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

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.

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

References

<A NAME="RG19301ST-1">1</A> Nagel M. Ph.D. Thesis   University of Zürich; Switzerland: 2001. 

For examples of so-called ”internal" (or also ”intramolecular") [1,5]-H shift reactions of the general retro-ene type under flash thermolysis conditions, see :

<A NAME="RG19301ST-2A">2a</A> Rippol J.-L. Vallée Y. Synthesis  1993,  659 

<A NAME="RG19301ST-2B">2b</A> Brown RFC. In Pyrolytic Methods in Organic Chemistry   Wasserman RH. Academic Press; New York: 1980.  Chap. 7. p.229-246  ; and references therein

<A NAME="RG19301ST-2C">2c</A> Gajewski JJ. Hydrocarbon Thermal Isomerizations   Academic Press; New York: 1981. 

<A NAME="RG19301ST-2D">2d</A> Karpf M. Angew. Chem., Int. Ed. Engl.  1986,  25:  414 ; Angew. Chem. 1986, 98, 413; and references therein

<A NAME="RG19301ST-3">3</A>

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.

<A NAME="RG19301ST-4A">4a</A> Dimitrov V. Bratovanov S. Simova S. Kostova K. Tetrahedron Lett.  1994,  35:  6713 

<A NAME="RG19301ST-4B">4b</A>

Typical Procedure for the Synthesis of Vinylcycloalkanols: Drying of cerium chloride: CeCl₃ heptahydrate (100 g, 0.268 mol) was heated under reduced pressure (HV pump) in a Büchi Kugelrohr oven with continuous rotation of the bulb, at first with an air bath temperature of 70-80 °C for 5-6 h, then for 3-4 h at 110-120 °C, and finally for about 12 h (overnight) at 150-160 °C. The vaporized water was collected in cooling traps (liquid N₂) and the thawed condensates were collected (about 34 mL). The dried (strongly hygroscopic) ivory-colored CeCl₃ was stored under an argon atmosphere at r.t. in the dark. No loss in activity could be observed during storage over several months. Precomplexation of the ketone: Cyclododecanone (36.4 g, 0.2 mol) was, with stirring, added to a suspension of 5.0 g anhyd CeCl₃ (0.02 mol, 0.1 mol equiv.) in anhyd THF (100 mL) at r.t. under an inert atmosphere. After 0.5-2 h, the yellowish colored suspension became homogenous and uniformly gel- (or yogurt-)like. To this mixture, of a 1 M solution of vinyl magnesium bromide (320 mL) in anhyd THF (0.32 mol, ca 1.6 mol equiv.) was added with stirring via a cannula within 10 min, whereby the temperature of the reaction mixture increased to 35-40 °C. After the exothermic phase of the reaction, stirring was continued for 20-30 min and the conversion of the starting ketone was monitored by TLC and GC analyses (normally more than 80% had been consumed after 15 min). Work-up: The now greyish-brown reaction mixture was poured into cold water (1 L ) and t-BuOMe (500 mL) were added. With stirring, a 10% aqueous HCl solution was added until the slimy or gel-like consistency of the mixture disappeared, and the mixture became clear and two-phased (pH < 3). The organic phase was washed several times with water, then with sat. NaHCO₃ solution, and brine. After drying (MgSO₄) and evaporation of the solvent under reduced pressure, the crude 1-vinylcyclododecanol 6 (GC purity about 90%) was purified either by bulb-to-bulb distillation (HV) and subsequent crystallization from hexane-t-BuOMe (95:5, v/v) or by chromatography on a short column (silica gel, eluent, hexane-t-BuOMe 97:3-95:5). Allylic alcohol 6 was obtained in yields of 75-85% as a colorless waxy solid (mp 53 °C). ¹H NMR (300 MHz, CDCl₃): 5.98 (dd, J = 10.8, 17.4 Hz, 1 H), 5.20 (dd, J = 1.4, 17.4 Hz, 1 H), 5.01 (dd, J = 1.4, 10.8 Hz, 1 H), 1.9-1.2 (m, 23 H). ¹³C NMR (75 MHz, CDCl₃): 145.3 (d); 111.0 (t); 75.3 (s); 34.6(2), 26.3(2), 25.9, 22.5(2), 22.1(2), 19.5(2)(6 t). EI-MS (GC/MS): 210.2 (2, M ⁺ ), 192.2 (50, M - 18), 77.7(98), 67(100), 55(97). Also see:

<A NAME="RG19301ST-4C">4c</A> Marcou A. Normant H. Bull. Soc. Chim. Fr.  1965,  3491 

<A NAME="RG19301ST-4D">4d</A> Herz W. Juo R.-R. J. Org. Chem.  1985,  50:  618 

<A NAME="RG19301ST-4E">4e</A>

Ref. 6a.

