butoxide and ethylene glycol, compound 7 was isolated
directly from the reaction mixture as a solid in 87% yield
upon addition of water. Conversion of the alcohol 7 to the
corresponding bromide 8 was carried out in toluene with
PBr3, and the bromide was used without purification.5b
Treatment of the bromide with n-butyllithium led to lithium-
bromide exchange followed by intramolecular alkylation of
the resulting aryllithium to give the desired 6-bromo-2,3-
dihydrobenzofuran 5 in 80% yield from the alcohol 7.5c This
compound was isolated from methanol-water as a crystalline
solid.5d
Scheme 1
Preparation of the Michael Reaction Acceptor 12. The
key Michael acceptor 12 was synthesized according to
Scheme 3. Starting with the readily available 2,6-dibromo-
pyridine, direct displacement of one of the bromides with
lithium benzylisopropyl amide in toluene went smoothly to
give the aminopyridine 10.6a,7 Interestingly, the desired
product was not formed in THF as reaction solvent. Formy-
lation with Vilsmeier’s reagent generated from DMF/POCl3
gave the aldehyde 11 with the desired regiochemistry. The
side reaction in this step was the displacement of the bromide
by the chloride, which was minimized by using excess (4
equiv) Vilsmer’s reagent and lower temperature (35-40 °C).
Bromoaldehyde 11 was converted into the tert-butyl ester
12 in 85% yield via a Heck reaction with 1.05 equiv of tert-
butyl acrylate in N,N-dimethyl acetamide with NaOAc‚3H2O
and PdCl2(dppf) (CH2Cl2 complex) as the catalyst at 80 °C.6b
Compounds 10-12 were oils and therefore were not purified.
Synthesis of 6-Bromo-2,3-dihydrobenzofuran (5). As
shown in Scheme 2, the commonly used synthetic route to
Scheme 2
Conjugate Addition. To introduce the bottom chiral
center in 2, we envisioned the strategy of using chiral amino
alcohol or diamine auxiliary to form the intermediate like
13, which could undergo diastereoselective conjugate addi-
tion to the unsaturated ester by the bottom arylmetal species.
On the basis of our earlier experience with conjugate
additions of this type, we expected the addition of the
aryllithium to intermediate such as 13 would be straightfor-
ward.3,4 However, we found that extensive screening was
necessary to find the right protecting groups on the substrates,
the right chiral auxiliary, and conditions for the reaction to
proceed with high yield and diastereoselectivity. As shown
in Scheme 3, the best combination we found was N-benzyl
protection for the amino substituent of 12 along with the
trityl protecting group on the alcohol of the bottom aryl
compound (Ar2)8 and (S,S)-pseudoephedrine as the auxiliary.
The bottom aryllithium (Ar2Li) was prepared at low tem-
perature (typically e50 °C), and the enoate 13 (prepared by
reacting 12 with (S,S)-pseudoephedrine) was added to the
aryllithium solution at temperatures typically lower than -50
°C. After the auxiliary was removed with citric acid, the
this compound is from 3-bromophenol, relying on a non-
regioselective Friedel-Crafts cyclization of 3 to 4 followed
by low yielding reduction (due to debromination).5a We
desired a practical synthesis of this compound that obviated
both of these problems. Thus, when readily available 1,4-
dibromo-2-fluorobenzene (6) was treated with potassium tert-
(4) (a) Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. D.; Dolling,
U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1998, 63, 3120. (b)
Alexakis, A.; Sedrani, R.; Mangeney, P.; Normant, J. F. Tetrahedron Lett.
1988, 29, 411.
(5) (a) Paper from Banyu Medicinal Chemistry, manuscript in preparation.
(b) The reaction was carried out at 90 °C with 0.45 equiv of PBr3. After 2
h, an additional 0.1 equiv of PBr3 and 0.3 equiv of water were added to get
complete conversion. (c) Bradsher, C. K.; Reames, D. C. J. Org. Chem.
1981, 46,1384. (d) Data for 5: white crystals, mp 42-45 °C; 1H NMR
(250 MHz, CDCl3, ppm) 3.15 (t, 2H, J ) 8.8 Hz), 4.58 (t, 2H, J ) 8.8
Hz), 6.9-7.1 (m, 3H); 13C NMR (100 MHz, CDCl3, ppm) 161.1, 126.2,
125.8, 123.3, 120.8, 112.9, 71.9, 29.3; HPLC 95% pure by area.
(6) (a) Data for 10: colorless oil; 1H NMR (250 MHz, CDCl3, ppm)
1.21 (d, J ) 6.7 Hz, 6 H), 4.52 (s, 2H), 5.11 (hep, J ) 6.7 Hz, 1H), 6.18
(d, J ) 8.4 Hz, 1H), 6.0.68 (d, H)7.4 Hz, 1H), 7.14 (dd, J ) 8.4, 7.4 Hz,
1H), 7.2-7.4 (m, 5H). (b) Data for 12: 1H NMR (250 MHz, CDCl3, ppm)
1.25 (d, 6H, J ) 6.7 Hz), 1.54 (s, 9H), 4.68 (s, 2H), 5.35 (br, m, 1H), 6.41
(d, J ) 10 Hz, 1H), 6.89 (d, J ) 15 Hz, 1H), 7.15-7.36 (m, 5H), 7.83 (d,
J ) 10 Hz, 1H), 8.29 (d, J ) 15 Hz, 1H), 10.20 (s 1H).
(7) Satisfactory 13C NMR and elemental analysis results were obtained.
(8) The trityl ether (Ar2Br) was made from 2-bromo-5-methoxybenzyl
chloride and Ph3COH in the presence of t-BuOK.
3358
Org. Lett., Vol. 3, No. 21, 2001