A novel macroreticular-type fluorous polystyrene resin and its application to the synthesis of a 3-amino-β-carboline derivative with N-methyl-N-nitrosourea conjugation via fluorous solid-phase reaction: A comparative study of fluorous solid-, solid-, and

Article abstract of DOI:10.1016/j.tet.2015.05.072

A novel fluorous polystyrene (FPS) MR-resin was applied to a fluorous solid-phase (FSP) reaction. The MR-FPS resin actually was developed previously and possessed excellent chemical resistance to acids and alkalis, and a fluorous-tagged compound was homog

Full text of DOI:10.1016/j.tet.2015.05.072

Tetrahedron 71 (2015) 4999e5012
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel macroreticular-type fluorous polystyrene resin and its
application to the synthesis of a 3-amino-b-carboline derivative
with N-methyl-N-nitrosourea conjugation via fluorous solid-phase
reaction: a comparative study of fluorous solid-, solid-, and liquid-
phase reactions
Keiko Suzuki, Munenori Kumagai, Masamichi Utsunomiya, Norio Sakai,
*
Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science & Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel fluorous polystyrene (FPS) MR-resin was applied to a fluorous solid-phase (FSP) reaction. The
MR-FPS resin actually was developed previously and possessed excellent chemical resistance to acids and
alkalis, and a fluorous-tagged compound was homogeneously and loosely immobilized on the resin. The
Received 11 February 2015
Received in revised form 20 May 2015
Accepted 21 May 2015
synthesis of an antitumor drug, an N-methyl-N-nirosourea conjugated 3-amino-
was accomplished with a high yield by using this new fluorous reaction system. Using only filtration, the
fluorous 3-amino- -carboline derivatives immobilized on the MR-FPS resin were easily recovered from
the reaction mixtures. As an extention of this approach, a diversity synthesis of 3-amino-9-benzyl-
b-carboline derivative,
Available online 29 May 2015
b
Keywords:
b
-
Fluorous polystyrene
Fluorous synthesis
Fluorous trityl chloride
carboline derivatives was applied to the FSP method giving high yields. Finally, the FSP synthesis was
compared with the corresponding conventional solid- and liquid-phase methods of synthesis. The FSP
reaction was superior in terms of the reactivity of the substrate and the ease of product separation.
Ó 2015 Elsevier Ltd. All rights reserved.
b
-carboline
Nitrosourea
Fluorous-solid phase reaction
1. Introduction
biphasic catalysis (FBC) in 1994,2 it has attracted much attention
3
with great effort devoted to developing fluorous chemistry.
A
Fluorous chemistry has shown promise as a new field of green
fluorous catalyst can be recycled, and the same conditions for re-
actions in usual non-fluorous solvents are applicable in the fluorous
biphasic reactions, which is a methodology that has been widely
sustainable chemistry based on its capacity for reaction recycla-
1
bility. Generally speaking, fluorous chemistry utilizes the tem-
4
perature dependency of the perfluoroalkanes in oleophobicity.
These are typical properties of fluorous solvents, and they are ably
utilized in fluorous biphasic systems (FBS). Although the fluorous-
common organic biphase becomes homogeneous by mixing or
heating, it returns to a biphasic state upon standing or cooling to
room temperature following a reaction. As a result, a catalyst pos-
sessing a fluorous tag in a fluorous phase can be recovered without
lixiviation from the fluorous phase to the organic phase, and the
catalyst solution can be recycled in the next reaction as the fluorous
phase. Since Horv ꢀa th and R ꢀa bai introduced the concept of fluorous
applied to various reactions by many chemists. Recently, the
manufacture, the import/export, and the use of per-
fluorooctanesulfonic acid (PFOS) all were regulated by the Stock-
holm Convention on Persistent Organic Pollutants (POPs) because
of its difficult degradability, its persistency, and its bio-
accumulative toxicity. Sometimes, even the fluorous solvents
5
used in fluorous chemistry present problems in these areas. In
order to accomplish a FBS reaction without a fluorous solvent and
6
,7
to improve its general applicability, perfluoroalkylated silica gels
8
and Teflon tape/shavings or Rastex fibers have been used as solid-
extraction materials and solid supports for fluorous catalysts.
Originally, the silica gels have been used as packing material for
9
reverse-phase HPLC columns and as solideliquid extraction car-
*
Corresponding author. Fax: þ81 4 7123 9326; e-mail address: konaka@rs.noda.
tridges to separate fluorinated compounds from organic com-
tus.ac.jp (T. Konakahara).
URL: http://www.tus.ac.jp
pounds. However, silica gels have a tendency to dissolve in acidic or
http://dx.doi.org/10.1016/j.tet.2015.05.072
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5000
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
basic solutions, and it is particularly sensitive to bases. This prop-
erty is a fatal flaw in green chemistry, and the development of
a new type of fluorous support is desired.
analogous method, as reported previously (Scheme 1),9a and was
then co-polymerized with divinylbenzene to obtain a fluorous
10
polystyrene (FPS) resin. Prior to the polymerization of 3, styrene
was copolymerized with divinylbenzene via suspension polymeri-
zation for use as a model reaction to obtain completely-spherical
particles in the presence of AIBN (0.019 equiv) as an initiator,
dodecane (1.2 equiv) as a poor dilution solvent, toluene (1.0 equiv)
as a good dilution solvent, and 0.6% aqueous poly(vinyl acetate)
(PVA) solution as a dispersing agent in a 10 mL round-bottomed
Previously, we reported the development of a novel fluorous
macroreticular polystyrene (MR-FPS) and its application to the
acetylation of cyclohexanol, in which a fluorous Lewis acid immo-
bilized on an MR-FPS resin was repeatedly used as a catalyst to give
10
the ester in a high yield. However, the yield of the cyclohexyl
acetate decreased to only 48% in this esterification when the MR-
FPS resin was not used. Although we believed that the porous
MR-FPS resin may had acted as an effective reaction field through
the homogeneous immobilization of the fluorous compound on the
resin, we were not always able to examine the homogeneity of the
12
flask (Table 1). The obtained resin was passed through sieves
(Table 1, entries 1e3). The stirring velocity (r) controlled the par-
ticle size so that when r was larger, the particle size became smaller.
According to the results of the polystyrene, compound 3 was co-
polymerized with divinylbenzene (0.58 equiv) under the same
conditions with a stirring velocity of 1000 rpm (entry 4). However,
10
immobilized fluorous compounds in detail in the previous report.
In this paper, we validated the homogeneity of the immobilized
fluorous compound on the MR-FPS resin, and advocated a concept
of the fluorous-solid phase (FSP) synthesis using MR-FPS resin, and
then applied the FSP system to the synthesis of an N-methyl-N-
the yield of particle size fractions >355 mm increased from 58 to
92%. This tendency toward a particle size increase was caused by
values for the hydrophobicity and density for 3 that were larger
than those for styrene. Therefore, the reaction vessel was changed
from a 10 mL round-bottomed flask to an 18 mm test tube to de-
crease the particle size, because vessel shape affects the efficiency
of stirring. The yield of smaller particles was increased to 28% (entry
5). Furthermore, the increased stirring velocity reduced the particle
nirosourea-conjugated 3-amino-
previously developed as a new antitumor drug. We finally com-
pared FSP synthesis of 3-amino- -carboline derivative with the
b-carboline derivative, which we
11
b
corresponding solid- and liquid-phase syntheses. A conceptual di-
agram for FSP system is briefly illustrated in Fig. 1.
Fig. 1. Illustrated conceptual diagram for fluorous-solid phase (FSP) system.
2
2
. Results and discussion
size. The yield of particles 355e250
mm in size was 70% at 1300 rpm
and that of particles 250e180 m in size was 67% at 1600 rpm. A
m
.1. Preparation of a macroreticular-type fluorous poly-
resin particle with a larger surface area seemed better suited to
solid-phase support. Although small particles result in a large
styrene (MR-FPS) resin
surface area, particles smaller than 180
ficult to handle because of static electrical charges. Therefore, entry
7, which produced 250e180 m-sized particles as major products,
was selected as the optimal reaction conditions.
mm in diameter were dif-
First, 1-(3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pen-
tyl-4-vinylbenzene (3) was prepared from perfluoro(2-methyl-2-
pentene) (1) and p-chloromethylstyrene (2) in a 90% yield via an
m

