A convenient approach to fused indeno-1,4-diazepinones through hypervalent iodine chemistry

Article abstract of DOI:10.1021/jo9013063

(Chemical Equation Presented) Indenocarboxamides, resulting from the sequential addition of two arylamine equivalents to indanedione ketene dimer, are oxidized by [bis(trifluoroacetoxy)iodobenzene] to fused indeno-1,4- diazepinones in yields depending on the substituents on both aromatic rings. A plausible reaction pathway explaining the formation of the title compounds, as well as the formation of the two other minor products of the reaction, through a common intermediate, is suggested. 2009 American Chemical Society.

Full text of DOI:10.1021/jo9013063

pubs.acs.org/joc
A Convenient Approach to Fused Indeno-1,4-diazepinones through
Hypervalent Iodine Chemistry
Elizabeth Malamidou-Xenikaki,*,† Spyros Spyroudis,† Maria Tsanakopoulou,† and
Dimitra Hadjipavlou-Litina‡
†Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece, and
‡Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki,
54124 Thessaloniki, Greece
malamido@chem.auth.gr
Received June 29, 2009
Indenocarboxamides, resulting from the sequential addition of two arylamine equivalents to
indanedione ketene dimer, are oxidized by [bis(trifluoroacetoxy)iodobenzene] to fused indeno-1,4-
diazepinones in yields depending on the substituents on both aromatic rings. A plausible reaction
pathway explaining the formation of the title compounds, as well as the formation of the two other
minor products of the reaction, through a common intermediate, is suggested.
Introduction
As a result of this expansion, a number of books1 and
numerous reviews2 on the subject have been published.
The majority of hypervalent iodine compounds exhibit
oxidative properties, but those that have found widespread
application as oxidizing agents are [bis(acyloxy)iodo]arenes
(BAIs), ArI(OCOR)2. Among them, [bis(acetoxy)iodo]ben-
zene, PhI(OAc)2, and [bis(trifluoroacetoxy)iodo]benzene, PhI-
(OCOCF3)2, are the most representative examples.2v In recent
publications, the latter is named as phenyliodine(III) bis-
(trifluoroacetate) and is usually referred by the acronym PIFA.
BAIs’ reactivity resembles that of heavy metal reagents.
They can oxidize chemoselectively a wide range of function-
alities such as alcohols, amines, sulfides, and carbonyl
compounds among others, and they are commonly used as
effective reagents in various cationic rearrangements and
fragmentations. BAIs can serve as excellent oxidants in the
degradation of aliphatic and aromatic carboxamides. They
have been used for the conversion of amides to alkyl carba-
mates in alcohol solvents, as well as for the facile oxidative
rearrangement of primary aliphatic amides directly to the
corresponding amines under extremely mild conditions.3
The chemistry of organic polyvalent iodine compounds
has witnessed a great expansion during the last decades, an
expansion which continues at an increasing pace. The avail-
ability of iodine III and iodine IV compounds and the
development of new reagents, along with their selectivity un-
der a variety of conditions, their tolerance to different func-
tional groups, and their low toxicity and ease of handling,
made these compounds valuable tools in organic synthesis.
(1) (a) Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine;
VCH: New York, 1992. (b) Varvoglis, A. Hypervalent Iodine in Organic
Synthesis; Academic Press: London, 1997. (c) Wirth, T., Ed. Hypervalent Iodine
Chemistry; Springer-Verlag: Berlin, 2003.
(2) Reviews that appeared after 2000 are cited here. (a) Koser, G. F.
Aldrichim. Acta 2001, 34, 89. (b) Togo, H.; Katoghi, M. Synlett 2001, 566. (c)
Togo, H.; Sakurani, M. Synlett 2002, 1966. (d) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2002, 102, 2523. (e) Dauban, P.; Dodd, R. H. Synlett 2003, 11. (f)
Stang, P. J. J. Org. Chem. 2003, 68, 2997. (g) Tohma, H.; Kita, Y. Adv. Synth.
Catal. 2004, 346, 111. (h) Koser, G. F. Adv. Heterocycl. Chem. 2004, 86, 225.
(i) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893. (j) Wirth, T. Angew. Chem.,
Int. Ed. 2005, 44, 3656. (k) Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006,
ix, 26. (l) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402.
(m) Matveeva, E. D.; Proskurina, M. V.; Zefirov, N. S. Heteroatom Chem.
2006, 17, 595. (n) Silva, L. F., Jr. Molecules 2006, 11, 421. (o) Zhdankin, V. V.
