Synthesis of 5-[(indol-2-on-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6- diones and spirocyclopropyloxindole derivatives. Potential aldose reductase inhibitors

Full text of DOI:10.1021/jo981673r

J . Org. Chem. 1999, 64, 1369-1371
1369
ing oxindolyl derivatives. Thus, it was our aim to
synthesize 5-[(oxindol-3-yl)methyl]-2,2-dimethyl-1,3-di-
oxane-4,6-diones (oxindolyl derivatives of 3b) and also
5-[(oxindol-3-hydroxy-3-yl)methyl]-2,2-dimethyl-1,3-diox-
ane-4,6-diones (dioxindolyl derivatives of 3b) to be able
to evaluate them as inhibitors of aldose reductase.
Syn th esis of
5-[(In d ol-2-on -3-yl)m eth yl]-2,2-d im eth yl-1,3-
d ioxa n e-4,6-d ion es a n d
Sp ir ocyclop r op yloxin d ole Der iva tives.
P oten tia l Ald ose Red u cta se In h ibitor s†
Walajapet G. Rajeswaran,*,‡ Rita B. Labroo,§ and
Louis A. Cohen
Resu lts a n d Discu ssion
Treatment of indoles 1a -d with Meldrum’s acid 2 and
formaldehyde, following the procedure of Farlow et al.,6
gave indolyl derivatives 3a -d in 80-96% yield. The
indolyl derivatives 3a -c were treated with 1 equiv of
N-bromosuccinimide in 95% tert-butyl alcohol/water fol-
lowing the procedure of Hinman et al.7 to yield the
corresponding oxindolyl derivatives 4a -c in 62-67%
yield. Surprisingly, similar treatment of 5-[(5-nitroindol-
3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione 3d with
NBS yielded only the bromo derivative 5 (Scheme 1).
It was also of interest to oxidize the oxindolyl deriva-
tives to the corresponding 2,3-dioxindolyl derivatives.
Treatment of oxindolyl derivative 4a with oxygen8 in 1
N sodium hydroxide solution did not give the desired
dioxindolyl derivative 6 but resulted in the cleavage of
the heterocyclic ring to yield aniline derivative 7 in 63%
yield. This type of cleavage of an oxindole ring under
basic oxidative conditions has precedence in the litera-
ture.9 Consequently, we decided to synthesize the 3-bro-
mooxindolyl derivative and then convert it into the
corresponding dioxindole. Treatment of indolyl deriva-
tives 3a and 3b with 2 equiv of N-bromosuccinimide at
room temperature gave only the unusual spirocyclopro-
pane derivatives 8a and 8b in 47-52% yield, presumably
via the 3-bromooxindolyl intermediate. Although, we
managed to isolate 3-bromooxindole derivative 9 under
very meticulous conditions (e.g., the reaction workup was
done at or below room temperature), our attempted
hydrolysis resulted in the isolation of only the spirocy-
clopropane derivative 8a (Scheme 2). The 3-bromooxin-
dole derivative 9 was not stable, and NMR studies
indicated its slow conversion to the spirocyclopropane
derivative 8a . Further attempts to synthesize dioxinolyl
derivative 6 were abandoned.
Laboratory of Bioorganic Chemistry, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892
Michael M. King*
Department of Chemistry, The George Washington
University, Washington, D.C. 20052
Received August 17, 1998
In tr od u ction
Aldose reductase is an enzyme found in the eye lens
and in a variety of other tissues which display diabetes-
associated pathology in humans.1-3 This enzyme has been
implicated in diabetic cataract, and there has been
increasing evidence of its involvement in other diabetic
complications such as corneal wound healing defects,
neuropathy, retinopathy, nephropathy, and platelet ag-
gregation. To treat and prevent such diabetic complica-
tions arising from elevated levels of sorbitol, research has
focused on the development of potent aldose reductase
inhibitors (ARIs).
