Cu(II)/TBAI-Catalyzed Esterification of Acid Hydrazides via C(sp³)–H Oxidative Coupling

Abstract

A Cu²⁺/TBAI-cocatalyzed allylic ester synthesis was developed, which allows a direct coupling of acid hydrazides and cycloalkanes. This process makes use of commercially available, inexpensive, and abundant starting materials. Based on the extensive experimental data, a plausible radical mechanism was suggested.

During the past ten years, C–H activation has emerged as an attractive strategy to prepare organic building blocks in a step- and atom-economical fashion.[1] Much research has been devoted to this C–H functionalization, and a lot of selective conversions have been achieved, including C–C, C–O, C–N, and C–X (X = F, Cl, Br, I) bond formation.[2] Among these, some expensive metal catalysts containing palladium, rhodium, and iridium salts were always needed,[1] [2] the high price of which limits the practical industrial applications. The use of inexpensive, nontoxic and commercially available iron or copper salts would be of great value.

The C–O bond is a major structural motif found in a broad range of natural and unnatural structures.[3] Due to the biomedical and industrial importance of these molecules, the efficient and selective construction of C–O bonds has been paid a topic of long-standing attention. Recently, the catalytic synthesis of C–O bonds via C–H functionalization is of great interest.[4] Among them, C–H activation to form C(sp³)–O bond is a more challenging task. In the late 1950s, Kharasch and Sosnovsky reported the allylic oxidation of olefins to afford allyl esters with tert-butyl peroxybenzoates (the Kharasch–Sosnovsky reaction)[5] in the presence of a copper catalyst. After that, a great deal of research effort has been directed to improve the efficiency of this allylic oxidation of olefins.[6]

A few decades later, direct esterfication of an alkenes using aromatic acids were also attached.[7] Recently, some further significant progress in this area that cycloallyl esters were synthesized directly from cycloalkanes using aromatic aldehydes[8] or alkylbenzenes[9] as benzoyl source, respectively, has been made. Herein, we report the synthesis of cycloallyl esters via C(sp³)–H oxidative coupling process using stable and accessible solids of acid hydrazides as benzoyl source and Cu(II)/TBAI as catalyst (Scheme [1]).

Table 1 Optimization of Conditions^a

Entry	Catalyst	Oxidant	Additive	Yield (%)b
1	Cu(OAc)2	TBHP	–	35
2	CuCl	TBHP	–	5
3	CuBr	TBHP	–	8
4	CuI	TBHP	–	14
5	Cu(OAc)2	TBHP	TBAI	61
6	Cu(OAc)2	TBHP	KI	47
7	Cu(OAc)2	TBHP	KCl	<5
8	Cu(OAc)2	TBHP	KBr	<5
9	–	TBHP	–	0
10	–	TBHP	TBAI	24
11	Cu(OAc)2	No	TBAI	0

^a Reaction conditions: 1a (0.2 mmol), cyclohexane (2a, 2 mL), catalyst (10 mol%), oxidant (0.6 mmol), additive (20 mol%), 140 °C, N₂, 36 h.

^b Isolated yield.

We began our investigation by examining the coupling of benzoic acid hydrazide (1a, 0.2 mmol) and cyclohexane (2a, 2 mL) in the presence of different copper salts and oxidants to optimize the reaction conditions. The catalytic system using 10 mol% of Cu(OAc)₂ as catalyst and TBHP (3 equiv) as oxidant gave an encouraging yield of 35% for 3a (Table [1], entry 1). However, other copper salts gave poor results (Table [1], entries 2–4). When adding 20 mol% additive of TBAI (Bu₄NI), the yield of 3a increased to 61% (Table [1], entry 5) unexpectedly. KI could not afford the higher yield (entry 6), but KCl and KBr reduced the yield (<5%, Table [1], entries 7 and 8). Control experiments carried out in the absence of either Cu(OAc)₂/TBAI or TBHP failed to give the target product (Table [1], entries 9, 11), but TBAI only manifested some catalytic activity (Table [1], entry 10). Increasing the amount of catalyst, oxidant, additive, or using other oxidants did not improve the yield (Supporting Information Table [1], entries 11–20).

