Post on 25-Mar-2022
J. Org. Chem., 1997, 62(8), 2332-2336, DOI:10.1021/jo962423i
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Copyright © 1997 American Chemical Society
HELVIlbtU
SUPPORTING INFORMATION
Shortcut Syntheses of Naturally Occuring 5-Alkylresorcinols
with DNA Cleaving Properties
Alois Fiirstner* and Ginter Seidel
Max-Planck-Institutfiir Kohlenforschung
Kaiser-Wilhelm-Platz 1, D-45470 Millheim/Ruhr, Germany
Instrumentation and Spectra Formats. NMR: Spectra were recorded on a Bruker AC
200 spectrometer at 200.2 MHz (1H) and 50.3 MHz (13C) in CDCl3 unless stated otherwise.
Chemical shifts (8) are given in ppm relative to TMS, coupling constants (J) in Hz. The
multiplicity in the 13C NMR spectra refers to the geminal protons (DEPT). 1 1B NMR spectra
were recorded on a Bruker AC 200 (64 MHz) with BF 3'Et 2O as external standard. MS:
Finnigan MAT 8200 (70 eV). Melting points: Gallenkamp apparatus (uncorrected) or DSC
(Mettler Toledo Star System). Elemental analyses: Dornis & Kolbe, Mlilheim. Flash chromato-
graphy: Merck silica gel 60 (230-400 mesh).
Large Scale Preparation of 7-lodo-1-heptene (10)
1. MgHBr 2. CO 2
dibenzoyl peroxide
COOH LiAIH4 X
X=OH
10 X = I 2, PPh 3 , imidazole
Scheme 5.
6-Bromo-1-hexene. A three necked flask equipped with a gas inlet and a reflux
condenser cooled to -78 oC is charged with 1,5-hexadiene (174.64 g, 2.1 mmol) and dibenzoyl
peroxide (0.9 g). HBr gas (8 g) is bubbled into this mixture at -4oC - OoC, with the HBr up-
take being monitored by weighting the gas bomb. Another portion of dibenzoyl peroxide (0.45
g) is then added, followed by condensation of another 8 g of HBr. This portionwise process is
repeated 4 times until a total amount of 42 g of HBr and 2.77 g of dibenzoyl peroxide have
been introduced into the flask. The resulting solution is stirred at 00 C for 60 min. For work-up
the reaction is quenched with water, the organic layer is washed twice with saturated aqueous
NaHCO 3 and dried (Na 2SO4 ), unreacted 1,5-hexadiene is distilled off (125.4 g) through a
Vigreux column, followed by distillation of 6-bromo-1-hexene (54.12 g). bp = 41-42 oC (15
torr). The analytical data of the product were identical to that of a commercially available
sample.
6-Heptenoic Acid. To a suspension of Mg turnings (8.75 g, 360 mmol) activated by a
crystal of iodine in Et 20 (250 mL) is added 6-bromo-1-hexene (55.22 g, 339 mmol) at such a
rate that the solvent is gently refluxing. Once the addition is complete, the mixture is stirred for
5 h at ambient temperature. Unreacted Mg is filtered off and the resulting solution of 5-
hexenylmagnesium bromide is slowly added at -20 oC under an atmosphere of CO 2 to Et2 0
(500 mL) saturated with CO2 . The resulting suspension is allowed to warm to ambient
temperature, carefully quenched by slowly adding HCI (250 mL, 15% w/w), the organic layer
is separated and dried (Na2 SO 4 ), the solvent is evaporated and the residue purified by
distillation using a concentric tube column to afford 6-heptenoic acid (26.2 g, 60%). bp = 95-
96 oC/5 torr. The product was identical to a commercially available sample in all analytical
respects.
6-Hepten-1-ol. A solution of 6-heptenoic acid (4.66 g, 36 mmol) in Et 2 0 (20 mL) is
slowly added to a suspension of LiAlH 4 (1.656 g, 44 mmol) in Et 20 (100 mL) causing the
solvent to boil. After complete addition the mixture was refluxed for another 4 h, carefully
quenched with crushed ice, the organic layer was separated and dried (Na 2 SO 4 ) and the
solvent evaporated in vacuo. The resulting product (3.86 g, 93%) was pure enough (GC:
98%) for direct further use. 1H NMR: 8 = 5.81 (ddt, 1H), 4.90-5.05 (m, 2H), 3.62 (t, 2H, J =
7), 2.07 (q, 2H, J = 7), 2.01 (br. s, -OH), 1.35-1.60 (m, 6H).- 13C NMR: 8 = 138.8, 114.3,
62.7, 33.5, 32.5, 28.6, 25.2.- MS, n/z (rel. intensity): 114 (< 1) [M+], 96 (7), 81 (42), 68 (65),
67 (72), 57 (26), 55 (91), 54 (100), 43 (40), 41 (84), 39 (51), 31 (67), 27 (44).