There have been a number of reports4 in the literature
on structurally diverse ARIs. During previous studies5
from this laboratory, 5-[(5-fluoroindol-3-yl)methyl]-2,2-
dimethyl-1,3-dioxane-4,6-dione 3b displayed high aldose
reductase inhibitory activity. On the basis of those
studies,5 certain structural and functional requirements
for a good inhibitor were noted. For example, the inhibi-
tory activities of oxindolyl derivatives were better than
the corresponding indolyl derivatives and the activity of
dioxindolyl derivatives were better than the correspond-
† Dedicated to the memory of the late Dr. Louis A. Cohen.
‡ Current address: Peptide Research Labs SL12, Department of
Medicine, Tulane University Medical Center, 1430 Tulane Avenue,
New Orleans, LA 70112. Email: wrajesw@mailhost.tcs.tulane.edu.
Fax: (504)-584-3586.
The structures of spirocyclopropyloxindole derivatives
1
8a and 8b were supported by H and 13C spectral data.
1
The H NMR of compound 8a showed two doublets at δ
§ Current address: Department of Pharmaceutics, Box 357610,
University of Washington, Seattle, WA 98195.
2.83 and 3.09 due to the cyclopropyl CH2 group, and the
corresponding peaks were observed at δ 2.81 and 3.0 in
the 1H spectrum of 8b. The downfield shifts of the
cyclopropyl protons could be attributed to the spatial
orientations of these protons. A 3D structure of the
skeleton of 8a , sans the methyl groups for greater clarity,
is depicted in Figure1. As suggested by the figure, one of
the cyclopropyl protons is situated in the deshielding zone
of the ring current as well as one of the carbonyl groups
and the other proton is in the deshielding zone of two
carbonyl groups. 13C NMR of 8a and 8b displayed peaks
at δ 21.5 and 21.3, respectively, for the cyclopropyl
Deceased September 1996.
(1) Pfeiffer, M. A.; Schumer, M. P.; Gelber, D. A. Diabetes Suppl. 2
1997, 46, S82-S89.
(2) Cameron, N. E.; Cotter, M. A.; Basso, M.; Hohman, T. C.
Diabetologia 1997, 40, 271.
(3) Tomlinson, D. R.; Stevens, E. J .; Diemel, L. T. Trends Pharmacol.
Sci. 1994, 15, 293.
(4) (a) Donkor, I. O.; Abdel-Ghany, Y. S.; Kador, P. F.; Mizoguchi,
T.; Bartoszko-Malik, A.; Miller, D. D. Eur. J . Med. Chem. 1998, 33,
15. (b) Rastelli, G.; Vianello, P.; Barlocco, D.; Costantino, L.; Corso, A.
D.; Mura, U. Bioorg. Med. Chem. Lett. 1997, 7, 1897. (c) Malamas, M.
S.; Guanwan, I. U.S. Patent 5,677,342, 1997. (d) Aotsuka, T.; Abe, N.;
Fukushima, K.; Ashizawa, N.; Yoshida, M. Bioorg. Med. Chem. Lett.
1997, 7, 1677. (e) Yonezawa, Y.; kasugawa, H. J pn. Kokai Tokkyo Koho
J P 09295977, 1996; Chem. Abstr. 1998, 128, 48234. (f) Unno, R.;
Yamaguchi, T.; Usui, T.; Kakigami, T.; Fukushima, M.; Mizuno, K.;
Baba, Y.; Kurono, M. Chem. Pharm. Bull. 1994, 42, 1474. (g) Costan-
tino, L.; Rastelli, G.; Cignarella, G.; Vianello, P.; Barlocco, D. Expert
Opin. Ther. Pat. 1997, 7, 843; Chem. Abstr. 1997, 127, 229014.
(5) Labroo, R. B. Ph.D. Dissertation. Submitted to the George
Washington University, 1990.
(6) Farlow, D. S.; Flaugh, M. E.; Horvath, S. D.; Lavagnino, E. R.;
Pranc, P. Org. Prep. Proc. Int. 1981, 13, 39.
(7) Hinman, R. L.; Bauman, C. P. J . Org. Chem. 1964, 29, 1206.
