A novel, short and repeatable two-carbon ring expansion reaction by thermo-isomerization: Easy synthesis of macrocyclic ketones

Article abstract of DOI:10.1055/s-2002-19758

A novel two-carbon ring enlargement procedure, in which medium- and large-ring 1-vinylcycloalkanols are thermoisomerized 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.

Full text of DOI:10.1055/s-2002-19758

LETTER
275
A Novel, Short and Repeatable Two-Carbon Ring Expansion Reaction by
Thermo-Isomerization: Easy Synthesis of Macrocyclic Ketones
Novel and Repeatable
a
T
w
o
C
arbo
t
n Ring
t
Expans
h
ion Reaction
i
by
T
h
a
ermo-Isom
s
erization Nagel,*a Hans-Jürgen Hansen,a 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
Received 3 September 2001
O
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 cycloun-
decanone in two repetitive cycles. Thermo-isomerization of the cor-
responding ethynylic cycloalkanols gives in moderate yields the
bishomologous , -unsaturated macrocyclic (E)-2-cycloalkenones.
A reaction mechanism via alkyl hydroxyallyl biradical intermedi-
ates is proposed.
OH
OH
∆T
(FVP)
(CH2)n
(CH2)n
(CH2)n
H
H
"[1,5]H"
(?)
C
A
B
(only traces)
O
OH
OH
∆T
(FVP)
(CH2)n
(CH2)n
(CH2)n
"[1,3]C"
(?)
E
A
D
Key words: ring expansions, macrocyclic ketones, thermo-isomer-
ization, ring-insertion reactions, hydroxyallyl radicals
main product
n ≥ 5
Scheme 1
On search on new access to -campholenic derivatives by
pyrolysis of borneol precursors,1 a novel two-carbon ring
expansion reaction has been discovered.
ane solution at -20 °C or by column chromatography on
silica gel (eluant, hexane–t-BuOMe, 97:3-95:5).
The cyclic ketone 7 was directly used as the starting ma-
terial for a subsequent ring enlargement step, analogous to
the first expansion cycle. Indeed, allylic alcohol 8, ob-
tained from ketone 7,3 was transformed into the isomeric
16-membered homologous cycloalkanone7 9 in compara-
bly good yields by application of the same thermo-isomer-
ization conditions. This repeatable11 ring-enlargement
procedure4,5 was also applied to the corresponding vinyl-
cycloalkanols derived from odd-membered cyclic ketones
(Scheme 2). In this way, the 17-membered cycloalkanone
13 (“dihydrocivetone”)8 was obtained by three iterative
ring expansion cycles, starting from commercially avail-
able cycloundecanone via cyclotridecanone9 (11) and
cyclopentadecanone10 (12).
In our thermo-isomerization experiments with medium
and large ring-sized 1-vinylcycloalkan-1-ols of type A,
which were performed at temperatures in the range of
600-650 °C, we obtained not the expected open-chain alk-
enone isomers C (hypothetically formed via an intramo-
lecular [1,5]H shift reaction2 and the subsequent enol
intermediate B). Instead the ring-expanded isomeric cy-
clic ketones E were formed as the main products in good
yields. According to Scheme 1, the reaction pathway for
the formation of ketones E from allylic alcohols A would
formally include the reorganization of the involved bonds,
which corresponds to a [1,3]C shift reaction via enol inter-
mediate D.
