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7. (a) Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166–1173; (b)
Dickstein, J. S.; Fennie, M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J.
Am. Chem. Soc. 2008, 130, 15794–15795.
8. Svete et al. reported double N-alkylation with unprotected oxime-ester and
large excess Grignard reagents. To the best of our knowledge, this is the sole
example. See: Grošelj, U.; Bevk, D.; Jakše, R.; Meden, A.; Stanovnik, B.; Svete, J.
Tetrahedron: Asymmetry 2005, 16, 2187–2197.
9. Bertrand, M.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148–1150.
10. Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T. Tetrahedron Lett. 1996, 37, 2045–
2048.
11. Van Vliet, M. R. P.; Van Koten, G.; Buysingh, P.; Jastrzebski, J. T. B. H.; spek, A. L.
Organometallics 1987, 6, 537–546.
12. Yamamoto, T.; Ito, W. Tetrahedron 1988, 44, 5415–5423.
13. For selective preparation of (E)-oxime, see: Moriyama, N.; Kobayashi, R. PCT
Int. Appl. WO/2011/093423.
14. E/Z chemistry of starting materials was determined by X-ray crystallographic
analysis. Deposited Crystallographic data for 1a, 1i, and 3a with the Cambridge
Crystallographic Data Center are as follows: CCDC 871698, 871699, and
872157. These crystallographic information can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
15. Solvents of Grignard reagents are as follows: MeMgBr, EtMgBr, and BnMgCl
were THF solution and others were ether solution. See also general information
in experimental section.
16. Compound 2a is known and analytical data of our 2a were identical to the data
in the following report. See: Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.;
Haigh, D.; Moody, C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem .Soc., Perkin Trans.
1 1996, 2879–2893.
reagent, which activates imine, is difficult. Moreover, compared to
imines, protected oxime did not isomerize during reaction. It is
also reported that SN2-type N-alkylation of oxime with Grignard
reagent in THF is sluggish.5b,c Successful results with silyl and
methyl oximes 1c and 1d and charge calculation also support this
pathway because siloxy and methoxy groups are leaving groups in
b-elimination reactions (e.g., Peterson olefination) but are not well
in SN2 reaction. For these reasons, the initial N-alkylation would
proceed by 1,4-addition mechanism followed by b-elimination
and thus, our (Z)-oxime 1b could not produce N-alkyl compounds.
Considering the limitation of Grignard reagents as in Table 3, these
N-substitution reactions might proceed via a single electron trans-
fer (SET) mechanism.11,24
In conclusion, double nucleophilic N-alkylation with substi-
tuted
a-oxime-ester to give N,N-dialkyl-a-amino acids was dem-
onstrated. The double umpolung reactions are achieved with
Grignard reagent and dialkylated products are afforded in 15 min
with or without chelating additives. Both electron-withdrawing
and -donating groups are acceptable on oxime. The stereochemis-
try of oxime is important on this cascade. This N-alkylation with
oxime-ester provides a concise synthetic pathway toward biologi-
cally useful compounds. Exploration of the extensions of this
methodology toward alkaloid synthesis is currently underway.25
17. Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998–9999.
18. 1H NMR spectra of crude reaction mixture did not indicate the presence of
ethylimine in any other conditions except entries 4 and 6 of Table 1 and entries
1 and 15 of Table 2.
Acknowledgments
19. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem.
Soc. 1989, 111, 4392–4398.
20. Funatomi, T.; Nakazawa, S.; Matsumoto, K.; Nagase, R.; Tanabe, Y. Chem.
Commun. 2008, 771–773.
We are grateful for the support of this research from Otsuka
Pharmaceutical Co. Award in Synthetic Organic Chemistry, Japan.
We wish to acknowledge Kuraray Co., Ltd for the gift of 4-MTHP
(4-methyltetrahydro-2H-pyran). We also thank Ms. Mika Yamam-
ura and Ms. Yuriko Nishiyama for HRMS measurements and to Mr.
Shohei Katao for X-ray crystallographic analysis.
21. Because 1a was not well dissolved in DME, 4-MTHP or toluene, the volumes of
used solvents were doubled in entry 16, and four times in entries 17 and 19.
Diethyl ether, tert-butyl methyl ether, or cyclopentyl methyl ether did not
dissolve 1a.
22. General experimental procedure of double N-alkylation is as follows: (E)-
oxime-ester (0.1 mmol) was dissolved in THF (0.1 M) under nitrogen
atmosphere in a flame-dried flask and was cooled down to 0 °C. Grignard
reagent (THF or ether solution, 2.5–3.0 equiv.) was then added within 10–20
sec. After 15 min, the reaction was quenched with water at 0 °C. Organic layer
was extracted with ethyl acetate and was washed with water and brine. Drying
collected organic layer over magnesium sulfate followed by silica gel column
chromatography (ethyl acetate / hexane elution) gave N,N-dialkylamino acid
ester.
Supplementary data
Supplementary data (preparation methods and analytical data
of all compounds) associated with this article can be found, in the
23. Jie, Y.; Livant, P.; Li, H.; Yang, M.; Zhu, W.; Cammarata, V.; Almond, P.; Sullens,
T.; Qin, Y.; Bakker, E. J. Org. Chem. 2010, 75, 4472–4479.
24. Yamataka, H.; Matsuyama, T.; Hanafusa, T. J. Am. Chem. Soc. 1989, 111, 4912–
4918.
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