Synthesis of Functionalized Indanes via Palladium-Catalyzed Carboannulation of Diazabicyclic Olefins with o-Iodostyrenes

Abstract

Palladium-catalyzed carboannulation of bicyclic and tricyclic hydrazines with substituted o-iodostyrenes produced functionalized indanes in good to excellent yields. The methodology provides an important carbocyclic ring system under relatively mild conditions.

Transition-metal-catalyzed annulation processes have proven to be a versatile route for the construction of complex cyclic systems.[1] The palladium-catalyzed annulation of alkenes,[2] alkynes[3] and arynes[4] with various substituted aryl and vinylic halides has been extensively studied by various groups. The reaction of o-iodostyrene with alkynes and norbornene was reported by Grigg and co-workers,[5] while the reactivity of o-iodostyrenes was efficiently utilized by Worlikar and Larock for the synthesis of substituted fluorenylidenes.[6] To the best of our knowledge, the reactivity of o-iodostyrenes towards diazabicyclic systems has not been investigated. Herein, we report the palladium-catalyzed reaction of o-iodostyrenes with diazanorbornene derivatives and with tricyclic olefins.

The reactivity of azabicyclic olefins with mono- and bicentered­ nucleophiles has been extensively studied.[7] [8] Desymmetrization of azabicyclic olefins utilizing monocentered nucleophiles results in the formation of either 3,4- or 3,5-disubstituted cyclopentenes. The heteroannulation and carboannulation of bicyclic hydrazines with various aromatic species having an ortho-bicentered reactive site, such as o-iodophenol, o-iodoaniline, o-iodobenzonitrile and 2-formylphenylboronic acids, enabled a novel and simple strategy for the synthesis of functionalized heterocycles and carbocycles.[9] [10] Our continued interest in the chemistry of bicyclic systems prompted us to carry out the reaction of various o-iodostyrenes with aza­bicyclic olefins. The results of our investigation are presented in this paper.

We initiated our studies with the reaction of diethyl 2,3-diazabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (1a) and ethyl 3-(2-iodophenyl)acrylate (2a) in the presence of Pd₂(dba)₃·CHCl₃, triphenylphosphine and triethylamine in acetonitrile at 85 °C for 12 hours. The reaction afforded the functionalized indane as two separable isomers, 3aa and 4aa, in 40% yield (Scheme [1]). The structures of the products were established using various spectroscopic techniques.

We carried out detailed optimization studies in order to establish the best catalyst system for the reaction. The results are summarized in Table [1].

Of the various palladium catalysts screened, palladium(II) acetate furnished the product in highest yield (Table [1], entry 2). Triphenylphosphine was found to be most proficient among the different ligands examined (Table [1], entries 2, 4 and 5). The use of toluene as solvent delivered the indane derivatives in only 42% yield (Table [1], entry 6). From the detailed optimization studies, a 1:1 mixture of ethyl 3-(2-iodophenyl)acrylate (2a) and diethyl 2,3-diazabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (1a) with palladium(II) acetate (5 mol%), triphenylphosphine (10 mol%) and triethylamine (2.0 equiv) in anhydrous acetonitrile medium at 85 °C were found to be the best conditions for the reaction.

Table 1 Optimization Studies^a

Entry	Catalyst	Ligand	Base	Solvent	Yield (%)
					3aa	4aa
1	Pd2(dba)3·CHCl3	Ph3P	Et3N	MeCN	30	10
2	Pd(OAc)2	Ph3P	Et3N	MeCN	65	23
3	[Pd(allyl)Cl]2	Ph3P	Et3N	MeCN	25	15
4	Pd(OAc)2	dppm	Et3N	MeCN	35	10
5	Pd(OAc)2	dppe	Et3N	MeCN	30	21
6	Pd(OAc)2	Ph3P	Et3N	toluene	25	17

^a Reaction conditions: 1a (1.0 equiv), 2a (1.0 equiv), catalyst (5 mol%), ligand (10 mol%), base (2.0 equiv), solvent (2 mL), 85 °C, 12 h.

With the optimal conditions in hand, the scope of the reaction was tested with various diazabicyclic olefins; all the bicyclic hydrazines produced functionalized indanes in excellent yield. Table [2] lists the results of the palladium-catalyzed reaction of diazabicyclic olefins 1a–d with ethyl 3-(2-iodophenyl)acrylate (2a).

Table 2 Reaction of Various Diazabicyclic Olefins with o-Iodostyrene 2a

Entry	Alkene	R	Product, yield
			3	4
1	1a	Et	3aa 65%	4aa 23%
2	1b	i-Pr	3ba 69%	4ba 28%
3	1c	t-Bu	3ca 65%	4ca 32%
4	1d	Bn	3da 74%	4da 22%

The reactivity of various o-iodostyrenes was also tested under the optimal conditions. o-Iodostyrenes with functional groups such as ester, nitrile and ketone on the double bond were exploited to check the generality of the reaction; all these o-iodostyrenes rendered the corresponding functionalized indanes in excellent yield (Table [3]). In the case of (2-iodophenyl)acrylates (Table [3], entries 3, 6 and 11) and 3-(2-iodophenyl)-1-phenylprop-2-en-1-one (Table [3], entries 1, 4, 7 and 9), the Z-isomer 3 was generally obtained as the major product, but the selectivity was found to be reversed with 3-(2-iodophenyl)acrylonitrile. Thus, high E-selectivity was observed with this 2-iodostyrene having a nitrile functional group (Table [3], entries 2, 5, 8 and 10).

Table 3 Palladium-Catalyzed Reaction of Diazabicyclic Olefins with Various o-Iodostyrenes

Entry	Alkene		o-Iodostyrene		Product, yield
	1	R1	2	R2	3	4
1	1a	Et	2b	COPh (E)	3ab 64%	4ab 33%
2	1a	Et	2c	CN (E)	3ac trace	4ac 69%
3	1a	Et	2d	CO2 t-Bu (Z/E)	3ad 61%	4ad 21%
4	1b	i-Pr	2b	COPh (E)	3bb 41%	4bb 42%
5	1b	i-Pr	2c	CN (E)	3bc trace	4bc 95%
6	1b	i-Pr	2d	CO2 t-Bu (Z/E)	3bd 63%	4bd 17%
7	1c	t-Bu	2b	COPh (E)	3cb 56%	4cb 40%
8	1c	t-Bu	2c	CN (E)	3cc trace	4cc 80%
9	1d	Bn	2b	COPh (E)	3db 75%	4db 20%
10	1d	Bn	2c	CN (E)	3dc trace	4dc 78%
11	1d	Bn	2d	CO2 t-Bu (Z/E)	3dd 40%	4dd 46%

The product 4bc was crystallized from ethyl acetate, and the structure and stereochemistry were unambiguously confirmed by single-crystal X-ray analysis (Figure [1]).[11] NOE experiments were also carried out to determine the geometry of the double bond in the products (Figure [2]). There was an NOE between the olefinic proton and the neighboring aromatic proton in the E-isomer 4ba, but no NOE was observed in the Z-isomer 3ba.

To further exploit the scope of the reaction, we extended our strategy to tricyclic and spirotricyclic olefins. The tricyclic hydrazine 1e delivered the products in lower yield than the spirotricyclic olefins 1f,g. This may be attributed to the low stability of the starting material under basic conditions.[12] The carboannulation of spirotricyclic olefins 1f,g with o-iodostyrenes having an ester functionality afforded the Z-isomer as the major product (Table [4], entries 3, 4 and 6). A reversal in the selectivity was observed when a keto functional group was present at the β-position to the aryl group (Table [4], entry 5). The same selectivity pattern was seen with the tricyclic hydrazine 1e (Table [4], entries 1 and 2).

