A Tuneable Ge-based Linker that Enables Application-led Solid Phase ­Synthesis Optimisation - Towards a Robust Iterative Synthesis of Oligothiophenes

Abstract

A convenient synthesis of a new dichlorogermanium-based linker-precursor for solid phase synthesis is described that allows facile introduction of a range of ‘spectator’ substituents (R) onto germanium. Variation of these R groups allows modulation of the stability of the key germanium-carbon bond between the linker and the aryl library. The tuning process is exemplified by application to the optimisation of a linker for the iterative solid-phase synthesis (SPS) of oligothiophenes.

Key words

solid-phase synthesis - electrophilic aromatic substitutions - heterocycles - cross-coupling - combinatorial chemistry

References

• 2 Beck-Sickinger A. Weber P. Combinatorial Strategies in Biology and Chemistry   Wiley; Chichester: 2002. 
• 3 Guillier F. Orain D. Bradley M. Chem. Rev.  2000,  100:  2091 
• 4 Congreve MS. Ley SV. Scicinski JJ. Chem.-Eur. J.  2002,  8:  1768 
• 5 James IW. Tetrahedron  1999,  55:  4855 
• 6 Spivey AC. Turner DJ. Turner ML. Yeates S. Org. Lett.  2002,  4:  1899 
• Reviews:
• 7a Katz HE. Bao Z. Gilat SL. Acc. Chem. Res.  2001,  34:  359 
• 7b Dimitrakopoulos CD. Mascaro DJ. IBM J. Res & Dev.  2001,  45:  11 
• 8a Spivey AC. Diaper CM. Rudge AJ. Chem. Commun.  1999,  835 
• 8b Spivey AC. Diaper Adams HCM. Rudge A. J. Org. Chem.  2000,  65:  5253 
• 8c Spivey AC. Srikaran R. Diaper C. Turner DJ. Org. Biomol. Chem.  2003,  1:  1638 
• 9 Ph₂GeBr₂ can be prepared similarly by the action of Br₂ on Ph₄Ge but the reaction is less selective (57% yield after distillation): Kraus CA. Brown CL. J. Am. Chem. Soc.  1930,  52:  3690 
• 12 For the analogous ‘activation’ of an arylsilane linker precursor see: Woolard FX. Paetsch J. Ellman JA. J. Org. Chem.  1997,  62:  6102 
• 13 Tour JM. Wu R. Macromolecules  1992,  25:  1901 
• 14a Benkeser RA. Krysiak HR. J. Am. Chem. Soc.  1954,  76:  6353 
• 14b Eaborn C. Moore RC. J. Chem. Soc.  1959,  3640 
• 16 The insensitivity of Ge cf. Si towards steric shielding has been noted previously and attributed to longer Ge-C vs Si-C bond lengths: Eaborn C. J. Organomet. Chem.  1975,  100:  43 
• 18 Galvao DS. Dos Santos DA. Laks B. Dos Santos MC. Synth. Met.  1991,  43:  3521 

1

Current address: Department of Chemistry, Imperial College London SW7 2AZ, UK.

10

Dichlorogermane 4a. To oven dried Mg turnings (1.01 g, 42.1 mmol) in THF (25 mL) was added 4-bromoanisole (5.21 mL, 41.6 mmol) dropwise. The resulting mixture was heated briefly, stirred for 1 h and then added dropwise to a solution of germyl trichloride 3a [8b] (1.25 g, 4.17 mmol) in THF (10 mL) at r.t. before heating to 70 ºC. After stirring for 16 h the reaction mixture was quenched by dropwise addition of water, concentrated to dryness in vacuo, and the residue dissolved in CH₂Cl₂ (30 mL). HCl (1 N, 5mL) and then concd HCl (60 mL) were added successively with stirring and the resultant mixture was stirred vigorously for 40 min. The aq layer was extracted with CH₂Cl₂ (3 × 50mL), the combined organic extracts dried (MgSO₄) and the solvent removed in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL), extracted with 0.5 M NaOH(aq) (100 mL) and the aq layer washed with CH₂Cl₂ (3 × 50 mL). To the aq layer was added 1 N HCl (15 mL) and then concd HCl (100mL) with shaking, before extracting with CH₂Cl₂ (3 × 100 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo to give dichlorogermane 4a as an orange oil (1.30 g, 84%). IR (neat): 3019 (broad, OH), 2935-2835 (CH), 2361, 1591, 1514, 1442, 1403, 1290, 1254 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.96-2.02 (2 H), 2.83-2.90 (2 H), 3.75 (s, 3 H), 4.84 (br s, 1 H), 6.65 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 2 H), 6.99 (d, J = 8.5 Hz, 2 H), 7.40 (d, J = 9.0 Hz, 2 H). ¹³C NMR (63 MHz, CDCl₃): δ = 27.8 (t), 28.6 (t), 55.4 (q), 114.6 (2 × d), 115.5 (2 × d), 126.7 (s), 129.4 (2 × d), 133.8 (2 × d, s), 154.1 (s), 162.1 (s). MS (EI+): m/z = 372 [M⁺]. HRMS: m/z [M⁺] calcd for C₁₅H₁₆Cl₂Ge⁷⁴O₂: 371.9739; found: 371.9749.

