Enamino derivatives of 1,3-dioxoindane-2-carboxylic acid

Article abstract of DOI:10.1021/jo8014903

(Chemical Equation Presented) Although 1,3-dioxoindane-2-carboxylic acid is highly unstable, its enamino derivatives can be isolated by careful hydrolysis of their esters with 2,4-dihydroxy-1,4-naphthoquinone. Crystal structure determination reveals the formation of two intramolecular hydrogen bonds, offering thus a possible explanation for the stability of these acids.

Full text of DOI:10.1021/jo8014903

Enamino Derivatives of 1,3-Dioxoindane-2-carboxylic Acid
Elizabeth Malamidou-Xenikaki,*,† Spyros Spyroudis,† Maria Tsanakopoulou,† and
Harald Krautscheid‡
Department of Chemistry, Aristotle UniVersity of Thessaloniki, 54124 Thessaloniki, Greece, and
Institute of Inorganic Chemistry, UniVersity of Leipzig, D-04103 Leipzig, Germany
malamido@chem.auth.gr
ReceiVed July 7, 2008
Although 1,3-dioxoindane-2-carboxylic acid is highly unstable, its enamino derivatives can be isolated
by careful hydrolysis of their esters with 2,4-dihydroxy-1,4-naphthoquinone. Crystal structure determination
reveals the formation of two intramolecular hydrogen bonds, offering thus a possible explanation for the
stability of these acids.
Introduction
preparation and isolation, but that is not the case for R-acyl-
ꢀ-keto acids. To our knowledge no unambiguous preparation
and characterization of compounds of the general types 1 or 2
has been reported.
It is well-known that ꢀ-keto acids are easily decarboxylated1
and that their decarboxylation is an important transformation
in organic chemistry2 as well as in biological systems.3 It is
generally accepted that this decarboxylation proceeds through
a cyclic transition state2 with the participation of the keto group
and that both electronic4 and steric factors5 influence the rate
of decarboxylation. The tendency of ꢀ-keto acids to decarboxy-
late has as a consequence that a considerable number of them
cannot be isolated in pure form. Their formation usually is
detected by their reaction with alcohols and their transformation
to the more stable ꢀ-keto esters, although the latter can also be
dealkoxycarbonylated.6
Exploring the chemistry of aryliodonium ylides of hydrox-
yquinones and using the phenyl iodonium ylide of lawsone 3
as a model compound, we found that its thermal decomposition
in moistened acetonitrile afforded indanedione 7 in quantitative
yield.7a The same type of ring contraction was observed with
phenyliodonium ylides of other hydroxyquinones.7b-d The
reaction pathway involves the formation of 1,3-dioxoindane-
2-carboxylic acid (6), the product of the reaction of R,R-
dioxoketene 4 with water present in the solvent. This ketene is
a result of a Wolff-type rearrangement following the thermal
degradation of ylide 3. This rearrangement was initially thought
to proceed through carbenes, but it was shown recently that it
follows a single-step concerted mechanism, via a four-membered
[1,1,0] bicyclic ring transition state for the ketene formation.8
The ketene is very reactive and it can be trapped with aromatic
Despite their instability, certain ꢀ-keto acids can be isolated,
especially if elevated temperatures are avoided during their
† Aristotle University of Thessaloniki.
‡ University of Leipzig.
(1) Oshry, L.; Rosenfeld, S. M. Org. Prep. Proced. Int. 1982, 14, 249.
(2) Logue, M. W.; Pollack, R. M.; Vitullo, V. P. J. Am. Chem. Soc. 1975,
97, 6868.
(3) Walsh, C. Enzymatic Reaction Mechanism; W. H. Freeman and Co.: New
York, 1979.
(4) Bach, R. D.; Canepa, C. J. Org. Chem. 1996, 61, 6346.
(5) (a) Kayser, R. H.; Brault, M.; Pollack, R. M.; Bantia, S.; Sadoff, S. F. J.
Org. Chem. 1983, 48, 4497. (b) Meier, H.; Wengenroth, H.; Lauer, W.; Krause,
V. Tetrahedron Lett. 1989, 30, 5253.
(6) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P. ARKIVOC
2007, ii, 1. (c) Krapcho, A. P. ARKIVOC. 2007, ii, 54.
(7) (a) Hatzigrigoriou, E.; Spyroudis, S.; Varvoglis, A. Liebigs Ann. Chem.
