A Modular Access to (±)-Tubocurine and (±)-Curine - Formal Total Synthesis of Tubocurarine

Article abstract of DOI:10.1021/acs.joc.6b02647

Two consecutive Cu-catalyzed Ullmann-type C-O couplings permitted the first successful entry toward the curare alkaloids (±)-tubocurine and (±)-curine. Starting from vanillin, the synthetic sequence comprises 15 linear steps and includes a total of 24 transformations. In addition, the total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison alkaloid tubocurarine.

Full text of DOI:10.1021/acs.joc.6b02647

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Article
A Modular Access to (+/-)-Tubocurine and (+/-)-
Curine - Formal Total Synthesis of Tubocurarine
Nicola Otto, Dorota Ferenc, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02647 • Publication Date (Web): 20 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
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A Modular Access to (±)ꢀTubocurine and (±)ꢀCurine ꢀ Formal Total Synthesis
of Tubocurarine
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Nicola Otto, Dorota Ferenc, and Till Opatz*
Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-
55128 Mainz, Germany
Abstract:
Two consecutive Cuꢀcatalyzed Ullmannꢀtype C–O couplings permitted the first successful entry
towards the curare alkaloids (±)ꢀtubocurine and (±)ꢀcurine. Starting from vanillin, the synthetic
sequence comprises of 15 linear steps and includes a total of 24 transformations. In addition, the
total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison
alkaloid tubocurarine.
Introduction
The curare alkaloids belong to the class of bisbenzylisoquinolines which constitute a family of
1ꢀ2
almost 400 natural products found in diverse plant species (see figure 1).
They are
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characterized by at least one diaryl ether moiety linking two aromatic rings of each
benzylisoquinoline unit. The most prominent representative of this compound class is (+)ꢀ
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tubocurarine ((+)ꢀ1) which is widely known as the active ingredient of the arrow poison curare.
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Curare was used for hunting animals for centuries by indigenous peoples in South America and
also found application in modern medicine as a muscle relaxant in anesthesia since 1942. (+)ꢀ
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Tubocurarine ((+)ꢀ1) acts by inhibiting the nicotinic acetylcholine receptor (nAChR). While the
bisbenzylisoquinoline alkaloids in general exhibit a wide variety of biological activities, only
little is known about the biological activity of the other curare alkaloids. Nevertheless, this
subgroup has been a target for total synthesis for decades and first attempts were made by
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Hellmann and Elser and Tolkachev and coꢀworkers. In 1979, Naghaway and Soine reported the
total synthesis of semisynthetic (+)ꢀtubocurarine ((+)ꢀ1) by using natural tubocurarine which was
Nꢀdemethylated to (+)ꢀtubocurine ((+)ꢀ2) by sodium thiophenolate and subsequently
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remethylated to result in (+)ꢀtubocurarine ((+)ꢀ1) again.
We aimed to develop a modular synthetic strategy towards the group of curare alkaloids to
establish structureꢀactivity relationships to these alkaloids. Herein, the first total synthesis of (±)ꢀ
curine ((±)ꢀ3) and (±)ꢀtubocurine ((±)ꢀ2) is presented which also represents a formal total
synthesis of tubocurarine (1).
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Figure 1: Structure of curare alkaloids.
Results and Discussion
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It was decided to perform two subsequent C–Oꢀcouplings of two 1ꢀbenzyltetrahydroisoquinoline
subunits for the synthesis of the macrocyclic skeleton (see scheme 1).
Scheme 1: Retrosynthesis of curare alkaloids.
One benzylisoquinoline subunit should be equipped with two phenolic groups (diol 4a) and one
dihalogenated benzylisoquinoline (dihalide 4b). The dihalide subunit 4b should comprise one
bromo substituent and one iodo substituent, which is installed at the less hindered and hence
more reactive benzylic arene ring and the bromo substituent should be installed at the less
reactive tetrohydroisoquinoline core. For the diol subunit 4a, a benzylic protecting group and an
orthogonally stable protecting group such as TIPS or MOM should be used. The 1ꢀbenzylꢀ
1,2,3,4ꢀtetrahydroisoquinolines should either be prepared by
a
selfꢀdeveloped
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umpolung/alkylationꢀreduction sequence
starting from a deprotonated αꢀaminonitrile 5 and
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the corresponding benzylic bromide 6 or by BischlerꢀNapieralski cyclization
of suitable
amide precursors.
The construction of the diol compound 4a should be accomplished by umpolung/alkylation
reduction sequence from aminonitrile 5a and the corresponding benzylic bromide 6a. The
synthesis of the aminonitrile 5a started with vanillin (7), which was Oꢀbenzylated and condensed
with nitromethane to the corresponding βꢀnitrostyrene (scheme 2, A). Subsequent reduction with
lithium aluminum hydride gave phenylethylamine 8 in 74% yield over three steps. NꢀFormylation
of amine 8 with ethyl formate to the formamide and subsequent BischlerꢀNapieralski cyclization
gave 3,4ꢀdihydroisoquinoline 9 which was then Nꢀmethylated with iodomethane to furnish the Nꢀ
methyliminium salt. Reaction with potassium cyanide then furnished aminonitrile 5a in a yield of
34% over seven linear steps. The benzylic bromide 6a was synthesized starting from pꢀ
hydroxybenzaldehyde (10) by TIPS protection and reduction to the benzylic alcohol 11 and
transformation to the benzylic bromide 6a by phosphorous tribromide (scheme 2, B).
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Scheme 2: Synthesis of αꢀaminonitrile 5a (A) and benzylic bromide 6a (B).
The syntheses of the aminonitrile 5a and of the benzylic bromide 6a are devoid of
chromatographic purifications. The umpolung/alkylationꢀreduction sequence starting from
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aminonitrile 5a was performed by deprotonation in THF with KHMDS at –78 °C followed by
addition of the benzylic bromide 6a at this temperature and subsequent reduction with sodium
borohydride (scheme 3). The TIPS protected 1ꢀbenzyltetrahydroisoquinoline 4a was obtained in
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7% yield, quantitative hydrogenolytic debenzylation furnished building block 12.
Scheme 3: Synthesis of 1ꢀbenzyltetrahydrosioquinoline 4a and deprotection to 12.
For the preparation of the dihalide subunit 4b, aminonitrile 5b bearing a bromo substituent in 8ꢀ
position was synthesized starting from vanillin (7) over nine steps (scheme 4).
Scheme 4: Synthesis of αꢀaminonitrile 5b.
The iodinated benzylic bromide 6b was synthesized starting from pꢀanisaldehyde (15) (scheme 5,
A). Unfortunately, the umpolung/alkylation reduction sequence only gave low yields of the
desired product 4b in this case due to the steric hindrance imposed by the 8ꢀbromo substituent
(scheme 5, B).
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Scheme 5: Synthesis of benzylic bromide 6b (A) and 1ꢀbenzyltetrahydrosioquinoline 4b (B).
In order to improve the yields, a BischlerꢀNapieralski approach starting from the amide precursor
19 was attempted instead (scheme 6).
Scheme 6: Synthesis of dihalide 4b through BischlerꢀNapieralski cyclization.
Synthesis of the amide precursor 19 was accomplished by coupling of the respective phenylacetic
acid derivative 18 and phenylethylamine 14 with EDC hydrochloride and catalytic amounts of
DMAP. Acid 18 was synthesized starting from pꢀhydroxyphenylacetic acid (17) by iodination
with iodine monochloride and subsequent benzyl protection with benzyl bromide and was
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obtained in 43% yield over 2 steps (scheme 6). Phenylethylamine 14 was obtained from vanillin
(7) in 6 steps over 45% yield (see scheme 4). The cyclization of amide 19 was performed by a
synthetic procedure of Movassaghi and coꢀworkers using triflic anhydride and 2ꢀchloropyridine
as the activating agents (scheme 6). The crude cyclic imine 20 was subsequently reduced with
sodium borohydride to the secondary amine which was then Nꢀformylated by formic acid/acetic
acid anhydride to give formamide 21. Reduction with borane tetrahydrofuran complex and gave
the desired Nꢀmethylated dihalide building block 4b in 25% yield over 11 linear steps (scheme
6).
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Having both 1ꢀbenzylisoquinoline building blocks 12 and 4b at hand, the reaction conditions for
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the first C–O coupling were explored.
In preliminary studies with the electron rich model
system pꢀbromoanisole and pꢀmethoxyphenol, we found out that ligands such as N,Nꢀ
dimethylglycine as well as nꢀbutylimidazole and copper bromideꢀdimethylsulfide complex
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showed a high catalytic activity in the Ullmann diaryl ether synthesis.
However, when the reaction conditions of the model system were applied to the more complex
and sterically hindered system of 12 and 4b (see scheme 7), only low conversions were observed
when using N,Nꢀdimethylglycine, copper iodide and potassium phosphate as the base. Even
increasing the catalyst loading to equimolar amounts did not improve this situation. Furthermore,
the application of reaction conditions already applied successfully by us in the total synthesis of
the bisbenzylisoquinoline natural products Oꢀmethyldauricine and tetramethylmagnolamine
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proved to be unsuccessful (N,Nꢀdimethylglycine, Cs CO , DMF, microwave heating). Instead,
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nearly quantitative deiodination of 4b was observed as judged by HPLC/MS (scheme 7).
