Oxidative ring expansion of spirocyclic oxindole derivatives

Article abstract of DOI:10.1021/jo501269f

Oxidation of the spirocyclic oxindole derivative, isamic acid 1, led to decarboxylation and ring expansion to quinazolino[4,5-b]quinazoline-6,8-dione 7 rather than, as previously believed, its isomer 6. The structure of 7 was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro[3H-indole-3,2′(1H)quinazoline]-2,4′(1H,3H)dione 8, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of 7 gave the 10-membered molecule 22. Isamic acid could easily be converted to N-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, 38, of compound 6. The structure of 38 was confirmed by X-ray crystallography.

Full text of DOI:10.1021/jo501269f

Article
pubs.acs.org/joc
Oxidative Ring Expansion of Spirocyclic Oxindole Derivatives
Jan Bergman,*,† Carl-Johan Arewang,‡ and Per H. Svensson§,∥
̊
†Unit of Organic Chemistry, Department of Biosciences at Novum, Karolinska Institute, SE-14157 Huddinge, Sweden
‡AstraZeneca R&D, SE-15185 Sodertalje, Sweden
̈
̈
§SP Process Development, SE-15121 Sodertalje, Sweden
̈
̈
∥Department of Applied Physical Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Oxidation of the spirocyclic oxindole derivative, isamic acid 1, led to decarboxylation and ring expansion to
quinazolino[4,5-b]quinazoline-6,8-dione 7 rather than, as previously believed, its isomer 6. The structure of 7 was confirmed by
X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule,
spiro[3H-indole-3,2′(1H)quinazoline]-2,4′(1H,3H)dione 8, which was also identified as an intermediate in the oxidation of
isamic acid. Mild hydrolysis of 7 gave the 10-membered molecule 22. Isamic acid could easily be converted to N-nitrosoisamic
acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, 38, of compound 6. The structure of
38 was confirmed by X-ray crystallography.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Although isamic acid 1, C16H11N3O3, which can easily be
prepared from isatin 2 in the presence of ammonium ions, has
been known since 1842,1 its true nature as a spirocyclic derivative
of oxindole was not revealed until 1969, when Field was the first
to assign the correct structure.2 One year later, this assignment
was confirmed by an X-ray crystallographic investigation of p-
bromophenacyl isamate.3 Over the years, several research groups
have contributed to the study of isamic acid, notably Reissert and
Hoppmann,4 who developed an excellent procedure for the
preparation of isamic acid. Jasini,5−9 in particular, prepared
several derivatives (many of them unassigned), and de Mayo and
Ryan,10 who after a comprehensive study in 1967, were the first
to suggest a structure (albeit incorrect) with the right
composition, namely, 3, of isamic acid. Previously, Reissert and
Hoppmann had assigned structure 4 in 1924. This incorrect
formulation was based on the composition C16H13N3O4, due to
the fact that isamic acid strongly adheres one molecule of water
(Figure 1).
Isamic acid could readily be prepared as described by Reissert
and Hoppmann by treating isatin with a hot aqueous solution of
ammonium chloride and sodium acetate.4 The 13C NMR
spectrum of isamic acid featured a diagnostic signal from the
carbon atom in spiro-position at 75.4 ppm.
In connection with attempts to elucidate the structure of
isamic acid, Jasini, as well as de Mayo, treated this molecule with
hydrogen peroxide in sodium hydroxide under forcing
conditions and isolated three compounds A (C14H11N2O), B
(C15H9N2O2), and C (correctly identified as 2,4(1H,3H)-
quinazolinedione). Compound A was correctly assigned
structure 5, and de Mayo obtained certain evidence that B
should have structure 6. The isomer 7 was also discussed by Jasini
as well as by de Mayo but disregarded as an alternative. However,
it will now be shown that the correct structure is indeed
quinazolino[4,3-b]quinazoline-6,8-dione (7) (vide infra).
The old experiments just discussed have now been repeated
but with careful control of the reaction temperatures. Under such
conditions, the known12 (since 2003) spirocyclic molecule 8
A few years after the establishment of its true structure,
Cornforth in 1976 resolved isamic acid with the help of brucin.11
Cornforth also noted that the pure enantiomer readily
underwent racemization when dissolved in methanol.
Received: June 25, 2014
Published: September 4, 2014
© 2014 American Chemical Society
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Figure 1. Graphical representation of molecules 1−9.
could now be isolated as an intermediate. Mechanistically, such a
reaction pathway is in line with similar oxidative decarboxylations
described in the literature.13 It is assumed, as outlined in Scheme
1, that the addition product 9 is an intermediate.
a consecutive product formed by ring cleavage of 7. Actually, this
molecule of low solubility is relatively insensitive to alkaline
oxidative conditions. Rather, it is suggested that 5 is formed
during the ring expansion process as outlined in Scheme 2. Ring
expansions of oxindoles involving isocyanates have been invoked
previously in mechanistic discussions.12,14
Scheme 1
At this stage, it became of interest to resolve the spirocyclic
molecule 8, and in this context, some details of the synthesis of
the racemate were studied as outlined in Scheme 3.
Scheme 3
Compound 8, which featured a diagnostic signal from the
carbon atom in the spiro-position at 71.0 ppm in the 13C NMR
spectrum, underwent quickly and in almost quantitative yield a
ring expansion to the quinazolinoquinoline 7 when treated with
potassium permanganate under alkaline conditions at ambient
temperature. 2-(2-Aminophenyl)quinazoline-4(3H)-one (5)
was formed as one of the products (together with 7) when
isamic acid was treated with a hot alkaline solution containing
considerable amounts of hydrogen peroxide. Compound 5 is not
Scheme 2
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Scheme 4
Scheme 5
The yellow-orange intermediate 13, which also is the chain
tautomer of the spiro-compound 8, could easily be obtained in
high yields by heating 2 and 11 for 3 h in ethanol. The unstable
intermediate 12 could be obtained by treating 2 and 11 under
ultrasound at 25 °C. When the yellow-orange imine 13 was
treated with an aqueous solution of sodium hydroxide at 45 °C, a
colorless solution (presumably containing 12 after addition of
water) was obtained. Acidification of this solution with acetic acid
yielded, however, the spiro-compound 8. Reduction of the imine
with sodium dithionite in aqueous ethanol readily gave the 3-
amino-substituted oxindole 14. The intermediates 12 and 13
could be fully characterized by NMR spectroscopy. Molecule 12
featured a diagnostic singlet at 78.7 ppm and molecule 14 a
doublet at 55.6 ppm in their 13C NMR spectra.
present. The new results are summarized in Scheme 4. The
kinetic molecule 6, 13H-quinazolino[3,4-a]quinazolin-5,13-
dione, quite readily isomerized to the more stable isomer 7, for
instance, by dissolution in methanol (50 °C) or pyridine (60 °C).
