Alkali metal-mediated synthesis of 1- and 4-substituted N-alkyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.3987/COM-03-9936

Reductive cleavage by electron transfer from Li or K metal of 1-alkoxy-substituted N-alkyltetrahydroisoquinolines led to the formation of organometallic derivatives. Quenching of these intermediates with electrophilic reagents afforded 1- or 4-substituted

Full text of DOI:10.3987/COM-03-9936

HETEROCYCLES, Vol. 63, No. 2, 2004, pp. 401 - 409
Received,14th October, 2003, Accepted, 11th December, 2003, Published online, 15th December, 2003
ALKALI METAL-MEDIATED SYNTHESIS OF 1- AND 4-SUBSTITUTED
N-ALKYL-1,2,3,4-TETRAHYDROISOQUINOLINES
Ugo Azzena,* Luisa Pisano, and Mario Pittalis
Department of Chemistry, University of Sassari, via Vienna 2, I – 07100 Sassari,
Italy; E-mail: ugo@uniss.it
Abstract – Reductive cleavage by electron transfer from Li or K metal of
1-alkoxy-substituted N-alkyltetrahydroisoquinolines led to the formation of
organometallic derivatives. Quenching of these intermediates with electrophilic
reagents afforded 1- or 4-substituted N-alkyl-1,2,3,4-tetrahydroisoquinolines,
depending upon the nature of the metal.
INTRODUCTION
Generation of α-N,N-dialkylamino-substituted benzyllithium derivatives is a topic of current interest in
synthetic organic chemistry. Indeed, besides their potential synthetic utility, there is an increasing interest
in the reactivity and structural features of α-tertiary amino-substituted alkali metal organometallics.1-3
Following our interest in the reductive metalation of benzyl alkyl ethers derivatives,4 we demonstrated that
reductive cleavage of open chain and cyclic α-N,N-dialkylamino-substituted benzyl alkyl ethers, by
electron trasfer from alkali metals in THF, is a highly regioselective reaction, resulting in the exclusive
cleavage of the benzylic carbon – oxygen bond, and disclosing an original approach to the generation of
α-N,N-dialkylamino-substituted arylmethyllithium reagents.5,6
1. Li, C H , THF
10 10
N
N
2. EX
CH3
CH3
E
O
CH3
1
2 a-g
Scheme 1. Reductive metalation and reaction with electrophiles of tetrahydroisoquinoline (1). 2a, E = H;
2b, E = D; 2c, E = CH2Ph; 2d, E = C6H13; 2e, E = (CH3)2COH; 2f, E = (CH2)5COH; 2g, E = (CH2)4COH.

We wish now to report an extension of this procedure to the regioselective synthesis of substituted
1,2,3,4-tetrahydroisoquinoilines.
Indeed, application of this procedure to 1-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1),allows the
generation of the corresponding organolithium derivative,which can be trapped with different electrophiles,
leading to the synthesis of 1-substituted 2-methyl-1,2,3,4-tetrahydroisoquinolines (2) (Scheme 1).
Potassium-mediated reduction of 2,3,6,10b-tetrahydro-5H-oxazolo[2,3-a]isoquinoline (3), led to benzylic
carbon – oxygen bond cleavage; however, quenching this reaction mixture with different electrophiles led
to the recovery of 4-substituted 2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)ethanols (4), via an
unprecedented prototropic rearrangement (Scheme 2).
E
1. K, C
H , THF
10 10
N
N
2. EX
O
CH2OH
3
4 a-c
Scheme 2. Reductive metalation and reaction with electrophiles of tetrahydroisoquinoline (3). 4a, E = H;
4b, E = D; 4c, E = C4H9.
RESULTS AND DISCUSSION
Tetrahydroisoquinoline (1) was obtained in 56% overall yield by reacting 3,4-dihydroisoquinoline with
CH3I,7,8 followed by reaction of the resulting dihydroisoquinolinium iodide with CH3ONa.
Tetrahydroisoquinoline (3) was obtained according to a literature procedure,9 in 76% overall yield, by the
reaction of 3,4-dihydroisoquinoline with 2-bromoethanol, followed by reaction with aqueous NaOH
(Scheme 3).
I-
CH3ONa
+
N
N
CH3I
CH3
CH3
O
1
CH3
N
Br-
NaOH
Br(CH2)2OH
+
N
N
CH2OH
O
3
Scheme 3. Synthesis of tetrahydroisoquinolines (1) and (3).

