Chloro- and Bromopyridines
FULL PAPER
Metalation of 2,5-dichloropyridine (10a): Using the general procedure
(M=Zn) with 0.33 equiv of base instead of 0.5 equiv, a nonseparable
mixture of 2,5-dichloro-4-iodopyridine (10b1), 3,6-dichloro-2-iodopyri-
dine (10c), 3,6-dichloro-2,4-diiodopyridine (10d), 2,5-dichloro-3-iodopyri-
dine (10 f), and starting material was obtained.
2,5-Dichloro-4-iodopyridine (10b1): 1H NMR (CDCl3, 300 MHz): d=
7.84 (s, 1H), 8.33 ppm (s, 1H). These data are consistent with those re-
ported in the literature.[24] The structure was identified unequivocally by
X-ray structure analysis.
2,6-Dichloropyridin-4-yl phenyl ketone (8b2): Eluent: heptane/EtOAc
(90:10). White powder. M.p. 888C; 1H NMR (CDCl3, 300 MHz): d=7.51
(s, 2H), 7.51–7.58 (m, 2H), 7.68 (tt, J=7.4, 1.3 Hz, 1H), 7.75–7.82 ppm
(m, 2H); 13C NMR (CDCl3, 75 MHz): d=122.5 (2C), 129.1 (2C), 130.2
(2C), 134.4, 135.0, 149.8, 151.3 (2C), 192.2 ppm; HRMS (ESI): m/z calcd
for C12H835L2NO [M+H+]: 251.9983; found: 251.9980.
2,6-Dichloropyridin-3-yl phenyl ketone (8c2): Eluent: heptane/EtOAc
(90:10). Yellow powder. M.p. 678C (lit.[66] 67–688C); 1H NMR (CDCl3,
300 MHz): d=7.41 (d, J=7.9 Hz, 1H), 7.44–7.54 (m, 2H), 7.64 (tt, J=
7.4, 1.3 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.75–7.81 ppm (m, 2H);
13C NMR (CDCl3, 75 MHz): d=123.1, 129.0 (2C), 130.0 (2C), 133.5,
134.5, 135.6, 140.3, 147.3, 151.8, 192.6 ppm.
3,6-Dichloro-2-iodopyridine (10c): 1H NMR (CDCl3, 300 MHz): d=7.24
(d, J=8.3 Hz, 1H), 7.58 ppm (d, J=8.3, 1H); 13C NMR (CDCl3,
75 MHz): d=119.3, 124.1, 137.4, 137.9, 147.8 ppm.
3,6-Dichloro-2,4-diiodopyridine (10d): 1H NMR (CDCl3, 300 MHz): d=
7.78 ppm (s, 1H). The structure was identified unequivocally by X-ray
structure analysis.
2,5-Dichloro-3-iodopyridine (10 f): 1H NMR (CDCl3, 300 MHz): d=8.13
(d, J=2.4 Hz, 1H), 8.31 ppm (d, J=2.4 Hz, 1H).
2,5-Dichloropyridin-4-yl phenyl ketone (10b2): Eluent: heptane/EtOAc
(90:10). White powder. M.p. 1318C; 1H NMR (CDCl3, 500 MHz): d=
7.32 (s, 1H), 7.49–7.53 (m, 2H), 7.67 (tt, J=1.2, 7.4 Hz, 1H), 7.77–7.81
(m, 2H), 8.48 ppm (s, 1H); 13C NMR (CDCl3, 125 MHz): d=123.1,
127.4, 129.2 (2C), 130.1 (2C), 134.7, 135.0, 148.4, 149.9, 150.0, 191.5 ppm;
HRMS (ESI): m/z calcd for C12H735L2NNaO [M+Na]+: 273.9802; found:
273.9801.
Metalation of 2,3-dibromopyridine (11a): Using the general procedure
(M=Zn), a nonseparable mixture of 2,3-dibromo-4-iodopyridine (11b),
2,4-dibromo-3-iodopyridine (11c1), and starting material was obtained.
2,3-Dibromo-4-iodopyridine (11b): 1H NMR (CDCl3, 300 MHz): d=7.73
(d, J=5.0 Hz, 1H), 7.90 ppm (d, J=2.3 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=113.9, 131.5, 134.3, 142.8, 147.5 ppm.
