Multicomponent reaction access to complex quinolines via oxidation of the Povarov adducts

Article abstract of DOI:10.3762/bjoc.7.110

The tetrahydroquinolines obtained through the Povarov multicomponent reaction have been oxidized to the corresponding quino-line, giving access to a single product through a two-step sequence. Several oxidizing agents were studied and manganese dioxide pr

Full text of DOI:10.3762/bjoc.7.110

Multicomponent reaction access to complex
quinolines via oxidation of the Povarov adducts
Esther Vicente-García1, Rosario Ramón1, Sara Preciado1
and Rodolfo Lavilla*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 980–987.
1Barcelona Science Park, Baldiri Reixac 10–12, 08028, Barcelona,
Spain and 2Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, Avda. Joan XXIII sn, 08028, Barcelona,
Spain
doi:10.3762/bjoc.7.110
Received: 06 May 2011
Accepted: 22 June 2011
Published: 13 July 2011
Email:
Rodolfo Lavilla* - rlavilla@pcb.ub.es
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
* Corresponding author
Keywords:
© 2011 Vicente-García et al; licensee Beilstein-Institut.
License and terms: see end of document.
manganese dioxide; multicomponent reactions; oxidation; Povarov;
quinolines; tetrahydroquinolines
Abstract
The tetrahydroquinolines obtained through the Povarov multicomponent reaction have been oxidized to the corresponding quino-
line, giving access to a single product through a two-step sequence. Several oxidizing agents were studied and manganese dioxide
proved to be the reagent of choice, affording higher yields, cleaner reactions and practical protocols.
Introduction
Heterocycles are ubiquitous scaffolds in pharmaceuticals, gence, and exploratory power, together with new avenues in
natural products and biologically active compounds. Quinoline connectivity, leading to the straightforward synthesis of previ-
systems in particular constitute a privileged substructure and are ously unobtainable scaffolds [3]. In this context, it is possible to
present in a large number of compounds with remarkable bio- obtain a wide variety of complex tetrahydroquinolines through
logical activity [1]. Although a variety of methods are used to the Povarov MCR (the interaction of anilines, aldehydes and
prepare these heterocyclic compounds, the synthetic access to activated olefin inputs under acid catalysis) [4-8]. Interestingly,
polysubstituted-polyfunctionalized derivatives remains a serious this process allows cyclic enol ethers and enamines to be used
challenge [2]. Multistep sequences are widespread in the litera- as electron-rich alkenes, leading to heterocycle-fused tetrahy-
ture, but even in these cases the preparation of some substitu- droquinolines, usually as a mixture of stereoisomers [9-13].
tion patterns and functional group combinations is particularly Unfortunately, no general methods for enantioselective Povarov
difficult. The recent introduction of multicomponent reactions reactions have been developed (for examples of catalytic
(MCRs) into this field has brought interesting features typical of enantioselective transformations operating in particular systems,
the ideal reaction, such as atom- and step economy, conver- see [14,15]), and this constitutes a serious drawback in the use
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Beilstein J. Org. Chem. 2011, 7, 980–987.
of this reaction for library preparation, as one reaction affords quinoline, such as O-, N- and C-linked residues (Scheme 2)
several products, when ideally it should give only one. [8,9,12,13,16-18]. Unfortunately, the alternative
However, these adducts can be subjected to oxidation, which oxidation–elimination products (5 and 8) are often observed,
will lead to the corresponding quinolines, preserving the therefore suggesting an acid catalyzed process. This would
substituents and functionalization already introduced in the account for the elimination of alcohol and amine moieties,
preceding MCR. Despite the loss of all stereochemical informa- leading to dihydroquinoline intermediates that, after spontan-
tion, in this way it would be feasible to obtain a single product eous oxidation in air, provide the final fragmented quinolines.
from a multicomponent process (Scheme 1).
The ability of DDQ to act as a Lewis acid and promote this
alternative pathway has some precedent in the literature [19].
The oxidation step itself is challenging as it involves the formal Furthermore, TFA treatment of Povarov adducts in oxygenated
removal of four hydrogens from a tetrahydropyridine moiety to atmospheres also affords the oxidation–elimination products 5
reach the fully aromatic species. The literature contains scat- and 8 (Scheme 2) [8,12,20].
tered reports of the use of oxidants for this transformation: 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), ceric ammoni- The alternative oxidation–elimination pathway is predominant
um nitrate (CAN), nitrobenzene, elemental sulfur, palladium in some CAN-promoted oxidations of different Povarov adducts
and manganese dioxide among others, all of them far from 3. Incidentally, this reagent is also used as a catalyst in the
being ideally suited for these substrates.
