Stereoselective Synthesis of Pyrroloquinolines by a Br?nsted Acid Catalyzed [4+2]-Heterocyclization of Indole-7-Carbaldehydes, Anilines and Electron-Rich Alkenes

Article abstract of DOI:10.1002/adsc.201600154

The pyrrolo[3,2,1-ij]quinoline heterocyclic core is found in the structure of a variety of compounds with interesting applications and then, new efficient and flexible strategies to construct this skeleton are required. Here, a new diastereoselective tetrafluoroboric acid (HBF₄)-catalyzed three-component coupling reaction of 1H-indole-7-carbaldehyde derivatives, anilines and electron-rich alkenes to give pyrrolo[3,2,1-ij]quinolines is described. The reaction involves an unusual [4+2]-heterocyclization between an in situ formed imine and an alkene. The new catalytic method, where water is the only by-product, is efficient, robust and flexible, and allows for multigram-scale synthesis.

Full text of DOI:10.1002/adsc.201600154

COMMUNICATIONS
DOI: 10.1002/adsc.201600154
Stereoselective Synthesis of Pyrroloquinolines by a Brønsted Acid
Catalyzed [4+2]-Heterocyclization of Indole-7-Carbaldehydes,
Anilines and Electron-Rich Alkenes
a
a
a,
a,
Alicia Galvµn, Raquel Fontaneda, Francisco J. FaÇanµs, * and FØlix Rodríguez *
a
Instituto Universitario de Química Organometµlica “Enrique Moles”, Universidad de Oviedo, Juliµn Clavería 8, 33006
Oviedo, Spain
E-mail: fjfv@uniovi.es or frodriguez@uniovi.es
Received: February 3, 2016; Revised: March 9, 2016; Published online: May 3, 2016
th
Dedicated to our friend and colleague Angel R. de Lera on the occasion of his 60 birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600154.
[
6]
Abstract: The pyrrolo[3,2,1-ij]quinoline heterocyclic
core is found in the structure of a variety of com-
pounds with interesting applications and then, new
efficient and flexible strategies to construct this
skeleton are required. Here, a new diastereoselec-
emitting diodes (OLEDs). As a consequence, pyrro-
lo[3,2,1-ij]quinolines have become the subject of in-
tense study for the synthetic organic community.
[7]
However, there is still a need for new approaches to
this interesting heterocycle. The development of
novel protocols based on multicomponent coupling
reactions is particularly appealing because it allows
the rapid synthesis of small libraries of products by
simple variations on each component of the process.
In this context, we considered the possibility of syn-
thesizing functionalized pyrrolo[3,2,1-ij]quinoline de-
rivatives 4 in a single synthetic operation through an
acid-catalyzed three-component coupling reaction of
indole-7-carbaldehydes 1, amines 2 and electron-rich
alkenes 3 (Scheme 1). Thus, we hypothesized that
under acidic conditions the imine 5, formed by con-
densation of 1 and 2, would deliver the aza-o-quinone
tive tetrafluoroboric acid (HBF )-catalyzed three-
4
component coupling reaction of 1H-indole-7-carbal-
dehyde derivatives, anilines and electron-rich al-
kenes to give pyrrolo[3,2,1-ij]quinolines is de-
scribed. The reaction involves an unusual [4+2]-het-
erocyclization between an in situ formed imine and
an alkene. The new catalytic method, where water
is the only by-product, is efficient, robust and flexi-
ble, and allows for multigram-scale synthesis.
Keywords: acid catalysis; heterocycles; homogene-
ous catalysis; indoles; synthetic methods
[8]
methide derivative (aza-oQM) 6. This electron-poor
The pyrrolo[3,2,1-ij]quinoline skeleton is the core
structure of a range of interesting compounds in the
area of drug discovery, agrochemistry and materials
science (Figure 1).
For example, compound I and some other similar
molecules have been tested for their ability to bind
the recombinant human MT1 and MT2 melatonin re-
[
1]
ceptor subtypes expressed in NIH 3T·cells. The in-
[
2]
terest of compound II as anticonvulsant and III as
a potential drug for the treatment of type II diabetes
[
3]
has also been demonstrated. Other pyrrolo[3,2,1-ij]-
quinoline derivatives with potential application in
[
4]
medicine are IV, for the management of epilepsy
and obesity, and V (KC11404) for the treatment of
[
5]
asthma. Finally, compound VI (DCQTB) has found Figure 1. Pyrrolo[3,2,1-ij]quinolines. Some examples of inter-
utility as red-light-emitting dopant in organic light- esting compounds containing this heterocyclic core.
