Radical intermediates in the photorearrangement of 3-hydroxyindolic nitrones

Article abstract of DOI:10.1016/j.tet.2011.06.094

A number of 3-hydroxy substituted indolic nitrones were found to quantitatively photorearrange to (2-benzoylamino)phenyl ketones upon UV-A irradiation. EPR-Spin Trapping experiments suggest that the process, which is believed to proceed via the formation

Full text of DOI:10.1016/j.tet.2011.06.094

Tetrahedron 67 (2011) 6889e6894
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical intermediates in the photorearrangement of 3-hydroxyindolic nitrones
a
b
b
c
b
,
d
*
€
Angelo Alberti , Paola Astolfi , Patricia Carloni , Dietrich Dopp , Lucedio Greci , Corrado Rizzoli ,
Pierluigi Stipa b
a ISOF-CNR, Area della Ricerca di Bologna, Via P. Gobetti 101, I-40129 Bologna, Italy
Dipartimento ISAC-Sezione Chimica, Universita Politecnica delle Marche, Via Brecce Bianche, I-60131 Ancona, Italy
Fachgebiet Organische Chemie, Universitat Duisburg-Essen, D-45117 Essen, Germany
b
ꢀ
c
€
d
ꢀ
Dipartimentio di Chimica Generale, Chimica Analitica e Chimica Fisica, Universita di Parma, Viale delle Scienze 17/4, I-43100 Parma, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 3-hydroxy substituted indolic nitrones were found to quantitatively photorearrange to
(2-benzoylamino)phenyl ketones upon UV-A irradiation. EPR-Spin Trapping experiments suggest that
the process, which is believed to proceed via the formation of an oxaziridine, follows a homolytic
pathway. Although DFT calculations do not allow to totally exclude alternative routes involving singlet
intermediates, they do provide support to the proposed homolytic mechanism, which would be driven
by a 1,5-hydrogen transfer subsequent to the oxaziridine ring opening. When this hydrogen transfer was
made impossible by methylation of the 3-OH group, a benzoxazine was isolated as the sole reaction
product.
Received 7 March 2011
Received in revised form 9 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Keywords:
Nitrone photochemistry
Oxaziridine intermediates
DFT calculations
Ó 2011 Elsevier Ltd. All rights reserved.
EPR spectroscopy
Spin trapping
1. Introduction
We report here on the photo-induced rearrangement of
2-phenyl-3-hydroxy-3-alkyl/aryl-indoline-N-oxides 1aef to alkyl/
The photochemistry of nitrones and N-oxides has been exten-
sively studied and since the ‘70s a number of papers and reviews on
this topic have appeared.1e10 In most cases, the reaction is de-
scribed to proceed through the intermediate formation of an oxa-
ziridine derivative, which can be isolated or, being itself
photochemically reactive, rearranges to an amide, lactam, ben-
zoxazine, etc. Different ionic, radical or concerted mechanisms
have been proposed for the subsequent transformation of the
oxaziridine,6,11,12 but in very few occasions the involvement of
a particular intermediate has been evidenced. For example, the re-
arrangement of 2-phenylisatogen to 2-phenyl-4H-3,1-benzoxazin-
4-one is described to proceed via a biradical intermediate,4 as
a precursor of a ketene, but without any experimental evidence.
Similar results are reported for 2-phenyl-3-arylimino-3H-indole
N-oxides.13 Trapping experiments using 2,3-dimethylbut-2-ene or
other less substituted alkenes or dienes supported the involvement
of a biradical in the photochemistry of phenanthridine N-oxides,5,7
although only in particular cases and according to the nature of the
aryl-(2-benzoylamino)phenyl ketones 2aef (see Scheme 1) in al-
most quantitative yield and propose a radical-based mechanism for
the process. When the reactions were carried out inside the cavity
of an Electron Paramagnetic Resonance (EPR) spectrometer in the
presence of the spin-trap PBN (N-tert-butyl-a-phenyl-nitrone),
radical intermediates were trapped in the form of nitroxidic spin-
adducts in agreement with the suggested mechanism, which was
also supported by the results of Density Functional Theory (DFT)
calculations.
solvent and of the substituents on the a-carbon.
Scheme 1.
* Corresponding author. Tel.: þ39 071 2204408; fax: þ39 071 2204714; e-mail
address: l.greci@univpm.it (L. Greci).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.094

6890
A. Alberti et al. / Tetrahedron 67 (2011) 6889e6894
2. Results and discussion
more than 90% yield in all the reactions performed, without the
significant formation of any side products. For example, from the
irradiation of 2-unsubstituted 3H-indole N-oxides,15e17 several
products were isolated derived from ring enlargement to form
a benzoxazine derivative, ring opening and H-shift to generate an
isocyanate, and isomerization to a lactam.
When acetonitrile solutions of compounds 1aef were irradiated
with a UV-A lamp in a quartz tube for 20 min under stirring, the
sole products obtained in the reactions were the amidic derivatives
2aef (Scheme 1), identified on the basis of their IR and 1H NMR
spectral data. In particular, all products 2aef showed in their IR
spectra a broad band at ca. 3200 cmꢀ1 and absorptions at ca.
