Regioselective synthesis of 3-acylindolizines and benzo- analogues via 1,3-dipolar cycloadditions of N-ylides with maleic anhydride

Article abstract of DOI:10.1039/c000277a

3-Acylindolizines (5a-5f) and their benzo- analogues 1-acylpyrrolo[1,2-a] quinolines (6a-6f) and 1-acylpyrrolo[2,1-a]isoquinolines (7a-7i) are regioselectively synthesized by a convenient one pot reaction of the corresponding pyridinium (quinolinium, isoquinolinium) ylide with maleic anhydride (MA) in the presence of the mild oxidant tetrakispyridinecobalt(ii) dichromate (TPCD). These reactions proceed via a tandem reaction sequence of 1,3-dipolar cycloaddition of azomethine ylide with MA, anhydride hydrolysis and oxidative bisdecarboxylation of the primary cycloadducts followed by dehydrogenative aromatization of the dihydroindolizines. TPCD serves as both decarboxylation and dehydrogenation reagent in the reactions. These results show that TPCD is a promising new reagent for bisdecarboxylation of aliphatic carboxylates.

Full text of DOI:10.1039/c000277a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Regioselective synthesis of 3-acylindolizines and benzo- analogues via
1,3-dipolar cycloadditions of N-ylides with maleic anhydride†
Yun Liu,a,b Yan Zhang,a,d Yong-Miao Shen,c Hong-Wen Hua and Jian-Hua Xu*a
Received 12th January 2010, Accepted 8th March 2010
First published as an Advance Article on the web 24th March 2010
DOI: 10.1039/c000277a
3-Acylindolizines (5a–5f) and their benzo- analogues 1-acylpyrrolo[1,2-a]quinolines (6a–6f) and
1-acylpyrrolo[2,1-a]isoquinolines (7a–7i) are regioselectively synthesized by a convenient one pot
reaction of the corresponding pyridinium (quinolinium, isoquinolinium) ylide with maleic anhydride
(MA) in the presence of the mild oxidant tetrakispyridinecobalt(II) dichromate (TPCD). These
reactions proceed via a tandem reaction sequence of 1,3-dipolar cycloaddition of azomethine ylide with
MA, anhydride hydrolysis and oxidative bisdecarboxylation of the primary cycloadducts followed by
dehydrogenative aromatization of the dihydroindolizines. TPCD serves as both decarboxylation and
dehydrogenation reagent in the reactions. These results show that TPCD is a promising new reagent for
bisdecarboxylation of aliphatic carboxylates.
Tschitschibabin reaction),14 1,3-dipolar cycloadditions of pyri-
dinium (quinolinium, isoquinolinium) methylides with electron
Introduction
deficient acetylenes15 or alkenes,16,17 1,5-dipolar cyclizations18 and
metal-catalyzed intramolecular C–N bond formation of alkynyl
pyridines or propargylic pyridines.19 Despite these advances, a
comprehensive structure–activity relationship (SAR) study in drug
and optoelectronic material design has raised a growing demand
for new chemo- and regioselective synthetic strategies that allow
access to indolizines with a well-defined substitution pattern, while
many present synthetic methodology have severe limitations in
achieving this. Recently, 3-monofunctionalized indolizines have re-
ceived much attention because of their occurrence in alkaloids and
their biological properties.20 However, in the above mentioned gen-
eral synthetic approaches towards indolizines, the Tschitschibabin
reaction cannot be used to synthesize the 1,2-unsubstituted
indolizines, and the pyridinium ylide 1,3-dipolar cycloadditions
require the olefinic or acetylenic dipolarophiles to have one or
two electron withdrawing substituent(s) and are also not suitable
for the synthesis of 3-indolizines except in a few cases using
special alkene substrates not easily accessible such as nitroketene
dithioacetals.21 As a result, the synthesis of 3-indolizines proves
to be rather difficult. Recently, several successful syntheses for 3-
indolizines relying on other strategies have been reported. There-
fore, 3-aminoindolizines were synthesized by Pd/Cu-catalyzed
cross-coupling–cycloisomerization reactions of propargyl amines
or amides with 2-bromopyridines.22 Reaction of pyridine silylated
vinylacetylenes with alcohol in the presence of an inorganic
base afforded 3-alkoxymethylindolizines.23 3-Alkynylindolizines
were synthesized by palladium-catalyzed reactions of indolizine
with alkynyl bromides.24 3-Alkylindolizines can be obtained
by copper-promoted cyclization of alkynyl pyridines,25 while
palladium catalyzed regioselective Heck arylation of indolizines
leads to 3-arylindolizines.26 More recently, 3-acylindolizines were
synthesized by intermolecular cyclization of picolinium salts and
a methoxymethylene-dimethyl ammonium salt.27 Because direct
Friedel–Crafts acylation of the indolizines is hampered by low
regioselectivity and low yield,28 and the unsubstituted indolizine
Indolizines and hydrogenated indolizines are widely found in
the indolizidine alkaloids.1 These natural and many synthetic
indolizines have a diversity of biological activity and are playing
an increasingly important role in developing new pharmaceuticals
for the treatment of cancer,2 cardiovascular diseases3 and HIV
infection.4 The special electronic structure and reactivity caused
by the bridgehead nitrogen atom is of long standing theoretical
interest.5 The high fluorescence quantum yield of indolizine
derivatives in the UV-visible region have also received much
research attention in designing novel classes of dyes, biological
markers6 and electroluminescent materials.7
Pyrrolo[1,2-a]quinolines and pyrrolo[2,1-a]isoquinolines are
5,6- and 7,8- benzo-fused indolizines, respectively. These structures
occur in several marine alkaloids (gephyrotoxin,8a lamellarines,8b
