Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with amines and hydrazines. A new and efficient synthetic approach to 3-amino-5,8- dichloroflavazoles

Article abstract of DOI:10.1016/j.tet.2011.03.104

Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with primary amines and hydrazines under different experimental conditions were investigated. Alkylamines provided novel 3-alkylamino-5,8-dichloro-2-cyanoquinoxalines and N-alkyl-(5,8-dichloro-3-alkylamino-

Full text of DOI:10.1016/j.tet.2011.03.104

Tetrahedron 67 (2011) 4123e4129
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Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with amines and hydrazines.
A new and efficient synthetic approach to 3-amino-5,8-dichloroflavazoles
*
ꢀ
ꢀ
ꢀ
Antonio Guirado , Jose I. Lopez Sanchez, Delia Bautista
ꢀ
Departamento de Química Organica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30071 Murcia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with primary amines and hydrazines under different
experimental conditions were investigated. Alkylamines provided novel 3-alkylamino-5,8-dichloro-2-
cyanoquinoxalines and N-alkyl-(5,8-dichloro-3-alkylamino-2-quinoxalinyl)carboxamidines in high
yields. Alkylhydrazines and lithium arylhydrazinides gave previously unattainable 1-alkyl-3-amino-
5,8-dichloroflavazoles and 3-amino-1-aryl-5,8-dichloroflavazoles in good to near quantitative yields
whose molecular structure was confirmed by X-ray crystallography of 3-[N,N-bis(4-chlorobenzoyl)
amino]-5,8-dichloro-1-phenylflavazole. Reaction with hydrazine gave 5,8-dichloro-3-hydrazino-2-qui-
noxalinylcarboxamidrazone quantitatively, which was converted to the parent compound of this class of
flavazoles, 3-amino-5,8-dichloroflavazole, in high yield by a pyrolytic process involving loss of hydrazine.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 February 2011
Received in revised form 24 March 2011
Accepted 29 March 2011
Available online 8 April 2011
Keywords:
Flavazoles
Quinoxalines
Amines
Hydrazines
Lithium hydrazinides
1. Introduction
a plausible approach to unprecedented 3-amino-5,8-dichloro-
flavazoles, whose synthesis appears to be unfeasible by previously
established preparative methods. Thus, 2-cyano-3,5,8-trichloroqui-
noxaline could be considered as a good intermediate for the synthesis
of compounds 7,8,10. However, it is an unknown substance whose
preparation would involve either 3,6-dichloro-1,2-phenylenediamine
or 4,7-dichlorobenzofuroxane. Nevertheless, these are rare, expensive
and unavailable intermediates in practice. The most efficient prepa-
rations yielded only 15%36,41 and 10%,42,43 respectively. On the other
hand, chlorination at C(5) and C(8) of the flavazole rings system seems
unfeasible since the only chlorination products reported for flavazoles
are 3-chloroflavazole1 and 1-(p-chlorophenyl)flavazole.44
Recently, we developed a newand efficient synthetic approach to
7,10-dichlorofluoflavines.36 This paper reported the first synthesis of
5,8-dichloro-2,3-dicyanoquinoxaline 3, which was used as a key
intermediate able to act as a synthetic equivalent of unavailable
2,3,5,8-tetrachloroquinoxaline. Quinoxaline 3 reacted with subs-
tituted 1,2-diaminobenzenes providing the targeted new fluoflavine
products in fair to high yields. Compound 3 was easily obtained in
quantitative yield36 from 3,3,6,6-tetrachloro-1,2-cyclohexanodione
1 (Scheme 1), a cheap and readily available intermediate,40 which
we used in developing efficient synthetic methods for different
families of chlorinated phenazines37e40 as well as specifically chlo-
rinated 1,2-epoxycyclopentane-1-carboxylic acids and their alkyl
esters.45 Given that 1 can be used as a synthetic equivalent of un-
available 3,6-dichloro-1,2-benzoquinone, we successfully attemp-
ted to react it with diaminomaleonitrile 2 to provide product 3 in
quantitative yield (Scheme 1).
Over the last years the chemistry of flavazoles has received
much attention mainly due to the pharmacological properties.1e11
These substances have also been reported useful as dyes,12e15 as
photoinitiators for free radical polymerization reactions,16 and as
UV filters in the manufacture of skin lotions.17 Particularly, 3-ami-
noflavazole is currently under intense investigation as a specific
inhibitor of certain proteins.3,4,18
The preferred methodology for preparing 3-aminoflavazoles
uses 3-chloro-2-cyanoquinoxaline as starting material,3,18e21 which is
obtainable from benzofuroxane,22e28 or from 2-carboxamido-3-
hydroxyquinoxaline.20,29 Other methodologies involve intermediates
with the previously formed flavazole ring system. These compounds
are subjected to C(3)-chlorination and subsequent amination,30 Hof-
mann degradation (of 3-carboxamidoflavazoles)30 or Curtius rear-
rangement (of 3-hydrazinocarbonylflavazoles).31e35 It should be
pointed out that the need for 3-aminoflavazoles functionalized at the
benzene ring has been underlined in order to establish a good re-
lationship between structure and biological activity of these sub-
stances.3 In view of this, and regarding our methodology for the
synthesis of selectively chlorinated heterocyclic compounds
throughout polychloro-cyclohexanediones,36e40 which demonstrated
to be excellent synthetic equivalents of unavailable chlorinated o-
benzoquinones, we recognised the opportunity to investigate
* Corresponding author. Tel.: þ34 868 887 490; fax: þ34 868 884 148; e-mail
address: anguir@um.es (A. Guirado).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.104

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A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
Scheme 1.
