Dual reactivity of diazonium salts derived from 1-amino-2-ethynyl-9,10- anthraquinones

Article abstract of DOI:10.1007/s11172-012-0292-2

Diazotization of vicinal 1-amino-2-ethynyl-4-R-9,10-anthraquinones followed by a reaction with NaN₃ gave 5-hydroxy-3-R-1H-naphtho[2,3-g] indazole-6,11-diones or 3-ethynyl-5-R-6H-anthra[1,9-cd]isoxazol-6-ones, depending on the substituents at th

Full text of DOI:10.1007/s11172-012-0292-2

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2088—2095, November, 2012
2088
Dual reactivity of diazonium salts derived from
1ꢀaminoꢀ2ꢀethynylꢀ9,10ꢀanthraquinones
S. F. Vasilevsky,a A. A. Stepanov,a and D. S. Fadeevb
aInstitute 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
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrentґeva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752
Diazotization of vicinal 1ꢀaminoꢀ2ꢀethynylꢀ4ꢀRꢀ9,10ꢀanthraquinones followed by a reacꢀ
tion with NaN3 gave 5ꢀhydroxyꢀ3ꢀRꢀ1Hꢀnaphtho[2,3ꢀg]indazoleꢀ6,11ꢀdiones or 3ꢀethynylꢀ
5ꢀRꢀ6Hꢀanthra[1,9ꢀcd]isoxazolꢀ6ꢀones, depending on the substituents at the triply bonded
C atom and in position 4 of the anthraquinone framework.
Key words: diazotization, heterocyclization, naphthoindazoles, anthraisoxazoles.
Preparation of hybrid molecules combining two (or
more) structural elements is one of the leading trends in
modern organic chemistry. Such natural and synthetic
conjugates often exhibit high biological activity. Ethynyl
fragments are common structural elements in such comꢀ
pounds since many natural metabolites with a triple bond
show high antitumor activity.1—3 In addition, high cytoꢀ
toxicity against various types of tumors has been found4 in
fused anthraquinonoid rings capable of being inserted into
the DNA chain. It has been demonstrated that compounds
combining ethynyl and anthraquinone fragments are
promising for these purposes.5,6
Earlier,7 our attempted synthesis of ethynylisoxazolanꢀ
thrones from appropriate 3ꢀhaloisoxazolanthrones and
1ꢀalkynes or their copper salts has failed. Instead of the
expected products, we obtained 1ꢀaminoꢀ2ꢀ(phenylethynꢀ
yl)ꢀ9,10ꢀanthraquinones in reactions with HCCPh for
the crossꢀcoupling is accompanied by ring opening
and naphtho[2,3ꢀg]indoleꢀ6,11ꢀdiones in reactions with
CuCCPh because of recyclization of an intermediate
amine (Scheme 1).
The recently proposed8 synthetic route to the target
alkynylisoxazoles involves the preparation of vicinal
1ꢀaminoꢀ2ꢀethynylꢀ9,10ꢀanthraquinones, their diazotizaꢀ
Scheme 1
R = Cu or H
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2071—2078, November, 2012.
1066ꢀ5285/12/6111ꢀ2088 © 2012 Springer Science+Business Media, Inc.

2ꢀEthynylꢀ9,10ꢀanthraquinone, 1ꢀdiazonium
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2089
Scheme 2
i. R =
,
; ii. R =
,
,
.
tion, and closure of the isoxazole ring (Scheme 2). Howꢀ
ever, this reaction can also follow two pathways, dependꢀ
ing on the substituent at the triply bonded C atom. When
the substituent is an electron acceptor, the reaction folꢀ
lows pathway (ii) leading to the target ethynylisoxazoles,
while the presence of an electron donor favors the formaꢀ
tion of fused anthrapyrazoles (pathway i).
As a next step in our investigations, as well as for revealꢀ
ing general features and/or limitations of these reactions, we
synthesized a number of the starting vicinal 1ꢀaminoꢀ2ꢀ
ethynylꢀ9,10ꢀanthraquinones in which the ethynyl fragment
bears an electronꢀwithdrawing, electronꢀdonating, or no
substituent at all (Scheme 3). In addition, the substituent
in position 4 of the anthraquinone framework was also
varied (NHAr, OH) in the starting compounds.
Prepared 1ꢀaminoꢀ4ꢀhydroxyꢀ2ꢀ[(trimethylsilyl)ethynꢀ
yl]ꢀ9,10ꢀanthraquinone (1) was decomposed with K2CO3
in methanol to 2ꢀethynylꢀ9,10ꢀanthraquinone 2b. Since
the substrates with the protected OH group (3a—c) proved
to undergo smoother diazotization than amines 2a—c, the
hydroxyl group in the latter was selectively protected by
acylation with Ac2O in pyridine prior to diazotization.9
Diazotization of aminoanthraquinones 3a,b with nitroꢀ
sylsulfuric acid for 15 min gave diazonium salts, which
were treated with a solution of NaN3 at room temperature
and kept for 5 h. The yields of crude 1ꢀazidoꢀ9,10ꢀanthraꢀ
quinones 4a,b were 88 and 91%, respectively (Scheme 4).
The crude azides were employed in further transforꢀ
mations, regardless of some content of isoxazolanthrone
as a result of N2 elimination and O—N bond formation.
Scheme 3
R =
(a), H (b),
(c)

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Vasilevsky et al.
Схема 4
R =
(a), H (b),
(c)
Attempted purification of these compounds only increased
the amount of the cyclization products. Note that the acyl
protection was removed from the hydroxyl group during
the diazotization.
