Photooxygenation of indolizines via selective excitation of their charge transfer complexes with molecular oxygen

Full text of DOI:10.1021/jo015769o

8230
J . Org. Chem. 2001, 66, 8230-8235
air exposure. However, thermal oxidation reactions usu-
P h otooxygen a tion of In d olizin es via
Selective Excita tion of Th eir Ch a r ge
Tr a n sfer Com p lexes w ith Molecu la r
Oxygen
ally result in deep oxidation with ring fission and
extensive C-C bond cleavage to give R-picolinic acid
derivatives.8 These reactions have therefore mainly
been used for the purpose of structural elucidation.
Photoinduced oxygenation reactions of indolizines, on the
other hand, have not been investigated. Many organic
compounds are known to interact with ground-state
molecular oxygen to form contact charge transfer (CT)
complexes9 which are characterized by the occurrence
of new long wavelength absorption in the electronic
spectrum of the substrate’s oxygen-saturated solution in
inert solvent which reversibly disappears when oxygen
is excluded from the solution. Although there is no
substantial charge separation in these weakly bound
ground-state complexes, excitation of them leads to the
formation of excited CT complex with profound ion-
radical pair character.9 The chemical consequences of the
excitation of the contact CT pair of different organic
substrates with oxygen and the formation of excited CT
complex are interesting in view of exploring diversified
reaction pathways of the substrate cation radicals.
However, photochemistry resulting from the excitation
of CT complexes with oxygen have not been extensively
explored,10 although it has been reported that in a few
favorable cases photooxygenation reactions of the sub-
strates (e.g. amines,11 ethers,12 polymethylbenzenes,13
and other electron rich compounds14) can result. We
report here photooxygenation reactions of indolizine
derivatives 1a -d in mixed solvents benzene-methanol
which proceed via the selective excitation of their ground-
state CT complex with molecular oxygen by long wave-
length irradiation. In contrast to thermal oxidation
reactions, under our conditions, mild oxidation without
C-C bond cleavage takes place to give R-phenyl-â-(2-
pyridinyl)propenoic acids 4 and their methyl esters 2 and
3 as main products.
J ing-Zhi Tian,† Zhao-Guo Zhang,‡ Xiao-Liang Yang,†
Hoong-Kun Fun,§ and J ian-Hua Xu*,†
Department of Chemistry, Nanjing University,
Nanjing 210093, China, Institute of Organic Chemistry,
Academia Sinica, Shanghai, 200032, China, and X-ray
Crystallography Unit, School of Physics, Universiti Sains
Malaysia, 11800, USM, Penang, Malaysia
xujh@nju.edu.cn
Received May 18, 2001
Indolizines have 10 π-electrons and are isoelectronic
with indole and naphthalene. However, the bridgehead
nitrogen atom has drastic influence on the properties of
the two constituted rings. Being nonalternant and hetero-
aromatic, indolizine inherently has a large dipole moment
(1.3 D)1 that renders the pyrrole ring to behave as
electron rich and the pyridine ring as electron poor. Due
to their special electronic structure, their high fluores-
cence efficiency,2 and the fact that their partially and
fully hydrogenated derivatives make up a large group of
naturally occurring alkaloids,3 indolizines have been of
theoretical and practical interest, and calculations at
different levels of sophistication on their ground state and
excited-state electronic structures1,4 and synthesis5,6 as
well as reactions6 have been widely investigated and
reviewed.6 Indolizine is among the most π-electron exces-
sive heteroaromatics, has a very low ionization potential
(7.15 eV7), and as such behaves as a strong nucleophilic
substrate in most chemical reactions. They are also
susceptible to oxygen attack and are easily oxidized upon
* Corresponding author.
† Nanjing University.
‡ Academia Sinica.
§ Universiti Sains Malaysia.
(1) (a) Glier, C.; Dietz, F.; Scholz, M.; Fischer, G. Tetrahedron 1972,
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10, 499.
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10.1021/jo015769o CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8231
Ta ble 1. P h otooxygen a tion s of th e In d olizin es 1a -d via
th e Excita tion of Th eir CT Com p lex w ith Molecu la r
Oxygen a
irradiation conversion
products and yields
(%)b
substrate
time (h)
(%)
1a
1b
1c
1d
10
10
8
100
100
100
100
2a (29), 3a (26), 4a (17)
2b (25), 3b (23), 4b (12)
2c (26), 3c (25), 4c (19)
2d (20), 3d (23), 4d (18)
8
a
b
[substrate] ) 0.025 M. Yield based on consumed 1.
(26%), and 4a (17%) as products. The two esters 2a and
3a are viscous oils. The Z-configuration of 2a was
established by a 1H NMR NOESY measurement of the
corresponding Z-2d (vide infra) which revealed the steric
proximity of olefinic proton H3 with the pyridine proton
at C(3′) (formula 2) and the phenyl protons. The spec-
troscopic data of the ester 3a are closely parallel to that
of the acid 4a , and their E-configuration was further
confirmed by an X-ray crystallographic analysis of prod-
uct 4c (vide infra).
