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. 2022 Mar 3;41(5):649–658. doi: 10.1021/acs.organomet.2c00015

Synthesis of Benzofused O- and N-Heterocycles through Cascade Carbopalladation/Cross-Alkylation of Alkynes Involving the C–C Cleavage of Cyclobutanols

Marta Pérez-Gómez †, Piedad Herrera-Ramírez †, Delia Bautista ‡, Isabel Saura-Llamas †, José-Antonio García-López †,*
PMCID: PMC8925021  PMID: 35308581

Abstract

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We report a Pd-catalyzed route to heterocycles bearing a tetrasubstituted alkene fragment. Our approach merges the intramolecular carbopalladation of tethered alkynes with an alkylation step produced by the C–C cleavage of cyclobutanol derivatives. An alkenyl-Pd(II) intermediate has been isolated and characterized by X-ray diffraction studies. Interestingly, the nature of the tethering alkynyl chain influences the E/Z stereochemistry of the alkenyl fragment in the functionalized heterocycles.

Introduction

The development of Pd-catalyzed cascade reactions based on the carbopalladation of alkynes has become a direct entry to the synthesis of substituted alkenes.1−9 Such reactions have been performed in either intra- or intermolecular fashion, with the resulting alkenyl-Pd intermediate being coupled afterward with different species, such as boronic acids,10−12 organotin reagents,13−18 and C-,19N-,20,21 and O-nucleophiles,22 among many others (a, Scheme 1).23−28

Scheme 1. Merger of Carbopalladation of Alkynes and C–C Cleavage of Cycloalkanols.

Scheme 1

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Parallel studies have demonstrated the ability of Pd to perform the opening of strained cycloalkanols through β-carbon elimination (b, Scheme 1).29,30 This process leads to a σ-alkyl-Pd(II) intermediate, which can evolve in different manners, depending on the substitution pattern of the cycloalkanol.31−37 For instance, they can participate in further intramolecular steps, or be cross-coupled with aryl-,38−42 alkenyl-,43,44 and alkynylhalides,45 or propargylcarbonates,46 among others.29,47,48 Therefore, cyclopropyl- or cyclobutyl alcohols can behave as alkylating reagents under the appropriate conditions.

The merging of both aspects of palladium chemistry (carbopalladation/alkylation via opening of cycloalkanols) has rarely been reported in the literature. Werz et al. disclosed an interesting cascade reaction relying on the formal anti-carbopalladation of an internal alkyne, evolving through further intramolecular trapping of the alkenyl-Pd(II) intermediate by a tethered cyclopropanol moiety (c, Scheme 1).49 Very recently, Murakami, Chen, and co-workers reported the synthesis of 2,3-dihydrobenzofurans through the use of alkenyl-tethered aryliodides and benzocyclobutanols (d, Scheme 1).50,51

With these precedents in mind, and given our interest in the topics of Pd chemistry and the processes related to C–C cleavage,52−57 we aimed to extend the applicability of these types of cascades to the synthesis of heterocycles bearing an alkylated olefine moiety (Scheme 1).

Results and Discussion

We studied the feasibility to perform the envisioned carbopalladation/alkylation cascade reaction employing the 2-bromoarylether 1a and the cyclobutanol derivative 2a (Table 1). Initial screening of experimental conditions revealed the formation of some amounts of the byproduct 4a, likely arising from the protodepalladation of the plausible alkenyl-Pd(II) intermediate generated upon the carbopalladation of the internal alkyne moiety. The use of 10 mol% of [Pd(dba)2] along with 20 mol% of PPh3 showed good selectivity to give the desired compound 3a in THF or toluene as solvents (entries 3 and 4, Table 1). Replacing PPh3 by other ligands such as JohnPhos, PCy3, or Xantphos did not improve the yields of 3a (entries 5–7, Table 1). The increase of the amount of Cs2CO3 in the reaction mixture could not suppress the protodepalladation process leading to the byproduct 4a, and other organic bases like NEt3 precluded the formation of 3a. We tested Pd sources like Pd(OAc)2, [PdCl2(PPh3)2], and [Pd(PPh3)4]. While the first two were not effective for this transformation, [Pd(PPh3)4] showed a comparable activity to [Pd(dba)2], reaching a 70% yield of the desired product.

Table 1. Optimization of the Carbopalladation/Alkylation Cascadea.

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entrya Pd source (10 mol %) ligand (20 mol %) solvent yield 3ab
1 [Pd(dba)2] PPh3 1,2-DCE traces
2 [Pd(dba)2] PPh3 1,4- dioxane traces
3 [Pd(dba)2] PPh3 THF 62
4 [Pd(dba)2] PPh3 toluene 68
5 [Pd(dba)2] JohnPhos toluene –
6 [Pd(dba)2] PCy3 toluene 60
7 [Pd(dba)2] Xantphos toluene 32
8 [Pd(OAc)2] PPh3 toluene traces
9 [PdCl2(PPh3)2] – toluene traces
10 [Pd(PPh3)4] – toluene 70 (67)c
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a

The reactions were carried out using 0.14 mmol of 1-bromo-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a), 1.2 equiv of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a), and 1.2 equiv of Cs2CO3 in 4 mL of dry solvent, under nitrogen atmosphere at 100 °C, in a Carius tube for 16 h.

b

NMR yields using trimethylbenzene-1,3,5-tricarboxylate as standard.

c

Isolated yield.

With the optimized conditions in hand, we proceeded to study the scope and limitations of the reaction. Several aspects were assessed: the presence of electron-donating/withdrawing groups in the haloaryl moiety, the nature and length of the chain tethering the internal alkyne, and the use of different substituted cyclobutanols.

The reactions of haloaryl ethers bearing methyl, methoxy, fluoro, or trifluoromethyl substituents with the 3,3-substituted cyclobutanol 2a afforded good yields of the expected dihydrobenzofuran derivatives 3b–3e (Scheme 2). The pyridine derivative 1g gave rise to the heterocycle 3f, albeit in moderate yield, perhaps due to competing coordination of the pyridine moiety to Pd(II). C3-unsubstituted cyclobutanol derivatives 2 were also productive in the cascade reaction, giving the functionalized dihydrobenzofuran derivatives 3g–j in comparable yields to those obtained with 2a (Scheme 2); therefore, the possible byproduct formation arising from β-H elimination processes seem to be overridden. The cyclobutanol derivative bearing a mesityl group in α-position led to mixtures where the desired compound 3k could not be identified. The compound 3l could be isolated in 44% yield from the reaction carried out employing the tertiary cyclobutanol bearing an i-Pr group.

Scheme 2. Scope of the Carbopalladation/Alkylation Cascade for the Synthesis of Dihydrobenzofurane Derivatives.

Scheme 2

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Finally, the cross-coupling reactions of 2b and Me- or TMS-substituted alkynyl substrates were tested. We observed that among such substrates, only the silylated alkyne was competent to deliver the desired product 3m in 56% yield (Scheme 2). Possibly, the substrate leading to 3n could experience a β-H elimination upon the carbopalladation step to render an allenyl moiety, as described in other Pd-catalyzed reactions dealing with alkyl-substituted alkynes.58,59

In order to assess the stereochemistry of the exocyclic double bond present in the dihydrobenzofuran cores, a NOESY NMR experiment was carried out for compound 3d. The NOE contacts between the methylene group CH2c and the o-H atoms from the Ph ring, as well as the Ha of the heterocycle with the CH2b group of the aliphatic chain, pointed out the Z-stereochemistry for these compounds (Scheme 3).

