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Synthesis 2010(21): 3649-3656  
DOI: 10.1055/s-0030-1258227
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Trapping the π-Allylpalladium Intermediate from Fulvene-Derived Azabicyclic Olefin with Soft Nucleophiles

Rani Rajan, Jubi John, Sreeja Thulasi, Nayana Joseph, K. V. Radhakrishnan*, R. C. Sawant
Organic Chemistry Section of Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (NIIST)-CSIR, Trivandrum 695 019, India
Fax: +91(471)2491712; e-Mail: radhupreethi@rediffmail.com;

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Publication History

Received 17 June 2010
Publication Date:
25 August 2010 (online)

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Abstract

A facile method for the synthesis of a new class of disubstituted alkylidenecyclopentenes has been introduced. The methodology involves the palladium-catalyzed ring opening of pentafulvene-derived bicyclic hydrazines with phenols and active methylene compounds, furnishing 1,4-disubstituted alkylidenecyclopentenes in good yield. The utility of multiple points of functionalization was effectively demonstrated by the synthesis of a substituted cyclopentanone and 2-hydrazinofulvene.

Key words

azabicyclic olefin - palladium - soft nucleophile - alkylidenecyclopentene - substituted cyclopentanone - 2-hydrazinofulvene

Cyclopentane derivatives are important synthons for a variety of natural products and biologically active molecules; [¹] hence the synthesis of substituted cyclopentanes has garnered a great deal of interest. [²] Among various substituted cyclopentanes, alkylidenecyclopentanes hold special attention as intermediates in the construction of biologically interesting molecules including (+)- and (-)-nigellamine A2, [³] guanacastepene A, [4] etc. The synthesis of (+)-allocyathin B2, which has interesting biological activity, by Trost and co-workers involves an alkylidenecyclopentenone as the key intermediate. [5] Some bioactive molecules containing the alkylidenecyclopentane core are shown in Figure  [¹] .

Figure 1 Bioactive molecules containing the alkylidenecyclopen­tane core

Various methods are known in the literature for the preparation of alkylidenecyclopentane derivatives. Trost has elegantly utilized trimethylenemethane chemistry for the synthesis of alkylidenecyclopentanes. [6] Other important strategies [7] towards the synthesis of alkylidenecyclopentanes involve the rhodium-catalyzed regioselective ring-expanding rearrangement of allenylcyclopropane, [8] catalytic enantioselective intramolecular Conia-Ene reaction of β-dicarbonyl compounds and alkynes, [9] and the stereoselective [3+2] cyclization of activated and deactivated allenes with alkenyl Fischer carbene complexes. [¹0] Recently, Shi et al. reported the synthesis of trans-substituted alkylidenecyclopentenes via the ring-opening rearrangement of methylenecyclopropyl-substituted alkenyl derivatives. [¹¹]

In the context of our general interest in pentafulvene-derived­ bicyclic hydrazines, we have unraveled a facile method for the construction of alkylidenecyclopentenes through palladium/Lewis acid catalyzed ring opening of fulvene-derived azabicyclic olefins with hard nucleophiles like organostannanes, [¹²] silanes, boronic acids, [¹³] and allylindium reagents. [¹4] All these reactions furnished trans-4,5-disubstituted 1-alkylidenecyclopent-2-ene derivatives. The reactivity of soft nucleophiles like phenols and active methylene compounds towards fulvene-derived­ azabicyclic olefins under palladium catalysis remained­ unexplored. Micouin and co-workers have reported­ the palladium-catalyzed ring opening of cyclopentadiene derived bicyclic olefins with soft nucleophiles towards the synthesis of cis-3,5-disubstituted cyclopentenes. [¹5] Herein we disclose a facile route towards cis-1,4-disubstituted 5-alkylidenecyclopent-2-enes and the synthetic transformations of the latter to functionalized cyclopentanones and substituted fulvenes.

Our studies started with the reaction of diethyl 7-(diphenylmethylene)-2,3-diazabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (1a) with 4-methoxyphenol (2a) in the presence of [Pd(allyl)Cl]2 (5 mol%), 1,1′-bis(diphenylphosphino)ferrocene (dppf, 10 mol%), and sodium hydride (1.0 equiv) in tetrahydrofuran at 60 ˚C. The reaction afforded the cis-1,4-disubstituted 5-alkylidenecyclopent-2-ene 3a in 43% yield (Table  [¹] , entry 1).

Detailed optimization studies were carried out to find the best condition for this transformation (Table  [¹] ). Among the different bases examined, potassium carbonate was found to be more proficient than sodium hydride and potassium tert-butoxide (entries 1-3). We then went on to optimize the palladium catalyst. The reactions with Pd2(dba)3˙CHCl3 and PdCl2(PPh3)2 afforded the product in only 38% and 21%, respectively (entries 5 and 6). The desired product 3a was isolated in 80% yield when the reaction was performed in presence of Pd(PPh3)4 (entry 8). However Pd(OAc)2 and PdCl2 gave only trace amounts of the expected product (entries 4 and 7). We then turned our attention to other parameters such as ligand and solvent. Ligands 1,2-bis(diphenylphosphino)ethane and triphenylphosphine were found to be less efficient compared to 1,1′-bis(diphenylphosphino)ferrocene (entries 8-10). In the case of solvents tested, tetrahydrofuran gave a superior result compared to acetonitrile and N,N-dimethyl­formamide (entries 11 and 12). It was interesting to observe an increase in yield to 96% when the reaction was performed at room temperature (entry 13). After the optimization studies, the best conditions for the reaction were found to be a 1:1.5 mixture of phenol 2a and bicyclic hydrazine 1a with Pd(PPh3)4 (5 mol%), 1,1′-bis(diphenylphosphino)ferrocene (10 mol%), and potassium carbonate (1.0 equiv) in dry tetrahydrofuran as solvent at room temperature.

