Development of an Enyne Metathesis/Isomerization/Diels-Alder One-Pot Reaction for the Synthesis of a Novel Near-Infrared (NIR) Dye Core

Article abstract of DOI:10.1002/chem.201502313

N-Alkyl-N-allyl-2-alkynylaniline derivatives undergo a tandem ring-closing enyne metathesis/isomerization/Diels-Alder cycloaddition sequence in the presence of a second-generation Grubbs catalyst and dienophiles. In practice, the acyclic enyne in the pres

Full text of DOI:10.1002/chem.201502313

DOI: 10.1002/chem.201502313
Full Paper
&
Synthetic Methods
Development of an Enyne Metathesis/Isomerization/Diels–Alder
One-Pot Reaction for the Synthesis of a Novel Near-Infrared (NIR)
Dye Core
Kohei Yamashita, Yuki Fujii, Shohei Yoshioka, Hiroshi Aoyama, Hirofumi Tsujino,
Tadayuki Uno, Hiromichi Fujioka, and Mitsuhiro Arisawa*[a]
Abstract: N-Alkyl-N-allyl-2-alkynylaniline derivatives undergo
a tandem ring-closing enyne metathesis/isomerization/Diels–
Alder cycloaddition sequence in the presence of a second-
generation Grubbs catalyst and dienophiles. In practice, the
acyclic enyne in the presence of the ruthenium alkylidene
first undergoes ring-closing metathesis to generate cyclic 4-
vinyl-1,2-dihydroquinolines; following diene isomerization
and then the addition of a dienophile, these ring-closing
metathesis products are selectively converted into a 7-
methyl-4H-naphtho[3,2,1-de]quinoline-8,11-dione core. Over-
all, the reaction sequence converts simple aniline derivatives
into p-conjugated small molecules, which have characteristic
absorption in the near-infrared region, in a single operation
through three unique ruthenium-catalyzed transformations.
Introduction
New applications have recently sparked interest in near-infra-
red (NIR) dyes, and strong NIR absorption and fluorescence
emission are important and useful phenomena. Whereas fluo-
rescence is especially applicable for labeling purposes in mi-
croscopy,[1] organic molecules with eminent NIR absorption
have attracted much interest because of the wide range of ap-
plications of their optical and electronic properties.[2,3] NIR-
emitting molecules are even more appealing. Their applica-
tions include night vision, optical communication, bioimaging,
and sensing, among others.[4,5] NIR-active molecules with mini-
mal UV/Vis absorption are useful for transparent photovoltaics,
heat-block coating, optical filters, and information-security dis-
plays.[6]
The range of reported NIR dye molecular skeletons is, how-
ever, limited and the development of a novel NIR dye core
structure is highly desired. Olefin metathesis of a ruthenium
carbene catalyst (Figure 1) is a versatile carbon–carbon double
bond-forming reaction that is widely used to prepare complex
organic compounds.[7] Several reaction sequences comprising
an olefin metathesis step and subsequent nonmetathesis
transformation[8] of the newly generated carbon–carbon
double bond have been developed. For example, by conver-
sion of a Ru-carbene into a Ru-hydride in situ (Figure 1),[9]
Figure 1. Ruthenium carbene catalysts.
olefin metathesis can be coupled with hydrogenation[10] or iso-
merization.[11] The tandem transformations catalyzed by ruthe-
nium alkylidenes developed to date include olefin metathesis,
followed by cyclopropanation,[12] hydrovinylation,[13] hydroary-
lation,[14] the aza-Michael reaction,[15] the hetero-Pauson-Khand
reaction,[16] or oxidation.[17]
In our search for novel and efficient Ru-catalyzed reac-
tions,[8c,9,17d,18] we developed a one-pot ring-closing metathe-
sis/oxidation and a one-pot ring-closing metathesis/1,3-dipolar
cycloaddition to produce various 2-quinolones and isoindolo-
quinolines (Scheme 1), respectively, from N-allyl-2-alkynylaniline
derivatives.[17d,18] Considering the importance of streamlining
syntheses toward complex molecular targets, we describe
[a] K. Yamashita, Y. Fujii, S. Yoshioka, Dr. H. Aoyama, Dr. H. Tsujino,
Prof. Dr. T. Uno, Prof. Dr. H. Fujioka, Dr. M. Arisawa
Graduate School of Pharmaceutical Sciences, Osaka University
1-6 Yamada-oka, Suita, Osaka 565-0871 (Japan)
E-mail: arisaw@phs.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502313. It contains experimental proce-
dures and full characterizations of compounds.
