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Synthesis 2010(18): 3179-3187  
DOI: 10.1055/s-0030-1258180
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Multicomponent Approach for the Synthesis of Phenanthridine and Acridine Ring Systems via the Coupling of Fischer Carbene Complexes with Hetero­aromatic o-Alkynyl Carbonyl Derivatives

Gouranga P. Jana, Soumita Mukherjee, Binay K. Ghorai*
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711103, India
Fax: +91(33)26682916; e-Mail: bkghorai@yahoo.co.in;

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Publication History

Received 5 May 2010
Publication Date:
16 July 2010 (online)

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Abstract

A one-pot multicomponent synthesis of phenanthridine and acridine derivatives is described. This method includes the in situ generation of furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates by the coupling of heteroaromatic o-alkynyl carbonyl derivatives with Fischer carbene complexes and subsequent trapping of these intermediates by suitable dienophiles.

Key words

azaisobenzofuran - heterocycles - Diels-Alder reaction - chromium - carbene complexes

Fused azaheterocycles are a family of biological agents with particularly interesting pharmacological properties related to the planarity of the system. Substituted phenanthridines and acridines are important classes of heterocyclic compounds in medicinal chemistry and are attractive synthetic targets due to their widespread occurrence in nature and broad range of biological activity including antitumor and antiviral activity. [¹] A large number of acridine drugs, natural alkaloids or synthetic molecules, have been tested as antibacterial and antimalarial agents. [²] Classical synthetic methods for these heterocyclic molecules involve multistep condensation reactions resulting in the desired azaheterocycles; [³] [4] however, many synthetic routes require harsh conditions and thus appear to be unsuitable for the synthesis of functionalized heterocycles incorporating sensitive functional groups. In multistep reactions, the limited substrate scope and the frequent requirement of harsh reaction conditions, with extremely high temperatures, limit the usefulness and generality of these methods. This has led to the search for new synthetic methods that would facilitate the preparation of an appropriate series of compounds. Thus, a synthesis suitable for both of these heterocyclic compounds and also their analogues is required. As a contrast to this multistep strategy, a new concept for the synthesis of a target compound with a higher chemical efficiency is emerging. Multicomponent reactions (MCRs) are responsible for this higher efficiency. [5] MCRs provide a complementary approach to a number of structures and should find applications in library generation. In a preliminary communication, we described the synthesis of phenanthridine ring systems using the MCR approach. [6] In this paper, we wish to report full details of the multicomponent coupling approach for the synthesis of phenanthridine derivatives, along with the synthesis of acridine derivatives, using Fischer carbene chemistry. This process involves the first-time generation of furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates by the coupling of Fischer carbene complexes [7] with heteroaromatic o-alkynyl carbonyl derivatives. These intermediates can actively participate in inter- and intramolecular cycloaddition reactions. Hence, our synthetic strategy includes the generation of the furo[3,4-c]isoquinoline intermediates 3 formed by the coupling of o-alkynylisoquinolinecarbonyl derivatives 1 with Fischer carbene complex 2 and of the furo[3,4-b]quinoline intermediates 7 formed by the coupling of o-alkynylquinolinecarbonyl derivatives 5 with Fischer carbene complex 6, and trapping of these intermediates using suitable dienophiles for the synthesis of phenanthridine and acridine derivatives (Scheme  [¹] ).

Scheme 1 Tandem generation and trapping of furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates

The requisite 3-alkynylisoquinoline-4-carbonyl derivatives necessary for our study were readily prepared using the series of reactions depicted in Scheme  [²] . 3-Chloro-1-phenylisoquinoline-4-carbaldehyde (10) was prepared from dihydroisoquinolinone 9 [8] by a two-step procedure involving a Vilsmeier-Haack reaction followed by oxidation with potassium permanganate under acidic conditions. [9] The Sonogashira coupling of chloride 10 with (trimethylsilyl)acetylene afforded 1-phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11), which on treatment with the appropriate Grignard reagent and subsequent oxidation with pyridinium dichromate resulted in the ketones 12-14.

Scheme 2 Synthesis of isoquinolines substituted with an aldehyde or a ketone group. Reagents and conditions: (a) POCl3, DMF, THF, 0 ˚C; then KMnO4, H2SO4, r.t., 42%; (b) (trimethylsilyl)acetylene, (Ph3P)2PdCl2, Ph3P, CuI, Et3N, THF, r.t., 67%; (c) (i) R¹MgBr; (ii) CrO3˙2py, 12 (72%), 13 (52%), 14 (47%).

Similarly, the corresponding quinoline derivative 16 [¹0] was prepared by the palladium-catalyzed Sonogashira reaction of 3-formyl-2-iodoquinoline (15) [¹¹] with (trimethylsilyl)acetylene (Scheme  [³] ). Exposure of aldehyde 16 to an aryl or alkyl Grignard reagent in diethyl ether followed by pyridinium dichromate oxidation resulted in the alkynyl carbonyl derivatives 17-19.

Scheme 3 Synthesis of functionalized quinolines. Reagents and conditions: (a) (trimethylsilyl)acetylene, (Ph3P)2PdCl2, CuI, Et3N, THF, r.t., 86%; (b) (i) R²MgBr; (ii) CrO3˙2py, 17 (70%), 18 (69%), 19 (45%).