1989, 167. (b) Papoutsis, I.; Spyroudis, S.; Varvoglis, A. Tetrahedron Lett. 1994,
35, 8449. (c) Spyroudis, S.; Xanthopoulou, N. J. Org. Chem. 2002, 67, 4612.
(d) Spyroudis, S.; Xanthopoulou, N. ARKIVOC 2003, Vi, 95.
(8) Bakalbassis, E. G.; Spyroudis, S.; Tsipis, C. A. Eur. J. Org. Chem. 2008,
1783.
8392 J. Org. Chem. 2008, 73, 8392–8397
10.1021/jo8014903 CCC: $40.75 2008 American Chemical Society
Published on Web 10/14/2008

Enamino DeriVatiVes of 1,3-Dioxoindane-2-carboxylic Acid
SCHEME 1
SCHEME 3
SCHEME 4
conducted in one or two steps. Aiming to the isolation of acid
6 or at least some of its derivatives from the carbonyl group,
we used the tetraoxo-oxetanone 8 and the esters 9 as starting
materials and we report the results of our efforts herein.
SCHEME 2
Results and Discussion
Oxetanone 8 is a labile compound and its yellow color turns
slowly into reddish after exposure to air for some time. It was
found that the red color belongs to 2,3-dihydroxy-1,4-naphtho-
quinone (11) and that indanedione (7) was the other product of
the decomposition. The same compounds, 11 and 7, were also
the only products of the decomposition of a dispersion of 8 in
CH2Cl2 saturated with water (Scheme 3). Presumably indanedi-
one resulted from the decarboxylation of the intermediately
formed acid 6, (Scheme 2). The formation of indanedione is
indicative of the instability of acid 6 even at room temperature.
When methanol or ethanol was added to a suspension of 8
in CH2Cl2, the corresponding alkoxy alkyl esters of indenone
carboxylic acid 12 were obtained along with dihydroxyquinone
11 (Scheme 4). Esters 12 were isolated by column chromatog-
raphy, although they are labile compounds and have the
tendency to decompose to indanedione 7 after exposure to air
for some time. Indanedione 7 was the sole product of the
attempted hydrolysis of esters 12 with water at room temper-
ature, verifying again the instability of acid 6.
Regarding the reaction pathway, it is most possible that it
is analogous to the one proposed previously for the reaction
of 8 with amines.11 The reaction starts with nucleophilic
attack of the alcohol on one of the carbonyls of the spiro-
cyclopentenedione moiety to form 13, which gives the
oxonium intermediate 14. The latter initiates a skeletal
rearrangement, which leads to the esters 15 through ring
expansion and attack of the hydroxy anion to the ethylenic
carbon of the indanedione moiety, as shown in Scheme 5.
These esters through a transesterification reaction with excess
alcohol afford 11 and the isolated esters 12.
After the unsuccessful attempts to isolate dioxo acid 6 we
examined the possibility to prepare arylimino derivatives of this
acid starting from the available esters 9, products from the
reaction of 8 with 1 equiv of amine (Scheme 2).
Indeed, a transesterification reaction of 9a-c with alcohols
afforded the esters 16a-c, but most important, careful hydrolysis
of 9a-c led to the isolation of the acids 18a-c, while
dihydroxyquinone 11 was the other product of the reaction in
both cases (Scheme 6). Esters 16 as well as acids 18 can exist
in solution in equilibrium with their enamino forms 17 and 19,
respectively.
amines to the anilides 5, existing in solution in the enol form,9
as illustrated in Scheme 1. Analogous dioxoketenes produced
in the same manner from the thermal decomposition of other
iodonium ylides can be trapped by methanol affording the
methyl esters of the corresponding to 6 acids.7b,c Although the
amides of acid 6 can be isolated, the acid itself is spontaneously
decarboxylated to indanedione 7, especially under the conditions
of the reaction.
Ylide 3 decomposes in refluxing CH2Cl2 to dioxoketene 4,
which in the absence of water (or other nucleophiles) dimerizes
quantitatively to tetraoxo-oxetanone 8.10,11 The latter reacts with
1 and 2 equiv of primary aromatic amines to afford the esters
9 and the amides 10, respectively (Scheme 2). Besides 10, 2,3-
dihydroxy-1,4-naphthoquinone (11) was the other product of
the reaction of 8 with 2 equiv of amine, regardless if it was
(9) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M. J. Org. Chem.
