Novel alternative for the N-N bond formation through a PIFA-mediated oxidative cyclization and its application to the synthesis of indazol-3-ones

Article abstract of DOI:10.1021/jo060070+

The synthesis of a series of N,N′-disubstituted indazolone derivatives starting from methyl anthranilates is presented. This general approach features a novel and easy way for access to the target N-heterocycles by formation of a new N-N single bond. The

Full text of DOI:10.1021/jo060070+

Novel Alternative for the N-N Bond Formation through a
PIFA-Mediated Oxidative Cyclization and Its Application to the
Synthesis of Indazol-3-ones†
Arkaitz Correa, Imanol Tellitu,* Esther Dom´ınguez,* and Raul SanMartin
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad del Pa´ıs Vasco,
Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
imanol.tellitu@ehu.es.
ReceiVed January 12, 2006
The synthesis of a series of N,N′-disubstituted indazolone derivatives starting from methyl anthranilates
is presented. This general approach features a novel and easy way for access to the target N-heterocycles
by formation of a new N-N single bond. The key cyclization step embraces the formation of an
N-acylnitrenium intermediate, mediated by the hypervalent iodine reagent PIFA, and its succeeding
intramolecular trapping by the amine moiety under rather mild experimental conditions.
Introduction
The maturity of the organic synthesis gained over the decades
is the result of significant contributions from all aspects of
chemistry, and most of them rely on the discovery of simple
reaction conditions for complex transformations.1 In this context,
there is a plethora of tools available for carbon-carbon and
carbon-heteroatom bond formation, but the field of hetero-
atom-heteroatom bond formation remains comparatively less
developed. Accordingly, an evident entrance to this area is based
on the generation of heteroatom-centered intermediates.
Nitrenium ions are highly reactive intermediates which
continue to receive attention not only because of their suspected
role in the carcinogenesis initiated by nitro and aminoaromatic
compounds2 but also, particularly, because of their utility in
organic synthesis.3 However, synthetic applications of these
electrophilic intermediates remain limited except when such
nitrenium ions are stabilized by the electron-donating effect of
FIGURE 1. Some stabilized acylnitreniun ions.
a proper neighboring group (aryl, alkoxy, or nitrogen, inter alia).4
In these cases, the so-stabilized nitrenium ions (I, II, and III;
see Figure 1) exist for a long enough time to be useful as
synthetic intermediates.
Despite the fact that N-acylnitrenium ions can be generated,
for example, by the treatment of N-alkoxy-N-chloroamides with
a variety of Lewis acids, such as silver4a or zinc salts,5 the use
of the hypervalent iodine reagent PIFA [phenyliodine(III)bis-
(trifluoroacetate)] for this purpose overcomes the limitations
associated with those protocols,6 and therefore, its use has been
widely applied to the synthesis of a number of different
heterocyclic compounds.7 In this context, these powerful elec-
* To whom correspondence should be addressed. Phone: (34) 94 601 5438.
Fax: (34) 94 601 2748.
(3) For reviews concerning the chemistry of nitrenium ions, see: (a)
Abramovitch, R. A.; Jeyaraman, R. In Azides and Nitrenes: ReactiVity and
Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando, 1984; pp 297-
357. (b) Falvey, D. E. In ReactiVe Intermediate Chemistry; Moss, R. A.,
Platz, M. S., Jones, M., Eds.; Wiley-Interscience: Hoboken, NJ, 2004; pp
594-650.
(4) (a) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.
Tetrahedron 1987, 43, 2577-2592. (b) Kikugawa, Y.; Nagashima, A.;
Sakamoto, T.; Miyazama, E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739-
6744. (c) Falvey, D. E.; Kung, A. C. J. Org. Chem. 2005, 70, 3127-3132.
(5) Kawase, M.; Miyake, Y.; Sakamoto, T.; Shimada, M.; Kikugawa,
Y. Tetrahedron 1989, 45, 1653-1660.
† This paper is dedicated to the memory of our collegue and friend Professor
Marcial Moreno-Man˜as.
(1) (a) Nicolaou, K. C., Sorensen, E. J., Eds. In Classics in Total
Synthesis; VCH Publishers: New York, 1995. (b) Corey, E. J., Cheng, X.-
M., Eds. In The Logic of Chemical Synthesis; John Wiley & Sons: New
York, 1995.
