Stereocontrolled metalloenamine alkylations: Application to the asymmetric synthesis of 4-alkyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/S0957-4166(00)00343-8

A procedure for the asymmetric synthesis of 4-alkyl-1,2,3,4-tetrahydroisoquinolines is described. The key step in the synthetic route is a stereocontrolled metalloenamine alkylation using (R)-(+)-phenylglycinol methyl ether as the chiral auxiliary. Subseq

Full text of DOI:10.1016/S0957-4166(00)00343-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3779–3788
Stereocontrolled metalloenamine alkylations: application to
the asymmetric synthesis of
4-alkyl-1,2,3,4-tetrahydroisoquinolines
Jose L. Vicario, Dolores Bad´ıa,* Esther Dom´ınguez and Luisa Carrillo
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad del Pais Vasco, PO Box 644,
48080 Bilbao, Spain
Received 31 July 2000; accepted 28 August 2000
Abstract
A procedure for the asymmetric synthesis of 4-alkyl-1,2,3,4-tetrahydroisoquinolines is described. The
key step in the synthetic route is a stereocontrolled metalloenamine alkylation using (R)-(+)-phenyl-
glycinol methyl ether as the chiral auxiliary. Subsequent N-methylation, hydrogenolysis and cyclization
afforded the target heterocycles with enantiomeric excesses higher than 99%. © 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
In recent years the stereoselective synthesis of isoquinoline alkaloids has been a field of
increasing interest in synthetic organic chemistry.1 Many methods have already been published
for highly stereoselective syntheses of 1-substituted tetrahydroisoquinolines,2 which are very
useful intermediates for the preparation of a wide range of enantiopure alkaloids.3 However,
although chiral non racemic 4-substituted tetrahydroisoquinoline derivatives are of considerable
interest due to their biological activity and as naturally occurring alkaloids,4 the research
towards their stereoselective synthesis is not as extensive as in the case of the 1-substituted
tetrahydroisoquinolines. Some papers have appeared for the asymmetric synthesis of tetra-
hydroisoquinoline derivatives when the substituent at C-4 bears a hydroxy function,5 but only
a few reports can be found when the substitution at this position is not a heteroatom,6 which
occurs in nature quite often, e.g. in nomifemsine,7 cherylline8 and the spermidine alkaloids
cyclocelabencine and isocyclocelabencine (Fig. 1).9
* Corresponding author. E-mail: qopbaurm@lg.ehu.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00343-8

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Figure 1.
In this context, and in connection with our studies in the field of the asymmetric synthesis of
isoquinoline alkaloids5b,10 we have developed a suitable and general enantioselective synthetic
method to obtain 4-alkyl-1,2,3,4-tetrahydroisoquinolines starting from chiral arylethylamine
precursors (Scheme 1), which were prepared employing an asymmetric metalloenamine alkyl-
ation protocol starting from an imine derived from homoveratraldehyde and (R)-(+)-phenyl-
glycinol methyl ether.11 The developed protocol is interesting from a synthetic point of view
taking into account the possibility of introducing any kind of alkyl chain at the 4-position of the
isoquinoline core. This can lead to the synthesis of a wide range of naturally and unnaturally
occurring isoquinoline derivatives.
Scheme 1.
2. Results and discussion
The starting imine 1 was subjected to deprotonation with LDA at −78°C followed by
alkylation with several alkyl halides at the same temperature and the crude reaction mixture was
reduced in situ with NaBH4 yielding the aminoethers 2a–d in good yields and moderate to good
diastereoselectivities. It was observed that when increasing the steric bulk of the incoming
electrophile the 2/2% ratio noticeably improved varying from 67/33 when R=Me to 93/7 when
R=Bn (see Table 1). In all cases, it was possible to isolate and characterize each of the obtained
diastereomers by flash column chromatography purification of the reaction crude. The stereo-
chemistry of the newly created stereogenic center in the major isomers 2a–d was provisionally
assigned as (S) on the basis of the mechanism proposed by Meyers for a similar case (Scheme
2).11g

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 3779–3788
3781
Table 1
Asymmetric alkylation-reduction of 1
Product
R
Yield (%)a
2/2%b
2a
2b
2c
2d
Me
Et
i-Pr
Bn
66
88
90
78
67/33
86/14
89/11
93/7
a Global yield as mixture of diastereoisomers 2/2%.
b Calculated by HPLC (Chiralcel OD column, UV detector, hexane/i-PrOH 95/5, flow rate 0.75 mL/min.