2003, 68, 5627.
(10) Koulouri, S.; Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou,
M. J. Org. Chem. 2005, 70, 8780.
(11) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M.; Krautsc-
heid, H. J. Org. Chem. 2007, 2, 502.
J. Org. Chem. Vol. 73, No. 21, 2008 8393

Malamidou-Xenikaki et al.
SCHEME 5
SCHEME 7
and methanol a ring opening occurred and the ester 16c/17c
was isolated quantitatively. In an analogous reaction, hydrolysis
of 20 under mild conditions this time (suspension of a few drops
of H2O in CH2Cl2, 34 °C, 5 days) led to the isolation of the
acid 18c/19c in pure form and excellent yield (Scheme 7).
In the NMR spectra in CDCl3 of esters 16a-c/17a-c and
acids 18a-c/19a-c signals for only one species are observed.
No broadening of peaks was observed when the NMR spectra
of ester 17a were recorded at low temperatures (till -50 °C).
13C NMR spectra display signals at three low field regions,
specifically at δ 186.8-188.0 and 191.2-192.9 for C-1 (ketone
CdO, Figure 1), at δ 170.6-172.9 and 167.9-168.9 for C-3
and at δ 169.1-172.2 and 167.1-168.0 for the carboxylic
carbon, for esters 16a-c/17a-c and acids 18a-c/19a-c,
respectively. Another quaternary carbon signal, which is at-
tributed to C-2, is observed at δ 95.1-101.5 for the esters and
SCHEME 6
1
94.7-99.3 for the acids. In the H NMR spectra, the OH and
NH protons resonate at δ 10.50-11.83 (one signal for the esters
and two for the acids).
Enols of acids and esters are rare species and only a few
cases of stable compounds have been reported in the literature.13,14
The hydrogen bonded enolic protons of poly(methoxycarbon-
yl)cyclopentadienes, forming a seven-membered pseudocyclic
ring, resonate at 19-20 ppm,13 whereas the non-hydrogen
bonded enolic protons of carboxylic acid enols resonate at
7.65-9.33, depending on the solvent.14 More examples of stable
enols of amides have been reported in contrast to the limited
number of enols of carboxylic esters and acids.9,15,16 In the case
of the substituted 2-carbanilido-1,3-indanediones, both isomeric
solid enols on amide carbonyl and on ring carbonyl were isolated
and their spectra in solid state and in solution (CDCl3) were
obtained.16 The solid state NMR spectra of the two tautomers
differ in contrast to the spectra in CDCl3 solution which are
identical and resemble those of the amide enol tautomer. Signals
for the NH and OH protons are observed at ca. δ 9.9-10.6 in
CDCl3 solution, values identical to those reported earlier9 for
2-carbanilido-1,3-indanediones and analogous to those found
for esters 16/17 and acids 18/19. In the spectrum in CDCl3
solution, two signals at ca. δ 193-190 for the nonequivalent
ketone carbonyls, a low field signal at ca. δ 164 for the enol
amide carbon and an upfield signal at ca. δ 95 for the other
carbon of the enol group are observed. These values strongly
resemble of the observed for the esters 16a-c/17a-c and acids
18a-c/19a-c.
Esters 16/17 are isolated from the reaction mixture by column
chromatography, but acids 18/19 are separated from quinone
11 by selective crystallization. This method gave satisfactory
results for 18a/19a and 18b/19b (yield 74% and 87%, respec-
tively), but the acid 18c/19c was detected only in traces. Acid
18c/19c and the corresponding methyl ester 16c/17c were
obtained by another approach, namely, the solvolysis of 2,4-
dimethoxyindeno[1,2-d]pyrimido[1,2-a]pyrimidine (20). This
compound, as well as analogous derivatives with a similar
template and interesting biological activities, was prepared by
the reaction of tetraoxo-oxetanone 8 with 4,6-dimethoxy-2-
aminopyrimidine.12 Bearing an amidic group at a position
corresponding to that of the ester group in compounds 9, the
polycyclic compound 20 could be susceptible to nucleophilic
attack. Indeed, upon heating 20 in a mixture of dichloromethane
On the basis of the above it is difficult to distinguish which
of the imino 16, 18 or enamino 17, 19 structures exists in
solution. A strong evidence in favor of the enamino structure
was provided by the 15N NMR spectrum of compound 17a/
18a: only one signal is observed at δ -250.9 (reference
(12) Tsanakopoulou, M.; Cottin, T.; Bu¨ttner, A.; Sarli, V.; Malamidou-
Xenikaki, E.; Spyroudis, S.; Giannis, A. ChemMedChem. 2008, 3, 429.
