A NMR and theoretical study of the aggregates between alkyllithium and chiral lithium amides: Control of the topology through a single asymmetric center

Article abstract of DOI:10.1021/ja016945d

The complexes between methyllithium and chiral 3-aminopyrrolidine (3-AP) lithium amides bearing a second asymmetric center on their lateral amino group were studied using multinuclear (¹H, ⁶Li, ¹³C, ¹⁵N) low-temperature NMR spectroscopies in tetrahydrofuran-d₈. The results indicate that lithium chelation forces the pyrrolidine ring of the 3-AP to adopt a norbornyl-like conformation and that robust 1:1 noncovalent complexes between methyllithium and 3-AP lithium amides form in the medium. A set of ¹H-¹H and ¹H-⁶Li NMR cross-coupling correlations shows that the binding of methyllithium can take place along the "exo" or the "endo" face of this puckered structure, depending on the relative configuration of the lateral chiral group. This aggregation step renders the nitrogen of the 3-amino group chiral, the "exo" and "endo" topologies corresponding to the (S) and (R) configurations, respectively, of this atom. Density functional theory calculations show that the "exo" and "endo" arrangements are, for both diastereomers, almost isoenergetic even when solvent is taken into account. This result suggests that the formation of the mixed aggregates is under strict kinetic control. A relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aromatic aldehydes by alkyllithiums is proposed.

Full text of DOI:10.1021/ja016945d

A NMR and Theoretical Study of the Aggregates Between Alkyllithium
and Chiral Lithium Amides: Control of the Topology Through a Single
Asymmetric Center.
†
‡
‡
†
Aline Corruble, Daniel Davoust, Stéphanie Desjardins, Catherine Fressigné,
§*
†
†
^
Claude Giessner-Prettre, Anne Harrison-Marchand, Henri Houte, Marie-Claire Lasne,
†*
‡
†
Jacques Maddaluno, Hassan Oulyadi and Jean-Yves Valnot.
________________________
Supporting information

Experimental Part
General Considerations.
1H NMR and 13C NMR spectra for compounds 7, 8 and 1 were recorded at room temperature
on a Bruker DPX300 spectrometer at 300 MHz and 75 MHz respectively and on a Bruker
Avance DMX 500 spectrometer at 500 MHz (1H) and 125 MHz (13C). J Values are given in
Hz. IR spectra were realized on a PERKIN-ELMER 16PC IRTF spectrometer. The mass
spectra were obtained on a JEOL AX500 apparatus, under electron impact conditions (EI) at
70 eV ionizing potential; isobutane (t-BuH) and ammonia (NH3) were used for chemical
ionization (CI). Melting points were determined using a C. REICHERT microscope
apparatus. Thin layer chromatography (TLC) was carried out on Merk 5735 Kieselgel 60 F254
fluorescent plates. Flash chromatography was performed with silica gel (Merck Geduran SI
60 Art 11567). Optical rotations, [α]D, were measured in quartz cells (d = 1 dm), using Na
and Hg lights, with solvents and concentrations indicated.
Argon was dried and deoxygenated by bubbling through a commercial solution of
butyllithium in hexane. Commercial tetrahydrofuran-d8 was distilled over sodium and
6
benzophenone. Li (95%) was purchased from Aldrich and washed in freshly distilled
pentane.
N-(tert-Butoxycarbonyl)-3-(R)-hydroxypyrrolidine 7
A solution of trans-4-(R)-hydroxy-(L)-proline (5 g, 38,2 mmol) and 2-cyclohexen-1-one (0,5
mL, 5,16 mmol) in cyclohexanol (50 mL) was heated at 160°C for 6 h, until all the solid was
dissolved. The resulting red solution was cooled to room temperature and an aqueous solution
of acetic acid (20%; 50 mL) and toluene (30 mL) were added. The aqueous layer was washed
twice with toluene then potassium carbonate (15 g) was introduced until pH = 9. Dioxane (50
mL) followed by di-tert-butyl dicarbonate (8,73 g, 40 mmol) were introduced to the basic
resulting solution at 0°C and the reaction mixture was stirred at room temperature for 20 h.
The organic materials were extracted twice with ether and the combined organic layers were
concentrated. Ethanol (40 mL) was added and the solution was heated under reflux for 20 h.
After evaporation of the solvent, the residue was eventually purified by flash chromatography
on silica (heptane:ethyl acetate, 30:70) to give 7 as a white solid (6,15 g, 86%): mp 59-61°C
(from ethanol); 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9H), 1.83-1.89 (m, 2H), 3.25-3.39 (m,
13
4H), 3.70 (s,1H), 4.34 (s, 1H); C NMR (75 MHz, CDCl3) δ 28.8, 33.8 and 34.2, 43.9 and
44.3, 54.5,70.2 and 71.0, 79.7, 155.2; IR (film, NaCl) υ /cm-1 1123, 1168, 1412, 1676,
max
3424; CIMS (200 eV, NH3) m/z (relative intensity) 188 (M+H+, 40), 149 (100); HRMS calcd

