Novel ring contraction of 3-hydroxy-2,4(1H,3H)-quinolinediones in aqueous alkali. The first convenient route to 2-hydroxyindoxyls

Article abstract of DOI:10.1021/jo015786d

Ring contraction of 3-hydroxy-2,4(1H, 3H)-quinolinediones (1) in aqueous potassium hydroxide resulted in the formation of 2-hydroxyindoxyls and/or dioxindoles. The choice of N-substituent and the reaction conditions govern the chemoselectivity of the reaction. N-Phenyl-substituted derivatives 1 give 2-hydroxyindoxyls, while N-alkyl- and N-benzyl-substituted derivatives afford the corresponding dioxindols. On the basis of byproduct analysis, as well as independent experiments, the most plausible reaction mechanism is proposed.

Full text of DOI:10.1021/jo015786d

6394
J . Org. Chem. 2001, 66, 6394-6399
Novel Rin g Con tr a ction of 3-Hyd r oxy-2,4(1H,3H)-qu in olin ed ion es
in Aqu eou s Alk a li. Th e F ir st Con ven ien t Rou te to
2-Hyd r oxyin d oxyls
Stanislav Kafka,*,† Anton´ın Kla´sek,† and J anez Kosˇmrlj*,‡
Faculty of Technology, Tomas Bata University, 762 72 Zl´ın, Czech Republic, and Faculty of Chemistry
and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
janez.kosmrlj@uni-lj.si
Received May 23, 2001
Ring contraction of 3-hydroxy-2,4(1H,3H)-quinolinediones (1) in aqueous potassium hydroxide
resulted in the formation of 2-hydroxyindoxyls and/or dioxindoles. The choice of N-substituent and
the reaction conditions govern the chemoselectivity of the reaction. N-Phenyl-substituted derivatives
1 give 2-hydroxyindoxyls, while N-alkyl- and N-benzyl-substituted derivatives afford the corre-
sponding dioxindols. On the basis of byproduct analysis, as well as independent experiments, the
most plausible reaction mechanism is proposed.
In tr od u ction
While dioxindoles are relatively easily obtained by
Grignard reaction on isatins13 and by oxidation of 1,3-
disubstituted 2-indolinones,14 the preparation of 2-hy-
droxyindoxyls still remains a synthetic challenge. Most
of the reported methods involve the oxidation of indolic
compounds whereby using m-CPBA,5a,15 monoperphthalic
acid,16 and dimethyldioxirane,17 2-hydroxyindoxyls are
often formed only as byproducts. Better results were
obtained with Davis’ reagent.3 Sakamoto et al.18 carried
out extensive work on oxidation of 2-substituted N-
acylindoles by MoO5‚HMPA, which directly afforded
1-acetyl-2-hydroxyindoxyls. However, relatively long re-
action times and rather low yields render such an
approach less attractive. Other approaches to N-acyl-2-
hydroxyindoxyls involve oxidation of 2,3,6-trimethyl-4-
(1H)-quinolinone by NaOCl19 and 2-methyl-3-phenylquin-
olinone by acidic potassium permanganate,20 in 30% and
12% yields, respectively. To our knowledge, there is only
one example in the literature for the synthesis of N-aryl
(or alkyl)-substituted 2-hydroxyindoxyls, where 3-(1-
adamantyl)-3-hydroxy-1-methylindolin-2-one was formed
by the oxidation of the corresponding indole derivative
with dimethyldioxirane at -78 °C, in 10% yield.17
Indoxyls play a role in chemistry and biochemistry.
They have proved to be useful synthetic intermediates
for the synthesis of various natural products and biologi-
cally active compounds1 such as the naturally occurring
antitumor antibiotic FR900482,2 mitomycin C,3 dragma-
cidin A,4 and others.5 2-Hydroxyindoxyl alkaloid me-
lochicorin was found in the plant Melochia corchorifolia,6
while other indoxyl alkaloids are documented as well.7
Similarly, dioxindole derivatives are encountered in
nature. Dioxindole derivatives were isolated from the
culture of a marine Streptomyces species.8,9 A rare
example of sulfur-containing phytoalexins, exemplified
by dioxindole dioxibrassinin,10 was isolated from cabbage
inoculated with Pseudomonas cichorii.11 Very recently,
four proteasome inhibitors of dioxindole structure were
isolated from the fermentation broth of Apiospora mon-
tagnei Sacc. TC 1093.12
† Tomas Bata University.
‡ University of Ljubljana.
(1) Kawasaki, T.; Masuda, K.; Baba, Y.; Terashima, R.; Takada, K.;
Sakamoto, M. J . Chem. Soc., Perkin Trans. 1 1996, 729-733 and
references cited therein.
Recently, we reported the unique reactivity of 3-hy-
droxy-2,4(1H,3H)-quinolinediones (1) in the presence of
a base under nonaqueous conditions, where 3-acyloxy-
1,3-dihydro-2H-indol-2-ones were formed via an R-ketol
(2) Zhang, W.; Wang. C.; J imenez, L. S. Synth. Commun. 2000, 30,
351-366.
(3) Wang, Z.; J imenez, L. S. J . Am. Chem. Soc. 1994, 116, 4977-
4978.
(4) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.; Inagawa,
M.; Sakamoto, M. Org. Lett. 2000, 2, 3027-3029.
(5) For example, see: (a) Desarbre, E.; Savelon, L.; Cornec, O.;
Me´rour, J . Y. Tetrahedron 1996, 52, 2983-2994. (b) Kawasaki, T.;
Tang, C.-Y.; Koizumi, E.; Nakanishi, H.; Sakamoto, M. Heterocycles,
1998, 48, 975-980. (c) Nonaka, Y.; Kawasaki, T.; Sakamoto, M.
Heterocycles 2000, 53, 1681-1684. (d) Me´rour, J .-Y.; Gadonneix, P.;
Malapel-Andrieu, B.; Desarbre, E. Tetrahedron, 2001, 57, 1995-2002
and references cited therein.
(6) Bhakuni, R. S.; Shukla, Y. N.; Thakur, R. S. Phytochemistry
1991, 30, 3159-3160.
(7) Seigler, D. S. Plant Secondary Metabolism; Kluwer Academic
Publishers: Norwell, MA, 1998.
