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. Author manuscript; available in PMC: 2020 Mar 15.
Published in final edited form as: J Org Chem. 2019 Mar 6;84(6):3652–3655. doi: 10.1021/acs.joc.8b03223

Concise Approach to Cyclohexyne and 1,2-Cyclohexadiene Precursors

Jason V Chari 1,†, Francesca M Ippoliti 1,†, Neil K Garg 1,*
PMCID: PMC6935045  NIHMSID: NIHMS1064248  PMID: 30840455

Abstract

Silyl triflate precursors to cyclic alkynes and allenes serve as valuable synthetic building blocks. We report a concise and scalable synthetic approach to prepare the silyl triflate precursors to cyclohexyne and 1,2-cyclohexadiene. The strategy involves a retro-Brook rearrangement of an easily accessible cyclohexanone derivative, followed by triflation protocols. This simple, yet controlled, method should enable the further study of strained alkynes and allenes in chemical synthesis.

Graphical Abstract

graphic file with name nihms-1064248-f0001.jpg

The existence of arynes, cyclic alkynes, and cyclic allenes was once considered scientific conjecture.1 However, following a series of seminal studies in the 1950s and 1960s by Roberts and Wittig, strained intermediates such as benzyne (1), cyclohexyne (2), and 1,2-cyclohexadiene (3) were experimentally validated (Figure 1).2 In the modern era, these intermediates and their derivatives, such as heterocycles 4 and 5, have become valuable synthetic building blocks. Indeed, these strained intermediates have been used to synthesize important ligands,3 agrochemicals,4 medicinal agents,5 natural products,6 and materials.7 Studies of 1–5 have also led to new insights regarding reactivities and selectivities,8–10 particularly as a result of the distortion/interaction model investigated by Houk.11

Figure 1.

Figure 1.

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Strained cyclic alkynes and allenes.

In comparison to arynes, strained cyclic alkynes and allenes are less well studied. However, as exemplified in Figure 2 in the context of 2 and 3, cyclic alkynes and allenes can be trapped in an array of cycloadditions to give a diverse range of products.6,9,10 For example, cycloadducts 7, 9, and 11 have been obtained by (3 + 2) and (4 + 2) cycloadditions of cyclohexyne (2).9c,15 Analogously, 13, 15, and 16 have been prepared using (3 + 2), (2 + 2), and (4 + 2) cycloaddition reactions of 1,2-cyclohexadiene (3).9b,d,12,15 In all cases, the reactions proceed by the controlled formation of two new bonds, which may be either carbon–carbon bonds or carbon–heteroatom bonds. By virtue of using heteroatom-containing trapping agents, the carbocyclic strained intermediates can be used to access heterocyclic products (e.g., 7, 9, 11, 13, 16) that are of value to the pharmaceutical community. Lastly, it should be noted that the cycloadducts can bear one or more stereocenters, as seen in 11, 13, 15, and 16. In the case of substituted variants of 3, it has been shown that regioselectivities, relative stereochemistry, and even absolute stereo-chemistry can be controlled in reactions of cyclic allenes, thus boding well for future synthetic applications.9,10,13

Figure 2.

Figure 2.

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Cycloadditions of cyclohexyne (2) and 1,2-cyclohexadiene (3).