Science of Synthesis: Houben-Weyl Methods of Molecular Transformations;
Georg Thieme Verlag: Stuttgart, Germany, 2007; Vol. 31a, Chapter 31.4.1, pp
161-234. (p) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924. (q)
Ochiai, M. Chem. Record 2007, 7, 12. (r) Ciufolini, M. A.; Braun, N. A.; Canesi,
S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 3759. (s) Canty, A. J.;
Rodemann, T.; Ryan, J. H. Adv. Organomet. Chem. 2008, 5, 279. (t) Quideau, S.;
(3) (a) Radhakrishna, A. S.; Parham, M. E.; Riggs, R. M.; Loudon, G. M.
J. Org. Chem. 1979, 44, 1746. (b) Loudon, G. M.; Radhakrishna, A. S.;
Almond, M. R.; Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272.
(c) Boutin, R. H.; Loudon, G. M. J. Org. Chem. 1984, 49, 4277. (d) Almond,
M. R.; Stimmel, J. B.; Thompson, E. A.; Loudon, G. M. Org. Synth. 1988, 66,
132. (e) Song, H.; Chen, W.; Wang, Y.; Qin, Y. Synth. Commun. 2005, 35,
2735. (f) Davis, M. C.; Stasko, D.; Chapman, R. D. Synth. Commun. 2003,
33, 2677.
ꢀ
Pouysegu, L.; Deffiieux, D. SynLett. 2008, 467. (u) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2008, 108, 5299. (v) Zhdankin, V. V. ARKIVOC 2009, No. i, 1.
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r
Published on Web 09/04/2009
J. Org. Chem. 2009, 74, 7315–7321 7315
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Malamidou-Xenikaki et al.
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SCHEME 1. General PIFA-Mediated Intramolecular Amida-
tion Process
SCHEME 2. PIFA-Mediated Cyclisation of Mercaptobenza-
mides and Anthranilamides
SCHEME 3. Retrosynthetic Analysis for Fused Indenodiazepi-
nones and Indenopyrazolinones
The mechanism of this reaction, an acidic Hofmann rear-
rangement, has been extensively studied.3c An application of
this rearrangement in peptide chemistry is the formation of
gem-aminoamides from N-protected amides of natural ami-
no acids4 and oligopeptides.5 More recent examples include
the oxidative rearrangement of anthranilamides or salicyla-
mides to the respective 2-benzimidazolones or 2-benzoxazo-
lones mediated by PhI(OAc)2-KOH/MeOH.6
BAIs have also been widely used in several cationic cycli-
zations. Tellitu and co-workers have developed approaches
to the synthesis of nitrogen-containing five-, six-, and seven-
membered heterocycles using properly substituted amides as
synthetic precursors via PIFA-mediated intramolecular ami-
dation reactions. The oxidation of the amide group by the
hypervalent iodine reagent proceeds through the generation
of an acylnitrenium intermediate that can react intramole-
cularly with a nucleophilic moiety properly attached to the
substrate. The application of this approach on alkylamides 1
or benzamides 2 bearing alkenyl,7 alkynyl,8 aryl,9,10 or
heteroaryl10 substituents, as well as on properly substituted
anilides,11 led to the synthesis of a plethora of heterocycles
through C-N bond formation (Scheme 1).
through intramolecular trapping of the N-acylnitrenium
intermediates by the thiol and the amine functionality and
formation of N-S and N-N bonds, respectively (Scheme 2).
In the frame of our ongoing interest in the chemistry of
hypervalent iodine compounds14 and the chemistry of ar-
yliodonium ylides of hydroxyquinones more specifically,15
we reported the synthesis of indenocarboxamides 3 starting
from the phenyliodonium ylide of lawsone 10.16 The coex-
istence of the amide together with the arylamino group
renders these molecules suitable substrates for oxidation
with hypervalent iodine reagents. Having in mind the pre-
viously reported methodology, in which the key steps in the
oxidation of alkyl amides or benzamides with PIFA are the
generation of an N-acylnitrenium ion and its subsequent
intramolecular trapping by an existing nucleophile, we
decided to explore the feasibility of this strategy in the
synthesis of the fused indenodiazepinones 4 and/or indeno-
pyrazolinones 5 through a BAI-promoted intramolecular
amidation process. A possible retro-synthetic pathway is
depicted in Scheme 3.
