Short and Versatile Two-Carbon Ring Expansion Reactions by Thermo-Isomerization: Novel Straightforward Synthesis of (±)-Muscone, Nor- and Homomuscones, and Further Macrocyclic Ketones

Abstract

Thermo-isomerization of 1-vinyl substituted medium- and large-ring cycloalkanol derivatives in a flow reactor system at temperatures of 600 °C to about 650 °C leads directly to the ring-expanded macrocyclic ketones. Alkyl substituents at the vinylic moiety are transferred locospecifically to the ring-expanded ketone as corresponding α-, and β-substituents, respectively. This novel thermal 1,3-C shift reaction therefore provides a new access to short syntheses of many alkyl-substituted macrocyclic ketone derivatives [e.g. (±)-muscone and analogues] in a systematic manner.

ring expansions - macrocyclic ketones - dynamic gas phase thermo-isomerization - two- carbon ring insertion reactions - (±)-muscone syntheses

References

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For a description of the thermo-izomerization procedure and the experimental setup, see ref. [1] and references therein.

3

All mentioned cycloalkanols were synthesized by addition of the corresponding commercially available vinylic halides (normally the bromide) to the ketone by using a Grignard reaction. The yields could be improved significantly by pre-complexation of the ketone with CeCl₃, according to the analogous procedure described in ref. 1 for the simple 1-vinylcycloalkanols. The propynyl substituted alcohol derivatives 16 and 20 were obtained in a similar manner by addition of propynyl magnesium bromide to the parent ketone. The 1-cyclohexen-1-yl-cyclododecanol 28 was obtained via addition of the lithio cyclohexenyl intermediate according to ref. [27]

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8a

3a: ¹H NMR (300 MHz, CDCl₃): 5.94 and 5.74 [br s, H₂-C(1)], 1.86 [br s, Me-C(2)], 0.87 [t-type m, H₃C(ω)]. ¹³C NMR (75 MHz, CDCl₃): 202.3 [s, C(3)], 144.6 [s, C(2)], 124.1 [t, C(1)], 17.7 [q, Me-C(2)], 13.5 [q, C(ω)].

8b

5a: ¹H NMR (300 MHz, CDCl₃): 2.52 [t-type m, 2 H, H₂-C(13)], 1.68-1.63 (m, 2 H), 1.54-1.49 (m, 2 H), 1.33-1.15 (m, 16 H), 1.12 [s, 6 H, Me₂-C(2)]. ¹³C NMR (75 MHz, CDCl₃): 216.0 (s), 47.84 (s), 40.83, 35.68, 26.96, 26.69, 26.63, 25.45, 25.26 (7 t), 24.70 (q, 2), 24.56, 24.48, 22.27, 21.86 (4 t).

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18

Selected characteristic data of enones 8: ¹H NMR (300 MHz, CDCl₃): (E)-8a: 6.84 [dq, J = 15.5, 7 Hz, H-C(2)], 6.12 [dq, J = 15.5, 1.7 Hz, H-C(3)], 1.87 (dd, J = 7, 1.5 Hz). (Z)-8a: 6.19 [m, 2 H, H-C(2,3)], 2.11 (d, J = 7 Hz). ¹³C NMR (75 MHz, CDCl₃): 200.4 [s, C(4)], (E)-8a: 141.9 [d, C(2)], 131.9 [d, C(3)], 18.0 [q, C(1)]. (Z)-8a: 142.2 [d, C(2)], 127.6 [d, C(3)], 15.9 [q, C(1)].

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20d

Modification of the work-up procedure: To dissolve all the aminoalcohol during the washing procedure, the white granular precipitate was digested in a glass filter with hot t-BuOMe several times and finally with one portion of hot THF.

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24

Cyclododecanone (12, 60 g, 0.33 mol) was melted by keeping it at 65-70 °C, then t-BuOH (15 mL) and trimethyl sulfoxonium iodide (117 g, 0.52 mol, 1.6 mol equiv.) were added with stirring. The resulting pulpy suspension was kept at 70 °C and potassium t-butoxide (56 g, 0.5 mol) were added in several portions. After an induction period of several minutes the insoluble precipitates slowly dissolved, due to the formation of equimolar amounts of DMSO during the spiroepoxide formation. After stirring for 1.5 h, powdered KOH (2 g) was added to the mixture. The course of the reaction was then followed by GC (conversion up to 95%). When further addition of KOH resulted in no additional epoxide formation, the mixture was allowed to cool to r.t. and water (100 mL) was added slowly with stirring. The mixture was diluted with t-BuOMe and then washed several times with water and brine. The organic layer was dried on MgSO₄ and the solvent removed. After bulb-to-bulb distillation, oxirane 15 was obtained as a colorless oil (61 g, containing 5-10% 12) and was used for the transformation into 14 without further purification.

The mixture of the (E/Z)-isomers 17, and 21, respectively, was found already earlier to be difficult to separate, cf. ref.^14k For 21 see also:

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25c

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25f

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25i

See ref. [14b]

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