Divergent Synthesis of 2-Aminofurans via Palladium

Jul 6, 2015 - A fine-tunable transformation, including Pd-catalyzed acetoxylative, alkoxylative, and hydroxylative cycloisomerization of homoallenyl a...
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Divergent Synthesis of 2‑Aminofurans via Palladium-Catalyzed Acetoxylative, Alkoxylative, and Hydroxylative Cycloisomerization of Homoallenyl Amides Cungui Cheng, Shuiyou Liu, and Gangguo Zhu* Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China S Supporting Information *

ABSTRACT: A fine-tunable transformation, including Pd-catalyzed acetoxylative, alkoxylative, and hydroxylative cycloisomerization of homoallenyl amides, has been realized with hypervalent iodine organic compounds as the oxidants, giving polysubstituted 2-aminofurans in promising yields at room temperature. The selective formation of three different types of products from the same starting materials makes this reaction particularly attractive and useful for organic synthesis.

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INTRODUCTION

for instance, with the oxygenation process constitutes an appealing strategy in this field because this methodology can not only form a new C−O bond but also establish a carbo- or heterocycle in a single chemical transformation (Scheme 1b).7 In this paper, we report an operationally simple oxygenative, including acetoxylative, alkoxylative, and hydroxylative, cycloisomerization of homoallenyl amides catalyzed by Pd(OAc)2 with hypervalent iodine organic compounds as the oxidants,8 producing three different types of polysubstituted furans under very mild reaction conditions (Scheme 2b). Taken together with our9 recent report on the Pd-catalyzed cycloisomerization and aerobic oxidative cycloisomerization of homoallenyl amides (Scheme 2a),10,11 it provides a mild, highly efficient, and divergent method for the synthesis of 2-aminofurans, which may be interesting and useful for the diversity-oriented synthesis.12

1,2

Palladium-catalyzed C−H oxygenation, such as acetoxylation, alkoxylation,3,4 and hydroxylation,5 has been considerably advanced over the past decades due to its high efficiency in the establishment of C−O bonds. Along this line, a few elegant strategies, including the directing group-controlled, electronically activated, and catalyst-controlled approaches, have been developed to achieve high efficiency and site selectivity.6 It should be noted that, however, these transformations usually involve the formation of only one chemical bond (Scheme 1a). As compared with the traditional methods, the incorporation of Pd-catalyzed annulation, an intramolecular nucleopalladation, Scheme 1. Comparison of Pd-Catalyzed C−H Oxygenation with Pd-Catalyzed Annulative Oxygenation

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RESULTS AND DISCUSSION Initially, the homoallenyl amide 1a was treated with 5 mol % of Pd(OAc)2 and 0.7 equiv of PhI(OAc)2 in MeCN at room temperature (rt) under an air atmosphere for 3 h. As a result, the acetoxylative cycloisomerization product 2a was obtained in 76% yield, together with the formation of 2a′ in a 5% yield (Table 1, entry 1), which was believed to be generated by the Pd-catalyzed aerobic oxidative cycloisomerization reaction.9 Received: May 27, 2015 Published: July 6, 2015 © 2015 American Chemical Society

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DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

Article

The Journal of Organic Chemistry Scheme 2. Divergent Approaches to 2-Aminofurans

Table 1. Optimization of the Reaction Conditionsa

entry

PdX2

solvent

yieldb (%)

c

Pd(OAc)2 Pd(OAc)2 PdBr2 PdCl2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 /

MeCN MeCN MeCN MeCN THF DMF DMSO NMP HOAc PhMe CH2Cl2 MeCN MeCN MeCN

76 83 64 67 37 72 25 26 0 42 45 52 65 0

1 2 3 4 5 6 7 8 9 10 11 12d 13e 14 a

Reaction conditions: 1a (0.25 mmol), PdX2 (5 mol %), PhI(OAc)2 (0.175 mmol), solvent (1 mL), under N2, rt, 3 h. bIsolated yield. cThe reaction was run under an air atmosphere, and 2a′ was obtained as a byproduct in 5% yield. d0.3 mmol of PhI(OAc)2 was used. e0.125 mmol of PhI(OAc)2 was used.

With the optimum reaction conditions in hand, we then investigated a series of homoallenyl amides, and the results are summarized in Scheme 3. Amide 1c with an electron-donating methoxy group underwent the Pd-catalyzed acetoxylative cycloisomerization smoothly to afford 2c in 78% yield, while 1d possessing an electron-withdrawing nitro group provided 2d in 82% yield, implying that the electronic effect of R3 group has little impact on this reaction. Halogen atoms such as F, Cl, and Br were well compatible under the reaction conditions, thus enabling further functionalization at the halogenated positions (2e−h). In addition to 2-arylamides, 2-alkyl and 2-alkenyl substrates, 1j and 1k, for example, were successfully converted into the desired acetoxylation products in high yields (2j and 2k). An increase of the steric hindrance of N-substituents had no significant correlation with the reaction yield, as demonstrated by the facile formation of 2o. Moreover, this reaction was applicable to 1t, giving trisubstituted furan 2t in a good yield.

Not surprisingly, conducting the reaction under a N 2 atmosphere successfully suppressed the production of 2a′ and led to 83% yield of 2a as the sole product (Table 1, entry 2). Other palladium sources, such as PdCl2 and PdBr2, proved to be less effective for this reaction (Table 1, entries 3 and 4). A series of solvents, namely THF, DMF, DMSO, NMP, HOAc, PhMe, and CH2Cl2, were tested, and MeCN was shown to be the best-performing medium (Table 1, entries 5−11). Both increasing and decreasing the loading of PhI(OAc)2 gave diminished efficiency (Table 1, entries 12 and 13). Additionally, the reaction resulted in no detectable product 2a in the absence of Pd(OAc)2, indicating that the palladium catalyst is essential for this transformation (Table 1, entry 14). Therefore, the optimized reaction conditions for Pd-catalyzed acetoxylative cycloisomerization of homoallenyl amides comprised 5 mol % of Pd(OAc)2 and 0.7 equiv of PhI(OAc)2 in MeCN at rt under a N2 atmosphere for 3 h. 7605

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

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The Journal of Organic Chemistry Scheme 3. Scope of Pd-Catalyzed Acetoxylative Cycloisomerization of Homoallenyl Amidesa

Scheme 4. Scope of Pd-Catalyzed Alkoxylative Cycloisomerization of Homoallenyl Amidesa

a

Reaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol %), PhI(O2CCF3)2 (0.175 mmol), ROH (1 mL), under N2, rt, 6 h; yields refer to isolated yields. bPhI(OAc)2 was used.

as the oxidant, 1a produced methoxylation product 3a in 80% yield with a small amount of 2a (3%). To our delight, the formation of 2a was completely inhibited by replacing PhI(OAc)2 with PhI(O2CCF3)2, which delivered 3a in 85% yield upon isolation. We confirmed the structure of 3a by X-ray crystallography.13 As such, we have accomplished a simple, mild, and highly efficient Pd-catalyzed alkoxylative cycloisomerization of homoallenyl amides. The generality of this reaction was then evaluated. Indeed, we observed broad scope with regard to homoallenyl amides. The yield was not affected by electron-donating or electronwithdrawing substituents (3b and 3c). The sterically demanding substrates could also undergo the Pd-catalyzed cycloisomerizative methoxylation reaction as well exemplified by the production of 3h and 3i. Meanwhile, alcohols were also varied. Primary and secondary alcohols, including CD3OD, EtOH, nBuOH, and 2-propanol, could be incorporated successfully in high yields, while t-BuOH was almost unreactive under the reaction conditions, probably due to the increased steric environment (3j−n). Notably, the reaction with allyl and propargyl alcohols took place efficiently to generate the expected products in good yields, leaving the C−C double

a

Reaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol %), PhI(OAc)2 (0.175 mmol), MeCN (1 mL), under N2, rt, 3 h; yields refer to isolated yields.