Pyrazolinones and especially diazepinones constitute im-
portant classes of compounds. Pyrazolinones and their fused
analogues have found considerable utility as pharmaceutical
agents, synthetic scaffolds in combinatorial and medicinal
chemistry, photographic couplers, chelating agents, and
agrochemical products.17 Benzodiazepine derivatives exhibit
widespread biological activities and consist one of the most
important classes of bioavailable therapeutic agents. In addi-
tion to their well-known anxiolytic, anticonvulsant, sedative,
antihypnotic and muscle-relaxant activities found in thera-
peutics, benzodiazepines also act as selective cholecystokinin
The same methodology has been successfully applied on 2-
mercaptobenzamides12 and anthranilamides13 leading to the
synthesis of benzisothiazol-3-ones and indazol-3-ones
(4) (a) Moutevelis-Minakakis, P.; Photakis, I. J. Chem. Soc., Perkin
Trans. 1 1985, 2277. (b) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis
1981, 266.
(5) (a) Kemp, D. S.; Stites, W. E. Tetrahedron Lett. 1988, 29, 5057. (b)
Blodgett, J. K.; Loudon, G. M. J. Am. Chem. Soc. 1989, 111, 6813.
(6) (a) Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.;
Tuladhar J. Org. Chem. 1993, 58, 2478. (b) S. M. Prakash, O.; Batra, H.;
Kaur, H.; Sharma, P. K.; Sharma, V.; Singh, S. P.; Moriarty, R. M. Synthesis
2001, 541.
(7) (a) Tellitu, I.; Urrejola, A.; Serna, S.; Moreno, I.; Herrero, M. T.;
Dominguez, E.; SanMartin, R.; Correa, A. Eur. J. Org. Chem. 2007, 437. (b)
Serna, S.; Tellitu, I.; Dominguez, E.; Moreno, I.; SanMartin, R. Tetrahedron
Lett. 2003, 44, 3483. (c) Tsukamoto, M.; Murata, K.; Sakamoto, T.; Saito, S.;
Kikugawa, Y. Heterocycles 2008, 75, 1133. (d) Kikugawa, Y. Heterocycles
2009, 78, 571.
(8) (a) Serna, S.; Tellitu, I.; Dominguez, E.; Moreno, I.; SanMartin, R.
Org. Lett. 2005, 7, 3073. (b) Tellitu, I.; Serna, S.; Herrero, M. T.; Moreno, I.;
Dominguez, E.; SanMartin, R.; Correa, A. J. Org. Chem. 2007, 72, 1526.
(9) (a) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581. (b) Wardrop, D.
J.; Burge, M. S. Chem. Comm. 2004, 1230.
(10) Correa, A.; Tellitu, I.; Dominguez, E.; Moreno, I.; SanMartin, R. J.
Org. Chem. 2005, 70, 2256. (b) Correa, A.; Herrero, M. T.; Tellitu, I.;
Dominguez, E.; Moreno, I.; SanMartin, R. Tetrahedron 2003, 59, 7103.
(11) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. J. Org. Chem.
2006, 71, 8316.
(14) Varvoglis, A.; Spyroudis, S. Synlett 1998, 221.
(15) Malamidou-Xenikaki, E.; Spyroudis, S. Synlett 2008, 2725.
(16) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M.;
Krautscheid, H. J. Org. Chem. 2007, 72, 502.
(12) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. Org. Lett.
2006, 8, 4811.
(13) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. J. Org. Chem.
2006, 71, 3501.
(17) Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009, 11,
1015.
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SCHEME 4. Preparation of the Starting Indenonarboxamides 3
FIGURE 1. Representative examples of 1,5-benzodiazepin-2-ones.
(CCK) receptor subtype A or B antagonists, platelet activat-
ing factor antagonists, human immunodeficiency virus
(HIV) transactivator Tat antagonists, and enzyme inhibi-
tors.10b Due to their capability of binding to multiple recep-
tors with high affinity, benzodiazepines were the class of
compounds to which the term “privileged structure” was first
applied by Evans et al. in 1988.18
In particular, molecules containing the 1,5-benzodiazepin-
2-one as well as the dibenzo[b,e][1,4]diazepin-11-one scaffold
exhibit a wide range of biological properties acting among
others as antinflammatories, antitumor agents, and antic-
onvulsivants.18,19 Representative examples are the interleu-
kin-1β converting enzyme (ICE) inhibitor 6, the delayed
rectifier potassium current blocker (IK) 7, the antidepressant
dibenzepine 8a, and the antihistaminic tarpane 8b (Figure 1).
Containing the 1,5-benzodiazepin-2-one core and a fused
indenone nucleus, the potentially accessible diazepinones 4
could be considered as promising biologically active com-
pounds.
from the oxidation of the amide functionality through an
alternative pathway that will be discussed below. When the
reaction was performed at room temperature, the yields of
the desired cyclization products 4a and 5a improved to 68%
and 16%, respectively (Table 1, entry 1). Reducing of the
stoichiometric amount of the oxidant (1.1 equiv) resulted
only in partial conversion of the starting material.
