Photoelectrocyclization Reactions of Amidonaphthoquinones

Article abstract of DOI:10.1021/acs.joc.9b03417

Readily available acrylamide naphthoquinones can be converted into the corresponding aza-anthraquinones using 6?-photoelectrocyclization reactions. Not only do these reactions not proceed thermally but, as demonstrated here, they can also be used to generate a range of aza-anthraquinone and aza-tetracycline derivatives including the natural products griffithazanone A and marcanine A. Several of the aza-anthraquinones generated in this work showed antibacterial activity.

Full text of DOI:10.1021/acs.joc.9b03417

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Article
Photoelectrocyclization Reactions of Amidonaphthoquinones
Jinya Yin, Michael B. Landward, and Jon Douglas Rainier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03417 • Publication Date (Web): 19 Feb 2020
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Photoelectrocyclization Reactions of Amidonaphthoquinones
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Jinya Yin, Michael B. Landward, and Jon D. Rainier*
315 South, 1400 East
Department of Chemistry
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University of Utah
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Email address: rainier@chem.utah.edu
Abstract. Readily available acrylamide naphthoquinones can be converted into the
corresponding aza-anthraquinones using 6-photoelectrocyclization reactions. Not
only do these reactions not proceed thermally but, as demonstrated here, they can
be used to generate a range of aza-anthraquinone and aza-tetracycline derivatives
including the natural products griffithazanone A and marcanine A. Several of the
aza-anthraquinones generated in this work showed anti-bacterial activity.
TOC Entry
Introduction
In addition to being ubiquitous in biologically active natural and non-natural
products, quinones have demonstrated impressive properties in both synthetic and
biological chemistry.1 In spite of this, there are very few examples of the use of
quinones in either thermal or photochemical electrocyclization reactions (3 to 4,
Scheme 1).2 This comes in spite of their wide use in [2+2] photocycloaddition
reactions,3 the use of quinone methides and derivatives in 6 electrocyclizations,4
and the rich photochemical and electron transport properties of quinones.5 In
contrast to the dearth of examples of quinone reactivity, the photoelectrocyclization
chemistry of the corresponding acrylanilides has received a significant amount of
attention (1 to 2, Scheme 1).6 These transformations were first reported by
Chapman in 1967 and have subsequently been shown to be a valuable means of
synthesizing substituted quinolines.7,8 From an interest in using the reactions in the
synthesis of complex targets, we set out to determine whether the
photoelectrocyclization reactions of quinones have simply been overlooked or
whether they might have inherent problems. Outlined here are experiments that
address these questions and that demonstrate that acrylamide containing
naphthoquinones undergo photoelectrocyclization reactions. In addition, also
included in this work is the first total synthesis of the aza-anthraquinone natural
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product griffithazanone A, the total synthesis of the quinolone natural product
marcanine A,10 and preliminary anti-bacterial activity of the substrates generated as
a consequence of these investigations.
Scheme 1. Photoelectrocyclizations to Lactams.
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Results and Discussion
To the synthesis of the requisite acrylamide and cinnamide cyclization
precursors, we initially explored the coupling of 2-aminonaphthoquinone with
acrylic and cinnamic acid derivatives. As has been reported by other laboratories,11
this reaction proved to be capricious in our hands. To date, a much more reliable
route to the cyclization precursors has involved a two-step process that has coupled
acrylamide or cinnamide formation from the reaction of 2-amino-1,4-dimethoxy
naphthalene 6 and unsaturated acids or acid chlorides with oxidation of the
resulting hydroquinone to the corresponding quinone (Table 1).12 In turn,
aminohydroquinone 6 resulted from the nitration and reduction of 1,4-
dimethylhydroquinone 5.13
Table 1. Generation of Aza-Anthraquinones via Photoelectrocyclization Reactions
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With the precursors in hand, we explored their photoelectrocyclization
reactions using a 419 nm light source (Table 1). While we were pleased that the
reactions proceeded and that they gave the requisite aza-anthraquinones, we were
surprised that the substitution pattern on the acrylamide starting materials was
important in the efficacy of the reactions. For example, when -methyl acrylamide 7
was exposed to light, we isolated a 1:1 mixture of quinoline 8 and the corresponding
oxidized product, quinolone 9, in an overall yield of 97% (entry 1). In contrast, the
reaction of the isomeric -methyl acrylamide 10 not only gave much less of the
oxidized product (12) but the reaction required less time to go to completion (entry
2). Our presumption was that 9 arose from the oxidation of 8 by O2 in spite of our
efforts to deoxygenate the reaction mixture by bubbling N2 through it immediately
prior to subjecting the mixture to light.14 It was interesting and ultimately telling
that this deoxygenation protocol was used in the reaction of the -methyl analog 10
without the same oxidation issues. In addition to the cyclization and the oxidation,
other interesting features of this reaction includes the fact that 9 is the natural
product marcanine A.10 Marcanine A was originally isolated from the bark of the
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Thai flowering plant Goniothalamus marcanii and although it was not our initial
focus, it is interesting in its own right as it has shown impressive activity against a
number of cancer cell lines and malaria including a drug-resistant strain of
Plasmodium falciparum.15 The use of photochemistry was critical here, our attempts
to carry out the electrocyclization reaction of 7 and 10 using thermal conditions
were unsuccessful resulting in the recovery of starting material.16
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In a reaction that was more similar to the reaction of 10 than 7, 2,3-dimethyl
acrylamide 13 gave exclusively cis-dimethyl quinoline 14 (see Table 1, entry 3)17
unless the reaction was allowed to proceed for >1 hour after which we began
observing the formation of a by-product that we presume was oxidized quinolone
15 (entry 3). Assuming a photochemically allowed conrotatory electrocyclization,
the relative stereochemistry of 14 would be consistent with a mechanism involving
the tautomerization of the electrocyclization product 27 and not a [1,5]-hydride
shift mechanism (Scheme 2).18 This result was particularly interesting to us in light
of the fact that the related acrylanilide reactions have not only shown lower levels of
selectivity but they provide a predominance of the trans-product in the absence of a
proton source.7
Scheme 2. Proposed Mechanism for the Photoelectrocyclization of Naphthoquinone
Acrylamides.
In contrast to the acrylamide substrates, the photoelectrocyclization
reactions of cinnamide derivatives 16, 19, and 22 were problematic; while the
corresponding quinolines 17, 20, and 23 were isolated, the yields were low (Table
1, entries 4-6). These reactions resulted in the formation of a number of intractable
by-products that we presume arose from the oxidation of the electrocyclization
starting materials, intermediates, or products.
As was mentioned above, we assumed that the oxidation problems that were
outlined arose from the presence of residual O2 in the reaction mixture. In an
attempt to overcome this we explored the use of a more rigorous deoxygenation
protocol by subjecting a solution of 7 to 3 freeze-pump-thaw cycles prior to
subjecting it to 419 nm light.19 This resulted in the generation of aza-anthraquinone
8 in 88% yield without any noticeable quinolone 9 (Scheme 3). Unfortunately this
solution to the oxidation problem was not general; when we applied the freeze-
pump-thaw technique to the cinnamide derivatives 16, 19 and 22 we continued to
isolate a low yield of the corresponding quinolines along with a predominance of
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what appeared to be the same intractable oxidized material that we had observed
previously.
Scheme 3. The Detrimental Role of O2 on Acrylamide Naphthoquinone
Photoelectrocyclizations
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Having established that the photoelectrocyclization reactions of acrylamide
and cinnamide naphthoquinones can be utilized to generate relatively simple aza-
anthraquinones, we set out to examine the scope of the reactions by exploring more
elaborate substrates. Along these lines, the presence of spirocyclic quinones in
antibacterial and anti-virulence natural products inspired us to examine geminal
20
disubstituted substrates 29, 31, 33, 35, and 37.
These cyclization precursors
were generated in a similar fashion to those examined previously, namely from the
coupling of aminonaphthalene 6 with the corresponding acrylic acid or acid
chlorides followed by oxidation (Table 2). We were ultimately pleased to find that
geminal disubstituted acrylamides could be converted into the corresponding
quaternary substituted aza-anthraquinones in moderate (45-60%) to high (92%)
yields when they were exposed to 419 nm light. With tetrasubstituted acrylamide
31 as the exception, it was not surprising that these substrates generally required
much longer reaction times to go to completion when compared to the non-geminal
disubstituted substrates. 21 With regard to the affect of pre-existing stereocenters on
the stereochemical outcome of the reactions, we were encouraged that the
photoelectrocyclization of unsymmetrical acrylamide 37 resulted in the generation
of spirocycle 38 in 92% yield as a single diastereomer by 1H NMR.
Table 2. Photoelectrocyclizations to Quaternary Substituted Aza-Anthraquinones
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As a final substrate class for these studies we examined the formation of
angularly fused aza-tetracyclic quinones. Related substrates have shown a wealth of
interesting properties including anticancer and antibiotic activity.22 As illustrated in
Table 3 the cyclization precursors for these studies were accessed in the same
fashion as those that were described previously. We were pleased to find that the
photoelectrocyclization was general; exposing acrylamides 39 and 41 to 419 nm
light efficiently resulted in the formation of 40, 42, and 43 (entries 1 and 3).23 Of
note was that no oxidized material was observed and that these reactions gave
exclusively the cis-fused products.24 As was mentioned earlier, it was interesting
that the analogous acrylanilide cyclizations were both less selective and gave a
predominance of the trans-fused products unless the reaction was run in the
presence of a proton source.8 In contrast to our results with 37, the presence of the
multiple stereocenters in shikimic acid cyclization precursor 41 complicated the
reaction giving the two cis-isomers 42 and 43 in essentially equal quantities.
Table 3. Angularly Fused Aza-Tetracycles
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In an effort to better understand the nature of the excited state, we carried
out the photoreaction of 39 in the presence of
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equivalents of
tetramethylbutadiene as a triplet quencher (Table 3, entry 2). That the yield of
cyclized product was much lower in the presence of the quencher than it was in its
absence is suggestive of a triplet excited state.25
Assuming that the NEER (non-equilibration of excited state rotomers)
principle was operative here, 26 we carried out DFT calculations on 7 representative
substrates in an effort to better understand their relative reaction rates.27,28 We
focused on 3 relevant conformations, the s-trans conformation (Conformer 1) and
the two s-cis conformations (Conformers 2 and 3, Table 4). In all instances the s-
trans conformation (Conformer 1) was lowest in energy and therefore was
arbitrarily assigned a value of 0 kcal/mol. We then compared the differences in the
energies between Conformers 2 and 3 with the amount of time required for the
starting materials to be consumed. It was interesting that the rate of each reaction
correlated reasonably well with the differences in energy between the two
conformers. The substrates that decomposed the fastest had substitution at the -
position (8, 9, 31, 40) and either had a product forming conformation (Conformer
3) that was lower in energy or one that was relatively close in energy to their non-
product forming conformation (Conformer 2). In contrast, Conformer 2 was much
more stable for those substrates that lacked the -substituent. These substrates also
required much longer reaction times (see 7, 29, 35).
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Table 4. The Relative Energetics of Acrylamide Naphthoquinone Conformations
Affect Their Photoelectrocyclization Rates.
