Origin of the detrimental effect of lithium halides on an enantioselective nucleophilic alkylation of aldehydes

Article abstract of DOI:10.1021/jo071160x

(Chemical Equation Presented) The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal·mol^-1 provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.

Full text of DOI:10.1021/jo071160x

Origin of the Detrimental Effect of Lithium Halides on an
Enantioselective Nucleophilic Alkylation of Aldehydes
Franck Pate´,† Nicolas Duguet,‡ Hassan Oulyadi,† Anne Harrison-Marchand,‡
Catherine Fressigne´,‡ Jean-Yves Valnot,‡ Marie-Claire Lasne,§ and Jacques Maddaluno*,‡
Laboratoire de Chimie Organique et Biologique Structurale, Laboratoire des Fonctions Azote´es &
Oxyge´ne´es Complexes de l’IRCOF, UMR CNRS 6014, UniVersite´ et INSA de Rouen,
76821 Mont St Aignan Cedex, France, and Laboratoire de Chimie Mole´culaire et Thioorganique de
l’ISMRA, UMR CNRS 6507, 6 BouleVard du Mal Juin, 14050 Caen Cedex, France
jmaddalu@crihan.fr
ReceiVed June 1, 2007
The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde,
in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been
investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition
of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the
lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR
spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral
lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex
involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs
with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly
stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed
aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the
LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal‚mol-1
provided THF is explicitly taken into account. These results suggest that a sequestration of the source of
chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the
model reaction.
Introduction
aldehydes (Scheme 1). Most of our efforts focused on the
influence of parameters such as the structure of the chiral amine,1
the nature of the nucleophilic organolithium,2-4 and the solvent5
Previous results obtained by our group showed that 3-ami-
nopyrrolidine lithium amides (3APLis) are efficient chiral
auxiliaries in the enantioselective condensation of halide-free
alkyl-,1,2 aryl-,3 and vinyllithium4 derivatives on aromatic
(2) (a) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J. Org.
Chem. 1998, 63, 8266-8275. (b) Corruble, A.; Davoust, D.; Desjardins,
S.; Fressigne´, C.; Giessner-Prettre, C.; Harrison-Marchand, A.; Houte, H.;
Lasne, M.-C.; Maddaluno, J.; Oulyadi, H.; Valnot J.-Y. J. Am. Chem. Soc.
2002, 124, 15267-15279.
(3) Flinois, K.; Yuan, Y.; Bastide, C.; Harrison-Marchand, A.; Madd-
aluno, J. Tetrahedron 2002, 58, 4707-4716.
(4) Yuan, Y.; Harrison-Marchand, A.; Maddaluno, J. Synlett 2005, 1555-
1558.
† Laboratoire de Chimie Organique et Biologique Structurale de l’IRCOF.
‡ Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF.
§ Laboratoire de Chimie Mole´culaire et Thioorganique de l’ISMRA.
(1) Harrison-Marchand, A.; Valnot, J.-Y.; Corruble, A.; Duguet, N.;
Oulyadi, H.; Desjardins, S.; Fressigne´, C.; Maddaluno, J. Pure Appl. Chem.
2006, 78, 321-331.
10.1021/jo071160x CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/07/2007
6982
J. Org. Chem. 2007, 72, 6982-6991

Detrimental Effects of LiX on EnantioselectiVe Addition of Alkyllithiums
SCHEME 1. Asymmetric Nucleophilic Addition Mediated by 3APLi Chiral Lithium Amide
on the outcome of the reaction. Thus, ee’s up to 80% could be
obtained in pure THF at reasonably low temperatures (-78 or
-20 °C).
interactions between lithium chloride or bromide and lithium
amides,9,10 alkyllithiums,11 or lithium enolates12 have been
fathomed on several occasions on chemical, spectroscopic, and
theoretical grounds. However, the salt effects have been
relatively seldom examined in asymmetric synthesis. A positive
role of added salts on the ee’s have been noted in the
enantioselective protonation13 and deprotonation9,14 reactions.
The influence of salts on the behavior of lithiated mixed
aggregates has also been clearly pointed out as being either
beneficial in the case of the 1,4-nucleophilic addition of enolates
Multinuclear (1H, 6Li, 13C, 15N) NMR spectroscopy and
theoretical investigations were run in parallel.2b,6 An azanor-
bornyl folding of the amide was evidenced in ethers (THF,
Et2O), and the formation of two 1:1 mixed aggregates 3APLi:
R′Li, namely the endo and exo arrangements, was pointed out
(Scheme 1). The endo arrangements, in which the R′Li lies along
the concave face of the norbornyl skeleton, were shown to be
obtained with the (3S,8S) diastereomers of the 3AP (1a,
Scheme 1). The exo complexes correspond to those in which
R′Li is oriented toward the convex part of the structure and
were observed with the (3S,8R) diastereomers (1b, Scheme 1).
These two topologies seem to be closely related to the sense of
the induction since the (3S,8S) amide led to the (S) alcohol (2a)
while its (3S,8R) counterpart yielded the (R) enantiomer (2b).
Minor signals on the NMR spectrum were left unassigned
after the original investigations on the above structure of the
complexes in solution. The synthetic route we followed to
(9) (a) Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron
Lett. 1996, 37, 7377-7380. (b) Toriyama, M.; Sugasawa, K.; Shindo, M.;
Tokutake, N.; Koga, K. Tetrahedron Lett. 1997, 38, 567-570.
