Solid-Phase Friedl?nder Synthesis Using an Alkoxyamine Linker

Article abstract of DOI:10.1002/ejoc.201500426

A quinoline library was prepared by combinatorial synthesis using an alkoxyamine linker. Substrates were loaded onto a solid support containing an oxime linkage. After selected reactions on the solid support, the products were cleaved by a Friedl?nder-typ

Full text of DOI:10.1002/ejoc.201500426

FULL PAPER
DOI: 10.1002/ejoc.201500426
Solid-Phase Friedländer Synthesis Using an Alkoxyamine Linker
Kota Yamaguchi,[a] Takeshi Noda,[b] Toshiki Tomizawa,[a] Eriko Kanai,[a] and
Hideaki Hioki*[a]
Keywords: Combinatorial chemistry / Synthetic methods / Solid-phase synthesis / Nitrogen heterocycles
A quinoline library was prepared by combinatorial synthesis
using an alkoxyamine linker. Substrates were loaded onto
a solid support containing an oxime linkage. After selected
reactions on the solid support, the products were cleaved by
a Friedländer-type reaction with ketones under acidic condi-
tions to afford the corresponding quinolines. The recycl-
ability of the solid support was also investigated.
Introduction
Linkers should satisfy these two opposing requirements. We
previously reported a new traceless alkoxyamine linker 1
that can anchor ketones and aldehydes as ketoximes or al-
doximes on a solid support. It has been applied to the solid-
phase synthesis of benzodiazepines,[11] benzo-fused
azoles,[12,13] and quinazolines.[13] The oxime linkage formed
by anchoring carbonyl compounds onto 1 has been shown
to be highly robust under various reaction conditions, such
as those encountered in the Mitsunobu reaction, nucleo-
philic substitution reactions, condensations, and Pd-cata-
lyzed reactions. In addition, the linkage is easily cleaved by
an intramolecular nitrogen nucleophile or by using para-
formaldehyde under weakly acidic conditions.
In the present study, we used linker 1 for the combinato-
rial synthesis of quinolines. We focused on the Friedländer
synthesis among the various conventional methods for the
preparation of quinolines because 2-aminobenzoyl com-
pounds could easily be anchored onto the alkoxyamine
linker 1 as oximes. A related strategy for the synthesis of
quinolines was reported by Levacher et al.,[14] who used an
alkoxyaniline linker for anchoring aldehydes as azome-
thines. However, the application of their method is very lim-
ited because the azomethine linkage represents a fragile
structural element under the various reaction conditions. In
addition, ketones were not easily loaded onto the solid sup-
port because of their low reactivity.[15]
Quinoline is one of the most important structural com-
ponents of many biologically active and medicinally signifi-
cant compounds, including compounds that exhibit anti-
cancer,[1] antimycobacterial,[2] antimicrobial,[3] anticonvul-
sant,[4] anti-inflammatory,[5] and cardiovascular activities.[6]
In addition, quinolines can be utilized for advanced materi-
als such as organic light-emitting diodes[7] and liquid crys-
tals.[8] The great potential of quinolines has facilitated the
synthesis of a large number of structurally diverse deriva-
tives. Combinatorial synthesis is effective in providing a
large number of compounds. As a consequence, the combi-
natorial synthesis of quinolines has been reported by some
groups.[9,10] Most of the library syntheses are performed
through two-component coupling reactions in one step in
solution-phase synthesis.[10] These reactions are useful for
preparing combinatorial libraries when many desired build-
ing blocks are readily available or can be easily prepared.
In contrast, solid-phase combinatorial synthesis is a multi-
step synthesis. Nevertheless, it is a very easy process and
fewer building blocks are required to prepare a large-mem-
bered library.
Linkers, which connect the substrates to the solid sup-
port, play an important role in solid-phase syntheses. The
connection between a linker and the substrates should be
highly robust under a range of reaction conditions. How-
ever, the linkage should be easily cleaved under mild condi-
tions without damage to the product in the final stage.