Table 4 Palladium-Catalyzed Reaction of Tricyclic and Spirotricyclic Olefins with o-Iodostyrenes

Entry	Alkene	o-Iodostyrene	Product, yield
			3	4
1	1e		3ea 40%	4ea trace
2	1e		3eb trace	4eb 53%
3	1f		3fa 73%	4fa trace
4	1g		3ga 77%	4ga trace
5	1g		3gb 40%	4gb 56%
6	1g		3gd 68%	4gd 25%

Based on the results, we propose a plausible mechanism (Scheme [2]). The first step of the catalytic cycle involves the oxidative addition of palladium(0) to the aryl iodide to generate the arylpalladium species A. In the next step, syn addition of the arylpalladium species to the C–C double bond of the bicyclic hydrazine generates the intermediate B. Then, the palladium–carbon bond in this intermediate adds across the neighboring olefin to give intermediate C.[13] β-Hydride elimination from intermediate C results in the formation of the product.

Molecules containing an indane scaffold exhibit a wide range of biological activities,[14] and possess great interest as functional materials[15] as well as precursors of metallocene complexes for catalytic polymerization processes.[16] Functionalized indanes obtained from the palladium-catalyzed reaction can be further utilized for the synthesis of cyclopentane-fused diaminoindanes by N–N bond cleavage using platinum-catalyzed hydrogenation.[17] Two bioactive molecules containing an indane core are shown in Figure [3].

In conclusion, functionalized indanes were efficiently synthesized by the palladium-catalyzed carboannulation of o-iodostyrenes with diazabicyclic olefins. The reaction also proceeds smoothly with tricyclic and spirotricyclic olefins. A variety of functional groups, such as ester, ketone and nitrile, as substituents on the iodostyrenes were well tolerated in the reaction, indicating the synthetic potential of the product indanes for further transformations. Studies toward the synthesis of cyclopentane-fused diaminoindanes are under way and will be reported in due course.

All reactions were conducted in oven-dried glassware. Solvents used for the experiments were distilled or dried as specified. Progress of the reactions was monitored by thin-layer chromatography, which was performed on Merck precoated plates (silica gel 60 F₂₅₄, 0.25 mm) with visualization by fluorescence quenching under UV light or by staining with Enholm yellow. Column chromatography was done using 100–200 mesh silica gel and the appropriate mixture of hexane (60–80 °C) and EtOAc for elution. The solvents were removed using a Buchi rotary evaporator. IR spectra were recorded on a Bruker Alpha T FT-IR spectrophotometer. NMR spectra were recorded on Bruker Avance DPX 300 and AMX 500 FT-NMR spectrometers using CDCl₃ or, for ¹³C NMR, a CDCl₃–CCl₄ mixture (7:3) as solvent. TMS was used as an internal standard and chemical shifts are in the δ-scale. High-resolution mass spectra were recorded under EI-HRMS conditions (at 60000 resolution) using a Thermo Scientific Exactive mass spectrometer.

Indanes by the Reaction of Azabicyclic Olefins with o-Iodostyrenes; General Procedure

An azabicyclic olefin (50 mg, 1 equiv), an o-iodostyrene (1 equiv), Pd(OAc)₂ (5 mol%) and Ph₃P (10 mol%) were weighed in a Schlenk tube and placed under vacuum for 15 min. Et₃N (2 equiv) and MeCN (2 mL) were added to the tube, and the mixture was stirred at 85 °C for 12 h. The solvent was removed under reduced pressure and the residue was subjected to column chromatography (silica gel, EtOAc–hexane) to afford the functionalized indane in excellent yield.

Diethyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3aa)

Yellow viscous liquid; yield: 56 mg (65%); R_f  = 0.23 (EtOAc–hexane, 3:7).

IR (neat): 3327, 3064, 2956, 2925, 2856, 2311, 1746, 1709, 1625, 1596, 1462, 1374, 1317, 1196, 1164, 1126, 1100, 1028, 862, 766, 646 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.92 (d, J = 7.8 Hz, 1 H), 7.39–7.32 (m, 3 H), 6.04 (s, 1 H), 4.46 (br s, 2 H), 4.27–4.20 (m, 6 H), 3.62 (s, 1 H), 3.44 (s, 1 H), 1.59 (s, 1 H), 1.51 (m, 1 H), 1.37–1.25 (m, 9 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.9, 165.7, 157.4, 148.3, 138.8, 132.1, 129.2, 128.5, 124.9, 113.9, 65.1, 64.9, 63.3, 62.5, 60.1, 52.1, 48.3, 30.2, 14.6, 14.5, 14.4.

MS (FAB): m/z [M⁺] calcd for C₂₂H₂₆N₂O₆: 414.18; found [M⁺ + 1]: 415.39.

Diethyl (E)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4aa)

Yellow viscous liquid; yield: 20 mg (23%); R_f  = 0.15 (EtOAc–hexane­, 3:7).

IR (neat): 3322, 2924, 2857, 2383, 2348, 2313, 1745, 1593, 1462, 1368, 1118, 1036, 860, 780, 665, 611 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.55 (d, J = 7.8 Hz, 1 H), 7.39 (m, 2 H), 7.32–7.29 (m, 1 H), 6.36 (d, J = 2.1 Hz, 1 H), 4.91 (s, 1 H), 4.54 (s, 1 H), 4.31–4.29 (m, 6 H), 3.99 (s, 1 H), 3.74 (s, 1 H), 1.63 (br s, 2 H), 1.38–1.28 (m, 9 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.9, 165.9, 158.0, 146.8, 141.1, 131.5, 128.1, 125.3, 121.6, 110.9, 64.9, 63.9, 63.4, 63.2, 62.4, 60.2, 50.1, 49.3, 31.7, 14.5, 14.4, 14.3.

HRMS (ESI): m/z [M⁺] calcd for C₂₂H₂₆N₂O₆: 414.17909; found [M⁺ + 1]: 415.17912.

Diethyl (Z)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3ab)

Yellow viscous liquid; yield: 59 mg (64%); R_f  = 0.19 (EtOAc–hexane, 3:7).

IR (neat): 3294, 3060, 2957, 2925, 2855, 2381, 2310, 1743, 1700, 1655, 1594, 1455, 1400, 1373, 1316, 1252, 1228, 1165, 1124, 1100, 1018, 907, 857, 786, 751, 697, 645 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.02 (d, J = 8 Hz, 2 H), 7.59–7.56 (m, 1 H), 7.51–7.48 (m, 2 H), 7.41 (m, 2 H), 7.30–7.26 (m, 1 H), 7.06–7.02 (s, 1 H), 4.69–4.52 (m, 2 H), 4.29 (m, 4 H), 3.66–3.55 (m, 2 H), 1.55–1.49 (m, 2 H), 1.35 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 190.5, 156.3, 148.5, 138.8, 132.8, 131.9, 128.6, 128.3, 128.1, 62.5, 52.1, 49.0, 31.7, 14.6.

HRMS (ESI): m/z [M⁺] calcd for C₂₆H₂₆N₂O₅: 446.18417; found [M⁺ + 1]: 447.18432.

Diethyl (E)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4ab)

Yellow viscous liquid; yield: 31 mg (33%); R_f  = 0.13 (EtOAc–hexane, 3:7).