Table 1 Optimization Studiesa

Entry Catalyst Ligand Base Solvent Yieldb (%)
 1 [Pd(allyl)Cl]2 dppf NaH THF 43
 2 [Pd(allyl)Cl]2 dppf K2CO3 THF 73
 3 [Pd(allyl)Cl]2 dppf t-BuOK THF 38
 4 Pd(OAc)2 dppf K2CO3 THF trace
 5 PdCl2(PPh3)2 dppf K2CO3 THF 21
 6 Pd2(dba)3˙CHCl3 dppf K2CO3 THF 38
 7 PdCl2 dppf K2CO3 THF trace
 8 Pd(PPh3)4 dppf K2CO3 THF 80
 9 Pd(PPh3)4 dppe K2CO3 THF 35
10 Pd(PPh3)4 PPh3 K2CO3 THF 42
11 Pd(PPh3)4 dppf K2CO3 MeCN 34
12 Pd(PPh3)4 dppf K2CO3 DMF 50
13 Pd(PPh3)4 dppf K2CO3 THF 96c
a Reaction conditions: alkene 1a (1.5 equiv), phenol 2a (1.0 equiv), catalyst (5 mol%), ligand (10 mol%) base (1.0 equiv), solvent (2 mL), 60 ˚C, 16 h.
b Isolated yield.
c Solvent (4 mL), r.t., 1.5 h.

The generality of the new ring-opening reaction was tested by repeating the reaction under the optimized condition with various phenols. Different fulvene-derived bicyclic adducts 1a-c were subjected to the desymmetrization with substituted phenols 2a-e. The results are summarized in Table  [²] .

This was further generalized with 6,6′-dialkylfulvene-derived­ bicyclic hydrazines (Table  [³] ). The adduct 4a was prepared from adamantanone-derived fulvene and 4b from cyclohexanone-derived fulvene, respectively.

We were then interested in extending our investigation to another class of soft nucleophile, namely active methylene compounds. We commenced our investigation with the reaction of dimethyl malonate (6a) with the bicyclic alkene 1a in presence of Pd(PPh3)4 as catalyst, 1,1′-bis(diphenylphosphino)ferrocene as ligand, and potassium carbonate as the base in tetrahydrofuran at room temperature. The reaction afforded the product 7a in 43% yield (Table  [4] , entry 1).

Table  [4] describes our effort towards optimizing different parameters. After the optimization studies, a combination of [Pd(allyl)Cl]2 (5 mol%), 1,1′-bis(diphenylphosphino)ferrocene (10 mol%), and sodium hydride (1.0 equiv) was found to be the best conditions for this transformation.

To explore the scope and generality of the method, the reaction was repeated using different fulvene-derived bicyclic hydrazines 1 and 4 and active methylene compounds 6. The results of the investigations are summarized in Table  [5] .

We propose a plausible mechanism for this trans­formation [¹6] that involves two stages, the initial one being the ring opening of the bicyclic alkene (Scheme  [¹] ). The first step of the catalytic cycle involves the formation of π-allylpalladium intermediate B by the attack of Pd(0) on the double bond (allylic species), and subsequent oxidative addition to C-N bond leading to the ring opening. In the second stage, the nucleophile regio- and stereospecifically attacks the π-allylpalladium species B thereby forming the intermediate C. The reason for the cis stereo­chemistry can be attributed to a classical mechanistic pathway involving a double inversion.

Scheme 1 Mechanistic rationale

To explore the synthetic utility of the synthesized alkylidenecyclopentenes and also to get further confirmation on the assigned structure, we carried out the hydrogenation of 7d over palladium on carbon; the reaction afforded the reduced product 8 in quantitative yield. When 8 was treated with a system consisting of ruthenium(III) chloride trihydrate and sodium periodate in acetonitrile-carbon­ tetrachloride-water (1:1:1 ), oxidative cleavage of the tetrasubstituted double bonds occurred furnishing the substituted cyclopentanone 9 in 74% yield (Scheme  [²] ). This reaction can be viewed as an alternative route to cis-α,α′-disubstituted cyclopentanones.

