4
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T. Iida et al. / Tetrahedron Letters 42 (2001) 4841–4844
References
(l 8.9) from n-BuLi (l 9.1) and n-BuMgCl (l 6.8).
Purchased n-Bu Mg (Fluka) showed resonance at l −0.49
2
1
13
1
. Mitsuya, M.; Kobayashi, K.; Kawakami, K.; Satoh, A.;
Ogino, Y.; Kakikawa, T.; Ohtake, N.; Kimura, T.;
Hirose, H.; Sato, A.; Numazawa, T.; Hasegawa, T.;
Noguchi, K.; Mase, T. J. Med. Chem. 2000, 43, 5017–
( H NMR) and l 7.2 ( C NMR). D O in a sealed
2
capillary was used for NMR locking. THF was used to
obtain a homogeneous solution.
12. 11% of hexane and 6% of THF in toluene. The reaction
in absolute toluene, by the evaporation of THF (from
n-BuMgCl) and hexane (from n-BuLi), gave similar
results.
13. The mono-metallated intermediate was identified as 2-
bromopyridine (HPLC) after quenching a reaction mix-
ture aliquot with methanol.
14. (a) Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J.
Org. Chem. 1993, 58, 2958–2965; (b) Harada, T.; Kat-
suhira, T.; Hara, D.; Kotani, Y.; Maejima, K.; Kaji, R.;
Oku, A. J. Org. Chem. 1993, 58, 4897–4907; (c) Kondo,
Y.; Matsudaira, T.; Sato, J.; Nurata, N.; Sakamoto, T.
Angew. Chem., Int. Ed. Engl. 1996, 35, 736–738; (d)
Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1996, 118, 8733–8734;
(e) Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1996, 37, 5377–5380; (f) Hojo, M.; Harada, H.; Ito,
H.; Hosomi, A. J. Am. Chem. Soc. 1997, 119, 5459–5460;
(g) Hojo, M.; Harada, H.; Ito, H.; Hosomi, A. Chem.
Commun. 1997, 2077–2078; (h) Inoue, R.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 1998, 63, 910–911.
5
029.
2
. (a) Burgos, C. E.; Nidy, E. G.; Johnson, R. A. Tetra-
hedron Lett. 1989, 30, 5081–5084; (b) De Vos, E.;
Esmans, E. L.; Alderweireldt, F. C. J. Heterocyclic Chem.
1
993, 30, 1245–1252.
3
. (a) Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron
Lett. 1996, 37, 2537–2540; (b) Paterson, M. A.; Mitchell,
J. R. J. Org. Chem. 1997, 62, 8237–8239 and references
cited therein.
. Tr e´ court, F.; Breton, G.; Bonnet, V.; Mongin, F.; Mar-
sais, F.; Qu e´ guiner, G. Tetrahedron Lett. 1999, 40, 4339–
4
4
342.
5
. The use of EtMgBr, vinyl-MgBr, PhMgBr, and t-
BuMgCl, instead of i-PrMgCl, gave less satisfactory
results.
6
. Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett.
1
999, 40, 7449–7453.
. Our work was initially applied for the following patent:
a) Iida, T.; Wada, T.; Mase, T. Japan Application No.
JP 2000-024613 20000202. For contemporaneous work,
see: (b) Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima,
K. Angew. Chem., Int. Ed. 2000, 39, 2481–2483. The date
Feb. 2nd, 2000) of our patent application is consistent
with the date that their work was received by the journal.
. (a) Malpass, D. B.; Eastham, J. F. J. Org. Chem. 1973,
8, 3718–3723; (b) Ashby, E. C.; Chao, L.-C.; Laemmle,
J. J. Org. Chem. 1974, 39, 3258–3263.
. Wakefield, B. J. Organomagnesium Methods in Organic
Synthesis; Academic Press: New York, 1995; pp. 61–71.
0. The reagent, prepared from n-Bu Mg and n-BuLi (1:1),
showed similar reactivity to the reagent from n-BuMgCl.
1. H NMR (toluene–THF (2:1), 25°C) for the mixture of
7
(
15. Procedure for the formylation of 1 using n-Bu MgLi: To
3
a solution of n-BuLi (1.63 M in hexane, 45.8 kg, 109 mol)
in toluene (52 L) was added n-BuMgCl (1.95 M in THF,
26.9 kg, 54.5 mol) at −10 to 0°C over 0.5 h, and the
mixture was stirred at −10°C for 0.5 h. A solution of 1
(34.9 kg, 145 mol) in toluene (262 L) was added dropwise
over 1 h while maintaining the temperature of the mix-
ture below −5°C. The resulting suspension was stirred at
−10°C for 2.5 h and then transferred into a cooled
(−10°C) solution of DMF (14.0 kg, 189 mol) in toluene
(50 L) over ca. 0.5 h. The mixture was aged at −10 to
−5°C for 0.5 h and then quenched with aq. citric acid
(
8
9
3
1
2
1
1
n-BuLi and n-BuMgCl (2:1) showed one triplet peak
(56.6 kg in 105 L of H O). After stirring the mixture
2
(
metal-CH -) at l −0.54, while both n-BuLi and n-
below 20°C for 10 min, the organic layer was separated,
2
BuMgCl showed a doublet-of-triplets at −0.87 and −0.42,
respectively. C NMR also showed different resonance
washed with H O (105 L), and then assayed by mean of
HPLC: 25.0 assay kg of 3 (91% assay yield).
2
13
.