1748
G. Satyanarayana, M.E. Maier / Tetrahedron 68 (2012) 1745e1749
(2.1 g, 9.2 mmol), and NaHCO3 (1.58 g, 18.3 mmol) in DMF (15 mL)
was added 4-methyliodobenzene 4a (2.0 g, 9.2 mmol) and the
resulted solution was heated at 40 ꢀC for 24 h. The reaction was
quenched with aqueous NH4Cl solution and the mixture extracted
with ethyl acetate (3ꢁ20 mL). The combined organic layers were
washed with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the solvent and purification of the crude material by
flash chromatography (ethyl acetate/hexane, 2:98 to 1:24) fur-
nished the aldehyde 6a (60 mg, 4%) as colorless oil. Further elution
(ethyl acetate/hexane, 1:24 to 1:8) as eluent gave the desired
propanal 5a (1.1 g, 80%) as brown viscous oil.
(3ꢁ12 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and filtered. Concentration of the filtrate followed
by flash chromatography (ethyl acetate/hexane, 1:6 to 2:3) fur-
nished the cyclic enamide 9aa (480 mg, 80%) as brown viscous oil.
Rf¼0.45 (ethyl acetate/hexane, 2:3); 1H NMR (400 MHz, CDCl3):
d
¼7.55 (d, J¼7.9 Hz,1H, 300-H), 7.29 (dd, J¼7.3, 7.3 Hz,1H, AreH), 7.17
(d, J¼7.3 Hz, 1H, 600-H), 7.14 (dd, J¼7.3, 7.3 Hz, 1H, AreH), 7.09 (d,
J¼7.9 Hz, 2H, AreH), 7.02 (d, J¼7.9 Hz, 2H, AreH), 5.86 (s, 1H, 6-H),
4.76 (s, 2H, NCH2Ar), 3.26 (s, 2H, CH2Ar), 2.55 (t, J¼7.9 Hz, 2H, 4-H),
2.32 (s, 3H, ArCH3), 2.22 (t, J¼7.9 Hz, 2H, 3-H); 13C NMR (100 MHz,
CDCl3):
d
¼168.9 (NC]O), 136.1 (C), 136.0 (C), 135.6 (C), 132.8 (CH),
Compound 5a: Rf¼0.45 (ethyl acetate/hexane, 1:9); 1H NMR
129.1 (2C, CH), 128.8 (CH), 128.6 (CH), 128.5 (2C, CH), 127.6 (CH),
125.3 (C-6), 123.2 (C-200), 119.9 (C-5), 49.1 (NCH2Ar), 39.6 (CH2Ar),
31.2 (C-3), 23.9 (C-4), 21.0 (CH3, ArCH3); HRMS (ESI) calcd for
C20H21BrNO [MþH]þ 370.0801, found 370.0801.
(400 MHz, CDCl3):
d
¼9.81 (s, 1H, CH]O), 7.10 (d, J¼8.4 Hz, 2H,
AreH), 7.08 (d, J¼8.4 Hz, 2H, AreH), 2.92 (t, J¼7.4 Hz, 2H, 3-H), 2.75
(t, J¼7.4 Hz, 2H, 2-H), 2.31 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
¼201.7 (CH]O), 137.2 (C), 135.8 (C), 129.3 (2C, CH), 128.1 (2C, CH),
45.4 (C-3), 27.7 (C-2), 21.0 (CH3).
4.4. 1-(2-Bromobenzyl)-5-(4-methylbenzyl)-3,4-dihydropyri-
din-2(1H)-one (9aa)
Compound 6a: Rf¼0.6 (ethyl acetate/hexane, 1:9); 1H NMR
(400 MHz, CDCl3):
d
¼9.66 (s, 1H, CH]O), 7.19 (d, J¼7.9 Hz, 2H,
AreH), 7.09 (d, J¼7.9 Hz, 2H, AreH), 3.60 (q, J¼7.1 Hz, 1H, 2-H), 2.34
To a magnetically stirred solution of the formyl ester 8a
(400 mg, 1.6 mmol) in CH2ClCH2Cl (5 mL) at room temperature,
were added sequentially 2-bromobenzylamine 3a (420 mg,
2.2 mmol) and AcOH (0.14 mL, 2.4 mmol) followed by refluxing of
the mixture for 12 h. After cooling, the reaction mixture was treated
with aqueous NaHCO3 solution and extracted with ethyl acetate
(3ꢁ12 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and filtered. Concentration of the filtrate followed
by flash chromatography (ethyl acetate/hexane, 1:6 to 2:3) fur-
nished the cyclic enamide 9aa (480 mg, 80%) as brown viscous oil.
