Palladium(0)-Catalyzed Allylation of Heterocyclic Nucleophiles with Unsaturated Carbohydrates

Ronaldo N. de Oliveira; Francisco J. B. Mendonça Jr; Denis Sinou; Sebastiao J. de Melo; Rajendra M. Srivastava

doi:10.1055/s-2006-951507

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Synlett 2006(18): 3049-3052
DOI: 10.1055/s-2006-951507

LETTER

Palladium(0)-Catalyzed Allylation of Heterocyclic Nucleophiles with Unsaturated Carbohydrates

Ronaldo N. de Oliveira^a,b, Francisco J. B. Mendonça Jr.^a,c, Denis Sinou*^a, Sebastiao J. de Melo^c, Rajendra M. Srivastava^b
^a Laboratoire de Synthèse Asymétrique, UMR 5181,ESCPE Lyon, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)78898914; e-Mail: sinou@univ-lyon1.fr;
^b Departamento de Quimica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, 50740-540 Recife, PE, Brazil
^c Departamento de Antibioticos, Universidade Federal de Pernambuco, Cidade Universitaria, 50670-901 Recife, PE, Brazil

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Publication History

Received 10 April 2006
Publication Date:
25 October 2006 (online)

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Abstract

Palladium(0)-catalyzed reaction of heterocyclic ambident nucleophiles with the carbonate of ethyl 6-O-tert-butyldimethylsilyl-2,3-dideoxy-4-α-d-erythro-hex-2-enopyranoside afforded the corresponding 4-aminated 2,3-unsaturated glycosides in quite good yields.

