The Journal of Organic Chemistry
Article
CDCl3) δ 175.8, 171.9, 135.9, 129.5, 128.7, 127.8, 127.7, 127.5, 51.0,
45.3, 44.0, 41.3, 34.8, 27.0, 25.6. HRMS: m/z calcd for C17H20NO3,
286.1443; found, 286.1466.
5.80−5.65 (d, J = 10.0 Hz, 1H), 3.57−3.41 (td, J = 7.8, 4.8 Hz, 1H),
3.34−3.24 (m, 1H), 3.24−3.15 (dd, J = 13.0, 5.6 Hz, 1H), 3.09−2.98
(ddd, J = 12.2, 5.0, 2.3 Hz, 1H), 2.98−2.87 (br s, 1H), 2.60−2.34 (m,
2H), 2.31−2.22 (s, 3H), 2.21−2.10 (m, 4H), 2.10−1.97 (m, 4H). 13C
NMR (101 MHz, CDCl3) δ 175.1, 172.3, 138.3, 136.5, 134.1, 133.6,
130.0, 129.7, 129.6, 127.9, 46.3, 46.1, 41.1, 35.0, 27.5, 26.2, 21.0, 17.3,
17.1. HRMS: m/z calcd for C19H24NO3, 314.1756; found, 314.1771.
2-(2-Fluorobenzyl)-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquino-
line-8-carboxylic Acid (2i). White solid; yield 577 mg (76%); Mp
170−172 °C; Rf = 0.53 (“wet” ether). IR (film): 2929, 1704 cm−1. 1H
NMR (400 MHz, CDCl3) δ 7.27−7.14 (m, 2H), 7.12−7.06 (td, J =
7.5, 1.2 Hz, 1H), 7.06−6.99 (m, 1H), 5.95−5.79 (m, 1H), 5.59−5.46
(d, J = 10.1 Hz, 1H), 4.84−4.69 (d, J = 14.9 Hz, 1H), 4.62−4.44 (d, J
= 14.9 Hz, 1H), 3.27−3.22 (m, 1H), 3.22−3.12 (m, 2H), 2.95−2.76
(m, 2H), 2.49−2.26 (m, 2H), 2.08−1.92 (m, 1H), 1.92−1.79 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 176.2, 171.8, 161.0 (d, J = 244.9 Hz),
1-Oxo-2-phenyl-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-car-
boxylic Acid (2b).6 White solid; yield 474 mg (70%); Mp 199−204
1
°C; Rf = 0.45 (“wet” ether). IR (film): 3004, 1702 cm−1. H NMR
(400 MHz, CDCl3) δ 7.50−7.36 (m, 2H), 7.36−7.28 (tt, J = 7.4, 1.4
Hz, 1H), 7.20−7.05 (m, 2H), 6.06−5.92 (m, 1H), 5.75−5.56 (d, J =
10.0 Hz, 1H), 3.70−3.55 (td, J = 12.6, 4.5 Hz, 1H), 3.55−3.43 (m,
1H), 3.39−3.26 (dd, J = 5.3, 2.4 Hz, 1H), 3.00−2.86 (m, 2H), 2.55−
2.37 (m, 2H), 2.25−2.11 (m, 1H), 2.06−1.93 (dtd, J = 13.8, 4.2, 1.9
Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 175.5, 172.4, 142.1, 129.7,
129.5, 127.8, 127.3, 126.1, 48.4, 45.1, 41.7, 34.8, 27.3, 25.4. HRMS: m/
z calcd for C16H18NO3, 272.1287; found, 272.1297.
2-(Cyclohexylmethyl)-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoqui-
noline-8-carboxylic Acid (2c). White solid; yield 572 mg (79%); Mp
1
82−84 °C; Rf = 0.44 (“wet” ether). IR (film): 2923, 1705 cm−1. H
130.1 (d, J = 3.9 Hz), 129.5, 129.4 (d, J = 8.1 Hz), 127.4, 124.4 (d, J =
3.5 Hz), 123.0 (d, J = 14.8 Hz), 115.3 (d, J = 21.6 Hz), 44.7, 44.32,
44.28, 41.5, 34.7, 27.0, 25.2. HRMS: m/z calcd for C17H19FNO3,
304.1349; found, 304.1367.