Scheme 3. Selected NOE Contacts Observed for Dihydrobenzofurane and Oxindole Derivatives.

Scheme 3

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As a general feature of compounds 3a–3m, we observed their relative sensitivity to chromatography purification in either silica gel or alumina. The decomposition of the compounds could be minored by using silica gel previously deactivated with Et3N, and Et3N/hexane/EtOAc mixtures as eluents. Solutions of these compounds in CDCl3 also evolved to more complex mixtures over time (see the Supporting Information). The instability of these compounds might be due to the migration of the exocyclic double bond to form benzofuran derivatives, a process that could be catalyzed by Lewis acids.60

We examined the influence of the length and nature of the chain linking the 2-haloryl and alkyne fragments. The alkenylated indoline derivative 3o was obtained in good yield from the corresponding amine precursor (Scheme 4). Nevertheless, no desired product 3p was produced from the related ester starting material. Substrates with one extra carbon atom in the chain reacted smoothly under the optimized conditions to produce the six-membered heterocycles 3q and 3r. The 1H NMR of the crude reaction mixture arising from N-(2-bromo-phenyl)-N-methyl-3-phenylpropiolamide showed the formation of the corresponding coupling product 3s as the main component, which could be isolated in 58% yield (Scheme 5). Similarly, the oxindole derivatives 3t and 3u could be isolated in moderate yields from the reactions of the corresponding propiolamides and the C3-unsubstituted cyclobutanol 2b. The 1H NMR spectra of compounds 3s–u showed an aromatic signal belonging to the oxindole core at a relatively low chemical shift (5.8–6.0 ppm). This shielding on Ha (compound 3u, Scheme 3) is provoked by the phenyl ring on the exocyclic olefine moiety, as observed in related structures reported in the literature.23,61,62 In addition, the NOESY NMR analysis of 3u also confirmed the E-stereochemistry of the exocyclic double bond. The presence of minor Z-stereoisomers in the reaction mixtures leading to 3s–u cannot be discarded; however, we were unable to isolate such minor components of the crude mixtures and identify their nature unambiguously.

Scheme 4. Scope of the Carbopalladation/Alkylation Cascade Varying the Nature of the Linking Chain.

Scheme 4

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Scheme 5. Use of Propiolamide Substrates.

Scheme 5

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The plausible mechanistic pathway for this reaction is depicted in Scheme 6. The aryl-Pd species A would form upon oxidative addition of the C–Br bond present in the starting material 1a to Pd(0) (Chart 1). Next, the intramolecular syn carbopalladation of the tethered alkyne would render the intermediate B. At this stage, Cs2CO3 would assist the deprotonation of the cycloalkanol, along with the removal of the halogen ligand from the coordination sphere, allowing the formation of the alkoxide complex C. The opening of the strained cycloalkanol through β-C cleavage would render the σ-alkyl-Pd(II) intermediate D, from which reductive elimination could take place to deliver the substituted olefin 3a upon C(sp2)–C(sp3) bond formation.

Scheme 6. Proposed Reaction Mechanism.

Scheme 6

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Chart 1. Structure and Numbering of the Staring Materials 1.

Chart 1

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The fact that propiolamide substrates afford the E-alkenylated oxindoles 3s–u as main coupling products reveals that in those cases the alkenyl-Pd(II) intermediate, arising from the syn carbopalladation step, could undergo an isomerization process. There are several precedents in the literature of related Pd-catalyzed cascade reactions involving the syn carbopalladation of alkynes and subsequent isomerization prior to the final C–Pd bond functionalization.14,22,25,63−67 Generally, the isomerization of the alkenyl-Pd intermediates is driven by steric factors. Nevertheless, α-alkyl-substituted alkynyl substrates, such as 1a, require the use of bulky phosphine ligands (Q-Phos, X-Phos, or PtBu3 among others) to increase the steric hindrance around the Pd center and therefore promote the isomerization.25,63,64 In the case of α-acyl-substituted alkynyl substrates, such as propiolamides 1m–o, the isomerization is a frequent feature in a range of different conditions, probably due to the conjugation of the alkenyl-Pd moiety and the carbonyl group, which might lower the energy barrier for the C–C rotation process (Scheme 6).28,62,68,69 Likely the coordination of the carbonyl moiety might facilitate such processes. Nevertheless, the opposite isomerization has been observed in related systems (that is, the steric factors seemed to predominate over the possible coordination of the carbonyl group in intermediates such as E).68,69

We carried out the reaction of substrate 1b with a stoichiometric amount of [Pd(PPh3)4] in CH2Cl2 at 50 °C for 18 h under N2 atmosphere (Scheme 7). From the reaction mixture, the vinyl-Pd(II) complex 4 (analogous to the intermediate B) could be isolated in 84% yield. The complex 4 was subsequently heated in toluene at 100 °C in the presence of cyclobutanol 2a and Cs2CO3. The 1H NMR spectra of the crude reaction mixture confirmed the formation of the functionalized dihydrobenzofuran 3a in 70% yield.

Scheme 7. Synthesis of Intermediate B.

Scheme 7

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The crystal structure of complex 4 was solved by X-ray diffraction studies (Figure 1, Chart 2). The PPh3 ligands adopted a trans disposition. The palladium atom was in a slightly distorted square-planar environment, with a mean deviation of the Pd(II) coordination plane of 0.088 Å. The exocyclic double bond exhibited a E geometry, with the phenyl ring located cis to the methylene group of the dihydrobenzofuran ring. The heterocyclic nucleus formed angles of 38.1° and 77.1° with the phenyl substituent at the double bond and the Pd(II) coordination plane, respectively. This way, the phenyl ring was rotated 23.3° with respect to the exocyclic double bond plane.

Figure 1.

Figure 1

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Thermal ellipsoid plot (50% probability) of complex 4 along with the labeling scheme. The hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angles (deg): Pd(1)–I(1) = 2.6995(4), Pd(1)–P(1) = 2.3376(8), Pd(1)–P(2) = 2.3501(9), Pd(1)–C(1) = 2.051(4), C(1)–C(2) = 1.339(5), C(1)–C(11) = 1.505(5); I(1)–Pd(1)–P(1) = 90.85(2), P(1)–Pd(1)–C(1) = 89.59(10), C(1)–Pd(1)–P(2) = 89.91(10), P(2)–Pd(1)–I(1) = 90.15(2), C(2)–C(1)–Pd(1) = 123.4(3), C(2)–C(1)–C(11) = 122.9(3), C(11)–C(1)–Pd(1) = 113.7(2).

Chart 2. Structure and Numbering of the Intermediate Complex 4.

Chart 2

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Conclusion

In summary, we have expanded the versatility of Pd cascades relying on intramolecular carbopalladation processes through its merging with the opening of strained cycloalkanols. Thus, the carbopalladation of tethered alkynes followed by an alkylation process delivers interesting O- and N-heterocyclic cores bearing a fully substituted exocyclic double bond. In addition, we observed a different behavior of haloarylether and propiolamide substrates, being the last ones prone to afford the coupling products arising from isomerization of the alkenyl-Pd(II) intermediate.

