Divergent Total Syntheses to Azafluoranthene and Dehydroaporphine Alkaloids

Article abstract of DOI:10.1002/ejoc.201500866

Facile divergent total syntheses for azafluoranthene and dehydroaporphine alkaloids have been successfully developed. A common intermediate, a biarylsulfonamide-protected amino aldehyde, underwent either a cascade or a stepwise cyclization to furnish a tetracyclic skeleton related to the azafluoranthene alkaloids. Natural products, triclisine and telitoxine, were prepared to illustrate the use of this approach. Subsequent C-homologation of the aldehyde moiety on the same intermediate by means of a Wittig reaction allowed the synthesis of aporphine alkaloids, as exemplified by the preparation of dehydronornuciferine. This synthetic approach could be applicable to the syntheses of other azafluoranthene-related as well as aporphine-related alkaloids. Facile divergent syntheses for azafluoranthene and dehydroaporphine alkaloids are reported by using a biarylsulfonamide-protected amino aldehyde as a common intermediate. The natural azafluoranthenes, triclisine and telitoxine, and an aporphine alkaloid, dehydronornuciferine, were prepared to illustrate the use of this approach.

Full text of DOI:10.1002/ejoc.201500866

FULL PAPER
DOI: 10.1002/ejoc.201500866
Divergent Total Syntheses to Azafluoranthene and Dehydroaporphine Alkaloids
Nisachon Khunnawutmanotham,[a] Poolsak Sahakitpichan,[b] Nitirat Chimnoi,[b] and
Supanna Techasakul*[a,c]
Keywords: Alkaloids / Synthetic methods / Natural products / Divergent synthesis / Polycycles / Domino reactions
Facile divergent total syntheses for azafluoranthene and de- proach. Subsequent C-homologation of the aldehyde moiety
hydroaporphine alkaloids have been successfully developed.
common intermediate, biarylsulfonamide-protected
amino aldehyde, underwent either a cascade or a stepwise
cyclization to furnish a tetracyclic skeleton related to the
azafluoranthene alkaloids. Natural products, triclisine and
telitoxine, were prepared to illustrate the use of this ap-
on the same intermediate by means of a Wittig reaction al-
lowed the synthesis of aporphine alkaloids, as exemplified
by the preparation of dehydronornuciferine. This synthetic
approach could be applicable to the syntheses of other aza-
fluoranthene-related as well as aporphine-related alkaloids.
A
a
ties of both natural and unnatural azafluoranthenes as well
as their structurally modified analogs through total synthe-
sis. Hence, it is critical to devise an efficient and high-yield-
ing synthetic approach for this class of alkaloids.
Introduction
Azafluoranthene or indeno[1,2,3-ij]isoquinoline is a rela-
tively small class of naturally occurring alkaloids. To date,
only six azafluoranthene alkaloids have been reported, and
all of them have been isolated from plants in the Menisper-
maceae family. They are triclisine (1), rufescine (2), imelut-
eine (3), telitoxine (4), norrufescine (5), and norimeluteine
(6; Figure 1). Biological activities of azafluoranthene alka-
loids have not been well studied owing to their low natural
abundance. Cytotoxicity of some azafluoranthenes was re-
ported such as that of imeluteine against HCT-116 colon
adenocarcinoma, ACHN renal carcinoma, and A549 lung
carcinoma at IC50 values of 20.0, 10.2 and 31.0 μm, respec-
tively,[1] and those of norimeluteine and norrufescine
against P-388 cells at IC50 values of 3.6 and 5.6 μg/mL,
respectively.[2] Norrufescine was also reported to exhibit in-
hibitory activity against human immunodeficiency virus
(HIV-1) with an EC50 value of 10.9 μm in C8166 cells.[3] To
further evaluate additional biological activities of this class
of compounds, it is imperative to obtain sufficient quanti-
Figure 1. Natural azafluoranthene alkaloids.
Aporphine alkaloids (Figure 2), which contain a tetra-
cyclic isoquinoline core, are much more naturally abundant.
They are distributed in many plant families such as Annon-
aceae, Papaveraceae, Lauraceae, Magnoliaceae, Menisperm-
aceae, Monimiaceae, and Ranunculaceae,[4] but are most
abundant in the Menispermaceae family of which the Ste-
phania genus is the richest source. Aporphine alkaloids were
known to exhibit various pharmacological properties in-
cluding antimalarial,[5] antiprotozoal,[6] cytotoxic and anti-
cancer[7] activities, and acetylcholinesterase inhibition.[8]
Their wide range of biological activities has stimulated
chemists to develop some methodologies to synthesize
aporphine alkaloids, and various successful synthetic routes
have been reported.[9] A number of different synthesis stra-
tegies have been devised for azafluoranthenes, which
[a] Laboratory of Organic Synthesis, Chulabhorn Research
Institute,
54 Kamphaeng Phet 6, Talat Bang Khen, Lak Si,
Bangkok 10210, Thailand
E-mail: fscispt@ku.ac.th
supanna@cri.or.th
www.cri.or.th
[b] Laboratory of Natural Products, Chulabhorn Research
Institute,
54 Kamphaeng Phet 6, Talat Bang Khen, Lak Si,
Bangkok 10210, Thailand
[c] Department of Chemistry and Center of Excellence for
Innovation in Chemistry, Faculty of Science, Kasetsart
University,
Bangkok 10900, Thailand
www.ku.ac.th
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500866.
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Total Syntheses of Azafluoranthene and Dehydroaporphine Alkaloids
include microwave-assisted direct arylation of phenyl- duction of 10 with NaBH4 in the presence of BF3·OEt2 in
tetrahydroisoquinolines,[10] electrocyclization-mediated ap- tetrahydrofuran at reflux temperatures led to the corre-
proach,[11] combined aza-Wittig/electrocyclic ring closure/ sponding phenethylamine, which was protected as the carb-
intramolecular oxidative biaryl coupling,[12] ortho- and re- amate 11. Suzuki cross-coupling reaction of 11 with (form-
mote metalation/cross coupling,[13] utilization of the in- ylphenyl)boronic acid provided biarylcarbaldehyde 12 in
verse-electron-demand Diels–Alder reactions of 3-meth- high yield. Afterwards, cyclization of 12 under acidic condi-
oxycarbonyl-2-pyrones,[14] Pschorr-based cyclization,[15] tions was performed with trifluoroacetic acid (TFA) in
and photocyclization.[16] As part of our efforts to develop dichloromethane (1:9) at room temperature for 1 h. After
a new approach for the aporphine alkaloids, we developed workup and purification, 9H-fluorene 13a and 9-oxo-9H-
a facile strategy that could be applicable for the synthesis fluorene 13b were separated and obtained in a 1:1 ratio
of both azafluoranthene and aporphine alkaloids, and the (Table 1, Entry 1). These two products seemed to be pro-
details are reported herein.
duced from a disproportionation reaction of the hydroxy
intermediate from the cyclization. When hydrobromic acid/
acetic acid (HBr/AcOH, 1:1) was used instead, tetracyclic
product 13d was obtained in 43% isolated yield as the
major product, accompanied with hydroxy compound 13c
in 10% yield and disproportionation reaction products 13a
and 13b in 5 and 12% yields, respectively (Table 1, Entry 2).
The formation of tetracyclic compound 13d supported our
hypothesis that the cascade cyclization of the biaryl-pro-
Figure 2. Aporphine alkaloid scaffold.
Results and Discussion
We anticipated that the core of the azafluoranthene skel-
eton could arise from a cascade cyclization of the corre-
sponding biaryl-protected amino aldehyde as depicted in
the retrosynthetic analysis (Figure 3). The biaryl-protected
amino aldehyde, in turn, could be obtained from Suzuki
cross-coupling reaction of the corresponding aryl halide
and (formylphenyl)boronic acid. We also envisioned that
the common biaryl-protected amino aldehyde, which con-
tains the formyl group, might serve as a handle to affect C-
homologation to furnish the corresponding product that
may undergo a similar cascade cyclization to provide the
aporphine alkaloids.
Scheme 1. Reagents and conditions: (a) Br2, KOAc, AcOH, room
temp. (90%); (b) MeI. K2CO3, acetone. reflux, 6 h (92%);
(c) CH3NO2, NH4OAc, AcOH, 90 °C, 7 h (83%); (d) NaBH4,
BF3·OEt2, THF, reflux, 4 h; (e) for R = COOMe, ClCOOMe,
CH2Cl2, Na2CO3, H2O, room temp., 24 h; for R = SO2(p-
C6H4NO2), ClSO2(p-C6H4NO2), Na2CO3, CH2Cl2, room temp.,
40 h; (f) (formylphenyl)boronic acid, Pd(PPh3)4, K2CO3, toluene,
Figure 3. Retrosynthetic analysis of azafluoranthene and aporphine
alkaloids.
