Reaction Modes and Mechanism in Indolizine Photooxygenation Reactions

Article abstract of DOI:10.1021/jo035070d

Photooxygenations of 1,2-, 1,3-, and 2,3-di- and 1,2,3-trisubstituted indolizines 1a-1f under different reaction conditions in methanol and acetonitrile have been investigated to establish the general reaction pattern and mechanism in indolizine photooxygenation in view of the influence of the ring substituents and substitution pattern. Photooxygenations of 1-acyl-2-phenylindolizines 1a and 1b and 1,3-dibenzoyl-2-phenylindolizine (1d) are self-sensitized, while those of 1-(p-nitrobenzoyl)-2-phenylindolizine (1c) and 2-phenyl-3-(p-chlorobenzoyl)indolizine (1e) need to be sensitized by rose bengal (RB) or methylene blue (MB). These reactions proceed via a singlet oxygen mechanism yet follow different pathways in methanol and in acetonitrile, with peroxidic zwitterion D (in methanol) and dioxetane E across the indolizine C2-C3 bond (in acetonitrile) as the intervening intermediates. Methanol trapping of the peroxidic zwitterion results in C3-N bond cleavage and pyrrole ring opening to give the corresponding (E)- and (Z)-3-(2-pyridinyl)-3-benzoylpropenoic acid methyl esters (2 and 3) and 4-(2-pyridinyl)-3-phenyl-5-aryl-5-hydroxyfuran-2-one (4) as products in methanol, while 0-0 bond homolysis of the dioxetane furnishes 3-(2-pyridinyl)-3-benzoyl-2-phenyloxirane-2-carboxaldehyde (6) and 1-(6-methyl-2-pyridinyl)-2-phenylethanedione (5) as products in acetonitrile. 3-Benzoyl-1-indolizinecarboxylic acid methyl ester (1f) is unreactive toward singlet oxygen; however, it could be photooxygenated under electron transfer conditions with 9,-10-dicyanoanthracene (DCA) as a sensitizer. This reaction takes place by the combination of the indolizine cation radical with the superoxide anion radical (or molecular oxygen) to give the pyridine ring oxidized methyl 3-benzoyl-5-methoxy-8-hydroxy-1-indolizinecarboxylate (9f), dimethyl 2-(2-pyridinyl)fumarate (8f), and dimethyl 2-(2-pyridinyl)maleate (7f) as products.

Full text of DOI:10.1021/jo035070d

Rea ction Mod es a n d Mech a n ism in In d olizin e P h otooxygen a tion
Rea ction s
†
†
‡
§
†
,†
Yun Li, Hua-You Hu, J ian-Ping Ye, Hoong-Kun Fun, Hong-Wen Hu, and J ian-Hua Xu*
Department of Chemistry, Nanjing University, Nanjing 210093, People’s Republic of China; Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China; and X-ray
Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
xujh@nju.edu.cn
Received J uly 23, 2003
Photooxygenations of 1,2-, 1,3-, and 2,3-di- and 1,2,3-trisubstituted indolizines 1a -1f under different
reaction conditions in methanol and acetonitrile have been investigated to establish the general
reaction pattern and mechanism in indolizine photooxygenation in view of the influence of the
ring substituents and substitution pattern. Photooxygenations of 1-acyl-2-phenylindolizines 1a and
1
2
b and 1,3-dibenzoyl-2-phenylindolizine (1d ) are self-sensitized, while those of 1-(p-nitrobenzoyl)-
-phenylindolizine (1c) and 2-phenyl-3-(p-chlorobenzoyl)indolizine (1e) need to be sensitized by
rose bengal (RB) or methylene blue (MB). These reactions proceed via a singlet oxygen mechanism
yet follow different pathways in methanol and in acetonitrile, with peroxidic zwitterion D (in
methanol) and dioxetane E across the indolizine C2-C3 bond (in acetonitrile) as the intervening
intermediates. Methanol trapping of the peroxidic zwitterion results in C3-N bond cleavage and
pyrrole ring opening to give the corresponding (E)- and (Z)-3-(2-pyridinyl)-3-benzoylpropenoic acid
methyl esters (2 and 3) and 4-(2-pyridinyl)-3-phenyl-5-aryl-5-hydroxyfuran-2-one (4) as products
in methanol, while O-O bond homolysis of the dioxetane furnishes 3-(2-pyridinyl)-3-benzoyl-2-
phenyloxirane-2-carboxaldehyde (6) and 1-(6-methyl-2-pyridinyl)-2-phenylethanedione (5) as prod-
ucts in acetonitrile. 3-Benzoyl-1-indolizinecarboxylic acid methyl ester (1f) is unreactive toward
singlet oxygen; however, it could be photooxygenated under electron transfer conditions with 9,-
1
0-dicyanoanthracene (DCA) as a sensitizer. This reaction takes place by the combination of the
indolizine cation radical with the superoxide anion radical (or molecular oxygen) to give the pyridine
ring oxidized methyl 3-benzoyl-5-methoxy-8-hydroxy-1-indolizinecarboxylate (9f), dimethyl 2-(2-
pyridinyl)fumarate (8f), and dimethyl 2-(2-pyridinyl)maleate (7f) as products.
6
In tr od u ction
oxygen mechanism have been extensively investigated
in both synthetic and mechanistic aspects.1 Reaction
patterns and mechanisms in view of the heterocyclic
structure and ring substituents have been largely clari-
fied. In sharp contrast, photooxygenation of the indoliz-
ines has not been widely investigated. Our recent inves-
tigation on the photooxygenation of indolizine derivatives
,2
Photoinduced oxygenation reactions of many N-con-
1
-3
1,2,4
taining heterocycles such as pyrroles,
indoles,
by the singlet
imi-
dazoles,1
,2,5
oxazoles, and thiazoles
1,2
1,2
*
Corresponding author. Fax: 086-025-3317761.
Nanjing University.
Chinese Academy of Sciences.
Universiti Sains Malaysia.