Experimental Section

General Remarks

Infrared spectra were recorded on a PerkinElmer spectrum 100 spectrophotometer. High-resolution ESI mass spectra were recorded on an Agilent 6220 Accurate Mass TOF LC-MS spectrometer. Melting points were determined using a Reichert apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded on a 300, 400, or 600 MHz Bruker NMR spectrometers in CDCl3 at 298 K (unless stated otherwise). All chemical shift values are reported in parts per million (ppm) with coupling constant (J) values reported in Hz. All spectra were referenced to TMS for 1H NMR and the CDCl3 solvent peak for 13C{1H} NMR. The anhydrous solvents were purchased from commercial sources and used as received. TLC tests were run on TLC Alugram Sil G plates and visualized under UV light at 254 nm. Chromatography: Separations were carried out on silica gel. The general procedures and characterization for the substrates 1a–o are included in the Supporting Information.

Representative Procedure A for the Synthesis of the Carbopalladation/Alkylation Cascade Products 3

A Carius tube equipped with a magnetic stirrer was charged with [Pd(PPh3)4] (16 mg, 10 mol %), Cs2CO3 (51 mg, 0.17 mmol, 1.2 equiv), 3-methyl,-1,3-diphenylcyclobutan-1-ol (40 mg, 0.17 mmol, 1.2 equiv), and the corresponding substrate (1a) (40 mg, 0.14 mmol). The tube was set under a nitrogen atmosphere, and dry toluene (4 mL) was added. The tube was sealed, and the reaction mixture was stirred for 16 h at 100 °C. After cooling the tube, the crude was diluted with CH2Cl2 (50 mL) and filtered through a plug of Celite. The filtrate was concentrated under a vacuum, and the crude mixture was purified by column chromatography to afford the desired cascade product (3a). Compounds 3a–o are sensitive to purification in silica gel chromatography; therefore, the silica gel was previously deactivated with Et3N. In addition, n-hexane containing 1% Et3N and EtOAc mixtures were used as eluents.

Compound (Z)-5-(Benzofuran-3(2H)-ylidene)-3-methyl-1,3,5-triphenylpentan-1-one (3a)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1a and 0.17 mmol of 3-methyl-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 15% gradient EtOAc in n-hexane to afford the heterocycle 3a as an orange oil (42 mg, 0.095 mmol, 67%). IR (cm–1) ν̅ 1599 (s), 1493 (s), 1445 (s), 1242 (s), 1113 (s), 1039 (s), 1024 (s), 755 (s), 691 (s). 1H NMR (300 MHz, CDCl3) δ 7.62 (dd, J = 7.9, 1.3 Hz, 1 H), 7.56–7.50 (m, 2 H), 7.48–7.39 (m, 2 H), 7.37–7.24 (m, 6 H), 7.22–7.07 (m, 6 H), 6.92–6.76 (m, 2 H), 5.10–4.60 (m, 2 H), 3.44–3.39 (m, 3 H), 3.10 (d, J = 17.2 Hz, 1 H), 1.65 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.9 (s, Cq), 164.4 (s, Cq), 147.5 (s, Cq), 143.9 (s, Cq), 137.7 (s, Cq), 135.8 (s, Cq), 132.5 (s, CH), 130.9 (s, Cq), 129.8 (s, CH), 128.7 (s, CH), 128.2 (s, CH), 128.0 (s, CH), 127.7 (s, CH), 127.6 (s, CH), 126.9 (s, CH), 125.7 (s, CH), 125.6 (s, CH), 125.1 (s, Cq), 124.1 (s, CH), 120.3 (s, CH), 110.5 (s, CH), 75.4 (s, CH2), 49.3 (s, CH2), 46.1 (s, CH2), 42.0 (s, Cq), 24.2 (s, CH3). HRMS (+ESI) m/z calculated for C32H28NaO2 [M + Na]+ 467.1981, found 467.1986.

Compound (Z)-3-Methyl-5-(5-methylbenzofuran-3(2H)-ylidene)-1,3,5-triphenylpentan-1-one (3b)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1d and 0.17 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3b as a yellow oil (41 mg, 0.09 mmol, 64%). IR (cm–1) ν̅ 1688.4 (s), 1596.8 (s), 1492.6 (s), 1480.1 (s), 1445.4 (s), 1213.9 (s), 755.7 (s), 691.3 (s). 1H NMR (300 MHz, CDCl3) δ 7.60–7.52 (m, 2 H), 7.50–7.41 (m, 1 H), 7.39–7.37 (m, 1 H), 7.36–7.31 (m, 3 H), 7.31–7.24 (m, 3 H), 7.23–7.18 (m, 2 H), 7.18–7.12 (m, 3 H), 7.11–7.04 (m, 1 H), 6.99–6.93 (m, 1 H), 6.70 (d, J = 8.1 Hz, 1 H), 4.87 (br s, 2 H), 3.61–3.26 (m, 3 H), 3.09 (d, J = 17.2 Hz, 1 H), 2.28 (s, 3 H), 1.66 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 198.0 (s, Cq), 162.6 (s, Cq), 147.6 (s, Cq), 144. 2(s, Cq), 137.9 (s, Cq), 136.2 (s, Cq), 132.7 (s, CH), 130.6 (s, Cq), 130.5 (s, CH), 129.5 (s, Cq), 128.8 (s, CH), 128.4 (s, CH), 128.2 (s, CH), 127.9 (s, CH), 127.8 (s, CH), 127.0 (s, CH), 125.8 (s, CH), 125.7 (s, CH), 125.2 (s, Cq), 124.7 (s, CH), 110.1 (s, CH), 75.7 (s, CH2), 49.3 (s, CH2), 46.6 (s, CH2), 42.3 (s, Cq), 24.3 (s, CH3), 21.2 (s, CH3). HRMS (+ESI) m/z calculated for C33H30NaO2 [M + Na]+ 481.2138, found 481.2130.

Compound (Z)-5-(5-Methoxybenzofuran-3(2H)-ylidene)-3-methyl-1,3,5-triphenylpentan-1-one (3c)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1c and 0.17 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using gradient from 0 to 20% EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3c as a light-yellow oil (52 mg, 0.11 mmol, 78%). IR (cm–1) ν̅ 1681 (s), 1598 (s), 1481 (s), 1202 (s), 1021 (s), 755 (s), 691 (s). 1H NMR (400 MHz, CDCl3) δ 7.60–7.53 (m, 2 H), 7.46 (ddt, J = 7.8, 6.9, 1.3 Hz, 1 H), 7.36–7.31 (m, 4 H), 7.31–7.26 (m, 2 H), 7.25–7.19 (m, 2 H), 7.20–7.16 (m, 2 H), 7.16–7.11 (m, 2 H), 7.12–7.02 (m, 1 H), 6.83–6.71 (m, 2 H), 5.05–4.78 (m, 2 H), 3.77 (s, 3 H), 3.52–3.48 (m, 1 H), 3.39–3.34 (m, 2 H), 3.11 (d, J = 17.2 Hz, 1 H), 1.69 (s, 3 H). 13C NMR (101 MHz, CDCl3) δ 197.8 (s, Cq), 158.8 (s, Cq), 153.6 (s, Cq), 147.5 (s, Cq), 143.9 (s, Cq), 137.7 (s, Cq), 136.2 (s, Cq), 132.6 (s, CH), 130.9 (s, Cq), 128.6 (s, CH), 128.2 (s, CH), 128.0 (s, CH), 127.7 (s, CH), 127.6 (s, CH),126.9 (s, CH), 125.8 (s, CH), 125.6 (s, CH), 125.5 (s, Cq), 116.4 (s, CH), 110.5 (s, CH), 109.1 (s, CH), 75.8 (s, CH2), 56.1 (s, CH3), 49.4 (s, CH2), 46.1 (s, CH2), 42.0 (s, Cq), 24.0 (s, CH3). HRMS (+ESI) m/z calculated for C33H30NaO3 [M + Na]+ 497.2087, found 497.2066.

