A Straightforward Synthesis of Functionalized cis-Perhydroisoquinolin-1-ones

Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones.


Introduction
Nitrogen heterocycles exhibit a broad range of significant biological and pharmacological activities, and many of them have been developed as therapeutic drugs [1,2].
Together with the intramolecular Diels−Alder cyclization of suitable azatrienes [11,12], one of the most straightforward approaches for the construction of the hydroisoquinoline ring system involves the generation of the carbocyclic ring by an annulation reaction from appropriate 5,6-dihydro-2(1H)-pyridone derivatives. The latter strategy was developed some years ago in our laboratory using the classical Diels−Alder methodology with a variety of dienes [13]. Bearing in mind that Nazarov reagents (γ,δ-unsaturated β-keto esters) are able to participate in double Michael addition reactions with α,β-unsaturated carbonyl derivatives, we envisaged an alternative annulation procedure to directly access functionalized hydroisoquinolines from 5,6-dihydro-2(1H)-pyridones.

Introduction
Nitrogen heterocycles exhibit a broad range of significant biological and pharmacological activities, and many of them have been developed as therapeutic drugs [1,2]. In particular, the partially or totally reduced isoquinoline ring system is present in a large number of biologically active natural products (such as the alkaloids of the yohimbine [3,4], manzamine [5], and madangamine [6] groups) and medicinally useful synthetic compounds (e.g., the Nazarov reagents are versatile annulating agents, extensively used in a variety of Robinson-type and double Michael addition annulations [14][15][16]. In the former, the reagent sequentially acts as an electrophilic Michael acceptor and as a nucleophile to promote an aldol condensation. In the latter, however, it successively acts as a nucleophilic Michael donor and an electrophilic Michael acceptor, a reactivity pattern that has been successfully applied to assemble pentacyclic yohimbine-type derivatives from unsaturated indolo [2,3-a]quinolizidine-derived lactams [17][18][19].

Results and Discussion
Compounds 6a,b,c and 8, which incorporate an additional phenylsulfonyl or ethoxycarbonyl activating electron-withdrawing group conjugated to the carbon-carbon double bond, were selected as the starting dihydropyridones.
Lactams 6a,b, bearing an easily removable phenylsulfonyl group, were prepared in acceptable overall yield from 2-piperidone (1a) by bis-sulfenylation, followed by reaction with either (Boc) 2 O or MeI, and subsequent stepwise m-CPBA oxidation of the resulting N-substituted piperidones 3a,b via unsaturated sulfenyl and sulfinyl derivatives 4a,b and 5a,b. A similar reaction sequence from N-tosyl-2-piperidone 3c led to unsaturated lactam 6c in low overall yield. Due to their instability, lactams 6a,b,c were used in the annulation step without purification. In turn, ethoxycarbonyl lactam 8 was prepared in high yield from N-Boc-2-piperidone (1b) via seleno derivative 7, as outlined in Scheme 1.
Molecules 2018, 23, x FOR PEER REVIEW 2 of 14 HIV protease inhibitors saquinavir and nelfinavir [7,8], the antimigraine drugs tezampanel and LY466195 [9], and the antiobesity agent AMG 076 [10]) ( Figure 1). Together with the intramolecular Diels−Alder cyclization of suitable azatrienes [11,12], one of the most straightforward approaches for the construction of the hydroisoquinoline ring system involves the generation of the carbocyclic ring by an annulation reaction from appropriate 5,6dihydro-2(1H)-pyridone derivatives. The latter strategy was developed some years ago in our laboratory using the classical Diels−Alder methodology with a variety of dienes [13]. Bearing in mind that Nazarov reagents (γ,δ-unsaturated β-keto esters) are able to participate in double Michael addition reactions with α,β-unsaturated carbonyl derivatives, we envisaged an alternative annulation procedure to directly access functionalized hydroisoquinolines from 5,6-dihydro-2(1H)pyridones.