In the first phase of these studies, a three-component coupling reaction of carbene complex 2, 3-alkynylisoquinoline-4-carbaldehyde 11 and dimethyl maleate in refluxing tetrahydrofuran was carried out, which on exposure to silica gel led to the synthesis of the phenanthridine derivative 21 (Scheme  [4] ). Formation of compound 21 occurs through the generation of the transient furo[3,4-c]isoquinoline intermediate 20, followed by Diels-Alder reaction with the dimethyl maleate present in the reaction mixture. When N-methylmaleimide was used as the dienophile, however, the [4+2] oxa-bridged adduct 22 could be isolated together with the phenanthridine derivative 23. The chemical shift values of the HB and HC protons (<4 ppm), the 0-Hz coupling between HA and HB, and the N-Me signal (˜3.0 ppm) [7a] [¹²] confirm the exo stereochemistry of the oxa-bridged adduct 22. This oxa-bridged adduct 22 was converted into the phenanthridine derivative 23 on treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing toluene. [¹³] In contrast, in the analogous coupling of 11 with carbene complex 2 in the presence of N-phenylmaleimide as dienophile, the phenanthridine derivative 24 was isolated as the only product (Scheme  [4] ).

Scheme 4 Synthesis of phenanthridine derivatives

The tandem generation and intramolecular trapping of furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates was studied using unactivated alkenyl tethers of various length. The reaction of carbene complex 2 with ketone 13 bearing an unactivated alkenyl tether afforded a mixture of the oxa-bridged adduct 27 and the [1,7]-hydrogen-shift product 29 (Scheme  [5] ). Interestingly, under similar reaction conditions, no intramolecular cycloaddition leading to the oxa-bridged adduct 28 was obtained when the dienophile tether to the ketone was increased by one methylene unit (i.e., ketone 14). In this reaction, the [1,7]-hydrogen-shift product 30 was the only product isolated from the reaction mixture. Formation of the [1,7]-hydrogen-shift products 29/30 suggests either (i) that unactivated dienophile lowers the rate of the Diels-Alder step of the tandem reaction process, or (ii) that the furo[3,4-c]isoquinoline intermediates 25/26 can directly hydrolyze to form the [1,7]-hydrogen-shift products 29/30, respectively. [7a] [¹4] In contrast, the reaction of carbene complex 2 with alkynylquinolinyl ketone 19 bearing an unactivated alkenyl tether, under the same reaction conditions, gave exclusively the alcohol 32 with no [1,7]-hydrogen-shift product (Scheme  [6] ).

Scheme 5 Generation and Diels-Alder trapping of furo[3,4-c]isoquinoline intermediates using an intramolecular approach

Scheme 6 Generation and intramolecular Diels-Alder trapping of a furo[3,4-b]quinoline intermediate

The reaction process was also tested using a γ,δ-unsaturated Fischer carbene complex. The coupling of monoprenylated carbene complex 6 with alkynyl carbonyl derivatives 11/12 under the same conditions as previously described underwent intramolecular Diels-Alder reaction through the generation of the furo[3,4-c]isoquinoline intermediates 33/34 leading to the tetracyclic skeletons 37/38, respectively (Scheme  [7] ). The initial Diels-Alder adducts 35/36, resulting from 33/34, appear to be unstable with respect to the ring-opening process. [¹5] Compounds 37 and 38, bearing the tetracyclic skeleton, are aza analogues of tetracyclic triterpenes. Thus, the reaction may be useful for the synthesis of analogues of natural products.

Scheme 7 Synthesis of phenanthridines using a monoprenylated Fischer carbene complex

The intramolecular trapping of transient furo[3,4-b]quinoline intermediates was also studied by using carbene complex 6 and its bisprenylated species 39. [¹6] The o-alk­ynylquinolinecarbonyl derivatives 16/17/18 [¹0] underwent similar reaction with carbene complexes 6/39 which led to acridine derivatives 41-44 through the generation of the furo[3,4-b]quinoline intermediates 40 (Scheme  [8] ).

Scheme 8 Synthesis of acridines using mono-/bisprenylated Fischer carbene complexes

In summary, we have developed a convenient one-pot synthesis of phenanthridine and acridine ring systems by the coupling of Fischer carbene complexes with hetero­aromatic o-alkynyl carbonyl derivatives, with the generation of reactive furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates.

Melting points were determined on a Sunbim melting point apparatus and are uncorrected. IR spectra were recorded neat or as KBr discs on a Jasco FT/IR-460 Plus spectrometer. ¹H and ¹³C NMR spectra were recorded using tetramethylsilane as internal reference on Bruker AC 400, DRX 500, DPX 300, Avance 600 and UltraShield™­ 500 spectrometers (chemical shift values in δ, J in Hz). Mass spectra were obtained using an Agilent 6120 mass spectrometer.

1-Phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11)

A mixture of 3-chloro-1-phenylisoquinoline-4-carbaldehyde (10; 1.34 g, 5.0 mmol), (Ph3P)2PdCl2 (0.176 g, 0.25 mmol), Ph3P (33 mg, 0.125 mmol), (trimethylsilyl)acetylene (736 mg, 7.5 mmol) and Et3N (759 mg, 7.5 mmol) in THF (20 mL) was stirred at r.t. for 20 min, and then CuI (10 mg, 0.05 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, then the solvent was removed on a rotary evaporator. The residue was treated with CH2Cl2 (10 mL) and the mixture was filtered through Celite®. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc-petroleum ether, 1:9) to afford alkyne 11.

Yield: 1.1 g (67%); white solid; mp 126 ˚C; R f  = 0.69 (EtOAc-petroleum­ ether, 1:9).

