Novel synthetic routes to nitrogen-bridged tricyclic derivatives of pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]quinolizine derived from 2-acyl-N-(acylmethyl)pyridinium halides

Article abstract of DOI:10.1039/b102449n

Novel synthetic routes to nitrogen-bridged derivatives of pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]-quinolizine were developed starting from 2-acyl-N-(acylmethyl)pyridinium halides. Thus, 2-benzoyl-N-phen-acylpyridinium bromide (1) afforded 3,4-di

Full text of DOI:10.1039/b102449n

View Article Online / Journal Homepage / Table of Contents for this issue
Novel synthetic routes to nitrogen-bridged tricyclic derivatives of
pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]quinolizine derived
from 2-acyl-N-(acylmethyl)pyridinium halides
1
Jiaxin Hu,a Xin Jiang,a Ting He,a Jian Zhou,a Yuefei Hu*a,b and Hongwen Hua,b
a Department of Chemistry, Nanjing University, Nanjing 210093,
People’s Republic of China
b Coordination Chemistry Institute, Nanjing University, Nanjing 210093,
People’s Republic of China
Received (in Cambridge, UK) 15th March 2001, Accepted 29th May 2001
First published as an Advance Article on the web 6th July 2001
Novel synthetic routes to nitrogen-bridged derivatives of pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]-
quinolizine were developed starting from 2-acyl-N-(acylmethyl)pyridinium halides. Thus, 2-benzoyl-N-phen-
acylpyridinium bromide (1) afforded 3,4-diphenylpyrrolo[2,1,5-cd]indolizines (4) via 1,3-dipolar cycloaddition,
to yield 3,5-dibenzoylindolizines (3), followed by intramolecular McMurry coupling. Similarly, 2-(1,3-dioxolan-
2-yl)-N-phenacylpyridinium bromide (5) gave 3-phenylpyrrolo[2,1,5-cd]indolizine (7) together with the unexpected
product 3-phenyl-4-hydroxypyrrolo[2,1,5-cd]indolizines (8). However, 2-acetyl-N-phenacylpyridinium bromide
(13) or 2-benzoyl-N-acetonylpyridinium bromide (16) underwent a tandem reaction of aldol condensation and
1,3-dipolar cycloaddition to form 3-phenyl-5H-pyrrolo[2,1,5-de]quinolizin-5-ones (15) or 5-phenyl-3H-pyrrolo-
[2,1,5-de]quinolizin-3-ones (17) in a single step. These novel procedures are general and can be carried out under
convenient conditions.
C1–C4 of the pyrrolo[2,1,5-cd]indolizine. Unfortunately, these
Introduction
drawbacks also arose in the very few published procedures for
the preparation of pyrrolo[2,1,5-de]quinolizine derivatives.7
As part of our research project, a series of nitrogen-bridged
bicyclic and tricyclic heterocyclic compounds have been
designed and synthesized recently.8 In continuation of our
efforts, we describe herein an efficient and practical synthetic
sequence for pyrrolo[2,1,5-cd]indolizines and an unexpected
tandem reaction for the preparation of pyrrolo[2,1,5-de]quinol-
izinones derived from 2-acyl-N-(acylmethyl)pyridinium halides.
These methods overcome some of the limitations of the pub-
lished procedures and afford a broad range of functionalized
derivatives.
Pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]quinolizine are
members of the cyclazine family (Chart 1). They have received
Results and discussion
Intramolecular reductive coupling of dicarbonyls induced by
McMurry reaction has been widely used in the synthesis of
heterocyclic compounds.9 In view of the fact that 3,5-diacyl-
indolizines can be obtained readily by oxidant-promoted 1,3-
dipolar cycloadditions of 2-acyl-N-(acylmethyl)pyridinium
halides (precursors to the corresponding ylides) to electron-
deficient alkenes,8 McMurry coupling makes possible an
efficient route to prepare pyrrolo[2,1,5-cd]indolizines by intra-
molecular reductive coupling of 3,5-diacylindolizines. Our
strategy is shown in Scheme 1.
Chart 1
considerable attention in the field of synthetic organic chem-
istry because of their special structural properties,1,2 increasing
biological interest1,3 and their partially saturated frameworks
that are found in natural products.4
Among the methods for the preparation of pyrrolo[2,1,5-
cd]indolizine derivatives,5 [8+2]-cycloaddition of indolizines
with electron-deficient acetylenes was mainly employed in
the past decade.6 Since most electron-deficient acetylenes are
not commercially available and a 3-cyano- or 3-unsubstituted
indolizine without electron-withdrawing substituents on C1
and C2 is required for this reaction mechanism, such methods
very often suffer from the problems of inaccessible precursors
and of limitations on the range of substituents possible on
McMurry coupling of 3,5-dibenzoylindolizines
As aryl carbonyls usually give better coupling results in the
McMurry reaction, 3,5-dibenzoylindolizines (3) were initially
chosen for test studies. Following the known procedure,8d
a
mixture of 2-benzoyl-N-phenacylpyridinium bromide (1),
acrylonitrile (2a), CrO3 and Et3N in DMF was warmed to 90 ЊC
for 4 h. After normal work-up, 3,5-dibenzoylindolizine-1-carbo-
nitrile (3a) was obtained as yellow crystals in 72% yield. Using
1820
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102449n

View Article Online
Scheme 1
2b and 2c as dipolarophiles, the corresponding compounds 3b
and 3c were obtained in 80 and 68% respectively.
