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C–C or C–N Reactions Catalyzed byDiadamanthylphosphine Palladium-Based CatalystSupported on Dab-Dendrimers

C–C or C–N Reactions Catalyzed byDiadamanthylphosphine Palladium-Based CatalystSupported on Dab-Dendrimers

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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 of

Bis(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 to

bis(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 H2 O (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 the

mixture is stirred at 80◦ C for 1 h under nitrogen. The organic layer is

separated under nitrogen atmosphere and dried over MgSO4 . The solution

is concentrated to a few milliliters, the supernatent is removed, and the

gommy precipitate is dissolved again in toluene. Methanol is added until a

new precipitate appeared. The supernantent is removed, and the precipitate

is dried under vacuum to yield bis(adamantyl)aminomethylphosphine 1

(193 mg, 21%), (note 5).



1.2 General Procedure for the Synthesis of

Bis(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 nitrogen atmosphere (note 1). The mixture is stirred for 10 min at 70◦ C and

cooled down to RT. DAB-dendr-(NH2 )n (note 6) (0.423 mmol) in 10 mL

of toluene is added, and the mixture is stirred for 1 h at 70◦ C and then

at RT overnight. The solution is concentrated to a few milliliters, and

methanol is added until a precipitate appears. The precipitate is washed

twice with fresh methanol under nitrogen and dried under vacuum to yield

the DAB-dendrimer-supported bis(adamantyl)aminomethylphosphine 2 and

3 (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-Coupling

Reactions

Synthesis of palladium complexes catalysts: palladium complexes of phosphine compounds were freshly made under nitrogen atmosphere by the

addition of Pd(OAc)2 (0.02 mmol in the case of 1, 0.08 mmol in the case

of 2, and 0.16 mmol in the case of 3) in a solution of phosphine (0.02 mmol)

in CH2 Cl2 at RT (note 7).

Copper-free Sonogashira C–C cross-coupling reaction: in an oven-dried

Schlenk tube cooled to RT under an argon purge were added aryl halide

(2 mmol), phenylacetylene (3 mmol), and Et3 N (6 mL). Dried palladium

complex of phosphine compounds (1 mol% [Pd]) freshly made was then

added to the mixture. The reaction mixture was stirred at 80◦ C and monitored by gas chromatography (GC) or GC–mass spectrometry (GC-MS).

Suzuki C–C cross-coupling reaction: in an oven-dried Schlenk tube

cooled to RT under an argon purge were added aryl halide (2 mmol)

with phenylboronic acid (3 mmol) and NaOH (6 mmol) in THF/H2 O (2/1)

(10 mL). Freshly made dried palladium complex of phosphine compound

(1 mol% [Pd]) was then added to the mixture. The reaction mixture was

stirred at 65◦ C and monitored by GC or GC-MS.

Amination C–N cross-coupling reaction: in an oven-dried Schlenk tube

cooled to RT under an argon purge were added aryl halide (2 mmol) with

amine (2.4 mmol), NaOtBu (3 mmol), and toluene (10 mL). Freshly made

dried palladium complex of phosphine compounds (1 mol% [Pd]) was

then added to the mixture. The reaction mixture was stirred at 110◦ C and

monitored by GC or GC-MS.

Catalytic activities of phosphine palladium complexes are shown in

Table 1.

2 DISCUSSION

We have synthesized efficient phosphino palladium catalysts with electronrich and sterically hindered diadamantyl phosphines ligands for C–C or

C–N coupling reactions. We have shown that adamantyl (Ada) phosphines

palladium complex displayed a better reactivity than Cy and t-Bu phosphine

complexes toward cross-coupling reactions [2, 3]. Indeed, in Sonogashira

cross coupling, unreactive aryl chlorides were coupled successfully in good

yields and under mild conditions (Table 1, entries 1–9). In this series, no

dendritic effect was observed. In Suzuki cross coupling, an excellent reactivity was observed in all cases, and a dendritic effect could be pointed

out since catalysts made up of 2 and 3 promoted better coupling yields

than catalysts made up of 1 (Table 1, entries 10–15). It is noteworthy that



DISCUSSION



TABLE 1

Entry



101



C–C and C–N Cross-Coupling Reactions



Substrate



Product



Phosphine-Based

Catalyst (1 mol%)



Reaction

Time (h)



Conversion

(%)