(10) (a) DePue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5518-
5524. (b) DePue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5524-
5533. (c) Mair, F. S.; Clegg, W.; O’Neil P. A. J. Am. Chem. Soc. 1993,
115, 3388-3389. (d) Galiano-Roth, A. S.; Kim, Y. J.; Gilchrist, J. H.;
Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113,
5053-5055. (e) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.;
Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9575-9585. (f) Romesberg,
F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9187-9197. (g)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9198-
9202. (h) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.;
Schleyer, P. v. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118, 1339-
1347. (i) Clegg, W.; Greer, J. C.; Hayes, J. M.; Mair, F. S.; Nolan, P. M.;
O’Neil, P. A. Inorg. Chim. Acta 1997, 258, 1-9. (j) Pratt, L. M. Bull. Chem.
Soc. Jpn. 2005, 78, 890-898.
6
prepare the halide-free labeled Li alkyllithiums2b,7,8 led us to
think that these unsorted peaks could be due to a contamination
by residual amounts of lithium salts, still possible in spite of
considerable efforts undertaken to eliminate inorganic salts. We
then decided to study in detail the effects of such entities on
the induction of a model hydroxyalkylation reaction. The
(11) (a) Waak, R.; Doran, M. A.; Baker, E. B. Chem. Commun. 1967,
1291-1293. (b) Novak, P. D.; Brown, T. L. J. Am. Chem. Soc. 1972, 94,
3793-3798. (c) Kieft, R. L.; Novak, D. P.; Brown, T. L. J. Organomet.
Chem. 1974, 77, 299-305. (d) Williard, P. G. ComprehensiVe Organic
Chemistry, 1991, 1, 1-47. (e) Gu¨nther, H. J. Braz. Chem. Soc. 1999, 10,
241-262. (f) Desjardins, S.; Flinois, K.; Oulyadi, H.; Davoust, D.; Giessner-
Prettre, C.; Parisel, O.; Maddaluno, J. Organometallics 2003, 22, 4090-
4097. (g) Fox, T. Hausmann, H.; Gu¨nther, H. Magn. Reson. Chem. 2004,
42, 788-794.
(5) Yuan, Y.; Desjardins, S.; Harrison-Marchand, A.; Oulyadi, H.;
Fressigne´, C.; Giessner-Prettre, C.; Maddaluno, J. Tetrahedron 2005, 31,
3325-3334.
(6) (a) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Prigent, Y.; Davoust,
D.; Duhamel, P. J. Am. Chem. Soc. 1997, 119, 10042-10048. (b) Fressigne´,
C.; Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Giessner-Prettre, C. J.
Organomet. Chem. 1997, 549, 81-88. (c) Fressigne´, C.; Maddaluno, J.;
Giessner-Prettre, C. J. Chem. Soc., Perkin Trans. 1999, 2, 2197-2201. (d)
Parisel, O.; Fressigne´, C.; Maddaluno, J.; Giessner-Prettre, C. J. Org. Chem.
2003, 68, 1290-1294.
(12) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-
1654. (b) Juaristi, E., Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T; Simson, M.; Seebach, D. Synthesis 1993, 1271-1290.
(13) See, for instance: (a) Yanagisawa, A.; Kikuchi, T.; Kuribayashi,
T.; Yamamoto, H. Tetrahedron 1998, 54, 10253-10264. (b) Yanagisawa,
A.; Kikuchi, T.; Yamamoto, H. Synlett 1998, 2, 174-176. (c) Asensio, G.;
Aleman, P. A.; Domingo, L. R.; Medio-Simo´n, M. Tetrahedron Lett. 1998,
39, 3277-3280. (d) Asensio, G.; Aleman, P. A.; Gil, J.; Domingo, L. R.;
Medio-Simo´n, M. J. Org. Chem. 1998, 63, 9342-9347. (e) Duhamel, L.;
Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2004, 15, 3653-
3691.
(7) 6Li-labeled methyllithium was prepared at room temperature by
6
reacting methyl chloride and Li metal in diethyl ether. Lithium chloride,
the side product of this reaction, is not soluble in the solvent and could be
separated from the reaction medium by centrifugation. For fundamental
references on the synthesis of alkyllithium compounds from alkyl halides,
see: (a) Ziegler, K.; Colonius, H. Ann. Chem. 1930, 479, 135. (b) Gilman,
H.; Zoellner, E. A.; Selby, W. M. J. Am. Chem. Soc. 1932, 54, 1967-
1962. (c) Brown, T. L.; Rogers, M. T. J. Am. Chem. Soc. 1957, 79, 1859-
1861. (d) Kamiensky, C. W.; Esmay, D. L. J. Org. Chem. 1960, 25, 1807-
1809. (e) Lusch, M. J.; Phillips, W. V.; Sieloff, R. F.; Nomura, G. S.; House,
H. O. Org. Synth. 1984, 62, 101-110.
(14) See, for instance: (a) Bunn, B. J.; Simpkins, N. S. J. Org. Chem.
1993, 58, 533-534. (b) Majewski, M.; Lazny, R.; Nowak, P. Tetrahedron
Lett. 1995, 36, 5465-5468. (c) O’Brien, P. J. Chem. Soc. Perkin Trans.
1998, 1, 1439-1457. (d) Simoni, D.; Roberti, M.; Rondanin, R.; Kozikows-
ki, A. P. Tetrahedron Lett. 1999, 40, 4425-4428. (e) Laumer, J. M.; Kim,
D. D.; Beak, P. J. Org. Chem. 2002, 67, 6797-6804. (f) Butler, B.; Schultz,
T.; Simpkins, N. S. Chem. Commun. 2006, 3634-3636.
(8) Hilmersson, G.; Davidsson, O¨ . J. Organomet. Chem. 1995, 489, 175-
179.
J. Org. Chem, Vol. 72, No. 18, 2007 6983

Pate´ et al.
