Synthesis of 1,1-disubstituted tetrahydroisoquinolines by lithiation and substitution, with in situ IR spectroscopy and configurational stability studies

Article abstract of DOI:10.1021/ja500485f

Lithiation of N-Boc-1-phenyltetrahydroisoquinolines was optimized by in situ IR spectroscopy. The kinetics for rotation of the carbamate group and for the enantiomerization of the organolithium were determined. The organolithium is configurationally stable at low temperature, and the asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines can be achieved with high yields and high enantiomer ratios. The chemistry was applied to the preparation of FR115427 and provides a way to recycle the undesired enantiomer in the synthesis of solifenacin.

Full text of DOI:10.1021/ja500485f

Communication
pubs.acs.org/JACS
Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines by Lithiation
and Substitution, with in Situ IR Spectroscopy and Configurational
Stability Studies
Xiabing Li and Iain Coldham*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
S
* Supporting Information
phenylpiperidine (or pyrrolidine) gives an organolithium that
is configurationally stable at −50 °C for a few minutes.9 With
ABSTRACT: Lithiation of N-Boc-1-phenyltetrahydroiso-
quinolines was optimized by in situ IR spectroscopy. The
kinetics for rotation of the carbamate group and for the
enantiomerization of the organolithium were determined.
The organolithium is configurationally stable at low
temperature, and the asymmetric synthesis of 1,1-
disubstituted tetrahydroisoquinolines can be achieved
with high yields and high enantiomer ratios. The chemistry
was applied to the preparation of FR115427 and provides
a way to recycle the undesired enantiomer in the synthesis
of solifenacin.
only a few methods known for the synthesis of 1,1-disubstituted
tetrahydroisoquinolines, we were interested in studying the
lithiation and electrophilic quench of N-Boc-1-phenyltetrahy-
droisoquinolines and the configurational stability of the
intermediate organolithium species.
This paper describes the successful optimization of the
lithiation of two N-Boc-1-phenyltetrahydroisoquinolines by in
situ IR spectroscopy.10 This method provides information on
the extent of lithiation over time due to the directing effect of
the carbonyl group (only rotamer 4a can be lithiated at the 1-
position by BuLi, Scheme 1). The rates of Boc rotation of 4 and
1-Substituted 1,2,3,4-tetrahydroisoquinolines are found in
many important biologically active natural products and
pharmaceutical compounds.1 For example, solifenacin 1 (Figure
1) is a potent selective muscarinic M3 receptor antagonist with
Scheme 1. Rotamers of N-Boc-1-
phenyltetrahydroisoquinoline
of enantiomerization of the lithiated intermediate have been
determined. High enantiomer ratios of 1,1-disubstituted
products can be obtained, indicating substantial configurational
stability of the organolithium intermediate.
Treatment of racemic 6,7-dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinoline, which was synthesized according to a
literature procedure,11 with Boc2O in THF gave N-Boc-6,7-
dimethoxy-1-phenyltetrahydroisoquinoline 5 (89% yield).
Initially, lithiation of 5 was carried out using sec-BuLi, Et2O,
TMEDA at −78 °C (Scheme 2). After 1 h, addition of benzyl
bromide gave a good yield of the 1,1-disubstituted tetrahy-
Figure 1. Some hydrogenated isoquinoline drugs.
urinary antispasmodic properties.2 1,1-Disubstituted tetrahy-
droisoquinolines have received much less attention, but this
arrangement is present in drug compounds such as MK801
(dizocilpine) 2 and (+)-FR115427 3, which are noncompetitive
antagonists of the N-methyl-D-aspartate (NMDA) subclass of
receptors for the excitatory amino acid L-glutamate in brain
tissue.3
One approach to 1,1-disubstituted tetrahydroisoquinolines
uses the Pictet−Spengler reaction involving a 3-hydroxyphe-
nethylamine and a ketone.4 There are only a few asymmetric
approaches, such as the alkylation of 1-cyanotetrahydroisoqui-
nolines using a chiral phase-transfer catalyst,5 or the lithiation−
alkylation of a 1-alkyl-tetrahydroisoquinoline bearing a chiral
formamidine auxiliary.6 Meyers and co-workers found that 1-
lithio-1-methyltetrahydroisoquinolines bearing an N-formami-
dine group racemize rapidly.7 Likewise, we have found that N-
Boc-1-lithiotetrahydroisoquinoline is configurationally labile
even at −100 °C.8 In contrast, lithiation of N-Boc-2-
Scheme 2. Initial Studies of the Lithiation−Substitution of
rac-5
Received: January 24, 2014
Published: April 2, 2014
© 2014 American Chemical Society
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Communication
droisoquinoline 6. However, the strong base sec-BuLi was not a
requirement, as n-BuLi was found to result in a similar yield
(79% of 6).
