New synthesis of (±)-cherylline and mono- and dimethyl ethers

Article abstract of DOI:10.1080/00397911.2014.891745

The synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines is achieved via the ether rearrangement methodology. Subsequent reactions yielded cherylline and ether derivatives of amaryllidaceac alkaloids. Copyright

Full text of DOI:10.1080/00397911.2014.891745

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New Synthesis of (±)-Cherylline and
Mono- and Dimethyl Ethers
Uma Reddy Pailla a b , Veera Reddy Arava a & Ravindhranath L. K. b
a Research and Development Centre , Suven Life Sciences Ltd. ,
Hyderabad , India
b Department of Chemistry , Sri Krishnadevaraya University ,
Ananthapur , Andhra Pradesh , India
Accepted author version posted online: 22 Apr 2014.Published
online: 06 Jun 2014.
To cite this article: Uma Reddy Pailla , Veera Reddy Arava & Ravindhranath L. K. (2014) New
Synthesis of (±)-Cherylline and Mono- and Dimethyl Ethers, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:15, 2232-2238,
DOI: 10.1080/00397911.2014.891745
To link to this article: http://dx.doi.org/10.1080/00397911.2014.891745
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Synthetic Communications1, 44: 2232–2238, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.891745
NEW SYNTHESIS OF (ꢀ)-CHERYLLINE AND
MONO- AND DIMETHYL ETHERS
Uma Reddy Pailla,1,2 Veera Reddy Arava,1 and
Ravindhranath L. K.2
1Research and Development Centre, Suven Life Sciences Ltd.,
Hyderabad, India
2Department of Chemistry, Sri Krishnadevaraya University,
Ananthapur, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract The synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines is achieved via the ether
rearrangement methodology. Subsequent reactions yielded cherylline and ether derivatives
of amaryllidaceac alkaloids.
Keywords Cherylline; dimethyl cherylline; ether rearrangement; monomethyl cherylline
INTRODUCTION
Tetrahydroisoquinoline (THIQ) is an interesting structure present in a number
of biologically active molecules[1] such as cherylline (1), latifine (2), nomifensine (3),
and dichlorofensine (4). These are some of the naturally occurring 4-Aryl THIQ
alkaloids. Nomifensine and dichlorofensine[2] exhibit central nervous system activity
and inhibit serotonin and dopamine uptake mechanisms (Fig. 1).
Several syntheses are reported for (ꢀ)-cherylline and its derivatives.[3g]
We report here an alternative and efficient synthesis of (ꢀ)-cherylline and its
mono- and dimethyl ethers. The key steps in the syntheses are acid-catalyzed ether
rearrangement and Pictet–Spengler cyclization.
Received December 28, 2013.
Address correspondence to Veera Reddy Arava, Research and Development Centre, Suven Life
Sciences Ltd., Plot No. 18, Phase III, Jeedimetla, Hyderabad 500055, India. E-mail: reddyvenis@
rediffmail.com
2232