(12) Kohno, J .; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.;
Shimizu, R.; Ohnuki, T.; Komatsubara, S. J . Org. Chem. 2000, 65, 990-
995.
(13) (a) Ogata, M.; Matsumoto, H.; Tawara, K. Eur. J . Med. Chem.
Chim. Ther. 1981, 16, 373-379. (b) Wierenga, W.; Griffin, J .; Warpe-
hoski, M. A. Tetrahedron Lett. 1983, 24, 2437-2440.
(14) Nishio, T. J . Chem. Soc., Perkin Trans. 1 1991, 1717-1720.
(15) Bourlot, A. S.; Desarbre, E.; Me´rour, J . Y. Synthesis 1994, 411-
416.
(16) Braudeau, E.; David, S.; Fischer, J .-C. Tetrahedron 1974, 30,
1445-1455.
(8) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.-Z.
Eur. J . Org. Chem. 2001, 261-267.
(17) Zhang, X.; Foote, C. S. J . Am. Chem. Soc. 1993, 115, 8867-
(9) Balk-Bindseil, W.; Helmke, E.; Weyland, H.; Laatsch, H. Liebigs
Ann. Chem. 1995, 1291-1294.
8868.
(18) Chien, C.-S.; Takanami, T.; Kawasaki, T.; Sakamoto, M. Chem.
Pharm. Bull. 1985, 33, 1843-1848.
(19) Staskun, B. J . Org. Chem. 1988, 53, 5287-5291 and ref 3 cited
therein.
(10) Soledade, M.; Pedras, C.; Okanga, F. I. Chem. Commun. 1998,
67-68.
(11) Monde, K.; Sasaki, K.; Shirata, A.; Takasugi, M. Phytochemistry
1991, 30, 2915-2917.
(20) Rees, C. W.; Sabet, C. R. J . Chem. Soc. 1965, 870-875.
10.1021/jo015786d CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/24/2001

Ring Contraction of 3-Hydroxy-2,4(1H,3H)-quinolinediones
J . Org. Chem., Vol. 66, No. 19, 2001 6395
Ta ble 1. Rea ction of 1a -j w ith Aqu eou s KOH
Sch em e 1
sub-
strate
1
products
(yield)a
3
reaction
entry
R1 R2 time (h)
2
others
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1f
1g
1h
1i
Ph Me
Ph Et
Ph Pr
Ph Bu
Ph Ph
Ph Ph
Me Bu
Et Bn
Bn Bn
Me Ph
Bn Ph
0.5
6
3
2a (52)
2b (71)
2c (73)
2d (51)
2e (57)
4.5
2.5
4
4 (21)
4 (21)
2e (25) 3e (11)
3f (64)
7b
rearrangement.21 Since these types of rearrangements
are of great importance in metabolism,22-24 we were
prompted to investigate the reactivity of 1 under aqueous,
basic conditions in the presence of air.25,26 Although our
primary goal was aimed at better understanding the
metabolism of 1, the high product yields in these reac-
tions led us to explore their synthetic utility as well.
Herein, we wish to demonstrate that 3-hydroxy-2,4-
(1H,3H)-quinolinediones (1) react with aqueous potas-
sium hydroxide to produce 2-hydroxy-1,2-dihydroindol-
3-ones (2-hydroxyindoxyls, 2) and/or isomeric 3-hydroxy-
1,3-dihydroindol-2-ones (dioxindoles, 3) in good yields.
39b
43b
12
3g (45) 6g (29), 8g (38)
3h (42)
3i (57) 6i (10), 8i (5)
10
11
1j
160
3j (33)
5 (16), 6j (5),
7j (9), 8i (10)
a
Refers to isolated percent yield. b Reaction conducted at reflux.
Resu lts a n d Discu ssion
Starting compounds 1a -j were readily obtained ac-
cording to the literature procedure by condensation of
N-substituted anilines with diethyl malonates to the
corresponding 4-hydroxy-2(1H)-quinolones, followed by
oxidation with peroxyacetic acid.27-29 In a typical ring-
contraction experiment, the reaction of 1a (Scheme 1,
Table 1) was conducted in a vigorously stirred mixture
of 1.3 M aqueous KOH and benzene at room temperature
and in the presence of air. The reaction mixture turned
yellow, and after 0.5 h the reaction was complete.
According to TLC analysis, one major product was
formed, accompanied by small amounts of a few byprod-
ucts. Layers were separated, and the aqueous phase was
extracted with benzene. The combined organic layers
were concentrated, and the crude product was subjected
to column chromatography to yield 2a . Similarly, four
other N-phenyl-substituted quinolinediones 1b-e (Table
1, entries 2-5) were reacted to yield 2-hydroxyindoxyls
2b-e. In the case of 1e, benzoin 4 was also formed and
was isolated in low yield (Figure 1, Table 1).
F igu r e 1. Structures of byproducts.
was observed for N-alkyl-substituted analogues 1f-j
(Table 1, entries 7-11). In reactions with these com-
pounds, two products were initially formed (as indicated
by TLC analysis), and according to the characteristic
yellow color, one was tentatively identified as 2-hydroxy-
indoxyl. However, along with the consumption of the
starting material, the yellow product disappeared from
the reaction mixture as well. Isolation as described above
yielded colorless dioxindoles 3f-j. In some cases, we
succeeded in isolating some byproducts as indicated in
Table 1.
A plausible reaction path leading to the formation of
2 is presented in Scheme 2. First, the quinolinedione 1
may undergo base-catalyzed ketol rearrangement to
intermediate A. This is in accord with our previous
findings on the reaction of quinolinediones 1 with differ-
ent organic bases in the absence of water.21 The formation
of intermediate A in the proposed mechanism is sup-
ported by the isolation of the ester 5 (Figure 1 and Table
1, entry 11), a result of an “R-hydroxy-â-diketone to
R-acyloxy amide” rearrangement of A. However, from this
point on the course of the reaction differs substantially
from the one under nonaqueous conditions. In the pres-
ence of water, hydrolysis of the lactam ring in A can take
place, followed by decarboxylation leading to the inter-
mediate B. Alternatively, A can first undergo a molecular
rearrangement to the 3,1-benzoxazin-2-one intermedi-
ate,21 which is then hydrolyzed and decarboxylated to B.