†
‡
§
via the selective excitation of their ground state charge
3
(1) For reviews on singlet oxygen reactions of N-containing hetero-
transfer complex with triplet oxygen ( ∑
g
O
2
) is the first
7
cycles, see: (a) George, M. V.; Bhat, V. Chem. Rev. 1979, 79, 447. (b)
Matsuura, T. Tetrahedron 1977, 33, 2869.
report on indolizine photooxygenation. Indolizines and
their partially and fully hydrogenated derivatives stand
for a large family of naturally occurring alkaloids with
(
2) Wasserman, H. H., Murray, R. W., Eds. Singlet Oxygen; Aca-
demic Press: New York, 1979; Chapter 9, p 447.
3) (a) Wasserman, H. H.; Petersen, A. K.; Xia, M.; Wang, J .
(
Tetrahedron Lett. 1999, 40, 7587. (b) Wasserman, H. H.; Xia, M.; Wang,
J .; Petersen, A. K.; J orgensen, M. Tetrahedron Lett. 1999, 40, 6145.
(6) For reviews on singlet oxygen reactions: (a) Frimer, A. A. Chem.
Rev. 1979, 79, 359. (b) Wasserman, H. H., Murray, R. W., Eds. Singlet
Oxygen; Academic Press: New York, 1979. (c) Frimer, A. A., Ed. Singlet
Oxygen; CRC Press: Boca Raton, FL, 1985; Vols. 1-4. (d) Foote, C. S.;
Clennan, E. L. Properties and Reactions of singlet oxygen. In Active
oxygen in chemistry; Foote, C. S., Valentine, J . S., Greenberg, A.,
Liebman, J . F., Eds.; Chapman and Hall: New York, 1995; p 105. (e)
Clennan, E. L. Tetrahedron 1991, 47, 1343. (f) Clennan, E. L.
Tetrahedron 2000, 56, 9151. (g) Stephenson, L. M.; Grdina, M. J .;
Orfanopoulos, M. Acc. Chem. Res. 1980, 13, 419. (h) Stratakis, M.;
Orfanopoulos, M. Tetrahedron 2000, 56, 1595. (i) Adam, W.; Prein, M.
Acc. Chem. Res. 1996, 29, 275. (j) Prein, M.; Adam, W. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 477.
(
c) Wasserman, H. H.; Rotllo, V. M.; Frechette, R.; DeSimone, R. W.;
Yoo, J . U.; Baldino, C. M. Tetrahedron 1997, 53, 8731. (d) Wasserman,
H. H.; Niu, C. Bioorg. Med. Chem. Lett. 1992, 2, 1101. (e) Boger, D. L.;
Baldino, C. M. J . Am. Chem. Soc. 1993, 115, 11418. (f) Muratake, H.;
Abe, I.; Natsume, M. Tetrahedron Lett. 1994, 35, 2573. (g) Li, H.-Y.;
Drummond, S.; Delucca, I.; Boswell, G. A. Tetrahedron 1996, 52, 11153.
(4) (a) Zhang, X.; Foote, C. S. J . Org. Chem. 1993, 58, 5524. (b) Saito,
I.; Nakagawa, H.; Kuo, Y. H.; Obata, K.; Matsuura, T. J . Am. Chem.
Soc. 1985, 107, 5279. (c) Santamaria, J .; Kaddachi, M. T.; Ferroud, C.
Tetrahedron Lett. 1992, 33, 781.
(5) (a) Kang, P.; Foote, C. S. J . Am. Chem. Soc. 2002, 124, 9629. (b)
Kang, P.; Foote, C. S. J . Am. Chem. Soc. 2002, 124, 4865. (c) Sheu, C.;
Kang, P.; Khan, S.; Foote, C. S. J . Am. Chem. Soc. 2002, 124, 3905.
(7) Tian, J .-Z.; Zhang, Z.-G.; Yang, X.-L.; Fun, H.-K.; Xu, J .-H. J .
Org. Chem. 2001, 66, 8230.
(d) Chawla, H. M.; Pathak, M. Tetrahedron 1990, 46, 1331.
1
0.1021/jo035070d CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/28/2004
2
332
J . Org. Chem. 2004, 69, 2332-2339

Indolizine Photooxygenation Reactions
CHART 1
TABLE 1. P h otooxygen a tion Rea ction s of Com p ou n d s
1
a -1f
sub-
strate
irrad
conver-
solvent
time (h) sion (%)
product (yielda (%))
b
1
1
1
1
1
1
1
1
1
1
a
a
a
b
b
c
c
d
d
e
MeOH-MeCN
MeCN
MeOH-MeCN
MeOH-MeCN
MeCN
MeOH-MeCN
MeCN
MeOH-MeCN
MeCN
9
10
9
8
10
8
12
12
14
10
11
20
100
100
100
100
100
100
100
100
100
100
100
64
2a (22), 3a (23), 4a (40)
5a (25), 6a (64)
2a (25), 3a (24), 4a (38)
2b (28), 3b (32), 4b (9)
5b (11), 6b (62)
2c (35), 3c (11), 4c (44)
5c (20), 6c (31)
2d (71)
b
c
b
b
d
d
b
b
d
d
6d (90)
2e (73)
MeOH-MeCN
MeCN
MeOH-MeCN
8
biological activities. Indolizines are also special in their
1e
1
6e (81)
7f and 8f (63), 9f (27)
e
f
f
electronic structure among N-containing heterocycles by
having a bridgehead nitrogen atom which causes a large
dipole moment in the molecule so that the pyridine and
the pyrrole rings are electron deficient and electron rich,
a
The yield of isolated pure product. b Self-sensitized reactions.
c
Irradiation with light of λ > 400 nm. Photolysis with light of λ >
3
00 nm. d Rose bengal (RB)/methylene blue (MB) sensitized.
e
Irradiation with light of λ > 500 nm. 9,10-Dicyanoanthracene
9
respectively. This special electronic structure should be
f
(
DCA) sensitized. Irradiation with light of λ > 400 nm. Yield
reflected in the reaction pathways in their photooxygen-
ation reactions. Indolizines are also known to be suscep-
tible to oxygen attack and are easily oxidized upon air
and light exposure. In relation to this, it has recently been
found that indolizines are highly active antioxidants that
based on consumed 1f.
group in 1a -1f serves to promote the intersystem cross-
ing (ISC) of the singlet excited state to the triplet state,
resulting in a diminished Φ
phosphorescence. The Φ values of 1b, 1d , and 1f are
1
0
F
and the occurrence of strong
inhibit lipid peroxidation in vitro. Our previous inves-
tigation on indolizine photooxygenation was based on the
F
7
measured to be 0.008, 0.008, and 0.005, respectively.
reactions of four 2-phenylindolizines. To further estab-
lish the scope and general reaction modes and to examine
the mechanisms in indolizine photooxygenation in regard
to ring substituents and substitution patterns, we have
investigated photoinduced oxygenation of a series of
indolizines covering a wide range of substitution patterns
under different conditions.