Compound (Z)-3-Methyl-1,3,5-triphenyl-5-(5-(trifluoromethyl)benzofuran-3-(2H)-ylidene)pentan-1-one (3d)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1f and 0.17 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 5% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3d as a light-yellow oil (50 mg, 0.097 mmol, 69%). IR (cm–1) ν̅ 1688 (s), 1597 (s), 1442 (m), 1481 (m), 1333 (m), 1316 (s), 1114 (s), 734 (s), 698 (s). 1H NMR (300 MHz, CDCl3) δ 7.79 (br d, J = 1.8 Hz, 1 H), 7.63–7.55 (m, 2 H), 7.49–7.43 (m, 2 H), 7.41 (ddd, J = 8.5, 2.0, 0.8 Hz, 1 H), 7.36–7.27 (m, 5 H), 7.24–7.21 (m, 2 H), 7.19–7.14 (m, 3 H), 7.10–7.04 (m, 1 H), 6.85–6.82 (m, 1 H), 5.02–4.89 (m, 2 H), 3.47–3.26 (m, 3 H), 3.08 (d, J = 17.3 Hz, 1 H), 1.66 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.7 (s, Cq), 166.5 (q, JCF = 1.0 Hz, Cq), 146.7 (s, Cq), 143.5 (s, Cq), 137.7 (s, Cq), 134.2 (s, Cq), 133.2 (s, Cq), 132.6 (s, CH), 128.8 (s, CH), 128.3 (s, CH), 128.2 (s, CH), 127.7 (s, CH), 127.4 (s, CH), 127.3 (s, CH), 127.2 (q, JCF = 3.3 Hz, CH), 126.0 (s, CH), 125.7 (s, Cq), 125.5 (s, CH), 122.6 (q, JCF = 32,1 Hz, Cq), 121.3 (q, JCF = 3.9 Hz, CH), 110.4 (s, CH), 76.3 (s, CH2), 48.9 (s, CH2), 46.7 (s, CH2), 42.2 (s, Cq), 24.4 (s, CH3). One quaternary carbon signal is overlapped. 19F-NMR (376.5 MHz, CDCl3) δ −61.02 (s). HRMS (+ESI) m/z calculated for C33H27F3NaO2 [M + Na]+ 535.1855, found 535.1850.

Compound (Z)-5-(5-Fluorobenzofuran-3(2H)-ylidene)-3-methyl-1,3,5-triphenylpentan-1-one (3e)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1e and 0.17 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3e as a yellow oil (39 mg, 0.084 mmol, 60%). IR (cm–1) ν̅ 1690 (s), 1597 (s), 1474 (s), 1323 (s), 1117 (s), 743 (s), 697 (s). 1H NMR (300 MHz, CDCl3) δ 7.59–7.52 (m, 2 H), 7.52–7.40 (m, 1 H), 7.33 (dt, J = 8.4, 0.9 Hz, 4 H), 7.31–7.26 (m, 2 H), 7.26–7.24 (m, 1 H), 7.24–7.16 (m, 3 H), 7.15–7.09 (m, 2 H), 7.09–7.04 (m, 1 H), 6.86 (td, J = 8.7, 2.7 Hz, 1 H), 6.71 (dd, J = 8.8, 4.4 Hz, 1 H), 4.90 (s, 2 H), 3.46–3.27 (m, 3 H), 3.09 (d, J = 17.2 Hz, 1 H), 1.66 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.8 (s, Cq), 160.3 (s, Cq), 156.9 (d, JCF = 235.4 Hz, Cq), 147.0 (s, Cq), 143.5 (s, Cq), 137.7 (s, Cq), 135.4 (d, J = 2.9 Hz, Cq), 132.6 (s, CH), 132.2 (s, Cq), 128.7 (s, CH), 128.2 (s, CH), 128.1 (s, CH), 127.7 (s, CH), 127.5 (s, CH), 127.1 (s, CH), 125.9 (s, CH), 125.6 (s, CH), 116.0 (d, J = 24.6 Hz, CH), 110.8 (d, J = 26.5 Hz, CH), 110.4 (d, J = 8.7 Hz, CH), 76.1 (s, CH2), 49.3 (s, CH2), 46.0 (s, CH2), 42.0 (s, Cq), 24.3 (s, CH3). The signal of one Cq is overlapped. 19F-NMR (376.5 MHz, CDCl3) δ −123.57 (s). HRMS (+ESI) m/z calculated for C32H27FNaO2 [M + Na]+ 485.1887, found 485.1868.

Compound (Z)-5-(Furo[3,2-b]pyridin-3(2H)-ylidene)-3-methyl-1,3,5-triphenylpentan-1-one (3f)

Prepared according to the representative procedure A from 0.10 mmol of substrate 1g and 0.12 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3f as a light-yellow oil (22 mg, 0.05 mmol, 49%). IR (cm–1) ν̅ 1690 (s), 1597 (s), 1436 (s), 1253 (s), 798 (s), 699 (s). 1H NMR (300 MHz, CDCl3) δ 8.21 (t, J = 3.1 Hz, 1 H), 7.58 (dd, J = 8.4, 1.4 Hz, 2 H), 7.45–7.31 (m, 3 H), 7.27–7.15 (m, 6 H), 7.15–7.07 (m, 2 H), 7.06–6.97 (m, 4 H), 5.18–4.74 (m, 2 H), 4.10–3.99 (m, 1 H), 3.89 (d, J = 17.1 Hz, 1 H), 3.64 (d, J = 13.0 Hz, 1 H), 3.22 (d, J = 17.1 Hz, 1 H), 1.41 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 198.8 (s, Cq), 158.5 (s, Cq), 148.0 (s, Cq), 147.7 (s, Cq), 143.3 (s, Cq), 141.6 (s, CH), 138.2 (s, Cq), 136.3 (s, Cq), 132.9 (s, Cq), 132.3 (s, CH), 128.5 (s, CH), 128.1 (s, CH), 127.8 (s, CH), 127.7 (s, CH), 127.3 (s, CH) 127.2 (s, CH), 126.2 (s, CH), 125.4 (s, CH), 123.0 (s, CH), 116.4 (s, CH), 75.1 (s, CH2), 48.4 (s, CH2), 45.1 (s, CH2), 42.7 (s, Cq), 24.8 (s, CH3). HRMS (+ESI) m/z calculated for C31H27NNaO2 [M + Na]+ 468.1934, found 468.1927.

