Gold catalyzed intramolecular hydroalkoxylation assisted ring opening of furans to the corresponding saturated γ-keto esters

Accepted Manuscript Gold Catalyzed Intramolecular Hydroalkoxylation Assisted Ring Opening of Furans to the Corresponding Saturated γ-Keto Esters Chinta Nagaraju, Kavirayani R. Prasad PII:

S0040-4020(15)30119-8

DOI:

10.1016/j.tet.2015.10.017

Reference:

TET 27189

To appear in:

Tetrahedron

Received Date: 2 September 2015 Revised Date:

4 October 2015

Accepted Date: 6 October 2015

Please cite this article as: Nagaraju C, Prasad KR, Gold Catalyzed Intramolecular Hydroalkoxylation Assisted Ring Opening of Furans to the Corresponding Saturated γ-Keto Esters, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Graphical Abstract

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Gold Catalyzed Intramolecular Hydroalkoxylation Assisted Ring Opening of Furans to the Corresponding Saturated γ-Keto Esters Chinta Nagaraju and Kavirayani R. Prasad*

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Tetrahedron journal hom epage: www. elsevi er.c om

Chinta Nagaraju and Kavirayani R. Prasad*

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Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA FAX: +0091-80-23600529; E-mail: [email protected]

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Gold Catalyzed Intramolecular Hydroalkoxylation Assisted Ring Opening of Furans to the Corresponding Saturated γ-Keto Esters

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A facile ring opening of furans in furyl propargyl alcohols to the corresponding saturated γ-keto esters is observed in the gold(III) chloride catalyzed reaction with MeOH. It is found that the ring opening of furan is driven by the intramolecular hydroalkoxylation. Mitigating the intramolecular hydroalkoxylation led to the expected conjugated enyne resulting from the dehydration.

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Keywords: Gold catalysis Keto esters Ring opening reactions hydroalkoxylation

1. Introduction

propargyl alcohol 3 leading to dihydrofuran 2 and subsequent hydrogenation of 2. The furyl propargyl alcohols 3 can be procured easily by the addition of the substituted alkynes 4 to furfural 5 (Scheme-2).

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The availability of chiral furyl carbinols by simple methods has led to their use as effective building blocks in total synthesis of natural products.1 Notable reactions such as the Achmatowicz and Piancatelli reactions are extensively utilized for the synthesis of chiral dihydropyrones and cyclopentenones respectively from furyl carbinols.2,3 Some other transformations of furyl carbinols reported in the literature include the dehydrative dihydrofuran formation4 as well as nucleophilic substitution of the alcohol functionality (Scheme-1).5 During the course of our investigations concerning gold catalyzed intramolecular hydroalkoxylation reactions,6 we observed an interesting ring opening of furans in furyl propargyl alcohols to the corresponding saturated γ-keto esters driven by an intramolecular hydroalkoxylation of the alkyne, which is discussed in detail in this article.

2014 Elsevier Ltd. All rights reserved.

Scheme-1: Reactions of furyl carbinols 2. Results and Discussion In our program concerning the synthesis of analogues of Annonacae acetogenins, we required tetrahydrofuryl appended furyl carbinols of type 1. Synthesis of the furyl carbinols 1 was anticipated from the intramolecular hydroalkoxylation of furyl

Scheme 2. Retrosynthesis for furyl carbinol 1 Accordingly, at the outset, furyl propargyl alcohol 3a was synthesized by addition of the substituted alkyne 4a to furfural 5. AuCl3 catalyzed hydroalkoxylation reaction of 3a in MeOH, to our surprise furnished the saturated γ-keto ester 6a in 86% yield (Scheme-3).

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Scheme 3. Reaction of 3a with AuCl3

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Although, oxidative as well as acid mediated ring opening of furans to the corresponding E-but-2-en-1,4-diones and saturated 1,4-diones is documented in literature,7 to the best of our knowledge, facile opening of furan to the saturated γ-keto ester is not reported.8 A plausible mechanism for the formation of the product 6a is outlined in Scheme-4.

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Chart-1: Synthesis of saturated γ-keto esters 6b-k

Scheme-4: Plausible mechanism for the formation of 6a

Structure of the formed product was further confirmed by X-ray crystal structure analysis of the compound 6j (fig. 1).9

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It is proposed that the initial intramolecular hydroalkoxylation of 3a generates the dihydrofuryl furyl carbinol 2a, which under acidic conditions furnishes the stable carbocation 7. Activation of the furan in 7 and further reaction with MeOH leads to the 5methoxyfuryl substituted enol ether 9, which rearranges to the saturated γ-keto ester 6a.

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The transformation was found to be general and the reaction of a series of structurally diverse furyl propargyl alcohols 3b-k with MeOH in presence of catalytic amount of AuCl3 afforded the corresponding tetrahydrofuryl appended saturated γ-keto esters 6b-k in good yields (Chart-1).

Fig 1: ORTEP diagram of 6j with displacement ellipsoids at 50% probability Interestingly, presence of other reactive functional groups such as allyl, benzyl and 4-methoxybenzyl in the substrate carbinols, which can compete in hydroalkoxylation as well as in the enyne cyclization reaction also furnished the product saturated γ-keto esters 6b-f in good yields. It was worth noting that the furyl propargyl alcohol 3l possessing a prenyl unit also afforded the product 6l in 60% yield. No enyne cyclization product was isolated in the reaction. Interestingly, reaction of the furyl propargyl alcohol 3m possessing a methyl substitution at the 5position of furan afforded an unidentifiable mixture of products (Scheme-5).

ACCEPTED MANUSCRIPT 3 grade MeOH was used. Melting points were uncorrected. 1H NMR and 13C NMR spectra were recorded either on a 400 MHz machine in CDCl3 as solvent with TMS as reference. HRMS was obtained using a micromass-QTOF spectrometer using electrospray ionization (ESI).

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Scheme-5: Synthesis of saturated γ-keto ester 6l We reasoned that the driving force for the furan ring opening to form the saturated γ-keto ester is the formation of the triene 8 from 3a which under the reaction conditions rearranges to the product 6a. We anticipated that simple furyl propargyl alcohols lacking the pendant hydroxy group for intramolecular hydroalkoxylation should lead to simple dehydration of the secondary alcohol with concomitant nucleophilic addition of MeOH at the 5-position of furan. This was found to be the case and the reaction of simple furyl propargyl alcohols 11a-d with MeOH in presence of catalytic AuCl3 cleanly led to the formation of the conjugated enynes (as a scalemic E/Z mixture) 12a-d in good yields (Chart-2). Although Lewis acid catalyzed dehydrative dihydrofuran formation from furylcarbinols is known,4 the present procedure under mild reaction conditions compliments the existing procedures.

General Procedure for the synthesis of compound 4a: To a stirred solution of the alcohol (0.30 g, 1.37 mmol) in EtOAc (3 mL) was added IBX (1.16 g, 4.13 mmol) and the resulting suspension was refluxed for 8 h. After completion of the reaction (TLC), the reaction mixture was passed through a short pad of silica gel and the silica gel pad was washed with EtOAc (10 mL). The solvent was removed in vacuo to give the crude aldehyde. To a stirred solution of aldehyde thus obtained above in MeOH (5 mL) under a nitrogen atmosphere at 0 °C, was added The diazophosphonate (Ohira–Bestmann reagent) (0.45 g, 2.05 mmol) followed by anhydrous K2CO3 (0.28 g, 2.05 mmol) in one portion. The resulting reaction mixture was allowed to stir for 5 h at rt. After completion of the reaction (TLC), it was diluted with pet ether, quenched by addition of H2O and was extracted with pet ether (2 × 20 mL). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of solvent followed by silica gel column chromatography of the resulting crude residue with petroleum ether:Ether afforded the known alkyne 4a.

Chart-2: Formation of the conjugated enynes 12a-e from the furyl propargyl alcohols 11a-e. In conclusion, an unusual gold catalyzed ring opening of furan to the corresponding saturated γ-keto esters is observed in the reaction of furyl propargyl alcohols with AuCl3 in MeOH. The intramolecular hydroalkoxylation is essential for the ring opening of the furan to the saturated γ-keto esters, while simple furyl propargyl carbinols under similar conditions afforded the conjugated enynes involving dehydration/ ketalization. 3. General Information: Column chromatography was performed on Silica gel, Acme grade 100-200 mesh. TLC plates were visualized either with UV, in an iodine chamber, or with phosphomolybdic acid spray. All reagents were purchased from commercial sources and used without additional purification. THF was freshly distilled over Na-benzophenone ketyl. HPLC

Tert-butyl((2,2-dimethylbut-3-yn-1-yl)oxy)dimethylsilane (4a): 92% yield (0.27 g) as a colorless liquid. IR (neat) 3310, 2952, 2869, 2110, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.45 (s, 2H), 2.05 (s, 1H), 1.18 (s, 6H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 90.6, 71.1, 68.1, 33.3, 25.9, 25.3, 18.3, –5.4; HRMS for C12H24OSi+Na calcd 235.1494; found 235.1499. Tert-butyl((2-ethynyl-2-methylpent-4-en-1yl)oxy)dimethylsilane (4b): 84% yield (0.25 g) as a colorless oil. IR (neat) 3308, 2952, 2856, 2116, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.98-5.87 (m, 1H), 5.11-5.06 (m, 2H), 3.53 and 3.45 (ABq, J = 9.2, 2H), 2.30 (dd, J = 13.6, 7.2 Hz, 1H), 2.15 (dd, J = 13.2, 7.2 Hz, 1H), 2.11 (s, 1H), 1.17 (s, 3H), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 134.7, 117.5, 88.7, 69.7, 69.1, 41.6, 36.9, 25.8, 23.3, 18.3, –5.4, –5.5; HRMS for C14H26OSi+Na calcd 261.1651; found 261.1651.

((2-Benzyl-2-methylbut-3-yn-1-yl)oxy)(tertbutyl)dimethylsilane (4c): 88% yield (0.26 g) as a colorless oil. IR (neat) 3308, 2944, 2856, 2111, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 3.48 and 3.41 (ABq, J = 9.6 Hz, 2H), 2.86 (d, J = 12.8 Hz, 1H), 2.73 (d, J = 12.8 Hz, 1H), 2.14 (s, 1H), 1.19 (s, 3H), 0.96 (s, 9H), 0.093 (s, 3H), 0.087 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.8, 130.7, 127.6, 126.3, 88.6, 70.8, 68.4, 42.6, 38.2, 25.9, 23.6, 18.3, –5.4, –5.5: HRMS for C18H28OSi+Na calcd 311.1807; found 311.1810. ((2-Allyl-2-ethynylpent-4-en-1-yl)oxy)(tertbutyl)dimethylsilane (4d): 72% yield (0.21 g) as a colorless oil. IR (neat) 3301, 2965, 2859, 2121, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.98-5.87 (m, 2H), 5.12-5.08 (m, 4H), 3.49 (s, 2H), 2.29 (dd, J = 13.2, 7.6 Hz, 2H), 2.21 (dd, J = 13.6, 6.8 Hz, 2H), 2.16 (s, 1H), 0.91 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 134.4, 117.8, 86.7, 71.3, 65.8, 40.5, 39.9, 25.8, 18.2, –5.5; HRMS for C16H28OSi+Na calcd 287.1807; found 287.1819.

