Synthesis of 4-aryltetrahydroisoquinolines: Application to the synthesis of cherylline

Article abstract of DOI:10.3987/COM-01-9167

A concise route for the synthesis of 4-aryltetrahydroisoquinolines was developed using the addition of Grignard reagents to nitrostyrene derivatives as the key step. The application to the synthesis of cherylline was described.

Full text of DOI:10.3987/COM-01-9167

HETEROCYCLES, Vol. 55, No. 4, 2001, pp. 635 - 640, Received, 29th January, 2001
SYNTHESIS OF 4-ARYLTETRAHYDROISOQUINOLINES:
APPLICATION TO THE SYNTHESIS OF CHERYLLINE
Somsak Ruchirawat 1-3*, Sopchok Tontoolarug2, and Poolsak Sahakitpichan1
1Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210.
Thailand
2Department of Chemistry, Mahidol University, Rama 6 Road, Bangkok 10400,
Thailand
3Programme on Research and Development of Synthetic Drugs, Institute of
Science and Technology for Research and Development, Mahidol University,
Salaya Campus, Thailand
Abstract- A concise route for the synthesis of 4-aryltetrahydroisoquinolines was
developed using the addition of Grignard reagents to nitrostyrene derivatives as
the key step. The application to the synthesis of cherylline was described.
Cherylline has been isolated from Crinum powellii var. alba and other Crinum species.1 It is a
representative of the very rare natural 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloids. Due to the
uniqueness of the structure and potential medicinal properties of the 4-arylisoquinoline derivatives,2 many
synthetic routes for these compounds3 and especially cherylline (1)4 have been reported. In the course of
our synthetic work on alkaloids, we have successfully developed a new approach for the synthesis of
cherylline.
OH
CH3O
HO
N
CH3
Cherylline 1
The key step of our approach involved conjugate addition of the Grignard reagents to the appropriate
nitrostyrene derivative. Nitroalkene chemistry5 has been exploited for various synthetic operations,
particularly the potential usefulness of the conjugate addition of various organometallic reagents to the
nitroalkenes as a means of forming carbon-carbon bonds, which may be followed by further

transformation of the derived nitroalkane products to various nitrogen heterocycles.6 Recent application
of the nitroalkene chemistry has been extended to the asymmetric synthesis7 of various compounds as
well as the solid phase synthesis.8 The strategy of our approach is illustrated for the synthesis of (±)-
dimethylcherylline and cherylline as shown (Scheme 1).
OR
OR
CH3O
RO
CH3O
RO
NO2
/ THF
MgBr
NO2
-15°C→rt
2 a,b
3 a,b
LiAlH4 / ether, rt
OR
OR
HCHO
HCOOH, ∆
CH3O
RO
CH3O
RO
N
NH2
a,b
CH3
a,b
5
4
Series a R = CH3
Series b R = Bn
Scheme 1
We have found that by control of the exothermic reaction, 1,4-addition of Grignard reagent to nitrostyrene
occurs smoothly at below room temperature in satisfactory yield. The Grignard reagent was prepared by
addition of a solution of 4-bromoanisole in dry tetrahydrofuran to a stirred suspension of magnesium
turning in dry tetrahydrofuran while maintaining a gentle reflux under nitrogen atmosphere. A solution of
3,4-dimethoxynitrostyrene in dry tetrahydrofuran was then added dropwise to the Grignard reagent which
was maintained at –15 °C. The product (3a) was obtained in 69% yield after purification by column
chromatography on silica gel. The nitro compound so obtained could be conveniently reduced by lithium
aluminium hydride in ether at room temperature to give the amine (4a) in 75% yield. The amine was
purified by preparative layer chromatography on silica gel and could be further purified by
recrystallization of the derived oxalate salt. Treatment of the amine derivative with 37% formaldehyde