TABLE 1. Influence of LiCl Addition on the Model Reaction of
Scheme 1 Using Amide 1aLi or 1bLi
aggregated to lithium amides on nitro olefins studied by Seebach
et al.12b or unfavorable in the case of the 1,2-condensation of
n-butyllithium mixed with a chiral lithium aminoalkoxide
examined by Jackman and co-workers.15 Overall, it appears
difficult to draw generalities on the structure of the resulting
aggregates, even restricting the study to the “popular” lithium
amides. It seems that lithium bromide tends to favor mixed
dimers (as observed for Ph2NLi10a,b and LiTMP10c,d), while
lithium chloride rather leads to mixed trimers involving two
amide units (with LiTMP10c,d).
amide
1Li
MeLia
(equiv)
LiClb
(equiv)
conv
(%)
eec
(%)
entries
induction
1
2
3
4
5
1aLi
1aLi
1aLi
1bLi
1bLi
1.7 (MeLi) 0.0 (LiCl)
1.7 (MeLi) 1.0 (LiCl)
1.7 (MeLi) 2.7 (LiCl)
1.0 (MeLi) 0.0 (LiCl)
1.0 (MeLi) 1.0 (LiCl)
96
80
90
94
70
56 (57)
37 (25)
4 (5)
79
S
S
S
R
R
48
a Equiv/1 equiv of amide. b Equiv/1 equiv of complex. c Values in
parentheses measured when LiCl was added at -20 °C instead of -78 °C.
We present here observations regarding the effects of lithium
chloride and bromide on the enantioselective hydroxyalkylation
depicted in Scheme 1. Actually, the global system involves four
highly polar entities that are the lithium amide, the methyl-
lithium, the lithium halides and the lithium alkoxide formed
during the reaction. Considering this latter is progressively
accumulating in the medium, the problem is finally to probe
the competitive interactions between four partners with time-
depending concentrations. This thorny task required us to focus,
at least the first time, the investigation on the sole partners
present at t ) 0, i.e., excluding lithium 1-o-tolylethoxide, the
alkoxide formed during the reaction, from the model system.
To analyze the initial course of the reaction, it was indeed
essential to have a clear picture of the static composition of the
reaction medium before the introduction of the aldehyde, viz.
the last reagent introduced according to the procedure presented
below. Evaluating the relative affinities between lithium amide,
methyllithium, and lithium chloride or bromide was yet
relatively complex. A 3-fold study was thus conducted which
included a parallel (i) chemical evaluation of the impact of these
additives on the enantioselectivity of the known hydroxyalky-
lation of o-tolualdehyde, (ii) description by NMR spectroscopy
of the competition between the various aggregates in THF, and
(iii) DFT study of the relative (thermodynamic) stabilities of
the complexes. A comparable approach has been successfully
applied by Gschwind and colleagues to the understanding of
the structure into solution of dimethylcuprate mixed with LiI
and LiCN.16
SCHEME 2
undertake an in depth spectroscopic and theoretical investigation
on the state of the solution before the introduction of the
aldehyde.
Multinuclear NMR Spectroscopy Characterization of New
Aggregates between 3APLi and LiX. The occurrence of
noncovalent interactions between lithium halides and lithium
amides in solution, leading to robust aggregates of well-defined
stoichiometry, has been previously established in many cases,
and the fine structure of these species has been studied in
detail.10 With these models in mind, we first examined the
putative mixed aggregates arising between amide 1aLi (3S,8S)
and LiX (X ) Cl, Br).
1aLi:LiCl Mixed Aggregate. This aggregate was prepared
directly in the NMR tube by first adding, at -78 °C, 1.1 equiv
of Me6Li in THF-d8 (0.6 M) to a precooled 0.2 M solution of
amine in THF-d8. Then, a 0.9 M solution of 6LiCl17 (1.2 equiv)
in THF-d8 was introduced, and the tube was shaken for a few
minutes at the same temperature (Scheme 2).
Results and Discussion
Impact of LiX on the Enantioselectivity of the Model
Reaction. The study was conducted for the model reaction
depicted in Scheme 1, methyllithium being the nucleophile,
3-aminopyrrolidine lithium amides 1aLi or 1bLi the chiral
inductors, and o-tolualdehyde the electrophile.1b,2 The selected
protocol consisted in preforming the 1:1 lithium amide:MeLi
aggregate in THF at -20 °C by mixing 1aLi or 1bLi and
methyllithium. This solution was then cooled to -78 °C and
subjected to the addition of LiX in THF. The aldehyde was
then introduced after another 30 min of stirring at -78 °C. The
results are summarized in Table 1.
The course of the reaction seems hardly altered upon addition
of LiCl on the preformed mixed aggregates 1Li:MeLi as judged
from the little variations undergiven by the conversions. In
contrast, the ee’s progressively decrease to finally plummet when
an excess of LiCl is introduced (entry 3). Interestingly, these
ee’s are relatively insensitive to the temperature of the introduc-
tion of LiCl (entries 1-3). This set of results prompted us to
1
The H spectra (Figure 1S in the Supporting Information)
and 6Li (Figure 1, bottom) recorded from this sample illustrate
the evolution of the amide. The monodimensional 1H spectrum
displays, for the main species, a strong splitting of the H2, H5,
and H6 proton pairs, characteristic of the folding of the amide
1aLi.6a The 6Li spectrum exhibits two major singlets of similar
intensities (at 1.52 and 2.24 ppm),18 plus a set of two little
singlets (also of comparable intensities, at 1.42 and 1.83 ppm).
A broad signal, probably corresponding to an excess of LiCl,
was also observed at high field (0.87 ppm). Analogies between
this spectrum and those recorded previously6 for 3APLi:MeLi
complexes deserve to be noted. The ∆δ measured for each pair
of signals (0.72 ppm for the major species and 0.41 ppm for
(17) 6LiCl was recovered from the methyllithium synthesis mentioned
(15) Ye, M.; Logaraij, S.; Jackman, L. M.; Hillegass, K.; Hirsh, K. A.;
Bolliger, A. M.; Grosz, A. L. Tetrahedron 1994, 50, 6109-6116.
