Intramolecular hydroaminations mediated by reductive mercuration or n-butyllithium to afford 3-methyl- and 3,4-dimethyl-1,2,3,4- tetrahydroisoquinolines

Article abstract of DOI:10.1002/ejoc.200700580

The synthesis of 3-methyl- and 3,4-dimethyltetrahydroisoquinolines from aromatic aminoalkenes using intramolecular hydroamination reactions is described. This reaction was achieved by way of a reductive aminomercuration using mercuric acetate followed by

Full text of DOI:10.1002/ejoc.200700580

FULL PAPER
DOI: 10.1002/ejoc.200700580
Intramolecular Hydroaminations Mediated by Reductive Mercuration or
n-Butyllithium To Afford 3-Methyl- and 3,4-Dimethyl-1,2,3,4-
tetrahydroisoquinolines
Rakhi Pathak,[a] Prevashni Naicker,[a] Warren A. Thompson,[a] Manuel A. Fernandes,[a]
Charles B. de Koning,[a] and Willem A. L. van Otterlo*[a]
Keywords: Hydroamination / Tetrahydroisoquinolines / Reductive mercuration / n-Butyllithium
The synthesis of 3-methyl- and 3,4-dimethyltetrahydroiso-
quinolines from aromatic aminoalkenes using intramolecular
hydroamination reactions is described. This reaction was
achieved by way of a reductive aminomercuration using mer-
curic acetate followed by sodium borohydride, or by using
sub-stoichiometric amounts of n-butyllithium.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
an intermediate. This was followed by an intramolecular
reaction to give compound 5 (Figure 1). Another sequential
intramolecular hydroamination published by Molander and
Pack, facilitated by a neodymium catalyst, also gave rise to
fused THIQs in good yields.[10a]
Introduction
The intramolecular addition of an amine or amine equiv-
alent to an unsaturated carbon fragment (alkene, alkyne or
allene) has seen much investigation in the last few years.[1]
Recently developed methodologies include the use of many
elements in the Periodic Table. Examples including transi-
tion metals, e.g. rhodium,[2] group 4 metals (e.g. zirconium,
titanium)[3] and zinc,[4] alkali earth metals, e.g., calcium[5]
and numerous reports outlining the use of lanthanide com-
plexes have been reported.[6] Much effort has also been ex-
pended into the development of catalytic asymmetric hy-
droamination procedures, especially with rare earth lantha-
nides.[7]
It is of interest that while intramolecular hydroamina-
tions have been extensively used to synthesise simple N-con-
taining heterocycles such as substituted pyrrolidines and
piperidines, application to the synthesis of benzo-fused het-
erocycles has seen little activity. Apart from the synthesis of
indoles using a hydroamination approach, only a few exam-
ples of the use of this methodology to afford isoquinolines
has been reported. Dyker and co-workers reported an inter-
esting approach to dihydroisoquinolines by making use of
the Ugi-four component reaction to synthesize 1. This com-
pound then underwent hydroamination with a gold catalyst
to afford compounds of type 2.[8] A fascinating set of exam-
ples reported by Marks and co-workers demonstrated that
treatment of the divinylarenes 3 with a lanthanum catalyst
afforded 1-methyltetrahydroisoquinolines (1-MeTHIQ) 5 in
excellent yields.[9] These products were presumably pro-
duced by an intermolecular hydroamination to afford 4 as
Figure 1. Published approaches to THIQs using hydroamination.
THIQs are of great interest to the synthetic, medicinal
and natural products chemistry community. THIQs have
found much application in pharmaceutical chemistry due
to the interesting biological activities displayed by THIQ-
containing molecules in natural and synthetic compounds.
Natural products containing the THIQ motif range from
the very simple, such as carnegine 6[11a] and salsolidine
7,[11b] to compounds with THIQs imbedded in their com-
plex structure (see for instance saframycin A).[12] Examples
of medicinally important THIQ compounds with a complex
skeleton would include ecteinascidin 743 9, a THIQ ex-
tracted from a marine tunicate,[13a] which is now in several
anti-cancer clinical trials.[13b] Finally, 1-MeTHIQ 10 is an
example of a simple THIQ which has elicited much interest
from the pharmaceutical world (Figure 2).[14]
[a] Molecular Sciences Institute, School of Chemistry, University
of the Witwatersrand,
PO Wits, 2050, Johannesburg, South Africa
Fax: +27-11-717-6749
E-mail: Willem.vanOtterlo@wits.ac.za
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Results and Discussion
Hydroamination by a Reductive Mercuration Procedure
The first part of this project involved the synthesis of
the ortho-allylbenzylamines 18a–d (Scheme 1, Table 1). The
substituted benzaldehyde 17 was synthesized as described
previously[20] and a subsequent reliable two-step reductive
amination procedure then afforded the amines 18a–d in ex-
cellent yields. An advantage of this approach was that com-
pounds 18a–d could be obtained in high purity without la-
borious chromatographic procedures. Finally compounds
18e was synthesized from compound 20 in a similar man-
ner.
Figure 2. Topical examples of THIQs.
In recent years we have been interested in synthesising
analogues of naturally-occurring naphthylisoquinoline al-
kaloids,[15] e.g. korupensamine B 11 and michellamine B
12.[16] To this end we published details of a novel mercury-
mediated reductive amidation of compounds such as 13 to
afford the corresponding N-acetyl-1,3-dimethyl-THIQs
14.[17] In this full paper we describe an extension of this
methodology to include the synthesis of 3-methyl-THIQs
and 3,4-dimethyl-THIQs 16 (Figure 3) from aromatic ami-
noalkenes 15 using intramolecular hydroamination reac-
tions.[18] In this paper we will divulge details of a reductive
mercuration as well as a n-butyllithium-mediated hydro-
amination approach to the THIQ skeletons.[19]
Scheme 1. Reagents and conditions: (a) R2NH2, p-TSA, benzene
or toluene, Dean–Stark apparatus, reflux, 18 h; (b) NaBH4,
MeOH, H2O (1 drop), 0 °C, 1 h (for yields see Table 1); (c)
Hg(OAc)2, THF/H2O (1/1), room temp., 18 h; (d) aq. NaOH,
NaBH4, 0 °C to room temp., 18 h (for yields see Table 1).
Table 1. Yields for tetrahydroisoquinolines 19a–d (reductive mercu-
ration procedure).
Entry
R1
R2
17Ǟ18[a]
18Ǟ19
a
b
c
H
H
Me
Me
Bn
nPr
Bn
99%
99%
92%
97%
82%
90%
63% (2:1 cis:trans)
86% (2:3 cis:trans)
d
nPr
20Ǟ18[a]
[b]
e
Ph
nBu
90%
–
[a] Yields over two steps. [b] Only starting material recovered.
The ortho-allylated benzylamines 18a–e were then treated
with a stoichiometric amount of mercury(II) acetate in a
water/THF (1:1) solvent mixture (Scheme 1). Sodium
borohydride-mediated reduction of the in situ formed or-
ganomercury intermediate under basic conditions then led
to the formation of the corresponding THIQs 19a–d in
1
moderate to excellent yields. Both the H and 13C NMR
Figure 3. Our group’s approaches to substituted THIQs.
spectra confirmed the formation of the desired THIQ sys-
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Intramolecular Hydroaminations
Figure 4. ORTEP diagram of the X-ray crystal structure of compound 21 (ellipsoids shown at 30% probability).
tems. A point of interest is that this approach afforded 3,4- sub-stoichiometric quantities of n-butyllithium at 60 °C
dimethyl compounds 19c and 19d in reasonable yields, each (Scheme 2). Satisfyingly, the THIQs 19a–d were obtained in
as a cis and trans diasteriomeric mixture. In our hands it reasonable yields after purification by chromatography and
was found to be difficult to separate these isomers but care- their NMR spectra compared well with the compounds
ful interpretation of the spectra of compounds 19c and 19d synthesised by the aminomercuration procedure. To the
after chromatography, allowed us to estimate the cis/trans best of our knowledge this represents the first application
ratio of the compounds obtained (see later in this paper for of this methodology towards the synthesis of THIQs.[18] We
details). A literature search revealed that there are only a also attempted the reaction on substrate 18f,[24] which con-
few published routes to this type of 3,4-dialkyl-THIQ.[21] tains an additional N-allyl functional group, in the hope
Unfortunately, the treatment of the substrate 18e with the of achieving a tandem ring-closure but this reaction was
reductive mercuration procedure did not generate the de- unfruitful.[10] Unfortunately, substrate 18e also failed to
sired THIQ; only unchanged starting material was reco- give the desired product.
vered. The failure of the reaction probably is due to the
electron-rich nature of the 1,1-diphenylethene although ste-
ric factors could also be important.