F igu r e 1. UV spectrum of CTC complex of 1a . Curve a:
oxygen-saturated solution of 1a in benzene. Curve b: oxygen-
free solution of 1a in benzene.
1
Main difference in the H NMR of the Z- and E-esters
is in the absorption of the olefinic proton H3. In the
Z-isomer, H3 resonates at ≈6.9 ppm, while in the E-
isomer, the absorption of this proton moves downfield for
about 1 ppm to occur at ≈7.9 ppm due to the deshielding
effect of the nearby carbonyl and the pyrridine ring.
Irradiation of benzene-methanol (1:1, v/v) solution of
compounds 1b-d under same conditions as mentioned
for 1a gave similar results with the Z- and E-esters 2b-
d , 3b-d , and the E-acids 4b- d as products respectively
(Table 1).
Resu lts a n d Discu ssion
For compound 1a , the absorption caused by the transi-
tion from its ground-state CT complex with molecular
oxygen to the excited CT complex can be measured by
direct recording the UV spectra of oxygen saturated and
oxygen free solutions of the indolizine, respectively. This
is shown in Figure 1 with 1a as an example. This CTC
absorption could also be measured by differential method.
Solutions of same concentration (5 M) of 1a in benzene
were placed in the sample and reference cells in a UV
spectrometer. When the sample solution was saturated
with oxygen and the reference solution was oxygen-free,
a broad absorption band occurred in the electronic
spectrum in the region 450-600 nm. This band disap-
pears on extruding oxygen from the solution in the
sample cell by purging dry argon. For compounds 1b, 1c,
and 1d , this measurement of the differential spectrum
of the ground-state CT complexes with oxygen was
hampered by their limited solubility in benzene and in
other common solvents. In these cases, due to the
small concentration of the substrates, the CT complex
concentration may be too low for their absorption to be
measured.
Since compounds 1a -d have no measurable absorption
in the wavelength region used for photolysis, these
photooxygenations could not have proceeded via direct
excitation of the indolizines. At the same time, as shown
in Figure 1 for 1a , ground-state CT complex absorbs in
this region. Therefore, they can be ascribed to take place
by the excitation of the contact CT complex which
resulted in the formation of the excited CT complex, i.e.,
the indolizene’s cation radicals and superoxide anion
radicals. Both theoretical and experimental studies have
shown that the excited CT complex are coupled with a
suite of other electronic states of the substrate-O2
complex.9,15 Based on thermodynamic considerations, the
possibility to transform to triplet substrates and singlet
oxygen (1∆g) can be ruled out. Nevertheless, transforma-
tion to triplet indolizines and ground-state oxygen may
be possible.16 Following the formation of the triplet
Irradiation of a benzene solution of 1a with light of
wavelength longer than 400 nm led to continuous con-
sumption of the starting material but resulted in a
complex intractable black tarry material from which no
discrete products can be isolated in significant amounts.
However, when the photolysis was carried out in benzene-
methanol (1:1, v/v) with methanol as a nucleophile, the
reaction proceeded smoothly, and gave 2a (29%), 3a
indolizines, energy transfer with ground state (3∑g
)
-
oxygen would yield singlet oxygen. The excited CT
complex, after relaxing to ion radical pairs, could also
undergo further dissociation into solvent separated ion
radical pairs and free ions. In this case, the indolizine
(15) (a) Tsubomura, H.; Mullikm, R. S.J . Am. Chem. Soc. 1960, 82,
5966. (b) Birks, J . B.; Pantos, E.; Hamilton, T. D. S. Chem. Phys. Lett.
1973, 20, 544. (c) Kawaoka, K.; Khan, A. U.; Kearns, D. R. J . Chem.
Phys. 1967, 46, 1842. (d) Kawaoka, K.; Khan, A. U.; Kearns, D. R. J .
Chem. Phys. 1967, 47, 1883. (e) Khan, A. U.; Kearns, D. R. J . Chem.
Phys. 1968, 48, 3272. (f) Murrell, J . N. Mol. Phys. 1960, 3, 319. (g)
Scurlock, R. D.; Ogilby, P. R. J . Am. Chem. Soc. 1988, 110, 640.
(16) The energy of the blue edge of the ground-state CTC absorption
(Figure 1) is ∼72 kcal mol-1. The triplet energy (ET) of indolizine
and 2-phenylindolizine have not been reported since they have
no detectable phosphorescence either at room temperature or at
77 K. Nevertheless, these ET values should be lower than 72 kcal
(11) Tsubomura, H.; Yagishita, T.; Toi, H. Bull. Chem. Soc. J pn.
1973, 46, 3051.
(12) (a) Stenberg, V. I.; Olson, R. D.; Wang, C. T.; Kulevsky, N. J .
