Synthesis of tetrahydroisoquinoline-diamine ligands and their application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2010.04.017

The use of the tetrahydroisoquinoline scaffold is well documented in biologically active compounds. However, reports of the utilisation of tetrahydroisoquinoline compounds in asymmetric catalysis are limited. The synthesis of novel diamine ligands possessing the tetrahydroisoquinoline (tetrahydroisoquinoline) backbone and evaluation of their activity in the asymmetric transfer hydrogenation of acetophenone are presented. The diamine ligands in conjunction with i-PrOH as the hydrogen source and [RhCl₂(Cp*)]₂ as the metal precursor proved to be the most effective of the tetrahydroisoquinoline derivatives for this catalytic system. Water was found to have a profound influence on the enantioselectivity of the reaction. Optimisation of the amount water, i-PrOH and catalytic loading content rendered the best result of 70% enantioselectivity for the (S)-1-phenylethanol isomer product.

Full text of DOI:10.1016/j.tetasy.2010.04.017

Tetrahedron: Asymmetry 21 (2010) 679–687
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of tetrahydroisoquinoline-diamine ligands and their application
in asymmetric transfer hydrogenation
Byron K. Peters a, Sai Kumar Chakka a, Tricia Naicker a, Glenn E. M. Maguire a, Hendrik G. Kruger a,
,
*
Pher G. Andersson c, Thavendran Govender b,
*
a School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
b School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban, South Africa
c Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of the tetrahydroisoquinoline scaffold is well documented in biologically active compounds.
However, reports of the utilisation of tetrahydroisoquinoline compounds in asymmetric catalysis are lim-
ited. The synthesis of novel diamine ligands possessing the tetrahydroisoquinoline (tetrahydroisoquino-
line) backbone and evaluation of their activity in the asymmetric transfer hydrogenation of acetophenone
are presented. The diamine ligands in conjunction with i-PrOH as the hydrogen source and [RhCl2(Cp*)]2
as the metal precursor proved to be the most effective of the tetrahydroisoquinoline derivatives for this
catalytic system. Water was found to have a profound influence on the enantioselectivity of the reaction.
Optimisation of the amount water, i-PrOH and catalytic loading content rendered the best result of 70%
enantioselectivity for the (S)-1-phenylethanol isomer product.
Received 2 February 2010
Accepted 19 April 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
an electron-withdrawing group. Inherently the p-toluene sulfonyl
(tosyl) proved effective, which in turn spawned the (1S,2S)-N-(p-
Since the isolation of naphthyridinomycin in 1974, the biologi-
cal activity of tetrahydroisoquinoline carboxylic acid derivatives
has been widely investigated.1–3 Previous reports on the use of tet-
rahydroisoquinoline derivatives as catalytic ligands have yielded
limited success, with poor to moderate enantioselectivities in
asymmetric catalysis such as allylic alkylation4 and borane-medi-
ated hydrogenation reactions.5,6 However, in a related study the
use of different tetrahydroisoquinoline ligands for the addition of
diethylzinc to benzaldehyde gave promising results.7 We have
recently reported the use of tetrahydroisoquinoline amino alcohol
derivatives to catalyse the asymmetric transfer hydrogenation of
prochiral ketones with high reaction rates and moderate to good
selectivities.8
It has been shown in the literature that amine and diamine-
based ligands can be used for various asymmetric catalytic
reactions.9–13 Noyori et al. reported a variety of simple amino alco-
hols and diamines with a ruthenium precursor, an i-PrOH source
and KOH as a co-catalyst for the reduction of acetophenone (see
Fig. 1).14,15 It was noted that a two carbon bridge between the do-
nors formed the ideal chelator, and that unlike the amino alcohols,
the diamines required one of the amines to be functionalised with
toluenesulfony1)-1,2-diphenylethylenediamin (Ts-DPEN) 1.15
Tos NH
NH2
1
Since this discovery there has been a surge of interest into
asymmetric transfer hydrogenation, with the development of
many successful catalysts.16–20 Other studies have attempted to
optimise the performance of these catalysts, by varying sterics,
electronics and the solubility properties.21,22 Development of the
triethylamine: formic acid azeotrope (TEAF) and more recently for-
mate salts in aqueous media have also broadened the scope for
activity and selectivity.23,20 The aqueous systems show promise
and in many cases enhanced overall performance have been ob-
served in the presence of water. A rigorous screening of these vari-
ables is necessary to discover the potential of any new ligand.
Herein we report a systematic study of novel diamine ligands
possessing the tetrahydroisoquinoline as a rigid and tunable chiral
backbone for pre-catalysts to the asymmetric reduction of
acetophenone.
* Corresponding author.
E-mail address: govenderthav@ukzn.ac.za (T. Govender).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.017

680
B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
R
N
H
NH
2
(S)
(R)
b
a
c
e
d
f
g
O
O
N
H
NH
Ts
N
NH2
H
NH
NH
2i
2h
2j
Figure 1. Diamine ligands studied for activity in asymmetric transfer hydrogenation.
Ligand 2i (Scheme 2) was prepared as previously reported.24,25
Esterification of 3 via an in situ reaction to form the acyl chloride
with thionyl chloride followed by condensation with methanol
gave the methyl ester hydrochloride salt 7. Conversion to the
amide 8 was achieved by the treatment of this salt with a large ex-
cess of 25% ammonium hydroxide with stirring for several hours
followed by reduction of the amide with LiAlH4 in refluxing THF
afforded the desired ligand 2h.
Ligand 2h (Scheme 3) could not be prepared following the
same approach as for 2a–g, due to racemisation, which was ob-
served under LiAlH4 reduction conditions. Therefore an alternate
procedure employing a milder reduction condition was sought.
2. Results and discussion
2.1. Synthesis
Ligands 2a–g (Scheme 1) were synthesised from commercially
available tetrahydroisoquinoline amino acid 3. Benzyl carbamate
(Cbz) protection of 3 allowed for subsequent coupling of the
respective amines to yield 5a–g. Thereafter, removal of the Cbz
group with palladium on carbon (Pd/C) and one atmosphere of
hydrogen (H2) gas afforded the amides 6a–g. The desired diamine
products were obtained by lithium aluminium hydride (LiAlH4)
reduction of 6a–g.
O
O
O
R
OH
NH.HCl
OH
Cbz
N
H
i
ii
N
N
Cbz
3
4
5a-g
iii
O
R
R
vi
N
H
N
H
NH
NH
6a-g
2a-g
Scheme 1. Synthetic route used to prepare 2a–g. Reagents and conditions: (i) KHCO3, dioxane, water, Cbz-Cl; (ii) EDCꢀHCl, HOBt, R-NH2, DMAP, DMF; (iii) 10% wt. Pd/C, H2,
MeOH, THF; (iv) LiAlH4, THF.

B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
681
O
O
O
NH2
NH2
i
ii
iii
3
NH.HCl
NH
NH
8
2h
7
Scheme 2. Synthetic route used to prepare 2h. Reagents and conditions: (i) SOCl2, MeOH; (ii) 25% NH4OH; (iii) LiAlH4, THF.
O
O
O
O
O
OH
Cbz
OH
H
i
ii
N
NH
N
O
O
Cbz
9
10
11
iii
O
O
O
N
H
N
H
N
NH
iv
O
Cbz
2i
12
Scheme 3. Synthetic route used to prepare 2i. Reagents and conditions: (i) KHCO3, dioxane/water, Cbz-Cl; (ii) PCC, dry DCM; (iii) benzylamine, NaCNBH4, MeOH/THF; (iv) 10%
wt. Pd/C H2 1 atm, MeOH/THF.
Cbz protection of the amino alcohol 98 yielded 10 which was sub-
sequently oxidised with pyridinium chlorochromate to obtain
compound 11. Reductive amination on 11 using benzyl amine
and sodium cyanoborohydride afforded the desired product 12.
Selective deprotection of the N-Cbz group of 12 with Pd/C at
one atm H2 furnished 2i.
