Ag(I)-Catalyzed Oxidative Cyclization of 1,4-Diynamide-3-ols with N-Oxide for Divergent Synthesis of 2-Substituted Furan-4-carboxamide Derivatives

Abstract

This work reports Ag(I)-catalyzed oxidative cyclizations of 1,4-diynamide-3-ols with 8-methylquinoline oxide to form 2-substituted furan-4-carboxamides. The reaction chemoselectivity is distinct from that reported in previous work by Hashmi. We performed density functional theory calculations to elucidate our proposed mechanism after evaluation of the energy profiles of two possible pathways. In this Ag(I) catalysis, the calculations suggest that the amide and alkyne groups of the 3,3-dicarbonyl-2-alkyne intermediates tend to chelate with the Ag(I) catalyst, further inducing a formyl attack at the Ag(I)-π-alkyne moiety to deliver the observed products.

Introduction

Furan derivatives serve as versatile building blocks in synthetic chemistry. The furan cores are prevalent in numerous natural products and pharmaceuticals,¹ showing a wide range of biological properties. Numerous efforts have been made to develop new synthetic methods for highly functionalized furans.² In gold catalysis,^3,4 initial studies of furan synthesis rely heavily on catalytic cycloisomerization of oxygen-containing alkynes^5,6 such as 1-allenyl n-ketones (n = 4 and 5),^5a,5b−5c 1-butyn-4-ones,^5d pent-4-yn-1-ol,^5e,5f 1,4-diyn-3-ols,^5g alk-1-ynyl oxiranes,^6a,6b 2-(alk-2-yn-1-ylidine)-1,3-diones,^6c 2-(1-alkynyl)-2-alken-1-ones,^6d 1-(1-alkynyl)cyclopropyl ketone,^6e β-alkynylallylic alcohols,^6f propargyl vinyl ether,^6g and enyne 1,6-diols.^6h Furan synthesis using oxygen-free alkynes is highly desirable to expand the scope of synthetic utility. We have recently developed a new furan synthesis from catalytic oxidations of enynamides using pyridine-based N-oxides⁷ (eq 1, Scheme 1); the generation of α-oxo gold carbenes Int-I in the mechanism is particularly noteworthy.⁸ Hashmi and co-workers^9a employed these alkyne oxidations on 1,4-diyn-3-ols 1̀ to access highly substituted furan derivatives (eq 2). The mechanism of these reactions involves gold carbenes Int-I′, followed by a 1,2-alkyne migration. Furthermore, the key 1,3-dicarbonyl-2-alkyne intermediates Int-II preferentially undergo a subsequent cyclization to afford 2,4,5-trisubstituted furan derivatives.⁹ Herein, the substituted ketone group (RCO, R = alkyl or aryl) participates in the construction of a furan ring, whereas the aldehyde group of species Int-II remains intact. This regioselectivity can be rationalized by the fact that a ketone group (RCO) is a better nucleophile than an aldehyde. To continue our interest in gold-catalyzed reactions of 1,4-diyn-3-ols,¹⁰ we reveal herein how the introduction of an ynamide provides distinct new chemoselectivity in Hashmi’s 1,3-diynol system using a Ag (I) catalyst. In this approach, furan construction involves the formed aldehyde to yield the 2,4-disubstituted furans, rather than the amide derived from the ynamide. We postulate that the Ag(I) ion chelates with an amide and an alkyne ligand, as depicted by intermediate Int-IV, further inducing an aldehyde attack at this Ag-π-alkyne functionality (eq 3). This proposed mechanism is further supported by density functional theory (DFT) calculations in comparison with the energy profiles of Hashmi reactions (eq 2).

Scheme 1. Oxidative Cyclizations by N-Oxides.

Results and Discussion

We tested the reactions of N-(3-hydroxy-5-phenylpenta-1,4-diyn-1-yl)-N,4-dimethylbenzenesulfonamide 1a with 8-methylquinoline N-oxide 2a using various gold and silver catalysts; the results are summarized in Table 1.

