A Novel and Highly Efficient Two-Carbon Ring Expansion

Article abstract of DOI:10.1021/ol035700y

(Equation presented) Dynamic gas-phase thermoisomerization (DGPTI) of medium- and large-ring 3-vinylcycloalkanones at 600-630°C produces isomeric γ,δ-unsaturated cycloalkanones expanded by two carbon atoms. A reaction mechanism involving an open-chain diradical intermediate, followed by intramolecular recombination under insertion of the vinyl group is proposed. Substituents on the vinyl moiety are transferred locospecifically to the ring-expanded ketones as corresponding β- and γ-substituents, respectively. The preparation of extraordinary cyclic allenes can be accomplished by DGPTI (540°C) of 3-ethinylcyclododecanone.

Full text of DOI:10.1021/ol035700y

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4211-4213
A Novel and Highly Efficient
Two-Carbon Ring Expansion
Georg Ru1edi,* Matthias Nagel,† and Hans-Ju1rgen Hansen
Organisch-Chemisches Institut der UniVersita¨t, 8057 Zu¨rich, Switzerland
georg@access.unizh.ch
Received September 5, 2003
ABSTRACT
Dynamic gas-phase thermoisomerization (DGPTI) of medium- and large-ring 3-vinylcycloalkanones at 600−630 °C produces isomeric γ,δ-
unsaturated cycloalkanones expanded by two carbon atoms. A reaction mechanism involving an open-chain diradical intermediate, followed
by intramolecular recombination under insertion of the vinyl group is proposed. Substituents on the vinyl moiety are transferred locospecifically
to the ring-expanded ketones as corresponding â- and γ-substituents, respectively. The preparation of extraordinary cyclic allenes can be
accomplished by DGPTI (540 °C) of 3-ethinylcyclododecanone.
Methods for expanding carbocyclic rings of different sizes
are important tools for the preparation of various biologically
active macrocyclic target molecules as well as synthetically
useful intermediates.1 We recently described the transforma-
tion of medium- and large-ring 1-vinylcycloalkanols into the
isomeric, ring-expanded bishomologous macrocyclic ketones
by means of dynamic gas-phase thermoisomerization (DGP-
TI) in a flow reactor at 650 °C.2 Promoted by the synthetic
and mechanistic importance associated with radical-mediated
ring expansion reactions,3 we report herein the first two-
carbon ring expansion reaction from 3-vinylcycloalkanones
1 to nicely functionalized ring-expanded 3-cycloalkenones
2 and the first studies of the scope and regiochemistry of
this remarkably efficient transformation.
The design of this new ring expansion reaction was based
on the mechanistic hypothesis outlined in Scheme 1.
Scheme 1
Considering the reactor temperatures of about 600 °C, initial
cleavage of the weakest single bond4 in molecule a would
result in the formation of a stabilized R-acyl ω-allyl diradical
species b.5 Intramolecular recombination within the open-
chain diradical intermediate would then be expected to occur
in the terminal vinylogous position, leading to the two-carbon
ring-expanded γ,δ-unsaturated cyclic ketone c. This se-
quence, corresponding to a nonconcerted thermal 1,3-C shift
† Swiss Federal Laboratories for Materials Testing and Research (EMPA),
CH-8600 Du¨bendorf, Switzerland.
(1) (a) Zhang, W.; Dowd, P. Tetrahedron Lett. 1996, 37, 957. (b) Hesse,
M. Ring Enlargement in Organic Chemistry; VCH: Weinheim, 1991. (c)
Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573. (d) Wovkulich, P. M. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamom Press: Oxford, 1991; Vol. 1, Chapter 3. (e) Gutsche, C. D.;
Redmore, D. Carbocyclic Ring Expansion Reactions; Academic Press: New
York, 1968.
(2) (a) Nagel, M.; Fra´ter, G.; Hansen, H.-J. Chimia 2003, 57, 196 and
references therein. (b) Nagel, M.; Fra´ter, G.; Hansen, H.-J. Synlett 2002,
275, 280.
(3) (a) Yet, L. Tetrahedron 1999, 55, 9649. (b) Dowd, P.; Zhang, W.
Chem. ReV. 1993, 93, 2091.
(4) (a) Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Org. Lett. 2003, 5, 2691. (b)
Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Synlett 2003, 1210.
(5) (a) McNab, H. Contemp. Org. Synth. 1996, 3, 373. (b) Cadogan, J.
I.; Hickson, C.; McNab, H. Tetrahedron 1986, 42, 2135.
10.1021/ol035700y CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/08/2003

