Reactive & Functional Polymers 43 (2000) 117–122www.elsevier.com/ locate / react

First activation of sodium amide by polymer-supportedalkoxides and amino-alkoxides

*ˆ´Philippe Gros, Jerome Boni, Sabine Choppin, Yves Fort` ´ ´ ´ ´ ´Synthese Organique et Reactivite, UMR 7565, Faculte des Sciences, Universite Henri Poincare, Nancy 1, B.P. 239,

54506 Vandoeuvre les Nancy, France

Received 8 October 1998; received in revised form 3 November 1998; accepted 10 December 1998

Abstract

Polystyrene-supported alkoxides and amino-alkoxides are shown to act as efficient and reusable activating agents ofsodium amide. This constitutes an unprecedented example of heterogeneous activation in sodium carbanion chemistry. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Heterogeneous activation; Supported amino-alcohol; Sodium amide; Carbanion chemistry

activators. However, despite their high ef-1. Introductionficiency, amino-alkoxides are often expensive

The activation of sodium amide by tertiary and some exhibit toxicity. As a consequence,alkoxides and monoethers of glycolates is well- their recovery becomes a crucial problem andknown [1–3]. The basic systems obtained allow grafting these species on a polymer-supportremarkable changes in selectivities and reac- appears as the most promising solution. In thistivities. More recently, studies dealing with the paper we report our first results on the activa-

tion of NaNH by polystyrene-supported alkox-activation of BuLi have demonstrated a par- 2

ides and amino-alkoxides A and B (Scheme 1).ticular effect of amino-alkoxides [4,5] whichalso have to be considered as potential NaNH2

2. Experimental

2.1. General methods

1H-NMR spectra were recorded on a Brukerspectrometer at 400 MHz with TMS as internalstandard and CDCl as solvent. GC analysesScheme 1. 3

were performed with the internal standard meth-od (eicosane) on a Shimadzu GC8A apparatus*Corresponding author. Fax: 1 33-3-8340-4558.

E-mail address: yves.fort@sor.u-nancy.fr (Y. Fort) using a 5-m HP1 column. GC-MS was per-

1381-5148/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S1381-5148( 99 )00010-3

118 P. Gros et al. / Reactive & Functional Polymers 43 (2000) 117 –122

formed on a HP5890 spectrometer. IR spectra methylated resin (30 g; 66 mmol Cl). A solutionwere performed on a Perkin Elmer 841 spec- of 2-(methylamino)ethanol (15 g; 0.2 mole) intrometer. Elemental analyses (combustion) were toluene (25 ml) was then added and the suspen-performed by the Service Central d’Analyse du sion was refluxed for 48 h. After cooling atCNRS (Vernaison, France). room temperature, the suspension was poured

into water (200 ml), the resin was filtered andwashed with DMF and MeOH using a soxhlet2.2. Reagents and solventsapparatus. After drying (24 h; 258C; 20 mmHg),

Bis(phenylthio)methane 1 was prepared ac- 34 g of B were obtained as a white powder.cording to a known procedure [6]. Glycol C andamino-alcohol D were prepared according to the 2.3.3. Method for titration of free OH in AWeber [7] and Hunter et al. [8] procedures, and Brespectively. Powdered sodium amide was pur- In a 100-ml Schlenck tube connected to achased from Merck and handled under argon. graduated water-containing funnel was addedSodium hydride was purchased from Fluka NaH (640 mg; 17 mmol), after classical wash-(64% in mineral oil). The chloromethylated ing, DMF (40 ml) was added and the suspen-resin was purchased from Acros (2% DVB sion was heated at 458C. Resin A or B (3 g) wascrosslinked; 200–400 mesh; 2.2 meq Cl /g). All placed in a closed funnel and added portionwisecommercially available reagents were purified to the suspension. After 4 h, hydrogen evolutionor used as such. All solvents were distillated stopped and the volume obtained was measured.before use; DME, THF and toluene were stored The OH concentration (meq. /g) was thus de-over sodium wires. ducted from the measured H volume (molar2

volume of H 5 24 l /mol).22.3. Preparation of polystyrene-supportedactivating agents

