Deracemization of diarylmethanes via lateral lithiation-protonation sequences by means of sparteine

Article abstract of DOI:10.1016/S0957-4166(98)00228-6

Deracemization of diarylmethane derivatives was investigated by lateral lithiation-protonation mediated by (-)sparteine. Treatment of racemic 4- phenyltetrahydroisoquinoline 1 with s-butyllithium-(-)-sparteine followed by protonation of the resulting anio

Full text of DOI:10.1016/S0957-4166(98)00228-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2509–2516
Deracemization of diarylmethanes via lateral
lithiation–protonation sequences by means of sparteine
Laurence Prat, Ljubica Mojovic, Vincent Levacher,∗ Georges Dupas, Guy Quéguiner and
Jean Bourguignon
Laboratoire de Chimie Organique Fine et Hétérocyclique de l’IRCOF, associé au CNRS, Institut National des Sciences
Appliquées de Rouen, BP 08, F-76131 Mont Saint Aignan, France
Received 26 May 1998; accepted 9 June 1998
Abstract
Deracemization of diarylmethane derivatives was investigated by lateral lithiation–protonation mediated by (−)-
sparteine. Treatment of racemic 4-phenyltetrahydroisoquinoline 1 with s-butyllithium–(−)-sparteine followed by
protonation of the resulting anion afforded (R)-phenyltetrahydroisoquinoline 1 in up to 88% e.e. Following the
same procedure, racemic 2-(1-phenylethyl)pyridine 2 was subjected to the lithiation–protonation sequence. The
stereochemical outcome of the sequence proved to be highly dependent on the proton sources giving either (S)- or
(R)-2-(1-phenylethyl)pyridine 2 with EtOH or t-BuOH respectively in up to 50% e.e. © 1998 Elsevier Science Ltd.
All rights reserved.
1. Introduction
A large number of bioactive molecules possessing a chiral diarylmethane unit are reported in the
literature. For instance, 4-aryltetrahydroisoquinolines,1a–i hexahydropyrrolo[2,1-a]isoquinolines2 and
sertraline3 are of considerable interest due to their ability to inhibit uptake of the important central
neurotransmitters such as serotonine, norepinephrine or dopamine at postsynaptic receptors. Another
example is illustrated by pheniramines,4 one of the most important classes of antihistaminic agents.
Although most of these compounds demonstrated pharmocological enantioselectivity of action they
are usually synthesized in their racemic form, requiring a supplementary step of resolution, generally
expensive, time-consuming and inefficient.
To fill in this gap and as part of a research program on the development of asymmetric syntheses of
diarylmethane derivatives, we intended to explore deracemization of racemic diarylmethane derivatives
via the lateral lithiation–protonation sequence in the presence of an enantiodiscriminating ligand.
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00228-6

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The readily available, naturally occurring alkaloid (−)-sparteine has been reported extensively as an
effective chiral ligand in the deprotonation of prochiral benzyl compounds followed by an electrophilic
substitution with various electrophiles. In numerous cases this methodology provided a high level of
asymmetric induction and found practical development in asymmetric synthesis.5
Although this sequence has been abundantly studied during the asymmetric functionalization of a
prochiral benzylic substrate, no synthetic application using this approach in the deracemization of a
chiral racemic diarylmethane derivative via a lithiation–protonation sequence mediated by (−)-sparteine
has been reported. As a result of these observations, we speculated that it might be of interest to evaluate
the potential of a lateral lithiation–protonation sequence in the presence of RLi/(−)-sparteine to achieve
the deracemization of diarylmethane derivatives (Scheme 1).
Scheme 1.
2. Results and discussion
We first focused on the deracemization of N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 1, an
analog of nomifensine.1a,e,f A summary of the most significant results is listed in Table 2. Lateral
lithiation of N-methyl-1,2,3,4-tetrahydroisoquinoline at C-4 has been reported with good yields in THF.6
In initial experiments, deprotonation of 1 in THF at −78°C with s-BuLi or t-BuLi in the presence
of (−)-sparteine and quenching with MeOD afforded a high deuterium incorporation of 90% at C-4,
nevertheless with a poor enantioenrichment of 4% (entries 1 and 2). The 1-d1/1 ratio was readily assessed
1
by integration of the H NMR spectra (Table 1) and enantiomeric excesses were measured by chiral
HPLC analysis after flash chromatography. The rather disappointing results observed in THF may be a
result of its strong coordinating properties which displaces sparteine from Li+.7
We next surveyed a variety of solvents to optimise conditions to achieve good yields of lithiation
and to promote strong associations between the benzylic carbanion and (−)-sparteine; both of these
conditions being necessary to open up opportunities to attain high degrees of enantiomeric enrichments.
The use of non-coordinating solvents such as toluene or hexane proved to be ineffective in terms
of reactivity, yielding between 10% and 17% of the deuterium incorporation respectively when s-
BuLi was employed at −78°C for 2 hours. Taking into account of the low deuterium incorporation,
enantiomeric excesses were not measured in these experiments. However, changing the solvent from
THF to Et2O resulted in a high level of enantioselectivity (e.e.=65%) with respect to the percentage
of deuterium incorporation (1-d1/1=65/35) (entry 3). Finally, deprotonation proceeded to completion
(1-d1/1>95/5) within 24 h at −45°C affording 1-d1 in up to 88% e.e. in 60% isolated yield (entry