Ring closure and subsequent oxidation of a glycol inter-
mediate C with air finally results in 2. Attempts to isolate
intermediates A, B, or C were unsuccessful, which,
considering their instability, is not surprising. The
intermediate B can be, under the basic conditions em-
ployed, transformed via enediol to the isomeric benzoin
4 (Table 1, entries 5 and 6). The fact that 4 was obtained
from 1e thus additionally supports the mechanism
In contrast to N-phenyl-3-hydroxy-2,4(1H,3H)-quino-
linediones 1a -e, a significant decrease in the reactivity
(21) Kla´sek, A.; Korˇistek, K.; Polis, J .; Kosˇmrlj, J . Tetrahedron 2000,
56, 1551-1560.
(22) Crout, D. H. G.; Lee, E. R.; Rearson, D. P. J . J . Chem. Soc.,
Perkin Trans. 1 1991, 381-385 and references cited therein.
(23) Brunner, H.; Sto¨hr, F. Eur. J . Org. Chem. 2000, 2777-2786
and references cited therein.
(24) Sprecher, M. Chemtracts: Org. Chem. 1991, 4, 307-311 and
references cited therein.
(25) Quinolines and their derivatives are often involved as inter-
mediates in biochemical processes. For reviews, see: Fetzner, S.;
Tshisuaka, B.; Lingens, F.; Kappl, R.; Hu¨ttermann, J . Angew. Chem.,
Int. Ed. Engl. 1998, 37, 576-597. For example, see: Boyd, D. R.;
Sharma, N. D.; Carroll, J . G.; Malone, J . F.; Mackerracher, D. G.; Allen,
C. C. R. Chem. Commun. 1998, 683-684 and references cited therein.
(26) Compounds 1 were found as metabolites produced by Pseudomo-
nas species: (a) Neuenhaus, W.; Budzikiewicz, H. Z. Naturforsch. B
1979, 34, 313-315. (b) Budzikiewicz, H.; Schaller, U.; Korth, H.;
Pulverer, G. Monatsh. Chem. 1979, 110, 947-953. (c) Kitamura, S.;
Hashizume, K.; Iida, T.; Miyashita, E.; Shirahata, K.; Kase, H. J .
Antibiot. 1986, 39, 1160-1166.
(27) Kla´sek, A.; Korˇistek, K.; Polis, J .; Kosˇmrlj, J . Heterocycles 1998,
48, 2309-2326.
(28) Kafka, S.; Kova´rˇ, M.; Kla´sek, A.; Kappe, T. J . Heterocycl. Chem.
1996, 33, 1977-1982.
(29) Stadlbauer, W.; Lutschounig, H.; Schindler, G.; Witoszynskyj,
T.; Kappe, T. J . Heterocycl. Chem. 1992, 29, 1535-1540.

6396 J . Org. Chem., Vol. 66, No. 19, 2001
Kafka et al.
Sch em e 2
Sch em e 3
proposed in Scheme 2. For the benzoin B it is known to
exist in the equilibrium with the dihydrodiol C.30-32
conditions for 4 h, the mixture of 2e (25%), 3e (11%), and
4 (21%) was isolated (Table 1, entry 6). Additionally, the
consistent yield of 4 in these two experiments indicates
that 4 must be formed in an early stage in the reaction
path, such as proposed in Scheme 2.
A
rapid oxidation of the latter removes it from the equilib-
rium, giving 2. Such a facile oxidation of indole-2,3-
dihydrodiols has been reported by several authors.2,5a,30,33
From the observations discussed above, it can be
concluded that the primary products of the base-mediated
ring contraction of 1a -j are the 2-hydroxyindoxyls 2a -
j. They are stable under the relatively mild reaction
conditions required for the transformation of N-phenyl-
substituted 1a -e and can be isolated from the reaction
mixture. This, however, does not account for the more
vigorous conditions necessary to achieve the reaction of
the N-alkyl (or benzyl) analogues 1f-j where 2-hydroxy-
indoxyls, only detected during the progress of the reac-
tion, rearrange further to dioxindoles (Table 1, entries
7-11). The resistance of 2 to the rearrangement also
depends on the basic conditions used. For example,
compound 2e, initially obtained in the reaction of 1e with
1.3 M KOH/benzene as described above, was in an
independent experiment easily transformed to 3e using
a mixture of solid KOH in benzene. With a view to
achieving the highest yield of 2, careful optimization of
the reaction time is important, which is illustrated by
the following example. Compound 1e reacted completely
within a period of 2.5 h to the mixture of 2e (57%) and 4
(21%), with 3e being undetected (Table 1, entry 5).
However, when 1e was subjected to the same reaction
Observations of a similar rearrangement, leading to
dioxindoles, have been reported.20,34 Kalb showed that
ethyl 2-hydroxyindoxyl-2-carboxylate with aqueous so-
dium hydroxide yielded ethyl 3-hydroxyoxindole-3-car-
boxylate (Scheme 3; R1 ) H, R2 ) CO2Et).35 Two
mechanistic possibilities have been discussed for the
migration of the ester group.36 One (path a) involves
removal of a proton from 2-hydroxy group with the
subsequent 1,2-shift of carbethoxy group (base-catalyzed
R-ketol rearrangement).37 The other route (path b) re-
quires the opening of the carbinolamine function, followed
by the benzilic acid rearrangement38 and recyclization to
lactam.
For the formation of 3 in our example (Scheme 3; R1,
R2 ) alkyl, Bn, Ph), both scenarios could be plausible.39
Though in the case of Kalb’s rearrangement, ingenious
18O isotope labeling experiments revealed the R-ketol
rearrangement as the most plausible, we sought another,
simpler experiment that would provide us with an
adequate answer to this issue. Thus, we subjected
compound 2e to acetylation with a mixture of pyridine
(34) For recent example, see: Malapel-Andrieu, B.; Me´rour, J .-Y.
Tetrahedron Lett. 1998, 39, 39-42.
(35) Kalb, L. Ber. Dtsch. Chem. Ges. 1911, 44, 1455-1464.
(36) Acheson, R. M.; Booth, S. R. G. J . Chem. Soc. C 1968, 30-32.
(37) Smith, M. B.; March, J . March’s Advanced Organic Chemistry,
5th ed.; Wiley-Interscience: New York, 2001; p 1402.
