Reaction of guanidine with peri-substituted (R-ethynyl)-9,10-anthraquinones bearing electron-donating substituents

Article abstract of DOI:10.1007/s11172-010-0200-6

2-Amino-3-aroyl-7H-dibenzo[de,h]quinolin-7-ones were synthesized by the reaction of guanidine with peri-(R-ethynyl)-9,10-anthraquinones in boiling n-butanol.

Full text of DOI:10.1007/s11172-010-0200-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 1031—1034, May, 2010
1031
Reaction of guanidine with periꢀsubstituted (Rꢀethynyl)ꢀ9,10ꢀanthraquinones
bearing electronꢀdonating substituents
D. S. Baranov and S. F. Vasilevsky
Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
3 ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 7350. Eꢀmail: vasilev@kinetics.nsc.ru
2ꢀAminoꢀ3ꢀaroylꢀ7Hꢀdibenzo[de,h]quinolinꢀ7ꢀones were synthesized by the reaction of
guanidine with periꢀ(Rꢀethynyl)ꢀ9,10ꢀanthraquinones in boiling nꢀbutanol.
Key words: alkynes, crossꢀcoupling, heterocyclization, guanidine, 7Hꢀdibenzo[de,h]ꢀ
quinolinꢀ7ꢀones.
Recently,1,2 we have reported on the new heteroꢀ
cyclizations and unusual rearrangements accompanying
reactions of guanidine with 1ꢀarylꢀ and 1ꢀalkylethynylꢀ
9,10ꢀanthraquinones. These transformations are of interest
from the point of view of exo/endoꢀselective ring formaꢀ
tions (the Baldwin’s rules).3 For instance, it was shown1,2
that the reaction of periꢀ(Rꢀethynyl)ꢀ9,10ꢀanthraquinones
with guanidine leads to 1ꢀarylꢀ7Hꢀdibenzo[de,h]isoꢀ
quinolineꢀ3,7ꢀdione (I), 2ꢀaminoꢀ3ꢀaroylꢀ7Hꢀdibenzoꢀ
[de,h]quinolinꢀ7ꢀone (II), 2ꢀarylꢀ7Hꢀdibenzo[de,h]ꢀ
quinolinꢀ7ꢀone (III), 3Hꢀ4ꢀ(2ꢀhydroxypropꢀ2ꢀyl)anthraꢀ
[9,1ꢀde][1,3]diazocineꢀ2,9ꢀdione (IV), 12ꢀ(9,10ꢀdioxoꢀ
anthracenꢀ1ꢀyl)ꢀ2,2ꢀdimethylꢀ2Hꢀphenanthro[2,1,10ꢀdef]ꢀ
chromenꢀ1,6ꢀdione (V), and 12ꢀaminoꢀ2,2ꢀdimethylꢀ2Hꢀ
chromeno[4,5,6ꢀcde]benzo[h]quinolineꢀ1,6ꢀdione (VI)
systems (Scheme 1), with the ratio and type of the reaction
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1008—1011, May, 2010.
1066ꢀ5285/10/5905ꢀ1031 © 2010 Springer Science+Business Media, Inc.

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Baranov and Vasilevsky
products being dependent on the structure of acetylene
substituent.
starting anthraquinones on reflux with the lowest degree
of resinification.
The compounds obtained can be of significant interest
for medicinal chemistry, since the 7Hꢀdibenzo[de,h]ꢀ
quinolinꢀ7ꢀone skeleton relates them to the natural alkaꢀ
loids of the isoaporphine family (Isoaporphines) exhibiting
anticancer activity4,5 and enhanced effect of acetylchoꢀ
linesterase suppression.6
The optimum reaction time is 28 h with incomplete
conversion of the starting acetylenes. Attempts to reach
higher conversion using longer reaction time led to sigꢀ
nificant resinification, which complicated isolation of
final products. Components of the reaction mixture were
separated by chromatography on Alumina.
