An efficient synthesis of (+/-) cherylline dimethyl ether

Article abstract of DOI:10.3184/030823409X466744

A concise route for the synthesis of (+/-) cherylline dimethyl ether is reported. The key steps involved are Grignard reaction, conversion of alcohol to nitrile using (N-(p-toluene sulfonyl)imidazole and sodium cyanide), reduction of the nitrile intermedi

Full text of DOI:10.3184/030823409X466744

482 RESEARCH PAPER
AUGUST, 482–484
JOURNAL OF CHEMICAL RESEARCH 2009
An efficient synthesis of (+/-) cherylline dimethyl ether
A.Sanjeev Kumara, Samir Ghosha, Kale Bhimaa and G.N. Mehtab*
aChemical Research and Development Department, Pfizer Ltd, Mumbai-400705, India
bChemistry Section, Applied Sciences and Humanities Department, SVNIT, Surat-395 007, India
A concise route for the synthesis of (+/-) cherylline dimethyl ether is reported. The key steps involved are Grignard
reaction, conversion of alcohol to nitrile using (N-(p-toluene sulfonyl)imidazole and sodium cyanide), reduction
of the nitrile intermediate followed by Pictet–Spengler cyclisation and reductive N-methylation in a single step to
provide cherylline dimethyl ether as a racemate.
Keywords: Grignard reaction, reduction, tetrahydroisoquinolines, Pictet-Spengler cyclisation, reductive N-methylation
Synthetic studies on aryl-l,2,3,4-tetrahydroisoquinolines
have attracted much attention from the synthetic community
owing to the potential biological activities of this class of
compounds and their increasing medicinal interest, Among
these heterobicyclic compounds cherylline 1, a rare phenolic
4-phenyltetrahydroisoquinoline alkaloid and its dimethylether
5, whose structures are unique for Amaryllidaceae alkaloids
have long been fascinating targets for organic chemists as
witnessed by a number of articles dealing with biogenesis,
isolation, characterisation and synthesis. Cherylline 1 and
latifine 2 are the two 4-aryltetrahydroisoquinoline alkaloids
isolated from Amaryllidaceae plants.1-2 Apart from the
natural existence, 4-aryltetrahydroisoquinolines are of interest
due to various pharmacological activities.3,4 For example,
nomifensine5,6 3 and dichlofensine7,8 4 exhibit central nervous
system activity and inhibit serotonin and dopamine uptake
mechanisms (Fig. 1).
be constructed from amine 6 via a Pictet–Spengler ring
annulation which, in turn, could be obtained by reduction of
the corresponding nitrile intermediate 7. The required nitrile
intermediate would arise from the Grignard reaction of
p-methoxyphenyl magnesium bromide with 3, 4-dimethoxy-
benzaldehyde 8, followed by conversion of alcohol to nitrile
by N-(p-toluene sulfonyl) imidazole and sodium cyanide.
Veratraldehyde was subjected to Grignard reaction
with p-methoxyphenyl magnesium bromide to obtain
(3,4-dimethoxyphenyl)(4-methoxyphenyl)methanol
9
in
90% yield. The obtained alcohol was converted to 2-(3,4-
dimethoxyphenyl)-2-(4-methoxy phenyl) acetonitrile 7 using
(N-(p-toluene sulfonyl)imidazole and sodium cyanide) in
60% yield. Reduction of the nitrile group with LAH in THF
at reflux temperature gave 2-(3,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)ethanamine 6 in 90% yield. Reaction with
formaldehyde and formic acid for 18 hours at reflux leads
to Pictet–Spengler reaction with N-methylation reaction in a
single step and provides (+/-) cherylline dimethyl ether 5 in
60% yield (Scheme 2).
In short, we have devised a short and efficient method for
the synthesis of (+/-) cherylline dimethyl ether. The simple
nature of tetrahydroisoquinoline synthesis should allow
the construction of a wide variety of interesting and useful
analogous molecules.
There are several reports9-29 on the syntheses of (+/-)
cherylline and of (+/-) latifine which include some efficient
chiral syntheses. Most of the reported methods for the
synthesis of (+/-) cherylline are multistep. We report herein an
alternative synthesis of (+/-) cherylline dimethyl ether.
Results and discussion
Our retrosynthetic analysis of (+/-) cherylline dimethyl
ether 5 is depicted in Scheme 1. We anticipated that 5 could
Cl
Cl
OH
OH
OH
O
O
N
N
N
N
O
HO
NH2
4
1
2
3
Fig. 1
O
O
O
O
O
O
O
O
CN
N
NH2
O
5
7
6
Scheme 1
* Correspondent. E-mail: drgnmehta@rediffmail.com