Povarov MCR without oxidative interference [18]. The same
trend (oxidation–fragmentation) can be observed using
One of the most commonly used is DDQ, which affords quino- nitrobenzene [21] as the oxidant. Analogously, elemental sulfur
lines in acceptable yields. The main advantages of this and palladium, although requiring drastic conditions, also lead
oxidizing agent lie in its chemoselectivity and a requirement for to the fragmented quinolines when the substrates bear O- and
relatively mild conditions, allowing it to be used in the pres- N-substituents [22-25] (for related isoquinoline oxidations, see
ence of a wide range of substituents of the starting tetrahydro- [26,27]).
Scheme 1: Povarov oxidation access to substituted quinolines.
Scheme 2: Tetrahydroquinoline oxidation.
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Beilstein J. Org. Chem. 2011, 7, 980–987.
Related oxidative processes involve, for instance, a cascade larly important [32-36]. A systematic study was therefore
Povarov–hydrogen transfer reaction using Tf2NH as a catalyst conducted to determine the influence of different reaction
and the imine as an oxidant, as recently described [28]. In addi- conditions, commercial reagents and additives on the oxidation
tion, Povarov adducts resulting from the reaction between of an elimination-prone Povarov tetrahydroquinoline substrate.
3-aminocoumarin, aldehydes and cyclic enol ethers have been
oxidized with different types of reagents, such as bromide, In this way, tetrahydroquinolines 17,17' were synthesized as a
palladium, DDQ, sodium periodate, manganese dioxide or mixture of isomers from the enol ether 14, p-bromoaniline (15)
CAN, but in all cases the main product was the elimination–oxi- and p-chlorobenzaldehyde (16) under Sc(OTf)3 catalysis using
dation compound [29].
standard reaction conditions (Scheme 3) [9]. Subsequently,
these adducts 17,17' were oxidized with DDQ by the standard
Finally, chemical manganese dioxide (CMD) has been widely protocol [9], to isolate the desired quinoline 18 and its frag-
used in this type of transformations, and already in 1982 the mented derivative 19, and they could also be subjected to an
oxidation of tetrahydroisoquinoline (11, Scheme 2) was acid treatment to obtain selectively the latter product [8]. All
reported to yield the corresponding isoquinoline 12, the inter- compounds were purified and unequivocally characterized by
mediate dihydroisoquinoline 13 being obtained as a by-product NMR and HPLC methods.
[26]. Later, Thompson et al. described the oxidation of fused
pyrrolohydroquinolines (type 6) using MnO2 obtained from Taking into account that the oxidation of thiazolidines to thia-
batteries. A kinetic competition between two processes was zoles with MnO2 (25 equiv) in toluene (55 °C) in the presence
observed, and the desired double oxidation to the corres- of pyridine (1.25 equiv) is a clean and efficient method [35], a
ponding fused quinoline 7 took place, along with the first experiment was set up to test these conditions with an old
oxidation–elimination sequence leading to 8. A large excess of (≈40 years) MnO2 sample of unknown origin (particle size
oxidant was required in order to obtain the desired quinoline 7 11.46 µm, see below). A promising result was obtained,
as the major product (Scheme 2) [30,31].
achieving a 39% conversion to the desired product 18, albeit
with a high ratio of the elimination–oxidation compound 19.
Next, the equivalents of oxidant and pyridine were increased to
Results and Discussion
Experiments were performed with the goal of developing a 100 and 6, respectively, and under these optimized conditions, a
general and practical protocol for the oxidation of Povarov 72% isolated yield of quinoline 18 was obtained, and no starting
adducts to furnish the corresponding fused quinolines, avoiding material or elimination–oxidation compound was detected.
elimination by-products. After unsuccessful attempts using
palladium on carbon (decomposition), CuCl (partial oxidative Unfortunately, we were not able to reproduce the above results
elimination), Fremy’s salt (unreactive) and IBX (a complex when using brand new samples of MnO2. It was decided to test
reaction leading to unknown compounds), we focused our atten- different commercially available MnO2 sources (Aldrich, Acros
tion on MnO2 as the oxidant of choice. A literature search and Wako) of distinct activation degrees (particle size, powder
revealed different reactivity patterns depending on the type and or activated reagent, Table 1) in order to find a suitable reagent
origin of the reagent, with the commercial source being particu- leading to comparable results.
Scheme 3: Synthesis of the Povarov adducts and their oxidation products.
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Beilstein J. Org. Chem. 2011, 7, 980–987.
