Synthesis and screening of C1-substituted tetrahydroisoquinoline derivatives for asymmetric transfer hydrogenation reactions

Article abstract of DOI:10.1002/ejoc.200901159

Tetrahydroisoquinoline (TIQ) derivatives exhibit good biological activity, However, utilization of TIQ compounds in asymmetric catalysis is limited. This paper presents a series of TIQ derivatives in asymmetric transfer hydrogenation (ATH) reactions. Chiral TIQ amino alcohol ligands were synthesized and screened for the ATH reaction of aromatic ketones. The effect of a cis - and trans-phenyl substitution at the C¹ position on the ligand backbone was investigated both experimentally and computationally. The results showed that the trans orientation on the TIQ scaffold yields higher turnover rates with a selectivity of 94 % ee obtained at room temperature with an Ru complex. The cis isomer results in a high turnover rate with no selectivity. The frans isomer gave 99 % ee at lower temperatures. Furthermore, it was observed that substitution at the C³-α position results in a drop of the enantioselectivity and the reactivity of the catalyst.

Full text of DOI:10.1002/ejoc.200901159

FULL PAPER
DOI: 10.1002/ejoc.200901159
Synthesis and Screening of C1-Substituted Tetrahydroisoquinoline Derivatives
for Asymmetric Transfer Hydrogenation Reactions
Sai Kumar Chakka,[a] Pher G. Andersson,[b] Glenn E. M. Maguire,[a] Hendrik G. Kruger,*[a]
and Thavendran Govender*[c]
Keywords: Tetrahydroisoquinoline / Amino alcohols / Ruthenium / Hydrogenation / Asymmetric catalysis
Tetrahydroisoquinoline (TIQ) derivatives exhibit good bio-
logical activity. However, utilization of TIQ compounds in
asymmetric catalysis is limited. This paper presents a series
of TIQ derivatives in asymmetric transfer hydrogenation
(ATH) reactions. Chiral TIQ amino alcohol ligands were syn-
thesized and screened for the ATH reaction of aromatic
ketones. The effect of a cis- and trans-phenyl substitution at
the C1 position on the ligand backbone was investigated both
experimentally and computationally. The results showed that
the trans orientation on the TIQ scaffold yields higher turn-
over rates with a selectivity of 94% ee obtained at room tem-
perature with an Ru complex. The cis isomer results in a high
turnover rate with no selectivity. The trans isomer gave 99%
ee at lower temperatures. Furthermore, it was observed that
substitution at the C3-α position results in a drop of the
enantioselectivity and the reactivity of the catalyst.
interest in the development of novel chiral backbones
prompted us to investigate the application of the TIQ scaf-
fold as a source of chirality in ATH reactions. Previous re-
ports on the use of TIQ derivatives as catalytic ligands have
yielded limited success, with poor to moderate enantio-
selectivities in asymmetric catalysis such as allylic alky-
lation[9] and borane-mediated hydrogenation reactions.[10,11]
Recently, a related study of different TIQ ligands on the
addition reaction of diethylzinc to benzaldehyde was re-
ported with promising results.[12]
Introduction
Chiral amino alcohol containing ligands (Figure 1) are
among the more successful classes of compounds in asym-
metric transfer hydrogenation reactions (ATH).[1–3] In these
reactions transfer hydrogenation has been applied to
ketones and imines.[4,5] In particular it has been very suc-
cessful for the reduction of a range of unsymmetrical
ketones. Nevertheless, there is still significant interest in the
development of new chiral scaffolds as potential ligands in
asymmetric catalysis.
Given the reports in literature thus far, we aimed to cou-
ple the catalytic success of the chiral amino alcohol contain-
ing class of ligands, with the innovation of the TIQ scaffold
towards the development of a novel series of efficient C1-
phenyl and C3-α-phenyl substitutions. The ligands were co-
ordinated to (arene)ruthenium, -rhodium, and -iridium pre-
cursors, and their efficiency was investigated as ATH cata-
lysts for the reduction of prochiral ketones.[13–15] To the best
of our knowledge, this is the first successful application of
a TIQ ligand to effect high enantioselective transfer hydro-
genations yielding high turnover rates at reasonable catalyst
loading.
Figure 1. Examples of chiral amino alcohol ligands reported with
high selectivity in ATH reactions.
Since the isolation of naphthyridinomycin in 1974, the
biological activity of tetrahydroisoquinoline (TIQ) carbox-
ylic acid derivatives have been widely investigated.[6–8] Our
Results and Discussion
[a] School of Chemistry, University of KwaZulu-Natal,
Westville, Durban, South Africa
Mechanistic studies on non-TIQ-related ligands[1,3] de-
veloped by Noyori have demonstrated that typically two
stereogenic centers, a cyclic secondary amine and a second-
ary alcohol are required for optimal chiral activity.[16–18]
For maximum activity these two metal coordination sites
are typically within three bonds of each other. In this paper,
we introduce the tetrahydroisoquinoline (TIQ) ligands,
Fax: +27-72603091
E-mail: kruger@ukzn.ac.za
[b] Department of Organic Chemistry, Uppsala University,
Uppsala, Sweden
[c] Department of Pharmacy, University of KwaZulu-Natal,
Durban, South Africa
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901159.
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Tetrahydroisoquinolines for Asymmetric Transfer Hydrogenations
which have initially a single chiral center, a secondary amine
in a six-membered ring with a primary alcohol as a side
chain. Our first choice was ligand 4, which represents a sim-
ple TIQ backbone (Figure 2) from literature.[19] The ATH
reduction of acetophenone proved to be inefficient with this
ligand after coordination with a [Ru(p-cymene)Cl2]2 com-
plex and with isopropyl alcohol as the hydride source
(Table 1, Entry 1).
Scheme 1. Reagents for the synthesis of ligand 8: (i) benzyl bro-
mide, K2CO3, CH3CN, reflux, 3 h; (ii) PhMgBr, dry THF, reflux,
6 h; (iii) 10 wt.-% Pd/C, H2 (1 atm), MeOH.
Figure 2. Unsubstituted TIQ ligand for ATH reactions.
Aubry et al. reported on the effect of solvent on the
stereocontrol of Pictet–Spengler reactions.[20] For ligand 14,
-DOPA (9) was treated with benzaldehyde in the presence
of K2CO3 and aqueous EtOH to afford the trans-substi-
tuted TIQ compound 10 in 20% yield (Scheme 2).[20] The
cis-substituted TIQ compound 11 was obtained from benz-
aldehyde and K2CO3 in water giving a 20% yield.
