anti-1,2,2,3,4,4-Hexamethylphosphetane 1-oxide

Graphical Abstarct

Procedure (Note 1)

A. 1-Chloro-2,2,3,4,4-pentamethylphosphetane 1-oxide (1).

To a flame-dried 500 mL round-bottomed flask (cooled under vacuum) equipped with a magnetic stir bar (1.25 in, egg-shaped) is added aluminum chloride (28.0 g, 210 mmol, 1.0 equiv) and the flask is sealed with rubber septum (Note 2). After evacuating the flask and back-filling with nitrogen three times, dry dichloromethane (125 mL, 1.7 M) is added via syringe and the heterogeneous mixture is cooled to 0–2 °C with an ice bath while stirring under positive nitrogen pressure (Notes 3 and 4) (Figure 1A). Phosphorus trichloride (18.3 mL, 210 mmol, 1.0 equiv) is added via syringe and stirred for 5 min (Note 5). Lastly, 2,4,4-trimethyl-2-pentene (32.7 mL, 210 mmol, 1.0 equiv) is added via syringe over a period of five min and stirring is continued at 0–2 °C for 2 h (Notes 6, 7, and 8) (Figure 1B).

Figure 1.

A) Reaction set-up/aluminum chloride stirring in CH₂Cl₂ at 0 °C. B) Five min after the addition of 2,4,4-trimethyl-2-pentene, white precipitate is observed. C) Quench set-up. (Photos provided by the checkers)

The reaction is quenched by the slow addition of distilled water (125 mL) via a 250-mL pressure-equalized dropping funnel over 45 min while maintaining the temperature at 0–2 °C (Note 9) (Figure 1C). The reaction mixture is then transferred to a 500-mL separatory funnel and shaken. The organic phase is separated and the aqueous layer is extracted with one 125-mL portion of dichloromethane. The combined organic layers are washed with saturated NaCl solution (100 mL) and the brine solution is back-extracted with dichloromethane (125 mL). The combined organic phases are dried over anhydrous sodium sulfate (50 g, 15 min), filtered, and concentrated via rotary evaporation (ca. 100 mmHg, 23 °C) (Notes 10 and 11).

The crude residue is further dried in vacuo (ca. 0.2 mmHg, 23 °C) for a period of 45 min, backfilling the flask with nitrogen and breaking up the solids into smaller pieces every ten min with a spatula before placing the flask back under vacuum. Crude product 1, a white crystalline solid, is transferred to a tared 100-mL round-bottom flask and weighed to give 36.7 g (90% crude), and to this solid is added hexanes (55 mL, ca. 1.5 mL/1 g of 1). The mixture is rotated and heated to ca. 65 °C using a rotary evaporator in a fume hood, at atmospheric pressure and with a cold finger, until the solids are completely dissolved (Note 12). The hot vessel is wrapped and covered with aluminum foil and cooled slowly over 45 min to 23 °C, then placed in a freezer at –20 °C for 60 min. The resulting solids are collected on a coarse-porosity fritted funnel, then covered by a watch glass and dried by suction. The solid is broken up with a spatula to give phosphetane oxide 1 (29.3 g, 72%, 97:3 anti:syn) (Notes 13 and 14) (Figure 2).

Figure 2.

Recrystallized phosphetane oxide 1. Crystals are thick needles and tend to clump together during the recrystallization. (Photo provided by the submitters)

B. anti-1,2,2,3,4,4-Hexamethylphosphetane 1-oxide (2).

To a flame-dried 500 mL round-bottomed flask (cooled under vacuum) equipped with a magnetic stir bar (1.25 in, egg-shaped) is added phosphetane oxide 1 (15.0 g, 77 mmol, 1.0 equiv) and the flask is sealed with a rubber septum. After evacuating the vessel and back-filling with nitrogen three times, dry tetrahydrofuran (52 mL) is added via syringe and the homogeneous mixture is cooled to 0–2 °C with an ice bath while stirring (Note 15). A solution of methylmagnesium bromide (3 M in diethyl ether, 28 mL, 84 mmol, 1.1 equiv) is added over a period of 10 min with stirring (Note 16). After the addition, the mixture is warmed to 23 °C and then heated at 35 °C in a water bath for 2 h and then returned to 23 °C (Note 17) (Figure 3A).

Figure 3.