IR (neat): 3291, 3049, 2959, 2855, 2381, 2310, 1746, 1705, 1655, 1592, 1455, 1407, 1373, 1252, 1226, 1165, 1129, 1100, 1015, 907, 859, 761, 694, 645 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.05 (d, J = 7.5 Hz, 2 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.58–7.43 (m, 6 H), 7.36–7.33 (m, 1 H), 5.00–4.58 (m, 2 H), 4.27–4.16 (m, 5 H), 3.77 (br s, 1 H), 1.46–1.43 (m, 2 H), 1.34–1.26 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 189.0, 147.9, 141.8, 139.3, 132.4, 132.0, 128.6, 128.1, 125.7, 121.6, 113.6, 62.5, 62.4, 50.5, 48.1, 31.9, 14.6, 14.5.

MS (FAB): m/z [M⁺] calcd for C₂₆H₂₆N₂O₅: 446.18; found: 446.71.

Diethyl (E)-9-(Cyanomethylene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4ac)

Off-white solid; yield: 53 mg (69%); mp 136–139 °C; R_f  = 0.08 (EtOAc–hexane, 3:7).

IR (neat): 3311, 3048, 2955, 2922, 2854, 2211, 1714, 1597, 1460, 1375, 1251, 1125, 1101, 854, 787, 699, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.51–7.46 (m, 3 H), 7.36–7.30 (m, 1 H), 5.77 (d, J = 1.8 Hz, 1 H), 4.91 (s, 1 H), 4.67 (s, 1 H), 4.32–4.25 (m, 4 H), 3.78–3.69 (m, 2 H), 1.57–1.54 (m, 2 H), 1.40–1.25 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 163.6, 147.2, 139.4, 132.6, 128.6, 125.9, 121.7, 116.5, 88.8, 62.8, 62.1, 50.0, 31.9, 14.5.

HRMS (ESI): m/z [M⁺] calcd for C₂₀H₂₁N₃O₄: 367.15352; found: 367.15321.

Diethyl (Z)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3ad)

Yellow viscous liquid; yield: 56 mg (61%); R_f  = 0.31 (EtOAc–hexane, 3:7).

IR (neat): 3313, 2977, 2927, 2855, 1747, 1706, 1624, 1595, 1464, 1371, 1251, 1218, 1101, 1044, 1015, 985, 863, 798, 748, 698 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.86 (d, J = 7.8 Hz, 1 H), 7.36–7.26 (m, 3 H), 5.96 (s, 1 H), 4.43 (m, 2 H), 4.26 (m, 4 H), 3.56 (s, 1 H), 3.39 (s, 1 H), 1.53–1.24 (m, 17 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.8, 165.2, 157.6, 155.8, 148.1, 139.0, 131.3, 129.2, 128.0, 124.9, 116.1, 80.2, 65.1, 64.9, 63.4, 62.5, 52.0, 48.2, 31.6, 28.2, 14.6, 14.5.

HRMS (ESI): m/z [M⁺] calcd for C₂₄H₃₀N₂O₆: 442.21039; found [M⁺ + 1]: 443.21052.

Diethyl (E)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4ad)

Yellow viscous liquid; yield: 19 mg (21%); R_f  = 0.22 (EtOAc–hexane, 3:7).

IR (neat): 3305, 2955, 2923, 2854, 2312, 1742, 1704, 1628, 1597, 1459, 1371, 1254, 1146, 968, 853, 769, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.52 (d, J = 7.8 Hz, 1 H), 7.37 (m, 2 H), 7.30–7.24 (m, 1 H), 6.28 (d, J = 2.1 Hz, 1 H), 4.84 (s, 1 H), 4.52 (s, 1 H), 4.25 (m, 4 H), 4.01 (s, 1 H), 3.74 (br s, 1 H), 1.65 (m, 1 H), 1.56 (m, 10 H), 1.46–1.22 (m, 6 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 172.8, 165.5, 157.5, 146.7, 141.4, 131.4, 128.1, 125.3, 122.2, 116.0, 112.7, 80.6, 65.2, 63.3, 62.5, 62.3, 50.4, 49.2, 31.9, 28.2, 14.6, 14.4.

MS (FAB): m/z [M + Na]⁺ calcd for C₂₄H₃₀N₂NaO₆: 465.20; found: 465.31.

Diisopropyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3ba)

Yellow viscous liquid; yield: 57 mg (69%); R_f  = 0.3 (EtOAc–hexane, 3:7).

IR (neat): 2980, 2930, 1706, 1625, 1595, 1462, 1375, 1309, 1254, 1165, 1103, 1036, 972, 916, 856, 770, 665 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.91 (d, J = 7.8 Hz, 1 H), 7.38–7.12 (m, 3 H), 6.03 (s, 1 H), 5.01 (s, 2 H), 4.41 (m, 2 H), 4.23 (q, J = 9.3 Hz, 2 H), 3.59 (s, 1 H), 3.42 (s, 1 H), 1.71 (s, 1 H), 1.42–1.25 (m, 16 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 174.1, 165.8, 157.5, 148.5, 138.9, 131.6, 129.2, 128.1, 125.0, 113.8, 70.4, 70.2, 65.1, 64.7, 60.1, 52.0, 48.2, 31.5, 22.6, 22.0, 14.3.

HRMS (ESI): m/z [M⁺] calcd for C₂₄H₃₀N₂O₆: 442.21039; found [M⁺ + 1]: 443.21027.

Diisopropyl (E)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4ba)

Yellow viscous liquid; yield: 23 mg (28%); R_f  = 0.2 (EtOAc–hexane, 3:7).

IR (neat): 3325, 2979, 2929, 1706, 1631, 1599, 1462, 1373, 1306, 1258, 1166, 1103, 1043, 973, 914, 862, 769, 643 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.55 (d, J = 7.8 Hz, 1 H), 7.39 (s, 2 H), 7.31–7.27 (m, 1 H), 6.36 (d, J = 2.1 Hz, 1 H), 5.01–4.95 (m, 2 H), 4.91 (s, 1 H), 4.51 (s, 1 H), 4.30–4.28 (m, 2 H), 3.99 (s, 1 H), 3.71 (s, 1 H), 1.65 (s, 2 H), 1.42–1.26 (s, 15 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.9, 166.0, 157.9, 156.2, 146.9, 141.2, 131.5, 128.1, 125.3, 121.6, 110.8, 70.2, 69.8, 64.0, 63.3, 60.2, 50.3, 49.3, 31.9, 22.6, 21.9, 14.3.

MS (FAB): m/z [M⁺] calcd for C₂₄H₃₀N₂O₆: 442.21; found: 442.75.

Diisopropyl (Z)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3bb)

Yellow viscous liquid; yield: 36 mg (41%); R_f  = 0.29 (EtOAc–hexane, 3:7).

IR (neat): 3305, 3106, 3061, 2956, 2925, 2854, 2377, 2311, 1742, 1699, 1658, 1602, 1583, 1462, 1374, 1309, 1252, 1228, 1170, 1103, 1017, 973, 851, 786, 694, 646 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.02 (d, J = 7.2 Hz, 2 H), 7.59–7.46 (m, 5 H), 7.30–7.27 (m, 1 H), 7.00 (s, 1 H), 5.04 (s, 2 H), 4.66–4.50 (m, 2 H), 3.64 (m, 2 H), 1.70 (s, 1 H), 1.46–1.33 (m, 13 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 190.4, 157.3, 156.6, 148.7, 139.1, 138.6, 132.7, 132.3, 131.8, 128.5, 128.0, 125.1, 121.5, 119.0, 70.1, 64.7, 63.3, 52.2, 50.2, 29.6, 22.6, 22.0, 21.7.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₃₀N₂O₅: 474.21547; found [M⁺ + 1]: 475.21577.

Diisopropyl (E)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4bb)

Yellow viscous liquid; yield: 37 mg (42%); R_f  = 0.2 (EtOAc–hexane, 3:7).

