Azaanthraquinone assembly from N-propargylamino quinone via iodine-induced 6-endo-dig electrophilic cyclization

Article abstract of DOI:10.1039/c004896h

An efficient methodology taking advantage of the excellent nucleophilicity of aminoquinone to assemble the azaanthraquinone framework was developed via an iodine-induced 6-endo-dig electrophilic cyclization. Therefore, starting from N-propargylaminoquinon

Full text of DOI:10.1039/c004896h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Azaanthraquinone assembly from N-propargylamino quinone via
iodine-induced 6-endo-dig electrophilic cyclization†
Na Fei,a Qiwen Hou,a Shaozhong Wang,*a Huaqin Wangb and Zhu-Jun Yaoa
Received 6th April 2010, Accepted 17th June 2010
First published as an Advance Article on the web 23rd July 2010
DOI: 10.1039/c004896h
An efficient methodology taking advantage of the excellent nucleophilicity of aminoquinone to
assemble the azaanthraquinone framework was developed via an iodine-induced 6-endo-dig electrophilic
cyclization. Therefore, starting from N-propargylaminoquinones, various 3-iodo-1-azaanthraquinones
were obtained in yields ranging from 45% to 90%. The metal-free protocol features facile installation of
an iodine atom on the azaanthraquinone ring and benign functional group compatibility.
molecular iodine and bis(pyridine)iodonium tetrafluoroborate
Introduction
(IPy2BF4) as electrophiles.5,6 The general mechanism includes
activation of the C–C triple bond by iodine cation and subse-
quent nucleophilic attack by an intramolecular nucleophile. Thus,
alkynes containing N, O, S functionalities undergo iodocyclization
to afford heterocycles such as indoles,5a,5b,6a,7a isoindolinones,5c
isoquinolines,5d,5e,8 isocoumarins,5g isochromenes,5h,6b,6c furans,5i,9
benzo[b]furans5j and benzo[b]thiophenes.5l,5m,7b,7c Besides N, O, S
functionalities, arenes may also act as nucleophiles in electrophilic
cyclization, furnishing quinolines5f and 2H-benzopyrans.5k,6e This
metal-free methodology features robust conditions and facile
installation of an iodine atom on the heterocycle ring.
Recently, we have developed an alternative route to attain aza-
anthraquinones from N-propargylaminoquinones by employing a
Au(I)-catalyzed 6-endo cycloisomerization (Fig. 1, route III).10 The
nucleophilicity of aminoquinone in the metal-catalyzed cycloiso-
merization differs significantly from that of electron-rich double
bonds such as enamide and enamine, as well as enaminone.11
This finding prompted us to further investigate the reactivity
of N-propargylaminoquinone in electrophilic cyclization and to
explore the possibility of another strategy for the assembly of
azaanthraquinones. As illustrated in Scheme 1, molecular iodine
selectively coordinates with the C–C triple bond to form an
iodonium ion, promoting nucleophilic attack from the double
bond of the aminoquinone in a 6-endo manner. Then, the cyclized
intermediate undergoes oxidative aromatization to afford the
1-azaanthraquinone.
Considerable efforts have been devoted to the assembly of
the 1-azaanthraquinone framework because naturally occurring
alkaloids with this skeleton display diversified biological activities
ranging from antimicrobial capacity to cytotoxicity.1 Two kinds
of synthetic approach based on Diels–Alder reaction have been
applied extensively.2,3 One involves pyridine annelation from aza-
1,3-diene and 1,4-naphthoquinone (Fig. 1, route I), the other
concerns benzene ring construction from 1,3-diene and 5,8-
quinolinedione (Fig. 1, route II). However, these reactions suffered
from low regioselectivity when asymmetric 1,3-dienes or quinone
dienophiles were employed. Furthermore, the dimethylamine
eliminated from the initial aza-Diels–Alder adduct is apt to react
with the quinone dienophiles, significantly decreasing the reaction
efficiency. Consequently, the development of new methodology for
1-azaanthraquinones is still highly desirable and challenging.
Fig. 1 Strategies for azaanthraquinone assembly.
Electrophilic cyclization has attracted much attention in recent
decades and proven to be a powerful means to elaborate car-
bocycles and heterocycles.4 Larock and Barluenga independently
explored the electrophilic cyclization of alkynes by utilizing
aSchool of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. China.
E-mail: wangsz@nju.edu.cn; Fax: +86 25 83317761; Tel: +86 25 83593732
bModern Analytical Center of Nanjing University, Nanjing 210093, P. R.
China
† Electronic supplementary information (ESI) available: NMR spectra.
CCDC reference number 748375. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c004896h
Scheme 1 Proposed synthesis of 1-azaanthraquinone by iodine-induced
6-endo-dig electrophilic cyclization.