Table 1. Asymmetric transfer hydrogenation of acetophenone using
different ligands complexed with [Ru(p-cymene)Cl2]2.
Entry Ligand Time [h]
Conversion [%][a] ee [%] (R/S)[b]
1
2
3
4
4
8
14
17
24.0
24.0
0.75
0.75
28
n. r.[c]
94
35 (S)
n.r.[c]
94 (R)
racemic
80
[a] Determined by chiral GC analysis. [b] Absolute configuration
determined by comparison with reported retention times. Values
reported are the average of three runs. [c] No reaction observed.
From our lead molecule we thought conversion of the
primary alcohol 4 to a secondary alcohol could potentially
improve the ligand activity. However, due to the difficulty
in the synthesis as will be demonstrated later, we designed
and synthesized the amino tertiary alcohol 8, introducing
phenyl moieties as bulky groups at the C3 position. Ligand
8 was synthesized from the TIQ amino ester 5,[19] and the
benzyl protection of the secondary amine was carried out
with benzyl bromide and K2CO3 in acetonitrile. Sub-
sequently, a Grignard reaction was attempted on 6 afford-
ing 7 in less than 20% yields. Ultimately, deprotection of 7
resulted in the formation of ligand 8 as shown in Scheme 1.
Disappointingly, phenyl substitution at the C3-α position
did not improve the catalytic system, in fact, no reactivity
Scheme 2. Reagents for the synthesis of TIQ acids 10 and 11: (i)
PhCHO, K2CO3, EtOH/H2O, 0 °C to room temp.; (ii) PhCHO,
K2CO3, H2O, 0 °C to room temp.
To obtain compound 12, C1-substituted N-Cbz-protected
was observed with this ligand (Table 1, Entry 2). To further methyl ester, an in situ reaction was performed on 10 with
investigate the factors affecting the efficiency of our TIQ benzyl chloroformate (Cbz) and monitored with LCMS.
backbone, we returned to the primary alcohol system and After completion of the reaction, the solvent was evapo-
substituted a phenyl group creating a stereogenic center at rated under vacuum and the crude product was used di-
the C1 position while increasing the pKa of the secondary rectly and methylated at the phenolic and carboxylic acid
nitrogen atom and the steric bulk of the ligand. All attempts positions. This was achieved by refluxing the compound in
to achieve substitution at the C1 position through a Pictet– acetone in the presence of Me2SO4 and KHCO3.[21] The
Spengler reaction between phenylalanine and benzaldehyde crude product was purified by column chromatography to
were met with limited success. It was essential to employ obtain the desired compound 12 in 80% yield. Deprotection
the activated aromatic group of -DOPA (9) to facilitate of the Cbz group gave 13, which was reduced to the amino
product formation.
alcohol 14 (Scheme 3). It was observed that partial racemi-
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H. G. Kruger, T. Govender et al.
FULL PAPER
Scheme 3. Reagents for the synthesis of ligand 14: (i) KHCO3, Cbz-Cl, dioxane/water, in situ solvent evaporation, KHCO3, Me2SO4,
acetone, reflux, overnight; (ii) 10 wt.-% Pd/C, H2 (1 atm), MeOH, room temp.; (iii) LiAlH4, dry THF, 0 °C, 2 h.
zation had occurred during the reduction of the ester at
elevated temperatures (diastereomers were observed by
HPLC and TLC). To afford maximum optical purity, the
reduction of 13 was subsequently repeated at 0 °C yielding
the pure ligand 14 (Scheme 3).
A similar synthetic route was applied to produce the cis
TIQ amino alcohol 17 starting from 11 (Scheme 4).
Scheme 5. Reagents for the synthesis of ligand 20: (i) benzyl bro-
Scheme 4. Synthesis of ligand 17.
mide, K2CO3, CH3CN, reflux, 3 h; (ii) PhMgBr, dry THF, reflux,
6 h; (iii) 10 wt.-% Pd/C H2 (1 atm), MeOH.
Interesting results were observed for the ATH reduction
reaction of acetophenone utilizing ligands 14 and 17. Li-
gand 14 showed good catalytic activity with 94% conver-
Table 2. Asymmetric transfer hydrogenation of acetophenone using
different ligands with [Ru(p-cymene)Cl2]2.
sion and 94% ee (R) in 45 min. In the case of 17, a racemic
mixture was observed with an 80% conversion (Table 1, En-
tries 3 and 4).
The reason for this difference in catalytic activity is not
readily understood. With the encouraging results from li-
Entry
Ligand
Time [h] Conversion [%][a] ee [%] (R/S)[b]
gand 14, however, we decided to modify the ligand by intro-
ducing phenyl groups at the C3-α position to re-investigate
the effect of steric bulk. To obtain this ligand, intermediate
13 could be converted into the N-benzyl methyl ester 18. In
order to introduce the phenyl groups, the secondary amine
was first benzyl-protected, after which a Grignard reaction
with phenylmagnesium bromide afforded 19. Deprotection
of 19 (Scheme 5) resulted in the formation of ligand 20.
It was comparative to ligand 8 (Table 2, Entry 1) and thus
1
2
3
20
major 24
minor 24
1.0
0.5
0.5
n.r.[c]
33
30
n.r.[c]
94 (R)
70 (S)
[a] Determined by chiral GC analysis. [b] Absolute configuration
determined by comparison with reported retention times. Values
reported are the average of three runs. [c] No reaction observed.
From the results of ligand 14 and 20, it was decided to
confirmed that bulky groups present on the C3-α position investigate the effect of less bulkier substitution at the C3-α
hinder the catalytic activity.
position. There were two reasons for this: (i) it is known
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Tetrahydroisoquinolines for Asymmetric Transfer Hydrogenations
Scheme 6. Reagents for the synthesis of ligands major 24 and minor 24: (i) LiAlH4, dry THF, room temp.; (ii) DMSO, oxalyl chloride,
TEA, CH2Cl2, –78 °C; (iii) CH3MgI, dry THF, 0 °C; (iv) 10 wt.-% Pd/C, H2 (1 atm), MeOH, room temp. All experimental details are
available in the Supporting Information.
from the literature that amino alcohols with a secondary substitution at the C3-α position of ligands 8 (Table 1, En-
alcohol exhibit excellent reactivity and selectivity;[22,23] (ii) try 2) and 20 (Table 2, Entry 1) reduced the activity of the
this allows us to introduce another chiral center into our catalyst. Similar phenyl substitution at the C1 position gave
catalytic ligand design. The reduction of ester 18 with Li- cis and trans configurations, which enhanced the turnover
AlH4 followed by a Swern oxidation afforded the aldehyde rates in ATH reactions. In this system, ligand 14 (trans)
22 in 82% yield. Subsequently, a Grignard reaction with provided better selectivity than ligand 17 (cis) (Table 2, En-
methylmagnesium iodide under reflux conditions afforded try 3, 4). The TIQ amino alcohols with smaller substituents
two diastereomeric alcohols in a 1:1 mixture. To improve at the C3-α position (ligands major 24 and minor 24)
the selectivity, the Grignard reaction was repeated at 0 °C showed a decrease in activity compared to ligand 14.
giving the diastereomers in a 9:1 ratio and in good yields.
