Sequential Photo-oxidative [3 + 2] Cycloaddition/Oxidative Aromatization Reactions for the Synthesis of Pyrrolo[2,1-a]isoquinolines Using Molecular Oxygen as the Terminal Oxidant

Article abstract of DOI:10.1021/acs.joc.6b00439

We report an efficient method for the synthesis of pyrrolo[2,1-a]isoquinoline derivatives using sequential [3 + 2] cycloaddition/oxidative aromatization reactions catalyzed by methylene blue with fluorescent light irradiation under an oxygen atmosphere. T

Full text of DOI:10.1021/acs.joc.6b00439

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Note
Sequential Photo-oxidative [3+2] Cycloaddition/Oxidative
Aromatization Reactions for the Synthesis of Pyrrolo[2,1-
a]isoquinolines using Molecular Oxygen as the Terminal Oxidant
Akitoshi Fujiya, Masanori Tanaka, Eiji Yamaguchi, Norihiro Tada, and Akichika Itoh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00439 • Publication Date (Web): 17 May 2016
Downloaded from http://pubs.acs.org on May 19, 2016
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The Journal of Organic Chemistry
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Sequential Photo-oxidative [3+2] Cycloaddition/Oxidative Aromati-
zation Reactions for the Synthesis of Pyrrolo[2,1-a]isoquinolines us-
ing Molecular Oxygen as the Terminal Oxidant
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Akitoshi Fujiya, Masanori Tanaka, Eiji Yamaguchi, Norihiro Tada, Akichika Itoh*
Gifu Pharmaceutical University 1ꢀ25ꢀ4, Daigakuꢀnishi, Gifu 501ꢀ1196, Japan
Eꢀmail: itoha@gifuꢀpu.ac.jp
ABSTRACT: We report an efficient method for the synthesis of pyrrolo[2,1ꢀa]isoquinoline derivatives using seꢀ
quential [3+2] cycloaddition/oxidative aromatization reactions catalyzed by methylene blue (MB) with fluorescent
light irradiation under an oxygen atmosphere. The products were obtained in moderate to good yields.
Pyrrolo[2,1ꢀa]isoquinoline, often found in the core of marine polycyclic lamellarin alkaloids, is a type of the Nꢀ
bridgehead heterocyclic compound that possesses unique biological activities.1 These type of alkaloids are often highly
cytotoxic toward tumor cell lines, and thus exhibit great potential as antitumor drugs. For example, lamellarin D has
the ability to inhibit human topoisomerase I,2a and lamellarin αꢀ20ꢀsulfate is expected to be a selective HIV integrase
inhibitor.2b,2c The related lamellarin I and lamellarin K also exhibit anticancer activity.2d,2e In the past, various methods
for the construction of pyrrolo[2,1ꢀa]isoquinoline scaffolds have been reported, including dipolar3 or azadiene Diels–
Alder cycloaddition,4 oxidative dimerization,5 and doubleꢀbarreled Heck cyclization.6 However, these methods require
multistep processes or suffer from limited substrate scope.
1,3ꢀDipolar cycloaddition is one strategy that may be used to efficiently construct the complex pyrrolo[2,1ꢀ
a]isoquinoline scaffold (Scheme 1). Several strategies that use fewer steps and allow more flexible construction have
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been investigated: Cu,7a Rh,7b [Ru(bpy)3]2+,7c Ru polypyridine complexes,7d C60ꢀBodipy hybrids,7e and iodoꢀBodipy
1
immobilized on porous material7f have all been employed. In addition, a method using an organophotocatalyst has been
reported.8
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However, most of these methods require further oxidation by the addition of a stoichiometric oxidant, such as NBS, to
aromatize the pyrrolidine ring. Thus, it is highly desirable to develop a more facile and atom economical method for
the synthesis of pyrrolo[2,1ꢀa]isoquinoline scaffolds. Many reports describing the use of tandem reactions for the synꢀ
thesis of complex structures have appeared to date.9−11 Wang et al.7a and Gao et al.12a have reported excellent methods
for the oneꢀstep construction of pyrrolo[2,1ꢀa]isoquinoline scaffolds (Scheme 2 (a)). Wang et al. used catalytic CuBr2
in combination with TBHP as a reoxidant while Gao et al. used catalytic I2 with H2O2. And when we are preparing of
this paper, Shankaraiah’s group reported similar reaction employing TBAI/TBHP system.12b
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Scheme 1: Sequential 1,3ꢀdipolar cycloaddition/aromatization reactions.
Scheme 2: (a) Previous reports of sequential 1,3ꢀdipolar cycloaddition/aromatization reactions, and (b) the reaction
reported in this work.
