To the cooled suspension 2-oxo-2-phenylacetyl chloride (6.05 g,
0.036 mol) was added drop-wise and the mixture stirred at rt for
1 h. The mixture was washed with water (2 × 30 cm3), the
organic layer was collected, dried (anhydrous Na2SO4), filtered
and concentrated to afford 10d as a colourless, mobile oil (4.58
g, 63%) [mixed rotamers, 1 : 1.1], which was not purified further.
Rf 0.265 Et2O–petroleum spirit;1 : 1 (Found: C, 70.70; H, 6.40;
N, 6.79. C12H13NO2 requires: C, 70.92; H, 6.45; N, 6.89%);
δH (400 MHz) 2.85, 3.02 (3H, s, Me), 3.76, 4.12 (2H, d, J 5.9,
purified by flash chromatography (Et2O–petroleum spirit; 1 : 1)
yielding (E)-8c (0.43 g, 20%) and (Z )-8c (0.56 g, 25%) each as a
pair of rotamers; (E)-8c (rotamer ratio 1 : 1.2), a colourless
mobile oil, solidifying in the cold, mp 90–92 ЊC (Found: C,
54.10; H, 7.65; N, 17.84. C7H12N2O2 requires: C, 53.85; H, 7.69;
N, 17.95); δH (400 MHz) 2.06, 2.08 (3H, s, Me), 2.96, 3.01 (3H,
s, N–Me), 4.03 (2H, t, J 7.3, ᎐CH ), 5.21 (2H, d, J 10.3, –CH ),
᎐
2
2
5.78 (1H, m, CH᎐CH ), 9.47, 9.55 (1H, s, OH); δ (100 MHz)
᎐
2
C
12.08, 12.25 (CH3), 32.93, 36.03 (N–CH3), 50.00, 53.48 (–CH2–),
117.93 (᎐CH ), 131.86, 133.09 (–CH᎐CH ), 151.98, 152.07
–CH –), 5.16, 5.27 (2H, 2 × m, ᎐CH ), 5.67, 5.81 (1H, m, CH᎐),
᎐
᎐
᎐
᎐
2
2
2
2
7.48 (2H, m, 2 × o-ArH), 7.58 (1H, m, p-ArH), 7.90 (2H, m,
2 × m-ArH); δC (100 MHz) 31.27, 34.29 (N–Me), 48.60, 52.12
(C᎐N), 166.67, 167.23 (C᎐O); (Z )-8c (rotamer ratio 1 : 1.1), a
᎐ ᎐
colourless mobile oil which solidified on standing in the cold,
mp 91–93 ЊC (Found: C, 53.23; H, 7.83; N, 18.02. C7H12N2O2
requires: C, 53.85; H, 7.69; N, 17.95); δH (400 MHz) 2.01, 2.04
(3H, s, CH3), 2.88, 2.91 (3H, s, N–CH3), 3.81, 4.02 (2H, d, J 5.9,
(–CH –), 118.52, 119.16 (᎐CH ), 128.88, 129.52 (CH᎐CH ),
᎐
᎐
2
2
2
131.26 (ArC), 131.64 (ArC), 132.88 (n-ArC), 134.62 (ArC),
166.63, 167.01 (amide C᎐O), 191.34 (ester C᎐O).
᎐
᎐
–CH – and J 5.4, –CH –), 5.20 (2H, m, ᎐CH ), 5.75 (1H, m,
᎐
2
2
2
CH᎐CH ), 9.35 (1H, br s, NOH); δ (100 MHz) 16.88, 17.26
᎐
N-Allyl-2-(hydroxyimino)propanamide 8a
2
C
(ϩ) (CH3), 31.31, 34.16 (ϩ) (N–CH3), 48.51, 52.37 (Ϫ) (–CH2–),
117.68, 118.27 (Ϫ) (᎐CH ), 131.60, 132.79 (ϩ) (CH᎐CH ),
α-Keto amide 10a (4.0 g, 0.032 mol), pyridine (3.76 g,
0.048 mol) and NH2OHؒHCl (3.31 g, 0.048 mol) were stirred in
EtOH (362 cm3) at rt for 15 h. The mixture was concentrated,
taken up in CHCl3 (300 cm3) and washed with water (3 × 100
cm3). The organic layer was collected, dried, filtered and con-
centrated to afford the crude product (3.74 g, 84%) which was
purified by crystallisation; E-8a, colourless cubic crystals, mp
87–89.5 ЊC (from C6H6–petroleum spirit, 3.19 g, 71%) (Found:
C, 50.55; H, 6.86; N, 19.72. C6H10N2O2 requires: C, 50.70; H,
7.04; N, 19.70%); δH (400 MHz) 2.06 (3H, s, CH3), 3.94 (2H,
᎐
᎐
2
2
151.52 (abs.) (C᎐N), 166.25, 166.46 (abs.) (C᎐O).