1675 cmꢀ1 and 1580 cmꢀ1, corresponding to the ketonic and amidic
carbonyl groups, respectively. Moreover, the structure of compound
2d was unambiguously determined by X-ray diffractometry as
shown in Fig. 1. Bond lengths and angles are not unusual and in
good agreement with those observed in the strictly related com-
pound 4-acetyl-2,N-dibenzoylaniline.14 In compound 2d, the ami-
dic and ketonic carbonyl groups are slightly twisted with respect to
the central benzene ring, as indicated, also in the molecular ge-
ometry computed ‘in vacuo’ at the B3-LYP/6-31G(d) level (values in
parenthesis), by the angles of 4.60ꢁ (2.74) and 10.55ꢁ (23.30)
formed by the C8eC13 benzene ring with the mean planes of the
C7/O1/N1/C8 and C13/C14/C15/O2 groups, respectively. The angles
between the C8eC13 benzene ring with the C1eC6 and C15eC20
phenyl rings are 15.31ꢁ (12.32) and 61.88ꢁ (64.36), respectively. In
addition, the molecular conformation is stabilized by an intra-
molecular NeH$O hydrogen bond forming a six-membered ring:
Scheme 2.
In order to verify the radical nature of the photorearrangement
of nitrones by evidencing the formation of the radical in-
termediates shown in Scheme 2, we repeated the reactions in the
presence of a radical scavenger and monitored them by means of
the EPR-Spin Trapping technique. In particular, benzene solutions
of compounds 1a and 1d containing a small amount of the spin trap
PBN were irradiated in a flat SuprasilÒ quartz cell for 5 min using an
UV-A lamp. Immediately after irradiation, the cell was inserted in
the cavity of an EPR spectrometer and spectra were recorded. For
both compounds, the recorded spectra (see Fig. 2) resulted from the
overlapping of the signals from three different species, their spec-
tral parameters (see Table 1) being fairly similar for the two com-
pounds and only slightly dependent on the nature of the
substituent R in position 3 of the indolinic derivatives. Irradiation of
compounds 1a and 1d in acetonitrile solution, i.e., the same solvent
used in the macroscale reactions, also led to the EPR detection of
the same spin adducts, with slight variations of their spectral pa-
rameters due to the higher solvent polarity (data not shown).
ꢁ
ꢁ
ꢁ
N1eH1, 0.86 A (1.02); H1$O2, 1.92 A (1.80); N1$O2, 2.63 A (2.66);
N1eH1$O2,139ꢁ (139). The crystal packing, likely responsible of the
slight differences between experimental and computed geome-
tries, is governed only by Van der Waals interactions.
Fig. 1. Molecular structure of 2d, with displacement ellipsoids drawn at the 50%
probability level.
Photorearrangement of nitrones and N-oxides is commonly
described to proceed with formation of oxaziridines, whose three-
membered rings are in many cases rather unstable and easily react
further following different reaction pathways. In particular, the
initially formed oxaziridines, which are photo- and thermolabile,
generally rearrange to amides.3 This is what happens also in the
reactions described in the present work: compounds 2aef obtained
upon UV-irradiation of the studied nitrones could actually derive
from an oxaziridine intermediate
3 through a radical path
(Scheme 2). In fact, the homolytic cleavage of the NeO bond in the
oxaziridine ring could lead to an alkoxy-aminyl biradical 4 and,
upon cleavage of the Ca-Cb bond, to the biradical 5/50, that may exist
either in a singlet or in a triplet state. An H-transfer in 50 accounts
for the eventual formation of the isolated compound 2. Although in
most cases photorearrangement of nitrones via oxaziridine in-
termediates is described as a reaction leading to a fairly complex
products distribution, noteworthily we obtained products 2 in
Fig. 2. Room temperature experimental (blue) and computer simulated (red) EPR
spectra observed following a 5 min UV-A irradiation of deoxygenated benzene solu-
tions of (a): 1a and (b): 1d ( , 6a,d; , 7a, d; A, 8a, d).

A. Alberti et al. / Tetrahedron 67 (2011) 6889e6894
6891
Table 1
As indicated by the
D
G values shown in Scheme 3, the first step
EPR hfsc and g-factors for the radicals observed after UV-A irradiation of benzene
solutions of compounds 1a and 1d. DFT computed values in parenthesis
of the process, i.e., the opening of the oxaziridine ring and the
consequent formation of biradical 5/50, experimentally supported
by the detection of nitroxide 8 in the spin trapping experiments, is
almost thermoneutral, the overall process being ‘driven’ by the
hydrogen shift leading to the final product. Taking into account the
OHeN and the OeHN distances in 50 and 2 also reported in the
scheme, the possibility of a hydrogen bond, with formation of six-
membered rings, in both the intermediate 50 and the final product
2, seems relevant.
Radical
aH/mT
aN/mT
g
Amount %
6a
6d
7a
7d
8a
8d
0.221 (0.132)
0.215
0.150 (0.118)
0.143
0.456 (0.409)
0.452
1.440 (1.403)
1.442
1.333 (1.304)
1.334
1.427 (1.376)
1.424
2.00578 (2.00575)
2.00581
2.00604 (2.00604)
2.00601
2.00581 (2.00591)
2.00580
w58
w34
w39
w30
w3
w36
An additional confirmation to our hypothesis came from the
results obtained in the photorearrangement of compound 9
(Scheme 4). Indeed 9, obtained via methylation of the 3-OH group
in 1e, gave upon irradiation benzoxazine 10, easily identified from
its 1H NMR spectrum characterized by two doublets at 8.23 and
8.27 ppm (J¼1.62 Hz) typical of the ortho protons in the C-2 phenyl
ring of the N]CePh moiety.