Org. Chem. 1967, 32, 3227. (b) Von Sonntag, C.; Newwald, K.;
Schuchmann, H.-P.; Weeke, F.; J anssen, E. J . Chem. Soc., Perkin
Trans. 2. 1975, 171.
(13) Onodera, k.; Furusawa, G.-I.; Kojima, M.; Tsuchiya, M.; Aihara,
S.; Akaba, R.; Sakuragi, H.; Tokumaru, K. Tetrahedron 1985, 41, 2215
and references therein.
(14) (a) Kulevski, N.; Sneeringer, P. V.; Stenberg, V. I. J . Org. Chem.
1972, 37, 438. (b) Kojima, M.; Sakuragi, H,; Tokumaru, K. Bull. Chem.
Soc. J pn. 1987, 60, 3331.
mol-1 considering that 2-phenylindolizine has a singlet energy of
1
74 kcal mol-1. At the same time, the energy of the
22.1 kcal/mol.
∆ oxygen is
g

8232 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
Sch em e 1
hydrogen atom summing up to the corresponding carbon
atom, C3 and C5 are the most positively charged carbon
atoms in the indolizine ring. Reaction outcomes in the
photooxygenations are in full accord with these structural
features of the indolizine’s cation radical. The reaction
mechanisms for this cation radical route are outlined in
Scheme 1. In-cage indolizine cation radical-superoxide
anion radical coupling or triplet oxygen attack at C3 in
the cation radical (C), escaped out-of-cage from the triplet
ion radical pairs, furnishes the zwitterionic peroxidic
intermediate D. This was followed by nuleophilic trap-
ping of the cation center by methanol to give the peroxide
intermediate E, in which the homolytic scission of the
O-O bond furnishes products 2 and 3. The acids 4 may
be obtained by trapping of the cation center in D by the
trace amount of water in the solvent.
In the second reaction route, substrate may react with
singlet oxygen formed either by energy transfer between
triplet indolizine and ground-state oxygen or by back
electron transfer in the singlet ion radical pairs formed
after the intersystem crossing.9,15 To test the reactivity
of the indolizines 1 toward singlet oxygen, we have
investigated reactions of the substrate 1a with singlet
oxygen thermally generated in two different ways: (1)
mixing of hydrogen peroxide-sodium hypochlorite23 and
(2) thermal decomposition of the 9,10-diphenylanthracene
endoperoxide.24 It was found that, although 1a could not
react with either hydrogen peroxide or sodium hyper-
chlorite alone, it is oxidized by the mixture of the two in
aqueous methanol to give the ester 2a (19%) and the acid
4a (17%) as products. Compound 1a could also be
oxidized when heating with 9,10-diphenylanthracene
endoperoxide in a benzene solution. After treating the
reaction mixture with diazomethane, the ester 4a (48%)
cation radicals can be trapped by ground state oxygen
in the bulk solution. As a third possibility, the triplet ion
radical pairs initially formed in the excitation of the
ground-state CT complex may undergo back electron
transfer after intersystem crossing to give ground-state
indolizine and singlet oxygen.9,15 Summing up, two pos-
sible reaction pathways may be operative in these
photooxygenationssthe ion radical route and the singlet
oxygen route.
In the first reaction pathway, the cation radicals
escaping out of solvent cage can be trapped at the radical
center by molecular oxygen and at the cation center by
methanol.
As has been repeatedly shown by both electronic
structure calculations4 and by many reactions of electro-
philes with indolizines, e.g., in protonation,17 nitration
and nitrosation,18 acylation,19 oxidative dimerization,20
coupling reactions with electron acceptors such as methyl
acrylate21 and tetracyanoethene (TCNE),22 etc., the pyr-
role ring is more electron rich than the pyridine ring and
is the site of attack by electrophiles. In all these reactions,
nucleophilic reactivity at the indolizine ring is found to
decrease in the order 3 > 1 . 5. Theoretical calculations
on indolizine ground-state electronic structure have given
contradictory results concerning the electron density at
different sites at the pyrrole ring,4 but all these calcula-
tions uniformly confirm that the pyrrole ring shares the
majority of the π-electron density. Therefore, indolizine
could be described by the structures A and B with A
being more favorable. Loss of one electron from the
neutral molecule leads to the formation of the cation
radicals which can consequently be envisaged to have
the structure shown by C (see Scheme 1). Our AM1
calculations of the spin density and charge density in the
cation radicals of 1b have substantiated this situation
and show that the spin density distribution in the cation
radical of 1b is indeed largely concentrated at C3 and to
a less extent, at C1 (Figure 2). Meanwhile, the three
carbon atoms directly linked to the nitrogen atom (C3,
C5, and C9) are the least negatively charged or positively
charged (C5 and C9), and with the charge density at the
was obtained as product.