Scheme 2. Reagents and conditions: (i) LDA, THF, −78°C; (ii) RX, THF, −78°C; (iii) NaBH4, MeOH, −20°C
Proceeding with the planned synthesis, the aminoethers 2a–d were N-methylated under standard
conditions12 and the obtained products 3a–d were subjected to a hydrogenolysis procedure to
remove the benzylic part of the chiral appendage yielding the corresponding 2-substituted
2-arylethylamines 4a–d in good yields. Their analysis by chiral HPLC under conditions optimized
with the help of a racemic standard13 showed that they were obtained as only one detectable
enantiomer indicating that both processes, N-methylation and hydrogenolysis, proceeded without
racemization in the previously formed stereogenic center (Scheme 3, Table 2).
Scheme 3. Reagents and conditions: (i) HCHOaq, NaBH3CN, CH3CN, rt; (ii) H2 (60 psi), Pd/C, 1 M HCl, EtOH
Table 2
N-Methylation/hydrogenolysis of aminoethers 2a–d
Product
R
Yield (%)
Product
Yield (%)
E.e. (%)a
3a
3b
3c
3d
Me
Et
i-Pr
Bn
93
91
93
90
4a
4b
4c
4d
83
84
88
87
\99
\99
\99
\99
a Calculated by HPLC (Chiralcel OD column, UV detector, hexane/i-PrOH 90/10, flow rate 0.80 mL/min).

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The fact that amine 4a is a known product6h allowed us to establish unambiguously the
absolute configuration of its stereogenic center by comparison of the obtained specific rotation
value {[h]2D0=−16.3, (c=1.75, CHCl3)} with that reported in the literature {[h]2D0=+13.0,
(c=1.75, CHCl3) for the (R) enantiomer}, thus confirming the previously assigned (S)-configu-
ration for 4a and by extension to the rest of amines 4 and all the obtained aminoethers 2a–d,
and 3a–d.
Finally, the amines 4a–d were converted into the target heterocycles by Pictet–Spengler
heterocyclization reaction14 by reacting them with aqueous formaldehyde and 1 M HCl at 60°C.
The isoquinolines 5a–d were obtained in excellent yields and again as only one detectable
enantiomer as indicated by chiral HPLC analysis (Scheme 4, Table 3).
Scheme 4. Reagents and conditions: (i) HCHO aq., 1 M HCl, 60°C
Table 3
Pictet–Spengler cyclization of amines 3a–d
Product
R
Yield (%)
E.e. (%)a
5a
5b
5c
5d
Me
Et
i-Pr
Bn
96
92
95
93
\99
\99
\99
\99
In conclusion, we have developed a procedure to stereoselectively prepare 4-alkyl-1,2,3,4-tetra-
hydroisoquinolines employing a diastereoselective metalloenamine alkylation procedure of an
imine derived from homoveratraldehyde and (R)-phenylglycinol methyl ether as the key step
with respect to the stereochemical control. Although this key reaction proceeds with moderate
to good stereoselectivities, the final diastereoisomers are easily separated by flash column
chromatography which allows, after a series of simple transformations, the access to the target
heterocycles in good yields and as enantiomerically pure compounds.
3. Experimental
3.1. General procedures
Melting points were determined in unsealed capillary tubes and are uncorrected. IR spectra
were obtained on KBr pellets (solids) or CHCl3 solution (oils). NMR spectra were recorded at
1
20–25°C, running at 250 MHz for H and 62.8 MHz for 13C in CDCl3 solution and resonances

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 3779–3788
3783
are reported in ppm relative to tetramethylsilane unless otherwise stated. Assignment of
individual 13C resonances are supported by DEPT experiments. 1H–{1H} NOE experiments were
carried out in the difference mode by irradiation of all the lines of a multiplet.15 Mass spectra
were recorded under electron impact at 70 eV. TLC was carried out with 0.2 mm thick silica gel
plates (Merck Kiesegel GF254). Visualization was accomplished by UV light or by spraying with
Dragendorff’s reagent.16 Flash column chromatography17 on silica gel was performed with
Merck Kiesegel 60 (230–400 mesh). Determination of enantiomeric excesses was performed by
chiral HPLC analysis of non crystallized samples using a Chiracel OD column with a UV
detector with the eluents and flow rates as indicated in each case. All solvents used in reactions
were dried and purified according to standard procedures.18 n-BuLi was titrated with diphenyl-
acetic acid periodically prior to use. All air- or moisture-sensitive reactions were performed
under argon. The glassware was oven dried (140°C) overnight and purged with argon.
