One-Pot Olefin Isomerization/Aliphatic Enamine Ring-Closing Metathesis/Oxidation/1,3-Dipolar Cycloaddition for the Synthesis of Isoindolo[1,2-a]isoquinolines

Article abstract of DOI:10.1002/adsc.201500680

N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-amine derivatives undergo a one-pot olefin isomerization/aliphatic enamine ring-closing metathesis (RCM)/oxidation/1,3-dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh₃)₃, a second generation Hoveyda-Grubbs catalyst, and a 1,3-dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2-a]isoquinolines with a π-conjugated four-ring system, through three unique ruthenium-catalyzed transformations.

Full text of DOI:10.1002/adsc.201500680

UPDATES
DOI: 10.1002/adsc.201500680
One-Pot Olefin Isomerization/Aliphatic Enamine Ring-Closing
Metathesis/Oxidation/1,3-Dipolar Cycloaddition for the Synthesis
of Isoindolo[1,2-a]isoquinolines
Yuki Fujii,a,b Tsunayoshi Takehara,c Takeyuki Suzuki,c Hiromichi Fujioka,a
Satoshi Shuto,b and Mitsuhiro Arisawaa,b,*
a
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan
E-mail: arisaw@phs.osaka-u.ac.jp
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
Comprehensive Analysis Center, The Institute of Scientific and Industrial Research, Osaka University, Mihogaoka 8-1,
b
c
Ibaraki, Osaka 567-0047, Japan
Received: July 17, 2015; Revised: August 22, 2015; Published online: December 9, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500680.
Abstract:
N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-
ous publications. For example, by in situ conversion of
a Ru-carbene into a Ru-hydride,[3] olefin metathesis
can be coupled with hydrogenation[4] or isomeriza-
tion.[5] The tandem transformations catalyzed by
ruthenium alkylidenes developed to date include
olefin metathesis, followed by cyclopropanation,[6] hy-
drovinylation,[7] hydroarylation,[8] aza-Michael reac-
tion,[9] hetero-Pauson–Khand reaction,[10] and oxida-
tion.[11]
amine derivatives undergo a one-pot olefin isomeri-
zation/aliphatic enamine ring-closing metathesis
(RCM)/oxidation/1,3-dipolar
sequence with the
Ru(CO)HCl(PPh3)3, a second generation Hoveyda–
Grubbs catalyst, and a 1,3-dipolarophile. Overall, in
a single operation the reaction sequence converts
simple benzylamine derivatives into isoindolo[1,2-
cycloaddition
complex,
ruthenium
a]isoquinolines with
system, through three unique ruthenium-catalyzed
transformations.
a
p-conjugated four-ring
[RuClCp*] and “first generation” Grubbs metathe-
sis complex A can catalyze an azide-alkyne cycloaddi-
tion reaction to give 1,5-substituted triazoles[12] and
intramolecular [3+2] cycloaddition of alk-5-ynylidene-
cyclopropanes to give bicyclo[3.3.0]octanes.[13]
In our search for novel and efficient Ru-catalyzed
reactions,[2c,3,11d,14] we developed a one-pot RCM/oxi-
dation/1,3-dipolar cycloaddition to produce various
isoindolo[2,1-a]quinolines (Scheme 1) from N-allyl-2-
alkenylaniline derivatives.[15] The key intermediate in
Keywords: cycloaddition; domino reactions; hetero-
cycles; metathesis; ruthenium
Olefin metathesis using ruthenium carbene catalysts this reaction is likely to be azomethine ylide I, de-
(Figure 1) is one of the most important carbon-carbon rived from the 1,2-dihydroquinoline. Azomethine
double bond forming reactions, and has been used ylides have also recently been used in various organic
widely in the preparation of functionalized organic synthesis.[16] We therefore envisaged a similar 1,3-di-
compounds.[1] Over the past decade, Ru-catalyzed polar cycloaddition between a 1,3-dipolarophile and
olefin metathesis followed by a non-metathesis[2] azomethine ylide II, generated from a 1,2-dihydroiso-
transformation is
a typical example of assisted quinoline (Scheme 2). The enamine would be generat-
tandem catalysis, and has been the subject of numer- ed by a ruthenium hydride-catalyzed selective olefin
isomerization of the allylamine moiety of an N-alkyl-
N-(2-vinylbenzyl)prop-2-en-1-amine derivative as the
first step.[17] Subsequent ruthenium alkylidene-cata-
lyzed aliphatic enamine RCM[18] of the resulting acy-
clic enamine derivative, followed by oxidation and
1,3-dipolar cycloaddition would produce the corre-
sponding isoindolo[1,2-a]isoquinoline 2.
Considering the importance of streamlining synthe-
Figure 1. Ruthenium carbene catalysts.
ses towards complex molecular targets, we report
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Scheme 1. Our previous work: the ring-closing metathesis
(RCM)/oxidation/1,3-dipolar cycloaddition one-pot reaction.
Scheme 3. Preparation of 1.
lysts under various reaction conditions (Table 1). In
the first step, isomerization of the terminal olefin,
Ru(CO)HCl(PPh3)3 (E) was shown to be the best cat-
alyst throughout our detailed chemical experiments.