11

Di-para-tolylgermane 5a (R = p-Tol). To oven dried Mg turnings (120 mg, 5.00 mmol) in THF (3 mL) was added 4-bromotoluene (855 mg, 5.00 mmol) dropwise. The resulting mixture was heated briefly, stirred for 1 h and then added dropwise to a solution of dichlorogermane 4a (186 mg, 0.50 mmol) in THF (3mL) at r.t. After heating at 110 °C for 16 h the reaction mixture was quenched with sat. NH₄Cl (aq) (100 mL) and extracted with Et₂O (3 × 100 mL). The combined organic extracts were dried (MgSO₄), concentrated in vacuo and the residue purified by flash chromatography (SiO₂, petroleum ether-EtOAc, 3:1) to give ditolylgermane 5a (R = p-Tol) as a yellow oil (231 mg, 92%); R_f 0.4 (petroleum ether-EtOAc, 3:1). IR (neat): 3409 (broad), 3012, 2921, 2861, 1593, 1568, 1512, 1442, 1392, 1281, 1247, 1180, 1089, 1031 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.72-1.80 (2 H), 2.36 (s, 6 H), 2.70-2.77 (2 H), 3.81 (s, 3 H), 4.64 (s, 1 H), 6.71 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 4 H), 7.38 (d, J = 8.0 Hz, 4 H), 7.40 (d, J = 8.5 Hz, 2 H). ¹³C NMR (63 MHz, CDCl₃): δ = 16.6 (t), 21.6 (2 × q), 30.4 (t), 55.2 (q), 114.2 (2 × d), 115.3 (2 × d), 128.2 (s), 129.0 (2 × d), 129.2 (4 × d), 133.8 (2 × s), 135.0 (4 × d), 136.3 (2 × d), 137.1 (s), 138.8 (2 × s), 153.6 (s), 160.3 (s). MS (EI+): m/z = 484 [M⁺]. HRMS (EI+): m/z [M⁺] calcd for C₂₉H₃₀Ge⁷⁴O₂: 484.1458; found: 484.1446.

15

Hexylthiophene immobilisation (2b→11b) proceeded smoothly in all cases except for the para-fluorophenyl case, which gave a complex mixture of products, tentatively ascribed to fragmentation pathways following nucleophilic attack at the carbon ipso to the fluorine substituent.

17

Quadragel^TM-OH (Avecia Ltd.) is a DVB crosslinked PS-based resin with hydroxyl-terminated PEG grafts containing 4 oxyethyl repeat units.

19

Resin 5c. To Quadragel^TM-Br (20.0 g, 18.6 mmol, from Quadragel^TM-OH [18] 0.93 mmol g^-1 by treatment with CBr₄ and PPh₃ in CH₂Cl₂) swollen in a minimum of MeCN (200mL) were added germane 5a (R = p-Tol, 19.4 g, 81.2 mmol), tetra-n-butylammonium iodide (740 mg, 2.00 mmol) and Cs₂CO₃ (26.2 g, 74.3 mmol) and the resulting mixture heated at 85 °C for 20 h. The reaction mixture was cooled and the resin was washed successively with MeCN (3 × 350 mL), DMF (3 × 350 mL), THF-water (1:1, 3 × 350 mL), THF (3 × 350 mL) and MeOH (3 × 350 mL) and then dried in vacuo to give resin 5c as light brown granules (13.4 g, 74% conversion by the weight increase of the resin and the amount of phenol returned, LL = 0.52 mmolg^-1). IR (neat): 3030-2865 (CH), 1593, 1510, 1494, 1453, 1281, 1245, 698 (strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 1.15-1.65 [CH(Ar)CH₂], 1.65-2.10 [ArCH₂, CH(Ar)CH₂], 2.37 (s, ArCH₃), 2.70-2.80 (GeCH₂), 3.50-4.15 (OCH₃, OCH₂), 6.10-6.70 (ArH), 6.70-7.30 (m, ArH), 7.41 (d, J = 4.5 Hz, ArH). ¹³C MAS-NMR (100 MHz, CDCl₃): δ = 17.6, 21.8, 24.9, 25.2, 25.5, 25.7, 26.0, 31.7, 37.4, 41.6, 67.0, 67.3, 67.6, 67.9, 68.2, 71.7, 72.2, 128.9.

