Synthesis of 1-substituted tetrahydroisoquinolines by lithiation and electrophilic quenching guided by in situ IR and NMR spectroscopy and application to the synthesis of salsolidine, carnegine and laudanosine

Article abstract of DOI:10.1002/chem.201301096

The lithiation of N-tert-butoxycarbonyl (N-Boc)-1,2,3,4- tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using n-butyllithium in THF at -50 °C for less than 5 min. The intermediate organolithium was quenched with electrophiles to give 1-substituted 1,2,3,4-tetrahydroisoquinolines. Monitoring the lithiation by IR or NMR spectroscopy showed that one rotamer reacts quickly and the barrier to rotation of the Boc group was determined by variable-temperature NMR spectroscopy and found to be about 60.8 kJ mol^-1, equating to a half-life for rotation of approximately 30 s at -50 °C. The use of (-)-sparteine as a ligand led to low levels of enantioselectivity after electrophilic quenching and the "poor man's Hoffmann test" indicated that the organolithium was configurationally unstable. The chemistry was applied to N-Boc-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine. Copyright

Full text of DOI:10.1002/chem.201301096

FULL PAPER
DOI: 10.1002/chem.201301096
Synthesis of 1-Substituted Tetrahydroisoquinolines by Lithiation and
Electrophilic Quenching Guided by In Situ IR and NMR Spectroscopy and
Application to the Synthesis of Salsolidine, Carnegine and Laudanosine
Xiabing Li, Daniele Leonori, Nadeem S. Sheikh, and Iain Coldham*[a]
In memory of Robert E. Gawley
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Abstract: The lithiation of N-tert-bu-
toxycarbonyl (N-Boc)-1,2,3,4-tetrahy-
droisoquinoline was optimized by in
situ IR (ReactIR) spectroscopy. Opti-
mum conditions were found by using
n-butyllithium in THF at À508C for
less than 5 min. The intermediate orga-
nolithium was quenched with electro-
philes to give 1-substituted 1,2,3,4-tet-
rahydroisoquinolines. Monitoring the
lithiation by IR or NMR spectroscopy
showed that one rotamer reacts quickly
and the barrier to rotation of the Boc
group was determined by variable-tem-
perature NMR spectroscopy and found
to be about 60.8 kJmolÀ1, equating to a
half-life for rotation of approximately
30 s at À508C. The use of (À)-sparteine
as a ligand led to low levels of enantio-
selectivity after electrophilic quenching
and the “poor manꢁs Hoffmann test”
indicated that the organolithium was
configurationally unstable. The chemis-
try was applied to N-Boc-6,7-dime-
thoxy-1,2,3,4-tetrahydroisoquinoline
and led to the efficient synthesis of the
racemic alkaloids salsolidine, carne-
gine, norlaudanosine and laudanosine.
Keywords: alkaloids · carbanions ·
heterocyclic compounds · IR spec-
troscopy · metalation
Introduction
The tetrahydroisoquinoline moiety is a very common fea-
ture in natural products. 1-Substituted 1,2,3,4-tetrahydroiso-
quinolines are the most abundant class of such alkaloids and
comprise a core ring system from which many structural
groups are derived. Some of these are quite complex[1] but
even simple derivatives possess a wide range of biological
activities. For example, 1-methyl-1,2,3,4-tetrahydroisoquino-
line, which exists in mammalian brains, is connected to the
pathogenesis of Parkinsonꢁs disease.[2] 1-Phenyl- and 1-
benzyl-1,2,3,4-tetrahydroisoquinoline are dopamine receptor
antagonists.[3] The tetrahydroisoquinolines salsolidine and
laudanosine (Figure 1) inhibit the uptake of 5-hydroxytrypt-
amine by human blood platelets[4] and affect the cardiovas-
cular system,[5] respectively. Synthetic tetrahydroisoquino-
lines form the basis of several pharmaceutical drugs, includ-
ing solifenacin (which has urinary antispasmodic proper-
ties)[6] and noscapine (an antitussive agent; Figure 1).[7]
Classical approaches to the preparation of 1-substituted
1,2,3,4-tetrahydroisoquinolines involve the Pictet–Spengler
and Bischler–Napieralski reactions, starting from b-aryle-
thylamines.[8] Alternative approaches include the addition of
nucleophiles to, or reduction of, 3,4-dihydroisoquinolines.[8,9]
An interesting approach involves lithiation of 1,2,3,4-tetra-
hydroisoquinolines followed by electrophilic quenching; typ-
ically, tert– or sec-butyllithium have been used as the base,
for example, in reports by Seebach and co-workers using N-
Figure 1. Some biologically active 1,2,3,4-tetrahydroisoquinolines.