An interesting side issue was that when the initial re-
ductive mercuration experiment was performed on 18a an
off-white solid was obtained prior to the sodium borohyd-
Scheme 2. Reagents and conditions: (a) nBuLi (2 ϫ16 mol-%),
ride reduction step. A small amount of this material was
recrystallised and this compound’s structure was deter-
mined by single-crystal X-ray crystallography. Quite sur-
prisingly, the crystalline material consisted of the dimeric
THIQ-mercury compound 21 (Figure 4). A search of the
Cambridge Crystallographic database revealed that there
are not many bis-organic mercury complexes known[22] and
that compound 21 is one of the most complex compounds
of this sort now characterized by crystallography.
The use of stoichiometric amounts of mercury in organic
synthesis has obvious disadvantages when taking environ-
mental issues into account. We thus considered the use of
hydroaminations mediated by alternative methods, of which
there are numerous recent literature examples as shown in
the introductory paragraphs of this paper. To us, the work
described by several research groups,[23] on the intramolecu-
lar transamination of styrenes and allyl aryl compounds
with amines, utilizing n-butyllithium as a catalyst, seemed
the most promising.
room temp., 6 h, then 60 °C, 18 h (for yields see Table 2).
Table 2. Yields for tetrahydroisoquinolines 19a–d (procedure using
sub-stoichiometric amounts of n-butyllithium).
Entry
R1
R2
18Ǟ19
a
b
c
d
e
f
H
H
Me
Me
Ph
H
Bn
nPr
Bn
nPr
nBu
allyl
87%
65%
63% (5:1 cis:trans)
62%[b]
[a]
–
[a]
–
[a] Only starting material recovered. [b] cis:trans ratio not deter-
mined due to impurities in spectrum.
As a consequence we decided to do some preliminary
investigation into the mechanistic details of the nBuLi-cata-
lysed reaction and found that when similar reaction condi-
tions were employed on substrate 18a, albeit at room tem-
perature, isomerized compound 22 was isolated in good
yield. Subsequent reaction of compound 22 with a sub-
stoichiometric amount of n-butyllithium at 60 °C gratify-
ingly affforded the expected THIQ 19a (Scheme 3). This
suggests that the initial step in this reaction involves isomer-
ization of the allyl group to the thermodynamically more
Hydroamination Mediated by Sub-Stoichiometric Amounts
of n-Butyllithium
The ortho-allylated benzylamines 18a–e, used previously stable styrene compound followed by the intramolecular
in the aminomercuration procedure, were thus treated with transamination. This proposed mechanism is also sup-
Eur. J. Org. Chem. 2007, 5337–5345
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W. A. L. van Otterlo et al.
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ported by the work of Marks et al.[9] and Molander and Of interest is that irradiation of 3-H only showed nOe inter-
Pack,[10] in which styrenes were converted into THIQs by actions with the 3-C methyl substituent, the 4-H proton and
way of intramolecular hydroamination using lanthanide one of the benzylic methylene protons. On the other hand,
catalysts.
irradiation at 4-H showed an nOe interaction with the 4-C
methyl substituent, 3-H proton and the C-H proton of the
isopropyl group. Of importance is that the strong 3-H···4-
H interaction supports the cis-arrangement of the methyl
groups (Figure 5). Of additional interest is that the 3-H and
4-H protons do not show nOe interactions with the methyl
substituents on the opposing carbons which would be ex-
pected if there was a trans relationship. Simple molecular
modelling[26] of a model compound also showed a coupling
constant of about 3.0 Hz in the case of cis hydrogen atoms
(torsional angle between 3-H and 4-H of 44–50o), while for
trans hydrogen atoms a value of about 1.0 Hz was to be
expected (torsional angle between 3-H and 4-H of 80–84o).
Thus the molecular modelling values were also in agree-
Scheme 3. Reagents and conditions: (a) nBuLi (2 ϫ16 mol-%),
room temp., 18 h, 96%; (b) nBuLi (16 mol-%), 60 °C, 18 h, NMR
spectra identical to that obtained in Scheme 1.
1
ment with those obtained from the H NMR spectrum of
cis-19c.
Stereochemical Aspects of the Hydroamination Reactions
The determination of the stereochemical outcomes of the
hydroaminations were done by analysis of the NMR spectra
of the products 19c and 19d. As the crude NMR spectra for
the compounds synthesized were often difficult to interpret,
careful chromatography was performed before estimation of
the cis:trans ratios. A literature search reveals a modest col-
lection of papers describing the synthesis of 3,4-disubsti-
tuted THIQs[25] with only a few authors investigating the
stereochemical arrangement of the substituents on the het-
erocyclic ring.[25a–c] Pedrosa, Andrés and co-workers argue
Figure 5. nOe interactions for the cis-isomer of 19c.
1
The H NMR spectrum of compound 19d proved to be
that a coupling constant of zero Hertz between the hydro- fairly complex in the aliphatic region depicting the methyl
gens 3-H and 4-H is indicative of a trans 3,4-disubstituted groups, as there were ten methyl groups in total. However,
1
THIQ as a dihedral angle of 90o is only possible for a trans the region 2–4 ppm, in the H NMR spectrum, proved to
1
relationship.[25a] Perusal of the NMR spectroscopic data for be much more informative. It was clear from the H NMR
a number of trans-3,4-disubstituted THIQs described in the spectrum that there were two isomers in a ratio of 2:3, and
literature confirmed that coupling constant for the interac- a doublet of quartets (3.3 and 6.6 Hz) was evident for the
tion between the 3-H and 4-H protons was invariably zero minor diastereoisomer. A CH-correlation NMR spectrum
Hertz[25b,25c] or very close to it (for example 0.6 Hz).[21a] allowed us to identify this signal as belonging to 4-H of
Unfortunately we were unable to find well characterized ex- the minor isomer. Furthermore, a multiplet (δ = 2.85–2.96)
amples of 3,4-disubstituted THIQs bearing substituents in contained another two doublet of quartets: one for the
a cis relationship.
minor and major isomer’s 3-H protons with coupling con-
The 1H NMR spectrum of THIQ 19c, synthesized by stants 3.0 and 6.7 Hz, and 1.9 and 6.6 Hz, respectively. The
both the reductive mercuration and nBuLi methods, indi- minor component in the 1H NMR spectrum is probably the
cated it to contain a mixture of cis and trans isomers with cis-isomer by direct comparison with the 19c example. Of
what appeared to be the cis isomer being the major product. interest is that the 3-H and 4-H coupling constant for the
This was determined by looking at the coupling constant trans-isomer, although not zero, is smaller at 1.9 Hz. Per-
between the 3-H (dq, J = 3.0 and 6.7 Hz) and 4-H protons haps it is due to the constraints imposed on the molecule
(dq, J = 3.0 and 6.6 Hz) of this isomer, which turned out by the peri interactions between the 4-CH3 and the isopro-
to be 3.0 Hz. Evaluation of the coupling constant for the pyloxy group which prevents the 90o angle between the
other isomer proved to be impossible due to overlapping methyl groups and the subsequent coupling constant of
signals in this instance. Due to the paucity of examples zero Hertz.
which described cis-3,4-disubstituted THIQs we decided to
Due to the strong focus on stereoselective syntheses of
see if we could support the existence of the cis relationship natural compounds, including the THIQs,[27] we attempted
by way of other NMR spectroscopy techniques. It would to devise a strategy that would allow for a diastereoselective
not be unreasonable to assume that the 4-C methyl substit- hydroamination reaction, promoted by n-butyllithium. We
uent occupies a pseudo-axial position due to peri interac- thus synthesised the amines (R)-23a and (S)-23b, both con-
tions with the adjacent isopropyl group and that the 3-C taining the chiral 1-phenylethyl group, from precursor 17a.
methyl substituent is in an equatorial position (Figure 5). This chiral auxiliary has been used recently in the directed
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Intramolecular Hydroaminations
reductions of,[28a] or Grignard addition to,[28b] substituted tion or a n-butyllithium mediated approach is useful for the
isoquinolinium salts, with acceptable diastereoselectivities. synthesis of polysubstituted THIQs. Unfortunately these
We thus hoped that this auxiliary would also facially direct methodologies did not allow for the stereospecific synthesis
attack by the amine onto the styrene intermediate. Com- of the THIQ compounds by utilizing a chiral auxiliary.
pounds (R)-23a and (S)-23b were thus individually sub- However, we will continue to evaluate hydroamination reac-
jected to sub-stoichiometric amounts of n-butyllithium and tions as ways of synthesizing interesting THIQs and these
the reaction products were evaluated by NMR spectroscopy investigations will be divulged in due course.
1
(Scheme 4, Table 3). Evaluation of the H NMR spectra of
the crude products (1ЈR)-24a and (1ЈS)-24b, showed disap-
pointingly, that only a mixture of diastereomers with no
diastereoselectivity bias had been formed in the hydroamin-
ation reaction. In a similar fashion, the use of the reductive
mercuration methodology only afforded a diastereomeric
mixture. These results then confirmed that the cyclizations
involving the chiral benzylamine derivatives were unselec-
tive under our hydroamination conditions.
