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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Heterocycles. Author manuscript; available in PMC 2011 January 1.
Published in final edited form as:
Heterocycles. 2010 January 1; 81(1): 117–143.
doi:  10.3987/COM-09-11840
PMCID: PMC2844783
NIHMSID: NIHMS160343

EXPLORATION OF BRAVERMAN REACTION CHEMISTRY. SYNTHESIS OF TRICYCLIC DIHYDROTHIOPHENE DIOXIDE DERIVATIVES FROM BISPROPARGYL SULFONES

Abstract

The base-mediated bicyclization of unsymmetrical bispropargyl sulfones furnishes varying yields of dihydroisobenzothiophene dioxides through a presumed diradical intermediate. Attempts to trap a putative thiophene dioxide intermediate via Diels-Alder reaction with a pendant alkyne were not successful.

Introduction

The spontaneous thermal cyclization of bisallenyl sulfones to furnish thiophene dioxide derivatives was first reported by Braverman in 1974.1 Subsequent studies revealed that this transformation likely proceeds through a diyl intermediate, 45678 (Scheme 1), followed by several tautomerizations rather than an intramolecular Diels-Alder reaction of either a bis(3-aryl)allenyl sulfone (i.e., 46 directly) or a related allenyl, propargyl sulfone.2-4 The key to successful development of this transformation involved identifying mild methods to access the reactive bisallenyl sulfone, and in 2000/2001 Braverman described a facile procedure based upon simple treatment of the propargyl alcohol 1 with SCl2; a series of [2,3]-sigmatropic shifts then delivers the bisallenyl sulfone 4.2,3 In addition, a base-mediated alternative process that begins with bispropargylic sulfone 9 was introduced in this work, 98. The reported yield for this latter process approached quantitative, although there was no report of a yield or description of an experimental procedure for the 18 reaction.3 The formation of a thiophene dioxide such as 7, whether transiently or as an isolable intermediate,1,4 raised the possibility of linking the Braverman chemistry with the rich Diels-Alder chemistry of thiophene dioxides5-8 in a multi-step transformation that could forge several new rings from simple precursors. Thus, tethering a dienophile trap to a nascent thiophene dioxide emerging from the Braverman chemistry might test the hypothesis that intramolecular Diels-Alder cycloaddition might compete with proton transfer within an intermediate like 7 and ultimately deliver a pentacyclic product. Probing this hypothesis first would require the development of Braverman chemistry with an unsymmetrical bisallenyl sulfone, a type of substrate heretofore unexamined, in order to introduce both the dienophile and the thiophene dioxide into the same molecule. Our preliminary attempts to access such substrates and execute an unsymmetrical Braverman reaction, as well as a test of the premise that the intermediate thiophene dioxide can be trapped by a pendant dienophile, are described below.

Scheme 1
Braverman's early contributions.2,3

Results and Discussion

Our initial attempts to reproduce the Braverman chemistry with propargyl alcohol 1 led to mixed results. The base-mediated cyclization of the bispropargylic sulfone 9 to furnish tricycle 8 proceeded in moderate yield (44%) in our hands (Scheme 1). However, the more intriguing process starting from two equivalents of the propargyl alcohol 1 and SCl2 could not be brought to a satisfying endpoint. After much exploration of temperatures, solvents, reagent concentrations, etc., we were able to achieve no better than a 9% yield of the same tricycle 8 that was formed from the DBU-mediated isomerization of 9. Under alternative conditions where the SCl2 is metered into the reaction slowly so as to ensure that its concentration is never high, the reaction takes a different course and delivers the symmetrical ether 10 as the only identifiable product. Presumably this ether results from simple SN2-like substitution of X (X = SCl or SOR) within an intermediate HC[equivalent]C−CH(X)Ph. This disappointing turn of events served to focus our attention on the bispropargyl sulfone route.

Synthesis of Bispropargyl Sulfone Substrates

The unsymmetrically substituted bispropargyl sulfone substrates 15a-15e were prepared by convergent coupling of the 1,8-nonadiynylmercaptans 13a and 13b with the propargyl bromides 14a-14d to furnish a thioether product, which was immediately oxidized to the requisite sulfone, Scheme 3. The inaugural substrate chosen for study was the bispropargylic sulfone 15a. An alternative convergent coupling plan utilizing the mercaptan equivalent of 14a and the bromide analogue of 13a did not provide any sulfide product. The mercaptan of 13a was introduced via tosylation of the alcohol 12a followed by SN2 displacement of the derived tosylate with thioacetic acid and then reductive removal of the acetate fragment (sequence A). In subsequent substrate syntheses, a route employing Mitsunobu chemistry for direct displacement of the alcohol in 12b with thioacetic acid gave superior yields (sequence B). The propargyl bromides 14b-14d were assembled from the corresponding aryl bromides or iodides 16a, 16b, and 16d, respectively. The conversion of the aryl propargyl alcohol derived by Sonogashira coupling of 16a into the corresponding bromide 14b was particularly challenging and accounts for the low yield for this sequence; it appeared that the lability of the bromide 14b during workup/purification is the likely culprit. The bismethoxymethyl ether bromide 16c combined with propargyl alcohol under standard Sonogashira conditions to provide the arylated propargyl alcohol in poor yield, and so recourse was made to the corresponding iodide 16d, prepared by metalation of 16c followed by I2 quench of the intermediate lithiate.

Scheme 3
Synthesis of bispropargyl sulfone substrates.

The cyclization substrates 15a-15e all were obtained as spectroscopically pure light yellow oils that displayed no tendency to decompose upon storage at room temperature. No partial isomerization of a propargyl moiety into an allene unit was observed. Characteristic 1H NMR signals at δ 4.2–4.6 indicate the presence of propargylic sulfone substructures, and the geminal coupling of the diastereotopic methylene protons (J ~ 17 Hz) confirms this assignment.

Base-Mediated Bicyclization of The Bispropargyl Sulfone Substrates

The base promoted bicyclizations (Braverman reaction) of the bispropargyl sulfones prepared as illustrated in Scheme 3 were explored next. The simple methoxyphenyl-bearing substrate 15a was chosen to probe the influence of different bases and solvents on the efficiency of the reaction. The pendant alkyne was introduced to assess the possibility that the putative intermediate thiophene dioxide (cf. 7, Scheme 1) could be intercepted in an IMDA reaction prior to its isomerization into the naphthalene product (cf. 78, Scheme 1).

Exposure of bispropargyl sulfone 15a to a range of bases in a variety of solvents helped delineate the optimum conditions for product formation (Table 1). It is evident that several distinct sets of reaction conditions successfully produced the tricyclic product 17, whose structure was suggested by key spectral data (H @ δ8.19; triplet for methine proton next to sulfur) and later confirmed by single crystal X-ray analysis.10 Essentially quantitative yield of 17 could be achieved when the relatively mild base triethylamine was used in either CHCl3 or toluene. The temperature of the reaction medium did not seem to be a critical parameter, at least within the range 25 °C to 110 °C; both temperature extremes led to the same high yield of tricyclic product. However, no set of reaction conditions could be identified where the presumptive thiophene dioxide intermediate could be trapped in a Diels-Alder cycloaddition with the tethered alkyne. In all cases, even when exogenous base was omitted (Table 1, entry 10), Diels-Alder cycloaddition was not competitive with the tautomerizations from a presumed thiophene dioxide/dihydronaphthalene intermediate to the observed naphthalene/dihydrothiophene dioxide product 17.

Table 1
Optimizing the yield of 17 formation from bicyclization of 15a.

One approach that might circumvent the tautomerization leading to the naphthalene-containing product is to force an otherwise labile methylene proton into the plane of the π-system in order to suppress deprotonation. Scheme 5 describes the Braverman cyclization chemistry of one such substrate, 15b.

Scheme 5
Base-mediated cyclization of a bispropargyl sulfone bearing an o-methoxyphenyl ring and a TBS group; formation of a dihydronaphthalene product.

Subjection of this silylated bispropargyl sulfone to the optimized conditions from Table 1 led to a good yield of tricyclic material. Thus, at the very least, the terminal silyl group did not complicate the Braverman cascade sequence. Furthermore, the formation of a partially unisomerized product 19 was in line with the expectations of the tautomerization suppression hypothesis; reaction through an unobserved intermediate thiophene dioxide 18 will engender A1,3-type interactions between the alkyl tether and the pseudoequatorial substituent at the benzylic position. This interaction should be less sterically penalizing when the equatorial substituent is a proton, but in that arrangement, poor overlap between the C–H bond and the π-system is likely to suppress deprotonation. However, once again, the putative thiophene dioxide intermediate was not long-lived enough to participate in an IMDA reaction with the attached alkyne; isomerization of the other alkene apparently was just too fast.

One workaround to this olefin positioning issue might involve raising the oxidation level of a tricyclic species like 19 to generate, at least in situ, an orthonaphthoquinonedimethane-thiophene dioxide species (cf. 24, Scheme 8). Two distinct approaches to accomplish the introduction of another oxidized substituent into the bispropargyl sulfone cyclization precursor were explored. One manifestation of this plan is illustrated in Scheme 6, where an additional ortho-OMe group serves as this sacrificial oxidation level marker. The idea behind this substrate choice derived from the expectation that an intermediate such as 20 might eliminate the elements of either MeOH or MeOTBS to furnish the extended orthonaphthoquinonedimethane system, a potentially very reactive Diels-Alder partner for the alkyne. However, in one of the more surprising twists of this research, attempted Braverman cyclization of the o,o′-blocked substrate 15c furnished a low yield of the familiar tricycle 19! Clearly, a formal reduction has occurred, but the source of the reducing agent and the mechanism by which putative intermediate 20 is processed further into 19 remains mysterious.

