A carbanion induced ring switching synthesis of spiranes: an unprecedented approach

Abstract

An unique approach to the synthesis of heterocyclic spiranes through ring switching transformation of suitably functionalized 2H-pyran-2-ones, benzo[h]chromene and thiochromeno[4,3-b]pyrans has been developed. The spirane dimer 11d displayed interesting halogen-hydrogen bonding to generate an elliptical cavity and may be relevant to the generation of a host guest assembly for specific cations and also a low helimerization energy barrier of spirane 17a.

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Introduction

The unique topography and interesting conformational features of spiranes and their structural implication on biological systems have drawn the attention of organic chemists towards the development of their chemistry. There are numerous biologically active natural products^1,2 in which spiranes feature in the sub-structure. However, in the spiranes the plane of both rings are mutually perpendicular along the tetrahedral spiro carbon. The asymmetric characteristic of the spiro carbon also gives the pronounced pharmacological properties.³ Fridericamycin (1),⁴ Pronuciferine (2),⁵ and Spirofomabuxine (3)⁶ are some of the representatives of this large family of compounds. Besides natural products, synthetic carbocyclic and heterocyclic spiranes have demonstrated various medicinal properties.⁷ Amongst these (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1′-indane]-5,5′-diol (4)⁸ is one of the most potent nonsteroidal estrogen agonists (Fig. 1). Due to steric constraints, spiranes exhibit various photochemical phenomena⁹ and are used as building blocks in the thermotropic liquid crystals, employed in optical displays and screens.¹⁰

Fig. 1 Naturally occurring and synthetic spiranes.

Results and discussion

Chemistry

Amongst numerous approaches for the construction of spiranes, the most prominent are through alkylation,¹¹ transition metal catalyzed reactions,¹² rearrangement based reactions,¹³ ring expansion and contraction reactions,¹⁴ photochemical reactions,¹⁵ Diels–Alder cyclo-addition reactions,¹⁶ radical cyclization,¹⁷ and metathesis.¹⁸ However, these procedures suffer with limitations of functional group incompatibility and restriction to substitution patterns. A comprehensive literature survey revealed that there are only a few instances where useful functional groups attached to spiranes are transformed to newer molecules through synthetic manipulation. We envisaged a novel approach to the synthesis of functionalized spiro systems, free from the limitations of earlier protocols. This approach also opens a new avenue for functional group transformation to generate molecular diversity under mild reaction conditions.

We report herein an unprecedented synthesis through ring switching transformation of suitably functionalized 6-aryl-4-sec-amino-2H-pyran-2-ones (8) by 2-tetralone (9) in dry THF using NaH as a base at 15–20 °C to produce spiranes. 6-Aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles (8) used as precursors for the synthesis of spiranes were prepared¹⁹ in two steps. The first step was the synthesis of 6-aryl-4-methylthio-2H-pyran-2-ones (7) from the reaction of methyl 2-cyano-3,3-dimethylthioacrylate (5) and aryl methyl ketone (6). Amination of 7 with piperidine in boiling ethanol afforded 8 as depicted in Scheme 1.

Scheme 1 Synthesis of the 2H-pyran-2-ones, precursors for the synthesis of phenanthrenes 10 and spiranes 11.

Thus, a reaction of an equivalent amount of 6-phenyl-4-methylthio-2H-pyran-2-one-3-carbonitrile¹⁹ (7) and 2-tetralone (9a) in dry THF in the presence of 5 equivalent NaH (60%) as a base at 15–20 °C for 7 days led to yield a complex mixture with recovery of major unreacted starting lactone (7). However, the reaction of 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles¹⁹ (8) with 2-tetralones (9) under analogous reaction conditions gave two compounds in which one was characterized as a phenanthrene derivative (10) and the other major product as a spirane (11), Scheme 2 (Table 1). The structure of 11d has been confirmed by X-ray diffraction analysis²⁴ (Fig. 2).

Scheme 2 Synthesis of phenanthrenes 10 and spiranes 11 (Table 1).

Table 1 Yields of phenanthrenes 10 and spiranes 11 (Scheme 2)

Entry	8,10,11	Ar	R	Yields (%)
				10	11
a Absolute configuration represented on the basis of X-ray analysis.^24
1	a	Phenyl	H	10	40
2	b	4-Methylphenyl	H	11	34
3	c	4-Methylphenyl	OMe	19	31
4	d	4-Bromophenyl	OMe	17	29^a^,24

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Fig. 2 Perspective view of 11d and 17a with atom numbering.

The reaction is possibly initiated with a Michael addition and liberation of carbon dioxide followed by ring switching to give the spirane (11) and highly functionalized phenanthrene (10) following path A and path B respectively. A plausible mechanism for the formation of 10 and 11 is depicted in Scheme 3.

Scheme 3 A plausible mechanism for the formation of 10 and 11.

In order to optimize the reaction conditions, a model experiment was performed using 8a and 9a as reactants in different solvent, base, temperature and time to improve the yields and these results are summarized in Table 2. As is evident from Table 2, the increase of the reaction time beyond 7 days did not enhance the yield. However, reaction is very sensitive to temperature and above 20 °C, there was almost complete loss of yield. Change of solvent from THF to DMF and base from NaH to KOH/NaOH at room temperature exclusively gave phenanthrene derivatives (10).

