Synthesis 2018; 50(17): 3540-3548
DOI: 10.1055/s-0036-1591591
paper
© Georg Thieme Verlag Stuttgart · New York

A Metal-Free Approach for the Synthesis of 2-Tetralones via Carbanion-Induced Ring Transformation of 2H-Pyran-2-ones

Samata E. Shetgaonkar
Chemistry Division, School of Advanced Science, VIT University, Chennai Campus, Chennai-600127, Tamil Nadu, India   Email: [email protected]
,
Fateh V. Singh*
Chemistry Division, School of Advanced Science, VIT University, Chennai Campus, Chennai-600127, Tamil Nadu, India   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 24 April 2018

Accepted after revision: 27 April 2018

Publication Date:
28 June 2018 (online)

 


Abstract

A metal-free, ultrasound-assisted approach for the synthesis of highly functionalized 2-tetralones in high yields is described. The process involves ring transformation of 2H-pyran-2-ones with the spirocyclic ketone 1,4-cyclohexandione monoethylene ketal to yield spiro­cyclic ketals and subsequent acid-mediated hydrolysis. This protocol is free from any organometallic reagents, is economical and tolerates a wide range of functional groups.


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Tetralone-cored systems have been identified as important synthetic intermediates in organic[1] [2] and medicinal chemistry.[3–6] Among all aromatic bicyclic ketones, 2-tetralones constitute a significant class of building blocks due to their versatile reactivity. They are important starting materials for the synthesis of various biologically active synthetic[7] and naturally occurring compounds.[8] Moreover, these scaffolds are potential precursors for the synthesis of different drug molecules such as nepinalone,[9] treprostinil,[10] idarubicine,[11] (±)-daunomycinone[12] and rotigotine.[13] In addition, 2-tetralones have been used as key substrates for the construction of merocyanine dyes[14] and some fluorescent polycyclic compounds.[15]

Over the years, numerous synthetic methodologies have been employed for the preparation of 2-tetralones. In 2009, Hon and Devulapally[16] developed the titanium(IV)-mediated synthesis of 2-tetralones by intramolecular cyclization of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones. Subsequently, the same group reported a new synthetic route to obtain a variety of substituted 2-tetralone derivatives via cyclization of 4-aryl-2-hydroxybutanal diethyl acetals using TiCl4 as the promoter.[17] In 2013, Flowers and co-workers[18] developed a Ce(IV)-mediated approach for the intramolecular cyclization of β-dicarbonyl compounds to functionalized β-tetralones. In 2015, the intramolecular hydroarylation/isomerization of propargyl alcohols leading to a diverse array of 2-tetralones was reported using Bi(OTf)3 as the catalyst.[19] Furthermore, Lei and co-workers[20] synthesized similar systems by the oxidation of β-alkyl styrenes using a combination of Fukuzumi’s catalyst with cobaloxime. Recently, the Au-catalyzed oxidation of terminal alkynes in the presence of 2,6-dichloropyridine 1-oxide was used to achieve the synthesis of similar compounds.[21]

However, most of the available methods are associated with limitations such as the use of toxic metals, prolonged reaction times, poor yields and harsh reaction conditions. Thus, this prompted us to develop an efficient, simple and economical synthetic protocol to produce 2-tetralones that would overcome the drawbacks of existing approaches.

2H-Pyran-2-ones are of great interest as they are versatile synthons for the construction of functionally crowded benzenes,[22] polyarylbenzenes[23] and nitrogen-[24] and oxygen-containing[25] heterocyclic compounds, all of which find wide-scale application in biological and materials chemistry. 2-oxo-2H-Pyran-3-carbonitriles possess three electrophilic centers: C-2, C-4, C-6, and the latter is highly prone to nucleophilic attack because of the extended conjugation and presence of a cyano group at position 3 of the pyran ring.

The synthesis of substrates 3 was achieved by the reaction of ketene dithioacetal 1 with various substituted aryl ketones 2 in DMSO using KOH as the base.[22b] [23b] [e] [26] The methylsulfanyl group of 2-pyranones 3 is a good leaving group which can be easily replaced by several cyclic secondary amines 4 under refluxing conditions in methanol for 6–8 hours to yield compounds 5 (Scheme [1]). The parent precursor ketene dithioacetal 1 was synthesized by the reaction of ethyl cyanoacetate, carbon disulfide and dimethyl sulfate in the presence of sodium methoxide as the base in absolute methanol.[23e] [26]

Zoom Image
Scheme 1 Synthesis of 2H-pyran-2-one precursors 3 and 5

Herein, we report a new synthetic route for the preparation of highly functionalized spirocyclic ketals 7an via carbanion-induced ring transformation of 2H-pyran-2-ones 5an with 1,4-cyclohexanedione monoethylene ketal 6 at room temperature in an ultrasonic bath. Subsequent acid-mediated hydrolysis of ketals 7an yields 2-tetralones 11af in high yields. This protocol is free from any organometallic reagents and transition-metal catalysts and tolerates a wide range of functional groups.