As expected, when compounds 3a–c were treated with
low-valent titanium (produced from the TiCl4–Zn system) at
room temperature for 30 min, the desired 3,4-diphenyl-
pyrrolo[2,1,5-cd]indolizines 4a–c were obtained as yellow
crystals in excellent yields (90–95%, Scheme 2).
Scheme 3
Scheme 2
McMurry coupling of 3-benzoylindolizine-5-carbaldehydes
Our next attempt was to test the McMurry reaction of 3-
benzoylindolizine-5-carbaldehydes 6a–c, which were obtained
from 2-(1,3-dioxolan-2-yl)-N-phenacylpyridinium bromide (5)
by the published procedure.10 When 6a was treated with low-
valent titanium, two products were separated. The less polar
product was identical with an authentic sample of 3-phenyl-
pyrrolo[2,1,5-cd]indolizine-1-carbonitrile (7a, 30%).8f In con-
trast, the more polar one was assigned as an “unexpected”
product of the McMurry reaction, 3-phenyl-4-hydroxypyr-
rolo[2,1,5-cd]indolizine-1-carbonitrile (8a, 29%), from its IR,
1H NMR and MS spectra. A change in the reaction conditions
altered the ratio of 7a to 8a, but did not cause any increase in
the total yield. For example, in the presence of two equivalents
of pyridine, 7a and 8a were obtained in 39 and 16% yields
respectively. However, when the reaction was carried out in
boiling THF, 17% of 7a and 35% of 8a were obtained. Under
similar conditions, 6b and 6c yielded the pairs 7b–8b and 7c–8c
(Scheme 3).
To our knowledge, this is the first example of a diacyl com-
pound that affords a phenol product in the McMurry reaction.
This might result from the aromatic stability of pyrrolo[2,1,5-
cd]indolizine. As shown in Scheme 4, two electrons are trans-
ferred initially from titanium to the carbonyls of compound 6
generating a diradical 9. Intramolecular coupling of 9 yields 10,
which is followed by loss of TiO to give the intermediate 11.
Another TiO is then lost to afford the usual product 7. How-
Scheme 4
ever, if a proton is lost from 11, a stable titanium phenoxide 12
is formed, which is subsequently converted into the unexpected
product 8.
Tandem reaction for the formation of pyrrolo[2,1,5-
de]quinolizinones
Given the successful application of the McMurry reaction in
the above two protocols, the coupling of 3-benzoyl-5-acetyl-
indolizine (14) was investigated as an extended example. To
our surprise, yellow crystals were obtained when 2-acetyl-N-
phenacylpyridinium bromide (13) was treated with acrylonitrile
(2a) under the conditions reported for the preparation of 3a. Its
IR and 1H NMR do not show any features of the acetyl group
and its MS and the results of elemental analyses are fully
consistent with the formulation 1-cyano-3-phenyl-5H-pyrrolo-
[2,1,5-de]quinolizin-5-one (15a, 30%)—the product of loss of
H2O from 3-benzoyl-5-acetylindolizine-1-carbonitrile (14a).
This result indicated that the nitrogen-bridged tricyclic struc-
ture of pyrrolo[2,1,5-de]quinolizine could be constructed by a
tandem reaction from 13 in a single step. Thus, the correspond-
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825
1821

View Article Online
ing compounds 15b–d were also prepared successfully in
21–35% by using 2b, 2d and 2e as dipolarophiles (Scheme 5).
step, salts 13 or 16 yield betaines 18 or 20 by base-catalyzed
intramolecular aldol condensation. They are then converted
into 19 or 21 followed by 1,3-dipolar cycloaddition to an alkene
to yield pyrrolo[2,1,5-de]quinolizinone 15 or 17, promoted by
the oxidant Cr3O–Et3N.
In order to confirm that the betaines are reasonable possible
intermediates, 1-hydroxy-3-phenylquinolizinium bromide (22),
obtained from salt 13, in the presence of Et3N, was allowed to
undergo 1,3-dipolar cycloaddition to the dipolarophile 2a in the
presence of Cr3O–Et3N. As expected, 15a was obtained in 34%
yield (Scheme 8).