Compound
Conformer
3
7
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8.39
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4.95
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8.22
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6.46
(kcal/mol)
Conformer
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7.24
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4.14
5.03
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(kcal/mol)
E (3-2)
Reaction
time1
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255
min
-0.84
75 min 25 min
-0.64
3.39
960
min
0.81
40 min
3.19
600
min
-0.78
45 min
1reactions were removed from the photochamber when the starting material had
disappeared by TLC.
Having established the photoelectrocyclization reaction of quinones as a
powerful means of generating aza-anthraquinones, we set out to utilize the reaction
in the synthesis of the natural product griffithazanone A (Scheme 4). Griffithazanone
A was originally isolated from the roots of the tropical plant Goniothalamus griffithii,
a member of the Annonaceae family.29 Griffithazanone A has demonstrated
cytotoxicity against the colon cancer cell line HCT-116 with an IC50 value of 2.39 M
(doxorubicin had an IC50 value of 9.74 M in the same assay) and to the best of our
knowledge has not been targeted in total synthesis studies. 30 Our initial efforts to its
synthesis focused on the direct oxidation of 8. These experiments either resulted in
the recovery of starting material or its decomposition to unrecognizable material.31
We then turned to the incorporation of a heteroatom into the cyclization precursor
and examined the photochemistry of -bromoacrylamide 44 and -
acetoxyacrylamide 45. The photoelectrocyclizations of these substrates resulted in
the formation of 46 and 47, respectively. While these reactions led to the cis-
isomers as the major products, in contrast to the reactions of 13, 39, and 41, they
gave a measurable quantity of the corresponding trans-products. It was not
surprising that the -bromo analog 46 proved to be unstable to isolation,
chromatographic purification, and the attempted displacement with nucleophiles. In
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contrast, -acetoxy aza-anthraquinone 47 was relatively stable and underwent
hydrolysis when exposed to K2CO3 and H2O to give griffithazanone A.
Scheme 4. Syntheses of Marcanine A and Griffithazanone A.
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A selection of the above quinolines and quinolones were tested for their ability to
inhibit bacterial growth (Table 5). The minimum inhibitory concentration (MIC) for
these compounds was determined according the Clinical and Laboratory Standards
Institute guidelines.32 While the compounds did not show inhibitory activity against
E. coli (ATCC-25922) or E. faecalis (ATCC-19433), several aza-anthraquinones and
aza-angucyclinones did show promising activity against S. aureus (ATCC-12600).
Interestingly, of the compounds tested, marcanine A was the most active with an
MIC of 1 µg/mL.
Table 5. Activity of Photoproducts against S. Aureus.
Compound
MIC (S. aureus)
32 g/mL
1 g/mL
Compound
MIC (S. aureus)
2 g/mL
8
32
34
Marcanine A
8 g/mL
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30
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47
4 g/mL
64 g/mL
>64 g/mL
8 g/mL
64 g/mL
64 g/mL
32 g/mL
16 g/mL
32 g/mL
32 g/mL
16 g/mL
32 g/mL
16 g/mL
N.D.
(±)-Griffithazanone
A
In conclusion, the work described here shows that photoelectrocyclization reactions
of acrylamide naphthoquinones are an effective means of generating aza-
anthraquinones and angularly fused aza-angucyclinone derivatives. In addition to
demonstrating the breadth of substrates that undergo this transformation, we have
also shown that this class of targets has interesting and in some cases impressive
activity against S. aureus. In our future studies we will continue to examine the use
of photoelectrocyclization reactions to synthesize complex small molecules while
also exploring the antibiotic properties of aza-anthraquinones.
Experimental Information
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General Information.
Glassware was dried in an oven at 130 °C or flame dried and cooled under a N2 atmosphere prior
to use. All reactions were performed using common dry, inert atmosphere techniques. Solvents
were purified according to the guidelines in Purification of Common Laboratory Chemicals
(Perrin, Armarego, and Perrin: Oxford, 1966). Dichloromethane was distilled from CaH2. All
photoreactions were conducted in 10 mm pyrex tubes using a Rayonet®-100 Photo-reactor. Pyrex
tubes were placed in the center of the photoreactor. The distances from the pyrex tubes to the
light source were ca. 9 cm. The light source used in the photoreactions was manufactured by
Southern New England Ultraviolet Company (RPR-4190A) with a peak intensity of 419 nm. The
emission spectrum of this light source ranged from 373 nm to 460 nm with an intensity at 419 nm
of 1.20 x 10-5 W/cm2; please see the SI for the emission spectrum. Reactions were monitored by
TLC and visualized by a dual short wave/long wave UV lamp and stained with an ethanolic
solution of potassium permanganate or p-anisaldehyde. Column flash chromatography was
performed using hexanes and ethyl acetate as eluents with SilicaFlash® F60 grade silica gel, 230-
400 mesh, from Silicycle. NMR spectra were recorded on a Varian Inova-500, or a Varian Inova-
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1
400 spectrometer. Chemical shifts for H NMR were reported as δ, parts per million (ppm),
relative to the tetramethylsilane signal at 0 ppm or for the CHCl3 signal at 7.26 ppm. Mass spectra
were recorded at the Mass Spectrometry Facility in the Department of Chemistry at the
University of Utah on a Finnigan MAT® 95 double focusing high resolution mass spectrometer.
Crystal structures were obtained at the X-ray crystallography center in the Department of
Chemistry at the University of Utah.
1,4-dimethoxynaphthalene (5). To a solution of 1,4-naphthoquinone (20.0 g, 126 mmol) in THF
(500 mL) at rt was added 10% Pd/C (1 g). The resulting mixture was charged with H2 gas (1 atm)
and allowed to stir for 4h after which the reaction mixture was cooled to 0 °C. To this was slowly
added NaH (60% dispersion in mineral oil. 15.2 g, 379 mmol). This resulted in the reaction
mixture undergoing a color change to green. Dimethyl sulfate (60.0 mL, 632.3 mmol) was then
added dropwise to the mixture. The reaction mixture was allowed to stir for 1 h and then was
warmed to rt and stirred for an additional 16 h at that temperature. The mixture was passed
through a short pad of celite using THF (50 mL) as the eluent. Concentration gave a brown paste
×
that was dissolved in EtOAc (200 mL) and washed sequentially with NH4OH (33% aq., 2 40
×
mL), H2O (2
50 mL), and brine (50 mL). The organic phase was dried (Na2SO4) and
concentrated. Flash chromatography (hexanes:ethyl acetate = 20:1) gave 21.4 g of 5 (90%) as a
white solid.
mp 86-87 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.30-8.28 (m, 2H), 7.38-7.56 (m, 2H), 6.72 (s, 2H),
3.99 (s, 6H); 13C{1H} (126 MHz, CDCl3) δ 149.6, 126.5, 125.9, 121.9, 103.3, 55.8; IR (neat)
3070, 3011, 2953, 2920, 2841, 1630, 1593, 1463, 1445, 1384, 1270, 1239, 1159, 1086, 1023, 955,
803, 764, 720 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C12H13O2 189.0916; Found 189.0915.
1,4-dimethoxy-2-nitronaphthalene (S1). Preparation of nitric acid impregnated silica gel: To a
beaker charged with 50 g of silica gel (GFS chemical, 50-200 mesh) was carefully added 60 mL
of con. nitric acid (aq.). The mixture was sonicated at rt for 2 h and then allowed to sit for an
additional 24 h. The mixture was filtered and the solid was air dried at rt. The nitric acid content
of the SiO2 was determined to be 2.3 mmol/g through its titration with 0.1 N NaOH (aq.) using
phenolthalein as the indicator.
To a solution of 5 (11.0 g, 58.4 mmol) in CH2Cl2 (500 mL) at rt was slowly added silica
gel supported nitric acid (28 g, 64 mmol HNO3) in three equal portions. The resulting reaction
mixture was stirred for 15 min and then filtered. Concentration and flash column chromatography
(hexanes:ethyl acetate = 20:1) gave 8.30 g of S1 (61%) as a yellow solid.
mp 95-96 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.28-8.24 (m, 2H), 7.66-7.65 (m, 2H), 7.21 (s, 1H),
4.08 (s, 3H), 4.03 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.0, 145.8, 138.8, 129.1, 129.0,
128.9, 128.3, 124.2, 122.8, 98.6, 63.7, 56.2; IR (neat) 2936, 2844, 1587, 1526, 1503, 1462, 1417,
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1329, 1265, 1212, 1110, 1088, 992, 967, 750, 720 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C12H12NO4 234.0766; Found 234.0771.
1,4-dimethoxynaphthalen-2-amine (6). To a solution of S1 (6.00 g, 25.7 mmol) in anhydrous
EtOH (100 mL) at rt was added 10% Pd/C (0.6 g). The resulting mixture was charged with H2 gas
(1 atm) and allowed to stir for 8 h after which it was quickly passed through a short pad of celite.
Concentration under reduced pressure followed by flash column chromatography (hexanes:ethyl
acetate = 3:1) using a positive pressure of N2 to avoid oxidation provided 4.8 g of 6 (92%) as an
air-sensitive white solid.
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mp 102-103 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H),
7.45 (td, J = 7.6, 1.1 Hz, 1H), 7.24 (td, J = 8.0, 0.9 Hz, 1H), 6.31 (s, 1H), 3.93 (s, 2H), 3.88 (s,
13
3H), 3.84 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 152.8, 135.4, 133.1, 129.2, 127.0, 122.4,
121.8, 120.7, 119.8, 97.4, 60.0, 55.7; IR (neat) 3458, 3362, 2935, 2834, 1628, 1602, 1462, 1447,
1398, 1380, 1261, 1222, 1156, 1081, 999, 827, 764 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C12H14NO2 204.1025; Found 204.1026.
(E)-N-(1,4-dimethoxynaphthalen-2-yl)but-2-enamide (S2). To a solution of 6 (203 mg, 1.00
mmol) in CH2Cl2 (5 mL) at rt was added crotonoyl chloride (105 μL, 1.10 mmol). After the
resulting reaction mixture had stirred for 15 min, a solution of Et3N (139 μL, 1.00 mmol) in
CH2Cl2 (5 mL) was added dropwise over 10 min. The reaction mixture was stirred for an
additional 20 min and then concentrated. The residue was dissolved in EtOAc (20 mL) and then
washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (aq., 10 mL). The
organic layer was dried (Na2SO4) and concentrated. Flash column chromatography (hexanes:ethyl
acetate = 5:1) gave 206 mg of S2 (76%) as a white solid.
mp 135-137 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 8.11 (broad s, 1H), 7.94-
7.93 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.05 (dq, J = 13.7, 6.7 Hz, 1H),
6.07 (d, J = 15.0 Hz, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 1.93 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 164.2, 152.2, 141.8, 136.7, 128.1,127.5, 126.9, 125.7, 124.3, 123.2, 122.7, 120.9,
98.9, 61.6, 55.8, 17.9; IR (neat) 3277, 2937, 2850, 1674, 1627, 1601, 1522, 1496, 1457, 1371,
1216, 1093, 975, 927, 830, 764 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C16H18NO3 272.1287;
Found 272.1287.