Having identified an efficient and selective ligand for
These diastereomers were named major 23 and minor 23. catalytic purposes, the system was varied with the introduc-
Separation of the isomers followed by deprotection afforded tion of different metal complexes. Half-sandwich π com-
ligands major 24 and minor 24 in 60% yield (Scheme 6).
plexes such as ruthenium, rhodium or iridium complexes
Ligands major 24 and minor 24 were tested for transfer are the most important metal sources associated with
hydrogenation activity under identical conditions. Ligand amino alcohol ligands in ATH reactions.[1,3,24] In this study,
major 24 gave a 94% ee (R), and minor 24 gave 70% ee (S), we measured the reactivity of 14 with various organometal-
albeit both with low conversions (Table 2, Entries 2, 3).
lic complexes i.e. [Ru(p-cymene)Cl2]2, [RhCl2Cp*]2 and
To summarize, a total of seven ligands were prepared and [IrCl2Cp*]2.
evaluated in the ruthenium-catalyzed ATH of acetophen-
All of the new complexes, catalytic conversions and selec-
one; the results are found in Tables 1 and 2. Unsubstituted tivities are shown in Table 3. Also the reactions at lower
amino alcohol 4 reduced acetophenone with low conversion temperatures provided improved selectivities. We repeated
rates and enantiomeric excess (Table 1, Entry 1). Phenyl the hydrogenation of acetophenone at 0 °C using [Ru(p-cy-
Table 3. ATH of acetophenone of different metal complexes and 14 as the chiral ligand.
Entry
Metal complex
Temperature
Time [h]
Conversion [%][a]
ee [%] (R/S)[b]
1
2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[RhCl2Cp*]2
r.t.
0 °C
r.t.
0.75
1.0
1.25
0.25
0.5
0.5
0.5
94
35
85
94
86
42
94
35
94 (R)
99 (R)
94 (R)
90 (R)
94 (R)
99 (R)
91 (R)
75 (R)
3[c]
4
r.t.
5
[RhCl2Cp*]2
[RhCl2Cp*]2
[RhCl2Cp*]2
[IrCl2Cp*]2
0 °C
–15 °C
r.t.
6
7[c]
8
r.t.
0.5
[a] Determined by chiral GC analysis. [b] Absolute configuration determined by comparison with reported optical rotation. Values
reported are the average of three runs. [c] Reaction was performed using 0.5 mol-% of metal/substrate.
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H. G. Kruger, T. Govender et al.
Table 4. ATH of various alkyl aryl ketones with [Ru(p-cymene)Cl2]2 and 14 as chiral ligand at ambient temperature.
FULL PAPER
Entry
Substrate
Time [h]
Conversion (%)[a]
ee [%] (R/S)[b]
1
2
3
4
5
6
7
8
4-methylacetophenone
4-nitroacetophenone
2-methoxyacetophenone
1-indanone
1.0
1.0
1.0
1.0
24.0
1.0
80
98
94
31
40
92 (R)
68 (R)
82 (S)
65 (S)
69 (S)
racemic
n.r.[c]
1-indanone
tetralone
2-acetylpyridine
2-acetylpyridine
40
1.0
24.0
n.r.[c]
n.r.[c]
n.r.[c]
[a] Determined by chiral GC analysis. [b] Absolute configuration determined by comparison with reported optical rotation. Values
reported are the average of two runs. [c] No reaction observed.
mene)Cl2]2, and an excellent selectivity was observed with single-point
calculations
at
B3LYP/LACV3p+**.
99% ee but with a low conversion of 35%. [RhCl2Cp*]2 LACV3p+** differs from LACVP by using the 6-311+G**
gave a higher reactivity (94% conversion) than [Ru(p-cy- basis set in place of 6-31G.
mene)Cl2]2, but with a diminished enantioselectivity of 90%
ee (Table 3, Entry 4). The reaction was repeated at different
temperatures affording respectable selectivities with moder-
ate conversions (Table 3, Entries 5, 6). Due to the higher
rates when rhodium was used, we attempted the same reac-
tion with a low catalyst loading of 0.5 mol-% (metal/sub-
strate). The reaction rate was reduced providing good selec-
tivity and conversion rates (Table 3, Entry 7). Replacing
rhodium with iridium gave poorer selectivity and conver-
sion results.
Figure 3. The calculated (S) (left) and (R) (right) transition states
for the reduction of acetophenone using ligand 14. The (S)-transi-
Having identified the most efficient metal complex in our
system we then undertook studies on different substrates.
The results are summarized in Table 4. In general, when
compared to the reduction of acetophenone, all of the other
substrates tested led to decreased conversions. The sub-
strates can be grouped based on their electronic and steric
properties. Electron-donating (4-methylacetophenone) or
electron-withdrawing (4-nitroacetophenone) groups de-
creased the rate of conversion. Replacing the phenyl ring
with a pyridyl species completely arrests any reactivity. This
could be due to transient coordination of the sp2 nitrogen
atom to the metal center thereby disrupting the active tran-
sition state. An increase in steric bulk (indanone and tet-
ralone) renders a loss in selectivities and conversion rates.
The observed enantioselectivity could be explained by
the mechanism proposed for Ru-catalyzed transfer hydro-
tion state showing a close-contact between the phenyl of the sub-
strate and the arene ligand, making it less favorable. The Cartesian
coordinates of the optimized structures are available as Supporing
Information.
The energy of the transition state leading to the (S)-
alcohol product is significantly higher in energy than that
of the (R)-alcohol product. This theoretical result supports
the observed experimental result for ligand 14 reported in
Tables 1, 2, 3, and 4.
