LETTER
Application of Hydrazone Linkers for Alkylation of Ketones
1933
Table 1 Alkylation of Ketones on Solid-Phase through Hydrazone
(7) (a) McArthur, C. R.; Worster, P. M.; Jiang, J. L.; Leznoff, C.
Linker Strategy
Can. J. Chem. 1982, 60, 1836. (b) Worster, P. M.;
McArthur, C. R.; Leznoff, C. Angew. Chem., Int. Ed. Engl.
1979, 18, 221.
Entry Resin Ketone
(loading of starting hydrazine,
R–X
Yield of
alkylation
(puritya)
(8) (a) Kirchhoff, J. H.; Bräse, S.; Enders, D. J. Comb. Chem.
2001, 3, 71. (b) Enders, D.; Kirchhoff, J. H.; Köbberling, J.;
Peiffer, T. Org. Lett. 2001, 3, 1241.
(9) Galiano-Roth, A. S.; Collum, D. B. J. Am. Chem. Soc. 1989,
111, 6772.
(10) (a) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 18, 11.
(b) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 18, 3.
(11) CAUTION: N-Nitrosoamines are potentially carcinogenic.
Therefore we recommend special caution during handling
and preparation.
(12) (a) Hird, N. W.; Irie, K.; Nagai, K. Tetrahedron Lett. 1997,
38, 7111. (b) Bräse, S.; Schroen, M. Angew. Chem. Int. Ed.
1999, 38, 1071.
mmol/g)
1
2
17
17
17
17
17
17
17
17
16
16
13
13
3-Pentanone (0.58)
3-Pentanone (0.58)
Tropinone (0.57)
Tropinone (0.57)
Pr–I
82 (85%)
91 (83%)
74 (90%)b
54 (91%)c
82 (81%)d
74 (86%)e
92 (93%)
84 (96%)
70 (85%)
88 (86%)
26 (63%)
19 (68%)
Bn–Br
Pr–I
3
4
Bn–Br
5
4-t-Bu-cyclohexanone (0.59) Pr–I
4-t-Bu-cyclohexanone (0.59) Bn–Br
6
(13) Procedure for Reduction of Nitrosoamine to Hydrazine
on Polymeric Support: The resin 14 (2.175 g, 2 mmol,
theoretical loading 0.95 mmol/g, prepared from
7
Cyclohexanone (0.59)
Cyclohexanone (0.59)
Cyclohexanone (0.52)
Cyclohexanone (0.52)
Cyclohexanone (0.38)
Cyclohexanone (0.38)
Pr–I
8
Bn–Br
Pr–I
Novabiochem Merrifield polymer HL, 1.10 mmol/g, 1%
DVB, 200-400 mesh), swollen in anhyd THF (15 mL) was
heated with LAH (0.46 g, 12 mmol) under argon atmosphere
to 55 ºC for 48 h. Then the reaction mixture was treated
carefully with NH3 aq and KOH aq to decompose the grey
suspension of LAH. The resulting white precipitate was
dissolved and removed by washing with 2 M HCl aq. The
resin was washed with a mixture of concd HCl and THF
(4.5:5.5, 2 10 mL), repeatedly with THF, methanol,
dichloromethane followed by 10% (v/v) solution of
triethylamine in dichloromethane (3 8 mL, under argon)
and repeatedly with methanol and dichloromethane. The
resulting resin was dried under high vacuum to constant
mass (2.130 g, 93%).
9
10
11
12
Bn–Br
Pr–I
Bn–Br
a Purities of the products were measured by GC/MS analysis.
b Mixture of diastereomers 30:1. c Mixture of diastereomers 32:1.
d Mixture of diastereomers 3:1. e Mixture of diastereomers 11:3.
(14) Microanalytical data (% of N) did not always show
accurately the loading of hydrazine or hydrazone on the
resins. Therefore a better method based on gravimetric
measurement was developed.15 The results of loading
determinations based on Et3N HCl and t-butylcyclo-
hexanone were usually in good agreement.
Acknowledgement
We are grateful to the University of Bialystok (BST-125 and BW-
173) and the State Committee for Scientific Research, Poland
(Grant No. 3 T09A 03617) for financial support. We also thank Dr.
L. Siergiejczyk for assistance in recording NMR spectra.
(15) Procedure for Determination of Loading of Hydrazine
on Polymeric Support: (a) Based on amine hydrochloride:
The resin 17 (0.500 g) was washed twice with a solution of
aq concd HCl in THF (v/v 4.5:5.5) and washed repeatedly
with THF, methanol and dichloromethane. Then the resin
was washed three times with a 10% (v/v) solution of
triethylamine in dichloromethane and repeatedly with
methanol and dichloromethane. The combined amine
solutions were concentrated and the residue was dried under
vacuum to give white crystalline solid, Et3N HCl (0.122 g,
0.59 mmol/g). (b) Based on 4-t-butylcycohexanone(20):
The resin 17 (0.500 g) was swollen in a solution of 20 (0.462
g, 3 mmol) in THF (5 mL) and heated in the presence of
molecular sieves 4 Å under reflux over 12 h. Then the sieves
were removed with tweezers and the resin was washed
repeatedly with THF and ether. Then the resin was washed
three times with 10% (v/v) solution of TFA in
dichloromethane and repeatedly with methanol and
dichloromethane. The combined acid solutions were washed
with aq K2CO3, dried, and concentrated under moderate
vacuum to give crystalline solid (0.045 g, 0.58 mmol/g).
(16) Typical Procedure for the Alkylation of a Ketone on
Solid-Phase: The resin 17 (0.500 g, 0.295 mmol, 0.59
mmol/g, prepared from Novabiochem Merrifield polymer
HL, 1.10 mmol/g, 1% DVB, 200-400 mesh) loaded with
cyclohexanone was washed under argon atmosphere with
anhyd THF (2 3 mL). The resin was cooled to 0 ºC for
References
(1) (a) Caine, D. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I., Eds.; Pergamon: New York, 1991.
(b) Enders, D. In Asymmetric Synthesis, Vol. 3; Morrison, J.
D., Ed.; Academic: New York, 1984.
(2) (a) Handbook of Combinatorial Chemistry; Nicolaou, K. C.;
Hanko, R.; Hartwig, W., Eds.; Wiley: New York, 2002.
(b) Seneci, P. Solid-Phase Synthesis and Combinatorial
Technologies; Wiley: New York, 2000.
(3) (a) Leznoff, C. C.; Wong, J. Y. Can. J. Chem. 1973, 51,
3756. (b) Leznoff, C. C.; Greenberg, S. Can. J. Chem. 1976,
54, 3824. (c) Hodge, P.; Waterhouse, J. J. Chem. Soc.,
Perkin Trans. 1 1983, 2319. (d) Xu, Z. H.; McArthur, C. R.;
Leznoff, C. Can. J. Chem. 1983, 61, 1405. (e) Chamoin, S.;
Houldsworth, S.; Kruse, C. G.; Bakker, W. I.; Snieckus, V.
Tetrahedron Lett. 1998, 39, 4179.
(4) Murphy, A. M.; Dagnino, R.; Vallar, P. L. Jr.; Trippe, A. J.;
Sherman, S. L.; Lumpkin, R. H.; Tamura, S. Y.; Webb, T. R.
J. Am. Chem. Soc. 1992, 114, 3156.
(5) Huwe, C. M.; Künzer, H. Tetrahedron Lett. 1999, 40, 683.
(6) Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999,
121, 9907.
Synlett 2002, No. 11, 1931–1934 ISSN 0936-5214 © Thieme Stuttgart · New York