Table 1. Optimization of Reaction Conditions.

entry	catalyst	solvent	time (h)	yield (%)b
1	LAuCl/NaBARF	toluene	8	37
2	LAuCl/AgNTf2	DCE	8	58
3	IPrAuCl/AgNTf2	DCE	9	52
4	(PhO)3PAuCl/AgNTf2	DCE	8	29
5	PPh3AuCl/AgNTf2	DCE	7	48
6	LAuCl/AgOTf	DCE	12	73
7	LAuCl/AgSbF6	DCE	12	55
8	AuCl3	DCE	4	23
9	AgOTf	DCE	6	81
10	AgOTf	DCM	6	83
11	AgSbF6	DCM	8	74
12	AgNTf2	DCM	7	78
13	AgBF4	DCM	6	75
14	CF3COOAg	DCM	6	61
15	AgOTf	THF	6	65
16	AgOTf	Toluene	12	63
17	AgOTf	CH3CN	7	54
18	AgOTf	dioxane	8	76
19	HOTf	DCM	24
20	Zn(OTf)2	DCM	24
21	AgOTf	DCM	6	45

^aReaction conditions: 1a = 0.1 M.

^bProduct yields are reported after separation from a silica column. L = P(t-Bu)₂(o-biphenyl), IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine, BARF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, DCM = dichloromethane, DCE = 1,2-dichloroethane, THF = tetrahydrofuran, and dioxane = 1,4-dioxane.

Our initial test with P(t-Bu)₂(o-biphenyl)AuCl/NaBARF (10 mol %) in toluene (25 °C, 8 h) led to the formation of N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 3a in a 37% yield (entry 1). NaBARF was replaced with AgNTf₂ using P(t-Bu)₂(o-biphenyl)AuCl (10 mol %) in DCE (25 °C, 8 h); the yield of desired product 3a was increased to 58% (entry 2). With IPrAuCl/AgNTf₂ (10 mol %), the yield of compound 3a decreased to 52% (entry 3). Other gold phosphine catalysts, including L’AuCl/AgOTf (L’=(PhO)₃P, PPh₃), delivered substituted furan 3a in 29% and 48% yields, respectively (entries 4–5). For P(t-Bu)₂(o-biphenyl)AuCl, its AgX (X = OTf and SbF₆) salts furnished compound 3a in 73% and 55% yields, respectively (entries 6 and 7). AuCl₃ (10 mol %) gave the yield of compound 3a in 23% (entry 8). A test with AgOTf alone gave the best yield, surprisingly up to 83% (entry 9–10). We have tested several silver catalysts including AgSbF₆, AgNTf₂, and AgBF₄, affording our target 3a in 74%, 78%, and 75% yields, respectively (entries 11–13). CF₃COOAg was also compatible with this reaction, giving product 3a in a 61% yield (entry 14). For AgOTf, the yields of compound 3a in different solvents were as follows (entries 15–18): THF (65%), toluene (63%), CH₃CN (54%), and 1,4-dioxane (76%). Further, we have checked the Bronsted (HOTf) and Lewis acid (Zn(OTf)₂) activation for the reaction and consequently failed to catalyze this reaction (entries 19–20). In addition, we examined the reaction with other N-oxides such as pyridine N-oxide (2b) instead of 2a under standard conditions (entry 10) resulting in the desired product 3a with only a 45% yield (entry 21). The molecular structure of compound 3a was inferred from X-ray diffraction.¹¹

Next, we have prepared the same substrate 1,4-diyn-3-ol 5 as prepared by Hashmi et al.^9a to examine the reaction chemoselectivity under our standard condition and 80 °C in DCE over a protracted period. In both of these cases, the reactions only led to recovery of the starting materials (eq 4). Accordingly, formation of 3a from reactants 1a and 2a is not due to the use of a AgOTf catalyst. Diynamides (1a) can form key intermediate H (vide infra, Scheme 3), in which silver is chelated with one amide and one alkyne group to afford 2,4-disubstituted furan derivatives (3), whereas diyne (5) fails to form such a chelate complex.

4

Scheme 3. Gibbs Free Energy Profiles for Two Independent Routes.