The substrate 1a was first treated with 5 mol% of E
in refluxing toluene for 5 min to form the correspond-
ing acyclic aliphatic enamine derivative. The crude
acyclic aliphatic enamine was treated with 10 mol%
of Grubbs II catalyst (B) in refluxing toluene, and ali-
phatic enamine RCM proceeded to give the corre-
sponding six-membered cyclic enamine. Subsequent
addition of 1,4-benzoquinone (10 equiv.) gave the de-
sired 1,3-dipolar cycloaddition product 2a in 76%
yield (entry 1). This preliminary study revealed that
the proposed catalytic cascade reaction of 1a indeed
occurred to afford 2a, probably via the proposed azo-
methine ylide intermediate. Changing the ruthenium
carbene catalyst to Hoveyda–Grubbs II catalyst (D)
Scheme 2. This work: the olefin isomerization/aliphatic en-
amine RCM/oxidation/1,3-dipolar cycloaddition one-pot re-
action.
herein a one-pot olefin isomerization/aliphatic enam- increased the product yield (entries 1 and 2), but cata-
ine RCM/oxidation/1,3-dipolar cycloaddition se- lysts A and C, without the nitrogen-containing hetero-
quence to afford the isoindolo[1,2-a]isoquinoline core cyclic carbene (NHC) ligand, did not work in the ali-
2.[19] These heterocycles are novel solution-process- phatic enamine RCM. When the enamine RCM and
able p-conjugated small molecules.[20]
1,3-dipolar cycloaddition were conducted at 808C or
N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-amine deriv- at reflux in toluene, 2a was isolated in 72% or 77%
atives 1 were systematically and efficiently prepared yield, respectively (entries 3 and 4). The crystal struc-
as shown in Scheme 3. Our tandem catalysis strategy ture of novel compound 2a was determined by single-
was first investigated using N-benzyl-N-(2-vinylben- crystal X-ray diffraction (Figure 2).[21]
zyl)prop-2-en-1-amine derivative 1a, benzoquinone,
Experiments to probe the substrate scope are sum-
metal hydride catalysts and ruthenium carbene cata- marized in Table 2. A range of substituents was toler-
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One-Pot Olefin Isomerization/Aliphatic Enamine Ring-Closing Metathesis
Table 1. Optimization of the one-pot olefin isomerization/aliphatic enamine RCM/oxidation/1,3-dipolar cycloaddition reac-
tion.
Aliphatic enamine RCM
Temperature [8C]
[3+2]
Temperature [8C]
Isolated Yield
[%] for 3 steps
Entry
Ru Catalyst
1
2
3
4
B
reflux
reflux
80
80
80
80
Reflux
76
81
72
77
D
D
D
reflux
ated on the nitrogen or at the a position of the sty-
rene (entries 1–5), although the aliphatic enamine
RCM of 1c, with a phenyl group at the styrene alpha
position, required 20 mol% of D and a longer reac-
tion time due to the sluggish enamine metathesis.[22]
Olefin isomerization of 1d and 1e, with ethoxycarbo-
nylmethyl on the nitrogen, required 10 mol% of E
and a longer reaction time. Furthermore, 1,4-naphtho-
quinone also worked as a 1,3-dipolarophile (entries 6–
8) in this reaction.[23]
All of the obtained isoindolo[1,2-a]isoquinolines 2
were orange- or yellow-colored solids, while isoindo-
lo[2,1-a]quinolines (Scheme 1) were red- or blue-col-
ored solids. We then investigated the absorption and
emission profiles of compounds 2a, b and d-h, as
shown in Figure 3 and in Figure S1 of the Supporting
Information. It is interesting that the characteristic
Figure 2. X-ray structure of 2a.
Table 2. Scope of the one-pot olefin isomerization/aliphatic enamine RCM/oxidation/1,3-dipolar cycloaddition reaction.
Entry
R1
R2
Dipolarophile
Product
Yield [%] for 3 steps
1
2
1a
1b
1c
1d
1e
1a
1b
1d
H
Ph
Ph
Ph
CO2Et
CO2Et
Ph
Ph
CO2Et
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-benzoquinone
1,4-naphthoquinone
1,4-naphthoquinone
1,4-naphthoquinone
2a
2b
2c
2d
2e
2f
2g
2h
81
92
8
66
57
49
62
18
Me
Ph
H
Me
H
3[a]
4[b]
5[b]
6
7
Me
H
8[b]
[a]
20 mol% of D were used and the reaction time for aliphatic enamine RCM was 24 h.
In the isomerization step (1st step), 10 mol% of E were used and the reaction time was 2 h.
[b]
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otherwise noted, at 100 or 125 MHz. Column chromatogra-
phy was performed with silica gel 60N (spherical, neutral,
63–210 mm, Kanto Chemical Co., Inc.) unless otherwise
noted. Melting points were determined on a heated plate
and are uncorrected. HR-MS (m/z) were measured using
MALDI (matrix assisted laser desorption/ionization) tech-
niques unless otherwise noted.
General Procedure for N-Allyl-(2-vinylbenzyl)amine
Derivatives (3a, 3b, and 3c)
To
a solution of the o-vinylbenzaldehyde derivative
(1.0 equiv.) and allylamine (2.0 equiv.) in CH2Cl2 (0.5M)
was added MgSO4 (2.0 equiv.) and the mixture was stirred
overnight at room temperature. The mixture was filtered
through celite and the filtrate was concentrated under
vacuum. The mixture was dissolved in MeOH (0.5M) and
the whole was cooled to 08C. To the mixture was added
NaBH4 (1.5 equiv.) and stirred for 1.5 h. The reaction was
quenched by the addition of saturated aqueous NH4Cl. Or-
ganic compounds were extracted with AcOEt. Organic
layers were washed with brine, dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The ob-
tained residue was subjected to column chromatography
(NH silica gel, hexane/AcOEt=50:1) to give the corre-
sponding 3 as an oil.