(16) Henze, W.; Vyater, A.; Krause, N.; Gschwind, R. M. J. Am. Chem.
Soc. 2005, 127, 17335-17342.
in ref 7. The 0.9 M solution in THF-d8 was prepared from a weighted
6
amount of dry LiCl dissolved overnight in this solvent.
(18) All chemical shifts for 6Li are given with respect to an external
6
reference of 0.3 M LiCl in MeOH-d4 (δ 0.0).
6984 J. Org. Chem., Vol. 72, No. 18, 2007

Detrimental Effects of LiX on EnantioselectiVe Addition of Alkyllithiums
FIGURE 1. 6Li spectra in THF-d8 at T ) 195 K of pure exo 1a6Li:Me6Li (top) and endo 1b6Li:Me6Li (middle) aggregates plus mixture of putative
endo and exo complexes 1a6Li:6LiCl (bottom).
the minor one) are indeed remarkably comparable with those
measured from the known endo-1aLi:MeLi aggregate (0.72
ppm) and exo-1bLi:MeLi (0.42 ppm), respectively. This,
together with the 1:1 peaks, suggest that 1aLi and LiCl form
two 1:1 mixed aggregates, viz. endo-3 and exo-4, in a ∼3:1
ratio (Scheme 2).
The 35Cl atom being a poor nucleus for NMR spectroscopy
investigations, the direct determination of the new complex(es)
structure was limited to proton, carbon, and lithium spec-
troscopies. However, the analogies between the spectra obtained
for 3 and 4 and those obtained before for comparable aggregates
leave little doubt regarding their structures. Thus, the simulta-
neous correlations between H2 and H8 and H6′ and H4 observed
in the NOESY experiment (Figure 2S, Supporting Information)
are in full agreement with a puckered pyrrolidine core. The
FIGURE 2. 6Li spectrum of 1a6Li:6LiBr mixed aggregates in THF-d8
at T ) 195 K in the presence of 0.6 equiv of excess of LiBr.
6
structure of the major complex 3 could be evidenced by a -
Li,1H HOESY (Figure 3S, Supporting Information), which
exhibits correlations between (i) Li1 and H4, H5 and H6′ (other
clues of the folding) and (ii) Li2 and H3 and H4 (suggesting
LiCl is tightly “bound” along the endo face of the amide).
Therefore, it seems that the (S,S) configuration of amide 1aLi
mainly leads to an endo mixed aggregate with LiCl, as in the
case of MeLi.
6
case in a 4:1 ratio. A NOESY experiment (Figure 5S, Supporting
Information) supports this hypothesis, at least for the major
complex.
Competitive Aggregations of 3APLi, MeLi, and LiCl. Once
the LiX mixed aggregates were identified, we turned our
attention to the relative affinities between the species possibly
competing in solutions contaminated by lithium halides.
Addition of MeLi on 1aLi:LiCl. The stability of the main
1aLi:LiCl complex toward methyllithium was first evaluated
by adding a solution of Me6Li (0.2 M in THF-d8) to a solution
of 1aLi:LiCl prepared as above (see the top spectrum of Figure
3; the large signal at ∼1.0 ppm is due to an excess of LiCl).
1aLi:LiBr Mixed Aggregate. The above study was repeated
with lithium amide 1aLi, at similar temperature (-78 °C) and
concentration in THF-d8, but adding, this time, a 0.7 M solution
of 6LiBr19 in THF-d8 (1.6 equiv). The resulting 1H (Figure 4S,
Supporting Information) and 6Li (Figure 2) spectra are like those
registered with LiCl, suggesting once again the formation of
two 1:1 mixed aggregates. The comparable ∆δ’s (0.70 ppm for
the major species and 0.40 ppm for the minor one) led us to
regard those as the endo and exo complexes, formed in this
1
6
The H and Li spectra did not show significant alteration of
the signals associated with the two isomers of 1aLi:LiCl. Only
6
the singlets corresponding to the Me and Li signals of free
J. Org. Chem, Vol. 72, No. 18, 2007 6985

Pate´ et al.
1
6
FIGURE 3. Evolution of the H and Li spectra, in THF-d8 at T ) 195 K, of 1a6Li:6LiCl main complex (top) upon progressive addition of 0.6
equiv (middle) and 1.3 equiv (bottom) Me6Li. *Unidentified peaks. The signal at 0.23 ppm has been assigned to methane according to: Lampert,
H.; Mikenda, W.; Karpfen, A.; Ka1hlig, H. J. Phys. Chem. A 1997, 101, 9610-9617.
Me6Li increased progressively upon addition of up to 1.3 equiv,
simultaneously with the disappearance of the free LiCl signal
(Figure 3). These results indicate that LiCl aggregated to the
lithium amide is not substituted by the methyllithium, whatever
the topology of the complex. Note that a broad signal progres-
sively superimposes over the baseline. It corresponds to the
formation of (MeLi)x(LiCl)y aggregates that we are currently
studying.
complexes. It is, however, difficult to determine if the substitu-
tion of the alkyllithium takes place with some degree of
epimerization of the chiral nitrogen as both endo- and exo-1aLi:
LiCl complexes were already present in the starting sample.
The final endo/exo ratio, as measured by the integration (after
deconvolution) of the peaks on the bottom spectrum of Figure
4 (2 equiv LiCl), can only be evaluated as ∼5:1.