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5001
Scheme 1. Synthesis of fluorous styrene 3.
Table 1
Preparation of polystyrene resin and fluorous polystyrene (FPS) MR type resin
Entry
r/rpma
Vessel
Monomer
Particle size/
m
m, wt %
>355
355e250
250e180
180e125
125e90
<90
b
1
2
3
4
5
6
7
700
1000
1300
1000
1000
1300
1600
Flask
Flask
Flask
Flask
4
4
4
3
3
3
3
94
58
17
92
67
3
3
35
56
7
28
70
21
2
6
23
1
4
25
67
1
1
3
1
1
0
0
1
0
0
1
1
0
0
0
0
0
0
0
b
b
b
Test tubec
c
Test tube
1
10
Test tubec
1
a
r: Stirring velocity.
Flask: 10 mL round-bottomed flask.
Test tube: 18 mm-diameter test tube.
b
c
Second, SEM was used to carefully monitor the thus-prepared
enegy dispersive X-ray spectroscopy (SEM-EDX). In order to sup-
port the compound 5 on the MR-FPS resin, the MR-FPS particles
were added to the solution of 5 in ethanol, and the solvent was
rotary-evaporated under reduced pressure following stirring. The
dried MR-FPS-supported 5 (5/MR-FPS) was not sticky and was
easily handled unlike the fluorous Lewis acid 5 itself. The amount of
5 supported on the G-FPS resin was much smaller than that on the
MR-FPS resin. The presence of the fluorous Lewis acid 5 on the MR-
FPS particles was affirmed by SEM-EDX, which was operated under
the conditions that are described in Fig. 2. A characteristic X-ray of
FPS particles for micropores, and the particles were partially
crashed in order to observe the fracture cross-sections (Fig. 2a).
Many micropores with diameters that ranged from tens to hun-
dreds of nm were evenly observed not only on the surfaces but also
on the insides of the completely spherical FPS particles as evidence
of the MR resin (Fig. 2bee). These micropores were not observed in
the gel-type FPS (G-FPS), which was obtained in the reaction using
excess amounts of toluene (good solvent) or insufficient amounts of
the diluent (Fig. 3aec). The SEM images of the surface of the G-FPS
resin were compared with those of the MR type FPS (MR-FPS) resin
at almost the same magnification ratio (Fig. 3b vs Fig. 3d). The
rough surface of the MR-FPS resin (Fig. 3d) was more characteristic
than the smooth surface (Fig. 3b). A magnified image (ꢀ40,000) of
the smooth surface is shown in Fig. 3c.
scandium was observed at 4.1 (Ka) and 4.5 (Kb) keV in EDX of the 5/
MR-FPS particles, which were coated with a vacuum-deposited
platinum film and set on a copper stage (Fig. 5). The EDX map-
pings are shown for F, S and Sc in Fig. 6bed, respectively, in a SEM
image (Fig. 6a). The existence and homogeneous distribution of 5
on a MR-FPS particle was established by the EDX mapping of F, S,
and Sc elements as shown in Fig. 6bed.
Next, the MR-FPS resin was treated with bases and acids to
clarify its limits of tolerance, as we daringly selected very severe
conditions in order to explore the possible use of the MR-FPS resin
as a fluorous support in various kinds of reactions. When the MR-
FPS resin was treated with water, 10 M sodium hydroxide, trie-
2.3. Fluorous solid-phase (FSP) synthesis of 3-(3-amino-9H-
pyrido[3,4-b]indol-9-yl)-N-(2-(3-methyl-3-nitrosoureido)
ethyl)propanamide (13)
ꢁ
thylamine, and 10 M sulfuric acid at 80 C, there was no apparent
change, which was verified spectroscopically after even one week
In the esterification of cyclohexanol reported previously,10 the
reaction gave very low yields in the absence of an MR-FPS support
as well as in the absence of a fluorous catalyst. The former result
suggests that the fluorous Lewis acid catalyst was loosely immo-
bilized on the surface of the MR-FPS resin. This loosely-
immobilized catalyst prevented the steric hindrance observed in
solid-phase syntheses, and resulted in high reactivity, such as that
seen in liquid-phase synthesis. This MR-FPS resin had micropores,
strong hydrophobicity and oleophobicity; and enabled a reaction
with the advantages of both solid-phase synthesis as well as those
of liquid-phase synthesis, which resulted in a novel reaction field
that was highly functional. On the basis of the above-mentioned
attributes of the MR-FPS resin (microporocity, hydrophobicity,
in each sample of the MR-FPS resin, as shown in Fig. 4 by the ab-
ꢂ1
sorption bands of the CeF bonds in the 1200e1300 cm region in
2
their micro-ATR-FTIR spectra. PFO-SiO , however, was easily
decomposed when it was treated with 10 M sodium hydroxide for
only 2 daysdeven at room temperature. This result shows that FPS
indicates tolerance against bases and acids that is higher than that
of PFO-SiO
2
.
2
.2. Preparation of fluorous Lewis acid supported on MR-FPS
(
5/MR-FPS) and SEM-EDX analysis
We selected a scandium(III) salt 5 of the fluorous sulfon-
amide1
0,13
for use as a probe in the scanning electron microscope-

5002
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
Fig. 2. SEM images of MR type fluorous polystyrene (MR-FPS) particles: (a) whole image (x70), (b) a completely-spherical shaped particle and its surface (x3,300), (c) macropores on
the surface of FPS particle (x27,000), (d) view of the fracture cross-section (x850), (e) macropores on the surface of the fracture cross-section in FPS particle (x19,000). MR-FPS
particles were coated with a vacuum-deposited platinum film (thickness: 26.5 nm) and set on a cupper stage. SEM was operated at 15.0 kV (electron accelerating voltage).
oleophobicity, high chemical tolerance, and homogeneous immo-
bilization of fluorous compounds), we advocated a new concept of
the fluorous-solid phase (FSP) synthesis using the MR-FPS resin. A
conceptural diagram for FSP system is briefly illustrated in Fig. 1 to
make it understandable. We attempted to employ the MR-FPS resin
trityl alcohol (11) in an 84% yield. When 11 was stirred in excess
amounts of acetyl chloride at 65 C for 3 h, the fluorous trityl
chloride 7 was obtained in an 80% yield. Because the fluorine
content in this molecule was 55 wt %, it could be a good fluorous tag
in either an FBS reaction or in the FSP reaction.
ꢁ
as a support for FSP synthesis using fluorous-tagged reagents or
substances.3
(
b,14
In this application, we planned the synthesis of 3-
-9-yl)-N-(2-(3-methyl-3-
nitrosoureido)ethyl)propanamide (6), which is a novel antitumor
3-amino-9H-pyrido[3,4-b]indoL
11c
agent that we recently developed.
Therefore, we designed
F
0
a novel fluorous trityl chloride ( Tr-Cl): 4,4 -(chloro(phenyl)meth-
ylene)bis((3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)
benzene) (7). This was a fluorous tag with a functional group that
15
was analogous to the trityl chloride resin. The synthetic strategy is
shown in Scheme 2. First, the Heck reaction of p-bromobenzene-
diazonium
tetrafluoroborate
(8)
with
3
,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecene in the
F
Next, 3-amino-
b
-carboline (12) was treated with Tr-Cl 7 in the
presence of Pd(II) acetate (0.5 mol %) gave the corresponding 1-(p-
bromophenyl)-2-perfluorooctylethene (9) in a 93% yield, which
was followed by hydrogenation with 1 MPa H in the presence of
2
a Rh/C catalyst at room temperature for 24 h to yield p-bro-
mo(1H,1H,2H,2H)perfluorodecylbenzene (10) in a 95% yield. After
presence of N,N-diisopropylethylamine (DIPEA) in DMF. The re-
action, however, would not proceed, because 7 was only minutely
soluble in DMF. When THF was used as a solvent instead of DMF, 3-
Tr-amino)-b-carboline (13a) was obtained in a quantitative yield
Table 2, entries 1 and 2, 98%). The yield was comparable to that of
F
(
(
ꢁ
lithiation with n-BuLi in THF at ꢂ40 C, 10 was treated with methyl
the reaction of o-chlorotrityl chloride resin in a solid phase (entries
and 4, 13b:99%). However, the corresponding o-chlorotrityl-
0
benzoate (0.32 equiv) to give 4,4 -bis((1H,1H,2H,2H)perfluorodecyl)
3

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5003
Fig. 3. SEM images of the gel type fluorous polystyrene (G-FPS) particles and MR-FPS particles: (a) Whole image, completely-spherical shaped particles (x110), (b) the surface of gel
type FPS resin particle (x9,000), (c) the surface of gel type FPS resin particle (x40,000), (d) the surface of the MR type FPS resin particle in the almost same magnification ratio
(
(
x9,500) as Fig. 2b. The gel type FPS particles were coated with a vacuum-deposited platinum film (thickness: 26.5 nm) and set on a cupper stage. SEM was operated at 15.0 kV
electron accelerating voltage).
protected compound 13c was produced by an analogous reaction in
a yield of 82% (entry 5). The obtained 13a was immobilized on the
MR-FPS resin by rotary-evaporation of the solvent from the mixture
of the resin and 13a, which was dissolved in a minimum amount of
methanol. In order to synthesize 3-(3-amino-9H-pyrido[3,4-b]
indol-9-yl)-N-(2-(3-methyl-3-nitrosoureido)ethyl)propanamide
acetonitrile was added, the product would not immobilize on the
resin (entries 6, 7, and 8). Toluene (5 mL) as a nonpolar work-up
solvent, however, led to a complete immobilization of 14a on the
MR-FPS resin (93%). The recovery of 14a was unaffected by the use
of increased amounts of toluene (entries 10 and 11). As a conse-
quence of many trials, we decided that 5 mL of toluene was optimal
as the work-up solvent (see Table 2, entry 2). After filtration of the
reaction mixture, the fluorous-tagged product 14a was recovered
from the resin by washing with methanol. However, the yield of 14a
also was 93% when the reaction was performed without MR-FPS
resin (Table 2, entry 1). The reactions of 13b and 13c gave 14b
and 14c in 90, 90 and 78% yields, respectively (Table 2, entries 3e5).
Furthermore, treating compound 14a, immobilized on MR-FPS
resin, with excess amounts of ethylenediamine (EDA) under
reflux for 3 days ensured the complete formation of amide 15a in
a high yield (84%; Table 2, entry 2). Although the excess amounts of
EDA frequently disturbed the isolation of the product, 15a was
easily isolated from the reaction mixture in the FSP system. How-
ever, compound 14b scarcely reacted with EDAdeven in DMF and
THF, which greatly swelled the resin (entry 3). Therefore, an excess
amount of pyridine was added. As a result, the yield of 15b was
drastically improved (77% yield, entry 4), and the purity of com-
pound 16, obtained by the cleavage of the resin 15b, was about 80%
(
6), a Michael addition of 13a to methyl acrylate was performed,
and led to the formation of 14a via FSP synthesis. The fluorous-
tagged 3-amino- -carboline 13a was immmobilized on the MR-
b
FPS resin, and treated with 1 equiv of sodium ethoxide in 2 mL of
THF for 1 h at room temperature, and then, it was reacted with an
excess amount of methyl acrylate for 1 h. After completion of the
reaction, the reaction mixture was diluted with a work-up solvent
to re-immobilize the fluorous-tagged product on the surface of the
MR-FPS resin, because compound 13a was loosely bound on the
surface of the MR-FPS resin (or partially released from its surface)
during the reaction described above. As a work-up solvent, we se-
16
lected three solvent systems that are generally used in FBS. When
mL of 20% H O-DMF was used, the recovery of the product was
only 31%, and 61% of product 14a was lost in the filtrate (Table 3,
entry 1). Although we increased both the volume of the 20% H O-
DMF work-up solvent and the water content in DMF, the recovery of
4a did not improve (Table 3, entries 2, 3, and 4). When aqueous
5
2
2
1