for C9H18NO3 188.1286, found 188.1284; Anal. Calcd for C9H17NO3: C, 57.73; H, 9.15; N,
7.48%. Found: C, 57.75; H, 9.45; N, 7.42%. [α]D26 -21.9 (c 1.42, CH2Cl2).
N-(tert-Butoxycarbonyl)-3-(S)-(1'-(S)-phenylethyl) aminopyrrolidine 8e
A solution of di-iso-propylethylamine (5.85 mL, 33.58 mmol) in dichloromethane (5 mL) was
added to a solution of N-(tert-butoxycarbonyl)-3-(R)-hydroxypyrrolidine 7 (3 g, 16.04 mmol)
in cold (-30°C) dichloromethane (22 mL) and placed under nitrogen atmosphere.
Trifluoromethanesulfonic anhydride (2.87 mL, 17.1 mmol) was slowly syringed over a period
of 25 min, the reaction mixture was then stirred for 45 min at -30°C. A solution of (S)-(-)-α-
methylbenzylamine (3 mL, 23.2 mmol) in dichloromethane (9 mL) was introduced in 5 min,
and the resulting mixture was stirred at room temperature for 20 h. The solution was washed
with saturated aqueous potassium hydrogen carbonate (2x30 mL) and brine (1x30 mL). The
organic layer was collected, dried (MgSO4), filtered and concentrated. Purification by
chromatography on silica (dichloromethane:ethyl acetate, 50:50) gave 8e as pale yellow oil
(2.6 g, 55%): 1H NMR (300 MHz, CDCl3) δ 1.27 (d, 3H, J = 6.4), 1.37 (s, 9H), 1.40 (s, 1H),
1.45-1.60 (m, 1H), 1.75-1.87 (m, 1H), 2.97-3.20 (m,3H), 3.27-3.53 (m, 2H), 3.72 (q, 1H, J =
13
6.4), 7.19-7.26 (m, 5H); C NMR (75 MHz, CDCl3) δ 25.4, 29.2, 32.6 and 33.4, 44.7 and
45.0, 52.0 and 52.6, 55.1 and 56.0, 57.3, 79.8, 127.2, 127.7, 129.2, 146.0, 155.3; IR (film,
NaCl) υ /cm-1 1118, 1164, 1402, 1682, 2972, 3316; CIMS (200 eV, t-BuH) m/z (relative
max
intensity) 291 (M+H+, 100); HRMS calcd for C17H27N2O2 291.2072, found 291.2064; Anal.
Calcd for C17H26N2O2: C, 70.31; H, 9.02; N, 9.65%. Found: C, 70.27; H, 9.22; N, 9.54%.
[α]D25 -92.8 (c 1.52, CHCl3).
N-(tert-Butoxycarbonyl)-3-(S)-(1'-(R)-phenylethyl) aminopyrrolidine 8f
8f was prepared from 7 (2 g, 10.7 mmol) in a similar way to 8e using (R)-(+)-α-
methylbenzylamine and led to a pale yellow oil (1.92 g, 62%); 1H NMR (300 MHz, CDCl3) δ
1.27 (d, 3H, J = 6.8), 1.38 (s, 9H), 1.43 (s, 1H), 1.48-1.67 (m, 1H), 1.89-2.04 (m, 1H), 2.80-
13
3.50 (3m,5H), 3.72 (q, 1H, J = 6.8), 7.17-7.26 (m, 5H); C NMR (75 MHz, CDCl3) δ 25.2
and 25.3, 29.1, 31.7 and 32.5, 44.6 and 45.1, 52.5 and 52.9, 55.2 and 56.0, 57.0, 79.7 and
79.9, 127.2, 127.8, 129.2, 146.0, 155.2; IR (film, NaCl) υ /cm-1 1110, 1166, 1412, 1704,
max
2972, 3307; CIMS (200 eV, t-BuH) m/z (relative intensity) 291 (M+H+, 100); HRMS calcd
for C17H27N2O2 291.2072, found 291.2067. [α]D25 +25.4 (c 0.885, CHCl3).
N-Methyl-3-(S)-(1'-(S)-phenylethyl) aminopyrrolidine 1e