Reductive cleavage reactions of compounds (1) and (3) were carried out under Ar with an excess of alkali
metal in the presence of a catalytic amount of naphthalene10 in tetrahydrofuran (THF).
Selected results obtained in the reductive metalation of tetrahydroisoquinoline (1) are reported in Table 1
(Scheme 1). Reduction of tetrahydroisoquinoline (1) with 10 equivalents of Li metal in the presence of 20
mol% of naphthalene in THF at –30 °C for 2 h quantitatively afforded, after aqueous work up,
tetrahydroisoquinoline (2a) (Entry 1). Formation of an intermediate organolithium derivative was
evidenced quenching the reduction mixture with D2O. Under this conditions, 61% deuterium incorporation
at C-1 was detected by 1H NMR spectroscopy of the crude reaction mixture (Table 1, Entry 2). It is worth
noting that the intermediate organometal is stable under the reaction conditions, as demonstrated by
quenching the reduction mixture with D2O, after 7 h stirring at –30 °C (Table 1, Entry 3). However, a
relatively better result can be obtained running the reduction at –60 °C; under these conditions, deuterium
incorporation increased to 69% (Table 1, Entry 4). We were unable to further improve this result, either
increasing the relative amount of the metal (up to 20 equivalents, not reported in Table 1), or the relative
amount of the catalyst (up to 1 equivalent, not reported in the Table).
Table 1. Reductive lithiation of tetrahydroisoquinoline (1) and reaction with electrophilesa
Entry
T (°C)
-30
t (h)
2
EX
Product, E =
2a, H
Yield (%)b
>95c
61d
1
2
3
4
5
6
7
8
H2O
-30
2
D2O
2b, D
-30
7
D2O
2b, D
59d
-60
2.5
2
D2O
2b, D
69d
-30
PhCH2Cl
C6H13Br
(CH3)2CO
(CH2)5CO
2c, PhCH2
2d, C6H13
2e, (CH3)2COH
2f, E = (CH2)5COH
40
-30
2
36
-60
2.5
2.5
45
-60
44
2g, E = (CH2)4COH
9
-60
2.5
52
(CH2)4CO
aAll reactions were run in the presence of 10 equivalents of Li metal and in the presence of 20 mol% of
C10H10. bIsolated yield, unless otherwise indicated. cAs determined by 1H NMR spectroscopy. dDeuterium
content, as determined by 1H NMR spectroscopy (see EXPERIMENTAL).
The organolithium intermediate, obtained as described above, was trapped with different electrophiles,
including alkyl halides (Table 1, Entries 5 and 6) and enolizable ketones (Table 1, Entries 7-9). The

corresponding 1-substituted tetrahydroisoquinolines (2c-g) were obtained in 36-52% yields. Taking into
account the relative amount of the organolithium derivative formed in the reductive cleavage step, these
results can be considered as satisfactory.
It is worth noting that our procedure represents an umpolung of the known reactivity of
1-alkoxy-substituted tetrahydroisoquinolines towards nucleophilic reagents,11-13 thus allowing the coupling
of the 1-tetrahydroisoquinolyl skeleton with alkyl halides, as well as its addition to carbonyl derivatives.
As a further extension of this procedure, we investigated the reductive cleavage of the polycyclic
tetrahydroisoquinoline (3). Selected results are reported in Table 2 (Scheme 2).
Table 2. Reductive lithiation of tetrahydroisoquinoline (3) and reaction with electrophilesa
Entry
Metal
Li
T (°C)
-30
-20
0
t (h)
4
EX
Product, E = Yield (%)
1
2
3
4
5
6
H2O
H2O
H2O
H2O
D2O
C4H9Br
3 + 4a, H
3 + 4a, H
4a, H
n.d.b
n.d.b
n.d.b
50c
Li
4
Li
5
K
-30
-30
-30
5
4a, H
K
5
4b, D
75d
K
5
4c, C4H9
33c
aAll reactions were run in the presence of 10 equivalents of metal and in the presence of 20 mol% of
b
c
C10H10. n.d. = not determined, several unidentified products also formed; see text. Isolated yield.
dDeuterium content, as determined by 1H NMR spectroscopy (see EXPERIMENTAL).
Attemps to obtain selective reductive cleavage of tetrahydroisoquinoline (3) under the reaction conditions
reported above, were unsuccessful. Indeed, reduction of tetrahydroisoquinoline (3) with Li metal and a
catalytic amount of naphthalene (20 mol%), between –30 and –20 °C, led to relative complex reaction
mixtures containing, besides the desired alcohol (4a) unreacted starting material as well as several
unindentified reaction products (Table 2, Entries 1 and 2). A reaction run at 0 °C,under otherwise identical
conditions, led to complete conversion of the starting material, but afforded an intractable reaction mixture
(Table 2, Entry 3).
Better results were obtained employing, as a reducing agent, K in the presence of a catalytic amount of
naphthalene (20 mol%), at –30 °C. Under the new conditions, aqueous work up allowed the recovery of
tetrahydroisoquinoline (4a) in 50% isolated yield (Table 2, Entry 4). Under similar conditions, D2O
quenching evidenced the formation of an intermediate organometal derivative. To our surprise, however,
the resulting tetrahydroisoquinoline (4b) incorporated deuterium at C-4, not at C-1 (Table 2, Entry 5).