ACCEPTED MANUSCRIPT Tetrahedron

((2,2-Bis(4-methoxybenzyl)but-3-yn-1-yl)oxy)(tertbutyl)dimethylsilane (4f): 90% yield (0.27 g) as a white crystalline compound. mp 58-60 °C; IR (neat) 3306, 2940, 2858, 2111, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.8 Hz, 4H), 6.83 (d, J = 8.4 Hz, 4H), 3.81 (s, 6H), 3.31 (s, 2H), 2.87 (d, J = 13.2 Hz, 2H), 2.70 (d, J = 13.2 Hz, 2H), 2.19 (s, 1H), 1.02 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.2, 131.7, 129.6, 113.0, 86.5, 73.9, 55.1, 43.3, 40.7, 26.0, 18.2, –5.4; HRMS for C26H36O3Si+Na calcd 447.2331; found 447.2334.

General Procedure for the synthesis of compound 3a: To a pre cooled (−78 °C) stirred solution of alkyne 4a (0.20 g, 0.94 mmol) in dry THF (2 mL) was added n-BuLi (0.69 mL of 1.5 M solution in hexanes, 1.03 mmol) dropwise and the resulting solution was stirred for 1 h at the same temperature. To the lithium acetylide thus generated, was added a solution of furfural 5 (0.086 mL, 1.03 mmol) in THF (1 ml). The reaction mixture was slowly allowed to warm up to room temperature over a period of 1 h and after completion of the reaction (as indicated by TLC), it was quenched by addition of sat. NH4Cl solution (4 mL), extracted with Et2O (2 × 10 mL). The combined ethereal extracts were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed by silica gel column chromatography of the resulting crude residue with petroleum ether:EtOAc as eluent afforded the propargyl alcohol 3a. 5-((Tert-butyldimethylsilyl)oxy)-1-(furan-2-yl)-4,4dimethylpent-2-yn-1-ol (3a): 94% yield (0.27 g) as a yellow color oil. IR (neat) 3426, 2931, 2923, 2858, 2215, 1636 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 6.43 (d, J = 3.2 Hz, 1H), 6.33 (s, 1H), 5.42 (d, J = 6.8 Hz, 1H), 3.46 (s, 2H), 2.30 (d, J = 6.8 Hz, 1H), 1.20 (s, 6H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.6, 142.8, 110.2, 107.6, 92.3, 77.5, 71.0, 58.2, 33.5, 25.8, 25.2, 18.3, –5.5; HRMS for C17H28O3Si+Na calcd 331.1705; found 331.1710.

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Tert-butyl((1-ethynylcyclohexyl)methoxy)dimethylsilane (4g): 82% yield (0.28 g) as a colorless oil. IR (neat) 3307, 2930, 2852, 2114, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.48 (s, 2H), 2.11 (s, 1H), 1.70-1.58 (m, 7H), 1.40-1.31 (m, 2H), 1.22-1.06 (m, 1H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 88.7, 71.2, 70.3, 39.2, 33.4, 26.0, 25.9, 22.6, 18.3, –5.4; HRMS for C15H28OSi+Na calcd 275.1807; found 275.1809.

(2-Ethynyl-2-(methoxymethyl)propane-1,3-diyl)dibenzene (4m): 91% yield (0.27 g) as a colorless oil. IR (neat) 3306, 2962, 2859, 2111, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 10H), 3.37 (s, 3H), 3.01 (s, 2H), 3.00 (d, J = 13.2 Hz, 2H), 2.83 (d, J = 13.2 Hz, 2H), 2.24 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 137.3, 130.8, 127.7, 126.4, 85.9, 73.8, 58.4, 42.4, 42.1; HRMS for C19H20O+Na calcd 287.1412; found 287.1417.

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Tert-butyl((2,2-dibenzylbut-3-yn-1-yl)oxy)dimethylsilane (4e): 83% yield (0.33 g) as a colorless oil. IR (neat) 3306, 2962, 2859, 2111, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.2 Hz, 4H), 7.31-7.22 (m, 6H), 3.34 (s, 2H), 2.95 (d, J = 12.8 Hz, 2H), 2.78 (d, J = 12.8 Hz, 2H), 2.21 (s, 1H), 1.03 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 137.5, 130.9, 127.6, 126.4, 86.1, 74.2, 64.5, 43.1, 41.7, 26.0, 18.2, –5.5; HRMS for C24H32OSi+Na calcd 387.2120; found 387.2122.

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Tert-butyl((1-ethynylcyclopentyl)methoxy)dimethylsilane (4h): 84% yield (0.29 g) as a colorless oil. IR (neat) 3308, 2940, 2859, 2115, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.55 (s, 2H), 2.08 (s, 1H), 1.79-1.58 (m, 8H), 0.90 (s, 9H), 0.06 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 91.2, 77.3, 68.3, 44.2, 36.2, 25.9, 25.2, 18.3, –5.3; HRMS for C14H26OSi+Na calcd 261.1651; found 261.1655.

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Tert-butyl((2-ethynyl-2,3-dihydro-1H-inden-2yl)methoxy)dimethylsilane (4j): 93% yield (0.27 g) as a colorless oil. IR (neat) 3302, 2942, 2858, 2112, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.21-7.15 (m, 4H), 3.63 (s, 2H), 3.22 and 3.15 (ABq, J = 15.6 Hz, 4H), 2.12 (s, 1H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 141.4, 126.4, 124.5, 89.8, 68.4, 67.9, 44.2, 42.4, 25.8, 18.3, –5.4; HRMS for C18H26OSi+Na calcd 309.1651; found 309.1661.

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1-(2-Ethynyl-2,3-dihydro-1H-inden-2-yl)ethan-1-ol (4k): 94% yield. mp 108-110 °C; IR (neat) 3400, 2992, 2123, 1641, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 4H), 3.78 (qn, J = 6.4 Hz, 1H), 3.28 (s, 2H), 3.14 and 3.06 (ABq, J = 16.0 Hz, 2H), 2.17 (s, 1H), 1.91 (d, J = 7.6 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.2, 141.0, 126.7, 126.6, 124.6, 124.3, 88.0, 72.6, 70.3, 49.5, 44.0, 42.8, 19.4; HRMS for C13H14O+Na calcd 209.0942; found 209.0940. (S)-Tert-butyl((2-ethynyl-2,6-dimethylhept-5-en-1yl)oxy)dimethylsilane (4l): 91% yield (0.31 g) as a colorless oil. IR (neat) 3309, 2929, 2858, 2111, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.14 (t, J = 7.2 Hz, 1H), 3.54 and 3.46 (ABq, J = 9.6 Hz, 2H), 2.16-2.08 (m, 2H), 2.10 (s, 1H), 1.69 (s, 3H), 1.63 (s, 3H), 1.59-1.49 (m, 1H), 1.45-1.30 (m, 1H), 1.18 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 131.5, 124.4, 89.1, 69.5, 69.3, 37.2, 37.1, 25.8, 25.7, 23.8, 23.5, 18.3, 17.6, –5.5; HRMS for C17H32OSi+Na calcd 303.2120; found 303.2124.

4-(((Tert-butyldimethylsilyl)oxy)methyl)-1-(furan-2-yl)-4methylhept-6-en-2-yn-1-ol (3b): 91% yield (0.25 g) as a yellow color oil. IR (neat) 3440, 2965, 2923, 2860, 2241, 1649 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 6.44 (d, J = 2.8 Hz, 1H), 6.34 (s, 1H), 5.98-5.86 (m, 1H), 5.44 (d, J = 6.8 Hz, 1H), 5.115.07 (m, 2H), 3.54 (dd, J = 9.2, 2.4 Hz, 1H), 3.46 (d, J = 9.6 Hz, 1H), 2.33 (dd, J = 13.6, 7.2 Hz, 1H), 2.22 (d, J = 7.2 Hz, 1H), 2.17 (dd, J = 13.2, 7.2 Hz, 1H), 1.18 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.6, 142.9, 134.6, 117.7, 110.2, 107.6, 90.7, 79.2, 69.1, 58.2, 41.6, 37.1, 25.8, 23.2, 18.2, – 5.48, –5.51; HRMS for C19H30O3Si+Na calcd 357.1862; found 357.1868. 4-Benzyl-5-((tert-butyldimethylsilyl)oxy)-1-(furan-2-yl)-4methylpent-2-yn-1-ol (3c): 92% yield (0.24 g) as a yellow color oil. IR (neat) 3438, 2942, 2922, 2858, 2222, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.32-7.20 (m, 5H), 6.34 (s, 2H), 5.42 (d, J = 5.6 Hz, 1H), 3.50 (dd, J = 9.6, 5.2 Hz, 1H), 3.43 (dd, J = 9.6 Hz, 2.4, 1H), 2.16 (d, J = 6.4 Hz, 1H), 1.20 (s, 3H), 0.95 (s, 9H, 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.4, 142.8, 137.8, 130.7, 127.7, 126.3, 110.2, 107.6, 90.6, 80.3, 68.4, 58.2, 42.6, 38.4, 25.9, 23.6, 23.5, 18.3, –5.4, –5.5; HRMS for C23H32O3Si+Na calcd 407.2018; found 407.2022. 4-Allyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(furan-2yl)hept-6-en-2-yn-1-ol (3d): 84% yield (0.23 g) as a yellow color oil. IR (neat) 3440, 2916, 2211, 1641, 1600 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 0.4 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 6.35 (dd, J = 2.8, 2.0 Hz, 1H), 5.97-5.87 (m, 2H), 5.46 (d, J = 7.2 Hz, 1H), 5.12-5.08 (m, 4H), 3.51 (s, 2H), 2.32 (dd, J = 13.6, 7.6 Hz, 2H), 2.25 (d, J = 7.2 Hz, 1H), 2.23 (dd, J = 14.0,

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4-(((Tert-butyldimethylsilyl)oxy)methyl)-1-(furan-2-yl)-4,8dimethylnon-7-en-2-yn-1-ol (3l): 91% yield (0.24 g) as a yellow color oil. IR (neat) 3426, 2931, 2858, 2215, 1636 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 6.43 (d, J = 2.8 Hz, 1H), 6.33 (s, 1H), 5.44 (d, J = 6.8 Hz, 1H), 5.12 (t, J = 6.4, 1H), 3.54 (dd, J = 9.6, 3.2 Hz, 1H), 3.47 (d, J = 9.2 Hz, 1H), 2.22 (d, J = 6.8 Hz, 1H), 2.12-2.07 (m, 2H), 1.68 (s, 3H), 1.58-1.51 (m, 1H), 1.421.34 (m, 1H), 1.19 (s, 3H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.6, 142.8, 131.5, 124.3, 110.2, 107.6, 91.1, 79.0, 69.2, 58.3, 37.3, 37.2, 25.8, 25.7, 23.65, 23.63, 18.3, 17.6, –5.5; HRMS for C22H36O3Si+Na calcd 399.2331; found 399.2334.