The reaction of 1u produced 2-aminofuran 2u in 66% yield, whereas the bulkier substrate 1v failed to provide the desired product 2v due to the formation of some unidentified byproducts, indicating that the steric environment of the C5 site may be detrimental to the reaction. Furthermore, the use of PhI(OPiv)2 in place of PhI(OAc)2 was also effective, producing 2w in a satisfactory yield. One of the structures of 2aminofurans, 2p, was established by an X-ray diffraction analysis.13 Subsequently, we set out to investigate the Pd-catalyzed alkoxylative cycloisomerization of homoallenyl amides (Scheme 4). With MeOH as the solvent as well as coupling partner, 5 mol % of Pd(OAc)2 as the catalyst, and 0.7 equiv of PhI(OAc)2 7606

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

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The Journal of Organic Chemistry

provides the acetoxylation products 2 together with the regeneration of Pd(II) catalyst. Meanwhile, a ligand exchange may occur in the presence of ROH, delivering a Pd(IV) intermediate IV under the reaction conditions. Likewise, the C−OR bond-forming reductive elimination generates the alkoxylation products 3 and closes the catalytic cycle.

and triple bonds untouched under the standard conditions (3p and 3q). In contrast to the Pd-catalyzed acetoxylation and alkyoxylation,1−4 the Pd-catalyzed hydroxylation5 appears to be a more demanding task. In light of the above results, we then turned our attention to the Pd-catalyzed cycloisomerization/ acetoxylation/deacetylation domino process (Scheme 5).

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CONCLUSION In conclusion, an operationally simple, highly efficient, and divergent transformation including Pd-catalyzed acetoxylative, alkoxylative, and hydroxylative cycloisomerization of homoallenyl amides has been realized with hypervalent iodine organic compounds as the oxidants, giving three different types of 2-aminofurans in promising yields at room temperature. The selective construction of different types of products from the same starting materials under mild reaction conditions makes this reaction particularly attractive for organic synthesis. Moreover, the incorporation of oxidative C−H functionalization with Pd(II)-catalyzed cyclization process may result in the realization of new synthetically useful reactions. Further studies are currently underway to investigate the synthetic application of this method.

Scheme 5. Pd-Catalyzed Hydroxylative Cycloisomerization of Homoallenyl Amidesa

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EXPERIMENTAL SECTION

General Methods. Melting points were measured by a melting point instrument and were uncorrected. Unless otherwise noted, chemicals were used directly from commercial suppliers without further purification. 1H, 13C, and 19F NMR spectra were measured on a 600 or 400 MHz NMR spectrometer using CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard. Chemical shifts are given in δ relative to TMS, and the coupling constants are given in hertz. High-resolution mass spectra (HRMS) analyses were carried out using a TOF MS instrument with an ESI source. Column chromatography was performed with silica gel (300−400 mesh) using petroleum ether/EtOAc as the eluent. General Procedure for Pd-Catalyzed Acetoxylation of Homoallenyl Amides. To a solution of 1a (80 mg, 0.25 mmol) and PhI(OAc)2 (56 mg, 0.175 mmol) in 1 mL of MeCN was added Pd(OAc)2 (2.8 mg, 0.0125 mmol) under a nitrogen atmosphere. After being stirred at room temperature for 3 h, the reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated. Column chromatography on silica gel (EtOAc/petroleum ether = 1:4) gave 79 mg (yield: 83%) of (5-(N-butylmethylsulfonamido)-3-methyl-4-phenylfuran-2-yl)methyl acetate (2a) as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.48−7.44 (m, 2H), 7.42−7.38 (m, 2H), 7.35−7.31 (m, 1H), 5.06 (s, 2H), 3.42 (t, J = 7.1 Hz, 2H), 3.04 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.28−1.23 (m, 2H), 1.12−1.04 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.6, 143.0, 140.9, 130.8, 129.1, 128.3, 127.6, 124.6, 121.3, 56.2, 50.9, 39.6, 30.2, 20.8, 19.4, 13.4, 9.1; IR (KBr) 3052, 1742, 1644, 1606, 1582, 1479, 1445, 1375, 1342, 1148, 1080 cm−1; HRMS (ESI) calcd for C19H25NNaO5S (M + Na)+ 402.1351, found 402.1350. (5-(N-Butylmethylsulfonamido)-3-methyl-4-p-tolylfuran-2-yl)methyl acetate (2b): 80 mg, 81% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 5.05 (s, 2H), 3.42 (t, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.30−1.25 (m, 2H), 1.14−1.07 (m, 2H), 0.70 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170. 6, 142.8, 140.8, 137.3, 129.0, 128.9, 127.8, 124.5, 121.4, 56.2, 50.8, 39.6, 30.3, 21.1, 20.8, 19.4, 13.4, 9.1; IR (KBr) 3028, 1750, 1646, 1616, 1587, 1514, 1456, 1380, 1324, 1145, 1078 cm−1; HRMS (ESI) calcd for C20H27NNaO5S (M + Na)+ 416.1508, found 416.1507. (5-(N-Butylmethylsulfonamido)-4-(4-methoxyphenyl)-3-methylfuran-2-yl)methyl acetate (2c): 80 mg, 78% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.41−7.37 (m, 2H), 6.97−6.92 (m, 2H), 5.04 (s, 2H), 3.83 (s, 3H), 3.42 (t, J = 7.2 Hz, 2H), 3.04 (s, 3H), 2.10

a Reaction conditions: 1a (0.25 mmol), Pd(OAc)2 (5 mol %), Pd(O2CCF3)2 (0.175 mmol), MeCN/H2O (v/v = 1:1), under N2, rt, 6 h; yields refer to isolated yields.

Treating 1a with Pd(OAc)2 (5 mol %), PhI(O2CCF3)2 (0.7 equiv), and K2CO3 (1.0 equiv) in MeCN or alcohols like tBuOH gave the desired product 4a in low yields. After some trials, using 0.3 equiv of KOH as the base, PhI(O2CCF3)2 as the oxidant, and a 1:1 mixture of MeCN and H2O as the solvent, 4a was obtained in 80% yield. It represents a formal Pd-catalyzed hydroxylative cycloisomerization of homoallenyl amides. The scope of this reaction proved to be satisfactory, as indicated by the convenient synthesis of 2-aminofurans 4b−e. In contrast, no product formation was observed when 1v was employed as the substrate (4f). On the basis of the above results and previous reports,1−4 a possible mechanism for this Pd-catalyzed oxygenative cycloisomerization reaction is proposed in Scheme 6.14 First, an intramolecular oxypalladation of 1 followed by a deprotonation gives the furfurylpalladium intermediate II,9 which is subsequently oxidized with the hypervalent iodine organic compounds as the oxidants8 to form a high-valent palladium species III. The reductive elimination of C−OAc bonds of III Scheme 6. Plausible Mechanism

