Synthesis of oxychelerythrine using lithiated toluamide-benzonitrile cycloaddition

Article abstract of DOI:10.1248/cpb.53.118

Oxychelerythrine, benzo[c]phenanthridine alkaloid, was synthesized from easily available starting toluamide 5 and benzonitrile 6 using toluamide-benzonitrile cycloaddition reaction in 6 steps.

Full text of DOI:10.1248/cpb.53.118

118
Notes
Chem. Pharm. Bull. 53(1) 118—120 (2005)
Vol. 53, No. 1
Synthesis of Oxychelerythrine Using Lithiated Toluamide-Benzonitrile
Cycloaddition
Thanh Nguyen LE and Won-Jea CHO*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University; Yong-Bong dong, Buk-
gu, Kwangju 500–757, South Korea. Received August 13, 2004; accepted October 7, 2004
Oxychelerythrine, benzo[c]phenanthridine alkaloid, was synthesized from easily available starting tolu-
amide 5 and benzonitrile 6 using toluamide-benzonitrile cycloaddition reaction in 6 steps.
Key words benzo[c]phenanthridine; oxychelerythrine; cycloaddition
Chelerythrine, a natural benzo[c]phenanthridine alkaloid, hol 9 in 86% yield, which was oxidized with PDC to
has been reported to mediate a variety of biological activities afford aldehyde 10 in 90% yield, which was then treated with
including anti-tumor,1) inhibition of protein kinase C,2,3) Ph3PCH2OMe/n-BuLi to give the olefins 11 as E/Z (1 : 1)
induction of apoptosis through generation of reactive mixture in 56% yield. Hydrolysis of 11 with 10% HCl pro-
oxygen4) and stimulation of GSH transport.5) Recently, chel- duced the desired benzo[c]phenanthridine compound oxy-
erythrine was also proved to inhibit the BclXL function6) and chelerythrine 13 in 73% yield. In this reaction we assumed
it was considered to open up new therapeutic treatments, that hydrolysis produced the aldehyde 12 and the consecutive
while the diverse modification of chemical structures has not intramolecular enamide–aldehyde cyclization occurred under
been systematically exploited yet. Due to the interesting bio- an acidic condition. After ring formation, dehydration would
logical activities, the synthesis of fully aromatized benzo[c]- easily occur thus producing a fully aromatized ring system of
phenanthridine alkaloids has been attractive target for benzo[c]phenanthridine. Herein, we have also accomplished
organic chemists.7—11) For overcoming the disadvantages of the formal synthesis of chelerythrine because the process to
reported methods we have investigated the efficient and rapid this alkaloid from the corresponding oxychelerythrine was
methods for above alkaloids and recently reported a versatile
synthetic ways for these alkaloids such as oxynitidine,
oxysanguinarine and oxyavicine using lithiated toluamide-
benzonitrile cycloaddition.12,13) To validate the general appli-
cation of our developed cycloaddition method, we attempted
to apply this to synthesis of oxychelerythrine.
Our strategy is based on the formation of 3-arylisoquino-
Fig. 1. Structure of Chelerythrine
line which could be transformed to benzo[c]phenanthridine
alkaloid via intramolecular enamide ring formation reaction.
The advantages of this methodology include easy access to
the starting material and a one-pot procedure for constructing
essential carbon atoms for desired alkaloid. Retrosynthetic
consideration of oxychelerythrine indicates that the coupling
of o-toluamide 5 with benzonitrile 6 affords 3-arylisoquino-
line, which could be converted to an aldehyde and consecu-
tive C ring construction of oxychelerythrine could be per-
formed by an intramolecular ring cyclization method as out-
lined in Chart 1.
