Amide rotamers of N-acetyl-1,3-dimethyltetrahydroisoquinolines: Synthesis, variable temperature NMR spectroscopy and molecular modelling

Article abstract of DOI:10.1016/j.tet.2003.09.001

Mercury(II)-mediated ring closure of N-[1-(2-allyl-3-benzyloxy-4,6-dimethoxyphenyl)ethyl]acetamide 9 afforded N-acetyl-5-benzyloxy-6,8-dimethoxy-1,3-trans-dimethyl-1,2,3, 4-tetrahydroisoquinoline 8. The product was shown to exist as a mixture of amide rot

Full text of DOI:10.1016/j.tet.2003.09.001

Tetrahedron 59 (2003) 8337–8345
Amide rotamers of N-acetyl-1,3-dimethyltetrahydroisoquinolines:
synthesis, variable temperature NMR spectroscopy
and molecular modelling
*
Charles B. de Koning, Willem A. L. van Otterlo and Joseph P. Michael
*
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO Wits, 2050, Johannesburg,
South Africa
Received 11 July 2003; accepted 4 September 2003
Abstract—Mercury(II)-mediated ring closure of N-[1-(2-allyl-3-benzyloxy-4,6-dimethoxyphenyl)ethyl]acetamide 9 afforded N-acetyl-5-
benzyloxy-6,8-dimethoxy-1,3-trans-dimethyl-1,2,3,4-tetrahydroisoquinoline 8. The product was shown to exist as a mixture of amide
rotamers by NMR spectroscopy, since signals coalesced at higher temperatures. Variable temperature NMR spectroscopy and molecular
modelling were used to investigate these rotamers and gave average values for the barrier of rotation in the range of 15–16 kcal mol21. 2-[2-
[1-(Acetylamino)ethyl]-6-(benzyloxy)-3,5-dimethoxyphenyl]-1-methylethyl methanesulfonate 17 was also cyclized with sodium hydride to
afford the same rotameric products with the same tetrahydroisoquinoline skeleton, but as a mixture of 1,3-trans- and cis-dimethyl isomers.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
tetrahydroisoquinoline, e.g. 3, and the coupling of this unit
with an appropriate substituted naphthalene 4.7 Published
syntheses of the tetrahydroisoquinoline nucleus8 of many
naturally occurring products, including the michellamines,
frequently make use of well-known named reactions such as
(a) the Bischler–Napieralski reaction which entails the
formation of the C-1/Ar bond followed by reduction,9
(b) the Pictet–Spengler9a,10 reaction (N/C-1/Ar), (c) the
Pummerer11 reaction (C-4/Ar) or (d) the Pomeranz–Fritsch
reaction.12 The traditional disconnections for the first three
methods are shown in Figure 1.
Our interest in the isoquinoline alkaloids arises from their
fascinating range of biological activities.1 We2 have been
specifically interested in the naphthylisoquinoline
alkaloids,3 of which the korupensamines such as 1
(korupensamine B) and their binaphthyl dimers 2 (e.g.
michellamine B) are prime examples. These intriguing
compounds have been shown to possess anti-malarial and
anti-HIV properties respectively.4
A number of groups have reported syntheses of these
compounds5 and their analogues.2a,b,d,6 In general (Fig. 1),
the syntheses rely on the assembly of a suitably substituted
Keywords: isoquinolines; amides; mercury and compounds; rotamers;
NMR; molecular modelling.
*
Corresponding authors. Tel.: þ27-11-717-6724; þ27-11-717-6707; fax:
þ27-11-717-6749; e-mail: dekoning@aurum.chem.wits.ac.za;
Figure 1. Traditional disconnections for naphthyltetrahydroisoquinoline
alkaloids and substituted tetrahydroisoquinolines.
willem@aurum.chem.wits.ac.za
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.001

8338
C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
In a previous communication we have described the
synthesis of N-acetyltetrahydroisoquinolines using novel
methodology.2d Two of the compounds thus synthesized
were obtained as amide rotamers in solution. This
phenomenon in N-acyltetrahydroisoquinolines has been
reported by other researchers, for example; Bringmann
1
observed doubling of signals in the H NMR spectra of
tetrahydroisoquinolines 5 due to N-acetyl and N-formyl
rotational isomers.13 A literature search revealed a small
number of publications describing the hindered rotation of
N-acyltetrahydroisoquinoline derivatives. These included
the work of Noyori14 on compounds such as 6 and that done
by Fraenkel15 on compound 7.
Scheme 1. Reagents and conditions: (a) Phthalimide, DEAD, Ph3P, THF
(11, 86%; 12 ,5%); (b) MeNH2, EtOH/C6H6; (c) Ac2O, pyridine (9, 61%
over 2 steps; 14, ,17% over 2 steps).
attempted Ing–Manske hydrazinolysis19 of 11 led to the
undesired reduction of the alkene. However, exposure of 11
to methylamine20 afforded an unstable primary amine 13
that was immediately treated with acetic anhydride and
pyridine to produce amide 9 in acceptable yields. The
cleavage of the phthalimide group of 11 tended to be a fickle
reaction and quite difficult to monitor by thin layer
chromatography. One of the side products sometimes
isolated was the partially cleaved phthalimide derivative
14 in yields of up to 17%.
In this paper we describe the full experimental details of our
communication on the synthesis of N-acetyltetrahydroiso-
quinoline possessing a substitution pattern common to
several of the korupensamine and michellamine naphthyli-
soquinoline alkaloids.2d The products obtained by this
method were a mixture of N-acetyl rotamers. Furthermore,
we describe how this phenomenon was investigated using
variable temperature NMR spectroscopy and molecular
modelling.
In the synthesis described in this paper we have utilized
amidomercuration methodology for the construction of the
N-acetyltetrahydroisoquinoline 8 from 9. This methodology
relies on an unusual N/C-3 disconnection16 as shown in
Figure 2 below rather than the traditional disconnections
outlined in Figure 1.
