H. Waldmann et al.
FULL PAPER
nylphosphonium iodide (489 mg, 1.17 mmol) and potassium tert-butoxide
(131 mg, 1.17 mmol) in THF (10 mL) to yield an off-white resin (148 mg).
(155 mg, 96 mmol) was treated with [Cu(OAc)2] in n-propylamine followed
by work-up with solid-phase extraction to yield a white solid (15.4 mg,
60 mmol, 62%), HPLC: 99% (260 nm). Rf 0.42 (cyclohexane/ethyl
acetate 10:1); m.p. 1598C; 1H NMR (CDCl3, 400 MHz): d 7.35 7.26
(m, 15H, arom. CH), 2.79 (s, 1H, OH); GCMS (70 eV, EI): m/z (%): 260
IR (KBr): nÄ 3313 (NH), 1671 (C O), 1607 (C C) cmÀ1. According to
Method A, the resin (133 mg, 102 mmol) was treated with [Cu(OAc)2] in n-
propylamine followed by work-up with solid-phase extraction to yield a
yellowish solid (7.8 mg, 40 mmol, 43%, cis:trans 43:57), HPLC: 99%
(29) [M] , 207 (21), 183 (100), 165 (20), 154 (32), 105 (97), 77 (54). The
spectroscopic data are in agreement with reported values[38]
1
(260 nm). Rf 0.52 (cyclohexane/ethyl acetate 10:1); m.p. 938C; H NMR
(CDCl3, 400 MHz): d 7.64 7.53 (m, 4H, arom. CH), 7.47 7.31 (m, 5H,
4-Phenylhepta-1,6-dien-4-ols (67): According to Procedure M, the poly-
mer-bound 4-hydrazinobenzoic acid methyl ester (65, 200 mg, 0.17 mmol)
was treated with allylmagnesium bromide (2 Â 1.7 mL, 2m in THF,
3.4 mmol) in THF (10 mL) to yield an off-white resin (199 mg). IR
arom. CH), 6.50 6.43 (m, 1H, Ar-CH CH-CH3, cis trans isomers), 6.30
3
3
(dq, 1H, Jtrans(H,H) 15.8, J(H,H) 6.5 Hz, Ar-CH CH-CH3, trans),
3
3
5.84 (dq, 1H, Jcis(H,H) 11.6, J(H,H) 7.3 Hz, Ar-CH CH-CH3, cis),
4
1.97 (dd, 3H, 3J(H,H) 7.3, J(H,H) 1.8 Hz, Ar-CH CH-CH3, cis), 1.92
(KBr): nÄ 3308 (OH, NH), 1681 (C O) cmÀ1. According to Method A for
3
4
(dd, 3H, J(H,H) 6.5, J(H,H) 1.8 Hz, Ar-CH CH-CH3, trans); GCMS
the oxidative cleavage of the hydrazide linker, the resin prepared above
(113 mg, 97 mmol) was treated with [Cu(OAc)2] in n-propylamine followed
by work-up with solid-phase extraction to yield a yellowish oil (10.9 mg,
58 mmol, 60%), HPLC: 97% (260 nm). Rf 0.33 (cyclohexane/ethyl
acetate 10:1); 1H NMR (CDCl3, 400 MHz): d 7.35 7.09 (m, 5H, arom.