The spectral parameters of the three radical species detected
following UV-A irradiation of solutions of 1a or 1d in the presence
of PBN are in line with nitroxides with a b-alkoxy or a g-hydroxy
substituent,18e20 resulting from the PBN trapping of whatever
radicals may be formed from 1a,d. We then identified the radicals
responsible for the observed spectra as nitroxides 6a,d, 7a,d, and
8a,d (Block 1). DFT calculations employing an already published21
multistep procedure were performed to corroborate our hypothe-
ses. Indeed, as shown in Table 1, a fairly good agreement between
experimental and computed data was found concerning both EPR
hyperfine splitting constants (hsfc) and g-factors.
Scheme 4.
In fact, benzoxazine 10 could derive from a radical intermediate
analogous to 5/50 shown in Scheme 2: since in this case no hy-
drogen transfer is possible due to the methylation of the OH group,
an intramolecular coupling may lead to the isolated product 10.
Even if spin trapping experiments do support the participation
of radical intermediates in the photorearrangement of nitrones,
other mechanisms not involving the participation of radical species
may not be excluded. In this context it should be borne in mind that
EPR spectroscopy is a very sensitive technique (radical concentra-
tion ꢂ10ꢀ7 M) and that the detection of free radicals in the course
of a reaction does not necessarily mean that they are the only
possible intermediates or even lie on the main reaction coordinate.
For this reason, DFT calculations were carried out by imposing
a singlet state for each intermediate (11 and 12, Block 2) and in
Scheme 5 a mechanism, chosen among the possible pathways, is
Block 1.
Nitroxides 6e8 can be considered as deriving from the in-
teraction of the trap PBN with biradicals 4 and 5/50, respectively,
followed by hydrogen abstraction, and their identity provides
support for the mechanism outlined in Scheme 2.
In order to verify the feasibility of the mechanism as proposed in
Scheme 2, a thermochemical study was carried out by means of DFT
calculations (details in the Experimental section) in which the ge-
ometry of each intermediate taken into account corresponds to the
conformer lowest in energy among the possible ones, obtained by
means of appropriate relaxed Potential Energy Surface (PES) Scans.
In Scheme 3, the computed structure of 3a, 50a, and 2a have been
reported in a tube-style representation along with the computed
shown together along with the computed
each step.
D
G0298 (in kcal/mol) for
Gibbs Free Energy changes (
D
G0298 in kcal/mol) for each step.
Block 2.
Contrary to the radical mechanism previously proposed, in this
case the most exergonic process is now the first step, i.e., the for-
mation of 11, which would rearrange to give the final reaction
product through isomer 12. The OeHO distances in 11 and 12 are
1.43 and 1.78 Ǻ, respectively, and also in this case the possibility of
hydrogen bonding could play an important role, although with the
formation of eight-membered rings.
Scheme 3.

6892
A. Alberti et al. / Tetrahedron 67 (2011) 6889e6894
298 K by means of frequency calculations performed employing
the M06-2X27 functional in conjunction with the 6-31þG(d,p)
basis set.
4.3. Instrumentation
Melting points are uncorrected and were measured with an
Electrothermal apparatus. 13C and 1H NMR spectra were recorded
at room temperature in CDCl3 or DMSO-d6 solution on a Varian
400 spectrometer using TMS as reference; J values are given in
hertz. IR spectra were recorded in the solid state with a Per-
kineElmer MGX1 spectrophotometer equipped with Spectra Tech.
Mass spectra and exact mass measurements were performed with
a Finnigan Mat95XP spectrometer in EI ionization mode. EPR
spectra were run with a Bruker EMX EPR spectrometer equipped
with an NMR Gauss meter for field calibration and an XL Model
3120 microwave frequency counter meter for g-factor de-
termination. Typical instrumental settings were: modulation fre-
quency 100 kHz, modulation amplitude 0.04 mT, sweep width
4.0 mT, microwave power 5 mW, time constant 1.28 s, receiver
gain 5ꢄ103.
Scheme 5.
3. Conclusion
Irradiation was carried out using a Philips Original Home So-
larium, model HB 406/A equipped with a Philips HPA/400 W lamp,
whose irradiance in the range 300e400 nm was 0.75 mW/cm2.
The ring-opening photoisomerization of the title compounds 1
to N-(acylphenyl)benzamides 2 is logically explained by initial
conversion of 1 into the corresponding indolooxaziridines 3. NeO
bond homolysis of the latter with concomitant homolytic indole
C2eC3 bond breakage, followed by hydrogen migration (from OH
to N), is regarded feasible on the basis of DFT calculations. In ad-
dition, spin trapping experiments serve well as direct experimental
support of the (at least in part) homolytic character of the ring-
opening reactions of the oxaziridine intermediates.