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The Journal of Organic Chemistry

2.39−2.31 (m, 2H), 2.07 (s, 3H), 2.01 (s, 3H), 1.52−1.44 (m, 4H), 1.39−1.28(m, 8H), 0.94−0.87 (m, 6H); 13C NMR (151 MHz, CDCl3) δ 170.6, 142.5, 140.2, 124.3, 121.9, 56.2, 50.2, 38.6, 31.5, 30.5, 29.6, 29.0, 23.6, 22.6, 20.8, 19.6, 14.0, 13.6, 8.7; IR (KBr) 3027, 1740, 1651, 1589, 1459, 1375, 1345, 1162, 1076 cm−1; HRMS (ESI) calcd for C19H33NNaO5S (M + Na)+ 410.1977, found 410.1979. (E)-(5-(N-Butylmethylsulfonamido)-3-methyl-4-styrylfuran-2-yl)methyl acetate (2k): 81 mg, 80% yield, white solid, mp: 95−97 °C; 1 H NMR (600 MHz, CDCl3) δ 7.49−7.45 (m, 2H), 7.37−7.31 (m, 2H), 7.27−7.23 (m, 1H), 7.05 (d, J = 16.8 Hz, 1H), 6.91 (d, J = 16.8 Hz, 1H), 5.02 (s, 2H), 3.59 (t, J = 7.3 Hz, 2H), 3.06 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H), 1.52−1.46 (m, 2H), 1.40−1.34 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.5, 143.5, 141.6, 137.3, 130.8, 128.5, 127.6, 126.3, 121.2, 120.5, 117.7, 55.8, 50.4, 39.0, 30.3, 20.8, 19.6, 13.5, 10.3; IR (KBr) 3055, 1733, 1650, 1597, 1567, 1497, 1371, 1344, 1165, 1078 cm−1; HRMS (ESI) calcd for C21H27NNaO5S (M + Na)+ 428.1508, found 428.1506. (5-(N-Butyl-4-methylphenylsulfonamido)-3-methyl-4-phenylfuran-2-yl)methyl acetate (2l): 98 mg, 86% yield, white solid, mp: 109− 111 °C; 1H NMR (600 MHz, CDCl3) δ 7.75−7.69 (m, 2H), 7.49− 7.26 (m, 7H), 5.00 (s, 2H), 3.24 (t, J = 7.1 Hz, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.21−1.13 (m, 2H), 1.05−0.97 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.6, 143.7, 142.7, 140.9, 136.1, 131.1, 129.4, 129.2, 128.3, 128.2, 127.4, 125.2, 121.2, 56.3, 50.2, 29.9, 21.6, 20.9, 19.4, 13.4, 9.2; IR (KBr) 3059, 1737, 1642, 1608, 1587, 1495, 1446, 1377, 1342, 1162, 1082 cm−1; HRMS (ESI) calcd for C25H29NNaO5S (M + Na)+ 478.1664, found 478.1671. (3-Methyl-5-(N-methylmethylsulfonamido)-4-phenylfuran-2-yl)methyl acetate (2m): 62 mg, 74% yield, white solid, mp: 73−75 °C; 1 H NMR (600 MHz, CDCl3) δ 7.46−7.31 (m, 5H), 5.05 (s, 2H), 3.15 (s, 3H), 2.95 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 170.5, 142.7, 142.4, 130.7, 128.8, 128.4, 127.5, 122.6, 121.2, 56.1, 38.5, 38.0, 20.7, 9.0; IR (KBr) 3060, 1729,1642, 1606, 1581, 1497, 1448, 1378, 1340, 1147, 1068 cm−1; HRMS (ESI) calcd for C16H19NNaO5S (M + Na)+ 360.0882, found 360.0884. (5-(N-Benzylmethylsulfonamido)-3-methyl-4-phenylfuran-2-yl)methyl acetate (2n): 88 mg, 85% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.32−7.26 (m, 3H), 7.23−6.99 (m, 7H), 5.03 (s, 2H), 4.56 (s, 2H), 2.99 (s, 3H), 2.11 (s, 3H), 1.94 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 170.5, 142.9, 140.8, 134.4, 130.5, 128.9, 128.9, 128.2, 128.1, 128.0, 127.4, 124.5, 121.3, 56.2, 54.8, 40.4, 20.8, 9.0; IR (KBr) 3032, 1737, 1643, 1607, 1583, 1496, 1455, 1377, 1344, 1153, 1080 cm−1; HRMS (ESI) calcd for C22H23NNaO5S (M + Na)+ 436.1195, found 436.1194. (5-(N-Cyclohexylmethylsulfonamido)-3-methyl-4-phenylfuran-2yl)methyl acetate (2o): 82 mg, 81% yield, white solid, mp: 68−70 °C; 1 H NMR (600 MHz, CDCl3) δ 7.52−7.46 (m, 2H), 7.41−7.30 (m, 3H), 5.06 (s, 2H), 3.76−3.68 (m, 1H), 3.11 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.70−1.44 (m, 5H), 1.23−1.15 (m, 2H), 0.95−0.81 (m, 3H); 13 C NMR (151 MHz, CDCl3) δ 170.6, 143.1, 139.3, 131.3, 129.3, 128.2, 127.5, 125.9, 121.2, 61.2, 56.3, 41.4, 32.2, 25.6, 24.8, 20.9, 9.2; IR (KBr) 3060, 1726, 1640, 1606, 1579, 1497, 1452, 1362, 1331, 1146, 1088 cm−1; HRMS (ESI) calcd for C21H27NNaO5S (M + Na)+ 428.1508, found 428.1510. (3-Methyl-4-phenyl-5-(N-phenylmethylsulfonamido)furan-2-yl)methyl acetate (2p): 88 mg, 88% yield, white solid, mp 133−135 °C; 1 H NMR (600 MHz, CDCl3) δ 7.40−7.25 (m, 10H), 5.11 (s, 2H), 3.10 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 170.7, 143.3, 141.5, 139.7, 130.6, 129.3, 129.0, 128.3, 127.9, 127.6, 126.9, 123.9, 121.7, 56.2, 39.6, 20.9, 9.1; IR (KBr) 3029, 1740, 1644, 1606, 1585, 1484, 1347, 1154, 1076 cm−1; HRMS (ESI) calcd for C21H21NNaO5S (M + Na)+ 422.1038, found 422.1044. Crystal data for 2p (C21H21NO5S, 399.46): monoclinic, space group P1̅, a = 9.9015(5) Å, b = 13.1057(7) Å, c = 16.6329(9) Å, U = 1990.33(18) Å3, Z = 4, T = 296(2) K, absorption coefficient 0.195 mm−1, reflections collected 68168, independent reflections 9278 [R(int) = 0.1029], refinement by full-matrix least-squares on F 2, data/restraints/ parameters 9278/0/505, goodness-of-fit on F2 = 1.085, final R indices [I > 2s(I)] R1 = 0.0811, wR2 = 0.1492, R indices (all data) R1 = 0.1413, wR2 = 0.1735, largest diff peak and hole 0.278 and −0.310 e·Å−3.