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 or

t-Bu phospines palladium complexes [2, 3]. Therefore, kinetics investigations on the overall reaction (i.e., based only on the isolated product) were

performed. This study was done on the Sonogashira C–C reaction with

phophine 1 ligand. In a typical Sonogashira reaction involving iodobenzene

(4 mmol) and phenylacetylene (6 mmol) in Et3 N (10 mL), we monitored



102



C–C OR C–N REACTIONS CATALYZED BY DIADAMANTHYLPHOSPHINE

0.5

y = −0.26629 −0.021149x R = 0.97449



in(C/C0)



0

−0.5

−1

−1.5

−2

0



FIGURE 1



20



40

60

80

Reaction time (min)



100



Kinetics of the disappearance of iodobenzene at 25◦ C.



the appearance of diphenylacetylene and the disappearance of iodobenzene, from which the rate constant was determined (note 8). As shown in

Figure 1, the variation of ln x versus time (x = c/c0 ) was linear; this established an overall reaction order of +1 (Table 1, entries 1–9). The observed

apparent constant rate constant kobs, for the overall reaction was then determined from the slope of the regression of the plot. The calculated rate

constant was 1.269 mol/L/h at 25◦ C compared to 0.925 mol/L/h at 25◦ C

for t-butylphosphine and 0.028 mol/L/h at 27◦ C for dicyclohexylphosphine

ligands [2]. This dramatic enhanced activity of the diadamantylphosphine

ligand should be explored in a wide range of substrates for C–C or C–N

cross-coupling reactions using dendritic supports, which made the recovery

of the catalyst possible, as we have demonstrated in the case of Cy and

t-Bu phosphine ligands [4].

WASTE DISPOSAL INFORMATION

All toxic materials were disposed of in accordance with Prudent Practices

in the Laboratory (Washington, D.C.: National Academy Press, 1995).

APPENDIX: EXPERIMENTAL SUPPLEMENT

Compound 1. 1 H NMR (300 MHz, CDCl3 ) δ 7.18 (m, 5H, Ar), 3.66

(s, 2H, ArCH2 N), 2.67 (s, 4H, NCH2 P), 1.80 (m, 36H, CH2 CP + CH),

1.60 (m, 24H, CH2 ). {1 H}13 C NMR (75 MHz, CDCl3 ) δ 139.8 (C),

126.6–130.4 (Ar), 62.1 (PhCH2 N), 48.8 (NCH2 P), 40.9 (CH2 ), 37.0



APPENDIX: EXPERIMENTAL SUPPLEMENT



103



(CH2 ), 28.7 (CH). {1 H}31 P NMR (121 MHz, CDCl3 ) δ 8.95. Elemental

analysis for C49 H71 NP2 , calc (%): C 79.96, H 9.72, N 1.90 ; found (%):

C 79.93, H 10.24, N 1.73. The 1 H, 13 C, and 31 P NMR spectra were

recorded using the following spectrometers: a Brucker DPX 200 FT

NMR spectrometer (1 H: 200.16 and 13 C: 50.33 MHz), a Brucker AC

250 FT NMR spectrometer (1 H: 250.13 and 13 C: 62.90 MHz), and an

Avance 300 FT NMR spectrometer (1 H: 300.13 and 13 C: 75.46 MHz).

Elemental analysis for C, H, and N were performed following the classical

Pregl-Dumas technique on a Thermo Fischer Flash EA1112.

Compound 2. 1 H NMR (300 MHz, CDCl3 ) δ 2.93 (s, 4H, NCH2 ),

2.75 (m, 24H, CH2 N and PCH2 N), 2.40 (s, 8H, NCH2 ), 1.90 (m, 144H,

CH2 CP + CH), 1.70 (m, 96H + 8H, CH2 ), 1.37 (m, 4H, CH2 ). {1 H}13 C

NMR (75 MHz, CDCl3 ) δ 138.0 (C), 52.7 (NCH2 P), 51.5 (CH2 N), 48.9

(CH2 N), 43.9 (CH2 N), 41.1 (CH2 ), 37.3 (CH2 ), 28.9 (CH), 25.5 (CH2 ),

23.1 (CH2 ). {1 H}31 P NMR (121 MHz, CDCl3 ) δ 8.64. Elemental analysis

for C184 H288 N6 P8 O8 (product appeared in the oxidized form because of the

experimental conditions) calc (%): C 74.66, H 9.81, N 2.84; found (%): C

74.58, H 10.51, N 3.22. The 1 H, 13 C, and 31 P NMR spectra were recorded

using the following spectrometers: a Brucker DPX 200 FT NMR spectrometer (1 H: 200.16 and 13 C: 50.33 MHz), a Brucker AC 250 FT NMR

spectrometer (1 H: 250.13 and 13 C: 62.90 MHz), and an Avance 300 FT

NMR spectrometer (1 H: 300.13 and 13 C: 75.46 MHz). Elemental analysis for C, H, and N were performed following the classical Pregl-Dumas

technique on a Thermo Fischer Flash EA1112.