Key words

allylation - carbohydrate - homogeneous catalysis - nucleoside - palladium

References and Notes

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8

General Procedure for the Preparation of Compounds 3. To a solution of Pd(PPh₃)₄ (16 mg, 14 µmol), dppb (12 mg, 28 µmol), and the unsaturated carbohydrate 2 (100 mg, 0.28 mmol) in THF (5 mL) was added the corresponding heterocyclic nucleophile (0.42 mmol, 1.5 equiv). The solution was stirred at 50 °C for 2 h. Evaporation of the solvent under reduced pressure gave a residue that was purified by column chromatography on silica gel to give the corresponding compound 3.
Compound 3a: colorless oil; R _f = 0.45 (PE-EtOAc, 4:6); [α]_D ²⁰ +73 (c 1.5, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Me₂Si), 0.87 (s, 9 H, Me₃C), 1.25 (t, J = 7.1 Hz, 3 H, CH₃), 3.40 (dd, J = 11.9, 3.4 Hz, 1 H, H-6), 3.55-3.65 (m, 2 H, H-6, OCH ₂CH₃), 3.84 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 4.19 (ddd, J = 9.8, 3.4, 2.3 Hz, 1 H, H-5), 5.14 (br s, 1 H, H-1), 5.22 (br d, J = 9.8 Hz, 1 H, H-4), 6.02 (br d, J = 10.2 Hz, 1 H, H-3), 6.07 (ddd, J = 10.2, 2.1, 2.1 Hz, 1 H, H-2), 7.21-7.28 (m, 2 H, H_arom), 7.56-7.60 (m, 1 H, H_arom), 7.76-7.80 (m, 1 H, H_arom), 7.92 (s, 1 H, N=CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, -4.9, 15.7, 18.8, 26.3, 50.3, 62.5, 64.5, 70.1, 94.5, 111.5, 120.8, 122.7, 123.3, 129.5, 129.7, 133.7, 142.4, 144.4. Anal. Calcd for C₂₁H₃₂N₂O₃Si: C, 64.91; H, 8.30. Found: C, 65.20; H, 8.43.
Compound 3b: colorless oil; R _f = 0.2 (PE-EtOAc, 9:1); [α]_D ²⁰ +94 (c 0.7, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.01 (s, 6 H, Me₂Si), 0.88 (s, 9 H, Me₃C), 1.34 (t, J = 7.1 Hz, 3 H, CH₃), 3.55 (dd J = 11.7, 4.5 Hz, 1 H, H-6), 3.65-3.75 (m, 2 H, H-6, OCH ₂CH₃), 3.96 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 4.52 (ddd, J = 10.0, 4.5, 2.1 Hz, 1 H, H-5), 5.27 (br s, 1 H, H-1), 5.77 (br d, J = 10.0 Hz, 1 H, H-4), 6.09 (br d, J = 10.3 Hz, 1 H, H-3), 6.18 (ddd, J = 10.3, 2.4, 2.4 Hz, 1 H, H-2), 7.43 (dd, J = 7.0, 7.0 Hz, 1 H, H_arom), 7.51 (dd, J = 7.0, 7.0 Hz, 1 H, H_arom), 7.79 (d, J = 8.4 Hz, 1 H, H_arom), 8.12 (d, J = 8.4 Hz, 1 H, H_arom). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.7, 18.7, 26.2, 54.3, 62.9, 64.5, 69.7, 94.3, 111.0, 120.5, 124.4, 127.7, 128.4, 129.5, 132.8, 146.8. Anal. Calcd for C₂₀H₃₁N₃O₃Si: C, 61.66; H, 8.02. Found: C, 62.29; H, 7.97.
Compound 3c: colorless oil; R _f = 0.4 (PE-EtOAc, 9:1); [α]_D ²⁰ +179 (c 0.7, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.02 (s, 6 H, Me₂Si), 0.90 (s, 9 H, Me₃C), 1.35 (t, J = 7.1 Hz, 3 H, CH₃), 3.63-3.79 (m, 3 H, H-6, OCH ₂CH₃), 4.00 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 4.70 (ddd, J = 9.8, 4.7, 2.6 Hz, 1 H, H-5), 5.26 (br s, 1 H, H-1), 5.69 (dd, J = 9.8, 1.7 Hz, 1 H, H-4), 6.09 (ddd, J = 10.2, 2.1, 2.1 Hz, 1 H, H-2), 6.16 (br d, J = 10.2 Hz, 1 H, H-3), 7.43-7.49 (m, 2 H, H_arom), 7.92-7.96 (m, 2 H, H_arom). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.7, 18.7, 26.2, 61.0, 63.2, 64.5, 71.0, 94.5, 118.5, 126.9, 128.4, 128.5, 144.7. Anal. Calcd for C₂₀H₃₁N₃O₃Si: C, 61.66; H, 8.02. Found: C, 62.21; H, 8.20.