jamtines,8c etc.) with anti-inflammatory,9a cardiovascular,9b
antidepressant,9c anticancer9d,e and HIV-1 integrase inhibiting
activity.9f
For these theoretical and practical reasons, the synthesis
of indolizines,10 pyrrolo[1,2-a]quinolines11 and pyrrolo[2,1-a]
isoquinolines12 has drawn much recent research interest. Var-
ious synthetic methods for indolizines and benzo-indolizines
have been reported. These include, among the more general
approaches, the reactions of 2-alkylpyridine with an alde-
hyde (the Scho¨ltz reaction)13 or with an a-haloketone (the
aInstitute of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, PR China. E-mail: xujh@nju.edu.cn; Fax: +86 25
83317761; Tel: +86 25 83592709
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, 221116, Jiangsu, P. R. China
cInstitute of Chemistry and Chemical Engineering, Shaoxing University,
Shaoxing, 312000, PR China
dKey Laboratory of Analytical Chemistry for Life Science, Ministry of
Education, Nanjing, 210093, PR China
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. CCDC reference number 602715. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c000277a
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Table 1 Synthesis of 3-acylindolizinesa
used for acylation needs to be prepared,21,28a general and regiose-
lective synthetic methods of 3-acylindolizines from easily available
starting materials are highly desirable. We report here a convenient
synthesis of 3-acylindolizines and their benzo- analogues by the
more general 1,3-dipolar cycloaddition reactions of pyridinium
(quinolinium, isoquinolinium) ylide by using maleic anhydride
as the olefinic substrate. This strategy has overcome the inherent
shortcomings of the 1,3-dipolar cycloadditions using conventional
alkynes and alkenes in accessing the 1,2-unsubstituted indolizines
by taking advantage of the novel tandem bisdecarboxylation–
dehydrogenation reactions of the primary cycloadducts under the
action of the mild oxidant tetrakispyridinecobalt(II) dichromate
[Py4Co(HCrO4)2] (TPCD).17a,b
Pyridinium salt
Product
Yield (%)b
1a R = Ph
5a R = Ph
71 (65)c
78 (71)c
75 (66)c
68
83
73
1b R = p-ClPh
1c R = p-MeOPh
1d R = 2-Naphthyl
1e R = p-FPh
1f R = p-PhPh
5b R = p-ClPh
5c R = p-MeOPh
5d R = 2-Naphthyl
5e R = p-FPh
5f R = p-PhPh
a All the reactions were carried out under N2 atmosphere, with 1 (1 mmol),
4 (2 mmol), TPCD (1 g) and potassium carbonate (0.483 g) in DMF at
90 ◦C for 3 h. b Isolated yield by silica gel column chromatography. c In
parentheses are the yields when using MnO2 as an oxidant.
Results and discussion
A recent advance in using the 1,3-dipolar cycloadditions of
pyridinium ylide for the indolizine synthesis is to apply alkenes
to replace alkynes (such as dimethyl acetylenedicarboxylate) as
the dipolarophile.16,17 An efficient approach in this respect is to use
electron deficient alkenes in combination with the mild oxidant
TPCD to effect the dehydroaromatization of the primary tetrahy-
droindolizine product.17 Although these [3+2] cycloadditions are
widely used for the indolizine synthesis, they are not applicable for
the synthesis of 1,2-unsubstituted indolizines because the alkene
dipolarophiles have to bear at least one electron-withdrawing
group. However, we have found that when maleic anhydride was
used as thedipolarophile, 3-monofunctionalized indolizines canbe
synthesized via oxidative bisdecarboxylation during the reaction
course. Therefore, under the established reaction conditions for
carrying out the TPCD-mediated 1,3-dipolar cycloadditions of
the pyridinium ylide with electron deficient alkenes with DMF
as the solvent and sodium carbonate as the base,17a,b reaction of
1-phenacylpyridinium salt (1a) (Chart 1) with maleic anhydride
(4) in the presence of TPCD and sodium carbonate in DMF
at 90 ◦C for 10 h gave the 3-benzoylindolizine 5a in 43% yield.
However, it was found that using potassium carbonate as the base
and shortening the reaction time to 3 h led to an improved yield
of 55%. Furthermore, if the reaction was carried out under a
nitrogen atmosphere, the yield was raised to 71%. Reactions of
pyridinium salts 1b–1f (Chart 1) with 4 under the same conditions
under a nitrogen atmosphere similarly afforded the corresponding
3-acylindolizines 5b–5f, respectively (Table 1).
These reactions are proposed to proceed by a mechanism as
shown in Scheme 1.
Scheme 1
The N-ylide generated by deprotonation of the pyridinium salt
with potassium carbonate as a base takes part in a 1,3-dipolar
cycloaddition with maleic anhydride to give the primary product
A. Hydrolysis of A in the presence of the base and adventitious
water in the solvent gives the dicarboxylate B, which undergoes
oxidative bisdecarboxylation under the action of TPCD to give
the dihydroindolizine C. Further dehydroaromatization of C by
TPCD leads to the 3-acylindolizine 5a. As a proof of the proposed
mechanism and as a variation of this synthetic protocol, we
examined the reaction of 1a with maleic acid in the presence
of potassium carbonate and TPCD in DMF at 90 ◦C for 3 h
under N2 atmosphere and found that, this indeed gave the 3-
benzoylindolizine 5a, albeit in lower yield (57%).
These results show that, as a mild oxidant, TPCD is not only
useful to achieve dehydroaromatization for partly hydrogenative
N-heterocycles, but is also an effective decarboxylation reagent
for carboxylates, and it performs these two functions in the above
mentioned reactions, leading to one pot tandem reactions to give
the 1,2-unsubstituted indolizines.