N-Allyl-(2-vinyl)benzylamine (3a):[24] Amine 3a was ob-
tained from 2-vinylbenzaldehyde[25] (1.08 g, 8.20 mmol) as
1
a pale yellow oil; yield: 1.02 g (5.91 mmol, 72%); H NMR
Figure 3. Fluorescence spectrum of
2 (450–750 nm) in
(300 MHz, CDCl3): d=7.51 (1H, dd, J=5.9, 3.0 Hz), 7.30
(1H, dd, J=5.9, 3.0 Hz), 7.26–7.22 (2H, m), 7.06 (1H, dd,
J=17.2, 11.0 Hz), 6.00–5.87 (1H, m), 5.68 (1H, dd, J=17.5,
1.4 Hz), 5.33 (1H, dd, J=11.0, 1.4 Hz), 5.20 (1H, dq, J=
17.2, 1.5 Hz), 5.12 (1H, dq, J=10.1, 1.5 Hz), 3.83 (2H, s),
3.29 (2H, dt, J=6.0, 1.5 Hz), 1.38 (1H, brs); HR-MS
(MALDI): m/z=174.12773, calcd. for C12H16N: 174.12773
[(M+H)+].
CH3CN. 2a: f=0.000511, lex =465 nm, lem =583 nm; 2b:
f=0.000335, lex =470 nm, lem =589 nm; 2d: f=0.000515,
lex =440 nm, lem =563 nm; 2e: f=0.000220, lex =444 nm,
lem =563 nm; 2f: f=0.0752, lex =436 nm, lem =537 nm, 2g:
f=0.137, lex =434 nm, lem =535 nm; 2h: f=0.337, lex =
437 nm, lem =535 nm.
N-Allyl-(2-isopropenylbenzyl)amine (3b): Amine 3b was
fluorescent absorption bands of 2 were observed from obtained from 2-isopropenylbenzaldehyde[25] (2.19 g,
15.0 mmol) as a colorless oil; yield: (1.61 g, 8.60 mmol,
57%); H NMR (300 MHz, CDCl3): d=7.40–7.37 (1H, m),
535–583 nm with a large Stokes shift (98–123 nm) in
CH3CN. Long Stokes shift dyes can be used individu-
ally or combined with other dyes for multiplexed
imaging analysis.
In summary, we have demonstrated the first exam-
ple of a one-pot olefin isomerization/aliphatic enam-
ine RCM/oxidation/1,3-dipolar cycloaddition method-
ology to give isoindolo[1,2-a]isoquinolines, which
have characteristic fluorescent absorption bands with
a large Stokes shift.
1
7.27–7.18 (2H, m), 7.15–7.10 (1H, m), 5.92 (1H, ddt, J=
18.8, 9.9, 5.8 Hz), 5.22–5.14 (2H, m), 5.09 (1H, dq, J=9.9,
1.4 Hz), 4.88 (1H, s), 3.80 (2H, s), 3.25 (2H, d, J=5.8 Hz),
2.06 (3H, dd, J=1.7, 1.0 Hz), 1.44 (1H, brs); 13C NMR
(125 MHz, CDCl3): d=147.42, 147.27, 136.82, 128.36, 127.82,
124.91, 120.58, 115.84, 103.57, 59.75, 49.77, 40.07; HR-MS
(MALDI): m/z=188.14388, calcd. for C13H18N: 188.14351
[(M+ H)+].
N-Allyl-[2-(a-styryl)benzyl]amine (3c): Amine 3c was ob-
tained from 2-(a-styryl)benzaldehyde[26] (2.81 g, 13.5 mmol)
as a pale yellow oil; yield: 2.28 g (9.16 mmol, 68%);
1H NMR (500 MHz, CDCl3): d=7.42 (1H, d, J=7.4 Hz),
7.34 (1H, dd, J=7.7, 6.6 Hz), 7.32–7.25 (7H, m), 5.77 (1H,
d, J=1.1 Hz) 5.76–5.70 (1H, m), 5.25 (1H, d, J=1.1 Hz),
5.03 (1H, dd, J=17.0, 1.4 Hz), 4.99 (1H, dd, J=10.4,
1.4 Hz), 3.52 (2H, s), 3.02 (2H, d, J=6.3 Hz), 1.20 (1H,
brs); 13C NMR (125 MHz, CDCl3): d=148.63, 140.85,
140.47, 137.70, 136.44, 129.98, 128.95, 128.07, 127.48, 126.56,
126.14, 115.29, 114.87, 51.48, 50.60; HR-MS (MALDI): m/
z=250.15903, calcd. for C18H20N: 250.15902 [(M+H)+].
Experimental Section
General Information
1H NMR spectra were recorded in CDCl3 at 258C unless
otherwise noted, at 300, 400 or 500 MHz, with TMS as an in-
ternal standard. 13C NMR spectra were recorded in CDCl3
solvent using TMS as the internal standard at 258C unless
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General Procedure for N-Allyl-N-benzyl-(2-
vinylbenzyl)amine Derivatives (1a, 1b, and 1c)
General Procedure for Ethyl-N-allyl-N-ethoxycar-
bonylmethyl(2-vinylbenzyl)amine Derivatives (1d and
1e)
To a solution of 3a–c (1.0 equiv.) in CH3CN (0.1m) were
added K2CO3 (3.0 equiv.) and benzyl bromide (1.2 equiv.)
and stirred at 808C for 1 h. The mixture was cooled to room
temperature. The whole was quenched by saturated K2CO3
in ethylene glycol then stirred overnight. Organic com-
pounds were extracted with AcOEt. Organic layers were
washed with brine, dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The obtained residue
was subjected to column chromatography (acid silica gel,
hexane/AcOEt=50:1) to give 1a–c as oils.
