Efficient synthesis of thalifoline and its analogs

Article abstract of DOI:10.1080/00397910802590894

Thalifoline (1) and its analogs were synthesized from methyl 3-hydroxy-4-methoxy benzoate by prenyl etherification, Claisen rearrangement, oxidation, imine formation, reductive amination and intramolecular amidation. The last three steps, imine formation,

Full text of DOI:10.1080/00397910802590894

This article was downloaded by: [Dokuz Eylul University ]
On: 04 November 2014, At: 16:40
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of
Thalifoline and Its Analogs
Qiang Li a , San-Qi Zhang a , Si-Cen Wang a & Ming-
Zhe Zhou a
a School of Medicine, Xi'an Jiaotong University ,
Xi'an, China
Published online: 15 Apr 2009.
To cite this article: Qiang Li , San-Qi Zhang , Si-Cen Wang & Ming-Zhe Zhou (2009)
Efficient Synthesis of Thalifoline and Its Analogs, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:10,
1752-1758, DOI: 10.1080/00397910802590894
To link to this article: http://dx.doi.org/10.1080/00397910802590894
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or

indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 39: 1752–1758, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802590894
Efficient Synthesis of Thalifoline and Its Analogs
Qiang Li, San-Qi Zhang, Si-Cen Wang, and Ming-Zhe Zhou
School of Medicine, Xi’an Jiaotong University, Xi’an, China
Abstract: Thalifoline (1) and its analogs were synthesized from methyl
3-hydroxy-4-methoxy benzoate by prenyl etherification, Claisen rearrangement,
oxidation, imine formation, reductive amination and intramolecular amidation.
The last three steps, imine formation, reductive amination, and intramolecular
amidation, were completed in one pot at room temperature.
Keywords: Claisen rearrangement, intramolecular amidation, isoquinolinone,
one-pot method, thalifoline
Isoquinolinone derivatives are present in a wide variety of natural
products[1] and exhibit a broad spectrum of biological activities.[2]
Thalifoline (1a), with a skeleton of 3,4-dihydroisoquinolin-1-one, was
first isolated from Thalictrum minus L. var. adiantifolium Hort in 1969
by Doskotch et al.[3] and was reported to possess vasorelaxing activity.[4]
So far, a few synthetic routes have been developed to thalifoline. The
initial chemical synthesis of thalifoline reported was achieved as a
by-product in a photolysis reaction.[5] Another one is through oxidative
cleavage reaction of substituted benzylisoquinolines.[6] In 2002, Wang
and Georeghiou[7] developed an eight-step approach for the synthesis
of thalifoline within 37% overall yield from vanillin using modified
Bischler–Napieralski cyclization. These approaches, however, are limited
by the application of special starting materials, poor selectivity, or
multiple steps. Here we report an efficient approach to the total synthesis
Received June 27, 2008.
Address correspondence to San-Qi Zhang, School of Medicine, Xi’an Jiaotong
University, Xi’an 710061, China. E-mail: sqzhang@mail.xjtu.edu.cn
1752

Efficient Synthesis of Thalifoline and Its Analogs
1753
Figure 1. Structure of thalifoline (1a) and its analogs.
of thalifoline (1a, Fig. 1) and its analogs (1b–e) from methyl 3-hydroxy-4-
methoxy benzoate (2). The synthetic route is outlined in Scheme 1.
The refluxing of 2 with prenyl bromide in the presence of anhydrous
K2CO3 in acetone quantitatively afforded prenyl ether 3. A solution of 3
in N,N-dimethylaniline was heated to reflux for 8 h to give the desired
methyl 5-hydroxy-4-methoxy-2-prenylbenzoate 4 in a yield of 75%.[8]
The prenyl group was moved into the para-position of hydroxyl in this
[9]
Claisen rearrangement process. The oxidation of 4 with OsO4=NaIO4
produced aldehyde 5, which is a key intermediate for the synthesis of
the target compounds. The reaction of 5 with methylamine or other fatty
amines, followed by reduction with NaBH(OAc)3,[10] directly gave
thalifoline (1a) and its analogs (1b–e). Actually, 1 was produced by intra-
molecular amidation of ester after reductive amination. The three steps,
imine formation, reduction, and intramolecular amidation, were com-
pleted in one pot at room temperature. When R in Fig. 1 is an aromatic
group, the nucleophilic property of an aromatic second amine is too weak
to undergo smoothly an intramolecular amidation of ester at room
temperature, so alkylamines were employed to synthesize thalifoline’s
analogs. This approach is mild in condition and short in steps compared
to the previously reported synthetic routes. The methodology reported
herein appears to be a general one and can be applied to the synthesis
of 2-substituted-3,4-dihydroisoquinolin-1-ones.
Scheme 1. Route for synthesis of thalifoline. Reagents and conditions: (a) prenyl
bromide, K2CO3, acetone, reflux, 3 h, quantitative; (b) N,N-dimethylaniline, N2,
reflux, 8 h, 75%; (c) OsO4, NaIO4, acetone=H2O=t-BuOH, rt, 12 h, 41.9%; (d)
RNH2=EtOH, NaBH(OAc)3, CH2Cl2, rt, 8 h, 55–80%.

