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Org. Synth. 2010, 87, 104

DOI: 10.15227/orgsyn.087.0104

PALLADIUM-CATALYZED CROSS-COUPLING USING AN AIR-STABLE TRIMETHYLALUMINUM SOURCE. PREPARATION OF ETHYL 4-METHYLBENZOATE

Submitted by Andrej Vinogradov and Simon Woodward¹.

Checked by Denise Rageot and Andreas Pfaltz.

1. Procedure

Caution! Trialkylaluminum compounds are pyrophoric and must not be allowed to come into contact with air or moisture. These compounds should only be handled by individuals trained in their proper and safe use.

A. [m-(1,4-Diazabicyclo[2.2.2]octane-kN1:kN4)]hexamethyldialuminum DABAL-Me₃ (1) (Note 1). A 250-mL, three-necked, round-bottomed flask is equipped with an egg-shaped, teflon-coated, magnetic stir bar (ca. 25 mm), a glass stopper, a reflux condenser and a 100-mL pressure-equalizing dropping funnel (Note 2). The reflux condenser is fitted at the top with a two-tap Schlenk adaptor connected to a bubbler and an argon/vacuum manifold (Note 3). A modest flow of argon is applied as judged by the exit bubbler (1-2 bubbles per second) and the reaction is kept under argon during the entire procedure. The glass stopper is removed and dry DABCO (5.40 g, 48.1 mmol, 1.00 equiv) (Note 4) is added in one portion using a powder funnel (Note 5). The open joint is sealed with a rubber septum and dry deoxygenated toluene (30 mL) (Note 6) is added via syringe. The solution is stirred for 10 min until all DABCO has dissolved (Note 7) and the rubber septum is replaced by a 0-150 °C thermometer in a gas-tight adaptor. The dropping funnel is charged with 2 m trimethylaluminum in toluene (47.0 mL, 94.0 mmol, 1.95 equiv) (Note 8) using a syringe. The trimethylaluminum solution is then added to the DABCO solution over 25 min at room temperature (Note 9) causing the formation of a white precipitate after ca. 10 min. Residual trimethylaluminum in the dropping funnel is rinsed with additional dry deoxygenated toluene (3 mL) (Note 6). The solution is stirred for 30 min at room temperature before DABAL-Me₃ (1) is allowed to settle for ca. 10 min. The dropping funnel is replaced by a rubber septum (Note 10, 11) and the toluene is removed by cannular filtration (Note 12). The colorless DABAL-Me₃ (1) is washed by injection of dry deoxygenated diethyl ether (40 mL) (Note 13), brief stirring and removal of the solvent by cannular filtration. This procedure is repeated twice (2 × 40 mL of dry deoxygenated diethyl ether). The product is dried under high vacuum (0.05 mmHg) at room temperature to afford DABAL-Me₃ (1) (9.97 g, 38.9 mmol, 81%) (Notes 14, 15) as a colorless solid.

B. Ethyl 4-methylbenzoate (2). A 500-mL, two-necked, round-bottomed flask is equipped with an egg-shaped, teflon-coated, magnetic stir bar (ca. 25 mm), a rubber septum and a reflux condenser fitted at the top with a two-tap Schlenk adaptor connected to a bubbler and an argon manifold (Note 2, 4). The flow of argon is reduced to a modest level as judged by the exit bubbler (1-2 bubbles per second), the rubber septum is removed and solid Pd₂(dba)₃ (550 mg, 0.600 mmol, 1.50 mol%) (Note 16) and X-Phos (573 mg, 1.20 mmol, 3.00 mol%) (Note 17) are added. The joint is sealed again with the rubber septum and dry THF (200 mL) (Note 18) and ethyl 4-bromobenzoate (9.16 g, 40.0 mmol, 1.00 equiv) (Note 19) are added by syringe. The joint is opened again to add DABAL-Me₃ (1) (8.31 g, 32.4 mmol, 0.801 equiv) using a powder funnel. The open socket is sealed with a glass stopper and the dark purple reaction mixture is heated at reflux for 4 h in an oil bath (90 °C). Completion of the reaction can by confirmed by working up an aliquot (1 mL) of the reaction mixture, as described below, and recording its ¹H NMR spectrum (Note 20). The argon flow is slightly increased (3-4 bubbles per second), heating is stopped and the reaction mixture is allowed to cool to room temperature over an hour. The flask is further cooled in an ice bath for 15 min and the reaction is quenched by cautious, portionwise, addition of 2 m aqueous HCl (160 mL) (Note 21). The resulting biphasic mixture is transferred into a separatory funnel (1 L) with diethyl ether (2 × 100 mL) (Note 22). The layers are separated, retained separately and the aqueous fraction is re-extracted with diethyl ether (3 × 150 mL). The organic layers are combined, dried over MgSO₄ (30 g) and filtered though a plug of activated charcoal (5 g) (Note 23) layered on the top of SiO₂ (50 g) (Note 24). The plug is further washed with diethyl ether (1 L). Removal of the solvent by rotatory evaporation (25 °C, 150 mmHg) affords the crude product as a clear brown oil in quantitative yield. Short-path distillation under reduced pressure (118-120 °C at 0.1 mmHg) gives the product 2 (6.11 g, 37.2 mmol, 93%) as a colorless oil (Note 25).