The synthesis began from commercially available vanillin
(7) as shown in Scheme 1 to the corresponding bromo-
nitrostyrene 10 in three steps with 68% overall yield. Re- EtOH, H2O, 120 °C, 24 h.
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S. Techasakul et al.
FULL PAPER
tected amino aldehyde could be achieved under acidic con- tempted but gave a lower yield. Alternatively, elimination
ditions. Analysis of Table 1, Entries 1 and 2 showed that use of the sulfonamide group and dehydrogenation of 16d to
of HBr/AcOH instead of TFA could promote the desired triclisine (1) was achieved by treatment with DBU in N,N-
cascade cyclization and suppress the disproportionation re- dimethylformamide at 100 °C for 24 h. This reported syn-
action. Then we observed the effect of the amino protecting thetic pathway provided a facile approach for the synthesis
group in a cascade cyclization by changing the substrate of azafluoranthene alkaloids.
from carbamate 12 to (nitrophenyl)sulfonamide 15. Treat-
ment of 15 with TFA in dichloromethane (1:9; Table 1, En-
try 3) yielded cascade-cyclized product 16d in 35% yield,
accompanied by disproportionation reaction products 16a
and 16b in 18 and 25% yields, respectively. Analysis of
Table 1, Entries 1 and 3 showed that with the (nitrophenyl)-
sulfonamide substrate the cascade cyclization was promoted
and the disproportionation reaction was suppressed. If
(nitrophenyl)sulfonamide 15 was subjected to HBr/AcOH
(1:1), the major isolated product was found to be hydroxy
compound 16c (64%) along with a small amount of cas-
cade-cyclized product 16d (10%) and a trace amount of 9-
oxo-9H-fluorene 16b (5%; Table 1, Entry 4). The amount
of undesired products from the disproportionation reaction
was greatly reduced under these conditions. We expected
that conversion of 16c into 16d could be driven by changing
the hydroxy group into a more labile leaving group. There-
fore, we turned our attention to study the amino cyclization
(c) DBU, DMF, room temp., 15 min; (d) DBU, DMF, 100 °C, 24 h.
of the crude product obtained from Table 1, Entry 4.
Scheme 2. Reagents and conditions: (a) HBr/AcOH (1:1), dioxane,
room temp., 2 h; (b) MsCl, Et3N, CH2Cl2, room temp., 1 h;
To illustrate the compatibility and scope of this approach
for the azafluoranthene synthesis, another natural azafluor-
anthene, telitoxine (4), was also synthesized. Required
boronic acid 18 was prepared in four steps from 3-hydroxy-
benzaldehyde (19) in 28% overall yield (Scheme 3). The se-
quence involved protection of the phenol as its isopropyl
ether, bromination, protection of the aldehyde moiety with
ethylene glycol followed by treatment with nBuLi and tri-
isopropyl borate and then hydrolysis under acidic condi-
tions.[17] Sulfonamide 14 and boronic acid 18 underwent
Suzuki cross-coupling reaction to yield 23 in high yield
(Scheme 4). Compound 23 was then treated with HBr/
Table 1. Treatment of substrates 12 (R = COOMe) and 15 [R =
SO2(p-C6H4NO2)] with acids.
Entry
1
R
Method
A[b]
Product (yield [%])[a]
COOMe
13a
13b
–
–
(44) (45)
2
3
4
COOMe
B[c]
A
13a
(5)
16a
13b
13c
13d
(12) (10) (43)
SO2(p-C6H4NO2)
SO2(p-C6H4NO2)
16b
–
16d
(35)
16d
(18) (25)
B
–
16b
(5)
16c
(64) (10)
[a] Isolated yield. [b] Method A: CF3COOH/CH2Cl2 (1:9), room
temp., 1 h. [c] Method B: HBr/AcOH (1:1), room temp., 2 h.
A crude mixture from the reaction in Table 1, Entry 4
was treated with methanesulfonyl chloride and triethyl-
amine in dichloromethane for 1 h (Scheme 2). As expected,
compound 16d was isolated in approximately 50% yield
over 2 steps from 15. Elimination of the sulfonamide group
in 16d took place smoothly by treatment with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in N,N-dimethylformamide
at room temperature, and dihydrotriclisine (17) was isolated
in high yield. Treatment of 17 with DBU in N,N-dimethyl-
formamide at 100 °C for 24 h converted 17 into natural
product triclisine (1) in good yield. Dehydrogenation with
Scheme 3. Reagents and conditions: (a) iPrBr, K2CO3, DMF, room
temp., 42 h; (b) Br2, CH2Cl2, room temp.; (c) HOCH2CH2OH,
pTsOH, toluene, reflux, 7 h; (d) nBuLi, THF, –78 °C, 1 h; then
B(iPrO)3, 0 °C to room temp., 2.5 h; then HCl (2 m), room temp.,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was at- 2 h.
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Total Syntheses of Azafluoranthene and Dehydroaporphine Alkaloids
AcOH (1:1) for 2 h. After workup, the resulting crude prod-
uct was further subjected to a mesylation reaction for 24 h.
It was found that with prolonged reaction time, according
to Scheme 2, Step b, the mesylation reaction gave the re-
sulting tricyclic (nitrophenyl)sulfonamide that underwent
elimination to furnish compound 24 in 57% yield over 2
steps from 23. It was shown that elimination of the (nitro-
phenyl)sulfonamide group occurs easily even in the presence
of a weak base such as triethylamine. Dehydrogenation of
24 with DBU in N,N-dimethylformamide at 100 °C for 24 h
provided 25 in good yield. In the final step, cleavage of the
isopropyl protecting group was performed by employing
aluminum(III) chloride in dichloromethane for 20 min to
provide telitoxine (4) in high yield.
Scheme 5. Reagents and conditions: (a) ClPPh3CH2OCH3,
LiHMDS, THF, 0 °C, 1 h; (b) HBr/AcOH (1:1), dioxane, room
temp., 2 h; (c) I2, K2CO3, CH3CN, room temp., 72 h; (d) Na,
naphthalene, DME, –30 °C.
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4, K2CO3, tolu-
ene/EtOH/H2O, reflux, 24 h; (b) HBr/AcOH (1:1), dioxane, room
temp., 2 h; (c) MsCl, Et3N, CH2Cl2, room temp., 24 h; (d) DBU,
DMF, 100 °C, 24 h; (e) AlCl3, CH2Cl2, room temp., 30 min.
group was also prepared via compounds 23, 30 and 31 to
illustrate the use of this method (Scheme 5). The modifica-
tion of this approach for the synthesis of other aporphine
alkaloids is in progress and will be reported in due course.
As designed, by means of C-homologation, it was antici-
pated that the developed approach would allow a divergent
synthesis of the aporphine alkaloids. Wittig reaction of 15
with
(methoxymethyl)triphenylphosphonium
chloride
Conclusions
yielded a mixture of (E)- and (Z)-enol ether 26, which
smoothly underwent cyclization under acidic conditions to
This work presents a facile divergent synthetic approach
provide phenanthrene 27 in excellent yield (Scheme 5). to azafluoranthene and aporphine alkaloids (Scheme 6). Bi-
Amino cyclization of 27 was accomplished by iodine- arylsulfonamide-protected amino aldehyde, obtained from
induced cyclization[18] in the presence of potassium carb- the Suzuki cross-coupling reaction between arylsulfonam-
onate, which led to (nitrophenyl)sulfonamide dehydroapor- ide-protected amine and (formylaryl)boronic acid served as
phine 28 in 54% yield based on recovered starting material the common intermediate. The reaction undergoes either a
(BRSM) presumably through a cyclization/elimination pro- cascade or a stepwise cyclization to furnish a tetracyclic
cess. It should be noted that this reaction required potas- skeleton, which was transformed into azafluoranthene alka-
sium carbonate as base; in the absence of potassium carb- loids. C-homologation through a Wittig reaction of this in-
onate, the cyclization did not take place. Other conditions termediate provided the corresponding enol ether that, in
for the amino cyclization were attempted but gave lower turn, was transformed smoothly to the corresponding phen-
yields. Finally, the sulfonamide protecting group could be anthrene under acidic conditions. Amino cyclization was
removed by using sodium naphthalenide, and alkaloid de- accomplished by using iodine in the presence of potassium
hydronornuciferine (29) was obtained in 83% yield. Com- carbonate as base to provide a tetracyclic skeleton related
pound 32, an analog of 28 that contains an isopropoxy to dehydroaporphine alkaloids.
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S. Techasakul et al.
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Scheme 6. Summary of divergent syntheses of azafluoranthene and dehydroaporphine alkaloids from the common intermediates 15 and
23.
