Synthesis of 3-substituted 2-amino-1-hydroxy-1H-Indole-5, 6-dicarbonitriles

Article abstract of DOI:10.1007/s10593-012-1010-6

A method of synthesizing new 3-substituted 2-amino-1-hydroxy-1H-indole-5, 6-dicarbonitriles has been developed based on the reductive cyclization of substituted 4-cyanomethyl-5-nitrophthalonitriles.

Full text of DOI:10.1007/s10593-012-1010-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
SYNTHESIS OF 3-SUBSTITUTED 2-AMINO-
1-HYDROXY-1H-INDOLE-5,6-DICARBONITRILES
S. I. Filimonov1*, Zh. V. Chirkova1, V. S. Sharunov1, I. G. Abramov1,
G. A. Stashina2, S. I. Firgang2, and K. Yu. Suponitsky3
A method of synthesizing new 3-substituted 2-amino-1-hydroxy-1H-indole-5,6-dicarbonitriles has been
developed based on the reductive cyclization of substituted 4-cyanomethyl-5-nitrophthalonitriles.
Keywords: 2,1-benzisoxazoles, 1-hydroxy-1H-indole-5,6-dicarbonitriles, phthalonitriles, C-nucleophi-
lic substitution, reductive cyclization.
Interest in hydroxyindoles is determined by their role in biochemistry [1-4]. In the last time,
investigations on the preparation of these heterocycles have been developing intensively. One of the main
methods of synthesizing hydroxyindoles is the oxidation of 2,3-dihydroindoles, obtained by the reduction of the
corresponding indoles [1]. One further direct method of synthesis of 1-hydroxyindoles [4] is the reductive
cyclization of 2-nitrophenylketone [5], 2-nitrostyrene [6], and 2-cyano-2-(2-nitrophenyl)acetate [7] derivatives.
There is not much information in the literature on the synthesis of substituted indole-5,6-dicarbo-nitriles [8-10],
and data on the synthesis of 2-amino-1-hydroxy-1H-indole-5,6-dicarbonitriles are in altogether absent.
The aim of the present work was the synthesis of 2-amino-1-hydroxy-1H-indole-5,6-dicarbonitriles by
the reductive cyclization of products of C-nucleophilic substitution of the bromine atom in 4-bromo-5-nitro-
phthalonitrile (1) (BNPN) with the sodium salts of 3-hydroxy-2-(4-R-phenyl)but-2-enenitriles 2a-d. The
characteristic special features of the chosen highly reactive substrate 1 in SNAr reactions were considered in
[11-15]. It should be mentioned that the substituted ortho-dicarbonitriles are promising for obtaining
hexazocyclanes [16], phthalocyanines [17, 18] and a series of other compounds containing anhydride, imide,
isoindoline, and tetrazole fragments.
2-Amino-1-hydroxyindoles are obtained by the reductive cyclization of ortho-nitrobenzyl cyanides [7],
therefore in the first stage of the investigation it was necessary for us to develop a method of synthesis of
substituted 4-cyanomethyl-5-nitrophthalonitriles based on BNPN. The direct method of obtaining such
_______
*To whom correspondence should be addressed, e-mail: filimonovsi@ystu.ru.
1Yaroslavl State Technical University, 88 Moskovskii Ave., Yaroslavl 150023, Russia.
2N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow
119991, Russia; e-mail: galina_stashina@chemical-block.com.
3A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 119991, Russia; e-mail: kirshik@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 455-464, March, 2012. Original
article submitted February 2, 2011.
0009-3122/12/4803-0427©2012 Springer Science+Business Media, Inc.