Rf¼0.45 (ethyl acetate/hexane, 2:3); 1H NMR (400 MHz, CDCl3):
(s, 3H, ArCH3) 1.42 (3H, d, J¼7.1 Hz, CH3); 13C NMR (100 MHz,
CDCl3):
d
¼201.2 (CH]O), 137.2 (C), 134.6 (C), 129.8 (2C, CH), 128.2
(2C, CH), 52.6 (C-2), 21.0 (ArCH3), 14.6 (CH3).
4.2. Ethyl 4-formyl-5-(4-methylphenyl)pentanoate (8a)
To a magnetically stirred solution of the aldehyde 5a (1.0 g,
6.7 mmol) in benzene (7 mL) was added anhydrous K2CO3 (2.8 g,
20.3 mmol) followed by pyrrolidine (1.12 mL, 13.5 mmol). The re-
action mixture was stirred for 6 h at room temperature. Then the
mixture was treated with saturated aqueous NaHCO3 solution, and
extracted with diethyl ether (3ꢁ20 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo to
provide the crude enamine 7a. To the crude enamine in CH3CN
d
¼7.55 (d, J¼7.9 Hz,1H, 300-H), 7.29 (dd, J¼7.3, 7.3 Hz,1H, AreH), 7.17
(d, J¼7.3 Hz, 1H, 600-H), 7.14 (dd, J¼7.3, 7.3 Hz, 1H, AreH), 7.09 (d,
J¼7.9 Hz, 2H, AreH), 7.02 (d, J¼7.9 Hz, 2H, AreH), 5.86 (s, 1H, 6-H),
4.76 (s, 2H, NCH2Ar), 3.26 (s, 2H, CH2Ar), 2.55 (t, J¼7.9 Hz, 2H, 4-H),
2.32 (s, 3H, ArCH3), 2.22 (t, J¼7.9 Hz, 2H, 3-H); 13C NMR (100 MHz,
ꢀ
ꢀ
(7 mL) at 5 C were added molecular sieves (4 A, 2 g) followed by
ethyl acrylate (1.17 mL, 10.8 mmol). The resulting mixture was
stirred for 2 h at room temperature, and then refluxed for 2 h. After
cooling of the mixture to room temperature, AcOH (2 mL) in H2O
(8 mL) was added followed by refluxing of the mixture for 2 h. After
cooling to ambient temperature, the mixture was treated with 3 N
HCl, and extracted with ethyl acetate (3ꢁ20 mL). The combined
organic extracts were washed with saturated NaCl solution, dried
(Na2SO4), and filtered. Concentration of the filtrate and purification
of the residue by flash chromatography (ethyl acetate/hexane, 2:98
to 1:7) furnished the aldehyde ester 8a (1.1 g, 66% for two steps) as
a colorless oil. Rf¼0.45 (ethyl acetate/hexane, 1:7); 1H NMR
CDCl3):
d¼168.9 (NC]O), 136.1 (C), 136.0 (C), 135.6 (C), 132.8 (CH),
129.1 (2C, CH), 128.8 (CH), 128.6 (CH), 128.5 (2C, CH), 127.6 (CH),
125.3 (C-6), 123.2 (C-200), 119.9 (C-5), 49.1 (NCH2Ar), 39.6 (CH2Ar),
31.2 (C-3), 23.9 (C-4), 21.0 (CH3, ArCH3); HRMS (ESI) calcd for
C20H21BrNO [MþH]þ 370.0801, found 370.0801.