(E)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)but-2-enamide (7). To a solution of S2 (272 mg,
1.00 mmol) in CH3CN (16 mL) at rt was added a solution of ceric ammonium nitrate (1.21 g, 2.20
mmol) in a mixture of CH3CN (4 mL) and of H2O (4 mL). The resulting reaction mixture was
stirred for 15 min and then poured into H2O (20 mL). The aqueous phase was extracted with
EtOAc (3 × 40 mL) and the combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated. Flash column chromatography (hexanes:ethyl acetate = 4:1) gave 181 mg of 7
(75%) as a yellow solid.
mp 218-222 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.34 (broad s, 1H), 8.11 (d, J = 7.7 Hz, 2H), 7.92
(s, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.07 (dq, J = 13.9, 6.9 Hz, 1H), 6.08-
13
6.06 (m, 1H), 1.97 (dd, J = 6.9, 1.4 Hz, 3H); C{1H} NMR (126 MHz, CDCl3) δ 185.3, 181.2,
164.6, 144.8, 140.3, 135.1, 133.3, 132.4, 130.1, 126.8, 126.6, 124.7, 117.3, 18.3; IR (neat) 3313,
1662, 1642, 1614, 1592, 1507, 1341, 1307, 1194, 1098, 736 cm–1; HRMS (ESI) m/z: [M+Na]+
Calcd. for C14H11NO3Na 264.0637; Found 263.0640.
4-methyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione
(8)
and
4-
methylbenzo[g]quinoline-2,5,10(1H)-trione (marcanine A, 9). A solution of 7 (12.1 mg,
0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and purged with Ar for 10
min. The solution was then placed in the center of a photoreactor and irradiated for 4.25 h using
419 nm light (spectral window: 373-460 nm). The reaction mixture was concentrated and the
resulting residue subjected to flash column chromatography (gradient from hexanes:ethyl acetate
= 3:1 to hexanes:ethyl acetate = 1:1) to give 5.6 mg of 8 (47%) and 6.1 mg of 9 (marcanine A,
50%), both as yellow solids.
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8: mp 186-189 ˚C; H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 7.5 Hz,
1H), 8.11 (partially obscured s, 1H), 7.77 (td, J = 7.5, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H),
3.50 (pd, J = 7.2, 1.1 Hz, 1H), 2.76 (dd, J = 16.7, 7.3 Hz, 1H), 2.56 (d, J = 16.8 Hz, 1H), 1.20 (d,
J = 7.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.2, 179.3, 169.2, 137.8, 135.0, 133.5,
132.4, 130.4, 126.8, 126.5, 125.0, 37.1, 25.2, 19.0; IR (neat) 3299, 3218, 2962, 2923, 1691, 1674,
1645, 1631, 1593, 1465, 1445, 1358, 1332, 1297, 1239, 1209, 722 cm–1; HRMS (ESI) m/z:
[M+H]+ Calcd. for C14H12NO3 242.0817; Found 242.0818.
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9 (marcanine A): mp 264-289 ˚C, decomposed; 1H NMR (500 MHz, CDCl3) δ 9.68 (broad s, 1H),
8.24 (dt, J = 7.7, 0.7 Hz, 1H), 8.19 (dt, J = 7.7, 0.7 Hz, 1H), 7.87 (td, J = 7.6, 0.7 Hz, 1H), 7.78
(td, J = 7.6, 0.7 Hz, 1H), 6.69 (q, J = 0.7 Hz, 1H), 2.71 (d, J = 0.7 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 181.5, 178.1, 160.4, 152.3, 139.9, 136.0, 133.9, 133.3, 130.1, 127.8, 127.7, 126.8,
116.2, 23.0; IR (neat) 2926, 2856, 1646, 1591, 1465, 1400, 1374, 1339, 1295, 1165 cm–1; HRMS
(ESI) m/z: Calcd. for C14H10NO3 [M+H]+ 240.0661; Found 240.0664.
N-(1,4-dimethoxynaphthalen-2-yl)methacrylamide (S3). To a solution of 6 (87.4 mg, 0.430
mmol) in CH2Cl2 (5 mL) at rt was added methacrylic acid (55 mg, 0.65 mmol), EDC•HCl (125
mg, 0.650 mmol) and 4-DMAP (10 mg, 0.090 mmol). The reaction mixture was stirred overnight
and then concentrated. The resulting residue was dissolved in EtOAc (5 mL) and washed
sequentially with sat. NH4Cl (aq., 5 mL), H2O (2 × 2 mL), and brine (2 mL). The organic layer
was dried (Na2SO4), concentrated, and purified using flash column chromatography
(hexanes:ethyl acetate = 5:1) to provide 65.1 mg of S3 (56%) as white solid and as a mixture of
amide rotomers.
mp 96-108 ˚C. 1H NMR (500 MHz, CDCl3) δ 8.36 (bs, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.10 (s,
1H), 7.92 (d, J = 8.3 Hz, 1H), 7.49 (dd, J = 8.0, 6.9 Hz, 1H), 7.38 (dd, J = 8.1, 7.0 Hz, 1H), 5.91
(s, 1H), 5.50 (s, 1H), 4.01 (s, 3H), 3.87 (s, 1.5H), 3.86 (s, 1.5H), 2.12 (s 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 166.2, 152.2, 140.6, 136.7, 127.8, 127.4, 126.9, 124.2, 123.1, 122.6, 120.7, 120.4,
98.4, 61.4, 55.7, 18.6; IR (neat) 3424, 3071, 2936, 2850, 1680, 1627, 1601, 1520, 1495, 1457,
1419, 1372, 1291, 1253, 1216,1162, 1122, 1091, 1032, 997, 974 cm–1; HRMS (ESI) m/z: [M+H]+
Calcd. for C16H18NO3 272.1287; Found 272.1293.
N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)methacrylamide (10). To a solution of S3 from
above in CH3CN (4 mL) at rt was added a mixture of ceric ammonium nitrate (290 mg, 0.53
mmol) in CH3CN (1 mL) and H2O (1 mL). The resulting reaction mixture was stirred for 15 min
and then poured into H2O (5 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL) and
the combined organic extracts were washed with brine (15 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (hexanes:ethyl acetate = 4:1) gave 46.7 mg of 10
(80%) as a yellow solid.
mp 116-118 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.84 (broad s, 1H), 8.10-8.09 (m, 2H), 7.87 (s,
1H), 7.77 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 5.93 (s, 1H), 5.62 (s, 1H), 2.08 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 185.2, 181.2, 166.8, 140.1, 139.8, 135.1, 133.4, 132.3, 130.1,
126.8, 126.5, 122.5, 117.2, 18.5; IR (neat) 3373, 1699, 1666, 1650, 1620, 1595, 1505, 1458,
1337, 1298, 1198, 1107, 723 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C14H12NO3 242.0817;
Found 242.0821.
3-methyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione
(11)
and
3-
methylbenzo[g]quinoline-2,5,10(1H)-trione (12). A solution of 10 (12.1 mg, 0.05 mmol) in
CHCl3 (20 mL) in two 10 mm NMR tubes was purged with Ar for 10 min. The resulting solution
was placed in the center of a photoreactor and irradiated with 419 nm light (spectral window:
373-460 nm) for 75 min after which the reaction mixture was concentrated. The resulting residue
was subjected to flash column chromatography (gradient from hexanes:ethylacetate = 2:1 to
hexanes:ethylacetate = 1:1) to give 9.2 mg of 11 (76%) along with 2.5 mg of 12 (21%), both as
yellow solids.
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11: mp 251-252 ˚C; H NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 7.6, 1.0 Hz, 1H), 8.00 (dd, J =
7.6, 1.3 Hz, 1H), 7.99 (broad s, 1H), 7.77 (td, J = 7.5, 1.4 Hz, 1H), 7.71 (td, J = 7.5, 1.4 Hz, 1H),
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3.21 (dd, J = 17.7, 6.9 Hz, 1H), 2.72-2.67 (m, 1H), 2.58 (dd, J = 17.7, 11.7 Hz, 1H), 1.35 (d, J =
6.9 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.7, 178.9, 172.5, 139.0, 135.0, 133.4, 132.4,
130.5, 126.8, 126.6, 120.1, 34.2, 26.5, 15.7; IR (neat) 3226, 2923, 2850, 1687, 1674, 1644, 1632,
1593, 1461, 1448, 1370, 1330, 1301, 1221, 791, 719 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C14H12NO3 242.0817; Found 242.0824.
12: mp 240-280 ˚C, decomposed, 1H NMR (500 MHz, CDCl3) δ 9.46 (broad s, 1H), 8.25 (d, J =
7.5 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.00 (s, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.79 (t, J = 7.5 Hz,
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1H), 2.31 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 180.4, 177.9, 161.9, 138.8, 137.2, 135.5,
134.1, 132.8, 132.3, 131.0, 127.5, 127.1, 117.0, 17.6; IR (neat) 2919, 2849, 1681, 1661, 1638,
1594, 1564, 1486, 1393, 1378, 1336, 1245 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C14H10NO3
240.0661; Found 240.0665.
(E)-N-(1,4-dimethoxynaphthalen-2-yl)-2-methylbut-2-enamide (S4). To a solution of 6 (203
mg, 1.00 mmol) in CH2Cl2 (10 mL) at rt was added tiglic acid (150 mg, 1.50 mmol), EDC•HCl
(290 mg, 1.5 mmol), and 4-DMAP (24.4 mg, 0.200 mmol). The reaction mixture was stirred
overnight and then concentrated. The resulting residue was dissolved in EtOAc (10 mL) and
washed with saturated NH4Cl (aq., 10 mL), H2O (2 × 5 mL), and brine (5 mL). The organic layer
was dried (Na2SO4) and concentrated. Flash column chromatography (hexanes:ethylacetate = 8:1)
gave 232 mg of S4 (81%) as a white solid.
mp 94-97 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.28 (broad s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.12 (s,
1H), 7.94 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.39 (td, J = 7.6, 1.1 Hz, 1H), 6.68-6.64
13
(m, 1H), 4.02 (s, 3H), 3.90 (s, 3H), 2.02 (d, J = 0.8 Hz, 3H), 1.87 (d, J = 6.9 Hz, 3H); C{1H}
NMR (126 MHz, CDCl3) δ 167.4, 152.4, 136.7, 132.8, 132.1, 128.4, 127.6, 127.0, 124.2, 123.1,
122.7, 120.9, 98.7, 61.6, 55.9, 14.4, 12.6; IR (neat) 3430, 2937, 1676, 1629, 1602, 1520, 1495,
1457, 1375, 1266, 1214, 1095, 997, 767 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C17H20NO3
286.1443; Found 286.1449.
(E)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-methylbut-2-enamide (13). To a solution of
S4 (57.1 mg, 0.200 mmol) in CH3CN (4 mL) at rt was added a mixture of ceric ammonium nitrate
(241 mg, 0.440 mmol) in CH3CN (1 mL) and H2O (1 mL). The reaction mixture was stirred for
15 min and then poured into H2O (5 mL). The aqueous phase was extracted with EtOAc (3 × 5
mL) and the combined organic extracts were washed with brine (15 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (toluene:ethyl acetate = 20:1) gave 48.5 mg of 13
(95%) as a yellow solid.
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mp 126-128 ˚C; H NMR (500 MHz, CDCl3) δ 1:1 mixture of two conformers, 8.78 (broad s,
1H), 8.10 (d, J = 7.7 Hz, 2H), 7.88 (s, 1H), 7.78 (td, J = 7.5, 1.3 Hz, 1H), 7.71 (td, J = 7.5, 1.4 Hz,
1H), 6.69-6.65 (m, 1H), 1.970 (s, 1.5H), 1.968 (s, 1.5H), 1.880 (d, J = 6.9 Hz, 1.5 H), 1.866 (d, J
= 6.9 Hz, 1.5 H); 13C{1H} NMR (126 MHz, CDCl3) δ 185.3, 181.5, 167.7, 140.4, 135.1, 134.5,
133.3, 132.4, 132.2, 130.2, 126.7, 126.5, 116.9, 14.5, 12.3; IR (neat) 3376, 1666, 1649, 1502,
1334, 1299, 1228, 1197, 1103, 885, 783, 716 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C15H14NO3 256.0974; Found 255.0975.
