Cyclization of Olefinic 1,3-Dicarbonyls

Mar 20, 2018 - Metal-catalyzed cyanoalkylation/cyclization of olefinic 1,3-dicarbonyls with cycloketone oxime esters has been developed under redox-ne...
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Cite This: J. Org. Chem. 2018, 83, 4239−4249

Redox-Neutral Cyanoalkylation/Cyclization of Olefinic 1,3‑Dicarbonyls with Cycloketone Oxime Esters: Access to Cyanoalkylated Dihydrofurans Jia-Yu Zhang, Xin-Hua Duan, Jun-Cheng Yang, and Li-Na Guo* Department of Chemistry, School of Science and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China S Supporting Information *

ABSTRACT: Metal-catalyzed cyanoalkylation/cyclization of olefinic 1,3-dicarbonyls with cycloketone oxime esters has been developed under redox-neutral conditions. This protocol provided a straightforward approach to diverse cyanoalkylated 2,3-dihydrofurans via a tandem ring-opening/addition/cyclization process.

D

elegant radical C−C bond cleavages of cycloketone oxime derivatives has been developed by the groups of Selander,5d,f Shi,5e Zhou,5g Leonori,5h Chen and Xiao,5i and Lu and Liu, respectively.5j Moreover, Nishimura, Uemura and co-workers developed a Pd-catalyzed direct ring opening of cycloketone oxime esters, in which the resulting cyanoalkylpalladium(II) species tend to favor β-hydride elimination.6 Currently, we are studying the radical C−C bond cleavage of cycloketone oxime esters and have successfully incorporated cyanoalkyl moieties, especially bearing longer aliphatic chains, into a variety of heterocycles and substituted alkenes.7 The cyanoalkyl moieties are versatile building blocks in organic synthesis, as well as widely present in natural products and pharmaceuticals.8 We intend to combine the cyanoalkylation process with oxidative cyclization transformations to establish direct access to the cyanoalkylated heterocycles.7,8 Unlike the previous oxidative cyclization, it would theoretically be a neutral redox transformation, wherein an external oxidant would be avoided. Herein, we wish to report the metal-catalyzed radical cyclization of olefinic 1,3-dicarbonyls with cycloketone oxime esters, thus providing a direct access to cyanoalkylated dihydrofurans. Initially, the cyclization reactions of olefinic 1,3-diphenylketone 1a with various cyclobutanone O-acyl oximes were conducted under NiCl2·glyme catalysis (see the Supporting Information). Primary optimization demonstrated that treatment of 1a with O-perfluorobenzoyl oxime 2a in the presence of 5 mol % NiCl2·glyme in 1,4-dioxane at 100 °C for 12 h led to the cyanoalkylated dihydrofuran 3a in 59% yield (Table 1, entry 1). Further screening of other catalysts including iron and cobalt catalysts revealed that inexpensive CuCl showed the best catalytic activity and gave the product 3a in 65% yield (entries 2−10). Thus, CuCl was chosen as the optimal catalyst. Solvent screening showed that MeCN, EtOAc, toluene, and DCE were

ihydrofurans represent an important class of heterocyclic scaffolds, which are found in large numbers of natural products and pharmaceuticals.1 Thus, many methods have been developed for the construction of this skeleton.2 In this field, the radical cyclization reaction based on the difunctionalization of alkenes has been developed as a powerful tool for the synthesis of polysubstituted dihydrofurans.3,4 For instance, utilizing Mn(OAc)3 and K2S2O8 to mediate the intermolecular radical cyclization of 1,3-dicarbonyls with styrenes has been established as an efficient approach to dihydrofuran derivatives.3a−e In 2015, Lei and co-workers reported transitionmetal-free radical oxidative cyclization for the synthesis of substituted dihydrofurans.3f Very recently, Yu demonstrated the iron-catalyzed oxidative annulation of internal olefins with activated carbonyl methylenes to tetrasubstituted furans.3h On the other hand, the intramolecular radical cyclization of olefinic 1,3-dicarbonyls with several radical precursors has also been developed, respectively.4 For example, the group of Li has successfully revealed a series of transition-metal catalyzed radical cyclizations of olefinic carbonyls with aldehydes and Togni’s reagent.4a,c Meanwhile, we also described the radical cyclization of olefinic 1,3-dicarbonyls with benzyl hydrocarbons and thiocyanate salts.4b,d Although many efficient protocols have been established, most of them still suffer from some limitations such as the use of a stoichiometric amount of oxidants. Additionally, the scope of radical precursors for this transformation remains very undeveloped at present. Recently, the C−C bond cleavage of cycloketone oxime derivatives has attracted much attention from chemists, which could generate reactive cyanoalkyl radicals through a singleelectron reduction.5 The pioneering work of Zard in the 1990s disclosed that radical C−C bond cleavage of cyclobutanone sulfenylimines resulted in the formation of alkylnitriles.5a,b Subsequently, Nishimura and Uemura have demonstrated the iridium-catalyzed radical ring cleavage of cyclobutanone Obenzoyloximes to a variety of nitriles.5c Very recently, a series of © 2018 American Chemical Society

Received: January 30, 2018 Published: March 20, 2018 4239

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

entry

catalyst (mol %)

solvent

yield of 3a (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

NiCl2·glyme (5) Cu2O (5) CuCl (5) Cu powder (5) CuCl2 (5) Cu(OAc)2 (5) CuSO4·5H2O (5) FeCl2 (5) FeCl3 (5) CoCl2 (5) CuCl (5) CuCl (5) CuCl (5) CuCl (5) CuCl (5) CuCl (5) CuCl (5) CuCl (5) −

1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane MeCN DMF EtOAc toluene DCE 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane

59 48 65(60)c 52 55 50 12 40 47 53 57 trace 45 28 25 54 61 56d trace

dihydrofurans 5a, 5b, and 5c in 70%, 50%, and 53% yields, respectively (Scheme 1). It should be noted that dimethyl substituted cyclopentanone oxime ester 4d also gave the desired product 5d in 80% yield. Unfortunately, the lessstrained cyclopentanone oxime ester 4e or unstrained cyclohexanone oxime esters 4f and 4g failed to afford any desired product under the standard conditions. Encouraged by the above-mentioned results, reactions of olefinic 1,3-dicarbonyls 6 bearing a phenyl group on the CC bond and O-acyl oximes 2 were then tested. After many trials, we found that using 5 mol % of NiCl2·glyme instead of CuCl gave the expected product 7a in a slightly higher yield (for details, see the Supporting Information). Thus, a variety of olefinic 1,3-dicarbonyls 6 were subjected to this Ni catalysis system with various O-acyl oximes 2 (Table 3). The reactions of 6 with 2a proceeded efficiently to afford the corresponding products 7b−7f in 50%−70% yields. Unfortunately, the olefinic 1,3-dicarbonyls bearing a methyl or no group on the CC bond did not give any desired product. In these cases, 85% and 90% of the unreacted starting materials were recovered, respectively (not shown). The 3-benzyl and 3-aryl substituted cyclobutanone oxime esters were efficient cyanoalkylation reagents, providing the corresponding products 7g−7o in moderate to good yields. Notably, chloro and bromo groups on the phenyl ring remained intact under the Ni catalyst system, offering opportunities for further functionalization (7l, 7n, and 7o). The tricyclic cyclobutanone oxime ester also engaged in this transformation to afford the desired product 7p in 77% yield with complete regioselectivity. In some cases, relatively low yields of the desired products were obtained, which were attributed to the low conversion (3o, 3r, 7n, and 7o). To clarify the possible mechanism of this reaction, several control experiments were conducted (Scheme 2). When 2.0 equiv of TEMPO, a well-known radical trapping reagent, were added to the standard reaction, the cyclization reaction was suppressed completely and the cyanoalkyl-TEMPO adduct 8a was isolated in 53% yield. These results indicated that the reaction should involve a cyanoalkyl radical species. Furthermore, radical clock substrates 9a and 9b were subjected to the reaction, respectively. The reaction of 9a with 1a delivered the ring-closed product 10a in 40% yield, which provided evidence to support a radical pathway, while the spirocyclic substrate 9b furnished the product 10b in 61% yield along with no further ring-expanded product observed. On the basis of these results, a proposed mechanism was depicted in Scheme 3. Copper species could act as an electronrelay catalyst in this reaction.10 First, a copper-catalyst induced single-electron transfer occurred between the catalyst and cyclobutanone O-acyl oxime 2a to give iminyl radical I, which undergoes C−C bond cleavage and rearrangement to afford γcyanoalkyl radical II.5 Subsequently, the radical II reacts with 1a to generate a new radical intermediate III, which undergoes a radical cyclization to afford the radical IV.4 Finally, the desired product was produced through single-electron oxidation by Cu (n + 1) followed by the loss of H+ and regenerated the catalyst. Alternatively, copper might also act as a radical-chain initiator in this reaction.10 In conclusion, we have developed an efficient radical cyclization of olefinic 1,3-dicarbonyls with cyclobutanone oxime esters under redox-neutral conditions. A variety of cyanoalkylated dihydrofurans have been directly synthesized in moderate to good yields via cyanoalkylation/oxygenation of functionalized alkenes. Besides cyclobutanone oxime esters,

a Reaction conditions: 5 mol % of catalyst, 1a (0.3 mmol, 1.0 equiv), 2a (0.6 mmol, 2.0 equiv), solvent (2 mL), 100 °C, 12 h, under N2. b Yield of isolated product. cYield on a 1.79 mmol scale is given in parentheses. d1.5 equiv of 2a was used.