Scheme 6
Base-mediated cyclization of a bispropargyl sulfone bearing an o,o'-dimethoxyphenyl ring and a TBS group; formation of the dihydronaphthalene product 19 again.
Scheme 8
Attempts to access orthonaphthoquinonedimethane-type intermediates from tricyclic naphthalene 17.

A second attempt to implement the same strategy for oxidation level elevation followed with the protected hydroquinone-containing substrates 15d and 15e, Scheme 7. In these instances, the introduction of a higher oxidation level (= orthonaphthoquinonedimethane-thiophene dioxide) was planned for post-cyclization chemistry, given the surprising course of the Braverman reaction with 15c. These species participated in triethylamine-mediated cyclization without event and furnished the expected dihydro tricycles 21 and 22, respectively, by analogy with the cyclization of 15b into 19.

Scheme 7
Base-mediated cyclization of a bispropargyl sulfone bearing either an o,m-dimethoxyphenyl ring or an o,m-dimethoxymethyeneoxyphenyl ring and a TBS group.

Attempts to Force Thiophene Dioxide Formation/Intramolecular Diels-Alder Cycloaddition

There are some precedents for the formation of orthoquinonedimethane intermediates from either photochemically or thermolytically induced chelatotrophic extrusion of SO2 from dihydroisobenzothiophene dioxides,11,12 and so heating the sulfone 17 over the temperature range 180 – 340 °C, as well as irradiation (254 - 300 nm, room temperature), were explored in an attempt to force Diels-Alder cycloaddition of the terminal alkyne. However, in no instance was anything other than returned starting material or uncharacterizable decomposition products observed. For the naphthalene system 17, decomposition began at ~ 240 °C, and irradiated returned only starting material. Oxidation of naphthalene 17 gave the paraquinone 23, a species that, in principle, offered two different approaches to generating a reactive intermediate (orthonaphthoquinonedimethane or thiophene dioxide) for Diels-Alder cycloaddition. Unfortunately, neither thermolysis nor photolysis of 23 led to anything characterizable. Decomposition set in at ~ 270 °C, whereas irradiation at 350 nm also destroyed the compound. Furthermore, treatment of 23 with a variety of bases (i.e., pyridine, Et3N, i-Pr2NEt, pyridine, DBU, KOt-Bu, and i-Pr2NLi) with the intent of effecting an internal redox reaction via proton tautomerization (= formal oxidation of the dihydrothiophene ring to a thiophene dioxide with concomitant reduction of the paraquinone to the hydroquinone or hydroquinone dianion) did not provide any reason to be optimistic. Thus, in the final analysis, the innate thermodynamic preference13 that favors a naphthalene/dihydrothiophene dioxide structure rather than the dihydronaphthalene/thiophene dioxide tautomer dominated the chemistry of this system, and no Diels-Alder-capable intermediates with sufficient lifetime to engage in cycloaddition could be accessed.

The acquisition of the non-naphthalenic tricycle 19 from Braverman cyclization of the TBS-substituted bispropargyl sulfone 15b offered the possibility of further manipulation into a thiophene dioxide intermediate without the burden of overcoming the naphthalene moiety's aromatic resonance energy. This strategy for generating the thiophene dioxide moiety from 19 involved oxidation to the aforementioned orthonaphthoquinonedimethane-thiophene dioxide construct, cf. 24. Efforts towards that end included treating 19 with epoxidizing reagents (H2O2/base, mCPBA, CF3CO3H), but only unconsumed starting material resulted. Direct, benzylic-type oxidation (CrO3, KMnO4, SeO2, DDQ) was no more promising, affording either unreacted 19 or decomposition products. Deprotonation of an acidic proton α- to the sulfonyl moiety did afford a tractable anion, and trapping of that anion with Ph2S2 produced the α-sulfide 25a in moderate yield. The corresponding sulfoxide 25b and sulfone 25c also were available from the sulfide. Treatment of the α-sulfonyl anion with other electrophiles (Br2, CN-Br, BrCCl3, TsCl) did not afford any of the oxidized product. Exposure of the sulfide 25a to a fluoride source did not promote the intended elimination of TBS-SPh, and only the naphthalene-containing product 26 resulted. A similar attempt with the sulfone 25c led only to decomposition of the starting material without formation of any isolable product. Attempts to effect [2,3]-sigmatropic rearrangement of the allylic sulfoxide within 25b might have generated a transient thiophene dioxide product, but only the formal direct displacement product, alcohol 27, was formed. The mechanism of this transformation remains a matter of speculation. Once again, our attempts to access a thiophene dioxide intermediate were thwarted.

The final attempts at accessing an IMDA-capable thiophene dioxide intermediate from the Braverman cyclization tricycles focused on the hydroquinone derivatives 21 and 22, Scheme 10. The objective in this instance was to convert the hydroquinone ethers to the paraquinone as per 1723 and in so doing provide a substrate whose tautomerization to a thiophene dioxide product might not be so unfavorable. Unlike the fully aromatic system of 23, we hoped that the cross-conjugated diene of such an oxidation product (cf. 28) might be more prone to isomerization and afford access to the desired orthonaphthoquinonedimethane-thiophene dioxide 24. Unfortunately, the first substrate examined, dimethyl ether 21, was not a competent oxidation substrate as it decomposed readily under a variety of oxidation conditions. Apparently, the diene of 21 confers an unwanted sensitivity to the system that is not shared by the fully aromatic naphthalene analogue 17.

Scheme 10
Oxidation of the tricyclic Braverman product; attempts to formulate a orthonaphthoquinonedimethane-thiophene dioxide intermediate.

The bis MOM ether analogue 22 did not suffer from this disadvantage. In this instance, removal of the MOM protecting groups provided a labile hydroquinone that decomposed upon standing but which could be oxidized immediately after acquisition to generate the requisite paraquinone containing tricycle 28. Base- and/or fluoride-mediated isomerization of 28 into the corresponding orthonaphthoquinonedimethane-thiophene dioxide 24 was attempted next, under the premise that the normal thermodynamic unfavorability13 (vide supra) might be mitigated somewhat by the gain in aromatic resonance energy upon concurrent paraquinone → hydroquinone reduction. However, treating this substrate with base and/or fluoride led only to uncharacterizable mixtures with no evidence for thiophene dioxide formation. Thus, in the final analysis, no evidence was forthcoming that supported the notion that introduction of a strategically placed oxygen function into the aromatic ring of the bispropargyl sulfone substrates promoted further oxidation of the remaining rings to generate a thiophene dioxide-containing species.

Conclusions

In summary, we have successfully prepared a range of unsymmetrical bispropargyl sulfones featuring a variety of OR (R = Me or MOM) placements on the aryl ring that caps one propargyl unit and either a proton or a TBS group at the terminus of the other propargyl unit. These species all participated in a Braverman cyclization cascade to furnish tricyclic products with varying efficiency. Depending upon the alkyne substituent (H or TBS), the tricyclic product either isomerized to a naphthalene-containing species (H substituent) or remained as a dihydronaphthalene isomer (TBS substituent). Unfortunately, all efforts to generate and then utilize a thiophene dioxide tautomer in intramolecular Diels-Alder cycloaddition with a pendant alkyne were frustrated by competitive isomerizations that consistently delivered the naphthalene product, presumably a thermodynamic sink. Thus, linking the Braverman sequence with thiophene dioxide Diels-Alder chemistry was not achieved.

Experimental

General Experimental

Moisture- and oxygen-sensitive reactions were carried out in flame-dried glassware under an inert nitrogen atmosphere. Dry ether (Et2O), toluene, acetonitrile (MeCN), dichloromethane (CH2Cl2), methanol (MeOH), tetrahydrofuran (THF) and dimethylformamide (DMF) were purified by passing these solvents through activated alumina columns. Reagents were purchased at the highest commercial quality and used without further purification unless otherwise stated. Reactions were monitored by thin layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) with UV visualization and PMA staining. Purification of products via flash chromatography was performed with 40-63 μm silica gel and the solvent system indicated. Melting points are uncorrected.

4-Phenyl-1,3-dihydro-naphtho[2,3-c]thiophene 2,2-Dioxide (8)

A stirring solution of alkyne 1 (50 mg, 0.39 mmol) in 5 mL of Et2O was treated with pyridine (35 μL, 0.44 mmol). After 1 h, the reaction mixture was cooled to -78 °C and freshly distilled SCl2 (13 μL, 0.94 mmol) was added dropwise. After 1 h at -78 °C, saturated aqueous NaHCO3 (10 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a light yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 25% Et2O/hexanes → 50% Et2O/hexanes as eluent) gave tetracycle 8 (4.9 mg, 9%) as a light yellow oil. Spectral data matched those reported by Braverman.3

1,1′-(Oxydi-2-propyn-1-ylidene)bis-benzene (10)

A stirring solution of alkyne 1 (0.100 g, 0.774 mmol) in 10 mL of Et2O was treated with pyridine (70 μL, 0.87 mmol). After 1 h, the reaction mixture was cooled to -78 °C and a solution of freshly distilled SCl2 (26 μL, 0.39 mmol) in 330 μL of CH2Cl2 was added to the reaction solution. After 1 h at -78 °C, saturated aqueous NaHCO3 (10 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a light yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 10% Et2O/hexanes → Et2O as eluent) gave bis-propargylic ether 10 (21.7 mg, 23%) as a colorless oil. Spectral data matched those reported by Bustelo.14

Nona-1,8-diyne-3-ol (12a)

To a stirring solution of hept-6-ynal15 (11) (1.01 g, 9.14 mmol) in 75 mL of THF at 0 °C was added a solution of ethynylmagnesium bromide in THF (0.5M, 21.9 mL, 11.0 mmol). The reaction mixture was stirred at 0 °C for 2 h and then saturated NH4Cl (100 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 100 mL). The combined organic fractions were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford nona-1,8-diyn-3-ol (12a) (0.717 g, 58%) as a colorless oil. A yield of 90% was obtained on a 32 mg scale. IR (thin film) 3950, 3500, 2115 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.32 (qd, J = 6.1, 2.0 Hz, 1H), 2.49 (br s, 1H), 2.43 (d, J = 2.1 Hz, 1H), 2.19-2.13 (m, 2H), 1.91 (t, J = 2.6, 1H), 1.71-1.64 (m, 2H), 1.57-1.46 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 84.8, 84.2, 72.9, 68.4, 65.8, 61.9, 36.9, 27.9, 24.1, 18.2; GC-MS (EI) m/z (relative intensity) 136.2 (5%, M+).