3,4-dimethyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (14). A solution of 13 (12.8 mg,
0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then purged with Ar
for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated with
419 nm light (spectral window: 373-460 nm) for 25 min. after which the reaction mixture was
concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 5:1) to give 11.5 mg of 14 (90%, cis:trans = 15.2:1) as a yellow solid.
mp 230 -233 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H),
8.02 (broad s, 1H), 7.76 (td, J = 7.5, 1.0 Hz, 1H), 7.70 (td, J = 7.5, 1.0 Hz, 1H), 3.37 (dq, J = 6.9,
6.9 Hz, 1H), 2.28 (qd, J = 6.8, 6.8 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.2 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 182.1, 179.4, 172.3, 138.0, 134.9, 133.3, 132.4, 130.5, 126.7,
126.5, 126.2, 38.8, 30.4, 12.4, 11.1; IR (neat) 3309, 2924, 2852, 1708, 1670, 1632, 1594, 1468,
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1454, 1330, 1301, 1213, 722 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C15H14NO3 256.0974;
Found 256.0976.
N-(1,4-dimethoxynaphthalen-2-yl)cinnamamide (S5). To a solution of 6 (203 mg, 1.00 mmol)
in CH2Cl2 (5 mL) at rt was added cinnamoyl chloride (183 mg, 1.10 mmol). After the resulting
reaction mixture had stirred for 15 min, a solution of Et3N (139 μL, 1.00 mmol) in CH2Cl2 (5 mL)
was added dropwise over a period of 10 min. The reaction mixture was allowed to stir for an
additional 2 h and then concentrated. The resulting residue was dissolved in EtOAc (20 mL) and
then washed with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (10 mL). The organic
phase was dried (Na2SO4) and concentrated. Flash column chromatography (hexanes:ethyl acetate
= 5:1) gave 260. mg of S5 (78%) as a pale yellow solid.
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mp 170-172 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.4 Hz, 1H), 8.19 (broad s, 1H), 8.09
(broad s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 15.5 Hz, 1H), 7.60-7.58 (m, 2H), 7.53 (t, J =
7.1, 7.1 Hz, 1H), 7.43-7.39 (m, 4H), 6.67 (d, J = 15.5 Hz, 1H), 4.04 (s, 3H), 3.93 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 164.2, 152.3, 142.7, 136.8, 134.7, 130.2, 129.0, 128.2, 127.6, 127.1,
124.4, 123.4, 122.8, 121.1, 121.0, 98.8, 61.8, 55.9; IR (neat) 3242, 3004, 2933, 2841, 1665, 1623,
1600, 1588, 1522, 1496, 1457, 1448, 1416, 1371, 1332, 1275, 1259, 1217, 1162, 1124, 1092,
1035, 993, 976, 824, 763, 734, 717 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C21H20NO3
334.1443; Found 334.1446.
N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)cinnamamide (16). To a solution of S5 (123 mg,
0.370 mmol) in CH3CN (5 mL) at rt was added a mixture of ceric ammonium nitrate (446 mg,
0.810 mmol) in CH3CN (1.5 mL) and H2O (1.5 mL). The resulting reaction mixture was stirred
for 15 min and then poured into H2O (8 mL). The aqueous phase was extracted with EtOAc (3 ×
15 mL) and the combined organic extracts were washed with brine (45 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (toluene:ethyl acetate = 20:1) gave 79 mg of 16
(70%) as a yellow solid.
mp 250-252 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.52 (broad s, 1H), 8.15 (ddd, J = 7.3, 5.9, 1.0 Hz,
2H), 7.99 (s, 1H), 7.81 (d, J = 15.5 Hz, 1H), 7.80 (td, J = 7.5, 1.3 Hz, 1H), 7.74 (td, J = 7.6, 1.3
Hz, 1H), 7.60-7.58 (m, 2H), 7.44-7.42 (m, 3H), 6.64 (d, J = 15.6 Hz, 1H); 13C{1H} NMR (126
MHz, CDCl3) δ 185.3, 181.3, 164.8, 144.9, 140.4, 135.2, 134.2, 133.4, 132.5, 130.9, 130.2, 129.2,
128.5, 126.9, 126.6, 119.7, 117.6; IR (neat) 3309, 1669, 1637, 1593, 1579, 1506, 1450, 1336,
1303, 1197, 1155, 1112, 984, 721 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for C19H13NO3Na
326.0793; Found 326.0788.
4-phenyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (17). A solution of 16 (15.0 mg,
0.0500 mmol) in CHCl3 (20 mL) that had been purged with N2 gas for 10 min was placed in a
photoreactor and irradiated with 419 nm light (spectral window of lamps: 373-460 nm). After
TLC indicated that the starting material had been consumed (ca. 6 h) the reaction mixture was
concentrated. Flash column chromatography (hexanes:ethyl acetate = 3:1) afforded 4.9 mg of 17
(33%) as a yellow solid.
mp 197-200 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.15 (broad s, 1H), 8.11 (partially obscured dd, J
= 6.9, 0.8 Hz, 1H), 8.09 (partially obscured dd, J = 6.9, 0.8 Hz, 1H), 7.77 (td, J = 7.5, 1.4 Hz,
1H), 7.72 (td, J = 7.5, 1.4 Hz, 1H), 7.29-7.27 (m, 4H), 7.24-7.21 (m, 1H), 4.67 (dd, J = 8.2, 1.3
Hz, 1H), 3.05 (dd, J = 17.1, 8.2 Hz, 1H), 2.95 (d, J = 17.0 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3) δ 182.2, 179.4, 168.8, 140.6, 138.4, 135.1, 133.6, 132.3, 130.4, 129.3, 127.8, 127.0,
127.0, 126.6, 122.6, 36.9, 35.4; IR (neat) 3296, 2922, 2851, 1708, 1672, 1635, 1594, 1579, 1464,
1452, 1350, 1330, 1301, 1222, 1159, 1145, 980, 936, 721, 707 cm–1; HRMS (ESI) m/z: [M+Na]+
Calcd. for C19H13NO3Na 326.0793; Found 326.0801.
(E)-3-(2-chlorophenyl)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)acrylamide (19). A mixture
of 6 (203 mg, 1.00 mmol) 2-chlorocinnamic acid (274 mg, 1.50 mmol), EDC•HCl (288 mg, 1.50
mmol) and 4-DMAP (24.4 mg, 0.200 mmol) in CH2Cl2 (10 mL) at rt was allowed to stir
overnight and then concentrated. The resulting residue was dissolved in EtOAc (10 mL) and
washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 × 5 mL), and brine (5 mL). The
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organic layer was dried (Na2SO4) and concentrated. The resulting hydroquinone (E)-3-(2-
chlorophenyl)-N-(1,4-dimethoxynaphthalen-2-yl)acrylamide was used without additional
purification.
To hydroquinone (E)-3-(2-chlorophenyl)-N-(1,4-dimethoxynaphthalen-2-yl)acrylamide
from above in CH3CN (5 mL) at rt was added a mixture of ceric ammonium nitrate (1.2 g, 2.2
mmol) in CH3CN (7.5 mL) and H2O (7.5 mL). The reaction mixture was stirred for 15 min and
then poured into H2O (15 mL). The aqueous phase was extracted with EtOAc (3 × 40 mL) and
the combined organic extracts were washed with brine (120 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (toluene:ethyl acetate = 20:1) gave 176 mg of 19
(52%, 2 steps) as a yellow solid.
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mp 261-263 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.56 (broad s, 1H), 8.20 (d, J = 15.6 Hz, 1H), 8.15
(d, J = 6.6 Hz, 1H), 8.14 (d, J = 7.0 Hz, 1H), 8.00 (s, 1H), 7.81 (td, J = 7.5, 1.1 Hz, 1H), 7.74 (td,
J = 7.6, 1.1 Hz, 1H), 7.67 (dd, J = 7.4, 1.8 Hz, 1H), 7.46 (dd, J = 8.8, 1.1 Hz, 1H), 7.37-7.31 (m,
2H), 6.65 (d, J = 15.6 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) 185.1, 180.4, 165.4, 141.8,
137.3, 134.9, 133.8, 133.7, 132.2, 131.8, 131.4, 130.3, 130.2, 127.9, 127.8, 126.4, 125.5, 124.5,
116.7; IR (neat) 3313, 3066, 2920, 1694, 1664, 1642, 1594, 1498, 1351, 1334, 1301, 1255, 1190,
1157, 1108, 981, 737, 721, 666 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for C19H12NO3Na35Cl
360.0403; Found 360.0403, Calcd. for C19H12NO3Na37Cl 362.0374; Found 362.0396.
4-(2-chlorophenyl)-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (20). A solution of 19 (15
mg, 0.050 mmol) in CHCl3 (20 mL) that had been purged with N2 gas for 10 min was placed in a
photoreactor and irradiated at 419 nm (spectral window of lamps: 373-460 nm). After TLC
indicated that the starting material had been consumed (ca. 7 h) the reaction mixture was removed
from the photoreactor and concentrated. Flash column chromatography (hexanes:ethyl acetate =
5:1) afforded 3 mg of 20 (20%) as a yellow solid.
mp 241-243 ˚C; 1H NMR (400 MHz, CDCl3) 8.20 (broad s, 1H), 8.17 (dd, J = 7.4, 1.3 Hz, 1H),
8.07 (dd, J = 7.3, 1.3 Hz, 1H), 7.78-7.76 (m, 2H), 7.44 (dd, J = 7.9, 1.3 Hz, 1H), 7.19 (td, J = 7.5,
1.7, Hz, 1H), 7.11 (td, J = 7.6, 1.4 Hz, 1H), 7.00 (dd, J = 7.7, 1.6 Hz, 1H), 5.12 (dd, J = 8.8, 1.6
Hz, 1H), 3.05 (dd, J = 17.2, 8.9 Hz, 1H), 2.90 (ddd, J = 17.3, 1.7, 1.0 Hz, 1H); 13C{1H} NMR
(126 MHz, CDCl3) δ 181.7, 179.2, 168.0, 140.2, 137.2, 135.3, 133.6, 133.4, 132.3, 130.8, 130.5,
129.2, 127.6, 127.1, 127.0, 126.7, 121.3, 36.5, 33.1; IR (neat) 3200, 3100, 2921, 2852, 1719,
1672, 1651, 1633, 1593, 1467, 1355, 1333, 1301, 1288, 1222, 1037, 750, 716 cm-1; HRMS (ESI)
m/z: [M+Na]+ Calcd. for C19H12NO3Na35Cl 360.0403; Found 360.0404, Calcd. for
C19H12NO3Na37Cl 362.0374; Found 360.0385.
(E)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-3-(3-methoxyphenyl)acrylamide
(22).
