Convenient synthesis of amaryllidaceae alkaloid, (+/-) latifine dimethyl ether

Article abstract of DOI:10.3184/030823409X12523442871697

A short route for the synthesis of (+/-) latifine dimethyl ether is reported. The key steps involved are Grignard reaction, conversion of alcohol to nitrile using trimethylsilyl cyanide, reduction of the nitrile intermediate followed by Pictet-Spengler cy

Full text of DOI:10.3184/030823409X12523442871697

JOURNAL OF CHEMICAL RESEARCH 2009
OCTOBER, 635–637
RESEARCH PAPER 635
Convenient synthesis of amaryllidaceae alkaloid, (+/–) latifine
dimethyl ether
A.Sanjeev Kumara, Samir Ghosha, Kale Bhimaa and G.N.Mehtab*
aChemical Research and Development Department, Pfizer Ltd, Mumbai-400705, India
bApplied Chemistry Department, S. V. National Institute of Technology, Surat-395 007, India
A short route for the synthesis of (+/–) latifine dimethyl ether is reported. The key steps involved are Grignard reaction,
conversion of alcohol to nitrile using trimethylsilyl cyanide, reduction of the nitrile intermediate followed by Pictet–
Spengler cyclisation and reductive N-methylation in a single step to provide latifine dimethyl ether as a racemate.
Key words: Grignard reaction, reduction, tetrahydroisoquinolines, Pictet–Spengler cyclisation, reductive N-methylation
Latifine 1 and cherylline 2 are the two 4-aryltetrahydro-
isoquinoline alkaloids isolated from Amaryllidaceae plants.1,2
Latifine 2, an isoquinoline alkaloid, has been isolated from
Crinum latifolium L. and is reported to be a possible anabolic
or catabolic metabolite of O, N-dimethylnorbelladine.
Latifine has two novel features (i) it has a 4-aryl group in an
isoquinoline system and (ii) it is oxygenated at the less usual
5,6-positions. Because of these features, synthesis by the usual
methods is difficult.
Apart from the natural existence, 4-aryltetrahydro-
isoquinolines 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). There are several
reports9-34 on the syntheses of (+/–) latifine and (+/–) cherylline
which include some efficient chiral syntheses. We report here
an alternative synthesis of (+/–) latifine dimethyl ether.
thionyl chloride and trimethylsilyl cyanide (TMSCN) in
60% yield. Reduction of the nitrile group with LAH in THF
at reflux temperature gave 2-(2,3-dimethoxyphenyl)-2-(4-
methoxyphenyl) ethanamine 6 in 27% yield. Reaction with
formaldehyde and formic acid for 18 hours at reflux leads
to Pictet-Spengler reaction then reductive N-methylation
reaction in a single step provides (+/–) latifine dimethyl ether
5 in 58% yield (Scheme 2).
To obtain the optimised reaction conditions for cyanation,
we chose the reaction of dibenzylic alcohol with various
readily available cyanides. The effect of various cyanides
on reaction times and yields were examined. The results are
summarised in Table 1. As the data in Table 1 demonstrate,
a higher yield of the nitrile and short time were obtained with
trimethylsilyl cyanide (TMSCN) in comparison with other
cyanides.
We have devised a short and efficient method for the
synthesis of (+/–) latifine dimethyl ether. The simple nature of
tetrahydroisoquinoline synthesis should allow the construction
of a wide variety of interesting and useful analogous molecules.
Results and discussion
The retrosynthetic analysis of (+/–) latifine dimethyl ether 5 is
depicted in Scheme 1.
2,3-Dimethoxy benzaldehyde was subjected to Grignard
reaction with p-methoxyphenyl magnesium bromide to obtain
Experimental
All solvents and reagents were purchased from Aldrich suppliers and
used without further purification. All non-aqueous reactions were
performed in dry glassware under an atmosphere of dry nitrogen.
Organic solutions were concentrated under reduced pressure.
(2,3-dimethoxyphenyl)(4-methoxyphenyl) methanol
8 in
85% yield. The obtained alcohol was converted to 2-(2,3-
dimethoxyphenyl)-2-(4-methoxyphenyl)acetonitrile 7 using
Cl
Cl
OH
OH
OH
O
O
N
N
N
N
O
HO
NH2
4
2
3
1
Fig. 1
O
O
O
O
O
O
O
O
O
O
O
O
CN
OH
N
NH2
5
6
7
8
Scheme 1
* Correspondent. E-mail: drgnmehta@rediffmail.com