1-(tert-Butyldimethylsilanyl)nona-1,8-diyne-3-ol (12b)

To a stirring solution of TBS acetylene (6.32 g, 44.9 mmol) in 80 mL of THF at 0 °C was added n-BuLi (2.5 M in hexanes, 18 mL, 45 mmol) dropwise. The reaction mixture was stirred for 10 min at 0 °C and then a solution of hept-6-ynal (4.95 g, 44.9 mmol) in 20 mL of THF was added. The reaction mixture was stirred at room temperature for 2 d, and then saturated NH4Cl (100 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 100 mL). The combined organic fractions were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a colorless oil. Purification of this oil by SiO2 flash column chromatography (gradient, 5% Et2O/hexanes → 10% Et2O/hexanes as eluent) afforded 1-(tert-butyldimethylsilanyl)nona-1,8-diyn-3-ol (12b) (4.78 g, 43%) as a colorless oil. A yield of 60% was obtained on a 1.41 g scale. IR (thin film) 3400, 3307, 2175 cm-1; 1H NMR (360 MHz, CDCl3) δ 4.36 (t, J = 5.1 Hz, 1H), 2.21-2.16 (m, 2H), 1.97 (brs, 1H), 1.93 (t, J = 2.1 Hz, 1H), 1.71-1.70 (m, 2H), 1.60-1.54 (m, 4H), 0.92 (s, 9H), 0.09 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 107.3, 87.7, 84.2, 68.4, 62.6, 37.3, 28.1, 26.0, 24.3, 18.3, 16.4, -4.7; LRMS (ESI) m/z (relative intensity) 251.3 (70%, M + H+).

Nona-1,8-diyne-3-thiol (13a)

To a stirring solution of nona-1,8-diyn-3-ol (12a) (0.668 g, 4.88 mmol) in 1.55 mL at 0 °C was added p-toluenesulfonyl chloride (0.998 g, 5.23 mmol). The reaction mixture was stirred for 3 h and then H2O (25 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic fractions were washed with 1M HCl (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of the oil by SiO2 flash column chromatography (5 % EtOAc/hexanes as eluent) gave toluene-4-sulfonic acid 1-ethynyl-hept-6-ynyl ester (0.988 g, 70%) as a yellow oil. IR (thin film) 3292, 2123 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.76 (dt, J = 8.4, 1.8 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.00 (td, J = 6.5, 2.1 Hz, 1H), 2.39 (s, 3H), 2.38 (s, 1H), 2.11 (td, J = 6.6, 2.6 Hz, 2H), 1.90 (t, J = 2.6 Hz, 1H), 1.83-1.73 (m, 2H), 1.56-1.40 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 144.8, 133.5, 129.6, 127.9, 83.7, 79.4, 76.2, 70.7, 68.6, 34.9, 27.4, 23.5, 21.5, 18.0; LRMS (ESI) m/z (relative intensity) 308.1 (100%, M + NH4+); HRMS (ESI) m/z calcd for [C16H22NO3S]+, 308.1320, found 308.1316.

To a stirring solution of CsF (0.44 g, 2.9 mmol) in 10 mL of DMF was added thioacetic acid (274 μL, 3.89 mmol). The reaction mixture was stirred for 20 min, and then a solution of toluene-4-sulfonic acid 1-ethynyl-hept-6-ynyl ester (0.832 g, 2.87 mmol) in 5 mL of DMF was added. The reaction mixture was stirred for 20 h at 50 °C and then H2O (10 mL) were added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic fractions were sequentially washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude yellow oil. Purification of the oil by SiO2 flash column chromatography (10% Et2O/hexanes as eluent) afforded thioacetic acid S-(1-ethynyl-hept-6-ynyl) ester (0.433 g, 78%) as a yellow oil. IR (thin film) 3294, 1695 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.22 (td, J = 6.8, 2.5 Hz, 1H), 2.31 (s, 3H), 2.26 (d, J = 2.6 Hz, 1H), 2.20-2.13 (m, 2H), 1.92 (t, J = 2.6 Hz, 1H), 1.77-1.70 (m, 2H), 1.62-1.50 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 193.9, 84.0, 82.2, 71.6, 68.5, 34.9, 33.3, 30.2, 27.7, 26.0, 18.2; GC-MS (EI) m/z (relative intensity) 194.0 (5%, M+).

To a stirring solution of LiAlH4 (49.1 mg, 1.29 mmol) in 10 mL of Et2O at 0 °C was added a solution of thioacetic acid S-(1-ethynyl-hept-6-ynyl) ester (346 mg, 1.78 mmol) in 5 mL of Et2O. The reaction mixture was warmed to room temperature, stirred for 14 h, and poured into ice-cold H2O. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic fractions were sequentially washed with 1M H3PO4 (60 mL) and then brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude yellow oil. Purification of this oil by passing through a thin pad of SiO2 (33% Et2O/hexanes as eluent) gave thiol 13a (125 mg, 46%) as a yellow oil. A yield of 60% was obtained on a 2.12 g scale. IR (thin film) 3293 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.53-3.51 (m, 1H), 3.26 (s, 1H), 2.17-2.14 (m, 3H), 1.93 (d, J = 2.4 Hz, 1H), 1.76-1.73 (m, 2H), 1.59-1.49 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 85.0, 84.0, 71.4, 68.5, 38.5, 28.3, 27.6, 26.1, 18.2; GC-MS (EI) m/z (relative intensity) 152.0 (100%, M+).

1-(tert-Butyldimethylsilanyl)nona-1,8-diyne-3-thiol (13b)

To a stirring solution of PPh3 (4.28 g, 19.5 mmol) and 1-(tert-butyldimethylsilanyl)nona-1,8-diyn-3-ol (12b) (4.44 g, 17.7 mmol) in 60 mL of THF at 0 °C was added DIAD (3.04 mL, 19.5 mmol) dropwise. The reaction mixture was stirred for 10 min at 0 °C and then treated with thiolacetic acid (1.06 mL, 19.5 mmol). After 2 h at 0 °C, the reaction mixture was concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (10% Et2O/hexanes as eluent) afforded thioacetic acid S-{1-[(tert-butyldimethylsilanyl)ethynyl]hept-6-ynyl} ester (3.84 g, 70%) as a yellow oil. IR (thin film) 3295, 2150, 1690 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.29 (t, J = 6.8 Hz, 1H), 2.32 (s, 3H), 2.19 (td, J = 6.7, 2.6 Hz, 2H), 1.93 (t, J = 2.7 Hz, 1H), 1.77-1.74 (m, 2H), 1.62-1.56 (m, 4H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 194.1, 104.2, 86.7, 84.1, 68.4, 35.5, 34.4, 30.2, 27.8, 26.0 (2), 18.2, 16.5, -4.7; LRMS (ESI) m/z (relative intensity) 309.2 (100%, M + H+).

To a stirring suspension of K2CO3 (1.89 g, 12.4 mmol) in 130 mL of MeOH was added thioacetic acid S-{1-[(tert-butyldimethylsilanyl)ethynyl]hept-6-ynyl} ester (3.84 g, 12.4 mmol) in 20 mL of MeOH. The reaction mixture was stirred for 3 h at room temperature at which time 1M H3PO4 (200 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 200 mL). The combined organic fractions were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give thiol 13b (2.84 g, 86%) as a yellow oil. A yield of 98% was obtained on a 4.91 g scale. IR (thin film) 3295, 2150 cm-1; 1H NMR (360 MHz, CDCl3) δ 3.60 (app q, J = 6.5 Hz, 1H), 2.20 (td, J = 6.8, 2.5 Hz, 2H), 2.13 (d, J = 6.5 Hz, 1H), 1.94 (t, J = 2.5 Hz, 1H), 1.79-1.77 (m, 2H), 1.64-1.56 (m, 4H), 0.93 (s, 9H), 0.09 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 107.4, 86.0, 84.1, 68.5, 38.9, 29.4, 27.9, 26.1, 26.05, 18.3, 16.6, -4.7; LRMS (ESI) m/z (relative intensity) 267.2 (30%, M + H+).