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K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
F
carboline derivatives 19aee (Table 4). First, the reaction of 3-( Tr-
amino)- -carboline (15a) immobilized on the MR-FPS resin with
b
benzyl bromide (18a) was performed in the presence of sodium
ethoxide in THF at room temperature for 3 days. After completion of
the reaction, a work-up solvent (toluene) was added to the reaction
mixture to re-immobilize the fluorous-tagged product on the resin,
and then the resin was separated by filtration followed by rinsing
with methanol to obtaine 19a in a 75% yield. The electron-
withdrawing groups (F and CF ) at the para position of benzyl
3
bromide enhanced the yields of the corresponding products 19b
and 19c (93 and 90%, respectively), while the electron-donating
3 3
groups (CH and OCH ) had no affect on the yields of the prod-
ucts 19d and 19e (72 and 74%, respectively). The protecting group
F
Tr could be removed by treatment with trifluoroacetic acid, as
described above.
2.5. Characteristcs of FSP and comparisons with solid and
liquid phases
Finally, we compared FSP (or the MR-FPS resin) with solid-
phase, liquid-phase, and fluorous-silica gels in order to highlight
the usefulness of the FSP reaction field. The characteristics of each
reaction field (or materials) are shown in Table 5. FSP (or the MR-
FPS resin) exhibited excellent characteristics such as high re-
activity, easy monitoring of the reaction, easy separation of the
intermediates and products, excellent recyclability of the fluorous
catalyst, easy application to the sequential reactions, and high tol-
erance to strong bases and acids. Specifically, the reactivity of the
substrate (or the reactant) in FSP was very high unlike that in the
solid phase, and the FSP reaction was similar in reactivity to that of
the liquid-phase reaction. In the solid-phase reaction, the solvent
was limited to polar aprotic solvents such as pyridine, THF and DMF
in order to swell the resin, whereas various kinds of solvents were
applicable in the FSP reaction when using a nonpolar solvent as
a work-up solvent. In the FSP reaction, the fluorous-tagged catalyst
and substrate were loosely bound on the surface of an MR-type
resin, or were partially released from it, whereas they were co-
valently bonded onto the surface of a resin in the solid-phase re-
action. This is why the reaction of the former was faster than that of
the latter. In addition, the progress of the reaction could be moni-
tored by conventional methods such as TLC, NMR, and UV in the FSP
reactions similar to the liquid-phase reaction. This was different
from the solid-phase reaction, in which the product was cleaved
from the resin at the corresponding step for quantitative analysis. In
the FSP reaction, the products including the intermediates were
easily separated from the reaction mixture by only the addition of
the work-up solvent followed by filtration, as with the solid-phase
reaction. The MR-FPS resin exhibited high chemical tolerance
against strong bases and acids such as sodium hydroxide, sodium
ethoxide, triethylamine, trifluoroacetic acid, and sulfuric acid.
However, the fluorous silica gel was easily decomposed with strong
bases. This is why the fluorous catalyst that was immobilized on the
surface of the MR-FPS resin could be used repetedly in the same
reaction, and it is also why the MR-FPS resin was able to be used like
a resin in sequential solid-phase reactions.
Fig. 4. Tolerance of FPS against bases and acid; micro-ATR-FTIR spectra of the FPS
particles after treatment with bases or acid: FPS particles were treated with H O (blue
3 2 4
line), 10 M NaOH (brown line), Et N (green line), 10 M H SO (red line) at 80 C for 1
2
ꢁ
week with shaking under atmosphere. No changes in absorbance were observed. (a)
Whole range of micro ATR-FTIR spectra of the samples and (b) offset spectra of the
ꢂ1
1
100e1700 cm range.
(
see Suporting Information). Pyridine may act as a catalyst that
activates the carbonyl carbon atom or a solvent and causes the resin
to swell.
The formations of 13b, 14b, and 15b were monitored by both
increasing and decreasing the absorption bands for NeH stretching
ꢂ1
ꢂ1
(
3407 cm ), the >C]O stretching of the ester group (1737 cm ),
ꢂ1
and the >C]O stretching of the amide group (1660 cm ) in the
microscopic ATR spectrum of the corresponding loaded resins (see
Supplementary data).
Generally, a trityl group is cleaved using trifluoroacetic acid
(
TFA) in dichloromethane. If the fluorous trityl group is cleaved at
the final stage in the FSP synthesis of 3-(3-amino-9H-pyrido[3,4-b]
indol-9-yl)-N-(2-(3-methyl-3-nitrosoureido)ethyl)propanamide
(
6), the N-methyl-N-nitrosourea group must decompose.17 For this
reason, we decided to synthesize 6 from the free amine derivative
6 via a liquid-phase reaction rather than a FSP reaction. Based on
1
this decision, compounds 13aec were treated with 10% (or 50%)
trifluoroacetic acid to obtain 16 in 84, 84, 77, and 54% yields, re-
spectively (Table 2, entries 1e4). Fluorous trityl alcohol 11 was re-
covered by immobilization on the MR-FPS resin, and it was
available for re-use after chlorination with acetyl chloride. When
compound 16 was treated with p-nitrophenyl N-methyl-N-nitro-
socarbamate (17) in the presence of DIPEA in methanol at room
temperature for 2 h, we succeeded in synthesizing the objective
compound 6 in a 79% yield, as shown in Scheme 3.
3. Conclusions
In conclusion, we succeeded in developing a new type of fluo-
rous polystyrene (FPS) for use as a fluorous reaction field, via the
suspension co-polymerization of 1-(3,3,4,4,5,5,5-heptafluoro-2,2-
bis(trifluoromethyl)-pentyl)-4-vinylbenzene (3) with divinylben-
zene as a cross-linking agent. SEM analysis revealed the FPS resin to
be that of a macroreticular type. As far as we could ascertain, there
is no report on the support of fluorous catalysts, with the exception
2
.4. Application of the fluorous solid-phase (FSP) system to
synthesize 3-amino-9-benzyl- -carboline derivatives (19)
b
In order to demonstrate the generality of the FSP synthesis, we
applied it to the synthesis of 5 kinds of 3-amino-9-benzyl-
6
9
b
-
2
of PFO-SiO and Teflon tape. The MR-FPS resin reported in this

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5005
Fig. 5. SEM-EDX of the 5/MR-FPS particles: FPS particles were coated with a vacuum-deposited platinum film and set on a cupper stage. SEM was operated at the following
conditions; electron accelerating voltage: 15.0 kV, multiplying factor: ꢀ350, sweeps: 101 times.
paper is the first example of using a fluorous resin as a support for
fluorous catalysts in FBS and in the FSP synthesis, which was newly
advocated in this paper. This resin showed excellent chemical re-
sistance to acids and bases. Furthermore, EDX mapping showed
that the fluorous Lewis acid supported on MR-FPS was homoge-
neously dispersed. This new fluorous reaction field using MR-FPS
2
were carried out under N atmosphere, unless otherwise noted.
Solid-phase synthesis was performed with EYELA Solid Organic
Synthesizer CCA-150M equipped with a polypropylene reaction
vessel and CCS-150M equipped with a glass reaction vessel. Melting
points were determined using a Yanaco micro-melting-point ap-
1
13
19
paratus and uncorrected values were reported. H, C, and F NMR
spectra were recorded using a JEOL JNM ECP-500 (500, 125 and
was applied to the synthesis of b-carboline derivatives using a flu-
1
13
19
orous tag. The products immobilized on the MR-FPS resin were
easily recovered from the reaction mixture by filtration after
completion of the reaction. Because the MR-FPS resin showed
strong chemical tolerance against bases and acids such as sodium
hydroxide, sodium ethoxide, trifluoroacetic acid and sulfuric acid, it
was applicable to sequential reactions 13 to 16 without isolation of
the intermediates. Furthermore, the MR-FPS resin allowed for an
effective novel reaction field, which had the advantages of liquid-
470 MHz for H, C, and F, respectively) and a JEOL JNM ECP 300
1
13
1
13
(300 and 75 MHz for H and C, respectively). The H, C chemical
shifts were referenced to TMS or dimethyl silapentanesulfonate
(
d
¼0.00) using the solvent residual peak as a reference and J values
19
are reported in Hertz. The F chemical shift was referenced to
CFCl . Mass spectra (LRMS and HRMS) were recorded on a JEOL
3
JMS-MS 700 mass spectrometer using NBA (3-nitrobenzyl alcohol),
glycerol, and diethanolamine as a matrix and xenon (6 kV, 10 mA)
as the fast atom bombardment (FAB) gas, or a JEOL JMS-T100CS
mass spectrometer at ESI mode. Attenuated total reflection (ATR)
FTIR was measured on Thermo Nicolet Continum Microscope IR.
HPLC was performed on CTO-10AVP (Shimadzu) using a Develosil
ODS-5 column (Nomura) eluting with a 20% MeOH in water con-
(
high reactivity) and solid-phase reactions (easy separation), which
was due to both the loose binding nature of a fluorous tag on the
surface of the FPS resin as well as to its porosity and a high chemical
tolerance to bases and acids.
3 4
taining 20 mM CH COONH as buffer over 20 min at 0.5 mL/min.
4
4
. Experimental section
SEM and SEM-EDX were determined on a JEOL JSM-6500F and were
operated at the following conditions for the sample coated with
a vacuum-deposited platinum film (thickness: 26.5 nm) and set on
a cupper stage; electron accelerating voltage: 15.0 kV, multiplying
factor: ꢀ350, sweeps: 101 times.
.1. Materials and methods
All organic solvents purchased from TCI were dried and distilled
prior to use. All reagents were commercially available (TCI) and
used without further purification unless otherwise noted. Reaction
progress and compound purity were monitored using thin-layer
chromatography (TLC) with hexaneeethyl acetate as the irrigat-
ing system and UV light at shorter wavelengths as the visualizer.
Column chromatography was performed using Silica gel 60
4.2. Synthesis
4 . 2 .1. S y n t h e s i s o f 1 - ( 3 , 3 , 4 , 4 , 5 , 5 , 5 - h e p t afl u o ro - 2 , 2 -
bis(trifluoromethyl)pentyl)-4-vinylbenzene (3). Perfluoro(2-methyl-
2-pentene) (2) (16.8 g), potassium fluoride (spray dried) (2.40 g),
potassium iodide (0.36 g), 18-crown-6 (0.15 g), p-Chloromethyl-
styrene (5.17 g), and DMA (13 mL) were placed in a 50 mL reaction
(
Merck), NH Silica (Fujigel) and ODS (YMC). 2-Chlorotrityl chloride
resin (100e200 mesh, 1% divinylbenzene, 1.3 mmol/g) was pur-
chased from Merck. Scandium(III) salt of bis(per-
-carboline derivertive
5
10,13
ꢁ
fluorooctanesulfonyl)imide,
3-amino-
and p-nitrophenyl N-methylcarbamate (17) were pre-
pared according to previously reported procedures. All reactions
b
flask under argon, and heated at 60 C for 24 h with stirring. The
11bed
18
12
reaction mixture was poured into ether, and washed with portions
of water. After the organic phase was separated, dried over

5006
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
Fig. 6. SEM images and SEM-EDX mappings of the 5/MR-FPS particle: MR-FPS particle was coated with a vacuum-deposited platinum film and set on a cupper stage. (a) SEM image
of 5/MR-FPS particle, (b) SEM-EDX map of the 5/MR-FPS particle by the F element, (c) SEM-EDX map of the 5/MR-FPS particle by the S element, (d) SEM-EDX map of the 5/MR-FPS
particle by the Sc element. SEM was operated at the following conditions; electron accelerating voltage: 15.0 kV, multiplying factor: ꢀ350, sweeps: 101 times.
Scheme 2. Synthesis of fluorous trityl chloride 7.