Our synthetic plan for a quinoline library is shown in
Scheme 1. 2-Aminobenzoyl compounds 2 are condensed
with an alkoxyamine linker 1 on the solid support to afford
resin-bound oximes 3. After some reactions on the solid
support to introduce diverse functional groups, the oximes
4 are treated with ketones 5 to afford quinolines 6 through
a Friedländer-type reaction. The key step in the synthesis is
the cleavage to release the quinolines from the solid sup-
port; that is, successive enamine formation and intramolec-
ular Mannich-type reactions for highly robust oximes.
[a] Faculty of Education, Gunma University,
Maebashi, Gunma 371-8510, Japan
E-mail: hioki@gunma-u.ac.jp
http://www.edu.gunma-u.ac.jp/en/
[b] Department of Applied Bioscience, Kanagawa Institute of
Technology,
Atsugi, Kanagawa 243-0292, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500426.
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Solid-Phase Friedländer Synthesis Using an Alkoxyamine Linker
Scheme 1. Synthetic plan for quinolines 6 on solid support 1.
Table 2. Loading and cleavage to synthesize quinolines 10 on a so-
lid support 1.
Results and Discussion
In preliminary studies, Friedländer-type reactions of
methyloxime 8, derived from 2-aminobenzophenone (7),
with some ketones 9 were explored in a solution-phase syn-
thesis, as shown in Table 1. Reaction with ethyl acetoacetate
(R1 = CO2Et, R2 = Me) gave the desired product when
simply heated under weakly acidic conditions in 1,2-dichlo-
roethane (DCE) (entries 1 and 2). The yield was slightly
reduced in EtOH (entry 3). Treatment with other ketones,
such as acetylacetone (R1 = Ac, R2 = Me), ethyl benzo-
ylacetate (R1 = CO2Et, R2 = Ph), and cyclohexanone [R1,
R2 = –(CH2)4–] also gave the corresponding quinolines 10
in good yields (entries 4–6). In contrast, the reaction with
acetophenone (R1 = H, R2 = Ph) afforded the correspond-
ing quinoline 10 in 43% yield (entry 7), which was slightly
improved through the use of a 15% trifluoroacetic acid
(TFA) solution (entry 8).
On the basis of the results for the solution-phase synthe-
sis, we investigated the solid-phase synthesis of these quin-
olines by using alkoxyamine linker 1. After 2-aminobenzo-
phenone (7) was loaded, the resin-bound oxime 11 was
treated under the same conditions as those used in the solu-
tion-phase synthesis. The yields for the two steps were com-
parable to those obtained by using the solution-phase syn-
thesis (Table 2).
Entry R1
R2
Additive
Yield [%][a]
1
2
3
4
5
CO2Et
Ac
CO2Et
–(CH2)4–
H
Me
Me
Ph
5% TFA
5% TFA
5% TFA
5% TFA
15% TFA
71
66
60
58
43
Ph
[a] Isolated yield after chromatography starting from 1.
Diverse substitutions on the aromatic ring of 13 were
performed to demonstrate the scope and versatility of our
Table 1. Friedländer-type reaction of methyloxime 8 derived from 2-aminobenzophenone (7).
Entry
R1
R2
Solvent
Additive
Yield [%]
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CO2Et
Ac
Me
Me
Me
Me
Ph
DCE
DCE
EtOH
DCE
DCE
DCE
DCE
DCE
–
0
5% TFA
5% TFA
5% TFA
5% TFA
5% TFA
5% TFA
15% TFA
84
67
85
75
94
43
50
CO2Et
–(CH2)4–
H
H
Ph
Ph
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solid-phase reactions under the optimized Friedländer-type acid or pyridylboronic acid. Oxime 13, with a carboxyl
reaction conditions (Table 3). First, three types of 2-substi- group on the aromatic ring (R3 = Me, R4 = COOH), was
tuted phenylketones 12, which possess bromo or carboxy applied to two types of reaction: a Mitsunobu reaction with
groups on the aromatic ring, were loaded onto the linker 1. n-butanol to afford the corresponding ester 14 (R5 = Me,
The oximes 13, with a bromo group on the aromatic ring R6 = CO2nBu) and a condensation reaction with n-but-
(R3 = p-BrPh, R4 = H, and R3 = Me, R4 = Br), were then ylamine in the presence of DIC and Oxyma[16] to give the
subjected to Suzuki–Miyaura coupling using phenylboronic corresponding amide (R5 = Me, R6 = CONHnBu). Finally,
Table 3. Combinatorial synthesis of quinolines 15.