Nazarov reagents are versatile annulating agents, extensively used in a variety of Robinson-type and double Michael addition annulations [14][15][16]. In the former, the reagent sequentially acts as an electrophilic Michael acceptor and as a nucleophile to promote an aldol condensation. In the latter, however, it successively acts as a nucleophilic Michael donor and an electrophilic Michael acceptor, a reactivity pattern that has been successfully applied to assemble pentacyclic yohimbine-type derivatives from unsaturated indolo [2,3-a]quinolizidine-derived lactams [17][18][19].

Results and Discussion
Compounds 6a,b,c and 8, which incorporate an additional phenylsulfonyl or ethoxycarbonyl activating electron-withdrawing group conjugated to the carbon-carbon double bond, were selected as the starting dihydropyridones.
Lactams 6a,b, bearing an easily removable phenylsulfonyl group, were prepared in acceptable overall yield from 2-piperidone (1a) by bis-sulfenylation, followed by reaction with either (Boc)2O or MeI, and subsequent stepwise m-CPBA oxidation of the resulting N-substituted piperidones 3a,b via unsaturated sulfenyl and sulfinyl derivatives 4a,b and 5a,b. A similar reaction sequence from N-tosyl-2-piperidone 3c led to unsaturated lactam 6c in low overall yield. Due to their instability, lactams 6a,b,c were used in the annulation step without purification. In turn, ethoxycarbonyl lactam 8 was prepared in high yield from N-Boc-2-piperidone (1b) via seleno derivative 7, as outlined in Scheme 1.

Scheme 1. Preparation of the starting unsaturated lactams.
To study the annulation reactions, we initially used unsaturated lactam 6a and the Nazarov reagent 9 [14], which incorporates a methyl group at the terminal olefinic carbon, in the presence of Cs2CO3, the most commonly used base for the generation of Nazarov enolates [20]. Reagent 9 has been used extensively by Deslongchamps to generate cis-decalin derivatives [20,21]. The reaction was carried out at room temperature, using an excess (6 equiv.) of Cs2CO3 in CH2Cl2 at different concentrations (from 50 mM to 5 mM). In all cases, the double Michael addition reaction occurred To study the annulation reactions, we initially used unsaturated lactam 6a and the Nazarov reagent 9 [14], which incorporates a methyl group at the terminal olefinic carbon, in the presence of Cs 2 CO 3 , the most commonly used base for the generation of Nazarov enolates [20]. Reagent 9 has been used extensively by Deslongchamps to generate cis-decalin derivatives [20,21]. The reaction was carried out at room temperature, using an excess (6 equiv.) of Cs 2 CO 3 in CH 2 Cl 2 at different concentrations (from 50 mM to 5 mM). In all cases, the double Michael addition reaction occurred satisfactorily, although with only moderate stereoselectivity, to give 3:1 C-8 stereoisomeric mixtures of cis-hydroisoquinolones 10a (cis Me/SO 2 Ph) and 10b (trans Me/SO 2 Ph), the chemical yield increasing (79% yield at 5 mM) with the dilution ( Table 1, entries [1][2][3]. Trace amounts of the monoaddition product 11 were detected by NMR, indicating that the annulation involves two successive Michael addition reactions. In contrast, when acetonitrile was used as the solvent the yield was very low (entry 4). Remarkably, the use of KF as the base in a polar solvent such as methanol (entry 5) resulted in a reversal of the stereoselectivity, leading to a mixture of bicyclic lactams 10a and 10b, in which the trans Me/SO 2 Ph isomer predominated (56% yield, ratio 1:2). The influence of the solvent polarity on the stereoselectivity of annulation reactions of 9 with β-keto esters has previously been observed [21]. The facial selectivity when using Cs 2 CO 3 as the base can be attributed to the coordination of the Cs + cation to the oxygen atoms of both the Nazarov reagent and the starting lactam [19].  [1][2][3]. Trace amounts of the monoaddition product 11 were detected by NMR, indicating that the annulation involves two successive Michael addition reactions. In contrast, when acetonitrile was used as the solvent the yield was very low (entry 4). Remarkably, the use of KF as the base in a polar solvent such as methanol (entry 5) resulted in a reversal of the stereoselectivity, leading to a mixture of bicyclic lactams 10a and 10b, in which the trans Me/SO2Ph isomer predominated (56% yield, ratio 1:2). The influence of the solvent polarity on the stereoselectivity of annulation reactions of 9 with β-keto esters has previously been observed [21]. The facial selectivity when using Cs2CO3 as the base can be attributed to the coordination of the Cs + cation to the oxygen atoms of both the Nazarov reagent and the starting lactam [19]. The relative Me/SO2Ph cis configuration of bicyclic lactam 10a was unambiguously established by X-ray crystallographic analysis ( Figure 2). Unsaturated lactam 6b behaved similarly to lactam 6a in the annulation reaction with Nazarov reagent 9, although the yields were slightly lower, probably due to the lower electrophilicity of the Michael acceptor as a consequence of the absence of an electron-withdrawing group on the piperidone nitrogen. cis-Hydroisoquinolone 12a, with a cis Me/SO2Ph relationship, was stereoselectively formed (4:1 12a/12b ratio) when the reaction was performed in CH2Cl2 solution using Cs2CO3 as the base ( The relative Me/SO 2 Ph cis configuration of bicyclic lactam 10a was unambiguously established by X-ray crystallographic analysis ( Figure 2).
Molecules 2018, 23, x FOR PEER REVIEW 3 of 14 (79% yield at 5 mM) with the dilution ( Table 1, entries [1][2][3]. Trace amounts of the monoaddition product 11 were detected by NMR, indicating that the annulation involves two successive Michael addition reactions. In contrast, when acetonitrile was used as the solvent the yield was very low (entry 4). Remarkably, the use of KF as the base in a polar solvent such as methanol (entry 5) resulted in a reversal of the stereoselectivity, leading to a mixture of bicyclic lactams 10a and 10b, in which the trans Me/SO2Ph isomer predominated (56% yield, ratio 1:2). The influence of the solvent polarity on the stereoselectivity of annulation reactions of 9 with β-keto esters has previously been observed [21]. The facial selectivity when using Cs2CO3 as the base can be attributed to the coordination of the Cs + cation to the oxygen atoms of both the Nazarov reagent and the starting lactam [19]. The relative Me/SO2Ph cis configuration of bicyclic lactam 10a was unambiguously established by X-ray crystallographic analysis ( Figure 2). Unsaturated lactam 6b behaved similarly to lactam 6a in the annulation reaction with Nazarov reagent 9, although the yields were slightly lower, probably due to the lower electrophilicity of the Michael acceptor as a consequence of the absence of an electron-withdrawing group on the piperidone nitrogen. cis-Hydroisoquinolone 12a, with a cis Me/SO2Ph relationship, was stereoselectively formed (4:1 12a/12b ratio) when the reaction was performed in CH2Cl2 solution using Cs2CO3 as the base ( Table 2, entries 1 and 2), the yield once again being higher with increasing dilution Unsaturated lactam 6b behaved similarly to lactam 6a in the annulation reaction with Nazarov reagent 9, although the yields were slightly lower, probably due to the lower electrophilicity of the Michael acceptor as a consequence of the absence of an electron-withdrawing group on the piperidone nitrogen. cis-Hydroisoquinolone 12a, with a cis Me/SO 2 Ph relationship, was stereo-selectively formed (4:1 12a/12b ratio) when the reaction was performed in CH 2 Cl 2 solution using Cs 2 CO 3 as the base ( Table 2, entries 1 and 2), the yield once again being higher with increasing dilution (40% yield at 5 mM). As before, a reversal of the stereoselectivity was observed and the trans Me/SO 2 Ph isomer predominated when using polar solvents, either MeOH in the presence of KF (1:4 ratio; entry 3) or DMF in the presence of Cs 2 CO 3 (1:5 ratio; entry 4). The Me/SO 2 Ph cis relationship of the adducts 10a and 12a was maintained unchanged after an additional treatment (20 h, rt) with Cs 2 CO 3 in CH 2 Cl 2 or KF in MeOH, thus suggesting the non-reversibility of the cyclization step.  