Addition of LiCl on 1bLi:MeLi. The next step consisted of
examining the stability of the exo aggregate, obtained upon
mixing amide 1bLi (3S,8R) and methyllithium, toward lithium
chloride. Here again, the addition of LiCl was responsible for
a dramatic attrition of the induction process. Indeed, the salt-
free reaction led to 79% ee (in favor of the R enantiomer 2b),
while in the presence of LiCl, this value dropped to 48% (1
equiv). An NMR spectroscopy experiment similar to the
previous one was performed starting from a 0.13 M solution of
the 1bLi:MeLi complex in THF-d8, which was prepared
following the above protocol. After quickly checking that the
known6 mixed aggregate was obtained, successive aliquots of
Addition of LiCl on 1aLi:MeLi. The effect of the reverse
addition of LiCl on the 1aLi:MeLi complex was probed next.
The 1aLi:MeLi mixed aggregate was prepared directly in THF-
d8 by adding, at -78 °C (195 K), 1.2 equiv (deprotonation)
then 1.2 equiv (aggregation) of a 0.2 M solution of Me6Li in
THF-d8 on a solution of 1a, also in THF-d8. A control by NMR
spectroscopy showed that the resulting sample consisted in the
expected 1aLi:MeLi aggregate,6 together with some free me-
thyllithium (about ≈14%) and a small amount of the endo/exo
mixture of the 1aLi:LiCl aggregates. The formation of this latter
at this stage can be explained by a contamination of the labeled
MeLi, despite all the care paid to eliminate LiCl by centrifuga-
6
a 0.66 M solution of LiCl in THF-d8 were added at -78 °C.
6
tion.20 A solution of LiCl in THF-d8 (1.0 equiv of a 0.8 M)
Two representative 1H and 6Li spectra are given below
(Figure 5) to illustrate the progressive fading of the MeLi
aggregate in favor of a major new complex.
was slowly introduced at -78 °C. The NMR spectra exhibits a
total disappearance of the signals of the original 1aLi:MeLi
mixed aggregate, both on the high field region of the 1H spectra
The top spectra of Figure 5 show the starting point consisting
6
(the rest of the spectrum being hardly altered) and on the Li
of the 1bLi:MeLi complex, contaminated by an excess meth-
6
one. Complementarily, the singlets corresponding to the 1aLi:
LiCl aggregates raised up (Figure 4). Thus, the pure endo-
methyllithium complex fully transforms into the 1aLi:LiCl
yllithium and another species characterized by two (1:1) Li
singlets at high field. These latter signals increase dramatically
6
upon addition of LiCl as they remain in the same 1:1 ratio
(middle spectra). Simultaneously, the original peaks assigned
6
to Li1 and Li2 of the 1bLi:MeLi aggregate vanish, and the Li
(19) 6LiBr is a byproduct of the 6Li n-butyllithium synthesis; see:
Fraenkel, G.; Henrichs, M.; Hewitt, J. M.; Su, B. M.; Geckle, M. J. J. Am.
Chem. Soc. 1980, 102, 3345-3350. The 0.7 M solution in THF-d8 was
singlet of the free methyllithium (at 2.74 ppm, superimposed
to the Li1 signal) increases. Finally (bottom spectra), the new
complex and tetrameric methyllithium become, by far, the main
species in solution. The above data suggest that a 1:1 complex
involving LiCl was already present in the starting sample and
accumulated in the medium. The structure of this entity was
characterized through the usual NOESY (Figure 6S, Supporting
6
prepared by dissolving overnight a weighted amount of dry LiBr in this
solvent.
(20) The formation of a mixed aggregate between MeLi and LiCl is not
6
easily evidenced by NMR at 195 K since the Li NMR spectrum shows a
broad singlet, due to the coalescence of the signals characteristics of the
species in solution. Therefore, a simple spectroscopic assay of small
quantities of LiCl is currently impossible at this temperature.
6986 J. Org. Chem., Vol. 72, No. 18, 2007

Detrimental Effects of LiX on EnantioselectiVe Addition of Alkyllithiums
6
FIGURE 4. 1H and Li spectra, recorded at T ) 195 K, of 1a6Li:Me6Li complex in THF upon addition of 1 (middle) and 2 (bottom) equiv of
6LiCl. The top spectrum corresponds to a 1a6Li:Me6Li sample containing an excess Me6Li. *Unidentified peaks.
1
6
FIGURE 5. Evolution of the H and Li spectra, recorded at T ) 195 K, of 1b6Li:Me6Li complex in THF upon addition of ∼0.5 (middle) and 1
6
(bottom) equiv of LiCl. The top spectra correspond to a 1b6Li:Me6Li sample containing an excess of Me6Li. *Unidentified peaks.
Information) and HOESY (Figure 7S, Supporting Information)
bidimensional experiments. All of the information made avail-
able from these spectra are in favor of an exo arrangement of a
1bLi:LiCl. This time, it thus seems that the MeLi-LiCl
substitution is more or less stereospecific.
Comparing the HOESY spectrum recorded for the latter exo
complex to that obtained at the beginning of our study from
the 1aLi:LiCl mixture of isomers (Figure 6) shows that excellent
correlations are found between the minor species formed in the
latter case and the main exo-1b6Li:6LiCl complex. This further
supports the hypothesis of an endo/exo mixture for 1aLi:LiCl.
Competitive Aggregations of 3APLi, MeLi, and LiBr. The
competitive aggregation phenomena were extended to the case
of LiBr, although this salt is not supposed to contaminate
methyllithium. However, trace amounts of LiBr are likely to
contaminate n-Bu6Li, which could play a comparable part in
the competitive aggregations.