Table 2 Palladium-Catalyzed Reaction of Azabicyclic Olefins with Phenolsa
Entry Alkene
 Nucleophile
 Product
 Yield (%)
 1 1a

2a

3a

96
 2 1a

2b

3b

88
 3 1a

2c

3c

86
 4 1a

2d

3d

87
 5 1a

2e

3e

78
 6 1b

2a

3f

81
 7 1b

2b

3g

80
 8 1b

2c

3h

75
 9 1c

2a

3i

60
10 1c

2b

3j

55
a Reaction conditions: alkene 1 (1.5 equiv), phenol 2 (1.0 equiv), Pd(PPh3)4 (5 mol%), dppf (10 mol%), K2CO3 (1.0 equiv), r.t., 1.5 h.
Table 3 Palladium-Catalyzed Reaction of 6,6′-Dialkylidenefulvene-Derived Alkenes with Phenola
Entry Alkene
 Phenol
 Product
 Yield (%)
1 4a

2a

5a

76
2 4a

2b

5b

73
3 4b

2a

5c

78
a Reaction conditions: alkene 4 (1.5 equiv), phenol 2 (1.0 equiv), Pd(PPh3)4 (5 mol%), dppf (10 mol%), K2CO3 (1.0 equiv), r.t., 1.5 h.
Table 4 Optimization Studiesa

Entry Nucleophile Conditions Yieldb (%)
1 CH2(CO2Me) Pd(PPh3)4, dppf, K2CO3 43
2 CH2(CO2Me) Pd(PPh3)4, dppf, NaH 73
3 CH2(CO2Me) [Pd(allyl)Cl]2, dppf, NaH 93
a Reaction conditions: alkene 1a (1.5 equiv), phenol 6a (1.0 equiv), catalyst (5 mol%), dppf (10 mol%), base (1.0 equiv), THF (2 mL), r.t., 1.5 h.
b Isolated yield.

Scheme 2 Synthesis of substituted cyclopentanones

Our next attempt was to oxidize the substituted alkylidenecyclopentene to check whether these molecules could act as precursors for substituted fulvenes. When 3f was refluxed with three equivalents of chloranil in xylene, the reaction afforded the 2-hydrazino-substituted fulvene 10 in 74% yield (Scheme  [³] ).

Scheme 3 Synthesis of substituted fulvenes

In conclusion, we have introduced a facile route towards the synthesis of a new class of disubstituted alkylidenecyclopentenes. The products are obtained in good to excellent yields. The possibility for further functionalization was effectively demonstrated by the synthesis of substituted cyclopentanones and 2-hydrazinofulvenes. To the best of our knowledge this is the first report on the synthesis of 2-hydrazinofulvenes. Efforts for utilizing the developed methodology towards the synthesis of bioactive molecules will be reported in due course.

Table 5 Palladium-Catalyzed Reaction of Azabicyclic Olefins with Active Methylene Compoundsa
Entry Alkene
 Nucleophile
 Product
 Yield (%)
1 1a

6a

7a

93
2 1a

6b

7b

86b
3 1b

6b

7c

76b
4 4a

6a

7d

79
5 4a

6b

7e

70b
a Reaction conditions: alkene 1a,b or 4a (1.5 equiv), phenol 6a,b (1.0 equiv), [Pd(allyl)Cl]2 (5 mol%), dppf (10 mol%), NaH (1.0 equiv), r.t., 1.5 h.
b 60 ˚C.

All reactions were conducted in oven-dried glassware. Solvents used for the experiments were distilled or dried as specified. All reactions were monitored by TLC (silica gel 60 F254, 0.25 mm, Merck) until conversion was complete; visualization was effected with UV and/or by staining with enholm yellow or with basic KMnO4. Column chromatography used silica gel (100-200 mesh) eluting with petroleum ether (PE)-EtOAc mixtures. The solvents were removed using a Buchi E.L rotary evaporator. HPLC analyses were conducted with a LC9101 Recycling Preparative chromatograph. IR spectra were taken on a Nicolet impact 400d FT-IR spectrophotometer. NMR spectra were recorded at 300 and 500 MHz (¹H) and 75 and 125 (¹³C) MHz, respectively on a Bruker DPX-300 and -500 MHz FT-NMR spectrometer. NMR spectra were obtained using CDCl3 as the solvent with TMS as internal standard. Mass spectra were recorded by FAB ionization technique using a Jeol JMS 600H mass spectrometer.

Diethyl 1-[ cis -5-(Diphenylmethylene)-4-(4-methoxyphen­oxy)cyclopent-2-enyl]hydrazine-1,2-dicarboxylate (3a); Typical Procedure

Pd(PPh3)4 (46.0 mg, 0.04 mmol), dppf (44.4 mg, 0.08 mmol), and K2CO3 (111.8 mg, 0.81 mmol) were added to a Schlenk tube and placed under vacuum for 15 min. Freshly distilled THF (2 mL) was degassed and then added to the mixture at r.t.; the soln was stirred for 15 min. To the Schlenk tube was added 2a (100.0 mg, 0.81 mmol) and 1a (484.8 mg, 1.2 mmol) dissolved in THF (2 mL) and the soln was stirred at r.t. (TLC monitoring). The solvent was removed under reduced pressure and the residue was subjected to chromatography (silica gel, EtOAc-hexane, 40:60) to afford 3a (412 mg, 96%) as a light-brown powder; mp 122-124 ˚C; R f = 0.52 (EtOAc-hexane, 4:6).

IR (KBr): 3368, 2983, 2928, 1748, 1727, 1599, 1510, 1374, 1231, 1034, 763 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.35-7.28 (m, 3 H), 7.22-7.12 (m, 7 H), 6.68-6.62 (m, 4 H), 6.13-6.09 (m, 2 H), 5.88-5.82 (m, 1 H), 5.60 (s, 1 H), 5.11 (m, 1 H), 4.10-4.03 (m, 2 H), 3.84-3.83 (m, 2 H), 3.69 (s, 3 H), 1.19-1.16 (m, 3 H), 1.05-0.98 (m, 3 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.0, 155.1, 153.7, 149.6, 141.4, 140.0, 138.0, 133.6, 133.0, 132.1, 130.0, 129.4, 129.1, 128.0, 127.8, 124.7, 116.0, 78.3, 62.5, 62.1, 61.8, 55.6, 14.7, 14.4.