On exploring reactions between nucleophilic reagents and 5,8-
alternative of addition. This was evidenced by experiments carried
out by lowering the amount of amine until a 1:1 ratio. Under these
conditions the formed products were 3-amino-5,8-dichloro-2-
cyanoquinoxalines 5, which were isolated in high yield and whose
formation corresponds to selective substitution in complete ab-
sence of competitive addition (Scheme 1). The reaction with am-
monia was similar. Moreover, the ability of compounds 5 to
undergo addition to the stationary cyano group was corroborated
by treatment with methylamine, propylamine and hydrazine at rt,
since these reactions provided the corresponding carboxamidines 4
and carboxamidrazones 6, respectively, in near quantitative yields.
The synthesis of compounds 4,5,6 has not been previously reported.
Taking into consideration that dinucleophilic reagents could
operate accordingly to experiments described above, promoting
first substitution followed by intramolecular addition, we envisaged
an attractive possibility of development of a good new preparative
method for previously unattainable 3-amino-5,8-dichloroflavazoles
by direct reaction of intermediate 3 with hydrazines, as shown in
Scheme 2. Working on this idea the reaction of 3 with alkylhy-
drazines at rt gave successful results. As expected, direct formation
of 1-alkyl-3-amino-5,8-dichloroflavazoles 7, in near quantitative
yields, was observed. However, a similar treatment of 3 with hy-
drazine (ratio 1:1) gave a disappointing result, leading to a complex
mixture of reaction products. The main component of this mixture
gave a mass spectrum proving to be a dimeric compound 12 instead
of 3-amino-5,8-dichloroflavazole 10. It should be noted that for-
mation of 12 would proceed from a cyanoquinoxalinyl hydrazine
intermediate, which would attack starting material molecules 3.
Such an intermolecular reactionwould be faster than the alternative
internal addition process to the vicinal cyano group leading to the
corresponding flavazole 10. This is a contrary behaviour to that ob-
served with alkylhydrazines. Nevertheless, it can be reasonably
explained in view of the expected electron withdrawing effect of
a quinoxalinyl group lowering the nucleophilic activity of hydrazine,
but being compensated by the presence of N-alkyl substituents. The
dichloro-2,3-dicyanoquinoxaline 3 we found a crucially different
chemicalbehaviourinthiscompound from thatof its non-chlorinated
analogous, 2,3-dicyanoquinoxaline. For example, 2,3-dicyanoqui-
noxaline reacts with ammonia46 or hydrazine47e49 undergoing nu-
cleophilic addition to cyano groups, whereas 3 gives products
involving nucleophilic aromatic substitution of a cyano group. It
seems clear that the opposite behaviour between these compounds
would be caused by the conjunction of electro-withdrawing groups
present in 3. Related reactions in quinoxaline derivatives have been
described for 2,3-dichloroquinoxaline47,50 and 3-chloro-2-cyanoqui-
noxaline,19,25 where nucleophilic displacement of the chlorine atom
occurs, but not for a cyano group. These facts strongly suggested the
opportunity to expand the range of synthetic applications of our
preparative methodologytoachievethesynthesis ofthetitleflavazole
compounds.
2. Results and discussion
Room temperature treatment of 5,8-dichloro-2,3-dicyanoqui-
noxaline 3 with methylamine or propylamine in excess, in the
presence of triethylamine, gave single products that were isolated
and identified as N-alkyl-(3-alkylamino-5,8-dichloro-2-quinox-
alinyl)carboxamidines 4 (Scheme 1). Yields were near to quantita-
tive. Obviously, the formation of these products implies two
different nucleophilic attack processes by part of alkylamine mol-
ecules: addition to cyano group and cyano group substitution.
Considering that the electronic effect of an amino group attached to
an aromatic nucleus causes a drastic lowering on electrophilic ac-
tivity, the observed disparity in behaviour between both cyano
groups of 3 is explainable as result of a reaction sequence involving
a first substitution process followed by a second addition step,
rather than a reaction occurring in the inverse order (first addition
followed by substitution). In this manner, a first substitution attack
would prevent a second substitution process, leaving only the

A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
4125
Scheme 2.
result of a similar reaction, but increasing the hydrazine amount
(ratio 1:2), quantitatively yielding 5,8-dichloro-3-hydrazino-2-qui-
noxalinylcarboxamidrazone 9 provided support to this hypothesis.
In spite of this fact, the targeted parent compound of this family of
flavazoles could be achieved by pyrolysis of 9, since when it was
heated up to 200 ꢀC it gave 3-amino-5,8-dichloroflavazole 10 in high
yield by loss of hydrazine.
In conclusion, a proficient and general new method for the
synthesis of 3-amino-5,8-dichloroflavazoles on the basis of 5,8-
dichloro-2,3-dicyanoquinoxaline chemistry is reported. Good
yields and easy availability of starting materials are valuable,
noteworthy advantages of the method, which allows a privileged
access to previously unattainable products. The high interest of 5,8-
dichloro-2,3-dicyanoquinoxaline as synthetic intermediate for
a wide range of quinoxaline derivatives has also been demon-
strated. Not only are the prepared compounds of interest in
themselves, but also their chlorine substituents suggest an attrac-
tive synthetic potential to be explored.
Continuing the work in this project, we attempted un-
successfully the synthesis of 3-amino-1-aryl-5,8-dichloroflavazoles
8 by direct reaction of intermediate 3 with arylhydrazines. It was
presumed that this failed result could be due to a relatively weaker
nucleophilic activity of arylhydrazines than alkylhydrazines. This
assumption was confirmed by testing the synthesis with lithium
arylhydrazinides generated by treatment arylhydrazines with LDA.
