Synthesis of [1,2-a ]-fused tricyclic dihydroquinolines by palladium-catalyzed intramolecular C–N cross-coupling of polarized heterocyclic enamines

A simple methodology for [1,2 -a ]-fused tricyclic dihydroquinolines is established. The key step of the methodology is an intramolecular Buchwald-Hartwig amination reaction of suitable halogenated (both bromo and chloro) cyclic enaminoketones, enaminoesters and enaminonitriles with various ring size (from five-to seven-membered). Optimal reaction conditions (palladium source, base, ligand) depend on the ring size of the starting enamine, giving 65–98% yield of the tricyclic product. A treatment of the products with perchloric acid gives respective quinolinium perchlorates.


Introduction
The term enaminone was first introduced by Greenhill 1 in 1977.3][4][5][6][7][8] A privileged status among them have cyclic enaminones and their derivatives. 9,10They can, in principle, be divided into three structural types I-III (Fig. 1).The synthons in Fig. 1 give access, by means of suitable synthetic transformations, to a number of structures that are the core of both natural and synthetic biologically active compounds (e.g.2][13] For example, intramolecular C-N cross-coupling reactions of cyclic enaminones and related compounds are an efficient method for the synthesis of polycyclic nitrogen-containing heterocycles.3][24][25][26] However, the situation is quite different in the case of their dihydroquinoline homologs and, to the best of our knowledge, there is only one paper 21 describing the mentioned transformation.Thus in 2003 Wang and coworkers 21 reported the Buchwald-Hartwig crosscoupling reaction of enaminoesters Ia providing tricyclic compounds IV with bridgehead nitrogen atom (Scheme 1).The yields were, however, only moderate-to-zero.Scheme 1. Previously reported results on intramolecular C-N cross-coupling reactions of Cbenzylated cyclic enaminoesters. 21milar structural motif can be found e.g. at Ochrosamines A,B (alkaloids from the Australian rainforest tree Ochrosia Moorei), 27,28 Strychnozairine (an alkaloid from the African tree Strychnos variabilis), 29 2,7-dihydroxyapogeissoschizine (the alkaloid isolated from the root bark of Strychnos gossweileri), 30 or valesiochotamine alkaloids 31 (Figure 2).Fused cyclic enaminones with bridgehead nitrogen served as intermediates in the synthesis of 10methoxydihydrocorynantheol, 10-methoxycorynantheidol, 32 or 6-oxo-16-episilicine. 33  Thus, tricyclic compounds like IV can be suitable scaffolds for further synthetic transformations leading to both natural and synthetic compounds with favourable biological activity.Recently Levacher et al. 34 suggested tricyclic fused 1,4-dihydroquinolines V (Fig. 2) as new chemical delivery agents for the transfer of AChE inhibitor galantamine to the brain.In this work we present a simple and superior protocol enabling to synthesize fused tricyclic dihydroquinolines by means of an intramolecular, palladium catalysed, C-N cross-coupling reaction of exocyclic enaminones, enaminoesters and enaminonitriles.

Results and Discussion
Synthesis of the starting enamines.The starting enamines 9 were prepared according to Scheme 2 and Scheme 3.All the procedures started from lactim ethers 2a-c, prepared in an ordinary way from the corresponding lactams 1a-c (Scheme 2).Enaminoesters 4a-c were prepared by means of modified literature 35 procedure through intermediates 3a-c using Meldrum's acid as C2 synthon.The decomposition of 3a-c by sodium methoxide gives 4a-c in high yields.
Similarly, the reaction of 2a-c with acetylacetone furnished enaminoketones 6a-c in two steps.Two methodologies for the synthesis of intermediates 5a-c were used.The published 36 procedure using catalytic amount of nickel(II) acetylacetonate (Method A) provided only low yields of 5 (17% for 5a, 23% for 5c).Catalyst-and solvent-free modification performed in a sealed tube (Method B) led to a substantially higher yield of 5c (71%).The synthesis of 5b proved to be the most problematic.Partial deacetylation took place during the condensation step to give 5:4 mixture of 5b and 6b.As 6b was the aim of the whole synthetic sequence the mixture was not separated and was used in the next reaction step.Deacetylation of 5a-c was performed in a similar way as in the case of 3a-c giving enaminoketones 6a-c.
The synthesis of exocyclic enaminonitriles 8a-c was carried out in the analogous way as in the previous cases (Scheme 2).However, intermediates 7b,c, synthesized from 2b,c upon heating with ethyl cyanoacetate in a pressure tube, contained 10-30% of methylester, probably generated via transesterification of 7b,c by methanol formed from 2. No such a by-product was observed in the case of 7a prepared by heating in a conventional apparatus.As the mixture of esters does not hinder the next step, they were used in the following step without purification.Saponification of 7a-c with aqueous sodium hydroxide followed with acidification/decarboxylation led to the formation of enaminonitriles 8a-c in moderate-to-low yields.(Upon careful neutralization of the mixture, intermediate cyanoacid 7'a was isolated in 22% yield at pH 7).No product 8 was formed using MeONa/MeOH system.The enaminonitriles, unlike 4 and 6, exist in CDCl3 as E/Z mixtures (for details see Experimental).The last step for the synthesis of 9 is C-benzylation of enamines 4, 6 and 8 (Scheme 3).In principle, enamines are ambident nucleophiles and can be alkylated both at the nitrogen and C2 carbon atom.Dannhardt et al. 37,38 systematically studied the alkylation of some exocyclic enaminones and specified principal factors affecting the regioselectivity of this reaction.

