1,3-benzyl migration in iminium ions: Evidence for a fast free-radical chain reaction

Article abstract of DOI:10.1002/ejoc.201101183

The "exocyclic" 1,3-benzyl shift observed in iminium salts derived from 1-benzyl-1,2,3,4-tetrahydroisoquinolines is related to the "endocyclic" Knabe rearrangement. A crossover experiment, isotopic labelling, the study of initiators and inhibitors as well as DFT calculations of gas-phase model structures provide evidence for a free-radical pathway under kinetic entropy control that is not affected by "slow" radical traps. An unexpected rearrangement of methyleneiminium ions derived from 1-benzyl-1,2,3,4-tetrahydroisoquinolines has been investigated by isotopic labelling, trapping experiments and DFT calculations. Theobserved benzyl migration proceeds by an exceptionally fast radical chain reaction closely related to the Knabe reaction.Remarkably, the process is inhibited byneither methyl acrylate nor dioxygen. Copyright

Full text of DOI:10.1002/ejoc.201101183

FULL PAPER
DOI: 10.1002/ejoc.201101183
1,3-Benzyl Migration in Iminium Ions: Evidence for a Fast Free-Radical Chain
Reaction
Nancy Blank,[a] Bernd F. Straub,*[b] and Till Opatz*[a]
Dedicated to Professor Paul Margaretha on the occasion of his retirement
Keywords: Rearrangement / Density functional calculations / Heterocycles / Alkaloids / Radical reactions
The “exocyclic” 1,3-benzyl shift observed in iminium salts
derived from 1-benzyl-1,2,3,4-tetrahydroisoquinolines is re-
lated to the “endocyclic” Knabe rearrangement. A crossover
experiment, isotopic labelling, the study of initiators and in-
hibitors as well as DFT calculations of gas-phase model
structures provide evidence for a free-radical pathway under
kinetic entropy control that is not affected by “slow” radical
traps.
Introduction
During an attempted synthesis of the tetrahydroproto-
berberine alkaloid tetrahydropalmatine[1] by Pictet–Speng-
ler reaction of the chlorinated benzyltetrahydroisoquinoline
1 with formaldehyde in aqueous trifluoroacetic acid and
subsequent dechlorination of the anticipated cyclization
product 3,[2] the rearranged iminium salt 4 was obtained in
high yield (Scheme 1).
A related process with similar characteristics is the acid-
promoted rearrangement of 1,2-disubstituted dihydroiso-
quinolines reported by Knabe and co-workers (Scheme 2).[3]
These authors at first suggested a chain reaction involv-
ing benzyl anions. This hypothesis was supported by the
detection of toluene derivatives. A radical hypothesis was
discarded based on the negative results of EPR and CIDNP
experiments and the preference of the reaction for polar
solvents.[4] However, kinetic studies by Rüchardt and co-
workers provided solid evidence for a radical chain mecha-
nism for the Knabe rearrangement.[5] Remarkably, in con-
trast to the Knabe reaction, the homologating rearrange-
ment described herein is not inhibited by dioxygen.
Scheme 1. Unexpected benzyl migration instead of the attempted
Pictet–Spengler cyclization.
Results and Discussion
whereas the use of deuterated trifluoroacetic acid as solvent
did not lead to the incorporation of deuterium into the
product. To rule out pathways involving free benzyl cations,
thioanisole (2 equiv., 0.46 m) was added as a scavenger but
this did not diminish the reaction rate. Thus, the initially
assumed fragmentation of the methyleneiminium ion 2 to
form an intermediate resonance-stabilized azomethine ylide
appeared less likely. On the other hand, iodine in amounts
as small as 1 mol-% (2.3 mm) was found to be an effective
inhibitor of the rearrangement, the same being true of cu-
When isoquinoline 1 was treated with deuterated para-
formaldehyde, the exocyclic NCH2 group carried the label
[a] Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-3922338
E-mail: opatz@uni-mainz.de
[b] Institute of Organic Chemistry, University of Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
E-mail: straub@oci.uni-heidelberg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101183.
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N. Blank, B. F. Straub, T. Opatz
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It was concluded that the reaction of 1 with an initiator
radical may lead to the scission of the exocyclic C–C bond,
producing a benzylic radical that attacks the next molecule
of 1 in a chain reaction with the formation of the re-
arranged product 4 (Scheme 4). As expected for an inter-
molecular reaction, high yields of 4 were only obtained in
reaction mixtures with high concentrations of amine 1.
DFT calculations at the UB3LYP/6-31G** level of theory
were performed for gas phase model structures to test this
hypothesis.[6] While closed-shell pathways are predicted to
involve prohibitive barriers, the results for the free-radical
mechanism are depicted in Scheme 4. The C–C bond-form-
ing reaction between the benzyl radical 13 and the iminium
ion 2 has no enthalpic barrier and is thus expected to be
kinetically entropy-controlled.[7]
Scheme 2. Radical mechanism of the Knabe rearrangement pos-
tulated by Rüchardt and co-workers.
prous chloride (20 mol-%, 46 mm) and TEMPO (2 equiv.,
0.46 m), whereas the addition of dibenzoyl peroxide led to
an accelerated reaction. The intermolecular nature of the
rearrangement could be proven in a crossover experiment:
an equimolar mixture of 1 and its hexadeuterated 7-ethyl
analogue 9 was subjected to the reaction and resulted in the
formation of all four possible reaction products in equal
amounts as judged by mass spectrometry (Scheme 3).
Scheme 4. Proposed reaction mechanism.
The Gibbs free energy of the transition state was com-
puted to have an approximate barrier of 31 kJmol–1 by a
structure optimization–frequency calculation scan of dis-
tances of the newly formed C–C bond. Apparently, the elec-
tron-rich benzyl radical 13 with its high-energy SOMO is
ideally suited to react with the electron-deficient iminium
cation 2 with its low-energy LUMO. In the next step, an
exergonic C–C bond cleavage in the tertiary aminyl radical
cation intermediate[8] proceeds rapidly with a predicted
Gibbs free-energy barrier of only 11.1 kJmol–1. The prod-
uct 4 and benzyl radical 13 are formed, thereby completing
one cycle in the radical chain reaction (Scheme 5). Attempts
to detect the proposed radicals by EPR spectroscopy were
unsuccessful. Surprisingly, the addition of methyl acrylate
Scheme 3. Statistical fragment exchange in a crossover experiment. (2 equiv., 0.46 m) did not lead to a reaction with the olefin
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1,3-Benzyl Migration in Iminium Ions
but instead resulted in the same rearrangement product free energies ΔG϶ for both the addition of the initial benzyl
with even higher purity. Moreover, replacement of argon radical 13 to methyl acrylate as well as the propagation
by air did not lead to a diminished yield either. Thus, the steps of the radical polymerization of methyl acrylate are
postulated propagation step has to proceed faster than the predicted to be Ͼ70 kJmol–1, therefore clearly proceeding
reaction of the benzyl radical 9 with dioxygen or methyl more slowly than diffusion or entropy control. The acti-
acrylate. The lower reactivity of the proposed intermediates vation energy Ea (60 °C) for the chain propagation step in
towards methyl acrylate is again consistent with the results methyl acrylate polymerization has been determined experi-
of quantum chemical model calculations. The activation mentally by Matheson et al. to be 6.3 kcalmol–1
Scheme 5. Gibbs free-energy diagram for the computed radical chain propagation step.
Scheme 6. Gibbs free-energy diagram for the computed trapping experiment with methyl acrylate.
Eur. J. Org. Chem. 2011, 7355–7365
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Scheme 7. Gibbs free-energy diagram for the computed radical trapping reaction with iodine.
(26.4 kJmol–1),[9] in reasonable accord with the computed
ΔH϶ (25 °C) = 4.5 kcalmol–1 (18.7 kJmol–1, Scheme 6, see
also the Supporting Information). The difference between
this activation enthalpy and the Gibbs activation energy
displayed in Scheme 6 arises from entropic contributions
caused by the reduced number of molecules.
In contrast to the slow reaction of acrylate esters with
alkyl radicals, our DFT calculations predict that an iodine
atom reacts with the iminium ion 2 under entropic or even
diffusion control (Scheme 7). In addition, the benzyl radical
13 is very efficiently trapped by an iodine molecule. Here,
the predicted Gibbs free activation energy of less than
23 kJmol–1 highlights the unsurpassed role of iodine as a
radical trap.[10] Several other 1-substituted 1,2,3,4-tetra-
hydroisoquinolines were subjected to the same reaction
conditions, but only in some cases could the rearranged
products be identified by HRMS as well as by their charac-
1
teristic H NMR resonances (Table 1).
None of these substrates underwent the homologating re-
arrangement more efficiently than compound 1. The same
holds true for the allyl-substituted compound 15b. The re-
action of its iminium derivative could involve a [3,3] sigma-
tropic rearrangement with a Gibbs free activation energy of
more than 120 kJmol–1 according to our model calculations
(Scheme 8).
Interestingly, this 2-azonia-Cope rearrangement[11] does
not proceed by a concerted C–C bond formation/C–C bond
cleavage reaction, but involves a high-energy carbocationic
Scheme 8. Gibbs free-energy diagram for the computed stepwise
intermediate. To the best of our knowledge, only theoretical [3,3] sigmatropic rearrangement.
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1,3-Benzyl Migration in Iminium Ions
Table 1. Suitability of other substrates for benzyl migration.
Experimental Section
Materials and Methods: All reactions were carried out under argon.
