T. K. Ellis et al. / Tetrahedron Letters 44 (2003) 1063–1066
1065
and methyl iodide (3g). We found that only 3.5 equiv.
of the alkylating reagent/base is enough for complete,
fast, and clean bis-methylation of 1 with 3g (entry 11).
Inspired by these results, we conducted the reaction of
complex 1 with pentyl iodide (3h), finding a similarly
excellent chemical outcome affording the bis-alkylated
complex 4h as an individual product in 93% yield (entry
12).10 As the prices of alkyl bromides and alkyl iodides
are very close, the application of iodides rather than
bromides becomes practically useful considering the
lower amounts of reagents needed and the enhanced
chemical outcome obtained.
3. For examples of a,a-AAs in natural bioactive peptides
see Ref. 3a. For examples of a,a-AAs in short, highly
structured peptides see Refs. b and c. (a) Nagaraj, R.;
Balaram, P. Acc. Chem. Res. 1981, 14, 356; (b) Yokum,
T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M.
L. J. Am. Chem. Soc. 1997, 119, 1167; (c) Rossi, P.;
Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Scrimin, P. J. Am. Chem. Soc. 1999, 121,
6948.
4. (a) Wheeler, H. L.; Hoffman, C. Am. Chem. J. 1911, 45,
368; (b) Dyker, G. Angew Chem., Int. Ed. Engl. 1997, 36,
1700; (c) Wysong, C. L.; Yokum, T. S.; Morales, G. A.;
Gundry, R. L.; McLaughlin, M. L.; Hammer, R. P. J.
Org. Chem. 1996, 61, 7650; (d) Kubik, S.; Meissner, R.
S.; Rebek, J. Tetrahedron Lett. 1994, 35, 6635.
5. Fu, Y.; Hammarstrom, L. G. J.; Miller, T. J.; Fronczek,
F. R.; McLaughlin, M. L.; Hammer, R. P. J. Org. Chem.
2001, 66, 7118.
6. (a) O’Donnell, M. J.; Delgado, F.; Alsina, J. J. Org.
Chem. 2002, 67, 2960; (b) Denmark, S. E.; Stavenger, R.
A.; Faucher, A.-M.; Edwards, J. P. J. Org. Chem. 1997,
62, 3375.
7. For recent publications of application of Ni(II)-com-
plexes of glycine for asymmetric synthesis of amino acids,
see: (a) Tang, X.; Soloshonok, V. A.; Hruby, V. J.
Tetrahedron: Asymmetry 2000, 11, 2917; (b) Soloshonok,
V. A.; Cai, C.; Hruby, V. J. Angew. Chem., Int. Ed. Engl.
2000, 39, 2172; (c) Qiu, W.; Soloshonok, V. A.; Cai, C.;
Tang, X.; Hruby, V. J. Tetrahedron 2000, 56, 2577; (d)
Soloshonok, V. A.; Cai, C.; Hruby, V. J. Org. Lett. 2000,
2, 747; (e) Soloshonok, V. A.; Cai, C.; Hruby, V. J.
Tetrahedron Lett. 2000, 41, 135; (f) Soloshonok, V. A.;
Cai, C.; Hruby, V. J. Tetrahedron: Asymmetry, 1999, 10,
4265.
8. For preparation of Ni(II)-complex 1, see: Belokon, Yu.
N.; Maleev, V. I.; Savel’eva, T. F.; Garbalinskaya, N. S.;
Saporovskaya, M. B.; Bakhmutov, V. I.; Belikov, V. M.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya
1989, 631–635.
Products 4a–h were isolated simply by first pouring the
reaction mixture into ice water containing a calculated
amount of acetic acid, followed by filtration of the
crystalline compound thus formed. To demonstrate the
isolation of the target sym-a,a-AA from their Ni(II)-
complexes 3, bis-alkylated complexes 3a and 3d were
decomposed without any purification under the stan-
dard conditions7,11 to yield free amino acids 6a and 6d
along with ligand 2, which was recovered and converted
back to the Ni(II)-complex 1.
In summary, we have demonstrated that the readily
available Ni(II)-complex 1 easily undergoes complete
bis-alkylation with various alkyl halides, and in particu-
lar iodides, affording a generalized and practical access
to the corresponding sym-a,a-AA. High chemical yields
combined with the extreme simplicity of the experimen-
tal procedure render this method worth immediate use
for multi-gram scale preparation of these amino acids.
Full scope of the method is currently under study and
will be reported in due course.
Acknowledgements
9. Reactions of Ni(II)-complex 1 with alkyl halides 3a–h.
Into a solution of sodium tert-butoxide (3 equiv.) in
DMF (10 ml/1g) was added complex 1 (1 equiv.) and
alkylating reagent (3 equiv.), allyl bromide 3a, benzyl
bromide 3b, or cinnamyl bromide 3c. The reaction was
stirred in a rt water bath for 15 min. The reaction
mixture was then poured into a solution of ice and 5%
acetic acid and the ice was allowed to melt. The resulting
solid was filtered off and washed with water and n-hex-
ane. Drying the solid resulted in the desired Ni(II)-com-
plexes 4a–c in yields from 89 to 94% and greater than
99% purity. When alkylations were performed with less
activated alkyl bromides such as ethyl bromide 3d, propyl
bromide 3e, butyl bromide 3f, the procedure was per-
formed as above with 4.0 equiv. of the alkylating reagent
and sodium tert-butoxide to afford the Ni(II)-complexes
4d–f in yields from 87 to 92% and 90 to 94% purity. This
procedure was also used for the alkyl iodides, methyl
iodide 3g, and pentyl iodide 3h using 3.0 equiv. of the
alkylating reagent and base to afford complexes 4g,h in
yields from 91 to 93% and greater than 99% purity.
10. As an example of typical spectral characteristics of prod-
ucts 4a–h: Ni(II)-complex of a,a-dipentylglycine Schiff
base with 2-[N-(a-picolyl)amino]benzophenone (PABP)
The work was supported by the start-up fund provided
by the Department of Chemistry and Biochemistry,
University of Oklahoma.
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1
4h: mp 221.8–223.4°C, H NMR (CDCl3) l 0.89 (6H, t,