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5-((Tert-butyldimethylsilyl)oxy)-1-(furan-2-yl)-4,4-bis(4methoxybenzyl)pent-2-yn-1-ol (3f): 91% yield (0.22 g) as a yellow color oil. IR (neat) 3447, 2953, 2930, 2065, 1612, 1512 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.26-7.21 (m, 4H), 6.81-6.78 (m, 4H), 6.34 (dd, J = 2.8, 1.6 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 5.39 (d, J =6.8 Hz, 1H), 3.80 (s, 6H), 3.32 (s, 2H), 2.89 (dd, J = 13.2, 2.8 Hz, 2H), 2.71 (d, J = 12.8 Hz, 1H), 2.17 (d, J = 6.8 Hz, 1H), 1.01 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.21, 158.20, 153.3, 142.7, 131.74, 131.73, 129.6, 113.0, 110.2, 107.5, 88.7, 83.4, 64.3, 58.2, 55.1, 43.6, 40.7, 25.9, 18.2, –5.45; HRMS for C31H40O5Si+Na calcd 543.2543; found 543.2546.

1-(Furan-2-yl)-3-(2-(1-hydroxyethyl)-2,3-dihydro-1H-inden2-yl)prop-2-yn-1-ol (3k) : 97% yield (0.29 g) as a yellow color oil. IR (neat) 3441, 2945, 2216, 1600 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.25-7.15 (m, 4H), 6.31 (s, 1H), 6.28 (s, 1H), 5.41 (d, J = 4.0 Hz, 1H), 3.80-3.75 (m, 1H), 3.31 and 3.25 (ABq, J = 16.4 Hz, 2H), 3.13 (dd, J = 15.6, 4.4 Hz, 1H), 3.04 (dd, J = 16.0, 4.0 Hz, 1H), 2.56 (bs, 1H), 1.86 (bs, 1H), 1.33 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 142.8, 141.0, 126.6, 124.3, 110.3, 107.5, 89.9, 79.5, 73.0, 58.0, 49.7, 44.1, 42.8, 19.5; HRMS for C18H18O3+Na calcd 305.1154; found 305.1157.

RI PT

4,4-Dibenzyl-5-((tert-butyldimethylsilyl)oxy)-1-(furan-2yl)pent-2-yn-1-ol (3e): 85% yield (0.21 g) as a yellow color oil. IR (neat) 3441, 2981, 2920, 2214, 1612, 1512 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.39-7.36 (m, 4H), 7.31-7.28 (m, 6H), 6.37 (d, J = 1.6 Hz, 1H), 6.27 (s, 1H), 5.42 (d, J = 6.8 Hz, 1H), 3.40 (s, 2H), 3.03 (d, J = 13.2 Hz, 2H), 2.85 (d, J = 12.8 Hz, 2H), 2.29 (bs, 1H), 1.09 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.2, 142.7, 137.5, 130.8, 127.6, 126.4, 126.3, 110.2, 107.5, 88.3, 83.6, 64.3, 58.1, 43.3, 41.6, 25.9, 18.2, –5.5; HRMS for C29H36O3Si+Na calcd 483.2331; found 483.2333.

3.62 (s, 2H), 3.20 and 3.16 (ABq, J = 16.4 Hz, 4H), 2.23 (bs, 1H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.5, 142.8, 141.3, 126.5, 124.5, 110.2, 107.7, 91.8, 91.8, 77.8, 67.8, 58.3, 44.3, 42.4, 25.8, 18.3, –5.4; HRMS for C23H30O3Si+Na calcd 405.1862; found 405.1862.

SC

7.2 Hz, 2H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.5, 142.9, 134.4, 117.9, 110.3, 107.6, 88.8, 81.0, 65.8, 58.2, 40.7, 39.9, 25.8, 18.2, –5.5; HRMS for C21H32O3Si+Na calcd 383.2018; found 383.2024.

TE D

3-(1-(((Tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-1(furan-2-yl)prop-2-yn-1-ol (3g): 91% yield (0.25 g) as a yellow color oil. IR (neat) 3438, 2940, 2918, 2878, 2241, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 6.47 (d, J = 2.8 Hz, 1H), 6.34 (d, J = 0.8 Hz, 1H), 5.47 (d, J = 6.4 Hz, 1H), 3.5 (s, 2H), 2.26 (bs, 1H), 1.68-1.61 (m, 7H), 1.42-1.30 (m, 3H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.9, 143.8, 110.2, 107.6, 90.7, 79.9, 71.1, 58.3, 39.4, 33.4, 26.0, 25.9, 22.8, 18.3, – 5.4; HRMS for C20H32O3Si+Na calcd 371.2018; found 371.2020.

AC C

EP

3-(1-(((Tert-butyldimethylsilyl)oxy)methyl)cyclopentyl)-1(furan-2-yl)prop-2-yn-1-ol (3h): 93% yield (0.26 g) as a yellow color oil. IR (neat) 2955, 2933, 2859, 2243, 1649 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 6.44 (d, J = 3.2 Hz, 1H), 6.33 (dd, J = 2.8, 1.6 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 3.56 (s, 2H), 2.24 (d, J = 6.4 Hz, 1H), 1.78 (bs, 6H), 1.68-1.62 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.8, 142.8, 110.2, 107.6, 93.0, 77.5, 68.3, 58.3, 44.4, 36.1, 25.8, 25.1, 18.3, –5.4; HRMS for C19H30O3Si+Na calcd 357.1862; found 357.1866.

5-((Tert-butyldimethylsilyl)oxy)-1-(furan-2-yl)pent-2-yn-1-ol (3i): 92% yield (0.28 g) as a yellow color oil. IR (neat) 3440, 2981, 2930, 2858, 2211, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 6.44 (d, J = 2.8 Hz, 1H), 6.35 (dd, J = 4.8, 1.6 Hz, 1H), 5.44 (d, J = 5.6 Hz, 1H), 3.76 (t, J = 7.2 Hz, 2H), 2.49 (td, J = 7.2, 2.0 Hz, 2H), 2.30 (d, J = 5.6 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.4, 142.8, 110.3, 107.5, 83.8, 78.6, 61.6, 58.3, 25.8, 23.1, 18.3, –5.3; HRMS for C15H24O3Si+Na calcd 303.1392; found 303.1392. 3-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1Hinden-2-yl)-1-(furan-2-yl)prop-2-yn-1-ol (3j): 95% yield (0.254 g) as a yellow color oil. IR (neat) 3441, 2945, 2216, 1600 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.20-7.14 (m, 4H), 6.38 (d, J = 3.2 Hz, 1H), 6.32 (s, 1H), 5.43 (d, J = 6.8 Hz, 1H),

4,4-Dibenzyl-1-(furan-2-yl)-5-methoxypent-2-yn-1-ol (11e): 93% yield (0.25 g) as a yellow color oil. IR (neat) 3440, 2981, 2930, 2858, 2211, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34-7.28 (m, 10H), 6.36 (s, 1H), 6.26 (s, 1H), 5.42 (d, J = 5.6 Hz, 1H), 3.37 (s, 3H), 3.09 (s, 2H), 3.03 (d, J = 13.2 Hz, 2H), 2.85 (d, J = 13.2 Hz, 2H), 2.47 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 153.2, 142.7, 137.3, 130.8, 127.7, 126.4, 110.2, 107.5, 88.0, 83.3, 73.6, 58.3, 58.1, 42.3, 42.27; HRMS for C24H24O3+Na calcd 383.1623; found 383.1624. General Procedure for the synthesis of compound 6a: To a stirred solution of alcohol 3a (0.10 g, 0.32 mmol) in MeOH (1 mL) at room temperature was added AuCl3 (0.002 g, 0.006 mmol) and the resulting reaction mixture was heated to reflux and stirred under reflux for 30 min. MeOH was evaporated off and the resulting crude residue was purified by silica gel column chromatography with petroleum ether:EtOAc as eluent afforded the keto ester 6a. Methyl (E)-5-(4,4-dimethyldihydrofuran-2(3H)-ylidene)-4oxopentanoate (6a): 86% yield (0.06 g) as a thick yellow color oil. IR (neat) 2955, 2858, 1736, 1678, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.75 (d, J = 0.8 Hz, 1H), 3.85 (s, 2H), 3.65 (s, 3H), 2.90 (s, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.55 (t, J = 6.8 Hz, 2H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 197.3, 177.0, 173.6, 98.5, 82.2, 51.6, 45.7, 37.84, 37.8, 28.1, 25.2; HRMS for C12H18O4+Na calcd 249.1103; found 249.1106. Methyl (E)-5-(4-allyl-4-methyldihydrofuran-2(3H)-ylidene)4-oxopentanoate (6b): 81% yield (0.06 g) as a thick yellow color oil. IR (neat) 2952, 1736, 1678, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.79-5.66 (m, 1H), 5.76 (s, 1H), 5.09 (d, J = 2.0 Hz, 1H), 5.05 (d, J = 11.2 Hz, 1H), 3.96 (d, J = 8.8 Hz, 1H), 3.82 (d, J = 8.4 Hz, 1H), 3.66 (s, 3H), 2.97 and 2.90 (ABq, J = 18.4,

ACCEPTED MANUSCRIPT Tetrahedron

Methyl (E)-5-(4-benzyl-4-methyldihydrofuran-2(3H)ylidene)-4-oxopentanoate (6c): 78% yield (0.06 g) as a thick yellow color oil. IR (neat) 2980, 2858, 1734, 1676, 1601 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.32-7.20 (m, 3H), 7.10 (d, J = 7.2 Hz, 2H), 5.78 (s, 1H), 4.06 (d, J = 8.8 Hz, 1H), 3.79 (d, J = 8.4 Hz, 1H), 3.68 (s, 3H), 3.05 and 2.93 (ABq, J = 18.0 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.69 (s, 2H), 2.58 (t, J = 6.8 Hz, 2H) 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.2, 176.4, 173.6, 137.3, 129.9, 128.2, 126.5, 98.8, 80.0, 51.6, 43.92, 43.88, 42.3, 37.8, 28.1, 23.0; HRMS for C18H22O4+Na calcd 325.1416; found 325.1418.