Table 2 Optimization of reaction conditions of phenanthrene 10a and spiranes 11a

Entry	Base^a	Solvent	Temperature/°C	Time	Products (%)
					10a	11a
a NaH (60%) was used.
1	KOH/NaOH	DMF	22–30	24 h	65	—
2	NaH(1.5 equi)	THF	22–30	24 h	40	1–2
3	NaH (3 equi)	THF	15–20	3 d	32	15
4	NaH (5 equi)	THF	15–20	5 d	10	30
5	NaH (5 equi)	THF	15–20	7 d	10	40
6	NaH (5 equi)	THF	15–20	10 d	10	40

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Further, to generalize this reaction for the construction of fused polycyclic spiro systems, 5,6-dihydro-4-sec-amino-2-oxo-2H-benzo[h]chromene-3-carbonitrile²⁰ were prepared from the reaction of 1-tetralone and thiochromen-4-ones (14a) and 4-sec.amino-2-oxo-2,5-dihydrothiochromeno-[4,3-b]pyran-3-carbo- nitriles (14b-e) with methyl 2-cyano-3,3-dimethyl thioacrylate²¹ (5) followed by amination with sec.amine in boiling ethanol, afforded 4 in good to excellent yields, Scheme 4.²³

Scheme 4 Synthesis of the substituted 5,6-dihydro-2-oxo-2H-benzo[h] chromene-3-carbonitriles (13a,14a) and 2,5-dihydro-2-oxo-thiochromeno [4,3-b]pyran-3-carbonitriles (13b–e,14b-e).²³

It was quite interesting that the ring transformation of 14 by 2-tetralones in the presence of 1.5 equivalents of NaH in THF at room temperature gave two products which were characterized as 5,6,9,10-tetrahydro-7-oxa[5]helicene (15) as the major product and the 8-sec-amino-5,6,9,10-tetrahydro[5]helicene (16) as the minor product,²²Scheme 5.

Scheme 5 Synthesis of tetrahydrooxahelicenes (15) and (16).

However, when this reaction was carried out by stirring an equimolar mixture of 14 and 9 using 5 equivalent NaH (60%) in dry THF at 15–20 °C for 7 days, it led to 3-sec-amino-2′-oxo-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]chromene/thiochromene-1,1′-naphthalene]-2-carbonitriles (17) along with recovery of starting material 14, Scheme 6. Optimized reaction conditions of 17 performed under various temperatures are shown in Table 3. The structure of isolated product (17) was confirmed by single crystal X-ray diffraction²⁴ (Fig. 2).

Scheme 6 Synthesis of spiranes 17 (Table 4).

Table 3 Optimized reaction conditions of spirane 17a under various temperatures

Entry	Time/d	Temperature/°C	Yield (%) (17a)	S^a
a Starting lactone (14) recovered (%). b Under light. c Other complex unidentified products.
1	5	5–10	0	98
2	7	15–20	45	50
3	10	15–20	45	45
4	7	25–30	25	45^c
5	4	32–35	1–2	40^c
6	4	40–45^b	1	20^c

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Our attempts failed to obtain spiro compounds by the ring transformation of 7 and 13 with 2-tetralone (9) under analogous reaction conditions. This indicated that the amino substituent has an immense electronic contribution in the formation of spiro compounds. It is also conspicuous that the synthesis of spiranes (17) is dependent on the reaction conditions (Table 3). It was interesting to note that the increase of temperature above 22 °C not only decreases the yield but leaves unreacted starting material and a non-separable complex mixture.

The reaction is possibly initiated with a Michael addition and liberation of carbon dioxide followed by framework rearrangement and cyclization to give spiranes (17) as shown in Scheme 6 (Table 4). A plausible mechanism for this reaction is also depicted in Scheme 7.

Table 4 Yields and melting points of spiranes 17 (Scheme 6)

Entry	R	R1	X	Y	Mp/°C	Yield (%)
a Absolute configuration represented on the basis of X-ray analysis.^24
17a ^a	H	7-OMe	S	O	270	45
17b	H	7-OMe	S	CH2	290	39
17c	H	6-OMe	S	CH2	256	40
17d	Cl	6-OMe	S	CH2	258	42
17e	H	6-OMe	CH2	CH2	246	37
17f	H	H	S	CH2	278	35
17g	H	6-OMe	S	N–Ph	216	31

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Scheme 7 A plausible mechanism for the formation of 3-sec-amino-2′-oxo-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c] thiochromene-1,1′-naphthalene]-2-carbonitriles (17).

Crystal structure and quantum chemical studies

Crystal structure analysis. Crystals of X-ray quality for 11d was obtained by slow evaporation of solvent (EtOAc : hexane; 1 : 25) and 17a was obtained by slow evaporation of solvent (DCM : THF; 10 : 3) at room temperature (15–18 °C). The molecular structures of the compounds with arbitrary numbering are presented in Fig. 2 illustrating the non-planar, helically distorted conformation of the molecule.

The compounds 11d and 17a crystallize in the P1̄ space group having one and two molecules in the triclinic unit cell respectively. When viewed from the rings C or B side of the compound, 11d displays the S configuration because of the presence of the chiral axis, whilst 17a displays the R configuration. The geometry around the spirane center C10 of 11d, is defined by the carbon atoms C9 and C11 of the five membered ring C and C19 and C23 belonging to six membered ring B. The two rings B and C are almost orthogonal with respect to each other having a dihedral angle of 82.11°. The dihedral angle between the rings A and C is 82.89°. The immediate geometry around the spirane center C1 of 17a is defined by the carbon atoms C2 and C12 belonging to five membered ring C and C13 and C21 belonging to six membered ring B. The two rings B and C are almost orthogonal with respect to each other having a dihedral angle of 77.44°. The dihedral angles between the rings A and C; C and E are 84.30° and 25.44°, respectively. In the solid state, 11d, displays intermolecular Br1⋯H21B interactions in antiparallel fashion with dimension 2.766 Å (symm. op.: −x, −y, 2 − z) and interaction angle 153.96° to generate a dimer configuration (Fig. 3).