Initially, our efforts were directed to find an appropriate base for the ring transformation of substrate 5a with spirocyclic ketone 6 in DMF and the results are shown in Table [1]. To begin with, potassium hydroxide was used as the base and the corresponding product 7a was isolated in 73% yield (Table [1], entry 1).

Table 1 Optimization of the Base for the Synthesis of Spirocyclic Ketal 7a by the Ring Transformation of 2H-Pyran-2-one 5a with Ketone 6

Entry

Base

Time (h)

Yield (%)

1

KOH

11

73

2

NaOH

14

60

3

Et3N

17

10

4

K2CO3

24

 –

5

KO t Bu

 8

69

6

NaH

 9

71

The same ring transformation reaction was attempted with sodium hydroxide and the desired product 7a was obtained in 60% yield (Table [1], entry 2). Reaction product 7a was obtained in only 10% yield when Et3N was used as the base (Table [1], entry 3), whereas no product formation was observed in the presence of potassium carbonate and starting materials were recovered (Table [1], entry 4). Finally, the reaction was also studied with KO t Bu and NaH and the desired product 7a was isolated in 69% and 71% yields, respectively (Table [1], entries 5 and 6).

Next, our efforts were directed to examine the solvent effect on the ring transformation of lactone 5a with spirocyclic ketone 6. The reaction was performed in a number of polar and non-polar solvents and the results are listed in Table [2]. Initially, the reaction was carried out in DMF and the desired product 7a was isolated in 73% yield (Table [2], entry 1). An improved yield of 77% of the ring-transformed product 7a was obtained when the reaction was carried out in the dipolar aprotic solvent DMSO (Table [2], entry 2). The same reaction was performed in chloroform and the reaction product 7a was isolated in only 20% yield along with unreacted starting materials (Table [2], entry 3). Further, the reaction was carried out in the polar protic solvent ethanol, but the desired product 7a was not observed and starting materials were recovered (Table [2], entry 4). The reaction was also tested in THF and diethyl ether, with the reaction product 7a being isolated in 27% and 10% yields, respectively, along with unreacted starting materials (Table [2], entries 5 and 6).

Table 2 Optimization of the Solvent for the Synthesis of Spirocyclic Ketal 7a by the Ring Transformation of 2H-Pyran-2-one 5a with Ketone 6

Entry

Solvent

Time

Yield (%)

1

DMF

11 h

73

2

DMSO

10 h

77

3

CHCl3

14 h

20

4

EtOH

24 h

 –

5

THF

14 h

27

6

Et2O

16 h

10

7a

DMSO

16 min

84

a The ring transformation reaction was performed in an ultrasonic bath.

Furthermore, our efforts were focused on reducing the reaction time for this ring transformation. Nowadays, ultrasound-assisted organic synthesis is a highly efficient and attractive green technique, widely used as alternative energy source in many organic reactions.[27] [28] [29] [30] [31] [32] [33] [34] Hence we carried out the same reaction of 2H-pyran-2-one 5a with spirocyclic ketone 6 under ultrasound irradiation at room temperature. Surprisingly, the reaction was complete in just 16 minutes and the ring-transformation product 7a was obtained in 84% yield (Table [2], entry 7). Thus, the optimized conditions for the synthesis of spirocyclic ketals 7 are: 2H-pyran-2-ones 5, spirocyclic ketone 6, powdered KOH (1.2 equiv), DMSO, ultrasound irradiation, room temperature.

Table 3 Synthesis of Spirocyclic Ketals 7an by the Ring Transformation of 2H-Pyran-2-ones 5an with Spirocyclic Ketone 6

Entry

Ar

R

Amine

Product

Time (min)

Yield (%)

 1

C6H5

H

piperidine

7a

16

84

 2

C6H5

H

N-phenylpiperazine

7b

25

87

 3

4-BrC6H4

H

piperidine

7c

18

94

 4

4-BrC6H4

H

N-phenylpiperazine

7d

27

90

 5

4-MeOC6H4

H

piperidine

7e

19

76

 6

4-MeOC6H4

H

N-phenylpiperazine

7f

24

78

 7

1-naphthyl

H

piperidine

7g

26

82

 8

1-naphthyl

H

N-phenylpiperazine

7h

38

79

 9

2-naphthyl

H

piperidine

7i

32

80

10

2-naphthyl

H

N-phenylpiperazine

7j

40

75

11

C6H5

Me

piperidine

7k

27

77

12

3-ClC6H4

Me

piperidine

7l

30

80

13

3-ClC6H4

Me

N-phenylpiperazine

7m

35

82

14

4-MeOC6H4

Me

N-phenylpiperazine

7n

37

75

Having optimized the conditions, we next examined the scope of different substrates in this ring transformation reaction (Table [3]). Thus, lactones 5aj were successfully converted into the corresponding spirocyclic ketals 7aj in yields of 75–94% (Table [3], entries 1–10). Interestingly, the reaction worked smoothly with bulky 6-naphthyl-2H-pyran-2-ones 5gj and the desired products 7gj were obtained in 75–82% yields (Table [3], entries 7–10). Additionally, highly congested 6-aryl-5-methyl-2H-pyran-2-ones 5kn were successfully converted into fully functionalized spirocyclic ketals 7kn in good yields under the optimized reaction conditions (Table [3], entries 11–14). Notably, various electron-donating and electron-withdrawing substituents on the phenyl ring in substrates 5 were successfully tolerated. Moreover, it was observed that ring-transformed products 7 were obtained in higher yields from substrates 5 having electron-withdrawing substituents on the phenyl ring (Table [3], entries 3 and 4). All the synthesized compounds were characterized by spectroscopic analysis.

