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D. Wiedenfeld et al.
PAPER
(89%) of a pale orange solid, which was purified by column chro-
matography on silica gel (hexanes–EtOAc, 4:1). A small amount
(10%) of a mixture of unreacted 6e, the corresponding debrominat-
ed material 6g, and the biaryl Ullmann coupling product were ob-
tained along with the desired product 6f (0.34 g, 80%) as pale
yellow, fine fibrous needles.
1H NMR (CDCl3): d = 7.02 (br s, 1 H, NH), 4.39 (d, J = 6.25 Hz, 2
H, CH2), 2.22 (s, 3 H, CH3-3), 2.04 (m, 3 H, CH3-5*), 2.03 (m, 3 H,
CH3-6*).
13C NMR (CDCl3): d = 187.5 (C-1), 187.0 (C-4), 157.0 (q,
JCF = 37.4 Hz, CF3CO), 143.4 (C-2), 141.7, (C-5*), 140.3 (C-6*),
136.7 (C-3), 115.6 (q, JCF = 287.4 Hz, CF3), 36.1 (CH2), 12.4 (CH3-
3*), 12.1 (CH3-5*), 11.9 (CH3-6*).
6f
1H NMR (CDCl3): d = 6.67 (br s, 1 H, NH), 4.55 (d, J = 5.9 Hz, 2
H, CH2), 4.05 (s, 3 H, OCH3-2), 3.68 (s, 3 H, OCH3-5), 2.46 (s, 3 H,
ArCH3-4), 2.38 (s, 3 H, ArCH3-6).
5-Chloro-3,6-dimethyl-2-{[(2,2,2-trifluoroacetyl)amino]meth-
yl}-2,5-cyclohexadiene-1,4-dione (8b)
A solution of CAN (9.85 g, 18 mmol, 3 equiv) in water (18 mL) was
added rapidly dropwise to a stirred solution of 6b (1.95 g, 6 mmol)
in MeCN (60 mL). A transient blue-black color was occasionally
observed during the addition. After stirring overnight at r.t., the or-
ange reaction mixture was partitioned between water (100 mL) and
CHCl3 (3 × 20 mL). The organic layer was filtered through cotton,
concentrated under reduced pressure, and dried under high vacuum.
The crude product was purified by column chromatography on sili-
ca gel (40 g; hexanes–EtOAc, 4:1) to give the quinone 8b (1.32 g,
74%) as an orange solid.
1H NMR (CDCl3): d = 7.00 (br s, 1 H, NH), 4.41 (d, J = 6.3 Hz, 2
H, CH2), 2.30 (s, 3 H, CH3-3), 2.20 (s, 3 H, CH3-6).
13C NMR (CDCl3): d = 185.1 (C-1), 179.3 (C-4), 157.0 (q,
JCF = 37.4 Hz, CF3CO), 143.8 (C-2), 141.9 (C-6*), 141.2 (C-5*),
137.4 (C-3), 115.6 (q, JCF = 287.7 Hz, CF3), 36.1 (CH2), 13.4 (CH3-
6), 12.6 (CH3-3).
13C NMR (CDCl3): d = 156.8 (q, JCF = 37.1 Hz, C=O), 157.7 (ArC-
2), 153.2 (ArC-5), 138.2 (ArC-6), 136.5 (ArC-4), 127.2 (ArC-1),
115.7 (q, JCF = 288.1 Hz, CF3), 115.2 (CN), 105.1 (ArC-3), 62.4
(OCH3-2), 60.3 (OCH3-5), 35.8 (CH2), 14.6 (ArCH3-4), 12.9
(ArCH3-6).
N-[(2,5-Dimethoxy-4,6-dimethylphenyl)methyl]-2,2,2-trifluo-
roacetamide (6g)
Amidomethylation of 1,4-dimethoxy-2,6-dimethylbenzene 5g7a
was carried out as for 6a, except that the reaction time was de-
creased to 2 d. Column chromatography on silica gel (hexanes–
EtOAc, 10:1) gave dimer 7g (20%), the corresponding trimer (5%),
and the desired adduct 6g (65%) as a white solid.
Bis(2,5-dimethoxy-4,6-dimethylphenyl)methane (7g)
1H NMR (CDCl3): d = 6.49, (s, 2 H, ArH), 4.00 (s, 2 H, CH2), 3.66
(s, 6 H, OCH3-2), 3.59 (s, 6 H, OCH3-5), 2.25 (s, 6 H, ArCH3-4),
2.08 (s, 6 H, ArCH3-6).
13C NMR (CDCl3): d = 153.8 (ArC-2), 150.8 (ArC-5), 131.4 (ArC-
1), 127.8 (ArC-4), 127.4 (ArC-6), 110.7 (ArC-3), 60.0 (OCH3-5),
55.8 (OCH3-2), 24.0 (CH2), 16.3 (ArCH3-4), 12.0 (ArCH3-6).
6-Chloro-3,5-dimethyl-2-{[(2,2,2-trifluoroacetyl)amino]meth-
yl}-2,5-cyclohexadiene-1,4-dione (8c)
Oxidative demethylation of 6c was carried out with CAN as for 8b.
The desired quinone 8c (71%) was obtained as a yellow solid, and
was recrystallized from EtOH.
Mp 109–110 °C.
1H NMR (CDCl3): d = 6.91 (br s, 1 H, NH), 4.41 (d, J = 6.6 Hz, 2
H, CH2), 2.27 (s, 3 H, CH3-3), 2.20 (s, 3 H, CH3-5).