To a solution of 3a, 3b (0.5 equiv.) in CH3CN (0.1M) were
added K2CO3 (3.0 equiv.) and ethyl bromoacetate
(2.0 equiv.) and stirred at 508C for 3 h. To the mixture was
added saturated K2CO3 in EtOH. The mixture was filtrated
through celite, then organic compounds were extracted with
AcOEt. Organic layers were washed with brine, dried over
Na2SO4 and the solvent was evaporated under reduced pres-
sure. The obtained residue was subjected to column chroma-
tography (acid silica gel, hexane/AcOEt=99:1) to give 1d,
1e each as an oil.
N-Allyl-N-benzyl-(2-vinylbenzyl)amine (1a): Amine 1a
was obtained from 3a (86.7 mg, 0.500 mmol) as a colorless
N-Allyl-N-ethoxycarbonylmethyl-(2-vinylbenzyl)amine
(1d): Amine 1d was obtained from 3a (86.6 mg, 0.500 mmol)
1
oil; yield: 107 mg (0.406 mmol, 81%); H NMR (500 MHz,
CDCl3): d=7.44–7.41 (1H, m), 7.31–7.29 (1H, m), 7.26–7.19
(4H, m), 7.16–7.12 (3H, m), 7.04 (1H, dd, J=17.4, 10.9 Hz),
5.87–5.81 (1H, m), 5.53 (1H, dd, J=17.4, 1.9 Hz), 5.16 (1H,
dd, J=10.9, 1.9 Hz), 5.13–5.06 (2H, m), 3.53 (2H, s), 3.47
(2H, s), 2.95 (2H, d, J=7.2 Hz); 13C NMR (125 MHz,
CDCl3): d=139.60, 137.63, 136.46, 135.65, 134.99, 130.19,
128.92, 128.74, 128.16, 128.09, 127.35, 127.17, 126.79, 125.59,
117.61, 114.72, 57.85, 56.44, 55.92; HR-MS (MALDI): m/z=
264.17468, calcd. for C19H22N: 264.17471 [(M+H)+]; anal.
calcd. for C19H21N: C 86.64, H 8.04, N 5.32; found: C 86.88,
H 8.01, N, 5.12.
as
a colorless oil; yield: 77.6 mg, 0.298 mmol, 59%);
1H NMR (500 MHz, CDCl3): d=7.52 (1H, d, J=7.4 Hz),
7.32 (1H, d, J=6.9 Hz), 7.27–7.19 (3H, m), 5.87 (1H, m),
5.64 (1H, d, J=17.8 Hz), 5.28 (1H, d, J=10.9 Hz), 5.22
(1H, d, J=17.2 Hz), 5.22 (1H, d, J=9.7 Hz), 4.14 (2H, q,
J=7.1 Hz), 3.84 (2H, s), 3.30 (2H, d, J=6.3 Hz), 3.29 (2H,
s), 1.26 (3H, t, J=7.2 Hz); 13C NMR (125 MHz, CDCl3): d=
171.46, 137.85, 135.61, 134.69, 130.39, 127.48, 127.45, 125.59,
117.91, 115.14, 60.15, 56.87, 55.44, 53.38, 14.26; HR-MS
(MALDI): m/z=260.16451, calcd. for C16H22NO2: 260.16484
[(M+H)+].
N-Allyl-N-benzyl-(2-isopropenylbenzyl)amine
(1b):
N-Allyl-N-ethoxycarbonylmethyl-(2-isopropenylbenzyl)-
amine (1e): Amine 1e was obtained from 3b (93.6 mg,
0.500 mmol) as a colorless oil; yield: 125 mg (0.457 mmol,
92%); 1H NMR (500 MHz, CDCl3): d=7.55 (1H, d, J
=7.4 Hz), 7.25–7.18 (2H, m), 7.10 (1H, dd, J=7.4, 1.7 Hz),
5.87–5.81 (1H, m), 5.20 (1H, dd, J=17.2, 1.7 Hz), 5.16 (1H,
d, J=1.1 Hz), 5.13 (1H, dd, J=10.8, 1.7 Hz), 4.78 (1H, d,
J=1.1 Hz), 4.13 (2H, q, J=7.2 Hz), 3.80 (2H, s), 3.29 (2H,
s), 3.26 (2H, d, J=5.7 Hz), 2.03 (3H, s), 1.25 (3H, t, J=
7.2 Hz); 13C NMR (125 MHz, CDCl3): d=171.59, 145.28,
144.22, 135.86, 135.61, 129.32, 127.91, 126.81, 126.63, 117.64,
114.73, 60.14, 56.84, 54.80, 53.68, 25.19, 14.25; HR-MS
(MALDI): m/z=274.18016, calcd. for C17H24NO2: 274.18024
[(M+H)+].