Ligand 2j (Scheme 4) was prepared from the amide 8, which
was Cbz protected to form 13. Using NaBH4 with acetic acid in
dioxane,26 the amide was reduced without cleavage of the Cbz
group to yield 14. Reaction of 14 with toluene sulfonyl with
base followed by removal of Cbz with Pd/C at one atm H2 ren-
dered 2i.
2.2. Structural modifications
Given the amines were designed to incorporate broad structural
diversity to investigate the scope of tetrahydroisoquinoline-dia-
mine ligands in asymmetric transfer hydrogenation, we proceeded
to modify the backbone by changing the structural features of the
substituent on the amine (see Fig. 1) and tested them for activity in
asymmetric transfer hydrogenation of acetophenone (see Table 1).
The groups were chosen to cover both steric and electronic charac-
ter. Ligand 2a was the first of the diamine derivatives to be pre-
pared and tested for its catalytic activity in asymmetric transfer
hydrogenation, producing reasonable results (81% conv., 70% ee,
O
Ts
NH2
NH2
Cbz
N
H
ii
iii
iv
i
8
N
N
NH
Cbz
13
14
2j
Scheme 4. Synthetic route used to prepare 2j. Reagents and conditions: (i) KHCO3, dioxane/water, Cbz-Cl; (ii) NaBH4, AcOH, dioxane, reflux; (iii) TsCl, DCM, TEA; (iv) 10% wt.
Pd/C H2 1 atm, MeOH/THF.

682
B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
Table 1
of water from 2 to 400 equiv showed the selectivity to improve
even more (entries 2–6). Thereafter raising the amount of water
to a 1000 and then further to 3000 equiv a maximum was
reached with an optimum of 70% enantioselectivity (entries 7–
9). Extending the amount to 50:50 i-PrOH/water (many times ex-
cess) destroyed the reactivity completely (entry 10). Since reac-
tivity dropped significantly at 3000, 1500 equiv was taken as
the best compromise between reactivity and selectivity for subse-
quent testing.
Asymmetric transfer hydrogenation of acetophenone by ligand 2a–j rhodium
complexes
OH
O
2a-i, [RhCl (Cp*)]
2
2
i-PrOH, t-BuOK, H O
2
Entry
Ligand
Conv. (%)
ee (%)
Isomer
2.4. Metal and donor study
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
81
22
—
70
11
—
S
S
—
—
S
R
S
—
—
—
Compound 2a was chosen as a representative of the di-second-
ary amine ligands for this study, the results of which are shown in
Table 3. Entries 1 and 4 show that very little activity is observed
—
—
67
24
5.5
—
—
—
71
77
51
—
—
—
Table 2
Results of the effect in varying the water content on of acetophenone by rhodium
complexes of ligands 2a–h
10
2j
OH
O
All reactions were carried out at 25 °C. In the case where the hydrogen source is
HCO2K the solvent used was water.
2a, [RhCl (Cp*)]
2
2
i-PrOH was used as the solvent when employed as the HS along with t-BuOK as the
base. Testing was carried out using a S/C of 100.
i-PrOH, t-BuOK, H O
2
aMeasured by GC with chiral capillary column b-DEX™ 120.
entry 1). Derivatives 2b and 2c (entries 2 and 3) possessing a di-
phenyl and aniline groups, respectively, inherently make the nitro-
gen more acidic. Unfortunately 2b demonstrated very poor
reactivity and little selectivity (22% conv., 11% ee, entry 2) while
2c showed no activity at all (entry 3). When the pKa on the nitrogen
was increased using derivatives 2d (methyl) and 2e (iso-propyl), 2d
also showed no activity (entry 4). However, 2e was found to pos-
sess moderate reactivity with fair selectivity (67% conv., 71% ee,
entry 5). It seemed apparent that the electronic effects of the sub-
stituent’s on the nitrogen were not the issue, but rather a steric
argument dictating the selectivity. To examine further, chiral
amines possessing a benzyl and methyl group were employed. This
would offer similar influence on the pKa as that for the benzyl on
2a and less steric crowding than the diphenyl group on 2b. Prom-
ising results were obtained with the (R)-benzyl-methyl amine
derivative 2f (24% conv., 77% ee, entry 6) yielding the (R)-1-phen-
ylethanol enantiomers, which then led us to try the (S) isomer. The
(S)-benzyl-methyl amine derivative 2g showed lower reactivity
and selectivity than the (R) enatiomer (5.5% conv., 51% ee, entry
7), but had preference for the expected (S)-1-phenylethanol enan-
tiomer. Compound 2h was prepared to determine whether the pri-
mary amine could also be used as a ligand in asymmetric transfer
hydrogenation reaction, but it was found to have no activity in this
reaction (entry 8). Out of curiosity, and given our recent success
with the amino alcohol derivative of the C1-substituted tetrahy-
droisoquinoline ligand 2i, was prepared (Scheme 3). Disappoint-
ingly, this auxiliary showed no activity (entry 9). Based on the
significant increase in rate an often selectivity observed upon tosy-
lation of one of the amine donors we investigated 2j for activity in
asymmetric transfer hydrogenation of acetophenone. However the
ligand was found to have no activity at all (entry 10).
Entry
Molar equiv H2O to rhodium
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
1
2
10
100
200
400
1000
1500
3000
50:50
64
81
88
92
88
92
94
81
61
—
27
43
45
54
62
66
68
70
70
—
9
10b
All reactions were carried out at 25 °C. In the case where the hydrogen source is
HCO2K the solvent used was water.
i-PrOH was used as the solvent when employed as the hydrogen source along with
t-BuOK as the base. Testing was carried out using a S/C of 100.
aMeasured by GC with chiral capillary column b-DEX™ 120.
b
A 50/50 mixture of water and i-PrOH was used.
Table 3
Asymmetric transfer hydrogenation of acetophenone by different hydrogen sources
and ligand 2a metal complexes
OH
O
2a, metal precursor
HS, solvent
Entry Metal complex
Hydrogen
source
Conv.a
(%)
eea
(%)
Isomer
1
[Ru(p-
KCO2H
2
10
R
cymene)Cl2]2
[IrCl2(Cp*)]2
[RhCl2(Cp*)]2
[Ru(p-
2
3
4
KCO2H
KCO2H
i-PrOH
10
43
—
25
50
—
R
R
—
2.3. Effect of the water
cymene)Cl2]2
[IrCl2(Cp*)]2
[RhCl2(Cp*)]2
[RhCl2(Cp*)]2
RhPPh3COH
5
6
7
8
i-PrOH
i-PrOH
TEAF
40
90
—
—
—
—
—
S
—
R
As stated earlier it has been demonstrated in the literature
that water has the potential to influence performance of a cata-
lyst in asymmetric transfer hydrogenation reactions.20,21,27–32 This
prompted us to investigate how much water was necessary to ob-
tain the highest enantiomeric excess using ligand 2a (Table 2).
Adding 1 equiv of water to the metal complex was found to in-
crease activity (27%, entry 1). Progressively increasing the amount
i-PrOH
10
48
All reactions were carried out at 25 °C. In the case where the hydrogen source is
HCO2K the solvent used was water.
i-PrOH was used as the solvent when employed as the hydrogen source along with
t-BuOK as the base. Testing was carried out using a S/C of 100.
a
Measured by GC with chiral capillary column b-DEX™ 120.