Fig. 3 Antiparallel dimeric structure for 11d displaying weak intermolecular C(Ar)–Br⋯H intermolecular halogen-hydrogen interaction.

This dimer in turn generates an elliptical cavity having a major axis of 11.20 Å and a minor axis of 4.46 Å. It is obvious that these interactions play an important role if the structure is to be rationalized in terms of interactions between the molecular fragments. However, the question as to what kind of intermolecular interaction(s) contribute to the binding energy between molecules and dimers in the structure need to be investigated. It is known that the covalent, H-bond, dipole–dipole, and van der Waals interaction energies are >1700, 70–50, 8–2, and <4 kJ mol⁻¹, respectively.

In order to analyze the various interactions that lead to the crystal structure, interaction energies and electrostatic potentials (Fig. 4) have been calculated for dimer keeping Br1⋯H21B distance fixed at values obtained from the X-ray single-crystal structure analyses. This analysis of the interaction energy in the crystal structure of 11d by means of dimer unit at the MP2 level of theory yields interaction energy in the Br1⋯H21B dimer of −7 kJ mol⁻¹. Hence this interaction can be regarded as the halogen-hydrogen bond.²⁵

Fig. 4 Electrostatic potentials plotted at the van der Waals surfaces for 11d calculated at the MP2 level of theory, yellow/blue denote areas of low/high charge density.

Computational analysis. In order to gain deeper insight into the stereochemical behaviour of 17a, the helimeric inversion barrier for this compound was calculated using quantum chemical methodology. The energy calculations reveal that the helimerization energy barrier for 17a is 11.70 kJ mol⁻¹. The calculated low inversion barrier of the enantiomers is an indicator for rapid interconversion at room temperature.

The electronic absorption recorded in a THF solution of 17a (Fig. 5) displays bands at ∼404, 374, 367, 322 and 278 nm. The observed electronic spectrum have been assigned with the help of time-dependent DFT (TD-DFT) calculations. Since each absorption line in a TD-DFT spectrum can arise from a several single orbital excitations, a description of the transition character is generally not straightforward. However, approximate assignments can be made, although they provide a simplified representation of the transitions. TD-DFT excitations were calculated both in the gas phase and in the solvent using dichloromethane (DCM). By comparing the calculated spectra it is evident that calculated transitions do not exhibit significant solvatochromic effects. In this view, only the DCM model results are presented in the Table 5. The first lower energy excitation calculated at 404 nm arises because of the π→π* transition within ring C. The next higher energy transition calculated at 374 nm occurs due to the π→π* transition between ring A and ring C. Also, in this case there is the involvement of the lone pair electron present on methoxy oxygen attached to ring A. The absorption calculated at 367 nm involves n→π* transition between the sulfur atom S1 of the ring D and π* orbitals of the ring C. The absorption calculated at 322 nm is ascribed to π→π* transitions from rings D and E to ring C; π→π* transition from ring C to ring B. The highest energy band calculated at 278 nm also arises because of the π→π* between ring C and rings B and E. Hence, from the TD-DFT calculations it can be concluded that the dominant electronic transition in 17a is π→π* with feeble contributions from the sulfur atom of the ring D. The morpholine ring does not play any role in the electronic absorption though it possesses lone pair of electrons at nitrogen and oxygen centers. This may also be due to inability of the morpholinyl moiety to undergo conjugation with the aromatic rings of the molecule.

Fig. 5 Electronic absorption spectra of 17a–g.

Table 5 TD-DFT calculated excitations & approximate assignments, 17a

E ^a	λ ^b	F ^c	Composition (%)	Nature^d
a Excitation Energy (eV). b Wavelength (nm). c Oscillator Strength. d Nature of the transition and approximate assignment of compound 17a (Fig. 2).
3.07	404	0.1773	HOMO→LUMO (45%)	π (C)→π*(C)
3.32	374	0.0025	HOMO-1→LUMO (46%)	π(A)→π*(C)
3.38	367	0.0175	HOMO-2→LUMO (43%)	n(D)→π*(C)
3.85	322	0.0453	HOMO-3→LUMO (19%)	π(D, E & C)→π*(C)
			HOMO→LUMO+1 (29%)
4.45	278	0.0260	HOMO→LUMO+2 (41%)	π(C)→π*(E)

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Conclusion

In conclusion, we have developed an unique, concise and economical one pot protocol for the construction of novel spiranes through base catalyzed ring contraction-cyclization reactions of suitably functionalized 2H-pyran-2-ones, benzo[h]chromene and thiochromeno[4,3-b]pyrans by 2-tetralones separately. This methodology provides a new avenue for the construction of highly functionalized spiranes and provides opportunity to transform functional groups present to newer heterocycles. The TD-DFT calculations indicated that the majority of electronic transitions are π→π* type but the presence of hetero atom in conjugation with aromatic ring may induce n→π* transition. Additionally, the compound 11d, displayed interesting halogen-hydrogen bonding to generate an elliptical cavity. This elliptical cavity may act as an excellent host for specific cations and may be relevant for the generation of host guest assembly. This will be our future target for investigation.

