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Org. Synth. 2022, 99, 174-189

DOI: 10.15227/orgsyn.099.0174

Synthesis of Triphenylene via the Palladium-Catalyzed Annulation of Benzyne

Submitted by Katie A. Spence, Milauni M. Mehta, and Neil K. Garg*¹

Checked by Hridaynath Bhattacharjee and Cathleen Crudden

1. Procedure (Note 1)

An oven-dried single-necked (24/40 joint) 500 mL round-bottomed flask, containing an over-dried Teflon-coated magnetic stir bar (4.0 × 1.5 cm, football-shaped), is fitted with a 24/40 rubber septum that is pierced with an 18G × 1.5" needle attached to a Schlenk line (Figure 1A). The flask is then dried by vacuum-heat-argon cycle (3×) prior to use. The flask is then opened to the air and charged with bis(dibenzylideneacetone)palladium(0) (444 mg, 772 μmol, 5.1 mol%) (Note 2) and tri(o-tolyl)phosphine (240 mg, 790 μmol, 5.2 mol%) (Note 3), each in one portion. 2-Bromobiphenyl (2.60 mL, 3.52 g, 15.1 mmol, 1 equiv) (Note 4) and 2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (4.40 mL, 5.41 g, 18.1 mmol, 1.2 equiv) (Note 5) are then added consecutively, each over 30 sec via syringe using 22G × 4" needles. The rubber septum with an argon inlet is restored and the flask is then placed under positive pressure of argon. Dry toluene (150 mL) (Note 6) and dry acetonitrile (50 mL) (Note 7) are added sequentially to the flask, each over one min by syringe using 20G × 12" needles, to give a suspension. Cesium fluoride (11.6 g, 76.4 mmol, 5.06 equiv) (Note 8) is added quickly in one portion. The rubber septum with an argon inlet is restored again and the reaction mixture is allowed to stir (400 rpm) at 23 °C for 15 min. During this time, an oven-dried reflux condenser (3.5 cm OD × 35 cm tall, 24/40 joint) is capped on the bottom end with a round-bottomed flask, and the top end is attached to a Schlenk line using a Schlenk adapter is allowed to cool to 23 °C under vacuum (Figure 1B). The apparatus is then dried by vacuum-heat-argon cycle (3×) prior to use.

Figure 1. Glassware preparation (photos provided by checkers)

After 15 min, the reaction flask is fitted with the condenser. The joint between the condenser and round-bottomed flask is greased and clamped with a 24/40 keck clip. The top of the condenser is attached to the Schlenk line. The apparatus is evacuated and backfilled with argon (3×), at which time cold water is flowed through the condenser. The flask is then placed in an oil bath preheated to 110 °C and allowed to stir (400 rpm) for 24 h while under positive pressure of argon (Figures 2 and 3).

Figure 2. Reaction Setup (photo provided by checkers)

Figure 3. Reaction mixture at A) 0 min, B) 30 min, C) 24 h after the reaction mixture is placed in the oil bath (photos provided by checkers)

After 24 h (Note 9), the flask is removed from the oil bath and allowed to cool to 23 °C over 30 min while stirring. The flask is then opened to the air and the stir bar is carefully removed. The contents of the flask are then transferred into a 1000 mL separatory funnel. Saturated sodium chloride solution (200 mL) and ether (200 mL) (Note 10) are then added to the flask and transferred to a 1000 mL separatory funnel. The funnel is shaken, and the layers are separated (Note 11) (Figure 4A). The aqueous layer is then extracted with ether (2 × 200 mL) (Note 12) (Figures 4B, 4C).

Figure 4. A) Reaction mixture after transferring to separatory funnel; B) Mixture after first extraction; C) Mixture after second extraction (photos provided by checkers)

The organic layers are combined, dried over anhydrous sodium sulfate (15 g), then gravity filtered into a 500 mL round-bottomed flask. The filtrate is concentrated on a rotary evaporator (30 °C, 175 mmHg) to afford a light brown solid (Figure 5).

Figure 5. Light brown reaction mixture after extraction and concentration under reduced pressure (photo provided by checkers)

The 500 mL round-bottomed flask with the crude product is charged with silica gel (8.0 g) (Note 13). The crude material and silica gel are suspended in methylene chloride (Note 14) and concentrated under reduced pressure (30 °C, 325 mmHg). The product-adsorbed silica is then dried on high vacuum (<1.0 mmHg) for 15 min until fine and powdery (Notes 15 and 16).