In this case the corresponding flavazoles 8 were obtained in mod-
erate to high yields. Unfortunately, single crystals suitable for an X-
ray diffraction analysis of one of the prepared flavazoles could not
be obtained despite intensive effort. Instead, we were successful in
an attempt to analyze a dibenzoylated derivative. The molecular
structure determined corresponds to 3-[N,N-bis(4-chlorobenzoyl)
amino]-5,8-dichloro-1-phenylflavazole 11, (Fig. 1). Selected intra-
molecular distances and bond angles for this crystal structure are
given in Table 1. Fig. 2 corresponds to a perspective of the crystal
packing, showing hydrogen interactions of molecules with a double
chain arrangement.
3. Experimental
3.1. General
NMR spectra were determined on Bruker AV-200, Bruker AV-
300 or Bruker AV-400 with tetramethylsilane as internal refer-
ence. Electron-impact mass spectra were obtained on Thermoquest
trace MS spectrometer under an ionizing voltage of 70 eV. IR
spectra (Nujol emulsions) were recorded on a Nicolet Impact 400
Spectrometer. Microanalyses were performed on a Carlo Erba EA-
€
1108 analyzer. Melting points were determined on a Buchi Melt-
ing point B-540, and are uncorrected. Compounds 1 and 3 were
prepared as previously described.36,40

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A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
Fig. 2. A perspective of the crystal packing of 11, showing the hydrogen interactions of
molecules with a double chain arrangement.
Fig. 1. Thermal ellipsoid plot (50% level) of compound 11 in the crystal.
149 (13), 88 (10), 57 (51); IR (Nujol) 3500, 3381, 1641, 1567, 1535,
Table 1
1229, 1192, 1167, 1133, 1109, 1052, 968, 935, 815, 794, 663 cmꢁ1
.
Selected bond lengths and bond angles in crystal structure of 11
ꢁ
Bond lengths (A)
3.2.2. N-Propyl-(5,8-dichloro-3-propylamino-2-quinoxalinyl)carbox-
amidine (4b). Yield: 92%; crystallization from methanol gave yel-
low needles; mp 80e81 ꢀC. (Found C 53.07; H 5.57; N 20.65;
Cl(1)eC(1)
C(1)eC(2)
C(2)eC(3)
C(4)eC(5)
N(1)eC(5)
N(1)eC(6)
1.730(2)
1.359(3)
1.409(3)
1.430(3)
1.355(3)
1.323(3)
N(4)eC(8)
C(6)eC(7)
N(2)eC(7)
N(2)eN(3)
N(5)eC(7)
N(5)eC(10)
1.314(3)
1.426(3)
1.310(3)
1.378(2)
1.413(3)
1.430(3)
C15H19Cl2N5 requires C 52.95; H 5.63; N 20.58); 1H NMR
d (CDCl3,
300 MHz) 1.02e1.09 (m, 6H, CH3), 1.69e1.82 (m, 4H, CH2CH3), 3.18
(t, 2H, J¼6.8 Hz, NCH2Et), 3.60 (q, 2H, J¼6.6 Hz, NHCH2Et), 5.82 (br s,
2H, NH2), 7.25 (d, 1H, J¼8.2 Hz, H-7), 7.54 (d, 1H, J¼8.2 Hz, H-6),
Bond angles (ꢀ)
N(2)eC(7)eC(6)
C(7)eN(5)eC(10)
C(7)eN(5)eC(11)
C(11)eN(5)eC(10)
C(7)eN(2)eN(3)
C(8)eN(3)eN(2)
111.46(18)
116.30(16)
118.06(16)
119.32(16)
107.41(17)
110.14(16)
N(2)eN(3)eC(41)
N(3)eC(8)eC(6)
C(8)eN(3)eC(41)
N(5)eC(10)eC(21)
N(5)eC(7)eC(6)
N(2)eC(7)eN(5)
119.84(16)
106.83(17)
130.02(17)
115.83(17)
127.97(19)
120.55(18)
10.78 (br s, 1H, NH); 13C NMR
d (CDCl3, 75.4 MHz) 11.84 (CH3), 12.01
(CH3), 22.07 (CH2), 23.71 (CH2), 42.61 (CH2), 49.90 (CH2), 122.45
(CH), 127.89 (C), 129.77 (CH), 131.18 (C), 131.39 (C), 133.56 (C), 141.04
(C), 152.09 (C), 154.26 (C); EM, m/z (%) 341 (Mþþ2, 12), 339 (Mþ, 19),
312 (67), 310 (100) 293 (14), 253 (60), 251 (86), 238 (11),197 (19); IR
(Nujol) 3433, 3326, 3165, 3071, 2963, 2924, 2870, 1643, 1569, 1534,
1449, 1377, 1353, 1333, 1289, 1224, 1192, 1102, 976, 934, 809, 765,
703, 669 cmꢁ1
.
3.2. Preparation of N-alkyl-(3-alkylamino-5,8-dichloro-2-
quinoxalinyl)carboxamidines 4
3.3. Preparation of 3-amino-5,8-dichloro-2-
cyanoquinoxalines 5
To a solution of 3 (2 mmol) in THF (10 ml) a solution of the
corresponding amine (6 mmol) and triethylamine (2.2 mmol) in
THF (5 ml) was added dropwise. The mixture was stirred at rt for
3 h. Then the solvent was concentrated to dryness under reduced
pressure and the solid obtained was washed with water, collected
by filtration and crystallized from the appropriate solvent.
To an ice-cooled solution of 3 (2 mmol) in THF (10 ml) a solution
of the corresponding amine (2 mmol) and triethylamine
(2.2 mmol) in THF (5 ml) was added dropwise, keeping the tem-
perature below 0 ꢀC. In the case of compound 5a a 5% solution of
ammoniaeTHF was used and the temperature was raised to rt. The
mixture was stirred until the consumption of 3 (detected by TLC).
Then the solvent was concentrated to dryness under reduced
pressure and the solid obtained was washed with water, collected
by filtration and crystallized from the appropriate solvent.
3.2.1. N-Methyl-(5,8-dichloro-3-methylamino-2-quinoxalinyl)car-
boxamidine (4a). Yield: 95%; crystallization from ethanol gave yel-
low needles; mp 155e156 ꢀC. (Found C 46.64; H 3.84; N 24.57;
C11H11Cl2N5 requires C 46.50; H 3.90; N 24.65); 1H NMR
d
(CDCl3,
, 6.76 (br s, 2H,
NH2), 7.42 (d,1H, J¼8.3 Hz, H-7), 7.69 (d,1H, J¼8.3 Hz, H-6),10.81 (br
s, 1H, NH); 13C NMR
(CDCl3, 100.8 MHz) 27.12 (CH3), 35.56 (CH3),
400 MHz) 3.03 (s, 3H, NCH3)
*
, 3.04 (s, 3H, NHCH3)
*
3.3.1. 3-Amino-5,8-dichloro-2-cyanoquinoxaline (5a). Yield: 95%;
crystallization from acetonitrile gave yellow plates; mp >320 ꢀC.
(dec). (Found C 45.36; H 1.72; N 23.36; C9H4Cl2N4 requires C 45.22;
d
122.82 (CH),126.82 (C),130.14 (CH),130.56 (C),130.61 (C),134.11 (C),
140.07 (C), 152.19 (C), 155.73 (C); MS m/z (%) 285 (Mþþ2, 64), 283
(Mþ, 100), 268 (21), 255 (21), 253 (35), 238 (47), 198 (25), 171 (12),
H 1.69; N 23.44); 1H NMR
d (DMSO-d6, 400 MHz) 7.54 (d, 1H,
J¼8.2 Hz, H-7), 7.83 (d, 1H, J¼8.2 Hz, H-6), 7.95 (br s, 2H, NH2); 13
C

A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
4127
NMR
d
(DMSO-d6, 100.8 MHz) 114.69 (C), 120.85 (C), 124.60 (CH),
3355, 1633, 1606, 1579, 1538, 1397, 1233, 1191, 1129, 1108, 968, 945,
840, 795, 665 cmꢁ1
127.43 (C), 131.15 (C), 132.54 (CH), 132.82 (C), 140.58 (C), 153.30 (C);
EM, m/z (%) 240 (Mþþ2, 67), 238 (Mþ, 100), 213 (27), 211 (40), 188
(21),186 (31), 158 (24),151 (32),144 (27),124 (22), 109 (31), 88 (27);
IR (Nujol) 3407, 3323, 3242, 3215, 2239, 1643, 1557, 1430, 1355,
.
3.4.3. 5,8-Dichloro-3-propylamino-2-quinoxalinylcarboxamidrazone
(6c). Yield: 95%; crystallization from methanolewater gave yellow
needles; mp 130e132 ꢀC. (Found C 45.91; H 4.58; N 26.79;
1225, 1206, 1105, 1154, 957, 944, 836, 665 cmꢁ1
.
C12H14Cl2N6 requires C 46.02; H 4.51; N 26.83); 1H NMR
d (DMSO-
3.3.2. 5,8-Dichloro-2-cyano-3-methylaminoquinoxaline (5b). Yield:
92%; crystallization from ethanol gave yellow needles; mp
249e251 ꢀC (Found C 47.54; H 2.45; N 22.23; C10H6Cl2N4 requires C
d6, 400 MHz) 0.96 (t, 3H, J¼7.3 Hz, CH3), 1.67 (sex, 2H, J¼7.3 Hz,
CH2CH3), 3.49e3.54 (m, 2H, CH2Et), 6.00 (br s, 2H, NH2), 6.14 (br s,
2H, NH2), 7.39 (d,1H, J¼8.2 Hz, H-7), 7.63 (d,1H, J¼8.2 Hz, H-6), 9.87
47.46; H 2.39; N 22.14); 1H NMR
d
(DMSO-d6, 400 MHz) 2.98 (d, 3H,
(t, 1H, J¼5.0 Hz, NH); 13C NMR
d (DMSO-d6, 100.8 MHz) 11.73 (CH3),
J¼4.3 Hz, CH3), 7.53 (d, 1H, J¼8.2 Hz, H-7), 7.84 (d, 1H, J¼8.2 Hz, H-
21.63 (CH2), 42.16 (CH2), 122.79 (CH),126.71 (C),128.92 (CH),129.99
(C), 131.15 (C), 134.20 (C), 138.66 (C), 143.75 (C), 150.38 (C); EM, m/z
(%) 314 (Mþþ2, 26), 312 (Mþ, 38), 298 (21), 296 (32), 285 (62), 283
(100), 268 (53), 266 (77), 239 (40), 214 (26), 197 (33), 186 (22), 158
(18), 149 (23), 124 (14), 88 (19); IR (Nujol) 3443, 3346, 3246, 1634,
6), 8.18 (q, 1H, J¼4.3 Hz, NH); 13C NMR
d (DMSO-d6, 50.4 MHz)
28.03 (CH3), 114.54 (C), 121.87 (C), 124.45 (CH), 127.70 (C), 131.12 (C),
132.35 (C), 132.53 (CH), 140.32 (C), 152.02 (C); EM, m/z (%) 254
(Mþþ2, 65), 252 (Mþ, 100), 227 (8), 225 (13) 198 (31), 171 (12), 158
(13), 144 (7), 109 (8), 88 (9); IR (Nujol) 3392, 2231, 1599, 1574, 1445,
1567, 1531, 1225, 1192, 1132, 1106, 979, 941, 817, 668 cmꢁ1
.