1-(3-Bromo-prop-1-ynyl)-2-methoxybenzene (14a)

To a stirring solution of 2-iodoanisole (13.9 mL, 107 mmol) in 350 mL of THF was sequentially added propargyl alcohol (21.6 mL, 371 mmol), Pd(PPh3)2Cl2 (1.09 g, 1.40 mmol), Et3N (40.5 mL, 291 mmol), and CuI (1.08 g, 5.67 mmol). After 14 h, the reaction mixture was poured into H2O (400 mL). The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 250 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a light yellow oil. Purification of this oil by SiO2 flash column chromatography (50% EtOAc/hexanes as eluent) gave 3-(2-methoxy-phenyl)-prop-2-yn-1-ol (17.3 g, 100%) as a light yellow solid. Spectral data matched those reported by Franks.16

A stirring solution of PPh3 (28.1 g, 107 mmol) in 350 mL of CH2Cl2 was cooled to 0 °C and Br2 (5.47 mL, 107 mmol) was added dropwise to the reaction mixture. A solution of 3-(2-methoxyphenyl)-prop-2-yn-1-ol (17.3 g, 107 mmol) in 100 mL of CH2Cl2 was added dropwise to the reaction mixture and solution was stirred for an additional 4 h at 0 °C. The reaction mixture was warmed to room temperature and concentrated in vacuo to give a light yellow oil. Purification of the oil by SiO2 flash column chromatography (10% benzene/hexanes) gave bromide 14a (18.9 g, 79%) as a colorless oil whose spectral data matched those reported by Dai.9

2-(3-Bromo-prop-1-ynyl)-1,3-dimethoxybenzene (14b)

To a stirring solution of 1-iodo-2,6-dimethoxybenzene (15.0 g, 56.8 mmol) in 120 mL of pyrrolidine was added propargyl alcohol (3.31 mL, 114 mmol) and Pd(PPh3)4 (3.33 g, 2.84 mmol). The reaction mixture was heated at 45 °C for 3 d and then saturated aqueous NH4Cl (120 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 12:7:1 Et2O/hexanes/CH2Cl2 → 8:1:1 Et2O/hexanes/CH2Cl2) afforded 3-(2,6-dimethoxy-phenyl)-prop-2-yn-1-ol (9.39 g, 86%) as a white solid. mp 92-94 °C; IR (thin film) 3378, 2214 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.20 (t, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 2H), 4.56 (d, J = 5.1 Hz, 2H), 3.84 (s, 6H), 2.26 (t, J = 5.4 Hz, 1H); 13C NMR (90 MHz, CDCl3) δ 161.4, 129.8, 103.3, 100.6, 96.0, 77.6, 55.9, 51.8; LRMS (ESI) m/z (relative intensity) 193.2 (100%, M + H+); HRMS (ESI) m/z calcd for [C11H13O3]+, 193.0865, found 193.0867.

To a stirring solution of PPh3 (12.8 g, 48.9 mmol) in 125 mL of CH2Cl2 at 0 °C was added Br2 (2.51 mL, 48.9 mmol). The reaction mixture was held at this temperature for 30 min and then a solution of 3-(2,6-dimethoxy-phenyl)-prop-2-yn-1-ol (9.39 g, 48.9 mmol) in 75 mL CH2Cl2 was added to the reaction solution. After an additional 2 h at 0 °C the reaction mixture was concentrated in vacuo to give an off-white solid. Purification of this solid by SiO2 flash column chromatography (gradient, 17:2:1 hexanes/Et2O/CH2Cl2 → 3:6:1 hexanes/Et2O/CH2Cl2) afforded bromide 14b (2.77 g, 23%) as an off-white solid. A yield of 31% was obtained on a 75 mg scale. mp 90-92 °C; IR (thin film) 2205 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.17 (app t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 3.78 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 161.5, 130.2, 103.1, 99.9, 92.1, 79.4, 55.7, 16.2; LRMS (ESI) m/z (relative intensity) 255.1 (100%, M + H+).

2-(3-Bromo-prop-1-ynyl)-1,4-dimethoxybenzene (14c)

To a stirring solution of 1-bromo-2,5-dimethoxybenzene (17.0 g, 78.1 mmol) in 250 mL of pyrrolidine was added propargyl alcohol (9.17 mL, 156 mmol) and Pd(PPh3)4 (4.76 g, 3.91 mmol). The reaction mixture was heated at reflux for 14 h, cooled to room temperature, and then saturated aqueous NH4Cl (120 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 20% EtOAc/hexanes → 30% EtOAc/hexanes) afforded 3-(2,5-dimethoxyphenyl)-prop-2-yn-1-ol (6.70 g, 45%) as an orange solid. Spectral data matched those reported by Franks.16

To a stirring solution of PPh3 (8.29 g, 31.6 mmol) in 80 mL of CH2Cl2 at 0 °C was added Br2 (1.63 mL, 31.7 mmol). After 30 min, a solution of 3-(2,5-dimethoxyphenyl)-prop-2-yn-1-ol (6.06 g, 31.5 mmol) in 40 mL CH2Cl2 was added to the reaction mixture. After an additional 5 h, the reaction solution was concentrated in vacuo to give an off-white solid. Purification of this solid by SiO2 flash column chromatography (10% EtOAc/hexanes as eluent) afforded bromide 14c (7.47 g, 93%) as an off-white solid. mp 47-48 °C; IR (thin film) 2205 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.91 (d, J = 2.9 Hz, 1H), 6.84-6.73 (m, 2H), 4.18 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 154.6, 152.9, 118.2, 116.2, 111.8, 111.5, 88.0, 83.0, 56.2, 55.6, 15.6; LRMS (ESI) m/z (relative intensity) 255.1 (80%, M + H+).

2-(3-Bromoprop-1-ynyl)-1,4-bis-methoxymethoxybenzene (14d)

To a stirring suspension of 60% NaH (2.8 g, 53 mmol) in 100 mL of DMF at 0 °C was added a solution of bromohydroquinone (5.00 g, 26.5 mmol) in 50 mL DMF. After 10 min, chloromethyl methyl ether (4.4 mL, 53 mmol) was added and the mixture was warmed to room temperature and stirred for an additional 14 h. To the reaction mixture was added H2O (300 mL). The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic fractions were washed with H2O (3 × 300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-bromo-1,4-bis-methoxymethoxy-benzene (16d) (7.34 g, 100%) as a colorless oil. IR (thin film) 1484 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.30 (d, J = 2.9 Hz, 1H), 7.09 (dd, J = 9.0, 0.8 Hz, 1H), 6.95 (ddd, J = 9.0, 2.9, 0.8 Hz, 1H), 5.18 (d, J = 1.0 Hz, 2H), 5.11 (d, J = 1.0 Hz, 2H), 3.53 (d, J = 1.0 Hz, 3H), 3.48 (d, J = 1.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 152.4, 148.8, 121.3, 117.4, 116.3, 113.2, 95.7, 94.9, 56.2, 55.8.

To a stirring suspension of NaH (0.174 g, 7.25 mmol) in 150 mL of THF was added a solution of 2-bromo-1,4-bis-methoxymethoxybenzene (16d) (7.07 g, 25.5 mmol) in 20 mL of THF. After 30 min, the reaction mixture was cooled to -84 °C and n-BuLi (2.5 M in hexanes, 12.3 mL, 30.6 mmol) was added dropwise via syringe. The reaction solution was held at this temperature for 10 min after which a solution of I2 (13.0 g, 51.0 mmol) in 45 mL was added. The reaction mixture was allowed to warm to room temperature and aqueous Na2S2O3 was added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 60 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give 2-iodo-1,4-bis-methoxymethoxybenzene (8.01 g, 97%) as a light brown oil. IR (thin film) 1478 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.08-6.92 (m, 2H), 5.14 (s, 2H), 5.07 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 152.6, 151.3, 127.2, 117.3, 115.8, 95.6, 95.0, 87.3, 56.3, 55.9. LRMS (ESI) m/z (relative intensity) 294.1 (10%, M + NH4+).

To a stirring solution of 2-iodo-1,4-bis-methoxymethoxybenzene (3.27 g, 10.1 mmol) in 100 mL of pyrrolidine was added propargyl alcohol (1.20 mL, 19.7 mmol) and Pd(PPh3)4 (0.563 g, 0.505 mmol). The reaction mixture was heated at reflux for 16 h, and then allowed to cool to room temperature. Saturated aqueous NH4Cl (100 mL) was added. The resulting solution was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (60% Et2O/hexanes as eluent) afforded 3-(2,5-bis-methoxymethoxy-phenyl)-prop-2-yn-1-ol (1.22 g, 48%) as a light brown oil. A yield of 66% was obtained on a 23 mg scale. IR (thin film) 3425 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.05-7.04 (m, 1H), 6.98 (dd, J = 9.0, 2.2 Hz, 1H), 6.91-6.88 (m, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 4.45 (d, J = 1.8 Hz, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 1.16 (t, J = 1.8 Hz, 1H); 13C NMR (90 MHz, CDCl3) δ 152.8, 151.6, 121.0, 118.2, 116.8, 114.0, 95.6, 94.9, 91.7, 81.3, 56.1, 55.8, 51.4; LRMS (ESI) m/z (relative intensity) 253.2 (100%, M + H+).

