One-pot, three-component synthesis of a library of new pyrrolo[1,2-a] quinoline derivatives

Article abstract of DOI:10.1055/s-0029-1217367

The synthesis of a library of pyrrolo[1,2-a]quinoline derivatives 4-33 was performed by an efficient one-pot, three-component reaction from quinolines 1a-c, 2-bromoacetophenones 2 and non-symmetrical acetylenic dipolarophiles 3a-c in 1,2-epoxypropane as b

Full text of DOI:10.1055/s-0029-1217367

LETTER
1795
One-Pot, Three-Component Synthesis of a Library of New
Pyrrolo[1,2-a]quinoline Derivatives
New
P
yrrolo[1,
m
2-
a
]quinoline
D
eriv
i
atives lian Georgescu,a Mino R. Caira,*b Florentina Georgescu,a Bogdan Drăghici,c Marcel M. Popa,c
Florea Dumitrascuc
a
Oltchim Research Center, St. Uzinei 1, 240050 Ramnicu Valcea, Romania
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b
Fax +27(21)6897499; E-mail: Mino.Caira@uct.ac.za
Centre of Organic Chemistry ‘C. D. Nenitzescu’, Romanian Academy, Spl. Independentei 202B, Bucharest 060023, Romania
c
Received 2 February 2009
electron-deficient alkynes or alkenes.7 Herein, we de-
scribe the synthesis of a library of pyrrolo[1,2-a]quino-
lines via 1,3-dipolar cycloaddition reactions in an efficient
one-pot, three-component synthesis based on a consecu-
Abstract: The synthesis of a library of pyrrolo[1,2-a]quinoline de-
rivatives 4–33 was performed by an efficient one-pot, three-compo-
nent reaction from quinolines 1a–c, 2-bromoacetophenones 2 and
non-symmetrical acetylenic dipolarophiles 3a–c in 1,2-epoxypro-
pane as both reaction medium and HBr scavenger. As this approach tive quaternization, 1,3-dipolar cycloaddition and aroma-
was unsuccessful in the case of DMAD, a different method was
tization sequence.
used for the synthesis of pyrrolo[1,2-a]quinolines 35–44. The struc-
tural features of the cycloadducts 19 and 44 were investigated by X-
Sequential transformations, multicomponent processes
and one-pot reactions provide opportunities for the syn-
theses of heterocycles.8 These synthetic pathways involve
reactions with at least three starting materials in one-pot,
which offers straightforward one-step transformations.
ray analysis.
Key words: 1,3-dipolar cycloaddition, N-ylide, pyrrolo[1,2-
a]quinoline, multicomponent reaction
The key components of the multi-stage process are qui-
nolines 1, bromoacetophenones 2, non-symmetrical elec-
tron-deficient alkynes 3 and 1,2-epoxypropane, which
acts both as solvent and proton scavenger.
In the last decade, interest in pyrrolo[1,2-a]quinolines has
been constant and, as a result, various new syntheses and
reconsiderations of previously known synthetic pathways
have been reported.1 The pyrrolo[1,2-a]quinoline deriva-
tives were found to possess interesting biological2 and
physical properties.3 For example, gephyrotoxin, a substi-
tuted perhydropyrrolo[1,2-a]quinoline isolated by Daly
and coworkers in 1977 from secretions of the frog dendro-
bates histrionicus,4 was studied for its biological activity
and has been a target for total synthesis.5
Usually, the synthesis of pyrrolo[1,2-a]quinolines via
quinolinium N-ylides requires the preparation and separa-
tion of quinolinium salts in the first step. Subsequently,
quinolinium salts are converted into pyrrolo[1,2-a]quino-
lines by treatment with a base, which generates the corre-
sponding quinolinium N-ylide in the presence of an
acetylenic dipolarophile.