Earlier,8 we have demonstrated that methoxy derivaꢀ
tive A, a product of a similar diazotization—cyclization
sequence and a close structural analog to compound 6,
contains a fiveꢀmembered fused heterocycle rather than
a sixꢀmembered ring as in structure B. This concluꢀ
sion was drawn from the HMBC spectra revealing couꢀ
plings between the C(12) atom and the H(14) and H(18)
protons but no coupling between the C(12) atom and the
H(4) proton.8 For structure B containing a new sixꢀmemꢀ
bered ring formed, the reverse spectral pattern would
be very likely, with the C(4) atom coupling with the
H(5) proton but not coupling with the H(14) and H(18)
protons.
Since the chemical shifts of analogous signals in the
1H and 13C NMR spectra of compounds 6 and A have
close values and the structure of derivative A is proved, we
concluded that the cyclization of the diazonium salt deꢀ
rived from amine 3c leads to a fiveꢀmembered rather than
sixꢀmembered ring. Otherwise, greater differences between
the corresponding chemical shifts could be expected. This
conclusion was confirmed by DFT/PBE/22 quantum
chemical calculations11—14 of the 13C and 1H NMR chemꢀ
ical shifts. The calculated  value for C(12) (201.63) in
compound 6 containing the fiveꢀmembered ring agrees
Cyclization of vicinal ethynylꢀcontaining azides 4a,b
was carried out in boiling toluene for 0.5—3 h; the yields
of the target ethynylisoxazolanthrones 5a and 5b were 81
and 83%, respectively. Therefore, the reaction involves
the azido and carbonyl groups of 9,10ꢀanthraquinones,
the alkynyl substituent in position 2 remaining intact.
The diazotization of aminoanthraquinone 3c containꢀ
ing an electronꢀdonating group at the triple bond occurred
in a different way, giving cyclization products 6 and 7
(10 : 1, 1H NMR) rather than diazonium salts. Free
phenol 7 is formed by partial deacylation of Oꢀacetyl deꢀ
rivative 6. The overall yield of compound 6 (as if no deꢀ
acylation occurred) was 80% (see Scheme 4). Hydrolysis
of the mixture of compounds 6 and 7 with KOH in ethanol
gave phenol 7 in the individual state (76% yield).
Since vicinal ethynylꢀcontaining diazonium salts can
undergo cyclization according to both the 5ꢀexoꢀdig
and 6ꢀendoꢀdig patterns,8,10 we used calculational
and experimental methods to prove the structure of comꢀ
pound 6.

2ꢀEthynylꢀ9,10ꢀanthraquinone, 1ꢀdiazonium
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2091
well with experimental data ( 195.83). This value differs
substantially from  166.55 for C(4) in plausible structure
8 with the sixꢀmembered ring.
To find out whether the outcome of the diazotization
depends on the substituent in position 4 of the anthraqꢀ
uinone framework, we diazotized a pꢀtoluidine analog (3d)
of the durene derivative 3c.
tion of byꢀproducts, with decreasing yields of the target
products. Earlier,8 it has been noted that the diazotizating
agent influences the reaction time, the reaction pathway
remaining unchanged. That is why we carried out the diꢀ
azotization with isopropyl nitrite at 50 C for 2 h (Scheme 5).
Treatment of a solution of the corresponding diazonium
salt with NaN3 gave 1ꢀazidoanthraquinone 4d in 94% yield.
A roomꢀtemperature reaction of isopropyl nitrite in
glacial AcOH with amine 3e for 1 h produced a solution of
Diazotization of pꢀtoluidineꢀcontaining derivatives
with nitrosylsulfuric acid was accompanied by the formaꢀ
Scheme 5
i. Isopropyl nitrite, NaN3, 20 C; ii. 110 C.
R =
(d),
(c)

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Vasilevsky et al.
3ꢀethynylꢀ6Hꢀanthra[1,9ꢀcd]isoxazolꢀ6ꢀones. In contrast,
a combination of an acyl substituent in position 4 of the
anthraquinone framework and an electronꢀdonating subꢀ
stituent at the triple bond leads to 5ꢀacetoxyꢀ3ꢀRꢀ1Hꢀ
naphtho[2,3ꢀg]indazoleꢀ6,11ꢀdiones, products of 5ꢀexoꢀ
dig cyclization.
Experimental
IR spectra were recorded on a Bruker Vector 22 spectroꢀ
meter (KBr pellets). NMR spectra were recorded on a Bruker
AV 400 spectrometer (400.13 MHz) in CDCl3 and DMSOꢀd6.
Mass spectra were measured on a Thermo Scientific DFS douꢀ
bleꢀfocusing mass spectrometer (Thermo Electron Corporation)
(direct inlet probe, ionization chamber temperature 220—270 C,
ionizing voltage 70 eV). For column chromatography, Merck 60
silica gel (0.063—0.2 mm) and Al2O3 (Brockmann activity II,
0.05—0.15 mm, Russian specification 6ꢀ09ꢀ3916ꢀ75). The course
of the reactions was monitored by TLC on Silufol 60 F254 plates.