Adv. Synth. Catal. 2016, 358, 1741 – 1745
1741
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

COMMUNICATIONS
asc.wiley-vch.de
ring for 2 h at room temperature. At this stage, the re-
action mixture was cooled to 08C and 2,3-dihydrofur-
an 3a (3 equiv.) was added. After 16 h at 08C the re-
action was quenched (95% conversion) and the analy-
sis of the crude of the reaction showed the presence
of a 2:1 mixture of the products 4a and 7a (Table 1,
entry 1). The major product 4a was the result of the
desired [4+2] heterocyclization reaction shown in
Scheme 1 while the minor product 7a was the result
of an alternative [4+2]-Povarov reaction involving the
[10]
aromatic ring coming from the aniline (Ar). These
two products were easily separated by column chro-
matography and thus compound 4a could be isolated
in 60% yield as a single diastereoisomer.
Scheme 1. Our multicomponent synthetic proposal to get
pyrrolo[3,2,1-ij]quinoline derivatives.
heterodiene derivative should react with an electron-
At this point, we suspected that the reaction could
rich alkene 3 through a formal inverse electron be modulated to selectively get the desired products 4
demand [4+2]-cycloaddition reaction to give the func- by varying the electronic properties of the aromatic
[11]
tionalized pyrrolo[3,2,1-ij]quinoline derivatives 4. This ring of the aniline counterpart. Thus, as expected,
unusual formal [4+2]-cycloaddition reaction where the use of the electron richer 4-methoxyaniline 2b led
the indole derivative acts as a heterodiene is unprece- to a higher proportion of the undesired Povarov prod-
dented. Herein, we report our results on this pro- uct 7 (4b/7b, ratio 1:1; Table 1, entry 2). On the con-
posed acid-catalyzed multicomponent coupling reac- trary, when the reaction was performed with the ani-
[
9]
tion.
line derivative 2c containing an electron-withdrawing
To test the feasibility of the proposed reaction, 1H- chlorine atom on the aromatic ring, the amount of the
indole-7-carbaldehyde 1a, aniline 2a and 2,3-dihydro- Povarov product was reduced (4c/7c, ratio 5:1;
furan 3a were selected as model starting materials Table 1, entry 3). This reaction had to be performed
and tetrafluoroboric acid (HBF ) was chosen as the at À308C because decomposition and formation of
4
Brønsted acid catalyst (Table 1, entry 1).
mixtures of unidentified products were observed at
After an evaluation of different conditions, it was higher temperatures. Under the optimized conditions,
found that the reaction of 1H-indole-7-carbaldehyde the desired pyrrolo[3,2,1-ij]quinoline derivative 4c
1
a with aniline 2a (1 equiv.) in the presence of could be isolated in 80% yield as a single diastereo-
15 mol% of HBF in dichloromethane as solvent led isomer. Interestingly, the structure and relative config-
4
to the formation of the expected imine 5a after stir- uration of the stereogenic centres of 4c were con-
[
a]
Table 1. Initial experiments. Optimization of the reaction conditions.
[
b]
[b]
[c]
Entry
ArNH (2)
T [8C]
t [h]
4/7 (ratio)
Conv. (Yield [%])
2
1
2
3
4
5
PhNH (2a)
0
0
À30
À50
À70
16
12
24
48
48
4a/7a (2:1)
4b/7b (1:1)
4c/7c (5:1)
95 (60)
67 (32)
97 (80)
95 (90)
>99 (96)
2
4-MeOC H NH (2b)
6
4
2
4-ClC H NH (2c)
6
4
2
[
d]
3,5-Cl C H NH (2d)
4d
[d,e]
2
6
3
2
3,5-(CF ) C H NH (2e)
4e
3
2
6
3
2
[a]
Reaction conditions: 1a (1 equiv.), 2 (1 equiv.) and 15 mol% of HBF were reacted for 2 h at room temperature to form
4
the imine 5. Then, 3a (3 equiv.) was added at the temperature shown and the reaction was stirred for the time shown.
Determined by H NMR analysis of the crude reaction mixture.