2. Notes

1. DABAL-Me₃ (1) is available from Aldrich (Catalog No. 682101) which may alternatively be used as received in part B. The preparation of 1 presented here requires the use of pyrophoric AlMe₃ solutions; the synthesis should be conducted in a fumehood.

2. The glassware was dried in a >120 °C oven overnight, assembled hot and a brisk flow of argon was applied until residual air had been swept out of the apparatus and through the dropping funnel (ca. 5 min).

3. A two-tap Schlenk adaptor connected to a bubbler and an argon/vacuum manifold is illustrated in Yu, J.; Truc. V.; Riebel, P.; Hierl, E.; Mudryk, B., Org. Synth. 2008, 85, 64-71.

4. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was purchased from Aldrich (98% grade). This slightly hygroscopic amine was sublimed (60-90 °C at 0.1 mm Hg) in a Kugelrohr distillation apparatus by cooling the collecting flask with dry ice. The checkers stored the freshly sublimed DABCO in a desiccator over P₂O₅ overnight.

5. The flow of argon should be moderate to facilitate addition without blowing the solid out of the addition funnel.

6. The submitters purchased toluene (> 99%) from Fisher Scientific. The solvent was dried over sodium overnight and deoxygenated by aerating with argon for 10 min. Alternatively, toluene can be distilled from sodium-benzophenone under argon. The checkers purchased toluene (>99%, over 4 Å molecular sieves from Fluka. It was deoxygenated by aerating with argon for 15 min and used without further drying.

7. The submitters warmed the mixture at 40 °C until the DABCO was completely dissolved. If necessary, to facilitate final dissolution of DABCO, submitters reported the possibility to add an additional quantity of toluene (5 mL). The checkers did not observe any need to help the dissolution of DABCO; it completely dissolved upon stirring.

8. Trimethylaluminum solutions in toluene were purchased from Aldrich (2 m) and used as received. Such solutions should be treated as pyrophoric and transferred by syringe under an argon atmosphere. Re-use of a 20 mL syringe proved to be the most effective method.

9. The temperature remained at <30 °C during addition. The submitters added the trimethylaluminum solution over 15 min and observed a ca. 20-30 °C rise in the temperature of the reaction mixture and formation of a white precipitate after 5-10 min. If the internal temperature rises above ca. 60 °C, the submitters reported the possibility to control the temperature by using a water bath.

10. Occasionally, slight smoking at the end of the addition funnel could be seen but ceased readily. To maximize safety, the discarded dropping funnel was opened and placed at the back of the fumehood overnight.

11. The set-up should be left under a slight positive pressure of argon to avoid ingress of air.

12. The cannular filtration was conducted under an argon atmosphere using Teflon tubing (800 mm × 2 mm). One side of the tubing was covered with filter paper, secured with a Teflon band, and fitted to the reaction flask with a rubber septum. The cannular filtration is described in detail in ref. 2. To the collected solvents and washings was added dropwise iso-propanol (ca. 5 mL) before storing them at the rear of the fumehood overnight and later subjected to appropriate disposal.