Trimethylsilylacetylene, 3ꢀphenoxypropyne, Et3N, Pd(PPh3)2Cl2,
and CuI (Aldrich) were used as purchased. 4ꢀEthynylisoquinoꢀ
line was prepared as described earlier.15
1ꢀAminoꢀ4ꢀhydroxyꢀ2ꢀ[(trimethylsilyl)ethynyl]ꢀ9,10ꢀanthraꢀ
quinone (1). Trimethylsilylacetylene (4.1 mL, 24 mmol) was addꢀ
ed to a solution of 1ꢀaminoꢀ2ꢀbromoꢀ4ꢀhydroxyꢀ9,10ꢀanthraꢀ
quinone16 (6.36 g, 20 mmol), Pd(PPh3)2Cl2 (60 mg), PPh3
(60 mg), CuI (30 mg), and Et3N (5 mL) in toluene (150 mL).
The reaction mixture was stirred under argon at 43 C for 10 h.
After completion of the reaction, the mixture was cooled and
evaporated to dryness. The product was isolated by column
chromatography on Al2O3 (d = 2.5 cm, h = 1 cm) with toluene
as an eluent. The solvent was removed in vacuo. Yield 5.91 g
(88%), m.p. 144—146 C (from benzene). 1H NMR (CDCl3),
: 0.34 (s, 9 H, H(13), H(14), H(15)); 7.33 (s, 1 H, H(3));
7.73—7.84 (m, 2 H, H(6), H(7)); 8.30—8.36 (m, 2 H, H(5),
H(8)); 13.34 (s, 1 H, OH). 13C NMR (CDCl3), : 0.33 (C(13),
C(14), C(15)); 98.42, 107.00 (C(11), C(12)); 108.84; 113.86;
121.18; 126.27; 126.75; 129.92; 132.67; 132.81; 134.10; 134.64;
146.29 (C(4)); 155.61 (C(1)); 182.79, 187.09 (C(9), C(10)).
HRMS, found: m/z 335.0970 [M]+. C19H17NO3Si. Calculatꢀ
ed: M = 335.0972. IR, /cm–1: 1629 (C=O); 2149 (CC);
3433 (NH2).
1ꢀAminoꢀ4ꢀhydroxyꢀ2ꢀ[(isoquinolinꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀanꢀ
thraquinone (2a) was obtained as described for compound 1. The
reaction was carried out at 65 C for 12 h. Yield 0.67 g (85%),
m.p. 281—282 C (from DMSO). 1H NMR (CDCl3), : 7.55
(s, 1 H, H(3)); 7.72—7.90 (m, 4 H, H(17), H(18), H(19), H(20));
8.07, 8.29 (both d, 1 H each, H(5), H(8), J = 8.3 Hz); 8.34—8.40
(m, 2 H, H(6), H(7)); 8.85, 9.29 (both s, 1 H each, H(14),
H(16)); 13.36 (s, 1 H, OH). 13C NMR (CDCl3), : 90.29, 95.23
(C(11), C(12)); 114.29; 114.35; 120.85; 124.51; 126.42; 126.91;
127.66; 128.17; 128.23; 129.96; 131.71; 132.76; 133.03; 133.11;
134.30; 134.70; 135.10; 146.09; 147.03; 153.17; 155.69; 183.16,
187.32 (C(9), C(10)). HRMS, found: m/z 390.1000 [M]+.
C25H14N2O3. Calculated: M = 390.0999. IR, /cm–1: 1625
(C=O); 2198 (CC); 3456 (NH2).
Fig. 1. Effect of the electronꢀdonating substituent on the elecꢀ
tron density of the alkyne fragment.
the corresponding diazonium salt, which was treated with
excess NaN3. The yield of 1ꢀazidoanthraquinone 4e was
60%. The IR spectra of the compounds obtained conꢀ
tain bands at 1624—1628 and 1660—1662 cm–1 (C=O).
The bands due to N3 and CC are unresolved for 4e
(2027—2233 cm–1) and appear at 2118 (N3) and 2194 cm–1
(CC) for 4d.
The electronꢀdonating effect of the substituent at the
triple bond increases the electron density of the alkyne
fragment, thus favoring the cyclization (Fig. 1).
This scenario is true for the formation of compound 6.
However, if the substituent in position 4 of the anꢀ
thraquinone framework has a stronger +M effect (toluiꢀ
dine group), it seems to be sufficient for the stabilization
of the diazonium salt, which allows the diazo group to be
replaced by an azido group.
Cyclization of azides 4d,e in boiling toluene for 5—10 min
gave compounds 5d,e in 67 and 80% yields, respectively.
To sum up, the present investigation confirmed our
previous results and conclusions that the outcome of the
diazotization of 1ꢀaminoꢀ2ꢀethynylꢀ9,10ꢀanthraquinones
depends on the substituents in both the ethynyl and anthraꢀ
quinone parts of the substrate molecule. The electronꢀ
donating substituents (NHAr, OH) in position 4 stabilize
the diazonium salt, preventing its electrophilic cyclization
by means of the triple bond. This allows replacement of
the diazo group by an azido group followed by closure of
the isoxazole ring, with the triple bond being intact. This
reaction opens up a new route to not easily accessible
1ꢀAminoꢀ4ꢀhydroxyꢀ2ꢀ[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ
9,10ꢀanthraquinone (2c) was obtained as described for comꢀ
pound 1. The reaction was carried out at 75 C for 1 h. Yield 0.72 g
(94%), m.p. 278—280 C (from dioxane). 1H NMR (CDCl3),

2ꢀEthynylꢀ9,10ꢀanthraquinone, 1ꢀdiazonium
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2093
: 2.22 (s, 6 H, C(15)—Me, C(17)—Me); 2.42 (s, 6 H, C(14)—Me,
C(18)—Me); 6.94 (br.s, 1 H, H(16)); 7.39 (s, 1 H, H(3)); 7.71—7.81
(m, 2 H, H(6), H(7)); 8.29—8.36 (m, 2 H, H(5), H(8)); 13.43
(s, 1 H, OH). 13C NMR (CDCl3), : 17.74 (C(15)—CH3,
C(17)—CH3); 19.74 (C(14)—CH3, C(18)—CH3); 90.92, 99.90
(C(11), C(12)); 113.55; 121.70; 122.60; 126.31; 126.84; 129.10;
132.73; 132.83; 132.91; 133.70; 134.03; 134.10; 134.81; 136.19;
146.11 (C(4)); 156.12 (C(1)); 183.04, 187.01 (C(9), C(10)).
