On the illusive nature of o-formylazobenzenes: Exploiting the nucleophilicity of the azo group for cyclization to indazole derivatives

Article abstract of DOI:10.1021/jo061288z

(Chemical Equation Presented) Facile rearrangement of azobenzenes is shown to occur in cases where the azo group is placed in the ortho position to carbonyl electrophiles to furnish the indazole skeleton. While this study demonstrates the illusive nature

Full text of DOI:10.1021/jo061288z

On the Illusive Nature of o-Formylazobenzenes:
Exploiting the Nucleophilicity of the Azo Group
for Cyclization to Indazole Derivatives
Maike V. Peters,† Ragnar S. Stoll,† Richard Goddard,† Gernot Buth,‡ and Stefan Hecht*,†
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mu¨lheim an der Ruhr, Germany,
and Forschungszentrum Karlsruhe GmbH, ANKA/ISS, Hermann-Von-Helmholtz-Platz 1, 76344
Eggenstein-Leopoldshafen, Germany
hecht@mpi-muelheim.mpg.de
ReceiVed June 22, 2006
Facile rearrangement of azobenzenes is shown to occur in cases where the azo group is placed in the
ortho position to carbonyl electrophiles to furnish the indazole skeleton. While this study demonstrates
the illusive nature of o-formylazobenzenes, it offers potential for the synthesis of indazoles and related
heterocycles.
Introduction
the E- and Z-isomers.4 We were aiming to incorporate azoben-
zene moieties directly into the framework of metalloporphyrins,
and by exploiting the large structural reorganization accompany-
ing the E-Z-photoisomerization we sought to photoswitch
accessibility of the porphyrin metal center, thereby potentially
enabling photomodulation of catalytic activity.5
The target meso-[2,6-bis(phenylazo)phenyl]-substituted met-
alloporphyrins 1 can, in principle, be synthesized from a pre-
formed metalloporphyrin precursor or via acid-catalyzed con-
densation of pyrrole or dipyrromethanes with the respective
aldehydes (Scheme 1).6 While the postfunctionalization approach
employing a versatile transition-metal-catalyzed cross-coupling/
oxidation sequence7 finally proved successful,5 several important
observations have been made during our attempt to prepare
Photochromism allowing for the light-triggered, selective, and
reversible transformation between two usually tautomeric or
isomeric types of chromophores constitutes a key design
principle to be harnessed for the design of future photoswitch-
able materials and devices.1 Several photochromic families have
been developed, and the chemical and physical differences
between the respective switching states have been used to
photomodulate properties from the molecular up to the macro-
scopic scale.2 While the discovery of photochromism of
azobenzenes dates back to 1937,3 these photochromes continue
to be among the most frequently explored mainly due to their
ease of preparation and the significantly differing properties of
† Max-Planck-Institut fu¨r Kohlenforschung.
‡ Forschungszentrum Karlsruhe GmbH.
(4) (a) Zollinger, H. Azo and Diazo Chemistry: Aliphatic and Aromatic
Compounds; Interscience Publishers: New York, 1961. For reviews,
consult: (b) Rau, H. In Photochromism - Molecules and Systems; Du¨rr,
H., Bouas-Laurent, H., Eds.; Elsevier: Amsterdam, 2003; pp 165-192.
(c) Fangha¨nel, D.; Timpe, G.; Orthman, V. In Organic Photochromes;
El’tsov, A. V., Ed.; Consultants Bureau: New York, 1990; pp 105-177.
(d) Griffiths, J. Chem. Soc. ReV. 1972, 481-493.
(1) (a) Photochromism - Molecules and Systems; Du¨rr, H., Bouas-
Laurent, H., Eds.; Elsevier: Amsterdam, 2003. (b) Molecular Switches;
Feringa, B. L., Ed.; Wiley-VCH: Weinheim, 2001. (c) Organic Photo-
chromic and Thermochromic Compounds; Crano, J. C., Guglielmetti, R.
J., Eds.; Kluwer Academic/Plenum Publisher: New York, 1999. (d) Organic
Photochromes; El’tsov, A. V., Ed.; Consultants Bureau: New York, 1990.
(e) Special Issue: Photochromism: Memories and Switches. Irie, M., Ed.
Chem. ReV. 2000, 100, 1683-1890. (f) Willner, I.; Rubin, S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 367-385.