We were now in a position to test whether we could access
the tetrahydroisoquinoline system by forming the N/C-3
bond. Formation of heterocycles by the hydroamination of
alkenes using transition metals21 has been extensively
studied but we decided to use the less popular amido-
mercuration methodology for the construction of the 1,3-
dimethyltetrahydroisoquinolines. Using as an analogy the
synthesis of isochromanes22 by oxymercuration of hydroxy-
alkenes related to 9, we envisaged making the target system
by intramolecular amidomercuration. Although this type of
reaction has been well investigated,23 it appears to have no
precedent in the isoquinoline series. Reaction of 9 with
mercury(II) acetate22 in a 1:1 water/tetrahydrofuran mixture
followed by reduction with sodium borohydride gave the
desired N-acetyl-1,3-trans-dimethyltetrahydroisoquinoline
8 as a mixture of rotamers in a poor yield of 21% (Scheme
2). The low yield was due to the competitive reaction of
water with the mercurinium intermediate23d,g to give the
secondary alcohol 15 as a mixture of diastereomers in 54%
yield. The formation of unwanted alcohol 15 could be
suppressed by reaction of amide 9 with mercury(II) acetate
in dry tetrahydrofuran, affording the 1,3-trans-dimethyl
product 8 as a mixture of rotamers in a yield of 56% as the
major product. A small amount (,5–10%) of the cis-isomer
16 was also evident as shown by NMR spectroscopy.
Figure 2. N/C-3 Disconnection of tetrahydroisoquinoline 8.
2. Results and discussion: synthesis of
1,3-dimethyltetrahydroisoquinolines
The aromatic alcohol (^)-10, an intermediate we have
previously employed for making isochromane ring
systems,2a,b was treated with phthalimide under Mitsunobu
conditions17 as shown in Scheme 1 to yield imide 11 and
small amounts of the styrene 12. Standard base-mediated
hydrolyis18 of compound 11 gave poor results and an

C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
8339
Scheme 2. Reagents and conditions: (a) Hg(OAc)2, THF/H2O, then
NaBH4/NaOH, then chromatography on SiO2 (8, 21%; 15, 54%; 16,
,10%); (b) Hg(OAc)2, THF, then NaBH4/NaOH, then chromatography on
SiO2 (8, 56%; 15, 0%; 16, ,10%).
Scheme 3. Reagents and conditions: (a) MsCl, CH2Cl2, Et3N (100%);
(b) NaH, THF (85%).
cyclization to afford the trans product was in line with the
findings of Harding and Burks who have reported similar
results.25
1
The H NMR spectrum of tetrahydroisoquinoline 8 was
quite complex owing to substantial peak doubling. It
seemed likely that rotamers of 8 exist in solution as a result
of hindered rotation of the amide C–N bond, giving rise to
this doubling phenomenon.13a Heating compound 8 in an
NMR tube in toluene-d8 up to 908C confirmed our
hypothesis as this resulted in coalescence of the two sets
of signals. We then decided to perform a more rigorous
NMR spectroscopic investigation into the structure and
conformation of these compounds. Initial nOe experiments
indicated that among other effects for isomer 8, the C-1
methyl substituent in both rotamers showed an nOe with the
H-4 pseudo-axial proton (Fig. 3(a)), indicating that the C-1
methyl substituent must be pseudo-axial. In addition, the
cis-isomer 16 exhibited the same nOe, as well as a nOe
between the 1-methyl and 3-methyl substituents, thereby
fixing the cis-arrangement. Therefore we infered that in
isomer 8 the C-1 methyl and C-3 methyl groups must
have a trans-relationship. This then implies that the
heterocyclic ring adopts an unusual boat-like conformation
(Fig. 3(a)) with both methyl substituents appearing to
adopt pseudo-axial positions to minimize 1,3-allylic strain24
(Fig. 3(b)). The high degree of stereoselectivity for the
With sufficient quantities of the alcohol 15 in hand we also
examined the conversion of this intermediate into the
desired N-acyltetrahydroisoquinolines. Reaction of 15 with
methanesulfonyl chloride and triethylamine (Scheme 3)
afforded mesylate 17 in quantitative yield. Exposure of 17 to
sodium hydride resulted in cyclisation to afford tetra-
hydroisoquinolines 8 and 16 (85% yield) as an equimolar,
inseparable mixture of 1,3-trans- and cis-dimethyl
isomers,26 each occurring as a pair of amide rotamers.27
As the 13C NMR spectrum clearly displayed four peaks for
most carbons in the 13C NMR spectrum, one each for the
cis- and trans- isomers, and then one for each of their
1
amide rotamers, comparison of the spectra and a H–13C
NMR correlation spectrum then facilitated the identification
of the cis-1,3-dimethyltetrahydroisoquinoline in the
mixture.
3. Variable temperature NMR spectroscopy
In view of the paucity of literature examples describing
N-acyltetrahydroisoquinoline amide rotamers we decided to
investigate the influence of temperature on the rotamers of
available trans-1,3-dimethyltetrahydroisoquinoline 8 using
1
1
variable temperature H NMR spectroscopy.28,29 The H
NMR spectra of 8 in deuterated toluene were thus obtained
over the temperature range 240–370 K. We identified four
sets of signals that were doubled at room temperature and
demonstrated coalescence over this temperature range.
These were the signals at: (a) d 3.2–2.8 (4-H), (b) 2.0–
1.9 (COCH3), (c) 1.6–1.3 (1-CH3) and (d) 1.1–0.2 (3-CH3)
(Fig. 4).
The free energies of activation were then calculated as
described by Bishop30 et al. from the Eyring equation
(Eq. (1))† in conjunction with the rate constant expression
(Eq. 2)30 to be in the range of 15.9^0.2 to 16.1^
†
R¼8.31 J mol21 K21
;
Tc¼convergence
temperature
(K);
Figure 3. (a) NOe interactions for 8, (b) postulated A1,3 strain interactions
for 8.
h¼6.63£10234 J s; kB¼1.38£10223 J K21; DdAB¼limiting d peak
separation (ppm); JAB¼coupling constant (Hz).

8340
C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
4. Molecular modelling
In addition to the results obtained by the variable
temperature NMR spectroscopy we also investigated the
rotameric phenomenon of the tetrahydroisoquinoline amide
peak doubling with simple molecular modelling studies. In
order to do so, we used the atomic coordinates determined in
a published tetrahydroisoquinoline crystal structure34 as a
template for our computer simulations. The model system
was modified35 to represent compound 18 (Fig. 5) and a
single point energy minimization36 was performed on the
molecule utilizing the MMþ force field.37 An iterative full
energy minimization calculation was then performed at 58
torsional angle intervals, with the torsional angle restrained
at this particular value. The energies calculated were then
scaled to the minimum at 21758 and plotted against the
torsional angle to afford energy-torsional angle plots for the
N-acetyl-1,3-trans-dimethyltetrahydroisoquinoline (Fig. 6).