(30) Harrison, D. M. Tetrahedron Lett. 1984, 25, 6063-6064.
(31) Kawasaki, T.; Ohtsuka, H.; Chien, C.-S.; Omata, M.; Sakamoto,
M. Chem. Pharm. Bull. 1987, 35, 1339-1346.
(32) It is noteworthy that related indole-2,3-dihydrodiol has been
postulated as an intermediate in the metabolism of indole by Pseudomo-
nas putida; see: (a) Ensley, B. D.; Ratzkin, B. J .; Osslund, T. D.; Simon,
M. J .; Wackett, L. P.; Gibson D. T. Science 1983, 222, 167-169. (b)
Boyd, D. R.; Sharma, N. D.; Boyle, R.; McMurray, B. T.; Evans, T. A.;
Malone, J . F.; Dalton, H.; Chima, J .; Sheldrake, G. N. J . Chem. Soc.,
Chem. Commun. 1993, 49-51.
(38) For review, see: Selman, S.; Eastham, J . F. Quart. Rev. 1960,
14, 221-235.
(39) Precedent for such aryl and alkyl migration in indolic com-
pounds is documented in the literature. For examples, see: (a) Witkop,
B.; Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 2188-2195. (b)
Giovannini, E.; Rosales, J . Helv. Chim. Acta 1963, 46, 1332-1338. (c)
Giovannini, E.; Karrer, F. Chimia, 1967, 21, 517-556. (d) Sukari, M.
A.; Vernon, J . M. J . Chem. Soc., Perkin Trans. 1 1983, 2219-2223.
(33) Carpentier, J .-F.; Mortreux, A. Tetrahedron: Asymmetry 1997,
8, 1083-1099.

Ring Contraction of 3-Hydroxy-2,4(1H,3H)-quinolinediones
J . Org. Chem., Vol. 66, No. 19, 2001 6397
Ta ble 2. Selected Ch a r a cter istic Sp ectr a l Da ta for
2-h yd r oxyin d oxyls 2a -e a n d Dioxin d oles 3e-j
compd
UV/vis (MeOH) λmax, nm (log ꢀ)
δ C-2, C-3a (ppm)
2a
207 (4.19), 228 (4.34), 254 (4.11),
281 (3.98), 418 (3.54)
89.1, 200.6
2b
2c
2d
2e
206 (4.19), 228 (4.31), 255 (4.14),
285 (4.05), 422 (3.54)
206 (4.21), 229 (4.32), 255 (4.14),
285 (4.04), 424 (3.53)
206 (4.22), 228 (4.34), 255 (4.16),
285 (4.06), 422 (3.54)
91.5, 200.9
91.0, 201.0
91.0, 200.9
91.6, 199.4
F igu r e 2. Selected correlations for 2e and 3e obtained from
HMBC data analysis.
Sch em e 4
207 (4.34), 230 (4.31), 253 (4.22),
286 (4.01), 424 (3.47)
2e
3e
3f
3g
3h
3i
(235, 255, 287, 420)b
214 (4.44), 246 (4.07)
213 (4.30), 258 (3.78)
214 (4.35), 260 (3.75)
213 (4.47), 259 (3.75)
214 (4.44), 259 (3.81)
212 (4.50), 259 (3.76)
177.0, 78.1
178.5, 76.7
177.4, 77.5
177.8, 77.6
177.5, 78.0
177.6, 78.0
3j
and acetic anhydride, resulting in 3-O-acetate 9 (Scheme
4). Since it is unlikely that the acetate of 2e transforms
to 9, the rearrangement to 3e should take place first,
accompanied by a slower acetylation process of the
tertiary alcohol 3e. The presumption that these reaction
conditions are hydroxyl anion-free makes the alternative
of the benzilic acid rearrangement path (path b) unlikely
in our case. The identity of 9 was confirmed by an
independent acetylation of 3e.
As expected, the quantity of byproducts formed in the
reactions of 1a -j is influenced by the experimental
conditions, being higher for the transformation of 1f-j
(Table 1, entries 7-11), and in a few cases we were
successful in isolating and identifying them. From a
mechanistic viewpoint, they additionally support the
proposed pathway via intermediate A (Scheme 2). For
instance, the alkaline hydrolysis of 5 leads to benzoic acid
(8i) and 1-benzyl-3-hydroxy-1,3-dihydro-2H-indol-2-one,
which is further oxidized to N-benzylisatin (6j). The
origin of N-benzylanthranilic acid (7j) can be explained
by hydrolysis of 6j with subsequent oxidation and de-
carboxylation.40 It is noteworthy that anthranilic acid was
found as a metabolite of quinoline by Pseudomonas
putida.41
Str u ctu r e Elu cid a tion . The infrared spectra without
supporting data cannot clearly identify the structure of
2 and 3, since the ν(CdO) vibrations for lactams 3e-j
appear in the same range (1698-1710 cm-1) as those of
2a -e (1678-1705 cm-1). Analysis of 1H, 13C, and 2D
NMR spectra suggested the molecular structure of 2 and
3. As a representative example, the carbonyl of 2e
resonates at δ 199.4 while that of 3e appears at δ 177.0
(typical for an amide group). In the HMBC spectrum of
2e, H-4 shows a correlation to the carbonyl at δ 199.4,
while in the case of 3e such a correlation is not observed
(Figure 2). Instead, both H-4 and the o-phenyl protons
show a correlation to the carbon resonating at δ 78.1
(C-3, carbinol C). In general, two carbon resonances are
strongly diagnostic of the structure of each isomeric
compound. In the isomer 2, carbons C-2 and C-3 resonate
in the range of δ 89-92 and 199-201, while in 3 the
lactam carbonyl (C-2) and carbon C-3 resonate at δ 177-
179 and 76-78, respectively (Table 2).
a
b
In CDCl3. Crystalline state, see text.
It has been reported that N-acyl-2-hydroxyindoxyls
exist in equilibrium with their open-chain tautomers,
o-acylaminobenzils, especially in less polar solvents, such
as deuteriochloroform.20,31 The presence of the open-chain
isomer 2′ (Figure 1), at least in deuteriochloroform
solution, was in our case easily ruled out by the appear-
ance of signals due to C-2 and C-3 (see above) and the
lack of the additional signal due to the keto carbonyl
(δ near 200) of 2′ (Figure 1).
