The Direct Conversion of Î±-Hydroxyketones to Alkynes - The Journal

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2019, 84, 983−993

The Direct Conversion of α‑Hydroxyketones to Alkynes Francesca Ghiringhelli,† Lukas Nattmann,† Sabine Bognar,† and Manuel van Gemmeren*,†,‡ †

Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany Max-Planck-Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr, Germany

‡

J. Org. Chem. 2019.84:983-993. Downloaded from pubs.acs.org by TULANE UNIV on 01/18/19. For personal use only.

S Supporting Information *

ABSTRACT: Alkynes are highly important functional groups in organic chemistry, both as part of target structures and as versatile synthetic intermediates. In this study, a protocol for the direct conversion of α-hydroxyketones to alkynes is reported. In combination with the variety of synthetic methods that generate the required starting materials by forming the central C−C bond, it enables a highly versatile fragment coupling approach toward alkynes. A broad scope for this novel transformation is shown alongside mechanistic insights. Furthermore, the utility of our protocol is demonstrated through its application in concert with varied α-hydroxyketone syntheses, giving access to a broad spectrum of alkynes.

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INTRODUCTION The alkyne group arguably ranks among the most important functional groups in organic chemistry.1 Accordingly, a variety of methods exists to prepare internal alkynes,2 the synthesis of which is at the center of this work (Scheme 1A). The most

formation at all. The latter is, for example, the case for methods based on the difunctionalization/double elimination starting from olefins2 or for fragmentation based approaches.5 On the basis of the realization that methods forming the central C−Cbond are scarce, we wondered whether a protocol could be devised that, analogously to olefination reactions, would enable the formation of internal alkynes from two separate fragments. Our attention was drawn to the fragmentation of tosylhydrazones bearing an α-leaving group.6 Such reactions have the inherent advantage that no regioselectivity issues arise, which would, for example, be expected in the dehydration of ketones with two aliphatic substituents,7 but the respective protocols typically require harsh conditions and activated starting materials that have to be accessed over several synthetic steps. In contrast, the simple α-hydroxy ketone or acyloin moiety can be accessed conveniently through a variety of established C−C bond-forming protocols.8 We concluded that, if we could develop a direct conversion of acyloins into alkynes, a highly flexible two-step approach for the fragment coupling synthesis of internal alkynes would result.6e,h,9 We furthermore hypothesized that achieving this target reaction would require us to couple the alkyne formation to the formation of highly stabilized species, in order to ensure an overall favorable energetic profile. Indeed, the groups of Rosenblum,10 Marshall Wilson,11 and Anselme12 have reported the formation of tolane 1a from substrate 3, which proceeds through the base induced formation of intermediate 4 and a subsequent thermal fragmentation leading to nitrogen and carbon dioxide as byproducts (Scheme 1B). Although in these studies substrate 3 was synthesized through different approaches, we wondered if it would be possible to generate this species from benzoin 2a by treatment with tosylhydrazine

Scheme 1. Common Approaches toward Internal Alkynes (A) and Concept for the Direct Conversion of Acyloins to Alkynes Developed in This Work (B)

common approaches can be divided into syntheses that start from preformed alkyne precursors and syntheses that build up this motif de novo. Notably, the majority of these methods, with the alkyne metathesis as a notable exception,3 do not involve the formation of the central C−C-bond but rather forge the neighboring bond,4 or do not involve a C−C-bond © 2018 American Chemical Society

Received: November 19, 2018 Published: December 19, 2018 983

DOI: 10.1021/acs.joc.8b02941 J. Org. Chem. 2019, 84, 983−993

Article

The Journal of Organic Chemistry

applicable to substrates bearing both electron-donating (1b,c) and electron-withdrawing (1d−g) substituents. Furthermore, the heteroaromatic product 1h could be obtained from furoin in good yield. Similarly, we could also apply our method for the synthesis of unsymmetrically substituted alkynes 1i−m. It is particularly noteworthy that both symmetric and nonsymmetric alkynes bearing halide substituents could be accessed. These substituents provide a handle for further functionalization and, at the same time, render the corresponding products challenging targets for other methods such as the Sonogashira reaction, especially in the case of bromine (1d,j) and iodine (1l) substituents. Finally, we could show that our method is also suited for the synthesis of alkynes bearing aliphtic substituents (1n−p). In order to guide the possible application of our protocol in more complex synthetic settings, we became interested in obtaining further data regarding the functional group tolerance. Toward this goal, we applied the additive based robustness screen developed by Glorius et al., which provides information on the influence of varied functional groups in cases where the respective functional group is sterically and electronically independent of the reactive center and is thus complementary to the explicitly studied scope.15 The results of the robustness screen show that most of the representative functional groups tested exerted either no or a very limited detrimental effect on the reaction itself, with free amines and to a lesser extent alcohols being the notable exceptions (see the Supporting Information for detailed documentation of the robustness screen). Similarly, the majority of additives remained intact under our reaction conditions. Overall, these results indicate that the present protocol for the conversion of acyloins to alkynes has a broad functional group tolerance and will therefore likely be applicable in complex synthetic settings. During the course of our optimization studies, we made a number of observations, which indicated that our reaction does not proceed through the initially targeted intermediate 3. This prompted us to study the reaction mechanism in more detail, ultimately leading to the mechanistic proposal shown in Scheme 3. During the separate optimization of the reaction steps, we could confirm the formation of tosylhydrazone 5, which was isolated as a single stereoisomer. Importantly, the isolated (E)-

and a suitable carbonate-derived electrophile such as carbonyl diimidazole (CDI).13

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RESULTS AND DISCUSSION We thus began our studies toward the development of suitable reaction conditions. After separately optimizing the formation of the hydrazone and the subsequent reaction with CDI, in both cases limiting ourselves to conditions that would be compatible with the respective other reaction step, we could indeed develop reaction conditions that enable the formation of tolane 1a from benzoin 2a (Scheme 2, for details on the Scheme 2. Scope of the Direct Conversion of αHydroxyketones to Alkynes

Scheme 3. Mechanistic Considerations

optimization studies, see the Supporting Information). The optimized protocol involves the formation of the tosylhydrazone at room temperature, catalyzed by diphenylphosphate and with magnesiumsulfate monohydrate as a drying agent, followed by the addition of CDI and heating to 100 °C. We began to explore the scope of the reaction using acyloin starting materials that are either commercially available or could easily be accessed through an NHC-catalyzed benzoin condensation from the corresponding aldehydes.14 Tolane 1a was obtained in 70% yield, and the method was shown to be scalable, giving 1a in 65% yield, when the reaction was conducted on a gram scale. The protocol proved to be 984


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The Journal of Organic Chemistry tosylhydrazone 5 could be employed in the subsequent part of the reaction without the need for the acid additive and drying agent used under the optimized conditions, thus proving that these components are irrelevant for the remainder of the reaction. When tosylhydrazone 5 was treated with CDI at room temperature, the almost instantaneous evolution of a gas (identified as CO2 based on the stoichiometry of the reaction) and a yellowish coloration of the reaction mixture were observed. When this step was performed in different solvents during the optimization studies, the precipitation of a colorless compound was observed in some cases, which could be identified as the imidazole adduct 7. On the basis of the known reactivity between alcohols and CDI,16 we propose the initial formation of an intermediate 6, which then extrudes CO2 to give imidazole adduct 7. Two features of this process are remarkable and suggest the noninnocence of the neighboring tosylhydrazone functionality: first, the reaction occurs in tertamyl alcohol as a solvent, i.e., in the presence of a large excess of competing OH-groups. Here, the hydrazone lone pair likely acts as an internal base to increase the reactivity of the OHgroup in the substrate, thereby allowing it to outcompete the solvent in the reaction with CDI. Second, the extrusion of CO2 from alkyl alcohol/CDI-derived carbamates typically requires very high temperatures, but an accelerating neighboring group effect (e.g., by amines) has been described in the literature.16 Thus, although the precise mode of action remains unclear, we propose an active participation of the tosylhydrazone moiety as an explanation for the unusual ease with which CO2 is released. We could next confirm that the isolated imidazole adduct 7 reacts to product 1a upon heating in tert-amyl alcohol, proving that none of the remaining species in the reaction mixture is required for this step. We concluded that the formation of 1a either proceeds through a unimolecular thermal fragmentation or with base assistance (where a second molecule of substrate 7 or the imidazole formed through the process could act as a base), leading to the overall formation of imidazole, nitrogen, p-toluenesulfinic acid, and product 1a.6a,b,d−i A notable feature of our protocol is that for nonsymmetric acyloins the two regioisomers are expected to converge into a single product. This is particularly relevant in light of the fact that many cross-acyloin or cross-benzoin reactions deliver mixtures of regioisomers. For example, the NHC-catalyzed cross-benzoin reaction of 4-chlorobenzaldehyde (8a) and isobutyraldehyde (8b) gave the benzoin product with a high selectivity for the crossed product, but the two regioisomers. 2q and 2q′ were formed in close to equal amounts (Scheme 4A). As expected, we could convert this mixture into a single product 1q using our protocol. In contrast to this generally occurring convergence, we have observed that in some cases, where one of the two regioisomers proves to be problematic, the use of the other isomer serves as a strategy to address this challenge. In particular, we encountered a side reaction when attempting to use substrate 2r bearing a benzyl-substituent on the OH-side of the α-hydroxyketone (Scheme 4B). Instead of the expected product 1r, we obtained heterocycle 10 in 53% yield, which is presumably formed by imidazole elimination from the intermediate analogous to 7, giving a stabilized, chalconederived tosylhydrazone, which can subsequently cyclize to give heterocycle 10. On the basis of this proposed mode of formation, we predicted that it should be possible to obtain the desired product 1r by using the regioisomeric starting material

Scheme 4. Convergence from Mixtures of Isomeric Substrates (A) and Use of Regioisomeric Starting Materials as a Strategy to Address Side Reactions (B/C)

2r′ (Scheme 4C). Indeed, using this starting material, product 1r was obtained in 68% yield using our standard protocol. As indicated in Scheme 4, different synthetic approaches can prove useful to access starting materials with the required substitution pattern. We thus wanted to probe the ability of our method to serve as part of a highly flexible fragment coupling two-step synthesis of internal alkynes. To this end, we combined our protocol with several well-established syntheses of α-hydroxyketones, which together give access to a broad spectrum of substitution patterns on the acyloins 2 and consequently the alkynes 1 obtained in the second step (Scheme 5). We began by synthesizing the 13-membered cyclic substrate 2s from diester 12 though a traditional acyloin condensation with Na/TMS-Cl,8b,e which could subsequently be converted to the corresponding cyclic alkyne 1s (Scheme 5A). In order to obtain crossed acyloin products, we turned our attention to the method developed by Donohoe and co-workers, which achieves the desired selectivities through an intramolecularization.17 Using this method, we could access the substrates 2t and 2t′ from the diester 13a, which as expected converged into a single alkyne 1t when we exposed the mixture to our reaction conditions (Scheme 5B). In an analogous approach, we could demonstrate the incorporation of a natural product scaffold by subjecting the litocholic acid-derived diester 13b to the conditions developed by Donohoe et al. As expected on the basis of the literature, substrate 2u was obtained as a single regioisomer and could subsequently be converted to the desired natural-product-derived alkyne 1u (Scheme 5C). Finally, we combined our protocol with a substrate synthesis based on a Stork−Hü nig-type stoichiometric umpolung (Scheme 5D). Accordingly, we could obtain substrate 2v, which is out of reach for typical NHC-catalyzed protocols, by reacting the silylated cyanohydrin 9 with pivaldehyde 8d and could further convert it to alkyne 1v using our protocol.