A similar process afforded an energy-angle plot for the cis-
compound 19. From the values obtained, the calculated
energy barrier for the amide N–CO bond rotation was
15.1 kcal mol21 for the trans compound 18 and
14.9 kcal mol21 for the related cis-compound, 19.38 For
the trans compound 18 the calculated energy difference
between the minima at þ175 and 08 was 0.71 kcal mol21
implying a Boltzmann distribution of ,3:1 which compared
well with the ratio observed from the peak integration in the
NMR spectrum of compound 18.
Figure 4. Portion of 1H NMR spectrum of compound 8 in toluene-d8
indicating signals used in variable temperature NMR spectroscopy work.
0.2 kcal mol21 31
The quantities DdAB at their limit were
estimated by graphical extrapolation from the measured Dd
.
values at the various temperatures.32
DG‡c ¼ 2RTclnðKCh=kBTcÞ
ð1Þ
ð2Þ
Figure 5. Simplified 1,3-trans-dimethyl- 18 and 1,3-cis-dimethyl- 19
N-acetyltetrahydroisoquinolines for molecular modelling. Preferred
rotamer as drawn; the torsion angle changed in the modelling was
C3–N2–C–O as labelled in the figure.
2
1=2
KC ¼ {p{ðDdABÞ þ 6JA2B
}
1=2=ð2Þ
}
Evaluation of the NMR spectral signals in the range of 2.0–
1.9 (COCH3) using an approach tailored for obtaining the
free energies of activation at the coalescence point of an
unequal doublet using the Eqs. (3) and (4) was also
performed.33 The calculated values obtained using this
method were DG‡A¼16.6^0.2 kcal mol21 (major isomer to
minor) and DG‡B¼16.1^0.2 kcal mol21 (minor isomer to
major) which are reasonable in comparison to the values
obtained from the first method.‡
DG‡A ¼ 4:57 £ Tc{10:62 þ log{X=2pð1 2 DPÞ}
þ logðTc=DdABÞ}
DG‡B ¼ 4:57 £ Tc{10:62 þ log{X=2pð1 þ DPÞ}
ð3Þ
ð4Þ
Figure 6. Plot of energy vs amide bond angle for simplified 1,3-trans-
dimethyl- 18 and 1,3-cis-dimethyl- 19 N-acetyltetrahydroisoquinolines.
þ logðTc=DdABÞ}
5. Discussion: molecular modelling and variable
temperature NMR spectroscopy
The variable temperature NMR spectroscopy and molecular
modelling (using the simplified analogues 18 and 19) gave
results that supported the existence of rotamers in solution
arising from hindered rotation around the amide C–N bond,
‡
DP¼PA2PB (PA and PB being the relative concentrations of species A
and B obtained from the area under peaks A and B). The values of
log{X/2p(1^DP)} could be extrapolated directly from Figure 2 in the
original reference.33a Tc¼330^2 K and DdAB¼63^2 ppm.

C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
8341
1
as evidenced by the H and 13C NMR spectra of the 1,3-
cm21 1707vs (CvO), 1597s (ArCvC) and 1487m
(ArCvC, phthalimide); dH (400 MHz; CDCl3; Me4Si)
7.87–7.73 (3H, m, 3£ArH), 7.66–7.63 (2H, m, 2£ArH),
7.47–7.45 (2H, m, 2£ArH), 7.38–7.27 0(2H, m, 2£ArH),
6.43 (1H, s, 5-H), 5.99–5.92 (1H, m, 2 -H), 5.51 (1H, q,
J¼7.4 Hz, CHCH3), 4.94–4.87 (4H, m, OCH2 and 30-H),
3.85 (3H, s, OCH3), 3.85–3.76 (2H, m, 10-H), 3.76 (3H, s,
OCH3) and 1.93 (3H, d, J¼7.4 Hz, CHCH3); dC
(100.625 MHz; CDCl3; Me4Si) 168.8 (2£NCvO), 154.9
and 152.4 (2£ArC–O), 139.9 (ArC–C), 138.1 (ArC–O),
137.3 (20-C), 133.5 (2£ArC–H), 133.2 (£2) and 132.2
(3£ArC–C), 128.3 (£2), 127.8 (£2), 127.6 and 122.6 (£2)
(7£ArC–H), 120.7 (ArC–C), 115.1 (30-C), 96.1 (5-C), 74.6
(OCH2), 55.8 and 55.7, (2£OCH3), 48.5 (CHCH3), 30.5
(10-C) and 18.0 (CHCH3); m/z (EI) 457.1878 (9%) (Mþ,
C28H27O5N requires 457.1889), 366 (44), 351 (1), 336 (1),
310 (3), 219 (36), 174 (100), 147 (11) and 91 (31).
trans-dimethyl- and 1,3-cis-dimethyltetrahydroisoquino-
lines 8 and 16. The former technique gave a rotational
barrier of approximately 16 kcal mol21 while the latter gave
a barrier of about 15 kcal mol21 for the model systems.
Both these barriers are in the range of 15–16 kcal mol21
,
within the accepted range of many literature values.39
Furthermore these barriers to rotation are high enough to
explain the observation of the existence of amide rotamers
in solution for compounds 8 and 16.40
6. Conclusion
We have been successful in synthesizing an N-acetyltetra-
hydroisoquinoline with the aromatic substitution pattern
common to several of the korupensamine and michellamine
alkaloids, albeit in racemic form, using a novel amido-
cyclization reaction. Furthermore the observation of
rotamers in solution due to hindered rotation about the
amide bond in the tetrahydroisoquinoline compound formed
was investigated by variable temperature NMR
spectroscopy and molecular modelling methods. Work is
now in progress to investigate the generality of this
approach for the preparation of substituted isoquinolines
and we plan to extend this to other natural products.