Generally, for the synthesis of pyrrolo[1,2-a]quinoline
derivatives, two main routes are available: the first start-
ing from quinoline and its derivatives and the second
starting from pyrrole derivatives substituted at the nitro-
gen atom with an aryl group. Additionally, examples of
the syntheses of pyrrolo[1,2-a]quinolines based on rear-
rangement reactions or starting from acyclic compounds
are reported in the literature.6
In the multicomponent pathway, the reaction mechanism
implies the intermediate formation of the quinolinum salt
from the corresponding quinoline and 2-bromoacetophe-
none. In the next step, the bromide ion from the salts at-
tacks the oxirane ring of 1,2-epoxypropane, resulting in
ring-opening and generation of the N-ylide by the alkox-
ide. The N-ylide reacts with the activated alkyne 3 to give
the corresponding dihydropyrroloquinoline. Finally, the
pyrroloquinolines 4–33 are obtained by dehydrogenation
of the dihydropyrroloquinoline intermediate (Scheme 1).
One of the most important methods for the synthesis of
pyrrolo[1,2-a]quinoline derivatives involves the 1,3-dipo-
lar cycloaddition reactions of heterocyclic N-ylides with
R1
R1
COR2
N
O
COR2
+
ArCOCH2Br
+
R3
N
O
4–33
3a–c
1a–c
2
Scheme 1
SYNLETT 2009, No. 11, pp 1795–1799
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217367; Art ID: D03809ST
© Georg Thieme Verlag Stuttgart · New York

1796
E. Georgescu et al.
LETTER
The reaction conditions are mild, involving only mixing The structures of the new pyrroloquinolines were as-
of the components under stirring at room temperature for signed by elemental analysis, IR and NMR spectroscopy.
30 hours, followed by partial evaporation of the solvent The characteristic IR spectral features of compounds 4–33
and subsequent precipitation by the addition of methanol.9 are the carbonyl bands observed in the range 1630–1740
The compounds 4–33 (Table 1) were obtained with yields cm–1. Additionally, the ester C–O vibration could be ob-
in the 50–70% range. The substituents of the new pyrro- served at 1080 cm–1 and 1230 cm–1 for compounds 4–11
1
lo[1,2-a]quinoline compounds 4–33 are given in Table 1. and 18–33. In the H NMR spectra of compounds 4–33,
the general characteristic feature is the chemical shifts of
atoms H-2, H-4 and H-9, which appear strongly deshield-
ed due to the spatial vicinity of the carbonyl groups at-
Table 1 One-Pot, Three-Component Synthesis of Pyrrolo[1,2-
a]quinolines 4–33
tached to the positions 1 and 3 of the pyrrole ring. The H-
2 proton appears as a singlet with d = 7.21–7.77 ppm. The
13C NMR spectra contain all the expected signals. Addi-
tionally, the regioselectivity of the cycloaddition reaction
and the stereochemistry of cycloadducts 4–33 were deter-
mined by X-ray analysis of compound 19 as a representa-
tive compound (see below).
Product
4
R1
R2
R3
Mp (°C)
166–167
160–161
146–147
180–181
132–133
152–153
210–211
164–165
174–176
193–195
144–145
154–155
174–176
183–184
143–144
173–175
173–174
182–183
184–185
199–200
187–188
159–161
216–217
231–232
171–172
149–150
177–178
157–159
227–228
184–186
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
H
5
H
4-F
6
H
4-Cl
7
H
4-Br
3-MeO
4-MeO
3-NO2
4-Ph
4-Me
4-Cl
Interestingly, under the same reaction conditions the
three-component method for the synthesis of pyrrolo[1,2-
a]quinolines 35–43 gave very poor yields in the case of
dimethyl acetylenedicarboxylate (DMAD). Most proba-
bly due to its high reactivity, DMAD reacts faster with the
nitrogen atom from the quinoline instead of acting as a di-
polarophile in the further 1,3-dipolar cycloaddition. Be-
cause of this competition, the reaction leading to the
formation of the pyrroloquinolines is inhibited, and only
traces of these compounds were observed.
8
H
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
H
H
H
H
Me
H
Ph
H
However, compounds 35–43 were obtained starting from
the corresponding quinolinium salts 34a–j, which were
obtained separately by reaction of the substituted quino-
lines 1 and bromoacetophenones 2. The reaction of the
salts with DMAD in epoxypropane medium led to the for-
mation of the corresponding pyrroloquinolines by a sim-
ple one-pot reaction (Scheme 2).10 Similar results were
obtained in the case of compound 44 when the dipolaro-
phile DMAD was replaced by diethyl acetylenedicarboxy-
late (DEAD). The pyrroloquinolines 35–44 (Table 2)
were obtained in yields of 48–58%.