427

phthalonitriles is the nucleophilic substitution of the bromine atom in BNPN with benzyl cyanides. However
classical methods of C-nucleophilic substitution according to Makosza (phase transfer catalysis) [19, 20] proved
to be unacceptable for BNPN, since in the presence of aqueous base more favored was the nucleophilic
substitution of the bromine atom by a hydroxyl group with the formation of 4-hydroxy-5-nitrophthalonitrile (1a)
(Scheme 1) [18] as a main product. Also, benzyl cyanides, being CH-acids [20], possess low pKa values
therefore on using dry potassium carbonate, formation of a C-nucleophile is probably reduced to the minimum
while the interaction of BNPN and potassium carbonate appears to be predominant, resulting in the formation of
a σ-complex [21, 22], which also gives nitrophenol 1a as a main product upon hydrolysis. All attempts to carry
out C-nucleophilic substitution of the bromine atom in BNPN using benzyl cyanides as nucleophiles were
unsuccessful; therefore we have used the sodium salts 2a-d obtained by Claisen condensation from benzyl
cyanides and ethyl acetate. These salts are ambident nucleophiles (they have both C- and O-nucleophilic
reaction centers). On interaction of BNPN dissolved in DMF with salts 2a-d at room temperature, the formation
of products 3a-d with a characteristic dark-green color begins straight away, and the reaction is completely
finished after 60-90 min (Scheme 1).
Scheme 1
ONa
N
N
O
Me
N
N
R
Me
Br
+
N+
O
O
N
N
N+
O
O
1
R
2a–d
1) B–
2) H+, H2O
2a–d
N
N
OH
N
N+
O
O
R
N
1a
N
H+
B–
N
N+
O –
N
O
N+
O
R
4a–d
O
N
3a–d
a R = H, b R = Me, c R = Cl, d R = OMe
It was determined experimentally that a twofold excess of salt 2 was necessary for the complete
conversion of BNPN. The second mole of base (salt 2) is probably required for the elimination of the acetyl
group [23]. Elimination of the cyano group was not detected. Products 3a-d were obtained after acidification of
the reaction mixture in a yield not exceeding 60% (Table 1). Attempts to substantially increase the yield of the
desired compounds 3a-d by matching the ratio of reactants, solvents, bases, and the temperature regime were
unsuccessful.
The product of C-substitution dominates, but the product of O-substitution was not isolated successfully
(possibly due to the instability of the resulting enolic esters). It is necessary to mention that, in the reaction
mixture, according to data of 1H NMR spectroscopy the methine proton characteristic of compounds 3 was not
observed, that points to the quinoid form 4, which is more advantageous for similar compounds in basic
solutions [24-26]. Compounds 3a-d, isolated after acidification of the reaction mixture, are white crystalline
428

substances, however, in polar solvents they are partially converted back into the quinoid form 4 (with
characteristic intense green coloration, which on standing at room temperature for a day turns into a yellow-
brown, which is apparently caused by oxidative polymerization of compounds 3). UV spectra were recorded in
various solvents for compounds 3b,d. Thus, in chloroform solution, two absorption maxima were observed at
λmax1 250 nm and λmax2 306 nm, but in DMSO solution two further maxima appeared at λmax3 422-420 nm and
λmax4 at 631-635 nm for compounds 3b and 3d, respectively, which confirmed the transition into the quinoid
form.
Various methods exist for reducing the nitro group [7, 27, 28] for the synthesis of 1-hydroxyindole
compounds, but under mild conditions hydroxylamine is usually formed first [28], and, after that, it is cyclized
into 2-amino-1-hydroxyindole.
As reducing agent we chose divalent tin (Scheme 2), which reduces nitro groups more selectively, not
affecting a cyano group. Compounds 3a-d at 40-50oC in a solution of divalent tin in hydrochloric acid are
reduced with simultaneous cyclization into the indole ring 5a-d. As side products for compounds having donor
substituents, substituted 2,1-benzisoxazole-5,6-dicarbonitriles 6a,b were found in yields of up to 10%. It is
known that analogous compounds are formed by the action of bases [29, 30] and on acidic decomposition of
1-hydroxyindoles [27]. Our attempts to synthesize 2,1-benzisoxazoles by the direct route on treating compounds
3 with sodium methylate were unsuccessful, but on heating compounds 3b,d in an alcoholic solution of
hydrochloric acid, 2,1-isoxazoles 6a,b were obtained in low yield (up to 15%).