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5007
Table 2
Synthesis of 3-(3-amino-9H-pyrido[3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide (16)
Entry
Methoda
Reaction from 12 to 13aec
13aec to 14aec
14aec to 15aec
15aec to 16
Amine
Solv.
Trb
Yield/%
Work-up solv.
Yield/%
Additive
Yield/%
TFA
Yield/%
F
1
2
3
LP
FSP
SP
DIPEA
DIPEA
None
THF
THF
DMF
Tr
Tr
13a:98
13a:98
13b:99
None
14a:93
None
None
None
15a:90
15a:84e
15b:0
10%
10%
d
84
84
F
c
Toluened
None
14a:93e
f,g
f,h,i
14b:90
d
4
SP
LP
None
None
DMF
DMF
13b:99f,g
13c:82
None
None
14b:90f,h,i
Pyj
15b:77f,k,l
50%
10%
77m
54
5
Tr(Cl)
14c:78n
None
15c:85
a
LP: Liquid Phase reaction, FSP: Fluorous-Solid Phase reaction using MR-FPS (macroreticular-type fluorous polystyrene), SP: Solid Phase reaction.
b
c
d
e
f
F
Tr: Fluorous trityl group generated from 7,
: o-Chlorotrityl group on the resin, Tr(Cl): o-Chlorotrityl group.
The reaction without MR-FPS resin.
The optimization of the work-up solvent is shown in Table 3.
The MR-FPS resin immobilized with the product was rinsed with MeOH to recover the product.
The yield was determined by cleavage of the loaded resin.
g
h
i
ꢂ1
An absorption band of the NeH stretching appeared at 3407 cm in the microscope ATR spectrum of the loaded resin 13b.
Excess amounts of EtONa (5 equiv) were used.
An absorption band for the >C]O stretching of the ester group appeared at 1737 cm in the microscope ATR spectrum of the loaded resin 14b.
ꢂ1
j
Thirty-six equivalent of pyridine was added.
Reaction time: 4 days.
An absorption band for the >C]O stretching of the amide group appeared at 1660 cm in stead of the ester absorption band at 1737 cm in the microscope ATR spectrum
k
l
ꢂ1
ꢂ1
of the loaded resin 15b.
m
Reaction time: 1 h.
The mixture of 13c and EtONa was stirred for 20 min in THF at rt.
n
magnesium sulfate, and the solvent evaporated, the desired crude
(
F
¼18 mm) containing AIBN were added diluents, divinylbenzene
product was purified by silica gel column chromatography (hexane)
and fluorous styrene 3, and then the mixture was stirred with the
stirring rod at 1600 rpm until AIBN was dissolved at rt. An aq so-
lution of 0.6% PVA was added to the test tube and stirred. The
1
to afford the monomer 3 (13.3 g, 90% yield) as a colorless liquid. H
NMR (300 MHz, CDCl
3
)
d
3.52 (s, 2H), 5.27 (dd, J¼11.0 Hz, J¼1.0 Hz,
ꢁ ꢁ
suspension was heated slowly to 90 C for 4 h (to 60 C during 1 h,
1
H), 5.75 (dd, J¼17.0 Hz, J¼1.0 Hz, 1H), 6.68 (dd, J¼17.0 Hz,
13
ꢁ
ꢁ
ꢁ
J¼11.0 Hz, 1H), 7.24 (d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H);
NMR (125 MHz, CDCl 32.4, 114.6, 116.0, 118.7, 120.9, 123.2, 126.0,
30.3, 131.7, 136.1, 137.4; F NMR (470 MHz, CDCl
C
held for 1 h at 60 C, to 90 C during 1 h, and then held 1 h at 90 C),
and finally held at 90 C for 24 h with slowly stirring at 400 rpm.
The obtained resin (MR-FPS) was filtered, successively washed with
boiling water (10ꢀ5 mL), water (2ꢀ5 mL), acetone (5ꢀ5 mL),
benzene (2ꢀ5 mL), and dried in vacuum. The results were sum-
marized in Table 1 (entries 4e7) with reaction conditions.
ꢁ
3
)
d
19
1
3
3
, CFCl )
d
ꢂ62.2,
þ
þ
ꢂ80.0, ꢂ105.9, ꢂ122.8; MS (FAB ) m/z 436 (M ).
4.2.2. Suspension copolymerization of styrene. To a reaction vessel
containing AIBN were added diluents, divinylbenzene and styrene,
and then the mixture was stirred with a stirring rod at 1000 rpm
until AIBN was dissolved at rt. An aq solution of 0.6% PVA was added
4.2.4. Procedure for the synthesis of FPS-supported Lewis acid 5/MR-
FPF. To a solution of fluorous Lewis acid 5 (200 mg) in ethanol
ꢁ
to the vessel and stirred. The suspension was heated slowly to 90 C
(10 mL), the MR-FPS resin (d¼250e180
mm, 630 mg) was added and
the resulting mixture was stirred for 1 h at rt. After removal of the
ꢁ
ꢁ
ꢁ
for 4 h (to 60 C during 1 h, held for 1 h at 60 C, to 90 C during 1 h,
ꢁ
ꢁ
and then held 1 h at 90 C), and finally held at 90 C for 24 h with
slowly stirring at 400 rpm. The obtained resin was filtered, suc-
cessively washed with boiling water (10ꢀ5 mL), water (2ꢀ5 mL),
acetone (5ꢀ5 mL), benzene (2ꢀ5 mL), and dried in vacuum. The
results were summarized in Table 1 (entries 1e3) with reaction
conditions.
solvent under reduced pressure, residual 5/MR-FPS resin was dried
ꢁ
in vaccuo at 80 C for 6 h.
4.2.5. Procedure
for
the
synthesis
of
1-bromo-4-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecen-1-yl)ben-
zene (9). To a stirred suspension of 4-bromobenzenediazonium
2
tetrafluoroborate (8) (5.0 g, 18.4 mmol) and Pd(OAc) (20.7 mg,
4
2
.2.3. Suspension copolymerization of 1-(3,3,4,4,5,5,5-heptafluoro-
,2-bis(trifluoromethyl)pentyl)-4-vinylbenzene (3). To a test tube
0.0923 mmol) in MeOH (18.5 mL) was added 1H,1H,2H-per-
fluorodecene (8.23 g, 18.5 mmol) under argon. The mixture was

5008
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
Table 3
Optimization of work-up solvents in the fluorous-solid phase (FSP) synthesis of 14a using the fluorous MR-type polystyrene resin (MR-FPS)
a
Entry
Work-up solv.
Added volume/mL
14a in the filtrate/%
14a on MR-FPS/%
1
2
3
4
5
6
7
8
9
20% H
20% H
20% H
30% H
20% H
20% H
20% H
30% H
2
2
2
2
2
2
2
2
O-DMF
O-DMF
O-DMF
O-DMF
OeMeCN
OeMeCN
OeMeCN
OeMeCN
5
10
15
5
61
46
45
45
93
92
93
93
31
45
46
46
0
0
0
0
5
10
15
5
5
10
15
Toluene
Toluene
Toluene
Trace
Trace
Trace
93
91
92
1
1
0
1
a
The mixture of 13a (0.020 mmol) immobilized on the MR-FPS (500 mg) and sodium ethoxide (10 mg, 0.14 mmol) was shaken in THF (2 mL) for 1 h at rt, and then methyl
acrylate (0.13 mL; 1.4 mmol) was added drop by drop. After the completion of the reaction, the work-up solvent was added to the reaction mixture and shaken for 30 min at rt
to immobilize the fluorous-tagged product 14a on the MR-FPS resin.
Scheme 3. Synthesis of 3-(3-amino-9H-pyrido[3,4-b]indol-9-yl)-N-(2-(3-methyl-3-nitrosoureido)ethyl)propanamide (6).
ꢁ
2.34 (m, 2H), 2.87 (m, 2H), 7.08 (m, 2H), 7.45 (m, 2H); 13
26.0, 32.6, 32.8, 32.9, 120.6, 130.0, 131.9,
, 470 MHz)
ꢂ126.1 (s, 2 F), ꢂ123.5 (s, 2 F),
ꢂ122.7 (s, 2 F), ꢂ121.9 (s, 4 F), ꢂ121.6 (s, 2 F), ꢂ114.6 (s, 2 F), ꢂ80.8
heated at 40 C until gas evolution ceased. The resulting mixture
CDCl
3
)
d
C
was stirred for additional 10 min and MeOH was removed under
reduced pressure. The crude product was purified by column
chromatography on silica gel (eluted with hexane) afforded 9 (10 g,
NMR (125 MHz, CDCl ) d
138.1; F NMR (CDCl
3
19
3
d
ꢁ
1
þ
þ
9
3% yield) as a white solid: mp 42.6e43.5 C. H NMR (500 MHz,
(s, 3 F); MS (FAB) m/z 602 [M] ; HRMS (FAB) found 601.9532 [M]
calcd for C16H BrF17 601.9538.
13
79
þ
CDCl
3
)
d
2.34 (m, 1H), 2.87 (m, 1H), 7.09 (m, 2H), 7.43 (m, 2H);
C
8
NMR (126 MHz, CDCl
29.1, 130.0, 132.0, 132.2, 132.5, 138.1, 138.5, 138.56, 138.64; F NMR
CDCl , 470 MHz)
ꢂ126.7 (s, 2 F), ꢂ123.5 (s, 2 F), ꢂ122.7 (s, 2 F),
ꢂ121.9 (s, 4 F), ꢂ121.7 (s, 2 F), ꢂ114.7 (s, 2 F), ꢂ80.8 (s, 3 F); MS (FAB)
3
) 26.0, 32.6, 115.0, 115.1, 115.3, 120.6, 124.5,
9
0
1
(
4.2.7. Procedure for the synthesis of 4,4 -bis((1H,1H,2H,2H)-per-
ꢁ
3
d
fluorodecyl)trityl alcohol (11). To a cooled (ꢂ40 C) mixture of
compound 10 (1.0 g, 1.66 mmol) in anhydrous THF (10 mL) was
added dropwise n-BuLi (1.2 mL, 1.59 M in hexane, 1.99 mmol)
þ
þ
m/z 601 [MþH] ; HRMS (FAB) found 600.9490 [MþH] calcd for
7
9
þ
ꢁ
C
16
H
7
BrF17 600.9454.
keeping the internal temperature below ꢂ40 C. The solution,
turned a yellow-green color, was stirred for 5 min. Methyl benzoate
ꢁ
4.2.6. Procedure for
the
synthesis
of
1-bromo-4-
(66
m
L, 0.53 mmol) was added dropwise at ꢂ40 C and the mixture
(
(
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)benzene
10). A suspension of 9 (9.1 g, 15.1 mmol) and 5% Rh/C (626 mg,
was stirred at room temperature for 30 min. The mixture was
quenched with water (excess), and then stirred for 1 h. The organic
layer was collected and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
0
.34 mol) in a degassed dichloromethane (61 mL) was placed under
1
.0 MPa of H and stirred at room temperature for 24 h. At the end
2
of the reaction, the mixture was filtered and evaporated. The resi-
due was purified by silica gel column chromatography (hexane) and
the solvent was removed under reduced pressure to afford 10 (8.7 g,
(hexaneeether¼100:1) to afford 11 (1.6 g, 84% yield) as a white
1
liquid. H NMR (300 MHz, CDCl
3
)
d
2.36 (m, 4H), 2.76 (s, 1H), 2.89
13
(m, 4H), 7.30 (m, 13H); C NMR (125 MHz, CDCl
3
) d 26.0, 32.9, 81.7,
ꢁ
1
19
9
5% yield) as a white solid; mp 49.6e50.7 C. H NMR (500 MHz,
127.4, 127.8, 127.9, 128.0, 128.3, 138.2, 145.4, 146.8; F NMR (CDCl ,
3