On the basis of available literature,[22] [23] a proposed mechanism for the ring transformation of lactones 5 into the corresponding ketals 7 is depicted in Scheme [2]. The reaction is initiated by nucleophilic attack of the carbanion generated from ketone 6 under basic conditions at C6 of 2H-pyran-2-one 5 to give intermediate 8, subsequent intramolecular cyclization of which yields the intermediate 9. Finally, intermediate 9 undergoes decarboxylation and dehydration to furnish the spirocyclic ketal product 7.

Zoom Image
Scheme 2 Proposed mechanism for the synthesis of spirocyclic ketals 7 by the ring transformation of 2H-pyran-2-ones 5 with ketone 6

Furthermore, spirocyclic ketals 7af were hydrolyzed with 4% ethanolic HCl under refluxing conditions to give highly substituted 2-tetralones 11af in 78–88% yields (Table [4], entries 1–6).[35] All the synthesized compounds were characterized by spectroscopic analysis.

Table 4 Synthesis of Functionalized 2-Tetralones 11af by Acidic Hydrolysis of Ketals 7af

Entry

Ar

R

Amine

Product

Yield (%)

1

C6H5

H

piperidine

11a

78

2

4-BrC6H4

H

piperidine

11b

81

3

4-BrC6H4

H

N-phenylpiperazine

11c

83

4

4-MeOC6H4

H

N-phenylpiperazine

11d

88

5

C6H5

Me

piperidine

11e

80

6

3-ClC6H4

Me

N-phenylpiperazine

11f

84

In summary, we have achieved a metal-free approach for the ultrasound-assisted synthesis of highly functionalized spirocyclic ketals 7an through carbanion-induced ring transformation of 2-pyranones 5an with 1,4-cyclohexanedione monoethylene ketal 6. Several examples of the spirocyclic ketal products 7 were converted into 2-tetralones 11af via ketal cleavage using 4% ethanolic HCl. The present synthetic route is inexpensive, is free from organometallic reagents, involves an easy work-up procedure and does not require harsh reaction conditions. Studies on the further application of this approach are currently in progress.

All experiments were performed without using an inert atmosphere. Dimethyl sulfoxide and other solvents were purchased from Avra Synthesis Pvt. Ltd. All other purchased chemicals were used without further purification. All reactions were monitored by thin-layer chromatography (TLC) performed on Merck KGaA pre-coated sheets of silica gel 60. Column chromatography was performed with silica gel or neutral alumina (Avra synthesis, 100–125 mesh). Eluting solvents are indicated in the text. Melting points were measured with a REMI DDMS 2545 melting point apparatus. IR spectra were recorded on a Thermo Scientific Nicolet Nexus 470FT-IR spectrophotometer and band positions are reported in reciprocal centimeters. Samples were prepared as KBr pellets. 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, on an AV-400 Bruker spectrometer. Deuterated chloroform (CDCl3) was used as the solvent and tetramethylsilane (Me4Si) as an internal standard. Mass spectra (m/z) were recorded under electron impact (EI), electrospray (ES) or chemical ionization (CI). CHN analysis was performed using an Elementar VarioMICRO Select 15162036 Analyzer.


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Ethyl 2-Cyano-3,3-dimethylsulfanylacrylate (1)[23e]

Ethyl cyano acetate (11.3 mL, 100.0 mmol) was added dropwise over a period of 15 min to an ice-cold solution of sodium methoxide, freshly prepared in situ by dissolving sodium metal (3.44 g, 150.0 mmol) in absolute MeOH (40 mL) at 0 °C. The resulting white-colored precipitate was stirred vigorously for another 15 min followed by the dropwise addition of carbon disulfide (6.4 mL, 100.0 mmol) at 20 °C to give a yellow-colored liquid. Next, dimethyl sulfate (23.6 mL, 248 mmol) was added slowly over a period of 30 min. The resulting yellow semi-solid material was stirred for another 15 min and excess MeOH was removed under high vacuum. Finally, the reaction mixture was poured onto crushed ice with constant stirring and the precipitate thus obtained was filtered, washed with cold H2O, dried and recrystallized from EtOAc/hexane (1:4) to give yellow, crystalline compound 1.[23e]


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6-Aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles 3a–n; General Procedure[23e] [26]