H
Ph
4-F
H
Ph
2-NO2
3-NO2
H
H
Ph
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
5-Me
5-Me
5-Me
5-Me
5-Me
5-Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4-Me
4-F
4-Cl
The structural assignments were made by elemental anal-
ysis, IR and NMR spectroscopy. The stereochemistry for
this series was confirmed by X-ray analysis of the repre-
sentative compound 44 (see below).
3-Br
4-Br
3-MeO
4-MeO
2-NO2
3-NO2
4-Me
4-Cl
The reaction pathway used in the case of DMAD
(Scheme 2) could also be successfully applied in the case
of compounds 4–33. Thus, starting from the salts of type
34 and non-symmetrical acetylenic dipolarophiles in pro-
penoxide medium, the pyrroloquinolines could be ob-
tained in yields differing by 3–5% from those obtained
using the one-pot, three-component method.
The X-ray structures of the representative compounds
1911 and 4412 are shown in Figure 1 and Figure 2 respec-
tively. Thermal ellipsoids are drawn at the 50% probabil-
ity level in each case and the rings of the tricyclic system
have been labeled for reference.
3-Br
4-MeO
3-NO2
4-CN
Given the paucity of explicit X-ray structural information
on the pyrrolo[1,2-a]quinoline system, and finding evi-
Synlett 2009, No. 11, 1795–1799 © Thieme Stuttgart · New York

LETTER
New Pyrrolo[1,2-a]quinoline Derivatives
1797
5
R1
7
6
5a
9a
4
R1
DMAD
or DEAD
R1
ArCOCH2Br
3a
8
CO2R2
N
9
3
Br–
CH2COAr
R3
+ N
N
1
2
CO2R2
O
O
1a–c
34a–j
35–44
Scheme 2
ues of 3.085(2) and 2.947(2) Å in 44]. More strikingly,
this steric strain results in carbonyl atom C15 being dis-
placed by ~0.50 Å above the plane of the pyrrole ring A in
both molecules, simultaneously inducing helical distor-
tion of the entire tricyclic system. One measure of this dis-
tortion is the sequence of interplanar angles A^B, B^C,
A^C (see Figure 1 and Figure 2), whose values are 6.6,
7.4 and 13.9°, respectively, in 19, and are somewhat larger
than those in 44, which are 1.9, 5.4 and 6.2° (all e.s.d.s
£0.1°). In both molecules, two C–H···O hydrogen bonds
determine the orientations of the carbonyl bond vectors
relative to the mean plane of the tricyclic system.
Table 2 Two-Step Synthesis of Pyrrolo[1,2-a]quinolines 35–44
Product
35
R1
R2
R3
Mp (°C)
210–211
196–198
191–193
245–247
192–194
190–191
198–199
211–212
214–216
167–168
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4-F
36
H
4-Br
37
H
3-NO2
3,4-(MeO)-
3-Br
38
H
39
7-Me
7-Me
7-Me
5-Me
5-Me
7-Me
40
3-NO2
3,4-(MeO)-
4-F
The distortions described above are virtually absent in 1-
aminopyrrolo[1,2-a]quinoline-2-carbonitrile,13a in which
the substituent at position C2 in the figures below is NH2,
the interplanar angles having values of only 0.8, 0.9 and
1.7° (e.s.d.s £0.1°) and the nitrogen atom being practically
coplanar with the pyrrole ring (deviation ~0.05 Å). A
small degree of helicity arises in 1-n-butylpyrrolo[1,2-
41
42
43
3,4-(MeO)-
3,4-(MeO)-
44
dence of unusual features in the representative molecules a]quinolin-3-yl acetate,13b the three interplanar angles of
19 and 44, we were prompted to examine their molecular the tricyclic system having values 2.4, 2.9 and 5.0° (e.s.d.s
conformations in some detail. Molecular strain, leading to ~0.2°). Finally, a somewhat larger helical distortion
significant deviations from planarity of the tricyclic sys- occurs in N-[3,5-bis(trifluoromethyl)benzyl]-5-phenyl-
tems in both 19 and 44, is evident. This originates from pyrrolo[1,2-a]quinoline-4-carboxamide2a (interplanar an-
intramolecular repulsion reflected in significantly short gles: 4.3, 3.3 and 7.2°, e.s.d.s ~0.2°). Here, however, the
contact distances between the carbonyl group C15=O16 only substituents on the pyrrole ring are hydrogen atoms,
and atom C12 in both molecules [C12···C15, 3.210(2) Å and the helicity originates from steric interactions remote
and C12···O16, 2.977(2) Å in 19, with corresponding val- from that site (i.e. on ring B, between a phenyl group at-
Figure 1 ORTEP plot of 19
Figure 2 ORTEP plot of 44
Synlett 2009, No. 11, 1795–1799 © Thieme Stuttgart · New York