Solvents were dried and distilled before use: THF was distilled from
potassium/benzophenone, Et2O from sodium/benzophenone and
CH2Cl2 from calcium hydride. Ethyl acetate was distilled from po-
tassium carbonate. All other solvents and reagents were purchased
from commercial suppliers and were used without further purifica-
tion. TLC was performed on TLC aluminium sheets (silica gel 60
F254). Flash chromatography was carried out on silica gel (35–
70 μm). 1H and 13C NMR spectra were recorded by using standard
pulse sequences on high-resolution FT NMR spectrometers
equipped with inverse or direct observe probes and gradient shim
units. Chemical shifts are referenced to the residual solvent signal
(CDCl3: δH = 7.26 ppm, δC = 77.0 ppm; CD3OD: δH = 3.31 ppm,
δC = 49.0 ppm). IR spectra were recorded with routine FTIR spec-
trometers in transmission mode or by using a diamond ATR unit.
Melting points were measured with a Dr. Tottoli apparatus or a
digital melting-point apparatus with electric heating and are uncor-
rected. MS spectra were recorded with double-focusing spectrome-
ters (FD-MS, FAB-MS, EI-MS) or with a linear ion trap LC/MSD
detector (ESI-MS). ESI-HRMS spectra were recorded with a high-
resolution Q-TOF spectrometer with a dual source and a suitable
external calibrant. The 1-substituted 1,2,3,4-tetrahydroisoquinol-
ines 15a,[13] 15b[14] and 15h[13] shown in Table 1 were prepared ac-
cording to known procedures.
1-(2-Chloro-4,5-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (1): A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-1-carbonitrile[13,15] (797 mg, 3.65 mmol) in dry THF
(12 mL) was cooled to –78 °C. A solution of KHMDS (1.46 g,
7.31 mmol) in dry THF (20 mL) was added slowly. The mixture
was stirred for 5 min and 2-chloro-4,5-dimethoxybenzyl bromide[16]
(1.02 g, 3.94 mmol) in dry THF (15 mL) was added. After stirring
for 110 min at –78 °C, the reaction mixture was gradually warmed
to ambient temperature. After the addition of 1 n NaOH (60 mL),
the mixture was extracted with ethyl acetate (5ϫ15 mL). The com-
bined organic layers were dried with Na2SO4 and the solvent was
removed in vacuo to yield the dihydroisoquinoline as a viscous
pale-yellow oil (1.66 g). Due to the sensitivity of the product to
air, this material was not further purified.[17] 1H NMR (400 MHz,
CDCl3): δ = 6.98, 6.85, 6.80, 6.65 (4 s, 4 H, 5-H, 8-H, 3Ј-H, 6Ј-H),
4.09 (s, 2 H, Ar-CH2), 3.87 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 3.72 (m, 2 H, 3-H2), 2.65
(m, 2 H, 4-H2) ppm. Sodium borohydride (346 mg, 9.14 mmol) was
added to a cooled solution of the dihydroisoquinoline in a mixture
of MeOH (5 mL) and THF (20 mL). The reaction mixture was
stirred at ambient temperature for 14 h. After addition of 1 n
NaOH (50 mL), the mixture was extracted with ethyl acetate
(5 ϫ 15 mL) and the combined organic layers were dried with
Na2SO4. Removal of the solvent in vacuo gave the crude product
(1.44 g) as a yellowish oil. This material was purified by column
chromatography (silica, cyclohexane/EtOAc/Et2NH, 6:1:1, Rf =
0.1) to give 1 as a light-yellow oil (932.4 mg, 67.5%). 1H NMR,
COSY (400 MHz, CDCl3): δ = 6.90 (s, 1 H, 3Ј-H), 6.76 (s, 1 H, 6Ј-
H), 6.69 (s, 1 H, 8-H), 6.60 (s, 1 H, 5-H), 4.22 (dd, J = 9.5, J =
4.0 Hz, 1 H, 1-H), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.84
(s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.31 (dd, J = 13.8, J = 4.0 Hz,
1 H, Ar-CHb), 3.25 (ddd, J = 12, J = 6.7, J = 5.2 Hz, 1 H, 3-Hb),
2.99–2.87 (m, 2 H, 3-Ha, Ar-CHa), 2.78–2.71 (m, 2 H, 4-H2), 1.67
(br. s, 1 H, NH) ppm. 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3): δ = 148.5 (C-5Ј), 147.9 (C-4Ј), 147.8 (C-7), 147.4 (C-6),
130.8 (C-4a), 129.1 (C-2Ј), 127.6 (C-8a), 125.5 (C-1Ј), 114.5 (C-
6Ј), 113.0 (C-3Ј), 112.1 (C-5), 110.0 (C-8), 56.4, 56.3, 56.2, 56.1
[a] Detected by 1H NMR spectroscopy and HRMS. [b] Pictet–
Spengler reaction occurred. [c] Addition of dibenzoyl peroxide was
necessary. [d] TIPS ether was partially cleaved under these condi-
tions.
calculations of 3-azonia-Cope and anionic 1-aza-Cope
rearrangements have been reported in the literature so
far.[12]
Conclusions
We have extended the Knabe rearrangement with its for-
mal 1,3-migration of benzyl substituents in 1,4-dihydroiso-
quinolinium salts to exocyclic derivatives. Experimental
data combined with theoretical model calculations provide
evidence for an extremely fast radical chain reaction that
operates under kinetic entropy control. We have demon-
strated that the absence of an effect of “slow” radical traps
does not rule out radical reactions altogether, but only of
even slower radical chain reactions.
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N. Blank, B. F. Straub, T. Opatz
(4ϫOCH3), 55.5 (C-1), 40.7 (Ar-CH2), 40.6 (C-3), 29.7 (C-4) ppm. 10 min at 0 °C, the mixture was warmed to ambient temperature
FULL PAPER
IR (NaCl): ν = 3401, 3058, 2935, 2823, 1608, 1510, 1354, 1261, and a small amount of ice was added. The mixture was extracted
˜
1221, 1167, 1112, 1033, 969, 859, 732 cm–1. MS (FAB): m/z (%) =
378.2 (30) [M + H]+, 192.1 (100) [M – C9H10ClO2]+. HRMS (FAB):
calcd. for [C20H24ClNO4 + H]+ 378.1472; found 378.1472.
with diethyl ether (3ϫ5 mL), the combined organic layers were
washed with brine, then with saturated aq. NaHCO3 and dried with
Na2SO4. The solvent was removed in vacuo to yield the title com-
pound (175 mg, 89.6%) as a colourless oil. The product was stored
in dry THF (2 mL) with a small amount of CaCO3 to avoid decom-
position. 1H NMR (400 MHz, CDCl3): δ = 6.89 (s, 1 H, 3-H), 6.86
(s, 1 H, 6-H), 4.58 (s, 2 H, Ar-CH2) ppm. MS (ESI): m/z (%) =
270.00 (100) [M]+.
3,4-Bis(trideuteriomethoxy)benzaldehyde: A solution of KOH
(9.90 g, 176 mmol) in MeOH (150 mL) was degassed by ultra-
sonication under a slow stream of argon. After addition of protoca-
techualdehyde (10.0 g, 72.4 mmol) and [2H3]methyl p-toluene-
sulfonate[18] (32.9 g, 173 mmol), the reaction mixture was heated at
reflux for 90 min. The mixture was poured into water (600 mL) and
extracted with diethyl ether (6ϫ75 mL). The combined organic
layers were washed twice with KOH (5% in water, 100 mL), water
(150 mL) and dried with Na2SO4. The solvent was removed in
vacuo and the crude product was purified by column chromatog-
raphy (silica, cyclohexane/EtOAc, 1:1, Rf = 0.68) to give the title
compound as colourless crystals (4.38 g, 35.1%). M.p. 43–44 °C.
1H NMR (400 MHz, CDCl3): δ = 9.86 (s, 1 H, CHO), 7.46 (dd, 3J
7-Ethoxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:
A solution of KCN (198 mg, 1.81 mmol) in water (1.04 mL) was
added to a solution of 7-ethoxy-6-methoxy-3,4-dihydroisoquino-
line[19] (198 mg, 964 μmol) in MeOH (253 μL). The mixture was
cooled to 0 °C and concentrated hydrochloric acid (1.01 mL) was
added slowly. The reaction mixture was stirred for 6 h at ambient
temperature. HCN vapour was removed by using a slow stream of
argon (CAUTION!). The mixture was carefully poured into satu-
rated aq. NaHCO3 (10 mL) and the resulting solution was ex-
tracted with ethyl acetate (3ϫ5 mL). The combined organic layers
were dried with Na2SO4 and the solvent was removed in vacuo.
The product crystallized upon addition of diethyl ether to give the
title compound (169 mg, 75.3%) as light-red crystals. M.p. 129–
2
= 8.2, 2J = 1.9 Hz, 1 H, 6-H), 7.41 (d, J = 1.9 Hz, 1 H, 2-H), 6.98
3
(d, J = 8.2 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 191.2 (CHO), 127.1 (C-2), 110.5 (C-6), 109.0 (C-5) ppm. IR
(KBr): ν = 3076, 2849, 2253, 2073, 1690, 1589, 1510, 1441, 1290,
˜
1145, 989, 802 cm–1. MS (ESI): m/z (%) = 173.11 (23.8) [M + H]+,
145.11 (100) [M – CHO]·+. HRMS (ESI): calcd. for [C9H4D6O3 +
H]+ 173.1079; found 173.1076.
