Double Functionalization of N-Boc-3-(Tosylmethyl)indole Exploiting the ­Activating Properties of the Tosyl Group

Abstract

The anion prepared from N-Boc-3-(tosylmethyl)indole using NaH in DMF can be readily functionalized by reaction with various electrophiles. The obtained sulfonyl indoles, upon removal of the N-protecting group, undergo nucleophilic attack via a vinylogous imino derivative, leading to branched 3-substituted indoles.

Key words

carbanions - eliminations - indoles - nucleophilic additions - sulfones

References and Notes

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15

Synthesis of N -Boc-3-(Tosylmethyl) indole (11) To a solution of N-Boc-3-(bromomethyl) indole (5 mmol, 1.55 g) in DMF (10 mL), Bu₄NI (0.5 mmol, 0.18 g) and TolSO₂Na were added at r.t. After stiring for 2 h at this temperature, cold H₂O (30 mL) was added and the mixture was extracted with EtOAc (3 × 30 mL). The organic phase was dried over MgSO₄, and after removal of the solvent the residue was purified by column chromatography (hexanes-EtOAc, 8:2) giving 1.54 g (80% yield) of pure 11 as a white solid; mp 124-126 ˚C. IR (Nujol): 1374, 1151 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.63 (s, 9 H), 2.37 (s, 3 H), 4.42 (s, 2 H), 7.08-7.12 (m, 1 H), 7.19 (d, 2 H, J = 10.7 Hz), 7.21-7.28 (m, 2 H), 7.45 (s, 1 H), 7.59 (d, 2 H, J = 8.5 Hz), 8.09 (d, 1 H, J = 8.1). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.7, 28.2, 54.0, 84.3, 107.9, 115.2, 119.0, 122.9, 124.8, 126.2, 127.4, 128.7, 129.7,135.2, 136.7, 144.9, 149.8.

16

Reaction of N -Boc-3-(Tosylmethyl) indole (11) with Electrophiles
To a mixture of NaH (2 mmol) in anhyd DMF (5 mL), sulfonyl indole 11 (1 mmol) was added at 0 ˚C. After 20 min stirring at this temperature, the electrophile (1.1 mmol) was added and stirring was continued for the appropriate time at 0 ˚C (see Table  [¹] ). The mixture was then cautiously quenched by addition of cold H₂O and then acidified with AcOH. After extraction with Et₂O (3 × 15 mL) the organic phase was dried over MgSO₄ and after removal of the solvent the residue was purified by column chromatography (hexanes-EtOAc, 8:2).
Spectroscopic Data for Representative Compounds
Compound 12a: mp 58-60 ˚C. IR (Nujol): 1598, 1370, 1155 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.67 (s, 9 H), 2.35 (s, 3 H), 2.83-3.06 (m, 1 H), 3.10-3.28 (m, 1 H), 4.39 (dd, 1 H, J = 4.0, 11.4 Hz), 4.92-5.12 (m, 2 H), 5.52-5.75 (m, 1 H), 7.05-7.21 (m, 3 H), 7.23-7.37 (m, 2 H), 7.44-7.60 (m, 3 H), 8.09 (d, 1 H, J = 8.4 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.8, 28.4, 32.6. 63.4, 84.5, 112.2, 115.3, 118.6, 119.4, 122.9, 124.8, 126.7, 129.4, 129.6, 133.3, 134.4, 135.3, 144.9, 149.5.
Compound 12f: mp 55-57 ˚C. IR (Nujol): 3310, 2133, 1368, 1151 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.67 (s, 9 H), 1.85 (s, 1 H), 2.36 (s, 3 H), 3.04-3.11 (m, 1 H), 3.27-3.32 (m, 1 H), 4.56 (dd, 1 H, J = 4.1, 10.7 Hz), 7.10-7.17 (m, 3 H), 7.20-7.27 (m, 2 H), 7.52-7.62 (m, 3 H), 8.10 (d, 1 H, J = 8.1 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.5, 21.8, 28.4, 62.2, 71.3, 79.3, 84.6, 115.4, 119.3, 123.0, 124.9, 126.7, 129.4, 129.5, 129.6, 129.8, 133.9, 135.2, 145.3, 149.5.
Compound 12l: mp 56-58 ˚C. IR (Nujol): 2248, 1376, 1153 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.67 (s, 9 H), 2.35 (s, 3 H), 2.46-2.62 (m, 2 H), 2.80-2.96 (m, 2 H), 4.46 (dd, 1 H, J = 4.7, 10.7 Hz), 7.12-7.18 (m, 3 H), 7.26-7.38 (m, 2 H), 7.51-7.60 (m, 3 H), 8.10 (d, 1 H, J = 8.1 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.5, 21.7, 24.7, 28.3, 62.3, 84.9, 110.5, 115.5, 118.3, 119.3, 123.3, 125.2, 126.7, 129.3, 129.8, 134.1, 137.8, 145.3, 149.7.
Compound 12m: mp 52-54 ˚C. IR (Nujol): 1742, 1374, 1156 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.66 (s, 9 H), 2.34 (s, 3 H), 2.36-2.49 (m, 2 H), 2.67-2.78 (m, 2 H), 3.58 (s, 3 H), 4.52 (dd, 1 H, J = 4.3, 10.7 Hz), 7.10-7.20 (m, 3 H), 7.22-7.34 (m, 2 H), 7.48 (s, 1 H), 7.55 (d, 2 H, J = 8.1 Hz), 8.09 (d, 1 H, J = 8.1 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.7, 24.1, 28.3, 31.1, 51.8, 62.5, 84.6, 111.9, 115.4, 119.4, 123.0, 125.0, 126.6, 129.3, 129.6, 134.5, 135.4, 144.9, 149.8, 172.8.