(2) (a) Kadlubar, K. K. In DNA Adducts Identification and Biological
Significance; Hemmink, K., Dipple, A., Shugar, D. E. G., Segerback, D.,
Bartsch, H., Eds.; University Press: Oxford, U.K., 1994; pp 199-126. (b)
McClelland, R. A.; Ahmad, A.; Dicks, A. P.; Licence, V. E. J. Am. Chem.
Soc. 1999, 121, 3303-3310.
10.1021/jo060070+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/21/2006
J. Org. Chem. 2006, 71, 3501-3505
3501

Correa et al.
SCHEME 1. Synthesis of Indazolone 3aa
FIGURE 2. Proposed strategy for the synthesis of indazolones.
trophiles readily undergo inter- and intramolecular substitution
reactions with a range of nucleophilic species. Nevertheless, as
far as we are aware, only the use of carbon nucleophiles as the
nucleophilic counterparts, such as (hetero)arene rings and C-C
multiple bonds, in an electrophilic amidation reaction8 and in a
novel amidohydroxylation protocol,9 respectively, has been
described. In our hands, these two PIFA-mediated transforma-
tions have provided the synthesis of a wide variety of N-
heterocyclic compounds via C-N bond formation. Herein, we
report a novel oxidative cyclization process, which features the
first successful intramolecular trapping of N-acylnitrenium ions
by amine functionalities (IV f V f VI in Figure 2) thus
developing a novel approach to the construction of new N-N
linkages.
Because several indazolone derivatives have gained note-
worthy importance in view of their promising pharmacological
properties, such as antiinflammatory,10 antipsychotic,11 or an-
tihyperlipidemic agents,12 we decided to focus on the synthesis
of indazol-3-one derivatives. The high-pressure transition-metal-
catalyzed carbonylation of azobenzenes,13 the cyclization of
o-arylhydrazinobenzoic acids,14 the isomerization of 3-aryl-2-
hydroxyindazoles, the base-catalyzed cyclization of o-azido-
benzanilides, and the reductive cyclization of o-nitrobenzanil-
ides15 can be cited among the most widely used protocols for
access to indazolone derivatives.16 Because the already men-
tioned synthetic procedures lack generality and require, in some
cases, not very accessible substrates, a novel and general
approach would be desirable and of high value (see Figure 2).
Thus, as part of our ongoing research for novel applications
of the hypervalent iodine reagents in organic chemistry,17 we
a Reagents and conditions: (i) AlMe3, p-anisidine, CH2Cl2, reflux (69%);
(ii) see Table 1.
TABLE 1. Selected Assays Performed on Amide 2a
3aa
entry
conditions
(%)
b
1
2
3
4
5
6
7
8
9
PIFA (0.05 M), CH2Cl2
51
21
10
51
33
36
15
51
54
68
7
b
b
PIDA (0.05 M), CH2Cl2
HTIB (0.05 M), CH2Cl2
PIFA (0.05 M), TFEAb
PIFA (0.05 M), CH3CNb
PIFA (0.05 M), tolueneb
PIFA (0.05 M), DMFb
c
PIFA (0.05 M), CH2Cl2
PIFA (0.05 M), CH2Cl2, TFAb
PIFA (0.01 M), CH2Cl2, TFAb
PIFA (0.01 M), CH2Cl2, BF3‚OEt2
10
11
b
a Isolated yield after purification by flash chromatography. b Reaction
carried out at 0 °C. c Reaction carried out at -78 °C.
would like to report a novel and alternative access to the
construction of the indazolone skeleton through a PIFA-mediated
oxidative cyclization.
Results and Discussion
Synthesis of Indazolone 3a. On the basis of our previous
experience, we selected the para-methoxyphenyl-substituted
benzamide 2a as a model system to optimize the experimental
conditions for the proposed cyclization step. This substrate was
easily prepared by treatment of the commercially available
methyl N-methylanthranilate (1a) with AlMe3 and para-anisidine
in the conditions depicted below (see Scheme 1).18 Next, as
shown in Table 1, we briefly examined the effect of different
solvents, sources of hypervalent iodine, temperature, and
additives on the success of the oxidative cyclization step.