IR (neat): 3308, 2959, 2918, 2854, 2319, 1740, 1693, 1656, 1600, 1585, 1464, 1374, 1253, 1227, 1160, 1108, 972, 857, 786, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.05 (d, J = 7.2 Hz, 2 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.56–7.43 (m, 5 H), 7.36–7.33 (m, 1 H), 7.22–7.16 (m, 1 H), 5.02 (m, 3 H), 4.57 (s, 1 H), 4.15 (s, 1 H), 3.77 (m, 1 H), 1.44–1.25 (m, 14 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 187.4, 155.1, 146.5, 140.4, 137.9, 137.3, 131.8, 131.4, 131.0, 127.2, 126.7, 126.5, 126.3, 124.2, 120.2, 112.3, 68.9, 63.8, 62.1, 49.0, 45.2, 30.6, 21.3, 20.6.

MS (FAB): m/z [M⁺] calcd for C₂₈H₃₀N₂O₅: 474.22; found: 474.53.

Diisopropyl (E)-9-(Cyanomethylene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4bc)

Yellow solid; yield: 70 mg (95%); mp 114–118 °C; R_f  = 0.14 (EtOAc­–hexane, 3:7).

IR (neat): 3308, 3045, 2980, 2931, 2210, 1742, 1619, 1464, 1372, 1311, 1255, 1165, 1102, 1006, 915, 830, 762, 698, 646 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.50–7.45 (m, 3 H), 7.35–7.26 (m, 1 H), 5.77 (s, 1 H), 5.04–4.98 (m, 2 H), 4.91 (s, 1 H), 4.64 (s, 1 H), 3.76–3.69 (m, 2 H), 1.53–1.50 (m, 1 H), 1.37–1.23 (m, 13 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 172.9, 163.3, 147.2, 139.4, 132.6, 128.5, 125.9, 121.6, 116.5, 88.7, 70.7, 70.2, 63.4, 61.6, 53.3, 49.9, 31.8, 22.7, 22.0, 21.9.

HRMS (ESI): m/z [M⁺] calcd for C₂₂H₂₅N₃O₄: 395.18451; found [M⁺ + 1]: 396.18486.

Diisopropyl (Z)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3bd)

Yellow viscous liquid; yield: 55 mg (63%); R_f  = 0.38 (EtOAc–hexane, 3:7).

IR (neat): 2975, 2925, 2858, 2366, 2334, 1746, 1592, 1473, 1403, 1371, 1313, 1262, 1120, 1039, 855, 777, 718, 664 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.85 (d, J = 7.8 Hz, 1 H), 7.36–7.14 (m, 3 H), 5.97 (s, 1 H), 5.02 (s, 2 H), 4.41 (m, 2 H), 3.57–3.39 (m, 2 H), 1.61–1.54 (m, 8 H), 1.41–1.31 (m, 15 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.8, 165.3, 155.9, 148.2, 139.0, 132.1, 131.3, 129.2, 128.2, 128.0, 125.3, 116.5, 80.3, 70.1, 65.0, 58.5, 51.9, 48.2, 31.6, 28.3, 26.9, 22.0.

MS (FAB): m/z [M + Na]⁺ calcd for C₂₆H₃₄N₂NaO₆: 493.23; found: 493.52.

Diisopropyl (E)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4bd)

Yellow viscous liquid; yield: 15 mg (17%); R_f  = 0.29 (EtOAc–hexane, 3:7).

IR (neat): 2957, 2924, 2855, 1739, 1698, 1594, 1460, 1371, 1257, 1118, 1040, 977, 853, 771, 699, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.52 (d, J = 7.5 Hz, 1 H), 7.37 (s, 2 H), 7.29–7.24 (s, 1 H), 6.28 (d, J = 2.1 Hz, 1 H), 5.01 (m, 2 H), 4.84 (s, 1 H), 4.49 (br s, 1 H), 4.00 (s, 1 H), 3.73 (br s, 1 H), 1.57 (m, 11 H), 1.42–1.26 (m, 12 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.0, 166.0, 161.7, 157.6, 146.8, 140.8, 131.6, 126.8, 126.2, 125.3, 117.0, 80.4, 70.3, 64.2, 61.7, 50.1, 48.7, 31.8, 28.3, 28.2, 22.7, 22.0.

HRMS (ESI): m/z [M⁺] calcd for C₂₆H₃₄N₂O₆: 470.24169; found [M⁺ + 1]: 471.24168.

Di-tert-butyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3ca)

Yellow viscous liquid; yield: 50 mg (65%); R_f  = 0.48 (EtOAc–hexane­, 3:7).

IR (neat): 3478, 3065, 2960, 2927, 2858, 1741, 1709, 1627, 1597, 1461, 1367, 1254, 1194, 1162, 1131, 1101, 1036, 965, 897, 859, 770, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.91 (d, J = 7.5 Hz, 1 H), 7.39–7.19 (m, 3 H), 6.05 (s, 1 H), 4.58–4.33 (m, 2 H), 4.26–4.19 (m, 2 H), 3.58–3.39 (m, 2 H), 1.71 (s, 1 H), 1.51–1.42 (m, 19 H), 1.36–1.25 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.5, 165.7, 157.7, 148.7, 138.9, 137.6, 131.5, 128.9, 128.1, 125.2, 113.8, 81.6, 81.3, 64.6, 63.6, 60.0, 51.9, 48.2, 31.5, 28.2, 14.3.

HRMS (ESI): m/z [M⁺] calcd for C₂₆H₃₄N₂O₆: 470.24169; found [M⁺ + 1]: 471.24829.

Di-tert-butyl (E)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4ca)

Yellow solid; yield: 24 mg (32%); mp 119–121 °C; R_f  = 0.39 (EtOAc­–hexane, 3:7).

IR (neat): 2976, 2929, 2381, 2311, 1706, 1630, 1598, 1457, 1366, 1338, 1257, 1161, 1101, 1042, 859, 770, 664, 611, 557 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.54 (d, J = 7.5 Hz, 1 H), 7.39 (s, 2 H), 7.31–7.21 (m, 1 H), 6.35 (s, 1 H), 4.87 (s, 1 H), 4.69–4.26 (m, 3 H), 3.98 (s, 1 H), 3.81–3.69 (m, 1 H), 1.65–1.34 (m, 23 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.6, 165.8, 156.4, 146.8, 140.8, 131.1, 127.6, 125.0, 121.2, 113.5, 80.9, 63.7, 62.9, 59.8, 49.8, 49.1, 31.5, 27.9, 27.7, 13.9.

MS (FAB): m/z [M + Na]⁺ calcd for C₂₆H₃₄N₂NaO₆: 493.23; found: 493.29.

Di-tert-butyl (Z)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3cb)

Yellow viscous liquid; yield: 48 mg (56%); R_f  = 0.45 (EtOAc–hexane­, 3:7).

IR (neat): 3553, 2924, 2856, 2385, 2347, 2310, 1737, 1593, 1461, 1421, 1367, 1317, 1258, 1123, 1040, 858, 779, 719 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.63 (s, 1 H), 8.04 (d, J = 6.9 Hz, 2 H), 7.59–7.41 (m, 5 H), 7.28–7.26 (m, 1 H), 7.03 (s, 1 H), 4.63–4.45 (m, 2 H), 3.66–3.53 (m, 2 H), 1.54–1.42 (m, 20 H).

¹³C NMR (125 MHz,CDCl₃–CCl₄): δ = 190.3, 156.8, 148.9, 139.1, 138.7, 132.7, 132.3, 131.8, 128.5, 128.0, 127.9, 125.5, 125.2, 125.0, 121.4, 119.6, 118.8, 113.5, 81.7, 81.4, 65.4, 64.3, 52.1, 48.3, 31.6, 28.2, 28.1.