(s, 3H), 2.03 (s, 3H), 1.29−1.24 (m, 2H), 1.14−1.07 (m, 2H), 0.70 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.6, 159.0, 142.8, 140.7, 130.3, 124.3, 123.1, 121.4, 113. 8, 56.2, 55.1, 50.8, 39.6, 30.3, 20.8, 19.4, 13.4, 9.2; IR (KBr) 3008, 1740, 1645, 1613, 1585, 1512, 1458, 1375, 1341, 1147, 1077 cm−1; HRMS (ESI) calcd for C20H27NNaO6S (M + Na)+ 432.1457, found 432.1457. (5-(N-Butylmethylsulfonamido)-3-methyl-4-(4-nitrophenyl)furan-2-yl)methyl acetate (2d): 87 mg, 82% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 3.45 (t, J = 7.2 Hz, 2H), 3.14 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 1.27−1.19 (m, 2H), 1.12−1.04 (m, 2H), 0.69 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.5, 147.1, 143.9, 141.6, 137.9, 129.9, 123.6, 123.2, 120.8, 55.9, 50.8, 39.3, 30.1, 20.8, 19.3, 13.3, 9.2; IR (KBr) 3080, 1751, 1640, 1600, 1579, 1518, 1456, 1340, 1147, 1078 cm−1; HRMS (ESI) calcd for C19H24N2NaO7S (M + Na)+ 447.1202, found 447.1199. (5-(N-Butylmethylsulfonamido)-4-(4-fluorophenyl)-3-methylfuran-2-yl)methyl acetate (2e): 75 mg, 76% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.48−7.43 (m, 2H), 7.14−7.07 (m, 2H), 5.05 (s, 2H), 3.42 (t, J = 7.1 Hz, 2H), 3.08 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.26−1.20 (m, 2H), 1.12−1.03 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.6, 162.3 (d, J = 247.1 Hz), 143.1, 140.9, 130.9 (d, J = 8.0 Hz), 126.8 (d, J = 3.3 Hz), 123.9, 121.3, 115.4 (d, J = 21.5 Hz), 56.2, 50.8, 39.5, 30.2, 20.8, 19.4, 13.4, 9.1; 19F NMR (565 MHz, CDCl3) δ −114.2; IR (KBr) 3024, 1739, 1645, 1608, 1585, 1509, 1456, 1343, 1159, 1078 cm−1; HRMS (ESI) calcd for C19H24FNNaO5S (M + Na)+ 420.1257, found 420.1259. (4-(4-Bromophenyl)-5-(N-butylmethylsulfonamido)-3-methylfuran-2-yl)methyl acetate (2f): 97 mg, 85% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 5.05 (s, 2H), 3.42 (t, J = 7.1 Hz, 2H), 3.08 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.27−1.20 (m, 2H), 1.14−1.04(m, 2H), 0.70 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 143.3, 140.9, 131.5, 130.7, 129.8, 123.7, 121.9, 121.0, 56.1, 50.8, 39.5, 30.2, 20.8, 19.4, 13.4, 9.1; IR (KBr) 3016, 1739, 1644, 1601, 1578, 1489, 1456, 1343, 1160, 1072 cm−1; HRMS (ESI) calcd for C19H2479BrNNaO5S (M + Na)+ 480.0456, found 480.0454. (5-(N-Butylmethylsulfonamido)-4-(4-chlorophenyl)-3-methylfuran-2-yl)methyl acetate (2g): 86 mg, 83% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.46−7.36 (m, 4H), 5.05 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 3.08 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.27−1.20 (m, 2H), 1.14−1.05 (m, 2H), 0.70 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 143.2, 140.9, 133.6, 130.4, 129.3, 128.6, 123.7, 121.1, 56.1, 50.8, 39.5, 30.1, 20.8, 19.4, 13.3, 9.1; IR (KBr) 3012, 1739, 1644, 1605, 1581, 1493, 1456, 1343, 1160, 1090 cm−1; HRMS (ESI) calcd for C19H2435ClNNaO5S (M + Na)+ 436.0961, found 436.0963. (5-(N-Butylmethylsulfonamido)-4-(2-chlorophenyl)-3-methylfuran-2-yl)methyl acetate (2h): 84 mg, 81% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.60−7.53 (m, 1H), 7.48−7.40 (m, 1H), 7.36− 7.29 (m, 2H), 5.06 (s, 2H), 3.49−3.33 (m, 2H), 3.06 (s, 3H), 2.11 (s, 3H), 1.93 (s, 3H), 1.39−1.29 (m, 2H), 1.14−1.00 (m, 2H), 0.74 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 142.7, 141.2, 133.9, 132.8, 129.9, 129.6, 129.1, 126.9, 123.1, 122.8, 56.2, 50.7, 39.5, 30.0, 20.8, 19.3, 13.4, 8.9; IR (KBr) 3030, 1735, 1645, 1601, 1581, 1475, 1339, 1148, 1081 cm − 1 ; HRMS (ESI) calcd for C19H2435ClNNaO5S (M + Na)+ 436.0961, found 436.0964. (5-(N-Butylmethylsulfonamido)-3-methyl-4-(naphthalen-2-yl)furan-2-yl)methyl acetate (2i): 86 mg, 80% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.91−7.84 (m, 2H), 7.67−7.59 (m, 2H), 7.54−7.44 (m, 3H), 5.12 (s, 2H), 3.35 (t, J = 6.8 Hz, 2H), 2.91 (s, 3H), 2.14 (s, 3H), 1.80 (s, 3H), 1.26−1.18 (m, 2H), 1.00−0.82 (m, 2H), 0.46 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.6, 142.7, 141.8, 133.4, 132.0, 128.6, 128.5, 128.3, 128.2, 126.1, 125.7, 125.4, 125.4, 123.3, 123.1, 56.3, 50.7, 39.6, 30.3, 20.9, 19.2, 13.1, 9.0; IR (KBr) 3049, 1748, 1645, 1599, 1575, 1508, 1379, 1341, 1147, 1051 cm−1; HRMS (ESI) calcd for C23H27NNaO5S (M + Na)+ 452.1508, found 452.1509. (5-(N-Butylmethylsulfonamido)-4-hexyl-3-methylfuran-2-yl)methyl acetate (2j): 73 mg, 75% yield, colorless oil; 1H NMR (600 MHz, CDCl3): δ 4.96 (s, 2H), 3.53 (t, J = 7.3 Hz, 2H), 3.00 (s, 3H), 7608