(70 eV, EI): m/z (%): 194 (100) [M] , 178 (46), 165 (30), 152 (15), 115 (14),
89 (3), 63 (3). The spectroscopic data are in agreement with reported
values.[36]
4-Phenyl-cinnamic methyl ester (64): According to Procedure L, the
polymer-bound biphenylaldehyde (39, 150 mg, 0.117 mmol) was treated
with methoxycarbonylmethyl-triphenylphosphonium bromide (486 mg,
1.17 mmol) and potassium tert-butoxide (131 mg, 1.17 mmol) in THF
(10 mL) to yield an off-white resin (151 mg). IR (KBr): nÄ 3309 (NH),
CH), 5.51 (m, 2H, CH2-CH CH2), 5.02 (m, 4H, CH2-CH CH2), 2.65 2.34
(m, 4H, CH2-CH CH2); GCMS (70 eV, EI): m/z (%): 147 (57) [M À allyl],
105 (100), 91 (22), 77 (75), 51 (16), 63 (3). The spectroscopic data are in
agreement with reported values.[39]
1673 (C O), 1609 (C C) cmÀ1. According to Method A for the oxidative
cleavage of the hydrazide linker, the resin prepared above (142 mg,
109 mmol) was treated with [Cu(OAc)2] in n-propylamine followed by
work-up with solid-phase extraction. Yield: 6.8 mg (29 mmol, 27%), HPLC:
96% (260 nm); yellow solid. Rf 0.24 (cyclohexane/ethyl acetate 10:1);
4-Biphenyl-phenyl-methanol (68): According to Procedure M, the poly-
mer-bound 4-biphenylaldehyde (39, 200 mg, 0.14 mmol) was treated with
phenyllithium (2 Â 1.4 mL, 2m in cyclohexane/diethyl ether (7:3),
2.8 mmol) in THF (10 mL) to yield an off-white resin (204 mg). IR
(KBr): nÄ 3315 (OH, NH), 1676 (C O) cmÀ1. According to Method A for
3
m.p. 1478C; 1H NMR (CDCl3, 250 MHz): d 7.75 (d, Jtrans(H,H)
the oxidative cleavage of the hydrazide linker, the resin prepared above
(125 mg, 85 mmol) was treated with [Cu(OAc)2] in n-propylamine followed
by work-up with solid-phase extraction to yield a white solid (7.7 mg,
30 mmol, 35%), HPLC: 98% (260 nm). Rf 0.17 (cyclohexane/ethyl
acetate 5:1); m.p. 918C; 1H NMR (CDCl3, 400 MHz): d 7.60 7.56 (m,
4H, arom. CH), 7.48 7.30 (m, 10H, arom. CH), 5.91 (s, 1H, benzyl-CH);
16.0 Hz, 1H, Ar-CH CH-OCH3), 7.63 7.61 (m, 5H, arom. CH), 7.48
3
7.44 (m, 4H, arom. CH), 6.49 (d, Jtrans(H,H) 16.0 Hz, 1H, Ar-CH CH),
3.83 (s, 3H, -OCH3); GCMS (70 eV, EI): m/z (%): 238 (100) [M] , 207 (66),
178 (95), 165 (44), 152 (41), 89 (24), 76 (19). The spectroscopic data are in
agreement with reported values.[37]
GCMS (70 eV, EI): m/z (%): 260 (100) [M] , 181 (52), 155 (80), 105 (54), 77
4-Hydrazinobenzoic methyl ester: To a solution of 4-hydrazinobenzoic acid
(10 g, 66 mmol) in methanol (300 mL) was added slowly conc. H2SO4
(3.5 mL, 66 mmol). The mixture was refluxed for 15 h, cooled to room
temperature, and the solvent was removed under reduced pressure. The
residue was suspended in methylene chloride (700 mL), washed 3 Â with a
saturated solution of NaHCO3 (150 mL) and a saturated solution of NaCl
(100 mL). The organic layer was dried over MgSO4, and the solvent was
removed under reduced pressure to yield the 4-hydrazino benzoic acid
methyl ester as an off-white solid (6.8 g, 51%). M.p. 2278C; 1H NMR
(DMSO, 400 MHz): d 10.40 (b, 2H, NH), 8.93 (b, 1H, NH), 7.90 (d,
3J(H,H) 8.8 Hz, 2H, arom. CH), 7.00 (d, 3J(H,H) 8.8 Hz, 2H, arom.
CH), 3.82 (s, 3H, OCH3); 13C NMR (DMSO, 100.6 MHz): d 166.2 (-
COOCH3), 150.1 (C-N), 130.9, 113.4 (4 arom. CH), 52.1 (OCH3); GCMS
(34). The spectroscopic data are in agreement with reported values.[40]
2-Biphenyl-pent-4-en-2-ol (69): According to Procedure M, the polymer-
bound 4-biphenylketone (40, 200 mg, 0.14 mmol) was treated with allyl-
magnesium bromide (2 Â 1.4 mL, 2m in THF, 2.8 mmol) in THF (10 mL) to
yield the off-white resin (201 mg). IR (KBr): nÄ 3333 (OH, NH), 1681
(C O) cmÀ1. According to Method A for the oxidative cleavage of the
hydrazide linker, the resin prepared above (158 mg, 108 mmol) was treated
with [Cu(OAc)2] in n-propylamine followed by work-up with solid-phase
extraction to yield a colorless oil (9.5 mg, 40 mmol, 37%), HPLC: 97%
(260 nm). Rf 0.15 (cyclohexane/ethyl acetate 10:1); 1H NMR (CDCl3,
400 MHz): d 7.72 7.69 (m, 1H, arom. CH), 7.62 (dd, 3J(H,H) 8.4 Hz,
2H, arom. CH), 7.51 7.42 (m, 5H, arom. CH), 7.38 7.34 (m, 1H, arom.