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Scheme 7: C–O coupling with 12 and 4b to 22.
A further efficient ligand/catalyst system which had been identified in our previous model studies
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was the copper bromide–dimethyl sulfide complex without any additional ligand. The same
protocol proved to be successful in the synthesis of nelumboferin and isomeric headꢀtoꢀtail linked
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bisbenzylisquinolines reported by Yamada and coworkers. Furthermore, this catalyst was
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applied in the total synthesis of the vancomycin aglycone by Nicolaou and coworkers.
The use of copper bromideꢀdimethyl sulfide in combination with pyridine as the solvent and
cesium carbonate as the base which is based on a protocol by Yamada and coꢀworkers finally
allowed conversion of 12 and 4b to the secoꢀheterodimer 22 detected by HPLC/MS (scheme 7).
Interestingly, the TIPS protecting group of the formed secoꢀheterodimer is cleaved under these
conditions to result in 22 whereas the TIPSꢀprotecting group of diol 12 remained untouched.
Notably, due to cleavage of the TIPSꢀgroup of the secoꢀheterodimer 22, the second C–O coupling
furnishing the ring closed macro cyclic structure 23 was also detected by HPLCꢀMS (scheme 7).
The isolation of the secoꢀheterodimer 22 proved very difficult due to its amphoteric properties.
The desired product was always isolated along with traces of unreacted starting material 12.
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For the next set of experiments, a MOMꢀprotected diol unit 4c was synthesized in order to
achieve regioselectivity in the first Ullmann coupling under complete conversion of the diol 4c.
The MOM protecting group is not cleaved under basic conditions and orthogonally stable to the
benzyl group. The deprotected MOMꢀbenzyltetrahydroisoquinoline subunit 25 was obtained
starting from aminonitrile 5a (scheme 2A) and the MOMꢀprotected benzylic bromide 6c (scheme
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8A) by the umpolung/alkylation reduction sequence and subsequent benzyl cleavage described
above for the TIPSꢀprotected diol 12 (see scheme 8B).
Scheme 8: Synthesis of benzylic bromide 6c (A) and 1ꢀbenzyltetrahydrosioquinoline 25 (B).
Synthesis of the secoꢀheterodimer from 25 and 4b was performed under the same set of reaction
conditions as described in scheme 7 and the secoꢀheterodimer 26 bearing the MOM group was
obtained in a yield of 53% (scheme 9). The Pdꢀcatalyzed C–O coupling with Pd(OAc) and tꢀ
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BuXPhos was also tested, but in terms of yield and byproduct formation (deiodination), the
palladiumꢀcatalyzed reactions were not competitive compared to the copperꢀmediated synthetic
protocols.
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Scheme 9: Synthesis of (±)ꢀtubocurine ((±)ꢀ2) and (±)ꢀcurine ((±)ꢀ3).
Removal of the MOMꢀprotecting group of 26 with trifluoroacetic acid furnished the secoꢀ
heterodimer 22 which was obtained in high purity and could be used without further purification
as crude product for the subsequent C–O coupling. The second C–O coupling of 22 was
performed under the same reactions conditions as described for the synthesis of 26 at 130 °C and
the O,Oꢀdibenzyl protected macrocyclic ring structure 23 was obtained in a yield of 17% over
two steps as a mixture of diastereomers in a 1:1.8 ratio. The origin of this deviation from
equimolarity is currently unclear. There may be a preferred ring closure in one of the
diastereomeric secoꢀcompounds 22 or an enrichment during chromatographic purification. The
initial ratio could not be determined from the crude reaction mixture of 23 due to its complex
composition. The lower yield of the second Ullmann reaction can be explained by competitive
debromination of 22 (scheme 9), the corresponding product could be identified by HPLCꢀMS
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(m/z 398.3 for [M+2H] ) and ESIꢀHRMS (m/z calculated for C H N O [M+H] : 777.3904,
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found: 777.3937). Removal of the benzyl ether protecting groups of 23 with BCl furnished the
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natural product (±)ꢀtubocurine ((±)ꢀ2) along with its natural occurring diastereomer (±)ꢀcurine
((±)ꢀ3) in a yield of 72% in a diastereomeric ratio of 1:2 (scheme 8). Reis and coꢀworkers have
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shown that the C NMR spectra of curine and tubocurine can be distinguished by the fact that
C3’ of curine is slightly deshielded compared to C3’ of tubocurine. On the contrary, C8’ of
tubocurine has a high field shift compared to curine. In both diastereomers, the Bꢀring exhibits a
halfꢀchair conformation and in curine, Cα' occupies a pseudoꢀaxial position in this case. For
tubocurine, Cα' takes a pseudoꢀequatorial position. As a result, the Cα'/C3' interaction is
decreased and the Cα'/C8' interaction increases (anisotropy effect). These observations suggest
that the obtained chemical shifts of the main diastereomer correspond to (±)ꢀcurine ((±) ꢀ2) and
the chemical shifts of the minor diastereomer to (±) ꢀtubocurine ((±)ꢀ3). The completed total
synthesis of (±)ꢀtubocurine ((±)ꢀ2) represents a formal total synthesis of tubocurarine (1).
In summary, the first racemic total synthesis of (±)ꢀtubocurine ((±)ꢀ2) and (±)ꢀcurine ((±)ꢀ3) is
accomplished starting from vanillin (7) by two subsequent Ullmann couplings of the two
benzylisoquinoline subunits 25 and 4b. The synthetic route involves 15 steps in the longest linear
sequence and a total of 24 transformations. The combined overall yield of the diastereomeric
mixture of 2 and 3 along the longest sequence amounts to 1.9%, the greatest losses result from
the expectedly difficult C–O couplings in the final stages.
Experimental Section
All reactions involving airꢀ or moistureꢀsensitive reagents or intermediates were performed under
an inert atmosphere of argon in ovenꢀdried glassware. If not mentioned otherwise, all reagents
and solvents were obtained from commercial suppliers and used without further purification.
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Anhydrous THF and diethyl ether were distilled from sodium/benzophenone under argon.
Anhydrous dichloromethane was destilled from calcium hydride. NMR spectra were recorded
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with a 300 MHz (300 MHz H and 75.5 MHz C), 400 MHz (400 MHz H and 100.6 MHz C),
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or 600 MHz spectrometer (600 MHz H and 151 MHz C) with digital architecture equipped
with 5 mm probes. The δ values were referenced to the residual solvent signal (for example
CHCl , 7.26 ppm). IR spectra were recorded using a diamond ATR. ESIꢀHRMS spectra were
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recorded on a QꢀTOF instrument with a dual source and a suitable external calibrant. Thin layer
chromatography (TLC) was carried out on 0.25 mm silica gel plates with a fluorescence
indicator. Flash chromatography was performed on 35−70 ꢁm silica gel using the solvent systems
indicated.
4ꢀ(Benzyloxy)ꢀ3ꢀmethoxybenzaldehyde Synthesized according to a modified procedure of
2
5
Detterbeck et al. To vanillin (7) (30.0 g, 197 mmol, 1.0 eq.), dissolved in ethanol (400 mL), it is
added benzyl bromide (28.1 mL, 40.4 g, 236 mmol, 1.2 eq.) and potassium carbonate (40.9 g, 296
mmol, 1.5 eq.) and the reaction mixture is stirred for 12 hours under reflux. After complete
conversion (TLC) EtOH is removed by rotary evaporation and the residue is taken up in water
(400 mL). It is extracted with diethyl ether (3 x 150 mL) and the combined organic phases are
dried over Na SO . The solvent is removed in vacuo and the product is obtained as yellow solid
2
4
(42.4 g, 175 mmol, 89%). The product is sufficiently pure and can be used without further
purification in the next step. R : 0.60 (cyclohexan/EtOAc = 2:1, Seebach reagent, UV). mp:
f
2
6 1
6
1.0–62.0 °C (Et O). (Lit.: 60–62°C). H NMR (300 MHz, CDCl ): δ [ppm] = 9.84 (s, 1H,
2
3
CHO), 7.29–7.46 (m, 7H, Hꢀ2, Hꢀ6, Hꢀ2ꢀPh, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀPh), 6.99 (d, J = 8.1
26
Hz, 1H, Hꢀ5), 5.25 (s, 2H, CH ꢀPh), 3.95 (s, 3H, OCH ).
