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L. A. Bonner et al. / Bioorg. Med. Chem. 18 (2010) 6763–6770
(1.28 g, 5.36 mmol) was added and the mixture was stirred until all
solids dissolved. KBH4 (1.45 g, 0.0268 mol) was then added care-
fully in three portions over 10 min. The black solution was re-
moved from the ice bath and stirred at ambient temperature for
1 h. The reaction was then quenched by the addition of 10 mL of
concd HCl, and the bright blue solution was evaporated to near
dryness. The residue was re-dissolved in H2O (50 mL) and washed
once with Et2O (10 mL). The aqueous layer was basified with
NH4OH and extracted with CH2Cl2 (3 Â 20 mL). The organic layers
were combined, dried over Na2SO4, filtered, and evaporated to
yield the desired product (0.813 g, 2.45 mmol, 91%) as a white so-
lid; mp 208 °C (decomp.). 1H NMR: (300 MHz, CDCl3): d 6.82 (d, 1H,
J = 8.4 Hz, ArH); 6.76 (d, 1H, J = 8.4 Hz, ArH); 3.84 (s, 3H, ArOCH3);
3.79 (s, 3H, ArOCH3); 3.59 (dd, 1H, J = 6.0, 15.6 Hz, CH2NH2); 3.50
(s, 2H, OCH2C(CH3)2); 3.22 (dd, 1H, J = 10.8, 15.6 Hz, CH2NH2);
3.04–2.95 (m, 1H, ArCH2); 2.88–2.79 (m, 1H, ArCH); 2.72–2.55
(m, 2H, CH2C(N)O); 2.22–2.13 (m, 1H, ArCH2CH2CH); 2.11–2.01
(m, 1H, ArCH2); 1.77–1.65 (m, 2H, ArCH2CH2); 1.28 (s, 3H,
C(CH3)2); 1.26 (s, 3H, C(CH3)2). EIMS: (M+) = 332. Anal. Calcd for
tal 78%) of product; mp 185–187 °C. 1H NMR: (300 MHz, CDCl3): d
6.83 (d, 1H, J = 8.4 Hz, ArH); 6.75 (d, 1H, J = 8.4 Hz, ArH); 5.91 (br s,
1H, NH); 3.84 (s, 3H, ArOCH3); 3.80 (s, 3H, ArOCH3); 3.42–3.37 (m,
2H, CH2NH); 3.19–2.99 (m, 2H, ArCH, ArCH2); 2.80–2.63 (m, 2H,
ArCH2, C(O)CH2); 2.33 (d, 1H, J = 17.1 Hz, C(O)CH2); 2.32–2.21
(m, 1H, ArCH2CH2CH); 1.90–1.59 (m, 2H, ArCH2CH2). ESIMS:
(M+H+) = 262. HR ESIMS: calcd mass = 262.1443, actual
mass = 262.1445.
5.1.1.13. trans-7,8-Dimethoxy-1,2,4,4a,5,6-hexahydrobenzo[h]
isoquinolin-3(10bH)-one, 15b. In an identical fashion, 1.24 g
(3.73 mmol) of the trans amine 13b was converted into 0.656 g
(2.51 mmol, 67%) of the trans lactam as a white solid; mp 240 °C
(decomp.). 1H NMR: (300 MHz, CDCl3): d 6.86 (d, 1H, J = 8.4 Hz,
ArH); 6.78 (d, 1H, J = 8.4 Hz, ArH); 6.09 (br s, 1H, NH); 3.94 (dt,
1H, J = 4.1, 11.4 Hz, CH2NH); 3.85 (s, 3H, ArOCH3); 3.81 (s, 3H, Ar-
OCH3); 3.18 (t, 1H, J = 11.4, CH2NH); 3.09 (dd, 1H, J = 3.9, 17.7 Hz,
ArCH2); 2.78 (dt, 1H, J = 5.4, 11.4, ArCH); 2.71–2.59 (m, 1H, ArCH2);
2.60 (dd, 1H, J = 4.8, 17.4, COCH2); 2.19 (dd, 1H, J = 12.3, 17.4,
C(O)CH2); 2.03–1.93 (m, 1H, ArCH2CH2); 1.90–1.74 (m, 1H,
ArCH2CH2CH); 1.42 (dq, 1H, J = 5.4, 12.4 Hz, ArCH2CH2). ESIMS:
(M+H+) = 262. Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N,
5.36. Found: C, 68.60; H, 7.01; N, 5.38.
C19H28N2O3 (0.5 equiv MeOH): C, 67.21; H, 8.68; N, 8.04. Found:
C, 66.86; H, 8.35; N, 8.07.
