The Palladium-Catalyzed Intramolecular Alder-Ene Reactions of O

Article pubs.acs.org/joc

The Palladium-Catalyzed Intramolecular Alder-Ene Reactions of O- and N‑Linked 1,6-Enynes Incorporating Triethylsilyl Capping Groups Jeremy Nugent, Eliška Matoušová, Martin G. Banwell,* and Anthony C. Willis Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia S Supporting Information *

ABSTRACT: A series of O- and N-linked 1,6-enynes (e.g., 11) have been prepared with each subjected to a palladiumcatalyzed intramolecular Alder-ene (IMAE) reaction, thus producing the isomeric and cyclic 1,4-diene (e.g., 12). These processes proceed most effectively when a triethylsilyl group is attached to the alkyne moiety and so generating alkenylsilanes that can be manipulated in various useful ways, including via iododesilylation (to give, for example, iodoalkene 62).

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INTRODUCTION The intramolecular Alder-ene (IMAE) reaction of 1,6-enynes provides a powerful method for C−C bond formation and has been exploited in various formats.1,2 Such processes were originally effected under thermal conditions, but the seminal report of Trost and Lautens3 that various of these can take place under milder conditions in the presence of palladium catalysts has significantly expanded their utility. We have exploited these catalyzed processes by engaging O- and N-linked 1,6-enynes in IMAE reactions2 so as to generate angularly substituted polyhydrobenzofurans or polyhydroindoles that have served as precursors to natural product targets such as the alkaloids hamayne,4 galanthamine,5 gracilamine,6 and 3-O-demethylmacronine.7,8 A key observation made during the course of such studies was that substrates incorporating terminal alkynes often undergo dimerization rather than IMAE reactions.9 In order to prevent these dimerization processes the alkyne was capped with a methyl residue. While efficient cyclization reactions thus took place, it was now rather difficult to selectively manipulate the olefinic residues in the product 1,4-diene.4,6−8 The studies detailed here were initially directed at identifying capping groups that not only facilitated the IMAE reactions but also delivered product dienes capable of selective manipulation. A survey of the other functionalities and substituents that could be accommodated during the course of such IMAE reactions was also undertaken, and the outcomes of all such studies are reported herein.

alkenyl silanes that are themselves capable of engaging in a range of electrophilic ipso-substitution reactions10 provided a further motivation for such pursuits. To these ends, 2cyclohexen-1-ol (1) (Scheme 1) was treated with propargyl bromide in the presence of tetra-n-butylammonium iodide and sodium hydride and thereby affording, in 88% yield, the Olinked 1,6-enyne 2. A THF solution of compound 2 was then treated with either n-butyllithium or lithium hexamethyldisilazide and the ensuing acetylide anion quenched with the relevant silyl chloride. By such means the capped alkynes 3a−e were obtained in 45−98% yield. When a benzene solution of compound 3a containing 10 mole % palladium acetate and the same amount of the classically effective ligand N,N′-bis(benzylidene)ethylenediamine (BBEDA)11 was placed in a sealed tube and subjected to microwave irradiation at 140 °C (conditions found necessary to ensure reasonable reaction rates in all of the key IMAE processes reported herein), then a ca. 9:1 mixture of the anticipated product 4a and isomer 5a was obtained in 70% yield (Table 1). The presence of these two products was evident from an analysis of the 1H NMR spectrum of the product mixture that revealed diagnostic resonances due to the allylic proton H3 of product 4a and the homoallylic proton H3 of isomer 5a. In the corresponding 13C NMR spectrum of this mixture, two sets of resonances were observed. Compound 5a is presumed to arise through palladium hydride mediated isomerization of the primary reaction product 4a. Successive replacement of the trimethylsilyl cap within compound 3a by various other silicon-based groups, as seen in congeners 3b−d, provided, after heating at 140 °C under microwave irradiation conditions, the corresponding IMAE products 4b−e and 5b-d. In the case of the dimethylphenylsilylcapped substrate 3e only the primary IMAE product 4e was obtained, albeit in just 43% yield (the origin of the lack of a

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RESULTS AND DISCUSSION 1. Identification of a Utilitarian Capping Group. Given the likely ready availability of the relevant substrates, an examination of the utility of various trialkylsilyl and related capping groups was conducted in the first instance. Of course, the fact that the successful participation of the trialkylsilylated alkynes in the foreshadowed IMAE reactions would deliver © 2017 American Chemical Society