2
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1ꢀ(Benzyloxy)ꢀ2ꢀmethoxyꢀ4ꢀ[(E)ꢀ2ꢀnitroethenyl]benzene Synthesized according to a modified
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procedure of Bergner et al. 4ꢀ(benzyloxy)ꢀ3ꢀmethoxybenzaldehyde (40.0 g, 165 mmol, 1.0 eq.)
is dissolved in nitromethane (330 mL) and ammonium acetate (12.7 g, 165 mmol, 1.0 eq.) is
added. The reaction mixture is stirred for two hours at 55 °C under TLCꢀcontrol at specific time
intervals. The temperature is increased to 80 °C until complete conversion is detected. The
solvent is removed in vacuo and the residue is dissolved in dichloromethane (200 mL) and water
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(
100 mL) is added. The organic phase is separated and the aqueous phase is extracted with
dichloromethane (3 x 200 mL). The combined organic phases are washed with water (150 mL)
and dried over Na SO . After filtration, the solvent is removed in vacuo and furnishes the product
2
4
(
44.7 g, 157 mmol, 95%). The obtained yellow solid is sufficiently pure and can be used without
further purification. R : 0.62 (cyclohexan/EtOAc=2:1, Seebach reagent, vanillin/H SO reagent,
f
2
4
28 1
UV). mp: 116.0–118.0 °C (dichloromethane). (Lit.: 119–121°C (EtOH)). H NMR (300 MHz,
CDCl ): δ [ppm] = 7.95 (d, J = 13.6 Hz, 1H, =CH ), 7.51 (d, J = 13.6 Hz, 1H, =CH ), 7.30–7.45
3
α
β
(
m, 5H, Hꢀ2ꢀPh, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀPh), 7.10 (dd, J = 8.4 Hz, 2.1 Hz, 1H, Hꢀ6), 7.02
(
d, J = 2.1 Hz, 1H, Hꢀ2), 6.92 (d, J = 8.4 Hz, 1H, Hꢀ5), 5.22 (s, 2H, CH ꢀPh), 3.93 (s, 3H,
2
28
OCH3).
2
ꢀ[4ꢀ(Benzyloxy)ꢀ3ꢀmethoxyphenyl]ethylamine (8) Synthesized according to a modified
2
9
procedure of Bermejo et al. To a suspension of lithium aluminum hydride (7.97 g, 210 mmol,
.0 eq.) in anhydrous THF (200 mL) at 0 °C, 1ꢀ(benzyloxy)ꢀ2ꢀmethoxyꢀ4ꢀ[(E)ꢀ2ꢀ
4
nitroethenyl]benzene (15.0 g, 52.6 mmol, 1.0 eq.) dissolved in THF (200 mL) is added dropwise.
After complete addition the reaction mixture is heated to reflux for 12 hours. The reaction is then
cooled to 0 °C and sodium sulfate decahydrate is added cautiously in small portions until the
exothermic reaction and the gas evolution deceases. It is warmed to room temperature and the
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reaction mixture is filtered and it is washed with diethyl ether. The filtrate is evaporated to
dryness and the crude product is obtained as a yellow oil (11.4 g, 44.0 mmol, 83%). The product
8 is sufficiently pure and can be used without further purification. R : 0.55
f
0
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1
2
3
4
5
6
7
8
9
0
1
(
dichloromethane/MeOH/NEt = 2:2:1, ninhydrin reagent, UV). H NMR (300 MHz, CDCl ): δ
3
3
[ppm] = 7.45–7.43 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.38–7.29 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 6.82
(
d, J = 8.1 Hz, 1H, Hꢀ5), 6.74 (d, J = 2.0 Hz, 1H, Hꢀ2), 6.66 (dd, J = 8.1, 2.0 Hz, 1H, Hꢀ6), 5.12
s, 2H, CH ꢀPh), 3.88 (s, 3H, OCH ), 2.92 (t, J = 6.8 Hz, 2H, CH NH ), 2.67 (t, J = 6.8 Hz, 2H,
(
2
3
2
2
2
8
CH CH NH ), 1.56 (s, br, 2H, NH ).
2
2
2
2
Nꢀ{2ꢀ[4ꢀ(Benzyloxy)ꢀ3ꢀmethoxyphenyl]ethyl}formamide Synthesized according to a procedure
3
0
of Elliott et al. Amine 8 (9.30 g, 36.1 mmol, 1.0 eq.) is dissolved in formic acid ethylester and
the reaction mixture is stirred for 12 hours under reflux. After complete reaction the solvent is
removed in vacuo to furnish the product as a brownish oil (10.3 g, 36.1 mmol, quant.). The
obtained product is sufficiently pure and can be used without further purification in the next step.
1
R : 0.29 (EtOAc/cyclohexane =100:1, Seebach reagent, UV). Major rotamer: H NMR (300
f
MHz, CDCl ): δ [ppm] = 8.08 (d, J = 1.7 Hz, 1H, CHO), 7.44–7.29 (m, 5H, Hꢀ2ꢀPh, Hꢀ3ꢀPh, Hꢀ
3
4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀPh), 6.81 (d, J = 8.1 Hz, 1H, Hꢀ5), 6.73 (d, J = 2.0 Hz, 1H, Hꢀ2), 6.65 (d, J =
8.1, 2.0 Hz, 1H, Hꢀ6), 5.75 (s, br, 1H, NH), 5.12 (s, 2H, CH ꢀPh), 3.86 (s, 3H, OCH ), 3.51
2
3
(pseudoꢀq, J ≈ 6.8 Hz, 2H, CH CH Ar), 2.75 (t, J = 6.8 Hz, 2H, CH Ar). IR (ATR): ν = 3291
2 2 2
(w), 3033 (w), 2935 (w), 2867 (w), 1663 (s), 1591 (w), 1511 (vs), 1453 (m), 1418 (m), 1383 (m),
–
1
1260 (vs), 1223 (vs), 1158 (m), 1139 (vs), 1024 (s), 913(w), 736 (s), 696 (s) cm . MS (ESI): m/z
+
+
(
%) = 286.1 (100) [M+H] , 308.1 (67) [M+Na] . method C. The analytical data are in accordance
3
1
with the literature
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7ꢀ(Benzyloxy)ꢀ6ꢀmethoxyꢀ3,4ꢀdihydroisoquinoline (9) Synthesized according to a modified
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6
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2
procedure of Rohloff et al. To a suspension of phosphorous pentachloride (3.45 g, 16.5 mmol,
1.1 eq.) in anhydrous toluene (10 mL) is added Nꢀ{2ꢀ[4ꢀ(benzyloxy)ꢀ3ꢀ
methoxyphenyl]ethyl}formamide (4.32 g, 15.1 mmol, 1.0 eq.) dissolved in dichloromethane (10
mL) at room temperature. The reaction mixture is stirred for 15 hours at room temperature and
water (100 mL) is added. The organic phase is separated and the brown residue that forms during
the reaction is taken up in methanol (20 mL). The aqueous phase and the methanol phase are
combined and will be adjusted to pH 12 with solid potassium hydroxide at 0 °C. It is extracted
with dichloromethane (3 x 75 mL) and the combined organic phases are dried over Na SO . After
0
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filtration the solvent is removed in vacuo and gives the crude product as a brown viscous oil
(2.96 g, 11.0 mmol, 74%). The crude product 9 can be used without further purification. R : 0.50
f
1
(
cyclohexane/EtOAc/NEt = 6:4:1, Seebach reagent, ninhydrin reagent, UV). H NMR (300
3
MHz, CDCl ): δ [ppm] = 9.01 (s, 1H, Hꢀ1), 7.49 (s, 1H, Hꢀ8), 7.39–7.35 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀ
3
Ph), 7.30–7.21 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 6.75 (s, 1H, Hꢀ5), 5.08 (s, 2H, CH ꢀPh), 3.88
2
1
3
(
s, 3H, OCH ), 3.85 (t, J = 8.4 Hz, 2H, Hꢀ3), 3.00 (t, J = 8.4 Hz, 2H, Hꢀ4). C NMR, HSQC,
3
HMBC (100.6 MHz, CDCl ): δ [ppm] = 164.0 (C=N), 157.6 (Cꢀ6), 147.7 (Cꢀ7), 135.8 (Cꢀ1ꢀPh),
3
1
33.1 (Cꢀ8a), 128.6 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.2 (Cꢀ4ꢀPh), 127.7 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 117.5 (Cꢀ8),
1
16.7 (Cꢀ5a), 111.2 (Cꢀ5), 71.2 (CH ꢀPh), 56.6 (OCH ), 41.1 (Cꢀ3), 24.6 (Cꢀ4). MS (ESI): m/z
2
3
+
26
(%) = 268.1 (100) [M+H] . method A. The analytical data are in accordance with the literature.
7
9
1
ꢀ(Benzyloxy)ꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ3,4ꢀdihydroisoquinolinium iodide To a solution of imine
(2.49 g, 9.34 mmol, 1.0 eq.) in diethyl ether (20 mL) it is added dropwise iodomethane (1.59 g,
1.2 mmol, 1.2 eq.) at room temperature. The reaction mixture is stirred at room temperature
until complete conversion (15 hours). The yellow precipitate is filtered and washed with diethyl
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ether. The product is obtained as a yellow solid (2.64 g, 6.45 mmol, 69%). R : 0.26
f
(dichloromethane/MeOH/NEt3 = 1:1:0.5, Seebach reagent, UV). mp: 177.0–178.0 °C
3
3 1
(
dichloromethane). (Lit.: 193–195°C). H NMR, COSY (400 MHz, CDCl ): δ [ppm] = 9.71 (s,
3
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1H, Hꢀ1), 7.63 (s, 1H, Hꢀ8), 7.28–7.48 (m, 5H, Hꢀ2ꢀPh, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀPh), 6.82
(s, 1H, Hꢀ5), 5.15 (s, 2H, CH ꢀPh), 3.94–3.98 (m, 5H, Hꢀ3, NCH ), 3.87 (s, 3H, OCH ), 3.27 (t, J
2
3
3
1
3
=
8.2 Hz, 2H, Hꢀ4). C NMR, HSQC, HMBC (100.6 MHz, CDCl ): δ [ppm] = 165.2 (Cꢀ1),
3
158.2 (Cꢀ7), 148.0 (Cꢀ6), 135.7 (Cꢀ1ꢀPh), 131.9 (Cꢀ4a), 128.8, 128.4, 128.0 (Cꢀ2ꢀPh, Cꢀ3ꢀPh, Cꢀ
4ꢀPh, Cꢀ5ꢀPh, Cꢀ6ꢀPh), 117.6 (Cꢀ8), 116.9 (Cꢀ8a), 111.1 (Cꢀ5), 71.4 (CH ꢀPh), 56.9 (NCH ), 50.2
2
3
+
(
Cꢀ3), 47.9 (OCH ), 25.7 (Cꢀ4). MS (ESI): m/z (%) = 282.2 (100) [M–I] . method C. HPLCꢀMS
3
+
(
ESI): m/z (%) = 282.2 (100) [M–I] . method A, t = 0.3 min. The analytical data are in
R
3
3
accordance with the literature.