We have found that 1a , 1b, and 1d undergo self-
sensitized photooxygenation in oxygen saturated solution.
-1
Therefore, irradiation of 1a (0.025 mol L ) in a methanol
solution with light of λ > 400 nm under constant oxygen
purging led to the smooth consumption of 1a , and a
complete conversion was reached within 9 h. Chromato-
graphic separation of the reaction mixture on a silica gel
column gave (E)-2-phenyl-3-benzoyl-3-(6-methyl-2-py-
ridinyl)acrylic acid methyl ester (2a ) (10%), its (Z)-isomer
Resu lts a n d Discu ssion
Indolizines 1a -1f, bearing 1,2-, 1,3-, 2,3-, and 1,2,3-
substituents, have been synthesized, and their photo-
oxygenations under various conditions have been inves-
tigated (Chart 1). As compared with the case of the
unsubstituted indolizine, the introduction of the acyl and
aryl groups in 1a -1f causes drastic change in both the
absorption (1) and luminescence (2) properties. (1) In the
electronic spectra of 1a -1f, absorptions are red shifted
to show strong absorptions in the visible region so that
these compounds are yellow colored. As examples, 1a has
two absorption bands at 243.4 nm (ꢀmax ) 39200) and
(
3a ) (58%), and 3,5-diphenyl-5-hydroxy-4-(6-methyl-2-
pyridinyl)dihydrofuran-2-one (4a ) (25%). Photooxygen-
ation of 1a in acetonitrile-methanol (1:1, v/v) similarly
gave 2a (22%), 3a (23%), and 4a (40%) (Table 1). The
structures and steric configurations of these compounds
1
are elucidated by their spectral (IR, H NMR, and MS)
data and are further confirmed by X-ray crystallographic
analysis. On the other hand, irradiation of 1a in aceto-
nitrile solution under otherwise the same conditions and
silica gel chromatographic separation of the reaction
mixture after photolysis gave 2-phenyl-1-(6-methyl-2-
pyridinyl)ethanedione (5a ) (25%) and oxirane product 6a
3
78.1 nm (ꢀmax ) 14900). Similarly, 1b absorbs at 246.1
nm (ꢀmax ) 35100) and 378.4 nm (ꢀmax ) 15200). The long
wavelength band at ∼378 nm tails well into the visible
region. Therefore, excitation of these indolizines can be
achieved by irradiation with light of λ > 400 nm. (2)
1
(
64%). However, H NMR and TLC monitoring of the
reaction course showed that 5a is not a primary product
in the photooxygenation but is derived from 6a during
the photolysis. In a control experiment, 6a was found to
decompose to give 5a upon photolysis under photooxy-
genation conditions.
While indolizine (Φ
methanol) and 2-phenylindolizine (Φ
and 0.67 in methanol) have high fluorescence quantum
F
) 0.84 in hexane and 0.72 in
F
) 0.6 in hexane
Similar irradiation of 1b in methanol-acetonitrile (1:
, v/v) gave the corresponding 2b (28%), 3b (32%), and
-phenyl-3-(4-methoxybenzoyl)-3-(6-methyl-2-pyridinyl)-
yields1 and are nonphosphorescent (Φ
< 0.01), the acyl
1a
P
1
2
(
8) For reviews, see, for example: (a) Michael, J . P. Nat. Prod. Rep.
001, 18, 520. (b) Michael, J . P. Nat. Prod. Rep. 2000, 17, 579 and
references therein.
9) (a) Glier, C.; Dietz, F.; Scholz, M.; Fischer, G. Tetrahedron 1972,
acrylic acid (4b) (9%). A significant amount of p-meth-
oxybenzoic acid (16%) was also obtained (Table 1).
Photolysis of 1b in acetonitrile and workup of the
photolysate as before, on the other hand, gave 1-(6-
methyl-2-pyridinyl)-2-(4-methoxyphenyl)ethanedione (5b)-
2
(
2
1
8, 5779. (b) Paudler, W. W.; Chasman, J . N. J . Heterocycl. Chem. 1973,
0, 499.
(
10) Østby, O. B.; Dalhus, B.; Guandersen, L.-L.; Rise, F.; Bast, A.;
Haenen, G. R. M. M. Eur. J . Org. Chem. 2000, 3763.
11) (a) Lerner, D. A.; Horowitz, P. M.; Evleth, E. M. J . Phys. Chem.
(
(
11%) and 6b (62%) together with p-methoxybenzoic acid
16%). Photoinduced oxygenation of 1d in methanol-
(
1
977, 81, 12. (b) Catalan, J .; Mena, E.; Fabero, F. J . Chem. Phys. 1992,
6, 2005.
9
acetonitrile (1:1, v/v) resulted in the formation of 2d (71%)
J . Org. Chem, Vol. 69, No. 7, 2004 2333

Li et al.
CHART 2
1
and benzoic acid (23%), while irradiation in acetonitrile
gave oxirane 6d (90%) (Chart 2).
We have measured the UV-visible absorption spectra
of 1a in oxygen saturated and oxygen free solutions in
acetonitrile. The absorption curves in these two cases
(SCE, MeCN),18 single electron transfer (SET) to ∆
g
O
2
is exothermic only for those electron donors with half-
1
8-20
wave oxidation potentials lower than ∼0.11 V.
