Synthesis of 3,4-Dihydro-2-pyridones
J . Org. Chem., Vol. 65, No. 26, 2000 9111
1
7
1
5
5
7.3 Hz, 1 H), 3.58 (dd, J ) 8.7, 17.3 Hz, 1 H); 13C NMR (CDCl
3
,
Dip r op -2-en yl 2-[1-(2,6-Dich lor op h en yl)-3-(4-ca r ba m -
5 MHz) δ 195.9, 167.4, 166.9, 148.2, 146.0, 142.3, 139.3, 135.2,
31.0, 130.8, 129.5, 128.8, 126.8, 122.9, 122.5, 119.3, 66.5, 66.3,
6.6, 42.3, 40.0; LCMS LC (214 nm) 5.31 min; MS (ES+) m/z
oylp h en yl)-3-oxop r op yl]p r op a n e-1,3-d ioa te (11i). HPLC
1
(220 nm) 30.61 min; H NMR (CDCl
3
, 300 MHz) δ 7.99 (d, J )
8.4 Hz, 2 H), 7.88 (d, J ) 8.4 Hz, 2 H), 7.30-7.92 (m, 2 H),
7.07 (t, J ) 7.8 Hz, 1 H), 5.97-5.82 (m, 1 H), 5.66-5.52 (m, 1
H), 5.37-5.06 (m, 5 H), 4.74-4.60 (m, 2 H), 4.50 (d, J ) 11.4
17.1 (C24
Dip r op -2-en yl 2-[1-(4-Cya n op h en yl)-3-oxo-3-(4-su lfa -
m oylp h en yl)p r op yl]p r op a n e-1,3-d ioa te (11d ). HPLC (220
24 2 9
H N O S + H requires 517.13).
Hz, 1 H), 4.41-4.26 (m, 2 H), 3.89 (dd, J ) 9.0, 16.5 Hz, 1 H),
1
13
nm) 30.21 min; H NMR (CDCl
H), 7.56 (d, J ) 7.8 Hz, 2 H), 7.42 (d, J ) 7.8 Hz, 2 H), 5.94-
.79 (m, 1 H), 5.73-5.59 (m, 1 H), 5.35-5.12 (m, 4 H), 5.23
3
, 300 MHz) δ 8.06-7.93 (m, 4
3.65 (dd, J ) 4.8, 16.8 Hz, 1 H); C NMR (CDCl , 75 MHz) δ
3
196.8, 169.7, 167.8, 166.7, 139.3, 137.8, 136.4, 134.8, 134.7,
131.2, 131.0, 129.9, 129.0, 128.5, 127.8, 119.1, 118.8, 66.5, 66.1,
53.8, 40.4, 36.8; LCMS LC (220 nm) 1.91 min; MS (ES+) m/z
5
(
4
3
br s, 2 H), 4.65 (d, J ) 5.0 Hz, 2 H), 4.43 (d, J ) 5.0 Hz, 2 H),
.30 (ddd, J ) 3.1, 4.3, 9.3 Hz, 1 H), 3.90 (d, J ) 9.3 Hz, 1 H),
.65 (dd, J ) 4.5, 17.7 Hz, 1 H), 3.52 (dd, J ) 3.1, 17.7 Hz, 1
2 6
504.3 (C25H23Cl NO + H requires 504.10).
Dipr op-2-en yl 2-[1-(4-Br om oph en yl)-3-(4-car bam oylph e-
1
3
H); C NMR (CDCl
3
, 75 MHz) δ 195.9, 167.4, 166.9, 146.0,
n yl)-3-oxop r op yl]p r op a n e-1,3-d ioa te (11j). HPLC (220 nm)
1
1
1
4
45.6, 139.3, 132.6, 132.3, 131.0, 130.8, 129.2, 128.9, 128.7,
31.48 min; H NMR (acetone-d
6
, 300 MHz) δ 8.04-7.96 (m, 5
27.4, 126.8, 119.3, 119.2, 118.5, 111.3, 66.5, 66.3, 56.5, 42.2,
0.5; LCMS LC (214 nm) 5.14 min; MS (ES+) m/z 497.0
H), 7.42 (d, J ) 8.7 Hz, 2 H), 7.34 (d, J ) 8.7 Hz, 2 H), 5.98-
5.85 (m, 1 H), 5.74-5.60 (m, 1 H), 5.36-5.08 (m, 3 H), 4.73-
4.59 (m, 2 H), 4.40 (dt, J ) 1.2, 5.4 Hz, 2 H), 4.21-4.11 (m, 1
H), 4.06 (d, J ) 10.2 Hz, 1 H), 4.75 (dd, J ) 9.3, 17.4 Hz, 1 H),
25 24 2 7
(C H N O S + H requires 497.14).