Experimental Section
1
General Remarks: The H and 13C NMR spectra were recorded on
a
Bruker AC-200 (200.13 MHz), Bruker AVANCE 300
(300.13MHz) or Bruker DRX 400 (400.13 MHz) spectrometer at
the frequency indicated. The chemical shifts are reported in parts
per million (ppm) with TMS as the internal standard in the 1H
NMR spectra and using δ = 77.00 (CDCl3) as reference peak in
the 13C NMR spectra. 1H and 13C NMR spectroscopic assignments
with the same superscript are interchangeable. IR spectra were re-
corded on a Bruker IFS-25 Fourier Transform spectrometer or on a
Bruker Vector-22 Fourier Transform spectrometer (liquid samples:
NaCl plates, solid samples: KBr plates). High resolution mass spec-
tra (HRMS) were recorded on a VG70 MS (Mass Spectrum CC
Pyramid data system) or on a VG70 SEQ (VG 11-250J or Marc II
data systems). Optical rotations were determined on a Jasco DIP
3-70 instrument at 22 °C at the sodium D line. [α]D values are given
in 10–1 deg·cm2·g–1. The melting points were determined on a Re-
ichert hot-stage microscope and are uncorrected. For the silica gel
chromatography Macherey–Nagel Kieselgel 60 (particle size 0.063–
2.00 mm) was used. Aluminium-backed Macherey–Nagel ALUG-
RAM Sil G/UV254 was used for thin layer chromatography (TLC).
All the solvents used for reactions and chromatography were dis-
tilled prior to use according to the standard procedures.[29]
Scheme 4. Reagents and conditions: (a) (R)- or (S)-1-phenylethyla-
mine, p-TSA, benzene or toluene, Dean–Stark apparatus, reflux, 18
h; (b) NaBH4, MeOH, H2O (1 drop), 0 °C to room temp., 18 h; (c)
nBuLi (2ϫ16 mol-%), room temp., 6 h, then 60 °C, 18 h. For yields
see Table 3.
Representative Procedure for the Preparation of Substituted Amines
18: Aldehyde 17 (ca. 1 g, ca. 4 mmol), the amine (ca. 3 mol equiv.)
and p-TSA (ca. 0.1 mol equiv.) were dissolved in benzene (50 cm3)
and were heated at reflux, with stirring, using a Dean–Stark head
under N2 for 24 h. On completion of the reaction (monitored by
TLC) the benzene was evaporated under reduced pressure. The re-
sulting material was diluted with CH2Cl2 (30 cm3) and washed with
aqueous saturated NaHCO3 (30 cm3). The organic layer was then
dried (MgSO4) to obtain the imine in reasonably pure form. The
residue was then dissolved in MeOH (10 cm3) and cooled to 0 °C
over ice. To this solution, NaBH4 (ca. 1.2 mol equiv.) was added
together with a drop of H2O and the mixture was stirred for one
hour at 0 °C. On completion of the reaction, the MeOH was re-
moved under reduced pressure. The residue was diluted with EtOAc
(30 cm3) and washed with H2O (2ϫ30 cm3). The organic layer was
then separated and dried (MgSO4). The solvent was then removed
under reduced pressure to afford amine 18 as a yellow oil, in yields
of 89% to quantitative. The amines 18 were used without any fur-
ther purification in the next reaction.
Table 3. Yields for tetrahydroisoquinolines 24a and 24b (reductive
mercuration and sub-stoichiometric n-butyllithium procedure).
Entry
Chiral auxilary
17Ǟ23[a] Hg(OAc)2/NaBH4 nBuLi
23Ǟ24
23Ǟ24
a
b
(R)-CH(Me)Ph
(S)-CH(Me)Ph
89%
98%
76%
87%
75%
79%
[a] Yields over two steps.
Finally, quaternization of the diastereomeric mixture 24a
with methyl iodide gave a solid from which 3-(1ЈR,3R)-25
was recrystallized from MeOH/EtOAc (Scheme 5). A sin-
gle-crystal X-ray structural determination was subsequently
done to confirm the postulated structure.[18a]
N-[(2-Allyl-3-isopropoxy-4-methoxyphenyl)methyl]benzylamine (18a):
This product was isolated as a yellow oil (1.39 g, 99%), starting
from aldehyde 17a (1.01 g, 4.27 mmol) and benzylamine. IR (film):
Scheme 5. Reagents and conditions: (a) MeI, recrystallized from
MeOH/EtOAc.
ν
max = 3322, 3062, 2974, 2835, 1637, 1600, 1580, 1487, 1437, 1380,
˜
1271 cm–1. H NMR (300 MHz, CDCl3): δ = 1.26 [d, J = 6.2 Hz,
6 H, CH(CH3)2], 1.56 (br. s, 1 H, NH), 3.51 (br. d, J = 5.8 Hz, 2
H, ArCH2CH), 3.75 (s, 2 H, ArCH2N),a 3.79–3.84 (m, 2 H,
NHCH2Ph),a 3.80 (s, 3 H, OCH3), 4.50 [sept, J = 6.2 Hz, 1 H,
CH(CH3)2], 4.80–4.94 (m, 2 H, CH=CH2), 5.86–5.95 (m, 1 H,
1
Conclusions
In this paper we have thus demonstrated that the hydro-
amination approach, utilizing either a reductive mercura- CH=CH2), 6.74 (d, J = 8.4 Hz, 1 H, ArH), 7.02 (d, J = 8.4 Hz, 1 H,
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W. A. L. van Otterlo et al.
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ArH) and 7.22–7.33 (m, 5 H, 5ϫArH) ppm. 13C NMR (75 MHz,
137.6 (C), 143.4 (CH), 144.4 (C), 151.5 (C) ppm. MS: m/z 291 (M+,
CDCl3):
δ
=
22.6 [CH(CH3)2], 30.7 (ArCH2CH), 50.5 46%), 248 (77), 206 (26), 176 (34), 143 (100), 115 (27), 91 (22), 43
(ArCH2NH),b 53.5 (NHCH2Ph),b 55.5 (OCH3), 74.4 [CH(CH3)2], (42). HRMS: calcd. for C18H29NO2: 291.2194, found: 291.2198.
109.9 (CH), 114.6 (CH), 124.1 (CH), 126.8 (CH), 128.2 (2 ϫ CH),
N-{[4-Methoxy-2-(1-phenylprop-1-enyl)-3-propoxyphenyl]-
128.3 (2ϫCH), 131.6 (C), 132.6 (C), 137.3 (CH), 140.4 (C), 145.1
methyl}butylamine (18e): This product was isolated as a orange-
(C), 151.8 (C) ppm. MS: m/z 325 (M+, 15%), 234 (29), 218 (23), 177
brown oil (0.46 g, 90 %), starting from aldehyde 20 (0.43 g,
(36), 176 (100), 161 (38), 91 (96). HRMS: calcd. for C21H27NO2:
1.39 mmol) and n-butylamine. IR (film): ν
= 2955, 1588, 1446,
˜
max
325.2042, found: 325.2050.
1271 cm–1. H NMR (300 MHz, CDCl3): δ = 0.70 (t, J = 7.2 Hz,
3 H, CH2CH3), 1.06 [d, J = 6.1 Hz, 3 H, CH(CH3)CH3], 1.11 [d,
J = 6.1 Hz, 3 H, CH(CH3)CH3], 1.20–1.53 (m, 4 H, 2ϫCH2), 1.62
(d, J = 6.9 Hz, 3 H, C=CHCH3), 2.04 (s, 1 H, NH), 2.22–2.50 (m,
2 H, NHCH2CH2), 3.75–3.95 (m, 5 H, OCH3 and ArCH2NH),
4.22–4.30 [m, 1 H, CH(CH3)2], 6.50 (q, J = 6.9 Hz, 1 H,
C=CHCH3), 6.99 (d, J = 8.5 Hz, 1 H, ArH), 7.20–7.30 (m, 5 H,
5ϫArH), 7.70 (d, J = 8.5 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.3 (CH3), 16.2 (CH3), 19.8 (CH2), 22.4 [CH(CH3)-
CH3], 22.7 [CH(CH3)CH3], 28.0 (CH2), 45.9 (NHCH2CH2),a 47.2
(ArCH2NH),a 55.5 (OCH3), 75.1 [CH(CH3)2], 111.9 (CH), 125.5
(C), 125.8 (2ϫCH), 126.5 (CH), 127.2 (CH), 128.3 (CH), 128.6
(2ϫCH), 134.4 (C), 135.7 (C), 140.3 (C), 145.0 (C), 153.7 (C) ppm.
MS: m/z 367 (M+, 91%), 368 (27), 352 (19), 324 (35), 310 (30), 253
(61), 252 (100), 237 (24), 225 (18), 213 (18), 165 (23), 91 (22).
HRMS: calcd. for C24H33NO2: 367.2511, found: 367.2510.