Thermo-isomerization of 1-vinylcyclododecanol3,4
6
No reaction or only the formation of olefins was observed
previously when 4 was submitted to a static thermolysis at
420 °C.12 The thermo-isomerization of the same alcohol 4
under the dynamic high temperature conditions which we
applied in our experiments, proceeded smoothly to give
the bishomologous cycloalkanone 5 in excellent average
yields of more than 80% (Scheme 2). We also tested the
transformation of vinylcyclooctanol (2) into cyclode-
canone (3). However, the corresponding isomerization
experiments under different conditions gave only moder-
ate conversion rates. Besides ca. 50% recovered starting
material plus further dehydration and disproportionation
products, the expected ketone 3 was formed in yields of
(which is derived in one step from ketone 5 by addition of
vinylmagnesium reagent) in a flow reactor system5 under
reduced pressure (1-4 mbar) and at temperatures around
650 °C gave directly cyclotetradecanone (7) in average
yields of 75% (Scheme 2).6 Cycloalkanone 7 could easily
be separated from by-products (mostly more volatile and
less polar alkene fractions formed by dehydration of the
starting material) either by crystallization of 7 from hex-
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0275,0279,ftx,en;G19301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

276
M. Nagel et al.
LETTER
ponents, apparently generated by predominantly destruc-
tive fragmentation processes of the “retro-Grignard” type
(mainly formation of alkenes, polymers, tars).13
O
O
HO
b)
a)
12
14
12
Destructive fragmentation
OH
Complex product mixture
5
6
(Alkenes, polymers, tars)
7
(80 - 90%)
14
(70 - 80%)
(75 - 90%)
Scheme 3 Conditions: Flash vacuum pyrolysis (FVP, 650 °C, 1–
4 mbar, N2 flow)
a)
b)
Repeatable
Ring
Enlargement
Reaction
HO
HO
With regard to the reactor temperatures of more than
about 600 °C that are necessary for the thermo-isomeriza-
tion processes, a plausible pathway for the reaction in-
volves a biradical intermediate5b in analogy to the well
investigated vinylcyclopropane-to-cyclopentene rear-
rangement.14–17
14
10
O
4
8
8
1
b)
OH
O
a)
OH
a)
O
(CH2)n
(CH2)n
(CH2)n
O
HO
8
17
15
homolysis
18
16
= two carbon insertion
(main products)
b)
recombination
(→ [1.3]C shift)
10
O
OH
3
2
9
(70 - 80%)
disproportionation
(hydrogen transfer)
(CH2)n
(CH2)n
16
1,ω-diradical
19
OH
= fragmentation
(sideproducts)
O
O
O
a)
a)
b)
b)
(CH2)9
(CH2)11
(CH2)13
(CH2)15
b)
Scheme 4
65%
10
11
12
13
70%
75%
According to the mechanism shown in Scheme 4, a ho-
molytic cleavage of the C(1)-C(2) bond in 15 results in an
open-chained biradical intermediate 16 with an alkyl rad-
ical at the one end and a resonance-stabilized hydroxyallyl
species at the opposite of the chain. Intramolecular recom-
bination of the biradical 16 in the terminal vinylogous po-
sition leads via the ring-expanded cyclic enol intermediate
17 and subsequent tautomerization to the cycloalkanones
18 as a formal [1,3]C shift product under insertion of the
C2-unit of the former vinylic side chain. Intramolecular
hydrogen abstraction reaction within the biradical inter-
mediate 16 (disproportionation by H-transfer) leads to
open-chain vinyl alkyl ketone derivatives6a 19, which are
also identified as rearranged by-products with identical
molecular masses in the thermo-isomerization reactions.18
Scheme 2 Reagents and Conditions: a) 1. Anhyd CeCl3, THF, r.t.,
0.5 h; 2. Vinyl magnesium bromide (THF solution.), 25 °C, 0.5 h. b)
Dynamic gas phase thermo-isomerization (DGPTI, FVP conditions,
650 °C, 1–4 mbar, N2 flow).
only 25–30%. Whereas experiments with prolonged con-
tact times in the flow reactor system led only to an in-
crease of the undesired dehydration products,5 the yields
of 3 could be raised significantly when the crude isomer-
ization mixture was subjected to the thermo-isomerization
process at least a second time (recycling procedure).
However, only starting material and dehydration products
were obtained, when the corresponding six- or seven-
membered ring systems were subjected to the same reac-
tion conditions.