iliary.[15] Activation of N-methyl-1,2,3,4-tetrahydroisoquino-
line for lithiation is possible by prior complexation of the
amine with BF3 or BH3.[16] One of the most versatile nitro-
gen substituents for adjacent lithiation is the tert-butoxycar-
bonyl (Boc) group, developed by Beak and co-workers.[17] In
an isolated report, Coppola used tert-butyllithium in a mix-
ture of THF and tetramethylethylenediamine (TMEDA) at
À788C for 40 min for the lithiation of N-Boc-1,2,3,4-tetrahy-
droisoquinoline followed by trapping with iodomethane or a
benzyl bromide.[18]
Following our work with N-Boc-pyrrolidine and piperi-
dine, we became interested in the lithiation of 1,2,3,4-tetra-
hydroisoquinolines.[19,20] In particular, we wanted to investi-
gate whether it was necessary to use a strong base, what the
best conditions (temperature, time and solvent) were for the
lithiation, and whether a range of electrophiles could be in-
troduced. We were also interested in whether any asymme-
try could be induced by using a chiral ligand, and hence the
extent of the configurational stability of N-Boc-1-lithio-
1,2,3,4-tetrahydroisoquinoline. In addition, we wanted to
apply the chemistry to the synthesis of some 1-substituted
1,2,3,4-tetrahydroisoquinoline alkaloids.
[10]
À
pivaloyl (N COtBu) 1,2,3,4-tetrahydroisoquinolines,
by
[11]
À
Meyers and co-workers using formamidines (N CNtBu),
or by Katritzky and Akutagawa using the N-lithiocarboxy-
[12]
À
late salt (N CO2Li).
Diastereoselective substitutions have been reported with
chiral formamidines,[13] oxazolines,[14] or a sugar-derived aux-
[a] X. Li, Dr. D. Leonori, Dr. N. S. Sheikh, Prof. I. Coldham
Department of Chemistry, University of Sheffield
Brook Hill, Sheffield S3 7HF (UK)
Herein, we describe our successful optimisation of the
lithiation conditions, which makes use of in situ IR and
1H NMR spectroscopic monitoring of the reaction.[21] Re-
cently, we reported the benefit of using these techniques to
optimise the lithiation of N-Boc-2-phenylpyrrolidine and pi-
Fax : (+44)114-222-9346
E-mail: i.coldham@sheffield.ac.uk
Supporting information (experimental details) for this article is avail-
able on the WWW under http://dx.doi.org/10.1002/chem.201301096.
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1-Substituted Tetrahydroisoquinolines
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peridine.[22] Monitoring with ReactIR provides information
on the extent of lithiation at different temperatures over dif-
ferent time periods and therefore on the rate of interconver-
sion of the N-Boc rotamers. This is important, as the carbon-
yl group directs the lithiation by complexation to the
base,[23] so that only rotamer 1a (Scheme 1) is able to under-
Table 1. Initial optimisation of the lithiation followed by TMSCl quench-
ing reaction of 1 at À788C.