MS (FAB): m/z [M]+ calcd for C31H32N2O6: 528.23; found: 528.90.

5-(Diphenylmethylene)-4-(4-methylphenoxy) Diethyl Ester 3b

Light-brown powder; yield: 88%; mp 78-80 ˚C; R f = 0.62 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 3055, 2974, 2928, 1750, 1715, 1508, 1412, 1227, 1063, 930, 772 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.32-7.10 (m, 10 H), 6.94-6.93 (m, 2 H), 6.68-6.62 (m, 2 H), 6.16-6.08 (m, 2 H), 5.89-5.82 (m, 1 H), 5.61 (s, 1 H), 5.22-5.17 (m, 1 H), 4.06-4.01 (m, 2 H), 3.83-3.77 (m, 2 H), 2.21 (s, 3 H), 1.18-0.97 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 155.2, 154.7, 153.7, 141.3, 137.9, 133.7, 132.2, 129.9, 129.5, 129.3, 129.1, 128.0, 127.8, 124.7, 115.1, 79.4, 62.7, 62.3, 61.9, 21.0, 14.5, 14.4.

MS (FAB): m/z [M]+ calcd for C31H32N2O5: 512.23; found: 512.20.

5-(Diphenylmethylene)-4-phenoxy Diethyl Ester 3c

Light-brown powder; yield: 86%; mp 124-126 ˚C; R f = 0.62 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 3055, 2978, 2932, 1748, 1715, 1597, 1493, 1383, 1227, 1028, 966, 752 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 7.38-7.16 (m, 12 H), 6.95-6.90 (m, 1 H), 6.82-6.80 (m, 2 H), 6.25-6.21 (m, 2 H), 5.98-5.92 (m, 1 H), 5.72 (s, 1 H), 5.31 (m, 1 H), 4.12 (m, 2 H), 3.91 (m, 2 H), 1.23-1.09 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.9, 156.2, 154.7, 141.1, 140.3, 135.1, 134.9, 134.6, 134.3, 133.0, 132.6, 129.4, 128.6, 128.1, 127.6, 127.5, 127.3, 121.1, 116.1, 78.8, 62.6, 62.3, 61.7, 14.4, 14.2.

MS (FAB): m/z [M]+ calcd for C30H30N2O5: 498.22; found: 498.58.

4-(4-Bromophenoxy)-5-(diphenylmethylene) Diethyl Ester 3d

Light-brown powder; yield: 87%; mp 130-134 ˚C; R f = 0.62 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 3057, 2980, 2859, 1743, 1713, 1585, 1412, 1227, 1063, 930, 772 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.37-7.16 (m, 12 H), 6.72-6.66 (m, 2 H), 6.21-6.15 (m, 2 H), 5.97-5.91 (m, 1 H), 5.70 (s, 1 H), 5.28-5.25 (m, 1 H), 4.14-4.06 (m, 2 H), 3.95-3.90 (m, 2 H), 1.26-1.04 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.3, 156.1, 154.7, 147.0, 140.6, 140.1, 135.7, 135.1, 134.0, 133.5, 132.2, 131.9, 128.7, 128.5, 128.1, 127.8, 127.6, 127.5, 127.1, 117.8, 79.3, 63.6, 62.4, 62.2, 14.5, 14.2.

MS (FAB): m/z [M]+ calcd for C30H29BrN2O5: 576.13; found: 578.22 [M + 2].

5-(Diphenylmethylene)-4-(1-naphthyloxy) Diethyl Ester 3e

Brown powder; yield: 78%; mp 128-130 ˚C; R f = 0.60 (EtOAc-hexane, 4:6).

IR (KBr): 3364, 3053, 2982, 2930, 1750, 1719, 1595, 1489, 1381, 1231, 1061, 795, 754, 702 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 8.33 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.52-7.50 (m, 2 H), 7.42-7.38 (m, 5 H), 7.32-7.24 (m, 4 H), 7.00-6.98 (m, 3 H), 6.63 (d, J = 8.0 Hz, 1 H), 6.36 (br s, 1 H), 6.26 (m, 1 H), 6.07 (m, 1 H), 5.81 (s, 1 H), 5.52 (m, 1 H), 4.15-4.12 (m, 2 H), 3.97 (m, 2 H), 1.14-1.09 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.5, 156.1, 152.9, 141.1, 140.9, 140.3, 135.4, 134.7, 132.6, 132.1, 128.7, 128.5, 128.0, 127.8, 127.4, 126.2, 125.8, 125.6, 124.9, 122.9, 120.4, 106.3, 79.3, 63.7, 62.6, 61.9, 14.5, 14.3.

MS (FAB): m/z [M]+ calcd for C34H32N2O5: 548.23; found: 548.71.

5-(Diphenylmethylene)-4-(4-methoxyphenoxy) Diisopropyl Ester 3f

Light-brown powder; yield: 81%; mp 148-150 ˚C; R f = 0.54 (EtOAc-hexane, 4:6).