The dynamic thermo-isomerization procedure is also ap-
plicable to 1-ethynyl cycloalkanols (Scheme 5), e.g. 20
and 21, which are easily accessible in excellent yields
from the correspondig cyclic ketones by CeCl3 mediated
addition of ethynyl magnesium bromide.19 The product
mixtures contained the , -unsaturated ring-expanded cy-
clic ketones 22 and 24, respectively,20,21 in about 20-25%
In sharp contrast to the smooth rearrangement reactions of
the macrocyclic vinylcycloalkanols, the thermolysis ex-
periments involving comparable acyclic (open-chained)
allylic alcohols, such as 14 (Scheme 3),4 resulted, under
the same reaction conditions, in the formation of complex
product mixtures with mainly low molecular mass com-
Synlett 2002, No. 2, 275–279 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel, Short and Repeatable Two-Carbon Ring Expansion Reaction by Thermo-Isomerization
277
yields, besides nearly equal amounts of the open-chained Useful extensions in the application of this novel ring-ex-
, -dienone isomers22 23 and 25, respectively. Highly panding bishomologation methodology by thermo-
volatile by-products and also the starting saturated ke- isomerization reactions to the synthesis of alkyl substitut-
tones 5 and 11, respectively, which seem to be the prod- ed macrocyclic ketones, e.g. a new short and straightfor-
ucts of a retro-Grignard fragmentation process at the high ward synthesis of ( )-muscone, will be presented in a
reactor temperatures, have been observed. The NMR subsequent communication.
spectra show that the 2-cycloalkenones 22 and 24, respec-
tively, which were separated by column chromatography
Acknowledgement
from the thermolysates, possess the thermodynamically
favorable (E)-configuration.20,21
Financial support of this work by a grant from the Givaudan Rese-
arch Ltd, Dübendorf (Switzerland) to MN is gratefully acknowled-
ged. We also thank W. Eisele and K. Hochreutener (mechanic and
electronic workshops of the Organisch-chemisches Institut) for pro-
fessional support in the planning and construction of the prototype
thermo-isomerization apparatus. The assistance of Dr. A. Linden
with proof-reading of this manuscript is gratefully acknowledged.
MN is also indebted to Dr. Ch. Weymuth for stimulating discussi-
ons during this work.
O
O
HO
O
a)
(E)
+
(CH2)n
(CH2)n
+
(CH2)n
(CH2)n
20 n = 8
21 n = 9
(20 - 25%)
(15 - 25%)
(20 - 25%)
n = 8
22 n = 8
24 n = 9
23 n = 8
25 n = 9
5
11 n = 9
References
(1) Nagel, M. Ph.D. Thesis; University of Zürich: Switzerland,
2001.
OH
OH
(2) For examples of so-called “internal” (or also
H
H
22
24
“intramolecular”) [1,5]-H shift reactions of the general retro-
ene type under flash thermolysis conditions, see :
H
(a) Rippol, J.-L.; Vallée, Y. Synthesis 1993, 659.
(path a)
(b) Brown, R. F. C. In Pyrolytic Methods in Organic
Chemistry; Wasserman, R. H., Ed.; Academic Press: New
York, 1980, Chap. 7, 229–246; and references therein.
(c) Gajewski, J. J. Hydrocarbon Thermal Isomerizations;
Academic Press: New York, 1981. (d) Karpf, M. Angew.
Chem., Int. Ed. Engl. 1986, 25, 414; Angew. Chem. 1986, 98,
413; and references therein.
OH
OH
H
23
25
(path b)
b
H
H
a
H
(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.
b)
c)
d)
a)
11
10
O
11
24
21
e)
refs. 21,22
O
ref. 23
(4) (a) Dimitrov, V.; Bratovanov, S.; Simova, S.; Kostova, K.