Given the synthetic utility of 2 and 3 (and derivatives thereof), chemists have sought to design practical synthetic precursors to these strained intermediates. Kobayashi’s breakthrough in the context of benzyne14 has unveiled silyl triflates as ideal precursors to strained intermediates by enabling mild reaction conditions, as will be highlighted later. In seminal studies, Guitián and co-workers demonstrated that silyl triflate precursors to 2 and 3 could be synthesized from cyclohexenone (17) (Figure 3).9a,b As depicted, Guitián’s approach initially utilized trimethylsilyl groups. The sequence involves α-bromination of 17, ketone protection and silylation, followed by deprotection to give 18. 1,4-Reduction of 18 furnishes intermediate 19a, which can undergo direct triflation to give cyclohexyne precursor 20a. Alternatively, protonation of 19a, followed by kinetic enolate formation and triflation, delivers 1,2-cyclohexadiene precursor 21a. Our laboratory questioned if intermediates reminiscent of 19a could be more rapidly accessed by another means. However, it should be emphasized that during our efforts, Mori disclosed an elegant method to prepare triethylsilyl derivatives 20b and 21b.15 Silyl enol ether 22 was treated with LDA and t-BuOK. This led to allylic deprotonation, followed by in situ silyl migration, to afford 23. Triflation of 23 provided 1,2-cyclohexadiene precursor 21b. On the other hand, the authors found that 23 could isomerize to 19b under modified reaction conditions, which, in turn, underwent triflation to give cyclohexyne precursor 20b. It should be noted that silyl triflates 20b and 21b required purification by conventional chromatography, followed by size-exclusion chromatography/HPLC. Nonetheless, Mori’s use of 22 as the key building block offers a clever strategy.

Figure 3.

Figure 3.

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Synthetic approaches to cyclohexyne precursors 20a and 20b and 1,2-cyclohexadiene precursors 21a and 21b.

We have developed an alternative means to access 20b and 21b, which is depicted in Figure 4. Our route begins with α-bromocyclohexanone (24), which is commercially available or can be easily prepared from cyclohexanone.16 Treatment of 24 with DABCO and triethylsilyl chloride in DMF at 0 °C gives silyl enol ether 25 as a single constitutional isomer. Next, we perform halogen–metal exchange using sec-BuLi. This proceeds with retro-Brook rearrangement to intercept anionic intermediate 19b in a highly controlled and concise manner. This strategy was conceived based on the well-established retro-Brook approach to aryne precursors.17 Following rearrangement, simply quenching 19b with PhNTf2 provides cyclohexyne precursor 20b in 97% yield. Alternatively, 19b can be quenched by the addition of aqueous sodium bicarbonate to furnish α-silyl ketone 26 in 95% yield. Our laboratory has previously reported the final step, wherein 26 can be converted to 21b by kinetic enolate formation, followed by triflation. This earlier result is depicted based on the literature yield.9d The routes to silyl triflates 20b and 21b are only two and three steps from 24, respectively, and notably do not require challenging chromatographic separations. Furthermore, all steps can be performed on gram-scale.

Figure 4.

Figure 4.

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Retro-Brook approach to silyl triflates 20b and 21b.

To illustrate the mildness and simplicity of strained cyclic alkyne and allene chemistry using silyl triflate precursors, two known examples from the literature are depicted (Figure 5). In the first, silyl triflate 20b is treated with 10 in the presence of TBAF in THF.15 This presumably leads to the formation of 2 in situ, which undergoes cycloaddition to give Diels–Alder adduct 11. In the second example, silyl triflate 21b is treated with CsF using nitrone 27 as the trapping agent.9d Interception of 1,2-cyclohexadiene (3) gives 28. The reactions proceed without the rigorous exclusion of water or oxygen, with 1.5−2.0 equiv of the trapping agents, and with minimal byproduct formation. As such, silyl triflates 20b and 21b can be transformed to value-added products using simple reaction conditions.

Figure 5.

Figure 5.

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Examples of cycloadditions using silyl triflates 20b and 21b.

In summary, we have developed a concise approach to silyl triflate precursors to cyclohexyne (2) and 1,2-cyclohexadiene (3). Our strategy relies on a retro-Brook rearrangement of a readily available silyl enol ether. The resulting enolate intermediate can be diverted through two different sequences. Direct triflation gives cyclohexyne precursor 20b, whereas protonation, followed kinetic enolization and triflation, affords 1,2-cyclohexadiene precursor 21b. We expect this concise and controlled strategy to access silyl triflate precursors will ultimately enable further studies involving strained alkynes and allenes in chemical synthesis.

EXPERIMENTAL SECTION

Materials and Methods.

Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (either freshly distilled or passed through activated alumina columns). All commercially obtained reagents were used as received unless otherwise specified. 1,4-Diazabicyclo[2.2.2]-octane (DABCO) was purchased from Acros Organics. sec-Butyllithium 1.4 M solution in cyclohexane (sec-BuLi) and cyclohexanone were obtained from Sigma-Aldrich. N-Phenylbis(trifluoromethanesulfonimide) and triethylsilyl chloride (TESCl) were purchased from Oakwood Chemical. Cyclohexanone and TESCl were distilled over CaH2 prior to use. Unless stated otherwise, reactions were performed at 23 °C. Thin-layer chromatography was conducted with EMD gel 60 F254 precoated plates (0.25 mm) and visualized using anisaldehyde or potassium permanganate staining. Silicycle Siliaflash P60 (particle size 0.040–0.063 mm) was used for flash column chromatography. 1H NMR spectra were recorded on Bruker spectrometers (at 500 MHz) and are reported relative to the residual solvent signal. Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR spectra were recorded on Bruker spectrometers (at 100 MHz) and are reported relative to the residual solvent signal. Data for 13C NMR spectra are reported in terms of chemical shift (δ ppm). IR spectra were obtained on a PerkinElmer UATR Two FT-IR spectrometer and are reported in terms of frequency of absorption (cm−1). DART-MS spectra were collected on a Thermo Exactive Plus MSD (Thermo Scientific) equipped with an ID-CUBE ion source, a Vapur Interface (IonSense Inc.), and an Orbitrap mass analyzer. Both the source and MSD were controlled by Excalibur software v. 3.0. The analyte was spotted onto OpenSpot sampling cards (IonSense Inc.) using CDCl3 as the solvent. Ionization was accomplished using UHP He (Airgas Inc.) plasma with no additional ionization agents. The mass calibration was carried out using Pierce LTQ Velos ESI (+) and (−) ion calibration solutions (Thermo Fisher Scientific).

Silyl Enol Ether 25:

To a stirred solution o16f known bromo ketone 2416 (2.01 g, 11.3 mmol, 1.00 equiv) in DMF (10.3 mL, 1.10 M) at 0 °C were added DABCO (2.93 g, 26.1 mmol, 2.30 equiv) and TESCl (3.1 mL, 18 mmol, 1.6 equiv) sequentially. The reaction mixture was stirred for 45 min before being quenched with deionized H2O (5 mL). The reaction was then allowed to warm to 23 °C before being diluted with hexanes (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted with hexanes (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resultant crude oil was purified via flash chromatography (100% hexanes) to afford silyl enol ether 25 (1.81 g, 55% yield) as a colorless oil: Rf 0.40 (100% hexanes); 1H NMR (500 MHz, CDCl3) δ 2.48–2.44 (m, 2H), 2.18–2.14 (m, 2H), 1.74–1.67 (m, 2H), 1.67–1.61 (m, 2H), 1.01 (t, J = 7.9, 9H), 0.71 (q, J = 7.9, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.7, 102.2, 34.4, 31.6, 24.6, 23.2, 6.9, 5.8; IR (film) 2937, 2876, 1666, 1215 cm−1; HRMS-APCI (m/z) [M + H]+ calcd for C12H24BrOSi+, 291.0780; found, 291.0780.

Cyclohexyne Precursor 20b:

A solution of silyl enol ether 25 (1.01 g, 3.47 mmol, 1.00 equiv) in THF (25 mL, 0.14 M) was cooled to −78 °C, and sec-BuLi (0.84 M in cyclohexane, 10 mL, 8.7 mmol, 2.5 equiv) was added dropwise over 13 min. After being stirred at −78 °C for 2 h, N-phenylbis(trifluoromethanesulfonimide) (6.19 g, 17.3 mmol, 5.00 equiv) as a solution in THF (15 mL, 1.2 M) was added dropwise over 15 min. After being stirred at −78 °C for 10 min, the reaction mixture was allowed to warm to 23 °C. After being stirred at 23 °C for 14 h, the reaction was quenched with saturated aqueous NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude oil was purified via flash chromatography (100% hexanes) using silica gel neutralized with triethylamine to afford cyclohexyne precursor 20b (1.15 g, 97% yield) as a light yellow oil: Rf 0.52 (100% hexanes); spectral data match those previously reported.15