5.1.1.10. trans -(2-((4,4-Dimethyl-2-oxazolin-2-yl)methyl)-5,6-
dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine,
13b. A procedure identical to that above was used to convert
0.500 g of trans nitrile 11b (1.52 mmol) into the desired amine
(0.480 g, 1.45 mmol, 94%), recovered as a white solid; mp 181 °C
(decomp.). 1H NMR: (300 MHz, CDCl3): d 6.93 (d, 1H, J = 8.4 Hz,
ArH); 6.78 (d, 1H, J = 8.4 Hz, ArH); 4.18 (dd, 1H, J = 5.1, 15.3 Hz,
CH2NH2); 3.84 (s, 3H, ArOCH3); 3.80 (s, 3H, ArOCH3); 3.53 (d, 1H,
J = 17.4 Hz, OCH2C(CH3)2); 3.49 (d, 1H, J = 17.4 Hz, OCH2C(CH3)2);
3.17 (dd, 1H, J = 11.1, 15.3 Hz, CH2NH2); 3.03 (dd, 1H, J = 3.9,
17.4 Hz, ArCH2); 2.70–2.56 (m, 1H, ArCH2); 2.49 (dt, 1H, J = 5.1,
11.1 Hz, ArCH); 2.30 (dd, 1H, J = 4.2, 15.9, CH2C(N)O); 2.04 (dd,
1H, J = 12.0, 15.9, CH2C(N)O); 1.94–1.87 (m, 1H, ArCH2CH2);
1.77–1.62 (m, 1H, ArCH2CH2CH); 1.38 (dq, 1H, J = 3.0, 12.6 Hz,
ArCH2CH2); 1.27 (s, 3H, C(CH3)2); 1.25 (s, 3H, C(CH3)2). EIMS:
(M+) = 332. Anal. Calcd for C19H28N2O3 (+0.33 equiv MeOH): C,
67.68; H, 8.62; N, 8.16. Found: C, 67.81; H, 8.43; N, 7.96.
5.1.1.14. trans-7,8-Dimethoxy-5-phenyl-1,2,4,4a,5,6-hexahydro
benzo[h]isoquinolin-3(10bH)-one, 16. Following the method for
the synthesis of 15 above, amine 14 (0.200 g, 0.490 mmol) was
converted into the desired lactam as a white solid (0.110 g,
0.326 mmol, 67%). The filtrate was extracted with EtOAc to recover
an additional 0.032 g (0.095 mmol, 19%) of the product; mp
>250 °C. 1H NMR: (300 MHz, CDCl3): d 7.38–7.19 (m, 5H, PhH);
6.93 (d, 1H, J = 8.7 Hz, ArH); 6.82 (d, 1H, J = 8.7 Hz, ArH); 5.98 (br
s, 1H, NH); 4.00 (dt, 1H, J = 4.6, 11.4 Hz, CH2NH); 3.86 (s, 3H, Ar-
OCH3); 3.78 (s, 3H, ArOCH3); 3.37–3.21 (m, 2H, CH2NHCOCH2);
3.20 (dt, 1H, J = 5.1, 10.5 Hz, ArCHCH2); 2.83 (dd, 1H, J = 12.3,
17.4 Hz, NHCOCH2); 2.66 (dt, 1H, J = 4.2, 10.5 Hz, ArCH2CH(Ph)CH);
2.23 (dd, 1H, J = 4.2, 17.1 Hz, ArCH2); 2.17–2.04 (m, 1H, ArCH2CH);
1.94 (dd, 1H, J = 12.6, 17.1 Hz, ArCH2). ESIMS: (M+H+) = 338. HR
ESIMS: calcd mass = 338.1756, actual mass = 338.1753.
5.1.1.11. trans -(2-((4,4-Dimethyl-2-oxazolin-2-yl)methyl)-5,6-
dimethoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)meth-
anamine, 14. Using the method employed for 13, nitrile 12
(0.157 g, 0.389 mmol) was converted to the title compound
(0.149 g, 0.365 mmol, 94%) as a white solid; mp 213 °C (decomp.).