There-
fore, a large number of these singlet oxygen quenchings
are of charge transfer character without ion radical pair
formation taking place. Indolizine ranks among the most
π-electron excessive heterocycles, and simple alkyl- and
aryl-substituted indolizines have half-wave oxidation
potentials (E1/2 ) in the range 0.4-0.8 V (SCE, MeCN).
However, with the electron withdrawing acyl in the
indolizine ring, substrates 1a , 1b, and 1d must have their
1/2 higher than 0.8 V. Therefore, SET from 1a , 1b, and
coincide with each other, indicating that a ground state
3
charge transfer complex (CTC) between 1a and Σ
g
O
2
is
not formed to any detectable degree. Therefore, these
photoxygenations of 1a , 1b, and 1d take place via direct
excitation of the substrate and are self-sensitized. The
triplet energies for compounds 1b, 1d , and 1f are
measured from their phosphorescence spectra to be 59.0,
ox
21
ox
E
-
1
6
0.2, and 61.9 kcal mol , respectively. These E
T
-1
values
1d to singlet oxygen would have ∆GET values more
positive than 16 kcal/mol and would be highly endergonic,
1
are well above the energy of ∆
from S to T followed by energy transfer from the
indolizine T state to Σ
as the active oxygen species. Photooxygenation of
g
O
2
(22.6 kcal mol ). ISC
2
2
1
1
as estimated by the empirical Weller equations. These
photooxygenations are therefore suggested to proceed by
the mechanisms shown in Scheme 1. In singlet oxygen
reactions of cyclic enamines such as pyrroles, indoles,
imidazoles, oxazoles, and thiazoles, dioxetane and en-
doperoxide formed by [2 + 2] and [2 + 4] cycloadditions
3
1
g 2
O results in the generation of
1
g 2
∆ O
1
a in methanol-acetonitrile with short wavelength ir-
radiation (λ > 300 nm) was also carried out, and this gave
similar results to those in the long wavelength photolysis
(Table 1). Singlet oxygen is known to be a good excited
of singlet oxygens to the enamine moiety are often
-5,23
state electron acceptor, and quenching of singlet oxygen
by highly nucleophilic substrates with low ionization
suggested as the primary products.1
To rationalize
the results of the singlet oxygen reactions of 1a -1e, we
have carried out a DFT calculation of the frontier
molecular orbitals and the charge density distribution
in indolizines 1a -1e at the B3LYP 6-31G level, and the
results are given in Table 2. The calculation shows that
1
2
13
14
potentials such as enamines, aliphatic and aromatic
amines, phenols,15 sulfides, and hydrazines has been
reported. However, since singlet oxygen is estimated to
have a half-wave reduction potential (E1/2) of ∼0.11 V
16
17
1
9a
(
12) Foote, C. S.; Dzakpasu, A. A.; Lin, J . W.-P. Tetrahedron Lett.
975, 1247.
13) CT quenching of ∆
(18) The half-wave reduction potential of oxygen is -0.82 V (SCE)
19b
1
or -0.87 V (SCE).
The half-wave reduction potential of singlet
20
1
(
g
O
2
by aliphatic amines: (a) Ouannes, C.;
oxygen (E ) 22.6 kcal/mol) is therefore -0.11 V (SCE).
s
Wilson, T. J . Am. Chem. Soc. 1968, 90, 6527. (b) Matheson, I. B. C.;
Lee, J . J . Am. Chem. Soc. 1972, 94, 3310. (c) Young, R. H.; Martin, R.
L.; Feriozi, D.; Brewer, D.; Kayser, R. Photochem. Photobiol. 1973, 17,
(19) (a) Mann, C. K.; Barnes, K. K. Electrochemical Reduction in
Nonaqueous Systems; Marcel Dekker: New York, 1990. (b) Sawyer,
D. T.; Chiericato, G., J r.; Angells, C. T.; Nanni, E. J ., J r.; Tsuchiya, T.
Anal. Chem. 1982, 54, 1720.
2
33. (d) Monroe, B. M. J . Phys. Chem. 1977, 81, 1861. (e) Thomas, M.
J .; Foote, C. S. Photochem. Photobiol. 1978, 27, 683.
(20) Fukuzumi, S.; Fujita, S.; Suenobu, T.; Yamada, H.; Imahori,
H.; Araki, Y.; Ito, O. J . Phys. Chem. A 2002, 106, 1241.
(21) (a) Colonna, M.; Greci, L.; Poloni, M.; Marrosu, G.; Trazza, A.;
Colonna, F. P.; Distefano, G. J . Chem. Soc., Perkin Trans. 2 1986, 1229.
(b) Andruzzi, R.; Cardellini, L.; Greci, L.; Stipa, P.; Poloni, M.; Trazza,
A. J . Chem. Soc., Perkin Trans. 1 1988, 3067. (c) Sonnenschein, H.;
Kosslick, H.; Tittelbach, F. Synthesis 1998, 1596.
1
g 2
(14) CT quenching of ∆ O by aromatic amines: (a) Young, R. H.;
Brewer, D.; Kayser, R.; Martin, R.; Feriozi, D.; Keller, R. A. Can. J .
Chem. 1974, 52, 2889. (b) Darmanyan, A. P.; J enks, W. S. J . Phys.
Chem. A 1998, 102, 7420.
(
15) (a) Saito, I.; Matsuura, T. Tetrahedron Lett. 1970, 4987. (b)
Matsuura, T.; Yoshimura, N.; Nishinaga, A.; Saito, I. Tetrahedron
972, 4933. (c) Mukai, K.; Itoh, S.; Daifuku, K.; Morimoto, H.; Inoue,
K. Biochim. Biophys. Acta 1993, 1183, 323.
1
(22) (a) Weller, A. Z. Phys. Chem. (Muenchen) 1982, 133, 93. (b)
Rehm, A.; Weller, A. Isr. J . Chem. 1970, 8, 259.
(
(
16) Foote, C. S.; Peters, J . W. J . Am. Chem. Soc. 1971, 93, 3795.