Scheme 8
Since the aldol condensation was hypothesized as the initial
step, the reactivities of the methyl groups in salts 13 and 16
might be the yield-controlling factor. Unfortunately, the
experiment with 2-acetyl-N-acetonylpyridinium bromide (23)
produced the opposite conclusion. As shown in Scheme 9, the
Scheme 5
Similarly, 2-benzoyl-N-acetonylpyridinium bromide (16)
afforded 5-phenyl-3H-pyrrolo[2,1,5-de]quinolizin-3-ones 17a–d
in 59–87% yields respectively (Scheme 6). However, the fact that
Scheme 6
Scheme 9
the yields of 17a–d are more than twice those of their counter-
parts, 15a–d, caught our interest because this meant that the
tandem reaction route could not be explained simply by
a sequence of 1,3-dipolar cycloaddition, to yield the 3,5-
diacylindolizine, followed by an aldol condensation.
methyl group on the 2-acetyl group showed a much higher
reactivity than that on the N-acetonyl group, yielding 3-methyl-
5H-pyrrolo[2,1,5-de]quinolizin-5-one (24a) in 31% yield as the
major product.
Thus, we believe that the difference in yield between 15 and
17 may depend upon the reactivities of the 1,3-dipoles 19 and
21. As shown in Scheme 7, as the betaine 18 is converted into
1,3-dipole 19, the negative charge not only passes through three
carbons, but also is distributed partially on its α-phenyl group.
In contrast, betaine 20 could be converted directly into 1,3-
dipole 21.
In summary, methods for the preparation of nitrogen-
bridged tricyclic heterocyclic derivatives of pyrrolo[2,1,5-cd]-
indolizine and pyrrolo[2,1,5-de]quinolizine were developed
starting from 2-acyl-N-(acylmethyl)pyridinium halides. 2-
Benzoyl-N-phenacylpyridinium bromide (1) yielded 3,4-di-
phenylpyrrolo[2,1,5-cd]indolizines (4) via the sequence of 1,3-
dipolar cycloaddition to yield 3,5-dibenzoylindolizines (3)
followed by McMurry coupling. Similarly, 2-(1,3-dioxolan-2-
yl)-N-phenacylpyridinium bromide (5) gave the expected prod-
uct 3-phenylpyrrolo[2,1,5-cd]indolizines (7) together with the
unexpected product 3-phenyl-4-hydroxypyrrolo[2,1,5-cd]-
indolizines (8). However, 2-acetyl-N-phenacylpyridinium
bromide (13) and 2-benzoyl-N-acetonylpyridinium bromide
(16) gave 3-phenyl-5H-pyrrolo[2,1,5-de]quinolizin-5-ones (15)
Exploration of the mechanism of the tandem reaction
It is well known that salts 13 and 16 can provide betaines 18
and 20 by intramolecular aldol condensation under basic
conditions.11 As illustrated in Scheme 7, a contrary route via
the sequence of aldol condensation to yield a betaine followed
by 1,3-dipolar cycloaddition has been proposed. In the initial
and
5-phenyl-3H-pyrrolo[2,1,5-de]quinolizin-3-ones
(17),
respectively, by a tandem reaction in one single step. These
Scheme 7
1822
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825

View Article Online
novel procedures are general and can be carried out under
convenient conditions.
which was purified by chromatography (silica gel, EtOAc–PE)
to give compound 4 as yellow crystals.
3,4-Diphenylpyrrolo[2,1,5-cd]indolizine-1-carbonitrile
(4a).
Experimental
Yellow crystals, mp 196–197 ЊC (EtOAc–PE) (Found: C, 86.75;
H, 4.51; N, 9.03. C23H14N2 requires: C, 86.77; H, 4.43; N,
8.80%); νmax/cmϪ1 2200; δH 8.16 (d, J 7.8, 1H), 8.01 (d, J 7.6,
1H), 7.96 (s, 1H), 7.92 (t, J 7.7, 1H), 7.62 (d, J 7.3, 2H), 7.54 (d,
J 7.3, 2H), 7.47–7.38 (m, 6H); m/z 319 (M + 1, 25%), 318 (M+,
100).
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. IR spectra were recorded on a
Nicolet FT-IR 5DX spectrometer as KBr pellets. 1H NMR
spectra were recorded on a Bruker ACF-300 spectrometer in
CDCl3 with TMS as internal reference unless specified other-
wise. The J values are given in Hz. MS spectra were obtained on
a VG-ZAB-HS mass spectrometer operating at 70 eV. The
elemental analyses were performed on a Perkin-Elmer 240C
instrument. PE is petroleum ether (60–90 ЊC). 3-Benzoyl-
indolizine-5-carbaldehydes (5a–c) were obtained by the known
procedure.10
Methyl 3,4-diphenylpyrrolo[2,1,5-cd]indolizine-1-carboxylate
(4b). Yellow crystals, mp 146–147 ЊC (EtOAc–PE) (Found: C,
82.01; H, 4.84; N, 3.93. C24H17NO2 requires: C, 82.03; H, 4.88;
N, 3.99%); νmax/cmϪ1 1690; δH 8.40 (d, J 7.6, 1H), 8.20 (s, 1H),
7.94 (d, J 7.6, 1H), 7.88 (t, J 7.6, 1H), 7.67 (d, J 7.6, 2H), 7.55
(d, J 7.6, 2H), 7.34–7.45 (m, 6H), 4.03 (s, 3H); m/z 352 (M + 1,
26%), 351 (M+, 100).