With the optimized reaction conditions (Table [1], entry 5), the substrate scope was then examined (Scheme [2]). Substrates bearing various aryl-substituted acid hydrazides could afford the corresponding borate esters in good to excellent yields (Scheme [2]). Both electron-withdrawing and electron-donating substitutions on the aromatic ring were successfully esterificated (Scheme [2], 3a–h), however, the substrates with electron-withdrawing group reduced the reaction yield (3b–d vs. 3e–h). In addition, heterocyclic aromatic acid hydrazides also gave the target products in a lower yield (3i,j). It is a pity that aliphatic acid hydrazides gave no results (3k,l). Other cycloalkanes also gave the good yield of target products (3m–o) except hexane (3p).

To gain some insight of the reaction mechanism and understand the roles of each component in the transformation, control experiments were performed (Scheme [3]). We found that the addition of radical scavengers, such as 1,1-diphenylethene or TEMPO (Scheme [3, a]), completely inhibited the reaction, and no desired products were obtained. This result indicated that the current transformation might proceed via formation of radical species.[6] [7] [8] [9] Furthermore, benzoic acid hydrazide reacted in MeCN under standard conditions without cyclohexane gave 45% yield of benzoic acid (Scheme [3, a]). Subsequently, benzoic acid was used to react with cyclohexane under standard conditions giving 58% yield of 3a (based on benzoic acid, Scheme [3, c]). When the reaction was carried out in the absence of 1a, cyclohexene were detected by ¹H NMR spectroscopy (Scheme [3, d]). Finally, 1a was used to react with ten equivalents cyclohexene giving 71% yield of 3a (Scheme [3, e]). It is suggested that the catalytic cycle might proceed via cyclohexene and benzoic acid as the intermediates.

On the basis of these preliminary results, possible mechanisms are proposed (Scheme [4]). Initially, TBHP can give the t-Bu and OH radicals catalyzed by TBAI, according to Szabó[6d] and Wan.[7c] Subsequently, benzoic acid hydrazide is oxidized to give benzoic acid. Meanwhile, cyclohexane undergoes dehydrogenation to cyclohexene, according to Pérez’s suggestion.[10] This dehydrogenative olefination of cyclohexane to give cyclohexene has been reported with various platinum, iridium, or rhenium catalysts.[11] Finally, a similar oxidative coupling as described in Wan’s work[7c] to form the target product 3a [12] was performed.

In summary, we have successfully developed a Cu²⁺/TBAI cocatalyzed allylic ester synthesis allowing a direct coupling of acid hydrazides and cycloalkanes. This radical process makes use of commercially available, inexpensive, and abundant starting materials. Based on the extensive experimental data, we have proposed a plausible radical mechanism. Further studies concerning the detailed mechanism are currently under way in our laboratory.

Acknowledgment

The authors are grateful for the support of the Special Fund for Fundamental Research from the Institute of New Technology of the Chinese Academy of Forestry (CAFINT2012C04).