IR (KBr): 2155, 1686 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 11.04 (s, 1 H), 9.33 (d, J = 8.5 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.86 (td, J = 7.8, 1.0 Hz, 1 H), 7.73-7.66 (m, 2 H), 7.60 (t, J = 7.7 Hz, 1 H), 7.57-7.50 (m, 3 H), 0.30 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 194.3, 166.2, 143.3, 138.3, 133.6, 133.1, 130.0 (2 C), 129.5, 128.4 (3 C), 128.3, 126.1, 125.0, 124.9, 103.6, 100.8, -0.3 (3 C).

MS: m/z (%) = 330 (100) [M + H]+, 258 (10).

Anal. Calcd for C21H19NOSi: C, 76.56; H, 5.81; N, 4.25. Found: C, 76.21; H, 5.72; N, 4.02.

Alkynyl(iso)quinolinecarbonyl Derivatives; General Procedure

To a stirred soln of aldehyde (2 mmol) in anhyd Et2O (10 mL) was added dropwise a soln of aryl-/alkylmagnesium bromide (2.2 mmol) in anhyd Et2O [prepared from aryl/alkyl bromide (3 mmol) and magnesium (4 mmol) in anhyd Et2O (10 mL)] over a period of 20 min at 0 ˚C. After being stirred for 3 h, the mixture was allowed to warm to r.t. and the reaction was then quenched with sat. aq NH4Cl (5 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layer was washed with brine (5 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude alcohol was used in the next step.

A soln of the crude alcohol in anhyd CH2Cl2 (2 mL) was added to a red soln of CrO3˙2py [prepared from a vigorously stirred suspension of CrO3 (6 mmol) and pyridine (12 mmol) in anhyd CH2Cl2 (12 mL) at r.t. for 1.5 h] and the mixture was stirred at r.t. for 4 h. The mixture was then diluted with Et2O (10 mL) and passed through a bed of silica gel (5 g). The solution was then concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc-petroleum ether, 2:8).

Phenyl[1-phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]methanone (12)

Yield: 0.583 g (72%); white solid; mp 117-119 ˚C; R f  = 0.43 (EtOAc-petroleum ether, 1:9).

IR (KBr): 2160, 1666 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.5 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.60-7.52 (m, 4 H), 7.49 (t, J = 7.5 Hz, 2 H), -0.06 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 196.2, 162.3, 138.6, 137.1, 134.4, 133.9, 133.9, 132.4, 131.3, 130.0 (4 C), 129.0, 128.7 (2 C), 128.3 (2 C), 128.2, 128.1, 125.8, 124.6, 102.4, 101.3, -0.77 (3 C).

MS: m/z (%) = 406 (100) [M + H]+.

Anal. Calcd for C27H23NOSi: C, 79.96; H, 5.72; N, 3.45. Found: C, 79.73; H, 5.59; N, 3.57.

1-[1-Phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]hex-5-en-1-one (13)

Yield: 0.412 g (52%); thick liquid; R f  = 0.78 (EtOAc-petroleum ether, 1:4).

IR (neat): 2157, 1702 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 3.6 Hz, 2 H), 7.67-7.61 (m, 2 H), 7.59-7.47 (m, 4 H), 5.83 (m, 1 H), 5.06 (d, J = 17.2 Hz, 1 H), 5.01 (d, J = 10.0 Hz, 1 H), 3.15 (t, J = 7.5 Hz, 2 H), 2.21 (q, J = 6.8 Hz, 2 H), 1.94 (pentet, J = 7.5 Hz, 2 H), 0.25 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 206.2, 162.1, 138.5, 137.7, 136.1, 132.9, 131.3 (2 C), 130.9, 129.9 (2 C), 129.0, 128.3, 128.2, 128.1, 125.8, 124.0, 115.4, 102.3, 100.2, 43.9, 33.2, 22.9, -0.36 (3 C).

MS: m/z (%) = 399 (35) [MH+ + 1], 398 (100) [M + H]+.

Anal. Calcd for C26H27NOSi: C, 78.54; H, 6.84; N, 3.52. Found: C, 78.71; H, 6.65; N, 3.68.

1-[1-Phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]hept-6-en-1-one (14)

Yield: 0.386 g (47%); thick liquid; R f  = 0.47 (EtOAc-petroleum ether, 1:9).

IR (neat): 2158, 1701, 1640 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.5 Hz, 1 H), 7.73-7.67 (m, 2 H), 7.66-7.61 (m, 2 H), 7.63-7.42 (m, 4 H), 5.82 (m, 1 H), 5.03 (dd, J = 17.0, 1.0 Hz, 1 H), 4.97 (d, J = 10.0 Hz, 1 H), 3.16 (t, J = 7.5 Hz, 2 H), 2.13 (q, J = 7.0 Hz, 2 H), 1.86 (pentet, J = 7.5 Hz, 2 H), 1.55 (pentet, J = 7.5 Hz, 2 H), 0.26 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 206.3, 162.1, 138.5, 138.3, 136.1, 132.9, 131.3, 130.9, 129.9 (2 C), 129.0, 128.3 (2 C), 128.2, 128.1, 125.8, 124.0, 114.8, 102.3, 100.2, 44.5, 33.6, 28.6, 23.2, -0.36 (3 C).

MS: m/z (%) = 413 (30) [MH+ + 1], 412 (100) [M + H]+.