4.4. EPR measurements
Nitrones 1a and 1d (4 mg in 0.5 mL of benzene) and PBN (4 mg
in 0.5 mL of benzene) were put separately into the two arms of an
inverted U tube equipped with a flat quartz cell.29 The thoroughly
nitrogen purged solutions were mixed, transferred into the aque-
ous flat cell and irradiated for 5 min maintaining the cell at 30 cm
from the UV-A lamp. The cell was then put into the EPR cavity and
the signal recorded.
Computer simulation of EPR spectra was achieved using the
WinSim program in the NIEHS public ESR software tools package
(www.epr.niehs.nih.gov),30 or a program based on a Montecarlo
minimization procedure.31
4. Experimental
4.1. Chemicals
PBN, methylmagnesium chloride, i-propylmagnesium chloride,
n-butylmagnesium chloride, phenylmagnesium bromide, p-
methoxyphenylmagnesium bromide, benzylmagnesium chloride,
methyl iodide, and potassium hydroxide were purchased from
Aldrich. Benzene, acetonitrile, and dimethyl sulfoxide were of pure
grade and used without any further purification. 2-Phenylisatogen
was prepared as reported in the literature.22
4.5. Synthesis of nitrones 1aef
Nitrones 1aef were synthesized according to a literature pro-
cedure:28 the appropriate Grignard reagent (10 mmol) was added
dropwise to a solution of 2-phenylisatogen (5 mmol, 1.12 g in 80 mL
of anhydrous THF), under stirring and in a current of nitrogen. After
2 h the reaction mixture was poured into 10% aqueous NH4Cl
(100 mL) and extracted with diethyl ether. The organic layer, dried
over Na2SO4, was evaporated to dryness and the residue was
washed with diethyl ether/hexane 80:20. The insoluble product
was the expected nitrone, which was separated by filtration under
vacuum.
4.2. Calculations
Density Functional Theory23 calculations were carried out us-
ing the GAUSSIAN 09 suite of programs24 on an IBM SP-6 at Cineca
Supercomputing Center.25 All calculations on paramagnetic spe-
cies were carried out with the unrestricted formalism, giving
<S2>¼0.7501ꢃ0.0003 for spin contamination (after annihilation),
and performed following the multistep procedure previously de-
scribed.21 In addition, in frequency calculations, imaginary (neg-
ative) values were never found, confirming that the computed
geometries were always referred to a minimum. Isotropic g-factors
was determined by means of the Gauge Independent Atomic Or-
bital method26 as the average of the xx, yy, and zz corresponding
components. It should be noted that all radicals and all closed-
shell species considered in this study were true minimum en-
ergy structures (i.e., having no imaginary frequencies). All geom-
etries were optimized at the B3-LYP/6-31G(d) level of theory, with
conformations systematically screened by means of appropriate
relaxed (i.e., with optimization at each point) Potential Energy
Surface Scans to ensure that species were global minimum energy
structures. Thermodynamic quantities have been computed at
4.5.1. 3-Hydroxy-3-methyl-2-phenyl-3H-indole N-oxide 1a. Yield
70%. Mp 246e247 ꢁC from acetic acid/ligroin 80e100 ꢁC; FT-IR,
n,
cmꢀ1 3152, 1450, 764; dH (400 MHz DMSO-d6) 1.67 (3H, s, Me), 6.44
(1H, br s, OH), 7.50e7.58 (5H, m, arom), 7.67e7.69 (2H, m, arom),
8.84e8.86 (2H,m, arom); dC (100.49 MHz DMSO-d6) 145.0, 145.0,
139.8, 130.0, 129.6, 129.4, 128.3, 128.0, 127.4, 121.9, 114.2, 78.0, 25.6;
m/z 239 (23, Mþ), 207 (17.5), 196 (53.4), 105 (89.3), 77 (84.2). HRMS
(EI) m/z calcd for C15H13NO2 (Mþ): 239.0946; found 239.0949.
4.5.2. 3-Hydroxy-2-phenyl-3-(2-propyl)-3H-indoleN-oxide1b. Yield
73%. Mp 224e225 ꢁC from acetone/ligroin 80e100 ꢁC; FT-IR, , cmꢀ1
n
3150, 1465, 763; dH (400 MHz, CDCl3) 0.07 (3H, d, Me, J 7.0 Hz), 1.25
(3H, d, Me, J 7.0 Hz), 2.35e2.45 (1H, septet, CH, J 7.0 Hz), 5.89 (1H, br
s, OH), 6.91e6.95 (1H, m, arom), 7.08 (1H, d, arom, J 7.8 Hz), 7.15 (1H,

A. Alberti et al. / Tetrahedron 67 (2011) 6889e6894
6893
p-triplet, arom), 7.19e7.28 (3H, m, arom), 7.45 (1H, d, arom, J
7.0 Hz), 8.48 (2H, d, arom, J 7.8 Hz); dC (100.49 MHz, CDCl3) 144.8,
135.0, 130.6, 129.4, 128.5, 127.8, 127.1, 123.4, 114.2, 84.8, 35.8, 16.4,
15.8; m/z 267 (Mþ, 6.5), 223 (100), 207 (20.7), 179 (60.05), 105
(56.9), 77 (55.8). HRMS (EI) m/z calcd for C17H17NO2 (Mþ): 267.1259;
found 239.1255.
