Synthesis of epoxyisoindolo[2,1ꢀa]quinolines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1075
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyꢀ
was refluxed for 3 h. The white crystals that precipitated were
filtered off. Isoindoloquinolinecarboxylic acids transꢀ10A,
cisꢀ13B, and cisꢀ14B were obtained.
Compound 10A. MS, m/z (Irel (%)): 353 [M]+ (32), 294
(30), 254 (100), 196 (76), 99 (75), 77 (45). 1H NMR (DMSOꢀd6),
δ: 7.91 (br.d, 1 H, H(8), J7,8 = 8.0 Hz); 7.46 (dd, 1 H, H(5),
J5,7 = 1.0 Hz, J5,6 = 7.7 Hz); 7.28 (ddd, 1 H, H(7), J7,8 = 8.0 Hz,
furo[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone
(11bB),
(3aS*,9aS*,11R*,13aR*,13bS*,13cS*)ꢀ5ꢀmethoxyꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyꢀ
furo[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone
(11cA),
(3aS*,9aR*,11S*,13aS*,13bS*,13cS*)ꢀ5ꢀmethoxyꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyꢀ
furo[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone
(11cB),
J6,7 = 7.7 Hz, J5,7 = 1.0 Hz); 7.18 (dt, 1 H, H(6), J6,7 = J5,6 =
( 3 a S* , 9 aS* , 1 1R * , 1 3 aR *, 1 3 b S* , 1 3 cS* ) ꢀ 5 ꢀ c h l o r o ꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyꢀ
7.7 Hz, J6,8 = 1.0 Hz); 6.88 (d, 1 H, H(14), J13,14 = 5.7 Hz); 6.54
(dd, 1 H, H(13), J13,14 = 5.7 Hz, J12,13 = 1.7 Hz); 5.19 (br.d,
furo[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone
( 3 aS* , 9 aR * , 1 1 S* , 1 3 a S* , 1 3 b S* , 1 3 cS* ) ꢀ 5 ꢀ c h l o r o ꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyꢀ
(11dA),
1 H, H(4a), J4a,14c = 6.0 Hz); 5.05 (d, 1 H, H(12), J12,13
1.7 Hz); 4.35 (d, 1 H, H(14b), J14b,14c = 1.8 Hz); 3.56 (m, 1 H,
H(3A)); 3.09 (m, 1 H, H(3B)); 2.94 (d, 1 H, H(11), J10a,11
9.1 Hz); 2.61 (d, 1 H, H(10a), J10a,11 = 9.1 Hz); 2.57 (m, 1 H,
=
=
furo[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone
(11dB),
( 3 a S* , 9 a S * , 1 1 R * , 1 3 aR * , 1 3 bS* , 1 3 cS* ) ꢀ 5 ꢀ f l u o r o ꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyfuroꢀ
[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone (11eA), and
( 3 a S * , 9 aR * , 1 1 S *, 1 3 a S * , 1 3 bS * , 1 3 c S * ) ꢀ 5 ꢀ f l u o r o ꢀ
1,2,9,9a,10,11,13b,13cꢀoctahydroꢀ3aHꢀ11,13aꢀepoxyfuroꢀ
[3,2ꢀc]isoindolo[2,1ꢀa]quinolinꢀ9(9aH )ꢀone (11eB) (general proꢀ
cedure). A solution of tetrahydroquinoline 3a—e (4.15 mmol,
1.1 mL), acryloyl chloride (12 mmol), and triethylamine (2.4 mL,
16.7 mmol) in benzene (50 mL) was refluxed for 2—4 h (TLC
monitoring), cooled, and poured into water (50 mL). The orꢀ
ganic layer was separated, and the aqueous layer was extracted
with ethyl acetate (3×40 mL). The organic fractions were comꢀ
bined and dried with magnesium sulfate. After evaporation of
the solvent, mixtures of isomers A and B of furoisoindoloꢀ
quinolines 11a—e were obtained as white crystals. The ratios of
isomers and spectroscopic characteristics are given in Tables 1,
12, and 13.