IR (KBr): 3323, 3053, 2980, 2934, 1742, 1713, 1466, 1385, 1225, 1036, 966, 826, 750 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.28-7.20 (m, 3 H), 7.18-7.10 (m, 7 H), 6.67-6.60 (m, 4 H), 6.41 (s, 1 H), 6.11-6.05 (m, 2 H), 5.87-5.82 (m, 1 H), 5.14-5.10 (m, 1 H), 4.86-4.82 (m, 1 H), 4.54-4.50 (m, 1 H), 3.68 (s, 3 H), 1.18-0.99 (m, 12 H).

¹³C NMR (125 MHz, CDCl3): δ = 155.6, 154.2, 153.9, 140.9, 140.3, 134.9, 134.8, 134.4, 134.0, 132.8, 128.7, 128.0, 127.5, 127.4, 127.3, 114.6, 79.9, 70.2, 69.5, 62.2, 55.3, 22.1, 21.9.

MS (FAB): m/z [M]+ calcd for C33H36N2O6: 556.26; found: 556.46.

5-(Diphenylmethylene)-4-(4-methylphenoxy) Diisopropyl Ester 3g

Light-brown powder; yield: 80%; mp 94-96 ˚C; R f = 0.48 (EtOAc-hexane, 4:6).

IR (KBr): 3325, 3054, 2980, 2939, 1748, 1715, 1612, 1508, 1491, 1468, 1385, 1229, 1036, 963, 752, 702 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.28-7.09 (m, 10 H), 6.94-6.92 (m, 2 H), 6.67-6.61 (m, 2 H), 6.40 (s, 1 H), 6.14-6.06 (m, 2 H), 5.88-5.82 (m, 1 H), 5.23-5.16 (m, 1 H), 4.83-4.82 (m, 1 H), 4.53-4.52 (m, 1 H), 2.21 (s, 3 H), 1.19-0.96 (m, 12 H).

¹³C NMR (125 MHz, CDCl3): δ = 155.7, 154.7, 153.5, 140.9, 132.6, 132.1, 130.2, 130.0, 129.7, 128.7, 128.0, 127.7, 127.4, 127.3, 124.6, 115.1, 79.4, 69.7, 69.4, 62.2, 22.0, 21.8, 20.5.

MS (FAB): m/z [M]+ calcd for C33H36N2O5: 540.26; found: 540.46.

5-(Diphenylmethylene)-4-phenoxy Diisopropyl Ester 3h

Light-brown powder; yield: 75%; mp 114-116 ˚C; R f = 0.43 (EtOAc-hexane, 4:6).

IR (KBr): 3325, 3054, 2980, 2939, 1748, 1715, 1612, 1508, 1491, 1468, 1385, 1229, 1109, 1036, 963, 752, 702 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.43-7.34 (m, 4 H), 7.29-7.15 (m, 8 H), 6.93-6.90 (m, 1 H), 6.85-6.80 (m, 2 H), 6.50 (s, 1 H), 6.24-6.12 (m, 2 H), 5.98-5.92 (m, 1 H), 5.34-5.28 (m, 1 H), 4.91-4.85 (m, 1 H), 4.63-4.59 (m, 1 H), 1.32-1.03 (m, 12 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.9, 155.7, 155.6, 140.9, 135.1, 134.5, 133.9, 132.5, 132.4, 129.2, 128.8, 128.7, 128.2, 128.0, 127.4, 121.0, 78.7, 69.6, 69.4, 62.2, 21.8, 21.7.

MS (FAB): m/z [M]+ calcd for C32H34N2O5: 526.25; found: 526.46.

5-(Diphenylmethylene)-4-(4-methoxyphenoxy) Di- tert -butyl Ester 3i

Light-brown powder; yield: 60%; mp 94-96 ˚C; R f = 0.35 (EtOAc-hexane, 4:6).

IR (KBr): 3333, 3057, 2978, 2932, 1748, 1711, 1504, 1393, 1368, 1238, 1157, 1032, 968, 752 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.34-7.12 (m, 10 H), 6.68-6.66 (m, 4 H), 6.35 (s, 1 H), 6.09-6.01 (m, 1 H), 5.84-5.80 (m, 1 H), 5.39 (m, 1 H), 5.09-5.06 (m, 1 H), 3.68 (s, 3 H), 1.34 (s, 9 H), 1.21 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 155.8, 155.1, 154.9, 141.1, 140.8, 135.0, 134.8, 132.4, 129.8, 129.7, 128.9, 128.8, 128.7, 128.0, 127.6, 127.4, 116.0, 80.8, 80.0, 61.8, 61.6, 55.6, 28.2, 28.1.

MS (FAB): m/z [M]+ calcd for C35H40N2O6: 584.29; found: 584.82.

5-(Diphenylmethylene)-4-(4-methylphenoxy) Di- tert -butyl Ester 3j

Light-brown powder; yield: 55%; mp 156-158 ˚C; R f = 0.54 (EtOAc-hexane, 4:6).

IR (KBr): 3337, 3050, 2984, 2938, 1752, 1717, 1506, 1389, 1371, 1226, 1148, 1031, 961, 751 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.44-7.34 (m, 3 H), 7.25-7.15 (m, 7 H), 7.03-7.00 (m, 2 H), 6.75-6.73 (m, 2 H), 6.48 (s, 1 H), 6.20-6.15 (m, 2 H), 5.96-5.88 (m, 1 H), 5.28-5.20 (m, 1 H), 2.28 (s, 3 H), 1.40 (s, 9 H), 1.28 (s, 9 H).