also effective for the reaction, except DMF (entries 11−15). Decreasing or increasing the amount of catalyst resulted in slight lower yields (entries 16−17). Changing the ratio of 1a and 2a from 1.0/2.0 to 1.0/1.5 also decreased the yield of 3a to 56% (entry 18). Finally, only a trace amount of product 3a was observed in the absence of catalyst (entry 19). To evaluate the scope and generality of this protocol, various olefinic 1,3-dicarbonyls 1 were subjected to the optimized reaction conditions with O-acyl oxime 2a (Table 2). Satisfactorily, not only olefinic β-diketones but also olefinic βketo esters were suitable substrates, producing the desired dihydrofurans 3b−3f in moderate to good yields with excellent chemoselectivity. The methyl and chloro- substituents on the para position of phenyl ring did not affect the reaction efficiency (3d and 3e). Substrate 1g with a SO2Ph group was also an amenable substrate, delivering the desired product 3g in 68% yield. Besides methyl ester, a substrate bearing a benzyl ester at the CC bond moiety also afforded the product 3h in 70% yield. Subsequently, the scope of cyclobutanone oxime esters 2 was examined with 1a. A variety of O-acyl oximes having aryl and benzyl groups on the 3-position reacted well to give the corresponding target products 3i−3o in moderate to good yields. Notably, the carbamate (NHBoc) substituent on the 3-position of cyclobutanone oxime ester was also welltolerated (3p). In addition, the 3,3-disubstituted cyclobutanone oxime esters also led to the desired products 3q and 3r in 76% and 32% yields, respectively. Moreover, the oxime esters derived from norcamphor, camphor, and tricyclo[5.2.1.0(2,6)]decan-8-one reacted successfully with 1a to furnish the corresponding cyanoalkylated 4240

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Table 2. Scope of Olefinic 1,3-Dicarbonyls 1 and Cyclobutanone O-Acyl Oximes 2a

Reaction conditions: 5 mol % of CuCl, 1 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), 1,4-dioxane (2 mL), 100 °C, 12 h, under N2. bYield of isolated product. cThe ratio was determined by 1H NMR spectroscopy. a

General Procedure for the Preparation of Olefinic 1,3Dicarbonyls 1 and 6. A 100 mL oven-dried three-neck flask equipped with a magnetic sir bar was charged with β-diketone or βketone ester (5.0 mmol, 1.0 equiv). Then, the flask was evacuated and backfilled with nitrogen (three times). Afterward, 10 mL of anhydrous DMF followed by the NaH (1.1 equiv) were added under nitrogen at 0 °C. After the mixture was stirred for 15 min, the allylic bromide (1.2 equiv) was added dropwise by syringe. The resulting mixture was stirred at room temperature for 3 h, then diluted with EtOAc, and transferred to a separatory funnel. The organic phase was washed successively with H2O and brine, dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (gradient eluent of EtOAc/petroleum ether: 1/20) to afford the substrate 1 and 6. Characterization of New Starting Materials. 1a. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.5 Hz, 4H), 7.56 (t, J = 7.4 Hz, 2H), 7.45 (t, J = 7.7 Hz, 4H), 6.22 (s, 1H), 5.86 (s, 1H), 5.75 (t, J = 6.9 Hz, 1H), 3.77 (s, 3H), 3.10 (d, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 195.3, 167.3, 136.2, 135.9, 133.5, 129.9, 128.8, 128.6, 54.9, 51.9, 32.4 ppm; IR (neat): υmax 2926, 1695, 1670, 1595, 1133, 750, 692 cm−1; HRMS (ESI) calcd for C20H18NaO4 [M + Na]+ 345.1097, found 345.1083. 1b. 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 5.95 (d, J = 0.7 Hz, 1H),

oxime esters derived from norcamphor, tricyclo[5.2.1.0(2,6)]decan-8-one, and camphor were also amenable cyanoalkyl sources.

■

EXPERIMENTAL SECTION

General Methods. Unless otherwise specified, all reactions were carried out under an atmosphere of nitrogen in oven-dried Schlenk tubes. Column chromatography was carried out on silica gel. 1H NMR and 13C NMR spectra were recorded on a Bruker Advance III-400 spectrometer with CDCl3 as the solvent and TMS as an internal standard. IR spectra were recorded on a Bruker V 70 spectrometer, and only major peaks are reported in cm−1. HRMS mass spectra were recorded on a Q-TOF micro spectrometer. All solvents and reagents were purchased from commercial sources or synthesized via literature protocol and used without further purifications. Starting Materials. All olefinic 1,3-dicarbonyls 1 and 6 were synthesized according to the literature.2,4b,c All cyclobutanone O-acyl oximes 2 were synthesized from the corresponding cyclobutanones and carboxylic acids according to the literature.6b The substituted cyclobutanones were prepared according to the reported procedure.5e,9 All of the NMR spectra of the know compounds were in full accordance with the data in the literature. 4241

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Scheme 1. Ring Opening of Less-Strained or Unstrained Cycloketone O-Acyl Oximes 4

1e. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 6.22 (s, 1H), 5.75 (d, J = 0.4 Hz, 1H), 4.76 (t, J = 7.3 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 2.98 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 193.1, 169.0, 166.6, 139.9, 135.9, 133.8, 129.9, 128.8, 128.6, 52.4, 52.2, 51.7, 31.6 ppm; IR (neat): υmax 2953, 2257, 1715, 1683, 1588, 1436, 1141, 728, 648 cm−1; HRMS (ESI) calcd for C15H15ClNaO5 [M + Na]+ 333.0500, found 333.0497. 1f. 1H NMR (400 MHz, CDCl3): δ = 8.03−7.91 (m, 2H), 7.47 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 6.12 (d, J = 1.1 Hz, 1H), 5.64 (d, J = 1.0 Hz, 1H), 4.67 (t, J = 7.4 Hz, 1H), 4.03 (m, 2H), 3.66 (d, J = 3.8 Hz, 3H), 2.91 (d, J = 7.5 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 194.1, 168.7, 166.5, 136.1, 135.5, 133.2, 128.3, 128.2, 60.9, 52.5, 51.5, 31.5, 13.6 ppm; IR (neat): υmax 2953, 2256, 1716, 1683, 1440, 1234, 1140, 728, 688 cm−1; HRMS (ESI) calcd for C16H18NaO5 [M + Na]+ 313.1046, found 313.1039. 1g. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.52 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 6.10 (s, 1H), 5.68−5.52 (m, 2H), 3.66 (s, 3H), 3.14 (m, 1H), 3.02 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 191.6, 166.5, 136.9, 136.8, 134.3, 134.2, 134.0, 129.8, 129.5, 128.9, 128.8, 128.7, 67.8, 52.0, 31.1 ppm; IR (neat): υmax 2953, 1714, 1679, 1446, 1308,

5.47 (s, 1H), 4.78 (t, J = 7.0 Hz, 1H), 3.55−3.46 (m, 3H), 2.85−2.67 (m, 2H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 201.8, 195.1, 166.0, 136.1, 135.6, 133.0, 128.2, 128.0, 59.9, 51.0, 30.6, 28.0 ppm; IR (neat): υmax 2952, 2255, 1715, 1674, 1596, 1140, 909, 727, 691 cm−1; HRMS (ESI) calcd for C15H16NaO4 [M + Na]+ 283.0941, found 283.0935. ̀̀ 1c. 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 6.21 (s, 1H), 5.73 (s, 1H), 4.80 (t, J = 7.3 Hz, 1H), 3.76 (s, 3H), 3.65 (d, J = 2.8 Hz, 3H), 3.00 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 194.2, 169.3, 166.6, 136.1, 135.5, 133.4, 128.5, 128.4, 52.4, 52.1, 51.6, 31.6 ppm; IR (neat): υmax 2953, 2256, 1715, 1682, 1596, 1437, 1140, 908, 727, 687 cm−1; HRMS (ESI) calcd for C15H16NaO5 [M + Na]+ 299.0890, found 299.0886. 1d. 1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.18 (s, 1H), 5.70 (s, 1H), 4.75 (t, J = 7.4 Hz, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 2.96 (d, J = 7.3 Hz, 2H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ = 193.6, 169.3, 166.5, 144.3, 136.1, 133.0, 129.1, 128.5, 128.2, 52.2, 51.9, 51.5, 31.6, 21.2 ppm; IR (neat): υmax 2953, 2255, 1715, 1680, 1436, 1141, 908, 727, 647 cm−1; HRMS (ESI) calcd for C16H18NaO5 [M + Na]+ 313.1046, found 313.1036. 4242

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Table 3. Scope of Olefinic 1,3-Dicarbonyls 6 and Cyclobutanone O-Acyl Oximes 2a

Reaction conditions: 5 mol % of NiCl2·glyme, 6 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), 1,4-dioxane (2 mL), 100 °C, 24 h, under N2. bYield of isolated product. cThe ratio was determined by 1H NMR spectroscopy.

a

Scheme 2. Mechanistic Experiments

1147, 749, 686 cm−1; HRMS (ESI) calcd for C19H19O5S [M + H]+ 359.0948, found 359.0970. 1h. 1H NMR (400 MHz, CDCl3): δ = 7.98 (t, J = 6.5 Hz, 4H), 7.55 (t, J = 7.3 Hz, 2H), 7.40 (m, 9H), 6.28 (d, J = 4.0 Hz, 1H), 5.87 (s, 1H), 5.84−5.69 (m, 1H), 5.31−5.19 (m, 2H), 3.13 (t, J = 6.9 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ = 195.3, 166.6, 136.2, 136.0, 135.7,

133.5, 130.3, 128.8, 128.6, 128.3, 128.1, 66.6, 54.8, 32.6 ppm; IR (neat): υmax 2948, 1696, 1670, 1447, 1271, 1143, 709, 688 cm−1; HRMS (ESI) calcd for C26H22NaO4 [M + Na]+ 421.1410, found 421.1407. 4d. 1H NMR (400 MHz, CDCl3): δ = 2.67 (t, J = 7.5 Hz, 2H), 1.87−1.77 (m, 2H), 1.71 (m, 2H), 1.27 (s, 6H); 13C NMR (100 MHz, 4243

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Scheme 3. Proposed Mechanism

