A convenient synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines by combined Strecker/Bruylants reaction

Article abstract of DOI:10.1007/s00706-004-0204-8

Strecker reaction of iodophenethylamines with phenylacetaldehydes afforded the corresponding α-aminonitriles, which on treatment with i-propyl magnesium chloride underwent a Bruylants reaction to give the title compounds. Their structures were deduced by NMR and by an independent preparation starting from papaverine. The educts were easily available by standard procedures. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-004-0204-8

Monatshefte f€ur Chemie 135, 1289–1295 (2004)
DOI 10.1007/s00706-004-0204-8
A Convenient Synthesis of 1-Benzyl-1,2,3,4-
tetrahydroisoquinolines by Combined
Strecker/Bruylants Reaction
ꢀ
Eberhard Reimann and Christian Ettmayr
Department Pharmazie – Zentrum f€ur Pharmaforschung, Ludwig-Maximilians-
€
€
€
Universitat Munchen, D-81377 Munchen, Germany
Received March 8, 2004; accepted March 29, 2004
Published online June 24, 2004 # Springer-Verlag 2004
Summary. Strecker reaction of iodophenethylamines with phenylacetaldehydes afforded the corre-
sponding ꢀ-aminonitriles, which on treatment with i-propyl magnesium chloride underwent a Bruylants
reaction to give the title compounds. Their structures were deduced by NMR and by an independent
preparation starting from papaverine. The educts were easily available by standard procedures.
Keywords. Alkaloids; Cyclizations; Hydrogenation; Iodination; Iodine–magnesium exchange
reaction.
Introduction
The structure of many alkaloids exhibiting significant physiological activities is
based on substituted 1,2,3,4-tetrahydroisoquinolines. The most important ones in
this field are the 1-benzyl derivatives, which are known to be central key precursors
in the biosynthesis of a variety of alkaloids, e.g. aporphines, bisbenzylisoquinolines,
cularine and erythrina alkaloids, protoberberines, and morphine [1, 2]. On the other
hand substituted tetrahydroisoquinolines have been found to exhibit a broad spec-
trum of biological activities [3] and furthermore being relevant to pathogenesis of
Parkinson’s disease [4–6]. Finally 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
should be mentioned representing an interesting constrained analogue of phenylala-
nine and being used for the construction of conformationally restricted analogues of
biological active peptides [7, 8]. In this regard tetrahydroisoquinolines also have
received increasing attention from the viewpoint of medicinal chemistry.
In this connection we envisioned the combined Strecker=Bruylants reactions
previously established for our synthesis of erythrinanes [9] to be a general and
efficient approach to 1-substituted 1,2,3,4-tetrahydro-isoquinolines IV mentioned
ꢀ
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de

1290
E. Reimann and C. Ettmayr
Fig. 1. General route to 1-substituted 1,2,3,4-tetrahydroisoquinolines
above starting from iodinated phenethylamines I and appropriate carbonyl com-
pounds II via the ꢀ-aminonitriles III according to Fig. 1. Herein we wish to report
a further example of this strategy by synthesizing the title compounds.
Results and Discussion
The synthesis route is depicted in Scheme 1. Thus, the iodophenethylamines 1
were reacted with the phenylacetaldehydes 2 affording the ꢀ-aminonitriles 3.
The yields obtained were satisfactory (70–89%) when the initial Strecker reaction
was performed in the presence of sodium hydrogen sulfite according to Ref. [10].
In contrast to the aminonitriles recently prepared [9] the products 3 contained
remarkable amounts of impurities, which had to be removed by FC or crystal-
lization (Experimental). Finally, the nitriles 3 were treated with i-propyl magne-
sium chloride in THF providing the 1-benzyltetrahydoisoquinolines 4, among
others the alkaloid (ꢁ)-laudanosine (4c).
Scheme 1