Methyl (E)-5-(1',3'-dihydro-2H-spiro[furan-3,2'-inden]5(4H)-ylidene)-4-oxopentanoate (6j): 78% yield (0.06 g) as a white crystalline compound. mp 113-115 °C; IR (neat) 3021, 2916, 1736, 1676, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19-7.14 (m, 4H), 5.85 (s, 1H), 4.11 (s, 2H), 3.68 (s, 3H), 3.21 (s, 2H), 2.98 (s, 4H), 2.76 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.3, 176.2, 173.7, 141.3, 126.7, 124.6, 98.8, 81.0, 51.7, 49.6, 43.6, 42.6, 37.9, 28.1; HRMS for C18H20O4+Na calcd 323.1259; found 323.1259. Methyl (E)-5-(2-methyl-1',3'-dihydro-2H-spiro[furan-3,2'inden]-5(4H)-ylidene)-4-oxopentanoate (6k): 83% yield (0.05 g) as a light yellow color oil. IR (neat) 3021, 2916, 1736, 1676, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.16 (bs, 4H), 5.80 (s, 1H), 4.40 (q, J = 6.4 Hz, 1H), 3.67 (s, 3H), 3.33-3.26 (m, 2H), 3.11-3.01 (m, 2H), 2.93 (s, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.56 (t, J =6.4 Hz, 2H), 1.23 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.4, 175.1, 173.7, 141.3, 140.9, 126.7, 126.6, 124.5, 124.5, 98.6, 85.6, 52.0, 51.6, 44.5, 42.8, 38.3, 37.9, 28.1, 15.7; HRMS for C19H22O4+Na calcd 337.1416; found 337.1411.

M AN U

Methyl (E)-5-(4,4-diallyldihydrofuran-2(3H)-ylidene)-4oxopentanoate (6d): 79% yield (0.06 g) as a thick yellow color oil. IR (neat) 3021, 2916, 1738, 1674, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.78-5.67 (m, 2H), 5.75 (s, 1H), 5.11 (d, J = 3.6 Hz, 2H), 5.08 (d, J = 10.8 Hz, 2H), 3.95 (s, 2H), 3.66 (s, 3H), 2.98 (d, J = 1.6 Hz, 2H), 2.71 (t, J J = 6.8 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H), 2.15 (d, J = 7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 197.2, 176.6, 173.6, 133.1, 119.0, 98.3, 78.5, 51.6, 44.2, 42.0, 40.4, 37.8, 28.2; HRMS for C16H22O4+Na calcd 301.1416; found 301.1420.

Methyl (E)-5-(dihydrofuran-2(3H)-ylidene)-4-oxopentanoate (6i): 68% yield (0.05 g) as a thick yellow color oil. IR (neat) 2955, 2858, 1736, 1678, 1604 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.78 (s, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.66 (s, 3H), 3.09 (t, J = 8.0 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.13-2.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 197.1, 176.9, 173.6, 97.5, 71.5, 51.5, 37.7, 30.9, 28.1, 23.5; HRMS for C10H14O4+Na calcd 221.0790; found 221.0792.

RI PT

2H), 2.71 (t, J = 6.4, 2H), 2.56 (t, J = 6.8, 2H), 2.13 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.2, 176.7, 173.6, 133.5, 118.7, 98.5, 86.4, 51.6, 44.0, 42.7, 41.0, 37.8, 28.2, 23.1; HRMS for C14H20O4+Na calcd 275.1259; found 275.1259.

SC

6

TE D

Methyl (E)-5-(4,4-dibenzyldihydrofuran-2(3H)-ylidene)-4oxopentanoate (6e): 85% yield (0.07 g) as a thick yellow color oil. IR (neat) 3027, 2916, 1738, 1677, 1600 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 6H), 7.11 (d, J = 7.2 Hz, 4H), 5.61 (s, 1H), 4.02 (s, 2H), 3.69 (s, 3H), 3.07 (s, 2H), 2.75 (s, 4H), 2.67 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.1, 176.1, 173.6, 136.7, 130.4, 128.3, 126.7, 98.5, 76.4, 51.6, 46.4, 42.1, 40.4, 37.8, 28.2; HRMS for C24H26O4+Na calcd 401.1729; found 401.1732.

AC C

EP

Methyl (E)-5-(4,4-bis(4-methoxybenzyl)dihydrofuran-2(3H)ylidene)-4-oxopentanoate (6f): 82% yield (0.07 g) as a thick yellow color oil. IR (neat) 2994, 2913, 1738, 1676, 1600 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 8.4, 4H), 6.82 (d, J = 8.4 Hz, 4H), 5.61 (s, 1H), 4.00 (s, 2H), 3.80 (s, 6H), 3.69 (s, 3H), 3.03 (s, 2H), 2.70-2.66 (m, 2H), 2.67 (s, 4H), 2.58 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.1, 176.4, 173.6, 158.4, 131.4, 128.8, 113.7, 98.5, 76.6, 55.2, 51.6, 46.6, 41.2, 40.4, 37.8, 28.2; HRMS for C26H30O6+Na calcd 461.1940; found 461.1941.

Methyl (E)-4-oxo-5-(2-oxaspiro[4.5]decan-3ylidene)pentanoate (6g): 80% yield (0.06 g) as a thick yellow color oil. IR (neat) 2955, 2858, 1738, 1676, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 3.94 (s, 2H), 3.68 (s, 3H), 2.95 (s, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.601.40 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 197.3, 177.1, 173.7, 98.4, 51.7, 41.8, 37.8, 34.7, 28.2, 25.6, 23.3; HRMS for C15H22O4+Na calcd 289.1416; found 289.1422. Methyl (E)-4-oxo-5-(2-oxaspiro[4.4]nonan-3ylidene)pentanoate (6h): 79% yield (0.06 g) as a thick yellow color oil. IR (neat) 2952, 1738, 1676, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 3.98 (s, 2H), 3.67 (s, 3H), 3.02 (d, J = 1.2 Hz, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 1.70-1.56 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 197.3, 177.1, 173.7, 98.3, 81.0, 51.6, 48.8, 44.0, 37.8, 36.1, 28.2, 24.4; HRMS for C14H20O4+Na calcd 275.1259; found 275.1265.

Methyl (S,E)-5-(4-methyl-4-(4-methylpent-3-en-1yl)dihydrofuran-2(3H)-ylidene)-4-oxopentanoate (6l): 60% yield (0.05 g) as a thick yellow color oil. IR (neat) 2955, 2858, 1736, 1678, 1601 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 5.04 (t, J = 6.0 Hz, 1H), 3.92 and 3.87 (ABq, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.01 (d, J = 18.4 Hz, 1H), 2.84 (d, J = 18.0, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.01-1.90 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.43 (t, J = 8.4 Hz, 2H), 1.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 177.0, 173.7, 132.1, 123.7, 98.5, 81.4, 51.7, 44.5, 41.2, 38.7, 28.2, 25.6, 23.7, 23.1, 17.6; HRMS for C17H26O4+Na calcd 317.1729; found 317.1732. General Procedure for the synthesis of compound 12a: To a stirred solution of propargyl alcohol 11a (0.10 g, 0.73 mmol) in MeOH (1 mL) at room temperature was added AuCl3 (0.004 g, 0.015 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (TLC), MeOH was evaporated off and the resulting crude residue was purified by silica gel column chromatography with petroleum ether:EtOAc as eluent afforded the isomeric acetals 12a. 2-(But-2-yn-1-ylidene)-5-methoxy-2,5-dihydrofuran (12a) (Data for Major Isomer): 64% yield (0.07 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 6.34 (d, J = 5.2 Hz, 1H), 6.12 (s, 2H), 4.64 (d, J =2.0 Hz, 1H), 3.47 (s, 3H), 2.04 (d, J = 2.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3, 131.4, 128.8, 110.1, 91.3, 80.9, 74.6, 54.8, 4.9; HRMS for C9H10O2+Na calcd 173.0578; found 173.0580. Data for Minor Isomer: 25% yield (0.028 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 6.0 Hz, 1H), 6.17 (d, J = 5.6 Hz, 1H), 6.04 (s, 1H), 5.00 (s, 1H), 3.41 (s, 3H), 1.97 (s, 3H); 13C NMR (100

ACCEPTED MANUSCRIPT

We thank Prof. Martin E. Maier, Institute for Organic Chemistry, University of Tuebingen, Germany for the helpful discussions concerning the mechanism of the reaction. C. N. thanks CSIR, New Delhi for a research fellowship. References and notes 1. 2.

3.