(13) Lei, Y. X.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2000, 65, 4028.
(14) Frey, J.; Rappoport, Z. J. Am. Chem. Soc. 1996, 118, 5169.
(15) Lei, Y. X.; Cerioni, G.; Rappoport, Z. J. Org. Chem. 2001, 66, 8379.
(16) Song, J.; Mishima, M.; Rappoport, Z. Org. Lett. 2007, 9, 4307.
8394 J. Org. Chem. Vol. 73, No. 21, 2008

Enamino DeriVatiVes of 1,3-Dioxoindane-2-carboxylic Acid
SCHEME 8
FIGURE 1. Shielding effect in enamino esters 17a,b and acids 18a,b/
19a,b.
SCHEME 9
Me15NO2) in CDCl3, which is ascribed to the nitrogen of the
enamine group of the tautomer 17a and certainly not to the imine
nitrogen of 18a.17 Due to the instability of carboxylic acids 18/
19, especially in solution, it was difficult to record 15N NMR
spectra.
Another interesting spectroscopic feature of these compounds
1
is the shift of 4-H in H NMR. In compounds 17a,b and 18a,b/
19a,b this proton appears as a doublet at low δ values (6.15-6.53)
indicated in Figure 1. This shielding effect is attributed to the
restricted rotation of the aryl ring, a phenomenon that has been
observed also in the spectra of compounds 9 and 10. Interestingly
enough, the same 4-H in the corresponding 2-iminopyrimidyl
derivatives 17c and 18c/19c, appears at δ 8.09 and 8.35, respec-
tively. 3D models indicate that in these compounds no restriction
in the rotation of the aryl ring exists, due to the lack protons at the
ortho positions of the ring which are occupied by nitrogen atoms.
In this case, all rings lie on a plane and the deshielding effect of
the iminopyrimidyl ring explains the spectacular (almost 2 ppm)
downfield shift of 4-H.
In acids 18a-c/19a-c the existence of two intramolecular
hydrogen bonds may account for their relative stability despite
the instability of ꢀ-ketoacids generally. Crystal structure deter-
mination for acid 18a/19a showed the existence of such
hydrogen bonds (O1-H2, 189 pm and O3-H1, 216 pm) and
that, at least in the solid state, this compound exists in the
enamino form 19a, shown in Figure 2 in Supporting Information.
The tilt of the p-tolyl ring verifies the observed shielding effect
for H on C-4.
As we reported in a previous publication11 the reaction of
indanedionketene dimer 8 with N-methylaniline (as well as with
other secondary amines) affords the ester 24. In spite of our
efforts, this ester resisted hydrolysis even in refluxing DME and
acid 26, or even its decarboxylation product, were not formed.
On the contrary, transesterification with methanol, a stronger
than H2O nucleophilic agent, afforded good yields of ester 25
and dihydroxyquinone 11 (Scheme 9), albeit after a prolonged
reaction time. This ester undoubtedly exists in the enamino form,
as there is no hydrogen on the nitrogen atom and hence the
imino isomer cannot be formed. In the 13C NMR spectrum, ester
25 lacks the characteristic peak for C-2 at δ 94-96, which is
observed for esters 17, and the most upfield signal for sp2
carbons is recorded at δ 121.7. This indicates that in this
compound the carbon in question is not protected by the lone
pair of nitrogen, due probably to the inability of formation of
the pseudo six-membered ring, through hydrogen bonding,
occurring in esters 17.
There is a striking difference in the reactivity of esters 9 and
ester 24 toward alcohols and water. Whereas it takes only 4 h
for the conversion of the former to esters 17 and acids 18/19
respectively, the conversion of the latter to ester 25 is completed
after 7 days and the same compound does not react at all with
water. We attribute this difference in reactivity of esters 9 and
ester 24 to the capability of the former to adopt in solution an
imino form analogous to 16. This imino form is more susceptible
to Michael-type addition of the nucleophile (alcohol or water)
to the carbon of the ester group and afford easily the intermediate
27, which decomposes to dihydroxyquinone 11 and esters 17
or acids 18/19 (Scheme 10). Ester 24 lacks the enone moiety
that can be found in 9. As a consequence, Michael-type addition
is not possible and hence the observed resistance toward the
same nucleophiles.