Conclusions
We have synthesized and evaluated seven ligands of a
genations using amino alcohol ligands.[16,25] According to new class of N,O TIQ compounds. These ligands were coor-
this mechanism, a ruthenium hydride and a proton from dinated with ruthenium, and they were evaluated in the
the ligand are simultaneously transferred from the catalyst asymmetric transfer hydrogenation of acetophenone. C1-
to the prochiral carbonyl group. The structures of the two substituted TIQ amino primary alcohol 14 gave rise to a
possible diastereomeric transition states were calculated catalyst that induced good enantioselectivity, 94% ee. The
using the Jaguar program.[26] The transition-state structures reaction was repeated under various conditions, affording
were located using the quadratic synchronous transit (QST) 99% ee at lower temperature as the best result. The rho-
method and the B3LYP functional together with the dium complex with amino alcohol ligand 14 showed the
LACVP ECP basis set. Normal mode analysis revealed one fastest rate of all complexes evaluated in this study, 94%
imaginary frequency for each structure (Figure 3). LACVP conversion in 0.5 h using a 0.5 mol-% ratio of metal/sub-
in Jaguar defines a combination of the LANL2DZ basis set strate with a lower selectivity of 91% ee. Considering the
for ruthenium[27] and the 6-31G basis set for other atoms. good selectivity at ambient temperature, we screened dif-
LACVP implies the use of an effective core potential for 28 ferent alkyl aryl ketone substrates, rendering moderate to
core electrons of ruthenium and a (5s,6p,4d) primitive basis reasonable results. Acetophenone as substrate gave the best
contracted to [3s,3p,2d]. Final energies were retrieved from results.
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Tetrahydroisoquinolines for Asymmetric Transfer Hydrogenations
2.1 mmol) in THF (20 mL) was added to a suspension of activated
10 wt.-% Pd/C (500 mg) in dry MeOH (20 mL). The mixture was
stirred at room temperature with H2 under atmospheric pressure
for 1 h. The reaction was monitored with TLC in hexane/ethyl ace-
tate (40:50; Rf = 0.4). The Pd/C was filtered off through a Celite
pad and then washed with methanol (20 mL). The filtrate was con-
centrated under reduced pressure affording the crude amino ester,
which was purified by column chromatography using 0–50% ethyl
acetate in hexane as the eluent to yield approximately 0.65 g (95%
yield) of pure compounds 12 and 16.
Experimental Section
General: Reagents and solvents were purchased from Aldrich,
Merck and Fluka. All NMR spectra were recorded with Bruker
AVANCE III 400 MHz or 600 MHz instruments. Chemical shifts
are expressed in ppm relative to TMS, and coupling constants are
reported in Hz. NMR spectra were obtained at room temperature,
except where stated otherwise. Thin layer chromatography (TLC)
was performed on Merck Kieselgel 60 F254. Crude compounds
were purified by column chromatography with silica gel (60–
200 mesh except if stated different). All solvents were dried accord-
ing to standard procedures. IR spectra were recorded with a Per-
kin–Elmer spectrum 100 instrument with a universal ATR attach-
ment. Optical rotations were recorded with a Perkin–Elmer Polari-
meter. Melting points are uncorrected. Testing reactions were car-
ried out under dry UHP argon gas. The results of all testing reac-
tions that were analyzed using GC analysis was performed with
an Agilent capillary gas chromatograph with a CP-Chirasil-β-Dex
column (25 m with 0.25 mm inner diameter), nitrogen as carrier
gas, and a flame-ionization detector. LC traces were recorded with
an Agilent 1100 HPLC with reverse phase using 0.1% formic acid
in acetonitrile and Millipore water. High-resolution mass spectro-
metric data was obtained with a Bruker microTOF-Q II instrument
operating at ambient temperatures, using a sample concentration
of approximately 1 ppm.
General Procedure for the Preparation of 14 and 17: A solution of
amino ester (0.5 g, 1.5 mmol) in dry THF (20 mL) was added drop-
wise to a suspension of LiAlH4 (0.18, 4.5 mmol) in dry THF
(20 mL) under N2 at 0 °C. The mixture was stirred at 0 °C for 2 h,
and the reaction was monitored by TLC in hexane/ethyl acetate
(50:50; Rf = 0.5). Excess lithium aluminum hydride was quenched
with saturated sodium sulfate solution at 0 °C. The reaction mix-
ture was filtered, and the solid was washed with THF (20 mL). The
solvent was evaporated to dryness, ethyl acetate (20 mL) was
added, the mixture washed with water (2ϫ5 mL), the organic layer
was separated and dried with anhydrous MgSO4 to afford the crude
amino alcohol. This was purified by gradient column chromatog-
raphy [solvent A: saturated ammonia in DCM/DCM (10:90) and
solvent B: MeOH/DCM (2:98)] to yield approximately 0.33 g (70%
yield) of pure amino alcohols 14 and 17.
General Procedure for the Transfer Hydrogenation of Aromatic
Ketones: To an oven-dried Schlenk tube was added [Ru(p-cymene)-
Cl2]2 (3.0 mg, 4.8 µmol), ligand (4 equiv.), and the tube was evacu-
ated for 10 min. Thereafter, freshly distilled isopropyl alcohol was
added under dry argon. The mixture was stirred for 15 min, and
freshly prepared 0.1  KOtBu solution was added to the complex,
followed by the substrate. An aliquot of the reaction mixture was
tested at different intervals by quenching with 5% acetic acid in
isopropyl alcohol, passed through a pad of silica gel and monitored
by GC with a chiral β-dex column. The percentage ee values were
calculated from the integration values of the GC peaks for each
enantiomer. The experiment was repeated two or three times, and
the average values are reported in the tables.
(S)-Diphenyl(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (8): White
solid, m.p. 104–106 °C (MeOH). Spectroscopic data identical to
literature values.[28] [α]D20 = –130 (c = 0.26, in CHCl3). HR ESI MS:
m/z = 316.1774 [M + H]+ (calcd. for C22H22NO 316.1701).
2-Benzyl 3-Methyl (1R,3S)-6,7-Dimethoxy-1-phenyl-3,4-dihydroiso-
quinoline-2,3(1H)-dicarboxylate (12): Rf = 0.6 (hexane/EtOAc, 6:4).