B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
683
when the asymmetric transfer hydrogenation reaction is carried out
in water using potassium formate on the hydrogen source (2%, entry
1), and no activity with the i-PrOH (entry 4) when [Ru(p-cyme-
me)Cl2]2 is employed as the metal precursor. The same held for
the formate hydrogen source with [IrCl2(Cp*)]2 (10%, entry 2). How-
ever a marked increase in activity was observed when the hydrogen
source was changed to i-PrOH (40%, entry 5). Implementing a
[RhCl2(Cp*)]2 precursor rendered significant activity with the for-
mate (43%, entry 3), but the greatest catalytic activity was seen
when the i-PrOH was used instead (90%, entry 6). The results for
the [RhCl2(Cp*)]2 prompted us to investigate whether using the
TEAF hydrogen source could increase activity. Unfortunately this
proved unsuccessful (entry 7). Changing from the [RhCl2(Cp*)]2
(arene) to the RhPPh3COH (hydride) did not improve on the
[RhCl2(Cp*)]2 system (10%, entry 8). Therefore optimised conditions
were found to be with the use of [RhCl2(Cp*)]2 precursor and i-PrOH.
was allowed to cool to ambient temperature. The desired amount
of acetophenone was then added (S/C = 100) followed by freshly
prepared 0.1 M t-BuOK (2 equiv to metal) in i-PrOH. To monitor
the reactions, small aliquots were drawn, diluted with i-PrOH
and then run through a small plug of silica to remove any catalyst.
The eluted sample was then injected into the GC.
4.2.2. i-PrOH hydrogen source in water
The reaction was carried out as reported above with the excep-
tion that the water was added after complexation and just before
the addition of acetophenone. Monitoring of the progress of the
reaction remained the same.
4.2.3. Formate hydrogen source
The metal precursor and ligand were complexed as describe
above. Water was then added (2 mL), and the reaction mixture
heated to 40 °C and stirred for 30 min. The mixture was then cooled
and the acetophenone (S/C = 100) was added followed by the potas-
sium formate. To monitor the reactions, small aliquots were drawn
and extracted with hexane, which were then used for GC analysis.
3. Conclusions
We have prepared a series of diamine ligands possessing the
tetrahydroisoquinoline backbone and tested them for activity in
the asymmetric transfer hydrogenation of acetophenone. The
amine donors were all secondary in nature, ligands 2a–g and i,
with the exception of 2h which possessed both a primary and sec-
ondary amine. It was found that when using [RhCl2(Cp*)]2 in con-
junction with an i-PrOH, the best conversion achieved was 92% in
1 h. Furthermore, it was determined that no selectivity was ob-
tained under anhydrous conditions, and that an optimum of
1500 equiv of water to rhodium gave the best selectivity of 77%
ee for ligand 2f. However with regards to the best overall catalytic
performance, ligands 2a and 2d bearing the benzyl and isopropyl
substituents, respectively, shared both good reactivity and selec-
tivity for the asymmetric reduction of acetophenone. We believe
that these ligands could be successfully employed as catalysts for
other asymmetric transformations.
4.2.4. TEAF hydrogen source
The TEAF was prepared as reported in the literature.23 The metal
precursor and ligand were stirred in DCM for 30 min, followed by the
addition of acetophenone (S/C = 100) and TEAF (0.9 ml). The reaction
was monitored similar to that when using the i-PrOH hydrogen source.
4.2.5. (S)-2-(Benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-
3-carboxylic acid 4
To a suspension of 3 (5 g, 19.45 mmol) in dioxane (80 ml) and
water (40 ml) was added NaHCO3 (77.80 mmol) at 0 °C following
Schotten–Baumann conditions. After addition of the base, Cbz-Cl
was added and the reaction mixture was allowed to stir at 0 °C
for 1.5 h and then at room temperature for a further 1.5 h. The
product was extracted twice with ethyl acetate, the organic layer
dried with anhydrous magnesium sulfate and concentrated to dry-
ness affording 4 (5.56 g, 92% yield) that was carried forward with-
out any purification.
4. Experimental
4.1. General
4.3. General procedure for the preparation of 5a–g
(S)-2-(Benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid 4 (1.5 g, 4.8 mmol) was dissolved in DMF (15 mL)
followed by addition of EDCꢀHCl (1.1 g, 5.8 mmol), HOBt (0.81 g,
5.3 mmol), a catalytic amount of DMAP and the appropriate
amines (5.3 mmol). The reaction mixture was then stirred at room
temperature until no more starting material could be detected by
TLC analysis (approximately 1 h). The reaction mixture was poured
into 30 volumes of chilled water; the mixture was then extracted
twice with ethyl acetate. The extracts were combined, washed
with 10% HCl (aq) to remove latent EDC urea, dried over anhydrous
magnesium sulfate and then concentrated to dryness affording the
crude product which was purified by column chromatography.
All reagents and solvents were purchased from Aldrich, Merck
and Fluka unless stated otherwise. All NMR analysis was carried
out on either a Bruker AVANCE III 400 or 600 MHz instrument.
Chemical shifts are expressed in parts per million (ppm) downfield
from a TMS signal, and coupling constants are reported in Hertz.
NMR spectra were obtained at room temperature, except if stated
differently. Thin layer chromatography (TLC) was performed using
Merck Kiesel gel 60 F254. Crude compounds were purified via col-
umn chromatography using Silica Gel (60–200 mesh except if sta-
ted otherwise). All solvents were dried using standard procedures
for example, Vogel.26 All IR spectra were recorded on a Perkin El-
mer spectrum 100 instrument with a universal ATR attachment.
Optical rotations were measured on a Perkin Elmer Polarimeter.
All melting points are uncorrected. High resolution mass spectro-
metric data were obtained using a Bruker micrOTOF-Q II instru-
ment, using a sample concentration of approximately 1 ppm. All
gas chromatography was carried out on an Agilent 6820.
4.4. General procedure for the preparation of 6a–g
The precursors 5a–g in 50/50 MeOH/THF with half an equiva-
lent by mass of 10% palladium on carbon Pd/C was stirred under
hydrogen (approximately 1 atm) for 2 h. The reaction was limited
for this period as additional side products were observed. The
crude product was obtained by filtering off the Pd/C through a plug
of Celite, the filtrate was then concentrated to dryness and purified
by column chromatography.
4.2. General procedure for transfer hydrogenation of
acetophenone
4.2.1. i-PrOH hydrogen source
4.5. General procedure for the preparation of 2a–g
To an oven-dried Schlenk tube was added metal precursor
(3.0 mg) followed by the ligand (4 mol equiv) and freshly distilled
i-PrOH (5 mL) under a dry argon atmosphere. The mixture was
heated to 60 °C and stirred for 20 min, after which the solution
The amine amides 6a–g were reduced with 4 equiv of LiAlH4 in
refluxing dry THF under a nitrogen atmosphere for 3–4 days or

684
B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
alternatively the reductions could be carried out at 85 °C in a
microwave reactor for 4–5 h. The reactions were quenched by slow
addition of saturated sodium sulfate solution and the white alu-
minium sulfate precipitate was then filtered off. The filtrate was
washed with water, dried over anhydrous magnesium sulfate
and concentrated to dryness affording the crude product which
was purified by column chromatography.
477.2155 m/z. NMR spectra are reported for a mixture of two rota-
mers.33 1H NMR (400 MHz, DMSO) d = 8.95–8.69 (m, 1H), 7.64–
6.88 (m, 19H), 6.11–5.85 (m, 1H), 5.30–4.37 (m, 5H), 3.02–3.27
(m, 2H). 13C NMR (101 MHz, DMSO) d = 170.2, 155.3–125.9, 86.6,
66.4, 54.8, 44.8 and 32.1.
4.5.5. Synthesis of (S)-N-benzhydryl-1,2,3,4-tetrahydroisoquino
line-3-carboxamide 6b
4.5.1. Synthesis of (S)-benzyl 3-(benzylcarbamoyl)-3,4-dihydro-
isoquinoline-2(1H)-carboxylate 5a
Removal of Cbz and purification by column chromatography
(DCM/MeOH/10% NH3 in CHCl3 = 87:3:10, Rf ꢁ0.4) gave the diphe-
nylmethamide tetrahydroisoquinoline 6b (80%) as a light brown
The resultant product from reaction with benzyl amine was
purified by column chromatography (EtOAc/Hex = 50:50, Rf
ꢁ0.45) to afford the benzyl-substituted tetrahydroisoquinoline
solid. ½a 2D0
ꢂ
¼ ꢃ105:7 (c 0.35 g/100 mL, CH2Cl2). IR
mmax: 402, 406,
619, 683, 734, 1159, 1219, 1365, 1451, 1493, 1544, 1640, 2929,
derivative 5a (1.44 g, 75%) as a white powder. ½a D20
ꢂ
¼ ꢃ8:3 (c
2973 and 3292 cmꢃ1
.