The thermo-isomerization process was performed in flow reactor systems with different dimensions: e.g., a quartz tube reactor (40 cm length, 22 mm, and 40 mm i.d., respectively) heated by a tube furnace (35 cm single temperature zone, in a nearly horizontal position), cf. also:

<A NAME="RG19301ST-5A">5a</A> Nagel M. Diploma Thesis   University of Zürich; Switzerland: 1998. 

<A NAME="RG19301ST-5B">5b</A> Nagel M. Hansen H.-J. Helv. Chim. Acta  2000,  83:  1022 

<A NAME="RG19301ST-5C">5c</A>

Typical Procedure: After evacuation of the apparatus with a high-vacuum oil pump, the starting material (typically 0.5-2 g) was distilled slowly (within 10-20 min, about 5-20 g/h) through the preheated reactor tube (contact times estimated at about 1-2 s). A flow of inert gas (N₂ or Ar) was adjusted from 15 mL/min to over 50 mL/min (1-3 L/h). At the end of the reactor unit the high boiling isomerization products were collected in the first cooling trap at about 0 °C (85-90% recovery), and the more volatile side products in subsequent traps, which were cooled to lower temperatures. By adding filling materials into the reactor, surface-catalyzed side reactions (e.g. dehydration) become predominant (cf. ref. [2b] and also ref. [13] ). For more general reviews on short contact time reactions and synthetic applications of gas phase flash vacuum pyrolysis techniques, see also:

<A NAME="RG19301ST-5D">5d</A> McNab H. Contemp. Org. Synth.  1996,  3:  373 ; and references therein

<A NAME="RG19301ST-5E">5e</A> Cadogen JIG. Hickson CL. McNab H. Tetrahedron  1986,  42:  2135 

<A NAME="RG19301ST-5F">5f</A> Schiess P. Thermochim. Acta  1987,  112:  31 ; and references therein

<A NAME="RG19301ST-5G">5g</A> Wiersum UE. Alrdrichimica Acta  1984,  17:  31 

For syntheses of 7, see e.g.:

<A NAME="RG19301ST-6A">6a</A> Galatsis P. Millan SD. Faber T. J. Org. Chem.  1993,  58:  1215 

<A NAME="RG19301ST-6B">6b</A> Bienz S. Hesse M. Helv.Chim. Acta  1987,  70:  2146 

<A NAME="RG19301ST-6C">6c</A> Drotloff H. Rotter H. Emeis D. Moeller M. J. Am. Chem. Soc.  1987,  109:  7797 

<A NAME="RG19301ST-6D">6d</A> Porter NA. Chang VH.-T. Magnin DR. Wright BT. J. Am. Chem. Soc.  1988,  110:  3554 

<A NAME="RG19301ST-6E">6e</A> Porter NA. Magnin DR. Wright BT. J. Am. Chem. Soc.  1986,  108:  2787 

<A NAME="RG19301ST-6F">6f</A> Wender PA. Sieburth McNS. Petraitis JJ. Singh SK. Tetrahedron  1981,  37:  3967 

<A NAME="RG19301ST-6G">6g</A> Karpf M. Dreiding AS. Helv. Chim. Acta  1975,  58:  2409 

<A NAME="RG19301ST-6H">6h</A> Mühlstädt M. Gräfe J. Chem. Ber.  1967,  100:  223 

<A NAME="RG19301ST-6I">6i</A> Müller E. Bauer M. Justus Liebigs Ann. Chem.  1962,  654:  92 

For syntheses of 9, see:

<A NAME="RG19301ST-7A">7a</A> Weiper-Idelmann A. Kahmen M. Schäfer HJ. Gockeln M. Acta Chem. Scand.  1998,  52:  672 

<A NAME="RG19301ST-7B">7b</A> Nishino M. Kondo H. Miyake A. Chem. Lett.  1973,  667 

<A NAME="RG19301ST-8A">8a</A> Ruzicka L. Helv. Chim. Acta  1926,  9:  245 

<A NAME="RG19301ST-8B">8b</A> Mathur HH. Bhattacharyya SC. J. Chem. Soc.  1963,  114 

