Li et al.
SCHEME 1. The Trimeric 2:1 Complex 1, Ligand 2, and
Asymmetric Addition
complex. As proof of principle of the applicability of DOSY to
study organolithium compounds, we have previously reported
the use of H DOSY to differentiate dimeric and tetrameric
1
n-BuLi,22 lithium allylic amide aggregates,23 and bis(diisopro-
pylamino)boron enolate of tert-butyl methyl ketone24 in the
solution state based on their mobilities. DOSY has also been
utilized in the identification of a magnesium enolate25 and other
transition metal complexes.26,27 In this article we have utilized
1H and 13C INEPT DOSY to identify and characterize different
aggregates in solution at 25 and -78 °C as the stoichiometry
of n-BuLi increases relative to the valinol derived amine 2. The
mixed trimeric 2:1 complex of lithium amide and n-BuLi 1 was
identified as the major species in solution under different
conditions. This chiral 2:1 complex 1 will be shown to be the
asymmetric intermediate for the chiral addition reaction. We
also report that it is possible to estimate the formula weight of
these aggregates in solution by using an internal reference
correlation DOSY method. Additional 6Li and 15N NMR
experiments also corroborated these results.
up to 82.7% were obtained in the case of the addition of n-BuLi
to pivaldehyde.
We now present results correlating the aggregate 1 in solution
with the previously reported crystal structure.4 A significant
question is whether aggregate 1 is the only or the major
aggregate in solution or whether it is one of several species
that could be responsible for the asymmetric induction. We
studied the solution structure of this aggregate by Diffusion-
Ordered NMR Spectroscopy (DOSY) as a means of obtaining
the formula weight and aggregation number of the mixed
aggregate that exists in solution. DOSY has emerged as a
promising technique in combinatorial chemistry and enzymatic
dynamic studies.15 DOSY can separate different species16,17 by
their hydrodynamic radii18,19 and even their MW.20,21 This makes
DOSY a powerful technique for elucidation of the components
of a mixture and identification of the aggregation state of a
Results and Discussion
1
1. Identification of Chiral Amine Ligand (2a) by H and
13C DOSY Experiments: 1H DOSY Characterization of
Ligand (2a) and Internal References. The chiral amino ether
ligand 2a is easily synthesized from valinol in two steps.28 On
1
the basis of H, 13C, and other 2D NMR techniques and ms,
the ligand structure is confirmed as N-isopropyl-O-triisopropyl
silyl valinol 2a. The complete assignments of the proton and
13C signals are given in Table S1 (Supporting Information).
To establish the internal reference-correlated DOSY meth-
odology, we first applied 1H and 13C INEPT DOSY to identify
the ligand 2a in the toluene-d8 solution. To avoid artifacts
generated by temperature fluctuation, viscosity change, and
convection, we choose 1-octadecene (ODE), cyclododecene29
(CDDE), and benzene30 as the internal references in the DOSY
experiments. The 1H DOSY spectrum of ligand 2a with the three
internal references in toluene-d8 solution separates into four
components in the diffusion dimension. These are clearly
identifiable in the DOSY spectrum reproduced in Figure 1. In
(7) Jones, A. C.; Sanders, A. W.; Bevan, M. J.; Reich, H. J. J. Am. Chem.
Soc. 2007, 129, 3492-3493.
(8) (a) Granander, J.; Eriksson, J.; Hilmersson, G. Tetrahedron: Asym-
metry 2006, 17, 2021-2027. (b) Sott, R.; Granander, J.; Williamson, C.;
Hilmersson, G. Chem.-Eur. J. 2005, 11, 4785-4792. (c) Sott, R.;
Granander, J.; Hilmersson, G. J. Am. Chem. Soc. 2004, 126, 6798-6805.
(d) Sott, R.; Granander, J.; Diner, P.; Hilmersson, G. Tetrahedron:
Asymmetry 2004, 15, 267-274. (e) Sott, R.; Granander, J.; Hilmersson, G.
Chem.-Eur. J. 2002, 8, 2081-2087. (f) Granander, J.; Sott, R.; Hilmersson,
G. Tetrahedron 2002, 58, 4717-4725. (g) Arvidsson, P. I.; Ahlberg, P.;
Hilmersson, G. Chem.-Eur. J. 1999, 5, 1348-1354.
(15) For leading references, see: (a) Cohen, Y.; Avram, L.; Frish, L.