The results obtained from these experiments indicated that
the hypervalent iodine reagent PIFA was the most efficient
oxidant. Indeed, the use of other related I(III) reagents, such as
PIDA [phenyliodine(III)diacetate] (entry 2) and HTIB [hy-
droxytosyloxyiodobenzene] (entry 3), was also tested but, unlike
PIFA, rendered the indazolone 3a in very low yields. On the
other hand, the nature of the solvent had a significant influence
on the success of the reaction. Thus, whereas the employment
of polar aprotic solvents such as CH3CN (entry 5) or DMF (entry
7) afforded the desired product in low yields, the use of either
(6) When the easily handled and environmentally friendly I(III) reagent
is used, an undesirable aromatic chlorination process is avoided because
prior chlorination is not required to generate acylnitrenium ions. See:
Kikugawa, Y. ReV. Heteroatom Chem. 1996, 15, 263-299.
(7) (a) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353-2356. (b)
Wardrop, D. J.; Landrie, C. L.; Ort´ız, J. A. Synlett 2003, 1352-1354.
(8) (a) Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230-1231.
(b) Correa, A.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R. J.
Org. Chem. 2005, 70, 2256-2264. (c) Wardrop, D. J.; Burge, M. S. J.
Org. Chem. 2005, 70, 10271-10284.
(9) (a) Serna, S.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R.
Tetrahedron Lett. 2003, 44, 3483-3486. (b) Serna, S.; Tellitu, I.;
Dom´ınguez, E.; Moreno, I.; SanMartin, R. Org. Lett. 2005, 7, 3073-3076.
(10) (a) Tse, E.; Butner, L.; Huang, Y.; Hall, I. H. Arch. Pharm. Pharm.
Med. Chem. 1996, 329, 35-40. (b) Abouzid, K. A.; El-Abhar, H. S. Arch.
Pharmacal Res. 2003, 1, 1-8.
(11) Norman, M. H.; Rigdon, G. C.; Navas, F., III; Cooper, B. R. J.
Med. Chem. 1994, 37, 2552-2563.
(12) Wyrick, S. D.; Voorstad, P. J.; Cocolas, G.; Hall, I. H. J. Med.
Chem. 1984, 27, 768-772.
(17) For recent reviews on polyvalent iodine reagents, see: (a) Zhdankin,
V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-2284. (b) Stang, P. J. J.
Org. Chem. 2003, 68, 2997-3008. (c) Wirth, T. Top. Curr. Chem. 2003,
224, 1-264. (d) Tohma, H.; Kita, Y. AdV. Synth. Catal. 2004, 346, 111-
124. (e) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893-2903. (f) Wirth,
T. Angew. Chem., Int. Ed. 2005, 44, 3656-3665.
(13) Zhou, D.-Y.; Koike, T.; Suetsugu, S.; Onitsuka, K.; Takahashi, S.
Inorg. Chim. Acta 2004, 357, 3057-3063.
(14) Baiocchi, L.; Corsi, G.; Palazzo, G. Synthesis 1978, 633-648.
(15) Bird, C. W.; Chng, J. C. W.; Rama, N. H.; Saeed, A. Synth.
Commun. 1991, 21, 545-548.
(16) For a comprehensive review of the chemistry of indazoles, see:
Stadbauer, W. Sci. Synth. 2002, 12, 227-324.
(18) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989-993.
3502 J. Org. Chem., Vol. 71, No. 9, 2006

PIFA-Mediated OxidatiVe Cyclization
SCHEME 2. Synthesis of Indazolones 3a-ga
CH2Cl2 (entries 1 and 8-10) or trifluoroethanol (entry 4) proved
to be a better solution because the desired heterocycle 3a was
obtained in slightly higher yields. Because both solvents behaved
similarly, the selection of CH2Cl2 over TFEA was made on the
basis of economical costs. Furthermore, although the results did
not improve at all when carrying out the reaction at low
temperatures (entry 8), the use of TFA as an additive (entry 9)
made the reaction take place much more cleanly, and even the
yields were not highly effected. In contrast, the use of other
additives, such as the Lewis acid BF3‚OEt2 (entry 11), which
had been extensively reported to increase the reactivity of this
kind of reagents,19 failed in our case and provided only traces
of the desired product. Interestingly, the use of more dilute
solutions (entry 10) turned out to be the key for the best
conditions leading to indazolone 3a in 68% yield.
a Reagents and conditions: (i) AlMe3, p-anisidine, CH2Cl2, reflux; (ii)
(a) LiOH‚H2O, THF/H2O, room temperature, (b) p-anisidine, Et3N,
EDC‚HCl, HOBt, CH2Cl2, 0 °C f room temperature; (iii) PIFA (0.01 M),
CH2Cl2, TFA, 0 °C.
