A short synthesis of (±)-cherylline dimethyl ether

Article abstract of DOI:10.3762/bjoc.5.80

A synthesis of (±)-cherylline dimethyl ether is reported. The key steps involved are Michael-type addition, radical azidonation of an aldehyde, Curtius rearrangement, and reduction of an isocyanate intermediate followed by Pictet-Spengler cyclization.

Full text of DOI:10.3762/bjoc.5.80

A short synthesis of (±)-cherylline dimethyl ether
Bhima Y. Kale1, Ananta D. Shinde1, Swapnil S. Sonar1,
Bapurao B. Shingate1, Sanjeev Kumar2, Samir Ghosh2,
Soodamani Venugopal2 and Murlidhar S. Shingare*1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 80.
1Organic Research Laboratory, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad – 431
004 (M.S.), India and 2Chemistry Section, Applied Sciences and
Humanities Department, SVNIT, Surat – 395 007, India
doi:10.3762/bjoc.5.80
Received: 29 August 2009
Accepted: 17 November 2009
Published: 16 December 2009
Email:
Murlidhar S. Shingare* - prof_msshingare@rediffmail.com
Editor-in-Chief: J. Clayden
* Corresponding author
© 2009 Kale et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Curtius rearrangement; Michael reaction; Pictet–Spengler cyclization;
radical azidonation
Abstract
A synthesis of (±)-cherylline dimethyl ether is reported. The key steps involved are Michael-type addition, radical azidonation of an
aldehyde, Curtius rearrangement, and reduction of an isocyanate intermediate followed by Pictet–Spengler cyclization.
Introduction
Aryl-1,2,3,4-tetrahydroisoquinolines have attracted much atten- various pharmacological activities [3]. For example, nomifen-
tion from the synthetic community owing to the potential bio- sine (3) [3] and dichlofensine (4) [4] exhibit CNS activity and
logical activities of this class of compounds and their increasing inhibit serotonin and dopamine uptake mechanisms.
medicinal interest. Among these heterobicyclic compounds
cherylline (1) (Figure 1), a rare phenolic 4-phenyltetrahydroiso- There are several reports on the syntheses [5-15] of (±)-cheryl-
quinoline alkaloid, and its dimethyl ether 5 (Scheme 1). Their line and of (±)-latifine [13,16,17] which include some efficient
structures are unique among the Amaryllidaceae alkaloids [1,2] asymmetric syntheses. Most of the reported methods for the
and they have long been fascinating targets for organic chem- synthesis of (±)-cherylline are lengthy. We report herein an
ists as witnessed by a number of articles dealing with biogen- alternative efficient synthesis of (±)-cherylline dimethyl ether.
esis, isolation, characterization and synthesis. Cherylline (1) and The key steps involved are Michael addition, radical azidona-
latifine (2) are the two 4-aryltetrahydroisoquinoline alkaloids tion of aldehydes [18], Curtius rearrangement, and reduction of
isolated from Amaryllidaceae plants. Apart from their natural an isocyanate intermediate followed by Pictet–Spengler cycliza-
occurence, 4-aryltetrahydroisoquinolines are of interest due to tion.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 80.
Figure 1: Aryl-1,2,3,4-tetrahydroisoquinolines.
Scheme 1: Retrosynthetic analysis of 5.
Results and Discussion
In short, we have devised a short and efficient method for the
Our retrosynthetic analysis of (±)-cherylline dimethyl ether (5) synthesis of (±)-cherylline dimethyl ether. The simple and facile
is depicted in Scheme 1. It can be anticipated that 5 could be nature of this tetrahydroisoquinoline synthesis should allow the
constructed via a Pictet–Spengler ring annulation from amine 6 construction of a wide variety of interesting and useful analo-
which, in turn, could be obtained by reduction of the corres- gous molecules.
ponding isocyanate. The required isocyanate would arise from
Experimental
the aldehyde 7 via radical azidonation followed by Curtius reac-
tion. Lastly, aldehyde 7 could be assembled by Michael addi-
Materials and Instruments
tion of 1,2-dimethoxybenzene to p-methoxycinnamonitrile.