(5) Peters, M. V.; Goddard, R.; Hecht, S. J. Org. Chem. 2006, 71, 7846-
7849.
(6) For a review, consult: Lindsey, J. S. In The Porphyrin Handbook;
Kadish, K., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego,
1999; Vol. 1, pp 45-118.
(2) Hecht, S. Small 2005, 1, 26-29.
(3) Hartley, G. S. Nature (London) 1937, 140, 281.
10.1021/jo061288z CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/29/2006
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J. Org. Chem. 2006, 71, 7840-7845

IllusiVe Nature of o-Formylazobenzenes
SCHEME 1. Motivation
noteworthy since it occurs with concomitant chemoselective
oxidation of the benzylic alcohol to the corresponding aldehyde
and represents the by far most practical route to this common
porphyrin precursor.10 While the nitro functionalities in 5 could
unfortunately not be reduced without concurrent reduction of
the aldehyde, 8 and 12 were successfully transformed into the
corresponding phenylenediamines 9 and 13. Please note that
catalytic hydrogenation over Pd/C could not be employed for
the reduction of 8 due to debromination. Protection of the amine
functionalities provided 10 in moderate yield; however, formy-
lation by a metalation/DMF-trapping sequence failed. In the final
symmetrical attempt, 2-fold Mills coupling8 of nitrosobenzene
to 14, prepared by reduction of 13, was not successful. A
thorough search of the literature11 revealed that similar problems
had been encountered by Ruggli and co-workers11b when trying
to perform 2-fold Mills couplings on phenylenediamine.12 We
therefore decided to synthesize the desired m-bis(phenylazo)-
benzene derivatives by sequential formation of the azo groups.
Nonsymmetric Approach. Stepwise introduction of the azo
moieties requires the protection of one aniline terminus, most
conveniently as the oxidized nitro group, and involves initial
Mills coupling to the nitroaniline followed by reduction of the
nitro group and subsequent second Mills coupling.11 To avoid
potential chemoselectivity problems during nitro group reduc-
tion, we chose 4-tert-butyltoluene 16 as commercially available
and inexpensive starting material (Scheme 3). Two-fold nitration
gave 17, which could be reduced to provide 18 in almost
quantitative yield. This highly selective and high-yielding
monoreduction process could be achieved by using ammonium
sulfide in refluxing ethanol and represents the key step in the
synthesis.13,14 Mills reaction afforded 19, which subsequently
was reduced to azoaniline 20 and subjected to another Mills
reaction to yield bis(phenylazo) derivative 21.
bisazoaldehyde precursor 3. Several synthetic routes involving
symmetric and nonsymmetric approaches, in which the azoben-
zene moiety is either simultaneously or stepwise formed via
condensation of aniline with nitrosobenzene derivatives, i.e.,
the so-called Mills reaction,8 have been explored. In the course
of these studies, we realized that o-arylazobenzaldehydes are
not isolable compounds but rather undergo intramolecular
cyclization due to the close proximity of the formyl electrophile
and the nucleophilic azo group. Here, we present our synthetic
results including the unambiguous characterization of the
rearrangement products and propose a mechanism for this poten-
tially practical synthesis of the indazole heterocyclic skeleton.
Depending on the relative orientation of the trans-configured
azo bonds, meta-linked bisazobenzene derivative 21 can adopt
three stable conformations, namely anti-anti, syn-anti, or syn-
syn conformations (Figure 1a). While H NMR spectroscopy
does not allow a distinction of these three conformations,
presumably due to a rapid exchange between these energetically
rather similar structures, X-ray crystallographic analysis9 on
several crystals showed that 21 adopts the anti-anti conformation
in the solid state (Figure 1b). Interestingly, this finding is in
contrast to the recently reported example of alternating pyr-
idinedicarboxamide-bis(phenylazo)benzene foldamers,12 in which
the m-bisazobenzene segments show a preference for the syn-
syn conformation.
Results and Discussion
Symmetric Approaches. To establish the 2,6-bis(arylazo)-
phenyl substitution pattern, 2,6-diaminobenzenes carrying a
substituent in the 1-position that can be transformed into an
aldehyde, e.g. alcohol, ester, methyl, or bromide, are needed.