Received: September 18, 2017 Published: October 24, 2017 12569

DOI: 10.1021/acs.joc.7b02355 J. Org. Chem. 2017, 82, 12569−12589

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The Journal of Organic Chemistry Scheme 1. Selecting the Most Appropriate Capping Group for the IMAE Reaction of Hetereoatom Linked 1,6-Enynes

The capacity of these types of processes to generate products embodying quaternary carbon centers is highlighted by the conversion of the R-carvone-derived substrate 11 (entry 3) into the hexahydrobenzofuran 12 (80%) bearing an angular methyl group and the conversion of compound 13 (entry 4) into congener 14 (74%) incorporating a β-hydroxyethyl unit at the ring junction. Interestingly, the conversion 15 → 16 (entry 5) reveals a capacity for the introduction of a heteroatom at ring junctions while the formation of 1,4-diene 18 (entry 6) from precursor 17 shows that trisubstituted, endo-cyclic olefins can also be generated in these IMAE processes. Nitrogen-linked 1,6-enynes also effectively participate in these types of IMAE reactions as evidenced by the sulfonamide 19 (entry 7) readily cyclizing to give the azadiquinane 20 (97%), the structure of which was confirmed by single-crystal Xray analysis [see Experimental Section and Supporting Information (SI)] for details. While the higher homologue of compound 19, viz. 21 (entry 8) smoothly rearranged to give a single IMAE product, namely the hexahydroindole 22 (98%), the analogous p-nosylate 23 (entry 9) afforded a 3:1 mixture of the IMAE products 24 and 25 (84% combined yield). The latter outcome parallels that seen with the oxygen analogue 3b (entry 2, Table 1). A similar situation was encountered with the sevenmembered ring system 26 (entry 10) that afforded a ca. 4:1 mixture of the IMAE products 27 and 28 (89% combined yield) on reaction under the same conditions. In contrast, the trisubstituted olefin 29 (entry 11) afforded the single hexahydroindole 30 in 95% yield. Spirocyclic systems can also be assembled using the abovementioned protocols with the (−)-myrtenol-derived ether 31 (entry 12) affording compound 32 (80%) under standard conditions and with the stereoselective formation of the illustrated product being dictated by steric factors in this case. In a related vein, the readily produced and open chain ether 33 (entry 13) afforded, in a highly diastereoselective manner and through the palladated substrate adopting a clearly preferred conformation,11 monocyclic product 34 (74%) in a completely diastereoselective manner. The successful conversion of the more heavily functionalized O-linked 1,6-enyne 35 (entry 14) into the IMAE product 36 (87%) without other potential transformations intruding

Table 1. Outcomes of the IMAE Reactions of 1,6-Enynes 3a− e in the Presence of Pd(OAc)2 and BBEDA Entry

Substrate

X

Product(s)

1 2 3 4 5

3a 3b 3c 3d 3e

SiMe3 SiEt3 Si(i-Pr)3 SiMe2t-Bu SiMe2Ph

4a/5a 4b/5b 4c/5c 4d/5d 4e (5e not observed)

Yield (ratio of 4:5) 70% 86% 82% 74% 43%

(9:1) (95:5) (7:3) (9:1)

secondary isomerization process in this case remains unclear). These outcomes led us to conclude that the triethylsilyl capping group was likely to be the most useful one for further studies, as detailed below, on the other functionalities and substituents that could be accommodated during the course of these types of IMAE reactions. 2. Functional Group and Other Tolerances in the IMAE Reactions of O- and N-Linked and Triethylsilyl-Capped 1,6-Enynes. In order to develop a sense of the functional groups and substituents that could be accommodated during the course of the IMAE reactions of triethylsilyl capped and Oor N-linked 1,6-enynes, the substrates shown in Table 2 were prepared by relatively conventional means. Each of these was then subjected to the same sorts of reaction conditions as employed above although on occasions somewhat more forcing conditions (180 °C vs 140 °C) were required in order to drive the reactions to completion. Invariably this requirement arose when products incorporating more congested stereogenic centers were being formed. When a benzene solution of the lower homologue, 6 (entry 1), of compound 3b was subjected to reaction with Pd(OAc)2 and BBEDA under microwave irradiation conditions (140 °C for 4 h), then the oxadiquinane 7 was obtained in 92% yield. No evidence for the formation of regioisomeric products was observed in this case. In contrast, when the higher homologue of compound 3b (entry 2), viz. 8, was subjected to the same conditions, then a ca. 8:1 mixture of the IMAE products 9 and 10 was obtained in 90% combined yield. Some evidence for the formation of a third product, probably the corresponding Δ6,7isomer, could be seen in the 1H NMR spectrum of this product mixture. 12570