A solution of N-(tert-butoxycarbonyl)-3-(S)-(1'-(S)-phenylethyl) aminopyrrolidine 8e in dry
THF (30 mL) was added for 30 min to a suspension of lithium aluminum hydride (0.21 g,
5.51 mmol) in freshly distilled THF (10 mL), placed under nitrogen atmosphere and cooled to
0°C. The solution was stirred at room temperature for 6h then warmed at 60°C for an hour.
After cooling at 0°C, the excess of LAH was hydrolized by successive addition of cold water
(0.6 mL), 4N aqueous sodium hydroxide (0.6 mL) and cold water (0.8 mL). The white
precipitate was filtered on celite and washed with dichloromethane (10 mL). The filtrate was
concentrated and the residue was dissolved in ether (10 mL). 1N aqueous hydrochloric acid
(10 mL) was added and the solution was stirred at room temperature for 15 min. The acidic
aqueous layer was extracted and sodium hydrogen carbonate was slowly introduced until pH
= 9 followed by a few drops of 4N aqueous sodium hydroxide. The medium was then
extracted with dichloromethane (3x10mL). The organic layer was collected, dried (MgSO4),
filtered and concentrated to give 1e as a pale yellow oil (0,195 g, 69%); 1H NMR (500 MHz,
CDCl3) δ 1.28 (d, 3H, J = 6.6), 1.42-1.46 (m, 1H), 1.97-2.13 (m, 1H), 2.22-2.25 (m, 1H), 2.26
(s, 3H), 2.44-2.46 and 2.55-2.58 (2m,3H), 3.06-3.08 (m, 1H), 3.71 (q, 1H, J = 6.6), 7.16-7.25
(m, 5H); 13C NMR (125 MHz, CDCl3) δ 25.2, 34.0, 42.9, 55.8, 55.9, 57.0, 63.2, 127.4, 127.6,
129.1, 146.1; IR (film, NaCl) υ /cm-1 1450, 2964, 3386; EIMS (70 eV) m/z (relative
max
intensity) 204 (M+., 20), 99 (70), 85 (100); HRMS calcd for C13H20N2 204.1626, found
204.1631. [α]D24.5 -79.4 (c 0.54, CHCl3).
N-Methyl-3-(S)-(1'-(R)-phenylethyl) aminopyrrolidine 1f
1f was prepared from 8f (0.31 g, 8.26 mmol) in a similar way to 1e and led to a pale yellow
1
oil (0.218 g, 65%); H NMR (300 MHz, CDCl3) δ 1.27 (d, 3H, J = 6.4), 1.40-1.48 (m, 1H),
1.50-1.60 and 1.94-2.05 (2m, 2H), 2.15-2.24 and 2.41-2.47 (2m, 2H), 2.21 (s, 3H), 2.29-2.37
and 2.50-2.58 (2m,2H), 3.05-3.11 (m, 1H), 3.72 (q, 1H, J = 6.4), 7.13-7.24 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 25.1, 33.3, 42.9, 56.0, 57.0, 64.1, 127.4, 127.6, 129.0, 146.2; IR (film,
NaCl) υ /cm-1 1450, 2962, 3306; EIMS (70 eV) m/z (relative intensity) 204 (M+., 18); 99
max
25
(65), 85 (100); HRMS calcd for C13H20N2 204.1626, found 204.1635. [α]D +65.6 (c 0.76,
CHCl3).
[6Li] Methyllithium salt-free solution in ether
Finely cut 6-lithium metal ribbon (0.5 g, 83 mmol), 0.5% (weight) of sodium (ca. 2,5 mg,
0,11 mmol) and three small pieces of broken glass were introduced in a two necked pear-
shaped flask (50 mL) equipped with a glass stopper and a condenser fitted with a balloon of
dry argon. The metallic cuttings were covered with octadecane (10 mL) and the solution was
heated (reflux of octadecane : 317°C) with a hot air gun while vigorously stirring. When a

