Non-covalently dendronized flavins as organocatalysts for aerobic reduction of olefins

Article abstract of DOI:10.1016/j.tet.2013.07.082

A variety of association complexes of synthetic flavin with diaminopyridine and melamine receptors are described in terms of synthesis, association properties, and catalytic activities for aerobic hydrogenation of olefins. The 1:1 association complex of l

Full text of DOI:10.1016/j.tet.2013.07.082

Tetrahedron 69 (2013) 8572e8578
Contents lists available at ScienceDirect
Tetrahedron
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Non-covalently dendronized flavins as organocatalysts for aerobic
reduction of olefins
,
Yasushi Imada a b, Yudai Kugimiya a, Shotaro Iwata a, Naruyoshi Komiya a,
,
Takeshi Naota a
*
a Department of Chemistry, Graduate School of Engineering Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-8531, Japan
b Department of Chemical Science and Technology, Institute of Technology and Science, The University of Tokushima, Minamijosanjima, Tokushima 770-
8506, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2013
Received in revised form 23 July 2013
Accepted 25 July 2013
Available online 1 August 2013
A variety of association complexes of synthetic flavin with diaminopyridine and melamine receptors are
described in terms of synthesis, association properties, and catalytic activities for aerobic hydrogenation
of olefins. The 1:1 association complex of lumiflavin 1 with 2,6-bis(acylamino)pyridine receptor bearing
3,4,5-trialkoxybenzyl ether dendron unit 2 acts as an efficient supramolecular organocatalyst for the
aerobic reduction of styrene at ambient temperature under atmospheric air pressure.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Flavin
Dendrimer
Diimide
Reduction
Olefin
1. Introduction
Flavin is a model compound of various flavin-containing oxi-
dases1 and monooxygenases2 that has attracted much attention as
an environmentally benign organocatalyst for aerobic oxidative
organic transformations.3,4 Fig. 1 shows a common catalytic cycle
for aerobic oxidative transformation with flavoenzymes and syn-
thetic flavins. Reduction of oxidized flavin (Flox) to the reduced
flavin (Flred) and subsequent O2 incorporation affords 4a-hydro-
dioxyflavin (FlOOH). This species undergoes dissociation of H2O2 or
oxygen transfer to substrates (S) to regenerate Flox. Oxidases em-
ploy the first dehydrogenation process as a crucial step for oxidative
transformation.1 Simulation of these enzymatic functions with
neutral5 and cationic6 flavin catalysts provides the dehydrogenative
transformation of alcohols,5a,b,e amines,5e,6a hydrazines,6b thiols,5c,d
NADH model compounds,5d and nitroalkanes.5c Monooxygenases
promote oxygen transfer to the substrate with FlOOH.2 The aerobic
oxygenation of various heteroatom compounds including amine-
s,7a,c sulfides,7a,c and ketones7b can be also performed using this
catalytic process with the synthetic flavin catalysts under O2 at-
mospheric pressure.
Fig. 1. Catalytic cycle for oxidative transformations with flavoenzymes and synthetic
flavins.
In 2005, we reported that a series of synthetic flavins act as ef-
ficient catalysts for generation of the reducing agent diimide NH]
NH,8 using these aerobic and anaerobic processes for the oxidation
of hydrazine. This principle can be applied to provide a convenient
method for the aerobic reduction of olefins that proceeds under
mild conditions of 1 atm of molecular oxygen or air (Eq. 1).9 The
catalytic hydrogenation of olefins can be performed with a small
amount of hydrazine, 1 atm of O2 or air, and an organocatalyst, to
produce water and nitrogen gas as the sole waste products. This is
a useful alternative to transition-metal catalysts and H2 gas10 with
* Corresponding author. Tel.: þ81 6 6850 6220; e-mail address: naota@chem.-
es.osaka-u.ac.jp (T. Naota).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.082

Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
8573
respect to atom efficiency and safety. As part of our program, which
2. Results and discussion
is aimed at the formation of new organic functional materials, we
have investigated the development of efficient organocatalysts en-
hanced by molecular association and aggregation. Association
complexes of neutral flavins with 2,6-bis(acylamino)pyridines
bearing poly(benzyl ether) dendron units act as efficient supramo-
lecular organocatalysts for aerobic reduction.9c
2.1. Synthesis and characterization of association complexes
of lumiflavin
The synthetic routes to 2,6-diaminopyridines 2 and 3, and to
melamine derivatives 4 and 5 are shown in Fig. 2. Dendronized
bis(acylamino)pyridine 2 and its non-dendronized analogue 3 were
prepared by the reaction of 2,6-bis[3-(4-hydroxyphenyl)prop-
anoylamino]pyridine (9) with the corresponding dendritic and
nondendritic 3,4,5-trisubstituted benzyl halides (8 and 7), re-
spectively, in the presence of K2CO3 in acetone. N2,N4-Didecyl-
1,3,5-triazine-2,4,6-triamine (4) was prepared by the reaction of
2,4,6-trichloro-1,3,5-triazine (10) with decylamine and subsequent
amination of the resulting 6-chloro-N2,N4-didecyl-1,3,5-triazine-
2,4-diamine (11) with ammonium hydroxide in aqueous solution.