A mixture of ethyl 2-cyano-3,3-dimethylsulfanylacrylate (1) (2.17 g, 10.0 mmol, 1.0 equiv), aryl ketone 2 (12 mmol, 1.2 equiv) and powdered KOH (0.84 g, 15 mmol, 1.5 equiv) in dry DMSO was stirred at room temperature for 14–18 h. On completion of the reaction, the mixture was poured into ice-cold H2O with constant stirring. The residue thus obtained was removed by filtration and purified by silica gel chromatography using CHCl3 as the eluent. The isolated products were characterized as 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles 3an by spectroscopic analysis. The NMR data was found to correlate with those reported in the literature.[23e] [26]


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6-Aryl-4-amino-2-oxo-2H-pyran-3-carbonitriles 5a–n; General Procedure[23e] [26]

A mixture of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitrile 3an (1.0 mmol, 1.0 equiv) and secondary amine 4 (1.2 mmol, 1.2 equiv) was refluxed in MeOH for 6–8 h. The course of the reaction was monitored by TLC. On completion, the reaction mixture was cooled, filtered and the remaining solid rinsed with MeOH (2 × 5 mL) to give products 5an.[23e] [26]


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Functionalized Spirocyclic Ketals 7a–n; General Procedure

A mixture of 2H-pyran-2-one 5an (1.0 mmol, 1.0 equiv), 1,4-cyclohexanedione monoethylene ketal 6 (1.2 mmol, 1.2 equiv) and powdered KOH (1.2 mmol) in dry DMSO (3.0 mL) was irradiated in an ultrasonic bath for 16–40 min at room temperature. The progress of the reaction was monitored by TLC. On completion of the reaction, ice-cold H2O (10 mL) was added and the mixture was neutralized with dilute HCl. After that, the reaction mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layer was dried over Na2SO4, filtered and evaporated under vacuum. The obtained crude residue was purified through a neutral alumina column using EtOAc/hexane (1:4) as the eluent. Finally, the isolated ketals 7an were characterized by spectroscopic analysis.


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8-Phenyl-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7a)

Yield: 0.315 g, 0.841 mmol (84%); white solid; mp 165–167 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2214 cm–1 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.44–1.53 (m, 2 H, CH2), 1.62–1.74 (m, 4 H, 2 CH2), 1.91 (t, J = 6.8 Hz, 2 H, CH2), 2.63 (s, 2 H, CH2), 2.97–3.07 (m, 4 H, 2 NCH2), 3.14 (t, J = 6.8 Hz, 2 H, CH2), 3.78–3.92 (m, 4 H, 2 OCH2), 6.66 (s, 1 H, ArH), 7.13–7.20 (m, 2 H, ArH), 7.25–7.39 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 27.9, 30.8, 37.6, 53.4, 64.5, 105.4, 107.9, 117.5, 118.4, 126.1, 127.6, 128.4, 128.6, 140.5, 140.7, 147.3, 155.7.

GC–MS: m/z = 375 [M + 1]+.

Anal. Calcd for C24H26N2O2: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.62; H, 6.81; N, 7.34.


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8-Phenyl-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7b)

Yield: 0.393 g, 0.871 mmol (87%); yellow solid; mp 170–173 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2218 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.88–1.99 (m, 2 H, CH2), 2.65 (s, 2 H, CH2), 3.04–3.41 (m, 10 H, 4 NCH2 + CH2), 3.75–3.98 (m, 4 H, 2 OCH2), 6.71 (s, 1 H, ArH), 6.76–6.93 (m, 3 H, ArH), 7.12–7.24 (m, 4 H, ArH), 7.28–7.40 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 28.0, 30.8, 37.6, 49.6, 51.8, 64.5, 105.6, 107.8, 116.4, 118.3, 120.0, 121.8, 127.2, 127.8, 128.4, 128.6, 129.2, 130.4, 140.3, 141.2, 151.2, 154.2.

GC–MS: m/z = 452 [M + 1]+.

Anal. Calcd for C29H29N3O2: C, 77.13; H, 6.47; N, 9.31. Found: C, 76.82; H, 6.07; N, 9.10.


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8-(4-Bromophenyl)-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7c)

Yield: 0.426 g, 0.940 mmol (94%); white solid; mp 179–183 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2211 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.44–1.59 (m, 2 H, CH2), 1.62–1.74 (m, 4 H, 2 CH2), 1.90 (t, J = 7.0 Hz, 2 H, CH2), 2.59 (s, 2 H, CH2), 2.98–3.07 (m, 4 H, 2 NCH2), 3.13 (t, J = 6.8 Hz, 2 H, CH2), 3.79–3.93 (m, 4 H, 2 OCH2), 6.62 (s, 1 H, ArH), 7.04 (d, J = 8.0 Hz, 2 H, ArH), 7.47 (d, J = 8.4 Hz, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 27.9, 30.8, 37.6, 53.4, 64.6, 105.6, 107.8, 117.3, 118.1, 121.9, 125.9, 130.3, 131.6, 139.4, 140.9, 145.9, 155.7.

GC–MS: m/z = 453 [M + 1]+.

Anal. Calcd for C24H25BrN2O2: C, 63.58; H, 5.56; N, 6.18. Found: C, 63.30; H, 5.21; N, 6.01.