Only the substitution of MeLi by LiBr was studied in this
case. Thus, a 0.20 M solution of amine 1a in THF was reacted
two times with 1.2 equiv of Me6Li (0.67 M in THF) to yield
the expected 1aLi:MeLi complex. Increasing amounts of a
0.70 M solution of LiBr in the same solvent were then added
1
6
at -78 °C, and the corresponding H and Li spectra were
recorded (Figure 8S, Supporting Information). The same
complete displacement of methyllithium by lithium bromide was
observed, leading to a 5:1 mixture of the two endo- and exo-
J. Org. Chem, Vol. 72, No. 18, 2007 6987

Pate´ et al.
FIGURE 6. Superimposition of HOESY spectra (recorded at 195 K) of 1a6Li:6LiCl endo + exo (black) and 1b6Li:6LiCl exo (red) complexes in
THF-d8. A good match between the correlations of both exo isomers can be noted.
1aLi:LiBr complexes. However, the presence of residual LiCl
in the methyllithium used to form the initial mixed aggregate,
affording the corresponding endo and exo aggregates with 1a
in the starting sample, did not permit an accurate determination
of the stereospecificity of the exchange.
investigations.21 The large size of the systems considered here
led us to restrict our computations to the DFT level. The B3P86
functional and the 6-31G** basis set, which behaved satisfac-
torily in related situations,22 were retained. All of the calculations
have been performed using the Jaguar 4.1 software.23 Note that
the basis set superposition errors (BSSE), the zero-point energy
(ZPE) corrections, and the entropic contribution have not been
included in our results. We preferred dedicating our computa-
tional resources to the explicit treatment of the three THF
molecules in the first solvation shell. The BSSE and ZPE are
probably of lesser importance6c,d since they are not expected to
modify the relative order of the complex stabilities or that of
the activation barriers.
In conclusion, to this part of the NMR spectroscopy study,
the data presented above show that the amides 1aLi and 1bLi
aggregate with lithium chloride and bromide in THF, to provide
1
6
robust 1:1 complexes, characterized by H and Li mono- and
bidimensional NMR spectra. These complexes arise either by
direct association between the “naked” lithium amide and the
lithium halide or by substitution of methyllithium out of a
preformed lithium amide:methyllithium mixed aggregate. This
latter substitution (i) is complete and irreversible, as demon-
strated in the case of 1aLi:LiCl, (ii) is stereospecific for the
exo complexes, (iii) could partly epimerize the chiral nitrogen
N7 for the endo arrangements. Note that these observations
match extremely well those reported by Collum et al. for
diphenyllithium amide.10a,b
We have first considered the complexes involving the lithium
amides 1aLi and 1bLi and the three additives in vacuo. The
full optimizations (B3P86, 6-31G**) led to folded aggregates
similar to those described previously for the MeLi aggregates.
The aggregation energies were calculated according to
Eaggr ) Ecomplex - E3APLi - ELiX (- 3ETHF
)
These results hint that the lithium amide:methyllithium
aggregates supposed to be at the origin of the induction
phenomenon during the reaction displayed in Scheme 1, are
destabilized, in the presence of lithium halides, to the benefit
of the lithium amide:lithium halide complexes. The source of
chirality would thus be sequestrated into a chemically irrelevant
entity, leaving the tetrameric methyllithium almost free to add
on the aldehydes in the absence of a closely associated inductor.
However, the fact that a significant excess of LiCl is necessary
for the ee to plummet (Table 1, entry 3) suggests another
parameter has to be taken into account. The interference between
the above complex and the alcoholate progressively formed in
the reaction media could be involved in this phenomenum. We
are currently examining this point.
where Ecomplex is the total energy of the optimized aggregate,
E3APLi the energy of the isolated lithium amide optimized in a
conformation similar to that it adopts within the complex, ELiX
the energy of the additive (MeLi, LiCl, or LiBr), and ETHF the
energy of THF, this latter being taken into account for the
solvated species only. The corresponding values are displayed
in Tables 2 and 3.
The data in Table 2 show that the endo and exo arrangements
are more or less isoenergetic, as noted before.6b The conforma-
(21) Sapse, A.-M.; Jain, D. C.; Raghavachari, K. In Lithium Chemistry:
A Theoretical and Experimental OVerView; Sapse, A.-M., Schleyer, P. v.
R., Eds.; J. Wiley & Sons: New York, 1995. For a recent paper dealing
with this problem, see: Matito, E.; Poater, J.; Bickelhaupt, F. M.; Sola, M.
J. Phys. Chem. B 2006, 110, 7189-7198.
(22) See, for instance: (a) Pratt, L. M.; Streitwieser, A. J. Org. Chem.
2000, 65, 290-294. b() Fressigne´, C.; Maddaluno, J.; Marquez, A.;
Giessner-Prettre, C. J. Org. Chem. 2000, 65, 8899-8907. (c) Pratt, L. M.;
Nguyeˆn, N. V.; Ramachandran, B. J. Org. Chem. 2005, 70, 4279-4283.
(d) Fressigne´, C.; Lautrette, A.; Maddaluno, J. J. Org. Chem. 2005, 70,
7816-7828.
Theoretical Study of the Competitive Aggregations of
3APLi, MeLi, and LiX. It was next tempting to evaluate the
relative stabilities of the various aggregates formed between the
3APLi and MeLi, LiCl, and LiBr. The aggregation of organo-
lithium compounds has been the object of many theoretical
(23) Jaguar 4.1, release 53, Schro¨dinger, LLC., Portland, OR, 2000.
6988 J. Org. Chem., Vol. 72, No. 18, 2007

Detrimental Effects of LiX on EnantioselectiVe Addition of Alkyllithiums
TABLE 2. Aggregation Energies (B3P86, 6-31G**) of the Unsolvated Complexes between 1aLi and 1bLi and LiX (X ) Me, Br, Cl)
a E(MeLi) ) -47.613361 au; E(LiBr) ) -20.973194 au; E(LiCl) ) -468.161964 au. b Values in au. c Values in kcal‚mol-1
.