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5009
Table 4
Synthesis of 3-amino-9-benzyl-b
-carboline derivatives 19aeea
a
FTr is a fluorous trityl group generated from 7.
Table 5
Comparison of FSP (or the MR-FPS resin) with solid-phase, liquid-phase, and fluorous silica gels
No
Function
Fluorous-solid phase (FSP)
or MR-FPS resin
Solid-phase
Liquid-phase
Fluorous SiO
2
1
2
3
Reactivity
Solvent
Association state
High (rapid reaction)
Not limited
Loosely bound on or partially
released from the resin surface
Easy: direct analysis with TLC, NMR etc.
Low (needs long time)
Limited
Covalently bonded
High (rapid reaction)
Not limited
Dissolved
3
4
Reaction Monitoring
Not easy
Easy: direct analysis
with TLC, NMR etc.
Not easy: requires time
and effort
Separation of the product
Easy: addition of work-up solvent
followed by filtration
Easy: filtration
(Distillation, recrystallization,
chromatography)
Widely used
5
6
7
Application
Repetitive use of fluorous catalyst,
sequential reactions, solid extraction
High tolerance against NaOH, NaOEt,
Sequential reactions
Solid extraction
Chemical tolerance
Recyclability
Decomposed by NaOH
N(Et)
High
3 2 4
, TFA, H SO
Difficult
4
8
70 MHz)
d
ꢂ126.1 (s, 4 F), ꢂ123.4 (s, 4 F), ꢂ122.7 (s, 4 F), ꢂ121.9 (s,
4H), 7.1e7.2 (m, 13H); 13C NMR (125 MHz, CDCl
127.7, 127.8, 127.9, 128.3, 129.6, 130.1, 138.8, 143.8; F NMR (CDCl
470 MHz)
3
) d 26.0, 32.8, 112.3,
19
F), ꢂ121.6 (s, 4 F), ꢂ114.6 (s, 4 F), ꢂ80.8 (s, 6 F); MS (FAB) m/z 1135
3
,
þ
þ
þ
[
C
MꢂOH] ; HRMS (ESI ) found 1175.10046 [MþNa] calcd for
d
ꢂ126.6 (s, 4 F), ꢂ124.0 (s, 4 F), ꢂ123.2 (s, 4 F), ꢂ122.4 (s,
þ
H
39 22
F34NaO 1175.10254.
8 F), ꢂ122.2 (s, 4 F), ꢂ115.1 (s, 4 F), ꢂ81.3 (s, 6 F); MS (FAB) m/z 1135
þ
[
MꢂCl] .
0
.2.8. Procedure for the synthesis of 4,4 -bis((1H,1H,2H,2H)-per-
4
fluorodecyl)trityl chloride (7). A solution of 11 (200 mg, 0.17 mmol)
in acetyl chloride (0.67 mL) was stirred at 65 C for 3 h. After the
4.2.9. Fluorous liquid-phase synthesis of
13e16
b
-carboline derivatives
ꢁ
reaction, the solution was evaporated under reduced pressure. The
crude product was purified by recrystallization from acetyl chlo-
ride/MeCN afforded 7 (159 mg, 80% yield) as a white solid; mp
0
4
.2.9.1. Procedure for the synthesis of 3-(4,4 -(4-(1H,1H,2H,2H)-
perfluorodecyl)trity)amino-b-carboline (13a). Compound 7 (410 mg,
.35 mmol) was added to a solution of 12 (50 mg, 0.27 mmol) in
THF (15 mL). The mixture was stirred for 1 h at room temperature
0
ꢁ
1
1
34.0e135.7 C. H NMR (500 MHz, CDCl ) d 2.32 (m, 4H), 2.86 (m,
3