The isomer 6 featured a characteristic absorption (CO) at
1794 cm−1 in the IR spectrum, whereas the corresponding signal
from the isomer 7 appeared at 1752 cm−1. Both isomers (6 and
7) are of low solubility, and DMSO, used as solvent during NMR
studies, was aggressive and caused partial decarboxylation to 2-
(2-aminophenyl)-4(3H)-quinazolinone, 5.
A similar transformation in the quinazolinobenzotriazine
series has been reported by Eddy, Vaughan, and Stevens.17
Their results are outlined in Scheme 5. It should be noted that
only compound 18 actually could be isolated.
Excellent resolution of the racemate of 8 could be effected with
supercritical fluid chromatography. The separation of the
enantiomers was excellent. Fraction A gave [α] = −210, and
fraction B gave [α] = +248. Both values might be too low due to
relatively rapid racemization. One of the enantiomers had
previously been prepared using a chiral Brønsted acid in impure
form by List et al.15 These workers failed, however, to recognize
the signal from the spiro-carbon atom, and hence, we initially
believed that their sample mainly contained the chain tautomer.
A closer examination of their published spectrum (in CD3OD)
revealed the presence of a tiny but ignored signal around 73 ppm
and more importantly the nonpresence of the chain tautomer.
Five years later, Shi et al.16 also obtained an enantiomer of 8 using
a similar methodology. However, previous work was not cited.
During the early days of this investigation, it was assumed
(following de Mayo) that the oxidation product of 1 (or 8) had
structure 6 (rather than its isomer 7). This concept started to
sway when it was found that treatment of the amino compound 5
with phosgene (or its trimer) in dioxane initially gave 6, which
readily rearranged to the isomer 7 (Scheme 4). These results
called for an X-ray investigation which finally proved that 7 (vide
infra) is the correct structure of the oxidation product, as already
outlined in Scheme 1. In DMSO solution, 7 exists as an
equilibrium between 7a and 7b, in a 65:35 ratio, as indicated by
nice NMR data. In the solid state, the hydroxyl tautomer 7b is not
The isomers 6 and 7 gave quite different products when
treated with sodium hydroxide in water−dioxane. Thus,
compound 6 readily underwent ring opening to the known18
molecule 20, whereas 7 via the addition product 21 (ring
tautomer) gave the 10-membered molecule 22 (chain tautomer).
This conversion required a short period of heating at 80−85 °C.
Prolonged heating at reflux temperature resulted in cleavage to
2,4(1H,3H)-quinazolinedione and anthranilic acid. Dissolution
of 7 under alkaline conditions at ambient temperature (or even at
60 °C) followed by acidification regenerated 7. Heating of the
pair 21/22 in acetic anhydride resulted in recyclization to 7. The
assignment of 22 is based primarily on its conversions but also on
a trio of signals (169.6, 159.0, and 155.9 Hz) in the 13C NMR
spectrum that should exclude any cyclol (e.g., 21) as an
alternative.
Treatment of 7 with amino compounds resulted in a different
type of ring cleavage, as exemplified by the formation of the new
molecule 23 and the already known molecule 24. Isomer 6 when
treated similarly gave, as expected, identical products. Com-
pound 22 has a low solubility in many solvents, and in
connection with a recrystallization experiment with N,N-
dimethylformamide, it was found that another (as distinct from
22 → 7) transannular reaction occurred, namely, formation of
25, a known compound.19−21 The results are outlined in Scheme
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Scheme 6
Scheme 7
a
Scheme 8
a
DIC= diisopropylcarbodiimide.
6. Similar cases of 10-membered cycloamides in equilibrium with
the corresponding cyclols have been reported by Pinnen.22,23
Reduction of the quinazolinoquinazoline 7 with sodium
cyanoborohydride in acetic acid gave the dihydro derivative 26,
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whereas the isomer 6 gave the dihydro derivative 27, which also
could be obtained from the known24 compound 28 by treatment
with phosgene in dioxane (Scheme 7).
oxidative decarboxylation. Intramolecular delivery of the element
of hydroxylamine to the carbonyl group in the 13-position is vital
for the formation of the 13-hydroximino compound 38 (Scheme
10).
In this paper, we have shown that several papers wherein
compound 6 has been claimed were in fact dealing with its isomer
7. A parallel case has recently been revealed by Venkateswarlu et
al.,29,30 where the originally claimed31 13H-quinazolino[3,4-
a]quinazoline-13-one 40 has been shown to be 8H-quinazolino-
[4,3-b]quinazoline-8-one 41 (Figure 2). Compound 41 has been
known at least since 195632 and is easy to prepare from 2-(2′-
aminophenyl)quinazoline-4(3H)-one 5 and ethyl orthofor-
mate.33
During the late 1960s, Doleschall and Lempert25−27 prepared
and correctly identified the quinazolino[4,3-b]quinazoline 7
using the route outlined in Scheme 8. Molecule 31 had been
prepared by this route already in 1904 by Konig,28 although the
̈
structure that he assigned to it was incorrect. By this route, large
amounts of 7 could readily be prepared.
Nitrosation of 8 readily gave the unstable nitroso derivative 33,
and when heated for 3−5 min in ethanol, a ring expansion
occurred with separation of molecule 7. Isamic acid similarly gave
the nitroso derivative 34, which had been shown by Jasini to
undergo a series of transformations under acidic conditions to
give a number of unstable intermediates. One of the molecules
was described as deeply yellow and considerably more stable
than the others. Like isamic acid 1, its nitroso derivative 34 is a
monohydrate, and Jasini,5 based on Reissert’s structure 4,
assigned the incorrect structure 39, a molecule that never has
been isolated nor described (Scheme 9).