Another reason for the stabilization of acid 19a is possibly
the development of intramolecular hydrogen bonds with the
symmetry molecule, between O3 · · ·H1′ and H1 · · ·O3′ with a
length of 218 pm, as illustrated in Figure 3 in Supporting
Information.
It must be noted that the crystal structure of the only ester
analogue to 17 reported in the literature, enamino ester 23, is
in complete analogy with the structure of acid 19a. This ester
was prepared (rather by serendipity) by Padwa et al.,18 on their
way to prepare functionalized azomethine ylides: The cyclo-
pentenone ring is formed by intramolecular insertion of the
carbene obtained through catalytic action of Rh(II) on the diazo
imino ester 22, existing as a single E isomer. The latter is
prepared by the reaction of aniline with the corresponding
aldehyde 21, as illustrated in Scheme 8. Ester 23 exhibits
spectroscopic data completely analogous to those of esters 17,
with most characteristic features the shielding of 4-H (doublet
at δ 6.41 in 1H NMR) and C-2 resonating at δ 96.6 in 13C NMR.
(17) Marek, R.; Lycˇka, A. Curr. Org. Chem. 2002, 6, 35.
(18) Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A.
J. Org. Chem. 1994, 59, 5347.
J. Org. Chem. Vol. 73, No. 21, 2008 8395

Malamidou-Xenikaki et al.
SCHEME 10
120.4, 103.8, 70.7, 61.1, 15.0, 14.3; GC-MS m/z 246 (M+, 32),
201 (27), 173 (100), 146 (37), 104 (50). Anal. Calcd for C14H14O4:
C, 68.28; H, 5.73. Found: C, 68.26; H, 5.48.
Transesterification Reaction of Esters 9a-c with Methanol.
A suspension of the proper ester 9a-c (0.5 mmol) in CH2Cl2 (4
mL) and MeOH (1 mL) was stirred at room temperature for 4 h,
after which time the red crystals of dihydroxyquinone 11 were
removed by filtration. In the case of the ester 9c reflux for 15 h
was required for the completion of the reaction. The filtrate was
concentrated and chromatographed on column (silica gel, hexanes-
ethyl acetate 3:1) to afford the methyl esters 17a-c, as yellow
solids, which can be recrystallized from dichloromethane-hexanes.
Reaction of p-Tolyl-ester 9a with Methanol. Methyl 3-[(4-
Methylphenyl)amino]-1-oxo-1H-indene-2-carboxylate (17a). Yield
84%; mp 155-157 °C; IR (KBr) cm-1 1693, 1654; 1H NMR
(CDCl3, 300 MHz) δ 11.19 (brs, 1H), 7.63 (d, J ) 7.3 Hz, 1H),
7.42 (t, J ) 7.3 Hz, 1H), 7.30 (d, J ) 8.6 Hz, 2H), 7.27 (d, J ) 8.6
Hz, 2H), 7.13 (t, J ) 7.3 Hz, 1H), 6.45 (d, J ) 7.3 Hz, 1H), 3.91
(s, 3H), 2.47 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 186.8, 170.6,
167.9, 139.1, 136.9, 134.5, 134.0, 132.8, 131.2, 130.3, 126.6, 124.0,
122.2, 96.2, 51.2, 21.2; 15N NMR (CDCl3, 40 MHz) δ -250.9
(reference Me15NO2); EI-MS m/z 293 (M+, 19), 261 (100), 232
(37). Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found:
C, 73.47; H, 5.12; N, 4.61.
It must be noted that Michael-type addition intermediates
analogous to 27, with amines as nucleophiles, have been isolated
and their structure has been elucidated in a previous publica-
tion.11
In conclusion, by mild hydrolysis of the esters 9 we have
isolated the enamino derivatives of 1,3-dioxoindane-2-carboxylic
acid 18/19, belonging to a class of compounds that are
considered unstable. In this case the existence of the two
intramolecular hydrogen bonds assists their stabilization. Esters
of the same acids were also isolated from the transesterification
of esters 9.