UV-visible spectra of 2-hydroxyindoxyls 2a -e (Table
2) show four distinct bands in the ultraviolet region and
one in the visible region (λmax (MeOH) 418-424 nm, log
ꢀ 3.47-3.54). This is in a fairly good agreement with λmax
(MeOH) literature reports for some structurally related
N-unsubstituted 2-hydroxyindoxyls (λmax 400-406 nm,
log ꢀ 3.39-3.46).16 For comparison, the spectra of N-
methylisatin42 (λmax (EtOH) 420 nm, log ꢀ 2.70) and spiro-
[cyclopentane-1,2′-indoxyl]39a (λmax (EtOH) 400 nm, log ꢀ
3.57) that contain similar chromophors are notable.
However, any conclusion based only on the comparison
with the sparse examples of the UV-vis spectra of
2-hydroxyindoxyls reported in the literature is not un-
ambiguous. As pointed out by Rees and Sabet, the yellow
color of N-acetyl-2-phenyl-2-hydroxyindoxyl in various
solvents is probably due to the presence of the open-chain
tautomer (benzil derivative).20 Unfortunately, these au-
thors did not provide any UV-vis evidence. The yellow
color of benzils is well-known. Although their absorption
maxima in neutral solutions are typically at 370 nm,
bathochromic shifts of up to 90 nm have also been
reported.43,44 Moreover, in favor of Rees and Sabet’s
discussion is also the fact that some 2-O-protected
2-hydroxyindoxyls do not show maxima in the visible
region of the spectra.45 Therefore, to avoid any specula-
tion on the origin of the visible absorption for 2, we
decided to compare the UV-vis spectrum of the metha-
nolic solution of 2e (λmax 228, 255, 285, 422 nm) to that
in crystalline state (λmax 235, 255, 287, 420 nm). Nearly
(42) Ault, R. G.; Hirst, E. L.; Morton, R. A. J . Chem. Soc. 1935,
1653-1657.
(40) Casey, L. A.; Galt, R.; Page, M. I. J . Chem. Soc., Perkin Trans.
2 1993, 23-28.
(41) (a) Boyd, D. R.; McMordie, R. A. S.; Porter, H. P.; Dalton, H.;
J enkins, R. O.; Howarth, O. W. J . Chem. Soc., Chem. Commun. 1987,
1722-1724. (b) Boyd, D. R.; Sharma, N. D.; Dorrity, M. R. J .; Hand,
M. V.; McMordie, R. A. S.; Malone, J . F.; Porter, H. P.; Dalton, H. J .
Chem. Soc., Perkin Trans. 1 1993, 1065-1071.
(43) Kwart, H.; Baevsky, M. M. J . Am. Chem. Soc. 1958, 80, 580-
588.
(44) Leonard, N. J .; Rapala, R. T.; Herzog, H. L.; Blout, E. R. J .
Am. Chem. Soc. 1949, 71, 2997-3002.
(45) (a) Szmuszkovicz, J . J . Org. Chem. 1964, 29, 178-184. (b)
Letcher, R. M.; Kwok, N.-C. Lo, W.-H.; Ng, K.-W. J . Chem. Soc., Perkin
Trans. 1 1998, 1715-1719.

6398 J . Org. Chem., Vol. 66, No. 19, 2001
Kafka et al.
crude product was subjected to column chromatography using
chloroform to give N-ethylisatin (6g, mp 92-93 °C from hexane
(lit.46 mp 94 °C), and phenylacetic acid (8g, mp 75-77 °C from
hexane).
(b) The alkaline aqueous phase remaining after the benzene
extraction from the reaction of 1i was acidified with concen-
trated hydrochloric acid and extracted with benzene. The
combined organic layer was concentrated in vacuo and the
crude product was subjected to column chromatography using
solvent system S1 to yield bezoic acid (8i) and N-methylisatin
(6i, mp 131-133 °C from benzene (lit.48 mp 132-134 °C)).
(c) The alkaline aqueous phase remaining after the benzene
extraction from the reaction of 1j was acidified with concen-
trated hydrochloric acid and extracted with chloroform. The
combined organic layers were concentrated in vacuo and
subjected to column chromatography using solvent system S2.
Two fractions were collected. The more polar fraction (Rf ≈
0.25; benzene/ethyl acetate 4:1) was after evaporation sus-
pended in benzene and filtered, and the filtrate was concen-
trated in vacuo to give benzoic acid (8i). The less polar fraction
(Rf ≈ 0.65, benzene/ethyl acetate 4:1) was concentrated in
vacuo and subjected to column chromatography using chloro-
form as eluant, to give N-benzylisatin (6j, mp 128-131 °C from
benzene (lit.48 mp 129-131 °C)) and N-benzylanthranilic acid
(7j, mp 174.5-175.5 °C from cyclohexane/benzene (lit.49 mp
175-176 °C)).
identical absorption maxima in both cases confirm that
the wavelengths above 418 nm are indeed attributable
to 2-hydroxyindoxyl structure of 2 and not to its open-
chain tautomer form (2′, Figure 1).
Con clu sion s
In summary, the novel base-mediated ring transforma-
tion of 3-hydroxy-2,4(1H,3H)-quinolinediones described
above provides a direct access to N-aryl-2-hydroxy-
indoxyls or N-alkyldioxindoles. The chemoselectivity of
the reaction is governed by the choice of the N-substitu-
ent. N-Phenyl substituted 3-hydroxy-2,4(1H,3H)-quino-
linediones give 2-hydroxyindoxyls while the N-alkyl
derivatives afford the corresponding dioxindols. With
respect to the choice of the substrates discussed, the
selectivity seems to be general. The simple experimental
procedure and the good yields of the products render this
protocol superior to the existing strategies and attractive
for additional applications, especially for the synthesis
of 2-hydroxyindoxyls.
Exp er im en ta l Section
2-Hyd r oxy-2-m eth yl-1-p h en yl-1,2-d ih yd r o-3H-in d ol-3-
on e (2a ): yellow crystals; mp 124-126 °C (benzene/cyclohex-
Gen er a l Meth od s. UV-visible (UV-vis) spectra were
obtained either from methanol solutions or as Nujol mulls. 1H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
at 302 K. Chemical shifts are in ppm (δ) and are referenced
to internal TMS. Coupling constants (J ) are given in Hz.
Multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or br (broadened). High-
resolution mass spectra were obtained using EI ionization at
70 eV. Data are reported as m/z (relative intensity). Analytical
TLC was performed on Kavalier silica plates with UV 254 nm
indicator. Column chromatography was carried out on Kavalier
silica gel L 100/160 µm. Benzene and subsequently benzene-
ethyl acetate (19:1) (solvent system S1), benzene and subse-
quently benzene-ethyl acetate (9:1) (solvent system S2), or
chloroform were used as eluants.
1
ane); H NMR (CDCl3) δ 1.35 (s, 3H, CH3), 2.76 (s, 1H, OH),
6.84 (dd, J ) 7.0, 7.0 Hz, 1H, H-5), 6.90 (m, 1H, H-7), 7.28-
7.36 (m, 1H, o-Ph), 7.41-7.50 (m, 5H, Ph, H-6), 7.67 (m, 1H,
H-4); 13C NMR (CDCl3) δ 21.4 (CH3), 89.0 (C-2), 111.0 (C-7),
117.9 (C-3), 119.5 (C-5), 125.6 (C-4), 126.2, 126.7, 129.6, 138.2
(C-6), 138.4, 158.3 (C-7a), 200.6 (C-3).
2-E t h yl-2-h yd r oxy-1-p h en yl-1,2-d ih yd r o-3H -in d ol-3-
1
on e (2b): yellow crystals; mp 120-123 °C (cyclohexane); H
NMR (CDCl3) δ 0.70 (t, J ) 7.4 Hz, 3H), 1.75-2.01 (m, 2H),
2.74 (br s, 1H), 6.84 (dd, J ) 7.7, 7.2 Hz, 1H), 6.97 (d, J ) 8.3
Hz, 1H), 7.28-7.32 (m, 1H), 7.40-7.47 (m, 3H), 7.51-7.55 (m,
2H), 7.65 (d, J ) 7.7 Hz, 1H); 13C NMR (CDCl3) δ 7.2, 28.0,
91.5, 110.5, 118.8, 119.3, 125.3, 125.6, 126.3, 129.5, 138.1,
138.2, 159.1, 200.9.
Isatins 6g,46 6i,47 and 6j,47 phenylacetic acid (8g), and
benzoic acid (8i), were identified by comparison of their
spectral data to literature reports and to those of the authentic
samples.
2-Hyd r oxy-1-p h en yl-2-p r op yl-1,2-d ih yd r o-3H-in d ol-3-
1
on e (2c): yellow crystals; mp 106-108 °C (cyclohexane); H
NMR (CDCl3) δ 0.72 (t, J ) 7.3 Hz, 3H), 0.97-1.30 (m, 2H),
1.68-1.92 (m, 2H), 2.70 (br s, 1H), 6.82 (dd, J ) 7.5, 7.1 Hz,
1H), 6.94 (d, J ) 8.3 Hz, 1H), 7.25-7.33 (m, 1H), 7.39-7.48
(m, 3H), 7.49-7.54 (m, 2H), 7.62 (d, J ) 7.5 Hz, 1H); 13C NMR
(CDCl3) δ 13.9, 16.2, 37.2, 91.0, 110.5, 118.7, 119.3, 125.3,
125.6, 126.4, 129.5, 138.1, 138.1, 159.0, 201.0.
Gen er a l P r oced u r e for th e Rea ction of 3-Hyd r oxy-2,4-
(1H,3H)-qu in olin ed ion es (1a -j) w ith P ota ssiu m Hyd r ox-
id e. A mixture of 1 (5 mmol) in 1.3 M aqueous potassium
hydroxide in the presence of air (30 mL) and benzene (60 mL
for 1d ,f-i, and 120 mL for 1a -c,e,j) was vigorously stirred
at the temperature and the duration indicated in Table 1.
Layers were separated, and the aqueous phase was extracted
with benzene (5 × 20 mL). The combined organic layer was
shortly dried over K2CO3. The solvent was evaporated to
dryness, and the residue was crystallized from the solvent
indicated in Table 2 to give the corresponding products 2a -d
and 3f-i. In the case of the reaction of 1j (Table 1, entry 11),
the residue was purified by column chromatography using
solvent system S1, to give 3j and 5. The residue from the
reaction of 1e was subjected to column chromatography using
S1 to give 2e and 4 (Table 1, entry 5) or 2e, 3e, and 4 (Table
1, entry 6).
In the case of 1g, 1i, and 1j (Table 1, entries 6, 9-11), we
were successful in isolating the byproducts from the alkaline
aqueous phase remaining after the benzene extraction de-
scribed above, as follows:
(a) The alkaline aqueous phase remaining after the benzene
extraction from the reaction of 1g was acidified with concen-
trated hydrochloric acid and extracted with chloroform. The
combined organic layer was concentrated in vacuo and the
2-Bu t yl-2-h yd r oxy-1-p h en yl-1,2-d ih yd r o-3H -in d ol-3-
on e (2d ): yellow crystals; mp 81-83 °C (cyclohexane); 1H NMR
(CDCl3) δ 0.70 (t, J ) 6.8 Hz, 3H, CH3), 0.88-1.20 (m, 4H, 2
× CH2), 1.71-1.95 (m, 2H, CH2), 2.96 (s, 1H, OH), 6.83 (dd, J
) 7.7, 7.2 Hz, 1H, H-5), 6.95 (d, J ) 8.4 Hz, 1H, H-7), 7.28-
7.32 (m, 1H, p-Ph), 7.40-7.48 (m, 3H, m-Ph, H-6), 7.49-7.54
(m, 2H, o-Ph), 7.63 (dd, J ) 7.7, 1.3 Hz, 1H, H-4); 13C NMR
(CDCl3) δ 13.6, 22.5, 24.7, 34.7, 91.0 (C-2), 110.5 (C-7), 118.7
(C-3a), 119.3 (C-5), 125.3 (C-4), 125.6 (C-2 and C-6 of Ph), 126.3
(C-4 of Ph), 129.5 (C-3 and C-5 of Ph), 138.1, 138.1, 159.0 (C-
7a), 200.9 (C-3).