Compound 3d: colorless solid; mp 174-176 °C; R _f = 0.4 (PE-EtOAc, 1:1); [α]_D ²⁰ -6 (c 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.01 (s, 6 H, Me₂Si), 0.84 (s, 9 H, Me₃C), 1.23 (t, J = 7.1 Hz, 3 H, CH₃), 3.56 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 3.67 (dd, J = 11.6, 6.0 Hz, 1 H, H-6), 3.71 (dd, J = 11.6, 4.2 Hz, 1 H, H-6), 3.80-3.91 (m, 2 H, H-5, OCH ₂CH₃), 5.04 (br s, 1 H, H-1), 5.20 (br d, J = 9.2 Hz, 1 H, H-4), 5.70 (br d, J = 10.4 Hz, 1 H, H-3), 5.74 (d, J = 8.1 Hz, 1 H, =CHCO), 6.06 (ddd, J = 10.4, 2.6, 2.6 Hz, 1 H, H-2), 7.24 (d, J = 8.1 Hz, 1 H, =CH-N), 9.7 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.6, 18.7, 26.2, 51.2, 64.2, 64.6, 71.3, 93.9, 103.3, 128.8, 131.4, 141.7, 151.6, 163.7. Anal. Calcd for C₁₈H₃₀N₂O₅Si: C, 56.52; H, 7.90. Found: C, 56.50; H, 8.02.
Compound 3e: colorless oil; R _f = 0.4 (PE-EtOAc, 7:3); [α]_D ²⁰ -11 (c 1.9, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.01 (s, 6 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.23 (t, J = 7.1 Hz, 3 H, CH₃), 3.56 (dq, J = 9.8, 7.1 Hz, 1 H, OCH ₂CH₃), 3.67 (dd, J = 11.2, 5.6 Hz, 1 H, H-6), 3.71 (dd, J = 11.2, 4.3 Hz, 1 H, H-6), 3.79-3.90 (m, 2 H, H-5, OCH ₂CH₃), 5.04 (br s, 1 H, H-1), 5.19 (br d, J = 9.2 Hz, 1 H, H-4), 5.70 (dd, J = 10.2, 1.7 Hz, 1 H, H-3), 6.07 (ddd, J = 10.2, 2.6, 2.6 Hz, 1 H, H-2), 7.30 (d, J _HF = 5.8 Hz, 1 H, =CH-N), 9.30 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.6, 18.7, 26.2, 51.8, 64.2, 64.7, 70.9, 93.8, 128.2, 132.0, 141.0 (d, ¹ J _CF = 237.8 Hz), 150.2, 156.8, 157.2 (d, ² J _CF = 26.2 Hz). HRMS (CI): m/z calcd for C₁₈H₃₀FN₂O₅Si: 401.1908; found: 401.1905.
Compound 3f: colorless solid; mp 115-117 °C; R _f = 0.4 (PE-EtOAc, 7:3); [α]_D ²⁰ +66 (c 1.4, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.25 (t, J = 7.1 Hz, 3 H, CH₃), 3.57 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 3.66 (dd, J = 11.1, 5.5 Hz, 1 H, H-6), 3.71 (dd, J = 11.1, 4.5 Hz, 1 H, H-6), 3.79-3.91 (m, 2 H, H-5, OCH ₂CH₃), 5.05 (br s, 1 H, H-1), 5.20 (br d, J = 8.3 Hz, 1 H, H-4), 5.73 (dd, J = 10.0, 1.7 Hz, 1 H, H-3), 6.09 (ddd, J = 10.0, 2.5, 2.5 Hz, 1 H, H-2), 7.52 (br s, 1 H, =CH-N), 9.20 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.6, 18.8, 26.2, 52.1, 64.3, 64.8, 71.1, 94.0, 97.6, 128.6, 131.7, 141.2, 150.8, 159.2. Anal. Calcd for C₁₈H₂₉BrN₂O₅Si: C, 46.85; H, 6.33. Found: C, 47.14; H, 6.31.
