Synthesis of 3′-aroyl-4′-hydroxyspiro-[indole-3,2′-furan] -2,5′(1H)-diones

Article abstract of DOI:10.1007/s10593-010-0603-1

It was found that adducts of 3′-aroyl-4′-hydroxyspiro[indole-3, 2′-furan]-2,5′(1H)-diones with tetramethylguanidine are formed when equimolar amounts of methyl aroylpyruvates, isatin, and N,N,N',N'- tetramethylguanidine are heated briefly in dioxane.

Full text of DOI:10.1007/s10593-010-0603-1

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
SYNTHESIS OF 3'-AROYL-4'-HYDROXYSPIRO-
[INDOLE-3,2'-FURAN]-2,5'(1H)-DIONES
V. L. Gein1*, E. B. Levandovskaya1, and V. N. Vichegjanina1
It was found that adducts of 3'-aroyl-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-diones with
tetramethylguanidine are formed when equimolar amounts of methyl aroylpyruvates, isatin, and
N,N,N',N'-tetramethylguanidine are heated briefly in dioxane.
Keywords: 3'-aroyl-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-diones, methyl 4-aroylpyruvates, isatin,
tetramethylguanidine.
It is known that the reaction of acylpyruvic esters with a mixture of an aromatic aldehyde and an
alkylamine leads to the formation of 4-acyl-1-alkyl-5-aryl-3-hydroxy-3-pyrrolin-2-ones [1]. If the aromatic
aldehyde is replaced by ninhydrin alkylammonium 4-acetyl-2,1',3'-trioxospiro[2,5-dihydrofuran-5,2'-indane]-
olates are formed [2], while 1-substituted 4-acetyl-3-hydroxyspiro[2,5-dihydropyrrole-5,3'-indole]-2,2'-diones
are obtained by the reaction of methyl acetylpyruvate, isatin, and methylamine (tryptamine) [3].
We found that adducts of 3'-aroyl-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-diones with tetramethyl-
guanidine 1a,b are formed when equimolar amounts of methyl aroylpyruvates, isatin, and N,N,N',N'-tetra-
methylguanidine are briefly heated in dioxane. Treatment of the adducts with dilute hydrochloric acid at room
temperature gave 3'-aroyl-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-diones 2a,b.
The obtained compounds 1 and 2 are colorless crystalline substances readily soluble in DMSO, DMF,
alcohol, and acetone and insoluble in chloroform and water.
The IR spectra of compounds 1a,b contain bands for the stretching vibrations of the carbonyl in the side
chain (1672-1736), the carbonyl group of the isatylidene radical (1724-1736), the lactone carbonyl group
(1768-1772), the enolic hydroxyl group (3160), and the NH bonds (at 3312 and 3328 cm−1 respectively).
The 1H NMR spectra of compounds 1a,b contain signals for the 12 protons of the four methyl groups of
tetramethylguanidine in the form of a singlet at 2.87-2.88, multiplets for the aromatic protons at 6.82-8.04,
singlets for the two protons of the NH and HO groups at 7.68 and 7.76, and singlets for the proton of the NH
group at 10.34 and 10.37 ppm.
The IR spectra of compounds 2a,b contain bands for the stretching vibrations of the carbonyl group in
the side chain (1688), the carbonyl group of the isatylidene radical (1716), the lactone carbonyl group
(1788-1792), the enolic hydroxyl group, and the NH bonds at 3288 and 3296 cm−1.
_______
* To whom correspondence should be addressed, e-mail: perm@pfa.ru, geinvl48@mail.ru.
1Perm State Pharmaceutical Academy, Perm 614990, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1154-1156, August, 2010.
Original article submitted December 29, 2009.
0009-3122/10/4608-0931©2010 Springer Science+Business Media, Inc.
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O
O
OH
tetramethylguanidine
OMe
O
+
N
O
H
R
R
R
Me
Me
O
O
N Me
N Me
HCl
N Me
N Me
OH
+
·
· HCl
OH
O
HN
HN
O
O
Me
N
Me
O
H
N
O
1a,b
H
O
2a,b
Unlike the 1H NMR spectra of the adducts 1a,b the 1H NMR spectra of compounds 2a,b do not contain
signals for the protons of tetramethylguanidine and the HO and NH= groups, but there is a downfield shift of the
signal for the proton of the NH group in the isatylidene fragment: 10.90 and 10.92 ppm respectively.