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Table 2. Outcomes of the IMAE Reactions of Variously Substituted Triethylsilyl-Capped, O- and N-Linked 1,6-Enynes in the Presence of Pd(OAc)2 and BBEDA

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DOI: 10.1021/acs.joc.7b02355 J. Org. Chem. 2017, 82, 12569−12589

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the corresponding IMAE cyclization product 40 in just 16% yield12 and the hydroxymethylated substrate 41 behaved similarly in giving a low yield of congener 42,12 acetoxymethyl capping groups function very well. Thus, the acetylated derivative of alcohol 41, viz. ester 43, cyclized efficiently under relatively mild conditions to give hexahydrofuran 44 (72%) while the less substituted 1,6-enyne 45 reacted under very similar conditions to give product 46 in 68% yield. It is also instructive to consider those substrates that did not engage in IMAE reactions. So, for example, the series of Rcarvone-derived substrates 47−53 (Figure 1) all failed to cyclize under any of the various conditions employed in the successful examples detailed above. This was also the case with the lesssubstituted systems 54−60. Of particular note is the lack of formation of products incorporating angular aryl groups as would have been expected if the last four of these substrates had, in fact, participated in the desired IMAE reaction. The origins of such failures are the subject of ongoing investigations, the outcomes of which will be reported in due course. 3. Manipulations of the Alkenylsilane Residues Associated with the IMAE Reaction Products. In keeping with expectations, various triethylsilyl-substituted olefinic residues associated with the IMAE reaction products shown in Table 2 selectively participated in electrophilic ipsosubstitution reactions. So, for example, as shown in entry 1 of Table 3, on treating compound 7 with N-bromosuccinimide (NBS) in acetonitrile the anticipated transformation took place to afford the bromoalkene 61 in 67% yield. This product was obtained as a single geometric isomer, and the illustrated Zconfiguration about the brominated double bond was assigned, in the first instance, by analogy with literature processes wherein the counterion associated with the electrophile is relatively nonnucleophilic in character.13 Reaction of the R-carvone-derived hexahydrobenzofuran 12 (entry 2) with N-iodosuccinimide (NIS) proceeded in an analogous fashion to give the alkenyl iodide 62 (82%) while reaction of the same substrate with NBS (entry 3) gave the corresponding bromide 63 in 69%. Treatment of the 3:1 mixture of hexahydroindoles 24 and 25 (entry 4) with

provides some indication of the functional group tolerances associated with the title processes. Interestingly, the sulfonamide analogue 37 (entry 15) of carbamate 35 also engaged in the analogous IMAE reaction but the yield of the corresponding hexahydroindole 38 was only 50%. The outcomes of the IMAE processes shown in Table 2 clearly suggest that the capping triethylsilyl group is an effective one, but this is not to say that other such groups cannot be employed. So, for example, while the uncapped analogue of compound 11, viz. the terminal alkyne 39 (Scheme 2), afforded Scheme 2. Impact of Other Alkyne Capping Groups on the IMAE Reaction

Figure 1. Heteroatom linked 1,6-enynes that failed to engage in IMAE reactions. 12572

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Table 3. Electrophilic ipso-Substitution Reactions of Certain of the Alkenylsilane-Containing Products of the IMAE Reactions

fluoroboric acid resulted in protodesilylation and so affording the corresponding mixture of dienes 64 and 65 in 67% combined yield. Similarly, the 4:1 mixture of IMAE products 27 and 28 (entry 5) gave the dienes 66 and 67 in 63% combined yield on treatment of the former compounds with the same acid. These protodesilyation reactions serve to confirm that compound pairs 24/25 and 27/28 arise, in the relevant IMAE reactions, because of the differing locations of the endocyclic double bonds and not because of varying configurations (E or Z) about the triethylsilyl-substituted double bonds. The successful conversion of the alkenylsilane 36 (entry 6) into the bromo-olefin 68 (84%) serves to highlight the exceptional levels of chemoselectivity observed during the electrophilic ipsosubstitution reactions of these IMAE products. In an initial attempt to provide definitive proof of the stereochemical outcomes of these ipso-substitution reactions, the crystalline compound 20 was treated with NBS to give the bromide 69 (70%) (Figure 2) but this could not be crystallized. Accordingly this product was subjected to a series of nOe difference experiments that revealed the tabulated throughspace interactions and so unequivocally establishing that the ipso-substitution reaction leading to this compound proceeded

with retention of configuration. The illustrated structures of compounds 61, 62, 63, and 68 were assigned by analogy.