To further test the involvement of
1
∆ O2 in the
g
photooxgenations, singlet oxygen quenching experiments
with DABCO as a physical quencer25 have been carried
out. It is found that, the photooxygenation of 1a (0.02
M, MeOH) could be quenched by DABCO in different
degrees, depending on the concentration of DABCO.
Therefore, while the presence of DABCO at a concen-
tration of 0.05 M causes only a slight quenching (5%) of
the photooxygenation, a [DABCO] of 0.25 M results in a
1
33% quenching. These results show that
∆ O2 is
g
involved in the photooxygenations. In these singlet
oxygen reactions, the same zwitterionic peroxidic inter-
mediate D shown in Scheme 1 could also be formed by
electrophilic attack of singlet oxygen at C3 or derived from
the endoperoxide F and the perepoxide intermediate H.
Upon trapping by methanol, this peroxide gave products
2, 3, and 4. Since the reactions of 1a with thermally
generated singlet oxygen gave similar products as in the
photooxygenations via the CTC excitation (although in
different product ratio), it is difficult to assess the relative
contributions of the radical cation pathway and the
singlet oxygen pathway. However, it is worth noting that,
although in the singlet oxygen reactions of electron rich
N-containing heterocycles26 which can be viewed as
conjugated enamines, dioxetane27 derived from [2 + 2]
(17) Fraser, M.; Mckenzie, S.; Reid, D. H. J . Chem. Soc. B 1966, 44.
(18) (a) Greci, L.; Ridd, J . H. J . Chem. Soc., Perkin Trans. 2 1979,
312. (b) Hickman, J . A.; Wibberlay, D. G. J . Chem. Soc., Perkin Trans.
1 1972, 2954.
(19) Babaev, E. V.; Babrovskii, S. I.; Bundel, Yu. G. Khim. Geterotsikl.
Soedin. 1988, 1570; Chem. Abstr. 111, 97031g.
(20) Andruzzi, R.; Cardellini, L.; Greci, L.; Stipa, P.; Poloni, M.;
Trazza, A. J . Chem. Soc., Perkin Trans. 1 1988, 3067.
(21) Yamashita, Y.; Suzuki, D.; Masumura, M. Heterocycles 1984,
22, 791.
(23) Collins, D. J .; Hobbs, J . J . Aust. J . Chem. 1967, 20, 1905.
(24) Wasserman, H. H.; Scheffer, J . R. J . Am. Chem. Soc. 1967, 89,
3073.
(25) (a) Ouannes, C.; Wilson, T. J . Am. Chem. Soc. 1968, 90, 6527.
(b) Monroe, B. M. J . Phys. Chem. 1977, 81, 1861.
(26) George, M. V.; Bhat, V. Chem. Rev. 1979, 79, 447.
(22) Ceder, O.; Hall, B. J . Heterocycl. Chem. 1978, 15, 1471.

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8233
F igu r e 2. (a) Spin density of distribution in the cation radical of 1b. (b) Charge density distribution in the cation radical of 1b
(the values in parentheses are the charge densities at the hydrogen atoms).
cycloaddition of singlet oxygen to the CdC bond and
It is also noted that, direct exciation of the indolizine
monomer in benzene-methanol (1:1, v/v) with light of λ
> 300 nm also gives the same products as in the selective
excitation of the CTC complex with oxygen, however, in
significantly lower yields. As an example, photolysis of
1a (0.025M) in oxygen saturated PhH-MeOH (1:1, v/v)
solution for 10 h led to total conversion of the starting
material and afforded 2a (21%), 3a (22%), and 4a (17%).
Here excitation of 1a monomer and CTC of 1a with
oxygen occur concomitantly, and besides the mechanism
shown in Scheme 1, other mechanistic possibilities arise.
(1) Energy transfer from S1 or T1 state of 1a to ground-
1
endoperoxide28 derived from [4 + 2] cycloaddition of ∆g
O2 with the conjugated diene are well-recognized inter-
mediates along with the zwitterionic peroxide (as D), yet
we have not found any products such as 5 and 6 which
are derived from the endoperoxide (F ) and the dioxetane
(G) intermediates in the photooxygenation reactions. This
raises the possibility that singlet oxygen may serve as
electron acceptor to initiate SET process with the in-
dolizines as electron donors. Charge-transfer quenching
1
of ∆g O2 by strong electron donors such as enamines,29
amines,30 phenols,31 sulfides,32 hydrazines,33 etc., have
been reported. In polar solvents, full SET may be resulted
to give the substrate’s cation radical and superoxide
anion radical30c,d which may take part in further reactions
to give products.30f
1
state oxygen to generate ∆g O2. (2) SET from the singlet
excited 1a to ground-state oxygen to give the cation
radical of 1a and the superoxide anion radical which
subsequently react to give the products.34 Therefore, 1∆g
O2 and superoxide anion radicals (O2-•) are still the active
oxygen species responsible for the oxygenations.