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CONCLUSION In conclusion, we have developed a direct protocol for the conversion of α-hydroxyketones to alkynes that, in combination with the multitude of C−C bond-forming syntheses of 985


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ppm, δC = 77.16 ppm). NMR data are reported as follows: chemical shift (multiplicity [s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet, m = multiplet, br = broad], coupling constants (J, Hz), and integration). For the spectra of regioisomeric mixtures, signals clearly assigned to a particular regioisomer are labeled with a superscript at the integration. The number of protons in such cases refers to the number of protons of the respective isomer. The absence of such an index indicates that the signals of all observed regioisomers overlap; the integration given corresponds to the number of protons in each isomer. All spectra were processed using the MestReNova program. High resolution mass spectra (HRMS) were recorded on a Bruker Daltonics MicroTof or on a ThermoFisher Scientific Orbitrap LTQ XL spectrometer using electron spray ionization (ESI). Infrared (IR) spectra were recorded neat on a Shimadzu FTIR 8400S or a Varian Associates FTIR 3100 Excalibur spectrometer. The wave numbers (ν) of recorded IR-signals are quoted in cm−1. GC-FID analyses were performed using an Agilent Technologies 7890B setup equipped with an HP5 column (30 m, 0.32 mm × 0.25 μm). GC-MS spectra were recorded on an Agilent Technologies 7890A GC-system with an Agilent 5975C VL MSD or an Agilent 5975 inert Mass Selective Detector (EI) and an HP-5MS column (30 m, 0.32 mm × 0.25 μm). The major signals are quoted in m/z with the relative intensity in parentheses. General Procedure 1 for the Synthesis of Symmetric Acyloins.14a DBU (0.4 equiv) was added to a solution of aldehyde (1 equiv) and 1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (5 mol %) in dioxane or THF (0.4 M). The mixture was refluxed for 3 h, allowed to cool to room temperature, and concentrated under reduced pressure. H2O (0.4 M) was added to the residue, and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over MgSO4 and filtered, the solvent was evaporated under reduced pressure, and the crude reaction mixture was purified by flash column chromatography (pentane/EtOAc = 8:2). General Procedure 2 for the Synthesis of Nonsymmetric Acyloins.14b 3-Mesityl-4,5-dimethylthiazol-3-ium perchlorate (10 mol %) and Et3N (20 mol %) were added to a solution of aldehyde A (1 equiv) and aldehyde B (1 equiv) in dry THF (1.7 M). The resulting reaction mixture was stirred at 60 °C for 22 h, allowed to cool to room temperature, adsorbed on silica, and purified by flash column chromatography (pentane/EtOAc = 8:2). General Procedure 3 for the Synthesis of Nonsymmetric Acyloins via Stork−Hünig-Type Umpolung.18 TMPMgCl·LiCl (1 M in THF, 1.3 equiv) was added to a solution of 2-phenyl-2-((trimethylsilyl)oxy)acetonitrile (1.0 equiv) in THF (0.25 M) at −20 °C and stirred for 2 h at this temperature. The reaction mixture was cooled to −78 °C, and the corresponding aldehyde (1.3 equiv) was added dropwise. The resulting mixture was stirred overnight while letting it warm to room temperature and quenched with sat. aq NH4Cl solution. The aqueous phase was extracted with EtOAc (3×), and the combined organic layers were washed with H2O (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude OTMSether was dissolved in MeOH (0.5 M), and aq HCl (1 M, 1.0 equiv) was added. The mixture was stirred at room temperature overnight and extracted with EtOAc (3×). The combined organic layers were washed with sat. aq NaHCO3, H2O, and brine, dried over Na2SO4, and filtered. The crude product was concentrated under reduced pressure and purified by flash column chromatography (pentane/ EtOAc = 9:1). 2-Hydroxy-1,2-di-p-tolylethan-1-one (2b).19 Following General Procedure 1 with 4-methylbenzaldehyde (240 mg, 2.00 mmol) as the aldehyde component in dioxane, the target compound 2b was obtained as a colorless solid (204 mg, 85%): 1H NMR (CDCl3, 400 MHz): δ = 7.82 (d, J = 6.7 Hz, 2H), 7.26−7.16 (m, 4H), 7.12 (d, J = 7.7 Hz, 2H), 5.89 (s, 1H), 4.55 (s, 1H), 2.35 (s, 3H), 2.29 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 198.7, 145.0, 138.5, 136.5, 131.1, 130.2, 129.9, 129.8, 129.5, 129.4, 127.8, 75.9, 21.9, 21.3 ppm. 2-Hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one (2c).20 Following General Procedure 1 with 4-methoxybenzaldehyde (272 mg, 2.00 mmol) as the aldehyde component in THF, the target compound 2c

Scheme 5. Synthetic Utility of Our Protocol: Applications in Concert with Different Syntheses of α-Hydroxyketones

these starting materials, constitutes a highly versatile approach to alkynes. Unlike in most established methods for alkyne synthesis, the central C−C bond is formed de novo and the protocol utilizes simple laboratory reagents exclusively, such that it can be carried out easily in a typical synthetic organic chemistry lab. We could demonstrate a broad scope and the applicability in concert with different substrate syntheses as well as provide substantial insights into the mechanism of the reaction. Our method provides a novel way of retrosynthetically analyzing alkynes (α-hydroxyketones as retrons), which is complementary to established approaches and will thus likely prove to be a valuable new tool in the many areas of chemistry where alkynes play an important role as target molecules and synthetic intermediates.

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, all reactions were carried out in oven-dried glassware and under a dry argon atmosphere. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F254 aluminum plates (Merck). Visualization was achieved by exposure to ultraviolet light (254 nm, 366 nm) and/or by staining. Flash column chromatography was performed on silica gel (35−70 μm mesh, 60 Å, Acros) with a positive argon overpressure. 1H and 13C NMR spectra were recorded at room temperature on a Bruker Avance II 300 MHz, Bruker Avance II 400 MHz, Agilent DD2 500, or Agilent DD2 600 spectrometer. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) using the residual solvent peaks for calibration (CDCl3: δH = 7.26 986