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CONCLUSIONS A wide range of O- and N-linked 1,6-enynes carrying a triethylsilyl capping group on the alkyne carbon remote from the alkene engage in efficient IMAE reactions on exposure to Pd(OAc)2 and BBEDA at elevated temperatures. Various functionalities that can and cannot be accommodated in these processes have been identified. A number of the product alkenylsilanes have been shown to undergo efficient and stereoselective electrophilic ipso-substitution reactions, thus affording a range of usefully substituted 1,4-dienes.

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EXPERIMENTAL SECTION

General Experimental Procedures. Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded at room temperature in base-filtered CDCl3 on a spectrometer operating at 400 MHz for proton and 100 MHz for carbon nuclei. The signal due to residual CHCl3 appearing at δH 7.26 and the central resonance of the CDCl3 triplet appearing at δC 77.0 were used to reference 1H and 13C NMR spectra, respectively. 1H NMR data are recorded as follows: chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is defined as s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the above. Infrared spectra (νmax) were recorded on an FTIR spectrometer. Samples were analyzed as thin films on KBr plates. Low-resolution ESI mass spectra were recorded on a single-quadrupole liquid chromatograph−mass spectrometer, while high-resolution measurements were conducted on a time-of-flight instrument. Low- and high-resolution EI mass spectra were recorded on a magnetic-sector machine. Melting points were measured on an automated melting point system and are uncorrected. Analytical thin layer chromatography (TLC) was performed on aluminum-backed 0.2 mm thick silica gel 60 F254.

Figure 2. Bromination product 69 and the nOe measurements used in determining its structure. 12573

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phases were then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography to give the desired triethylsilylated alkyne. (v) E: General Procedure for Effecting IMAE Reactions Using Pd(OAc)2 and BBEDA. A magnetically stirred solution of the relevant O- or N-linked 1,6-enyne (0.2 mmol) in dry benzene (3 mL) was treated with palladium acetate (7.2 mg, 0.023 mmol) and BBEDA (7.5 mg, 0.023 mmol), and the ensuing mixture was heated in a sealed vessel in a microwave reactor at 140 °C (250 W of power, temperature measured using an external surface sensor) for 4 h before being cooled and then concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography to give the desired IMAE product. Specific Chemical Transformations. Cyclohex-2-en-1-ol (1). Luche reduction of 2-cyclohexen-1-one according to general procedure A afforded, after flash chromatographic purification of the crude reaction mixture (Rf = 0.5 in 9:1 v/v dichloromethane/diethyl ether), compound 116 (520 mg, 89%) as a clear, colorless oil. The derived spectral data matched those reported in the literature.16 3-(Prop-2-yn-1-yloxy)cyclohex-1-ene (2). Propargylation of allylic alcohol 1 according to general procedure B and subjection of the crude reaction mixture to flash column chromatography (silica, 4:1 v/v petroleum ether/ethyl acetate elution) gave, after concentration of the appropriate fractions (Rf = 0.7 in 3:1 v/v petroleum ether/ethyl acetate), compound 217 (360 mg, 88%) as a clear, colorless oil. The derived spectral data matched those reported in the literature.17 (3-(Cyclohex-2-en-1-yloxy)prop-1-yn-1-yl)trimethylsilane (3a). Treatment of the terminal alkyne 2 according to the general procedure D but using n-butyllithium instead of LiHMDS and chlorotrimethylsilane rather than chlorotriethylsilane gave a light-yellow oil on workup. Subjection of this material to flash column chromatography (silica, 95:5 v/v petroleum ether/diethyl ether elution) and concentration of the relevant fractions (Rf = 0.4) gave compound 3a (480 mg, 77%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.87 (m, 1H), 5.78 (m, 1H), 4.19 (m, 2H), 4.05 (m, 1H), 2.10−1.89 (complex m, 2H), 1.87−1.66 (complex m, 3H), 1.60−1.46 (complex m, 1H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 131.4, 127.3, 102.3, 90.7, 71.8, 56.1, 28.0, 25.2, 19.1, −0.2; IR (KBr) νmax 3028, 2939, 2864, 2173, 1650, 1437, 1396, 1346, 1320, 1250, 1082, 1022, 1003, 988, 917, 844, 760, 725, 699 cm−1; MS (EI, +ve) m/z 207 [(M − H•)+, 14%], 193 (33), 180 (71), 163 (39), 156 (53), 111 (33), 97 (68), 83 (85), 81 (92), 73 (100), 55 (31), 41 (36); HRMS (EI, +ve) m/z (M − H•)+ calcd for C12H19OSi 207.1205, found 207.1205. (3-(Cyclohex-2-en-1-yloxy)prop-1-yn-1-yl)triethylsilane (3b). Alkynyl silane 3b was prepared from propargyl ether 2 according to general procedure D but wherein n-BuLi (1.6 M solution in hexanes, 3.6 mmol) was used in place of LiHMDS. The reaction mixture was subjected to flash column chromatography (silica, 4:1 v/v petroleum ether/dichloromethane elution) and gave, after concentration of the appropriate fractions (Rf = 0.7 in 1:1 v/v petroleum ether/ dichloromethane), compound 3b (380 mg, 51%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.88 (m, 1H), 5.79 (m, 1H), 4.25 (d, J = 16.2 Hz, 1H), 4.21 (d, J = 16.2 Hz, 1H), 4.12 (m, 1H), 2.10− 1.90 (complex m, 2H), 1.87−1.67 (complex m, 3H), 1.56 (m, 1H), 0.99 (t, J = 7.9 Hz, 9H), 0.61 (q, J = 7.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 131.5, 127.5, 103.6, 88.3, 71.6, 56.3, 28.3, 25.4, 19.2, 7.6, 4.5; IR (KBr) νmax 3028, 2954, 2912, 2875, 2171, 1458, 1236, 1081, 989, 726 cm−1; MS (EI, +ve) m/z 250 (M+•, 3%), 222 (45), 221 (47), 191 (39), 97 (64), 81 (100); HRMS (EI, +ve) m/z M+• calcd for C15H26OSi 250.1753, found 250.1756. (3-(Cyclohex-2-en-1-yloxy)prop-1-yn-1-yl)triisopropylsilane (3c). Propargyl ether 2 was subjected to the reaction conditions defined in general procedure D but wherein chlorotri-isopropylsilane was used in place of chlorotriethylsilane. Subjection of the material obtained on workup to flash column chromatography (silica, 6:1 v/v petroleum ether/dichloromethane elution) gave, after concentration of the appropriate fractions (Rf = 0.7 in 4:1 v/v petroleum ether/ethyl acetate), compound 3c (860 mg, 98%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.88 (m, 1H), 5.79 (m, 1H), 4.25 (s, 2H), 4.18 (m, 1H), 2.07−1.95 (complex m, 2H), 1.90−1.66 (complex m,

Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a suitable dip followed by heating. These dips included phosphomolybdic acid/ceric sulfate/sulfuric acid (conc.): water (37.5 g/7.5 g/37.5 g/720 mL) or potassium permanganate/potassium carbonate/5% w/v sodium hydroxide aqueous solution/water (3 g/ 20 g/5 mL/300 mL). Flash chromatographic separations were carried out following protocols defined by Still et al.14 with silica gel 60 (40− 63 μm) as the stationary phase and using the AR- or HPLC-grade solvents indicated. The melting points of solids purified by such means were recorded directly (i.e., after they had crystallized from the concentrated chromatographic fractions). Starting materials, reagents, drying agents, and other inorganic salts were generally available from commercial sources and used as supplied. Tetrahydrofuran (THF), methanol, and dichloromethane were dried using a solvent purification system that is based upon a technology originally described by Grubbs et al.15 Where necessary, reactions were performed under a nitrogen atmosphere. General Synthetic Protocols. (i) A: General Procedure for the Luche Reduction of Enones Leading to Allylic Alcohols. A magnetically stirred solution of the relevant enone (6 mmol) and CeCl3·7H2O (2.22 g, 6 mmol) in methanol (30 mL) was cooled to 0 °C and then treated, in portions, with sodium borohydride (257 mg, 7 mmol) (CAUTION: EVOLUTION OF HYDROGEN GAS). The resulting mixture was stirred at 0 °C for 1 h before being quenched with water (10 mL) and then concentrated under reduced pressure. The residue so-formed was extracted with ethyl acetate or diethyl ether (3 × 20 mL), and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the desired allylic alcohol. This was used, generally without purification, in the next step (see below) of the reaction sequence. (ii) B: General Procedure for the Propargylation of Allylic Alcohols Leading to O-Linked 1,6-Enynes. A magnetically stirred solution of the relevant allylic alcohol (3 mmol) in dry THF (6 mL) maintained under an atmosphere of nitrogen was treated with propargyl bromide (470 μL, 5.4 mmol) and tetra-n-butylammonium iodide (111 mg, 0.3 mmol), and the ensuing mixture was cooled to 0 °C. Then, sodium hydride (216 mg of a 60% dispersion in mineral oil, 5.4 mmol) was added to it. After 0.17 h at 0 °C, the reaction mixture was allowed to warm to 22 °C, stirred at this temperature for 16 h then quenched with NH4Cl (15 mL of a saturated aqueous solution), and extracted with ethyl acetate or diethyl ether (3 × 15 mL). The combined organic phases were then dried (Na2SO4) and filtered before being concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography to give the desired propargyl ether. (iii) C: General Procedure for the Mitsunobu Reaction of Allylic Alcohols with Propargylated Sulfonamides Leading to N-Linked 1,6-Enynes. A magnetically stirred solution of the relevant allylic alcohol (2.15 mmol), triphenylphosphine (5 mmol), and the relevant propargyl sulfonamide (4 mmol) in dry THF (25 mL) maintained under an atmosphere of nitrogen was cooled to 0 °C and then treated dropwise with diethyl azodicarboxylate (DEAD) (5 mmol). The resulting mixture was stirred at this temperature for 0.17 h, then warmed to 22 °C, and maintained at 0 °C for 16 h before being quenched with NH4Cl (20 mL of a saturated aqueous solution) and extracted with diethyl ether (3 × 20 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography to give the desired N-linked 1,6-enyne. (iv) D: General Procedure for the Triethylsilyl Capping of N- and O-Linked 1,6-Enynes. A magnetically stirred solution of the relevant propargyl ether or sulfonamide (3 mmol) in dry THF (3 mL) maintained under an atmosphere of nitrogen was cooled to −78 °C then treated with LiHMDS (3.6 mL of a 1 M solution in THF, 3.6 mmol). The resulting mixture was stirred at −78 °C for 1 h, and then chlorotriethylsilane (3.6 mL of a 1 M solution in THF, 3.6 mmol) was added dropwise. The reaction mixture thus obtained was allowed to warm to 22 °C and then stirred at this temperature for 1 h before being quenched with NH4Cl (20 mL of a saturated aqueous solution) and extracted with diethyl ether (3 × 20 mL). The combined organic 12574