L. Prat et al. / Tetrahedron: Asymmetry 9 (1998) 2509–2516
2511
Table 1
Deracemization of N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 1
7). As can be seen, the main drawback of this deracemization procedure is the long lithiation time
required to ensure complete deuterium incorporation. Our attempts to circumscribe this problem by
conducting the deprotonation at a higher temperature (−45°C), led to complications arisen from the
formation of by-products resulting from Emde-type 1,2-elimination.6 The use of 2 equiv. of s-BuLi–(−)-
sparteine complex did not affect significantly the asymmetric induction (entries 4 and 6). Upon decreasing
the amount of s-BuLi–(−)-sparteine under 2 equiv., the percentage of deuterium incorporation was
substantially diminished resulting in a drop in the enantiomeric excess. Lastly, under the best conditions
selected [−45°C/24 h/Et2O/s-BuLi–(−)-sparteine, 4 equiv.], the resultant carbanion was trapped with a
variety of proton sources (EtOH, t-BuOH, AcOH, H2O, DMSO) at −45°C leading in each case to no
discernible change in enantioselectivity. Performing the protonation step at a lower temperature (−78°C)
did not improve the enantiomeric excess (entry 8). Comparison of the optical rotation of 1 with literature
values1b,d revealed that the major enantiomer obtained possesses in all experiments the (R) configuration
at C-4.
In the course of this study, a particularly unexpected result was observed when 1-d1 (e.e.=88%) was
treated with 4 equiv. of s-BuLi–(−)-sparteine complex (2 h/−78°C). In contrast to 1, deprotonation of 1-
d1 took place exclusively at C-1 affording the dideuterated compound 1-d2 (1-d2/1-d1>95/5) in 67%
yield after deuterolysis of the organolithium intermediate with MeOD (Scheme 2). It is noteworthy
that deprotonation of 1,2,3,4-tetrahydroisoquinoline at C-1 is usually accomplished in the presence of
a protecting group on the nitrogen which activates through chelate and dipole stabilization.8
1
Chiral HPLC of 1-d2 indicates that no racemization occurred at C-4. According to the H NMR
spectrum, 1-d2 was obtained as a 6:4 diastereoisomeric mixture. Thus, this deuterium isotope effect
inverts the lithiation site from C-4 to C-1 when 1-d1 is subjected to deprotonation. This finding could open
up the opportunities to provide a straightforward way to functionalized 1-d1 at C-1 without preliminary
activation of this position.