᎐
᎐
N-Allyl-2-(hydroxyimino)-N-methyl-2-phenylacetamide 8d
α-Keto amide 10d (2 g, 14.9 mmol), pyridine (1.17 g, 14.9
mmol) and NH2OHؒHCl (1.03 g, 14.9 mmol) were stirred in
EtOH (200 cm3) at reflux temperature for 15 h. The mixture was
allowed to cool to rt was concentrated, taken up in CH2Cl2 (200
cm3) and washed with water (2 × 100 cm3). The organic layer
was collected, dried (anhydrous Na2SO4), filtered and concen-
trated affording the crude product which was purified by flash
chromatography (Et2O–petroleum spirit, 1 : 4) to afford (Z )-8d
as a pair of rotamers (1.24 g, 58%); (Z )-8d (rotamer ratio
1 : 1.2), fine colourless needles, mp 104–106 ЊC, (from C6H6–
petroleum spirit) (Found: C, 65.82; H, 5.96; N, 13.20.
C12H14N2O2 requires: C, 66.04; H, 6.47; N, 12.84%); δH (400
MHz) 2.86, 3.05 (3H, s, N–Me), 3.78, 4.18 (2H, d, J 6.3, –CH2–
m, –CH –), 5.18 (2H, m, ᎐CH ), 5.82 (1H, m, CH᎐CH ), 6.97
᎐
᎐
2
2
2
(1H, br s, N–H), 9.57 (1H, br s, OH). Addition of D2O causes
∼50% reduction in signal intensity of both broad peaks);
δC (100 MHz) 9.19 (CH ), 41.76 (–CH –), 116.61 (᎐CH ),
᎐
3
2
2
133.56 (᎐CH), 151.52 (C᎐N), 164.00 (C᎐O); νmax/cmϪ1 3376
᎐
᎐
᎐
(sharp, NH), 3178 (small broad, OH), 1663 (C᎐O), 1630 (C᎐N);
᎐
᎐
m/z 142 (Mϩ), 143 (Mϩ ϩ 1), 125, 56.
and J 5.4, –CH –), 5.14, 5.26 (2H, m, ᎐CH ), 5.62, 5.82 (1H, m,
᎐
2
2
N-Allyl-2-(hydroxyimino)-2-phenylacetamide 8b
CH᎐CH ), 7.36 (3H, m, o- and p-ArH), 7.59 (2H, m, 2 ×
᎐
2
α-Keto amide 10b (5.13 g, 27 mmol), pyridine (3.22 g, 41 mmol)
and NH2OHؒHCl (2.83 g, 41 mmol) were stirred in EtOH (282
cm3) for 15 h at rt. The mixture was concentrated, taken up in
CHCl3 (300 cm3) and washed with water (3 × 200 cm3). The
organic layer was collected, dried (anhydrous Na2SO4), filtered
and concentrated to afford the crude products, (E)-8b and
(Z )-8b in a 1 : 2 ratio (4.13 g, 75%). The oximes, inseparable by
column chromatography, were purified by crystallisation. (E)-
8b and (Z )-8b, colourless plates (60%), mp 127–128 ЊC (from
C6H6–petroleum spirit) (Found: C, 64.28; H, 5.80; N, 13.23.
C11H12N2O2 requires: C, 64.71; H, 5.88, N, 13.73%); (E)-8b
m-ArH); δC (100 MHz) 31.10 and 34.33 (ϩ) (N–Me), 48.72 and
52.93 (Ϫ) (–CH –), 118.02 and 119.12 (Ϫ) (᎐CH ), 126.25 (ϩ)
᎐
2
2
(ArC), 128.71 (ϩ) (ArC), 130.16 (ϩ) (ArC), 130.88
(abs.) (n-ArC), 131.77 and 132.58 (ϩ) (CH᎐CH ), 153.47 (abs.)
᎐
2
(C᎐N), 164.93 (abs.) (C᎐O).