Furthemore, quenching a similar reduction mixture with C4H9Br, led to the formation of the
4-alkyl-substituted tetrahydroisoquinoline (4c) in 33% isolated yield (Table 2, Entry 6).
Structures of tetrahydroisoquinolines (4b) and (4c) were unambiguously determined by means of their
NMR spectra (see EXPERIMENTAL). Indeed, the 1H NMR spectrum of compound (4b) showed a 2 H’s
singlet at 3.71, assigned to protons at C-1, and amultiplet at 2.88-2.95, assigned at C-4, with an integration
corresponding to 1.25 protons. The last resonance has to be compared with a 2 H’s multiplet (2.92-2.98),
assigned to protons at C-4 in the 1H NMR spectrum of non-deuterated tetrahydroisoquinoline (4a).
1
Accordingly, the H NMR spectrum of the 4-butyl-substituted tetrahydroisoquinoline (4c) showed two
doublets corresponding to 1 H each, at δ 3.62 and 3.83 (J = 15.2 Hz), assigned to diastereotopic protons at
C-1.Finally, its off-resonance decoupled 13CNMR spectrum exhibits adoublet at δ38.0, in agreement with
the chemical shift of a benzylic carbon, not substituted with a nitrogen atom.
These results represents a strong evidence that reductive metalation of tetrahydroisoquinoline (3) occurs
with generation of a carbanionic center at C-1 which, successively, rearranges to the corresponding C-4
carbanion. To the best of our knowledge, such aprototropic rearrangement is without precedent, and it has
no similarities with the results observed in the reductive lithiation of tetrahydroisoquinoline (1).
To rationalize these results, we assume that the carbanionic center at C-4 is less basic than the carbanionic
center at C-1, due to the presence of the nitrogen atom. Furthermore, K as a counter ion enhances this
difference, as compared with Li, thus promoting the prototropic rearrangement. From this point of view, it
is worth noting that metalation of tetrahydroisoquinolines occurs selectively at C-4,2 whilst the higher
basicity of potassium organometals, with respect to lithium organometals, is well documented.14,15
Although unexpected, these findings disclose a new approach to 4-substituted N-alkyltetrahydro-
isoquinilines.
EXPERIMENTAL
Boiling and melting points are uncorrected; the air bath temperature on bulb-to-bulb distillation are given as
boiling points. Starting materials were of the highest commercial quality and were purified by distillation
immediately prior to use. Li wire, 99.9 % purity, was 3.2 mm diam., and D2O was 99.8% isotopic purity.
THF was distilled from Na/K alloy under N2 immediately prior to use. 1H NMR spectra were recorded at
13
300 MHz and C NMR spectra were recorded at 75 MHz in CDCl3 (unless otherwise indicated), with
SiMe4 as internal standard, on a Varian VXR 300. Deuterium incorporation was calculated by monitoring
1
the H NMR spectra of crude reaction mixtures, and by comparing the integration of the signal
corresponding to protons in the arylmethyl position with that of known signals. IR spectra were obtained on
thin films with a Perkin Elmer 1310 spectrophotometer. Flash chromatography were performed on Merck
silica gel 60 (40-63 µm), and TLC analyses on Macherey-Nagel silica gel pre-coated plastic sheets (0.20