White solid, m.p. 127–129 °C (hexane/ethyl acetate). [α]2D0 = +9.54
(c = 0.26, in CHCl3). 1H NMR (400 MHz, DMSO, 100 °C): δ =
7.36–7.15 (m, 9 H), 7.09 (s, 1 H), 6.76 (s, 1 H), 5.16–5.05 (m, 3 H),
3.78 (s, 3 H), 3.73 (s, 3 H), 3.48 (s, 3 H), 3.21 (dd, J = 15.69,
5.97 Hz, 1 H), 3.13–3.04 (m, 2 H) ppm. 13C NMR (100 MHz,
DMSO, 100 °C): δ = 172.1, 155.9, 149.0, 148.9, 137.0, 130.3, 128.6,
128.1, 127.7, 126.9, 126.4, 124.2, 113.4, 113.2, 67.2, 59.6, 56.8, 56.6,
General Procedure for Compounds 12 and 15: To a solution of C1-
substituted TIQ carboxylic acid (1.0 g, 3.5 mmol) in dioxane
(20 mL) and water (10 mL) at 0 °C was added dropwise a solution
of potassium hydrogen carbonate (2.1 g, 21.1 mmol) over 15 min
followed by addition of Cbz-Cl (0.65 g, 3.8 mmol). The solution
was stirred at 0 °C for 1.5 h and then at ambient temperature for a
further 1.5 h. The reaction was monitored by LC-MS (neutralizing
the reaction mixture with 10% HCl and extracting with ethyl ace-
tate). The solvent was evaporated under reduced pressure and the
residue dried under high vacuum. The crude residue obtained was
dissolved in acetone (40 mL), and potassium hydrogen carbonate
(7.01 g, 70.17 mmol) was added followed by dimethyl sulfate
(4.45 g, 35.28 mmol) and stirred for 16 h (overnight) at reflux.
Completion of the reaction was monitored with TLC using hexane/
ethyl acetate (60:40; Rf = 0.6). The reaction solvent was evaporated
under reduced pressure, and ethyl acetate (60 mL) was added and
the mixture washed with 20 mL (2ϫ10 mL) of water followed by
10 mL of brine. The organic layer was separated and dried with
anhydrous MgSO4, and the solvent was evaporated under reduced
pressure to afford the crude Cbz-ester, which was purified by col-
umn chromatography using 0–40% ethyl acetate in hexane as the
eluent to yield approximately 1.3 g (80% yield) of pure compounds
12 and 15.
55.9, 55.8, 52.1, 30.9 ppm. IR (neat): ν = 2942, 1744, 1714, 1204,
˜
735, 698 cm–1. HR ESI MS: m/z = 462.1896 [M + 1 H]+ (calcd. for
C27H28NO6 462.1916), 484.1720 [M
C27H27NNaO6 484.1736).
+
Na]+ (calcd. for
Methyl (1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquin-
oline-3-carboxylate (13): Rf = 0.5 (hexane/EtOAc, 6:4). Colorless
oil. [α]2D0 = +15.38 (c = 0.26, in CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.35–7.24 (m, 3 H), 7.23–7.16 (m, 2 H), 6.65 (s, 1 H),
6.34 (s, 1 H), 5.25 (s, 1 H), 3.88 (s, 3 H), 3.80 (q, J = 8.58, 5.06 Hz,
1 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.15 (dd, J = 5.08 Hz, 1 H) 3.01
(dd, J = 8.68 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
173.8, 147.9, 147.4, 144.5, 128.6, 128.4, 127.9, 127.3, 125.6, 111.1,
110.8, 58.8, 55.8, 52.0, 51.3, 31.0 ppm. IR (neat): ν = 2928, 2600,
˜
1746, 1516, 1250, 1123, 727 cm–1. HR ESI MS: m/z = 328.1547 [M +
H]+ (calcd. for C19H22NO4 328.1548).
[(1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl]-
methanol (14): Rf = 0.4 (CH2Cl2/MeOH/satd. NH3 in CHCl3
9.5:0.5:1). Pale yellow solid, m.p. 115–117 °C (CH2Cl2). [α]2D0 = +3.7
1
(c = 0.27, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.32–7.21
(m, 3 H), 7.18–7.13 (m, 2 H), 6.64 (s, 1 H), 6.42 (s, 1 H), 5.19 (s, 1
H), 3.88 (s, 3 H), 3.72 (s, 3 H), 3.66–3.60 (dd, J = 10.76, 2.96 Hz,
1 H), 3.49–3.41 (dd, J = 10.64, 7.81 Hz, 1 H), 3.12–3.02 (m, 1 H),
General Deprotection Procedure for the Preparation of Amino Esters
2.70 (dd, J = 4.56 Hz, 1 H), 2.57 (dd, J = 10.28 Hz, 1 H) ppm. 13
C
13 and 16: A solution of the Cbz-protected TIQ ester (1.0 g,
NMR (100 MHz, CDCl3): δ = 147.9, 147.2, 144.6, 128.7, 128.2,
Eur. J. Org. Chem. 2010, 972–980
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
977

H. G. Kruger, T. Govender et al.
FULL PAPER
127.1, 126.7, 111.5, 110.9, 65.7, 58.9, 55.9, 55.8, 48.8, 30.5 ppm. IR [(1R,3S)-2-Benzyl-6,7-dimethoxy-1-p-tolyl-1,2,3,4-tetrahydroiso-
(neat): ν = 3264, 2832, 1515, 1222, 1066, 981, 726, 694 cm–1. HR
quinolin-3-yl]diphenylmethanol (19): A solution of compound 18
(500 mg, 1.19 mmol) in THF (10 mL) was added to freshly pre-
pared Grignard reagent of phenylmagnesium bromide (2.17 g,
11.9 mmol) under a dry inert gas at ambient temperature for
15 min. Completion of the reaction was monitored by TLC, and
the reaction was quenched by adding a saturated ammonium chlo-
ride solution to the mixture at 0 °C. The reaction mixture was fil-
tered off and washed with ethyl acetate (20 mL). The filtrate was
concentrated under reduced pressure to yield approximately 0.52 g
(80% yield) of the crude product. Rf = 0.5 (hexane/EtOAc, 6:4).