The product-adsorbed silica is charged on a column (5.0 cm OD × 17 cm tall) of 250 g of silica gel (Notes 13 and 15) (Figure 6) . The column is eluted with 1:9 ethyl acetate:hexanes (2.5 L) (Notes 18 and 19) and collected into 10 mL culture tubes. The desired product elutes as a light-yellow solution. These fractions are pooled and concentrated under reduced pressure (30 °C bath, 75 mmHg) in a 500 mL round-bottomed flask to afford a yellow-orange solid (Figure 7).

Figure 6 Column dry-loaded with product-adsorbed silica
(photo provided by submitters)

Figure 7. Pooled and concentrated collected fractions after column chromatography (photo provided by checkers)

The solid is suspended in methylene chloride (30 mL) (Note 14) in a single-necked (24/40 joint) 500 mL round-bottomed flask and charged with a Teflon-coated magnetic stir bar (4.0 × 2.5 cm, football shaped). The 500 mL round-bottom flask is then fitted with an air condenser open to air. The joint between the air condenser and the round-bottomed flask is fitted with a green 24/40 keck clamp. The apparatus is then placed in an oil bath preheated to 45 °C and stirred for 10 min (Figure 8).

Figure 8 Product mixture after stirring in the oil bath for 10 min
(photo provided by checkers)

After the allotted time, pentane (60 mL) (Note 21) is poured slowly down the wall of the air condenser into the solution, over 5 min (Note 22).

Figure 9. Precipitation of a white solid during recrystallization
(photo provided by checkers)

The apparatus is then removed from the oil bath and placed in an ice bath for 30 min. A white solid precipitates out of the yellow-orange solution (Figure 9). The solution is then poured through a Büchner funnel fitted with a piece of Whatman 4 qualitative filter paper, and the white crystals are collected onto the filter paper. The crystals are washed with pentane (2 × 30 mL), collected into a 100 mL round-bottomed flask, and weighed (2.185 g). The filtrate is then concentrated under reduced pressure to afford an orange solid, which is recrystallized again (Note 23). The product collected during this second recrystallization is combined with the triphenylene crystals in the 100 mL round-bottomed flask and dried under vacuum (<1.0 mmHg) for 30 min (Note 24) to afford a white crystalline solid (2.61 g, 76%) (Figure 10) (Notes 25 and 26).

Figure 10. Isolated Triphenylene (1) (photo provided by checkers)

2. Notes

1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guideline for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog/12654/prudent-practices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with bis(dibenzylideneacetone)palladium(0), tri(o-tolyl)phosphine, 2-bromobiphenyl, 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, cesium fluoride, acetonitrile, toluene, diethyl ether, dichloromethane, hexanes, ethyl acetate, pentane, magnesium sulfate, and silica gel.

2. Bis(dibenzylideneacetone)palladium(0) was purchased from Strem Chemicals, Inc. and used as received.

3. Tri(o-tolyl)phosphine (99%) was purchased from Strem Chemicals, Inc. and used as received.

4. 2-Bromobiphenyl (98%) was purchased from Combi-Blocks and used as received.

5. 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate (95%) was purchased from Combi-Blocks and used as received.

6. DriSolv®Toluene was purchased from Millipore Sigma and used under an atmosphere of argon.

7. DriSolv® Acetonitrile was purchased from Millipore Sigma and used under an atmosphere of argon.

8. Cesium fluoride (99+%) was purchased from Strem Chemicals, Inc. and used as received.

9. The progress of the reaction is monitored by TLC analysis on silica gel with 10% ethyl acetate in hexanes used as an eluent. The plate is visualized using a UV lamp (254 nm). The 2-bromobiphenyl starting material has R_f = 0.67 and the triphenylene product has R_f = 0.50 (Figure 11).

Figure 11. TLC of the crude reaction mixture after 24 h (photo provided by checkers)

10. Diethyl ether anhydrous (99%) was purchased from Fisher Scientific and used as received.

11. A black emulsion forms at the interface of the organic and aqueous layers. The emulsion is collected with the aqueous layer.

12. During the second extraction, the black emulsion is collected with the aqueous layer. In the third extraction, the black emulsion is collected with the organic layer.

