The synthesis of 3-methyl- and 3,4-dimethyltetrahydroisoquinolines by intramolecular hydroamination with n-butyllithium

Article abstract of DOI:10.1016/j.tetlet.2004.10.155

The synthesis of 3-methyltetrahydroisoquinolines and 3,4- dimethyltetrahydroisoquinolines from aromatic aminoalkenes using intramolecular hydroamination reactions, mediated by sub-stoichiometric amounts of n-butyllithium, is described.

Full text of DOI:10.1016/j.tetlet.2004.10.155

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9561–9563
The synthesis of 3-methyl- and
3,4-dimethyltetrahydroisoquinolines by intramolecular
hydroamination with n-butyllithium
Willem A. L. van Otterlo,* Rakhi Pathak, Charles B. de Koning and Manuel A. Fernandes
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, South Africa
Received 21 September 2004; accepted 27 October 2004
Available online 11 November 2004
Abstract—The synthesis of 3-methyltetrahydroisoquinolines and 3,4-dimethyltetrahydroisoquinolines from aromatic aminoalkenes
using intramolecular hydroamination reactions, mediated by sub-stoichiometric amounts of n-butyllithium, is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The tetrahydroisoquinoline (THIQ) skeleton is one of
NatureÕs most popular motifs as evinced by the large
number of natural products that have this organic
component in their structure.1–4 Some representative
examples of these include the naphthylisoquinoline
alkaloids, for example korupensamine B 1 and michell-
amine B 2,5 and saframycin A 32 (Fig. 1). As a result,
numerous THIQ alkaloids and their synthetic analogues
possessing useful pharmacological properties have been
studied. A topical example of this is 1-MeTHIQ 4, a
simple compound with activity against endogenous
ParkinsonÕs disease.6
cury-mediated method for the synthesis of the N-acetyl-
1,3-dimethyltetrahydroisoquinoline portion of these
molecules.9–11 This novel approach utilized an intra-
molecular amidomercuration-reduction to form the
tetrahydroisoquinoline ring system. Examples of hydro-
amination12–16 reactions are becoming increasingly
more important in academic and industrial applications
and include a recent paper describing the use of organo-
lanthanides as catalysts to synthesize 1-substituted
THIQs.17 This letter has prompted us to disclose our
work towards 3-methyl- and 3,4-dimethyl-THIQs utiliz-
ing an intramolecular hydroamination reaction medi-
ated by sub-stoichiometric amounts of n-butyllithium.18
We have been interested in the synthesis of analogues of
alkaloids 1 and 2,7,8 and recently disclosed a novel mer-
The initial experimental work involved in this project
entailed the synthesis of the ortho-allylbenzylamines 6a–
d (Scheme 1). This was accomplished by performing a
standard two-step reductive amination procedure on pre-
cursor 5.19 The amines 6a–d were thus obtained in excel-
lent yields and high purity without chromatography.
OMe
Me OH
O
Me
HN
Me
O
O
Me
O
OH
N
Me
Me
N
We next considered the use of hydroamination method-
ology, of which there are a plethora of recent literature
examples,20 to form the THIQ nucleus. In our hands,
work based on that accomplished by Seijas et al.21 and
Beller and co-workers22 on the intermolecular transam-
ination of styrenes with amines utilizing n-butyllithium
as catalyst gave interesting results.23 The ortho-allylated
benzylamines 6a–d were thus treated with sub-stoichio-
metric quantities of n-butyllithium at 60ꢁC (Scheme 2).
To our satisfaction, the THIQs 7a–d were obtained in
reasonable yields after purification by chromatogra-
phy.24 To the best of our knowledge this represents
MeO
CN
NH
n
3
MeO OH
O
O
1 (n =1)
2 (n =2)
NH
Me
Me
4
Figure 1. Topical examples of THIQs.
Keywords: Tetrahydroisoquinolines; Hydroamination; n-Butyllithium.
*
Corresponding author. Tel.: +27 11 717 6707; fax: +27 11 717
6749; e-mail: willem@aurum.chem.wits.ac.za
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.155