Dip r op -2-en yl 2-[1-(2,6-Dich lor op h en yl)-3-oxo-3-(4-su l-
fam oylph en yl)pr opyl]pr opan e-1,3-dioate (11e). HPLC (220
3.65 (dd, J ) 4.2, 17.4 Hz, 1 H); 13C NMR (acetone-d
, 75 MHz)
6
1
nm) 32.58 min; H NMR (CDCl
Hz, 2 H), 7.89 (d, J ) 8.5 Hz, 2 H), 7.21 (d, J ) 8.1 Hz, 1 H),
.15 (d, J ) 8.1 Hz, 1 H), 7.01 (d, J ) 8.1 Hz, 1 H), 5.91-5.51
m, 1 H), 5.60-5.43 (m, 1 H), 5.31-4.98 (m, 5 H), 5.19 (br s, 2
3
, 300 MHz) δ 7.95 (d, J ) 8.5
δ 197.0, 167.7, 167.2, 140.5, 139.1, 132.2, 132.0, 131.4, 131.0,
128.1, 128.0, 118.0, 117.8, 66.0, 65.6, 57.2, 42.7, 40.6; LCMS
7
(
6
LC (220 nm) 3.09 min; MS (ES+) m/z 514.3 (C25H24BrNO +
H requires 514.09).
H), 4.68-4.53 (m, 2 H), 4.50 (d, J ) 11.4 Hz, 1 H), 4.34-4.18
Gen er a l P r oced u r e for th e P r ep a r a tion of Rin k -Resin -
Cou p led 4-Su lfon a m id oben zen e-2-p yr id on es (13a -r ). To
dry Rink-coupled sulfonamide malonate compounds 11a -g
(200 mg, 0.1 mmol) was added alkylamine (1.0 mmol) followed
by dry toluene (10 mL). After the mixture was shaken for 1
min, glacial acetic acid (0.8 mL) was added, resulting in a
white slurry which clears upon heating. Predried (flame heated
under vacuum) 3 Å molecular sieves (∼0.5-1 g) were then
added followed by a second addition after 24 h (∼0.25 g) of
heating at 70 °C. After the mixture was shaken for 48-60 h,
the resin was transferred to a large disposable plastic filter
rinsing first with MeOH (2 × 10 mL) to dissolve any solid
(m, 2 H), 3.80 (dd, J ) 9.6, 16.4 Hz, 1 H), 3.56 (dd, J ) 4.4,
13
1
1
1
3
6.4 Hz, 1 H); C NMR (CDCl , 75 MHz) δ 196.4, 167.8, 166.7,
45.8, 139.4, 137.7, 134.8, 134.5, 131.1, 130.9, 129.9, 129.0,
28.9, 126.7, 119.1, 118.9, 66.5, 66.1, 53.7, 40.5, 36.7; LCMS
LC (214 nm) 5.49 min; MS (ES+) m/z 540.1 (C24
H requires 540.07).
Dip r op -2-en yl 2-[1-(2-F u r yl)-3-oxo-3-(4-su lfa m oylp h e-
n yl)p r op yl]p r op a n e-1,3-d ioa te (11f). HPLC (220 nm) 30.07
2 7
H23Cl NO S
+
1
min; H NMR (CDCl
3
, 300 MHz) δ 8.05 (d, J ) 8.2 Hz, 2 H),
7
6
5
2
1
.99 (d, J ) 8.2 Hz, 2 H), 7.26 (s, 1 H), 6.26-6.19 (m, 1 H),
.13-6.08 (m, 1 H), 5.96-5.73 (m, 2 H), 5.35-5.17 (m, 4 H),
.05 (br s, 2 H), 4.64 (d, J ) 5.5 Hz, 2 H), 4.54 (d, J ) 5.5 Hz,
H), 4.30 (ddd, J ) 5.7, 8.4, 8.4 Hz, 1 H), 3.98 (d, J ) 8.4 Hz,
H), 3.69 (dd, J ) 8.4, 17.4 Hz, 1 H), 3.58 (dd, J ) 5.7, 17.4
developed in the reaction and then with CH
The resin was separated from the 3 Å molecular sieves by
addition of CH Cl allowing the floating resin to be drained
away. The recovered resin is then washed using the standard
method. Cleavage of resin (100 mg) with 10% TFA in CH Cl
2
Cl
2
(2 × 10 mL).