NMR (400 MHz, CDCl3) δ 6.00−5.80 (m, 1H), 5.66−5.45 (dd, J =
10.0, 1.6 Hz, 1H), 3.50−3.36 (dd, J = 13.3, 8.6 Hz, 1H), 3.36−3.20
(td, J = 12.6, 4.8 Hz, 1H), 3.20−3.08 (m, 2H), 3.08−2.97 (dd, J =
13.3, 6.7 Hz, 1H), 2.97−2.86 (ddd, J = 12.3, 4.8, 2.3 Hz, 1H), 2.86−
2.73 (br s, 1H), 2.49−2.37 (m, 1H), 2.37−2.19 (m, 1H), 2.06−1.83
(m, 2H), 1.80−1.48 (m, 6H), 1.24−1.08 (m, 3H), 1.00−0.84 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 175.5, 172.1, 129.7, 127.5, 54.3, 46.1,
2-Allyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carbox-
ylic Acid (2j). Off-white solid; yield 426 mg (91%); Mp 128−130 °C;
1
Rf = 0.32 (“wet” ether). IR (film): 3017, 1706 cm−1. H NMR (400
MHz, CDCl3) δ 5.88−5.71 (m, 1H), 5.71−5.54 (m, 1H), 5.54−5.42
(d, J = 10.2 Hz, 1H), 5.12−4.93 (m, 2H), 4.03−3.89 (dd, J = 15.3, 5.5
Hz, 1H), 3.89−3.75 (dd, J = 15.3, 6.1 Hz, 1H), 3.23−2.98 (m, 3H),
2.83−2.73 (br s, 1H), 2.72−2.65 (m, 1H), 2.33−2.14 (m, 2H), 2.04−
1.89 (m, 1H), 1.89−1.72 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
177.1, 170.7, 131.8, 129.2, 127.6, 117.2, 49.9, 44.0, 43.6, 41.7, 34.5,
27.0, 24.6. HRMS: m/z calcd for C13H18NO3, 236.1287; found,
236.1300.
45.2, 40.9, 35.5, 34.8, 30.9, 30.3, 27.1, 26.3, 25.9, 25.74, 25.67. HRMS:
m/z calcd for C17H26NO3, 292.1913; found, 292.1935.
2-Cyclohexyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-
carboxylic Acid (2d).5 White solid; yield 389 mg (56%); Mp 167−169
1
°C; Rf = 0.48 (“wet” ether). IR (film): 2927, 1704 cm−1. H NMR
(400 MHz, CDCl3) δ 5.98−5.76 (m, 1H), 5.64−5.43 (d, J = 9.9 Hz,
1H), 4.53−4.27 (m, 1H), 3.26−3.15 (dt, J = 12.4, 4.0 Hz, 1H), 3.15−
2.97 (m, 2H), 2.92−2.81 (ddd, 12.2, 5.1, 2.7 Hz, 1H), 2.81−2.69 (br s,
1H), 2.48−2.19 (m, 2H), 1.93−1.49 (m, 7H), 1.43−1.22 (m, 4H),
1.18−0.89 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 176.1, 171.1,
129.5, 127.2, 53.9, 45.6, 41.4, 38.3, 34.1, 29.5, 29.4, 27.1, 25.63, 25.55,
25.5. HRMS: m/z calcd for C16H24NO3, 278.1756; found, 278.1770.
2-Butyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carbox-
ylic Acid (2e).5 White solid; yield 593 mg (95%); Mp 122−124 °C; Rf
= 0.34 (“wet” ether). IR (film): 2929, 1709 cm−1. 1H NMR (400 MHz,
CDCl3) δ 5.85−5.66 (m, 1H), 5.54−5.39 (d, J = 10.0 Hz, 1H), 3.41−
3.31 (m, 1H), 3.22−2.96 (m, 4H), 2.77−2.56 (m, 2H), 2.31−2.04 (m,
2H), 1.99−1.67 (m, 2H), 1.46−1.25 (m, 2H), 1.25−1.05 (m, 2H),
0.85−0.66 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.7,
170.7, 129.1, 127.5, 47.5, 44.3, 44.1, 41.4, 34.5, 28.7, 26.9, 24.9, 19.8,
13.7. HRMS: m/z calcd for C14H22NO3, 252.1600; found, 252.1614.
2-(tert-Butyl)-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-
carboxylic acid (2f). Clear crystalline solid; yield 276 mg (44%); Mp
142−143 °C; Rf = 0.60 (“wet” ether). IR (film): 2923, 1704 cm−1. 1H
NMR (400 MHz, CDCl3) δ 5.96−5.76 (m, 1H), 5.61−5.42 (d, J =
10.2 Hz, 1H), 3.43−3.27 (dt, J = 12.6, 4.2 Hz, 1H), 3.21−3.05 (m,
2H), 2.91−2.78 (ddd, J = 12.0, 5.0, 2.4 Hz, 1H), 2.78−2.63 (br s, 1H),
2.48−2.21 (m, 2H), 1.90−1.79 (m, 2H), 1.44−1.33 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ 176.6, 172.8, 129.3, 127.3, 59.3, 45.8, 42.9, 40.8,
33.9, 28.1, 27.7, 25.5. HRMS: m/z calcd for C14H22NO3, 252.1600;
found, 252.1607.