TABLE 3. Variation of the Differences between Aggregation
Energies (B3P86, 6-31G**) of the Unsolvated Complexes 1aLi:MeLi
or 1bLi:MeLi and 1aLi:LiX or 1bLi:LiX (X ) Cl, Br) with the
Aggregation State of the Reacting (LiX)n
into account. We thus decided to study the respective influence
of these two parameters on the thermodynamics of the exchange.
The influence of the aggregation state of (LiX)n on the energy
balance of the equilibrium was evaluated by computing the ∆E
values for the following reaction
1aLi:LiMe
1bLi:LiMe
X
n
∆E (kcal‚mol-1
)
∆E (kcal‚mol-1
)
Cl
1
2
4
1
2
4
-7.28
-4.46
-3.68
-6.69
-6.38
-6.39
-6.42
-3.60
-2.82
-7.67
-7.36
-7.37
1aLi:LiMe + (LiX)n ) 1aLi:LiX + (LiX)n-1(LiMe)
with an associated ∆E ) (EII + En-1) - (EI + En), where EII
is the energy associated to 1aLi:LiX, EI that associated with
1aLi:LiMe, En that of (LiX)n, and En-1 that of (LiX)n-1(MeLi).
The results are shown Table 3, LiCl and LiBr being considered
as monomers, dimers, or tetramers (n ) 1, 2, or 4).
In the two topologies, the two halides behave quite differ-
ently: the aggregation has little impact on LiBr aggregation
energy while it changes considerably that of LiCl. In this latter
case, the 1a,bLi:LiCl energy formation decreases significantly
(by∼50%) when the aggregation of LiCl increases. This
difference is probably due to the homogeneous aggregation
energy of LiCl and LiBr. This assumption was confirmed by
comparing the dissociation energy of (LiCl)2 to that of (LiBr)2
and the aggregation energy of 1aLi:LiCl to that of 1aLi:LiBr.
While the dissociation [(LiX)2 f 2 LiX] favors LiBr over LiCl
Br
tion of the complexes is hardly altered upon substitution of MeLi
by LiCl or LiBr. This explains the high similarity between the
1H NMR spectra of 1a,bLi:MeLi and of 1a,bLi:LiX. In contrast,
the energy values indicate that the substitution is thermodynami-
cally favored: the aggregates with the lithium halides are
preferred by 6.4 to 7.3 kcal‚mol-1 for LiCl and by 5.0 to
6.7 kcal‚mol-1 for LiBr, in line with the data from the NMR
spectroscopy. The energy gain is slightly larger for the endo
complexes.
In the above calculations, neither the degree of aggregation
of LiX nor the solvation of the interacting species were taken
J. Org. Chem, Vol. 72, No. 18, 2007 6989

Pate´ et al.
TABLE 4. Aggregation Energies (B3P86, 6-31G**) of the
Complexes between 1aLi, 1bLi and LiX (X ) Me, Br, Cl) Solvated
by Three THF
Conclusions
A drop of the enantiomeric excess of the 1-o-tolylethanol
resulting from the addition of methyllithium on o-tolualdehyde
in the presence of chiral lithium amides derived from chiral
3-aminopyrrolidines (3APLi) was observed upon addition of
LiCl to the medium. The formation of the various possible
aggregates between the LiX, the lithium amide, and the
methyllithium was thus examined by multinuclear NMR spec-
troscopy in THF. The results show that the initial mixed
aggregate of the chiral lithium amide and methyllithium is
rapidly, totally, and irreversibly replaced by a 1:1 complex
involving one lithium chloride or bromide and one lithium
amide. The overall conformation of these new aggregates is
similar to the original ones. However, the MeLi/LiX substitution
occurs with some degree of epimerization at the nitrogen for
the endo-MeLi:3APLi complex. In contrast, the substitution is
more or less stereospecific for the exo arrangements of the
aggregate. DFT calculations confirm the thermodynamic prefer-
ence for the 3APLi:LiX mixed aggregates (by more than
10 kcal‚mol-1 when THF is explicitly taken into account). This
phenomenon can explain the detrimental effect of these additives
on the ee of the model reaction.
b,c
b
complex
Ea
Eaggr
∆Eaggr
endo-1aLi:MeLi-3THF
endo-1aLi:LiCl-3THF
endo-1aLi:LiBr-3THF
exo-1bLi:MeLi-3THF
exo-1bLi:LiCl-3THF
exo-1bLi:LiBr-3THF
-1759.123499
-2179.692188
-1732.504632
-1759.122528
-2179.688705
-1732.501999
-80.3
-93.0
-93.7
-77.9
-89.7
-90.3
0.0
-12.6
-13.4
0.0
-11.8
-12.3
a Energies in au. b Energies in kcal‚mol-1 c E(THF) ) -233.183081 au.
.
FIGURE 7. Endo-1aLi:MeLi-3THF-optimized aggregate.
by 3.8 kcal‚mol-1, the aggregation [1aLi + LiX f 1aLi:LiX]
favors LiCl over LiBr but by only 0.6 kcal‚mol-1. To conclude
on the influence of the aggregation, it is worth emphasizing
that LiBr which appears, when considering only the monomers,
to be equivalent to LiCl actually has a higher affinity for lithium
amide 1aLi than LiCl for both the endo and exo topologies.
Note finally that these figures are to be taken with some caution
since only the 1a,bLi:MeLi + (LiX)2 f 1a,bLi:LiX + MeXLi2
reactions are isodesmic.