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Scheme 1. Our previous work: ring-closing metathesis/1,3-dipolar cycloaddi-
tion one-pot reaction.
herein our novel one-pot metathesis/nonmetathesis process;
that is, a one-pot enyne metathesis/isomerization/Diels–Alder
reaction, to give 7-methyl-4H-naphtho[3,2,1-de]quinoline-8,11-
dione derivatives, which are novel NIR dyes.
Figure 2. 1H NMR spectroscopic analysis of 1a (10 mg) and Grubbs II (A,
10 mol%) in C6D6 (0.75 mL).
We envisioned the development of a one-pot enyne meta-
thesis/isomerization/Diels–Alder reaction by using N-allyl-2-al-
kynylaniline derivatives 1 (Scheme 2), which could lead to
a new solution-processable p-conjugated nitrogen-containing
heterocycle, 7-methyl-4H-naphtho[3,2,1-de]quinoline.
Through optimization of Time 1, Time 2, the number of
equivalents of 1,4-benzoquinone, and solvent concentration
(Table 1), we found that the reaction conditions given in
entry 8 was optimal. A 47% yield of 2a was obtained with tet-
rahydrofuran (THF) as a solvent (entries 8–12). Of ruthenium
carbene catalysts A–H (Figure 1), only reactions using catalyst
B and D gave 2a in 5 and 24% yields (entries 13 and 14), re-
spectively, probably due to the activity of Ru catalysts on iso-
merization. When, as a control experiment, isolated compound
I was heated in benzene at 608C for 1 h under the conditions
shown in Figure 2, only unreacted I was observed. This result
suggests that the isomerization is Ru-catalyzed. Based on the
Scheme 2. This work: enyne metathesis/isomerization/[4+2] cycloaddition
one-pot reaction.
Table 1. Optimization of enyne metathesis/isomerization/[4+2] cycloaddition one-pot
reaction.
Results and Discussion
In 1H NMR experiments, the N-allyl-N-benzyl-2-ethy-
nylaniline derivative 1a was first treated with
10 mol% A in [D6]benzene at 508C for 30 min to
form the corresponding 1,2-dihydoroquinoline deriv-
ative I. When the resulting I was further treated at
608C for 1 h, the desired isomerized product II was
formed (Figure 2). Encouraged by these results, we
continued our experiments to establish an eyene
metathesis/isomerization/[4+2] cycloaddition one-
pot reaction.
Entry “Ru”
Solvent
Time 1 Benzoquinone Time 2 Yield of
([mol%]) ([m])
[min]
[equiv]
[min]
2a [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
B (10)
E (10)
A (5)
benzene (0.01)
benzene (0.01)
benzene (0.01)
benzene (0.01)
benzene (0.01)
benzene (0.01)
benzene (0.1)
benzene (0.005)
toluene (0.005)
ClCH2CH2Cl (0.005) 60
THF (0.005) 60
1,4-dioxane (0.005) 60
THF (0.005)
THF (0.005)
THF (0.005)
THF (0.005)
10
60
60
60
60
60
60
60
60
5
5
5
5
10
3
5
5
5
5
5
5
5
5
5
5
10
10
60
120
60
60
60
60
60
60
60
60
60
60
60
60
13
18
33
31
32
15
6
38
22
9
47
46
3
24
3
After treatment of 1a with 10 mol% A in refluxing
benzene for 10 min, the corresponding compound II
formed, which, without purification, was treated with
5 equivalents of 1,4-benzoquinone to form the de-
sired Diels–Alder cycloaddition product 2a in as blue
crystals in 13% yield (Table 1, entry 1). The crystal
structure of novel compound 2a was determined by
single-crystal X-ray diffraction methods and found to
be composed of four essentially planar rings
(Figure 3).[19] This preliminary study revealed that the
proposed catalytic cascade of 1a afforded 2a via the
proposed diene intermediate II.[20]
60
60
60
60
A (20)
34
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results of the experiments shown
in entries 11, 15, and 16, it was
concluded that 10 mol% A was
necessary to produce 2a in better
yield.