maximum amount of the lithium was melted, the flask was placed in a cold bath (- 40°C)
allowing the lithium to precipitate as a fine shiny shot. The octadecane was extracted with
freshly distilled (over lithium aluminum hydride) heptane (10 mL) using a syringe. After
intensive stirring, the heptane was removed and the metal washed twice with this same
solvent. Diethylether was syringed and the condenser was quickly replaced by a CO2
condenser fitted with a balloon of dry argon. Chloromethane (2,3 mL, 41,5 mmol) was
condensed directly from the sealed cylinder to a graduated trap at -40°C and then added very
slowly (2,3 mL were added over a period of 45 min) connecting the trap to the top of the CO2
condenser. The formation of a grey salt corresponding to LiCl was observed and the
disappearance of the 6Li metal was noticed. After replacing the CO2 condenser with a septum,
the resulting reaction mixture was stirred for 20 h at room temperature under dry argon. The
stirring was stopped allowing LiCl to settle. The etheral solution was then pumped off the
flask with a syringe and directly inserted into centrifugation tubes placed under dry argon.
The residual traces of salt were centrifuged and the clear final solution was collected in a dry
flask flushed under dry argon then titrated1 (1,4 M, 55% yield) and kept until further use.
[6Li] Methyllithium salt-free solution in tetrahydrofuran-d8
A solution of [6Li]-methyllithium in ether prepared above (2,5 mL) was syringed in a tube
fitted with a septum and flushed under dry argon. The tube was then placed under vacuum (20
mmHg) for 1 h to evaporate the ether. The resulting white solid was then dissolved in freshly
distilled tetrahydrofuran-d8 and concentrated under vacuum for 1 h to evaporate the last traces
of ether. THF- d8 (3 to 3.5 mL) was finally added and the resulting solution was titrated25 (0.5
to 0.7 M).
[6Li]-Lithium amides 2e or 2f, 2c or 2d
A solution of amine (1e (27,9 mg; 0,137 mmol) or 1f (29,0 mg; 0.142 mmol) in freshly
distilled tetrahydrofuran- d8 (0,2 mL) was transferred into a dry 5-mm NMR tube fitted with a
septum and flushed under argon., 0.5 to 0.7 M [6Li]-Methyllithium (1 eq) in tetrahydrofuran-
d8 was added dropwise at –78°C with a syringe to the above solution,. The tube was then
vigorously shaken and quickly dropped in the pre-cooled (-93°C) NMR probe. All the spectra
of the corresponding amide 2e and 2f were recorded at this temperature. The lithium amide 2c
and 2d were prepared following a similar procedure.