N2,N4-Didecyl-N6,N6-dihexyl-1,3,5-triazine-2,4,6-triamine (5) was
prepared by amination of 11 with dihexylamine.
The association properties of lumiflavin 1 with receptors 2e5
and 2,6-bis(acetylamino)pyridine (6) were examined in CDCl3 us-
ing 1H NMR (270 MHz) analysis. Job’s plots for the association of 1
with 4 indicated that flavin 1 forms a 1:1 complex with 2,6-
diaminopyridine receptors (Fig. 3). The association constants Ka
for complexes 1$2, 1$3, 1$4, and 1$5 in CDCl3 at 303 K were de-
termined to be 306, 341, and 387, and 30 Mꢀ1, respectively, on the
basis of the concentration dependence of the 1H NMR chemical
shift of the N(3)H proton signal (Fig. 4). The Ka values for receptors
2e4 are in the range of 306e387 Mꢀ1, which are similar to that with
less bulky receptor 6 (437 Mꢀ1).9c This result strongly suggests that
lumiflavin 1 is sufficiently associated with these receptors via
typical 3-point hydrogen bonding, as shown in Scheme 2. It is
reasonable to assume that asymmetrical didodecylaminotriazine 4
In an attempt to produce novel enzyme-like catalytic functions,
we have been investigating the association properties and catalytic
activities of new supramolecular flavin complexes with a variety of
2,6-bis(acylamino)pyridine and melamine (1,3,5-triazine-2,4,6-
triamine) receptors. This has lead to association complexes of
lumiflavin (1) with 2,6-bis(acylamino)pyridine doubly-linked to
a poly(3,4,5-trisubstituted benzyl ether)dendron unit bearing long
alkoxy chains as terminal groups (2), which are efficient supra-
molecular organocatalysts for the aerobic oxidation of olefins. The
catalytic activity is much higher than those of non-associated 1 or
its association complexes with non-dendronized receptors 3e5
(Scheme 1). This is a rare example of an organocatalyst that is en-
hanced by the hydrogen-bonding association of organic molecules,
although a variety of metallic11 and non-metallic dendrimers12
have been widely used as catalysts for organic transformation.
Rotello and colleagues reported that neutral flavins covalently
linked to a benzyl ether dendron unit at the 3-position exhibit high
catalytic activity for the aerobic oxidation of 1-benzyl-1,4-
dihydronicotinamide in water.13 The present strategy is an alter-
native, unique supramolecular approach to the development of
next-generation artificial flavoenzymes. In this paper, we describe
the full details of the synthesis and characterization of the supra-
molecular flavin complexes, with focus on the dynamic association
behavior and catalytic activity for the aerobic reduction of olefins in
air under mild conditions.
R1
R2
R3
R4
H
H
flavin cat.
1
–
2
R1
R3
+
+
H2O
N2
O
+
NH2NH2
ð1Þ
+
2
R2 R4
Scheme 1. Lumiflavin 1 and receptors 2e6.

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Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
the aromatic rings of 2, which overcomes the original deshielding
effect of the hydrogen-bonding associations. Thus, the 7-CH3 group
of associated 1 in complex 1$2 is located closely to the 3,4,5-
trialkoxyphenyl groups of 2, as shown in Scheme 2a, which in-
dicates that an enzyme-like, deep cavity for the catalytic reaction is
generated in this association complex.
Fig. 4. Change in 1H NMR chemical shift of the N(3)H proton signal for 1 as a function
of the receptor concentration;
2 (B), 3 (-), and 4 (C) in CDCl3 at 303 K.
[1]0¼2.09ꢂ10ꢀ4 (for 2), 2.11ꢂ10ꢀ4 (for 3), and 1.49ꢂ10ꢀ4 (for 4) M.
2.2. Aerobic reduction of styrene with supramolecular flavin
catalysts
The catalytic activities of various supramolecular flavin catalysts
for the reduction of styrene with NH2NH2$H2O (4 equiv) in the
presence of flavin catalyst (4 mol %) and various 2,6-
diaminopyridine receptors (20 mol %) in CHCl3 were examined at
30 ꢁC and under air at atmospheric pressure (Eq. 2). The yields of
the ethylbenzene product were periodically determined by
gaseliquid chromatography (GLC) analysis using an internal stan-
dard (decane). Fig. 6 shows the reaction profiles for the aerobic
reduction of styrene with supramolecular lumiflavin catalyst with
various dendritic and nondendritic receptors 2e5. The fla-
vinedendrimer association complex 1$2 exhibits a significant ac-
celeration effect, while the nondendritic analogue 1$3 also shows
better catalytic activity than non-associated lumiflavin 1. However,
the positive effect of receptors 2 and 3 is not observed for reduction
with receptors 4 and 5.
Fig. 2. Synthetic routes for 2e5.
1 (4 mol%), receptor (20 mol%)
Fig. 3. Continuous variation plot (Job’s plot) derived from the 1H NMR data for 1 and
receptor 4 in CDCl3 at 303 K. [1]þ[4]¼3.13ꢂ10ꢀ4 M.