Diels–Alder reactions of maleic anhydride with cyclic dienes
followed by oxidative bisdecarboxylation of the cycloadduct have
been applied for the synthesis of several bicyclic dienes.29 The
bisdecarboxylation process was conducted either electrolytically30
Chart 1
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Table 2 Synthesis of 1-acylpyrrolo[1,2-a]quinolinesa
Quinolinium salt
Product
Yield (%)b
2a R = Ph
6a R = Ph
78
86
80
73
89
82
2b R = p-ClPh
2c R = p-MeOPh
2d R = 2-Naphthyl
2e R = p-FPh
2f R = p-MePh
6b R = p-ClPh
6c R = p-MeOPh
6d R = 2-Naphthyl
6e R = p-FPh
6f R = p-MePh
a All the reactions were carried out under N2 atmosphere, with 2 (1 mmol),
4 (2 mmol), TPCD (1 g) and potassium carbonate (0.483 g) in DMF at
90 ◦C for 6 h. b Isolated yield by silica gel column chromatography.
or with chemical oxidants such as lead oxide,31 lead tetraacetate,32
copper(II) oxide,33 etc. Although electrolytic decarboxylation gave
rather high yields of the alkene products, chemical oxidants
usually resulted in low yield of the bisdecarboxylation products
because of the harsh reaction conditions or the strongly oxidizing
character of the oxidants which led to the further oxidation of
the alkene products. Our own experiments showed that using lead
tetraacetate instead of TPCD in the reaction of the pyridinium
ylide with maleic anhydride under otherwise the same reaction
conditions (heating in DMF at 90 ◦C for 3 h with potassium
carbonate as base) resulted in a complicated reaction mixture,
from which no significant amount of the desired 3-acylindolizine
could be detected. However, we have found that newly prepared
manganese dioxide can be used to replace TPCD under these
reaction conditions to effect the decarboxylation to give the
3-acylindolizines. However, the yields are significantly lower
(Table 1, yields in parentheses). An additional advantage of TPCD
over MnO2 is the ease of its preparation and storage,19a,b while
MnO2 has to be prepared by cumbersome procedures and to be
used when it is newly prepared, and loses its activity quickly upon
storage. Therefore, the successful one pot synthesis of our target
compounds has taken advantage of TPCD’s mild oxidizing ability
that is well tolerated by such highly p-electron excessive and easily
oxidizable substrates as indolizines.
Fig. 1 ORTEP drawing of 6e.
synthesis of pyrrolo[1,2-a]quinoline derivatives, and these 1,3-
dipolar cycloadditions with maleic anhydride as a dipolarophile
turned out to be a general regioselective synthetic approach to the
1-acylpyrrolo[1,2-a]quinolines.
Similar reactions of the isoquinolinium ylides derived from
the isoquinolinium salts 3a–3i with maleic anhydride under
the same conditions gave the corresponding 2,3-unsubstituted
1-acylpyrrolo[2,1-a]isoquinolines 7a–7i in satisfactory yields
(Table 3). Therefore, these reactions prove to be a gen-
eral and convenient synthetic approach toward the previously
unknown 1-acylpyrrolo[1,2-a]quinolines and 1-acylpyrrolo[2,1-
a]isoquinolines.
Reactions of the N-ylides derived from the quinolinium salts 2a–
2f and from the isoquinolinium salts 3a–3i with maleic anhydride
under similar conditions were further investigated. The reactions
of the ylides derived from 2a–2f afforded the corresponding 1-
acylpyrrolo[1,2-a]quinoline products 6a–6f, leaving C2 and C3
in the pyrrole ring unsubstituted (Table 2). The structure of
product 6e is unambiguously established on the basis of an X-
ray crystallographic analysis (Fig. 1).
Table 3 Synthesis of 1-acylpyrrolo[2,1-a]isoquinolinesa
Isoquinolinium salt
Product
Yield (%)b
It is noteworthy that, among the more general synthesis
of benzo-indolizines, the Tschitschibabin reaction can not be
used for the synthesis of pyrrolo[1,2-a]quinoline derivatives be-
cause the reaction of 2-methylquinoline with either phenacyl
bromide or a-chloroacetate gives merely the corresponding 2-
methylquinoline hydrohalide.34 Although several syntheses of
pyrrolo[1,2-a]quinolines have been reported,11 more general and
convenient one pot synthetic methods are still needed. Our results
and other recent reports11b,17a,d showed that, [3+2] cycloaddition
of the N-ylide with electron deficient alkenes in the presence
of TPCD serves as a convenient and regioselective one pot
3a R = Ph
7a R = Ph
80
88
83
77
92
83
67
82
3b R = p-ClPh
3c R = p-MeOPh
3d R = 2-Naphthyl
3e R = p-FPh
7b R = p-ClPh
7c R = p-MeOPh
7d R = 2-Naphthyl
7e R = p-FPh
7f R = p-MePh
7g R = OEt
3f R = p-MePh
3g R = OEt
3h R = p-PhPh
3i CN in place of COR
7h R = p-PhPh
7i CN in place of COR 63
a All the reactions were carried out under N2 atmosphere, with 3 (1 mmol),
4 (2 mmol), TPCD (1 g) and potassium carbonate (0.483 g) in DMF at
90 ◦C for 6 h. b Isolated yield by silica gel column chromatography.
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carbonate (0.483 g, 3.5 mmol) in DMF (15 ml) was heated at
90 C under N2 atmosphere for 3 h with magnetic stirring. The
Conclusions
◦
In summary, 1,2-unsubstituted 3-acylindolizines, 2,3-unsubsti-
tuted 1-acylpyrrolo[1,2-a]quinolines and 1-acylpyrrolo[2,1-a]-
isoquinolines have been regioselectively synthesized by reactions
of the corresponding pyridinium (quinolinium, isoquinolinium)
ylide with maleic anhydride in the presence of the mild ox-
idant TPCD. These syntheses proceed via tandem reactions
involving [3+2] cycloaddition, bisdecarboxylation of the pri-
mary cycloadduct and further dehydroaromatization of the dihy-
droindolizines (and their benzo- analogues). TPCD serves both
as a decarboxylation and a dehydroaromatization reagent in
the reactions. This strategy provides a general synthesis of 3-
acylindolizines and their benzo- analogues via easily accessible
starting materials by a simple one pot procedure. The results
reveal that TPCD is not only an efficient dehydrogenative reagent
for partly hydrogenated heterocycles as previously known, but
is also a promising new decarboxylation reagent for aliphatic
carboxylates, whose mild oxidation ability can be tolerated by
such highly sensitive products as indolizines. It is anticipated that
this strategy to use maleic anhydride as a dipolarophile (or a
dienophile) in a reaction sequence of 1,3-dipolar cycloaddition
with an azomethine ylide (or Diels–Alder reaction with a diene)
followed by oxidative decarboxylation and dehydrogenation of
the primary cycloadduct under the action of TPCD would be of
general utility for the regioselective synthesis of other bridgehead
nitrogen atom heterocycles (or other cyclic compounds) with a
distinct substitution pattern.