1-Benzyl-1,2,3,4-tetrahydroisoquinolines
1291
Scheme 2
The lower yields obtained in comparison to the erythrinanes (41–66 vs.
71–78% [9]) may be attributed to the sensitivity of the products towards light
and air as indicated by an intensive fluorescence, which could be observed after
thin layer chromatography on silica gel. The structures of 4 were easily deduced
from NMR spectroscopy and additionally by an independent synthesis of 4c. Thus,
papaverine V was catalytically hydrogenated affording rac-norlaudanosine 5 which
in turn was N-methylated to give the target product 4c (Scheme 2).
The educts 1 were prepared according to known procedures starting from 2-
iodophenethylamine (6) and N-methylhomoveratrylamine (7) [9, 11, 12] (Scheme 3);
the dimethoxyphenylacetaldehyde 2b, not described until now, was nearly quanti-
tatively obtained by oxidation of the corresponding phenylethanol 8 with the Dess-
Martin reagent [13–15] (Scheme 4).
In summary we have shown the combined Strecker=Bruylants reactions to be a
convenient two-step route for the preparation of synthetically valuable 1-benzyl-
Scheme 3
Scheme 4

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E. Reimann and C. Ettmayr
1,2,3,4-tetrahydroisoquinolines starting from easily available phenethyl deriva-
tives. This method suggests to be a useful, general approach to a wide range of
similar 1-substituted targets and should be an alternative route to overcome limita-
tions arising from the classical constructions of tetrahydroisoquinoline derivatives,
e.g. Bischler-Napieralski, Pictet-Spengler, and Pomeranz-Fritsch reaction [16].
Further work is currently undertaken in our laboratory to explore the scope and
limitation of the route presented herein.
Experimental
Melting points are measured with a Reichert hot-stage microscope and are uncorrected. IR: Perkin
Elmer FT-IR Paragon 1000 and Jasco FT-IR 410. NMR: Jeol GSX 400 and Jeol GSX 500 (1H: 400 and
500 MHz, 13C: 100 and 125 MHz, CDCl3, TMS as internal reference); MS (70 eV): Hewlett Packard
MS-Engine. Elemental analyses: Heraeus CHN-Rapid and Elementar Vario EL; the results were in
good agreement with the calculated values. Thin layer chromatography (TLC): Al sheets Kieselgel 60
F254 (Merck) and Al sheets Aluminiumoxid F254 (Fluka), each thickness of layer 0.2mm. Flash
chromatography (FC): ICN-Sili Tech 32–63, 60 A and Aluminiumoxid Typ 507 C neutral 0.05–
0.15mm. Compound 6 was prepared according to Ref. [9]; 90% phenylacetaldehyde (2a), N-methyl-
homoveratrylamine (7), and 2-(3,4-dimethoxyphenyl)ethanol (8) are commercial products.
Benzyl-[2-(2-iodophenyl)ethyl]amine (1a)
A mixture of 835 mg of 6 and 369 mg of benzaldehyde (each 3.38mmol) in 20cm3 of dry toluene was
refluxed with H2O separation by a Dean-Stark trap for 2 h. After removing the solvent in vacuo the
residue was dissolved in 20 cm3 of MeOH and 278 mg (7.32 mmol) of NaBH4 were added under ice-
cooling. The mixture was refluxed for 1 h, the solvent was evaporated in vacuo and then 50cm3 of H2O
were added to the residue. After extracting with 3ꢂ50 cm3 of Et2O and drying the extracts (Na2SO4)
the solvent was removed in vacuo and the residue was purified by FC (silica gel; CH2Cl2:MeOH:25%
NH3 ¼ 100:3:0.5). Yield 1.08 g (85%) colourless oil; TLC (eluent see FC): Rf ¼ 0.46; MS (CI): m=z
1
(%) ¼ 366 (Mþꢃ þ 29, 3), 338 (Mþꢃ þ 1, 100), 210 (12), 120 (94), 91 (43); H and 13C spectra were
identical with those reported in Ref. [11].
[2-(2-Iodo-4,5-dimethoxyphenyl)ethyl]methylamine (1b, C11H16INO2)
To a solution of 1.0 g (5.13 mmol) of 7 in 25cm3 of dry CH2Cl2 was added 2.39 g of F3CCO2Ag and
2.74g of I2 (each 10.8mmol) at ꢄ5ꢅC under vehement stirring. After 20min the yellow solid was
filtered off and washed with 25 cm3 of CH2Cl2. The filtrate was washed with 3ꢂ50 cm3 of a 3:1
mixture of saturated Na2S2O3 and saturated Na2CO3, dried (Na2SO4), and evaporated in vacuo. The
residue was purified by FC (silica gel; CH2Cl2:MeOH:25% NH3 ¼ 100:1:1). Yield 1.19 g (72%)
colourless oil; TLC (eluent see FC): Rf ¼ 0.35; MS (CI): m=z (%) ¼ 322 (Mþꢃ þ 1, 100), 278 (3),
194 (27); 1H NMR: ꢁ ¼ 7.21 and 6.76 (2s, 2arom H), 3.85 and 3.84 (2s, 2OCH3), 2.89–2.83 and 2.82–
2.76 (2m, aryl-CH2 and N-CH2), 2.48 (s, N-CH3). 2.19 (s, NH) ppm; 13C NMR: ꢁ ¼ 149.28, 147.96,
135.07, 121.74, 112.55, 88.06, 56.13, 55.91, 52.10, 40.62, 36.48ppm.
(3,4-Dimethoxyphenyl)acetaldehyde (2b)
Preparation according to Ref. [17], but starting from 2-(3,4-dimethoxyphenyl)ethanol (8) and without
purifying by FC: 8 911 mg (5.0mmol), Dess-Martin reagent [14, 15] 2.54 g (6.0 mmol), 20cm3
CH2Cl2. Yield 891 mg (99%) light yellow oil; TLC (CH2Cl2:MeOH ¼ 100:1): Rf ¼ 0.41; IR (film):