NH2NH2 H2O (4 eq), CHCl3, 30oC
air (1 atm)
ð2Þ
is bound with 1 at a less bulky binding site including 2-amino and
6-decylamino groups, as depicted in Scheme 2b, because the as-
sociation at the much more bulky binding site including 2- and 4-
decylamino groups generates steric congestion, as clearly evi-
denced by the low Ka (30 Mꢀ1) of the 1$5 complex.
The present flavin-catalyzed aerobic reduction can be rational-
ized by the consecutive anaerobic and aerobic processes shown in
Scheme 3. Lumiflavin 1 undergoes nucleophilic attack and a sub-
sequent 1,3-hydrogen shift to give the reduced flavinediimide
complex 12. The active diimide in 12 reacts with styrene to afford
ethylbenzene as the product with the liberation of nitrogen gas and
reduced flavin 13. The incorporation of O2 into 13 gives 4a-hydro-
dioxyflavin 14, which performs oxygen transfer to a second
NH2NH2 molecule to afford the flavinediimide complex 15. Diimide
reduction of the second olefin with 15 regenerates 1 to complete
the catalytic cycle. Kinetic studies on the reduction of 5-decene
with catalyst 1 revealed that the nucleophilic attack of NH2NH2 to
1 is the rate-determining step for the overall process.9c
Fig. 5 shows the change in the 1H NMR chemical shift of the 7-
CH3 proton signals for 1 with variation in the concentrations of 2, 3,
and 6. Nondendritic receptors 3 and 6 exhibit a typical downfield
shift of the 7-CH3 proton signal with increase in the concentration
of the receptors. This phenomenon can be ascribed to a decrease in
the electron density of the flavin rings by the hydrogen-bonding
association. In contrast, a significant upfield shift is observed for
similar treatment with dendritic receptor 2. This unusual upfield
shift can be rationalized by assuming a remote shielding effect of

Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
8575
(a)
(b)
Scheme 2. Proposed major binding mode of the (a) 1$2 and (b) 1$4 complexes.
Fig. 5. Change in the 1H NMR chemical shift of the 7-CH3 signals for lumiflavin 1 as
a function of the receptor concentration; 2 (C), 3 (-), and 6 (:) in CDCl3 at 303 K.
[1]0¼4.00ꢂ10ꢀ4 M.
Fig. 6. Time dependence of the product yields for the flavin-catalyzed aerobic re-
duction of styrene. Conditions: styrene (6.3ꢂ10ꢀ2 M), NH2NH2$H2O (2.5ꢂ10ꢀ1 M),
flavin catalyst 1 (2.5ꢂ10ꢀ3 M), additional receptor 2e5 (1.25ꢂ10ꢀ2 M), CHCl3, 30 ꢁC.
Product yields were determined by GLC analysis based on an internal standard
(decane).
The positive effectof dendriticreceptor 2 on this catalytic reaction
can be ascribed to the acceleration of the rate-determining NH2NH2
addition, as shown in Fig. 7. Complex 1$2 could include several
NH2NH2 molecules inside the cavity of 3,4,5-trialkoxyphenyl units
through hydrogen bonding interaction. This induces a high concen-
tration of NH2NH2 around the reactive 4a-position of associated 1,
which leads to an acceleration of the second-order addition of
NH2NH2. SuchanequilibratedinclusioneadditionprocessofNH2NH2
would be much faster than the ordinary nucleophilic addition of free
NH2NH2 to non-associated 1. The slight acceleration effect of non-
dendritic receptor 3 (Fig. 6) is also attributed to the significant in-
clusionabilitiesof trialkoxyphenyl groups. Therefore, theeffectof the
dendritic receptor is the result of collaborative effects of outer and
inner alkoxides toward the capture, penetration, and holding of
NH2NH2 in the reactive cavity of the catalytically active species. In-
ternal alkenes, such as more bulky stilbene do not react under the
present conditions. This would arise from specific catalytic activities
of the dendrimereflavin supramolecular catalysts, which can dis-
criminate the bulky substrate with high shape selectivity.
Scheme 3. Mechanism for the aerobic reduction of styrene with catalyst 1.

8576
Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
fast
r.d.s.
1 2
12 2
Fig. 7. Schematic representation of the effect of NH2NH2 concentration on the rate-determining formation of flavinediimide active intermediates.
3. Conclusions
29.74, 30.3, 31.91, 31.93, 52.1, 69.2, 73.5, 108.0, 124.6, 152.8, 166.9;
MS (FAB) m/z 689 [Mþ].
We have found that the association complex of lumiflavin 1 with
dendritic 2,6-bis(acylamino)pyridine receptor 2 bearing 3,4,5-
trialkoxybenzyl dendron units act as a highly efficient supramo-
lecular organocatalyst for the aerobic reduction of olefins at am-
bient temperature under atmospheric pressure. Systematic studies
on the association properties and catalytic effects of various re-
ceptors revealed that 3,4,5-tribenzyloxy unit and its dendritic
structure is the key to enhancing catalytic activity. This is a rare case
of a supramolecular organocatalyst that provides significant en-
hancement of the catalytic activity by association with enzyme-like
receptors bearing high inclusion properties.