Figure 2. Graphical representation of molecules 40 and 41.
Scheme 9
Finally, one can ask the question why de Mayo’s suggested
structure for isamic acid was the indazole derivative 3. Actually,
the immediate precursor to 3 was suggested to be 39, which is the
chain tautomer of isamic acid 1. In other words, de Mayo was
quite close to the truth.
CRYSTALLOGRAPHIC SECTION
■
Some of these intermediates have now been studied by NMR
spectroscopy (Scheme 9), and in particular, the structure of the
yellow stable compound 38 has been determined by X-ray
crystallography. The intermediate 35, formed via trans-nitro-
sation of 34, could be isolated and featured a signal at 81.8 ppm
for the carbon atom in the spiro-position. This intermediate
subsequently undergoes ring expansion and an intramolecular
The structure of 7 was confirmed by a single-crystal X-ray
analysis. The details of the X-ray analysis can be found in the
Experimental Section. The molecular and crystal structure of 7 is
visualized in Figure 3. The molecule forms dimers via hydrogen
bonding in the [010] direction, and in the [100] direction, the
molecules have significant π−π stacking interactions. The
packing coefficient (percent filled van der Waals space in the
Scheme 10
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resulted in a whitish solid: 23.8 g (88%); mp 277−278 °C (lit.12 277−
278 °C); the spectroscopic data were identical to those in the
literature;12 IR 3488, 3233, 2967, 1709, 1685, 1646, 1610, 1524, 1474,
1327, 1195, 1050, 877, 757 cm−1; 1H NMR δ 6.62 (d, 1H, J = 7.8 Hz),
6.09 (m, 1H), 6.85 (d, 1H, J = 6.8 Hz), 7.05 (m, 1H), 7.25 (m+d, 3H, J =
1.16 Hz), 7.46 (d, 1H, J = 6.8 Hz), 7.60 (d, 1H, J = 7.8 Hz), 8.33 (d, 1H, J
= 1.16 Hz), 10.3 (br s, 1H); 13C NMR δ 71.0 (s), 110.1 (d), 113.9 (d),
114.3 (s), 117.2 (d), 122.3 (d), 125.3 (d), 126.8 (d), 129.5 (s), 130.8
(d), 133.3 (d), 142.1 (s), 146.8 (s), 163.9 (s), 176.0 (s).
Quinazolino[4,5-b]quinazoline-6,8-dione (7). Method A. Oxi-
dation of the spiro-compound 8 occurred with addition of potassium
permanganate (vide infra). Method B. Isomer 6 (100 mg) was heated in
dioxane (25 mL) for 5 min; the solid was obtained upon cooling,
isolated, washed with dioxane, and dried to yield 98 mg of isomer 7.
Method C. The benzoxazinone 32 was added to acetic acid (60 mL)
containing sulfuric acid (10 mL) and heated to 110 °C for 15 min,
whereupon the solution was added to ice/water. The solid formed was
collected, washed with water, and dried. Method D. The N-nitroso
compound 33 (294 mg, 1 mmol) was dissolved in ethanol and heated at
reflux temperature for 5 min. The solid formed was collected after being
cooled and washed: 228 mg (91%); mp 291−293 °C (lit.10 291−293
°C); in solution, 7 appears as a mixture of tautomers (7a and 7b); IR
3205, 3148, 3009, 2933, 1752, 1689, 1581, 1563, 1372, 1258, 1125, 891,
757, 747 cm−1; 1H NMR (7a) δ 7.15 (d, 1H), 7.26 (dd, 1H), 7.55 (dd,
1H), 7.61 (dd, 1H), 7.69 (d, 1H), 7.86 (dd, 1H), 8.15 (dd, 1H), 8.38
(dd, 1H), 11.50 (s, 1H); 1H NMR (7b) δ 7.23 (dd, 1H), 7.31 (dd, 1H),
7.61 (dd, 1H), 7.71 (dd, 1H), 7.83 (dd, 1H), 8.17 (dd, 1H), 8.36 (dd,
1H), 8.96 (d, 1H), 12.10 (s, 1H); 13C NMR (7) δ 110.5 (s), 115.3 (d),
119.9 (d), 121.5 (d), 121.6 (d), 123.8 (d), 125.8 (s), 129.8 (d), 131.1
(d), 133.3 (d), 141.2 (s), 142.5 (s), 155.9 (s), 158.9 (s), 169.6 (s).
3-Hydroxy-3-(2-carboxamido)phenylamino-oxindole (12).
Isatin (1.47 g, 10 mmol) and 2-amino-benzamide (1.36 g, 10 mmol)
were added to ethanol (20 mL), and the mixture was stirred at ambient
temperature under the influence of ultrasound until all isatin was
consumed (4 h): 1.10 g (38%); mp 150 °C decomp (loss of water); IR
3585, 3440, 3225, 1710, 1655, 1584, 1508, 1470, 1211, 1044, 750 cm−1;
1H NMR δ 5.66 (d, 1H), 6.50 (dd, 1H), 6.91 (m, 3H), 7.20 (m, 3H),
7.54 (d, 1H), 7.91 (s, 1H), 9.07 (s, 1H), 10.64 (s, 1H), 78.7 (s), 109.8
(d), 112.3 (d), 115.6 (d), 116.8 (s), 121.3 (d), 125.4 (d), 127.1 (s),
128.9 (d), 129.1 (d), 131.9 (d), 142.6 (s), 147.0 (s), 171.4 (s), 174.7 (s).
Anal. Calcd for C15H13N3O3: C, 63.59; H, 4.63; N, 14.83. Found: C,
63.65; H, 4.35; N, 14.86.