To a stirring solution of 3-(2,5-bis-methoxymethoxyphenyl)prop-2-yn-1-ol (1.22 g, 4.83 mmol) and Et3N (2.0 mL, 14 mmol) in 20 mL of Et2O at 0 °C was added MsCl (416 μL, 5.40 mmol). After 1 h, saturated aqueous NaHCO3 (30 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (25 mL) followed by EtOAc (25 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give the mesylate. To the crude mesylate was added 20 mL of CHCl3 and NBu4Br (2.46 g, 7.63 mmol). The resulting solution was refluxed 30 min and concentrated in vacuo. EtOAc (20 mL) was added to the crude mixture, washed with H2O (20 mL) followed by brine (20 mL). The organic fraction was dried with Na2SO4 and concentrated in vacuo to give bromide 14d (1.48 g, 97%) as a tacky orange solid. This material was used without further purification. IR (thin film) 2226 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.06 (d, J = 2.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.92 (dd, J = 9.0, 2.9 Hz, 1H), 5.13 (s, 2H), 5.05 (s, 2H), 4.15 (s, 2H), 3.47 (s, 3H), 3.41 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 153.0, 151.6, 120.9, 118.7, 116.9, 113.5, 95.6, 94.8, 87.9, 82.8, 56.1, 55.7, 15.3; LRMS (ESI) m/z (relative intensity) 315.0 (90%, M + H+).

1-Methoxy-2-[3-(nona-1,8-diyne-3-sulfonyl)prop-1-ynyl]benzene (15a)

To a stirring suspension of K2CO3 (0.254 g, 1.84 mmol) in 7 ml of MeCN was added a solution of thiol 13a (0.432 g, 2.83 mmol) in 3 mL of MeCN. The reaction mixture was stirred for 10 min and then bromide 14a (404 μL, 2.83 mmol) was added. The reaction mixture was heated at 60 °C for 14 h, cooled to room temperature, and then 1M phosphoric acid (10 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the sulfide as a yellow oil, which was carried on without further purification. IR (thin film) 3284, 2214 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36 (dd, J = 7.5, 1.7 Hz, 1H), 7.26 (td, J = 7.9, 1.7 Hz, 1H), 6.87 (td, J = 7.5, 1.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.92-3.86 (m, 1H), 3.85 (s, 3H), 3.81 (d, J = 16.8 Hz, 1H), 3.62 (d, J = 16.8 Hz, 1H), 2.39 (d, J = 2.4 Hz, 1H), 2.19 (td, J = 6.9, 2.6 Hz, 2H), 1.92 (t, J = 2.6 Hz, 1H), 1.82 (t, J = 7.0 Hz, 2H), 1.69-1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 159.9, 133.3, 129.6, 120.2, 111.9, 110.4, 89.3, 83.9, 82.8, 79.5, 72.1, 68.4, 55.5, 34.0, 33.7, 27.7, 26.2, 20.1, 18.1; LRMS (ESI) m/z (relative intensity) 297.1 (60%, M + H+).

A stirring suspension of crude sulfide from above and Na2CO3 (1.07 g, 10.1 mmol) in 65 ml of CH2Cl2 was treated with 70% mCPBA (0.917 g, 5.04 mmol). The reaction mixture was heated at reflux for 12 h, cooled to room temperature, and then saturated aqueous NaHCO3 (70 mL) was added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic fractions were sequentially washed with 1M H3PO4 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude yellow oil. Purification of this oil by SiO2 flash column chromatography (5% Et2O/hexanes, then CH2Cl2 as eluent) gave sulfone 15a (0.343 g, 37% over 2 steps) as a light yellow oil. IR (thin film) 3272, 2359 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 7.5 Hz, 1H), 7.31 (tdd, J = 8.0, 1.7, 1.0 Hz, 1H), 6.88 (tt, J = 7.5, 1.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.55 (dd, J = 17.0, 1.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.13 (d, J = 17.0 Hz, 1H), 3.84 (s, 3H), 2.60 (d, J = 2.5 Hz, 1H), 2.20 (td, J = 6.1, 2.0 Hz, 2H), 2.13-2.07 (m, 1H), 2.01-1.92 (m, 1H), 1.93 (t, J = 2.6 Hz, 1H), 1.85-1.79 (m, 1H), 1.60-1.53 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 160.6, 133.5, 130.6 (2), 120.4, 110.6, 84.5, 83.7, 79.9, 75.8, 68.7 (2), 55.7, 44.3, 44.2, 27.7, 25.8, 25.7, 18.1; LRMS (ESI) m/z (relative intensity) 346.2 (50%, M + NH4+). HRMS (ESI) m/z calcd for [C19H24NO3S]+, 346.1477, found 346.1474.

tert-Butyl-{3-[3-(2-methoxyphenyl)-prop-2-yne-1-sulfonyl]nona-1,8-diynyl}dimethylsilane (15b)

To a stirring solution of solid LHMDS (3.39 g, 20.3 mmol) in 120 mL of THF at 0 °C was added a solution of thiol 13b (5.14 g, 19.3 mmol) in 120 mL of THF. The reaction mixture was stirred for 5 min at 0 °C and treated with bromide 14a (2.9 mL, 19 mmol). After 14 h, the reaction mixture was warmed to room temperature and H2O (120 mL) was added. The resulting mixture was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 200 mL). The combined organic fractions were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl-{3-[3-(2-methoxyphenyl)prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane as a yellow oil that was used without further purification. IR (thin film) 3295, 2150 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.38 (dd, J = 7.2, 1.6 Hz, 1H), 7.26 (td, J = 7.9, 1.8 Hz, 1H), 6.90-6.83 (m, 2H), 3.91 (t, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.80 (d, J = 16.9 Hz, 1H), 3.65 (d, J = 16.6 Hz, 1H), 2.19 (td, J = 6.5, 2.5 Hz, 2H), 1.93 (t, J = 2.5 Hz, 1H), 1.83 (q, J = 7.0 Hz, 2H), 1.75-1.66 (m, 2H), 1.58 (q, J = 7.2 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 160.0, 133.5, 129.4, 120.2, 112.1, 110.4, 105.1, 89.1, 86.9, 84.0, 79.4, 68.3, 56.0, 35.1, 34.0, 27.8, 26.1, 26.0, 20.2, 18.2, 16.4, -4.6; LRMS (ESI) m/z (relative intensity) 433.0 (100%, M + Na+). HRMS (ESI) m/z calcd for M + NH4+, [C25H38NOSSi]+, 428.2443, found 428.2427. To a stirring solution of tert-butyl-{3-[3-(2-methoxyphenyl)-prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane (7.15 g, 17.3 mmol) in 500 mL of CH2Cl2 was added 70-75% mCPBA (8.57 g, 34.6 mmol). The reaction mixture was stirred for 1.5 h and then treated with Et3N (5.2 mL, 37 mmol) followed by H2O (500 mL). The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 400 mL). The organic fractions were washed with brine (800 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (8:1:1 hexanes/Et2O/CH2Cl2 as eluent) afforded linear sulfone 15b (3.74 g, 44% over 2 steps) as a yellow oil. IR (thin film) 3284, 2355, 1326, 1126 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.33 (td, J = 3.9, 1.7 Hz, 1H), 6.93-6.85 (m, 2H), 4.55 (d, J = 16.9 Hz, 1H), 4.42 (dd, J = 10.5, 4.3 Hz, 1H), 4.13 (d, J = 16.9 Hz, 1H), 3.85 (s, 3H), 2.22 (td, J = 6.7, 2.6 Hz, 2H), 2.17-2.00 (m, 1H), 1.93 (t, J = 2.5 Hz, 1H), 1.88-1.75 (m, 1H), 1.74-1.58 (m, 4H), 0.94 (s, 9H), 0.13 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.6, 133.5, 130.5, 120.3, 110.8, 110.6, 97.4, 93.0, 84.3, 83.7, 79.9, 68.6, 55.7, 54.7, 44.1, 27.7, 26.0, 25.9, 25.8, 18.1, 16.6, -5.0; LRMS (ESI) m/z (relative intensity) 460.3 (90%, M + NH4+). HRMS (ESI) m/z calcd for M + NH4+, [C25H38NO3SSi]+, 460.2342, found 460.2342.

tert-Butyl-{3-[3-(2,6-dimethoxyphenyl)prop-2-yne-1-sulfonyl]nona-1,8-diynyl}dimethylsilane (15c)

To a stirring solution of NaH (75 mg, 1.9 mmol) in 14 mL of THF at 0 °C was added a solution of thiol 13b (0.50 g, 1.9 mmol) in 3 mL of THF. The reaction mixture was held at this temperature for 15 min and then bromide 14b (0.479 g, 1.88 mmol) in 3 mL of CH2Cl2 was added to the reaction solution. After an additional 30 min at 0 °C, H2O (10 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (5% Et2O/hexanes) afforded tert-butyl-{3-[3-(2,6-dimethoxyphenyl)prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane (0.657 g, 80%) as a yellow oil. IR (thin film) 3295, 2155 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.17 (app t, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 2H), 4.01 (t, J = 6.9 Hz, 1H), 3.85-3.79 (m, 1H), 3.83 (s, 6H), 3.66 (d, J = 16.8 Hz, 1H), 2.16 (td, J = 6.9, 2.6 Hz, 2H), 1.89 (t, J = 2.6 Hz, 1H), 1.82-1.77 (m, 2H), 1.73-1.52 (m, 4H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 161.5, 129.4, 105.4, 103.3, 101.3, 93.5, 86.6, 84.1, 75.7, 68.3, 55.9, 34.9, 33.9, 27.9, 26.4, 26.0, 20.6, 18.2, 16.5, -4.6; LRMS (ESI) m/z (relative intensity) 441.1 (100%, M + H+).