7ꢀ(Benzyloxy)ꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (5a) 7ꢀ
Benzyloxy)ꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ3,4ꢀdihydroisoquinolinium iodide (1.95 g, 4.76 mmol 1.0 eq.)
(
is dissolved in MeOH (40 mL) and potassium cyanide (776 mg, 11.9 mmol, 2.5 eq.) is added
portionwise at room temperature. The reaction mixture is stirred for 18 hours at room
temperature. Sat. NaHCO solution is added (50 mL) and it is extracted with dichloromethane (3
3
x 75 mL). The combined organic phases are dried over Na SO and the solvent is removed in
2
4
vacuo. The product is obtained as brown oil (1.50 g, quant.) and crystallizes as a brown solid.
The product 5a is sufficiently pure and can be used without further purification. R : 0.23
f
(dichloromethane/MeOH/NEt3 = 10:1:0.5, Seebach reagent, UV). mp: 125.0–126.0 °C
1
(
dichloromethane). H NMR, COSY (400 MHz, CDCl ): δ [ppm] = 7.28–7.44 (m, 5H, Hꢀ2ꢀPh,
3
Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀPh), 6.69 (s, 1H, Hꢀ8), 6.64 (s, 1H, Hꢀ5), 5.06–5.16 (m, 2H, CH2ꢀ
13
Ph), 4.57 (s, 1H, Hꢀ1), 3.86 (s, 3H, OCH ), 2.67–3.02 (m, 4H, Hꢀ3, Hꢀ4), 2.57 (s, 3H, NCH ). C
3
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NMR, HSQC, HMBC (100.6 MHz, CDCl ): δ [ppm] = 150.1 (Cꢀ6), 147.0 (Cꢀ7), 136.8 (Cꢀ1ꢀ
3
Ph), 128.7 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.1 (Cꢀ4ꢀPh), 127.5 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 127.0 (Cꢀ4a), 121.2 (Cꢀ
8a), 116.7 (CN), 112.5, 112.1 (Cꢀ8, Cꢀ5), 71.4 (CH ꢀPh), 55.6 (Cꢀ1), 55.1 (OCH ), 48.5 (Cꢀ3),
2
3
10
11
12
13
14
15
16
17
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25
26
27
28
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33
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35
36
37
38
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
3.8 (NCH ), 28.2 (Cꢀ4). IR (ATR): ν = 3033 (w), 2937 (w), 2805 (w), 1610 (m), 1517 (s), 1255
3
–
1
(vs), 1222 (vs), 1139 (s), 1127 (s), 734 (vs), 697 (vs) cm . MS (ESI): m/z (%) = 282.1 (100) [M–
+
+
CN] . method A. HRꢀMS (ESI): m/z (%) = calculated for C H N O [M+H] : 309.1603, found:
19
21
2
2
3
09.1601.
3
ꢀBromoꢀ4ꢀhydroxyꢀ5ꢀmethoxybenzaldehyde Vanillin (7) (25.0 g, 0.164 mol, 1.0 eq.) is
dissolved in conc. acetic acid (300 mL) and bromine (9.90 mL, 29.9 g, 0.197 mol, 1.2 eq.) is
added dropwise at 0 °C. The reaction mixture is warmed to room temperature within three hours
and is stirred at room temperature for 15 hours. After completion of reaction water is added (500
mL) and the formed precipitate is filtered and washed with water. The offꢀwhite solid is dried in
oil pump vacuum to furnish the title compound (37.9 g, 0.164 mol, quant.). R : 0.33
f
(cyclohexane/EtOAc = 2:1, Seebach reagent, UV). mp: 162.0–163.0 °C (H O). (Lit.: 162–
2
34 1
164 °C). H NMR (300 MHz, CDCl ): δ [ppm] = 9.78 (s, 1H, CHO), 7.64 (d, J = 1.7 Hz, 1H,
3
Hꢀ2), 7.36 (d, J = 1.7 Hz, 1H, Hꢀ6), 6.58 (s, 1H, OH), 3.98 (s, 3H, OCH ). The analytical data are
3
3
4
in accordance with the literature.
4
ꢀ(Benzyloxy)ꢀ3ꢀbromoꢀ5ꢀmethoxybenzaldehyde Synthesized according to the procedure
described for the benzylation of vanillin. 3ꢀbromoꢀ4ꢀhydroxyꢀ5ꢀmethoxybenzaldehyde (35.0 g,
151 mmol, 1.0 eq.) is reacted with benzyl bromide (21.5 mL, 31.0 g, 181 mmol, 1.2 eq.) and
potassium carbonate (31.4 g, 227 mmol, 1.5 eq.) in ethanol (500 mL). The product (37.3 g, 116
mmol, 77%) crystallizes as a yellow solid. The product is sufficiently pure and can be used
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without further purification. R : 0.59 (cyclohexane/EtOAc = 2:1, Seebach reagent, UV). mp:
f
3
5 1
4
3.5–45.0 °C (Et O). (Lit.: 44°C (nꢀhexane). H NMR (400 MHz, CDCl ): δ [ppm] = 9.84 (s,
2
3
1H, CHO), 7.66 (d, J = 1.7 Hz, 1H, Hꢀ2), 7.54–7.51 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.40–7.34 (m, 4H,
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Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6), 5.16 (s, 2H, CH ꢀPh), 3.94 (s, 3H, OCH ). The analytical data are
2
3
3
6
in accordance with the literature.
[4ꢀ(Benzyloxy)ꢀ3ꢀbromoꢀ5ꢀmethoxyphenyl]methanol (13) Sodium borohydride (10.2 g, 270
mmol, 1.5 eq.) is dissolved in ethanol (300 mL) and 4ꢀ(benzyloxy)ꢀ3ꢀbromoꢀ5ꢀ
methoxybenzaldehyde (57.9 g, 180 mmol, 1.0 eq.) dissolved in ethanol (200 mL) is added
dropwise at 0 °C. The reaction mixture is warmed to room temperature and stirred for 2 hours. It
is added water to the reaction mixture and ethanol is removed by rotary evaporation. The residue
is extracted with dichloromethane and the combined organic phases are dried over Na SO . The
2
4
solvent is removed in vacuo and the product is obtained as yellow oil (54.1 g, 167 mmol, 93%).
The product 13 is sufficiently pure and can be used without further purification. R : 0.33
f
1
(
cyclohexane/EtOAc = 2:1, Seebach reagent, UV). H NMR (300 MHz, CDCl ): δ [ppm] =
3
7.54–7.56 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.31–7.41 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 7.12 (d, J = 1.9
Hz, 1H, Hꢀ2), 6.89 (d, J = 1.9 Hz, 1H, Hꢀ6), 5.01 (s, 2H, CH ꢀPh), 4.61 (s, 2H, CH OH), 3.87 (s,
2
2
3
7
3H, OCH ), 1.80 (s, 1H, OH). The analytical data are in accordance with the literature.
3
2ꢀ(Benzyloxy)ꢀ1ꢀbromoꢀ5ꢀ(bromomethyl)ꢀ3ꢀmethoxybenzene Synthesized according to a
38
modified procedure of van Oeveren et al. Alcohol 13 (30.0 g, 92.9 mmol, 1.0 eq.) is dissolved
in anhydrous diethyl ether and it is cooled to 0 °C. Phosphorous tribromide (8.65 mL, 25.0 g,
92.9 mmol, 1.0 eq.) dissolved in anhydrous diethyl ether (250 mL) is added dropwise at this
temperature and it is stirred for 30 minutes. The reaction mixture is then warmed to room
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temperature and water is added. It is extracted with diethyl ether and the combined organic
phases are dried over Na SO . The solvent is removed in vacuo and the title compound is
2
4
obtained as yellow oil (35.2 g, 91.2 mmol, 98%). The product is sufficiently pure and can be used
10
11
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14
15
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44
45
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54
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56
57
58
59
60
1
without further purification. R : 0.70 (cyclohexane/EtOAc = 2:1, Seebach reagent, UV). H NMR
f
(300 MHz, CDCl ): δ [ppm] = 7.53–7.57 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.297.43 (m, 3H, Hꢀ3ꢀPh, Hꢀ
3
4
ꢀPh, Hꢀ5ꢀPh), 7.19 (d, J = 2.0 Hz, 1H, Hꢀ6), 6.90 (d, J = 2.0 Hz, 1H, Hꢀ4), 5.03 (s, 2H, CH ꢀPh),
2
13
4
.42 (s, 2H, CH Br), 3.88 (s, 3H, OCH ). C NMR, HSQC, HMBC (75.5 MHz, CDCl ): δ
2
3
3
[ppm] = 154.0 (Cꢀ3), 145.5 (Cꢀ2), 137.0 (Cꢀ1ꢀPh), 134.9 (Cꢀ5), 128.6 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.4
(
(
(
Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.2 (Cꢀ4ꢀPh), 125.4 (Cꢀ6), 118.0 (Cꢀ1), 112.5 (Cꢀ4), 74.9 (CH ꢀPh), 56.3
2
OCH ), 32.7 (CH Br). IR (ATR): ν = 3063 (w), 2938 (w), 1568 (m), 1483 (s), 1276 (vs), 1215
3
2
–
1
+•
s), 1145 (s), 1044 (vs), 969 (m), 696 (s) cm . MS (FD): m/z (%) = 386.1 [M ]. HRMS data
could not be obtained due to decomposition of the sample in aqueous acetonitrile.