Isatin-2′-carboxamidophenylimine (13). Isatin (2.94 g, 20
mmol) and 2-aminobenzamide (2.72 g, 20 mmol) were heated in
ethanol (40 mL) at reflux temperature for 3 h. The orange-yellow solid
formed was collected, washed with ethanol, and dried: 4.85 g (91%); mp
>260 °C; IR 3372, 3209, 3080, 2975, 1725, 1655, 1605, 1483, 1462,
1394, 1339, 1210, 1147, 736 cm−1; 1H NMR δ 6.37 (d, 1H), 6.89 (dd,
1H), 6.88 (d, 1H), 6.99 (d, 1H), 7.31−7.70 (m, 7H), 7.83 (d, 1H), 11.0
(s, 1H); 13C NMR δ 111.6 (d), 116.1 (s), 117.9 (d), 121.9 (d), 125.0 (s),
125.1 (d), 125.7 (d), 129.6 (d), 131.6 (d), 134.7 (d), 147.1 (s), 148.4
(s), 155.2 (s), 163.5 (s), 167.5 (s). Anal. Calcd for C15H11N3O2: C,
67.91; H, 4.18; N, 15.84. Found: C, 67.77; H, 4.30; N, 15.61. When
dissolved in DMSO, compound 13 readily underwent cyclization to its
ring tautomer, 8.
3-(2-Carboxamido)phenylamino-oxindole (14). Method A.
The imine 13 (265 mg, 1 mmol) was added to acetic acid (5 mL)
followed by sodium cyanoborohydride (125 mg, 2 mmol). The mixture
was stirred at 40 °C, which changed the yellow-orange coloration to
colorless within 30 min, whereupon the solution was diluted with water
and the precipitate formed was collected, washed, and dried: 230 mg
(77%); mp 118−120 °C. Anal. Calcd for C15H13N3O2: C, 67.40; H,
4.90; N, 15.72. Found: C, 67.32; H, 5.00; N, 15.63. Method B. The imine
13 (2.65 g, 10 mmol) was added to a stirred solution of ethanol (30 mL)
and water (30 mL), wherein sodium dithionite (3.50 g) had been
dissolved. The mixture was kept at 50 °C until it became almost colorless
when it was concentrated and then diluted with water. The precipitate
was collected, washed, and dried: 2.25 g (81%); mp 118−120 °C; IR
3413, 3197, 3078, 1702, 1615, 1578, 1513, 1473, 1378, 1324, 1274,
1233, 1192, 1139, 1119, 836, 731 cm−1; 1H NMR δ 5.35 (d, 1H, J = 6.2
Figure 3. (a) Molecular and (b) crystal structure of 7. A more detailed
version can be found in the Supporting Information.
unit cell) is 73%, indicating an efficient molecular framework in
the solid state.
The structure of the hydroximino compound 38 was
confirmed by X-ray analysis, the details of which are given in
the Experimental Section. The molecular and crystal structure is
shown in Figure 4. The molecules are linked together via
Figure 4. (a) Molecular and (b) crystal structure of 38. Panel a shows
one of the four symmetry-independent molecules in the asymmetric
unit. Panel b also displays the hydrogen bonds in the [001] direction.
More detailed versions of panels a and b can be found in the Supporting
Information.
hydrogen bonds ([001] direction) and strong π−π stacking
interactions ([100] direction) (Figure 4) to form a 3D network.
The packing coefficient (percent filled van der Waals space in the
unit cell) is 74%, indicating a very efficient molecular framework
in the solid state.
EXPERIMENTAL SECTION
■
1H and 13C NMR spectra were recorded on an instrument at 300.1 MHz
for H and 75.5 for 13C using the residual (DMSO-d6) resonances as
1
reference, unless otherwise stated. The IR spectra were obtained on a
300 FT-IR spectrometer. All chemicals originated from commercial
sources and were used as received, except THF, which was distilled from
sodium and stored under nitrogen.
Isamic Acid (1). Isatin (14.7 g, 0.1 mol) was added to a stirred
solution of ammonium chloride (10.0 g) and sodium acetate (16.5 g) in
water (150 mL) at 70 °C. After a period (20 min) at 95 °C, the reaction
mixture (now containing the yellow-beige sodium−ammonium salt of
isamic acid) was allowed to reach 30−45 °C when the mixture was
acidified with hydrochloric acid and cooled with crushed ice. The title
compound was isolated as a red solid: 12.6 g (88%); IR 3385, 3170,
1
3122, 1726, 1643, 1619, 1473, 1389, 1189, 1136, 1029, 752 cm−1; H
NMR δ 3.5 (br s, 1H), 6.59 (m, 2H), 6.87 (d, 1H), 7.00 (dd, 1H), 7.20
(m, 2H), 7.30 (m, 2H), 10.3 (s, 1H); 13C NMR δ 75.4 (s), 110.1 (d),
111.5 (s), 113.6 (d), 116.9 (d), 122.3 (d), 126.8 (d), 130.3 (d), 133.2
(s), 134.1 (d), 140.6 (s), 145.6 (s), 159.7 (s), 165.9 (s), 175.1 (s).
Spiro[3H-indole-3,2′(1H)quinazoline]-2,4′(1H,3′H)-dione (8).
Isatin (14.7 g, 0.1 mol) and 2-amino benzamide (13.6 g, 0.1 mol) were
heated in acetic acid (110 mL) at reflux temperature for 1 h, whereupon
the clear solution was evaporated and treated with 2-propanol, which
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Hz), 6.54 (dd, 1H), 6.63 (dd, 1H), 6.92−6.99 (m, 2H), 7.19−7.32 (m,
4H), 7.68 (d, 1H), 7.97 (s, 1H), 8.67 (d, 1H, J = 6.2 Hz); the signal from
the NH in the oxindole ring was not observed; 13C NMR δ 55.6 (d),
110.0 (d), 112.5 (d), 114.9 (s), 115.3 (d), 121.9 (d), 124.0 (d), 127.8
(s), 128.9 (d), 129.1 (d), 132.4 (d), 141.9 (s), 148.8 (s), 171.6 (s), 176.8
(s).
1657, 1605, 1572, 1462, 1397, 1292, 1162, 868, 753 cm−1; 1H NMR δ
7.20−7.24 (s+d, 3H), 7.40 (d, 1H), 7.52 (dd, 1H), 7.61 (dd, 1H), 7.67
(dd, 1H), 7.75 (d, 1H), 7.81 (s, 1H), 7.94 (d, 1H), 11.5 (s, 1H); 13C
NMR δ 114.3 (s), 115.2 (d), 122.4 (d), 127.6 (d), 128.4 (d), 128.5 (d),
130.8 (d), 130.9 (d), 133.5 (s), 134.4 (s), 135.2 (d), 139.9 (s), 150.2 (s),
162.2 (s), 167.8 (s).