1754
Q. Li et al.
EXPERIMENTAL
All melting points were determined on a Beijing micromelting-point
1
apparatus and were uncorrected. H NMR spectra were recorded on a
Bruker Avance 300-MHz instrument in CDCl3 solution with tetremethyl-
silane (TMS) as an internal standard. Mass spectra were performed on a
Shimadzu GC-MS-QP2010 instrument. Infrared (IR) spectra were recor-
ded on an Avatar 330 (Fourier transform FT)-IR instrument. Purifica-
tion of reagents and solvents was done according to standard methods.
Flash–column chromatography was performed on silica gel.
Methyl 5-Hydroxy-4-methoxy-2-prenylbenzoate (4)
Prenyl bromide (4.25 mL, 32.88 mmol) was added to a mixture of 2
(5.00 g, 27.4 mmol), anhydrous K2CO3 (11.36 g, 82.3 mmol), and acetone
(80 mL). The resulting mixture was refluxed for 3 h with stirring, cooled
to room temperature, and filtered. The filtrate was evaporated under
vacuum, and the residue was dissolved in ethyl acetate (100 mL). The
solution was washed with 1 M NaOH solution (2 ꢀ 25 mL), water
(2 ꢀ 25 mL), and brine (2 ꢀ 25 mL); dried over anhydrous Na2SO4; and
then filtered. The evaporation of solvent quantitatively afforded 3 as light
yellow oil, which was used for the next step without further purification.
A solution of 3 (4.00 g, 16.0 mmol) in N,N-dimethylaniline (20 mL) was
refluxed under nitrogen for 8 h, cooled to room temperature, and was
added to ethyl acetate (200 mL). The mixture was washed with 2 M
HCl (6 ꢀ 25 mL), saturated NaHCO3(2 ꢀ 25 mL), and brine (2 ꢀ 25 mL);
dried over anhydrous Na2SO4; filtered; and concentrated. Flash chroma-
tography of the residue over silica gel using petroleum ether–ethyl acetate
(8:1) gave 4 (3.00 g, 75%) as a white solid. Recrystallization of the solid in
ethyl acetate gave colorless prismatic crystals. Mp 78.0–79.0ꢁC. 1H NMR
(300 MHz, CHCl3) d 1.73 [6H, s, C(CH3)2], 3.66 (2H, d, CH2,
J ¼ 6.49 Hz), 3.90 (3H, s, OCH3), 4.05 (3H, s, CO2CH3), 5.26 (1H, t,
CH¼), 5.50 (1H, s, OH), 6.71 (1H, s, H-5), 7.50 (1H, s, H-2); EI-MS
m=z (%) 250.0 (Mþ, 80), 218.0 (100); IR (KBr) 3400–3100, 3091, 2969,
2911, 2850, 1687, 1595, 1521 cmꢂ1. Anal. calcd. for C14H18O4: C,
67.18; H, 7.25. Found: C, 67.21; H, 7.06.
Methyl 2-(2-Oxoethyl)-5-hydroxy-4-methoxybenzoate (5)
OsO4 (50 mg, 5 mol%) was added to a stirred solution of 4 (2.00 g,
7.99 mmol) in 3:1:1 acetone–t-BuOH–H2O (60 mL). After the stirred
solution was kept from light at room temperature for 30 min, NaIO4