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Table 1 Preparation of N-Propargylaminoquinone by Au(III)-catalyzed
Results and discussion
1,4-nucleophilic addition-oxidationa
Preparation of N-propargylaminoquinone by Au(III)-catalyzed
sequential 1,4-nucleophilic addition–oxidation
Entry
1
Quinone
Amine
Aminoquinone
Yield (%)
65
1a
Gold salts exhibit excellent Lewis acid properties in various
chemical transformations involving the formation of C–C, C–O
and C–N bonds.12 As one of simplest salts, NaAuCl4·2H2O
can selectively activate the carbonyl group in some conden-
sation and addition reactions.13,14 In our previous study, we
developed a catalytic process to prepare aminoquinones by
utilizing NaAuCl4·2H2O (Scheme 2).15 The gold(III) catalyst not
only promoted the 1,4-nucleophilic addition through activation
the carbonyl group of the quinone but also accelerated the
oxidation of the adduct amino-hydroquinone. Various aliphatic
and aromatic amines underwent the sequential 1,4-nucleophilic
addition–oxidation with quinones smoothly. However, what sur-
prised us was the stability of the adduct derived from 2-
butynylamine and 1,4-naphthoquinone in the reaction system,
since Acradi reported that the enamines tethered by alkyne units
proceeded through Au(III)-catalyzed cycloisomerization efficiently
to afford pyridine derivatives.11a To further explore the nucle-
ophilicity of N-propargylaminoquinones and screen the scope
of the Au(III)-catalyzed sequential process, different quinones
and propargylamines were examined. As shown in Table 1,
1,4-naphthoquinone reacted with various substituted aromatic
propargylamines (p-Me, p-OMe, p-NO2, o-NO2, o-CO2Me, o-Br),
as well as 2-hexynylamine and 2-butynylamine, smoothly to afford
corresponding N-propargylaminoquinones 1a–1i in 60–78% yield
(Table 1, entries 1–9). 2-Butynylamine reacted with different
quinones including 8-methoxy-1,4-naphthoquinone, 8-hydroxy-
1,4-naphthoquinone, 6,7-dimethoxy-1,4-naphthoquinone, 2,5,8-
quinolinetrione and 5,8-quinolinedione regioselectively, the cor-
responding adducts 1j–1n were obtained in yields ranging from
55% to 80% (Table 1, entries 10–14).
2
1b
1c
1d
1e
1f
70
65
60
72
74
60
78
70
60
80
65
60
55
3
4
5
6
7
1g
1h
1i
8
9
10b
11b
12
13b
14b
1j
1k
1l
Scheme 2 Au(III)-catalyzed 1,4-nucleophilic addition–oxidation.
1m
1n
Assembly of azaanthraquinone by I2-induced 6-endo-dig
electrophilic cyclization
To examine the feasibility of the electrophilic cyclization, we
initiated the study by choosing enyne 1a as substrate (Scheme 3,
Table 2). By treating compound 1a with molecular iodine and
NaHCO3 in CH2Cl2 at room temperature for 12 h, the desired
azaanthraquinone 2a was achieved in 42% yield (Table 2, entry
1). A side-product 3 generated from 1,2-addition of iodine to the
alkyne bond was also isolated. However, the amount of this 1,2-
adduct can be reduced dramatically by raising the reaction temper-
ature. When the cyclization was performed in 1,2-dichloroethane
or acetonitrile at 80 ◦C, the yield of 2a increased to 56% and 65%,
respectively (Table 2, entries 2–3). To further raise the temperature
a 1 mol% NaAuCl4·2H2O, 80 ◦C, 2 h. b 1 mol% NaAuCl4·2H2O, rt, 4 h.
and we found that the electrophilic cyclization gave the best yield
in nitromethane (Table 2, entries 4–5). Attempts to employ other
additives such as Na2CO3, K2CO3 and K3PO4 resulted in inferior
results (Table 2, entries 6–8). Although the transformation could
be carried out by utilizing electrophiles NIS and ICl (Table 2,
entries 9–10), the optimized condition was established to be a
◦
to 100 C, the solvent was switched to dioxane or nitromethane,
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Table 2 Optimization of reaction conditions
Entry
Electrophilea
Conditionsb
Yield (%)c
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
NaHCO3, CH2Cl2, rt, 12 h
NaHCO3, (ClCH2)2, 80 ◦C, 12 h
NaHCO3, CH3CN, 80 ◦C, 12 h
NaHCO3, dioxane, 100 ◦C, 12 h
NaHCO3, CH3NO2, 100 ◦C, 4 h
Na2CO3, CH3NO2, 100 ◦C, 4 h
K2CO3, CH3NO2, 100 ◦C, 4 h
K3PO4, CH3NO2, 100 ◦C, 4 h
CH3NO2, 100 ◦C, 4 h
42
56
65
40
77
60
56
60
70
67
Fig. 2 X-Ray crystal structure of 1-azaanthraquinone 2e·CH3CN.
9
10
NIS
ICl
CH3NO2, 100 ◦C, 4 h
Conclusion
a 3.0 equivalents of electrophile was used. b The amount of additive is 2.0
equivalents. c Isolated yields.
In conclusion,
a methodology to assemble the azaan-
thraquinone and diazaanthraquinone skeletons from N-
propargylaminoquinones was developed by utilizing an iodine-
induced 6-endo-dig electrophilic cyclization. The excellent nucle-
ophilicity of the double bond of aminoquinone was examined.
Besides, the protocol features mild conditions and benign func-
tional group compatibility. Application of the methodology in
tricycloquinone alkaloid synthesis and structural modification will
be pursued.
Experimental
Melting points are uncorrected. IR spectra were recorded on a
Nicolet FT-IR 5DX spectrometer as KBr pellets. NMR spectra
were recorded on a Bruker ACF-300 spectrometer by using
tetramethylsilane (TMS) or residue solvent as internal standards.
The J values are given in Hz. Mass spectra were taken on a VG-
ZAB-HS spectrometer in the electron impact ionization mode.
Elemental analyses were performed with a Perkin–Elmer 240C
analyzer.
Scheme 3 Azaanthraquinone assembly by electrophilic cyclization.
combination of iodine and nitromethane (Table 2, entry 5) after
comparing the reaction efficiency and practicality.
