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D. M. Barnes et al. / Tetrahedron 62 (2006) 11311–11319
3. Experimental
3.1.5. 2-[1-(4-Bromophenyl)ethylidene]-malononitrile
(3e). Reaction run using 40-bromoacetophenone (10.00 g,
50.3 mmol). Crystallization with heptane (88 mL) provided
10.55 g (86.0%) of yellow crystalline 3e. Mp¼93.5–
3.1. Knoevenagel condensation
1
Hexamethyldisilazane (1.2 equiv) was added to acetic acid
(0.67 mL/mmol ketone 2) at a rate to maintain the internal
temperature at or below 74 ꢀC. (Caution—this addition is
very exothermic!) The HMDS/acetic acid mixture is added
to a solution of ketone 2 and malononitrile (2 equiv) in acetic
acid (0.33 mL/mmol). After reaction completion, the mix-
ture is cooled to ambient temperature with chilled toluene
(1.67 mL/mmol, at 0 ꢀC) and diluted with water (1.33 mL/
mmol). The aqueous layer was separated and extracted
with toluene (0.67 mL/mmol). The combined organic ex-
tracts were washed four times with water and dried over
MgSO4. The products 3 were isolated by crystallization or
chromatography.
94.5 ꢀC; H NMR (400 MHz, CDCl3) d 2.44 (s, 3H), 7.23
(ddd, J¼8.89, 2.47, 2.23 Hz, 2H), 7.46 (ddd, J¼8.89, 2.47,
2.23 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) d 24.4,
85.1, 112.2, 112.3, 126.8, 128.5, 132.1, 134.2, 173.3 ppm;
MS (APCI+) m/z 247.0; Anal. Calcd for C11H7BrN2: C,
53.47; H, 2.86; N, 11.34. Found: C, 53.26; H, 2.87; N, 11.19.
3.1.6. 2-[1-(2,6-Difluorophenyl)ethylidene]-malononitrile
(3f). Reaction run using of 20,60-difluoroacetophenone
(10.21 g, 65.4 mmol). Crystallization with heptane (100 mL)
provided 8.48 g (63.5%) of yellow crystalline 3f. Mp¼
80–81 ꢀC; 1H NMR (400 MHz, CDCl3) d 2.78 (s, 3H), 7.22
(dd, J¼8.51, 7.96 Hz, 2H), 7.65 (tt, J¼8.51, 6.38 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) d 24.2, 91.4, 110.9,
111.0, 112.1, 112.1, 112.1, 112.3, 112.3, 112.3, 113.3,
113.5, 113.7, 132.8, 132.9, 133.0, 156.7, 156.8, 159.2,
159.3, 165.3 ppm; MS (APCI+) m/z 203.0 (MꢁH); Anal.
Calcd for C11H6F2N2: C, 64.71; H, 2.96; N, 13.72. Found:
C, 64.47; H, 2.83; N, 13.78.
3.1.1. 2-[1-(4-Nitrophenyl)ethylidene]-malononitrile
(3a). Reaction run using 40-nitroacetophenone (10.00 g,
60.6 mmol). Crystallization with heptane (93 mL) provided
11.49 g (89.0%) of yellow crystalline 3a. Mp¼87–88 ꢀC; 1H
NMR (400 MHz, CDCl3) d 2.68 (s, 3H), 7.69 (ddd, J¼9.09,
2.40, 2.23 Hz, 2H), 8.36 (dt, J¼9.16, 2.28 Hz, 2H) ppm; 13C
NMR (100 MHz, CDCl3) d 24.7, 87.6, 111.5, 111.5, 124.1,
128.1, 141.2, 149.1, 172.3 ppm; MS (APCI+) m/z 212.0
(MꢁH); Anal. Calcd for C11H7N3O2: C, 61.97; H, 3.31; N,
19.71. Found: C, 61.69; H, 3.30; N, 19.74.
3.1.7. 2-[1-(4-Methoxyphenyl)ethylidene]-malononitrile
(3g). Reaction run using 40-methoxyacetophenone (2.89 g,
19.3 mmol). Crystallization with heptane (30 mL) provided
3.14 g (82.3%) of yellow crystalline 3g. Mp¼79.5–
1
80.5 ꢀC; H NMR (400 MHz, CDCl3) d 2.89 (s, 3H), 4.15
3.1.2. 2-[1-(Phenyl)ethylidene]-malononitrile (3b). Reac-
tion run using acetophenone (9.7 mL, 83 mmol). Crystalliza-
tion with heptane provided 11.48 g (82.3%) of white
crystalline 3b. Mp¼94.5–95.5 ꢀC; 1H NMR (400 MHz,
CDCl3) d 2.43 (s, 3 H), 7.31 (m, 5 H) ppm; 13C NMR
(100 MHz, CDCl3) d 24.5, 84.6, 112.5, 112.5, 127.0, 128.8,
131.9, 135.5, 174.9 ppm; MS (APCI+) m/z 167.1 (MꢁH);
Anal. Calcd for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found:
C, 78.24; H, 4.47; N, 16.81.