2,4-Dibromo-3-iodopyridine (11c1): 1H NMR (CDCl3, 300 MHz): d=
7.49 (d, J=5.1 Hz, 1H), 8.12 ppm (d, J=5.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=108.2, 126.6, 142.1, 148.7, 149.7 ppm.
2,3-Dichloropyridin-4-yl phenyl ketone (12b2): Eluent: heptane/EtOAc
(80:20). Beige powder. M.p. 1128C; 1H NMR (CDCl3, 300 MHz): d=
7.22 (d, J=4.8 Hz, 1H), 7.46–7.55 (m, 2H), 7.66 (tt, J=1.3, 7.4 Hz, 1H),
7.74–7.82 (m, 2H), 8.42 ppm (d, J=4.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d=121.4, 127.0, 129.2 (2C), 130.1 (2C), 134.6, 134.9, 147.3,
148.8, 150.6, 192.0 ppm; HRMS (ESI): m/z calcd for C12H735L2NNaO
[M+Na]+: 273.9802; found: 273.9803.
2-Chloro-6-methoxypyridin-3-yl phenyl ketone (13b1): This compound
was identified in the crude by 1H NMR spectroscopy. 1H NMR (CDCl3,
300 MHz): d=3.89 (s, 3H), 7.04 (d, J=7.7 Hz, 1H), 7.71 ppm (d, J=
7.7 Hz, 1H).
2,4-Dibromopyridine (11c2): This compound was obtained using the gen-
eral procedure (M=Zn), but trapping with water instead of I2. 1H NMR
(CDCl3, 300 MHz): d=7.41 (dd, J=1.6 and 5.3 Hz, 1H), 7.68 (d, J=
1.5 Hz, 1H), 8.19 ppm (d, J=5.3 Hz, 1H). These data are consistent with
those obtained from a commercial sample (Alfa).
2-Chloro-6-methoxypyridin-4-yl phenyl ketone (13c): Eluent: heptane/
1
EtOAc (80:20). Yellow powder. M.p. 948C; H NMR (CDCl3, 300 MHz):
Metalation of 2,3-dichloropyridine (12a): Using the general procedure
(M=Zn) with 0.33 equiv of base instead of 0.5 equiv, 2,3-dichloro-4-iodo-
pyridine (12b1) was obtained.
2,3-Dichloro-4-iodopyridine (12b1): White solid. M.p. 1118C; 1H NMR
(CDCl3, 300 MHz): d=7.73 (d, J=5.1 Hz, 1H), 7.89 ppm (d, J=5.1 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d=111.2, 134.0, 135.4, 146.6,
148.5 ppm. The structure was identified unequivocally by X-ray structure
analysis.
d=4.00 (s, 3H), 6.91 (d, J=1.1 Hz, 1H), 7.18 (d, J=1.1 Hz, 1H), 7.46–
7.55 (m, 2H); 7.65 (tt, J=1.3, 7.4 Hz, 1H), 7.77–7.85 ppm (m, 2H);
13C NMR (CDCl3, 75 MHz): d=54.7, 109.6, 115.7, 128.9 (2C), 130.3
(2C), 133.9, 135.6, 149.2, 149.8, 164.1, 193.8 ppm; HRMS (ESI): m/z
calcd for C13H1035ClNNaO2 [M+Na]+: 270.0298; found: 270.0299.
2-Chloro-6-methoxypyridin-5-yl phenyl ketone (13d): This compound
was identified in the crude by 1H NMR spectroscopy. 1H NMR (CDCl3,
300 MHz): d=4.02 (s, 3H), 6.79 (d, J=8.3 Hz, 1H), 7.68 ppm (d, J=
8.3 Hz, 1H).
General procedure for the cupration (using (TMP)2CuLi) followed by
benzoylation: BuLi (1.6 m hexanes solution, 2.0 mmol) and, 15 min later,
a solution of LiACHTUNGTRENNUNG(TMP) prepared in THF (2 mL) at 08C from 2,2,6,6-tetra-
2-Chloro-6-methoxypyridin-3-yl 2-chlorophenyl ketone (13b2): Eluent:
heptane/EtOAc (80:20). Yellow powder. M.p. 448C; 1H NMR (CDCl3,
300 MHz): d=3.81 (s, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.31–7.47 (m, 4H),
7.96 ppm (d, J=7.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=54.8, 117.1,
120.1, 127.0, 129.7, 129.9, 131.4, 131.8, 139.4, 142.9, 152.9, 161.8,
192.5 ppm; HRMS (ESI): m/z calcd for C13H935L2NNaO2 [M+Na]+:
303.9908; found: 303.9909.