1
N-[(2-Allyl-3-isopropoxy-4-methoxyphenyl)methyl]propylamine (18b):
This product was isolated as a yellow oil (1.18 g, 99%), starting
from aldehyde 17a (1.01 g, 4.31 mmol) and n-propylamine. IR
(film): νmax = 2972, 2835, 1637, 1600, 1487, 1438, 1380, 1273 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 7.4 Hz, 3 H, CH3),
1.18 [d, J = 6.2 Hz, 6 H, CH(CH3)2], 1.37–1.49 (m, 2 H, CH2CH3),
2.51 (t, J = 7.2 Hz, 2 H, NHCH2CH2), 3.46–3.47 (m, 2 H, ArCH2-
CH),a 3.61 (s, 2 H, ArCH2N),a 3.73 (s, 3 H, OCH3), 4.43 [sept, J
= 6.2 Hz, 1 H, CH(CH3)2], 4.81–4.91 (m, 2 H, CH=CH2), 5.81–
5.94 (m, 1 H, CH=CH2), 6.67 (d, J = 8.4 Hz, 1 H, ArH), 6.92 (d,
J = 8.4 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.8
(CH3), 22.5 [CH(CH3)2], 23.1 (CH2CH3), 30.7 (ArCH2CH), 51.2
(ArCH2N),b 51.6 (NHCH2CH2),b 55.5 (OCH3), 74.3 [CH(CH3)2],
109.9 (CH), 114.5 (CH), 123.9 (CH), 132.0 (C), 132.3 (C), 137.4
(CH), 145.0 (C), 151.7 (C) ppm. MS: m/z 276 (M+, 85%), 177 (76),
176 (100), 161 (31), 147 (28). HRMS: calcd. for C17H26NO2 (M+
H): 276.1964, found: 276.1964.
–
(1R)-N-[(2-allyl-3-isopropoxy-4-methoxyphenyl)methyl]-(1-phenyl-
ethyl)amine (23a): This product was isolated as a yellow oil
(0.644 g, 89%), starting from aldehyde 17a (0.50 g, 2.13 mmol) and
(R)-(+)-α-methylbenzylamine. [α]2D5 = +26.0 (c = 1.00, CHCl3); see
below 23b for characterization details.
N-{[3-Isopropoxy-4-methoxy-2-(1-methylprop-2-en-1-yl)phenyl]-
methyl}benzylamine (18c): This product was isolated as a yellow oil
(0.445 g, 92%), starting from aldehyde 17b (0.35 g, 1.42 mmol) and
benzylamine. IR (film): νmax = 2975, 2935, 2836, 1632, 1598, 1484,
˜
(1S)-23b: This compound was isolated as a yellow oil (0.710 g,
98%), starting from aldehyde 17a (0.50 g, 2.13 mmol) and (S)-(–)-
α-methylbenzylamine. [α]2D5 = –25.3 (c = 0.83, CHCl3). IR (film):
1453, 1439, 1381, 1284 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.24 [d, J = 6.2 Hz, 3 H, CH(CH3)CH3], 1.27 [d, J = 6.2 Hz, 3 H,
CH(CH3)CH3], 1.36 (d, J = 7.2 Hz, 3 H, CHCH3), 1.40–1.50 (br.
s, 1 H, NH), 3.67–3.80 (m, 2 H, ArCH2N),a 3.80 (s, 3 H, OCH3),
3.87 (s, 2 H, NHCH2Ph),a 4.27–4.31 [m, 1 H, ArCH(CH3)], 4.57
[sept, J = 6.2 Hz, 1 H, CH(CH3)2], 4.92–4.99 (m, 2 H, CH=CH2),
6.08–6.16 (m, 1 H, CH=CH2), 6.75 (d, J = 8.4 Hz, 1 H, ArH), 7.09
(d, J = 8.4 Hz, 1 H, ArH), 7.22–7.36 (m, 5 H, 5ϫArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 18.7 [ArCH(CH3)], 22.4 and 22.5
[CH(CH3 )2 ], 34.4 [ArCH(CH3 )], 50.4 (ArCH2 N),b 53.7
(NHCH2Ph),b 55.5 (OCH3), 74.0 [CH(CH3)2], 110.0 (CH), 112.3
(CH), 124.9 (CH), 126.4 (C), 126.7 (CH), 127.7 (2ϫCH), 128.2
(2ϫCH), 131.8 (C), 137.7 (C), 140.5 (C), 143.2 (CH), 151.5 (C)
ppm. MS: m/z 339 (M+, 13%), 296 (7), 248 (46), 191 (42), 190
(100), 175 (61). HRMS: calcd. for C22H29NO2: 339.2198, found:
339.2196.
ν
= 2975, 1637, 1601, 1487, 1435, 1370, 1271 cm–1. 1H NMR
˜
max
(300 MHz, CDCl3, no signal observed for NH): δ = 1.25 [d, J =
6.2 Hz, 6 H, CH(CH3)2], 1.34 (d, J = 6.6 Hz, 3 H, CH3), 3.44–3.46
(m, 2 H, ArCH2CH), 3.52 (distorted AB system, 2 H, J ≈ 6 Hz,
ArCH2NH), 3.77–3.82 [s and m, 4 H, OCH3 and NHCH(CH3)],
4.49 [sept, J = 6.2 Hz, 1 H, CH(CH3)2], 4.77 [br. d, J = 17.1 Hz, 1
H, CH=C(H)H], 4.87 [dd, J = 10.2 and 1.3 Hz, 1 H, CH=C(H)H],
5.82–5.92 (m, 1 H, CH=CH2), 6.73 (d, J = 8.4 Hz, 1 H, ArH), 6.95
(d, J = 8.4 Hz, 1 H, ArH), 7.24–7.26 (m, 1 H, ArH), 7.22–7.28 (m,
4 H, 4 ϫ ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.7
[CH(CH3)2], 24.4 (ArCH2CH), 30.7 (CH3), 49.3 (ArCH2N)b, 55.6
(OCH3), 58.1 [NHCH(CH3)]b, 74.4 [CH(CH3)2], 110.0 (CH), 114.5
(CH), 124.3 (CH), 126.8 (2ϫCH), 126.9 (CH), 128.4 (2 ϫ CH),
132.0 (C), 132.6 (C), 137.5 (CH), 145.1 (C), 145.7 (C), 151.8 (C)
ppm. MS: m/z 339 (M+, 22%), 248 (60), 218 (42), 177 (88), 161 (60),
144 (40), 17 (52), 105 (100), 77 (42). HRMS: calcd. for C22H29NO2:
339.2198, found: 339.2198.
N-{[3-Isopropoxy-4-methoxy-2-(1-methylprop-2-en-1-yl)phenyl]-
methyl}propylamine (18d): This product was isolated as a yellow oil
(1.14 g, 97%) starting from aldehyde 17b (1.00 g, 4.03 mmol) and
n-propylamine. IR (film): ν
= 3079, 2979, 2934, 2873, 1633,
Representative Procedure for Preparing Substituted 5-Isopropoxy-6-
˜
max
1598, 1577, 1485, 1381, 1376, 1274 cm–1 1H NMR (300 MHz, methoxy-1,2,3,4-tetrahydroisoquinolines 19. Reductive Mercuration
.
CDCl3, no signal observed for NH): δ = 0.92 (t, J = 7.2 Hz, 3 H,
CH2CH3), 1.24 [d, J = 6.2 Hz, 3 H, CH(CH3)CH3], 1.27 [d, J =
6.2 Hz, 3 H, CH(CH3)CH3], 1.40 [d, J = 7.2 Hz, 3 H, ArCH(CH3)],
1.45–1.55 (m, 2 H, CH2 CH3 ), 2.58 (t, J = 7.2 Hz, 2 H,
Procedure: Hg(OAc)2 (1.1 mol equiv.) was added to amine 18 (0.3–
0.7 mmol) dissolved in a solution of THF (10 cm3) and H2O
(10 cm3), and the reaction mixture was stirred at room temp. for
24 h. NaOH solution (3 , 5 cm3) was then added and the mixture
NHCH2CH2), 3.63–3.74 (m, 2 H, ArCH2NH), 3.80 (s, 3 H, OCH3), was stirred for a further 20 min. A solution of NaBH4 (1.1 mol
4.28–4.34 [m, 1 H, ArCH(CH3)], 4.57 [sept, J = 6.2 Hz, 1 H, equiv.) in NaOH (3 , 5 cm3) was then added and the reaction
CH(CH3)2], 4.98–5.04 (m, 2 H, CH=CH2), 6.11–6.22 (m, 1 H, mixture was then stirred for 24h at room temp. After standing for
CH=CH2), 6.75 (d, J = 8.4 Hz, 1 H, ArH), 7.06 (d, J = 8.4 Hz, 1
30 min the mixture was decanted and filtered twice through Celite.