A
solution containing 6 (203 mg, 1.00 mmol) 3-methoxycinnamic acid (267 mg, 1.50 mmol),
EDC•HCl (288 mg, 1.50 mmol) and 4-DMAP (24.4 mg, 0.200 mmol) in CH2Cl2 (10 mL) at rt
was allowed to stir overnight. After the reaction mixture was concentrated, the resulting residue
was dissolved in EtOAc (10 mL) and washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 ×
5 mL), and brine (5 mL). The organic layer was dried (Na2SO4) and concentrated. The resulting
hydroquinone (E)-N-(1,4-dimethoxynaphthalen-2-yl)-3-(3-methoxyphenyl)acrylamide was used
in the subsequent oxidation without additional purification.
To
a solution of the hydroquinone (E)-N-(1,4-dimethoxynaphthalen-2-yl)-3-(3-
methoxyphenyl)acrylamide from above in CH3CN (15 mL) at rt was added a mixture of ceric
ammonium nitrate (1.2 g, 2.2 mmol) in CH3CN (4 mL) and H2O (4 mL). The reaction mixture
was stirred for 15 min and then poured into H2O (15 mL). The aqueous phase was extracted with
EtOAc (3 × 40 mL) and the combined organic extracts were washed with brine (120 mL), dried
(Na2SO4), and concentrated. Flash column chromatography (toluene:ethyl acetate = 20:1) gave
150 mg of 22 (45%, 2 steps) as a yellow solid.
mp 197-199 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.52 (broad s, 1H), 8.13 (t, J = 7.1 Hz, 2H), 7.98
(s, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 15.5 Hz, 1H), 7.73 (partially obscured t, J = 7.3 Hz,
1H), 7.33 (dd, J = 8.0, 7.9 Hz, 1H),7.18 (d, J = 7.7 Hz, 1H), 7.09 (broad s, 1H), 6.97 (dd, J = 8.2,
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2.2 Hz, 1H), 6.62 (d, J = 15.5 Hz, 1H), 3.86 (s, 3H) C{1H} NMR (126 MHz, CDCl3) δ 185.3,
181.3, 164.7, 160.2, 144.8, 140.3, 135.5, 135.2, 133.4, 132.5, 130.2, 130.2, 126.9, 126.6, 121.1,
119.9, 117.5, 116.8, 113.4, 55.5; IR (neat) 3285, 3098, 2918, 1670, 1633, 1593, 1527, 1353,
1304, 1232, 1201, 1163, 1109, 974, 783, 732 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for
C20H15NO4Na 356.0899; Found 356.0897.
4-(3-methoxyphenyl)-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (23). A solution of 22
(34.0 mg, 0.100 mmol) in CHCl3 (40 mL) was purged with N2 gas for 10 min, placed in a
photoreactor and irradiated at 419 nm (spectral window of lamps: 373-460 nm). After TLC
indicated that the starting material had been consumed (ca. 12 h) the reaction mixture was
concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1) afforded 6.9 mg of 23
(20%) as a yellow solid.
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mp 225-228 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.15 (broad s, 1H), 8.11 (td, J = 7.1, 7.1, 0.9 Hz,
1H), 8.10 (d, J = 6.5 Hz, 1H), 7.76 (td, J = 7.4, 1.4 Hz, 1H), 7.71 (td, J = 7.4, 1.5 Hz, 1H), 7.20 (t,
J = 8.0 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.84 (t J = 1.8 Hz, 1H), 6.76 (dd, J = 7.5, 1.8 Hz, 1H),
4.64 (d, J = 7.9 Hz, 1H), 3.76 (s, 3H), 3.03 (dd, J = 17.0, 8.2 Hz, 1H), 2.93 (d, J = 16.7 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3) δ 182.2, 179.3, 168.7, 160.1, 142.1, 138.5, 135.1, 133.5, 132.3,
130.4, 130.3, 127.0, 126.6, 122.4, 119.1, 113.3, 112.7, 55.4, 37.0, 35.4; IR (neat) 3296, 2924,
2854, 1706, 1672, 1633, 1594, 1489, 1463, 1452, 1331, 1299, 1219, 1140, 1050, 733 cm–1;
HRMS (ESI) m/z: [M+Na]+ Calcd. for C20H15NO4Na 356.0899; Found 356.0894.
N-(1,4-dimethoxynaphthalen-2-yl)-3-methylbut-2-enamide (S6). To a solution of 6 (203 mg,
1.00 mmol) in CH2Cl2 (5 mL) at rt was added 3,3-dimethylacryloyl chloride (122 μL, 1.10
mmol). After the reaction mixture had stirred for 15 min a solution of Et3N (139 μL, 1.00 mmol)
in CH2Cl2 (5 mL) was added to it dropwise over 10 min. After stirring for an additional 2 h the
reaction mixture was concentrated. The resulting residue was dissolved in EtOAc (20 mL) and
washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (10 mL). The
organic phase was then dried (Na2SO4) and concentrated. Flash column chromatography
(hexanes:ethyl acetate = 9:1) gave 265 mg of S6 (93%) as a white solid and a 1:1 mixture of two
conformational isomers.
mp 122-123 ˚C; 1H NMR (500 MHz, CDCl3) δ, 8.20 (d, J = 8.4 Hz, 1H), 8.12 (broad s, 1H), 7.93
(d, J = 8.4 Hz, 1H), 7.84 (broad s, 1H), 7.50 (dd, J = 7.8, 7.0 Hz, 1H), 7.38 (dd, J = 7.8, 7.1 Hz,
1H), 5.82 (s, 0.5H), 5.821 (s, 0.5H), 4.03 (s, 3H), 3.887 (s, 1.5H), 3.886 (s, 1.5H), 2.28 (s, 3H),
1.93 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 165.2, 153.8, 152.2, 136.3, 128.5, 127.6, 126.9,
124.0, 123.0, 122.7, 120.9, 119.0, 98.7, 61.6, 55.9, 27.5, 20.1; IR (neat) 3313, 2934, 2850, 1669,
1626, 1599, 1491, 1454, 1416, 1368, 1279, 1255, 1211, 1158, 1140, 1095, 1030, 992, 976 cm–1;
HRMS (ESI) m/z: [M+H]+ Calcd. for C17H20NO3 286.1443; Found 286.1445.
N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-3-methylbut-2-enamide (29). To a solution of S6
(143 mg, 0.500 mmol) in CH3CN (8 mL) at rt was added a mixture of ceric ammonium nitrate
(603 mg, 1.10 mmol) in CH3CN (2 mL) and H2O (2 mL). The resulting reaction mixture was
stirred for 15 min and then poured into H2O (10 mL). The aqueous phase was extracted with
EtOAc (3 × 20 mL) and the combined organic extracts were washed with brine (60 mL), dried
(Na2SO4), and concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1) gave
111 mg of 29 (87%) as a yellow solid.
mp 193-195˚C; 1H NMR (500 MHz, CDCl3) δ 8.25 (broad s, 1H), 8.09 (d, J = 7.5 Hz, 2H), 7.90
(s, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 5.83 (s, 1H), 2.24 (s, 3H), 1.96 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 185.3, 181.3, 165.3, 158.0, 140.6, 135.0, 133.2, 132.4, 130.2,
126.8, 126.5, 117.9, 116.5, 27.8, 20.5; IR (neat) 3308, 3079, 1667, 1639, 1612, 1594, 1493, 1338,
1308, 1218, 1200, 1146, 1105,1084 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C15H14NO3
256.0974; Found 256.0975.
4,4-dimethyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (30). A solution of 29 (12.8 mg,
0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then purged with Ar
for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated with
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419 nm light (spectral window: 373-460 nm) for 16 h after which the reaction mixture was
concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 2:1) to give 7.2 mg of 30 (56%) as a yellow solid.
mp 198-201 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.26 (broad s, 1H), 8.08 (dd, J = 7.7, 1.4 Hz, 1H),
8.06 (dd, J = 7.7, 1.3 Hz, 1H), 7.77 (td, J = 7.4, 1.3 Hz, 1H), 7.69 (td, J = 7.6, 1.3 Hz, 1H), 2.52
(s, 2H), 1.48 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.8, 179.5, 168.8, 138.1, 135.1,
133.5, 133.1, 129.8, 127.2, 126.8, 126.2, 46.7, 35.3, 27.0; IR (neat) 3208, 3132, 2962, 2921,
1717, 1689, 1674, 1645, 1611, 1594, 1465, 1327, 1296, 1210 cm–1; HRMS (ESI) m/z: [M+H]+
Calcd. for C15H14NO3 256.0974; Found 256.0977.
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N-(1,4-dimethoxynaphthalen-2-yl)-2,3-dimethylbut-2-enamide (S7). To a solution of 2,3-
dimethylbut-2-enoic acid (28.5 mg, 0.250 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (20
μL, 0.25 mmol) and a drop of DMF. The resulting reaction mixture was stirred at rt for 1 h after
which a solution of 6 (55.9 mg, 0.280 mmol) in CH2Cl2 was added. After stirring for an additional
10 min, Et3N (35 μL, 0.25 mmol) was added to the reaction mixture. After stirring for an
additional 1h, the reaction mixture was concentrated. The residue was dissolved in EtOAc (5 mL)
and washed with sat. NH4Cl (aq., 2 mL), H2O (2 × 2 mL), and brine (2 mL). The organic phase
was dried (Na2SO4) and concentrated. Flash column chromatography (hexanes:ethyl acetate =
5:1) gave 40.7 mg (54%) of S7 as a colorless viscous oil.
1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H),
7.89 (broad s, 1H), 7.51 (dd, J = 7.9, 7.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 4.04 (s, 3H), 3.89 (s,
3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.81 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 170.7, 152.4,
136.5, 134.1, 128.2, 127.9, 127.6, 127.0, 124.2, 123.2, 122.8, 120.9, 98.6, 61.9, 56.0, 22.5, 20.6,
16.3; IR (neat) 3418, 2936, 2853, 1673, 1628, 1601, 1589, 1491, 1456, 1417, 1372, 1291, 1217,
1110, 1088, 996, 767 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for C18H21NO3Na 322.1419;
Found 322.1423.
N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,3-dimethylbut-2-enamide (31). To a solution of
S7 (21.1 mg, 0.0700 mmol) in CH3CN (2 mL) at rt was added a mixture of CAN (85.0 mg, 0.155
mmol) in CH3CN (1 mL) and H2O (1 mL). The resulting reaction mixture was stirred for 15 min
and then poured into H2O (2 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL), and
the combined organic extracts were washed with brine (15 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1) gave 14.8 mg (75%) of
31 as yellow solid.
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mp 106-108 ˚C; H NMR (500 MHz, CDCl3) δ 8.39 (broad s, 1H), 8.11-8.09 (m, 2H), 7.91 (s,
1H), 7.78 (td, J = 7.5, 1.3 Hz, 1H), 7.71 (td, J = 7.5, 1.3 Hz, 1H) 1.94 (m, 3H), 1.92 (m, 3H),
1.81-1.80 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 185.4, 181.4, 170.9, 140.2, 138.2, 135.1,
133.3, 132.3, 130.2, 126.8, 126.5, 126.2, 117.0, 22.6, 21.2, 16.1; IR (neat) 3376, 2919, 1666,
1649, 1616, 1594, 1495, 1334, 1300, 1198, 1083, 721 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd.
for C16H15NO3Na 292.0950; Found 292.0948.