Experimental section

General

The reagents and the solvents used in this study were of analytical grade and were used without further purification. The melting points were determined on an electrically heated Townson Mercer melting point apparatus and are uncorrected. Commercial reagents were used without purification. ¹H and ¹³C NMR spectra were recorded on a Bruker WM-300 (300 MHz)/Jeol-400 using CDCl₃ and DMSO-d₆ as the solvents. Chemical shifts are reported in parts per million (δ-value) from Me₄Si (δ 0 ppm for ¹H) or based on the middle peak of the solvent (CDCl₃/DMSO-d₆) (δ 100.00 ppm for ¹³C NMR) as the internal standard. Signal patterns are indicated as s, singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet; brm, broad multiplet. Coupling constants (J) are given in Hertz. Infrared (IR) spectra were recorded on a Perkin-Elmer AX-1 spectrophotometer in KBr disc and reported in wave number (cm⁻¹). JEOL MSRoute/ESIMS spectrometers were used for mass/HRMS spectra.

General procedure for the synthesis of 9,10-dihydrophenanthrenes (10) and 3′,4′-dihydro-2′H-spiro[cyclopenta[2,4]diene-1,1′-naphthalene]-2-carbonitrile (11)

2-Tetralone (9) (1.0 mmol) was added in 5 equivalent NaH (60%) in THF (8 mL). After stirring five minutes, 2-oxo-6-phenyl-4-sec-amino-2H-pyran-3-carbonitrile (8) (1.0 mmol) was added and stirred at 15-20 °C for 7 days, monitoring TLC at regular interval. The excess THF was evaporated or distilled at reduced pressure and reaction mixture was poured onto crushed ice with vigorous stirring and neutralized with 10% HCl. The crude product obtained was filtered, washed with water and purified by silica gel column chromatography using chloroform/DCM in hexane.

4-phenyl-2-(piperidin-1-yl)-9,10-dihydrophenanthrene-1-carbonitrile (10a). White powder; R_f 0.78 (CHCl₃); yield 10%; mp 184 °C; IR (KBr): 2213 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.58–1.62 (m, 2H, CH₂), 1.77–1.80 (m, 4H, CH₂), 2.85 (t, J = 6.96 Hz, 2H, CH₂), 3.04 (t, J = 6.96 Hz, 2H, CH₂), 3.20 (t, J = 4.76 Hz, 4H, CH₂), 6.64 (d, 1H, J = 7.28 Hz, Ar–H), 6.74–6.79 (m, 1H, Ar–H), 6.83 (s, 1H, Ar–H), 7.02 (dd, 1H, J = 6.96, Ar–H), 7.19 (d, 1H, J = 7.28 Hz, Ar–H), 7.24–7.27 (m, 2H, Ar–H), 7.31–7.35 (m, 3H, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 24.1, 26.1(2C), 28.9, 29.2, 53.2 (2C), 104.6, 120.1, 125.5, 126.5, 127.1, 127.3, 127.5, 128.6 (2C), 129.1(2C), 129.1(2C), 132.7, 138.3, 142.3, 144.7, 145.8, 155.5; MS: m/z = 364.22 (M⁺); HRMS (ESI): calc. for C₂₆H₂₄N₂: 365.1973 (M⁺+1); found: 365.1978.

2′-oxo-5-phenyl-3-(piperidin-1-yl)-3′,4′-dihydro-2′H-spiro [cyclopenta[2,4]diene-1,1′-naphthalene]-2-carbonitrile (11a). Light yellow-greenish solid; R_f 0.40 (CHCl₃); yield 40%; mp 182 °C; IR (KBr): 2162 (CN), 1708 (C=O) cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.67–1.71 (brm, 6H, CH₂), 2.81–2.85 (m, 1H, CH₂), 3.20–3.32 (m, 2H, CH₂), 3.38–3.43 (m, 1H, CH₂), 3.63–3.67 (brm, 4H, CH₂), 6.87 (d, J = 7.64 Hz, 1H, Ar–H), 6.97 (s, 1H, Ar–H), 7.04–7.11 (m, 4H, Ar–H), 7.15–7.24 (m, 4H, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 24.0, 25.7(2C), 29.1, 39.5, 49.6(2C), 70.7, 84.6, 120.7, 124.6, 126.7(2C), 127.3, 127.4, 127.5, 128.5(2C), 128.7(2C), 128.9, 132.4, 135.1, 135.4, 158.7, 160.8, 206.3; MS: m/z = 380.25 (M⁺); HRMS (ESI): calc. for C₂₆H₂₄N₂O: 381.1922 (M⁺+1); found: 381.1929.

2-(piperidin-1-yl)-4-p-tolyl-9,10-dihydrophenanthrene-1-carbonitrile (10b). White powder; R_f 0.25 (CHCl₃:Hexane; 1 : 1); yield 11%; mp 144 °C; IR (KBr): 2203 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.58–1.61 (m, 2H, CH₂), 1.75–1.80 (m, 4H, CH₂), 2.37 (s, 3H, CH₃), 2.85 (t, J = 6.60 Hz, 2H, CH₂), 3.03 (t, J = 6.60 Hz, 2H, CH₂), 3.18 (t, J = 5.52 Hz, 4H, CH₂), 6.69 (d, 1H, J = 7.32 Hz, Ar–H), 6.77–6.85 (m, 2H, Ar–H), 6.99–7.05 (m, 1H, Ar–H), 7.11–7.16 (m, 4H, Ar–H), 7.18 (d, 1H, J = 7.32 Hz, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 21.2, 24.1, 26.1(2C), 28.9, 29.2, 53.2(2C), 104.4, 118.9, 120.2, 125.5, 126.5, 127.3, 128.9(2C), 129.1(2C), 129.3(2C), 132.8, 137.4, 138.2, 139.4, 144.8, 145.8, 155.4; MS: m/z = 379.40 (M⁺+1); HRMS (ESI): calc. for C₂₇H₂₆N₂: 379.2130 (M⁺+1); found: 379.2136.