5010
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
and MeOH was added to quench the reaction. The mixture was
extracted with ether and dried over anhydrous Na SO , and evap-
99.6, 110.6, 120.1, 122.0, 123.0, 129.2, 130.0, 133.0, 134.3, 143.9, 153.6,
þ
2
4
174.3; MS (FAB) m/z 298 [MþH] ; HRMS (FAB) found 298.1671
orated under reduced pressure. The crude product was purified by
column chromatography on silica gel (hexane/AcOEt¼4/1) afforded
[MþH]þ calcd for C16
5
H20ON 298.1668.
ꢁ
1
1
3a (349 mg, 98% yield) as a yellow solid; mp 92.6e93.5 C. H NMR
4.2.10. Fluorous solid-phase (FSP) synthesis of
b
-carboline derivatives
(
1
(
1
300 MHz, CDCl
H) 7.37 (m, 16H), 7.62 (s, 1H), 7.931 (s, 1H), 8.32 (s, 1H); C NMR
75 MHz, CDCl 25.9, 32.6, 70.7, 99.2, 111.2, 119.1, 121.5, 126.9,
3
)
d
2.33 (m, 4H), 2.84 (m, 4H), 6.00 (s, 1H), 6.41 (s,
14a, 15a, and 16
13
0
4.2.10.1. Procedure for the synthesis of methyl 3-(3-(4,4 -(4-
3
) d
(
1H,1H,2H,2H)-perfluorodecyl)trityl)amino-9H-pyrido[3,4-b]indol-9-
yl)propanoate (14a). To a suspension of MR-FPS-supported 13a
500 mg, 0.020 mmol) in THF (2 mL), sodium ethoxide (10 mg,
19
27.8, 128.3, 129.1, 130.4, 131.4, 137.6, 141.6, 143.9, 145.2, 151.1;
F
NMR (CDCl
3
, 470 MHz)
d-126.7 (s, 4 F), ꢂ123.9 (s, 4 F), ꢂ123.2 (s, 4
(
F), ꢂ122.4 (s, 8 F), ꢂ122.2 (s, 4 F), ꢂ115.1 (s, 4 F), ꢂ81.4 (s, 6 F); MS
0
1
.14 mmol) was added. Then, the reaction mixture was shaken for
h at room temperature, and methyl acrylate (0.13 mL, 1.4 mmol)
þ
þ
þ
(
FAB) m/z 1318 [MþH] ; HRMS (ESI ) found 1318.18723 [MþH]
þ
calcd for C50
H
30
34
F N
3
1318.18913.
was added dropwise. After the reaction completed, toluene (5 mL)
was added, and the mixture was shaken for 30 min at room tem-
perature. The resin was filtrated and dried in vacuo. Methanol was
added to the dry resin to extract the crude product. The filtrate was
evaporated under reduced pressure to obtain the crude product,
which was purified by column chromatography on silica gel (hex-
ane/AcOEt¼3/2) to afford 14a (26 mg, 93% yield).
0
4
.2.9.2. Procedure for the synthesis of methyl 3-(3-(4,4 -(4-
(
1H,1H,2H,2H)-perfluorodecyl)trityl)amino-9H-pyrido[3,4-b]indol-9-
yl)propanoate (14a). Sodium ethoxide (18 mg, 0.26 mmol) was
added to a solution of 13a (340 mg, 0.26 mmol) in THF (10 mL). The
mixture was stirred for 20 min at rt and methyl acrylate (0.24 mL,
2
.6 mmol) was added dropwise. The mixture was stirred for 2 h at
room temperature. After the reaction, the solution was evaporated
under reduced pressure. The residue was extracted with ethyl ac-
etate and dried over anhydrous Na SO , and evaporated under re-
2 4
0
4
.2.10.2. Procedure for the synthesis of 3-(3-(4,4 -(4-
(
1H,1H,2H,2H)-perfluorodecyl)trityl)amino-9H-pyrido[3,4-b]indol-9-
yl)-N-(2-aminoethyl)propanamide (15a). The MR-FPS-supported
4a (500 mg, 0.019 mmol) was added to ethylenediamine
1.5 mL, excess), and the mixture was refluxed for 3 days. After the
reaction completed, toluene (5 mL) was added to the mixture and
shaken for 30 min at room temperature. The resin was filtrated and
dried in vacuo. Methanol was added to the dry resin to extract the
crude product. The filtrate was evaporated under reduced pressure
to obtain the crude product, which was purified by column chro-
matography on NH silica gel (AcOEt/MeOH¼9/1) to afford 15a
duced pressure. The crude product was purified by column
chromatography on silica gel (hexane/AcOEt¼3/2) afforded 14a
1
(
ꢁ
1
(
(
339 mg, 93% yield) as a yellow solid; mp 102.9e103.4 C. H NMR
3
300 MHz, CDCl ) d 2.2e2.4 (m, 4H), 2.7e2.9 (m, 4H), 3.42 (t,
J¼6.6 Hz, 2H), 3.57 (s, 3H), 4.42 (m, 2H), 6.47 (s, 1H), 7.10 (m, 5H),
1
3
7
(
1
1
.15e7.38 (m, 10H), 7.50 (d, J¼7.5 Hz, 1H), 8.18 (s, 1H); C NMR
75 MHz, CDCl 25.9, 33.4, 51.7, 51.9, 70.0, 99.1, 110.3, 118.4, 121.3,
21.7, 125.2, 126.2, 127.8, 127.9, 128.4, 129.1, 137.6, 141.7, 143.8, 145.2,
51.0, 171.6; 19F NMR (CDCl
, 470 MHz)
3
) d
3
d
ꢂ126.7 (s, 4 F), ꢂ123.9 (s, 4
(
23 mg, 84% yield).
F), ꢂ123.2 (s, 4 F), ꢂ122.4 (s, 8 F), ꢂ122.2 (s, 4 F), ꢂ115.1 (s, 4 F),
þ
ꢂ81.4 (s, 6 F); MS (FAB) m/z 1404 [MþH] .
4
.2.10.3. Procedure for the synthesis of 3-(3-amino-9H-pyrido
3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide (16). A solution of
compound 15a (20 mg, 0.014 mmol) in a mixture of CH Cl and
trifluoroacetic acid (5 mL of a 9:1 mixture) was stirred at room
temperature for 1 min and then neutralized with aqueous Na CO
The solution was washed with CHCl and the water layer was
[
0
4
.2.9.3. Procedure for the synthesis of 3-(3-(4,4 -(4-
2
2
(
1H,1H,2H,2H)-perfluorodecyl)trityl)amino-9H-pyrido[3,4-b]indol-9-
yl)-N-(2-aminoethyl)propanamide (15a). A solution of 14a (330 mg,
.24 mmol) in ethylenediamine (11 mL, excess) was stirred under
2
3
.
0
3
reflux for 3 days. After the reaction, the solution was evaporated
under reduced pressure. The crude product was purified by column
chromatography on NH silica gel (AcOEt/MeOH¼9/1) afforded 15a
evaporated to dryness under reduced pressure. The crude product
was purified by column chromatography on ODS silica gel (water/
MeOH¼10/1) and NH silica gel (AcOEt/MeOH¼3/2), to afford pure
ꢁ
1
(
(
309 mg, 90% yield) as a yellow solid; mp 89.4e90.2 C. H NMR
16 (4 mg, 84% yield).
300 MHz, CDCl
3
)
d
2.29 (m, 4H), 2.59 (t, J¼7.5 Hz, 2H), 2.83 (m, 4H),
2
.88 (t, J¼6.6 Hz, 2H), 3.16 (t, J¼7.5 Hz, 2H), 4.50 (t, J¼6.6 Hz, 2H),
4.2.11. Solid-phase synthesis of
b
-carboline derivatives 13be15b and
13
7
.36 (m, 16H), 7.62 (s, 1H), 8.31 (s, 1H); C NMR (75 MHz, CDCl
25.7, 32.5, 36.4, 41.0, 50.6, 51.0, 69.8, 99.0, 110.1, 117.9, 120.7, 121.2,
24.9, 126.0, 127.2, 127.6, 128.0, 128.9, 137.1, 141.2, 143.2, 144.9,
50.5, 170.8; 19F NMR (470 MHz, CDCl
3
)
16
d
4
.2.11.1. Procedure for the synthesis of 3-amino- -carboline
b
1
1
loaded on 2-chlorotrityl resin at the 3-amino nitrogen atom 13b. 2-
Chlorotrityl chloride resin (140 mg, 0.17 mmol; loading 1.3 mmol/
g) was swollen in DMF (1.0 mL). Compound 12 (100 mg, 0.55 mmol)
was added to the supension of the resin. After the reaction mixture
was shaken for 1 h at room temperature, the resin was filtrated and
3
)
d
ꢂ126.0 (4F), ꢂ123.4 (4F),
ꢂ122.7 (4F), ꢂ121.8 (12F), ꢂ114.6 (4F), ꢂ80.7 (6F); MS (FAB) m/z
þ
1
432 [MþH] .
4.2.9.4. Procedure for the synthesis of 3-(3-amino-9H-pyrido[3,4-
successively washed with DMF (3ꢀ2 mL), THF (3ꢀ2 mL), CHCl
3
b]indol-9-yl)-N-(2-aminoethyl)propanamide (16). A solution of
compound 15a (300 mg, 0.21 mmol) in a mixture of dichloro-
methane and trifluoroacetic acid (5 mL of a 9:1 mixture) was stirred
at room temperature for 1 min and then made alkaline with
(
3ꢀ2 mL) and MeOH (3ꢀ2 mL). And then, the resin was dried in
vacuo. The corresponding loaded resin 13b exhibited the IR ab-
ꢂ1
sorption band at 3407 cm for the NH streching.
2 3 3
aqueous Na CO . The solution was extracted with CHCl and the
4
.2.11.2. Procedure for the synthesis of methyl 3-(3-amino-9H-
combined organic layer was evaporated to dryness under reduced
pressure. The crude product was purified by column chromatog-
raphy on ODS (water/MeOH¼9/1) and NH silica gel (AcOEt/
MeOH¼3/2), to afford pure 16 (52 mg, 84% yield) as a yellow solid;
pyrido[3,4-b]indol-9-yl)propanoate loaded on 2-chlorotrityl resin at
the 3-amino nitrogen atom 14b. Resin 13b(140 mg, 0.17 mmol;
loading 1.3 mmol/g) was swollen in THF (1.0 mL). Sodium ethoxide
(
58 mg, 0.85 mmol) was added to the suspension of the resin. After
ꢁ
1
mp 178.0e178.5 C. H NMR (500 MHz, CD
3
OD)
d
2.59 (t, J¼6.5 Hz,
the reaction mixture was shaken for 1 h at room temperature,
methyl acrylate (0.77 mL, 8.5 mmol) was added dropwise. When
the reaction was completed, the resin was filtrated and successively
2
2
1
H), 2.70 (t, J¼6.5 Hz, 2H), 3.15 (t, J¼6.5 Hz, 2H), 4.62 (t, J¼6.5 Hz,
H), 7.16 (t, J¼7.5 Hz,1H), 7.27 (s, 1H), 7.51 (m, 2H), 8.02 (d, J¼7.5 Hz,
H), 8.34 (s, 1H); 13C NMR (125 MHz, CD
OD) 36.4, 40.5, 40.7, 41.0,
3
d