Table 1: Survey of different MnO2 reagents.
entry
MnO2 trademark,
particle size (median
reaction conditions
product ratios
characteristics (reagent code) diameter, d50, µm)a
(17,17')/18/19
1
2
3
4
5
6
7
8
9
10
Aldrich, reagent grade
(310700)
4.3
25 equiv of oxidant
pyridine (50 equiv)
54/3/43
48/8/44
Aldrich, reagent grade
(310700)
4.3
Aldrich, reagent grade
(310700)
4.3
25 equiv of oxidant K2CO3 (6 equiv)
55 °C for 14 h
37/6/57
37/13/50
51/0/49
100/0/0
61/0/39
8/14/78
75/0/25
0/100/0
Aldrich, reagent grade
(310700)
4.3
Aldrich, reagent grade
(310700)
4.3
rt for 48 h
Aldrich, reagent plus
(243442)
138.4
138.4
4.2
general conditionsb
110 °C for 14 h
Aldrich, reagent plus
(243442)
Aldrich, activated
(217646)
general conditionsb
general conditionsb
general conditionsb
Acros, powder
(213490010)
7.6
Wako, 1st grade powder
(138-09675)
25.7
aAll manganese dioxide samples were analyzed with a LSTM 13 320 series Laser diffraction particle size analyzer. For more details, see Supporting
Information File 1. bUnless otherwise stated, the reactions were performed in toluene as the solvent, using 100 equiv of oxidant, 6 equiv of pyridine at
55 °C for 2 h.
Aldrich MnO2 (reagent grade) did not afford the desired quino- were reproducible, allowing the isolation of quinoline 18 in
line 18 (entry 1, Table 1), the main products being the frag- 66% yield in gram scale quantities.
mented quinoline 19 and starting material. Modifications
including the use of a greater excess of pyridine, the addition of In an attempt to improve the reaction conditions, Et3N was
K2CO3 as a heterogeneous base (entries 2 and 3), and adjust- tested as a base, and molecular sieves (4 Å) and MgSO4 were
ment of the reaction time or temperature (entries 4 and 5) did introduced as dehydrating agents, but no meaningful changes
not substantially change the outcome. MnO2 (Aldrich, reagent were observed in any case. As the elimination–oxidation prod-
plus) was completely inefficient at 55 °C (entry 6), and on uct 19 is thought to be generated by the acid characteristics of
heating to 110 °C for 14 h it promoted a 39% conversion but led the oxidation reagents, an activated MnO2 sample was treated
exclusively to the elimination product (entry 7). On the other with an aqueous basic (NaCO3) solution, in an attempt to
hand, using activated MnO2 (Aldrich), some oxidized quinoline neutralize the acidic impurities, but the ratio of the
18 was observed, although again the predominant product was elimination–oxidation product did not decrease. We then
the fragmentation compound 19 (entry 8). Next, the reagents analysed the particle size of all samples using a laser diffrac-
from Acros (entry 9) and Wako (entry 10) were tested, the latter tion technique (see Supporting Information File 1). Although a
being selective in the formation of the desired oxidation prod- straightforward conclusion is not evident, it seems that all
uct, completely avoiding the elimination pathway. The results samples with a small (around 4 µm) or large particle size (138
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Beilstein J. Org. Chem. 2011, 7, 980–987.
µm) were inefficient in promoting the desired oxidation. On the pyridine (up to 20 equiv). As such large amounts of pyridine
other hand, medium size samples (Wako and the old sample of were not beneficial, the use of 6 equiv of this reagent was a
unknown origin) were the most selective oxidants (see practical compromize, leading to the same essential outcome. In
Supporting Information File 1).
an attempt to disaggregate the Wako MnO2 powder, and in this
way reduce the amount of reagent, the reaction was performed
Using this reliable reagent, different reaction conditions were in an ultrasonic bath under the general conditions, but no
tested in order to optimize the process, especially regarding improvement was observed in the reaction profile.