(8) Labroo, R. B.; Cohen, L. A. J . Org. Chem. 1990, 55, 4901.
(9) Aeberli, P.; Houlihan, W. J . J . Org. Chem. 1968, 33, 1640.
10.1021/jo981673r CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

1370 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
Sch em e 2a
F igu r e 1.
Sch em e 3a
a
(i) t-BuOK/t-BuOH, rt. (ii) NaOH/aqueous MeOH, rt.
aqueous methanol, to yield 3-methyloxindole-3-propionic
acid 11 in 64% yield (Scheme 3).
Aldose reductase inhibitory activity of the oxindole
derivatives reported in this paper will be reported in due
course. It is expected that the azidoindole and azidoox-
indole derivatives 3c and 4c, respectively, will be of use
in photoaffinity labeling studies of AR to learn more
about its binding pockets. Such information would help
in designing still better inhibitors.
a
Exp er im en ta l Section
(i) 1 N NaOH/air, rt 20 h. (ii) 2NBS, t-BuOH/H2O, rt 3 h. (iii)
Dioxane/H2O, reflux, 2 h (or) MeOH/H2O/HCl, rt.
Gen er a l Meth od s. Elemental analyses were done at Atlantic
Microlab, Norcross, GA. Silica gel 60 (230-400 mesh) was used
for column chromatography.
methylene carbon. This observation was further cor-
roborated by an APT experiment, which showed that
these carbons were attached to an even number of
hydrogens.
We also wanted to study the effect of a methyl group
at the 3-position of oxindole. Since earlier work5 from this
laboratory indicated moderately high inhibitory activity
for dioxindole-3-propionic acid, it was desirable to replace
the OH group with the CH3 group at the three position
of oxindole. Thus, 1-acetyl-3-methyloxindole 10 was
treated with ethyl acrylate and potassium tert-butoxide
in tert-butyl alcohol, followed by sodium hydroxide in
Syn th esis of 5-(In d ol-3-ylm eth yl)-2,2-d im eth yl-1,3-d iox-
a n e-4,6-d ion es 3a -d . Gen er a l P r oced u r e. To a solution of
appropriate indole 1a -d (10 mmol) in CH3CN (10 mL) were
added Meldrum’s acid 2, formaldehyde (37%, 0.81 mL, 10 mmol),
and L-proline (0.06 g, 0.5 mmol), and the reaction mixture was
stirred at room temperature for 5 h (20 h for 1d ). After removal
of the solvent under reduced pressure, the residue was dissolved
in warm ethanol or methanol and crystallized.
5-(In d ol-3-ylm e t h yl)-2,2-d im e t h yl-1,3-d ioxa n e -4,6-d i-
on e 3a : yield 2.29 g (84%); mp 123 °C (dec) (lit.6 mp 106-108
°C); 1H NMR (CDCl3) δ 1.45 (s, 3H, Me), 1.7 (s, 3H, Me), 3.65
(d, J ) 3.2 Hz, 2H, CH2), 3.77 (t, J ) 3.2 Hz, 1H, CH), 7.1-7.21

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1371
(m, 3H, arom), 7.32 (d, J ) 7.8 Hz, 1H, arom), 7.72 (d, J ) 7.8
Hz, 1H, arom), and 8.1 (bs, 1H, NH).