<A NAME="RG19301ST-8C">8c</A> Motoda O. Chem. Abstr.  1950,  5828 

<A NAME="RG19301ST-8D">8d</A> Williams AS. Synthesis  1999,  1707 ; and references therein

<A NAME="RG19301ST-9A">9a</A> Baldwin JE. Vollmer HR. Lee V. Tetrahedron Lett.  1999,  40:  5401 

<A NAME="RG19301ST-9B">9b</A> Satoh T. Itoh N. Gengyo K. Takada S. Asakawa N. Tetrahedron  1994,  50:  11839 

<A NAME="RG19301ST-9C">9c</A> Hashimoto N. Aoyama T. Shioiri T. Chem. Pharm. Bull.  1982,  30:  119 

<A NAME="RG19301ST-9D">9d</A> Karpf M. Dreiding AS. Helv. Chim. Acta  1975,  58:  2409 

<A NAME="RG19301ST-9E">9e</A> Taguchi H. Yamamoto H. Nozaki H. J. Am. Chem. Soc.  1974,  96:  6510 

<A NAME="RG19301ST-9F">9f</A> Kirchhof W. Stumpf W. Franke W. Liebigs Ann. Chem.  1965,  681:  32 

<A NAME="RG19301ST-9G">9g</A> Parham WE. Sperley RJ. J. Org. Chem.  1967,  926 ; see also ref.

For leading references to Exaltone ^®(12), see:

<A NAME="RG19301ST-10A">10a</A> Fráter G. Bajgrowicz JA. Kraft P. Tetrahedron  1998,  54:  7633 

<A NAME="RG19301ST-10B">10b</A> Fráter G. Lamparsky D. In Perfumes: Art, Science and Technology   Müller PM. Lamparsky D. Elsevier; London, New York: 1991.  Chap. 20. p.533-555  

<A NAME="RG19301ST-10C">10c</A> Ohloff G. Helv. Chim. Acta  1992,  75:  2041 ; and literature cited therein

<A NAME="RG19301ST-10D">10d</A> Ohloff G. Riechstoffe und Geruchssinn. Die molekulare Welt der Düfte   Springer; Berlin: 1990.  Chap. 9. p.195-219  

<A NAME="RG19301ST-10E">10e</A> Mookherjee BD. Wilson RA. In Fragrance Chemistry: The Science of the Sense of Smell   Theimer ET. Academic Press; New York: 1982.  Chap. 12. p.433-494  

<A NAME="RG19301ST-10F">10f</A> Bienz S. Hesse M. Helv. Chim. Acta  1988,  71:  1704 ; see also ref.

<A NAME="RG19301ST-10G">10g</A> Suginome H. Yamada S. Tetrahedron Lett.  1987,  28:  3963 

<A NAME="RG19301ST-10H">10h</A> Feldhues M. Schäfer HJ. Tetrahedron  1986,  42:  1285 

<A NAME="RG19301ST-10I">10i</A> Mehta G. Rao KS. Tetrahedron Lett.  1984,  25:  1839 

<A NAME="RG19301ST-10K">10k</A> Fehr Ch. Helv. Chim. Acta  1983,  66:  2512 

<A NAME="RG19301ST-10L">10l</A> Kato T. Kondo H. Miyake A. Bull. Chem. Soc. Jpn.  1980,  53:  823 

<A NAME="RG19301ST-10M">10m</A> Karpf M. Dreiding AS. Helv. Chim. Acta  1977,  60:  3045 

To the best of our knowledge, this two-carbon ring enlargement procedure is one of the shortest repeatable ring expansion reactions applied to carbocyclic systems: Examples of preparatively useful and efficiently repeatable ring expansion reactions by more than one carbon atom in carbocyclic systems are only rarely reported in the literature. For a definition and examples, see:

<A NAME="RG19301ST-11A">11a</A> Heimgartner H. Chimia  1980,  34:  333 ; and references therein

<A NAME="RG19301ST-11B">11b</A> Hesse M. Ring Enlargement in Organic Chemistry   VCH; Weinheim, Germany: 1990.  Chap. 5. p.73-95  ; and references therein

<A NAME="RG19301ST-12">12</A> Thies RW. Billigmeier JE. J. Am. Chem. Soc.  1974,  96:  200 ; and references therein

<A NAME="RG19301ST-13A">13a</A> Failes RL. Stimson VR. In The Chemistry of the Hydroxy Group   Patai S. Wiley; Chichester: 1980.  Chap. 11. p.449-468  ; and references therein.