2
2
1
3
Hz, 1 H); C NMR (CDCl
3
, 75 MHz) δ 196.3, 167.5, 167.3,
52.8, 145.7, 141.8, 139.7, 131.2, 128.8, 126.7, 118.9, 110.3,
07.3, 66.3, 54.9, 40.1, 34.3; LCMS LC (214 nm) 5.10 min; MS
S + H requires 462.12).
Dip r op -2-en yl 2-[1-(3-Meth yl(2-th ien yl))-3-oxo-3-(4-su l-
fam oylph en yl)pr opyl]pr opan e-1,3-dioate (11g). HPLC (220
1
1
2
2
(4 mL) yielded 13a -r following filtration through a plug of
silica (eluting with EtOAc/hexane (4:6)). The crude product was
approximately 90% pure directly cleaved from the resin as
judged by HPLC, LCMS, and NMR.
(ES+) m/z 461.8 (C22H23NO
8
1
nm) 31.92 min; H NMR (CDCl
H), 7.04 (d, J ) 5.4 Hz, 1 H), 6.67 (d, J ) 5.4 Hz, 1 H), 5.97-
5
3
, 300 MHz) δ 8.13-7.92 (m, 4
Meth yl 2-Oxo-4-ph en yl-1-ben zyl-6-(4-su lfam oylph en yl)-
1,3,4-tr ih yd r op yr id in e-3-ca r boxyla te (13a ). HPLC (220
1
.81 (m, 1 H), 5.78-5.63 (m, 1 H), 5.37-5.13 (m, 4 H), 5.16
nm) 30.09 min; H NMR (CDCL
3
, 300 MHz) δ 7.89 (d, J ) 8.4
(
(
br s, 2 H), 4.73-4.39 (m, 5 H), 3.84 (d, J ) 9.3 Hz, 1 H), 3.51
Hz, 2 H), 7.32 (d, J ) 8.4 Hz, 2 H), 7.28-7.09 (m, 8 H), 6.87-
6.80 (m, 2 H), 5.47 (d, J ) 4.8 Hz, 1 H), 4.94 (br s, 2 H), 4.77
(s, 2 H), 4.24 (dd, J ) 4.8, 7.5 Hz, 1 H), 3.88 (d, J ) 7.5 Hz, 1
1
3
3
d, J ) 6.9 Hz, 2 H), 2.18 (s, 3 H); C NMR (CDCl , 75 MHz)
δ 196.3, 167.6, 167.1, 145.7, 139.7, 136.5, 135.4, 131.2, 129.9,
1
1
28.8, 126.7, 122.9, 119.1, 118.7, 66.4, 66.2, 57.8, 44.2, 34.3,
H), 3.74 (s, 3 H); 13C NMR (CDCl
141.9, 141.0, 139.6, 139.0, 136.3, 128.8, 128.5, 128.3, 127.9,
3
, 75 MHz) δ 169.0, 166.4,
3.9; LCMS LC (214 nm) 5.38 min; MS (ES+) m/z 492.1
(C
23
H
25NO
7
S
2
+ H requires 492.12).
127.5, 127.4, 126.6, 114.9, 55.6, 52.8, 46.6, 40.6; HRMS (FAB+)
Gen er a l P r oced u r e for th e P r ep a r a tion of Rin k -Resin -
24 2 5
m/z 477.1474 (C26H N O S + H requires 477.1484).