1
130 °C. H NMR (400 MHz, CDCl3): δ = 6.67, 6.61 (2 s, 2 H, 5-
H, 8-H), 4.95 (s, 1 H, 1-H), 4.14–4.04 (m, 2 H, OCH2CH3), 3.85
(s, 3 H, OCH3), 3.30–3.23 (m, 2 H, 3-H2), 2.90–2.82 (m, 1 H, 2-
2-Chloro-4,5-bis(trideuteriomethoxy)benzaldehyde: 3,4-Bis(tri-
deuteriomethoxy)benzaldehyde (300 mg, 1.73 mmol) was dissolved
in CHCl3 (0.4 mL) and sulfuryl chloride (393 μL, 4.87 mmol) was
added at 0 °C. The reaction mixture was stirred overnight. The re-
sulting yellow solution was quenched by the addition of saturated
aq. NaHCO3 (25 mL) and the crude product was extracted with
ethyl acetate (3 ϫ5 mL). Concentration of the organic layer af-
forded a yellow oil that was recrystallized from tert-butyl methyl
ether to give the title compound as colourless crystals (91.2 mg,
25.5%). M.p. 137–138 °C. 1H NMR (400 MHz, CDCl3): δ = 10.32
(s, 1 H, CHO), 7.39 (s, 1 H, 3-H), 6.89 (s, 1 H, 6-H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 188.8 (CHO), 132.2 (C-1), 125.5
3
Hb), 2.71–2.65 (m, 1 H, 2-Ha), 2.10 (br. s, 1 H, NH), 1.46 (t, J =
7 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
149.7 (C-7), 147.4 (C-6), 127.1 (C-8a), 121.2 (C-4a), 120.4 (CN),
112.5 (C-8), 111.1 (C-5), 64.8 (OCH2CH3), 56.1 (OCH3), 48.2 (C-
1), 41.0 (C-3), 28.0 (C-3), 14.9 (OCH CH ) ppm. IR (NaCl): ν =
˜
2
3
3385, 3055, 2983, 2208, 1677, 1608, 1518, 1465, 1266, 1223, 1120,
1040, 736 cm–1. MS (ESI): m/z (%) = 233.13 (100) [M + H]+.
HRMS (ESI): calcd. for [C13H16N2O2 + H]+ 233.1285; found
233.1281.
1-[2-Chloro-4,5-bis(trideuteriomethoxy)benzyl]-7-ethoxy-6-methoxy-
1,2,3,4-tetrahydroisoquinoline (9): A solution of 7-ethoxy-6-meth-
oxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (160 mg,
688 μmol) in dry THF (4 mL) was cooled to –78 °C. KHMDS
(274 mg, 1.37 mmol) in dry THF (4 mL) was added slowly. The
mixture was stirred for 5 min and 2-chloro-4,5-bis(trideuteriome-
thoxy)benzyl bromide (187 mg, 688 μmol) in dry THF (2 mL) was
added. After stirring for 2 h, the reaction mixture was gradually
warmed to ambient temperature. After the addition of 1 n NaOH
(10 mL), the mixture was extracted with ethyl acetate (4ϫ5 mL).
The combined organic layers were dried with Na2SO4 and the sol-
vent was removed in vacuo to yield the dihydroisoquinoline as a
viscous yellow oil (279.5 mg). Due to its instability against aerial
oxidation, this material was used without further purification.[17]
1H NMR (400 MHz, CDCl3): δ = 6.97, 6.84, 6.79, 6.65 (4 s, 4 H,
5-H, 8-H, 3Ј-H, 6Ј-H), 4.13–4.01 (m, 4 H, Ar-CH2, OCH2CH3),
(C-2), 112.6 (C-6), 110.0 (C-3) ppm. IR (NaCl): ν = 3074, 2874,
˜
2238, 2076, 1672, 1594, 1508, 1406, 1290, 1228, 980, 868 cm–1. MS
(ESI): m/z (%) = 207.07 (100) [M + H]+. HRMS (ESI): calcd. for
[C9H3D6ClO3 + H]+ 207.0690; found 207.0688.
2-Chloro-4,5-bis(trideuteriomethoxy)benzyl Alcohol: Sodium
borohydride (13.6 mg, 368 μmol) was added to solution of 2-
chloro-4,5-bis(trideuteriomethoxy)benzaldehyde (152 mg,
736 μmol) in a mixture of MeOH (5 mL) and THF (5 mL). The
reaction mixture was stirred at ambient temperature for 40 min.
The solvent was removed in vacuo and 1 n HCl (5 mL) was added.
This mixture was extracted with dichloromethane (4ϫ5 mL) and
the combined organic layers were dried with Na2SO4. Removal of
the solvent in vacuo gave the title compound (154 mg, quant.) as a
colourless oil. 1H NMR (400 MHz, CDCl3): δ = 6.99 (s, 1 H, 3-
H), 6.86 (s, 1 H, 6-H), 4.72 (d, J = 6.3 Hz, 2 H, Ar-CH2), 1.84 (t,
J = 6.3 Hz, 1 H, OH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
130.5 (C-1), 123.7 (C-6), 112.6, 111.8 (C-2, C-5), 62.9 (Ar-
3
3
3.87 (s, 3 H, OCH3), 3.72 (t, J = 7.5 Hz, 2 H, 3-H2), 2.65 (t, J =
7.5 Hz, 2 H, 4-H2), 1.39 (t, 3J = 7.0 Hz, 2 H, OCH2CH3) ppm.
Sodium borohydride (65.2 mg, 1.72 mmol) was added to a solution
of the dihydroisoquinoline in MeOH (2.5 mL) and THF (2.5 mL).
The reaction mixture was stirred at ambient temperature for 16 h.
After the addition of 1 n NaOH (5 mL), the mixture was extracted
with ethyl acetate (4ϫ5 mL). The combined organic layers were
dried with Na2SO4. Removal of the solvent in vacuo gave the crude
product (265.6 mg) as a yellowish oil. This material was purified
by column chromatography (silica, cyclohexane/EtOAc/Et2NH,
7:1:0.5, Rf = 0.1) to give 9 as a light-yellow oil (222.7 mg, 81.3%).
1H NMR, COSY (400 MHz, CDCl3): δ = 6.89 (s, 1 H, 3Ј-H), 6.75
CH ) ppm. IR (NaCl): ν = 3400, 2954, 2881, 2254, 2073, 1646,
˜
2
1503, 1402, 1280, 1228, 1178, 1103, 995, 862 cm–1. MS (ESI): m/z
(%) = 191.07 (100) [M – OH]+ . HRMS (ESI): calcd. for
[C9H4D6ClO2]+ 191.0740; found 191.0742.
2-Chloro-4,5-bis(trideuteriomethoxy)benzyl Bromide: Pyridine
(14.7 μL, 180 μmol) and PBr3 (26.9 μL, 286 μmol) were added to a
solution of 2-chloro-4,5-bis(trideuteriomethoxy)benzyl alcohol
(150 mg, 719 μmol) in dry THF (3 mL) at 0 °C. After stirring for
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1,3-Benzyl Migration in Iminium Ions
(s, 1 H, 6Ј-H), 6.72 (s, 1 H, 8-H), 6.60 (s, 1 H, 5-H), 4.23–4.20 (m,
(10 mL) and NaBH4 (160 mg, 4.17 mmol). The reaction yielded a
3
1 H, 1-H), 4.07–4.02 (q, J = 13.8 Hz, 2 H, OCH2CH3), 3.85 (s, 3 yellow oil (1041 mg). Purification of the crude product by flash
H, OCH3), 3.33–3.23 (m, 2 H, 3-Hb, Ar-CHb), 2.98–2.86 (m, 2 H, chromatography (silica, cyclohexane/EtOAc/Et2NH, 7:1:0.5, Rf =
3-Ha, Ar-CHa), 2.81–2.68 (m, 2 H, 4-H2), 1.92 (br. s, 1 H, NH), 0.1) gave 15d as a light-yellow oil (568 mg, 84.6 %). 1H NMR,
1.44 (t, 3J = 13.8 Hz, 3 H, OCH2CH3) ppm. 13C NMR, HSQC,
HMBC (100.6 MHz, CDCl3): δ = 148.4, 148.2 (C-4Ј, C-5Ј), 147.9
COSY (400 MHz, CDCl3): δ = 7.65–7.63 (d, J = 8.4 Hz, 2 H, 2Ј-
3
3
H, 6Ј-H), 7.02–6.70 (d, J = 8.4 Hz, 2 H, 3Ј-H, 5Ј-H), 6.59 (s, 1 H,
(C-6), 146.6 (C-7), 130.6 (C-8a), 128.9 (C-2Ј), 127.6 (C-4a), 125.4 5-H), 6.55 (s, 1 H, 8-H), 4.15 (dd, J = 14, J = 4.4 Hz, 1 H, 1-H),
(C-1Ј), 114.4 (C-8), 112.9 (C-3Ј), 112.2 (C-5), 111.6 (C-6Ј), 64.8 3.86 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.22–3.11 (m, 2 H, Ar-
(OCH2CH3), 56.1 (C-1), 55.5 (OCH3), 40.7 (C-3), 40.4 (Ar-CH2), CHb, 3-Hb), 2.97–2.87 (m, 2 H, Ar-CHa, 3-Ha), 2.80–2.67 (m, 2
29.6 (C-4), 15.0 (OCH CH ) ppm. IR (NaCl): ν = 3345, 3047, 2926,
H, 4-H2), 2.23 (br. s, 1 H, NH) ppm. 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3): δ = 148.02, 147.45 (C-6, C-7), 139.03 (C-1Ј),
137.96 (C-2Ј, C-6Ј), 131.88 (C-3Ј, C-5Ј), 130.14 (C-4a), 127.57 (C-
8a), 112.26 (C-5), 109.81 (C-8), 92.07 (C-4Ј), 56.97 (C-1), 56.32,
56.20 (2 OCH3), 42.60 (Ar-CH2), 40.93 (C-3), 29.58 (C-4) ppm. IR
˜
2
3
2831, 2218, 2070, 1608, 1505, 1394, 1263, 1225, 1109, 1036, 968,
860, 732 cm–1. MS (ESI): m/z (%) = 398.20 (100) [M + H]+. HRMS
(ESI): calcd. for [C21H20D6NO4 + H]+ 398.2000; found 398.1997.
