Reduction of quinolines to 1,2,3,4-tetrahydroquinolines with hydrosilane/ethanol catalyzed by TiO 2 -supported gold nanoparticles under solvent free conditions

Gold nanoparticles supported on TiO 2 (1 mol%) catalyze the reduction of a series of functionalized quinolines into 1,2,3,4-tetrahydroquinolines using hydrosilanes/ethanol (hydride/proton) as the reductant system. A typical reaction requires 4 molar equivalents of phenyldimethylsilane (reductant of choice), 4 molar equivalents of ethanol as a reagent and heating to 70 o C under solvent free conditions. The isolated yields are moderate to excellent and in certain cases the reaction rate is exceedingly fast. Mechanistic analysis revealed the stereoselective addition of two hydrides (from hydrosilane) on positions C2 and C4 of the quinoline ring and two protons (from ethanol) on positions C3 and the nitrogen atom.


Introduction
Heterogeneous reductive processes catalyzed by supported gold nanoparticles (Au NPs) [1][2][3][4][5] and nanoporous gold 6 have received considerable attention especially over the past decade.The reductants employed are H 2 (direct hydrogenation) and CO/H 2 , formates, alcohols, hydrosilanes or hydroborane (transfer hydrogenation).It is generally accepted that reduction takes place via the formation of gold hydride species.Owing to the relative instability and the difficulty for the formation of Au-hydrides, Au NPs-catalyzed reduction protocols are more controllable and selective relative to the analogous Pd or Pt-catalyzed processes; the facile accumulation of Pd or Pt-hydrides on the catalyst's surface often leads to side reactions (e.g., dehalogenation or overeduction pathways). 7While much effort has been devoted to Au-catalyzed reduction of carbonyl and nitro compounds, there are only a few examples regarding the reduction of π systems.Cao and co-workers have shown that Au NPs supported on high surface area titania (HAS-TiO 2 ) catalyze the chemoselective reduction of quinolines into 1,2,3,4-tetrahydroquinolines using H 2 . 8At the same time, Yamamoto's group reported a nanoporous gold catalyst which employs hydrosilane/H 2 O to semireduce alkynes into cis-alkenes. 9More recently, further progress has been achieved in the direct hydrogenation of terminal alkynes over supported Au NPs 10 or Au nanoclusters. 11he reports by Cao 8 and Yamamoto 9 urged us to examine the possible reduction of quinolines into 1,2,3,4-tetrahydroquinolines via supported Au NPs-catalyzed transfer hydrogenation using hydrosilanes, 1,2-disilanes or ammonia borane.3][14][15][16][17][18] The endeavours for this specific reduction arise from the fact that 1,2,3,4-tetrahydroquinones constitute a very important class of heterocyclic compounds, since they appear as the core skeleton in a variety of bioactive naturally occurring substances or pharmaceutical products.Thus, the interest of organic chemists for their synthesis is continuous 19 with a great body of publications focusing on the reduction of precursor quinolines.While our research efforts towards this goal using supported Au NPs were in progress and had reached a level of maturity, an efficient method for the reduction of quinolines by hydrosilanes catalyzed by an unsupported nanoporous gold catalyst was reported. 20erein, we present our results which employ hydrosilanes/ethanol as the reducing system under solvent free conditions and Au nanoparticles supported on TiO 2 as the most suitable catalyst.In addition, a stepwise pathway was established with an initially fast 1,2-reduction mode to form 1,2-dihydroquinolines, while the new C2 and C4 hydrogen atoms on reduction products arise from the hydrosilane as supported via labelling experiments.Alternative approaches using 1,2-disilanes or ammonia borane as reductants provided inferior results.