Under the optimized condition, a wide range of 1,4-diynamide-3-ols 1 and 8-methylquinoline N-oxide 2a were examined using the AgOTf catalyst (10 mol %) in DCM; the results are summarized in Table 2. We tested the reaction with several 1,4-diynamide-3-ols (1b–1e) bearing various alkyl groups at sulfonamides (R = n-butyl, isopropyl, cyclopropyl, and cyclohexyl), further rendering the desired furans-3-carboxamides (3b–3e) in 69–81% yields. 1,4-Diynamide-3-ols 1f–1h bearing various aryl groups 4-XC₆H₄ (X = H, CH₃, and Br) at sulfonamides afforded the expected products (3f–3h) in 73–79% yields. For the sulfonamide bearing a MeSO₂ group 1i, its silver-catalyzed reaction delivered the desired furan 3i in a 59% yield. 1,4-Diynoxazolidin-2-one-3-ol 1j worked well to furnish the expected product 3j in a 45% yield. Our next task is to alter the alkynyl substituents as in 1,4-diynamide-3-ols (1k–1n) bearing R¹ = 4-XC₆H₄ (X = Me, Cl, and OMe), and R¹ = 2-MeC₆H₄ effectively providing furan derivatives 3k–3n in 56–83% yields. Alkyl variations at the alkynyl substituents as in 1,4-diynamide-3-ols (1o–1p, R¹ = n-Bu and cyclopropyl) were also feasible with this oxidative cyclization to deliver the furan products 3o and 3p in 78% and 81% yields, respectively. The presence of a heteroaryl group at the alkyne position (1q, R¹ = thienyl) was also compatible with this catalysis, yielding the desired product 3q in an 82% yield. We also prepared 1-methylvinyl-containing substrates 1r, yielding a 2,4-disubstituted furan 3r in a 61% yield.

Table 2. Substrate Scope for the Synthesis of 2,4-Disubstituted Furans.

^a1 = 0.1 M.

^bProduct yields are obtained after purification from a silica column, DCM = dichloromethane.

Chemical functionalizations of one representative compound 3a are provided in Scheme 2; a gram-scale reaction of 1a (3.0 mmol) was carried out under standard conditions, delivering the desired product 3a in a 72% yield. Treatment of furan 3a with N-bromosuccinimide led to formation of 2-bromo-N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 4a in a 67% yield. LiAlH₄ reduction of furan 3a afforded (5-phenylfuran-3-yl)methanol 4b in an 86% yield. Treatment of furan 3a with MeMgBr furnished one single addition product, 1-(5-phenylfuran-3-yl)ethan-1-one 4c, in a 42% yield. Notably, the use of PhMgBr on furan 3a enabled 1,3-double addition reactions, affording (2,5-diphenylfuran-3-yl)(phenyl)methanone 4d in a 61% yield. In this case, we postulate that the first addition occurs at the amide to form a phenylketone intermediate such as species 4c; the second addition occurs at the furan C(5)-carbon in a Michael-type enone addition before aerobic oxidation.

Scheme 2. Chemical Functionalizations of 3a.

We utilized DFT calculations to elucidate the reaction mechanism of this silver-catalyzed reaction. Scheme 3 presents the Gibbs free energy diagram for the conversion of 1,4-diynamide-3-ol (1a) into substituted furans-3-carboxamides (3a) using a AgOTf catalyst in DCM. Two independent cyclization pathways were computed for the intramolecular cyclization of key intermediate F. Detailed calculation procedures are provided in the Supporting Information. As depicted in Scheme 3, the formation of silver-π alkyne complex A from 1a is exothermic with a ΔG of −14.0 kcal/mol. A nucleophilic attack by the N-oxide species on the silver-π alkyne generates vinyl silver intermediate B with a small activation barrier (ΔG^⧧ = 5.9 kcal/mol). The formation of α-oxo silver carbenes C from intermediate B proceeds with an activation barrier of ΔG^⧧ = 14.1 kcal/mol. Subsequently, a 1,2-alkyne migration occurs on C to form D,⁹ with this process presenting a relatively high yet accessible barrier (ΔG^⧧ = 19.9 kcal/mol). Deprotonation of D forms E with a ΔG of −5.3 kcal/mol. Finally, a protodemetalation of species E yields the free 1,3-dicarbonyl-2-alkyne species F.

There are two possible cyclization routes for intermediate F, indicated by the blue and red pathways. F can coordinate with Ag⁺ to form either G or g. Our DFT calculations show that G is more stable than g by ΔG = 5.7 kcal/mol. Subsequently, deprotonation occurs, generating H and h from G and g, respectively. The conversion of G to H is uphill with ΔG = 10.1 kcal/mol, whereas the conversion of g to h is slightly downhill with ΔG = −2.9 kcal/mol. Cyclization then occurs, producing I and i from H and h, respectively. Finally, demetalation and protonation lead to the formation of J and j. Our DFT calculations indicate that the blue route is kinetically more favorable (ΔΔG^⧧ = −0.9 kcal/mol) and thermodynamically more favorable than the red route (ΔΔG = −9.2 kcal/mol), suggesting that J (3a) is the major product of the reaction, consistent with our experimental results. The change in chemoselectivity observed with our sulfonamide-containing 1,4-diyn-3-ols (1) is likely due to the electron-rich effect of sulfonamide amides, which enhances their ability to chelate a Ag(I) ion. As shown in Table 1, the use of Au(I) catalysts can also produce such 2,4-disubstituted furans, although with a lower efficiency.