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L. Prat et al. / Tetrahedron: Asymmetry 9 (1998) 2509–2516
Scheme 2. (a) s-BuLi–(−)-sparteine/Et2O, 4 equiv./−78°C; (b) MeOD/−78°C
Table 2
Deracemization of 2-(1-phenylethyl)pyridine 2. (a) s-BuLi–(−)-sparteine, 2 equiv./Et2O/−78°C/2 h;
(b) proton source/−78°C/15 min
Then we turned our attention to the deracemization of 2-(1-phenylethyl)pyridine 2, an analogue of
pheniramines. The asymmetric synthesis of 2 has been previously reported in the literature either by a
coupling reaction of optically pure 1-phenylethyl-2-sulfoxide with methylmagnesium bromide9 or by a
co-cyclotrimerization reaction of (S)-2-phenylpropanenitrile with acetylene.10 A number of deproton-
ation/MeOD quench experiments were examined in order to attain optimum deuterium incorporation.
Initial attempts to lithiate 2 in toluene or hexane in the presence of 2 equiv. of s-BuLi at −78°C for
2 hours led to the recovery of the starting material along with a low amount of 2-d1 (5–10%) after
treatment with MeOD. The use of the former protocol in Et2O gave the best result affording 80% of
deuterium incorporation. In a last attempt, when the lithiation was conducted in Et2O at 0°C for 2 hours,
the percentage of the deuterium incorporation was not improved.
In spite of incomplete lithiation, 2 was subjected to deracemization in the presence of 2 equiv.
of s-BuLi–(−)-sparteine for 2 hours at −78°C in Et2O. Treating the organolithium intermediate with
EtOD at −78°C afforded 2-d1 (2-d1/2=80/20) in 50% e.e and in 85% yield (Table 2, entry 1). The
absolute configuration of the so-obtained major enantiomer was assigned as (S) by comparison of the
sign of the optical rotation with the literature data.9 In contrast to 1, the stereochemical outcome of
the lithiation–protonation sequence is highly influenced by the nature of the achiral proton source.
While EtOH led to (S)-2, t-BuOH preferentially afforded the opposite enantiomer (R)-2 with the same
magnitude of stereoselection (entry 3).
This result is of particular interest since the alkaloid sparteine is only available in one enantiomeric
form. Independent to this practical consideration, it is noteworthy that only a few reports mentioned such
inversion of stereoselectivity in stereoselective protonation processes simply on changing the achiral
proton source. These include the stereoselective protonation of non-racemic chiral alkyllithium species11
and the diastereoselective protonation of boron enolates.12
Hoppe and Beak carried out extensive work to elucidate the mechanism of asymmetric induction
during deprotonation–substitution sequences of a prochiral benzylic substrate in the presence of (−)-
sparteine.5 Depending on the configurational stability of the benzylic carbanion, the enantioselectivity
originates either from the lithiation step via an asymmetric deprotonation or from a post-lithiation step
via a dynamic resolution. In the present deracemization process, the enantiodetermining step occurs

L. Prat et al. / Tetrahedron: Asymmetry 9 (1998) 2509–2516
2513
after the lithiation step to form either a configurationally unstable α-lithiated species which could
undergo a dynamic resolution or a planar delocalized structure followed by an asymmetric protonation.
In contrast to 1 affording most likely a pyramidal carbonion,13 previous X-ray structural studies and
NMR spectroscopic studies of 2-picolyllithium derivatives, closely related to 2-Li species, revealed a
strong tendency of these organolithiums to adopt either an ‘enamido’ or ‘η3-azaallyl’ type of lithium
complex.14 Consequently, as the case may be, deracemization of 2 may be regarded either as a dynamic
resolution process or an asymmetric protonation (Scheme 3).
Scheme 3. Possible pathways of asymmetric induction during the deracemization of 2
As can be noted, if one wants to gain insight into the stereochemical course of this deracemization
process, structural studies of organolithium intermediates should be addressed. NMR spectroscopic
studies are in progress to decide between these different pathways of asymmetric induction and to be
in a position to propose an explanation regarding the unusual inversion of stereoselection observed
in the course of the deracemization of 2. In summary, the asymmetric deprotonation–protonation
sequence which has been widely used with success in the field of enolate chemistry13 has been applied
herein to the deracemization of diarylmethanes providing modest to good enantioselectivities. Lastly,
in view of the lack of general methods for asymmetric electrophilic arylation of benzyl derivatives,
this methodology should find synthetic applications for the preparation of further enantioenriched
diarylmethanes, precursors of biological active compounds.
3. Experimental section
4-Phenyl-1,2,3,4-tetrahydroisoquinoline was prepared following the literature procedure by reduc-
tive amination of 1-phenyl-2-aminoethanol with benzaldehyde followed by cyclization under acidic
conditions.1a,f,i Commercially available reagents were used unless otherwise stated. (−)-Sparteine was
1
distilled under vacuum before use. H and 13C NMR spectra were recorded on a 200 MHz Bruker
apparatus. Elemental analyses were performed on a Carlo–Erba 1106 analyser. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were distilled on benzophenone/Na. tert-Butyllithium, sec-butyllithium and n-
butyllithium were purchased from Fluka and their concentration was determined by titration of diphenyl-
acetic acid15 prior to use. Optical rotations were determined with a Perkin–Elmer 341 polarimeter using
10 cm cells.
3.1. rac-N-Methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 1
To a stirred solution of 4-phenyl-1,2,3,4-tetrahydroisoquinoline (4.66 g, 22.27 mmol) in methanol (150
ml) was added paraformaldehyde (800 mg, 26.7 mmol). The mixture was stirred at reflux for 45 min and
then allowed to reach room temperature. After addition of 20% Pd(OH)2 (1 g), the solution was stirred
under a hydrogen atmosphere for 12 h. After removal of the catalyst by filtration through Celite and