[
4ꢀ(Benzyloxy)ꢀ3ꢀbromoꢀ5ꢀmethoxyphenyl]acetonitrile According to a modified procedure of
39
Javier et al. 2ꢀ(Benzyloxy)ꢀ1ꢀbromoꢀ5ꢀ(bromomethyl)ꢀ3ꢀmethoxybenzene (14.3 g, 37.0 mmol,
1
.0 eq.) is dissolved in dichloromethane/water (110 mL, 10:1) and it is cooled to 0 °C. Potassium
cyanide (3.60 g, 56.0 mmol, 1.5 eq.) and tetrabutylammonium bromide (3.01 g, 9.30 mmol, 0.3
eq.) is added at this temperature and the reaction mixture is stirred for one hour. It is warmed to
room temperature and stirred for 12 hours. To the reaction mixture it is added sat. sodium
hydrogencarbonate solution and it is extracted with toluene. The combined organic phases are
dried over Na SO and the solvent is removed in vacuo. The title compound is obtained as
2
4
colorless solid (10.9 g, 33.0 mmol, 89%) and can be used without further purification. Traces of
the phase transfer catalyst can be removed extraction with diethyl ether/water or by flash column
chromatography on silica gel (cyclohexane/ethyl acetate = 4:1). R : 0.24 (cyclohexane/EtOAc =
f
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4
:1, Seebach or ninhydrin reagent, UV). mp: 76.5–77.5 °C (dichloromethane). H NMR (300
MHz, CDCl ): δ [ppm] = 7.51–7.56 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.30–7.42 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀ
3
Ph, Hꢀ5ꢀPh), 7.10 (d, J = 2.1 Hz, 1H, Hꢀ2), 6.83 (d, J = 2.1 Hz, 1H, Hꢀ6), 5.03 (s, 2H, CH ꢀPh),
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0
1
2
3
4
5
6
7
8
9
0
13
3
.88 (s, 3H, OCH ), 3.69 (s, 2H, CH CN). C NMR, HSQC, HMBC (75.5 MHz, CDCl ): δ
3
2
3
[ppm] = 154.2 (Cꢀ5), 145.2 (Cꢀ4), 136.8 (Cꢀ1ꢀPh), 128.5 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.4 (Cꢀ3ꢀPh, Cꢀ5ꢀ
Ph), 128.2 (Cꢀ4ꢀPh), 126.8 (Cꢀ1), 124.2 (Cꢀ6), 118.6 (Cꢀ3), 117.4 (CN), 111.3 (Cꢀ2), 74.8 (CH2-
Ph), 56.2 (OCH ), 23.1 (CH CN). IR (ATR): ν = 3089 (w), 3064 (w), 3032 (w), 3009 (w), 2941
3
2
(w), 2918 (w), 2879 (w), 2843 (w), 2252 (w), 1598 (m), 1571 (m), 1484 (m), 1463 (m), 1454 (m),
–
1
416 (s), 1274 (s), 1231 (s), 1145 (s), 1045 (vs), 972 (s), 915 (w), 819 (w), 732 (m), 698 (m) cm
1
+
+
.
MS (ESI): m/z (%) = 332.1 (27) [M+H] , 354.1 (100) [M+Na] method C. HRꢀMS (ESI): m/z
+
=
calculated for C H BrNO [M+Na] : 354.0106, found: 354.0106.
1
6
14
2
2ꢀ[4ꢀ(Benzyloxy)ꢀ3ꢀbromoꢀ5ꢀmethoxyphenyl]ethylamine (14) [4ꢀ(Benzyloxy)ꢀ3ꢀbromoꢀ5ꢀ
methoxyphenyl]acetonitrile (10.9 g, 33.0 mmol, 1.0 eq.) is dissolved in anhydrous THF (100 mL)
and borane tetrahydrofuran complex (1 M, 66 mL, 66.0 mmol, 2.0 eq.) is added at room
temperature. The reaction mixture is stirred for 15 hours at room temperature. Water is added and
it is extracted with dichloromethane. The combined organic phases are dried over Na SO and the
2
4
solvent is removed in vacuo. The obtained yellow oil is purified by flash column chromatography
on silica gel (chloroform/MeOH/NEt = 5:1:1). The product 14 is furnished as a colorless viscous
3
oil (9.00 g, 26.8 mmol, 81%). R : 0.47 (chloroform/MeOH/NEt = 5:1:1, ninhydrin reagent, UV).
f
3
1
H NMR (400 MHz, CDCl ): δ [ppm] = 7.58–7.55 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.42–7.34 (m, 3H,
3
Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 7.03 (d, J = 1.9 Hz, 1H, Hꢀ2), 6.75 (d, J = 1.9 Hz, 1H, Hꢀ6), 5.01 (s,
2
H, CH ꢀPh), 4.15 (s, br, 2H, NH ), 3.86 (s, 3H, OCH ), 3.05 (t, J = 7.2 Hz, 2H, CH CH Ar),
2 2 3 2 2
13
2
.81 (t, J = 7.2 Hz, 2H, CH CH Ar). C NMR, HSQC, HMBC (100.6 MHz, CDCl ): δ [ppm] =
2
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153.8 (Cꢀ5), 143.9 (Cꢀ4), 137.1 (Cꢀ1ꢀPh), 136.0 (Cꢀ1), 128.5 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.3 (Cꢀ3ꢀPh,
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C.ꢀ5ꢀPh), 128.1 (Cꢀ4ꢀPh), 124.7 (Cꢀ2), 118.0 (Cꢀ3), 112.5 (Cꢀ6), 74.7 (CH ꢀPh), 56.2 (OCH ),
2
3
42.4 (CH CH Ar), 37.3 (CH CH Ar). IR (ATR): ν = 3367 (w), 3089 (w), 3063 (w), 3031 (w),
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
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3005 (w), 2937 (w), 2867 (w), 1661 (w), 1595 (m), 1565 (s), 1483 (s), 1462 (s), 1453 (s), 1412
(
(
s), 1374 (m), 1300 (m), 1271 (s), 1225 (s), 1143 (s), 1044 (vs), 1002 (m), 975 (m), 914 (m), 842
–1
+
m), 817 (s), 696 (s) cm . MS (ESI): m/z (%) = 338.0 (100) [M+H] , method C. HRꢀMS (ESI):
+
m/z = calculated for C H BrNO [M+H] : 336.0599, found: 336.0602.
1
6
19
2
7ꢀ(Benzyloxy)ꢀ8ꢀbromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydroisoquinoline Amine 14 (1.41
g, 4.19 mmol, 1.0 eq.) is dissolved in formic acid (90%ꢀig, 250 mL) and paraformaldehyde (630
mg, 21.0 mmol, 5.0 eq.) is added. The reaction mixture is stirred for 42 hours at 40 °C. Formic
acid is removed in vacuo and the residue is purified by flash column chromatography on silica
gel (cyclohexane/EtOAc/NEt = 6:4:1). The title compound is obtained as yellow oil (831 mg,
3
1
2.29 mmol, 55%). R : 0.34 (cyclohexane/EtOAc/NEt = 6:4:1, Seebach reagent, UV). H NMR,
f
3
COSY (400 MHz, CDCl ): δ [ppm] = 7.53–7.58 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.29–7.40 (m, 3H, Hꢀ
3
3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 6.65 (s, 1H, Hꢀ5), 4.98 (s, 2H, CH ꢀPh), 3.83 (s, 3H, OCH ), 3.50 (s, 2H,
2
3
13
Hꢀ1), 2.89 (t, J = 5.7 Hz, 2H, Hꢀ3), 2.64 (t, J = 5.7 Hz, 2H, Hꢀ4), 2.50 (s, 3H, NCH ). C NMR,
3
HSQC, HMBC (100.6 MHz, CDCl ): δ [ppm] = 151.8 (Cꢀ6), 143.3 (Cꢀ7), 137.3 (Cꢀ1ꢀPh), 131.4
3
(Cꢀ4a), 128.5 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.3 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.0 (Cꢀ4ꢀPh), 126.5 (Cꢀ8a), 118.3 (Cꢀ
8
), 111.7 (Cꢀ5), 74.6 (CH ꢀPh), 58.0 (Cꢀ1), 56.1 (OCH ), 52.0 (Cꢀ3), 45.9 (NCH ), 29.5 (Cꢀ4). IR
2 3 3
(ATR): ν = 3064 (w), 2940 (w), 2807 (w), 1646 (w), 1598 (m), 1566 (m), 1483 (vs), 1464 (m),
–
1
1
454 (m), 1324 (s), 1278 (m), 1215 (m), 1143 (s), 1028 (s), 698 (m) cm . MS (ESI): m/z (%) =
+
+
3
62.1 (100) [M+H] , method C. HRꢀMS (ESI): m/z = calculated for C H BrNO [M+H] :
18 21 2
362.0756, found: 362.0750.