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The Journal of Organic Chemistry was obtained as a colorless solid (190 mg, 70%): 1H NMR (CDCl3, 400 MHz): δ = 7.92 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 6.87 (m, 4H), 5.87 (s, 1H), 4.60 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.5, 164.1, 159.8, 132.0, 131.7, 129.1, 126.4, 114.6, 114.0, 75.4, 55.6, 55.4 ppm. 1,2-Bis(4-bromophenyl)-2-hydroxyethan-1-one (2d).20 Following General Procedure 1 with 4-bromobenzaldehyde (370 mg, 2.00 mmol) as the aldehyde component in THF, the target compound 2d was obtained as a pale yellow solid (240 mg, 65%): 1H NMR (CDCl3, 400 MHz): δ = 7.74 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 6.8 Hz, 2H), 5.86 (s, 1H), 4.49 (s, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.6, 137.6, 132.4, 132.2, 131.9, 130.5, 129.6, 129.4, 123.0, 75.5 ppm. 1,2-Bis(4-chlorophenyl)-2-hydroxyethan-1-one (2e).20 Following General Procedure 1 with 4-chlorobenzaldehyde (281 mg, 2.00 mmol) as the aldehyde component in THF, the target compound 2e was obtained as a yellow solid (216 mg, 77%): 1H NMR (CDCl3, 400 MHz): δ = 7.69 (d, J = 7.0 Hz, 2H), 7.25 (d, J = 7.0 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 5.75 (s, 1H), 4.37 (s, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.6, 140.9, 137.3, 134.9, 131.7, 130.6, 129.6, 129.3, 129.2, 75.6 ppm. Dimethyl 4,4′-(1-Hydroxy-2-oxoethane-1,2-diyl)dibenzoate (2f).21 Following General Procedure 1 with methyl 4-formylbenzoate (328 mg, 2.00 mmol) as the aldehyde component in dioxane, the target compound 2f was obtained as a yellow solid (223 mg, 68%): 1H NMR (CDCl3, 400 MHz): δ = 8.03 (d, J = 6.9 Hz, 2H), 7.96 (d, J = 6.7 Hz, 2H), 7.91 (d, J = 6.9 Hz, 2H), 7.39 (d, J = 6.7 Hz, 2H), 6.01 (s, 1H), 4.57 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 198.3, 166.5, 165.9, 143.1, 136.7, 134.8, 130.6, 130.5, 130.0, 129.0, 127.8, 76.3, 52.7, 52.3 ppm. 1,2-Bis(3-chlorophenyl)-2-hydoxyethan-1-one (2g).19 Following General Procedure 1 with methyl 3-chlorobenzaldehyde (281 mg, 2.00 mmol) as the aldehyde component in THF, the target compound 2g was obtained as a yellow solid (185 mg, 66%): 1H NMR (CDCl3, 400 MHz): δ = 7.90 (dd, J = 1.9, 1.9 Hz, 1H), 7.73 (ddd, J = 7.9, 1.4, 1.4 Hz, 1H), 7.52 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.36 (dd, J = 7.9, 7.9 Hz, 1H), 7.33−7.30 (m, 1H), 7.27−7.25 (m, 2H), 7.21−7.18 (m, 1H), 5.87 (d, J = 4.5 Hz, 1H), 4.45 (d, J = 5.8 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.5, 140.4, 135.4, 135.3, 134.9, 134.3, 130.7, 130.3, 129.2, 128.0, 127.3, 126.0, 75.8 ppm. Methyl 4-(1-Hydroxy-2-(4-methoxyphenyl)-2-oxoethyl)benzoate (2i). Following General Procedure 2 with 4-methoxybenzaldehyde (272 mg, 2.00 mmol) and 4-formylbenzoate (328 mg, 2.00 mmol, 1.0 equiv) as the aldehyde components, the target compound 2i was obtained as a yellow solid (168 mg, 56%): 1H NMR (CDCl3, 400 MHz): δ = 7.99 (dm, J = 8.4 Hz, 2H), 7.88 (dm, J = 9.0 Hz, 2H), 7.42 (dm, J = 8.4 Hz, 2H), 6.87 (dm, J = 9.0 Hz, 2H), 5.93 (d, J = 5.4 Hz, 1H), 4.71 (d, J = 5.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H) ppm; 13 C{1H} NMR (CDCl3, 101 MHz): δ = 196.7, 166.7, 164.4, 144.4, 131.7, 130.5, 127.9, 126.1, 114.2, 75.4, 55.7, 52.3 ppm; HRMS (ESI+) m/z calcd for C17H16O5Na+ [M + Na]+ 323.0895, found 323.0894; IR: (cm−1) = 3441, 1720, 1667, 1597, 1281, 1257, 1173, 972, 609. 2-(2-Bromophenyl)-1-(4-bromophenyl)-2-hydroxyethan-1-one (2j).22 Following General Procedure 2 with 4-bromobenzaldehyde (370 mg, 2.00 mmol) and 2-bromobenzaldehyde (370 mg, 2.00 mmol, 1.0 equiv) as the aldehyde components, the target compound 2j was obtained as a yellow solid (237 mg, 64%): 1H NMR (CDCl3, 400 MHz): δ = 7.78 (d, J = 8.6 Hz, 2H), 7.62 (dm, J = 7.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.23 (ddm, J = 7.6, 7.6 Hz, 1H), 7.15 (ddm, J = 7.9, 7.6 Hz, 1H), 7.05 (dm, J = 7.6 Hz, 1H), 6.31 (s, 1H), 4.44 (br s, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.9, 138.1, 133.8, 132.2, 131.9, 130.5, 130.4, 129.5, 129.2, 128.5, 124.2, 75.4 ppm. 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-2-hydroxyethan-1-one (2k).14b Following General Procedure 2 with 4-chlorobenzaldehyde (281 mg, 2.00 mmol) and 2-chlorobenzaldehyde (281 mg, 2.00 mmol, 1.0 equiv) as the aldehyde components, the target compound 2k was obtained as a yellow solid (196 mg, 70%): 1H NMR (CDCl3, 400 MHz): δ = 7.85 (dm, J = 8.7 Hz, 2H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (dm, J = 8.7 Hz, 2H), 7.23 (ddd, J = 7.9, 7.4, 1.9 Hz, 1H),

7.18 (ddd, J = 7.6, 7.4, 1.4 Hz, 1H), 7.10 (dd, J = 7.6, 1.9 Hz, 1H), 6.33 (s, 1H), 4.52 (br s, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 197.8, 140.8, 136.5, 133.7, 131.6, 130.5, 130.3, 129.3, 127.9, 73.0 ppm. 2-Hydroxy-2-(4-iodophenyl)-1-phenylethan-1-one (2l). Following General Procedure 3 with 4-iodobenzaldehyde (278 mg, 1.20 mmol, 1.2 equiv) as the aldehyde component, the target compound 2l was obtained as a colorless solid (270 mg, 80%): 1H NMR (CDCl3, 300 MHz): δ = 7.92−7.85 (m, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.59− 7.51 (m, 1H), 7.46−7.37 (m, 2H), 7.08 (d, J = 8.3 Hz, 2H), 5.90 (d, J = 6.0 Hz, 1H), 4.55 (d, J = 6.0 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 198.6, 138.8, 138.4, 134.3, 133.3, 129.7, 129.2, 129.0, 94.7, 75.7 ppm; HRMS (ESI+) m/z calcd for C13H24O2Na+ [M + Na]+ 235.1674, found 235.1676; IR: (cm−1) = 3472, 3379, 1682, 1450, 1249, 1180, 1080, 972, 802, 702. 2-(2-Chlorophenyl)-1-(3-chlorophenyl)-2-hydroxyethanone (2m).14b Following General Procedure 2 with methyl 2-chlorobenzaldehyde (281 mg, 2.00 mmol) and 3-chlorobenzaldehyde (281 mg, 2.00 mmol, 1.0 equiv) as the aldehyde components, the target compound 2m was obtained as a yellow solid (210 mg, 71%): 1H NMR (CDCl3, 400 MHz): δ = 7.94 (dd, J = 1.9, 1.9 Hz, 1H), 7.75 (ddd, J = 7.8, 1.3, 1.3 Hz, 1H), 7.50 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.43 (dd, J = 7.8, 1.6 Hz, 1H), 7.34 (dd, J = 7.9, 7.9 Hz, 1H), 7.25 (ddd, J = 7.7, 7.6, 1.9 Hz, 1H), 7.20 (ddd, J = 7.6, 7.5, 1.4 Hz, 1H), 7.11 (dd, J = 7.5, 1.9 Hz, 1H), 6.34 (s, 1H), 4.45 (s, 1H) ppm; 13 C{1H} NMR (CDCl3, 101 MHz): δ = 197.9, 136.3, 135.3, 134.9, 134.2, 133.7, 130.6, 130.4, 130.2, 129.3, 129.0, 128.0, 127.0, 73.2 ppm. 1,2-Dicyclohexyl-2-hydroxyethan-1-one (2n).17 Following General Procedure 1 with cyclohexanecarbaldehyde (224 mg, 2.00 mmol) as the aldehyde component in dioxane, the target compound 2n was obtained as a colorless solid (145 mg, 65%): 1H NMR (CDCl3, 400 MHz): δ = 4.15 (d, J = 2.4 Hz, 1H), 3.36 (br s, 1H), 2.54 (m, 1H), 1.87−1.59 (m, 10H), 1.57−1.40 (m, 2H), 1.38−1.00 (m, 9H) ppm; 13 C{1H} NMR (CDCl3, 101 MHz): δ = 215.5, 79.4, 46.3, 41.2, 30.5, 30.2, 27.3, 26.7, 26.1, 26.0, 26.0, 25.8, 25.6, 25.3 ppm. 4-Hydroxy-1,6-diphenylhexan-3-one (2p).23 3-Mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium perchlorate (74.8 mg, 0.200 mmol, 10 mol %) and Et3N (55.0 μL, 0.400 mmol, 20 mol %) were added to a solution of 3-phenylpropanal (268 mg, 2.00 mmol) in dry THF (1.2 mL). The resulting reaction mixture was stirred at 60 °C for 22 h, cooled to room temperature, adsorbed on silica, and purified by flash column chromatography (pentane/EtOAc = 8:2). The target compound 2p was obtained as a yellow oil (188 mg, 70%): 1H NMR (CDCl3, 400 MHz): δ = 7.39−7.36 (m, 4H), 7.32−7.24 (m, 6H), 4.21 (d, J = 5.0 Hz, 1H), 3.64 (s, 1H), 3.03−2.99 (m, 2H), 2.91−2.73 (m, 4H), 2.23−2.15 (m, 1H), 1.92−1.83 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 211.3, 141.1, 140.5, 128.7, 128.6, 128.4, 126.5, 126.3, 75.9, 39.7, 35.5, 31.2, 29.6 ppm. 1-(4-Chlorophenyl)-2-hydroxy-3-methylbutan-1-one + 1-(4Chlorophenyl)-1-hydroxy-3-methylbutan-2one (2q + 2q′).14b 3Mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium perchlorate (74.8 mg, 0.200 mmol, 10 mol %) and Et3N (165 μL, 1.20 mmol, 60 mol %) were added to a mixture of 4-chlorobenzaldehyde (281 mg, 2.00 mmol) and isobutyraldehyde (547 μL, 6.00 mmol, 3 equiv), and the resulting mixture was dissolved in dry ethanol (1.5 mL). The resulting reaction mixture was stirred at 60 °C for 22 h, allowed to cool to room temperature, adsorbed on silica, and purified by flash column chromatography (pentane/EtOAc = 8:2). The mixture of the target compounds 2q and 2q′ was obtained as a yellow solid (254 mg, 60%): 1H NMR (CDCl3, 400 MHz): δ = 7.84 (d, J = 8.6 Hz, 2Hq), 7.47 (d, J = 8.6 Hz, 2Hq), 7.35 (d, J = 8.5 Hz, 2Hq′), 7.25 (d, J = 8.5 Hz, 2Hq′), 5.19 (s, 1Hq′), 4.93 (s, 1Hq), 4.39 (s, 1Hq′), 3.55 (s, 1Hq), 2.68 (qq, J = 6.9, 6.9 Hz, 1Hq′), 2.09 (qqd, J = 6.8, 6.8, 2.5 Hz, 1Hq), 1.16 (d, J = 6.8 Hz, 3Hq), 1.13 (d, J = 6.9 Hz, 3Hq′), 0.84 (d, J = 6.9 Hz, 3Hq′), 0.65 (d, J = 6.8 Hz, 3Hq) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 213.1, 201.2, 140.5, 136.6, 134.8, 132.5, 130.0, 129.4, 129.3, 129.0, 128.9, 127.3, 77.7, 77.4, 36.1, 32.8, 20.2, 19.5, 18.1, 14.5 ppm. 987


