A R T I C L E S
Saito et al.
(E)-7a (101 mg, yield 91%) in a ratio of 13:1 as a colorless liquid.
2,6-Diphenylphenol could be recovered in more than 90% isolated yield.
In all experiments where R,â-unsaturated aldehydes and ketones were
employed, the above procedure was followed, except that ATPH (2.2
equiv), LDA (1.2 equiv), R1CHO (1.0 equiv), and R,â-unsaturated
carbonyl compound (1.0 equiv) were used.
s-trans conformation of carbonyl compounds; (3) the deproto-
nation site; (4) s-cis versus s-trans conformation of extended
dienolates; and (5) the alkylation site.
Experimental Section
General. Infrared (IR) spectra were recorded on a Shimadzu FTIR-
8100 spectrometer. 1H NMR spectra were measured on a Varian
Gemini-300 spectrometer (300 MHz) at ambient temperature. Data were
recorded as follows: chemical shift in ppm from internal tetrameth-
ylsilane on the δ scale, multiplicity (b ) broad, s ) singlet, d ) doublet,
t ) triplet, and m ) multiplet), coupling constant (Hz), integration,
and assignment. 13C NMR spectra were recorded on a Varian Gemini-
300 (75 MHz) spectrometer. Chemical shifts were recorded in ppm
from the solvent resonance employed as the internal standard (deutero-
chloroform at 77.07 ppm). All experiments were carried out under an
atmosphere of dry argon. For thin-layer chromatography (TLC) analysis
throughout this work, Merck precoated TLC plates (silica gel 60 GF254
0.25 mm) were used. The products were purified by preparative column
chromatography on silica gel (E. Merck Art. 9385). Microanalyses were
conducted at the Faculty of Agriculture, Nagoya University.
In experiments that required dry solvent toluene, toluene-d8, CH2-
Cl2, and CD2Cl2 were freshly distilled from calcium hydride, and
tetrahydrofuran (THF) was freshly distilled from sodium metal using
benzophenone ketyl as indicator. Organic substrates 1, 3, 4, and 6 were
commercially available and were used after distillation. A mixture of
ketones 2 and 5 was available from Wako, each being used after
separating by column chromatography. n-BuLi (hexane solution) was
obtained from Mitsuwa. Aldehydes 9a,27 12,28 and (E)- and (Z)-1329 as
well as esters 1030 and (E)- and (Z)-1531 are all known compounds,
and the former two were prepared by oxidation of geraniol (Wako)
and nerol (Wako) over MnO2, respectively. The latter two were prepared
by methylation (BF4OMe3, i-Pr2NEt; room temperature, 4 h) of an E
and Z mixture of geranic acid (Aldrich), followed by separation of the
resulting methyl ester isomers by column chromatography on silica
gel. Ketones (E)- and (Z)-1432 are also known compounds.
Methyl (Z)-5-Hydroxy-3-methyl-5-phenyl-2-pentenoate ((Z)-7a).
1
IR (neat): 3441, 1714, 1645, 1435, 1174 cm-1. H NMR (300 MHz,
CDCl3): δ 7.46-7.24 (m, 5H), 5.90 (s, 1H), 4.91 (ddd, 1H, J ) 3.7,
5.5, 9.6 Hz), 3.90 (d, 1H, J ) 5.5 Hz), 3.73 (s, 3H), 3.25 (dd, 1H, J )
9.6, 12.8 Hz), 2.66 (dd, 1H, J ) 3.7, 12.8 Hz), 1.91 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 168.4, 157.2, 144.8, 128.2 (two peaks are
overlapped), 127.2, 118.2, 73.0, 51.3, 43.7, 26.0. Anal. Calcd for
1
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.67; H, 7.48. ((E)-7a) H
NMR (300 MHz, CDCl3): δ 7.40-7.22 (m, 5H), 5.78 (s, 1H), 4.89
(dd, 1H, J ) 4.8, 8.7 Hz), 3.69 (s, 3H), 2.60 (dd, 1H, J ) 8.7, 13.8
Hz), 2.51 (dd, 1H, J ) 5.2, 14.0 Hz), 2.23 (s, 3H).