Sometimes the styrene 12 was also isolated from the
reaction mixture in yields of up to 5%. nmax (film)/cm21
2837w (C–H, OCH3) and 1595m (ArCvC); dH (200 MHz;
CDCl3; Me4Si) 7.50–7.23 (5H, m, 5£ArH), 6.69 (1H, dd,
J¼17.8, 11.8 Hz, ArCHvCH2), 6.47 (1H, s, 5-H),
6.03–5.86 (1H, m, 20-H), 5.67 (1H, dd, J¼17.8, 2.5 Hz,
trans-ArCHvHCH), 5.41 (1H, dd, J¼11.8, 2.5 Hz, cis-
ArCHvHCH), 5.04–4.84 (2H, m, 30-H), 4.91 (2H, s,
OCH2), 3.89 and 3.83 (each 3H, s, OCH3) and 3.54–3.50
(2H, m, 10-H); dC (50.32 MHz; CDCl3; Me4Si) 154.4 and
152.1 (2£ArC–O), 140.1 (ArC–C), 138.1 (ArC–O), 137.0
(20-C), 132.9 (ArC–C), 130.7 (ArCHvCH2), 128.3 (£2),
127.8 (£2) and 127.6 (5£ArCH), 119.1 (1-C), 118.4
(ArCHvCH2), 115.2 (30-C), 95.7 (5-C), 74.8 (OCH2),
55.9 (2£OCH3) and 31.2 (10-C); m/z (EI) 310.1573 (6%)
(Mþ, C20H22O3 requires 310.1569), 219 (100), 204 (6), 189
(6), 174 (6) and 91 (33).
7. Experimental
7.1. General
1H NMR and 13C NMR spectra were recorded either on a
Bruker AC-200 or Bruker DRX 400 spectrometer at the
frequency indicated. DEPT, CH-correlated and HMBC
spectra were run on some samples to enable complete
assignments of all the signals. NMR spectroscopic assign-
ments with the same superscript may be interchanged. Infra-
red spectra were recorded on either a Bruker IFS 25 Fourier
Transform spectrometer or on a Bruker Vector 22 Fourier
Transform spectrometer. Mass spectra were recorded on a
Kratos MS 9/50, VG 70E MS or a VG 70 SEQ mass
spectrometer. Elemental analyses were performed on a
Perkin–Elmer 2400 CHN Elemental Analyser. Macherey–
Nagel kieselgel 60 (particle size 0.063–0.200 mm) was
used for conventional silica gel chromatography and
Macherey–Nagel kieselgel 60 (particle size 0.040–
0.063 mm) was used for preparative flash chromatography.
All solvents used for reactions and chromatography were
distilled prior to use.
7.1.2. N-{1-[2-Allyl-3-(benzyloxy)-4,6-dimethoxy-
phenyl]-ethyl}-acetamide 9, N 1-{1-[2-allyl-3-(benzyl-
oxy)-4,6-dimethoxy-phenyl]ethyl}-N 2-methyl-phthala-
mide 14 and 1-[2-Allyl-3-(benzyloxy)-4,6-
dimethoxyphenyl]-ethylamine, 13. Phthalimido derivative
11 (0.60 g, 1.3 mmol) was dissolved in absolute ethanol
(10 cm3) and benzene (4 cm3). Aqueous methylamine
solution (25%, 1 cm3) was added under nitrogen and the
reaction was monitored by thin layer chromatography. A
further portion of methylamine solution (1 cm3) was added
and the reaction was deemed complete after 2 h. Amine 13
could be isolated as an intermediate but proved to be
unstable and susceptible to decomposition. nmax (film)/
cm21 3360br (NH2), 1597s (ArCvC); dH (400 MHz;
CDCl3; Me4Si) 7.45–7.29 (5H, m, 5£ArH), 6.47 (1H, s,
5-H), 5.92–5.88 (1H, m, 20-H), 5.02 (1H, br d, J¼10.9 Hz,
30-cis-H) 4.92–4.85 (1H, m, 30-trans-H), 4.89 and 4.84
(each 1H, d, J¼10.8 Hz, OCH2), 4.49–4.48 (1H, m,
CHCH3), 3.90 and 3.88 (each 3H, s, OCH3), 3.64–3.52
(2H, m, 10-H), 3.60–3.20 (2H, br, NH2) and 1.61 (3H, d,
J¼6.5 Hz, CHCH3); dC (100.63 MHz; CDCl3; Me4Si)
154.5, 153.2 and 140.2 (3£ArC–O), 137.8 (ArC–C),
136.7 (20-C), 132.5 (ArC–C), 128.4 (£2), 127.9 (£2) and
127.8 (5£ArC–H and ArC–C), 116.0 (30-C), 95.9 (5-C),
75.1 (OCH2), 55.9 and 55.7 (2£OCH3), 47.0 (CHCH3), 30.4
(10-C) and 18.4 (CHCH3). The solvent was removed in
vacuo and replaced with excess pyridine (10 cm3) and acetic
7.1.1. N-2-{1-[2-Allyl-3-(benzyloxy)-4,6-dimethoxy-
phenyl]-ethyl}-phthalimide 11 and 2-allyl-3-benzyloxy-
4,6-dimethoxy-styrene,
12.
Phthalimide
(0.56 g,
3.8 mmol), freshly distilled diethyl azodicarboxylate
(DEAD) (0.60 cm3, 0.67 g, 3.8 mmol) and triphenyl-
phosphine (1.01 g, 3.8 mmol) were added sequentially to
alcohol 10 (1.05 g, 3.20 mmol) dissolved in dry tetra-
hydrofuran (THF) (50 cm3). The reaction mixture was
stirred at room temperature under argon, for 18 h, after
which the solvent was removed in vacuo. Silica gel column
chromatography (5–20% ethyl acetate/hexane) yielded the
product 11 as a clear semi-solid (1.36 g, 93%). nmax (film)/

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C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
anhydride (5 cm3). Sodium sulfate (5 g) was added and the
reaction mixture was stirred at ambient temperature for 18 h
under an argon atmosphere, after which the solvent was
removed in vacuo. The residue was purified by silica gel
preparative layer chromatography (PLC) (50% ethyl
acetate/49% hexane/1% aq. ammonia solution) to afford
amide 9 (0.297 g, 61% over two steps). nmax (film)/cm21
3331br (N–H), 1637vs (CvO) and 1597 (ArCvC); dH
(400 MHz; CDCl3; Me4Si) 7.47–7.30 (5H, m, 5£ArH), 6.79
(1H,0br d, J¼9.3 Hz, NH), 6.49 (1H, s, 5-H), 6.01–5.93 (1H,
m, 2 -H), 5.44 (1H, dq, J¼9.3, 6.9 Hz, CHCH3), 5.02 (1H,
dd, J¼9.9, 1.7 Hz, 30-cis-H), 4.94–4.82 (1H, m, 30-trans-H),
4.91 and 4.86 (each 1H, d, J¼10.8 Hz, OCH2), 3.90 and
3.87 (each 3H, s, OCH3), 3.65–3.62 (2H, br d, J¼6.3 Hz,
10-H), 1.92 (3H, s, COCH3) and 1.40 (3H, d, J¼6.9 Hz,
CHCH3); dC (100.63 MHz; CDCl3; Me4Si) 168.4 (CvO),
154.4, 152.1 and 140.2 (3£ArC–O), 137.9 (ArC–C), 136.9
(20-C), 132.5 (ArC–C), 128.2 (£2), 127.8 (£2) and 127.6
(5£ArC–H), 122.2 (ArC–C), 115.4 (30-C), 96.2 (5-C), 74.9
(OCH2), 55.9 and 55.6 (2£OCH3), 43.7 (CHCH3), 30.7
(10-C), 23.6 (COCH3) and 20.9 (CHCH3); m/z (EI) 369.1933
(14%) (Mþ, C22H27NO4 requires 369.1940), 326 (1), 278
(77), 219 (86), 204 (16), 193 (84), 189 (16), 91 (40) and 43
(16).