2′-oxo-3-(piperidin-1-yl)-5-p-tolyl-3′,4′-dihydro-2′H-spiro[cyclopenta[2,4]diene-1,1′-naphthalene]-2-carbonitrile (11b). Light yellow-greenish solid; R_f 0.47 (DCM); yield 34%; mp 204 °C; IR (KBr): 2152 (CN), 1705 (C=O) cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.65–1.69 (brm, 6H, CH₂), 2.22 (s, 3H, CH₃), 2.80 (td, J = 5.12 and 13.9 Hz, 1H, CH₂), 3.15–3.32 (m, 2H, CH₂), 3.39 (td, J = 5.12 and 13.9 Hz, 1H, CH₂), 3.60–3.67 (brm, 4H, CH₂), 6.83 (d, J = 8.76 Hz, 1H, Ar–H), 6.91 (s, 1H, Ar–H), 6.94–6.98 (m, 4H, Ar–H), 7.05–7.09 (m, 1H, Ar–H), 7.14–7.22 (m, 2H, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 21.2, 24.0, 25.7(2C), 29.2, 39.5, 49.7(2C), 70.6, 84.2, 120.9, 123.6, 126.6(2C), 127.3(2C), 127.4, 128.7, 129.3, 129.6(2C), 135.0, 135.6, 139.1, 158.7, 160.9, 206.3; MS: m/z = 395.10 (M⁺+1); HRMS (ESI): calc. for C₂₇H₂₆N₂O: 395.2079 (M⁺+1); found: 395.2082.

6-methoxy-2-(piperidin-1-yl)-4-p-tolyl-9,10-dihydrophenanthrene-1-carbonitrile (10c). White powder, R_f 0.21 (CHCl₃:Hexane; 1 : 1); yield 19%; mp 170 °C; IR (KBr): 2201 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.64–1.70 (m, 2H, CH₂), 1.83–1.87 (m, 4H, CH₂), 2.43 (s, 3H, CH₃), 2.85 (t, J = 6.56 Hz, 2H, CH₂), 3.09 (t, J = 6.56 Hz, 2H, CH₂), 3.25–3.30 (m, 7H, OCH₃ and CH₂), 6.35 (d, 1H, J = 2.20 Hz, Ar–H), 6.67 (dd, 1H, J = 2.20 and 8.76 Hz, Ar–H), 6.90 (s, 1H, Ar–H), 7.15 (d, 1H, J = 8.76 Hz, Ar–H), 7.20–7.26 (m, 4H, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 21.1, 24.1, 26.1(2C), 27.9, 29.5, 53.2(2C), 54.4, 104.6, 113.3, 113.9, 117.6, 120.0, 127.2, 128.0(2C), 129.0(2C), 129.4, 130.4, 133.5, 137.3, 139.6, 144.7, 145.8, 155.5, 157.0; MS: m/z = 408.90 (M⁺+1); HRMS (ESI): calc. for C₂₈H₂₈N₂O: 409.2235 (M⁺+1); found: 409.2238.

7′-methoxy-2′-oxo-3-(piperidin-1-yl)-5-p-tolyl-3′,4′-dihydro-2′H-spiro[cyclopenta[2,4]diene-1,1′-naphthalene]-2-carbonitrile (11c). Light yellow-greenish solid; R_f 0.20 (CHCl₃); yield 31%; mp 234 °C; IR (KBr): 2150 (CN), 1701 (C=O) cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.65–1.68 (brm, 6H, CH₂), 2.23 (s, 3H, CH₃), 2.75–2.80 (m, 1H, CH₂), 3.08–3.16 (m, 1H, CH₂), 3.21–3.26 (m, 1H, CH₂), 3.28–3.36 (m, 1H, CH₂), 3.62–3.68 (brm, 7H, CH₃ and CH₂), 6.37 (d, 1H, J = 2.20 Hz, Ar–H), 6.73 (dd, 1H, J = 2.20 and 8.76 Hz, Ar–H),6.88 (s, 1H, Ar–H), 6.95–6.99 (m, 4H, Ar–H), 7.12 (d, 1H, J = 8.76 Hz, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 21.2, 24.0, 25.8(2C), 28.4, 39.7, 49.6(2C), 55.1, 70.6, 76.7, 84.0, 112.5, 113.0, 120.9, 123.5, 126.6(2C), 127.4, 129.3(2C), 129.5, 129.6, 136.9, 139.1, 158.7, 160.9, 206.3; HRMS (ESI): calc. for C₂₈H₂₈N₂O₂: 425.2184 (M⁺+1); found: 425.2187.

4-(4-bromophenyl)-6-methoxy-2-(piperidin-1-yl)-9,10-dihydrophenanthrene-1-carbonitrile (10d). White (light yellowish) rod shaped crystal from hexane : CHCl₃ (1 : 1); R_f 0.31 (CHCl₃ : hexane; 1 : 1); yield 17%; mp 178 °C; IR (KBr): 2209 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.57–1.62 (m, 2H, CH₂), 1.77–1.80 (m, 4H, CH₂), 2.77 (t, J = 7.32 Hz, 2H, CH₂), 3.01 (t, J = 7.32 Hz, 2H, CH₂), 3.20 (t, J = 5.12 Hz, 4H, CH₂), 3.26 (s, 3H, OCH₃), 6.20 (d, 1H, J = 2.92 Hz, Ar–H), 6.61 (dd, 1H, J = 2.92 and 8.0 Hz, Ar–H), 6.77 (s, 1H, Ar–H), 7.08 (d, 1H, J = 8.0 Hz, Ar–H), 7.14 (d, 2H, J = 6.6 Hz, Ar–H), 7.48 (d, 2H, J = 6.6 Hz, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 24.0, 26.1(2C), 27.8, 29.5, 53.1(2C), 54.2, 54.6, 105.0, 113.6, 113.9, 117.4, 119.6, 127.0, 128.2, 130.4, 130.8(2C), 131.8(2C), 133.0, 141.3, 143.2, 146.1, 155.5, 157.2; MS: m/z = 473.20 (M⁺+1); HRMS (ESI): calc. for C₂₇H₂₅BrN₂O: 473.1184 (M⁺+1); found: 473.1193.