<A NAME="RG19301ST-13B">13b</A> Grignard V. Chambret F. C. R. Hebd. Acad.Sci.  1926,  182:  299 

<A NAME="RG19301ST-13C">13c</A> Holmes JL. Lossing FP. J. Am. Chem. Soc.  1982,  104:  2648 

<A NAME="RG19301ST-13D">13d</A> Chuchani G. Rotinov A. Dominguez R. Int. J. Chem. Kinet.  1999,  31:  401 

<A NAME="RG19301ST-14">14</A> For a recent general survey and leading references, see: Hudlicky T. Becker DA. Fan RL. Kozhushkov SI. In Houben-Weyl   Vol. E17c:  de Meijere A. Thieme; Stuttgart: 1997.  p.2538-2565  

See also:

<A NAME="RG19301ST-15A">15a</A> Gutsche CD. Redmore D. Carbocyclic Ring Expansion Reactions   Academic Press; New York: 1968.  Chap. 9. p.161-173  

<A NAME="RG19301ST-15B">15b</A> Gajewsky JJ. Hydrocarbon Thermal Isomerizations   Academic Press; New York: 1982.  p.81-87 and 177-185  

<A NAME="RG19301ST-15C">15c</A> Salaün J. In The Chemistry of the Cyclopropyl Group   Patai S. Rappoport Z. Wiley; New York: 1987.  p.809-878  

<A NAME="RG19301ST-15D">15d</A> Baldwin JE. In The Chemistry of the Cyclopropyl Group   Vol 2:  Rappoport Z. Wiley; Chichester: 1995.  p.469-494  

<A NAME="RG19301ST-15E">15e</A> Salaün J. Top. Curr. Chem.  2000,  207:  1-67  

<A NAME="RG19301ST-15F">15f</A> Trost BM. Bogdanowicz MJ. J. Am. Chem. Soc.  1973,  95:  5311 

<A NAME="RG19301ST-15G">15g</A> Salaün J. Ollivier J. Nouv. J. Chim.  1981,  5:  587 

<A NAME="RG19301ST-15H">15h</A> Salaün J. Chem. Rev.  1983,  83:  619 ; and references therein

For kinetic investigations, see:

<A NAME="RG19301ST-16A">16a</A> Trost BM. Scudder PH. J. Org. Chem.  1981,  46:  506 

<A NAME="RG19301ST-16B">16b</A> Mc Gaffin G. de Meijere A. Walsh R. Chem. Ber.  1991,  124:  939 ; and references therein.

For theoretical studies, see:

<A NAME="RG19301ST-17A">17a</A> Baldwin JE. J. Comput. Chem.  1998,  19:  222 

<A NAME="RG19301ST-17D">17d</A> Nendel M. Sperling D. Wiest O. Houk KN. J. Org. Chem.  2000,  65:  3259 

<A NAME="RG19301ST-18">18</A>

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)].

<A NAME="RG19301ST-19">19</A>

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

For 22 see:

<A NAME="RG19301ST-20A">20a</A> Leonhard NJ. Owens FH. J. Am. Chem. Soc.  1958,  80:  6039 

<A NAME="RG19301ST-20B">20b</A> Stork G. MacDonald TL. J. Am. Chem. Soc.  1975,  97:  1264 

For 24 see:

<A NAME="RG19301ST-21A">21a</A> Prelog V. Frenkiel L. Kobelt M. Barman P. Helv. Chim. Acta  1947,  30:  1741 

<A NAME="RG19301ST-21B">21b</A> Stoll M. Rouvé A. Helv. Chim. Acta  1947,  30:  1822 

<A NAME="RG19301ST-21C">21c</A> Zountsas J. Meier H. Liebigs Ann. Chem.  1982,  1366 

<A NAME="RG19301ST-21D">21d</A> Engman L. J. Org. Chem.  1988,  53:  4031 

<A NAME="RG19301ST-21E">21e</A> Tanaka K. Ushio H. Yasuyuki K. Suzuki H. J. Chem. Soc., Perkin Trans. 1  1991,  1445 