Compound 3. 1 H NMR (300 MHz, CDCl3 ) δ 2.90 (m, 4H, NCH2 ),

2.71 (m, 56H, NCH2 P + CH2 N), 2.35 (m, 24H, CH2 N), 1.87 (m, 288H,

CH2 CP + CH), 1.66 (m, 192H + 16H, CH2 ), 1.21 (m, 8H, CH2 ), 0.81 (m,

4H, CH2 ). {1 H}13 C NMR (75 MHz, CDCl3 ) δ 137.8 (C), 54.4 (NCH2 P),

52.8 (CH2 N), 48.8 (CH2 N), 43.6 (CH2 N), 41.1 (CH2 ), 37.3 (CH2 ), 28.9

(CH), 28.8 (CH2 ), 26.1 (CH2 ), 23.2 (CH2 ). {1 H}31 P NMR (121 MHz,

CDCl3 ) δ 8.61. Elemental analysis for C376 H592 N14 P16 O16 (product

appeared 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 1 H, 13 C, and 31 P NMR spectra were recorded using the following

spectrometers: a Brucker DPX 200 FT NMR spectrometer (1 H: 200.16 and

13

C: 50.33 MHz), a Brucker AC 250 FT NMR spectrometer (1 H: 250.13

and 13 C: 62.90 MHz), and an Avance 300 FT NMR spectrometer (1 H:

300.13 and 13 C: 75.46 MHz). Elemental analysis for C, H, and N were

performed following the classical Pregl-Dumas technique on a Thermo

Fischer 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 Company

and 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 the

bis(adamantyl)hydroxymethylphosphonium salt. 1 H NMR (300 MHz, MeOH-d4 )

δ 4.79 (s, 2H, OH), 4.53 (s, 4H, CH2 OH), 2.27 (m, 12H, CH2 -C-P), 2.0 (m, 6H, CH),

1.79 (m, 12H, CH2 ). {1 H}13 C NMR (75 MHz, MeOH-d4 ) δ 51.06 (CH2 OH), 40.2 (C-P),

38.3 (CH2 -C-P), 36.9 (CH2 ), 29.3 (CH). {1 H}31 P NMR (121 MHz, MeOH-d4 ) δ 21.3.

(ESI-MS) m/z 363 (M-Cl). Elemental analysis for C22 H36 ClO2 P, calc (%): C 66.23,

H 9.10; found (%): C 65.77, H 9.70. The 1 H, 13 C, and 31 P NMR spectra were recorded

using the following spectrometers: a Brucker DPX 200 FT NMR spectrometer (1 H:

200.16 and 13 C: 50.33 MHz), a Brucker AC 250 FT NMR spectrometer (1 H: 250.13

and 13 C: 62.90 MHz), and an Avance 300 FT NMR spectrometer (1 H: 300.13 and 13 C:

75.46 MHz). Elemental analysis for C, H, and N were performed following the classical

Pregl-Dumas technique on a Thermo Fischer Flash EA1112. The electrospray ionization

mass spectra (ESI-MS) were acquired on spectrometer Qstar-Applied biosystems in an

appositive 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 oxidation

reaction.

6. DAB-dendr-(NH2n ): n = 4, DAB-Am-4 (polypropylenimine tetraamine dendrimer, generation 1, CAS [120239-63-6] and n = 8, DAB-Am-8 (polypropyleneimine octaamine

dendrimer, generation 2, CAS [154487-83-9] were purchased from Aldrich.

7. This unstable complex was rapidly analyzed by 31 P NMR to confirm the complete complexation of phosphines with palladium, since only one 31 P NMR signal was recorded

for each complex: {1 H}31 P NMR (121 MHz, CDCl3 ) δ (ppm) = 28.4 for 1, 27.7 for 2

and 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. Heuz´e K, M´ery D, Gauss D, Blais J-C, Astruc D. Chem Eur J 2004;10:3936.

3. (a) Lemo J, Heuz´e K, Astruc D. Org Lett 2005;7:2253; (b) Heuz´e K, M´ery D, Gauss

D, Astruc D. J Chem Commun 2003:2274.

4. (a) Rosario-Amorin D, Wang X, Gaboyard M, Cl´erac R, Nlate S, Heuz´e K. Chem Eur

J 2009;15:12636; (b) Rosario-Amorin D, Gaboyard M, Cl´erac R, Nlate S, Heuz´e K.