2.3.4. Characterisation of supported activatingagents A and B2.3.1. Preparation of the supported alcohol A

See Table 1.NaH (10 g; 0.26 mole) was washed twicewith THF (40 ml) and DMF (200 ml) wasadded. To the suspension was added dropwise a 2.4. Functionalisation ofsolution of diethyleneglycol (13.8 g; 0.13 mole) bis(phenylthio)methane in the presence ofin DMF (50 ml) and the reaction mixture was supported activating agents A or Bstirred under nitrogen for 1 h at room tempera-ture. The chloromethylated resin (30 g; 66 2.4.1. General proceduremmol Cl) was then added portionwise and the A suspension of NaNH (0.67 g; 17 mmol) in2

obtained suspension was stirred at 808C for 48 DME (26 ml) was heated at 45–508C underh. After cooling at room temperature, the sus- nitrogen. Resin A or B (5.7 mmol OH) was thenpension was poured into water (200 ml), the added in small portions and the temperatureresin was filtered and washed with DMF and maintained at 45–508C for 4 h. After cooling atMeOH using a soxhlet apparatus. After drying room temperature, a solution of bis-(24 h; 258C; 20 mmHg), 35 g of A were (phenylthio)methane (1.33 g; 5.7 mmol) inobtained as an orange powder. DME (2 ml) was added dropwise (5 min). The

reaction medium rapidly turned from orange todark brown. After 2 h at room temperature, the2.3.2. Preparation of the supported amino-reaction mixture was cooled at 2 58C and aalcohol Bsolution of electrophile (6.88 mmol) in DME (2To a suspension of K CO (9.1 g; 66 mmol)2 3

ml) was slowly added (the temperature must notin toluene (250 ml) was added the chloro-

P. Gros et al. / Reactive & Functional Polymers 43 (2000) 117 –122 119

Table 1Characterisation of resins A and B

a,bResin Elemental analysis (combustion) [OH] titration IR (KBr)

Element, % meq OH/g VH (ml) meq OH/g2

21A O, 7.71; Cl, 0.62 1.6 115 1.6 n (3500 cm )O–H21B N, 2.65; O, 3.05; Cl, 0.47 1.9 136 1.9 n (3500 cm )O–H

No detection of21

n (1260 cm )C–Cl

a Reaction performed on 3 g of resin with NaH (17 mmol) in DMF (40 ml) at 458C.b OH concentration was deducted from measured H volume (molar H volume 5 24 l /mole).2 2

exceed 08C). After 1 h, hydrolysis was per-formed by adding crushed ice portionwise. Theresin A or B was then filtered off and washedtwice with THF (50 ml). The organic phase was Scheme 2.extracted from the filtrate and after aqueouswork-up, the functionalised bis(phenyl-thio)methane was purified by flash-chromato- Beside the expected alkylated product 2graphy. After extraction with MeOH (soxhlet) formed after substrate deprotonation, variableand drying under reduced pressure (20 mTorr), amounts of product 3 were obtained, resultingthe resins were immediately reused. from the nucleophilic attack of amide at the

sulfur atom [13]. An increase in the yield of 2will be related to an increase of the basicity /2.4.2. Productsnucleophilicity ratio ([B/N]) of the basic sys-1,1-Bis(phenylthio)heptane 2a [9], 1,1-bis(phenyl-tem which depends on the activating propertiesthio)pentane 2b [10], 3,3-bis(phenylthio)-of the alkoxide towards NaNH . From previous1-phenyl-1-propanol 2c [9], 2,29-bis(phenyl- 2

results [9], DME appeared as the best solvent tothio)-1-phenyl-1-ethanol 2d [11] were found1 perform such a reaction. However, toluene–identical ( H-NMR and MS data) to authentic

DME mixtures have also been used in order tosamples.evaluate the probable change of polarity due tothe polystyrene backbone in further experi-ments. In addition, whatever the solvent, we3. Resultsdetermined that the best NaNH /activating2