Heterocycles in Natural Products Synthesis Majumdar, K. C.; Chattopadhyay, S. K (Eds); Wiley-VCH, Weinheim, 2011. (a) Cuccarese, M. F., O’Doherty, G. A. In Asymmetric Synthesis II: More Methods and Applications; Christmann, M.; Braese, S. (Eds). Wiley−VCH: Weinheim, 2012 (b) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973-1996. (a) Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976, 17, 3555-3558. For a review, see: (b) Piutti, C.; Quartieri, F. Molecules 2013, 18, 12290. For recent examples, see: (c) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2010, 49, 9484. (d) Palmer, L. I.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2011, 50, 7167. (c) Palmer, L. I.; Read de Alaniz, J. Org. Lett. 2013, 15, 476. (d) Wenz, D. R.; Read de Alaniz, J. Org. Lett. 2013, 15, 3250. (e) Yu, D.; Tahai, V. T.; Palmer, L. I.; Veits, G. K.; Cook, J. E.; Read de Alaniz, J.; Hein, J. E. J. Org. Chem. 2013, 78, 12784. (f) Fisher, D.; Palmer, L. I.; Cook, J. E.; Davis, J. E.; Read de Alaniz, J. Tetrahedron 2014, 70, 4105. (g) Lebœuf, D.; Gandon, V.; Schulz, E. Org. Lett. 2014, 16, 6464-6467. (a) Denisov, V. R.; Shevchenko, Z. A.; Khlebova, G. N.; Alekseeva, E. M.; Favorskaya, I. A. J. Org. Chem. U.S.S.R. (Engl. Transl.) 1984, 20, 2530-2533. (b) Gao, Y.; Wu, W. –L.; ; Ye, B.; Zhou, R.; Wu, Y. –L. Tetrahedron Lett, 1996, 37, 893-896. (c) Gao, Y.; Wu, W. –L.; ; Ye, B.; Wu, Y. –L.; Zhou, R. Tetrahedron, 1998, 54, 12523-12538. (a) Dhiman, S.; Ramasastry, S. S. V. Org. Biomol. Chem. 2013, 11, 4299-4303. (b) Dhiman, S.; Ramasastry, S. S. V. Indian J. Chem., Sect. A 2013, 52, 1103. (c) Dhiman, S.; Ramasastry, S. S. V. J. Org. Chem. 2013, 78, 10427−10436. (a) Prasad, K. R.; Nagaraju, C. Org. Lett., 2013, 15, 2778-2781. (b) Nagaraju, C.; Prasad, K. R. Angew. Chem., Int. Ed. 2014, 53, 10997-11000. For a strategy of oxidative ring opening of furan to the corresponding E-but-2-en-1,4-dione in natural product synthesis see: (a) Kobayashi, Y; Nakano, M; Kumar, G. B; Kishihara, K. J. Org. Chem. 1998, 63, 7505-7515. (b) Prasad, K. R; Pawar, A. B. Org. Lett. 2011, 13, 4252-4255. (c) Prasad, K. R.; Revu. O. J. Org. Chem. 2014, 79, 1461−1466. For acid mediated ring opening of 2,5-di substituted furans to the corresponding 1,4-diones see: (d) Büchi, G.; Wüest, H. J. Org. Chem. 1966, 31, 977–978. (e) Waidmann, C. R.; Pierpont, A. W.;Batista, E. R.; John C. Gordon, J. C.; Martin, R. L.; Silks, L. A. P.; West, R. M.; Wu, R. Catal. Sci. Technol., 2013, 3, 106-115. The reported synthesis for saturated γ-keto esters from furans involve the initial oxidation of furans to the 2,5-dialkoxy furans followed by reaction with ruthenium hydride or TMSI. (a) Hirai, K., Suzuki, H., Kashiwagi, H., Moro-oka, Y.; Ikawa, T. Chem. Lett, 1982, 23 (b) Feringa, B. L.; Dannenberg, W. Tetrahedron Lett, 1983, 13, 509-514. Feringa and Dannenberg also reported a procedure involving the conversion of furans to γmethoxybutyrolactone and subsequent reduction/esterification sequence. The crystallographic data has been deposited with the Cambridge Crystallographic Data Center. CCDC No. 1027186 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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2-(Hex-2-yn-1-ylidene)-5-methoxy-2,5-dihydrofuran (12c): DATA for Major Isomer: 68% yield (0.07 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 6.34 (d, J =5.2 Hz, 1H), 6.12 (d, J = 5.2 Hz, 1H), 6.11 (s, 1H), 4.70 (s, 1H), 3.47 (s, 3H), 2.37 (td, J = 6.8, 1.6 Hz, 2H), 1.63-1.55 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2, 131.3, 128.8, 110.0, 95.6, 81.0, 75.5, 54.8, 22.2, 21.9, 13.5; HRMS for C11H14O2+Na calcd 201.0891; found 201.0891. Data for Minor Isomer: 22% yield (0.02 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 5.6 Hz, 1H), 6.17 (d, J = 5.6 Hz, 1H), 6.05 (s, 1H), 5.02 (s, 1H), 3.41 (s, 3H), 2.31 (td, J = 7.2, 1.2 Hz, 2H), 1.61-1.53 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 131.9, 127.4, 109.7, 92.1, 81.8, 76.1, 54.4, 22.4, 21.6, 13.5; HRMS for C11H14O2+Na calcd 201.0891; found 201.0891.

Acknowledgments

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2-Methoxy-5-(3-phenylprop-2-yn-1-ylidene)-2,5dihydrofuran (12b): DATA for Major Isomer: 55% yield (0.059 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.2 Hz, 2H), 7.33-7.28 (m, 3H), 6.42 (d, J = 5.6 Hz, 1H), 6.22 (d, J = 5.6 Hz, 1H), 6.17 (s, 1H), 4.91 (s, 1H), 3.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 132.4, 131.3, 128.8, 128.1, 127.7, 123.9, 110.3, 94.5, 85.0, 80.5, 55.0; HRMS for C14H12O2+Na calcd 235.0735; found 235.0737. Data for Minor Isomer: 32% yield (0.03 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 6.8 Hz, 2H), 7.33-7.26 (m, 3H), 6.91 (d, J = 6.0 Hz, 1H), 6.28 (d, J = 6.0 Hz, 1H), 6.11 (s, 1H), 5.26 (s, 1H), 3.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 132.9, 131.0, 128.2, 127.6, 127.4, 123.9, 110.1, 91.6, 85.9, 81.4, 54.7; HRMS for C14H12O2+Na calcd 235.0735; found 235.0731.

7 Isomer: 21% yield (0.02 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 10H), 6.44 (d, J = 5.6 Hz, 1H), 6.13 (d, J = 5.6 Hz, 1H), 6.03 (s, 1H), 5.00 (s, 1H), 3.43 (s, 3H), 3.36 (s, 3H), 3.04 (s, 2H), 3.20 (d, J = 12.8 Hz, 2H), 2.81 (d, J = 12.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 137.8, 131.9, 130.8, 127.7, 127.5, 126.3, 109.8, 93.3, 81.9, 81.4, 73.8, 58.3, 54.7, 43.2, 42.8; HRMS for C25H26O3+Na calcd 397.1780; found 397.1777.

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MHz, CDCl3) δ 166.1, 131.9, 127.3, 109.7, 87.5, 81.7, 75.1, 54.4, 4.5; HRMS for C9H10O2+Na calcd 173.0578; found 173.0580.

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2-(5-(Benzyloxy)pent-2-yn-1-ylidene)-5-methoxy-2,5dihydrofuran (12d): DATA for Major Isomer: 60% yield (0.06 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 5H), 6.35 (d, J = 5.6, 1H), 6.15 (d, J = 5.6, 1H), 6.12 (s, 1H), 4.66 (s, 1H), 4.58 (s, 2H), 3.65 (t, J = 7.2, 2H), 3.46 (s, 3H), 2.73 (t, J = 7.2, 2H); 13 C NMR (100 MHz, CDCl3) δ 164.6, 138.1, 131.7, 128.8, 128.3, 127.6, 127.5, 110.1, 91.8, 80.6, 76.5, 72.8, 68.5, 54.7, 21.3; HRMS for C17H18O3+Na calcd 293.1154; found 293.1158. Data for Minor Isomer: 20% yield (0.02 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5H), 6.77 (d, J = 5.6 Hz, 1H), 6.18 (d, J = 5.6 Hz, 1H), 6.05 (s, 1H), 5.01 (s, 1H), 4.57 (s, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.42 (s, 3H), 2.66 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.5, 138.1, 132.2, 128.4, 127.7, 127.6, 127.4, 109.8, 88.5, 81.4, 77.2, 72.9, 68.6, 54.5, 21.1; HRMS for C17H18O3+Na calcd 293.1154; found 293.1158. 2-(4,4-Dibenzyl-5-methoxypent-2-yn-1-ylidene)-5-methoxy2,5-dihydrofuran (12e): Data for Major Isomer: 64% yield (0.07 g) as a yellow color oil. IR (neat) 3000, 2929, 2838, 2221, 1639; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2 Hz, 4H), 7.34-7.24 (m, 6H), 6.36 (d, J = 5.6 Hz, 1H), 6.18 (s, 2H), 4.65 (s, 1H), 3.54 (s, 3H), 3.35 (s, 3H), 3.04 (d, J = 12.8 Hz, 2H), 3.04 (s, 2H), 2.88 (d, J = 12.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 164.8, 137.8, 131.6, 130.9, 129.0, 127.6, 126.2, 110.0, 96.6, 81.1, 80.7, 73.6, 58.3, 54.7, 43.2, 42.83, 42.79; HRMS for C25H26O3+Na calcd 397.1780; found 397.1777. Data for Minor

4.

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Tetrahedron Supplementary Material

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General experimental procedures and copies of 1H NMR and 13C NMR spectra for all the new compounds synthesized are provided.

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Supporting Information Gold Catalyzed Intramolecular Hydroalkoxylation Assisted Ring Opening of Furans to the Corresponding Saturated γ-Keto Esters

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Chinta Nagaraju and Kavirayani R. Prasad*

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Department of Organic Chemistry Indian Institute of Science, Bangalore 560 012, INDIA E-mail: [email protected]; FAX:0091-80-23600529

1. 1H and 13CNMR Spectra……………………..……………………………..……....…S2

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2. ORTEP diagram of the compound 6j ………………………………………………S52

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77.319 77.001 76.684 71.103 68.072

H NMR spectrum of compound 4a 90.568

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6.433

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9.918

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6.465

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25.821 25.188

33.521

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1.005

2.189

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58.215

77.540 77.315 76.998 76.680 71.038

92.352

1.004

M AN U 110.205 107.619

1.012 1.022

1.000

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142.841

153.651

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1.198

2.311 2.294

3.462

5.431 5.414

6.439 6.431 6.327

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37.843 37.792 6.317

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45.681

51.621

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2.063 2.114 2.125

2.070 3.107

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82.223 77.315 76.997 76.679

M AN U 1.000

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98.549

177.007 173.660

197.285

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1.092

2.898 2.724 2.707 2.690 2.569 2.552 2.536

3.847 3.652

5.757 5.755

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41.593 36.954 29.282 27.421 25.847 23.332 18.295 13.736 8.738

77.320 77.003 76.686 69.672 69.145

2.047

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117.553

134.690

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0.056

3.540 3.517 3.459 3.436 2.333 2.314 2.299 2.281 2.175 2.157 2.142 2.122 2.111 1.167 0.907

7.264 5.980 5.962 5.954 5.940 5.936 5.921 5.915 5.904 5.894 5.876 5.111 5.085 5.069

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25.816 23.195 18.263

1.065 2.100

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41.654 37.165

2.211

2.152

1.011

1.062

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58.259

79.248 77.317 76.999 76.681 69.085

90.686

110.247 107.632

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117.676

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134.662

1.000

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142.871

153.630

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0.049

3.552 3.546 3.529 3.522 3.475 3.451 2.358 2.340 2.324 2.306 2.229 2.211 2.196 2.178 2.163 2.144 1.182 0.900