Dalton Trans 2011;40:44; (c) Rosario-Amorin D, Gaboyard M, Cl´erac R, Vellutini L,

Nlate S, Heuz´e K. Chem Eur J 2012;18:3305.



PART IV

PALLADIUM-MEDIATED MULTIFUNCTIONAL

CLEAVAGE



105



CHAPTER 12



SOLID-PHASE REACTIONS OF RESIN-SUPPORTED BORONIC ACIDS

Franc¸ois Carreaux and Bertrand Carboni

Universit´e de Rennes 1, Rennes, France

Herve Deleuze

Universit´e de Bordeaux, Talence, France

Christelle Pourbaix-L’Ebraly

Galapagos, Romainville, France



1

1.1

1.1.1



PROCEDURES



Synthesis of the Macroporous Diol Resin 2



Synthesis of the Monomer Precursor 1



Under argon, a 250-mL flame-dried two-necked round flask equipped with a

rubber septum, a magnetic stirring bar, and a reflux condenser was charged

with sodium hydride (4.21 g, 105.3 mmol, 1.4 equiv., 60% dispersion

in mineral oil) (note 1) and anhydrous diethyl ether (20 mL) (note 2)

[1]. The resulting suspension was stirred for 5 min and allowed to settle. The diethylether was slowly removed with a syringe, and the process

was repeated twice (note 3). After the third wash, the residual ether was

removed under reduced pressure. The flask was regassed with nitrogen, and

anhydrous THF (40 mL) (note 2) was added. A solution of 2,2-dimethyl5-hydroxymethyl-5-methyl-1,3-dioxane [2] (12.1 g, 75.2 mmol, 1 equiv.)

in 40 mL of anhydrous THF was added dropwise (caution: gas evolution).

When effervescence ceases, the reaction mixture was heated for 3 h at 70◦ C

and then allowed to spontaneously cool to room temperature (rt). A solution of 4-vinyl-zylchloride (10.7 mL, 75.2 mmol, 1.4 equiv.) in anhydrous

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.



107



108



SOLID-PHASE REACTIONS OF RESIN-SUPPORTED BORONIC ACIDS



SCHEME 1



Synthesis of the macroporous diol resin.



THF (40 mL) was slowly added over 20 min at a rate sufficient to maintain

the reaction temperature below 30◦ C. The solution was heated at reflux for

15 h. After cooling to rt, the reaction mixture was transferred by a cannula

to a vigorously stirred slurry of ice (50 g) and brine (50 mL). Diethylether

(50 mL) was added, and the layers were separated. The aqueous layer was

extracted with diethyl ether (2 × 50 mL). The combined organic layers

were dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue

was purified by column chromatography on 400 g of silica gel packed in

a 7.5-cm × 20-cm column. The column was eluted with cyclohexane:ethyl

acetate (8:2, then 5:5) to give 15.5 g of 1 (74%) (Scheme 1).



1.1.2



Preparation of the Polymeric Support



Polymeric supports were prepared using the suspension polymerization

technique (note 4). In a typical experiment, an organic phase containing a

mixture of 1 (44.1 g, 16 mmol), styrene (7.4 g, 71 mmol), divinylbenzene

(commercial mixture, 80% w m+p DVB, 20%w ethylbenzene, 3.4 g,

26 mmol) as the cross-linking agent, 2-ethylhexanol (14 g, 16 mL,

100 mmol) as the porogen, and AIBN (200 mg) as the initiator was

suspended in an aqueous phase (400 mL) containing poly(diallyldimethyl

ammonium chloride) (1.75% w/v) as the stabilizer and gelatin (0.37%

w/v) as the dispersant agent. The stirring speed was adjusted between

500 and 600 rpm in order to obtain droplets of visually satisfactory size.

The reactor was then placed in a thermostat bath, and the polymerization

was run out at 80◦ C for 12 h. After cooling, the reaction mixture was

filtered, and the polymer beads were washed with water (5 × 30 mL),

ethanol (5 × 30 mL), and diethylether (5 × 30 mL) before being extracted

with THF using a Soxhlet apparatus over a period of 24 h. After a

last washing with diethylether, the beads were dried under vacuum at

60◦ C for 24 h. Yield of usable recovered beads: 13 g (84%); sizing:

(diameter range (μm)/weight%) >800/38; 500–800/23; 315–500/17;

200–315/12; and <200/10. Specific surface area (BET) = 68 m2 /g; pore



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