Mild Conversion of Esters Lacking Acidic α-Hydrogens into Amides via Samarium(III) Tris[hexamethyldisilazide] and Amines

Abstract

Samarium(III) tris[hexamethyldisilazide] (Sm[(Me₃Si)₂N]₃ = Sm[HMDS]₃) promotes the direct conversion of an ester admixed with an amine into the corresponding carboxamide under exceptionally mild conditions (≤0 ˚C) and in high yields. Only a slight excess of amine and the lanthanide complex are required to effect complete conversion of the ester into the amide. Esters with acidic α-hydrogens undergo a competing Claisen-like condensation along with the desired conversion into amides.

esters - amides - lanthanides - HMDS - samarium

References

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11

The lanthanide reagents were prepared according to the procedure of Bradley et al.⁶ Briefly, to a suspension of anhyd lanthanum chloride^¹² in THF at r.t. was added dropwise 3 equiv of LiHMDS (Aldrich) as a 1.0 M solution in THF. Following completion of the addition, the mixture was warmed to 50 ¡C for 15 min and then cooled to the prescribed temperature for use in the amidation reactions. Other lanthanide HMDS complexes were prepared by an analogous procedure.

12a

Preparation of anhyd lanthanide halides can be capricious as cited in ref. 12b. We found no difference in reactivity of the Ln[HMDS]₃ complexes using lanthanide chlorides prepared by the Taylor procedure compared with using salts treated by drying of the commercially available LnCl₃×7H₂O salts under high vacuum at 140 ˚C overnight

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18

Procedure for Conversion of Esters into Amides Using Sm[HMDS] ₃ Synthesis of Amide 4a Anhyd samarium chloride (0.280 g, 0.73 mmol) was dried under high vacuum at 140 ˚C for 15 h, then cooled to ambient temperature under argon. The residue was suspended in anhyd THF (4 mL) and LiHMDS (2.2 mL of a 1.0 M solution in THF, 2.20 mmol) was added dropwise. The suspension was placed in a 50 ˚C bath and stirred 15 min. The heating bath was removed and the suspension allowed to cool back to ambient temperature over 30 min. Morpholine (0.065 mL, 0.73 mmol) was then added as a neat liquid and the mixture stirred 15 min at ambient temperature. The reaction flask was placed in an ice-bath and stirred 15 min to equilibrate. Methyl benzoate (0.082 mL, 0.66 mmol) was added dropwise as a neat liquid, and the reaction was stirred for 1 h in the ice bath. MeOH (1 mL) was added to quench the reaction. The mixture was poured directly onto a short plug of silica gel using EtOAc washes (5 ¥ 5 mL) for elution. The combined extracts were concentrated, and the residual green oil was chromatographed [Chromatotron radial chromatography, silica gel, elution solvent EtOAc-hexanes (1:5)]. The combined eluent was concentrated to provide 0.126 g of a clear, colorless oil (ca. 99% yield). ^¹H NMR (300 MHz, CDCl₃): δ = 3.33 (br s, 4 H), 3.59 (br s, 4 H), 7.387.46 (m, 5 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 40.31, 66.04, 126.97, 128.41, 129.55, 135.57, 166.90. MS: m/z = 192 [M⁺].

19

Most of the products are simple amides previously described in the literature and/or commercially available. Thus, products were characterized by NMR (^¹H, ^¹³C) and MS comparing data to authentic samples or data acquired from the literature.
Selected Examples with Data
N -Benzylbenzamide (4b)
^¹H NMR (300 MHz, CDCl₃): δ = 4.48 (d, 2 H, J = 6.02 Hz), 7.23 (m, 1 H), 7.31 (m, 4 H), 7.51 (m, 3 H), 7.88 (m, 2 H), 9.04 (t, 1 H, J = 5.70 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 42.59, 126.73, 127.19, 127.25, 128.29, 128.33, 131.26, 134.33, 139.72, 166.19. MS: m/z = 212 [M⁺].^²0a
(4-Bromophenyl)(morpholino)methanone (4e)
^¹H NMR (300 MHz, CDCl₃): δ = 2.49 (br s, 4 H), 3.58 (br s, 4 H), 7.36 (d, 2 H, J = 8.68), 7.64 (d, 2 H, J = 8.58). ^¹³C NMR (75 MHz, CDCl₃): δ = 66.03, 122.99, 129.29, 131.47, 134.75, 168.09.^²0b
(4-Methoxyphenyl)(morpholino)methanone (4f)
^¹H NMR (300 MHz, CDCl₃): δ = 3.48 (br s, 4 H), 3.82 (br s, 4 H), 3.79 (s, 3 H), 6.98 (d, 2 H, J = 6.68 Hz), 7.38 (d, 2 H, J = 6.76). ^¹³C NMR (75 MHz, CDCl₃): δ = 55.25, 66.11, 113.66, 127.47, 129.13, 160.24, 169.02. MS: m/z = 206 [M⁺].^²0c
Morpholino(pyridin-3-yl)methanone (4h)
^¹H NMR (300 MHz, CDCl₃): δ = 3.64 (br s, 8 H), 7.49 (m, 1 H), 7.85 (m, 1 H), 8.64 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 66.04, 123.59, 131.48, 134.96, 147.76, 150.55, 166.90. MS: m/z = 192 [M⁺].^²0d

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