Conclusions

In conclusion, we have developed efficient and mild silver-catalyzed oxidative cyclizations of 1,4-diynamide-3-ols (1) with 8-methylquinoline N-oxide (2a), affording 2-substituted furans-4-carboxamides. This silver catalysis serves as a complementary tool to access substituted furans, distinct from those obtained by Hashmi and co-workers. DFT calculations support a reaction mechanism that the amide and alkyne groups of key 1,3-dicarbonyl-2-alkyne intermediates enable to chelate with the Ag(I) catalyst, further inducing an aldehyde attack at the Ag(I)-π-alkyne moiety.

Experimental Section

General Information

Unless otherwise noted, all of the reactions for the preparation of the substrates were performed in oven-dried glassware under a nitrogen atmosphere with freshly distilled solvents. The catalytic reactions were performed under a nitrogen atmosphere. DCM, diethyl ether, and toluene were distilled from CaH₂ under nitrogen. THF was distilled from the Na metal under nitrogen. All other commercial reagents were used without further purification, unless otherwise indicated. 1H NMR and 13C NMR spectra were recorded on Varian 700 and Bruker 400 MHz spectrometers using chloroform-d (CDCl₃) as the internal standard. High-resolution mass spectroscopy (HRMS) data were measured on a JMST100LP4G (JEOL) mass spectrometer or a TOF mass analyzer equipped with an ESI source, JEOL model JMS-T200GC AccuTOF GCx equipped with a field desorption source and a magnetic sector mass analyzer (MStation) equipped with an EI source. Single-crystal X-ray diffraction intensity data were collected on a Bruker X8 APEX diffractometer equipped with a CCD area detector and Mo Kα radiation (λ = 0.71073 Å) at 100 K; all data calculations were performed by using the PC version of the APEX2 program package.

Standard Procedures for Catalytic Operations

Typical Procedure for the Synthesis of N-Methyl-5-phenyl-N-tosylfuran-3-carboxamide (3a)

To a stirred suspension of AgOTf (3.78 mg, 0.0147 mmol) in DCM (0.5 mL) was fitted a N₂ balloon. To this suspension was added a DCM (1.0 mL) solution of N-(3-hydroxy-5-phenylpenta-1,4-diyn-1-yl)-N,4-dimethylbenzenesulfonamide 1a (50 mg, 0.1473 mmol) and 8-methylquinoline N-oxide 2a (46.90 mg, 0.2946 mmol) at room temperature. The resulting mixture was stirred at room temperature for 6 h. The solution was filtered over a short Celite bed and evaporated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate/hexane (15:75) as the eluent to give compound 3a as a white solid (43.50 mg, 0.1238 mmol, 83%).

N-Methyl-5-phenyl-N-tosylfuran-3-carboxamide (3a)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (43.5 mg, 0.12 mmol, 83%); mp: 115–118 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.90 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.31 ∼ 7.29 (m, 3H), 6.83 (s, 1H), 3.41 (s, 3H), 2.41 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.6, 154.7, 146.3, 144.9, 135.2, 129.6, 129.4, 128.8, 128.4, 128.3, 124.1, 123.0, 104.9, 35.0, 21.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₉H₁₇NO₄SNa, 378.0776; found, 378.0778.

N-Butyl-5-phenyl-N-tosylfuran-3-carboxamide (3b)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (40 mg, 0.10 mmol, 77%); mp: 75–78 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.87 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.31–7.27 (m, 3H), 6.78 (s, 1H), 3.84 (t, J = 7.7 Hz, 2H), 2.39 (s, 3H), 1.73 (quint, J = 7.7 Hz, 2H), 1.37–1.32 (m, 2H), 0.91 (t, J = 7.7 Hz, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.7, 154.7, 145.8, 144.6, 136.1, 129.5, 129.4, 128.8, 128.4, 128.3, 124.1, 123.6, 104.9, 47.4, 32.0, 21.6, 19.9, 13.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₂H₂₃NO₄SNa, 420.1245; found, 420.1245.

N-Isopropyl-5-phenyl-N-tosylfuran-3-carboxamide (3c)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (41 mg, 0.11 mmol, 78%); mp: 80–82 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.80 (s, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.0 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.30–7.26 (m, 3H), 6.71 (s, 1H), 4.49–4.45 (m, 1H), 2.39 (s, 3H), 1.50 (d, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 165.3, 154.7, 145.9, 144.5, 137.1, 129.51, 129.50, 128.8, 128.34, 128.32, 125.2, 124.1, 104.5, 53.6, 30.3, 21.7, 21.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₁H₂₁NO₄SNa, 406.1089; found, 406.1090.