Scheme 2
R
R
N
N
(3b,d)
H+
SnCl2
3a–d
– HOCN
HCl
40–50°C
N
NH2
O
N
N
N
6a,b
5a–d
OH
5a R = H; 5b, 6a R = Me; 5c R = Cl; 5d, 6b R = OMe
TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 3a-d, 5a-d, 6a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, ºC
Yield, %
C
H
N
C16H8N4O2
66.46
66.67
67.43
67.55
59.28
59.55
64.02
64.15
65.55
65.75
66.47
66.66
58.70
58.82
63.15
63.35
2.75
2.80
3.21
3.33
2.05
2.19
3.14
3.17
4.08
4.14
4.53
4.61
3.33
3.39
4.25
4.38
19.40
19.44
18.46
18.53
17.29
17.36
17.50
17.60
19.15
19.17
18.24
18.29
17.05
17.15
17.32
17.38
152-154
163-165
189-190
202-205
48
54
58
46
64
68
71
69
15
11
3a
3b
3c
3d
5a
5b
5c
5d
6a
6b
C17H10N4O2
C16H7ClN4O2
C17H10N4O3
C16H10N4O·H2O
C17H12N4O·H2O
C16H9ClN4O·H2O
C17H12N4O2 ·H2O
C16H9N3O
189-190
(decomp.)
209-211
(decomp.)
246-248
(decomp.)
223-225
(decomp.)
73.98
74.12
69.62
69.81
3.41
3.50
3.27
3.30
16.19
16.21
15.21
15.27
161-163
C16H9N3O2
161-162
429

The structures of compounds 3, 5, 6 were confirmed by data of NMR spectroscopy and mass
spectrometry (Tables 2-4). It is necessary to mention that recording of spectra for compounds 3 is possible only
in CDCl3 (in DMSO-d6 solution, the formation of a mixture of products difficult to identify was observed 2-3 h
after dissolution). However, their solubility in CDCl3 was minimal so that it was not possible to record 13C
NMR spectra for the majority of compounds. In the 1H NMR spectra of freshly prepared samples of compounds
3 signals were observed for aromatic protons in the 8.10-8.40 ppm region, two singlets for the phthalonitrile
fragment, at 7.00-7.50 ppm for the second benzene ring, and a singlet for the methine proton in the 6.1 ppm
region. Signals for the OH group were observed for 2-amino-1-hydroxyindoles 5 in 1H NMR spectra as a singlet
in the 11.70-11.80 ppm region and a broadened singlet for NH2 at 6.60-6.90 ppm, and also signals of the
protons of the phthalonitrile ring shifted upfield at 7.70-7.90 ppm. In the 13C NMR spectra of compounds 3, 5, 6
all the carbon signals characteristic of these compounds were present. A precise assignment of the signals of the
protons and carbon atoms was made for the case of compound 5c with the aid of two-dimensional spectroscopy
(ROESY, HSQC, HMBC).
The mass spectra of compounds 3 were characterized by low intensity signals of the molecular ion, and
further fragmentation occurs through the formation of a quinoid form. The [M-OH]+ signal was the most
intense. The presence of a hydroxyl group in indoles 5 followed from analysis of those mass spectra in which
the most intense signals were [M-O]+ and [M-CH-NH2]+ (Scheme 3), corresponding to products of
decomposition of the quinoid form.