All solvents and reagents were purchased from the suppliers
and used without further purification. All non-aqueous reac-
1,2-Dimethoxybenzene (veratrole) was subjected to a Michael- tions were performed in dry glassware under an atmosphere of
type reaction with p-methoxycinnamonitrile (8) in the presence dry nitrogen. Organic solutions were concentrated under
of trifluoroacetic acid to obtain 3-(3,4-dimethoxyphenyl)-3-(4- reduced pressure. Thin layer chromatography was performed on
methoxyphenyl)propanenitrile (9) in 90% yield (Scheme 2). Merck precoated Silica-gel 60F254 plates. 1H and 13C NMR
The formation of compound 9 was confirmed by physical spec- spectra were recorded in DMSO-d6 and CDCl3 using 400 MHz,
troscopic data. Reduction of the nitrile group in compound 9 on a Varian Gemini 400 MHz FT NMR spectrometer. The
with DIBAL-H in dichloromethane at −78 °C, gave 3-(3,4-di- chemical shifts were reported in δ ppm relative to TMS. The IR
methoxyphenyl)-3-(4-methoxyphenyl)propanal (7) in 70% spectra were recorded in the solid state as KBr dispersion using
yield. The conversion of the nitrile to an aldehyde group was Perkin Elmer FT-IR spectrophotometer. The mass spectra were
confirmed by its IR spectroscopy in which the peak at recorded on Shimadzu LCMS-QP 800 LC-MS and AB-4000
1715 cm−1 was observed. Radical azidonation of aldehyde 7 Q-trap LC-MS/MS. Melting points were obtained by using the
with iodine azide generated in situ by the reaction of sodium open capillary method and are uncorrected.
azide with ICl) at room temperature gave an acyl azide and
subsequent Curtius rearrangement provided isocyanate 10 in 3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)propaneni-
moderate yield. Immediate reduction of the isocyanate 10 by trile (9). A solution of p-methoxycinnamonitrile (6.0 g,
lithium aluminium hydride in tetrahydrofuran gave N-methyl- 0.037 mol) and veratrole (10.4 g, 0.75 mol) in trifluoroacetic
amine 6 in 90% yield. The crude amine 6, on Pictet–Spengler acid (TFA) (30 mL) was refluxed for 3 h. TFA was removed by
reaction with formaldehyde in acetic acid, gave (±)-cherylline evaporation under reduced pressure and saturated NaHCO3
dimethyl ether [15] 5 in 45% yield.
(50 mL) was added. The mixture was extracted with ethyl
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Beilstein Journal of Organic Chemistry 2009, 5, No. 80.
Scheme 2: (a) 1,2-Dimethoxybenzene, TFA, reflux, 3 h, 90%; (b) DIBAL-H, CH2Cl2, −78 °C, 3 h, 65%; (c) (i) NaN3, ICl, acetonitrile, CH2Cl2, 0–5 °C
(ii) toluene, 110 °C, 1 h, 65%; (d) LiAlH4, THF, reflux, 24 h, 90% (e) HCHO, acetic acid, 90 °C, 2 h, 45%.
acetate (3 × 30 mL) and combined extracts were dried over (Ar–CH–Ar), 55.4 (OCH3), 55.8 (OCH3), 55.8 (OCH3), 111.9
sodium sulfate and concentrated. The residue was purified by (CHar), 112.1 (CHar), 114.1 (2 × CHar), 119.6 (CHar) 128.8 (2 ×
column chromatography on silica gel (7:3 hexane and ethyl CHar), 136.6 (Car), 137.2 (Car), 147.6 (OCar), 149.0 (OCar),
acetate) to yield 9 as a residue (10 g, 90 %); IR (KBr, cm−1): 158.0 (OCar), 202.8 (CHO). MS (m/z): 299 [M+− H], 323 [M+
2240 (CN); 1H NMR (CDCl3) (δ ppm): 2.96 (2H, d, J = 8.0 Hz, + Na].
–CH–CH2–), 3.76 (3H, s, –OCH3), 3.79 (3H, s, –OCH3), 3.83
(3H, s, –OCH3), 4.25 (1H, t, J = 8.0 Hz, CH–CH2), 6.65–7.12 2-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)-N-methyl-
(7H, m, ArH); 13C NMR (CDCl3) (δ ppm); 23.6, 44.5, 55.1, ethanamine (6). To a stirred slurry of sodium azide (1.3 g,
55.8, 56.1, 110.9, 114.9, 119.4, 121.4, 128.4, 132.9, 133.0, 0.02 mol) in acetonitrile (30 mL) in an ice bath was added
148.3, 148.8, 157.6; MS (m/z): 298 [M+ + 1].