To ensure the necessary regiochemistry in the nitration to the
dinitro precursors, we chose to introduce a 4-tert-butyl group,
which sterically shields its ortho positions, i.e., 3- and 5-posi-
tions, thereby forcing the incoming nitro groups into the required
2- and 6-positions, i.e., ortho to the latent aldehyde. Several
commercially available starting materials, i.e., 4, 7, and 11, were
employed (Scheme 2). Two-fold nitration using forcing condi-
tions9 was achieved in good yields to provide the 2,6-dinitro-
derivatives 5, 8, and 12. In particular, the conversion 4 f 5 is
(10) Rose, E.; Kossanyi, A.; Quelquejeu, M.; Soleilhavoup, M.; Duwav-
ran, F.; Bernard, N.; Lecas, A. J. Am. Chem. Soc. 1996, 118, 1567-1568.
(11) The synthesis of differently connected oligo(azobenzene)s has been
been pioneered by Ruggli and co-workers, who exploited iterative Mills
coupling and nitro-reduction sequences. For o-bis(phenylazo)benzenes,
see: (a) Ruggli, P.; Rohner, J. HelV. Chim. Acta 1942, 25, 1533-1542.
For m-bis(phenylazo)benzenes, see: (b) Ruggli, P.; Wust, W. HelV. Chim.
Acta 1945, 28, 781-791. For p-oligo(phenylazo)benzenes, see: (c) Ruggli,
P.; Bartusch, G. HelV. Chim. Acta 1944, 27, 1371-1384. (d) Ruggli, P.;
Iselin, E. HelV. Chim. Acta 1947, 30, 739-742.
(12) Similar synthetic problems have recently been encountered in the
construction of oligomers containing m-bis(phenylazo)benzenes: Tie, C.;
Gallucci, J. C.; Parquette, J. R. J. Am. Chem. Soc. 2006, 128, 1162-1171.
(13) Chemoselective reduction to nitroaniline: (a) Finger, G. C.; Reed,
F. H. J. Am. Chem. Soc. 1944, 66, 1972-1974 using the ammonium sulfide
method developed by: (b) Murray, M. J.; Waters, D. E. J. Am. Chem. Soc.
1938, 60, 2818-2819.
(14) A potential route via nitration of 2-amino-4-tert-butyltoluene failed
in our hands and gave complex product mixtures, contradictory to literature
reports: Rosevear, J.; Wilshire, J. F. K. Aust. J. Chem. 1985, 38, 723-733.
(7) (a) Lim, Y.-K.; Lee, K.-S.; Cho, C.-G. Org. Lett. 2003, 5, 979-982.
(b) Lim, Y.-K.; Choi, S.; Park, K. B.; Cho, C.-G. J. Org. Chem. 2004, 69,
2603-2606.
(8) It should be noted that the formation of azobenzenes from condensa-
tion of nitrosobenzenes with anilines in acetic acid, frequently referred to
as the Mills reaction: (a) Mills, C. J. Chem. Soc. 1895, 67, 925-933, was
first described by Baeyer: (b) Baeyer, A. Chem. Ber. 1874, 7, 1638-1640.
(9) See the Supporting Information.
J. Org. Chem, Vol. 71, No. 20, 2006 7841

Peters et al.
SCHEME 2. Symmetric Approaches
SCHEME 3. Nonsymmetric Approach
To prepare the desired porphyrin precursor 3, the benzylic
methyl group had to be oxidized to the corresponding benzal-
dehyde (Scheme 3). Radical bromination provided benzyl bro-
mide 22, which was converted to the benzyl alcohol 15 via the
acetate 23. Several oxidation procedures including Kornblum
oxidation of 22 as well as PCC-mediated and Swern oxidations
of 15 were employed; however, no aldehyde product could be
obtained. Instead, the main product of the Kornblum oxidation
of 22, also present in the oxidation of 15, was isolated, and its
NMR spectroscopic data indicated the loss of symmetry while
UV/vis spectroscopy showed a bathochromic shift of the ab-
sorption maximum indicative of an electronic change and/or
extension of the chromophore.9 Finally, the nature of the re-
arrangement product 24 was unambiguously revealed by a
single-crystal X-ray structural analysis9 (Figure 2).
The unexpected presence of the indazole skeleton shows an
involvement of the azo group in the observed rearrangement.
Clearly, a reaction of the benzylic substituent with the distant
azo nitrogen atom is occurring followed by rearomatization (vide
infra). Interestingly, in 24 the reacting azo group is locked in a
syn conformation during the course of the reaction, while the
remaining azo fragment adopts a syn conformation as well.