Anal. Calcd for C27H29NOSi: C, 78.79; H, 7.10; N, 3.40. Found: C, 78.57; H, 6.83; N, 3.54.

Phenyl[2-(trimethylsilylethynyl)quinolin-3-yl]methanone (17)

Yield: 0.460 g (70%); thick yellow liquid; R f  = 0.60 (EtOAc-petroleum ether, 1:9).

IR (neat): 2180, 1668 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1 H), 8.19 (d, J = 8.5 Hz, 1 H), 7.91-7.81 (m, 4 H), 7.68-7.61 (m, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 0.01 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 195.3, 148.4, 138.4, 136.6, 133.5, 131.4, 130.2 (2 C), 129.4, 128.8, 128.5 (2 C), 128.1 (2 C), 127.9, 126.3, 102.2, 101.8, -0.7 (3 C).

MS: m/z (%) = 331 (30) [MH+ + 1], 330 (100) [M + H]+, 268 (20).

Anal. Calcd for C21H19NOSi: C, 76.56; H, 5.81; N, 4.25. Found: C, 76.31; H, 5.92; N, 4.10.

1-[2-(Trimethylsilylethynyl)quinolin-3-yl]hex-5-en-1-one (19)

Yield: 0.288 g (45%); thick yellow liquid; R f  = 0.35 (EtOAc-petroleum ether, 1:9).

IR (neat): 2158, 1703 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.35 (s, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 8.5 Hz, 1 H), 7.79 (td, J = 8.5, 1.0 Hz, 1 H), 7.59 (td, J = 8.5, 1.0 Hz, 1 H), 5.81 (m, 1 H), 5.04 (dd, J = 17.0, 1.2 Hz, 1 H), 4.99 (dd, J = 10.5, 1.2 Hz, 1 H), 3.23 (t, J = 7.0 Hz, 2 H), 2.17 (q, J = 7.0 Hz, 2 H), 1.88 (pentet, J = 7.0 Hz, 2 H), 0.31 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 202.5, 148.5, 139.4, 137.8, 136.5, 135.6, 131.7, 129.2, 128.4, 128.1, 126.3, 115.4, 103.0, 100.4, 41.7, 33.1, 23.6, -0.3 (3 C).

MS: m/z (%) = 323 (20) [MH+ + 1], 322 (70) [M + H]+, 279 (28), 261 (15), 260 (100).

Anal. Calcd for C20H23NOSi: C, 74.72; H, 7.21; N, 4.36. Found: C, 74.51; H, 7.09; N, 4.49.

Coupling of Carbene Complex 2 with Alkynylisoquinolinecarbaldehyde 11 and Maleimides/Dimethyl Maleate; General Procedure

To a refluxing soln of alkynyl aldehyde 11 (1 mmol) and a maleimide or dimethyl maleate (1 mmol) in THF (5 mL) was added a soln of carbene complex 2 (1.1 mmol) in THF (10 mL) over a period of 1 h. After the addition was complete, the mixture was heated to reflux for a period of 12 h. The mixture was allowed to cool to r.t. and was concentrated on a rotary evaporator. EtOAc (20 mL) was added and the mixture was filtered through Celite® (1.0 g). The solvent was removed on a rotary evaporator, and the crude product was dissolved in Et2O (20 mL).

To this solution of crude product in Et2O was added aq HCl (1:1, 0.5 mL) and the mixture was stirred at r.t. for 6 h. The organic layer was separated. The aqueous layer was neutralized with sat. NaHCO3 soln (3 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer (Et2O layer and EtOAc extracts) was washed with H2O (3 mL) and brine (3 mL), and dried (Na2SO4). Evaporation of solvent and purification of the residue by chromatography gave the pure products.

Compound 21 by the Coupling of Carbene Complex 2 with 1-Phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11) and Dimethyl Maleate

The general procedure above was followed using alkynyl aldehyde 11 (165 mg, 0.50 mmol), dimethyl maleate (72 mg, 0.50 mmol) and carbene complex 2 (138 mg, 0.55 mmol). The only exception was that, instead of HCl treatment, the crude product was dissolved in CHCl3 (20 mL) and stirred with silica gel (2 g) for 6 h. The solvent was evaporated and the residue was purified by silica gel column chromatography.

Yield: 0.093 g (44%); white solid; mp 122 ˚C (dec); R f  = 0.30 (EtOAc-petroleum ether, 3:7).

IR (KBr): 1736, 1712 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 9.24 (s, 1 H), 8.79 (d, J = 8.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.94 (t, J = 8.0 Hz, 1 H), 7.77-7.73 (m, 2 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.60-7.53 (m, 3 H), 4.44 (s, 2 H), 4.02 (s, 3 H), 3.99 (s, 3 H), 2.22 (s, 3 H).

¹³C NMR (125 MHz, CDCl3): δ = 205.6, 169.3, 166.3, 162.9, 143.8, 139.2, 134.5, 134.0, 133.5, 131.3, 130.1 (2 C), 129.2, 129.1, 128.3 (3 C), 125.7, 125.3, 124.6, 123.5, 122.8, 52.8 (2 C), 43.7, 30.0.

MS: m/z (%) = 450 (11) [M + Na]+, 428 (100) [M + H]+, 396 (58).

HRMS: m/z [M + Na]+ calcd for C26H21NNaO5: 450.1317; found: 450.1311.

Compounds 22 and 23 by the Coupling of Carbene Complex 2 with 1-Phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11) and N -Methylmaleimide

Compound 22

Yield: 0.124 g (30%); white solid; mp 171 ˚C (dec); R f  = 0.25 (EtOAc-petroleum ether, 3:7).