DOI: 10.1021/acs.joc.7b02355 J. Org. Chem. 2017, 82, 12569−12589

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The Journal of Organic Chemistry 3H), 1.56 (m, 1H), 1.10−1.05 (complex m, 21H); 13C NMR (100 MHz, CDCl3) δ 131.4, 127.6, 104.3, 87.1, 71.3, 56.3, 28.3, 25.4, 19.2, 18.7, 11.3; IR (KBr) νmax 2942, 2891, 2865, 2170, 1463, 1081, 997, 986, 883, 678 cm−1; MS (EI, +ve) m/z 292 (M+•, 5%), 249 (64), 219 (20), 207 (20), 169 (27), 81 (100); HRMS (EI, +ve) m/z M+• calcd for C18H32OSi 292.2222, found 292.2225. tert-Butyl(3-(cyclohex-2-en-1-yloxy)prop-1-yn-1-yl)dimethylsilane (3d). Propargyl ether 2 was subjected to the reaction conditions defined in general procedure D but wherein n-BuLi (1.6 M solution in hexanes, 3.6 mmol) and chloro-tert-butyldimethylsilane (3.6 mmol) were used in place of LiHMDS and chlorotriethylsilane, respectively. The reaction mixture obtained on workup was subjected to flash column chromatography (silica, 4:1 v/v petroleum ether/dichloromethane elution) and gave, after concentration of the appropriate fractions (Rf = 0.7 in 1:1 v/v petroleum ether/dichloromethane), compound 3d (340 mg, 45%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.87 (m, 1H), 5.77 (m, 1H), 4.22 (m, 2H), 4.12 (m, 1H), 2.11−1.90 (complex m, 2H) 1.87−1.67 (complex m, 3H), 1.55 (m, 1H), 0.94 (s, 9H), 0.11 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 131.5, 127.5, 103.2, 89.1, 71.7, 56.3, 28.3, 26.2, 25.3, 19.2, 16.6, −4.5; IR (KBr) νmax 2930, 2857, 2172, 1470, 1361, 1251, 1079, 988, 838, 825, 811, 776 cm−1; MS (EI, +ve) m/z 250 (M+•,