Dendritic HMPA as a Promoter for the Mukaiyama Aldol and Allylation Reaction

Abstract

We synthesized a hexamethylphosphoramide (HMPA) analogue that was immobilized on hyperbranched polyglycerol (hPG) via a covalent approach. This polymeric analogue (hPG-­HMPA) can potentially replace carcinogenic HMPA as a Lewis base additive in many reactions involving trichlorosilyl substrates. We investigated immobilized HMPA in the Mukaiyama aldol and allylation reactions. In most cases, yields and selectivities of supported and nonsupported HMPA were similar. Moreover, in the allylation reaction a positive dendritic effect could be observed, and the loading of HMPA could be lowered with hPG-HMPA to catalytic quantities (0.5 mol%). These results demonstrate that the use of HMPA can be avoided by hPG-HMPA without loss in terms of yield or selectivity.

Key words

aldol reaction - homogeneous catalysis - supported catalysts - organocatalysis - HMPA - polymeric support

• References

• 1a Normant H. Angew. Chem., Int. Ed. Engl. 1967; 6: 1046
• 1b Normant H. Angew. Chem. 1967; 79: 1029
• 1c Stowell JC. Carbanions in Organic Synthesis. Wiley; New York: 1979
• 1d Reichardt C, Welton T. Solvents and Solvent Effects in Organic Chemistry . Wiley-VCH; Weinheim: 2010
• 2 Denmark SE, Pham SM, Stavenger RA, Su X, Wong K.-T, Nishigaichi Y. J. Org. Chem. 2006; 71: 3904
• 3 Denmark SE, Fu J, Coe DM, Su X, Pratt NE, Griedel BD. J. Org. Chem. 2006; 71: 1513
• 4 Berndt M, Hölemann A, Niermann A, Bentz C, Zimmer R, Reissig H.-U. Eur. J. Org. Chem. 2012; 1299
• 5 Flowers R, Xu X, Timmons C, Li G. Eur. J. Org. Chem. 2004; 2988
• 6 Meise M, Haag R. ChemSusChem 2008; 1: 637
• 7 Keilitz J, Haag R. Eur. J. Org. Chem. 2009; 3272
• 8a Regen SI, Nigam A, Besse JJ. Tetrahedron Lett. 1978; 19: 2757
• 8b Flowers R, Xu X, Timmons C, Li G. Eur. J. Org. Chem. 2004; 2988
• 9a Dahan A, Portnoy M. Chem. Commun. 2002; 2700
• 9b Dahan A, Portnoy M. Org. Lett. 2003; 5: 1197
• 9c Kehat T, Portnoy M. Chem. Commun. 2007; 2823
• 9d Dahan A, Portnoy M. J. Polym. Sci., Part A: Polym. Chem. 2005; 43: 235
• 9e Mansour A, Kehat T, Portnoy M. Org. Biomol. Chem. 2008; 6: 3382
• 10 Marcato PD, Caverzan J, Rossi-Bergmann B, Pinto EF, Machado D, Silva RA, Justo GZ, Ferreira CV, Dur N. J. Nanosci. Nanotechnol. 2011; 11: 1880
• 11 Hansen CM, Andersen BH. Am. Ind. Hyg. Assoc. J. 1988; 49: 301
• 12a Sunder A, Mülhaupt R, Haag R, Frey H. Adv. Mater. 2000; 12: 235
• 12b Sunder A, Hanselmann R, Frey H, Mülhaupt R. Macromolecules 1999; 32: 4240
• 13 Roller S, Zhou H, Haag R. Mol. Diversity 2005; 9: 305
• 14a Haag R, Sunder A, Hebel A, Roller S. J. Comb. Chem. 2002; 4112
• 14b Hebel A, Haag R. J. Org. Chem. 2002; 67: 9452
• 15a Hajji C, Roller S, Beigi M, Liese A, Haag R. Adv. Synth. Catal. 2006; 348: 1760
• 15b Beigi M, Haag R, Liese A. Adv. Synth. Catal. 2008; 350: 919
• 15c Beigi M, Roller S, Haag R, Lieses A. Eur. J. Org. Chem. 2008; 2135
• 16 All experiments were carried out under an argon atmosphere using dried glassware. Chemicals were purchased from commercial suppliers and used as received unless otherwise noted. Benzaldehyde was freshly distilled prior to use. Dry CH₂Cl₂ was purchased from Sigma-Aldrich and dried via a Solvent Purification System MB-SPS 800 from MBraun. Column chromatography was performed on Merck Silica Gel 60 (230–400 mesh). Ultrafiltration was performed with a 300 mL solvent-resistant stirred cell with regenerated cellulose membranes (molecular weight cut-off 5000 g mol^–1), both from Millipore. ¹H, ¹³C and ³¹P NMR spectra were recorded at room temperature using a Jeol ECX 400 and Bruker AV 700. 2D spectra were recorded on a Jeol Eclipse 500. Chemical shifts (δ) were reported in parts per million (ppm) relative to tetramethylsilane and coupling constants (J) in hertz (Hz). The spectra were referenced against the internal solvent (CDCl₃, δ ¹H = 7.26 ppm, ¹³C = 77.0 ppm). O-Mesylpolyglycerol was synthesized according to the literature procedure.¹³