Article

The Journal of Organic Chemistry 2-Hydroxy-1,3-diphenylpropan-1-one (2r).24 Following General Procedure 3 with phenylacetaldehyde (0.30 mL, 2.6 mmol, 1.3 equiv) as the aldehyde component, the target compound 2r was obtained as a colorless solid (0.33 g, 72%). 1H NMR (CDCl3, 400 MHz): δ = 7.92 (d, J = 8.1 Hz, 2H), 7.63 (dd, J = 7.4, 7.4 Hz, 1H), 7.51, (dd, J = 7.3, 7.3 Hz, 2H), 7.30−7.17 (m, 3H), 7.11 (d, J = 7.3 Hz, 2H), 5.33 (d, J = 4.4 Hz, 1H), 3.69 (d, J = 6.5 Hz, 1H), 3.19 (dd, J = 14.1, 3.8 Hz, 1H), 2.89 (dd, J = 14.1, 6.9 Hz, 1H) ppm. 13C{1H} NMR (CDCl3, 101 MHz): δ = 201.2, 136.6, 134.2, 134.0, 129.6, 129.1, 128.8, 128.5, 127.0, 73.9, 42.1 ppm. 1-Hydroxy-1,3-diphenylpropan-2-one (2r′). Freshly prepared benzyl magnesium bromide (approximately 1 M in Et2O, 1.2 mL, 1.2 mmol, 6.0 equiv) was added dropwise to a solution of the Weinreb amide 11 (0.04 g, 0.20 mmol, 1.0 equiv) in Et2O (2 mL) at 0 °C. The resulting mixture was stirred for 1.5 h at 0 °C and then allowed to warm to room temperature while stirring overnight. Sat. aq NH4Cl solution (5 mL) was added, the phases were separated, and the organic layer was washed with aq HCl (1 M, 5 mL) and H2O (2 × 5 mL). The crude product was dried over Na2 SO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (pentane/EtOAc = 10:1). The target compound 2r′ was obtained as a colorless solid (37 mg, 82%): 1H NMR (CDCl3, 300 MHz): δ = 7.38−7.28 (m, 3H), 7.28−7.13 (m, 5H), 6.94 (dd, J = 7.4, 1.9 Hz, 2H), 5.12 (d, J = 4.5 Hz, 1H), 4.18 (d, J = 4.5 Hz, 1H), 3.58 (s, 2H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 207.1, 137.7, 133.0, 129.5, 129.3, 129.1, 128.8, 127.9, 127.4, 79.3, 44.7 ppm; HRMS (ESI+): m/z calcd for C15H14O2Na+ [M + Na]+ 249.0886, found 249.0895; IR: (cm−1) = 3418, 3387, 1705, 1381, 1335, 1226, 1126, 1273, 1042, 748, 694, 602, 586, 556. 2-Hydroxycyclotridecan-1-one (2s). In analogy to a procedure by Hisanaga et al.,25 a suspension of sodium (92.2 mg, 4.00 mmol, 4 equiv) in toluene (2.00 mL) was heated at 110 °C until all of the sodium melted. The resulting suspension was allowed to cool to room temperature and trimethylsilyl chloride (507 μL, 4.00 mmol, 4 equiv) was added dropwise, followed by the addition of a solution of tridecanedioic acid dimethyl ester (273 mg, 1.00 mmol) in toluene (0.500 mL). The reaction mixture was heated to 110 °C and stirred at this temperature for 1 h (the reaction color turned purple). The reaction mixture was allowed to cool to room temperature, and the unreacted sodium was removed by filtration and quenched with isopropanol. The filtrate was extracted with EtOAc (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in THF (5 mL), and p-toluenesulfonic acid (688 mg, 4.00 mmol, 4 equiv) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9:1), and the target compound 2s was obtained as a colorless solid (144 mg, 68%): 1H NMR (CDCl3, 300 MHz): δ = 4.28 (t, J = 4.6 Hz, 1H), 3.44 (s, 1H), 2.79− 2.68 (m, 1H), 2.36−2.26 (m, 1H), 2.06−1.82 (m, 2H), 1.80−1.69 (m, 1H), 1.58−1.16 (m, 17H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 213.0, 76.4, 36.9, 32.8, 27.0, 26.5, 26.3, 25.3, 25.2, 25.1, 24.8, 21.9, 21.1 ppm; HRMS (ESI+) m/z calcd for C13H24O2Na+ [M + Na]+ 235.1674, found 235.1676; IR: (cm−1) = 3356, 2931, 1712, 1450, 1064, 1033, 702, 648. 1-Cyclohexyl-2-hydroxydecan-1-one + 1-Cyclohexyl-1-hydroxydecan-2-one (2t + 2t′). In an oven-dried Schlenk flask, lithium (120 mg, 20.0 mmol, 20 equiv) was added to a solution of 4,4′-di-tertbutylbiphenyl (DBB) (532 mg, 2.00 mmol, 2.0 equiv) in THF (20 mL) at 0 °C. The resulting teal-blue-colored Li/DBB solution was stirred at this temperature for 2 h and was then cooled to −78 °C. A solution of (rac)-3-(nonanoyloxy)bicyclo[2.2.1]heptan-2-yl cyclohexane-carboxylate (13a) (378 mg, 1.00 mmol) in THF (5 mL) was slowly added to the stirred solution of Li/DBB at −78 °C. After the addition was completed, the reaction mixture was stirred at −78 °C for 2 h and was quenched by dropwise addition of a saturated aqueous solution of NH4Cl (5 mL). The reaction mixture was allowed

to warm to ambient temperature and was transferred via cannula into brine (the remaining Li was quenched by slow addition of isopropanol). The solution was extracted with diethyl ether (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9:1), and the mixture of the target compounds 2t + 2t′ (1:1.1) was obtained as a colorless oil (208 mg, 82%): 1H NMR (CDCl3, 600 MHz): δ = 4.28 (ddd, J = 7.4, 5.2, 3.5 Hz, 1Ht), 4.02 (dd, J = 5.1, 2.5 Hz, 1Ht′), 3.48 (d, J = 5.2 Hz, 1Ht), 3.40 (d, J = 5.1 Hz, 1Ht′), 2.54 (tt, J = 11.4, 3.5 Hz, 1Ht), 2.44 (td, J = 7.4, 2.8 Hz, 2Ht′), 1.85−1.75, 1.75−1.58, 1.55−1.41, 1.36−1.21, 1.21−1.08 (5m, 24Ht + 23Ht′), 0.87 (2t, J = 7.1, 0.8 Hz, 3Ht + 3Ht′) ppm; 13C{1H} NMR (CDCl3, 151 MHz): δ = 215.5, 212.6, 80.9, 75.1, 46.1, 41.5, 38.4, 33.9, 32.0, 31.9, 30.3, 30.0, 29.6, 29.6, 29.4, 29.4, 29.3, 29.2, 27.6, 26.7, 26.2, 26.0, 26.0, 25.8, 25.3, 25.3, 25.3, 23.8, 22.8, 22.8, 14.2, 14.2 ppm; HRMS (ESI+) m/z calcd for C16H30O2Na+ [M + Na]+ 277.2143, found 277.2138; IR: (cm−1) = 3480, 2924, 2854, 1705, 1450, 1365, 1119, 1065, 955, 725. (5R)-1-Hydroxy-5-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17yl)-1-phenylhexan-2-one (2u). In an oven-dried Schlenk flask, lithium (120 mg, 20.0 mmol, 20 equiv) was added to a solution of 4,4′-di-tert-butylbiphenyl (DBB) (532 mg, 2.00 mmol, 2.0 equiv) in THF (20 mL) at 0 °C. The resulting teal-blue-colored Li/DBB solution was stirred at this temperature for 2 h and was then cooled to −78 °C. A solution of 13b (632 mg, 1.00 mmol) in THF (5 mL) was slowly added to the stirred solution of the Li/DBB at −78 °C. After the addition was completed, the reaction mixture was stirred at −78 °C overnight and was quenched by dropwise addition of a saturated aqueous solution of NH4Cl (5 mL). The reaction mixture was allowed to warm to ambient temperature and was transferred via cannula into brine. The solution was extracted with diethyl ether (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 7:3), and the target compound 2u was obtained as a colorless solid (181 mg, 39%): 1 H NMR (CDCl3, 400 MHz): δ = 7.34−7.21 (m, 5H), 5.03 (d, J = 6.59 Hz, 1H), 4.36 (s, 1H), 3.54 (dt, J = 11.08, 5.99 Hz, 1H), 2.31− 2.11 (m, 2H), 1.92−1.39 (m, 12H), 1.36−0.80 (m, 24H), 0.71 (d, J = 6.53 Hz, 1H), 0.61 (d, J = 6.02 Hz, 1H), 0.51 (d, J = 11.39 Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 210.3, 210.2, 138.2, 138.2, 129.0, 128.7, 127.5, 127.5, 79.9, 79.7, 71.8, 56.5, 56.5, 56.0, 55.9, 42.8, 42.2, 42.1, 40.5, 40.2, 36.5, 35.9, 35.4, 35.3, 34.9, 34.8, 34.6, 30.6, 30.1, 30.0, 28.2, 28.1, 27.3, 26.5, 24.2, 24.2, 23.4, 20.9, 18.4, 18.2, 12.1, 12.1 ppm (presence of two diastereomers, similar results were observed by Donohoe and co-workers for analogous compounds17); HRMS (ESI+) m/z calcd for C31H46O3Na+ [M + Na]+ 489.3345, found 489.3344; IR: (cm−1) = 33945, 2932, 2862, 2337, 2252, 1713, 1450, 1373, 1033, 856, 648, 609. 2-Hydroxy-3,3-dimethyl-1-phenylbutan-1-one (2v). Following General Procedure 3 with pivaldehyde (0.56 mL, 5.2 mmol, 1.3 equiv) as the aldehyde component, the target compound 2v was obtained as a colorless oil (0.57 g, 74%): 1H NMR (CDCl3, 300 MHz): δ = 7.90−7.83 (m, 2H), 7.63−7.54 (m, 1H), 7.54−7.41 (m, 2H), 4.83 (dd, J = 8.1, 5.1 Hz, 1H), 3.50 (dd, J = 8.1, 5.0 Hz, 1H), 0.87 (d, J = 5.1 Hz, 9H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 204.3, 137.6, 133.7, 128.8, 128.6, 79.4, 36.5, 26.8 ppm; HRMS (ESI+) m/z calcd for C12H16O2Na+ [M + Na]+ 215.1043, found 215.1049; IR: (cm−1) = 2963, 2253, 1677, 1280, 1226, 1180, 979, 602. General Procedure 4 for the Synthesis of Alkynes. In a 10 mL Schlenk tube attached to the Ar line, acyloin (0.20 mmol, 1.0 equiv), diphenylphosphate (5.0 mg, 20 μmol, 0.1 equiv), and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv) were dissolved in t-amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. After the consumption of the acyloin was confirmed by TLC analysis, 1,1′carbonyldiimidazole (72 mg, 0.44 mmol, 2.2 equiv) was added (immediately after the addition, the reaction turned yellow/orange and CO2 evolution was observed); the resulting mixture was heated to 988