¹³C NMR (125 MHz, CDCl3): δ = 154.9, 154.8, 153.3, 141.0, 135.1, 135.0, 132.4, 132.2, 130.3, 129.8, 128.9, 128.7, 128.0, 127.7, 127.4, 116.6, 80.4, 79.1, 61.6, 28.2, 21.0.

MS (FAB): m/z [M]+ calcd for C35H40N2O5: 568.29; found: 569.01 [M + 1].

5-(Adamantan-2-ylidene)-4-(4-methoxyphenoxy) Diethyl Ester 5a

Light-green viscous liquid; yield: 76%; R f = 0.54 (EtOAc-hexane, 4:6).

IR (KBr): 3306, 3054, 2909, 2856, 1753, 1707, 1504, 1412, 1302, 1225, 1063, 955, 756 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 6.88-6.76 (m, 4 H), 6.57 (s, 1 H), 6.25-6.16 (m, 2 H), 5.87 (m, 1 H), 5.38 (m, 1 H), 4.21-4.19 (m, 2 H), 4.07-4.06 (m, 2 H), 3.77 (s, 3 H), 2.81-2.77 (m, 2 H), 1.95-1.92 (m, 12 H), 1.27-1.25 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.4, 155.8, 153.7, 135.1, 133.3, 130.1, 129.9, 121.9, 115.8, 77.7, 62.4, 61.7, 55.8, 40.2, 39.5, 38.5, 38.3, 36.8, 35.3, 34.8, 28.0, 14.7, 14.3.

MS (FAB): m/z [M]+ calcd for C28H36N2O6: 496.26; found: 496.32.

5-(Adamantan-2-ylidene)-4-(4-methylphenoxy) Diethyl Ester 5b

Light-green viscous liquid; yield: 73%; R f = 0.52 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 3057, 2916, 2850, 1758, 1714, 1502, 1414, 1302, 1225, 1063, 968, 750 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.07 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.54 (s, 1 H), 6.27-6.26 (m, 1 H), 6.17-6.16 (m, 1 H), 5.88 (m, 1 H), 5.44 (s, 1 H), 4.26-4.18 (m, 2 H), 4.05-4.04 (m, 2 H), 2.80-2.74 (m, 2 H), 2.29 (s, 3 H), 1.97-1.82 (m, 12 H), 1.60-1.26 (m, 4 H), 1.13-1.11 (m, 2 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.4, 155.8, 153.7, 135.1, 133.1, 130.0, 129.9, 121.9, 115.8, 77.6, 62.4, 61.7, 61.3, 40.2, 39.5, 38.5, 38.3, 36.8, 35.3, 34.8, 28.0, 20.5, 14.7, 14.3.

MS (FAB): m/z [M]+ calcd for C28H36N2O5: 480.26; found: 480.32.

5-Cyclohexylidene)-4-(4-methoxyphenoxy) Diethyl Ester 5c

Light-green viscous liquid; yield: 78%; R f = 0.72 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 3057, 2916, 2850, 1758, 1714, 1502, 1414, 1302, 1225, 1063, 968, 750 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 6.87-6.68 (m, 4 H), 6.41 (s, 1 H), 6.14-6.10 (m, 2 H), 5.77-5.71 (m, 1 H), 5.29 (s, 1 H), 4.17-4.15 (m, 2 H), 4.02 (m, 2 H), 3.70 (s, 3 H), 2.16 (m, 4 H), 1.56-1.53 (m, 6 H), 1.21-1.09 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 156.0, 155.7, 153.4, 132.8, 132.6, 127.1, 125.1, 124.8, 116.0, 64.9, 62.8, 61.8, 60.4, 55.6, 26.0, 25.9, 22.6, 22.2, 21.0, 14.6, 14.2.

MS (FAB): m/z [M]+ calcd for C24H32N2O6: 444.23; found: 445.03 [M + 1].

Diethyl 1-{ cis -4-[Bis(methoxycarbonyl)methyl]-5-(diphenyl­methylene)cyclopent-2-enyl}hydrazine-1,2-dicarboxylate (7a); Typical Procedure

[Pd(allyl)Cl]2 (14.6 mg, 0.04 mmol), dppf (44.4 mg, 0.08 mmol), and NaH (18.2 mg, 0.76 mmol) were added to a Schlenk tube and placed under vacuum for 15 min. Freshly distilled THF (2 mL) was degassed and then added to the mixture at r.t.; the soln was stirred for 15 min. 6a (100.0 mg, 0.76 mmol) and 1a (460.1 mg, 1.14 mmol) dissolved in THF (2 mL) were added and the mixture was stirred at r.t. (TLC monitoring). The solvent was removed under reduced pressure and the residue was subjected to chromatography (silica gel, EtOAc-hexane, 40:60) to afford 7a (377 mg, 93%) as a light-brown viscous liquid; R f = 0.57 (EtOAc-hexane, 4:6).

IR (KBr): 3317, 3049, 2981, 2940, 2900, 1730, 1720, 1601, 1489, 1370, 1216, 1061, 750, 705 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.35-7.20 (m, 10 H), 6.15-6.10 (m, 1 H), 5.90 (s, 1 H), 5.78 (m, 1 H), 4.46 (m, 1 H), 4.18-4.10 (m, 4 H), 3.67 (s, 6 H), 3.28 (m, 1 H), 1.26-1.10 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 168.7, 168.4, 156.5, 156.0, 141.0, 135.1, 134.8, 128.6, 128.1, 127.6, 127.4, 127.0, 126.7, 63.0, 61.7, 61.4, 53.4, 45.2, 28.3, 14.7, 14.5.