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.8 (CH3), 18.8
H2O (30 cm3) was added and the mixture was extracted with Et2O
(CH2CH3), 22.5 and 22.6 [CH(CH3)2], 23.2 (ArCHCH3), 34.5 (3ϫ10 cm3). The organic phase was dried (MgSO4) and then evap-
(ArCHCH3), 51.0 (ArCH2N),a 51.8 (NHCH2CH2),a 55.5 (OCH3), orated under reduced pressure to obtain the crude residue. This
74.1 [CH(CH3)2], 110.1 (CH), 112.4 (CH), 124.9 (CH), 132.1 (C),
was purified by column chromatography (10% MeOH/CH2Cl2) to
5342
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5337–5345

Intramolecular Hydroaminations
afford 5-isopropoxy-6-methoxy-1,2,3,4-tetrahydroisoquinolines 19
as oils.
isomer, not all carbon atoms accounted for): δ = 9.9 (CHCH3),
21.5 and 22.1 [CH(CH3)2], 49.0 (CH2), 55.7 (OCH3),e 57.4 (1-C),e
59.4 (3-C),e 74.3 [CH(CH3)2], 110.0 (CH), 120.8 (CH), 128.7 (CH),
139.7 (C), 144.9 (C), 150.6 (C) ppm. MS: m/z 339 (M+, 36%), 325
(33), 324 (89), 206 (55), 164 (94), 91 (100), 43 (61). HRMS: calcd.
for C22H29NO2: 339.2198, found: 339.2200.
2-Benzyl-5-isopropoxy-6-methoxy-3-methyl-1,2,3,4-tetrahydroiso-
quinoline (19a): This product was isolated as a yellow oil (0.082 g,
82%), starting from amine 18a (0.10 g, 0.31 mmol). IR (film): ν
˜
max
= 1645, 1575, 1277 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.13
(d, J = 6.5 Hz, 3 H, CHCH3), 1.28 [d, J = 6.1 Hz, 3 H, CH(CH3)-
CH3], 1.29 [d, J = 6.1 Hz, 3 H, CH(CH3)CH3], 2.64 (dd, J = 5.9
and 16.9 Hz, 1 H, 4-Heq), 2.91 (dd, J = 4.9 and 16.9 Hz, 1 H, 4
(؎)-5-Isopropoxy-6-methoxy-3,4-cis-dimethyl-2-propyl-1,2,3,4-tetra-
hydroisoquinoline and (؎)-5-Isopropoxy-6-methoxy-3,4-trans-di-
methyl-2-propyl-1,2,3,4-tetrahydroisoquinoline (19d): This product
was isolated as a yellow oil (0.086 g, 86%) (2:3 cis:trans), starting
H
ax), 3.04–3.10 (m, 1 H, 3-H), 3.48–3.81 (m, 4 H, 1-H and
NCH2Ph), 3.80 (s, 3 H, OCH3), 4.48 [sept, J = 6.2 Hz, 1 H,
CH(CH3)2], 6.64 (d, J = 8.4 Hz, 1 H, ArH), 6.71 (d, J = 8.4 Hz, 1
H, ArH), 7.22–7.38 (m, 5 H, 5ϫArH) ppm. 13C NMR (75 MHz,
CDCl3, 1 C signal not observed in aromatic region of spectrum): δ
= 15.0 (CH3), 22.6 and 22.7 [CH(CH3)2], 30.8 (4-C), 51.0 (1-C),a
51.7 (NCH2Ph),a 55.7 (3-C), 57.2 (OCH3), 74.1 [CH(CH3)2], 110.2
(CH), 121.0 (CH), 126.7 (CH), 127.5 (C), 128.4 (2ϫCH), 128.8
(2ϫCH), 139.3 (C), 144.6 (C), 150.6 (C) ppm. MS: m/z 325 (M+,
64%), 310 (100), 266 (37), 192 (72), 176 (41), 150 (99), 149 (64), 91
(55). HRMS: calcd. for C21H27NO2: 325.2042, found: 325.2042.
from amine 18d (0.10 g, 0.34 mmol). IR (film): ν
= 1647, 1597,
˜
max
1493, 1465, 1439, 1380, 1278 cm–1. 1H NMR (300 MHz, CDCl3,
signals observed for cis isomer): δ = 0.84 (d, J = 6.6 Hz, 3 H,
ArCHCH3), 0.91 (t, J = 7.4 Hz, 3 H, NCH2CH2CH3), 1.12–1.17
[m, 6 H, CH(CH3)2], 1.37 (d, J = 6.0 Hz, 3 H, NCHCH3), 1.50–
1.57 (m, 2 H, NCH2CH2CH3), 2.24 [dt, J = 12.4 and 6.9 Hz, 1 H,
NC(H)HCH2CH3], 2.60 (dq, J = 3.3 and 6.6 Hz, 1 H, 4-H), 2.75
[dt, J = 12.4 and 8.0 Hz, 1 H, NC(H)HCH2CH3], 2.85–2.95 (m, 1
H, 3-H), 3.32 [d, J = 14.9 Hz, 1 H, ArC(H)HN], 3.79 (s, 3 H,
OCH3), 3.95 [d, J = 14.9 Hz, 1 H, ArC(H)HN], 4.54–4.58 [m, 1 H,
CH(CH3)2], 6.71 (br. s, 2 H, 2 ϫ ArH); (300 MHz, CDCl3, signals
observed for trans isomer): δ = 0.94 (t, J = 7.3 Hz, 3 H,
NCH2CH2CH3), 1.12–1.17 [m, 6 H, CH(CH3)2], 1.28 (d, J =
6.7 Hz, 3 H, ArCHCH3), 1.37 (d, J = 6.0 Hz, 3 H, NCHCH3),
1.50–1.57 (m, 2 H, NCH2CH2CH3), 2.47 (t, J = 7.2 Hz, 2 H,
NCH2CH2CH3), 2.85–2.95 (m, 2 H, 3-H and 4-H), 3.42 [d, J =
15.1 Hz, 1 H, ArC(H)HN], 3.72 [d, J = 15.1 Hz, 1 H, ArC(H)HN],
3.80 (s, 3 H, OCH3), 4.54–4.58 [m, 1 H, CH(CH3)2], 6.71 (br. s, 2
H, 2ϫArH) ppm. 13C NMR (75 MHz, CDCl3, signals observed
for cis isomer): δ = 9.9 (CH3), 14.8 (CH3), 17.3 (CH3), 19.6 (CH2),
22.3 (CH3), 23.0 (CH3), 35.9 (4-C), 54.8 (1-C), 55.0 (NCH2), 55.8
(OCH3), 56.8 (3-C), 74.1 [CH(CH3)2], 110.3 (CH), 120.7 (CH),
127.9 (C), 136.5 (C), 143.8 (C), 150.5 (C); (75 MHz, CDCl3, signals
observed for trans isomer): δ = 11.9 (CH3), 11.9 (CH3), 20.8 (CH2),
21.4 (CH3), 22.2 (CH3), 23.1 (CH3), 36.1 (4-C), 49.5 (1-C), 55.7
(OCH3), 56.5 (NCH2), 56.9 (3-C), 73.9 [CH(CH3)2], 110.0 (CH),
120.8 (CH), 127.4 (C), 134.3 (C), 144.9 (C), 150.6 (C) ppm. MS:
m/z 291 (M+, 56%), 276 (100), 262 (78), 248 (31), 206 (51), 164
(99). HRMS: calcd. for C18H29NO2: 291.2198, found: 291.2199.
5-Isopropoxy-6-methoxy-3-methyl-2-propyl-1,2,3,4-tetrahydroiso-
quinoline (19b): This product was isolated as a yellow oil (0.18 g,
90%), starting from amine 18b (0.20 g, 0.72 mmol). IR (film): ν
˜
max
= 1646, 1599, 1473, 1449, 1377, 1278 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H, NCH2CH2CH3), 1.07 (d, J
= 6.5 Hz, 3 H, CHCH3), 1.26 [d, J = 6.2 Hz, 3 H, CH(CH3)CH3],
1.27 [d, J = 6.2 Hz, 3 H, CH(CH3)CH3], 1.54–1.59 (m, 2 H,
NCH2CH2), 2.38–2.45 [m, 1 H, NC(H)HCH2], 2.53–2.63 [m, 2 H,
NC(H)HCH2 and 4-Hax], 2.88 (dd, J = 4.9 and 16.9 Hz, 1 H, 4
Heq), 2.95–3.00 (m, 1 H, 3-H), 3.62–3.75 (m, 2 H, 1-H), 3.80 (s, 3
H, OCH3), 4.47 [br. sept, J = 6.2 Hz, 1 H, CH(CH3)2], 6.72 (s, 2
H, 2 ϫ ArH) ppm. 13 C NMR (75 MHz, CDCl3 ): δ = 12.0
(NCH2CH2CH3), 15.4 (CHCH3), 20.4 (NCH2CH2), 22.6 and 22.7
[CH(CH3)2], 31.1 (4-C), 51.6 (NCH2CH2),a 51.9 (1-C),a 54.9 (3-
C),a 55.8 (OCH3), 74.1 [CH(CH3)2], 110.2 (CH), 121.0 (CH), 127.8
(C), 129.0 (C), 144.6 (C), 150.7 (C) ppm. MS: m/z 277 (M+, 47%),
276 (26), 262 (97), 248 (100), 150 (42), 43 (75). HRMS: calcd. for
C17H27NO2: 277.2042, found: 277.2042.