reaction course was monitored by TLC. After the reaction was
completed, the solvent was removed under reduced pressure, and
the residue was separated by flash chromatography on a silica gel
column with petroleum ether (bp 60–90 ◦C)/ethyl acetate as an
eluent to give the products 5.
3-Benzoylindolizine (5a). Yield: 158 mg, ◦71%. Yellow s◦olid
from petroleum ether–ethyl acetate, mp 90–92 C (lit:27 91–92 C).
1H NMR (300 MHz, CDCl3): d 6.54 (d, J = 4.5 Hz, 1H), 6.96 (t,
J = 6.9 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 4.5 Hz, 1H),
7.47–7.60 (m, 4H), 7.82 (d, J = 7.2 Hz, 2H), 9.99 (d, J = 6.9 Hz,
1H). IR (KBr): 1595, 1566, 1467, 1388, 1357, 1234, 1130, 1053,
872, 772, 756. MS (EI): m/z (%) 221 (100) [M+], 193 (66), 192 (46),
144 (91), 116 (61), 89 (16), 77 (11). Anal. Calcd for C15H11NO: C,
81.45; H, 4.98; N, 6.33. Found: C, 81.40; H, 5.01; N, 6.35.
3-(4-Chlorobenzoyl)indolizine (5b). Yield: 199 mg, 78%. Yel-
low solid from petroleum ether–ethyl acetate, mp 123–125 ◦C. 1H
NMR (300 MHz, CDCl3): d 6.56 (d, J = 4.7 Hz, 1H), 6.97 (td,
J = 7.0, 1.3 Hz, 1 H), 7.23 (td, J = 6.8, 1.1 Hz, 1H), 7.32 (d, J =
4.7 Hz, 1H), 7.48 (dt, J = 9.0, 2.1 Hz, 2H), 7.60 (d, J = 8.7 Hz,
1H), 7.76 (dt, J = 9.0, 2.1 Hz, 2H), 9.96 (d, J = 7.1 Hz, 1H). IR
(KBr): 1603, 1589, 1563, 1469, 1394, 1361, 1234, 1052, 879, 750.
MS (EI): m/z (%) 255 (100) [M+], 227 (13), 226 (2), 192 (12), 144
(57), 116 (27), 89 (9). Anal. Calcd for C15H10NOCl: C, 70.59; H,
3.92; N, 5.49. Found: C, 70.63; H, 3.89; N, 5.47.
3-(4-Methoxybenzoyl)indolizine (5c). Yield: 189 mg, 75%. Pale
yellow solid from petroleum ether–ethyl acetate, mp 140–141 ◦C.
1H NMR (300 MHz, CDCl3): d 3.91 (s, 3H), 6.54 (d, J = 4.5 Hz,
1H), 6.92 (t, J = 6.9 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 7.17 (t, J =
7.8 Hz, 1H), 7.37 (d, J = 4.5 Hz, 1H), 7.56 (t, J = 9.0 Hz, 1H),
7.83 (d, J = 8.7 Hz, 2H), 9.93 (d, J = 7.2 Hz, 1H). IR (KBr): 1601,
1569, 1505, 1463, 1384, 1352, 1236, 1168, 879, 751. MS (EI): m/z
(%) 251 (100) [M+], 223 (8), 222 (11), 208 (48), 144 (37), 116 (22),
89 (13). Anal. Calcd for C16H13NO2: C, 76.49; H, 5.18; N, 5.58.
Found: C, 76.55; H, 5.22; N, 5.56.
Experimental
General
Melting points are uncorrected. 1H NMR spectra were measured
on a Bruker DPX 300 spectrometer at 300 MHz with CDCl3 as
solvent. The chemical shifts (d) are reported in parts per million
relative to the residual deuterated solvent signal, and coupling
constants (J) are given in Hertz. 13C NMR spectra were measured
on a Bruker Avance 300 spectrometer at 75 MHz with CDCl3
as solvent. IR spectra were recorded with a Shimadzu IR 440
spectrometer as KBr pellets. Mass spectra were taken on a VG
ZAB-HS spectrometer in the electron impact ionization mode.
Elemental analyses were performed with a Perkin–Elmer 240C
analyzer. For X-ray crystallographic analysis, the X-ray diffraction
intensities and the unit cell parameters were determined on a
Siemens P4 diffractometer employing graphite-monochromated
3-(2-Naphthoyl)indolizine (5d). Yield: 184 mg, 68%. Yellow
solid from petroleum ether–ethyl acetate, mp 141–143 ◦C. 1H
NMR (300 MHz, CDCl3): d 6.58 (d, J = 4.6 Hz, 1H), 6.99 (t,
J = 7.0 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 4.6 Hz,
1H), 7.58–7.62 (m, 3H), 7.92–7.99 (m, 4H), 8.31 (s, 1H), 10.03 (d,
J = 7.0 Hz, 1H). IR (KBr): 1583, 1567, 1469, 1385, 1356, 1240,
1120, 1051, 817, 768, 758. MS (EI): m/z (%) 271 (100) [M+], 243
(11), 242 (20), 144 (17), 127 (9), 116 (10), 89 (4). Anal. Calcd for
C19H13NO: C, 84.13; H, 4.80; N, 5.17. Found: C, 84.19; H, 4.85;
N, 5.13.