6.447 6.440 6.341 5.954 5.933 5.907 5.887 5.449 5.432 5.111 5.083 5.071

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51.630 43.996 42.762 41.062 37.821

80.461 77.319 77.001 76.683

98.528

118.668

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133.513

176.722 173.640

197.247

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5.777 5.759 5.735 5.716 5.692 5.674 5.090 5.085 5.068 5.040 3.975 3.953 3.829 3.808 3.659 2.995 2.949 2.921 2.875 2.728 2.712 2.695 2.578 2.561 2.544 2.141 2.122 1.074

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42.567 38.173

77.317 77.000 76.682 70.782 68.448

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88.649

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130.668 127.632 126.301

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25.874 23.569 23.539 18.302

42.634 38.403

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2.296

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80.301 77.320 77.002 76.685 68.375 68.345

90.619

110.247 107.607

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130.675 127.660 126.303

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142.825

153.414

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1.204

3.514 3.501 3.490 3.478 3.442 3.436 3.418 3.413 2.901 2.869 2.734 2.701 2.168 2.152

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79.972 77.321 77.003 76.685

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129.947 128.252 126.557

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77.317 76.999 76.682 71.347 65.868

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40.705 39.938

58.254

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80.970 77.321 77.003 76.686

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110.283 107.649

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142.900

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2.346 2.327 2.312 2.293 2.260 2.242 2.225 2.208

3.510

7.409 7.408 7.267 6.451 6.443 6.356 6.351 6.349 6.344 5.975 5.957 5.937 5.932 5.918 5.910 5.890 5.872 5.467 5.449 5.125 5.096 5.085

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51.638 44.238 41.999 40.426 37.810

78.523 77.317 76.999 76.681

98.352

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133.099

176.637 173.633

197.227

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3.954 3.666 2.985 2.981 2.733 2.716 2.699 2.585 2.569 2.552 2.163 2.144

5.778 5.752 5.741 5.734 5.717 5.711 5.699 5.692 5.673 5.117 5.108 5.093 5.066

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25.981

43.125 41.714

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2.109 2.131

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64.542

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86.131 77.321 77.003 76.686 74.172

4.139 6.542

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130.876 127.607 126.389

137.504

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0.084

1.029

2.209

3.336 2.967 2.935 2.799 2.767

7.375 7.357 7.309 7.292 7.274 7.264 7.247 7.229

ACCEPTED MANUSCRIPT

1 0

10

0

C NMR spectrum of compound 4e

S14

ppm

ppm

AC C EP TE D

180

170

160

150 1

140

130 13

120 6

H NMR spectrum of compound 3e

110

100

90

80

70

60

50

40

30

20

6.271

9.522

2

-5.503

18.202

3

25.933

0.983

2.085 2.073

2.048

4

43.304 41.666

58.151

5

64.339

88.295 83.605 77.318 76.999 76.682

M AN U 1.000

7

110.214 107.491

8 0.998 1.013

9

137.482 130.825 127.611 126.381 126.358

1.003 4.134 6.413

10

142.691

153.212

SC

RI PT

0.142

1.087

2.288

3.404 3.046 3.013 2.862 2.830

5.431 5.414

6.376 6.372 6.269

7.449 7.383 7.369 7.305 7.287

ACCEPTED MANUSCRIPT

1 ppm

10

0

C NMR spectrum of compound 3e

S15

ppm

AC C

200

EP TE D

190 8

180

170

160 7

1 6

H NMR spectrum of compound 6e

150 140 13

130

120

110

100

90

80

4

70

3

60

50

40

28.210

2.035 4.074 2.105 2.101

3.000

2.002

5

51.693 46.442 42.189 40.491 37.800

77.319 77.002 76.684 76.467

98.573

M AN U 1.000

6.607 4.160

9

136.766 130.456 128.341 126.723

176.165 173.648

197.118

SC

RI PT

3.075 2.750 2.692 2.676 2.660 2.598 2.582 2.565

3.695

4.026

5.606

7.311 7.294 7.276 7.264 7.246 7.119 7.101

ACCEPTED MANUSCRIPT

2 1

30

20

ppm

10 ppm

C NMR spectrum of compound 6e

S16

AC C EP

TBSO

MeO

190

180

OMe

170

160

150

TE D 1

140 7 6

H NMR spectrum of compound 4f

130 13

120

110

100

90

80

70

60

50

40

30

20

6.400

9.351

2

-5.465

18.246

3

25.973

1.000

4

2.071 2.183

2.079

SC

RI PT

OMe

43.319 40.733

55.136

5

64.468

86.490 77.317 77.000 76.682 73.941

M AN U 6.367

8

113.005

9 4.233

4.306

MeO

131.744 129.627

158.192

0.080

1.018

2.192

3.315 2.884 2.851 2.720 2.687

3.808

7.279 7.267 7.257 6.839 6.818

ACCEPTED MANUSCRIPT

TBSO

1 ppm

10

0

C NMR spectrum of compound 4f

S17

ppm

AC C EP

190

180

170

160

150

140

TE D

130 13

120 1.000

7 6

H NMR spectrum of compound 3f

110

100

90

80

70

60

50

40

30

20

6.191

9.431

2

-5.450

18.234

3

25.959

0.981

2.082 2.067

2.054

4

43.570 40.728

58.253 55.156

6.240

5

64.346

88.775 83.430 77.317 77.000 76.682

M AN U

113.049 110.250 107.538

1 1.005 1.005

4.131

8

131.747 131.734 129.654

1.005 4.403

9

142.753

158.215 158.197 153.305

SC

RI PT

0.084

1.017

3.796 3.326 2.912 2.905 2.879 2.872 2.732 2.700 2.184 2.167

7.428 7.267 7.250 7.233 7.229 7.213 6.811 6.801 6.795 6.790 6.780 6.352 6.348 6.345 6.340 6.250 6.242 5.399 5.382

ACCEPTED MANUSCRIPT

1 ppm

10

0

C NMR spectrum of compound 3f

S18

ppm

AC C

200

EP

190

180

MeO

MeO

O

170

160 1

150

140 13 1.000

8 7 6

H NMR spectrum of compound 6f

130

120

110

100

RI PT

O

4

90

3

80

70

60

50

40

28.248

SC

OMe

6.129 2.418

5

2.093

2.112 6.605 3.323

O

55.217 51.674 46.622 41.261 40.411 37.812

77.316 76.999 76.681 76.589

98.494

113.746

M AN U

131.406 128.842

4.537 4.694

9

O

OMe

TE D

158.419

176.418 173.648

197.112

3.035 2.692 2.674 2.660 2.598 2.582 2.565

3.997 3.797 3.694

5.608

7.267 7.028 7.007 6.837 6.816

ACCEPTED MANUSCRIPT

MeO

MeO O

2 1

30

ppm

O

20

10 ppm

C NMR spectrum of compound 6f

S19

AC C EP TE D 88.735

2.287

9 8

180

170 7

160

150 6

1

140

H NMR spectrum of compound 4g

130 13

120

110

100

90

80

70

60

50

40

30

20

6.979

1.147 12.555

2.232

7.961

2

-5.404

33.398 26.013 25.907 22.657 18.365

3

39.241

4

1.000

5

77.318 77.001 76.683 71.239 70.272

M AN U

SC

RI PT

2.108 1.682 1.644 1.639 1.627 1.618 1.610 1.588 1.397 1.385 1.364 1.354 1.332 1.319 1.119 1.109 1.088 0.903 0.053

3.482

7.265

ACCEPTED MANUSCRIPT

1 0

10 ppm

0

C NMR spectrum of compound 4g

S20

ppm

AC C EP

180

170

TE D

160

150

140 6

1

130

13

120

110

100

90

80

70

60

50

40

30

20

-5.428

6.480

2 10.370

2.973

7.438

3

33.428 26.012 25.873 22.825 18.330

0.984

4

39.425

1.996

5

58.338

79.922 77.316 76.999 76.681 71.150

90.682

1.006

7

H NMR spectrum of compound 3g

M AN U

110.235 107.605

8 0.948 1.020

1.000

9

142.835

153.900

SC

RI PT

2.258 1.682 1.648 1.633 1.623 1.616 1.401 1.391 1.372 1.362 1.348 1.333 0.900 0.051

3.500

5.474 5.458

6.476 6.469 6.345 6.343

7.402

ACCEPTED MANUSCRIPT

1 ppm

10

0

C NMR spectrum of compound 3g

S21

ppm

AC C EP

O

200

190

O

180

170 98.396

9 8 7

1

160 6

H NMR spectrum of compound 6g

150 13

140

130

120

110

100

90

80

70

60

12.901

3

50

41.831 37.836 34.734 28.223 25.610 23.267

4

2.023 2.142 2.161

1.000

3.125

2.051

5

51.673

77.315 76.998 76.680

M AN U 1.036

SC

RI PT

O

OMe

O

TE D

10

177.089 173.728

197.278

1.661 1.513 1.450

3.938 3.678 3.328 2.951 2.742 2.725 2.708 2.595 2.578 2.561

5.758

7.265

ACCEPTED MANUSCRIPT

O

O OMe

2 1

40

30

ppm

20

10 ppm

C NMR spectrum of compound 6g

S22

180

TE D

170

160 7

150

140 6

1

H NMR spectrum of compound 4h

130 13

120

110

100

90

80

70

60

50

40

30

20

-5.398

6.017

2 9.301

2.622

6.170 5.707

3

36.196 29.053 25.972 25.885 25.163 18.339

4

44.203

5

1.128

M AN U 2.000

8

77.317 77.000 76.683 68.310 68.095

EP

9

91.169

AC C

SC

RI PT

10

0.063

2.084 1.767 1.629 1.619 1.306 1.269 1.240 1.229 0.904

3.546

7.265

ACCEPTED MANUSCRIPT

1 0 ppm

0

C NMR spectrum of compound 4h

S23

ppm

AC C EP

180

TE D

170

160

150 6

1

140

130 120 13

110

100

90

80

70

60

50

40

30

20

-5.426

6.490

10.089

2

18.305

25.850 25.153

6.465 3.150

0.966

3

36.142

44.389

4

58.339

2.179

5

77.563 77.316 76.999 76.681 68.271

92.985

1.001

7

H NMR spectrum of compound 3h

M AN U

110.214 107.588

8 1.012 1.035

1.000

9

142.824

153.821

SC

RI PT

0.055

0.897

2.251 2.235 1.777 1.673 1.637 1.627

3.557

5.442 5.429

6.445 6.437 6.341 6.337 6.334 6.329

7.396 7.265

ACCEPTED MANUSCRIPT

1 0

10 ppm

0

C NMR spectrum of compound 3h

S24

ppm

AC C

200

EP TE D

190 8

180

170 7

1

160

H NMR spectrum of compound 6h

150 13

140

130

120

110

100

90

80

70

60

50

40

28.214 24.382

9.194

3

37.854 36.145

51.649 48.842 44.000

2.094 2.291

4

2.053

5

3.220

2.055

6

80.978 77.316 76.998 76.680

M AN U 1.000

9

98.303

177.104 173.689

197.315

SC

RI PT

3.984 3.671 3.023 3.020 2.742 2.725 2.708 2.588 2.571 2.555 1.688 1.679 1.664 1.657 1.650 1.635 1.628 1.608 1.602 1.597