5,6,9,10-Dibenzo-1,3,7-triaza-2,4,8-trioxodecane (22). Com-
pound 7 (1.32 g, 5 mmol) was dissolved in water (30 mL) containing
potassium hydroxide (2.0 g) at 50 °C. This solution was then heated to
80−85 °C for 5 min. The solution was allowed to cool and acidified with
acetic acid, and the precipitate of 22 was collected, washed with water,
and dried: 0.98 g (70%); mp 150 °C decomp; IR 3116, 2848, 1647,
1581, 1498, 1455, 1427, 1379, 1340, 1291, 824, 750 cm−1; 1H NMR δ
6.98 (dd, 1H), 7.02−7.18 (m, 2H), 7.35 (dd, 1H), 7.58 (dd, 1H), 8.05
(d, 1H), 8.19 (d 1H), 9.13 (d, 1H), 10.8 (s, 1H); 13C NMR δ 110.5 (s),
115.3 (d), 119.9 (d), 121.5 (d), 121.6 (d), 123.9 (d), 125.8 (s), 129.8
(d), 131.1 (d), 133.3 (d), 141.2 (s), 142.5 (s), 155.9 (s), 159.0 (s), 169.6
(s). Anal. Calcd for C15H11N3O3: C, 64.05; H, 3.94; N, 14.95. Found: C,
63.92; H, 4.05; N, 14.92.
Cyclization of 22 to 7. Compound 22 (281 mg, 1 mmol) was
heated at reflux temperature in acetic anhydride (3.0 mL) for 5 min. The
solid that formed on cooling was collected and identified as compound 7
(220 mg, 83%).
Cyclization of 22 to 25. Compound 22 (282 mg, 1 mmol) was
dissolved in DMF (4.0 mL) and heated at 120 °C for 15 min. Cooling
and addition of some water precipitated compound 25: 195 mg (72%).
This compound was identical to a sample of 25 prepared according to ref
18.
Ring Opening of Compound 7 with Dimethylamine and
Formation of the Urea Derivative 23. Compound 7 (263 mg, 1
mmol) was added to dioxane (6 mL), whereupon dimethylamine (30%
in water, 1 mL) was added to the stirred suspension. Light heating to 70
°C resulted in a clear solution which was diluted with water and acidified
with acetic acid which immediately resulted in the formation of a
precipitate, which was collected, washed with water, and dried: 294 mg
(88%); mp 230−232 °C; IR 3150, 1668, 1533, 1443, 1265, 771 cm−1;
1H NMR δ 3.03 (s, 6H), 3.9 (br, 2H), 7.08 (dd, 1H), 7.45 (dd, 1H), 7.52
(dd, 1H), 7.67 (d, 1H), 7.81 (dd, 1H), 7.92 (d, 1H), 8.17 (d, 1H), 8.33
(d, 1H); 13C NMR δ 36.2 (q), 119.6 (s), 120.6 (d), 120.9 (d), 121.5 (s),
125.9 (d), 126.1 (d), 126.4 (d), 129.3 (d), 131.3 (d), 134.4 (d), 140.5
(s), 147.4 (s), 154.5 (s), 155.3 (s), 162.7 (s). Anal. Calcd for
C17H16N4O2: C, 66.22; H, 5.23; N, 18.17. Found: C, 65.99; H, 5.35; N,
18.03.
Ring Opening of Compound 7 with Aniline and Formation of
Compound 24. Compound 7 (263 mg, 1 mmol) was added to aniline
(4 mL) and after a period of heating (140 °C, 30 min), and the reaction
mixture was allowed to cool and then treated with water (35 mL)
containing acetic acid (3 mL). The solid formed was collected, washed
with water, and dried: 294 mg (83%); mp 208−210 °C (lit.37 208−210
°C).
Oxidation of Isamic Acid (1) under Previously Used
Conditions. Isamic acid (1.0 g) was dissolved in aqueous sodium
hydroxide (10%, 10 mL), and hydrogen peroxide (30%, 2 mL) was
added. A vigorous reaction ensued, and a yellowish precipitate was
formed after approximately 5 min. After 4 h at rest, this precipitate was
collected and recrystallized from acetic acid (210 mg, 24%). This
compound was later identified as molecule 7 (vide infra). Acidification
of the aqueous phase with acetic acid gave a precipitate of 2-(o-
aminophenylquinazoline-4(3H)-one 5 (180 mg, 33%) (vide infra).
Oxidation of Isamic Acid (1) under Controlled Conditions.
Isamic acid (7.0 g, 25 mmol) was dissolved in water (300 mL)
containing potassium hydroxide (7.0 g), whereupon hydrogen peroxide
(30%, 7.0 mL) was added in portions during 45 min, keeping the
temperature in the stirred solution between 30 and 40 °C. After a period
of 3 h, the precipitate that formed was collected (2.10 g, 51%) and
identified as the spiro-compound 8. Acidification of the mother liquor
gave a precipitate of the starting material (i.e., isamic acid, 3.80 g).
Oxidation of the Spiro-Compound 8 with Potassium
Permanganate under Alkaline Conditions. The spiro-compound
8 (2.65 g, 10 mmol) was dissolved in water (120 mL) containing
potassium hydroxide (2.5 g). A solution of potassium permanganate
(0.75 g) dissolved in water (150 mL) was added dropwise to the stirred
solution at 25 °C, during 10 min. An initial green coloration was
observed; however, soon, manganese(IV) oxide appeared. The
precipitates that formed were collected and treated with a solution of
sodium hydrogensulfite. The manganese(IV) oxide quickly dissolved,
and the whitish precipitate of compound 7 could be observed and
collected (2.15 g, 87%).