17) Clennan, E. L.; Noe, L. J .; Szneler, E.; Wen, T. J . Am. Chem.
(23) (a) Saito, I.; Imuta, M.; Takahashi, Y.; Matsugo, S.; Matsuura,
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Soc. 1990, 112, 5080.
2
334 J . Org. Chem., Vol. 69, No. 7, 2004

Indolizine Photooxygenation Reactions
SCHEME 1
TABLE 2. F MOs of 1a -1ea
compound
energy (eV)
atomic coefficient
1
1
1
1
1
a
b
c
d
e
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
-5.37
-1.41
-4.96
1.54
C1, 0.302 27; C2, -0.034 58; C3, -0.034 58; N4, -0.066 09; C5, 0.223 64;
C6, 0.110 96; C7, -0.202 04; C8, -0.179 78; C9, 0.147 608
C1, 0.173 39; C2, -0.183 12; C3, -0.065 58; N4, 0.197 58; C5, -0.192 28;
C6, -0.022 61; C7, 0.248 92; C8, -0.154 68; C9, -0.167 42
C1, -0.268 07; C2, 0.041 25; C3, 0.273 30; N4, 0.067 71; C5, -0.206 10;
C6, -0.106 44; C7, 0.178 84; C8, 0.161 29; C9, 0.161 29
C1, 0.167 61; C2, -0.197 89; C3, 0.041 66; N4, -0.033 95; C5, 0.024 30;
C6, 0.017 17; C7, -0.038 73; C8, -0.068 64; C9, 0.245 69
-5.32
-3.08
-5.77
-1.97
-5.55
-1.94
C1, 0.304 15; C2, 0.059 44; C3, -0.190 73; N4, 0.117 55; C5, 0.198 66;
C6, 0.163 39; C7, -0.145 27; C8, -0.204 62; C9, 0.081 25
C1, 0.062 18; C2, -0.069 37; C3, -0.013 36; N4, -0.011 27; C5, 0.007 98;
C6, 0.004 20; C7, -0.015 63; C8, -0.032 76; C9, 0.109 00
C1, 0.301 70; C2, -0.050 19; C3, -0.283 16; N4, -0.080 36; C5, 0.203 85;
C6, 0.109 65; C7, -0.182 02; C8, -0,173 31; C9, 0.125 50
C1, -0.041 85; C2, -0.167 78; C3, -0.165 91; N4, -0.207 53; C5, 0.136 72;
C6, -0.081 31; C7, -0.161 40; C8, 0.076 59; C9, 0.126 29
C1, 0.296 75; C2, 0.052 66; C3, -0.293 06; N4, -0.096 20; C5, 0.203 83;
C6, 0.116 36; C7, -0.186 10; C8, -0.171 22; C9, 0.143 72
C1, -0.026 33; C2, -0.148 32; C3, -0.158 61; N4, -0.214 25; C5, 0.145 26;
C6, -0.083 33; C7, -0.172 59; C8, 0.091 26; C9, 0.126 61
a
Only the atomic coefficients for the atoms at the indolizine nucleus are listed.
C3 is always the carbon atom with the highest electron
density and with the largest atomic coefficient in the
HOMO, and it should be the preferential site of attack
by an electrophile such as singlet oxygen. The photooxy-
genation results can be rationalized by the involvement
of peroxidic zwitterion intermediate D (Scheme 1), which
can be formed by electrophilic attack of singlet oxygen
at C3 or derived from preformed perepoxide exciplex C
peroxidic zwitterions D. This is substantiated by a control
experiment in which photolysis of a solution of 1a in
methanol-H O (10:1, v/v) under oxygen purging gave 4a
2
as the sole product.
A possible pathway to zwitterionic intermediate D is
from cyclic perepoxide C (Scheme 1). Figure 1 shows the
FMOs of 1a as an example. In singlet oxygen reactions
1
with alkenes, the HOMO (alkene)-LUMO ( ∆
g 2
O )
(vide infra).
interaction is always predominant over the LUMO (alk-
1
Nucleophilic attack at C3 by methanol and hemolytic
g 2
ene)-HOMO ( ∆ O ) interaction because of the electro-
O-O bond cleavage in zwitterion D resulted in the
formation of 2 and 3. Alternatively, in the aprotic solvent
acetonitrile where zwitterions D could not be protonated,
transformation of D into dioxetane E is favored, and this
is followed by O-O bond homolytic scission to furnish
oxirane 6. This later pathway operates preferentially in
the absence of methanol as a nucleophile when the
reactions are carried out in acetonitrile. Furanones 4 are
formed by cyclization via intramolecular nucleophilic
attack of the carboxy group at the benzoyl carbonyl in
acrylic acid F (Scheme 1), which in turn is formed by
attack of the trace amount of water in the solvent on
philic character of the singlet oxygen. Figure 1 shows
that, in the HOMO of the indolizine, the atomic coef-
ficients at C9 and C3 always have opposite signs, while
those at C2 and C3 are always of the same sign.
Nevertheless, the absolute magnitude at C9 is larger
than that at C2 in all cases. Therefore, FMO interaction
consideration allows the formation of endoperoxide A and
cyclic perepoxide C intermediates (Scheme 1), with the
former being more favored. However, it has been known
that, in singlet oxygen reactions of alkenes, solvent
acidity plays an important role in deciding the [4 + 4]
and [4 + 2] intermediate distribution. Protic solvents
J . Org. Chem, Vol. 69, No. 7, 2004 2335

Li et al.
SCHEME 2
such as methanol, or aprotic solvents with added acid
ion G (Scheme 1) to lead to dimeric product.2,23 In the
case of indolizine, trapping of zwitterion D by methanol
results in C3-N bond cleavage to give the methyl ester
of 3-(2-pyridinyl)propenoate, while, in acetonitrile, the
main products are formed by the thermal decomposition
of the dioxetane intermediate derived from zwitterion D
and endoperoxide A.