Optimization studies
As a model substrate we examined 8-methoxyquinoline (1), and in all experiments the loading of catalyst (Au/TiO 2 , ~ 1 wt%) was kept at 1 mol% (Table 1).Although not shown, we have also tested other supported Au NPs catalysts (Au/Al 2 O 3 and Au/ZnO) having identical gold content and size of nanoparticles (~2-3 nm on the average) to Au/TiO 2 but the results were inferior to those of Au/TiO 2 .The first crucial observation in the reduction of the methoxyquinoline 1 was that apart from hydrosilane (hydride donor) a proton source was required (e.g., ethanol) as also exemplified by labelling experiments presented in the accompanying mechanistic discussion.Thus, 8-methoxyquinoline is smoothly reduced into 8-methoxy-1,2,3,4-tetrahydroquinoline (1a) by hydrosilanes with the best results obtained using phenyldimethylsilane (PhMe 2 SiH, 4 equiv) and equimolar amounts of ethanol as a proton source in the absence of any solvent and within a few minutes at 70 o C.Under these conditions, 100% consumption of the quinoline 1 was observed, and the tetrahydroquinoline 1a was isolated in 84% yield after column chromatography.It is important to stress that solvent free conditions in a given chemical process are highly desired.Triethylsilane exhibited inferior results, while 1,1,3,3-tetramethyldisiloxane (TMDS) which is an extremely reactive hydrosilane in other Au-catalyzed transformations 15,18,22 did not show better activity to PhMe 2 SiH.Hexamethyldisilane (Me 3 Si-SiMe 3 ) exhibited a moderate activity arising from transient in situ generated trimethylsilane during its Au/TiO 2catalyzed ethanolysis. 16Disappointingly, the use of ammonia borane (NH 3 BH 3 ), a powerful and rapidly reductant of nitro compounds in the presence of Au/TiO 2 , 17 provided only traces of the reduction product.

Scope and limitations
Having identified the optimum experimental conditions for reducing the methoxyquinoline 1, we then studied the scope and limitations of the reduction on a series of functionalized quinolines using 4 molar equivalents of the mixture PhMe 2 SiH/EtOH and 1 mol% of catalyst (Au/TiO 2 ) under solvent free conditions (Table 2).Quinolines substituted at C2 or C3 are smoothly reduced providing the corresponding 1,2,3,4-tetrahydroquinolines in very good yields.2,4-Disubstituted quinolines 5 and 6 provided mainly the thermodynamically favourable cis-2,4-disubstituted tetrahydroquinolines (cis/trans ~ 10:1).Parent quinoline (2) was rather unreactive compared to the substituted analogues, and a large excess (>10 equiv) of reducing agents was required to achieve a decent conversion yield.The same poor reactivity was also observed with quinoxaline (12) that gave under standard reaction conditions 1,2,3,4-tetrahydroquinoxaline (12a) in very low yield (5%); this can be improved to 14% in the presence of 10 molar excess of hydrosilane/ethanol.On the other hand, the C4 methyl-substituted quinolines (lepidine 13 and 6-chlorolepidine 14) were surprisingly completely unreactive, which was difficult to explain given that disubstituted 5 and 6 bearing a methyl group at C4 are readily reduced.Fortunately, the halide-substituted quinolines 7-11 did not suffer any protodehalogenation upon reduction, which is a typical, often undesireable sidereaction seen under Pd, Pt or Ru catalysis conditions. 8y studying the reduction of the slowly reacting parent quinoline (2) with 1 H NMR we found that initially the N-C double bond was reduced to form intermediate 1,2-dihydroquinoline (2b) which then slowly gave 1,2,3,4-tetrahydroquinoline (2a) (Scheme 1).We were able to isolate the dihydroquinoline 2b by column chromatography as a mixture with final product 2a (see Supporting Information).The intermediate 1,2-dihydroquinoline 2b is known to gradually reoxidized to quinoline 2 in atmospheric air.