To a stirring solution of tert-butyl-{3-[3-(2,6-dimethoxyphenyl)prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane (0.108 g, 0.243 mmol) in 10 mL of CH2Cl2 at room temperature was added 70-75% mCPBA (0.123 g, 0.498 mmol). The reaction mixture was stirred for 3 h and then saturated aqueous NaHCO3 (10 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 18:1:1 hexanes/Et2O/CH2Cl2 → 4:5:1 hexanes/Et2O/CH2Cl2) afforded sulfone 15c (98 mg, 85%) as a yellow oil. IR (thin film) 3284, 1326, 1114 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.29 (app t, J = 8.4 Hz, 1H), 6.56 (d, J = 8.5 Hz, 2H), 4.61 (dd, J = 10.5, 4.1 Hz, 1H), 4.57 (d, J = 17.0 Hz, 1H), 4.15 (d, J = 16.9 Hz, 1H), 3.86 (s, 6H), 2.24 (td, J = 6.7, 2.6 Hz, 2H), 2.08-2.05 (m, 1H), 1.98 (t, J = 2.6 Hz, 1H), 1.95-1.82 (m, 1H), 1.75-1.60 (m, 4H), 0.97 (s, 9H), 0.16 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 162.6, 131.3, 104.0, 98.3, 97.6, 93.2, 84.9, 84.4, 81.4, 69.0, 56.6, 54.8, 45.1, 28.4. 26.6, 26.5, 26.3, 18.6, 17.1, -4.6; LRMS (ESI) m/z (relative intensity) 490.2 (100%, M + NH4+); HRMS (ESI) m/z calcd for M + NH4+, [C26H40NO4SiS]+, 490.2447, found 490.2453.

tert-Butyl-{3-[3-(2,5-dimethoxyphenyl)-prop-2-yne-1-sulfonyl]nona-1,8-diynyl}dimethylsilane (15d)

To a stirring solution of NaH (0.118 g, 2.96 mmol) in 30 mL of THF at 0 °C was added a solution of thiol 13b (0.789 g, 2.96 mmol) in 10 mL of THF. After 15 min, a solution of bromide 14c (0.755 g, 2.96 mmol) in 5 mL of CH2Cl2 was added to the reaction solution. After an additional 30 min at 0 °C, H2O (50 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl-{3-[3-(2,5-dimethoxyphenyl)-prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane as a yellow oil. This material was used without further purification. IR (thin film) 3284 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.90 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.77 (s, 1H), 3.87 (t, J = 8.3 Hz, 1H), 3.80 (s, 3H), 3.78 (d, J = 19.3 Hz, 1H), 3.72 (s, 3H), 3.62 (d, J = 16.7 Hz, 1H), 2.17 (td, J = 6.9, 2.6 Hz, 2H), 1.90 (t, J = 2.6 Hz, 1H), 1.81-1.77 (m, 2H), 1.70-1.66 (m, 2H), 1.64-1.53 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 154.6, 153.1, 118.3, 115.4, 112.7, 111.9, 105.0, 89.3, 87.1, 84.1, 79.4, 68.4, 56.3, 55.7, 35.3, 34.1, 27.9, 26.4, 26.1, 20.2, 18.2, 16.5, -4.6; LRMS (ESI) m/z (relative intensity) 441.3 (100%, M + H+).

To a stirring solution of the crude tert-butyl-{3-[3-(2,5-dimethoxyphenyl)-prop-2-ynylsulfanyl]nona-1,8-diynyl}dimethylsilane in 45 mL of CH2Cl2 at room temperature was added 70-75% mCPBA (1.61 g, 5.92 mmol). The reaction mixture was stirred for 1 h and then Et3N (883 μL, 6.34 mmol) followed by saturated aqueous NaHCO3 (50 mL) were added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. Purification of this oil by SiO2 flash column chromatography (10% EtOAc/hexanes as eluent) afforded linear sulfone 15d (0.657 g, 47% over 2 steps) as an orange oil. IR (thin film) 3284, 1326, 1126 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.90 (d, J = 2.9 Hz, 1H), 6.85 (d, J = 3.2 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4.51 (d, J = 16.6 Hz, 1H), 4.39 (dd, J = 10.4, 4.3 Hz, 1H), 4.10 (d, J = 16.9 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 2.19 (td, J = 6.7, 2.7 Hz, 2H), 2.13-2.03 (m, 1H), 1.90 (t, J = 2.5 Hz, 1H), 1.86-1.72 (m, 1H), 1.64-1.50 (m, 4H), 0.92 s, 9H), 0.11 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 155.1, 153.0, 118.1, 116.4, 111.9, 111.2, 97.4, 92.9, 84.1, 83.6, 79.9, 68.6, 56.2, 55.7, 54.8, 44.0, 27.6, 25.9 (2), 25.8, 18.0, 16.5, -5.1; LRMS (ESI) m/z (relative intensity) 490.2 (100%, M + NH4+); HRMS (ESI) m/z calcd for M + NH4+, [C26H40NO4SiS]+, 490.2447, found 490.2438.

{3-[3-(2,5-Bis-methoxymethoxyphenyl)-prop-2-yne-1-sulfonyl]nona-1,8-diynyl}tert-butyldimethylsil ane (15e)

To a stirring solution of LHMDS (0.742 g, 4.19 mmol) in 30 mL of THF at 0 °C was added a solution of thiol 13b (1.12 g, 4.19 mmol) in 15 mL of THF. After 15 min, a solution of bromide 14d (1.32 g, 4.19 mmol) in 10 mL of THF was added to the reaction solution and after an additional 14 h at 0 °C, H2O (60 mL) was added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 60 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (95:4:1 hexanes/Et2O/CH2Cl2 as eluent) afforded {3-[3-(2,5-bis-methoxymethoxyphenyl)-prop-2-ynylsulfanyl]nona-1,8-diynyl}tert-butyldimethylsilane (1.33 g, 63%) as a yellow oil. A yield of 68% was obtained on a 0.389 g scale. IR (thin film) 3295, 2155 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.05 (d, J = 2.9 Hz, 1H), 6.99 (d, J = 9.0, 1H), 6.91 (dd, J = 9.0, 2.9 Hz, 1H), 5.14 (s, 2H), 5.07 (s, 2H), 3.87 (t, J = 7.0 Hz, 1H), 3.76 (d, J = 16.9 Hz, 1H), 3.60 (d, J = 16.6 Hz, 1H), 3.49 (s, 3H), 3.44 (s, 3H), 2.18 (td, J = 6.8, 2.5 Hz, 2H), 1.91 (t, J = 2.7 Hz, 1H), 1.82-1.76 (m, 2H), 1.70-1.60 (m, 2H), 1.60-1.53 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 153.0, 151.8, 121.0, 117.9, 117.1, 114.7, 105.0, 95.7, 95.0, 89.2, 87.1, 84.1, 79.2, 68.4, 56.2, 55.9, 35.2, 34.0, 27.9, 26.4, 26.1, 20.2, 18.2, 16.5, -4.6; LRMS (ESI) m/z (relative intensity) 518.3 (100%, M + NH4+).

To a stirring solution of {3-[3-(2,5-bismethoxymethoxyphenyl)-prop-2-ynylsulfanyl]nona-1,8-diynyl}tert-butyldimethylsilane (0.830 g, 1.66 mmol) in 50 mL of CH2Cl2 was added mCPBA (0.857 g, 3.49 mmol). After 90 min, additional mCPBA (82 mg, 0.33 mmol) was added to the reaction mixture. After 30 min, saturated aqueous NaHCO3 (50 mL) was added. The resulting solution was partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic fractions were washed with 1M phosphoric acid (50 mL). The aqueous fraction was back-extracted with CH2Cl2 (50 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 5% Et2O/hexanes → 15% Et2O/hexanes as eluent) afforded linear sulfone 15d (0.528 g, 60%). IR (thin film) 3284, 1331, 1149 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.03 (d, J = 2.5 Hz, 1H), 6.98-6.90 (m, 2H), 5.10 (s, 2H), 5.02 (s, 2H), 4.48 (d, J = 16.9 Hz, 1H), 4.35 (dd, J = 10.4, 4.1 Hz, 1H), 4.10 (d, J = 16.9 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 2.16-2.13 (m, 2H), 2.09-1.92 (m, 2H), 1.90 (t, J = 2.5 Hz, 1H), 1.82-1.69 (m, 1H), 1.62-1.47 (m, 3H), 0.86 (s, 9H), 0.07 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 153.2, 151.4, 120.6, 118.7, 116.5, 112.8, 97.3, 95.2, 94.6, 92.8, 83.7, 83.5, 79.9, 68.7, 55.9, 55.6, 54.7, 43.7, 27.5, 25.7 × 2, 25.6, 17.8, 16.3, -5.2; LRMS (ESI) m/z (relative intensity) 550.0 (100%, M + NH4+).