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ꢀ(Benzyloxy)ꢀ8ꢀbromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ3,4ꢀdihydroisoquinolinium iodide According to
4
0
a modified procedure of Leonard and Leubner. 7ꢀ(Benzyloxy)ꢀ8ꢀbromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ
,2,3,4ꢀtetrahydroisoquinoline (1.30 g, 3.59 mmol, 1.0 eq.) is dissolved in EtOH (100 mL) and
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1
potassium acetate (1.90 g, 19.5 mmol, 4.3 eq.) is added at room temperature. Subsequently,
iodine (3.81 g, 29.8 mmol, 6.5 eq.), dissolved in EtOH (50 mL), is added at room temperature
and it is stirred for about 30 minutes at this temperature until TLC control shows complete
conversion. To the reaction mixture it is added water (150 mL) and it is extracted with
dichloromethane (3 x 100 mL). The combined organic phases are washed with sat. sodium
thiosulfate solution (3 x 75 mL) and dried over Na SO . After filtration, the solvent is removed in
2
4
vacuo and the product 25 is obtained as yellow solid (1.50 g, 3.07 mmol, 86%). R : 0.65
f
(dichloromethane/MeOH = 5:1, Seebach reagent, UV). mp: 144.0–155.0 °C under
1
decomposition. H NMR, COSY (400 MHz, CDCl ): δ [ppm] = 8.96 (s, 1H, Hꢀ1), 7.49–7.47 (m,
3
2
H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.39–7.36 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 7.02 (s, 1H, Hꢀ5), 5.02 (s,
2
H, CH ꢀPh), 4.14 (t, J = 8.1 Hz, 2H, Hꢀ3), 4.02 (3H, OCH ), 3.99 (s, 3H, NCH ), 3.50 (t, J = 8.1
2
3
3
1
3
Hz, 2H, Hꢀ4). C NMR, HSQC, HMBC, NOESY (100.6 MHz, CDCl ): δ [ppm] = 163.6 (Cꢀ1),
3
161.8 (Cꢀ6), 145.4 (Cꢀ7), 137.6 (Cꢀ4a), 136.0 (Cꢀ1ꢀPh), 128.6 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.6 (Cꢀ4ꢀPh),
#
#
128.5 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 124.5 (Cꢀ8 ), 117.0 (Cꢀ8a ), 111.5 (Cꢀ5), 75.2 (CH ꢀPh), 57.4 (OCH ),
2
3
#
50.3 (Cꢀ3), 49.6 (NCH ), 26.6 (Cꢀ4). signals may be reversed. IR (ATR): ν = 3064 (w), 2940
3
(w), 2807 (w), 1658 (m), 1590 (m), 1544 (m), 1320 (m), 1295 (s), 1127 (m), 1022 (m), 909 (s),
–
1
+
7
27 (s) cm . MS (ESI): m/z (%) = 362.0 (100) [M–I] . method C. HRꢀMS (ESI): m/z =
+
calculated for C H BrNO [M–I] : 360.0599, found: 360.0597.
1
8
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7ꢀ(Benzyloxy)ꢀ8ꢀbromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile
4
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9
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6
(
5b) Synthesized according to the procedure described for compound 5a. 7ꢀ(Benzyloxy)ꢀ8ꢀ
bromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ3,4ꢀdihydroisoquinolinium iodide (1.50 g, 3.07 mmol, 1.0 eq.) is
reacted with potassium cyanide (1.00 g, 15.3 mmol, 5.0 eq.). The product is obtained as brown oil
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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7
8
9
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8
9
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(1.02 g, 2.64 mmol, 86 %). The product 5b is sufficiently pure and can be used without further
1
purification. R : 0.62 (toluene/EtOAc/NEt = 10/10/1, Seebach reagent, UV). H NMR, COSY
f
3
(400 MHz, CDCl ): δ [ppm] = 7.55–7.53 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.40–7.33 (m, 3H, Hꢀ3ꢀPh,
3
Hꢀ4ꢀPh, Hꢀ5ꢀPh), 6.68 (s, 1H, Hꢀ5), 5.00 (s, 2H, CH ꢀPh), 4.84 (s, 1H, Hꢀ1), 3.85 (s, 3H, OCH ),
2
3
13
3
.09–2.70 (m, 4H, Hꢀ3, Hꢀ4), 2.62 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6 MHz,
3
CDCl ): δ [ppm] = 153.6 (Cꢀ6), 144.0 (Cꢀ7), 137.0 (Cꢀ1ꢀPh), 132.1 (Cꢀ4a), 128.5 (Cꢀ2ꢀPh, Cꢀ6ꢀ
3
#
#
Ph), 128.4 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.2 (Cꢀ4ꢀPh), 121.8 (Cꢀ8a ), 118.7 (Cꢀ8 ), 115.2 (CN), 112.0 (Cꢀ
#
5
), 74.8 (CH ꢀPh), 57.5 (Cꢀ1), 56.1 (OCH ), 47.8 (Cꢀ3), 43.5 (NCH ), 28.7 (Cꢀ4). signals may be
2
3
3
reversed. IR (ATR): ν = 3032 (w), 2839 (w), 1597 (m), 1566 (m), 1482 (s), 1464 (s), 1454 (s),
–
1
1
371 (m), 1323 (m), 1278 (s), 1228 (s), 912 (s), 732 (s), 698 (s) cm . MS (ESI): m/z (%) = 362.1
+
+
(100) [M–CN] . method C. HRꢀMS (ESI): m/z = calculated for C H BrN O [M+H] :
19 20 2 2
387.0708, found: 387.0699.
4
ꢀ{[Tri(propanꢀ2ꢀyl)silyl]oxy}benzaldehyde Synthesized according to a modified procedure of
41
Ramaciotti et al. To a solution of 4ꢀhydroxybenzaldehyde (10) (8.00 g, 65.5 mmol, 1.0 eq.) and
imidazole (15.6 g, 223 mmol, 3.5 eq.) in DMF (25 mL) is added triisopropylsilyl chloride (12.6 g,
1
3.9 mL, 65.5 mmol, 1.0 eq.) and the reaction mixture is stirred for 2 hours at room temperature.
Water (20 mL) is added and is extracted with nꢀhexane (3 x 20 mL). The combined organic
layers are washed with brine and are dried over Na SO . The solvent is removed in vacuo and the
2
4
product is obtained as yellow oil (16.8 g, 60.4 mmol, 92%). The product is sufficiently pure and
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can be used without purification in the next step. R : 0.78 (cyclohexane/EtOAc = 2:1, Seebach
f
1
reagent, UV). H NMR (300 MHz, CDCl ): δ [ppm] = 9.87 (s, 1H, CHO), 7.79–7.76 (AA’ꢀpart
3
of a AA’XX’ꢀsystem, 2H, Hꢀ2, Hꢀ6), 6.99–6.96 (XX‘ part of a AA’XX‘ system, 2H, Hꢀ3, Hꢀ5),
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.34–1.22 (m, 3H, CH), 1.12–1.05 (m, 18H, CH ). The analytical data are in accordance with the
3
4
2
literature.
(4ꢀ{[Tri(propanꢀ2ꢀyl)silyl]oxy}phenyl)methanol (11) Synthesized according to the procedure
described for compound 13. 4ꢀ{[Tri(propanꢀ2ꢀyl)silyl]oxy}benzaldehyde (16.8 g, 60.3 mmol, 1.0
eq.) is reacted with NaBH (4.10 g, 108 mmol, 1.8 eq.) in EtOH (100 mL). The product is
4
obtained as light yellow oil (15.8 g, 56.3 mmol, 93%). The product 11 is sufficiently pure and can
be used without purification in the next step. R : 0.52 (cyclohexane/EtOAc = 2:1, Seebach
f
1
reagent, UV). H NMR (300 MHz, CDCl ): δ [ppm] = 7.24–7.19 (AA’ part of a AA’XX’ system,
3
2
H, Hꢀ3, Hꢀ5), 6.89–6.82 (XX‘ part of a AA’XX‘ system, 2H, Hꢀ2, Hꢀ6), 4.60 (s, 2H, CH OH),
2
1
.31–1.19 (m, 3H, CH), 1.67 (s, br, 1H, OH), 1.11–1.05 (m, 18 H, CH ). The analytical data are
3
4
2
in accordance with the literature.
[4ꢀ(Bromomethyl)phenoxy][tri(propanꢀ2ꢀyl)]silane (6a) According to the procedure described
for 2ꢀ(Benzyloxy)ꢀ1ꢀbromoꢀ5ꢀ(bromomethyl)ꢀ3ꢀmethoxybenzene. Alcohol 11 (4.50 g, 16.0
mmol, 1.0 eq.) is reacted with phosphorous tribromide (1.50 mL, 16.0 mmol, 1.0 eq.) in
anhydrous diethyl ether (220 mL). The product is obtained as light yellow oil (4.97 g, 14.4 mmol,
90%). The product 6a is sufficiently pure and can be used without purification in the next step.
