One-pot ring-closing metathesis/1,3-dipolar cycloaddition through assisted tandem ruthenium catalysis: Synthesis of a dye with isoindolo[2,1-a]quinoline structure

Article abstract of DOI:10.1002/anie.201206765

The one-pot tandem reaction of N-alkyl-N-allyl-2-vinylaniline derivatives with benzo- or naphthoquinones and a ruthenium-alkylidene catalyst leads to isoindolo[2,1-a]quinolines in a variety of colors, which can be altered by exchanging the substituent on the core heterocycle (see scheme). This reaction offers a new synthetic method for π-conjugated small molecules from simple aniline derivatives. Copyright

Full text of DOI:10.1002/anie.201206765

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DOI: 10.1002/anie.201206765
Ruthenium Catalysis
One-Pot Ring-Closing Metathesis/1,3-Dipolar Cycloaddition through
Assisted Tandem Ruthenium Catalysis: Synthesis of a Dye with
Isoindolo[2,1-a]quinoline Structure**
Mitsuhiro Arisawa,* Yuki Fujii, Hiroshige Kato, Hayato Fukuda, Takashi Matsumoto, Mika Ito,
Hiroshi Abe, Yoshihiro Ito, and Satoshi Shuto*
Assisted tandem catalytic reactions are defined as catalyzed
reaction sequences that proceed through more than one
mechanism, but with just one precatalyst.[1] In these reactions,
the catalyst of the first cycle is transformed into the catalyst of
the second cycle by a chemical initiator, for example, an
additive that induces an organometallic transformation
in situ. Over the past decade, several reaction sequences
Figure 1. Ruthenium alkylidenes. Cy=cyclohexyl, Mes=2,4,6-trimethyl-
phenyl.
comprising an olefin-metathesis step and a subsequent non-
metathesis[2] transformation of the newly generated carbon
=
carbon bond were developed. For example, olefin metathesis
can be combined with hydrogenation[3] or isomerization[4] by
in situ conversion of a Ru–carbene into a Ru–hydride.[5]
Ruthenium–alkylidene-catalyzed tandem transformations
that were developed to date include olefin metathesis,
followed by cyclopropanation,[6] hydrovinylation,[7] hydroar-
ylation,[8] the aza-Michael reaction,[9] the hetero-Pauson–
Khand reaction,[10] or oxidation.[11]
On the other hand, [RuClCp*] and the “first generation”
Grubbs metathesis complex A (Figure 1) catalyze an azide–
alkyne cycloaddition reaction to give 1,5-substituted tria-
zoles,[12] and an intramolecular [3+2] cycloaddition of alk-5-
ynylidenecyclopropanes to give bicyclo[3.3.0]octane,[13]
respectively.
Scheme 1. One-pot RCM/oxidation reaction. Bn=benzyl.
In our search for novel and efficient Ru-catalyzed
reactions,[2c,3,11d,14] we developed a one-pot ring-closing meta-
thesis/oxidation methodology to produce various 2-quino-
lones from N-allyl-2-vinylaniline derivatives (Scheme 1).[11d]
Oxidation of the a-methylene group of amines to the
corresponding amides is very difficult.[15] The key intermedi-
ate in this reaction might be the azomethine ylide I,
equivalent to 1,2-dihydroquinoline. If the azomethine ylide
is generated as the intermediate, we envisaged 1,3-dipolar
cycloaddition of azomethine ylide from the 1,2-dihydroquino-
line, generated by a ruthenium–alkylidene-catalyzed ring-
closing metathesis (RCM) of an N-alkyl-N-allyl-2-vinylani-
line derivative as the first step in the tandem reaction, with
1,3-dipolarophile would be proceeded by the active ruthe-
nium species derived from the catalyst precursor, the
ruthenium–alkylidene catalyst.
Considering the importance of streamlining syntheses
toward complex molecular targets, we report herein a new
tandem process that combines a ruthenium-catalyzed RCM
with a ruthenium-catalyzed intermolecular 1,3-dipolar cyclo-
addition to afford an isoindolo[2,1-a]quinoline core. These
heterocycles are novel solution-processable p-conjugated
small molecules whose color can be altered dramatically by
exchanging a substituent on the core.
[*] Dr. M. Arisawa, Y. Fujii, H. Kato, Dr. H. Fukuda, Dr. T. Matsumoto,
M. Ito, Dr. H. Abe, Dr. Y. Ito, Prof. Dr. S. Shuto
Faculty of Pharmaceutical Sciences, Hokkaido University
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 (Japan)
and
Rigaku Corporation, X-ray Research Laboratory
3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666 (Japan)
and
Nano Medical Engineering Laboratory
RIKEN Advanced Science Institute
2-1, Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis” from the Ministry of Education, Culture, Sports,
Science, and Technology (Japan) (MEXT) and ACT-C from Japan
Science and Technology Agency (JST).