Compound (Z)-5-(Benzofuran-3(2H)-ylidene)-1,5-diphenylpentan-1-one (3g)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1a and 0.17 mmol of 1-phenylcyclobutan-1-ol (2b). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3g as a yellow oil (28 mg, 0.08 mmol, 56%). IR (cm–1) ν̅ 1678 (s), 1595, 1497 (s), 1231 (s), 1123 (s), 998 (s), 752 (s), 697 (s). 1H NMR (300 MHz, CDCl3) δ 7.96–7.89 (m, 2 H), 7.65 (dd, J = 7.7, 1.3 Hz, 1 H), 7.57–7.51 (m, 1 H), 7.46–7.43 (m, 2 H), 7.39–7.40 (m, 1 H), 7.38–7.35 (m, 1 H), 7.31–7.24 (m, 1 H), 7.23–7.19 (m, 2 H), 7.18–7.15 (m, 1 H), 6.93 (td, J = 7.6, 1.1 Hz, 1 H), 6.84 (dd, J = 8.0, 1.0 Hz, 1 H), 4.91 (s, 2 H), 3.04 (t, J = 7.1 Hz, 2 H), 2.90–2.84 (m, 2 H), 2.03–1.93 (m, 2 H). 13C NMR (75.45 MHz, CDCl3) δ 199.8 (s, Cq), 164.1 (s, Cq), 142.9 (s, Cq), 136.9 (s, Cq), 133.3 (s, Cq), 133.0 (s, CH), 132.5 (s, Cq), 129.5 (s, CH), 128.8 (s, CH), 128.5 (s, CH), 128.0 (s, CH), 127.4 (s, CH), 127.2 (s, CH), 125.5 (s, Cq), 124.1 (s, CH), 120.7 (s, CH), 110.4 (s, CH), 75.1 (s, CH2), 38.0 (s, CH2), 33.6 (s, CH2), 17.0 (s, CH2). HRMS (+ESI) m/z calculated for C25H22NaO2 [M + Na]+ 377.1512, found 377.1494.

Compound (Z)-5-(Benzofuran-3(2H)-ylidene)-1-(4-fluorophenyl)-5-phenylpentan-1-one (3h)

Prepared according to the representative procedure A from 0.12 mmol of substrate 1b and 0.14 mmol of 1-(4-fluorophenyl)cyclobutan-1-ol (2d). The crude was purified by column chromatography over silica gel using 0 to 5% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3h as a light-yellow oil (32 mg, 0.086 mmol, 72%). IR (cm–1) ν̅ 3060 (m), 2933 (m), 1682 (s), 1599 (s), 1454 (m), 1408 (m), 1228 (s), 1156 (m), 1098 (w), 832 (w), 747 (s), 700 (s). 1H NMR (300 MHz, CDCl3) δ 8.00–7.87 (m, 2 H), 7.65 (dd, J = 7.8, 1.3 Hz, 1 H), 7.43–7.34 (m, 2 H), 7.32–7.27 (m, 1 H), 7.24–7.15 (m, 3 H), 7.15–7.05 (m, 2 H), 6.93 (td, J = 7.6, 1.1 Hz, 1 H), 6.85 (dt, J = 8.1, 0.7 Hz, 1 H), 4.91 (s, 2 H), 3.01 (t, J = 7.1 Hz, 2 H), 2.87 (tt, J = 7.3, 1.4 Hz, 2 H), 2.22–1.89 (m, 2 H). 13C NMR (75.45 MHz, CDCl3) δ 198.3 (s, Cq), 165.6 (d, JCF = 254.3 Hz, Cq), 164.2 (s, Cq), 142.9 (s, Cq), 133.3 (d, JCF = 3.1 Hz, Cq), 133.2 (s, Cq), 132.6 (s, Cq), 131.6 (d, JCF = 9.4 Hz, CH), 129.6 (s, CH), 128.8 (s, CH), 127.4 (s, CH), 127.3 (s, CH), 125.5 (s, Cq), 124.0 (s, CH), 120.7 (s, CH), 116.6 (d, JCF = 21.8 Hz, CH), 110.4 (s, CH), 75.2 (s, CH2), 37.9 (s, CH2), 33.6 (s, CH2), 22.4 (s, CH2). 19F-NMR (282.4 MHz, CDCl3) δ −104.7 (s). HRMS (+ESI) m/z calculated for C25H21FNaO2 [M + Na]+ 395.1418, found 395.1406.

Compound (Z)-5-(Benzofuran-3(2H)-ylidene)-5-phenyl-1-(p-tolyl)pentan-1-one (3i)

Prepared according to the representative procedure A from 0.12 mmol of substrate 1b and 0.14 mmol of 1-(p-tolyl)cyclobutan-1-ol (2e). The crude was purified by column chromatography over alumina using 0 to 5% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3i as a light-yellow oil (34 mg, 0.09 mmol, 76%). IR (cm–1) ν̅ 2924 (m), 1683 (s), 1603 (s), 1464 (s), 1362 (m), 1226 (s), 1181 (m), 985 (m), 807 (s), 746 (s). 1H NMR (300 MHz, CDCl3) δ 7.85–7.76 (m, 2 H), 7.69–7.55 (m, 1 H), 7.38 (ddd, J = 7.7, 6.6, 1.3 Hz, 2 H), 7.32–7.13 (m, 6 H), 6.99–6.89 (m, 1 H), 6.87–6.76 (m, 1 H), 4.91 (br s, 2 H), 3.01 (td, J = 7.2, 1.1 Hz, 2 H), 2.93–2.62 (m, 2 H), 2.40 (s, 3 H), 2.06–1.78 (m, 2 H). 13C NMR (75.45 MHz, CDCl3) δ 199.6 (s, Cq), 164.2 (s, Cq), 152.2 (s, Cq), 143.7 (s, Cq), 143.0 (s, Cq), 134.5 (s, Cq), 133.4 (s, Cq), 132.5 (s, Cq), 129.5 (s, CH), 129.2 (s, CH), 128.8 (s, CH), 128.1 (s, CH),127.4 (s, CH), 127.2 (s, CH), 124.1 (s, CH), 120.7 (s, CH), 110.4 (s, CH), 75.2 (s, CH2), 38.0 (s, CH2), 33.7 (s, CH2), 22.6 (s, CH2), 21.6 (s, CH3). HRMS (+ESI) m/z calculated for C26H24NaO2 [M + Na]+ 391.1669, found 391.1656.