We next considered the influence of THF in trisolvated5
complexes.24 The data show that the endo and exo bicyclic cores
of the complexes are preserved upon solvation. For the sake of
space economy, only the endo 1aLi:MeLi-3THF-optimized
aggregate is illustrated in Figure 7. Note that (i) the THF-
lithium interactions impose steric constraints on the lateral
substituents which rotate out of their original position, (ii) the
aggregation energies are considerably increased upon solvation
since the calculation now incorporate the interactions between
the two lithium and the three THF, and (iii) the thermodynamic
preference for the complexes with lithium halides is amplified
by the solvation (>11 kcal‚mol-1), the lithium bromide leading
to complexes more stable than LiCl. The aggregation energy
of the endo complexes remains slightly larger than for the exo
ones. Similar calculations run for the 3APLi bearing an
R-naphthyl appendage led to comparable conclusions, but for
the orientation of the lateral chain bearing the naphthyl
appendage.25
Experimental Section
Under an argon atmosphere, MeLi (0.75 mmol, 1.6 M in ether)
was added to a solution of 1a (0.75 mmol) in THF (15 mL) at
-20 °C. After the solution was stirred for 20 min, a second aliquot
of MeLi (1.25 mmol, 1.7 equiv against 1aLi, 1.6 M solution in
ether) was added dropwise to the 1aLi, and the resulting mixture
was stirred 30 min at -20 °C. The mixture was then cooled to
-78 °C and aged 30 min at the same temperature. LiCl (0-
2.7 equiv against 1aLi, 0.3 M in THF) was added dropwise at -78
°C, and the resulting mixture was aged for 30 min. A solution of
o-tolualdehyde (0.5 mmol) in THF (2 mL) was added at -78 °C
over a 5 min period, and the mixture was stirred at -78 °C for
2 h. The medium was quenched at -78 °C with a 3 M aqueous
HCl solution (3 mL) and extracted with ether (3 × 10 mL) after
reaching room temperature. The combined organic layers were
washed with NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was purified
by column chromatography (Et2O/cyclohexane 30:70) to give 1-o-
tolylethanol as a colorless oil.
General Aspects for the NMR Study. Argon was dried and
deoxygenated by bubbling through a commercial solution of
n-butyllithium in hexane. Commercial tetrahydrofuran-d8 was
distilled over sodium and benzophenone. 6Li (95%) washed in
freshly distilled pentane. All NMR experiments were performed
on a 500 MHz spectrometer, equipped with z-gradient unit and a
5 mm {1H, 6Li, 13C, and 15N} quadruple-resonance probe. Measuring
frequencies were 500 MHz (1H), 125 MHz (13C), and 73 MHz (6-
Li). 1H and 13C chemical shifts were referenced to the solvent THF-
d8 signals at δ 1.73 and 25.37, respectively. Lithium spectra were
referenced to external 0.3 M 6LiCl in MeOH-d4 (d 0.0). Processing
of NMR data was performed on SGI O2 computer, using the
manufacturer’s program Xwinnmr 2.1 (Bruker).
Overall, the theoretical data computed for the solvated
complexes are in good agreement with the above results from
NMR spectroscopy, the large energy differences calculated
(>10 kcal‚mol-1) warranting the irreversibility of the MeLi f
LiX substitution. Note that these conclusions are perfectly in
line with previous results obtained by Williard, Schleyer, and
colleagues10d on different systems.
1D NMR Measurements. Proton and lithium one-dimensional
experiments were recorded with standard parameters.
2D NMR Measurements. 1H/1H NOESY. The following
parameters were used for acquiring and processing the spectra in
phase sensitive-sensitive mode: 256 experiments with 2048 data
points and 16 scans each were recorded; pure phase line shapes
were obtained by using time proportional phase incrementation
phase cycling, variable mixing times, depending on the sample,
were used; one time zero filling in f1; p/2 shifted sine square
window functions were applied to f2 and f1 dimension before FT.
(24) For a very recent paper dealing with the theoretical solvation of
alkyllithiums, see: Pratt, L. M.; Truhlar, D. G.; Cramer, C. J.; Kass, S. R.;
Thompson, J. D.; Xidos, J. D. J. Org. Chem. 2007, 72, 2962-2966.
(25) Pate´, F. Ph.D. thesis, Universite´ de Rouen, 2006.
6990 J. Org. Chem., Vol. 72, No. 18, 2007

Detrimental Effects of LiX on EnantioselectiVe Addition of Alkyllithiums
6Li/1H HOESY. The following parameters were used for
acquiring and processing the spectra in phase sensitive-sensitive
mode: 128 experiments with 1024 data points and 16 scans each
were recorded; pure phase line shapes was obtained by using time
proportional phase incrementation phase cycling; variable mixing
times, depending on the sample, were used; one time zero filling
in f1; p/2 and p/3 shifted sine square window functions were applied
to f2 and f1 dimension respectively before FT.
(CRIHAN, St Etienne-du-Rouvray, France). We also acknowl-
edge the CINES and IDRIS for additional allocations of
computer time. This study was conducted within the frame of
the PUNCHorga interregional network supported by the Re´gion
Haute-Normandie, Re´gion Basse-Normandie, as well as national
funds through the DRRT.
Supporting Information Available: Detailed experimental
protocols and copies of mono- and bidimensional 1H and 6Li NMR
spectra for 1a alone and 1aLi:LiCl, 1aLi:LiBr, and 1aLi:MeLi
aggregates. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. N.D. thanks the “Ministe`re de la Re-
cherche et de la Technologie” for a PhD grant. We are grateful
to Dr H. Ge´rard (Universite´ Paris VI) for stimulating discussions
throughout this work. Most computations have been carried out
at the Centre de Ressources Informatiques de Haute-Normandie
JO071160X
J. Org. Chem, Vol. 72, No. 18, 2007 6991