and formic acid at 100 °C for 3 h gave directly (±)-O,O-dimethylcherylline (5a) in 93% yield according
to our previous finding that formaldehyde and formic acid promoted the cyclization and N-methylation of
activated phenylethylamine in a "one pot" reaction.9
The successful preparation of (±)-O,O-dimethylcherylline prompted us to further investigate the
generality of this method for the preparation of (±)-cherylline. Reaction of nitrostyrene (2b) with the
Grignard reagent generated from 4-bromo-O-benzylphenol furnished nitro compound (3b) in 74% yield.
Reduction of the addition product (3b) with LAH gave amine (4b) in 70% yield. The reaction of the
amine with formaldehyde and formic acid gave the expected isoquinoline compound (5b) in 89% yield.
The final step was accomplished by hydrogenolytic removal of the benzyl protecting groups of (±)-O,O-
dibenzylcherylline in ethyl acetate-ethanol (1:1 by volume) containing 10 % palladium on charcoal at 1
atm. The reaction proceeded in 94 % yield to give(±)-cherylline (1). All the spectral data of the synthetic
(±)-cherylline exhibited good correlation with those of (±)-cherylline reported in the literature.4d All new
compounds exhibit satisfactory analytical and spectroscopic data.10
In conclusion, we have developed an efficient synthesis of (±)-O,O-dimethylcherylline (5a) and (±)-
cherylline (1) from readily available starting materials and the reactions involved are operationally simple
which we view as a very attractive process. The key step employed in the synthesis, i.e., the addition of
Grignard reagents to the nitrostyrenes works well under the employed conditions. The application of this
approach to the synthesis of other alkaloids is under further investigation.
ACKNOWLEDGEMENTS
We are grateful to the generous financial support of the Thailand Research Fund (TRF). We also
acknowledge the facilities provided by the PERCH programme.
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10. All compounds have been fully characterized : Compound (3a), oil, IR (neat) 1605, 1590, 1545,
1510, 1460, 1375, 1250, 1140, 1025 cm-1. NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 3.83 (s, 3H), 3.84
(s, 3H), 4.80 (br t, 2H), 4.915 (d, 1H, J = 7.2 Hz), 4.918 (d, 1H, J = 9.4 Hz), 6.70 (d, 1H, J = 2.0 Hz),
6.77 (dd, 1H, J = 8.0, 2.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.86, 7.15 (AA′BB′, 2H each, J = 8.7 Hz).
13C (100 MHz) δ 47.83, 55.22, 55.86, 79.61, 111.14, 111.34, 114.33, 119.27, 128.58, 131.35, 131.92,
148.35, 149.23, 158.86. MS 317(M+, 55.43), 271(22.44), 270(100), 257(53.92), 239(15.35). Anal.
Calcd for C17H19NO5 : C, 64.34; H, 6.03; N, 4.41. Found : C, 64.21; H, 6.17; N, 4.29. Compound
(3b), oil, IR (neat) 1600, 1580, 1545, 1510, 1500, 1450, 1375, 1235, 1140, 1020 cm-1. NMR (400
MHz, CDCl3) δ 3.83 (s, 3H), 4.78 (br t, 1H), 4.888 (d, 1H, J = 7.5 Hz), 4.890 (d, 1H, J = 8.7 Hz),
5.02 (s, 2H), 5.11 (s, 2H), 6.69 (dd, 1H, J = 8.0, 2.0 Hz), 6.72 (d, 1H, J = 2.0 Hz), 6.82 (d, 1H, J = 8.0
Hz), 6.92, 7.13 (AA′BB′, 2H each, J = 8.7 Hz), 7.26-7.43 (m, 10H). 13C (100 MHz) δ 47.86, 56.03,
70.02, 70.99, 79.57, 111.72, 114.02, 115.24, 119.30, 127.21, 127.45, 127.86, 128.02, 128.54, 128.59,
128.65, 131.58, 132.41,136.76, 136.98, 147.57, 149.86, 158.10. MS 469(M+, 5.90), 422(2.20),
331(6.13), 92(8.67), 91(100). Anal. Calcd for C29H27NO5 : C, 74.18; H, 5.80; N, 2.98. Found : C,
74.01; H, 6.10; N, 2.65. Compound (4a), m.p. (oxalate salt, MeOH-ether) 108-109 °C. IR (KBr)
2930(br), 1610, 1590, 1515, 1250, 1150, 1025 cm-1. NMR (400 MHz, CDCl3) δ 1.56 (br s, 2H), 3.27
(br s, 2H), 3.77 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 3.88 (t, 2H, J = 7.5 Hz), 6.73 (d, 1H, J = 1.6 Hz),
6.79 (dd, 1H, J = 8.0, 1.7 Hz), 6.82 (d, 1H, J = 8.3 Hz), 6.85, 7.16 (AA′BB′, 2H each, J = 8.7 Hz).
13C (100 MHz) δ 7.16, 53.77, 55.19, 55.81, 55.84, 111.24, 111.53, 113.97, 119.67, 128.84, 135.01,
135.59, 147.59, 148.99, 158.14. MS 287(M+, 4.49), 258(26.96), 257(100). Anal. Calcd for
.
C19H23NO7 1/2 H2O : C, 59.06; H, 6.26; N, 3.62. Found : C, 59.40; H, 6.18; N, 3.61. Compound (4b),
m.p. (oxalate salt, MeOH-ether) 114-116 °C. IR (KBr) 3050-2950(br), 1605, 1580, 1505, 1250, 1225,
1140, 1020 cm-1. NMR (400 MHz, CDCl3) δ 1.4 (br s, 2H), 3.23 (d, 2H, J = 7.7 Hz), 3.86 (t, 1H, J =
7.6 Hz), 3.84 (s, 3H), 5.03 (s, 2H), 5.12 (s, 2H), 6.72 (dd, 1H, J = 8.0, 2.0 Hz), 6.75 (d, 1H, J = 2.0
Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.92, 7.15 (AA′BB′, 2H each, J = 8.7 Hz), 7.26-7.44 (m, 10H). 13C (100
MHz) δ 7.26, 53.85, 55.99, 69.99, 71.16, 112.13, 114.03, 114.89, 119.72, 127.21, 127.44, 127.74,
127.91, 128.48, 128.54, 128.90, 135.29, 136.17, 137.28, 146.81, 149.63, 157.39. MS 439(M+, 1.47),
.
410(15.02), 409(38.12), 92(8.33), 91(100), 44(11.28). Anal. Calcd for C31H31NO7 1/2 H2O: C, 69.13;
H, 5.99; N, 2.60. Found : C, 68.73; H, 5.90; N, 2.82. Compound (5a), m.p. (ether-hexane) 97-99 °C
(lit.,4d 97-99 °C). IR (CHCl3) 1610, 1580, 1515, 1460, 1250, 1140, 1035 cm-1. NMR (400 MHz,
CDCl3) δ 2.41 (s, 3H), 2.48 (dd, 1H, J = 8.0, 11.4 Hz), 2.97 (ddd, 1H, J = 11.6, 5.5, 1.0 Hz), 3.54 (d,
1H, J = 14.3 Hz), 3.66 (d, 1H, J = 14.3 Hz), 3.64 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H), 4.16 (br t, 1H),

