Scheme 2. Solid-Phase Synthesis Approach
Table 1. Parallel Solid-Phase Synthesis of Quinolines 3a-f
derivatives 3 (Scheme 2). This solid-phase approach com-
bines two highly desirable characteristics in SPS: (a) a
6
cyclative cleavage step releasing the desired quinolines 3
from the polymer support and (b) the regeneration and
recycling of the resin. Last, immobilization of azomethine 1
will minimize self-condensation reaction and facilitate the
workup procedure (Scheme 2).
We first investigated the preparation of resin-bound
azomethine 1 on TentaGel resin. This choice was mainly
motivated by the good compatibility of this resin with
ethanol, the solvent used in the overall process. Although a
wide variety of resin-bound amines are commercially avail-
able, a polymer-bound equivalent of aniline was inaccessible
7
until the recent work of Balasubramanian and co-workers.
According to this work, the Boc-protected aminophenol
4 7
0
was treated with commercial TentaGel-Br resin (loading
.30 mmol/g) to furnish resin 5, which was characterized
13
by C-gel-phase NMR and FT-IR. The yield was determined
by nitrogen microanalysis (0.37% N; loading 0.25 mmol/g).
Subsequent cleavage of the Boc group under classical
conditions (TFA/CH
.25 mmol/g). The removal of the Boc group was confirmed
by the complete disappearance of the Boc carbonyl stretch
2 2
Cl ) afforded resin 6 (0.39% N; loading
a Yield calculated from the loading of resin 1. b Yield obtained by
conventional solution-phase synthesis.
0
-
1
(
1715 cm ). The supported azomethine 1b was prepared in
disappeared in 1a and 1b after the reduction step. In contrast,
two steps from resin 6 by treatment with 3,4-dimethoxy-6-
nitrobenzaldehyde in refluxing ethanol, affording resin-bound
o-nitroimine 7b (0.76% N; loading 0.25 mmol/g). Subsequent
reduction of the nitro group was accomplished in the presence
of sodium sulfide in refluxing ethanol to furnish the desired
resin-bond “masked” o-aminobenzaldehyde 1b (0.79% N;
loading 0.25 mmol/g). The FT-IR spectra of both resins 7b
and 1b were compared with that of solution-phase models
-
1
the imine stretch in the range 1630-1567 cm present in
the IR spectra of 7a,b is still observed in 1a,b, providing
evidence for the chemoselective reduction of 7b into 1b. The
resulting resin 1b could be stored for several weeks without
significant deterioration of chemical properties (Scheme 3).
The synthesis of quinoline derivatives 3a-f was accomp-
lished on a Quest 210 parallel synthesizer by treating resin
1
b with the various ketones 2a-f under the typical Borsche
7
a and 1a, respectively, showing common bands. In par-
ticular, it is informative to note that the peak for nitro
stretching at 1286 cm-1 of 7a and 7b has completely
conditions, i.e., in refluxing ethanol in the presence of piperi-
dine. Quinoline derivatives 3a-f were obtained in 50-81%
yields (Table 1). In all cases, the Friedl a¨ nder parallel solid-
phase synthesis of quinolines 3a-f led to similar yields when
compared to those obtained under homogeneous conditions
from azomethine 1a and ketones 2 (piperidine/ethanol/reflux/
(4) (a) Borsche, W.; Ried, W. Liebigs Ann. Chem. 1943, 554, 269. (b)
Borsche, W.; Barthenheier, J. Liebigs Ann. Chem. 1941, 548, 50.
(
5) Porter, H. K. Org. React. 1973, 20, 455.
(6) For reviews on cyclative cleavage strategies, see: (a) van Maarseveen,
1
2 h). Their purification is made easier by simple filtration
J. H. Comb. Chem. High Throughput Screening 1998, 1, 185. (b) Tzschucke,
C. C.; Market, C.; Bannwarth, W.; Roller, S.; Hebel, A.; Haag, R. Angew.
Chem., Int. Ed. 2002, 41, 3964. (c) Park, K. H.; Kurth, M. J. Drug Future
000, 25, 1265. (d) Blaney, P.; Grigg, R.; Sridharan, V. Chem. ReV. 2002,
02, 2607.
of the polymer-bound aniline 6. It should be noted that flash
chromatography is, however, required to eliminate piperidine
and ketones 2 having been used in excess to drive the reac-
tion to completion. The regeneration of resin 1b was also
2
1
(7) Gordon, K. H.; Balasubramanian S. Org. Lett. 2001, 3, 53.
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Org. Lett., Vol. 5, No. 17, 2003