The starting benzylamine 1 was treated with ethyl chloro-
formate and n-BuLi to give benzoate 2, which was then
reduced with NaBH4 in DMSO to afford o-methyl benzoate 3
in 84% overall yield.14) After the hydrolysis of 3 with 10%
NaOH, benzoic acid 4 was treated with oxalyl chloride/40%
MeNH2 to provide the o-methyl toluamide 5 in good yield as
shown in Chart 2.
Chart 1. Retrosythesis of Chelerythrine
The toluamide-benzonitrile cycloadditon reaction and the
synthesis of oxychelerythrine are shown in Chart 3. The
deprotonation of 5 with two equivalent n-BuLi gave dianion,
which was treated with MOM protected benzonitrile 6 to
afford the 3-arylisoquinolin-1(2H)-one 7 in 40% yield. 7 was
then reacted with MeI in the presence of 60% NaH to give
N-methylated compounds 8 without giving O-methylated one
in 80% yield. Deprotection of 8 with 10% HCl gave the alco-
Chart 2. Synthesis of N-Methyltoluamide 5
∗ To whom correspondence should be addressed. e-mail: wjcho@jnu.ac.kr
© 2005 Pharmaceutical Society of Japan

January 2005
119
Chart 3. Synthesis of Chelerythrine
already established.15)
Thus we have synthesized oxychelerythrine in six steps
from toluamide 5 and benzonitrile 6 using our developed
synthetic methodology.
2,3-Dimethoxy-N-6-dimethylbenzamide (5) To a suspension of ben-
zoic acid 4 (16.5 g, 84 mmol) and pyridine (12 ml) in CH2Cl2 (80 ml) was
slowly added oxalyl chloride (45 ml, 515 mmol) with stirring. After an addi-
tional 2 h stirring, the excess of oxalyl chloride was removed by co-distilla-
tion with benzene. The residue was dissolved in CH2Cl2 (60 ml) and 40%
methylamine (52.2 g, 1.68 mol) was added at 0 °C. After 1 h, the reaction
was diluted with water and the organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The organic layers were washed with
water, brine, dried and then concentrated. The residue was purified by re-
crystallization with ether to give amide 5 as a yellow solid (10.9 g, 62%). mp
132.1—133.9 °C. IR (KBr) cmꢀ1: 3280 (NH), 1640 (CꢁO). 1H-NMR
(300 MHz, CDCl3) d: 6.87 (d, Jꢁ8.1 Hz, 1H), 6.80 (d, Jꢁ8.1 Hz, 1H), 5.85
(s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.00 (d, Jꢁ4.9 Hz, 3H), 2.26 (s, 3H). MS
m/z (%): 209 (Mꢂ, 75), 179 (100), 136 (20). Anal. Calcd for C11H15NO3: C,
63.14; H, 7.23; N, 6.69. Found: C, 63.28; H, 7.38; N, 6.70.
Experimental
Melting points were determined on an Electrothermal IA9200 melting
point apparatus and are uncorrected. Nuclear magnetic resonance spectra
(1H-NMR) were recorded on a Bruker AC 80 and a Varian 300 spectrometer,
using TMS as the internal standard; chemical shifts are reported in parts per
million and signals are quoted as s (singlet), d (doublet), t (triplet), q (quar-
tet), and m (multiplet). IR spectra were recorded on a Perkin-Elmer 783
spectrometer and a Nicolet instrument using KBr pellets. Elemental analyses
were performed on a CaHo Erba elemental analyzer. Solvents were routinely
distilled prior to use. Anhydrous THF was distilled from sodium-benzophe-
non ketyl. Column chromatography was performed on Merck silica gel 60
(70—230 mesh). TLC was carried out using plates coated with silicagel 60F
254 purchased from Merck Co. Reagents were obtained from commercial
suppliers and were used without purification.