Entry
R1
R2
R5
R6
H
Yield [%][a]
1
2
3
CO2Et
Ac
CO2Et
Me
Me
Ph
biphenyl
66
69
58
67
42
50
54
53
61
22
73
56
45
53
40
68
57
51
43
55
78
71
59
66
46
4
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
5[b]
6
H
CO2Et
Ac
Ph
Me
Me
Ph
4-Py-Ph
Me
H
7
8
9
CO2Et
10[b]
11
12
13
14
15[b]
16
17
18
19
20[b]
21
22
23
24
25[b]
H
CO2Et
Ac
Ph
Me
Me
Ph
Ph
CO2Et
H
CO2Et
Ac
Ph
Me
Me
Ph
Me
CO2nBu
CONHnBu
CO2Et
H
CO2Et
Ac
Ph
Me
Me
Ph
Me
CO2Et
H
Ph
[a] Isolated yields after chromatography starting from 1. [b] 5% TFA was used for the cleavage step.
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Solid-Phase Friedländer Synthesis Using an Alkoxyamine Linker
resin 14 was treated with five types of ketones 9 under the carboxylate derivatives (R5 = Me, R6 = CO2nBu) (entries
same reaction conditions as those listed in Table 2 to obtain 16–20). Condensation of carboxylic acid 13 (R3 = Me, R4
the corresponding quinolines 15. The isolated yields for all = COOH) with n-butylamine in the presence of DIC/
of the 25 members are summarized in Table 3. The yields Oxyma as coupling reagents gave the corresponding amides
of the 4-biphenylquinoline derivatives 15 (R5 = biphenyl, (R5 = Me, R6 = CONHnBu) in acceptable yields (entries
R6 = H) (entries 1–5) are comparable to those of the 4- 21–25).
phenylquinolines 10 in Table 2, indicating that the coupling
From the point of view of atom economy, solid-phase
step with phenylboronic acid on the solid support pro- synthesis is less efficient than conventional solution-phase
ceeded in good yields. Coupling with pyridylboronic acid synthesis because the molecular weight per unit function
to form 4-(pyridylphenyl)quinoline derivatives (R5 = 4-Py- connecting the substrate is very high. In addition, solid sup-
Ph, R6 = H) show slightly reduced yields (entries 6–10). ports are generally expensive. Hence, recycling of the solid
Suzuki–Miyaura coupling of 13 (R3 = Me, R4 = Br) and support is highly desirable. Notably, linker 1 can be reco-
cleavage to form 6-phenylquinolines (R5 = Me, R6 = Ph) vered after cleavage of the resin-bound oxime 11 by a Fried-
also show slightly reduced yields (entries 11–15). Mitsu- länder-type reaction. Thus, we examined the feasibility of
nobu reaction of 13 (R3 = Me, R4 = COOH) with n-butanol the recycling of 1; the results are shown in Scheme 2. After
and successive cleavage formed the n-butyl quinoline-6- cleavage of the oxime linkage in 11 by ethyl acetoacetate
Scheme 2. Recycling of alkoxyamine linker 1 for the synthesis of quinoline 17 by simple loading and cleavage.
Scheme 3. Recycling of alkoxyamine linker 1 for the synthesis of quinolines 20, 21, and 22 by loading, reactions on a solid support, and
cleavage.
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H. Hioki et al.