MS (FAB): m/z [M]+ calcd for C29H32N2O8: 536.22; found: 536.30.

4-[Bis(ethoxycarbonyl)methyl]-5-(diphenylmethylene) Diethyl Ester 7b

Viscous liquid; yield: 86%; R f = 0.50 (EtOAc-hexane, 4:6).

IR (KBr): 3324, 3046, 2975, 2936, 2910, 1730, 1722, 1584, 1493, 1368, 1223, 1061, 760, 705 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.35-7.13 (m, 10 H), 6.11 (m, 1 H), 5.89 (s, 1 H), 5.77 (m, 1 H), 4.45-4.40 (m, 1 H), 4.18-4.10 (m, 4 H), 3.93-3.89 (m, 2 H), 3.74 (m, 2 H), 3.28-3.22 (m, 1 H), 1.26-1.19 (m, 6 H), 1.05-0.96 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 168.4, 168.1, 156.4, 154.2, 144.5, 143.8, 142.0, 141.8, 141.3, 141.1, 135.4, 135.1, 135.0, 128.6, 127.0, 62.4, 61.7, 61.3, 53.1, 29.8, 14.5, 14.1.

MS (FAB): m/z [M]+ calcd for C31H36N2O8: 564.25; found: 564.93.

4-[Bis(ethoxycarbonyl)methyl]-5-(diphenylmethylene) Diisopropyl Ester 7c

Viscous liquid; yield: 76%; R f = 0.63 (EtOAc-hexane, 4:6).

IR (KBr): 3312, 3055, 2981, 2936, 2908, 1726, 1715, 1597, 1489, 1371, 1223, 1061, 754, 705 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.20-7.18 (m, 10 H), 6.14-6.08 (m, 1 H), 5.89-5.88 (m, 1 H), 5.80-5.70 (m, 1 H), 4.89-4.88 (m, 1 H), 4.54-4.40 (m, 2 H), 4.13 (m, 2 H), 3.94 (m, 2 H), 3.29-3.22 (m, 1 H), 1.21-0.83 (m, 18 H).

¹³C NMR (125 MHz, CDCl3): δ = 168.1, 167.7, 155.5, 153.6, 141.8, 141.2, 135.1, 134.7, 130.4, 128.7, 128.5, 128.3, 127.9, 127.2, 126.9, 126.6, 69.5, 69.3, 63.9, 61.1, 60.9, 45.4, 26.9, 22.1, 21.9, 14.0, 13.7.

MS (FAB): m/z [M]+ calcd for C33H40N2O8: 592.28; found: 592.93.

5-(Adamantan-2-ylidene)-4-[bis(methoxycarbonyl)methyl] Diethyl Ester 7d

Light-brown viscous liquid; yield: 79%; R f = 0.50 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 2980, 2907, 2849, 1728, 1711, 1694, 1504, 1412, 1306, 1219, 1061, 959, 812 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 6.05-6.01 (m, 1 H), 5.92 (s, 1 H), 5.79-5.76 (m, 1 H), 4.19-4.16 (m, 4 H), 3.92 (d, J = 9.0 Hz, 1 H), 3.75 (s, 6 H), 3.42-3.40 (m, 1 H), 2.79-2.75 (m, 1 H), 2.54-2.50 (m, 1 H), 1.92-1.80 (m, 12 H), 1.25 (s, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 168.9, 168.7, 156.0, 155.2, 150.8, 137.1, 130.5, 121.8, 62.4, 61.7, 57.4, 52.4, 44.9, 39.2, 38.8, 38.6, 36.7, 35.0, 34.5, 27.7, 14.6, 14.5.

MS (FAB): m/z [M]+ calcd for C26H36N2O8: 504.25; found: 505.05 [M + 1].

5-(Adamantan-2-ylidene)-4-[bis(ethoxycarbonyl)methyl] Diethyl Ester 7e

Viscous liquid; yield: 70%; R f = 0.63 (EtOAc-hexane, 4:6).

IR (KBr): 3311, 2975, 2910, 2849, 1730, 1715, 1698, 1510, 1414, 1306, 1225, 1064, 950, 754 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 6.07-6.04 (m, 1 H), 5.91 (s, 1 H), 5.79-5.76 (m, 1 H), 4.32-4.14 (m, 8 H), 3.93-3.91 (m, 1 H), 3.47-3.35 (m, 1 H), 2.80-2.77 (m, 1 H), 2.57-2.54 (m, 1 H), 1.94-1.62 (m, 12 H), 1.27-1.26 (m, 12 H).

¹³C NMR (125 MHz, CDCl3): δ = 168.7, 168.4, 155.9, 155.2, 150.7, 137.3, 130.2, 121.9, 62.8, 62.3, 61.6, 61.3, 57.8, 44.6, 39.2, 39.0, 38.7, 36.7, 34.9, 34.5, 27.7, 14.5, 14.0.

MS (FAB): m/z [M]+ calcd for C28H40N2O8: 532.28; found: 533.09 [M + 1].