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The Journal of Organic Chemistry 100 °C in an aluminum block and stirred at this temperature for 9 h. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the crude product was adsorbed onto silica and purified by flash column chromatography (pentane). General Procedure 5 for the Synthesis of Alkynes. In a 10 mL Schlenk tube attached to the Ar line, acyloin (0.20 mmol, 1.0 equiv), diphenylphosphate (5.0 mg, 20 μmol, 0.1 equiv), and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv) were dissolved in t-amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. After the consumption of the acyloin was confirmed by TLC analysis, 1,1′carbonyldiimidazole (72 mg, 0.44 mmol, 2.2 equiv) was added (immediately after the addition, the reaction turned yellow/orange and CO2 evolution was observed). The resulting mixture was heated to 100 °C in an aluminum block and stirred at this temperature for 24 h. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the crude product was adsorbed onto silica and purified by flash column chromatography (pentane/Et2O = 8:2). General Procedure 6 for the Synthesis of Alkynes. In a 10 mL Schlenk tube, acyloin (0.20 mmol, 1.0 equiv), diphenylphosphate (5.0 mg, 20 μmol, 0.1 equiv), and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv) were dissolved in t-amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. After the consumption of the acyloin was confirmed by TLC analysis, 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol, 2.2 equiv) was added (immediately after the addition, the reaction turned yellow/orange and CO2 evolution was observed) and the reaction vessel was tightly sealed. The resulting mixture was heated to 100 °C in an aluminum block, stirred for 4 h, and allowed to cool to room temperature, and the pressure was then released. The flask was resealed, and the reaction mixture was heated to 100 °C and stirred at this temperature for 32 h. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the crude product was adsorbed onto silica and purified by flash column chromatography (pentane). 1,2-Diphenylacetylene (1a).26 Following General Procedure 4 with benzoin (2a) (42.6 mg, 0.200 mmol) as the acyloin component, the target compound 1a was obtained as a colorless solid (24.9 mg, 70%): 1H NMR (CDCl3, 300 MHz): δ = 7.50−7.47 (m, 4H), 7.29− 7.24 (m, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 131.7, 128.5, 128.4, 123.4, 89.5 ppm. 1,2-Di-p-tolylacetylene (1b).26 Following General Procedure 4 with 2-hydroxy-1,2-di-p-tolylethan-1-one (2b) (48.3 mg, 0.200 mmol) as the acyloin component, the target compound 1b was obtained as a colorless solid (30.5 mg, 71%): 1H NMR (CDCl3, 400 MHz): δ = 7.43 (d, J = 8.1, 4H), 7.16 (d, J = 8.1, 4H), 2.37 (s, 6 H) ppm; 13 C{1H} NMR (CDCl3, 101 MHz): δ = 138.3, 131.6, 129.2, 120.5, 89.0, 21.7 ppm. 1,2-Bis(4-methoxyphenyl)ethyne (1c).26 Following General Procedure 5 with 2-hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one (2c) (54.4 mg, 0.200 mmol) as the acyloin component, the target compound 1c was obtained as a colorless solid (26.2 mg, 55%): 1H NMR (CDCl3, 400 MHz): δ = 7.45 (d, J = 8.9 Hz, 4H), 6.87 (d, J = 8.9 Hz, 4H), 3.83 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 159.4, 132.9, 115.7, 114.0, 88.0, 55.3 ppm. 1,2-Bis(4-bromophenyl)ethyne (1d).26 Following General Procedure 4 with 1,2-bis(4-bromophenyl)-2-hydroxyethan-1-one (2d) (74.0 mg, 0.200 mmol) as the acyloin component, the target compound 1d was obtained as a colorless solid (40.8 mg, 61%): 1H NMR (CDCl3, 300 MHz): δ = 7.49 (d, J = 8.5, 4H), 7.38 (d, J = 8.5, 4H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 133.1, 131.8, 122.9, 122.0, 89.6 ppm. 1,2-Bis(4-chlorophenyl)ethyne (1e).26 Following General Procedure 4 with 1,2-bis(4-chlorophenyl)-2-hydroxyethan-1-one (2e) (56.2 mg, 0.200 mmol) as the acyloin component, the target compound 1e was obtained as a colorless solid (31.6 mg, 64%): 1H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 8.6, 4H), 7.33 (d, J = 8.6, 4H) ppm;

C{1H} NMR (CDCl3, 75 MHz): δ = 134.7, 132.9, 128.9, 121.6, 89.3 ppm. Dimethyl 4,4′-(Ethyne-1,2-diyl)dibenzoate (1f).26 Following General Procedure 5 with 4,4′-(1-hydroxy-2-oxoethane-1,2-diyl)dibenzoate (2f) (65.6 mg, 0.200 mmol) as the acyloin component, the target compound 1f was obtained as a colorless solid (31.1 mg, 53%): 1H NMR (CDCl3, 300 MHz): δ = 8.04 (d, J = 8.5 Hz, 4H), 7.60 (d, J = 8.5 Hz, 4H), 3.93 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 166.6, 131.8, 130.2, 130.1, 129.7, 127.5, 126.8, 91.5, 52.4 ppm. 1,2-Bis(3-chlorophenyl)ethyne (1g).26 Following General Procedure 4 with 1,2-bis(3-chlorophenyl)-2-hydroxyethan-1-one (2g) (56.2 mg, 0.200 mmol) as the acyloin component, the target compound 1g was obtained as a colorless solid (32.1 mg, 65%): 1H NMR (CDCl3, 400 MHz): δ = 7.52 (t, J = 1.8 Hz, 2H), 7.40 (dt, J = 7.1, 1.7 Hz, 2H), 7.36−7.25 (m, 4H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 134.4, 131.6, 129.9, 129.8, 129.0, 124.6, 89.2 ppm. 1,2-Di(furan-2-yl)ethyne (1h).27 Following General Procedure 5 with furoin (2h) (38.4 mg, 0.200 mmol) as the acyloin component, the target compound 1h was obtained as a colorless solid (15.8 mg, 50%): 1H NMR (CDCl3, 400 MHz): δ = 7.44 (dd, J = 1.9, 0.7 Hz, 2H), 6.71 (dd, J = 3.4, 0.7 Hz, 2H), 6.43 (dd, J = 3.4, 1.9 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 144.4, 136.6, 116.6, 111.3, 83.4 ppm. Methyl 4-((4-Methoxyphenyl)ethynyl)benzoate (1i).26 Following General Procedure 5 with methyl 4-(1-hydroxy-2-(4-methoxyphenyl)2-oxoethyl)benzoate (2i) (60.0 mg, 0.200 mmol) as the acyloin component, the target compound 1i was obtained as a colorless solid (27.6 mg, 52%): 1H NMR (CDCl3, 400 MHz): δ = 8.01 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 166.8, 160.2, 133.4, 131.4, 129.6, 129.3, 128.5, 114.9, 114.2, 92.7, 87.7, 55.5, 52.4 ppm. 1-Bromo-2-((4-bromophenyl)ethynyl)benzene (1j).28 Following General Procedure 4 with 2-(2-bromophenyl)-1-(4-bromophenyl)-2hydroxyethan-1-one (2j) (74.0 mg, 0.200 mmol) as the acyloin component, the target compound 1j was obtained as a colorless solid (42.3 mg, 63%): 1H NMR (CDCl3, 400 MHz): δ = 7.62 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.50 (dm, J = 8.6 Hz, 2H), 7.44 (dm, J = 8.6 Hz, 2H), 7.30 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 7.7, 1.7 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 133.2, 133.1, 132.5, 131.7, 129.7, 127.1, 125.6, 125.1, 123.0, 121.9, 92.8, 89.1 ppm. 1-Chloro-2-((4-chlorophenyl)ethynyl)benzene (1k). Following General Procedure 4 with 2-(2-chlorophenyl)-1-(4-chlorophenyl)-2hydroxyethan-1-one (2k) (56.2 mg, 0.200 mmol) as the acyloin component, the target compound 1k was obtained as a colorless solid (33.0 mg, 67%): 1H NMR (CDCl3, 400 MHz): δ = 7.57−7.53 (m, 1H), 7.50 (dm, J = 8.5 Hz, 2H), 7.45−7.42 (m, 1H), 7.34 (dm, J = 8.5 Hz, 2H), 7.30−7.20 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 136.1, 134.8, 133.3, 133.1, 129.6, 129.5, 128.9, 126.6, 123.0, 121.5, 93.5, 87.2 ppm; HRMS (pAPCI) m/z calcd for C14H8Cl2+ [M]+ 245.9998, found 245.9993; IR: (cm−1) = 2322, 2222, 1489, 1088, 1057, 826, 748. 1-Iodo-4-(phenylethynyl)benzene (1l).29 Following General Procedure 6 with 2-hydroxy-2-(4-iodophenyl)-1-phenylethan-1-one (2l) (67.6 mg, 0.200 mmol) as the acyloin component, the target compound 1l was obtained as a colorless solid (40.0 mg, 65%): 1H NMR (CDCl3, 300 MHz): δ = 7.69 (d, J = 8.4 Hz, 2H), 7.61−7.46 (m, 2H), 7.40−7.32 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 137.5, 133.1, 131.6, 128.6, 128.4, 122.9, 122.8, 94.1, 90.8, 88.5 ppm. 1-Chloro-2-((3-chlorophenyl)ethynyl)benzene (1m).30 Following General Procedure 4 with 2-(2-chlorophenyl)-1-(3-chlorophenyl)-2hydroxyethan-1-one (2m) (56.2 mg, 0.200 mmol) as the acyloin component, the target compound 1m was obtained as a colorless solid (33.0 mg, 67%): 1H NMR (CDCl3, 300 MHz): δ = 7.56−7.53 (m, 2H), 7.46−7.40 (m, 2H), 7.35−7.21 (m, 4H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 136.1, 134.3, 133.3, 131.6, 129.9, 129.7, 129.7, 129.4, 128.9, 126.5, 124.6, 122.8, 93.0, 87.3 ppm. 13