In this connection, we continued our systematic
study on the reaction of guanidine with 1ꢀ(Rꢀethynyl)ꢀ
9,10ꢀanthraquinones. In the present work, the substrates
bearing electronꢀdonating substituents on the acetylene
fragment have been studied.
In all the cases, quinolinꢀ7ꢀones 2a—c are formed
in 25, 64, and 33% yield, respectively, i.e., products of
the 6ꢀexoꢀdigꢀcyclization. For compound 1a, a partial
Oꢀ5ꢀexoꢀdigꢀcyclization was observed leading to the forꢀ
mation of isoquinolineꢀ3,7ꢀdione system 3 (19%). It
should be noted that for the substrates containing elecꢀ
tronꢀwithdrawing substituents, if the corresponding amino
ketones 2 were formed, then only as minor products.1
The data obtained agree with the results reported earlier,1
according to which the reaction of guanidine with
1ꢀ[(4ꢀmethoxyphenyl)ethynyl]ꢀ9,10ꢀanthraquinone
mainly gives amino ketone of the type 2.
The structures of compounds synthesized were conꢀ
firmed by analytical and spectral data (Tables 1 and 2).
The IR spectra of amino ketones 2a—c contain band
of the stretching vibrations of the NH2 group (3303—3471
cm–1) and two C=O groups (1611—1660 cm–1). A combiꢀ
nation of spectral and analytical data allows us to assign
to compounds 2a—c the structure of 2ꢀaminoꢀ3ꢀaroylꢀ
7Hꢀdibenzo[de,h]quinolinꢀ7ꢀones.
Results and Discussion
The heterocyclization of 1ꢀ(het)arylethynylꢀ9,10ꢀ
anthraquinones 1a—c with guanidine was carried out in
boiling nꢀbutanol (Scheme 2).
Note that in these transformation, the choice of solꢀ
vent and temperature is crucial: anthraquinones 1 are
poorly soluble in methanol, ethanol, propanꢀ2ꢀol, pyriꢀ
dine, and no reaction takes place in these solvents at
temperatures about 40—50 °C. Reflux of compounds 1 in
aliphatic alcohols, pyridine, DMF, and DMSO is accomꢀ
panied by deep resinification. Out of all solvents, nꢀbuꢀ
tanol proved the most appropriate: it completely dissolves
The IR spectrum of isoquinolineꢀ3,7ꢀdione 3 exhibits
bands of the stretching vibrations of the NH group
(3059 cm–1) and two C=O groups (1650, 1681 cm–1). The
1H and 13C NMR spectra, as well as HRMS, allows us to
unambiguously establish the structure of 1ꢀ(1,5ꢀdimethylꢀ
pyrazolꢀ4ꢀyl)ꢀ7Hꢀdibenzo[de,h]isoquinolineꢀ3,7ꢀdione
(3). In addition, the determining the structure of this
compound was facilitated by a possibility of comparison
with the spectra of its analogs, the structure of which has
been established by us earlier,1 including by Xꢀray diffracꢀ
tion analysis.