General Procedure for the Preparation of the Tetrahydroisoquinolines
15: A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-
carbonitrile[13,15] (797 mg, 3.65 mmol) in dry THF (12 mL) was co-
oled to –78 °C. A solution of KHMDS (1.46 g, 7.31 mmol) in dry
THF (20 mL) was added slowly. The mixture was stirred for 5 min
and the benzyl bromide (3.94 mmol) in dry THF (15 mL) was
added. After stirring for 3–4 h at –78 °C, the reaction mixture was
gradually warmed to ambient temperature. After the addition of
1 n NaOH (60 mL), the mixture was extracted with ethyl acetate
(5ϫ15 mL). The combined organic layers were dried with Na2SO4
and the solvent was removed in vacuo to give the crude imine. Due
to the sensitivity of the product to air, this material was not further
purified.[17] Sodium borohydride (346 mg, 9.14 mmol) was added
to a cooled solution of the 1-benzyl-3,4-dihydroisoquninoline in a
mixture of MeOH (5 mL) and THF (20 mL). The reaction mixture
was stirred at ambient temperature overnight. After the addition
of 1 n NaOH (50 mL), the mixture was extracted with ethyl acetate
(5 ϫ 15 mL) and the combined organic layers were dried with
Na2SO4. Removal the solvent in vacuo gave the crude product,
which was purified by column chromatography.
(NaCl): ν = 2994, 2932, 2831, 1609, 1510, 1463, 1353, 1257, 1220,
˜
1111, 1006, 909, 726 cm–1. MS (ESI): m/z (%) = 410.06 (100) [M +
H]+. HRMS (ESI): calcd. for [C18H20INO2 + H]+ 410.0611; found
410.0612.
1-(2-Methoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(15e): The reaction was conducted according to the general pro-
cedure. Reagents: KHMDS (365 mg, 1.83 mmol) in THF (5 mL),
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(200 mg, 916 μmol) in THF (5 mL), 2-methoxybenzyl bromide
(194 mg, 962 μmol) in THF (5 mL), MeOH (5 mL) and NaBH4
(86.6 mg, 2.29 mmol). The reaction yielded a yellow oil (355 mg).
Purification of the crude product by flash chromatography (silica,
cyclohexane/EtOAc/Et2NH, 8:1:0.5, Rf = 0.1) gave 15e as a pale-
1
yellow oil (261 mg, 91.0%). H NMR, COSY (400 MHz, CDCl3):
δ = 7.28–7.25 (m, 1 H, 4Ј-H), 7.20–7.19 (m, 1 H, 6Ј-H), 6.96–6.92
(m, 2 H, 3Ј-H, 5Ј-H), 6.70 (s, 1 H, 5-H), 6.61 (s, 1 H, 8-H), 4.19
(dd, J = 9.4, J = 3.5 Hz, 1 H, 1-H), 3.89 (s, 3 H, OCH3), 3.88 (s, 3
H, OCH3), 3.85 (s, 3 H, OCH3), 3.30–3.24 (m, 2 H, 3-Hb, Ar-CHb),
2.97–2.85 (m, 2 H, 3-Ha, 4-Hb), 2.78–2.75 (m, 2 H, 4-H2), 1.75 (br.
s, 1 H, NH) ppm. 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3):
δ = 157.9 (C-2Ј), 147.4, 146.1 (C-6, C-7), 131.5 (C-1Ј), 131.4 (C-
6Ј), 128.0 (C-8a), 127.9 (C-4Ј), 127.3 (C-4a), 120.6 (C-5Ј), 111.8 (C-
8), 110.6 (C-3Ј), 110.0 (C-5), 56.1 (OCH3), 56.0 (OCH3), 55.5
(OCH3), 55.2 (C-1), 40.3 (C-4), 38.0 (Ar-CH2), 29.7 (C-4) ppm. IR
1-(4-Bromobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(15c): The reaction was conducted according to the general pro-
cedure. Reagents: KHMDS (910 mg, 4.56 mmol) in THF (10 mL),
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(500 mg, 2.29 mmol) in THF (10 mL), 4-bromobenzyl bromide
(510 mg, 2.40 mmol) in THF (10 mL), MeOH (10 mL), THF
(10 mL) and NaBH4 (216 mg, 5.71 mmol). The reaction yielded a
yellow oil (981 mg). Purification of the crude product by flash
chromatography (silica, cyclohexane/EtOAc/Et2NH, 7:1:0.5, Rf =
0.1) gave 15c as a light-yellow oil (551 mg, 66%). 1H NMR, COSY
(NaCl): ν = 3006, 2931, 2832, 1601, 1511, 1492, 1462, 1241, 1222,
˜
1112, 1028, 909, 727 cm–1. MS (FAB): m/z (%) = 314.2 (61) [M +
H]+, 192.1 (100) [M – C8H9O]+. HRMS (FAB): calcd. for
[C19H23NO3 + H]+ 314.1756; found 314.1759.
1-[4-(Triisopropylsilyloxy)benzyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (15f): The reaction was conducted according to the ge-
neral procedure. Reagents: KHMDS (78.6 mg, 394 μmol) in THF
(1.5 mL), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-
bonitrile (39.5 mg, 182 μmol) in THF (2 mL), 4-triisopropylsilylo-
xybenzyl bromide[20] (67.9 mg, 198 μmol) in THF (1.5 mL), MeOH
(10 mL) and NaBH4 (24.7 mg, 653 μmol). The reaction yielded a
light-yellow oil (122.4 mg). Purification of the crude product by
flash chromatography (silica, cyclohexane/EtOAc/Et2NH, 8:1:0.5,
Rf = 0.15) gave 15f as a light-yellow oil (75.9 mg, 92.2 %). 1H
3
(400 MHz, CDCl3): δ = 7.44 (d, J = 8 Hz, 2 H, 2Ј-H, 6Ј-H), 7.12
3
(d, J = 8 Hz, 2 H, 3Ј-H, 5Ј-H), 6.58 (s, 1 H, 5-H), 6.51 (s, 1 H, 8-
H), 4.19 (dd, J = 8.6, J = 5 Hz, 1 H, 1-H), 3.85 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 3.23–3.12 (m, 2 H, Ar-CHb, 3-Hb), 3.00–2.94
(m, 2 H, Ar-CHa, 3-Ha), 2.77–2.73 (m, 2 H, 4-H2) ppm. 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3): δ = 148.16 (C-7), 147.52 (C-
6), 138.12 (C-1Ј), 131.99 (C-3Ј, C-5Ј), 131.60 (C-2Ј, C-6Ј), 129.6 (C-
4a), 127.3 (C-8a), 120.8 (C-4Ј), 112.3 (C-5), 109.9 (C-8), 56.9 56.3,
56.2 (C-1, 2ϫ OCH3), 42.4 (Ar-CH2), 40.8 (C-3), 29.3 (C-4) ppm.
3
NMR, COSY (400 MHz, CDCl3): δ = 7.08 (d, J = 8.0 Hz, 2 H,
IR (NaCl): ν = 2999, 2931, 2831, 1609, 1510, 1487, 1463, 1324,
˜
2Ј-H, 6Ј-H), 6.83 (d, 3J = 8.0 Hz, 2 H, 3Ј-H, 6Ј-H), 6.82 (s, 1 H, 8-
H), 6.58 (s, 1 H, 5-H), 4.12 (dd, J = 12, J = 4 Hz, 1 H, 1-H), 3.86
(s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.23–3.17 (m, 1 H, 3-Hb),
3.13 (dd, J = 12, J = 4 Hz, 1 H, Ar-CHb), 2.91–2.85 (m, 2 H, Ar-
CHa, 3-Ha), 2.75–2.71 (m, 2 H, 4-H2), 2.08 (br. s, 1 H, NH), 1.29–
1.20 (m, 3 H, CH), 1.11–1.09 (d, J = 7.1 Hz, 18 H, CH3) ppm. 13C
1259, 1221, 1111, 1011, 857, 801, 781 cm–1. MS (ESI): m/z (%) =
362.07 (100) [M + H]+. HRMS (ESI): calcd. for [C18H20BrNO2 +
H]+ 362.0750; found 362.0747.