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8-(4-Bromophenyl)-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7d)

Yield: 0.477 g, 0.900 mmol (90%); yellow solid; mp 178–181 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2213 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.85–1.98 (m, 2 H, CH2), 2.62 (s, 2 H, CH2), 3.08–3.38 (m, 10 H, 4 NCH2 + CH2), 3.76–3.96 (m, 4 H, 2 OCH2), 6.68 (s, 1 H, ArH), 6.75–6.95 (m, 3 H, ArH), 7.01–7.12 (m, 2 H, ArH), 7.14–7.27 (m, 2 H, ArH), 7.44–7.55 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 28.0, 30.8, 37.7, 49.5, 51.8, 64.6, 105.8, 107.7, 116.4, 117.1, 118.0, 120.1, 122.1, 126.9, 129.2, 130.3, 131.7, 139.1, 141.4, 146.2, 151.2, 154.3.

GC–MS: m/z = 530 [M + 1]+.

Anal. Calcd for C29H28BrN3O2: C, 65.66; H, 5.32; N, 7.92. Found: C, 65.29; H, 5.06; N, 7.58.


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8-(4-Methoxyphenyl)-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7e)

Yield: 0.307 g, 0.760 mmol (76%); white solid, mp 170–173 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2216 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.43–1.54 (m, 2 H, CH2), 1.62–1.74 (m, 4 H, 2 CH2), 1.90 (t, J = 6.8 Hz, 2 H, CH2), 2.65 (s, 2 H, CH2), 2.96–3.05 (m, 4 H, 2 NCH2), 3.12 (t, J = 6.8 Hz, 2 H, CH2), 3.77 (s, 3 H, OCH3), 3.78–3.92 (m, 4 H, 2 OCH2), 6.65 (s, 1 H, ArH), 6.87 (d, J = 8.8 Hz, 2 H, ArH), 7.10 (d, J = 8.8 Hz, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 27.9, 30.9, 37.7, 53.5, 55.4, 64.5, 105.1, 107.9, 113.8, 117.5, 118.5, 126.3, 129.8, 132.8, 140.7, 147.0, 155.7, 159.1.

GC–MS: m/z = 405 [M + 1]+.

Anal. Calcd for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93. Found: C, 73.92; H, 6.73; N, 6.76.


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8-(4-Methoxyphenyl)-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7f)

Yield: 0.376 g, 0.780 mmol (78%); yellow solid; mp 186–188 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2219 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.93 (t, J = 6.8 Hz, 2 H, CH2), 2.68 (s, 2 H, CH2), 3.15 (t, J = 6.8 Hz, 2 H, CH2), 3.23–3.40 (m, 8 H, 4 NCH2), 3.78 (s, 3 H, OCH3), 3.80–3.93 (m, 4 H, 2 OCH2), 6.73 (s, 1 H, ArH), 6.89 (d, J = 8.4 Hz, 3 H, ArH), 6.99 (d, J = 8.0 Hz, 2 H, ArH), 7.12 (d, J = 8.4 Hz, 2 H, ArH), 7.24 (t, J = 7.8 Hz, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 28.0, 30.8, 37.8, 50.3, 51.5, 55.4, 64.6, 105.3, 107.8, 113.9, 117.0, 117.3, 118.6, 121.2, 127.6, 129.3, 129.8, 132.5, 141.1, 147.4, 150.1, 154.0, 159.3.

GC–MS: m/z = 482 [M + 1]+.

Anal. Calcd for C30H31N3O3: C, 74.82; H, 6.49; N, 8.73. Found: C, 74.38; H, 6.28; N, 8.35.


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8-(Naphthalen-1-yl)-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7g)

Yield: 0.348 g, 0.820 mmol (82%); white solid; mp 140–143 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2213 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.40–1.76 (m, 6 H, 3 CH2), 1.89 (s, 2 H, CH2), 2.26–2.48 (m, 2 H, CH2), 2.93–3.28 (m, 6 H, 2 NCH2 + CH2), 3.57–3.88 (m, 4 H, 2 OCH2), 6.71 (s, 1 H, ArH), 7.12–7.50 (m, 5 H, ArH), 7.74–7.88 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 28.0, 30.9, 36.7, 53.4, 64.4, 105.6, 107.8, 117.5, 118.9, 125.4, 125.5, 126.1, 126.5, 127.6, 128.1, 128.4, 131.2, 133.5, 138.2, 140.6, 145.8, 155.7.

GC–MS: m/z = 425 [M + 1]+.

Anal. Calcd for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 78.92; H, 6.53; N, 6.27.


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8-(Naphthalen-1-yl)-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7h)

Yield: 0.396 g, 0.790 mmol (79%); yellow solid; mp 195–197 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2211 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.83–2.09 (m, 2 H, CH2), 2.29–2.49 (m, 2 H, CH2), 3.12–3.38 (m, 10 H, 4 NCH2 + CH2), 3.58–3.89 (m, 4 H, 2 OCH2), 6.73–6.95 (m, 4 H, ArH), 7.12–7.27 (m, 3 H, ArH), 7.28–7.51 (m, 4 H, ArH), 7.76–7.89 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 28.0, 30.9, 36.8, 49.6, 51.8, 64.5, 105.8, 107.7, 116.4, 117.3, 118.8, 120.1, 125.4, 125.5, 126.1, 126.2, 126.6, 128.3, 128.5, 128.6, 129.2, 131.1, 133.6, 137.9, 140.9, 146.1, 151.1, 154.2.