Therefore, we propose that the optimal reaction conditions
imply the use of 1.5 equiv of PIFA (0.01 M) in CH2Cl2 at 0 °C
in the presence of 3 equiv of TFA (entry 10). Besides, these
preliminary results suggest that N-acylnitrenium ions generated
by PIFA, as we presumed before, can also be trapped intramo-
lecularly by amine moieties, featuring consequently an interest-
ing approach to the construction of new N-N linkages.
Synthesis of Indazolones 3a-o. Having established an
optimal protocol for the projected process, we performed a more
detailed examination of the electronic requirements of the
structure of the substrates. Thus, the behavior of a variety of
substrates, which include different amine functionalities as well
as different amide moieties, under the action of the hypervalent
iodine reagent PIFA was examined.
TABLE 2. Scope of the Cyclization with Respect to Amides 2a-g
2
3
entry
R1
Me
allyl
PhCH2
Ph
(%)a
(%)b
1
2
3
4
5
6
7
2a (69)c
2b (77)c
2c (67)c
2d (68)c
2e (71)c
2f (85)d
2g (86)d
3a (68)
3b (62)
3c (67)
3d (61)
3e (0)
H
CO2Et
TolSO2
3f (0)
3g (0)
a Isolated yield after purification by crystallization. b Isolated yield after
purification by flash chromatography. c Synthesis through conditions i.
d Synthesis through conditions ii.
SCHEME 3. Synthesis of Indazolones 3a,h-oa
First of all, we analyzed the influence of the nature of the
amine moiety on the efficiency of the cyclization step. Thus, a
series of the required p-methoxyphenylbenzamide derivatives
2a-g were effectively prepared starting from easily accessible
or commercially available anthranilates 1a-g either by treatment
with AlMe3 and p-anisidine or through basic hydrolysis followed
by a known amidation protocol (Scheme 2).20,21 As shown in
Table 2, the proposed PIFA-mediated cyclization process proved
to be suitable for substrates in which the amine functionality
was substituted by either alkyl (entries 1-3) or aryl groups
(entry 4). Once again, the positive effect of the presence of TFA
as an additive was confirmed in all cases. On the other hand,
neither aminobenzamide 2e (entry 5) nor the ones substituted
by an electron-withdrawing group, 2f,g (entries 6 and 7),
rendered the desired indazolones 3e-g. Thus, it can be
concluded that the scope of this PIFA-promoted oxidative
cyclization requires highly nucleophilic amines.
a Reagents and conditions: (i) AlMe3, R2NH2, CH2Cl2, reflux; (ii) PIFA
(0.01 M), CH2Cl2, TFA, 0 °C.
TABLE 3. Scope of the Cyclization with Respect to Amides
2a,h-o
2
3
entry
R2
(%)a
(%)b
A second part of the research was designed to determine the
scope of the cyclization process with respect to the amide
functionality. Thus, a series of amides were successfully
prepared in a single step by an AlMe3-mediated aminolysis of
methylanthranilate 1a in the presence of different amines
1
2
3
4
5
6
7
8
9
p-OMePh
Ph
1-Naph
p-EtPh
p-BrPh
H
PhCH2
allyl
OMe
2a (69)
2h (88)
2i (91)
2j (89)
2k (22)
2l (90)
2m (88)
2n (65)
2o (18)
3a (68)
3h (60)
3i (61)
3j (60)
3k (45)
3l (0)
3m (0)
3n (0)
3o (0)
(19) Romero, A. G.; Darlington, W. H.; McMillan, M. W. J. Org. Chem.
1997, 62, 6582-6587.
(20) For a recent review on the general synthesis of amides, see:
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827-10852.