IR (KBr): 1703 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.18 (d, J = 8.5 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.79 (t, J = 7.5 Hz, 1 H), 7.66 (d, J = 6.5 Hz, 2 H), 7.60-7.49 (m, 4 H), 6.18 (s, 1 H), 3.85 (d, J = 17.2 Hz, 1 H), 3.49 (d, J = 17.2 Hz, 1 H), 3.30 (d, J = 6.5 Hz, 1 H), 3.14 (d, J = 6.5 Hz, 1 H), 3.07 (s, 3 H), 2.30 (s, 3 H).

¹³C NMR (125 MHz, CDCl3): δ = 203.2, 175.6, 174.6, 160.8, 158.1, 139.1, 131.1, 130.6, 130.3 (2 C), 130.2, 128.9 (2 C), 128.3 (2 C), 127.2, 125.7, 122.8, 87.9, 78.7, 51.1, 50.2, 41.3, 31.4, 25.2.

MS: m/z (%) = 435 (10) [M + Na]+, 413 (100) [M + H]+, 302 (90), 260 (9).

HRMS: m/z [M + H]+ calcd for C25H21N2O4: 413.1501; found: 413.1492.

Compound 23

Yield: 0.126 g (32%); white solid; mp 203 ˚C (dec); R f  = 0.55 (EtOAc-petroleum ether, 3:7).

IR (KBr): 1759, 1713 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 9.03 (s, 1 H), 8.80 (d, J = 8.5 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 7.97 (t, J = 8.0 Hz, 1 H), 7.80-7.70 (m, 3 H), 7.62-7.50 (m, 3 H), 4.99 (s, 2 H), 3.25 (s, 3 H), 2.42 (s, 3 H).

¹³C NMR (125 MHz, CDCl3): δ = 205.6, 168.7, 168.1, 162.4, 145.2, 139.1, 135.7, 134.0, 131.5, 130.1 (2 C), 129.3, 129.1, 128.9, 128.6, 128.3 (2 C), 128.2, 127.1, 125.5, 123.2, 117.2, 41.0, 30.8, 24.2.

MS: m/z (%) = 395 (100) [M + H]+.

Anal. Calcd for C25H18N2O3: C, 76.13; H, 4.60; N, 7.10. Found: C, 76.01; H, 4.79; N, 6.94.

9-Methyl-7-(2-oxopropyl)-5-phenyl-6,9-diaza-8 H -cyclopenta[ b ]phenanthrene-8,10(9 H )-dione (23)

To a stirred soln of oxa-bridged compound 22 (21 mg, 0.05 mmol) in toluene (3 mL), DBU (76 mg, 0.5 mmol) was added dropwise at r.t. The mixture was heated to reflux for 1.5 h. After being cooled to r.t., the mixture was washed with 10% aq HCl (1.0 mL) and dried (Na2SO4). After evaporation of the solvent, the crude product was purified by preparative thin-layer silica gel chromatography (EtOAc-petroleum ether, 1:1) to give aromatized product 23 as a yellow solid; yield: 8 mg (42%).

Compound 24 by the Coupling of Carbene Complex 2 with 1-Phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11) and N -Phenylmaleimide

Yield: 0.178 g (39%); white solid; mp 216 ˚C; R f  = 0.38 (EtOAc-petroleum ether, 3:7).

IR (KBr): 1767, 1712 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 9.14 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.97 (td, J = 7.5, 1.0 Hz, 1 H), 7.81-7.74 (m, 3 H), 7.63-7.57 (m, 3 H), 7.56-7.49 (m, 4 H), 7.43 (t, J = 7.5 Hz, 1 H), 5.05 (s, 2 H), 2.43 (s, 3 H).

¹³C NMR (125 MHz, CDCl3): δ = 205.4, 167.6, 166.9, 162.7, 145.5, 139.1, 136.4, 134.0, 131.8, 131.6, 130.1 (2 C), 129.4, 129.2, 129.1 (2 C), 129.0, 128.4 (2 C), 128.2, 128.1, 127.7, 127.6, 126.7 (2 C), 125.6, 123.3, 117.9, 41.1, 30.8.

MS: m/z (%) = 458 (33) [MH+ + 1], 457 (100) [M + H]+.

Anal. Calcd for C30H20N2O3: C, 78.93; H, 4.42; N, 6.14. Found: C, 78.71; H, 4.67; N, 6.31.

Coupling of Carbene Complex 2 with Alkynyl(iso)quinolinecarbonyl Derivatives; General Procedure

To a refluxing soln of an alkynyl carbonyl derivative 13/14/19 (1 mmol) in THF (10 mL) was added a soln of carbene complex 2 (1.1 mmol) in THF (10 mL) over a period of 1 h. After the addition was complete, the mixture was heated to reflux for a period of 24 h. The mixture was allowed to cool to r.t. and was concentrated on a rotary evaporator. EtOAc (20 mL) was added and the mixture was filtered through Celite® (1.0 g). The solvent was removed on a rotary evaporator, and the crude product was dissolved in CHCl3 (20 mL) and stirred with silica gel (2 g) at r.t. for 6 h. Evaporation of solvent and purification of the residue by chromatography gave the pure products.

Compounds 27 and 29 by the Coupling of Carbene Complex 2 with 1-[1-Phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]hex-5-en-1-one (13)

Compound 27

Yield: 0.074 g (20%); gummy solid; R f  = 0.55 (EtOAc-petroleum ether, 1:4).