Preparation of 3,5-dibenzoylindolizines 3a–c
A mixture of 2-benzoylpyridine (183 mg, 10 mmol) and
phenacyl bromide (199 mg, 10 mmol) was heated at 90 ЊC for
4–5 h without solvent. It was then cooled to room temperature
and EtOAc (20 cm3) was added. Crude 2-benzoyl-N-phenacyl-
pyridinium bromide (1) was obtained as an off-white solid in
95% yield (mp 137–138 ЊC) by filtration, and was used for the
next step without further purification or characterization.
CrO3 (650 mg, 6.5 mmol), alkene 2 (1.3 g, 25 mmol) and salt 1
(1.9 g, 5 mmol) were added in sequence to a stirred solution of
Et3N (3.0 g, 30 mmol) in DMF (20 cm3). After the resultant
mixture had been stirred for 4–5 h at 90 ЊC, it was poured into a
solution of 5% HCl in brine. The crude product was filtered and
purified by chromatography (silica gel, acetone–PE) to give
compound 3.
Diethyl
3,4-diphenylpyrrolo[2,1,5-cd]indolizine-1,2-dicarb-
oxylate (4c). Yellow crystals, mp 213–214 ЊC (EtOAc–PE)
(Found: C, 76.85; H, 5.35; N, 3.39. C28H23NO4 requires: C,
76.87; H, 5.30; N, 3.20%); νmax/cmϪ1 1730, 1690; δH 8.46 (d,
J 8.2, 1H), 8.03 (d, J 7.9, 1H), 7.94 (t, J 8.1, 1H), 7.52–7.47 (m,
4H), 7.42–7.33 (m, 6H), 4.48 (q, J 7.1, 2H), 4.28 (q, J 7.1, 2H),
1.47 (t, J 7.1, 3H), 1.13 (t, J 7.1, 3H); m/z 438 (M + 1, 16%), 437
(M+, 50), 291 (100).
McMurry coupling of 3-benzoylindolizine-5-carbaldehydes 6a–c
By the same procedure as the preparation of compounds
4a–c, the titanium-promoted coupling reaction of 3-benzoyl-
indolizine-5-carbaldehydes 6a–c yielded the corresponding
3-phenylpyrrolo[2,1,5-cd]indolizines 7a–c and 3-phenyl-4-
hydroxypyrrolo[2,1,5-cd]indolizines 8a–c.
3,5-Dibenzoylindolizine-1-carbonitrile (3a). Yellow needles,
mp 234–235 ЊC (EtOAc–PE) (Found: C, 78.94; H, 3.95; N, 7.94.
C23H14N2O2 requires: C, 78.84; H, 4.03; N, 7.99%); νmax/cmϪ1
2220, 1666, 1622; δH 8.02 (d, J 7.8, 2H), 7.94 (d, J 8.8, 1H), 7.84
(d, J 7.6, 2H), 7.64 (t, J 7.3, 1H), 7.58 (t, J 7.3, 1H), 7.53–7.50
(m, 3H), 7.48–7.44 (m, 3H), 7.16 (d, J 7.1, 1H); m/z 350 (M+,
31%), 245 (100).
3-Phenylpyrrolo[2,1,5-cd]indolizine-1-carbonitrile (7a) and 3-
phenyl-4-hydroxypyrrolo[2,1,5-cd]indolizine-1-carbonitrile (8a).
Compound 7a was obtained as yellow crystals, mp 118–120 ЊC
(EtOAc–PE, lit.8f 118–120 ЊC) (Found: C, 84.77; H, 4.42; N,
11.35. C17H10N2 requires: C, 84.28; H, 4.16; N, 11.56%); νmax
/
cmϪ1 2200; δH 8.14 (d, J 7.6, 1H), 8.10 (s, 1H), 8.00–7.98 (m,
3H), 7.91 (t, J 7.7, 1H), 7.66 (s, J 7.3, 1H), 7.55 (t, J 7.4, 2H),
7.45 (t, J 7.4, 1H); m/z 242 (M+, 100%).
Methyl 3,5-dibenzoylindolizine-1-carboxylate (3b). Yellow
needles, mp 198–200 ЊC (EtOAc–PE) (Found: C, 75.42; H, 4.56;
N, 3.87. C24H17NO4 requires: C, 75.18; H, 4.47; N, 3.65%); νmax
/
Compound 8a was obtained as yellow crystals, mp 261–
263 ЊC (EtOAc–PE) (Found: C, 79.35; H, 3.50; N, 10.65.
C17H10N2O requires: C, 79.06; H, 3.90; N, 10.85%); νmax/cmϪ1
3400, 2200; δH 8.04–7.94 (m, 3H), 7.67–7.62 (m, 2H), 7.58–7.47
(m, 4H); m/z 258 (M+, 100%).
cmϪ1 1690, 1655, 1625; δH 8.57 (d, J 8.8, 1H), 8.02 (d, J 7.8, 2H),
7.85 (d, J 7.6, 2H), 7.71 (s, 1H), 7.62 (t, J 7.3, 1H), 7.56 (t, J 7.4,
1H), 7.51–7.48 (m, 2H), 7.47–7.41 (m, 3H), 7.13 (d, J 7.0, 1H),
3.91 (s, 3H); m/z 384 (M + 1, 11%), 279 (100).