(21) It is interesting to remark that some o-aminobenzamides have been
reported to show antipsychotic activity. See: (a) Norman, M. H.; Navas,
F., III; Thompson, J. B.; Rigdon, G. C. J. Med. Chem. 1996, 39, 4692-
4703. (b) Yee, Y. K.; Tebbe, A. L.; Linebarger, J. H.; Beight, D. W.; Craft,
T. J.; Gifford-Moore, D.; Goodson, T.; Herron, D. K.; Klimkowski, V. J.;
Kyle, J. A.; Sawyer, J. S.; Smith, G. F.; Tinsley, J. M.; Towner, R. D.;
Weir, L.; Wiley, M. R. J. Med. Chem. 2000, 43, 873-882. For further
details of the preparation and spectral data of benzamides 2a-g, see the
Supporting Information.
a Isolated yield after purification by crystallization. b Isolated yield after
purification by flash chromatography.
(Scheme 3). When the amides 2a,h-o were treated with the
trivalent iodine reagent PIFA under the optimized conditions
(see Table 3), the effectiveness for this cyclization reaction
proved to be restricted to N-arylamides (entries 1-5). Although
a wide range of experimental conditions was tested on either
J. Org. Chem, Vol. 71, No. 9, 2006 3503

Correa et al.
7.43 (d, J ) 9.1, 2H), 7.53-7.59 (m, 1H), 7.88-7.91 (m, 1H); 13
NMR (CDCl3) δ 52.9, 55.4, 112.5, 114.4, 119.6, 120.6, 122.7,
124.3, 126.1, 127.7, 129.5, 132.3, 149.5, 158.3, 162.3; IR (KBr)
1679 cm-1; MS (EI) m/z (%) 280 (M+, 24), 240 (18), 239 (100),
196 (17), 168 (50), 140 (12), 135 (34), 107 (15), 92 (16), 77 (34);
HRMS calcd for C17H16N2O2 280.1212, found 280.1221.
C
alkyl (entries 7 and 8) or alkoxyamides (entry 9), they all failed
to afford the desired indazolone, and a complex mixture of
products was obtained in all cases. Similar results were observed
with amide 2l.22,23 Consequently, it must be pointed out that an
aromatic ring seems to be necessary to stabilize the correspond-
ing N-acylnitrenium intermediate.
Because of the obtained results and taking into account that
a radical mechanism can be discarded, supported by the fact
that either an oxygen atmosphere or an addition of a radical
trap such as TEMPO or DPPH24 did not affect the projected
reaction at all, it can be proposed that this novel N-N bond
formation takes place through an N-acylnitrenium ion generated
by the action of the mild oxidant PIFA on aromatic amides.
These intermediates react intramolecularly with the amine
moiety, as the nucleophilic partner of the reaction, giving rise
to the highly valued heterocyclic systems 3.
1-Benzyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-
one (3c). According to the general procedure, indazolone 3c was
obtained from benzamide 2c in 67% yield as a yellowish solid after
purification by column chromatography (hexanes/EtOAc, 1:1)
followed by crystallization from hexanes: mp 148-149 °C
1
(hexanes); H NMR (CDCl3) δ 3.86 (s, 3H), 4.72 (s, 2H), 6.89-
7.28 (m, 9H), 7.45-7.57 (m, 3H), 7.82-7.85 (m, 1H); 13C NMR
(CDCl3) δ 54.2, 55.4, 112.9, 114.4, 119.5, 122.6, 124.3, 125.9,
127.8, 128.2, 128.4, 132.1, 133.5, 149.5, 158.2, 162.3; IR (KBr)
1678 cm-1; MS (EI) m/z (%) 330 (M+, 20), 239 (100), 196 (15),
168 (35), 135 (27), 107 (12), 91 (35), 77 (38); HRMS calcd for
C21H18N2O2 330.1368, found 330.1368.
2-(4-Methoxyphenyl)-1-phenyl-1,2-dihydro-3H-indazol-3-
one (3d). According to the general procedure, indazolone 3d was
obtained from benzamide 2d in 61% yield as a white solid after
purification by column chromatography (hexanes/EtOAc, 1:1)
followed by crystallization from hexanes: mp 146-147 °C
(hexanes); 1H NMR (CDCl3) δ 3.74 (s, 3H), 6.86 (d, J ) 8.7, 2H),
7.15-7.53 (m, 10H), 7.95-7.98 (m, 1H); 13C NMR (CDCl3) δ 55.3,
112.2, 114.1, 118.0, 123.1, 124.2, 124.4, 125.2, 127.5, 128.5, 129.5,
132.7, 141.9, 149.7, 157.6, 162.5; IR (KBr) 1678 cm-1; MS (EI)
m/z (%) 316 (M+, 100), 301 (29), 273 (13), 193 (18), 167 (52), 77
(90), 51 (45); HRMS calcd for C20H16N2O2 316.1212, found
316.1213.