Our tandem-catalysis strategy was first examined using N-
allyl-N-benzyl-2-vinylaniline derivative 1a, dipolarophile 3a,
and second-generation Grubbs catalyst B under various
reaction conditions (Table 1). Compound 1a was first treated
with B (10 mol%) in benzene (reflux) for 30 min to form the
corresponding 1,2-dihydroquinoline derivative 2a.[16] When
Supporting information for this article (including experimental
procedures and full characterization of compounds) is available on
the WWW under http://dx.doi.org/10.1002/anie.201206765.
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Table 1: Ruthenium-catalyzed one-pot RCM/1,3-dipolar cycloaddition.
Table 2: Scope of ruthenium-catalyzed one-pot RCM/1,3-dipolar cyclo-
addition.
Entry
[Ru]
Solvent[a]
3a [equiv]
Yield of 4a [%][b,c]
Entry
1
R1
R2
3
4
Yield
1
2
3
4
5
6
7
8
9
B
B
B
B
B
B
B
A
C
D
benzene
benzene
benzene
benzene
benzene
toluene
toluene
benzene
benzene
benzene
2
3
4
5
10
2
10
10
10
10
39
67
82
86
95
35
82 (84)
12
13
90
[%][b,c]
1
1a Ph
Ph
3a 4a:
95 (84)
10
2
3
4
1b Me Ph
3a 4b:
3a 4c:
3a 4d:
15
[a] The same solvent was used in steps 1 and 2. [b] According to TLC
analysis, 1a was completely converted to 2a. [c] Yield in parenthesis:
both steps performed at 808C.
1c
H
Ph
H
51 (34)
the resulting 2a was treated without purification with two
equivalents of 1,4-benzoquinone 3a, the desired 1,3-dipolar
cycloaddition product 4a was formed in 39% yield (Table 1,
entry 1). This preliminary study showed that the proposed
catalytic cascade of 1a was indeed possible to afford 4a,
probably via the proposed azomethine ylide intermediate.
Increasing the number of equivalents of 3a afforded the
product in increased yield (Table 1, entries 1–5). When ten
equivalents of 3a were used, 4a was isolated in 95% yield
(Table 1, entry 5).[17,18] Moderate to good yields of 4a were
obtained with toluene as the solvent (Table 1, entries 6 and 7).
The structure of compound 4a was determined by single-
crystal X-ray diffraction (see Figure S1 in the Supporting
Information).[19]
Experiments to probe the substrate scope of the tandem
reaction are summarized in Table 2. Substituents on the
nitrogen atom or at the a position of the styrene were not
limited to phenyl, and differently substituted products were
obtained in 15, 51, 32, and 45% yield (Table 2, entries 2–5,
respectively). Furthermore, in addition to 1,4-benzoquinone,
1,4-naphthoquinone and 1,2-naphthoquinone could also be
used as 1,3-dipolarophiles in this reaction (Table 2, entries 6–
8).
Although the core structure in these compounds was the
same novel isoindolo[2,1-a]quinolone system, these com-
pounds showed a variety colors, including blue, yellow,
orange, and red (Figure 2). Hence, the absorption and
emission profiles of compounds 4a–h were investigated (see
Figures 3 and 4, and Figures S2–S4 in the Supporting
Information).
The isoindolo[2,1-a]quinolines 4b and 4h, which bear
a methyl substituent at position 4 of the quinolone, clearly
display absorption peaks in the near-infrared region with
a maximum at 657–720 nm, and the other compounds display
absorption peaks with a maximum at 447–480 nm (Figur-
es S2–S4). Figures 3 and 4, and Figures S5 and S6 in the
1d Ph
1e Ph
1a Ph
32
5
6
7
CO2Et 3a 4e:
45 (64)
Ph
3b 4 f:
79
1b Me Ph
3b 4h:
11 (9)
[a] The same solvent was used in steps 1 and 2. [b] According to TLC
analysis, 1 was completely converted to 2. [c] Yields in parenthesis: both
steps performed in toluene at 808C. Dienophiles: 3a=1,4-benzoqui-
none, 3b=1,4-naphthoquinone.
Supporting Information show the fluorescence properties of
4a–h. The characteristic fluorescence signals of compounds 4
were observed from 540 to 620 nm in chloroform. We found
that 4a–h exhibited fluorescent emissions, and studied the
emission of 4a in several different solvents (Figure 4).
Notably, these studies of 4a–h provide the first direct
experimental evidence that the isoindolo[2,1-a]quinoline
skeleton is a fluorescent chromophore.