Compound (Z)-5-(Furo[3,2-b]pyridine-3(2H)-ylidene)-1,5-diphenylpentan-1-one (3j)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1g and 0.17 mmol of 1-phenylcyclobutan-1-ol (2b). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3j as a yellow oil (23 mg, 0.065 mmol, 46%). IR (cm–1) ν̅ 1678 (s), 1594 (s), 1427 (s), 1258 (m), 1125 (m), 897 (s), 764 (s), 699 (s). 1H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 4.8, 1.5 Hz, 1 H), 7.84 (dd, J = 8.4, 1.3 Hz, 2 H), 7.44 (ddt, J = 8.7, 7.1, 1.3 Hz, 1 H), 7.36–7.29 (m, 4 H), 7.22 (tt, J = 7.0, 1.4 Hz, 1 H), 7.20–7.15 (m, 2 H), 6.99–6.90 (m, 2 H), 4.97 (s, 2 H), 3.60–3.19 (m, 2 H), 3.13–2.80 (m, 2 H), 2.16–1.59 (m, 2 H). 13C NMR (151 MHz, CDCl3) δ 200.5 (s, Cq), 158.3 (s, Cq), 148.0 (s, Cq), 141.9 (s, Cq), 141.8 (s, CH), 138.2 (s, Cq), 137.1 (s, Cq), 133.1 (s, CH), 129.9 (s, Cq), 128.8 (s, CH), 128.4 (s, CH), 128.1 (s, CH), 127.5 (s, CH), 127.1 (s, CH), 122.7(s, CH), 116.22 (s, CH), 74.8 (s, CH2), 38.2 (s, CH2), 31.7 (s, CH2), 23.3 (s, CH2). HRMS (+ESI) m/z calculated for C24H22NO2 [M + H]+ 356.1645, found 356.1654.

Compound (Z)-7-(Benzofuran-3(2H)-ylidene)-2-methyl-7-phenylheptan-3-one (3l)

Prepared according to the representative procedure A from 0.12 mmol of substrate 1b and 0.14 mmol of 1-isopropyl-clobutan-1-ol (2f). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3l as a light-yellow oil (17 mg, 0.053 mmol, 44%). IR (cm–1) ν̅ 1708 (s), 1606 (s), 1586 (s), 1465 (s), 1223 (m), 1128 (m), 1087 (m), 755 (s), 697 (s). 1H NMR (300 MHz, CDCl3) δ 7.66–7.63 (m, 1 H), 7.43–7.35 (m, 2 H), 7.31–7.27 (m, 1 H), 7.22–7.16 (m, 3 H), 6.97 (td, J = 7.6, 1.1 Hz, 1 H), 6.84 (ddd, J = 8.0, 1.1, 0.5 Hz, 1 H), 4.90 (s, 2 H), 2.79–2.74 (m, 2 H), 2.57–2.48 (m, 3 H), 1.85–1.75 (m, 2 H), 1.05 (d, J = 6.9 Hz, 6 H). 13C NMR (151 MHz, CDCl3) δ 214.4 (s, Cq), 164.2 (s, Cq), 143.0 (s, Cq), 133.4 (s, Cq), 132.5 (s, Cq), 129.6 (s, CH), 128.8 (s, CH), 127.4 (s, CH), 127.2 (s, CH), 125.5 (s, Cq), 124.1 (s, CH), 120.7 (s, CH), 110.4 (s, CH), 75.1 (s, CH2), 40.8 (s, CH), 39.6 (s, CH2), 33.5 (s, CH2), 21.9 (s, CH2), 18.2 (s, CH3). HRMS (+ESI) m/z calculated for C22H24NaO2 [M + Na]+ 343.1668, found 343.1659.

Compound (Z)-5-(Benzofuran-3(2H)-ylidene)-1-phenyl-5-(trimethylsilyl)pentan-1-one (3m)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1h and 0.17 mmol of 1-phenylcyclobutan-1-ol (2b). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3m as a light-yellow oil (28 mg, 0.08 mmol, 57%). IR (cm–1) ν̅ 1685 (s), 1648 (s), 1498 (s), 1379 (s), 1253 (m), 1124 (m), 876 (s), 787 (s), 695 (s). 1H NMR (400 MHz, CDCl3) δ 7.80–7.77 (m, 2 H), 7.40–7.35 (m, 2 H), 7.29–7.25 (m, 2 H), 6.99–6.95 (m, 1 H), 6.68–6.64 (m, 2 H), 4.87 (s, 2 H), 2.90 (t, J = 7.1 Hz, 2 H), 2.40 (ddd, J = 11.5, 4.8, 2.8 Hz, 2 H), 1.75–1.67 (m, 2 H), 0.00 (s, 9 H). 13C NMR (100.1 MHz, CDCl3) δ 200.0 (s, Cq), 164.5 (s, Cq), 144.2 (s, Cq), 136.9 (s, Cq), 133.0 (s, CH), 131.1 (s, Cq), 129.9 (s, CH), 128.6 (s, CH), 128.1 (s, CH), 126.2 (s, Cq), 125.3 (s, CH), 120.6 (s, CH), 110.6 (s, CH), 75.1 (s, CH2), 38.6 (s, CH2), 31.2 (s, CH2), 23.40 (s, CH2), 0.74 (s, CH3). HRMS (+ESI) m/z calculated for C22H27O2Si [M + H]+ 351.1780, found 351.1769.

Compound (Z)-3-Methyl-1,3,5-triphenyl-5-(1-tosylindolin-3-ylidene)pentan-1-one (3o)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1j and 0.17 mmol of 1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 30% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3o as a yellow oil (60 mg, 0.10 mmol, 71%). IR (cm–1) ν̅ 1693 (s), 1593 (s), 1489 (s), 1365 (s), 1136 (s), 905 (s), 763 (s), 698 (s). 1H NMR (300 MHz, CDCl3) δ 7.75–7.64 (m, 3 H), 7.57–7.51 (m, 4 H), 7.51–7.48 (m, 1 H), 7.48–7.41 (m, 3 H), 7.35–7.27 (m, 3 H), 7.25–7.17 (m, 4 H), 7.17–7.12 (m, 2 H), 7.11–7.05 (m, 1 H), 7.05–6.99 (m, 2 H), 4.37–4.26 (m, 2 H), 3.50–3.17 (m, 3 H), 2.99 (d, J = 17.2 Hz, 1H), 2.38 (s, 3 H), 1.56 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.7 (s, Cq), 147.2 (s, Cq), 145.1 (s, Cq), 144.0 (s, Cq), 143.6 (s, Cq), 137.6 (s, Cq), 133.9 (s, Cq), 133.8 (s, Cq), 132.6 (s, CH), 129.6 (s, CH), 129.1 (s, CH), 128.8 (s, CH), 128.2 (s, CH), 128.0 (s, CH), 127.64 (s, CH), 127.60 (s, CH), 127.19 (s, CH), 127.15 (s, CH), 125.7 (s, CH), 125.5 (s, CH), 124.3 (s, CH), 123.6 (s, CH), 115.6 (s, CH), 55.8 (s, CH2), 49.4 (s, CH2), 45.8 (s, CH2), 41.7 (s, Cq), 24.0 (s, CH3), 21.5 (s, CH3). Some Cq signals are overlapped. HRMS (+ESI) m/z calculated for C39H35NNaO3S [M + Na]+ 620.2230, found 620.2202.