Ethyl 2,3-Dimethoxy-6-methylbenzoate (3) To a solution of benzyl-
amine 1 (39 g, 200 mmol) in dry THF (500 ml) was added n-BuLi (88 ml of
2.5 M in hexane, 220 mmol) at 0 °C and the reaction was stirred at the same
temperature for 1 h. After cooling the reaction vessel to ꢀ78 °C, ethyl chlo-
roformate (45.6 g, 420 mmol) was added all at once. The reaction mixture
was warmed to room temperature and stirred for 12 h. The solvent was evap-
orated off and the residue was dissolved with DMSO (300 ml). To this
NaBH4 (7.6 g, 200 mmol) was added and the reaction was stirred for 4 h at
60 °C. The reaction was quenched with water and extracted with ether. The
organic layers were washed with water, brine and dried over anhydrous
sodium sulfate. After removing the solvent, the residue was purified by col-
umn chromatography with n-hexane–ethyl acetate (10 : 1) to afford the ben-
zoate 3 as a yellow oil16) (37.6 g, 84%). 1H-NMR (300 MHz, CDCl3) d: 6.88
(s, 1H), 6.85 (s, 1H), 4.39 (q, Jꢁ7.1 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.23
(s, 3H), 1.37 (t, Jꢁ7.1 Hz, 3H). MS m/z (%): 224 (Mꢂ, 100).
7,8-Dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-
2H-isoquinolin-1-one (7) To a solution of amide 5 (1.96 g, 9.4 mmol) in
dry THF (30 ml) was added n-BuLi (9 ml of 2.5 M in hexane, 22.5 mmol) at
ꢀ20 °C and maintained the reaction temperature never exceeded to 20 °C.
After the addition was completed, the red orange solution was stirred for 1 h
at 0 °C. The reaction vessel was cooled to ꢀ50 °C and benzonitrile 6 (1.4 g,
6.3 mmol) was added. The reaction mixture was stirred for 20 min at the
same temperature and then allowed to warm up to room temperature. The
reaction was quenched with water and extracted with ethyl acetate. The
organic layers were washed with water, brine and dried over sodium sulfate.
After removing the solvent in vacuo, the residue was purified by column
chromatography with n-hexane–ethyl acetate (1 : 1) to afford 3-arylisoquino-
line 7 as a yellow solid (1.01 g, 40%). mp 151.0—154.2 °C. IR (KBr) cmꢀ1
:
3400 (NH), 1650 (CꢁO). 1H-NMR (300 MHz, CDCl3) d: 7.34 (d, Jꢁ9.0 Hz,
1H), 7.27 (d, Jꢁ9.0 Hz, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.37 (s, 1H), 6.04
(s, 2H), 4.83 (s, 2H), 4.47 (s, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.43 (s, 3H).
MS, m/z (%): 399 (Mꢂ, 18), 354 (42), 336 (70), 222 (100), 162 (38). Anal.
Calcd for C21H21NO7: C, 63.15; H, 5.30; N, 3.51. Found: C, 63.45; H, 5.27;
N, 3.66.
7,8-Dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-2-
methyl-2H-isoquinolin-1-one (8) To a solution of amide 7 (600 mg,
1.5 mmol) in THF (10 ml) was added 60% NaH dispersion (128 mg,
3.2 mmol) at 0 °C under nitrogen. The resulting mixture was stirred at the
same temperature for 1 h. After removal of the ice bath, methyl iodide
(425 mg, 3 mmol) in THF (3 ml) was added and the reaction mixture was
warmed up to 60 °C and stirred for 2 h. The reaction was quenched with
water and extracted with ethyl acetate. The combined ethyl acetate extracts
were washed with water, brine and dried over anhydrous sodium sulfate.