MS (FAB): m/z [M + Na]⁺ calcd for C₃₀H₃₄N₂NaO₅: 525.24; found: 525.39.

Di-tert-butyl (E)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4cb)

Yellow solid; yield: 34 mg (40%); mp 95–99 °C; R_f  = 0.38 (EtOAc–hexane, 3:7).

IR (neat): 3305, 2924, 2853, 2310, 1736, 1694, 1658, 1592, 1454, 1365, 1338, 1251, 1136, 1083, 1016, 855, 754, 695, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.05–8.03 (m, J = 6.9 Hz, 3 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.56–7.44 (m, 5 H), 7.17 (m, 1 H), 4.50 (m, 2 H), 4.14 (s, 1 H), 3.76–3.52 (m, 1 H), 1.56–1.43 (m, 20 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 190.3, 156.8, 149.2, 148.1, 147.9, 146.3, 142.8, 142.1, 141.7, 133.1, 132.7, 132.3, 128.5, 128.0, 127.7, 127.6, 121.4, 113.5, 81.3, 64.5, 63.7, 52.0, 46.6, 31.5, 29.0, 28.1.

HRMS (ESI): m/z [M⁺] calcd for C₃₀H₃₄N₂O₅: 502.24677; found [M⁺ + 1]: 503.24696.

Di-tert-butyl (E)-9-(Cyanomethylene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4cc)

White solid; yield: 57 mg (80%); mp 178–181 °C; R_f  = 0.25 (EtOAc­–hexane, 3:7).

IR (neat): 3330, 3046, 2976, 2929, 2211, 1740, 1704, 1619, 1458, 1366, 1326, 1254, 1215, 1135, 1102, 1039, 1003, 968, 919, 887, 853, 760, 701, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.50–7.43 (m, 3 H), 7.33–7.31 (m, 1 H), 5.78 (s, 1 H), 4.84–4.48 (m, 2 H), 3.75–3.65 (m, 2 H), 1.57–1.41 (m, 20 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 163.6, 160.6, 155.2, 147.4, 139.5, 132.5, 128.5, 125.8, 121.6, 116.6, 88.5, 81.8, 71.0, 63.2, 63.0, 61.7, 50.8, 50.2, 31.8, 28.3, 28.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₉N₃NaO₄: 446.20558; found: 446.20547.

Dibenzyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3da)

Yellow viscous liquid; yield: 53 mg (74%); R_f  = 0.35 (EtOAc–hexane­, 3:7).

IR (neat): 3403, 3064, 3033, 2955, 2929, 1744, 1708, 1626, 1595, 1497, 1459, 1387, 1317, 1253, 1198, 1165, 1125, 1100, 1027, 911, 861, 743, 698, 648 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.90 (d, J = 7.8 Hz, 1 H), 7.33–7.14 (m, 13 H), 6.02 (s, 1 H), 5.22 (s, 4 H), 4.62–4.46 (m, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 3.56–3.36 (m, 2 H), 1.59 (s, 1 H), 1.50–1.46 (m, 1 H), 1.37–1.33 (m, 3 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 173.0, 165.7, 157.2, 148.3, 138.9, 136.0, 131.6, 129.3, 128.6, 128.3, 128.2, 128.0, 124.9, 114.2, 68.2, 60.1, 53.9, 49.2, 31.7, 14.4.

HRMS (ESI): m/z [M⁺] calcd for C₃₂H₃₀N₂O₆: 538.21039; found [M⁺ + 1]: 539.21051.

Dibenzyl (E)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4da)

Yellow viscous liquid; yield: 15 mg (22%); R_f  = 0.25 (EtOAc–hexane­, 3:7).

IR (neat): 3063, 3031, 2925, 2857, 2377, 2311, 1954, 1877, 1705, 1628, 1596, 1456, 1387, 1298, 1254, 1198, 1161, 1125, 1032, 862, 742, 697, 665, 609, 557 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.53 (d, J = 7.5 Hz, 1 H), 7.36–7.29 (m, 13 H), 6.35 (d, J = 2.1 Hz, 1 H), 5.23 (s, 4 H), 4.98 (s, 1 H), 4.55 (br s, 1 H), 4.24 (m, 2 H), 4.00 (s, 1 H), 3.67 (br s, 1 H), 1.60–1.43 (m, 2 H), 1.37–1.26 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.9, 165.6, 157.1, 148.2, 141.1, 138.8, 135.8, 131.6, 128.8, 128.5, 128.3, 128.1, 127.9, 125.3, 121.6, 113.9, 68.0, 65.1, 63.3, 60.1, 50.2, 49.4, 30.2, 14.3.

MS (FAB): m/z [M⁺] calcd for C₃₂H₃₀N₂O₆: 538.21; found [M⁺ + 1]: 539.98.

Dibenzyl (Z)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3db)

Brown viscous liquid; yield: 58 mg (75%); R_f  = 0.38 (EtOAc–hexane­, 3:7).

IR (neat): 3303, 3062, 3031, 2953, 2856, 2315, 1744, 1707, 1658, 1602, 1583, 1496, 1452, 1389, 1252, 1229, 1163, 1126, 1101, 940, 855, 751, 697, 648 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.62 (s, 1 H), 7.99 (s, 2 H), 7.71–7.69 (m, 1 H), 7.59 (t, J = 7 Hz, 1 H), 7.50 (t, J = 8 Hz, 2 H), 7.47–7.29 (m, 11 H), 7.19–7.16 (m, 1 H), 7.01 (m, 1 H), 5.24 (m, 4 H), 4.71–4.50 (m, 2 H), 3.66–3.52 (m, 2 H), 1.58–1.45 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 190.4, 168.4, 156.2, 148.5, 136.2, 136.0, 135.9, 133.2, 132.0, 128.6, 128.5, 128.3, 128.2, 128.1, 127.7, 125.1, 68.3, 68.0, 65.0, 63.2, 52.3, 46.5, 32.0.

HRMS (ESI): m/z [M⁺] calcd for C₃₆H₃₀N₂O₅: 570.21547; found [M⁺ + 1]: 571.21562.

Dibenzyl (E)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4db)

Brown viscous liquid; yield: 16 mg (20%); R_f  = 0.27 (EtOAc–hexane­, 3:7).

IR (neat): 3301, 3052, 3024, 2974, 2841, 2326, 1741, 1719, 1642, 1601, 1573, 1474, 1461, 1369, 1258, 1238, 1151, 1113, 1103, 956, 842, 768, 698, 664 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.03 (s, 2 H), 7.57–7.26 (m, 18 H), 5.23 (m, 4 H), 5.09 (br s, 1 H), 4.69–4.59 (m, 1 H), 4.19–4.14 (m, 1 H), 3.90–3.60 (m, 1 H), 1.54–1.44 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 190.9, 157.4, 156.6, 141.6, 139.2, 136.1, 135.7, 135.0, 132.7, 132.4, 131.9, 128.5, 128.4, 128.3, 128.1, 127.8, 121.1, 69.2, 67.9, 50.6, 46.4, 31.9.

HRMS (ESI): m/z [M⁺] calcd for C₃₆H₃₀N₂O₅: 570.21547; found [M⁺ + 1]: 571.21487.

Dibenzyl (E)-9-(Cyanomethylene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4dc)

Yellow solid; yield: 52 mg (78%); mp 156–158 °C; R_f  = 0.13 (EtOAc–hexane, 3:7).