The conditions giving the best results for 4a (PIFA 1.5
equiv, rt, CH2Cl2) were then applied to indenocarboxamides
3b-d. The reaction of compound 3d was rather unproduc-
tive. Indenodiazepinone 4d was the only product isolated in
poor 14% yield along with a complex mixture of products
(Table 1, entry 4). The low yield of the desired oxidation
products in this case could be attributed to a competitive
oxidation process that can possibly take place on the en-
riched aromatic rings, as has already been mentioned.20 In
the cases of indenocarboxamides 3b,c and despite the high
total yield (73-84%) of the oxidation products, the desired
indenodiazepinones 4b and 4c were obtained in 30% and
23% yield, respectively (Table 1, entries 2 and 3). R-Hydro-
xyamides 15b and 15c were the main reaction products, in
54% and 50% yield, respectively. On the basis of previously
accepted mechanisms,7-13 the presence of a proper neigh-
boring group, such as an aryl-, alkoxy-, or nitrogen-contain-
ing group on the amide nitrogen atom, able to stabilize the
positively charged acylnitrenium intermediate (Scheme 1), is
usually required for the success of the reported PIFA-
promoted amide oxidations. For the intramolecular trap-
ping of this electron-deficient intermediate the presence of a
nucleophilic counterpart is considered crucial. The increase
in nucleophilicity of this functionality implies facilitation of
the cyclization. Taking into account these assumptions and
estimating that the amide group was almost quantitatively
oxidized in the cases of compounds 3b and 3c, we reasonably
Results and Discussion
Indenocarboxamide 3b and the known compounds 3a,c,d
were easily prepared from 2-hydroxy-1,4-naphthoquinone
(lawsone, 9) according to a previously reported method.16
Oxidative treatment of the hydroxyquinone 9 with PhI(O-
Ac)2 affords phenyliodonium ylide 10, which is thermally
converted in refluxing dry CH2Cl2 to oxetanone 12 quanti-
tatively (Scheme 4). Oxetanone 12 is the dimerization pro-
duct of the nonisolable ketene 11, the initial product of the
thermal degradation reaction, and due to its relative instabil-
ity, fresh crops of the compound are usually required.
Indenocarboxamides 3a-d were prepared by treatment of
oxetanone 12 with 2 equiv of the respective arylamine in
CH2Cl2 in 82-85% yield.16
Indenocarboxamide 3a was oxidized overnight with 1.5
equiv of PIFA in CH2Cl2 at 0 °C and three products, namely
indenodiazepinone 4a, indenopyrazolinone 5a, the predicted
oxidative cyclization products, and R-hydroxyamide 15a
(Scheme 5) were obtained in 50%, 15%, and 12% yield,
respectively. R-Hydroxyamide 15a is a byproduct resulting
(18) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893.
(19) Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C. Tetrahedron
2005, 61, 61.
(20) Reference 1a, p 218; ref 1c, p 44.
J. Org. Chem. Vol. 74, No. 19, 2009 7317

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TABLE 1. Yields of Isolated Products from the Oxidation of Enaminoamides 3
products (yield, %)
entry
starting enaminoamide 3
indenodiazepinones 4
indenopyrazolinones 5
R-hydroxyamides 15
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Ar = p-tolyl
Ar = Ph
Ar = p-ClC6H4
Ar = p-MeOC6H4
4a (68)
4b (30)
4c (23)
4d (14)
4e (43)
4f (74)
4g (26, 41)
4h (57) b
4i (42)
5a (16)
5b (0)
5c (0)
5d (0)
5e (3)
5f (11)
5g (10, 15)
5h (14)
5i (4)
5j (5)
5k (8)
5l (0)
15a (7)
15b (54)
15c (50)
Ar = Ph, Ar1 = p-tolyl
Ar = p-EtC6H4, Ar1 = p-tolyl
Ar = o-tolyl, Ar1 = p-tolyl
Ar = 2,4-di-MeC6H3, Ar1 = p-tolyl
Ar = p-ClC6H4, Ar1 = p-tolyl
Ar = p-tolyl, Ar1 = p-ClC6H4
Ar = p-tolyl, Ar1 = Ph
Ar = p-tolyl, Ar1 = mesityl
Ar = m-MeOC6H4, Ar1 = p-tolyl
Ar = p-NO2C6H4, Ar1 = p-tolyl
15a (24)
15a (12)
15a (21, 18)
15a (10)
15a (31)
15c (15)
15b (17)
15d (11)
15a (21)
15a (65)
9
10
11
12
13
14
4j (65)
4k (75)
4l (24)a
4m (35)a
4n (25)
5m (0)
5n (0)
aStarting material 3g (23%), 3l (45%), or 3m (8%) was recovered unchanged under the usual reaction conditions. bYields when 2.0 equiv of PIFA was
used and all the starting enaminoamide was consumed.