CDCl3): δ = 182.1, 156.5, 146.5 (m), 144.4 (m), 143.9 (m), 141.9 (m), 138.9 (m), 136.3 (m), 107.3 (m), 43.6, 40.9, 29.3, 26.1, 20.5 ppm; 19F NMR (376 MHz, CDCl3) δ −137 (m, 2F), −148 (d, 1F), −160 (m, 2F) ppm; IR (neat): υmax 2966, 1760, 1651, 1495, 1325, 1198, 1180, 993, 851 cm−1; HRMS (ESI) calcd for C14H13F5NO2 [M + H]+ 322.0861, found 322.0855. 4g. 1H NMR (400 MHz, CDCl3): δ = 7.30−7.21 (m, 4H), 7.18 (t, J = 6.5 Hz, 1H), 3.81 (t, J = 5.8 Hz, 1H), 2.62 (m, 2H), 2.34 (m, 1H), 2.13−2.00 (m, 1H), 1.89−1.61 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 171.9, 157.4, 145.7 (m), 143.9 (m), 143.1 (m), 141.3 (m), 138.3 (m), 136.0 (m), 127.9, 127.4, 126.2, 107.6 (m), 107.4, 46.1, 31.4, 25.9, 25.7, 22.5 ppm; 19F NMR (376 MHz, CDCl3) δ −138 (d, 2F), −149 (s, 1F), −160 (m, 2F) ppm;IR (neat): υmax 2942, 1756, 1495, 1324, 1194, 992, 852, 733, 697 cm−1; HRMS (ESI) calcd for C19H14F5NNaO2 [M + Na]+ 406.0837, found 406.0832. General Procedure for the Cyclization of Olefinic 1,3Dicarbonyls 1 with Cyclobutanone O-Acyl Oximes 2. A 10 mL oven-dried Schlenk tube equipped with a magnetic stirrer was charged with olefinic 1,3-dicarbonyls 1 (0.3 mmol, 1.0 equiv), cyclobutanone O-acyl oxime 2 (0.6 mmol, 2.0 equiv), CuCl (1.5 mg, 5 mol %), and 1,4-dioxane (2.0 mL), and the resulting mixture was stirred at 100 °C, under nitrogen, for 12 h. Afterward, the resulting mixture was quenched with H2O and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient eluent of EtOAc/petroleum ether: 1/4−1/2) to give the corresponding products 3 in yields listed in Table 2. Methyl 4-Benzoyl-2-(4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2carboxylate (3a). Faint yellow liquid (65%, 75.9 mg); Rf 0.2 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.44−7.39 (m, 2H), 7.27−7.17 (m, 4H), 7.10−7.04 (m, 4H), 3.87 (s, 3H), 3.51 (d, J = 15.6 Hz, 1H), 3.36 (d, J = 15.6 Hz, 1H), 2.38 (t, J = 6.9 Hz, 2H), 2.27−2.14 (m, 1H), 2.11−2.00 (m, 1H), 1.75−1.72 (m, 3H), 1.62−1.47 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 192.9, 172.6, 164.7, 138.3, 131.3, 130.2, 129.4, 129.3, 128.8, 127.6, 119.2, 110.9, 88.1, 52.8, 42.5, 36.6, 25.1, 23.2, 16.9 ppm; IR (neat): υmax 2953, 2246, 1732, 1720, 1595, 1243, 714, 693 cm−1; HRMS (ESI) calcd for C24H23NNaO4 [M + Na]+ 412.1519, found 412.1515. Methyl 4-Acetyl-2-(4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2carboxylate (3b). Faint yellow liquid (57%, 55.9 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.60−7.55 (m, 2H), 7.49−7.42 (m, 3H), 3.81 (s, 3H), 3.38 (d, J = 15.7 Hz, 1H), 3.10 (d, J = 15.7 Hz, 1H), 2.36−2.33 (m, 2H), 2.14−2.07 (m, 1H), 2.03−1.96 (m, 1H), 1.94 (s, 3H), 1.73−1.65 (m, 3H), 1.53− 1.43 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 194.1, 172.4, 165.0, 130.8, 130.0, 129.2, 128.3, 119.2, 113.8, 88.1, 52.8, 41.0, 36.8, 28.7, 25.1, 22.9, 16.9 ppm; IR (neat): υmax 2955, 2247, 1737, 1622, 1593, 1264, 1245, 730, 699 cm−1; HRMS (ESI) calcd for C19H22NO4 [M + H]+ 328.1543, found 328.1548. Dimethyl 2-(4-Cyanobutyl)-5-phenyl-2,3-dihydrofuran-2,4-dicarboxylate (3c). Faint yellow liquid (52%, 53.5 mg); Rf 0.2 (EtOAc/

petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.85−7.80 (m, 2H), 7.45−7.36 (m, 3H), 3.82 (s, 3H), 3.67 (s, 3H), 3.42 (d, J = 15.8 Hz, 1H), 3.11 (d, J = 15.8 Hz, 1H), 2.36 (t, J = 6.9 Hz, 2H), 2.17−2.06 (m, 1H), 2.03−1.95 (m, 1H), 1.75−1.65 (m, 3H), 1.56− 1.44 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 172.7, 164.8, 164.2, 130.7, 129.3, 129.1, 127.7, 119.2, 101.3, 87.6, 52.8, 51.1, 41.0, 37.0, 25.2, 22.9, 17.0 ppm; IR (neat): υmax 2954, 2248, 1737, 1706, 1264, 730, 702 cm−1; HRMS (ESI) calcd for C19H21NNaO5 [M + Na]+ 366.1312, found 366.1308. Dimethyl 2-(4-Cyanobutyl)-5-(p-tolyl)-2,3-dihydrofuran-2,4-dicarboxylate (3d). Faint yellow liquid (57%, 61.1 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.66 (s, 3H), 3.40 (d, J = 15.7 Hz, 1H), 3.09 (d, J = 15.8 Hz, 1H), 2.38 (s, 3H), 2.35 (t, J = 6.9 Hz, 2H), 2.14−2.06 (m, 1H), 2.01−1.94 (m, 1H), 1.76−1.65 (m, 3H), 1.54−1.45 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 172.8, 164.9, 164.4, 141.1, 129.3, 128.4, 126.2, 119.2, 100.6, 87.4, 52.8, 51.0, 41.0, 36.9, 25.2, 22.9, 21.5, 17.0 ppm; IR (neat): υmax 2952, 2246, 1737, 1705, 1627, 1610, 1435, 1247, 1075, 761, 733 cm−1; HRMS (ESI) calcd for C20H24NO5 [M + H]+ 358.1649, found 358.1652. Dimethyl 5-(4-Chlorophenyl)-2-(4-cyanobutyl)-2,3-dihydrofuran2,4-dicarboxylate (3e). Faint yellow liquid (65%, 73.5 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.84−7.78 (m, 2H), 7.40−7.33 (m, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.40 (d, J = 15.9 Hz, 1H), 3.09 (d, J = 15.9 Hz, 1H), 2.35 (t, J = 6.9 Hz, 2H), 2.13−2.06 (m, 1H), 2.01−1.93 (m, 1H), 1.74−1.64 (m, 3H), 1.55−1.40 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 172.5, 164.6, 162.8, 136.6, 130.8, 127.9, 127.4, 119.2, 101.8, 87.6, 52.8, 51.1, 41.0, 36.8, 25.1, 22.8, 16.9 ppm; IR (neat): υmax 2953, 2253, 1738, 1704, 1633, 1489, 1264, 1247, 906, 725, 648 cm−1; HRMS (ESI) calcd for C19H21ClNO5 [M + H]+ 378.1103, found 378.1103. 4-Ethyl 2-Methyl 2-(4-Cyanobutyl)-5-phenyl-2,3-dihydrofuran2,4-dicarboxylate (3f). Faint yellow liquid (70%, 75.0 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.84−7.79 (m, 2H), 7.43−7.35 (m, 3H), 4.17−4.07 (m, 2H), 3.81 (s, 3H), 3.41 (d, J = 15.8 Hz, 1H), 3.10 (d, J = 15.9 Hz, 1H), 2.37−2.33 (m, 2H), 2.14−2.07 (m, 1H), 2.02−1.95 (m, 1H), 1.73−1.65 (m, 3H), 1.54−1.46 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 172.7, 164.4, 163.8, 130.5, 129.3, 129.2, 127.5, 119.2, 101.6, 87.5, 59.9, 52.8, 41.0, 36.9, 25.1, 22.9, 16.9, 14.1 ppm; IR (neat): υmax 2916, 2248, 1737, 1703, 1635, 1264, 1246, 730, 695 cm−1; HRMS (ESI) calcd for C20H24NO5 [M + H]+ 358.1649, found 358.1647. Methyl 2-(4-Cyanobutyl)-5-phenyl-4-(phenylsulfonyl)-2,3-dihydrofuran-2-carboxylate (3g). Faint yellow liquid (68%, 86.7 mg); Rf 0.1 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.76−7.65 (m, 4H), 7.54 (t, J = 7.4 Hz, 1H), 7.49−7.37 (m, 5H), 3.71 (s, 3H), 3.34 (d, J = 15.3 Hz, 1H), 3.19−3.08 (m, 1H), 2.34−2.26 (m, 2H), 2.09−2.01 (m, 1H), 1.96−1.89 (m, 1H), 1.68−1.62 (m, 2H), 1.59−1.49 (m, 1H), 1.47−1.35 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 171.6, 163.0, 141.4, 132.9, 131.3, 129.7, 128.9, 127.8, 127.6, 126.8, 119.0, 109.8, 88.0, 52.9, 41.3, 36.5, 25.0, 22.7, 16.9 ppm; 4244