6,7-Dimethoxy-1-(4-iodobenzyl)-1,2,3,4-tetrahydroisoquinoline
(15d): The reaction was conducted according to the general pro-
cedure. Reagents: KHMDS (670 mg, 3.35 mmol) in THF (10 mL), NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ = 155.1 (C-4Ј),
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(360 mg, 1.64 mmol) in THF (10 mL), 4-iodobenzyl bromide
(510 mg, 1.72 mmol) in THF (5 mL), MeOH (10 mL), THF
147.8 (C-6), 147.3 (C-7), 131.5 (C-1Ј), 130.6 (C-2Ј, C-6Ј), 129.6 (C-
4a), 127.6 (C-8a), 120.3 (C-2Ј, C-5Ј), 112.1 (C-5), 109.9 (C-8), 57.2
(C-1), 56.3, 56.2 (2 OCH3), 42.2 (Ar-CH2), 41.0 (C-3), 29.7 (C-4),
Eur. J. Org. Chem. 2011, 7355–7365
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7361

N. Blank, B. F. Straub, T. Opatz
FULL PAPER
18.3 (6 CH ), 13.0 (3 CH) ppm. IR (NaCl): ν = 2944, 2866, 1608, H, 5-H), 4.44 (s, 2 H, CH2), 3.80 (s, 3 H, OCH3), 1.29–1.22 (m, 3
˜
3
1508, 1464, 1260, 1226, 1114, 1012, 883, 854 cm–1. MS (ESI): m/z
(%) = 456.29 (100) [M + H]+ . HRMS (ESI): calcd. for
[C27H41NO3Si + H]+ 456.2928; found 456.2928.
H, CH), 1.10–1.05 (m, 18 H, CH3) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 151.4 (C-4), 145.8 (C-3), 130.4 (C-1), 122.3, 121.5 (C-
2, C-6), 112.0 (C-5), 55.6 (OCH3), 34.4 (Ar-CH2), 18.1 (6 CH3),
13.1 (3 CH) ppm.
6,7-Dimethoxy-1-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydroiso-
quinoline (15g): The reaction was conducted according to the gene-
1-(4-Methoxy-3-triisopropylsilyloxybenzyl)-6,7-dimethoxy-1,2,3,4-
ral procedure. Reagents: KHMDS (53.4 mg, 268 μmol) in THF tetrahydroisoquinoline (15i): The reaction was conducted according
(1.5 mL), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-
bonitrile (29.3 mg, 134 μmol) in THF (1 mL), 3,4-methylenedioxy-
benzyl bromide (30.4 mg, 141 μmol) in THF (1.5 mL), MeOH
to the general procedure. Reagents: KHMDS (910 mg, 4.58 mmol)
in THF (10 mL), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-
carbonitrile (500 mg, 2.29 mmol) in THF (10 mL), 4-methoxy-3-
(2 mL) and NaBH4 (14.3 mg, 378 μmol). The reaction yielded a (triisopropylsilyloxy)benzyl bromide (900 mg, 2.41 mmol) in THF
brown oil (122.4 mg). Purification of the crude product by flash
(8.6 mL), MeOH (10 mL) and NaBH4 (220 mg, 5.73 mmol). The
reaction yielded a yellow oil (958 mg). Purification of the crude
chromatography (silica, cyclohexane/EtOAc/Et2NH, 8:1:0.5, Rf =
0.1) gave 15g as a light-brown oil (30.6 mg, 69.8 %). 1H NMR, product by flash chromatography (silica, cyclohexane/EtOAc/
COSY (400 MHz, CDCl3): δ = 6.77 (d, J = 7.9 Hz, 1 H, 5Ј-H),
6.75 (d, J = 1.8 Hz, 1 H, 2Ј-H), 6.70 (dd, J = 7.9, J = 1.8 Hz, 1 H,
Et2NH, 8:1:1, Rf = 0.1) gave 15i as a light-yellow oil (774 mg,
69.5%). H NMR, COSY (500 MHz, CDCl3): δ = 6.79–6.74 (m, 3
1
6Ј-H), 6.63 (s, 1 H, 8-H), 6.59 (s, 1 H, 5-H), 5.94 (m, 2 H, OCH2O), H, 2Ј-H, 5Ј-H, 6Ј-H), 6.67 (s, 1 H, 5-H), 6.57 (s, 1 H, 8-H), 4.08
4.10 (dd, J = 9.0, J = 4.2 Hz, 1 H, 1-H), 3.86 (s, 3 H, OCH3), 3.83 (dd, J = 8.8, J = 4.4 Hz, 1 H, 1-H), 3.87 (s, 3 H, OCH3), 3.85 (s, 3
(s, 3 H, OCH3), 3.23–3.17 (m, 1 H, 3-Hb), 3.12 (dd, J = 13.8, J = H, OCH3), 3.83 (s, 3 H, OCH3), 3.20–3.15 (m, 1 H, 3-Hb), 3.10–
4
4.4 Hz, 1 H, Ar-CHb), 2.96–2.90 (m, 1 H, 3-Ha), 2.84 (dd, J = 13.8, 3.07 (dd, J = 17.0, J = 4.4 Hz, 1 H, Ar-CHb), 2.90–2.84 (m, 2 H,
J = 9.5 Hz, 1 H, Ar-CHa), 2.78–2.69 (m, 2 H, 4-H2), 2.04 (br. s, 1 Ar-CHa, 3-Ha), 2.71–2.67 (m, 2 H, 4-H2), 1.80 (br. s, 1 H, NH),
H, NH) ppm. 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ
1.24–1.17 (m, 3 H, CH), 1.08–1.06 (d, J = 7.5 Hz, 18 H, CH3) ppm.
= 147.9 (C-3Ј), 147.7 (C-6), 147.3 (C-7), 146.3 (C-4Ј), 132.9 (C-1Ј), 13C NMR, HSQC, HMBC (125.8 MHz, CDCl3): δ = 149.7, 147.5,
130.5 (C-4a), 127.5 (C-8a), 122.5 (C-6Ј), 112.1 (C-5), 109.7 (C-8), 147.2, 145.6 (C-6, C-7, C 3Ј, C-4Ј), 131.3 (C-1Ј), 130.6 (C-8a), 127.6
109.7 (C-2Ј), 108.5 (C-5Ј), 101.0 (OCH2O), 57.1 (C-1), 56.2, 56.0 (C-4a), 122.5 (C-2Ј), 121.5 (C-6Ј), 112.3 (C-5), 111.9 (C-5Ј), 109.5
(2 OCH3), 42.5 (Ar-CH2), 40.8 (C-3), 29.6 (C-4) ppm. IR (NaCl): (C-8), 56.9 (C-1), 56.1, 55.9, 55.7 (3 OCH3), 41.6, 41.1 (Ar-CH2,
ν = 3000, 2939, 2838, 1609, 1503, 1488, 1441, 1247, 1223, 1112, C-3), 29.7 (C-4), 18.1 (6 CH ), 13.0 (3 CH) ppm. IR (NaCl): ν =
˜
˜
3
1038, 929, 860, 811 cm–1. MS (ESI): m/z (%) = 192.1 (27) [M –
2942, 2865, 1509, 1463, 1269, 1225, 1111, 1032, 994, 882, 834 cm–1.
C8H7O2]+, 328.2 (100) [M + H]+. HRMS (ESI): calcd. for MS (ESI): m/z (%) = 486.4 (86) [M + H]+, 971.7 (100) [2M]+.
[C19H21NO4 + H]+ 328.1543; found 328.1541.
HRMS (ESI): calcd. for [C28H43NO4Si +H]+ 486.3032; found
486.3032.
4-Methoxy-3-(triisopropylsilyloxy)benzyl Alcohol: Sodium boro-
hydride (1.44 g, 38.6 mmol) was dissolved in dry EtOH (5 mL) and
cooled to 0 °C. A solution of 4-methoxy-3-(triisopropylsilyloxy)-
benzaldehyde[21] (9.93 g, 32.2 mmol) in dry EtOH (15 mL) was
added slowly. The resulting mixture was stirred for 2 h at room
1-(2,6-Difluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(15j): The reaction was conducted according to the general pro-
cedure. Reagents: KHMDS (730 mg, 3.66 mmol) in THF (10 mL),
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
temperature and the solvents evaporated to dryness. Water (50 mL) (400 mg, 1.83 mmol) in THF (10 mL), 2,6-difluorobenzyl bromide
was added to the residue and the mixture extracted with EtOAc
(4ϫ80 mL). The combined organic layers were washed with sat.
aq. NH4Cl (100 mL), water (100 mL) and brine (100 mL), dried
(Na2SO4), filtered and evaporated to give the title compound
(9.74 g, 96.0%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ
(408 mg, 1.97 mmol) in THF (8 mL), MeOH (10 mL) and NaBH4
(173 mg, 4.58 mmol). The reaction yielded a colourless oil
(600 mg). Purification of the crude product by flash chromatog-
raphy (silica, cyclohexane/EtOAc/Et2NH, 8:1:0.5, Rf = 0.15) gave
15j as a colourless solid (419 mg, 71.7%). M.p. 77–79 °C. 1H NMR,
COSY (400 MHz, CDCl3): δ = 7.24–7.16 (A part of ABBЈXXЈ sys-
3
= 6.89–6.85 (m, 2 H, 2-H, 6-H), 6.80 (d, J = 8.0 Hz, 1 H, 5-H),
4.53 (s, 2 H, CH2), 3.79 (s, 3 H, OCH3), 2.00 (br. s, 1 H, OH), tem, m, 1 H, 4Ј-H), 6.92–6.89 (BBЈ part of ABBЈXXЈ system, m, 2
1.30–1.21 (m, 3 H, CH), 1.10 (d, 3J = 7.6 Hz, 18 H, CH3) ppm. 13
H, 3Ј-H, 5Ј-H), 6.63 (s, 1 H, 5-H), 6.60 (s, 1 H, 8-H), 4.17 (t, J =
NMR (100.6 MHz, CDCl3): δ = 150.5 (C-4), 145.6 (C-3), 133.7 (C- 7.0 Hz, 1 H, 1-H), 3.86 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.32–
1), 120.2, 119.7 (C-2, C-6), 112.1 (C-5), 65.1 (Ar-CH2), 55.6 3.26 (m, 1 H, 3-Hb), 3.10 (d, J = 7.0 Hz, 2 H, Ar-CH2), 3.01–2.95
C
(OCH ), 18.0 (6 CH ), 13.0 (3 CH) ppm. IR (NaCl): ν = 3332, (m, 1 H, 3-Ha), 2.75–2.71 (m, 2 H, 4-H2), 1.64 (br. s, 1 H,
˜
3
3
2944, 2867, 1513, 1464, 1427, 1289, 1136, 883, 832 cm–1. MS (FD):
m/z (%) = 310.0 (52) [M]+, 311.3 (100) [M + H]+. HRMS (ESI):
calcd. for [C17H30O3Si + Na]+ 333.1862; found 333.1853.