Reaction of Mesityl-ester 9b with Methanol. Methyl 3-(Mesi-
tylamino)-1-oxo-1H-indene-2-carboxylate (17b). Yield 86%; mp
1
172-174 °C; IR (KBr) cm-1 1691, 1650; H NMR (CDCl3, 300
Experimental Section
MHz) δ 10.86 (brs, 1H), 7.64 (d, J ) 7.4 Hz, 1H), 7.43 (t, J ) 7.4
Hz, 1H), 7.12 (t, J ) 7.4 Hz, 1H), 7.02 (s, 2H), 6.15 (d, J ) 7.4
Hz, 1H), 3.92 (s, 3H), 2.39 (s, 3H), 2.20 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 186.8, 171.9, 168.0, 139.1, 136.8, 135.4, 134.1, 133.0,
132.6, 131.8, 129.6, 122.3, 122.1, 95.1, 51.1, 21.1, 18.2; EI-MS
m/z 321 (M+, 49), 289 (100), 274 (12), 260 (27). Anal. Calcd for
C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.59; H, 6.13;
N, 4.66.
Indanedioneketene dimer, 4′-(1,3-dioxo-1,3-dihydro-2H-inden-
2-ylidene)spiro[indene-2,3′-oxetane]-1,2′,3-trione (8), was prepared
as described in previous publications.9,10 Esters 9a-c and 24 were
prepared from the reaction of dimer 8 with 1 equiv of the
appropriate amine.11,12
Hydrolysis of Oxetanone 8. A suspension of oxetanone 8 (0.5
mmol) in CH2Cl2 (4 mL) saturated with water was stirred at room
temperature for 4 h. After 1 h, red crystals of dihydroxynaphtho-
quinone 11 began to deposit. Hexanes (5 mL) was added to facilitate
precipitation, and 11 was obtained by filtration in almost quantitative
yield. The filtrate was concentrated to a small volume, and the
residue was chromatographed on column (silica gel, hexanes-
ethyl acetate 3:1) to afford indanedione (7) as the only product,
again in almost quantitative yield.
Reaction of Oxetanone 8 with Alcohols. Alcohol (2 mL) was
added to a stirred suspension of oxetanone 8 (0.5 mmol) in CH2Cl2
(4 mL), and stirring was continued until a clear solution resulted
(6 h). The solution was concentrated to a small volume, the resulting
red crystals of dihydroxynaphthoquinone 11 (yields 80-85%) were
filtered off, and the filtrate was chromatographed, as quickly as
possible, on column (silica gel, hexanes-ethyl acetate 3:1) to afford
the alkoxy esters 12a,b. The isolated derivatives 12a,b were pure
enough, and no further purification was possible, as they have the
tendency to decompose upon attempted recrystallization. It must
be noted that compound 12b is considerably more unstable than
the methyl derivative 12a.
Reaction with Methanol. Methyl 3-methoxy-1-oxo-1H-indene-
2-carboxylate (12a). Yield 99%; yellow solid, mp 110-112 °C;
IR (KBr) cm-1 1720, 1691; 1H NMR (CDCl3, 300 MHz) δ
7.57-7.52 (m, 1H), 7.48-7.38 (m, 3H), 4.34 (s, 3H), 3.88 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 190.0, 178.6, 163.9, 138.5, 132.8,
131.9, 131.7, 122.0, 120.5, 103.4, 61.9, 52.1; GC-MS m/z 218
(M+, 36), 187 (100), 173 (32), 104 (12). Anal. Calcd for C12H10O4:
C, 66.05; H, 4.62. Found: C, 65.96; H, 4.62.
Reaction of 4,6-Dimethoxy-2-pyrimidyl-ester 9c with Metha-
nol. Methyl 1-Oxo-3-(pyrimidin-2-ylamino)-1H-indene-2-car-
boxylate (17c). Yield 54%; mp 195-197 °C; IR (KBr) cm-1 1710,
1
1663; H NMR (CDCl3, 300 MHz) δ 11.54 (s, 1H), 8.09 (d, J )
7.7 Hz, 1H), 7.64 (d, J ) 7.1 Hz, 1H), 7.50 (t, J ) 7.4 Hz, 1H),
7.41 (t, J ) 7.4 Hz, 1H), 5.90 (s, 1H), 3.93 (s, 3H), 3.91 (s, 6H);
13C NMR (CDCl3, 75 MHz) δ 188.0, 172.1, 168.9, 167.3, 155.8,
135.5, 134.8, 132.8, 131.7, 127.4, 122.2, 101.5, 86.7, 54.7, 51.7;
ESI-HRMS m/z calcd for C17H15N3O5 + Na (MNa+) 364.09039,
found 364.09012.
