Promotion of Asymmetric Aza-Claisen Rearrangement of N-Allylic Carboxamides Using Excess Base

Abstract

The aza-Claisen rearrangement of the enolate of N-(Z)-crotyl-N-(S)-phenethylpropanamide did not proceed in the presence of 1.5 equivalents of LHMDS as a base. However, the use of a large excess of base (10 equiv) promoted the reaction to give N-(S)-phenethyl-anti-2,3-dimethylpent-4-enamide with good stereoselectivities (anti/syn = ca. 95:5). An excess of base stabilized the amide enolates and prevented the decomposition to the ketene to prompt the rearrangement of various carboxamides with good stereoselectivity. This reaction provided a new method for the construction of asymmetric quaternary carbon centers.

Key words

aza-Claisen rearrangement - amide enolate - asymmetric reaction

References and Notes

• Percent review of aza-Claisen rearrangement:
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3

The stereochemistry of the products was determined by the comparison with the samples, which had been obtained by the rearrangement of 1a; see ref. 2a.

4

It was suspected that the basicity of LHMDS was not sufficient to deprotonate the amides, and stronger bases must be required. However, the reaction with LDA gave lower yields and stereoselectivities; see ref. 2a. Furthermore, the reaction of 9a utilizing s-BuLi (1.5 equiv) gave the same results as with LHMDS (1.5 equiv).

5

Typical Procedure for the Aza-Claisen Rearrangement To a solution of LHMDS (1.0 M in toluene, 5.0 mL) in toluene (3 mL) was added a toluene solution (3 mL) of carboxamide 9d (231 mg, 1.0 mmol) at -78 ˚C under an argon atmosphere in a pressure tube.⁶ After 30 min with stirring, the reaction mixture was allowed to warm to r.t. and was sealed. After heating of the sealed solution at 120 ˚C for 24 h, a sat. aq NaHCO₃ (24 mL) was added, and the mixture was extracted with CH₂Cl₂ (30 mL), dried (Na₂SO₄), and evaporated.⁷ The residual mixture was purified by SiO₂ column chromatography (n-hexane-EtOAc = 3:1) to give 156 mg (68%) of 11d and 39 mg (17%) of a mixture of 10d and 11d as colorless needles, respectively.
Compound 10d: mp 84.5-85.5 ˚C (n-hexane-EtOAc). [α]_D ^²¹ -94.7 (c 0.65, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.20 (m, 5 H), 5.65 (br d, J = 7.2 Hz, 1 H), 5.13 (quin, J = 7.6 Hz, 1 H), 4.76 (m, 1 H), 4.73 (m, 1 H), 2.45-2.30 (m, 2 H), 2.09 (ddd, J = 12.5, 5.2, 0.8 Hz, 1 H), 1.72 (dd, J = 1.2, 0.8 Hz, 3 H), 1.47 (d, J = 6.8 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 174.9, 143.24, 143.21, 128.6, 127.3, 126.2, 112.4, 48.5, 42.2, 39.6, 22.4, 21.6, 17.6. IR (ATR): 3269, 2970, 1637, 1542, 1450 cm^-¹. MS (CI): m/z = 232 [M + H]⁺ (base peak), 231 [M]⁺, 128, 105. HRMS (CI): m/z [M + H]⁺ calcd for C₁₅H₂₂ON: 232.1701; found: 232.1701.
Compound 11d: mp 54.2-55.5 ˚C (n-hexane-EtOAc); [α]_D ^²¹ -84.6 (c 0.43, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.20 (m, 5 H), 5.66 (br d, J = 6.8 Hz, 1 H), 5.13 (quin, J = 7.2 Hz, 1 H), 4.74 (br s, 1 H), 4.68 (br s, 1 H), 2.45-2.30 (m, 2 H), 2.07 (dd, J = 17.2, 10.8 Hz, 1 H), 1.67 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.14 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 175.0, 143.2, 143.1, 128.6, 127.3, 126.2, 112.4, 48.4, 42.1, 39.6, 22.3, 21.5, 17.6. IR (ATR): 3285, 2970, 1639, 1538, 1450 cm^-¹. MS (CI):
m/z = 232 [M + H]⁺ (base peak), 231 [M]⁺, 128, 105. HRMS (CI): m/z [M + H]⁺ calcd for C₁₅H₂₂ON: 232.1701; found: 232.1701.

6

An air-tight cylinder for high-pressure experiments is available at Alltech Associates, Inc.

7

At this point, the diastereomeric ratio was determined by GLC or LC.

8

Determination of the Stereochemistry of the Products
A 88:12 mixture of 10b and 11b was subjected to hydroboration(disiamylborane), oxidation (aq NaOH-H₂O₂), and heating with PTSA to give 3-methylvalero-lactone whose specific rotation {[α]_D ^²³ -19.8 (c 4.5, CHCl₃)} was compared with its 3R-isomer {[α]_D ^²5 +27.6 (c 5.6, CHCl₃)}.⁹ Thus, the major product 10b was determined to have the S configuration at the C-3 position.

10

Determination of the Stereochemistry of the Products
A: A 91:9 mixture of 10c and 11c was subjected to hydroboration(disiamylborane), oxidation (aq NaOH-H₂O₂), and heating with PTSA to give 2-methylvalero-lactone whose specific rotation {[α]_D ^²² -56.3 (c 2.48, MeOH)} was compared with its 2S-isomer {[α]_D ^²5 +67.3 (c 6.59, CHCl₃)}.^¹¹ Thus, the major product 10c was determined to have the R configuration at the C-2 position.
B: The stereochemistry of the major product 10d was confirmed by X-ray analysis as shown in Figure  [¹] . Crystallographic data (excluding structure factors) for this structure have been deposited with the Cambridge Crystallo-graphic Data Centre as supplementary publication numbers CCDC 832610. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or
e-mail: [e-mail]].
C: The stereochemistries of the major products 10e and 10f were estimated empirically.

Figure 1 The crystallographic analysis of 10d

12

It was reported that enolates of esters decomposed completely to ketene at 0 ˚C; see ref. 11.

13

Although it was suspected that there were several decomposition pathways, we could not isolate any meaningful compounds, not even Claisen-type condensation products, from the reaction mixtures.