PAPER
Polymeric Supports with Hydrazone Linkers
2863
ed under moderate vacuum to give the alkylated ketone, which was
subjected to GC-MS analysis.
Iterative Deprotonation/Alkylation of a Ketone Hydrazone and
Reductive Cleavage; General Procedure
Equation 2
The resin 13 or 14 (0.500 g, 0.265 mmol, 0.53 mmol/g) loaded with
acetone was washed under argon with anhyd THF (2 × 3 mL). The
resin was cooled to 0 °C for 10 min and treated with a solution of
LDA in THF (3.60 mL, 0.98 M, 13 equiv) for 4 h. The resulting red-
dish resin was filtered under argon, cooled to –78 °C, and treated
with a solution of alkyl halide (10–13 equiv) in THF (3 mL). The
reaction mixture was allowed to warm up slowly to r.t. over 12 h,
washed with anhyd THF (5 × 3 mL), cooled to 0 °C for 10 min and
treated with a solution of LDA in THF (3.60 mL, 0.98 M, 13 equiv)
for 4 h. The resulting resin was filtered under argon, cooled to –78
The obtained solid should give good quality NMR spectrum.
1H NMR (200 MHz, CDCl3): = 2.40–2.25 (m, 4 H), 2.15–2.00 (m,
2
H), 1.55–1.40 (m, 3 H), 0.92 (s, 9 H).
Anchoring of a Ketone via the Hydrazone Linker; General Pro-
cedure
The hydrazine hydrochloride gel was washed under argon with 10%
Et N–CH Cl , (3 × 2 mL), CH Cl (2 × 2 mL), MeOH (2 × 2 mL),
3
2
2
2
2
CH Cl (2 × 2 mL) and anhyd THF (3 × 2 mL). Then a solution of
2
2
°
C, and treated with a solution of the second alkyl halide (10–13
a ketone (6–10 mmol, 5–10 equiv) in THF (2.5 mL) was added. The
suspension was refluxed for 48 h in the presence of molecular sieves
equiv) in THF (3 mL). The reaction mixture was allowed to warm
up slowly to r.t. over 12 h, and was quenched with wet THF (3 mL).
The resin was washed repeatedly with THF, Et O, CH Cl and twice
4
Å. Then the molecular sieves were removed with tweezers and the
gel was wshed with THF, MeOH, THF, MeOH, CH Cl , MeOH,
2
2
2
2
2
with anhyd THF (2 × 3 mL). The polymer was swollen in BH ·THF
CH Cl , and MeOH. The resulting gel was dried to a constant mass
3
2
2
solution (1 M, 5 mL, 15–20 equiv) and the suspension was heated
to 60–65 °C under argon over 12 h. Then the mixture was cooled
and treated carefully with 6 M HCl (2 mL). After stirring for 2 h, the
polymer was washed with MeOH (2 × 3 mL), 2 M HCl (5 mL), THF
under high vacuum and used for alkylation.
Representative Examples of Polymeric Gels with a Ketone An-
chored via Hydrazone Linkers
(
2 × 3 mL), MeOH (2 × 3 mL), and THF (2 × 3 mL). The collected
washings were partially concentrated in vacuo, washed with hexane
2 × 8 mL), basified with aq KOH, and extracted with CH Cl (4 × 8
3
-[2-(4-tert-Butylcyclohexylidene)-1-methylhydrazyno]prop-
oxymethylpolystyrene
(
Loading: 0.53 mmol NH /g (based on amine hydrochloride), 0.55
2
2
2
mL). The organic extract was dried (MgSO ) and concentrated to
mmol NH /g (based on mass of 4-tert-butylcyclohexanone).
4
2
give a primary amine, which was subjected to GC-MS analysis.
IR (KBr): 1640 (C=N), 1365 (C–N), 1098 cm–1 (C–O).
13C NMR (50.3 MHz, CDCl3): = 68.0, 46.7, 41.3, 34.5, 32.5, 27.6,
Acknowledgment
2
7.0, 25.6, 25.0.