NH) ppm. 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ =
164.1, 160.9 (C-2Ј, C-6Ј), 147.7, 147.3 (C-6, C-7), 130.7 (C-8a),
128.1 (C-4Ј), 127.3 (C-4a), 115.7 (C-1Ј), 111.9 (C-8), 111.5, 111.2
(C-3Ј, C-5Ј), 109.8 (C-5), 56.1, 56.0 (2 OCH3), 55.4 (C-1), 39.5 (C-
4-Methoxy-3-(triisopropylsilyloxy)benzyl Bromide: PPh3 (847 mg,
3.24 mmol) and NBS (573 mg, 3.24 mmol) were added to a stirred
solution of 4-methoxy-3-(triisopropylsilyloxy)benzyl alcohol
(672 mg, 217 mmol) in dry CH2Cl2 (5 mL) cooled to 0 °C. The re-
action mixture was warmed up to room temperature, stirred for an
additional 20 min and poured into water (10 mL). The product was
extracted with Et2O (3ϫ20 mL), washed with NaOH (1 m, 20 mL)
and brine (20 mL) and dried (Na2SO4). The solvent was removed
in vacuo to give the title compound (768 mg, 94.8%) as a colourless
oil. The product was stored in dry THF (10 mL) with a small
amount of CaCO3 to avoid decomposition. 1H NMR (400 MHz,
3), 30.0 (Ar-CH ), 29.4 (C-4) ppm. IR (NaCl): ν = 3006, 3003,
˜
2
2935, 2907, 2833, 1623, 1590, 1510, 1467, 1353, 1262, 1223, 1110,
1012, 937, 856, 778 cm–1. MS (FAB): m/z (%) = 320.2 (44) [M +
H]+, 192.1 (100) [M – C7H5F2]+. HRMS (FAB): calcd. for
[C18H19F2NO2 + H]+ 320.1462; found 320.1473.
2-Chloro-4-methoxy-5-(triisopropylsilyloxy)benzyl Alcohol: 4-Meth-
oxy-3-(triisopropylsilyloxy)benzyl alcohol (see above, 1.00 g,
3.22 mmol) was dissolved in CHCl3 (1 mL) and sulfuryl chloride
(280 μL, 3.54 mmol) was added at 0 °C. The reaction mixture was
stirred at ambient temperature overnight. The resulting yellow solu-
tion was quenched by the addition of sat. aq. NaHCO3 (15 mL)
3
CDCl3): δ = 6.93–6.90 (m, 2 H, 2-H, 6-H), 6.77 (d, J = 8.8 Hz, 1
7362
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7355–7365

1,3-Benzyl Migration in Iminium Ions
and the crude product was extracted with ethyl acetate (3ϫ10 mL).
(606 mg, 92.8%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3):
Concentration of the organic layer afforded the title compound as
δ = 10.12 (s, 1 H, CHO), 7.41 (s, 1 H, 6-H), 7.08 (s, 1 H, 3-H), 3.84
(s, 3 H, OCH3), 1.32–1.22 (m, 3 H, CH), 1.10 (d, J = 7.2 Hz, 18
1
3
a colourless oil (1.01 g, 90.0%). H NMR (400 MHz, CDCl3): δ =
6.96 (s, 1 H, 3-H), 6.82 (s, 1 H, 6-H), 4.64 (s, 2 H, Ar-CH2), 3.79 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 191.2 (CHO),
(s, 3 H, OCH3), 1.89 (br. s, 1 H, OH), 1.28–1.19 (m, 3 H, CH),
152.2 (C-5), 150.9 (C-4), 127.1 (C-1), 124.6 (C-3), 111.2 (C-6), 110.7
1.08 (d, 3J = 7.5 Hz, 18 H, CH3) ppm. 13C NMR (100.6 MHz, (C-2), 55.7 (OCH ), 17.9 (6 CH ), 13.0 (3 CH) ppm. IR (NaCl): ν
˜
3
3
CDCl3): δ = 150.9 (C-4), 144.6 (C-5), 130.2 (C-1), 127.4 (C-2), = 2941, 2867, 1690, 1584, 1495, 1463, 1389, 1290, 1212, 1159, 993,
120.9 (C-6), 113.2 (C-3), 62.7 (Ar-CH2), 56.0 (OCH3), 17.9 (6 CH3),
880, 749 cm–1. MS (FAB): m/z (%) = 387.1 (100) [M]+.
13.0 (3 CH) ppm. IR (NaCl): ν = 3381, 2943, 2866, 1501, 1463,
˜
2-Bromo-5-methoxy-4-(triisopropylsilyloxy)benzyl Alcohol: The title
compound was prepared from 2-bromo-5-methoxy-4-(triisopro-
pylsilyloxy)benzaldehyde (583 mg, 1.51 mmol) and NaBH4
(28.5 mg, 7.52 mmol) according to the procedure used for the prep-
aration of 4-methoxy-3-(triisopropylsilyloxy)benzyl alcohol. The ti-
tle compound (550 mg, 93.8%.) was obtained as a colourless oil.
1H NMR (400 MHz, CDCl3): δ = 7.03, 6.96 (s, 2 H, 3-H, 6-H),
4.67 (d, J = 6.2 Hz, 2 H, Ar-CH2), 3.81 (s, 3 H, OCH3), 1.93 (t, J
1440, 1270, 1160, 880, 856, 680 cm–1. MS (FAB): m/z (%) = 344.3
(100) [M]+.
2-Chloro-4-methoxy-5-(triisopropylsilyloxy)benzyl Bromide: Pyr-
idine (28.2 μL, 346 μmol) and PBr3 (54 μL, 579 μmol) were added
to a solution of 2-chloro-4-methoxy-5-(triisopropylsilyloxy)benzyl
alcohol (500 mg, 1.45 mmol) in dry CH2Cl2 (2 mL) at 0 °C. After
stirring for 10 min at 0 °C, the mixture was warmed to ambient
temperature and a small amount of ice was added. The mixture
was extracted with diethyl ether (3ϫ15 mL). The combined or-
ganic layers were washed with brine and sat. aq. NaHCO3 and
dried with Na2SO4. The solvent was removed in vacuo to yield the
title compound (533 mg, 90.1%) as a colourless oil. The product
was stored in dry THF (10 mL) with a small amount of CaCO3 to
3
= 6.2 Hz, 1 H, OH), 1.28–1.19 (m, 3 H, CH), 1.09 (d, J = 7.4 Hz,
18 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 150.6 (C-5),
146.0 (C-4), 132.4 (C-1), 124.3 (C-3), 112.6 (C-6), 112.1 (C-2), 65.2
(Ar-CH2), 55.7 (OCH3), 18.0 (6 CH3), 13.0 (3 CH) ppm. IR
(NaCl): ν = 3363, 2942, 2868, 1601, 1468, 1382, 1311, 1205, 1156,
˜
901, 883 cm–1. MS (FAB): m/z (%) = 389.1 (100) [M]+.
1
avoid decomposition. H NMR (400 MHz, CDCl3): δ = 6.91 (s, 1
2-Bromo-5-methoxy-4-(triisopropylsilyloxy)benzyl Bromide: The ti-
tle compound was prepared from 2-bromo-5-methoxy-4-(triiso-
propylsilyloxy)benzyl alcohol (550 mg, 1.41 mmol), pyridine
(27.5 μL, 337 μmol) and PBr3 (53 μL, 565 μmol) according to the
procedure used for the preparation of 2-chloro-4-methoxy-5-(triiso-
propylsilyloxy)benzyl bromide. The title compound (589 mg,
92.2%) was obtained as a colourless oil. The product was stored
in dry THF (10 mL) with a small amount of CaCO3 to avoid de-
H, 3-H), 6.82 (s, 1 H, 6-H), 4.52 (s, 2 H, Ar-CH2), 3.80 (s, 3 H,
OCH3), 1.28–1.19 (m, 3 H, CH), 1.09 (d, 3J = 7.2 Hz, 18 H,
CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 152.0 (C-4), 144.8
(C-5), 127.2 (C-1), 126.1 (C-2), 122.6 (C-6), 113.4 (C-3), 55.8
(OCH3), 31.3 (Ar-CH2), 18.0 (6 CH3), 13.0 (3 CH) ppm.