1-Hex-5-ynyl-5-methoxy-1,3-dihydro-naphtho[2,3-c]thiophene 2,2-Dioxide (17)

A stirring solution of sulfone 15a (209 mg, 0.635 mmol) in 20 mL of CHCl3 was treated with Et3N (136 μL, 0.953 mmol). The reaction mixture was stirred for 3 d and concentrated in vacuo to give tricycle 17 (209 mg, 100%) as a yellow solid. mp 141-143 °C; IR (thin film) 3284, 1308, 1126 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.68 (s, 1H), 7.44-7.39 (m, 2H), 6.84 (d, J = 6.8 Hz, 1H), 4.43 (s, 2H), 4.29 (t, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.27 (td, J = 7.0, 2.1 Hz, 2H), 2.25-2.04 (m, 2H), 1.98 (t, J = 2.2 Hz, 1H), 1.88-1.76 (m, 2H), 1.75-1.60 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.1, 134.3, 134.0, 127.05, 127.02, 125.1, 124.1, 120.0, 119.8, 104.6, 83.9, 68.7, 64.9, 55.6, 55.2, 29.0, 28.2, 25.6, 18.1; LRMS (ESI) m/z (relative intensity) 346.1 (100%, M + NH4+).

tert-Butyl-(3-hex-5-ynyl-8-methoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophen-4-yl)dime thylsilane (19)

To a refluxing solution of linear sulfone 15b (0.125 g, 0.282 mmol) in 10 mL of toluene was added Et3N (59 μL, 0.42 mmol). The reaction mixture was held at reflux for 14 h and then cooled to room temperature and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient 10% Et2O/hexanes → 20% Et2O/hexanes as eluent) afforded tricycle 19 (80 mg, 64%) as a yellow oil. IR (thin film) 3300, 1290, 1120 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.10 (app t, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 4.01-3.82 (m, 3H), 3.82 (s, 3H), 2.58-2.50 (m, 1H), 2.45-2.36 (m, 1H), 2.21 (td, J = 7.0, 2.7 Hz, 2H), 1.93 (t, J = 2.7 Hz, 1H), 1.86-1.79 (m, 2H), 1.62-1.58 (m, 2H), 0.91 (s, 9H), 0.00 (s, 3H), -0.35 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 155.4, 146.6, 137.9, 131.8, 128.5, 125.8, 120.2, 120.1, 119.6, 107.8, 84.0, 68.6, 55.5, 53.3, 34.6, 28.1, 27.3, 26.8, 23.5, 18.4, 18.0, -4.5, -6.2; LRMS (ESI) m/z (relative intensity) 443.3 (100%, M + H+). HRMS (ESI) m/z calcd for [C25H38NO3SSi]+, 460.2342, found 460.2350.

Conversion of Dimethoxy Sulfone 15c to Tricycle 19

To a refluxing solution of linear sulfone 15c (66 mg, 0.14 mmol) in 5 mL of toluene was added Et3N (29 μL, 0.21 mmol). The reaction mixture was heated at reflux for 14 h, cooled to room temperature and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 5% Et2O/hexanes → 30% Et2O/hexanes as eluent) afforded tricycle 19 (17 mg, 28%) as a yellow oil.

tert-Butyl-(3-hex-5-ynyl-5,8-dimethoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophen-4-yl)d imethylsilane (21)

To a solution of sulfone 15d (0.206 g, 0.434 mmol) in 10 mL of toluene at 110 °C was added Et3N (90 μL, 0.65 mmol). The reaction mixture was held at reflux for 14 h, cooled to room temperature and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (10% Et2O/hexanes as eluent) afforded tert-butyl-(3-hex-5-ynyl-5,8-dimethoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophen-4-yl)dime thylsilane (21) (95 mg, 46%) as a tacky yellow solid. IR (thin film) 3284, 1284, 1114 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.93 (s, 1H), 6.64 (d, J = 9.0 Hz, 1H), 6.57 (d, J = 9.0 Hz, 1H), 4.25 (s, 1H), 3.95 (d, J = 15.1 Hz, 1H), 3.86 (d, J = 15.5 Hz, 1H), 3.74 (s, 6H), 2.53-2.44 (m, 2H), 2.16 (td, J = 5.6, 2.2 Hz, 2H), 1.91-1.87 (m, 1H), 1.86-1.73 (m, 2H), 1.59-1.53 (m, 2H), 0.84 (s, 9H), -0.04 (s, 3H), -0.38 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 149.7, 148.5, 147.1, 132.1, 126.6, 125.7, 120.9, 120.0, 109.9, 107.5, 83.9, 68.5, 55.8, 54.8, 53.3, 28.0, 27.8, 27.0, 26.7, 23.7, 18.3, 17.9, -4.3, -5.7; LRMS (ESI) m/z (relative intensity) 473.2 (100%, M + H+).

tert-Butyl-(3-hex-5-ynyl-5,8-bis-methoxymethoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiop hen-4-yl)dimethylsilane (22)

A solution of sulfone 15e (0.528 g, 0.991 mmol) in 10 mL of benzene was heated to reflux and then treated with Et3N (242 μL, 1.49 mmol). The reaction mixture was held at this temperature for 3 d, cooled to room temperature, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 10% Et2O/hexanes → 40% Et2O/hexanes as eluent) afforded tricycle 22 (0.237 g, 45 %) as yellow oil. IR (thin film) 3284, 1284, 1114 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.92 (s, 1H), 6.89 (d, J = 9.4 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 5.16-5.02 (m, 4H), 4.23 (s, 1H), 3.95 (d, J = 15.1 Hz, 1H), 3.86 (d, J = 15.1 Hz, 1H), 3.42 (s, 3H), 3.39 (s, 3H), 2.53-2.40 (m, 2H), 2.12 (td, J = 5.6, 2.2 Hz, 2H), 1.87 (s, 1H), 1.80-1.74 (m, 2H), 1.56-1.50 (m, 2H), 0.83 (s, 9H), -0.05 (s, 3H), -0.34 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 148.0, 147.3, 146.6, 132.3, 126.3, 121.7, 119.9, 119.8, 114.6, 111.9, 95.1, 95.0, 83.7, 68.4, 56.1, 55.8, 53.2, 27.8, 26.89, 26.87, 26.6, 23.5, 18.1, 17.7, -4.5, -5.7; LRMS (ESI) m/z (relative intensity) 533.3 (100%, M + H+).

1-Hex-5-ynyl-2,2-dioxo-2,3-dihydro-1H-2λ6-naphtho[2,3-c]thiophene-5,8-dione (23)

A stirring solution of sulfone 17 (0.209 g, 0.635 mmol) in 15 ml of acetone was treated with Jones reagent (695 μL, 2.54 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 14 h after which time additional Jones reagent (695 μL, 2.54 mmol) was added. The reaction mixture was stirred for 1 h at room temperature and then isopropanol (15 mL) and H2O (15 mL) were added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this yellow oil by SiO2 flash column chromatography (15:4:1 hexanes/Et2O/CH2Cl2, then 13:5:2 hexanes/Et2O/CH2Cl2 as eluent) gave quinone 23 (126 mg, 60%) as a yellow oil. IR (thin film) 3272, 1666, 1314, 1132 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.02 (app d, J = 5.1 Hz, 2H), 7.01 (s, 2H), 7.68 (s, 1H), 4.41 (app s, 2H), 4.29 (dd, J = 8.4, 6.0 Hz, 1H), 2.25 (td, J = 6.8, 2.6 Hz, 2H), 2.19-2.11 (m, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.84-1.76 (m, 2H), 1.67 (q, J = 4.4 Hz, 2H); 13C NMR (90 MHz, CDCl3) δ 183.9, 183.8, 142.4, 138.7 (2), 136.6, 132.0, 131.8, 124.2, 123.5, 83.6, 69.0, 65.3, 55.3, 28.7, 28.0, 25.6, 18.1; LRMS (ESI) m/z (relative intensity) 351.2 (100%, M + Na+).

tert-Butyl-(3-hex-5-ynyl-8-methoxy-2,2-dioxo-1-phenylsulfanyl-2,4-dihydro-1H-2λ6-naphtho[2,3-c]th iophen-4-yl)dimethylsilane (25a)

To a stirring solution of tricycle 19 (0.24 g, 0.55 mmol) in 7 mL of THF at -78 °C was added n-BuLi (2.5M in hexanes, 220 μL, 0.55 mmol) dropwise. The reaction mixture was held at this temperature for 15 min and then diphenyl disulfide (1.2 g, 5.5 mmol) was added and the solution was warmed to 0 °C over 30 min. The mixture was held at this temperature for 4 h and then H2O (10 mL) was added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (95:5:2 hexanes/Et2O/CH2Cl2 as eluent) afforded thiophenyl adduct 25a (0.197 g, 65%) as a yellow oil. IR (thin film) 3284, 1297, 1108 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.65 (dd, J = 9.4, 1.8 Hz, 2H), 7.37-7.29 (m, 3H), 7.22 (s, 1H), 7.12 (dd, J = 7.9, 7.9 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.06 (d, J = 1.1 Hz, 1H), 3.92 (s, 1H), 3.83 (s, 3H), 2.58-2.50 (m, 1H), 2.43-2.37 (m, 1H), 2.21 (td, J = 7.0, 2.7 Hz, 2H), 1.92 (t, J = 2.7 Hz, 1H), 1.87-1.81 (m, 2H), 1.64-1.54 (m, 2H), 0.94 (s, 9H), 0.08 (s, 3H), -0.34 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 158.8, 145.3, 138.3, 133.0, 131.9, 130.4, 129.3, 129.2, 128.2, 127.5, 123.9, 120.3, 119.8, 107.9, 84.0, 68.7, 67.7, 56.3, 34.8, 28.2, 27.7, 26.8, 24.1, 18.5, 18.0, -4.0, -6.2; LRMS (ESI) m/z (relative intensity) 568.3 (100%, M + NH4+). HRMS (ESI) m/z calcd for M + NH4+, [C31H42NO3S2Si]+, 568.2375, found 568.2397.