In summary, selective excitation of the contact charge-
transfer complex between the indolizines 1a -d and
triplet oxygen in benzene-methanol (1:1, v/v) resulted
in mild oxidation of the substrate to give 3-(2-pyridinyl)-
2-phenylacrylic acids and their esters as products without
C-C bond cleavage in the substrate.
Exp er im en ta l Section
As enamines with highly extended π-system, indol-
ox
izines 1a -d have very low oxidation potentials (E of
1/2
Melting points were measured on
a Yanaco microscopic
1b is 0.737V, SCE, MeCN7). Also, the photooxygenations
have proceeded in a highly polar solvent system. There-
fore, SET from the substrates 1a -d to 1∆g O2 is a
possibility that should be taken into consideration in
the photooxygenation of 1a -d , and in case these SET
processes take place, the overall reactions can be ac-
counted for by a unified mechanistic picture involving
the cation radicals of the indolizines (C) as the reactive
intermediates shown in Scheme 1.
1
melting point apparatus and are uncorrected. H NMR spectra
were recorded on a Bruker spectrometer at 300 MHz with CDCl3
as internal standard and solvent. J -Values are given in Hz. IR
spectra were taken with a Shimadzu IR 440 spectrometer for
samples in KBr pellets. Mass spectra were recorded with a VG
ZAB-HS spectrometer. Elemental analyses were obtained using
(34) The thermodynamic feasibility of this SET process can be
estimated by the Weller equation35 which takes the form of eq 1 in a
∆GET ) E1/2ox(D/D+•) - E1/2red(O2/O2-•) - 3.21 - e2/ꢀ
(1)
ox
(27) (a) Bartlett, P. D.; Schaap, A. P. J . Am. Chem. Soc. 1970, 92,
3223. (b) Wasserman, H. H.; Terao, S. Tetrahedron Lett. 1975, 1735.
(c) Orito, K.; Manske, R. H.; Rodrigo, R. J . Am. Chem. Soc. 1974, 96,
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(28) (a) Foote, C. S.; Lin, J . W.-P. Tetrahedron Lett. 1968, 3267. (b)
Matsuura, T.; Saito, I. Tetrahedron Lett. 1968, 3273. (c) Dewer, M. J .
S.; Thiel, W. J . Am. Chem. Soc. 1975, 97, 3978.
polar solvent where E1/2 is the halfwave oxidation potential of
7
the indolizine (0.737 V for 1b, vs SCE, MeCN. Value vs Ag/AgNO3
red
was transformed to that vs SCE by adding 0.337V36), E1/2
(O2/O2-•) is the halfwave reduction potential of triplet oxygen
(0.75 V, SCE, MeCN),37 3.21 is the excitation energy of the
indolizine 1b, and the last term takes into account of the
Coulombic interaction between the ion radicals which is 0.06 eV
in MeCN, assuming an interionic separation of 7 Å.35b The ∆GET
value for 1b in MeCN is -1.78 eV (-41 kcal/mol), indicating that
SET is highly exergonic. Although this estimation is made in
MeCN, this large negative ∆GET value strongly suggests that in
MeOH-PhH (1:1, v/v) which is also highly polar, SET between
singlet excited indolizine and ground-state oxygen could be
energetically feasible (The value of the e2/ꢀ term is usually small
in a polar solvent system).
(29) Foote, C. S.; Dzakpasu, A. A.; Lin, J . W.-P. Tetrahedron Lett.
1975, 1247.
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Keller, R. A. Can. J . Chem. 1974, 52, 2889. (c) Manring, L. E.; Foote,
C. S. J . Phys. Chem. 1982, 86, 1257. (d) Saito, I.; Matsuura, T.; Inoue,
K. J . Am. Chem. Soc. 1983, 105, 3200. (e) Darmanyan, A. P.; J enks,
W. S.; J ardon, P. J . Phys. Chem. A 1998, 102, 7420. (f) Ferroud, C.;
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hedron 1972, 28, 4933.
(35) (a) Weller, A. Z. Phys. Chem. (Wiesbaden) 1982, 133, 193. (b)
Rehm, D.; Weller, A. Isr. J . Chem. 1970, 8, 259.
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8234 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
a Perkin-Elmer 240 C analyzer. Benzene (AR grade) was dried
with sodium and distilled before use. Methanol was treated with
magnesium and distilled before use. Other reagents were CP or
AR grade and were used as received without further purification.
Petroleum ether refers to the fraction with boiling point in the
range 60-90 °C.
Gen er a l P r oced u r es. 1. Mea su r em en t of th e Absor p tion
Sp ectr u m of th e Gr ou n d -Sta te Ch a r ge-Tr a n sfer Com p lex
betw een 1a a n d Oxygen . (a ) UV Sp ectr u m of th e Oxygen -
Sa tu r a ted Solu tion of 1a in Ben zen e. The oxygen-saturated
and oxygen-free solutions of 1a in benzene (0.3 M) were prepared
by purging dry nitrogen and oxygen, respectively, to the solution
for 30 min. The UV spectra of these solutions were recorded with
pure benzene as reference (Figure 1).