The yield of isolated product 4 based on starting material 1a is shown in parenthesis.
The corresponding product 7 was not detected.
Reaction scaled up to get 4.6 g of 4e.
[
[
[
[
b]
c]
d]
e]
1
Adv. Synth. Catal. 2016, 358, 1741 – 1745
1742
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

COMMUNICATIONS
asc.wiley-vch.de
[
12]
firmed by single crystal X-ray analysis. Formation
of the undesired Povarov product 7 could be finally
suppressed by using the relatively electron-poor ani-
lines 2d (3,5-dichloroaniline) and 2e [3,5-bis(trifluoro-
methyl)aniline] (Table 1, entries 4 and 5). Thus, pyrro-
lo[3,2,1-ij]quinoline derivatives 4d and 4e were clean-
ly formed as single diastereoisomers and isolated in
very high yields (90 and 96%, respectively).
Further attempts to perform the reaction with ali-
phatic amines instead of anilines were unsuccessful.
Regarding the catalyst of the reaction, it should be
noted that other typical Brønsted acids (strong such
as triflic acid and other similar, or soft acids such as
diphenyl phosphate and other similar species) were
completely ineffective. To further demonstrate the ro-
bustness and efficiency or this new protocol for the
synthesis of pyrroloquinoline derivatives we per-
formed an experiment at a multigram scale. Accord-
ingly, 4.6 g of 4e were easily prepared in a reaction
that proceeded without noticeable erosion in yield or
stereoselectivity.
Next, the scope of the reaction was explored on dif-
ferent substrates (Scheme 2). As shown, diverse sub-
stitution was allowed on the 1H-indole-7-carbalde-
[
13]
hyde counterpart (products 4h–m). Aniline deriva-
tives 2 substituted with one (products 4f, g, q) or two
electron-withdrawing atoms or groups (products 4h–
p) were also appropriate substrates. Interestingly, the
reaction worked not only with 2,3-dihydrofuran 3a as
electron-rich alkene but also with substituted enol
ethers (4n) and the simple linear butyl vinyl ether
(4o). Some reactions were attempted with N-protect-
ed enamine derivatives instead of enol ethers. As
shown, these reagents were appropriate partners in
this multicomponent coupling reaction and, thus,
compounds 4p and 4q were isolated in high yields as
single diastereoisomers and as mixtures of two rotam-
ers at room temperature. It is important to remark
that in all these examples we did not detect the for-
mation of the alternative Povarov product 7 as evi-
1
denced by H NMR analyses of the crude reaction
mixtures. Moreover, compounds 4 were formed as
single diastereoisomers in all cases.
Scheme 2. Synthesis of pyrrolo[3,2,1-ij]quinoline derivatives
. Reaction conditions: 1 and 2 were stirred with 15 mol% of
To further expand the synthetic utility of the new
reaction here described we developed a very simple
protocol to remove the aniline moiety in compounds
4
HBF for 2 h at room temperature and then 3 (3 equiv.) was
4
added at the temperature T shown.
4
(Scheme 3). Thus, oxidation of pyrrolo[3,2,1-ij]qui-
noline derivative 4e with DDQ provided the imine 8,
which, after hydrolysis, afforded the (6aR*,9aS*)-
1,2,6a,7,8,9a-hexahydro-6H-furo[2,3-b]pyrrolo[3,2,1-
ij]quinolin-6-one 9 in a basically quantitative global
yield. This pyrroloquinolone derivative 9 could be fur-
ther transformed into different compounds by con-
ventional transformations of the ketone functional
group. Interestingly, the aniline 2e was easily recov-
ered at the end of the sequence shown in Scheme 3 Scheme 3. Transformation of aniline derivative 4e into
and reused in subsequent reactions.
ketone 9.
Adv. Synth. Catal. 2016, 358, 1741 – 1745
1743
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

COMMUNICATIONS
asc.wiley-vch.de
formal [4+2]-heterocyclization between the in situ
formed imine and the electron-rich alkene. Interest-
ingly, an appropriate choice of the aniline counterpart
allowed reversing the reaction from the usual Povar-
ov-pathway to the novel [4+2]-heterocyclization
route. The new reaction is high yielding, scalable, the
only by-product is water and it offers the opportunity
to easily generate molecular diversity by simple varia-
tions on the starting materials. These remarkable fea-
tures coupled with the importance of pyrrolo[3,2,1-ij]-
quinolines derivatives in medicinal chemistry makes
the reaction described herein an appropriate tool for
the discovery of some new bioactive compounds. Fur-
ther studies on this subject are being currently consid-
ered.