HRMS, found: m/z 395.1510 [M]+. C26H21NO3. Calculated:
M = 395.1516. IR, /cm–1: 1620, 1633 (C=O); 2187 (CC);
3460 (NH2).
1ꢀAminoꢀ2ꢀethynylꢀ4ꢀhydroxyꢀ9,10ꢀanthraquinone (2b). Poꢀ
tassium carbonate (0.28 g, 2 mmol) was added to a solution of
1ꢀaminoꢀ4ꢀhydroxyꢀ2ꢀ[(trimethylsilyl)ethynyl]ꢀ9,10ꢀanthraꢀ
quinone (1) (6.7 g, 20 mmol) in MeOH (55 mL). The reaction
mixture was stirred at ~20 C for 3 h and diluted with water
(60 mL). The precipitate that formed was filtered off. Yield 4.93 g
(93%), m.p. 212—214 C. 1H NMR (DMSOꢀd6), : 5.03 (s, 1 H,
H(12)); 7.48 (s, 1 H, H(3)); 7.8 (br.s, 2 H, NH2); 7.85—7.94
(m, 2 H, H(6), H(7)); 8.18—8.24 (m, 2 H, H(5), H(8)); 13.22
(s, 1 H, OH). 13C NMR (DMSOꢀd6), : 92.80, 108.40 (C(11),
C(12)); 114.13; 121.02; 126.59; 127.04; 130.88; 131.99; 132.56;
133.97; 134.76; 135.45; 147.38; 155.08; 182.47, 187.40 (C(9),
C(10)). HRMS, found: m/z 263.0578 [M]+. C16H9NO3. Calcuꢀ
lated: M = 263.0577. IR, /cm–1: 1626 (C=O); 2104 (CC);
3278 (C—H); 3406 (NH2).
4ꢀAcetoxyꢀ1ꢀaminoꢀ2ꢀ[(isoquinolinꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀanꢀ
thraquinone (3a). Acetic anhydride (2 mL) was added to a soluꢀ
tion of 1ꢀaminoꢀ4ꢀhydroxyꢀ2ꢀ[(isoquinolinꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀ
anthraquinone (2a) (0.67 g, 1.71 mmol) in pyridine (15 mL).
The reaction mixture was stirred at 85 C for 17 h. After compleꢀ
tion of the reaction, the mixture was cooled and poured onto ice.
The precipitate that formed was filtered off and washed with
water and ethanol. The product was isolated by column chromatoꢀ
graphy on SiO2 (d = 2 cm, h = 5 cm) with ethyl acetate as an
eluent. The solvent was removed in vacuo. Yield 0.63 g (86%),
m.p. 288—291 C (from DMF). 1H NMR (CDCl3), : 2.47 (s, 3 H,
C(21)Me); 7.50 (s, 1 H, H(3)); 7.68—7.78 (m, 3 H, H(17), H(18),
H(19)); 7.75 (t, 1 H, H(6) (or H(7)), J = 8.0 Hz); 8.04 (d, 1 H,
H(20), J = 8.0 Hz); 8.18 (dd, 1 H, H(5) (or H(8)), J = 7.1 Hz,
J = 1.8 Hz); 8.24—8.29 (m, 2 H, H(8) (or H(5)), H(7) (or H(6));
8.81, 9.26 (both s, 1 H each, H(14), H(16)). 13C NMR (CDCl3),
: 21.06 (C(21)—CH3); 90.12, 95.14 (C(11), C(12)); 113.10;
114.50; 116.51; 124.55; 124.69; 126.58; 126.67; 127.67; 128.15;
128.20; 131.65; 133.44; 133.48; 133.64; 133.83; 133.91; 135.07;
140.22; 146.90 (C(16)); 149.74 (C(1)); 153.04 (C(14)); 170.12
(C(21)); 181.98, 184.93 (C(9), C(10)). HRMS, found: m/z
432.1103 [M]+. C27H16N2O4. Calculated: M = 432.1105. IR,
/cm–1: 1633, 1660, 1757 (C=O); 2200 (CC); 3429 (NH2).
4ꢀAcetoxyꢀ1ꢀaminoꢀ2ꢀethynylꢀ9,10ꢀanthraquinone (3b) was
obtained from compound 2b as described for compound 3a. The
reaction was carried out at 55 C for 3.5 h. Yield 0.49 g (69%),
m.p. 295—296 C (from dioxane). 1H NMR (CDCl3), : 2.46
(s, 3 H, C(21)Me); 3.71 (s, 1 H, H(12)); 7.35 (s, 1 H, H(3)); 7.72,
7.77 (both td, 1 H each, H(6), H(7), J = 7.5 Hz, J = 1.6 Hz);
8.17, 8.27 (both dd, 1 H each, H(5), H(8), J = 7.5 Hz, J = 1.6 Hz).