H(14c)); 1.70 (m, 2 H, H(2)); 1.47 (m, 1 H, H(1A), J1A,1B
13.6 Hz); 1.11 (m, 1 H, H(1B), J1A,1B = 13.6 Hz).
=
Compound 13B. MS, m/z (Irel (%)): 341 [M]+ (5), 242 (25),
167 (20), 130 (52), 93 (100), 77 (60), 65 (45). 1H NMR
(DMSOꢀd6), δ: 8.57 (dd, 1 H, H(1), J1,2 = 8.4 Hz, J1,3 = 1.1 Hz);
7.48 (dd, 1 H, H(4), J3,4 = 7.6 Hz, J2,4 = 1.1 Hz); 7.21 (ddd,
1 H, H(2), J1,2 = 8.4 Hz, J2,3 = 7.6 Hz, J2,4 = 1.1 Hz); 7.07 (dt,
1 H, H(3), J1,3 = 1.1 Hz, J2,3 = J3,4 = 7.6 Hz); 6.58 (d, 1 H,
H(7), J7,8 = 5.7 Hz); 6.51 (dd, 1 H, H(8), J8,9 = 1.7 Hz, J7,8
5.7 Hz); 5.04 (d, 1 H, H(9), J8,9 = 1.7 Hz); 4.75 (dd, 1 H, H(5),
J5,6 = 11.4 Hz, J5,6 = 5.7 Hz); 4.72 (dd, 1 H, H(6a), J6a,6
=
=
ax
ax
eq
12.4 Hz, J6a,6 = 2.4 Hz); 3.71 (dq, 1 H, OCHAHBCH3, J =
eq
7.0 Hz, J = 9.4 Hz); 3.58 (dq, 1 H, OCHAHBCH3, J = 7.0 Hz,
J = 9.4 Hz); 3.11 (d, 1 H, H(10), J10,10a = 9.2 Hz); 2.57 (d, 1 H,
H(10a), J10,10a = 9.2 Hz); 2.44 (ddd, 1 H, Heq(6), J6
=
,6
eq ax
12.4 Hz, J5,6 = 5.7 Hz, J6a,6eq = 2.4 Hz); 1.69 (dt, 1 H, Hax(6),
eq
J6
= J6a,6 = 12.4 Hz, J5,6 = 11.4 Hz); 1.21 (t, 3 H,
,6
eq ax
ax ax
(4aS*,10aS*,11R*,12S*,14aR*,14bS*,14cS*)ꢀ10ꢀOxoꢀ
2,3,10,10a,11,12,14b,14cꢀoctahydroꢀ1H,4aHꢀ12,14aꢀepoxyꢀ
isoindolo[2,1ꢀa]pyrano[3,2ꢀc]quinolineꢀ11ꢀcarboxylic acid (10A),
(4aS*,10aR*,11S*,12R*,14aS*,14bS*,14cS*)ꢀ10ꢀoxoꢀ
2,3,10,10a,11,12,14b,14cꢀoctahydroꢀ1H,4aHꢀ12,14aꢀepoxyꢀ
isoindolo[2,1ꢀa]pyrano[3,2ꢀc]quinolineꢀ11ꢀcarboxylic acid
OCH2CH3, J = 7.0 Hz).
Compound 14B. MS, m/z (Irel (%)): 380 [M]+ (3), 281 (10),
206 (32), 196 (100), 167 (20), 130 (25), 91 (30), 44 (35). 1H NMR
(DMSOꢀd6), δ: 8.63 (dd, 1 H, H(1), J1,2 = 8.5 Hz, J1,3 = 1.1 Hz);
7.24 (ddd, 1 H, H(2), J1,2 = 8.5 Hz, J2,3 = 7.5 Hz, J2,4 = 0.7 Hz);
7.07 (dt, 1 H, H(3), J1,3 = 1.1 Hz, J3,4 = J2,3 = 7.5 Hz); 6.96
(10B),
oxoꢀ 6, 6a, 9, 10, 10a, 11ꢀhexahydroꢀ5Hꢀ 6 b , 9 ꢀ e p o x y ꢀ
isoindolo[2,1ꢀa]quinolineꢀ10ꢀcarboxylic acid (13A),
(5S*,6aS*,6bR*,9S*,10R*,10aS*)ꢀ5ꢀethoxyꢀ11ꢀ
(br.d, 1 H, H(4), J3,4 = 7.5 Hz); 6.60 (d, 1 H, H(7), J7,8 =
5.7 Hz); 6.51 (dd, 1 H, H(8), J8,9 = 1.7 Hz, J7,8 = 5.7 Hz); 5.48
(br.s, 1 H, H(6a)); 5.04 (d, 1 H, H(9), J8,9 = 1.7 Hz); 4.87 (dd,
(5S*,6aS*,6bS*,9R*,10S*,10aR*)ꢀ5ꢀethoxyꢀ11ꢀoxoꢀ
6 , 6 a , 9 , 1 0 , 1 0 a , 1 1 ꢀ h e x a h y d r o ꢀ 5 H ꢀ 6 b , 9 ꢀ e p o x y ꢀ