Since all oxidative attempts to prepare 3 have failed in our hands
yet not due to oxidation of the azo group, we were eager to
find out if o-formylazobenzenes, placing both azo and aldehyde
functionalities into close proximity, represent isolable com-
7842 J. Org. Chem., Vol. 71, No. 20, 2006

IllusiVe Nature of o-Formylazobenzenes
SCHEME 4. Synthesis and Reactivity of Model Compounds
FIGURE 1. Conformational preference of m-bis(phenylazo)benzene
derivative 21. (a) Potential minimum conformations. (b) Single-crystal
X-ray structural analysis of 21, showing that the molecule adopts the
anti-anti conformation.
When 28 was treated with dilute acid at room temperature
to unmask the aldehyde functionality in the presence of the
preinstalled azobenzene moiety, decoloration within few minutes
was observed. In analogy to the previous experiments, com-
pound 30 could not be detected. Instead, two colorless products
were formed and isolated. Structural identification using NMR
spectroscopy, mass spectrometry, and single-crystal X-ray
structure analysis (in the case of 32, see Figure 3) provided
clear evidence for the formation of indazoles 31 and 32.9 Both
compounds belong to the indazole heterocyclic family as already
observed in the case of the rearrangement 22 f 24 (vide supra).
Figure 3 shows the structure of 32 obtained by single-crystal
X-ray structural determination. The analysis reveals that in the
solid the H atom attached to N2 is bent 38° out of the mean
plane of the indazolone moiety in order to engage in a favorable
H-bonding N-H‚‚‚O intermolecular interaction with a neigh-
boring molecule in the crystal [N‚‚‚O distance 2.808(5) Å].9 A
similar pyramidalization of the N atom has been observed in
the crystal structures of 2-N-acetyl-3-indazolinone15 and 2-N-
benzylindazolone.16
FIGURE 2. Single-crystal X-ray structural analysis of rearrangement
product 24.
In view of the observed acid-induced rearrangement of 28
giving rise to formation of 31 and 32, we propose the following
mechanism for this transformation (Scheme 5). Initial proto-
nation and ring opening of the acetal generates the first electro-
phile, which can be intercepted by intramolecular nucleophilic
attack of the azo group to generate product 31 after final de-
protonation/rearomatization. Hydrolysis competes with cycliza-
tion and generates the protonated aldehyde as another potent
electrophile, which can undergo ring closure to yield 32 after
deprotonation and tautomerization. It should be pointed out that
the employed acidic conditions are needed to initiate the reac-
tion sequence by transforming the acetal to an electrophilic
moiety; however, cyclization to the indazole skeleton does not
necessarily involve acid catalysis. If an electrophilic group is
pounds or if they undergo such a rearrangement process in
general. For the purpose of simplicity, further studies were
carried out on a minimalistic model system.
Rearrangement Model Studies. Initially, synthesis of 30 was
attempted via NBS-mediated oxidation of 29, which was readily
obtained by N-arylation of 25 (Scheme 4).7a However, addition
of NBS to 29 led to rapid disappearance of the typical orange
color associated with the azo dye. While this finding provided
further support that the azo group actively participates in the
observed transformation, a more convenient investigation of the
rearrangement process was achieved by monitoring the acid-
catalyzed hydrolysis of acetal 28. Azo dye 28 was prepared
from acetal 26 by N-arylation followed by NBS-mediated
oxidation. The successful oxidation step to furnish the azo
chromophore in the presence of the protected aldehyde, i.e.,
27 f 28, furthermore showed that previously the aldehyde
moiety was involved in the attempted rearrangement 29 f 30.
(15) Smith, D.; L.; Barrett, E. K. Acta Crystallogr., Sect B: Struct.
Crystallogr. Cryst. Chem. 1969, 25, 2355-2361.
(16) Kurth, M. J.; Olmstead, M. M.; Haddadin, M. J. J. Org. Chem.
2005, 70, 1060-1062.
J. Org. Chem, Vol. 71, No. 20, 2006 7843

Peters et al.
except for the early work by Freundler.19,20 In view of the large
variety of azobenzene precursors, which are readily available
from different precursors including aniline, nitrobenzene, and
halobenzene derivatives, this transformation has considerable
potential for indazole heterocycle synthesis. Furthermore, the
observed facile rearrangement implies that for a few of the many
reported azo dyes carrying o-aldehyde substituents reassign-
ments of the respective chemical structures should be seriously
considered.21,22
FIGURE 3. Single-crystal X-ray structural analysis of rearrangement
product 32.