1-Benzyl-1,2,3,4-tetrahydroisoquinolines
1293
ꢂꢀ¼ 1722 (C¼O) cmꢄ1; MS (CI): m=z (%) ¼ 181 (Mþꢃ þ 1, 100), 167 (10), 151 (7); 1H NMR: ꢁ ¼ 9.73
(t, J ¼ 2.3Hz, CHO), 6.87 (d, J ¼ 8.2 Hz, 1arom H), 6.77 (dd, J ¼ 8.2, 2.0 Hz, 1arom H), 6.71 (d,
J ¼ 2.0 Hz, 1arom H), 3.88 (s, 2OCH3), 3.63 (d, J ¼ 2.3 Hz, CH2) ppm; 13C NMR: ꢁ ¼ 199.45, 149.20,
148.30, 124.01, 121.74, 112.49, 111.50, 55.81, 55.77, 50.02 ppm.
General Procedure for the Synthesis of ꢀ-Aminonitriles 3
To a solution of the aldehyde 2 and NaHSO3 (each 1 molquiv) in a mixture of 1 cm3 of H2O and 3 cm3
of MeOH was added 1 molquiv amine 1 and 1.02 molquiv KCN and the mixture was heated under
reflux for 1 h. After cooling to ambient temperature the mixture was diluted with H2O and Et2O (each
15cm3), rendered alkaline with saturated Na2CO3, and extracted with 3ꢂ15 cm3 of Et2O. The com-
bined ether extracts were washed with 20cm3 of brine, dried (Na2SO4), and evaporated in vacuo. The
residue (3a and 3c) was purified by FC (silica gel; eluent see TLC), that of 3b was crystallized from
Et2O.
2-{Benzyl-[2-(2-iodophenyl)ethyl]amino}-3-phenylpropionitrile (3a, C24H23IN2)
90% 2a 122 mg (0.92 mmol), NaHSO3 96 mg (0.92mmol), 1a 310 mg (0.92 mmol), KCN 61 mg
(0.94 mmol), H2O 1 cm3, MeOH 3 cm3; yield 300 mg (70%) colourless oil; TLC (n-
hexane:EtOAc¼ 9:1): Rf ¼ 0.45; IR (film): ꢂꢀ¼ 2223 (CꢆN) cmꢄ1; MS (CI): m=z (%) ¼ 440
1
(Mþꢃ þ 1 ꢄ HCN, 100), 314 (16), 222 (24), 91 (14); H NMR (500MHz): ꢁ ¼ 7.80 (dd, J ¼ 7.8,
1.2 Hz, 1arom H), 7.30–7.21, 7.20–7.14, and 7.11–7.06 (3m, 7, 2, and 3arom H), 6.91 (dt, J ¼ 7.8,
1.6 Hz, 1arom H), 4.14 and 3.56 (2d, each J ¼ 13.5 Hz, N-CH2-aryl), 3.81 (t, J ¼ 7.8 Hz, CH), 3.09–
2.85 (m, 5H), 2.77–2.70 (m, 1H) ppm; 13C NMR (100MHz): ꢁ ¼ 141.87, 139.54, 137.20, 135.77,