FULL PAPER
oxyamine 1 (loading: 75ϫ 1 μmol) was treated with 2-aminobenzo-
phenone 7 (59.2 mg, 300 μmol, 4.0 equiv.) in EtOH (3 mL) and
heated to reflux for 24 h. The reaction mixture was allowed to come
to room temp. The solution was removed by decantation and the
resulting resin was washed with DMF (3ϫ 2 min) and CH2Cl2
(3ϫ 2 min). The solid supported ketoxime 11 was mixed with ethyl
acetoacetate 9 (R1 = CO2Et, R2 = Me, 38.2 μL, 300 μmol,
4.0 equiv.) in 5% TFA-DCE solution (3 mL). After heating to re-
flux for 24 h, the reaction mixture was allowed come to to room
temp. The resulting resin was washed with CH2Cl2 (3ϫ 2 min) and
(16) to afford quinoline 17, the resin was again employed
in loading ketone 7 and cleavage by 16. However, only a
trace amount of quinoline 17 was obtained, suggesting that
the released linker reacted with excess ethyl acetoacetate
(16) to form oxime 18 during the first cycle. The yield after
the second cycle was drastically improved by treatment of
the used resin with O-methylhydroxylamine hydrochloride
to release ethyl acetoacetate (16) as oxime 19 from the solid
support before quinoline 17 was resynthesized. The yield
was maintained even after the third cycle (see the table in the combined CH2Cl2 solutions were evaporated and neutralized
by addition of a few drops of trimethylamine and evaporated again.
The residue was purified by silica gel chromatography (hexane/
EtOAc = 10:1) to give quinoline 10 (R1 = CO2Et, R4 = Me;
15.5 mg, 53.2 μmol, 71%) as a colorless solid.
Scheme 2).
The recyclability of the used resin for the reaction se-
quence, including a Suzuki–Miyaura coupling, Mitsunobu
reaction or condensation with n-butylamine on a solid sup-
port, was investigated. As a result, yields were decreased by
approximately 10% at each recycling (see tables in
Scheme 3). The reason for the reduced yields is unclear at
this stage. Recycling was limited to two or three runs in the
present study.
Suzuki–Miyaura Coupling on a Solid Support: Four pieces of the
solid supported ketoxime 13 (R3 = Me, R4 = Br, loading: 75 μmol
ϫ4, 300 μmol) was mixed with phenylboronic acid (219 mg,
1.80 mmol, 6 equiv.) and PdCl2(dppf)·CH2Cl2 (24.4 mg, 30.0 μmol,
0.1 equiv.) in degassed dimethoxyethane (20 mL) and aqueous
Na2CO3 solution (2 M, 1.2 mL, 2.40 mmol, 8 equiv.) under an ar-
gon atmosphere. The mixture was heated to reflux for 16 h. The
reaction mixture was allowed to come to room temp. The solution
was removed by decantation and the resulting resins were washed
with MeOH (3ϫ 2 min), DMF (3ϫ 2 min), and CH2Cl2 (3ϫ
2 min) to give solid supported 14 (R5 = Me, R6 = Ph).
Conclusions
We have demonstrated a solid-phase combinatorial syn-
thesis of quinolines consisting of 25 members using our
linker 1 and the recycling of the solid support. 2-Aminoben-
zoyl compounds were anchored as ketoximes. After some
functional groups were introduced onto the aromatic ring
through a Suzuki–Miyaura coupling, Mitsunobu reaction,
and condensation with an amine, the desired quinolines
were released by a Friedländer-type reaction of solid-sup-
ported 2-aminophenyloximes with some ketones under mild
reaction conditions. In the recycling process, the total yields
Mitsunobu Reaction with n-Butanol on a Solid Support: To a mix-
ture of six pieces of the solid supported ketoxime 13 (R3 = Me,
R4 = COOH, loading: 75 μmol ϫ6, 450 μmol), triphenylphosphine
(2.36 g, 9.0 mmol) and n-butanol (826 μL, 9.0 mmol) in CH2Cl2
(10 mL), was added dropwise diisopropyl azodicarboxylate
(1.75 mL, 9.0 mmol) under an argon atmosphere at 0 °C. The reac-
tion mixture was allowed to come to room temp. After stirring for
4 h, the solution was removed by decantation and the resulting res-
ins were washed with CH2Cl2 (3ϫ 2 min), DMF (3ϫ 2 min), and
were slightly decreased at each recycling. Application to the CH2Cl2 (3ϫ 2 min) to give solid supported ester 14 (R5 = Me, R6
= CO2nBu).
synthesis of other heterocycles by using the alkoxyamine
linker 1 is under investigation.