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• 12 Synthesis of 3a–p A mixture of 1 (0.2 mmol), cycloalkane (2 mL), Cu(OAc)₂ (10 mol%), TBAI (20 mol%), and TBHP (3 equiv) was stirred at 140 °C under N₂ atmosphere for 36 h. The reaction mixture was washed with H₂O and the aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding product. Compound 3a: yield 61%. ¹H NMR (500 MHz, CDCl₃): δ = 8.06 (d, J = 8.4 Hz, 2 H), 7.55 (m, 1 H), 7.42 (dd, J = 8.2, 7.0 Hz, 2 H), 6.01 (m, 1 H), 5.85 (m, 1 H), 5.51 (m, 1 H), 2.15 (m, 1 H), 2.04 (m, 1 H), 1.96 (m, 1 H), 1.84 (m, 1 H), 1.68 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 132.8, 132.7, 130.8, 129.5, 128.2, 125.7, 68.5, 28.4, 24.9, 18.9. HRMS: m/z calcd for C₁₃H₁₄O₂ [M]⁺: 202.2491; found: 202.2488. Compound 3b: yield 70%. ¹H NMR (500 MHz, CDCl₃): δ = 8.00 (d, J = 9.0 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 5.96 (m, 1 H), 5.81 (m, 1 H), 5.45 (m, 1 H), 3.82 (s, 3 H), 2.04 (m, 3 H), 1.82 (m, 2 H), 1.67 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.9, 163.2, 132.5, 131.5, 125.9, 123.2, 113.4, 68.2, 55.3, 28.4, 24.9, 18.9. HRMS: m/z calcd for C₁₄H₁₆O₃ [M]⁺: 232.2750; found: 232.2755. Compound 3c: yield 58%. ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (m, 2 H), 7.13 (m, 2 H), 5.80 (m, 1 H), 5.68 (m, 1 H), 5.35 (m, 1 H), 2.20 (m, 3 H), 1.99–1.65 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.8, 137.5, 133.1, 132.2, 130.3, 129.6, 127.7, 126.4, 125.2, 68.0, 28.1, 24.6, 20.8, 18.6.. HRMS: m/z calcd for C₁₄H₁₆O₃ [M]⁺: 232.2750; found: 232.2753 Compound 3d: yield 72%. ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (dd, J = 8.4, 2.0 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 1 H), 6.69 (m, 1 H), 5.83 (m, 1 H), 5.68 (m, 1 H), 5.28 (m, 1 H), 3.75 (s, 3 H), 3.70 (s, 3 H), 2.20–1.40 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.4, 152.4, 148.1, 132.0, 125.5, 123.0, 122.8, 111.5, 109.7, 67.9, 55.4, 28.1, 24.5, 18.2. HRMS: m/z calcd for C₁₅H₁₈O₄ [M]⁺: 262.3010; found: 262.3013. Compound 3e: yield 39%. ¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 8.6 Hz, 2 H), 6.01 (m, 1 H), 5.832 (m, 1 H), 5.50 (m, 1 H), 2.05 (m, 3 H), 1.83 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.3, 132.8, 131.4, 130.99, 129.7, 127.67, 125.9, 68.8, 28.4, 24.8, 18.2.. HRMS: m/z calcd for C₁₃H₁₃BrO₂ [M]⁺: 281.1451; found: 281.1450. Compound 3f: yield 30%. ¹H NMR (500 MHz, CDCl₃): δ = 8.28 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H), 6.05 (m, 1 H), 5.84 (m, 1 H), 5.55 (m, 1 H), 2.19–1.72 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 164.0, 150.1, 135.9, 133.9, 130.4, 124.7, 123.2, 69.6, 28.0, 24.7, 18.6. HRMS: m/z calcd for C₁₃H₁₃NO₄ [M]⁺: 247.2466; found: 247.2463. Compound 3g: yield 33%. ¹H NMR (500 MHz, CDCl₃): δ = 8.07 (m, 2 H), 7.10 (m, 2 H), 6.01 (m, 1 H), 5.82 (m, 1 H), 5.50 (m, 1 H), 2.06 (m, 3 H), 1.85 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.9, 165.2, 164.3, 132.9, 132.1, 132.0, 126.9, 125.5, 115.4, 115.2, 68.7, 28.3, 24.9, 18.9. HRMS: m/z calcd for C₁₃H₁₃FO₂ [M]⁺: 220.2395; found: 220.2393. Compound 3h: yield 45%. ¹H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 6.01 (m, 1 H), 5.82 (m, 1 H), 5.50 (m, 1 H), 2.05 (m, 3 H), 1.83 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2, 139.0, 132.9, 130.9, 129.1, 128.5, 125.4, 68.8, 28.3, 24.8, 18.8. HRMS: m/z calcd for C₁₃H₁₃ClO₂ [M]⁺: 236.6941; found: 236.6945. Compound 3i: yield 37%. ¹H NMR (500 MHz, CDCl3): δ = 7.80 (m, 1 H), 7.53 (m, 1 H), 7.08 (m, 1 H), 6.00 (m, 1 H), 5.81 (m, 1 H), 5.47 (m, 1 H), 2.03 (m, 3 H), 1.84 (m, 2 H), 1.68 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 161.8, 134.3, 133.1, 132.9, 132.0, 127.5, 125.4, 68.8, 28.2, 24.8, 18.8. HRMS: m/z calcd for C₁₁H₁₂SO₂ [M]⁺: 208.2768; found: 208.2770. Compound 3j: yield 21%. ¹H NMR (500 MHz, CDCl₃): δ = 7.92 (m, 1 H), 7.64 (m, 1 H), 7.15 (m, 1 H), 6.21 (m, 1 H), 5.89 (m, 1 H), 5.67 (m, 1 H), 2.3 (m, 3 H), 1.88 (m, 2 H), 1.78 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.5, 134.9, 134.1, 132.9, 132.0, 128.3, 125.9, 68.8, 28.5, 24.3, 18.1. HRMS: m/z calcd for C₁₁H₁₂O₃ [M]⁺: 192.2112; found: 192.2110. Compound 3m: yield 65%. ¹H NMR (500 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.40 (m, 2 H), 6.18 (m, 1 H), 5.92 (m, 2 H), 2.65 (m, 1 H), 2.33 (m, 2 H), 1.90 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.6, 137.7, 132.7, 130.7, 129.5, 129.4, 128.2, 81.1, 31.2, 29.9. HRMS: m/z calcd for C₁₂H₁₂O₂ [M]⁺: 288.2225; found: 188.2220. Compound 3n: yield 43%. ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (m, 2 H), 7.57 (m, 1 H), 7.42 (m, 2 H), 5.91 (m, 1 H), 5.79 (m, 1 H), 5.66 (m, 1 H), 2.27 (m, 1 H), 2.14 (m, 1 H), 2.01 (m, 2 H), 1.90–1.66 (m, 3 H), 1.53–1.45 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.1, 133.7, 133.0, 132.2, 130.9, 129.8, 128.5, 74.9, 33.1, 28.8, 26.9, 26.8. HRMS: m/z calcd for C₁₄H₁₆O₂ [M]⁺: 216.2756; found: 216.2751. Compound 3o: yield 68%. ¹H NMR (500 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.55 (t, J = 8.4 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 5.93 (m, 1 H), 5.72 (m, 1 H), 5.61 (m, 1 H), 2.33 (m, 1 H), 2.15 (m, 1 H), 2.04 (m, 1 H), 1.66 (m, 6 H), 1.42 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.0, 132.7, 130.7, 130.7, 129.8, 129.5, 128.2, 73.0, 35.1, 28.8, 26.4, 25.9, 23.4. HRMS: m/z calcd for C₁₅H₁₈O₂ [M]⁺: 230.3022; found: 230.3019.