Efficient Synthesis of Thalifoline and Its Analogs
1755
(5.13 g, 23.97 mmol) was added in one portion. Stirring was continued for
12 h. The reaction mixture was filtered through diatomite (1 cm) and
washed with acetone. The filtrate was concentrated in vacuo at room
temperature, added to CH2Cl2 (150 mL), washed with water (2 ꢀ 25 mL)
and brine (2 ꢀ 25 mL), dried, and concentrated. Flash chromatography
of the residue over silica gel using petroleum ether–ethyl acetate (2:1)
1
gave 5 (0.75 g, 41.9%) as a white solid. Mp 112.5–113.5ꢁC. H NMR
(300 MHz, CHCl3) d 3.94 (3H, s, OCH3), 4.00 (2H, d, CH2), 4.05 (3H,
s, CO2CH3), 5.58 (1H, s, OH), 6.65 (1H, s, H-5), 7.66 (1H, s, H-2), 9.76
(1H, s, CHO); EI-MS m=z (%) 224.0 (Mþ, 30), 196.0 (100); IR (KBr)
3400–3100, 2945, 2845, 1710, 1618, 1585, 1518, cmꢂ1. Anal. calcd. for
C11H12O5: C, 58.93; H, 5.39. Found: C, 59.23; H, 5.30.
Thalifoline (1a)
A solution of methylamine in dry EtOH (4 M, 0.27 ml, 1.07 mmol) was
added dropwise to a stirred and cooled (0ꢁC) solution of 5 (0.20 g,
0.89 mmol) in CH2Cl2 (15 ml) under nitrogen. The reaction mixture was
stirred for 30 min. The cooling bath was removed, and NaBH(OAc)3
(Alfa Aesar, 95%, 0.40 g, 1.78 mmol) was added. Stirring was continued
under nitrogen at room temperature for 8 h. The reaction mixture was
filtered, and the solid was washed with CH2Cl2. The filtrate was evapo-
rated under vacuum. Flash chromatograph of the residue, using
CHCl3–MeOH (30:1), gave 1a (102 mg, 55.3%) as a colorless solid.
Recrystallization of the solid in chloroform gave colorless crystals. Mp
209.5–210.5 (lit.[3]: 210–212ꢁC); 1H NMR (300 MHz, CHCl3) d 2.91
(2H, t, J ¼ 6.39 Hz, ArꢂCH2), 3.13 (3H, s, NꢂCH3), 3.53 (2H, t,
J ¼ 6.47 Hz, NꢂCH2), 3.92 (3H, s, OꢂCH3), 6.61 (1H, s, H-5), 7.68
(1H, s, H-8); EI-MS m=z (%) 207.0 (Mþ, 70), 164.0 (75), 136.1 (100);
IR (KBr) 3400–3100, 2955, 2839, 1646, 1613, 1574, 1498, 1293 cmꢂ1
.
2-Cyclohexyl-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-
one (1b)
Aldehyde 5 (100 mg, 0.45 mmol) was dissolved in 10 mL of freshly
distilled CH2Cl2 in a 50-mL round-bottomed flask under a nitrogen
atmosphere cooled by an ice-water bath, and cyclohexylamine (0.061 mL,
0.53 mmol) diluted by CH2Cl2 (2 mL) was added. After stirring for
30 min, NaBH(OAc)3 (95%, 0.20 g, 0.89 mmol) was added. The mixture
was stirred for another 8 h at room temperature and filtered. The solvent
was removed under reduced pressure. Flash chromatography of the