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry IR (neat): υmax 2955, 2249, 1741, 1627, 1596, 1245, 722, 688 cm−1; HRMS (ESI) calcd for C23H24NO5S [M + H]+ 426.1370, found 426.1375. Benzyl 4-Benzoyl-2-(4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2carboxylate (3h). Faint yellow liquid (70%, 97.7 mg); Rf 0.2 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.45−7.40 (m, 2H), 7.39−7.32 (m, 5H), 7.23−7.14 (m, 4H), 7.06−6.99 (m, 4H), 5.35 (d, J = 12.1 Hz, 1H), 5.24 (d, J = 12.1 Hz, 1H), 3.49 (d, J = 15.6 Hz, 1H), 3.37 (d, J = 15.6 Hz, 1H), 2.27 (t, J = 7.0 Hz, 2H), 2.23−2.17 (m, 1H), 2.08−2.03 (m, 1H), 1.72−1.61 (m, 3H), 1.52−1.38 (m, 1H); 13 C NMR (100 MHz, CDCl3): δ = 192.9, 171.9, 164.8, 138.2, 135.0, 131.2, 130.1, 129.3, 129.2, 128.7, 128.6, 128.5, 128.4, 127.5, 127.5, 119.2, 111.0, 88.1, 67.4, 42.5, 36.3, 25.1, 23.1, 16.8 ppm; IR (neat): υmax 2956, 2248, 1737, 1612, 1594, 1264, 730, 695 cm−1; HRMS (ESI) calcd for C30H28NO4 [M + H]+ 466.2013, found 466.2027. Methyl 4-Benzoyl-2-(4-cyano-3-phenylbutyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3i). Faint yellow liquid (57%, 79.5 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.2:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.42−7.37 (m, 1H), 7.36−7.34 (m, 3H), 7.31−7.27 (m, 1H), 7.26− 7.15 (m, 6H), 7.10−7.03 (m, 4H), 3.85 (s, 1.6H), 3.83 (s, 1.4H), 3.48−3.42 (m, 1H), 3.28−3.22 (m, 1H), 3.04−2.88 (m, 1H), 2.63− 2.61 (m, 2H), 2.15−1.81 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 192.96, 172.48, 172.45, 164.71, 164.63, 140.60, 140.47, 138.35, 131.35, 131.33, 130.24, 130.22, 129.46, 129.43, 129.32, 129.29, 129.04, 129.01, 128.82, 127.68, 127.63, 127.60, 127.12, 127.11, 118.10, 110.99, 110.92, 88.12, 87.92, 52.89, 52.81, 42.61, 42.32, 42.01, 41.92, 35.12, 35.05, 29.14, 28.94, 25.34, 25.25 ppm; IR (neat): υmax 2954, 2250, 1739, 1611, 1594, 1244, 729, 696 cm −1; HRMS (ESI) calcd for C30H27NNaO4 [M + Na]+ 488.1832, found 488.1829. Methyl 4-Benzoyl-2-(4-cyano-3-(p-tolyl)butyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3j). Faint yellow liquid (57%, 81.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.2:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.41−7.34 (m, 2H), 7.26−7.17 (m, 4H), 7.16−7.14 (m, 2H), 7.12− 7.04 (m, 6H), 3.85 (s, 1.6H), 3.83 (s, 1.4H), 3.48−3.42 (m, 1H), 3.28−3.22 (m, 1H), 3.01−2.87 (m, 1H), 2.61−2.58 (m, 2H), 2.33 (s, 3H), 2.11−1.81 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 192.98, 172.52, 172.48, 164.76, 164.71, 138.37, 137.52, 137.39, 137.33, 131.35, 131.33, 130.24, 130.21, 129.69, 129.67, 129.47, 129.44, 129.32, 128.84, 128.83, 127.62, 127.61, 127.60, 126.98, 126.96, 118.23, 118.21, 111.01, 110.93, 88.17, 87.97, 52.88, 52.80, 42.59, 42.29, 41.65, 41.55, 35.15, 35.08, 29.13, 28.95, 25.48, 25.38, 21.00 ppm; IR (neat): υmax 2924, 2247, 1739, 1611, 1594, 1244, 729, 695 cm−1; HRMS (ESI) calcd for C31H30NO4 [M + H]+ 480.2169, found 480.2169. Methyl 4-Benzoyl-2-(3-(4-(tert-butyl)phenyl)-4-cyanobutyl)-5phenyl-2,3-dihydrofuran-2-carboxylate (3k). Faint yellow liquid (72%, 112.6 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.4:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.41−7.33 (m, 4H), 7.26−7.17 (m, 4H), 7.15−7.05 (m, 6H), 3.85 (s, 1.7H), 3.83 (s, 1.3H), 3.49−3.43 (m, 1H), 3.30−3.25 (m, 1H), 3.03−2.89 (m, 1H), 2.62−2.59 (m, 2H), 2.14− 1.82 (m, 4H), 1.31 (s, 4H), 1.30 (s, 5H); 13C NMR (100 MHz, CDCl3): δ = 192.98, 172.58, 172.54, 164.75, 164.71, 150.51, 150.49, 138.39, 137.48, 137.37, 131.37, 131.34, 130.26, 130.22, 129.50, 129.45, 129.36, 128.86, 128.84, 127.65, 127.63, 126.74, 126.72, 125.90, 125.88, 118.31, 118.28, 111.05, 110.96, 88.22, 88.04, 52.90, 52.83, 42.61, 42.32, 41.52, 41.41, 35.19, 34.45, 31.26, 29.04, 28.89, 25.43, 25.34 ppm; IR (neat): υmax 2958, 2247, 1738, 1612, 1594, 1244, 732, 695 cm−1; HRMS (ESI) calcd for C34H36NO4 [M + H]+ 522.2639, found 522.2658. Methyl 4-Benzoyl-2-(3-(4-chlorophenyl)-4-cyanobutyl)-5-phenyl2,3-dihydrofuran-2-carboxylate (3l). Faint yellow liquid (75%, 112.3 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.2:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.41−7.34 (m, 2H), 7.34−7.31 (m, 1H), 7.30 (m, 1H), 7.25 (s, 0.5H), 7.24−7.16 (m, 4H), 7.15−7.14 (m, 1H), 7.12 (s, 0.5H), 7.10−7.02 (m, 4H), 3.85 (s, 1.6H), 3.84 (s, 1.4H), 3.47−3.41 (m, 1H), 3.29−3.23 (m, 1H), 3.01−2.92 (m, 1H), 2.63−2.56 (m, 2H), 2.12− 1.79 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 192.97, 192.96,

172.42, 164.68, 164.60, 139.04, 138.90, 138.32, 138.31, 133.54, 131.43, 130.31, 130.30, 129.46, 129.42, 129.30, 129.26, 129.23, 128.84, 128.56, 128.54, 127.67, 117.82, 117.78, 111.00, 110.93, 88.02, 87.80, 52.96, 52.90, 42.69, 42.41, 41.48, 41.36, 35.04, 35.01, 29.15, 28.94, 25.34, 25.20 ppm; IR (neat): υmax 2959, 2250, 1738, 1611, 1594, 1492, 1259, 729, 695 cm−1; HRMS (ESI) calcd for C30H27ClNO4 [M + H]+ 500.1623, found 500.1638. Methyl 4-Benzoyl-2-(4-cyano-3-(m-tolyl)butyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3m). Faint yellow liquid (73%, 104.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.3:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.43−7.37 (m, 1H), 7.37−7.32 (m, 1H), 7.29−7.16 (m, 5H), 7.11−7.03 (m, 5H), 7.03−6.97 (m, 2H), 3.85 (s, 1.7H), 3.83 (s, 1.3H), 3.49−3.42 (m, 1H), 3.29−3.22 (m, 1H), 3.01−2.87 (m, 1H), 2.62−2.59 (m, 2H), 2.32 (s, 3H), 2.14−1.79 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 192.97, 192.95, 172.48, 164.73, 164.63, 140.57, 140.44, 138.68, 138.62, 138.37, 131.35, 131.33, 130.24, 130.22, 129.48, 129.43, 129.34, 129.31, 128.90, 128.84, 128.82, 128.43, 127.98, 127.80, 127.63, 127.61, 124.09, 123.99, 118.21, 118.18, 110.99, 110.92, 88.18, 87.94, 52.88, 52.80, 42.61, 42.33, 41.99, 41.84, 35.12, 35.10, 29.17, 28.94, 25.35, 25.27, 21.40 ppm; IR (neat): υmax 2954, 2249, 1739, 1609, 1594, 1244, 728, 695 cm−1; HRMS (ESI) calcd for C31H30NO4 [M + H]+ 480.2169, found 480.2173. Methyl 4-Benzoyl-2-(3-benzyl-4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3n). Faint yellow liquid (57%, 81.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.5:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.43−7.40 (m, 2H), 7.31−7.29 (m, 1H), 7.26 (d, 1H), 7.25−7.19 (m, 5H), 7.19−7.16 (m, 1H), 7.17−7.14 (m, 1H), 7.09−7.05 (m, 4H), 3.85 (s, 3H), 3.56−3.50 (m, 1H), 3.38−3.34 (m, 1H), 2.88−2.82 (m, 1H), 2.65−2.57 (m, 1H), 2.36−2.29 (m, 1H), 2.28−2.20 (m, 2H), 2.18−2.02 (m, 2H), 1.87−1.74 (m, 1H), 1.65−1.52 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 192.97, 192.95, 172.51, 172.45, 164.78, 138.38, 138.32, 138.31, 131.39, 131.38, 130.27, 130.24, 129.48, 129.31, 128.95, 128.94, 128.86, 128.66, 128.64, 127.65, 126.66, 126.65, 118.08, 117.97, 110.99, 110.95, 88.15, 88.13, 52.91, 42.65, 42.49, 39.56, 39.24, 37.03, 37.00, 34.73, 34.66, 27.65, 27.61, 21.14, 20.82 ppm; IR (neat): υmax 2952, 2245, 1738, 1611, 1594, 1243, 729, 695 cm−1; HRMS (ESI) calcd for C31H30NO4 [M + H]+ 480.2169, found 480.2185. Methyl 4-Benzoyl-2-(3-(3-((tert-butyldiphenylsilyl)oxy)-4methoxybenzyl)-4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3o). Faint yellow liquid (41%, 93.9 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); the title compound as a 1.1:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 6.8 Hz, 4H), 7.45−7.36 (m, 4H), 7.36−7.29 (m, 4H), 7.27−7.13 (m, 4H), 7.13−6.98 (m, 4H), 6.62 (t, J = 8.1 Hz, 1H), 6.53−6.52 (m, 1H), 6.44−6.38 (m, 1H), 3.83(s, 1.5H), 3.84(s, 1.5H) 3.55−3.49 (m, 4H), 3.35 (d, J = 15.7 Hz, 1H), 2.77−2.71 (m, 1H), 2.46−2.39 (m, 1H), 2.27−2.20 (m, 2H), 2.18−2.04 (m, 2H), 2.01−1.87 (m, 1H), 1.85−1.69 (m, 1H), 1.63−1.48 (m, 1H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 193.02, 192.99, 172.56, 172.50, 164.85, 164.82, 150.52, 143.75, 138.39, 135.36, 133.45, 131.53, 131.49, 131.41, 131.40, 130.30, 130.27, 129.56, 129.49, 129.48, 129.32, 128.88, 127.68, 127.40, 120.76, 120.25, 118.18, 118.06, 112.83, 111.02, 110.98, 88.18, 56.69, 55.28, 55.27, 52.93, 42.72, 42.52, 39.17, 38.88, 37.12, 34.84, 34.73, 27.74, 27.68, 26.62, 20.94, 20.60, 19.71 ppm; IR (neat): υmax 2959, 2247, 1742, 1610, 1594, 1259, 728, 698 cm−1; HRMS (ESI) calcd for C48H49NNaO6Si [M + Na]+ 786.3221, found 786.3190. Methyl 4-Benzoyl-2-(3-((tert-butoxycarbonyl)amino)-4-cyanobutyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (3p). Faint yellow liquid (58%, 87.7 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.5:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.45−7.38 (m, 2H), 7.26−7.17 (m, 4H), 7.09−7.05 (m, 4H), 4.70 (t, J = 8.1 Hz, 1H), 3.88 (s, 3H), 3.87−3.81 (m, 1H), 3.53−3.47 (m, 1H), 3.39−3.34 (m, 1H), 2.85−2.69 (m, 1H), 2.59−2.54 (m, 1H), 2.36−2.20 (m, 1H), 2.19−2.02 (m, 1H), 2.01− 1.85 (m, 1H), 1.77−1.63 (m, 1H), 1.44 (s, 5H), 1.43(s, 4H); 13C NMR (100 MHz, CDCl3): δ = 192.93, 172.42, 172.39, 164.60, 164.58, 154.99, 138.34, 131.43, 130.31, 129.47, 129.46, 129.25, 128.87, 127.68, 117.01, 116.95, 110.99, 87.80, 87.64, 80.30, 60.33, 58.33, 53.02, 53.00, 4245