3.2. Synthesis of (1%R)-(−)-(3,4-dimethoxyphenyl)-N-(1%-phenyl-2%-methoxyethyl)ethylideneamine
1
A dissolution of (R)-phenylglycinol methyl ether (0.16 g, 1.08 mmol) and homoveratraldehyde
(0.16 g, 1.08 mmol) in Et2O (10 mL) and in the presence of Na2SO4 was stirred for 5 min and
was then filtered and the solvent was removed in vacuo affording imine 1, which was directly
1
employed in the alkylation reaction. Yield: 96%. H NMR: 3.24 (s, 3H); 3.33 (m, 2H); 3.55 (d,
2H, J=5.3 Hz); 3.87 (s, 6H); 4.12 (m, 1H); 6.73–6.88 (m, 3H); 7.12–7.36 (m, 5H); 7.77 (t, 1H,
J=5.3 Hz). 13C NMR: 43.6, 55.5, 58.2, 59.3, 65.5, 76.8, 110.5, 112.8, 123.6, 127.4, 128.2, 129.1,
133.6, 138.2, 147.5, 148.9, 163.3. MS (EI) m/z (int. rel.): 313 (M+, 13), 268 (92), 151 (100). IR
(CHCl3): 1631.
3.3. General procedure for the alkylation-reduction of metalloenamine 1
A solution of 1 (0.20 mmol) was slowly added over a cold (−78°C) LDA solution (0.20 mmol)
in dry THF (15 mL). The mixture was stirred for 1 h at this temperature and then a solution
of RX (0.20 mmol) in dry THF (10 mL) was dropwise added within 40 min. The reaction was
stirred for a further 2 h and a solution of NaBH4 (0.40 mmol) in MeOH (10 mL) was added at
once. The mixture was allowed to reach to rt and was stirred for 30 min after which it was
quenched with a saturated solution of NH4Cl. The mixture was extracted with CH2Cl2 (3×15
mL) and the combined organic fractions were dried over Na2SO4, filtered and the solvent was
removed in vacuo. The amines 2 and 2% were obtained separately by flash column chromatogra
phy separation (hexane/AcOEt 1/1).
3.3.1. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)propyl]-2-methoxy-1-phenylethylamine 2a
Yield: 44%. Mp 52–54°C (Et2O/pentane 1/1). [h]2D0=−29.7 (c=1.4, CH2Cl2). H NMR: 1.21
1
(d, 3H, J=6.9 Hz); 2.07 (sa, 1H); 2.58 (d, 2H, J=7.4 Hz); 2.83 (m, 1H); 3.26 (s, 3H); 3.35 (m,
2H); 3.79 (m, 1H); 3.84 (s, 3H); 3.85 (s, 3H); 6.71–6.82 (m, 3H); 7.22–7.39 (m, 5H). 13C NMR:
20.2, 39.7, 55.0, 55.7, 55.8, 58.5, 62.8, 77.7, 110.4, 111.2, 118.7, 127.3, 127.5, 128.2, 138.1, 140.8,
147.2, 148.9. MS (EI) m/z (rel. int.): 329 (M+, 1), 135 (100). IR (KBr): 3425. Anal. calcd for
C20H27NO3: C, 72.92; H, 8.26; N, 4.25. Found: C, 73.00; H, 8.23; N, 4.28.

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J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 3779–3788
3.3.2. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)butyl]-2-methoxy-1-phenylethylamine 2b
Yield: 75%. Mp 63–65°C (Et2O/pentane 1/1). [h]2D0=−32.2 (c=1.2, CH2Cl2). H NMR: 0.75
1
(t, 3H, J=7.3 Hz); 1.44 (m, 1H); 1.72 (m, 1H); 2.00 (sa, 1H); 2.66 (m, 3H); 3.21 (s, 3H);
3.31 (m, 2H); 3.77 (m, 1H); 3.83 (s, 3H); 3.84 (s, 3H); 6.66–6.81 (m, 3H); 7.19–7.36 (m, 5H).