˚
(Mo-Ka) radiation (l = 0.71073 A) and operating in the w-2q scan
mode. Data collection and cell refinement were performed with
XSCANS. Structures were solved by direct methods and refined
by full-matrix least-squares on F2 with SHELXTL. Non-hydrogen
atoms were refined by anisotropic displacement parameters, and
the positions of all H-atoms were fixed geometrically and included
in estimated positions using a riding model.
3-(4-Fluorobenzoyl)indolizine (5e). Yield: 198 mg, 83%. Pale
yellow solid from petroleum ether–ethyl acetate, mp 92–94 ◦C. 1H
NMR (300 MHz, CDCl3): d 6.55 (d, J = 4.5 Hz, 1H), 6.96 (td,
J = 6.9, 1.0 Hz, 1H), 7.15–7.22 (m, 3H), 7.32 (d, J = 4.5 Hz, 1H),
7.58 (d, J = 9.0 Hz, 1H), 7.82–7.86 (m, 2H), 9.95 (d, J = 7.2 Hz,
1H). IR (KBr): 1607, 1586, 1503, 1471, 1361, 1235, 752. IR (KBr):
1607, 1601, 1586, 1503, 1471, 1361, 1235, 1155, 1051, 833, 753.
MS (EI): m/z (%) 239 (100) [M+], 211 (67), 210 (32), 144 (92), 116
(73), 89 (20). Anal. Calcd for C15H10NOF: C, 75.31; H, 4.18; N,
5.86. Found: C, 75.37; H, 4.21; N, 5.89.
Crystallographic data (excluding structure factors) for the
structure in this paper is available as ESI.† CCDC 602715.
General procedure for the preparation of 3-acylindolizines (5a-5f)
A mixture of 1-phenacyl pyridinium salt 1 (1 mmol), maleic
anhydride 4 (0.196 g, 2 mmol), TPCD (1 g) and potassium
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3-(4-Phenylbenzoyl)indolizine (5f). Yield: 216 mg, 73%. Yellow
solid from petroleum ether–ethyl acetate, mp 144–146 ◦C. 1H
NMR (300 MHz, CDCl3): d 6.56 (d, J = 4.5 Hz, 1H), 6.97 (td, J =
6.9, 1.1 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.39–7.53 (m, 4H), 7.59
(d, J = 9.0 Hz, 1H), 7.67–7.74 (m, 4H), 7.92 (d, J = 8.4 Hz, 2H),
9.95 (d, J = 6.8 Hz, 1H). IR (KBr): 1592, 1578, 1469, 1387, 1356,
1235, 879, 768, 752, 740. MS (EI): m/z (%) 297 (100) [M+], 269
(57), 268 (43), 152 (23), 144 (59), 116 (26), 89 (8). Anal. Calcd for
C21H15NO: C, 84.85; H, 5.05; N, 4.71. Found: C, 84.80; H, 5.08;
N, 4.73.
for C20H15NO2: C, 79.73; H, 4.98; N, 4.65. Found: C, 79.77; H,
4.95; N, 4.66.
1-(2-Naphthoyl)pyrrolo[1,2-a]quinoline (6d). Yield: 235 mg,
73%◦. Yellow solid from petroleum ether–ethyl acetate, mp 135–
137 C. 1H NMR (300 MHz, CDCl3): d 6.57 (d, J = 4.2 Hz, 1H),
7.28 (d, J = 4.2 Hz, 1H), 7.41–7.44 (m, 3H), 7.52–7.67 (m, 3H),
7.75 (d, J = 7.7 Hz, 1H), 7.98 (t, J = 9.0 Hz, 3H), 8.16 (d, J =
8.5 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.63 (s, 1H). IR (KBr):
1606, 1572, 1555, 1483, 1452, 1335, 1321, 1271, 1052, 893, 810,
759. MS (EI): m/z (%) 321 (100) [M+], 293 (10), 292 (17), 194 (15),
166 (14), 127 (8). Anal. Calcd for C23H15NO: C, 85.98; H, 4.67; N,
4.36. Found: C, 86.05; H, 4.71; N, 4.31.
General procedure for the preparation of 1-acylpyrrolo[1,2-
a]quinolines (6a–6f)
1-(4-Fluorobenzoyl)pyrrolo[1,2-a]quinoline
(6e). Yield:
A mixture of quinolinium salt 2 (1 mmol), maleic anhydride 4
(0.196 g, 2 mmol), TPCD (1 g) and potassium carbonate (0.483 g,
3.5 mmol) in DMF (15 ml) was heated under N2 atmosphere at
90 ◦C for 6 h with magnetic stirring. The reaction was monitored by
TLC. After the reaction was completed, the solvent was removed
under reduced pressure, and the residue was separated by flash
chromatography on a silica gel column with petroleum ether (bp
60–90 ◦C)/ethyl acetate as an eluent to give the products 6.
258 mg, 89%◦. Yellow solid from petroleum ether–ethyl acetate,
1
mp 120–121 C. H NMR (300 MHz, CDCl3): d 6.56 (d, J =
4.5 Hz, 1H), 7.19–7.25 (m, 3H), 7.40–7.45 (m, 3H), 7.54 (td, J =
7.2, 1.5 Hz, 1H), 7.73 (dd, J = 7.8, 1.3 Hz, 1H), 8.09–8.16 (m,
3H). IR (KBr): 1614, 1595, 1452, 1338, 1225, 1156, 879, 812, 754.