Scheme 3
M+
M+
R
R
N
N
NH2
NH2
N+
O
N
N
N
OH
5
M+ – 16
M+ – 29
R
R
N
N
NH2
N
N
O
N
N
H
Determination of the orientation of substituents in 2-amino-1-hydroxyindoles was performed by the
single crystal X-ray structural analysis for the case of compound 5a. In the crystal, compound 5a exists as a
monohydrate (Fig. 1). The indole fragment has a planar structure. The effect of donor and acceptor substituents
leads to significant redistribution of bond lengths in the six-membered ring of the indole fragment. The C(3)–C(8)
and C(5)–C(6) bonds are significantly longer than the remainder (Table 5). The N(1)–C(8) and C(2)–C(3) bonds
are somewhat shortened, while the C(1)–C(2) bond is elongated relative to the mean length values for such
bonds (1.372, 1.434, and 1.364 Å, respectively [31]). The amino group is characterized by a nonplanar structure
(sum of the angles at the nitrogen atom is 355.1o), the hydroxyl group is rotated perpendicularly (torsion angle
C(1)–N(1)–O(1)–H(1) is equal to 91.6o) relative to the indole fragment. Apparently, such a structure is governed
by the participation of donor substituents in hydrogen bonding. However, the H(1)N atom does not form an H-
bond, which may be caused by steric factors from the presence of a phenyl substituent adjacent to the NH2
430

group. The phenyl group is disordered over two positions with equal occupancies, however, both components
are rotated relative to the indole fragment on opposite sides by 37.95(9) and 38.09(7)o.
In the crystal structure, the H-bonded layers are formed parallel to the ab crystallographic plane (Fig. 2)
by the water and compound 5a molecules (Tables 5, 6). The interactions between the layers are brought about
by hydrogen bonds and Van der Waals forces.
TABLE 2. 1H NMR Spectra of the Synthesized Compounds 3a-d, 5a-d, 6b,d*
Com-
pound
Chemical shifts, , ppm (J, Hz)
6.13 (1H, s, CH); 7.28-7.31 (2H, m, H Ph); 7.43-7.47 (3H, m, H Ph);
3a
3b
3c
3d
5a
5b
5c
5d
6a
6b
8.11 (1H, s, H-3); 8.42 (1Н, s, H-6)
2.48 (3H, s, СН3); 6.09 (1H, s, CH); 7.16 (2H, d, 3J = 8.0, H-3',5');
7.24 (2H, d, 3J = 8.0, H-2',6'); 8.11 (1H, s, H-3); 8.41 (1H, s, H-6)
6.12 (1H, s, CH); 7.25 (2H, d, 3J = 8.5, H-3',5'); 7.44 (2H, d, 3J = 8.5, H-2',6');
8.13 (1H, s, H-3); 8.44 (1H, s, H-6)
3.82 (1H, s, OСН3); 6.06 (1H, s, CH); 6.94 (2H, d, 3J = 8.8, H-3',5');
7.20 (2H, d, 3J = 8.8, H-2',6'); 8.11 (1H, s, H-3); 8.41 (1H, s, H-6)
6.77 (2H, s, NH2); 7.25 (1H, t, 3J = 7.7, H Ph); 7.44 (2H, t, 3J = 7.7, H Ph);
7.54 (2H, d, 3J = 7.7, H Ph); 7.74 (1H, s, H-7); 7.90 (1H, s, H-4); 11.76 (1H, s, ОH)
2.33 (3H, s, СН3); 6.60 (2H, br. s, NH2); 7.28 (2H, d, 3J = 8.0, H-3',5');
7.42 (2H, d, 3J = 8.0, H-2',6'); 7.71 (1H, s, H-7); 7.81 (1H, s, H-4); 11.75 (1H, s, ОH)
6.85 (2H, s, NH2); 7.47 (2H, d, 3J = 8.5, H-3',5'); 7.56 (2H, d, 3J = 8.5, H-2',6');
7.75 (1H, s, H-7); 7.91 (1H, s, H-4); 11.77 (1H, s, ОH)
3.80 (3H, s, OСН3); 6.65 (2H, s, NH2); 7.01 (2H, d, 3J = 8.8, H-3',5');
7.44 (2H, d, 3J = 8.8, H-2',6'); 7.71 (1H, s, H-7); 7.79 (1H, s, H-4); 11.70 (1H, s, ОH)
2.47 (3H, s, СН3); 7.47 (2H, d, 3J = 8.1, H-3',5'); 8.14 (2H, d, 3J = 8.1, H-2',6');
8.73 (1H, s, H-4); 9.22 (1H, s, H-7)
3.93 (3H, s, OСН3); 7.19 (2H, d, 3J = 8.8, H-3',5'); 8.20 (2H, d, 3J = 8.8, H-2',6');
8.74 (1H, s, H-7); 9.24 (1H, s, H-4)
_______
*Solvents: CDCl3 (compounds 3a-d) and DMSO-d6 (compounds 5a-d and 6a,b).