4.2.2. Preparation of 3,4,5-tridodecyloxybenzyl alcohol.14 A mixture
of methyl 3,4,5-tridodecyloxybenzoate (6.15 g, 8.92 mmol) and
LiAlH4 (0.406 g, 10.7 mmol) was stirred in dry THF (20 mL) for 1 h at
room temperature. After the reaction was quenched with excess
Na2SO4$10H2O, the resulting mixture was filtered, dried over
MgSO4, and evaporated under reduced pressure to give the product
alcohol (5.49 g, 93%) as a colorless solid. 1H NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 9H, CH3), 1.17e1.39 (m, 48H), 1.39e1.54 (m, 6H),
1.69e1.84 (m, 6H, eOCH2CH2e), 3.93 (t, J¼6.6 Hz, 2H, eOCH2e),
3.97 (t, J¼6.6 Hz, 4H, eOCH2e), 4.59 (s, 2H, CH2OH), 6.56 (s, 2H,
ArH); 13C NMR (68 MHz, CDCl3)
d 14.1, 22.7, 26.09, 26.13, 29.35,
4. Experimental section
4.1. General
29.38, 29.41, 29.61, 29.65, 29.69, 29.72, 29.74, 30.32, 31.91, 31.93,
65.7, 69.1, 73.4, 105.4, 136.0, 137.6, 153.3.
4.2.3. Preparation of 3,4,5-tridodecyloxybenzyl chloride (7).14
A
NMR spectra were obtained on Jeol JNM-GSX270 and Varian
Unity-Inova 500 spectrometers. IR spectra were recorded on
a Bruker EQUINOX 55/s. Mass spectra were obtained on a Jeol JMS-
DX303HF mass spectrometer. Elemental analyses were carried out
on a J-Science Lab JM10 micro corder. GLC analyses were conducted
on a Shimadzu GC-18A using a DB-1 glass capillary column
(0.25 mmꢂ30 m).
mixture of 3,4,5-tridodecyloxybenzyl alcohol (5.49 g, 8.30 mmol),
thionyl chloride (0.844 mL, 11.6 mmol), and DMF (0.10 mL) was
stirred in CH2Cl2 (55 mL) for 30 min at room temperature. Removal
of the solvent and excess thionyl chloride under reduced pressure
gave 7 (5.20 g, 92%) as a colorless solid. 1H NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 9H, CH3), 1.15e1.40 (m, 48H), 1.40e1.54 (m, 6H,
eO(CH2)2CH2e), 1.73 (tt, J¼7.2, 7.2 Hz, 2H, eOCH2CH2e), 1.79 (tt,
J¼7.2, 7.2 Hz, 4H, eOCH2CH2e), 3.94 (t, J¼7.2 Hz, 2H, eOCH2e), 3.97
4.2. Materials
(t, J¼7.2 Hz, 4H, eOCH2e), 4.51 (s, 2H, CH2Cl), 6.56 (s, 2H, ArH); 13
C
NMR (68 MHz, CDCl3)
d 14.1, 22.7, 26.08, 26.11, 29.35, 29.37, 29.39,
Commercially available methyl 3,4,5-trihydroxybenzoate, 1-
bromododecane, 2,6-diaminopyridine, 2,4,6-trichloro-1,3,5-triaz-
ine (9), decylamine, dihexylamine, and NH2NH2$H2O were used
without further purification. 7,8,10-Trimethylisoalloxazine (lumi-
flavin, 1)7c and 2,6-bis[3-(4-hydroxyphenyl)propanoylamino]pyri-
dine (9)9c were prepared according to procedures given in the
literature.
29.60, 29.63, 29.65, 29.69, 29.72, 29.74, 30.32, 31.92, 31.94, 47.0,
69.1, 73.4, 107.1, 132.3, 153.2.
4.2.4. Preparation of methyl 3,4,5-tris(3,4,5-tridodecyloxybenzyloxy)
benzoate.15 A mixture of methyl 3,4,5-trihydroxybenzoate (1.03 g,
5.59 mmol), 7 (11.4 g, 16.8 mmol), and K2CO3 (6.95 g, 50.3 mmol)
was stirred in DMF (80 mL) for 5 h at 70 ꢁC. After the reaction
mixture was poured into water, the resulting precipitate was col-
lected by filtration and subjected to column chromatography (SiO2,
CHCl3) to afford the product ester (10.7 g, 91%) as a colorless solid.