7-lodo-1-heptene (10). To a rapidly stirred solution of 6-hepten-l-ol (2.75 g, 24 mmol)
in toluene (200 mL) are successively added PPh3 (6.63 g, 25 mmol), imidazole (4.92 g, 72
mmol) and iodine (6.73 g, 53 mmol). The mixture is stirred for 1.5 h at ambient temperature,
the solvent is decanted, the residue is washed twice with toluene (50 mL each), the combined
fractions are evaporated and the residue is purified by distillation affording the product as a
colorless liquid (3.78 g, 70%). bp = 34-35 oC (10-2 torr). 1H NMR: 8 = 5.80 (ddt, 1H, J = 7,
9, 15), 4.92-5.05 (m, 2H), 3.19 (t, 2H, J = 7), 2.06 (q, 2H, J = 7), 1.84 (quint., 2H, J = 7),
1.41 (m, 4H).- 13C NMR: 6 = 138.5, 114.6, 33.5, 33.4, 29.9, 27.8, 7.0.- MS, m/z (rel.
intensity): 224 (9) [M+], 155(3), 97 (40), 69 (8), 55 (100), 41 (27).
Alternative Synthesis of Compound 16
[b]
R= H [a]R = OSO 2Me+-1
- '- [d]
X =OSO Me [C
e= I- : 1
[e]-/ 16 + double bond isomers
Scheme 6: [a] MeSO 2C, CH2Cl2 , Et3 N, 1h, OoC, 93%; [b] (i) 9-H-9-BBN, THF, 2h, r.t.; (ii)
NaOMe, 0.5h, r.t.; (iii) 7, PdCl2(dppf) (3 mol%), THF, 1h, reflux, 85%; [c] LiI, THF, 3h, r.t.,
97%; [d] 1-propynyl lithium, THF, 20h, reflux, 76%; [e] Lindlar catalyst, H2 (1 atm), hexane,
3h, r.t., 95% (inseparable mixture of isomers, see 1H and 13C NMR).
b
130.5 130.0 129.5ppm
131.0 130.0ppM
129.0
Olefinic region in the 13C NMR spectrum of compound 16 prepared (a) by the boron-reaction
manifold according to Scheme 2, (b) by Lindlar hydrogenation according to Scheme 6.
a
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DATE 27-11-96TIME 13:31
SA.NA FUESBSA.NO N027 120SOLVENT CDC13SF 200.132SY 80.001 3239.000SI 32768TO 32768SW 4032.258HZ/PT .246
PW 0.0RD 0.0AG 4.063RG 4NS 32TE 300
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Aexo FUE-SB-227-02 11.12.1996 09:02:2
FUE-SB-227-02, 10.12.1996 15:15:31 Methodenname: 0-80OC/50C/MIN
UE-SB-227-02, 4.5500 mg
HO
2
OH
2
mW
Integral -82.28 mJ Cnormalis. -18.08 JgA-1
Onset 15.64 OC
Peakh6he 0.99 mWPeak 22.18 OC
Extrapol. Peak 22.01 oC
Peakweite 16.47 OC
Integral -167.74 mJnormalis. -36.87 JgA-1
Onset 25.42 OC
Peakh6he 2.12 mWPeak 31.97 OC
Extrapol. Peak 32.30 aC
Peakweite 7.28 OC
0 10 20 30 40 50 60 70 0
L: Dreier METTLER TOLEDO STARe Syste
FUE-SA-224-01/VIRGIN 27.11.1996 09:16:1S
FUE-SB-224- 0 1 , 27.11.1996 08:15:03 Methodenname: 25>1600CJC/MIN
FUE-SB-224-01, 5.3900 mg Bemerkungen: C26H3804
Integralnormalis
OnsetPeakh6hePeakExtrapol.Peakweite
-909.19 mJ-168.68 JgA-1
125.21 aC
12.11 mW137.59 oC
Peak 138.07 OC10.79 aC
3
OH
Son 140 0
METTLER TOLEDO STARe Syster
Aexo
10
mW
L: Dreler
10080
Aexo FUE-SB-226-01 11.12.1996 08:51:5C
]1 [UE-SB6226-01, 11.12.1996 08:49:00 OHFUE SB-226-01, 7.2300 mg '-%
5VIRGIN
5
mW
L: Dreier
Integralnormalis
OnsetPeakh~hePeakExtrapol.Peakweite
-390.42 mJ-54.00 JgA-1
49.16 oC3.96 mW53.30 oC
Peak 53.38 oC
5.07 OC
[EAT
40 60METTLER TOLEDO STARe Systen