7.72 mmol) in dichloromethane (30 mL). After stirring at room
temperature for 40 h, the reaction mixture was added to water and
extracted with dichloromethane. The combined organic layers were
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
Avance 300 spectrometer. Chemical shifts are reported relative to
tetramethylsilane. Mass spectra were obtained with a Finnigan Pol-
aris ion-trap mass spectrometer, and HRMS data were recorded
with a Bruker MicroTOF mass spectrometer. Infrared spectra were
determined with a Perkin–Elmer Spectrum One FTIR spectrome-
ter. Column chromatography was performed on Merck silica gel 60
(70–230 mesh).
washed with water, dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography to yield 14 as a yellow viscous oil
1
(1.73 g, 55% from 10). H NMR (CDCl3, 300 MHz): δ = 8.33 (d,
J = 8.4 Hz, 2 H), 7.96 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 1.8 Hz, 1
H), 6.59 (d, J = 1.8 Hz, 1 H), 4.94 (br. t, 1 H), 3.82 (s, 3 H), 3.80
(s, 3 H), 3.28 (q, J = 6.6 Hz, 2 H), 2.73 (t, J = 6.6 Hz, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 153.7, 150.0, 145.7, 134.5, 134.4,
128.1 (2 C), 124.5, 124.4 (2 C), 117.7, 112.3, 60.5, 56.1, 44.1,
Compound 11: Boron trifluoride–diethyl ether (2.8 mL) was added
dropwise to
a suspension of sodium borohydride (626 mg,
35.5 ppm. FTIR: ν
= 3293, 1528, 1489, 1347, 1160, 1045, 852,
˜
max
16.54 mmol) in tetrahydrofuran (20 mL), and the reaction mixture
was stirred at room temperature under argon for 15 min. Then a
solution of 10 (1.00 g, 3.48 mmol) in tetrahydrofuran (30 mL) was
added dropwise, and the reaction mixture was heated to reflux for
4 h. The reaction mixture was then cooled with an ice bath, and
water was added dropwise until gas evolution had ceased. The reac-
tion mixture was then acidified with 10% aqueous hydrochloric
acid, the ice bath was removed, and the solution was heated at
80–85 °C for 2 h. After cooling to room temperature, the reaction
mixture was washed twice with diethyl ether. The aqueous layer
was basified with 10% aqueous sodium hydroxide and extracted
with dichloromethane. The combined organic layers were washed
with water, dried with anhydrous sodium sulfate, filtered, and con-
centrated under reduced pressure to give a colorless oil of 2-(3-
bromo-4,5-dimethoxyphenyl)ethanamine (628 mg). The above
compound was redissolved in dichloromethane (20 mL). Methyl
chloroformate (0.37 mL, 4.81 mmol) and a solution of sodium
carbonate (643 mg, 6.07 mmol) in water (1 mL) were then added
to the solution. After stirring at room temperature for 24 h, the
reaction mixture was added to water and extracted with dichloro-
methane. The combined organic layers were washed with water,
dried with anhydrous sodium sulfate, filtered, and concentrated un-
der reduced pressure. The residue was purified by column
chromatography to yield 11 as a colorless oil (705 mg, 64% from
734 cm–1. MS (EI): m/z (%) = 444 (25) [M+], 242 (25), 229 (100),
215 (25), 186 (24). HRMS (ESI-POS): calcd. for C16H21BrN3O6S
[M + NH4]+ 462.0329; found 462.0335.
Compound 12: A mixture of 11 (650 mg, 2.05 mmol), (2-form-
ylphenyl)boronic acid (369 mg, 2.46 mmol), tetrakis(triphenylphos-
phine)palladium(0) (94.8 mg, 0.082 mmol) and potassium carb-
onate (567 mg, 4.10 mmol) in toluene/ethanol/water (3:3:2; 80 mL)
was heated at 120 °C under argon for 24 h. After cooling to room
temperature, the reaction mixture was added to water and extracted
with ethyl acetate. The combined organic layers were washed with
water, dried with anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography to yield 12 as a yellow gum (670 mg, 95%). 1H
NMR (CDCl3, 300 MHz): δ = 9.84 (d, J = 0.6 Hz, 1 H), 8.02 (dd,
J = 7.7, 1.2 Hz, 1 H), 7.64 (dt, J = 7.5, 1.5 Hz, 1 H), 7.50 (t, J =
7.5 Hz, 1 H), 7.39 (dd, J = 7.7, 0.9 Hz, 1 H), 6.84 (d, J = 1.2 Hz,
1 H), 6.72 (d, J = 2.1 Hz, 1 H), 4.87 (br. s, 1 H), 3.91 (s, 3 H), 3.67
(s, 3 H), 3.45 (s, 3 H), 3.45 (q, J = 7.2 Hz, 2 H), 2.82 (t, J = 7.2 Hz,
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 192.1, 157.0, 152.6,
145.0, 141.2, 134.9, 133.7, 133.3, 132.0, 130.9, 127.9, 126.9, 123.1,
113.1, 60.3, 55.9, 52.0, 42.1, 36.0 ppm. FTIR: ν
= 3357, 1694,
˜
max
1521, 1422, 1250, 1197, 1137, 1004, 764 cm–1. MS (EI): m/z (%) =
343 (46) [M+], 325 (54), 312 (23), 268 (100), 255 (38), 237 (74),
225 (87). HRMS (ESI-POS): calcd. for C19H21NO5Na [M + Na]+
366.1312; found 366.1306.
1
10). H NMR (CDCl3, 300 MHz): δ = 6.96 (d, J = 1.2 Hz, 1 H),
6.68 (d, J = 1.2 Hz, 1 H), 4.83 (br. s, 1 H), 3.85 (s, 3 H), 3.83 (s, 3
H), 3.67 (s, 3 H), 3.41 (q, J = 6.6 Hz, 2 H), 2.74 (t, J = 6.6 Hz, 2
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 157.0, 153.6, 145.0,
136.0, 124.6, 117.6, 112.3, 60.5, 56.1, 52.1, 42.0, 35.7 ppm. FTIR:
Compound 15: Prepared from 14 (1.2 g, 2.70 mmol) and (2-form-
ylphenyl)boronic acid (486 mg, 3.24 mmol) by the same method as
described for 12, compound 15 was obtained as a yellow solid
ν
= 3340, 1701, 1525, 1464, 1270, 1235, 1045, 1000 cm–1. MS
˜
1
max
(78%). H NMR (CDCl3, 300 MHz): δ = 9.79 (s, 1 H), 8.31 (d, J
(EI): m/z (%) = 317 (28) [M+], 242 (100), 229 (58), 120 (14), 88
(74). HRMS (ESI-POS): calcd. for C12H16BrNO4Na [M + Na]+
340.0155; found 340.0149.
= 8.7 Hz, 2 H), 8.01 (d, J = 8.7 Hz, 2 H), 7.97 (d, J = 1.5 Hz, 1
H), 7.63 (dt, J = 7.5, 1.2 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.33
(dd, J = 7.6, 0.9 Hz, 1 H), 6.76 (d, J = 2.1 Hz, 1 H), 6.58 (d, J =
2.1 Hz, 1 H), 3.88 (s, 3 H), 3.45 (s, 3 H), 3.31 (q, J = 6.6 Hz, 2 H),
2.83 (t, J = 6.6 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
192.2, 152.8, 150.0, 145.9, 145.3, 140.8, 133.6, 133.4, 133.3, 132.4,
Compound 14:
A crude product of 2-(3-bromo-4,5-dimeth-
oxyphenyl)ethanamine, prepared from 10 (1.92 g, 6.69 mmol) by
the same method as mentioned for 11, was dissolved in dichloro-
methane (30 mL) and added to a mixture of p-nitrobenzenesulfonyl 130.9, 128.2 (2 C), 128.1, 127.5, 124.4 (2 C), 123.0, 113.1, 60.4,
chloride (1.28 g, 8.21 mmol) and sodium carbonate (818 mg,
56.0, 44.3, 35.8 ppm. FTIR: ν
= 3285, 1693, 1528, 1347, 1160,
˜
max
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Total Syntheses of Azafluoranthene and Dehydroaporphine Alkaloids
853, 733 cm–1. MS (EI): m/z (%) = 470 (60) [M+], 439 (35), 256 2.70–2.60 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.3,
(58), 241 (50), 225 (100), 197 (20), 151 (20). HRMS (ESI-POS):
153.3, 147.5, 143.6, 138.9, 133.6, 131.4, 128.2 (2 C), 126.9, 126.3,
123.6, 109.7, 60.5, 58.9, 56.4, 52.9, 44.7, 29.8 ppm. FTIR: ν
calcd. for C23H22N2O7SNa [M + Na]+ 493.1040; found 493.1058.