The scope of the transformation was next investigated. As
shown in Table 3, enyne substrates containing various aryl groups
at the alkyne terminus underwent the iodine-induced 6-endo-
dig electrophilic cyclization smoothly to afford the 4-aryl-1-
azaanthraquinones with 53% to 77% yield (Table 3, entries 1–
7). An electron-donating substituent (p-OMe) on the aryl ring
facilitated the cyclization while electron-withdrawing substituents
(p-NO2, o-NO2, o-CO2Me, o-Br) hindered the conversion. For a Ph
group, the yield was moderate. The structure of azaanthraquinone
2e was further confirmed by X-ray crystallographic analysis
(Fig. 2).16 Different from the arylated 1-azaanthraquinones, alkyl-
substituted 1-azaanthraquinone was obtained in higher yield
(Table 3, entry 8). Considering that the alkaloid cleistopholine
and its hydroxyl/methoxy derivatives feature a 4-methyl group on
the 1-azaanthraquinone ring, we then turned our attention to the
electrophilic cyclization of enynes derived from 2-butylnylamine
and different 1,4-naphthoquinones. Enyne 1i with a less sterically
demanding methyl group converted to 3-iodocleistopholine 2i
in 90% yield (Table 3, entry 9). In a similar manner, 3-iodo-8-
methoxycleistopholine 2j, 5-hydroxy-3-iodocleistopholine 2k and
6,7-dimethoxy-3-iodocleistopholine 2l were prepared from enynes
1j–l conveniently (Table 3, entries 10–12). Notably, the incorpo-
ration of an iodine atom on cleistopholine would definitely offer
new opportunities for structure–activity relationship study and
for further structural elaboration. In addition, enynes containing
pyridone and pyridine moieties were well tolerated to afford 1,8-
diazaanthraquinone 2m and 1,5-diazaanthraquinone 2n (Table 3,
entries 13–14), demonstrating the synthetic versatility of the
transformation.
General procedure for the preparation of aminoquinones by
Au(III)-catalyzed sequential 1,4-nucleophilic addition–oxidation
Quinone (2.0 mmol) and NaAuCl4·2H2O (8.0 mg, 0.02 mmol)
were dissolved in ethanol (4.0 mL) under oxygen atmosphere.
Then the amine (1.3 mmol) was added to the above solution.
The resulting reaction mixture was heated at 80 ◦C or at room
temperature for a certain time (monitored by TLC). After cooling,
the mixture was poured into water (40 mL), and extracted with
CH2Cl2 (30 mL ¥ 3). The combined organic extracts were dried
by anhydrous MgSO4. After filtration, the solvent was removed
by distillation. The remaining crude product was purified by flash
chromatography to give the aminoquinone.
2-[3-(4-Methylphenyl)-2-propynylamino]-1,4-naphthoquinone
◦
(1a). Red brown solid, mp 188–190 C (EtOH); IR (KBr) nmax
3336, 1681, 1594, 1493, 812, 774, 725 cm-1; 1H NMR (300 MHz,
CDCl3) d 8.08 (dd, J1 = 16.5 Hz, J2 = 7.8 Hz, 2H), 7.73 (t, J =
7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H),
7.11 (d, J = 7.5 Hz, 2H), 6.12 (br s, 1H), 5.90 (s, 1H), 4.20 (d,
J = 5.4 Hz, 2H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3) d
183.1, 181.5, 147.2, 138.9, 134.7, 133.3, 132.1, 131.6, 130.4, 129.1,
126.3, 126.2, 118.9, 102.3, 85.1, 81.6, 33.2, 21.4; MS (EI) m/z 302
(M+1, 3), 301 (M+, 100), 300 (M-1, 28), 129(26). Anal. Calcd for
C20H15NO2: C, 79.72; H, 5.02; N, 4.65. Found: C, 79.67; H, 4.89;
N, 4.69.
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Table 3 Azaanthraquinone assembly by iodine-induced 6-endo-dig electrophilic cyclizationa
Entry
1
Aminoquinone
Azaanthraquinone
Yield (%)b
77
Entry
8
Aminoquinone
Azaanthraquinone
Yield (%)b
84
2
3
72
58
9
90
75
10
4
5
6
7
53
56
54
62
11
12
13
14
60
87
84
45
a All reactions were performed in 0.05 M. b Isolated yield.
2-[3-(4-Methoxyphenyl)-2-propynylamino]-1,4-naphthoquinone
(1b). Red brown solid, mp 172–175 C (EtOH); IR (KBr) nmax
132.3, 132.1, 131.9, 129.9, 128.2, 125.4, 124.9, 123.3, 100.9, 89.8,
81.0, 31.5; MS (EI) m/z 332 (M+, 11), 331 (M-1, 8), 330 (M-2, 67),
102 (100). Anal. Calcd for C19H12N2O4: C, 68.67; H, 3.64; N, 8.43.
Found: C, 68.69; H, 3.74; N, 8.47.
◦
3351, 1679, 1595, 1566, 1492, 1355, 834, 725 cm-1; 1H NMR (300
MHz, CDCl3) d 8.10 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.5 Hz,
1H), 7.72 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.36 (d,
J = 8.7 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 6.10 (br s, 1H), 5.89 (s,
1H), 4.18 (d, J = 5.7 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 183.1, 181.6, 159.9, 147.2, 134.7, 133.4, 133.2, 132.1,
130.4, 126.23, 126.18, 114.0, 113.9, 102.3, 84.9, 81.0, 55.2, 33.2;
MS (EI) m/z 318 (M+1, 2), 317 (M+, 24), 315 (M-2, 63), 173 (44),
145 (100). Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N, 4.41.
Found: C, 75.87; H, 4.87; N, 4.61.
2-[3-(2-Nitrophenyl)-2-propynylamino]-1,4-naphthoquinone (1d).