mm). Elemental analyses were performed by the microanalytical laboratory of the Dipartimento di
Chimica, Università di Sassari.
1-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1): Methyl iodide (12.83 g,90.4 mmol) was added,
under dry N2, to a well stirred suspension of 3,4-dihydroisoquinoline7 (5.93 g,45.2 mmol) in 70 mL of dry
acetone. The resulting mixture was stirred at rt overnight, during which time a yellow solid separated. The
yellow solid was filtered off, washed with cold acetone and dried, to afford
2-methyl-3,4-dihydroisochinolinium iodide (9.87 g, 80%), mp 127-128 °C (lit.,8 mp 127-128 °C), which
was not further characterized.
Na metal (0.84 g, 36.5 mg atom) was dissolved, under N2, in dry CH3OH (60 mL).The solution was chilled
to 0°C, and the yellow solid was added in small portions. The resulting mixture was stirred for 20 min,then
allowed to warm to rt, filtered and the solvent evaporated in vacuo.
The residue was dissolved in Et2O (100 mL), filtered again, and the solvent evaporated to afford a residue
which, distilled in vacuo, afforded a colourless oil (4.50 g, 56% overall), characterized as follows: bp
65 °C/1 mmHg ; 1H NMR (CD3OD) δ 2.57 (3H, s, NCH3), 2.64-3.36 (4H, m, 2 xCH2), 3.39 (3H, s,OCH3),
13
4.82 (1H, s, CH), 7.14-7.33 (4H, m, 4 x ArH); C NMR (CD3OD) δ 28.5, 41.5, 47.4, 49.8, 93.7, 126.9,
128.9, 129.1, 129.6, 135.6, 136.3; Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C,74.37;
H, 8.65; N, 8.15.
2,3,6,10b-Tetrahydro-5H-oxazolo[2,3-a]isoquinoline (3):Compound (3) was synthesized according to a
literature procedure,9 in 76%overall yield, and was characterized as follows:mp 48-50 °C (lit.,9 mp 50 °C);
1
Rf = 0.35 (petroleum ether/AcOEt/Et3N = 4:6:1); H NMR (DMSO-d6) δ 2.56-2.88 (4H, m, 2 x CH2),
3.08-3.18 (1H, m, CH) 3.23-3-31 (1H, m, CH), 3.60-3.67 (1H, m, CHO), 3.72-3.80 (1H, m, CHO), 5.06
(1H, s, ArCHO), 7.15-7.32 (4H, m, 4 x ArH); 13C NMR (DMSO-d6) δ 29.1, 44.7, 54.1, 61.4, 89.6, 125.9,
127.9, 128.0, 128.8, 132.3, 135.0.
Reductive cleavage of tetrahydroisoquinolines (1) and (3) and reaction with electrophiles. General
procedure: Li wire (210 mg, 30 g atom) was placed under Ar in a two-necked flask equipped with reflux
condenser and magnetic stirrer, and suspended in dry THF (15 mL).A catalytic amount of naphthalene (77
mg, 0.6 mmol) was added to the suspended metal, each metal piece was cut into 2-3smaller pieces with a
spatula, and the mixture stirred until a dark green colour appeared.
Alternatively, K dispersion was prepared in asimilar apparatus by vigorously stirring the freshly cut metal
(1.17 g, 30 gatom) in dry THF (15 mL) at reflux temperature for 10 min; the metal suspension was allowed