=
˜
max
3358, 1697, 1499, 1445, 1376, 1272, 1250, 1110, 774, 749 cm–1. MS
(EI): m/z (%) = 325 (46) [M+], 310 (42), 294 (78), 266 (100), 254
(37), 239 (24), 178 (27). HRMS (ESI-POS): calcd. for C19H20NO4
[M + H]+ 326.1387; found 326.1391.
Reaction of 12 with Trifluoroacetic Acid: Compound 12 (55 mg,
0.16 mmol) was dissolved in a solution of trifluoroacetic acid in
dichloromethane (1:9, 10 mL), and the reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was then added
to water, washed with saturated aqueous sodium hydrogen carb-
onate and extracted with dichloromethane. The combined organic
layers were washed with water, dried with anhydrous sodium sulf-
ate, filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography to yield 13a as a colorless
gum (23 mg, 44%) and 13b as a yellow solid (24 mg, 45%).
Reaction of 15 with Trifluoroacetic Acid: Compound 15 (110 mg,
0.23 mmol) was treated with trifluoroacetic acid according to the
same method as described for compound 12 to yield 16a (19 mg,
18%), 16b (28 mg, 25%), and 16d (37 mg, 35%) all as a yellow
solids.
Reaction of 15 with Hydrobromic Acid: Compound 15 (344 mg,
0.73 mmol) was treated with HBr/AcOH by the same method as
described for compound 12 to yield 16b (17 mg, 5%), 16c (221 mg,
64%), and 16d (34 mg, 10%) all as a yellow solids.
Reaction of 12 with Hydrobromic Acid: A mixture of hydrobromic
acid/acetic acid (1:1, 3 mL) was added to a solution of 12 (110 mg,
0.32 mmol) in dioxane (3 mL), and the reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was then added
to water, neutralized with NaOH (1 m) and extracted with ethyl
acetate. The combined organic layers were washed with water, dried
with anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy to yield 13a as a colorless gum (5 mg, 5%), 13b as a yellow
solid (13 mg, 12%), 13c as a yellow solid (11 mg, 10%), and 13d as
a colorless gum (44 mg, 43%).
Compound 16a: 1H NMR (CDCl3, 300 MHz): δ = 8.17 (d, J =
9.0 Hz, 2 H), 8.07 (d, J = 7.5 Hz, 1 H), 7.84 (d, J = 9.0 Hz, 2 H),
7.44 (d, J = 7.2 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.30 (dd, J =
7.2, 1.2 Hz, 1 H), 6.58 (s, 1 H), 4.86 (t, J = 6.0 Hz, 1 H), 3.95 (s, 3
H), 3.87 (s, 3 H), 3.61 (s, 2 H), 3.35 (q, J = 6.6 Hz, 2 H), 2.87 (t,
J = 6.6 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 152.2,
149.8, 145.6, 143.9, 142.7, 140.1, 134.9, 128.6, 128.1, 127.9 (2 C),
127.1, 126.8, 124.5, 124.2 (2 C), 123.6, 111.8, 60.2, 56.4, 43.2, 35.1,
Compound 13a: 1H NMR (CDCl3, 300 MHz): δ = 8.13 (d, J =
7.5 Hz, 1 H), 7.50 (d, J = 7.5 Hz, 1 H), 7.38 (t, J = 6.6 Hz, 1 H),
7.29 (dt, J = 7.4, 1.2 Hz, 1 H), 6.69 (s, 1 H), 4.82 (br. s, 1 H), 3.97
(s, 3 H), 3.90 (s, 3 H), 3.78 (s, 2 H), 3.67 (s, 3 H), 3.48 (q, J =
6.9 Hz, 2 H), 2.88 (t, J = 6.9 Hz, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 157.0, 152.1, 143.6, 143.1, 140.4, 135.1, 134.7, 130.1,
126.9, 126.5, 124.6, 123.5, 111.9, 60.2, 56.4, 52.0, 41.2, 35.2,
33.5 ppm. FTIR: ν
= 3293, 1528, 1504, 1347, 1160, 1092, 1037,
˜
max
852, 734 cm–1. MS (EI): m/z (%) = 454 (31) [M+], 437 (5), 268
(17), 239 (100), 225 (12), 208 (7). HRMS (ESI-POS): calcd. for
C23H26N3O6S [M + NH4]+ 472.1537; found 472.1546.
Compound 16b: 1H NMR (CDCl3, 300 MHz): δ = 8.09 (d, J =
8.7 Hz, 2 H), 7.81 (d, J = 8.7 Hz, 2 H), 7.77 (d, J = 7.5 Hz, 1 H),
7.54 (d, J = 7.2 Hz, 1 H), 7.49 (dt, J = 7.5, 1.2 Hz, 1 H), 7.30 (dt,
J = 7.5, 0.9 Hz, 1 H), 6.41 (s, 1 H), 5.31–5.27 (m, 1 H), 3.93 (s, 3
H), 3.92 (s, 3 H), 3.44 (q, J = 6.9 Hz, 2 H), 3.12 (t, J = 6.9 Hz, 2
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 194.0, 158.8, 149.5,
146.2, 144.0, 141.6, 136.7, 136.4, 135.0, 134.9, 129.0, 127.7 (2 C),
124.7, 124.0 (3 C), 123.7, 113.3, 60.3, 56.2, 44.7, 31.2 ppm. FTIR:
33.6 ppm. FTIR: ν
= 3352, 1698, 1501, 1453, 1248, 1104, 1026,
˜
max
750 cm–1. MS (EI): m/z (%) = 327 (49) [M+], 266 (51), 252 (42),
239 (100), 221 (32), 178 (63), 161 (24), 149 (28). HRMS (ESI-POS):
calcd. for C19H21NO4Na [M + Na]+ 350.1363; found 350.1363.
Compound 13b: 1H NMR (CDCl3, 300 MHz): δ = 7.84 (d, J =
7.2 Hz, 1 H), 7.59 (d, J = 7.2 Hz, 1 H), 7.46 (dt, J = 7.6, 1.2 Hz, 1
H), 7.27 (t, J = 7.6 Hz, 1 H), 6.52 (s, 1 H), 5.10 (br. s, 1 H), 3.94
(s, 3 H), 3.93 (s, 3 H), 3.64 (s, 3 H), 3.47 (q, J = 6.9 Hz, 2 H), 3.18
(t, J = 6.9 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 193.5,
158.6, 157.1, 143.7, 141.9, 137.8, 136.7, 135.3, 134.4, 128.7, 124.6,
ν
= 3289, 1696, 1528, 1501, 1348, 1306, 1253, 1162, 854,
˜
max
736 cm–1. MS (EI): m/z (%) = 468 (10) [M+], 282 (100), 266 (19),
254 (78), 239 (35), 224 (8), 211 (8). HRMS (ESI-POS): calcd. for
C23H21N2O7S [M + H]+ 469.1064; found 469.1070.
Compound 16c: 1H NMR ([D6]acetone, 300 MHz): δ = 8.20 (d, J
= 8.7 Hz, 2 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 2
H), 7.59 (d, J = 7.2 Hz, 1 H), 7.42–7.27 (m, 3 H), 6.59 (s, 1 H),
5.59 (d, J = 5.7 Hz, 1 H), 5.40 (d, J = 6.3 Hz, 1 H), 3.87 (s, 3 H),
3.75 (s, 3 H), 3.50–3.40 (m, 1 H), 3.40–3.28 (m, 1 H), 2.97 (dd, J
= 7.5, 5.7 Hz, 2 H) ppm. 13C NMR ([D6]acetone, 75 MHz): δ =
154.4, 150.4, 147.4, 147.3, 144.3, 139.5, 137.3, 133.3, 132.7, 129.6,
123.8, 123.5, 113.4, 60.3, 56.2, 51.9, 41.8, 31.5 ppm. FTIR: ν
=
˜
max
3359, 1698, 1501, 1454, 1226, 1191, 1108, 1019, 751 cm–1. MS (EI):
m/z (%) = 341 (3) [M+], 325 (68), 310 (44), 294 (22), 266 (100), 254
(41), 239 (47), 149 (26). HRMS (ESI-POS): calcd. for
C19H19NO5Na [M + Na]+ 364.1155; found 364.1158.