IR (neat): 1707 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.72-7.62 (m, 3 H), 7.57-7.40 (m, 4 H), 3.59 (d, J = 14.8 Hz, 1 H), 3.35 (d, J = 14.8 Hz, 1 H), 2.97 (m, 1 H), 2.43 (m, 1 H), 2.26 (s, 3 H), 2.20-2.02 (m, 4 H), 1.98-1.80 (m, 2 H), 1.69 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 206.3, 160.0, 159.2, 139.8, 131.1, 130.6, 130.3 (2 C), 130.1, 128.9, 128.5, 128.3 (2 C), 125.9, 125.7, 122.3, 97.6, 86.2, 48.8, 44.9, 39.9, 31.9, 31.6, 29.6, 27.1.

MS: m/z (%) = 370 (100) [M + H]+, 352 (40) [MH+ - H2O], 312 (20).

HRMS: m/z [M + H]+ calcd for C25H24NO2: 370.1807; found: 370.1801.

Compound 29

Yield: 0.118 g (32%); yellow solid; mp 135-136 ˚C; R f  = 0.25 (EtOAc-petroleum ether, 1:4).

IR (KBr): 1635, 1623 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.23 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.83 (t, J = 7.5 Hz, 1 H), 7.75-7.68 (m, 2 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.59-7.50 (m, 3 H), 6.32 (s, 1 H), 6.19 (dd, J = 7.5, 2.2 Hz, 1 H), 5.75 (m, 1 H), 5.01 (d, J = 17.2 Hz, 1 H), 4.98 (d, J = 14.4 Hz, 1 H), 2.46 (s, 3 H), 2.42 (m, 1 H), 2.20-2.10 (m, 2 H), 2.00 (m, 1 H), 1.75-1.48 (m, 2 H).

¹³C NMR (125 MHz, CDCl3): δ = 197.2, 164.9, 164.0, 144.7, 138.8, 137.9, 132.4, 131.6, 131.1, 130.3, 130.2 (2 C), 129.7, 129.3, 128.5 (2 C), 127.6, 123.4, 115.3, 97.7, 86.5, 34.4, 33.3, 31.2, 23.8.

MS: m/z (%) = 370 (100) [M + H]+, 330 (35).

HRMS: m/z [M + Na]+ calcd for C25H23NNaO2: 392.1626; found: 392.1625.

Compound 30 by the Coupling of Carbene Complex 2 with 1-[1-Phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]hept-6-en-1-one (14)

Yield: 0.180 g (47%); yellow solid; mp 144-145 ˚C; R f  = 0.24 (EtOAc-petroleum ether, 1:4).

IR (KBr): 1625, 1581 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.76-7.70 (m, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.60-7.50 (m, 3 H), 6.32 (s, 1 H), 6.19 (dd, J = 7.5, 2.5 Hz, 1 H), 5.76 (m, 1 H), 4.98 (d, J = 17.5 Hz, 1 H), 4.93 (d, J = 10.5 Hz, 1 H), 2.47 (s, 3 H), 2.46 (m, 1 H), 2.10-2.00 (m, 3 H), 1.55-1.41 (m, 4 H).

¹³C NMR (150 MHz, CDCl3): δ = 197.1, 164.9, 163.9, 144.6, 138.7, 138.4, 132.4, 131.5, 131.0, 130.1 (2 C), 129.6, 129.2, 128.5, 128.4 (2 C), 127.5, 123.3, 114.7, 97.6, 86.6, 34.9, 33.4, 31.2, 28.6, 24.1.

MS: m/z (%) = 384 (100) [M + H]+, 366 (7), 344 (8), 326 (9).

HRMS: m/z [M + Na]+ calcd for C26H25NNaO2: 406.1783; found: 406.1782.

Compound 32 by the Coupling of Carbene Complex 2 with 1-[2-(Trimethylsilylethynyl)quinolin-3-yl]hex-5-en-1-one (19)

Yield: 0.125 g (43%); gummy solid; R f  = 0.42 (EtOAc-petroleum ether, 1:3).

IR (neat): 3430, 1638 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.11 (d, J = 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.83 (s, 1 H), 7.82 (d, J = 8.5 Hz, 1 H), 7.72 (td, J = 7.5, 1.3 Hz, 1 H), 7.55 (td, J = 7.5, 1.3 Hz, 1 H), 3.69 (m, 1 H), 3.06 (ddd, J = 19.0, 12.5, 3.0 Hz, 1 H), 2.43 (s, 3 H), 2.16-2.08 (m, 3 H), 2.09-1.90 (m, 4 H), 1.79 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 199.6, 152.3, 149.7, 147.5, 136.4, 131.8, 129.8 (2 C), 128.1, 127.5, 127.3, 125.1, 78.3, 44.1, 35.9, 32.7, 28.4, 27.7, 21.5.

MS: m/z (%) = 295 (20) [MH+ + 1], 294 (100) [M + H]+, 276 (20).

Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.84; H, 6.62; N, 4.89.

Coupling of Mono-/Bisprenylated Carbene Complexes 6/39 with Alkynyl(iso)quinolinecarbonyl Derivatives; General Procedure

To a soln of an alkynyl carbonyl derivative 11/12/16/17/18 (1 mmol) in THF (5 mL) at reflux was added a soln of a γ,δ-unsaturated carbene complex 6/39 (1.1 mmol) in THF (10 mL) over a period of 1 h. After the addition was complete, the mixture was heated to reflux for 24 h. The mixture was cooled to r.t. The THF was removed under reduced pressure, EtOAc (10 mL) was added and the mixture was filtered through Celite® (1.0 g). After evaporation of the solvent, the crude product was purified by column chromatography.