White solid, m.p. 205–207 °C (hexane/EtOAc). [α]2D0 = +20.37 (c =
0.27, in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J =
1.16 Hz, 2 H), 7.32–7.10 (m, 14 H), 7.0–6.88 (m, 6 H), 6.69 (s, 1
H), 6.38 (s, 1 H), 4.74 (s, 1 H), 4.21 (d, J = 13.60 Hz, 1 H), 4.14
(q, J = 3.70, 12.74 Hz, 1 H), 3.89 (s, 3 H), 3.72 (s, 3 H), 3.57 (s, 1
H), 3.30–3.18 (m, 2 H), 2.60 (dd, J = 3.60, 16.48 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.8, 147.5, 146.1, 145.5, 143.4,
140.2, 129.8, 129.1, 128.2, 128.1, 127.7, 127.6, 127.0, 126.7, 126.3,
126.1, 125.5, 112.1, 111.6, 79.4, 64.6, 56.8, 55.8, 55.8, 51.8,
˜
ESI MS: m/z = 300.1622 [M + H]+ (calcd. for C28H22NO3
300.1600).
2-Benzyl 3-Methyl (1S,3S)-6,7-Dimethoxy-1-phenyl-3,4-dihydroiso-
quinoline-2,3(1H)-dicarboxylate (15): Colorless oil. [α]2D0 = –38.27 (c
= 0.39, in CHCl3). 1H NMR (400 MHz, DMSO, 100 °C): δ = 7.40–
7.15 (m, 10 H), 7.02 (s, 1 H), 6.93 (s, 1 H), 5.16 (s, 1 H), 4.43 (dd,
1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.49 (s, 3 H), 3.02 (dd, J = 15.09,
5.67 Hz, 1 H), 2.70 (dd, J = 14.73, 11.13 Hz, 1 H) ppm. 13C NMR
(100 MHz, DMSO, 100 °C): δ = 172.1, 156.1, 149.4, 148.8, 142.0,
136.9, 129.6, 128.7, 128.2, 128.2, 127.9, 127.5, 127.1, 126.2, 113.5,
67.6, 67.6, 58.8, 56.9, 56.8, 56.7, 56.7, 56.5, 51.9, 30.2, 30.1 ppm.
IR (neat): ν = 1752, 1693, 1514, 1404, 1295, 1216, 1102, 697,
˜
596 cm–1. HR ESI MS: m/z = 462.1906 [M + H]+ (calcd. for
C
27H28NO6 462.1916), and 484.1730 [M + Na]+ (calcd. for
C27H27NNaO6 484.1736).
Methyl (1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquin-
oline-3-carboxylate (16): Rf = 0.6 (hexane/EtOAc, 6:4). Colorless
oil. [α]2D0 = –42.0 (c = 0.24, in CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.38–7.28 (m, 5 H), 6.64 (s, 1 H), 6.17 (s, 1 H), 5.09
(s, 1 H), 3.91–3.86 (m, 4 H), 3.85–3.74 (m, 4 H), 3.56–3.61 (s, 3 H),
3.41–3.05 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9,
147.7, 147.3, 143.8, 130.2, 129.0, 128.5, 127.8, 126.0, 111.2, 110.5,
23.4 ppm. IR (neat): ν = 3589, 1509, 1240, 1093, 694 cm–1. HR ESI
˜
MS: m/z = 542.2698 [M + H]+ (calcd. for C37H36NO3 542.2695).
[(1R,3S)-6,7-Dimethoxy-1-p-tolyl-1,2,3,4-tetrahydroisoquinolin-3-yl]-
diphenylmethanol (20): A solution of compound 19 (400 mg,
0.73 mmol) in methanol (10 mL/mmol) was added to a suspension
of activated Pd/C (200 mg, 10 wt.-%) in dry MeOH under an inert
gas. The reaction mixture was connected to an H2 source at 1 atm
and stirred at room temperature for 6 h. Completion of the reaction
was monitored by TLC using hexane/ethyl acetate (40:60; Rf = 0.5).
The Pd/C was filtered off through a Celite pad and washed with
methanol (10 mL). The filtrate was concentrated under reduced
pressure affording the crude amino ester, which was purified by
column chromatography using 0–2% methanol in dichloromethane
as the eluent to yield approximately 0.30 g (92 % yield) of pure
product. Rf = 0.3 (hexane/EtOAc, 5:5). Pale yellow solid, m.p. 77–
79 °C (CH2Cl2). [α]D20 = –119.5 (c = 0.26, in CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.42–7.34 (m, 5 H), 7.29–7.24 (t, J =
15.20 Hz, 1 H), 7.05–7.21 (m, 6 H), 7.02–6.96 (m, 2 H), 6.56 (s, 1
H), 6.43 (s, 1 H), 5.23 (s, 1 H), 3.89–3.85 (q, J = 10.94, 3.86 Hz, 1
H), 3.81 (s, 3 H), 3.72 (s, 3 H), 3.03–2.92 (dd, J = 16.42, 10.94 Hz,
1 H), 2.24–2.16 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.0, 147.2, 145.1, 144.6, 144.0, 128.4, 128.0, 127.7, 127.4, 126.9,
126.5, 126.2, 126.0, 125.4, 111.4, 110.6, 78.3, 60.0, 55.9, 55.8, 51.9,
62.8, 56.5, 55.8, 55.8, 52.1, 32.2 ppm. IR (neat): ν = 3020, 1737,
˜
1514, 1244, 1213, 749, 665 cm–1. HR ESI MS: m/z = 328.1548 [M
+ H]+ (calcd. for C19H22NO4 328.1548).
[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl]-
methanol (17): Rf = 0.4 (CH2Cl2/MeOH/satd. NH3 in CHCl3
9.5:0.5:1). Off-white solid, m.p. 175–177 °C (CH2Cl2). [α]2D0 = –24.0
1
(c = 0.25, in CHCl3). H NMR (600 MHz, CDCl3): δ = 7.39–7.27
(m, 5 H), 6.62 (s, 1 H), 6.14 (s, 1 H), 5.04 (s, 1 H), 3.85 (s, 1 H),
3.79–3.72 (m, 1 H), 3.62–3.53 (m, 4 H), 3.26–3.10 (m, 1 H), 3.00–
2.52 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 147.0, 143.7,
130.2, 128.9, 128.5, 127.7, 126.8, 111.4, 110.7, 65.5, 66.5, 62.8, 55.8,
55.7, 55.7, 31.2 ppm. IR (neat): ν = 3256, 2919, 1511, 1453, 1258,
˜
1215, 1100, 1073, 822, 737, 700, 561 cm–1. HR ESI MS: m/z =
300.1594 [M + H]+ (calcd. for C18H22NO3 300.1600).