Condensation with n-Butylamine on a Solid Support: To a mixture
of nine pieces of the solid supported ketoxime 13 (R3 = Me, R4 =
COOH, loading: 75 μmol ϫ9, 675 μmol), Oxyma[16] (384 mg,
2.7 mmol), and n-butylamine (269 μL, 2.7 mmol) in CH2Cl2
(20 mL) was added dropwise N,N-diisopropylcarbodiimide
(836 μL, 5.4 mmol). After stirring for 24 h at room temp., the solu-
tion was removed by decantation and the resulting resins were
washed with CH2Cl2 (3ϫ 2 min), DMF (3ϫ 2 min), and CH2Cl2
Experimental Section
General Remarks: Solid support 1 was prepared from aminometh-
ylated SynPhase Lantern (surface polymer: polystyrene) purchased
from Mimotopes Pty Ltd. (Victoria, Australia) according to the
previously reported procedure.[11] All commercially available chemi-
cals purchased from Wako Pure Chemical Industries, Ltd. and TCI,
and Aldrich were used without further purification.
(3ϫ 2 min) to give solid supported amide 14 (R5 = Me, R6
CONHnBu).
=
Recycling of an Alkoxyamine Linker 1: A piece of the solid sup-
ported alkoxyamine 1 (loading: 75 μmol) was treated with 2-amino-
benzophenone 7 (59.2 mg, 300 μmol, 4.0 equiv.) in EtOH (3 mL)
and the mixture was heated to reflux for 24 h. The reaction mixture
was allowed to come to room temp. The solution was removed by
decantation and the resulting resins were washed with CH2Cl2
(3ϫ 2 min), DMF (3ϫ 2 min), and CH2Cl2 (3ϫ 2 min). The re-
sulting solid supported ketoxime 11 was mixed with ethyl aceto-
acetate (16) (38.2 μL, 300 μmol, 4.0 equiv.) in 5% TFA-DCE solu-
tion (3 mL). After heating to reflux for 24 h, the reaction mixture
was allowed to come to room temp. The resulting resins were
washed with CH2Cl2 (3ϫ 2 min) and the combined CH2Cl2 solu-
tions were evaporated and neutralized by addition of a few drops
of trimethylamine and evaporated again. The residue was purified
by silica gel chromatography (hexane/EtOAc = 10:1) to give quinol-
Synthesis of 10 by Friedländer-Type Reaction of Oxime 8 with
Ketones in the Solution Phase. Typical Procedure: To a solution of
8 (2:1 mixture of geometrically isomers, 50 mg, 221 μmol) in 5%
TFA-DCE solution (3 mL) was added ethyl acetoacetate 9 (R1
=
CO2Et, R2 = Me, 42.3 μL, 332 μmol, 1.5 equiv.). The reaction mix-
ture was heated to reflux for 24 h. After the mixture was concen-
trated, the residue was neutralized by addition of a few drops of
triethylamine. The mixture was again concentrated. The residue
was purified by silica gel chromatography (hexane/EtOAc = 10:1)
to give 10 (R1 = CO2Et, R2 = Me; 54.0 mg, 185 μmol, 84%) as a
colorless solid. The spectroscopic data are identical to those re-
ported previously.[10a]
Simple Loading and Cleavage to Synthesize Quinolines 10 on Solid
Support 1. Typical Procedure: A piece of the solid supported alk-
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Solid-Phase Friedländer Synthesis Using an Alkoxyamine Linker
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Received: April 1, 2015
Published Online: June 30, 2015
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