CHAPTER 11

C–C OR C–N REACTIONS CATALYZED BYDIADAMANTHYLPHOSPHINE PALLADIUM-BASED CATALYST

SUPPORTED ON DAB-DENDRIMERS

Karine Heuze, Agnes Fougeret, Julietta Lemo, and DanielRosario-Amorin

Universite de Bordeaux 1/CNRS, Talence, France

Library synthesis route

Building block 1

Solid-Phase Organic Syntheses, Volume 2: Solid-Phase Palladium Chemistry, First Edition.Edited by Peter J. H. Scott.© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

97

98 C–C OR C–N REACTIONS CATALYZED BY DIADAMANTHYLPHOSPHINE

Building block 2

Building block 3

PROCEDURE 99

1 PROCEDURE

1.1 Procedure for the Synthesis ofBis(adamantyl)aminomethylphosphine 1

A mixture of formaldehyde (37% in water, 1.92 mL, 69.61 mmol),HCl (35%, 1 mL, 48.19 mmol), and water (8 mL) are added tobis(adamantyl)phosphine (3.24 g, 10.71 mmol) under nitrogen atmosphere(note 1). The mixture is stirred for 2 h 30 min at room temperature (RT)(note 2). The precipitate is filtered out and recrystalized in methanol(note 3) to yield the bis(adamantyl)hydroxymethylphosphonium salt (3.2 g,80%). To a suspension of this salt (971 mg, 2.43 mmol) in MeOH (4 mL)and H2O (2 mL), at 80◦C under nitrogen atmosphere, triethylamine(338 μL, 2.43 mmol) and benzylamine (133 μL, 1.21 mmol) are added(note 4). Toluene (2–4 mL) is added to dissolve the precipitate, and themixture is stirred at 80◦C for 1 h under nitrogen. The organic layer isseparated under nitrogen atmosphere and dried over MgSO4. The solutionis concentrated to a few milliliters, the supernatent is removed, and thegommy precipitate is dissolved again in toluene. Methanol is added until anew precipitate appeared. The supernantent is removed, and the precipitateis dried under vacuum to yield bis(adamantyl)aminomethylphosphine 1(193 mg, 21%), (note 5).

1.2 General Procedure for the Synthesis ofBis(adamantyl)aminomethylphosphine-Supported

DAB-Dendrimers (2, 3)

A mixture of paraformaldehyde (740 mg, 24.6 mmol) in methanol (5 mL)is added to bis(adamantyl)phosphine (1.244 g, 4.11 mmol) under nitro-gen atmosphere (note 1). The mixture is stirred for 10 min at 70◦C andcooled down to RT. DAB-dendr-(NH2)n (note 6) (0.423 mmol) in 10 mLof toluene is added, and the mixture is stirred for 1 h at 70◦C and thenat RT overnight. The solution is concentrated to a few milliliters, andmethanol is added until a precipitate appears. The precipitate is washedtwice with fresh methanol under nitrogen and dried under vacuum to yieldthe DAB-dendrimer-supported bis(adamantyl)aminomethylphosphine 2 and3 (respectively, 77% and 65%) (note 5).

100 C–C OR C–N REACTIONS CATALYZED BY DIADAMANTHYLPHOSPHINE

1.3 General Procedure for the C–C or C–N Cross-CouplingReactions

Synthesis of palladium complexes catalysts: palladium complexes of phos-phine compounds were freshly made under nitrogen atmosphere by theaddition of Pd(OAc)2 (0.02 mmol in the case of 1, 0.08 mmol in the caseof 2, and 0.16 mmol in the case of 3) in a solution of phosphine (0.02 mmol)in CH2Cl2 at RT (note 7).

Copper-free Sonogashira C–C cross-coupling reaction: in an oven-driedSchlenk tube cooled to RT under an argon purge were added aryl halide(2 mmol), phenylacetylene (3 mmol), and Et3N (6 mL). Dried palladiumcomplex of phosphine compounds (1 mol% [Pd]) freshly made was thenadded to the mixture. The reaction mixture was stirred at 80◦C and moni-tored by gas chromatography (GC) or GC–mass spectrometry (GC-MS).