4.5. 1-(4-Methylbenzyl)-2,6-dihydropyrido[2,1-a]isoindol-
4(3H)-one (10aa)
To a solution of bromoenamide 9aa (100 mg, 0.3 mmol) in an-
hydrous DMF (2 mL), in an oven dried Schlenk tube fitted with
a rubber septum, were added PPh3 (14.2 mg, 20 mol %), Cs2CO3
(352 mg, 1.1 mmol), and Pd(OAc)2 (6.1 mg, 10 mol %) at room tem-
perature under nitrogen atmosphere. The stirred reaction mixture
was heated in an oil bath at 120 ꢀC for 3 days. The mixture was
cooled to room temperature, treated with saturated aqueous NH4Cl
solution, and then extracted with ethyl acetate (3ꢁ10 mL). The
combined organic layers were washed with saturated NaCl solu-
tion, dried (Na2SO4), and filtered. Evaporation of the filtrate and
purification of the crude material by flash chromatography (ethyl
acetate/hexane, 1:4 to 3:2) furnished the tricyclic isoindole 10aa
(64 mg, 82%) as a colorless solid, which was recrystallized from
a mixture of CH2Cl2 and hexane; mp 120e122 ꢀC. Rf¼0.45 (ethyl
(400 MHz, CDCl3):
d
¼9.66 (s, 1H, CH]O), 7.09 (d, J¼8.1 Hz, 2H,
AreH), 7.04 (d, J¼8.1 Hz, 2H, AreH), 4.10 (q, J¼7.1 Hz, 2H, OCH2CH3),
2.96 (dd, J¼13.2, 6.4 Hz, 1H, 5-H), 2.69 (dd, J¼13. 2, 6.4 Hz, 5-H)
2.80e2.55 (m, 1H, 4-H), 2.45e2.20 (m, 2H, 2-H), 2.30 (3H, s, ArCH3),
2.05e1.86 (m, 1H, 3-H), 1.86e1.70 (m, 1H, 3-H), 1.22 (t, J¼7.1 Hz, 3H,
OCH2CH3); 13C NMR (100 MHz, CDCl3):
d¼203.8 (CH]O), 172.8
(OC]O), 136.1 (C), 135.0 (C), 129.3 (2C, CH), 128.8 (2C, CH), 60.5
(OCH2CH3), 52.5 (C-4), 34.7 (CH2Ar), 31.5 (C-2), 23.4 (C-3), 20.9
(ArCH3), 14.1 (OCH2CH3); due to the somewhat instable nature of
the aldehydes, no HRMS data were acquired.
4.3. 1-(2-Bromobenzyl)-5-(4-methylbenzyl)-3,4-dihydropyri-
din-2(1H)-one (9aa)
acetate/hexane, 4:1); 1H NMR (400 MHz, CDCl3):
d
¼7.68 (d,
J¼7.1 Hz, 1H, AreH), 7.37 (d, J¼7.1 Hz, 1H, AreH), 7.32 (dd, J¼7.1,
7.1 Hz,1H, AreH), 7.28 (dd, J¼7.1, 7.1 Hz,1H, AreH), 7.16 (d, J¼7.9 Hz,
2H, AreH), 7.11 (d, J¼7.9 Hz, 2H, AreH), 4.89 (s, 2H, NCH2Ar), 3.85
(s, 2H, CH2Ar), 2.52 (t, J¼7.9 Hz, 2H, 3-H), 2.42 (t, J¼7.9 Hz, 2H, 2-H),
To a magnetically stirred solution of the formyl ester 8a
(400 mg, 1.6 mmol) in CH2ClCH2Cl (5 mL) at room temperature,
were added sequentially 2-bromobenzylamine 3a (420 mg,
2.2 mmol) and AcOH (0.14 mL, 2.4 mmol) followed by refluxing of
the mixture for 12 h. After cooling, the reaction mixture was treated
with aqueous NaHCO3 solution and extracted with ethyl acetate
2.32 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3):
137.6 (C), 136.0 (C), 135.4 (C), 135.3 (C), 134.1 (C), 129.3 (2C, CH),
128.3 (CH), 128.1 (2C, CH), 127.9 (CH), 123.3 (CH), 122.8 (CH), 112.0
d
¼168.1 (NC]O),