13. The submitters purchased diethyl ether (>99%) from Sigma-Aldrich. The solvent was distilled from sodium-benzophenone under an argon atmosphere and collected by syringe. The checkers used diethyl ether (VWR, HPLC grade) dried and degassed using a Pure-Solve^TM system.

14. The submitters obtained 9.20-10.0 g (74-81%) of DABAL-Me₃ (1). When carried out at half of the scale reported in the procedure, the checkers obtained 4.87 g (79%) of 1.

15. Combustion of neat DABAL-Me₃ (1) can be induced by water, aqueous acids and other strong proton sources. It should be regarded as incompatible with strong oxidizing agents. Samples can be stored in air-tight containers under argon or nitrogen at room temperature (storage lifetime under these conditions is at least one year). The compound can be handled in air (15 min to 4 h, depending on the moisture content of the laboratory air). Longer exposure results in slow controlled decomposition to aluminum hydroxides/oxides. Unwanted samples of DABAL-Me₃ (1) can be disposed of by cautious, slow hydrolysis with alcohols or for small amounts even ice/ice-water mixtures. The reagent should be considered as harmful by ingestion and strongly irritating to the eyes and mucous membranes. DABAL-Me₃ (1) has the following properties: mp 230 °C (dec., in air chars from 160 °C); it is soluble in THF, CH₂Cl₂, C₆H₆ and CHCl₃, but only sparingly soluble in Et₂O or in toluene at room temperature. Its physical properties are as follows: ¹H NMR pdf (400 MHz, C₆D₆, 25 °C) δ: -0.64 (s, 18 H), 1.97 (s, 12 H) ppm; ¹³C NMR pdf (101 MHz, C₆D₆, 25 °C) δ: -9.8, 43.6 ppm. NMR samples need to be prepared in dry, non-protic solvents. Recrystallization of 1 from dry benzene under argon (crude 1 (1.00 g) dissolved in hot C₆H₆ (8-10 mL) provides 0.55-0.60 g of colorless rhomboidal crystals (unit cell parameters and X-ray structure identical to literature values⁵).

16. Pd₂(dba)₃ (dba = dibenzylideneacetone) was purchased from Alpha Aesar by the submitters and used as received. The checkers obtained Pd₂(dba)₃ from Sigma-Aldrich and used it without further purification. Literature preparations of this compound are available in ref. 3.

17. X-Phos was purchased from Alfa Aesar by the submitters and used as received. The checkers obtained X-Phos (97%) from Sigma-Aldrich.

18. The submitters obtained tetrahydrofuran (THF, >99%) from Sigma-Aldrich and distilled it from sodium-benzophenone under an argon atmosphere. The checkers used tetrahydrofuran (VWR, HPLC-grade) dried using a Pure-Solve^TM system.

19. Ethyl 4-bromobenzoate (Aldrich, 98%) was dried overnight using activated 4Å molecular sieves before use.

20. Complete consumption of ethyl 4-bromobenzoate is easily identified by the absence of the two apparent doublets of the phenylene group in its ¹H NMR spectrum. Its physical properties are as follows: ¹H-NMR (400 MHz, CDCl₃, 25 °C) d: 1.42 (t, J = 7.1 Hz, 3 H), 4.40 (q, J = 7.1 Hz, 2 H), 7.60 (app. d, J = 8.5 Hz, 2 H), 7.92 (app. d, J = 8.5 Hz, 2 H) ppm. Alternatively, the submitters reported that GC analysis can be used to confirm completion of the reaction: 15 m factorFOUR column, column flow: He, 1.5 mL•min^-1, run isothermally at 120 °C, t_R = 2.75 min (2), t_R = 4.95 min (ethyl 4-bromobenzoate).

21. The quenching procedure releases methane. Care should be taken to add the acid at such rate that excessive foaming is avoided. If the flask is re-stoppered the rate of the hydrolysis reaction can be judged by the rate of out-gassing from the exit bubbler. Typically, addition of the 2 m HCl over 10-15 min is required.

22. The submitters purchased diethyl ether (>99%) from Sigma-Aldrich and used it as supplied. The checkers obtained diethyl ether (>99%) from J. T. Baker and used it as received.