20

Resin 2c. To germylanisole resin 5c (13.1 g, LL = 0.52 mmolg^-1, 6.8 mmol) swelled in CH₂Cl₂ (50 mL) was added HCl (65 mL, 1.0 M, 65 mmol) in Et₂O and the reaction mixture left to stir for 16 h. The solvent was then removed by filtration to give resin 2c as brown granules (11.7 g, 100% conversion by ¹H NMR, LL = 0.54 mmol g^-1). IR(neat): 3030-2865 (CH), 1601, 1509, 1493, 1452, 1243, 697(strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 1.00-2.30 [ArCH₂, CH(Ar)CH₂], 2.47 (s, ArCH₃), 2.85-2.95 (GeCH₂), 3.60-4.20 (OCH₂), 6.10-6.70 (ArH), 6.70-7.30 (ArH), 7.56 (d, J = 4.5 Hz, ArH).

21

Resin 13c. A solution of LDA (1.11 mL, 2.0 M, 2.21 mmol) in hexanes-THF-ethylbenzene (6:5:3) was added dropwise to a degassed solution of silylthiophene 12 (616 mg, 2.18 mmol) in THF (4 mL) at -50 °C. This solution was warmed to -40 °C, stirred for 40 min at this temperature and recooled to -50 °C. The solution was then transferred by cannula to a degassed suspension of germylchloride resin 2c (777 mg,
LL = 0.54 mmolg^-1, 0.42 mmol) in THF (10 mL) at -50 °C. The reaction mixture was stirred for 1 h at -40 °C, warmed to r.t. and stirred for a further 1 h. After quenching with sat. NH₄Cl (aq) (50 mL), the solvent was removed by filtration and the resin washed with DMF (3 × 50 mL), THF-water (1:1, 3 × 50 mL), THF (3 × 50 mL) and MeOH (3 × 50 mL). The resin was then dried in vacuo at 60 °C to give resin 13c as yellow/orange granules (876 mg, 83% conversion by weight increase of resin, LL = 0.40 mmolg^-1). IR (neat): 3030-2865 (CH), 1601, 1509, 1492, 1451, 1244, 697 (strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 0.41 [s, Si(CH₃)₂], 0.91 (t, J = 4.5 Hz, CH₂CH ₃), 0.95-2.30 [C(CH₃)₃, (CH ₂)₄CH₃, ArCH ₂CH₂Ge, CH(Ar)CH₂], 2.47 (s, ArCH₃), 2.54 [t, J = 5.0 Hz, CH ₂(CH₂)₄CH₃], 2.80-2.95 (GeCH₂), 3.60-4.25 (OCH₂), 6.10-6.80 (ArH), 6.80-7.30 (ArH), 7.53 (d, J = 4.5 Hz, ArH).

22

Resin 14c. To germylthiophene resin 13c (642 mg, LL = 0.40 mmolg^-1, 0.26 mmol) swelled in DMF (8 mL) was added CsF (341 mg, 2.24 mmol) and the mixture left to stir for 72 h at 110 °C. The solvent was then removed by filtration and the resin washed with DMF (2 × 75 mL), THF-water (1:1, 3 × 75 mL), THF (3 × 75 mL) and MeOH (3 × 75 mL). The resin was then dried in vacuo at 60 °C to give resin 14c as brown granules (560 mg, 100% conversion by ¹H NMR, LL = 0.42 mmol g^-1). IR (neat): 3030-2865 (CH), 1601, 1508, 1492, 1451, 1242, 697 (strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 0.82 (t, J = 4.5 Hz, CH₂CH ₃), 0.85-2.20 [(CH ₂)₄CH₃, ArCH ₂CH₂Ge, CH(Ar)CH₂], 2.37 (s, ArCH₃), 2.45-2.50 [CH ₂(CH₂)₄CH₃], 2.70-2.85 (GeCH₂), 3.60-4.15 (OCH₂), 6.10-7.30 (ArH), 7.44 (d, J = 4.5 Hz, ArH), 7.50-7.55 (SCH).