5-(4-bromophenyl)-7′-methoxy-2′-oxo-3-(piperidin-1-yl)-3′,4′-dihydro-2′H-spiro[cyclopenta[2,4]diene-1,1′-naphthalene]-2-carbonitrile (11d). Light yellow-greenish crystalline solid crystallized from EtOAc and hexane (1 : 25); R_f 0.20 (CHCl3); yield 29%; mp 262 °C; IR (KBr): 2152 (CN), 1708 (C=O) cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.65–1.68 (brm, 6H, CH₂), 2.74–2.80 (m, 1H, CH₂), 3.08–3.13 (m, 1H, CH₂), 3.21–3.30 (m, 2H, CH₂), 3.61–3.65 (brm, 4H, CH₂), 3.68 (s, 3H, OCH₃), 6.34 (d, 1H, J = 2.8 Hz, Ar–H), 6.74 (dd, 1H, J = 2.8 and 8.8 Hz, Ar–H), 6.88–6.96 (m, 3H, Ar–H), 7.13 (d, 1H, J = 8.8 Hz, Ar–H), 7.29 (d, 2H, J = 8.8 Hz, Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ 23.9, 25.8(2C), 28.4, 39.7, 49.7(2C), 55.2, 70.7, 84.5, 112.5, 113.1, 120.5, 123.2, 125.1, 127.3, 128.2(2C), 129.9, 131.4(2C), 131.8, 136.3, 157.4, 158.8, 160.4, 206.0; MS: m/z = 489.30 (M⁺+1); HRMS (ESI): calc. for C₂₇H₂₅BrN₂O₂: 489.1133 (M⁺+1); found: 489.1139.

General procedure for the synthesis of spiranes (17)

2-Tetralone (9) (1.0 mmol) was added to a suspension of 5 equivalent NaH (60%) in THF (8 mL). After stirring five minutes 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile/4-sec-amino-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitrile (14) (1.0 mmol) was added and reaction mixture was stirred at 15–20 °C for 7 days by monitoring TLC at regular interval. The excess THF was distilled at reduced pressure and thereafter, reaction mixture was poured onto crushed ice with vigorous stirring and neutralized with 10% HCl. The crude product obtained was filtered, washed with water, purified by silica gel column chromatography using pure chloroform/DCM as eluent and finally crystallized with DCM:THF (10 : 3).

7′-methoxy-3-morpholino-2′-oxo-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17a). Light yellow-greenish tiny prism shaped crystal crystallized from THF:DCM (3 : 10); R_f 0.83 (DCM); yield 45%; mp 270 °C; IR (KBr): 2182 (CN), 1708 (C=O) cm⁻¹; ¹HNMR (300 MHz, DMSO-d₆): δ 2.82 (m, 2H, CH₂), 2.99 (m, 2H, CH₂), 3.33 (m, 4H, CH₂), 3.61 (s, 3H, OCH₃), 3.72 (brm, 4H, OCH₂), 3.9 (d, J = 15.3 Hz, 1H, SCH₂), 4.0 (d, J = 15.3 Hz, 1H, SCH₂), 6.24 (d, J = 2.1 Hz, 1H, Ar–H), 6.43 (d, J = 8.1 Hz, 1H, Ar–H), 6.89 (m, 2H, Ar–H), 7.11 (t, J = 7.5 Hz, 1H, Ar–H), 7.30 (d, J = 6.6 Hz, 2H, Ar–H); ¹³CNMR (100 MHz, CDCl₃): δ 22.9, 27.1, 39.0, 39.2, 39.4, 49.6(2C), 54.5, 65.6(2C), 68.8, 94.5, 111.0, 112.8, 117.6, 124.6, 125.1, 126.5, 128.2, 129.3, 132.1, 132.9, 134.1, 150.7, 158.0, 162.3, 204.2; MS: m/z = 457.3 (M⁺+1); HRMS (ESI): calc. for C₂₇H₂₄N₂O₃S: 457.1541 (M⁺+1); found: 457.1545.

7′-methoxy-2′-oxo-3-(piperidin-1-yl)-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17b)

Greenish-yellow solid; R_f 0.22 (CHCl₃); yield 39%; mp 290 °C; IR (KBr): 2175 (CN), 1712 (C=O) cm⁻¹; ¹HNMR (300 MHz, CDCl₃): δ 1.70 (brm, 6H, , CH₂), 2.81–2.87 (m, 1H, CH₂), 3.16–3.31 (m, 2H, CH₂), 3.37 (brm, 5H, CH₂), 3.68 (s, 3H, OCH₃), 3.77 (d, J = 6.7 Hz, 2H, SCH₂), 6.33 (d, J = 2.4, 1H, Ar–H), 6.50 (d, J = 7.7, 1H, Ar–H), 6.78 (dd, J = 2.5, 8.4, 1H, Ar–H), 6.86 (t, J = 7.2, 1H, Ar–H), 7.05 (t, J = 7.0, 1H, Ar–H), 7.18 (d, J = 8.5, 1H, Ar–H), 7.28 (m, 1H, Ar–H); ¹³CNMR (100 MHz, CDCl₃): δ 23.8, 23.9, 25.8(2C), 28.1, 29.6, 39.7, 51.3(2C), 55.1, 69.4, 94.2, 112.0, 113.3, 119.9, 125.4, 125.8, 127.3, 127.4, 128.7, 129.8, 133.9, 134.1, 135.9, 151.3, 158.7, 164.0, 205.4; HRMS (ESI): calc. for C₂₈H₂₆N₂O₂S: 455.1749 (M⁺+1); found: 455.1754.