methylpiperidine (0.68 mL, 4.0 mmol) and BuLi (1.6 m hexanes solution,
4.0 mmol) were successively added to a stirred, cooled (08C) suspension
of CuCl2·TMEDA (0.5 g, 2.0 mmol) in THF (5 mL). The mixture was
stirred for 15 min at this temperature before introduction of the substrate
(2.0 mmol). After 2 h at room temperature, the electrophile (4.0 mmol)
was added at 08C. The mixture was stirred for 16 h at the required tem-
perature before addition of brine (5 mL) and extraction with Et2O (3ꢄ
10 mL). The combined organic layers were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure
before purification by column chromatography on silica gel (the eluent is
given in the product description).
3,5-Dichloropyridin-4-yl phenyl ketone (4c2):[64] Eluent: heptane/EtOAc
(90:10). Yellow powder. M.p. 518C; 1H NMR (CDCl3, 300 MHz): d=
7.46–7.54 (m, 2H), 7.66 (tt, J=7.4, 1.3 Hz, 1H), 7.76–7.82 (m, 2H),
8.58 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d=128.8 (2C), 129.3
(2C), 129.6 (2C), 134.3, 135.1, 144.7, 147.8 (2C), 190.2 ppm. These data
are consistent with those reported in the literature.
2-Chloro-6-(trifluoromethyl)pyridin-3-yl
2-chloropyridin-5-yl
ketone
(14b1): Eluent: heptane/EtOAc (80:20). Yellow powder. M.p. 1108C;
1H NMR (CDCl3, 300 MHz): d=7.52 (dd, J=0.7, 8.4 Hz, 1H), 7.82 (d,
J=7.8 Hz, 1H), 7.98 (dd, J=0.6, 7.8 Hz, 1H), 8.11 (dd, J=2.5, 8.4 Hz,
1H), 8.70 ppm (dd, J=0.7, 2.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=
119.7 (q, J=2.8 Hz), 120.3 (q, J=275 Hz), 125.2, 129.8, 136.5, 139.3,
139.9, 148.3, 150.0 (q, J=37 Hz), 151.6, 157.3, 190.0 ppm; HRMS
(APCI): m/z calcd for C12H535L2F3N2O [M]+: 319.97255, m/z calcd for
C12H535L2F3N2O [M+H]+: 320.98038; found: 319.9726 and 320.9803, re-
spectively.
2-Chloro-6-(trifluoromethyl)pyridin-4-yl
2-chloropyridin-5-yl
ketone
(14b2): Eluent: heptane/EtOAc (80:20). Beige powder. M.p. 1058C;
1H NMR (CDCl3, 300 MHz): d=7.57 (d, J=8.3 Hz, 1H), 7.79 (d, J=
0.6 Hz, 1H), 7.89 (d, J=1.1 Hz, 1H), 8.13 (dd, J=2.4, 8.3 Hz, 1H),
8.77 ppm (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=118.3 (q,
J=2.8 Hz), 120.3 (q, J=275 Hz), 125.3, 126.9, 129.5, 139.7, 147.4, 149,7
(q, J=37 Hz), 151.3, 153.4, 157.2, 189.7 ppm; HRMS (APCI): m/z calcd
for C12H535L2F3N2O [M]+: 319.97255, m/z calcd for C12H535L2F3N2O:
4-Chlorophenyl 2-chloropyridin-3-yl ketone (6b3): Eluent: heptane/
EtOAc (80:20). Orange powder. M.p. 568C; 1H NMR (CDCl3,
300 MHz): d=7.40 (dd, J=4.8, 7.5 Hz, 1H), 7.47 (m, 2H), 7.75 (m, 3H),
8.57 ppm (dd, J=1.9, 4.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=122.5,
129.4 (2C), 131.4 (2C), 134.2, 134.6, 138.1, 141.0, 147.8, 151.2, 192.3 ppm.
These data are consistent with those reported in the literature.[65]
Chem. Eur. J. 2011, 17, 13284 – 13297
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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