α-Silyl Ketone 26:

To a solution of silyl enol ether 25 (1.00 g, 3.43 mmol, 1.00 equiv) in THF (40 mL, 0.085 M) at −78 °C was added sec-BuLi (0.84 M in cyclohexane, 10 mL, 8.6 mmol, 2.5 equiv) dropwise over 13 min. The solution was stirred for 2 h at −78 °C, and then the reaction was quenched with saturated aqueous NaHCO3 (15 mL) and allowed to warm to 23 °C. The reaction mixture was then diluted with EtOAc (15 mL) and H2O (15 mL). The layers were then separated and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (100% hexanes → 9:1 hexanes/EtOAc) to afford silyl ketone 26 (691 mg, 95% yield) as a light yellow oil: Rf 0.39 (9:1 hexanes/EtOAc); spectral data match those previously reported.15

Supplementary Material

SI

ACKNOWLEDGMENTS

The authors are grateful to the University of California, Los Angeles, NIH-NIGMS (R01 GM123299), the Trueblood Family (N.K.G.), and the Foote Family (J.V.C. and F.M.I.) for financial support. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). The authors thank Michael M. Yamano (UCLA) for insightful discussions and suggestions.

Footnotes

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b03223.

1H NMR spectra for compounds 25, 20b, and 26; 13C NMR spectrum for compound 25 (PDF)

The authors declare no competing financial interest.