130.25, 129.24 (2C), 128.63 (2C), 128.60 (2C), 128.50 (2C), 128.39, 128.28, 127.56, 127.20, 117.45,
100.44, 56.40, 56.06, 51.50, 39.11, 38.03 ppm.
2-{[2-(2-Iodo-4,5-dimethoxyphenyl)ethyl]methylamino}-3-phenylpropionitrile
(3b, C20H23IN2O2)
90% 2a 172 mg (1.29 mmol), NaHSO3 135mg (1.29mmol), 1b 415mg (1.29 mmol), KCN 85 mg
(1.31 mmol), H2O 1 cm3, MeOH 3 cm3; yield 517 mg (89%) colourless crystals; mp 123ꢅC (Et2O);
TLC (EtOAc): Rf ¼ 0.65; IR (KBr): ꢂꢀ¼ 2221 (CꢆN) cmꢄ1; MS (CI): m=z (%) ¼ 424 (Mþꢃ þ 1 ꢄ
HCN, 100), 298 (18), 206 (6), 146 (17); 1H NMR (400MHz): ꢁ ¼ 7.34–7.23 (m, 5arom H), 7.20 and
6.70 (2s, 2arom H), 3.84 and 3.83 (2s, 2OCH3), 3.79 (t, J ¼ 7.7 Hz, CH), 3.08–2.96 (m, 2H), 2.91–2.74
(m, 3H), 2.68–2.56 (m, 1H), 2.50 (s, N-CH3) ppm; 13C NMR (100 MHz): ꢁ ¼ 149.36, 148.15, 135.94,
134.38, 129.11 (2C), 128.68 (2C), 127.29, 121.67, 116.92, 112.57, 88.10, 59.83, 56.15, 55.95, 55.36,
38.74, 38.59, 38.15ppm.
3-(3,4-Dimethoxyphenyl)-2-{[2-(2-iodo-4,5-dimethoxyphenyl)ethyl]methylamino}
propionitrile (3c, C22H27IN2O4)
2b 245 mg (1.36 mmol), NaHSO3 141 mg (1.36 mmol), 1b 430 mg (1.34 mmol), KCN 88mg
(1.34 mmol), H2O 1 cm3, MeOH 3 cm3; yield 519 mg (76%) colourless oil; TLC (CH2Cl2:MeOH ¼
100:3): Rf ¼ 0.56; IR (film): ꢂꢀ¼ 2222 (CꢆN) cmꢄ1; MS (CI): m=z (%) ¼ 484 (Mþꢃ þ 1 ꢄ HCN, 100),
1
358 (18), 206 (28); H NMR (500MHz): ꢁ ¼ 7.20 (s, 1arom H), 6.82–6.78 (m, 3arom H), 6.72 (s,
1arom H), 3.88 and 3.87 (2s, 2OCH3), 3.84 (s, 2OCH3), 3.76 (dd, J ¼ 8.9, 6.4 Hz, CH), 3.03–2.92 and
2.90–2.76 (2m, 2 and 3H), 2.65–2.58 (m, 1H), 2.50 (s, N-CH3) ppm; 13C NMR (125MHz):
ꢁ ¼ 149.42, 149.01, 148.32, 148.21, 134.32, 128.36, 121.71, 121.34, 117.02, 112.59, 112.30, 111.35,
88.13, 60.14, 56.17, 55.98, 55.95, 55.90, 55.41, 38.79, 38.63, 37.85 ppm.