N-Cyclopropyl-5-phenyl-N-tosylfuran-3-carboxamide (3d)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (42 mg, 0.11 mmol, 81%); mp: 120–125 °C; ¹H NMR (700 MHz, CDCl₃): δ 8.00 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.32 ∼ 7.23 (m, 3H), 6.93 (s, 1H), 2.88 ∼ 2.85 (m, 1H), 2.41(s, 3H), 0.97 (q, J = 7.0 Hz, 2H), 0.83 (q, J = 4.2 Hz, 2H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 165.4, 154.8, 147.3, 144.8, 135.9, 129.53, 129.50, 128.8, 128.7, 128.4, 124.5, 124.1, 104.7, 29.3, 21.6, 10.1; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₁H₁₉NO₄SNa, 404.0932; found, 404.0938.

N-Cyclohexyl-5-phenyl-N-tosylfuran-3-carboxamide (3e)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (36 mg, 0.08 mmol, 69%); ¹H NMR (700 MHz, CDCl₃): δ 7.83 (s, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.31–7.24 (m, 3H), 6.73 (s, 1H), 3.99–3.96 (m, 1H), 2.39 (s, 3H), 2.12 (q, J = 12.6 Hz, 2H), 1.88–1.79 (m, 4H), 1.60–1.57 (m, 1H), 1.23 (q, J = 13.3 Hz, 2H), 1.17–1.11 (m, 1H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 165.6, 154.9, 146.4, 144.3, 137.2, 129.5, 129.4, 128.8, 128.4, 128.3, 125.5, 124.1, 104.5, 61.9, 31.9, 26.6, 25.0, 21.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₄H₂₅NO₄SNa, 446.1402; found, 446.1401.

N,5-Diphenyl-N-tosylfuran-3-carboxamide (3f)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (39 mg, 0.09 mmol, 75%); mp: 122–124 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.94 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 8.4 Hz, 2H), 7.43–7.42 (m, 2H), 7.37–7.34 (m, 4H), 7.30 (t, J = 7.7 Hz, 2H), 7.24–7.22 (m, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 2.44 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 162.3, 154.0, 146.3, 144.9, 136.4, 135.9, 130.8, 130.4, 129.7, 129.4, 129.3, 129.2, 128.7, 128.2, 123.9, 122.9, 105.5, 21.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₄H₁₉NO₄SNa, 440.0932; found, 440.0930.

5-Phenyl-N-(p-tolyl)-N-tosylfuran-3-carboxamide (3g)

Purified on silica gel column using ethyl acetate/hexane: (15: 85) as the eluent; white solid (38 mg, 0.09 mmol, 73%); mp: 131–135 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.94 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.34 ∼ 7.29 (m, 6H), 7.24–7.23 (m, 3H), 6.56 (s, 1H), 6.50 (s, 1H), 2.44 (s, 6H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 162.4, 153.9, 146.1, 144.9, 140.9, 136.0, 133.7, 130.5, 130.4, 129.4, 129.3, 128.7, 128.2, 123.9, 122.9, 105.8, 21.7, 21.4; one carbon merge with other peak; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₅H₂₁NO₄SNa, 454.1089; found, 454.1084.

N-(4-Bromophenyl)-5-phenyl-N-tosylfuran-3-carboxamide (3h)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; brown solid (41 mg, 0.08 mmol, 79%); mp: 160–163 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.89 (d, J = 7.0 Hz, 2H), 7.61 (d, J = 7.0 Hz, 2H), 7.44 (d, J = 7.0 Hz, 2H), 7.34–7.30 (m, 4H), 7.25 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H), 6.72 (s, 1H), 6.49 (s, 1H), 2.43 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 162.0, 154.4, 146.2, 145.2, 135.53, 135.50, 133.0, 132.2, 129.44, 129.40, 129.1, 128.8, 128.4, 124.7, 123.9, 122.8, 105.3, 21.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₄H₁₈BrNO₄SNa, 518.0037; found, 518.0038.