After removal of the solvent, the residue was purified by column chromatog-
raphy on silica gel with n-hexane–ethyl acetate (1 : 1) to give N-methylated
2,3-Dimethoxy-6-methylbenzoic Acid (4) The reaction mixture of ben-
zoate 3 (22.4 g, 100 mmol) and 10% NaOH (150 ml) in MeOH (150 ml) was
refluxed for 12 h. After cooling the reaction mixture, methanol was evapo-
rated off and the mixture was extracted with methylene chloride. The aque-
ous layer was separated and acidified with concentrated HCl. The residue
was then extracted with methylene chloride. The organic layers were washed
with water, brine, dried and concentrated to provide benzoic acid 4 as a yel-
low solid (16.5 g, 84%). mp 89.8—91.7 °C. (lit.16) 89—90 °C). IR (KBr)
cmꢀ1: 1700 (CꢁO). 1H-NMR (300 MHz, CDCl3) d: 6.92 (m, 2H), 3.93
(s, 3H), 3.86 (s, 3H), 2.39 (s, 3H). MS m/z (%): 196 (Mꢂ, 30).

120
Vol. 53, No. 1
amide 8 as a yellow oil (496 mg, 80%). IR neat cmꢀ1: 1650 (CꢁO). 1H-
NMR (300 MHz, CDCl3) d: 7.33 (d, Jꢁ9.0 Hz, 1H), 7.20 (d, Jꢁ9.0 Hz, 1H),
7.03 (s, 1H), 6.72 (s, 1H), 6.29 (s, 1H), 6.04 (s, 2H), 4.57 (s, 2H), 4.35 (s,
2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.25 (s, 3H), 3.25 (s, 3H). MS m/z (%): 413
(Mꢂ, 46). HR-MS-EI (Calcd for C22H23NO7): 413.4196, found: 413.4193.
3-(6-Hydroxymethylbenzo[1,3]dioxol-5-yl)-7,8-dimethoxy-2-methyl-
2H-isoquinolin-1-one (9) To a solution of N-methyl amide 8 (415 mg,
1 mmol) in methanol (15 ml) was added concentrated HCl (1 ml) and the
reaction mixture was refluxed for 3 h. After removal of the methanol in
vacuo, the residue was poured into water and extracted with ethyl acetate.
The ethyl acetate extracts were washed with water, brine and dried over
anhydrous sodium sulfate. The solvent was evaporated off and the residue
was purified by column chromatography on silica gel with n-hexane–ethyl
acetate (1 : 2) to give the alcohol 9 as a white solid (317 mg, 86%). mp
extracted with ethyl acetate. The ethyl acetate extracts were washed with
water, brine and dried over anhydrous sodium sulfate. The solvent was evap-
orated off and the residue was purified by column chromatography on silica
gel with n-hexane–ethyl acetate (1 : 2) to give oxychelerythrine 13 as a solid
(16 mg, 73%). mp 198—199 °C. (lit.17) 197—198 °C). IR (KBr) cmꢀ1: 1645
(CꢁO). 1H-NMR (300 MHz, CDCl3) d: 8.00 (d, Jꢁ9.0 Hz, 1H), 7.98
(d, Jꢁ9.0 Hz, 1H) 7.58 (d, Jꢁ9.0 Hz, 1H), 7.38 (d, Jꢁ9.0 Hz, 1H), 7.52 (s,
1H), 7.16 (s, 1H), 6.10 (s, 2H), 4.08 (s, 3H), 3.98 (s, 3H), 3.90 (s, 3H). MS
m/z (%): 363 (M, 35), 348 (15), 334 (14), 305 (18), 190 (20), 57 (100). Anal.
Calcd for C21H17NO5: C, 69.41; H, 4.72; N, 3.85. Found: C, 69.63; H, 4.69;
N, 3.87.
Acknowledgement This work was supported by KOSEF (RO5-2004-
000-12578-0).
171.6—173.2 °C. IR (KBr) cmꢀ1 3400 (OH), 1645 (CO). 1H-NMR
:
References and Notes
(300 MHz, CDCl3) d: 7.32 (d, Jꢁ9.0 Hz, 1H), 7.19 (d, Jꢁ9.0 Hz, 1H), 7.08
(s, 1H), 6.71 (s, 1H), 6.29 (s, 1H), 6.04 (s, 2H), 4.46 (s, 2H), 4.01 (s, 3 H),
3.95 (s, 3H), 3.24 (s, 3H). MS, m/z (%): 369 (Mꢂ, 100). Anal. Calcd for
C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.23; H, 5.48; N, 3.97.