4.2.1. Preparation of methyl 3,4,5-tridodecyloxybenzoate.14 A mix-
ture of methyl 3,4,5-trihydroxybenzoate (1.84 g, 10.0 mmol), 1-
bromododecane (7.44 mL, 31.0 mmol), and K2CO3 (13.4 g,
97.0 mmol) was stirred in DMF (60 mL) for 5 h at 70 ꢁC. After the
reaction mixture was poured into water, the resulting precipitate
was collected by filtration and subjected to column chromatogra-
phy (SiO2, CHCl3) to afford the product ester (6.28 g, 91%) as a col-
1H NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 27H, CH3), 1.17e1.52
(m, 162H), 1.62e1.82 (m, 18H), 3.75 (t, J¼6.6 Hz, 4H, eOCH2e), 3.88
(s, 3H, eOCH3), 3.88 (t, J¼6.6 Hz, 10H, eOCH2e), 3.93 (t, J¼6.6 Hz,
4H, eOCH2e), 5.03 (s, 4H, ArCH2OR), 5.04 (s, 2H, ArCH2OR), 6.60 (s,
2H, ArH), 6.63 (s, 4H), 7.38 (s, 2H, ArH).
orless solid. 1H NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 9H, CH3),
1.20e1.40 (m, 48H), 1.43e1.53 (m, 6H), 1.74 (tt, J¼7.2, 7.2 Hz, 2H,
eOCH2CH2e), 1.81 (tt, J¼7.2, 7.2 Hz, 4H, eOCH2CH2e), 3.89 (s, 3H,
OCH3), 4.007 (t, J¼7.2 Hz, 4H, eOCH2e), 4.014 (t, J¼7.2 Hz, 2H,
4.2.5. Preparation of 3,4,5-tris(3,4,5-tridodecyloxybenzyloxy)benzyl
alcohol.15 A mixture of methyl 3,4,5-tris(3,4,5-tridodecyloxybenzyl-
oxy)benzoate (10.7 g, 5.06 mmol) and LiAlH4 (1.77 g, 46.6 mmol)
was stirred in dry THF (100 mL) for 2 h at room temperature. After the
reactionwas quenched by the addition of aqueous NaOH solution, the
eOCH2e), 7.25 (s, 2H, ArH); 13C NMR (68 MHz, CDCl3)
d 14.1, 22.7,
26.04, 26.07, 29.30, 29.35, 29.38, 29.55, 29.62, 29.65, 29.68, 29.71,

Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
8577
resulting mixture was filtered, dried over MgSO4, and evaporated
d 14.1, 22.68, 22.69, 29.36, 29.39, 29.4, 29.64, 29.69, 29.73, 29.75,
under reduced pressure to give the product alcohol (9.06 g, 85%) as
30.27, 30.34, 31.9, 39.6, 69.2, 70.5, 73.4, 106.16, 106.21, 109.4, 115.0,
129.3, 131.9, 132.7, 138.0, 149.2, 153.3, 157.5, 170.6; Anal. Calcd for
C109H179N3O10: C, 77.39; H, 10.67; N, 2.48. Found: C, 77.07; H, 10.81;
N, 2.37.
a colorless solid. 1H NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 27H,
CH3), 1.16e1.52 (m, 162H), 1.65e1.80 (m, 18H), 3.77 (t, J¼6.4 Hz, 4H,
eOCH2e), 3.87 (t, J¼6.4 Hz, 8H, eOCH2e), 3.88 (t, J¼6.4 Hz, 2H,
eOCH2e), 3.92 (t, J¼6.4 Hz, 4H, eOCH2e), 4.57 (s, 2H, ArCH2OR), 4.97
(s, 2H, ArCH2O), 5.01 (s, 4H, ArCH2OR), 6.61 (s, 4H, ArH), 6.63 (s, 2H),
6.66 (s, 2H, ArH); MS (FAB) m/z 2084 [Mþ].
4.2.9. Preparation of 6-chloro-N2,N4-didecyl-1,3,5-triazine-2,4-
diamine (11).16 A mixture of 10 (0.555 g, 3.01 mmol), decyl-
amine (0.944 g, 6.00 mmol), and K2CO3 (1.00 g, 7.26 mmol) was
stirred in acetone (4.1 mL) for 15 h at 60 ꢁC. The reaction mixture
was extracted with CHCl3 and water, and the organic layer was
dried over Na2SO4. After evaporation of the solvent, the residue
was washed with a small portion of acetone to afford 11
(0.629 g, 49%) as a colorless solid. IR (KBr) 3254, 3120, 2957,
4.2.6. Preparation of 3,4,5-tris(3,4,5-tridodecyloxybenzyloxy)benzyl
bromide (8). A mixture of 3,4,5-tris(3,4,5-tridodecyloxybenzyloxy)
benzyl alcohol (1.04 g, 0.499 mmol), CBr4 (0.413 g, 1.25 mmol), and
PPh3 (0.327 g, 1.25 mmol) was stirred in dry THF (8 mL) for 3.5 h at
room temperature under an argon atmosphere. The reaction mix-
ture was extracted with CH2Cl2 and water, and the organic layer
was dried over MgSO4. After evaporation of the solvent, the residue
was subjected to column chromatography (SiO2, hexane/
EtOAc¼10:1) to afford 8 (0.637 g, 60%) as a colorless solid. 1H NMR
2920, 2851, 1641, 1557, 1468, 1410, 1363, 1107 cmꢀ1
(270 MHz, CDCl3)
0.88 (t, J¼6.6 Hz, 6H, CH3), 1.19e1.41 (m,
28H), 1.50e1.63 (m, 4H, NCH2CH2e), 3.27e3.43 (m, 4H,
eCH2Ne), 5.87 (br, 2H, eNH); 13C NMR (CDCl3, 68 MHz)
14.7,
;
1H NMR
d
d
(270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 27H, CH3), 1.17e1.52 (m, 162H),
23.3, 27.4, 29.90, 29.96, 30.2, 32.5, 41.5, 165.5, 167.9; MS (FAB) m/
z 426 [(MþH)þ].