Red brown solid, mp 195–197 ◦C (EtOH); IR (KBr) nmax 3350,
1680, 1600, 1568, 1522, 1493, 1341, 744, 726 cm-1; 1H NMR (300
MHz, DMSO-d6) d 8.06 (d, J = 7.8 Hz, 1H), 7.99 (dd, J1 = 7.5 Hz,
J2 = 1.2 Hz, 1H), 7.95 (dd, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.90 (t, J =
6.0 Hz, 1H), 7.83 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.76–7.68 (m,
3H), 7.64–7.59 (m, 1H), 5.89 (s, 1H), 4.37 (d, J = 6.3 Hz, 2H); 13
C
NMR (75 MHz, DMSO-d6) d 181.2, 181.0, 149.1, 147.4, 134.4,
134.1, 133.1, 132.3, 131.9, 129.9, 129.3, 125.4, 124.9, 124.0, 115.9,
101.2, 91.9, 77.7, 31.6; MS (EI) m/z 332 (M+, 0.1), 315 (19), 224
(19), 130 (37), 104 (82), 76 (100). Anal. Calcd for C19H12N2O4: C,
68.67; H, 3.64; N, 8.43. Found: C, 68.54; H, 3.66; N, 8.46.
2-[3-(4-Nitrophenyl)-2-propynylamino]-1,4-naphthoquinone (1c).
Red brown solid, mp 228–230 ◦C (HOAc); IR (KBr) nmax 3349,
1682, 1601, 1567, 1523, 1493, 1341, 856, 726 cm-1; 1H NMR (300
MHz, DMSO-d6) d 8.21–8.18 (m, 2H), 8.01–7.94 (m, 2H), 7.84
(td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.75 (td, J1 = 7.5 Hz, J2 = 1.5 Hz,
1H), 7.70–7.66 (m, 2H), 5.89 (s, 1H), 4.38 (d, J = 5.7 Hz, 2H); 13
C
2-[3-(2-Methoxycarbonylphenyl)-2-propynylamino]-1,4-naphth-
NMR (75 MHz, DMSO-d6) d 181.2, 180.9, 147.4, 146.4, 134.3,
oquinone (1e). Red brown solid, mp 188–190 ◦C (EtOH); IR
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(KBr) nmax 3384, 1722, 1610, 1496, 1260, 751, 725 cm-1; 1H NMR
(300 MHz, DMSO-d6) d 8.00–7.80 (m, 5H), 7.73 (t, J = 7.2 Hz,
1H), 7.57–7.45 (m, 3H), 5.89 (s, 1H), 4.33 (d, J = 5.7 Hz, 2H),
3.78 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 181.2, 181.0, 147.5,
134.4, 133.3, 132.4, 131.9, 131.7, 131.6, 129.8, 129.4, 128.2, 125.4,
124.9, 121.2, 101.0, 89.0, 81.0, 51.7, 31.7; MS (EI) m/z 345 (M+,
2), 343 (M-2, 10), 330 (12), 284 (100). Anal. Calcd for C21H15NO4:
C, 73.03; H, 4.38; N, 4.06. Found: C, 72.98; H, 4.39; N, 4.01.
2-(2-Butynylamino)-8-methoxy-1,4-naphthoquinone (1j).. Yel-
low solid, mp 232 ◦C (EtOH); IR (KBr) nmax 3338, 1669, 1612,
1586, 1509, 1357, 1298, 818, 795, 738 cm-1; 1H NMR (300 MHz,
CDCl3) d 7.78 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.66 (t, J = 8.4 Hz,
1H), 7.18 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz, 1H), 6.09 (br s, 1H), 5.75
(s, 1H), 4.00 (s, 3H), 3.93–3.89 (m, 2H), 1.82 (t, J = 2.4 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 182.6, 179.8, 160.0, 148.2, 135.9,
135.8, 119..0, 118.2, 116.0, 100.5, 81.1, 72.6, 56.4, 32.7, 3.4; MS
(EI) m/z 256 (M+1, 1), 255 (M+, 46), 254 (M-1, 30), 240 (52), 228
(76), 212 (100). Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N,
5.49. Found: C, 70.48; H, 5.04; N, 5.38.
2-[3-(2-Bromophenyl)-2-propynyla◦mino]-1,4-naphthoquinone
(1f). Red–brown solid, mp 180–182 C (EtOH); IR (KBr) nmax
3446, 1678, 1599, 1570, 1494, 750, 724 cm-1; 1H NMR (300 MHz,
CDCl3) d 8.11 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 8.06 (dd, J1 =
7.8 Hz, J2 = 1.2 Hz, 1H), 7.73 (td, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H),
7.63 (td, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 7.56 (dd, J1 = 7.8 Hz, J2 =
1.2 Hz, 1H), 7.45 (dd, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H), 7.25 (td, J1 =
7.5 Hz, J2 = 1.2 Hz, 1H), 7.17 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H),
6.16 (br, s, 1H), 5.97 (s, 1H), 4.28 (d, J = 5.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 183.0, 181.5, 147.1, 134.7, 133.6, 133.3, 132.4,
132.1, 130.4, 129.9, 127.0, 126.24, 126.21, 125.6, 124.2, 102.8, 87.0,
83.5, 33.1; MS (EI) m/z 367 (M+2, 4), 366 (M+1, 2), 365 (M+,
7), 286 (100). Anal. Calcd for C19H12BrNO2: C, 62.32; H, 3.30; N,
3.82. Found: C, 62.27; H, 3.37; N, 3.72.
2-(2-Butynylamino)-5-hydroxy-1,4-naphthoquinone (1k). Red
◦
brown solid, mp 172–174 C (EtOH); IR (KBr) nmax 3357, 1625,
1601, 1512, 1468, 1247, 829, 775 cm-1; 1H NMR (300 MHz, CDCl3)
d 12.96 (s, 1H), 7.61–7.58 (m, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.26–
7.23 (m, 1H), 6.15 (br, s, 1H), 5.71 (s, 1H), 3.96–3.92 (m, 2H), 1.84
(t, J = 2.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 189.1, 180.8,
161.1, 147.9, 134.0, 130.4, 125.9, 119.1, 114.8, 101.1, 81.6, 72.1,
32.8, 3.5; MS (EI) m/z 242 (M+1, 2), 241 (M+, 71), 240 (M-1, 79),
199 (71), 198 (100). Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60;
N, 5.81. Found: C, 69.71; H, 4.70; N, 5.84.