(s, 3H), 7.26 (ddd, J¼9.43, 3.16, 2.64 Hz, 2H), 7.88 (ddd, J¼
9.50, 3.09, 2.64 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 24.1, 81.9, 113.1, 113.4, 114.2, 127.6, 129.5, 162.6,
173.4 ppm; MS (APCI+) m/z 197.1 (MꢁH); Anal. Calcd
for C12H10N2O: C, 72.71; H, 5.08; N, 14.13. Found: C,
72.38; H, 4.78; N, 14.07.
3.1.8. 2-[1-(2-Thiophene-yl)ethylidene]-malononitrile
(3h). Reaction run using 2-acetylthiophene (8.5 mL,
78.9 mmol). At the end of the reaction, ethanol (60 mL)
was added and the mixture was filtered. After drying the
solids were stirred in ethanol (45 mL) and filtered. Drying
in vacuo provided 7.67 g (56%) of crystalline 3h. Mp¼87–
3.1.3. 2-[1-(3-Nitrophenyl)ethylidene]-malononitrile
(3c). Reaction run using 30-nitroacetophenone (10.00 g,
60.6 mmol). Crystallization with heptane (93 mL) provided
10.76 g (83.4%) of yellow crystalline 3c. Mp¼99–100 ꢀC;
1H NMR (400 MHz, CDCl3) d 2.71 (s, 3H), 7.74 (t,
J¼8.03 Hz, 1H), 7.89 (ddd, J¼7.75, 1.78, 1.03 Hz, 1H),
8.36 (t, J¼1.85 Hz, 1H), 8.40 (ddd, J¼8.23, 2.13, 1.03 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) d 24.6, 87.4, 111.5,
111.6, 122.1, 126.1, 130.3, 132.6, 136.9, 148.0, 171.9 ppm;
MS (APCI+) m/z 212.1 (MꢁH); Anal. Calcd for
C11H7N3O2: C, 61.97; H, 3.31; N, 19.71. Found: C, 61.04;
H, 3.10; N, 19.37.
1
88 ꢀC; H NMR (400 MHz, CDCl3) d 2.70 (s, 3H), 7.24
(dd, J¼4.87, 4.19 Hz, 1H), 7.77 (dd, J¼4.94, 0.82 Hz, 1H),
8.04 (dd, J¼4.05, 0.75 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) d 23.9, 78.7, 113.3, 113.8, 128.8, 133.2, 134.1,
137.9, 162.1 ppm; MS (APCI+) m/z 173.0 (MꢁH); Anal.
Calcd for C9H6N2S: C, 62.05; H, 3.47; N, 16.08. Found: C,
60.66; H, 2.99; N, 15.84.
3.1.9. 2-[1-(Phenyl)benzylidene]-malononitrile (3i). Re-
action run using deoxybenzoin (10.01 g, 51.0 mmol).
Crystallization with heptane (100 mL) provided 9.98 g
(80.0%) of white crystalline 3i. Mp¼78.7–79.7 ꢀC; 1H NMR
(400 MHz, CDCl3) d 4.31 (s, 2H), 7.10 (dd, J¼7.20,
2.26 Hz, 2H), 7.28 (m, 3H), 7.49 (m, 5H) ppm; 13C NMR
(100 MHz, CDCl3) d 43.4, 85.4, 112.4, 112.6, 127.5, 128.7,
131.6, 133.9, 134.4, 176.9 ppm; Anal. Calcd for C17H12N2:
C,83.58;H, 4.95;N,11.47.Found:C,83.27;H,4.78;N,11.33.
3.1.4. 2-[1-(4-Methylsulfonylphenyl)ethylidene]-malono-
nitrile (3d). Reaction run using 40-methylsulfonylacetophe-
none (10.00 g, 50.5 mmol). The product crystallized during
the reaction. After drying, the solids were stirred in ethanol
(50 mL) and filtered. Drying in vacuo provided 9.47 g
1
(76.2%) of crystalline 3d. Mp¼138.5–139.5 ꢀC; H NMR
(400 MHz, CDCl3) d 2.67 (s, 3H), 3.11 (s, 3H), 7.69 (d,
J¼8.37 Hz, 2H), 8.08 (d, J¼8.37 Hz, 2H) ppm; 13C NMR
(100 MHz, CDCl3) d 24.7, 44.5, 87.3, 111.6, 111.7, 128.0,
140.6, 143.1, 172.8 ppm; MS (APCI+) m/z 245.1 (MꢁH);
Anal. Calcd for C12H10N2O2S: C, 58.52; H, 4.09; N,
11.37. Found: C, 58.41; H, 3.78; N, 11.45.
3.2. Gewald reaction
Ylidene 3 and elemental sulfur (1.2 atom equiv) are sus-
pended in tetrahydrofuran (10 mL/g 3) and warmed to an