1756
Q. Li et al.
residue, using CHCl3–MeOH (50:1), gave 1b (80 mg, 65.1%) as a colorless
solid. Recrystallization of the solid in petroleum ether–ethyl acetate gave
colorless crystals. Mp 221.5–222.5ꢁC. 1H NMR (300 MHz, CHCl3) d
1.42–1.52 (4H, m, 2 ꢀ CH2), 1.67–1.80 (6H, m, 3 ꢀ CH2), 2.83 (2H, t,
J ¼ 6.12 Hz, ArꢂCH2), 3.42 (2H, t, J ¼ 6.14 Hz, NꢂCH2), 3.92 (3H, s,
OꢂCH3), 4.64 (1H, m, NꢂCH), 6.61 (1H, s, H-5), 7.67 (1H, s, H-8);
EI-MS m=z (%) 275.1 (Mþ, 70), 192.1 (25), 164.1 (100), 136.1 (80); IR
(KBr) 3400–3100, 2950, 1650, 1610 cmꢂ1. Anal. calcd. for C16H21NO3:
C, 69.79; H, 7.69; N, 5.09. Found: C, 70.07; H, 7.35; N, 4.96.
2-(2-Methylbenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-
one (1c)
Procedure for the preparation of compound 1c was the same as that of
compound 1b with a yield of 67.9%. Mp 200.5–202.0ꢁC. 1H NMR
(300 MHz, CHCl3) d 2.33 (3H, s, ArꢂCH3), 2.84 (2H, t, J ¼ 6.32 Hz,
ArꢂCH2), 3.40 (2H, t, J ¼ 6.17 Hz, NꢂCH2), 3.93 (3H, s, OꢂCH3),
4.79 (2H, s, ArꢂCH2ꢂN), 6.61 (1H, s, H-5), 7.19–7.26 (4H, m, ArꢂH),
7.70 (1H, s, H-8); EI-MS m=z (%) 297.0 (Mþ, 100), 282.1 (20), 192.0
(70), 164.0 (70), 136.1 (45); IR (KBr): 3400–3100, 2956, 1647, 1612 cmꢂ
1. Anal. calcd. for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.60; H, 6.16; N, 4.62.
2-(2-Chlorobenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-
one (1d)
Procedure for the preparation of compound 1d was the same as that of
compound 1b with a yield of 80.2%. Mp 191.5–193.0ꢁC. 1H NMR
(300 MHz, CHCl3) d 2.90 (2H, t, J ¼ 6.27 Hz, ArꢂCH2), 3.52 (2H, t,
J ¼ 6.27 Hz, NꢂCH2), 3.93 (3H, s, OꢂCH3), 4.90 (2H, s, ArꢂCH2ꢂN),
5.80 (1H, s, ꢂOH), 6.62 (1H, s, H-5), 7.21–7.37 (4H, m, ArꢂH), 7.73
(1H, s, H-8); EI-MS m=z (%) 317.0 (Mþ, 10), 282.1 (100), 192.1 (15),
164.0 (75); IR (KBr): 3400–3100, 2960, 2840, 1651, 1608, 1580 cmꢂ1
.
Anal. calcd. for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C,
64.07; H, 4.90; N, 4.20.
2-(2-Fluorobenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-
one (1e)
Procedure for the preparation of compound 1e was the same as that of
compound 1b with a yield of 74.4%. Mp 191.5–192.5ꢁC. 1H NMR

Efficient Synthesis of Thalifoline and Its Analogs
1757
(300 MHz, CHCl3) d 2.88 (2H, t, J ¼ 6.30 Hz, Ar-CH2), 3.53 (2H, t,
J ¼ 6.32 Hz, NꢂCH2), 3.92 (3H, s, OꢂCH3), 4.82 (2H, s, ArꢂCH2ꢂN),
5.72 (1H, s, ꢂOH), 6.61 (1H, s, H-5), 7.02–7.46 (4H, m, ArꢂH), 7.70
(1H, s, H-8); EI-MS m=z (%) 301.1 (Mþ, 100), 192.1 (15), 164.0 (75),
136.1 (55); IR (KBr): 3400–3100, 2958, 2837, 1646, 1606, 1578 cmꢂ1
.
Anal. calcd. for C17H16FNO3: C, 67.76; H, 5.35; N, 4.65. Found: C,
67.75; H, 5.13; N, 4.49.
REFERENCES
1. (a) Xie, C.; Veitch, N. C.; Houghton, P. J.; Simmonds, M. S. J. Flavonoid
glycosides and isoquinolinone alkaloids from Corydalis bungeana. Phyto-
chemistry 2004, 65, 3041–3047; (b) Zhang, X.-Q.; Ye, W.-C.; Zhao, S.-X.;
Che, C.-T. Isoquinoline and isoindole alkaloids from Menispermum dauri-
cum. Phytochemistry 2004, 65, 929–932; (c) Pettit, G. R.; Meng, Y.-H.;
Herald, D. L.; Graham, K. A. N.; Pettit, R. K.; Doubek, D. L. J. Nat. Prod.
2003, 66, 1065–1069; (d) Alves, T. M. A.; Zani, C. L. New tetrahydroisoqui-
nolinones from Hyeronima oblonga (Euphorbiaceae). Tetrahedron Lett. 1999,
40, 205–208.
2. (a) Roth, J.; Madoux, F.; Hodder, P.; Roush, W. R. Synthesis of small mole-
cule inhibitors of the orphan nuclear receptor steroidogenic factor-1
(NR5A1) based on isoquinolinone scaffolds. Bioorg. Med. Chem. Lett.
2008, 18, 2628–2632: (b) Seitz, W.; Geneste, H.; Backfisch, G.; Delzer, J.;
Graef, C.; Hornberger, W.; Kling, A.; Subkowski, T.; Zimmermann, N.
Design and synthesis of novel potent and selective integrin avb3 antago-
nists—Novel synthetic routes to isoquinolinone, benzoxazinone, and quina-
zolinone acetates. Bioorg. Med. Chem. Lett. 2008, 18, 527–531; (c) Ikeda,
Y.; Hokamura, K.; Kawai, T.; Ishiyama, J.; Ishikawa, K.; Anraku, T.;
Uno, T.; Umemura, K. Neuroprotective effects of KCL-440, a new poly(-
ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion
model. Brain Res. 2005, 1060, 73–80; (d) Ukita, T.; Nakamura, Y.; Kubo, A.;
Yamamoto, Y.; Moritani, Y.; Saruta, K.; Higashijima, T.; Kotera, J.; Takagi,
M.; Kikkawa, K.; Omori, K. Novel, potent, and selective phosphodiesterase
5 inhibitors: Synthesis and biological activities of a series of 4-aryl-1-isoqui-
nolinone derivatives. J. Med. Chem. 2001, 44, 2204; (e) Watson, C. Y.; Whish,
W. J. D.; Threadgill, M. D. Synthesis of 3-substituted benzamides and 5-
substituted isoquinolin-1(2H)-ones and preliminary evaluation as inhibitors
of poly(ADP-ribose)polymerase (PARP). Bioorg. Med. Chem. 1998, 6,
721–734.
3. Doskotch, R. W.; Schiff, P. L. Jr.; Beal, J. L. Alkaloids of thalictrum, X: Two
new alkaloids from T. minus var. adiantifolium: Noroxyhydrastinine and
thalifoline. Tetrahedron 1969, 25, 469–475.
4. Chen, J.-J.; Chang, Y.-L.; Teng, C.-M.; Chen, I.-S. Vasorelaxing and
antioxidant constituents from Hernandia nymphaeifolia. Planta Medica
2001, 67, 593–598.