13C NMR: 11.8, 27.3, 47.7, 53.5, 55.6, 58.3, 62.9, 77.6, 110.8, 111.0, 119.5, 127.1, 127.4,
128.1, 136.3, 140.7, 147.2, 148.7. MS (EI) m/z (rel. int.): 343 (M+, 1), 135 (100). IR (KBr):
3436. Anal. calcd for C21H29NO3: C, 73.44; H, 8.51; N, 4.08. Found C, 73.48; H, 8.49; N,
4.03.
3.3.3. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)-3-methylbutyl]-2-methoxy-1-phenylethylamine
2c
Yield: 79%. Mp 74–76°C (Et2O/pentane 1/1). [h]2D0=−25.7 (c=1.1, CH2Cl2). H NMR: 0.75
1
(d, 3H, J=6.8 Hz); 0.98 (d, 3H, J=6.8 Hz); 1.44 (m, 1H); 2.03 (sa, 1H); 2.62 (m, 3H); 3.23
(s, 3H); 3.32 (m, 2H); 3.75 (m, 1H); 3.82 (s, 3H); 3.85 (s, 3H); 6.71–6.89 (m, 3H); 7.12–7.29
(m, 5H). 13C NMR (l, ppm): 9.7, 11.5, 27.8, 47.5, 53.4, 55.5, 58.3, 62.7, 77.5, 110.8, 111.2,
119.4, 127.2, 127.6, 128.1, 136.2, 140.5, 147.1, 148.4. MS (EI) m/z (rel. int.): 357 (M+, 1), 135
(100). IR (KBr): 3433. Anal. calcd for C22H31NO3: C, 73.91; H, 8.74; N, 3.92. Found C,
73.99; H, 8.77; N, 3.87.
3.3.4. (1R,2%S)-(+)-N-[2%-(3,4-Dimethoxyphenyl)-3%-phenylpropyl]-2-methoxy-1-phenylethylamine
2d
1
Yield 73%. Mp 57–59°C (Et2O/pentane 1/1). [h]2D0=+84.8 (c=0.8, CH2Cl2). H NMR: 1.35
(sa, 1H); 2.04 (m, 3H); 2.22 (m, 2H); 3.27 (s, 3H); 3.55 (m, 2H); 3.78 (s, 3H); 3.81 (m, 1H);
3.86 (s, 3H); 6.64 (d, 1H, J=1.6 Hz); 6.56 (dd, 1H, J=1.2, 8.2 Hz); 6.77 (s, 1H); 6.98 (dd,
2H, J=1.6, 7.6 Hz); 7.05 (m, 3H); 7.27 (m, 5H). 13C NMR: 41.2, 47.8, 52.7, 55.6, 58.4, 62.8,
77.5, 110.8, 111.0, 119.4, 125.5, 127.2, 127.4, 127.8, 127.9, 128.2, 128.9, 135.4, 140.1, 140.7,
147.2, 148.4. MS (EI) m/z (rel. int.): 405 (M+, 1), 135 (100). IR (KBr): 3436. Anal. calcd for
C26H31NO3: C, 77.01; H, 7.71; N, 3.45. Found C, 77.02; H, 7.69; N, 3.40.
3.4. General procedure for the N-methylation of aminoethers 2a–d
Aqueous formaldehyde (0.50 mmol) NaBH3CN (0.20 mmol) was added over a solution of
amine 2a–d (0.10 mmol) in acetonitrile (20 mL). The mixture was stirred at rt for 6 h,
quenched with water and extracted with CH2Cl2 (3×15 mL). The combined organic fractions
were dried over Na2SO4, filtered and the solvent was removed in vacuo. Yielding the amines
3a–d after flash column chromatography purification (hexane/AcOEt 1/1).
3.4.1. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)propyl]-2-methoxy-N-methyl-1-phenylethylamine
3a
Yield: 93%. Mp 65–67°C (Et2O). [h]2D0=−36.5 (c=0.5, CH2Cl2). H NMR: 1.19 (d, 3H,
1
J=7.0 Hz); 2.43 (s, 3H); 2.55 (d, 2H, J=7.4 Hz); 2.80 (m, 1H); 3.31 (s, 3H); 3.43 (m, 2H);
3.68 (m, 1H); 3.83 (s, 3H); 3.85 (s, 3H); 6.77–6.93 (m, 3H); 7.15–7.28 (m, 5H). 13C NMR:
20.0; 39.6; 45.5; 55.1; 55.7; 55.9; 58.4; 62.9; 77.3; 110.6, 111.2, 118.9, 127.4, 127.5, 128.4;
138.5, 140.7; 147.3, 149.4. MS (EI) m/z (rel. int.): 343 (M+, 12), 151 (100).