A) Reaction set-up/reaction mixture heating at 35 °C after Grignard addition with precipitate formation. B) Reaction mixture after quenching with saturated ammonium chloride. (Photo provided by the checkers)

The reaction vessel is immersed in an ice bath and the reaction is quenched by addition of saturated ammonium chloride (20 mL) (Note 18). Additional distilled water (60 mL) is added and the mixture is vigorously stirred until all solids went into solution. The reaction mixture is poured into a 0.5-L separatory funnel and the organic and aqueous layers are partitioned. The aqueous layer is separated and set aside temporarily. The organic layer is transferred directly into a 500 mL round-bottomed flask. The ethereal solvents are removed via rotary evaporation (ca. 100 mmHg, 23 °C) (Note 19) and the resulting residue is redissolved in dichloromethane (15 mL). The aqueous layer is reintroduced to the separatory and extracted with dichloromethane (two portions, 80 mL then 50 mL) (Note 20). The combined dichloromethane phases are then transferred back into the separatory funnel and washed with brine (50 mL). The aqueous brine phase is back-extracted with dichloromethane (50 mL) and all of the aqueous layers are combined and back-extracted with one last portion of dichloromethane (75 mL). The combined dichloromethane phases are dried over anhydrous sodium sulfate (25 g, 15 min), filtered through a plug of cotton, and concentrated by rotary evaporation (ca 100 mmHg, 23 °C). The product is further dried in vacuo (ca. 0.2 mmHg, 23 °C) giving crude phosphetane oxide 2 as a white amorphous solid. To purify, crude 2 is placed inside a 150 mL beaker and then diethyl ether (90 mL) is added at 23 °C. The resulting slurry is stirred by hand with a spatula thoroughly for 3 min and then cooled in an ice bath. After chilling for 10 min, the solids are collected in a medium-porosity fritted funnel via vacuum filtration and the product is rinsed with additional diethyl ether (15 mL) that is cooled in an ice bath (~2 mL portions via pipette). Thereafter, the fritted funnel is covered with a watch glass and compound 2 is dried via vacuum suction filtration for 10 min before transferring to an appropriately sized tared vial (11.7 g, 87%, single isomer) (Notes 21, 22 and 23) (Figure 4).

Figure 4.

Product 2 after Et₂O slurry and vacuum filtration. (Photo provided by the submitters)

Working with Hazardous Chemicals

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Discussion

Trivalent phosphorus compounds are good O-atom acceptors for synthetic chemistry. Typically, the resulting phosphine oxide is generated as terminal stoichiometric waste. Rendering the phosphine oxide susceptible to reductive turnover opens possibilities for catalytic O-atom transfer chemistry (Scheme 1).

Scheme 1.

A general representation of P^III/P^V=O redox cycling in which starting material A is converted to product B and generalized reductant [R] is employed

It is known that small-ring phosphine oxides undergo rapid rates of deoxygenation when exposed to hydrosilane reductants.² Our group has demonstrated that four-member phosphacycles (i.e. phosphetanes) are good candidates for catalysis involving interconversion of R₃P^III and R₃P^V=O compounds.³ Phosphetanes are most conveniently prepared by the McBride reaction, which is initiated by phosphenium addition to a suitable unsaturated hydrocarbon, followed by cationic rearrangement and ring formation.⁴ The procedure detailed above is a representative example of such a McBride synthesis that is adaptable with minor modification to a range of phosphetane targets.

As an illustration of catalytic P^III/P^V=O redox applications, our group disclosed in 2017 that phosphetane 2, in conjunction with a terminal hydrosilane reductant, catalyzes the reductive N–N bond forming Cadogan cyclization of o-nitrobenzaldimines, o-nitroazobenzenes, and related substrates.⁵ This catalytic route to 2H-indazoles, 2H-benzotriazoles, and related heterocycles serves as a catalytic complement to the traditional stoichiometric Cadogan method, which is typically conducted by exhaustive deoxygenation with an excess of a tricoordinate phosphine reagent to provide heterocyclic products.⁶ Despite longstanding utility, one practical limitation of (super)stoichiometric phosphine-mediated Cadogan cyclizations concerns efficiency and ease of isolation; two equivalents of phosphine oxide are generated per cyclization reaction and excess equivalents of phosphine reagent remain in the reaction mixture. Also, phosphine reagents are often air-sensitive and require special handling and storage in order to ensure their quality. By contrast, the developed catalytic protocol employs the solid, bench-stable, cyclic phosphine oxide 2, which can be handled and manipulated on scale. While many methods exist for the preparation of each of these heterocycles, the generality of the Cadogan protocol has made this transformation distinctive and useful in synthesis.⁷

Subsequently, our group demonstrated in 2018 an extension of the catalytic Cadogan reaction to C–N bond forming substrate classes. Use of 20 mol% of 1,2,2,3,4,4-hexamethylphosphetane 1-oxide (2) with phenylsilane as terminal reductant converts o-nitrobiphenyl and o-nitrostyrenes into carbazole and indole products, respectively (Table 1).⁸ The method is robust, scalable, and operationally simple. In the case of carbazole formation, the products precipitate from solution following cooling and pure material can be obtained after rinsing the solid products with dichloromethane. One limitation of the reaction is that substrates bearing multiple nitro moieties undergo unselective functionalization, as the P^III phosphetane apparently does not discriminate between the o-nitro group and others present in the molecule. Furthermore, a small amount of unproductive reduction of the nitroarene to aniline was observed in electron-withdrawn o-nitrobiaryl and -styrenyl derivatives. In almost all cases, this byproduct could be easily removed during purification. Overall, a diverse set of heterocyclic products (>50 examples published to date) can be synthesized by using a substoichiometric amount of anti-1,2,2,3,4,4-hexamethylphosphetane 1-oxide (2) in combination with phenylsilane as terminal reductant.