Experimental Section
General Procedure for the Synthesis of Pyrrolo[3,2,1-
ij]quinoline Derivatives 4
Scheme 4. Proposed mechanism for the formation of com-
pounds 4.
The corresponding 1H-indole-7-carbaldehyde derivative
1
(1 equiv., 0.2 mmol), aniline 2 (1 equiv., 0.2 mmol) and 4Š
powder molecular sieves (50 mg) were placed in a glass re-
action tube equipped with a magnetic stirring bar under an
The mechanism proposed to explain the formation
of products 4 is shown in Scheme 4 and involves a cat- argon atmosphere. Then, dichloromethane (2 mL) was
alytic process where the tetrafluoroboric acid pro- added, the slurry was cooled to 08C and HBF (15 mol%)
was added. The mixture was allowed to warm to room tem-
4
motes two different reactions.
perature and stirred for 2 h. Then, the mixture was cooled
to the appropriate temperature (see Scheme 2) and the cor-
responding electron-rich alkene 3 (3 equiv., 0.6 mmol) was
added. The reaction was kept at the corresponding tempera-
ture and followed by TLC until total consumption of the in
situ formed imine derivative (9–72 h). The resulting slurry
was filtered through a pad of basic alumina (except for the
case of compounds 4p and 4q where silica gel was used)
Thus, condensation of 1H-indole-7-carbaldehyde
derivatives 1 and anilines 2 affords the imines 5 that
enter the second catalytic cycle to form the species 6.
This intermediate may be represented as the proton-
ated imine 6A or the aza-o-quinone methide reso-
nance form 6B. The subsequent formal [4+2]-hetero-
cyclization reaction between the heterodiene shown
in the aza-o-quinone methide resonance form 6B and eluting with ethyl acetate, the solvent was removed under
the electron-rich alkene 3 delivers the new intermedi- vacuum and the crude was purified by flash column chroma-
ate 10. A final deprotonation step closes the catalytic tography on silica gel using mixtures of hexane and diethyl
ether as eluent to give the corresponding pure pyrrolo[3,2,1-
ij]quinoline derivative 4.
cycle affording the final pyrrolo[3,2,1-ij]quinoline de-
rivatives 4 and regenerates the acid catalyst. The rela-
tive configuration observed at the new stereogenic
centres in the final products 4 can be explained con-
sidering the approach shown in I (Scheme 4). Thus, in
the first place, we propose that the azadiene counter- Acknowledgements
part 6B adopts a cis-configuration favoured by the
formation of an intramolecular hydrogen bond. The
We acknowledge financial support from MINECO-Spain
(grant CTQ2013-41336-P) and MEC (FPU-predoctoral grant
subsequent approach of the alkene following an exo-
trajectory would form the intermediate 10 with the
stereochemistry observed in the final products. Re-
markably, as shown in the mechanism, the only by-
product of this reaction is water.
In summary, we have developed a new multicompo-
nent coupling reaction of 1H-indole-7-carbaldehydes,
anilines and electron-rich alkenes for the efficient dia-
stereoselective synthesis of pyrrolo[3,2,1-ij]quinolines
in a process catalyzed by tetrafluoroboric acid. The
reaction could be considered as an unprecedented
to A. G.)
References
[1] A. Tsotinis, M. Panoussopoulou, A. Eleutheriades, K.
Davidson, D. Sugden, Eur. J. Med. Chem. 2007, 42,
1004–1013.
[2] J. L. Stanto, M. H. Ackerman, J. Med. Chem. 1983, 26,
986–989.
Adv. Synth. Catal. 2016, 358, 1741 – 1745
1744
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

COMMUNICATIONS
asc.wiley-vch.de
[
[
3] M. Layek, M. A. Reddy, R. A. V. Dhanunjaya, M.
Alvala, M. K. Arunasree, A. Islam, K. Mukkanti, J.
Iqbal, M. Pal, Org. Biomol. Chem. 2011, 9, 1004–1007.
4] M. Isaac, A. Slassi, A. OꢁBrien, L. Edwards, N. Ma-
cLean, D. Bueschkens, D. K. H. Lee, K. McCallum, I.