2-(3-Phenyl-2-propynylamino)-1,4-naphthoquinone
(1g).
Brown solid, mp 175–177 ◦C (EtOH); IR (KBr) nmax 3330,
2-(2-Butynylamino)-6,7-dimethoxy-1,4-naphthoquinone
(1l).
1683, 1594, 1564, 1494, 1355, 753 cm-1; H NMR (300 MHz,
Red brown solid, mp 240–242 ◦C (EtOH); IR (KBr) nmax 3295,
1
1
CDCl3) d 8.10 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H),
7.72 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.43–7.41 (m,
2H), 7.31–7.29 (m, 3H), 6.12 (br s, 1H), 5.90 (s, 1H), 4.21 (d, J =
5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 183.1, 181.5, 147.2,
134.7, 133.3, 132.1, 131.8, 130.4, 128.7, 128.3, 126.3, 126.2, 122.0,
102.4, 85.0, 82.4, 33.1; MS (EI) m/z 287 (M+, 15), 285 (M-2, 43),
230 (12), 115 (100). Anal. Calcd for C19H13NO2: C, 79.43; H, 4.56;
N, 4.88. Found: C, 79.47; H, 4.65; N, 4.86.
1675, 1604, 1567, 1505, 1344, 792 cm-1; H NMR (300 MHz,
CDCl3) d 7.54 (s, 1H), 7.46 (s, 1H), 5.95 (br s, 1H), 5.68 (s,
1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.83 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 183.0, 180.7, 154.3, 151.9, 147.4, 128.8, 124.5, 108.2,
107.9, 101.0, 81.2, 72.6, 56.5, 56.4, 32.8, 3.5; MS (EI) m/z 286
(M+1, 7), 285 (M+, 100), 284 (M-1, 35), 242 (94). Anal. Calcd for
C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.27; H, 5.17;
N, 4.89.
2-(2-Hexynylamino)-1,4-naphthoquinone (1h). Orange solids,
mp 138–139 ◦C (EtOH); IR (KBr) nmax 3342, 1681, 1609, 1594,
7-(2-Butynylamino)-4-methyl-2,5,8-quinolinetrione (1m). Red
solid, mp 201–203 ◦C (EtOH); IR (KBr) nmax 3239, 1654, 1592,
1509, 852 cm-1; 1H NMR (300 MHz, DMSO-d6) d 11.30 (br s, 1H),
8.16 (br s, 1H), 6.36 (d, J = 0.9 Hz, 1H), 5.60 (s, 1H), 4.00 (q, J =
1
1563, 1495, 1356, 725 cm-1; H NMR (300 MHz, CDCl3) d 8.09
(dd, J1 = 7.5 Hz, J2 = 0.9 Hz, 1H), 8.04 (dd, J1 = 7.5 Hz, J2 =
0.9 Hz, 1H), 7.72 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.62 (td, J1 =
7.5 Hz, J2 = 0.9 Hz, 1H), 5.98 (br s, 1H), 5.81 (s, 1H), 3.97–3.94
(m, 2H), 2.19–2.13 (m, 2H), 1.52 (h, J = 7.5 Hz, 2H), 0.96 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 183.0, 181.6, 147.2,
134.7, 133.4, 132.1, 130.4, 126.23, 126.18, 102.1, 85.8, 73.4, 32.8,
21.9, 20.6, 13.4; MS (EI) m/z 253 (M+, 1), 252 (M-1, 13), 224 (100).
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.63; H, 6.03; N, 5.66.
2.7 Hz, 2H), 2.45 (d, J = 0.6 Hz, 3H), 1.78 (t, J = 2.4 Hz, 3H); 13
C
NMR (75 MHz, DMSO-d6) d 178.6, 174.5, 160.0, 149.8, 148.5,
142.2, 122.4, 110.6, 95.5, 79.3, 73.2, 31.2, 21.1, 2.5; MS (EI) m/z
257 (M+1, 1), 256 (M+, 100), 255 (M-1, 12), 229 (15). Anal. Calcd
for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93. Found: C, 65.63; H,
4.78; N, 11.04.
2-(2-Butynylamino)-1,4-naphthoquinone (1i). Orange solids,
mp 189–192 ◦C (EtOH); IR (KBr) nmax 3281, 1677, 1609, 1573,
1499, 1357, 1335, 828, 777, 722 cm-1; 1H NMR (300 MHz, CDCl3)
d 8.10 (dd, J1 = 7.5 Hz, J2 = 0.6 Hz, 1H), 8.04 (dd, J1 = 7.5 Hz, J2 =
0.6 Hz, 1H), 7.73 (td, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.62 (td, J1 =
7.5 Hz, J2 = 1.2 Hz, 1H), 6.02 (br s, 1H), 5.81 (s, 1H), 3.91 (q, J =
2.4 Hz, 2H), 1.83 (t, J = 2.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 183.0, 181.5, 147.2, 134.6, 133.4, 132.0, 130.4, 126.19, 126.15,
102.1, 81.2, 72.5, 32.7, 3.4; MS (EI) m/z 225 (M+, 41), 224 (M-1,
90), 183 (100), 182 (92). Anal. Calcd for C14H11NO2: C, 74.65; H,
4.92; N, 6.22. Found: C, 74.78; H, 4.91; N, 6.31.