5.766

7.265

ACCEPTED MANUSCRIPT

2 1

30

20

ppm

10 ppm

C NMR spectrum of compound 6h

S25

AC C EP TE D

190

180

170

160

150

140 7 6

1

H NMR spectrum of compound 3i

130 13

120

110

100

90

80

70

60

50

40

2

30

20

6.252

9.874

3

-5.317

25.857 23.145 18.305

4

2.114 0.973

2.133

5

61.631 58.306

83.811 78.572 77.321 77.004 76.686

1.000

M AN U 110.309 107.540

8 1.011 1.076

1.065

9

142.856

153.389

SC

RI PT

10

0.075

0.900

2.514 2.509 2.496 2.492 2.479 2.474 2.300 2.286

3.779 3.761 3.743

5.449 5.435

6.440 6.433 6.352 6.348 6.340

7.406 7.267

ACCEPTED MANUSCRIPT

1 ppm

0

C NMR spectrum of compound 3i

S26

ppm

AC C

210

200

EP TE D

9

190 8

180

170 7

1

160

H NMR spectrum of compound 6i

150 13

140

130

120

110

100

90

80

70

60

50

40

30.911 28.114 23.550

2.692

3

37.692

51.540

4

2.487 2.536

2.012

5

3.779

2.000

6

77.232 76.914 76.596 71.527

M AN U 0.966

10

97.529

176.886 173.586

197.142

SC

RI PT

4.226 4.209 4.191 3.660 3.110 3.090 3.071 2.729 2.713 2.696 2.589 2.572 2.556 2.105 2.087 2.068 2.050 2.032

5.784

7.267

ACCEPTED MANUSCRIPT

2 1

30

20

ppm

10

C NMR spectrum of compound 6i

S27

ppm

180

170

160

150

140

TE D 2.106

4.177 7 6

1

H NMR spectrum of compound 4j

130

13

120

110

100

90

80

70

60

50

40

30

20

6.312

9.451

2

-5.370

18.308

3

25.832

1.000

4

44.224 42.465

5

4.190

M AN U

126.451 124.516

8

77.316 76.999 76.681 68.442 67.870

EP 141.381

9

89.832

AC C

SC

RI PT

0.075

0.899

2.123

3.634 3.234 3.195 3.172 3.133

7.267 7.215 7.205 7.193 7.188 7.179 7.168 7.157

ACCEPTED MANUSCRIPT

1 0

10

0

C NMR spectrum of compound 4j

S28

ppm

ppm

AC C EP

180

170

TE D

160

150

140 6

1

H NMR spectrum of compound 3j

130 13

120

110

100

90

80

70

60

50

40

30

20

-5.411

6.332

10.147

2

18.279

3

25.800

1.201

4

44.331 42.453

4.182

2.178

5

58.302

77.788 77.320 77.002 76.685 67.870

91.792

M AN U 1.000

7

110.229 107.689

8

126.477 124.535

1.078 4.182

9

142.857 141.328

153.520

SC

RI PT

0.042

0.871

2.255 2.232 2.226

3.623 3.225 3.184 3.178 3.138

7.392 7.267 7.200 7.189 7.177 7.168 7.156 7.145 6.389 6.381 6.328 6.324 6.316 5.442 5.425

ACCEPTED MANUSCRIPT

1 ppm

10

0 ppm

C NMR spectrum of compound 3j

S29

AC C

200

EP TE D

190

180

170

160 7

1 6

H NMR spectrum of compound 6j

150

13

140

130

120

110

100

90

80

4

70

3

60

50

40

28.152

2.113 4.461 2.069 2.191

3.202

2.118

5

51.680 49.589 43.639 42.667 37.895

81.039 77.321 77.003 76.685

98.796

M AN U 1.000

8

126.732 124.612

4.425

9

141.283

176.221 173.678

197.346

SC

RI PT

0.003

3.680 3.211 3.208 2.986 2.774 2.757 2.740 2.597 2.581 2.564

4.113

5.848

7.267 7.195 7.184 7.172 7.165 7.154 7.142

ACCEPTED MANUSCRIPT

2 1

30

20

ppm

10 ppm

C NMR spectrum of compound 6j

S30

AC C EP TE D

180

9

170

8

1

160

150

140

130 13

7 6

H NMR spectrum of compound 4k

120

110

100

90

80

70

60

50

40

19.465

2.989

3 1.037

0.980

4

2.071 2.120

5

49.566 44.063 42.844

77.320 77.002 76.685 72.657 70.325

87.967

M AN U 1.000

4.297

10

126.690 126.603 124.575 124.355

141.205 140.989

SC

RI PT

1.339 1.323

2.171 1.919 1.900

3.809 3.793 3.777 3.761 3.745 3.284 3.160 3.121 3.080 3.040

7.268 7.224 7.213 7.188 7.166

ACCEPTED MANUSCRIPT

2 1

30

ppm

C NMR spectrum of compound 4k

20

ppm

S31

AC C EP TE D

190

180

170 8

1

160

150 7

140 130 13 6

H NMR spectrum of compound 3k

120

110

100

90

80

70

60

50

40

19.522

3.141

3 0.831

0.939

4

49.711 44.151 42.819 42.757

2.710 2.249

1.015

1.000

5

58.030

89.959 89.904 79.562 77.318 77.000 76.683 72.968 72.867

110.295 107.594 107.530

M AN U

2.015

9

126.680 126.587 124.592 124.363

1.021 4.090

10

142.804 141.276 141.041

153.390 153.333

SC

RI PT

3.789 3.775 3.330 3.289 3.277 3.235 3.154 3.143 3.115 3.104 3.067 3.057 3.027 3.017 2.558 1.861 1.335 1.320

5.413 5.403

6.309 6.279

7.371 7.268 7.176

ACCEPTED MANUSCRIPT

2 1

30

ppm

C NMR spectrum of compound 3k

20

10 ppm

S32

AC C

200

EP TE D

190

8

1

180

170

160

7

150 140 13

6

H NMR spectrum of compound 6j

130

120

110

100

90

80

70

60

3 2

50

40

30

15.714

3.471

4

28.157

2.163 2.477 2.481 2.744 2.166

2.983

1.125

5

52.026 51.664 44.462 42.784 38.289 37.875

85.648 77.316 76.999 76.681

98.587

M AN U 1.000

9

126.722 126.643 124.532 124.480

5.199

10

141.325 140.898

175.069 173.709

197.397

SC

RI PT

4.428 4.413 4.397 4.381 3.672 3.334 3.307 3.261 3.107 3.061 3.021 2.930 2.757 2.741 2.724 2.580 2.564 2.547 1.241 1.225

5.803

7.267 7.160

ACCEPTED MANUSCRIPT

1 ppm

20

ppm

C NMR spectrum of compound 6j

S33

AC C EP

180

170

160

150

TE D

140 1

130 13

120 1.002

7 6

H NMR spectrum of compound 3l

110

100

90

80

70

60

50

40

30

20

10

-5.495

6.346

2 9.628

3

3.631 4.207 1.108 3.148

1.005 2.080

4

37.328 37.207 25.817 25.681 23.656 23.630 18.264 17.593

2.155

1.039

5

58.268

79.019 77.317 76.999 76.681 69.259

91.072

M AN U

110.232 107.572

1.012 1.012

8

124.355

131.525

1.000

9

142.847

153.653

SC

RI PT

3.567 3.559 3.543 3.536 3.485 3.462 2.241 2.224 2.121 2.101 2.082 1.682 1.605 1.577 1.566 1.524 1.425 1.396 1.350 1.197 0.894 0.049

5.453 5.436 5.148 5.131 5.114

6.441 6.434 6.337

7.395 7.263

ACCEPTED MANUSCRIPT

1 ppm

0

C NMR spectrum of compound 3l

S34

ppm

AC C

200

EP

8

O

190

180 7

O

170

160 6

1

150

13

140 5

H NMR spectrum of compound 6l

130

120

110

100

90

80

70

2

60

50

40

3.189

3

2.215 3.255 3.256 2.210

1.066 1.128 2.167 2.256

2.066 3.301

1.027

4

51.673 44.499 41.195 38.709 37.831 28.200 25.621 23.657 23.045 17.596

81.348 77.316 76.998 76.680

98.454

123.664

M AN U

1.000

9

132.071

SC

RI PT

O

O

OMe

TE D

177.008 173.707

197.332

5.058 5.043 5.026 3.928 3.906 3.877 3.855 3.672 3.038 2.992 2.869 2.824 2.741 2.724 2.708 2.589 2.572 2.555 1.979 1.958 1.937 1.663 1.579 1.450 1.429 1.408 1.073

5.767

7.257

ACCEPTED MANUSCRIPT

O OMe

O

1 0

30

20

ppm

10

C NMR spectrum of compound 6l

S35

ppm

AC C EP TE D

190

180

170

160

150 8 7

1

140

13

130 6

H NMR spectrum of compound 11a

120

110

100

90

80

70

60

3.578

3

50

3.116

4

1.007

5

58.169

82.337 77.316 76.999 76.681 76.594

1.000

M AN U 110.262 107.330

9 0.992 1.007

0.992

10

142.746

153.455

SC

RI PT

1.899 1.895

2.556

5.421 5.410

6.418 6.410 6.337

7.394

ACCEPTED MANUSCRIPT

2

40

1

30

20

ppm

10

C NMR spectrum of compound 11a

S36

ppm

6

5

2.040 2.035 3

2

1

ppm

4.913

54.782

80.946 77.315 76.998 76.680 74.600

91.134

110.127

AC C

EP

TE D

131.431 128.834

H NMR spectrum of compound 12a (Major isomer)

164.297

1

4

3.824

7

4.207

8

1.000

9

1.175 2.211

10

M AN U

SC

RI PT

3.473

4.642 4.637

6.347 6.334 6.125

7.268

ACCEPTED MANUSCRIPT

180

170

160

150 13

140

130

120

110

100

90

80

70

60

50

40

30

20

10

C NMR spectrum of compound 12a (Major isomer)