Amine 1b was obtained from 3b (281 mg, 1.50 mmol) as
1
a colorless oil; yield: 422 mg (1.52 mmol, quant); H NMR
(500 MHz, CDCl3): d=7.67 (1H, d, J =7.4 Hz), 7.35 (2H, d,
J=7.4 Hz), 7.29 (1H, d, J=7.7 Hz), 7.26–7.21 (2H, m),
7.20–7.16 (1H, m), 7.08 (1H, dd, J=7.4, 1.1 Hz), 5.88 (1H,
ddt, J=17.2, 10.3, 5.7 Hz), 5.18 (1H, dd, J=17.2, 1.7 Hz),
5.14 (1H, d, J=1.7 Hz), 5.11 (1H, dd, J=10.3, 1.7 Hz), 4.77
(1H, d, J=1.7 Hz), 3.59 (2H, s), 3.54 (2H, s), 3.01 (2H, d,
J=5.7 Hz), 2.02 (3H, s); 13C NMR (125 MHz, CDCl3): d=
145.22, 144.00, 139.78, 136.30, 136.12, 128.96, 128.73, 128.10,
127.80, 126.80, 126.70, 126.31, 117.13, 114.87, 58.00, 56.46,
54.83, 25.21; HR-MS (MALDI): m/z=278.19033, calcd. for
C20H24N: 278.19045 [(M+H)+]; anal. calcd. for C20H23N: C
86.59, H 8.36, N 5.05; found: C 86.69, H 8.48, N 5.02.
N-Allyl-N-benzyl-[2-(a-styryl)benzyl]amine (1c): Amine
1c was obtained from 3c (125 mg, 0.500 mmol) as a pale
yellow oil; yield: 154 mg (0.452 mmol, 90%); 1H NMR
(500 MHz, CDCl3): d=7.67 (1H, d, J =7.4 Hz), 7.27 (1H, d,
J=7.4 Hz), 7.21–7.15 (10H, m), 7.11 (2H, m), 5.71–5.65
(1H, m), 5.68 (1H, d, J=1.1 Hz), 5.07 (1H, d, J=1.1 Hz),
5.00 (1H, dd, J=17.5, 1.4 Hz), 4.96 (1H, dd, J=10.3,
1.4 Hz), 3.30 (2H, s), 3.28 (2H, s), 2.79 (2H, d, J=5.7 Hz);
13C NMR (125 MHz, CDCl3): d=148.61, 141.40, 140.68,
139.70, 137.91, 135.96, 130.06, 128.79, 128.65, 128.25, 128.04,
127.55, 126.61, 126.52, 126.41, 117.02, 115.00, 57.72, 56.18,
55.02; HR-MS (MALDI): m/z=340.20598, calcd. for
C25H26N: 340.20620 [(M+H)+]; anal. calcd. for C25H25N: C
88.45, H 7.42, N 4.13; found: C 88.39, H 7.57, N 4.16.
General Procedure for 8-Phenylisoindolo[1,2-a]iso-
quinoline-9,12-diones (2a–c, 2f and 2g)
To a solution of 1 (1.0 equiv.) in toluene (0.01M) was added
Ru(CO)HCl(PPh3)3 (5 mol%) in a glove box. The mixture
was refluxed for 5 min. To the mixture was added Hoveyda–
Grubbs II (10 mol%) and the mixture was continuously
stirred for 1 h. The mixture was cooled to 808C. To the mix-
ture was added quinone (10 equiv.) and the whole was con-
tinuously stirred for 30 min. The mixture was carried out
from the glove box and was quenched by saturated aqueous
NH4Cl. Organic compounds were extracted with AcOEt.
Organic layers were washed with brine, dried over Na2SO4
and the solvent was evaporated under reduced pressure.
The obtained residue was subjected to column chromatogra-
phy (neutral flash silica gel, hexane/AcOEt=24:1!hexane/
toluene/AcOEt=9:10:1) to give the corresponding product
2 as a powder.
8-Phenylisoindolo[1,2-a]isoquinoline-9,12-dione
(2a):
Product 2a was obtained from 1a (26.3 mg, 0.100 mmol) as
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1
a red powder; yield: 26.2 mg (0.0808 mmol, 81%; H NMR
4.15, N 3.70; found: C 82.48, H 4.24, N 3.87; mp 272.0–
(500 MHz, CDCl3): d=10.26 (1H, d, J=8.6 Hz), 7.73–7.71
(2H, m), 7.68–7.67 (2H, m), 7.61–7.57 (3H, m), 7.54–7.53
(2H, m), 7.04 (1H, d, J=7.4 Hz), 6.90 (1H, d, J=10.0 Hz),
6.66 (1H, d, J=10.0 Hz); 13C NMR (125 MHz, CDCl3): d=
183.10, 180.65, 142.56, 137.93, 133.43, 131.66, 130.73, 129.91,
129.89, 128.98, 128.55, 128.38, 128.08, 126.86, 125.68, 121.56,
120.36, 116.24, 113.26; HR-MS (MALDI): m/z=324.10191,
calcd. for C22H14NO2: 324.10201 [(M+H)+]; anal. calcd. for
C22H14NO2 +0.1H2O: C 81.27, H 4.09, N 4.31; found: C
80.97, H 4.22; N, 4.23; mp 235.0–236.0 (recrystallized from
hexane/AcOEt, a red column crystal).
273.08C (recrystallized from hexane/toluene, a yellow
needle crystal).