MS (EI): m/z (%) 289 (100) [M+], 261 (40), 260 (23), 194 (61), 166
(58), 84 (22). Anal. Calcd for C19H12NOF: C, 78.89; H, 4.15; N,
4.84. Found: C, 78.84; H, 4.18; N, 4.82.
1-(4-Methylbenzoyl)pyrrolo[1,2-a]quinoline
(6f). Yield:
1-Benzoylpyrrolo[1,2-a]quinoline (6a). Yield: 211 mg, 78%.
Yellow solid from petroleum ether–ethyl acetate, mp 93–95 ◦C.
1H NMR (300 MHz, CDCl3): d 6.55 (d, J = 4.3 Hz, 1H), 7.22 (d,
J = 4.3 Hz, 1H), 7.40–7.45 (m, 3H), 7.52–7.57 (m, 3H), 7.63 (t, J =
7.3 Hz, 1H), 7.73 (dd, J = 7.7, 1.0 Hz, 1H), 8.09 (d, J = 7.1 Hz,
2H), 8.20 (d, J = 8.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): d
184.3, 139.5, 139.4, 133.7, 132.2, 130.1, 128.9, 128.6, 128.5, 128.2,
128.0, 125.7, 125.0, 124.6, 120.1, 117.9, 104.0. IR (KBr): 1614,
1597, 1575, 1452, 1337, 1207, 871, 811, 719. MS (EI): m/z (%)
271 (100) [M+], 243 (20), 242 (15), 194 (34), 166 (25), 77 (6). Anal.
Calcd for C19H13NO: C, 84.13; H, 4.80; N, 5.17. Found: C, 84.10;
H, 4.83; N, 5.18.
233 mg, 82%. Yellow oil. 1H NMR (300 MHz, CDCl3): d 2.50 (s,
3H), 6.55 (d, J = 4.5 Hz, 1H), 7.22 (d, J = 4.5 Hz, 1H), 7.35 (d,
J = 8.0 Hz, 2H), 7.38–7.44 (m, 3H), 7.52 (td, J = 7.2, 1.5 Hz,
1H), 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H),
8.16 (d, J = 8.5 Hz, 1H). IR (KBr): 1625, 1605, 1483, 1454, 1338,
1269, 1176, 1051, 876, 807, 748. MS (EI): m/z (%) 285 (100) [M+],
257 (22), 256 (17), 194 (23), 166 (18), 91 (6). Anal. Calcd for
C20H15NO: C, 84.21; H, 5.26; N, 4.91. Found: C, 84.27; H, 5.29;
N, 4.89.
General procedure for the preparation of 1-acylpyrrolo[2,1-
a]isoquinolines (7a–7i)
1-(4-Chlorobenzoyl)pyrrolo[1,2-a]quinoline
(6b). Yield:
A mixture of isoquinolinium salt 3 (1 mmol), maleic anhydride 4
(0.196 g, 2 mmol), TPCD (1 g) and potassium carbonate (0.483 g,
3.5 mmol) in DMF (15 ml) was heated under N2 atmosphere at
90 ◦C for 6 h with magnetic stirring. The reaction was monitored by
TLC. After the reaction was completed, the solvent was removed
under reduced pressure, and the residue was separated by flash
chromatography on a silica gel column with petroleum ether (bp
60–90 ◦C)/ethyl acetate as an eluent to give the products 7.
262 mg, 86%. Yellow solid from petroleum ether–ethyl acetate, mp
110–112 ◦C. 1H NMR (300 MHz, CDCl3): d 6.56 (d, J = 4.4 Hz,
1H), 7.22 (d, J = 4.4 Hz, 1 H), 7.40–7.46 (m, 3H), 7.50–7.58 (m,
3H), 7.73 (dd, J = 7.8, 1.4 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 8.15
(d, J = 7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 182.8, 139.7,
138.5, 137.9, 133.7, 131.4, 129.0, 128.7, 128.6, 128.1, 126.0, 125.0,
124.8, 120.1, 117.9, 104.3. IR (KBr): 1626, 1611, 1587, 1454,
1399, 1329, 1089, 1054, 879, 806, 750. MS (EI): m/z (%) 305 (100)
[M+], 277 (15), 276 (6), 194 (32), 166 (24), 139 (4). Anal. Calcd
for C19H12NOCl: C, 74.75; H, 3.93; N, 4.59. Found: C, 74.80; H,
3.95; N, 4.61.
1-Benzoylpyrrolo[2,1-a]isoquinoline (7a). Yield: 216 mg, 80%.
Colorless solid from petroleum ether–ethyl acetate, mp 140–
◦
1
142 C. H NMR (300 MHz, CDCl3): d 7.07 (d, J = 4.5 Hz,
1H), 7.14 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 4.5 Hz, 1H), 7.49–7.60
(m, 5H), 7.75 (dd, J = 6.6, 2.4 Hz, 1H), 7.87 (dd, J = 8.1, 1.5 Hz,
2H), 8.20 (dd, J = 6.6, 2.2 Hz, 1H), 9.62 (d, J = 7.5 Hz, 1H).
13C NMR (75 MHz, CDCl3): d 185.4, 140.6, 136.9, 131.2, 129.2,
128.9, 128.2, 128.0, 127.7, 126.9, 126.0, 125.8, 124.6, 123.6, 113.4,
102.0. IR (KBr): 1610, 1573, 1468, 1357, 1234, 1053, 875, 797, 760,
723, 695. MS (EI): m/z (%) 271 (100) [M+], 243 (6), 242 (19), 194
(24), 166 (15), 139 (7), 77 (4). Anal. Calcd for C19H13NO: C, 84.13;
H, 4.80; N, 5.17. Found: C, 84.09; H, 4.82; N, 5.17.