GC–MS: m/z = 502 [M + 1]+.

Anal. Calcd for C33H31N3O2: C, 79.01; H, 6.23; N, 8.38. Found: C, 78.69; H, 6.03; N, 8.13.


#

8-(Naphthalen-2-yl)-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7i)

Yield: 0.339 g, 0.800 mmol (80%); yellow solid; mp 203–206 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2210 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.42–1.78 (m, 6 H, 3 CH2), 1.86–2.00 (m, 2 H, CH2), 2.67 (s, 2 H, CH2), 2.96–3.23 (m, 6 H, 2 NCH2 + CH2), 3.69–3.93 (m, 4 H, 2 OCH2), 6.75 (s, 1 H, ArH), 7.24–7.34 (m, 1 H, ArH), 7.39–7.51 (m, 2 H, ArH), 7.58–7.67 (m, 1 H, ArH), 7.72–7.87 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 28.0, 30.9, 37.7, 53.5, 64.5, 105.4, 107.9, 117.5, 118.6, 126.3, 126.4, 126.5, 126.7, 127.5, 127.8, 127.9, 128.1, 132.6, 133.2, 138.0, 140.8, 147.2, 155.8.

GC–MS: m/z = 425 [M + 1]+.

Anal. Calcd for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 79.03; H, 6.23; N, 6.49.


#

8-(Naphthalen-2-yl)-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7j)

Yield: 0.376 g, 0.750 mmol (75%); yellow solid; mp 200–203 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2219 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.88–1.99 (m, 2 H, CH2), 2.69 (s, 2 H, CH2), 3.10–3.42 (m, 10 H, 4 NCH2 + CH2), 3.71–3.92 (m, 4 H, 2 OCH2), 6.75–6.93 (m, 4 H, ArH), 7.14–7.25 (m, 3 H, ArH), 7.41–7.50 (m, 2 H, ArH), 7.60–7.67 (m, 1 H, ArH), 7.73–7.86 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 28.0, 30.9, 37.8, 49.6, 51.9, 64.5, 105.6, 107.8, 116.4, 117.2, 118.4, 120.0, 126.5, 126.6, 127.4, 127.5, 127.8, 128.1, 129.2, 132.7, 133.2, 137.8, 141.3, 147.5, 151.2, 154.2.

GC–MS: m/z = 502 [M + 1]+.

Anal. Calcd for C33H31N3O2: C, 79.01; H, 6.23; N, 8.38. Found: C, 78.69; H, 6.08; N, 8.08.


#

7-Methyl-8-phenyl-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7k)

Yield: 0.298 g, 0.770 mmol (77%); white solid; mp 158–163 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 2220 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.29–1.89 (m, 11 H, CH3 + 4 CH2), 2.38 (s, 2 H, CH2), 2.78–3.38 (m, 6 H, CH2 + 2 NCH2), 3.61–3.91 (m, 4 H, 2 OCH2), 6.88–7.00 (m, 2 H, ArH), 7.21–7.40 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.0, 24.2, 26.9, 27.4, 30.7, 38.4, 51.8, 64.5, 107.8, 109.0, 118.0, 127.2, 128.2, 128.9, 129.7, 133.4, 137.4, 139.9, 147.8, 153.3.

GC–MS: m/z = 389 [M + 1]+.

Anal. Calcd for C25H28N2O2: C, 77.29; H, 7.26; N, 7.21. Found: C, 76.95; H, 7.04; N, 6.78.


#

8-(3-Chlorophenyl)-7-methyl-6-(piperidin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7l)

Yield: 0.338 g, 0.800 mmol (80%); white solid; mp 171–174 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2210 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.46–1.67 (m, 6 H, 3 CH2), 1.79–1.91 (m, 5 H, CH3 + CH2), 2.37 (s, 2 H, CH2), 2.89–3.33 (m, 6 H, CH2 + 2 NCH2), 3.76–3.93 (m, 4 H, 2 OCH2), 6.84–6.91 (m, 1 H, ArH), 6.99 (s, 1 H, ArH), 7.26–7.33 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.1, 24.2, 26.9, 27.4, 30.6, 38.5, 51.8, 64.5, 107.7, 109.4, 117.8, 126.6, 127.6, 128.4, 129.4, 130.3, 133.2, 134.8, 137.6, 141.7, 146.2, 153.4.

GC–MS: m/z = 423 [M + 1]+.

Anal. Calcd for C25H27ClN2O2: C, 70.99; H, 6.43; N, 6.62. Found: C, 70.71; H, 6.07; N, 6.45.