(؎)-2-Benzyl-5-isopropoxy-6-methoxy-3,4-cis-dimethyl-1,2,3,4-tetra-
hydroisoquinoline and (؎)-2-benzyl-5-isopropoxy-6-methoxy-3,4-
trans-dimethyl-1,2,3,4-tetrahydroisoquinoline (19c): This product
was isolated as a yellow oil (0.126 g, 63%) (2:1 cis:trans), starting
5-Isopropoxy-6-methoxy-3-methyl-2-[(1R)-1-phenylethyl]-1,2,3,4-
tetrahydroisoquinoline (24a): This product was isolated as a yellow
oil (0.152 g, 76%) (1:1 diastereoisomeric mixture), starting from
from amine 18c (0.20 g, 0.59 mmol). IR (film): ν
= 1648, 1600, amine 23a (0.20 g, 0.59 mmol). After chromatography the dia-
˜
max
1494, 1435, 1381, 1368, 1281 cm–1. 1H NMR (300 MHz, CDCl3, stereoisomers were obtained in a 4:1 ratio with the major product’s
signals observed for cis isomer): δ = 1.18 (d, J = 6.2 Hz, 3 H,
CHCH3), 1.23–1.27 [m, 6 H, CH(CH3)2], 1.38 (d, J = 6.1 Hz, 3 H,
CHCH3), 2.78 (dq, J = 3.0 and 6.6 Hz, 1 H, 4-H), 3.03 (dq, J =
3.0 and 6.6 Hz, 1 H, 3-H),a 3.11 [d, J = 13.2 Hz, 1 H, ArC(H)-
HN],a 3.18 [d, J = 15.0 Hz, 1 H, NC(H)HPh],a 3.72–3.80 [m under
data being reported below (the minor diasteriosiomer was epimeric
to that reported for 24b in the next experiment). IR (film): ν
=
˜
max
1668, 1601, 1493, 1440, 1369, 1338, 1278 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 0.84 (d, J = 6.6 Hz, 3 H, CH3), 1.22 [d, J
= 6.2 Hz, 3 H, CH(CH3)CH3], 1.24 [d, J = 6.2 Hz, 3 H, CH(CH3)-
OCH3, 1 H, NC(H)HPh],b 3.78 (s, 3 H, OCH3), 4.22 [d, J = CH3], 1.40 [d, J = 6.6 Hz, 3 H, NCH(CH3)Ph], 2.62 (dd, J = 16.7
13.2 Hz, 1 H, ArC(H)HN],b 4.56 [sept, J = 6.2 Hz, 1 H, CH- and 2.0 Hz, 1 H, 4-Heq), 2.76 (dd, J = 16.7 and 5.3 Hz, 1 H, 4-
(CH3)2], 6.55 (d, J = 8.4 Hz, 1 H, ArH), 6.67 (d, J = 8.4 Hz, 1 H,
ArH), 7.20–7.32 (m, 3 H, 3ϫArH), 7.39–7.41 (m, 2 H, 2ϫArH);
(300 MHz, CDCl3, signals observed for trans isomer, not all pro-
tons accounted for): δ = 0.90 (d, J = 6.6 Hz, 3 H, CHCH3), 2.90–
Hax), 3.10–3.17 (m, 1 H, 3-H), 3.58 [d, J = 15.2 Hz, 1 H, ArC(H)-
HN], 3.65 [q, J = 6.6 Hz, 1 H, NCH(CH3)Ar], 3.81 (s, 3 H, OCH3),
4.01 [d, J = 15.2 Hz, 1 H, ArC(H)HN], 4.43 [sept, J = 6.2 Hz, 1
H, CH(CH3)2], 6.75 (br. s, 2 H, 2 ϫ ArH), 7.20–7.41 (m, 5 H,
2.94 (m,2 H, 3-H and 4-H), 3.45 [br. d, J = 15.0 Hz, 1 H, C(H)- 5ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.4 (CHCH3),
H], 3.79 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3, signals
observed for cis isomer): δ = 14.9 (CHCH3), 17.9 (CHCH3), 22.3
22.4 and 22.5 [CH(CH3)2], 22.9 (CHCH3), 30.9 (4-C), 46.5 (1-C),a
47.3 (NCHCH3),a 55.8 (OCH3), 61.0 (3-C), 74.2 [CH(CH3)2], 110.2
[CH(CH3)2], 23.1 (4-C)c, 36.2 (3-C)c, 55.8 (OCH3), 57.4 (1-C)d, 57.7 (CH), 121.3 (CH), 126.8 (CH), 127.2 (2ϫCH), 127.8 (C), 128.4
(NCH2Ph)d, 74.1 [CH(CH3)2], 110.3 (CH), 120.6 (CH), 126.6 (CH), (2ϫCH), 128.8 (C), 145.1 (C), 145.9 (C), 150.7 (C) ppm. MS: m/z
128.2 (2 ϫ CH), 128.5 (2ϫCH), 134.1 (C), 136.4 (C), 140.6 (C),
143.7 (C), 150.5 (C); (75 MHz, CDCl3, signals observed for trans
339 (M+, 19%), 324 (81), 166 (34), 148 (26), 105 (100), 43 (43).
HRMS: calcd. for C22H29NO2: 339.2198, found: 339.2198.
Eur. J. Org. Chem. 2007, 5337–5345
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5343

W. A. L. van Otterlo et al.
5-Isopropoxy-6-methoxy-3-methyl-2-[(1S)-1-phenylethyl]-1,2,3,4- amine 18 (0.3–0.7 mmol) in THF (10 cm3). The solution was stirred
FULL PAPER
tetrahydroisoquinoline (24b): This product was isolated as a yellow
oil (0.174 g, 87%) (1:1 diastereoisomeric mixture), starting from
amine 6d (0.20 g, 0.59 mmol). After chromatography the diastereo-
isomers were obtained in a 3:2 ratio with the major product’s data
being reported below. (the minor diasteriosiomer was epimeric to
for 6 h at room temp. after which a further portion of nBuLi (0.16
equiv., 1.4 ) was added if required, and the mixture was sub-
sequently heated for another 24 h at 60 °C. The resulting mixture
was then extracted with Et2O (3 ϫ 10 cm3) which was dried
(MgSO4). The organic solvent was removed in vacuo and the crude
residue was then purified using column chromatography (5–20%
EtOAc/hexane) to afford the substituted 5-isopropoxy-6-methoxy-
3-methyl-1,2,3,4-tetrahydroisoquinolines 19, as light oils. The fol-
lowing THIQs 19 were synthesized according to this procedure. See
that reported for 24a in the previous experiment). IR (film): ν
˜
max
= 1665, 1600, 1493, 1451, 1371, 1314, 1278 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 1.00 (d, J = 6.6 Hz, 3 H, CHCH3), 1.27
[d, J = 6.2 Hz, 3 H, CH(CH3)CH3], 1.30 [d, J = 6.3 Hz, 3 H,
CH(CH3)CH3], 1.36 [d, J = 6.6 Hz, 3 H, NCH(CH3)Ph], 2.71 (dd, also the reductive mercuration section for characterization details.
J = 3.3 and 16.7 Hz, 1 H, 4-Heq), 2.95 (dd, J = 5.3 and 16.7 Hz, 1
19a: This product was isolated as a yellow oil (0.087 g, 87%), start-
H, 4-Hax), 3.39–3.59 (m, 3 H, 1-H and 3-Ha), 3.68 (q, J = 6.6 Hz,
ing from amine 18a (0.10 g, 0.31 mmol). When the nBuLi-mediated
1 H, NCH(CH3)],a 3.77 (s, 3 H, OCH3), 4.45 [sept, J = 6.2 Hz, 1
cyclization was performed at room temperature on 18a (0.10 g,
H, CH(CH3)2], 6.56 (d, J = 8.4 Hz, 1 H, ArH), 6.66 (d, J = 8.4 Hz,
0.31 mmol) an intermediate 22 was observed by TLC. Work-up as
described above and purification by a short silica gel plug afforded
N-{(3-Isopropoxy-4-methoxy-2-[(1E)-prop-1-en-1-yl]phenyl)-
1 H, ArH), 7.19–7.41 (m, 5 H, 5ϫArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.9 (CHCH3), 19.7 [NCH(CH3)Ph], 22.6 and 22.8
[CH(CH3)2], 31.2 (4-C), 47.2 [NCH(CH3)Ph and 3-C], 55.8
methyl}benzylamine (22) which was identified by NMR spec-
(OCH3), 60.3 (1-C), 74.3 [CH(CH3)2], 110.1 (CH), 120.9 (CH),
1
troscopy. H NMR (300 MHz, CDCl3): δ = 1.20 [d, J = 6.1 Hz, 6
126.6 (CH), 127.4 (2 ϫ CH), 128.1 (C), 128.2 (2 ϫ CH), 128.8 (C),
H, CH(CH3)2], 1.52 (dd, J = 6.8 and 1.6 Hz, 3 H, CHCHCH3),
144.9 (C), 146.0 (C), 150.6 (C) ppm. MS: m/z 339 (M+, 26%), 324
1.91 (br. s, 1 H, NH), 3.66 (s, 2 H, ArCH2N),a 3.72 (s, 2 H,
(75), 192 (29), 150 (53), 105 (100), 43 (52). HRMS: calcd. for
C22H29NO2: 339.2198, found: 339.2196.