5-Methyl-8-phenylbenzo[5,6]isoindolo[1,2-a]isoquinoline-
9,14-dione (2g): Product 2g was obtained 1b (27.7 mg,
0.100 mmol) as an orange powder; yield: 24.2 mg
1
(0.0623 mmol, 62%); H NMR (500 MHz, CDCl3): d=10.59
(1H, d, J=7.4 Hz), 8.45–8.44 (1H, m), 8.15 (1H, dd, J=7.4,
1.1 Hz), 7.83–7.71 (4H, m), 7.67–7.57 (7H, m), 2.44 (3H, d,
J=1.1 Hz); 13C NMR (100 MHz, CDCl3, 508C): d=181.40,
178.91, 137.25, 134.96, 133.52, 133.31, 132.38, 131.34, 131.01,
130.68, 129.70, 129.61, 129.50, 129.02, 128.84, 128.30, 127.55,
126.23, 126.12, 123.35, 122.68, 121.75, 119.85, 114.63, 16.65;
HR-MS (MALDI): m/z=388.13321, calcd. for C27H18NO2:
388.13386 [(M+H)+]; anal. calcd. for C27H17NO2: C 83.70,
H 4.42, N 3.62; found: C 83.55, H 4.60, N 3.64; mp 266.5–
267.0 (recrystallized from hexane/toluene, an orange needle
crystal).
5-Methyl-8-phenylisoindolo[1,2-a]isoquinoline-9,12-dione
(2b): Product 2b was obtained from 1b (27.7 mg,
0.100 mmol) as a red powder; yield: 31.2 mg (0.0922 mmol,
1
92%); H NMR (500 MHz, CDCl3): d=10.34 (1H, dd, J=
7.7, 1.1 Hz), 7.80 (1H, dd, J=7.7, 1.4 Hz), 7.76–7.71 (2H,
m), 7.62–7.57 (4H, m), 7.55–7.53 (2H, m), 6.89 (1H, d, J=
10.0 Hz), 6.65 (1H, d, J=10.0 Hz), 2.42 (3H, d, J=1.1 Hz);
13C NMR (125 MHz, CDCl3): d=183.17, 180.59, 142.59,
137.82, 133.22, 131.26, 130.76, 130.62, 129.92, 129.81, 128.98,
128.57, 128.36, 128.31, 123.40, 122.43, 120.21, 119.64, 113.04,
16.75; HR-MS (MALDI): m/z=338.11756, calcd. for
C23H16NO2: 338.11771 [(M+H)+]; mp 243.5–244.5 (recrys-
tallized from hexane/AcOEt, a red needle crystal).
General Procedure for 8-Ethoxycarbonylisoin-
dolo[1,2-a]isoquinoline-9,12-diones (2d, 2e, and 2h)
To a solution of 1d or 1e (1.0 equiv.) in toluene (0.1M) was
added Ru(CO)HCl(PPh3)3 (10 mol%) in a glove box. The
mixture was refluxed for 2 h. The mixture was diluted by
the addition of toluene (0.1M!0.01M), then to the mixture
was added Hoveyda–Grubbs II (10 mol%) and the mixture
was continuously stirred for 1 h. The mixture was cooled to
808C. To the mixture was added quinone (10 equiv.) and the
whole was continuously stirred for 30 min. The mixture was
carried out from the glove box and was quenched by satu-
rated aqueous NH4Cl. Organic compounds were extracted
with AcOEt. Organic layers were washed with brine, dried
over Na2SO4 and the solvent was evaporated under reduced
pressure. The obtained residue was subjected to column
chromatography (neutral flash silica gel, hexane/AcOEt=
24:1!hexane/toluene/AcOEt=9:10:1) to give 2d, 2e or 2h
as a powder.
5,8-Diphenylisoindolo[1,2-a]isoquinoline-9,12-dione (2c):
To a solution of 1c (33.9 mg, 0.100 mmol) in toluene
(0.01M) was added Ru(CO)HCl(PPh3)3 (4.8 mg, 5.00 mmol,
5 mol%) in a glove box. The mixture was refluxed for 5 min.
To the mixture was added Hoveyda–Grubbs II (12.6 mg,
0.0200 mmol, 20 mol%) and the mixture was continuously
stirred for 24 h. The mixture was cooled to 808C. To the
mixture was added 1,4-benzoquinone (10 equiv.) and the
whole was continuously stirred for 30 min. The mixture was
carried out from glove box and was quenched by saturated
aqueous NH4Cl. Organic compounds were extracted with
AcOEt. Organic layers were washed with brine, dried over
Na2SO4 and the solvent was evaporated under reduced pres-
sure. The obtained residue was subjected to column chroma-
tography (neutral flash silica gel, hexane/AcOEt=24:1!
hexane/toluene/AcOEt=9:10:1) to give 2c as a red powder;
yield: 3.1 mg 0.00776 mmol (8%); 1H NMR (400 MHz,
CDCl3): d=10.51 (1H, d, J=8.2 Hz), 8.46 (1H, dd, J=7.7,
1.4 Hz), 8.17 (1H, dd, J=7.7, 1.1 Hz), 7.81–7.74 (3H, m),
7.72–7.58 (8H, m), 7.09 (1H, d, J=7.3 Hz); 13C NMR
(125 MHz, CDCl3): d=183.11, 180.69, 142.66, 137.94, 135.90,
133.11, 131.77, 130.68, 129.98, 129.89, 129.27, 129.06, 128.71,
128.53, 128.38, 128.29, 128.20, 125.82. 125.63, 122.84, 121.91,
120.58, 120.41, 113.08; HR-MS (MALDI): m/z=400.13321,
calcd. for C28H18NO2: 400.13345 [(M+H)+].