636 JOURNAL OF CHEMICAL RESEARCH 2009
O
O
O
O
O
CHO
O
a
b
c
O
O
Cl
OH
O
9
8
10
O
O
O
O
O
e
O
d
O
O
CN
NH2
N
6
7
5
Scheme 2 (a) 4-Bromoanisole, Mg, THF, 0-5 oC, 5 h, 85%; (b) SOCl2, CH2Cl2, 25 oC, 10 h, 100%; (c) trimethylsilycyanide, TiCl4,
CH2Cl2, 25–30 oC, 24 h, 60%; (d) LAH, THF, 70 oC, 24 h, 27%; (e) formaldehyde, formic acid, 90 oC, 18 h, 58%.
Table 1 Effect of various cyanides on conversion of dibenzylic alcohols into dibenzylic nitriles
Entry
Reagent
Catalyst
Solvent
Time/h
Yield/%
1
2
AgCN
AgCN
CuCN
KCN
–
MeCN
24
6
16
15
6
10
10
24
10
24
24
–
18-crown-6
–
DMF
12
10
12
16
–
3
EtOH/H2O
EtOH/H2O
EtOH/H2O
MeCN
4
–
5
KCN
18-crown-6
18-crown-6
18-crown-6
–
6
KCN
KCN
NaCN
NaCN
TMSCN
TMSCN
7
DMF
16
10
16
55
60
8
EtOH/H2O
EtOH/H2O
CH2Cl2
9
18-crown-6
SnCl4
TiCl4
10
11
CH2Cl2
Thin layer chromatography was performed on Merck precoated
and water (30 mL) and diluted with CH2Cl2 (30 mL). The separated
organic layer was washed with saturated aqueous sodium bicarbonate
(30 mL) and water (30 mL), dried over magnesium sulfate, filtered
and evaporated under vacuum to get the crude product. 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 calculated for C17H17NO3–284.1208 [M + 1], found –284.1231;
1H NMR (400 MHz, CDCl3) (d ppm): 3.76 (3H, s, –OCH3), 3.77 (3H,
s, –OCH3), 3.78 (3H, s, –OCH3), 5.47 (1H, s, Ar-CH-Ar), 6.83–7.03
(5H, m, ArH), 7.25 (2H, d, J = 8.8 Hz, ArH); 13C NMR (400 MHz,
CDCl3) (d ppm); 35.9, 55.2, 55.7, 60.6, 112.6, 114.2, 120.2, 120.3,
124.3, 127.8, 1278.7, 130.1, 146.1, 152.7, 159.2.
1
Silica-gel 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. Melting points were
obtained by using the open capillary method and are uncorrected.
(2,3-Dimethoxyphenyl)(4-methoxyphenyl)methanol (8): p-Methoxy-
phenyl magnesium bromide was prepared in the usual manner from
magnesium, (3.0 g, 0.13 mol) and 4-bromoanisole (20.0 g, 0.11 mol)
in tetrahydrafuran (100 mL). To this solution was added a solution of
2,3-dimethoxybenzaldehyde 9 (12.0 g, 0.07 mol) in THF (35 mL) at
0–5 oC, this solution was stirred at 25 oC for 5 hours. After completion
of the reaction, the reaction mixture was cooled to 0–5 oC and to this
was added saturated ammonium chloride solution (50 mL) and ethyl
acetate (100 mL). The separated organic layer was washed twice
with water (50.0 mL). The separated organic layer was dried over
sodium sulfate, filtered and evaporated under vacuum. The residue
was chromatographed on silica gel eluting with hexane/ethyl acetate
80:20 to get the title compound 8 as an oil (16.9 g, 85%); HRMS
m/z calculated for C16H18O4 –275.1205 [M + 1], found –275.1212;
1H NMR (400 MHz, DMSO-d6) (d ppm): 3.52 (3H, s, –OCH3), 3.65