REFERENCES

  • (1).For reviews of arynes and related strained intermediates, see:; (a) Bronner SM; Goetz AE; Garg NK Understanding and Modulating Indolyne Regioselectivities. Synlett 2011, 2599–2604. [Google Scholar]; (b) Tadross PM; Stoltz BM A Comprehensive History of Arynes in Natural Product Total Synthesis. Chem. Rev 2012, 112, 3550–3577. [DOI] [PubMed] [Google Scholar]; (c) Gampe CM; Carreira EM Arynes and Cyclohexyne in Natural Product Synthesis. Angew. Chem., Int. Ed 2012, 51, 3766–3778. [DOI] [PubMed] [Google Scholar]; (d) Dubrovskiy AV; Markina NA; Larock RC Use of Benzynes for the Synthesis of Heterocycles.Org. Biomol. Chem 2013, 11, 191–218. [DOI] [PubMed] [Google Scholar]; (e) Hoffmann RW; Suzuki K. A “Hot, Energized” Benzyne. Angew. Chem., Int. Ed 2013, 52, 2655–2656. [DOI] [PubMed] [Google Scholar]; (f) Goetz AE; Garg NK Enabling the Use of Heterocyclic Arynes in Chemical Synthesis. J. Org. Chem 2014, 79, 846–851. [DOI] [PubMed] [Google Scholar]; (g) Yoshida S; Hosoya T The Renaissance and Bright Future of Synthetic Aryne Chemistry. Chem. Lett 2015, 44, 1450–1460. [Google Scholar]; (h) Takikawa H; Nishii A; Sakai T; Suzuki K Aryne-Based Strategy in the Total Synthesis of Naturally Occurring Polycyclic Compounds. Chem. Soc. Rev 2018, 47, 8030– 8056. [DOI] [PubMed] [Google Scholar]; (i) Dhokale RA; Mhaske SB Transition-Metal-Catalyzed Reactions Involving Arynes. Synthesis 2018, 50, 1–16. [Google Scholar]
  • (2).(a) Roberts JD; Simmons HE; Carlsmith LA; Vaughan CW Rearrangement in the Reaction of Chlorobenzene-1-C14 with Potassium Amide. J. Am. Chem. Soc 1953, 75, 3290–3291. [Google Scholar]; (b) Scardiglia F; Roberts JD Evidence for Cyclohexyne as an Intermediate in the Coupling of Phenyllithium with 1-Chlorocyclohexene. Tetrahedron 1957, 1, 343–344. [Google Scholar]; (c) Wittig G; Fritze P On the Intermediate Occurrence of 1,2-Cyclohexadiene. Angew. Chem., Int. Ed. Engl 1966, 5, 846. [Google Scholar]; (d) Wenk HH; Winkler M; Sander W One Century of Aryne Chemistry. Angew. Chem., Int. Ed 2003, 42, 502–528. [DOI] [PubMed] [Google Scholar]
  • (3).(a) Surry DS; Buchwald SL Biaryl Phosphane Ligands in Palladium-Catalyzed Amination. Angew. Chem., Int. Ed 2008, 47, 6338–6361. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Mauger CC; Mignani GA An Efficient and Safe Procedure for the Large-Scale Pd-Catalyzed Hydrazonation of Aromatic Chlorides Using Buchwald Technology. Org. Process Res. Dev 2004, 8, 1065–1071. [Google Scholar]
  • (4).Schleth F; Vettiger T; Rommel M; Tobler H Process for the Preparation of Pyrazole Carboxylic Acid Amides. Patent Appl. WO 2011131544 A1, 2011. [Google Scholar]
  • (5).(a) Carroll FI; Robinson TP; Brieaddy LE; Atkinson RN; Mascarella SW; Damaj MI; Martin BR; Navarro HA Synthesis and Nicotinic Acetylcholine Receptor Binding Properties of Bridged and Fused Ring Analogues of Epibatidine. J. Med. Chem 2007, 50, 6383–6391. [DOI] [PubMed] [Google Scholar]; (b) Kametani T; Kigasawa K; Hiiragi M; Wagatsuma N; Uryu T; Araki K Syntheses of Heterocyclic Compounds. 509. Syntheses of Analgesics. 