SCHEME 5. PIFA-Mediated Oxidation of Indenocarboxamides 3
assumed that the deviation from the desired oxidative cycli-
zation could rather be attributed to the relatively diminished
donating properties of the phenyl and p-chlorophenyl
groups of the nucleophilic arylamino (ArNH) moiety, in
respect to the p-tolylamino group in 3a.
dependence on the substituents of the arylamino (ArNH)
fragment. More specifically, the PIFA-mediated oxidations
of indenocarboxamides 3f-h bearing activated alkyl-substi-
tuted phenyl rings afforded good to excellent total yields of
the target cyclization products 4f-h (41-74%) and 5f-h
(11-15%) and low yields (10-18%) of the byproduct 15a
(entries 6-8). The lower yield (41%) of indenodiazepinone
4g with respect to that of 4f (74%) could be attributed to both
the loss of one ortho active site of the aryl ring and the steric
effects of the ortho methyl substituent. On the other hand,
the effectiveness of the reaction of 2,4-dimethylphenylami-
noindenocarboxamide 3h, that afforded better yields (57%)
of indeno-diazepinone 4h, is ascribed to the increased elec-
tron-donating properties of the 2,4-dimethylphenyl group
compared to those of the tolyl group (in carboxamide 4g)
that can counterbalance the steric effect of the ortho sub-
stituent. In accordance with this, the outcome of the reac-
tions of the substrates bearing a nonactivated phenyl (3e,
entry 5), a moderately deactivated p-chlorophenyl (3i, entry 9),
or a strongly deactivated p-nitrophenyl group (3n, entry 14)
is predictable. Indeed, indenodiazepinones 4e and 4i were
obtained in moderate yields (43% and 42%) from the
reactions of the corresponding indenocarboxamides 3e and
3i, whereas the yield of the isolated corresponding product 4n
was considerably lower (25%). In these cases, the yield of R-
hydroxyamide 15a gradually increased (24%, 31%, and 65%
from 3e, 3i, and 3n, respectively) in a retrograde to the
activation of the arylamino (ArNH) group manner. Our
Therefore, in order to get more information and determine
the scope of the proposed cyclization with respect to the
amine functionality, we decided to explore the influence of
the nature of the aryl substituent of the ArNH group on the
efficiency of the cyclization step. For this purpose and
selecting the p-tolyl group as the optimal substituent for
the amide nitrogen atom, a series of indenocarboxamides
3e-n differently substituted at the two N-aryl rings of the
amine (N-Ar) and the amide (N-Ar1) groups were prepared.
This can be accomplished by the successive treatment of
oxetanone 12 with two different arylamines (1 equiv each
time). The reaction of oxetanone 12 with 1 equiv of aryla-
mine is known to produce the enaminoesters 14 that can be
isolated in good yields by crystallization (Scheme 4).16 Treat-
ment of the enaminoesters 14 with one more equivalent of the
arylamine leads to indenocarboxamides 3. By implemen-
tation of this process and using aniline, p-ethylaniline,
o-toluidine, 2,4-dimethylaniline, p-chloroaniline, p-nitroani-
line, or m-anisidine in the first step and p-toluidine in the
second one, indenocarboxamides 3e-i,m,n, were prepared in
53-76% total yield for the two steps.
As shown in Table 1, the outcome of the reactions of
these indenocarboxamides with PIFA indicates a significant
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Malamidou-Xenikaki et al.
SCHEME 6. Proposed Mechanistic Pathway for the Formation of Diazepinones 4, Pyrazolinones 5, and R-Hydroxyamides 15
JOCArticle
assumption was also verified by the results of the PIFA-
mediated reactions of indenocarboxamides 3j and 3k
(Table 1, entries 10 and 11). The yields of indenodiazepi-
nones 4j and 4k (65% and 75%) compared to those of 4c and
4b (23% and 30%), derived from the oxidations of indeno-
carboxamides 3c and 3b, reflect the reinforcement of the
electron-donating properties of p-tolyl group in respect to
those of the p-chlorophenyl or phenyl group in 3c and 3b.