Methyl (1R,3S)-2-Benzyl-6,7-dimethoxy-1-p-tolyl-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylate (18): To a solution of compound 13
(500 mg, 1.52 mmol) in acetonitrile (20 mL) was added solid
K2CO3 (635 mg, 4.58 mmol) followed by benzyl bromide (286 mg,
1.67 mmol) at ambient temperature. Thereafter, the reaction mix-
ture was refluxed for 3 h. Completion of the reaction was moni-
tored by TLC using hexane/ethyl acetate (60:40; Rf = 0.5). The
solvent was evaporated, and ethyl acetate (30 mL) was added, the
mixture washed with 2ϫ10 mL of water, the organic layer was sep-
arated and dried with anhydrous MgSO4. The solvent was evapo-
rated under reduced pressure to afford a crude product, which was
purified by column chromatography using 0–20% ethyl acetate/hex-
ane as the eluent to yield approximately 0.44 g (90% yield) of pure
product. Rf = 0.7 (hexane/EtOAc, 6:4). White solid, m.p. 146–
148 °C (hexane/EtOAc). [α]2D0 = –164.3 (c = 0.28, in CHCl3). 1H
28.5 ppm. IR (neat): ν = 2926, 1512, 1447, 1243, 1063, 698 cm–1.
˜
HR ESI MS: m/z = 452.2220 [M + H]+ (calcd. for C30H30NO3
452.2226).
[(1R,3S)-2-Benzyl-6,7-dimethoxy-1-p-tolyl-1,2,3,4-tetrahydroiso-
quinolin-3-yl]methanol (21): A solution of compound 18 (1.3 g,
3.11 mmol) in dry THF (20 mL) was added dropwise to a suspen-
sion of LiAlH4 (0.35 g, 9.3 mmol) in dry THF (30 mL) under N2
at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Comple-
tion of the reaction was monitored by TLC using hexane/ethyl ace-
tate (80:20; Rf= 0.6). Excess lithium aluminum hydride was
quenched with a saturated sodium sulfate solution at 0 °C. The
NMR (600 MHz, CDCl3): δ = 7.38 (d, J = 7.26 Hz, 2 H), 7.32– reaction mixture was filtered and washed with THF (20 mL). The
7.16 (m, 9 H), 6.54 (s, 1 H), 6.26 (s, 1 H), 5.19 (s, 1 H), 3.85–3.72 solvent was evaporated to dryness under reduced pressure. Ethyl
(m, 6 H), 3.61 (s, 6 H), 3.23 (dd, J = 5.10, 15.66 Hz, 1 H), 2.98 acetate (20 mL) was added and washed with water (2ϫ5 mL). The
(dd, J = 3.00, 15.72, Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 173.5, 147.4, 147.3, 145.4, 139.3, 129.7, 128.7, 128.3, 128.2,
127.1, 127.0, 123.8, 111.5, 110.9, 64.7, 55.7, 55.7, 55.3, 54.6, 51.2,
organic layer was separated and dried with anhydrous MgSO4 to
give the crude amino alcohol. The crude product was purified by
column chromatography using silica gel as a stationary phase and
0–40% ethyl acetate in hexane as a mobile phase to yield 0.85 g
(70% yield) of pure amino alcohol. Rf = 0.3 (hexane/EtOAc, 5:5).
Yellow solid, m.p. 108–110 °C. [α]2D0 = +66.0 (c = 0.25, in CHCl3).
31.5 ppm. IR (neat): ν = 2944, 1729, 1511, 1152, 753, 699 cm–1.
˜
HR ESI MS: m/z = 418.2012 [M + H]+ (calcd. for C26H28NO4
418.2018).
978
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 972–980

Tetrahydroisoquinolines for Asymmetric Transfer Hydrogenations
1H NMR (400 MHz, CDCl3): δ = 7.43–7.28 (m, 5 H), 7.24–7.12 (m, 3 H), 2.37–2.13 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
(m, 3 H), 6.98 (d, J = 6.88 Hz, 2 H), 6.70 (s, 1 H), 6.41 (s, 1 H),
4.85 (s, 1 H), 3.98–3.89 (m, 4 H), 3.77–3.69 (m, 4 H), 3.58–3.49 (m,
1 H), 3.41–3.29 (m, 2 H), 2.69 (dd, J = 11.60, 11.56 Hz, 1 H), 2.53
(dd, J = 4.68, 4.68 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 147.9, 147.5, 143.7, 139.2, 129.2, 129.0, 128.5, 127.9, 127.2,
126.9, 125.9, 112.3, 111.6, 62.6, 61.2, 55.8, 52.2, 49.0, 25.5 ppm. IR
δ = 148.0, 147.6, 143.3, 139.0, 129.4, 128.6, 127.3, 126.9, 125.2,
112.3, 111.6, 65.7, 62.3, 57.9, 55.9, 55.8, 49.3, 24.5, 19.3 ppm. IR
(neat): ν = 2931, 2850, 1510, 1493, 1450, 1222, 1102, 751, 699 cm–1.
˜
HR ESI MS: m/z = 404.2220 [M + H]+ (calcd. for C26H30NO3
404.2226).
(S)-1-[(1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquin-
olin-3-yl]ethanol (24): A solution of benzyl-protected TIQ sec-
alcohol (300 mg, 0.74 mmol) in methanol (10 mL) was added to a
suspension of 10 wt.-% Pd/C (0.2 g) in methanol (10 mL). The reac-
tion mixture was connected to an H2 source at atmospheric pres-
sure and stirred at room temperature for 6 h. The Pd/C was filtered
off on a Celite pad, and the filtrate was concentrated under reduced
pressure to afford the crude amino ester. The products were puri-
fied by column chromatography using hexane/ethyl acetate as an
eluent to yield a combined mass of 0.14 g (60% yield) for major 24
and minor 24.
(neat): ν = 3511, 2919, 1609, 1514, 1292, 1127, 1029, 697 cm–1.
˜
HR ESI MS: m/z = 390.2060 [M + H]+ (calcd. for C25H28NO3
390.2069).