(3H, s, –OCH3), 3.72 (3H, s, –OCH3), 5.85 (1H, d, J = 4.4 Hz, Ar-
CH-Ar), 6.78–7.01 (5H, m, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH);
13C NMR (400 MHz, CDCl3) (d ppm); 55.3, 55.8, 60.2, 68.6, 111.6,
113.6, 119.0, 124.1, 128.1, 138.1, 139.7, 145.6, 152.5, 158.5.
2-(2,3-Dimethoxyphenyl)-2-(4-methoxyphenyl) ethanamine (6):
To a slurry of lithium aluminuim hydride (0.72 g, 0.02 mol) in THF
o
(20 mL) at 0 C, was added a solution of 2-(2,3-dimethoxyphenyl)-
2-(4-methoxyphenyl)acetonitrile 7 (1.8 g, 0.01 mol) in THF (20 mL).
After refluxing for 24 h, the reaction was cooled to 0–5 oC 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 0.49 g (27%); HRMS
m/z calculated for C17H21NO3–288.1521 [M + 1], found –288.1522;
1H NMR (400 MHz, DMSO-d6) (d ppm): 3.03 (2H, d, J = 7.8 Hz,
–CH2–NH2), 3.54 (3H, s, –OCH3), 3.66 (3H, s, –OCH3), 3.72 (3H, s,
–OCH3), 4.21 (1H, t, J = 7.8 Hz, CH–CH2), 6.78–6.98 (5H, m, ArH),
7.13 (2H, d, J = 8.0 Hz ArH); 13C NMR (400 MHz, DMSO-d6) (d
ppm); 47.2, 46.8, 55.3, 55.9, 60.4, 111.0, 114.0, 119.6, 124.2, 129.4,
135.9, 137.5, 147.0, 152.9, 157.9.
2-(2,3-Dimethoxyphenyl)-2-(4-methoxyphenyl)acetonitrile
(7).
To a mixture of (2,3-dimethoxyphenyl)(4-methoxyphenyl)methanol
8 (3.0 g, 0.01 mol) in CH2Cl2 (30 mL) at 25 oC, was added a
solution of thionyl chloride (2.6 g, 0.02 mol) in CH2Cl2 (20 mL).
The mixture was stirred for 10 h. The solvent was evaporated under
vacuum. To the obtained dibenzylic chloride 10 in CH2Cl2 (30 mL)
was added trimethylsilyl cyanide (2.73 mL, 0.021 mol) and titanium
tetrachloride (2.73 mL). After stirring under argon at 25 oC for
24 h, the reaction mixture was quenched with methanol (20 mL)
(+/–) Latifine 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
o
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 ethyl acetate (3 ¥ 25 mL), dried, filtered and concentrated to

JOURNAL OF CHEMICAL RESEARCH 2009 637
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obtain the crude product. Purification of the crude product by column
chromatography using 1% methanol in dichloromethane as an eluent
gave 5 (0.94 g, 58%), as a solid, m.p. 86–88 oC (lit30 m.p. 86–88 oC);
HRMS m/z calculated for C19H23NO3 314.1756 [M + 1], found –
314.1758; 1H NMR (400 MHz, CDCl3) (d ppm): 2.32 (3H, s, NCH3),
2.70 (2H, d, J = 4.4 Hz, CH–CH2–N), 3.20 (3H, s, OCH3), 3.75 (3H,
s, OCH3), 3.79 (3H, s, OCH3), 3.34 and 3.80 (each 1H, d, J = 14.4 Hz,
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Received 16 August 2009; accepted 4 September 2009
Paper 09/0743 doi: 10.3184/030823409X12523442871697
Published online: 9 October 2009
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