Cou p led 4-Ca r boxa m id e Dia llylm a lon a te Ad d u cts (11h -
j). To dry Rink bound carboxamide chalcone 10l-n (1.0 g, ∼0.5
mmol) was added diallylmalonate (0.9 mL, 5.0 mmol) followed
by THF (10 mL) and lastly DBU (0.15 mL, 1.0 mmol). After
the mixture was shaken for 8 h at 50 °C, the resin was drained
and washed using the standard method. Cleavage of resin (200
Meth yl 2-Oxo-4-ph en yl-1-pr op-2-en yl-6-(4-su lfam oylph e-
n yl)-1,3,4-tr ih yd r op yr id in e-3-ca r boxyla te (13b). HPLC
1
(220 nm) 27.55 min; H NMR (CDCl
3
, 300 MHz) δ 7.95 (d, J )
7.8 Hz, 2 H), 7.48 (d, J ) 7.8 Hz, 2 H), 7.37-7.23 (m, 4 H),
5.70-5.55 (m, 1 H), 5.48 (d, J ) 4.5 Hz, 1 H), 5.12-4.97 (m, 1
H), 4.94 (br s, 2 H), 4.86 (d, J ) 17.1 Hz, 1 H), 4.28 (dd, J )
4.5, 9.0 Hz, 1 H), 4.20 (dd, J ) 5.5, 15.6 Hz, 1 H), 4.06 (dd, J
) 5.5, 15.9 Hz, 1 H), 3.84 (d, J ) 9.0 Hz, 1 H), 3.74 (s, 3 H);
mg) with 10% TFA in CH
lyophilization.
2 2
Cl (4 mL) yielded 11h -j following
1
3
Dip r op -2-en yl 2-[3-(4-Ca r ba m oylp h en yl)-3-oxo-1-p h e-
3
C NMR (CDCl , 75 MHz) δ 169.2, 166.3, 142.2, 141.2, 139.6,
139.4, 132.2, 129.0, 128.6, 127.7, 127.5, 126.9, 126.7, 117.7,
114.7, 55.5, 52.6, 46.0, 40.8; LCMS LC (214 nm) 4.72 min; MS
n ylp r op yl]p r op a n e-1,3-d ioa te (11h ). HPLC (220 nm) 28.97
min; H NMR (DMSO-d
7
5
4
J ) 3.9, 9.9, 10.6 Hz, 1 H), 3.69 (dd, J ) 9.6, 11.1 Hz, 1 H),
3
MHz) δ 197.6, 167.5, 167.1, 140.4, 138.4, 132.0, 131.7, 128.9,
1
4
1
6
, 300 MHz) δ 8.14-7.73 (m, 4 H),
.58-7.09 (m, 5 H), 5.92-5.79 (m, 1 H), 5.61-5.45 (m, 1 H),
.32-5.16 (m, 2 H), 5.11-4.98 (m, 2 H), 4.79-4.38 (m, 2 H),
.29 (d, J ) 5.7 Hz, 2 H), 4.08 (d, J ) 10.6 Hz, 1 H), 3.97 (ddd,
(ES+) m/z 427.4; HRMS (FAB+) m/z 427.1326 (C22
22 2 5
H N O S
+ H requires 427.1327).
Met h yl 2-Oxo-4-p h en yl-1-(2-p h en ylet h yl)-6-(4-su lfa -
m oylp h en yl)-1,3,4-tr ih yd r op yr id in e-3-ca r boxyla te (13c).
.54-3.34 (dd, J ) 8.9, 17.4 Hz, 1 H); 13C NMR (CDCl
, 75
HPLC (220 nm) 31.16 min; H NMR (CDCl
1
, 300 MHz) δ 7.92
3
3
(d, J ) 8.1 Hz, 2 H), 7.39-7.12 (m, 10 H), 6.91 (s, 2 H), 5.37
(d, J ) 4.6 Hz, 1 H), 4.99 (br s, 2 H), 4.14 (dd, J ) 4.5, 7.6 Hz,
1 H), 4.04-3.89 (m, 1H), 3.81 (d, J ) 7.6 Hz, 1 H), 3.77 (s, 3
28.7, 128.2, 127.8, 127.6, 126.9, 118.2, 117.9, 65.7, 65.2, 56.9,
2.5, 40.7; LCMS LC (220 nm) 2.87 min; MS (ES+) m/z 436.4
(C
25
H
25NO
6
+ H requires 436.18).
H), 2.84-2.71 (m, 1 H), 2.70-2.57 (m, 1H); 13C NMR (CDCl
,
3