1 H, H(5), J5,6 = 11.5 Hz, J5,6eq = 3.1 Hz); 3.19—3.28 (m, 2 H,
ax
H(5´A), Hax(6)); 3.13 (d, 1 H, H(10), J10,10a = 9.1 Hz); 2.94 (m,
1 H, H(5´B)); 2.58 (d, 1 H, H(10a), J10,10a = 9.1 Hz); 2.36 (m,
2 H, H(3´)); 1.95 (m, 2 H, H(4´), Heq(6)).
( 4 a S * , 1 0 a S * , 1 2 R * , 1 4 a R * , 1 4 b S * , 1 4 c S * ) ꢀ
2 , 3 , 1 1 , 1 2 , 1 4 b , 1 4 c ꢀ H e x a h y d r o ꢀ 1 H , 4 a H ꢀ 1 2 , 1 4 a ꢀ
epoxyisoindolo[2,1ꢀa]pyrano[3,2ꢀc]quinolinꢀ10(10aH )ꢀ
isoindolo[2,1ꢀa]quinolineꢀ10ꢀcarboxylic
acid
(13B),
(5S*,6aS*,6bR*,9S*,10R*,10aS*)ꢀ11ꢀoxoꢀ5ꢀ(2ꢀoxopyrrolidinꢀ
1ꢀyl)ꢀ6,6a,9,10,10a,11ꢀhexahydroꢀ5Hꢀ6b,9ꢀepoxyisoꢀ
indolo[2,1ꢀa]quinolineꢀ10ꢀcarboxylic acid (14A), and
(5S*,6aS*,6bS*,9R*,10S*,10aR*)ꢀ11ꢀoxoꢀ5ꢀ(2ꢀoxopyrrolidinꢀ
1ꢀyl)ꢀ6,6a,9,10,10a,11ꢀhexahydroꢀ5Hꢀ6b,9ꢀepoxyisoindoꢀ
lo[2,1ꢀa]quinolineꢀ10ꢀcarboxylic acid (14B) (general proceꢀ
dure A). A solution of maleic anhydride (0.43 g, 4.36 mmol) in
toluene (10 mL) was added to a solution of furylꢀsubstituted
amine 4a, 5, or 6a (4.15 mmol) in toluene (10 mL) at 0—3 °C.
The reaction mixture was kept at 0—3 °C for 3 days (TLC
monitoring). The crystals that formed were filtered off and
washed with diethyl ether. Mixtures of isomers A and B of the
corresponding isoindoloquinolinecarboxylic acids 10, 13, and 14
were obtained as white crystals. The ratios of isomers and the
yields are given in Table 1.
one
(12A),
(4aS*,10aR*,12S*,14aS*,14bS*,14cS*)ꢀ
2,3,11,12,14b,14cꢀhexahydroꢀ1H,4aHꢀ12,14aꢀepoxyꢀ
isoindolo[2,1ꢀa]pyrano[3,2ꢀc]quinolinꢀ10(10aH )ꢀone (12B),
(5S*,6aS*,6bS*,9S*,10aR*)ꢀ5ꢀethoxyꢀ6,6a,10,10aꢀtetrahydroꢀ
5Hꢀ6b,9ꢀepoxyisoindolo[2,1ꢀa]quinolinꢀ11(9H )ꢀone (15B), and
(5S*,6aS*,6bS*,9S*,10aR*)ꢀ5ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)ꢀ
6,6a,10,10aꢀtetrahydroꢀ5Hꢀ6b,9ꢀepoxyisoindolo[2,1ꢀa]quinolinꢀ
11(9H )ꢀone (16B) (general procedure). A solution of amine 4a,
5, or 6a (4.15 mmol, 1.1 mL), acryloyl chloride (12 mmol), and
triethylamine (2.3 mL, 16.7 mmol) in benzene (50 mL) was
refluxed for 2 h. Then the reaction mixture was poured into
water (50 mL), the organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (3×40 mL). The organic
fractions were combined and dried with magnesium sulfate. After
General procedure B. A solution of tetrahydroquinoline 4a,
5, or 6a (4.15 mmol) and maleic anhydride (0.43 g, 4.36 mmol)
in toluene (20 mL) (for 5 and 6a) or oꢀxylene (20 mL) (for 4a)