HRMS calculated for C23H22N2O
0.12, CH2Cl2). IR
m
max: 695, 729, 1118, 1216, 1302, 1322, 1400,
(M+H+) = 343.1795 m/z, found 343.1805 m/z. 1H NMR (400 MHz,
CDCl3) d = 7.97–8.10 (m, 1H), 7.42–6.95 (m, 14H), 7.09–7.02 (m,
1H), 4.08–3.95 (m, 2H), 3.58–3.40 (m, 1H), 3.31–3.19 (m, 1H),
2.99–2.87 (m, 1H), the NH proton of the amine was not observed
in the spectra. 13C NMR (101 MHz, CDCl3) d = 172.0, 141.6, 141.5,
129.1–125.3, 56.4, 56.2, 47.1 and 30.3.
1650, 1680, 3029 and 3331 cmꢃ1. Melting point 105–107 °C. HRMS
calculated for C25H24N2O3 (M+H+) = 401.1867 m/z, found 401.1860
m/z. NMR spectra are reported for a mixture of two rotamers.33 1H
NMR (400 MHz, DMSO) d = 8.42 (m, 1H), 7.51–7.07 (m, 12H), 6.91–
6.76 (m, 2H), 5.27–5.07 (m, 2H), 4.87–4.42 (m, 3H), 4.28–4.05 (m,
2H), 3.26–3.06 (m, 2H); 13C NMR (101 MHz, DMSO) d = 170.6,
139.2–126.1, 66.4, 54.5, 44.7, 41.8 and 31.8.
4.5.6. Synthesis of (S)-1,1-diphenyl-N-((1,2,3,4-tetrahydroisoqui
nolin-3-yl)methyl)methanamine 2b
4.5.2. Synthesis of (S)-N-benzyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxamide 6a
After the reduction of 6b, the crude compound was purified by
column chromatography (MeOH/Et2O = 5:95, Rf ꢁ0.6) to afford the
N-diphenylmethanamine amine derivative 2b (21%) as a yellow so-
Removal of Cbz and purification by column chromatography
(DCM/MeOH/10% NH3 in CHCl3 = 87:3:10, Rf ꢁ0.4) gave the benzyl
lid. ½a 2D0
ꢂ
¼ ꢃ55:8 (c 0.52, CH2Cl2). IR
mmax: 430, 696, 706, 743, 800,
1027, 1429, 1447, 1490, 1580, 1595, 2780, 2911, 3289, and
amide tetrahydroisoquinoline 6a (85%) as
a
white solid.
½
a 2D0
ꢂ
¼ ꢃ54:8 (c 0.42, CH2Cl2). IR
797, 1029, 1222, 1453, 1546, 1643, 2925, 3033, 3057, 3279 and
3330 cmꢃ1
Melting point 83–85 °C. HRMS calculated for
m
max: 435, 467, 613, 694, 736,
3324 cmꢃ1
.
Melting point 89–91 °C. HRMS calculated for
C23H24N2 (M+H+) = 329.2012 m/z, found 329.2004 m/z. 1H NMR
(600 MHz, CDCl3) d = 7.43–6.98 (m, 14H), 4.87 (s, 1H), 4.06 (s,
2H), 3.00 (m, 1H), 2.83 (dd, J = 11.8 and 3.8 Hz, 1H), 2.73 (dd,
J = 16.2 and 3.9 Hz, 1H), 2.64 (dd, J = 11.8 and 8.7 Hz, 1H), 2.56
(dd, J = 16.2 and 10.8 Hz, 1H), the two NH protons were not ob-
served. 13C NMR (151 MHz, CDCl3) d = 144.2, 143.9, 135.9, 134.5,
129.2, 128.5, 127.3, 127.3, 127.04, 127.02, 126.1, 126.0, 125.7,
67.7, 53.7, 53.6, 48.3 and 33.4.
.
C17H18N2O (M+H+) = 267.1492 m/z, found 267.1504 m/z. 1H NMR
(400 MHz, CDCl3) d = 7.56 (s, 1H), 7.42–7.12 (m, 9H), 4.48 (d,
J = 5.6 Hz, 2H), 4.05–3.91 (d, J = 6.52 Hz, 2H), 3.61 (dd, J = 10.3
and 5.2 Hz, 1H), 3.28 (dd, J = 16.4 and 5.2 Hz, 1H), 2.88 (dd,
J = 16.4 and 10.3 Hz, 1H), The NH proton was not observed. 13C
NMR (101 MHz, CDCl3) d = 173.0, 138.3, 135.9, 134.4, 129.2,
128.7, 127.7, 127.4, 126.6, 126.2, 125.5, 56.5, 47.5, 43.1 and 31.0.
4.5.7. Synthesis of (S)-benzyl 3-(phenylcarbamoyl)-3,4-dihydro-
isoquinoline-2(1H)-carboxylate 5c
4.5.3. Synthesis of (S)-N-benzyl-1-(1,2,3,4-tetrahydroisoquinolin-
3-yl)methanamine 2a
The resultant product from reaction with aniline was purified
by column chromatography purified (EtOAc/Hex = 40:60, Rf ꢁ0.5)
to afford the aniline-substituted tetrahydroisoquinoline derivative
After reduction of 6a, the crude compound was purified by col-
umn chromatography (DCM/MeOH/Et2O/10% NH3 in CHCl3 =
66:4:20:10, Rf ꢁ0.4) to afford the N-benzyl amine derivative 2a
5c (1.54 g, 83%) light yellow oil. ½a D20
¼ ꢃ38:1 (c 0.42, CH2Cl2). IR
ꢂ
(31%) as an off white/yellow solid. ½a D20
ꢂ
¼ ꢃ70:9 (c 0.43, CH2Cl2).
mmax: 487, 693, 736, 749, 960, 1099, 1127, 1184, 1413, 1546,
IR
m
max: 695, 729, 1118, 1216, 1302, 1322, 1400, 1650, 1680,
1665, 1701, 3027 and 3301 cmꢃ1. Melting point 137–139 °C. HRMS
calculated for C24H22N2O3 (M+H+) = 387.1703 m/z, found 387.1689
m/z. NMR spectra are reported for a mixture of two rotamers.33 1H
NMR (400 MHz, DMSO) d = 10.04 (d, J = 5.1 Hz, 1H), 7.62–6.85 (m,
14H), 5.22–5.02 (m, 3H), 4.90–4.51 (m, 2H), 3.33–3.02 (m, 2H).
13C NMR (101 MHz, DMSO) d = 169.9, 155.3–119.2, 66.5, 54.9,
44.8 and 31.8.
3029 and 3331 cmꢃ1. Melting point 85–87 °C. HRMS calculated
for C17H20N2 (M+H+) = 253.1699 m/z, found 253.1708 m/z. 1H
NMR (400 MHz, CDCl3) d = 7.38–7.30 (m, 3H), 7.28–7.23 (m, 2H),
7.16–6.99 (m, 4H), 4.04 (s, 2H), 3.84 (d, J = 2.8 Hz, 2H), 3.05–2.96
(m, 1H), 2.86 (dd, J = 11.9 and 3.8 Hz, 1H), 2.73 (dd, J = 16.3 and
4.0 Hz, 1H), 2.64 (dd, J = 11.9 and 8.9 Hz, 1H), 2.59–2.51 (m, 1H),
the two NH protons were not observed. 13C NMR (101 MHz, CDCl3)
d = 140.3, 135.8, 134.4, 129.2, 128.4, 128.1, 127.0, 126.1, 126.0,
125.7, 54.4, 54.1, 53.4, 48.2 and 33.3.