Once again, the poor yield of the desired 4m from the
reaction of methoxy-substituted indenocarboxamide 3m
with PIFA (Table 1, entry 13) could probably be ascribed
to byproducts resulting from a contemporary oxidation of
the enriched aromatic ring. Finally, the effect of the bulky
mesityl substituent on the oxidation of the amide group is
obvious in the case of indenocarboxamide 3l (Table 1, entry
12) where the product yields are notably reduced.
The above results are consistent with the plausible me-
chanistic proposal described in Scheme 6. Initially, the amide
group of indenocarboxamide 3, known to exist in solution in
two tautomeric forms 3-A and 3-B,16 reacts with PIFA to
give intermediate 16, which is then transformed to the
acylnitrenium ion 17 via an oxidative process. The acylni-
trenium ion reacts intramolecularly with the nucleophilic
aryl (Ar) group to furnish eventually the fused indenoben-
zodiazepinones 4 through abstraction of TFA. Alternative
intramolecular nucleophilic attack of the nitrogen atom
of the ArNH fragment on the nitrenium active center
followed again by TFA abstraction produces pyrazolinones
5. The lower efficiency of the latter pathway, impressed in
the yields of pyrazolinones 5, is undoubtedly ascribed to the
limited nucleophilicity of this nitrogen atom due to its ami-
dic nature (vinylogous amide). Regarding R-hydroxyamide
15, it originates from the common intermediate 17 which
is attacked by the trifluoroacetate anion delivered by
PIFA, as depicted in Scheme 6. Both the ester and the
arylimino (ArNd) group of the intermediate 18 are pro-
bably hydrolyzed during workup. Alternatively, a PIFA-
promoted oxidative degradation of the arylimino group21
could not be excluded, although the anticipated oxida-
tion product ArNdNAr, formal product from the dimeri-
zation of nitrene [ArN:], of such a process has never been
isolated.
An alternative pathway based on the acceptance that
PIFA reacts initially with the ArNH group and the amide
N-aryl substituent (Ar1NH) attacks the generated electron-
deficient center in 19 could rather be excluded. In this case,
structurally different diazepinones, fused with the Ar1 ring
and having the substituent Ar on nitrogen, would be formed.
Such products were never isolated, and moreover, the reac-
tion of indenocarboxamide bearing a bis-ortho-substituted
arylamino group (Ar = mesityl, Ar1 = p-tolyl) with PIFA
failed to give any cyclization products, the only isolated
product being R-hydroxyamide 15a.
Structure elucidation of compounds 4, 5, and 15 was based
on their analytical and spectral data. The most discernible
difference in the 1H NMR spectra of indenodiazepinones 4
and pyrazolinones 5 is the absence of the peak for one of the
ortho protons of the arylamino (ArNH) group, as well as the
appearance of a broad singlet at δ 11.22-11.91 for the -NH
group in the spectra of compounds 4. Due to the difficulty of
chromatographic separation of pyrazolinones 5 from hydro-
xyamides 15, no satisfactory 13C NMR spectra could be
(21) Reference 1a, p 98.
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Malamidou-Xenikaki et al.
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SCHEME 7. Independent Preparation of R-Hydroxyamides 15
known hypervalent iodine reagents, PhI(OCOCH3)2 and
PhI(OCOCF3)2, play a crucial role: the former for the
preparation of phenyliodonium ylide of lawsone and the
latter for the final oxidation and hence the title of this paper.
Experimental Section
Preparation of Indenocarboxamides 3a-d. These amides were
prepared by addition of 2 equiv of arylamine to a stirred
suspension of oxetanone 12 in CH2Cl2 according to the pre-
viously reported method, in 82-85% yield.16
Preparation of Indenocarboxamides 3e-n. These amides hav-
ing different aryl groups were prepared by sequential addition of
1 equiv of a different arylamine each time to a stirred suspension
of oxetanone 12 in CH2Cl2 in analogy to the previously reported
method.16
measured for some pyrazolinones 5, such as 5i and 5j
obtained in very low yields.
Regarding R-hydroxyamides 15, their structure was
further verified through their independent synthesis based
on the PIFA-mediated oxidation of indanedionecarboxa-
mides 20 (Scheme 7). The latter can arise from the thermal
degradation of phenyliodonium ylide 10 curried in the pre-
sence of 1 equiv of arylamine.22 The oxidation reactions of
amides 20 were performed under the previously applied
conditions for the oxidation of amides 3 furnishing R-
hydroxyamides 15 in 66-85% yield. In this case as there is
no second arylamino group in the molecule, carboxamides
20 are inevitably converted to R-hydroxyamides 15.