Scheme 3. C-Benzylation of the exocyclic enamines.
In most cases the reaction proceeded chemoselectively at C2 carbon atom.Only in the case of seven-membered exocyclic enaminonitrile 8c the procedure afforded predominantly N-benzylated product 9´i (Scheme 3) with N-benzyl/C-benzyl ratio ca 2:1 (according to 1 H NMR). The desired product 9i was then separated by means of column chromatography.Interestingly, the reaction of 2-bromobenzylbromide with enaminoketone 6b gave a by-product (11%), which was identified as tris-C-benzylated compound 10a (Scheme 3).The structure was confirmed by means of 1D and 2D NMR, HRMS and also X-ray crystallography (see Figure 3 and Supporting Info).Analogous product 10b was isolated in 11% yield from enaminoketone 6c and 2-chlorobenzylbromide.The intramolecular C-N cross-coupling.Wang et al. 21described the intramolecular cyclization of exocyclic enamino esters Ia to the corresponding tricyclic compounds IV (Scheme 1) using Pd(dba)2/DPPP/tBuONa system in toluene.The reactions were strongly affected by the ring size of the starting substrate and the yields for five, six and seven-membered tricyclic compounds were 51%, 36% and 0% respectively.Optimization study.Starting from these results and with the aim to improve the efficiency of the catalytic system, we chose to reinvestigate the intramolecular C-N bond forming reaction using enamino ester 9b as the model substrate.Firstly, we turned our attention to 2 nd generation XPhos palladacycle precatalyst (L1, Fig. 4), introduced by Buchwald's group. 43Three molar per cents of this precatalyst in the presence of common base (Cs2CO3) in tBuOH at 80 °C provided quantitative conversion of 9b to 11b in 7 h (Table 1, Entry 1).Half amount of the precatalyst was still capable to complete the reaction in a reasonable time of 13 h (Table 1, Entry 2).Changing the base to the cheaper potassium carbonate, however, substantially worsen the results (Table 1, Entry 3).The best results were obtained using cheap tribasic potassium phosphate as the base (Table 1, Entry 4) providing quantitative conversion of 9b in 10 h.Moreover, no reaction was observed in the absence of L1 (Table 1, Entry 5).An attempt to apply the best conditions from Table 1 to achieve the transformation of fivemembered analogue 9a to 11a failed (Table 2, Entry 1).Neither increasing the amount of the palladacycle L1 nor changing the base improved the situation (Table 2, Entries 2, 3).The change for 3rd generation BrettPhos palladacycle (L2, X = OTf, Fig. 4) did not improve the situation at all (Table 2, Entry 4).An improvement took place on using well-known Pd2(dba)3 as the metal source although relative high amounts (5%) were required (Table 2, Entries 5-10).The best results were obtained with 1,3-bis(diphenylphosphino)propane (DPPP, Fig. 4) as the ligand.It allowed to lower the amount of the catalyst to 3.5% with the same conversion (Table 2, Entry 9).The conditions and results are very similar to those obtained in ref. 21with lower amount of palladium in our protocol (10% Pd(dba)2, DPPP, tBuONa, toluene vs. 3.5% Pd2(dba)3, DPPP, tBuONa, toluene).Decline in the amount of the metal source to 1.5% led to decrease in the conversion (Table 2, Entry 10).Palladium diacetate, pre-activated by the methodology developed by Buchwald's group 44 also showed to be promising (Table 2, Entries 11, 12).Increase in the catalyst loading and temperature led to the quantitative conversion in a short time (Table 2, Entry 13).The protocol, however, suffered from difficulties during the purification of the reaction mixture (large amount of the ligand).We therefore preferred the conditions shown in Table 2, Entry 9. PEPPSI family of ligands is another important class of ligands widely used for cross-coupling reactions. 45,46e tested PEPPSI-IPr (Fig. 4) for the transformation of 9a to 11a.The performance under the conditions studied was worse than in the case of Pd2(dba)3 (Table 2, Entries 14, 15).The optimization study thus furnished two protocols for the cyclization of 9: Pd2(dba)3/DPPP/tBuONa/toluene/100 °C (Table 2, Entry 9) for five-membered representatives and L1/K3PO4/tBuOH/80 °C for six-membered ones (Table 1, Entry 4). a Conditions: substrate 0.5 mmol, solvent 2 mL.b Water-mediated preactivation.