In the case of 1d , the benzoyl at C3 in the starting
material is lost in product 2d . This fact can also be
accounted for by the intervention of peroxidic zwitterion
H, which is derived from the electrophilic attack of singlet
oxygen at C3 or from a perepoxide intermediate (Scheme
2). Methanol trapping of zwitterions H (pathway a) or
cleavage of the C3-N bond followed by methanol trap-
ping of tertiary carbocation I (pathway b) and subsequent
O-O bond hemolytic cleavage gave 2d .
Photooxygenations of 1-(p-nitrobenzoyl)-2-phenyl-5-
methylindolizine (1c) and 2-phenyl-3-(p-chlorobenzoyl)-
indolizine (1e) are extremely sluggish with direct irra-
diation of the indolizine in oxygen saturated solution with
light of λ > 400 nm, and they need sensitization. Pre-
sumably, these more electron deficient indolizines are
less reactive than 1a , 1b, and 1d , and higher concentra-
tions of singlet oxygen produced by more efficient sen-
sitizers are needed. Photolysis of 1c with methylene blue
(MB) as a sensitizer in methanol-acetonitrile (1:1, v/v)
gave (E)-3-(6-methyl-2-pyridinyl)-3-(p-nitrobenzoyl)-2-
phenyl arcylate (2c) (35%), its (Z)-isomer 3c (10%), and
furan-2-one 4c (44%) (Table 1). MB sensitized photooxy-
genation of 1e in methanol-acetonitrile (1:1, v/v) fur-
nished ester 2e (73%) together with p-chlorobenzoic acid
(e.g., benzoic acid), promote the formation of the [2 + 2]
intermediate derived from a cyclic perepoxide in equi-
librium with the peroxidic zwitterions, at the cost of the
[
1
4 + 4] intermediate.24 In the photooxygenation of 1a ,
b, and 1d , products directly derived from endoperoxide
A such as B were not found. These results may lend
themselves as further evidence to show that, in the
photooxygenation in methanol, the protic alcoholic sol-
vent favors the formation of cyclic perepoxide C at the
expense of endoperoxide A, while C is in equilibrium with
zwitterions D. In acetonitrile, the involvement of unstable
endoperoxide A could not be excluded, which can also
transform into zwitterions D and dioxetane E.
Here, it is interesting to compare the reaction patterns
in the singlet oxygen reactions of indolizine and indole,
which are isoelectronic to each other and are both
annulated pyrroles. The singlet oxygen reactions of these
two heterocycles share the common mechanistic feature
of having a peroxidic zwitterion as the intervening
intermediate leading to the products. However, since, in
both indolizine and indole, C3 is the carbon atom with
the highest electron density, 1,4-peroxidic zwitterions G
(
1
Scheme 1) are formed in the indole reaction,2,23 while
,6-zwitterion D is formed in the indolizine reaction.
These zwitterions result in different subsequent reaction
pathways. In the case of indole, the peroxidic zwitterion
is intercepted by alcohol to give 2-methoxy-3-indolinone
as a trapping product when the reaction is carried out
in methanol. In acetonitrile, another indole molecule
serves as a nucleophile to attack the C2 atom in zwitter-
(29%). Similar MB sensitized reactions of 1e in acetoni-
trile gave 6e (81%). The singlet oxygen reactions of 1c
follow the same mechanism as those of 1a and 1b
(Scheme 1), while the reaction of 1e takes place by a
similar pathway to that of 1d (Scheme 2).
The participation of singlet oxygen in these reactions
was further substantiated by a quenching experiment.
The photooxygenation of 1 was found to be quenched by
1
added DABCO as a
g 2
∆ O physical quencher. In the
-
3
-1
presence of 5 × 10 mol L DABCO, the photooxygen-
ation was completely quenched.
In contrast to 1a -1e, 1,3-disubstituted indolizine 1f
is inert toward singlet oxygen and cannot undergo
photooxygenation under either self-sensitized or RB/MB
F IGURE 1. FMOs of 1a . Atomic orbital coefficients in the
HOMO (the upper number) and LUMO (the lower number).
(24) Greer, A.; Vassilikogiannakis, G.; Lee, K. C.; Koffas, T. S.;
Nahm, K.; Foote, C. S. J . Org. Chem. 2000, 65, 6876.
2
336 J . Org. Chem., Vol. 69, No. 7, 2004

Indolizine Photooxygenation Reactions
F IGURE 2. (a) Charge and (b) spin density distributions in the cation radical of 1f•+
.
SCHEME 3
sensitized conditions. However, we have found that 1f
can be smoothly photooxygenated with 9,10-dicyanoan-
thracene (DCA) as a sensitizer under electron transfer
The formation of products 7f-9f could be rationalized
by the electronic structure in the cation radical of 1f. We
•+
have calculated the charge and spin densities in 1f with
the DFT method at the UB3LYP 6-31G level, and the
results are given in Figure 2. One can see that C3 is the
carbon atom with the largest spin density and should be
the preferential site for radical pair recombination with
the superoxide anion radical. This leads to zwitterions
N (Scheme 3), which upon methanol trapping and O-O
bond homolysis furnish 7f and 8f. A possible mechanism
of the formation of 9f may involve methanol trapping of
the carbocation at C5 and further oxidation of the radical
center in J into carbocation K followed by proton loss to
furnish methoxy-substituted indolizine 10, which is an
even better electron donor than 1f. Further electron
conditions.2
5,26
Photolysis of 1f (0.025 mol L ) in the
-1
-4
-1
presence of DCA (10 mol L ) in methanol-acetonitrile
1:1, v/v) under oxygen atmosphere gave the nucleus
(
oxidized methyl 3-benzoyl-8-hydroxy-5-methoxyindoliz-
ine-1-carboxylate (9f) (27%) and a mixture of dimethyl
2
-(2-pyridinyl)maleate (7f) and dimethyl 2-(2-pydidinyl)-
fumarate (8f) (total yield 63%, isomer ratio ∼ 97:3).