3,4,4-trimethyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione (32). A solution of 31 (13.5
mg, 0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and purged with Ar
for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated with
419 nm light (spectral window of lamps: 373-460 nm) for 40 min after which the reaction mixture
was concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 5:1) to give 12.3 mg of 32 (91%) as a yellow solid.
mp 172-174 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.18 (broad s, 1H), 8.08 (dd, J = 7.2, 1.1 Hz, 1H),
8.06 (dd, J = 7.2, 1.1 Hz, 1H), 7.77 (td, J = 7.6, 1.2 Hz, 1H), 7.69 (td, J= 7.6, 1.2 Hz, 1H), 2.38
(q, J = 7.2 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.22 (d, J= 7.2 Hz, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 183.2, 179.4, 172.7, 137.8, 135.1, 133.8, 133.0, 129.7, 126.8, 126.6, 126.1, 48.1, 38.1,
26.3, 21.9, 11.4; IR (neat) 3309, 2972, 1709, 1671, 1646, 1611, 1464, 1450, 1329, 1297 cm–1;
HRMS (ESI) m/z: [M+Na]+ Calcd. for C16H15NO3Na 292.0950; Found 292.0954.
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2-cyclopentylidene-N-(1,4-dimethoxynaphthalen-2-yl)acetamide (S8). To a solution of 2-
cyclopentylideneacetic acid (121 mg, 0.960 mmol) in CH2Cl2 (10 mL) at rt was added oxalyl
chloride (82 μL, 0.96 mmol) and one drop of DMF. After stirring for 1 h, amine 6 (162 mg, 0.800
mmol) was added to the reaction mixture. After an additional 10 min, Et3N (134 μL, 0.96 mmol)
was added dropwise and the reaction mixture was stirred for another 1 h after which it was
concentrated. The resulting residue was dissolved in EtOAc (20 mL) and washed sequentially
with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (10 mL). The organic phase was then
dried (Na2SO4) and concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1)
gave 157 mg of S8 (63%) as a white solid.
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mp 136-137˚C; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 8.15 (broad s, 1H), 7.92
(d, J = 8.4 Hz, 1H), 7.83 (broad s, 1H), 7.51 (td, J = 6.8, 1.0 Hz, 1H), 7.38 (td, J = 7.6, 1.0 Hz,
1H), 5.98 (t, J = 2.1 Hz, 1H), 4.03 (s, 3H), 3.88 (s, 3H), 2.94 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 7.1
Hz, 2H), 1.81 (p, J = 6.9 Hz, 2H), 1.70 (p, J = 6.8 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ
166.6, 165.2, 152.2, 136.1, 128.7, 127.6, 126.9, 124.0, 122.9, 122.7, 120.8, 114.6, 98.6, 61.6,
56.0, 36.2, 32.5, 26.7, 25.5; IR (neat) 3314, 2954, 2926, 2854, 1669, 1627, 1603, 1520, 1495,
1456, 1417, 1377, 1255, 1216, 1190, 1118, 1094 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C19H22NO3 312.1600; Found 312.1603.
2-cyclopentylidene-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetamide (33). To a solution of
S8 (141 mg, 0.500 mmol) in CH3CN (7 mL) at rt was added a mixture of ceric ammonium nitrate
(603 mg, 1.10 mmol) in CH3CN (2 mL) and H2O (2 mL). The reaction mixture was stirred for 15
min and then poured into H2O (10 mL). The aqueous phase was extracted with EtOAc (3 × 20
mL) and the combined organic extracts were washed with brine (60 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1) gave 115 mg of 33
(92%) as a yellow solid.
mp 166-167 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.28 (broad s, 1H), 8.08 (d, J = 7.3 Hz, 2H), 7.91
(s, 1H), 7.76 (td, J = 7.5, 1.3 Hz, 1H), 7.70 (td, J = 7.6, 1.3 Hz, 1H), 5.99 (p, J = 2.1 Hz, 1H), 2.87
(t, J = 7.3 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.79 (p, J = 6.9 Hz, 2H), 1.69 (p, J = 7.0 Hz, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 185.3, 181.4, 170.9, 165.3, 140.6, 135.0, 133.2, 132.4, 130.1,
126.7, 126.4, 116.2, 113.5, 36.5, 33.0, 26.6, 25.5; IR (neat) 3274, 2947, 1668, 1634, 1611, 1593,
1512, 1340, 1302, 1201, 1106 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C17H16NO3 282.1130;
Found 282.1131.
1H-spiro[benzo[g]quinoline-4,1'-cyclopentane]-2,5,10(3H)-trione (34). A solution of 33 (14.1
mg, 0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then purged with
Ar for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated
with 419 nm light (spectral window: 373-460 nm) for 26 h after which the reaction mixture was
concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 5:1) to give 6.8 mg of 34 (48%) as a yellow solid.
mp 196-198 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.21 (broad s, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.77
(td, J = 7.5, 0.8 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 2.57 (s, 2H), 2.30 (dt, J = 12.5, 7.4 Hz, 2H),
2.04-1.96 (m, 2H), 1.81-1.73 (m, 2H), 1.61 (dt, J = 12.1, 6.0 Hz, 2H); 13C{1H} NMR (126 MHz,
CDCl3) δ 182.7, 179.3, 168.6, 138.6, 135.1, 133.5, 133.1, 129.8, 127.7, 126.8, 126.2, 44.7, 44.6,
38.4, 26.2; IR (neat) 3010, 2956, 2868, 1716, 1667, 1642, 1608, 1594, 1578, 1465, 1329, 1299,
1288, 1207, 1147, 998, 714 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C17H16NO3 282.1130;
Found 282.1131.
2-cyclohexylidene-N-(1,4-dimethoxynaphthalen-2-yl)acetamide (S9). To a solution of 2-
cyclohexylideneacetic acid (168 mg, 1.20 mmol) in CH2Cl2 (10 mL) at rt was added oxalyl
chloride (103 μL, 1.20 mmol) and one drop of DMF. After stirring for 1 h a solution of 6 (203
mg, 1.00 mmol) in CH2Cl2 (2 mL) was added to the reaction mixture. After 10 min, Et3N (167
μL, 1.20 mmol) was added dropwise and the reaction mixture was stirred for an additional 1 h
after which it was concentrated. The resulting residue was dissolved in EtOAc (20 mL) and
washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (10 mL). The
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organic phase was then dried (Na2SO4) and concentrated. Flash column chromatography
(hexanes:ethyl acetate = 10:1) gave 215 mg of S9 (66%) as a white solid.
mp 132-134 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 8.14 (broad s, 1H), 7.93
(d, J = 8.4 Hz, 1H), 7.86 (broad s, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 5.76 (s
1H), 4.03 (s, 3H), 3.89 (s, 3H), 2.96-2.94 (m, 2H), 2.27-2.24 (m, 2H), 1.73-1.67 (m, 4H), 1.65-
1.61 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 165.4, 161.0, 152.3, 136.2, 128.5, 127.6,
127.0, 124.1, 123.0, 122.7, 120.9, 116.3, 98.6, 61.7, 56.0, 38.2, 29.9, 28.8, 28.1, 26.5; IR (neat)
3316, 2924, 2852, 1665, 1627, 1601, 1519, 1493, 1455, 1417, 1370, 1255, 1217, 1163, 1124,
1092, 995, 978, 847, 765 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C20H24NO3 326.1756;
Found 326.1756.
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2-cyclohexylidene-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetamide (35). To a solution of
S9 (163 mg, 0.500 mmol) in CH3CN (7 mL) at rt was added a mixture of ceric ammonium nitrate
(603 mg, 1.10 mmol) in CH3CN (2 mL) and H2O (2 mL). The reaction mixture was stirred for 15
min and then poured into H2O (10 mL). The aqueous phase was extracted with EtOAc (3 × 20
mL) and the combined organic extracts were washed with brine (60 mL), dried (Na2SO4), and
concentrated. Flash column chromatography (hexanes:ethyl acetate =10:1) gave 132 mg of 35
(90%) as a yellow solid.
mp 182-184 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.29 (broad s, 1H), 8.08 (d, J = 7.7 Hz, 2H), 7.89
(s, 1H), 7.76 (td, J = 7.4, 1.3 Hz, 1H), 7.69 (td, J = 7.6, 1.3 Hz, 1H), 5.75 (s, 1H), 2.88 (t, J = 5.5
Hz, 2H), 2.24 (t, J = 5.5 Hz, 2H), 1.69-1.61 (m, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 185.3,
181.3, 165.5, 165.0, 140.5, 135.0, 133.2 132.4, 130.1, 126.7, 126.4, 116.5, 115.0, 38.3, 30.0, 28.9,
28.0, 26.3; IR (neat) 3330, 2927, 2854, 1664, 1643, 1609, 1594, 1500, 1339, 1307, 1192, 1151,
1101 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for C18H17NO3Na 318.1106; Found 318.1111.
1H-spiro[benzo[g]quinoline-4,1'-cyclohexane]-2,5,10(3H)-trione (36). A solution of 35 (14.8
mg, 0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then purged with
Ar for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated
with 419 nm light (spectral window: 373-460 nm) for 10 h after which the reaction mixture was
concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 5:1) to give 12.1 mg of 36 (82%) as a yellow solid.
mp 227-229 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.32 (broad s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 8.04
(d, J = 7.3 Hz, 1H), 7.76 (td, J = 7.6, 1.0 Hz, 1H), 7.67 (td, J = 7.6, 0.8 Hz, 1H), 2.79 (s, 2H), 2.55
(t, J = 3.5 Hz, 1H), 2.54 (t, J = 4.3 Hz, 1H), 1.76-1.74 (m, 1H), 1.66-1.63 (m, 2H), 1.56-1.47 (m,
4H), 1.43-1.34 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.1, 179.5, 168.7, 138.6, 135.1,
133.9, 133.0, 129.6, 127.3, 126.9, 126.0, 39.4, 39.1, 32.5, 25.3, 21.1; IR (neat) 3230, 3124, 2923,
2852, 1715, 1666, 1641, 1604, 1464, 1367, 1296, 712 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C18H18NO3 296.1287; Found 296.1291.
(E)-N-(1,4-dimethoxynaphthalen-2-yl)-2-(2-methylcyclohexylidene)acetamide (S10). To a
solution of (E)-2-(2-methylcyclohexylidene)acetic acid (254 mg, 1.65 mmol) in CH2Cl2 (30 mL)
at rt was added oxalyl chloride (154 μL, 1.80 mmol) and one drop of DMF. After stirring for 1h a
solution of 6 (305 mg, 1.5 mmol) in CH2Cl2 (10 mL) was added to the reaction mixture. This was
followed by the dropwise addition of NEt3 (209 μL, 1.50 mmol) after 10 min. The resulting
reaction mixture was stirred for another 1h and then concentrated. The resulting residue was
dissolved in EtOAc (30 mL) and washed sequentially with sat. NH4Cl (aq., 20 mL), H2O (2 × 20
mL), and brine (20 mL). The organic phase was dried (Na2SO4) and concentrated. Flash column
chromatography (hexanes:ethyl acetate = 10:1) gave 214 mg of S10 (42%) as a white solid as its
E isomer.
mp 167-169 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 8.15 (broad s, 1H), 7.94
(d, J = 8.4 Hz, 1H), 7.88 (broad s, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 5.72 (s,
1H), 4.03 (s, 3H), 3.90 (s, 3H), 3.55-3.52 (m, 1H), 2.35-2.27 (m, 2H), 1.92-1.76 (m, 3H), 1.60-
13
1.51 (m, 2H), 1.36-1.30 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H); C{1H} NMR (126 MHz, CDCl3) δ
166.0, 164.0, 152.3, 136.3, 128.6, 127.6, 126.9, 124.1, 123.1, 122.7, 120.9, 114.2, 98.7, 61.7,
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56.0, 39.9, 37.0, 29.4, 28.6, 25.2, 18.7; IR (neat) 2930, 2852, 1663, 1626, 1601, 1520, 1494,
1456, 1418, 1371, 1216, 1170, 1094, 994, 849, 767 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for
C21H26NO3 340.1913; Found 340.1912.