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In the past, we have reported photoꢀoxidative reactions using molecular oxygen and fluorescent lamp irradiation.13 In
2014, we reported a photoꢀoxidative crossꢀdehydrogenative coupling reaction, catalyzed by anthraquinone derivatives,
in which the tetrahydroisoquinoline substrate was oxidized to an iminium intermediate.13e Iminium intermediates are
known to be precursors in 1,3ꢀdipolar cycloaddition reactions, and we envisioned that our photoꢀoxidative method
could be a foothold to synthesize pyrrolo[2,1ꢀa]isoquinolines. In this paper, we report the novel and straightforward
photoꢀoxidative synthesis of the pyrrolo[2,1ꢀa]isoquinoline scaffold (Scheme 2 (b)).
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Table 1: Optimization of the reaction conditions.
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Entry
Catalyst (mol%)
Solvent (mL)
Yield of 3aa (%)a
1
2ꢀtBuꢀAQN (10)
9,10ꢀDCA (10)
RB (10)
Eosin Y (1)
MB (1)
iPrOH (5)
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iPrOH (5)
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iPrOH (5)
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iPrOH (5)
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iPrOH (5)
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MB (1)
MeCN (5)
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MB (1)
iPrOH/MeCN (4/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
iPrOH/MeCN (2/1)
64
8
MB (1)
69 (75)
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9b
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11d
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14 f
MB (1)
MB (1)
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MB (1)
54
MB (1)
trace
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MB (1)
0
a Yields are determined by 1H NMR spectroscopy using 1,1,2,2ꢀtetrachloroethane as an internal standard. The number
in parentheses is the isolated yield. b Irradiation with 300 W Xe lamp at 405 nm. c Irradiation with 300 W Xe lamp at
610 nm. d Irradiation with 300 W Xe lamp at 660 nm. e Under Ar atmosphere. f The reaction was conducted without
irradiation of fluorescent lamp (covered with aluminium foil).
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Firstly, the reaction conditions were optimized (Table 1). 1,4ꢀNaphthoquinone (1a) and ethyl 2ꢀ(3,4ꢀ
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dihydroisoquinolinꢀ2ꢀ(1H)ꢀyl)acetate (2a) were chosen as test substrates, and the reaction mixture containing 1a, 2a,
and an organophotocatalyst was irradiated with a fluorescent lamp under an oxygen atmosphere for 20 h in order to
yield the pyrrolo[2,1ꢀa]isoquinoline product 3aa. After extensive investigations, we found that various organophotoꢀ
catalysts, including 2ꢀtertꢀbutylꢀanthraquinone (2ꢀtBuꢀAQN), 9,10ꢀdicyanoanthracene (9,10ꢀDCA), rose bengal (RB),
eosin Y, and methylene blue (MB) catalyzed the reaction. In iPrOH, MB resulted in a higher product yield than the othꢀ
er organophotocatalysts tested (entries 1–5). During the study, we found the use of MeCN as the solvent prevented a
side reaction 2a was oxidized into 2a'. Thus, we tried the mixed iPrOH/MeCN solvent system and determined their
optimum ratio (entries 7 and 8). Thereafter, we confirmed that the reaction required visible light irradiation. Entries 9–
11 show the results of irradiation with a 300 W Xe lamp (irradiation at 350–800 nm) equipped with bandpass filters
allowing selective irradiation at λ = 405, 610, and 660 nm, respectively. Without a bandpass filter, no product was obꢀ
tained, likely because of decomposition of substrates caused by the highꢀenergy irradiation (the result is not shown).
While the product was obtained with all the bandpass filters studied, the highest product yield was obtained with the
irradiation at 660 nm (entry 11). Because the maximum absorption wavelength of MB is known to be around 660 nm,14
this result suggests that the reaction is catalyzed by appropriately excited MB. We performed some additional experiꢀ
ments (entries 12–14) in order to elucidate the reaction mechanism. As the results show, the reaction requires molecular
oxygen as a terminal oxidant and irradiation of the fluorescent lamp. On the other hand, we found that the reaction can
be proceeded without photocatalyst. This result implies that the substrates can act as sacrificial catalysts. In the next,
we added 0.3 mmol (1 equiv) of 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO), which is known as a quencher of the singlet
oxygen, to the reaction mixture (0.1 M of DABCO solution). When DABCO was added, we confirmed that the reacꢀ
tion rate is inhibited partially (See SI for detail). Thus, we assume that singlet oxygen is involved in the reaction mechꢀ
anism.
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With the optimized reaction conditions in hand, we examined the scope and limitations of the reaction. As shown in
Table 2, naphthoquinoneꢀtype substrates reacted smoothly. We found that alternation of the ester moieties in the tetraꢀ
hydroisoquinoline derivatives (3aa–3ac), and the inclusion of substituents on the aromatic rings, both in the naphthoꢀ
quinoneꢀtype substrates and tetrahydroisoquinoline derivatives (3ba–3ca, 3ad and 3bd), did not inhibit the reaction.
The reason why that the yield of 3ad is lower than that of the other products is not known till date.