Conditions for 9b (Table 1, Entry 4) worked well also for seven-membered homolog 9c (Table 3).The optimized reaction conditions, mentioned above, represent not only a substantial improvement of the methodology published by Wang, 21 (95% yield vs. 36%, 9a) but it worked also in the case of seven-membered ester 9c (yield 97%) where Wang's protocol failed.The protocols were further used for the cyclization of other enamines (enaminoesters, enaminoketones, enaminonitriles) (Table 3).Method B, 24 h, 97% Method B, 24 h, 98% a Method A: substrate 9 (0.5 mmol), Pd2(dba)3 (3.5-5 mol.%),DPPP (7-10 mol.%), tBuONa (0.6 mmol, 1.2 eq.), toluene (2 mL), 100 °C 24-36 h.Method B: substrate 9 (0.5 mmol), L1 (1.5-2 mol.%),K3PO4 (1 mmol, 2 eq.), tBuOH (2 mL), 80 °C, 16-24 h.b Isolated yields given Having an efficient protocol for the cyclization of bromo derivatives in hand, we turned our attention to the chloro derivatives.The optimization study (Table 4) provided available protocol to bring about the cyclization of chloro substituted exocyclic enamines: Pd2(dba)3/RuPhos/Cs2CO3 in toluene.The conditions worked well for all kinds of substrates with the exception of five-membered ketone 9k where only moderate conversion was achieved (Table 4, Entry 4).The conditions successful for the bromo derivatives failed (Table 4, Entry 1) as well as the application of tBuXPhos as the ligand (Table 4, Entry 7).For RuPhos and tBuXPhos see Figure 4. DPPP Ligand, successful in the cyclization of five-membered bromo derivatives, brought about the cyclization in the case of nitrile 9m (Table 4, Entry 9).On the other hand, its application for enamino ketone 9k led to only low conversion (Table 4, Entry 5).It is clear that substrates 9 must adopt E-configuration prior to the cyclization to 11.However, due to the possibility of formation of an intramolecular N-H•••O hydrogen bond (for enaminones and enaminoesters) one would suppose the prevalence of Z-configuration which is not prone to cyclize to 11.The Z-configuration was in the case of 9d proved by means of X-ray (Figure S1).Enaminonitriles 9g-i,m are E/Z-mixtures in solution.An explanation of successful transformation of 9 to 11 lies in decreased C-C bond order of the double bond due to the push-pull effect (see mesomeric structures in Scheme 4).Energy of rotation is then also decreased 47 which facilitates mutual interconversion of E/Z isomers.
Compounds 11 are rather unstable oils.Especially unstable are five-membered derivatives 11a,d that rapidly decompose on air to give dark tarry substances during few days even in a refrigerator.Recently Levacher et al. 34 have described interesting fused dihydroquinolinequinolinium redox system potentially applicable as chemical delivery system (CDS) for braintargeting drugs.Inspired by this work we performed preliminary study on the oxidative quarternization of selected compounds 11.On treatment by perchloric acid compounds 11 oxidize to the corresponding quinolinium perchlorates 12 (Scheme 5) that were confirmed and characterized by means of multinuclear magnetic resonance, X-ray diffraction and HRMS (see Supporting Info and Experimental).To the best of our knowledge, compounds 12 with n > 1 have not been prepared hitherto.The larger ring could improve the lipophilicity of the molecules which can be important, with respect to the applicability of this kind of molecules as CDS.Scheme 4. Mesomeric structures of 4a used for the explanation of mutual interconversion of E/Z isomers accounting for high conversions of the cross coupling even in Z-predominant mixtures.Scheme 5. Oxidation of selected dihydroquinolines to the corresponding quinolinium perchlorates.