(E)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-(2-methylcyclohexylidene)acetamide (37).
To a solution of S10 (163 mg, 0.410 mmol) in CH3CN (16 mL) at rt was added a mixture of ceric
ammonium nitrate (499 mg, 0.910 mmol) in CH3CN (2 mL) and H2O (2 mL). The reaction
mixture was stirred for 15 min and then poured into H2O (10 mL). The aqueous phase was
extracted with EtOAc (3 × 30 mL) and the combined organic extracts were washed with brine (60
mL), dried (Na2SO4), and concentrated. Flash column chromatography (hexanes:ethyl acetate =
10:1) gave 99 mg of 37 (81%) as a yellow solid.
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mp 140-142 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.32 (broad s, 1H), 8.08 (dd, J = 7.5, 1.1 Hz, 1H),
8.07 (dd, J = 7.5, 1.1 Hz, 1H), 7.89 (s, 1H), 7.75 (td, J = 7.5, 1.3 Hz, 1H), 7.68 (td, J = 7.6, 1.3
Hz, 1H), 5.70 (s, 1H), 3.54-3.50 (m, 1H), 2.31-2.19 (m, 2H), 1.90-1.73 (m, 3H), 1.55-1.47 (m,
2H), 1.31-1.24 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 185.2,
181.3, 168.4, 166.0, 140.6, 135.0, 133.2, 132.4, 130.1, 126.7, 126.4, 116.5, 112.9, 40.2, 37.2,
29.6, 28.6, 25.1, 18.5; IR (neat) 3332, 2928, 2854, 1696, 1667, 1644, 1612, 1594, 1496, 1335,
1301, 1230, 1198, 1151, 1102, 1082, 886, 783 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for
C19H19NO3Na 332.1263, Found 332.1262.
2'-methyl-1H-spiro[benzo[g]quinoline-4,1'-cyclohexane]-2,5,10(3H)-trione (38). A solution of
37 (14.8 mg, 0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then
purged with Ar for 10 min. The resulting solution was placed in the center of a photoreactor and
irradiated with 419 nm light (spectral window of lamps: 373-460 nm) for 10 h after which the
reaction mixture was concentrated. The resulting residue was subjected to flash column
chromatography (hexanes:ethylacetate = 5:1) to give 13.6 mg of 38 (92%, d.r. > 20:1) as a yellow
solid.
mp 158-160 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.22 (broad s, 1H), 8.07 (ddd, J = 7.9, 6.8, 1.2 Hz,
2H), 7.77 (td, J = 7.5, 7.5, 1.4 Hz, 1H), 7.68 (td, J = 7.6, 7.6, 1.3 Hz, 1H), 2.99 (ddq, J = 10.7,
6.9, 3.9 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H), 2.63 (d, J = 16.9 Hz, 1H), 2.34 (td, J = 13.8, 13.8, 5.0
Hz, 1H), 1.78-1.74 (m, 1H), 1.67-1.44 (m, 5H), 1.32-1.23 (m, 1H), 0.79 (d, J = 6.9 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 183.1, 179.3, 169.2, 139.7, 135.1, 133.8, 133.0, 129.7, 127.0,
126.1, 126.0, 44.1, 35.4, 34.9, 34.3, 29.3, 25.9, 20.8, 18.0; IR (neat) 3307, 2927, 2856, 1705,
1669, 1645, 1611, 1595, 1579, 1497, 1463, 1452, 1334, 1292, 1231, 1200, 1152, 1103, 721 cm–1;
HRMS (ESI) m/z: [M+Na]+ Calcd. for C19H19NO3Na 332.1263, Found 332.1263.
N-(1,4-dimethoxynaphthalen-2-yl)cyclohex-1-ene-1-carboxamide (S11). To a solution of 6
(203 mg, 1.00 mmol) in CH2Cl2 (10 mL) at rt was added 1-cyclohexene-1-carboxylic acid (189
mg, 1.50 mmol), EDC•HCl (288 mg, 1.50 mmol) and 4-DMAP (24.4 mg, 0.200 mmol). The
reaction mixture was stirred overnight and then concentrated. The resulting residue was dissolved
in EtOAc (10 mL) and washed sequentially with saturated NH4Cl (aq., 10 mL), H2O (2 × 5 mL),
and brine (5 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was
purified using flash column chromatography (hexanes:ethyl acetate = 10:1) to provide 207 mg of
S11 (66%) as purple foam.
1H NMR (500 MHz, CDCl3): δ 8.26 (bs, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.94 (d, J =
8.4 Hz, 1H), 7.51 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.39 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 6.87 (septet,
J = 1.9 Hz, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 2.46-2.42 (m, 2H), 2.30-2.26 m, 2H), 1.81-1.77 (m,
2H), 1.71-1.66 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.6, 152.4, 136.7, 135.1, 134.0,
128.4, 127.6, 127.0, 124.2, 123.1, 122.7, 120.9, 98.8, 61.6, 55.9, 25.8, 24.5, 22.3, 21.6; IR (neat)
3423, 2999, 2934, 2857, 1672, 1627, 1600, 1588, 1520, 1493, 1455, 1417, 1372, 1271, 1259,
1221, 1161, 1098, 1081, 995, 970 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C19H22NO3 312.
1600; Found 312.1603.
N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)cyclohex-1-ene-1-carboxamide (39).To a solution of
S11 (207 mg, 0.736 mmol) in CH3CN (6 mL) at rt was added a mixture of ceric ammonium
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nitrate (800 mg, 1.46 mmol) in CH3CN (1 mL) and H2O (1 mL). The resulting reaction mixture
was stirred for 15 min and then poured into H2O (5 mL). The aqueous phase was extracted with
EtOAc (3 × 8 mL) and the combined organic extracts were washed with brine (15 mL), dried
(Na2SO4), and concentrated. Flash column chromatography (toluene:ethyl acetate = 20:1) gave
148 mg of 39 (80%) as a yellow solid.
mp 177-180 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 8.12-8.10 (m, 2H), 7.90 (s, 1H), 7.78
(td, J = 7.5, 1.4 Hz, 1H), 7.72 (td, J = 7.6, 1.3 Hz, 1H), 6.88 (ddd, J = 5.6, 3.8, 1.6 Hz, 1H), 2.40-
2.37 (m, 2H), 2.30-2.26 (m, 2H), 1.78-1.73 (m, 2H), 1.68-1.64 (m, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 185.2, 181.4, 166.8, 140.2, 137.4, 135.0, 133.4, 133.2, 132.4, 130.1, 126.7, 126.4,
116.8, 25.8, 24.1, 22.0, 21.4; IR (neat) 3371, 2933, 1666, 1648, 1500, 1334, 1298, 1213, 1081
cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C17H16NO3 282.1130; Found 282.1126.
2,3,4,4a,6,12b-hexahydrobenzo[b]phenanthridine-5,7,12(1H)-trione (40). A solution of 39
(14.1 mg, 0.05 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes that had been
purged with Ar for 10 min. The resulting solution was placed in the center of a photoreactor and
irradiated with 419 nm light (spectral window: 373-460 nm) for 45 min after which the reaction
mixture was concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 5:1) to give 12 mg of 40 (85%, cis:trans ≥ 20:1) as a yellow solid.
mp 255-257 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H),
8.03 (broad s, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 3.31 (ddd, J = 12.7, 6.1, 4.0
Hz, 1H), 2.78 (broad s, 1H), 2.55 (broad d, J = 13.4 Hz, 1H), 1.81-1.76 (m, 2H), 1.68-1.65 (m,
1H), 1.55-1.33 (m, 3H), 1.25-1.17 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.2, 179.3,
171.4, 137.8, 134.9, 133.3, 132.5, 130.5, 126.7, 126.5, 124.8, 39.8, 32.9, 27.5, 26.0, 24.0, 22.3;
IR (neat) 3298, 2926, 2843, 1709, 1666, 1632, 1593, 1468, 1453, 1366, 1333, 1307, 1210, 718
cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C17H16NO3 282.1130; Found 282.1128.
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(1R,2S,3R)-5-((1,4-dimethoxynaphthalen-2-yl)carbamoyl)cyclohex-4-ene-1,2,3-triyl
triacetate (S12). To a solution of 6 (203 mg, 1.00 mmol) in CH2Cl2 (20 mL) at rt was added
(3R,4S,5R)-3,4,5-triacetoxycyclohex-1-ene-1-carboxylic acid (901 mg, 3.00 mmol), EDC•HCl
(575 mg, 3.00 mmol), and 4-DMAP (24.4 mg, 0.200 mmol). The reaction mixture was stirred
overnight and then concentrated. The resulting residue was dissolved in EtOAc (20 mL) and
washed sequentially with sat. NH4Cl (aq., 10 mL), H2O (2 × 10 mL), and brine (10 mL). The
organic layer was dried (Na2SO4) and concentrated. Purification using flash column
chromatography (hexanes:ethyl acetate = 3:1) provided 471 mg of S12 (97%) as a white solid.
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mp 84-86 ˚C; H NMR (500 MHz, CDCl3) δ 1:1 mixture of two conformers, 8.28 (broad s, 1H),
8.19 (d, J = 8.3 Hz, 1H), 7.94 (s, 1H), 7.92 (partially obscured d, J = 8.5 Hz, 1H), 7.50 (ddd, J =
8.2, 6.8, 1.2 Hz, 1H), 7.39 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 6.51 (dt, J = 4.1, 2.1 Hz, 1H), 5.78 (t, J
= 4.0, 4.0 Hz, 1H), 5.42-5.36 (m, 1H), 5.32-5.26 (m, 1H), 3.98 (s, 1.5H), 3.97 (s, 1.5H), 3.89 (s,
3H), 3.17-3.08 (m, 1H), 2.59-2.51 (m, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 170.1, 170.0, 169.9, 164.2, 152.2, 137.0, 136.2, 127.4, 127.3, 127.1, 124.6,
123.4, 122.7, 120.9, 98.3, 68.0, 66.7, 66.1, 61.8, 55.8, 29.0, 21.0, 20.9, 20.8; IR (neat) 3422,
2940, 1748, 1680, 1603, 1499, 1373, 1248, 1226, 1043 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd.
for C25H27NO9Na 508.1584; Found 508.1590.
(1R,2S,3R)-5-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamoyl)cyclohex-4-ene-1,2,3-triyl
triacetate (41). To a solution of S12 (336 mg, 0.690 mmol) in CH3CN (9 mL) at rt was added a
mixture of ceric ammonium nitrate (883 mg, 1.52 mmol) in CH3CN (2.5 mL) and H2O (2.5 mL).
The resulting reaction mixture was stirred for 15 min and then poured into H2O (20 mL). The
aqueous phase was extracted with EtOAc (3 × 20 mL) and the combined organic extracts were
washed with brine (60 mL), dried (Na2SO4), and concentrated. Flash column chromatography
(hexanes:ethyl acetate = 2:1) gave 272 mg of 41 (86%) as a yellow solid.