1,2-Diph en yl-2-h ydr oxy-1,2-dih ydr o-3H-in dol-3-on e (2e):
yellow crystals; mp 107-109 °C (hexane); 1H NMR (CDCl3) δ
3.34 (s, 1H, OH), 6.90 (dd, J ) 7.8, 7.8 Hz, 1H, H-5), 7.08 (d,
J ) 8.4 Hz, 1H, H-7), 7.10-7.46 (m, 10H, 2 × Ph), 7.47-7.54
(m, 1H, H-6), 7.64-7.69 (m, 1H, H-4); 13C NMR (CDCl3) δ 91.6
(C-2), 110.9 (C-7), 118.2 (C-3a), 120.0 (C-5), 124.9, 125.9, 126.1,
126.2, 128.6, 128.8, 129.3, 136.9, 138.2, 138.4 (C-6), 159.3 (C-
7a), 199.4 (C-3).
(48) Katritzky, A. R.; Fan, W.-Q.; Liang, D.-S.; Li, Q.-L. J . Heterocycl.
Chem. 1989, 26, 1541-1545.
(49) Nonnenmacher, E.; Hever, A.; Mahamound, A.; Aubert, C.;
Molnar, J .; Barbe, J . Org. Prep. Proced. Int. 1997, 29, 711-715.
(46) Kaupp, G.; Matthies, D. Chem. Ber. 1987, 120, 1897-1903.
(47) Morales-Rios, M. S.; J oseph-Nathan, P. Magn. Reson. Chem.
1991, 29, 893-896.

Ring Contraction of 3-Hydroxy-2,4(1H,3H)-quinolinediones
J . Org. Chem., Vol. 66, No. 19, 2001 6399
1,3-Dip h en yl-3-h yd r oxy-1,3-d ih yd r o-2H -in d ol-2-on e
(3e): colorless crystals; mp 169-171 °C (methanol); 1H NMR
(CDCl3) δ 3.55 (br s, 1H, OH), 6.89 (d, J ) 7.9 Hz, 1H, H-7),
7.10 (ddd, J ) 7.5, 7.5, 0.9 Hz, 1H, H-5), 7.29 (dd, J ) 6.8, 1.3
Hz, 1H, H-6), 7.28-7.60 (m, 11H, H-4, 2 × Ph); 13C NMR
(CDCl3) δ 78.1 (C-3), 110.0 (C-7), 124.0 (C-5), 125.3 (C-4), 125.3
(C-2 and C-6 of C3-Ph), 126.5, 128.3, 128.4, 128.7, 129.7, 129.7
(C-6), 131.4 (C-3a), 134.0, 140.4, 143.5 (C-7a), 177.0 (C-2).
3-Bu t yl-3-h yd r oxy-1-m et h yl-1,3-d ih yd r o-2H -in d ol-2-
on e (3f): colorless crystals; mp 98 °C (cyclohexane); 1H NMR
(CDCl3) δ 0.81 (t, J ) 7.2 Hz, 3H), 0.95-1.32 (m, 4H), 1.84-
2.02 (m, 2H), 3.14 (s, 1H), 3.18 (s, 3H), 6.83 (d, J ) 7.8 Hz,
1H), 7.10 (ddd, J ) 7.7, 7.2, 0.7 Hz, 1H), 7.32 (ddd, J ) 7.8,
7.7, 1.2 Hz, 1H), 7.37 (d, J ) 7.2 Hz, 1H); 13C NMR (CDCl3) δ
13.8, 22.7, 25.3, 26.2, 38.4, 76.7, 108.4, 123.1, 123.9, 129.5,
130.3, 143.5, 178.5.
3-Be n zyl-1-e t h yl-3-h yd r oxy-1,3-d ih yd r o-2H -in d ol-2-
on e (3g): colorless crystals; mp 144-145 °C (cyclohexane); 1H
NMR (CDCl3) δ 0.90 (t, J ) 7.2 Hz, 3H), 3.22 and 3.33 (2 × d,
J ) 12.6 Hz, 2H), 3.33-3.43 and 3.59-3.73 (2 × m, 2H), 6.63
(d, J ) 7.8 Hz, 1H), 6.87-6.90 (m, 2H), 7.03-7.13 (m, 4H),
7.24 (ddd, J ) 7.8, 7.7, 1.2 Hz, 1H), 7.30 (d, J ) 7.2 Hz, 1H);
13C NMR (CDCl3) δ 12.1, 34.4, 45.2, 77.5, 108.3, 122.7, 124.5,
126.8, 127.7, 129.6, 130.3, 134.0, 142.4, 177.4.
(C-3 and C-5 of C-Ph), 131.9 (C-6), 135.4 (C-4), 139.8 (C-1 of
N-Ph), 140.3 (C-1 of C-Ph), 149.2 (C-2), 199.8 (CdO).
1-Ben zyl-2-oxo-1,3-d ih yd r o-2H-in d ol-3-yl ben zoa te (5):
colorless crystals; mp 124-125 °C (cyclohexane); 1H NMR
(CDCl3) δ 4.91 and 5.00 (2 × d, J ) 15.7 Hz, 2H, CH2), 6.27 (s,
1H, H-3), 6.74 (d, J ) 7.7 Hz, 1H, H-7), 7.01 (ddd, J ) 7.7,
7.7, 0.5 Hz, 1H, H-5), 7.22 (d, J ) 7.8 Hz, 1H, H-6), 7.23-7.60
(m, 9H), 8.12 (d, J ) 7.7 Hz, 2H); 13C NMR (CDCl3) δ 44.1
(CH2), 70.4 (C-3), 109.6 (C-7), 123.1 (C-5), 124.5 (C-3a), 125.6
(C-4), 127.4, 127.8, 128.4, 128.9, 129.1, 130.2 (C-2 and C-6 of
COPh), 130.2 (C-6), 133.6, 135.3, 143.7 (C-7a), 165.9 (COO),
172.3 (C-2).
Isom er iza tion of 1,2-Dip h en yl-2-h yd r oxy-1,2-d ih yd r o-
3H-in d ol-3-on e (2e) to 3e. Powdered KOH (50 mg, 0.9 mmol)
was added to the solution of 2e (175 mg, 0.58 mmol) in benzene
(5 mL), and the reation mixture was vigorously stirred at room
temperature for 1 h. The precipitate was filtered, and the
filtrate was evaporated to dryness. The residue was crystal-
lized from methanol to give 3e (53 mg, 30%), mp 168-171 °C.