1.65e1.80 (m,18H), 3.76 (t, J¼6.4 Hz, 4H, eOCH2e), 3.88 (t, J¼6.4 Hz,
8H, eOCH2e), 3.92 (t, J¼6.4 Hz, 6H, eOCH2e), 4.38 (s, 2H, eCH2Br),
4.96 (s, 2H, 4-(ArCH2O)Ar), 4.99 (s, 4H, 3,5-(ArCH2O)2Ar), 6.60 (s,
4H, ArH), 6.67 (s, 2H, ArH), 7.26 (s, 2H, ArH); MS (FAB) m/z 2146
[Mþ].
4.2.10. Preparation of N2,N4-didecyl-1,3,5-triazine-2,4,6-triamine
(4).17 A mixture of 11 (159 mg, 0.374 mmol) and 30% ammonium
hydroxide (3 mL) was stirred in 1,4-dioxane and water (2:1 v/v,
8 mL) for 24 h at 150 ꢁC in an autoclave. After the addition of water
(150 mL), the reaction mixture was stirred for 24 h at room tem-
perature. The resulting precipitate was collected by filtration to give
4 (99.8 mg, 66%) as a colorless solid. IR (KBr) 3489, 3385, 3355,
3134, 2955, 2918, 2849, 1679, 1608, 1582, 1526, 1480, 1367 cmꢀ1; 1H
4.2.7. Preparation of 2,6-bis(3-{4-[3,4,5-tris(3,4,5-tridodecyloxyben-
zyloxy)benzyloxy]phenyl}propanoylamino)pyridine (2). A mixture
of 8 (430 mg, 0.200 mmol), 9 (38.6 mg, 0.095 mmol), and K2CO3
(79.0 mg, 0.572 mmol) was refluxed in acetone (7 mL) for 24 h.
After evaporation of the solvent, the residue was extracted with
CHCl3 and water, and the organic layer was dried over MgSO4.
Evaporation of the solvent followed by column chromatography
(Al2O3, CH2Cl2) gave 2 (351 mg, 81%) as a colorless solid. Mp
75e76 ꢁC; IR (KBr) 2954, 2924, 2851, 1681, 1591, 1505, 1465, 1436,
NMR (270 MHz, CDCl3)
d
0.88 (t, J¼6.6 Hz, 6H, CH3), 1.21e1.39 (m,
28H), 1.54 (tt, J¼6.6, 6.6 Hz, 4H, NCH2CH2e), 3.24e3.44 (m, 4H,
eCH2Ne), 4.70 (br, 4H, eNH); FABeHRMS (m/z): [MþH]þ calcd for
C23H47N6, 407.3862; found 407.3833.
1368, 1336, 1237, 1117, 996, 810 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
4.2.11. Preparation of N2,N4-didecyl-N6,N6-dihexyl-1,3,5-triazine-
2,4,6-triamine (5). A mixture of 11 (94 mg, 0.221 mmol) and
dihexylamine (0.5 mL, 2 mmol) was refluxed in THF (4 mL) for 24 h.
The reaction mixture was extracted with CHCl3 and water, and the
organic layer was dried over Na2SO4. Evaporation of the solvent
followed by column chromatography (SiO2, hexane/EtOAc¼4:1)
gave 5 (77 mg, 61%) as a colorless solid. IR (KBr) 3342, 2956, 2872,
d
0.85e0.90 (m, 54H, CH3), 1.20e1.50 (m, 324H), 1.66e1.77 (m,
36H), 2.64 (t, J¼7.7 Hz, 4H, CH2CH2CONH), 2.99 (t, J¼7.7 Hz, 4H,
CH2CH2CONH), 3.77 (t, J¼6.4 Hz, 8H), 3.84e3.90 (m, 40H), 3.92 (t,
J¼6.4 Hz, 8H), 4.89 (s, 4H), 4.97 (s, 4H), 5.00 (s, 8H), 6.61 (s, 8H,
ArH), 6.62 (s, 4H, ArH), 6.72 (s, 4H, ArH), 6.87 (d, J¼8.6 Hz, 4H,
ArH), 7.14 (d, J¼8.6 Hz, 4H, ArH), 7.52 (br, 2H, NH), 7.70 (dd, J¼8.3,
8.3 Hz, 1H, PyH), 7.90 (d, J¼8.3 Hz, 2H, PyH); 13C NMR (CDCl3,
1542, 1466, 1234, 1167, 1162, 1109, 1076 cmꢀ1
CDCl3)
1.20e1.40 (m, 40H, CH3(CH2)7e), 1.45e1.65 (m, 8H, NCH2CH2e),
3.32 (dt, J¼6.6, 6.6 Hz, 4H, eCH2Ne), 3.45 (t, J¼6.6 Hz, 4H,
eCH2Ne), 4.66 (br, 2H, eNH); MS (FAB) m/z 575 [(MþH)þ].