#

8-(3-Chlorophenyl)-7-methyl-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7m)

Yield: 0.410 g, 0.820 mmol (82%); yellow solid; mp 163–166 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 2219 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.81–1.95 (m, 5 H, CH3 + CH2), 2.39 (s, 2 H, CH2), 2.94–3.56 (m, 10 H, CH2 + 4 NCH2), 3.77–3.95 (m, 4 H, 2 OCH2), 6.80 (t, J = 7.2 Hz, 1 H, ArH), 6.85–6.95 (m, 3 H, ArH), 6.99 (s, 1 H, ArH), 7.16–7.25 (m, 2 H, ArH), 7.27–7.35 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.4, 27.4, 30.6, 38.5, 50.4, 50.5, 64.5, 107.6, 110.3, 116.6, 117.5, 119.9, 126.5, 127.7, 128.4, 129.1, 130.4, 130.5, 133.3, 134.9, 138.1, 141.4, 146.4, 151.6, 151.7.

GC–MS: m/z = 501 [M + 1]+.

Anal. Calcd for C30H30ClN3O2: C, 72.06; H, 6.05; N, 8.40. Found: C, 71.73; H, 5.93; N, 8.09.


#

8-(4-Methoxyphenyl)-7-methyl-6-(4-phenylpiperazin-1-yl)-3,4-dihydro-1H-spiro[naphthalene-2,2′-[1,3]dioxolane]-5-carbonitrile (7n)

Yield: 0.371 g, 0.750 mmol (75%); yellow solid; mp 207–210 °C; Rf = 0.3 (EtOAc/hexane, 1:4).

IR (KBr): 2218 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.82–1.95 (m, 5 H, CH3 + CH2), 2.42 (s, 2 H, CH2), 3.04–3.60 (m, 10 H, CH2 + 4 NCH2), 3.78 (s, 3 H, OCH3), 3.80–3.91 (m, 4 H, 2 OCH2), 6.79 (t, J = 7.4 Hz, 1 H, ArH), 6.84–6.96 (m, 6 H, ArH), 7.15–7.25 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.4, 27.5, 30.7, 38.6, 50.5, 50.6, 55.3, 64.5, 107.8, 109.8, 114.4, 116.6, 117.7, 120.1, 129.1, 129.3, 131.2, 131.8, 133.9, 137.7, 147.9, 151.5, 151.6, 158.8.

GC–MS: m/z = 496 [M + 1]+.

Anal. Calcd for C31H33N3O3: C, 75.13; H, 6.71; N, 8.48. Found: C, 74.82; H, 6.40; N, 8.32.


#

Functionalized 2-Tetralones 11a–f; General Procedure[35]

A solution of spirocyclic ketal 7af (0.25 mmol) in 4% ethanolic HCl (5 mL) was refluxed for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the mixture was cooled to room temperature and the solvent was evaporated under high vacuum. The reaction mixture was diluted with H2O (5 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using EtOAc/hexane (1:4) as the eluent to give tetralones 11af.


#

6-Oxo-4-phenyl-2-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11a)

Yield: 0.064 g, 0.195 mmol (78%); white solid; mp 165–167 °C; Rf = 0.5 (EtOAc/hexane, 1:4).

IR (KBr): 1719 (CO), 2221 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.47–1.62 (m, 2 H, CH2), 1.64–1.78 (m, 4 H, 2 CH2), 2.49 (t, J = 6.6 Hz, 2 H, CH2), 3.04–3.13 (m, 4 H, 2 NCH2), 3.28 (t, J = 6.8 Hz, 2 H, CH2), 3.36 (s, 2 H, CH2), 6.76 (s, 1 H, ArH), 7.10–7.18 (m, 2 H, ArH), 7.28–7.40 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.0, 26.1, 27.5, 37.0, 42.4, 53.4, 104.8, 117.3, 118.8, 124.3, 128.0, 128.6, 128.7, 139.4, 142.2, 146.5, 155.8, 209.3.

GC–MS: m/z = 331 [M + 1]+.

Anal. Calcd for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.64; H, 6.45; N, 8.35.


#

4-(4-Bromophenyl)-6-oxo-2-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11b)

Yield: 0.082 g, 0.202 mmol (81%); white solid; mp 180–183 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 1720 (CO), 2223 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.47–1.60 (m, 2 H, CH2), 1.65–1.77 (m, 4 H, 2 CH2), 2.49 (t, J = 6.8 Hz, 2 H, CH2), 3.04–3.12 (m, 4 H, 2 NCH2), 3.28 (t, J = 6.8 Hz, 2 H, CH2), 3.32 (s, 2 H, CH2), 6.71 (s, 1 H, ArH), 7.02 (d, J = 8.4 Hz, 2 H, ArH), 7.49 (d, J = 8.4 Hz, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 24.0, 26.1, 27.5, 36.9, 42.3, 53.4, 105.1, 117.2, 118.6, 122.4, 124.0, 130.4, 131.8, 138.2, 142.5, 145.2, 155.9, 208.9.

GC–MS: m/z = 409 [M + 1]+.

Anal. Calcd for C22H21BrN2O: C, 64.55; H, 5.17; N, 6.84. Found: C, 64.35; H, 4.79; N, 6.53.