Scheme 2
The starting compounds were obtained from 1ꢀiodoꢀ
9,10ꢀanthraquinone (4) and terminal acetylenes 5a—c
under standard conditions of the Sonogashira reaction7 in
the system PdCl2(PPh3)2—CuI—Et3N (Scheme 3). The
Scheme 3
3 (for 1a)

7HꢀDibenzo[de,h]quinolinꢀ7ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
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1
Table 1. H and 13C NMR (in CDCl3) and IR spectra of alkynes 1a—c
Comꢀ
pound
NMR, δ (J/Hz)
IR,
ν/cm–1
1H
13C
1a
1b
1c
2.59 (s, 3 H, C(14)Me); 3.82 (s, 3 H, NMe); 10.44 (C(17)); 36.81 (C(16)); 89.16 (C(11)); 91.91 (C(12));
7.65—7.68 (m, 2 H, H(3), H(15)); 7.73—7.77 102.63 (C(13)); 124.58 (C(1)); 126.76 (C(8)); 126.99 (C(5));
1671
(С=О),
(m, 2 H, H(6), H(7)); 7.75 (dd, 1 H, H(2),
J = 7.8, J = 1.2); 8.24—8.26 (m, 2 H, H(5),
H(8)); 8.30—8.33 (m, 1 H, H(4))
127.58 (C(4)); 132.60 (C(10a)); 132.87 (C(7)); 132.93 (C(9a)); 2205
133.79 (C(6)); 134.36 (C(3)); 134.41 (C(8a)); 134.58 (C(4a));
139.79 (C(2)); 141.14 (C(15)); 143.27 (C(14)); 182.01 (C(10));
183.07 (C(9))
(С≡С)
3.01 (s, 6 H, Me); 6.69 (d, 2 H, Hm, J = 8.9); 39.95 (С(13), С(14)); 88.05 (C(11)); 92.21 (C(12)); 109.69 (Ci); 1671
7.60 (d, 2 H, Hо, J = 8.9); 7.67 (t, 1 H, H(3), 111.64 (Cm); 124.76 (C(1)); 126.20 (C(8)); 126.64 (C(5)); 127.36 (С=О),
J = 7.7); 7.74—7.79 (m, 2 H, H(6), H(7)); 7.91 (C(4)); 132.35 (C(10a)); 132.47 (C(7)); 132.70 (C(9a)); 133.38 2185
(dd, 1 H, H(2), J = 7.8, J = 1.2); 8.22—8.27
(m, 2 H, H(5), H(8)); 8.35 (dd, 1 H, H(4),
J = 7.7, J = 1.2)
(C(6)); 134.09 (C(3)); 134.23 (C(8a)); 134.34 (C(4a)); 150.48
(Cp); 139.75 (C(2)); 133.46 (Co); 181.78 (C(10)); 182.92 (C(9))
(С≡С)
2.30 (s, 3 H, СpMe); 2.64 (s, 6 H, СoMe);
6.92 (s, 2 H, Hm); 7.71 (t, 1 H, H(3),
J = 7.8); 7.75—7.79 (m, 2 H, H(6), H(7));
7.97 (dd, 1 H, H(2), J = 7.8, J = 1.4);
8.26—8.36 (m, 3 H, H(4), H(5), H(8))
20.98 (C(13), C(15)); 21.33 (C(14)); 94.61 (C(11)); 96.61 (C(12)); 1672
119.78 (Ci); 124.37 (C(1)); 126.65 (C(8)); 126.69 (C(5)); 126.79 (С=О),
(C(4)); 127.41 (Cm); 132.46 (C(10a)); 132.54 (C(7)); 132.66
(C(9a)); 133.48 (C(6)); 134.14 (C(3)); 134.16 (C(8a)); 134.38
(C(4a)); 138.59 (Cp); 140.18 (C(2)); 141.19 (Co), 181.85
(C(10)); 182.85 (C(9))
2195
(С≡С)
Table 2. 1H and 13C NMR (in CDCl3) and IR spectra of 7Hꢀdibenzo[de,h]quinolinꢀ7ꢀones 2a—c and 7Hꢀdibenzo[de,h]isoquinolineꢀ
3,7ꢀdione 3
Comꢀ
pound
NMR, δ (J/Hz)
IR,
ν/cm–1
1H
13C
2a
2.58 (s, 3 H, Me); 3.82 (s, 3 H, NMe); 5.57
(br.s, 2 H, NH2); 7.34 (s, 1 H, H(15));