1-(4-Methoxybenzoyl)pyrrolo[1,2-a]quinoline
(6c). Yield:
242 mg, 80%. Yellow solid from petroleum ether–ethyl acetate,
mp 109–111 ◦C. 1H NMR (300 MHz, CDCl3): d 3.93 (s, 3H), 6.55
(d, J = 4.3 Hz, 1H), 7.03 (dt, J = 8.8, 2.0 Hz, 2H), 7.19 (d, J =
4.3 Hz, 1H), 7.36–7.43 (m, 3H), 7.51 (td, J = 7.2, 1.5 Hz, 1H),
7.71 (dd, J = 7.8, 1.5 Hz, 1H), 8.09 (dd, J = 9.0, 1.8 Hz, 3H).
13C NMR (75 MHz, CDCl3): d 183.8, 163.1, 138.8, 133.7, 132.4,
131.9, 128.6, 128.4, 127.9, 127.7, 125.1, 125.0, 124.5, 120.0, 118.0,
113.6, 103.8, 55.5. IR (KBr): 1600, 1556, 1453, 1338, 1261, 1168,
1025, 881, 808, 755. MS (EI): m/z (%) 301 (100) [M+], 273 (7),
272 (14), 258 (10), 194 (13), 166 (18), 135 (11), 77 (5). Anal. Calcd
1-(4-Chlorobenzoyl)pyrrolo[2,1-a]isoquinoline
(7b). Yield:
268 mg, 88%. Yellow solid from petroleum ether–ethyl acetate,
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◦
1
mp 208–210 C. H NMR (300 MHz, CDCl3): d 7.08 (d, J =
4.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1 H), 7.29 (d, J = 4.5 Hz, 1H),
7.50 (dt, J = 8.6, 2.1 Hz, 2H), 7.58–7.62 (m, 2H), 7.74–7.77 (m,
1H), 7.80 (dt, J = 8.6, 2.1 Hz, 2H), 8.21 (dd, J = 6.6, 2.5 Hz, 1H),
9.59 (d, J = 7.5 Hz,1H). 13C NMR (75 MHz, CDCl3): d 183.9,
138.9, 137.4, 137.2, 130.5, 129.0, 128.5, 128.2, 127.8, 127.0, 125.8,
125.7, 124.6, 124.4, 123.7, 113.6, 102.2. IR (KBr): 1610, 1590,
1565, 1467, 1452, 1352, 1233, 1088, 878, 806, 756, 748. MS (EI):
m/z (%) 305 (100) [M+], 277 (5), 276 (10), 241 (7), 194 (31), 166
(23), 139 (13). Anal. Calcd for C19H12NOCl: C, 74.75; H, 3.93; N,
4.59. Found: C, 74.67; H, 3.92; N, 4.58.
(13), 256 (60), 194 (46), 166 (35), 139 (12), 91 (6). Anal. Calcd for
C20H15NO: C, 84.21; H, 5.26; N, 4.91. Found: C, 84.25; H, 5.23;
N, 4.92.
Ethyl pyrrolo[2,1-a]isoquinoline-1-carboxylate (7g). Yield:
161 mg, 67%. Colorless solid from petroleum ether–ethyl acetate,
◦
◦
1
mp 95–97 C (lit:21 94 C). H NMR (300 MHz, CDCl3): d 1.45
(t, J = 6.9 Hz, 3H), 4.42 (q, J = 6.9 Hz, 2H), 7.00–7.02 (m, 2H),
7.47–7.55 (m, 3H), 7.66 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.5 Hz,
1H), 9.23 (d, J = 7.5 Hz, 1H). IR (KBr): 1688, 1533, 1471, 1452,
1342, 1247, 1179, 1104, 1066, 801, 737. MS (EI): m/z (%) 239 (100)
[M+], 211 (44), 194 (30), 167 (27), 166 (16), 139 (6). Anal. Calcd
for C15H13NO2: C, 75.31; H, 5.44; N, 5.86. Found: C, 75.38; H,
5.42; N, 5.83.
1-(4-Methoxybenzoyl)pyrrolo[2,1-a]isoquinoline (7c). Yield:
251 mg, 83%. Yellow solid from petroleum ether–ethyl acetate,
mp 187–189 ◦C. 1H NMR (300 MHz, CDCl3): d 3.92 (s, 3H), 7.02
(d, J = 8.7 Hz, 2H), 7.06 (d, J = 4.3 Hz, 1H), 7.10 (d, J = 7.6 Hz,
1H), 7.33 (d, J = 4.4 Hz, 1H), 7.55–7.62 (m, 2H), 7.73 (dd, J =
6.6, 1.9 Hz, 1H), 7.88 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 7.2 Hz,
1H), 9.55 (d, J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): d
184.5, 162.3, 133.1, 131.3, 128.8, 127.9, 127.7, 126.9, 125.8, 125.2,
124.8, 123.6, 113.5, 113.1, 101.7, 55.5. IR (KBr): 1604, 1573,
1451, 1353, 1252, 1026, 880, 841, 796, 757. MS (EI): m/z (%) 301
(100) [M+], 273 (3), 272 (11), 258 (4), 194 (8), 166 (8), 139 (3).
Anal. Calcd for C20H15NO2: C, 79.73; H, 4.98; N, 4.65. Found: C,
79.66; H, 4.95; N, 4.70.
1-(4-Phenylbenzoyl)pyrrolo[2,1-a]isoquinoline
(7h). Yield:
285 mg, 82%◦. Yellow solid from petroleum ether–ethyl acetate,
1
mp 238–240 C. H NMR (300 MHz, CDCl3): d 7.10 (d, J =
4.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 4.5 Hz, 1H),
7.43 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.57–7.62 (m,
2H), 7.68–7.76 (m, 5H), 7.95 (d, J = 8.1 Hz, 2H), 8.22 (dd, J =
6.6, 2.1 Hz, 1H), 9.64 (d, J = 7.6 Hz, 1H). IR (KBr): 1610, 1579,
1530, 1468, 1451, 1353, 1236, 1055, 880, 796, 760, 739. MS (EI):
m/z (%) 347 (100) [M+], 319 (7), 318 (15), 194 (12), 166 (11), 139
(4), 84 (3). Anal. Calcd for C25H17NO: C, 86.46; H, 4.90; N, 4.03.