2-(4-Methoxyphenyl)-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquino-
line-8-carboxylic Acid (2g). Off-white solid; yield 746 mg (98%); Mp
183−188 °C; Rf = 0.31 (“wet” ether). IR (film): 2931, 1704 cm−1. 1H
NMR (400 MHz, CDCl3) δ 7.11−6.99 (m, 2H), 6.94−6.83 (m, 2H),
6.02−5.89 (m, 1H), 5.70−5.58 (d, J = 10.0 Hz, 1H), 3.83−3.72 (s,
3H), 3.61−3.49 (td, J = 12.5, 4.36 Hz, 1H), 3.48−3.37 (dd, J = 12.4,
5.1 Hz, 1H), 3.37−3.27 (dd, J = 5.4, 2.6 Hz, 1H), 2.98−2.80 (m, 2H),
2.47−2.32 (m, 2H), 2.24−2.08 (m, 1H), 2.04−1.88 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 175.8, 172.4, 158.8, 134.9, 129.6, 127.4,
127.1, 114.7, 55.5, 48.6, 45.0, 41.7, 34.8, 27.3, 25.4. HRMS: m/z calcd
for C17H20NO4, 302.1392; found, 302.1407.
1-Oxo-3,4,4a,7,8,8a-hexahydro-1H-isochromene-8-carboxylic
Acid (2k). White solid; yield 398 mg (81%); Mp 164−166 °C; Rf =
1
0.33 (“wet” ether). IR (film): 2927, 1710 cm−1. H NMR (400 MHz,
CDCl3) δ 5.94−5.76 (m, 1H), 5.61−5.43 (d, J = 10.1 Hz, 1H), 4.38−
4.27 (m, 1H), 4.27−4.11 (m, 1H), 3.54−3.36 (dd, J = 6.8, 3.3 Hz,
1H), 3.06−2.91 (br s, 1H), 2.75−2.62 (ddd, J = 11.0, 5.9, 3.3 Hz, 1H),
2.56−2.29 (m, 2H), 2.29−2.12 (m, 1H), 1.84−1.67 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 178.0, 171.5, 128.4, 128.0, 66.3, 41.0, 40.2,
32.7, 28.5, 23.0. HRMS: m/z calcd for C10H13O4, 197.0814; found,
197.0817.
2-Benzyl-8-methyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquino-
line-8-carboxylic Acid (4). (E)-N-Benzylhexa-3,5-dien-1-amine (1a)
(5.0 mmol, 935 mg) was added to a round-bottomed flask, dissolved in
dichloroethane (1.0 mL), and cooled to 0 °C. Citraconic anhydride
(5.50 mmol, 616 mg) was then weighed and added in one portion to
the diene solution. The resulting mixture was allowed to stir at 0 °C
for 10 min, then heated to 60 °C and maintained there for 8 h. Upon
cooling, the reaction was diluted with dichloromethane (4.0 mL) and
loaded directly onto a silica gel column. Product isolation occurred by
gradient elution with 0−100% hexanes/“wet” ether. White solid; yield
798 mg (53%); Mp 167−170 °C; Rf = 0.51 (“wet” ether). IR (film):
2922, 1698 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.36−7.18 (m, 3H),
7.18−7.04 (m, 2H), 5.86−5.67 (m, 1H), 5.58−5.39 (d, J = 10.1 Hz,
1H), 4.87−4.69 (d, J = 14.8 Hz, 1H), 4.41−4.22 (d, J = 14.8 Hz, 1H),
3.15−2.95 (m, 3H), 2.86−2.71 (br s, 1H), 2.71−2.50 (d, J = 18.6 Hz,
1H), 2.14−1.80 (m, 3H), 1.32−1.16 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 182.1, 170.0, 137.0, 128.6, 128.4, 127.8, 127.2, 126.2, 50.4,
47.3, 43.9, 42.3, 30.6, 30.1, 27.0, 23.1. HRMS: m/z calcd for
C18H22NO3, 300.1600; found, 300.1607.
2-Benzyl-1-oxo-8a-phenyl-1,2,3,4,4a,7,8,8a-octahydroisoquino-
line-8-carboxylic Acid (5). (E)-N-Benzylhexa-3,5-dien-1-amine (1a)
(2.50 mmol, 468 mg) was added to a round-bottomed flask, dissolved
in dichloroethane (0.5 mL), and cooled to 0 °C. The phenyl maleic
anhydride (2.75 mmol, 479 mg) was then weighed and added in one
portion to the diene solution. The resulting mixture was allowed to stir
at 0 °C for 10 min, then heated to 60 °C and maintained there for 8 h.
Upon cooling, the reaction was diluted with dichloromethane (2.0
mL) and loaded directly onto a silica gel column. Product isolation
occurred by gradient elution with 0−100% hexanes/“wet” ether. White
2-Mesityl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-car-
boxylic Acid (2h). White solid; yield 565 mg (72%); Mp 228−230 °C;
1
Rf = 0.37 (“wet” ether). IR (film): 2923, 1707 cm−1. H NMR (400
MHz, CDCl3) δ 7.00−6.83 (d, J = 12.4 Hz, 2H), 6.08−5.94 (m, 1H),
I
J. Org. Chem. XXXX, XXX, XXX−XXX