Compound 3g: colorless solid; mp 126-128 °C; R _f = 0.5 (PE-EtOAc, 3:2); [α]_D ²⁰ +72 (c 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.25 (t, J = 7.0 Hz, 3 H, CH₃), 3.57 (dq, J = 9.6, 7.0 Hz, 1 H, OCH ₂CH₃), 3.60 (dd, 1 H, J = 11.1, 5.5 Hz, H-6), 3.70 (dd, 1 H, J = 11.1, 4.5 Hz, H-6), 3.80-3.90 (m, 2 H, H-5, OCH ₂CH₃), 5.04 (br s, 1 H, H-1), 5.18 (br d, J = 8.1 Hz, 1 H, H-4), 5.73 (br d, J = 10.1 Hz, 1 H, H-3), 6.07 (ddd, J = 10.1, 2.6, 2.6 Hz, 1 H, H-2), 7.58 (s, 1 H, =CH-N), 8.48 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.6, 18.9, 26.2, 51.9, 64.3, 64.7, 69.2, 71.3, 92.0, 128.8, 131.5, 146.2, 151.4, 160.5. Anal. Calcd for C₁₈H₂₉IN₂O₅Si: C, 42.52; H, 5.75. Found: C, 42.53; H, 5.68.
Compound 3h: colorless solid; mp 157-159 °C; R _f = 0.5 (PE-EtOAc, 7:3); [α]_D ²⁰ -24 (c 0.8, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.22 (t, J = 7.1 Hz, 3 H, CH₃), 3.56 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 3.69 (dd, J = 11.3, 6.6 Hz, 1 H, H-6), 3.80 (dd, J = 11.3, 3.8 Hz, 1 H, H-6), 3.83-3.92 (m, 2 H, H-5, OCH ₂CH₃), 5.06 (br s, 1 H, H-1), 5.70 (dd, J = 10.0, 1.9 Hz, 1 H, H-3), 6.00 (dd, J = 8.0, 2.1 Hz, 1 H, =CH-CO), 6.08 (ddd, J = 10.2, 2.8, 2.8 Hz, 1 H, H-2), 6.23 (dd, J = 9.0, 1.3 Hz, 1 H, H-4), 7.36 (d, J = 8.0 Hz, 1 H, =CH-N), 10.6 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.0, 15.6, 18.7, 26.2, 56.6, 64.1, 64.7, 72.3, 93.8, 107.8, 128.2, 131.7, 142.1, 160.0, 177.8. Anal. Calcd for C₁₈H₃₀N₂O₄SSi: C, 54.24; H, 7.59. Found: C, 54.38; H, 7.30.
Compound 3i: colorless solid; mp 37-39 °C; R _f = 0.3 (PE-EtOAc, 8:2); [α]_D ²⁰ +148 (c 1, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.01 (s, 6 H, Me₂Si), 0.79 (s, 9 H, Me₃C), 1.10 (t, J = 7.0 Hz, 3 H, CH₃), 3.42 (dq, J = 9.4, 7.0 Hz, 1 H, OCH ₂CH₃), 3.69 (dq, J = 9.4, 7.0 Hz, 1 H, OCH ₂CH₃), 3.83-3.96 (m, 2 H, H-6), 4.02-4.06 (m, 2 H, H-4, H-5), 4.90 (br s, 1 H, H-1), 5.75 (ddd, J = 10.0, 3.2, 3.2 Hz, 1 H, H-2), 5.97 (dd, J = 10.0, 2.0 Hz, 1 H, H-3), 7.00-7.07 (m, 2 H, H_arom), 7.14-7.19 (m, 1 H, H_arom), 7.46-7.51 (m, 1 H, H_arom), 10.58 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -4.7, -4.6, 15.7, 18.9, 26.4, 41.1, 63.9, 64.3, 71.9, 94.1, 122.7, 127.4, 128.1, 128.9, 131.2, 149.2. Anal. Calcd for C₂₁H₃₂N₂O₃SSi: C, 59.96; H, 7.67. Found: C, 59.46; H, 7.61.
Compound 3j: colorless oil; R _f = 0.4 (PE-EtOAc, 9.5:0.5); [α]_D ²⁰ +157 (c 1.4, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 3 H, Me₂Si), 0.01 (s, 3 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.22 (t, J = 7.1 Hz, 3 H, CH₃), 3.54 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 3.87 (dq, J = 9.6, 7.1 Hz, 1 H, OCH ₂CH₃), 3.90-3.95 (m, 2 H, H-6), 4.01 (ddd, J = 10.4, 4.9, 2.3 Hz, 1 H, H-5), 4.65 (br d, J = 10.4 Hz, 1 H, H-4), 5.05 (br s, 1 H, H-1), 5.84 (ddd, J = 10.0, 2.8, 2.8 Hz, 1 H, H-2), 6.13 (br d, J = 10.0 Hz, 1 H, H-3), 7.28 (dd, J = 7.9, 7.9 Hz, 1 H, H_arom), 7.39 (dd, J = 7.9, 7.9 Hz, 1 H, H_arom), 7.73 (d, J = 7.9 Hz, 1 H, H_arom), 7.84 (d, J = 7.9 Hz, 1 H, H_arom). ¹³C NMR (75.5 MHz, CDCl₃): δ = -4.9, 15.7, 18.8, 26.3, 42.5, 64.1, 71.1, 94.2, 121.4, 122.2, 124.9, 126.5, 127.6, 131.1, 136.0, 153.4, 164.8. Anal. Calcd for C₂₁H₃₂NO₃S₂Si: C, 57.63; H, 7.14. Found: C, 57.90; H, 7.23.