Although in oxygen saturated solutions DCA can sensi-
tize the formation of singlet oxygen via energy transfer
from both DCA* and 3DCA* to triplet oxygen, the
active oxygen species in the DCA sensitized photooxy-
genation of singlet oxygen inert 1f is the superoxide anion
radical formed by electron transfer from the DCA anion
radical to triplet oxygen which is exothermic for -5 kcal
1
26
1
•+
•-
transfer from 10 to DCA* and subsequent 10 -O
2
recombination (or, alternatively, trapping of the radical
center in 10 by triplet oxygen) followed by proton loss
-
1 25c
•+
mol
.
gave hydroperoxide L, and O-O bond homolysis in L
resulted in the formation of product 9f.
(
25) (a) Kanner, R. C.; Foote, C. S. J . Am. Chem. Soc. 1992, 114,
82. (b) Eriksen, J .; Foote, C. S. J . Am. Chem. Soc. 1980, 102, 6083.
c) Eriksen, J .; Foote, C. S.; Parker, T. L. J . Am. Chem. Soc. 1977, 99,
455.
26) (a) Foote, C. S. Tetrahedron 1985, 41, 2221. (b) Araki, Y.;
6
(
6
In summary, singlet oxygen reactions of indolizines
2
a -2e, with 1,2-, 2,3-, and 1,2,3-substituents, follow the
(
general reaction pattern by initial attack of singlet
oxygen at the C3 atom in indolizine to give a 1,6-peroxidic
zwitterion intermediate. However, subsequent reaction
pathways and products are decided by the solvent. In
Dobrowolski, D. C.; Goyne, T. E.; Hanson, D. C.; J iang, Z. Q.; Lee, K.
J .; Foote, C. S. J . Am. Chem. Soc. 1984, 106, 4570. (c) Kanner, R. C.;
Foote, C. S. J . Am. Chem. Soc. 1992, 114, 678. (d) Mattes, S. L.; Farid,
S. J . Am. Chem. Soc. 1986, 108, 7356.
J . Org. Chem, Vol. 69, No. 7, 2004 2337

Li et al.
methanol, this peroxidic zwitterion is intercepted by the
alcohol at the C3 atom to lead to C3-N bond cleavage to
furnish the methyl 3-(2-pyridinyl)propenoates. In aceto-
nitrile, dioxetane in equilibrium with the peroxidic zwit-
terion is the intervening intermediate leading to the
products. O-O bond homolysis in the dioxetane gives
P h otooxygen a tion of 1a w ith Ligh t of λ > 300 n m .
Photolysis of a solution of 1a (1.00 g, 3.2 mmol) in MeOH-
MeCN (130 mL, 1:1, v/v) with light of λ > 300 nm with oxygen
purging for 9 h (100% conversion) and workup as before gave
2
a (286 mg, 25%), 3a (275 mg, 24%), and 4a (418 mg, 38%).
P h otooxygen a tion of 1b. (a ) In MeCN-MeOH. Photoly-
sis of 1b (1.53 g, 4.5 mmol) in MeCN-MeOH (180 mL, 1:1,
v/v) under oxygen purging for 8 h (100% conversion) gave 2b
(488 mg, 28%), 3b (557 mg, 32%), and 4b (151 mg, 9%).
3
-(2-pyridinyl)-2-oxiranecarboxaldehyde as the product.
Electron deficient and singlet oxygen inert 1f can be
photooxygenated under electron transfer conditions via
its cation radical to give the 2-(2-pyridinyl)-2-butenedioic
acid dimethyl esters and pyridine ring oxidized 8-hy-
droxy-5-methoxyindolizine.
(
b) In MeCN. Photolysis of 1a (1534 mg, 4.5 mmol) in
MeCN (180 mL) under oxygen purging for 10 h (100%
conversion) gave 5b (126 mg, 11%) and 6b (1041 mg, 62%).
P h otooxygen a tion of 1c. (a ) In MeCN-MeOH. Irradia-
tion of a MeCN-MeOH solution (180 mL, 1:1, v/v) of 1c (0.800
g, 2.25 mmol) and MB (30 mg) with oxygen purging for 8 h
Exp er im en ta l Section
(100% conversion) gave 2c (317 mg, 35%), 3c (100 mg, 11%),
Gen er a l P r oced u r es for th e P h otooxygen a tion of 1a -
and 4c (384 mg, 44%). Compound 2c can be isomerized to 3c
on a silica gel column. Therefore, the two compounds were
collected together as one fraction during the chromatographic
separation. The yields given here are determined from the H
NMR spectrum of the product mixture.
1
f. The light source was a medium-pressure mercury lamp (500
W) in a cooling water jacket which was further surrounded
by a filter solution (1 cm thickness, 10% aq sodium nitrite for
λ > 400 nm and 10% aq potassium dichromate for λ > 500
1
-1
nm). The solution of indolizines (0.025 mol L ) in acetonitrile
(b) In MeCN. Irradiation of a MeCN solution (120 mL) of
1c (1.00 g, 2.81 mmol) and RB (30 mg) with oxygen purging
for 12 h (100% conversion) gave 5c (150 mg, 20%) and 6c (320
mg, 31%).
P h otooxygen a tion of 1d . (a ) In MeCN-MeOH. Photoly-
sis of 1d (0.900 g, 2.25 mmol) in MeCN-MeOH (180 mL, 1:1,
v/v) with oxygen purging for 12 h (100% conversion) gave 2d
(548 mg, 71%).
(b) In MeCN. Photolysis of 1d (0.900 g, 2.25 mmol) in
MeCN (180 mL) with oxygen purging for 14 h (100% conver-
sion) gave 6d (877 mg, 90%)
P h otooxygen a tion of 1e. (a ) In MeCN-MeOH. Irradia-
tion of a MeCN-MeOH solution (180 mL, 1:1, v/v) of 1e (0.773
g, 2.25 mmol) and MB (30 mg) with oxygen purging for 10 h
(100% conversion) gave 2e (393 mg, 73%).
(b) In MeCN. Irradiation of a MeCN solution (180 mL) of
1e (773 mg, 2.25 mmol) and MB (30 mg) with oxygen purging
for 11 h (100% conversion) gave 6e (439 mg, 81%).