Entry
Base[a]
Solvent
Additive[a]
Yield [%]
1
2
3
4
5
6
7
8
sBuLi
sBuLi
sBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
THF
Et2O
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
–
–
–
–
56
63
47
62
55
51
30
52
35
54
PhMe
THF
2-methylTHF
PhMe
Et2O
THF
THF
THF
9[b]
10[c]
Scheme 1. Rotamers of N-Boc-1,2,3,4-tetrahydroisoquinoline.
[a] 1.2–1.3 equivalents. [b] Lithiation time: 1 min. [c] Lithiation time: 2 h.
go subsequent benzylic lithiation at the 1-position. We
report herein the spectroscopic analysis of N-Boc-1,2,3,4-tet-
rahydroisoquinoline 1, which reveals the conformation of
this compound and the rate of rotation of the Boc group
that is critical to achieve efficient metallation. This has led
to improved metallation conditions and we have applied
these to the total synthesis of several tetrahydroisoquinoline
alkaloids.
Attempts to improve reaction yields by using this type of
optimization by stepwise variation of the conditions are typ-
ical of the approach taken by synthetic chemists when devel-
oping new methodology. The use of nBuLi or sBuLi at
À788C in THF, or in Et2O/TMEDA, is typical of organo-
lithium reactions, however, these conditions may not be op-
timal.[24] To gain a better insight into what is happening in
solution, and thereby aid the identification of more suitable
conditions, we used in situ monitoring of the reaction by
spectroscopy. The reaction of N-Boc-tetrahydroisoquinoline
1 is well suited to in situ IR spectroscopy because of the
ease of monitoring the carbonyl stretching frequency and
the shift of this peak as a result of coordination of the car-
bonyl oxygen atom with the metal.
Results and Discussion
The tetrahydroisoquinoline 1 was prepared in high yield by
simple treatment of 1,2,3,4-tetrahydroisoquinoline with
Boc2O in THF (08C, 2 h, 96% yield). For the deprotonation,
we opted to avoid the hazardous reagent tert-butyllithium
and to screen other bases and conditions. The electrophile
trimethylsilyl chloride (TMSCl) was used for these studies
(Scheme 2).
Tetrahydroisoquinoline 1 exhibited a peak for nC
at
=
O
1696 cmÀ1 in the IR spectrum. On addition of nBuLi, there
was rapid (<2 min) but partial loss of this peak, followed by
further slow (>1 h) loss over time (Figure 2). At the same
time, a new peak for nC O at 1635 cmÀ1 was rapidly produced
=
at first and then further slow formation occured over the
same time frame.
The partial rapid lithiation followed by slow further lithia-
tion can be seen clearly in the 2D plot in Figure 2 (nC at
=
O
1635 cmÀ1). This result indicates that there is slow rotation
of the Boc group at À788C and that this limits the rate of
metallation at this temperature. This can be explained by
the rapid lithiation of the rotamer 1a together with slow ro-
tation of 1b and thus further lithiation of 1a as it forms.
To improve the rate of metallation, the reaction was car-
ried out at À508C and the IR plots are shown in Figure 3.
At this temperature, the rotation of the Boc group must be
rapid as the reaction is complete within a few minutes, even
with nBuLi as the base. At the higher temperature of 08C,
lithiation was again rapid but the organolithium was unsta-
ble and decomposed.
To gain further insight into the effect of the rotamers on
the lithiation, we investigated the reaction by using
1H NMR spectroscopy. In the 1H NMR spectrum of 1 in
[D8]THF at À458C, the signals for the rotamers of the ben-
zylic CH2 were clearly separated, at d=4.55 and 4.52 ppm,
and were found to exist in a 51:49 ratio (Figure 4c). Addi-
tion of nBuLi at À458C resulted in the rapid loss of one of
these peaks (Figure 4b) followed by the loss of the other
Scheme 2. Lithiation, then TMSCl quenching of N-Boc-1,2,3,4-tetrahy-
droisoquinoline.