Table 3 and 4 show the results for other dipolarophiles such as alkynes, maleimides, and alkenes. Using previously
optimized conditions, the yields of the products were found to be low. In most cases, however, substitution of iPrOH in
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the solvent mixture allowed to improve the yield of the corresponding products. When we employed ethylacrylate, alꢀ
kyne with amide, alkyne with ketone, Nꢀmethylmaleimide, acrylonitrile or maleic anhydride as the reaction substrate,
products were either obtained in low yield (3e'a, 3ga, 3gd, 3ha, 3ja, 3ka and 3kd) or were not obtain at all (3la), perꢀ
haps because of in situ decomposition of the substrates. We also tried to apply this reaction to a tetrahydroisoquinoline
derivative bearing a nitrile substituent. Surprisingly, the desired product was obtained cleanly, albeit in a relatively low
yield (3ae).
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Table 2: Substrate Scope (1)
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Yields shown in the table are all pure, isolated yields.
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Table 3: Substrate Scope (2)
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Yields shown in the table are all pure, isolated yields.
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Table 4: Substrate Scope (3)
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Yields shown in the table are all pure, isolated yields.
Scheme 3: Plausible mechanistic pathway for the reaction.
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Based on the results obtained above and previous reports demonstrating that MB can oxidize tertiary amines via a sinꢀ
gle electron transfer (SET),15 we propose that the reaction occurs via the mechanism as shown in Scheme 3. In the first
step, irradiation from the fluorescent lamp excites a molecule of MB, which oxidizes the tetrahydroisiquinoline derivaꢀ
tive to a radical cation; this assumption is consistent with the redox potentials of MB (3MB+/MB•: +1.21 V)16 and the
tetrahydroisoquinoline derivative (2a) (2a/2a•+: +0.75 V).17 And then after involvement of singlet oxygen and peroxy
anion, an azomethine ylide is formed, generating up to 1 equivalent of hydrogen peroxide. Iodometry results18 and
some reports19 employing singlet oxygen to abstract hydrogen atoms also support this step of the mechanism. Next,
1,3ꢀdipolar cycloaddition occurs between the azomethine ylide and the dipolarophile to yield a pyrrolidineꢀtype cyꢀ
cloadduct. Finally, the cycloadduct is oxidized again, and the corresponding product bearing the pyrrolo[2,1ꢀ
a]isoquinoline scaffold is formed. Although, this oxidative aromatization may be proceeded by the secondary photoꢀ
induced electron transfer process, we can’t deny the involvement of singlet oxygen or peroxide in situ generated under
photooxidative condition.
CONCLUSIONS
In summary, we demonstrated a sequential [3+2] cycloaddition/oxidative aromatization to efficiently construct the pyrꢀ
rolo[2,1ꢀa]isoquinoline scaffold. In this method, a tetrahydroisoquinoline derivative seems to be oxidized to an iminiꢀ
um intermediate under photoꢀoxidative conditions through a SET. This hypothesis is consistent with previous reports
suggesting that methylene blue can oxidize tertiary amine via a SET process. Subsequently, reaction with a dipolaroꢀ
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phile bearing an activated multiple bond followed by further oxidation yields the desired aromatized product. This
method allows the construction of complex molecular architecture in a safe and facile way.
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EXPERIMENTAL SECTION
1. General Information
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Substrates 1b,20 1c,21 1g,22 1h,23 2a7d, and 2e24 and are synthesized according to reported procedure. Because of their
similarity of 2a, 2bꢀ2d are synthesized by the method providing 2a with minor changes. 1H NMR and 13C NMR specꢀ
tra were recorded at 500 MHz for 1H and 125 MHz for 13C, respectively. Chemical shifts (δ) are expressed in parts per
million and are internally referenced [0.00 ppm (tetramethylsilane) for 1H NMR and 77.0 ppm (CDCl3) for 13C NMR]
and coupling constants (J) are reported in hertz. The pure product was separated by flash column chromatography perꢀ
formed on silica gel. Highꢀresolution mass spectra (HRMS) were measured in DART mode and the mass analyzer of
the HRMS was TOF. Melting points are uncorrected. Known compounds are confirmed by the comparison of their 1H
and 13C spectra in literatures.