(b) Mea su r em en t of th e Differ en tia l Sp ectr u m . In the
reference cell and sample cell were placed the same solution of
1a (1 g in 10 mL of methanol, 4.8 M). The sample cell was purged
with oxygen while the reference cell was purged with argon for
30 min, and the absorption spectrum was then measured. In
this case, the absorption of 1a was counteracted and the
spectrum displays only the absorption of the CTC complex. After
purging argon into the sample cell to remove oxygen, this CTC
absorption band disappeared. The CTC absorption band is
between 450 and 600 nm region with absorption maximum at
500 nm.
2. P h otooxygen a tion of 1a -d . The light source was a
medium-pressure mercury lamp (500 W) in a cooling water
jacket which was further surrounded by a layer of filter solution
(10% aq sodium nitrite, 1 cm thickness, λ > 400 nm). The
solution of indolizines (0.025 mol L-1) in benzene-methanol (1/
1, v:v) was placed in glass tubes (25 mL each) and was then
irradiated at room temperature under continuous oxygen purg-
ing. At the end of the reaction (TLC monitoring), the solvent
was removed in vacuo, and the residue was separated by flash
chromatography on silica gel column with petroleum ether (bp
60-90 °C)-ethyl acetate as eluents to afford the products. The
reaction scale, irradiation time and yields of the products are
listed in Table 1.
Reaction s of 5-Meth yl-2-ph en ylin dolizin e (1a) with Th er -
m a lly Gen er a ted Sin glet Oxygen . 1. Rea ction s w ith So-
d iu m Hyp och llor ite-Hyd r ogen P er oxid e. To a solution of
1a (0.6 g) in methanol (50 mL) was added hydrogen peroxide
(4.5 mL, 30%), and the mixture was cooled in an ice bath. To
this solution was added with stirring an aqueous sodium
hypochlorite solution (18 mL, 21%) slowly (during 2 h) through
an injector with the tip of the needle submerged beneath the
surface of the reaction mixture.25 The reaction mixture was
diluted with water and was extracted with ethyl acetate (3 ×
20 mL). The extract was dried by anhydrous magnesium sulfate,
the solvent was removed in vacuo, and the residue was separated
by flash chromatography on silica gel column with petroleum
ether (bp 60-90 °C)-ethyl acetate as eluents to afford 2a (0.14
g, 19%) and 4a (0.12 g, 17%) as products.
2. Rea ction s w ith 9,10-Dip h en yla n th r a cen e En d op er -
oxide. 9,10-Diphenylanthracene endoperoxide and diazomethane
were prepared by literature procedures. 5-Methyl-2-phenyl-
indolizine (1a , 0.41 g, 2 mmol) and 9,10-diphenylanthracene
endoperoxide (1.44 g, 4 mmol) were desolved in benzene, and
the solution was heated under reflux for 2-3 days until 1a was
completely consumed (TLC monitoring). The solution was cooled
to room temperature, and a solution of diazomethane in ether
(20 mL, 0.2mol/L) was slowly added. The reaction mixture was
stirred for 0.5 h, the solvent was removed in vacuo, and the
residue was separated by flash chromatography on silica gel
column with petroleum ether (bp 60-90 °C)-ethyl acetate as
eluents to afford 0.24 g of 2a (48%).
7.52 (m, 6H), 7.95 (s, 1H); m/z (%) 253 (M+, 42.15), 252 (base),
238 (18.65), 194 (88.50), 153 (11.66), 122 (55.14), 105 (85.27),
78 (10.65) (Found: C, 75.66; H, 5.77; N, 5.49. C16H15NO2 requires
C, 75.89; H, 5.93; N, 5.54).
4a : E-2-p h en yl-3-[2-(6-m et h ylp yr id in yl)]p r op en -2-oic
Acid . Colorless crystals from petroleum ether - ethyl acetate,
mp 175-176 °C; υmax/cm-1 2400-3100 (b), 1680, 1625, 1585,
1560, 1460, 1370, 1235, 1200, 1095, 1000, 805, 780, 700; δH 2.66
(s, 3H, CH3), 6.64 (d, J 7.9, 1H), 7.07 (d, J 7.7, 1H), 7.22-7.42
(m, 6H), 8.13 (s, 1H), 13.00-13.08 (b, 1H, COOH); m/z (%) 239
(M+, 15.79), 238 (33.49), 194 (base), 180 (6.95), 152 (8.79), 78
(2.62) (Found: C, 75.55; H, 5.42; N, 6.02. C15H13NO2 requires
C, 75.30; H, 5.48; N, 5.85%).
2b : Z-Met h yl 2-P h en yl-3-(2-p yr id in yl)p r op en -2-oa t e.