The relative configuration of both hydroisoquinolones, 12a and 12b, was unambiguously established by X-ray crystallographic analysis ( Figure 3). The activating phenylsulfonyl group of bicyclic lactams 10a, 12a, and 12b was stereoselectively removed, with retention of configuration, by treatment with sodium amalgam [22] to give the respective cis-hydroisoquinolones 13a, 14a, and 14b (Scheme 2). Alternatively, removal of the N-Boc protecting group of hydroisoquionolones 10a and 13a quantitatively afforded the potentially useful N-unsubstituted derivatives 15 and 16, respectively. The cis ring function was evident from the observation of a positive NOE effect between the 4a and 8a methine protons. The relative configuration of both hydroisoquinolones, 12a and 12b, was unambiguously established by X-ray crystallographic analysis ( Figure 3).  The relative configuration of both hydroisoquinolones, 12a and 12b, was unambiguously established by X-ray crystallographic analysis ( Figure 3). The activating phenylsulfonyl group of bicyclic lactams 10a, 12a, and 12b was stereoselectively removed, with retention of configuration, by treatment with sodium amalgam [22] to give the respective cis-hydroisoquinolones 13a, 14a, and 14b (Scheme 2). Alternatively, removal of the N-Boc protecting group of hydroisoquionolones 10a and 13a quantitatively afforded the potentially useful N-unsubstituted derivatives 15 and 16, respectively. The cis ring function was evident from the observation of a positive NOE effect between the 4a and 8a methine protons.  The activating phenylsulfonyl group of bicyclic lactams 10a, 12a, and 12b was stereoselectively removed, with retention of configuration, by treatment with sodium amalgam [22] to give the respective cis-hydroisoquinolones 13a, 14a, and 14b (Scheme 2). Alternatively, removal of the N-Boc protecting group of hydroisoquionolones 10a and 13a quantitatively afforded the potentially useful N-unsubstituted derivatives 15 and 16, respectively. The cis ring function was evident from the observation of a positive NOE effect between the 4a and 8a methine protons.
To expand the scope of the methodology and access hydroisoquinolones lacking the methyl substituent on the B ring, we decided to study double Michael annulations using the silylated Nazarov reagent 17 [17], which constitutes a stable synthetic equivalent of the original Nazarov reagent (methyl or ethyl 3-oxo-4-pentenoate) [15] that avoids the polymerization problems associated with the latter under basic conditions.
The activating phenylsulfonyl group of bicyclic lactams 10a, 12a, and 12b was stereoselectively removed, with retention of configuration, by treatment with sodium amalgam [22] to give the respective cis-hydroisoquinolones 13a, 14a, and 14b (Scheme 2). Alternatively, removal of the N-Boc protecting group of hydroisoquionolones 10a and 13a quantitatively afforded the potentially useful N-unsubstituted derivatives 15 and 16, respectively. The cis ring function was evident from the observation of a positive NOE effect between the 4a and 8a methine protons. To expand the scope of the methodology and access hydroisoquinolones lacking the methyl substituent on the B ring, we decided to study double Michael annulations using the silylated Nazarov reagent 17 [17], which constitutes a stable synthetic equivalent of the original Nazarov reagent (methyl or ethyl 3-oxo-4-pentenoate) [15] that avoids the polymerization problems associated with the latter under basic conditions. Scheme 2. Desulfonylation reactions and removal of the N-Boc protecting group.