Suzuki C–C cross-coupling reaction: in an oven-dried Schlenk tubecooled to RT under an argon purge were added aryl halide (2 mmol)with phenylboronic acid (3 mmol) and NaOH (6 mmol) in THF/H2O (2/1)(10 mL). Freshly made dried palladium complex of phosphine compound(1 mol% [Pd]) was then added to the mixture. The reaction mixture wasstirred at 65◦C and monitored by GC or GC-MS.

Amination C–N cross-coupling reaction: in an oven-dried Schlenk tubecooled to RT under an argon purge were added aryl halide (2 mmol) withamine (2.4 mmol), NaOtBu (3 mmol), and toluene (10 mL). Freshly madedried palladium complex of phosphine compounds (1 mol% [Pd]) wasthen added to the mixture. The reaction mixture was stirred at 110◦C andmonitored by GC or GC-MS.

Catalytic activities of phosphine palladium complexes are shown inTable 1.

2 DISCUSSION

We have synthesized efficient phosphino palladium catalysts with electron-rich and sterically hindered diadamantyl phosphines ligands for C–C orC–N coupling reactions. We have shown that adamantyl (Ada) phosphinespalladium complex displayed a better reactivity than Cy and t-Bu phosphinecomplexes toward cross-coupling reactions [2, 3]. Indeed, in Sonogashiracross coupling, unreactive aryl chlorides were coupled successfully in goodyields and under mild conditions (Table 1, entries 1–9). In this series, nodendritic effect was observed. In Suzuki cross coupling, an excellent reac-tivity was observed in all cases, and a dendritic effect could be pointedout since catalysts made up of 2 and 3 promoted better coupling yieldsthan catalysts made up of 1 (Table 1, entries 10–15). It is noteworthy that

DISCUSSION 101

TABLE 1 C–C and C–N Cross-Coupling Reactions

Phosphine-Based Reaction ConversionEntry Substrate Product Catalyst (1 mol%) Time (h) (%)

1 1 1 100

3 1 1 98

4 1 20 56

5 1 20 75

6 1 20 71

7 2 20 43

8 2 20 61

9 3 20 34

10 1 2 77

12 2 1 95

13 2 1 97

14 3 1 99

15 3 1 99

16 1 20 35

17 1 20 60

an moderate reactivity was encountered for the C–N reaction (Table 1,entries 16–17), whereas no reactivity was observed in the case of Cy ort-Bu phospines palladium complexes [2, 3]. Therefore, kinetics investiga-tions on the overall reaction (i.e., based only on the isolated product) wereperformed. This study was done on the Sonogashira C–C reaction withphophine 1 ligand. In a typical Sonogashira reaction involving iodobenzene(4 mmol) and phenylacetylene (6 mmol) in Et3N (10 mL), we monitored

102 C–C OR C–N REACTIONS CATALYZED BY DIADAMANTHYLPHOSPHINE

0

0.5

−0.5

−1

−1.5

−2

0

Reaction time (min)

y = −0.26629 −0.021149x R = 0.97449

20

in(C

/C0)

40 60 80 100

FIGURE 1 Kinetics of the disappearance of iodobenzene at 25◦C.

the appearance of diphenylacetylene and the disappearance of iodoben-zene, from which the rate constant was determined (note 8). As shown inFigure 1, the variation of ln x versus time (x = c/c0) was linear; this estab-lished an overall reaction order of +1 (Table 1, entries 1–9). The observedapparent constant rate constant kobs, for the overall reaction was then deter-mined from the slope of the regression of the plot. The calculated rateconstant was 1.269 mol/L/h at 25◦C compared to 0.925 mol/L/h at 25◦Cfor t-butylphosphine and 0.028 mol/L/h at 27◦C for dicyclohexylphosphineligands [2]. This dramatic enhanced activity of the diadamantylphosphineligand should be explored in a wide range of substrates for C–C or C–Ncross-coupling reactions using dendritic supports, which made the recoveryof the catalyst possible, as we have demonstrated in the case of Cy andt-Bu phosphine ligands [4].

WASTE DISPOSAL INFORMATION

All toxic materials were disposed of in accordance with Prudent Practicesin the Laboratory (Washington, D.C.: National Academy Press, 1995).