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The Journal of Organic Chemistry 1,2-Dicyclohexylethyne (1n).31 Following General Procedure 6 with 1,2-dicyclohexyl-2-hydroxyethan-1-one (2n) (44.9 mg, 0.200 mmol) as the acyloin component, the target compound 1n was obtained as a colorless oil (19.7 mg, 52%): 1H NMR (CDCl3, 300 MHz): δ = 2.37−2.29 (m, 2H), 1.78−1.64 (m, 8H), 1.50−1.23 (m, 12H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 84.7, 33.4, 29.2, 26.2, 25.0 ppm; GC-MS (EI) m/z (%) = 190.1 (18), 119.0 (20), 105.0 (29), 93.0 (63), 91.0 (89), 79.0 (100), 77.0 (44), 67.0 (69), 55.0 (37), 41.0 (57), 39.0 (26). Oct-4-yne (1o).6 Following General Procedure 6 with butyroin (2o) (28.8 mg, 0.200 mmol) as the acyloin component, the target compound 1o was obtained as a colorless oil (10.8 mg, 49%): 1H NMR (CDCl3, 400 MHz): δ = 2.12 (t, J = 7.2 Hz, 4H), 1.50 (qt, J = 7.2, 7.2 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 80.2, 22.6, 20.8, 13.5 ppm. 1,6-Diphenylhex-3-yne (1p).32 Following General Procedure 6 with 4-hydroxy-1,6-diphenylhexan-3-one (2p) (53.6 mg, 0.200 mmol) as the acyloin component, the target compound 1p was obtained as a colorless oil (24.8 mg, 53%): 1H NMR (CDCl3, 300 MHz): δ = 7.33−7.25 (m, 4H), 7.25−7.17 (m, 6H), 2.79 (t, J = 7.5 Hz, 4H), 2.44 (t, J = 7.5 Hz, 4H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 141.0, 128.5, 128.3, 126.2, 80.3, 35.5, 21.0 ppm. 1-Chloro-4-(3-methylbut-1-yn-1-yl)benzene (1q). Following General Procedure 6 with a 1:0.87 mixture of 1-(4-chlorophenyl)-2hydroxy-3-methylbutan-1-one and 1-(4-chlorophenyl)-1-hydroxy-3methylbutan-2-one (2q + 2q′) (42.4 mg, 0.200 mmol) as the acyloin component, the target compound 1q was obtained as a pale yellow solid (19.3 mg, 53%): 1H NMR (CDCl3, 300 MHz): δ = 7.35 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 2.79 (sept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 133.5, 132.9, 128.6, 122.7, 96.9, 78.8, 23.1, 21.3 ppm; HRMS (pAPCI) m/z calcd for C11H10Cl [M − H]+ 177.0466, found 177.0466; IR: (cm−1) = 2986, 2931, 2376, 2222, 1489, 1280, 1087, 1010, 710. Prop-1-yne-1,3-diyldibenzene (1r).33 Following General Procedure 6 with 1-hydroxy-1,3-diphenylpropan-2-one (2r′) (45.2 mg, 0.200 mmol) as the acyloin component, the target compound 1r was obtained as a colorless oil (26.1 mg, 68%): 1H NMR (CDCl3, 500 MHz): δ = 7.46 (dd, J = 6.5, 3.3 Hz, 2H), 7.44−7.41 (m, 2H), 7.35 (dd, J = 7.6, 7.6 Hz, 2H), 7.30 (dd, J = 4.9, 2.0 Hz, 3H), 7.28−7.24 (m, 1H), 3.85 (s, 2H) ppm; 13C{1H} NMR (CDCl3, 126 MHz): δ = 136.9, 131.8, 128.7, 128.4, 128.1, 128.0, 126.8, 123.8, 87.7, 82.8, 25.9 ppm. Cyclotridecyne (1s).34 Following General Procedure 6 with 2hydroxycyclotridecan-1-one (2s) (42.4 mg, 0.200 mmol) as the acyloin component, the target compound 1s was obtained as a colorless oil (18.5 mg, 52%): 1H NMR (CDCl3, 500 MHz): δ = 2.20−2.15 (m, 4H), 1.52−1.44 (m, 8H), 1.44−1.34 (m, 10H) ppm; 13 C{1H} NMR (CDCl3, 126 MHz): δ = 81.3, 27.7, 26.4, 25.9, 25.6, 25.5, 18.8 ppm. Dec-1-yn-1-ylcyclohexane (1t). Following General Procedure 6 with 1-cyclohexyl-2-hydroxydecan-1-one (2t) (50.8 mg, 0.200 mmol) as the acyloin component, the target compound 1t was obtained as a colorless oil (23.2 mg, 53%): 1H NMR (CDCl3, 400 MHz): δ = 2.36−2.28 (m, 1H), 2.15 (td, J = 7.04, 2.24 Hz, 2H), 1.83−1.64 (m, 4H), 1.53−1.45 (m, 3H), 1.42−1.34 (m, 3H), 1.33−1.23 (m, 12H), 0.91−0.80 (m, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 84.8, 80.3, 33.4, 32.0, 29.9, 29.4, 29.4, 29.3, 29.3, 29.0, 26.1, 25.1, 22.8, 18.9, 14.3 ppm; HRMS (pAPCI) m/z calcd for C16H28 [M]+ 220.2191, found 220.2186; IR: (cm−1) = 2924, 2854, 1450, 1373, 1157, 748, 570, 555. (3R,5R,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-phenylhex-5-yn-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1u). In a 10 mL Schlenk tube attached to the Ar line, (5R)-1hydroxy-5-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-phenylhexan-2-one (2u) (93.3 mg, 0.200 mmol), diphenylphosphate (5.0 mg, 20 μmol, 0.1 equiv), and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv) were dissolved in t-amyl-OH (2.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2 equiv) was added. The reaction mixture was

stirred at room temperature for 30 h. After the consumption of the acyloin was confirmed by TLC analysis, 1,1′-carbonyldiimidazole (90 mg, 0.55 mmol, 2.75 equiv) was added (immediately after the addition, the reaction turned yellow/orange and CO2 evolution was observed). The resulting mixture was heated to 100 °C in an aluminum block and stirred at this temperature for 30 h. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the crude product was adsorbed onto silica and purified by flash column chromatography (pentane/EtOAc = 8:2). The target compound 1u was obtained as a colorless solid (32.8 mg, 38%; since the isolation of this compound proved to be challenging, an NMR yield was determined and found to be 47%): 1H NMR (CDCl3, 400 MHz): δ = 7.42−7.36 (m, 2H), 7.28−7.26 (m, 3H), 3.69−3.56 (m, 1H), 2.51−2.39 (m, 1H), 2.38− 2.25 (m, 1H), 2.03−1.94 (m, 1H), 1.93−1.72 (m, 4H), 1.70−1.50 (m, 5H), 1.46−1.03 (m, 17H), 1.00−0.89 (m, 6H), 0.68−0.63 (m, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 131.6, 128.3, 127.6, 124.3, 91.0, 80.5, 72.0, 56.7, 56.2, 43.0, 42.3, 40.6, 40.3, 36.6, 36.0, 35.5, 35.5, 35.2, 34.7, 30.7, 28.4, 27.4, 26.6, 24.4, 23.5, 21.0, 18.5, 16.7, 12.2 ppm; HRMS (ESI+) m/z calcd for C31H44ONa+ [M + Na]+ 455.3290, found 455.3294; IR: (cm−1) = 2924, 2862, 2238, 1697, 1450, 1374, 1033, 910, 756, 733, 563. (3,3-Dimethylbut-1-yn-1-yl)benzene (1v).35 Following General Procedure 6 with 2-hydroxy-3,3-dimethyl-1-phenylbutan-1-one (2v) (39.5 mg, 0.200 mmol) as the acyloin component, the target compound 1v was obtained as a colorless oil (19.5 mg, 50%): 1H NMR (CDCl3, 300 MHz): δ = 7.32−7.23 (m, 2H), 7.21−7.10 (m, 3H), 1.22 (s, 9H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 131.7, 128.3, 127.5, 124.2, 98.7, 79.1, 31.2, 28.1 ppm. (E)-N′-(2-Hydroxy-1,2-diphenylethylidene)-4-methylbenzenesulfonohydrazide (5). Benzoin 2a (0.42 g, 2.0 mmol) was stirred in MeOH (2.0 mL), and tosylhydrazine (4.5 g, 24 mmol, 1.2 equiv) was added. The slurry was stirred overnight at rt. After filtration, the solid was washed with MeOH (20 mL) several times until the filtrate was colorless. The colorless solid was dried under reduced pressure (0.59 g, 81%): 1H NMR (500 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.23−7.13 (m, 3H), 6.97 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 7.2 Hz, 2H), 5.35 (d, J = 5.1 Hz, 1H), 4.10 (d, J = 5.1 Hz, 1H), 2.49 (s, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ = 157.4, 144.5, 139.0, 134.9, 130.3, 129.9, 129.6, 129.5, 128.3, 128.1, 127.9, 127.4, 127.0, 76.2, 21.7 ppm; HRMS (ESI+) m/z calcd for C21H20N2O3SNa+ [M + Na]+ 403.1087, found 403.1108. IR: (cm−1) = 3518, 3187, 1420, 1335, 1173, 772, 634. (E)-N′-(2-(1H-Imidazol-1-yl)-1,2-diphenylethylidene)-4-methylbenzenesulfonohydrazide (7). The hydrazone 5 (1.14 g, 3.00 mmol) was stirred in toluene (0.500 mL), and CDI (0.400 g, 3.00 mmol, 1 equiv) was added. The reaction mixture turned yellow, and gas evolution (CO2) was observed. The mixture was stirred at room temperature for 12 h. The reaction mixture was filtered, and the filtrate was dried under reduce pressure. The product was obtained as a colorless solid without further purification (0.864 g, 67%): 1H NMR (500 MHz, DMSO-d6): δ = 7.60 (t, J = 1.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.40−7.35 (m, 5H), 7.32 (m, 1H), 7.31 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.23−7.19 (m, 2H), 7.04 (t, J = 1.3 Hz, 1H), 6.89 (t, J = 1.1 Hz, 1H), 6.67 (s, 1H), 2.39 (s, 3H) ppm; 13C{1H} NMR (126 MHz, DMSO-d6): δ = 152.6, 143.1, 137.1, 136.9, 135.5, 132.2, 129.6, 129.1, 128.6, 128.6, 128.3, 128.3 127.8, 127.8, 127.7, 119.4, 63.8, 21.0 ppm; HRMS (ESI+) m/z calcd for C24H23N4O2S+ [M + H]+ 431.1536, found 431.1548; IR: (cm−1) = 1343, 1227, 1165, 1073, 918, 818, 650. 2-Phenyl-2-((trimethylsilyl)oxy)acetonitrile (9).36 Benzaldehyde (0.81 mL, 8.0 mmol, 1.0 equiv) was added dropwise to a solution of ZnI2 (tip of a spatula) in trimethylsilylcyanide (1.1 mL, 8.8 mmol, 1.1 equiv) at room temperature. The resulting reaction mixture was stirred for 5 h at 100 °C. The reaction mixture was allowed to cool to room temperature and was directly purified by flash column chromatography (pentane/EtOAc = 9:1). The product 9 was obtained as a light yellow oil (1.4 g, 85%): 1H NMR (CDCl3, 300 MHz): δ = 7.51−7.45 (m, 2H), 7.45−7.38 (m, 3H), 5.50 (s, 1H), 990