As expected, the Cs 2 CO 3 -promoted annulation of the Nazarov reagent 17 with unsaturated lactam 6a under the usual reaction conditions (5 mM in CH 2 Cl 2 as the solvent) stereoselectively afforded cis-hydroisoquinolone 18a, in which protodesilylation had occurred, in acceptable yield ( Table 3, entry 1). The yield was not improved by increasing the excess of reagent and base (entry 2) and was lower when operating at a higher concentration (entry 3) or when using KF in MeOH as the solvent (entry 4). Similar moderate yields were obtained in the generation of cis-hydroisoquinolones 18b and 18c from lactams 6b (entries 5-7) and 6c (entry 8) under a variety of conditions. As expected, the Cs2CO3-promoted annulation of the Nazarov reagent 17 with unsaturated lactam 6a under the usual reaction conditions (5 mM in CH2Cl2 as the solvent) stereoselectively afforded cis-hydroisoquinolone 18a, in which protodesilylation had occurred, in acceptable yield ( Table 3, entry 1). The yield was not improved by increasing the excess of reagent and base (entry 2) and was lower when operating at a higher concentration (entry 3) or when using KF in MeOH as the solvent (entry 4). Similar moderate yields were obtained in the generation of cis-hydroisoquinolones 18b and 18c from lactams 6b (entries 5-7) and 6c (entry 8) under a variety of conditions. Remarkably, the yield of the annulation with the silylated Navarov reagent 17 was higher when using unsaturated lactam 8, which incorporates an ester group as an additional activating substituent. Operating under the previously optimized reaction conditions, cis-hydroisoquinolone 19 was obtained in 60% yield (Scheme 3). In conclusion, base-promoted annulation reactions of Nazarov reagents 9 and 17 with 5,6dihydro-2(1H)-pyridones bearing an additional activating electron-withdrawing group α to the lactam carbonyl constitute a straightforward procedure for the stereoselective synthesis of highly substituted cis-hydroisoquinolin-2-ones. In the reactions with the methyl-substituted reagent 9, leading to 8-substituted derivatives, the use of Cs2CO3 in CH2Cl2 leads to cis-hydroisoquinolones with a cis 8-Me/8a-SO2Ph relationship as the major stereoisomers. The stereoselectivity is reversed in a polar solvent such as DMF or when the annulation is performed using KF in MeOH.
The methodology developed here provides access to polyfunctionalized bicyclic scaffolds with potential use as precursors of bioactive hydroisoquinoline-containing natural products and synthetic Remarkably, the yield of the annulation with the silylated Navarov reagent 17 was higher when using unsaturated lactam 8, which incorporates an ester group as an additional activating substituent. Operating under the previously optimized reaction conditions, cis-hydroisoquinolone 19 was obtained in 60% yield (Scheme 3).
Molecules 2018, 23, x FOR PEER REVIEW 5 of 14 As expected, the Cs2CO3-promoted annulation of the Nazarov reagent 17 with unsaturated lactam 6a under the usual reaction conditions (5 mM in CH2Cl2 as the solvent) stereoselectively afforded cis-hydroisoquinolone 18a, in which protodesilylation had occurred, in acceptable yield ( Table 3, entry 1). The yield was not improved by increasing the excess of reagent and base (entry 2) and was lower when operating at a higher concentration (entry 3) or when using KF in MeOH as the solvent (entry 4). Similar moderate yields were obtained in the generation of cis-hydroisoquinolones 18b and 18c from lactams 6b (entries 5-7) and 6c (entry 8) under a variety of conditions. Remarkably, the yield of the annulation with the silylated Navarov reagent 17 was higher when using unsaturated lactam 8, which incorporates an ester group as an additional activating substituent. Operating under the previously optimized reaction conditions, cis-hydroisoquinolone 19 was obtained in 60% yield (Scheme 3). In conclusion, base-promoted annulation reactions of Nazarov reagents 9 and 17 with 5,6dihydro-2(1H)-pyridones bearing an additional activating electron-withdrawing group α to the lactam carbonyl constitute a straightforward procedure for the stereoselective synthesis of highly substituted cis-hydroisoquinolin-2-ones. In the reactions with the methyl-substituted reagent 9, leading to 8-substituted derivatives, the use of Cs2CO3 in CH2Cl2 leads to cis-hydroisoquinolones with a cis 8-Me/8a-SO2Ph relationship as the major stereoisomers. The stereoselectivity is reversed in a polar solvent such as DMF or when the annulation is performed using KF in MeOH.