6-(7,8-Dimethoxy-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-
yl)benzo[1,3]dioxole-5-carbadehyde (10) To a solution of alcohol 9
(290 mg, 0.78 mmol) in methylene chloride (15 ml) was added PDC
(440 mg, 1.17 mmol) and the mixture was stirred for 2 h. Reaction mixture
was filtered and washed with methylene chloride. The solvent was evapo-
rated off and the residue was purified by column chromatography on silica
gel with n-hexane–ethyl acetate (2 : 1) to afford the aldehyde 10 as a pale
white solid (257 mg, 90%). mp 209.6—212 °C. IR (KBr) cmꢀ1: 1680, 1650
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1
(CꢁO). H-NMR (300 MHz, CDCl3) d: 9.80 (s, 1H), 7.47 (s, 1H), 7.34 (d,
Jꢁ9.0 Hz, 1H), 7.20 (d, Jꢁ9.0 Hz, 1H), 6.83 (s, 1H), 6.31 (s, 1H), 6.16 (s,
2H), 4.08 (s, 3H), 3.99 (s, 3H), 3.30 (s, 3H). MS m/z (%): 367 (Mꢂ, 100),
352 (40), 338 (25), 190 (50). Anal. Calcd for C20H17NO6: C, 65.39; H, 4.66;
N, 3.81. Found: C, 65.47; H, 4.89; N, 3.68.
7,8-Dimethoxy-3-[6-(2-methoxyvinyl)benzo[1,3]dioxol-5-yl]-2-methyl-
2H-isoquinolin-1-one (11) To a solution of (methoxymethyl)triphen-
ylphosphonium chloride (178 mg, 0.52 mmol) in dry THF (15 ml) was added
n-BuLi (0.35 ml of 1.6 M in hexane, 0.56 mmol) at 0 °C and the mixture was
stirred for 1 h at 0 °C. To this a solution of aldehyde 10 (50 mg, 0.14 mmol)
in THF (5 ml) was added and the reaction mixture was stirred for 3 h at room
temperature. The reaction was quenched with water and extracted
with ethyl acetate. The organic layers were washed with water, brine and
dried over sodium sulfate. After removal of the solvent, the residue was
purified by column chromatography with n-hexane–ethyl acetate (3 : 1) to
1
afford the mixture 11 as cis/trans (1 : 1) as a brown oil (30 mg, 56%). H-
NMR (300 MHz, CDCl3) d (cis): 7.77 (s, 1H), 7.31 (d, Jꢁ9.0 Hz, 1H), 7.19
(d, Jꢁ8.9 Hz, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 6.00 (s, 2H), 5.98
(d, Jꢁ7.1 Hz, 1H), 4.86 (d, Jꢁ7.1 Hz, 1H), 4.02 (s, 3H), 3.96 (s, 3H), 3.75
(s, 3H), 3.25 (s, 3H). d (trans): 7.20 (d, Jꢁ9.0 Hz, 1H), 7.19 (d, Jꢁ9.0 Hz,
1H), 6.89 (s, 1H), 6.88 (d, Jꢁ12.8 Hz, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 6.00
(s, 2H), 5.48 (d, Jꢁ12.8 Hz, 1H), 3.47 (s, 3H), 3.25 (s, 3H). MS m/z (%):
395 (Mꢂ, 30), 258 (42), 229 (100), 201 (58).
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Oxychelerythrine (13) A solution of cis/trans isomer 11 (25 mg,
0.06 mmol) in methanol (5 ml) and HCl 10% (3 ml) was refluxed for 3 h.
After the removal of methanol, the residue was poured into water and