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3785
3.4.2. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)butyl]-2-methoxy-N-methyl-1-phenylethylamine
3b
Yield: 91%. [h]2D0=−40.2 (c=0.1, CH2Cl2).1H NMR: 0.73 (t, 3H, J=7.1 Hz); 1.41 (m, 1H); 1.68
(m, 1H); 2.45 (s, 3H); 2.60 (m, 3H); 3.11 (s, 3H); 3.28 (m, 2H); 3.76 (m, 1H); 3.83 (s, 3H); 3.85
(s, 3H); 6.68–6.79 (m, 3H); 7.06–7.28 (m, 5H).13C NMR: 11.9, 27.0, 45.1, 47.9, 53.2, 55.6, 58.5,
70.4, 77.9, 110.6, 111.0, 119.4, 127.3, 127.4, 128.5, 136.0, 140.7, 147.5, 148.6. MS (EI) m/z (rel.
int.): 357 (M+, 1), 151 (100).
3.4.3. (1R,2%S)-(−)-N-[2%-(3,4-Dimethoxyphenyl)-3-methylbutyl]-2-methoxy-N-methyl-1-phenyl
ethylamine 3c
Yield: 93%. [h]2D0=−43.6 (c=0.3, CH2Cl2). 1H NMR: 0.74 (d, 3H, J=6.8 Hz); 1.02 (d, 3H, J=6.9
Hz); 1.41 (m, 1H); 2.41 (s, 3H); 2.65 (m, 3H); 3.21 (s, 3H); 3.30 (m, 2H); 3.77 (m, 1H); 3.82 (s,
3H); 3.84 (s, 3H); 6.76–6.99 (m, 3H); 7.15–7.31 (m, 5H). 13C NMR: 9.3, 11.2, 27.6, 45.0, 47.3,
53.9, 55.5, 58.6, 62.0, 77.7, 110.9, 111.4, 119.4, 127.6, 127.9, 128.6, 136.7, 140.3, 147.4, 148.2. MS
(EI) m/z (rel. int.): 371 (M+, 1), 151 (100).
3.4.4. (1R,2%S)-(+)-N-[2%-(3,4-Dimethoxyphenyl)-3%-phenylpropyl]-2-methoxy-N-methyl-1-phenyl-
ethylamine 3d
1
Yield 90%. [h]2D0=+77.6 (c=0.1, CH2Cl2). H NMR: 2.07 (m, 3H); 2.19 (m, 2H); 3.26 (s, 3H);
2.47 (s, 3H); 3.50 (m, 2H); 3.78 (s, 3H); 3.86 (m, 1H); 3.91 (s, 3H); 6.58 (d, 1H, J=1.4 Hz); 6.44
(dd, 1H, J=1.4, 8.2 Hz); 6.77 (s, 1H); 7.03 (dd, 2H, J=1.4, 7.6 Hz); 7.08 (m, 3H); 7.33 (m, 5H).
13C NMR: 41.9, 45.2, 47.6, 52.7, 55.6, 58.3, 62.9, 77.1, 110.4, 111.0, 119.8, 125.3, 127.7, 127.9,
128.2, 128.3, 128.6, 128.9, 135.6, 140.7, 140.9, 147.2, 148.6. MS (EI) m/z (rel. int.): 419 (M+, 7),
151 (100).
3.5. General procedure for the hydrogenolysis of amines 3a–d
A solution of 3a–d (0.10 mmol) in EtOH was stirred in the presence of Pd/C (0.5 g) and 10%
HCl (2 mL) under 2 atm H2 pressure. When the reaction was finished (tlc), the catalyst was filtered
and water (20 mL) was added. Amines 4a–d were obtained pure by NMR after a standard
acid–base work-up. An analytically pure sample was obtained by crystallization in Et2O of the
corresponding HCl salt.