The methodology developed here provides access to polyfunctionalized bicyclic scaffolds with potential use as precursors of bioactive hydroisoquinoline-containing natural products and synthetic In conclusion, base-promoted annulation reactions of Nazarov reagents 9 and 17 with 5,6-dihydro-2(1H)-pyridones bearing an additional activating electron-withdrawing group α to the lactam carbonyl constitute a straightforward procedure for the stereoselective synthesis of highly substituted cis-hydroisoquinolin-2-ones. In the reactions with the methyl-substituted reagent 9, leading to 8-substituted derivatives, the use of Cs 2 CO 3 in CH 2 Cl 2 leads to cis-hydroisoquinolones with a cis 8-Me/8a-SO 2 Ph relationship as the major stereoisomers. The stereoselectivity is reversed in a polar solvent such as DMF or when the annulation is performed using KF in MeOH.
The methodology developed here provides access to polyfunctionalized bicyclic scaffolds with potential use as precursors of bioactive hydroisoquinoline-containing natural products and synthetic derivatives.

General Information
All air sensitive manipulations were carried out under a dry argon or nitrogen atmosphere. THF and CH 2 Cl 2 were dried using a column solvent purification system. Analytical thin-layer chromatography was performed on SiO 2 (silica gel Carlo Erba,Val de Reuil Cedex,France), and the spots were located with 1% aqueous KMnO 4 . Chromatography refers to flash chromatography and was carried out on SiO 2 (SDS silica gel 60 ACC, [230][231][232][233][234][235][236][237][238][239][240]. NMR spectra were recorded at 300 or 400 MHz ( 1 H) and 100.6 MHz ( 13 C), and chemical shifts are reported in δ values downfield from TMS or relative to residual chloroform (7.26 ppm, 77.0 ppm) as an internal standard. Data are reported in the following manner: chemical shift, multiplicity, coupling constant (J) in hertz (Hz), integrated intensity, and assignment (when possible). Assignments and stereochemical determinations are given only when they are derived from definitive two-dimensional NMR experiments (HSQC-COSY). IR spectra were performed in an Avatar 320 FT-IR spectrophotometer (Thermo Nicolet, Madison, WI, USA) and only noteworthy IR absorptions (cm −1 ) are listed. High resolution mass spectra (HMRS; LC/MSD TOF, Agilent Technologies, Santa Clara, CA, USA) were performed by Centres Científics i Tecnològics de la Universitat de Barcelona.

General Procedure for the Double Michael Addition Reactions
A solution of unsaturated lactam 6a,b,c or 8 (1 equiv.) in anhydrous CH 2 Cl 2 , MeCN or MeOH was added at 0 • C under an argon atmosphere to a solution of the Nazarov reagent (9 or 15) and Cs 2 CO 3 or KF in anhydrous CH 2 Cl 2 , MeCN or MeOH, and the resulting mixture was allowed to warm slowly to room temperature. After 20 h of stirring at room temperature, the mixture was concentrated under reduced pressure. Flash chromatography (9:1 hexane-EtOAc) of the residue afforded the corresponding adduct/s (10a,b, 12a,b, 16a,b,c or 17) as yellow foams (detailed data in supplementary materials).