K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
5011
washed with DMF (3ꢀ2 mL), THF (3ꢀ2 mL), CHCl
3
(3ꢀ2 mL) and
J¼7.5 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H), 7.22e7.18 (m, 10H), 7.45 (t,
J¼7.5 Hz, 5H), 7.62 (d, J¼7.0 Hz, 1H), 7.74 (d, J¼7.0 Hz, 1H), 8.34 (s,
MeOH (3ꢀ2 mL). And then, the resin was dried in vacuo. The cor-
13
responding loaded resin 14b exhibited the IR absorption band at
3
1H); C NMR (125 MHz, CDCl ) d 33.3, 38.8, 51.8, 71.5, 98.7, 108.9,
ꢂ1
1
737 cm for the >C]O streching of the ester group.
118.6, 121.2, 121.6, 125.5, 126.7, 127.97, 128.0, 128.4, 128.7, 128.80,
28.84, 130.6, 131.1, 132.0, 132.1, 132.96, 133.03, 134.5, 134.6, 140.0,
1
þ
þ
4.2.11.3. Procedure for the synthesis of 3-(3-amino-9H-pyrido
141.5, 144.6, 150.8, 171.5; MS (FAB) m/z 546 [MþH] ; MS (ESI )
found 546.19455 [MþH]þ calcd for C34
H29ClN
O
þ
546.19483.
[
3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide loaded on 2-
3
2
chlorotrityl resin at the 3-amino nitrogen atom 15b. To a solution
of pyridine and ethylenediamine (2.5 mL of a 1:4 mixture) was
added the resin 14b (140 mg, 0.17 mmol; loading 1.3 mmol/g). The
reaction mixture was reflux for 4 days. After the reaction com-
pleted, the resin was filtrated and successively washed with DMF
4.2.12.3. Procedure for the synthesis of 3-(3-(2-chlorotrityl)
amino-9H-pyrido[3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide
(15c). A solution of 14c (60 mg, 0.11 mmol) in ethylenediamine
(5.0 mL, excess) was stirred under reflux for 3 days. After the re-
action completed, the solution was evaporated under reduced
pressure. The crude product was purified by column chromatog-
raphy on NH silica gel (AcOEt/MeOH¼10/1) to afford 15c (54 mg,
(
3ꢀ2 mL), THF (3ꢀ2 mL), CHCl (3ꢀ2 mL) and MeOH (3ꢀ2 mL), and
3
dried under reduced pressure. An absorption band for the >C]O
ꢂ1
stretching of the amide group appeared at 1660 cm in stead of
ꢂ1
ꢁ
1
the ester absorption band at 1737 cm in the microscope ATR
85% yield) as a yellow solid; mp 178.2e178.5 C; H NMR (500 MHz,
CDCl
spectrum of the corresponding loaded resin 15b.
3
)
d
2.45 (t, 2H, J¼7.0 Hz), 2.63 (t, 2H, J¼7.5 Hz), 3.46 (t, 2H,
J¼7.0 Hz), 4.57 (t, 2H, J¼7.5 Hz), 6.30 (s, 1H), 6.49 (s, 1H), 7.03 (t, 1H,
4
.2.11.4. Procedure for the synthesis of 3-(3-amino-9H-pyrido
3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide (16); cleavage of
the resin 15b. The resin 15b (140 mg, 0.17 mmol; loading 1.3 mmol/
g) was swollen in CH Cl (1 mL), and then trifluoroacetic acid
1 mL) was added to the suspension of the resin. After the reaction
mixture was shaken for 1 h at room temperature, the resin was
J¼6.5 Hz), 7.15 (t, 2H, J¼6.5 Hz), 7.26 (m, 10H) 7.45 (m, 4H), 7.62 (d,
1
3
[
1H, J¼6.5 Hz) 7.75 (d, 1H, J¼6.5 Hz), 8.20 (s, 1H), 8.36 (s, 1H);
C
3
NMR (125 MHz, CDCl ) d 36.0, 39.7, 40.7, 41.9, 71.5, 98.6,101.8,109.7,
2
2
118.6, 121.0, 121.5, 125.6, 126.4, 128.0, 128.2, 128.4, 128.8, 129.1,
þ
(
131.2, 132.1, 140.0, 141.7, 144.6, 150.9, 170.5; MS (FAB) m/z 573 [M] ;
þ
þ
HRMS (FAB) found 573.1804 [M] calcd for C35H32ClN O 573.1810.
5
filtrated and successively washed with CH
trate was made alkaline with aqueous Na
was extracted with CHCl
evaporated under reduced pressure. The obtained crude product
was purified by ODS (MeOH/H
O¼1/10) and NH silica gel column
2
Cl
CO
2
and MeOH. The fil-
. The aqueous layer
2
3
4.2.12.4. Procedure for the synthesis of 3-(3-amino-9H-pyrido
[3,4-b]indol-9-yl)-N-(2-aminoethyl)propanamide (16). A solution of
compound 15c (80 mg, 0.14 mmol) in a mixture of dichloromethane
and trifluoroacetic acid (5 mL of a 9:1 mixture) was stirred at room
temperature for 1 min and then made alkaline with aqueous
3
, and the combined organic layer was
2
chromatography (AcOEt/MeOH¼10/1) to afford pure 16 (39 mg,
7
7% yield).
2 3 3
Na CO . The solution was extracted with CHCl and the organic
layer was evaporated under reduced pressure. The crude product
was purified by column chromatography on ODS (water/
MeOH¼10/1) and NH silica gel (AcOEt/MeOH¼10/1) to afford 16
4
.2.12. Liquid-phase synthesis of b-carboline derivatives 13ce15c
and 16
(
22 mg, 54% yield) as a yellow solid.
4.2.12.1. Procedure for the synthesis of 3-(2-chlorotrityl)amino-b-
carboline (13c). 2-Chlorotrityl chloride (50 mg, 0.21 mmol) was
added to a solution of 12 in DMF (2.0 mL). The mixture was stirred
for 1 h at room temperature and MeOH was added to quench the
4
.2.13. Procedure for the synthesis of 3-(3-amino-9H-pyrido[3,4-b]
indol-9-yl)-N-(2-(3-methyl-3-nitrosoureido)ethyl)propanamide
6). A solution of compound 16 (50.3 mg, 0.17 mmol), p-nitro-
(
reaction. The mixture was extracted with CHCl
anhydrous Na SO , and evaporated under reduced pressure. The
crude product was purified by column chromatography on silica gel
hexane/AcOEt¼4/1) to afforded 13c (79 mg, 82% yield) as a yellow
3
and dried over
phenyl-N-methyl-N-nitrosocarbamate (17) (47 mg, 0.21 mmol) and
N,N-diidopropylethylamine (0.25 mL, 1.30 mmol) in MeOH was
stirred at rt for 2 h, and then evaporated under reduced pressure.
The residue was solved in MeOH (18.0 mL) and poured on Amberlist
A-21. After agitating for 5 min, the mixture was filtered. Then the
filtrate was evaporated under reduced pressure to give the crude
product, which was purified by column chromatography on NH
silica (AcOEt/MeOH¼1/1) to afford 6 (63 mg, 79% yield) as a yellow
2
4
(
ꢁ
1
solid; mp 141.0e141.2 C. H NMR (500 MHz, CDCl
.50 (s, 1H), 7.04 (t, J¼7.0 Hz, 1H), 7.10e7.13 (m, 1H), 7.24 (m, 10H),
.37 (t, J¼7.0 Hz, 4H), 7.45 (d, J¼7.5 Hz, 1H), 7.63 (d, J¼8.0 Hz, 1H),
3
) d 6.29 (1H, s),
6
7
1
3
7
.74 (d, J¼8.0 Hz, 1H), 8.01 (s, 1H), 8.33 (s, 1H); C NMR (125 MHz,
DMSO-d 71.6, 98.7, 111.2, 118.9, 121.4, 121.5, 125.5, 126.7, 128.0,
28.4, 128.8, 130.6, 130.8, 131.0, 132.7, 133.0, 134.6, 140.0, 141.5,
6
) d
ꢁ
1
2
solid; mp 271.1e272.4 C. H NMR (D O, 500 MHz) d 2.64 (t,
1
þ
þ
J¼6.5 Hz, 2H), 2.97 (s, 3H), 3.19 (m, 4H), 4.54 (t, J¼6.5 Hz, 2H), 7.20
1
44.7, 150.8; MS (FAB) m/z 459 [M] ; HRMS (ESI ) found 460.15548
þ
þ
(
1
t, J¼8.0 Hz, 1H), 7.47 (s, 1H), 7.50 (d, J¼8.0 Hz 1H), 7.64 (t, J¼8.0 Hz,
[MþH] calcd for C30
H
23ClN
3
460.15805.
þ
H), 8.07 (d, J¼8.0 Hz, 1H), 8.26 (s, 1H); MS (FAB) m/z 384 [MþH] ;
HRMS
C
(FAB)
found
384.1777
[MþH]þ
calcd
for
4
.2.12.2. Procedure for the synthesis of methyl 3-(3-(2-
þ
18
H
22
O
3
N
7
384.1772.
chlorotrityl)amino-9H-pyrido[3,4-b]indol-9-yl)propanoate
14c). Sodium ethoxide (15 mg, 0.22 mmol) was added to a solu-
(
4
.2.14. General procedure for the synthesis of 3-amino-9-benzyl-
carboline derivatives (19aee). To a mixture of MR-FPS-supported
5a (500 mg, 0.020 mmol) in THF (2 mL) was added sodium eth-
b-
tion of 13c (100 mg, 0.22 mmol) in THF (5 mL). The mixture was
stirred for 20 min at room temperature and methyl acrylate
1
(
0.20 mL, 2.20 mmol) was added dropwise. The mixture was stirred
oxide (10 mg, 0.14 mmol). After the reaction mixture was shaken
for 1 h at room temperature, 4-substituted benzyl bromide 18
for 2 h at room temperature. After the reaction completed, the
solution was evaporated under reduced pressure. The residure was
extracted with ethyl acetate and dried over anhydrous Na SO , and
2 4
(0.020 mmol) was added dropwise, and then stirred at room
temperature for 3 days. After the reaction completed, toluene was
added to the mixture and was shaken for 30 min at room tem-
perature. The resin was filtrated, and then dried in vacuo. Methanol
was added to the dry resin to extract the crude product. The mix-
ture was filtrated, and the methanolic filtrate was evaporated under
reduced pressure to dryness. The thus-obtained crude product was
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel (hexane/AcOEt¼9/1)
afforded 14c (94 mg, 78% yield) as
a yellow solid; mp
ꢁ
1
106.3e107.0 C. H NMR (500 MHz, CDCl
3
)
d
2.78 (t, J¼7.0 Hz, 2H),
3
.59 (s, 3H), 4.48 (t, J¼7.0 Hz, 2H), 6.31 (s, 1H), 6.51 (s, 1H), 7.04 (t,