6-(2-Butynylamino)-5,8-quinolinedione (1n). Orange solid, mp
198 ◦C dec. (EtOH); IR (KBr) nmax 3207, 1679, 1605, 1568, 1333,
793 cm-1; 1H NMR (300 MHz, DMSO-d6) d 8.96 (dd, J1 = 4.8 Hz,
J2 = 1.6 Hz, 1H), 8.33 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.84 (t, J =
6.0 Hz, 1H), 7.73 (dd, J1 = 7.8 Hz, J2 = 4.5 Hz, 1H), 5.86 (s, 1H),
4.00 (q, J = 2.70 Hz, 2H), 1.79 (t, J = 2.2 Hz, 3H); 13C NMR (75
MHz, DMSO-d6) d 181.5, 180.2, 154.5 148.4, 147.5, 133.9, 127.5,
126.6, 102.2, 79.6, 74.0, 31.5, 3.0; MS (EI) m/z 227 (M+1, 1), 226
(M+, 71), 225 (M-1, 32), 224 (M-2, 95), 103(100). Anal. Calcd for
C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.27; H, 4.76;
N, 12.35.
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General procedure for the preparation of azaanthraquinones by
molecular iodine-induced 6-endo-dig electrophilic cyclization of
N-propargylaminoquinones
8.25 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 8.02 (dd, J1 = 7.5 Hz, J2 =
1.2 Hz, 1H), 7.82–7.68 (m, 3H), 7.61 (td, J1 = 7.5 Hz, J2 = 1.2 Hz,
1H), 7.00 (d, J = 7.5 Hz, 1H), 3.67 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 182.1, 181.6, 165.9, 161.2, 159.6, 148.7, 144.3, 134.6,
134.4, 133.2, 132.9, 132.7, 130.7, 128.6, 128.5, 127.8, 127.6, 127.4,
127.3, 107.7, 52.1; MS (EI) m/z: 410 (24), 342 (100), 255 (24).
Anal. Calcd for C21H12INO4: C, 53.75; H, 2.58; N, 2.99. Found: C,
53.65; H, 2.71; N, 3.06.
Molecular iodine (230 mg, 0.9 mmol) was added in portions to a
stirred solution containing N-propargylaminoquinone (0.3 mmol)
and NaHCO3 (44 mg, 0.6 mmol) in nitromethane (6.0 mL) at
room temperature. Then the reaction was heated at 100 ◦C for
4 h. After cooling to room temperature, the reaction mixture
was diluted with chloroform (30 mL). The resulting solution
was washed successively by saturated Na2S2O3 solution (15 mL)
and brine (15 mL). The organic phase was dried with anhydrous
MgSO4, filtered and concentrated. The residue was purified by
flash chromatography to give pure product.
3-Iodo-4-(2-bromophenyl)-benzo[g]quinoline-5,10-dione
(2f)..
Brown solids, mp 288–290 ◦C (CH3CN); IR (KBr) nmax 1685,
1
1672, 1287, 960, 760 cm-1; H NMR (300 MHz, DMSO-d6) d
9.55 (s, 1H), 8.23–8.20 (m, 1H), 8.00–7.89 (m, 3H), 7.78 (dd, J1 =
7.8 Hz, J2 = 0.9 Hz, 1H), 7.53 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H),
7.42 (td, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 7.16 (dd, J1 = 7.5 Hz,
J2 = 1.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 181.6, 180.8,
161.0, 152.8, 148.7, 142.9, 134.8, 134.7, 132.6, 132.2, 129.8, 128.8,
128.0, 126.8, 126.6, 120.8, 109.9; MS (EI) m/z: 410 (100), 255
(12). Anal. Calcd for C19H9BrINO2: C, 46.56; H, 1.85; N, 2.86.
Found: C, 46.47; H, 1.92; N, 2.76.
3-Iodo-4-(4-methylphenyl)-benzo[g]quinoline-5,10-dione
(2a).
Yellow solids, mp 200–202 ◦C (THF); IR (KBr) nmax 1677, 1606,
1571, 730 cm-1; 1H NMR (300 MHz, CDCl3) d 9.48 (s, 1H),
8.38–8.35 (m, 1H), 8.10–8.07 (m, 1H), 7.84–7.75 (m, 2H), 7.36 (d,
J = 7.8 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 2.49 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 182.0, 181.5, 161.3, 155.7, 149.0, 139.1,
138.2, 134.8, 134.4, 133.2, 132.5, 129.4, 129.1, 127.5, 127.3, 126.7,
110.2, 21.6; MS (EI) m/z 425 (M+, 34), 424 (M-1, 9), 410 (100).
Anal. Calcd for C20H12INO2: C, 56.49; H, 2.84; N, 3.29. Found:
C, 56.50; H, 2.69; N, 3.10.
3-Iodo-4-phenyl-benzo[g]quinoline-5,10-dione
(2g). Yellow
solids, mp 263–265 ◦C (THF); IR (KBr) nmax 1683, 1587, 1284,
960, 723 cm-1; 1H NMR (300 MHz, CDCl3) d 9.50 (s, 1H), 8.39–
8.36 (m, 1H), 8.09–8.06 (m, 1H), 7.84–7.77 (m, 2H), 7.58–7.54
(m, 3H), 7.12–7.09 (m, 2H); 13C NMR (75 MHz, CDCl3) d 181.9,
181.5, 161.4, 155.5, 149.0, 142.1, 134.8, 134.4, 133.1, 132.5, 128.7,
128.4, 127.6, 127.3, 126.8, 109.8; MS (EI) m/z 411 (M+, 74), 410
(M-1, 100), 284 (71). Anal. Calcd for C19H10INO2: C, 55.50; H,
2.45; N, 3.41. Found: C, 55.34; H, 2.49; N, 3.57.
3-Iodo-4-(4-methoxyphenyl)-benzo[g]quinoline-5,10-dione (2b).