NEW SYNTHESIS OF (ꢀ)-CHERYLLINE
2233
Figure 1. 4-Aryl THIQ.
RESULTS AND DISCUSSION
A novel method of building 4-aryl-1,2,3,4-tetrahydroisoquinolines was envi-
saged via an ether rearrangement method. Retrosynthetic analysis of cheryllines lead
to guiacol (5) as shown in Fig. 2.
For the synthesis, cherylline dimethylether (1b) guiacol was methylated and
acetylated to give 1-(3,4-dimethoxy-phenyl)-ethanone 7 (R2 ¼ Me). This ketone
was converted to 1-(3,4-dimethoxy-phenyl)-2-dimethylamino-ethanone 9 (R2 ¼ Me)
via bromination followed by aqueous dimethyl amine reaction. The base of 9 was
reduced with NaBH4 to give 1-(3,4-dimethoxy-phenyl)-2-dimethylamino-ethanol
10 (R2 ¼ Me). Compound 10 was reacted with fluorobenzene in the presence of
KOH to give [2-(3,4-dimethoxy-phenyl)-2-phenoxy-ethyl]-dimethyl-amine 11 (R2 ¼
Me). The compound 11 was reacted with ethylchloroformate, followed by BF3 ꢁ OEt2
rearrangement to give 4-(3, 4-dimethoxy-phenyl)-4-(4-hydroxy-phenyl)-2-methyl-
butyric acid ethyl ester 13 (R1 ¼ H, R2 ¼ Me). Compound 13, a phenol derivative,
was methylated with dimethylsulfate to give [2-(3,4-dimethoxy-phenyl)-2-(4-
methoxy-phenyl)-ethyl]-methyl-carbamic acid ethyl ester 14 (R1 ¼ R2 ¼ Me), which
on hydrolysis gave [2-(3,4-dimethoxy-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-
amine 15. On Pictet–Spengler reaction this gave 1b (R1 ¼ Me, R2 ¼ Me) in good
overall yields. Dimethyl cherylline was characterized by spectral means and in
concordance with the reported data.
For the synthesis of cherylline monomethyl ether, [2-(3,4-dimethoxy-phenyl)-2-
phenoxy-ethyl]-methyl-carbamic acid ethyl ester 12 was hydrolyzed to give [2-(3,4-
dimethoxy-phenyl)-2-phenoxy-ethyl]-methyl-amine 16, which on Pictet–Spengler
Figure 2. Retrosynthetic analysis of cheryllines: 1, R1 ¼ R2 ¼ H, cherylline; 1a, R2 ¼ H, R1 ¼ Me, cheryl-
line monomethyl ether; and 1b, R1 ¼ R2 ¼ Me, cherylline dimethyl ether.

2234
U. R. PAILLA ET AL.
reaction gave [2-(3,4-dimethoxy-phenyl)-2-phenoxy-ethyl]-methyl-amine 17. This
tetrahydro isoquinolinyl ether derivative 17 was reacted with BF3 ꢁ OEt2 to give cher-
ylline monomethyl ether (1a) in good yields. The sequence of reactions performed is
given in Scheme 1.
Cherylline is prepared in a slightly different way. Guiacol was chloroacetylated
followed by benzylation to give 1-(4-benzyloxy-3-methoxy-phenyl)-2-chloro-
ethanone 19. The compound 19 was converted to 1-(4-benzyloxy-3-methoxy-
phenyl)-2-dimethylamino-ethanol 21, by routine chemical transformations.
Compound 21 was converted to ether [2-(4-benzyloxy-3-methoxy-phenyl)-2-
phenoxy-ethyl] dimethyl-amine 22, which was reacted with ethyl chloroformate
and rearranged to give compound 4-f1-(4-benzyloxy-3-methoxy-phenyl)-2-
[(1-ethoxy-vinyl)-methyl-amino]-ethylg-phenol 24. Compound 24 was protected by
Scheme 1. Synthesis of cherylline monomethyl ether (1a) and dimethyl ether (1b): (a) DMS, 55 ꢂC; (b)
AlCl3, CH3COCl, rt; (c) Br2, CHCl3, rt; (d) aqueous DMA, EtOH, 0–5 ꢂC; (e) NaBH4, MeOH, rt; (f)
F-benzene, KOH, DMSO, 125 ꢂC; (g) ethyl chloroformate, toluene, NaHCO3, 125 ꢂC; (h) BF3 ꢁ OEt2,
EtOAc, (i) DMS, K2CO3, acetone; (j) NaOH, DMSO; and (k) HCHO, AcOH, 90 ꢂC.

NEW SYNTHESIS OF (ꢀ)-CHERYLLINE
2235
Scheme 2. Synthesis of cherylline: (a) AlCl3, ClCH2COCl, DCM, 0–5 ꢂC; (b) PhCH2Br, K2CO3, acetone,
45 ꢂC; (c) aqueous DMA, EtOH, 0–5 ꢂC; (d) NaBH4, MeOH, rt; (e) F-benzene, KOH, DMSO, 125 ꢂC;
(f) ethyl chloroformate, NaHCO3, toluene, 120 ꢂC; (g) BF3.OEt2, EtOAc, rt; (h) PhCH2Br, K2CO3,
acetone, 45 ꢂC; (i) NaOH, DMSO, 125 ꢂC; and (j) HCHO, AcOH, 90 ꢂC.
benzylation, was hydrolyzed, and on Pictet–Spengler cyclization gave 7-benzyloxy-4-
(4-benzyloxy-phenyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 27 in good
yields.
Compound 27 is a known dibenzyl cherylline.[3g] It was identified by spectral
comparison. The sequence of reactions are given in Scheme 2.
The dibenzyl cherylline is converted to cherylline by a known methodology.[3g]
In conclusion we have developed a new methodology based on ether rearrange-
ment for the synthesis of cherylline derivatives.
EXPERIMENTAL
Materials and Instruments
Most of the reagents used in this work were obtained from commercial suppliers
and were of laboratory reagent or analytical reagent grade. Solvents were purified