1339, 1227, 1199, 1155, 1105, 967, 951, 827, 797, 698, 665, 607 cmꢁ1
.
3.5. Preparation of 1-alkyl-3-amino-5,8-dichloroflavazoles 7
3.3.3. 5,8-Dichloro-2-cyano-3-propylaminoquinoxaline (5c). Yield:
90%; crystallization from acetonitrile gave yellow plates; mp
177e179 ꢀC (Found C 51.38; H 3.54; N 19.88; C12H10Cl2N4 requires C
To a solution of 3 (2 mmol) in THF (10 ml) a solution of the cor-
responding alkylhydrazine (3 mmol) and triethylamine (2.2 mmol)
inTHF (5 ml) was added dropwise. The mixturewas stirred at rt until
the consumption of 3 (detected by TLC). Then the solvent was con-
centrated to dryness under reduced pressure and the solid obtained
was washed with water, collected by filtration and crystallized from
the appropriatesolvent. In the case of compound 7b the solvent used
was DMFtoallowa highersolubilityof thecommercial oxalatesaltof
ethylhydrazine used. The isolation of product was carried out by
pouring the reaction mixture into cold brine (200 ml), followed by
filtration and crystallization of the precipitated solid.
51.27; H 3.59; N 19.93); 1H NMR
d (CDCl3, 400 MHz) 1.06 (t, 3H,
J¼7.2 Hz, CH3), 1.79 (sex, 2H, J¼7.2 Hz, CH2CH3), 3.65 (q, 2H,
J¼7.2 Hz, CH2Et), 5.70 (br s, 1H, NH), 7.42 (d, 1H, J¼8.2 Hz, H-7), 7.68
(d, 1H, J¼8.2 Hz, H-6); 13C NMR
d (CDCl3, 100.8 MHz) 11.56 (CH3),
22.10 (CH2), 43.50 (CH2), 114.22 (C), 120.74 (C), 125.12 (CH), 129.23
(C), 132.46 (C), 132.55 (CH), 133.72 (C), 140.74 (C), 151.55 (C); EM,
m/z (%) 282 (Mþþ2, 27), 280 (Mþ, 41), 267 (9), 265 (14), 253 (49),
251 (70), 240 (66), 238 (100), 213 (16), 197 (37), 170 (12), 134 (13),
88 (9); IR (Nujol) 3365, 2235,1598,1567,1342,1225,1153,1104, 982,
945, 829, 665 cmꢁ1
.
3.5.1. 3-Amino-5,8-dichloro-1-methylflavazole (7a). Yield: 98%; crys-
tallization from ethanol gave red needles; mp 217e219 ꢀC. (Found C
44.93; H 2.72; N 26.03; C10H7Cl2N5 requires C 44.80; H 2.63; N 26.12.);
3.4. Preparation of 3-alkylamino-5,8-dichloro-2-
quinoxalinylcarboxamidrazones 6
1H NMR
d (DMSO-d6, 300 MHz) 3.83 (s, 3H, CH3), 6.40 (br s, 2H, NH2),
To a solution of the corresponding 3-amino-5,8-dichloro-2-
cyanoquinoxaline 5 (2 mmol) in THF (10 ml) an aqueous solution of
hydrazine 55% (2 ml) was added dropwise. The mixture was stirred
at rt for 4 h. Then the solvent was concentrated to dryness under
reduced pressure and the solid obtained was washed with water,
collected by filtration and crystallized from the appropriate solvent.
7.67 (d, 1H, J¼8.1 Hz, H-6), 7.84 (d, 1H, J¼8.1 Hz, H-7); 13C NMR
d
(DMSO-d6, 75.4 MHz) 33.16 (CH3), 125.07 (CH), 129.35 (C), 129.82
(CH),131.69 (C),131.98 (C),134.97 (C),138.62 (C),141.59 (C),147.89 (C);
MS m/z (%) 269 (Mþþ2, 63), 267 (Mþ,100), 241 (8), 239 (13),199 (11),
197 (18), 161 (12), 134 (13); IR (Nujol) 3388, 3302, 1631, 1607, 1559,
1204, 1186, 1094, 1050, 986, 938, 836 cmꢁ1
.
3.4.1. 3-Amino-5,8-dichloro-2-quinoxalinylcarboxamidrazone
(6a). Yield: 89%; crystallization from ethanol gave yellow needles;
mp >320 ꢀC (dec) (Found C 39.99; H 2.91; N 30.92; C9H8Cl2N6 re-
3.5.2. 3-Amino-5,8-dichloro-1-ethylflavazole (7b). Yield: 96%; crys-
tallization from acetonitrile gave red needles; mp 174e176 ꢀC.