1758
Q. Li et al.
5. (a) Kametani, T.; Koizumi, M.; Fukumoto, K. Syntheses of heterocyclic
compounds, CCCXCI: Total synthesis of O-methylandrocymbine by a
photo-Pschorr reaction and synthesis of thalifoline. J. Chem. Soc. C 1971,
1792–1796; (b) Kametani, T.; Shibuya, S.; Sugi, H.; Kusama, O.; Fukumoto,
K. Syntheses of heterocyclic compounds, CDVII: Total photolytic syntheses
of alkaloids, V: Total syntheses of flavinantine, amurine, bracteoline, and
domesticine by photolysis of 1-(2-bromobenzyl)isoquinolines. J. Chem. Soc.
C 1971, 2446–2448; (c) Kametani, T.; Fukumoto, K.; Kigasawa, K.;
Wakisaka, K. Syntheses of heterocyclic compounds, CMII: Chemical and
enzymic phenol oxidation of (R)(ꢂ)-N-methylcoclaurine and (S)(þ)-reticu-
line. Chem. Pharm. Bull. 1971, 19, 714–717.
6. Irie, H.; Shiina, A.; Fushimi, T.; Katakawa, J.; Fujii, N.; Yajima, H. New
synthesis of isoquinoline alkaloids, thalifoline, corypalline, and cherylline.
Chem. Lett. 1980, 875–878.
7. Wang, Y.-C.; Georghiou, P. E. An efficient synthesis of thalifoline. Synthesis
2002, 2187–2190.
8. Tan, W.-F.; Li, W.-D. Z.; Li, Y.-L. First total synthesis of (ꢃ)-glyflavanone-
A. Synth. Commun. 2002, 32, 1077–1083.
9. Tsang, K. Y.; Brimble, M. A. Synthesis of aromatic spiroacetals related to
c-rubromycin based on a 3H-spiro[1-benzofuran-2,20-chromane] skeleton.
Tetrahedron 2007, 63, 6015–6034.
10. Lysek, R.; Schutz, C.; Favre, S.; O’Sullivan, A. C.; Pillonel, C.; Kruelle, T.;
¨
Jung, P. M. J.; Clotet-Codina, I.; Este, J. A.; Vogel, P. Search for
a-glucosidase inhibitors: New N-substituted valienamine and conduramine
F-1 derivatives. Bioorg. Med. Chem. 2006, 14, 6255–6282.