The bases sBuLi and nBuLi were tested by using various
solvents, with or without the additive TMEDA, at À788C
for 1 h. In all cases (Table 1), similar yields of the product 2
were obtained. The base nBuLi (Table 1, entries 4–10) gave
similar results to reactions with sBuLi (Table 1, entries 1–3),
demonstrating that the metallation takes place without the
need for the stronger base. In addition, it appears that the
use of TMEDA is unnecessary to promote this reaction
(compare Table 1, entries 4 and 8) at least when using THF
as the solvent. There was a noticeable reduction in the yield
after the use of a short reaction time of 1 min (Table 1,
entry 9), although there was no significant improvement
from the use of a longer reaction time of 2 h (Table 1,
entry 10).
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Figure 4. Partial 1H NMR spectra of 1 on addition of nBuLi in [D8]THF
at À458C. Signals at ꢀ4.5 ppm for the benzylic protons of c) the two ro-
tamers of 1; b) compound 1 and nBuLi after immediate acquisition; and
a) compound 1 and nBuLi, after about 1 min.
ers. In a separate experiment without BuLi, a sample of tet-
rahydroisoquinoline 1 in [D8]THF was warmed to observe
coalescence of the signals for the benzylic protons, which oc-
curred at about 5.58C (see the Supporting Information).
From this coalescence temperature and the difference in
chemical shift between the rotamers at low temperature, it
can be determined that the barrier for rotation, DG°, is 60.8
kJmolÀ1 at 5.58C. Assuming similar barriers at lower tem-
peratures (see the Supporting Information), the half-life
(t1/2) for rotation of the Boc group in 1 was estimated to be
about 30 s at À508C. In contrast, the half-life for rotation of
the Boc group in 1 was estimated to be about 50 min at
Figure 2. In situ IR 3D and 2D plots of the lithiation of 1 at À788C in
THF/TMEDA. One line represents the intensity of the C=O stretching
frequency of 1 (1696 cmÀ1), while the other represents that of lithiated 1
(1635 cmÀ1) over time.
1
À788C. These results, gained by H NMR spectroscopy, are
consistent with those from the in situ IR spectroscopy and
experimental data.
On the basis of the aforementioned spectroscopic data,
we opted to conduct the lithiation of tetrahydroisoquinoline
1 by using nBuLi in THF without TMEDA at À508C for
4 min. Addition of the electrophile TMSCl then gave tetra-
hydroisoquinoline 2 in an improved yield (74% yield after
purification by column chromatography) in comparison with
the conditions described in Table 1. Other electrophiles
were used under the same conditions and the results are
given in Scheme 3.
The electrophilic quenching of lithiated compound 1 was
successful with a variety of electrophiles, including benzyl
bromide, allyl bromide, iodomethane and 1-bromobutane,
giving the racemic products 3–6 (Scheme 3). The electro-
phile tributyltin chloride provided stannane product 7, and
the use of benzaldehyde gave a separable mixture of the di-
astereomeric alcohols 8 in high yield. Reduction of the Boc
group of tetrahydroisoquinoline 3 with LiAlH4 gave product
9 with the secoaporphine alkaloid structure (Scheme 4).
Figure 3. In situ IR 3D and 2D plots of the lithiation of 1 at À508C in
THF. One line represents the intensity of the C=O stretching frequency
of
1 1
(1698 cmÀ1), while the other represents that of lithiated
(1635 cmÀ1) over time.
peak (Figure 4a). This experiment fits with the in situ IR
spectroscopic data, supporting the theory that only one ro-
tamer is lithiated and there is rotation between the rotam-
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trophile TMSCl gave the product 2 with similar or the same
e.r. by using stoichiometric (3.5 equiv) or substoichiometric
(0.3 equiv) amounts of the electrophile, even at very low
temperature (Scheme 5; enantiomeric ratio determined by
Scheme 5. Probing the configurational stability of the organolithium.