1
R : 0.86 (cyclohexane/EtOAc = 20:1, Seebach reagent, UV). HꢀNMR (300 MHz, CDCl ): δ
f
3
[
ppm] = 7.26–7.23 (AA’ part of a AA’XX’ system, 2H, Hꢀ3, Hꢀ5), 6.85–6.82 (XX‘ part of a
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AA’XX‘ system, 2H, Hꢀ2, Hꢀ6), 4.49 (s, 2H, CH Br), 1.31–1.19 (m, 3H, CH), 1.12–1.05 (m,
2
4
2
1
8H, CH ). The analytical data are in accordance to the literature.
3
6
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3ꢀIodoꢀ4ꢀmethoxybenzaldehyde Synthesized according to a modified procedure of Fujita et al.
pꢀAnisaldehyde (15) (10.0 g, 73.4 mmol, 1.0 eq.) is dissolved in acetic acid (50 mL) and iodine
monochloride (13.9 g, 85.6 mmol, 1.2 eq.) is added. The reaction mixture is heated to 140 °C for
2–4 hours. After complete conversion, the reaction mixture is cooled to room temperature and the
pH of the reaction mixture is adjusted to pH 8 with 1 M NaOH solution and it is extracted with
chloroform (3 x 75 mL). The combined organic phases are dried over Na SO and the solvent is
2
4
removed in vacuo. The title compound is obtained as an offꢀwhite crystalline solid (15.0 g, 57.3
mmol, 78%). R : 0.56 (cyclohexane/EtOAc = 2:1, dinitrophenyl hydrazine reagent, UV). mp:
f
1
103.0–107.0°C (chloroform). H NMR (300 MHz, CDCl ): δ [ppm] = 9.84 (s, 1H, CHO), 8.33
3
(
d, J = 2.0 Hz, 1H, Hꢀ2), 7.88 (dd, J = 8.5, 2.0 Hz, 1H, Hꢀ6), 6.95 (d, J = 8.5 Hz, 1H, Hꢀ5), 4.00
4
3
(
s, 3H, OCH ). The analytical data are in accordance with the literature.
3
4
ꢀ(Benzyloxy)ꢀ3ꢀiodobenzaldehyde (16) Step 1: 3ꢀIodoꢀ4ꢀmethoxybenzaldehyde (4.00 g, 15.3
mmol, 1.0 eq.) is dissolved in anhydrous dichloromethane (50 mL) and boron tribromide (4.29
mL, 45.3 mmol, 11.4 g, 3.0 eq.) is added dropwise at –78 °C. The reaction mixture is stirred for
1
2 h and it is slowly warmed to room temperature within this time interval. To the reaction
mixture it is added water (50 mL) and it is extracted with dichloromethane (3 x 50 mL). The
combined organic phases are washed with brine (75 mL) and dried over Na SO . After filtration
2
4
the solvent is removed in vacuo and the obtained crude 4ꢀhydroxyꢀ3ꢀiodobenzaldehyde (5.15 g)
4
4
is directly used for the next step. mp: 110.0–111.0 °C (dichloromethane). (Lit: 108–110 °C).
1
R : 0.37 (cyclohexane/EtOAc = 6:1, dinitrophenyl hydrazine reagent, UV). H NMR (300 MHz,
f
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CDCl ): δ [ppm] = 9.80 (s, 1H, CHO), 8.22 (d, J = 2.0 Hz, 1H, Hꢀ2), 7.79 (dd, J = 8.4, 2.0 Hz,
3
1H, Hꢀ6), 7.10 (d, J = 8.4 Hz, 1H, Hꢀ5), 6.23 (s, br, 1H, OH). MS (ESI): m/z (%) = 248.9 (86)
+
44
[
M+H] . method C. The analytical data are in accordance with the literature. Step 2: Crude 4ꢀ
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hydroxyꢀ3ꢀiodobenzaldehyde (5.15 g, max. 15.3 mmol, 1.0 eq.) is dissolved in EtOH (30 mL)
and potassium carbonate (4.30 g, 31.1 mmol, 2.0 eq.) and benzyl bromide (3.20 mL, 4.61 g, 26.9
mmol, 1.8 eq.) are added at room temperature. The reaction mixture is stirred for 5 hours at 60
°
C. After complete reaction, the reaction mixture is cooled to room temperature, water is added
(50 mL) and it is extracted with diethyl ether (3 x 100 mL). the combined organic phases are
dried over Na SO and filtered. The solvent is removed in vacuo and the residue is purified by
2
4
flash column chromatography on silica gel (cyclohexane/EtOAc = 10:1). The product 16 is
obtained as an offꢀwhite crystalline solid (3.98 g, 11.8 mmol, 77% over 2 steps). R : 0.40
f
(cyclohexane/EtOAc = 5:1, dinitrophenyl hydrazine reagent, UV). mp: 65.4–68.6 °C
1
(cyclohexane/EtOAc). H NMR (300 MHz, CDCl ): δ [ppm] = 9.81 (s, 1H, CHO), 8.33 (d, J =
3
2.0 Hz, 1H, Hꢀ2), 7.81 (dd, J = 8.5, 2.0 Hz, 1H, Hꢀ6), 7.51–7.48 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.44–
1
3
7
.35 (m, 3H, Hꢀ4ꢀPh, Hꢀ3ꢀPh, Hꢀ5ꢀPh), 6.95 (d, J = 8.5 Hz, 1H, Hꢀ5), 5.25 (s, 2H, CH ꢀPh). C
2
NMR, HSQC, HMBC (75.5 MHz, CDCl ): δ [ppm] = 189.5 (CHO), 161.9 (Cꢀ4), 141.3 (Cꢀ2),
3
135.6 (Cꢀ1ꢀPh), 132.0 (Cꢀ6), 131.6 (Cꢀ1), 128.9 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.4 (Cꢀ4ꢀPh), 127.1 (Cꢀ3ꢀ
Ph, Cꢀ5ꢀPh), 112.1 (Cꢀ5), 87.2 (Cꢀ3), 71.3 (CH ꢀPh). IR (ATR): ν = 3089 (w), 3063 (w), 3032
2
(w), 2929 (w), 2834 (w), 2810 (w), 2778 (w), 2727 (w), 1690 (vs), 1586 (vs), 1564 (s), 1485 (s),
1453 (s), 1369 (m), 1258 (vs), 1191 (vs), 1039 (m), 1013 (m), 890 (m), 812 (m), 736 (m), 696
–
1
+
(m) cm . HRꢀMS (ESI): m/z = calculated for C H IO Na [M+Na] : 360.9702 , found:
1
4
11
2
360.9690.
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[
4ꢀ(Benzyloxy)ꢀ3ꢀiodophenyl]methanol Synthesized according to the procedure described for
compound 13. Aldehyde 16 (1.98 g, 5.86 mmol, 1.0 eq.) is reacted with sodium borohydride
(0.33 g, 8.79 mmol, 1.5 eq.) in EtOH (100 mL). The title compound is obtained as an offꢀwhite
4
5
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crystalline solid (1.94 g, 5.70 mmol, 97%). R : 0.15 (cyclohexane/EtOAc = 5:1, Seebach reagent,
f
1
UV). mp: 95.0–98.4 °C (Et O). H NMR (400 MHz, CDCl ): δ [ppm] = 7.81 (d, J = 2.1 Hz, 1H,
2
3
Hꢀ2), 7.51–7.48 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.42–7.32 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 7.26 (dd,
J = 8.3, 2.1 Hz, 1H, Hꢀ6), 6.83 (d, J = 8.3 Hz, 1H, Hꢀ5), 5.15 (s, 2H, CH ꢀPh), 4.58 (s, 2H,
2
1
3
CH OH), 1.78 (s, br, 1H, OH). C NMR, HSQC, HMBC (100.6 MHz, CDCl ): δ [ppm] = 156.8
2
3
(Cꢀ4), 138.5 (Cꢀ2), 136.5 (Cꢀ1ꢀPh), 135.5 (Cꢀ1), 128.7 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.5 (Cꢀ6), 128.0 (Cꢀ
4
ꢀPh), 127.1 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 112.7 (Cꢀ5), 87.0 (Cꢀ3), 71.1 (CH ꢀPh), 64.2 (CH OH). IR
2
2
(ATR): ν = 3332 (w, br), 3031 (w), 2925 (w), 1598 (m), 1488 (vs), 1453 (s), 1278 (s), 1252 (vs),
–1
+•
1
044 (s), 1012 (s), 809 (s), 734 (s) cm . MS (FD): m/z (%) = 340.2 [M ]. MS (LIFDIꢀFD): m/z
+
•
(%) = 340.0 [M ]. HRMS data could not be obtained due to poor ionization in ESI.