pressure. Saturated brine solution (10 cm3) and ether
(10 cm3) were added to the residue and the mixture was
subsequently extracted with diethyl ether (3£10 cm3). The
organic solvents were combined, filtered through alumina to
remove traces of mercury residues, dried (MgSO4) and
evaporated in vacuo. Purification by silica gel preparative
layer chromatography (20% hexane/79% ethyl acetate/1%
aq. ammonia solution) afforded the trans-cyclized product 8
(mixture of two rotamers, 0.11 g, 56%) as a yellow oil. nmax
(film)/cm21 2820m (C–H, OCH3), 1635vs (CvO) and
1583m (ArCvC); dH (400 MHz; CDCl3; Me4Si) 7.43–7.32
(10H, m, 10£ArH), 6.44 (1H, s, 7-H), 6.43 (1H, s, 7-H), 5.50
(1H, q, J¼6.4 Hz, 1-H), 5.16 (1H, q, J¼6.6 Hz, 1-H), 4.95–
4.86 (4H, m, 2£OCH2), 4.68–4.62 (1H, m, 3-H), 4.23–4.15
(1H, m, 3-H), 3.91 (6H, s, 2£OCH3), 3.86 (3H, s, OCH3),
3.82 (3H, s, OCH3), 2.99 (2H, dd, J¼15.2, 2.4 Hz, 2£4-H
pseudo-equatorial), 2.64–2.54 (2H, m, 2£4-H pseudo-
axial), 2.24 (3H, s, COCH3), 2.17 (3H, s, COCH3), 1.28
(3H, d, J¼6.6 Hz, 1-CH3), 1.23 (3H, d, J¼6.4 Hz, 1-CH3),
0.84 (3H, d, J¼6.4 Hz, 3-CH3), 0.83 (3H, d, J¼6.3 Hz,
3-CH3); dC (50.32 MHz; CDCl3; Me4Si) 170.0, 169.7
(2£NCOCH3), 151.9, 151.5, 151.4, 150.7, 139.1, 139.0
(6£ArC–O), 137.6, 137.5, 129.0 (3£ArC–C), 128.5, 128.5,
128.3, 128.0 (4£ArC–H), 119.5, 118.6 (2£ArC–C), 95.2,
94.9 (2£7-C), 75.2 (OCH2), 55.9, 55.6, 55.6 (3£OCH3),
49.1, 46.7 (2£1-C), 46.3, 44.4 (2£3-C), 28.6, 27.8 (2£4-C),
23.3, 22.3, 22.3, 21.3, 20.9, 19.2 (6£CH3); m/z (EI)
369.1931 (20%) (Mþ, C22H27NO4 requires 369.1940), 354
(83), 278 (95), 263 (9), 219 (78), 193 (100), 91 (34) and 43
(16).
Compound 14 (0.108 g, 17%, over two steps) was also
recovered from the column. nmax (film)/cm21 3296br
(N–H), 1643vs (CvO), 1597m (ArCvC) and 1514m
(N–CvO); dH (400 MHz; CDCl3; Me4Si) 7.70–7.67 (1H,
m, ArH), 7.49–7.31 (9H, m, 8£ArH and NCH3H), 6.79 (1H,
br d, J¼4.4 Hz, NH [D2O exchangeable]), 6.49 (1H, s, 5-H),
6.02–5.98 (1H, m, 20-H), 5.57 (1H, dq, J¼9.2, 6.9 Hz,
CHCH3), 5.04 (1H, dd, J¼10.2, 1.6 Hz, 30-cis-H), 4.99 (1H,
dd, J¼17.1, 1.6 Hz, 30-trans-H), 4.89 (2H, s, OCH2), 3.89
and 3.87 (each 3H, s, OCH3), 3.84–3.65 (2H, m, 10-H), 2.66
(3H, d, J¼4.4 Hz, NHCH3) and 1.46 (3H, d, J¼6.9 Hz,
COCH3); dC (100.63 MHz; CDCl3; Me4Si) 168.9 and 168.3
(2£NCvO), 154.6, 152.4 and 140.1 (3£ArC–O), 137.9
(ArC–C), 136.9 (20-C), 135.1, 134.4 and 132.3 (3£ArC–C),
130.1, 129.9, 129.0, 128.4 (£2), 128.0 (£2), 127.8 and
127.5 (9£ArC–H), 121.1 (ArC–C), 115.6 (30-C), 96.0
(5-C), 75.1 (OCH2), 56.0 and 55.6 (2£OCH3), 44.7
(CHCH3), 30.8 (10-C), 26.4 (NCH3) and 20.7 (CHCH3);
m/z (EI) 488.2303 (3%) (Mþ, C29H32N2O5 requires
488.2311), 397 (9), 219 (100), 204 (9), 162 (39), 91 (21)
and 43 (4).