11

Synthesis of Compound 4.
A solution of Pd(OAc)₂ (4.5 mg, 0.02 mmol) and PPh₃ (15.6 mg, 0.06 mmol) in DMF (2 mL) was added to a mixture of iodouracil derivative 3g (101 mg, 0.2 mmol), CuI (7.6 mg, 0.04 mmol), and Et₃N (0.81 mL, 6.0 mmol) in DMF (1 mL). After being stirred for 2 h at r.t., the solvent was evaporated and the product purified by column chromatography on silica to give compound 4 (94.5 mg, 98% yield) as a yellow solid. Mp 68-69.5 °C; R _f = 0.4 (CHCl₃-EtOAc, 19:2); [α]_D ²⁰ +130 (c 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.04 (s, 3 H, Me₂Si), 0.05 (s, 3 H, Me₂Si), 0.87 (s, 9 H, Me₃C), 1.28 (t, J = 7.0 Hz, 3 H, CH₃), 3.61 (dq, J = 9.7, 7.0 Hz, 1 H, OCH ₂CH₃), 3.70 (dd, 1 H, J = 11.3, 5.5 Hz, H-6), 3.75 (dd, 1 H, J = 11.3, 4.5 Hz, H-6), 3.81-3.89 (m, 2 H, H-5, OCH ₂CH₃), 5.09 (br s, 1 H, H-1), 5.25 (br d, J = 8.2 Hz, 1 H, H-4), 5.79 (br d, J = 10.1 Hz, 1 H, H-3), 6.12 (ddd, J = 10.1, 2.6, 2.6 Hz, 1 H, H-2), 7.32-7.35 (m, 3 H, H_arom), 7.51-7.54 (m, 2 H, H_arom), 7.55 (s, 1 H, =CH-N), 8.13 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, 15.6, 18.7, 26.2, 51.5, 64.1, 64.7, 71.2, 80.2, 94.0, 94.5, 101.3, 122.9, 128.6, 128.8, 128.9, 131.4, 132.0, 143.5, 150.6, 161.6. Anal. Calcd for C₂₆H₃₄N₂O₅Si: C, 42.52; H, 5.75. Found: C, 42.53; H, 5.68.

12

Synthesis of Compound 5.
To a solution of Pd(OAc)₂ (4.5 mg, 0.02 mmol), PPh₃ (15.6 mg, 0.06 mg), Et₃N (0.12 mL, 0.9 mmol), in dioxane (1 mL) at 95 °C was added a solution of iodouracil derivative 3g (101 mg, 0.2 mmol), methyl acrylate (0.11 mL, 1.2 mmol), and Et₃N (0.04 mL, 0.3 mmol) in dioxane (1 mL). After being stirred at reflux for 1 h, the solvent was evaporated and the residue purified by column chromatography on silica to give compound 5 (18.6 mg, 18% yield) as a colorless solid. Mp 84-87 °C; R _f = 0.4 (PE-EtOAc, 3:2); [α]_D ²⁰ +100 (c 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Me₂Si), 0.83 (s, 9 H, Me₃C), 1.26 (t, J = 7.2 Hz, 3 H, CH₃), 3.58 (dq, J = 9.6, 7.2 Hz, 1 H, OCH ₂CH₃), 3.64-3.76 (m, 2 H, H-6), 3.76 (s, 3 H, CH₃), 3.81-3.92 (m, 2 H, H-5, OCH ₂CH₃), 5.07 (br s, 1 H, H-1), 5.27 (br d, J = 8.1 Hz, 1 H, H-4), 5.73 (br d, J = 10.0 Hz, 1 H, H-3), 6.11 (ddd, J = 10.0, 2.6, 2.6 Hz, 1 H, H-2), 7.00 (d, J = 15.7 Hz, 1 H, =CH-), 7.26 (d, J = 15.7 Hz, 1 H, =CH-), 7.44 (s, 1 H, =CH-N), 8.87 (br s, 1 H, NH). ¹³C NMR (75.5 MHz, CDCl₃): δ = -5.1, -5.0, 15.5, 18.7, 26.2, 51.0, 54.0, 61.8, 64.3, 69.4, 97.7, 105.6, 111.0, 121.0, 122.9, 123.5, 132.0, 140.0, 145.0, 169.6, 170.4. HRMS (CI Na): m/z calcd for [C₂₂H₃₄N₂O₇Si + Na⁺]: 489.2033; found: 489.2030.