The structures are confirmed by the presence of the peaks of fragment ions in the mass spectra of
compounds 1a and 2a,b.
EXPERIMENTAL
The IR spectra were obtained in vaseline oil on a Specord M-89 instrument. The 1H NMR spectra were
obtained in DMSO-d6 on a Bruker DRX 500 spectrometer (500 MHz) with TMS as internal standard. The mass
spectra were obtained on a Finnigan MAT Incos 50 instrument at 70 eV.
Adduct of 4'-Hydroxy-3'-(4-methylbenzoyl)spiro[indole-3,2'-furan]-2,5'(1H)-dione with Tetra-
methylguanidine (1a). A mixture of methyl 4-methylbenzoylpyruvate (4.40 g, 0.02 mol) and isatin (2.94 g,
0.02 mol) in dioxane (10 ml) was heated until dissolved, and tetramethylguanidine (2.53 ml, 0.02 mol) was
added to the solution cooled to room temperature. The reaction mixture was kept at 20°C for 24 h. The
precipitate was filtered off and recrystallized from 2-propanol. The yield was 6.60 g (73%); mp 144-146°C
1
(isopropyl alcohol). IR spectrum, ν, cm−1: 1676 (СО), 1724 (NСО), 1768 (СОО), 3160 (НО), 3328 (NH). H
NMR spectrum, δ, ppm (J, Hz): 2.31 (3Н, s, СН3); 2.87 (12Н, s, 4СН3); 6.82 (1Н, d, J = 7.7, Н-4); 6.85 (1Н, t,
J = 7.7, Н-5); 7.03 (1Н, d, J = 7.7, Н-7); 7.12 (2Н, d, J = 8.1, Н-3,5, C6H4CH3); 7.18 (1Н, t, J = 7.7, Н-6); 7.68
(2Н, s, NH2); 7.85 (2Н, d, J = 8.1, Н-2,6, C6H4CH3); 10.34 (1H, s, NH). Mass spectrum, m/z (Irel, %): 291
[М-СО2]+ (2.10), 119 [М-СОC6H4СН3]+ (58.56), 115 [C5H13N3]+ (17.52), 44 [СО2]+ (100). Found, %: С 63.85;
Н 5.85; N 12.52. C19H13NO5·C5H13N3. Calculated, %: С 63.99; Н 5.82; N 12.44.
Adduct of 3'-(4-Fluorobenzoyl)-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-dione with Tetra-
methylguanidine (1b). This compound was obtained similarly. The yield was 6.20 g (68%); mp 134-136°C
1
(2-propanol). IR spectrum, ν, cm−1: 1672 (СО), 1736 (NСО), 1772 (СОО), 3160 (НО), 3312 (NH). H NMR
spectrum, δ, ppm (J, Hz): 2.88 (12Н, s, 4СН3); 6.82 (1Н, d, J = 7.5, Н-4); 6.86 (1Н, t, J = 7.5, Н-5); 7.04 (1Н, d,
J = 7.5, Н-7); 7.12 (2Н, t, J = 8.9, Н-3,5, C6H4F); 7.20 (1Н, t, J = 7.5, Н-6); 7.76 (2Н, s, NH2); 8.04 (2Н, t,
J = 8.9, Н-2,6, C6H4F); 10.37 (1H, s, NH). Found, %: 60.98; Н 5.07; F 4.06; N 12.40. C18H10FNO5·C5H13N3.
Calculated, %: C 60.79; Н 5.10; F 4.18; N 12.33.
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4'-Hydroxy-3'-(4-methylbenzoyl)spiro[indole-3,2'-furan]-2,5'(1H)-dione (2a). The adduct of
compound 1a was treated with a solution of 8.3% HCl at room temperature, and the precipitate was filtered off
and recrystallized from alcohol. The yield was 5.65 g (84%); mp 211-213°C (alcohol). IR spectrum, ν, cm−1:
1
1688 (СО), 1716 (NСО), 1792 (СОО), 3288 (НО, NH). H NMR spectrum, δ, ppm (J, Hz): 2.37 (3Н, s, СН3);
6.91 (1Н, d, J = 7.55, Н-4); 6.93 (1Н, t, J = 7.55, Н-5); 7.29 (2Н, d, J = 8.2, Н-3,5, C6H4CH3); 7.31 (1Н, t,
J = 7.55, Н-6'); 7.50 (1Н, d, J = 7.55, Н-7'); 7.74 (2Н, d, J = 8.2, Н-2,6, C6H4CH3); 10.90 (1H, s, NH). Mass
spectrum, m/z (Irel, %): 291 [М-СО2]+ (5.01), 119 [М-СОC6H4СН3]+ (73.17), 44 [СО2]+ (100). Found, %: С 68.20;
Н 3.88; N 4.26. C19H13NO5. Calculated, %: С 68.06; Н 3.91; N 4.18.
3'-(4-Fluorobenzoyl)-4'-hydroxyspiro[indole-3,2'-furan]-2,5'(1H)-dione (2b). This compound was
obtained similarly with a yield of 5.40 g (79%); mp 207-209°C (alcohol). IR spectrum, ν, cm−1: 1688 (СО),
1716 (NСО), 1788 (СОО), 3296 (НО, NH). 1H NMR spectrum, δ, ppm (J, Hz): 6.93 (1Н, d, J = 7.3, Н-4); 6.96
(1Н, t, J = 7.3, Н-5); 7.30 (1Н, t, J = 7.3, Н-6); 7.34 (2Н, d, J = 8.85, Н-2,6, C6H4F); 7.53 (1Н, d, J = 7.3, Н-7);
7.94 (2Н, d, J = 8.85, Н-3,5, C6H4F); 10.92 (1H, s, NH). Mass spectrum, m/z (Irel, %): 339 [М]+ (2.30), 295
[М-СО2]+ (32.53), 146 [C7H5NО]+ (33.63), 123 [СОC6H4F]+ (100), 44 [СО2]+ (43.24). Found, %: С 63.68;
Н 2.93; F 5.56; N 4.09. C18H10FNO5. Calculated, %: С 63.72; Н 2.97; F 5.60; N 4.13.
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