Diethyl 3,5-dibenzoylindolizine-1,2-dicarboxylate (3c). Yellow
needles, mp 149–150 ЊC (EtOAc–PE) (Found: C, 71.82; H, 4.91;
Methyl 3-phenylpyrrolo[2,1,5-cd]indolizine-1-carboxylate (7b)
and methyl 3-phenyl-4-hydroxypyrrolo[2,1,5-cd]indolizine-1-
carboxylate (8b). Compound 7b was obtained as yellow
crystals, mp 109–110 ЊC (EtOAc–PE) (Found: C, 78.53; H,
4.77; N, 4.98. C18H13NO2 requires: C, 78.53; H, 4.76; N, 5.09%);
νmax/cmϪ1 1700; δH 8.30 (d, J 7.6, 1H), 8.25 (s, 1H), 7.97 (d, J 7.3,
2H), 7.83 (d, J 7.5, 1H), 7.79 (t, J 7.8, 1H), 7.50 (s, 1H), 7.46
(t, J 7.3, 2H), 7.35 (t, J 7.2, 1H), 3.96 (s, 3H); m/z 275 (M+,
95%), 244 (100).
Compound 8b was obtained as yellow crystals, mp
224–226 ЊC (EtOAc–PE) (Found: C, 74.38; H, 4.50; N, 4.91.
C18H13NO3 requires: C, 74.22; H, 4.50; N, 4.81%); νmax/cmϪ1
3250, 1650; δH (DMSO) 11.17 (s, 1H), 8.33 (d, J 8.2, 1H), 8.29–
8.23 (m, 4H), 7.90 (t, J 7.9, 1H), 7.54 (t, J 7.4, 2H), 7.36 (t, J 7.2,
1H), 3.92 (s, 3H); m/z 291 (M+, 100%).
N, 2.72. C28H23NO6 requires: C, 71.63; H, 4.94; N, 2.98%); νmax
/
cmϪ1 1720, 1690, 1660, 1620; δH 8.58 (d, J 9.1, 1H), 7.93 (d,
J 7.4, 2H), 7.78 (d, J 7.3, 2H), 7.61 (t, J 7.3, 1H), 7.54 (t, J 7.3,
1H), 7.49–7.46 (m, 2H), 7.42–7.37 (m, 3H), 7.13 (d, J 7.1, 1H),
4.36 (q, J 7.2, 2H), 3.64 (q, J 7.2, 2H), 1.35 (t, J 7.2, 3H), 1.02 (t,
J 7.2, 3H); m/z 470 (M + 1, 11%), 364 (100).
McMurry coupling of 3,5-dibenzoylindolizines 3a–c
To a stirred suspension of zinc powder (2.6 g, 40 mmol) in dry
THF was added TiCl4 (2.2 cm3, 20 mmol) under nitrogen and
the mixture was refluxed for 2 h. After the mixture had been
cooled to room temperature, a solution of indolizine (3, 5
mmol) in dry THF was added within 40 min. The resultant
mixture was stirred for another 30 min (monitored by TLC) and
then the THF was evaporated. The residue was treated with a
1% aqueous solution of HCl and was extracted with CH2Cl2.
The combined organic layers were washed with brine and dried
over MgSO4. The solvent was removed to yield crude product,
Diethyl 3-phenylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate
(7c) and diethyl 3-phenyl-4-hydroxypyrrolo[2,1,5-cd]indolizine-
1,2-dicarboxylate (8c). Compound 7c was obtained as yellow
crystals, mp 82–84 ЊC (EtOAc–PE) (Found: C, 73.30; H, 5.39;
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825
1823

View Article Online
N, 3.84. C22H19NO4 requires: C, 73.11; H, 5.30; N, 3.88%); νmax
/
PE) (Found: C, 75.74; H, 4.22; N, 4.43. C19H13NO3 requires: C,
75.23; H, 4.32; N, 4.62%); νmax/cmϪ1 1710, 1600; δH 8.77 (d,
J 7.4, 1H), 8.43 (s, 1H), 7.78–7.75 (m, 2H), 7.55–7.53 (s, 5H),
7.30 (s, 1H), 4.01 (s, 3H); m/z 304 (M + 1, 22%), 303 (M+, 100).
cmϪ1 1720, 1685; δH 8.44 (d, J 7.6, 1H), 8.00–7.91 (m, 2H), 7.83
(d, J 7.3, 2H), 7.53–7.40 (m, 4H), 4.54–4.44 (m, 4H), 1.50 (t,
J 7.1, 3H), 1.32 (t, J 7.1, 3H); m/z 361 (M+, 100%).