13. SiliaFlash® P60 (particle size 0.040-0.063 nm) was purchased from SiliCycle and used as received.

14. Methylene chloride (99.9%) was purchased from Fisher Scientific and used as received.

15. A Kim-wipe is packed into the opening of the vacuum adapter in order to reduce loss of silica gel.

16. If portions of the product-adsorbed silica are stuck to the wall of the flask after 15 min under high vacuum, a spatula can be used to scrape the sides and collect all of the solid.

17. The column is loaded using 250 mL of hexanes.

18. Ethyl acetate (99.5%) was purchased from VWR and used as received.

19. Hexanes (>98.5%) was purchased from Fisher Scientific and used as received.

20. All fractions containing product were collected. Any impurities in these fractions will be removed in the subsequent recrystallization.

21. Pentane (>98%) was purchased from Fisher Scientific and used as received.

22. It is important to pour the pentane down the wall of the reflux condenser slowly to avoid obstruction of the air passage and any resulting pressure build-up.

23. The filtrate is recrystallized a second time following the same recrystallization procedure, except that 5 mL of methylene chloride and 10 mL of pentane are utilized, respectively.

24. A Kim-wipe was inserted between the mouth of the round-bottomed flask and the vacuum adapter in order to minimize loss of product (Figure 10).

25. ¹H NMR pdf (700 MHz, CDCl₃) d: 8.67 (m, 6H), 7.67 (m, 6H); ¹³C NMR pdf (176 MHz, CDCl₃) d: 129.8, 127.2, 123.3; EI-HRMS (m/z) [M]⁺ calcd. for C₁₈H₁₂, 228.0939; found 228.0931; IR (ATR): 3077.41, 3021.94, 1497.21, 1433.36, 1243.91, 740.14 cm⁻¹; mp = 198-199°C; TLC (10% ethyl acetate in hexanes), R_f = 0.50.

26. The purity of 1 was assessed at 98% by quantitative NMR pdf using trimethoxybenzene as an internal standard.

27. A second reaction on identical scale provided 2.540 g (74%) of the white crystalline product (1) at 98% purity.

Working with Hazardous Chemicals

The procedures in Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.

The procedures described in Organic Syntheses are provided as published and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Triphenylene, a symmetrical aromatic hydrocarbon, began receiving significant attention from the scientific community following the discovery of discotic liquid crystals (DLCs) in 1977.² Triphenylene's symmetry and thermal and chemical stability make it an ideal core for DLCs.² Additionally, triphenylene and its derivatives are attractive in materials and supramolecular chemistry due to their stability, conjugation, planarity and rigidity.³

A number of different approaches have been used in the synthesis of triphenylene scaffolds, the majority of which possess harsh reaction conditions or limited opportunities for derivatization.^4,5,6,7,8,9 Arynes have been used previously in the synthesis of triphenylene, however, the aryne is typically trimerized during these procedures.^4,5,6 This precludes the synthesis of asymmetric triphenylene derivatives. Other methods of synthesizing triphenylene scaffolds have relied on the use of pyrophoric reagents,⁷ a glovebox,⁷ or sublimation.⁹ Another method for accessing triphenylene scaffolds that addresses many of these drawbacks was recently developed by the Yang group.¹⁰ It involves an intermolecular decarboxylative coupling of bromobenzoic acids and aryl iodides and allows for the synthesis of asymmetric triphenylene derivatives.¹⁰

The procedure described herein offers a quick and facile means for accessing polycyclic aromatic hydrocarbon scaffolds.¹¹ During the course of the reaction, an aryne is formed in situ and acts as a substrate in a palladium-catalyzed annulation with a biaryl bromide. Ultimately, two C-C bonds are formed in a single synthetic step.¹¹ Although historically avoided because of their high reactivity, arynes have demonstrated increased utility over the past two decades.¹² The reported procedure allows chemists to harness the inherent reactivity of arynes using mild generation conditions.

This method, pioneered by Larock, offers synthetic chemists the opportunity to functionalize either the biaryl halide or the silyl triflate before performing the annulation (Table 1).¹¹ By adding different functionalities to either of these substrates, chemists can utilize this method to form a variety of triphenylene derivatives.
Table 1. Scope of the Annulation Reaction¹¹

Notably, this method tolerates nitro, methoxy and methyl groups on the A ring of the biaryl halide as demonstrated by the formation of products 2-4. A number of different heterocyclic biaryl halides have also been utilized to afford products 5-7 in excellent yields. Additionally, this method allows for prior functionalization of the C ring with methoxy or methyl groups (6-8).