(1R,3S)-2-Benzyl-6,7-dimethoxy-1-p-tolyl-1,2,3,4-tetrahydroisoquin-
oline-3-carbaldehyde (22): To a solution of oxalyl chloride (0.34 g,
2.68 mmol) in dry CH2Cl2 (12 mL) at –78 °C was added a solution
of DMSO (0.45 g, 5.85 mmol) in CH2Cl2 (1.2 mL) over 5 min, and
the reaction mixture was stirred at –78 °C for 10 min. Compound
21 (0.95 g, 2.43 mmol) was added as a solution in CH2Cl2 (1 mL)
over 5 min. The reaction mixture was stirred for 15 min, and an
excess of Et3N (0.86 g, 8.53 mmol) was added over 5 min. The cool-
ing bath was removed for the temperature to rise to room tempera-
ture. Water (30 mL) was added, and the phases were separated. The
aqueous phase was extracted with CH2Cl2 (3ϫ10 mL), and the
combined organic extracts were washed with brine and dried with
MgSO4. Filtration and concentration afforded a residue that was
purified by column chromatography using silica gel as a stationary
phase and 0–30% ethyl acetate in hexane as a mobile phase to yield
approximately 0.80 g (85% yield) of the product as a yellow oil. Rf
major 24: Rf = 0.3 (hexane/EtOAc, 4:6). Brown oil. [α]2D0 = –11.11
1
(c = 0.27, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.30–7.19
(m, 3 H), 7.13–7.03 (m, 2 H), 6.66 (s, 1 H), 6.39 (s, 1 H), 5.19 (s, 1
H), 3.86 (s, 3 H), 3.73–3.65 (m, 4 H), 2.83–2.74 (m, 1 H), 2.92–2.85
(m, 1 H), 2.67–2.59 (dd, J = 4.20, 4.21 Hz, 1 H), 1.12 (d, J =
6.40 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.9, 147.1,
145.0, 128.5, 128.2, 127.7, 127.2, 127.1, 111.5, 110.8, 69.5, 59.6,
55.8, 51.5, 27.7, 18.2 ppm. IR (neat): ν = 2930, 1589, 1520, 1454,
˜
1346, 1226, 1124, 755, 702 cm–1. HR ESI MS: m/z = 314.1761 [M
1
+ H]+ (calcd. for C19H24NO3 314.1756).
= 0.8 (hexane/ethyl acetate, 7:3). H NMR (400 MHz, CDCl3): δ =
9.76 (s, 1 H), 7.40–7.16 (m, 10 H), 6.68 (s, 1 H), 6.33 (s, 1 H), 5.0
(s, 1 H), 3.87 (s, 3 H), 3.77–3.63 (m, 6 H), 3.01–2.95 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 204.2, 147.9, 147.6, 144.1, 138.8,
129.1, 129.0, 127.4, 127.3, 127.2, 124.7, 111.9, 111.3, 63.8, 60.9,
minor 24: Rf = 0.3 (hexane/EtOAc, 4:6). Colorless oil. [α]2D0 = –10.71
(c = 0.28, in CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.40–7.15 (m, 5 H), 6.66 (s, 1 H), 6.40 (s, 1 H), 5.50 (s, 1 H), 3.88 (s,
3 H), 3.81–3.67 (m, 4 H), 2.97–2.69 (m, 3 H), 1.16 (d, J = 5.72 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.7, 147.9, 139.7,
129.3, 128.5, 125.0, 111.2, 110.5, 68.0, 57.9, 55.9, 55.8, 54.3, 29.4,
55.8, 55.8, 54.1, 25.2 ppm. IR (neat): ν = 2931, 2832, 1726, 1511,
˜
1238, 1220, 697 cm–1.
1-[(1R,3S)-2-Benzyl-6,7-dimethoxy-1-p-tolyl-1,2,3,4-tetrahydroiso-
quinolin-3-yl]ethanol (23): A solution of compound 22 (0.65 g,
1.67 mmol) in dry THF (10 mL) was added to a freshly prepared
Grignard reagent of methylmagnesium iodide (1.4 g, 8.48 mmol)
under an inert gas at 0 °C for 15 min. The reaction mixture was
stirred at 0 °C for 3 h and the progress monitored by TLC using
ethyl acetate/hexane (30:70); the reaction was quenched by adding
a saturated ammonium chloride solution at 0 °C for 15 min. The
reaction mixture was filtered and washed with ethyl acetate
(20 mL). Concentration of the filtrate gave 0.54 g (80% yield) of
the crude product as a 9:1 mixture. The diastereomers were sepa-
rated by column chromatography using silica gel (230–400 mesh)
as a stationary phase and 0–40% ethyl acetate/hexane as a mobile
phase.
19.5 ppm. IR (neat): ν = 2933, 1694, 1513, 1451, 1243, 1089,
˜
751 cm–1. HR ESI MS: m/z = 314.1756 [M + H]+ (calcd. for
C19H24NO3 314.1756).
Supporting Information (see footnote on the first page of this arti-
cle): NMR, LC traces, HRMS and Cartesian coordinates for DFT
calculations.
Acknowledgments
This work was supported by the National Research Foundation
(South Africa) (GUN no. 2073251), a SA/Swedish Research Links
Programme grant and Aspen Pharmacare, SA. The technical staffs
at the UKZN chemistry department, Westville campus is thanked
for their assistance. The rest of the group members are thanked for
their help and support.
major 23: Rf = 0.6 (hexane/EtOAc, 7:3). Yellow oil. [α]2D0 = +64.15
1
(c = 0.26, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.46–7.05
(m, 12 H), 6.74 (s, 1 H), 6.39 (s, 1 H), 4.74 (s, 1 H), 3.92–3.98 (m,
1 H), 3.91 (s, 3 H), 3.84 (d, 1 H), 3.73 (s, 3 H), 3.48 (d, 1 H),
2.95–2.76 (m, 3 H), 2.34–2.15 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 147.8, 147.2, 144.1, 139.9, 129.0, 128.9, 128.4, 127.7,
127.0, 126.6, 125.9, 112.3, 111.7, 69.7, 63.1, 57.2, 55.8, 55.8, 50.7,
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31.9, 29.6, 29.3, 25.7, 21.6 ppm. IR (neat): ν = 2924, 2853, 1510,
˜
1449, 1243, 1219, 1099, 1028, 749, 698 cm–1. HR ESI MS: m/z =
404.2225 [M + H]+ (calcd. for C26H30NO3 404.2226).
minor 23: Rf = 0.65 (hexane/EtOAc, 7:3). Yellow oil. [α]2D0 = +57.69
1
(c = 0.28, in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.42–7.37
(m, 4 H), 7.21–7.14 (s, 3 H), 6.92 (d, 2 H), 6.73 (s, 1 H), 6.42 (s, 1
H), 4.86 (s, 1 H), 4.0 (d, J = 12.92 Hz, 1 H), 3.92 (s, 3 H), 3.91–
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Received: October 14, 2009
Published Online: December 17, 2009
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