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry

1H), 1.07 (s, 1.6H), 0.95 (s, 1.4H), 0.92 (s, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 193.07, 193.04, 174.08, 173.91, 165.03, 138.49, 131.39, 130.22, 130.21, 129.54, 129.50, 128.91, 127.68, 127.64, 127.62, 119.77, 110.61, 110.56, 88.16, 88.10, 52.76, 52.68, 47.03, 46.91, 46.85, 46.58, 46.52, 44.19, 43.93, 43.90, 43.53, 34.49, 32.53, 28.25, 28.13, 23.37, 22.74, 22.14, 19.65, 19.48, 19.40, 18.83, 18.55 ppm; IR (neat): υmax 2959, 2252, 1742, 1595, 1245, 904, 723, 648 cm−1; HRMS (ESI) calcd for C30H34NO4 [M + H]+ 472.2482, found 472.2489. Methyl 4-Benzoyl-2-((3-(cyanomethyl)octahydropentalen-1-yl)methyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (5c). Faint yellow liquid (53%, 74.6 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 2.7:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.43−7.37 (m, 2H), 7.27−7.16 (m, 4H), 7.09−7.04 (m, 4H), 3.85 (s, 0.8H), 3.83 (s, 2.2H), 3.53−3.44 (m, 1H), 3.40−3.29 (m, 1H), 2.47−2.32 (m, 2H), 2.31−2.24 (m, 1H), 2.24− 2.06 (m, 3H), 2.03−1.93 (m, 1H), 1.74−1.62 (m, 2H), 1.60−1.34 (m, 6H), 1.15−1.04 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.11, 173.29, 165.05, 165.00, 138.54, 138.50, 131.38, 131.34, 130.20, 129.60, 129.52, 128.89, 127.67, 127.65, 118.83, 111.15, 110.91, 88.96, 88.27, 52.85, 52.76, 52.71, 51.15, 51.01, 48.53, 48.41, 43.69, 43.51, 43.41, 43.08, 42.99, 42.92, 42.80, 42.43, 42.29, 41.21, 40.31, 34.54, 32.08, 32.00, 31.95, 31.85, 25.06, 25.01, 23.44, 21.79 ppm; IR (neat): υmax 2949, 2248, 1740, 1611, 1594, 1258, 1245, 726, 694 cm−1; HRMS (ESI) calcd for C30H32NO4 [M + H]+ 470.2326, found 470.2326. Methyl 4-Benzoyl-2-(5-cyano-2,2-dimethylpentyl)-5-phenyl-2,3dihydrofuran-2-carboxylate (5d). Faint yellow liquid (80%, 103.5 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 7.2 Hz, 2H), 7.31−7.25 (m, 2H), 7.24−7.15 (m, 2H), 7.06 (m, 4H), 3.83 (s, 3H), 3.40 (m, 2H), 2.28 (d, J = 14.9 Hz, 1H), 2.15 (t, J = 6.9 Hz, 2H), 2.06 (d, J = 15.0 Hz, 1H), 1.64−1.48 (m, 3H), 1.44−1.33 (m, 1H), 1.01 (s, 3H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 192.9, 173.7, 164.9, 138.4, 131.3, 130.2, 129.4, 129.4, 128.8, 127.6, 119.5, 110.4, 87.7, 52.6, 48.4, 46.6, 41.9, 33.6, 27.6, 27.5, 20.3, 17.5 ppm; IR (neat): υmax 2955, 2245, 1745, 1613, 1594, 1446, 1364, 1243, 888, 723, 695 cm−1; HRMS (ESI) calcd for C27H30NO4 [M + H]+ 432.2169, found 432.2168. General Procedure for the Cyclization of Olefinic 1,3Dicarbonyls 6 with Cyclobutanone O-Acyl Oximes 2. A 10 mL oven-dried Schlenk tube equipped with a magnetic stirrer was charged with olefinic 1,3-dicarbonyls 6 (0.3 mmol, 1.0 equiv), cyclobutanone O-acyl oxime 2 (0.6 mmol, 2.0 equiv), CuCl (1.5 mg, 5 mol %), and 1,4-dioxane(2.0 mL), and the resulting mixture was stirred at 100 °C, under nitrogen, for 24 h. Afterward, the resulting mixture was quenched with H2O and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient eluent of EtOAc/petroleum ether: 1/5−1/2) to give the corresponding products 7 in yields listed in Table 3. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)pentanenitrile (7a). White solid (69%, 84.3 mg); Rf 0.2 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.4 Hz, 2H), 7.44−7.38 (m, 4H), 7.34−7.29 (m, 3H), 7.26−7.19 (m, 2H), 7.12− 7.04 (m, 4H), 3.54 (s, 2H), 2.29 (t, J = 6.8 Hz, 2H), 2.25−2.16 (m, 1H), 2.15−2.03 (m, 1H), 1.74−1.56 (m, 3H), 1.45−1.35 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.3, 164.4, 144.5, 138.8, 131.1, 130.0, 129.9, 129.3, 128.8, 128.5, 127.6, 127.6, 127.4, 124.5, 119.4, 111.5, 90.3, 45.8, 41.8, 25.4, 23.2, 17.0 ppm; IR (neat): υmax 2942, 2246, 1716, 1609, 1592, 1247, 720, 695 cm−1; HRMS (ESI) calcd for C28H26NO2 [M + H]+ 408.1958, found 408.1965. 5-(4-Benzoyl-5-phenyl-2-(p-tolyl)-2,3-dihydrofuran-2-yl)pentanenitrile (7b). Faint yellow liquid (70%, 88.5 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.37 (t, J = 7.4 Hz, 4H), 7.32−7.27 (m, 2H), 7.23−7.19 (m, 4H), 7.12−7.03 (m, 4H), 3.52 (s, 2H), 2.38 (s, 3H), 2.29 (t, J = 6.9 Hz, 2H), 2.23−2.14 (m, 1H), 2.12−2.02 (m, 1H), 1.69−1.59 (m, 3H), 1.44−1.36 (m, 1H); 13 C NMR (100 MHz, CDCl3): δ = 193.3, 164.5, 141.5, 138.9, 137.0, 131.0, 130.0, 130.0, 129.3, 129.2, 128.8, 127.6, 127.5, 124.5, 119.4, 111.6, 90.4, 45.8, 41.8, 25.4, 23.3, 21.0, 17.0 ppm; IR (neat): υmax 2920,