<A NAME="RG19301ST-21F">21f</A> Butlin RJ. Linney ID. Mahon MF. Tye H. Wills M. J. Chem. Soc., Perkin Trans. 1  1996,  95 ; selected spectroscopic data: For 22: ¹H NMR (300 MHz, CDCl₃): 6.83 (dt, J = 15.8, 7.4 Hz, 1 H), 6.20 (dt, J = 15.8, 1.3 Hz, 1 H), 2.53-2.48 (m, 2 H), 2.30-2.26 (m, 2 H), 1.80-1.67 (m, 2 H), 1.58-1.52 (m, 2 H), 1.45-1.2 (m, 14 H). ¹³C NMR (75 MHz, CDCl₃): 202.1 (s), 148.2, 130.3 (2 d), 40.4, 31.4, 26.6, 26.3, 26.2, 26.0, 25.8, 25.7, 25.4, 25.0, 24.9 (11 t). For 24: ¹H NMR (300 MHz, CDCl₃): 6.81 (td, J = 15.7, 7.5 Hz, 1 H), 6.19 (dt, J = 15.7, 1.3 Hz, 1 H), 2.52-2.47 (m, 2 H), 2.30-2.23 (m, 2 H), 1.72-1.44 (m, 4H), 1.4-1.2 (m, 16 H). ¹³C NMR (75 MHz, CDCl₃): 201.7 (s), 147.9, 130.7 (2 d), 40.0, 31.6, 26.9, 26.8, 26.7, 26.6, 26.5, 26.2, 26.0, 25.4, 25.2 (12 t).

Tetradecadienone 23 was found to be a naturally occurring compound in the defense secretions produced by soldier termites:

<A NAME="RG19301ST-22A">22a</A> Prestwich GD. Kaib M. Wood WF. Meinwald J. Tetrahedron Lett.  1975,  16:  4701 

<A NAME="RG19301ST-22B">22b</A> Spanton SG. Prestwich GD. Tetrahedron  1982,  38:  1921 

For examples of (±)-muscone syntheses via enone 24, see:

<A NAME="RG19301ST-23A">23a</A> Stoll M. Chimia  1948,  2:  217 

<A NAME="RG19301ST-23B">23b</A> Stoll M. Commarmont K. Helv. Chim. Acta  1948,  31:  554 

<A NAME="RG19301ST-23C">23c</A> Mookherjee BD. Patel RR. Ledig WR. J. Org. Chem.  1971,  36:  4124 

<A NAME="RG19301ST-23D">23d</A> Korzienowsky SH. Vanderbilt DP. Hendry LB. Org. Prep. Proced. Int.  1976,  8:  81 

<A NAME="RG19301ST-23E">23e</A> Nokami J. Kusumoto Y. Jinnai K. Kawada M. Chem. Lett.  1977,  715 

<A NAME="RG19301ST-23F">23f</A> Takahashi T. Nagashima T. Tsuij J. Tetrahedron Lett.  1981,  22:  1359 

<A NAME="RG19301ST-23G">23g</A> Sakane S. Maruoka K. Yamamoto H. Tetrahedron Lett.  1983,  24:  943 

<A NAME="RG19301ST-23H">23h</A> Asaoka M. Abe M. Takei H. Bull. Chem. Soc. Jpn.  1985,  58:  2145 

<A NAME="RG19301ST-23I">23i</A> Kabbara J. Flemming S. Nickisch K. Neh H. Westermann J. Chem. Ber.  1994,  127:  1489 

<A NAME="RG19301ST-23K">23k</A>

See also ref. [7a]

For asymmetric muscone syntheses from enone 24, see:

<A NAME="RG19301ST-24A">24a</A> Nelson KA. Mash EA. J. Org. Chem.  1986,  51:  2721 

<A NAME="RG19301ST-24B">24b</A> Tanaka K. Matsui J. Suzuki H. J. Chem. Soc., Perkin Trans 1  1993,  153 ; and references therein

<A NAME="RG19301ST-24C">24c</A> Tanaka K. Matsui J. Somemiya K. Suzuki H. Synlett  1994,  351 

<A NAME="RG19301ST-24D">24d</A> Yamaguchi M. Shiraishi T. Hirama M. J. Org. Chem.  1996,  61:  3520 

<A NAME="RG19301ST-24E">24e</A> Alexakis A. Benheim C. Fournioux X. Van den Heuvel A. Levêque J.-M. March S. Rosset S. Synlett  1999,  11:  1811 

<A NAME="RG19301ST-24F">24f</A> Alexakis A. Chimia  2000,  54:  55 

<A NAME="RG19301ST-25">25</A> Hiyama T. Mishima T. Kitatani K. Nozaki H. Tetrahedron Lett.  1974,  3297