2. Electrochemical Measurements
Cyclic voltammetry was performed with a threeꢀelectrode system consisting of a glassy carbon (GC) working electrode,
a coiled platinum counter electrode, and an Ag/AgNO3 reference electrode. The voltammograms were recorded at a
scan rate of 100 mV/s at 25 °C. Temperature was controlled during the measurements by circulating constantꢀ
temperature ethanol throughout the cell compartment. The solvent used for the electrochemical measurements was
MeCN containing 0.1 M tetrapropylammonium perchlorate (TPAP) as a supporting electrolyte for MeCN. TPAP was
dried well under high vacuum just before use. The sample solutions were prepared in a drybox completely filled with
N2 gas to prevent contamination by moisture. The solutions were purged with N2 gas to remove oxygen, and N2 gas
was passed over the solution during the measurements. The ferrocene (Fc)/Fc+ redox couple was employed for potenꢀ
tialꢀscale calibration in aprotic solvents according to IUPAC recommendations. Typical voltammograms were shown in
Fig. S1. The redox potentials for reversible waves were obtained as the midpoint potentials and were calculated from
the average of the cathodic and anodic peak positions in the voltammograms of redox couples. In the case of irreversiꢀ
ble waves the oxidation and reduction potentials were obtained as anodic and cathodic peak potentials, respectively.
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Synthesis of ethyl 9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]-isoquinoline-8-carboxylate (3aa): A
solution of 1,4ꢀnaphthoquinone (1a, 47.4 mg, 0.3 mmol), ethyl 2ꢀ(3,4ꢀdihydroisoquinolinꢀ2ꢀ(1H)ꢀyl) acetate (2a, 78.9
mg, 0.36 mmol), methylene blue solution in MeCN (0.003 mmol/ mL, 1 mL) and iPrOH (2 mL) was stirred under oxyꢀ
gen atmosphere (balloon) with irradiation of a fluorescent lamp (Philips: mini Decorative T2 Twister EL/mdT2, 23 W,
120 V, 60 Hz, 360 mA, 2700 K, Lumens: 1600) for 20 h. The reaction mixture was concentrated in vacuo. Purification
of the crude by flash column chromatography (CHCl3) provided 3aa. Other products are also provided in same way in
which the solvent, the reaction time and the eluent of flash column chromatography depend on products.
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Ethyl 9,14ꢀdioxoꢀ5,6,9,14ꢀtetrahydrobenzo[5,6]isoindolo[1,2ꢀa]ꢀisoquinolineꢀ8ꢀcarboxylate (3aa).12a
Yellow solid, yield 75% (83.3 mg), 1H NMR (500 MHz, CDCl3): δ 9.01 (d, J = 7.5 Hz, 1H), 8.32−8.30 (m, 1H),
8.24−8.22 (m, 1H), 7.74−7.70 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29−7.26 (m, 1H), 4.55 (q, J
= 7.5 Hz, 2H), 4.30 (t, J = 6.3 Hz, 2H), 3.12 (t, J = 6.3 Hz, 2H), 1.51 (t, J = 7.5 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ
179.7, 179.5, 161.4, 135.6, 134.6, 133.6, 133.3, 132.9, 130.0, 128.8, 127.40 (2C), 127.38, 127.2, 126.6, 126.3, 123.2,
117.4, 62.5, 43.1, 29.1, 14.0 (the peak of 127.40 seems to be overlapped); Rf = 0.66 (CHCl3); IR ν/cm−1 (ATR) 1702,
1658, 1511, 1464, 1413, 1383, 1309, 1263, 1225, 1140, 1107, 1047, 1009, 984, 790, 728, 710.
Methyl 9,14ꢀdioxoꢀ5,6,9,14ꢀtetrahydrobenzo[5,6]isoindolo[1,2ꢀa]ꢀisoquinolineꢀ8ꢀcarboxylate (3ab).12a
O
N
OMe
O
O
3ab
Orange solid, yield 74% (79.8 mg), 1H NMR (500 MHz, CDCl3): δ 9.01 (d, J = 8.1 Hz, 1H), 8.32−8.31 (m, 1H),
8.24−8.22 (m, 1H), 7.75−7.72 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.30−7.28 (m, 1H), 4.32 (t, J
= 6.9 Hz, 2H), 4.09 (s, 3H), 3.13 (t, J = 6.6 Hz, 2H); 13C NMR (125 Hz, CDCl3): δ 179.6 (2C), 161.9, 135.8, 135.6,
134.6, 133.6, 133.4, 133.0, 130.1, 128.8, 127.4 (2C), 127.2, 126.6, 126.6, 125.4, 123.4, 117.5, 53.1, 43.2, 29.1 (both of
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the peaks of 179.6 and 127.4 seem to be overlapped); Rf = 0.57 (CHCl3); IR ν/cm−1 (ATR) 1710, 1655, 1465, 1412,
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tertꢀButyl 9,14ꢀdioxoꢀ5,6,9,14ꢀtetrahydrobenzo[5,6]isoindolo[1,2ꢀa]ꢀisoquinolineꢀ8ꢀcarboxylate (3ac).12a
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Orange solid, yield 58% (69.5 mg), 1H NMR (500 MHz, CDCl3): δ 9.01 (d, J = 8.0 Hz, 1H), 8.31−8.29 (m, 1H),
8.24−8.22 (m, 1H), 7.73−7.70 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 6.9 Hz, 1H), 7.38−7.26 (m, 1H), 4.27 (t, J
= 6.6 Hz, 2H), 3.12 (t, J = 6.9 Hz, 2H), 1.71 (s, 9H); 13C NMR (125 Hz, CDCl3): δ 179.8, 179.4, 160.6, 135.7, 135.0,
134.8, 133.5, 133.2, 132.9, 129.9, 128.7, 127.7, 127.7, 127.43, 127.40, 126.2, 126.5 (2C), 122.4, 117.1, 84.1, 43.0, 29.1,
28.0 (the peak of 126.5 seems to be overlapped); Rf = 0.74 (CHCl3); IR ν/cm−1 (ATR) 1719, 1668, 1467, 1421, 1369,
1266, 1228, 1140, 1010, 982, 712.