When this reaction was carried out using an equivalent
amount of THF and water as solvent the yield of the trans-
cyclized product 8 was only 21%. However, a large amount
of alcohol 15 (54%) was then also recovered from the
column as a clear oil. nmax (film)/cm21 3460br (OH st),
3345br (N–H), 1649s (CvO), 1597s (ArCvC); dH
(400 MHz; CDCl3; Me4Si; Assignments in brackets
tentatively refer to the other diastereomer) 7.46–7.31
(10H, m, 10£ArH), 6.82 (2H, br d, NH), 6.49, (6.48)
(each 1H, s, 5-H), 5.52–5.47 (2H, m, CHCH3), 4.96, (4.92)
(each 2H, d, J¼11.2 Hz, OCH2), 4.15–4.03, (3.90–3.88)
(each 1H, m, CHOH), 3.90, 3.89, (3.89), (3.88) (each 3H, s,
OCH3), 3.05 (1H, dd, J¼13.8, 3.9 Hz, 10-H), (2.98) (1H, dd,
J¼13.8, 8.0 Hz, 10-H), (2.84) (1H, dd, J¼13.8, 4.2 Hz,
10-H), 2.74 (1H, dd, J¼13.8, 8.8 Hz, 10-H), 2.50 (2H, br s,
OH), 1.93, (1.92) (each 3H, COCH3), 1.42, (1.42) (each 3H,
d, J¼7.0 Hz, CHCH3) and 1.26, (1.23) (each 3H, d,
J¼6.2 Hz, 30-H); dC (100.63 MHz; CDCl3; Me4Si) 169.1,
(168.7) (2£NCvO), 154.4, 151.9, (140.5), 140.3 (6£ArC–
O), 137.9, (137.7), 132.2, (131.9) (4£ArC–C), (128.4),
128.3, 127.8, (127.7), 127.7 (6£ArC–H), 122.2 (2£ArC–
C), 96.3, (96.3) (2£5-C), 74.6 (2£OCH2), 68.7, (68.6)
(2£CHCH3), 56.0, (55.9), 55.7, (55.6) (4£OCH3), 44.2
(2£20-C), 36.8, (36.3) (2£10-C), 24.3, 23.5, (23.5) and 21.0,
(20.8) (6£CH3); m/z (EI) 387.2033 (2%) (Mþ, C22H29NO5
requires 387.2044), 343 (7), 252 (35), 193 (56), 91 (26) and
44 (20).
7.1.3. N-Acetyl-5-benzyloxy-6,8-dimethoxy-1,3-trans-
dimethyl-1,2,3,4-tetrahydroisoquinoline 8 and N-{1-[3-
(benzyloxy)-2-(2-hydroxypropyl)-4,6-dimethoxy-
phenyl]ethyl}acetamide, 15. Mercury(II) acetate (0.27 g,
1.5 mmol) was added to amide 9 (0.19 g, 0.51 mmol)
dissolved in tetrahydrofuran (THF) (10 cm3). The yellow
mixture was then stirred in the dark, under argon for 21 h at
ambient temperature. A further portion of mercury(II)
acetate (0.18 g, 0.56 mmol) was added and the mixture
was stirred for a further 18 h. A mixture of sodium
borohydride (0.050 g, 1.3 mmol) in aqueous sodium
hydroxide (5 cm3, 2.5 M) was then added whilst stirring.
After stirring for a further 1 h a saturated aqueous Na2CO3
solution (5 cm3) was added and the reaction was stirred for
an extra 20 min. After the reaction had stood for a further
30 min, the THF was decanted and removed under reduced
7.1.4. 2-[2-[1-(Acetylamino)ethyl]-6-(benzyloxy)-3,5-
dimethoxy-phenyl]-1-methylethyl methanesulfonate, 17.
Alcohol 15 (0.050 g, 0.13 mmol) was dissolved in dichloro-
methane (5 cm3) and cooled to 08C under an argon

C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
8343
atmosphere. Methanesulfonyl chloride (0.015 cm3, 0.022 g,
0.19 mmol) and triethylamine (0.027 cm3, 0.020 g,
0.19 mmol) were added sequentially to afford a pale yellow
solution, which was warmed to ambient temperature. The
reaction mixture was stirred for 60 h, after which the solvent
was removed in vacuo. Purification by silica gel preparative
layer chromatography (plc) (60% ethyl acetate/29% hexane/
1% aq. ammonia solution) afforded the mesylate 17
(0.060 g, quantitative) as a dark oil. The product was
isolated as a mixture of two diastereomers in an approxi-
mately even ratio. nmax (film)/cm21 3442br (NH), 2868m
(CH, OCH2), 2842m (CH, OCH3), 1655s (CvO), 1597m
(ArCvC) and 1331s (R-SO-R); dH (400 MHz; CDCl3;
Me4Si; Assignments in brackets are tentatively for the other
diastereomer) 7.45–7.30 (10H, m, 10£ArH), 6.81, (6.74)
(each 1H, d, J¼9.3 Hz, NH), 6.52 (2H, s, 4-H), 5.47–5.42
(2H, m, 20-H), 5.13 (1H, q, J¼6.4 Hz, CHCH3), (4.98–4.88)
(1H, m, under OCH2, CHCH3), (5.06), 4.96 (each 1H, d,
J¼11.0 Hz, OCH2), 4.89, (4.83) (each 1H, d, J¼11.0 Hz,
OCH2), 3.91, (3.91) (each 3H, s, OCH3), 3.89 (6H, s,
OCH3), (3.32) (1H, dd, J¼14.0, 8.7 Hz, 10-H), 3.14 (2H, dd,
J¼7.0, 4.8 Hz, 10-H), (2.93) (1H, dd, J¼14.0, 5.4 Hz, 10-H),
2.86, (2.56) (each 3H, s, SO2CH3), 1.93 (6H, s, COCH3),
1.47, (1.44) (each 3H, d, J¼6.9 Hz, 30-H) and 1.42, (1.35)
(each 3H, d, J¼6.4 Hz, CHCH3); dC (100.63 MHz; CDCl3;
Me4Si) (168.7), 168.6 (2£NCvO), (154.5), 154.4, 151.9,
(151.8), 140.5 (6£ArC–O), (137.7), 137.6, (129.6), 129.1
(4£ArC–C), 128.4, 128.4, 127.9 (6£ArC–H), (122.6),
122.4 (2£ArC–C), 96.9, (96.8) (2£4-C), (80.9), 80.3
(2£20-C), (74.8), 74.7 (2£OCH2), 55.9, 55.7 (4£OCH3),
44.0 (2£CHCH3), 37.3, (37.2) (2£10-C), (33.9), 33.4
(2£SO2CH3), 23.5, (23.4), 21.3 and (20.8), 20.7 (6£CH3).