Since the prepared diazepinones 4 are new templates they
were tested for possible biological activity, at a first level.
Nine selected derivatives, namely 4a-c,e,g,i-k,m, were
screened for their antioxidant activity, according to a re-
ported methodology23 and more specifically for their redu-
cing ability determining their interaction percent values with
the stable radical 1,1-diphenylpicrylhydrazyl (DPPH) and
for their inhibition of soybean lipoxygenase, as well as for
their inhibitory activity on the lipid peroxidation of linoleic
acid. Compounds 4m and 4j showed significant reducing
activity (83% and 78%, respectively, compared to 81% of
the nordihydroguaeretic acid used as a reference compound).
Diazepinones 4b, 4e, and 4k were found to be the more
potent inhibitors of soybean lipoxygenase (IC50 values 50,
29.5, and 50 μM, respectively, compared to the 600 μM, the
IC50 value of caffeic acid, which was used as a standard).
Derivative 4b inhibits lipid peroxidation more effectively
(88%) in comparison to trolox (63%), used as a standard.
Almost all the screened compounds present antioxidant
activities as indicated (Table) in the Supporting Information.
These preliminary results seem promising. Further investi-
gation is in progress in order to delineate the possible
mechanism of action of these new compounds.
Typical Procedure for the Preparation of Indenocarboxamide
3e. Aniline (0.5 mmol) dissolved in CH2Cl2 (2 mL) was added
to a stirred suspension of oxetanone 12 (0.5 mmol) in CH2Cl2
(5 mL), and stirring was continued for 1 h. Hexanes (∼2 mL) was
added to the reaction solution to effect precipitation, and the
resulting yellow solid was filtered, dried, and used for the next step
without further purification (yield of the crude product 86%). The
enaminoester 14e (0.4 mmol) obtained in this manner was dis-
solved in CH2Cl2 (5 mL), p-toluidine (0.4 mmol) was added, and
the resulting suspension was stirred at room temperature for 4 h.
The precipitated 2,3-dihydroxy-1,4-naphthoquinone (13) was fil-
tered off, and the filtrate was concentrated and chromatographed
on column (silica gel, hexanes-ethyl acetate 5:1 up to 3:1) to afford
3-anilino-N-(4-methylphenyl)-1-oxo-1H-indene-2-carboxamide (3e)
1
in 66% yield: mp 189-191 °C; IR (KBr) cm-1 1671, 1644; H
NMR (CDCl3, 300 MHz) δ 11.99 (brs, 1H), 10.07 (brs, 1H),
7.62-7.53 (m, 3H), 7.53-7.45 (m, 3H), 7.45-7.35 (m, 3H),
7.19-7.07 (m, 3H), 6.47 (d, J = 7.7 Hz, 1H), 2.33 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 189.6, 169.1, 165.1, 137.1, 135.9 134.4,
133.2, 132.6, 131.6, 129.7, 129.5, 128.7, 126.6, 124.2, 121.9, 120.0,
98.2, 20.9; ESI-HRMS m/z calcd for C23H18N2O2 þ Na (MNaþ)
377.12605, found 377.12616.
Typical Procedure for the Oxidation of Indenocarboxamide 3a.
A solution of PIFA (0.3 mmol) in CH2Cl2 (5 mL) was added
during a period of 30 min to a stirred solution of indenocarbox-
amide 3a (0.2 mmol) in CH2Cl2 (15 mL), and the reaction was
monitored by TLC. After the disappearance of indenocarbox-
amide 3a (4-5 h), the reaction mixture was washed successively
with saturated solutions of NaHCO3 and NaCl and dried with
Na2SO4. The dried solution was concentrated and chromato-
graphed on column using silica gel and hexanes-ethyl acetate 3:1
for the elution of iodobenzene and diazepinone 4a, gradually
increasing to 1:1 for the elution of hydroxyamide 15a and finally
pure ethyl acetate for the elution of pyrazolinone 5a. Since
partial decomposition of 4a is observed on the column during
prolonged chromatography time, it is better to perform chro-
matography separation as soon as possible even if that implies a
second column chromatography for the complete separation of
15a and 5a. Isolated in order of eluance:
Conclusions
In conclusion, the preparation of fused indenodiazepi-
nones 4, new templates with possible biological activity,
through the oxidation of indenocarboxamides 3, is reported
in this paper. The yields of 4 compared to the yields of the
two other products of the reaction 5 and 15, in correlation to
the nature of the substituents on both aromatic rings, give
evidence for the reaction pathway. Indenodiazepinones 4 are
accessed by a sequence of reactions where two of the most
9-Methyl-7-(4-methylphenyl)-7,12-dihydrobenzo[b]indeno-
[1,2-e][1,4]diazepine-5,6-dione (4a). 68% yield; mp 205-208 °C;
IR (KBr) cm-1 1660, 1634; 1H NMR (CDCl3, 300 MHz) δ 11.88
(brs, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 6.7 Hz, 1H),
7.65-7.52 (m, 2H), 7.40-7.22 (m, 5H), 6.99 (d, J = 8.5 Hz, 1H),
6.66 (s, 1H), 2.40 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 189.7, 162.2, 161,9, 146.4, 141.7, 138.7, 138.6, 136.1,
136.0, 132.9, 132.8, 132.5, 131.0, 129.9, 127.7, 123.1, 121.6,
121.53, 121.47, 93.0, 21.0, 20.7; ESI-HRMS m/z calcd for
C24H18N2O2 þ H (MHþ) 367.14410, found 367.14405.