(Found C 46.95; H 3.17; N 24.73; C11H9Cl2N5 requires C 46.83; H 3.22;
quires C 39.87; H 2.97; N 31.00); 1H NMR
d
(DMSO-d6, 300 MHz)
N 24.82); 1H NMR
d
(CDCl3, 400 MHz) 1.54 (t, 3H, J¼7.1 Hz, CH3), 4.49
5.98 (br s, 2H, NH2), 6.13 (br s, 2H, NH2), 7.45 (d, 1H, J¼8.3 Hz, H-7),
(q, 2H, J¼7.1 Hz, CH2), 4.90 (br s, 2H, NH2), 7.64 (d,1H, J¼8.0 Hz, H-6),
7.66 (d,1H, J¼8.3 Hz, H-6), 7.99 (br s,1H, NH), 9.15 (br s,1H, NH); 13C
7.80 (d, 1H, J¼8.0 Hz, H-7); 13C NMR
d (CDCl3, 100.8 MHz) 14.29
NMR
d
(DMSO-d6, 75.4 MHz) 123.06 (CH), 126.39 (C), 128.99 (CH),
(CH3), 41.71 (CH2), 125.42 (CH), 129.74 (CH), 130.70 (C), 130.81 (C),
132.94 (C), 136.45 (C), 139.79 (C), 141.93 (C), 146.69 (C); MS m/z (%)
283 (Mþþ2, 55), 281 (Mþ, 86), 268 (64), 266 (100), 241 (18), 239 (27),
199 (15),197 (31),161 (19),134(16);IR (Nujol) 3285, 3160,1633,1607,
130.07 (C), 131.77 (C), 134.26 (C), 138.74 (C), 143.50 (C), 151.76 (C);
EM, m/z (%) 272 (Mþþ2, 69), 270 (Mþ, 100), 241 (49), 214 (30), 186
(19), 158 (11), 149 (14), 124 (7), 88 (7); IR (Nujol) 3428, 3303, 1651,
1605, 1577, 1239, 1131, 1108, 954, 909, 807, 743, 667 cmꢁ1
.
1566, 1394, 1199, 1180, 1122, 1090, 959, 938, 822, 696, 665 cmꢁ1
.
3.4.2. 5,8-Dichloro-3-methylamino-2-quinoxalinylcarboxamidrazone
(6b). Yield: 91%; crystallization from methanol gave yellow nee-
dles; mp 210e220 ꢀC (dec) (Found C 42.20; H 3.58; N 29.53;
3.5.3. 3-Amino-5,8-dichloro-1-(2-hydroxyethyl)flavazole
(7c). Yield: 92%; crystallization from acetonitrile gave purple
plates; mp 260e261 ꢀC. (Found
C
44.26;
H
3.11;
N
23.57;
C10H10Cl2N6 requires C 42.12; H 3.53; N 29.47); 1H NMR
d
(DMSO-
C11H9Cl2N5O requires C 44.32; H 3.04; N 23.49); 1H NMR
d
(DMSO-
d6, 400 MHz) 3.07 (d, 3H, J¼4.8 Hz, CH3), 5.99 (br s, 2H, NH2), 6.10
d6, 400 MHz): 3.87 (q, 2H, J¼5.8 Hz, CH2OH), 4.33 (t, 2H, J¼5.8 Hz,
(br s, 2H, NH2), 7.41 (d, 1H, J¼8.3 Hz, H-7), 7.64 (d, 1H, J¼8.3 Hz, H-
CH2), 4.75 (t, 1H, J¼5.8 Hz, OH), 6.38 (br s, 2H, NH2), 7.77 (d, 1H,
6), 9.73 (q, 1H, J¼4.8 Hz, NH); 13C NMR
d
(DMSO-d6, 100.8 MHz)
J¼8.1 Hz, H-6), 7.95 (d, 1H, J¼8.1 Hz, H-7); 13C NMR
d (DMSO-d6,
27.36 (CH3), 122.84 (CH), 126.73 (C), 128.96 (CH), 130.01 (C), 131.16
(C), 134.44 (C), 138.67 (C), 143.62 (C), 150.96 (C); EM, m/z (%) 286
(Mþþ2, 35), 284 (Mþ, 51), 270 (60), 268 (100), 253 (44), 239 (16),
199 (18),171 (15),149 (14),127 (10),109 (9),100 (8); IR (Nujol) 3465,
100.8 MHz): 48.69 (CH2), 58.61 (CH2), 125.13 (CH), 129.39 (C),
129.86 (CH), 131.94 (C), 131.96 (C), 135.21 (C), 138.74 (C), 142.21 (C),
147.93 (C); MS m/z (%) 299 (Mþþ2, 51), 297 (Mþ, 65), 268 (64), 266
(100), 253 (27), 239 (34), 212 (17), 197 (36), 170 (13), 161 (18), 134

4128
A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
(16); IR (Nujol) 3354, 3189, 1638, 1607, 1570, 1375, 1220, 1183, 1143,
1096, 1065, 1002, 938, 840, 820 cmꢁ1
the solid obtained was washed with water, collected by filtration
and crystallized from acetonitrile.
.
Yield: 96%; crystallization from acetonitrile gave yellow nee-
3.6. Preparation of 3-amino-1-aryl-5,8-dichloroflavazoles 8
dles; mp 287e296 ꢀC (dec). (Found C 37.93; H 3.30; N 34.39;
C9H9Cl2N7 requires C 37.78; H 3.17; N 34.27); 1H NMR
d (DMSO-d6,
To an ice-cooled solution of 3 (1.2 mmol) in dioxane (3 ml) a so-
lution of the corresponding lithium arylhydrazinide 0.5 M in di-
oxane (1.26 mmol) was added dropwise under nitrogen, keeping the
temperature below 10 ꢀC. The mixture was stirred at rt for 16 h.
Then, the reaction mixture was poured into an aqueous solution of
ammonium chloride 10% (100 ml) and the suspensionwas extracted
with ethyl acetate (2ꢂ75 ml). The organic layer was washed with
water (100 ml) and dried over anhydrous magnesium sulfate. Then
the solution was concentrated to dryness under reduced pressure
and the solid obtained was crystallized in the appropriate solvent.
Lithium arylhydrazinide solutions were prepared a few minutes
before being used by addition under nitrogen of a commercial 1.8 M
LDA solution in heptaneetetrahydrofuraneeethylbenzene to a so-
lution of the corresponding arylhydrazine in dioxane.