Mechanistic studies
To study the mechanism of reduction we prepared deuterium labelled PhMe 2 SiD (>98% D) by reaction of PhMe 2 SiCl with LiAlD 4 in THF.The smoothly reacting 8-methoxyquinoline (1) was chosen as a model substrate (Scheme 2).In the reaction of the methoxyquinoline 1 with PhMe 2 SiD/EtOH we found >95% and ~50% D incorporation at C2 and C4, respectively (see 1 H NMR spectrum in Supporting Information), while with PhMe 2 SiH/CD 3 OD, ~75% D incorporation was seen at C3 and ~10% on C2 (see Supporting Information).While it seems that the new C-H bonds on C2 and C4 arise from hydride Si-H functionality, and the new C-H bond on C3 from the proton of solvent (EtOH), the incomplete deuterium incorporation in both experiments on C3 and C4 was quite peculiar.To shed light on this, the reaction between the methoxyquinoline 1 and PhMe 2 SiD/EtOH was monitored by GC-MS.To our surprise, during the initial stages of reaction, PhMe 2 SiD gradually underwent isotopic exchange to PhMe 2 SiH (Figure 1).This observation nicely explained the incomplete deuteration patterns appearing in Scheme 2. First, we consider that the quinolines were reduced quickly to intermediate 1,2-dihydroquinolines and then slowly to 1,2,3,4-tetrahydroquinolines (Scheme 1).Thus, PhMe 2 SiD quickly reduces the methoxyquinoline 1 to the corresponding 1,2-dihydroquinoline before undergoing significant deuterium depletion (>95% deuteration at C2).Since the second reduction step (1,2-dihydroquinolines to 1,2,3,4-tetrahydroquinolines) was slow, and PhMe 2 SiD had in the meantime undergone substantial D/H exchange, only 50% D incorporation was seen on C4.The same holds in the experiment using PhMe 2 SiH/CD 3 OD.Owing to isotopic scrabbling between the Si-H and O-D bonds, incomplete deuteration occurs on C3, while a small amount of deuterium appears on C2 which is attributed to the partial formation of PhMe 2 SiD under the reaction conditions.The depletion of deuterium in PhMe 2 SiD is not clearly understood and apparently is catalyzed by Au NPs.An analogous metal-catalyzed depletion of deuteride (NaBD 4 ) by a protic solvent (EtOH) is known in the literature.The fast depletion of Si-D functionality under the reaction conditions did not allow the conclusive study of other slowly reacting quinolines such as the parent 2.For example, reduction of the slightly less reactive (compared to 1) fluoroquinoline 9 with PhMe 2 SiD, led to 60% D incorporation on C2, ~20% on C4 and ~10% on one of the two distereotopic protons of C3 (see Supporting Information).The minor deuteration on C3 can be attributed to the in situ formation of EtOD under the reaction conditions.
On the basis of the labelling experiments, we propose a reasonable stepwise mechanism that involves the regioselective addition of in situ formed silylgold hydride species 25,26 on C2 and C4 carbon atoms, accompanied by protonation with ethanol on C3 and nitrogen atoms, respectively (Scheme 3).Gold hydride PhMe 2 SiAuH has been postulated to be formed by insertion of Au NP on the Si-H bond. 27The side product of reaction (PhMe 2 SiOEt) was isolated and characterized (see Supporting Information).

Conclusions
We have demonstrated a solvent-free reduction of quinolines to 1,2,3,4-tetrahydroquinolines using PhMe 2 SiH/EtOH as the reductant system, and as catalyst gold nanoparticles supported on TiO 2 .This method complements a recently presented reduction protocol that uses a nanoporous gold catalyst. 20The hydrogen atoms in the reduction products arise from hydrosilane (2 C-H bonds on C2 and C4) and from EtOH (C-H bond at C3 and N-H bond).Furthermore, an unexpected exchange of Si-H hydride by protons from solvent can occur under the reaction conditions.[3][4][5][6]

Experimental Section
General.Nuclear magnetic resonance spectra were recorded on 300 and 500 MHz spectrometers in CDCl 3 .Isomeric purities were determined by 1 H NMR spectroscopy, by analytical gas chromatography and by GC-MS.8-Methoxyquinoline (1) 28 was synthesized by treatment commercially available 8-hydroxyquinoline with K 2 CO 3 and CH 3 I in DMF.Quinolines 5 29 and 6 30 were prepared by Friedlander condensation of 2'-aminoacetophenone with acetone or acetophenone, respectively, based on a literature procedure. 318-Bromo-2-methylquinoline (11) 32 was synthesized via a Doebner-Miller condensation protocol 33 between 2-bromoaniline and crotonaldehyde.The rest of quinolines are commercially available substances.

Table 1 .
Reduction of 8-methoxyquinoline (1) in the presence of various reducing agents catalyzed by Au/TiO 2 .
a Conversion yields.b See ref. 21.

Table 2 .
Reduction of quinolines by PhMe 2 SiH/EtOH catalyzed by Au/TiO 2 under solvent free conditions.