added and the mixture was extracted with ether (3 × 15 mL). The
combined organic layers were washed with saturated NH4Cl and
brine before drying over Na2SO4. After solvent evaporation, the
crude product was purified by radial chromatography (1:1 hexanes:
ethyl acetate on a 2 mm silica rotor, 7.5 mL/min flow rate) to
provide 5a as a pale yellow oil (0.429 g, 61%). When this procedure
was repeated with n-BuLi in place of LDA, 5a was isolated in 80%
yield after chromatographic purification. IR (neat) 3344 (br), 1594,
1578, 1458, 1376, and 1061 cm-1. 1H NMR (500 MHz, CDCl3) δ
7.49 (t, J ) 7.8 Hz, 1H), 6.97 (d, J ) 7.8 Hz, 2H), 5.25 (br s, 1H,
OH), 3.66 (m, 1H), 3.00, (ddd, J ) 14.7, 8.8, 5.4 Hz, 1H), 2.92
(ddd, J ) 14.7, 7.3, 5.4 Hz, 1H), 2.56 (s, 3H), 1.93 (dddd, J )
12.7, 8.3, 5.4, 2.9 Hz, 1H), 1.76 (dddd, J ) 12.7, 8.8, 7.8, 5.4 Hz,
1H), 1.6-1.4 (m, 3H), 1.4-1.2 (m, 7H), 0.86 (t, J ) 6.8 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 161.0, 157.3, 137.1, 120.6, 120.0,
71.6, 37.9, 36.0, 35.1, 31.9, 29.5, 25.9, 24.1, 22.6, and 14.1. HRMS
(FAB) calcd for (C15H25NO + H)+ 236.2014, found 236.2033. Anal.
Calcd for C15H25NO: C, 76.55; H, 10.71; N, 5.95. Found: C, 76.33;
H, 10.94; N, 5.91.
FIGURE 2. Reductive cleavage of the -SPh group from 5c.
than the nitrile. Furthermore, the thiophenyl group is preferable
to the sulfonylphenyl group if LDA is to be used in the
intramolecular reaction (Table 1, compare entries 7 and 9).
To gain further insight as to the suitability of the thiophenyl
substituent for the cananodine synthesis, we explored methods
to reductively cleave this group from adduct 5c. Samarium(II)
iodide,19 Raney nickel,20 and lithium di-tert-butylbiphenylide
(LDBB)21 all successfully converted 5b to 5a, but Raney nickel
gave the highest yield and the cleanest product mixture (Figure
2).
To summarize, the reaction of lutidyllithium with 1,2-
epoxyoctane provides good yields of adducts, with slightly
higher yields obtained when using n-BuLi versus LDA to
generate the alkyllithium species. (6-Methyl-2-pyridyl)methyl-
lithium species substituted in the R-position with a thiophenyl
or sulfonylphenyl group also react effectively with 1,2-epoxy-
octane, while the cyano-substituted substrate was less effective.
In contrast, a trisubstituted epoxide was a poor electrophile for
all picolyl-type lithium species studied. These results suggest a
monosubstituted epoxide is more likely to be successful in an
intramolecular reaction required for our planned synthesis of
cananodine.
2-Methyl-3-((6-methylpyridin-2-yl)methyl)nonan-2-ol (8a).
The procedure used for the preparation of 5a was followed with
use of LDA (3.0 mmol), 2,6-lutidine (4a) (0.35 mL, 0.322 g, 3.0
mmol), and 2-methyl-2,3-epoxynonane (7) (0.469 g, 3.0 mmol).