8-Ethoxycarbonylisoindolo[1,2-a]isoquinoline-9,12-dione
(2d): Product 2d was obtained from 1d (25.9 mg,
0.100 mmol) as an orange powder; yield: 21.2 mg
1
(0.0662 mmol, 66%); H NMR (500 MHz, CDCl3): d=10.21
(1H, d, J=7.4 Hz), 8.59 (1H, d, J=7.4 Hz), 7.77–7.70 (3H,
m), 7.26 (1H, d, J=7.4 Hz), 6.89 (1H, d, J=10.3 Hz), 6.77
(1H, d, J=10.3 Hz), 4.57 (2H, q, J=7.3 Hz), 1.51 (3H, t,
J=7.3 Hz); 13C NMR (100 MHz, CDCl3): d=182.01, 180.46,
161.19, 141.64, 137.49, 134.32, 130.39, 129.79, 128.61, 126.90,
125.02, 124.69, 122.81, 119.11, 117.33, 113.74, 62.42, 13.90;
HR-MS (FAB): m/z=320.0905, calcd. for C19H14NO4 [(M+
H)+]: 320.0922; anal. calcd. for C19H13NO4 +0.1H2O: C
71.07, H 4.14, N 4.36; found: C 71.13, H 4.23, N 4.31; mp
175.5–176.5 (from hexane/AcOEt, a red column crystal).
5-Methyl-8-ethoxycarbonylisoindolo[1,2-a]isoquinoline-
9,12-dione (2e): Product 2e was obtained from 1e (27.4 mg,
0.100 mmol) as an orange powder; yield: 19.1 mg
(0.0568 mmol, 57%); 1H NMR (500 MHz, CDCl3): d=
10.19–10.18 (1H, m), 8.38 (1H, s), 7.81–7.80 (1H, m), 7.74–
7.70 (2H, m), 6.83 (1H, d, J=10.3 Hz), 6.71 (1H, d, J=
10.3 Hz), 4.56 (2H, q, J=7.2 Hz), 2.52 (3H, s), 1.51 (3H, t,
J=7.2 Hz); 13C NMR (125 MHz, CDCl3): d=182.07, 180.34,
161.32, 141.63, 137.29, 133.94, 130.42, 130.32, 128.48, 128.34,
124.80, 124.39, 123.67, 123.37, 120.92, 118.67, 113.47, 62.34,
8-Phenylbenzo[5,6]isoindolo[1,2-a]isoquinoline-9,14-dione
(2f): Product 2f was obtained from 1a (26.3 mg,
0.100 mmol) as an orange powder; yield: 18.2 mg
1
(0.0486 mmol, 49%); H NMR (400 MHz, CDCl3): d=10.51
(1H, d, J=8.6 Hz), 8.46 (1H, d, J=8.6 Hz), 8.17 (1H, d, J=
7.4 Hz, 7.80–7.78 (1H, m), 7.76 (1H, d, J=7.4 Hz), 7.69–7.61
(9H, m); 13C NMR (100 MHz, CDCl3): d=181.44, 178.92,
136.92, 134.66, 133.90, 133.69, 133.47, 132.54, 131.80, 130.86,
129.85, 129.82, 129.65, 129.05, 128.47, 128.44, 127.49, 127.03,
126.88, 126.21, 125.98, 121.64, 116.54, 114.59; HR-MS
(MALDI): m/z=374.11756, calcd. for C26H16NO2: 374.11728
[(M+H)+]; anal. calcd. for C26H15NO2 +0.3H2O: C 82.44, H
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UPDATES
One-Pot Olefin Isomerization/Aliphatic Enamine Ring-Closing Metathesis
16.80, 13.90; HR-MS (MALDI): m/z=334.10738, calcd. for
C20H16NO4 [(M+H)+]: 334.10731; anal. calcd. for
C20H15NO4 +0.2H2O: C 71.29, H 4.61, N 4.16; found: C
71.68, H 4.57, N 4.12; mp 158.0–159.0 (from hexane/AcOEt,
a red needle crystal).
Krehl, Domino- and tandem olefin metathesis reactions,
in: Olefin Metathesis – Theory and Practice, (Ed.: K.
Grela), Wiley, Weinheim, 2014, pp 187–232.
[3] M. Arisawa, Y. Terada, K. Takahashi, M. Nakagawa,
A. Nishida, J. Org. Chem. 2006, 71, 4255–4261.
8-Ethoxycarbonylmethylbenzo[5,6]isoindolo[1,2-a]isoqui-
noline-9,14-dione (2h): Product 2h was obtained from 1d
(25.9 mg, 0.100 mmol) as a yellow powder; yield: 6.6 mg
[4] J. Louie, C. W. Bielawski, R. H. Grubbs, J. Am. Chem.
Soc. 2001, 123, 11312–11313.
[5] A. E. Sutton, B. A. Seigal, D. F. Finnegan, M. L. Snap-
per, J. Am. Chem. Soc. 2002, 124, 13390–13391.
[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
(0.0179 mmol, 18%); H NMR (CDCl3, 500 MHz): d=10.42
(1H, d, J=7.8 Hz), 8.51 (1H, d, J=7.4 Hz), 8.41 (1H, d, J=
7.4 Hz), 8.24 (1H, t, J=4.4 Hz), 7.87–7.69 (2H, m), 7.29
(4H, t, J=6.2 Hz), 4.62 (2H, q, J=7.2H), 1.54 (3H, t, J=
7.2 Hz); 13C NMR (125 MHz, CDCl3): d=180.58, 178.91,
161.64, 136.23, 134.88, 134.65, 134.27, 133.93, 133.76, 132.87,
130.20, 128.63, 127.55, 127.38, 127.06, 126.98, 126.50, 126.47,
126.07, 125.47, 122.76, 117.63, 115.16, 62.57, 14.00; HR-MS
(MALDI): m/z=392.08933, calcd. for C23H15NO4Na [(M+
Na)+]: 392.08924; m.p. 268.0–269.08C (recrystallized from
hexane/toluene, an orange needle crystal).