(3H, d, J¼6.9 Hz, CH3), 1.43 (3H, d, J¼6.8 Hz, CH3),
1.30–1.21 (12H, multiple doublets, 4£CH3), 0.84 (3H, d,
J¼6.4 Hz, 3-CH3 trans) and 0.83 (3H, d, J¼6.3 Hz, 3-CH3
trans); dC (50.32 MHz; CDCl3; Me4Si) 170.0, 169.7
(2£NCvO trans), 169.4, 169.0 (2£NCvO cis), 152.2,
151.8, 151.4, 151.1, 151.0, 139.5, 139.0, 138.7, 138.4
(12£ArC–O), 137.6, 137.5, 129.0, 128.6 (4£ArC–C),
128.6, 128.5, 128.4, 128.4, 128.3, 128.0, 128.0 (12£ArC–
H), 128.0, 127.9 (2£ArC–C cis), 119.5 (2£ArC–C trans),
119.2, 119.1 (2£ArC–C cis), 118.6 (ArC–C trans), 95.3 (7-
C cis), 95.2 (7-C trans), 95.0 (7-C cis), 94.9 (7-C trans),
75.3, 75.0, 74.7 (4£OCH2), 56.7, 56.1, 56.0, 56.0, 55.6, 55.6
(8£OCH3), 49.1 (3-C trans), 47.5 (1-C cis), 47.5 (2£1-C
cis), 46.7 (1-C trans), 46.3 (3-C trans), 44.4 (3-C trans),
44.4 (3-C cis), 43.6 (3-C cis), 29.1 (4-C cis), 28.6 (4-C
trans), 28.4 (4-C cis), 27.8 (4-C trans), 23.2, 22.9, 22.6,
22.4, 22.3, 22.2, 21.8, 21.3, 21.0, 20.9 and 19.2 (12£CH3).
Acknowledgements
This material is based upon work supported by the National
Research Foundation under Grant number 2053652. Sup-
port from the University of the Witwatersrand (University
Research Council) is also gratefully acknowledged. We
thank Mr R. W. M. Krause for assistance with the molecular
modelling and Professor H. M. Marques for comments
concerning this section. WALvO thanks AECI
(Modderfontein, South Africa) for a Postgraduate
Fellowship.
7.1.5. N-Acetyl-5-benzyloxy-6,8-dimethoxy-1,3-trans-
dimethyl-1,2,3,4-tetrahydroisoquinoline 8 and N-acetyl-
5-benzyloxy-6,8-dimethoxy-1,3-cis-dimethyl-1,2,3,4-
tetrahydroisoquinoline, 16. Sodium hydride (60% in oil,
0.03 g, 0.86 mmol) was added to mesylate 17 (0.040 g,
0.086 mmol) dissolved in dry tetrahydrofuran (THF)
(10 cm3), under an argon atmosphere. The reaction mixture
was stirred for 18 h, after which the mixture was cooled to
08C. Water (10 cm3) was added dropwise and the mixture
was extracted with diethyl ether (2£10 cm3). The combined
organic solvents were washed with brine (10 cm3), dried
(MgSO4) and concentrated in vacuo. Silica gel preparative
layer chromatography (65% ethyl acetate/33% hexane/1%
aq. ammonia solution) afforded the products 8 and 16
(0.027 g, 85%) as an equimolar mixture of cis- and trans-
isomers and their rotamers which were not separated; dH
(200 MHz; CDCl3; Me4Si) 7.43–7.31 (20H, m, 20£ArH),
6.44, 6.43, 6.43 (4H, 3£s, 7-H), 5.78 (1H, q, J¼6.8 Hz, 1-H
cis), 5.50 (1H, q, J¼6.4 Hz, 1-H trans), 5.15 (1H, q,
J¼6.5 Hz, 1-H cis), 5.16 (1H, q, J¼6.6 Hz, 1-H trans),
4.96–4.84 (8H, m, 4£OCH2), 4.68–4.62 (1H, m, 3-H
trans), 4.52 (1H, q, J¼6.8 Hz, 3-H cis), 4.23–4.15 (1H, m,
3-H trans), 4.08–3.99 (1H, m, 3-H cis), 3.91–3.82 (24H,
multiple singlets, 8£OCH3), 3.04–2.97 (2H, m, 4-H trans
and 4-H cis), 2.99 (1H, dd, J¼15.2, 2.4 Hz, 4-H pseudo-
equatorial trans), 2.84 (1H, dd, J¼16.4, 6.8 Hz, 4-H cis),
2.68 (1H, dd, J¼16.3, 4.4 Hz, 4-H cis), 2.64–2.54 (2H, m,
2£4-H pseudo-axial trans), 2.52 (1H, dd, J¼16.4, 7.4 Hz, 4-
H cis), 2.24 (3H, s, COCH3 trans), 2.20 (3H, s, COCH3 cis),
2.17 (3H, s, COCH3 trans), 2.12 (3H, s, COCH3 cis), 1.44
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preference for a chair-like transition state with an equatorial
methyl group. We attempted to derive a plausible transition
state configuration for our system using Dreiding models but
were unable to find a configuration that rationalized the
formation of the proposed trans-configuration of our tetra-
hydroisoquinoline product. Our results would thus support the
claim that amidomercuration reactions occur with greater
regio- and stereoselectivity than the analogous aminomercura-
tion reaction described in (b) Roussel, J.; Perie, J. J.; Laval,
J. P.; Lattes, A. Tetrahedron 1972, 28, 701–716. However, a
related example, (c) Clive, D. L. J.; Farina, V.; Singh, A.;
Wong, C. K.; Kiel, W. A.; Menchen, S. M. J. Org. Chem.
8. Balasubramanian, M.; Scriven, E. F. V. Isoquinoline and its
derivatives. In Heterocyclic Compounds, Parts F and G.
Second Supplements to the Second Edition of Rodd’s
Chemistry of Carbon Compounds; Sainsbury, M., Ed.;
Elsevier: Amsterdam, 1998; Vol. IV, pp 163–216.
9. (a) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.;
Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993,
877–888. (b) Hoye, T. R.; Chen, M. Tetrahedron Lett. 1996,
37, 3099–3100. (c) Watanabe, T.; Uemura, M. Chem.
Commun. 1998, 871–872. (d) Whaley, W. M.; Govindachari,
T. R. Org. React. 1951, 6, 74–150.
¨
10. (a) Bringmann, G.; Gotz, R.; Harmsen, S.; Holenz, J.; Walter,
R. Liebigs Ann. Chem. 1996, 2045–2058. (b) Whaley, W. M.;
Govindachari, T. R. Org. React. 1951, 6, 151–206.

C. B. de Koning et al. / Tetrahedron 59 (2003) 8337–8345
8345
1980, 45, 2120–2126, describing the cyclofunctionalization of
olefinic urethanes using benzeneselenenyl chloride affords
products with a 1,3-cis-relationship of the ring substituents in
contrast with the trans-relationship described for 8 in our
work.