Recently, the benzylic anchoring sites of agent ratio was 2/1. Selected results for thepolystyrene have been found stable in the alkylation of 1 are reported in Table 2.presence of BuLi [12] but, to the best of our At first, it appeared that C and D were goodknowledge, nothing was known about their activating agents of NaNH in DME or in2

behaviour towards sodium amide. So, as a toluene–DME (1/1) mixture. The results werepreliminary study, we decided to check the comparable to those obtained with the corre-stability in the reaction medium of the sponding not benzylated activating agents [6]. Itbenzylated alcohols C and D [7,8] (Scheme 2) is noteworthy that a decrease in the polarity ofwhich can be considered as the unsupported the reaction medium (runs 5 and 10) led to aanalogues of A and B. dramatic decrease of the reaction yields. In

In this study, we chose the alkylation of addition, although in DME the reaction wasbis(phenylthio)methane 1 as a model reaction poorly sensitive to dilution (run 7), a consider-(Scheme 3) [9]. able increase of yield was observed in toluene–

120 P. Gros et al. / Reactive & Functional Polymers 43 (2000) 117 –122

Scheme 3.

Table 2aActivation of NaNH by C-Na and D-Na: alkylation of bis(phenylthio)methane with HexBr2

c cRun Activating agent Solvent Conv. (%) 2a (%) 3a (%)

1 None DME 100 57 (54) 43 (39)2 None PhCH –DME (1/1) 100 47 52 (45)3

3 C-Na DME 100 84 (82) 154 C-Na PhCH –DME (1/1) 100 78 (76) 223

5 C-Na PhCH –DME (3/1) 22 7 153

6 D-Na DME 100 72 (69) 26b7 D-Na DME 85 69 (65) 15

8 D-Na PhCH –DME (1/1) 100 73 (70) 263b9 D-Na PhCH –DME (1/1) 98 95 (92) 23

10 D-Na PhCH –DME (3/1) 17 5 123

a Reaction performed on 5.7 mmol of bis(phenylthio)methane in 6 ml of solvent.b Reaction performed in 25 ml of solvent.c GC yields; in parentheses isolated yields after flash-chromatography.

DME in the same conditions (run 9). This latter glycol and 2-(methylamino)ethanol respectivelyresult encourages the possibility of performing in refluxing toluene (Scheme 4).reactions in DME with polystyrene-supported The functionalisation ratios were determinedalcohols and amino-alcohols. by elemental analysis and free OH concen-

After these first promising results, the sup- tration obtained by measurement of evolvedported activating agents A and B were prepared hydrogen after reaction of A or B with NaH inby base-mediated reaction of a 2% DVB cross- DMF at 458C. The two methods were in fulllinked chloromethylated polystyrene resin (2.2 agreement indicating the absence of secondarymeq Cl /g; 200–400 mesh) with diethylene crosslinking during the preparation of the sup-

Scheme 4.

P. Gros et al. / Reactive & Functional Polymers 43 (2000) 117 –122 121

Table 3aActivation of NaNH by A-Na and B-Na: functionalisation of bis(phenylthio)methane2

b bRun Activating agent Solvent Electrophile Conv. (%) 2a–d (%) 3a–d (%)c1 None DME HexBr 100 16 82

2 A-Na DME HexBr 100 70 (66) 283 A-Na PhCH –DME (1/1) HexBr 14 0 143

4 A-Na DME BuBr 100 55 (50) 445 A-Na DME Styrene oxide 70 67 (63) 26 A-Na DME PhCHO 70 45 (40) 257 B-Na DME HexBr 100 83 (77) 158 B-Na PhCH –DME (1/1) HexBr 73 0 723

9 B-Na DME BuBr 100 75 (70) 2510 B-Na DME Styrene oxide 78 74 (70) 311 B-Na DME PhCHO 84 62 (55) 22

a Reaction performed on 5.7 mmol of bis(phenylthio)methane in 25 ml of solvent.b GC yields; in parentheses isolated yields after flash-chromatography.c Reaction performed in the presence of nake polystyrene.

ported activating agents. The found OH con- efficient functionalisation by alkyl bromidescentrations were 1.6 and 1.9 meq/g for A and (70–77%), styrene oxide (70%) and benzal-B, respectively. dehyde (55%). This result contrasts with those