  Polyglycerylmethylamine (2): O-Mesylpolyglycerol (4.4 g, 28.6 mmol mesyl groups) was dissolved in p.a. DMF (20 mL) in a 48 mL ACE pressure tube using ultrasonication. In the next step, MeNH₂ gas (15 mL) was condensed into the tube and sealed afterwards. The mixture was stirred and heated up to 60 °C for 24 h. For workup the mixture was diluted with MeOH and filtered using a glass frit. The dissolved crude product was further purified by ultrafiltration with MeOH as solvent and Et₃N (2 mL) as an additive in the first run. After the third run the filtrate became colorless. The solvent was evaporated and a brown honey-like product was obtained. Yield: 95%, 8 mmol methylamine groups per gram polymer; ¹H NMR (400 MHz, CDCl₃): δ = 3.87–3.16 (br m, PG-backbone), 2.77–2.62 (m, functionalized PG groups), 2.42–2.17 (br m, NCH₃); ¹³C NMR (100 MHz, CDCl₃): δ = 78.6–68.7 (PG), 62.0–46.0 (functionalized PG groups); 43.0–34.0 (NHMe). PG-Hexamethylphosphoramide (4): Polyglycerylmethylamine (2) (1 g, 8 mmol) was dissolved in anhyd THF (20 mL) in a 50 mL Schlenk tube. The clear yellow solution was cooled to –78 °C and after 30 min, N,N,N′,N′-tetramethylphosphorodiamidic chloride (8 mmol, 1.2 mL) was added dropwise via syringe. The reaction was warmed to r.t. overnight and then quenched by addition of MeOH. The crude product was purified by ultrafiltration (membrane: 5 kDa, solvent: MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 3.85–3.28 (br m, PG-backbone), 2.65–2.16 (br m, NCH₃); ³¹P NMR (121.5 MHz, CDCl₃): δ = 26.0, 27.4 ppm. Loading: 1 mmol HMPA per gram polymer; determined by addition of triphenylphosphine oxide as internal standard, followed by integration in the ³¹P spectra. General procedure for the catalyzed aldol reaction with slow addition of aldehyde:² The catalyst PG-HMPA (50 mg, 0.05 mmol, 0.1 equiv) was dissolved in CH₂Cl₂ (0.5 mL), and the solution was cooled to –78 °C. 1-Cyclohexenyloxytrichlorosilane (100 µL, 0.55 mmol, 1.1 equiv) was added dropwise. A solution of benzaldehyde (50 µL, 0.5 mmol, 1.0 equiv) in CH₂Cl₂ (0.2 mL) was then added dropwise to the first solution with the help of a syringe pump (speed: 0.3 mL/h). During the addition the temperature remained constant at –78 °C. The reaction mixture was stirred at –78 °C for an additional 60 min and then quickly poured into cold (2 °C) sat. aq NaHCO₃ (2 mL). The mixture was allowed to warm to r.t. The phases were separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 10 mL). The organic phases were combined, dried over MgSO₄, filtered, and concentrated in vacuo. The syn/anti ratio was determined by ¹H NMR (400 MHz). The crude product was purified by column chromatography (SiO₂, CHCl₃) and was obtained as amixture of syn and anti products as a colorless solid. Analytical data for syn/anti ratio 1:1: ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.22 (m, 10 H, 2 Ph), 5.38 (d, J = 2.5 Hz, 1 H, syn-PhCHOH), 4.78 (d, J = 8.8 Hz, 1 H, anti-PhCHOH), 3.97 (s, 1 H, anti-OH), 3.06 (s, 1 H, syn-OH), 2.64–1.25 (m, 18 H, CH_ax + CH_eq). General procedure for the allylation reaction of benzaldehyde with allyl trichlorosilane: To a solution of PG-HMPA (2 mmol HMPA/g) (50 mg, 0.1 mmol, 10 mol%) in 0.2 mL of CH₂Cl₂ under N₂ at r.t. was added (i-Pr)₂NEt (0.5 mL), benzaldehyde (102 µL, 1.0 mmol, 1.0 equiv), and allyl trichlorosilane (290 µL, 2.0 mmol, 2.0 equiv). The resulting mixture was stirred for 1 h, before it was quenched with 2.0 mL NH₄Cl solution and 2.0 mL CH₂C1₂ were added. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 10mL). The combined organic layers were washed with brine and dried over MgSO₄ and the solvent was removed in vacuo. The crude product was analyzed by ¹H NMR. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.28 (m, 5 H, HC_aryl), 5.86–5.76 (m, 1 H, HC-3), 5.18–5.13 (m, 2 H, H₂C-4), 4.78 (dd, J = 7.3, 5.5, 1 H, HC-1), 2.57–2.45 (m, 1 H, HC-2), 2.05 (br s, 1 H, OH).