Ethyl 9,16ꢀdioxoꢀ5,6,9,16ꢀtetrahydronaphtho[5,6]isoindolo[1,2ꢀa]isoquinolineꢀ8ꢀcarboxylate (3ba).12a
Orange solid, yield 61% (77.4 mg), 1H NMR (500 MHz, CDCl3): δ 9.04 (d, J = 8.1 Hz, 1H), 8.80 (s, 1H), 8.71 (s, 1H),
8.04−8.02 (m, 2H), 7.63−7.61 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 4.58
(q, J = 6.9 Hz, 2H), 4.29 (t, J = 6.3 Hz, 2H), 3.11 (t, J = 6.9 Hz, 2H), 1.54 (t, J = 7.5 Hz, 3H); 13C NMR (125 Hz,
CDCl3): δ 179.6, 179.4, 161.6, 135.6, 134.9, 134.6, 133.6, 132.1, 131.2, 130.0, 129.9, 129.8, 129.3, 128.9 (2C), 128.6,
127.4, 127.40, 127.36, 126.4, 126.1, 124.0, 118.2, 62.5, 43.2, 29.1, 14.0 (the peak of 128.9 seems to be overlapped); Rf
= 0.66 (CHCl3); IR ν/cm−1 (ATR) 1706, 1666, 1619, 1464, 1262, 1185, 1158, 1029, 915, 758.
Ethyl 11,12ꢀdimethoxyꢀ9,16ꢀdioxoꢀ5,6,9,16ꢀtetrahydrobenzo[5,6]isoindolo[1,2ꢀa]isoquinolineꢀ8ꢀcarboxylate (3ca).
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Yellow solid, yield 73% (94.0 mg), 1H NMR (500 MHz, CDCl3): δ 9.01 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.76 (s, 1H),
7.46 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29−7.27 (m, 1H), 4.55 (q, J = 7.5 Hz, 2H), 4.28 (t, J = 6.3 Hz, 2H),
4.04 (s, 3H), 4.03 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H), 1.51 (t, J = 6.9 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ 179.3, 179.0,
161.6, 153.0, 152.8, 135.5, 133.7, 130.4, 130.0, 129.4, 128.8, 127.4, 127.3, 126.4, 126.0, 123.2, 117.4, 108.6, 108.0,
62.5, 56.4, 43.1, 29.1, 14.1; Rf = 0.51 (CHCl3); IR ν/cm−1 (ATR) 1695, 1662, 1582, 1506, 1464, 1421, 1364, 1276,
1207, 1189, 1086, 1015, 886, 803, 773, 743; HRMS (DART) m/z calcd for C25H22NO6 [M +H]+ 432.1447, found
432.1435; mp. 212−213 °C.
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Ethyl 2,3ꢀdimethoxyꢀ9,14ꢀdioxoꢀ5,6,9,14ꢀtetrahydrobenzo[5,6]ꢀisoindolo[1,2ꢀa]isoquinolineꢀ8ꢀcarboxylate (3ad).12a
Orange solid, yield 34% (44.0 mg), 1H NMR (500 MHz, CDCl3) δ: 8.93 (s, 1H), 8.30 (d, J = 6.9 Hz, 1H), 8.19 (d, J =
6.9 Hz, 1H), 7.71−7.68 (m, 2H), 6.75 (s, 1H), 4.55 (q, J = 7.5 Hz, 2H), 4.27 (t, J = 6.3 Hz, 2H), 4.1 (s, 3H), 3.94 (s,
3H), 3.06 (t, J = 6.3 Hz, 2H), 1.50 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ (ppm) 179.7, 179.6, 161.6,
150.2, 147.7, 136.3, 135.9, 134.7, 133.2, 132.8, 127.3, 127.0, 126.6, 126.0, 123.0, 119.1, 116.4, 112.4, 110.2, 62.5, 56.3,
56.0, 43.3, 28.6, 14.0; Rf = 0.23 (CHCl3); IR ν/cm−1 (ATR) 1717, 1654, 1531, 1470, 1385, 1280, 1253, 1204, 1152,
1127, 1043, 1015, 995, 722, 702.