2-(2-Aminophenyl)quinazoline-4(3H)-one (5). Method A. 2-(2-
Nitrophenyl)quinazolin-4(3H)-one34 (2.68 g, 10 mmol) was added to a
stirred solution composed of sodium dithionite (3.0 g) in water (25 mL)
and ethanol (25 mL). The mixture was heated at 65 °C and within 15
min resulted in a clear solution. Concentration followed by dilution with
water gave the crude product which was crystallized from ethanol: 2.05 g
(89%); mp 236−237 °C (lit. 236−237 °C).35 Method B. 2-(2-
Nitrophenyl)quinazolin-4(3H)-one34 (2.68 g, 10 mmol) was catalyti-
cally (Pd/C, 5%) hydrogenated and dissolved in 1:1 ethanol/dioxane
(100 mL). Filtration and evaporation gave a crude product, which was
crystallized from ethanol: 1.85 g (79%); the spectral data of molecule 5
were in agreement with data in the literature;35,36 1H NMR δ 6.61 (dd,
1H), 6.87 (d, 1H), 7.1 (br s, 2H), 7.22 (dd, 1H), 7.46 (dd, 1H), 7.71 (d,
1H), 7.76−7.80 (m, 2H), 8.15, (d, 1H), 12.1 (br s, 1H); 13C NMR δ
112.5 (s), 115.1 (d), 116.7 (d), 120.5 (s), 125.8 (d), 126.2 (d), 126.9
(d), 128.9 (d), 131.9 (d), 134.5 (d), 148.1 (s), 149.5 (s), 153.6 (s), 162.1
(s).
13H-Quinazoline[3,4-a]quinazolin-5,13-dione (6). 2-(2-
Aminophenyl)quinazoline-4(3H)one 5 (237 mg, 1 mmol) was
dissolved in dioxane (12 mL), and phosgene (150 mg, 1.5 mmol)
dissolved in dioxane (10 mL) was added at 35 °C to the stirred solution.
A yellowish precipitate formed within 1−2 min. After a stirring period of
30 min, the product was collected and dried: 245 mg (93%); mp >260
°C, decomp; IR 3350, 1794, 1732, 1626, 1561, 1482, 1392, 1253, 1165,
1081, 820, 755, 746 cm−1; 1H NMR δ 7.15 (m, 1H), 7.26 (d, 1H), 7.55−
7.76 (m, 3H), 8.05 (d, 1H), 8.30 (d, 1H), 8.89 (d, 1H), 11.5 (s, 1H); 13C
NMR δ 115.0 (d), 121.4 (s), 122.9 (d), 126.6 (d), 126.7 (d), 126.8 (d),
126.9 (d), 133.7 (d), 135.0 (d), 137.6 (s), 138.1 (s), 145.6 (s), 147.3 (s),
159.2 (s). Anal. Calcd for C15H9N3O2: C, 68.43; H, 3.45; N, 15.96.
Found: C, 68.22; H, 3.26; N, 15.82.
Ring Opening of Compound 6 and Formation of Compound
20. Compound 6 (262 mg, 1 mmol) was dissolved in water (15 mL)
containing sodium hydroxide (80 mg, 2 mmol) under stirring at 40 °C
for 10 min, whereupon acetic acid was added and the precipitate of the
known amide 20 was collected, washed, and dried: 212 mg (80%); mp
261−263 °C (lit.18 265−266 °C); IR 3390, 3207, 2900−2700, 1715,
2,4(1H,3H)-Quinazolinedione. Compound 7 (1.32 g, 5 mmol)
was treated as described for the preparation of compound 22 but now
under more severe conditions (heating at reflux for 15 min).
Acidification with acetic acid gave the title compound: 0.72 g (88%);
the spectral properties were in agreement with those in the literature;38
1H NMR δ 7.13−7.17 (m, 2H), 7.59 (dd, 1H), 7.87 (d, 1H), 11.1 (s,
1H), 11.3 (s, 1H); 13C NMR δ 114.2 (s), 115.3 (d), 122.5 (d), 127.1 (d),
134.7 (d), 138.4 (s), 148.8 (s), 159.4 (s).
Urea Derivative 31. Anthranilic acid (68.5 g, 0.5 mol) was dissolved
in water (1800 mL) at 96−98 °C, whereupon a solution of
bromocyanogene in water was added. This solution was prepared as
follows. Sodium cyanide (12.3 g, 0.25 mol) dissolved in water (110 mL)
was added to bromine (12.7 mL, 0.25 mol) in water (120 mL) under
stirring, while keeping the temperature at 5−8 °C. Upon addition of this
solution to the solution of anthranilic acid, a slurry of the product was
quickly obtained. The mixture was allowed to cool, and product 31 was
collected, washed with water, and dried; 70.5 g (81%); mp 208−210 °C
(lit.25 208−210 °C); the analytical sample was recrystallized from
DMF/H2O; IR 3414, 3300, 3225, 1648, 1609, 1525, 1448, 1363, 1314,
1228, 1027, 901, 7784, 740 cm−1, 1H NMR δ 6.5 (br, s, 2H), 7.07 (dd,
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1H), 7.20 (dd, 1H), 7.49 (dd, 1H), 7.63 (dd, 1H), 7.75 (d, 1H), 8.05 (d,
1H), 8.30 (d, 1H), 8.60 (d, 1H), 9.57 (s, 1H), 11.94 (s, 1H); 13C NMR δ
117.4 (s), 120.5 (d), 121.0 (d), 121.1 (d), 121.5 (s), 123.3 (d), 127.3
(d), 131.3 (d), 132.2 (d), 134.0 (d), 140.6 (s), 140.8 (s), 155.8 (s), 167.0
(s), 169.8 (s).
Cyclization of 31 to the Benzoxazinone 32. The urea derivative
31 (14.2 g, 50 mmol) in DMF (45 mL) was treated with
diisopropylcarbodiimide (8.0 g) and heated to 130 °C for 20 min.