Compound 13c: 1H NMR (CDCl3, 300 MHz): δ = 7.95 (d, J =
7.2 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.37 (dt, J = 7.5, 1.2 Hz, 1 128.9 (2 C), 128.2, 125.5, 124.6 (2 C), 124.1, 113.2, 73.7, 60.1, 56.1,
H), 7.29 (dt, J = 7.2, 1.2 Hz, 1 H), 6.59 (s, 1 H), 5.62 (d, J = 7.2 Hz,
44.7, 32.0 ppm. FTIR: ν
= 1528, 1503, 1348, 1310, 1160, 853,
˜
max
1 H), 5.36 (br. s, 1 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.64 (s, 3 H),
736 cm–1. MS (EI): m/z (%) = 470 (3) [M+], 452 (5), 282 (32), 266
3.54–3.45 (m, 2 H), 2.99 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (100), 254 (27), 239 (36), 195 (13). HRMS (ESI-POS): calcd. for
(CDCl3, 75 MHz): δ = 157.4, 153.7, 145.7, 143.4, 138.4, 136.7, C23H22N2O7SNa [M + Na]+ 493.1040; found 493.1036.
133.1, 132.4, 129.2, 127.6, 124.7, 123.6, 112.5, 73.8, 60.2, 56.1, 52.1,
Compound 16d: 1H NMR (CDCl3, 300 MHz): δ = 8.23 (d, J =
42.1, 32.5 ppm. FTIR: ν
= 3352, 1696, 1501, 1454, 1248, 1190,
˜
max
8.7 Hz, 2 H), 8.12 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 7.2 Hz, 1 H),
7.92 (d, J = 8.7 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.36 (dt, J =
7.6, 1.2 Hz, 1 H), 6.46 (s, 1 H), 5.34 (s, 1 H), 4.11–4.02 (m, 1 H),
3.93 (s, 3 H), 3.82 (s, 3 H), 3.33–3.23 (m, 1 H), 2.56–2.47 (m, 1 H),
2.42–2.32 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 153.9,
1109, 1013, 750 cm–1. MS (EI): m/z (%) = 343 (10) [M+], 325 (48),
310 (12), 294 (12), 280 (13), 266 (40), 241 (100). HRMS (ESI-POS):
calcd. for C19H21NO5Na [M + Na]+ 366.1312; found 366.1328.
Compound 13d: 1H NMR (CDCl3, 300 MHz): δ = 8.01 (d, J =
7.5 Hz, 1 H), 7.90 (br. s, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.26 (dt, 150.0, 145.5, 144.3, 143.7, 138.8, 131.7, 131.4, 129.4, 129.0, 128.9
J = 7.5, 1.2 Hz, 1 H), 6.65 (s, 1 H), 5.54 (s, 1 H), 4.51–4.49 (m, 1 (2 C), 127.4, 127.1, 124.1 (2 C), 123.7, 109.9, 60.5, 60.2, 56.4, 47.4,
H), 3.98 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 2.94–2.81 (m, 1 H),
26.9 ppm. FTIR: ν
= 1528, 1498, 1347, 1263, 1163, 854,
˜
max
Eur. J. Org. Chem. 2015, 6324–6332
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6329

S. Techasakul et al.
737 cm–1. MS (EI): m/z (%) = 452 (5) [M+], 265 (100), 250 (20), ium (1.6 m in hexane; 9.0 mL, 14.4 mmol) was added dropwise to
FULL PAPER
195 (14), 127 (12), 81 (13). HRMS (ESI-POS): calcd. for
a cooled (–78 °C) solution of 22 in tetrahydrofuran (50 mL), and
the mixture was stirred at –78 °C for 1 h. Triisopropyl borate
(5.5 mL, 24 mmol) was then added to the mixture at –78 °C, and
the reaction mixture was stirred at –78 °C for 15 min after which
the temperature was raised to 0 °C and then slowly warmed up
to room temperature. After stirring at room temperature for an
additional 2.5 h, hydrochloric acid (2 m, 20 mL) was added to the
reaction mixture, and the mixture was stirred at room temperature
for 2 h. The reaction mixture was then basified with aqueous so-
dium hydroxide (2 m) and extracted with ethyl acetate. The aqueous
layer was acidified with 10% hydrochloric acid and extracted with
ethyl acetate. The combined organic layers were washed with water,
dried with anhydrous sodium sulfate, filtered, and concentrated un-
der reduced pressure. The residue was recrystallized from hexane/
dichloromethane to yield 18 as a white solid (1.0 g, 38% from 21).
1H NMR (CDCl3, 300 MHz): δ = 9.84 (s, 1 H), 8.23 (d, J = 8.4 Hz,
1 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.17 (dd, J = 8.4, 2.7 Hz, 1 H),
4.74–4.66 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 198.6, 160.2, 141.6, 140.7 (2 C), 126.6, 119.8,
C23H21N2O6S [M + H]+ 453.1115; found 453.1103.
Conversion of 15 into 16d: Compound 15 (300 mg, 0.64 mmol) was
treated with HBr/AcOH according to the same method as de-
scribed for 12. The resulting crude product was dissolved in di-
chloromethane (20 mL). Methanesulfonyl chloride (0.25 mL,
3.19 mmol) and triethylamine (0.90 mL, 6.38 mmol) were then
added to the solution. After stirring at room temperature for 1 h,
the reaction mixture was added to water and extracted with di-
chloromethane. The combined organic layers were washed with
water, dried with anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography to yield 16d (145 mg, 50%).
Compound 17: DBU (50 μL) was added to a solution of 16d (40 mg,
0.09 mmol) in N,N-dimethylformamide (2 mL), and the reaction
mixture was stirred at room temperature for 15 min. The reaction
mixture was then added to water and extracted with ethyl acetate.
The combined organic layers were washed with water, dried with
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography to
yield 17 as a yellow solid (23 mg, 98%). 1H NMR (CDCl3,
300 MHz): δ = 7.93 (d, J = 7.2 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H),
7.44 (dt, J = 7.3, 0.9 Hz, 1 H), 7.30 (dt, J = 7.5, 0.9 Hz, 1 H), 6.54
(s, 1 H), 4.22 (t, J = 8.1 Hz, 2 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 2.83
(t, J = 8.1 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 166.0,
158.4, 143.5, 141.7, 135.9, 132.3, 130.5, 130.1, 128.3, 124.1, 123.6,
70.3, 21.8 (2 C) ppm. FTIR: ν
= 3376, 1682, 1594, 1339, 1302,
˜
max
1270, 1108 cm–1. MS (EI): m/z (%) = 208(46) [M+], 178 (16), 165
(100), 149 (66), 138 (23), 120 (90). HRMS (ESI-POS): calcd. for
C10H13BO4Na [M + Na]+ 231.0801; found 231.0813.
Compound 23: Prepared from 14 (1.64 g, 3.70 mmol) and 18 (1.0 g,
4.81 mmol) according to the same method as described for the
preparation of compound 12, 23 was obtained as a yellow solid
1
(1.5 g, 77%). H NMR (CDCl3, 300 MHz): δ = 9.72 (s, 1 H), 8.31
121.4, 109.9, 60.6, 56.4, 49.1, 22.7 ppm. FTIR: ν
= 1494, 1320,
˜
max
1268, 1239, 1123, 1008, 749 cm–1. MS (EI): m/z (%) = 265 (100)
[M+], 250 (17), 220 (18), 195 (14), 178 (9), 165 (7). HRMS (ESI-
POS): calcd. for C17H16NO2 [M + H]+ 266.1176; found 266.1120.
(d, J = 8.7 Hz, 2 H), 8.01 (d, J = 8.7 Hz, 2 H), 7.46 (d, J = 2.4 Hz,
1 H), 7.24 (d, J = 8.4 Hz, 1 H), 7.14 (dd, J = 8.4, 2.4 Hz, 1 H),
6.74 (d, J = 1.5 Hz, 1 H), 6.57 (d, J = 1.5 Hz, 1 H), 5.25–5.15 (m,
1 H), 4.73–4.63 (m, 1 H), 3.86 (s, 3 H), 3.44 (s, 3 H), 3.31 (q, J =
6.9 Hz, 2 H), 2.82 (t, J = 6.9 Hz, 2 H), 1.39 (s, 3 H), 1.37 (s, 3 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 192.1, 157.7, 152.7, 150.0,
145.9, 145.4, 134.5, 133.3, 133.2, 132.2, 132.1, 128.2 (2 C), 124.3 (2
C), 123.3, 122.2, 112.8, 112.0, 70.2, 60.2, 55.9, 44.3, 35.8, 21.9 (2
Conversion of 17 to 1: DBU (60 μL) was added to a solution of
17 (50 mg, 0.10 mmol) in N,N-dimethylformamide (3 mL), and the
reaction mixture was stirred at 100 °C for 24 h. The reaction mix-
ture was then cooled to room temperature, added to water and
extracted with ethyl acetate. The combined organic layers were
washed with water, dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography to yield 1 as a yellow solid (31 mg,
C) ppm. FTIR: ν
= 3288, 1688, 1529, 1347, 1162, 1091, 852,
˜
max
734 cm–1. MS (EI): m/z (%) = 528(87) [M+], 497 (66), 455 (18), 314
(57), 241 (100). HRMS (ESI-POS): calcd. for C26H28N2O8SNa [M
+ Na]+ 551.1459; found 551.1461.