IR (neat): 3581, 3288, 2924, 2855, 2379, 2210, 1744, 1597, 1459, 1418, 1384, 1256, 1119, 1020, 859, 751, 699, 646 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.49–7.26 (m, 14 H), 5.75 (s, 1 H), 5.27–5.16 (m, 4 H), 4.97 (s, 1 H), 4.66 (s, 1 H), 3.70 (m, 2 H), 1.64 (s, 1 H), 1.55–1.51 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃–CCl₄): δ = 163.5, 157.5, 147.0, 139.3, 135.9, 135.8, 132.6, 130.8, 128.5, 128.4, 128.2, 127.9, 125.8, 121.7, 116.5, 88.9, 68.2, 63.6, 62.0, 50.1, 32.1.

HRMS (ESI): m/z [M⁺] calcd for C₃₀H₂₅N₃O₄: 491.18451; found [M⁺ + 1]: 492.18470.

Dibenzyl (Z)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (3dd)

Yellow viscous liquid; yield: 31 mg (40%); R_f  = 0.38 (EtOAc–hexane­, 3:7).

IR (neat): 3056, 2956, 2925, 2854, 2313, 1739, 1706, 1624, 1456, 1388, 1251, 1146, 1022, 980, 860, 745, 695, 646 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.86 (d, J = 7.5 Hz, 1 H), 7.48–7.20 (m, 13 H), 6.39 (m, 1 H), 5.22 (s, 4 H), 4.45 (m, 2 H), 3.55 (m, 2 H), 1.54 (m, 11 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 174.0, 166.2, 165.2, 147.9, 134.6, 134.5, 132.1, 132.0, 131.8, 129.8, 128.5, 128.4, 128.3, 128.2, 128.0, 127.8, 127.6, 80.2, 70.2, 68.1, 65.1, 63.3, 52.8, 48.7, 31.9, 28.2.

MS (FAB): m/z [M + Na]⁺ calcd for C₃₄H₃₄N₂NaO₆: 589.23; found: 589.83.

Dibenzyl (E)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1,4-methano-1H-indeno[1,2-d]pyridazine-2,3-dicarboxylate (4dd)

Yellow viscous liquid; yield: 36 mg (46%); R_f  = 0.29 (EtOAc–hexane­, 3:7).

IR (neat): 3322, 2925, 2857, 1958, 1882, 1700, 1629, 1597, 1456, 1388, 1300, 1253, 1141, 1035, 911, 861, 761, 696, 609, 560 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.51 (d, J = 7.8 Hz, 1 H), 7.36–7.26 (m, 13 H), 6.27 (d, J = 2.1 Hz, 1 H), 5.22 (m, 4 H), 4.92 (s, 1 H), 4.53 (s, 1 H), 4.00 (s, 1 H), 3.65 (br s, 1 H), 1.58–1.50 (m, 11 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.0, 165.4, 157.3, 146.4, 141.2, 136.1, 135.8, 131.3, 128.3, 128.0, 127.9, 125.2, 121.5, 113.1, 80.6, 68.1, 67.8, 64.6, 63.0, 50.1, 48.9, 31.9, 28.1.

MS (FAB): m/z [M + Na]⁺ calcd for C₃₄H₃₄N₂NaO₆: 589.23; found: 589.33.

Ethyl (Z)-[2-(4-Methoxybenzyl)-1,3-dioxo-2,3,5,5a,10a,11-hexahydro-5,11-methanoindeno[1,2-d][1,2,4]triazolo[1,2-a]pyridazin-10(1H)-ylidene]acetate (3ea)

Brown viscous liquid; yield: 32 mg (40%); R_f  = 0.15 (EtOAc–hexane­, 3:7).

IR (neat): 3095, 2874, 2310, 1751, 1717, 1593, 1414, 1362, 1296, 1261, 1201, 1159, 1119, 1073, 1029, 958, 862, 816, 779, 723, 662 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.92 (d, J = 8.1 Hz, 1 H), 7.42–7.28 (m, 4 H), 7.21–7.13 (m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.09 (s, 1 H), 4.56 (m, 3 H), 4.47 (s, 1 H), 4.23 (q, J = 6.9 Hz, 2 H), 3.87 (s, 3 H), 3.63 (d, J = 6.6 Hz, 1 H), 3.42 (d, J = 6.6 Hz, 1 H), 1.36–1.26 (m, 5 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 165.5, 157.8, 157.6, 156.0, 155.0, 147.1, 138.7, 131.9, 130.5, 129.4, 128.5, 128.1, 124.9, 122.8, 114.9, 112.0, 64.5, 63.1, 60.2, 56.0, 52.0, 48.8, 42.4, 32.8, 29.7, 14.3.

MS (FAB): m/z [M⁺] calcd for C₂₆H₂₅N₃O₅: 459.18; found [M⁺ + 1]: 460.19.

(E)-2-(4-Methoxybenzyl)-10-(2-oxo-2-phenylethylidene)-5,5a,10a,11-tetrahydro-5,11-methanoindeno[1,2-d][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H,10H)-dione (4eb)

Brown viscous liquid; yield: 46 mg (53%); R_f  = 0.08 (EtOAc–hexane­, 3:7).

IR (neat): 3060, 2922, 2850, 2385, 2348, 2312, 1770, 1710, 1656, 1596, 1501, 1437, 1407, 1351, 1258, 1176, 1118, 1065, 1019, 956, 825, 753, 694, 611, 558 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.58 (d, J = 8.1 Hz, 1 H), 8.07–7.95 (m, 2 H), 7.58–7.40 (m, 6 H), 7.32–7.16 (m, 3 H), 7.04 (s, 1 H), 6.88–6.80 (m, 1 H), 4.58–4.54 (m, 4 H), 3.87 (s, 3 H), 3.68 (d, J = 6.9 Hz, 1 H), 3.54 (d, J = 6.6 Hz, 1 H), 1.64–1.61 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 190.5, 158.0, 157.8, 155.0, 154.8, 147.2, 139.0, 136.7, 133.3, 132.7, 132.2, 130.5, 128.3, 128.1, 128.0, 125.0, 122.7, 121.8, 120.2, 113.8, 112.1, 64.7, 63.2, 56.1, 52.4, 49.0, 42.5, 32.9, 29.7.

MS (FAB): m/z [M⁺] calcd for C₃₀H₂₅N₃O₄: 491.18; found [M⁺ + 1]: 492.19.

Diethyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (3fa)

Yellow viscous liquid; yield: 61 mg (73%); R_f  = 0.19 (EtOAc–hexane­, 3:7).

IR (neat): 3328, 2925, 2857, 2404, 2310, 1744, 1705, 1597, 1461, 1374, 1311, 1227, 1192, 1117, 1024, 857, 787, 700, 646 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 9.01 (d, J = 6.5 Hz, 1 H), 7.47–7.37 (m, 3 H), 6.04–6.00 (m, 1 H), 4.43–4.29 (m, 6 H), 4.23–4.18 (m, 1 H), 3.93–3.65 (m, 3 H), 1.46–1.35 (m, 10 H), 0.66–0.49 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.0, 166.1, 158.7, 149.2, 139.7, 131.7, 129.4, 128.3, 125.2, 114.3, 113.3, 68.3, 63.5, 63.2, 62.7, 60.4, 53.3, 49.7, 30.8, 15.0, 14.7, 6.8.

HRMS (ESI): m/z [M⁺] calcd for C₂₄H₂₈N₂O₆: 440.19474; found [M⁺ + 1]: 441.19493.

Diisopropyl (Z)-9-(2-Ethoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (3ga)

Yellow viscous liquid; yield: 62 mg (77%); R_f  = 0.29 (EtOAc–hexane­, 3:7).