NCH2Ph),a 3.82 (s, 3 H, OCH3), 4.23 [sept, J = 6.1 Hz, 1 H,
CH(CH3)2], 5.77–5.88 (m, 1 H, CHCHCH3), 6.34 (br. d, J =
6.1 Hz, 1 H, CHCHCH3), 6.79 (d, J = 8.3 Hz, 1 H, ArH), 7.03 (d,
J = 8.3 Hz, 1 H, ArH), 7.20–7.33 (m, 5 H, 5ϫArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 15.2 (CH3), 22.5 [CH(CH3)2], 50.8
(ArCH2N),b 53.0 (NCH2Ph),b 55.6 (OCH3), 75.2 [CH(CH3)2],
110.2 (CH), 123.8 (CH), 124.5 (CH), 126.8 (CH), 128.1 (2 ϫ CH),
128.3 (2ϫCH), 129.1 (CH), 131.3 (C), 131.6 (C), 140.4 (C), 144.7
(C), 152.1 (C). This compound was then subjected to nBuLi (0.16
equiv.) at 60 °C for 18 h and compound 19a was obtained, after
work-up and purification by silica gel column chromatography
(10% MeOH/CH2Cl2).
Bis[(2-benzyl-5-isopropoxy-6-methoxy-1,2,3,4-tetrahydroisoquinolin-
3-yl)methyl]mercury (21): During the preparation of THIQ 19a
some off-white solid was observed prior to the reduction step with
NaBH4. Some of this material was collected and crystals suitable
for structural determination by X-ray crystallography were ob-
tained (m.p. 130–132 °C recrystalised from EtOAc/hexane). IR
(film): ν
= 1727, 1602, 1493, 1439, 1381, 1332, 1279 cm–1. 1H
˜
max
NMR (300 MHz, CDCl3, NMR interpretation is for only one unit
of the dimeric pair): δ = 1.05 [dd, J = 13.1 and 5.1 Hz, 1 H, C(H)-
H-Hg], 1.05 [dd, J = 13.1 and 6.1 Hz, 1 H, C(H)H-Hg], 1.22–1.25
[m, 6 H, CH(CH3)2], 2.57 (dd, J = 6.5 and 16.9 Hz, 1 H, 4-Heq),
2.93 (dd, J = 4.6 and 16.9 Hz, 1 H, 4-Hax), 3.42–3.51 [m, 2 H,
ArC(H)HN and NC(H)HPh], 3.63 [d, J = 15.7 Hz, 1 H, NC(H)-
HPh], 3.76–3.80 (m under OCH3, 1 H, CHCH2Hg), 3.78 (s, 3 H,
OCH3), 3.87 [d, J = 13.5 Hz, 1 H, ArC(H)HN], 4.39–4.47 [m, 1 H,
CH(CH3)2], 6.58 (d, J = 8.4, 1 H, ArH), 6.66 (d, J = 8.4, 1 H, ArH),
7.21–7.38 (m, 5 H, 5ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 22.7 and 22.8 [CH(CH3)2], 33.5 (4-C), 43.5 (CH2-Hg), 51.7 (1-
C),a 55.9 (OCH3), 57.1 (NCH2Ph),a 57.4 (3-C),a 74.3 [CH(CH3)2],
19b: This product was isolated as a yellow oil (0.18 g, 90%), start-
ing from amine 18b (0.20 g, 0.72 mmol).
(؎)-19c (3,4-cis/trans isomers): This product was isolated as a yel-
low oil (0.126 g, 63 %) (5:1 cis:trans), starting from amine 18c
(0.20 g, 0.59 mmol).
(؎)-19d (3,4-cis/trans isomers): This product was isolated as a yel-
low oil (0.186 g, 62%), starting from amine 18d (0.30 g, 1.0 mmol).
Determination of the cis:trans ratio was not posssible due to over-
110.4 (CH), 121.2 (CH), 126.7 (CH), 127.8 (C), 128.2 (2 ϫ CH), lapping peaks in the 1H spectrum, caused by minor impurities
128.7 (2ϫCH), 129.7 (C), 139.9 (C), 144.8 (C), 150.8 (C) ppm. which we were unable to remove by chromatography.
MS: m/z 325 (M+, 64%), 310 (100), 266 (37), 192 (72), 176 (41).
24a: This product was isolated as a yellow oil (0.226 g, 75%) (1:1
HRMS: calcd. for C21H26NO2 (M+ – 1) for one THIQ unit:
diastereoisomeric mixture), starting from amine 23a (0.30 g,
324.1964, found: 324.1962.
0.88 mmol). See above for spectroscopy data.
X-ray Crystal Structure of 21: Formula: C42H52HgN2O4, M =
849.45, colourless needle (crystallized from EtOAc/hexane), crystal
24b: This product was isolated as a yellow oil (0.198 g, 79%) (1:1
diastereoisomeric mixture), starting from amine 23b (0.25 g,
0.74 mmol). After chromatography, one diastereoisomer was ob-
tained (Ͼ95%). This compound’s spectroscopic data were identical
size 0.46ϫ0.09ϫ0.08 mm, a = 28.068(4) Å, b = 7.4349(11) Å, c =
18.689(3) Å, V = 3900(1) Å3, µ = 3.988 mm–1, F(000) = 1720, Z =
4, orthorhombic, space group Pna21, T = 173(2) K, 23738 reflec-
to the major diasterioisomer reported for 24b, synthesized using
tions collected, 6751 independent reflections, θmax = 26.99°, 449
the reductive mercuration procedure as described above.
refined parameters, max./min. residual electron density: 0.988/
–1.854 e·Å–3. R1 = 0.0344, wR2 = 0.0611.
Acknowledgments
CCDC-637151 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
This work was supported by the Pretoria National Research Foun-
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
dation (NRF), GUN 2053652, and the University of the Witwat-
data_request/cif.
ersrand (University and Science Faculty Research Councils, Friedel
Representative Procedure for Preparing Substituted 5-Isopropoxy-6-
methoxy-1,2,3,4-tetrahydrisoquinolines. nBuLi-Mediated Cycliza-
tion: nBuLi (0.16 equiv., 1.4 ) was added to a stirring solution of
Sellschop Award). Prof. J. P. Michael is thanked for many helpful
discussions and Mr G. L. Morgans is thanked for comments re-
garding the manuscript. We also gratefully acknowledge Mr R.
5344
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5337–5345

Intramolecular Hydroaminations
[15] G. Bringmann, F. Pokorny, in The Alkaloids. Chemistry and
Pharmacology, vol. 46 (Ed.: G. A. Cordell), Academic Press,
New York, 1995, pp. 127–271.
Mampa and Mr T. van der Merwe for providing the NMR and
MS spectroscopy services, respectively.
[16] a) C. B. de Koning, J. P. Michael, W. A. L. van Otterlo, Tetra-
hedron Lett. 1999, 40, 3037–3040; b) C. B. de Koning, J. P.
Michael, W. A. L. van Otterlo, J. Chem. Soc. Perkin Trans. 1
2000, 799–811.
[17] a) C. B. de Koning, J. P. Michael, W. A. L. van Otterlo, Synlett
2002, 2065–2067; b) C. B. de Koning, W. A. L. van Otterlo, J. P.
Michael, Tetrahedron 2003, 59, 8337–8345.
[18] For a preliminary account of the nBuLi-mediated hydroamin-
ation portion of this work see: a) W. A. L. van Otterlo, R. Pa-
thak, C. B. de Koning, M. A. Fernandes, Tetrahedron Lett.
2004, 45, 9561–9563; b) Experimental work performed by R.
Pathak (PhD), P. Naicker (Hons.) and W. A. Thompson
(Hons.).
[19] For other examples of our work involving the imbedded THIQ
structure see: a) W. A. L. van Otterlo, R. Pathak, C. B. de Kon-
ing, Synlett 2003, 1859–1861; b) C. B. de Koning, J. P. Michael,
R. Pathak, W. A. L. van Otterlo, Tetrahedron Lett. 2004, 45,
1117–1119; c) A. N. C. Lötter, R. Pathak, T. S. Sello, M. A.
Fernandes, W. A. L. van Otterlo, C. B. de Koning, Tetrahedron
2007, 63, 2263–2274.
[1] For reviews on the hydroamination of alkenes and alkynes see:
a) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem. Int.