1
62%). H NMR (CDCl3, 300 MHz): δ = 8.59 (d, J = 5.7 Hz, 1 H),
8.10–8.02 (m, 2 H), 7.45–7.40 (m, 3 H), 7.00 (s, 1 H), 4.11 (s, 3 H),
4.04 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.0, 158.9,
147.6, 145.6, 139.2, 138.1, 130.6, 129.7, 128.3, 126.4, 124.7, 123.3,
Compound 24: Compound 23 (500 mg, 0.95 mmol) was subjected
to HBr/AcOH treatment and mesylation reaction as described for
15 except that the time for the mesylation reaction was prolonged
from 1 h to 24 h. Compound 24 was obtained as a yellow gum
(175 mg, 57%). 1H NMR (CDCl3, 300 MHz): δ = 7.71 (d, J =
8.1 Hz, 1 H), 7.37 (s, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 6.47 (s, 1 H),
4.68–4.58 (m, 1 H), 4.19 (t, J = 8.1 Hz, 2 H), 3.92 (s, 3 H), 3.90 (s,
3 H), 2.7 (t, J = 8.1 Hz, 2 H), 1.36 (s, 3 H), 1.34 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 165.7, 158.4, 157.7, 142.5, 139.0,
134.0, 130.4, 129.3, 124.8, 122.0, 119.7, 109.1, 108.7, 70.3, 60.5,
121.8, 117.0, 104.7, 61.3, 56.3 ppm. FTIR: νmax = 1586, 1474, 1406,
˜
1281, 1191, 1132, 1021, 849, 750 cm–1. MS (EI): m/z (%) = 263
(100) [M+], 248 (13), 220 (44), 205 (5), 190 (18), 177 (20). HRMS
(ESI-POS): calcd. for C17H14NO2 [M + H]+ 264.1019; found
264.1028.
Conversion of 16d to 1: Compound 16d (47 mg, 0.10 mmol) was
treated with DBU according to the same method as described for
compound 17 to yield 1 as a yellow solid (27 mg, 58%).
56.3, 50.1, 22.7, 22.1 (2 C) ppm. FTIR: ν
= 1601, 1494, 1466,
˜
max
1277, 1245, 1114, 1092 cm–1. MS (EI): m/z (%) = 323 (70) [M+],
281 (100), 266 (50), 238 (12), 211 (13), 149 (9). HRMS (ESI-POS):
calcd. for C20H22NO3 [M + H]+ 324.1594; found 324.1604.
Compound 18: A mixture of 21[19] (3.0 g, 0.012 mol), ethylene glycol
(6.7 mL, 0.12 mol), and p-toluenesulfonic acid (228 mg, 1.2 mmol)
in toluene (80 mL) was heated at reflux in an apparatus equipped
with a Dean–Stark trap until the evolution of water had ceased (ca.
7 h). Most of the toluene was then distilled off, and the residue was
cooled to room temperature. The residue was poured into saturated
aqueous sodium hydrogen carbonate and extracted with ethyl acet-
ate. The combined organic layers were washed with water, dried
with anhydrous sodium sulfate, and concentrated under reduced
pressure to give a crude product of acetal 22 as a colorless oil,
which was used in the next step without purification. n-Butyllith-
Compound 25: Compound 24 (175 mg, 0.54 mmol) was treated with
DBU according to the same method as described for the conversion
1
of 17 into 1 to yield 25 as a yellow gum (125 mg, 72%). H NMR
(CDCl3, 300 MHz): δ = 8.49 (d, J = 5.7 Hz, 1 H), 8.85 (d, J =
8.4 Hz, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.41 (d, J = 6.0 Hz, 1 H),
6.95 (dd, J = 8.4, 2.4 Hz, 1 H), 6.88 (s, 1 H), 4.77–4.69 (m, 1 H),
4.07 (s, 3 H), 4.02 (s, 3 H), 1.42 (s, 3 H), 1.40 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 159.8, 158.8, 157.6, 146.9, 139.9,
6330
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6324–6332

Total Syntheses of Azafluoranthene and Dehydroaporphine Alkaloids
131.2, 130.3, 126.7, 125.6, 124.0, 118.3, 117.5, 109.6, 103.4 (2 C),
7.96 (d, J = 8.7 Hz, 2 H), 7.90–7.85 (m, 1 H), 7.84 (d, J = 9.3 Hz,
70.4, 61.2, 56.4, 22.1 (2 C) ppm. FTIR: ν
= 1611, 1585, 1473, 1 H), 7.65–7.58 (m, 3 H), 7.39 (s, 1 H), 7.07 (br. s, 1 H), 4.00 (s, 3
˜
max
1281, 1234, 1204, 1111, 1083, 839 cm–1. MS (EI): m/z (%) = 321 H), 3.89 (s, 3 H), 3.49–3.40 (m, 2 H), 3.39–3.32 (m, 2 H) ppm. 13C
(48) [M+], 279 (100), 264 (17), 236 (39), 206 (11), 193 (3), 178 (4). NMR ([D6]acetone, 75 MHz): δ = 151.0, 149.8, 146.7, 146.3, 132.8,
HRMS (ESI-POS): calcd. for C20H20NO3 [M + H]+ 322.1438; 131.2, 130.0, 128.2, 128.0 (2 C), 127.8, 126.6, 126.4, 125.9, 125.6,
found 322.1453.
124.9, 124.1 (2 C), 122.2, 115.9, 58.9, 56.0, 44.1, 33.8 ppm. FTIR:
ν
= 1525, 1345, 1310, 1276, 1161, 734 cm–1. MS (EI): m/z (%)
˜
max
Compound 4: Aluminum(III) chloride (91 mg, 0.68 mmol) was
added to a solution of 25 (100 mg, 0.31 mmol) in dichloromethane
(10 mL), and the reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was then added to water and
stirred for additional 0.5 h. Dichloromethane was removed under
reduced pressure. The precipitates were collected by filtration and
= 466 (35) [M+], 366 (5), 251 (100), 237 (10), 151 (45). HRMS
(ESI-POS): calcd. for C24H26N3O6S [M + NH4]+ 484.1537; found
484.1525.
Compound 28: A solution of iodine (82 mg, 0.32 mmol) in aceto-
nitrile (2 mL) was added dropwise to a stirred mixture of 27 (50 mg,
0.11 mmol) and anhydrous potassium carbonate (44.5 mg,
1
dried to yield 4 as a yellow solid (75 mg, 86%). H NMR (CDCl3
+ MeOD, 300 MHz): δ = 8.43 (d, J = 5.7 Hz, 1 H), 7.84 (d, J = 0.32 mmol) in acetonitrile (8 mL) at 0 °C. After stirring at room
8.1 Hz, 1 H), 7.51–7.46 (m, 2 H), 6.98 (s, 1 H), 6.92 (dd, J = 8.1, temperature for 24 h, the reaction was quenched with saturated
2.4 Hz, 1 H), 4.09 (s, 3 H), 4.06 (s, 3 H) ppm. 13C NMR (CDCl3 aqueous sodium thiosulfate until the iodine color had disappeared,
+ MeOD, 75 MHz): δ = 160.1, 158.6, 158.5, 144.2, 140.5, 131.7,
129.9, 127.3, 126.2, 124.5, 118.1, 117.1, 116.1, 109.9, 103.7, 61.5,
and the mixture was extracted with ethyl acetate. The combined
organic layers were washed with water, dried with anhydrous so-
dium sulfate, filtered, and concentrated under reduced pressure.
56.6 ppm. FTIR: ν
= 1591, 1483, 1405, 1252, 1241, 1086, 1020,
˜
max
837 cm–1. MS (EI): m/z (%) = 279 (100) [M+], 264 (13), 236 (43), The residue was purified by column chromatography to yield 28
221 (6), 206 (17), 193 (11). HRMS (ESI-POS): calcd. for
as a yellow solid (18 mg, 36%, 54% BRSM). 1H NMR (CDCl3,
300 MHz): δ = 9.61–9.57 (m, 1 H), 8.07 (d, J = 9.0 Hz, 2 H), 7.97
(s, 1 H), 7.90–7.86 (m, 1 H), 7.75 (d, J = 9.0 Hz, 2 H), 7.64–7.61
(m, 2 H), 6.90 (s, 1 H), 4.19 (t, J = 6.0 Hz, 2 H), 3.94 (s, 3 H), 3.90
(s, 3 H), 2.86 (t, J = 6.0 Hz, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 151.3, 150.0, 146.4, 146.2, 132.1, 130.2, 128.8, 128.5,
128.2 (2 C), 127.8, 127.3, 127.0, 126.9, 125.7, 124.1 (2 C), 120.9,
C17H14NO3 [M + H]+ 280.0968; found 280.0965.
