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Synlett 2002(2): 0275-0279
DOI: 10.1055/s-2002-19758
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel, Short and Repeatable Two-Carbon Ring Expansion Reaction by Thermo-Isomerization: Easy Synthesis of Macrocyclic Ketones

Matthias Nagel*a, Hans-Jürgen Hansena, Georg Fráterb
a Organisch-chemisches Institut der Universität, Winterthurerstr. 190, CH 8057- Zürich, Switzerland
Fax: +41(1)63568 12; e-Mail: mnagel@access.unizh.ch;
b Givaudan Research Ltd, Überlandstr. 138, CH-8600 Dübendorf, Switzerland
Fax: +41(1)8242926; e-Mail: georg.frater@givaudan.com;
Further Information

Publication History

Received 3 September 2001
Publication Date:
02 February 2007 (online)

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Abstract

A novel two-carbon ring enlargement procedure, in which medium- and large-ring 1-vinylcycloalkanols are thermo-isomerized in a flow reactor system at temperatures of 600 °C to about 650 °C, produces the isomeric ring-expanded cycloalkanones directly and efficiently. This two-step ring expansion protocol can easily be applied several times successively. For e.g., the musk odorant cyclopentadecanone (Exaltone ®) is prepared from cycloundecanone in two repetitive cycles. Thermo-isomerization of the corresponding ethynylic cycloalkanols gives in moderate yields the bishomologous α,β-unsaturated macrocyclic (E)-2-cycloalkenones. A reaction mechanism via alkyl hydroxyallyl biradical intermediates is proposed.

Key words

ring expansions - macrocyclic ketones - thermo-isomerization - ring-insertion reactions - hydroxyallyl radicals

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3

All mentioned tertiary cyclic vinyl substituted alcohols as well as the ethynyl substituted alcohols were synthesized from the corresponding cycloalkanones by addition of vinyl or ethynyl magnesium bromide according to the general procedure described in ref. 4.

18

A mechanism via a free radical reaction is also involved in a recent two-carbon ring expansion procedure where a homolytic β-scission occurs in 1-alkenylcycloalkoxy radical systems, see ref. [6a] Selected characteristic data of enones 19. 1H NMR (300 MHz, CDCl3): 6.35 [dd, J = 17.5, 10, H-C(2)], 6.25 [dd, J = 17.5, 1.5, H trans -C(1)], 5.80 [dd, J = 10, 1.5, H cis -C(1)], 2.60 [t, J = 7.5, H2-C(4)]; 0.90-0.85 (t-type m), [H3C-(ω)]. 13C NMR (75 MHz): 201 [s, C(3)], 136.5 [d, C(2)], 127.5 [t, C(1)], 39.5 [t, C(4)], 13.5 [q, C(ω)].

19

Addition of a ethynyl magnesium bromide solution in analogy to ref. [4]