2236
U. R. PAILLA ET AL.
before use by standard procedures. Melting points were determined using open
capillary tubes on a Polmon melting-point apparatus (model 96) and are uncorrected.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded by using a Bruker 400
spectrometer with tetramethylsilane (TMS) as internal standard. Infrared (IR)
spectra were recorded on a Perkin-Elmer Spectrum 100 FTIR spectrophotometer
as KBr pellets or with the neat products. Mass spectra were recorded on an API
2000 liquid chromatograph=mass spectrometer, Applied BioSystems MDS Sciex
spectrometer. Microanalysis was performed on a Perkin-Elmer 240CHN elemental
analyzer. Analytical thin-layer chromatography (TLC) was conducted on E-Merck
60F254 aluminum-packed plates of silica gel (0.2 mm). Developed plates were visua-
lized by using ultraviolet (UV) light or in an iodine chamber. High-performance liquid
chromatography (HPLC) was performed by using a Shimadzu 2010 instrument.
General Procedure for the Synthesis of 4-(3,4-Dimethoxy-phenyl)-
4-(4-hydroxy-phenyl)-2-methyl-butyric Acid Ethyl Ester (13) (R1 ¼ H)
BF3 ꢁ OEt2 (47%) (10 g, 0.032 mol) was added over 15 min to a solution of
4-(3,4-dimethoxy-phenyl)-2-methyl-4-phenoxy-butyric acid ethyl ester (12) (10 g,
0.027 mol) and ethyl acetate (100 mL) at 0–5 ꢂC. The reaction mixture was stirred
at room temperature for 3 h. After completion of the reaction by TLC, the mixture
was poured into demineralized (DM) water (100 ml), and the aqueous layer was
extracted with ethyl acetate (2 ꢃ 50 mL). The combined organic extracts were washed
with water (2 ꢃ 50 mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure to get 11 g of crude product. Purification of crude product by
column chromatography on silica gel with 10% ethyl acetate in hexane gave 6.0 g
colorless liquid (60%) (13); IR (KBr, cmꢄ1): 3250,1620, 1240; mass for C20H25NO5
[M þ 1], found 360.3; 1H NMR (400 MHz, CDCl3) (d ppm): 1.25 (3H, s, -CH2-
CH3), 2.49 (3H, s, N-CH3), 3.77 (8H, m, OCH3 and, CH-CH2-N), 3.9 (2H, q,
O-CH2-CH3), 4.15 (1H, t, J ¼ 8.0 Hz, Ar-CH-Ar), 6.66 (2H, d, J ¼ 7.72 Hz, Ar),
6.77 (1H, d, J ¼ 8.16 Hz, Ar), 6.89 (2H, dd, J1 ¼ 8.7 Hz, J2 ¼ 8.6 Hz, Ar), 7.08 (2H,
d, J ¼ 8.32 Hz, Ar), 9.16 (1H, s, OH-Ar); 13C NMR (100 MHz, CDCl3) (d ppm);
13.7, 41.0, 56.0, 56.3, 57.2, 60.4, 114.6, 114.0, 115.6, 121.7, 129.4, 135.3, 136.3,
145.0, 148.1, 156.0, 159.5. Anal. calcd for C20H25NO5: C, 66.83; H, 7.01; N, 3.90.
Found: C, 66.79; H, 6.98; N, 3.88.
General Procedure for the Synthesis of 4-(6,7-Dimethoxy-2-methyl-
1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol (1a)
BF3 ꢁ OEt2 (47%) (15 g, 0.052 mol) was added over 15 min to a solution of
[2-(3,4-dimethoxy-phenyl)-2-phenoxy-ethyl]-methyl-amine (17) (10 g, 0.027 mol) and
ethyl acetate (100 mL) at 0–5 ꢂC. The reaction mixture was allowed to warm to room
temperature and stirred for 2 h. After completion of the reaction by TLC, the reac-
tion mixture was poured into DM water (100 ml) and the solution was extracted with
ethyl acetate (2 ꢃ 50 mL). The combined organic layer was dried over sodium sulfate,
filtered, and concentrated under reduced pressure to obtain 11 g of crude product.
Purification of crude product was achieved on column chromatography using 10%
ethyl acetate in hexane to get 6.0 g (60%) as a white solid (1a), mp 203.9–205.9 ꢂC;