Compound (Z)-5-(Isochroman-4-ylidene)-3-methyl-1,3,5-triphenylpentan-1-one (3q)

Prepared according to the representative procedure A from 0.12 mmol of substrate 1k and 0.14 mmol of 3-methyl,-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 10% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3q as a white solid (40 mg, 0.087 mmol, 73%). mp 130 °C. IR (cm–1) ν̅ 1690 (s), 1589 (s), 1494 (s), 1436 (s), 1224 (s), 1112 (s), 1024 (s), 757 (s), 692 (s). 1H NMR (300 MHz, CDCl3) δ 7.53–7.48 (m, 2 H), 7.49–7.42 (m, 1 H), 7.34–7.27 (m, 4 H), 7.25–7.20 (m, 2 H), 7.19–7.10 (m, 8 H), 7.08–7.06 (m, 2 H), 4.57 (s, 2 H), 4.14–4.05 (m, 2 H), 3.47–3.37 (m, 2 H), 3.23 (d, J = 17.2 Hz, 1 H), 2.90 (d, J = 17.2 Hz, 1 H), 1.44 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.9 (s, Cq), 147.0 (s, Cq), 142.1 (s, Cq), 137.8 (s, Cq), 137.2 (s, Cq), 137.1 (s, Cq), 134.7 (s, Cq), 132.5 (s, CH), 131.8 (s, Cq), 129.1 (s, CH), 128.3 (s, CH), 128.1 (s, CH), 127.9 (s, CH), 127.7 (s, CH), 127.6 (s, CH), 127.0 (s, CH), 126.9 (s, CH), 126.2 (s, CH), 125.9 (s, CH), 125.6 (s, CH), 124.6 (s, CH), 67.7 (s, CH2), 67.1 (s, CH2), 49.5 (s, CH2), 46.4 (s, CH2), 41.8 (s, Cq), 25.4 (s, CH3). HRMS (+ESI) m/z calculated for C33H30NaO2 [M + Na]+ 481.2138, found 481.2146.

Compound (Z)-3-Methyl-1,3,5-triphenyl-5-(2-tosyl-2,3-dihydroisoquinolin-4(1H)-ylidene)pentan-1-one (3r)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1l and 0.17 mmol of 3-methyl-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 15% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3r as a yellow oil (60 mg, 0.10 mmol, 70%). IR (cm–1) ν̅ 1688 (s), 1597 (s), 1462 (s), 1158 (s), 905 (s), 726 (s), 699 (s). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, J = 8.3, 1.4 Hz, 2 H), 7.48–7.40 (m, 3 H), 7.32 (dd, J = 8.2, 7.1 Hz, 2 H), 7.21 (m, 5 H), 7.14 (d, J = 8.4 Hz, 3 H), 7.10–7.02 (m, 4 H), 7.00–6.93 (m, 2 H), 6.91–6.85 (m, 2 H), 4.08 (m, 2 H), 3.75–3.56 (m, 2 H), 3.51–3.28 (m, 2 H), 3.09 (d, J = 17.1 Hz, 1 H), 2.84 (d, J = 17.0 Hz, 1 H), 2.37 (s, 3 H), 1.22 (s, 3 H). 13C NMR (75.45 MHz, CDCl3) δ 197.9 (s, Cq), 146.6 (s, Cq), 143.0 (s, Cq), 141.0 (s, Cq), 139.02 (s, Cq), 137.8 (s, Cq), 136.3 (s, Cq), 134.5 (s, Cq), 135.0 (s, Cq), 132.6 (s, CH), 129.9 (s, Cq), 129.4 (s, CH), 128.9 (s, CH), 128.4 (s, CH), 128.2 (s, CH), 127.8 (s, CH), 127.74 (s, CH), 127.70 (s, CH), 127.3 (s, CH), 127.2 (s, CH), 127.1 (s, CH), 126.8 (s, CH), 126.3 (s, CH), 125.8 (s, CH), 125.6 (s, CH), 49.1 (s, CH2), 47.6 (s, CH2), 45.1 (s, CH2), 41.8 (s, CH2), 29.7 (s, Cq), 25.7 (s, CH3), 21.5 (s, CH3). HRMS (+ESI) m/z calculated for C40H38NO3S [M + H]+ 612.2567, found 612.2568.

Compound (E)-1-Methyl-3-(3-methyl-5-oxo-1,3,5-triphenylpentylidene)indolin-2-one (3s)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1m and 0.17 mmol of 3-methyl-1,3-diphenylcyclobutan-1-ol (2a). The crude was purified by column chromatography over silica gel using 0 to 35% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3s as a yellow oil (38 mg, 0.081 mmol, 58%). IR (cm–1) ν̅ 1694 (s), 1616 (s), 1595 (s), 1490 (s), 1122 (s), 904 (s), 787 (s), 693 (s). 1H NMR (600 MHz, CDCl3) δ 7.69–7.67 (m, 2 H), 7.45 (ddt, J = 8.7, 7.1, 1.3 Hz, 1 H), 7.40–7.37 (m, 2 H), 7.35–7.31 (m, 3 H), 7.31–7.28 (m, 3 H), 7.16–7.10 (m, 4 H), 7.04 (ddt, J = 7.7, 6.9, 1.2 Hz, 1 H), 6.75 (ddd, J = 7.8, 1.0, 0.5 Hz, 1 H), 6.57 (td, J = 7.7, 1.1 Hz, 1 H), 6.06–5.99 (m, 1 H), 4.17 (d, J = 13.2 Hz, 1 H), 4.06 (d, J = 13.2 Hz, 1 H), 3.69 (d, J = 17.0 Hz, 1 H), 3.30 (s, 3 H), 3.24 (d, J = 17.1 Hz, 1 H), 1.48 (s, 3 H). 13C NMR (151 MHz, CDCl3) δ 198.3 (s, Cq), 168.0 (s, Cq), 157.2 (s, Cq), 147.4 (s, Cq), 142.2 (s, Cq), 141.5 (s, Cq), 138.0 (s, Cq), 132.4 (s, CH), 128.8 (s, CH), 128.44 (s, CH), 128.37 (s, CH), 128.2 (s, CH), 127.9 (s, CH), 127.8 (s, CH), 127.6 (s, CH), 126.2 (s, CH), 125.6 (s, CH), 123.1 (s, CH), 122.8 (s, Cq), 121.4 (s, CH), 107.4 (s, CH), 49.3 (s, CH2), 46.2 (s, CH2), 42.5 (s, Cq), 25.9 (s, CH3), 24.8 (s, CH3). Some signals are overlapped. HRMS (+ESI) m/z calculated for C33H30NO2 [M + H]+ 472.2271, found 472.2276.

Compound (E)-1,5-Dimethyl-3-(5-oxo-1,5-diphenylpentylidene)indolin-2-one (3t)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1n and 1-phenylcyclobutan-1-ol (2b). The crude was purified by column chromatography over silica gel using 0 to 20% gradient EtOAc in n-hexane containing 1% Et3N to afford the 3-alkylideneoxindole 3t as a yellow oil (25 mg, 0.063 mmol, 45%). IR (cm–1) ν̅ 1683 (s), 1646 (s), 1617 (s), 1593 (s), 1489 (s), 1368 (m), 1325 (m), 1098 (m), 767 (s), 698 (s). 1H NMR (300 MHz, CDCl3) δ 7.95–7.92 (m, 2 H), 7.56–7.40 (m, 6 H), 7.29–7.26 (m, 2 H), 6.94 (ddd, J = 7.9, 1.7, 0.8 Hz, 1 H), 6.64 (d, J = 7.9 Hz, 1 H), 5.84–5.83 (m, 1 H), 3.46–3.41 (m, 2 H), 3.23 (s, 3 H), 3.14–3.09 (m, 2 H), 2.01–1.91 (m, 5 H). Some signals are overlapped. 13C NMR (75.45 MHz, CDCl3) δ 200.0 (s, Cq), 167.8 (s, Cq), 157.9 (s, Cq), 141.2 (s, Cq), 140.2 (s, Cq), 137.0 (s, Cq), 132.8 (s, CH), 130.6 (s, Cq), 129.1 (s, CH), 128.53 (s, CH), 128.45 (s, CH), 128.4 (s, CH), 128.03 (s, CH), 126.9 (s, CH), 124.0 (s, Cq), 123.9 (s, CH), 122.6 (s, Cq), 107.1 (s, CH), 38.3 (s, CH2), 34.1 (s, CH2), 25.7 (s, CH3), 22.5 (s, CH2), 21.1 (s, CH3). HRMS (+ESI) m/z calculated for C27H26NO2 [M + H]+ 396.1958, found 396.1964.