De Lannoy, L. Demchyshyn, R. Kamboj, Bioorg. Med.
Chem. Lett. 2000, 10, 919–921.
5] D. Paris, M. Cottin, P. Demonchaux, G. Augert, P. Du-
passieux, P. Lenoir, M. J. Peck, D. Jasserand, J. Med.
Chem. 1995, 38, 669–685.
zµlez-PØrez, A. R. de Lera, R. lvarez, F. J. FaÇanµs, F.
Rodríguez, Chem. Sci. 2014, 5, 996–1007; f) A. Galvµn,
J. Calleja, A. B. Gonzµlez-PØrez, R. lvarez, A. R.
de Lera, F. J. FaÇanµs, F. Rodríguez, Chem. Eur. J.
2015, 21, 16769–16774.
[10] a) L. S. Povarov, Russ. Chem. Rev. (Engl. Transl.) 1967,
36, 656–670. For excellent reviews, see: b) V. V. Kouz-
[
netsov, Tetrahedron 2009, 65, 2721–2750; c) M. Fochi,
L. Caruana, L. Bernardi, Synthesis 2014, 46, 135–157.
11] The Povarov reaction is usually referred as an inverse
electron demand [4+2]-cycloaddition process. Howev-
er, this reaction is highly asynchronous or even, many
times, it can be considered as a stepwise process initiat-
ed by a reversible Mannich-type addition of the enol
ether to the imine followed by a Friedel–Crafts-type in-
tramolecular trapping of the so-formed oxonium ion by
the arene coming from the aniline. In our reaction we
assumed that the Povarov reaction would be favoured
with electron-rich aniline derivatives because the
above-mentioned Friedel–Crafts reaction should be
easier.
12] CCDC 982663 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
13] Substituted 1H-indole-7-carbaldehydes are easily avail-
able on a multigram scale from 7-bromo-1H-indoles
through a bromine-lithium exchange and formylation
with N,N-dimethylformamide. 7-Bromo-1H-indoles can
be synthesized from 1-bromo-2-nitrobenzene deriva-
tives following Bartoliꢁs procedure: R. Dalpozzo, G.
Bartoli, Curr. Org. Chem. 2005, 9, 163–178.
[
[
[
6] Y.-S. Yao, Q.-X. Zhou, X.-S. Wang, Y. Wang, B.-W.
Zhang, Adv. Funct. Mater. 2007, 17, 93–100.
7] For some recent examples, see: a) D. V. Patil, M. A.
Cavitt, P. Grzybowski, S. France, Chem. Commun.
2
012, 48, 10337–10339; b) H.-L. Cui, X. Feng, J. Peng,
J. Lei, K. Jiang, Y.-C. Chen, Angew. Chem. 2009, 121,
847–5850; Angew. Chem. Int. Ed. 2009, 48, 5737–5740;
5
c) M. Layek, A. V. D. Rao, V. Gajare, D. Kalita, D. K.
Barange, A. Islam, K. Mukkanti, M. Pal, Tetrahedron
Lett. 2009, 50, 4878–4881.
[
[
8] K. Wojciechowski, Eur. J. Org. Chem. 2001, 3587–3605.
9] For some multicomponent coupling reactions devel-
oped in our laboratories, see: a) J. Barluenga, A. Men-
doza, F. Rodríguez, F. J. FaÇanµs, Angew. Chem. 2008,
[
120, 7152–7155; Angew. Chem. Int. Ed. 2008, 47, 7044–
7047; Angew. Chem. 2008, 120, 7152–7155; b) J. Bar-
[
luenga, A. Mendoza, F. Rodríguez, F. J. FaÇanµs, Chem.
Eur. J. 2008, 14, 10892–10895; c) J. Barluenga, A. Men-
doza, F. Rodríguez, F. J. FaÇanµs, Angew. Chem. 2009,
121, 1672–1675; Angew. Chem. Int. Ed. 2009, 48, 1644–
1647; Angew. Chem. 2009, 121, 1672–1675; d) L. Cala,
A. Mendoza, F. J. FaÇanµs, F. Rodríguez, Chem.
Commun. 2013, 49, 2715–2717; e) J. Calleja, A. B. Gon-
Adv. Synth. Catal. 2016, 358, 1741 – 1745
1745
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim