Ruthenium(II)-Catalyzed Regioselective-Controlled Allenylation

Article Cite This: J. Org. Chem. 2018, 83, 8567−8580

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Ruthenium(II)-Catalyzed Regioselective-Controlled Allenylation/ Cyclization of Benzimides with Propargyl Alcohols Adapa Anukumar, Masilamani Tamizmani, and Masilamani Jeganmohan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India

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S Supporting Information *

ABSTRACT: A ruthenium(II)-catalyzed cyclization of benzimidates with substituted propargyl alcohols to provide 3,4disubstituted 1-alkoxy isoquinolines in a highly selective manner via the C−H allenylation is described. The proposed reaction mechanism of the ruthenium(II)-catalyzed cyclization reaction is strongly supported by the isolation of the key ruthenacycle intermediate, deuterium-labeling studies, and detailed DFT calculations including the transition states.

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as easily affordable propargyl alcohols via β-hydroxy elimination.5e Allenes are a versatile synthetic intermediate, and it has been widely used as a key intermediate for synthesizing natural products, biologically active molecules, and chiral molecules.5 Meanwhile, allenes show diverse reactivity as compared with other carbon−carbon π-components due to the presence of adjacent two orthogonal double bonds.5 Particularly, the center sp carbon of allene is highly electron deficient, and thus even a mild nucleophile can attack at the sp carbon to make carbocyclic or heterocyclic molecules in a highly selective manner. It is important to note that a ruthenium-catalyzed C− H bond allenylation reaction via challenging β-hydroxy elimination is not known in the literature. Herein, we report for the first time the unprecedented less expensive and airstable ruthenium(II)-catalyzed cyclization of benzimidates with unactivated propargyl alcohols providing 3,4-disubstituted 1alkoxy isoquinolines via the C−H bond allenylation reaction in a redox-free version.6−8 In the metal-catalyzed oxidative cyclization of benzimidates or aromatic imines or ketoximes with internal alkynes, 3,4-disubstituted isoquinolines can be prepared very efficiently (Figure 1).9 In the present C−H allenylation reaction, 3,4-disubstituted isoquinolines were prepared with the reverse selectivity at the 3- and 4-positions of isoquinolines (Figure 1).9 In the reaction, the hydroxyl group

INTRODUCTION

The transition-metal-catalyzed chelation-assisted cyclization of substituted aromatics or heteroaromatics with a carbon−carbon π-component is an efficient method for synthesizing heterocyclic molecules in a highly atom-economical manner from easily available starting materials.1−4 Alkynes, alkenes, and allenes are frequently used as a π-component for the cyclization reaction. It is well-known that the C−M bond of the organometallic reagents readily reacted with substituted propargylic acetates or carbonates yielding substituted allene derivatives.5 By employing this protocol, various disubstituted and trisubstituted allenes were prepared effectively. However, the synthesis of tetrasubstituted allenes is very challenging and less explored in the literature.2 Meanwhile, a stoichiometric amount of preactivated C−M is required for the reaction. Recently, Ma’s group prepared challenging tetrasubstituted allenes via a rhodium-catalyzed C−H allenylation of substituted aromatics with activated propargyl carbonates via β-oxygen elimination.5a,b Glorius’s group described a manganesecatalyzed C−H allenylation of substituted indoles with activated propargyl carbonates and cyclization of benzimidates with activated propargyl carbonates.5c,d The direct utilization of propargylic alcohol as a coupling partner instead of the corresponding carbonates would make this protocol more interesting in allene synthesis via β-oxygen elimination. Recently, Sundararaju’s group described a cobalt-catalyzed C−H allenylation of phenylpyrazoles with unactivated as well © 2018 American Chemical Society

Received: May 2, 2018 Published: May 25, 2018 8567

DOI: 10.1021/acs.joc.8b01123 J. Org. Chem. 2018, 83, 8567−8580

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The Journal of Organic Chemistry

Figure 1. Reverse chelation of the phenyl group with a ruthenium.

Scheme 1. Ruthenium(II)-Catalyzed Cyclization of 1a with 2a

Table 1. Optimization Studiesa

of propargyl alcohol acts as a traceless directing group and also plays a crucial role for the observation of reverse regioselectivity. It coordinates with the key five-membered ruthenacycle intermediate and allows for the C−H allenylation instead of the typical oxidative cyclization reaction. The weak coordination of the hydroxy group of propargyl alcohol with ruthenium leads to the formation of regioselective orthoallenylated benzimidates.

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RESULTS AND DISCUSSION Treatment of 4-methylbenzimidate (1a) with propargyl alcohol (2a) in the presence of an air-stable [Ru(CH3CN)3(pcymene)][SbF6]2 (10 mol %) and Na2HPO4 (1.0 equiv) in 1,2- dichloroethane (ClCH2CH2Cl) at 100 °C for 12 h gave 1ethoxyisoquinoline (3aa) in 85% isolated yield in a highly regioselective manner (Scheme 1). Initially, the cyclization reaction was examined with various bases (1.0 equiv) such as LiOAc, NaOAc, KOAc, Na2CO3, K2CO3, and Na2HPO4. Among them, Na2HPO4 was very effective, giving product 3aa in 92% GC and 85% isolated yield (entry 6). Na2CO3 and K2CO3 were also equally effective, giving product 3aa in 85% and 75% GC yields, respectively (entries 4 and 5). Other bases were partially effective, giving product 3aa in 30−57% yields (Table 1, entries 1−6). The [{RuCl2(p-cymene)}2] complex provided product 3aa in 10% yield (entry 14). However, no 3aa product was observed without a catalyst (entry 15). Various solvents such as ClCH2CH2Cl, THF, DMF, CH 3 CN, toluene, AcOH, 1,2-dichlorobenzene, and CF3CH2OH were examined (entries 7−13). Among them, ClCH2CH2Cl was very effective, giving 3aa in 92% GC yield (entry 6). Toluene was equally effective, giving 3aa in 86% GC yield (entry 10). 1,2-Dichlorobenzene, CF3CH2OH, and THF were less effective, yielding 3aa in 55%, 20%, and 30% yields, respectively. Other solvents were not effective. When the same reaction was performed in the presence of Adm-1-COOH (0.5

entry

solvent

additive (1 equiv)

yield of 3aa (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl THF DMF acetonitrile toluene acetic acid 1,2-dichlorobenzene CF3CH2OH ClCH2CH2Cl ClCH2CH2Cl

LiOAc NaOAc KOAc Na2CO3 K2CO3 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4

57 47 37 85 75 92 (85)c 30 NR NR 86 NR 55 20 10d NRe

a All reactions were carried out under the following conditions: 1a (50 mg), 2a (1.5 equiv), [{Ru(CH3CN)3(p-cymene)}{SbF6}2] (10 mol %), and solvent (2.0 mL) at 100 °C for 12 h under a N2 atmosphere. b GC yield. cIsolated yield. d[{RuCl2(p-cymene)}2] (5 mol %) instead of [{Ru(CH3CN)3(p-cymene)}{SbF6}2]. eWithout catalyst.

equiv) instead of Na2HPO4, product 4aa was observed in 25% yield along with 3aa in 40% yield (eq 1). In the reaction, H2 was formed as a side product. The liberation of H2 gas was confirmed by gas chromatography with a TCD detector.6b,8

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The Journal of Organic Chemistry Scheme 2. Ruthenium(II)-Catalyzed Cyclization of 1 with 2a

reacted efficiently with 1a, yielding products 3ab−ag in 75%, 45%, 72%, 73%, 75%, and 62% yields, respectively. orthoBromo-substituted phenyl propargyl alcohol 2h was also effectively involved in the reaction, giving cyclized product 3ah in 68% yield. Alkyl-substituted propargyl alcohols 2i and 2j also participated in the reaction, providing cyclized products 3ai and 3aj in 76% and 45% yields, respectively. The spiro propargyl alcohols 2k−l reacted with 1a giving products 3ak and 3al in 41% and 68% yields, respectively. It is very interesting to note that the bis-propargyl alcohol 2m reacted efficiently with 1a (3.0 equiv) yielding bis-isoquinoline 3am in 32% yield (eq 2). An acid hydrolysis of 1-ethoxyisoquinoline 3aa with concentrated HCl and 1,4-dioxane (1:1) at 100 °C for 12 h gave isoquinolone 5a in 90% yield (eq 3). Later, 1bromoisoquinoline 6a and 1-chloroisoquinoline 7a were prepared in 91% and 93% yields, respectively, by the reaction of 5a with PBr3 or POCl3 (eq 3). To gain more insight about the reaction mechanism, the following reactions were performed (Scheme 4). The reaction of 1a with CD3COOD (2.0 equiv) in the presence of [Ru(CH3CN)3(p-cymene)][SbF6]2 (10 mol %) in DCE at 60 °C for 12 h provided D-1a in 85% yield with 20% deuterium incorporation at both ortho-carbons. Further, the reaction of 1a

The cyclization reaction was examined with substituted benzimidates under the optimized reaction conditions (Scheme 2). The reaction of 4-methoxybenzimidate (1b) and benzimidate (1c) with 2a provided 3,4-disubstituted isoquinolines 3ba and 3ca in 78% and 65% yields, respectively. Halogen such as I, Br, Cl, and F substituents at the para-position of benzimidates 1d−g afforded the expected halogenated isoquinolines 3da−ga in 71%, 74%, 75%, and 80% yields, respectively. Electron-withdrawing para-CF3-substituted benzimidate 1h yielded product 3ha in a moderate 51% yield. A 2:1 regioisomeric mixture of products 3ia and 3ia′ was observed in the reaction of meta-methoxy benzimidate 1i with 2a. Methoxy (1j)- and OnPr (1k)-substituted benzimidates were also effectively involved in the reaction, giving 1-OMe- and 1OnPr-substituted isoquinolines 3ja and 3ka in 56% and 67% yields, respectively. The reaction of 2-thienyl imidate 1l and 3thienyl imidate 1m with 2a yielded products 3la and 3ma in 44% and 31% yields, respectively. The cyclization reaction was examined with diphenylmethanimine and propargyl alcohol (2a). However, no cycloaddition product was observed. The scope of cyclization reaction was further examined with substituted propargyl alcohols 2b−l (Scheme 3). 4-Methyl (2b)-, 4-iodo (2c)-, 4-bromo (2d)-, 4-chloro (2e)-, 4-fluoro (2f)-, and 4-CN (2g)-substituted phenyl propargyl alcohols 8569


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The Journal of Organic Chemistry Scheme 3. Ruthenium(II)-Catalyzed Cyclization of 1a with 2

with 2a under similar reaction conditions yielded product D3aa in 55% yield with 20% deuterium incorporation at the ortho-carbon. This result clearly reveals that the ortho-C−H bond activation is a reversible process. To prove that the reaction proceeds via a five-membered metalacycle intermediate, the reaction of 1a with a stoichiometric amount of [Ru(CH3CN)3(p-cymene)][SbF6]2 complex at 60 °C for 12 h was performed (Scheme 4). In the reaction, a five-membered ruthenacycle intermediate 9a was observed. The structure of complex 9a was confirmed by NMR, mass spectroscopy, and single-crystal X-ray crystallography (Figure 2). Later, intermediate 9a was treated with 2a in the presence of Na2HPO4 in DCE at 60 °C for 12 h. In the reaction, product

3aa was observed in 65% yield. However, only 20% yield of product 3aa was observed in the same reaction without a base. This result clearly reveals that the base is crucial for the cyclization reaction. A possible reaction mechanism involving the C−H allenylation as a key step is proposed in Scheme 5. The nitrogen atom of imidate 1 coordinates with a ruthenium catalyst 8 followed by ortho-metalation giving a five-membered ruthenacycle intermediate 9. Coordinative regioselective insertion of alkyne 2 into the Ru−carbon bond of intermediate 8570


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The Journal of Organic Chemistry Scheme 4. Mechanistic Investigation

(CH3CN)(OAc)]+ can be generated by the reaction of a cationic complex [(p-cymene)Ru(CH3CN)3]2+ with NaOAc (Figure 3). In the first step, benzimidate 1 replaces the CH3CN ligand in the active cationic complex 8, forming active intermediate 14. The active intermediate 14 has imidate coordination through the imine nitrogen atom, one κ2 acetate moiety and a p-cymene ligand around the ruthenium metal center. Concerted metalation−deprotonation of the ortho-C−H bond of benzimidate takes place via TS-1 forming the fivemembered metalacycle 9. The ortho-C−H bond is activated by an acetate moiety of active intermediate 14 via agostic interaction. The overall C−H activation barrier is found to be 15.9 kcal.mol−1. The replacement of acetic acid coordination by propargyl alcohol 2 in the ruthenacycle intermediate 9 can provide two isomers, which differ with respect to the orientation of propargyl alcohol at the metal center. The formation of isomers 15a and 15b were considered for calculation. It is noted that the formation of isomer 15a is more favorable than the formation of isomer 15b by −5.5 kcal mol−1. It is expected that the precoordination of the OH group of propargyl alcohol is considered to be the most important step for affording the final product. Hence, weak coordination of the hydroxyl group with a metal center helps in controlling the regioselectivity of the cyclization reaction.5b The insertion of propargyl alcohol into the Ru−C bond of intermediate 15a takes place via TS-2 (19.8 kcal mol−1). It results in the formation of a seven-membered ruthenacycle intermediate 10 and the calculated energy to be exergonic (−26 kcal mol−1). The overall energy barrier for this insertion reaction is 0.9 kcal mol−1 only. Further, the seven-membered ruthenacycle intermediate 10 undergoes β-hydroxy elimination to afford tetrasubstituted allene 11, along with the regeneration of an active catalyst.

Figure 2. ORTEP drawing (50% probability ellipsoids) of ruthenacycle 9a (CCDC 1825750).

9 gives intermediate 10. β-Hydroxy elimination of intermediate 10 affords ortho-allenylated benzimidate 11 and the ruthenium hydroxy species 12. Later, the ruthenium hydroxy species 12 reacts with CH3COOH, giving water, and regenerates the active catalyst. In the reaction, the whole catalytic reaction has occurred in the ruthenium(II) oxidation state. The observation of product 4 can be explained via formation of the ruthenium hydride species 13 from intermediate 10 under the acidic medium. The ruthenium hydride species 13 reacts with carboxylic acid, providing H2 gas, and regenerates the active catalyst 8. The DFT calculations were carried out with the M06 density functional theory for understanding the experimental observation of the reaction. The active catalyst [(p-cymene)Ru8571


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The Journal of Organic Chemistry Scheme 5. Proposed Mechanism

Figure 3. Gibb’s free energy profile (kcal/mol) obtained at the B3LYP/6-311G*, SDD (Ru) level of theory in DCM solvent.

Later, ortho-allenylated benzimidate was converted into the final cyclized product 3 in the presence of a base. This energy is calculated to be more exergonic (−43.6 kcal mol−1) in nature. Since the final product is more stabilized than allene, the isolation of allene becomes very difficult. The possibility of formation of product 4 under an acidic medium was also investigated. When the intermediate 10 was treated with acetic

acid, the formation of the intermediate truthenium hydride species 13 and product 4 was observed. Further, the ruthenium hydride species undergoes hydrogen gas elimination to regenerate the active catalyst exergonically (−4.9 kcal mol−1). The energy for formation of product 4 was found to be −26.0 kcal mol−1, whereas the formation of product 3 was −43.6 kcal mol−1. That is why we have observed product 4 as a minor 8572


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that the ortho-C−H bond cleavage of aromatic imidate in intermediate 9 is a reversible process. Further, the reaction of 1a with 2a under similar reaction conditions afforded D-3aa in 55% yield with 20% deuterium incorporation at the ortho-position. Procedure for the Preparation of a Five-Membered Ruthenacycle Intermediate 9. A 25 mL Schlenk tube with a septum containing [{Ru(CH3CN)3(p-cymene)}{SbF6}2] (1.0 equiv, 250 mg) was evacuated and purged with nitrogen gas three times. To the tube were then added benzimidate 1a (1.0 equiv), Na2HPO4 (1.0 equiv), and dichloroethane (3.0 mL) via syringe, and again the reaction mixture was evacuated and purged with nitrogen gas three times. After that, the septum was completely covered by Teflon tape. Then, the reaction mixture was allowed to stir at 70 °C for 12 h. The reaction mixture was filtered through Celite with DCM. The filtrate was concentrated and washed with diethyl ether to get the pure fivemembered intermediate 9. Later, intermediate 9 was treated with 2a in the presence of Na2HPO4 in DCE at 60 °C for 12 h . In the reaction, product 3aa was observed in 65% yield. However, only 20% yield of product 3aa was observed in the same reaction without a base. To get the single crystal, the compound, which contained DMSO-d6, was dissolved in 10 mL of methanol and left for a few days. After the solvent was removed, we found 9a as dark green crystals with DMSOd6 coordinated with the metal center. 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.63 (br, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.18 (d, J = 6.2 Hz, 1H), 5.76 (d, J = 7.4 Hz, 1H), 5.69 (d, J = 7.5 Hz, 1H), 5.46 (d, J = 7.3 Hz, 1H), 4.46−4.30 (m, 2H), 2.66−2.51 (m, 1H), 2.43 (s, 3H), 2.33 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 125 MHz): δ 174.1, 172.9, 142.9, 140.8, 135.4, 127.5, 125.3, 113.6, 109.2, 94.6, 90.3, 90.1, 89.9, 64.5, 30.9, 22.9, 22.0, 21.3, 18.8, 13.9. HRMS (ESI-QTOF) m/z: [M]+ calcd for (C22H26D6NO2RuS), 482.1574; found, 482.1591. Synthesis of Isoquinolone 5a.13 To a solution of 3aa (300 mg, 0.98 mmol) in 1,4-dioxane (12.0 mL) was added aqueous HCl (12 M, 12.0 mL), and the mixture was heated at 100 °C for 12 h. After that, the solution was neutralized with saturation NaHCO3 and extracted three times with dichloromethane (80 mL). The organic layer was washed with a brine solution (100 mL) and dried over Na2SO4, and the solvent was removed under reduced pressure to afford the crude product. The product was washed with acetone and pentane to yield 5a as a white solid (90% yield, 245.21 mg). Procedure for the Chlorination or Bromination Reaction.14 In a 50 mL round-bottom flask fitted with a condenser, a suspension of isoquinolone 5a (100 mg) in phosphorus oxychloride (POCl3) or phosphorus tribromide (PBr3) (2.0 mL) was heated at 100 °C for 2 h for chlorination (120 °C for 6 h for bromination). The reaction was monitored by TLC. After completion (approximately 2.0 h for chlorination and approximately 6.0 h for bromination), the reaction mixture was cooled to ambient temperature and poured in ice. Saturated NaHCO3 was added, and crude material was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2SO4. The solution was concentrated under reduced pressure to provide crude 1-halo isoquinolines 6a/7a. The crude residue was purified through a silica gel column using hexane as an eluent to give pure 6a/7a. Computational Details. DFT computations were carried out using the Gaussian 09 program (revision A.02).15 The model systems have been fully optimized using the B3LYP density functional theory via vibrational frequency calculations as either minima (all positive frequency) or transition states (one negative frequency) obtained the zero-point energy (ZPE) and thermal correction. The valence orbitals of ruthenium were described using the SDD basis set; nonmetal centers were described using the 6-311G(d) basis set. IRC calculations and subsequent geometry optimizations were used to confirm the minima linked by each transition state. A solvent correction (for DCE) was performed using the polarized continuum model (PCM).16 The M06 functional has been used to improve the treatment of noncovalent interactions in the model systems.17 Single-point energies including solvent effects were evaluated at the PCM (in DCE)/M06/ 6-311G(d), SDD(Ru). The energy profile diagram of the reaction

product in the course of the reaction. Overall, the calculated energy barriers and structural isolation of the key intermediate 9a clearly indicates that the proposed mechanism in Scheme 3 is energetically feasible process.

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CONCLUSION

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EXPERIMENTAL SECTION

In conclusion, we have demonstrated a highly regioselective synthesis of 3,4-disubstituted 1-alkoxy isoquinolines via a ruthenium(II)-catalyzed allenylation/cyclization of benzimidates with propargyl alcohols. The cyclization reaction was compatible with substituted benzimidates and propargyl alcohols. The reaction proceeds via the C−H allenylation at the ortho-position of benzimidate providing tetrasubstituted allene followed by the intramolecular nucleophilic addition of NH at the sp carbon of allene. The proposed reaction mechanism was strongly supported by the isolation of the key ruthenacycle intermediate, deuterium-labeling studies, and detailed DFT calculations including the transition state studies.

General Information. All reactions were carried out under a N2 atmosphere in flame-dried glassware. Syringes, which were used to transfer anhydrous solvents or reagents, were purged with nitrogen gas prior to use (three times). Dry solvents were used for the reaction. Column chromatographic purifications were performed using SiO2 (120−200 mesh ASTM) from Merck if not indicated otherwise. Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentat; hept, heptet; m, multiplet. Commercially available EtOH was used without further purification. Commercially available chemicals and metal salts were purchased from Sigma-Aldrich and Spectrochem Ind Pvt Lt. and used without further purification. All of the aromatic imidates 1 were prepared from the known literature procedure.10,7f All of the propargylic alcohols 2 were prepared from the known literature procedure.11 All of the Ruthenium catalysts were prepared from the known literature procedure.12 General Procedure for the Cyclization of Benzimidates with Propargylic Alcohol Catalyzed by the Ruthenium Complex. A 15 mL Schlenk tube with a septum containing [{Ru(CH3CN)3(pcymene)}{SbF6}2] (10.0 mol %) and Na2HPO4 (1.0 equiv) were evacuated and purged with nitrogen gas three times. To the tube were then added benzimidates 1 (50 mg), propargylic alcohol 2 (1.5 equiv), and dichloroethane (2.0 mL) via syringes, and again the reaction mixture was evacuated and purged with nitrogen gas three times. Then, the reaction mixture was allowed to stir at 100 °C for 12−24 h (the specific reaction time given in the Spectral Data section). Then, the reaction mixture was diluted with CH2Cl2 and filtered through Celite and silica gel, and the filtrate was concentrated. The crude residue was purified through a silica gel column using petroleum ether and ethyl acetate as an eluent to give products 3. Procedure for the Determination of H2 Gas Evolution by GC. A 15 mL Schlenk tube with a septum containing [{Ru(CH3CN)3(pcymene)}{SbF6}2] (10 mol %) and Adm-1-COOH (0.5 equiv) was evacuated and purged with nitrogen gas three times. To the tube were then added aromatic imitade 1a (75 mg), propargylic alcohol 2a (1.5equiv), and DCE (3.0 mL) via syringes, and again the reaction mixture was evacuated and purged with nitrogen gas three times. After that, the septum was completely covered by Teflon tape. Then, the reaction mixture was allowed to stir at 100 °C for 12 h. After that, the gaseous reaction mixture was taken by the syringe and injected into the gas chromatograph (GC) equipped with a TCD detector (Agilent 7890). The characteristic peak for H2 gas was observed in the exact region (retention time = 0.5−0.6 min). Deuterium-Labeling Studies. Compound 1a was treated with CD3COOD in the presence of [{Ru(CH3CN)3(p-cymene)}{SbF6}2] (10.0 mol %) in dichloroethane at 60 °C for 12 h. In the reaction, product D-1a was observed in 87% yield with 20% of deuterium incorporation at both ortho-carbons, respectively. It clearly indicates 8573


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154.1, 138.4, 138.3, 130.7, 129.9, 128.4, 127.0, 125.1, 125.1, 123.8, 122.9, 117.8, 61.7, 31.9, 22.4, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H22NO), 292.1701; found, 292.1679. 1-Ethoxy-6-iodo-3-isopropyl-4-phenylisoquinoline (3da). Colorless solid. Eluent: hexane. The representative general procedure was

pathway is presented as Gibbs free energy changes (ΔG’s) involving zero-point vibrational energy (ZPVE) and thermal corrections obtained at 298.15 K and 1 atm pressure. To estimate the Gibbs free energies of M06 calculations, the ZPVE and thermal corrections obtained from the B3LYP calculations have been used. Spectral Data of All Compounds. 1-Ethoxy-3-isopropyl-6methyl-4-phenylisoquinoline (3aa). Colorless solid. Eluent: hexane.

followed using 1d (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 80 mg and 71% yield. Mp: 114−116 °C. 1H NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.51− 7.42 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 4.64 (q, J = 7.0 Hz, 2H), 2.92− 2.80 (m, 1H), 1.51 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.5, 155.6, 139.8, 137.5, 134.0, 133.9, 130.6, 128.6, 127.3, 125.4, 121.7, 116.5, 97.7, 61.8, 32.0, 22.3, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H21INO), 418.0668; found, 418.0651. 6-Bromo-1-ethoxy-3-isopropyl-4-phenylisoquinoline (3ea). Colorless solid. Eluent: hexane. The representative general procedure was

The representative general procedure was followed using 1a (50 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 12 h. The desired product was isolated in 79.5 mg and 85% yield. Mp: 110−112 °C. 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 8.4 Hz, 1H), 7.44− 7.31 (m, 3H), 7.21−7.15 (m, 3H), 6.89 (s, 1H), 4.57 (q, J = 7.0 Hz, 2H), 2.86−2.72 (m, 1H), 2.27 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H), 1.11 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.4, 154.2, 140.0, 138.6, 138.5, 130.8, 128.3, 127.1, 126.9, 124.3, 123.6, 122.5, 115.9, 61.5, 31.8, 22.4, 22.1, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H24NO), 306.1858; found, 306.1851. 1-Ethoxy-3-isopropyl-6-methoxy-4-phenylisoquinoline (3ba). Colorless solid. Eluent: hexane. The representative general procedure

followed using 1e (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 90.6 mg and 74% yield. Mp: 124−126 °C. 1H NMR (CDCl3, 400 MHz): δ 8.03 (d, J = 8.8 Hz, 1H), 7.44−7.33 (m, 4H), 7.28 (d, J = 1.4 Hz, 1H), 7.17 (d, J = 7.3 Hz, 2H), 4.57 (q, J = 7.0 Hz, 2H), 2.87−2.74 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.10 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.4, 155.8, 139.8, 137.5, 130.7, 128.6, 127.4, 127.4, 125.7, 125.0, 122.1, 116.3, 61.9, 32.0, 22.3, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H21BrNO), 370.0807; found, 370.0782. 6-Chloro-1-ethoxy-3-isopropyl-4-phenylisoquinoline (3fa). Colorless solid. Eluent: hexane. The representative general procedure was

was followed using 1b (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 105 mg and 78% yield. Mp: 100−102 °C. 1H NMR (CDCl3, 400 MHz): δ 8.19 (d, J = 9.0 Hz, 1H), 7.51−7.42 (m, 3H), 7.30 (d, J = 7.3 Hz, 2H), 7.07 (d, J = 9.0 Hz, 1H), 6.53 (s, 1H), 4.66 (q, J = 7.0 Hz, 2H), 3.69 (s, 3H), 2.93−2.85 (m, 1H), 1.54 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 160.6, 159.3, 155.0, 140.3, 138.5, 130.7, 128.4, 127.0, 125.6, 122.5, 116.4, 112.8, 104.5, 61.4, 55.1, 31.9, 22.4, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H24NO2), 322.1807; found, 322.1801. 1-Ethoxy-3-isopropyl-4-phenylisoquinoline (3ca). Colorless solid. Eluent: hexane. The representative general procedure was followed

followed using 1f (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 99.89 mg and 75% yield. Mp: 118−120 °C. 1H NMR (CDCl3, 400 MHz): δ 8.22 (d, J = 8.8 Hz, 1H), 7.55−7.43 (m, 3H), 7.38 (dd, J = 8.8, 1.9 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.21 (s, 1H), 4.68 (q, J = 7.0 Hz, 2H), 2.99−2.85 (m, 1H), 1.55 (t, J = 7.0 Hz, 3H), 1.22 (d, J = 6.6 Hz, 6H). 13 C NMR (CDCl3, 100 MHz): δ 159.4, 155.8, 139.5, 137.6, 136.3, 130.7, 128.6, 127.4, 125.9, 125.7, 124.2, 122.2, 116.0, 61.8, 32.0, 22.3,

using 1c (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 95 mg and 65% yield. Mp: 92−94 °C. 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, J = 7.7 Hz, 1H), 7.45−7.30 (m, 5H), 7.20 (d, J = 6.8 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 4.60 (q, J = 6.7 Hz, 2H), 2.88−2.81 (m, 1H), 1.45 (t, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.4, 8574


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The Journal of Organic Chemistry 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H21ClNO), 326.1312; found, 326.1328. 1-Ethoxy-6-fluoro-3-isopropyl-4-phenylisoquinoline (3ga). Colorless solid. Eluent: hexane. The representative general procedure was

3-Isopropyl-1-methoxy-4-phenylisoquinoline (3ja). Colorless solid. Eluent: hexane. The representative general procedure was followed using 1j (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 86 mg and 56% yield. Mp: 108−110 °C. 1H NMR (CDCl3, 400 MHz): δ 8.16 (d, J = 7.9 Hz, 1H), 7.44−7.31 (m, 5H), 7.20 (d, J = 7.6 Hz, 2H), 7.18−7.12 (m, 1H), 4.10 (s, 3H), 2.91−2.77 (m, 1H), 1.13 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.7, 154.2, 138.3, 130.7, 129.9, 128.4, 127.0, 125.2, 123.6, 123.1, 117.7, 53.3, 31.9, 22.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C19H20NO), 278.1545; found, 278.1556. 3-Isopropyl-4-phenyl-1-propoxyisoquinoline (3ka). Colorless solid. Eluent: hexane. The representative general procedure was

followed using 1g (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 110.98 mg and 80% yield. Mp: 94−96 °C. 1H NMR (CDCl3, 400 MHz): δ 8.17 (dd, J = 9.0, 5.9 Hz, 1H), 7.43−7.30 (m, 3H), 7.16 (dd, J = 8.0, 1.3 Hz, 2H), 7.05 (td, J = 8.8, 2.5 Hz, 1H), 6.73 (dd, J = 10.9, 2.4 Hz, 1H), 4.56 (q, J = 7.0 Hz, 2H), 2.90−2.74 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 164.8, 162.3, 159.3, 155.7, 140.5, 140.4, 137.9, 130.6, 128.6, 127.3, 126.9, 126.8, 122.8, 122.7, 114.9, 114.8, 114.6, 109.3, 109.0, 61.7, 32.0, 22.3, 14.7. 19F NMR (CDCl3, 471 MHz): δ −108.50. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H21FNO), 310.1607; found, 310.1587. 1-Ethoxy-3-isopropyl-4-phenyl-6-(trifluoromethyl)isoquinoline (3ha). Colorless solid. Eluent: hexane. The representative general

followed using 1k (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 94 mg and 67% yield. Mp: 64−66 °C. 1H NMR (CDCl3, 400 MHz): δ 8.28 (d, J = 8.0 Hz, 1H), 7.52−7.39 (m, 5H), 7.29 (d, J = 6.7 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 4.57 (t, J = 6.6 Hz, 2H), 2.99−2.85 (m, 1H), 2.02−1.89 (m, 2H), 1.21 (d, J = 6.7 Hz, 6H), 1.14 (t, J = 7.4 Hz, 3H). 13 C NMR (CDCl3, 100 MHz): δ 159.5, 154.2, 138.4, 138.3, 130.7, 129.8, 128.4, 127.0, 125.1, 125.1, 123.7, 122.8, 117.8, 67.3, 31.9, 22.4, 22.4, 10.8. HRMS (ESI-QTOF) m/z: [M + H] + calcd for (C21H24NO), 306.1858; found, 306.1862. 7-Ethoxy-5-isopropyl-4-phenylthieno[2,3-c]pyridine (3la). Colorless solid. Eluent: hexane. The representative general procedure was

procedure was followed using 1h (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 20 h. The desired product was isolated in 63 mg and 51% yield. Mp: 56−58 °C. 1H NMR (CDCl3, 500 MHz): δ 8.36 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.51− 7.44 (m, 4H), 7.26−7.23 (m, 2H), 4.67 (q, J = 7.0 Hz, 2H), 2.97−2.86 (m, 1H), 1.53 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 125 MHz): δ 159.2, 156.1, 137.7, 137.2, 131.9, 131.6, 131.4, 131.1, 130.6, 128.6, 127.5, 125.1, 123.3, 122.7, 122.6, 122.6, 122.6, 120.89, 120.9, 120.8, 120.8, 119.0, 62.0, 32.0, 22.3, 14.6. 19F NMR (CDCl3, 471 MHz): δ −62.73. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C20H21ClNO), 326.1312; found, 326.1328. 1-Ethoxy-3-isopropyl-7-methoxy-4-phenylisoquinoline (3ia). Colorless solid. Eluent: 1% ethyl acetate and hexane mixture. The

followed using 1l (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 20 h. The desired product was isolated in 63 mg and 44% yield. Mp: 70−72 °C. 1H NMR (CDCl3, 400 MHz): δ 7.46− 7.43 (m, 3H), 7.40−7.36 (m, 1H), 7.32−7.30 (m, 2H), 6.87 (d, J = 5.3 Hz, 1H), 4.66 (q, J = 7.0 Hz, 2H), 3.04 (hept, J = 6.6 Hz, 1H), 1.50 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 156.9, 155.5, 148.2, 138.6, 130.1, 128.3, 127.1, 123.7, 123.2, 119.6, 61.7, 31.1, 22.9, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C18H20NOS), 298.1266; found, 298.1274. 4-Ethoxy-6-isopropyl-7-phenylthieno[3,2-c]pyridine (3ma). Colorless solid. Eluent: hexane. The representative general procedure was followed using 1m (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 44.5 mg

representative general procedure was followed using 1i (75 mg) and 2a (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired products were isolated in 47 mg and 35% yield. 1H NMR (CDCl3, 400 MHz): δ 7.46 (d, J = 2.2 Hz, 1H), 7.40−7.29 (m, 4H), 7.18 (d, J = 7.3 Hz, 2H), 7.11 (d, J = 7.1 Hz, 1H), 4.62−4.57 (m, 2H), 3.85 (s, 3H), 2.86−2.78 (m, 1H), 1.46−1.43 (m, 3H), 1.11 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 158.5, 157.2, 152.0, 138.5, 133.6, 130.7, 129.5, 128.3, 126.9, 121.9, 116.4, 110.8, 102.2, 61.5, 55.5, 31.6, 22.5, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H25NO2), 322.1807; found, 322.1825. 8575


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and 31% yield. Mp: 60−62 °C. 1H NMR (CDCl3, 400 MHz): δ 7.52− 7.47 (m, 3H), 7.45−7.42 (m, 1H), 7.41−7.38 (m, 2H), 7.25 (d, J = 5.5 Hz, 1H), 4.64 (q, J = 7.0 Hz, 2H), 3.05 (hept, J = 6.7 Hz, 1H), 1.51 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 157.3, 154.7, 151.5, 138.5, 129.6, 128.7, 127.6, 124.8, 122.3, 122.0, 121.1, 61.4, 31.3, 22.8, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C18H20NOS), 298.1266; found, 298.1242. 1-Ethoxy-3-isopropyl-6-methyl-4-(p-tolyl)isoquinoline (3ab). Colorless solid. Eluent: hexane. The representative general procedure was

(CDCl3, 400 MHz): δ 8.06 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.86 (s, 1H), 4.56 (q, J = 7.1 Hz, 2H), 2.76 (hept, J = 6.7 Hz, 1H), 2.29 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.6, 154.4, 140.2, 138.3, 137.5, 132.5, 131.6, 127.3, 124.0, 123.7, 121.2, 121.1, 115.9, 61.5, 31.9, 22.3, 22.1, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H23BrNO), 384.0963; found, 384.0933. 4-(4-Chlorophenyl)-1-ethoxy-3-isopropyl-6-methylisoquinoline (3ae). Colorless solid. Eluent: hexane. The representative general

followed using 1a (75 mg) and 2b (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 110 mg and 75% yield. Mp: 108−110 °C. 1H NMR (CDCl3, 400 MHz): δ 8.19 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.05 (s, 1H), 4.69 (q, J = 7.0 Hz, 2H), 3.00−2.92 (m, 1H), 2.51 (s, 3H), 2.40 (s, 3H), 1.56 (t, J = 7.0 Hz, 3H), 1.23 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.2, 154.4, 139.9, 138.7, 136.4, 135.4, 130.6, 129.0, 127.0, 124.3, 123.6, 122.4, 115.9, 61.4, 31.8, 22.4, 22.1, 21.3, 14.8. HRMS (ESI-QTOF) m/ z: [M + H]+ calcd for (C22H26NO), 320.2014; found, 320.2008. 1-Ethoxy-4-(4-iodophenyl)-3-isopropyl-6-methylisoquinoline (3ac). Colorless solid. Eluent: hexane. The representative general

procedure was followed using 1a (75 mg) and 2e (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 114 mg and 73% yield. Mp: 106−108 °C. 1H NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 6.6 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 4.63 (q, J = 7.0 Hz, 2H), 2.93−2.75 (m, 1H), 2.36 (s, 3H), 1.51 (t, J = 7.0 Hz, 3H), 1.17 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.6, 154.5, 140.2, 138.4, 137.1, 133.0, 132.1, 128.6, 127.2, 124.0, 123.7, 121.2, 115.9, 61.5, 31.9, 22.3, 22.1, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H23ClNO), 340.1468; found, 340.1447. 1-Ethoxy-4-(4-fluorophenyl)-3-isopropyl-6-methylisoquinoline (3af). Colorless solid. Eluent: hexane. The representative general