6′-methoxy-2′-oxo-3-(piperidin-1-yl)-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17c). Greenish-yellow solid; R_f 0.44 (CHCl₃); yield 40%; mp 256 °C; IR (KBr): 2180 (CN), 1714 (C=O) cm⁻¹; ¹HNMR (300 MHz, CDCl3): δ 1.70 (brm, 6H, CH₂), 2.81–2.87 (m, 1H, CH₂), 3.19–3.28 (m, 2H, CH₂), 3.37–3.47 (m, 5H, CH₂), 3.71–3.83 (m, 5H, CH₂), 6.49 (d, J = 7.9, 1H, Ar–H), 6.70 (m, 2H, Ar–H), 6.76 (s, 1H, Ar–H), 6.86 (t, J = 7.7, 1H, Ar–H), 7.05 (t, J = 7.5, 1H, Ar–H), 7.30 (s, 1H, Ar–H); HRMS (ESI): calc. for C₂₈H₂₆N₂O₂S: 455.1749 (M⁺+1); found: 455.1758.

8-chloro-6′-methoxy-2′-oxo-3-(piperidin-1-yl)-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17d). Greenish-yellow solid; R_f 0.69 (CHCl₃); yield 42%; mp 258 °C; IR (KBr): 2176 (CN), 1714 (C=O) cm⁻¹; ¹HNMR (300 MHz, CDCl₃): δ 1.69 (brm, 6H, CH₂), 2.80–2.88 (m, 1H, CH₂), 3.23–3.44 (m, 7H, CH₂), 3.75 (m, 2H, CH₂), 3.80 (s, 3H, OCH₃), 6.44 (d, J = 3.2, 1H, Ar–H), 6.68 (d, J = 2.3, 2H, Ar–H), 6.77 (s, 1H, Ar–H), 7.00 (dd, J = 3.3, 12.5, 1H, Ar–H), 7.27 (s, 1H, Ar–H); HRMS (ESI): calc. for C₂₈H₂₅ClN₂O₂S: 489.1359 (M⁺+1); found: 489.1368.

6′-methoxy-2′-oxo-3-(piperidin-1-yl)-3′,4,4′,5-tetrahydro-2′H-spiro[cyclopenta[a]naphthalene-1,1′-naphthalene]-2-carbonitrile (17e). Greenish-yellow solid; R_f 0.48 (CHCl₃); yield 37%; mp 246 °C; IR (KBr): 2175 (CN), 1714 (C=O) cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 1.65 (brm, 6H, CH₂), 2.65 (m, 2H, CH₂), 2.79 (m, 1H, CH₂), 2.86 (m, 1H, CH₂), 2.98 (m, 1H, CH₂), 3.19 (m, 2H, CH₂), 3.40 (m, 5H, CH₂), 3.77 (s, 3H, OCH₃), 6.39 (d, J = 8.0, 1H, Ar–H), 6.65–6.74 (m, 3H, Ar–H), 6.90 (m, 1H, Ar–H), 7.05–7.11 (m, 2H, Ar–H); HRMS (ESI): calc. for C₂₉H₂₈N₂O₂: 437.2184 (M⁺+1); found: 437.2188.

2′-oxo-3-(piperidin-1-yl)-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17f). Greenish-yellow solid; R_f 0.48 (DCM); yield 35%; mp 278 °C; IR (KBr): 2176 (CN), 1714 (C=O) cm⁻¹; ¹HNMR (300 MHz, CDCl₃): δ 1.69 (brm, 6H, CH₂), 3.24 (m, 2H, CH₂), 3.34 (m, 4H, CH₂), 3.44 (m, 2H, CH₂), 3.74 (m, 2H, CH₂), 6.43 (d, J = 8.0, 1H, Ar–H), 6.78–6.82 (m, 2H, Ar–H), 7.02–7.12 (m, 2H, Ar–H), 7.24 (m, 3H, Ar–H); ¹³CNMR (100 MHz, CDCl₃): δ 23.7, 23.9, 25.9(2C), 29.0, 39.5, 51.4(2C), 69.4, 94.5, 119.9, 125.4, 125.8, 127.0, 127.4, 127.7, 127.8, 128.8, 129.8, 131.8, 133.8, 135.0, 135.5, 151.4, 164.1, 166.2, 205.5; HRMS (ESI): calc. for C₂₇H₂₄N₂OS: 425.1643 (M⁺+1); found: 425.1646.