slowly iodine monochloride (2.16 g, 0.01 mol) in acetonitrile
(30 mL). The reaction mixture was stirred for an additional
3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)propanal (7). 5 – 1 0 m i n a n d 3 - ( 3 , 4 - d i m e t h o x y p h e n y l ) - 3 - ( 4 -
To solution of 3-(3,4-dimethoxyphenyl)-3-(4- methoxyphenyl)propanal (2.0 g, 0.006 mol) in acetonitrile (10
a
methoxyphenyl)propanenitrile (4.0 g, 0.012 mol) in dichloro- mL) was added. The reaction was allowed to reach room tem-
methane (40 mL) at −78 °C was added dropwise DIBAL-H perature and was stirred for 2.5 h. The red–brown slurry was
(1.0 M in CH2Cl2, 36.0 mL, 0.036 mol). The reaction mixture poured over water (50 mL), and the mixture was extracted with
stirred at −78 °C for 2–3 h. Saturated aqueous solution of dichloromethane (100 mL). The organic extracts were
Rochelle’s salt was added and it was stirred vigorously at room combined and washed with 3 × 50 mL of 5% sodium thiosulfate
temperature until the two layers became clear. The mixture was leaving a colorless solution, which was dried over anhydrous
extracted with ethyl acetate (3 × 50 mL) and combined extracts magnesium sulfate. Removal of the solvent under reduced pres-
were dried over anhydrous sodium sulfate and concentrated. sure produced acyl azide.
The residue was purified by column chromatography on silica
gel (7:3 hexane and ethyl acetate) to give aldehyde 7 as yellow Curtius rearrangement. The acyl azide was dissolved in dry
oil (2.5 g, 65%); IR (KBr, cm−1): 1725; 1H NMR (CDCl3) toluene (30 mL) and heated to reflux for 1 h. Concentration of
(δ ppm): 3.09 (2H, d, J = 7.8 Hz, –CH–CH2–), 3.77 (3H, s, reaction mixture under vacuum gave isocyanate 10 (1.25 g,
–OCH3), 3.82 (3H, s, –OCH3), 3.84 (3H, s, –OCH3), 4.52 (1H, 65%) . IR (KBr, cm−1): 2260 (N=C=O). Isocyanate 10 (1.25 g,
t, J = 7.8 Hz, CH–CH2), 6.69–7.14 (7H, m, ArH), 9.72 (1H, t, 0.003 mol) in dry THF (15 mL) was slowly added to the
–CHO); 13C NMR (CDCl3) (δ ppm); δ 43.5 (CH2), 49.0 suspension of lithium aluminium hydride (LAH) (0.6 g,
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refluxing the reaction mixture for 24 h, it was cooled to 5 °C
and cold water was slowly added to it. The aluminium
hydroxide formed was filtered over celite and washed with
chloroform. The filtrate was extracted with chloroform (3 ×
20 mL). All the organic extracts and washings were combined,
dried over anhydrous sodium sulfate, concentrated to obtain 6
as a brown residue 1.0 g (90%); IR (film, cm−1): 3120 (NH); 1H
NMR (CDCl3) (δ ppm): 2.44 (3H, s, NCH3), 3.12 (2H, d, J =
8.0 Hz, HCH–N–CH3), 3.78 (3H, s, OCH3), 3.83 (3H, s,
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(±)-Cherylline dimethyl ether (5). A mixture of 6 (2.0 g,
0.006 mol), formaldehyde (0.64 g, 0.007 mol) and acetic acid (5
mL) was stirred at 90 °C under nitrogen atmosphere for 2 h.
After cooling to room temperature, the reaction mixture was
basified using saturated NaHCO3 solution. This basified solu-
tion was extracted ethyl acetate (3 × 25 mL), dried, and concen-
trated to obtain 1.1 g of crude product. Purification of crude
product by column chromatography using 1% methanol in
dichloromethane as an eluent afforded compound 5 (0.93 g,
45%); IR (KBr, cm−1): 1610, 1514. 1H NMR (CDCl3) (δ ppm) :
2.41 (3H, s, NCH3), 2.48 (1H, s (br), Ar–HCH–N), 2.98 (1H, s
(br), Ar–HCH–N), 3.56 (2H, s (br), CH–CH2–N), 3.68 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 3.82 (3H, s, OCH3), 4.12 (1H, s
(br), Ar–CH–Ar), 6.31 (1H, s, 5–CH), 6.52 (1H, s, 8–CH), 6.82
(2H, d, J = 8.4 Hz, 2′–CH), 7.08 (2H, d, J = 8.4 Hz, 3′–CH).
13C NMR (CDCl3) (δ ppm); 43.9 (NCH3), 45.9 (ArCHAr), 55.3
(OCH3), 55.8 (OCH3), 55.9 (OCH3), 57.7 (NCH2–), 61.6
(NCH2Ar), 109.7 (CHar), 112.5 (CHar), 113.9 (2 × CHar), 127.7
(Car), 129.2 (Car), 130.0 (2 × Car), 137.7 (Car), 147.5 (OCar),
147.6 (OCar), 158.0 (OCar). HRMS m/z calculated for
C19H23NO3 314.1756 [M+1], found: 314.175.
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Acknowledgements
(http://www.beilstein-journals.org/bjoc)
Authors are grateful to the Head, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad,
India for providing laboratory facilities.
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.5.80
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