1-[2-Chloro-4-methoxy-5-(triisopropylsilyloxy)benzyl]-6,7-dimeth-
oxy-1,2,3,4-tetrahydroisoquinoline (15k): The reaction was con-
ducted according to the general procedure. Reagents: KHMDS
(487 mg, 2.44 mmol) in THF (10 mL), 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline-1-carbonitrile (266 mg, 1.22 mmol) in THF
(8 mL), 2-chloro-4-methoxy-5-(triisopropylsilyloxy)benzyl bromide
(522 mg, 1.28 mmol) in THF (10 mL), MeOH (10 mL), THF
(10 mL) and NaBH4 (115 mg, 3.05 mmol). The reaction yielded a
yellow oil (788 mg). Purification of the crude product by flash
chromatography (silica, cyclohexane/EtOAc/Et2NH, 8:1:0.5, Rf =
0.15) gave 15k as a colourless oil (524 mg, 82.7 %). 1H NMR,
COSY (400 MHz, CDCl3): δ = 6.87 (s, 1 H, 3Ј-H), 6.78 (s, 1 H, 6Ј-
H), 6.71 (s, 1 H, 8-H), 6.59 (s, 1 H, 5-H), 4.18 (dd, J = 9.5, J =
3.8 Hz, 1 H, 1-H), 3.86 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.79
(s, 3 H, 4Ј-OCH3), 3.22–3.19 (m, 2 H, Ar-CHb, 3-Hb), 2.96–2.87
(m, 2 H, Ar-CHa, 3-Ha), 2.74 (t, J = 6.0 Hz, 2 H, 4-H2), 1.63 (br.
s, 1 H, NH), 1.28–1.19 (m, 3 H, CH), 1.09–1.05 (m, 18 H,
CH3) ppm. 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ =
150.3 (C-4Ј), 147.8, 147.4 (C-6, C-7), 144.4 (C-5Ј), 130.9 (C-4a),
129.0 (C-1Ј), 127.5 (C-8a), 125.5 (C-2Ј), 123.1 (C-6Ј), 113.6 (C-3Ј),
112.0 (C-5), 109.9 (C-8), 56.2, 56.0, 55.9 (3 OCH3), 55.4 (C-1), 40.2
(C-3), 39.7 (Ar-CH2), 29.7 (C-4), 18.0 (6 CH3), 13.0 (3 CH) ppm.
1
composition. H NMR (400 MHz, CDCl3): δ = 7.03 (s, 1 H, 3-H),
6.90 (s, 1 H, 6-H), 4.57 (s, 2 H, Ar-CH2), 3.80 (s, 3 H, OCH3),
1.28–1.20 (m, 3 H, CH), 1.09 (d, 3J = 7.5 Hz, 18 H, CH3) ppm. 13
C
NMR (100.6 MHz, CDCl3): δ = 150.7 (C-5), 147.0 (C-4), 129.4 (C-
1), 124.6 (C-3), 114.6 (C-2), 114.3 (C-6), 55.8 (OCH3), 34.4 (Ar-
CH2), 18.0 (6 CH3), 13.0 (3 CH) ppm.
1-[2-Bromo-5-methoxy-4-(triisopropylsilyloxy)benzyl]-6,7-dimeth-
oxy-1,2,3,4-tetrahydroisoquinoline (15l): The reaction was con-
ducted according to the general procedure. Reagents: KHMDS
(487 mg, 2.44 mmol) in THF (8 mL), 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline-1-carbonitrile (266 mg, 1.22 mmol) in THF
(8 mL), 2-bromo-5-methoxy-4-(triisopropylsilyloxy)benzyl bromide
(580 mg, 1.28 mmol) in THF (10 mL), MeOH (10 mL), THF
(10 mL) and NaBH4 (115 mg, 3.05 mmol). The reaction yielded a
yellow oil (788 mg). Purification of the crude product by flash
chromatography (silica, cyclohexane/EtOAc/Et2NH, 7:1:0.5, Rf =
0.2) gave 15l as a colourless oil (380 mg, 55.1%). 1H NMR, COSY
(400 MHz, CDCl3): δ = 7.08 (s, 1 H, 3Ј-H), 6.72 (s, 2 H, 6Ј-H, 8-
H), 6.60 (s, 1 H, 5-H), 4.24 (dd, J = 9.4, J = 3.8 Hz, 1 H, 1-H),
3.86 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3),
3.30 (dd, J = 13.8, J = 4.2 Hz, 1 H, 3-Hb), 3.26–3.22 (m, 1 H, Ar-
CHb), 2.99–2.87 (m, 2 H, Ar-CHa, 3-Ha), 2.78–2.73 (m, 2 H, 4-
H2), 1.86 (br. s, 1 H, NH), 1.29–1.22 (m, 3 H, CH), 1.09 (d, J =
7.5 Hz, 18 H, CH3) ppm. 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3): δ = 150.3 (C-5Ј), 147.8, 147.3 (C-6, C-7), 145.2 (C-4Ј),
131.1 (C-1Ј), 130.6 (C-4a), 127.5 (C-8a), 124.5 (C-3Ј), 115.1 (C-6Ј),
112.0 (C-5), 110.0 (C-8), 56.2, 56.0, 55.9 (3 OCH3), 55.4 (C-1), 42.9
(C-3), 40.7 (Ar-CH2), 29.7 (C-4), 18.1 (6 CH3), 13.0 (3 CH) ppm.
IR (NaCl): ν = 2939, 2861, 1608, 1499, 1460, 1325, 1265, 1227,
˜
1114, 1014, 880, 851 cm–1. MS (ESI): m/z (%) = 520.3 (100) [M +
H]+. HRMS (ESI): calcd. for [C28H42ClNO4Si +H]+ 520.2644;
found 520.2645.
2-Bromo-5-methoxy-4-(triisopropylsilyloxy)benzaldehyde: Imidazole
(413 mg, 6.06 mmol) and TIPSCl (334 mg, 1.73 mmol) were added
to a stirred solution of 2-bromo-4-hydroxy-5-methoxybenzalde-
hyde[22] (400 mg, 1.73 mmol) in dry DMF (5 mL). The reaction
mixture was stirred for 15 min at room temperature and poured
into water (50 mL). The product was extracted with n-hexane
(3ϫ10 mL), washed with brine (10 mL) and dried (Na2SO4). The
solvent was removed in vacuo to afford the title compound
IR (NaCl): ν = 2950, 2971, 1602, 1496, 1463, 1386, 1255, 1216,
˜
1106, 1014, 908, 876, 734 cm–1. MS (ESI): m/z (%) = 564.2 (100)
[M + H]+. HRMS (ESI): calcd. for [C28H42BrNO4Si + H]+
564.2139; found 564.2127.
Eur. J. Org. Chem. 2011, 7355–7365
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7363

N. Blank, B. F. Straub, T. Opatz
FULL PAPER
1
General Procedure for the Rearrangement: The 1-substituted
1,2,3,4-tetrahydroisoquinoline (52.9 μmol) was dissolved in tri-
fluoroacetic acid (84 μL, 211 mg, 1.85 mmol) and formalin (37%
in H2O, 147 μL) was added. The mixture was stirred at 80 °C for
2.5 h. The solution was made alkaline with sat. aq. NaHCO3 and
extracted with ethyl acetate (3ϫ10 mL). The combined organic
layers were dried with Na2SO4 and the solvent was removed in
vacuo. Due to the limited stability of the products, no further puri-
fication was undertaken in most cases. The 3,4-dihydroisoquinolin-
ium salts produced were characterized by HRMS and the 1H NMR
spectra.
as a yellow wax. H NMR, COSY (200 MHz, CDCl3): δ = 9.85 (s,
1 H, 1-H), 7.56 (s, 1 H, 8-H), 7.14 (s, 1 H, 6Ј-H), 6.80 (s, 1 H, 3Ј-
H), 6.75 (s, 1 H, 5-H), 3.99 (s, 3 H, 7-OCH3), 3.96 (s, 3 H, 6-
OCH3), 3.88 (s, 3 H, 5Ј-OCH3), 3.83 (s, 3 H, 4Ј-OCH3), 3.88–3.83
(m, 2 H, 3-H2), 3.31 (s, 2 H, Ar-CH2), 3.10 (t, 3J = 8.1 Hz, 2 H, 4-
H2) ppm. MS (FAB): m/z (%) = 392 (19) [M]+, 208 (100) [M + H –
C9H10ClO2]+. HRMS (FAB): calcd. for [C21H23D2ClNO4 + H]+
392.1598; found 392.1601.
Crossover Experiment: Tetrahydrosioquinolines 1 (15.39 mg,
38.7 μmol) and 9 (14.63 mg, 38.7 μmol) were stirred with trifluoro-
acetic acid (122.6 μL) and formalin (37 % in H2O, 214.6 μL) at
80 °C for 2.5 h. The solution was made alkaline with sat. aq.
NaHCO3 and extracted with ethyl acetate (3ϫ5 mL). The com-
bined organic layers were dried with Na2SO4 and the solvent was
removed in vacuo. The products were detected by ESI-HRMS. 4:
calcd. for [C21H25ClNO4]+ 390.1467; found 390.1468; 10: calcd. for
[C21H19D6ClNO4]+ 396.1843; found 396.1840; 11: calcd. for
[C22H27ClNO4]+ 404.1623; found 404.1624; 12: calcd. for
[C22H21D6ClNO4]+ 410.2000; found 410.2001.