Compound 8c was obtained as yellow crystals, mp 187–
188 ЊC (EtOAc–PE) (as its 4-acetate. Found: C, 68.75; H, 5.10;
Dimethyl 3-oxo-5-phenyl-3H-pyrrolo[2,1,5-de]quinolizine-1,2-
dicarboxylate (17c). Yellow–green crystals, mp 254–255 ЊC
(acetone–PE) (lit.4d 252–257 ЊC); νmax/cmϪ1 1740, 1710, 1610;
δH 8.78–8.80 (m, 1H), 7.82–7.78 (m, 2H), 7.56–7.50 (m, 5H),
7.28 (s, 1H), 4.13 (s, 3H), 4.0 (s, 3H).
N, 3.29. C24H21NO6 requires C, 68.73; H, 5.05; N, 3.34%); νmax
/
cmϪ1 3350, 1720, 1660; δH (as its 4-acetate) 8.46 (m, 1H), 7.91
(m, 2H), 7.73 (d, 2H), 7.51 (m, 2H), 7.43 (t, 1H), 4.47 (q, J 7.2,
2H), 4.34 (q, J 7.2, 2H), 2.42 (s, 3H), 1.47 (t, J 7.2, 3H), 1.19 (t,
J 7.2, 3H); m/z 377 (M+, 100%).
1-Benzoyl-5-phenyl-3H-pyrrolo[2,1,5-de]quinolizin-3-one
(17d). Yellow crystals, mp 199–200 ЊC (acetone–PE) (Found: C,
82.59; H, 4.28; N, 3.94. C24H15NO2 requires: C, 82.50; H, 4.33;
N, 4.01%); νmax/cmϪ1 1615, 1590; δH 9.07–9.03 (m, 1H), 8.38 (s,
1H), 7.99–7.96 (m, 2H), 7.87 (d, J 6.2, 2H), 7.65–7.57 (m, 8H),
7.37 (s, 1H); m/z 350 (M + 1, 27%), 349 (M+, 100).
Tandem reaction for the preparation of 3-phenyl-5H-
pyrrolo[2,1,5-de]quinolizin-5-ones 15
To a stirred solution of Et3N (3.0 g, 30 mmol) in DMF was
added CrO3 (650 mg, 6.5 mmol). Five minutes later, alkene (2,
25 mmol) and 2-acetyl-N-phenacylpyridinium bromide (13, 5
mmol) were added and the resultant mixture was stirred for 4–5
hours at 90 ЊC. The mixture was then cooled to room temper-
ature and poured into 5% aqueous solution of HCl saturated
with NaCl. The crude product was collected as a solid, which
was purified by chromatography (20% EtOAc in PE) to give
pure product 15.
1-Cyano-3-methyl-5H-pyrrolo[2,1,5-de]quinolizin-5-one (24a)
and 1-cyano-5-methyl-3H-pyrrolo[2,1,5-de]quinolizin-3-one
(24b)
Compounds 24a and 24b were obtained from 2-acetyl-N-
acetonylpyridinium bromide (23) by the procedure used to
prepare 17a–d.
1-Cyano-3-phenyl-5H-pyrrolo[2,1,5-de]quinolizin-5-one (15a).
Yellow crystals, mp 271–272 ЊC (acetone–PE) (Found: C, 79.94;
H, 3.76; N, 10.32. C18H10N2O requires: C, 79.98; H, 3.73; N,
10.37%); νmax/cmϪ1 2200, 1640, 1590; δH 8.65 (d, J 7.6, 1H), 8.44
(d, J 8.4, 1H), 8.02 (t, J 7.8, 1H), 7.86 (s, 1H), 7.68–7.67 (m,
2H), 7.60–7.59 (m, 3H), 7.19 (s, 1H); m/z 271 (M + 1, 21%), 270
(M+, 100).
Compound 24a. Yellow needles, mp 290–291 ЊC (acetone–PE)
(Found: C, 74.86; H, 3.70; N, 13.29. C13H8N2O requires: C,
74.98; H, 3.87; N, 13.46%); νmax/cmϪ1 2210, 1640, 1600; δH 8.53
(d, J 7.2, 1H), 8.37 (s, 1H), 7.95–7.91 (m, 1H), 7.84 (s, 1H), 6.97
(s, 1H), 2.68 (s, 3H); m/z 209 (M + 1, 15%), 208 (M+, 100).
Compound 24b. Yellow needles, mp 251–252 ЊC (acetone–PE)
(Found: C, 75.02; H, 3.86; N, 13.53. C13H8N2O requires: C,
74.98; H, 3.87; N, 13.46%); νmax
Methyl
5-oxo-3-phenyl-5H-pyrrolo[2,1,5-de]quinolizine-1-
/cmϪ1 2210, 1610; δH 8.27 (d,
carboxylate (15b). Yellow crystals, mp 226–227 ЊC (acetone–
PE) (Found: C, 75.48; H, 4.46; N, 4.75. C19H13NO3 requires: C,
75.23; H, 4.32; N, 4.62%); νmax/cmϪ1 1700, 1630, 1590; δH 8.91
(d, J 8.5, 1H), 8.62 (d, J 7.5, 1H), 8.05 (s, 1H), 7.98 (t, J 7.9,
1H), 7.71–7.70 (m, 2H), 7.59–7.58 (m, 3H), 7.18 (s, 1H), 4.00 (s,
3H); m/z 304 (M + 1, 22%), 303 (M+, 100).