Extractive workup and flash chromatography (gradient elution 15:1
hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate) provided, in order
of elution, unreacted 7 (0.114 g, 24%), allylic alcohol 918 (0.120
g, 26%), unreacted 4a (0.153 g, 48%), tertiary alcohol 8a (0.092
g, 12%), and dialkylated product 10 (0.098 g, 8%) as a mixture of
diastereomers. When this procedure was repeated with n-BuLi in
the place of LDA, 8a was isolated in 40% yield after chromato-
graphic purification. Data for 8a: IR (neat) 3400 (br), 1594, 1578,
1
and 1159 cm-1. H NMR (500 MHz, CDCl3) δ 7.49 (t, J ) 7.8
Hz, 1H), 6.99 (d, J ) 7.8 Hz, 1H), 6.96 (d, J ) 7.3 Hz, 1H), 3.08
(dd, J ) 15.6, 6.3 Hz, 1H), 2.86 (dd, J ) 15.6, 2.9 Hz, 1H), 2.56
(s, 3H), 1.76 (m, 1H), 1.47 (m, 1H), 1.34 (s, 3H), 1.25 (m, 9H),
1.17 (s, 3H), 0.86 (t, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ 160.9, 157.3, 137.1, 120.7, 120.5, 71.9, 49.1, 37.4, 31.8, 30.7,
30.6, 29.4, 28.5, 25.9, 23.9, 22.6, and 14.1. CI-MS (MeOH) m/z
264 (M + H, 28), 247 (18), and 246 (100). HRMS (FAB) calcd
for (C17H29NO + H)+ 264.2327, found 264.2331. Anal. Calcd for
C17H29NO: C, 77.51; H, 11.10; N, 5.32. Found: C, 77.12; H, 11.39;
N, 5.42.
Experimental Section.22
1-(6-Methylpyridin-2-yl)nonan-3-ol (5a). A 25-mL round-
bottomed flask under argon was charged with LDA (3.0 mmol,
prepared from diisopropylamine and n-BuLi in ∼15 mL of THF)
and cooled in a dry ice/2-propanol bath. 2,6-Lutidine (0.35 mL,
0.322 g, 3.0 mmol) was added dropwise to the flask. The solution
turned red, and after 15 min the dry ice bath was removed and the
flask allowed to warm to room temperature. The flask was then
recooled in the dry ice slush bath, 1,2-epoxyoctane (0.46 mL, 0.38 g,
3.0 mmol) was added, and the solution was allowed to slowly warm
to room temperature overnight. Saturated NH4Cl solution was then
Data for 10: 1H NMR (500 MHz, CDCl3) major diastereomer δ
7.49 (t, J ) 7.8 Hz, 1H), 6.99 (d, J ) 7.8 Hz, 2H), 3.16 (dd, J )
15.1, 5.4 Hz, 2H), 2.65 (dd, J ) 15.1, 4.9 Hz, 2H), 1.86 (m, 2H),
1.45 (m, 2H), 1.30 (s, 6H), 1.3-1.1 (m, 20H), 1.15 (s, 6H), 0.83
(t, J ) 7 Hz, 6H). 13C NMR (125 MHz, CDCl3) major diastereomer
δ 161.2, 137.1, 120.7, 71.9, 50.0, 38.1, 31.7, 31.6, 29.7, 29.4, 28.7,
25.4, 22.6, and 14.1. CIMS (MeOH) m/z 420 (M + H, 48), 402
(52), 385 (56), and 59 (100).
(15) (a) Taylor, S. K.; DeYoung, D.; Simons, L. J.; Vyvyan, J. R.; Wemple,
M. A.; Wood, N. K. Synth. Commun. 1998, 28, 1691–1701. (b) Larcheveˆque,
M.; Debal, A. Synth. Commun. 1980, 10, 49.
(16) Canovese, L.; Visentin, F.; Uguagliati, P.; Chessa, G.; Pesce, A. J.
Organomet. Chem. 1998, 566, 61–71.
(17) Steinreiber, A.; Mayer, S. F.; Saf, R.; Faber, K. Tetrahedron: Asymmetry
2001, 12, 1519–1528.
(18) Katzenellenbogen, J. A.; Christy, K. J. J. Org. Chem. 1974, 39, 3315–
3318.
(19) Kuenzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R. Tetrahedron Lett.
1991, 32, 1949–1952.
(20) Bonner, W. A. J. Am. Chem. Soc. 1952, 74, 1034–1039.
(21) Hossain, M. T.; Timberlake, J. W. J. Org. Chem. 2001, 66, 6282–6285.
(22) For general experimental details, see the Supporting Information.
Acknowledgment. This work was supported by the National
Cancer Institute, National Institutes of Health (R15 CA122084).
Supporting Information Available: Additional experimental
1
procedures, compound characterization data, and copies of H
and 13C NMR spectra. This material is available free of charge
JO802267N
1376 J. Org. Chem. Vol. 74, No. 3, 2009