TABLE 3. 13C NMR Spectra of the Synthesized Compounds 3a,d, 5a,c,d, 6b*
Com-
pound
Chemical shifts, , ppm
38.2 (CH); 112.9; 113.2; 116.6; 117.6; 120.7; 127.9 (C-3',5'); 129.9 (C-4');
130.1 (C-2',6'); 130.3 (C-6); 131.5 (C-4); 136.0 (C-3); 136.4 (C-1'); 149.3 (C-5)
3a
3d
5a
37.6 (CH); 55.4 (OСH3); 112.9; 113.2; 115.4; 116.8; 117.4; 120.6; 123.1; 129.3;
130.2; 135.9; 136.9; 149.2 (C-5); 160.6 (C-4')
90.4 (C-3); 99.3 (C-6); 104.5 (C-5); 111.2 (C-7); 118.2 (C≡N); 118.5 (C≡N);
120.2 (C-4); 124.9 (C-3a); 125.3 (C-4'); 127.5 (C-2',6'); 129.0 (C-3',5');
130.7 (C-7a); 133.1 (C-1'); 146.3 (C-2)
89.2 (C-3); 99.7 (C-6); 104.6 (C-5); 111.3 (C-7); 118.1 (C≡N); 118.4 (C≡N);
120.2 (C-4); 124.7 (C-3a); 128.9 (C-3',5'); 129.3 (C-2',6'); 129.5 (C-4');
130.8 (C-7a); 132.0 (С-1'); 146.5 (С-2)
5c
5d
6b
55.2 (OСH3); 90.3 (C-3); 98.9 (C-6); 104.3 (C-5); 111.1 (C-7); 114.5 (C-3',5');
118.2 (C≡N); 118.6 (C≡N); 120.1 (C-4); 125.0 (C-3a); 125.2 (C-4');
128.9 (C-2',6'); 130.4 (C-7a); 146.1 (C-2); 157.2 (C-1')
55.7 (OСH3); 106.0 (C-5); 111.9 (C-6); 113.8; 115.2 (C-3',5'); 115.6 (C-3а);
116.2 (C≡N); 118.2 (C≡N); 125.4 (C-7); 129.4 (C-2',6'); 133.9 (C-4);
154.7 (C-3); 162.6 (C-7a); 168.8 (C-4')
______
*Solvents: CDCl3 (compounds 3a,d) and DMSO-d6 (compounds 5a,c,d and 6b).