1H NMR: (300 MHz, CDCl3): d 7.40–7.22 (m, 5H, PhH); 7.01 (d, 1H,
J = 8.7 Hz, ArH); 6.83 (d, 1H, J = 8.7 Hz, ArH); 4.25 (dd, 1H, J = 5.4,
15.0 Hz, ArCHCH2NH2); 3.86 (s, 3H, ArOCH3); 3.77 (s, 3H, ArOCH3);
3.73 (br s, 2H, NH2); 3.51–3.42 (m, 2H, OCH2C(CH3)2); 3.30–3.21
(m, 2H, ArCH2, ArCHCH2NH2); 2.85–2.46 (m, 3H, ArCHCH2NH2,
ArCH2CH); 2.01 (dq, 1H, J = 5.4, 11.1 Hz, ArCH2CH(Ph)CH); 1.89–
1.74 (m, 2H, CH2C(N)O); 1.20 (s, 3H, C(CH3)2); 1.16 (s, 3H,
C(CH3)2). ESIMS: (M+H+) = 409. Anal. Calcd for C25H32N2O3
(0.66 equiv H2O): C, 71.40; H, 7.99; N, 6.66. Found: C, 71.58; H,
7.70; N, 6.40.
5.1.1.15. cis-7,8-Dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo
[h]isoquinoline hydrochloride, 17a. A flame-dried single-neck
flask was charged with 50 mL of distilled THF, and 0.130 g
(0.498 mmol) of the cis lactam 15a were added. A 1.0 M solution
of BH3 in THF (2.49 mL, 2.49 mmol) was added dropwise to the flask
and the reaction was heated at reflux overnight. The reaction was
then cooled to room temperature, quenched carefully with H2O,
and evaporated to about one-third the volume. Following the addi-
tion of 10 mL 2 N HCl, the solution was stirred at ambient temper-
ature for 4 h. The aqueous solution was washed once with Et2O,
basified with NH4OH, and extracted with CH2Cl2 (3 Â 25 mL). The
organic layers were combined, dried over Na2SO4, filtered, and
evaporated to yield a colorless residue, which was dissolved in
Et2O and acidified with 6 N HCl in EtOH. The solid that formed
was collected by filtration to yield 0.084 g (0.297 mmol, 60%) of iso-
quinoline HCl 17a as a white powder and crystallized from MeOH;
mp 186 °C (decomp.). 1H NMR: (500 MHz, DMSO-d6): d 8.80 (br s,
2H, NH2); 6.87 (m, 2H, ArH); 3.75 (s, 3H, ArOCH3); 3.66 (s, 3H, Ar-
OCH3); 3.16 (dd, 1H, J = 4.2, 12.4 Hz, ArCHCH2NH2); 3.12–3.05 (m,
2H, CH2NH2CH2); 2.99–2.82 (m, 3H, ArCHCH2NH2CH2, ArCH2);
2.59–2.48 (m, 1H, ArCH2); 2.10–1.89 (m, 3H, ArCH2CH2CHCH2);
1.72 (br d, 1H, J = 11.8 Hz, NH2CH2CH2); 1.62–1.54 (m, 1H,
ArCH2CH2). ESIMS: (M+H+) = 248. Anal. Calcd for C15H22ClNO2: C,
63.48; H, 7.81; N, 4.94. Found: C, 63.37; H, 7.79; N, 5.00.
5.1.1.12. cis-7,8-Dimethoxy-1,2,4,4a,5,6-hexahydrobenzo[h]iso-
quinolin-3(10bH)-one, 15a. cis Amine 13a (0.530 g, 1.60 mmol)
was dissolved in 30 mL of a 10% solution of H2SO4 in absolute EtOH
and the solution was heated at 85 °C for 48 h. The reaction was
cooled to room temperature, 30 mL H2O were added and, with stir-
ring, 6 N NaOH was added until a white solid formed and the reac-
tion pH >12. The basic mixture was stirred for 15 min and the solid
was collected by filtration to afford the desired lactam as an off-
white solid (0.234 g, 0.870 mmol, 55%). The filtrate was extracted
with EtOAc to recover an additional 0.100 g (0.372 mmol, 23%, to-