N-Methyl-N-(methylsulfonyl)-5-phenylfuran-3-carboxamide (3i)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (31 mg, 0.11 mmol, 59%); ¹H NMR (700 MHz, CDCl₃): δ 7.95 (s, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 6.90 (s, 1H), 3.46 (s, 3H), 3.35 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 165.2, 155.2, 145.9, 129.2, 128.9, 128.6, 124.2, 122.5, 104.6, 41.4, 34.8; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₃H₁₃NO₄SNa, 302.0463; found, 302.0460.

3-(5-Phenylfuran-3-carbonyl)oxazolidin-2-one (3j)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow solid (24 mg, 0.09 mmol, 45%); mp: 142–145 °C; ¹H NMR (700 MHz, CDCl₃): δ 8.32 (s, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.07 (s, 1H), 4.47 (t, J = 7.7 Hz, 2H), 4.16 (t, J = 7.7 Hz, 2H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 162.1, 153.9, 153.0, 148.5, 129.7, 128.7, 128.1, 124.1, 121.0, 105.9, 62.4, 43.9; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₄H₁₁NO₄Na, 280.0586; found, 280.0582.

N-Methyl-5-(p-tolyl)-N-tosylfuran-3-carboxamide (3k)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (42 mg, 0.11 mmol, 80%); mp: 117–120 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.87 (s, 1H), 7.82 (d, J = 7.0 Hz, 2H), 7.51 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 7.0 Hz, 2H), 6.76 (s, 1H), 3.40 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.7, 154.9, 145.9, 144.8, 138.4, 135.3, 129.6, 129.5, 128.6, 129.5, 128.3, 126.7, 124.1, 123.0, 104.2, 35.0, 21.6, 21.3; HRMS (ESI-TOF) m/z: [M – H]⁻ calcd C₂₀H₁₈NO₄S, 368.0956; found, 368.0947.

5-(4-Chlorophenyl)-N-methyl-N-tosylfuran-3-carboxamide (3l)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; white solid (33 mg, 0.08 mmol, 63%); mp: 135–137 °C; ¹H NMR (700 MHz, CDCl₃): δ 7.89 (s, 1H), 7.80 (d, J = 4.9 Hz, 2H), 7.55 (d, J = 5.6 Hz, 2H), 7.36–7.31 (m, 4H), 6.83 (s, 1H), 3.38 (s, 3H), 2.41 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.5, 153.6, 146.4, 144.9, 135.2, 134.2, 129.6, 129.1, 128.3, 127.9, 125.3, 123.2, 105.4, 34.9, 21.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₉H₁₆ClNO₄SNa, 412.0386; found, 412.0383.

5-(4-Methoxyphenyl)-N-methyl-N-tosylfuran-3-carboxamide (3m)

Purified on silica gel column using ethyl acetate/hexane (20: 80) as the eluent; white solid (43.2 mg, 0.11 mmol, 83%); mp: 125–128 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.84–7.81 (m, 3H), 7.55–7.52 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.91–6.89 (m, 2H), 6.68 (s, 1H), 3.81 (s, 3H), 3.39 (s, 3H), 2.40 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.7, 159.7, 154.8, 145.6, 144.8, 135.3, 129.5, 128.3, 125.6, 122.9, 122.3, 114.2, 103.2, 55.3, 34.9, 21.5; HRMS-ESI⁺m/z: [M + Na]⁺ calcd C₂₀H₁₉NO₅SNa, 408.0882; found, 408.0883.

N-Methyl-5-(o-tolyl)-N-tosylfuran-3-carboxamide (3n)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (29.5 mg, 0.08 mmol, 56%); ¹H NMR (700 MHz, CDCl₃): δ 7.92 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.62–7.61 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.24–7.22 (m, 3H), 6.71 (s, 1H), 3.41 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.7, 154.2, 145.8, 144.8, 135.3, 135.0, 131.2, 129.6, 128.7, 128.4, 128.3, 127.2, 126.1, 122.7, 108.5, 34.9, 21.67, 21.62; HRMS-ESI⁺m/z: [M + Na]⁺ calcd C₂₀H₁₉NO₄SNa, 392.0932; found, 392.0934.

5-Butyl-N-methyl-N-tosylfuran-3-carboxamide (3o)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (41 mg, 0.12 mmol, 78%); ¹H NMR (700 MHz, CDCl₃): δ 7.81 (d, J = 7.7 Hz, 2H), 7.73 (s, 1H), 7.29 (d, J = 7.0 Hz, 2H), 6.20 (s, 1H), 3.36 (s, 3H), 2.57 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H), 1.58–1.56 (m, 2H), 1.34–1.31 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.9, 157.6, 145.6, 144.7, 135.5, 129.5, 128.6, 145.6, 144.7, 135.5, 135.5, 129.5, 128.3, 121.7, 105.3, 34.9, 29.7, 27.3, 22.1, 21.6, 13.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₇H₂₁NO₄SNa, 358.1089; found, 358.1089.