34. Synthesis of 3-Hydroxy-N-Cyclopropylmethyl-9-Azamorphinan. J. Med. Chem 1973, 16, 301–303. [DOI] [PubMed] [Google Scholar]; (c) Heindel ND; Fives WP; Lemke TF; Rowe JE; Snady HW; Carrano RA Synthesis, Transformation, and General Pharmacologic Activity in 1,4-Benzodiazepine-3,5-diones. J. Med. Chem 1971, 14, 1233–1235. [DOI] [PubMed] [Google Scholar]; (d) Bell MR; Zalay AW; Oesterlin R; Schane P; Potts G Basic Ethers of 1-(p-Hydroxyphenyl)-2-Phenyl-1,2,3,4-Tetrahydroquinoline and 1-(p-Hydroxyphenyl)-2-Phenyl Indole. Antifertility Agents. J. Med. Chem 1970, 13, 664–668. [DOI] [PubMed] [Google Scholar]; (e) Willis PG; Pavlova OA; Chefer SI; Vaupel DB; Mukhin AG; Horti AG Synthesis and Structure-Activity Relationship of a Novel Series of Aminoalkylindoles with Potential of Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography. J. Med. Chem 2005, 48, 5813–5822. [DOI] [PubMed] [Google Scholar]; (f) Jacob P III; Shulgin AT Sulfur Analogues of Psychotomimetic Agents. Monothio Analogues of Mescaline and Isomescaline. J. Med. Chem 1981, 24, 1348–1353. [DOI] [PubMed] [Google Scholar]; (g) Coe JW; Brooks PR; Wirtz MC; Bashore CG; Bianco KE; Vetelino MG; Arnold EP; Lebel LA; Fox CB; Tingley FD III; Schulz DW; Davis TI; Sands SB; Mansbach RS; Rollema H; O’Neill BT 3,5-Bicyclic Aryl Piperidines: A Novel Class of α4β2 Neuronal Nicotinic Receptor Partial Agonists for Smoking Cessation. Bioorg. Med. Chem. Lett 2005, 15, 4889–4897. [DOI] [PubMed] [Google Scholar]
  • (6).For examples of arynes and other strained cyclic alkynes in total synthesis, see:; (a) Kou KGM; Pflueger JJ; Kiho T; Morrill LC; Fisher EL; Clagg K; Lebold TP; Kisunzu JK; Sarpong R A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine). J. Am. Chem. Soc 2018, 140, 8105–8109. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Goetz AE; Silberstein AL; Corsello MA; Garg NK Concise Enantiospecific Total Synthesis of Tubingensin A. J. Am. Chem. Soc 2014, 136, 3036–3039. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Neog K; Borah A; Gogoi P Palladium(II)-Catalyzed C–H Bond Activation/C–C and C–O Bond Formation Reaction Cascade: Direct Synthesis of Coumestans. J. Org. Chem 2016, 81, 11971–11977. [DOI] [PubMed] [Google Scholar]; (d) Neumeyer M; Kopp J; Brückner R Controlling the Substitution Pattern of Hexasubstituted Naphthalenes by Aryne/Siloxyfuran Diels–Alder Additions: Regio and Stereocontrolled Synthesis of Arizonin C1 Analogs. Eur. J. Org. Chem 2017, 2883–2915. [Google Scholar]; (e) Corsello MA; Kim J; Garg NK Total Synthesis of (−)-Tubingensin B Enabled by the Strategic Use of an Aryne Cyclization. Nat. Chem 2017, 9, 944–949. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Gampe CM; Carreira EM Total Syntheses of Guanacastepenes N and O. Angew. Chem., Int. Ed 2011, 50, 2962–2965. [DOI] [PubMed] [Google Scholar]
  • (7).Lin JB; Shah TJ; Goetz AE; Garg NK; Houk KN Conjugated Trimeric Scaffolds Accessible from Indolyne Cyclotrimerizations: Synthesis, Structure, and Electronic Properties. J. Am. Chem. Soc 2017, 139, 10447–10455. [DOI] [PubMed] [Google Scholar]
  • (8).Fine Nathel NF; Morrill LA; Mayr H; Garg NK Quantification of the Electrophilicity of Benzyne and Related Intermediates. J. Am. Chem. Soc 2016, 138, 10402–10405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (9).(a) Atanes N; Escudero S; Pérez D; Guitián E; Castedo L Generation of Cyclohexyne and its Diels–Alder Reaction with α-Pyrones. Tetrahedron Lett 1998, 39, 3039–3040. [Google Scholar]; (b) Quintana I; Peña D; Pérez D; Guitián E Generation and Reactivity of 1,2-Cyclohexadiene under Mild Reaction Conditions. Eur. J. Org. Chem 2009, 5519–5524. [Google Scholar]; (c) Medina JM; McMahon TC; Jiménez-Osés G; Houk KN; Garg NK Cycloadditions of Cyclohexynes and Cyclopentyne. J. Am. Chem. Soc 2014, 136, 14706–14709. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Barber JS; Styduhar ED; Pham HV; McMahon TC; Houk KN; Garg NK Nitrone Cycloadditions of 1,2-Cyclohexadiene. J. Am. Chem. Soc 2016, 138, 2512–2515. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Lofstrand VA; West FG Efficient Trapping of 1,2-Cyclohexadienes with 1,3-Dipoles. Chem. -Eur. J 2016, 22, 10763–10767. [DOI] [PubMed] [Google Scholar]