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mp 146-148 ˚C; H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.13 (d, J = 7.5 Hz, 2H), 7.87 (s,
1H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 7.5, 1.2 Hz, 1H), 6.55-6.54 (m, 1H), 5.81 (broad
s, 1H), 5.36 (ddd, J = 7.7, 5.1, 5.1 Hz, 1H), 5.32 (dd, J = 7.7, 3.9 Hz, 1H), 3.04-3.00 (m, 1H),
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2.58-2.54 (m, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ
185.1, 181.1, 170.0, 169.9, 169.9, 164.7, 139.7, 135.3, 134.8, 133.5, 132.3, 129.9, 129.6, 126.9,
126.6, 117.7, 67.4, 66.6, 66.0, 28.3, 21.1, 20.9, 20.9; IR (neat) 3364, 2940, 1748, 1669, 1653,
1506, 1370, 1336, 1301, 1225, 1044, 719 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for
C23H21NO9Na 478.1114; Found 478.1105.
(1R,2S,3R,4aS,12bR)-5,7,12-trioxo-1,2,3,4,4a,5,6,7,12,12b-
decahydrobenzo[b]phenanthridine-1,2,3-triyl triacetate (42, 43). A solution of 41 (22.8 mg,
0.0500 mmol) in CHCl3 (20 mL) was placed in two 10 mm NMR tubes and then purged with Ar
for 10 min. The resulting solution was placed in the center of a photoreactor and irradiated with
419 nm light (spectral window: 373-460 nm) for 10.5 h after which the reaction mixture was
concentrated. The resulting residue was subjected to flash column chromatography
(hexanes:ethylacetate = 2:1) to give 18.5 mg of 42 and 43 (81%, 42:43 = 1.2:1) as yellow solids.
42: mp 252-254 ˚C; 1H NMR (500 MHz, CDCl3) δ 1:1 mixture of two conformers, 8.16 (broad s,
1H), 8.11 (dd, J = 8.0, 0.5 Hz, 2H), 7.79 (td, J = 7.4, 1.0 Hz, 1H), 7.73 (td, J = 7.4, 1.1 Hz, 1H),
5.34 (dd, J = 11.6, 2.6 Hz, 1H), 5.27 (t, J = 3.4 Hz, 1H), 5.03 (dd, J = 6.4, 2.8 Hz, 1H), 4.00 (dd, J
= 11.6, 6.7 Hz, 1H), 2.95-2.89 (m, 2H), 2.225 (s, 1.5H), 2.224 (s, 1.5H), 2.049 (s, 1.5H), 2.048 (s,
1.5H), 2.00 (ddd, J = 15.2, 5.9, 2.9 Hz, 1H), 1.807 (s, 1.5H), 1.806 (s, 1.5H); 13C{1H} NMR (126
MHz, CDCl3) δ 182.0, 178.6, 170.3, 169.7, 169.7, 169.6, 139.0, 135.2, 133.6, 132.1, 130.3, 126.8,
126.6, 119.8, 68.6, 68.1, 67.7, 37.6, 30.9, 21.8, 21.3, 21.1, 20.7; IR (neat) 3289, 2840, 1745,
1675, 1639, 1467, 1368, 1329, 1302, 1221, 1053, 724 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd.
C23H21NO9Na 478.1114; Found 478.1101.
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43: mp 286-288 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5 Hz,
1H), 7.95 (broad s, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 5.56 (t, J = 2.4 Hz, 1H),
5.38 (td, J = 11.0, 5.2 Hz, 1H), 5.11 (dd, J = 10.3, 2.5 Hz, 1H), 3.71 (dd, J = 7.6, 2.1 Hz, 1H),
3.07 (ddd, J = 13.4, 5.0, 1.8 Hz, 1H), 2.99 (t, J = 5.8 Hz, 1H), 2.06 (s, 3H), 1.96 (s, 3H), 1.93 (s,
3H), 1.76 (ddd, J = 13.0, 13.0, 5.7 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 181.4, 178.9,
170.0, 169.9, 169.8, 169.0, 140.4, 135.4, 133.7, 132.0, 130.2, 127.1, 126.7, 117.7, 73.3, 71.9,
66.5, 37.0, 35.5, 27.2, 21.1, 20.8, 20.7; IR (neat) 3282, 2930, 1742, 1673, 1635, 1594, 1467,
1454, 1370, 1330, 1299, 1210, 1161, 1046, 960, 722 cm–1; LRMS (ESI) m/z: [M+Na]+ Calcd.
C23H21NO9Na 478.1114; Found 478.1110.
(Z)-1-((1,4-dimethoxynaphthalen-2-yl)amino)-1-oxobut-2-en-2-yl acetate (S13). To a solution
of 6 (203 mg, 1.00 mmol) in CH2Cl2 (20 mL) at rt was added carboxylic acid (Z)-2-acetoxybut-2-
enoic acid (216 mg, 1.50 mmol), EDC•HCl (288 mg, 1.50 mmol) and 4-DMAP (24.4 mg, 0.200
mmol). The resulting reaction mixture was stirred overnight and then concentrated. The resulting
residue was dissolved in EtOAc (20 mL) and washed sequentially with sat. NH4Cl (aq., 10 mL),
H2O (2 × 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), concentrated, and
purified using flash column chromatography (hexanes:ethyl acetate = 5:1) to provide 233 mg of
S13 (71%, isolated as the Z isomer) as a white solid.
mp 102-104 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.47 (broad s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.02
(s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.51 (td, J = 7.6, 1.2 Hz, 1H), 7.40 (td, J = 7.7, 1.2 Hz, 1H), 6.73
(q, J = 7.2 Hz, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H), 1.76 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 167.7, 159.8, 152.4, 141.5, 136.9, 127.4, 127.3, 127.1, 124.5, 124.1,
123.4, 122.7, 120.8, 98.4, 61.7, 55.9, 20.5, 12.1; IR (neat) 3415, 3072, 2940, 2853, 1769, 1691,
1662, 1628, 1603, 0589, 1522, 1500, 1458, 1421, 1374, 1266, 1213, 1187, 1095, 1065 cm–1;
HRMS (ESI) m/z: [M+H]+ Calcd. for C18H20NO5 330.1341; Found 330.1348.
(Z)-1-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-1-oxobut-2-en-2-yl acetate (45). To a
solution of S13 (157 mg, 0.477 mmol) in CH3CN (7 mL) at rt was added a mixture of CAN (575
mg, 1.05 mmol) in CH3CN (1 mL) and H2O (1 mL). The reaction mixture was stirred for 15 min
and then poured into H2O (5 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL) and
the combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and
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concentrated. Flash column chromatography (hexanes:ethyl acetate = 5:1) gave 96 mg of 45
(67%) as a yellow solid.
mp 168-170 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.93 (broad s, 1H), 8.09 (dd, J = 7.5, 1.2 Hz, 1H),
8.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.84 (s, 1H), 7.78 (td, J = 7.6, 1.3 Hz, 1H), 7.72 (td, J = 7.6, 1.3
Hz, 1H), 6.74 (q, J = 7.2 Hz, 1H), 2.41 (s, 3H), 1.76 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 185.1, 181.0, 167.7, 160.5, 140.5, 139.7, 135.2, 133.5, 132.3, 130.0, 126.8, 126.6,
126.6, 117.7, 20.6, 12.3; IR (neat) 3363, 3073, 2923, 1771, 1706, 1650, 1620, 1592, 1500, 1342,
1297, 1226, 1181, 1018 cm–1; HRMS (ESI) m/z: [M+H]+ Calcd. for C16H14NO5 300.0872; Found
300.0878.
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4-methyl-2,5,10-trioxo-1,2,3,4,5,10-hexahydrobenzo[g]quinolin-3-yl acetate (47). A solution
of 45 (30.0 mg, 0.100 mmol) in CHCl3 (40 mL) in a glass tube was placed in the center of a
photoreactor and irradiated at 419 nm (spectral window of lamps: 373-460 nm) for 6 h after
which the reaction mixture was concentrated. The resulting residue was subjected to flash column
chromatography (hexanes:ethylacetate = 5:1) to give 21.4 mg of 47 (78%) as a yellow solid.
mp 223-280 ˚C, decomposed; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.4, Hz, 1H), 8.11 (d, J
= 7.6 Hz, 1H), 8.03 (broad s, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 5.65 (d, J =
6.7 Hz, 1H), 3.67 (p, J = 7.0 Hz, 1H), 2.26 (s, 3H), 1.21 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 181.6, 178.7, 169.8, 166.0, 137.3, 135.2, 133.7, 132.3, 130.3, 127.0, 126.7, 123.9,
69.9, 29.7, 20.8, 12.6; IR (neat) 3277, 2921, 2853, 1746, 1720, 1671, 1637, 1621, 1596, 1578,
1465, 1452, 1329, 1304, 1259, 1215, 1167, 1082, 941 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd.
for C16H13NO5Na 320.0691; Found 322.0700.
3-hydroxy-4-methyl-3,4-dihydrobenzo[g]quinoline-2,5,10(1H)-trione ((±)-Griffithazanone
A). To a solution of acetate 47 (36.1 mg, 0.120 mmol) in THF (6 mL) and MeOH (3 mL) at rt
was added K2CO3 (83 mg, 0.60 mmol). The reaction mixture was stirred for 2 h and then the
reaction was quenched with sat. NH4Cl (aq., 5 mL) and extracted with EtOAc (3 × 10 mL). The
organic extracts were combined, washed with brine (10 mL), dried (Na2SO4), and concentrated.
Flash column chromatography (hexanes:ethyl acetate = 2:1) gave 26.1 mg of griffithazanone
(84%) as a yellow solid.
mp 240-280 ˚C, decomposed; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz, 1H), 8.10 (d, J =
7.6 Hz, 1H), 8.04 (bs, 1H), 7.80 (td, J = 7.5, 1.1 Hz, 1H), 7.74 (td, J = 7.5, 1.1 Hz, 1H), 4.48 (dd,
J = 7.0, 1.8 Hz, 1H), 3.71 (d, J = 7.1 Hz, 1H), 3.43 (d, J = 1.8 Hz, 1H), 1.13 (d, J = 7.1 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 181.9, 178.9, 171.3, 137.1, 135.2, 133.7, 132.3, 130.3, 127.0,
126.6, 125.6, 69.4, 30.7, 11.4; IR (neat) 3471, 3298, 2922, 2849, 1706, 1663, 1629, 1592, 1468,
1451, 1334, 1302, 1213, 1158, 1103 cm–1; HRMS (ESI) m/z: [M+Na]+ Calcd. for C14H11NO4Na
280.0586; Found 280.0594.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications
website.
Experimental Protocols and spectral data for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
* rainier@chem.utah.edu.
Author Contributions
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The manuscript was written through contributions of all authors. / All authors have
given approval to the final version of the manuscript.
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ACKNOWLEDGMENT
The authors are grateful for financial support from the National Science Foundation
(CHE 1465113) and the National Institutes of Health (GM132531-01). We would
also like to thank Dr. Peter Flynn (University of Utah), Dr. Hsiaonung Chen
(University of Utah), and Dr. Ryan Vanderlinden (University of Utah) for help with
NMR, Mass spectrometry, and X-ray structure acquisition, respectively.
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