431

TABLE 4. Mass Spectra of Compounds 3a-d, 5a-d, 6b,d
Com-
m/z (Irel, %)
pound
288 [M]+ (1.4), 271 [M-17]+ (100), 254 (70), 245 (26) 240 (37), 231 (8), 217 (66),
3a
213 (30), 77 (46)
302 [M]+ (4), 285 [M-17]+ (55), 268 (55), 258 (32), 240 (62), 230 (75), 213 (21),
3b
201 (20), 176 (16), 119 (12), 107 (15), 103 (21), 91 (82), 77 (62), 65 (66), 63 (50),
51 (58), 39 (100)
322 [M]+ (3), 307 (10), 305 [M-17]+ (34), 288 (43), 279 (19), 251 (41), 240 (100),
3c
233 (46), 216 (67), 202 (20), 188 (10), 139 (8), 123 (8), 111 (19), 99 (10), 87 (9),
75 (25)
318 [M]+ (38), 301 [M-17]+ (100), 284 (98), 275 (59), 270 (30), 256 (30), 254 (42),
3d
232 (95), 228 (40), 201 (62), 175 (23), 123 (39), 92 (24), 77 (34)
274 [M]+ (18), 258 [M-16]+ (98), 257 (58), 245 [M-29]+ (44), 230 (28), 217 (12),
5a
105 (31), 77 (99), 51 (76), 44 (100)
288 [M]+ (1.4), 272 [M-16]+ (100), 255(18), 91 (24), 65 (19)
308 [M]+ (2), 294 (17), 292 [M-16]+ (59), 256 (37), 216 (16), 202 (22), 176 (21),
5b
5c
139 (68), 128 (50), 113 (52), 111 (100), 101 (35), 75 (90)
304 [M]+ (24), 288 [M-16]+ (100), 273 [M-29]+ (54), 256 (22), 232 (18), 217 (12),
5d
204 (9), 191 (7), 135 (5), 92 (5), 63 (15)
259 [M]+ (67), 230 [M-N-O]+ (40), 172 (27), 91 (68), 89 (30)
275 [M]+ (98), 232 (100), 204 (87), 178 (48), 177 (38), 92 (71), 77 (22), 64 (71)
6a
6b
Fig. 1. General form of the monohydrate 5a·H2O, representing atoms by ellipsoidal
atomic displacements with 50% probability. The second component of the disordered
phenyl fragment is shown by dashed lines.
We have therefore established that on interacting BNPN with the sodium salts of 3-hydroxy-2-(4-R-
phenyl)but-2-enenitriles in DMF solution a C-nucleophilic substitution of the bromine atom occurs in 4-bromo-
5-nitrophthalonitrile with the formation, as the main reaction product, of substituted 4-cyanomethyl-5-nitro-
phthalonitriles, which on chemical reduction of the nitro group led to 3-substituted 2-amino-1-hydroxy-1H-
indol-5,6-dicarbonitrile. The obtained 4-cyanomethyl-5-nitrophthalonitriles are transformed under the action of
base into the quinoid form, and under the action of strong acids they are cyclized into 2,1-benzisoxazoles.
432

Fig. 2. Fragment of the crystal packing of hydrate 5a·H2O. The second component of
the disordered phenyl fragment is not shown.
TABLE 5. Bond Lengths (l) in the Molecule of 5a·H2O
Bond
l, Å
Bond
l, Å
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
1.394(2)
1.390(2)
1.422(2)
1.389(2)
1.372(2)
C(3)–C(8)
N(1)–C(8)
C(2)–C(3)
C(1)–C(2)
1.427(2)
1.365(2)
1.434(2)
1.364(2)
TABLE 6. Interatomic Distances and Angles in the 5a·H2O Molecule
Н-bond
O(N)···O(N), Å
H···O(N), Å
O(N)–H···O(N), deg.
O(1)–H(1)···O(1)W
N(2)–H(2)N···O(1)W
O(1)W–H(1)W···N(4)
O(1)W–H(2)W···N(3)
2.607(2)
3.079(2)
2.845(2)
2.833(2)
1.76
2.21
2.03
1.99
178
161
162
174
433

EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Bruker DRX-500 instrument (at 500 and 125 MHz,
respectively) in CDCl3 or DMSO-d6 solution at 30oC, internal standard was TMS or the residual signals of the
1
13
solvent (2.50 ppm for DMSO-d6 or 7.26 ppm for CDCl3 in H NMR spectra, 39.5 ppm for DMSO-d6 in C
NMR spectra). Mass spectra were recorded on a Finnigan MAT Incos 50 chromato-mass spectrometer at an
ionizing voltage of 70 eV and ionization chamber temperature of 100-220oC. Elemental analysis was carried out
on a Perkin–Elmer 2400 instrument.
The starting BNPN was synthesized by the procedure of [32], sodium salts 2a-d were synthesized
analogously to the procedure of [33].