1
ꢀ(Benzyloxy)ꢀ4ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (6b) Synthesized according to the procedure
described for compound 6a. [4ꢀ(Benzyloxy)ꢀ3ꢀiodophenyl]methanol (1.27 g, 3.73 mmol, 1.0 eq.)
is reacted with phosphorous tribromide (1.00 g, 3.73 mmol, 1.0 eq.). The product is obtained as a
yellow viscous oil (1.16 g, 2.87 mmol, 78%). The product 6b is sufficiently pure and can be used
1
without further purification. R : 0.59 (cyclohexane/EtOAc = 5:1, Seebach reagent, UV). H NMR
f
(300 MHz, CDCl ): δ [ppm] = 7.84 (d, J = 2.2 Hz, 1H, Hꢀ2), 7.50–7.47 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh),
3
7.43–7.34 (m, 3H, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh), 7.30 (dd, J = 8.4, 2.2 Hz, 1H, Hꢀ6), 6.80 (d, J = 8.4
1
3
Hz, 1H, Hꢀ5), 5.16 (s, 2H, CH ꢀPh), 4.42 (s, 2H, CH Br). C NMR, HSQC, HMBC (75.5 MHz,
2
2
CDCl ): δ [ppm] = 157.4 (Cꢀ4), 140.3 (Cꢀ2), 136.3 (Cꢀ1ꢀPh), 132.3 (Cꢀ1), 130.4 (Cꢀ6), 128.8 (Cꢀ
3
3ꢀPh, Cꢀ5ꢀPh), 128.1 (Cꢀ4ꢀPh), 127.1 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 112.1 (Hꢀ5), 86.9 (Cꢀ3), 71.1 (CH ꢀPh),
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3
2.4 (CH Br). IR (ATR): ν = 3061 (w), 2921 (w), 1571 (m), 1467 (vs), 1251 (s), 1182 (s), 1044
2
–
1
+•
(m), 1030 (m), 783 (m), 754 (m) cm . MS (LIFDIꢀFD): m/z (%) = 401.9 [M ]. HRMS data
could not be obtained due to decomposition of the sample in aqueous acetonitrile.
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ꢀ(Benzyloxy)ꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ1ꢀ(4ꢀ{[tri(propanꢀ2ꢀyl)silyl]oxy}benzyl)ꢀ1,2,3,4ꢀ
1
0
tetrahydroisoquinoline (4a) According to a modified synthetic procedure of Werner et al. αꢀ
Aminonitrile 5a (1.51 g, 4.88 mmol, 1.0 eq.) is reacted with KHMDS (1.25 g, 6.26 mmol, 1.3
eq.), benzylic bromide 6a (2.18 g, 6.35 mmol, 1.3 eq.) and sodium borohydride (1.00 g, 26.5
mmol, 5.4 eq.). The brown oily residue is purified by flash column chromatography on silica gel
(cyclohexane/EtOAc/NEt = 6:2:1). The product 4a is obtained as light yellow oil (2.05 g, 3.76
3
1
mmol, 77%). R : 0.45 (cyclohexane/EtOAc/NEt = 6:2:1, Seebach reagent, UV). H NMR,
f
3
COSY (300 MHz, CDCl ): δ [ppm] = 7.38–7.26 (m, 5H, Hꢀ2ꢀPh, Hꢀ3ꢀPh, Hꢀ4ꢀPh, Hꢀ5ꢀPh, Hꢀ6ꢀ
3
Ph), 6.89–6.86 (AA‘ part of a AA’XX‘ system, 2H, Hꢀ2‘, Hꢀ6‘), 6.78–6.75 (XX‘ part of a
AA’XX‘ system, 2H, Hꢀ3‘, Hꢀ5‘), 6.56 (s, 1H, Hꢀ5), 6.12 (s, 1H, Hꢀ8), 4.87–4.76 (m, 2H, CH2ꢀ
Ph), 3.83 (s, 3H, OCH ), 3.61 (dd, J = 7.5, 4.6 Hz, 1H, Hꢀ1), 3.16–3.02 (m, 2H, Hꢀ3 , Hꢀα ),
3
A
A
2.79–2.55 (m, 4H, Hꢀ3 , Hꢀα , Hꢀ4), 2.51 (s, 3H, NCH ), 1.29–1.19 (m, 3H, CH), 1.09–1.03 (m,
B
B
3
13
1
8H, CH ). C NMR, HSQC, HMBC (75.5 MHz, CDCl ): δ [ppm] = 154.3 (Cꢀ4‘), 147.8 (Cꢀ6),
3 3
145.5 (Cꢀ7), 137.3 (Cꢀ1ꢀPh), 132.3 (Cꢀ1‘), 130.7 (Cꢀ2‘, Cꢀ6‘), 129.3 (Cꢀ8a), 128.4 (Cꢀ3ꢀPh, Cꢀ5ꢀ
Ph), 127.6 (Cꢀ4ꢀPh), 127.3 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 126.6 (Cꢀ4a), 119.5 (Cꢀ3‘, Cꢀ5‘), 113.7 (Cꢀ8),
11.6 (Cꢀ5), 70.8 (CH ꢀPh), 65.0 (Cꢀ1), 55.9 (OCH ), 47.2 (Cꢀ3), 42.7 (NCH ), 40.4 (Cꢀα), 25.9
1
2
3
3
(Cꢀ4), 18.0 (CH), 12.7(CH ). IR (ATR): ν = 3062 (w), 3031 (w), 2943 (m), 2866 (m), 1607 (m),
3
1
508 (vs), (m), 1373 (m), 1258 (vs), 1224 (s), 1101 (m), 1014 (m), 912 (s), 883 (s), 734 (m), 695
–1
+
(m) cm . MS (ESI): m/z (%) = 546.1 (100) [M+H] . Method A. HRꢀMS (ESI): m/z =
+
calculated for C H NO Si [M+H] : 546.3403, found: 546.3398.
3
4
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7ꢀ(Benzyloxy)ꢀ1ꢀ[4ꢀ(benzyloxy)ꢀ3ꢀiodobenzyl]ꢀ8ꢀbromoꢀ6ꢀmethoxyꢀ2ꢀmethylꢀ1,2,3,4ꢀ
6
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6
tetrahydroisoquinoline (4b) Method A: According to the procedure as described for compound
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a. αꢀaminonitrile 5b (156 mg, 0.403 mmol, 1.0 eq.) is reacted with KHMDS (161 mg, 0.807
mmol, 2.0 eq.), benzylic bromide 6b (179 mg, 0.444 mmol, 1.1 eq.) and sodium borohydride
2.00 g, 52.8 mmol, 34.8 eq.). The brown residue is purified by flash column chromatography on
(
silica gel (cyclohexane/EtOAc/NEt = 6:4:1). The product 4b is obtained as brown oil in a yield
3
of 69.0 mg (0.101 mmol, 25%). R : 0.59 (cyclohexane/EtOAc/NEt = 6:4:1, Seebach reagent,
f
3
UV). Method B: Formamide 21 (4.77 g crude product, max. 6.61 mmol, 1.0 eq.) is dissolved in
anhydrous THF (75 mL) and borane–THF complex (9.92 mL, 9.92 mmol, 1.5 eq.) ia added at
room temperature and the reaction mixture is stirred for 12 hours at this temperature. Water (50
mL) is added to the reaction mixture and it is extracted with EtOAc (4 x 70 mL). The combined
organic phases are dried over Na SO and the solvent is removed in vacuo. The residue is
2
4
purified by flash column chromatography on silica gel (cyclohexane/EtOAc/NEt = 6:4:1). The
3
product 4b is obtained as colorless oil (3.04 g, 4.44 mmol, 67% over 4 steps). R : 0.59
f
1
(
cyclohexane/EtOAc/NEt = 6:4:1, Seebach reagent, UV). H NMR, COSY (400 MHz, CDCl ):
3
3
δ [ppm] = 7.74 (d, J = 2.1 Hz, 1H, Hꢀ2‘), 7.62–7.59 (m, 2H, Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.53–7.50 (m, 2H,
Hꢀ2ꢀPh, Hꢀ6ꢀPh), 7.44–7.31 (m, 6H, 2 × Hꢀ3ꢀPh, 2 × Hꢀ4ꢀPh, 2 × Hꢀ5ꢀPh), 7.24 (dd, J = 8.4, 2.1
Hz, 1H, Hꢀ6‘), 6.79 (d, J = 8.4 Hz, 1H, Hꢀ5‘), 6.64 (s, 1H, Hꢀ5), 5.14 (s, 2H, 4‘ꢀOCH ꢀPh), 5.04
2
(
s, 2H, 7ꢀOCH ꢀPh), 3.97 (dd, J = 9.8, 3.0 Hz, 1H, Hꢀ1), 3.87 (s, 3H, OCH ), 3.42–3.32 (m, 1H,
2
3
1
3
Hꢀ3 ), 2.93–2.70 (m, 4H, Hꢀ3 , Hꢀα, Hꢀ4 ), 2.45–2.40 (m, 1H, Hꢀ4 ), 2.36 (s, 3H, NCH ). C
A
B
A
B
3
NMR, HSQC, HMBC (100.6 MHz, CDCl ) δ [ppm] = 155.6 (Cꢀ4‘), 151.9 (Cꢀ6), 143.7 (Cꢀ7),
3
140.1 (Cꢀ2‘), 137.4, 136.9 (2 × Cꢀ1ꢀPh), 135.4 (Cꢀ1‘), 132.0 (Cꢀ4a), 130.2 (Cꢀ6‘), 129.5 (Cꢀ8a),
128.6 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.5 (Cꢀ2ꢀPh, Cꢀ6ꢀPh), 128.4 (Cꢀ3ꢀPh, Cꢀ5ꢀPh), 128.1, 127.9 (2 × Cꢀ4ꢀ
ACS Paragon Plus Environment