Colorless oil; υmax/cm-1 3057, 1732, 1623, 1584, 1563, 1212, 1012,
778, 692; δH 3.87 (s, 3H, OCH3), 6.93 (s, 1H, H5), 7.04 (d, J 7.7,
1H), 7.11 (d, J 7.6, 1H), 7.33-7.60 (m, 6H, ArH), 8.54 (d, J 1H);
m/z (%) 239 (M+, 5.2), 238 (22.8), 180 (8.3), 84 (base), 78 (53.7)
(Found: C, 75.26; H, 5.38; N, 5.78. C15H13NO2 requires C, 75.31;
H, 5.44; N, 5.86).
3b : E-Met h yl 2-P h en yl-3-(2-p yr id in yl)p r op en -2-oa t e.
Colorless oil; υmax/cm-1 3055, 1710, 1625, 1580, 1565, 1240, 1200,
1080, 790, 710; δH 3.82 (s, 3H, OCH3), 6.72 (d, J 8.0, 1H), 7.08
(dd, J 4.9, 7.4, 1H), 7.21-7.41 (m, 6H), 7.96 (s, 1H), 8.59-8.61
(dd, J 7.8, 0.8, 1H); m/z (%) 239 (M+, 21.45), 238 (base), 224
(6.83), 180 (29.38), 152 (7.90), 78 (11.68) (Found: C, 75.19; H,
5.37; N, 5.87. C15H13NO2 requires C, 75.31; H, 5.44; N, 5.86).
4b: E-2-P h en yl-3-(2-p yr id in yl)p r op en -2-oic Acid . Color-
less crystals (petroleum ether-ethyl acetate), mp 170-171 °C;
υ
max/cm-1 2300-3600 (b), 1710, 1635, 1600, 1575, 1475, 1260,
1100, 1015, 805, 720; δH 6.84 (d, J 8.1, 1H), 7.23-7.52 (m, 7H),
8.20 (s, 1H), 8.95 (d, J 4.8, 1H); m/z (%) 225 (M+, 21.18), 224
(97.26), 180 (base), 152 (19.26), 78 (23.01) (Found: C, 74.67; H,
4.93; N, 6.18. C14H11NO2 requires C, 74.65; H, 4.92; N, 6.22).
2c: Z-Meth yl 2-(4-Ch lor op h en yl)-3-(2-p yr id in yl)p r op en -
2-oa te. Colorless wax solid, mp 45-47 °C; υmax/cm-1 3057, 1726,
1629, 1244, 1091, 832, 786, 753; δH 3.92 (s, 3H, OCH3), 6.94 (s,
1H), 7.17-7.71 (m, 7H), 8.58 (d, J 4.6, 1H); m/z (%) 273 (M+,
23.2), 272 (base), 258 (8.8), 242 (7.0), 214 (42.2), 178 (10.9), 78
(24.3) (Found: C, 65.44; H, 4.52; N, 5.28. C15H12ClNO2 requires
C, 65.82; H, 4.42; N, 5.12).
3c: E-Meth yl 2-(4-Ch lor op h en yl)-3-(2-p yr id in yl)p r op en -
2-oa te. Colorless wax solid, mp 55-56 °C; υmax/cm-1 3050, 1710,
1620, 1575, 1540, 1480, 1455, 1240, 1200, 1070, 1000, 835, 790,
750; δH 3.84 (s, 3H, OCH3), 6.79 (d, J 7.9, 1H), 7.13 (dd, J 7.9,
4.9, 1H), 7.17 (d, J 8.4, 2H), 7.36 (d, J 8.4, 1H), 7.41 (td, J 7.9,
1.7, 1H), 7.96 (s, 1H), 8.60 (dd, J 4.9, 1.7, 1H); m/z (%) 273 (M+,
33.28), 271 (base), 230 (16.97), 178 (18.07), 156 (27.03), 139
(47.72), 111 (29.38), 78 (43.54) (Found: C, 65.81; H, 4.63; N, 5.05.
C15H12ClNO2 requires C, 65.82; H, 4.42; N, 5.12).
4c: E-2-(4-Ch lor op h en yl)-3-(2-p yr id in yl)p r op en -2-oic
Acid . Colorless crystals from petroleum ether-ethyl acetate, mp
177-178 °C; υmax/cm-1 2200-3100 (b), 1690, 1630, 1600, 1575,
1490, 1440, 1380, 1260, 1215, 1080, 1015, 795, 765, 720; δH 6.89
(s, J 7.9, 1H), 7.26-7.29 (m, 3H), 7.39 (d, J 8.4, 2H), 7.55 (t, J
7.9, 1H), 8.19 (s, 1H), 8.96 (d, J 4.4, 1H), 12.4-13.08 (b, 1H,
COOH); m/z (%) 259 (M+, 16.61), 214 (base), 178 (21.50), 152
(13.35), 136 (6.84), 78 (34.17) (Found: C, 64.93; H, 4.08; N, 5.39.
C14H10ClNO2 requires C, 64.75; H, 3.88; N, 5.39%).