In summary, the procedure described herein offers a quick and robust approach for accessing triphenylene derivatives from biaryl bromides and silyl triflates. The mild reaction conditions and wide substrate scope, particularly the ability to form asymmetric products, render this protocol an attractive alternative for the synthesis of triphenylene derivatives.

References and Notes

Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States. E-mail: neilgarg@chem.ucla.edu. ORCID ID: 0000-0002-7793-2629. The authors are grateful to the University of California, Los Angeles. These studies were also supported by shared instrumentation grants from the NSF (CHE-1048804) and the National Center for Research Resources (S10RR025631).
Kumar, S. Liq. Cryst. 2005, 32, 1089-1113.
Murayama, K.; Sawada, Y.; Noguchi, K.; Tanaka, K. J. Org. Chem. 2013, 78, 6202-6210.
Peña, D.; Escudero, S.; Pérez, D.; Guitián, E.; Castedo, L. Angew. Chem. Int. Ed. 1998, 37, 2659-2661.
Chen, L.; Zhang, C.; Wen, C.; Zhang, K.; Liu, W.; Chen, Q. Catal. Commun. 2015, 65, 81-84.
Alonso, J.; Quiroga, S.; Codony, S.; Turcu, A.; Barniol-Xicota, M.; P érez, D.; Guitián, E.; Vásquez, S.; Peña, D. Chem. Commun. 2018, 54, 5996-5999.
Liu, Y.; Bergés, J.; Zaid, Y.; Chahdi, F. O.; Van Der Lee, A.; Harakat, D.; Clot, E.; Jaroschik, F.; Taillefer, M. J. Org. Chem. 2019, 84, 4413-4420.
Nagao, I.; Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2009 , 48, 7573-7576.
Heaney, H.; Millar, I. T. Org. Synth. 1960, 40, 105-107.
Yang, Y.; Zhou, B.; Zhu, X.; Deng, G.; Liang, Y.; Yang, Y. Org. Lett. 2018, 20, 5402-5405.
Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 15716-15717.
Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 15798- 15805.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

Bis(dibenzylideneacetone)palladium(0); (51364-51-3)

Tri(o-tolyl)phosphine; (6163-58-2)

2-Bromobiphenyl; (2052-07-5)

2-(Trimethylsilyl)phenyl trifluoromethanesulfonate; (88284-48-4)

Cesium fluoride; (13400-13-0)

Magnesium sulfate; (7487-88-9)

	Katie Spence received a B.A. degree in Chemistry and Psychology from Williams College in 2018. As an undergraduate, she studied the formation of atmospheric organic aerosol and completed a senior thesis on this topic under the advisement of Professor Anthony Carrasquillo. She is currently a fifth-year graduate student in Professor Neil K. Garg's lab at University of California, Los Angeles where she develops synthetic methodologies that employ strained intermediates.
	Milauni Mehta was born in Mumbai, India and raised in Princeton, New Jersey. In 2018, she received a B.A. degree in Chemistry from The Ohio State University where she carried out research under the direction of Professor T. V. RajanBabu. She then moved to the University of California, Los Angeles where she is currently a fifth-year graduate student in Professor Neil K. Garg's laboratory. Her graduate studies primarily focus on developing Ni-catalyzed cross-coupling reactions.
	Neil Garg is a Professor of Chemistry and the Kenneth N. Trueblood Endowed Chair at the University of California, Los Angeles. His laboratory develops novel synthetic strategies and methodologies to enable the total synthesis of complex bioactive molecules.
	Hridaynath Bhattacharjee was born and brought up in a small town named Durgapur in India. He completed his MSc in Chemistry in India before he moved to Canada to pursue his Ph.D. from Prof. Jens Müller's Lab at University of Saskatchewan. During his Ph.D. he worked on developing boron-bridged strained ferrocenophanes and boron-containing metallopolymers. He joined the Crudden Lab as a Postdoctoral Research Fellow in February 2019. His work has mainly focused on making bifunctional NHCs that can be used in various applications, such as in biosensors. Hridaynath is currently appointed as an Adjunct Assistant Professor at Queen's University.

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References/EndNotes

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