IR (neat): 3066, 2980, 2933, 2875, 2372, 2344, 1743, 1709, 1697, 1467, 1375, 1305, 1195, 1178, 1141, 1030, 957, 916, 859, 834, 772, 721, 667, 608, 554 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 9.01 (s, 1 H), 7.47–7.38 (m, 3 H), 6.17 (m, 1 H), 5.13 (s, 2 H), 4.34–4.33 (m, 2 H), 4.22–4.19 (m, 1 H), 3.99–3.64 (m, 3 H), 1.46–1.40 (m, 15 H), 1.00–0.94 (m, 1 H), 0.67–0.52 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.0, 166.2, 146.4, 140.0, 131.6, 130.1, 129.4, 128.2, 126.7, 126.4, 125.9, 125.3, 120.2, 70.8, 70.3, 69.3, 60.4, 45.6, 30.1, 20.0, 19.6, 14.7, 6.8.

HRMS (ESI): m/z [M⁺] calcd for C₂₆H₃₂N₂O₆: 468.22604; found [M⁺ + 1]: 469.22609.

Diisopropyl (Z)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (3gb)

Brown viscous liquid; yield: 34 mg (40%); R_f  = 0.26 (EtOAc–hexane­, 3:7).

IR (neat): 2979, 2929, 2382, 1741, 1694, 1655, 1592, 1462, 1372, 1177, 1107, 919, 856, 775, 702, 665, 611, 557 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.67–8.61 (m, 1 H), 8.01 (d, J = 7 Hz, 2 H), 7.58–7.55 (m, 1 H), 7.50–7.47 (m, 3 H), 7.39 (m, 2 H), 7.28 (m, 1 H), 5.05 (m, 2 H), 4.17 (s, 1 H), 3.99–3.67 (m, 3 H), 1.32–1.25 (m, 12 H), 0.98–0.96 (m, 1 H), 0.64–0.40 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 189.0, 156.4, 148.1, 137.7, 134.0, 131.6, 131.3, 130.5, 127.5, 127.4, 127.0, 126.8, 123.9, 69.3, 68.9, 67.2, 52.8, 52.0, 48.3, 30.8, 21.6, 20.8, 5.5.

MS (FAB): m/z [M + Na]⁺ calcd for C₃₀H₃₂N₂NaO₅: 523.22; found: 523.19.

Diisopropyl (E)-9-(2-Oxo-2-phenylethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (4gb)

Brown viscous liquid; yield: 48 mg (56%); R_f  = 0.18 (EtOAc–hexane­, 3:7).

IR (neat): 3064, 2978, 2928, 2856, 1740, 1692, 1657, 1591, 1464, 1370, 1305, 1226, 1176, 1106, 1016, 956, 856, 831, 755, 696, 644 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.09 (m, 1 H), 7.96 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.56–7.41 (m, 5 H), 7.35–7.32 (m, 1 H), 7.22–7.15 (m, 1 H), 5.02 (m, 2 H), 4.14–3.75 (m, 3 H), 3.39–3.27 (m, 1 H), 1.33–1.24 (m, 12 H), 0.90–0.86 (m, 1 H), 0.48–0.28 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 188.4, 173.3, 165.4, 146.2, 141.1, 132.1, 131.3, 130.5, 127.5, 127.4, 127.0, 126.8, 126.6, 126.3, 120.3, 69.1, 68.4, 67.6, 52.2, 45.8, 30.9, 20.9, 20.8, 5.5.

HRMS (ESI): m/z [M⁺] calcd for C₃₀H₃₂N₂O₅: 500.23112; found [M⁺ + 1]: 501.23124.

Diisopropyl (Z)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (3gd)

Brown viscous liquid; yield: 57 mg (68%); R_f  = 0.33 (EtOAc–hexane­, 3:7).

IR (neat): 3272, 2977, 2928, 1736, 1694, 1593, 1463, 1376, 1310, 1229, 1120, 1027, 924, 858, 776, 719, 667, 613, 560 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.83 (s, 1 H), 7.35–7.29 (m, 3 H), 6.00 (m, 1 H), 5.04 (s, 2 H), 4.12–4.09 (br s, 1 H), 3.84–3.51 (m, 3 H), 1.54 (s, 9 H), 1.43–1.30 (m, 12 H), 0.98–0.96 (m, 1 H), 0.59–0.37 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 173.8, 164.3, 155.6, 147.6, 138.5, 129.9, 127.9, 126.8, 123.8, 79.1, 69.3, 68.9, 67.2, 52.4, 48.2, 29.7, 27.3, 21.1, 6.0.

MS (FAB): m/z [M + Na]⁺ calcd for C₂₈H₃₆N₂NaO₆: 519.25; found: 519.77.

Diisopropyl (E)-9-(2-tert-Butoxy-2-oxoethylidene)-4,4a,9,9a-tetrahydro-1H-spiro[1,4-methanoindeno[1,2-d]pyridazine-10,1′-cyclopropane]-2,3-dicarboxylate (4gd)

Brown viscous liquid; yield: 21 mg (25%); R_f  = 0.28 (EtOAc–hexane­, 3:7).

IR (neat): 3307, 2978, 2926, 2855, 1713, 1626, 1594, 1513, 1463, 1377, 1233, 1175, 1108, 1040, 930, 853, 765 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.52 (d, J = 7.5 Hz, 1 H), 7.35–7.34 (m, 2 H), 7.28–7.27 (m, 1 H), 6.26 (s, 1 H), 5.05 (m, 2 H), 4.29 (s, 1 H), 4.14 (s, 1 H), 3.98–3.87 (m, 2 H), 1.55 (s, 9 H), 1.33–1.28 (m, 12 H), 0.91–0.86 (m, 1 H), 0.51–0.33 (m, 3 H).

¹³C NMR (125 MHz, CDCl₃–CCl₄): δ = 171.7, 164.7, 157.5, 146.0, 140.9, 134.1, 130.1, 130.0, 127.2, 127.1, 126.8, 124.0, 120.3, 111.2, 79.6, 69.0, 68.6, 68.1, 66.7, 50.5, 49.1, 29.4, 27.1, 20.9, 5.5.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₃₆N₂O₆: 496.25734; found [M⁺ + 1]: 497.25746.

Acknowledgment

J.E. and P.P. thank CSIR for research fellowships. Financial assistance from the Department of Science and Technology (DST No: SR/S1/OC-78/2009, INT/FINLAND/P-01/1) and Council of Scientific and Industrial Research (12th FYP, ORIGIN-CSC-0108), New Delhi is greatly acknowledged. We also thank Mr B. Adarsh, Ms Saumini Mathew, Mr Saran P. Raveendran, Mr Preethanuj Preethalayam­ and Ms S. Viji for recording the NMR and mass spectra.

• References

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  CrossrefSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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• 11 The crystal data of compound 4bc have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 933876. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk] or via www.ccdc.cam.ac.uk/data_request/cif. Unit cell parameters: a = 9.619(3) Å, b = 9.894(3) Å, c = 12.357(3) Å, α = 94.787(4)°, β = 112.510(4)°, γ = 105.294(4)°, space group P 1.
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• 13 Henderson JL, Edwards AS, Greaney MF. Org. Lett. 2007; 9: 5589
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• 14 Korte A, Legros J, Bolm C. Synlett 2004; 2397; and references cited therein
• 15a Yang J, Lakshmikantham MV, Cava MP, Lorcy D, Bethelot JR. J. Org. Chem. 2000; 65: 6739
  CrossrefSearch in Google Scholar
• 15b Barbera J, Rakitin OA, Ros MB, Toroba T. Angew. Chem. Int. Ed. 1998; 37: 296
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• 17a Joseph N, Rajan R, John J, Devika NV, Sarath Chand S, Suresh E, Pihko PM, Radhakrishnan KV. RSC Adv. 2013; 3: 7751
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• 17b Bournaud C, Bonin M, Micouin L. Org. Lett. 2006; 8: 3041
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• References