APPENDIX: EXPERIMENTAL SUPPLEMENT

Compound 1. 1H NMR (300 MHz, CDCl3) δ 7.18 (m, 5H, Ar), 3.66(s, 2H, ArCH2N), 2.67 (s, 4H, NCH2P), 1.80 (m, 36H, CH2CP + CH),1.60 (m, 24H, CH2). {1H}13C NMR (75 MHz, CDCl3) δ 139.8 (C),126.6–130.4 (Ar), 62.1 (PhCH2N), 48.8 (NCH2P), 40.9 (CH2), 37.0

APPENDIX: EXPERIMENTAL SUPPLEMENT 103

(CH2), 28.7 (CH). {1H}31P NMR (121 MHz, CDCl3) δ 8.95. Elementalanalysis for C49H71NP2, calc (%): C 79.96, H 9.72, N 1.90 ; found (%):C 79.93, H 10.24, N 1.73. The 1H, 13C, and 31P NMR spectra wererecorded using the following spectrometers: a Brucker DPX 200 FTNMR spectrometer (1H: 200.16 and 13C: 50.33 MHz), a Brucker AC250 FT NMR spectrometer (1H: 250.13 and 13C: 62.90 MHz), and anAvance 300 FT NMR spectrometer (1H: 300.13 and 13C: 75.46 MHz).Elemental analysis for C, H, and N were performed following the classicalPregl-Dumas technique on a Thermo Fischer Flash EA1112.

Compound 2. 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 4H, NCH2),2.75 (m, 24H, CH2N and PCH2N), 2.40 (s, 8H, NCH2), 1.90 (m, 144H,CH2CP + CH), 1.70 (m, 96H + 8H, CH2), 1.37 (m, 4H, CH2). {1H}13CNMR (75 MHz, CDCl3) δ 138.0 (C), 52.7 (NCH2P), 51.5 (CH2N), 48.9(CH2N), 43.9 (CH2N), 41.1 (CH2), 37.3 (CH2), 28.9 (CH), 25.5 (CH2),23.1 (CH2). {1H}31P NMR (121 MHz, CDCl3) δ 8.64. Elemental analysisfor C184H288N6P8O8 (product appeared in the oxidized form because of theexperimental conditions) calc (%): C 74.66, H 9.81, N 2.84; found (%): C74.58, H 10.51, N 3.22. The 1H, 13C, and 31P NMR spectra were recordedusing the following spectrometers: a Brucker DPX 200 FT NMR spec-trometer (1H: 200.16 and 13C: 50.33 MHz), a Brucker AC 250 FT NMRspectrometer (1H: 250.13 and 13C: 62.90 MHz), and an Avance 300 FTNMR spectrometer (1H: 300.13 and 13C: 75.46 MHz). Elemental analy-sis for C, H, and N were performed following the classical Pregl-Dumastechnique on a Thermo Fischer Flash EA1112.

Compound 3. 1H NMR (300 MHz, CDCl3) δ 2.90 (m, 4H, NCH2),2.71 (m, 56H, NCH2P + CH2N), 2.35 (m, 24H, CH2N), 1.87 (m, 288H,CH2CP + CH), 1.66 (m, 192H + 16H, CH2), 1.21 (m, 8H, CH2), 0.81 (m,4H, CH2). {1H}13C NMR (75 MHz, CDCl3) δ 137.8 (C), 54.4 (NCH2P),52.8 (CH2N), 48.8 (CH2N), 43.6 (CH2N), 41.1 (CH2), 37.3 (CH2), 28.9(CH), 28.8 (CH2), 26.1 (CH2), 23.2 (CH2). {1H}31P NMR (121 MHz,CDCl3) δ 8.61. Elemental analysis for C376H592N14P16O16 (productappeared in the oxidized form because of the experimental conditions),calc (%): C 74.52, H 9.85, N 3.24; found (%): C 74.47, H 10.44, N 3.29.The 1H, 13C, and 31P NMR spectra were recorded using the followingspectrometers: a Brucker DPX 200 FT NMR spectrometer (1H: 200.16 and13C: 50.33 MHz), a Brucker AC 250 FT NMR spectrometer (1H: 250.13and 13C: 62.90 MHz), and an Avance 300 FT NMR spectrometer (1H:300.13 and 13C: 75.46 MHz). Elemental analysis for C, H, and N wereperformed following the classical Pregl-Dumas technique on a ThermoFischer Flash EA1112.