2d were identified by comparison with authentic samples com-
mercially available.
4.6.1. N-[2-(2-Methylpropanoyl)phenyl]benzamide 2b. Mp 106e
107 ꢁC; FT-IR, , cmꢀ1 3210, 1673, 1586; dH (400 MHz, CDCl3) 1.26
n
(6H, d, 2ꢄMe, J 7.0 Hz), 3.71 (1H, septet, J 7.0 Hz), 7.17 (1H, t, arom, J
7.0 Hz),7.51e7.57 (3H, m, arom), 7.62 (1H, t, arom, J 8.6 Hz), 8.03
(1H, d, arom, J 8.6 Hz), 8.07 (2H, dd, arom, J 7.8 and 1.6 Hz), 8.97 (1H,
d, arom, J 8.6 Hz), 12.71 (1H, br, NH); dC (100.49 MHz, CDCl3) 209.5,
166.1, 141.8, 134.9, 131.9, 130.7, 128.8, 127.5, 122.5, 121.3, 121.0, 36.3,
15.6; m/z 267 (Mþ, 2.6), 224 (100), 196 (4.3), 146 (12.8), 105 (67.6),
77 (61.1); HRMS (EI) m/z calcd for C17H17NO2 (Mþ): 267.1259; found
267.1258.
4.5.3. 3-n-Butyl-3-hydroxy-2-phenyl-3H-indole N-oxide 1c. Yield
68%. Mp 155e156 ꢁC from acetone/ligroin 80e100 ꢁC; FT-IR, , cmꢀ1
n
3110, 1461, 755; dH (400 MHz, CDCl3) 0.28e0.5 (2H, m, CH2), 0.51
(3H, t, Me, J 7.0 Hz), 0.88e0.97 (2H, m, CH2), 2.01e2.18 (2H, m, CH2),
6.19(1H, br s, OH), 6.83 (1H, t, arom, J 7.8 Hz), 7.01 (1H, d, arom, J
7.8 Hz), 7.15 (1H, t, arom, J 7.8 Hz), 7.21e7.31 (3H, m, arom), 7.41 (1H,
d, arom, J 7.0 Hz), 8.48 (2H, d, arom, J 7.0 Hz); dC (100.49 MHz,
CDCl3) 147.9, 144.2, 137.4, 130.6, 129.2, 128.9, 128.3, 127.9, 127.0,
121.5, 119.5, 114.2, 81.8, 38.4, 24.7, 22.3, 13.5; m/z 281 (Mþ,5.0), 265
(11.3), 236 (41.5), 208 (100), 193 (17.4), 180 (12.8), 77 (17.3); HRMS
(EI) m/z calcd for C18H19NO2 (Mþ): 281.1416; found 281.1417.
4.6.2. N-(2-Butanoylphenyl)benzamide 2c. Mp 70e71 ꢁC; FT-IR,
n,
cmꢀ1 3208, 1673, 1585; dH (400 MHz, CDCl3) 0.98 (3H, t, Me, J
7.8 Hz), 1.41e1.47 (2H, m, CH2), 1.72e1.77 (2H, m, CH2), 3.07 (2H, t,
CH2, J 7.8 Hz), 7.16 (1H, t, arom, J 7.0 Hz), 7.52e7.64 (4H, m, arom),
7.98 (1H, d, arom, J 8.0 Hz), 8.08 (2H, d, arom, J 6.2 Hz), 8.98 (1H, d,
arom, J 7.8 Hz), 12.37 (1H, br, NH); dC (100.49 MHz, CDCl3) 205.6,
166.1, 141.4, 135.0, 131.9, 130.9, 128.8, 127.5, 122.4, 121.9, 121.0, 39.9,
27.0, 22.4, 13.9; m/z 281 (Mþ, 7.2), 224 (80.7), 196 (23.1), 146 (7.1),
105 (100), 77 (71.9); HRMS (EI) m/z calcd for C18H19NO2 (Mþ):
281.1416; found 281.1417.
4.5.4. 3-Hydroxy-2,3-diphenyl-3H-indole N-oxide 1d. Yield 80%. Mp
250e251 ꢁC from acetic acid; FT-IR, , cmꢀ1 3159, 1445, 758; dH
n
(400 MHz DMSO-d6) 7.15 (1H, s, OH), 7.20e7.23 (1H, m, arom),
7.28e7.31 (3H, m, arom), 7.34e7.45 (6H, m, arom), 7.53 (1H, t,
arom, J 7.8 Hz), 7.74 (1H, d, arom, J 7.8 Hz), 8.56e8.59 (2H, m,
arom); dC (100.49 MHz DMSO-d6) 146.0, 145.8, 141.9, 140.9, 130.6,
130.5, 130.1, 129.4, 128.7, 128.2, 128.1, 125.0, 123.4, 115.1, 82.0; m/z
301 (Mþ, 27.3), 281 (25.7), 207 (66.3), 196 (48.7), 105 (100), 77
(71.2); HRMS (EI) m/z calcd for C20H15NO2 (Mþ): 301.1103; found
301.1104.