procedure was followed using 1a (75 mg) and 2c (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 89 mg and 45% yield. Mp: 118−120 °C. 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 4.55 (q, J = 7.0 Hz, 2H), 2.83−2.68 (m, 1H), 2.29 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.10 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.6, 154.3, 140.2, 138.2, 138.2, 137.5, 132.8, 127.3, 124.0, 123.7, 121.2, 115.9, 92.7, 61.5, 31.9, 22.3, 22.1, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H23INO), 432.0824; found, 432.0832. 4-(4-Bromophenyl)-1-ethoxy-3-isopropyl-6-methylisoquinoline (3ad). Colorless solid. Eluent: hexane. The representative general procedure was followed using 1a (75 mg) and 2d (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 127 mg and 72% yield. Mp: 108−110 °C. 1H NMR

procedure was followed using 1a (75 mg) and 2f (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 111 mg and 75% yield. Mp: 106−108 °C. 1H NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 8.4 Hz, 1H), 7.28−7.13 (m, 5H), 6.93 (s, 1H), 4.64 (q, J = 7.0 Hz, 2H), 2.85 (hept, J = 6.6 Hz, 1H), 2.35 (s, 3H), 1.51 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 163.3, 160.8, 159.5, 154.6, 140.1, 138.6, 134.4, 134.3, 132.3, 132.3, 132.2, 127.2, 124.1, 123.7, 121.4, 115.9, 115.4, 115.2, 61.5, 31.8, 22.3, 22.1, 14.7. 19F NMR (CDCl3, 471 MHz): δ −115.9. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H23FNO), 324.1764; found, 324.1767. 4-(1-Ethoxy-3-isopropyl-6-methylisoquinolin-4-yl)benzonitrile (3ag). Colorless solid. Eluent: hexane. The representative general procedure was followed using 1a (75 mg) and 2g (1.5 equiv), and the 8576


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reaction was done at 100 °C for 16 h. The desired product was isolated in 94 mg and 62% yield. Mp: 158−160 °C. 1H NMR (CDCl3, 400 MHz): δ 8.08 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 6.75 (s, 1H), 4.56 (q, J = 7.0 Hz, 2H), 2.72−2.60 (m, 1H), 2.28 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H), 1.10 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 159.9, 154.3, 144.1, 140.6, 137.8, 132.2, 131.7, 127.5, 123.9, 123.6, 120.7, 119.0, 115.9, 111.0, 61.6, 32.1, 22.3, 22.1, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C22H23N2O), 331.1810; found, 331.1785. 4-(2-Bromophenyl)-1-ethoxy-3-isopropyl-6-methylisoquinoline (3ah). Colorless solid. Eluent: hexane. The representative general

done at 100 °C for 16 h. The desired product was isolated in 64.8 mg and 45% yield. 1H NMR (CDCl3, 400 MHz): δ 8.17 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 4.62 (q, J = 7.0 Hz, 2H), 3.45−3.36 (m, 1H), 2.96−2.92 (m, 2H), 2.57 (s, 3H), 1.67−1.59 (m, 2H), 1.52 (t, J = 7.0 Hz, 5H), 1.41−1.40 (m, 4H), 1.34 (d, J = 6.6 Hz, 6H), 0.97 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 158.1, 153.8, 139.6, 137.9, 126.6, 124.2, 122.2, 119.2, 116.3, 61.1, 31.8, 31.1, 30.8, 29.8, 26.9, 22.7, 22.5, 22.4, 14.7, 14.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H32NO), 314.2484; found, 314.2478. 3-Cyclopentyl-1-ethoxy-6-methyl-4-phenylisoquinoline (3ak). Colorless solid. Eluent: hexane. The representative general procedure

procedure was followed using 1a (75 mg) and 2h (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 119 mg and 68% yield. Mp: 90−92 °C. 1H NMR (CDCl3, 400 MHz): δ 8.15 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.31−7.19 (m, 3H), 6.79 (s, 1H), 4.65 (q, J = 7.0 Hz, 2H), 2.75−2.61 (m, 1H), 2.34 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 159.8, 154.4, 140.2, 139.5, 137.8, 132.8, 132.5, 128.9, 127.4, 127.3, 126.0, 123.9, 123.7, 121.7, 116.0, 61.5, 32.4, 22.5, 22.1, 21.5, 14.7. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H23BrNO), 384.0963; found, 384.0969. 4-Butyl-1-ethoxy-3-isopropyl-6-methylisoquinoline (3ai). Colorless liquid. Eluent: hexane. The representative general procedure was

was followed using 1a (75 mg) and 2j (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 62.4 mg and 41% yield. Mp: 90−92 °C. 1H NMR (CDCl3, 400 MHz): δ 8.13 (d, J = 8.4 Hz, 1H), 7.53−7.37 (m, 3H), 7.28−7.23 (m, 3H), 6.97 (s, 1H), 4.61 (q, J = 7.0 Hz, 2H), 2.94 (p, J = 8.2 Hz, 1H), 2.34 (s, 3H), 1.98−1.89 (m, 2H), 1.86−1.71 (m, 4H), 1.54−1.48 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 159.4, 152.9, 140.0, 138.7, 138.4, 130.9, 128.2, 127.0, 126.8, 124.2, 123.6, 123.3, 115.8, 61.4, 43.3, 33.6, 26.6, 22.1, 14.8. HRMS (ESI-QTOF) m/z: [M + H] + calcd for (C23H26NO), 332.2014; found, 332.1993. 4-Butyl-3-cyclopentyl-1-ethoxy-6-methylisoquinoline (3al). Colorless liquid. Eluent: hexane. The representative general procedure was