9562
W. A. L. van Otterlo et al. / Tetrahedron Letters 45 (2004) 9561–9563
CHO
Ref 19
CHO
CHO
MeO
MeO
MeO
OH
OiPr R1
OiPr
5
5
a,b
H
N
R2
a,b
MeO
Me
Me
H
N
H
N
Ph
or
MeO
Ph
OiPr R1
MeO
MeO
6
OiPr
9a
OiPr
c
Scheme 1. Reagents and conditions: (a) R2NH2, p-TSA, benzene or
toluene, Dean–Stark apparatus, reflux, 18h; (b) NaBH4, MeOH, H2O
(1 drop), 0ꢁC, 1h, yields over two steps: 6a, R1 = H, R2 = Bn, 99%; 6b,
R1 = H, R2 = n-Pr, 99%; 6c, R1 = Me, R2 = Bn, 92%; 6d, R1 = Me,
R2 = n-Pr, 97%.
9b
c
Me
Ph
Me MeO
Me
Ph
Me
N
N
OiPr
OiPr
10a
10b
H
N
R2
R2
d
N
a
Me
Me
MeO
MeO
c
Me
OiPr R1
OiPr R1
N
Ph
Me
7
6
MeO
b
OiPr
11
H
N
Bn
Scheme 3. Reagents and conditions: (a) (R)- or (S)-1-phenylethylam-
ine, p-TSA, benzene or toluene, Dean–Stark apparatus, reflux, 18h;
(b) NaBH4, MeOH, H2O (1 drop), 0ꢁC–rt, 18h, yields over two steps:
(R)-9a, 89%; (S)-9b, 98%; (c) n-BuLi (2 · 16mol%), rt, 6h, then 60ꢁC,
18h, yields: (10R)-10a, 75%, (10S)-10b, 79%; (d) MeI, recrystallized
from MeOH/EtOAc.
MeO
Me
8
OiPr
Scheme 2. Reagents and conditions: (a) n-BuLi (2 · 16mol%), rt, 6h,
then 60ꢁC, 18h, yields: 7a, R1 = H, R2 = Bn, 87%, 7b, R1 = H, R2 = n-
Pr, 65%, 7c, R1 = Me, R2 = Bn, 63% (5:1 cis:trans),26 7d, R1 = Me,
R2 = n-Pr, 62% (cis:trans ratio not determined); (b) for 6a, R1 = H,
R2 = Bn, n-BuLi (2 · 16mol%), rt, 18h, 96%; (c) n-BuLi (16mol%),
60ꢁC, 18h.
only gave a mixture of diastereomers with no diastereo-
selectivity bias. Careful inspection of the 1H NMR spec-
tra of (10R)-10a and (10S)-10b confirmed that the
cyclizations involving the chiral benzylamine derivatives
were unselective under these conditions.
the first application of this particular methodology to-
wards the synthesis of THIQs. Of interest was that when
similar reaction conditions were employed using sub-
strate 6a at ambient temperature, isomerized compound
8 was isolated in good yield. This suggests that the initial
step could involve isomerization of the allyl group to the
thermodynamically more stable styrene compound
followed by the intramolecular transamination. This
possibility is also supported by the work of Marks co-
workers17 and Molander and Pack,25 in which styrenes
are converted into THIQs by way of intramolecular
hydroamination using lanthanide catalysts. Subsequent
treatment of styrene 8 with n-butyllithium at 60ꢁC then
afforded the expected product 7a.
Quaternization of diastereomeric mixture 10a with
methyl iodide gave a solid from which 3-(10R, R)-11
was recrystallized (MeOH/EtOAc). A single crystal
X-ray structural determination was then done to con-
firm the postulated structure (Fig. 2).30
In summary, we have demonstrated the first examples of
intramolecular hydroaminations using sub-stoichiomet-
ric amounts of n-butyllithium to afford the ubiquitous
A point of interest is that this approach to THIQs
afforded 3,4-dimethyl compounds 7c and 7d in moderate
yields.26 A subsequent literature search revealed that
there are only a few published approaches to this type
of 3,4-dialkyl THIQs.27–29
At this point we attempted to see if the strategy de-
scribed in this letter was suitable for the stereoselective
synthesis of THIQs (Scheme 3). To this end, the precur-
sor 5 was readily converted into the amines (R)-9a and
(S)-9b, both containing the chiral 1-phenylethyl group.
Compounds (R)-9a and (S)-9b were then individually
subjected to n-butyllithium, but disappointingly this
Figure 2. ORTEP diagram of the X-ray crystal structure of compound
11 (iodide counter-ion not shown and ellipsoids at 50% probability).