4.5.8. Synthesis of (S)-N-phenyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxamide 6c
Removal of Cbz group the aniline amide tetrahydroisoquinoline
6c (88%) formed as a white solid, which required no further purifi-
4.5.4. Synthesis of (S)-benzyl 3-(benzhydrylcarbamoyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate 5b
cation. ½a 2D0
ꢂ
¼ ꢃ144:7 (c 0.38, CH2Cl2). IR
mmax: 440, 551, 695, 736,
The resultant product from the reaction with diphenylmetha-
nime was purified by column chromatography (EtOAc/
Hex = 50:50, Rf ꢁ0.4) to afford the diphenyl-substituted tetrahy-
droisoquinoline derivative 5b (1.62 g, 71%) light yellow oil.
1060, 1190, 1258, 1364, 1408, 1496, 1597, 1697, 2891, 2927, 2968,
3045 and 3299 cmꢃ1. Melting point 183–192 °C. HRMS calculated
for C16H16N2O (M+H+) = 253.1317 m/z, found 253.1335 m/z. 1H
NMR (400 MHz, CDCl3) d = 9.39 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H),
7.33 (t, J = 7.8 Hz, 2H), 7.01–7.25 (m, 5H), 4.05 (d, J = 5.4 Hz, 2H),
3.73 (dd, J = 10.3 and 5.3 Hz, 1H), 3.37 (dd, J = 16.4 and 5.2 Hz,
1H), 2.95 (dd, J = 16.3 and 10.3 Hz, 1H), the NH proton of the amine
was not observed. 13C NMR (101 MHz, CDCl3) d = 171.1, 137.7,
½
a 2D0
ꢂ
¼ ꢃ11:4 (c 0.36, CH2Cl2). IR
mmax: 528, 546, 604, 616, 639,
695, 738, 909, 1001, 1028, 1094, 1120, 1215, 1303, 1346, 1403,
1453, 1494, 1658, 1696, 2851, 2925, 3029 and 3300 cmꢃ1. HRMS
calculated for C31H28N2O3 (M+H+) = 477.2137 m/z, found

B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
685
135.8, 134.3, 129.2, 129.1, 126.9, 126.4, 125.5, 124.1, 119.4, 56.7,
47.3 and 30.5.
spectra. 13C NMR (101 MHz, MeOD) d = 130.9, 130.2, 129.5, 128.7,
128.4, 127.7, 51.8, 51.2, 46.0, 34.4, 30.4.
4.5.13. Synthesis of (S)-benzyl 3-(isopropylcarbamoyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate 5e
The resultant product from the reaction with isopropyl amine
was purified by column chromatography (EtOAc/Hex = 50:50, Rf
4.5.9. Synthesis of (S)-N-((1,2,3,4-tetrahydroisoquinolin-3-yl)
methyl) aniline 2c
After reduction of 6c, the crude compound was purified by col-
umn chromatography (100% diethyl ether, Rf ꢁ0.5), yielding a
ꢁ0.45) to afford the 5e (1.43 g, 85%) as
a beige powder.
max: 695, 733, 749, 1124, 1212,
white solid 2c (57%). ½a D20
ꢂ
¼ ꢃ64:3 (c 0.14, CH2Cl2). IR
mmax: 435,
½
a 2D0
ꢂ
¼ ꢃ3:5 (c 0.58, THF). IR
m
488, 513, 585, 690, 743, 805, 1258, 1346, 1494, 1600, 2792,
2929, 3218 and 3301 cmꢃ1. Melting point 90–92 °C. HRMS calcu-
lated for C16H18N2 (M+H+) = 239.1543 m/z, found 239.1543 m/z.
1H NMR (400 MHz, CDCl3) d = 7.23–6.99 (m, 6H), 6.76–6.62 (m,
3H), 4.07 (br s, 2H), 3.36 (d, J = 12.1 Hz, 1H), 3.26–3.17 (m, 1H),
3.14–3.06 (m, 1H), 2.85 (dd, J = 16.3 and 4.1 Hz, 1H), 2.66 (dd,
J = 16.3 and 10.5 Hz, 1H), the two NH protons were not observed.
13C NMR (101 MHz, CDCl3) d = 148.4, 135.7, 134.0, 129.3, 129.3,
126.2, 126.0, 125.9, 117.5, 113.0, 53.0, 49.2, 48.1 and 33.1.
1311, 1408, 1546, 1644, 1701, 2970 and 3299 cmꢃ1. Melting point
95–97 °C. HRMS calculated for C21H24N2O3 (M+H+) = 353.1860 m/z,
found 353.1860 m/z. NMR spectra are reported for a mixture of two
rotamers.33 1H NMR (400 MHz, DMSO) d = 7.69 (m, 1H), 7.53–7.01
(m, 9H), 5.33–4.84 (m, 2H), 4.78–4.35 (m, 3H), 3.72 (m, 1H), 3.21–
2.81 (m, 2H), 0.99–0.82 (m, 6H). 13C NMR (101 MHz, DMSO)
d = 169.6, 155.2–125.8, 67.0, 55.2, 44.6, 40.5, 31.8 and 22.1.
4.5.14. Synthesis of (S)-N-isopropyl-1,2,3,4-tetrahydroisoquino-
line-3-carboxamide 6e
4.5.10. Synthesis of (S)-benzyl 3-(methylcarbamoyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate 5d
Removal of Cbz and purification by column chromatography
(DCM/MeOH/10% NH3 in CHCl3 = 87:3:10, Rf ꢁ0.5) afforded the iso-
propyl amide tetrahydroisoquinoline 6e (92%) as a white solid.
The resultant product from the reaction with methyl amine was
purified by column chromatography purified by column chroma-
tography (EtOAc/Hex = 50:50, Rf ꢁ0.4) to afford the methyl-substi-
tuted tetrahydroisoquinoline derivative 5d (1.06 g, 68%) light
½
a 2D0
ꢂ
¼ ꢃ105:7 (c 0.35, CH2Cl2). IR
mmax: 402, 406, 619, 683, 734,
1159, 1219, 1365, 1451, 1493, 1544, 1640, 2929, 2973 and
3292 cmꢃ1. Melting point 87–89 °C. HRMS calculated for C13H18N2O
(M+H+) = 219.1492 m/z, found 219.1501 m/z. 1H NMR (400 MHz,
CDCl3) d = 7.12–7.19 (m, 3H), 7.08–6.93 (m, 2H), 4.10 (m, 1H), 4.00
(d, J = 4.1 Hz, 2H), 3.50 (dd, J = 10.7 and 5.0 Hz, 1H), 3.24 (dd,
J = 16.5 and 5.0 Hz, 1H), 2.80 (dd, J = 16.5 and 10.7 Hz, 1H), 1.19 (d,
J = 6.6 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H), the NH proton of the amine
was not observed. 13C NMR (101 MHz, CDCl3) d = 172.1, 135.8,
134.4, 129.2, 126.6, 126.1, 125.5, 56.6, 47.7, 40.8, 31.1, 22.8, 22.7.
yellow oil. ½a 2D0
ꢂ
¼ ꢃ6:4 (c 0.62, CH2Cl2). IR
mmax: 495, 616, 696,
742, 908, 1011, 1120, 1215, 1302, 1323, 1406, 1536, 1655, 1695,
2939, 3031, 3065 and 3314 cmꢃ1
.
HRMS calculated for
C19H20N2O3 (M+H+) = 325.1547 m/z, found 325.1546 m/z. NMR
spectra are reported for a mixture of two rotamers.33 1H NMR
(400 MHz, DMSO) d = 7.85 (m, 1H), 7.58–7.08 (m, 9H), 5.36–4.98
(m, 2H), 4.86–4.28 (m, 2H), 3.22–2.89 (m, 2H), 2.60–2.52 (m,
1H), 2.47 (d, 4.66 Hz, 3H). 13C NMR (101 MHz, DMSO) d = 170.8,
136.7–125.9, 66.4, 54.1, 44.4, 31.3 and 25.6.