• References and Notes

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For recent reviews on this topic, see:
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• 1i Kuhl N, Hopkinson MN, Wencel-Delord J, Glorius F. Angew. Chem. Int. Ed. 2012; 51: 10236
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• 1j Engle KM, Mei T.-S, Wasa M, Yu J.-Q. Acc. Chem. Res. 2012; 45: 788
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• 1k Engle KM, Yu J.-Q. J. Org. Chem. 2013; 78: 8927
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C–H functionalization in total synthesis:
• 2a Taber DF, Stiriba S.-E. Chem. Eur. J. 1998; 4: 990
  CrossrefSearch in Google Scholar
• 2b Godula K, Sames D. Science 2006; 312: 67
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  CrossrefPubMedSearch in Google Scholar
• 2e McMurray L, O’Hara F, Gaunt MJ. Chem. Soc. Rev. 2011; 40: 1885
  CrossrefPubMedSearch in Google Scholar
• 2f Brückl T, Baxter RD, Ishihara Y, Baran PS. Acc. Chem. Res. 2012; 45: 826
  CrossrefPubMedSearch in Google Scholar
• 2g Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
  CrossrefPubMedSearch in Google Scholar
• 3a Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400
  Search in Google Scholar
• 3b Science of Synthesis . Vol. 27. Forsyth CJ. Thieme; Stuttgart: 2008
  Search in Google Scholar

For selected references, see:
• 4a Wang DH, Engle KM, Shi BF, Yu J.-Q. Science 2010; 327: 315
  CrossrefSearch in Google Scholar
• 4b Engle KM, Mei T.-S, Wasa M, Yu J.-Q. Acc. Chem. Res. 2012; 45: 788
  Search in Google Scholar
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• 5b Kharasch MS, Sosnovsky G. J. Am. Chem. Soc. 1958; 80: 756
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• 5c Akermark B, Magnus Larsson E, Oslob JD. J. Org. Chem. 1994; 59: 5729
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• 5d Shi E, Shao Y, Chen S, Hu H, Liu Z, Zhang J, Wan X. Org. Lett. 2012; 14: 3384
  CrossrefSearch in Google Scholar