Compound (E)-5-Chloro-1-methyl-3-(5-oxo-1,5-diphenylpentylidene)indolin-2-one (3u)

Prepared according to the representative procedure A from 0.14 mmol of substrate 1o and 0.17 mmol of 1-phenylcyclobutan-1-ol (2b). The crude was purified by column chromatography over silica gel using 0 to 25% gradient EtOAc in n-hexane containing 1% Et3N to afford the heterocycle 3u as a yellow oil (25 mg, 0.06 mmol, 43%). IR (cm–1) ν̅ 1685 (s), 1602 (s), 1498 (s), 1338 (m), 1098 (m), 778 (s), 697 (s). 1H NMR (300 MHz, CDCl3) δ 7.93 (m, 2 H), 7.55–7.48 (m, 4 H), 7.45–7.41 (m, 2 H), 7.27–7.25 (m, 3 H), 6.66 (d, J = 8.4 Hz, 1 H), 5.98 (d, J = 2 Hz, 1 H), 3.47–3.39 (m, 2 H), 3.24 (s, 3 H), 3.11 (t, J = 7.6 Hz, 2 H), 1.96 (q, J = 7.8 Hz, 2 H). 13C NMR (100.1 MHz, CDCl3) δ 199.8 (s, Cq), 167.4 (s, Cq), 160.3 (s, Cq), 140. Eight (s, Cq), 140.5 (s, Cq), 136.9 (s, Cq), 132.9 (s, CH), 129.3 (s, CH), 128.9 (s, CH), 128.5 (s, CH), 128.0 (s, CH), 127.9 (s, CH), 126.74 (s, Cq), 126.70 (s, CH), 123.9 (s, Cq), 123.24 (s, CH), 108.2 (s, CH), 38.3 (s, CH2), 34.3 (s, CH3), 25.8 (s, CH2), 22.4 (s, CH2). Some signals are overlapped. HRMS (+ESI) m/z calculated for C26H23ClNO2 [M + H]+ 416.1412, found 416.1421.

Synthesis of Complex 4

A Carius tube was charged with the substrate 1b (100 mg, 0.30 mmol), [Pd(PPh3)4] (350 mg, 0.30 mmol), and a magnetic stirrer. The tube was set under a nitrogen atmosphere, and dry CH2Cl2 was added (7 mL). The tube was sealed, and the mixture was stirred at 50 °C for 18 h. After the tube was cooled, the solution was filtered through a Celite plug. The filtrate was concentrated to ca. 2 mL, and n-pentane (15 mL) was added. The suspension was filtered, and the solid was washed with n-pentane (2 × 3 mL) and air-dried to give crude 4 as a bright yellow solid. Yield: 243 mg, 0.25 mmol, 84%. Crude complex 4 was recrystallized from CH2Cl2/Et2O to give analytically pure 4. mp 204 °C (dec). 1H NMR (400.9 MHz, CDCl3) δ 9.24 (d, 3JHH = 7.2 Hz, 1 H, H6, C6H4), 7.52–7.42 (m, 12 H, o-H, PPh3), 7.37–7.30 (m, 6 H, p-H, PPh3), 7.25–7.18 (m, 12 H, m-H, PPh3), 7.03 (td, 3JHH = 7.8, 4JHH = 1.2 Hz, 1 H, H4, C6H4), 6.98 (“t”, 3JHH = 7.3 Hz, 1 H, p-H, Ph), 6.87 (td, 3JHH = 7.4, 4JHH = 0.8 Hz, 1 H, H5, C6H4), 6.84 (t, 3JHH = 7.7 Hz, 2 H, m-H, Ph), 6.51 (d, 3JHH = 7.3 Hz, 2 H, o-H, Ph), 6.45 (“d″, 3JHH = 7.7 Hz, 1 H, H3, C6H4), 4.35 (“t”, 2JHH = 3.2 Hz, 2 H, CH2). 13C NMR (100.8 MHz, CDCl3) δ 163.3 (s, C2), 155.5 (t, JPH = 2.1 Hz, Cq), 143.9 (t, JPH = 2.9 Hz, i-C, Ph), 135.2 (t, JPH = 5.9 Hz, o-CH, PPh3), 134.4 (t, JPH = 5.1 Hz, Cq), 131.9 (t, JPH = 22.9 Hz, i-C, PPh3), 130.2 (s, C1), 130.0 (s, p-CH, PPh3), 129.0 (s, o-CH, Ph), 128.7 (s, CH4, C6H4), 127.4 (t, JPH = 5.0 Hz, m-CH, PPh3), 126.9 (s, m-CH, Ph), 125.6 (s, p-CH, Ph), 121.9 (s, CH6, C6H4), 119.4 (s, CH5, C6H4), 109.1 (s, CH3), 77.1 (s, CH2). IR (Nujol, cm–1) ν̅ 1590 (w), 1231 (m), 1093 (m), 742 (s), 691 (s), 520 (s), 509 (s), 494 (m). Anal. Calcd for C51H41IOP2Pd: C, 63.47; H, 4.28. Found: C, 63.55; H, 4.33.

Single-Crystal X-ray Structure Determination

Single crystals of complex 4, suitable for an X-ray diffraction study, were obtained by slow diffusion of n-pentane into a solution of 4 in CHCl3.

Data Collection

A crystal suitable for X-ray diffraction was mounted in inert oil on a glass fiber and transferred to a Bruker diffractometer. Data were recorded at 100(2) K, using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) and omega and phi scan mode. Multiscan absorption correction was applied.

Structure Solution and Refinements

The crystal structure was solved by dual method, and all non-hydrogen atoms were refined anisotropically on F2 using the program SHELXL-2018/3.70 Hydrogen atoms were refined using the riding model.

Acknowledgments

We thank Ministerio de Ciencia, Innovación y Universidades (Spain), FEDER “Una manera de hacer Europa” (Project PGC2018-100719-BI00), and Fundación Séneca Región de Murcia (19890/GERM/15) for financial support. J.-A. García-López is thankful to MCIN for a Ramón y Cajal Fellowship RYC-2016-20137. M. Pérez-Gómez acknowledges CARM-Fundación Séneca for a postdoctoral fellowship cofinanced in 92% by the European Social Fund and “Iniciativa de Empleo Juvenil”. P. Herrera-Ramírez acknowledges the University of Murcia for a research initiation grant.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.organomet.2c00015.

  • Experimental procedures and compound characterization for staring materials 1 and NMR spectra of the new compounds (PDF)

Accession Codes

CCDC 2132049 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.

Supplementary Material

om2c00015_si_001.pdf (4.4MB, pdf)

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