Scheme 3. Lithiation−Substitution of ( )-5
The good yields obtained in this chemistry indicate that the
Boc group is able to rotate sufficiently rapidly at −78 °C to
allow lithiation at the benzylic position. Despite this, we carried
out optimization of the lithiation using in situ IR spectroscopy.
A solution of rac-5 in Et2O/TMEDA or THF/TMEDA at −78
°C exhibited a peak at νCO 1695 cm−1 (see Supporting
Information). Upon addition of n-BuLi, a new peak formed at
1645 cm−1, which was assigned to νCO in the lithiated
intermediate. The IR spectra showed that there was rapid (less
than 4 min) but partial lithiation at −78 °C, and this required
about 1 h to progress to completion (see Supporting
Information). The solvent THF alone can be suitable for
lithiation,8,12 and we were pleased to find that TMEDA could
be avoided by simply using THF at −50 °C. At this
temperature, the rotation of the Boc group is fast and lithiation
was complete within a few minutes (Figure 2 and Supporting
Information).
Scheme 4. Lithiation−Substitution of ( )-12
Figure 2. In situ IR 3-D and 2-D plots of the lithiation of 5 with n-
BuLi at −50 °C in THF. Blue line represents intensity of CO
stretching frequency of 5 (1692 cm−1) and red line of lithiated 5 (1645
cm−1) over time (in min).
Based on the results from the in situ IR spectroscopic studies,
we conducted the lithiation of rac-5 using n-BuLi in THF at
−50 °C for 4 min. A range of electrophiles was explored, and
1,1-disubstituted tetrahydroisoquinolines rac-6−11 were ob-
tained in 81−97% yield (Scheme 3). These conditions
represent an improvement over those given in Scheme 2.
Our attention then switched to N-Boc-1-phenyltetrahydroi-
soquinoline 12. The lithiation of racemic 12 was conducted
under the same conditions as for 5 (THF, −50 °C, 4 min). A
range of electrophiles was screened, and excellent yields (90−
98%) of rac-13−21 were obtained (Scheme 4).
group in 12 is slightly lower than that for N-Boc-
tetrahydroisoquinoline.8
To obtain the kinetics for rotation of the Boc group, variable
1
temperature H NMR spectroscopy studies were conducted
The configurational stability of the organolithium formed by
deprotonation of enantioenriched tetrahydroisoquinoline
12[enantiomer ratio (er) ≥99:1 by CSP HPLC] was
investigated. Table 1 shows the results of the lithiation of
(S)-1213 with n-BuLi in THF at different temperatures followed
by addition of MeOCOCN. Based on the literature,7,8 we
anticipated that the intermediate organolithium would be
configurationally unstable, so we were surprised that
enantiomerically enriched product 17 was obtained even at
(see Supporting Information). Coalescence of the signals (ratio
1.3:1) for the proton at the 1-position of racemic N-Boc-1-
phenyltetrahydroisoquinoline 12 in D8-THF occurred at about
25 °C. Using line shape analysis (see Supporting Information)
gave approximate activation parameters ΔH⧧ 56.7 kJ/mol and
ΔS⧧ −9.2 J/K·mol. The half-life for rotation of the Boc group
in 12 can therefore be determined to be t1/2 ∼9 s at −50 °C,
and ∼14 min at −78 °C. The barrier to rotation of the Boc
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Communication
Table 1. Lithiation−MeOCOCN Quench of (S)-12 (Er 99:1)
at Different Temperatures
Scheme 6. Synthesis of FR115427 and Ester 23
a
b
entry
temp (°C)
time (min)
yield (%)
er
1
2
3
4
−78
−50
−20
0
30
4
94
95
91
89
96:4
91:9
30
84:16
52:48
30
a
b
Yields after chromatography. Er by CSP-HPLC.
from the product 17 using TFA gave the amine 22, and
subsequent amide formation with 4-bromobenzoyl chloride
gave compound 23 (Scheme 6). Single crystal X-ray analysis of
compound 23 revealed that lithiation−trapping with MeO-
COCN had occurred with retention of configuration (see
Supporting Information). The absolute configuration of the
other compounds in Scheme 5 is based on assumed retention at
the organolithium center.
Trapping the enantioenriched organolithium with the
electrophile n-BuBr under the same conditions gave the
product 16 as a racemate (82% yield). Reaction of the
organolithium with BuBr was found to be slow and occurs only
on warming, such that racemization competes with electrophilic
quench.
(S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline is a key
intermediate in the preparation of the urinary antispasmodic
drug solifenacin 1.2 Industrially, classical resolution is used to
obtain the (S) enantiomer from the racemic secondary amine.