Conclusions
In this work we have prepared and characterized thirteen 2-halobenzyl-substituted polarized ethylenes (enaminoesters, enaminoketones and enaminonitriles) with exocyclic double bond.The enamines were subjected to the intramolecular Buchwald-Hartwig amination reaction to give corresponding fused tricyclic dihydroquinolines 11 in good yields.The optimal reaction conditions depend both on the ring size of the starting enamines and on the type of the halogen.The fivemembered substrates appeared to be more challenging than their six and seven membered analogues.The results presented here are a substantial improvement of the methodology published hitherto and extend both the possibilities for syntheses of interesting fused nitrogen heterocycles and the scope of cross-coupling reactions.Compounds 11 can be considered as β-EWG substituted heterocyclic enamines.Due to the importance of such enamines in organic synthesis, compounds 11 could serve as useful intermediates for further synthetic transformations.For example, they can be easily oxidized to their quinolinium salts 12.In addition to that, similar 3-EWG substituted dihydroquinolines were studied as carriers for brain-specific drug delivery 48,49 (just in the combination with their quinolinium salts), or as a novel class of ABCB1 inhibitors. 50

Experimental Section
General.All the solvents and reagents were used commercial without further purification.PEPPSI-IPr was prepared according to the published procedure. 51All the palladium sources, ligands and bases used in the cross-couplings were commercial (Aldrich, Acros, Strem) and stored under argon in a desiccator.Dry solvents were used commercial (Aldrich, Acros) and stored under argon using Sure/Seal™ or AcroSeal™ technology.TLC Analyses were performed on silica gel coated aluminium plates 60 F254 under UV visualization (254 or 365 nm).Column chromatography was performed using silica gel 60 (230-400 mesh) (Sigma Aldrich) containing ~ 0.1% Ca.Melting points were measured using Kofler hot plate microscope Boetius PHMK 80/2644.NMR Spectra were measured using either Bruker AVANCE III spectrometer operating at 400.13 ( 1 H) and 100.12MHz ( 13 C) or Bruker Ascend™ spectrometer operating at 500.13 ( 1 H) and 125.15 MHz ( 13 C).Multiplicity of the signals is depicted as s (singlet), d (doublet), t (triplet), quint (quintet), m (multiplet), dd (doublet of doublets), td (triplet of doublets), br (broad signal).Proton NMR spectra in CDCl3 were calibrated using internal TMS ( = 0.00) and in DMSO-d6 on the middle signal of the solvent multiplet ( = 2.50).Carbon NMR spectra were referenced against the middle signal of the solvent multiplet ( = 77.23 for CDCl3 and 39.51 for DMSO-d6).Measurement of 13 C NMR was done in an ordinary way using broadband proton decoupling or by means of APT pulse sequence.Elemental analyses were performed on a Flash EA 2000 CHNS automatic analyser (Thermo Fisher Scientific).HRMS were measured using dried droplet method on a MALDI LTQ Orbitrap XL (Thermo Fisher Scientific) with 2,5-dihydroxybenzoic acid (DHB) or 9-aminoacridine (9-AA) as the matrices for positive or negative mode respectively.Experimental procedures for compounds 2-8 as well as details for X-ray data are in Supporting Information.
General procedure for the synthesis of C-benzylated enamines 9.A modified procedure from ref. 21 was used.A dried Schlenk flask equipped with a magnetic stirring bar was charged with the starting substrate 4, 6 or 8 (10 mmol).The flask was 3 × evacuated and backfilled with argon.Dry DMF (20 mL) was added via syringe.The apparatus was then cooled to -40 °C (acetone-dry ice bath) and sodium hydride (12 mmol, 1.2 eq.) was added in one portion.The mixture was stirred at -40 °C until foaming ceased (ca 1.5 h).2-Bromobenzylbromide (12 mmol, 1.2 eq.) was then added in one portion under cooling.The flask was removed from cooling bath and heated under inert to 80 °C for 24 h.After cooling in an ice bath, the reaction was quenched with saturated aq.NH4Cl (50 mL).Organic layer was diluted with ethyl acetate (125 mL), washed with water (3 × 50 mL) and brine (2 × 50 mL) and dried over anhydrous sodium sulphate.Evaporation to dryness gave crude 9.For purification see details at individual compounds.

Figure 4 .
Figure 4. Ligands and precatalysts used in this work.

Table 1 .
Optimization study for palladacycle-catalysed cyclization of six-membered exocyclic enamino ester a c Isolated yield.

Table 4 .
Cyclization of chloro derivatives a

Table 4 (
continued) a Conditions: 0.5 mmol of the substrate, 2 mL of the solvent.b Conversion estimated from 1 H NMR, isolated yield.