13C NMR (CDCl3), : 21.02 (C(21)—CH3); 87.86, 112.89
(C(11), C(12)); 115.61; 122.18; 124.83; 126.04; 126.54; 126.65;
133.99; 133.63; 133.82; 134.43; 139.85; 150.27 (C(1)); 170.03
(C(21)); 182.02, 184.82 (C(9), C(10)). HRMS, found: m/z
305.0686 [M]+. C18H11NO4. Calculated: M = 305.0683. IR,
/cm–1: 1637, 1664, 1749 (C=O); 2096 (CC); 3246 (C—H);
3473 (NH2).
4ꢀAcetoxyꢀ1ꢀaminoꢀ2ꢀ[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ
9,10ꢀanthraquinone (3c) was obtained from compound 2c as deꢀ
scribed for compound 3a. The reaction was carried out at 75 C
for 22 h. Yield 0.71 g (89%), m.p. 268—270 C (from toluene).
1H NMR (CDCl3), : 2.22 (s, 6 H, C(15)Me, C(17)Me); 2.45
(s, 6 H, C(14)Me, C(18)Me); 2.45 (s, 3 H, C(21)Me); 6.94 (br.s,
1 H, H(16)); 7.36 (s, 1 H, H(3)); 7.67—7.75 (m, 2 H, H(6),
H(7)); 8.15 (d, 1 H, H(5) (or H(8)), J = 7.0 Hz); 8.15 (d, 1 H,
H(8) (or H(5)), J = 7.2 Hz). 13C NMR (CDCl3), : 17.92
(C(15)CH3, C(17)CH3); 19.94 (C(14)CH3, C(18)CH3); 21.23
(C(21)CH3); 90.83, 99.84 (C(11), C(12)); 112.81; 118.38; 121.94;
123.81; 126.63; 126.71; 132.68; 133.20; 133.38; 133.66; 133.77;
133.79; 133.83; 136.17; 140.51; 149.71; 170.27 (C(21)); 182.04,
184.97 (C(9), C(10)). HRMS, found: m/z 437.1616 [M]+.
C28H23NO4. Calculated: M = 437.1622. IR, /cm–1: 1633, 1656,
1764 (C=O); 2189 (CC); 3465 (NH2).
1ꢀAminoꢀ2ꢀ[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ4ꢀ(pꢀtoluꢀ
idino)ꢀ9,10ꢀanthraquinone (3d). 1ꢀEthynylꢀ2,3,5,6ꢀtetramethylꢀ
benzene (9) (0.52 g, 3.3 mmol) was added to a mixture of
1ꢀaminoꢀ2ꢀbromoꢀ4ꢀ(pꢀtoluidino)ꢀ9,10ꢀanthraquinone17 (1.22 g,
3 mmol), Pd(PPh3)2Cl2 (10 mg), CuI (10 mg), and Et3N (2 mL)
in toluene (10 mL). The reaction mixture was stirred under arꢀ
gon at 75 C for 9 h. After completion of the reaction, the mixꢀ
ture was cooled and the precipitate that formed was filtered off
and washed with methanol, water, and again methanol. Yield
1.17 g (79%), m.p. 232—234 C (from toluene). 1H NMR
(CDCl3), : 2.21 (s, 6 H, C(22)Me, C(24)Me); 2.37 (s, 3 H,
C(16)Me); 2.38 (s, 6 H, C(21)Me, C(25)Me); 6.93 (br.s, 1 H,
H(23)); 7.16—7.22 (m, 4 H, H(14), H(15), H(17), H(18)); 7.69
(s, 1 H, H(3)); 7.70—7.73 (m, 2 H, H(5), H(8)); 8.31—8.35
(m, 2 H, H(6), H(7)); 12.01 (br.s, 1 H, NH). 13C NMR (CDCl3),
: 17.79 (C(22)CH3, C(24)CH3); 19.77 (C(21)CH3, C(25)CH3);
20.85 (C(16)CH3); 91.06, 98.59 (C(11), C(12)); 110.18; 111.32;
121.43; 121.73; 123.66; 126.15; 126.22; 126.28; 130.02; 132.46;
132.49; 132.53; 133.61; 134.05; 134.22; 134.42; 136.10; 136.90;
142.52; 145.48; 183.01, 183.54 (C(9), C(10)). HRMS, found:
m/z 484.2139 [M]+. C33H28N2O2. Calculated: M = 484.2145.
IR, /cm–1: 1614 (C=O); 2187 (CC); 3066 (NH); 3456 (NH2).
1ꢀAminoꢀ2ꢀ(3ꢀphenoxypropꢀ1ꢀynyl)ꢀ4ꢀ(pꢀtoluidino)ꢀ9,10ꢀ
anthraquinone (3e) was obtained from 1ꢀaminoꢀ2ꢀbromoꢀ4ꢀ
(pꢀtoluidino)ꢀ9,10ꢀanthraquinone and 3ꢀphenoxypropyne as deꢀ
scribed for compound 3d. The reaction was carried out at 55 C
for 3.5 h. Yield 0.62 g (45%), m.p. 215—216 C (from benzene).