Yellow solids, mp 265–267 ◦C (THF); IR (KBr) nmax 1681, 1586,
1
1511, 960, 723 cm-1; H NMR (300 MHz, DMSO-d6) d 9.45 (s,
1H), 8.19–8.16 (m, 1H), 7.95–7.86 (m, 3H), 7.05 (s, 4H), 3.85 (s,
3H); 13C NMR (75 MHz, DMSO-d6) d 182.0, 181.1, 160.3, 158.8,
154.1, 148.8, 134.6, 134.5, 134.3, 133.3, 132.4, 129.5, 128.7, 126.7,
126.3, 113.6, 110.9, 55.1; MS (EI) m/z 441 (M+, 100), 440 (M-1,
19), 410 (20). Anal. Calcd for C20H12INO3: C, 54.44; H, 2.74; N,
3.17. Found: C, 54.27; H, 3.00; N, 3.23.
3-Iodo-4-propyl-benzo[g]quinoline-5,10-dione
(2h). Yellow
solids, mp 190–192 ◦C (THF); IR (KBr) nmax 1681, 1592, 1284,
988, 725 cm-1; 1H NMR (300 MHz, CDCl3) d 9.27 (s, 1H),
8.28–8.25 (m, 1H), 8.20–8.17 (m, 1H), 7.82–7.76 (m, 2H), 3.34
(t, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 183.7, 181.5,
161.6, 157.1, 149.5, 134.7, 134.2, 133.6, 132.1, 129.3, 127.4, 127.1,
109.9, 40.7, 22.2, 14.5; MS (EI) m/z: 377 (M+, 100), 360 (50).
Anal. Calcd for C16H12INO2: C, 50.95; H, 3.21; N, 3.71. Found:
C, 50.97; H, 3.20; N, 3.81.
3-Iodo-4-(4-nitrophenyl)-benzo[g]quinoline-5,10-dione
(2c).
Yellow solids, mp > 300 ◦C (THF); IR (KBr) nmax 1682, 1583,
1509, 1282, 958, 729 cm-1; 1H NMR (300 MHz, DMSO-d6) d 9.53
(s, 1H), 8.40 (dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 2H), 8.23–8.20 (m, 1H),
7.89 (m, 3H), 7.48 (dd, J1 = 6.9 Hz, J2 = 1.8 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6) d 181.9, 180.9, 160.6, 152.0, 149.6, 148.7,
147.0, 134.7, 134.6, 132.9, 132.5, 129.0, 126.8, 126.5, 123.6, 108.5;
MS (EI) m/z 456 (M+, 100), 455 (M-1, 13), 439 (12), 409 (24).
Anal. Calcd for C19H9IN2O4: C, 50.02; H, 1.99; N, 6.14. Found:
C, 50.43; H, 1.99; N 5.97.
3-Iodo-4-methyl-benzo[g]quinoline-5,10-dione
(2i). Yellow
solids, mp 233–235 ◦C (THF); IR (KBr) nmax 1682, 1664, 1589,
1281, 977, 721 cm-1; 1H NMR (300 MHz, CDCl3) d 9.30 (s, 1H),
8.32–8.19 (m, 1H), 8.22–8.19 (m, 1H), 7.82–7.79 (m, 2H), 3.02 (s,
3H); 13C NMR (75 MHz, CDCl3) d 184.2, 181.5, 161.2, 153.6,
149.2, 134.7, 133.7, 132.3, 129.9, 127.4, 127.2, 110.5, 27.3; MS
(EI) m/z: 349 (M+, 100), 321 (5). Anal. Calcd for C14H8INO2: C,
48.16; H, 2.31; N, 4.01. Found: C, 48.09; H, 2.49; N, 3.95.
3-Iodo-4-(2-nitrophenyl)-benzo[g]quinoline-5,10-dione
(2d).
Yellow solids, mp 275–278 ◦C (CH3CN); IR (KBr) nmax 1678,
1585, 1521, 1350, 1284, 960, 727 cm-1; 1H NMR (300 MHz,
DMSO-d6) d 9.50 (s, 1H), 8.43 (dd, J1 = 8.4 Hz, J2 = 0.9 Hz,
1H), 8.21–8.18 (m, 1H), 7.98–7.79 (m, 5H), 7.31 (dd, J1 = 7.8 Hz,
J2 = 1.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 182.3, 180.8,
160.6, 152.4, 148.5, 145.8, 138.0, 135.3, 134.8, 134.7, 132.7 132.5,
129.8, 128.4, 126.8, 126.7, 124.5, 107.6; MS (EI) m/z: 410 (100),
255 (17). Anal. Calcd for C19H9IN2O4: C, 50.02; H, 1.99; N, 6.14.
Found: C, 49.91; H, 2.07; N, 6.08.
3-Iodo-9-methoxyl-4-methyl-benzo[g]quinoline-5,10-dione (2j).
◦
Yellow solids, mp 181–183 C (THF); IR (KBr) nmax 1669, 1587,
1264, 977, 765 cm-1; 1H NMR (300 MHz, CDCl3) d 9.26 (s, 1H),
7.77 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.69 (t, J = 8.1 Hz, 1H),
7.30 (dd, J1 = 8.1 Hz, J2 = 0.9 Hz, 1H), 4.01 (s, 3H), 2.94 (s, 3H);
13C NMR (75 MHz, CDCl3) d 184.5, 180.2, 161.2, 160.0, 152.7,
136.0, 135.4, 128.8, 120.8, 119.6, 117.8, 109.2, 56.6, 26.9; MS (EI)
m/z: 379 (M+, 100), 350 (7). Anal. Calcd for C15H10INO3: C, 47.52;
H, 2.66; N, 3.69. Found: C, 47.43; H, 2.79; N, 3.52.
3-Iodo-4-(2-methoxycarbonylphenyl)-benzo[g]quinoline-5,10-
◦
dione (2e). Orange solids, mp 239–241 C (CH3CN); IR (KBr)
nmax 1708, 1680, 1288, 1273, 958, 731 cm-1; 1H NMR (300 MHz,
CDCl3) d 9.43 (s, 1H), 8.35 (dd, J1 = 8.1 Hz, J2 = 1.8 Hz, 1H),
6-Hydroxy-3-iodo-4-methyl-benzo[g]quinoline-5,10-dione (2k).