  • (10).(a) McMahon TC; Medina JM; Yang Y-F; Simmons BJ; Houk KN; Garg NK Generation and Regioselective Trapping of a 3,4-Piperidyne for the Synthesis of Functionalized Heterocycles. J. Am. Chem. Soc 2015, 137, 4082–4085. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Tlais SF; Danheiser RL N-Tosyl-3-Azacyclohexyne. Synthesis and Chemistry of a Strained Cyclic Ynamide. J. Am. Chem. Soc 2014, 136, 15489–15492. [DOI] [PubMed] [Google Scholar]; (c) Christl M; Braun M; Wolz E; Wagner W 1-Phenyl-l-aza-3,4-cyclohexadien, das erste Isodihydropyridin: Erzeugung und Abfangreaktionen. Chem. Ber 1994, 127, 1137–1142. [Google Scholar]; (d) Shah TK; Medina JM; Garg NK Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes. J. Am. Chem. Soc 2016, 138, 4948–4954. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Barber JS; Yamano MM; Ramirez M; Darzi ER; Knapp RR; Liu F; Houk KN; Garg NK Diels–Alder Cycloadditions of Strained Azacyclic Allenes. Nat. Chem 2018, 10, 953–960. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Johnson RP Strained Cyclic Cumulenes. Chem. Rev 1989, 89, 1111–1124. [Google Scholar]; (g) Nendel M; Tolbert LM; Herring LE; Islam MN; Houk KN Strained Allenes as Dienophiles in the Diels–Alder Reaction: An Experimental and Computational Study. J. Org. Chem 1999, 64, 976–983. [DOI] [PubMed] [Google Scholar]; (h) Yamano MM; Knapp RR; Ngamnithiporn A; Ramirez M; Houk KN; Stoltz BM; Garg NK Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes. Angew. Chem., Int. Ed 2019, DOI: 10.1002/anie.201900503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (11).(a) Medina JM; Mackey JL; Garg NK; Houk KN The Role of Aryne Distortions, Steric Effects, and Charges in Regioselectivities of Aryne Reactions. J. Am. Chem. Soc 2014, 136, 15798–15805. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Cheong PH-Y; Paton RS; Bronner SM; Im G-YJ; Garg NK; Houk KN Indolyne and Aryne Distortions and Nucleophilic Regioselectivities. J. Am. Chem. Soc 2010, 132, 1267–1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (12).Moore WR; Moser WR The Reaction of 6,6-Dibromobicyclo[3.1.0]hexane with Methyllithium. Efficient Trapping of 1,2-Cyclohexadiene by Styrene. J. Org. Chem 1970, 35, 908–912. [Google Scholar]
  • (13).Christl M; Fischer H; Arnone M; Engels B 1-Phenyl-1,2-cyclohexadiene: Astoundingly High Enantioselectivities on Generation in a Doering–Moore–Skattebøl Reaction and Interception by Activated Olefins. Chem. - Eur. J 2009, 15, 11266–11272. [DOI] [PubMed] [Google Scholar]
  • (14).Himeshima Y; Sonoda T; Kobayashi H Fluoride-induced 1,2-Elimination of o-Trimethylsilylphenyl Triflate to Benzyne Under Mild Conditions. Chem. Lett 1983, 12, 1211–1214. [Google Scholar]
  • (15).Inoue K; Nakura R; Okano K; Mori A One-Pot Synthesis of Silylated Enol Triflates from Silyl Enol Ethers for Cyclohexynes and 1,2-Cyclohexadienes. Eur. J. Org. Chem 2018, 3343–3347. [Google Scholar]
  • (16).Zhang G-B; Wang F-X; Du J-Y; Qu H; Ma X-Y; Wei MX; Wang C-T; Li Q; Fan C-A Toward the Total Synthesis of Palhinine A: Expedient Assembly of Multifunctionalized Isotwistane Ring System with Contiguous Quaternary Stereocenters. Org. Lett 2012, 14, 3696–3699. [DOI] [PubMed] [Google Scholar]
  • (17).Peña D; Cobas A; Pérez, D; Guitián E An Efficient Procedure for the Synthesis of ortho-Trialkylsilylaryl Triflates: Easy Access to Precursors of Functionalized Arynes. Synthesis 2002, 1454–1458. [Google Scholar]

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Supplementary Materials

SI
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