[6Li]-Complexes 3c, 3d 3e or 3f
The complexes obtained from amides 2c, 2d, 2e and 2f with [6Li]-methyllithium in
tetrahydrofuran- d8 were prepared in a similar way to the lithium amides, but using directly an
excess of Me6Li/amine (>2eq./1c, 1d, 1e or 1f) or adding a second equivalent of Me6Li on 2c,
2d, 2e or 2f.
Instrumental considerations.
The conformational study of 3AP lithium amides 2c-f and their complexes with MeLi 3c-f
were achieved by using one and two-dimensional NMR experiments.
All NMR experiments were performed on a Bruker Avance DMX 500 spectrometer, equipped
6
with z-gradient unit and a 5 mm {1H, Li, 13C and 15N} quadruple-resonance probe.
Measuring frequencies were 500 MHz (1H), 125 MHz (13C), 73 MHz (6Li) and 50 MHz (15N).
1H and 13C chemical shifts were referenced to the solvent THF-d8 signals at δ 1.73 and δ 25.37
6
respectively. Lithium spectra were referenced to external 0.3 M LiCl in MeOH-d4 (δ 0.0).
15
Nitrogen spectra were referenced to external 0.1 M N urea in DMSO-d6 (δ 75.9 ppm with
respect to NH3).
1D NMR measurements
The proton and lithium one dimensional experiments were recorded with standard parameters.
13
1
13
In order to remove C - H coupling, the one dimensional C spectra were recorded with
broad band proton decoupling.
2D NMR measurements
6Li/6Li COSY:2 The following parameters were used for acquiring and processing the spectra
in absolute values: 128 experiments with 1024 data points and 8 scans each were recorded; no
proton decoupling was used; one time zero filling in f ; pure sine bell window function was
1
applied before Fourier Transformation.
1H/1H COSY:3 The following parameters were used for acquiring and processing the spectra
in absolute values: 256 experiments with 2048 data points and 8 scans each were recorded;
one time zero filling in f ; pure sine bell window function was applied before Fourier
1
Transformation.
1H/13C HMQC:4 The following parameters were used for acquiring and processing the
spectra in phase sensitive-sensitive mode: 512 experiments with 2048 data points and 8 scans

each were recorded; pure phase line shapes was obtained by using Time Proportional Phase
Incrementation (TPPI) phase cycling5, one time zero filling in f ; π / 2 shifted sine square
1
window functions were applied to f and f dimension before Fourier Transformation.
2
1
1H/1H NOESY:6 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 was obtained by using Time Proportional
Phase Incrementation (TPPI) phase cycling, variable mixing times, depending on the sample,
were used; one time zero filling in f ; π / 2 shifted sine square window functions were applied
1
to f and f dimension before Fourier Transformation.
2
1
6Li/1H HOESY:7 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 (TPPI) phase cycling; variable mixing times, depending on the sample,
were used; one time zero filling in f ; π / 2 and π / 3 shifted sine square window functions
1
were applied to f and f dimension respectively before Fourier Transformation.
2
1
6Li/6Li EXSY:8 The following parameters were used: 256 experiments with 2048 data points
and 8 scans each were recorded; mixing time 4.0 s; pure phase line shapes was obtained by
using Time Proportional Phase Incrementation (TPPI) phase cycling; one time zero filling in
f ; π / 2 shifted sine square window functions were applied to f and f dimension before
1
2
1
Fourier Transformation.
Processing of NMR data was performed on SGI O2 computer, using the manufacturer’s
program Xwinnmr2.1 (Bruker).
Computational procedures. The quantum mechanical computations were performed using
the 6-31G**, 6-311G**, 6-31++G** and 6-311++G** basis set9 and the B3P86, B3LYP and
B3PW91 hybrid density functional.10 For all the systems considered, all geometrical
parameters were fully optimized. The gas-phase optimizations were obtained from
Gaussian98.11 Those including the dimehtyl ether molecules used as model of THF solvent
were carried out with Jaguar 4.1.12 The nuclear magnetic shielding constants were calculated
using the GIAO method,13 as implemented in Gaussian98.