Hydrolysis of Esters 9a-c. A suspension of the proper ester
9a-c (0.5 mmol) in CH2Cl2 (4 mL) and H2O (3-4 drops) was
stirred at room temperature for 4-6 h. The resulting solution was
dried with Na2SO4, and hexanes (2-3 mL) was added. The
precipitated red crystals of dihyhydroxynaphthoquinone 11 were
filtered off, the resulting solution was concentrated to dryness
(without heating), and ethyl acetate and ethyl ether were added to
afford the acids 18a-c/19a-c. For simplicity reasons the acids
are named after their enamino form 19, with the acid in its keto
form. For example the p-tolyl derivative in its imino form (and the
carboxyl group in its enol form) 18a should have been named (3E)-
2-(dihydroxymethylene)-3-[(4-methylphenyl)imino]indan-1-one.
Hydrolysis of p-Tolyl-ester 9a. 3-[(4-Methylphenyl)amino]-
1-oxo-1H-indene-2-carboxylic Acid (18a/19a). Yield 74%; yellow
solid, mp 159-160 °C; IR (KBr) cm-1 1697, 1659; 1H NMR
(CDCl3, 300 MHz) δ 11.14 (brs, 1H), 10.88 (brs, 1H), 7.63 (d, J
) 7.6 Hz, 1H), 7.47 (t, J ) 7.6 Hz, 1H), 7.33 (d, J ) 8.0 Hz, 2H),
7.28 (d, J ) 8.0 Hz, 2H), 7.20 (t, J ) 7.6 Hz, 1H), 6.53 (d, J ) 7.6
Hz, 1H), 2.48 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 191.3, 169.1,
167.1, 139.8, 136.7, 134.2, 133.6 133.3, 132.2, 130.5, 126.4, 125.1,
122.6, 95.6, 21.3; EI-MS m/z 279 (M+, 10), 261 (100), 232 (41).
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C,
72.87; H, 4.56; N, 4.92.
Reaction with Ethanol. Ethyl 3-Ethoxy-1-oxo-1H-indene-2-
carboxylate (12b). Yield 78%; oil; IR (KBr) cm-1 1716, 1700;
1H NMR (CDCl3, 300 MHz) δ 7.55-7.49 (m, 1H), 7.46-7.38 (m,
3H), 4.65 (q, J ) 7.0 Hz, 2H), 4.33 (q, J ) 7.2 Hz, 2H), 1.50 (t,
J ) 7.0 Hz, 3H), 1.37 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 190.3, 176.9, 163.8, 138.8, 132.8, 132.0, 131.7, 121.8,
8396 J. Org. Chem. Vol. 73, No. 21, 2008

Enamino DeriVatiVes of 1,3-Dioxoindane-2-carboxylic Acid
Hydrolysis of Mesityl-ester 9b. 3-(Mesitylamino)-1-oxo-1H-
indene-2-carboxylic Acid (18b/19b). Yield 87%; yellow solid, mp
to the initial CH2Cl2 suspension of 20. Ester 17c was isolated in
98% yield after reflux for 30 min.
1
222-226 °C; IR (KBr) cm-1 1691, 1665; H NMR (CDCl3, 300
Transesterification Reaction of Enamino Ester 24 with
Methanol. A suspension of ester 24 (0.5 mmol) in CH2Cl2 (4 mL)
and MeOH (1 mL) was stirred at room temperature for 7 d, after
which time the red crystals of dihydroxyquinone 11 were removed
by filtration. The filtrate was concentrated and chromatographed
on column (silica gel, hexanes-ethyl acetate 3:1) to afford methyl
3-[methyl(phenyl)amino]-1-oxo-1H-indene-2-carboxylate (25) as
yellow solid, which was recrystallized from dichloromethane-
hexanes. Yield 77%; mp 130-132 °C; IR (KBr) cm-1 1695, 1669;
1H NMR (CDCl3, 300 MHz) δ 7.56 (t, J ) 7.0 Hz, 1H), 7.53-7.47
(m, 3H), 7.41-7.35 (m, 2H), 7.29 (t, J ) 7.0 Hz, 1H), 6.99 (t, J )