5-Cyclopropyl-N-methyl-N-tosylfuran-3-carboxamide (3p)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (43 mg, 0.13 mmol, 81%); ¹H NMR (700 MHz, CDCl₃): δ 7.80 (d, J = 7.0 Hz, 2H), 7.67 (s, 1H), 7.28 (d, J = 7.7 Hz, 2H), 6.16 (s, 1H), 3.35 (s, 3H), 2.40 (s, 3H), 1.83 (br s, 1H), 0.88–0.87 (m, 2H), 0.74 (s, 2H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.8, 158.5, 145.2, 144.7, 135.4, 129.5, 128.3, 121.8, 103.9, 34.9, 21.6, 8.4, 6.8; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₆H₁₇NO₄SNa, 342.0776; found, 342.0774.

N-Methyl-5-(thiophen-2-yl)-N-tosylfuran-3-carboxamide (3q)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (43 mg, 0.12 mmol, 82%); ¹H NMR (700 MHz, CDCl₃): δ 7.81 (t, J = 8.4 Hz, 3H), 7.31–7.27 (m, 4H), 7.03 (t, J = 4.2 Hz, 1H), 6.66 (s, 1H), 3.38 (s, 3H), 2.41 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.4, 150.2, 145.7, 144.9, 135.3, 131.9, 129.6, 128.3, 127.8, 125.5, 124.1, 123.1, 104.7, 34.9, 21.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₇H₁₅NO₄S₂Na, 384.0340; found, 384.0347.

N-Methyl-5-(prop-1-en-2-yl)-N-tosylfuran-3-carboxamide (3r)

Purified on silica gel column using ethyl acetate/hexane (15: 85) as the eluent; yellow oil (32 mg, 0.10 mmol, 61%); ¹H NMR (700 MHz, CDCl₃): δ 7.80 (t, J = 7.7 Hz, 3H), 7.29 (d, J = 7.7 Hz, 2H), 6.46 (s, 1H), 5.51 (s, 1H), 5.03 (s, 1H), 3.36 (s, 3H), 2.41 (s, 3H), 1.97 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.6, 155.7, 146.3, 144.8, 135.3, 131.8, 129.6, 128.3, 122.6, 112.1, 106.0, 34.9, 21.6, 19.1; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₆H₁₇NO₄SNa, 342.0776; found, 342.0776.

Chemical Functionalizations of 3a

Gram-Scale Reaction

To a stirred suspension of AgOTf (77 mg, 0.3 mmol) in DCM (10 mL) was fitted a N₂ balloon. To this suspension was added a DCM (15 mL) solution of N-(3-hydroxy-5-phenylpenta-1,4-diyn-1-yl)-N,4-dimethylbenzenesulfonamide 1a (1.02 g, 3 mmol) and 8-methylquinoline N-oxide 2a (955 mg, 6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. The solution was filtered over a short Celite bed and evaporated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate/hexane (15:75) as the eluent to give compound 3a as a white solid (760 mg, 2.2 mmol, 72%).

Typical Procedure for the Synthesis of 2-Bromo-N-methyl-5-phenyl-N-tosylfuran-3-carboxamide (4a)

To a stirred solution of N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 3a (50.0 mg, 0.14 mmol) in DMF (2.0 mL) was added NBS (37.56 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with water (3.0 mL), and the solution was then extracted with ethyl acetate (5.0 mL) three times. The organic phase was washed with brine, dried with MgSO₄, and concentrated under reduced pressure. The residue was purified on a silica column using ethyl acetate/hexane (5:95) as the eluent to give compound 4a as a yellow oil (41 mg, 0.09 mmol, 67%).

2-Bromo-N-methyl-5-phenyl-N-tosylfuran-3-carboxamide (4a)

Purified on silica gel column using ethyl acetate/hexane (10: 90) as the eluent; yellow oil (41 mg, 0.09 mmol, 67%); ¹H NMR (700 MHz, CDCl₃): δ 7.81 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 7.7 Hz, 3H), 6.77 (s, 1H), 3.33 (s, 3H), 2.42 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 164.1, 155.7, 145.1, 134.9, 129.7, 128.9, 128.7, 128.7, 128.6, 128.3, 125.3, 123.8, 122.2, 107.2, 34.5, 21.6; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₉H₁₆BrNO₄SNa, 455.9881; found, 455.9884.

