G. N. Boice et al. / Tetrahedron 60 (2004) 11367–11374
11373
131.0, 123.0, 116.5, 112.5; IR (thin film) 3350, 3065, 2228,
1598 cmK1. Anal. Calcd for C12H7ClN2: C, 67.15; H, 3.29;
N, 13.05. Found: C, 67.04; H, 2.96; N, 12.86.
MeOH, and further concentrated to 60 L. The solution was
aged and the resulting slurry was cooled to 0 8C, filtered and
the filtercake washed with MeOH to afford an off-white
1
solid (5.31 kg, 57%). Mp 98–100 8C; H NMR (CDCl3,
400 MHz) d 7.60 (d, JZ2.2 Hz, 1H), 7.57 (dd, JZ8.5,
2.2 Hz, 1H), 7.44–7.35 (m, 6H), 7.01 (br d, JZ44.4 Hz,
2H), 5.27 (s, 2H), 4.93 (br d, JZ36.4 Hz, 2H), 4.65–4.63
(m, 1H); 13C NMR (CDCl3, 100 MHz) d 151.0, 147.2,
135.2, 133.6, 133.0, 132.1, 131.2, 128.6, 128.5, 128.3,
123.8, 123.3, 116.3, 112.1, 107.0, 106.5, 68.4, 36.8; IR (thin
film) 3058, 2955, 2221, 1729, 1681 cmK1. Anal. Calcd for
C20H15ClN2O2: C, 68.48; H, 4.31; N, 7.99. Found: C, 68.32;
H, 4.12; N, 7.89.
4.1.7. tert-Butyl 4-(4-chloro-2-cyanophenyl)-3,6-di-
hydropyridine-1(2H)-carboxylate (5). A flask under N2
was charged with 2-bromo-5-chlorobenzonitrile 2b (0.9 g,
4.2 mmol), boronate 3 (1.7 g, 5.6 mmol), K3PO4 (1.8 g,
8.4 mmol), Pd(PPh3)4 (0.24 g, 0.2 mmol), dioxane (60 mL),
and H2O (15 mL). The reaction mixture was heated to
85 8C. After 21 h, the reaction mixture was cooled to rt.
Purification of the concentrated reaction mixture by silica
gel chromatography (1:3 CH2Cl2/Hex) afforded the product
as a pale yellow oil that solidified upon standing (0.87 g,
65%). Mp 93–95 8C; 1H NMR (CDCl3, 400 MHz) d 7.64 (d,
JZ2.2 Hz, 1H), 7.52 (dd, JZ8.4, 2.4 Hz, 1H), 7.27 (d, JZ
8.4, 1H), 6.00 (br s, 1H), 4.10 (d, JZ2.8 Hz, 2H), 3.66 (t,
JZ5.6 Hz, 2H), 2.53–2.48 (m, 2H), 1.50 (s, 9H); 13C NMR
(CDCl3, 100 MHz) d 154.6, 144.4, 133.2, 133.1, 132.93,
132.90, 129.4, 126.9, 117.2, 111.7, 79.9, 43.5, 39.5, 28.8,
28.4; IR (thin film) 2968, 2228, 1688 cmK1. Anal. Calcd for
C17H19ClN2O2: C, 64.05; H, 6.01; N, 8.79. Found: C, 64.33;
H, 5.88; N, 8.61.
Acknowledgements
The authors thank Lisa DiMichele, Peter Dormer, and Bob
Reamer for assistance with NMR analysis; and Tom Novak
for assistance with HRMS analysis.
Supplementary data
4.1.8. Phenyl 4-(4-chloro-2-cyanophenyl)pyridine-1(4H)-
carboxylate (9a). General procedure for dihydropyri-
dines. To a K30 8C solution of 2b (835 g, 3.86 mol) in THF
(10 L) was added i-PrMgCl (1.71 M in THF, 2.5 L,
4.25 mol) at a rate such that the temperature !K20 8C.
Meanwhile, to a K10 8C solution of CuI (36 g, 190 mmol)
in THF (10 L) was added pyridine (624 mL, 7.72 mol) and
then phenyl chloroformate (532 mL, 4.25 mmol) such that
the temperature !0 8C. To this heterogeneous mixture was
added the previously formed Grignard at a rate such that
temperature !0 8C. The resulting solution was aged at 0 8C
for 30 min and allowed to warm up to rt. The reaction was
then quenched with 10% aqueous NH4Cl (20 L). EtOAc
(20 L) was added and the blue aqueous layer was removed.
The organic layer was washed with 10% aqueous NH4Cl
(20 L), 1 N HCl (20 L), and finally an aqueous 20% NaCl
solution (20 L). The organic layer was then concentrated,
solvent switched to MeOH and crystallized. The slurry was
filtered and the filtercake washed with MeOH, yielding an
Supplementary data associated with this article can be
References and notes
1. (a) Guzikowski, A. P.; Tamiz, A. P.; Acosta-Burruel, M.;
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1
off-white solid (584 g, 43%). Mp 128–130 8C; H NMR
(CDCl3, 400 MHz) d 7.63–7.59 (m, 2H), 7.50 (d, JZ8.4 Hz,
1H), 7.41 (app t, JZ7.8 Hz, 2 H), 7.27 (t, JZ7.2 Hz, 1H),
7.20–7.11 (m, 4H), 5.05 (br d, JZ15.5 Hz, 2H), 4.70 (br s,
1H); 13C NMR (CDCl3, 100 MHz) d 150.5, 149.7, 146.9,
133.7, 133.1, 132.3, 131.2, 129.5, 126.1, 123.7, 123.4,
121.4, 116.3, 112.3, 107.9, 107.3, 36.9; IR (thin film) 3065,
2228, 1736, 1688 cmK1; HRMS (ESI) m/z calcd for
C19H13ClN2O2 337.0744 (MCH), found 337.0740 (MCH).
4.1.9. Benzyl 4-(4-chloro-2-cyanophenyl)pyridine-1(4H)-
carboxylate (9b). The general procedure for dihydro-
pyridines was followed, using 2b (5.71 kg, 26.4 mol),
THF (114 L) and i-PrMgCl (1.74 M in THF, 23.9 L,
41.6 mol), CuI (250 g, 1.31 mol), THF (114 L), pyridine
(4.25 L, 52.5 mol) and benzylchloroformate (5.83 L,
40.9 mol), 10% aqueous NH4Cl (55 L), MTBE (55 L),
10% aqueous NH4Cl (55 L), 1 N HCl (55 L), and finally an
aqueous 5% NaHCO3/5% NaCl solution (55 L). The
organic layer was then concentrated, solvent switched to
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