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

Article

The Journal of Organic Chemistry

Column chromatography on silica gel (EtOAc/petroleum ether = 1:6) gave 75 mg (yield: 85%) of N-butyl-N-(5-(methoxymethyl)-4-methyl3-phenylfuran-2-yl)methanesulfonamide (3a) as a white solid: mp 104−106 °C. 1H NMR (400 MHz, CDCl3) δ 7.50−7.44 (m, 2H), 7.43−7.37 (m, 2H), 7.35−7.29 (m, 1H), 4.39 (s, 2H), 3.44−3.38 (m, 5H), 3.03 (s, 3H), 2.03 (s, 3H), 1.30−1.20 (m, 2H), 1.13−1.02 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.1, 140.4, 131.1, 129.2, 128.3, 127.5, 124.6, 120.2, 64.4, 57.8, 50.7, 39.6, 30.3, 19.4, 13.4, 9.2; IR (KBr) 3061, 1645, 1600, 1587, 1499, 1343, 1158, 1073 cm−1; HRMS (ESI) calcd for C18H25NNaO4S (M + Na)+ 374.1402, found 374.1410. Crystal data for 3a (C18H25NO4S, 351.45): triclinic, space group P1̅, a = 7.6255(3) Å, b = 9.5630(3) Å, c = 13.5894(5) Å, U = 950.48(6) Å3, Z = 2, T = 296(2) K, absorption coefficient 0.190 mm−1, reflections collected 32570, independent reflections 4428 [R(int) = 0.0688], refinement by full-matrix leastsquares on F2, data/restraints/parameters 4428/0/218, goodness-of-fit on F2 = 1.282, final R indices [I > 2s(I)] R1 = 0.0626, wR2 = 0.1845, R indices (all data) R1 = 0.0899, wR2 = 0.2045, largest diff peak and hole 0.433 and −0.398 e.Å−3. Crystallographic data for the structure 3a have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 1061729. N-Butyl-N-(5-(methoxymethyl)-3-(4-methoxyphenyl)-4-methylfuran-2-yl)methanesulfonamide (3b): 78 mg, 82% yield, colorless oil; 1 H NMR (600 MHz, CDCl3) δ 7.42−7.37 (m, 2H), 6.96−6.92 (m, 2H), 4.38 (s, 2H), 3.83 (s, 3H), 3.41 (t, J = 7.2 Hz, 2H), 3.39 (s, 3H), 3.04 (s, 3H), 2.02 (s, 3H), 1.30−1.22 (m, 2H), 1.12−1.06 (m, 2H), 0.69 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 159.0, 145.0, 140.2, 130.3, 124.2, 123.4, 120.3, 113.8, 64.4, 57.8, 55.2, 50.8, 39.7, 30.3, 19.5, 13.4, 9.2; IR (KBr) 3045, 1643, 1611, 1587, 1513, 1455, 1378, 1341, 1145, 1087 cm−1; HRMS (ESI) calcd for C19H27NNaO5S (M + Na)+ 404.1508, found 404.1519. N-Butyl-N-(5-(methoxymethyl)-4-methyl-3-(4-nitrophenyl)furan2-yl)methanesulfonamide (3c): 80 mg, 81% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 8.29−8.26 (m, 2H), 7.72−7.68 (m, 2H), 4.40 (s, 2H), 3.43 (t, J = 7.2 Hz, 2H), 3.40 (s, 3H), 3.12 (s, 3H), 2.06 (s, 3H), 1.24−1.18(m, 2H), 1.10−1.03 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 147.2, 146.1, 141.2, 138.2, 130.0, 123.7, 123.2, 119.7, 64.3, 58.0, 50.8, 39.4, 30.2, 19.4, 13.4, 9.3; IR (KBr) 3076, 1639, 1600, 1579, 1517, 1456, 1378, 1339, 1151, 1082 cm−1; HRMS (ESI) calcd for C18H24N2NaO6S (M + Na)+ 419.1253, found 419.1264. (E)-N-Butyl-N-(5-(methoxymethyl)-4-methyl-3-styrylfuran-2-yl)methanesulfonamide (3d): 70 mg, 74% yield, colorless oil; 1H NMR (600 MHz, CDCl3); δ 7.49−7.45 (m, 2H), 7.36−7.32 (m, 2H), 7.26− 7.22 (m, 1H), 7.05 (d, J = 16.8 Hz, 1H), 6.92 (d, J = 16.8 Hz, 1H), 4.37 (s, 2H), 3.60 (t, J = 7.3 Hz, 2H), 3.35 (s, 3H), 3.05 (s, 3H), 2.25 (s, 3H), 1.52−1.46 (m, 2H), 1.40−1.33 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 145.6, 141.3, 137.5, 130.6, 128.6, 127.6, 126.4, 121.2, 119.4, 118.1, 64.0, 57.7, 50.5, 39.1, 30.5, 19.7, 13.6, 10.4; IR (KBr) 3055, 3026, 1650, 1603, 1568, 1494, 1449, 1344, 1149, 1082 cm−1; HRMS (ESI) calcd for C20H27NNaO4S (M + Na)+ 400.1558, found 400.1571. N-Butyl-N-(3-hexyl-5-(methoxymethyl)-4-methylfuran-2-yl)methanesulfonamide (3e): 58 mg, 65% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 4.30 (s, 2H), 3.54−3.51 (m, 2H), 3.32 (s, 3H), 2.98 (s, 3H), 2.37−2.33 (m, 2H), 2.00 (s, 3H), 1.52−1.45 (m, 4H), 1.38−1.25 (m, 8H), 0.91−0.88 (m, 6H); 13C NMR (151 MHz, CDCl 3) δ 144.7, 139.8, 124.2, 120.8, 64.3, 57.6, 50.2, 38.7, 31.6, 30.6, 29.6, 29.1, 23.6, 22.6, 19.7, 14.0, 13.6, 8.8; IR (KBr) 1588, 1539, 1459, 1378, 1345, 1161, 1084 cm−1; HRMS (ESI) calcd for C18H33NNaO4S (M + Na)+ 382.2028, found 382.2037. N-(5-(Methoxymethyl)-3-phenylfuran-2-yl)-N-methylmethanesulfonamide (3f): 52 mg, 70% yield, white solid, mp: 100−102 °C; 1H NMR (600 MHz, CDCl3) δ 7.68−7.62 (m, 2H), 7.41−7.37 (m, 2H), 7.32−7.29 (m, 1H), 6.62 (s, 1H), 4.38 (s, 2H), 3.41 (s, 3H), 3.26 (s, 3H), 3.08 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 149.2, 141.8, 130.9, 128.7, 127.7, 126.9, 121.4, 110.9, 66.5, 58.1, 38.6, 37.9; IR (KBr) 3080, 3029, 1639, 1603, 1573, 1496, 1445, 1379, 1329, 1143, 1078 cm−1; HRMS (ESI) calcd for C14H17NNaO4S (M + Na)+ 318.0776, found 318.0781.

