568
A. E. Jensen et al.
PRACTICAL SYNTHETIC PROCEDURES
concd H2SO4 (a few drops) were added and the mixture heated to re-
flux with a Dean–Stark head and condenser until no more water was
separated (approx. 2 h). The solution was filtered and concentrated
in vacuo. Excess benzaldehyde was distilled off at 100 °C under
vacuum using an oil pump, the resulting yellow oil crystallized
upon standing. Recrystallization from Et2O yielded the product as
yellow needles. Yield (9.98 g, 87%); mp 73 °C.
0.040–0.060 mm) yielding the amine 8 as a pale yellow oil (868 mg,
81%).
IR (KBr): 2981 (w), 1715 (s), 1605 (m), 1250 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 7.78–7.72 (m, 2 H), 6.98 (d,
J = 8.4 Hz, 1 H), 6.18 (d, J = 1.5 Hz, 1 H), 5.71–5.62 (m, 2 H), 5.27
(d, J = 1.5 Hz, 1 H), 5.11–5.01 (m, 4 H), 4.26 (q, J = 7.1 Hz, 2 H),
4.12 (q, J = 7.1 Hz, 2 H), 3.67 (s, 2 H), 3.54 (s, 2 H), 3.52 (s, 2 H),
1.28 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 166.9, 166.5, 154.4, 139.9, 134.4,
133.7, 132.2, 128.2, 125.9, 124.9, 121.9, 177.4, 60.6, 60.5, 55.6,
33.1, 14.3, 14.1.
IR (KBr): 3436 (m), 1702 (s), 1626 (s), 1578 (s), 1290 (s), 1252 (s)
cm–1.
1H NMR (CDCl3, 300 MHz): = 8.46 (d, J = 1.8 Hz, 1 H), 8.19 (s,
1 H), 7.91 (dd, J = 1.8, 8.1 Hz, 1 H), 7.87 (m, 2 H), 7.44 (m, 3 H),
6.89 (d, J = 8.1 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 1.31 (t, J = 7.1
Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 357 (4), 316 (100), 286 (79), 242 (44),
168 (25), 115 (18).
13C NMR (CDCl3, 75 MHz): = 165.3, 162.2, 157.4, 140.7, 135.8,
132.6, 131.3, 129.7, 129.2, 127.5, 118.5, 94.0, 61.6, 14.8.
Anal. Calcd for C21H27O4N: C, 70.56; H, 7.61; N, 3.92. Found: C,
70.42; H, 7.68; N, 3.86.
MS (EI, 70 eV): m/z (%) = 379 (100), 350 (19), 334 (40), 178 (17).
Anal. Calcd for C16H14O2NI: C, 50.68; H, 3.72; N, 3.69. Found: C,
50.60; H, 3.76; N, 3.65.
Ethyl 4 -Cyano-6-{[(E)-phenylmethylidene]amino}[1,1’-biphe-
nyl]-3-carboxylate (12)
A dry, argon flushed 25 mL round-bottom flask, equipped with a
magnetic stirring bar was charged with the imine 9 (1.11 g, 3 mmol)
in anhyd THF (3 mL) and cooled to –20 °C. i-PrMgBr (3.0 mL, 1.3
M in THF, 3.9 mmol) was slowly added. After 1 h the exchange was
complete (monitored by TLC analysis) and ZnBr2 (2.0 mL, 1.5 M
in THF (3 mmol)) was added. The reaction mixture was allowed to
warm to r.t. Another dry, argon flushed 25 mL flask, equipped with
Methyl 4-[(4 -Cyanophenyl)(hydroxy)methyl]benzoate (4)
A dry and argon flushed 50 mL round-bottom flask, equipped with
a magnetic stirring bar, was charged with methyl 4-iodobenzoate (2:
788 mg, 3 mmol) in anhyd THF (6 mL) and cooled to –20 °C. i-
PrMgBr (6.2 mL, 0.54 M in THF, 3.3 mmol) prepared as described
above, was slowly added. After 1 h, the exchange was complete (as
indicated by GC analysis of reaction aliquots) and 4-cyanobenzal-
dehyde (3: 584 mg, 4.5 mmol) was added as a solution in THF (4
mL). The reaction mixture was allowed to warm to room tempera-
ture over 30 min. The reaction mixture was quenched with MeOH
(3 mL), poured into water (150 mL) and extracted with EtOAc
(3 100 mL). The combined organic fractions were washed with
brine (100 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (pentane–
EtOAc, 70:30, 50 g Merck Silica 60, 0.040–0.063 mm) yielding the
alcohol 5 as a white solid. Yield (668 mg, 83%); mp: 153 °C.