1798
E. Georgescu et al.
LETTER
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Acknowledgment
M.R.C. thanks the University of Cape Town and the NRF (Pretoria)
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(9) Synthesis of Pyrrolo[1,2-a]quinolines 4–33; General
Procedure: Quinoline 1 (5 mmol), phenacyl bromide 2 (5
mmol) and non-symmetrical acetylene 3 (ethyl propiolate, 3-
butyn-2-one or benzoylacetylene; 7 mmol) in 1,2-epoxy-
propane (40 mL) were stirred at room temperature for 30 h.
The solvent was partly removed by evaporation, then
methanol (10 mL) was added and the mixture was left
overnight at room temperature. The solid was filtered,
washed with a mixture of MeOH–Et2O (1:1) and
recrystallised from CHCl3–MeOH. Ethyl 1-(4-Methyl-
benzoyl)-7-methyl-pyrrolo[1,2-a]quinoline-3-carboxy-
late (19): Yellow crystals with mp 173–175 °C were
obtained by recrystallization from CHCl3–MeOH. Yield:
54%; Anal. Calcd for C24H21NO3: C, 77.61; H, 5.70; N, 3.77.
Found: C, 77.91; H, 5.94; N, 3.98. FT-IR: 1617, 1654, 1704,
2976 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.39 (t, J = 7.1
Hz, 3 H, MeCH2), 2.47 (s, 3 H, MeAr), 2.50 (s, 3 H, 7-Me),
4.39 (q, J = 7.1 Hz, 2 H, CH2), 7.35–7.38 (m, 3 H, H-8, H-3¢,
H-5¢), 7.57 (d, J = 2.1 Hz, 1 H, H-6), 7.62 (s, 1 H, H-2), 7.60
(d, J = 9.3 Hz, 1 H, H-5), 7.87 (d, J = 8.9 Hz, 1 H, H-9), 7.95
(d, J = 8.8 Hz, 2 H, H-2¢, H-6¢), 8.23 (d, J = 9.3 Hz, 1 H, H-
4). 13C NMR (75 MHz, CDCl3): d = 14.5 (MeCH2), 20.8,
21.6 (7-Me, MeAr), 59.9 (OCH2), 107.4 (C-3), 117.6 (C-4),
119.9 (C-9), 125.1, 128.0, 131.4, 135.9, 139.7 (C-1, C-3a, C-
5a, C-9a, C-7), 128.3 (C-6), 129.4 (C-5), 128.6 (C-8), 129.1
(p) Fürstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264.