2-[2-(2-Chloro-4,5-dimethoxyphenyl)ethyl]-6,7-dimethoxy-3,4-dihy-
droisoquinolinium Trifluoroacetate (4): The title compound was pre-
pared from 1 (20.0 mg, 53.0 μmol) following the procedure for the
rearrangement: 26.4 mg, 99 %, yellow wax. 1H NMR, COSY
(400 MHz, CDCl3): δ = 9.96 (s, 1 H, 1-H), 7.53 (s, 1 H, 8-H), 7.10
3
(s, 1 H, 6Ј-H), 6.80 (s, 1 H, 3Ј-H), 6.75 (s, 1 H, 5-H), 4.36 (t, J =
7.5 Hz, 2 H, N-CH2), 3.99 (s, 3 H, 7-OCH3), 3.93 (s, 3 H, 6-OCH3),
3.88 (s, 3 H, 5Ј-OCH3), 3.84 (s, 3 H, 4Ј-OCH3), 3.86–3.82 (m, 2 H,
3
3
3-H2), 3.31 (t, J = 7.5 Hz, 2 H, Ar-CH2), 3.11 (t, J = 8.0 Hz, 2
H, 4-H2) ppm. 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ
= 167.7 (C-1), 161.9 [q, 2J(C,F) = 33.2 Hz, C=O], 158.4 (C-7),
149.2 (C-6), 148.4 (C-5Ј), 148.1 (C-4Ј), 131.2 (C-8a), 125.3 (C-2Ј),
124.6 (C-1Ј), 117.8 (C-4a), 116.3 (C-8), 114.1 (C-6Ј), 112.6 (C-3Ј),
110.6 (C-5), 59.6 (N-CH2), 57.0 (7-OCH3), 56.9 (6-OCH3), 56.7 (5Ј-
OCH3), 56.5 (4Ј-OCH3), 48.4 (C-3), 32.3 (Ar-CH2), 26.0 (C-
2-(But-3-enyl)-6,7-dimethoxy-3,4-dihydroisoquinolinium Tri-
fluoroacetate (16b): Prepared following the procedure for the re-
arrangement starting from 1-allyl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (15b; 12.4 mg, 53.0 μmol), trifluoroacetic acid
1
(84 μL) and formalin (147 μL). H NMR (400 MHz, CDCl3): δ =
9.89 (s, 1 H, 1-H) ppm. MS (ESI): m/z (%) = 246.15 (100) [M]+.
HRMS (ESI): calcd. for [C15H20NO2]+ 246.1489; found 246.1487.
4) ppm. The CF resonance was not found. IR (NaCl): ν = 2970,
˜
3
2840, 1651, 1609, 1510, 1465, 1345, 1263, 1203, 1138, 1045,
801 cm–1. MS (FAB): m/z (%) = 390.2 (100) [M]+, 206.1 (41) [M +
H – C9H10ClO2]+. HRMS (FAB): calcd. for [C21H25ClNO4]+
390.1472; found 390.1463.
2-[2-(4-Bromophenyl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinolin-
ium Trifluoroacetate (16c): Prepared following the procedure for
the rearrangement starting from 15c (10.0 mg, 2.76 μmol), tri-
fluoroacetic acid (43.7 μL) and formalin (78.4 μL). 1H NMR
(400 MHz, CDCl3): δ = 9.73 (s, 1 H, 1-H) ppm. MS (ESI): m/z (%)
= 374.37/376.42 (60/55) [M]+ . HRMS (ESI): calcd. for
[C19H2179BrNO2]+ 374.0756; found 374.0741.
2-[2-(2-Chloro-4,5-dimethoxyphenyl)ethyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline: Crude 4 (27.4 μmol) was dissolved in MeOH
(1 mL) and NaBH4 (68.5 mg) was added. After stirring for 1 h at
room temperature, the reaction mixture was quenched with NaOH
(1 m, 5 mL) and extracted with ethyl acetate (3ϫ5 mL). The com-
bined organic layers were dried with Na2SO4 and the solvent was
removed in vacuo. The resulting material was purified by column
chromatography (silica, toluene/ethanol, 8:1, Rf = 0.1) to give the
title compound as a light-yellow oil (8.5 mg, 82 %). 1H NMR,
COSY (400 MHz, CD3OD): δ = 6.95 (s, 1 H, 6Ј-H), 6.94 (s, 1 H,
3Ј-H), 6.71 (s, 1 H, 5-H), 6.67 (s, 1 H, 8-H), 3.83 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3),
3.70 (s, 2 H, 1-H), 3.01–2.96 (m, 2 H, Ar-CH2), 2.90–2.84 (m, 4 H,
3-H2, 4-H2), 2.75–2.71 (m, 2 H, N-CH2) ppm. 13C NMR, HSQC,
HMBC (100.6 MHz, CD3OD): δ = 149.9, 149.7 (C-4Ј, C-5Ј), 149.30
(C-7), 148.9 (C-6), 130.6 (C-1Ј), 127.3, 127.2 (C-4a, C-8a), 125.9 (C-
2Ј), 115.2 (C-6Ј), 114.2 (C-3Ј), 112.9 (C-5), 111.2 (C-8), 59.1 (N-
CH2), 56.7 (OCH3), 56.6 (OCH3), 56.5 (OCH3), 56.4 (OCH3, C-1),
2-[2-(4-Iodophenyl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinolinium
Trifluoroacetate (16d): Prepared following the procedure for the re-
arrangement starting from 15d (10.0 mg, 2.44 μmol), trifluoroacetic
acid (38.9 μL) and formalin (68.1 μL). 1H NMR (400 MHz,
CDCl3): δ = 9.77 (s, 1 H, 1-H) ppm. MS (ESI): m/z (%) = 422.45
(77) [M]+. HRMS (ESI): calcd. for [C19H21INO2]+ 422.0617; found
422.0609.
6,7-Dimethoxy-2-[2-(2-methoxyphenyl)ethyl]-3,4-dihydroisoquinolin-
ium Trifluoroacetate (16e): Prepared following the procedure for
the rearrangement starting from 15e (10.0 mg, 31.9 μmol), tri-
fluoroacetic acid (50.4 μL), formalin (88.2 μL) and dibenzoyl per-
oxide (0.77 mg, 3.19 μmol). 1H NMR (400 MHz, CDCl3): δ = 9.50
(s, 1 H, 1-H) ppm. MS (ESI): m/z (%) = 326.17 (100) [M]+. HRMS
(ESI): calcd. for [C20H24NO3]+ 326.1751; found 326.1749.
52.0 (C-3), 31.5 (Ar-CH ), 29.1 (C-4) ppm. IR (NaCl): ν = 2926,
˜
2-{2-[2-Chloro-4-methoxy-5-(triisopropylsilyloxy)phenyl]ethyl}-6,7-
dimethoxy-3,4-dihydroisoquinolinium Trifluoroacetate (16k): Pre-
pared following the procedure for the rearrangement starting from
15k (10.0 mg, 19.2 μmol), trifluoroacetic acid (30.5 μL) and forma-
lin (53.3 μL). 1H NMR (400 MHz, CDCl3): δ = 9.76 (s, 1 H, 1-
H) ppm. MS (ESI): m/z (%) = 532.26 (100) [M]+, 376.13 (27) [M –
TIPS + H]+. HRMS (ESI): calcd. for [C29H43ClNO4Si]+ 532.2644;
found 532.2638.
2
2850, 1609, 1515, 1464, 1260, 1220, 1167, 1123 cm–1. MS (ESI):
m/z (%) = 392.1 (100) [M + H]+. HRMS (ESI): calcd. for
[C21H27ClNO4 + H]+ 392.1629; found 392.1623.
2-[2-(2-Chloro-4,5-dimethoxyphenyl)[1-2H2]ethyl]-6,7-dimethoxy-
3,4-dihydroisoquinolinium Trifluoroacetate: Tetrahydroisoquinoline
1 (52.9 μmol) was dissolved in a mixture of trifluoroacetic acid
(84 μL, 211 mg, 1.85 mmol), water (90.8 μL) and MeOH (12.8 μL).
[D2]Paraformaldehyde (59.3 mg) was added and the mixture was
stirred at 80 °C for 2.5 h. The solution was made alkaline with sat.
aq. NaHCO3 and extracted with ethyl acetate (3 ϫ10 mL). The
combined organic layers were dried with Na2SO4 and the solvent
was removed in vacuo to afford the title compound (18.2 mg, 87%)
2-{2-[2-Bromo-5-methoxy-4-(triisopropylsilyloxy)phenyl]ethyl}-6,7-
dimethoxy-3,4-dihydroisoquinolinium Trifluoroacetate (16l): Pre-
pared following the procedure for the rearrangement starting from
15l (10.0 mg, 17.7 μmol), trifluoroacetic acid (28 μL) and formalin
(49.1 μL). 1H NMR, (400 MHz, CDCl3): δ = 9.96 (s, 1 H, 1-
7364
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7355–7365

1,3-Benzyl Migration in Iminium Ions
H) ppm. MS (ESI): m/z (%) = 576.21/578.21 (100) [M]+. HRMS
Gordon, D. J. DeFrees, J. A. Pople, J. Chem. Phys. 1982, 77,
3654–3665; f) P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82,
299–310.
(ESI): calcd. for [C29H4379BrNO4Si]+ 576.2139; found 576.2113.
Supporting Information (see footnote on the first page of this arti-
cle): Spectra, Cartesian coordinates and energies of the computed
structures.
[7] K. N. Houk, N. G. Rondan, J. Am. Chem. Soc. 1984, 106,
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Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(T. O.), the University of Hamburg and the University of Heidel-
berg.
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Received: August 10, 2011
Published Online: November 4, 2011
Eur. J. Org. Chem. 2011, 7355–7365
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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