Compound 37 by the Coupling of Carbene Complex 6 with 1-Phenyl-3-(trimethylsilylethynyl)isoquinoline-4-carbaldehyde (11)

Yield: 0.198 g (48%); white solid; mp 168-169 ˚C; R f  = 0.25 (EtOAc-petroleum ether, 3:7).

IR (KBr): 3374, 1630 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.60 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 8.5 Hz, 1 H), 7.82 (t, J = 8.5 Hz, 1 H), 7.72-7.57 (m, 3 H), 7.57-7.50 (m, 3 H), 5.77 (t, J = 7.0 Hz, 1 H), 2.80 (m, 1 H), 2.70 (ddd, J = 15.0, 11.0, 4.5 Hz, 1 H), 2.56 (dt, J = 17.0, 3.5 Hz, 1 H), 2.38 (ddd, J = 17.0, 15.0, 4.5 Hz, 1 H), 2.24 (m, 1 H), 2.00 (s, 1 H, exchangeable with D2O), 1.92 (m, 1 H), 1.87 (m, 1 H), 0.0 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 203.1, 165.8, 160.6, 146.1, 141.5, 138.6, 135.4, 130.5, 129.9 (2 C), 129.2, 128.6, 128.3, 128.1 (2 C), 127.8, 127.6, 125.2, 66.0, 41.5, 37.6, 36.8, 28.2, 2.01 (3 C).

MS: m/z (%) = 436 (100) [M + Na]+, 414 (60) [M + H]+, 398 (8).

Anal. Calcd for C26H27NO2Si: C, 75.51; H, 6.58; N, 3.39. Found: C, 75.27; H, 6.32; N, 3.51.

Compound 38 by the Coupling of Carbene Complex 6 with Phenyl­[1-phenyl-3-(trimethylsilylethynyl)isoquinolin-4-yl]meth­anone (12)

Yield: 0.270 g (55%); white solid; mp >220 ˚C (dec); R f  = 0.2 (EtOAc-petroleum ether, 1:9).

IR (KBr): 3447, 1636 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.11 (dd, J = 8.0, 2.0 Hz, 1 H), 7.85 (dd, J = 8.0, 2.0 Hz, 1 H), 7.58-7.50 (m, 5 H), 7.45-7.40 (m, 2 H), 7.33-7.27 (m, 5 H), 2.70 (m, 1 H), 2.67 (s, 1 H, exchangeable with D2O), 2.51 (d, J = 12.0 Hz, 1 H), 2.43 (d, J = 17.5 Hz, 1 H), 2.34-2.20 (m, 2 H), 1.88 (m, 1 H), 1.68 (m, 1 H), -0.03 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 203.4, 165.4, 161.2, 146.4, 146.0, 142.5, 138.5, 134.9, 132.0, 129.8 (2 C), 129.7, 128.7, 128.6 (2 C), 128.3 (3 C), 128.0 (2 C), 127.5, 127.4, 126.1 (2 C), 76.2, 52.4, 36.7, 35.6, 27.7, 2.4 (3 C).

MS: m/z (%) = 491 (42) [MH+ + 1], 490 (100) [M + H]+.

HRMS: m/z [M + H]+ calcd for C32H32NO2Si: 490.2202; found: 490.2194.

Compound 41 by the Coupling of Carbene Complex 6 with 2-(Trimethylsilylethynyl)quinoline-3-carbaldehyde (16)

Yield: 0.116 g (42%); gummy solid; R f  = 0.57 (EtOAc-petroleum ether, 3:7).

IR (neat): 3390, 1619 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.26 (s, 1 H), 8.16 (d, J = 3.0 Hz, 1 H), 8.15 (d, J = 3.0 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.70 (td, J = 8.0, 1.0 Hz, 1 H), 7.52 (td, J = 8.0, 1.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 6.98 (dd, J = 8.0, 3.0 Hz, 1 H), 5.14 (m, 1 H), 3.96 (s, 3 H), 3.22 (dd, J = 15.0, 4.8 Hz, 1 H), 3.12 (dd, J = 15.0, 8.5 Hz, 1 H), 2.09 (br s, 1 H).

¹³C NMR (75 MHz, CDCl3): δ = 159.3, 151.7, 147.8, 134.8, 132.9, 132.2, 130.0, 129.4, 129.3, 127.7, 127.6, 127.3, 126.3, 117.4, 109.6, 77.2, 68.5, 36.9.

MS: m/z (%) = 279 (25) [MH+ + 1], 278 (100) [M + H]+, 261 (10), 260 (60).

Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.85; H, 5.61; N, 4.96.

Compound 42 by the Coupling of Carbene Complex 6 with Phenyl[2-(trimethylsilylethynyl)quinolin-3-yl]methanone (17)

Yield: 0.146 g (43%); gummy solid; R f  = 0.33 (EtOAc-petroleum ether, 3:7).