to cool to rt without stirring. A catalytic amount of naphthalene (77 mg, 0.6 mmol) was added to the
suspended metal, and the mixture stirred until a dark green colour appeared.
The mixture was chilled to the reported temperature (Tables) and a solution of the appropriate
tetrahydoisoquinoline (3 mmol), dissolved in 5 mL of dry THF, was added dropwise. The mixture was
stirred for the reported time (Tables), and a solution of the appropriate electrophile (1.2 equiv) in THF (2
mL) was slowly added. After stirring for 30 min, the mixture was quenched by slow dropwise addition of
H2O (10 mL, caution), the cold bath removed, and the resulting mixture extracted with Et2O (3 x 10 mL).
The organic phase was washed with brine (10 mL), dried (K2CO3) and the solvent evaporated.
Reaction products were characterized as follows.
2-Methyl-1,2,3,4-tetrahydroisoquinoline (2a): Purified by flash chromatography (petroleum
ether/AcOEt/Et3N = 6:4:1), Rf = 0.50; bp 102 °C/20 mmHg (lit.,16 bp 50-52/0.1 mm/Hg); 1H NMR δ 2.45
(3H, s, NCH3),2.68 (2H, t,J = 6.0 Hz, CH2), 2.92 (2H, t, J =6.0 Hz, CH2), 3.58 (2H, s, CH2), 6.98-7.04 (1H,
m, ArH), 7.06-7.18 (3H, m, 3 xArH); 13C NMR δ 29.2, 46.0, 52.8, 57.9, 125.5, 126.1, 126.4, 126.6, 133.8,
134.7.
1-Deutero-2-methyl-1,2,3,4-tetrahydroisoquinoline (2b): Purified by flash chromatography (petroleum
ether/AcOEt/Et3N =6:4:1), Rf = 0.50; 1H NMR δ 2.45 (3H, s, NCH3), 2.64-2.74 (2H, m, CH2), 2.92 (2H, t,
CH2, J = 6.0 Hz), 3.54 (1.4 H, br s, CHD, 60% D content), 6.98-7.04 (1H, m, ArH), 7.06-7.18 (3H, m, 3 x
ArH); 13C NMR δ 29.0, 45.9, 52,8, 57.4 (t, J = 21 Hz), 125.5, 126.1, 126.3, 127.6, 133.6, 134.3.
1-Benzyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (2c): Purified by flash chromatography (petroleum
ether/Et3N =10:1), Rf = 0.37; bp 95-100 °C/1 mmHg (lit.,17 177-180 °C/12 mmHg);1H NMR δ 2.50 (3H, s,
NCH3 ), 2.65 (1H, dt, J = 15.9, 4.8 Hz, CH), 2.76 (1H, dt, J = 12.0, 4.8 Hz, CH), 2.81-2.95 (2H, m, CH2),
3.12-3.26 (2H, m, CH2), 3.81 (1H, t, J=6.3 Hz, ArH), 6.75 (1H, d, J =7.8 Hz, ArH), 6.98-7.14 (5H, m, 5x
13
ArH), 7.15-7.29 (3H, m, 3 x ArH); C NMR δ 25.9, 41.5, 42.8, 47.0, 65.0, 125.3, 125.9, 125.9, 127.9,
128.0, 128.7, 129.6, 134.3, 137.8, 140.0.
1-Hexyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (2d): Purified by flash chromatography (petroleum
1
ether/AcOEt/Et3N = 9.5:0.5:1), Rf = 0.53; bp 90-95 °C/1 mmHg; H NMR δ 0.82-0.91 (3H, m, CH3),
1.16-1.45 (8H, m, 4 xCH2), 1.64-1.84 (2H, m, CH2), 2.45 (3H, s, NCH3), 2.62-2.74 (1H, m, CH), 2.76-2.88
(2H, m, CH2), 3.08-3.17 (1H, m, CH), 3.43 (1H, t, J = 5.4 Hz, CH), 6.98-7.20 (4H, m, 4 xArH); 13C NMR
δ 14.1, 22.7, 25.5, 26.2, 29.7, 31.8, 34.9, 42.9, 48.4, 63.8, 125.6, 125.6, 127.1, 128.6, 134.6, 138.6; Anal.
Calcd for C16H25N: C, 83.06; H, 10.89; N, 6.05. Found: C, 82.91; H, 11.02; N, 6.07.