Anal. Calcd for C H N O: C, 87.49; H, 8.55; N, 2.52. Found: C,
We are grateful to the University of Bialystok (BST-125) and the
State Committee for Scientific Research, Poland (Grant No. 3 T09A
81
95
2
8
5.89; H, 8.03; N, 1.71.
0
3617) for financial support. We also thank Dr. L. Siergiejczyk for
3
-[2-(4-tert-Butylcyclohexylidene)-1-methylhydrazyno]hexyl-
assistance in recording the NMR spectra.
oxymethylpolystyrene
Loading: 0.53 mmol NH /g (based on amine hydrochloride), 0.56
2
References
mmol NH /g (based on mass of 4-tert-butylocyclohexanone).
2
IR (KBr): 1640 (C=N), 1365 (C–N), 1095 cm–1 (C–O).
13C NMR (50.3 MHz, CDCl3): = 68.0, 60.5, 47.7, 45.5, 41.3, 35.7,
(1) (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
3
2.5, 28.4, 28.3, 27.7, 27.6, 27.2.
Technologies; Wiley: New York, 2000.
(2) Dörwald, F. Z. Organic Synthesis on Solid Phase, 2nd ed.;
Wiley-VCH: Weinheim, 2002.
Anal. Calcd for C H N O: C, 87.42; H, 8.76; N, 2.43. Found: C,
8
4
101
2
8
5.80; H, 8.55; N, 1.59.
(
3) (a) Caine, D. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I.; Pattenden, G., Eds.; Pergamon:
New York, 1991. (b) Enders, D. In Asymmetric Synthesis,
Vol. 3; Morrison, J. D., Ed.; Academic: New York, 1984.
4) Lazny, R.; Michalak, M. Synlett 2002, 1931.
5) Enders, D.; Lochtman, R.; Meiers, M.; Müller, S.; Lazny, R.
Synlett 1998, 1182.
6) (a) Kirchhoff, J. H.; Bräse, S.; Enders, D. J. Comb. Chem.
Deprotonation/Alkylation of Ketones Bound as Hydrazones on
Polymers 13 and 14; General Procedure
The resin 13 or 14 (0.5 g) loaded with a ketone was washed with an-
hyd THF (3 × 3 mL) and was cooled to 0 °C. Then a cooled solution
of LDA (3.60 mL, 0.98 M, 13 equiv) in THF was added and the sus-
pension was left for 4 h at 0 °C. The mixture was cooled to –78 °C,
the solution of LDA was removed by a positive pressure of argon,
and then a solution of an alkylating agent (10 equiv) in THF (3 mL)
was added. The resulting mixture was allowed to warm up slowly
from –78 °C to r.t. over 16 h. The gel was washed successively with
(
(
(
(
2001, 3, 71. (b) Enders, D.; Kirchhoff, J. H.; Köbberling, J.;
Peiffer, T. Org. Lett. 2001, 3, 1241.
7) (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. 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. (f) Huwe, C. M.;
Künzer, H. Tetrahedron Lett. 1999, 40, 683. (g)Murphy,A.
M.; Dagnino, R.; Vallar, P. L. Jr.; Trippe, A. J.; Sherman, S.
THF (2 × 5 mL), Et O (2 × 5 mL), THF (2 × 5 mL), Et O (2 × 5 mL),
2
2
CH Cl (2 × 5 mL), Et O (2 × 5 mL), CH Cl (2 × 5 mL), and Et O
2
2
2
2
2
2
(
2 × 5 mL). The alkylated ketone product was cleaved from the gel
by washing with a mixture of TFA–H O–THF (1:1: 8, 3 × 15 min.),
2
followed by THF, MeOH, THF, MeOH, CH Cl , and MeOH. The
2
2
combined acidic solutions were washed with an aq 20% solution of
K CO . The aqueous phase was back-washed with CH Cl (3 ×).
2
3
2
2
The combined organic extracts were dried (MgSO ) and concentrat-
4
Synthesis 2003, No. 18, 2858–2864 © Thieme Stuttgart · New York