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L. Prat et al. / Tetrahedron: Asymmetry 9 (1998) 2509–2516
washing with methanol (2×30 ml), the filtrate was evaporated under reduced pressure to give 3.88 g
1
(78%) of 1 as an oil. H NMR (CDCl3) δ 7.35–7.05 (m, 8H); 6.90 (d, 1H, J=7.5 Hz); 4.31 (t, 1H, J=7
Hz); 3.80 (d, 1H, J=15 Hz); 3.64 (d, 1H, J=15 Hz); 3.08 (dd, 1H, J= 11.5 and 5 Hz); 2.61 (dd, 1H, J=
11.5 and 8.5 Hz); 2.46 (s, 3H). 13C NMR (CDCl3) δ 144.85, 137.04, 135.12, 129.29, 129.02, 128.28,
126.39, 126.23, 126.11, 125.90, 61.79, 58.45, 45.96, 45.89.
3.2. Deracemization of N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 1
To a solution of (−)-sparteine (1.76 g, 7.52 mmol) in Et2O (5 ml) was added a solution of s-BuLi in
cyclohexane (5.8 ml, 1.3 M, 7.52 mmol). The resulting solution was stirred under Ar at −45°C for 1 h and
then added dropwise to a precooled solution of rac-N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline
1 (420 mg, 1.88 mmol) in Et2O (5 ml). The resultant purple solution was stirred for 24 h at −45°C
under Ar. Addition of MeOD (760 µl, 18.81 mmol) at −45°C over a period of 5 min afforded a
colourless solution which was kept at this temperature for a further 20 min. Saturated aqueous NH4Cl
(30 ml) was added and the solution was allowed to reach room temperature. Layers were separated
and the aqueous phase was extracted with Et2O (2×60 ml). The combined ether phases were dried
(MgSO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography
on silica gel (eluent: toluene/EtOH/NH4OH=9/0.9/0.1) to yield 250 mg (60%) of N-methyl-4-(phenyl-
deuterio)-1,2,3,4-tetrahydroisoquinoline 1-d1 as a colourless oil. According to the 1H NMR spectrum, the
1
nondeuterated starting material 1 could not be detected (1-d1/1>95/5). H NMR (CDCl3) δ 7.35–7.05
(m, 8H); 6.90 (d, 1H, J=7.5 Hz); 3.80 (d, 1H, J=14.85 Hz); 3.64 (d, 1H, J=14.85 Hz); 3.08 (d, 1H,
J=11.5 Hz); 2.61 (d, 1H, J=11.5 Hz); 2.46 (s, 3H). The enantiomeric purity was determined to be 88%.
Chromatographic conditions: Chiralcel OD (250×4.6 mm; 10 µm); UV detection (λ=230 nm); eluent:
hexane/2-propanol (90/10); flow rate: 1 ml/min; temperature: 22°C; injection: 20 µl (0.5 mg of sample in
10 ml of hexane); Rf of minor peak: 4.3 min, Rf of major peak: 5.5 min. The absolute configuration of 1-
d1 was assigned as R by comparison of the optical rotation of 1-d1, [[α]27D=−11.0 (c=1.03 in methanol)]
to the known rotation for R-1 [[α]24D=−16.7 (c=0.72 in methanol)].1b,d
3.3. N-Methyl-1,4-dideuterio-4-phenyl-1,2,3,4-tetrahydroisoquinoline 1-d2
Compound 1-d2 was obtained using a similar procedure to that described for the preparation of (R)-
1-d1 from a solution of (−)-sparteine (0.38 g, 1.61 mmol) in Et2O (1.5 ml) and a solution of s-BuLi in
cyclohexane (1.24 ml, 1.3 M, 1.61 mmol). The resulting solution was stirred under Ar at −78°C for 1 h
and then added dropwise to a precooled solution of (R)-1-d1 (e.e.=88%; 1-d1/1>95/5) (90 mg, 0.4 mmol)
in Et2O (1 ml). After stirring for 2 h at −78°C under Ar, the solution was treated with MeOD (160 µl).
Work-up and purification were carried out as described above affording 67 mg of 1-d2 (67%). 1H NMR
(CDCl3) δ 7.35–7.05 (m, 8H); 6.90 (d, 1H, J=7.5 Hz); 3.76 (s, 0.6H); 3.62 (s, 0.4H); 3.08 (d, 1H, J=11.5
Hz); 2.61 (d, 1H, J=11.5 Hz); 2.46 (s, 3H). MS 226 (MH+).
3.4. rac-2-(1-Phenylethyl)pyridine 2
To a stirred solution of 2-benzylpyridine (3.92 g, 23.16 mmol) in dry Et2O (100 ml) cooled to −78°C
was added under Ar a solution of butyllithium in hexane (13.90 ml, 2.5 M, 34.75 mmol). After the
solution was stirred at this temperature for 45 min, methyl iodide (9.86 g, 69.49 mmol) was added and the
solution stirred at −78°C for a further 4 hours. After treatment with saturated aqueous NH4Cl (50 ml), and
extraction with Et2O (2×50 ml), the organic layer was dried over MgSO4 and evaporated under vacuum