17

The free NH on the indole ring is mandatory for a successful process since none of the nucleophilic reagents tested in this reaction gives any result with N-Boc indoles 12.

18

Deprotection of N -Boc Sulfonyl Indoles 12 and Their Reaction with Nucleophiles N-Boc indole 12 (1 mmol) was dissolved in a mixture of TFA-CH₂Cl₂ (1:1, 10 mL) and stirring was continued for 3 h at r.t. After evaporation of the solvents at reduced pressure, the crude sulfonyl indole was purified by column chromatography (hexanes-EtOAc, 8:2). Reaction of sulfonyl indoles 13 with nucleophiles was carried out according to our previously published procedure (ref. 10c).
Spectroscopic Data for Representative Compounds
Compound 14a: oil. IR (neat): 3393, 1739, 1603, 1463 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, 2.3 H, J = 7.3 Hz), 1.27 (t, 2.5 H, J = 6.8 Hz), 1.28 (t, 1.2 H, J = 7.3 Hz), 2.55-2.69 (m, 2 H), 3.84-3.92 (m, 3 H), 4.16-4.28 (m, 3 H), 4.87-4.99 (m, 2 H), 5.61-5.68 (m, 1 H), 7.02 (d, 1 H, J = 2.1 Hz), 7.08-7.18 (m, 2 H), 7.31 (d, 1 H, J = 7.7 Hz), 7.66 (d, 1 H, J = 7.7 Hz), 8.24 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 14.3, 37.0, 38.0, 57.6, 57.6, 61.4, 61.7, 111.4, 115.2, 116.9, 119.5, 119.6, 122.1, 122.8, 127.0, 136.1, 136.4, 168.6, 168.9.
Compound 14b: oil. IR (neat): 3389, 1622, 1583, 1458 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.51 (s, 3 H), 1.65 (s, 3 H), 2.33-2.39 (m, 1 H), 2.59-2.68 (m, 1 H), 3.82 (dd, 1 H, J = 3.4, 11.5 Hz), 4.80 (d, 1 H, J = 9.9 Hz), 4.95 (dd, 1 H, J = 1.3, 17.1 Hz), 5.48-5.55 (m, 1 H), 7.04 (d, 1 H, J = 2.6 Hz), 7.13-7.23 (m, 2 H), 7.37 (d, 1 H, J = 8.1 Hz), 7.68 (d, 1 H, J = 7.7 Hz), 8.19 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.8, 26.8, 34.9, 45.7, 93.0, 111.5, 113.3, 116.7, 119.7, 120.1, 122.4, 123.4, 128.3, 136.1, 136.2.