JOURNAL OF CHEMICAL RESEARCH 2009 483
O
O
O
O
CHO
O
O
a
OH
O
b
CN
O
8
9
7
O
O
c
O
d
O
NH2
N
O
O
6
5
Scheme 2 (a) 4-bromoanisole, Mg, THF, 0–5ꢀ°C, 5.0 h, 80%; (b) N-(p-toluene sulfonyl) imidazole, NaCN, TEA, DMF, reflux, 12.0 h,
60.0%; (c) LAH, THF, 70ꢀ°C, 24.0 h, 90%; (d) formaldehyde, formic acid, 90ꢀ°C, 18.0 h, 60%.
2-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)ethanamine (6). To a
slurry of lithium aluminuim hydride (0.72 g, 0.019 mol) in THF
(20 mL) at 0°C, was added a solution of 2-(3,4-dimethoxyphenyl)-2-
Experimental
All solvents and reagents were purchased from Aldrich supplier and
used without further purification. All non-aqueous reactions were
(4-methoxyphenyl)acetonitrile 7 (1.8 g, 0.006 mol) in THF (20 mL).
After refluxing for 24 h, the reaction was cooled to 0–5°C and chilled
water was slowly added to it. The aluminium hydroxide formed was
filtered over celite and washed with chloroform. The filtrate also was
extracted with chloroform (3 ¥ 20 mL). All the organic extracts and
washings were combined, dried over sodium sulfate, filtered
and concentrated to obtain 6 as a brown residue 1.6 g (90.0%); HRMS
m/z calculated for C17H21NO3-288.1521 [M + 1], found – 288.1509;
1H NMR (400 MHz, CDCl3) (d ppm): 3.03 (2H, d, J = 7.8 Hz,
–CH–CH2–), 3.62 (3H, s, –OCH3), 3.63 (3H, s, –OCH3), 3.65 (3H, s,
–OCH3), 3.73 (1H, t, J = 7.8 Hz, CH–CH2), 6.69 (2H, d, J = 8.8 Hz,
ArH),6.76–6.78(2H,m,ArH),6.80(1H,s,ArH),7.11(2H,d,J=8.8Hz,
ArH); 13C NMR (400 MHz, CDCl3) (d ppm); 47.2, 53.7, 55.3,
55.8, 55.9, 112.2, 112.3, 114.1, 119.9, 129.1, 136.3, 136.8, 147.5,
149.0, 157.9.
(+/-) Cherylline dimethyl ether (5): A mixture of 6 (1.5 g, 0.005
mol), formaldehyde 37% solution in water (1.56 g, 0.052 mol) and
formic acid (6 mL) was stirred at 95°C under inert atmosphere for
18.0 h. After cooling to room temperature, the reaction mixture was
basified with 30% aqueous NaOH solution. This basified solution
was extracted with ethyl acetate (3 ¥ 25 mL); dried, filtered and
concentrated to obtain crude product (1.1 g.). Purification of the
crude product by column chromatography using 1% methanol in
dichloromethane as an eluent gave 5 (0.97 g, 60%), as a white solid,
m.p. 89–91°C (lit28 m.p. 90–92°C); and the solid was dissolved in
ethanol, acidified with ethanolic hydrogen chloride, and evaporated.
The resulting solid was recrystallised twice from methanol-ether to
give (0.8 g.) of 6.HC1: m.p. 226–228°C (lit20 m.p. 227–229°C);
HRMS m/z calculated for C19H23NO3 314.1677 [M + 1], found –
314.1651; 1H NMR (400 MHz, CDCl3) (d ppm): 2.41 (3H, s, NCH3),
2.44 (1H, dd, J = 11.8 Hz, CH–HCH–N), 2.98 (1H, dd, J = 11.8 Hz,
CH–HCH–N), 3.56 (2H, s (br), Ar-CH2-N), 3.65 (3H, s, OCH3), 3.80
(3H, s, OCH3), 3.86 (3H, s, OCH3), 4.12 (1H, t, J = 5.4 Hz, Ar-CH-
Ar), 6.34 (1H, s, ArH), 6.56 (1H, s, ArH), 6.84 (2H, d, J = 8.8 Hz,
ArH), 7.11 (2H, d, J = 8.8 Hz, ArH); 13C NMR (400 MHz, CDCl3) (d
ppm); 43.9, 45.9, 55.3, 55.81, 55.86, 57.7, 61.6, 109.7, 112.5, 113.9,
127.7, 129.2, 130.0, 137.7, 147.5, 147.6, 158.0.
performed in dry glassware under an atmosphere of dry nitrogen.
Organic solutions were concentrated under reduced pressure. Thin
layer chromatography was performed on Merck precoated silica-gel
1