The supported activating agents so obtained previously obtained with soluble activatingwere used in the model reaction (see Table 3). agents. Indeed, amino-alkoxides have neverNote that from unreported experiments, we been found to be efficient in activating NaNH2

determined that the base must be prepared by [3]. Finally, A-Na and B-Na were inefficient inadding A or B portionwise to a preheated toluene–DME, underlining the expected change(458C) suspension of NaNH in the solvent of polarity due to polystyrene moieties. These2

followed by stirring at 458C for 4 h, other results were in agreement with those obtainedconditions led to lower yields. with C-Na and D-Na in toluene–DME (3/1)

From these results it clearly appeared that (runs 5 and 10; Table 2).A-Na and B-Na readily activated NaNH lead- In all of the above experiments, the supported2

ing to yields comparable to those obtained with alcohol and amino-alcohol were easily recov-their unsupported analogues. To the best of our ered by simple filtration after hydrolysis. Weknowledge, these results constitute the first then performed some recycling runs with A andexample of heterogeneous activation in sodium B in the best conditions (see Table 3; runs 2 andcarbanionic chemistry. In fact, the two com- 7). The stabilities of the resins were checked byponents of the basic system are quite insoluble elemental analyses and free OH titration afterin ethereal solvents. We also found that B led to the third use (Table 4).the best supported base in DME allowing It clearly appeared that supported activating

Table 4Recycling capacity of resins A and B

a b,cResin 2a (%) Analysis after the 3rd use (combustion) [OH] titration

1st use 2nd use 3rd use Element, % meq OH/g VH (ml) meq OH/g2

A 66 60 54 O, 7.45; Cl, 0.45 1.55 104 1.45B 77 74 73 N, 2.59; O, 2.96; Cl, 0.35 1.85 134 1.85

a GC yields.b Reaction performed on 3 g of resin with NaH (12 mmol) in DMF (40 ml) at 458C.c OH concentration was deducted from measured H volume (molar H volume 5 24 l /mole).2 2

122 P. Gros et al. / Reactive & Functional Polymers 43 (2000) 117 –122

agents were reusable. B displayed a particular Referencesstability during the reaction since the yields of

`[1] P. Caubere, Chem. Rev. 93 (1993) 2317.2a remained quite unchanged after the third use.`[2] P. Caubere, Acc. Chem. Res. 7 (1974) 301.In addition no variation in the resin content was

`[3] G. Ndebecka, P. Caubere, S. Raynal, S. Lecollier, Polymerdetected. On the contrary, A appeared as more 22 (1981) 347.brittle and appreciable loss in activity and OH `[4] Ph. Gros, Y. Fort, P. Caubere, J. Chem. Soc., Perkin Trans. I

20 (1997) 3071.concentration were observed.`[5] Ph. Gros, Y. Fort, P. Caubere, J. Chem. Soc., Perkin Trans. I

24 (1997) 3597.[6] C.G. Screttas, M. Screttas, J. Org. Chem. 44 (5) (1979) 713.[7] C was prepared according to E. Weber, Chem. Ber. 118 (11)4. Conclusion

(1985) 4439.[8] D was prepared according to J. Wright, E. Lincoln, R.

We have demonstrated for the first time that Heinzelmann, J. Hunter, J. Am. Chem. Soc. 72 (1950) 3536.`NaNH can be activated by the use of grafted [9] Ph. Gros, Ph. Hansen, P. Caubere, Tetrahedron 52 (48)2

(1996) 15147.species. Polystyrene-supported amino-alkoxide[10] A. Froeling, J.F. Arens, Recl. Trav. Chim. Pays-Bas 81was found as the most efficient activating agent. (1962) 1009.

Its high stability in basic conditions ensured a [11] T. Sato, J. Otera, H. Nozaki, J. Org. Chem. 55 (25) (1990)6116.good recovery and allowed easy reuse. Work is

[12] T. Xue, M. Jones, J. Ebdon, C. Wilkie, J. Polym. Sci., Partin progress to extend these first results to theA: Polym. Chem. 35 (1997) 509.

field of carbanionic chemistry and particularly [13] H. Normant, T. Cuvigny, Bull. Soc. Chim. Fr. 6 (1965)to reactions using asymmetric alcohols. 1881.