CSP HPLC). The moderate enantioselectivity in the forma-
tion of 2 therefore likely arises from rapidly interconverting
organolithium·(À)-sparteine complexes and a slightly faster
reaction of one of these diastereomeric complexes with
TMSCl (dynamic kinetic resolution). Unfortunately, at-
tempts to obtain enantioenriched products such as 5 or 7 by
using the electrophiles MeI or Bu3SnCl resulted in only
poor enantiomeric ratios (e.r.ꢁ60:40).
Scheme 3. Lithiation, then quenching of N-Boc-1,2,3,4-tetrahydroisoqui-
noline 1.
The similar enantiomeric ratios with stoichiometric or
substoichiometric amounts of the electrophiles indicate that
N-Boc-1-lithiotetrahydroisoquinoline is configurationally
labile in toluene and that even at À1008C the enantioselec-
tivity arises from the faster reaction of one diastereomeric
complex. As the activation barriers for the reaction should
be different for different complexes, it may be possible to
find a chiral ligand that would promote good enantioselec-
tivity through dynamic resolution. We screened the ligands
shown in Figure 5 for the resolution of N-Boc-1-lithiotetra-
hydroisoquinoline, although all reactions resulted in essen-
tially racemic products by using TMSCl as the electrophile.
Many tetrahydroisoquinoline alkaloids contain hydroxy or
alkoxy substituents on the aromatic ring and these could in-
fluence the reactivity and/or configurational stability of the
organolithium intermediate in this chemistry. We therefore
prepared the 6,7-dimethoxytetrahydroisoquinoline deriva-
tive 10 for comparison with compound 1.
Scheme 4. Reduction of tetrahydroisoquinoline 3.
There are currently no reports on the configurational sta-
bility of N-Boc-1-lithiotetrahydroisoquinoline and we were
interested in whether the chiral organolithium could be gen-
erated in enantiomerically enriched form and whether it
could maintain its configuration. An alternative approach to
enantiomerically enriched products would be to promote a
dynamic resolution,[25] should the organolithium be configu-
rationally unstable, which is the finding for related com-
pounds.[26]
To probe the configurational stability of the organolithi-
um formed by deprotonation of tetrahydroisoquinoline 1,
we used Beakꢁs version of the Hoffmann test, sometimes re-
ferred to as the “poor manꢁs Hoffmann test” due to the lack
of requirement for a chiral electrophile.[27] In this test, the
organolithium is complexed with a chiral ligand and then re-
acted with an excess of the electrophile. The enantiomeric
ratio (e.r.) of the product is then compared with the same
product formed by using the same chiral ligand and a sub-
stoichiometric amount of the electrophile. If the enantiomer-
ic ratios are different then this indicates that the organolithi-
um has configurational stability on the timescale of the reac-
tion with the electrophile.
Tetrahydroisoquinoline 1 was treated with nBuLi and the
chiral ligand (À)-sparteine in toluene (to avoid any compet-
ing solvation with ethereal solvents). Addition of the elec-
Figure 5. Chiral ligands screened for the dynamic resolution. Ligand and
lithiated 1 at À788C in PhMe or Et2O, followed by addition of TMSCl
gave product 2 with e.r. values of 50:50–57:43.
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I. Coldham et al.
The organolithium derived from deprotonation of 10 was
found to be configurationally unstable, in the same way as
the deprotonated tetrahydroisoquinoline 1. Hence, similar
enantiomeric ratios of the product 11 were obtained on lith-
iation of 10 with nBuLi in PhMe and (À)-sparteine with ad-
dition of stoichiometric (3.5 equiv) or substoichiometric
(0.3 equiv) amounts of the electrophile TMSCl. In this case,
the selectivities were poorer (e.r.ꢀ70:30 at À1008C and e.r.
ꢀ55:45 at À788C) than those with tetrahydroisoquinoline 1.
Obtaining similar enantiomeric ratios under stoichiometric
and substoichiometric conditions indicates that the organo-
lithium is not configurationally stable even at À1008C.