• 1a Ojima I, Tzamarioudaki M, Li Z, Donovan RJ. Chem. Rev. 1996; 96: 635
  Search in Google Scholar
• 1b Rubin M, Sromek AW, Gevorgyan V. Synlett 2003; 2265
  Thieme Connect
• 1c Larock RC. Pure Appl. Chem. 1999; 71: 1435
  CrossrefSearch in Google Scholar
• 1d Larock RC In Topics in Organometallic Chemistry . Tsuji J. Springer; Berlin, Germany: 2005: 147
  Search in Google Scholar
• 2a Larock RC, Stinn DE. Tetrahedron Lett. 1988; 29: 4687
  CrossrefSearch in Google Scholar
• 2b Larock RC, Yang H, Weinreb SM, Herr J. J. Org. Chem. 1994; 59: 4172
  CrossrefSearch in Google Scholar
• 2c Larock RC, Yang H, Pace P, Narayanan K, Russell CE, Cacchi S, Fabrizi G. Tetrahedron 1998; 54: 7343
  Search in Google Scholar
• 2d Bertrand MB, Wolfe JP. Tetrahedron 2005; 61: 6447
  CrossrefSearch in Google Scholar
• 2e Wolfe JP, Rossi MA. J. Am. Chem. Soc. 2004; 126: 1620
  CrossrefPubMedSearch in Google Scholar
• 2f Lira R, Wolfe JP. J. Am. Chem. Soc. 2004; 126: 13906
  CrossrefPubMedSearch in Google Scholar
• 3a Larock RC. J. Organomet. Chem. 1999; 576: 111
  CrossrefSearch in Google Scholar
• 3b Larock RC. Palladium-Catalyzed Annulation. In Perspectives in Organopalladium Chemistry for the XXI Century . Tsuji J. Elsevier Press; Lausanne: 1999: 111
  Search in Google Scholar
• 3c Larock RC, Doty MJ, Cacchi S. J. Org. Chem. 1993; 58: 4579
  CrossrefSearch in Google Scholar
• 4a Worlikar SA, Larock RC. Curr. Org. Chem. 2011; 15: 3214; and references cited therein
  CrossrefSearch in Google Scholar
• 4b Pi S, Yang X, Huang X, Liang Y, Yang G, Zhang X, Li J. J. Org. Chem. 2010; 75: 3484
  CrossrefPubMedSearch in Google Scholar
• 4c Gerfaud T, Neuville L, Zhu J. Angew. Chem. Int. Ed. 2009; 48: 572
  CrossrefSearch in Google Scholar
• 4d Huang X, Sha F, Tong J. Adv. Synth. Catal. 2010; 352: 379
  CrossrefSearch in Google Scholar
• 5 Grigg R, Kennewell P, Teasdalea A, Sridharana V. Tetrahedron Lett. 1993; 34: 153
  CrossrefSearch in Google Scholar
• 6 Worlikar SA, Larock RC. Org. Lett. 2009; 11: 2413
  CrossrefSearch in Google Scholar
• 7a Storsberg J, Nandakumar MV, Sankaranarayanan S, Kaufmann DE. Adv. Synth. Catal. 2001; 343: 177
  CrossrefSearch in Google Scholar
• 7b Bournaud C, Chung F, Luna AP, Pasco M, Errasti G, Lecourt T, Micouin L. Synthesis 2009; 869
  Thieme Connect
• 7c Crotti S, Bertolini F, Macchia F, Pineschi M. Adv. Synth. Catal. 2009; 351: 869
  CrossrefSearch in Google Scholar
• 7d Martins A, Lemouzy S, Lautens M. Org. Lett. 2009; 11: 181
  CrossrefPubMedSearch in Google Scholar
• 7e Bournaud C, Falciola C, Lecourt T, Rosset S, Alexakis A, Micouin L. Org. Lett. 2006; 8: 3581
  CrossrefPubMedSearch in Google Scholar
• 7f Crotti S, Bertolini F, Macchia F, Pineschi M. Chem. Commun. 2008; 3127
• 7g Menard F, Lautens M. Angew. Chem. Int. Ed. 2008; 47: 2085
  CrossrefPubMedSearch in Google Scholar
• 8a Radhakrishnan KV, Sajisha VS, Anas S, Krishnan KS. Synlett 2005; 2273
  Thieme Connect
• 8b Sajisha VS, Mohanlal S, Anas S, Radhakrishnan KV. Tetrahedron 2006; 62: 3997
  CrossrefSearch in Google Scholar
• 8c Sajisha VS, Radhakrishnan KV. Adv. Synth. Catal. 2006; 348: 924
  CrossrefSearch in Google Scholar
• 8d John J, Sajisha VS, Mohanlal S, Radhakrishnan KV. Chem. Commun. 2006; 3510
• 8e Anas S, John J, Sajisha VS, John J, Rajan R, Suresh E, Radhakrishnan KV. Org. Biomol. Chem. 2007; 5: 4010
  CrossrefPubMedSearch in Google Scholar
• 8f John J, Anas S, Sajisha VS, Viji S, Radhakrishnan KV. Tetrahedron Lett. 2007; 48: 7225
  CrossrefSearch in Google Scholar
• 8g Anas S, Sajisha VS, John J, Joseph N, George SC, Radhakrishnan KV. Tetrahedron 2008; 64: 9689
  CrossrefSearch in Google Scholar
• 8h John J, Adarsh B, Radhakrishnan KV. Tetrahedron 2010; 66: 1383
  CrossrefSearch in Google Scholar
• 9a John J, Indu U, Suresh E, Radhakrishnan KV. J. Am. Chem. Soc. 2009; 131: 5042
  CrossrefPubMedSearch in Google Scholar
• 9b Bhanu Prasad BA, Buechele AE, Gilbertson SR. Org. Lett. 2010; 12: 5422
  CrossrefSearch in Google Scholar
• 10 Joseph N, John J, Rajan R, Thulasi S, Mohan A, Suresh E, Radhakrishnan KV. Tetrahedron 2011; 67: 4905
  CrossrefSearch in Google Scholar
• 11 The crystal data of compound 4bc have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 933876. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk] or via www.ccdc.cam.ac.uk/data_request/cif. Unit cell parameters: a = 9.619(3) Å, b = 9.894(3) Å, c = 12.357(3) Å, α = 94.787(4)°, β = 112.510(4)°, γ = 105.294(4)°, space group P 1.
• 12 Yao M.-L, Adiwidjaja G, Kaufmann DE. Angew. Chem. Int. Ed. 2002; 41: 3375
  CrossrefPubMedSearch in Google Scholar
• 13 Henderson JL, Edwards AS, Greaney MF. Org. Lett. 2007; 9: 5589
  CrossrefSearch in Google Scholar
• 14 Korte A, Legros J, Bolm C. Synlett 2004; 2397; and references cited therein
• 15a Yang J, Lakshmikantham MV, Cava MP, Lorcy D, Bethelot JR. J. Org. Chem. 2000; 65: 6739
  CrossrefSearch in Google Scholar
• 15b Barbera J, Rakitin OA, Ros MB, Toroba T. Angew. Chem. Int. Ed. 1998; 37: 296
  CrossrefPubMedSearch in Google Scholar
• 16 Alt HG, Koppl A. Chem. Rev. 2000; 100: 1205
  CrossrefPubMedSearch in Google Scholar
• 17a Joseph N, Rajan R, John J, Devika NV, Sarath Chand S, Suresh E, Pihko PM, Radhakrishnan KV. RSC Adv. 2013; 3: 7751
  CrossrefSearch in Google Scholar
• 17b Bournaud C, Bonin M, Micouin L. Org. Lett. 2006; 8: 3041
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material