400 MHz) 4.88 (br s, 2H, NH2), 5.95 (br s, 2H, NH2), 6.17 (br s, 2H,
NH2), 7.41 (d, 1H, J¼8.2 Hz, H-7), 7.65 (d, 1H, J¼8.2 Hz, H-6), 10.55
(br s, 1H, NH); 13C NMR
d (DMSO-d6, 100.8 MHz) 122.69 (CH),
126.34 (C), 129.02 (CH), 129.98 (C), 131.21 (C), 134.13 (C), 138.43 (C),
143.19 (C),150.30 (C); MS m/z (%) 287 (Mþþ2, 33), 285 (Mþ, 52), 256
(63), 254 (100), 241 (13), 224 (13), 213 (14),198 (12), 171 (9),149 (8),
136 (6); IR (Nujol) 3425, 3355, 3295, 3161, 1638, 1556, 1497, 1320,
1234, 1195, 1154, 1109, 993, 946, 857, 822, 809, 794, 668 cmꢁ1
.
3.8. Preparation of 3-amino-5,8-dichloroflavazole 10
Solid 5,8-dichloro-3-hydrazino-2-quinoxalinylcarboxamidrazone
9 was heated at 200 ꢀC under vacuum for 15 min. Crude 3-amino-5,8-
dichloroflavazole 10 (a red solid) was purified by crystallization in
ethanol.
3.6.1. 3-Amino-5,8-dichloro-1-phenylflavazole (8a). Yield: 67%; crys-
tallization from methanol gave red prisms; mp 226e228 ꢀC. (Found
C 54.69; H 2.69; N 21.28; C15H9Cl2N5 requires C 54.57; H 2.75;
Yield: 83%; crystallization from ethanol gave red needles; mp
293e295 ꢀC. (Found C 42.67; H 2.00; N 27.63; C9H5Cl2N5 requires C
42.54; H 1.98; N 27.56); 1H NMR
d
(DMSO-d6, 400 MHz) 6.21 (br s,
2H, NH2), 7.80 (d,1H, J¼8.1 Hz, H-6), 7.96 (d,1H, J¼8.1 Hz, H-7),12.67
(s, 1H, NH); 13C NMR
(DMSO-d6, 100.8 MHz) 125.34 (CH), 129.55
N 21.21); 1H NMR
d (DMSO-d6, 400 MHz) 6.91 (br s, 2H, NH2), 7.23
(t, 1H, J¼7.7 Hz, H-40), 7.56 (t, 2H, J¼7.7 Hz, H-30,50), 7.92 (d, 1H,
J¼8.1 Hz, H-6), 8.09 (d, 1H, J¼8.1 Hz, H-7), 8.43 (d, 2H, J¼7.7 Hz,
d
(C), 129.66 (CH), 131.37 (C), 131.97 (C), 135.41 (C), 138.74 (C), 143.29
(C), 148.53 (C); MS m/z (%) 255 (Mþþ2, 66), 253 (Mþ, 100), 211 (13),
198 (28), 170 (15), 161 (11), 149 (20); IR (Nujol) 3455, 3315, 1619,
H-20,60); 13C NMR
d (DMSO-d6, 100.8 MHz) 117.54 (CH), 123.99 (CH),
126.47 (CH), 129.18 (CH), 129.85 (C), 130.55 (CH), 132.01 (C), 134.39
(C), 135.74 (C), 138.72 (C), 139.22 (C), 141.25 (C), 149.36 (C); MS m/z
(%) 331 (Mþþ2, 60), 329 (Mþ, 100), 313 (4), 287 (12), 252 (6), 226 (7),
164 (11), 134 (6), 91 (15), 77 (38); IR (Nujol) 3329, 3183, 1597, 1567,
1579, 1555, 1276, 1199, 1128, 1092, 958, 940, 824, 690, 667 cmꢁ1
.
3.9. Preparation of 3-[N,N-bis(4-chlorobenzoyl)amino]-5,8-
dichloro-1-phenylflavazole 11
1505, 1393, 1262, 1196, 1117, 1092, 967, 941, 821, 751, 687 cmꢁ1
.
3.6.2. 3-Amino-5,8-dichloro-1-(4-methoxyphenyl)flavazole
(8b). Yield: 78%; crystallization from acetonitrile gave red plates;
mp 191e193 ꢀC. (Found C 52.48; H 3.01; N 19.37; C16H11Cl2N5O re-
To a solution of 8a (1 mmol) and triethylamine (10 mmol) in
dichloromethane (15 ml) a solution of p-chlorobenzoyl chloride
(10 mmol) in dichloromethane (6 ml) was added dropwise. The
mixture under nitrogen was stirred at rt for 12 h. Then the solution
was washed twice with aqueous solution of sodium bicarbonate 5%
(30 ml). The organic layer was dried over anhydrous magnesium
sulfate and concentrated to dryness under reduced pressure. The
solid obtained was crystallized in acetonitrile.