1-Methyl-2-phenyl-1,2-dihydro-3H-indazol-3-one (3h). Ac-
cording to the general procedure, indazolone 3h was obtained from
benzanilide 2h in 60% yield as a colorless oil after purification by
column chromatography (hexanes/EtOAc, 1:1). 1H NMR (CDCl3)
δ 3.13 (s, 3H), 7.20-7.29 (m, 3H), 7.44-7.62 (m, 5H), 7.88-
7.91 (m, 1H); 13C NMR (CDCl3) δ 39.5, 112.4, 118.9, 122.9, 123.5,
124.4, 126.2, 129.0, 132.7, 134.9, 151.6, 162.1; IR (KBr) 1684
cm-1; MS (EI) m/z (%) 224 (M+, 100), 209 (59), 153 (26), 152
(46), 132 (21), 105 (18), 77 (47); HRMS calcd for C21H18N2O
224.0950, found 224.0950.
1-Methyl-2-(1-naphthyl)-1,2-dihydro-3H-indazol-3-one (3i).
According to the general procedure, indazolone 3i was obtained
from benzamide 2i in 61% yield as a brown solid after purification
by column chromatography (hexanes/EtOAc, 1:1) followed by
crystallization from hexanes: mp 160-161 °C (hexanes); 1H NMR
(CDCl3) δ 3.06 (s, 3H), 7.25-7.31 (m, 2H), 7.50-7.67 (m, 5H),
7.78-8.02 (m, 4H); 13C NMR (CDCl3) δ 37.9, 111.8, 118.1, 122.4,
123.4, 124.4, 125.2, 126.4, 126.5, 127.0, 128.1, 129.4, 130.4, 130.9,
132.5, 134.3, 150.9, 162.7; IR (KBr) 1678 cm-1; MS (EI) m/z (%)
274 (M+, 100), 257 (14), 245 (22), 202 (21), 144 (27), 132 (28),
127 (28), 104 (19); HRMS calcd for C18H14N2O 274.1106, found
274.1106.
2-(4-Ethylphenyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (3j).
According to the general procedure, indazolone 3j was obtained
from benzamide 2j in 60% yield as a brown solid after purification
by column chromatography (hexanes/EtOAc, 1:1) followed by
crystallization from hexanes: mp 101-103 °C (hexanes); 1H NMR
(CDCl3) δ 1.25 (t, J ) 7.1, 3H), 2.67 (q, J ) 7.1, 2H), 3.12 (s,
3H), 7.19-7.31 (m, 4H), 7.45-7.58 (m, 3H), 7.88-7.91 (m, 1H);
13C NMR (CDCl3) δ 15.5, 28.4, 39.3, 112.3, 112.8, 118.9, 123.8,
124.3, 128.5, 132.5, 142.6, 151.4, 161.9; IR (KBr) 1684 cm-1; MS
(EI) m/z (%) 252 (M+, 100), 237 (49), 165 (17), 132 (22), 105
(14), 77 (30); HRMS calcd for C16H16N2O 252.1263, found
252.1262.
Conclusions
In conclusion, the powerful potential of the inexpensive and
easy-to-handle hypervalent iodine reagent PIFA in organic
synthesis, which includes its ability to generate N-acylnitrenium
ions from adequately substituted amides under rather mild
conditions, has been employed satisfactorily in the preparation
of a series of N,N′-disubstituted indazolones. Our approach
features the first successful intramolecular trapping of N-
acylnitrenium ions by amine functionalities, developing a novel
versatile method for the construction of new N-N linkages and
hence offering easy access to a diverse array of N-heterocyclic
compounds.