104 C–C OR C–N REACTIONS CATALYZED BY DIADAMANTHYLPHOSPHINE

NOTES

1. Bis(adamantyl)phosphine was synthesized according to the reported procedure [1], stored,and weighed in a glove box. Reactants were purchased from Aldrich Chemical Companyand degassed before use.

2. The reaction is exothermic, and the large precipitate could block the stirring.

3. Keep the methanol solution at least 24 h in a freezer to precipitate thebis(adamantyl)hydroxymethylphosphonium salt. 1H NMR (300 MHz, MeOH-d4)δ 4.79 (s, 2H, OH), 4.53 (s, 4H, CH2OH), 2.27 (m, 12H, CH2-C-P), 2.0 (m, 6H, CH),1.79 (m, 12H, CH2). {1H}13C NMR (75 MHz, MeOH-d4) δ 51.06 (CH2OH), 40.2 (C-P),38.3 (CH2-C-P), 36.9 (CH2), 29.3 (CH). {1H}31P NMR (121 MHz, MeOH-d4) δ 21.3.(ESI-MS) m/z 363 (M-Cl). Elemental analysis for C22H36ClO2P, calc (%): C 66.23,H 9.10; found (%): C 65.77, H 9.70. The 1H, 13C, and 31P NMR spectra were recordedusing the following spectrometers: a Brucker DPX 200 FT NMR spectrometer (1H:200.16 and 13C: 50.33 MHz), a Brucker AC 250 FT NMR spectrometer (1H: 250.13and 13C: 62.90 MHz), and an Avance 300 FT NMR spectrometer (1H: 300.13 and 13C:75.46 MHz). Elemental analysis for C, H, and N were performed following the classicalPregl-Dumas technique on a Thermo Fischer Flash EA1112. The electrospray ionizationmass spectra (ESI-MS) were acquired on spectrometer Qstar-Applied biosystems in anappositive mode.

4. All solvents and reagents were degassed before use.

5. Phosphines 1, 2, and 3 were stored in a glove box to avoid the phosphine oxidationreaction.

6. DAB-dendr-(NH2n): n = 4, DAB-Am-4 (polypropylenimine tetraamine dendrimer, gen-eration 1, CAS [120239-63-6] and n = 8, DAB-Am-8 (polypropyleneimine octaaminedendrimer, generation 2, CAS [154487-83-9] were purchased from Aldrich.

7. This unstable complex was rapidly analyzed by 31P NMR to confirm the complete com-plexation of phosphines with palladium, since only one 31P NMR signal was recordedfor each complex: {1H}31P NMR (121 MHz, CDCl3) δ (ppm) = 28.4 for 1, 27.7 for 2and 27.8 for 3.

8. Kinetics of the disappearance of iodobenzene at 25◦C. The variation of ln x versus time(x = c/c0). c, concentration of iodobenzene at t ; c0, initial concentration of iodobenzene.Samples were frozen in liquid nitrogen as soon as they were taken from the reaction,since the kinetics were too fast compared to the retention times for each GC experiment.

REFERENCES

1. Goerlich JR, Schmutzler R. Phosphorus, Sulfur Silicon 1995;102:211.

2. Heuze K, Mery D, Gauss D, Blais J-C, Astruc D. Chem Eur J 2004;10:3936.

3. (a) Lemo J, Heuze K, Astruc D. Org Lett 2005;7:2253; (b) Heuze K, Mery D, GaussD, Astruc D. J Chem Commun 2003:2274.

4. (a) Rosario-Amorin D, Wang X, Gaboyard M, Clerac R, Nlate S, Heuze K. Chem EurJ 2009;15:12636; (b) Rosario-Amorin D, Gaboyard M, Clerac R, Nlate S, Heuze K.Dalton Trans 2011;40:44; (c) Rosario-Amorin D, Gaboyard M, Clerac R, Vellutini L,Nlate S, Heuze K. Chem Eur J 2012;18:3305.