Typical Procedure for the Synthesis of (5-Phenylfuran-3-yl)methanol (4b)

To a stirred solution of N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 3a (50.0 mg, 0.14 mmol) in dry THF (2.0 mL) was added LAH (1 M in THF, 0.21 mL, 0.21 mmol) at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride (3.0 mL), and the solution was then extracted with ethyl acetate (5.0 mL) three times. The organic phase was washed with brine, dried with MgSO₄, and concentrated under reduced pressure. The residue was purified on a silica column using ethyl acetate/hexane (30:70) as the eluent to give compound 4b as a yellow oil (21 mg, 0.12 mmol, 86%).

(5-Phenylfuran-3-yl)methanol (4b)

Purified on silica gel column using ethyl acetate/hexane (30: 70) as the eluent; yellow oil (21 mg, 0.12 mmol, 86%); ¹H NMR (700 MHz, CDCl₃): δ 7.63 (d, J = 7.7 Hz, 2H), 7.43 (s, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.25 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 4.57 (s, 2H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 154.8, 139.3, 130.6, 128.7, 127.5, 127.2, 123.8, 105.0, 56.8; HRFD⁺ calcd for C₁₁H₁₀O2 [M]⁺, 174.0681; found, 174.0680.

Typical Procedure for the Synthesis of 1-(5-Phenylfuran-3-yl)ethan-1-one (4c)

To a stirred solution of N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 3a (50.0 mg, 0.14 mmol) in THF (2.0 mL) was added MeMgBr (3 M in diethyl ether, 0.19 mL, 0.56 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The solution was quenched with a saturated solution of ammonium chloride (3.0 mL) at 0 °C, and the solution was then extracted with ethyl acetate (5.0 mL) three times. The organic phase was washed with brine, dried with MgSO₄, and concentrated under reduced pressure. The residue was purified on a silica column using ethyl acetate/hexane (03:97) as the eluent to give compound 4c as a yellow oil (11 mg, 0.059 mmol, 42%).

1-(5-Phenylfuran-3-yl)ethan-1-one (4c)

Purified on silica gel column using ethyl acetate/hexane (5:95) as the eluent; yellow oil (11 mg, 0.06 mmol, 42%); ¹H NMR (700 MHz, CDCl₃): δ 8.01 (s, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 6.97 (s, 1H), 2.45 (s, 3H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 192.5, 155.8, 146.7, 129.8, 129.7, 128.8, 128.3, 124.1, 103.1, 27.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₁₂H₁₀O₂Na, 209.0578; found, 209.0584.

Typical Procedure for the Synthesis of (2,5-Diphenylfuran-3-yl)(phenyl)methanone (4d)

To a stirred solution of N-methyl-5-phenyl-N-tosylfuran-3-carboxamide 3a (50.0 mg, 0.14 mmol) in THF (2.0 mL) was added PhMgBr (1 M in THF, 0.56 mL, 0.56 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The solution was quenched with a saturated solution of ammonium chloride (3.0 mL) at 0 °C, and the solution was then extracted with ethyl acetate (5.0 mL) three times. The organic phase was washed with brine, dried with MgSO₄, and concentrated under reduced pressure. The residue was purified on a silica column using ethyl acetate/hexane (03:97) as the eluent to give compound 4d as a yellow oil (28 mg, 0.086 mmol, 61%).

(2,5-Diphenylfuran-3-yl)(phenyl)methanone (4d)

Purified on silica gel column using ethyl acetate/hexane (3: 97) as the eluent; yellow oil (28 mg, 0.09 mmol, 61%); ¹H NMR (700 MHz, CDCl₃): δ 7.87 (d, J = 7.7 Hz, 2H), 7.77–7.74 (m, 4H), 7.51 (t, J = 7.7 Hz, 1H), 7.43–7.38 (m, 4H), 7.32–7.29 (m, 4H), 6.92 (s, 1H); ¹³C{¹H} NMR (175 MHz, CDCl₃): δ 191.8, 154.9, 152.5, 137.9, 132.9, 129.76, 129.74, 129.70, 129.0, 128.8, 128.37, 128.35, 128.2, 127.4, 124.1, 122.8, 108.7; HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd C₂₃H₁₆O₂Na, 347.1048; found, 347.1050.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02096.

• Scheme of substrate preparation, single-crystal X-ray data, and ¹H NMR and ¹³C NMR spectra for representative compounds (PDF)

The authors declare no competing financial interest.