Experimental Section
Experimental details of the rearrangement of model compound
28 are given below. For a complete compilation of general methods,
crystallographic details, synthetic procedures, and characterization
data, see the Supporting Information.
SCHEME 5. Proposed Rearrangement Mechanism
Synthesis of Model Compound 28. N-tert-Butoxycarbonyl-
N′-[(1,3-dioxolan-2-yl)phenyl]-N-phenylhydrazine 27. In a sealed
tube, 0.63 mL (5.0 mmol) of 26,23 1.183 g (5.7 mmol) of N-tert-
butoxycarbonyl-N-phenylhydrazine,24 58 mg (0.25 mmol) of pal-
ladium(II) acetate, 0.062 g (0.3 mmol) of tri-tert-butylphosphine,
2.46 g (7.5 mmol) of Cs2CO3, and 30 mL of toluene were mixed
in a nitrogen atmosphere. The reaction mixture was stirred for 30
min at room temperature and then heated at 110 °C for 14 h. The
solid was filtered through Celite, the solvent was evaporated, and
the residue was recrystallized from hexane to yield 1.64 g (92%
yield) of the product as brown crystals. Rf (Hex/EA, 3/1) ) 0.4.
1H NMR (CD3CN, 400 MHz): δ (ppm) ) 7.65 (s, 1H, Ar-H),
7.57 (d, 1H, 3J ) 7.7 Hz, Ar-H), 7.33 (m, 3H, Ar-H), 7.22 (t, 1H,
4
3
4
3J ) 7.8 Hz, J ) 1.4 Hz, Ar-H), 7.13 (tt, 1H, J ) 7.4 Hz, J )
(18) The intramolecular coordination of the o-phenylazo group to various
heteroatoms has been exploited. For silicon, see: (a) Kano, N.; Komatsu,
F.; Kawashima, T. J. Am. Chem. Soc. 2001, 123, 10778-10779. (b) Kano,
N.; Yamamura, M.; Komatsu, F.; Kawashima, T. J. Organomet. Chem. 2003,
686, 192-197. (c) Kano, N.; Yamamura, M.; Kawashima, T. J. Am. Chem.
Soc. 2004, 126, 6250-6251. (d) Kano, N.; Komatsu, F.; Yamamura, M.;
Kawashima, T. J. Am. Chem. Soc. 2006, 128, 7097-7109. For boron, see:
(e) Kano, N.; Yoshino, J.; Kawashima, T. Org. Lett. 2005, 7, 3909-3911.
For phosphorous, see: (f) Yamamura, M.; Kano, N.; Kawashima, T. J.
Am. Chem. Soc. 2005, 127, 11954-11955.
(19) A thorough literature survey reveals that some initial evidence for
this type of rearrangement involving azobenzene precursors carrying either
o-aldehyde or o-acetal groups dates back to work by Freundler: (a)
Freundler, M. P. Bull. Soc. Chim. Fr. 1904, 31, 862-867. (b) Freundler,
M. P. Bull. Soc. Chim. Fr. 1904, 31, 868-875.
generated in the ortho position to the azo moiety, cyclization
occurs as indicated by the observed reactivity of 15, 22, and 29
under nonacidic conditions.
(20) The formation of 2H-indazolone derivatives from azobenzene
precursors has been reported in a few cases with the following ortho
substituents. For hydroxymethyl groups, see: (a) Freundler, M. P. Bull.
Soc. Chim. Fr. 1903, 29, 742-747. For ketones, see: (b) Alberti, A.;
Bedogni, N.; Benaglia, M.; Leardini, R.; Nanni, D.; Pedulli, G. F.; Tundo,
A.; Zanardi, G. J. Org. Chem. 1992, 57, 607-613. For carboxylic acids,
see: (c) Freundler, M. P. Bull. Soc. Chim. Fr. 1911, 9, 735-739.