23

Resin 15c. A solution of LDA (315 µL, 2.0 M, 0.63 mmol) in hexanes-THF-ethylbenzene (6:5:3) was added dropwise to a suspension of germylthiophene resin 14c (526 mg, LL = 0.42 mmolg^-1, 0.22 mmol) in THF (4 mL) at -50 °C. After stirring for 2 h at -30 °C, a solution of degassed 1,2-diiodoethane (296 mg, 1.05 mmol) in THF (2 mL) was added by cannula at -50 °C. The resulting mixture was stirred in the dark for 2 h at -30 °C, warmed to r.t. and stirred for a further 1 h. The solvent was then removed by filtration and the resin washed with Na₂S₂O₃ (aq) (3 × 75 mL), THF-water (1:1, 3 × 75 mL), THF (3 × 75 mL) and MeOH (3 × 75 mL). The resin was then dried in vacuo at 60 °C to give resin 15c as orange granules (533 mg, 100% conversion by ¹H NMR, LL = 0.40 mmol g^-1). IR(neat): 3030-2865 (CH), 1601, 1509, 1493, 1452, 1243, 697(strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 0.82 (t, J = 4.5 Hz, CH₂CH ₃), 0.85-2.20 [(CH ₂)₅CH₃, ArCH ₂CH₂Ge, CH(Ar)CH ₂, ArCH ₃], 2.70-2.85 (GeCH₂), 3.60-4.15 (OCH₂), 6.10-7.30 (ArH), 7.42 (d, J = 4.5 Hz, ArH).

24

Resin 17c. To a degassed solution of boronic ester 16 (242 mg, 0.59 mmol) and iodide resin 15c (493 mg, LL = 0.40 mmolg^-1, 0.20 mmol) swelled in DMF (4 mL) was added Pd(PPh₃)₄ (11.6 mg, 10.0 µmol) and the resulting mixture stirred at 60 °C for 48 h. The solvent was then removed by filtration and the resin washed with DMF (2 × 50mL), THF-water (1:1, 3 × 50 mL), THF (3 × 50 mL) and MeOH (3 × 50 mL). The resin was then dried in vacuo at 60 °C to give resin 17c as dark brown granules (508 mg, 87% conversion by the amount of bithiophene 18 [18] cleaved from the resin, cf. below, LL = 0.35 mmolg^-1). IR (neat): 3030-2865 (CH), 1601, 1509, 1492, 1451, 1244, 697 (strong) cm^-1. ¹H MAS-NMR (400 MHz, CDCl₃): δ = 0.31 [s, Si(CH₃)₂], 0.75-2.50 [C(CH₃)₃, (CH₂)₅CH₃, ArCH ₂CH₂Ge, CH(Ar)CH₂, ArCH₃], 2.70-2.90 (GeCH₂), 3.50-4.20 (OCH₂), 6.10-7.60 (ArH). ¹³C MAS-NMR (100 MHz, CDCl₃): δ = 14.5, 17.3, 18.6, 21.9, 22.9, 23.0, 26.8, 29.6, 29.7, 30.0, 31.1, 31.7, 32.0, 32.2, 40.9, 44.3, 67.9, 70.2, 71.1, 71.2, 114.6, 115.0, 126.1, 128.4, 128.8, 129.1, 129.5, 129.6, 130.5, 133.6, 134.2, 135.0, 135.1, 135.5, 137.4, 138.7, 139.2, 139.5, 140.1, 140.6, 141.6, 145.7, 151.4, 157.3.

25

Bithiophene 18. [18] To resin 17c (after double-coupling, 40.4 mg, 16.2 µmol) was added a 33% solution of TFA in CH₂Cl₂ (750 µL) and the mixture left to stir at r.t. for 2 h. The solvent was then removed by filtration and the resin washed with CH₂Cl₂ (3 × 50 mL). These washings were then passed through a plug of silica and concentrated in vacuo to afford bithiophene 18 as an orange oil (4.7 mg, 96% pure by HPLC: Phenomenex Jupiter ODS C-18 column, UV 254 nm detection, 1 mL/min, 5-100% MeCN in H₂O + 0.1% formic acid, R_t 22.4 min). Spectroscopic data identical to that previously reported. [18]