References:
1. Duhamel, L.; Plaquevent, J.C. J. Organomet. Chem. 1993, 448, 1-3.
2. Günther, H.; Moskau, D.; Dujardin, R.; Maercker, A. Tetrahedron Lett. 1986, 27, 2251-
2254.
3. Nagayama, K., Kumar, A., Wüthrich, K., Ernst, R. R. J. Magn. Reson. 1980, 40, 321-334.
4. Bax, A., Griffey, R.H., Hawkins, B.L. J. Magn. Reson. 1983, 55, 301-315.
5. Marion, D.; Wüthrich, K. Biochem. Biophys. Res. Comm. 1983, 113, 967-974.
6. States, D.J.; Haberkorn, R.A.; Ruben, D.J. J. Magn. Reson. 1982, 48, 286-292.
7. Bauer, W.; Schleyer, P.v.R. Magn. Reson. Chem. 1988, 26, 827-833.
8. a) Meier, B.H.; Ernst R.R. J. Am. Chem. Soc. 1979, 101, 6441-6442. b) Jeener, J.; Meier,
B.H.; Bachman, P.; Ernst, R.R. J. Chem. Phys. 1979, 71, 4546-4553.
9. Frisch, J. M.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984, 80, 3265-3269.
10. a) Perdew, J. P. Phys. Rev. 1986, B33, 8822-8824. b) Becke, A. D. J. Chem. Phys. 1989,
90, 5648-5652. c) Lee, C.; Yang, W.; Parr, R.G. Phys. Rev. B 1988, 37, 785-789. d)
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200-206. e)
Perdew, J.P.; Burke, K.; Wang, Y. Phys. Rev. B 1996, 54, 16533-16539.
11. GAUSSIAN 98 (Revision A5) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewfki, V. G.; Montgomery, J. A.; Stratmann, R.
E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, F.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma,
K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.;
Andres, J. L.; Head-Gordon, M.; Replogle E. S.; Pople, J. A. 1998, Gaussian Inc.,
Pittsburgh PA.
12. a) Jaguar 4.1; Schrödinger Inc., Portland OR, 2000. b) Greeley, B. H.; Russo, T. V.;
Mainz, D. T.; Friesner, R. A.; Langlois, J. M.; Goddard, W. A., III; Donnelly, R. E.;
Ringalda, M. N. J. Chem. Phys. 1994, 101, 4028-4041.
13. a) Ditchfield, R. Mol. Phys. 1974, 27, 789. b) Wolinski, K.; Himton, J. F.; Pulay, P. J. Am.
Chem. Soc. 1990, 112, 8251-8260.

2
Captions to Figures in Supporting Information.
Fig. 1S: Monodimensional 6Li spectrum of lithium amide 2c in THF-d8 at -78°C.
Fig. 2S: Two dimensional 1H/1H COSY contour plot of Me6Li mixed-aggregate 3c in THF-d8
solution at -78°C.
Fig. 3S: Two dimensional 1H/13C HMQC contour plot of Me6Li mixed-aggregate 3c in THF-
d8 solution at -78°C.
Fig. 4S: Monodimensional 1H spectrum of lithium amide 2d in THF-d8 solution at -78°C.
Fig. 5S: Monodimensional 6Li spectrum of lithium amide 2d in THF-d8 solution at -78°C.
1
Fig. 6S: Two dimensional H/1H COSY contour plot spectrum of Me6Li mixed-aggregate 3d
in THF-d8 solution at -78°C.
1
Fig. 7S: Two dimensional H/13C HMQC contour plot spectrum of Me6Li mixed-aggregate
3d in THF-d8 solution at -78°C.
13
Fig. 8S: Monodimensional C spectrum of Me6Li mixed-aggregate 3d in THF-d8 solution at
-78°C.
Fig. 9S: Monodimensional 1H spectrum of lithium amide 2e in THF-d8 solution at –93°C.
Fig. 10S: Monodimensional 6Li spectrum of lithium amide 2e in THF-d8 solution at –93°C.
Fig. 11S: Monodimensional 1H spectrum of lithium amide 3e in THF-d8 solution at -93°C.
Fig. 12S: Two dimensional 6Li/1H HOESY contour plot spectrum (τm = 1s) of Me6Li mixed-
aggregate 3e in THF-d8 solution at -93°C.
1
Fig. 13S: Two dimensional H/1H NOESY contour plot spectrum (τm = 300ms) of Me6Li
mixed-aggregate 3e in THF-d8 solution at -93°C.
Fig. 14S: Monodimensional 1H spectrum of lithium amide 2f in THF-d8 solution at -93°C.

3
Fig. 15S: Monodimensional 6Li spectrum of lithium amide 2f in THF-d8 solution at -93°C.
1
Fig. 16S: Monodimensional H spectrum of lithium amide 3f in THF-d8 solution at -93°C
obtained by two successive additions of one equivalent of Me6Li on amine 1e.
1
Fig. 17S: Monodimensional H spectrum of lithium amide 3f in THF-d8 solution at -93°C
obtained by the direct addition of 2.3 equivalents of Me6Li on amine 1e.
1
Fig. 18S: Two dimensional H/1H NOESY contour plot spectrum (τm = 300ms) of Me6Li
mixed-aggregate 3f in THF-d8 solution at -93°C.
Fig. 19S: Two dimensional 6Li /1H HOESY contour plot spectrum (τm = 1s) of Me6Li mixed-
aggregate 3f in THF-d8 solution at -93°C.
Table 1S. Calculated energy values (in a.u.) for the «exo» and «endo» arrangements of the 3e
complex.