23. The checkers purchased activated charcoal from Fluka.

24. Silica gel 60 (220 240 mesh) supplied by Fluka was used as received. The SiO₂ was slurried up in diethyl ether, before layering it with activated charcoal and filtering the organic phase.

25. The submitters obtained 5.98-6.31 g (91-96%) of 2. When carried out at half of the scale reported in the procedure the checkers obtained 2.95 g (90%) of 2. The compound has literature properties⁴ and is stable indefinitely. Its physical properties are as follows: ¹H NMR pdf (400 MHz, CDCl₃, 25 °C) δ: 1.38 (t, J = 7.1 Hz, 3 H), 2.40 (s, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 7.22 (app. d, J = 8.3 Hz, 2 H), 7.94 (app. d, J = 8.3 Hz, 2 H); ¹³C NMR pdf (101 MHz, CDCl₃, 25 °C) δ: 14.4, 21.7, 60.8, 127.9, 129.1, 129.7, 143.5, 166.8; Anal. calcd. for C₁₀H₁₂O₂: C, 73.15%; H, 7.37%; found: 72.90%; H, 7.38%. The purity of the compound was checked by GC analysis; Rtx-1701 column (30 m × 0.25 mm × 0.25 μm), 60 kPa He, 100 °C, 2 min isotherm, 7 °C•min^-1, 250 °C, 10 min isotherm, t_R = 13.6 min (2), t_R = 16.5 (ethyl 4-bromobenzoate).

Working with Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior 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 www.nap.edu). 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.

These procedures must be 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

The abnormally high air stability of the DABCO bis-AlMe₃ adduct (1) was first noted by Bradley in the early 1990s.⁵ However, synthetic applications of the material only recently became popular - especially since the commercialization of this reagent. Originally prepared in Et₂O, the combination of pyrophoric trimethylaluminium and a very low flash point of ether is less desirable on large scales for safety reasons, even though somewhat higher yields can be realized. The toluene-based procedure described here is effective and safe at scales up to at least 10 g. In combination with Pd₂(dba)₃ and Buchwald's X-Phos,⁶ DABAL-Me₃ (1) is effective for the methylation of aryl halides ArX (X = Cl, Br, I) and triflates (X = OTf).⁷ A wide range of other functional groups is tolerated under these reaction conditions (F, CF₃, vinyl, CO₂R, CN, CHO, OTs, NO₂, OMe, and OAc) (Table 1). Complete conversion is attained within 4 h at THF reflux (with 0.8 equiv of DABAL-Me₃), avoiding the often problematic post-reaction chromatographic separation of residual halide starting materials.

Chemoselective methylation (>95% selectivity) of C-Br over C-Cl bonds can be attained through use of Cy-JohnPhos.⁸ Aside from C(sp²)-X (X = Cl, Br, I, OTf), benzylic halides can be used in Pd⁰/X-Phos couplings (e.g., PhCH₂Br is methylated in 72% yield). One limitation of the methylation procedure is its present inability to tolerate the methylation of electron deficient heterocycles (e.g. halopyridines and isoquinolines; entries 34-35, Table 1). The low yields of methylated products isolated in these cases are believed to be due to competing Chichibabin-type processes. Additionally, enolizable substrates capable of self-condensation are not always tolerated (entry 26, Table 1). The use of 0.8 equiv of DABAL-Me₃ per coupled C-X, together with Pd⁰/X-Phos makes for a highly robust procedure. In small-scale reactions (0.25 mmol) the procedure can be carried out in undried THF under standard reflux conditions in air - the DABAL-Me₃ (1) acting simultaneously as a drying agent. However, the slower rates of heating in large-scale reactions (such as that presented here) slows the solvent drying/deoxygenation process too much, leading to non-reproducibility. Couplings with DABAL-Et₃ allow ethylation procedures in >85% yield without any issues associated with β-elimination. The ethyl analogue is not stable in air and is best prepared in situ from DABCO and AlEt₃.