#

4-(4-Bromophenyl)-6-oxo-2-(4-phenylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11c)

Yield: 0.101 g, 0.207 mmol (83%); white solid; mp 189–192 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 1718 (CO), 2220 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.51 (t, J = 6.8 Hz, 2 H, CH2), 3.22–3.41 (m, 12 H, 4 NCH2 + 2 CH2), 6.77 (s, 1 H, ArH), 6.82 (t, J = 7.4 Hz, 1 H, ArH), 6.90 (d, J = 8.4 Hz, 2 H, ArH), 7.03 (d, J = 8.4 Hz, 2 H, ArH), 7.22 (t, J = 8.4 Hz, 2 H, ArH), 7.51 (d, J = 8.4 Hz, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 27.5, 36.8, 42.3, 49.5, 51.8, 105.3, 116.5, 116.9, 118.6, 120.3, 122.6, 125.2, 129.2, 130.4, 131.9, 137.9, 142.8, 145.4, 151.0, 154.5, 208.5.

GC–MS: m/z = 487 [M + 1]+.

Anal. Calcd for C27H24BrN3O: C, 66.67; H, 4.97; N, 8.64. Found: C, 66.29; H, 4.81; N, 8.37.


#

4-(4-Methoxyphenyl)-6-oxo-2-(4-phenylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11d)

Yield: 0.096 g, 0.220 mmol (88%); white solid, mp 180–183 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 1716 (CO), 2221 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.44–2.55 (m, 2 H, CH2), 3.19–3.46 (m, 12 H, 4 NCH2 + 2 CH2), 3.79 (s, 3 H, OCH3), 6.77–6.86 (m, 2 H, ArH), 6.87–6.96 (m, 4 H, ArH), 7.05–7.13 (m, 2 H, ArH), 7.16–7.26 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 27.6, 36.9, 42.4, 49.6, 51.8, 55.5, 104.7, 107.7, 114.1, 116.5, 117.1, 118.9, 120.2, 125.5, 129.2, 130.0, 131.4, 142.6, 146.5, 154.4, 159.6, 208.9.

GC–MS: m/z = 438 [M + 1]+.

Anal. Calcd for C28H27N3O2: C, 76.86; H, 6.22; N, 9.60. Found: C, 76.41; H, 5.89; N, 9.37.


#

3-Methyl-6-oxo-4-phenyl-2-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11e)

Yield: 0.071 g, 0.206 mmol (80%); white solid; mp 122–125 °C; Rf = 0.4 (EtOAc/hexane, 1:4).

IR (KBr): 1717 (CO), 2219 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.44–1.73 (m, 6 H, 3 CH2), 1.89 (s, 3 H, CH3), 2.49 (t, J = 6.8 Hz, 2 H, CH2), 2.92–3.39 (m, 8 H, 2 CH2 + 2 NCH2), 6.89–7.00 (m, 2 H, ArH), 7.26–7.41 (m, 3 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.4, 24.2, 26.8, 27.0, 37.4, 43.0, 51.9, 108.4, 117.9, 127.7, 128.2 (3 C), 129.0, 134.3, 138.5, 138.9, 147.2, 153.6, 209.2.

GC–MS: m/z = 345 [M + 1]+.

Anal. Calcd for C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C, 79.91; H, 6.88; N, 7.75.


#

4-(3-Chlorophenyl)-3-methyl-6-oxo-2-(4-phenylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (11f)

Yield: 0.077 g, 0.169 mmol (84%); white solid; mp 171–174 °C; Rf = 0.3 (EtOAc/hexane, 1:4).

IR (KBr): 1720 (CO), 2222 (CN) cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.96 (s, 3 H, CH3), 2.47–2.56 (m, 2 H, CH2), 3.04–3.64 (m, 12 H, 2 CH2 + 4 NCH2), 6.82 (t, J = 7.2 Hz, 1 H, ArH), 6.84–6.89 (m, 1 H, ArH), 6.90–6.96 (m, 2 H, ArH), 6.97–7.01 (m, 1 H, ArH), 7.16–7.26 (m, 2 H, ArH), 7.28–7.37 (m, 2 H, ArH).

13C NMR (100 MHz, CDCl3): δ = 16.7, 27.1, 37.2, 42.9, 50.5, 50.6, 109.6, 116.7, 117.3, 120.1, 126.5, 128.1, 128.4, 129.0, 129.1, 130.5, 134.3, 135.1, 138.9, 140.4, 145.8, 151.6, 152.0, 208.5.

GC–MS: m/z = 456 [M + 1]+.

Anal. Calcd for C28H26ClN3O: C, 73.75; H, 5.75; N, 9.22. Found: C, 73.34; H, 5.49; N, 9.09.


#
#

Acknowledgment

The authors are thankful to VIT Chennai for providing financial assistance. We thank the SAIF department, VIT Vellore for spectrometric data.

Supporting Information

  • References

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Zoom Image
Scheme 1 Synthesis of 2H-pyran-2-one precursors 3 and 5
Zoom Image
Scheme 2 Proposed mechanism for the synthesis of spirocyclic ketals 7 by the ring transformation of 2H-pyran-2-ones 5 with ketone 6