Crystallographic data for the structure 2p have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 1061728. (3-Butyl-5-(N-butylmethylsulfonamido)-4-phenylfuran-2-yl)methyl acetate (2q): 95 mg, 90% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.44−7.32 (m, 5H), 5.05 (s, 2H), 3.40 (t, J = 7.1 Hz, 2H), 3.01 (s, 3H), 2.48−2.40 (m, 2H), 2.11 (s, 3H), 1.30−1.04 (m, 8H), 0.77 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 142.7, 141.0, 131.1, 129.2, 128.2, 127.5, 126.3, 124.4, 56.3, 50.8, 39.5, 32.3, 30.3, 23.1, 22.1, 20.8, 19.3, 13.5, 13.4; IR (KBr) 3052, 1740, 1639, 1606, 1581, 1496, 1375, 1347, 1161, 1093 cm−1; HRMS (ESI) calcd for C22H31NNaO5S (M + Na)+ 444.1821, found 444.1827. (5-(N-Butylmethylsulfonamido)-3,4-diphenylfuran-2-yl)methyl acetate (2r): 92 mg, 82% yield, white solid, mp: 102−104 °C; 1H NMR (400 MHz, CDCl3) δ 7.44−7.32 (m, 5H), 5.11 (s, 2H), 3.38 (t, J = 7.1 Hz, 2H), 2.96 (s, 3H), 2.49−2.38 (m, 1H), 2.12 (s, 3H), 1.79− 1.60 (m, 5H), 1.40−1.05 (m, 9H), 0.72 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 142.0, 140.8, 131.4, 131.1, 123.0, 128.1, 127.6, 124.5, 57.5, 50.8, 39.5, 35.3, 33.3, 30.3, 26.7, 25.7, 20.9, 19.3, 13.4; IR (KBr) 3055, 1730, 1637, 1600, 1577, 1493, 1449, 1347, 1146, 1076 cm−1; HRMS (ESI) calcd for C24H33NNaO5S (M + Na)+ 470.1977, found 470.1982. (5-(N-Butylmethylsulfonamido)-3,4-diphenylfuran-2-yl)methyl acetate (2s): 85 mg, 77% yield, white solid, mp: 104−106 °C; 1H NMR (400 MHz, CDCl3) δ 7.30−7.24 (m, 8H), 7.15−7.10 (m, 2H), 5.05 (s, 2H), 3.47 (t, J = 7.1 Hz, 2H), 3.08 (s, 3H), 2.13 (s, 3H), 1.35− 1.26 (m, 2H), 1.17−1.06 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 143.3, 141.8, 130.9, 130.3, 129.6, 129.5, 128.4, 128.2, 127.8, 127.6, 127.6, 123.7, 57.14, 51.2, 39.9, 30.4, 20.9, 19.5, 13.4; IR (KBr) 3034, 1735, 1630, 1608, 1574, 1494, 1443, 1347, 1147, 1076 cm−1; HRMS (ESI) calcd for C24H27NNaO5S (M + Na)+ 464.1508, found 464.1514. (5-(N-Methylmethylsulfonamido)-4-phenylfuran-2-yl)methyl acetate (2t): 53 mg, 65% yield, white solid, mp: 97−99 °C; 1H NMR (600 MHz, CDCl3) δ 7.68−7.60 (m, 2H), 7.43−7.39 (m, 2H), 7.34− 7.29 (m, 1H), 6.70 (s, 1H), 5.03 (s, 2H), 3.27 (s, 3H), 3.08 (s, 3H), 2.11 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 170.5, 147.1, 142.0, 130.6, 128.7, 127.8, 126.9, 121.6, 112.1, 57.9, 38.5, 37.9, 20.8; IR (KBr) 3117, 3053, 1740, 1638, 1602, 1573, 1498, 1439, 1378, 1345, 1151, 1070 cm−1; HRMS (ESI) calcd for C15H17NNaO5S (M + Na)+ 346.0725, found 346.0723. 1-(5-(N-Butylmethylsulfonamido)-4-phenylfuran-2-yl)ethyl acetate (2u): 63 mg, 66% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.70−7.64 (m, 2H), 7.41−7.35 (m, 2H), 7.32−7.27 (m, 1H), 6.61 (s, 1H), 5.93 (q, J = 6.7 Hz, 1H), 3.57−3.49 (m, 2H), 3.09 (s, 3H), 2.08 (s, 3H), 1.60 (d, J = 6.7 Hz, 3H), 1.39−1.32 (m, 2H), 1.25−1.16 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 151.1, 140.0, 130.9, 128.6, 127.7, 127.2, 123.2, 109.4, 64.8, 51.1, 39.6, 30.3, 21.2, 19.7, 17.9, 13.5; IR (KBr) 3110, 3058, 1735, 1639, 1595, 1578, 1492, 1436, 1375, 1342, 1156, 1078 cm−1; HRMS (ESI) calcd for C19H25NNaO5S (M + Na)+ 402.1351, found 402.1356. (5-(N-Butylmethylsulfonamido)-3-methyl-4-phenylfuran-2-yl)methyl pivalate (2w): 74 mg, 70% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.49−7.45 (m, 2H), 7.42−7.38 (m, 2H), 7.36−7.31 (m, 1H), 5.05 (s, 2H), 3.42 (t, J = 7.2 Hz, 2H), 3.02 (s, 3H), 2.04 (s, 3H), 1.29−1.24 (m, 2H), 1.22 (s, 9H), 1.12−1.06 (m, 2H), 0.69 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 178.1, 143.3, 140.8, 130.9, 129.1, 128.3, 127.6, 124.5, 120.8, 56.4, 50.9, 39.6, 38.8, 30.3, 27.1, 19.4, 13.4, 9.1; IR (KBr) 3052, 1728, 1643, 1607, 1584, 1497, 1397, 1347, 1142, 1082 cm−1; HRMS (ESI) calcd for C22H31NNaO5S (M + Na)+ 444.1821, found 444.1825. General Procedure for Pd-Catalyzed Alkoxylative Cycloisomerization of Homoallenyl Amides. To a solution of 1a (80 mg, 0.25 mmol) and PhI(OCOCF3)2 (75 mg, 0.175 mmol) in 1 mL of MeOH was added Pd(OAc)2 (2.8 mg, 0.0125 mmol) under a nitrogen atmosphere. After being stirred at room temperature for 6 h, the reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated. 7609