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filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9:1), and the target compound 13b was obtained as a colorless solid (379 mg, 60%): 1H NMR (CDCl3, 400 MHz): δ = 7.98 (d, J = 7.71 Hz, 2H), 7.52 (t, J = 7.48 Hz, 1H), 7.39 (t, J = 7.63 Hz, 2H), 4.95 (d, J = 5.98 Hz, 1H), 4.81 (d, J = 5.92 Hz, 1H), 4.68 (tt, J = 10.92, 4.79 Hz, 1H), 2.38 (s, 1H), 2.28 (s, 1H), 2.20−1.93 (m, 6H), 1.90−1.74 (m, 4H), 1.69−0.77 (m, 30H), 0.73−0.63 (m, 3H), 0.52 (d, J = 5.61 Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 101 MHz): δ = 173.3, 173.2, 170.7, 165.7, 133.0, 130.5, 129.7, 128.5, 77.6, 76.5, 76.5, 74.5, 56.6, 56.0, 55.9, 42.8, 42.1, 41.3, 41.3, 40.6, 40.3, 40.3, 35.9, 35.3, 35.3, 35.2, 34.7, 33.9, 32.4, 31.3, 31.2, 30.9, 30.8, 28.1, 27.2, 26.8, 26.5, 24.6, 24.4, 24.3, 23.5, 21.6, 21.0, 18.3, 12.2 ppm (presence of two diastereomers, similar results were observed by Donohoe and coworkers for analogous compounds17); HRMS (ESI+) m/z calcd for C40H56O6Na+ [M + Na]+ 655.3975, found 655.3948; IR: (cm−1) = 2947, 1720, 1273, 1250, 1172, 1118, 1026, 648, 570. (rac)-3-Hydroxybicyclo[2.2.1]heptan-2-yl Nonanoate (14a). A solution of nonanoyl chloride (352 mg, 2.00 mmol) in dichloromethane (10.0 mL) was added to a solution of bicyclo[2.2.1]heptane2,3-diol (384 mg, 3.00 mmol, 1.5 equiv) in dichloromethane (15.0 mL) at 0 °C over 1 h. The reaction mixture was stirred overnight and during this time allowed to slowly warm to room temperature. The reaction was quenched by addition of a saturated aqueous solution of sodium bicarbonate (25 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9:1), and the target compound 14a was obtained as a yellow oil (428 mg, 80%): 1H NMR (CDCl3, 300 MHz): δ = 4.55 (dd, J = 5.96, 1.73 Hz, 1H), 3.84 (d, J = 6.19 Hz, 1H), 2.34 (t, J = 7.58 Hz, 2H), 2.26−2.16 (m, 2H), 2.02 (s, 1H), 1.79 (dt, J = 10.37, 1.97 Hz, 1H), 1.70−1.57 (m, 2H), 1.55−1.45 (m, 2H), 1.30−1.22 (m, 10H), 1.20−1.10 (m, 3H), 0.91−0.84 (m, 3H) ppm; 13 C{1H} NMR (CDCl3, 75 MHz): δ = 174.0, 78.2, 75.8, 43.4, 40.9, 34.5, 32.8, 31.9, 29.3, 29.3, 29.2, 25.2, 24.6, 24.5, 22.8, 14.2 ppm; HRMS (ESI+) m/z calcd for C16H28O3Na+ [M + Na]+ 291.1936, found 291.1940; IR: (cm−1) = 3341, 2862, 1712, 1450, 1373, 1033, 648. (rac)-3-Hydroxybicyclo[2.2.1]heptan-2-yl(4R)-4((3R,5R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (14b). A solution of (3R,5R,8R,9S,10S,13R,14S,17R)-17-((R)-5-chloro-5-oxopentan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (872 mg, 2.00 mmol) in dichloromethane (10 mL) was added to a solution of bicyclo[2.2.1]heptane-2,3-diol (384 mg, 3.00 mmol, 1.5 equiv) in dichloromethane (15 mL) at 0 °C over 1 h. The reaction mixture was stirred overnight and allowed to slowly warm to room temperature during this time. The reaction was quenched by addition of a saturated aqueous solution of sodium bicarbonate (25 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9:1), and the target compound 14b was obtained as a colorless solid (739 mg, 70%): 1H NMR (CDCl3, 400 MHz): δ = 4.74−4.64 (m, 1H), 4.52 (d, J = 5.92 Hz, 1H), 3.82 (d, J = 5.90 Hz, 1H), 2.42−2.31 (m, 1H), 2.30−2.22 (m, 3H), 2.19 (d, J = 13.95 Hz, 1H), 2.09 (s, 3H), 2.00 (s, 1H), 1.86−1.73 (m, 6H), 1.71−1.60 (m, 1H), 1.56−0.96 (m, 24H), 0.90−0.88 (m, 6H), 0.62 (s, 3H) ppm; 13 C{1H} NMR (CDCl3, MHz): δ = 174.3, 174.2, 170.7, 78.2, 78.1, 75.7, 75.7, 74.5, 56.6, 56.1, 43.4, 42.8, 42.0, 40.8, 40.5, 40.2, 35.9, 35.4, 35.4, 35.1, 34.7, 32.8, 32.3, 31.3, 31.3, 31.1, 31.1, 28.3, 27.1, 26.7, 26.4, 24.6, 24.5, 24.3, 23.4, 21.5, 20.9, 18.4, 12.1 ppm (39 signals, due to the presence of two inseparable diastereomers, similar results were observed by Donohoe and co-workers for analogous compounds17); HRMS (ESI+) m/z calcd for C33H52O5Na+ [M + Na]+ 551.3712, found 551.3709; IR: (cm−1) = 2939, 2870, 1720, 1242, 1165, 1026, 648.

0.24 (s, 9H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 136.4, 129.5, 129.1, 126.5, 119.3, 63.8, −0.1 ppm. 3,5-Diphenyl-1H-pyrazole (10).37 Following General Procedure 6 with 2-hydroxy-1,3-diphenylpropan-1-one (2r) (45.2 mg, 0.200 mmol) as the acyloin component, the target compound 10 was obtained as a colorless solid (23.3 mg, 53%): 1H NMR (CDCl3, 500 MHz): δ = 7.72 (dd, J = 5.2, 3.3 Hz, 4H), 7.40−7.35 (m, 4H), 7.33 (ddd, J = 4.8, 2.0, 1.9 Hz, 2H), 6.83 (s, 1H) ppm; 13C{1H} NMR (CDCl3, 126 MHz): δ = 129.0, 128.3, 125.8, 100.2 ppm. 2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11).38 SOCl2 (0.80 mL, 11 mmol, 1.1 equiv) was added dropwise to a solution of mandelic acid (1.5 g, 10 mmol, 1.0 equiv) in dry MeOH (20 mL) at 0 °C, stirred for 45 min at this temperature, allowed to warm to room temperature, and stirred for an additional 90 min. The reaction was quenched by addition of sat. aq NaHCO3 solution (15 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting 2-hydroxy-2-phenylacetyl chloride was directly used in the following step. AlMe3 (2 M in toluene, 6.0 mL, 12 mmol, 2.0 equiv) was added dropwise to a solution of N,Odimethylhydroxylamine hydrochloride (1.2 g, 12 mmol, 2.0 equiv) in toluene (12 mL) at 0 °C, stirred at this temperature for 1 h, allowed to warm to room temperature, and stirred for an additional 2 h. The reaction mixture was cooled to 0 °C, and a solution of 2-hydroxy-2phenylacetyl chloride (6.0 mmol, 1.0 equiv) in toluene (6 mL) was added dropwise. The resulting mixture was stirred overnight while being allowed to slowly warm to room temperature. The reaction mixture was again cooled to 0 °C, and aq HCl (1 M, 6 mL) was added dropwise at this temperature. The crude mixture was extracted with EtOAc (3 × 7 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (pentane/EtOAc = 3:1). The target compound 11 was obtained as a colorless solid (0.83 g, 71%): 1H NMR (CDCl3, 500 MHz): δ = 7.39−7.32 (m, 4H), 7.32−7.28 (m, 1H), 5.34 (d, J = 5.8 Hz, 1H), 4.28 (d, J = 6.4 Hz, 1H), 3.21 (s, 6 H) ppm; 13C{1H} NMR (CDCl3, 126 MHz): δ = 173.7, 139.8, 128.8, 128.4, 127.7, 71.7, 60.8, 32.8 ppm. (rac)-3-(Nonanoyloxy)bicyclo[2.2.1]heptan-2-yl Cyclohexanecarboxylate (13a). A solution of cyclohexanecarbonyl chloride (584 mg, 4.00 mmol, 2 equiv) in dichloromethane (5.00 mL) was added to a solution of (rac)-3-hydroxybicyclo[2.2.1]heptan-2-yl nonanoate (14a) (536 mg, 2.00 mmol), DMAP (24.4 mg, 0.200 mmol, 1 mol %), and pyridine (355 μL, 4.40 mmol, 2.2 equiv) in dichloromethane (12.0 mL). The reaction mixture was stirred at room temperature overnight and was quenched with a saturated aqueous solution of sodium bicarbonate (25 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (pentane/EtOAc = 9.5:0.5), and the target compound 13a was obtained as a yellow oil (559 mg, 74%): 1H NMR (CDCl3, 300 MHz): δ = 4.70−4.64 (m, 2H), 2.28−2.17 (m, 5H), 1.91−1.68 (m, 5H), 1.67−1.47 (m, 5H), 1.43−1.34 (m, 2H), 1.34−1.10 (m, 16H), 0.91−0.80 (m, 3H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 175.1, 173.0, 76.6, 76.3, 43.3, 41.3, 41.2, 34.3, 33.6, 31.9, 29.4, 29.3, 29.2, 29.1, 29.1, 25.9, 25.5, 25.0, 24.5, 24.4, 22.7, 14.2 ppm; HRMS (ESI+) m/z calcd for C23H38O4Na+ [M + Na]+ 401.2668, found 401.2667; IR: (cm−1) = 2924, 2854, 1735, 1450, 1311, 1249, 1165, 1049, 732, 563. (rac)-3-(((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-Acetoxy-10,13dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)oxy)bicyclo[2.2.1]heptan-2-yl Benzoate (13b). A solution of benzoyl chloride (232 μL, 2.00 mmol, 2 equiv) in dichloromethane (2.00 mL) was added to a solution of 14b (528 mg, 1.00 mmol), DMAP (12.2 mg, 0.100 mmol, 1 mol %), and pyridine (178 μL, 2.20 mmol, 2.2 equiv) in dichloromethane (7.5 mL). The reaction mixture was stirred overnight and was quenched with a saturated aqueous solution of sodium bicarbonate (15 mL). The resulting mixture was extracted with dichloromethane (3 × 10 mL), and the combined organic layers were dried over MgSO4, 991