Table 1.

Scope of phosphetane catalyzed Cadogan cyclizations

Yields shown are for pure isolated material. Products 8–13 were conducted on 0.5 mmol scale (15 mol% 2, 100 °C, 1 M toluene) and 14–19 were conducted on 1-gram scale (20 mol% 2, 120 °C, 1 M butyl acetate). 2 equiv of phenylsilane in all reactions.

Beyond intramolecular reactions, our group reported in 2018 the intermolecular reductive C–N cross coupling of nitroarenes and boronic acids via P^III/P^V=O catalysis using 15 mol% of 1,2,2,3,4,4-hexamethylphosphetane 1-oxide (2) and phenylsilane.⁹ This organophosphorus-catalyzed synthesis of (hetero)arylamines represents a chemically orthogonal complement to transition metal catalyzed methods such as Buchwald-Hartwig, Ullmann, and Chan-Lam couplings.¹⁰ A diverse set of (hetero)arylamine products (>30 examples published to date) have been synthesized by the developed P^III/P^V=O method (Table 2).

Table 2.

Scope of phosphetane catalyzed C-N coupling

Yields shown are for pure isolated material, except for 33 which was determined by quantitative NMR. Reactions were conducted on 1 mmol scale in m-xylene (0.5 M), except as noted. Compound 22 (3 mmol); 28–30 (1 gram); 33 (0.5 mmol).

In summary, using a substoichiometric amount of anti-1,2,2,3,4,4-hexamethylphosphetane 1-oxide (2) in the presence of phenylsilane represents a general O-atom transfer system to drive the deoxygenative transformations of nitroarene substrates, including reductive cyclization and reductive C–N coupling. The optimized synthetic preparation of phosphetane 2 demonstrated in the above procedure provides access to decagram quantities of this useful compound.

Biography

Trevor Nykaza is from Oak Lawn, IL and attended Lake Forest College where he received his B.A. (2014). In 2014, he joined the Radosevich research group to investigate the design and application of geometrically constrained organophosphorus compounds in redox-driven synthetic methodology. He is now a senior graduate student focused on the application of phosphetane based P^III/P^V=O redox-cycling as a general deoxygenation platform, with a specific interest in the manipulation of nitro compounds.

Julian Cooper is from Houston, TX and attended Rice University where he received his B.S. (2014). Now a senior graduate student in the Radosevich Lab, Julian has focused on the development of new transformations that take advantage of the biphilic reactivity of geometrically constrained phosphorus compounds.

Alex Radosevich is originally from Waukegan, IL. He received his B.S. degree from the Univ. of Notre Dame (2002) and his Ph.D. degree from the Univ. of California, Berkeley with F. Dean Toste (2007). After an NIH postdoctoral fellowship stay with Daniel G. Nocera at MIT, he joined the faculty at the Pennsylvania State University in 2010. In August of 2016, he returned to MIT where he is Assoc. Professor.

Robert-Cristian Raclea is originally from Galati, Romania. Currently, he is a senior year undergraduate student in the chemistry department of Imperial College London, and his research interests include natural product synthesis and the development of new synthetic methodologies. In 2019, he completed a research internship in the laboratory of Prof. Mohammad Movassaghi at the Massachusetts Institute of Technology as part of the MIT-Imperial College London exchange program.

Kyan D’Angelo was born in Toronto, ON. He received his B.Sc. and M.Sc. degrees from the University of Toronto where he conducted research in the laboratory of Professor Mark Taylor on catalytic stereoselective glycosylation reactions. In 2016, he began his Ph.D. studies under the supervision of Professor Mohammad Movassaghi at the Massachusetts Institute of Technology. His current research focuses on the total synthesis of alkaloid natural products.

Appendix. Chemical Abstracts Nomenclature (Registry Number)

Aluminum chloride: Aluminum chloride; (7446-70-0)

Dichloromethane: Methane, dichloro-; (75-09-2)

Phosphorus trichloride: Phosphorous trichloride; (7719-12-2)

2,4,4-Trimethyl-2-pentene: 2-Pentene, 2,4,4-trimethyl-; (107-40-4)

Sodium chloride: Sodium chloride (NaCl); (7647-14-5)

Sodium sulfate: Sulfuric acid sodium salt (1:2); (7757-82-6)

1-Chloro-2,2,3,4,4-pentamethylphosphetane 1-oxide: Phosphetane, 1-chloro-2,2,3,4,4-pentamethyl-, 1-oxide; (29276-11-7)

Tetrahydrofuran: Furan, tetrahydro-; (109-99-9)

Methylmagnesium bromide: Magnesium, bromomethyl-; (75-16-1)

Ammonium chloride: Ammonium chloride ((NH₄)​Cl); (12125-02-9)