3.5.1. (2S)-(−)-2-(3,4-Dimethoxyphenyl)-N-methylpropylamine 4a
Yield 83%. Mp (as HCl salt): 188–191°C (Et2O). [h]2D0=−16.3 (c=1.75, CHCl3). 1H NMR: 1.21
(d, 3H, J=6.9 Hz); 2.35 (s, 3H); 2.71 (m, 2H); 2.88 (m, 1H); 3.83 (s, 3H); 3.86 (s, 3H); 6.74–6.88
(m, 3H). 13C NMR: 20.3, 36.5, 39.7, 55.8, 56.0, 60.1, 110.6, 111.4, 118.9, 137.8, 147.5, 149.0. MS
(EI) m/z (rel. int.): 209 (M+, 21), 151 (100). IR (CHCl3): 3440. Anal. calcd for C12H19NO2: C,
68.87; H, 9.15; N, 6.69. Found C, 68.93; H, 9.02; N, 6.58.
3.5.2. (2S)-(−)-2-(3,4-Dimethoxyphenyl)-N-methylbutylamine 4b
Yield: 84%. [h]2D0=−18.4 (c=1.0, CH2Cl2). H NMR: 0.68 (t, 3H, J=7.1 Hz); 1.43 (m, 1H);
1
1.59 (m, 1H); 2.37 (s, 3H); 2.68 (m, 2H); 2.79 (m, 1H); 3.84 (s, 3H); 3.88 (s, 3H); 6.65–6.77 (m,
3H). 13C NMR: 12.0, 25.4, 36.2, 39.4, 55.8, 56.1, 60.3, 110.2, 111.4, 118.7, 137.6, 147.9, 149.5.
IR (CHCl3): 3443. MS (EI) m/z (rel. int.): 223 (M+,15), 151 (100). Anal. calcd for C13H21NO2:
C, 69.92; H, 9.48; N, 6.27. Found C, 69.99; H, 9.45; N, 6.30.

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3.5.3. (2S)-(−)-N,3-Dimethyl-2-(3,4-dimethoxyphenyl)butylamine 4c
Yield 88%. [h]2D0=−21.3 (c=1.0, CH2Cl2). H NMR: 0.71 (d, 3H, J=6.8 Hz); 0.94 (d, 3H,
1
J=6.8 Hz); 1.37 (m, 1H); 2.35 (s, 3H); 2.65 (m, 2H); 2.84 (m, 1H); 3.82 (s, 3H); 3.86 (s,
3H); 6.79–7.03 (m, 3H). 13C NMR: 9.3, 11.5, 27.3, 36.5, 39.9, 55.8, 56.3, 60.4, 110.3, 111.4,
118.5, 137.4, 147.8, 149.7. IR (CHCl3): 3440. MS (EI) m/z (rel. int.): 237 (M+, 23), 151 (100).
Anal. calcd for C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found C, 70.92; H, 9.84; N, 6.03.
3.5.4. (2S)-(−)-2-(3,4-Dimethoxyphenyl)-N-methyl-l3-phenylpropylamine 4d
Yield 87%. [h]2D0=−75.4 (c=0.5, CH2Cl2). H NMR: 1.88 (dd, 1H, J=6.6, 10.4 Hz); 2.02
1
(dd, 1H, J=4.8, 10.4 Hz); 2.28 (m, 2H); 2.31 (s, 3H); 2.89 (m, 1H); 3.79 (s, 3H); 3.82 (s,
3H); 6.69–6.85 (m, 3H); 7.08–7.24 (m, 5H). 13C NMR: 36.1, 39.7; 40.4; 55.6; 56.1; 60.9;
110.3, 111.1, 111.4, 112.3, 117,4, 118.5; 137.4, 138.6; 147.5, 149.3. IR (CHCl3): 3445. MS (EI)
m/z (rel. int.): 285 (M+, 18), 91 (100). Anal. calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91.
Found C, 75.68; H, 8.04; N, 5.00.
3.6. General procedure for the Pictet–Spengler cyclization
A solution of amine 4a–d (0.10 mmol) and aqueous formaldehyde (0.60 mmol) in 1 M
HCl (5 mL) was stirred for 16 h at 60°C. A solution of saturated Na2CO3 (10 mL) was
added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo yielding
isoquinolines 5a–d after flash column chromatography purification (hexane/AcOEt 1/1).