;
1H NMR (270 MHz,
0.88 (t, J¼6.6 Hz, 6H, CH3), 0.89 (t, J¼6.6 Hz, 6H, CH3),
125 MHz)
d
14.1, 22.7, 26.15, 26.16, 26.19, 26.20, 26.21, 29.36, 29.37,
d
29.38, 29.44, 29.48, 29.49, 29.68, 29.72, 29.75, 30.2, 30.38, 30.41,
31.9, 39.5, 68.9, 69.0, 70.2, 71.7, 73.28, 73.36, 75.2, 105.57, 105.63,
106.3, 107.7, 109.5, 115.0, 129.2, 132.1, 132.7, 132.8, 132.9, 137.7,
137.8, 138.3, 149.3, 153.00, 153.02, 153.2, 157.3, 170.4. Anal. Calcd for
C295H503N3O28: C, 78.04; H, 11.17; N, 0.93. Found: C, 77.88; H, 11.04;
N, 0.88.
4.3. Determination of binding stoichiometry for the com-
plexation of 1 with 4
4.2.8. Preparation of 2,6-bis{3-[4-(3,4,5-tridodecyloxybenzyloxy)
phenyl]propanoylamino}pyridine (3). A mixture of 7 (143 mg,
0.210 mmol), 9 (40.5 mg, 0.100 mmol), and K2CO3 (82.9 mg,
0.600 mmol) was refluxed in acetone (4.0 mL) for 24 h. After
evaporation of the solvent, the residue was extracted with CHCl3
and water, and the organic layer was dried over MgSO4. Evapora-
tion of the solvent followed by column chromatography (Al2O3,
CH2Cl2) gave 3 (74.7 mg, 44%) as a colorless solid. Mp 53e54 ꢁC; IR
(KBr) 2955, 2923, 2851, 1685, 1591, 1512, 1458, 1379, 1334, 1299,
Nine 1H NMR samples were prepared by mixing solutions of 1
(3.13ꢂ10ꢀ4 M) and 4 (3.13ꢂ10ꢀ4 M) in CDCl3 in various ratios of 0:1,
0.2:0.8, 0.3:0.7, 0.4:0.6, 0.5:0.5, 0.6:0.4, 0.7:0.3, 0.8:0.2, and 1:0. The
1H NMR (270 MHz) spectrum of each sample was recorded at 303 K.
The change in the chemical shift of N(3)H for the flavin (Dd) was
plotted against the mole fraction of the flavin [X¼[1]/([1]þ[4])], as
shown in Fig. 3. A maximum was observed at X¼0.5, which in-
dicated the formation of a 1:1 complex.
1244, 1117, 1015 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
0.88 (t,
4.4. Determination of association constants (Ka)
J¼6.9 Hz, 18H, CH3), 1.15e1.50 (m, 96H), 1.41e1.51 (m, 12H),
1.66e1.87 (m, 12H), 2.66 (t, J¼7.7 Hz, 4H, CH2CH2CONH), 2.99 (t,
J¼7.7 Hz, 4H, CH2CH2CONH), 3.94 (t, J¼6.6 Hz, 4H), 3.96 (t,
J¼6.6 Hz, 8H), 4.90 (s, 4H), 6.60 (s, 4H, ArH), 6.90 (d, J¼8.8 Hz, 4H,
ArH), 7.14 (t, J¼8.8 Hz, 4H, ArH), 7.52 (br, 2H, NH), 7.69 (dd, J¼8.3,
8.3 Hz, 1H, PyH), 7.87 (br, 2H, PyH); 13C NMR (CDCl3, 125 MHz)
The titration experiment of
1 with dendritic 2,6-diac-
ylaminopyridine receptor 2 is described as a typical example. A
solution of 1 in CDCl3 (2.09ꢂ10ꢀ4 M) was titrated in an NMR tube
with a solution of 2 in CDCl3 (0e2.53ꢂ10ꢀ2 M) at 303 K. The N(3)H
signals of 1 were monitored as a function of the concentration of 2

8578
Y. Imada et al. / Tetrahedron 69 (2013) 8572e8578
4. Organocatalysts for aerobic oxidations: (a) Review:Modern Oxidation Methods,
2nd ed.; Backvall, J.-E., Ed.; Wiley-VCH: Weinheim, Germany, 2010; (b) Ohkubo,
K.; Suga, K.; Morikawa, K.; Fukuzumi, S. J. Am. Chem. Soc. 2003, 125,
12850e12859; (c) Ohkubo, K.; Nanjo, T.; Fukuzumi, S. Bull. Chem. Soc. Jpn. 2006,
79, 1489e1500; (d) Ohkubo, K.; Suga, K.; Fukuzumi, S. Chem. Commun. 2006,
2018e2020.
to the point at which the change in chemical shift reached satu-
ration, as shown in Fig. 4. The association constant Ka, was calcu-
lated to be 306ꢃ25 Mꢀ1 (R2¼0.995) from the obtained isotherms
€
(Dd N(3)H vs [2]) by nonlinear regression analysis using Origin 8.6
based on the following equation:
5. (a) Shinkai, S.; Ishikawa, Y.; Manabe, O. Chem. Lett. 1982, 11, 809e812; (b) Fu-
kuzumi, S.; Kuroda, S.; Tanaka, T. J. Am. Chem. Soc. 1985, 107, 3020e3027; (c)
Yano, Y.; Ohshima, M.; Yatsu, I.; Sutoh, S.; Vasquez, R. E.; Kitani, A.; Sasaki, K. J.