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The Journal of Organic Chemistry Bicyclo[2.2.1]heptane-2,3-diol (15).17 A solution of potassium permanganate (KMnO4) (2.4 g, 15 mmol, 1.5 equiv) and sodium hydroxide (0.52 g, 13 mmol, 1.3 equiv) in water (50 mL) was added to a solution of norbornene (1.0 g, 10 mmol) in tert-butanol (40 mL) and water (10 mL) at 0 °C. The reaction mixture was stirred for 1 h and was quenched with a saturated aqueous solution of sodium metabisulphite (Na2S2O5) until the solution turned colorless (40 mL). The mixture was filtered, and the tert-butanol was removed under reduced pressure. The remaining aqueous phase was extracted with EtOAc (4 × 30 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting product (15) was used in the following reaction without further purification (0.90 g, 70%): 1H NMR (CDCl3, 300 MHz): δ = 3.64 (d, J = 1.66 Hz, 2H), 3.50 (s, 2H), 2.11−2.09 (m, 2H), 1.72 (dt, J = 10.37, 1.94 Hz, 1H), 1.46−1.41 (m, 2H), 1.09−1.00 (m, 3H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 74.8, 43.1, 31.7, 24.6 ppm. Large Scale Synthesis of 1,2-Diphenylethyne (1a). In a 100 mL flask, benzoin (2a) (1.20 g, 5.60 mmol), diphenylphosphate (140 mg, 0.560 mmol, 0.1 equiv), and MgSO4·H2O (1.40 g, 10.1 mmol, 1.8 equiv) were dissolved in t-amyl-OH (40 mL) and tosylhydrazine (1.23 g, 6.72 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 36 h. After the consumption of the acyloin was confirmed by TLC, 1,1′-carbonyldiimidazole (2.01 g, 12.3 mmol, 2.2 equiv) was added (immediately after the addition, the reaction turned yellow/orange and CO2 evolution was observed) and the resulting mixture was heated to 100 °C in an oil bath and stirred at this temperature for 12 h. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the crude product was directly adsorbed onto silica and purified by flash column chromatography (pentane). The target compound 1a was obtained as a colorless solid (647 mg, 65%).

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(3) Fürstner, A. Alkyne metathesis. Handbook of Metathesis; WileyVCH Verlag GmbH & Co. KGaA: 2015; p 445. (4) (a) Sonogashira, K. Palladium-Catalyzed Alkynylation: Sonogashira Alkyne Synthesis. Handbook of Organopalladium Chemistry for Organic Synthesis; John Wiley & Sons, Inc.: 2003; p 493. (b) Le Vaillant, F.; Courant, T.; Waser, J. Room-temperature decarboxylative alkynylation of carboxylic acids using photoredox catalysis and EBX reagents. Angew. Chem., Int. Ed. 2015, 54, 11200. (c) Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y. Visible-light-induced chemoselective reductive decarboxylative alkynylation under biomolecule-compatible conditions. Chem. Commun. 2015, 51, 5275. (d) Huang, L.; Olivares, A. M.; Weix, D. J. Reductive decarboxylative alkynylation of Nhydroxyphthalimide esters with bromoalkynes. Angew. Chem. 2017, 129, 12063. (e) Smith, J. M.; Qin, T.; Merchant, R. R.; Edwards, J. T.; Malins, L. R.; Liu, Z.; Che, G.; Shen, Z.; Shaw, S. A.; Eastgate, M. D.; Baran, P. S. Decarboxylative alkynylation. Angew. Chem., Int. Ed. 2017, 56, 11906. (5) For example, see: Deng, J.; Wu, J.; Tian, H.; Bao, J.; Shi, Y.; Tian, W.; Gui, J. Alkynes from furans: A general fragmentation method applied to the synthesis of the proposed structure of Aglatomin B. Angew. Chem., Int. Ed. 2018, 57, 3617−3621 and references cited therein . (6) (a) Iwadare, T.; Adachi, I.; Hayashi, M.; Matsunaga, A.; Kitai, T. Decomposition of tosylhydrazones of benzoin, benzoin acetate and benzoin benzoate with alkali. Tetrahedron Lett. 1969, 10, 4447. (b) Wieland, P. Ü ber ein neues verfahren zur herstellung von. acetylenverbindungen. Helv. Chim. Acta 1970, 53, 171. (c) Bauer, D. P.; Macomber, R. S. A new route to acetylenes. J. Org. Chem. 1976, 41, 2640. (d) Kano, S.; Yokomatsu, T.; Ono, T.; Hibino, S.; Shibuya, S. A new synthesis of phenylalkynes from the p-Toluenesulfonylhydrazone of α-methylthioacetophenone. Synthesis 1978, 1978, 305. (e) Kano, S.; Yokomatsu, T.; Shibuya, S. New synthetic design for formation of carbon-carbon triple bonds. J. Org. Chem. 1978, 43, 4366. (f) Feldman, K. S.; Weinreb, C. K.; Youngs, W. J.; Bradshaw, J. D. Preparation and some subsequent transformations of tetraethynylmethane. J. Am. Chem. Soc. 1994, 116, 9019. (g) Iwadare, T.; Ichinohe, Y.; Orito, K. Decomposition of tosylhydrazones of benzoin, benzoin acetate, and benzoin benzoate with alkali and metal complex hydrides. Can. J. Chem. 1996, 74, 227. (h) Katritzky, A. R.; Wang, J.; Karodia, N.; Li, J. A novel transformation of esters to alkynes with 1-substituted benzotriazoles. J. Org. Chem. 1997, 62, 4142. (i) Gaber, A. E.-A. M.; Mohamed, O. S.; Aly, M. M. Thermal rearrangement of some benzoin arylsulfonylhydrazone derivatives. J. Anal. Appl. Pyrolysis 2005, 73, 53. (7) (a) Craig, J. C.; Moyle, M. The synthesis of acetylenes and allenes from enol phosphates. J. Chem. Soc. 1963, 3712. (b) Hargrove, R. J.; Stang, P. J. Vinyl triflates in synthesis. I. tert-Butylacetylene. J. Org. Chem. 1974, 39, 581. (c) Harrison, J. J. Dehydration of ketones to acetylenes. J. Org. Chem. 1979, 44, 3578. (d) Negishi, E.; King, A. O.; Klima, W. L.; Patterson, W.; Silveira, A. Conversion of methyl ketones into terminal acetylenes and (E)-trisubstituted olefins of terpenoid origin. J. Org. Chem. 1980, 45, 2526. (e) Hendrickson, J. B.; Hussoin, M. S. Facile Dehydration of Activated Ketones to Alkynes. Synthesis 1989, 1989, 217. (f) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.; Kerekes, A. D. A new method for the preparation of alkynes from vinyl triflates. Tetrahedron Lett. 1998, 39, 8613. (g) Yang, X.; Wu, D.; Lu, Z.; Sun, H.; Li, A. A mild preparation of alkynes from alkenyl triflates. Org. Biomol. Chem. 2016, 14, 5591. (8) (a) Seebach, D. Methods and possibilities of nucleophilic acylation. Angew. Chem., Int. Ed. Engl. 1969, 8, 639. (b) Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. The acyloin condensation. Organic Reactions 1976, 23, 259. (c) Hoyos, P.; Sinisterra, J.-V.; Molinari, F.; Alcántara, A. R.; Domínguez de María, P. Biocatalytic strategies for the asymmetric synthesis of α-hydroxy ketones. Acc. Chem. Res. 2010, 43, 288. (d) Pohl, M.; Dresen, C.; Beigi, M.; Müller, M. Acyloin and Benzoin Condensations. In Enzyme Catalysis in Organic Synthesis; Drauz, K., Gröger, H., May, O., Eds.; 2012. (e) Scheidt, K. A.; O’Bryan, E. A. Acyloin Coupling Reactions. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, The

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02941.

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Preparative procedures and analytical data (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Manuel van Gemmeren: 0000-0003-3080-3579 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the DFG (Project: GE 2945/1-1), Max Planck Society (Otto Hahn Award to M.v.G.), FCI (Liebig Fellowship to M.v.G.), Studienstiftung des deutschen Volkes (fellowship to F.G.), and WWU Münster. We thank the members of our NMR and MS departments for their excellent service. Furthermore, we are indebted to Prof. F. Glorius for his generous support.

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REFERENCES

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