(21) A search of the Beilstein database reveals more than 23000
entries of different azobenzene derivatives. In the few cases reporting
o-(arylazo)arylaldehydes, an alternative structural assignment to the re-
spective 2H-indazolone derivatives seems plausible: (a) Karame´, I.; Jahjah,
M.; Messaoudi, A.; Tommasino, M. L.; Lemaire, M. Tetrahedron: Asym-
metry 2004, 15, 1569-1581. (b) Radbakrishnan, T.; Kolawole, G. A.;
Revaprasadu, N.; Nair, P. S.; Sreekala, N. B. Synth. React. Inorg. Met.-
Org. Chem. 2002, 32, 1153-1175. (c) Saleh, A. A.; Aly, F. M.; El-Baradie,
K.; El-Dken, A. A. Egypt. J. Chem. 1990, 33, 255-266. (d) Ifrim, S. Bulet.
Inst. Polit. Iasi 1973, 19, 139-15.
(22) The oldest literature precedent of controversial assignment of an
o-(arylazo)arylaldehyde is related to the so-called “Azoopiansa¨ure”, the
product of reducing 2-formyl-5,6-dimethoxy-3-nitrobenzoic acid with zinc
under acidic conditions: (a) Prinz, O. J. Prakt. Chem. 1881, 24, 353-374.
(b) Liebermann, C. Chem. Ber. 1886, 19, 351-354. (c) Gru¨ne, H. Chem.
Ber. 1886, 19, 2299-2305. (d) Claus, A.; Predari, F. J. Prakt. Chem. 1897,
55, 171-185.
In control experiments, no equilibration between 31 and 32
under the same acidic conditions was observed; i.e., 31 was
not converted to 32, demonstrating that the final deprotonation
step to reestablish aromaticity in the system is essentially
irreversible (please note that subsequent tautomerization is not
possible in the case of 31). Therefore, the product distribution
31/32 ) 78:17 reflects the competition between intramolecular
cyclization and intermolecular hydrolysis. Both ring closures
belong to the class of highly favored 5-exo-trig cyclization
processes,17 in which the in situ generated, activated carbonyl-
based electrophiles are attacked by a considerably nucleophilic,
distant N-atom of the azo group.
The basicity of the azo group is well documented in the
literature,4 and the electron-donating capability of the azo group
has recently been utilized to achieve photoswitchable azo-
heteroatom interactions.18 However, the azo group’s nucleo-
philicity toward carbon electrophiles as a means to construct
nitrogen-containing heterocycles has been poorly explored,
(23) Franz, J. A.; Barrows, R. D.; Camaioni, D. M. J. Am. Chem. Soc.
1984, 106, 3964-3967.
(24) Wolters, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-
3805.
(17) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
7844 J. Org. Chem., Vol. 71, No. 20, 2006

IllusiVe Nature of o-Formylazobenzenes
1.1 Hz, Ar-H), 6.83 (m, 2H, Ar-H), 5.79 (s, 1H, CH), 4.07 (m, 4H,
CH2CH2), 1.38 (s, 9H, t-Bu-H). 13C NMR (CD3CN, 100.6 MHz):
δ (ppm) ) 154.74, 147.54, 143.97, 130.95, 129.31, 128.62, 125.50,
123.34, 122.30, 120.32, 112.67, 103.76, 82.46, 65.76, 28.3. MS
(EI, 110 °C): m/z ) 356 ([M]+), 300, 255, 93. 2-(2-Phenylazo)-
phenyl-1,3-dioxolane 28. In a nitrogen atmosphere, 47 mg (0.133
mmol) of 27 was dissolved in 2.5 mL dry dichloromethane. Then,
a solution of 0.013 mL of pyridine and 28 mg of NBS in 2.5 mL
of dichloromethane was added. The color immediately changed to
orange. The solution was stirred at room temperature for another 2
h, and the solvent was evaporated. After purification by column
chromatography (Hex/EA, 8/1), 43 mg (83%) of an orange oil was
H), 7.25 (m, 2H, Ar-H). 13C NMR (CD3CN, 400 MHz): δ (ppm)
)161.9, 148.1, 138.9, 133.5, 130.0, 126.0, 124.4, 123.57, 120.0,
113.8. MS (EI, 130 °C): m/z ) 210 ([M]+), 181, 104, 77. IR
(KBr): ν˜ (cm-1) ) 676 (arom, m), 747 (arom, s), 1360 (s, CdC),
1501 (s, CdC), 1654 (s, CdO), 3111 (NH, m). HRMS: m/z )
233.068210 (calcd 233.068530 for C13H10N2O1Na). 2-Phenyl-3-
(2′-hydroxyeth-1′-yl)-2H-indazole 32 (14% isolated yield). 1H
3
NMR (CDCl3, 400 MHz): δ (ppm) ) 7.78 (d, 2H, J ) 7.5 Hz,
Ar-H), 7.63 (d, 1H, 3J ) 8.5 Hz, Ar-H), 7.57 (d, 1H, 3J ) 8.9 Hz,
3
Ar-H), 7.45 (m, 2H, Ar-H), 7.37 (t, 1H, J ) 7.4 Hz, Ar-H), 7.23
3
3
(t, 1H, J ) 6.7 Hz, Ar-H), 6.95 (t, 1H, J ) 6.7 Hz, Ar-H), 4.50
3
3
(t, 2H, J ) 4.3 Hz, CH2), 3.88 (t, 2H, J ) 4.4 Hz, CH2). 13C
NMR (CDCl3, 100.6 MHz): δ (ppm) ) 147.8, 145.6, 138.4, 129.1,
128.1, 127.2, 124.1, 120.7, 119.3, 117.9, 108.5, 77.3, 77.0, 76.7,
75.6, 61.3. MS (EI): m/z ) 254 ([M]+), 210, 181, 104, 77.