7.55—7.65 (m, 2 H, H(9), H(10));
11.02 (C(16)); 36.09 (C(17)); 109.09 (C(3)); 117.75 (C(3b));
121.83 (C(14)); 125.50 (C(11)); 125.67 (C(6)); 127.37 (C(8));
129.02 (C(3a)); 130.08 (C(5)); 130.53 (C(4)); 130.79 (C(9));
1611,
1651
(С=О);
7.75 (t, 1 H, H(5), J = 7.6); 7.86 (d, 1 H,
132.45 (C(7a)); 133.71 (C(10)); 135.47 (C(11a)); 135.76 (C(6a)); 3347,
H(4), J = 7.6); 8.27 (d, 1 H, H(6), J = 7.6); 142.02 (C(15)); 143.53 (C(13)); 149.81 (C(11b)); 153.40 (C(2)); 3463
8.35 (d, 1 H, H(8), J = 7.8); 8.76 (d, 1 H,
H(11), J = 7.8)
183.33 (C(7)); 190.09 (C(12))
(NH2)
2b
2c
2.93 (s, 6 H, NMe); 5.21 (br.s, 2 H, NH2);
6.48 (d, 2 H, Hm, J = 9.1); 7.43 (t, 1 H, H(9), 125.36 (C(11)); 125.57 (C(6)); 125.86 (Cp); 127.31 (C(8)); 128.96 1658
J = 7.3); 7.52 (t, 1 H, H(10), J = 7.3);
7.59—7.67 (m, 4 H, Hо, H(5), H(4)); 8.17
(d, 1 H, H(6), J = 7.1); 8.26 (dd, 1 H, H(8), 149.02 (Ci); 153.37 (C(11b)); 153.84 (C(2)); 183.52 (C(7));
J = 7.8, J = 0.9); 8.68 (d, 1 H, H(11), J = 7.8) 194.31 (C(12))
2.06 (s, 6 H, CoMe); 2.34 (s, 3 H, CpMe);
39.87 (C(13), C(14)); 109.44 (C(3)); 110.7 (Cm); 117.46 (C(11c)); 1615,
(C(3a)); 130.22 (C(5)); 130.43 (C(4)); 130.64 (C(9)); 132.39 (Co), (С=О);
132.44 (C(7a)); 133.63 (C(10)); 135.92 (C(11a)); 136.15 (C(6a)); 3343,
3471
(NH2)
1611,
19.46 (C(13), C(15)); 21.07 (C(14)); 105.13 (C(3)); 117.97
6.90 (s, 2 H, Hm); 7.38—7.42 (m, 1 H, H(5)); (C(11c)); 124.93 (C(11)); 126.02 (C(6)); 127.27 (C(8)); 128.65 1660
7.54—7.56 (m, 1 H, H(4)); 7.69 (m, 1 H,
H(9)); 7.78—7.80 (m, 1 H, H(10));
8.20—8.22 (m, 1 H, H(6)); 8.37 (dd, 1 H,
H(8), J = 9.1, J = 1.2); 8.85 (dd, 1 H,
H(11), J = 9.1, J = 1.2)
(C(5)); 129.29 (Cm); 131.39 (C(4)); 131.48 (C(9)); 132.61 (Cp); (С=О);
133.71 (C(3a)); 133.73 (C(10)); 135.21 (C(7a)); 136.65 (C(11a)); 3303,
139.04 (Co); 140.72 (C(6a)); 148.31 (Ci); 153.11 (C(11b));
157.45 (C(2)); 183.44 (C(7)); 199.60 (C(12))
3442
(NH2)
3 *
2.00 (s, 3 H, Me); 3.84 (s, 3 H, NMe);
7.41—7.43 (m, 3 H, H(9), H(10), H(11));
7.64 (s, 1 H, H(14)); 7.85 (t, 1 H, H(5),
J = 7.7); 8.26—8.29 (m, 1 H, H(8));
8.63—8.70 (m, 2 H, H(4), H(6)),
11.80 (s, 1 H, NH)
10.10 (C(14)); 36.82 (C(16)); 105.19 (C(11b)); 114.82 (C(13)); 1650,
124.90 (C(3a)); 125.78 (C(11)); 126.69 (C(9)); 127.09 (C(5)); 1681
127.29 (C(8)); 127.73 (C(6a)); 130.14 (C(7a)); 132.62 (C(10)); (С=О);
132.76 (C(4)); 133.08 (C(6)); 134.84 (C(11c)); 136.01 (C(11a)); 3059
137.88 (C(14)); 138.45 (C(12)); 138.65 (C(1)); 161.51 (C(3));
182.00 (C(7))
(NH)
* The spectrum was recorded in DMSOꢀd6.