P h otooxygen a tion of 1f. In MeCN-MeOH. Irradiation
of a MeCN-MeOH solution (180 mL, 1:1, v/v) of 1f (627 mg,
2.25 mmol) and DCA (10 mg) with oxygen purging for 20 h
(64% conversion) gave 7f and 8f (201 mg, 63%, 7f/8f ) 97:3)
and 9f (126 mg, 27%).
or acetonitrile-methanol (1:1, v/v) was placed in glass tubes
30 mL each) and was irradiated at room temperature under
(
continuous oxygen purging. Photooxygenation of 1a , 1b, and
d was self-sensitized, 1c and 1e were sensitized by RB or
MB, while lf was sensitized by DCA. At the end of the reaction
TLC monitoring), the solvent was removed in vacuo and the
residue was separated by chromatography on a silica gel
column except in the case of photooxygenation of 1a in MeCN,
where the reaction mixture was separated by preparative thin-
layer chromatography at a temperature below 5 °C to afford
products 5a and 6a . The reaction scale, irradiation time, and
yields of the products are given below.
1
(
Deter m in a tion of F lu or escen ce Qu a n tu m Yield of
Com p ou n d s 1b, 1d , a n d 1f. The fluorescence quantum yields
of compounds 1a , 1d , and 1f were determined on a fluorescence
spectrophotometer in acetonitrile solution with 9,10-diphenyl-
anthracene (Φ ) 0.95) as a standard. Phosphorescence spectra
F
of 1a , 1d , and 1f were measured on the same spectrophotom-
eter in acetonitrile at 77 K.
Electr on ic Sp ectr a of 1a in th e P r esen ce a n d Absen ce
of Oxygen . An acetonitrile solution of 1a (0.028 M) was
divided into two parts. Through one solution was purged dry
oxygen for 1 h, and through the other solution was purged dry
argon for 1 h. The electronic spectra of these two solutions
were then measured in the 495-600 nm region.
3
Cr ysta l Str u ctu r e of Com p ou n d 2a . C23H19NO , M )
357.39. Monoclinic, space group C2/c with R ) 90.00°, â )
92.2420 (10)°, γ ) 90.00°, a ) 8.3158 (4) Å, b ) 15.9641 (7) Å,
3
Ca lcu la tion Meth od . FMOs of compounds 1a -1e are
calculated by the DFT method at the B3LYP 6-31G level, and
the charge and spin densities in the cation radical of 1f are
calculated by the DFT method at the UB3LYP 6-31G level with
c ) 28.9518 (13) Å, V ) 3840.5 (3) Å , Z ) 8, D
c
) 1.236 g
-3
-1
cm , µ ) 0.082 mm , and F(000) ) 1504. A colorless prismatic
3
crystal of 0.7 × 0.5 × 0.24 mm was used. Data were collected
on an area detector diffractometer with graphite monochro-
mated Mo KR (λ ) 0.710 73 Å) radiation in the range 2θ )
2.55-28.28°. The structure was solved by the direct method
(SHELXL-97) and refined on F2 by the full-matrix least-
squares method. A total of 4695 independent reflections [R(int)
) 0.0159 ] were used in the refinement which converged with
2
7
Gaussian 98 6.0 A.
P h otooxygen a tion of 1a . (a ) In MeCN-MeOH. Photoly-
sis of 1a (1.40 g, 4.5 mmol) in MeCN-MeOH (180 mL, 1:1,
v/v) under oxygen purging for 9 h (100% conversion) gave 2a
(
353 mg, 22%), 3a ( 369 mg, 23%), and 4a (617 mg, 40%).
b) In MeCN. Photolysis of 1a (0.600 g, 1.9 mmol) in MeCN
180 mL) under oxygen purging for 10 h (100% conversion)
(
R ) 0.0514 and R
Cr ysta l Str u ctu r e of Com p ou n d 4a . C22
343.37. Monoclinic, space group P21/c with R ) 90.00°, â )
0.600 (1)°, γ ) 90.00°, a ) 17.5447 (1) Å, b ) 10.6953 (1) Å,
w
) 0.1270.
(
H
3
17NO , M )
gave 5a (112 mg, 25.3%) and 6a (423 mg, 63.7%).
9
3
(27) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
c ) 18.3776 (2) Å, V ) 3448.29 (5) Å , Z ) 8, D ) 1.327 g
c
-3
-1
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Rega, N.; Salvador, P.; Dannenberg, J . J .; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .;
Ortiz, J . V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen, W.; Wong, M.
W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,
J . A. Gaussian 98, revision A.11.3; Gaussian, Inc.: Pittsburgh, PA,
cm , µ ) 0.088 mm , and F(000) ) 1448. A colorless prismatic
3
crystal of 0.32 × 0.22 × 0.14 mm was used. Data were
collected on an area detector diffractometer with graphite
monochromated Mo KR (λ ) 0.710 73 Å) radiation in the range
2θ ) 2.50-28.50°. The structure was solved by the direct
method (SHELXL-97) and refined on F2 by the full-matrix
least-squares method. A total of 5972 independent reflections
[
R(int) ) 0.1201] were used in the refinement which converged
with R ) 0.0721 and R ) 0.1730.
w
Ack n ow led gm en t. This work was supported by the
2
002.
National Natural Science Foundation of China (NSFC,
2
338 J . Org. Chem., Vol. 69, No. 7, 2004

Indolizine Photooxygenation Reactions
0072017) and the Specialized Research Fund for the
DoctoralProgramofHigherEducation(SRFDP,20010284033).
Partial support by the Modern Analytical Center at
Nanjing University is also gratefully acknowledged.
2
3b, 5a , 6d , and 9f, analytical and spectroscopic data for all
new compounds, H NMR spectra of all photooxygenation
products, 13C NMR of 6c, UV spectra of compounds 1a and
1b, UV spectra of 1a in the presence and absence of oxygen,
and phosphorescence spectra of 1b, 1d , and 1f. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal conditions, crystallographic information files of compounds
2
a , 4a , 3b, 3c, and 2d , crystallographic structure of 2a , 3a ,
J O035070D
J . Org. Chem, Vol. 69, No. 7, 2004 2339