Methyl (Z)-5-Cyclohexyl-5-hydroxy-3-methyl-2-pentenoate ((Z)-
7b). IR (KBr): 3306, 2920, 1715, 1705, 1646, 1443, 1252, 1198 cm-1
.
1H NMR (300 MHz, CDCl3): δ 5.84 (d, 1H, J ) 1.5 Hz), 3.69 (s,
3H), 3.52 (dtt, 1H, J ) 2.7, 7.5, 12.3 Hz), 3.13 (dd, 1H, J ) 10.8, 12.6
Hz), 2.97 (d, 1H, J ) 6.9 Hz, OH), 2.25 (dd, 1H, J ) 2.9, 10.8 Hz),
1.95 (d, 3H, J ) 1.5 Hz), 1.94-1.63 (m, 5H), 1.48-0.99 (m, 6H). 13
C
NMR (75 MHz, CDCl3): δ 168.5, 158.7, 117.7, 74.7, 51.2, 45.0, 38.2,
28.9, 27.7, 26.5, 26.27, 26.15, 25.7. Anal. Calcd for C13H22O3: C, 68.99;
H, 9.80. Found: C, 68.99; H, 9.89.
Methyl (E)-5-Cyclohexyl-5-hydroxy-3-methyl-2-pentenoate ((E)-
1
7b). IR (neat): 3450, 2926, 1718, 1705, 1647, 1226, 1151 cm-1. H
NMR (300 MHz, CDCl3): δ 5.76 (s, 1H), 3.69 (s, 3H), 3.64-3.50 (m,
1H), 2.37 (dd, 1H, J ) 2.1, 13.8 Hz), 2.20 (s, 3H), 2.17 (dd, 1H, J )
9.6, 13.6 Hz), 1.83-1.54 (m, 5H), 1.42-0.98 (m, 7H). 13C NMR (75
MHz, CDCl3): δ 166.8, 157.5, 117.6, 73.3, 50.9, 45.8, 43.7, 29.1, 27.8,
26.4, 26.2, 26.1, 18.9. Anal. Calcd for C13H22O3: C, 68.99; H, 9.80.
Found: C, 68.98; H, 9.78.
(E)-6-Hydroxy-4-methyl-6-phenyl-3-hexene-2-one ((E)-8a). IR
(neat): 3642, 1684, 1613, 1360, 1217, 1057, 968 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.32 (m, 5H), 6.08 (s, 1H), 4.87 (m, 1H), 2.54 (m,
1H), 2.45 (dd, 1H, J ) 5.1, 8.4 Hz), 2.15 (s, 3H), 2.12 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ 198.9, 154.1, 143.7, 128.4, 127.7, 126.1,
125.6, 72.0, 50.9, 31.7, 19.3 Anal. Calcd for C13H16O2: C, 76.44; H,
7.90. Found: C, 76.23; H, 8.10.
Preparation of ATPH. To a solution of 2,6-diphenylphenol (3.0
equiv) in toluene was added at room temperature a 1.0 M hexane
solution of Me3Al (1.0 equiv). Methane gas (∼3.0 equiv) evolved
immediately. The resulting pale-yellow solution was stirred at room
temperature for 0.5 h and used without further purification.