᎐
᎐
2,6-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrazin-1-ium-1-olate 1a
A solution of the oxime (E)-8a (0.5 g, 3.52 mmol) in xylene
(125 cm3), was heated at reflux in the presence of hydroquinone
(1% w/v; 1.25 g) under a nitrogen atmosphere for 24 h. The
mixture was allowed to cool to rt and the solvent removed
under reduced pressure. The residue was taken up in CHCl3
(10 cm3) and the hydroquinone which precipitated, was
removed (in vacuo). The filtrate was concentrated yielding the
crude product which was purified by flash column chromato-
graphy (Et2O–MeOH; 20 : 1) to afford nitrone (0.324g, 65%)
and returned oxime (0.143g, 29%); 1a, pale yellow cubic crystals
mp 144–146 ЊC (from Et2O) (Found: C, 50.82; H, 7.18; N, 19.37.
C6H10N2O2 requires: C, 50.70; H, 7.04; N, 19.72%); δH (400
MHz) 1.55 (3H, d, J 6.6, 2-Me), 2.18 (3H, s, 6-Me), 3.32 (1H,
ddd, J 13.4, 4.5, 4.5, 3b-H), 3.78 (1H, ddd, J 13.4, 4.7, 2.3,
3a-H), 4.12 (1H, m, 2-H), 7.46 (1H, br s, NH); δC (100 MHz)
11.15 (ϩ) (2-Me), 15.94 (ϩ) (6-Me), 42.57 (Ϫ) (3-C), 63.96 (ϩ)
(2-C), 138.44 (abs.) (C᎐N), 161.62 (abs.) (C᎐O); νmax/cmϪ1 3190
δH (400 MHz) 3.96 (2H, m, ᎐CH ), 5.26 (2H, m, N–CH ), 5.86
᎐
2
2
(1H, m, CH᎐CH ), 6.91 (1H, br m, N–H), 7.37 (3H, m, o-,
᎐
2
p-ArH), 7.55 (2H, m, m-ArH), 9.24 (1H, br s, OH); (Z )-8b
δH (400 MHz) 4.03 (2H, m, ᎐CH ), 5.16 (2H, m, N–CH ), 5.86
᎐
2
2
(1H, m, CH–CH2), 6.35 (1H, br m, N–H), 7.37 (3H, m, o- and
p-ArH), 7.55 (2H, m, m-ArH), 10.48 (1H, br s, OH); δC (E)-,
(Z )-8b (100 MHz) 41.72, 41.93 (Ϫ) (N–CH2), 116.66, 117.17 (Ϫ)
(᎐CH ), 126.21, 127.23, 127.78, 128.84, 129.52, 130.16, 132.92,
᎐
2
133.73 (ϩ) (10 × ArC), 128.67 (abs.) ((E)-oxime; n-ArC),
131.56 (abs.) ((Z )-oxime; n-ArC) 132.92, 133.73 (ϩ) (CH᎐
᎐
CH ), 151.18, 152.19 (abs.) (C᎐N), 163.15, 163.36 (abs.) (C᎐O);
᎐
᎐
2
m/z 204 (Mϩ), 187, 119, 104, 77, 56, νmax/cmϪ1 3321 and 3163
(NH and OH), 1634 and 1606 ((E)- and (Z )-isomers C᎐O).
᎐
᎐
᎐
(N–H), 1672 (C᎐O), 1462 (C᎐N); m/z 142 (Mϩ). Addition of
᎐
᎐
N-Allyl-2-(hydroxyimino)-N-methylpropanamide 8c
D2O causes ∼50% reduction in signal intensity of the signal
representing the NH proton.
α-Keto amide 10c (2 g, 14.2 mmol), pyridine (1.68 g, 21.3
mmol) and NH2OH.HCl (1.48 g, 21.3 mmol) were stirred in
EtOH (230 cm3) at rt for 15 h. The mixture was concentrated,
taken up in CH2Cl2 (200 cm3) and washed with water (2 ×
100 cm3). The organic layer was collected, dried (anhydrous
Na2SO4), filtered and concentrated. The crude mixture was
2-Methyl-5-oxo-6-phenyl-2,3,4,5-tetrahydropyrazin-1-ium-1-
olate 1b
A solution of (E)- and (Z )-8b (ratio 2 : 1) (0.20 g, 1.06 mmol) in
xylene (68 cm3) was heated at reflux in the presence of hydro-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 1 2 2 – 1 1 3 2
1128