S37

ppm

1.975

4

3

2

1

ppm

4.516

54.441

87.503 81.723 77.315 76.997 76.680 75.144

109.726

127.345

AC C

EP

TE D

131.958

H NMR spectrum of compound 12a (Minor Isomer)

166.107

1

5

3.433

6

3.380

7

1.000

8

1.104 1.077

9

1.081

10

M AN U

SC

RI PT

3.411

4.992

6.181 6.167 6.043

6.789 6.774

ACCEPTED MANUSCRIPT

180

170

160

150 13

140

130

120

110

100

90

80

70

60

50

40

30

20

10

C NMR spectrum of compound 12a (Minor Isomer)

S38

ppm

AC C EP

190

TE D

180

170 8

1

160

150

140 13 7

130 6

H NMR spectrum of compound 11b

120

110

100 4

90

80

70

1.005

1.000

5

58.571

86.136 85.700 77.319 77.001 76.683

110.383 107.825

M AN U

1.012 1.013

9

131.772 128.723 128.269 122.040

2.081 1.017 3.093

10

143.023

152.883

SC

RI PT

2.508 2.496

5.712 5.698

6.542 6.535 6.391

7.504 7.485 7.455 7.348 7.333

ACCEPTED MANUSCRIPT

3

60

2

50

40

1

30 ppm

20

10 ppm

C NMR spectrum of compound 11b

S39

AC C EP TE D

190

9

180

8

1

170

160 150 13

140

7

130

6

H NMR spectrum of compound 12b (Major isomer)

120

110

100

3.142

1.000

5

4

90

80

70

55.014

85.035 80.494 77.320 77.002 76.684

94.486

110.314

M AN U

1.033 1.019 1.029

2.059 3.228

10

132.452 131.311 128.831 128.143 127.715 123.870

165.012

SC

RI PT

3.521

4.910

7.490 7.472 7.328 7.313 7.295 7.280 6.423 6.409 6.226 6.212 6.172

ACCEPTED MANUSCRIPT

3 2

60

50

40

1

30

20

ppm

10 ppm

C NMR spectrum of compound 12b (Major isomer)

S40

AC C EP TE D

190

180

170 8

1

160

150 13

140

130 7 6

H NMR spectrum of compound 12b (Minor isomer)

120

110

100

90

3.253

1.000

5

4

80

70

60

54.664

85.861 81.413 77.314 76.996 76.678

91.597

110.073

M AN U

1.066 1.057

9 1.051

2.162 3.303

10

132.939 130.978 128.246 127.586 127.406 123.902

166.836

SC

RI PT

3.462

5.266

7.434 7.417 7.332 7.316 7.297 7.280 7.268 6.915 6.900 6.286 6.271 6.112

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10 ppm

C NMR spectrum of compound 12b (Minor isomer)

S41

AC C EP TE D

190

180

170 8

1

160

150

140 13 7

H NMR spectrum of compound 11c

130

120

110

100

90

80

70

60

50

40

30

3.181

2

20

13.423

21.823 20.639

3 2.079

4

1.030 2.082

5

58.234

6

86.670 77.560 77.317 76.999 76.681

1.000

M AN U 110.252 107.373

9 1.002 1.008

0.987

10

142.771

153.624

SC

RI PT

2.440 2.436 2.426 2.265 2.247 2.230 1.614 1.596 1.578 1.560 1.542 1.524 1.019 1.000 0.982

5.454 5.438

6.430 6.424 6.340

7.398 7.267

ACCEPTED MANUSCRIPT

1 ppm

10 ppm

C NMR spectrum of compound 11c

S42

AC C EP TE D

9

190

180 8

170 7

1

160

13

150

140

130 6

H NMR spectrum of compound 12c (Major isomer)

120

110

100

90

80

70

60

50

40

3.237

2

30

20

13.486

22.261 21.922

3

2.325

4

2.109

3.225

1.000

5

54.786

81.028 77.320 77.002 76.684 75.531

95.632

M AN U 110.046

1.064 2.032

10

131.351 128.837

164.254

SC

RI PT

2.390 2.386 2.373 2.369 2.355 1.629 1.611 1.593 1.575 1.557 1.026 1.007 0.989

3.469

4.662

6.345 6.332 6.128 6.114

7.268

ACCEPTED MANUSCRIPT

1 0 ppm

10 ppm

C NMR spectrum of compound 12c (Major isomer)

S43

AC C EP TE D

190

180

170 1

160

150 13 7

140

130 6

H NMR spectrum of compound 12c (Minor isomer)

120

110

100

90

80

70

60

50

40

30

3.335

2

13.524

22.371 21.665

3 2.490

4

2.235

3.189

0.918

5

54.420

81.828 77.316 76.998 76.680 76.140

92.123

M AN U 109.743

8 1.065 1.025

1.000

9

127.410

10

131.901

166.042

SC

RI PT

2.330 2.327 2.314 2.296 1.606 1.587 1.569 1.551 1.533 1.018 1.000 0.981

3.414

5.023

6.182 6.168 6.051

6.790 6.776

7.267

ACCEPTED MANUSCRIPT

1 ppm

20

ppm

C NMR spectrum of compound 12c (Minor isomer)

S44

AC C EP

190

TE D

180

170

160

150 7

140 130 13 6

H NMR spectrum of compound 11d

120

110

100

90

80

70

4

60

20.145

3.122

2.103

2.190

5

58.178

83.392 78.617 77.319 77.002 76.684 72.918 68.006

1.000

M AN U

0.991 1.056

8

110.295 107.544

1

128.391 127.699

1.075 5.519

9

137.870

10

142.819

153.313

SC

RI PT

2.613 2.597 2.580

3.645 3.628 3.611

4.565

5.452 5.436

7.406 7.360 7.349 7.320 7.311 7.299 6.436 6.429 6.343

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10

C NMR spectrum of compound 11d

S45

ppm

AC C EP TE D

190

9

180

170

8

1

160

150 13

140

7

130

6

H NMR spectrum of compound 12d (Major isomer)

120

110

100

90

80

70

60

21.315

4

2.088

2.096 3.127

1.000 2.071

5

54.751

80.617 77.318 76.999 76.682 76.497 72.864 68.470

91.800

110.096

M AN U

1.014 2.017

4.181 1.164

10

138.103 131.691 128.799 128.314 127.642 127.555

164.564

SC

RI PT

2.751 2.733 2.720

3.672 3.654 3.636 3.462

4.665 4.580

7.364 7.349 7.331 7.301 7.293 7.287 7.269 6.353 6.339 6.153 6.139 6.124

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10

C NMR spectrum of compound 12d (Major isomer)

S46

ppm

AC C EP TE D

190

180 8

1

170

160

150 13

140

130

7 6

H NMR spectrum of compound 12d (Minor isomer)

120

110

100

90

80

70

60 21.093

3

50

2.332

4

2.362

2.637 3.636

2.500

1.000

5

54.482

88.522 81.444 77.317 77.190 77.000 76.682 72.918 68.606

109.811

M AN U

1.101 1.091

9 0.990

6.255

10

138.092 132.175 128.376 127.673 127.637 127.436

166.464

SC

RI PT

2.680 2.666 2.662 2.649

3.638 3.621 3.603 3.421

4.573

5.013

7.363 7.352 7.314 7.305 7.294 7.268 6.777 6.763 6.185 6.171 6.055

ACCEPTED MANUSCRIPT

2

40

1

30

20

ppm

10 ppm

C NMR spectrum of compound 12d (Minor isomer)

S47

AC C EP TE D

180

170 1

160

150

140

130 13

7

120

110

100

90

80

70

60

50

1.000

4

42.453 42.071

5

58.418

6

77.318 77.001 76.683 73.768

3.035 2.012 2.043 2.226

8

85.952

9

H NMR spectrum of compound 4m

M AN U

10.359

10

130.798 127.717 126.443

137.299

SC

RI PT

2.245

3.374 3.067 3.018 2.985 2.850 2.818

7.366 7.349 7.322 7.303 7.289 7.271

ACCEPTED MANUSCRIPT

3 2

40

30

1 ppm

20

10 ppm

C NMR spectrum of compound 4m

S48

AC C EP

190

TE D

180

170

160 7

150

140 13

130 6

H NMR spectrum of compound 11e

120

110

100

90

80

70

60

0.981

4

42.354 42.272

3.044 2.046 2.092 2.062

5

58.359 58.119

88.026 83.267 77.319 77.001 76.684 73.576

1.000

M AN U 110.222 107.497

1

0.998 0.995

8

130.768 127.727 126.421

1.057 10.488

9

137.305

10

142.698

153.233

SC

RI PT

3.374 3.089 3.049 3.016 2.868 2.836 2.474

5.426 5.412

6.358 6.263

7.436 7.337 7.323 7.305 7.299 7.281

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10 ppm

C NMR spectrum of compound 11e

S49

AC C EP TE D

190

180

9

170

8

1

160

150 13

140

7

130

6

H NMR spectrum of compound 12e (Major isomer)

120

110

100

90

80

70

4

60

43.218 42.835 42.790

4.513 2.471

3.416 3.632

1.000

5

58.294 54.666

81.125 80.705 77.317 77.000 76.682 73.603

96.629

110.017

M AN U

1.003 1.953

4.059 6.208

10

137.773 131.652 130.906 128.980 127.591 126.195

164.812

SC

RI PT

3.543 3.531 3.355 3.056 3.044 3.025 2.900 2.868

4.649

7.465 7.447 7.335 7.317 7.299 7.272 7.254 6.369 6.355 6.183

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10

C NMR spectrum of compound 12e (Major isomer)

S50

ppm

AC C EP TE D

190

180 9

170 8

1

160

150 13

140 7

130 6

H NMR spectrum of compound 12e (Minor isomer)

120

110

100

90

80

70

4

60

43.204 42.833

4.752 2.628

3.428 3.923

1.000

1.109 1.070

5

58.354 54.689

81.917 81.446 77.314 76.997 76.679 73.861

93.323

109.849

M AN U

1.079

12.167

10

137.844 131.918 130.788 127.690 127.534 126.298

166.367

SC

RI PT

3.434 3.362 3.038 3.001 2.827 2.795

4.998

7.332 7.313 7.292 7.273 7.258 7.241 6.450 6.436 6.139 6.125 6.031

ACCEPTED MANUSCRIPT

3 2

50

40

1

30

20

ppm

10

C NMR spectrum of compound 12e (Minor isomer)

S51

ppm

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

ORTEP diagram of the compound 6j with displacement ellipsoids at 50% probability.

S52