Tetrahedron Lett. 1994, 35, 6713. (b) 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
7
15
12
muscone
Exaltone®
Scheme 5 Reagents and conditions: a) Dynamic gas phase thermo-
isomerization (FVP conditions, 640–670 °C, 1–4 mbar, N2 flow). b)
1. Anhyd CeCl3, r.t., 0.5 h; 2. vinyl magnesium bromide (THF soluti-
on), 25 °C, 0.5 h (85–95%). c) Cf. Scheme 2. d) 1. Anhyd CeCl3, r.t.,
0.5 h; 2. ethynyl magnesium bromide (THF solution), 25 °C, 0.5 h
(90–95%). e) H2, Pd/C ( quant.).
The musk odorant cyclopentadecanone 12 (Exaltone®, cf.
Scheme 2)10 can easily be obtained from 2-cyclopentade-
cenone 24 by catalytic hydrogenation. On the other hand,
24 is the well established direct precursor for the synthesis
of the valuable musk odorant muscone (3-methylcyclo-
pentadecanone) which is easily accessible from 24 by re-
ported short procedures.23,24 The straightforward
synthesis of muscone-precursor 24 starting from commer-
cial available cycloundecanone via cyclotridecanone (11)
as intermediate is outlined in Scheme 5. A muscone syn-
thesis via a one-carbon homologation with cyclotetrade-
canone 7 as the precursor ketone was also reported
earlier.25
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278
M. Nagel et al.
LETTER
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: (c) Marcou, A.; Normant, H. Bull. Soc. Chim. Fr. 1965,
3491. (d) Herz, W.; Juo, R.-R. J. Org. Chem. 1985, 50, 618.
(e) Ref. 6a.
(8) (a) Ruzicka, L. Helv. Chim. Acta 1926, 9, 245. (b) Mathur,
H. H.; Bhattacharyya, S. C. J. Chem. Soc. 1963, 114.
(c) Motoda, O. Chem. Abstr. 1950, 5828. (d) Williams, A.
S. Synthesis 1999, 1707; and references therein.
(9) (a) Baldwin, J. E.; Vollmer, H. R.; Lee, V. Tetrahedron Lett.
1999, 40, 5401. (b) Satoh, T.; Itoh, N.; Gengyo, K.; Takada,
S.; Asakawa, N. Tetrahedron 1994, 50, 11839.
(c) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm.
Bull. 1982, 30, 119. (d) Karpf, M.; Dreiding, A. S. Helv.
Chim. Acta 1975, 58, 2409. (e) Taguchi, H.; Yamamoto, H.;
Nozaki, H. J. Am. Chem. Soc. 1974, 96, 6510. (f) Kirchhof,
W.; Stumpf, W.; Franke, W. Liebigs Ann. Chem. 1965, 681,
32. (g) Parham, W. E.; Sperley, R. J. J. Org. Chem. 1967,
926; see also ref.6f,g
.
(10) For leading references to Exaltone®(12), see: (a) Fráter, G.;
Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633.
(b) Fráter, G.; Lamparsky, D. In Perfumes: Art, Science and
Technology; Müller, P. M.; Lamparsky, D., Eds.; Elsevier:
London, New York, 1991, Chap. 20, 533–555. (c) Ohloff,
G. Helv. Chim. Acta 1992, 75, 2041; and literature cited
therein. (d) Ohloff, G. Riechstoffe und Geruchssinn. Die
molekulare Welt der Düfte; Springer: Berlin, 1990, Chap. 9,
195–219. (e) Mookherjee, B. D.; Wilson, R. A. In
(5) 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) Nagel, M.
Diploma Thesis; University of Zürich: Switzerland, 1998.
(b) Nagel, M.; Hansen, H.-J. Helv. Chim. Acta 2000, 83,
1022. (c) 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: (d) McNab, H. Contemp. Org. Synth. 1996, 3, 373;
and references therein. (e) Cadogen, J. I. G.; Hickson, C. L.;
McNab, H. Tetrahedron 1986, 42, 2135. (f) Schiess, P.
Thermochim. Acta 1987, 112, 31; and references therein.
(g) Wiersum, U. E. Alrdrichimica Acta 1984, 17, 31.