Orange solids, mp 190–192 ◦C (THF); IR (KBr) nmax 1676, 1623,
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1260, 788 cm-1; 1H NMR (300 MHz, CDCl3) d 12.36 (s, 1H), 9.32
(s, 1H), 7.85 (dd, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.68 (t, J = 8.1 Hz,
1H), 7.33 (dd, J1 = 8.7 Hz, J2 = 1.2 Hz, 1H), 3.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 189.8, 180.8, 162.4, 161.8, 153.8, 149.3, 136.9,
132.2, 129.5, 125.2, 119.8, 116.0, 110.8, 27.9; MS (EI) m/z: 365
(M+, 100). Anal. Calcd for C14H8INO3: C, 46.05; H, 2.21; N, 3.84.
Found: C, 46.17; H, 2.41; N, 3.80.
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and M. J. Piggott, J. Nat. Prod., 2008, 71, 866.
2 (a) S. Mekideche and L. Desaubry, Tetrahedron Lett., 2008, 49, 5268;
(b) J. M. Perez, L. Vidal, M. T. Grande, J. C. Menendez and C.
Avendano, Tetrahedron, 1994, 50, 7923; (c) K. T. Potts, D. Bhattacharjee
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7,8-Dimethoxy-3-iodo-4-methyl-benzo[g]quinoline-5,10-dione
(2l). Yellow solids, mp 263–265 ◦C (THF); IR (KBr) nmax 1670,
1579, 1513, 1322, 1007, 778 cm-1; 1H NMR (300 MHz, CDCl3) d
9.28 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 4.07 (s, 3H), 4.05 (s, 3H),
3.02 (s, 3H); 13C NMR (75 MHz, CDCl3) d 183.4, 180.7, 160.8,
154.4, 154.0, 153.2, 149.5, 129.8, 128.6, 127.2, 110.3, 108.4, 108.1,
56.7, 56.5, 27.3; MS (EI) m/z: 409 (M+, 100), 378 (2). Anal. Calcd
for C16H12INO4: C, 46.97; H, 2.96; N, 3.42. Found: C, 46.91; H,
2.94; N, 3.52.
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4,6-Dimethyl-3-iodo-pyrido[3,2-g]quinoline-2,5,10(1H)-trione
(2m). Yellow solids, mp 285–287 ◦C (CH3OH–CHCl3); IR (KBr)
nmax 1646, 1552, 1296, 703 cm-1; 1H NMR (300 MHz, CDCl3 and
CF3CO2H) d 9.49 (s, 1H), 7.02 (s, 1H), 3.20 (s, 3H), 2.80 (s, 3H);
13C NMR (75 MHz, CDCl3 and CF3CO2H) d 176.0, 157.6, 155.8,
144.0, 139.6, 127.0, 125.6, 120.0, 116.2, 112.4, 110.0, 108.7, 27.6,
22.5; MS (EI) m/z: 381 (M+1, 1), 380 (M+, 100), 352 (3). Anal.
Calcd for C14H9IN2O3: C, 44.23; H, 2.39; N, 7.37. Found: C, 44.51;
H, 2.22; N, 7.38.
3-Iodo-4-methyl-pyrido[2,3-g]quinoline-5,10-dione
(2n).
◦
Brown solids, mp 220–222 C (THF); IR (KBr) nmax 2923, 1682,
1
1582, 1285, 980, 722 cm-1; H NMR (300 MHz, CDCl3) d 9.37
(s, 1H), 9.14 (dd, J1 = 4.5 Hz, J2 = 1.5 Hz, 1H), 8.67 (dd, J1 =
7.8 Hz, J2 = 1.5 Hz, 1H), 7.77 (dd, J1 = 8.1 Hz, J2 = 4.8 Hz, 1H),
3.07 (s, 3H); 13C NMR (75 MHz, CDCl3) d 182.5, 181.2, 161.7,
155.7, 154.3, 148.7, 148.6, 135.5, 130.1, 129.2, 128.2, 111.1, 27.4;
MS (EI) m/z: 352 (M+2, 15), 350 (M+, 100). Anal. Calcd for
C13H7IN2O2: C, 44.60; H, 2.02; N, 8.00. Found: C, 44.67; H, 2.08;
N, 7.81.
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2-[2,3-Diiodo-3-(4-methylphenyl)-2-propen-1-ylamino]-1,4-
naphthalenedione (3). Brown solids, mp 155–157 ◦C (EtOAc);
1
IR (KBr) nmax 1687, 1676, 1284, 726 cm-1; H NMR (300 MHz,
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CDCl3) d 8.13 (dd, J1 = 7.5 Hz, J2 = 0.9 Hz, 1H), 8.09 (dd, J1 =
7.5 Hz, J2 = 1.2 Hz, 1H), 7.75 (td, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H),
7.65 (td, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.19–7.10 (m, 4H), 6.32 (t,
J = 6.0 Hz, 1H), 5.90 (s, 1H), 4.40 (d, J = 6.3 Hz, 2H), 2.36 (s, 3H);
13C NMR (75 MHz, CDCl3) d 183.1, 181.6, 147.0, 144.3, 138.9,
134.8, 133.4, 132.2, 130.4, 129.2, 127.9, 126.34, 126.27, 103.2, 99.6,
99.0, 59.0, 21.4; MS (EI) m/z 301 (54), 129 (100). Anal. Calcd for
C20H15I2NO2: C, 43.27; H, 2.72; N, 5.76. Found: C, 43.20; H, 2.69;
N, 5.90.
Acknowledgements
This work was financially supported by National Science Founda-
tion of China (20802034), Natural Science Foundation of Jiangsu
Province (BK 2009229) and 973 Program (2007CB936404).
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4096–4103 | 4103
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