Ethyl 2,3ꢀdimethoxyꢀ9,16ꢀdioxoꢀ5,6,9,16ꢀtetrahydronaphtho[5,6]isoindolo[1,2ꢀa]isoquinolineꢀ8ꢀcarboxylate (3bd).12a
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Orange solid, yield 61% (87.4 mg), 1H NMR (500 MHz, CDCl3) δ: 9.01 (s, 1H), 8.86 (s, 1H), 8.76 (s,1H), 8.09−8.05
(m, 2H), 7.66−7.64 (m, 2H), 6.78 (s, 1H), 4.57 (q, J = 6.9 Hz, 1H), 4.30 (t, J = 6.3 Hz, 2H), 4.15 (s, 3H), 3.96 (s, 3H),
3.09 (t, J = 6.9 Hz, 2H), 1.53 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ (ppm) 179.7, 179.5, 161.8, 150.1,
147.7, 136.3, 134.9, 134.6, 132.3, 131.3, 129.8 (2C), 129.3, 128.9, 128.8, 128.5, 126.9, 126.1, 123.8, 119.2, 117.2,
112.4, 110.1, 62.5, 56.3, 55.9, 43.3, 28.6, 14.0 (the peak of 129.8 seems to be overlapped); Rf = 0.37 (CHCl3); IR
ν/cm−1 (ATR) 1717, 1660, 1530, 1482, 1382, 1256, 1238, 1234, 1184, 1132, 1036, 915, 761.
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Triethyl 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ1,2,3ꢀtricarboxylate (3da).7b
White solid, yield 48% (55.5 mg), 1H NMR (500 MHz, CDCl3): δ 8.19−8.17 (m, 1H), 7.32−7.31 (m, 2H), 7.26−7.25
(m, 1H), 4.54 (t, J = 6.3 Hz, 2H), 4.37 (q, J = 7.5 Hz, 2H), 4.34−4.29 (m, 4H), 3.00 (t, J = 6.9 Hz, 2H), 1.41 (t, J = 6.9
Hz, 3H), 1.36−1.32 (m, 6H). 13C NMR (125 Hz, CDCl3): δ 166.1, 163.4, 159.9, 136.7, 134.3, 129.2, 128.5, 127.3,
126.9 (2C), 126.4, 118.9, 110.7, 61.5, 61.0, 60.7, 42.5, 29.3, 14.10, 14.08, 14.03 (the peak of 126.9 seems to be
overlapped); Rf = 0.29 (Hexane : EtOAc = 4 : 1); IR ν/cm−1 (ATR) 1704, 1661, 1532, 1464, 1426, 1384, 1253, 1186,
1109, 1028, 760.
Diethyl 2,3ꢀdimethoxy 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ1,3ꢀdicarboxylate (3ea).12a
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Yellow solid, yield 69% (64.8 mg), 1H NMR (500 MHz, CDCl3): δ 8.43 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.35−7.27 (m,
2H), 7.25 (d, J = 8.6 Hz, 1H), 4.59 (t, J = 6.3 Hz, 2H), 4.35−4.30 (m, 4H), 3.01 (t, J = 6.9 Hz, 2H), 1.40−1.37 (m, 6H);
13C NMR (125 Hz, CDCl3): δ 164.5, 160.9, 137.7, 134.0, 128.8, 128.5, 127.2, 127.0, 126.8, 121.3, 121.0, 112.3, 60.3,
60.2, 42.3, 42.2, 29.4, 14.4; Rf = 0.66 (Hexane : EtOAc = 4 : 1); IR ν/cm−1 (ATR) 1702, 1538, 1452, 1417, 1252, 1206,
1156, 1078, 1028, 768, 753, 744.
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3ꢀEthyl 1ꢀmethyl 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ1,3ꢀdicarboxylate (3fa).7a
Yellow solid, yield 66% (59.2 mg), 1H NMR (500 MHz, CDCl3): δ 8.43 (d, J = 7.5 Hz, 1H), 7.49 (s, 1H), 7.35−7.28 (m,
2H), 7.25 (d, J = 8.6 Hz, 1H), 4.59 (t, J = 6.3 Hz, 2H), 4.31 (q, 7.5 Hz, 2H), 3.85 (s, 3H), 3.01 (t, J = 6.9 Hz, 2H), 1.38
(t, 7.2 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ 164.9, 160.9, 137.8, 134.0, 128.9, 128.4, 127.2, 127.0, 126.9, 121.3,
121.1, 111.8, 60.3, 51.4, 42.2, 29.4, 14.3; Rf = 0.57 (Hexane : EtOAc = 4 : 1); IR ν/cm−1 (ATR) 1698, 1540, 1458,
1407, 1252, 1205, 1164, 1079, 1015, 771, 755, 741.
Ethyl 1ꢀ(1ꢀpyrrolidinylcarbonyl) 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (3ga).