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Baranov and Vasilevsky
benzene and ethyl acetate as subsequent eluents. Pure comꢀ
pounds 2a—c and 3 were obtained by crystallization.
2ꢀAminoꢀ3ꢀ(1,5ꢀdimethylpyrazolꢀ4ꢀylcarbonyl)ꢀ7Hꢀdibenzoꢀ
[de,h]quinolinꢀ7ꢀone (2a). The yield was 25%, m.p. 220—221.5
°C (benzene). HRMS, found: m/z 368.1261 [M]+. C22H16N4O2.
Calculated: M = 368.1268.
1ꢀ(1,5ꢀDimethylpyrazolꢀ4ꢀyl)ꢀ7Hꢀdibenzo[de,h]isoquinolineꢀ
3,7ꢀdione (3). The yield was 19%, m.p. >360 °C (ethanol).
HRMS, found: m/z 341.1154 [M]+. C21H15N3O2. Calculated:
M = 341.1159.
2ꢀAminoꢀ3ꢀ(4ꢀdimethylaminobenzoyl)ꢀ7Hꢀdibenzo[de,h]ꢀ
quinolinꢀ7ꢀone (2b). The yield was 64%, m.p. 215.5—216.5 °C
(benzene). HRMS, found: m/z 392.1398 [M – H]+. C25H19N3O2.
Calculated: M = 393.1477.
2ꢀAminoꢀ3ꢀ(2,4,6ꢀtrimethylbenzoyl)ꢀ7Hꢀdibenzo[de,h]ꢀ
quinolinꢀ7ꢀone (2c). The yield was 33%, m.p. 201—202 °C
(benzene). HRMS, found: m/z 392.1523 [M]+. C26H20N2O2.
Calculated: M = 392.1519.
reaction time was 2—4 h, the product 1a—c yields were
82—96%.
In conclusion, it was shown that cyclocondensation of
guanidine with periꢀsubstituted (Rꢀethynyl)ꢀ9,10ꢀanthraꢀ
quinones containing Rꢀelectronꢀdonating substituent
follows the 6ꢀexoꢀdigꢀcyclization pathway, leading to a
predominant or exclusive formation of amino ketones.
Experimental
IR spectra were recorded on a Bruker Vector 22 spectrometer
in KBr pellets. NMR spectra were recorded on a Bruker AV 400
spectrometer (400.13 MHz) in CDCl3 and DMSOꢀd6. Mass
spectra were obtained on a DFS mass spectrometer (Thermo
Electron Corporation) with direct injection (70 eV, the
temperature of ionization chamber was 220—270 °C). Column
chromatography was performed on Alumins (50—150 μm,
TU 6ꢀ09ꢀ3916ꢀ75), TLC monitoring was carried out on Silufol 60
F254 plates.
1ꢀ(RꢀEthynyl)ꢀ9,10ꢀanthraquinones 1a—c (general proceꢀ
dure). A mixture of 1ꢀiodoꢀ9,10ꢀanthraquinone (4) (4.5 mmol),
terminal acetylene 5a—c (4.5 mmol), PdCl2(PPh3)2 (0.013 mmol),
CuI (0.027 mmol) and Et3N (12.7 mmol) in toluene (50 mL)
was stirred for 2—4 h under argon at 60 °C (TLC monitoring
with toluene as an eluent). The reaction mixture was cooled,
filtered through the Al2O3 layer (d = 25 mm, h = 30 mm), and
eluted with toluene. The solvent was evaporated in vacuo.