21
a magnetic stirring bar, was charged with Pd(dba)2 (87 mg, 0.15
mmol) and tfp21 (69 mg, 0.30 mmol) in anhyd THF (3 mL). After
formation of the active catalyst (indicated by a slight colour change
of the solution from red to yellow) 4-iodobenzonitrile (11; 481 mg,
2.1 mmol) was added followed by the zinc reagent, via syringe. The
reaction mixture was stirred at r.t. for 16 h, quenched with NH4Cl (5
mL), poured into water (50 mL) and extracted with Et2O (3 100
mL). The combined organic fractions were washed with brine (70
mL), dried over Na2SO4 and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (pentane–EtOAc–TEA,
20:1:1, 70 g Merck Silica 60, 0.040–0.060 mm) to yield the imine
12 as a pale yellow powder (581 mg, 74%); mp: 102 °C.
IR (KBr): 3514 (s), 2955 (w), 2227 (s), 1712 (s), 1604 (m), 1434
(m), 1294 (s), 1190 (m) cm–1.
IR (KBr): 3433 (m), 2229 (w), 1710 (s), 1627 (m), 1595 (s), 1578
(m), 1242 (s) cm–1.
1H NMR (CDCl3, 300 MHz): = 8.35 (s, 1 H), 8.00 (m, 2 H), 7.67
(m, 2 H), 7.54 (m, 4 H), 7.38 (m, 3 H), 7.03 (d, J = 9.0 Hz, 1 H),
4.31 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): = 166.4, 162.2, 153.8, 143.9, 136.1,
133.8, 132.5, 132.0, 131.8, 131.4, 131.2, 129.5, 129.3, 128.6, 119.6,
119.4, 111.3, 61.6, 14.8.
1H NMR (300 MHz, CDCl3): = 7.73 (d, J = 8.4 Hz, 2 H), 7.39 (d,
J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2
H), 5.63 (s, 1 H), 5.08 (bs, 1 H), 3.67 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 166.0, 149.1, 148.4, 131.5, 129.1,
128.6, 126.7, 126.0, 118.2, 110.2, 73.8, 51.4.
MS (EI, 70 eV): m/z (%) = 267 (9), 252 (4), 236 (19), 208 (28), 190
(20), 163 (42), 137 (100), 130 (52), 104 (31), 77 (25).
Anal. Calcd for C16H13O3N: C, 71.90; H, 4.90; N, 5.24. Found: C,
71.81; H, 4.74; N, 5.12.
MS (EI, 70 eV): m/z (%) = 354 (41), 277 (100), 249 (46), 177 (12).
HRMS calcd for C23H18O2N2: 354.1368. Found: 354.1357.
Ethyl 4-(N,N-Diallylamino)-3-[2-(ethoxycarbonyl)-2-prope-
nyl]-benzoate (8)
References
A dry, argon flushed 25 mL round-bottom flask, equipped with a
magnetic stirring bar, was charged with amine 5 (1.11 g, 3 mmol) in
anhyd THF (3 mL) and cooled to –20 °C. i-PrMgBr (3 mL, 1.3 M
in THF, 3.9 mmol) was slowly added. After 1 h, the exchange was
complete (as indicated by TLC analysis). CuCN 2LiCl (3.0 mL,
1 M in THF, 3 mmol) was slowly added. After 30 min, ethyl 2-(bro-
momethyl)acrylate17 (7; 1.15 g, 6 mmol) was added and the reaction
mixture allowed to warm to r.t. overnight. The reaction mixture was
quenched with NH4Cl–NH3, 9:1 (3 mL), poured into water (50 mL)
and extracted with Et2O (3 70 mL). The combined organic frac-
tions were washed with brine (100 mL), then dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (pentane–EtOAc, 95:5, 70 g Merck Silica 60,
(1) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem. Int. Ed. 2000, 39, 4415.
(2) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. A.
Organic Reactions, Vol. 58; Overman, L. E., Ed.; Wiley &
Sons Ltd.: New York, 2001, 417.
(3) (a) Villiéras, J. Bull. Soc. Chim. Fr. 1967, 1520.
(b) Paradies, H. H.; Goerbing, M. Angew. Chem. Int. Ed.
1969, 8, 279. (c) Furukawa, N.; Shibutani, T.; Fujihara, H.
Tetrahedron Lett. 1987, 28, 5845. (d) Nishiyama, H.; Isaka,
K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto, K.;
Yoshiwara, H. J. Org. Chem. 1992, 57, 407. (e) Bolm, C.;
Pupowicz, D. Tetrahedron Lett. 1997, 38, 7349.
Synthesis 2002, No. 4, 565–569 ISSN 0039-7881 © Thieme Stuttgart · New York