Yellow gum, yield 18% (18.3 mg), 1H NMR (500 MHz, CDCl3): δ 7.65−7.63 (m, 1H), 7.25−7.22 (m, 3H), 7.07 (s, 1H),
4.61 (t, J = 3.2 Hz, 2H), 4.30 (q, J = 7.5 Hz, 2H), 3.67 (t, J = 7.5 Hz, 2H), 3.26 (t, J = 6.9 Hz, 2H), 3.06 (t, J = 6.9 Hz,
2H), 1.93 (quint, J = 7.3 Hz, 2H), 1.80 (quint, J = 6.9 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ
166.5, 161.1, 132.6, 132.2, 128.0, 127.8, 127.6, 127.4, 124.8, 121.2, 117.2 (2C), 60.1, 48.5, 45.8, 42.2, 29.1, 25.9, 24.6,
14.4 (the peak of 117.2 seems to be overlapped); Rf = 0.31 (Hexane : EtOAc = 1 : 1); IR ν/cm−1 (ATR) 1696, 1615,
1549, 1455, 1401, 1241, 1185, 1082, 846, 757; HRMS (DART) m/z calcd for C20H23N2O3 [M +H]+ 339.1709, found
339.1698.
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Ethyl 1ꢀ(1ꢀpyrrolidinylcarbonyl) 2,3ꢀdimethoxy 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (3gd).
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Yellow gum, yield 12% (14.3 mg), 1H NMR (500 MHz, CDCl3): δ 7.36 (s, 1H), 7.07 (s, 1H), 6.74 (s, 1H), 4.58 (t, J =
6.6 Hz, 2H), 4.29 (q, J = 7.5 Hz, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.65 (t, J = 7.4 Hz, 2H), 3.25 (t, J = 6.9 Hz, 2H), 2.99
(t, J = 7.2 Hz, 2H), 1.92 (quint, J = 7.5 Hz, 2H), 1.80 (quint, J = 6.9 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H); 13C NMR (125
Hz, CDCl3): δ 166.8, 161.1, 148.8, 148.0, 132.5, 125.6, 120.8, 120.4, 117.4, 116.2, 110.7, 108.0, 60.1, 55.93, 55.88,
48.6, 45.9, 42.3, 28.8, 26.0, 24.7, 14.4; Rf = 0.23 (Hexane : EtOAc = 1 : 2); IR ν/cm−1 (ATR) 1691, 1609, 1463, 1399,
1241, 1215, 1190, 1145, 1077, 859, 759; HRMS (DART) m/z calcd for C22H27N2O5 [M +H]+ 399.1920, found
399.1908.
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Ethyl 1ꢀbenzoyl 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (3ha).
White gum, yield 10% (10.4 mg), 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H),
7.56 (m, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.25−7.24 (m, 2H), 7.19−7.17 (m, 2H), 4.66 (t, J = 6.9 Hz, 2H), 4.30 (q, J = 7.4
Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ 192.3, 161.0, 139.1, 137.5,
133.6, 132.4, 129.9, 128.8, 128.3, 127.5 (2C), 127.0 (2C), 122.2, 120.9, 120.0, 60.4, 42.4, 29.3, 14.4 (both of the peaks
of 127.5 and 127.0 seem to be overlapped); Rf = 0.32 (Hexane : EtOAc = 5 : 1); IR ν/cm−1 (ATR) 1698, 1645, 1449,
1410, 1247, 1214, 1184, 1082, 888, 731; HRMS (DART) m/z calcd for C22H20NO3 [M +H]+ 346.1443, found 346.1445.
Ethyl 9,11ꢀdioxoꢀ10ꢀphenylꢀ6,9,10,11ꢀtetrahydroꢀ5Hꢀpyrroloꢀ[3’,4’: 3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate
(3ia).7a
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White solid, yield 49% (56.7 mg), 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 8.1 Hz, 2H),
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1.47 (t, J = 7.5 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ 163.1, 161.6, 159.7, 133.5, 132.5, 132.5, 132.4, 130.3, 128.9,
128.0, 127.8, 127.7, 127.1, 125.5, 125.2, 118.6, 116.2, 61.7, 43.4, 28.3, 24.2, 14.2; Rf = 0.37 (Hexane : EtOAc = 3 : 1);
IR ν/cm−1 (ATR) 1756, 1699, 1547, 1472, 1418, 1383, 1345, 1276, 1196, 1155, 1111, 1089, 1049, 945, 894, 861, 822,
755, 724.