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

Article

The Journal of Organic Chemistry N-Butyl-N-(4-cyclohexyl-5-(methoxymethyl)-3-phenylfuran-2-yl)methanesulfonamide (3g): 82 mg, 78% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.40−7.32 (m, 5H), 4.44 (s, 2H), 3.41−3.36 (m, 5H), 2.94 (s, 3H), 2.45−2.37 (m, 1H), 1.78−1.59 (m, 5H), 1.44−1.36 (m, 2H), 1.30−1.25 (m, 2H), 1.20−1.04 (m, 5H), 0.71 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 144.6, 140.2, 131.8, 130.1, 130.0, 128.1, 127.5, 124.5, 65.5, 57.7, 50.8, 39.6, 35.4, 33.3, 30.4, 26.8, 25.9, 19.4, 13.5; IR (KBr) 3057, 1633, 1603, 1573, 1496, 1446, 1344, 1150, 1087 cm−1; HRMS (ESI) calcd for C23H33NNaO4S (M + Na)+ 442.2028, found 442.2044. N-Butyl-N-(5-(1-methoxyethyl)-3-phenylfuran-2-yl)methanesulfonamide (3h): 60 mg, 68% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.72−7.66 (m, 2H), 7.40−7.36 (m, 2H), 7.31− 7.27 (m, 1H), 6.56 (s, 1H), 4.34 (q, J = 6.6 Hz, 1H), 3.57−3.52 (m, 2H), 3.33 (s, 3H), 3.09 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H), 1.39−1.33 (m, 2H), 1.24−1.18 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 152.9, 139.8, 131.1, 128.6, 127.6, 127.2, 122.9, 108.9, 72.1, 56.2, 50.9, 39.6, 30.3, 19.7, 19.3, 13.4; IR (KBr) 3059, 3033, 1631, 1603, 1566, 1498, 1449, 1344, 1162, 1086 cm−1; HRMS (ESI) calcd for C18H25NNaO4S (M + Na)+ 374.1402, found 374.1406. N-Butyl-N-(5-(2-methoxypropan-2-yl)-3-phenylfuran-2-yl)methanesulfonamide (3i): 57 mg, 62% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.44−7.30 (m, 5H), 6.78 (s, 1H), 3.56−3.39 (m, 8H), 1.89 (s, 3H), 1.86 (s, 3H), 1.57−1.48 (m, 1H), 1.32−1.21 (m, 1H), 1.16−1.03 (m, 2H), 0.79−0.64 (M, 3H); 13C NMR (151 MHz, CDCl3) δ 148.2, 135.4, 131.1, 123.0, 128.3, 127.4, 125.6, 121.3, 59.8, 47.6, 42.3, 31.5, 19.8, 19.2, 18.5, 13.3; IR (KBr) 3057, 1589, 1572, 1494, 1448, 1346, 1163, 1072 cm−1; HRMS (ESI) calcd for C19H27NNaO4S (M + Na)+ 388.1558, found 388.1555. N-Butyl-N-(5-(trideuteromethoxymethyl)-4-methyl-3-phenylfuran-2-yl)methanesulfonamide (3j): 73 mg, 82% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.49−7.45 (m, 2H), 7.42−7.38 (m, 2H), 7.35−7.31 (m, 1H), 4.39 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 3.03 (s, 3H), 2.03 (s, 3H), 1.27−1.22 (m, 2H), 1.11−1.03 (m, 2H), 0.66 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 145.2, 140.4, 131.1, 129.2, 128.3, 127.5, 124.6, 120.2, 64.3, 50.8, 39.6, 30.3, 19.4, 13.4, 9.2; IR (KBr) 3061, 1608, 1587, 1499, 1465, 1344, 1158, 1083 cm−1; HRMS (ESI) calcd for C18H22D3NNaO4S (M + Na)+ 377.1590, found 377.1600. N-Butyl-N-(5-(ethoxymethyl)-4-methyl-3-phenylfuran-2-yl)methanesulfonamide (3k): 71 mg, 78% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.49−7.33 (m, 5H), 4.45 (s, 2H), 3.58 (q, J = 7.0 Hz, 2H), 3.43 (t, J = 7.1 Hz, 2H), 3.05 (s, 3H), 2.04 (s, 3H), 1.31− 1.23 (m, 5H), 1.11−1.04 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.5, 140.3, 131.2, 129.2, 128.3, 127.5, 124.6, 119.9, 65.6, 62.7, 50.9, 39.7, 30.3, 19.5, 15.2, 13.4, 9.2; IR (KBr) 3061, 1607, 1585, 1497, 1463, 1338, 1163, 1082 cm−1; HRMS (ESI) calcd for C19H27NNaO4S (M + Na)+ 388.1558, found 388.1567. N-(5-(Butoxymethyl)-4-methyl-3-phenylfuran-2-yl)-N-butylmethanesulfonamide (3l): 74 mg, 75% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.48−7.30 (m, 5H), 4.43 (s, 2H), 3.49 (t, J = 6.5 Hz, 2H), 3.41 (t, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.02 (s, 3H), 1.63−1.56 (m, 2H), 1.43−1.35 (m, 2H), 1.29−1.22 (m, 2H), 1.12−1.04 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 145.6, 140.3, 131.2, 129.2, 128.3, 127.5, 124.6, 119.9, 70.0, 62.8, 50.9, 39.6, 31.7, 30.3, 19.5, 19.3, 13.8, 13.4, 9.2; IR (KBr) 3059, 1606, 1582, 1497, 1458, 1344, 1149, 1083 cm−1; HRMS (ESI) calcd for C21H31NNaO4S (M + Na)+ 416.1871, found 416.1878. N-Butyl-N-(5-(isopropoxymethyl)-4-methyl-3-phenylfuran-2-yl)methanesulfonamide (3m): 67 mg, 71% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.48−7.30 (m, 5H), 4.44 (s, 2H), 3.73−3.66 (m, 1H), 3.41 (t, J = 7.2 Hz, 2H), 3.03 (s, 3H), 2.02 (s, 3H), 1.28−1.25 (m, 2H), 1.22 (d, J = 6.1 Hz, 6H), 1.11−1.04 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 145.8, 140.2, 131.3, 129.2, 128.3, 127.5, 124.6, 119.6, 70.9, 60.4, 51.0, 39.7, 30.4, 22.1, 19.5, 13.5, 9.2; IR (KBr) 3059, 1606, 1583, 1496, 1446, 1341, 1146, 1080 cm−1; HRMS (ESI) calcd for C20H29NNaO4S (M + Na)+ 402.1715, found 402.1725. N-(5-((Benzyloxy)methyl)-4-methyl-3-phenylfuran-2-yl)-N-butylmethanesulfonamide (3o). 66 mg, 62% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.47−7.30 (m, 10H), 4.57 (s, 2H), 4.48 (s, 2H),