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Chem. 1985, 50, 722. (c) Ager, I. R.; Barnes, A. C.;
Danswan, G. W.; Hairsine, P. W.; Kay, D. P.; Kennewell,
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1098. (d) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht,
J. A. J. Med. Chem. 1988, 31, 2097. (e) Cai, S. X.; Drewe,
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Synlett 2009, No. 11, 1795–1799 © Thieme Stuttgart · New York

LETTER
New Pyrrolo[1,2-a]quinoline Derivatives
1799
(C-3¢, C-5¢), 129.9 (C-2), 130.2 (C-2¢, C-6¢), 135.1 (C-1¢),
H-4). 13C NMR (75 MHz, CDCl3): d = 20.9 (7-Me), 51.7,
52.8 (CO2CH3), 105.5 (C-3), 117.7 (C-4), 118.8 (C-9), 122.7
(C-3¢), 125.3, 127.2, 128.8, 131.2, 135.7, 140.3 (C-1, C-3a,
C-5a, C-9a, C-7, C-2), 128.4 (C-6), 128.5 (C-2¢), 128.9 (C-
5), 130.2 (C-5¢), 130.4 (C-8), 132.7 (C-2¢), 136.5 (C-4¢),
139.5 (C-1¢), 163.5, 165.1 (2 × COO), 185.7 (COAr).
(11) X-ray crystal data for 19: C24H21NO3; yellow plate;
M = 371.42; triclinic; P(–1); a = 9.3086 (5) Å, b = 10.4631
(5) Å, c = 10.9389 (5) Å, a = 91.153 (2)°, b = 112.900(3)°,
g = 104.195 (3)°; V = 943.48 (7) Å3; Z = 2; T = 173 (2) K;
F000 = 392; R1 = 0.0428, wR2 = 0.1170. The CCDC
deposition number: 718544.
(12) X-ray crystal data for 44: C28H27NO7; pale-yellow plate;
M = 489.51; triclinic; P(–1); a = 7.5730 (3) Å, b = 13.0161
(3) Å, c = 13.4416 (6) Å, a = 97.269 (2)°, b = 104.946 (2)°,
g = 102.512 (3)°; V = 1226.13 (8) Å3; Z = 2; T = 173 (2) K;
F000 = 516; R1 = 0.0414, wR2 = 0.1132. The CCDC depo-
sition number: 718545.
143.4 (C-4¢), 164.1 (COO), 184.8 (COAr).
(10) Synthesis of Pyrrolo[1,2-a]quinolines 35–44; General
Procedure: Quaternary salt 34a–j (5 mmol) and DMAD or
DEAD (7 mmol) in 1,2-epoxypropane (40 mL) were stirred
at room temperature for 24 h. The solvent was partly
removed by evaporation, then methanol (10 mL) was added
and the mixture was left overnight at room temperature. The
solid was filtered, washed on filter with a mixture of MeOH–
Et2O (1:1) and recrystallised from CHCl3–MeOH.
Dimethyl 1-(3-Bromobenzoyl)-7-methylpyrrolo[1,2-
a]quinoline-2,3-dicarboxylate (39): Yellow crystals with
mp 192–194 °C were obtained by recrystallization from
MeOH–CHCl3. Yield: 44%. Anal. Calcd for C23H18BrNO3:
C, 63.32; H, 4.16; Br, 18.31; N, 3.21. Found: C, 63.44; H,
4.39; Br, 18.66; N, 3.56. FT-IR: 1617, 1654, 1704, 2976 cm–
1. 1H NMR (300 MHz, CDCl3): d = 2.54 (s, 3 H, 7-Me), 3.50,
3.90 (s, 6 H, 2-CO2Me, 3-CO2Me), 7.27 (dd, J = 8.8, 2.1 Hz,
1 H, H-8), 7.36 (t, J = 7.8 Hz, 1 H, H-5¢), 7.51 (d, J = 8.9 Hz,
1 H, H-9), 7.57 (d, J = 2.1 Hz, 1 H, H-6), 7.58 (d, J = 9.3 Hz,
1 H, H-5), 7.73–7.77 (m, 1 H, H-4¢), 7.84–7.87 (m, 1 H, H-
6¢), 8.15 (t, J = 2.0 Hz, 1 H, H-2¢), 8.23 (d, J = 9.3 Hz, 1 H,
(13) (a) Tayyari, F.; Wood, D. E.; Fanwick, P. E.; Sammelson,
R. E. Synthesis 2008, 279. (b) Yan, B.; Zhou, Y.; Zhang, H.;
Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783.
Synlett 2009, No. 11, 1795–1799 © Thieme Stuttgart · New York