followed using 1a (75 mg) and 2i (1.5 equiv), and the reaction was done at 100 °C for 16 h. The desired product was isolated in 99.5 mg and 76%. 1H NMR (CDCl3, 400 MHz): δ 8.03 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.32− 3.22 (m, 1H), 2.82−2.78 (m, 2H), 2.43 (s, 3H), 1.52−1.42 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.20 (d, J = 6.7 Hz, 6H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 158.1, 153.9, 139.6, 137.9, 126.6, 124.2, 122.2, 119.1, 116.4, 61.1, 33.3, 30.8, 26.6, 23.2, 22.5, 22.4, 14.7, 14.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C19H28NO), 286.2171; found, 286.2185. 1-Ethoxy-4-hexyl-3-isopropyl-6-methylisoquinoline (3aj). Colorless liquid. Eluent: hexane. The representative general procedure was followed using 1a (75 mg) and 2i (1.5 equiv), and the reaction was

followed using 1a (75 mg) and 2j (1.5 equiv), and the reaction was done at 100 °C for 20 h. The desired product was isolated in 97 mg and 68% yield. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.37 (p, J = 7.9 Hz, 1H), 2.87−2.76 (m, 2H), 2.42 (s, 3H), 1.92−1.74 (m, 6H), 1.67−1.54 (m, 2H), 1.53−1.38 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 158.1, 152.4, 139.6, 137.8, 126.6, 124.2, 122.2, 120.0, 116.3, 61.1, 42.3, 33.5, 33.4, 26.8, 26.7, 23.1, 22.4, 14.8, 14.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C21H30NO), 312.2327; found, 312.2346. 1,4-Bis(1-ethoxy-3-isopropyl-6-methylisoquinolin-4-yl)benzene (3am). Colorless solid. Eluent: hexanes. The representative general procedure was followed using 2j (100 mg) and 1a (2.5 equiv), and the 8577


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MHz): δ 8.17 (d, J = 8.6 Hz, 1H), 7.54−7.45 (m, 3H), 7.40 (d, J = 8.6 Hz, 1H), 7.28−7.22 (m, 2H), 7.03 (s, 1H), 2.97−2.83 (m, 1H), 2.39 (s, 3H), 1.22 (d, J = 6.7 Hz, 6H). 13C NMR (CDCl3, 125 MHz): δ 157.7, 144.3, 141.1, 138.1, 137.0, 130.0, 129.5, 129.3, 128.6, 128.4, 127.6, 125.4, 125.0, 31.8, 22.4, 22.0. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C19H19BrN), 340.0701; found, 340.0723. 1-Chloro-3-isopropyl-6-methyl-4-phenylisoquinoline (7a). Colorless solid. Eluent: hexanes. Mp: 118−120 °C. 1H NMR (CDCl3, 400

reaction was done at 100 °C for 16 h. The desired product was isolated in 77 mg and 32% yield. Mp: 218−220 °C. 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, J = 8.3 Hz, 2H), 7.373−7.365 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 7.09 (s, 1H), 4.68 (q, J = 7.0 Hz, 4H), 3.13−3.06 (m, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 1.54 (t, J = 7.1 Hz, 6H), 1.28 (d, J = 6.7 Hz, 12H). 13C NMR (CDCl3, 100 MHz): δ 159.4, 154.4, 140.0, 139.8, 138.8, 138.7, 137.1, 130.8, 127.1, 127.1, 124.4, 123.7, 123.7, 122.4, 122.4, 116.0, 116.0, 61.5, 32.0, 22.5, 22.5, 22.2, 14.8. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C36H41N2O2), 533.3163; found, 533.3133. 1-Ethoxy-6-methyl-4-phenyl-3-(prop-1-en-2-yl)isoquinoline (4aa). Red color liquid. Eluent: hexane. 1H NMR (CDCl3, 400 MHz):

MHz): δ 8.21 (d, J = 8.6 Hz, 1H), 7.55−7.45 (m, 3H), 7.40 (dd, J = 8.6, 1.4 Hz, 1H), 7.28−7.24 (m, 2H), 7.05 (s, 1H), 2.93 (hept, J = 6.7 Hz, 1H), 2.39 (s, 3H), 1.22 (d, J = 6.8 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 157.0, 150.4, 141.1, 138.4, 137.1, 130.1, 129.3, 129.0, 128.6, 127.6, 126.1, 125.0, 123.4, 31.8, 22.4, 22.0. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C19H19ClN), 296.1206; found, 296.1214.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01123. Gas chromatograph spectrum, 1H NMR and 13C NMR spectra of all compounds, X-ray analysis data, and Cartesian coordinates (PDF) Single-crystal X-ray diffraction data for compound 3aa (CIF) Single-crystal X-ray diffraction data for compound 9a (CIF)

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δ 8.11 (d, J = 8.4 Hz, 1H), 7.39−7.30 (m, 3H), 7.25−7.17 (m, 3H), 7.08 (s, 1H), 4.97 (s, 1H), 4.74 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.90 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 158.8, 149.3, 144.7, 140.4, 138.6, 138.5, 131.0, 128.1, 127.8, 126.8, 124.6, 123.8, 117.7, 116.5, 61.7, 23.2, 22.1, 14.7. HRMS (ESIQTOF) m/z: [M + H]+ calcd for (C21H22NO), 304.1701; found, 304.1715. 3-Isopropyl-6-methyl-4-phenylisoquinolin-1(2H)-one (5a). Colorless solid. Eluent: ethyl acetate and hexanes mixture (1:5). Mp: 280−

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Masilamani Tamizmani: 0000-0002-7168-6041 Masilamani Jeganmohan: 0000-0002-7835-3928 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the DST-SERB (EMR/2014/000978), India for the support of this research. A.A. thanks the CSIR for a fellowship. M.T. thanks the IITM for a postdoctoral fellowship. The authors thank Dr. R. Vinu, IIT-Madras, for H2 gas detection experiments.

282 °C. 1H NMR (CDCl3, 400 MHz): δ 9.19 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.53−7.39 (m, 3H), 7.26 (s, 1H), 7.25−7.24 (m, 2H), 6.80 (s, 1H), 2.90−2.78 (m, 1H), 2.32 (s, 3H), 1.21 (d, J = 7.0 Hz, 6H). 13 C NMR (CDCl3, 100 MHz): δ 163.3, 143.0, 142.7, 139.3, 136.4, 131.0, 128.7, 127.5, 127.5, 127.3, 125.2, 122.3, 115.2, 29.3, 22.0, 21.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for (C19H20NO), 278.1545; found, 278.1552. 1-Bromo-3-isopropyl-6-methyl-4-phenylisoquinoline (6a). Colorless solid. Eluent: hexanes. Mp: 116−118 °C. 1H NMR (CDCl3, 500

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