Diethyl 1-{ cis -2-(Adamantan-2-ylidene)-3-[bis(methoxycarbonyl)methyl]cyclopentyl}hydrazine-1,2-dicarboxylate (8)

Compound 7d (300.0 mg, 0.60 mmol) was dissolved in anhyd EtOAc. 10% Pd/C (cat.) was added and the mixture was stirred under H2 (1 atm) at r.t. for 6 h (TLC monitoring). When the reaction was complete, the mixture was filtered through a pad of Celite. The solvent was removed under reduced pressure and the residue was subjected to chromatography (silica gel, EtOAc-hexane, 30:70) to afford 8 (300.0 mg, yield: 100%) as a colorless viscous liquid; R f = 0.51 (EtOAc-hexane, 4:6).

IR (KBr): 3312, 2978, 2907, 2849, 1732, 1697, 1616, 1416, 1384, 1220, 1126, 1061, 925, 758 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 4.25-4.11 (m, 5 H), 3.74 (s, 6 H), 3.50-3.40 (m, 2 H), 2.68-2.63 (m, 2 H), 2.52-2.50 (m, 1 H), 2.32-2.26(m, 1 H), 2.04 (m, 1 H), 1.81-1.56 (m, 14 H), 1.30-1.23 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 169.2, 168.4, 156.3, 155.2, 150.6, 128.3, 62.3, 61.8, 61.1, 53.6, 52.4, 40.8, 39.2, 38.4, 36.7, 35.2, 33.6, 29.6, 28.9, 22.5, 14.4, 14.2.

MS (FAB): m/z [M]+ calcd for C26H38N2O8: 506.26; found: 506.81.

Diethyl 1-{ cis -3-[Bis(methoxycarbonyl)methyl]-2-oxocyclopentyl}hydrazine-1,2-dicarboxylate (9)

Compound 8 (160.0 mg, 0.32 mmol) was dissolved in MeCN-CCl4 (1:1, 10 mL). NaIO4 (409.0 mg, 1.92 mmol) was added to the soln and the mixture was stirred. A soln of RuCl3 (7.8 mg, 0.03 mmol) in H2O (5 mL) was added in one portion and vigorous stirring was continued for 5 h. The mixture was diluted with H2O (10 mL), it was extracted with CH2Cl2 (3 × 20 mL), and the combined organic extracts were filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel, EtOAc-hexanes) afforded 9 (90.0 mg, 74%) as a colorless viscous liquid; R f = 0.65 (EtOAc-hexane, 4:6).

IR (KBr): 3308, 2984, 2957, 1744, 1713, 1506, 1435, 1415, 1383, 1228, 1161, 1059, 926, 762 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 4.21-4.10 (m, 4 H), 3.93-3.92 (m, 1 H), 3.77 (s, 6 H), 2.73 (m, 1 H), 2.45 (br s, 1 H), 2.22-2.05 (m, 2 H), 1.86-1.85 (m, 2 H), 1.28-1.26 (m, 6 H).

¹³C NMR (125 MHz, CDCl3): δ = 211.7, 168.5, 168.0, 156.3, 155.4, 62.9, 62.3, 60.4, 52.8, 29.7, 24.3, 22.0, 14.4, 14.2.

MS (FAB): m/z [M]+ calcd for C16H24N2O9: 388.15; found: 388.17.

Diisopropyl 1-[5-(Diphenylmethylene)cyclopenta-1,3-di­enyl}hydrazine-1,2-dicarboxylate (10)

Compound 3f (53.0 mg, 0.10 mmol) and chloranil (73.8 mg, 0.3 mmol) were dissolved in xylene and heated at 110 ˚C for 3 h. The solvent was removed under reduced pressure and the residue was subjected to chromatography (silica gel, EtOAc-hexane, 20:80) to afford 10 (30.0 mg, 74%) as a blood-red-colored viscous liquid; R f  = 0.39 (EtOAc-hexane, 4:6).

IR (KBr): 3312, 3055, 2981, 2936, 2908, 1726, 1715, 1597, 1489, 1371, 1223, 1061, 754, 705 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 7.36-7.24 (m, 10 H), 6.80-6.66 (m, 1 H), 6.40-6.39 (m, 1 H), 6.14-6.12 (m, 1 H), 4.90-4.83 (m, 2 H), 1.27-1.12 (m, 12 H).

¹³C NMR (125 MHz, CDCl3): δ = 155.9, 154.3, 141.5, 140.5, 138.0, 132.4, 131.8, 130.3, 129.1, 128.4, 127.8, 125.0, 124.2, 70.0, 69.7, 22.2, 22.0.

MS (FAB): m/z [M]+ calcd for C26H28N2O4: 432.20; found: 432.86.

Acknowledgment

Financial assistance from Department of Science and Technology (DST No: SR/S1/OC-78/2009) and Council of Scientific and Industrial­ Research, New Delhi are greatly acknowledged. R.R. acknowledges the Council of Scientific and Industrial Research (CSIR) for a senior research fellowship. The authors thank Dr. R. Luxmi Varma and Ms. S. Viji, Chemical Sciences and Technology Division, for NMR and mass spectral analysis.

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Figure 1 Bioactive molecules containing the alkylidenecyclopen­tane core

Scheme 1 Mechanistic rationale

Scheme 2 Synthesis of substituted cyclopentanones

Scheme 3 Synthesis of substituted fulvenes