6′-methoxy-2′-oxo-3-(4-phenylpiperazin-1-yl)-3′,4′-dihydro-2′H,4H-spiro[cyclopenta[c]thiochromene-1,1′-naphthalene]-2-carbonitrile (17g). Orange solid; R_f 0.40 (DCM); yield 31%; mp 216 °C; IR (KBr): 2180 (CN), 1713 (C=O) cm⁻¹; ¹HNMR (300 MHz, CDCl₃): δ 2.83–2.90 (m, 1H, CH₂), 3.21–3.29 (m, 2H, CH₂), 3.33 (t, J = 4.6, 4H, CH₂), 3.43–3.50 (m, 1H, CH₂), 3.60 (d, J = 3.8, 4H, CH₂), 3.81 (s, 3H, OCH₃), 3.84 (s, 2H, SCH₂), 6.51 (d, J = 7.7, 1H, Ar–H), 6.71 (m, 2H, Ar–H), 6.79 (s, 1H, Ar–H), 6.88 (m, 1H, Ar–H), 6.96 (t, J = 7.6, 3H, Ar–H), 7.07 (t, J = 7.4, 1H, Ar–H), 7.29–7.34 (m, 3H, Ar–H); ¹³CNMR (100 MHz, CDCl₃): 23.94, 29.07, 39.41, 49.36(2C), 50.08(2C), 55.21, 69.44, 93.08, 113.27, 114.50, 116.58(2C), 119.50, 120.63, 125.52, 125.89, 128.13, 128.21, 128.90, 129.19, 129.26(2C), 131.89, 131.96, 132.01, 133.60, 150.74, 151.77, 159.02, 161.70, 205.38; HRMS (ESI): calc. for C₃₃H₂₉N₃O₂S: 532.2014 (M⁺+1); found: 532.2019.

Crystallography

Intensity data for the colorless crystals of 11d was collected at 298(2) K on Sapphire2-CCD, OXFORD diffractometer system and for 17a was collected at 132(2) K on a Bruker APEX-II CCD diffractometer system, both equipped with graphite monochromated Mo-Kα radiation λ = 0.71073 Å. The final unit cell determination, scaling of the data, and corrections for Lorentz and polarization effects were performed with CrysAlis RED²⁶ and Bruker SAINT.²⁷ Symmetry-related multi-scan absorption corrections have been applied. The structures were solved by direct methods (SHELXS-97)²⁸ and refined by a full-matrix least-squares procedure based on F².²⁹ All non-hydrogen atoms were refined anisotropically; hydrogen atoms were located at calculated positions and refined using a riding model with isotropic thermal parameters fixed at 1.2 times the U_eq value of the appropriate carrier atom.

Crystal data for 11d (CCDC No. 841513)³⁰. C₂₇H₂₅BrN₂O₂, formula mass 489.40, Triclinic space group P1̄, a = 7.883(5), b = 11.024(5), c = 14.736(5) Å, α = 110.363(5), β = 96.456(5) γ = 104.041(5)° V = 1137.1(10) ų, Z = 2, d_calcd = 1.429 mg m⁻³, linear absorption coefficient 1.835 mm⁻¹, F(000) = 504, crystal size 0.25 × 0.20 × 0.15 mm, reflections collected 10 971, independent reflections 5316 [R_int = 0.0334], Final indices [I > 2σ(I)] R₁ = 0.0595 wR₂ = 0.1195, R indices (all data) R₁ = 0.1148, wR₂ = 0.1409, gof 0.970, Largest difference peak and hole 0.377 and −0.434 e Å⁻³.

Crystal data for 17a (CCDC No. 831581)³⁰. C₂₇H₂₄N₂O₃S, formula mass 456.54, Triclinic space group P1̄, a = 7.7227(6), b = 11.4586(9), c = 13.0552(11) Å, α = 78.782(4), β = 81.895(4) γ = 80.857(4)° V = 1111.55(15) ų, Z = 2, d_calcd = 1.364 mg m⁻³, linear absorption coefficient 0.179 mm⁻¹, F(000) = 480, crystal size 0.54 × 0.08 × 0.05 mm, reflections collected 15 809, independent reflections 4535 [R_int = 0.0949], Final indices [I > 2σ(I)] R₁ = 0.0653 wR₂ = 0.1539, R indices (all data) R₁ = 0.0929, wR₂ = 0.1666, gof 1.181, Largest difference peak and hole 0.448 and −0.455 e Å⁻³.

Computational details

Density functional theory (DFT) calculations have been performed using the Gaussian 03 program.³¹ The optimized ground and transition state geometries were calculated using the B3LYP exchange–correlation functional³² and using GDIIS algorithm.³³ The triple zeta 6-311+G* basis set for all atoms and tight SCF convergence criteria were used for the geometry optimization. For ground state optimization, wave function stability calculations were performed to confirm that the calculated wave functions corresponded to the ground state. The presence of one negative frequency was observed in the case of the transitions state geometries. The optimized ground state structures of the compounds were used for molecular orbital analyses and time-dependent DFT (TD-DFT) calculations at the B3LYP/6-311G** level of theory with the polarized continuum model (PCM).³⁴ The solvent parameters were those of the chloroform. The energies and intensities of the 30 lowest energy spin-allowed electronic excitations were calculated using TD-DFT. The intermolecular interaction energies have been estimated at the MP2 level of theory. For the interaction energy calculations, the Br⋯H distance has been fixed for the dimer while all other degrees of freedom were relaxed in the geometry optimization. The magnitude of energy corresponding to this dimer was substracted from twice the energy of monomer. The intermolecular interaction strengths are significantly weaker than either ionic or covalent bonding, therefore it was essential to do basis set superposition error (BSSE) corrections. The BSSE corrections in the interaction energies were done using Boys-Bernardi Scheme.³⁵ In this paper all interaction energies have been reported after BSSE correction.

Acknowledgements

HKM is thankful to DST, New Delhi, India for DST Fast Track Young Scientist Project.VJR is also thankful to UGC, New Delhi, India for Emeritus fellowship.

References

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Footnotes

† Electronic supplementary information (ESI) available: Perspective view of 11d and 17a showing absolute configuration, crystallographic information files (CIF) of spiranes 11d and 17a, Optimized cartesian coordinates for dimer, monomer for 11d and transition state coordinates for 17a and copies of HRMS and NMRs Spectra of all new compounds. CCDC reference numbers 831581 and 841513. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21587j

‡ Responsbile for Quantum Chemical Study.

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