NEW SYNTHESIS OF (ꢀ)-CHERYLLINE
2237
IR (KBr, cmꢄ1): 3435, 2788, 1509, 1258; mass for C18H21NO3 [M þ 1] 300.2; 1H NMR
(400 MHz, DMSO) (d ppm): 2.25 (3H, s, -N-CH3), 2.42 (1H, m, CH-CH2-N), 2.78 (1H,
m, CH-CH2-N), 3.32 (2H, s,(br), Ar-CH2-N), 3.45 (3H, s, OCH3), 3.49 (3H, s, OCH3),
3.98 (1H, t, J ¼ 6.0 Hz Ar-CH-Ar), 6.27 (1H, s, Ar), 6.62 (1H, s, Ar), 6.65 (2H, d,
J ¼ 4.45 Hz, Ar), 6.95 (2H, d, J ¼ 8.36 Hz, Ar), 9.17 (1H, s, Ar-OH);13C NMR
(100 MHz, DMSO) (d ppm): 44.06, 45.97, 55.72, 55.76, 57.85, 61.80, 109.70, 112.48,
115.21, 127.64, 129.44, 129.88, 135.89, 147.45,147.50, 155.98.
General Procedure for the Synthesis of 4-f1-(4-Benzyloxy-3-
methoxy-phenyl)-2-[(1-ethoxy-vinyl)-methyl-amino]-ethylg-
phenol (24)
BF3 ꢁ OEt2 (47%) (15 g, 0.051 mol) was added over 25 min to a stirred solution
of [2-(4-benzyloxy-3-methoxy-phenyl)-2-phenoxy-ethyl]-methyl-carbamic acid ethyl
ester (23) (15 g, 0.0344 mol) and ethyl acetate (150 mL) at 0–5 ꢂC. The reaction
mixture was allowed to room temperature and stirred for 2 h. After completion of
the reaction by TLC, the reaction mixture was poured into DM water (100 ml)
and the solution was extracted with ethyl acetate (2 ꢃ 100 mL). Combined organic
extracts were dried over sodium sulfate, filtered, and concentrated under reduced
pressure to get 15 g of crude product. Purification of crude product was achieved
by column chromatography using 10% ethyl acetate in hexane as an eluent gave
yellow color oil (5.5 g, 55%) (24); IR (KBr, cmꢄ1): 3333, 3015, 1673, 1407; mass
1
for C26H29NO5 [M þ 1] 436.5; H NMR (400 MHz, DMSO) (d ppm): 1.11 (3H, s,
OCH2-CH3), 2.6 (3H, s, N-CH3), 3.38 (1H, s, CH-HCH-N), 3.73 (4H, m,
CH-HCH-N and OCH3), 4.02 (1H, t, J ¼ 7.6 Hz, Ar-CH-Ar), 5.04 (2H, s, CH2-Ph),
6.69 (2H, d, J ¼ 7.64 Hz, Ar), 6.76 (1H, d, J ¼ 8.0 Hz, Ar), 6.88 (1H, s, Ar), 6.93 (1H,
d, J ¼ 7.6 Hz, Ar), 7.10 (2H, d, J ¼ 8.32 Hz, Ar), 7.28–7.42 (5H, m, Ar), 9.23 (1H, s,
Ar-OH); 13C NMR (100 MHz, DMSO) (d ppm): 13.3, 34.7, 41.0, 56.3, 57.2, 60.4,
78.2, 115.6, 116.2, 121.7, 127.3, 127.4, 128.7, 129.8, 135.6, 136.3, 140.9, 145.1,
148.1, 154.8, 156.2. Anal. calcd. for C26H29NO5: C, 71.70; H, 6.71; N, 3.32. Found:
C, 71.68; H, 6.69; N, 3.28.
ACKNOWLEDGMENT
We thank Suven Life Sciences for the excellent analytical facilities and allowing
us to publish these results.
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
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