4.5.15. Synthesis of (S)-N-((1,2,3,4-tetrahydroisoquinolin-3-
yl)methyl)propan-2-amine 2e
4.5.11. Synthesis of (S)-N-methyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxamide 6d
After reduction of 6e, the crude compound was purified by col-
umn chromatography (EtOAc/MeOH = 95:5, Rf ꢁ0.5), yielding an
Removal of Cbz and purification by column chromatography
(DCM/MeOH/10% NH3 in CHCl3 = 87:3:10, Rf ꢁ0.4) afforded methyl
off white solid 2e (46%). ½a D20
ꢂ
¼ ꢃ8:3 (c 0.12, CH2Cl2). IR mmax
:
695, 729, 1118, 1216, 1302, 1322, 1400, 1650, 1680, 3029 and
amide tetrahydroisoquinoline 6d (77%) as
a white solid.
3331 cmꢃ1
.
Melting point 39–41 °C. HRMS calculated for
½
a 2D0
ꢂ
¼ ꢃ222:5 (c 0.20, CH2Cl2). IR
mmax: 399, 435, 515, 609, 674,
C13H20N2 (M+H+) = 205.1699 m/z, found 205.1708 m/z. 1H NMR
(400 MHz, CDCl3) d = 7.15–6.99 (m, 4H), 4.05 (s, 2H), 3.02–2.90
(m, 1H), 2.71–2.87 (m, 3H), 2.60–2.52 (m, 2H), 1.09 (overlapping-
d, J = 6.5 Hz, 6H), the two NH protons were not observed. 13C
NMR (101 MHz, CDCl3) d = 136.0, 134.5, 129.2, 126.0, 126.0, 25.7,
53.9, 52.9, 49.0, 48.3, 33.5, 23.1 and 23.0.
738, 797, 963, 1129, 1225, 1413, 1562, 1643, 2835, 2877, 2940
and 3302 cmꢃ1. Melting point 84–86 °C. HRMS calculated for
C11H14N2O (M+H+) = 191.1179 m/z, found 191.1183 m/z. 1H NMR
(400 MHz, CDCl3) d = 7.24 (br s, 1H), 7.19–7.11 (m, 3H), 7.03 (m,
1H), 3.99 (d, J = 3.6 Hz, 2H), 3.52 (dd, J = 10.8 and 5.1 Hz, 1H),
3.24 (dd, J = 16.5 and 5.1 Hz, 1H), 2.85 (d, J = 5.0 Hz, 3H), 2.80
(dd, J = 16.5 and 10.8 Hz, 1H), the NH proton of the amine was
not observed. 13C NMR (101 MHz, CDCl3) d = 173.7, 135.9, 134.4,
129.2, 126.6, 126.2, 125.5, 56.6, 47.6, 31.0 and 25.8.
4.5.16. Synthesis of (S)-benzyl 3-((R)-1-phenylethylcarbamoyl)-
3,4-dihydroisoquinoline-2(1H)-carboxylate 5f
The resultant product from the reaction with (R)-1-phenyle-
thanamine was purified by column chromatography (EtOAc/
Hex = 50:50, Rf ꢁ0.4) to afford the (R)-1-phenylethanamine-substi-
tuted tetrahydroisoquinoline derivative 5f (1.55 g, 78%) as a light
4.5.12. Synthesis of (S)-N-methyl-1-(1,2,3,4-tetrahydroisoquino-
lin- 3-yl)methanamine 2d
After reduction the crude product 2d was purified by column
chromatography (DCM/MeOH/10% NH3 in CHCl3 = 87:3:10, Rf
ꢁ0.4). However this purification was not sufficient, therefore fur-
ther refinement was achieved by precipitating the compound out
as the dihydrochloride salt using a solution of HCl gas bubbled in
ether, which generated a precipitate when added to the compound
in DCM. The precipitated salt was filtered and washed with a 90:10
mixture of ether/DCM affording 2d (15%) a light brown solid.
yellow oil. ½a 2D0
ꢂ
¼ þ10:7 (c 1.03, CH2Cl2). IR
mmax: 491, 599, 696,
740, 905, 1001, 1093, 1119, 1214, 1302, 1322, 1347, 1400, 1448,
1522, 1638, 1697, 2932, 3029, 3062 and 3315 cmꢃ1. HRMS calcu-
lated for C26H26N2O3 (M+H+) = 415.2016 m/z, found 415.1998 m/
z. NMR spectra are reported for a mixture of two rotamers.33 1H
NMR = (400 MHz, DMSO) d = 8.24 (m, 1H), 7.53–6.91 (m, 14H),
5.32–4.96 (m, 2H), 4.93–4.41 (m, 4H), 3.20–3.02 (m, 2H), 1.25 (d,
J = 7.07 Hz, 3H). 13C NMR (101 MHz, DMSO) d = 170.1, 144.1–
125.6, 66.4, 54.4, 47.5, 44.7, 32.0 and 22.0.
½
a 2D0
ꢂ
¼ ꢃ1:3 (c 0.1, MeOH). IR
mmax: 428, 448, 763, 1025, 1451,
2598, 2717, 2941 and 3395 cmꢃ1. HRMS calculated for C11H16N2
(M+H+) = 177.1386 m/z, found 177.1389 m/z. 1H NMR (400 MHz,
MeOD) d = 7.13–7.26 (m, 4H), 4.42 (s, 2H), 3.98–3.89 (m, 1H),
3.46 (dd, J = 13.6 and 6.5 Hz, 1H), 3.37 (dd, J = 13.7 and 5.6 Hz,
1H), 3.24 (d, J = 4.7 Hz, 1H), 3.03 (dd, J = 17.1 and 11.0 Hz, 1H)
and 2.76 (s, 3H), the two NH protons were not observed in the
4.5.17. Synthesis of (S)-N-((R)-1-phenylethyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide 6f
Removal of Cbz and purification by column chromatography
(Et2O/Acetone = 80:20, Rf ꢁ0.5) gave the (R)-1-phenylethanamide

686
B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
tetrahydroisoquinoline 6f (72%) as a white solid. ½a D20
ꢂ
¼ ꢃ33:82 (c
ꢁ0.5) to yield 2g (35%), a light yellow oil, which was then also
0.34 g/100 mL, CH2Cl2). IR
m
max: 430, 583, 617, 695, 733, 748, 790,
stored as the dihydrochloride salt. ½a D20
¼ ꢃ43:55 (c 0.93, CH2Cl2).
ꢂ
803, 1180, 1221, 1446, 1492, 1544, 1643, 2838, 2926 and
IR mmax: 431, 543, 695, 783, 1118, 1451, 1492, 2789, 2918, 2960,
3284 cmꢃ1
.
Melting point 119–121 °C. HRMS calculated for
3026 and 3240 cmꢃ1
.
HRMS calculated for C18H22N2
C18H20N2O (M+H+) = 281.1648 m/z, found 281.1645 m/z. 1H NMR
(400 MHz, CDCl3) d = 7.52 (d, J = 8.0 Hz, 1H), 7.34–7.27 (m, 2H),
7.26–7.20 (m, 3H), 7.20–7.12 (m, 3H), 7.04 (m, 1H), 5.14 (m, 1H),
3.99 (d, J = 11.82 Hz, 2H), 3.59 (dd, J = 10.2 and 5.2 Hz, 1H), 3.23
(dd, J = 16.4 and 5.2 Hz, 1H), 2.82 (dd, J = 16.4 and 10.2 Hz, 1H),
1.51 (d, J = 6.9 Hz, 3H), the NH proton of the amine was not ob-
served. 13C NMR (101 MHz, CDCl3) d = 172.2, 143.3, 135.9, 134.4,
129.2, 128.6, 127.2, 126.6, 126.2, 126.0, 125.5, 56.4, 48.1, 47.6,
31.0 and 22.0.
(M+H+) = 267.1856 m/z, found 267.1846 m/z. 1H NMR (400 MHz,
MeOD) d = 7.58–7.10 (m, 9H), 4.52–4.31 (m, 3H), 3.87 (m, 1H),
3.49 (m, 1H), 3.19–3.01 (m, 3H), 1.71 (d, J = 6.7, 3H). 13C NMR
(101 MHz, MeOD) d = 137.1, 131.0, 130.6, 130.1, 129.4, 129.0,
128.7, 128.6, 128.3, 127.7, 61.3, 52.5, 48.5, 46.0, 30.6 and 19.5.