Upon cooling, the product precipitated. After dilution with methanol,
the benzoxazinone 32 was collected, washed with methanol, and dried:
7.1 g (61%); mp 238−240 °C (lit.26 238−240 °C); IR 3362, 3195, 1771,
1666, 1604, 1566, 1536, 1467, 1449, 1245, 1219, 1167, 1035, 1005, 873,
768 cm−1 (lit. 1780, 1675 cm−1);26 1H NMR δ 6.7 (s, 2H), 7.07 (dd,
1H), 7.51 (dd, 1H), 7.63 (dd, 1H), 7.93 (dd, 1H), 8.02 (d, 1H), 8.13−
8.16 (m, 2H), 8.44 (d, 1H), 11.0 (s, 1H); 13C NMR δ 114.1 (s), 116.6
(s), 120.0 (d), 127.3 (d), 127.8 (d), 128.9 (d), 133.1 (d), 136.6 (d),
142.0 (s), 145.3 (s), 155.5 (s), 156.6 (s), 158.3 (s).
N-Nitrosospiro[indolo-3,2′-quinazoline]-2,4′-dione (33). The
spiro-compound 8 (2.65 g, 10 mmol) was dissolved in acetic acid (30
mL), and sodium nitrite (0,84 g, 12 mmol) was added in portions to the
stirred solution at 30 °C. Within 5−10 min, the product started to
appear as a whitish solid. After 45 min, water (30 mL) was added and the
product (33) collected, washed with water, and dried: 2.65 g (83%); mp
150 °C decomp; IR 3343, 3183, 3100, 1748, 1727. 1650, 1604, 1469,
1450, 1376, 1271, 1182, 1115, 1074, 936, 751 cm−1; 1H NMR δ 6.90−
7.04 (m, 3H), 7.31 (dd, 1H), 7.56 (dd, 1H), 7.79 (dd, 1H), 8.10 (d, 1H),
8.14 (dd, 1H), 9.5 (s, 1H), 11.1 (s, 1H); 13C NMR δ 75.7 (s), 110.5 (d),
114.7 (d), 114.8 (s), 122.5 (d), 122.7 (d), 124.4 (s), 127.5 (d), 128.2
(d), 130.9 (d), 134.9 (d), 138.2 (s), 142.2 (s), 159.0 (s), 169.1 (s). Anal.
Calcd for C15H10N4O3: C, 61.22; H, 3.43; N, 19.04. Found: C, 61.00; H,
3.28; N, 18.88.
N-Nitrosoisamic Acid (34). Isamic acid 1 (2.93 g, 10 mmol) was
added to a stirred solution of sodium nitrite (1.05 g, 15 mmol) in water
at 35 °C for 2 h. After that period of time, the solution was filtered and
cooled in ice/water. Acidification with hydrochloric acid precipitated the
product, which was washed with water and dried: 1.76 g (54%); mp
∼150 °C decomp; this monohydrate could be dried in an exciccator to
yield 34 free of water; IR 3276, 1723, 1618, 1604, 1443, 1193, 1142,
1095, 1051, 948, 753, 693 cm−1; 1H NMR δ 6.92−7.01 (m, 3H), 7.31
(dd, 1H), 7.55 (dd, 1H), 7.74−7.81 (m, 2H), 8.20 (d, 1H), 11.2 (s, 1H);
13C NMR δ 80.4 (s), 110.4 (d), 111.3 (s), 114.4 (d), 122.7 (d), 122.7
(d), 124.3 (s), 127.8 (d), 128.3 (d), 130.8 (d), 135.4 (d), 135.8 (s),
141.8 (s), 156.3 (s), 164.6 (s), 168.8 (s). Anal. Calcd for C16H10N4O4·
H2O: C, 56.47; H, 3.55; N, 16.47. Found: C, 56.48; H, 3.31; N, 16.46.
Zwitterionic Molecule 35. N-Nitrosoisamic acid 34 (644 mg, 2
mmol) in ethanol (20 mL) was treated (5 min) with hydrochloric acid
(2 mL) at 60 °C. The solid product obtained was washed with water and
dried: 610 mg (94%); mp 180 °C decomp; this decomposition is sudden
and violent; experiments with large amounts should be avoided; IR
3060−2900 (br), 1733, 1643, 1609, 1572, 1496, 1333, 1289, 1226, 1083,
760 cm−1; 1H NMR δ 7.13 (d, 1H), 7.19−7.25 (m, 2H), 7.33 (d, 1H),
7.37−7.44 (m, 2H), 7.56 (dd, 1H), 8.32 (d, 1H), 11.4 (s, 1H); 13C NMR
δ 81.8 (s), 114.7 (s), 114.8 (d), 123.0 (d), 124.0 (s), 125.3 (d) 125.6 (d),
125.6 (d), 126.4 (d), 129.8 (d), 133.4 (d), 137.4 (s), 138.5 (s), 143.9 (s),
148.8 (s), 170.5 (s). Anal. Calcd for C16H10N4O4: C, 59.63; H, 3.13; N,
17.39. Found: C, 59.42; H, 3.01; N, 17.02.
2-(2-Aminophenyl)-1,2-dihydroquinazoline-4(3H)one (28). 2-
(2-Nitrophenyl)-1,2-dihydroquinazoline-4(3H)one (2.69 g, 10 mmol)
was added to a stirred mixture of ethanol (40 mL) and water (40 mL),
wherein sodium dithionate (5.0 g) had been dissolved. The mixture was
heated to 65 °C for 45 min, concentrated, and diluted with water and the
solid formed collected, washed with water, and dried: 1.85 g (77%); mp
171−173 °C (lit. 170−173 °C);24 1H NMR δ 6.28 (d, 1H, J = 7.8 Hz),
6.58 (m, 2H), 7.16−7.97 (m, 9H), 9.14 (d, 1H, J = 7.8 Hz); 13C NMR δ
66.6 (d), 111.8 (d), 115.3 (s), 115.4 (d), 124.3 (d), 128.46 (d), 128.49
(d), 129.3 (d), 132.6 (d), 132.7 (d), 133.0 (s), 147.8 (s), 150.5 (s), 171.6
(s). This molecule has very recently also been described by Patil et al.39
13,14-Dihydroquinazolino[4,3-b]quinazolinedione (26).