reagent consumption (Figure 1). The effects of varying the
amounts of Wako MnO2 (from 10 to 100 equiv) and pyridine The optimized oxidation conditions were applied to another
(from 2 to 20 equiv) in the standard solvent (toluene), reaction class of tetrahydroquinolines, which contain a fused lactam ring
time and temperature (2 h, 55 °C) were studied. The gradual (20,20', Scheme 4) [12]. These new substrates were prepared
increment in the amount of oxidant resulted in a progressive through the Povarov MCR from the corresponding unsaturated
increase in the yield of compound 18 and the simultaneous lactam, aldehyde and aniline. The oxidation and elimination
decrease of the elimination quinoline 19. No productive trans- products (21 and 22, respectively) were independently prepared
formation to quinoline 18 was observed using 10 equiv of with DDQ under acid catalysis in an oxygenated atmosphere
oxidant, the fragmented compound 19 being the predominant (O2-TFA), and characterized by NMR and HPLC methods. The
species. It is worth noting that the conversion of the starting ma- optimized conditions with the Wako reagent were productive
terial was only complete when at least 80 equiv of MnO2 were and selectively afforded the corresponding quinolines 21 in high
used, but even in these conditions the elimination pathway yields, and the elimination product 22 was not detected. The
could not be completely avoided, despite the huge excess of processes were slower (5–8 h) than those involving the pyran-
Figure 1: Optimization of the reaction conditions for the preparation of quinoline 18.
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Beilstein J. Org. Chem. 2011, 7, 980–987.
Scheme 4: Oxidation of lactam-fused tetrahydroquinolines 20,20'.
fused substrates 17,17' (Scheme 3). Interestingly, although connectivity). IR spectra were recorded using a Thermo Nicolet
DDQ is also capable of promoting these transformations, it is Nexus spectrometer and are reported in wavenumbers (cm−1).
not as selective as Wako MnO2, and apart from yielding the High resolution mass spectrometry was performed by the
fragmented quinolines 22, it also oxidizes the benzylic hydro- University of Barcelona Mass Spectrometry Service.
gens (a series, R2 = Me) leading to the corresponding aldehyde
derivative 21c [12]. Studies are ongoing to expand this set of General procedure A [9,12]
transformations to fused oxygenated and nitrogenated To a solution of compound 17,17' or 20,20' (1 mmol) in 15 mL
5-membered ring systems.
of CHCl3, DDQ (2 mmol) was added and the mixture was
stirred for 24 h in an open vessel at room temperature. An
aqueous saturated NaHCO3 solution (10 mL) was added, and
Conclusion
In conclusion, we have described a fast, practical and reliable the resulting mixture was extracted with CHCl3 (3 × 10 mL).
methodology to oxidize complex polysubstituted tetrahydro- The combined organic layers were dried over Na2SO4, filtered
quinolines, arising from Povarov MCRs, to the corresponding and concentrated in vacuo. The reaction mixture was purified
quinolines, using MnO2. The influence of the reagent source, by flash chromatography (hexane–EtOAc) to afford the desired
stoichiometry, additives and reaction conditions has been deter- product.
mined. Wako CMD is the oxidant of choice and the presence of
pyridine is critical to avoid the fragmentation pathway, a side General procedure B [9,12]
reaction often found in this type of transformation. This process To a solution of compound 17,17' or 20,20' (1 mmol) in
enables the selective preparation of heterocycle-fused quino- CH3CN/H2O or CHCl3/H2O (1:1, 6 mL), TFA (2 mmol) was
lines arising from a single combination of aldehydes, anilines added. The reaction mixture was stirred for 24 h at room
and activated alkenes in a short sequence, involving Povarov temperature, quenched with an aqueous saturated NaHCO3
MCR and oxidation steps.
solution (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over Na2SO4, filtered and
concentrated in vacuo to give a residue which was purified by
flash chromatography (hexane–ethyl acetate) to afford the
Experimental
General
1H and 13C NMR spectra were recorded on a Varian Mercury desired product.
400 spectrometer. Unless otherwise stated, NMR spectra were
recorded in CDCl3 solution with TMS as an internal reference. General procedure C
Data for 1H NMR spectra are reported as follows: Chemical To a solution of compound 17,17' or 20,20' (1 mmol) in 50 mL
shift (δ ppm), multiplicity, integration and coupling constants of toluene, pyridine (6 mmol) and MnO2 Wako (100 mmol)
(Hz). Data for 13C NMR spectra are reported in terms of chem- were added and the mixture was stirred in an open vessel at
ical shift (δ ppm). Signals were assigned by means of two- 55 °C. The progress of the reaction was controlled by TLC or
dimensional NMR spectroscopy: 1H,1H-COSY, 1H,13C-COSY HPLC, until the starting material completely disappeared or no
(HSQC: heteronuclear single quantum coherence) and long- evolution was observed. The crude mixture was filtered through
range 1H,13C-COSY (HMBC: heteronuclear multiple bond Celite, and the filtrate was concentrated in vacuo. The reaction
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Beilstein J. Org. Chem. 2011, 7, 980–987.
mixture was purified by flash chromatography (hexane–EtOAc) Dr. Pedro Grima (Grupo Ferrer, R+D center, Barcelona) for
to afford the desired product.
useful comments.
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