4.6.3. N-[2-(p-Methoxybenzoyl)phenyl]benzamide2e. Mp 113e114 ꢁC;
FT-IR, n
, cmꢀ1 3229, 1672, 1624, 1583; dH (400 MHz, CDCl3) 3.89 (3H,
s, OMe), 6.98 (2H, d, arom, J 8.6 Hz), 7.14 (1H, p-triplet, arom),
7.49e7.55 (3H, m, arom), 7.61e7.64 (2H, m, arom), 7.76 (2H, d, arom, J
8.6 Hz), 8.04 (2H, dd, arom, J 1.6 and 7.9 Hz), 8.83 (1H, d, arom, J
7.8 Hz), 11.70 (1H, br, NH); dC (100.49 MHz, CDCl3) 198.5, 165.7, 163.3,
140.5, 134.6, 133.9, 133.3, 132.6, 131.9, 131.1, 128.8, 127.4, 124.1, 122.1,
121.6, 113.6, 55.5; m/z 331 (Mþ, 21.5), 226 (18.2), 196 (53.5), 135 (9.5),
105 (100), 77 (67); HRMS (EI) m/z calcd for C21H17NO3 (Mþ): 331.1208;
found 331.1206.
4.5.5. 3-Hydroxy-3-(p-methoxyphenyl)-2-phenyl-3H-indole N-oxide
1e. Yield 75%. Mp 240 ꢁC from acetic acid; FT-IR, , cmꢀ1 3081,1443,
n
752; dH (400 MHz DMSO-d6) 3.7 (3H, s, OMe), 6.85 (2H, d, arom, J
8.6 Hz), 7.1 (1H, s, OH), 7.25e7.28 (3H, m, arom), 7.39e7.43 (4H, m,
arom), 7.53 (1H, t, arom, J 7.8 Hz), 7.73 (1H, d, arom, J 8.0 Hz),
8.59e8.61 (2H, m, arom); dC (100.49 MHz DMSO-d6) 159.0, 145.7,
145.5, 141.0, 133.4, 130.4, 130.3, 129.8, 128.5, 128.1, 128.1, 126.2,
123.1, 114.8, 114.6, 81.6, 55.5; m/z 331 (Mþ, 22.6), 226 (25.2), 207
(20.4), 196 (45.1), 135 (11.4), 105 (100), 77 (78.8); HRMS (EI) m/z
calcd for C21H17NO3 (Mþ): 331.1208; found 331.1206.
4.6.4. N-(2-Phenylacetyl)phenylbenzamide 2f. Mp 142e143 ꢁC; FT-
IR, n
, cmꢀ1 3220, 1675,, 1587; dH (400 MHz, CDCl3) 4.38 (2H, s,
CH2Ph), 7.16 (1H, t, arom, J 7.0 Hz), 7.27e7.30 (3H, m, arom),
7.34e7.38 (2H, m, arom), 7.48e7.55 (3H, m, arom), 7.62 (1H, t, arom,
J 8.6 Hz), 8.05 (2H, d, arom, J 6.3 Hz), 8.1 (1H, d, arom, J 7.8 Hz), 8.99
(1H, d, arom, J 8.6 Hz), 12.6 (1H, br, NH); dC (100.49 MHz, CDCl3)
202.5, 166.2, 135.4, 134.7, 134.3, 131.9, 131.5, 129.4, 128.8, 128.8, 127.5,
127.1, 122.5, 121.1, 46.9; m/z 315 (Mþ, 0.8), 224 (100), 146 (15.5), 105
(57), 22 (52.7); HRMS (EI) m/z calcd for C21H17NO2 (Mþ): 315.1259;
found 315.1256.
4.5.6. 2-Phenyl-3-benzyl-3-hydroxy-3H-indole N-oxide 1f. Yield
72%; Mp 205e206 ꢁC from aceton/petrolether; FT-IR, , cmꢀ1 3214,
n
1445, 763; dH (400 MHz, CDCl3) 3.28 (2H, quartet, CH2Ph, J
13.32 Hz), 6.04 (1H, br s, OH), 6.21 (2H, d, arom, J 8.6 Hz), 6.64e6.72
(4H, m, arom), 6.80e6.83 (1H, m, arom), 6.94e6.98 (1H, m, arom),
7.08e7.22 (4H, m, arom), 8.38 (2H, d, arom, J¼8.6 Hz); dC
(100.49 MHz, CDCl3) 136.5, 133.7, 130.6, 129.8, 129.4, 128.5, 128.1,
127.6, 127.5, 126.7, 122.4, 119.2, 114.0, 82.1, 44.4; m/z 315 (Mþ, 20.6),
286 (100), 242(20.5), 207 (15.8), 105 (6.2), 77 (21.3); HRMS (EI) m/z
calcd for C21H17NO2 (Mþ): 315.1259; found 315.1257.
4.7. Synthesis of compound 9
To a suspension of potassium hydroxide (1.12 g, 20 mmol) in
dimethyl sulfoxide (20 mL), nitrone 1e (1.65 g, 5 mmol) and methyl
iodide (1.06 g, 7.5 mmol) were added and the reaction mixture was
stirred at room temperature for 30 min. Water (20 mL) was then
added to the reaction mixture that was afterward extracted with
methylene chloride (20 mL). The organic layer was repeatedly
washed with water (5e10 times), dried over anhydrous Na2SO4 and
the solvent was removed under reduced pressure.
4.6. Irradiation of 1aef. General procedure
The nitrone (0.33 mmol) was dissolved in 50 mL of dried ace-
tonitrile and put into a quartz tube. The solution was purged with
argon and then irradiated with an UV-A lamp under magnetic
stirring at 30 cm distance from the lamp. After 20 min, the starting
material was completely consumed as evidenced by TLC (thin layer
chromatography) and eluted with cyclohexane/ethylacetate 8:2.
Only the corresponding rearranged compound was quantitatively
recovered, demonstrating the complete transformation of the
nitrone. After the evaporation of the solvent, the residue was pu-
rified by crystallization from toluene/petroleum ether. N-(2-
Acetylphenyl)benzamide 2a and N-(2-benzoylphenyl)benzamide
4.7.1. 3-Methoxy-3-(p-methoxyphenyl)-2-phenyl-3H-indole N-ox-
ide 9. FT-IR, n
, cmꢀ1 1607, 1510, 1441, 794; dH (400 MHz, CDCl3) 3.06
(3H, s, eOCH3), 3.73 (3H, s, PheOCH3), 6.78 (2H, d, arom, J 9.4 Hz),
7.24 (1H, d, J 7.0 Hz), 7.32 (2H, d, J 8.6 Hz), 7.37e7.39 (5H, m, arom),
7.51 (1H, t, arom, J 7.8 Hz), 7.89 (1H, d, arom, J 7.8 Hz), 8.64e8.67 (2H,
m, arom,); dC (100.49 MHz, CDCl3) 159.2, 136.0, 131.9, 130.5, 128.3,
127.7, 126.1, 122.8, 115.0, 114.1, 87.9, 55.1, 52.1; m/z 345 (Mþ, 21.5),

6894
A. Alberti et al. / Tetrahedron 67 (2011) 6889e6894
314 (24.7), 240 (100), 210 (27.8), 135(22.0), 105 (63.5), 77 (45.5);
Supplementary data
HRMS (EI) m/z calcd for C22H19NO3 (Mþ): 345.1365; found 345.1363.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.06.094.
4.8. Irradiation of compound 9
References and notes
Nitrone 9 (114 mg, 0.33 mmol) was dissolved in 50 mL of ace-
tonitrile in a quartz tube. The solution was purged with argon and
then irradiated with the UV-A lamp under magnetic stirring at
30 cm distance. After 20 min a TLC (cyclohexane/ethylacetate 8:2)
showed the complete transformation of the starting material and
the only spot observed was that corresponding to the rearranged
compound, indicating the quantitative transformation of the
nitrone. Evaporation of the solvent gave a solid residue, which was
submitted to spectroscopic analysis.
1. Spence, G. G.; Taylor, E. C.; Buchardt, O. Chem. Rev. 1970, 70, 231e265.
2. Padwa, A. Chem. Rev. 1977, 77, 37e68.
3. Albini, A.; Alpegiani, M. Chem. Rev. 1984, 84, 43e71.
4. Eckroth, D. R.; Squire, R. H. J. Org. Chem. 1971, 36, 224e226.
5. Albini, A.; Fasani, E.; Buchardt, O. Tetrahedron Lett. 1982, 23, 4849e4852.
6. Albini, A.; Fasani, E.; Maggi Decrema, L. J. Chem. Soc., Perkin Trans. 1 1980,
2738e2742.
7. Albini, A.; Fasani, E.; Frattini, V. J. Chem. Soc., Perkin Trans. 2 1988, 235e240.
8. Kondo, H.; Tanaka, K.; Kubo, K.; Igarashi, T.; Sakurai, T. Heterocycles 2004, 63,
241e247.
ꢂ
9. Zeng, Y.; Smith, B. T.; Hershberger, J.; Aube, J. J. Org. Chem. 2003, 68, 8065e8067.
10. Bourguet, E.; Baneres, J.-L.; Girard, J.-P.; Parello, J.; Vidal, J.-P.; Lusinchi, X.;
4.8.1. 4-Methoxy-4-(p-methoxyphenyl)-2-phenyl-4H-benzo[1,3]ox-
Declercq, J.-P. Org. Lett. 2001, 3, 3067e3070.
11. Ogata, M.; Matsumoto, H.; Takahashi, S.; Kano, H. Chem. Pharm. Bull. 1970, 18,
azine 10. FT-IR,
n
, cmꢀ1 1599, 1511, 1253, 764; dH (400 MHz, CDCl3)
ꢃ
964e969.
3.30 (3H, s, eOCH3), 3.82 (3H, s, PheOCH3), 6.82 (2H, d, arom, J
8.6 Hz), 7.02e7.06 (1H, m, arom), 7.14e7.21 (1H, m, arom),
ꢀ
12. Oliveros, E.; Riviere, M.; Lattes, A. J. Heterocycl. Chem. 1980, 17, 1025e1027.
13. Colonna, M.; Poloni, M. Ann. Chim. (Rome, Italy) 1973, 63, 287e289.
14. Usman, A.; Razak, I. A.; Fun, H.-K.; Chantrapromma, S.; Tian, J.-Z.; Zhang, Y.; Xu,
J.-H. Acta Crystallogr. 2002, E58, o492eo494.
7.34e7.51 (7H, m, arom), 8.24 (2H, d, arom,
J 8.6 Hz); dC
(100.49 MHz, CDCl3) 159.8, 155.6, 140.0, 133.6, 131.4, 129.8, 128.4,
128.1,127.9.126.7,126.3,125.4,124.5,113.5,103.2, 55.3, 51.1; m/z 345
(Mþ, 39.4), 330 (14.6), 329 (41.0), 314 (100), 286 (35.8), 195 (15.5),
135 (53.9), 105 (26.7); HRMS (EI) m/z calcd for C22H19NO3 (Mþ):
345.1365; found 345.1362.
€
15. Dopp, D.; Weiler, H. Tetrahedron Lett. 1974, 15, 2445e2448.
€
16. Dopp, D. Chem. Ber. 1976, 106, 3849e3863.
€
17. Dopp, D. Tetrahedron Lett. 1972, 13, 3215e3218.
€
18. Forrester, A. R. In Landolt-BornsteindMagnetic Properties of Free Radicals;
Fischer, H., Hellwege, K.-H., Eds.; Springer: Heidelberg, 1979; II/9c1.
€
19. Forrester, A. R. In Landolt-BornsteindMagnetic Properties of Free Radicals;
Fischer, H., Ed.; Springer: Heidelberg, 1989; II/17d2.
€
20. Alberti, A. In Landolt-BornsteindMagnetic Properties of Free Radicals; Fischer, H.,
4.9. Single crystal X-ray analysis of compound 2d
Ed.; Springer: Heidelberg, 2005; II/26d.
21. Stipa, P. Chem. Phys. 2006, 323, 501e510.
22. Bond, C. C.; Hooper, M. Synthesis 1974, 6, 443.
Crystallographic data were collected at room temperature on
23. (a) Density Functional Theory of Atoms and Molecules; Parr, R. G., Yang, W., Eds.;
Oxford University: New York, NY, 1998; (b) A Chemists Guide to Density Func-
tional Theory; Koch, W., Holthausen, M. C., Eds.; Wiley-VCH: Weinheim, 2000.
24. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Fores-
man, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, C. Y. A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 09, Revision B.01; Gaussian: Wallingford, CT, 2010.
ꢁ
a Siemens AED diffractometer using Cu K
a
radiation (
l
¼1.54178 A).
Data were corrected for Lorentz and polarization effects but not for
absorption. The structures were solved by direct methods (SIR97)32
and anisotropically refined for all the non-H atoms. The re-
finements were performed on F2 using SHELXL-97.33 All H atoms
were placed at calculated positions and refined using a riding
ꢁ
ꢁ
model approximation, with CeH¼0.93e0.96 A, NeH¼0.86 A, and
with Uiso(H)¼1.2 Ueq(C, N). C20H15NO2, Mr¼301.33, triclinic, space
ꢁ
group Pꢀ1, a¼7.201 (2), b¼8.417 (2), c¼13.159 (3) A,
a
¼90.793 (3),
3
ꢁ
b
¼100.486 (3),
g
¼93.182 (3)ꢁ, V¼782.8 (3) A , Z¼2,
rcalc¼1.278 g cmꢀ3
,
m
¼0.661 mmꢀ1
; yellow block, crystal di-
mensions 0.18ꢄ0.23ꢄ0.28 mm, 212 parameters, R¼0.048,
wR2¼0.113 (for 2973 unique reflections, I>0), S¼0.993, Dr (min/
ꢁꢀ3
max)¼ꢀ0.12/0.15 e A . Crystallographic data for this structure
25. Cineca Supercomputing Center (via Magnanelli 6/3, I-40033 Casalecchio di
Reno, Italy; http://www.cineca.it/HPSystems).
have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 815157.
26. (a) London, F. J. Phys. Radium 1937, 397e409; (b) McWeeny, R. Physiol. Rev. 1962,
126, 1028e1034; (c) Ditchfield, R. Mol. Phys. 1974, 27, 789e807; (d) Cheeseman,
J. R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J. J. Chem. Phys. 1996, 104, 5497e5509;
(e) Wolinski, K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251e8261.
27. Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215e241.
28. Berti, C.; Colonna, M.; Greci, L.; Marchetti, L. Tetrahedron 1975, 31, 1745e1753.
29. Russell, G. A.; Janzen, E. G.; Strom, E. T. J. Am. Chem. Soc. 1964, 86, 1807e1814.
30. Duling, D. R. J. Magn. Reson., Ser. B 1994, 104, 105e110.
Acknowledgements
ꢀ
P.C. and P.S. would like to thank MIUR (Ministero dell’Universita
31. Lucarini, M.; Luppi, B.; Pedulli, G. F.; Roberts, B. P. Chem.dEur. J. 1999, 5,
e della Ricerca Scientifica e Tecnologica) for financial support (PRIN
2008); P.S. is grateful to Cineca Supercomputing Center for com-
putational resource allocation (ISCRA grant NMPNITRO, code:
HP10CAQFF04).
2048e2054.
32. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.; Guagliardi,
A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr.1999, 32,115e119.
33. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.