2-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (2e): Purified by flash chromatography
(AcOEt/MeOH/Et3N =10:0.1:1), Rf = 0.61; bp 65-70 °C/1 mmHg; vmax/ cm–1 3440; 1H NMR δ 0.89 (3H, s,
CH3), 1.34 (3H, s, CH3), 2.52-2.60 (1H, m, CH), 2.60 (3H, s, NCH3), 2.70-2.78 (1H, m, CH),2.79-2.87 (1H,
m, CH), 3.34 (1H, quint, J = 5.6 Hz, CH), 3.48 (1H, s, CH), 4.25 (1H, br s, OH), 7.10-7.20 (4H, m, 4 x
ArH); 13C NMR δ 25.8, 27.5, 29.0, 46.9, 50.6, 72.5, 73.3, 125.5, 126.5, 128.1, 129.0, 134.1, 136.2; Anal.
Calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.95; H, 9.42; N, 6.75.
1-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)cyclohexan-1-ol (2f): Purified by flash chromatography
(petroleum ether/AcOEt/Et3N = 6:4:1), Rf = 0.66; bp 90-95 °C/1 mmHg; vmax/ cm–1 3460; 1H NMR δ 0.84
(1H, td, J=13.2, 4.4 Hz, CH), 0.92-1.06 (1H, m, CH), 1.32-1.44 (2H, m, CH2), 1.50-1.75 (6H, m, 3 xCH2),
2.50 (1H, td, J=10.4, 4.0 Hz, CH), 2.58 (3H, s, NCH3), 2.67 (1H, dt, J=16.0, 4.8 Hz, CH), 2.68 (1H, dt, J
=16.0, 4.8 Hz, CH), 3.28-3.40 (2H, m, CH2), 3.84 (1H, br s, OH), 7.08-7.20 (4H, m, 4 xArH). 13C NMR δ
21.8, 22.3, 25.7, 28.1, 33.5, 36.8, 47.2, 51.3, 73.3, 74.1, 125.4, 126.4, 127.9, 129.4, 134.3, 136.8; Anal.
Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C, 78.21; H, 9.73; N, 5.60.
1-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)cyclopentan-1-ol
(2g):
Purified
by
flash
chromatography (petroleum ether/AcOEt/Et3N =6:4:1), Rf = 0.63; bp 85-90 °C/1 mmHg; vmax/ cm–1 3440;
1H NMR δ 1.18-1.88 (8H, m, 4 x CH2), 2.59 (3H, s, NCH3), 2.68-2.92 (4H, m, 2 xCH2), 3.32-3.46 (1H, m,
CH), 3.72 (1H, br s, OH), 7.11-7.21 (4H, m, 4 x ArH); 13C NMR δ 22.9, 23.9, 25.2, 36.3, 39.5, 44.5, 48.1,
69.8, 83.4, 125.6, 126.8, 128.6, 129.2, 134.5, 136.8; Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05.
Found: C, 77.73; H, 9.38; N, 5.94.
2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)ethanol
(4a):
Purified
by
flash
chromatography
(AcOEt/MeOH/Et3N =9:3:1); Rf =0.43; bp 140-145 °C/1 mmHg (lit.,18 164-166 °C/12 mmHg); vmax/ cm–1
3410; 1H NMR δ 2.75-2.80 (2H, m, CH2), 2.84-2.91 (2H, m, CH2), 2.92-2.98 (2H, m, CH2), 3.17 (1H, br s,
OH), 3.72-3.76 (2H, m, CH2O), 3.78 (2H, s, ArCH2N), 7.00-7.06 (1H, m, ArH), 7.10-7.19 (3H, m, 3 x
ArH);13C NMR δ 28.8, 50.5, 55.5, 57.9, 58.9, 125.7, 126.3, 126.5, 128.6, 133.9, 134.8.
2-(4-Deutero-1,2,3,4-tetrahydroisoquinolin-2-yl)ethanol (4b): Purified by flash chromatography
(AcOEt/MeOH/Et3N = 9:3:1); Rf = 0.43; 1H NMR δ 2.70-2.74 (2H, m, CH2), 2.79-2.84 (2H, m, CH2),
2.88-2.95 (1.25 H, m, CHD, 75% D content), 3.21 (1H, br s, OH), 3.68-3.74 (2H, m, CH2O), 3.71 (2H, s,
ArCH2N) 7.00-7.06 (1H, m, ArH), 7.10-7.19 (3H, m, 3 x ArH).

2-(4-Butyl-1,2,3,4-tetrahydroisoquinolin-2-yl)ethanol (4c): Purified by flash chromatography
1
(petroleum ether/AcOEt/Et3N = 4:6:1); Rf = 0.43; bp 105-110 °C/0.1 mmHg; vmax/ cm–1 3380; H NMR
δ 0.83-0.96 (3H, m, CH3), 1.28-1.46 (4H, m, 2 x CH2), 1.66-1.76 (2H, m, CH2), 2.66-2.90 (5H, m, 2xCH2,
CH), 3.08 (1H, br s, OH), 3.62 (1H, d, J=15.2 Hz, CH2), 3.72 (2H, t, CH2, J=5.6 Hz), 3.83 (1H, d, J=15.2
Hz, CH2), 7.01-7.04 (1H, d, J = 6.8 Hz, ArH), 7.11-7.23 (3H, m, 3 x ArH); 13C NMR δ 14.0 (q), 22.8 (t),
29.5 (t), 35.5 (t), 38.0 (d), 54.6 (t), 56.2 (t), 57.9 (t), 59.1 (t), 125.7 (d), 126.4 (d), 126.4 (d), 128.1 (d), 133.7
(s), 138.7 (s) ; Anal. Calcd for C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.04; H, 10.12; N, 6.13.
ACKNOWLEDGEMENTS
Financial support from the Università di Sassari, ex-60% funds, is gratefully acknowledged.
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