydroxymethylene)-(+)-camphorate] Yb(hfc)3 was used
as a shift reagent. Specific rotations were measured by a Perkin-
Elmer 243 polarimeter. For instance, for p-2a obtained by the
solution photolysis, [R]20D ) +44.5 (c 0.76, CH2Cl2) and for p-2a
obtained by the solid-state photolysis, [R]20 ) -23.8 (c 0.61,
D
CH2Cl2). The diastereomers (S,S)- and (R,S)-p-2a could not be
separated by chiral HPLC (Chiralcel OD, OJ , and OB columns).
Benzocyclobutenol p-2a obtained from the solid-state pho-
tolysis of (S)-p-1a : mp 187-188 °C; 1H NMR (CDCl3, 200 MHz)
δ 7.64 (2 H, d, J ) 8.6 Hz), 7.30 (2 H, d, J ) 8.3 Hz), 7.26-7.09
(5 H, m), 7.05 (1 H, d, J ) 1 Hz), 6.88 (1 H, d, J ) 1 Hz), 6.58