1H NMR (CDCl3), : 2.39 (s, 3 H, C(16)Me); 4.98 (s, 2 H,
H(20)); 7.01—7.06 (m, 3 H, H(22), H(24), H(26)); 7.14 (d, 2 H,
H(14), H(18), J = 8.3 Hz); 7.22 (d, 2 H, H(15), H(17), J = 8.3 Hz);
7.32—7.36 (m, 2 H, H(23), H(25)); 7.58 (s, 1 H, H(3)); 7.72—7.74
(m, 2 H, H(6), H(7)); 8.32—8.34 (m, 2 H, H(5), H(8)); 11.86
(br.s, 1 H, NH). 13C NMR (CDCl3), : 20.86 (C(16)—CH3);
56.30 (C(20)); 81.79, 93.76 (C(11), C(12)); 110.17; 111.69;
115.03; 119.28; 121.91; 124.17; 126.19; 126.27; 127.27; 129.55;
130.08; 132.64; 132.67; 133.99; 134.27; 134.57; 136.64; 142.34;
145.49; 157.12; 183.30, 183.54 (C(9), C(10)). HRMS, found: m/z
458.16058 [M]+. C30H22N2O3. Calculated: M = 458.16303. IR,
/cm–1: 1628 (C=O); 2232 (CC); 3058 (NH); 3443 (NH2).
1ꢀAzidoꢀ4ꢀhydroxyꢀ2ꢀ[(isoquinolinꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀanꢀ
thraquinone (4a). A solution of NaNO2 (0.1 g, 1.44 mmol) in
H2SO4 ( = 1.84 g cm–3, 1 mL) was added dropwise at ~20 C to
a suspension of 4ꢀacetoxyꢀ1ꢀaminoꢀ2ꢀ[(isoquinolinꢀ4ꢀyl)ethynꢀ

2094
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Vasilevsky et al.
yl]ꢀ9,10ꢀanthraquinone (3a) (0.38 g, 0.9 mmol) in glacial AcOH
(5 mL). The reaction mixture was stirred for 15 min. After comꢀ
pletion of the reaction, the mixture was diluted with an equal
volume of water and then a solution of NaN3 (0.12 g) in water
(2 mL) was added with stirring. The resulting mixture was kept
for 5 h. After the reaction was completed, the precipitate that
formed was filtered off and washed with water and ethanol. Yield
0.33 g (88%). IR, /cm–1: 1631, 1664 (C=O); 2119 (N3);
2206 (CC).
1ꢀAzidoꢀ2ꢀethynylꢀ4ꢀhydroxyꢀ9,10ꢀanthraquinone (4b) was
obtained from compound 3b as described for compound 4a. The
diazotization time was 15 min; the reaction with NaN3 was
carried out for 5 h. Yield 0.097 g (91%). IR, /cm–1: 1633,
1658 (C=O); 2047—2170 (N3 and CC, unresolved lines); 3263
(C—H).
1ꢀAzidoꢀ2ꢀ[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ4ꢀ(pꢀtoluꢀ
idino)ꢀ9,10ꢀanthraquinone (4d). Isopropyl nitrite (0.1 g, 1.5 mmol)
was added dropwise at ~20 C to a suspension of 1ꢀaminoꢀ2ꢀ
[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ4ꢀ(pꢀtoluidino)ꢀ9,10ꢀanꢀ
thraquinone (3d) (0.38 g, 0.79 mmol) in glacial AcOH (10 mL).
Then the reaction mixture was heated to 50 C and stirred for
2 h. After completion of the reaction, the mixture was diluted
with an equal volume of water and filtered. A solution of NaN3
(0.15 g) in water (2 mL) was added with stirring to the mother
liquor and the resulting mixture was kept for 2 h. The precipitate
that formed was filtered off and washed with water and ethanol.
Yield 0.38 g (94%). IR, /cm–1: 1624, 1660 (C=O); 2118 (N3);
2194 (CC).
1ꢀAzidoꢀ2ꢀ(3ꢀphenoxypropꢀ1ꢀynyl)ꢀ4ꢀ(pꢀtoluidino)ꢀ9,10ꢀanꢀ
thraquinone (4e) was obtained from compound 3e as described
for compound 4d, with the exception that the temperature of the
reaction mixture was always maintained at 25 C. The diazotizaꢀ
tion time was 55 min; the reaction with NaN3 was carried out for
2 h. Yield 0.14 g (60%). IR, /cm–1: 1628, 1662 (C=O); 2128
(N3, CC).
m/z 261.0418 [M]+. C16H7NO3. Calculated: M = 261.0421. IR,
/cm–1: 1635, 1683 (C=O); 2108 (CC); 3265 (C—H).
3ꢀ[(2,3,5,6ꢀTetramethylphenyl)ethynyl]ꢀ5ꢀ(pꢀtoluidino)ꢀ6Hꢀ
anthra[1,9ꢀcd]isoxazolꢀ6ꢀone (5d) was obtained from compound
4d as described for compound 5a. The reflux time was 10 min.
Yield 0.04 g (67%), m.p. 261—263 C. 1H NMR (CDCl3),
: 2.21 (s, 6 H, C(22)Me, C(24)Me); 2.41 (s, 3 H, C(17)Me); 2.46
(s, 6 H, C(21)Me, C(25)Me); 6.95 (br.s, 1 H, H(23)); 7.23—7.25
(m, 2 H, H(16), H(18)); 7.28—7.30 (m, 2 H, H(15), H(19));
7.56 (s, 1 H, H(4)); 7.63, 7.76 (both t, 1 H each, H(8), H(9),
J = 7.0 Hz); 8.12, 8.55 (both d, 1 H each, H(7), H(10), J = 8.0 Hz);
11.47 (br.s, 1 H, NH). 13C NMR (CDCl3), : 17.75 (C(22)CH3,
C(24)CH3); 19.73 (C(21)CH3, C(25)CH3); 21.00 (C(17)CH3);
91.62, 100.25 (C(12), C(13)); 101.53; 117.15; 121.66; 121.69;
122.16; 124.25; 125.36; 125.65; 128.26; 128.48; 130.31; 132.01;
132.58; 132.85; 133.52; 134.73; 136.61; 137.04; 149.45; 151.63;
156.28; 180.11 (C(6)). HRMS, found: m/z 482.1987 [M]+.