The racemic lithiation of tetrahydroisoquinoline 10 ap-
peared to follow similar kinetics to that of the unsubstituted
tetrahydroisoquinoline 1, so we conducted the reaction at
À508C for 4 min and screened a range of electrophiles
(Scheme 6). Good yields of 1-substituted products 11–16
were obtained by using the electrophiles TMSCl, Bu3SnCl,
alkyl halides or benzaldehyde. The diastereoisomers of
product 16 were separable by column chromatography.
Scheme 7. Synthesis of tetrahydroisoquinoline alkaloids.
Conclusion
We have found that the simple base nBuLi is capable of de-
protonating N-Boc-tetrahydroisoquinoline and N-Boc-6,7-
dimethoxytetrahydroisoquinoline in THF at À508C in less
than 5 min. The resulting organolithium compounds react
with a variety of electrophiles to give 1-substituted tetrahy-
droisoquinoline products. The kinetics for rotation of the
carbamate group were determined by NMR spectroscopy
and the use of in situ IR spectroscopy allowed the optimisa-
tion of the lithiation reaction. The organolithium com-
pounds are configurationally labile, even at À1008C in tol-
uene, and only low levels of asymmetric induction were ob-
tained by using a chiral ligand, presumably through a dy-
namic kinetic resolution pathway. The chemistry was applied
successfully to the total synthesis of several tetrahydroiso-
quinoline alkaloids.
Scheme 6. Lithiation, then quenching of N-Boc-tetrahydroisoquinoline
10.
Finally, we applied this chemistry to the synthesis of some
tetrahydroisoquinoline alkaloids (Scheme 7). Product 14 was
deprotected with trifluoroacetic acid (TFA) to give (Æ)-sal-
solidine in excellent yield. Alternatively, reduction by heat-
ing with LiAlH4 gave (Æ)-carnegine. Treatment of tetrahy-
droisoquinoline 10 with nBuLi in THF at À508C for 4 min,
followed by addition of 3,4-dimethoxybenzyl chloride gave
product 17, which was deprotected with TFA to give (Æ)-
norlaudanosine or reduced with LiAlH4 to give (Æ)-lauda-
nosine. The spectroscopic data for these products matched
those in the literature.[28]
Acknowledgements
We thank the China Scholarship Council and the Department for Busi-
ness Innovation & Skills (UK–China Scholarships for Excellence Pro-
gramme), the EPSRC (EP/E012272/1 and EP/F000340/1) and the Univer-
sity of Sheffield for support of this work. Simon Sedehizadeh is thanked
for preliminary studies and we are grateful to Brian Taylor for help with
the NMR spectroscopic studies.
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1-Substituted Tetrahydroisoquinolines
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Received: March 21, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

I. Coldham et al.
Spectroscopic optimization: Optimum
conditions for the lithiation of tetrahy-
droisoquinolines were established by
in situ IR and NMR spectroscopy. The
use of n-butyllithium in THF at À508C
for less than 5 min is preferable to the
reaction at À788C. The organolithium
was quenched with electrophiles to
give 1-substituted tetrahydroisoquino-
line products (see scheme).
Carbanions
X. Li, D. Leonori, N. S. Sheikh,
I. Coldham* ................... &&&& — &&&&
Synthesis of 1-Substituted Tetrahydroi-
soquinolines by Lithiation and Electro-
philic Quenching Guided by In Situ IR
and NMR Spectroscopy and Applica-
tion to the Synthesis of Salsolidine,
Carnegine and Laudanosine
Tetrahydroisoquinolines
Monitoring progress in organic reactions is possible by in
situ IR spectroscopy. This is particularly suited to organo-
metallic chemistry in which the metal coordinates to a
carbonyl group, changing the carbonyl stretching
frequency on reaction. This technique was used to opti-
mize the lithiation of N-Boc-tetrahydroisoquinolines.
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8
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!