Ed. 2004, 43, 3368–3398; b) F. Alonso, I. P. Beletskaya, M. Yus,
Chem. Rev. 2004, 104, 3079–3159; c) M. Beller, C. Breindl, M.
Eichberger, C. G. Hartung, J. Seayad, O. R. Thiel, A. Tillack,
H. Trauthwein, Synlett 2002, 1579–1594; d) J. Seayad, A. Til-
lack, C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002, 344,
795–813; e) T. E. Müller, M. Beller, Chem. Rev. 1998, 98, 675–
703.
[2] A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 6042–
6043.
[3] a) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L.
Schafer, Angew. Chem. Int. Ed. 2007, 46, 354–358 and refer-
ences cited therein; b) L. Ackerman, L. T. Kaspar, A. Al-
thammer, Org. Biomol. Chem. 2007, 5, 1975–1978 and refer-
ences cited therein; c) P. D. Knight, I. Munslow, P. N.
O’Shaughnessy, P. Scott, Chem. Commun. 2004, 894–895.
[4] M. Dochnahl, J.-W. Pissarek, S. Blechert, K. Löhnwitz, P. W.
Roesky, Chem. Commun. 2006, 3405–3407.
[5] M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am. Chem. Soc.
2005, 127, 2042–2043.
[20] C. B. de Koning, J. P. Michael, A. L. Rousseau, J. Chem. Soc.
Perkin Trans. 1 2000, 787–797.
[21] a) L. F. Tietze, O. Burkhardt, M. Henrich, Liebigs Ann./Recueil
1997, 1407–1413; b) S. Hanessian, E. Demont, W. A. L.
van Otterlo, Tetrahedron Lett. 2000, 41, 4999–5003; c) J. L. Vic-
ario, D. Badía, E. Domínguez, L. Carrillo, J. Org. Chem. 1999,
64, 4610–4616.
[22] a) T. R. van den Ancker, L. M. Engelhardt, M. J. Henderson,
G. E. Jacobsen, C. L. Raston, B. W. Skelton, A. H. White, J.
Organomet. Chem. 2004, 689, 1991–1999; b) H.-J. Oller, P. Kip-
rof, H. Schmidbaur, Z. Naturforsch., B: Chem. Sci. 1992, 47,
333–343; c) C. A. Ogle, P. A. Riley, J. J. Dorchak, J. L. Hub-
bard, J. Org. Chem. 1988, 53, 4409–4412.
[23] a) R. Lebeuf, F. Robert, Y. Landais, Org. Lett. 2005, 7, 4557–
4560; b) A. Ates, C. Quinet, Eur. J. Org. Chem. 2003, 1623–
1626; c) J. A. Seijas, M. P. Vázquez-Tato, C. Entenza, M. M.
Martínez, M. G. Ónega, S. Veiga, Tetrahedron Lett. 1998, 39,
5073–5076; for intermolecular examples see the next two refer-
ences: d) C. G. Hartung, C. Breindl, A. Tillack, M. Beller, Tet-
rahedron 2000, 56, 5157–5162; e) M. Beller, C. Breindl, Tetrahe-
dron 1998, 54, 6359–6368.
[6] For a review see the following paper: a) S. Hong, T. J. Marks,
Acc. Chem. Res. 2004, 37, 673–686; b) M. Rastätter, A. Zulys,
P. W. Roesky, Chem. Commun. 2006, 874–876; c) A. Zulys,
T. K. Panda, M. T. Gamer, P. W. Roesky, Chem. Commun.
2004, 2584–2585; d) Y. K. Kim, T. Livinghouse, J. E. Bercaw,
Tetrahedron Lett. 2001, 42, 2933–2935.
[7] For a review see the following paper: a) K. C. Hultzch, Org.
Biomol. Chem. 2005, 3, 1819–1824; b) D. V. Gribkov, K. C.
Hultzch, F. Hampel, J. Am. Chem. Soc. 2006, 128, 3748–3759;
c) D. Riegert, J. Collin, A. Meddour, E. Schulz, A. Trifonov, J.
Org. Chem. 2006, 71, 2514–2517; d) Y. K. Kim, T. Livinghouse,
Angew. Chem. Int. Ed. 2002, 41, 3645–3647; e) P. N. O’Shaugh-
nessy, P. Scott, Tetrahedron: Asymmetry 2003, 14, 1979–1983;
f) P. N. O’Shaughnessy, P. D. Knight, C. Morton, K. M. Gilles-
pie, P. Scott, Chem. Commun. 2003, 1770–1771; g) P. W. Roe-
sky, T. E. Müller, Angew. Chem. Int. Ed. 2003, 42, 2708–2710.
[8] a) D. Kadzimirsz, D. Hildebrandt, K. Merz, G. Dyker, Chem.
Commun. 2006, 661–662; for other gold-catalyzed hydroamida-
tions see: b) X.-Y. Liu, C.-H. Li, C.-M. Che, Org. Lett. 2006,
8, 2707–2710; c) J. Zhang, C.-G. Yang, C. He, J. Am. Chem. [24] J.-L. Panayides, R. Pathak, H. Panagiotopoulos, H. Davids,
Soc. 2006, 128, 1798–1799.
M. A. Fernandes, C. B. de Koning, W. A. L. van Otterlo, Tetra-
hedron 2007, 63, 4737–4747.
[9] J. S. Ryu, G. Y. Li, T. J. Marks, J. Am. Chem. Soc. 2003, 125,
12584–12605.
[25] a) R. Pedrosa, C. Andrés, J. M. Iglesias, M. A. Obeso, Tetrahe-
dron 2001, 57, 4005–4014; b) L. F. Tietze, O. Burkhardt, Syn-
thesis 1994, 1331–1336; c) D. Tourwé, E. Mannekens, T. N. T.
Diem, P. Verheyden, H. Jaspers, G. Tóth, A. Péter, I. Kertész,
G. Török, N. N. Chung, P. W. Schiller, J. Med. Chem. 1998, 41,
5167–5176; d) V. Kouznetsov, A. Palma, W. Rozo, E. Stash-
enko, A. Bahsas, J. Amaro-Luis, Synth. Commun. 2002, 32,
2965–2971; e) B. Bonnaud, A. Carlessi, D. C. H. Bigg, J. Heter-
ocycl. Chem. 1993, 30, 257–265.
[26] CS Chem3D Ultra, Version 6.0, CambridgeSoft.com, Cam-
bridge, MA, USA.
[27] a) J. L. Vicario, D. Badía, L. Carrillo, J. Etxebarria, Curr. Org.
Chem. 2003, 7, 1775–1792; b) M. Chrzanowska, M. D. Rozwa-
dowska, Chem. Rev. 2004, 104, 3341–3370.
[28] a) J.-J. Youte, D. Barbier, A. Al-Mourabit, D. Gnecco, C. Mar-
azano, J. Org. Chem. 2004, 69, 2737–2740; b) D. Barbier, C.
Marazano, C. Riche, B. C. Das, P. Potier, J. Org. Chem. 1998,
63, 1767–1772.
[29] D. D. Perrin, W. L. F. Armarego, Purification of laboratory
chemicals, Pergamon Press, London, 1988.
[10] a) G. A. Molander, S. K. Pack, Tetrahedron 2003, 59, 10581–
10591; b) G. A. Molander, S. K. Pack, J. Org. Chem. 2003, 68,
9214–9220.
[11] a) A. B. J. Bracca, T. S. Kaufman, Tetrahedron 2004, 60, 10575–
10610; b) T. S. Kaufman, Tetrahedron: Asymmetry 2004, 15,
1203–1237.
[12] J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669–1730.
[13] a) K. L. Rinehart, T. G. Holt, N. L. Fregeau, J. G. Stroh, P. A.
Keifer, F. Sun, L. H. Li, D. G. Martin, J. Org. Chem. 1990, 55,
4512–4515; b) Adis International Limited, Drugs R. & D. 2006,
7, 317–328; c) J. Chen, X. Chen, M. Bois-Choussy, J. Zhu, J.
Am. Chem. Soc. 2006, 128, 87–89.
[14] See for examples: a) K. Okuda, Y. Kotake, S. Ohta, Biol.
Pharm. Bull. 2006, 29, 1401–1403; b) J. J. Luszczki, L. Antkie-
wicz-Michaluk, S. J. Czuczwar, Neuropharmacology 2006, 50,
133–142; c) Y. Kotake, R. Taguchia, K. Okuda, Y. Sekiyaa, Y.
Tasakic, M. Hirobec, S. Ohta, Brain Research 2005, 1033, 143–
150; d) J. Parrado, E. Absi, A. Ayala, A. Castanˇo, J. Cano, A.
Machado, J. Neurochem. 2000, 75, 65–71; e) K. Ishiwata, Y.
Koyanagi, K. Abe, K. Kawamura, K. Taguchi, T. Saitoh, J.
Toda, M. Senda, T. Sano, J. Neurochem. 2001, 79, 868–876.
Received: June 22, 2007
Published Online: September 4, 2007
Eur. J. Org. Chem. 2007, 5337–5345
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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