IR (neat): 3407, 1660 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.43 (s, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 7.75 (td, J = 7.5, 1.0 Hz, 1 H), 7.64 (d, J = 2.0 Hz, 1 H), 7.55 (td, J = 7.5, 1.0 Hz, 1 H), 7.32-7.27 (m, 3 H), 7.13 (m, 2 H), 2.73 (s, 1 H), 2.60-2.49 (m, 3 H), 2.38 (ddd, J = 17.0, 15.0, 5.0 Hz, 1 H), 2.17 (t, J = 12.5 Hz, 1 H), 2.06 (m, 1 H), 1.90 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 200.1, 155.8, 149.4, 147.8, 145.8, 137.1, 135.2, 130.3, 130.0, 128.7, 128.4 (2 C), 128.0, 127.8, 127.7, 126.8 (2 C), 125.0, 75.5, 46.6, 37.7, 33.4, 30.2.

MS: m/z (%) = 343 (30) [MH+ + 1], 342 (100) [M + H]+, 322 (20).

Anal. Calcd for C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.74; H, 5.73; N, 3.98.

Compound 43 by the Coupling of Carbene Complex 39 with 2-(Trimethylsilylethynyl)quinoline-3-carbaldehyde (16)

Yield: 0.192 g (51%); gummy solid; R f  = 0.51 (EtOAc-petroleum ether, 3:7).

IR (neat): 3437, 1640 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.39 (s, 1 H), 8.11 (d, J = 8.5 Hz, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 7.73 (t, J = 8.5 Hz, 1 H), 7.56 (t, J = 8.5 Hz, 1 H), 5.84 (m, 1 H), 5.15 (m, 1 H), 5.10 (d, J = 6.0 Hz, 1 H), 5.07 (s, 1 H), 2.86 (m, 1 H), 2.60-2.53 (m, 2 H), 2.45 (ddd, J = 12.5, 5.5, 4.0 Hz, 1 H), 2.21-2.14 (m, 2 H), 2.08-2.01 (m, 2 H), 1.91 (q, J = 12.5 Hz, 1 H), 0.16 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 205.9, 161.4, 152.4, 146.7, 143.1, 136.5, 134.5, 134.2, 130.0, 129.1, 128.3, 127.7, 127.4, 116.6, 68.5, 44.4, 41.2, 34.1, 33.4, 33.2, 2.37 (3 C).

MS: m/z (%) = 379 (30) [MH+ + 1], 378 (100) [M + H]+, 363 (20), 362 (60).

Anal. Calcd for C23H27NO2Si: C, 73.17; H, 7.21; N, 3.71. Found: C, 73.12; H, 7.11; N, 3.83.

Compound 44 by the Coupling of Carbene Complex 39 with
p -Tolyl[2-(trimethylsilylethynyl)quinolin-3-yl]methanone (18)

Yield: 0.256 g (55%); gummy solid; R f  = 0.28 (EtOAc-petroleum ether, 1:9).

IR (neat): 3435, 1639 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.19 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 7.5 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 2 H), 5.73 (m, 1 H), 4.94 (d, J = 10.0 Hz, 1 H), 4.87 (d, J = 17.1 Hz, 1 H), 2.74 (m, 1 H), 2.53-2.45 (m, 4 H), 2.33 (s, 3 H), 2.31 (q, J = 12.5 Hz, 1 H), 2.07 (m, 1 H), 2.01-1.90 (m, 2 H), 0.18 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 206.1, 161.6, 152.7, 146.9, 143.5 (2 C), 137.6 (2 C), 136.4, 135.3, 130.3, 129.1, 129.0 (2 C), 128.4, 128.0, 127.4, 126.5 (2 C), 116.5, 75.7, 48.0, 44.6, 34.1, 33.3, 32.1, 21.0, 2.51 (3 C).

MS: m/z (%) = 469 (40) [MH+ + 1], 468 (100) [M + H]+, 463 (25), 452 (75).

Anal. Calcd for C30H33NO2Si: C, 77.05; H, 7.11; N, 2.99. Found: C, 77.31; H, 7.22; N, 2.81.

Acknowledgment

Financial support from CSIR [No. 01 (2215)/08-EMR-II], Government of India is gratefully acknowledged. We thank CPIPL, Kolkata and IICB, Kolkata for providing the NMR facility. The UGC, New Delhi is also thanked for the award of a Junior Research Fellowship to S.M.

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Scheme 1 Tandem generation and trapping of furo[3,4-c]isoquinoline and furo[3,4-b]quinoline intermediates

Scheme 2 Synthesis of isoquinolines substituted with an aldehyde or a ketone group. Reagents and conditions: (a) POCl3, DMF, THF, 0 ˚C; then KMnO4, H2SO4, r.t., 42%; (b) (trimethylsilyl)acetylene, (Ph3P)2PdCl2, Ph3P, CuI, Et3N, THF, r.t., 67%; (c) (i) R¹MgBr; (ii) CrO3˙2py, 12 (72%), 13 (52%), 14 (47%).

Scheme 3 Synthesis of functionalized quinolines. Reagents and conditions: (a) (trimethylsilyl)acetylene, (Ph3P)2PdCl2, CuI, Et3N, THF, r.t., 86%; (b) (i) R²MgBr; (ii) CrO3˙2py, 17 (70%), 18 (69%), 19 (45%).

Scheme 4 Synthesis of phenanthridine derivatives

Scheme 5 Generation and Diels-Alder trapping of furo[3,4-c]isoquinoline intermediates using an intramolecular approach

Scheme 6 Generation and intramolecular Diels-Alder trapping of a furo[3,4-b]quinoline intermediate

Scheme 7 Synthesis of phenanthridines using a monoprenylated Fischer carbene complex

Scheme 8 Synthesis of acridines using mono-/bisprenylated Fischer carbene complexes