Typical Procedure for the Regio- and Stereoselective Synthesis
of r,â-Unsaturated Carbonyl Compounds Using the Coupling of
Two Different Carbonyl Substrates Complexed with ATPH. The
following procedure for the reaction of 3-methyl-2-butenoate (1) with
benzaldehyde (PhCHO) is representative. To a solution of ATPH (1.65
mmol) in toluene (5.0 mL) were added 1 (131 µL, 1.0 mmol) and
PhCHO (51 µL, 0.50 mmol) at -78 °C under argon. After 5 min,
LTMP, generated by treatment of a THF (5.0 mL) solution of 2,2,6,6-
tetramethylpiperidine (194 µL, 1.1 mmol) with a 1.60 M hexane solution
of n-BuLi (0.72 mL, 1.1 mmol) at -78 °C for 30 min, was transferred
by a cannula to the toluene solution of the mixture of ATPH-1 and
ATPH-PhCHO complexes at -78 °C within ca. 2-3 min. The reaction
mixture was stirred at this temperature for 30 min, quenched with
aqueous NH4Cl, filtered through a pad of Celite, and extracted with
diethyl ether. The organic layer was dried over Na2SO4 and concen-
trated. The residue was purified by column chromatography on silica
gel (diethyl ether/hexane ) 1/3 to 1/4 as the eluent) to give (Z)- and
(E)-6-Hydroxy-4-methyl-6-cyclohexyl-3-hexene-2-one ((E)-8b). IR
(neat): 2926, 2858, 1684, 1615, 1451, 1356, 1219 cm-1. 1H NMR (300
MHz, CDCl3): δ 6.15 (s, 1H), 3.59 (tt, 1H, J ) 3.2, 9.6 Hz), 2.19 (s,
3H), 2.16 (d, 3H, J ) 0.6 Hz), 2.11 (ss, 1H, J ) 0.6, 9.6 Hz), 1.85-
1.60 (m, 5H), 1.42-0.99 (m, 6H). 13C NMR (75 MHz, CDCl3): δ
198.6, 155.7, 125.8, 73.3, 46.1, 43.8, 31.8, 29.1, 27.8, 26.4, 26.2, 26.1,
19.3. Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C, 74.08;
H, 10.81.
(E)-5-Cyclohexyl-5-hydroxy-3-methyl-2-pentenal ((E)-9b). IR
(neat): 3568, 2856, 1686, 1609, 1211, 1062 cm-1. 1H NMR (300 MHz,
CDCl3): δ 5.94 (dd, 1H, J ) 0.9, 8.1 Hz), 3.67-3.56 (m, 1H), 2.42
(dd, 1H, J ) 2.8, 14.1 Hz), 2.26 (dd, 1H, J ) 9.6, 13.5 Hz), 2.22 (s,
3H), 1.95-1.55 (m, 6H), 1.45-0.96 (m, 6H). 13C NMR (75 MHz,
CDCl3): δ 191.0, 162.0, 129.1, 73.7, 45.4, 43.9, 29.1, 27.7, 26.3, 26.1,
26.0, 17.9. Anal. Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C,
73.44; H, 10.48.
6-Hydroxy-6-phenyl-3-hexene-2-one (11). IR (neat): 3641, 1698,
1653, 1624, 1364, 1260, 978, 702 cm-1. 1H NMR (300 MHz, CDCl3):
δ 7.36 (m, 5H), 6.80 (dt, 1H, J ) 7.2, 15.9 Hz), 6.10 (d, 1H, J ) 15.9
Hz), 4.83 (m, 1H), 2.63 (m, 2H), 2.21 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ 198.7, 144.0, 143.4, 133.4, 128.6, 127.9, 125.6, 73.0, 42.0,
26.8. Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.88;
H, 7.51.
(27) Duhamel, P.; Cahard, D.; Poirier, J.-M. J. Chem. Soc., Perkin Trans. 1
1993, 2509. See also the Supporting Information of J. Am. Chem. Soc.
1998, 120, 813.
(28) Bellassoued, M.; Salemkour, M. Tetrahedron 1996, 52, 4607.
(29) Compared directly with commercially available samples. Also see: Bobbitt,
J. M. J. Org. Chem. 1998, 63, 9367.
(30) Dugger, R. W.; Heathcock, C. H. J. Org. Chem. 1980, 45, 1181.
(31) Burrel, J. W.; Garwood, R.; Jackman, L. M.; Oskay, E.; Weedon, B. C. J.
Chem. Soc. C 1966, 2145.
(32) Yoshioka, M.; Ishii, K.; Wolf, H. R. HelV. Chim. Acta 1980, 63, 571.
(E)-4-(1-Hydroxy-1-phenyl)methyl-3,7-dimethyl-2,6-octadienal (16).
1
IR (neat): 3427, 2916, 1670, 1454, 1024 cm-1. H NMR (300 MHz,
9
6208 J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003