3.42 (t, J = 7.2 Hz, 2H), 3.02 (s, 3H), 1.99 (s, 3H), 1.29−1.24 (m, 2H), 1.12−1.05 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 145.2, 140.5, 137.8, 131.2, 129.2, 128.4, 128.3, 127.8, 127.8, 127.5, 124.6, 120.3, 71.9, 62.1, 50.9, 39.7, 30.4, 19.5, 13.5, 9.2; IR (KBr) 3055, 1606, 1582, 1496, 1454, 1343, 1148, 1067 cm−1; HRMS (ESI) calcd for C24H29NNaO4S (M + Na)+ 450.1715, found 450.1730. N-(5-((Allyloxy)methyl)-4-methyl-3-phenylfuran-2-yl)-N-butylmethanesulfonamide (3p). 73 mg, 77% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.48−7.31 (m, 5H), 5.98−5.91 (m, 1H), 5.36− 5.30 (m, 1H), 5.26−5.21 (m, 1H), 4.45 (s, 2H), 4.07−4.03 (m, 2H), 3.42 (t, J = 7.2 Hz, 2H), 3.03 (s, 3H), 2.02 (s, 3H), 1.29−1.23 (m, 2H), 1.12−1.04 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 145.2, 140.4, 134.3, 131.2, 129.2, 128.3, 127.5, 124.6, 120.2, 117.6, 70.9, 62.0, 50.9, 39.6, 30.3, 19.5, 13.4, 9.2; IR (KBr) 3088, 3010, 1644, 1607, 1584, 1479, 1449, 1337, 1163, 1062 cm−1; HRMS (ESI) calcd for C20H27NNaO4S (M + Na)+ 400.1558, found 400.1569. N-(5-((But-2-yn-1-yloxy)methyl)-4-methyl-3-phenylfuran-2-yl)-Nbutylmethanesulfonamide (3q). 68 mg, 70% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.48−7.31 (m, 5H), 4.53 (s, 2H), 4.14 (q, J = 2.3 Hz, 2H), 3.41 (t, J = 7.1 Hz, 2H), 3.04 (s, 3H), 2.04 (s, 3H), 1.89 (t, J = 2.3 Hz, 3H), 1.28−1.21 (m, 2H), 1.12−1.02 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.7, 140.6, 131.1, 129.2, 128.4, 127.6, 124.6, 120.8, 83.0, 74.7, 61.1, 57.4, 50.9, 39.7, 30.3, 19.5, 13.4, 9.2, 3.6; IR (KBr) 3055, 2222, 1608, 1582, 1497, 1446, 1381, 1334, 1135, 1079 cm−1; HRMS (ESI) calcd for C21H27NNaO4S (M + Na)+ 412.1558, found 412.1565. General Procedure for the Pd-Catalyzed Hydroxylation of Homoallenyl Amides. To a solution of 1a (80 mg, 0.25 mmol), KOH (4.2 mg, 0.075 mmol), and PhI(O2CCF3)2 (75 mg, 0.175 mmol) in 1 mL of MeCN/H2O (v/v = 1:1) was added Pd(OAc)2 (2.8 mg, 0.0125 mmol) under nitrogen atmosphere. After being stirred at room temperature for 6 h, the reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated. Column chromatography on silica gel (EtOAc/petroleum ether = 1:1) gave 67 mg (yield: 80%) of N-butylN-(5-(hydroxymethyl)-4-methyl-3-phenylfuran-2-yl)methanesulfonamide (4a) as a white solid: mp 65−67 °C. 1H NMR (600 MHz, CDCl3) δ 7.45−7.32 (m, 5H), 4.59 (s, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.01 (s, 3H), 2.18−2.06 (m, 1H), 2.02 (s, 3H), 1.29−1.24 (m, 2H), 1.12−1.04 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 147.3, 140.2, 131.1, 129.1, 128.4, 127.6, 124.6, 118.8, 55.4, 50.9, 39.7, 30.4, 19.5, 13.4, 9.1; IR (KBr) 3301, 3059, 1606, 1583, 1496, 1446, 1340, 1145, 1079 cm−1; HRMS (ESI) calcd for C17H23NNaO4S (M + Na)+ 360.1245, found 360.1254. N-(5-(Hydroxymethyl)-4-methyl-3-phenylfuran-2-yl)-N-methylmethanesulfonamide (4b): 9 57 mg, 77% yield, white solid, mp: 110− 112 °C; 1H NMR (400 MHz, CDCl3) δ 7.43−7.31 (m, 5H), 4.57 (s, 2H), 3.16 (s, 3H), 2.92 (s, 3H), 2.53 (s, 1H), 2.02 (s, 3H); IR (KBr) 3337, 3026, 1605, 1579, 1496, 1446, 1340, 1145, 1079 cm−1. N-Butyl-N-(3-hexyl-5-(hydroxymethyl)-4-methylfuran-2-yl)methanesulfonamide (4c): 62 mg, 72% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 4.52 (s, 2H), 3.54−3.50 (m, 2H), 2.99 (s, 3H), 2.37−2.32 (m, 2H), 2.00 (s, 3H), 1.69−1.62 (m, 1H), 1.51−1.45 (m, 4H), 1.38−1.26 (m, 8H), 0.93−0.86 (m, 6H); 13C NMR (151 MHz, CDCl3) δ 146.8, 139.7, 124.2, 119.4, 55.4, 50.3, 38.8, 31.6, 30.6, 29.7, 29.1, 23.7, 22.6, 19.7, 14.1, 13.6, 8.7; IR (KBr) 3302, 1588, 1459, 1344, 1149, 1079 cm−1; HRMS (ESI) calcd for C17H31NNaO4S (M + Na)+ 368.1871, found 368.1882. (E)-N-Butyl-N-(5-(hydroxymethyl)-4-methyl-3-styrylfuran-2-yl)methanesulfonamide (4d): 68 mg, 75% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.47−7.24 (m, 5H), 7.03 (d, J = 16.8 Hz, 1H), 6.90 (d, J = 16.8 Hz, 1H), 4.55 (s, 2H), 3.59 (t, J = 7.3 Hz, 2H), 3.05 (s, 3H), 2.23 (s, 3H), 2.15−2.05 (m, 1H), 1.53−1.45 (m, 2H), 1.40− 1.32 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 147.8, 141.1, 137.4, 130.6, 128.6, 127.6, 126.3, 121.1, 117.9, 117.9, 55.0, 50.5, 39.2, 30.5, 19.6, 13.5, 10.2; IR (KBr) 3448, 3055, 3012, 1649, 1598, 1564, 1492,1455, 1335, 1139, 1087 cm−1; HRMS (ESI) calcd for C19H25NNaO4S (M + Na)+ 386.1402, found 386.1410. 7610

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

Article

The Journal of Organic Chemistry N-Butyl-N-(5-(1-hydroxyethyl)-3-phenylfuran-2-yl)methanesulfonamide (4e): 55 mg, 65% yield, colorless oil; 1H NMR (600 MHz, CDCl3) δ 7.70−7.63 (m, 2H), 7.40−7.27 (m, 3H), 6.53 (s, 1H), 4.86 (q, J = 6.5 Hz, 1H), 3.53 (t, J = 7.4 Hz, 2H), 3.08 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H), 1.51−1.44 (m, 1H), 1.39−1.33 (m, 2H), 1.23−1.16 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 155.3, 139.6, 131.1, 128.6, 127.7, 127.2, 123.1, 107.1, 63.7, 51.0, 39.7, 30.3, 21.2, 19.7, 13.5; IR (KBr) 3310, 3051, 1603, 1581, 1499, 1344, 1146, 1078 cm−1; HRMS (ESI) calcd for C17H23NNaO4S (M + Na)+ 360.1245, found 360.1241.

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ASSOCIATED CONTENT

S Supporting Information *

Spectroscopic data for products 2−4 as well as crystallographic data for 2p and 3a. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.joc.5b01182.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Science Technology Department of Zhejiang Province (2015C31030), National Natural Science Foundation of China (21172199), Natural Science Foundation of Zhejiang Province (LR12B02001), and Open Research Fund of Key Laboratory of the Ministry of Education for Advanced Catalysis Materials (ZJHX201405) for financial support.

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REFERENCES

(1) For selected reports on Pd-catalyzed sp2 C−H acetoxylation, see: (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem. 1996, 108, 35. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (c) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285. (d) Cook, A. K.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2013, 15, 5428. (e) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010, 12, 2511. (f) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236. (g) Gou, F.-R.; Wang, X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett. 2009, 11, 5726. (h) Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74, 7203. (i) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116. (j) Chernyak, N.; Dudnik, A. S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270. (k) Liu, Q.; Li, G.; Yi, H.; Wu, P.; Liu, J.; Lei, A. Chem. - Eur. J. 2011, 17, 2353. (l) Yang, M.; Jiang, X.; Shi, W.J.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2013, 15, 690. (m) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2014, 16, 968. (2) For selected reports on Pd-catalyzed sp3 C−H acetoxylation, see: (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (b) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532. (c) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387. (d) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133, 12584. (e) Ren, Z.; Mo, F.; Dong, G. J. Am. Chem. Soc. 2012, 134, 16991. (f) Ju, L.; Yao, J.; Wu, Z.; Liu, Z.; Zhang, Y. J. Org. Chem. 2013, 78, 10821. (g) Malik, H. A.; Taylor, B. L. H.; Kerrigan, J. R.; Grob, J. E.; Houk, K. N.; Du Bois, J.; Hamann, L. G.; Patterson, A. W. Chem. Sci. 2014, 5, 2352. (3) For selected reports on Pd-catalyzed sp2 C−H alkoxylation, see: (a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. (b) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203. (c) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250. (d) Li, W.; Sun, P. J. Org. Chem. 2012, 77, 8362. (e) Jiang, T. S.; Wang, G. W. J. Org. Chem. 7611

DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612

Article

The Journal of Organic Chemistry (14) The addition of 2 equiv of 2,2,6,6-tetramethylpiperidinooxy (TEMPO) or 1,1-diphenylethylene had no detrimental effect on the Pd-catalyzed acetoxylative and alkyoxylative cycloisomerization of 1a, implying a radical mechanism is less likely in this case.

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DOI: 10.1021/acs.joc.5b01182 J. Org. Chem. 2015, 80, 7604−7612