Experimental Section
Typical Procedure for the Synthesis of Indazolones 3a-d,h-
k. Synthesis of 2-(4-Methoxyphenyl)-1-methyl-1,2-dihydro-3H-
indazol-3-one (3a). A solution of PIFA (252 mg, 0.78 mmol) in
78 mL of CH2Cl2 was added at 0 °C to a solution of benzamide 2a
(100 mg, 0.39 mmol) and TFA (0.09 mL, 1.91 mmol) in 39 mL of
the same solvent, and the new solution was stirred for 1 h. Then,
the solvent was evaporated at reduced pressure, and the resulting
residue was purified by column chromatography (hexanes/EtOAc,
1:1) followed by crystallization from hexanes to afford indazolone
1
3a as a white solid (68% yield): mp 117-118 °C (hexanes); H
NMR (CDCl3) δ 3.17 (s, 3H), 3.89 (s, 3H), 7.07 (d, J ) 9.1, 2H),
7.29-7.35 (m, 2H), 7.52 (d, J ) 9.1, 2H), 7.62-7.68 (m, 1H),
7.95-5.98 (s, 1H); 13C NMR (CDCl3) δ 38.9, 55.3, 112.1, 114.2,
118.7, 122.6, 124.1, 125.6, 127.6, 132.3, 151.1, 158.1, 161.9; IR
(KBr) 1678 cm-1; MS (EI) m/z (%) 254 (M+, 100), 239 (44), 168
(30), 135 (16), 132 (18), 77 (24); HRMS calcd for C15H14N2O2
254.1055, found 254.1057.
1-Allyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-one (3b).
According to the general procedure, indazolone 3b was obtained
from benzamide 2b in 62% yield as a yellowish oil after purification
by column chromatography (hexanes/EtOAc, 1:1): 1H NMR
(CDCl3) δ 3.83 (s, 3H), 4.15-4.17 (m, 2H), 4.97-5.07 (m, 2H),
5.35-5.51 (m, 1H), 7.00 (d, J ) 9.1, 2H), 7.18-7.30 (m, 2H),
(22) Because the AlMe3-mediated aminolysis of methylanthranilate 1a
in the presence of NH3 failed to afford the desired primary amide, it was
prepared by treating the commercially available N-methylanthranilamide
with methyl iodide at 100 °C following a described protocol in: Chatterjee,
A.; Majudmar, S. G. J. Am. Chem. Soc. 1953, 75, 4365-4366.
(23) Primary amides have been reported to suffer Hofmann-type rear-
rangements using various iodine(III) reagents. However, in our case, such
types of products were not detected. See: Prakash, O.; Batra, H.; Kaur, H.;
Sharma, P. K.; Sharma, V.; Singh, S. P.; Moriarty, R. M. Synthesis 2001,
541-543.
2-(4-Bromophenyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (3k).
According to the general procedure, indazolone 3k was obtained
from benzamide 2k in 45% yield as a brown solid after purification
by column chromatography (hexanes/EtOAc, 1:1) followed by
crystallization from hexanes: mp 112-114 °C (hexanes); 1H NMR
(24) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989, 54,
3394-3403.
3504 J. Org. Chem., Vol. 71, No. 9, 2006

PIFA-Mediated OxidatiVe Cyclization
(CDCl3) δ 3.14 (s, 3H), 7.23-7.62 (m, 7H), 7.88-7.91 (m, 1H);
13C NMR (CDCl3) δ 39.9, 112.6, 118.8, 119.5, 123.3, 124.6, 124.8,
132.2, 133.1, 134.2, 151.9, 162.2; IR (KBr) 1688 cm-1; MS (EI)
m/z (%) 304 (M + 2, 99), 302 (M+, 100), 289 (54), 287 (53), 180
(65), 157 (24), 155 (23), 152 (62), 132 (27), 86 (30), 84 (44); HRMS
calcd for C12H11BrN2O 302.0055, found 302.0053.
Note Added after ASAP Publication. There was an error
in the spectra of the Supporting Information in the version
published ASAP March 21, 2006; the corrected version was
published ASAP March 29. 2006.
Supporting Information Available: Experimental details for
Acknowledgment. Financial support from the University of
the Basque Country (9/UPV 41.310-13656/2001) and the
Spanish Ministry of Science and Technology (CTQ 2004-
03706/BQU) is gratefully acknowledged. A.C. thanks the
Basque Government for a predoctoral scholarship.
1
compounds 2a-o and H NMR and 13C NMR spectra of all new
compounds are included. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060070+
J. Org. Chem, Vol. 71, No. 9, 2006 3505