In addition to the cross-coupling procedure illustrated here, DABAL-Me₃ (1) has found application in a wide range of transformations including: 1,2-additions to aldehydes⁹ and enones,¹⁰ 1,4-additions to enones,¹¹ methylation of allylic electrophiles¹² and direct conversion of esters to amides.¹³

Table 1. Methylation of aryl and vinyl halides and pseudohalides with DABAL-Me₃ 1.^a

Table 1. Methylation of aryl and vinyl halides and pseudohalides with DABAL-Me3 1.a

Table 1. (continued)

References and Notes

School of Chemistry, The University of Nottingham, NG7 2RD United Kingdom; e-mail
Bennett, B. K.; Richmond, T. G. J. Chem. Ed. 1998, 75, 1034.
Milani, B.; Anzilutti, A.; Vicentini, L.; o Santi, A. S.; Zangrando, E.; Geremia, S.; Mestroni, G. Organometallics 1997, 16, 5064-5075.
Minami, T., Nishimura, K.; Hirao, I.; Suganuma, H.; Agawa, T. J. Org. Chem.1982, 47, 2360-2363.
Bradford, A. M.; Bradley, D. C.; Hursthouse, M. B.; Motevalli, M. Organometallics 1992, 11, 111-115.
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
Cooper, T.; Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Adv. Synth. Catal. 2006, 348, 686-690.
Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561. Cy-JohnPhos (247940-06-3) is also widely commercially available in research quantities.
(a) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward S. Angew. Chem., Int. Ed. 2005, 44, 2232-2234. (b) Mata, Y.; Diéguez, M.; Pàmies, O.; Woodward, S. J. Org. Chem. 2006, 71, 8159-8165. (c) Biswas, K.; Chapron, A.; Cooper, T.; Fraser, P. K.; Novak, A.; Prieto, O.; Woodward, S. Pure Appl. Chem. 2006, 78, 511-518.
Siewert, J.; Sandmann, R.; von Zezschqitz, P. Angew. Chem., Int. Ed. 2007, 46, 7122-7124.
Alexakis, A.; Albrow, V.; Biswas, K.; d'Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun. 2005, 2843-2845.
(a) Novak, A.; Fryatt, R.; Woodward. S. C. R. Chimie 2007, 10, 206-212. (b) Novak, A.; Calhorda, M. J.; Costa, P. J.; Woodward, S. Eur. J. Org. Chem. 2009, 898-903.
(a) Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett. 2006, 47, 5767-5769. (b) Glynn, D.; Bernier, D.; Woodward, S. Tetrahedron Lett. 2008, 49, 5687-5688.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Trimethylaluminium: (75-24-1)

DABCO: 1,4-Diazabicyclo[2.2.2]octane; (280-57-9)

Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0); (51364-51-3)

X-Phos: 2-di-cyclo-hexylphosphino-2',4',6'-triisopropylbiphenyl; (564483-18-7)

Ethyl 4-bromobenzoate: (5798-75-4)

	Simon Woodward undertook both his undergraduate and Ph.D. at the University of Sheffield, the latter in the group of Dr. Mark J. Winter. After a period as a Fulbright Scholar in the group of Prof. M. David Curtis at the University of Michigan he was a postdoctoral researcher with Dr. John M. Brown, FRS at the University of Oxford. Initially appointed to a Lectureship in Organometallic and Catalytic Chemistry at The University of Hull, he moved to the University of Nottingham in 1999. His research group is interested in chemo, regio and stereoselective catalysis of organic reactions, under convenient/simple conditions.
	Andrej Vinogradov studied Chemistry at the University of Münster. He did his Ph.D. at the Inorganic Chemistry Department of the University of Münster under supervision of Prof. Dr. Werner Uhl. Since 2009 he is a postdoctoral research fellow at the University of Nottingham with Prof. Simon Woodward. Dr. Vinogradov's research interests centre round the preparation and use of organoalanes.
	Denise Rageot was born in 1985 in Basel, Switzerland. She studied Chemistry at the University of Basel, where she obtained her M.S. in 2008 under the supervision of Prof. Andreas Pfaltz. She began her Ph. D. work in summer 2008 in the group of Prof. Andreas Pfaltz, where she is currently working on the synthesis of new chiral ligands for asymmetric metal catalysis.

Notes