W. A. L. van Otterlo et al. / Tetrahedron Letters 45 (2004) 9561–9563
9563
22. Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M.
Tetrahedron 2000, 56, 5157–5162.
23. For a recent application of an intramolecular cyclization
mediated by n-butyllithium see: Ates, A.; Quinet, C. Eur.
J. Org. Chem. 2003, 1623–1626.
THIQ skeleton. Further studies will now focus on the
application of this methodology to the synthesis of sim-
ple natural products as well as the investigation of
related methods to invoke stereoselectivity in the hydro-
amination reactions.
24. 2-Benzyl-5-isopropoxy-6-methoxy-3-methyl-1,2,3,4-tetra-
hydroisoquinoline (7a): General n-butyllithium procedure.
n-BuLi (0.035cm3, 1.4M, 0.049mmol, 0.16molequiv) was
added to a stirring solution of N-(2-allyl-3-isopropoxy-4-
methoxybenzyl)-N-benzylamine 6a (0.10g, 0.31mmol) in
THF (10cm3). The solution was stirred for 6h at rt after
which a further portion of n-BuLi (0.035cm3, 1.4M,
0.049mmol, 0.16molequiv) was added and the mixture
was heated for another 24h at 60ꢁC. The resulting mixture
was then extracted with Et2O (3 · 10cm3) which was dried
(MgSO4). The organic solvent was removed in vacuo and
the crude residue was then purified using column
chromatography (5–20% EtOAc/hexane) to give 2-benz-
yl-5-isopropoxy-6-methoxy-3-methyl-1,2,3,4-tetrahydro-
isoquinoline 7a, as a light brown oil (0.087g, 87%). Found:
M+, 325.2042; C21H27NO2 requires 325.2042); mmax
(CHCl3)/cmꢀ1 1575 (ArC@C) and 1277 (C–O); dH
(300MHz; CDCl3; Me4Si) 1.13 (3H, d, J = 6.5Hz,
NCHCH3), 1.28 and 1.28 [6H, 2 · d, J = 6.1Hz,
OCH(CH3)2], 2.64 (1H, dd, J = 16.8 and 5.9Hz, 4-Hax),
2.91 (1H, dd, J = 16.9 and 4.9Hz, 4-Heq), 3.04–3.10 (1H,
m, 3H), 3.48–3.77 (4H, m, 1H and NCH2Ph), 3.80 (3H, s,
OCH3), 4.48 [1H, br sept, J = 6.2Hz, CH(CH3)2], 6.64
(1H, d, J = 8.4, ArH), 6.71 (1H, d, J = 8.4, ArH) and 7.22–
7.38 (5H, m, 5 · ArH); dC (75MHz; CDCl3, assignments
with the same superscript may be interchanged) 15.0
(CH3), 22.6 and 22.7 [CH(CH3)2], 30.8 (4C), 51.0 (1C)a,
51.7 (NCH2Ph)a, 55.6 (3C),b 57.2(OCH 3),b 74.1
[CH(CH3)2], 110.2 (CH), 121.0 (CH), 126.7 (CH), 127.5
(C), 128.1 (CH), 128.8 (C), 128.9 (CH), 139.3 (C), 144.6
(C–O) and 150.6 (C–O); m/z 325 (M+, 64%), 310 (100), 266
(37), 192(72) and 176 (41).
Acknowledgements
This work was supported by the National Research
Foundation (NRF, GUN 2053652), Pretoria and the
University of the Witwatersrand (University and Fac-
ulty Research Council). Prof. J. P. Michael is thanked
for many helpful discussions and Mr. R. Mampa is
thanked for providing the NMR spectroscopy service.
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and ꢀ0.343eAꢀ3; final R indices: R1 = 0.0321, wR2 =
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obtained free of charge at www.ccdc.cam.ac.uk/conts/
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Data Centre, 12, Union Road, Cambridge CB2 1EZ,
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