Compound 7 (0.53 g, 2 mmol) was added to acetic acid (12 mL) at
50 °C, whereupon sodium cyanoborohydride (0.5 g) in portions was
added to the suspension. A clear solution was obtained after 15 min, but
soon, the product started to partially precipitate. After 1 h, the mixture
was cooled, water added, and the product collected: 0.45 g (83%); mp
>260 °C; IR 3250, 2888, 1747, 1644, 1629, 1575, 1497, 1357, 1282, 763
cm−1; 1H NMR δ 6.76 (d, 1H, J = 6.6 Hz), 6.89 (d, 1H), 7.14−7.56 (m,
7H), 8.26 (d, 1H, J = 6.6 Hz), 11.2 (s, 1H); 13C NMR δ 71.2 (d), 114.9
(d), 115.4 (s), 122.7 (d), 124.7 (s), 124.8 (d), 125.4 (d), 125.9 (d),
127.5 (d), 129.3 (d), 132.9 (d), 137.6 (s), 139.9 (s), 144.2 (s), 149.2 (s).
Anal. Calcd for C15H11N3O2: C, 67.91; H, 4.18; N, 15.84. Found: C,
67.66; H, 4.30; N, 15.66.
5,6-Dihydroquinazolino[3,4-g]quinazoline-6,13(7H)-dione
(27). Method A. Compound 6 (0.53 mg, 2 mmol) was added to acetic
acid (12 mL) at 25 °C, wherein sodium borohydride (0.5 g) had been
dissolved. The mixture was stirred for 4 h and then quenched with water
and the precipitate formed collected: 0.39 mg (71%); mp >260 °C. Anal.
Calcd for C15H11N3O2: C, 67.91; H, 4.18; N, 15.84. Found: C, 67.81; H,
4.28; N, 15.72. Method B. The amino compound 28 (237 mg, 1 mmol)
was dissolved in dioxane (8 mL), and triphosgene (210 mg, 0.7 mmol)
in dioxane (3 mL) was added to the stirred solution at 25 °C. After 1 h,
water (5 mL) was added and the precipitate collected, washed with
water, and dried: 240 mg (90%); 1H NMR δ 6.27 (s, 1H), 6.99 (d, 1H),
7.05 (dd, 1H), 7.32−7.41 (m, 3H), 7.59 (m, 2H), 7.93 (d, 1H), 8.80 (s,
1H), 10.2 (s, 1H); 13C NMR δ 65.6 (d), 114.1 (d), 114.4 (s), 122.0 (d),
125.2 (s), 125.6 (d), 125.7 (d), 127.2 (d), 128.0 (d), 130.2 (d), 131.8
(d), 136.0 (s), 140.4. (s) 149.6 (s), 163.2 (s).
Single-Crystal X-ray Analysis. The crystal structures were
determined by direct methods and refined by full matrix least-squares
analyses with anisotropic temperature factors for all atoms except
protons. Proton positions were calculated using known molecular
geometries, refined in riding mode with fixed isotropic temperature
factors.
Crystal data for 7: C H N O , M = 263.25 g/mol, triclinic, P1 (No.
̅
15
9
3
2
r
2), a = 7.0598(4) Å, b = 8.4940(5) Å, c = 10.5944(6) Å, α = 97.816(3)°,
β = 93.664(2)°, γ = 113.447(3)°, V = 572.54(6) Å3, Z = 2, ρcalc = 1.527 g
cm−1, μ = 0.105 mm−1, R1 = 0.0415, wR2 = 0.1117, GOF = 1.056. The
data were collected at 200 K on a diffractometer with graphite-
monochromated Mo Kα radiation and employing a 0.15 × 0.05 × 0.05
mm crystal (Rint = 0.045).
Crystal data for 38: C15H10N4O2, Mr = 278.27 g/mol, triclinic, space
group P1 (No. 2), a = 8.1500(4) Å, b = 17.7300(8) Å, c = 17.8700(9) Å,
̅
α = 111.230(1)°, β = 90.190(1)°, γ = 98.070(2)°, V = 2379.0(2) Å3, Z =
8, ρcalc = 1.554 g cm−3, μ = 0.108 mm−1, R1 = 0.07, wR2 = 0.22, GOF =
1.00. The data were collected at 100 K on the Grenoble synchrotron
(beamline ID29) and employing a 0.11 mm × 0.02 mm × 0.01 mm
crystal (Rint = 0.05). CCDC-957012 and CCDC-915864 contains the
supplementary crystallographic data for 7 and 38. The data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Hydroximino Compound 38. The zwitterionic molecule 35 (322
mg, 1 mmol) or N-nitrosoisamic acid 34 (293 mg, 1 mmol) was heated
in ethanol (15 mL) containing NH3 (aqueous, 1 mL) for 15 min. The
yellow precipitate that formed was collected and dried: 295 mg (83%);
mp >260 °C; the analytical sample was recrystallized from DMF; IR
3110, 2950, 1716, 1618, 1605, 1533, 1442, 1410, 1382, 1269, 938, 750
cm−1; 1H NMR δ 7.12 (d, 1H), 7.21 (dd, 1H), 7.37 (dd, 1H), 7.47 (dd,
1H), 7.59 (dd, 1H), 7.83 (d, 1H), 8.30 (d, 1H), 8.42 (d, 1H), 10.3 (s,
1H), 11.5 (s, 1H); 13C NMR δ 114.7(d), 115.0 (s), 120.2 (s), 121.4 (d),
122.7 (d), 122.9 (d), 126.94 (d), 126.96 (d), 129.1 (d), 133.4 (s), 134.1
(s), 138.0 (s), 144.5 (s), 147.4 (s), 147.7 (s). Anal. Calcd for
C15H10N4O2: C, 64.74; H, 3.62; N, 20.14. Found: C, 64.69; H, 3.60; N,
20.08.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystal structural data of compounds 7 and 38 have been
deposited at Cambridge Data Centre and allocated the
deposition numbers CCDC-957012 and CCDC-915864,
respectively, CIFs for these two molecules are included in the
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Article
(39) Patil, N. T.; Konala, A.; Sravanti, S.; Singh, A.; Ummanni, R.;
Sridhar, B. Chem. Commun. 2013, 49, 10109.
Supporting Information, where also copies of NMR spectra are
provided for all new compounds and also for some already
known key compounds (like 1 and 8). The chromatogram
obtained during the resolution of the spiro-compound 8 is also
provided. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jan.bergman@ki.se.
Notes
The authors declare no competing financial interest.
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