Found: C, 86.49; H, 4.95; N, 4.01.
1-(2-Naphthoyl)pyrrolo[2,1-a]isoquinoline (7d). Yield: 248 mg,
77%◦. Yellow solid from petroleum ether–ethyl acetate, mp 216–
218 C. 1H NMR (300 MHz, CDCl3): d 7.10 (d, J = 4.5 Hz, 1H),
7.18 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 4.5 Hz, 1H), 7.56–7.64
(m, 4H), 7.76 (dd, J = 6.6, 2.4 Hz, 1H), 7.93–8.00 (m, 4H), 8.23
(dd, J = 6.6, 2.2 Hz, 1H), 8.37 (s, 1H), 9.65 (d, J = 7.5 Hz, 1H).
13C NMR (75 MHz, CDCl3): d 185.3, 137.9, 137.0, 134.7, 132.5,
129.9, 129.1, 129.0, 128.1, 128.0, 127.8, 127.7, 127.6, 126.9, 126.6,
126.0, 125.9, 125.8, 124.9, 124.7, 123.7, 113.4, 102.0. IR (KBr):
1603, 1590, 1449, 1354, 1242, 1112, 806, 752. MS (EI): m/z (%)
321 (100) [M+], 293 (8), 292 (23), 194 (18), 166 (18), 139 (11), 127
(8), 84 (8). Anal. Calcd for C23H15NO: C, 85.98; H, 4.67; N, 4.36.
Found: C, 85.95; H, 4.69; N, 4.38.
Pyrrolo[2,1-a]isoquinoline-1-carbonitrile (7i). Yield: 121 mg,
63%◦. Colorless solid from petroleum ether–ethyl acetate, mp 102–
104 C. 1H NMR (300 MHz, CDCl3): d 6.98 (d, J = 4.1 Hz, 1H),
7.08 (d, J = 7.4 Hz, 1H), 7.31 (d, J = 4.2 Hz, 1H), 7.51–7.62 (m,
2H), 7.69 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 8.11 (d,
J = 7.8 Hz, 1H). IR (KBr): 2217, 1637, 1527, 1455, 1354, 1126,
791, 739. MS (EI): m/z (%) 192 (100) [M+], 165 (14), 164 (9), 139
(5), 138 (5), 96 (6). Anal. Calcd for C13H8N2: C, 81.25; H, 4.17; N,
14.58. Found: C, 81.35; H, 4.21; N, 14.52.
Procedure for the preparation of 3-acylindolizines (5a-5c) with
manganese dioxide as an oxidant
1-(4-Fluorobenzoyl)pyrrolo[2,1-a]isoquinoline
(7e). Yield:
267 mg, 92%. Yellow solid from petroleum ether–ethyl acetate, mp
191–193 ◦C. 1H NMR (300 MHz, CDCl3): d 7.07 (d, J = 4.5 Hz,
1H), 7.14–7.23 (m, 3H), 7.30 (d, J = 4.5 Hz, 1H), 7.57–7.63 (m,
2H), 7.75 (dd, J = 6.4, 2.4 Hz, 1H), 7.87–7.92 (m, 2H), 8.19 (dd,
J = 6.6, 2.4 Hz, 1H), 9.58 (d, J = 7.5 Hz, 1H). IR (KBr): 1612,
1600, 1587, 1466, 1451, 1353, 1229, 1056, 881, 805, 750. MS (EI):
m/z (%) 289 (100) [M+], 261 (10), 260 (57), 194 (56), 166 (41),
139 (12). Anal. Calcd for C19H12NOF: C, 78.89; H, 4.15; N, 4.84.
Found: C, 78.81; H, 4.17; N, 4.81.
A mixture of the corresponding 1-phenacyl pyridinium salt 1a,
1b or 1c (1 mmol), maleic anhydride 4 (0.196 g, 2 mmol),
newly prepared MnO2 (0.7 g) and potassium carbonate (0.483 g,
3.5 mmol) in DMF (10 ml) was heated at 90 ◦C under N2
atmosphere for 3 h with magnetic stirring. The reaction course was
monitored by TLC. After the reaction, the solvent was removed
under reduced pressure, and the residue was separated by flash
chromatography on a silica gel column with petroleum ether (bp
60–90 ◦C)/ethyl acetate as an eluent to give the products 5a
(143 mg, 65%), 5b (181 mg, 71%) or 5c (165 mg, 66%).
1-(4-Methylbenzoyl)pyrrolo[2,1-a]isoquinoline
(7f). Yield:
236 mg, 83%◦. Yellow solid from petroleum ether–ethyl acetate,
1
mp 168–170 C. H NMR (300 MHz, CDCl3): d 2.48 (s, 3H),
7.05 (d, J = 4.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.28–7.35 (m,
3H), 7.56–7.59 (m, 2H), 7.73 (dd, J = 6.7, 1.8 Hz, 1H), 7.77 (d,
J = 8.0 Hz, 2H), 8.20 (dd, J = 6.8, 1.5 Hz, 1H), 9.60 (d, J =
7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 185.3, 141.7, 137.8,
136.7, 129.3, 128.9, 127.9, 127.7, 126.9, 125.8, 125.6, 124.8, 124.7,
123.6, 113.2, 101.8, 21.6. IR (KBr): 1599, 1563, 1466, 1452, 1347,
1234, 1051, 878, 748, 739. MS (EI): m/z (%) 285 (100) [M+], 257
Acknowledgements
This work was supported by the NSFC (20272024, 20742002),
41th China Planned Projects for Postdoctoral Research Funds
(20070411027), Jiangsu Planned Projects for Postdoctoral Re-
search Funds (0701009B), and Natural Science Foundation of
Jiangsu Province (BK 2007132).
2454 | Org. Biomol. Chem., 2010, 8, 2449–2456
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