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Faber, T. J. Org. Chem. 1993, 58, 1215. (b) Bienz, S.;
Hesse, M. Helv.Chim. Acta 1987, 70, 2146. (c)Drotloff,H.;
Rotter, H.; Emeis, D.; Moeller, M. J. Am. Chem. Soc. 1987,
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(e) Porter, N. A.; Magnin, D. R.; Wright, B. T. J. Am. Chem.
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1962, 654, 92.
Fragrance Chemistry: The Science of the Sense of Smell;
Theimer, E. T., Ed.; Academic Press: New York, 1982,
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Acta 1988, 71, 1704; see also ref.6b. (g) Suginome, H.;
Yamada, S. Tetrahedron Lett. 1987, 28, 3963. (h)Feldhues,
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3045.
(11) 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) Heimgartner, H.
Chimia 1980, 34, 333; and references therein. (b) Hesse, M.
Ring Enlargement in Organic Chemistry; VCH: Weinheim,
Germany, 1990, Chap. 5, 73–95; and references therein.
(12) Thies, R. W.; Billigmeier, J. E. J. Am. Chem. Soc. 1974, 96,
200; and references therein.
(13) (a) Failes, R. L.; Stimson, V. R. In The Chemistry of the
Hydroxy Group; Patai, S., Ed.; Wiley: Chichester, 1980,
Chap. 11, 449–468; and references therein.. (b) Grignard,
V.; Chambret, F. C. R. Hebd. Acad.Sci. 1926, 182, 299.
(c) Holmes, J. L.; Lossing, F. P. J. Am. Chem. Soc. 1982,
104, 2648. (d) Chuchani, G.; Rotinov, A.; Dominguez, R.
Int. J. Chem. Kinet. 1999, 31, 401.
(14) For a recent general survey and leading references, see:
Hudlicky, T.; Becker, D. A.; Fan, R. L.; Kozhushkov, S. I. In
Houben-Weyl, Vol. E17c; de Meijere, A., Ed.; Thieme:
Stuttgart, 1997, 2538–2565.
(15) See also: (a) Gutsche, C. D.; Redmore, D. Carbocyclic Ring
Expansion Reactions; Academic Press: New York, 1968,
Chap. 9, 161–173. (b) Gajewsky, J. J. Hydrocarbon
Thermal Isomerizations; Academic Press: New York, 1982,
81–87 and 177-185. (c) Salaün, J. In The Chemistry of the
Cyclopropyl Group; Patai, S.; Rappoport, Z., Eds.; Wiley:
New York, 1987, 809–878. (d) Baldwin, J. E. In The
Chemistry of the Cyclopropyl Group, Vol 2; Rappoport, Z.,
(7) For syntheses of 9, see: (a) Weiper-Idelmann, A.; Kahmen,
M.; Schäfer, H. J.; Gockeln, M. Acta Chem. Scand. 1998, 52,
672. (b) Nishino, M.; Kondo, H.; Miyake, A. Chem. Lett.
1973, 667.
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LETTER
A Novel, Short and Repeatable Two-Carbon Ring Expansion Reaction by Thermo-Isomerization
279
Ed.; Wiley: Chichester, 1995, 469–494. (e) Salaün, J. Top.
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)..
(22) Tetradecadienone 23 was found to be a naturally occurring
compound in the defense secretions produced by soldier
termites: (a) Prestwich, G. D.; Kaib, M.; Wood, W. F.;
Meinwald, J. Tetrahedron Lett. 1975, 16, 4701.
Curr. Chem. 2000, 207, 1–67. (f) Trost, B. M.;
Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5311.
(g) Salaün, J.; Ollivier, J. Nouv. J. Chim. 1981, 5, 587.
(h) Salaün, J. Chem. Rev. 1983, 83, 619; and references
therein.
(16) For kinetic investigations, see: (a) Trost, B. M.; Scudder, P.
H. J. Org. Chem. 1981, 46, 506. (b) Mc Gaffin, G.; de
Meijere, A.; Walsh, R. Chem. Ber. 1991, 124, 939; and
references therein..