J 8.3, 1H), 8.21 (s, 1H), 7.95 (d, J 7.55, 1H), 7.88–7.85 (m, 1H),
7.20 (s, 1H), 2.75 (s, 3H); m/z 209 (M + 1, 15%), 208 (M+
, 100).
Acknowledgements
We are grateful to the Natural Science Foundation of China for
financial support.
Dimethyl 5-oxo-3-phenyl-5H-pyrrolo[2,1,5-de]quinolizine-1,2-
dicarboxylate (15c). Orange crystals, mp 169–171 ЊC (acetone–
PE) (lit.4d 168–170 ЊC); νmax/cmϪ1 1740, 1710, 1640, 1600;
δH 8.93 (d, J 8.5, 1H), 8.65 (d, J 7.7, 1H), 8.01 (t, J 8.3, 1H),
7.52–7.49 (m, 5H), 7.02 (s, 1H), 3.97 (s, 3H), 3.42 (s, 3H).
References
1 (a) W. Flitsch and U. Kramer, Adv. Heterocycl. Chem., 1978, 22, 321;
(b) W. Flitsch, in Comprehensive Heterocyclic Chemistry, Vol. 4, eds.
A. R. Katritzky and C. W. Rees, Pergamon Press, 1984, p. 478; (c)
Y. Tominaga, Y. Shiroshita and A. Hosomi, Heterocycles, 1988, 27,
2251.
2 (a) M. J. S. Dewar and N. Trinajstic, J. Chem. Soc. A, 1969, 1754; (b)
K. Matsumoto, H. Katsura, J. Yamauchi, T. Uchida, K. Aoyama
and T. Machiguchi, Bull. Soc. Chim. Fr., 1996, 133, 891; (c) C. W.
Bird, Tetrahedron, 1998, 54, 10179.
3 (a) A. S. Jorgensen, P. Jacobsen, L. B. Christiansen, P. S. Bury,
A. Kanstrup, S. M. Thorpe, S. Bain, L. Nerum and K. Wassermann,
Bioorg. Med. Chem. Lett., 2000, 10, 399; (b) A. S. Jorgensen,
P. Jacobsen, L. B. Christiansen, P. S. Bury, A. Kanstrup, S. M.
Thorpe, S. Bain, L. Nerum and K. Wassermann, Bioorg. Med.
Chem. Lett., 2000, 10, 2383.
1-Benzoyl-3-phenyl-5H-pyrrolo[2,1,5-de]quinolizin-5-one
(15d). Yellow crystals, mp 200–201 ЊC (acetone–PE) (Found: C,
82.69; H, 4.37; N, 3.82%. C24H15NO2 requires: C, 82.50; H,
4.33; N, 4.01%); νmax/cmϪ1 1640, 1620, 1590; δH 9.12 (d, J 7.4,
1H), 8.70 (d, J 7.2, 1H), 8.08 (t, J 7.4, 1H), 7.93–7.90 (m, 2H),
7.84 (s, 1H), 7.72–7.69 (m, 2H), 7.63–7.53 (m, 6H), 7.21 (s, 1H);
m/z 350 (M + 1, 27%), 349 (M+, 100).
Tandem reaction for the preparation of 5-phenyl-3H-
pyrrolo[2,1,5-de]quinolizin-3-ones 17
Compounds 17a–d were obtained from 2-benzoyl-N-acetonyl-
pyridinium bromide 16 by the same procedure used for the
preparation of 15a–d.
4 (a) M. Timmermans, J. C. Braekman, D. Daloze, J. M. Pasteels,
J. Merlin and J. P. Declercq, Tetrahedron Lett., 1992, 33, 1281; (b)
F. Schroder, V. Sinnwell, H. Baumann and M. Kaib, Chem.
Commun., 1996, 2139; (c) F. Schroder, S. Franke, W. Francke,
H. Baumann, M. Kaib and J. M. Pasteels, Tetrahedron, 1996, 52,
13539; (d ) J. C. Shattuck and J. Meinwald, Tetrahedron Lett., 1997,
38, 347; (e) F. Schroder, V. Sinnwell, H. Baumann, M. Kaib and
W. Francke, Angew. Chem., Int. Ed. Engl., 1997, 36, 77; ( f )
F. Schroder and W. Francke, Tetrahedron, 1998, 54, 5259; (g)
Q. Huang, A. B. Attygalle, J. Meinwald, M. A. Houck and T. Eisner,
J. Nat. Prod., 1998, 61, 598; (h) G. V. Thanh, J. P. Celerier and
G. Lhommet, Tetrahedron Lett., 1999, 40, 3713; (i) B. Sayah,
N. Pelloux-Leon and Y. Vallee, J. Org. Chem., 2000, 65, 2824.
5 (a) W. K. Gibson, D. Leaver, J. E. Roff and C. W. Cummings,
J. Chem. Soc., Chem. Commun., 1967, 214; (b) R. M. Acheson and
1-Cyano-5-phenyl-3H-pyrrolo[2,1,5-de]quinolizin-3-one (17a).