C33H26N2O2. Calculated: M = 482.1989. IR, /cm–1: 1620, 1672
(C=O); 2194 (CC).
3ꢀ(3ꢀPhenoxypropꢀ1ꢀynyl)ꢀ5ꢀ(pꢀtoluidino)ꢀ6Hꢀanthra[1,9ꢀcd]ꢀ
isoxazolꢀ6ꢀone (5e) was obtained from compound 4e as described
for compound 5a. The reflux time was 5 min. Yield 0.1 g (80%),
m.p. 196—198 C (from benzene). 1H NMR (CDCl3), : 2.43
(s, 3 H, C(17)Me); 5.01 (s, 2 H, H(20)); 6.99—7.04 (m, 3 H, H(15),
H(19), H(24)); 7.22—7.34 (m, 6 H, H(16), H(18), H(22), H(23),
H(25), H(26)); 7.53 (s, 1 H, H(4)); 7.66, 7.79 (both t, 1 H each,
H(8), H(9), J = 8.0 Hz); 8.15, 8.55 (both d, 1 H each, H(7),
H(10), J = 7.8 Hz); 11.36 (s, 1 H, NH). 13C NMR (CDCl3),
: 21.12 (C(17)CH3); 56.64 (C(20)); 81.55, 94.57 (C(12), C(13));
101.91; 114.97; 117.14; 119.60; 121.79; 122.40; 124.69; 125.47;
128.36; 128.47; 128.83; 129.60; 130.54; 132.35; 132.61;
134.52; 137.08; 149.10; 151.22; 156.67; 157.59; 180.55 (C(6)).
HRMS, found: m/z 456.1465 [M]+. C30H20N2O3. Calculated:
M = 456.1468. IR, /cm–1: 1621, 1675 (C=O); 2211 (CC);
3057 (NH).
5ꢀHydroxyꢀ3ꢀ[(isoquinolinꢀ4ꢀyl)ethynyl]ꢀ6Hꢀanthra[1,9ꢀcd]ꢀ
isoxazolꢀ6ꢀone (5a). A solution of 1ꢀazidoꢀ4ꢀhydroxyꢀ2ꢀ[(isoꢀ
quinolinꢀ4ꢀyl)ethynyl]ꢀ9,10ꢀanthraquinone (4a) (0.33 g,
0.79 mmol) in toluene (3 mL) was refluxed for 3 h. After comꢀ
pletion of the reaction, the mixture was cooled. The precipitate
that formed was filtered off and washed with ethanol. Yield 0.25 g
(81%), m.p. 249—251 C (from DMSO). 1H NMR (CDCl3),
: 7.70—7.72 (m, 3 H, H(4), H(19), H(20)); 7.85—7.92 (m, 2 H,
H(8), H(9)); 8.08 (d, 1 H, H(18) (or H(21)), J = 8.0 Hz); 8.23
(d, 1 H, H(21) (or H(18)), J = 8.3 Hz); 8.40 (d, 1 H, H(7)
(or H(10)), J = 8.3 Hz); 8.49 (d, 1 H, H(10) (or H(7)), J = 7.5
Hz); 8.80, 9.26 (both s, 1 H each, H(15), H(17)). HRMS, found:
m/z 388.0844 [M]+. C25H12N2O3. Calculated: M = 388.0842.
IR, /cm–1: 1641, 1683 (C=O); 2202 (CC). The 13C NMR
spectrum of compound 5a was not recorded because of its low
solubility. Found (%): C, 76.49; H, 3.18; N, 6.38. C25H12N2O3.
Calculated (%): C, 77.31; H, 3.11; N, 7.21.
3ꢀEthynylꢀ5ꢀhydroxyꢀ6Hꢀanthra[1,9ꢀcd]isoxazolꢀ6ꢀone (5b)
was obtained from compound 4b as described for compound 5a.
The reflux time was 25 min. Yield 0.25 g (83%), m.p. 180 C
(decomp.). 1H NMR (CDCl3), : 3.84 (s, 1 H, H(13)); 7.18 (s, 1 H,
H(4)); 7.77, 7.91 (both td, 1 H each, H(8), H(9), J = 8.3 Hz,
J = 1.3 Hz); 8.32, 8.57 (both d, 1 H each, H(7), H(10), J = 8.0 Hz).
13C NMR (CDCl3), : 77.23, 89.68 (C(12), C(13)); 104.78;
116.00; 122.83; 123.64; 124.71; 127.25; 128.01; 128.92; 132.72;
137.30; 151.43; 155.96; 167.17; 178.29 (C(6)). HRMS, found:
5ꢀAcetoxyꢀ3ꢀ(2,3,5,6ꢀtetramethylbenzoyl)ꢀ1Hꢀnaphtho[2,3ꢀg]ꢀ
indazoleꢀ6,11ꢀdione (6). A solution of NaNO2 (0.1 g, 1.5 mmol)
in H2SO4 (1 mL) was added dropwise at ~20 C to a suspension
of 4ꢀacetoxyꢀ1ꢀaminoꢀ2ꢀ[(2,3,5,6ꢀtetramethylphenyl)ethynyl]ꢀ
9,10ꢀanthraquinone (3c) (0.44 g, 1 mmol) in glacial AcOH
(20 mL). The reaction mixture was stirred for 20 min. After
completion of the reaction, the mixture was poured onto ice.