Attem p ted syn th esis of d ioxin d ole d er iva tive 6. Air was
bubbled through a stirred suspension of compound 4a (0.1 g,
0.35 mmol) in a 1 N NaOH solution (5 mL) for 20 h at room
temperature. The solution was neutralized with a few drops of
AcOH at 0 °C, and the precipitated solid was washed with H2O,
dried, and crystallized from EtOAc/hexane. The compound was
5-(5-F lu or oin d ol-3-ylm eth yl)-2,2-d im eth yl-1,3-d ioxa n e-
4,6-d ion e10 3b: yield 2.8 g (96%); mp 121-123 °C (methanol);
1H NMR (CDCl3) δ 1.51 (s, 3H, Me), 1.72 (s, 3H, Me), 3.47 (d,
2H, J ) 4.8 Hz, CH2), 4.12 (t, 1H, J ) 4.8 Hz), 6.87-6.94 (m,
1H, arom), 7.17 (s, 1H, arom), 7.32-7.36 (m, 2H, arom), and 9.2
(bs, 1H, NH); MS (CI, NH3) m/z 292 (M + 1). Anal. Calcd for
1
found to be 7: yield 0.06 g (63%); mp 155 °C; H NMR (CDCl3)
δ 1.88 (s, 3H, Me), 1.91 (s, 3H, Me), 3.85 (t, 1H, J ) 3.63 Hz),
3.93 (d, 2H, J ) 3.63 Hz), 6.21 (bs, 2H, NH2), 6.64-6.72 (m, 2H,
arom), 7.3 (m, 1H, arom), and 7.75 (d, 1H, J ) 8.2 Hz arom);
MS (CI/NH3) m/z 278 (M + 1). Anal. Calcd for C14H15NO5: C,
60.65; H, 5.45; N, 5.05. Found: C, 60.55; H, 5.41; N, 5.01.
C
15H14NO4F: C, 61.85; H, 4.81; N, 4.81; F, 6.53. Found: C, 61.84;
H, 4.68; N, 4.66; F, 6.33.
5-(5-Azid oin d ol-3-ylm et h yl)-2,2-d im et h yl-1,3-d ioxa n e-
4,6-d ion e 3c: yield 2.51 g (80%); mp 160-62 °C (ethanol); 1H
NMR (CDCl3) δ 1.5 (s, 3H, Me), 1.7 (s, 3H, Me), 3.6 (d, 2H, J )
4.5 Hz), 3.75 (t, 1H, J ) 4.5 Hz), 6.86 (dd, 1H, arom), 7.2-7.4
(m, 3H, arom), and 8.08 (bs, 1H, NH); MS (CI/NH3) m/z 332 (M
+ 18). Anal. Calcd for C15H14N4O4: C, 57.32; H, 4.49; N, 17.83.
Found: C, 57.26; H, 4.54; N, 17.93.
Syn th esis of Sp ir ocyclop r op a n e Der iva tives 8a a n d 8b.
To a solution of compound 3a or 3b (1 mmol) in t-BuOH (19
mL) and H2O (1 mL) was added NBS (0.36 g, 2 mmol). The
reaction mixture was stirred for 3 h at room temperature,
whereupon the solvent was removed under reduced pressure.
Cold H2O was added to the reaction mixture, and the precipi-
tated solid was filtered, washed further with H2O, dried, and
crystallized from appropriate solvents.
5-(5-Nit r oin d ol-3-ylm et h yl)-2,2-d im et h yl-1,3-d ioxa n e-
4,6-d ion e 3d : yield 2.5 g (79%); mp 195 °C (dec, methanol) (lit.11
1
mp 182 °C); H NMR (DMSO-d6) δ 1.55 (s, 3H, Me), 1.8 (s, 3H,
Me), 3.48 (d, 2H, J ) 4.5 Hz), 4.87 (t, 1H, J ) 4.5 Hz), 7.36 (s,
1H, indole-2H), 7.51 (d, 1H, J ) 8.8 Hz), 7.98 (d, 1H, J ) 8.8
Hz), 8.67 (s, 1H, arom), and 11.7 (s, 1H, NH); MS (CI/NH3) m/z
318 (M+).
Sp ir ocyclop r op a n e d er iva tive 8a : yield 0.15 g (52%); mp
270 °C (dec, acetone/hexane); 1H NMR (CDCl3) δ 1.35 (s, 3H,
Me), 1.71 (s, 3H, Me), 2.83 (d, 1H, J ) 6.4 Hz), 3.09 (d, 1H, J )
6.4 Hz), 7.0 (d, 1H, J ) 7.74 Hz, arom), 7.09 (t, 1H, J ) 7.74 Hz,
arom), 7.31-7.4 (m, 2H, arom), and 8.05 (bs, 1H, NH); 13C NMR
(CDCl3) δ 21.5, 27.0, 29.5, 41.7, 44.9, 106.2, 111.5, 123.5, 124.5,
126, 131, 142, 159.5, 163.5, and 172; MS (CI/NH3) m/z 305 (M
+ 18). Anal. Calcd for C15H13NO5: C, 62.72; H, 4.56; N, 4.88.