6.35 (s, 1H), 6.56 (s, 1H), 6.83, 7.10 (AA′BB′, 2H each, J = 8.7 Hz). 13C (100 MHz) δ 44.64, 45.86,
55.14, 55.78, 58.07, 62.10, 108.70, 111.89, 113.65, 127.27, 129.15, 129.81, 136.82, 147.40, 147.49,
158.11. MS 313(M+, 35.43), 270(52.86), 269(20.66), 240(19.76), 239(100), 135(11.42). Compound
(5b), m.p. (ethyl acetate) 141-142 °C(lit.,4c,4g 144-145 °C). IR (CHCl3) 1610, 1580, 1505, 1255, 1240,
1140 cm-1. NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.47 (dd, 1H, J = 11.0, 8.0 Hz), 2.96 (dd, 1H, J =
11.0, 5.0 Hz), 3.48 (d, 1H, J = 14.5 Hz), 3.59 (d, 1H, J = 14.5 Hz), 3.65 (s, 3H), 4.15 (dd, 1H, J = 8, 6
Hz), 5.04 (s, 2H), 5.11 (s, 2H), 6.37 (s, 1H), 6.58 (s, 1H), 6.91, 7.10 (AA′BB′, J = 8.7 Hz), 7.27-7.46
(m, 10H). 13C (100 MHz) δ 44.69, 45.84, 55.99, 57.99, 62.04, 70.01, 71.06, 111.58, 112.59, 114.64,
127.27, 127.50, 127.74, 127.91, 128.48, 128.53, 129.82, 129.90, 137.12, 137.25, 146.66, 148.23,
157.42. MS 465(M+, 7.28), 422(10.06), 331(15.52), 91(100).