Experiments to probe the sub-
strate scope of the reaction are
summarized in Table 2. Substitu-
ents on the nitrogen, which might
influence the NIR absorption or
fluorescence and will be discussed
below, were not limited to benzyl,
and these derivatives afforded the
corresponding products in 16, 65,
37, and 27% yields, respectively
(entries 2–5).
However,
there
Figure 3. X-ray structure of
2a.
seems to be an electronic effect in
Table 2. Enyne metathesis/isomerization/[4+2] cycloaddition one-pot re-
action; substituent effect on nitrogen.
Figure 4. Absorption spectrum of 2a.
Entry
Substrate
Dienophile
[5 equiv]
Yield of 2
[%]
1
R
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1a
1c
C6H5-CH2
4-Br-C6H4-CH2
4-MeO-C6H4-CH2
3,4-diMeO-C6H3-CH2
3,4,5-triMeO-C6H2-CH2
C6H5-CH2
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-naphthoquinone
1,4-naphthoquinone
2a (47)
2b (16)
2c (65)
2d (37)
2e (27)
2 f (32)
2g (34)
4-MeO-C6H4-CH2
this reaction; a bromobenzyl substituent or a 4-methoxybenzyl
substituent, with electron-withdrawing or electron-releasing
group, respectively, gave less or more corresponding product,
respectively. The N-toluenesulfonyl derivative was not convert-
ed into the corresponding tetracyclic compound, because sub-
sequent isomerization of the generated 1,2-dihydroquinoline
was problematic. Furthermore, not only 1,4-benzoquinone, but
also 1,4-naphthoquinone worked as a dienophile (entries 6–7)
in this reaction.
Figure 5. Fluorescence spectrum of 2a (420–620 nm).
Given that all compounds of type 2 were blue solids, we
then investigated the absorption and emission profile of 2a–
c and 2 f, as shown in Figures 4, 5, 6, and 7. Compound 2a
showed similar absorption spectra in all the solvents investi-
gated (Figure 4). The fluorescence intensity of 2a was higher
in MeOH or dimethyl sulfoxide (DMSO) (Figure 5). Compounds
2a–c and 2 f displayed clear absorption peaks in the NIR, with
a maximum at 675–730 nm in all solvents examined (Figure 4
and Figure 6). The fluorescent properties of 2a–c and 2 f are
shown in Figure 5 and Figure 7. The characteristic fluorescent
absorption bands of 2a–c were observed from 471 to 472 nm
Figure 6. Absorption spectrum of 2a–c and 2 f in DMSO.
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Figure 7. Fluorescence spectrum of 2a–c and 2 f in DMSO.
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Conclusion
We report the first example of a ring-closing enyne metathe-
sis/isomerization/Diels–Alder cycloaddition sequence in the
presence of a second-generation Grubbs catalyst and dieno-
philes. The obtained 7-methyl-4H-naphtho[3,2,1-de]quinoline-
8,11-dione core is a novel NIR absorption dye.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
searchfrom the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (MEXT) and ACT-C from Japan Science
and Technology Agency (JST), and Takeda Science Foundation.
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[19] CCDC 1060726 (2a) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
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[20] Although the yields are low to moderate, we could not observe recov-
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the formation of any by-products (Figure 2).
Keywords: cycloaddition · domino reactions · dyes/pigments ·
heterocycles · metathesis
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Received: June 15, 2015
Published online on October 9, 2015
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