Compound 26: To a 0 °C cooled suspension of (methoxymethyl)-
triphenylphosphonium chloride (1.09 g, 3.18 mmol) in anhydrous
tetrahydrofuran (15 mL) was added dropwise lithium bis(trimethyl-
silyl)amide (LiHMDS, 1.0 m in tetrahydrofuran; 3.83 mL,
3.83 mmol). The deep red mixture was stirred at 0 °C under argon
for 20 min. A solution of 15 (500 mg, 1.06 mmol) in anhydrous
tetrahydrofuran (15 mL) was then added dropwise to the solution,
and the mixture was stirred at 0 °C for another 1 h. Then water
was added to the reaction mixture, and tetrahydrofuran was re-
moved under reduced pressure. The residue was extracted with
dichloromethane. The combined organic layers were washed with
water, dried with anhydrous sodium sulfate, and concentrated un-
der reduced pressure. The residue was purified by column
chromatography to provide enol ether 26 as a yellow gum (345 mg,
65%) as a 4:5 mixture of E/Z isomers. 1H NMR (CDCl3,
300 MHz): δ = 8.29 (d, J = 8.7 Hz, 2 H, E), 8.27 (d, J = 8.7 Hz, 2
119.4, 112.9, 59.8, 56.3, 45.2, 28.8 ppm. FTIR: ν
= 1527, 1348,
˜
max
1291, 1167, 1106, 1015, 852, 758 cm–1. MS (EI): m/z (%) = 464 (48)
[M+], 399 (15), 278 (100), 262 (50), 247 (65), 232 (27), 220 (15).
HRMS (ESI-POS): calcd. for C24H21N2O6S [M + H]+ 465.1115;
found 465.1128.
Compound 29: A solution of sodium naphthalenide in dry dimeth-
oxyethane (DME) was prepared by adding DME (4 mL) to a mix-
ture of sodium (97 mg, 4.22 mmol) and naphthalene (711 mg,
5.55 mmol) and stirring the resulting mixture at room temperature
for 2 h. A solution of 28 (30 mg, 0.065 mmol) in dry DME (3 mL)
was cooled with a dry-ice/isopropyl alcohol bath. The sodium
H, Z), 8.13 (d, J = 7.2 Hz, 1 H, Z), 7.98 (d, J = 8.7 Hz, 2 H, E), naphthalenide solution was added dropwise to the stirred solution
7.97 (d, J = 8.7 Hz, 2 H, Z), 7.41 (d, J = 7.8 Hz, 1 H, E), 7.33 (dt,
J = 7.3, 1.5 Hz, 1 H, Z), 7.26 (dd, J = 7.5, 1.2 Hz, 1 H, E), 7.22–
7.09 (m, 4 H), 6.85 (d, J = 12.6 Hz, 1 H, E), 6.64 (d, J = 1.8 Hz, 1
H), 6.40 (d, J = 2.1 Hz, 1 H, E), 6.37 (d, J = 2.1 Hz, 1 H, Z), 6.03
(d, J = 7.2 Hz, 1 H, Z), 5.60 (d, J = 12.6 Hz, 1 H, E), 4.95 (d, J =
of 28 until a light green color persisted. The reaction was quenched
by addition of saturated aqueous sodium hydrogen carbonate. An-
hydrous potassium carbonate (354 mg) was added, and the mixture
was stirred for 2 h. The mixture was filtered, and the precipitates
were rinsed with ethyl acetate. The combined filtrates were concen-
7.2 Hz, 1 H, Z), 4.75–4.65 (m, 2 H), 3.86 (s, 3 H, E), 3.85 (s, 3 H, trated under reduced pressure. The residue was purified by column
Z), 3.74 (s, 3 H, Z), 3.52 (s, 3 H, E), 3.51 (s, 3 H, E), 3.49 (s, 3 H, chromatography to yield 29 as a yellow solid (15 mg, 83%). 1H
Z), 3.29 (q, J = 6.6 Hz, 4 H), 2.80–2.73 (m, 4 H) ppm. 13C NMR
NMR (CDCl3, 300 MHz): δ = 9.46 (d, J = 8.4 Hz, 1 H), 7.54 (dd,
(CDCl3, 75 MHz): δ = 153.0, 150.0 (Z), 149.1 (E), 148.0 (Z), 145.9, J = 8.1, 1.2 Hz, 1 H), 7.44 (dt, J = 6.9, 1.2 Hz, 1 H), 7.36–7.32 (m,
145.7, 136.1 (Z), 136.0 (Z), 135.8 (E), 135.7 (E), 134.5 (E), 133.8 1 H), 7.04 (s, 1 H), 6.63 (s, 1 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 3.46
(Z), 132.3 (E), 132.1 (Z), 130.2 (E), 129.7 (Z), 128.9 (Z), 128.2, (t, J = 6.3 Hz, 2 H), 3.22 (t, J = 6.3 Hz, 2 H) ppm. 13C NMR
127.8 (E), 127.5 (Z), 125.4 (E), 125.3 (Z), 124.3, 124.2 (E), 123.3 (CDCl3, 75 MHz): δ = 151.2, 145.7, 141.4, 134.6, 129.6, 127.8,
(Z), 123.2 (E), 112.0 (E), 111.8 (Z), 104.5 (E), 103.4 (Z), 60.6 (4 126.8, 125.8, 125.6, 124.9, 122.6, 118.5, 111.6, 103.1, 59.7, 56.4,
C), 57.0 (E), 56.0 (E), 55.9 (Z), 44.2 (E), 44.1 (Z), 35.6 (E), 35.4
41.2, 31.1 ppm. FTIR: ν
= 3377, 1623, 1594, 1390, 1336, 1115,
˜
max
(Z) ppm. FTIR: ν
= 3291, 1645, 1528, 1347, 1160, 1084, 852,
1017, 827, 747 cm–1. MS (EI): m/z (%) = 279 (100) [M+], 264 (35),
˜
max
734 cm–1. MS (EI): m/z (%) = 498 (1) [M+], 366 (1), 251 (3), 225 236 (25), 220 (13), 149 (8). HRMS (ESI-POS): calcd. for
(3), 151 (10), 75 (100). HRMS (ESI-POS): calcd. for C25H30N3O7S C18H18NO2 [M + H]+ 280.1332; found 280.1342.
[M + NH4]+ 516.1799; found 516.1796.
Compound 30: This compound was prepared from 23 (500 mg,
Compound 27: Compound 26 (211 mg, 0.42 mmol) was treated with
HBr/AcOH according to the same method as described for com-
pound 12 to yield crude 27 as a yellow solid (190 mg, 96%), which
was used in the next step without purification. 1H NMR ([D6]acet-
0.95 mmol) according to the same method as described for 26 to
yield 30 as a yellow gum (315 mg, 60%) as a 4:5 mixture of E/Z
isomers. H NMR (CDCl3, 300 MHz): δ = 8.30 (d, J = 9.0 Hz, 2
1
H, E), 8.29 (d, J = 9.0 Hz, 2 H, Z), 7.98 (d, J = 9.0 Hz, 1 H, E),
one, 300 MHz): δ = 9.64–9.61 (m, 1 H), 8.24 (d, J = 8.7 Hz, 2 H), 7.97 (d, J = 9.0 Hz, 2 H, Z), 7.72 (d, J = 2.7 Hz, 1 H, Z), 7.04 (d,
Eur. J. Org. Chem. 2015, 6324–6332
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6331

S. Techasakul et al.
FULL PAPER
J = 8.4 Hz, 1 H, E), 7.02 (d, J = 8.4 Hz, 1 H, Z), 6.93 (d, J =
2.4 Hz, 1 H, E), 6.84 (d, J = 12.9 Hz, 1 H, E), 6.75–6.70 (m, 2 H),
6.63–6.60 (m, 2 H), 6.40 (d, J = 2.1 Hz, 1 H, E), 6.38 (d, J = 2.1 Hz,
1 H, E), 6.02 (d, J = 7.5 Hz, 1 H, Z), 5.58 (d, J = 12.9 Hz, 1 H,
E), 4.93 (d, J = 7.2 Hz, 1 H, Z), 4.80–4.70 (m, 2 H), 4.65–4.55 (m,
2 H), 3.85 (s, 3 H, E), 3.84 (s, 3 H, Z), 3.74 (s, 3 H, Z), 3.51 (s, 3
H, E), 3.50 (s, 3 H, E), 3.48 (s, 3 H, Z), 3.28 (q, J = 6.6 Hz, 4 H),
2.80–2.70 (m, 4 H), 1.39 (s, 3 H, Z), 1.38 (s, 3 H, E), 1.37 (s, 3 H,
Z), 1.36 (s, 3 H, E) ppm. 13C NMR (CDCl3, 75 MHz): δ = 157.4
(E), 157.2 (Z), 153.0, 150.0, 149.2 (E), 148.2 (Z), 145.9, 145.8, 135.8
(Z), 135.7 (E), 135.5 (E), 134.9 (Z), 132.2 (Z), 132.0 (E), 131.3 (E),
130.6 (Z), 128.5 (Z), 128.3 (E), 128.2, 124.4, 123.8 (E), 123.7 (Z),
115.9, 113.0 (Z), 112.7 (E), 111.7 (E), 111.6 (Z), 104.6 (E), 103.5
(Z), 69.8 (E), 69.7 (Z), 60.7 (Z), 60.5, 57.0 (E), 56.0 (E), 55.9 (Z),
Acknowledgments
We gratefully acknowledged Dr. Poonsakdi Ploypradith at the Chu-
labhorn Research Institute for critical reading of the manuscript.