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Ethyl 9,11ꢀdioxoꢀ10ꢀmethylꢀ6,9,10,11ꢀtetrahydroꢀ5Hꢀpyrroloꢀ[3’,4’: 3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate
(3ja).7b
White solid, yield 17% (16.8 mg), 1H NMR (500 MHz, CDCl3): δ 8.51 (d, J = 8.0 Hz, 1H), 7.41−7.39 (m, 1H),
7.38−7.36 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.71 (t, J = 7.2 Hz, 2H), 4.41 (q, J = 6.9 Hz, 2H), 3.15 (t, J = 6.9 Hz, 2H),
3.10 (s, 3H), 1.48 (t, J = 6.9 Hz, 3H); 13C NMR (125 Hz, CDCl3): δ 164.1, 162.8, 159.6, 132.8, 132.3, 130.1, 127.9,
127.8, 127.6, 125.8, 125.6, 118.1, 116.6, 61.5, 43.2, 28.3, 24.2, 14.1; Rf = 0.34 (Hexane : EtOAc = 3 : 1); IR ν/cm−1
(ATR) 1753, 1690, 1546, 1475, 1380, 1349, 1270, 1192, 980, 774, 738; HRMS (DART) m/z calcd for C18H17N2O4 [M
+ H]+ 325.1189, found 325.1217.
Ethyl 1ꢀcyano 5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (3ka).
White solid, yield 24% (19.2 mg), 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J = 7.5 Hz, 1H), 7.39−7.33 (m, 2H),
7.29−7.28 (1H, m), 4.66 (t, J = 7.2 Hz, 2H), 4.33 (q, J = 7.5 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H), 1.38 (t, J = 7.4 Hz, 3H);
13C NMR (125 Hz, CDCl3): δ 160.2, 139.3, 132.6, 129.6, 128.0, 127.8, 126.0, 124.8, 122.5, 121.5, 116.7, 88.8, 60.7,
42.6, 28.6, 14.3; Rf = 0.31 (Hexane : EtOAc = 5 : 1); IR ν/cm−1 (ATR) 2224, 1706, 1457, 1410, 1251, 1190, 1101, 836,
768, 722, 689; HRMS (DART) m/z calcd for C16H15N2O2 [M +H]+ 267.1134, found 267.1130; mp. 105−106 °C.
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White solid, yield 19% (18.6 mg), 1H NMR (500 MHz, CDCl3): δ 7.77 (s, 1H), 7.24 (s, 1H), 6.77 (s, 1H), 4.63 (t, J =
7.2 Hz, 2H), 4.31 (q, J = 7.5 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.03 (t, J = 6.9 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H); 13C
NMR (125 Hz, CDCl3): δ 160.3, 150.0, 148.4, 140.0, 125.8, 122.1, 121.3, 118.5, 117.2, 110.7, 107.5, 87.6, 60.6, 56.1,
56.0, 42.7, 28.2, 14.3; Rf = 0.31 (Hexane : EtOAc = 1 : 1); IR ν/cm−1 (ATR) 2213, 1697, 1612, 1546, 1466, 1251, 1217,
1196, 1151, 1015, 850, 721; HRMS (DART) m/z calcd for C18H19N2O4 [M +,H]+ 327.1345, found 327.1352; mp.
133−134 °C.
9,14ꢀdioxoꢀ5,6,9,14ꢀtetrahydrobenzo[5,6]isoindolo[1,2ꢀa]ꢀisoquinolineꢀ8ꢀcarbonitrile (3ae).
Yellow solid, yield 30% (28.9 mg), 1H NMR (500 MHz, CDCl3): δ 9.01 (d, J = 8.1 Hz, 1H), 8.33 (dd, 7.4 Hz, 1H),
8.28 (dd, 6.9 Hz, 1H), 7.80−7.77 (m, 2H), 7.50 (m, 1H), 7.46 (m, 1H), 7.35−7.33 (m, 1H), 4.37 (t, J = 6.9 Hz, 2H),
3.24 (t, J = 6.9 Hz, 2H).13C NMR (125 Hz, CDCl3): δ 178.7 (2C), 137.9, 135.7, 134.1, 133.6, 133.4, 133.3, 131.1,
129.8, 129.1, 127.9 (2C), 127.7, 126.8, 125.7, 117.9, 111.1, 104.7, 43.8, 28.7 (both of the peaks of 178.7 and 127.9
seem to be overlapped) ; Rf = 0.51 (CHCl3); IR ν/cm−1 (ATR) 2222, 1657, 1588, 1546, 1504, 1463, 1420, 1267, 1245,
1197, 1186, 1156, 1061, 1008, 985, 745, 730, 717, 689; HRMS (DART) m/z calcd for C21H13N2O2 [M + H]+ 325.0977,
found 325.0982; mp. >295 °C.
ASSOCIATED CONTENT
Supporting Information. Cyclic voltammogram of 2a, 1H NMR and 13C NMR for all compounds except 3e'a and 3ia
(PDF), and emission spectrum of the fluorescent lamp
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: itoha@gifuꢀpu.ac.jp
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Prof. Bunji Uno (Gifu Pharm. Univ.) for his generous assistance with the cyclic voltammetry experiment.
The authors would like to thank Enago (www.enago.jp) for the English language review.
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