13C NMR (CDCl3): d = 184.6 (C-4), 180.0 (C-1), 157.2 (q,
JCF = 37.4 Hz, CF3CO), 144.5 (C-2), 143.3 (C-5), 139.9 (C-6),
137.0 (C-3), 115.6 (q, JCF = 287.4 Hz, CF3), 36.3 (CH2), 14.0 (CH3-
5), 12.6 (CH3-3).
1,3-Bis[(2,5-dimethoxy-4,6-dimethylphenyl)methyl]-2,5-
dimethoxy-4,6-dimethylbenzene (trimer)
1H NMR (CDCl3): d = 6.54 (s, 2 H, ArH), 4.13 (s, 4 H, CH2), 3.77
(s, 6 H, OCH3-2¢), 3.58 (s, 6 H, OCH3-5¢), 3.55 (s, 3 H, OCH3-5),
3.45 (s, 3 H, OCH3-2), 2.27 (s, 6 H, ArCH3-4¢), 1.93 (s, 6 H, ArCH3-
6¢*), 1.89 (s, 6 H, ArCH3-4,6*).
13C NMR (CDCl3): d = 153.5 (2 C, ArC-2¢*), 153.4 (2 C, ArC-2,5*),
150.9 (2 C, ArC-5¢), 131.5 (2 C, ArC-1¢†), 131.1 (2 C, ArC-1,3†),
128.5 (2 C, ArC-4,6§), 128.0 (2 C, ArC-4¢), 127.1 (2 C, ArC-6¢§),
110.3 (2 C, ArC-3¢), 61.1 (OCH3-5), 60.0 (3 C, OCH3-2,5¢), 55.7 (2
C, OCH3-2¢), 24.2 (2 C, CH2), 16.3 (2 C, ArCH3-4¢), 12.3 (2 C,
ArCH3-4,6‡),12.0 (2 C, ArCH3-6¢‡).
3-Chloro-5,6-dimethyl-2-{[(2,2,2-trifluoroacetyl)amino]meth-
yl}-2,5-cyclohexadiene-1,4-dione (8d)
Oxidative demethylation of 6d was carried out with CAN as for 8b
except that the reaction time was extended to 2 d. In this case small
amounts of nitrooxymethyl by-products from side-chain oxidation24
were also formed. The desired quinone 8d (77%) was obtained as
an orange crystalline solid.
1H NMR (CDCl3): d = 7.00 (br s, 1 H, NH), 4.59 (d, J = 6.25 Hz, 2
H, CH2), 2.12 (q, J = 1.1 Hz, 3 H, CH3-5*), 2.08 (q, J = 1.1 Hz, 3 H,
CH3-6*).
13C NMR (CDCl3): d = 184.9 (C-1), 179.0 (C-4), 156.9 (q,
JCF = 37.4 Hz, CF3CO), 142.4 (C-3), 141.7 (C-5*), 141.3 (C-6*),
137.7 (C-2), 115.6 (q, JCF = 287.7 Hz, CF3), 36.9 (CH2), 12.9 (CH3-
5*), 12.4 (CH3-6*).
6g
1H NMR (CDCl3): d = 6.80 (br s, 1 H, NH), 6.59 (s, 1 H, ArH), 4.54
(d, J = 5.9 Hz, 2 H, CH2), 3.83 (s, 3 H, OCH3-2), 3.65 (s, 3 H,
OCH3-5), 2.33 (s, 3 H, ArCH3-4*), 2.30 (s, 3 H, ArCH3-6*).
13C NMR (CDCl3): d = 156.6 (q, JCF = 36.7 Hz, C=O) 154.0 (ArC-
2), 150.8 (ArC-5), 131.6 (ArC-4), 131.2 (ArC-1), 121.1 (ArC-6),
110.3 (ArC-3), 115.9 (q, JCF = 287.7 Hz, CF3), 60.1 (OCH3-5), 55.6
(OCH3-2), 36.1 (CH2), 16.5 (ArCH3-4), 12.1 (ArCH3-6).
Oxidative Demethylations7,8,10
2-{[(2,2,2-Trifluoroacetyl)amino]methyl}-3,5,6-trimethyl-2,5-
cyclohexadiene-1,4-dione (8a)
6-Bromo-3,5-dimethyl-2-{[(2,2,2-trifluoroacetyl)amino]meth-
yl}-2,5-cyclohexadiene-1,4-dione (8e)
Oxidative demethylation of 6e was carried out with HNO3 as de-
scribed below for 8f, column chromatography on silica gel (hex-
anes–EtOAc, 5:1) gave the quinone 8e (81%) as a yellow solid.
1H NMR (CDCl3): d = 7.04 (br s, 1 H, NH), 4.44 (d, J = 6.25 Hz, 2
H, CH2), 2.29 (s, 3 H, CH3-3*), 2.26 (s, 3 H, CH3-5*).
A solution of 6a (1.21 g, 3.95 mmol) in CH2Cl2 (85 mL) was cooled
to –10 °C in an ice-salt bath and nitrogen dioxide was bubbled
through the solution for 10 min. Stirring was continued for a further
10 min at –10 °C and then for 1 h at r.t., during which time the color
changed from green to yellow-brown. The mixture was concentrat-
ed and column chromatography of the crude product on silica gel
(20 g, hexanes–EtOAc, 8:1) gave the quinone 8a (1.0 g, 92%) as a
viscous yellow-orange oil.
Synthesis 2005, No. 10, 1611–1618 © Thieme Stuttgart · New York