The precipitate that formed was filtered off, washed with water
and methanol, and dried at 130 C for 20 min. Yield 0.34 g
1
(80%), m.p. 296—298 C. H NMR (600.30 MHz, DMSOꢀd6,
50 C), : 1.96 (s, 6 H, C(14)Me, C(18)Me); 2.23 (s, 6 H,
C(15)Me, C(17)Me); 2.47 (s, 3 H, C(19)Me); 7.09 (s, 1 H,
H(16)); 7.94—7.97 (m, 2 H, H(9), H(8)); 8.17—8.19 (m, 1 H,
H(10) (or H(7))); 8.21—8.23 (m, 1 H, H(7) (or H(10))); 8.44
(s, 1 H, H(4)). 13C NMR (150.96 MHz, DMSOꢀd6, 50 C), : 15.88
(C(14)CH3, C(18)CH3); 18.84 (C(15)CH3, C(17)CH3); 20.77
(C(19)CH3); 119.49; 122.60 (C(4)); 123.78 (C(5a)); 125.27;
125.87 (C(7), C(10)); 126.74 (C(10), C(7)); 128.99 (C(14),
C(18)); 131.44 (C(16)); 131.84 (C(6a) (or C(10a))); 133.18
(C(10a) (or C(6a))); 133.38 (C(15), C(17)); 134.32 (C(8) (or
C(9))); 134.71 (C(9) (or C(8))); 135.29 (C(3b)); 140.19 (C(13));
143.18 (C(3)); 145.01 (C(5)); 169.48 (C(19)); 181.57 (C(11) (or
C(6))); 182.79 (C(6) (or C(11))); 195.83 (C(12)). The HMBC
experiment was tuned to J = 7 Hz. HRMS, found: m/z 466.1519
[M]+. C28H22N2O5. Calculated: M = 466.1523. IR, /cm–1
:
1616, 1672, 1778 (C=O).

2ꢀEthynylꢀ9,10ꢀanthraquinone, 1ꢀdiazonium
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2095
5ꢀHydroxyꢀ3ꢀ(2,3,5,6ꢀtetramethylbenzoyl)ꢀ1Hꢀnaphthoꢀ
[2,3ꢀg]indazoleꢀ6,11ꢀdione (7). 5ꢀAcetoxyꢀ3ꢀ(2,3,5,6ꢀtetraꢀ
methylbenzoyl)ꢀ1Hꢀnaphtho[2,3ꢀg]indazoleꢀ6,11ꢀdione (6) (0.23 g,
0.5 mmol) was added to a stirred solution of KOH (0.4 g, 7 mmol)
in ethanol (4 mL). The reaction mixture was kept at ~20 C for
1 h. After completion of the reaction, the mixture was diluted
with water (20 mL) and acidified with HCl. The precipitate that
formed was filtered off, washed with water and methanol, dried
at 130 C for 1 h, and purified by column chromatography on
SiO2 (d = 1 cm, h = 3 cm) with CH2Cl2 as an eluent. Yield 0.16 g
(76%), m.p. 317—318 C. 1H NMR (DMSOꢀd6), : 1.91 (s, 6 H,
C(14)Me, C(18)Me); 2.19 (s, 6 H, C(15)Me, C(17)Me); 7.06
(s, 1 H, H(16)); 7.97—7.99 (m, 2 H, H(8), H(9)); 8.06 (br.s, 1 H,
H(4)); 8.20—8.22, 8.26—8.29 (both m, 1 H each, H(7), H(10));
12.04 (s, 1 H, NH); 14.48 (s, 1 H, OH). The 13C NMR spectrum
of compound 7 was not recorded because of its low solubility.
HRMS, found: m/z 424.1414 [M]+. C26H20N2O4. Calculated:
M = 424.1418. IR, /cm–1: 1614, 1639 (C=O).
1ꢀEthynylꢀ2,3,5,6ꢀtetramethylbenzene (9). A mixture of
2ꢀmethylꢀ4ꢀ(2,3,5,6ꢀtetramethylphenyl)butꢀ3ꢀynꢀ2ꢀol18 (4.32 g,
20 mmol) and KOH (1.46 g) was refluxed in anhydrous toluene
(50 mL) for 2 h. The final mixture was purified by column chroꢀ
matography on Al2O3 (d = 38 mm, h = 120 mm) and SiO2
(d = 38 mm, h = 40 mm) with toluene as an eluent (V = 4 L). The
solvent was removed in vacuo. Yield 1.75 g (55%), m.p. 50—51 C
(from hexane). 1H NMR (CDCl3), : 2.28 (s, 6 H, C(3)Me,
C(5)Me); 2.45 (s, 6 H, C(2)Me, C(6)Me); 3.53 (s, 1 H, (CC)H);
6.99 (s, 1 H, H(4)). 13C NMR (CDCl3), : 17.39 (C(3)CH3,
C(5)CH3); 19.76 (C(2)CH3, C(6)CH3); 82.27 (CCH); 84.35;
122.03; 131.51; 133.20; 136.48. HRMS, found: m/z 158.1091
[M]+. C12H14. Calculated: M = 158.1090. IR, /cm–1: 2090
(CC); 3284 (C—H).
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The assistance from the Chemical Service Center of
the Siberian Branch of the Russian Academy of Sciences
is gratefully acknowledged.
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Eur. J. Org. Chem., 1999, 1075.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ00257a
(2010—2012) and the Presidium of the Russian Academy
of Sciences (Program 5.9.3. (2009—2012)).
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Received May 10, 2012;
in revised form October 22, 2012