(22) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M. J. Org.
Chem. 2003, 68, 5627.
(23) (a) Kontogiorgis, C.; Hadjipavlou-Litina, D. J. Enzym. Inhib. Med.
Chem. 2003, 18, 63. (b) Liegois, C.; Lermusieau, G.; Colin, S. J. Agric. Food
Chem. 2000, 48, 1129.
2-Hydroxy-N-(4-methylphenyl)-1,3-dioxoindane-2-carboxa-
mide (15a). 7% yield; mp 140-142 °C; IR (KBr) cm-1 3345,
1757, 1716, 1666; 1H NMR (CDCl3, 300 MHz) δ 8.78 (brs, 1H),
7320 J. Org. Chem. Vol. 74, No. 19, 2009

Malamidou-Xenikaki et al.
JOCArticle
8.06-7.98 (m, 2H), 7.93-7.87 (m, 2H), 7.34 (d, J = 8.3 Hz, 2H),
7.06 (d, J = 8.3 Hz, 2H), 2.28 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 194.8, 163.5, 142.6, 136.7, 134.9, 133.8, 129.5, 124.3,
119.8, 82.4, 20.9; ESI-HRMS m/z calcd for C17H13NO4 þ H
(MHþ) 318.07361, found 318.07360.
A solution of PIFA (0.24 mmol) in CH2Cl2 (5 mL) was
added to a stirred solution of indanedionecarboxamide 20a
(0.2 mmol) in CH2Cl2 (15 mL), and the reaction was moni-
tored by TLC. After the disappearance of indandionecar-
boxamide 20a (2-3 h), the reaction mixture was washed
successively with saturated solutions of NaHCO3 and NaCl
and dried with Na2SO4. The dried solution was concen-
trated and chromatographed on column using silica gel
and hexanes-ethyl acetate from 3:1 to pure ethyl acetate.
The colorless hydroxyamide 15a was isolated after iodoben-
zene in 66% yield and it was in all respects identical to
R-hydroxycarboxamide 15a isolated as the minor product
in the previously described oxidation reaction of indenocar-
boxamide 3a.
1,2-Bis(4-methylphenyl)-1,2-dihydroindeno[1,2-c]pyrazole-
3,4-dione (5a). 16% yield; mp 253-255 °C; IR (KBr) cm-1 1720,
1666; 1H NMR (CDCl3, 300 MHz) δ 7.67 (d, J = 7.4 Hz, 1H),
7.42 (t, J = 7.4 Hz, 1H), 7.33-7.24 (m, 5H), 7.11 (s, 4H), 6.88
(d, J = 7.4 Hz, 1H), 2.39 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 181.8, 163.4, 157.9, 141.1, 140.8, 138.6, 132.35,
132.29, 132.1, 131.6, 130.6, 130.3, 129.9, 127.0, 126.4, 124.2,
120.8, 104.8, 21.4, 21.2; ESI-HRMS m/z calcd for C24H18N2O2
þ H (MHþ) 367.14410, found 367.14424.
Typical Procedure for the Preparation of r-Hydroxycarbox-
amide 15a from Oxidation of Indanedionecarboxamide 20a.
Indanedionecarboxamide 20a was prepared from the thermal
decomposition of iodonium ylide of lawsone 10 in the presence
of p-toluidine in 94% yield, as it was described.22
Supporting Information Available: Spectral and analytical
data for all new compounds 3b,e-n, 4a-n, 5a,e-k, and 15a-d
and the results of biological tests. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 19, 2009 7321