4.5.22. Synthesis of (1R,3S)-benzyl 3-(hydroxymethyl)-6,7-
dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
10
Compound 98 (1 g, 3.34 mmol) was protected with a Cbz group,
under the conditions described in the general procedure to afford
10 (1.31 g, 91%), a light yellow oil after column chromatography
4.5.18. Synthesis of (R)-1-phenyl-N-(((S)-1,2,3,4-tetrahydroiso-
quinolin-3-yl)methyl)ethanamine 2f
After reduction of 6f, the crude compound was purified by col-
umn chromatography (DCM/MeOH/10% NH3 in CHCl3 = 87:4:10, Rf
(EtOAc/Hex = 60:40, Rf ꢁ0.5).
CH2Cl2). IR max: 697, 1088, 1220, 1285, 1337, 1404, 1516, 1638,
1688, 2247, 3301 and 3553 cmꢃ1
HRMS calculated for
½
a 2D0
ꢂ
¼ þ40:38 (c 0.26 g/100 mL,
m
ꢁ0.5) to yield 2f (30%), a light yellow oil. ½a D20
ꢂ
¼ ꢃ43:55 (c 0.93,
.
CH2Cl2). IR
m
max: 431, 543, 695, 783, 1118, 1451, 1492, 2789,
C26H27NO5 (M+H+) = 434.1928 m/z, found 434.1962 m/z. NMR
spectra are reported for a mixture of two rotamers.33 1H NMR
(400 MHz, CDCl3) d = 7.43–6.92 (m, 10H), 6.78 (s, 1H), 6.66 (s,
1H), 6.01 (s, 1H), 5.38–4.87 (m, 2H), 4.47 (m, 1H), 3.86 (s, 3H),
3.83 (s, 3H), 3.63 (m, 1H), 3.34 (m, 1H), 3.02–2.89 (m, 2H). 13C
NMR (101 MHz, CDCl3) d = 148.4–125.3, 112.0, 110.7, 67.5, 64.4,
59.8, 56.1, 55.9, 54.7 and 29.4.
2918, 2960, 3026 and 3240 cmꢃ1. HRMS calculated for C18H22N2
(M+H+) = 267.1856 m/z, found 267.1846 m/z. 1H NMR (400 MHz,
CDCl3) d = 7.33–7.29 (m, 4H), 7.21 (m, 1H), 7.10–7.05 (m, 2H),
7.03–6.96 (m, 2H), 3.96 (d, J = 16.78 Hz, 2H), 3.74 (m, 1H), 2.82
(m, 1H), 2.66–2.61 (m, 2H), 2.51–2.42 (m, 2H), 1.37 (d, J = 6.7,
3H), the two NH protons were not observed. 13C NMR (101 MHz,
CDCl3) d = 145.6, 135.9, 134.5, 129.2, 128.4, 126.9, 126.5, 126.0,
126.0, 125.6, 58.2, 53.7, 52.8, 48.3, 33.3 and 24.6.
4.5.23. Synthesis of (1R,3S)-benzyl 3-formyl-6,7-dimethoxy-1-
phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 11
4.5.19. Synthesis of (S)-benzyl 3-((S)-1-phenylethylcarbamoyl)-
3,4-dihydroisoquinoline-2(1H)-carboxylate 5g
Oxidation of 10 (0.8 g, 1.84 mmol) with PCC (3 equiv) and
MgSO4 (3 equiv) in dry DCM34 gave 11 (0.45 g, 57%) as a yellow
oil after treatment with wet diethylether and filtration through a
small plug of silica to remove excess PCC and other metal spe-
The resultant product from reaction with (S)-1-phenylethan-
amine was purified by column chromatography (EtOAc/
Hex = 50:50, Rf ꢁ0.4) to afford the (S)-1-phenylethanamine-substi-
tuted tetrahydroisoquinoline derivative 5g (1.77 g, 89%) light yel-
cies. ½a 2D0
ꢂ
¼ þ41:5 (c 0.41, CH2Cl2). IR
mmax: 594, 697, 737, 994,
1028, 1092, 1221, 1264, 1339, 1397, 1513, 1692, 2838 and
2924 cmꢃ1. HRMS calculated for C26H25NO5 (M+Na+) = 454.1625
m/z, found 454.1606 m/z. NMR spectra are reported for a mix-
ture of two rotamers.33 1H NMR (400 MHz, CDCl3) d = 9.38 (m,
1H), 7.65–7.02 (m, 10H), 6.96–5.90 (m, 3H), 5.38–4.84 (m, 2H),
4.59 (m, 1H), 3.95–3.75 (m, 6H), 3.24–2.80 (m, 2H). 13C NMR
(101 MHz, CDCl3) d = 148.5–126.0, 110.7, 67.5, 60.6, 56.0, 55.9
and 29.7.
low oil. ½a 2D0
ꢂ
¼ ꢃ21:43 (c 0.70, CH2Cl2). IR
mmax: 696, 738, 1059,
1119, 1213, 1303, 1329, 1407, 1449, 1495, 1534, 1656, 1697,
2972, 3029, 3062 and 3299 cmꢃ1
.
HRMS calculated for
C26H26N2O3 (M+H+) = 415.2016 m/z, found 415.2009 m/z. NMR
spectra are reported for a mixture of two rotamers.33 1H NMR
(400 MHz, DMSO) d = 8.29 (m, 1H), 7.49–6.91 (m, 14H), 5.22–
4.99 (m, 2H), 4.86–4.41 (m, 4H), 3.23–2.97 (m, 2H), 1.30–1.13
(m, 3H). 13C NMR (101 MHz, DMSO) d = 169.9, 154.9–125.5, 66.3,
54.1, 47.5, 44.7, 31.8, 22.1.
4.5.24. Synthesis of (1R,3S)-benzyl 3-((benzylamino)methyl)-
6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 12
4.5.20. Synthesis of (S)-N-((S)-1-phenylethyl)-1,2,3,4-tetrahydro
isoquinoline-3-carboxamide 6g
To a 50% mixture of dry THF in MeOH (6 ml) was added com-
pound 11 (0.3 g, 0.69 mmol), followed by benzyl amine (0.23 g,
2 mmol) and the mixture was allowed to stir at room temperature
for 3 h. The reaction mixture was then cooled to 0 °C with an ice
bath, followed by slow addition of NaCNBH4 (ꢁ0.3 g) and stirred
for 30 min at 0 °C, and a further 30 min at rt. Water was added
to the reaction and the resultant mixture was extracted three times
with DCM. The crude product was purified by column chromatog-
raphy (EtOAc/Hex = 70:30, Rf ꢁ0.7) to afford 12 (0.21 g, 60%) yel-
Removal of Cbz and purification by column chromatography
(Et2O/Acetone = 80:20, Rf ꢁ0.5) afforded the (S)-1-phenylethana-
mide tetrahydroisoquinoline 6g (76%) as a cream/beige solid.