[9] S. Fustero, D. JimØnez, M. Sµnchez-Roselló, C. del Po-
zo, J. Am. Chem. Soc. 2007, 129, 6700–6701.
[10] D. F. Finnegan, M. L. Snapper, J. Org. Chem. 2011, 76,
3644–3653.
Experiments for Measurement of Photochemical
Properties[27]
[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, M. Arisawa,
S. Shuto, Adv. Synth. Catal. 2011, 353, 2676–2680.
[12] a) L. Zhang, X. G. Chen, P. Xue, H. H. Y. Sun, I. D.
Williams, K. B. Sharpless, V. V. Fokin, G. C. Jia, J. Am.
Chem. Soc. 2005, 127, 15998–15999; b) B. C. Boren, S.
Narayan, L. K. Rasmussen, L. Zhang, H. T. Zhao, Z. Y.
Lin, G. C. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130,
8923–8930; for a study focused 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. López, A. Delgado, J. R. Rodríguez, 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.
A 5 mM DMSO stock solution of each compound was pre-
pared. Each spectrum was maesured by using diluted stock
solution of the desired solvent. For determination of the
quantum efficiency of fluorescence (FF), fluorescein in
0.1M aqueous NaOH was used as a fluorescence standard.
The quantum efficiency of fluorescence was obtained with
the following equation (F denotes fluorescence intensity at
each wavelength, S[F] was calculated by summation of fluo-
rescence intensity and n denotes refractive index of the sol-
vents):
FFsample =FFstandard ”AbsstandardS[Fsample]/Abssample ”
S[Fstandard]”(nsample/nstandard)2.
Supporting Information
Spectral data for all new compounds, absorption spectra of
compounds 2, as well as the X-ray structures of compounds
2d and 2e are available in the Supporting Information.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan (MEXT), ACT-C from Japan
Science and Technology Agency (JST) and Takeda Science
Foundation.
[15] M. Arisawa, Y. Fujii, H. Kato, H. Fukuda, T. Matsumo-
to, M. Ito, H. Abe, Y. Ito, S. Shuto, Angew. Chem.
2013, 125, 1037–1041; Angew. Chem. Int. Ed. 2013, 52,
1003–1006; the obtained isoindolo[2,1-a]quinoline skel-
eton from the one-pot RCM/oxidation/1,3-dipolar cy-
cloaddition is a novel fluorescent chromophore.
[16] D. Seidle, Acc. Chem. Res. 2015, 48, 317–328.
[17] S. Krompiec, M. Krompiec, R. Penczek, H. Ignasiak,
Coord. Chem. Rev. 2008, 252, 1819–1841.
References
[1] a) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev.
2010, 110, 1746–1787; b) S. P. Nolan, H. Clavier, Chem.
Soc. Rev. 2010, 39, 3305–3316.
[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; e) B. Schmidt, S.
[18] During this research project, Liu in Boston College re-
ported the first example of aromatic enamine RCM; S.
Xu, F. Haeffner, B. Li, L. N. Zakharov, S. Liu, Angew.
Adv. Synth. Catal. 2015, 357, 4055 – 4062
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
4061

UPDATES
Yuki Fujii et al.
Chem. 2014, 126, 6913–6917; Angew. Chem. Int. Ed.
2014, 53, 6795–6799.
[23] Although we screened some combinations of oxidant
and 1,3-dipolalophile, at this stage, quinones work well
in this one-pot reaction. This is why we need an excess
amount of benzoquinones.
[24] B. Bradshaw, P. Evans, J. Fletcher, A. T. Lee, P. G.
Mwashimba, D. Oehlrich, E. Thomas, R. H. Davies,
B. C. P. Allen, K. J. Broadley, A. Hamrounic, C. Escar-
gueilc, Org. Biomol. Chem. 2008, 6, 2138–2157.
[25] E. Peyronx, F. Berthol, H. Doucet, M. Santelli, Eur. J.
Org. Chem. 2004, 1075–1082.
[19] Chemistry, including preparation and reactivity, of aro-
matic enamines and aliphatic enamines are different.
[20] a) C. R. Lee, Y. Lin, L. Lin, C. Li, T. Chu, S. Sun, J. T.
Lin, K. Ho, RSC Adv. 2015, 5, 23810–23825; b) Z. Guo,
S. Park, J. Yoon, I. Shin, Chem. Soc. Rev. 2014, 43, 16–
29.
[21] CCDC 1062688 contains the supplementary crystallo-
graphic data for 2a. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. X-ray
structures of 2d (CCDC 1062689) and 2e (CCDC
1062690) are shown in the Supporting Information.
[22] The olefin isomerization of compound 1c proceeded
quantitatively. However, the subsequent aliphatic en-
amine RCM did not proceed very well.
[26] K. Kundu, J. V. McCullagh, A. T. Morehead Jr, J. Am.
Chem. Soc. 2005, 127, 16042–16043.
[27] T. Kobayashi, Y. Urano, M. Kamiya, T. Ueno, H.
Kojima, T. Nagano, J. Am. Chem. Soc. 2007, 129, 6696–
6697.
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Adv. Synth. Catal. 2015, 357, 4055 – 4062