Asymmetric reduction, kinetic resolution, and deracemization
have been used as methods to prepare enantioenriched (S)-1-
phenyltetrahydroisoquinoline.15 A method to recycle one
enantiomer using oxidation and then reduction has been
reported.16 Our chemistry provides a method to recycle either
enantiomer through racemization of the N-Boc-1-lithio
derivative which is configurationally unstable at high temper-
ature, as shown for the enantiomer (S)-12 (Scheme 7).
Lithiation at 0 °C followed by addition of MeOH after 1 h gave
the (mostly) racemized compound 12 (91% yield, er 54:46).
−20 °C (Table 1, entries 1−3). A temperature of 0 °C for
approximately 30 min is required for racemization (Table 1,
entry 4). High er was obtained at −78 °C (Table 1, entry 1).
The yield of this reaction was high, indicating sufficiently fast
rotation of the Boc group. The high configurational stability
presumably arises from the slow movement of the lithium
cation (which is likely coordinated to the carbonyl oxygen
atom) across the space occupied by the phenyl group.
Experiments were conducted to determine the rate of
inversion of the organolithium. By measuring the er of product
17 over time, first order plots and an Eyring plot at three
temperatures (see Supporting Information) gave approximate
activation parameters ΔH⧧ 118 kJ/mol and ΔS⧧ 132 J/K·mol.
These equate to a half-life for inversion of the organolithium
t1/2 ∼73 min at −10 °C. The large positive entropy of activation
for inversion implies desolvation or solvent reorganization
perhaps due to movement of the large Boc group during
conducted tour of the lithium to the opposite face.14
In addition to product 17 (94%, er 96:4), 1,1-disubstituted
products 13, 14, and 18−21 were obtained in high yield and
high er at −78 °C (Scheme 5). By using MeOH as the
electrophile, the starting material (S)-12 was recovered (83%
yield) with er 98:2, demonstrating that protonation occurs with
retention of configuration. The absolute configuration of the
product 14 was determined by removal of the Boc group with
trifluoroacetic acid (TFA), which gave the NMDA antagonist
FR115427, er 91:9 (Scheme 6). Removal of the Boc group
Scheme 7. Racemization of (S)-12 (Er 99:1)
Scheme 5. Lithiation−Substitution of (S)-12
In conclusion, the lithiation of 1-phenyltetrahydroisoquino-
line has been optimized by in situ IR spectroscopy. 1,1-
Disubstituted tetrahydroisoquinolines can be prepared with
high yields at −50 °C in THF in less than 5 min. The kinetics
for rotation of the carbamate group and for the enantiomeriza-
tion of the organolithium were determined. Lithiated (S)-N-
Boc-1-phenyltetrahydroisoquinoline is configurationally stable
at low temperature, and electrophilic quench provides high
yields of highly enantioenriched 1,1-disubstituted tetrahydroi-
soquinolines. The chemistry was applied successfully to a
synthesis of FR115427 and to racemization of N-Boc-1-
phenyltetrahydroisoquinoline, which could have application to
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Communication
(14) Ashweek, N. J.; Brandt, P.; Coldham, I.; Dufour, S.; Gawley, R.
E.; Haeffner, F.; Klein, R.; Sanchez-Jimenez, G. J. Am. Chem. Soc. 2005,
127, 449.
recycle the undesired (R) enantiomer in the industrial synthesis
of the drug solifenacin.
(15) (a) Chang, M.; Li, W.; Zhang, X. Angew. Chem., Int. Ed. 2011,
50, 10679. (b) Binanzer, M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem. Soc.
2011, 133, 19698. (c) Limuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.;
Kita, Y.; Mashima, K. Angew. Chem., Int. Ed. 2013, 52, 2046. (d) Ye, Z.-
S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou, Y.-G. Angew.
Chem., Int. Ed. 2013, 52, 3685. (e) Wu, Z.; Perez, M.; Scalone, M.;
Ayad, T.; Ratovelomanana-Vidal, V. Angew. Chem., Int. Ed. 2013, 52,
4925. (f) Ghislieri, D.; Green, A. P.; Pontini, M.; Willies, S. C.; Rowles,
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and compound characterization
data, plus copies of NMR spectra and a CIF file. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*i.coldham@sheffield.ac.uk
Notes
(16) Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Straniero, V.; Valoti, E.
Org. Process Res. Dev. 2013, 17, 432.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Sheffield and the China Scholarship
Council/Department for Business Innovation & Skills (UK-
China Scholarships for Excellence). We are grateful to Susan
Bradshaw for help with the NMR spectroscopic studies, Harry
̌
̌ ̌
Adams for the single crystal X-ray analysis, and Milos Ruzic at
Krka Group for a sample of (S)-1-phenyltetrahydroisoquino-
line.
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