Deep orange crystals, mp 264–265 ЊC (acetone–PE) (Found: C,
79.96; H, 3.86; N, 10.40. C18H10N2O requires: C, 79.98; H, 3.73;
N, 10.37%); νmax/cmϪ1 2210, 1600; δH 8.33 (s, 1H), 8.32 (s, 1H),
7.86–7.81 (m, 2H), 7.59–7.54 (m, 5H), 7.34 (s, 1H); m/z 271
(M + 1, 20%), 270 (M+, 100).
Methyl
3-oxo-5-phenyl-3H-pyrrolo[2,1,5-de]quinolizine-1-
carboxylate (17b). Yellow crystals, mp 206–207 ЊC (acetone–
1824
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825

View Article Online
J. Woollard, J. Chem. Soc. C, 1971, 3296; (c) D. Johnson and
G. Jones, J. Chem. Soc., Perkin Trans. 1, 1972, 840; (d ) E. Pohjala,
Heterocycles,, 1974, 2, 585; (e) E. V. Babaev, V. V. Simonyan, K. Y.
Pasichnichenko, V. M. Nosova, A. V. Kisin and K. Jug, J. Org.
Chem., 1999, 64, 9057.
6 (a) A. J. Blake, J. W. Dick, D. Leaver and P. Strachan, J. Chem. Soc.,
Perkin Trans. 1, 1991, 2991; (b) H. Kojima, Y. Kinoshita,
N. Matsumura and H. Inoue, J. Heterocycl. Chem., 1991, 28, 2059;
(c) H. Kojima and K. Yamamoto, J. Heterocycl. Chem., 1992, 29,
1473; (d ) K. Matsumoto, T. Uchida, H. Yoshida, M. Toda and
A. Kakehi, J. Chem. Soc., Perkin Trans. 1, 1992, 2437; (e)
Y. Matsuda, S. Kohra, K. Katou, T. Itou and T. Uemura,
Heterocycles, 1997, 45, 2223; ( f ) J. O. Smith and B. K. Mandal,
J. Heterocycl. Chem., 1997, 34, 1441; (g) Y. Tominaga, K. Komiya,
S. Kataoka, Y. Shigemitsu, T. Hirota and K. Sasaki, Heterocycles,
1998, 48, 1985; (h) Y. Tominaga, K. Sasaki and R. N. Castle,
J. Heterocycl. Chem., 1998, 35, 1219.
J. F. Miller, J. W. Dick and M. A. Jessep, J. Chem. Soc., Perkin Trans.
1, 1984, 2553; (c) Y. Miki, H. Kinoshita, T. Yoshimaru and
S. Takemura, Heterocycles, 1987, 26, 199.
8 (a) X. Wei, Y. Hu, T. Li and H. Hu, J. Chem. Soc., Perkin Trans. 1,
1993, 2487; (b) J. Zhou, Y. Hu and H. Hu, Synthesis,, 1999, 166; (c)
B. Wang, X. Zhang, J. Li, X. Jiang, Y. Hu and H. Hu, J. Chem. Soc.,
Perkin Trans. 1, 1999, 1571; (d ) B. Wang, J. Hu, X. Zhang, Y. Hu
and H. Hu, J. Heterocycl. Chem., 2000, 37, 1527; (e) L. Zhang,
F. Liang, L. Sun, Y. Hu and H. Hu, Synthesis, 2000, 1733; ( f )
F. Liang, J. Hu, L. Zhang, Y. Hu and H. Hu, J. Heterocycl. Chem.,
2001, 38, in the press.
9 For recent reviews, see: (a) J. E. McMurry, Chem. Rev., 1989, 89,
1513; (b) A. Furstner and B. Bogdanovic, Angew. Chem., Int. Ed.
Engl., 1996, 35, 2442; (c) A. Furstner, Pure Appl. Chem., 1998, 70,
1071.
10 J. Zhou, Y. Hu and H. Hu, Synth. Commun., 1998, 28, 3397.
11 (a) F. Krohnke, H. Schnegelberger and W. Weis, Chem. Ber., 1964,
97, 3566; (b) P. A. Duke, A. Fozard and G. Jones, J. Org. Chem.,
1965, 30, 526.
7 (a) J. W. Dick, W. K. Gibson, D. Leaver and J. E. Roff, J. Chem. Soc.,
Perkin Trans. 1, 1981, 3150; (b) D. Farquhar, T. T. Gough, D. Leaver,
J. Chem. Soc., Perkin Trans. 1, 2001, 1820–1825
1825