Chem. Soc., Perkin Trans. 2 1985, 753e758; (d) Shinkai, S.; Honda, N.; Ishikawa,
V.; Manabe, O. J. Am. Chem. Soc. 1985, 107, 6286e6292; (e) Svoboda, J.;
ꢀ
Ddmax
2Ka½1ꢄ0
Ddobs
¼
1 þ Ka½2ꢄ0 þ Ka½1ꢄ0
ꢁ
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
À
Á
2
€
Schmaderer, H.; Konig, B. Chem.dEur. J. 2008, 14, 1854e1865.
ꢀ
1 þ Ka½2ꢄ þ Ka½1ꢄ 2 ꢀ 4Ka ½2ꢄ0½1ꢄ0
0
0
6. (a) Hoegy, S. E.; Mariano, P. S. Tetrahedron 1997, 53, 5027e5046; (b) Li, W.-S.;
Zhang, N.; Sayre, L. M. Tetrahedron 2001, 57, 4507e4522.
The association constants Ka for complexes 1$3, 1$4, and 1$5 in
CDCl3 at 303 K were determined to be 341ꢃ21 Mꢀ1 (R2¼0.997),
387ꢃ7 Mꢀ1 (R2¼0.998), and 30ꢃ8 Mꢀ1 (R2¼0.989), respectively, by
the same method.
7. (a) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2003, 125,
2868e2869; (b) Imada, Y.; Iida, H.; Murahashi, S.-I.; Naota, T. Angew. Chem., Int.
Ed. 2005, 44, 1704e1706; (c) Imada, Y.; Iida, H.; Ono, S.; Masui, Y.; Murahashi, S.-
I. Chem.dAsian J. 2006, 1e2, 136e147.
€
€
8. Reviews on diimide reduction: (a) Hunig, S.; Muller, H. R.; Thier, W. Angew.
Chem., Int. Ed. Engl. 1965, 4, 271e280; (b) Pasto, D. J.; Taylor, R. T. Org. React.
1991, 40, 91e155.
4.5. Aerobic reduction of styrene with supramolecular flavin
catalyst
9. (a) Imada, Y.; Iida, H.; Naota, T. J. Am. Chem. Soc. 2005, 127, 14544e14545; (b)
Imada, Y.; Kitagawa, T.; Ohno, T.; Iida, H.; Naota, T. Org. Lett. 2010, 12, 32e35;
(c) Imada, Y.; Iida, H.; Kitagawa, T.; Naota, T. Chem.dEur. J. 2011, 17,
5908e5920.
A solution of styrene (0.063 mmol), 1 (0.0025 mmol), receptors
2e5 (0.0125 mmol), NH2NH2$H2O (0.25 mmol), and decane (in-
ternal standard) was stirred in CH3CN (0.4 mL) at 30 ꢁC in a sealed
tube containing 3.14 mL of air. The yields of ethylbenzene were
determined by GLC analysis using an internal standard. The re-
action profiles are shown in Fig. 6.
10. (a) Chaloner, P. A.; Esteruelas, M. A.; Jo, F.; Oro, L. A. Homogeneous Hydroge-
nation; Kluwer: Dordrecht; (b) Handbook of Homogeneous Hydrogenation; de
Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007; Vols. 1e3.
11. Reviews: (a) Astruc, D.; Chardac, F. Chem. Rev. 2001, 101, 2991e3023; (b) Oos-
terom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Angew. Chem.
, Int. Ed. 2001, 40, 1828e1849; (c) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.;
Yeung, L. K. Acc. Chem. Res. 2001, 34, 181e190; (d) van Heerbeek, R.; Kamer, P. C.
J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Rev. 2002, 102, 3717e3756; (e)
Chase, P. A.; Gebbink, R. J. M. K.; van Koten, G. J. Organomet. Chem. 2004, 689,
Acknowledgements
ꢀ
4016e4054; (f) Helms, B.; Frechet, J. M. J. Adv. Synth. Catal. 2006, 348,
ꢀ
1125e1148; (g) Mery, D.; Astruc, D. Coord. Chem. Rev. 2006, 250, 1965e1979; (h)
Caminade, A.-M.; Servin, P. S.; Laurent, R.; Majoral, J.-P. Chem. Soc. Rev. 2008, 37,
56e67; (i) Kirkorian, K.; Ellis, A.; Twyman, L. J. Chem. Soc. Rev. 2012, 41,
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This work was supported by Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan.
12. Review: Caminade, A.-M.; Ouali, A.; Keller, M.; Majoral, J.-P. Chem. Soc. Rev.
2012, 41, 4113e4125.
References and notes
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