34. Peters, K.; Peters, E.-M.; Bringmann, G.; Keller, P. A.;
¨
Schaffer, M. Z. Naturforsch 1995, 50b, 1137–1139.
35. This included the removal of the benzyl protecting group to
decrease the complexity of the system and thereby decrease
the computational time required for each modelling
calculation.
36. HYPERCHEMw; Release 5 for Windowsw; Hypercube, Inc
and ALCHEMYw III, Tripos Associates, Inc.
26. The formation of a mixture of trans- and cis- cyclized products
by nucleophilic displacement of mesylate by the amide
nitrogen is a consequence of 17 being a mixture of
diastereomers.
37. (a) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127–8134.
(b) MMþ force field, N.L. Allinger, 1991. (c) Torsional
parameters for the bonds N2–C4–Ca–Ca, Ca–C4–N2–C4
and Ca–C4–N2–CO had to be provided (Ca¼aromatic
carbon, C4¼aliphatic carbon, N2¼amide nitrogen and CO¼
carbonyl carbon) and were left unconstrained (i.e. Fourier
terms: V1, V2 and V3 were entered as 0.000)
27. Spectroscopic comparison with the pure trans-compound 8
isolated from the amidomercuration reaction proved that
trans-1,3-dimethyltetrahydro-isoquinoline was present in the
mixture and the peaks for the cis- product were much clearer
because of its increased abundance.
˜
28. (a) Oki, M. In The Chemistry of Rotational Isomers; Hafner,
´
K., Lehn, J. M., Rees, C. W., von Rague Schleyer, P., Trost,
38. The minimum energy of the trans-compound 18
(5.4 kcal mol21) was 1.3 kcal mol21 lower in energy than
the minimum of the cis-compound 19 (6.7 kcal mol21). This
energy difference could be attributed to the relative values of
the angle strain [5.9 kcal mol21 (trans) vs 6.8 kcal mol21
(cis)—the origin of this angle strain was not evident when
comparing the two structures], Van der Waals repulsion
[10.6 kcal mol21 (trans) vs 11.5 kcal mol21 (cis)] and
dihedral angle contributions [24.4 kcal mol21 (trans) vs
25.0 kcal mol–1 (cis)].
´
B. M., Zahradnık, R., Eds.; Springer: Berlin, 1993; pp 1–19
¨
see also pages 20–50 and 51–97. (b) Sandstrom, J. Dynamic
NMR Spectroscopy; Academic: New York, 1982; pp 6–29,
77–92, and 93–109. (c) Akitt, J. W. NMR and Chemistry: An
Introduction to Modern NMR Spectroscopy; 3rd ed. Chapman
˜
& Hall: London, 1992; pp 135–147. (d) Oki, M. Methods in
Stereochemical Analysis: Applications of Dynamic NMR
Spectroscopy to Organic Chemistry; VCH: Weinheim, 1985;
Vol. 4. pp 1–12. (e) Kessler, H. Angew. Chem., Int. Ed. 1970,
9, 219–235.
39. Some general examples of calculated barriers to rotation
quoted in reviews on the structures of amides are 20, Robin,
M. B.; Bovey, F. A.; Basch, H. In The Chemistry of Amides;
Zabicky, J., Ed.; Interscience: New York, 1970; pp 1–72,
29. (a) Stewart, W. E.; Siddall, T. H., III. Chem. Rev. 1970, 70,
517–551. (b) Fraenkel, G.; Franconi, C. J. Am. Chem. Soc.
1960, 82, 4478–4483. (c) Gutowsky, H. S.; Holm, C. H.
J. Chem. Phys. 1956, 25, 1228–1234. (d) Rogers, M. T.;
Woodbrey, J. C. J. Phys. Chem. 1962, 66, 540–546.
(e) Takeda, M.; Stejskal, E. O. J. Am. Chem. Soc. 1960, 82,
25–29.
´
15.7, Drakenberg, T.; Dahlqvist, K.-I.; Forsen, S. Acta Chem.
Scand. 1970, 24, 694–702, and 15–22 kcal mol21 (Ref. 29a).
A barrier to rotation for the H2N(CvO)R system has also
recently been calculated by molecular modelling on the G2
theoretical level, Wiberg, K. B.; Murcko, M. A. Tetrahedron
1997, 53, 10123–10132, and a value of 16 kcal mol21 was
assigned to this rotation. For more information regarding this
topic see the following report: Wiberg, K. B. Acc. Chem. Res.
1999, 32, 922–929.
30. Bishop, G. J.; Price, B. J.; Sutherland, I. O. J. Chem. Soc.,
Chem. Commun. 1967, 672–674.
31. The fourth value of 15.6^0.3 kcal mol21, calculated for signal
a in Figure 4, lies on the edge of this range and was not
included in the calculation of the average free energy of
activation.
40. Energy barriers for the interconversion of tetrahydroisoquino-
line conformers have also been determined by Fraenkel et al.15
Olefirowicz and Eliel, Olefirowicz, E. M.; Eliel, E. L. J. Org.
Chem. 1997, 62, 9154–9158, report the experimentally
determined conformational barrier, DG 0, for 1,3-trans-
dimethyl-1,2,3,4-tetrahydroisoquinoline as 1.18 kcal mol21
(calculated 1.03 kcal mol21) and as ‘large’ (calculated
3.68 kcal mol21) for the cis compound. These values are
relatively small when compared to the barrier due to amide
rotation (about 16 kcal mol21) determined in our variable
32. This was not always easy as the Dd values did not always tend
to a constant over the temperature range used. The coalescence
temperature was taken to be the temperature at which the
separate signals merged to form a single signal. For a
discussion on the limitations of the approach used in this
study see: Allerhand, A.; Gutowsky, H. S.; Jonas, J.; Meinzer,
R. A. J. Am. Chem. Soc. 1966, 88, 3185–3194.
33. (a) Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74,
961–963. (b) Kost, D.; Carlson, E. H.; Raban, M. J. Chem.
Soc., Chem. Commun. 1971, 656–657, This approach has been
shown to afford reliable estimates within specified limits
which include that Dd be larger than 3 Hz for uncoupled
systems, and that for coalescing singlets and doublets of
different intensities (as in our case), good estimates are
achieved as long as Dd.4 Hz.
1
temperature H NMR spectroscopy and molecular modelling
work. We are therefore convinced that the doubling evident in
the NMR spectra of tetrahydroisoquinoline 8 and 16, is due to
the presence of amide rotamers in solution rather than the
presence of separate conformers.