(17) For theoretical studies, see: (a) Baldwin, J. E. J. Comput.
Chem. 1998, 19, 222. (b) Nendel, M.; Sperling, D.; Wiest,
O.; Houk, K. N. J. Org. Chem. 2000, 65, 3259.
(b) Spanton, S. G.; Prestwich, G. D. Tetrahedron 1982, 38,
1921.
(18) A mechanism via a free radical reaction is also involved in a
recent two-carbon ring expansion procedure where a
homolytic -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, Htrans-C(1)], 5.80 [dd, J = 10, 1.5, Hcis-
C(1)], 2.60 [t, J = 7.5, H2-C(4)]; 0.90-0.85 (t-type m), [H3C-
( )]. 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( )].
(23) For examples of ( )-muscone syntheses via enone 24, see:
(a) Stoll, M. Chimia 1948, 2, 217. (b) Stoll, M.;
Commarmont, K. Helv. Chim. Acta 1948, 31, 554.
(c) Mookherjee, B. D.; Patel, R. R.; Ledig, W. R. J. Org.
Chem. 1971, 36, 4124. (d) Korzienowsky, S. H.; Vanderbilt,
D. P.; Hendry, L. B. Org. Prep. Proced. Int. 1976, 8, 81.
(e) Nokami, J.; Kusumoto, Y.; Jinnai, K.; Kawada, M.
Chem. Lett. 1977, 715. (f) Takahashi, T.; Nagashima, T.;
Tsuij, J. Tetrahedron Lett. 1981, 22, 1359. (g) Sakane, S.;
Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1983, 24,
943. (h) Asaoka, M.; Abe, M.; Takei, H. Bull. Chem. Soc.
Jpn. 1985, 58, 2145. (i) Kabbara, J.; Flemming, S.;
Nickisch, K.; Neh, H.; Westermann, J. Chem. Ber. 1994,
127, 1489. (j) See also ref.7a
(19) Addition of a ethynyl magnesium bromide solution in
analogy to ref.4
(20) For 22 see: (a) Leonhard, N. J.; Owens, F. H. J. Am. Chem.
Soc. 1958, 80, 6039. (b) Stork, G.; MacDonald, T. L. J. Am.
Chem. Soc. 1975, 97, 1264.
(21) For 24 see: (a) Prelog, V.; Frenkiel, L.; Kobelt, M.; Barman,
P. Helv. Chim. Acta 1947, 30, 1741. (b) Stoll, M.; Rouvé,
A. Helv. Chim. Acta 1947, 30, 1822. (c) Zountsas, J.; Meier,
H. Liebigs Ann. Chem. 1982, 1366. (d) Engman, L. J. Org.
Chem. 1988, 53, 4031. (e) Tanaka, K.; Ushio, H.; Yasuyuki,
K.; Suzuki, H. J. Chem. Soc., Perkin Trans. 1 1991, 1445.
(f) Butlin, R. J.; Linney, I. D.; Mahon, M. F.; 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
(24) For asymmetric muscone syntheses from enone 24, see:
(a) Nelson, K. A.; Mash, E. A. J. Org. Chem. 1986, 51,
2721. (b) Tanaka, K.; Matsui, J.; Suzuki, H. J. Chem. Soc.,
Perkin Trans 1 1993, 153; and references therein.
(c) Tanaka, K.; Matsui, J.; Somemiya, K.; Suzuki, H. Synlett
1994, 351. (d) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J.
Org. Chem. 1996, 61, 3520. (e) Alexakis, A.; Benheim, C.;
Fournioux, X.; Van den Heuvel, A.; Levêque, J.-M.; March,
S.; Rosset, S. Synlett 1999, 11, 1811. (f) Alexakis, A.
Chimia 2000, 54, 55.
(25) Hiyama, T.; Mishima, T.; Kitatani, K.; Nozaki, H.
Tetrahedron Lett. 1974, 3297.
Synlett 2002, No. 2, 275–279 ISSN 0936-5214 © Thieme Stuttgart · New York