60F254 plates. H and 13C NMR spectra were recorded in DMSO-d6
using 400 MHz, on a Varian Gemini 400 MHz FT NMR spectrometer.
The chemical shifts were reported in d ppm relative to TMS. The
mass spectra were recorded on Shimadzu LCMS-QP 800 LC-MS and
AB-4000 Q-trap LC-MS/MS. Elemental analyses were performed on
a Flash EA-1112 instrument. Melting points were obtained by using
the open capillary method and are uncorrected.
(3,4-Dimethoxyphenyl)(4-methoxyphenyl)methanol (9): p-Methoxy-
phenyl magnesium bromide was prepared in the usual manner from
magnesium, (3.0 g, 0.128 mol) and 4-bromoanisole (20.0 g, 0.106 mol)
in tetrahydrofuran (100 mL). To this solution was added a solution of
3, 4-dimethoxybenzaldehyde 8 (12.0 g, 0.072 mol) in tetrahydrofuran
(35 mL) at 0–5°C, this solution was stirred at room temperature
for 5 hours. After completion of the reaction, the reaction mixture
was cooled to 0–5°C and to this was added (50 mL) of saturated
ammonium chloride solution and ethyl acetate (100 mL). The
separated organic layer was washed twice with water (50 mL).
The separated organic layer was dried over sodium sulfate and
evaporated under vacuum. The residue was chromatographed on
silica gel eluting with hexane:ethyl acetate 80:20 to get the title
compound 9 as an oil (17.9 g, 90%); HRMS m/z calculated for
C16H18O4 –275.1205 [M + 1], found –275.1212; 1H NMR (400 MHz,
CDCl3) (d ppm): 2.22 (1H, d, J = 3.2 Hz, –OH), 3.79 (3H, s, –OCH3),
3.84 (3H, s, –OCH3), 3.85 (3H, s, –OCH3), 5.75 (1H, d, J = 3.2 Hz,
Ar-CH-Ar), 6.82–6.91 (5H, m, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH);
13C NMR (400 MHz, CDCl3) (d ppm); 55.2, 55.8, 55.9, 75.5, 109.6,
110.8, 113.8, 118.7, 127.7, 136.2, 136.7, 148.3, 148.9, 158.9.
2-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)acetonitrile
(7):
A mixture of (3,4-dimethoxyphenyl)(4-methoxyphenyl)methanol
9 (3.0 g, 0.01 mol), N-(p-toluene sulfonyl)imidazole (3.6 g, 0.016
mol), triethylamine (2.2 g, 0.02 mol), NaCN (1.0 g, 0.02 mol) and
a catalytic amount of tetrabutylammonium bromide (0.1 g) in DMF
(30 mL). was refluxed for 12.0 h. Reflux was continued until TLC
monitoring indicated no further improvement in the conversion. The
solvent was evaporated under vacuum and the remaining foam was
dissolved in dichloromethane (50 mL) and subsequently washed
with water (2 ¥ 50 mL). The separated organic layer was dried over
sodium sulfate and evaporated under vacuum. The residue was
chromatographed on silica gel eluting with hexane:ethyl acetate
80:20 to get the title compound 7 as an oil (1.85 g, 60%); HRMS m/z
We are grateful to IICT (Hyderabad), Pfizer Ltd and SVNIT,
Surat, India.
1
calculated for C17H17NO3-284.1208 [M + 1], found –284.1231; H
NMR (400 MHz, CDCl3) (d ppm): 3.80 (3H, s, –OCH3), 3.84 (3H,
s, –OCH3), 3.86 (3H, s, –OCH3), 5.04 (1H, s, Ar-CH-Ar), 6.79–6.90
(5H, m, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH); 13C NMR (400 MHz,
CDCl3) (d ppm); 41.3, 55.4, 55.8, 55.9, 110.6, 111.3, 114.4, 120.0,
128.0, 128.7, 136.2, 136.5, 148.9, 149.4, 159.3.
Received 12 May 2009; accepted 12 June 2009
Paper09/0582 doi: 10.3184/030823409X466744
Published online: 10 August 2009

484 JOURNAL OF CHEMICAL RESEARCH 2009
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