47.22, 42.76, 42.68, 33.94, 28.23, 28.09, 24.03, 23.90, 20.99, 18.37, 14.14 ppm; IR (neat): υmax 2962, 2250, 1742, 1705, 1609, 1594, 1247, 727, 695 cm−1; HRMS (ESI) calcd for C29H32N2NaO6 [M + Na]+ 527.2153, found 527.2164. Methyl 4-Benzoyl-2-(4-cyano-3-methyl-3-phenylbutyl)-5-phenyl2,3-dihydrofuran-2-carboxylate (3q). Faint yellow liquid (76%, 109.3 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.1:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.39−7.30 (m, 6H), 7.29−7.26 (m, 1H), 7.25−7.17 (m, 4H), 7.09−7.03 (m, 4H), 3.84 (s, 1.5H), 3.82 (s, 1.5H), 3.47−3.40 (m, 1H), 3.24−3.17 (m, 1H), 2.73−2.60 (m, 2H), 2.07−1.66 (m, 4H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 192.96, 172.40, 164.64, 164.49, 143.00, 142.99, 138.42, 138.41, 131.36, 130.25, 130.23, 129.50, 129.46, 129.37, 129.35, 128.86, 128.83, 127.65, 127.64, 127.13, 127.10, 125.71, 125.64, 117.65, 117.63, 111.00, 88.04, 87.99, 52.86, 52.81, 42.53, 42.42, 39.75, 35.40, 35.24, 32.44, 32.40, 32.06, 31.55, 25.02, 24.45 ppm; IR (neat): υmax 2957, 2250, 1742, 1611, 1594, 1244, 726, 695 cm−1; HRMS (ESI) calcd for C31H29NNaO4 [M + Na]+ 502.1989, found 502.1992. tert-Butyl 4-(2-(4-Benzoyl-2-(methoxycarbonyl)-5-phenyl-2,3-dihydrofuran-2-yl)ethyl)-4-(cyanomethyl)piperidine-1-carboxylate (3r). Faint yellow liquid (32%, 53.6 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 7.2 Hz, 2H), 7.28−7.17 (m, 4H), 7.07 (t, J = 7.1 Hz, 4H), 3.89 (s, 3H), 3.53 (d, J = 15.6 Hz, 1H), 3.42−3.37 (m, 4H), 2.40 (s, 2H), 2.18−2.11 (m, 1H), 2.06−1.99 (m, 1H), 1.89−1.80 (m, 1H), 1.72 (s, 1H), 1.59−1.51 (m, 5H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 192.9, 172.3, 164.7, 154.5, 138.3, 131.4, 130.2, 129.4, 129.2, 128.8, 127.6, 117.0, 110.9, 87.9, 79.8, 53.0, 42.6, 33.8, 31.1, 30.4, 28.3, 25.7 ppm; IR (neat): υmax 2923, 2245, 1739, 1683, 1612, 1594, 1246, 732, 695 cm−1; HRMS (ESI) calcd for C33H38N2NaO6 [M + Na]+ 581.2622, found 581.2625. General Procedure for the Cyclization of Olefinic 1,3Dicarbonyls 1a with Cyclopentanone O-Acyl Oximes 4. A 10 mL oven-dried Schlenk tube equipped with a magnetic stirrer was charged with olefinic 1,3-dicarbonyls 1a (0.3 mmol, 1.0 equiv), cyclobutanone O-acyl oxime 4 (0.6 mmol, 2.0 equiv), CuCl (1.5 mg, 5 mol %), and 1,4-dioxane(2.0 mL), and the resulting mixture was stirred at 100 °C, under nitrogen, for 12 h. Afterward, the resulting mixture was quenched with H2O and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient eluent of EtOAc/petroleum ether: 1/4−1/2) to give the corresponding products 5 in yields listed in Scheme 1. Methyl 4-Benzoyl-2-((3-(cyanomethyl)cyclopentyl)methyl)-5phenyl-2,3-dihydrofuran-2-carboxylate (5a). Faint yellow liquid (70%, 90.1 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); the title compound as a 1.5:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 7.2 Hz, 2H), 7.26−7.16 (m, 4H), 7.05 (t, J = 7.7 Hz, 4H), 3.84 (s, 1.4H), 3.83 (s, 1.5H), 3.54−3.44 (m, 1H), 3.33 (d, J = 15.6 Hz, 1H), 2.37−2.26 (m, 3H), 2.26−2.14 (m, 2H), 2.13−1.83 (m, 4H), 1.73−1.56 (m, 1H), 1.47−1.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 192.97, 173.11, 173.08, 173.06, 164.82, 138.42, 131.27, 130.13, 129.41, 128.78, 127.58, 119.07, 110.88, 88.48, 88.45, 52.72, 52.69, 52.67, 43.40, 43.37, 43.32, 43.31, 43.19, 43.15, 40.40, 39.71, 38.41, 37.92, 36.45, 36.40, 35.55, 35.50, 34.95, 34.93, 34.85, 34.76, 33.94, 33.22, 32.28, 32.10, 32.02, 31.60, 30.40, 23.25, 22.89, 22.86 ppm; IR (neat): υmax 2952, 2251, 1739, 1610, 1594, 1244, 725, 695 cm−1; HRMS (ESI) calcd for C27H28NO4 [M + H]+ 430.2013, found 430.2024. Methyl 4-Benzoyl-2-((3-(cyanomethyl)-1,2,2-trimethylcyclopentyl)methyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (5b). Faint yellow liquid (50%, 70.7 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.1:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.45−7.37 (m, 2H), 7.31−7.25 (m, 2H), 7.21 (dt, J = 7.4, 4.3 Hz, 2H), 7.07 (t, J = 7.6 Hz, 4H), 3.85 (s, 1.3H), 3.84 (s, 1.7H), 3.48 (d, J = 15.6 Hz, 1H), 3.41−3.36 (m, 1H), 2.45−2.30 (m, 2H), 2.22−2.19 (m, 1H), 2.18− 2.09 (m, 1H), 2.07−1.92 (m, 2H), 1.74−1.67 (m, 2H), 1.43−1.30 (m, 4246

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry 2246, 1715, 1607, 1592, 1244, 733, 694 cm−1; HRMS (ESI) calcd for C29H28NO2 [M + H]+ 422.2115, found 422.2114. 5-(4-Benzoyl-2-(4-fluorophenyl)-5-phenyl-2,3-dihydrofuran-2-yl)pentanenitrile (7c). Faint yellow liquid (69%, 88.0 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.46−7.41 (m, 2H), 7.40−7.36 (m, 2H), 7.28−7.26 (m, 2H), 7.22 (t, J = 7.4 Hz, 2H), 7.13−7.04 (m, 6H), 3.58−3.44 (m, 2H), 2.34−2.29 (m, 2H), 2.25−2.16 (m, 1H), 2.11−2.01 (m, 1H), 1.69−1.60 (m, 3H), 1.45−1.32 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.3, 164.2, 163.2, 160.7, 140.3, 140.3, 138.7, 131.2, 130.1, 129.8, 129.3, 128.8, 127.7, 127.6, 126.4, 126.3, 119.3, 115.5, 115.3, 111.5, 89.9, 45.9, 41.8, 25.3, 23.2, 17.0 ppm; IR (neat): υmax 2934, 2246, 1715, 1593, 1508, 1235, 716, 694 cm−1; HRMS (ESI) calcd for C28H25FNO2 [M + H]+ 426.1864, found 426.1868. 5-(4-Benzoyl-2-(4-chlorophenyl)-5-phenyl-2,3-dihydrofuran-2yl)pentanenitrile (7d). Faint yellow liquid (69%, 91.3 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.44−7.34 (m, 6H), 7.27 (d, J = 8.2 Hz, 2H), 7.25−7.19 (m, 2H), 7.15−7.00 (m, 4H), 3.57−3.45 (m, 2H), 2.31 (t, J = 6.9 Hz, 2H), 2.26−2.14 (m, 1H), 2.10−2.02 (m, 1H), 1.71−1.60 (m, 3H), 1.42− 1.34 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.2, 164.1, 143.1, 138.7, 133.3, 131.2, 130.2, 129.8, 129.3, 128.8, 128.7, 127.7, 127.6, 126.1, 119.3, 111.5, 89.8, 45.9, 41.7, 25.4, 23.2, 17.0 ppm; IR (neat): υmax 2928, 2246, 1716, 1608, 1592, 1246, 714, 694 cm−1; HRMS (ESI) calcd for C28H25ClNO2 [M + H]+ 442.1568, found 442.1578. 5-(4-Benzoyl-2-(3-methoxyphenyl)-5-phenyl-2,3-dihydrofuran-2yl)pentanenitrile (7e). Faint yellow liquid (50%, 65.6 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.40−7.36 (m, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.30−7.27 (m, 2H), 7.23−7.19 (m, 2H), 7.12−7.08 (m, 3H), 7.06 (s, 1H), 7.04−7.02 (m, 2H), 6.89−6.78 (m, 1H), 3.84 (s, 3H), 3.52 (s, 2H), 2.29 (t, J = 6.9 Hz, 2H), 2.24−2.15 (m, 1H), 2.12−2.02 (m, 1H), 1.68−1.60 (m, 3H), 1.48−1.33 (m, 1H); 13C NMR (100 MHz, CDCl3); δ = 193.3, 164.3, 159.7, 146.3, 138.9, 131.1, 130.0, 129.9, 129.7, 129.3, 128.8, 127.6, 127.6, 119.4, 116.9, 112.1, 111.6, 111.0, 90.2, 55.2, 45.9, 41.7, 25.4, 23.2, 17.0 ppm; IR (neat): υmax 2940, 2245, 1715, 1607, 1592, 1247, 718, 695 cm−1; HRMS (ESI) calcd for C29H28NO3 [M + H]+ 438.2064, found 438.2067. 5-(4-Benzoyl-2-(3-chlorophenyl)-5-phenyl-2,3-dihydrofuran-2yl)pentanenitrile (7f). Faint yellow liquid (52%, 68.8 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.47 (s, 1H), 7.42−7.37 (m, 2H), 7.36−7.32 (m, 2H), 7.31−7.26 (m, 3H), 7.22 (t, J = 7.4 Hz, 2H), 7.15−7.03 (m, 4H), 3.57−3.43 (m, 2H), 2.31 (t, J = 6.8 Hz, 2H), 2.24−2.16 (m, 1H), 2.10−2.01 (m, 1H), 1.71−1.59 (m, 3H), 1.42−1.34 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.2, 164.0, 146.7, 138.7, 134.6, 131.2, 130.2, 129.9, 129.7, 129.3, 128.8, 127.7, 127.6, 124.9, 122.8, 119.3, 111.4, 89.6, 45.9, 41.7, 25.4, 23.1, 17.0 ppm; IR (neat): υmax 2933, 2246, 1716, 1609, 1593, 1257, 714, 694 cm−1; HRMS (ESI) calcd for C28H25ClNO2 [M + H]+ 442.1568, found 442.1579. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-benzylpentanenitrile (7g). White solid (52%, 77.6 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); the title compound as a 1.0:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.51− 7.49 (m, 2H), 7.46−7.40 (m, 4H), 7.38−7.33 (m, 1H), 7.32−7.27 (m, 3H), 7.26 (s, 1H), 7.25−7.21 (m, 3H), 7.15−7.06 (m, 6H), 3.58 (s, 1H), 3.57 (s, 1H), 2.83−2.78 (m, 1H), 2.62−2.53 (m, 1H), 2.37−2.26 (m, 1H), 2.24 (t, J = 5.1 Hz, 1H), 2.22−2.19 (m, 1H), 2.18−2.11 (m, 1H), 2.02−1.96 (m, 1H), 1.77−1.69 (m, 1H), 1.58−1.41 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.30, 193.28, 164.53, 164.40, 144.56, 144.48, 138.90, 138.45, 131.14, 131.11, 130.09, 130.06, 129.99, 129.40, 129.37, 128.96, 128.93, 128.83, 128.61, 127.70, 127.63, 127.62, 127.47, 126.58, 126.57, 124.60, 124.58, 118.20, 118.17, 111.64, 111.59, 90.32, 90.28, 45.93, 45.83, 39.78, 39.71, 39.48, 39.36, 37.17, 37.12, 27.67, 27.60, 21.18, 21.05 ppm; IR (neat): υmax 2926, 2245, 1715, 1593, 1264, 733, 696 cm−1; HRMS (ESI) calcd for C35H32NO2 [M + H]+ 498.2428, found 498.2441. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-phenylpentanenitrile (7h). White solid (54%, 78.3 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); the title compound as a 1.0:1 mixture of

inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 6.9 Hz, 2H), 7.37 (d, J = 7.2 Hz, 3H), 7.33−7.27 (m, 5H), 7.27− 7.16 (m, 5H), 7.15−7.01 (m, 5H), 3.51−3.38 (m, 2H), 2.95−2.91 (m, 0.5H), 2.90−2.83 (m, 0.5H), 2.56−2.52 (m, 2H), 2.13 (t, J = 12.2 Hz, 0.5H), 2.07−1.94 (m, 2H), 1.90−1.76 (m, 1H), 1.69−1.61 (m, 0.5H); 13 C NMR (100 MHz, CDCl3): δ = 193.36, 193.30, 164.38, 164.30, 144.32, 144.18, 140.97, 140.78, 138.90, 138.86, 131.13, 131.07, 130.09, 130.06, 130.00, 129.97, 129.39, 129.36, 128.98, 128.94, 128.81, 128.59, 128.57, 127.70, 127.64, 127.61, 127.57, 127.55, 127.45, 127.41, 127.20, 127.15, 124.60, 124.58, 118.24, 118.18, 111.71, 111.50, 90.34, 90.17, 46.35, 45.76, 42.09, 42.07, 39.84, 39.80, 29.08, 29.01, 25.46, 25.36 ppm; IR (neat): υmax 2929, 2244, 1731, 1605, 1590, 1234, 723, 696 cm−1; HRMS (ESI) calcd for C34H29NNaO2 [M + Na]+ 506.2091, found 506.2078. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(p-tolyl)pentanenitrile (7i). White solid (50%, 74.6 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); the title compound as a 2.6:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.46− 7.36 (m, 6H), 7.35−7.30 (m, 3H), 7.24−7.20 (m, 2H), 7.12 (t, J = 6.7 Hz, 4H), 7.08−7.02 (m, 3H), 6.95 (s, 1H), 3.52−3.39 (m, 2H), 2.94− 2.86 (m, 0.7H), 2.86−2.81 (m, 0.3H), 2.51 (t, J = 7.6 Hz, 2H), 2.33 (s, 3H), 2.17−1.86 (m, 3H), 1.71−1.57 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.32, 193.28, 164.44, 164.30, 144.39, 144.21, 138.90, 137.89, 137.70, 137.16, 131.10, 131.05, 130.07, 130.03, 130.00, 129.59, 129.38, 129.35, 128.80, 128.55, 128.53, 127.68, 127.62, 127.59, 127.54, 127.41, 127.37, 127.03, 126.99, 124.58, 118.33, 118.28, 111.70, 111.49, 90.37, 90.21, 46.30, 45.71, 41.71, 41.68, 39.89, 39.80, 29.07, 28.99, 25.57, 25.47, 21.02, 21.00 ppm; IR (neat): υmax 2925, 2247, 1731, 1609, 1593, 1264, 732, 696 cm−1; HRMS (ESI) calcd for C35H32NO2 [M + H]+ 498.2428, found 498.2434. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(4-(tertbutyl)phenyl)pentanenitrile (7j). White solid (60%, 96.5 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); the title compound as a 1.0:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.44− 7.35 (m, 5H), 7.34−7.27 (m, 5H), 7.26−7.17 (m, 3H), 7.14−6.96 (m, 6H), 3.52−3.39 (m, 2H), 2.93−2.83 (m, 0.5H), 2.82−2.79 (m, 0.5H), 2.52−2.49 (m, 2H), 2.18−1.85 (m, 3H), 1.80−1.59 (m, 1H), 1.30 (s, 4.5H), 1.29 (s, 4.5H); 13C NMR (100 MHz, CDCl3): δ = 193.31, 193.30, 164.48, 164.35, 150.33, 150.31, 144.44, 144.23, 138.90, 138.88, 137.82, 137.65, 131.10, 131.03, 130.07, 130.00, 129.39, 129.33, 128.79, 128.76, 128.56, 128.53, 127.68, 127.64, 127.60, 127.54, 127.41, 127.37, 126.76, 126.74, 125.78, 125.76, 124.60, 118.41, 118.35, 111.71, 111.49, 90.41, 90.25, 46.32, 45.69, 41.53, 41.49, 40.01, 39.78, 34.42, 31.27, 28.94, 28.89, 25.50, 25.41 ppm; IR (neat): υmax 2960, 2246, 1716, 1609, 1593, 1244, 735, 696 cm−1; HRMS (ESI) calcd for C38H38NO2 [M + H]+ 540.2897, found 540.2921. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(4-chlorophenyl)pentanenitrile (7k). White solid (65%, 100.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.9:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.45− 7.40 (m, 2H), 7.40−7.33 (m, 4H), 7.32−7.18 (m, 7H), 7.16−6.96 (m, 6H), 3.52−3.35 (m, 2H), 2.97−2.87 (m, 0.7H), 2.87−2.78 (m, 0.3H), 2.53−2.49 (m, 2H), 2.16−2.09 (m, 0.7H), 2.03−1.94 (m, 1H), 1.95− 1.80 (m, 1H), 1.79−1.70 (m, 0.3H), 1.66−1.55 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.33, 193.27, 164.22, 164.17, 144.19, 144.12, 139.38, 139.18, 138.84, 138.80, 133.39, 131.19, 131.18, 130.15, 129.96, 129.93, 129.38, 129.32, 129.18, 129.15, 128.82, 128.64, 128.61, 128.56, 127.74, 127.70, 127.64, 127.54, 127.51, 124.59, 124.55, 117.92, 117.87, 111.69, 111.50, 90.22, 90.04, 46.41, 45.81, 41.52, 39.82, 29.07, 29.02, 25.44, 25.33 ppm; IR (neat): υmax 2925, 2247, 1732, 1608, 1592, 1259, 720, 694 cm−1; HRMS (ESI) calcd for C34H29ClNO2 [M + H]+ 518.1881, found 518.1892. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(4bromophenyl)pentanenitrile (7l). White solid (62%, 104.4 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 1.0:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.47−7.40 (m, 4H), 7.39 (d, J = 5.9 Hz, 2H), 7.36 (s, 1H), 7.32− 7.29 (m, 3H), 7.25−7.17 (m, 3H), 7.14−7.11 (m, 2H), 7.06 (t, J = 6.9 Hz, 3H), 6.93 (d, J = 8.4 Hz, 1H), 3.56−3.33 (m, 2H), 2.94−2.87 (m, 0.5H), 2.85−2.77 (m, 0.5H), 2.52−2.48 (m, 2H), 2.13−2.83 (m, 3H), 4247

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry 1.67−1.45 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.31, 193.25, 164.22, 164.16, 144.16, 144.09, 139.89, 139.70, 138.82, 138.78, 132.11, 132.08, 131.18, 131.16, 130.14, 130.12, 129.94, 129.91, 129.36, 129.30, 128.95, 128.91, 128.79, 128.64, 128.63, 127.73, 127.69, 127.63, 127.53, 127.49, 124.57, 124.53, 121.45, 117.90, 117.84, 111.67, 111.48, 90.20, 90.02, 46.38, 45.79, 41.56, 39.79, 28.99, 28.94, 25.34, 25.22 ppm; IR (neat): υmax 2920, 2246, 1715, 1608, 1592, 1259, 720, 696 cm−1; HRMS (ESI) calcd for C34H28BrNNaO2 [M + Na]+ 584.1196, found 584.1185. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(m-tolyl)pentanenitrile (7m). White solid (80%, 120.3 mg); Rf 0.25 (EtOAc/ petroleum ether = 1:3); the title compound as a 1.2:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.45− 7.36 (m, 5H), 7.33−7.28 (m, 3H), 7.26−7.17 (m, 4H), 7.13 (d, J = 8.2 Hz, 1H), 7.10−7.04 (m, 3H), 7.03 (t, J = 5.7 Hz, 1H), 6.98 (d, J = 5.9 Hz, 1H), 6.86 (d, J = 9.3 Hz, 1H), 3.53−3.37 (m, 2H), 2.96−2.85 (m, 0.5H), 2.85−2.74 (m, 0.5H), 2.55−2.50 (m, 2H), 2.41−2.36 (m, 0.3H), 2.32 (d, J = 12.6 Hz, 3H), 2.21−2.07 (m, 0.7H), 2.03−1.55 (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 193.38, 193.30, 164.44, 164.34, 144.26, 144.17, 140.90, 140.68, 138.84, 138.57, 138.51, 131.10, 131.05, 130.08, 130.04, 129.94, 129.38, 129.36, 128.81, 128.78, 128.55, 128.52, 128.29, 128.27, 127.84, 127.81, 127.67, 127.62, 127.58, 127.54, 127.41, 127.36, 124.74, 124.60, 124.56, 124.21, 124.14, 118.34, 118.28, 111.70, 111.46, 90.38, 90.18, 46.40, 45.73, 42.00, 41.95, 39.78, 39.73, 29.04, 28.93, 25.49, 25.37, 21.42, 21.39 ppm; IR (neat): υmax 2945, 2247, 1731, 1608, 1592, 1264, 733, 698 cm−1; HRMS (ESI) calcd for C35H32NO2 [M + H]+ 498.2428, found 498.2447. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(3bromophenyl)pentanenitrile (7n). White solid (49%, 82.5 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 5.3:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.49− 7.37 (m, 5H), 7.37−7.33 (m, 1H), 7.33−7.30 (m, 2H), 7.29 (d, J = 1.3 Hz, 1H), 7.27−7.15 (m, 5H), 7.15−7.07 (m, 3H), 7.06−7.00 (m, 2H), 3.56−3.36 (m, 2H), 2.95−2.85 (m, 0.2H), 2.85−2.73 (m, 0.8H), 2.60−2.43 (m, 2H), 2.31−1.64 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 193.34, 193.27, 164.32, 164.19, 144.10, 144.04, 143.33, 143.10, 138.84, 138.80, 131.18, 131.13, 130.82, 130.59, 130.55, 130.15, 130.10, 129.91, 129.36, 128.81, 128.69, 128.66, 127.73, 127.61, 127.55, 126.06, 126.00, 124.59, 124.50, 123.09, 123.04, 117.82, 117.76, 111.68, 111.46, 90.22, 90.02, 46.52, 45.90, 41.81, 41.77, 39.73, 39.68, 29.06, 28.96, 25.21, 21.13 ppm; IR (neat): υmax 2927, 2247, 1732, 1608, 1592, 1243, 721, 694 cm−1; HRMS (ESI) calcd for C34H29BrNO2 [M + H]+ 562.1376, found 562.1379. 5-(4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)-3-(2bromophenyl)pentanenitrile (7o). White solid (48%, 80.8 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); the title compound as a 4.0:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.59− 7.56 (m, 1H), 7.41−7.36(m, 5H), 7.35−7.29 (m, 3H), 7.27−7.19 (m, 4H), 7.16−7.09 (m, 3H), 7.09−6.99 (m, 3H), 3.65−3.51 (m, 1H), 3.46 (s, 2H), 2.65−2.51 (m, 2H), 2.26−2.01 (m, 2H), 1.94−1.82 (m, 1H), 1.80−1.70 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.34, 164.33, 164.29, 144.19, 139.45, 138.89, 138.85, 134.71, 133.41, 131.16, 130.13, 129.97, 129.45, 129.38, 129.00, 128.97, 128.85, 128.67, 128.63, 128.11, 127.72, 127.64, 127.53, 127.50, 127.41, 127.37, 125.11, 125.08, 124.61, 117.72, 111.67, 111.55, 90.22, 90.16, 46.34, 45.88, 39.79, 39.71, 39.65, 39.59, 27.84, 27.81, 24.00, 23.92 ppm; IR (neat): υmax 2951, 2245, 1732, 1600, 1589, 1232, 722, 696 cm−1; HRMS (ESI) calcd for C34H29BrNO2 [M + H]+ 562.1376, found 562.1385. 2-((4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetonitrile (7p). Faint yellow liquid (45%, 66.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); d.r. = 1.4:1; 1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 7.5 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.42−7.31 (m, 5H), 7.27−7.20 (m, 3H), 7.18−7.09 (m, 4H), 7.06 (t, J = 7.6 Hz, 3H), 3.66−3.50 (m, 2H), 3.22 (q, J = 6.1 Hz, 1H), 2.78−2.53 (m, 4H), 2.48−2.27 (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 193.3, 164.0, 144.6, 142.5, 142.0, 138.8, 131.2, 130.2, 129.9, 129.4, 128.9, 128.8, 127.8, 127.7, 127.6, 126.8, 124.7, 124.6, 123.3, 118.5, 111.6, 90.3, 47.4, 47.3, 47.1, 41.9, 39.0, 21.3 ppm; IR (neat): υmax 2921, 2244, 1731, 1608, 1593, 1263, 733, 695 cm−1;