Several groups have described transition-metal-catalyzed C–H oxidation for allylic ester, see:
• 6a Grennberg H, Bäckvall J.-E. Chem. Eur. J. 1998; 4: 1083
  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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• 6e Stang EM, White MC. Nat. Chem. 2009; 1: 547
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• 6f Thiery E, Aouf C, Belloy J, Harakat D, Le Bras J, Muzart J. J. Org. Chem. 2010; 75: 1771
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• 12 Synthesis of 3a–p A mixture of 1 (0.2 mmol), cycloalkane (2 mL), Cu(OAc)₂ (10 mol%), TBAI (20 mol%), and TBHP (3 equiv) was stirred at 140 °C under N₂ atmosphere for 36 h. The reaction mixture was washed with H₂O and the aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding product. Compound 3a: yield 61%. ¹H NMR (500 MHz, CDCl₃): δ = 8.06 (d, J = 8.4 Hz, 2 H), 7.55 (m, 1 H), 7.42 (dd, J = 8.2, 7.0 Hz, 2 H), 6.01 (m, 1 H), 5.85 (m, 1 H), 5.51 (m, 1 H), 2.15 (m, 1 H), 2.04 (m, 1 H), 1.96 (m, 1 H), 1.84 (m, 1 H), 1.68 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 132.8, 132.7, 130.8, 129.5, 128.2, 125.7, 68.5, 28.4, 24.9, 18.9. HRMS: m/z calcd for C₁₃H₁₄O₂ [M]⁺: 202.2491; found: 202.2488. Compound 3b: yield 70%. ¹H NMR (500 MHz, CDCl₃): δ = 8.00 (d, J = 9.0 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 5.96 (m, 1 H), 5.81 (m, 1 H), 5.45 (m, 1 H), 3.82 (s, 3 H), 2.04 (m, 3 H), 1.82 (m, 2 H), 1.67 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.9, 163.2, 132.5, 131.5, 125.9, 123.2, 113.4, 68.2, 55.3, 28.4, 24.9, 18.9. HRMS: m/z calcd for C₁₄H₁₆O₃ [M]⁺: 232.2750; found: 232.2755. Compound 3c: yield 58%. ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (m, 2 H), 7.13 (m, 2 H), 5.80 (m, 1 H), 5.68 (m, 1 H), 5.35 (m, 1 H), 2.20 (m, 3 H), 1.99–1.65 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.8, 137.5, 133.1, 132.2, 130.3, 129.6, 127.7, 126.4, 125.2, 68.0, 28.1, 24.6, 20.8, 18.6.. HRMS: m/z calcd for C₁₄H₁₆O₃ [M]⁺: 232.2750; found: 232.2753 Compound 3d: yield 72%. ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (dd, J = 8.4, 2.0 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 1 H), 6.69 (m, 1 H), 5.83 (m, 1 H), 5.68 (m, 1 H), 5.28 (m, 1 H), 3.75 (s, 3 H), 3.70 (s, 3 H), 2.20–1.40 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.4, 152.4, 148.1, 132.0, 125.5, 123.0, 122.8, 111.5, 109.7, 67.9, 55.4, 28.1, 24.5, 18.2. HRMS: m/z calcd for C₁₅H₁₈O₄ [M]⁺: 262.3010; found: 262.3013. Compound 3e: yield 39%. ¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 8.6 Hz, 2 H), 6.01 (m, 1 H), 5.832 (m, 1 H), 5.50 (m, 1 H), 2.05 (m, 3 H), 1.83 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.3, 132.8, 131.4, 130.99, 129.7, 127.67, 125.9, 68.8, 28.4, 24.8, 18.2.. HRMS: m/z calcd for C₁₃H₁₃BrO₂ [M]⁺: 281.1451; found: 281.1450. Compound 3f: yield 30%. ¹H NMR (500 MHz, CDCl₃): δ = 8.28 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H), 6.05 (m, 1 H), 