Found: C, 62.56; H, 4.63; N, 4.83.
Syn th esis of 5-(In d ol-2-on -3-ylm eth yl)-2,2-d im eth yl-1,3-
d ioxa n e-4,6-d ion es 4a -c. Gen er a l P r oced u r e. To a solution
of the compound 3a -c (1 mmol) in 95% t-BuOH/H2O (10 mL)
was added NBS (0.18 g, 1 mmol) slowly over a period of 20 min.
The solution was stirred at room temperature for 2 h and
concentrated. The residue was extracted with EtOAc, washed
with H2O (3 × 15 mL), and dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue was dissolved in
the appropriate solvent(s) and crystallized.
Sp ir ocyclop r op a n e d er iva tive 8b: yield 0.14 g (47%); mp
1
280 °C (dec, acetone); H NMR (CDCl3) δ 1.4 (s, 3H, Me), 1.78
(s, 3H, Me), 2.81 (d, 1H, J ) 6.2 Hz), 3.0 (d, 1H, J ) 6.2 Hz),
6.9-7.18 (m, 3H, arom), and 7.9 (bs, 1H, NH); 13C NMR (CDCl3/
CD3OD) δ 21.3, 26.1, 28.3, 41.6, 44.5, 105.8, 111.4, 112.6, 112.9,
117, 123.9, 138.8, 159.5, 162.5, and 171.5; MS (CI/NH3) m/z 323
(M + 18). Anal. Calcd for C15H12NO5F: C, 59.02; H, 3.96; N, 4.59.
Found: C, 58.90; H, 3.97; N, 4.58.
5-(In d ol-2-on -3-ylm et h yl)-2,2-d im et h yl-1,3-d ioxa n e-4,6-
d ion e 4a : yield 0.19 g (66%); mp 148-49 °C (dec, EtOAc/
1
hexanes); H NMR (CDCl3) δ 1.8 (s, 3H, Me), 1.95 (s, 3H, Me),
2.44-2.53 (m, 1H), 2.61-2.71 (m, 1H), 3.96-4.02 (m, 1H), 4.93-
4.96 (dd, 1H), 6.8 (d, 1H, J ) 7.5 Hz, arom), 7.07 (t, 1H, arom),
7.22-7.30 (m, 2H, arom), and 7.73 (bs, 1H, NH); MS (CI/NH3)
m/z 290 (M + 1). Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23;
N, 4.84. Found: C, 62.22; H, 5.22; N, 4.81.
Syn th esis of 3-(3-Meth ylin d ol-2-on -3-yl)p r op ion ic Acid
11. Compound 10 (0.19 g, 1 mmol) was dissolved in t-BuOH (12
mL). t-BuOK (0.05 g, 0.5 mmol) and ethyl acrylate (0.12 mL,
1.1 mmol) were added to the solution at one time, and the
reaction mixture was stirred at room temperature under an N2
atmosphere for 6 h. Then the solvent was removed under
reduced pressure, and the residue was dissolved in 90% MeOH/
H2O (15 mL). To this solution was added NaOH (0.2 g, 5 mmol),
and the reaction mixture was stirred at room temperature for 3
h. The solvent was removed under reduced pressure, and the
residue was taken up in cold H2O (15 mL). The solution was
cooled and acidified with AcOH. The precipitated solid was
filtered, washed with H2O, and dried. The crude compound was
crystallized using MeOH/H2O: yield 0.14 g (64%); mp 133-35
5-(5-F lu or oin d ol-2-on -3-ylm eth yl)-2,2-d im eth yl-1,3-d iox-
a n e-4,6-d ion e 4b: yield 0.19 g (62%); mp 161-62 °C (dec,
1
EtOAc); H NMR (CDCl3) δ 1.83 (s, 3H, Me), 1.95 (s, 3H, Me),
2.46-2.69 (m, 2H), 4.0 (m, 1H), 6.82-7.07 (m, 3H, arom), and
7.72 (bs, 1H, NH); MS (CI/NH3) m/z 308 (M + 1). Anal. Calcd
for C15H14NO5F: C, 58.63; H, 4.59; N, 4.56. Found: C, 58.60; H,
4.66; N, 4.63.