Figure 1S
3.5
3.0
2.5
2.0
1.5
ppm

Figure 2S
10
Me
MeLi
9
Me
2
4/4'
2'
6
8
5'
6'
5
3
ppm
-2
-1
0
1
2
3
4
5
6
7
8
9
9
8
7
6
5
4
3
2
1
0
-1
-2
ppm

Figure 3S
10
Me
9
MeLi
Me
2
4/4'
2'
6
8
6'
5'
5
3
ppm
MeLi
10
Me
0
20
Me9
C4
40
C5
C3
60
C6
C2
C8
80
100
120
140
9
8
7
6
5
4
3
2
1
0
-1
-2 ppm

Figure 4S
8
7
6
5
4
3
2
1
0
-1
ppm

Figure 5S
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5 ppm

Figure 6S
10
Me
9
Me
2
6
3
6’
2’
8
5
4
4’
5’
ppm
-2
-1
0
1
2
3
4
5
6
7
8
9
9
8
7
6
5
4
3
2
1
0
-1
-2 ppm

Figure 7S
10
Me
9
Me
2
6
3
6’
2’
8
5
4
4’
5’
ppm
10
Me
0
20
9
Me
40
60
80
100
120
140
9
8
7
6
5
4
3
2
1
0
-1
-2 ppm

Figure 8S
10
Me
-12
ppm
160
140
120
100
80
60
40
20
0
ppm

Figure 9S
8
7
6
5
4
3
2
1
0
-1
ppm

Figure 10S
4
3
2
1
0
ppm

Figure 11S
8
7
6
5
4
3
2
1
0
-1
ppm

Figure 12S
Li1
Li2
ppm
10
10
Me
Me
-2
-1
0
1
2
3
4
5
6
7
8
9
9
Me
H4
Me
H2
H5
Ph
9
3.0
2.5
2.0
ppm

Figure 13S
6
9
Me
4/4'
Me
2
8
5'
2'
5
ppm
2.0
10
Me
ppm
H2'
1.5
2.0
2.5
3.0
3.5
H2
4.0
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

Figure 14S
8
7
6
5
4
3
2
1
0
-1
ppm

Figure 15S
Li1(11)
Li2(11)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm

Figure 16S
8
7
6
5
4
3
2
1
0
-1
ppm

Figure 17S
8
7
6
5
4
3
2
1
0
-1
-2 ppm

Figure 18S
9
Me
6
Me
3,2',5'
8
4
4'
5
2
ppm
10
Me
-2.2
-2.0
9
ppm
1.5
Me
H4
4
2
5
H5
2.0
2.5
3.0
3.5
4'
6
Me
H4'
3,2',5'
8
4.0
4.0
3.5
3.0
2.5
2.0
1.5
ppm

Figure 19S
Li1
Li2
Li1(11)
Li2(11)
(MeLi)4
(MeLi)2
ppm
-2
10
Me
MeLi
-1
0
1
2
3
4
5
6
7
9
Me
4
H2
2
H5
5
6
4'
Me
3,2',5'
8
Ph
8
3.0
2.5
2.0
1.5
ppm

Table 1S. Energy values (in a.u.) calculated for the «exo» and «endo» arrangements of complex 3e.
The energy differences are given in kcal/mol.
DFT
Basis set
3e «endo»
3e «exo»
Eendo – Eexo
B3LYP
B3LYP
B3LYP
B3P86
6-31G**
-671.3742
-671.5135
-671.3744
-671.5137
-671.3924
-673.6468
-671.1089
0.1
0.1
0.1
0.3
0.1
6-311G**
6-31++G** -671.3923
6-31G**
6-31G**
-673.6464
-671.1088
B3PW91