7.0 Hz, 1H), 5.69 (d, J ) 7.0 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 189.1, 168.8, 164.7, 145.1, 137.7,
137.0, 135.1, 131.4, 131.1, 130.0, 128.7, 126.6, 123.8, 121.7, 51.7,
47.4; EI-MS m/z 293 (M+, 60), 262 (71), 261 (100), 260 (83), 234
(33), 158 (35). Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N,
4.78. Found: C, 73.61; H, 5.29; N, 4.44.
X-ray Crystal Structure Determination. Single crystals suitable
for X-ray structure determinations were obtained by adding diethyl
ether to a solution of 19a in methylene chloride. All C, N, and O
atoms were refined with anisotropic thermal parameters. Hydrogen
atoms were located and their positions refined for the amine and
hydroxy hydrogen atoms; all other hydrogen positions were
calculated for idealized positions.
MHz) δ 11.83 (brs, 1H), 10.50 (brs, 1H), 7.64 (d, J ) 7.4 Hz,
1H), 7.48 (t, J ) 7.4 Hz, 1H), 7.19 (t, J ) 7.4 Hz, 1H), 7.05 (s,
2H), 6.23 (d, J ) 7.4 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 191.2, 170.4, 167.1, 139.6, 136.5, 135.0, 134.2,
133.5, 132.7, 131.7, 129.7, 123.5, 122.6, 94.7, 21.1, 18.1; EI-MS
m/z 307 (M+, 9), 289 (100), 274 (11), 263 (42), 260 (24). Anal.
Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 73.97;
H, 5.78; N, 4.84.
Hydrolysis of 4,6-Dimethoxy-2-pyrimidyl-ester (9c). 1-Oxo-3-
[(4,6-dimethoxy-pyrimidin-2-ylamino)-1H-indene-2-carboxylic Acid
(18c/19c). The hydrolysis proceeded as previously but the acid could
not be isolated in pure form and the alternative method was followed.
Hydrolysis of 2,4-Dimethoxyindeno[1,2-d]pyrimido[1,2-a]py-
rimidine-6,7-dione (20). Preparation of 1-Oxo-3-[(4,6-dimethoxy-
pyrimidin-2-ylamino)-1H-indene-2-carboxylic Acid (18c/19c).
2,4-Dimethoxyindeno[1,2-d]pyrimido[1,2-a]pyrimidine-6,7-dione
(20)12 (0.1 mmol) was suspended in CH2Cl2 (5 mL), a few drops
of H2O were added, and the suspension was heated at 34 °C under
stirring until the complete disappearance of 20 (∼5 days). The
resulting solution was dried (Na2SO4) and concentrated (without
heating). The semi-oily residue was triturated with ether, and the
resulting orange solid was collected by filtration. Yield 90%; mp
1
149-151 °C; IR (KBr) cm-1 1696, 1658; H NMR (CDCl3, 300
MHz) δ 11.45 (brs, 1H), 8.35 (d, J ) 7.7 Hz, 1H), 7.66 (d, J )
7.04 Hz, 1H), 7.58-7.43 (m, 2H), 5.96, (s, 1H), 3.95 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 192.9, 172.2, 168.0, 166.5, 155.1, 135.5,
135.0, 133.4, 132.8, 129.1, 122.8, 99.3, 87.4, 54.9; ESI-HRMS m/z
calcd for C16H13N3O5 + Na (MNa+) 350.07474, found 350.07478.
It must be noted that at room temperature the reaction was
completed in about 20 days, whereas at higher temperatures partial
decomposition of the acid occurred.
Acknowledgment. We wish to thank Dr. Lothar Hennig
(University of Leipzig) for NMR support.
Supporting Information Available: X-ray crystallographic
1
file (CIF) for 19a and copies of NMR and 13CNMR spectra
of compounds 12a,b, 17a-c, 18a-c/19a-c, and 25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Reaction of 2,4-Dimethoxyindeno[1,2-d]pyrimido[1,2-a]pyrim-
idine-6,7-dione (20) with Methanol. Methyl 1-Oxo-3-(pyrimidin-
2-ylamino)-1H-indene-2-carboxylate (17c). The previous meth-
odology was followed, but methanol instead of water was added
JO8014903
J. Org. Chem. Vol. 73, No. 21, 2008 8397