5.84 (m, 1 H), 5.55 (m, 1 H), 2.19–1.72 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 164.0, 150.1, 135.9, 133.9, 130.4, 124.7, 123.2, 69.6, 28.0, 24.7, 18.6. HRMS: m/z calcd for C₁₃H₁₃NO₄ [M]⁺: 247.2466; found: 247.2463. Compound 3g: yield 33%. ¹H NMR (500 MHz, CDCl₃): δ = 8.07 (m, 2 H), 7.10 (m, 2 H), 6.01 (m, 1 H), 5.82 (m, 1 H), 5.50 (m, 1 H), 2.06 (m, 3 H), 1.85 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.9, 165.2, 164.3, 132.9, 132.1, 132.0, 126.9, 125.5, 115.4, 115.2, 68.7, 28.3, 24.9, 18.9. HRMS: m/z calcd for C₁₃H₁₃FO₂ [M]⁺: 220.2395; found: 220.2393. Compound 3h: yield 45%. ¹H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 6.01 (m, 1 H), 5.82 (m, 1 H), 5.50 (m, 1 H), 2.05 (m, 3 H), 1.83 (m, 2 H), 1.70 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2, 139.0, 132.9, 130.9, 129.1, 128.5, 125.4, 68.8, 28.3, 24.8, 18.8. HRMS: m/z calcd for C₁₃H₁₃ClO₂ [M]⁺: 236.6941; found: 236.6945. Compound 3i: yield 37%. ¹H NMR (500 MHz, CDCl3): δ = 7.80 (m, 1 H), 7.53 (m, 1 H), 7.08 (m, 1 H), 6.00 (m, 1 H), 5.81 (m, 1 H), 5.47 (m, 1 H), 2.03 (m, 3 H), 1.84 (m, 2 H), 1.68 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 161.8, 134.3, 133.1, 132.9, 132.0, 127.5, 125.4, 68.8, 28.2, 24.8, 18.8. HRMS: m/z calcd for C₁₁H₁₂SO₂ [M]⁺: 208.2768; found: 208.2770. Compound 3j: yield 21%. ¹H NMR (500 MHz, CDCl₃): δ = 7.92 (m, 1 H), 7.64 (m, 1 H), 7.15 (m, 1 H), 6.21 (m, 1 H), 5.89 (m, 1 H), 5.67 (m, 1 H), 2.3 (m, 3 H), 1.88 (m, 2 H), 1.78 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.5, 134.9, 134.1, 132.9, 132.0, 128.3, 125.9, 68.8, 28.5, 24.3, 18.1. HRMS: m/z calcd for C₁₁H₁₂O₃ [M]⁺: 192.2112; found: 192.2110. Compound 3m: yield 65%. ¹H NMR (500 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.40 (m, 2 H), 6.18 (m, 1 H), 5.92 (m, 2 H), 2.65 (m, 1 H), 2.33 (m, 2 H), 1.90 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.6, 137.7, 132.7, 130.7, 129.5, 129.4, 128.2, 81.1, 31.2, 29.9. HRMS: m/z calcd for C₁₂H₁₂O₂ [M]⁺: 288.2225; found: 188.2220. Compound 3n: yield 43%. ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (m, 2 H), 7.57 (m, 1 H), 7.42 (m, 2 H), 5.91 (m, 1 H), 5.79 (m, 1 H), 5.66 (m, 1 H), 2.27 (m, 1 H), 2.14 (m, 1 H), 2.01 (m, 2 H), 1.90–1.66 (m, 3 H), 1.53–1.45 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.1, 133.7, 133.0, 132.2, 130.9, 129.8, 128.5, 74.9, 33.1, 28.8, 26.9, 26.8. HRMS: m/z calcd for C₁₄H₁₆O₂ [M]⁺: 216.2756; found: 216.2751. Compound 3o: yield 68%. ¹H NMR (500 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.55 (t, J = 8.4 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 5.93 (m, 1 H), 5.72 (m, 1 H), 5.61 (m, 1 H), 2.33 (m, 1 H), 2.15 (m, 1 H), 2.04 (m, 1 H), 1.66 (m, 6 H), 1.42 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.0, 132.7, 130.7, 130.7, 129.8, 129.5, 128.2, 73.0, 35.1, 28.8, 26.4, 25.9, 23.4. HRMS: m/z calcd for C₁₅H₁₈O₂ [M]⁺: 230.3022; found: 230.3019.

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