½
a 2D0
ꢂ
¼ ꢃ100:7 (c 0.36, CH2Cl2). IR
mmax: 428, 449, 525, 551, 609,
643, 697, 734, 750, 780, 1077, 1137, 1225, 1248, 1493, 1533,
1646, 2926, 2966 and 3333 cmꢃ1. Melting point 119–121 °C. HRMS
calculated for C18H20N2O (M+H+) = 281.1648 m/z, found 281.1644
m/z. 1H NMR (400 MHz, CDCl3) d = 7.48 (m, 1H), 7.38–7.11 (m,
8H), 7.04 (m, 1H), 5.13 (m, 1H), 3.99 (s, 2H), 3.53 (dd, J = 10.5
and 5.1 Hz, 1H), 3.23 (dd, J = 16.5 and 5.1 Hz, 1H), 2.85 (dd,
J = 16.4 and 10.5 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H), NH proton of
the amine was not observed. 13C NMR (101 MHz, CDCl3)
d = 172.1, 143.3, 135.7, 134.3, 129.2, 128.7, 128.5, 127.3, 126.6,
126.2, 125.5, 56.5, 48.3, 47.5, 31.0 and 22.0.
low oil. ½a 2D0
ꢂ
¼ þ27:3 (c 0.44, CH2Cl2). IR
mmax: 593, 697, 736, 999,
1028, 1092, 1219, 1338, 1397, 1452, 1514, 1689, 2931 and
3028 cmꢃ1. HRMS calculated for C33H34N2O4 (M+H+) = 523.2591
m/z, found 523.2579 m/z. NMR spectra are reported for a mixture
of two rotamers.33 1H NMR (400 MHz, CDCl3) d = 7.41–7.10 (m,
15H), 6.78 (s, 1H), 6.59 (s, 1H), 5.99 (s, 1H), 5.26–4.91 (m, 2H),
4.46 (m, 1H), 3.97–3.56 (m, 9H), 3.08–2.68 (m, 3H), NH proton of
the amine was not observed. 13C NMR (101 MHz, CDCl3)
d = 128.3–126.0, 112.2, 110.8, 77.3–77.0, 76.6, 67.5, 60.3, 56.1–
55.9, 53.5, 30.1 and 29.6.
4.5.21. Synthesis of (S)-1-phenyl-N-(((S)-1,2,3,4-tetrahydroiso-
quinolin-3-yl)methyl)ethanamine 2g
After reduction of 6g, the crude compound was purified by col-
umn chromatography (DCM/MeOH/10% NH3 in CHCl3 = 87:4:10, Rf

B. K. Peters et al. / Tetrahedron: Asymmetry 21 (2010) 679–687
687
4.5.25. Synthesis of N-benzyl-1-((1R,3S)-6,7-dimethoxy-1-
phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methanamine 2i
Compound 12 (0.1 g, 0.19 mmol) was treated with palladium on
carbon as mentioned in the general procedure to remove the Cbz
group. The reaction was monitored carefully to avoid removal of
the benzyl group. Purification by column chromatography (DCM/
MeOH/10% NH3 in CHCl3 = 87:3:10, Rf ꢁ0.5) yielded 2i (0.038 g,
m
max: 430, 457, 594, 696, 735, 808, 912, 1020, 1095, 1117, 1217,
1249, 1320, 1418, 1495, 1678, 2927, 3030, 3315 cmꢃ1 1H NMR
.
(400 MHz, CDCl3) d = 7.76 (d, J = 8.13 Hz, 2H), 7.30 (d,
J = 8.75 Hz, 2H), 7.14–6.96 (m, 4H), 3.94 (d, J = 4.66 Hz, 2H), 3.19
(dd, J = 3.86 and 12.66 Hz, 1H), 3.00 (m, 1H), 2.84 (dd, J = 8.99
and 12.65 Hz, 1H), 2.71 (dd, J = 4.43 and 16.27 Hz, 1H), 2.49 (dd,
J = 10.86 and 16.83 Hz, 1H), 2.41 (s, 3H), The NH protons were
not observed. 13C NMR (101 MHz, CDCl3) d = 143.4, 136.8, 135.1,
133.3, 129.8, 129.2, 127.2, 126.4, 126.1, 125.1, 68.3, 52.7, 47.4,
32.2 and 21.5.
52%) as a white oil. ½a D20
ꢂ
¼ ꢃ26:8 (c 0.41, CH2Cl2). IR
mmax: 573,
699, 753, 819, 1057, 1127, 1224, 1293, 1449, 1519, 1609, 2832,
2920, 2994 and 3060 cmꢃ1. HRMS calculated for C25H28N2O2
(M+H+) = 389.2224 m/z, found 389.2224 m/z. 1H NMR (400 MHz,
CDCl3) d = 7.38–7.13 (m, 10H), 6.63 (s, 1H), 6.41 (s, 1H), 5.10 (s,
1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.50 (s, 2H), 3.02 (m, 1H), 2.74–
2.67 (m, 2H), 2.59–2.47 (m, 2H), the two NH protons were not ob-
served. 13C NMR (101 MHz, CDCl3) d = 147.8, 147.1, 145.3, 140.3,
128.5, 128.33, 128.34, 128.32, 128.17, 128.10, 126.95, 126.86,
111.41, 111.09, 59.3, 55.89, 55.83, 53.87, 53.45, 46.2 and 33.1.
Acknowledgements
This work was supported by the UKZN productivity research
grant, a SA/ Swedish Research Links Programme grant (GUN No.
65387) and Aspen Pharmacare, SA. The NRF (South Africa) is
thanked for the support.
4.5.26. (S)-Benzyl 3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 13
References
Compound 8 (0.4 g, 2.27 mmol) was protected with a Cbz
group, under the conditions described in the general procedure
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ꢂ
m
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1216, 1348, 1403, 1496, 1605, 1661, 2158, 2586, 2882 and
3179 cmꢃ1. HRMS calculated for C18H18N2O3 (M+Na+) = 333.1210
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9H), 5.29–4.86 (m, 3H), 4.84–4.50 (m, 2H), 3.37–3.02 (m, 2H), the
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d = 156.1, 136.6, 132.5, 129.0, 128.5, 128.5, 128.0, 127.9, 126.7,
126.3, 126.0, 67.3, 52.5, 43.3, 43.1 and 30.7.
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4.5.27. (S)-Benzyl 3-(aminomethyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate 14
To a solution of 13 (0.5 g, 1.5 mmol) in dioxane (3 mL) was
added NaBH4 (0.17 g, 4.5 mmol). The mixture was then cooled to
0 °C and acetic acid (0.18 g, 4.5 mmol) was added dropwise, after
addition the reaction was set to reflux for 48 h to yield 14 as yellow
oil.26 Due to problems with stability the crude product 14 (0.07 g,
15% in ꢁ90% purity) was carried forward without further purifica-
tion. ½a 2D0
ꢂ
¼ ꢃ15:0 (c 0.16, CH2Cl2). IR
mmax: 426, 495, 548, 565, 658,
705, 746, 810, 850, 880, 1071, 1093, 1154, 1314, 1450, 1494, 1598,
1722, 2853, 2922, 3031 and 3288 cmꢃ1. HRMS calculated for
C18H20N2O2 (M+H+) = 297.1595 m/z, found 297.1598 m/z. NMR
spectra are reported for a mixture of two rotamers.33 1H NMR
(400 MHz, CDCl3) d = 7.46–7.24 (m, 5H), 7.23–6.98 (m, 4H), 5.26–
5.10 (m, 2H), 4.89 (m, 1H), 4.59–4.25 (m, 2H), 3.06 (m, 1H), 2.77
(m, 1H), 2.70 (dd, J = 7.94 and 13.24 Hz, 1H), 2.59 (m, 1H). 13C
NMR (101 MHz, CDCl3) d = 156.1, 136.6, 132.5, 129.0, 128.5,
128.5, 128.0, 127.9, 126.7, 126.3, 126.0, 67.3, 52.5, 43.3, 43.1 and
30.7.
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4.5.28. (S)-4-Methyl-N-((1,2,3,4-tetrahydroisoquinolin-3-
yl)methyl)benzenesulfonamide 2j
Compound 14 (0.06 g, 0.2 mmol) was first treated with TsCl
(0.042 g, 0.22 mmol) and TEA (0.045 g, 0.45 mmol) in CH2Cl2
(1.5 mL) for 12 h at room temperature. Water was then added,
and the organic layer washed with diluted HCl and then saturated
sodium carbonate. The resulting oil was dried and the deprotec-
tion of the Cbz group was carried out as described in the general
procedure. The crude oil was purified by column chromatography
(EtOH/Toluene, 20:80 Rf ꢁ0.7) to yield 2j (0.038 g, 60%) as a pale
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yellow oil: ½a 2D0
¼ ꢃ13:8 (c 0.17, CH2Cl2). HRMS calculated for
ꢂ
C17H20N2O2S (M+H+) = 317.1339 m/z, found 317.1318 m/z. IR