L. Prat et al. / Tetrahedron: Asymmetry 9 (1998) 2509–2516
2515
affording a crude product which after chromatography on silica gel (eluent: cyclohexane/Et2O=7/3)
1
yielded 3.90 g (92%) of 2-(1-phenylethyl)pyridine 2 as a slightly yellow oil. H NMR (CDCl3) δ 8.58
(ddd, 1H, J=4.9, 1.8 and 1 Hz); 7.56 (td, 1H, J=7.6 and 1.8 Hz); 7.34–7.06 (m, 7H); 4.33 (q, 1H, J=7.0
Hz); 1.73 (d, 3H, J=7.2 Hz). Anal. calcd for C13H13N: C, 85.20; H, 7.15; N, 7.64. Found: C, 85.05; H,
7.23; N, 7.77.
3.5. Deracemization of 2-(1-phenylethyl)pyridine 2
To a solution of (−)-sparteine (0.38 g, 1.64 mmol) in Et2O (3.5 ml) was added a solution of s-BuLi
in cyclohexane (1.26 ml, 1.3 M, 1.64 mmol). The resulting solution was stirred under Ar at −78°C for
1 h and then cannulated dropwise to a solution of rac-2-(1-phenylethyl)pyridine 2 (0.2 g, 1.09 mmol)
in Et2O (2 ml) cooled to −78°C. After 2 hours stirring at this temperature under Ar, the solution was
treated with EtOD (0.2 g, 4.37 mmol) and kept at −78°C for a further 15 min. After treatment with
saturated aqueous NH4Cl (10 ml) and phase separation, the aqueous phase was extracted with Et2O
(2×15 ml). The combined organic phases were washed with 10% aqueous acetic acid (10 ml) and dried
(MgSO4). Evaporation of the solvent afforded 260 mg of crude product as a yellow oil. Purification
by flash chromatography on silica gel with cyclohexane/Et2O (7/3) as eluent yielded 170 mg (85%)
of enantiomerically enriched 2-(1-phenylethyl)pyridine 2-d1. The deuterium content was determined to
1
be 80% by comparison with the H NMR spectrum of 2-(1-phenylethyl)pyridine 2. The enantiomeric
purity was measured as 50% by chiral stationary phase HPLC. Chromatographic conditions: Chiralcel
OD (250×4.6 mm; 10 µm). UV detection (λ=230 nm); eluent: hexane/2-propanol=99.5/0.5; flow rate: 1
ml/min; temperature: 22°C; injection: 20 µl (0.5 mg of sample in 10 ml of hexane); Rf of minor peak:
7.4 min, Rf of major peak: 8.0 min. The absolute configuration was assigned as S by comparison of the
optical rotation with literature values. [α]23D=+32 (c=1.18 in benzene). Literature value of (+)-(S)-2-(1-
phenylethyl)pyridine 2: e.e.=100%, [α]25D=+63 (c=1.00 in benzene).9
Acknowledgements
We thank les Régions de Haute et Basse Normandie for financial support of this work (Réseau
Interrégional Normand de Chimie Organique Fine).
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