Rea ction of 1,2-Dip h en yl-2-h yd r oxy-1,2-d ih yd r o-3H-
in d ol-3-on e (2e) w it h P yr id in e a n d Acet ic An h yd r id e.
Acetic anhydride (1 mL) was added to the solution of 2e (290
mg, 0.96 mmol) in pyridine (3 mL). After 12 h at room
temperature, the solution was evaporated to dryness. The
residue was crystallized from benzene to give 1,3-diphenyl-2-
oxo-1,3-dihydro-2H-indol-3-yl acetate (9, 89 mg, 27%).
9: colorless crystals; mp 202-204 °C (benzene); 1H NMR
(CDCl3) δ 2.19 (s, 3H, CH3), 6.83 (dd, J ) 7.7, 1.1 Hz, 1H),
7.12 (dt, J ) 7.9, 0.9 Hz, 1H), 7.25-7.54 (m, 12H); 13C NMR
(CDCl3) δ 20.9, 81.3, 109.9, 123.4, 124.4, 126.4, 126.9, 128.0,
128.3, 128.7, 129.0, 129.6, 130.0, 134.6, 136.4, 145.0, 169.3,
173.5.
1,3-Diben zyl-3-h ydr oxy-1,3-dih ydr o-2H-in dol-2-on e (3h ):
1
colorless crystals; mp 188-190 °C (benzene/cyclohexane); H
NMR (CDCl3) δ 3.32 and 3.43 (2 × d, J ) 12.7 Hz, 2H), 3.60
(s, 1H), 4.44 and 4.98 (2 × d, J ) 16.0 Hz, 2H), 6.43 (d, J )
7.4 Hz, 1H), 6.70-6.73 (m, 2H), 6.91-6.95 (m, 2H), 7.04-7.21
(m, 8H), 7.35-7.39 (m, 1H); 13C NMR (CDCl3) δ 43.7, 44.8,
77.6, 109.6, 123.0, 124.4, 126.7, 126.9, 127.3, 128.1, 128.7,
129.3, 129.7, 130.4, 133.9, 134.9, 142.7, 177.8.
Acetyla tion of 1,3-Dip h en yl-3-h yd r oxy-1,3-d ih yd r o-2H-
in d ol-2-on e (3e). Acetic anhydride (0.5 mL) was added to the
solution of 3e (55 mg, 0.18 mmol) in pyridine (1 mL), and the
reaction mixture was left at room temperature for 12 h. The
volatile compounds were evaporated in vacuo, and the result-
ing solid was crystallized from benzene to yield 9 (38 mg, 61%).
3-Hyd r oxy-1-m eth yl-3-p h en yl-1,3-d ih yd r o-2H-in d ol-2-
on e (3i): colorless crystals; mp 141-143 °C (benzene) (lit.50
mp 142-143 °C (diethyl ether), lit.51 mp 139-141 °C (metha-
1
nol)); H NMR (CDCl3) δ 3.24 (s, 3H), 3.47 (s, 1H), 6.90 (d, J
) 7.8 Hz, 1H), 7.08 (ddd, J ) 7.6, 7.6, 0.9 Hz, 1H), 7.25-7.40
(m, 7H); 13C NMR (CDCl3) δ 26.5, 78.0, 108.7, 123.5, 125.0,
125.4, 128.3, 128.6, 129.9, 131.6, 140.1, 143.6, 177.5.
1-Ben zyl-3-h yd r oxy-3-p h en yl-1,3-d ih yd r o-2H-in d ol-2-
on e (3j): colorless crystals; mp 144-145 °C (benzene/cyclo-
hexane); 1H NMR (CDCl3) δ 3.44 (s, 1H), 4.81 and 5.04 (2 × d,
J ) 15.6 Hz, 2H), 6.78 (d, J ) 7.8 Hz, 1H), 7.03 (dd, J ) 7.3,
8.0 Hz, 1H), 7.19-7.45 (m, 12H); 13C NMR (CDCl3) δ 44.1, 78.0,
109.7, 123.5, 125.0, 125.3, 127.3, 127.8, 128.3, 128.6, 128.9,
129.8, 131.6, 135.4, 140.2, 142.7, 177.6.
1-(2-An ilin oph en yl)-2-h ydr oxy-2-ph en yl-1-eth an on e (4):
yellow glass; 1H NMR (CDCl3) δ 4.66 (d, J ) 6.6 Hz, 1H, OH),
5.99 (d, J ) 6.6 Hz, 1H, CH), 6.60 (dt, J ) 6.5, 1.6 Hz, 1H,
H-5), 7.10-7.40 (m, 12H, H-3, H-4, and two Ph), 7.70 (dd, J )
8.0, 1.0 Hz, 1H, H-6), 10.38 (s, 1H, NH); 13C NMR (CDCl3) δ
75.4 (C-OH), 114.5 (C-3), 115.2 (C-1), 116.6 (C-5), 123.6 (C-2
and C-6 of N-Ph), 124.6 (C-4 of N-Ph), 127.6 (C-2 and C-6 of
C-Ph), 128.4 (C-4 of C-Ph), 129.1 (C-3 and C-5 of N-Ph), 129.5
Ackn owledgm en t. The Ministry of Education, Youth
and Sports of the Czech Republic (Grant No. 203/97/
0033) and the Ministry of Education, Science and Sport
of Slovenia (Grant No. PO-0503-103) supported this
study. We thank Drs. Bogdan Kralj and Dusˇan Zˇigon
(Mass Spectrometry Center, J ozˇef Stefan Institute,
Ljubljana, Slovenia) for mass spectral measurements.
We are also indebted to Mrs. Hana Gerzˇova´ (Faculty of
Technology, Tomas Bata University in Zl´ın, Czech
Republic) for technical help.
Su p p or tin g In for m a tion Ava ila ble: Synthesis and spec-
troscopic data (IR, NMR, and MS) for 4-hydroxy-2(1H)-
quinolones and compounds 1; IR and MS data for compounds
2-5 and 9; results of combustion analysis for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(50) Walker, G. N.; Alkalay, D.; Smith, R. T. J . Org. Chem. 1965,
30, 2973-2983.
(51) Aeberli, P.; Houlihan, W. J . J . Org. Chem. 1968, 33, 1640-
1643.
J O015786D