5012
K. Suzuki et al. / Tetrahedron 71 (2015) 4999e5012
purified by column chromatography on silica gel (chloroform) to
afford 19aee.
Supplementary data
Supplementary data (Copies of the H NMR, 13C NMR, MS, and IR
spectra for key intermediates and final products.) related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2015.05.072.
1
4
.2.14.1. 3-Amino-9-benzyl-
b
-carboline
(19a). Yellow
solid
2.29
ꢁ
1
(
(
yield 75%); mp 201.5e201.8 C. H NMR (300 MHz, CDCl ) d
3
m, 4H), 2.59 (t, 2H), 2.83 (m, 4H), 5.36 (s, 2H), 6.52 (s, 2H), 7.03 (t,
J¼7.5 Hz, 1H), 7.22 (m, 18H), 7.40 (m, 5H), 7.65 (d, J¼7.5 Hz, 1H), 7.75
References and notes
13
(
d, J¼7.5 Hz, 1H), 8.27 (s, 1H); C NMR (75 MHz, CDCl
3
) d 25.9, 33.5,
1. For selected reviews, see: Zhang, W.; Cue, B. Green Techniques for Organic
4
6.8, 99.5, 109.5, 118.9, 121.7125.8, 126.1, 126.4, 127.9, 128.0, 128.6,
19
Synthesis and Medicinal Chemistry; John Wiley & Sons, 2012.
128.9, 132.6,133.8, 134.8; F NMR (470 MHz, CDCl
3
, CFCl
3
)
d
ꢂ126.0
2
. Horv ꢀa th, I. T.; R ꢀa bai, J. Science 1994, 266, 72e75.
(
4F), ꢂ123.4 (4F), ꢂ122.7 (4F), ꢂ121.8 (12F), ꢂ114.6 (4F), ꢂ80.7 (6F);
3. For selected reviews and recent references, see: (a) Liu, B.; Zhang, F.; Zhang, Y.;
Liu, G. Org. Biomol. Chem. 2014, 12, 1892e1896; (b) Mizuno, M.; Matsumoto, H.;
Goto, K.; Hamasaki, K. Tetrahedron Lett. 2006, 47, 8831e8835; (c) Yamada, Y. M.
A. Chem. Pharm. Bull. 2005, 53, 723e739; (d) Gladysz, J. A.; Curran, D. P. Tet-
rahedron 2002, 58, 3823e3825; (e) Curran, D. P. Synlett 2001, 1488e1496; (f)
Xiang, J.; Toyoshima, S.; Orita, A.; Otera, J. Angew. Chem., Int. Ed. 2001, 40,
þ
MS (FAB) m/z 1408 [MþH] .
4
.2.14.2. 3-Amino-9-(p-trifluoromethylbenzyl)-
b
-carboline
ꢁ
1
(
19b). Yellow solid (yield 93%); mp 184.6e185.1 C. H NMR
3
670e3672; (g) Colonna, S.; Gaggero, N.; Montanari, F.; Pozzi, G.; Quici, S. Eur. J.
Org. Chem. 2001, 181e186; (h) Horv aꢀ th, I. T. Acc. Chem. Res. 1998, 31, 641e650;
i) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174e1196; (j) Nishikido, J.;
(
3
500 MHz, CDCl ) d 2.29 (m, 4H), 2.83 (m, 4H), 4.43 (s, 2H), 6.69 (s,
1
H), 7.12 (d, J¼7.5 Hz, 1H), 7.30 (m, 21H), 7.45 (d, J¼7.5 Hz, 2H), 7.50
(
13
(
4
d, J¼7.5 Hz, 1H), 8.31 (s, 1H); C NMR (75 MHz, CDCl
3
)
d
25.7, 33.7,
Nakajima, H.; Saeki, T.; Ishii, A.; Mikami, K. Synlett 1998, 1347e1348.
. For selected reviews and recent references, see: (a) Gladysz, J. A.; Curran, D. P.;
Horvath, I. T. Handbook of Fluorous Chemistry; John Wiley & Sons, 2006; (b)
Miriyala, B. Top. Curr. Chem. 2012, 308, 105e134; (c) Fustero, S.; Acena, J. L.;
Catalan, S. Top. Curr. Chem. 2012, 308, 45e68; (d) Zhang, W. Curr. Opin. Drug
Discov. Dev. 2004, 7, 784e797; (e) Zhang, W. Chem. Rev. 2004, 104, 2531e2556;
4
1.0, 82.6, 110.1, 117.7, 126.4, 127.2, 127.7, 127.8, 128.0, 128.6, 129.0,
19
129.1, 129.5, 130.1, 131.1, 133.3, 143.8, 145.6; F NMR (470 MHz,
CDCl
3
, CFCl
3
)
d
ꢂ126.0 (4F), ꢂ123.4 (4F), ꢂ122.7 (4F), ꢂ121.8 (12F),
þ
ꢂ114.6 (4F), ꢂ80.7 (6F); MS (FAB) m/z 1476 [MþH] .
(f) Curran, D. P. Actual. Chim. 2003, 67e71; (g) Jiang, Z.-X.; Zhi, S.; Zhang, W.
Mol. Divers. 2014, 18, 203e218; (h) Montanari, V.; Kumar, K. J. Fluorine. Chem.
2006, 127, 565e570; (i) Zhang, W. Tetrahedron 2003, 59, 4475e4489; (j) Studer,
A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science
4
.2.14.3. 3-Amino-9-(p-fluorobenzyl)-b-carboline (19c). Yellow
ꢁ
1
solid (yield 90%); mp 164.2e164.8 C. H NMR (300 MHz, CDCl
2.29 (m, 4H), 2.83 (m, 4H), 4.45 (s, 2H), 7.10 (s, 1H), 7.12 (d,
J¼7.5 Hz, 1H), 7.35 (m, 21H), 7.47 (d, J¼7.5 Hz, 2H), 7.61 (d, J¼7.5 Hz,
H), 8.30 (s, 1H); 13C NMR (75 MHz, CDCl
26.1, 33.9, 41.5, 82.4,
09.3, 117.5, 126.0, 127.3, 127.7, 127.9, 128.0, 128.9, 129.2, 129.5,
3
)
1997, 275, 823e826; (k) Kore, A. R.; Yang, B.; Srinivasan, B. Tetrahedron Lett.
d
2013, 54, 6264e6266.
5. (a) Yeung, L. W. Y.; So, M. K.; Jiang, G.; Taniyasu, S.; Yamashita, N.; Song, M.; Wu,
Y.; Jingguangli; Giesy, J. P.; Guruge, K. S.; Lam, P. K. S. Environ. Sci. Technol. 2006,
1
1
1
3
)
d
40, 715e720; (b) Hu, W.; Jones, P. D.; Celius, T.; Giesy, J. P. Environ. Toxicol.
Pharmacol. 2005, 19, 57e70; (c) Martin, J. W.; Whittle, D. M.; Muir, D. C. G.;
Marbury, S. Environ. Sci. Technol. 2004, 38, 5379e5385.
19
29.8, 130.0, 131.4, 133.7, 144.7, 145.9, 171.2; F NMR (470 MHz,
CDCl
3
, CFCl
3
)
d
ꢂ126.0 (4F), ꢂ123.4 (4F), ꢂ122.7 (4F), ꢂ121.8 (12F),
6. (a) Yamazaki, O.; Hao, X.; Yoshida, A.; Nishikido, J. Tetrahedron Lett. 2003, 44,
8791e8795; (b) Hao, X.; Yoshida, A.; Nishikido, J. Tetrahedron Lett. 2004, 45,
þ
ꢂ114.6 (4F), ꢂ80.7 (6F); MS (FAB) m/z 1426 [MþH] .
781e785; (c) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837e11865; (d)
Yoshida, A.; Hao, X.; Yamazaki, O.; Nishikido, J. Molecules 2006, 11, 627e640.
7. (a) Tzschucke, C. C.; Andrushko, V.; Bannwarth, W. Eur. J. Org. Chem. 2005,
5248e5261; (b) Tzschucke, C.; Markert, C.; Glatz, H.; Bannwarth, W. Angew.
Chem., Int. Ed. 2002, 41, 4500e4503.
4
.2.14.4. 3-Amino-9-(p-methylbenzyl)-
b
-carboline (19d). Yellow
solid (yield 72%); mp 147.9e148.3 C. H NMR (300 MHz, CDCl
2.28 (m, 4H), 2.85 (m, 4H), 3.32 (s, 3H), 4.46 (s, 2H), 7.01 (s, 1H),
.16 (d, J¼7.5 Hz, 1H), 7.35 (m, 21H), 7.48 (d, J¼7.5 Hz, 2H), 7.62 (d,
ꢁ
1
3
)
d
8. Dinh, L. V.; Gladysz, J. A. Angew. Chem., Int. Ed. 2005, 44, 4095e4097; (b) Seidel,
7
F. O.; Gladysz, J. A. Adv. Synth. Catal. 2008, 350, 2443e2449.
13
9
. (a) Konakahara, T.; Okada, S.; Monde, T.; Nakayama, N.; Furuhashi, J.; Sugaya, J.
Nippon. Kagaku Kaishi (J. Chem. Soc. Jpn.) 1991, 1638e1646; (b) Monde, T.; Na-
kayama, N.; Yano, K.; Yoko, T.; Konakahara, T. J. Colloid Interface Sci. 1997, 185,
111e118; (c) Kamiusuki, T.; Monde, T.; Yano, K.; Yoko, T.; Konakahara, T. Chro-
matographia 1999, 49, 649e656; (d) Wolf, E. d; Kotena, G. v; Deelman, B.-J.
Chem. Soc. Rev. 1999, 28, 37e41; (e) Kainz, S.; Zhiyong, L.; Curran, D. P.; Leitner,
W. Synthesis 1998, 1425e1427; (f) Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am.
Chem. Soc. 2002, 124, 5774e5781; (g) Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran,
D. P. J. Am. Chem. Soc. 2002, 124, 10443e10450.
J¼7.5 Hz, 1H), 8.30 (s, 1H); C NMR (75 MHz, CDCl
3
) d 21.5, 24.2,
3
1
3.3, 44.2, 82.8, 109.3, 115.0, 126.0, 127.4, 127.6, 127.8, 128.2, 128.7,
19
29.0, 129.3, 129.8, 130.8, 131.5, 133.4, 142.6, 145.9; F NMR
470 MHz, CDCl
ꢂ121.8 (12F), ꢂ114.6 (4F), ꢂ80.7 (6F); MS (FAB) m/z 1422 [MþH] .
(
3
, CFCl
3
)
d
ꢂ126.0 (4F), ꢂ123.4 (4F), ꢂ122.7 (4F),
þ
4
.2.14.5. 3-Amino-9-(p-methoxylbenzyl)-
b
ꢁ
-carboline
1
10. Previously, we reported the development of a novel fluorous macroreticular
polystyrene (MR-FPS) and its application to the acetylation of cyclohexanol, in
which a fluorous Lewis acid immobilized on an MR-FPS resin was used as
a catalyst to give the ester in a high yield. The recovered hybrid catalyst was
used 7 times in the same reaction for a high yield (80e99%), but the yield of the
ester decreased to 48% in the absence of the MR-FPS resin as well as in the
absence of the Lewis acid catalyst (yield 13%): Konakahara, T.; Utsunomiya, M.;
Tochimoto, T.; Sakai, N.; Tokyo University of Science, JP 2008-138077A.
11. (a) Tamura, S.; Konakahara, T.; Komatsu, H.; Ozaki, T.; Ohta, Y.; Takeuchi, H. Het-
erocycles 1998, 48, 2477e2480; (b) Ikeda, R.; Iwaki, T.; Iida, T.; Okabayashi, T.; Nishi,
E.; Kurosawa, M.; Sakai, N.; Konakahara, T. Eur. J. Med. Chem. 2011, 46, 636e646; (c)
Ikeda, R.; Kurosawa, M.; Okabayashi, T.; Takei, A.; Yoshiwara, M.; Kumakura, T.;
Sakai, N.; Funatsu, O.; Morita, A.; Ikekita, M.; Nakaike, Y.;Konakahara, T. Bioorg. Med.
Chem. Lett. 2011, 21, 4784e4787; (d) Ikeda, R.; Kimura, T.; Tsutsumi, T.; Tamura, S.;
Sakai, N.; Konakahara, T. Bioorg. Med. Chem. Lett. 2012, 22, 3506e3515.
(
(
19e). Yellow solid (yield 74%); mp 155.9e156.4 C. H NMR
300 MHz, CDCl
3
) d 2.27 (m, 4H), 2.86 (m, 4H), 3.30 (s, 3H), 4.43 (s,
2
H), 7.00 (s, 1H), 7.12 (d, J¼7.5 Hz, 1H), 7.36 (m, 21H), 7.50 (d,
13
J¼7.5 Hz, 2H), 7.64 (d, J¼7.5 Hz, 1H), 8.32 (s, 1H); C NMR (75 MHz,
CDCl 24.0, 33.7, 44.4, 55.3, 82.9, 109.6, 115.7, 126.4, 127.2, 127.6,
27.9, 128.3, 128.9, 129.1, 129.6, 129.9, 130.7, 131.8, 133.9, 142.3,
45.5, 159,9; 19F NMR (470 MHz, CDCl
, CFCl
3
) d
1
1
(
3
3
)
d
ꢂ126.0 (4F), ꢂ123.4
4F), ꢂ122.7 (4F), ꢂ121.8 (12F), ꢂ114.6 (4F), ꢂ80.7 (6F); MS (FAB) m/
þ
z 1438 [MþH] .
Acknowledgements
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1
2. Moore, J. C. J. Polym. Sci. 1964, Pt. B, 835e843.
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This work was partially supported by a Grant-in-Aid for Scien-
tific Research from MEXT, a matching fund subsidy from MEXT
Sim oꢀ n-Fuentes, A.; del Pozo, C. Chem.dEur. J. 2008, 14, 7019e7029; (b) Zhang,
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2
2
004e2006 (No. 16550148), 2009e2011 (No. 21590025), and
012e2014 (No. 24590025); a Grant from the Japan Private School
Promotion Foundation (2008-2009); a Grant from the Noguchi
Fluorous Project 2002e2004. We would like to thank NEOS Co. Ltd.
for kindly providing perfluoro(2-methyl-2-pentene) and Dr.
Masashi Nojima (Research Institute for Science and Technology,
Tokyo University of Science) for determination of SEM and SEM-
EDX.
1
S.; Curran, D. P.; Nagashima, T. Org. Lett. 2005, 7, 3677e3680.
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1