4-(Cyanophenylmethyl)-5-nitrophthalonitrile (3a), 4-(Cyano-p-tolylmethyl)-5-nitrophthalonitrile
(3b), 4-[(4-Chlorophenyl)cyanomethyl]-5-nitrophthalonitrile (3c), and 4-[(4-Methoxyphenyl)cyano-
methyl]-5-nitrophthalonitrile (3d) (General Method). Compound 2a-d (2.2 mmol) was added to a solution of
BNPN (1 mmol) in DMF (3 ml), and the mixture was stirred at room temperature for 1-2 h, then poured into
cold water (10 ml) containing AcOH (0.5 ml). The separated resiny solid was extracted with CH2Cl2, washed
thoroughly with water, and chromatographed on silica gel with eluent hexane–CH2Cl2, 2:1. The solvent was
evaporated, and the residual solid was recrystallized from alcohol.
2-Amino-1-hydroxy-3-phenyl-1H-indole-5,6-dicarbonitrile (5a), 2-Amino-1-hydroxy-3-p-tolyl-
1H-indole-5,6-dicarbonitrile (5b), 2-Amino-3-(4-chlorophenyl)-1-hydroxy-1H-indole-5,6-dicarbonitrile
(5c), and 2-Amino-1-hydroxy-3-(4-methoxyphenyl)-1H-indole-5,6-dicarbonitrile (5d) (General Method).
EtOH (2 ml) was added to a solution of SnCl2 (4 mmol) in conc. HCl (2 ml), and compound 3a-d (1 mmol) was
added portionwise at such a rate that the solution heated spontaneously to not higher than 40-50oC. The mixture
was maintained at this temperature for 1-2 h, and diluted with water (5 ml), the precipitated solid was filtered
off, and recrystallized from alcohol.
3-p-Tolylbenzo[c]isoxazole-5,6-dicarbonitrile (6a) and 3-(4-Methoxyphenyl)benzo[c]isoxazole-
5,6-dicarbonitrile (6b) (General Method). Conc. HCl (1 ml) was added to a suspension of compound 3b,d (1
mmol) in EtOH (10 ml) and the mixture was refluxed for 2-6 h (check by TLC, petroleum ether–ethyl acetate,
1:1) until complete disappearance of the starting compound. The mixture was cooled, diluted with water (10
ml), the precipitated solid was separated and chromatographed on silica gel, eluent hexane–CH2Cl2, 1:2. The
solvent was evaporated and the residual solid was recrystallized from alcohol.
X-ray Structural Analysis. Crystals of 5a·H2O (C16H11N4O·H2O) at 100 K are triclinic: a = 4.7298(4)
Å, b = 9.8790(9) Å, c = 15.2145(15) Å, α = 84.829(2)o, β = 81.839(2)o, γ = 8.088(2)o, V = 700.69(11) Å3, Z = 2,
space group P1, μ = 0.096 mm-1, dcalc = 1.385 g·cm-3. The intensities of 7743 reflections were collected on a
SMART APEX2 CCD diffractometer (λ(MoKα) = 0.71073 Å, graphite monochromator, ω-scanning, 2θ < 58o).
Treatment of the initial array of measurement intensities was carried out with the programs SAINT and
SADABS, included in the APEX2 program package [34]. The structure was solved by the direct method and
refined by the least squares method in an anisotropic approximation for non-hydrogen atoms on F2hkl. Hydrogen
atoms were placed in geometrically calculated positions, with the exception of hydrogen atoms at oxygen and
nitrogen atoms, the positions of which were localized from an electron density difference synthesis and were
then normalized at a distance of 0.85 (for O–H) and 0.9 Å (for N–H). The positions of all hydrogen atoms were
refined within the riding model (Uiso(H) = nUeq(C)(O)(N), where n = 1.5 for oxygen atoms, n = 1.2 for C, N
atoms). There were 3368 independent reflections (Rint = 0.0417) in the refinement. The convergence of
refinement at each independent reflection is wR2 = 0.1180 (R1 = 0.0446 at 2210 reflections with I > 2σ(I)). All
calculations were carried out using the SHELXTL program [35].
The X-ray structural analysis data have been deposited in the Cambridge Crystallographic Data Center
(deposition CCDC 810378).
434

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