CH), 5.75 5.64 (m, 1H, CH2-CH CH2), 5.21 5.13 (m, 2H, CH2-
(70 eV, EI): m/z (%): 166 (97) [M] , 135 (100), 119 (11), 107 (14), 90 (17), 77
CH CH2), 2.60 2.53 (m, 2H, CH2-CH CH2), 2.1 (b, 1H, OH), 1.62 (s,
(9), 63 (10). HRMS (70 eV, EI): calcd for C8H10N2O2 [M] : 166.0742, found:
3H, CH3); GCMS (70 eV, EI): m/z (%): 238 (1) [M] , 197 (100), 181 (17),
166.0746.
165 (7), 152 (39). The spectroscopic data are in agreement with reported
values.[41]
Polystyrene-bound 4-hydrazinobenzoic methyl ester (65): According to
Procedure E, polystyrene resin 17b (5.0 g, 5.05 mmol) was treated with
N,N-diisopropylcarbodiimide (2.4 mL, 15.2 mmol), 1-hydroxybenzotria-
zole (2.3 g, 15.2 mmol), triethylamine (2.1 mL, 15.2 mmol), and 4-hydrazi-
nobenzoic acid methyl ester (3.1 g, 15.2 mmol) in methylene chloride
Acknowledgements
(100 mL) to yield the off-white resin 65 (5.12 g). IR (KBr): nÄ 3298 (NH),
À1
1740 (C O), 1666 (C O) cm
.
This research was supported by the Bundesministerium f¸r Bildung und
Forschung (BMBF), the BASF AG, and the Fonds der Chemischen
Industrie (Kekule Fellowship for F.S.). F.S. is grateful to the State of Baden-
W¸rttemberg for a scholarship from the Landesgraduiertenfˆrderung.
General procedure for the addition of organometallic reagents to a
polymer-bound ester, aldehyde, or ketone (Procedure M): The correspond-
ing Grignard reagent (20 equiv) was added to a suspension of polymer-
bound ester, aldehyde, or ketone in THF and the mixture was shaken at
room temperature for 24 h. Subsequently, the addition of Grignard reagent
(20 equiv) was repeated. The mixture was shaken for further 48 h at room
temperature and filtered. The resin was washed with THF, THF/1n NH4Cl
(1:1), THF/water (1:1), THF, methanol, methylene chloride, and cyclo-
hexane (2 Â each), and then dried in vacuo.
[1] a) D. Obrecht, J. M. Villalgordo ™Solid-supported Combinatorial and
Parallel Synthesis of Small-Molecular-Weight Compound Libraries∫,
Pergamon Press, 1998; b) Handbook of Combinatorial Chemistry
(Eds.: K. C. Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Wein-
heim, 2002; c) S. Sommer, R. Breinbauer, H. Waldmann, Organic
Synthesis Highlights V (Eds.: G. Schmalz, T. Wirth), Wiley-VCH,
2003.
[2] For the development of traceless linkers see, for example: a) F. X.
Woolard, J. Paetsch, J. A. Ellman, J. Org. Chem. 1997, 62, 6102 6103;
b) M. J. Plunkett, J. A. Ellman, J. Org. Chem. 1997, 62, 2885 2893, and
Triphenylmethanols (66): According to Procedure M, the polymer-bound
4-hydrazinobenzoic acid methyl ester (65, 300 mg, 0.26 mmol) was treated
with phenyl lithium (2 Â 2.6 mL, 2m in cyclohexane/diethyl ether (7:3),
5.2 mmol) in THF (10 mL) to yield an off-white resin (295 mg). IR (KBr):
nÄ 3298 (OH, NH), 1682 (C O) cmÀ1. According to Method A for the
oxidative cleavage of the hydrazide linker, the resin prepared above
3280
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2003, 9, 3270 3281