Interestingly, the fluorescence emission enhanced in
hydrophobic solvents, such as chloroform or benzene, com-
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Figure 2. Colors of compounds 4 (solubilized in benzene, 100 mm).
Figure 3. Fluorescence spectra of compounds 4 in chloroform.
4a: 50 mm, lex =494 nm, Fmax =617 nm, f=0.017187, tf =0.61 ns;
4b: 50 mm, lex =402 nm, Fmax =529 nm, f=0.000804, tf =0.024ns;
4c: 50 mm, lex =476 nm, Fmax =612 nm, f=0.011698, tf =0.60 ns;
4d: 50 mm, lex =476 nm, Fmax =604 nm, f=0.018709, tf =0.52 ns;
4e: 50 mm, lex =471 nm, Fmax =598 nm, f=0.030312, tf =0.39 ns;
4 f: 50 mm, lex =452 nm, Fmax =549 nm, f=0.469622, tf =3.55 ns;
4h: 50 mm, lex =419 nm, Fmax =562 nm, f=0.000568, tf =0.13 ns.
Figure 4. Fluorescence spectra of 4a in various solvents.
DMSO: 50 mm, lex =474 nm, Fmax =524 nm, f=0.169758;
chloroform: 50 mm, lex =494 nm, Fmax =617 nm, f=0.017187;
acetonitrile: 50 mm, lex =477 nm, Fmax =621 nm, f=0.009385;
benzene: 50 mm, lex =480 nm, Fmax =618 nm, f=0.015255;
methanol: 50 mm, lex =484 nm, Fmax =634 nm, f=0.002867;
acetone: 50 mm, lex =473 nm, Fmax =613 nm, f=0.011969;
water: 50 mm, lex =493 nm, Fmax =621, 735 nm, f=0.002309.
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Figure 5. Fluorescence imaging of HeLa cells with probe 4a. HeLa cells were incubated with 4a (60 mm solution in Dulbecco’s Modified Eagle
Medium with 3% DMSO as cosolvent) for 30 min at 378C. Cells were fixed with formaldehyde (4%) for 15 min at room temperature, and treated
with Hoechst33342 (1 mgmLÀ1) for 10 min at room temperature to stain the DNA in the nuclei.
pared with hydrophilic solvents, such as water. This property
could be useful in sensing or imaging applications. Therefore,
we carried out investigations on cellular imaging using
compound 4a (Figure 5). HeLa cells were incubated with
probe 4a (60 mm solution in Dulbeccoꢀs Modified Eagle
Medium with 3% DMSO as cosolvent) for 30 min, treated
with Hoechst33342, which stains DNA in nuclei, and imaged
by fluorescence microscopy. The images showed that the
probe penetrated through the cell membrane and emitted
a fluorescence signal. Figure 5 shows that the probe was
mainly localized in and around the nucleus and provided
a strong fluorescence signal. These findings suggest that
compounds 4 can potentially be applied as fluorescent probes.
In summary, we demonstrated that the ruthenium–alky-
lidene catalyst B can be converted in situ into a catalyst that
affects a 1,3-dipolar cycloaddition by treatment with an 1,3-
dipolarophile.[18] The obtained isoindolo[2,1-a]quinoline skel-
eton is a novel fluorescent chromophore.
[9] S. Fustero, D. Jimꢁnez, M. Sꢂnchez-Rosellꢃ, C. del Pozo, J. Am.
Chem. Soc. 2007, 129, 6700 – 6701.
[10] D. F. Finnegan, M. L. Snapper, J. Org. Chem. 2011, 76, 3644 –
3653.
[11] a) S. Beligny, S. Eibauer, S. Maechling, S. Blechert, Angew.
Chem. 2006, 118, 1933 – 1937; Angew. Chem. Int. Ed. 2006, 45,
1900 – 1903; b) A. A. Scholte, M. H. An, M. L. Snapper, Org.
Lett. 2006, 8, 4759 – 4762; c) B. Schmidt, S. Krehl, Chem.
Commun. 2011, 47, 5879 – 5881; d) H. Kato, T. Ishigame, N.
Oshima, N. Hoshiya, K. Shimawaki, M. Arisawa, S. Shuto, Adv.
Synth. Catal. 2011, 353, 2676 – 2680.
[12] a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B.
Sharpless, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127,
15998; b) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang,
H. Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130,
8923; for a study focusing on the regioselectivity of internal
alkynes in this reaction, see also: c) M. M. Majireck, S. M.
Weinreb, J. Org. Chem. 2006, 71, 8680 – 8683; d) S. Grecian, V. V.
Fokin, Angew. Chem. 2008, 120, 8409 – 8411; Angew. Chem. Int.