(1-Benzenesulfinyl-3-hex-5-ynyl-8-methoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophen-4 -yl)-tert-butyldimethylsilane (25b)

To a stirring solution of phenyl sulfide 25a (0.173 g, 0.314 mmol) in 25 mL of CH2Cl2 was added 70-75% mCPBA (75 mg, 0.31 mmol). The reaction mixture was stirred for 2 h at room temperature and then saturated aqueous NaHCO3 (25 mL) was added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (17:3:1 hexanes/EtOAc/CH2Cl2 as eluent) afforded sulfoxide 25b (79 mg, 44%) as a yellow oil. A yield of 48% was obtained on a 427 mg scale. IR (thin film) 3295, 1291, 1149 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.94 (d, J = 4.0 Hz, 2H), 7.64-7.56 (m, 3H), 7.16 (app t, J = 7.9, 1H), 6.95 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.60 (s, 1H), 3.97 (s, 1H), 3.81 (s, 3H), 2.56-2.52 (m, 1H), 2.48-2.39 (m, 1H), 2.27-2.19 (m, 2H), 2.00-1.95 (m, 1H), 1.91-1.73 (m, 2H), 1.67-1.55 (m, 2H), 1.01 (s, 9H), 0.22 (s, 3H), -0.14 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 156.1, 146.9, 142.9, 138.3, 131.9, 130.3, 129.39, 129.38, 126.4, 125.4, 121.3, 120.1, 119.7, 107.5, 83.8, 80.7, 68.7, 56.2, 34.8, 28.0, 27.7, 26.6, 23.6, 18.4, 17.9, -6.7; LRMS (ESI) m/z (relative intensity) 567.3 (100%, M + H+).

(1-Benzenesulfonyl-3-hex-5-ynyl-8-methoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophen-4-yl)-tert-butyldimethylsilane (25c)

To a stirring solution of thiophene 25a (72 mg, 0.13 mmol) in 5 mL of CH2Cl2 at room temperature was added 70-75% mCPBA (86 mg, 0.34 mmol). The reaction mixture was stirred for 30 min at room temperature and saturated aqueous NaHCO3 (10 mL) was added. The resulting solution was partitioned between CH2Cl2 and H2O and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 5% Et2O/hexanes → 20% Et2O/hexanes as eluent) afforded sulfone 25c (45 mg, 59%) as a yellow oil. IR (thin film) 3284, 1303, 1108 cm-1; 1H NMR (360 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2H), 7.70-7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.45 (s, 1H), 7.14 (app t, J = 7.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 3.96 (s, 1H), 3.83 (s, 3H), 2.47-2.43 (m, 1H), 2.36-2.34 (m, 1H), 2.17 (td, J = 7.0, 2.5 Hz, 2H), 1.92 (t, J = 2.5 Hz, 1H), 1.82-1.64 (m, 2H), 1.63-1.53 (m, 2H), 0.93 (s, 9H), 0.07 (s, 3H), -0.18 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 156.2, 147.0, 138.3, 138.2, 134.6, 130.4, 130.0, 129.7, 129.0, 127.4, 120.1, 120.0, 119.9, 108.1, 83.8, 78.3, 68.7, 55.5, 35.5, 28.0, 27.8, 27.4, 26.6, 23.8, 18.6, 17.9, -5.5, -7.0; LRMS (ESI) m/z (relative intensity) 600.2 (100%, M + NH4+). HRMS (ESI) m/z calcd for [C31H42NO5S2Si]+, 600.2274, found 600.2277.

1-Hex-5-ynyl-5-methoxy-3-phenylsulfanyl-1,3-dihydro-naphtho[2,3-c]thiophene 2,2-Dioxide (26)

To a stirring solution of 25a (17 mg, 0.031 mmol) in 1 mL of THF at 0 °C was added Bu4NF (1.0 M in THF, 33 μL, 0.032 mmol). The reaction mixture was stirred for 20 min at 0 °C and then H2O (5 mL) were added. The resulting solution was partitioned between Et2O and H2O and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic fractions were washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated in vacuo to give a 1:1 mixture of diastereomers of thiophenyl adduct 26 (12 mg, 86%) as a yellow oil. IR (thin film) 3284, 1314, 1102 cm-1; 1H NMR (300 MHz, CDCl3, mixture of diastereomers) δ 8.52 (s, 1H), 8.46 (s, 1H), 7.76-7.59 (m, 6H), 7.44-7.30 (m, 10H), 6.85 (d, J = 7.3 Hz, 2H), 5.56 (s, 1H), 5.50 (s, 1H), 4.29 (t, J = 7.2 Hz, 1H), 4.17 (t, J = 7.1 Hz, 1H), 4.02 (s, 6H), 2.29-2.20 (m, 6H), 2.20-2.01 (m, 2H), 1.97-1.94 (m, 2H), 1.91-1.81 (m, 4H), 1.73-1.62 (m, 4H); 13C NMR (90 MHz, CDCl3, mixture of diastereomers) δ 155.4 (2), 134.52, 134.48, 133.9, 133.1, 132.9 (2), 132.5, 131.2, 129.3 (2), 129.2 (2), 128.95, 128.93, 128.65, 128.62, 127.7 (2), 125.30, 125.26, 124.01, 123.8, 121.7, 121.5, 119.86, 119.84, 83.96, 83.93, 71.7, 70.6, 68.7 (2), 63.9, 62.2, 55.6 (2), 29.7, 28.16, 28.13, 26.1, 25.8, 25.6, 18.1 (2); LRMS (ESI) m/z (relative intensity) 454.2 (100%, M + NH4+). HRMS (ESI) m/z calcd for M + NH4+, [C25H28NO3S2]+, 454.155, found 454.1510.

4-(tert-Butyl-dimethyl-silanyl)-3-hex-5-ynyl-8-methoxy-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c ]thiophen-1-ol (27)

To a stirring solution of sulfoxide 25b (0.213 g, 0.376 mmol) in 5 mL of toluene was added Et2NH (389 μL, 3.76 mmol). The reaction mixture was then heated at 65 °C for 36 h and then warmed to 110 °C for an additional 12 h. The reaction solution was cooled to room temperature and H2O (5 mL) was added. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Purification of this oil by SiO2 flash column chromatography (gradient, 5-15% Et2O/hexanes, then 30% EtOAc/hexanes as eluent) afforded a 3:1 mixture of diastereomers of alcohol 27 (49 mg, 28%) as a yellow oil. IR (thin film) 3389, 3295, 1269, 1120 cm-1; 1H NMR (400 MHz, CDCl3, major isomer) δ 7.24-7.07 (m, 2H), 6.65-6.60 (m, 2H), 5.35 (s, 1H), 3.93-3.78 (m, 1H), 3.78 (s, 3H), 2.60-2.44 (m, 1H), 2.44-2.30 (m, 1H), 2.26-2.10 (m, 2H), 1.89 (s, 1H), 1.86-1.69 (m, 2H), 1.69-1.48 (m, 2H), 0.86 (s, 9H), -0.05 (s, 3H), -0.37 (s, 3H), OH not observed; 13C NMR (90 MHz, CDCl3, major isomer) δ 155.9, 146.1, 138.5, 129.8, 129.1, 127.8, 121.0, 119.9, 119.6, 107.9, 84.4, 83.9, 68.6, 55.9, 34.8, 28.0, 27.2, 26.7, 23.7, 18.3, 17.9, -4.6, -6.2; LRMS (ESI) m/z (relative intensity) 476.3 (90%, M + NH4+).

4-(tert-Butyldimethylsilanyl)-3-hex-5-ynyl-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophene-5, 8-dione (28)

A stirring solution of MOM-protected hydroquinone 22 (47 mg, 0.088 mmol) in 1 mL of MeOH was treated with acetyl chloride (25.2 μL, 0.352 mmol). After 3 h, H2O (10 mL) was added to the reaction solution. The resulting solution was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(tert-butyldimethylsilanyl)-3-hex-5-ynyl-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophene-5,8-di ol as a colorless oil. This material was used without further purification.

To a stirring solution of this crude dihydroquinone in 1.5 mL of CH2Cl2 was added iodobenzene diacetate (31 mg, 0.097 mmol). After 15 min, the reaction mixture was concentrated in vacuo to give a pink oil. Purification of this oil by flash column chromatography (Florasil, 20% EtOAc/hexanes as eluent) afforded 4-(tert-butyldimethylsilanyl)-3-hex-5-ynyl-2,2-dioxo-2,4-dihydro-1H-2λ6-naphtho[2,3-c]thiophene-5,8-di one (28) (33 mg, 39% over 2 steps) as a pink oil. IR (thin film) 3284, 1643 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.78 (d, J = 10.1 Hz, 1H), 6.89 (d, J = 10.0 Hz, 1H), 6.71 (s, 1H), 4.22 (s, 1H), 3.97-3.96 (m, 2H), 2.55-2.44 (m, 2H), 2.22 (td, J = 6.9, 2.6 Hz, 2H), 1.98 (t, J = 2.6 Hz, 1H), 1.90-1.79 (m, 2H), 1.63-1.56 (m, 2H), 0.92 (s, 9H), 0.05 (s, 3H), -0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.8, 183.4, 143.9, 140.7, 136.7, 136.4, 135.6, 134.8, 132.1, 117.1, 83.7, 69.0, 52.9, 29.3, 28.0, 27.1, 26.5, 24.2, 18.0, 1.0, -4.0, -5.0; LRMS (ESI) m/z (relative intensity) 443.2 (100%, M + H+).

Scheme 2
Attempts to reproduce Braverman chemistry.
Scheme 4
Cyclization of bispropargyl sulfone 15a.
Scheme 9
Attempts to isomerize or oxidize 19 to furnish a thiophene dioxide intermediate.

Acknowledgments

Financial support from the National Institutes of Health, General Medical Sciences Division under the auspices of GM-37681 is gratefully acknowledged. The X-ray crystallography facility of the Huck Institutes for the Life Sciences is supported through CHE-0131112 from the National Science Foundation.

REFERENCES (AND NOTES)

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