Crystallization from toluene gives compounds 1a—c.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00048a),
the Division of Chemistry and Material Sciences of the
Russian Academy of Sciences (Grant 5.9.3.2009ꢀ2011),
the Siberian Branch of the Russian Academy of Sciences
(Integration Grant 93 (2009—2011)), and the Chemical
Service Center SB RAS.
References
1ꢀ[(1,5ꢀDimethylpyrazolꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀanthraquinone
(1a). The yield was 82%, m.p. 177—178 °C (toluene). HRMS,
found: m/z 325.0971 [M – H]+. C21H14N2O2. Calculated:
M = 326.1055.
1. S. F. Vasilevsky, D. S. Baranov, V. I. Mamatyuk, Y. V. Gatilov,
I. V. Alabugin, J. Org. Chem., 2009, 74, 6143.
2. D. S. Baranov, S. F. Vasilevsky, V. I. Mamatyuk, Y. V. Gatilov,
Mendeleev Commun., 2009, 19, 326.
3. J. E. Baldwin, J. Chem. Soc. Commun., 1976, 18, 734.
4. B.ꢀW. Yu, L.ꢀH. Meng, J.ꢀY. Chen, T.ꢀX. Zhou, K.ꢀF. Cheng,
J. Ding, G.ꢀW. Qin, J. Nat. Prod., 2001, 64, 968.
5. H. Tang, X.ꢀD. Wang, Y.ꢀB. Wei, S.ꢀL. Huang, Z.ꢀS. Huang,
J.ꢀH. Tan, L.ꢀK. An, J.ꢀY. Wu, A. S.ꢀC. Chan, L.ꢀQ. Gu,
Eur. J. Med. Chem., 2008, 43, 973.
6. H. Tang, F.ꢀX. Ning, Y.ꢀB. Wei, S.ꢀL. Huang, Z.ꢀS. Huang,
A. S.ꢀC. Chan, L.ꢀQ. Gu, Bioorg. Med. Chem. Lett., 2007, 17,
3765.
7. K. Sonogashira, Y. Tohda, N. A. Hagihara, Tetrahedron Lett.,
1975, 50, 4457.
1ꢀ(4ꢀDimethylaminophenylethynyl)ꢀ9,10ꢀanthraquinone (1b).
The yield was 96%, m.p. 223—224 °C (toluene). HRMS, found:
m/z 351.1249 [M]+. C24H17NO2. Calculated: M = 351.1254.
1ꢀ(2,4,6ꢀTrimethylphenylethynyl)ꢀ9,10ꢀanthraquinone (1c).
The yield was 95%, m.p. 188—189 °C (toluene). HRMS, found:
m/z 350.1306 [M]+. C25H18O2. Calculated: M = 350.1307.
Preparation of 1 M solution of guanidine in methanol. Sodium
metal (2.3 g, 0.1 mol) was dissolved in small portions in MeOH
(50 mL), the solution obtained was mixed with guanidine
hydrochloride (9.55 g, 0.1 mol) in MeOH (50 mL). A precipitate
of NaCl formed was filtered off.
Reaction of 1ꢀ(Rꢀethynyl)ꢀ9,10ꢀanthraquinones 1a—c with
guanidine (general procedure). A mixture of compound 1a—c
(3.25 mmol) and guanidine (27 mmol, 27 mL of 1 M solution
in methanol) in nꢀbutanol (60 mL) was refluxed for 28 h (TLC
monitoring with chloroform as an eluent). The solvent was
evaporated in vacuo. The mixture was separated by column
chromatography on Al2O3 (d = 25 mm, h = 170 mm) with
Received December 3, 2009;
in revised form February 17, 2010