Ed. 2008, 47, 8285 – 8287.
[13] F. Lꢃpez, A. Delgado, J. R. Rodrꢄguez, L. Castedo, J. L.
MascareÇas, J. Am. Chem. Soc. 2004, 126, 10262 – 10263.
[14] a) M. Arisawa, Y. Terada, M. Nakagawa, A. Nishida, Angew.
Chem. 2002, 114, 4926 – 4928; Angew. Chem. Int. Ed. 2002, 41,
4732 – 4734; b) Y. Terada, M. Arisawa, M. Nakagawa, A.
Nishida, Angew. Chem. 2004, 116, 4155 – 4159; Angew. Chem.
Int. Ed. 2004, 43, 4063 – 4067; c) K. Kajihara, M. Arisawa, S.
Shuto, J. Org. Chem. 2008, 73, 9494 – 9496; d) T. Ogawa, T.
Nakamura, T. Araki, K. Yamamoto, S. Shuto, M. Arisawa, Eur. J.
Org. Chem. 2012, 3084 – 3087.
Received: August 21, 2012
Revised: October 6, 2012
Published online: November 29, 2012
Keywords: cycloaddition · domino reactions · dyes/pigments ·
.
metathesis · ruthenium
[15] J. W. Kim, K. Yamaguchi, N. Mizuno, Angew. Chem. 2008, 120,
9389 – 9391; Angew. Chem. Int. Ed. 2008, 47, 9249 – 9251.
[16] According to TLC analysis and 1H NMR spectroscopy, this
reaction proceeded quantitatively.
[1] D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248,
2365 – 2379.
[2] For reviews, see: a) B. Alcaide, P. Almendros, Chem. Eur. J. 2003,
9, 1258 – 1262; b) B. Schmidt, Eur. J. Org. Chem. 2004, 1865 –
1880; c) M. Arisawa, Y. Terada, K. Takahashi, M. Nakagawa, A.
Nishida, Chem. Rec. 2007, 7, 238 – 253; d) B. Alcaide, P.
Almendros, A. Luna, Chem. Rev. 2009, 109, 3817 – 3858.
[3] J. Louie, C. W. Bielawski, R. H. Grubbs, J. Am. Chem. Soc. 2001,
123, 11312 – 11313.
[4] A. E. Sutton, B. A. Seigal, D. F. Finnegan, M. L. Snapper, J. Am.
Chem. Soc. 2002, 124, 13390 – 13391.
[5] M. Arisawa, Y. Terada, K. Takahashi, M. Nakagawa, A. Nishida,
J. Org. Chem. 2006, 71, 4255 – 4261.
[6] B. G. Kim, M. L. Snapper, J. Am. Chem. Soc. 2006, 128, 52 – 53.
[7] J. Gavenonis, R. V. Arroyo, M. L. Snapper, Chem. Commun.
2010, 46, 5692 – 5694.
[8] J.-R. Chen, C.-F. Li, X.-L. An, J.-J. Zhang, X.-Y. Zhu, W.-J. Xiao,
Angew. Chem. 2008, 120, 2523 – 2526; Angew. Chem. Int. Ed.
2008, 47, 2489 – 2492.
1
[17] According to TLC analysis and H NMR spectroscopy, the first
step (RCM) proceeded quantitatively, no matter what ruthe-
nium catalyst A–D was employed. Although we investigated
other reaction conditions by changing catalyst, solvent, temper-
ature, number of equivalents of the 1,3-dipolarophile, ect., the
yields of compounds 4, with exception of 4a and 4 f, were still
rather low. The control experiment, which included the removal
of the ruthenium species between steps 1 and 2 by column
chromatography on silica gel was very difficult because of the
instability of the 1,2-dihydroquinoline intermediate and the wide
polarity range of the ruthenium species.
[18] An alternative scenario is that after the ruthenium-catalyzed
RCM, a non-ruthenium-catalyzed oxidation of the RCM prod-
uct by the excess amount of quinone generates the reactive
dipolarophile, which then traps a second quinone, again in
a noncatalytic fashion. A third equivalent of the quinone would
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then be required to further oxidize the direct cycloadducts to the
observed product. According to TLC analyses of the experi-
ments shown in Table 1, entries 5 and 8–10, 1a was completely
converted to 2a in all cases, irrespective of the ruthenium
catalyst that was used. However, the yield of 4a depended
dramatically on the nature of the ruthenium catalyst (with or
without NHC ligand). Therefore, we consider that the ruthenium
species derived from the original ruthenium–carbene catalyst
plays an important role in the generation of compound 4a during
the second step of the reaction.
[19] CCDC 897064 (1a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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