HRMS (ESI) calcd for C35H29NNaO2 [M + Na]+ 518.2091, found 518.2106. 2-((4-Benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetonitrile (7p′). Faint yellow liquid (32%, 48.5 mg); Rf 0.3 (EtOAc/petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 7.55−7.53 (m, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.42− 7.36 (m, 4H), 7.35−7.32(m, 1H), 7.29−7.27 (d, J = 1.2 Hz, 0.3H), 7.25−7.20 (m, 2.7H), 7.18−7.13 (m, 5H), 7.07 (t, J = 7.7 Hz, 2H), 3.66−3.56 (m, 2H), 3.26−3.20 (m, 1H), 3.08−3.02 (m, 1H), 2.84− 2.78 (m, 1H), 2.61−2.57 (m, 1H), 2.53−2.41 (m, 3H), 2.14−2.01 (m, 1H); 13C NMR (101 MHz, CDCl3): δ = 193.2, 164.0, 144.4, 142.7, 141.9, 138.8, 131.2, 130.1, 129.9, 129.3, 128.8, 128.7, 127.7, 127.6, 127.6, 127.5, 126.7, 124.6, 124.5, 123.1, 118.4, 111.4, 90.7, 47.6, 47.1, 47.0, 42.6, 39.1, 20.9 ppm. 4-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)butanenitrile (8a). (Known compound)5e 1H NMR (400 MHz, CDCl3): δ = 3.83 (t, J = 5.8 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.94−1.81 (m, 2H), 1.62−1.48 (m, 1H), 1.43 (d, J = 6.9 Hz, 4H), 1.31 (d, J = 12.2 Hz, 1H), 1.14 (s, 6H), 1.08 (s, 6H); 13C NMR (101 MHz, CDCl3): δ = 119.6, 73.5, 59.7, 39.5, 33.0, 25.0, 20.0, 16.9, 14.3 ppm. Methyl 4-Benzoyl-2-(2-(3-(cyanomethyl)cyclopentyl)ethyl)-5phenyl-2,3-dihydrofuran-2-carboxylate (10a). Faint yellow liquid (40%, 50.2 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); the title compound as a 1.5:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.43−7.37 (m, 2H), 7.28−7.15 (m, 4H), 7.09−7.04 (m, 4H), 3.86 (s, 3H), 3.50 (d, J = 15.6 Hz, 1H), 3.34 (d, J = 15.6 Hz, 1H), 2.39−2.26 (m, 3H), 2.15−2.10 (m, 1H), 2.07−2.00 (m, 1H), 2.00−1.85 (m, 3H), 1.58−1.47 (m, 1H), 1.43−1.26 (m, 3H), 1.23−1.14 (m, 1H), 0.95−0.82 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 193.09, 172.94, 164.89, 138.57, 131.32, 130.19, 129.72, 129.58, 129.50, 128.89, 128.61, 128.45, 128.05, 127.66, 127.65, 119.21, 119.09, 111.15, 88.59, 53.40, 52.79, 42.28, 39.97, 39.57, 39.53, 38.61, 37.72, 36.59, 36.51, 36.12, 35.12, 32.58, 32.55, 32.17, 31.28, 31.22, 30.84, 30.10, 30.06, 23.16, 22.94 ppm; IR (neat): υmax 2951, 2246, 1742, 1612, 1594, 1257, 725, 695 cm−1; HRMS (ESI) calcd for C28H29NNaO4 [M + Na]+ 466.1989, found 466.1977. Methyl 4-Benzoyl-2-(2-(1-(cyanomethyl)-3-phenylcyclobutyl)ethyl)-5-phenyl-2,3-dihydrofuran-2-carboxylate (10b). Faint yellow liquid (61%, 92.5 mg); Rf 0.25 (EtOAc/petroleum ether = 1:3); the title compound as a 1.1:1 mixture of inseparable diastereomers; 1H NMR (400 MHz, CDCl3): δ = 7.46−7.39 (m, 2H), 7.33−7.27 (m, 3H), 7.27−7.15 (m, 6H), 7.12−7.03 (m, 4H), 3.91 (s, 1.6H), 3.89− 3.84 (m, 1.4H), 3.64−3.46 (m, 2H), 3.44−3.33 (m, 1H), 2.67 (s, 1H), 2.47 (s, 1H), 2.43−2.32 (m, 2H), 2.24−2.07 (m, 4H), 2.04−1.89 (m, 1H), 1.85−1.78 (m, 0.5H), 1.72−1.64 (m, 0.5H); 13C NMR (100 MHz, CDCl3): δ = 193.02, 192.99, 172.54, 172.45, 164.77, 144.40, 144.36, 138.45, 138.43, 131.44, 131.40, 130.32, 130.27, 129.52, 129.40, 129.37, 128.91, 128.90, 128.45, 128.44, 127.72, 127.69, 127.67, 126.39, 126.24, 126.22, 126.20, 118.05, 117.67, 111.12, 111.06, 88.11, 87.99, 53.01, 52.95, 42.59, 42.53, 38.41, 38.30, 38.25, 38.02, 36.13, 35.16, 34.23, 33.04, 32.60, 32.54, 31.99, 31.73, 28.35, 26.41 ppm; IR (neat): υmax 2956, 2248, 1741, 1611, 1594, 1245, 726, 696 cm−1; HRMS (ESI) calcd for C33H32NO4 [M + H]+ 506.2326, found 506.2349.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00271. 1

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H and 13C spectra of all new compounds; the primary mechanistic studies of the reactions (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Li-Na Guo: 0000-0002-9789-6952 4248

DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249

Note

The Journal of Organic Chemistry Notes

Guo, L.-N. Org. Lett. 2018, 20, 1034. (d) Zhao, J.-F.; Gao, P.; Duan, X.-H.; Guo, L.-N. Adv. Synth. Catal. 2018, 360. (8) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (b) May, E. L.; Jacobson, A. E.; Mattson, M. V.; Traynor, J. R.; Woods, J. H.; Harris, L. S.; Bowman, E. R.; Aceto, M. D. J. Med. Chem. 2000, 43, 5030. (c) Fleming, F. F.; Zhang, Z. Y. Tetrahedron 2005, 61, 747. (d) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902. (e) Yang, L. F.; Koh, S. L.; Sutton, P. W.; Liang, Z. X. Catal. Sci. Technol. 2014, 4, 2871. (f) Mac Sweeney, A.; Grosche, P.; Ellis, D.; Combrink, K.; Erbel, P.; Hughes, N.; Sirockin, F.; Melkko, S.; Bernardi, A.; Ramage, P.; Jarousse, N.; Altmann, E. ACS Med. Chem. Lett. 2014, 5, 937. (g) López, R.; Palomo, C. Angew. Chem., Int. Ed. 2015, 54, 13170. (9) Xu, H.-J.; Zhu, F.-F.; Shen, Y.-Y; Wan, X.; Feng, Y.-S. Tetrahedron 2012, 68, 4145. (10) (a) Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 13278. (b) Foo, K.; Sella, E.; Thome, I.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5279. (c) Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.; Ritter, T. Nat. Chem. 2016, 8, 810. (d) Svejstrup, T. D.; Ruffoni, A.; Julia, F.; Aubert, V. M.; Leonori, D. Angew. Chem., Int. Ed. 2017, 56, 14948.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from Natural Science Basic Research Plan in Shaanxi Province of China (No. 2016JZ002), and the Fundamental Research Funds of the Central Universities (Nos. zrzd2017001, xjj2016056 and 2015qngz17) is greatly appreciated. We thank Miss Lu at Instrument Analysis Center of Xi’an Jiaotong University for assistance with HRMS analysis.

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DOI: 10.1021/acs.joc.8b00271 J. Org. Chem. 2018, 83, 4239−4249