5-(5-Azid oin d ol-2-on -3-ylm eth yl)-2,2-d im eth yl-1,3-d iox-
1
a n e-4,6-d ion e 4c: yield 0.22 g (67%); mp 150-55 oC (dec); H
NMR (CDCl3) δ 1.8 (s, 3H, Me), 1.9 (s, 3H, Me), 2.43-2.66 (m,
2H, CH2), 3.98 (dd, 1H), 4.87 (dd, 1H), 6.83-6.97 (m, 3H, arom),
and 7.52 (bs, 1H, NH); MS (EI) m/z 330 (M+). Anal. Calcd for
C
15H14N4O5: C, 54.55; H, 4.27; N, 16.96. Found: C, 54.73; H, 4.36;
N, 16.75.
Syn th esis of 5-(5-Nitr oin d ol-3-ylm eth yl)-5-br om o-2,2-
1
°C; H NMR (CDCl3) δ 1.4 (s, 3H, Me), 2.0-2.32 (m, 4H), 6.89
(d, 1H, J ) 7.8 Hz, arom), 7.03 (t, 1H, J ) 7.8 Hz, arom), 7.13-
7.22 (m, 2H, arom), and 8.73 (bs, 1H, NH); 13C NMR (CD3CN) δ
23.9, 29.9, 33.7, 48.6, 110.7, 123.3, 124.2, 129.1, 134.69, 142.2,
174.8 (CONH-), and 182.6 (COOH); MS (EI) m/z 219. Anal. Calcd
for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.84; H,
6.03; N, 6.33.
d im eth yl-1,3-d ioxa n e-4,6-d ion e 4d . The compound 3d (0.32
g, 1 mmol) was dissolved in a mixture of THF (10 mL), t-BuOH
(5 mL), and H2O (1 mL). NBS (0.18 g, 1 mmol) was then added,
and the reaction mixture was stirred for 3 h. Then the solvents
were removed under reduced pressure, and the precipitated solid
was filtered, washed with H2O, and dried. The crude compound
4d was crystallized from acetone/hexane: yield 0.23 g (58%);
mp 154-56 °C (dec); 1H NMR (CDCl3) δ 1.2 (s, 3H, Me), 1.82 (s,
3H, Me), 4.1 (s, 2H), 7.4 (d, 1H, J ) 1.7 Hz, arom), 7.6 (d, 1H, J
) 9.3 Hz, arom), 8.05 (dd, 1H, arom), 8.72 (d, 1H, J ) 1.4 Hz,
arom), and 10.98 (bs, 1H, NH); MS (CI/NH3) m/z 396 and 398
(M+). Anal. Calcd for C15H13N2O6Br: C, 45.36; H, 3.3; N, 7.05.
Found: C, 45.45; H, 3.36; N, 7.00.
Ack n ow led gm en t. We thank Dr. Peter F. Kador,
National Eye Institute, for his interest in the biological
evaluation of the compounds for aldose reductase activ-
ity. We also would like to thank Noel Whittaker and
Wesley White for providing the mass spectral data
reported in this paper. W.G.R. thanks the National
Institutes of Health, Bethesda, MD, for a visiting
fellowship.
(10) The data for this compound was taken from ref 5.
(11) Gylys, J . A.; Ruediger, E. H.; Smith, D. W.; Solomon, C.; Yevich,
J . P.; Dextraze, P. U.S. Patent 5,521,188, 1996.
J O981673R