3.6.1. (4S)-(+)-6,7-Dimethoxy-N,4-dimethyl-1,2,3,4-tetrahydroisoquinoline 5a
1
Yield 96%. [h]2D0=+6.3 (c=0.3, CH2Cl2). H NMR: 1.48 (d, 3H, J=6.9 Hz); 2.19 (s, 3H);
2.55 (dd, 1H, J=4.2, 11.4 Hz); 3.08 (m, 1H); 3.24 (dd, 1H, J=3.0, 11.4 Hz); 3.53 (d, 1H,
J=13.3 Hz); 3.62 (d, 1H, J=13.3 Hz); 3.81 (s, 3H); 3.85 (s, 3H); 6.62 (s, 1H); 6.94 (s, 1H).
13C NMR: 20.6, 33.4, 36.3, 49.5, 55.8, 56.2, 58.9, 110.5, 111.0, 129.3, 131.4, 147.7, 148.4. MS
(EI) m/z (rel. int.): 221 (M+, 15), 56 (100).
3.6.2. (4S)-(+)-6,7-Dimethoxy-4-ethyl-N-methyl-1,2,3,4-tetrahydroisoquinoline 5b
Yield 92%. [h]2D0=+7.5 (c=0.5, CH2Cl2). H NMR: 0.90 (t, 3H, J=7.4 Hz); 1.65 (m, 1H);
1
1.88 (m, 1H); 2.28 (s, 3H); 2.61 (dd, 1H, J=4.6, 11.2 Hz); 2.81 (dd, 1H, J=2.8, 11.2 Hz);
2.98 (m, 1H); 3.21 (d, 1H, J=13.3 Hz); 3.58 (d, 1H, J=13.3 Hz); 3.79 (s, 3H); 3.82 (s, 3H);
6.35 (s, 1H); 6.86 (s, 1H). 13C NMR: 11.2, 26.4, 33.6, 36.5, 50.4, 55.7, 56.0, 59.4, 110.3,
111.5, 129.4, 131.2, 147.8, 148.9. MS (EI) m/z (rel. int.): 235 (M+, 18), 56 (100).
3.6.3. (4S)-(+)-6,7-Dimethoxy-N-methyl-4-(2-methylethyl)-1,2,3,4-tetrahydroisoquinoline 5c
Yield 95%. [h]2D0=+8.4 (c=0.5, CH2Cl2). H NMR: 0.97 (d, 3H, J=7.5 Hz); 1.02 (d, 3H,
1
J=7.3 Hz); 2.03 (m, 1H); 2.28 (s, 3H); 2.65 (dd, 1H, J=4.3, 11.4 Hz); 2.79 (dd, 1H, J=2.7,
11.4 Hz); 3.04 (m, 1H); 3.26 (d, 1H, J=13.3 Hz); 3.66 (d, 1H, J=13.3 Hz); 3.79 (s, 3H);
3.81 (s, 3H); 6.21 (s, 1H); 6.89 (s, 1H). 13C NMR: 11.3, 12.4, 27.1, 33.2, 36.7, 49.9, 55.6,
56.0, 58.7, 110.4, 111.0, 129.5, 131.7, 147.9, 148.2. MS (EI) m/z (rel. int.): 249 (M+, 21), 56
(100).

J. L. Vicario et al. / Tetrahedron: Asymmetry 11 (2000) 3779–3788
3787
3.6.4. (4S)-(+)-4-Benzyl-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline 5d
Yield 93%. [h]2D0=+31.6 (c=0.7, CH2Cl2). H NMR: 2.31 (s, 3H); 2.59 (dd, 1H, J=4.6, 11.2
Hz); 2.77 (dd, 1H, J=2.8, 11.2 Hz); 3.05–3.54 (m, 5H); 3.81 (s, 3H); 3.84 (s, 3H); 6.23 (s, 1H);
6.88 (s, 1H); 7.03–7.16 (m, 5H). 13C NMR: 33.2, 36.7, 42.6, 50.9, 55.5, 56.8, 58.9, 110.3, 111.4,
112.6, 116.5, 117.3, 128.6, 129.3, 131.0, 147.7, 148.2. MS (EI) m/z (rel. int.): 297 (M+, 31), 91
(100).
1
Acknowledgements
Financial support from the Basque Government (a fellowship to J.L.V.) from the University
of the Basque Country (project UPV 37/98) and from the Spanish DGES (project PB98-0600)
is gratefully acknowledged.
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