2d : Z-Meth yl 2-(3,4-Dim eth ylp h en yl)-3-(2-p yr id in yl)p r o-
p en -2-oa te. Colorless wax solid, mp 60-62 °C; υmax/cm-1 3050,
1725, 1615, 1580, 1495, 1420, 1365, 1195, 1025, 900, 820, 765,
735; δH (H-H COSY) 2.30 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.94
(s, 3H, OCH3), 6.93 (s, H3), 7.15 (t, J 7.7, H5′), 7.13-7.33 (m,
4H, H3′, H2′′, H5′′, H6′′), 7.67 (td, J 1.7, 7.7, H4′), 8.59 (dd, J 7.7,
7.7, H6′); m/z (%) 267 (M+, 28.06), 266 (base), 236 (21.95), 208
(48.62), 193 (11.58), 133 (18.82), 115 (10.23), 78 (17.27) (Found:
C, 76.14; H, 6.77; N, 5.18. C17H17NO2 requires C, 76.09; H, 6.76;
N, 5.22).
3d : E-Meth yl 2-(3,4-Dim eth ylp h en yl)-3-(2-p yr id in yl)p r o-
p en -2-oa te. Colorless crystals (petroleum ether-ethyl acetate),
mp 82-83 °C; υmax/cm-1 3050, 1735, 1640, 1605, 1580, 1520,
1475, 1450, 1260, 1220, 1165, 1055, 805, 760; δH 2.20 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.74 (d, J 8.3, 1H),
6.89 (dd, J 7.5, 1.0, 1H), 6.95 (s, 1H), 7.02-7.17 (m, 2H), 7.31
(td, J 7.5, 1.8, 1H), 7.86 (s, 1H), 8.56 (m, 1H); m/z (%) 267 (M+,
2a : Z-Meth yl 2-P h en yl-3-[2-(6-m eth ylp yr id in yl)]p r op en -
2-oa te. Colorless oil; υmax/cm-1 3060, 1725, 1622, 1580, 1565,
1368, 1205, 1013, 784, 735, 685; δH 2.56 (s, 3H, CH3), 3.96 (s,
3H, OCH3), 6.93 (s, 1H), 7.08 (d, J 7.7, 1H), 7.11 (d, J 7.7, 1H),
7.33-7.59 (m, 6H); m/z (%) 253 (M+, 43), 252 (base), 238 (18.6),
222 (28.1), 194 (89.6), 78 (22.7) (Found: C, 75.17; H, 5.98; N,
5.30. C16H15NO2 requires C, 75.89; H, 5.93; N, 5.54).
3a : E-Meth yl 2-P h en yl-3-[2-(6-m eth ylp yr id in yl)]p r op en -
2-oa te. Wax solid, mp 44-45 °C; υmax/cm-1 3060, 1710, 1635,
1585, 1500, 1460, 1265, 1235, 820, 760, 710; δH 2.55 (s, 3H, CH3),
3.82 (s, 3H, OCH3), 6.54 (d, J 7.9, 1H), 6.97 (d, J 7.6, 1H), 7.21-

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8235
25.33), 266 (base), 209 (31.98), 153 (11.67), 105 (17.38) (Found:
C, 76.05; H, 6.98; N, 5.09. C17H17NO2 requires C, 76.09; H, 6.76;
N, 5.22).
Ack n ow led gm en t. This work was supported by the
National Natural Science Foundation of China (Project
20072017).
4d : E-2-(3,4-Dim eth ylp h en yl)-3-(2-p yr id in yl)p r op en -2-
oic Acid . Colorless crystals from petroleum ether-ethyl acetate,
mp 183-184 °C; υmax/cm-1 3060, 1695, 1590, 1560, 1500, 1460,
1375, 1245, 1375, 1245, 1210, 1050, 820, 790, 735; δH 2.26 (s,
3H, CH3), 2.30 (s, 3H, CH3), 6.90 (d, J 8.0, 1H), 7.02 (dd, J 7.7,
1.3, 1H), 7.10 (s, 1H), 7.15-7.22 (m, 2H), 7.46 (td, J 7.7, 1.1,
1H), 8.15 (s, 1H), 8.97 (d, J 4.5, 1H), 10.75-12.42 (b, 1H, COOH);
m/z (%) 253 (M+, 16.59), 252 (49.25), 208 (base), 193 (9.09), 152,
(2.50), 115 (6.62), 78 (10.53) (Found: C, 75.36; H, 6.24; N, 5.62.
C16H15NO2 requires C, 75.57; H, 6.34; N, 5.53).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 2d , 3d , and 4d , H-H COSY and NOESY spectra
of 2d , tables of crystal data, atomic coordinates, bond length
and angles, anisotropic thermal parameters for 4c. Differential
UV spectrum of 1a -oxygen CTC. This material is available
free of charge via the Internet at http:/pubs.acs.org.
J O015769O