HRMS: m/z ) 277.094841 (calcd 277.094749 for C15H14N2O2Na).
1
isolated. Rf (Hex/EA, 5/1) ) 0.3. H NMR (CD3CN, 400 MHz):
3
4
δ (ppm) ) 7.69 (m, 2H, Ar-H), 7.56 (dd, 1H, J ) 7.6 Hz, J )
3
4
1.6 Hz, Ar-H), 7.43 (dd, 1H, J ) 7.8 Hz, J ) 1.4 Hz, Ar-H),
7.34 (m, 5H, Ar-H), 6.55 (s, 1H, CH), 3.85 (m, 4H, CH2CH2). 13
C
NMR (CD3CN, 100.6 MHz): δ (ppm)) 153.7, 151.1, 137.5, 132.4,
132.2, 130.75, 130.3, 127.8, 123.7, 115.7, 100.0, 66.3. MS (EI,
254 °C) m/z ) 254 ([M]+), 181, 105. HRMS (ESI pos): m/z )
277.094773 (calcd 277.094750 for C15H14N2O2Na). GC: 98.8%
peak area.
Acknowledgment. Part of this work was carried out at Freie
Universita¨t Berlin (FUB), Germany. We thank Irene Bru¨dgam
and Hans Hartl (FUB) for initial crystallographic assistance.
Generous support by the Sofja Kovalevskaja Program of the
Alexander von Humboldt Foundation sponsored by the Federal
Ministry of Education and Research and the Program for
Investment in the Future (ZIP) of the German Government and
the Max Planck Society (MPG) is gratefully acknowledged. We
acknowledge the ANKA Angstro¨mquelle Karlsruhe for the
provision of beamtime on the beamline PX.
Hydrolysis of Model Compound 28. In a one-necked flask, 123
mg (0.49 mmol) of 28 was dissolved in 2 mL of acetone, and 0.98
mL of 1 M HCl were added. The solution was stirred at room
temperature for 75 min during which time the orange color
completely disappeared. The mixture was diluted with ethyl acetate,
washed with saturated aqueous NaHCO3 solution, and dried over
MgSO4, and the solvent was evaporated. Both products were
separated by preparative HPLC (MeOH/H2O, 55/45) prior to
characterization. 2-Phenyl-1,2-dihydroindazol-3-one 31.25 60%
Supporting Information Available: Experimental procedures
including general methods, crystallographic details, syntheses,
characterization data, and copies of 1H NMR and 13C NMR spectra.
Crystallographic information files (CIF) for compounds 21, 24, and
32. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
isolated yield. Rf (Hex/EA, 1/1) ) 0.38. H NMR (CD3CN, 400
MHz): δ (ppm) ) 7.91 (m, 2H, Ar-H), 7.78 (dt, 1H, 3J ) 7.9 Hz,
4J ) 1.3 Hz, Ar-H), 7.61 (t, 1H, 3J ) 7.2 Hz, 4J ) 1.2 Hz, Ar-H),
3
4
7.49 (m, 2H, Ar-H), 7.37 (dt, 1H, J ) 8.2 Hz, J ) 0.8 Hz, Ar-
(25) Freundler, M. P. Bull. Soc. Chim. Fr. 1907, 1, 234-237.
JO061288Z
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