excess (10 equiv) relative to the aldehyde. Excess halide is
often necessary to obtain good yields due to side reactions
involving reduction and coupling.7 In our case the iodide is
too valuable to be used in excess, so it was hoped that
conditions could be found to allow the NHK reaction to
proceed with 1 equiv of halide.
Scheme 2
Previously in our laboratories was developed a C-5
iodination of dihydropyridones 1 using NIS/catalytic HTIB.6
This procedure requires a long reaction time (3 d) and uses
an expensive iodine source. To circumvent these drawbacks,
ICl (1 M in CH2Cl2)10 was examined as an alternative reagent
for the preparation of iodides 2. Treatment of dihydropyri-
dones 1 with ICl (1.5 equiv) in methylene chloride (0 °C, 1
h) provided high yields of the desired iodides 2 via a
convenient procedure. Initial attempts at coupling dihydro-
pyridones 2 with benzaldehyde under standard NHK condi-
tions resulted in poor results with reduction products 1
predominating. Conditions were eventually found, involving
DMSO as solvent and adding the iodide last to the reaction
mixture, which allowed the iododihydropyridones 2 to couple
with various aldehydes (3 equiv) to give the desired alcohols
3 in moderate to good yields as shown in Table 1.
a quantitative yield of allylated dihydropyridone 4 (Scheme
3). Several other nucleophiles (Et3SiH, methanol, thiophenol,
Scheme 3
Table 1. Preparation of Hydroxyalkyldihydropyridones 3 from
2
and furan) were examined, and the results are depicted in
Scheme 4. In all cases γ-attack occurred exclusively to afford
the observed products.
entrya
R1
R2
R3
product yield,b %
(dr)c
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Bn PhCH2CH2
Bn n-C5H11
Bn Ph
Bn 3-furanyl
Bn C6H11
3a
3b
3c
3d
3e
3f
64
57
80
68
64
64
57
(1/2.5)
(1/1.7)
(1/7)
(1/2.6)
d
Using this procedure, the hydroxyl group of 3 can be
Scheme 4a
Me Bn n-C5H11
Me Bn Ph
(1/2.6)
(1/3.5)
3g
a The reactions were generally performed on a 0.5-1.0 mmol scale in 6
mL of DMSO using 3 equiv of aldehyde (R3CHO). b Yield of products
obtained from radial preparative-layer chromatography. c The ratio of
diastereomers (dr) was determined by 1H NMR. d The dr was not determined.
Interestingly, some aldehyde facial selectivity was ob-
served due to chirality transfer from the C-2 center of the
dihydropyridone. The selectivity was low in most cases with
the exception of entry 3, where the combination of the
2-phenyl derivative 2c and benzaldehyde resulted in a 7/1
mixture of diastereomers 3c. Except for alcohols 3e (entry
5), all diastereomers could be separated by chromatography.11
Since the hydroxyl group of 3 is γ to the nitrogen, it was
anticipated that the addition of a Lewis acid would effect
N-acyliminium ion formation.12 In the presence of a nucleo-
phile, R- or γ-attack could proceed to give substitution
products (Scheme 2). In this vein, exploratory reactions were
carried out with 3g, allyltrimethylsilane, and a Lewis acid
(SnCl4 or BF3‚Et2O) in methylene chloride.
a Reagents and conditions: (a) Et3SiH, TFA, CH2Cl2, -20 °C,
R3 ) Ph (77%), R3 ) PhCH2CH2 (72%); (b) MeOH, catalytic
PPTS, rt (100%); (c) PhSH, CH2Cl2, catalytic TMSOTf, rt (73%);
(d) toluene BF3‚OEt2, furan, -78 °C (80%); (e) MnO2, CH2Cl2, rt,
R3 ) Ph (62%), R3 ) cyclohexyl (50%), R3 ) 3-furanyl (50%);
(f) NaBH4, CeCl3, MeOH, -40 °C (77%).
To our satisfaction, the use of 1.5 equiv of BF3‚Et2O and
1.2 equiv of allyltrimethylsilane (-30 °C, 30 min) afforded
(8) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(9) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett. 1995, 36,
9141.
770
Org. Lett., Vol. 3, No. 5, 2001
Comins