1294
E. Reimann and C. Ettmayr
General Procedure for the Synthesis of Tetrahydroisoquinolines 4 by Intramolecular
Bruylants Reaction
To a solution of 1 molquiv aminonitrile 3 in cm3 of dry THF was added a solution of 1.05 molquiv 2 M
i-PrMgCl in the same solvent at ꢄ50ꢅC under N2. After stirring at ꢄ50ꢅC for an additional h the
mixture was slowly warmed up to ambient temperature during 3–4 h and then refluxed under N2 at
60ꢅC for 3 h. The cold mixture was poured into 30cm3 of H2O, rendered alkaline with an aqueous
solution of Na2CO3, and extracted with 3ꢂ30cm3 of Et2O. The combined organic layers were dried
(Na2SO4) and evaporated in vacuo. The residue was purified by FC (eluents were the same as used for
TLC).
1,2-Dibenzyl-1,2,3,4-tetrahydroisoquinoline (4a, C23H23N)
3a 195 mg (0.42 mmol), 2 M i-PrMgCl 0.22cm3 (0.44 mmol), THF 5 cm3; yield 53mg (41%) pale
yellow oil; TLC (n-hexane:EtOAc¼ 9:1): Rf ¼ 0.54; MS (CI): m=z (%) ¼ 314 (Mþꢃ þ 1, 100), 222
1
(87); H NMR (400MHz): ꢁ ¼ 7.30–7.06 (m, 13arom H), 6.86 (d, J ¼ 7.4Hz, 1arom H), 3.90 (dd,
J ¼ 5.5, 8.2 Hz, CH), 3.75 and 3.71 (2d, each J ¼ 13.7Hz, N-CH2-aryl), 3.37 (ddd, J ¼ 13.2, 10.8,
4.9 Hz, 1H), 3.15 (dd, J ¼ 8.2, 13.9Hz, 1H), 3.00 (ddd, J ¼ 16.8, 10.8, 6.0 Hz, 1H), 2.90 (dd, J ¼ 13.9,
5.5 Hz, 1H), 2.90–2.84 (m, 1H), 2.57 (ddd, J ¼ 16.8, 4.9, 2.5 Hz, 1H) ppm; 13C NMR (100MHz):
ꢁ ¼ 140.13, 139.40, 138.05, 134.55, 129.71 (2C), 128.96, 128.61 (2C), 128.26, 128.04 (2C), 127.90
(2C), 126.67, 126.05, 125.82, 125.46, 62.65, 57.83, 42.96, 42.39, 24.34 ppm.
1-Benzyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (4b)
3b 150 mg (0.33 mmol), 2 M i-PrMgCl 0.18 cm3 (0.36 mmol), THF 5 cm3; yield 65mg (66%) pale
yellow oil; TLC (CH2Cl2:MeOH:NH3 25% ¼ 100:3:0.5): Rf ¼ 0.30; MS (CI): m=z (%) ¼ 298
1
(Mþꢃ þ 1, 53), 206 (100); the H NMR spectrum is in accordance with that reported in Ref. [18];
13C NMR (100 MHz): ꢁ ¼ 147.33, 146.28, 139.95, 129.90 (2C), 129.00, 128.19, 126.00 (2C), 125.65,
111.19, 111.06, 64.90, 55.77, 55.43, 46.71, 42.59, 41.20, 25.41 ppm.
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
(rac-laudanosine, 4c)
A. According to the General Procedure (see above): 3c 260mg (0.51 mmol), 2 M i-PrMgCl 0.27 cm3
(0.54 mmol), THF 5 cm3; yield 101 mg (55%) colourless crystals; mp 117ꢅC (EtOH, Ref. [19]
117–119ꢅC); TLC (CH2Cl2:MeOH:NH3 25% ¼ 100:8: 0.5): Rf ¼ 0.35; MS (CI): m=z (%) ¼ 358
1
(Mþꢃ þ 1, 100), 206 (67); H and 13C spectra were in line with those reported in Ref. [19].
B. From norlaudanosine (5) (see below) according to Ref. [20]: To a solution of the crude product 5
(0.27 mmol) in 3 cm3 of MeOH was added 0.6 cm3 of 37% formaldehyde. The mixture was stirred at
ambient temperature for 1 h, then 90mg (2.4mmol) of NaBH4 were slowly added and stirring was
continued for 18h at the same temperature. Further work up was accomplished following Ref. [20].
Yield 86 mg (89%); the analytical data were completely in line with those obtained under A.
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(rac-norlaudanosine, 5)
To a solution of 102 mg (0.3mmol) of papaverine (V) in 5 cm3 of acetic acid p.a. was added 15 mg of
Adams catalyst (PtO2–H2O) and the mixture was hydrogenated for 15h at ambient temperature and
1.05ꢂ107 Pa initial pressure of H2. The catalyst was centrifuged off, and after diluting with 5 cm3of
H2O the solution was rendered alkaline with saturated Na2CO3 and extracted with 4ꢂ5 cm3 of CHCl3.
The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo. Yield 94 mg (91%)

1-Benzyl-1,2,3,4-tetrahydroisoquinolines
1295
nearly colourless oil; TLC (CHCl3:MeOH:NH3 25% ¼ 16:1:0.3): Rf ¼ 0.40 (V: Rf ¼ 0.68); MS (CI):
m=z (%) ¼ 344 (Mþꢃ þ 1, 63), 192 (100); the 1H spectrum was in line with that reported in Ref. [19].
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