We also thank Miss Kittiporn Trisupphakant for recording EI-MS
and IR spectra data.
[1] D. S. Swaffar, C. J. Holley, R. W. Fitch, K. R. Elkin, C. Zhang,
J. P. Sturgill, M. D. Menachery, Planta Med. 2012, 78, 230–232.
[2] H. Morita, K. Matsumoto, K. Takeya, H. Itokawa, Chem.
Pharm. Bull. 1993, 41, 1307–1308.
[3] M.-H. Yan, P. Cheng, Z.-Y. Jiang, Y.-B. Ma, X.-M. Zhang, F.-
X. Zhang, L.-M. Yang, Y.-T. Zheng, J.-J. Chen, J. Nat. Prod.
2008, 71, 760–763.
[4] J. Chen, K. Gao, T. Liu, H. Zhao, J. Wang, H. Wu, B. Liu, W.
Wang, Asian J. Chem. 2013, 25, 10015–10027.
[5] K. Kaur, M. Jain, T. Kaur, R. Jain, Bioorg. Med. Chem. 2009,
17, 3229–3256.
[6] E. J. Osorio, S. M. Robledo, J. Bastida in The Alkaloids: Chem-
istry and Biology, vol. 66 (Ed.: G. A. Cordell), Academic Press,
The Netherlands, 2008, pp. 113–190.
[7] C. Stévigny, C. Bailly, J. Quetin-Leclercq, Curr. Med. Chem.
Anti-Cancer Agents 2005, 5, 173–182.
[8] A. P. Murray, M. B. Faraoni, M. J. Castro, N. P. Alza, V. Caval-
laro, Curr. Neuropharmacol. 2013, 11, 388–413.
44.2 (E), 44.1 (Z), 35.6 (E), 35.5 (Z), 22.2 ppm. FTIR: νmax = 3291,
˜
1646, 1530, 1347, 1228, 1162, 1103, 1078, 852, 734 cm–1. MS (EI):
m/z (%) = 556 (2) [M+], 267 (2), 241 (1), 75 (100), 57 (1). HRMS
(ESI-POS): calcd. for C28H32N2O8SNa [M + Na]+ 579.1772; found
579.1794.
Compound 31: Compound 30 (215 mg, 0.39 mmol) was treated with
HBr/AcOH according to the same method as described for 12 to
yield a crude product of 31 as a yellow solid (200 mg, 98%), which
1
was used in the next step without purification. H NMR (CDCl3,
[9] a) M. Hellal, S. Singh, G. D. Cuny, Tetrahedron 2012, 68, 1674–
1681; b) G. D. Cuny, Tetrahedron Lett. 2004, 45, 5167–5170; c)
M. Lafrance, N. Blaquière, K. Fagnou, Chem. Commun. 2004,
2874–2875; d) O. Hoshino in Studies in Natural Products
Chemistry, vol. 16 (Ed.: A.-ur-Rahman), Elsevier Science B. V.,
The Netherlands, 1995, pp. 503–546 and references cited
therein.
300 MHz): δ = 9.48 (d, J = 9.3 Hz, 1 H), 8.07 (d, J = 9.0 Hz, 2 H),
7.75 (d, J = 9.0 Hz, 2 H), 7.56 (d, J = 9.0 Hz, 1 H), 7.42 (d, J =
9.0 Hz, 1 H), 7.23 (dd, J = 9.3, 2.7 Hz, 1 H), 7.18 (d, J = 2.7 Hz,
1 H), 7.05 (s, 1 H), 4.80–4.70 (m, 2 H), 4.00 (s, 3 H), 3.88 (s, 3 H),
3.44–3.37 (m, 2 H), 3.30–3.25 (m, 2 H), 1.45 (s, 3 H), 1.43 (s, 3 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 156.5, 150.7, 149.7, 145.8,
145.4, 134.3, 129.8 (2 C), 127.8 (2 C), 125.8, 125.6, 124.9, 124.0 (2
C), 123.7, 121.8, 117.8, 114.3, 110.9, 69.9, 59.7, 56.6, 43.9, 34.1,
[10] S. Ponnala, W. W. Harding, Eur. J. Org. Chem. 2013, 1107–
1115.
22.1 (2 C) ppm. FTIR: ν
= 3292, 1594, 1528, 1347, 1265, 1160, [11] C. C. Silveira, E. L. Larghi, S. R. Mendes, A. B. J. Bracca, F.
˜
max
1113, 852, 734 cm–1. MS (EI): m/z (%) = 524 (99) [M+], 482 (8),
309 (81), 295 (15), 267 (100), 253 (22), 223 (2). HRMS (ESI-POS):
calcd. for C27H28N2O7SNa [M + Na]+ 547.1509; found 547.1516.
Rinaldi, T. S. Kaufman, Eur. J. Org. Chem. 2009, 27, 4637–
4645.
[12] P. Molina, S. Garcia-Zafra, P. M. Fresneda, Synlett 1995, 43–
45.
[13] J.-M. Fu, B.-P. Zhao, M. J. Sharp, V. Snieckus, Can. J. Chem.
1994, 72, 227–236.
[14] D. L. Boger, C. E. Brotherton, J. Org. Chem. 1984, 49, 4050–
4055.
[15] a) M. G. Banwell, E. Hamel, N. K. Ireland, M. F. Mackay,
A. K. Serelis, J. Chem. Soc. Perkin Trans. 1 1993, 1905–1911;
b) M. P. Cava, K. T. Buck, A. I. daRocha, J. Am. Chem. Soc.
1972, 94, 5931.
[16] M. M. V. Ramana, R. H. Sharma, J. A. Parihar, Tetrahedron
Lett. 2005, 46, 4385–4386.
[17] M. Lautens, T. Marquardt, J. Org. Chem. 2004, 69, 4607–4614.
[18] D. W. Knight, A. L. Redfern, J. Gilmore, J. Chem. Soc. Perkin
Trans. 1 2001, 2874–2883.
[19] J. C. C. Morales, A. G. Torres, E. González-Zamora, Eur. J.
Org. Chem. 2011, 3165–3170.
Compound 32: This compound was prepared from 31 (200 mg,
0.38 mmol) according to the same method as described for the
preparation of compound 28 to yield 32 as a yellow solid (58 mg,
1
29%, 46% BRSM). H NMR (CDCl3, 300 MHz): δ = 9.47 (d, J =
9.3 Hz, 1 H), 8.07 (d, J = 9.0 Hz, 2 H), 7.90 (s, 1 H), 7.74 (d, J =
9.0 Hz, 2 H), 7.26 (d, J = 2.7 Hz, 1 H), 7.22 (dd, J = 9.3, 2.7 Hz,
1 H), 6.81 (s, 1 H), 4.82–4.74 (m, 1 H), 4.17 (t, J = 6.0 Hz, 2 H),
3.93 (s, 3 H), 3.88 (s, 3 H), 2.82 (t, J = 6.0 Hz, 2 H), 1.46 (s, 3 H),
1.44 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 156.8, 151.3,
149.9, 146.4, 145.3, 134.0, 130.6, 129.6, 128.1 (2 C), 126.9, 125.8,
124.1 (2 C), 122.3, 120.6, 118.4, 118.0, 111.8, 111.1, 69.9, 59.7, 56.2,
45.2, 28.6, 22.1 (2 C) ppm. FTIR: ν
= 1594, 1529, 1347, 1165,
˜
max
1107, 853, 740 cm–1. MS (EI): m/z (%) = 522 (46) [M+], 458 (12),
415 (8), 336 (100), 305 (21), 278 (21), 263 (24). HRMS (ESI-POS):
calcd. for C27H27N2O7S [M + H]+ 523.1533; found 523.1523.
Received: July 1, 2015
Published Online: August 20, 2015
6332
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6324–6332