quiresC 53.35;H 3.08; N 19.44); 1H NMR
d (DMSO-d6, 400 MHz) 3.81
(s, 3H, OCH3), 6.85 (br s, 2H, NH2), 7.14 (d, 2H, J¼9.2 Hz, H-30,50), 7.88
(d, 1H, J¼8.1 Hz, H-6), 8.06 (d, 1H, J¼8.1 Hz, H-7), 8.29 (d, 2H,
J¼9.2 Hz, H-20,60); 13C NMR
d (DMSO-d6, 100.8 MHz) 55.33 (CH3),
114.40 (CH), 119.19 (CH), 126.16 (CH), 129.75 (C), 130.48 (CH), 132.05
(C),132.64 (C),134.04 (C),135.57 (C),138.84 (C),140.62 (C),149.11 (C),
155.97 (C); MS m/z (%) 361 (Mþþ2, 66), 359 (Mþ, 100), 346 (47), 344
(68), 316 (9), 302 (6), 179 (7), 92 (6), 78 (20); IR (Nujol) 3308, 1605,
Yield: 95%; crystallization from acetonitrile gave orange nee-
dles; mp 221e223 ꢀC; 1H NMR
d (DMSO-d6, 300 MHz) 7.34e7.37
(m, 5H), 7.57 (t, 2H, J¼7.7 Hz), 7.81e7.88 (m, 5H), 7.94 (d, 1H,
1565, 1513, 1301, 1246, 1195, 1175, 1033, 969, 943, 824 cmꢁ1
.
J¼8.1 Hz), 8.39 (d, 2H, J¼7.7 Hz); 13C NMR
d (DMSO-d6, 75.4 MHz)
119.75 (CH), 126.61 (CH), 128.14 (CH), 129.13 (CH), 129.40 (CH),
130.59 (CH), 130.80 (CH), 131.69 (C), 132.11 (C), 133.34 (C), 138.48
(C), 138.80 (C), 139. 47 (C), 139.51 (C), 141.72 (C), 141.84 (C), 170.93
(C); HRMS (ESI) m/z: calcd for C29H15Cl4N5O2: 604.9980, found:
604.9968; IR (Nujol) 3467, 2958, 2924, 2853,1704, 1590, 1568, 1504,
1473, 1431, 1356, 1256, 1243, 1191, 1092, 1013, 969, 946, 919, 871,
3.6.3. 3-Amino-1-(4-tert-butylphenyl)-5,8-dichloroflavazole
(8c). Yield: 63%; crystallization from methanol gave red prisms; mp
230e233 ꢀC. (Found C 59.21; H 4.51; N 18.02; C19H17Cl2N5 requires C
59.08; H 4.44; N 18.13); 1H NMR
d (DMSO-d6, 400 MHz) 1.34 (s, 9H,
C(CH3)3), 6.73 (br s, 2H, NH2), 7.57 (d, 2H, J¼8.9 Hz, H-30,50), 7.88 (d,
1H, J¼8.1 Hz, H-6), 8.05 (d, 1H, J¼8.1 Hz, H-7), 8.32 (d, 2H, J¼8.9 Hz,
847, 801, 760, 748, 729, 684, 673 cmꢁ1
.
H-20,60); 13C NMR
d (DMSO-d6, 100.8 MHz) 30.96 (CH3), 33.94 (C),
117.35 (CH), 125.56 (CH), 126.10 (CH), 129.69 (C), 130.24 (CH), 131.85
(C), 133.86 (C), 135.56 (C), 136.56 (C), 138.63 (C), 140.84 (C), 146.45
(C), 148.99 (C); MS m/z (%) 387 (Mþþ2, 22), 385 (Mþ, 33), 372 (63),
370(100), 355 (11), 211 (6),185 (9),171 (39),115 (30); IR (Nujol) 3327,
3.10. X-ray structure determination of compound 11
Crystal data: C30H16Cl7N5O2, Mr¼726.63, triclinic, space group
ꢁ
Pꢁ1, a¼9.3816(5), b¼10.1595(5), c¼16.6314(9) A,
a
¼91.319(2)ꢀ,
3
ꢁ
1609, 1567, 1519, 1267, 1191, 1094, 973, 944, 834, 812, 667 cmꢁ1
.
b
¼91.806(2)ꢀ,
g
¼106.854(2) , V¼1515.48(14) A at ꢁ173 ꢀC; Z¼2,
ꢀ
Dx¼1.592 g cmꢁ3, F(000)¼732,
m
¼0.69 mmꢁ1. Data collection: A
3.7. Preparation of 5,8-dichloro-3-hydrazino-
2-quinoxalinylcarboxamidrazone 9
yellow lath 0.32ꢂ0.13ꢂ0.06 mm was mounted in inert oil on a glass
fibre and transferred to the cold gas stream of the diffractometer
(Bruker SMART APEX CCD). Measurements were performed to
To a solution of 3 (2 mmol) in THF (10 ml) a solution of aqueous
hydrazine (55%; 2 ml) and triethylamine (2.2 mmol) in THF (5 ml)
was added dropwise. The mixture was stirred at rt for 2 h. Then, the
solvent was concentrated to dryness under reduced pressure and
2 a radiation. Of 16,911 mea-
qmax 56ꢀ with monochromated Mo K
sured reflections, 6778 were unique (Rint¼0.0256) and were used
for all calculations. Structure refinement: The structures were re-
fined anisotropically against F2 (program SHELXL-97)51 The

A. Guirado et al. / Tetrahedron 67 (2011) 4123e4129
4129
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Complete crystallographic data (excluding structure factors)
have been deposited at the Cambridge Crystallographic Data Centre
under the number CCDC 809717. Copies may be requested free of
charge from The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, England (E-mail: deposit@ccdc.cam.ac.uk).
3
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Acknowledgements
We gratefully acknowledge the financial support of the
ꢀ
ꢀ
ꢀ
ꢀ
Fundacion Seneca of the Comunidad Autonoma de la Region de
Murcia (project 08755/PI/08).
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Supplementary data
Org. Biomol. Chem. 2004, 2, 2507.
X-ray structural data of compound 11. 13C and 1H NMR spectra of
compounds 4e11. Supplementary data related to this article can be
found online at doi:10.1016/j.tet.2011.03.104.
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