Angew. Chem., Int. Ed. 2005, 44, 520-554. (b) Dehner, A.; Kessler, H.
ChemBioChem 2005, 6, 1550-1565. (c) Valentini, M.; Ruegger, H.;
Pregosin, P. S. HelV. Chim. Acta 2001, 84, 2833-2853. (d) Johnson, C. S.
Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203-256.
(16) Groves, P.; Rasmussen, M. O.; Molero, M. D.; Samain, E.; Canada,
F. J.; Driguez, H.; Jimenez-Barbero, J. Glycobiology 2004, 14, 451-456.
(17) Viel, S.; Capitani, D.; Mannina, L.; Segre, A. Biomacromolecules
2003, 4, 1843-1847.
(18) Sato, S.; Iida, J.; Suzuki, K.; Kawano, M.; Ozeki, T.; Fujita, M.
Science 2006, 313, 1273-1276.
(19) Schlorer, N. E.; Cabrita, E. J.; Berger, S. Angew. Chem., Int. Ed.
2002, 41, 107-109.
(9) (a) Delong, G. T.; Pannell, D. K.; Clarke, M. T.; Thomas, R. D. J.
Am. Chem. Soc. 1993, 115, 7013-7014. (b) Bates, T. F.; Clarke, M. T.;
Thomas, R. D. J. Am. Chem. Soc. 1988, 110, 5109-5112. (c) Thomas, R.
D.; Clarke, M. T.; Jensen, R. M.; Young, T. C. Organometallics 1986, 5,
1851-1857.
(10) (a) Arvidsson, P. I.; Hilmersson, G.; Davidsson, O. Chem.-Eur. J.
1999, 5, 2348-2355. (b) Hilmersson, G.; Arvidsson, P. I.; Davidsson, O.;
Hakansson, M. Organometallics 1997, 16, 3352-3362. (c) Hilmersson, G.;
Davidsson, O. J. Org. Chem. 1995, 60, 7660-7669.
(11) Wijkens, P.; van Koten, E. M.; Janssen, M. D.; Jastrzebski, J. T. B.
H.; Spek, A. L.; van Koten, G. Angew. Chem., Int. Ed. Engl. 1995, 34,
219-222.
(20) Nishinari, K.; Kohyama, K.; Williams, P. A.; Phillips, G. O.;
Burchard, W.; Ogino, K. Macromolecules 1991, 24, 5590-5593.
(21) Keresztes, I. Ph.D. Thesis, Brown University, 2002.
(22) Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 10228-
10229.
(12) (a) Corruble, A.; Valnot, J. Y.; Maddaluno, J.; Prigent, Y.; Davoust,
D.; Duhamel, P. J. Am. Chem. Soc. 1997, 119, 10042-10048. (b) Prigent,
Y.; Corruble, A.; Valnot, J. Y.; Maddaluno, J.; Duhamel, P.; Davoust, D.
J. Chim. Phys. Phys.-Chim. Biol. 1998, 95, 401-405.
(23) Jacobson, M. A.; Keresztes, I.; Williard, P. G. J. Am. Chem. Soc.
2005, 127, 4965-4975.
(13) (a) 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. (b) Yuan, Y.; Desjardins, S.; Harrison-Marchand, A.;
Oulyadi, H.; Fressigne, C.; Giessner-Prettre, C.; Maddaluno, J. Tetrahedron
2005, 61, 3325-3334. (c) 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.
(24) Ma, L.; Hopson, R.; Li, D.; Zhang, Y.; Williard, P. G. Organome-
tallics 2007, 26, 5834-5839.
(25) He, X. Y.; Morris, J.; Noll, B. C.; Brown, S. N.; Henderson, K. W.
J. Am. Chem. Soc. 2006, 128, 13599-13610.
(26) Pichota, A.; Pregosin, P. S.; Valentini, M.; Worle, M.; Seebach, D.
Angew. Chem., Int. Ed. 2000, 39, 153-156.
(27) Megyes, T.; Jude, H.; Grosz, T.; Bako, I.; Radnai, T.; Tarkanyi,
G.; Palinkas, G.; Stang, P. J. J. Am. Chem. Soc. 2005, 127, 10731-10738.
(14) Liu, J. Ph.D. Thesis, Brown University, 2007.
2374 J. Org. Chem., Vol. 73, No. 6, 2008