reaction, generally allows the formation of both possible
diastereoisomers, i.e., the (E)- as well as the (Z)-forms.
We started our studies with 3-vinylcyclododecanone (1d),
which was easily prepared from R,â-unsaturated cyclodode-
canone by 1,4-addition of vinylmagnesium bromide in the
presence of cuprous iodide in 90% yield.6 Subjecting 1d to
DGPTI in a flow reactor system under reduced pressure (2-4
× 10-2 mbar) at 580 °C delivered ring-expanded 3-cyclotet-
radecenone 2d as a 1:1 mixture of (E)- and (Z)-isomers in
78% yield.7 Additional studies on the influence of the
reaction temperature on the thermal isomerization revealed
optimal conversion to occur at 600 °C providing 2d in 85%
yield.8 However, at higher temperatures (>600 °C), the
efficiency of the reaction decreases due to the formation of
decarbonylation products as well as complex product mix-
tures with mainly low molecular mass components.
Table 1. DGPTI of 3-Vinylcycloalkanones in Dependence of
the Ring Size
entry
n
product
T (°C)
yield (%)a
E/Z ratiob
1
2
3
4
5
6
8
a
b
c
d
e
f
630
620
610
600
600
600
ca. 5c
35d
6de
1.0
1.3
1.7
2.0
1.6
1.7
9
10
12
13
15
85e
87e
75d
a Based on isolated material. b E/Z ratio was determined by 1H NMR
spectroscopic analysis. c Not isolated. d Isolated as an E/Z mixture. e Both
(E)- and (Z)-forms could be separated by column chromatography.
To more fully explore the generality of this finding, we
systematically investigated the effect of the ring size on this
amazing transformation. In agreement with the results
obtained with substrate 1d, the homologous 3-vinylcyclo-
tridecanone 1e was thermally isomerized at 600 °C into
3-cyclopentadecenone 2e in 87% yield, which upon hydro-
genation quantitatively afforded the valuable macrocyclic
musk odorant cyclopentadecanone.9 The 17-membered γ,δ-
unsaturated compound 2f was easily obtained from 15-
membered ketone 1f in the same manner in good yields
(75%).10 In sharp contrast to the smoothly convertible
macrocyclic substrates 1d-f, thermolysis under the same
reaction conditions of medium ring-sized 3-vinylcycloal-
kanones 1b and 1c afforded the corresponding ring-expanded
products 2b and 2c, respectively, only in moderate yields
(entries 2 and 3). Almost no conversion could be detected
in the case of the eight-membered analogue 1a (entry 1),
even at elevated temperatures (>650 °C). However, besides
5% of the expected 3-cyclodecenone (2a), only starting
material and low-boiling fragmentation products could be
detected. The findings summarized in Table 1 reflect the ring
strain in the range of 8- to 17-membered carbocyclic systems.
In contrast to the smooth reaction conditions of cyclic
3-vinyl-substituted ketones, DGPTI of comparable acyclic
substrates under the same conditions, to yield open-chain
3-enones, yielded only low molecular weight products
(according to GC/MS analysis), which were not further
characterized. Also no reaction or only tar formation was
observed by heating 1d under static conditions in an ampule
at 400 °C.
To gain additional insight into regiochemical aspects and
to obtain a clear picture of how substituents on the alkene
moiety effect the isomerization process, we have further
studied the thermal behavior of selected γ-substituted cy-
clododecanones 3a-d (Table 2).11 In accord with the parent
Table 2. Influence of Methyl Substituents on the Vinyl Moiety
on DGPTI of 3-Vinylcyclododecanones
(6) Williams, D. R.; Benbow, J. W.; McNutt, J. G.; Allen, E. E. J. Org.
Chem. 1995, 60, 833.
(7) Both isomers could be separated by column chromatography and/or
by crystallization from 60:1 hexane/AcOEt.
R1
R2
R3
product T (°C) 4 yield (%)a 5 yield (%)a
(8) In a representative procedure, 3-vinylcyclododecanone (1d) (4.82 g,
23.14 mmol) was evaporated in a kugelrohr oven and directly distilled under
reduced pressure (2 mbar) through a preheated (600 °C) quartz tube (110
cm length, 3 cm i.d., contact time estimated at about 1-2 s) applying a
flow of N2 (1.4 L/h). At the outlet part of the reactor, the ring expansion
product was collected in a cooling trap (-196 °C). Purification by flash
chromatography (silica gel, 40:1 hexanes/ethyl acetate) gave (E)-2d (2.75
g, 57%) as a first fraction, followed by (Z)-2d (1.35 g, 28%). Both isomers
could be crystallized from 60:1 hexanes/ethyl acetate, affording colorless
needles. All new compounds were fully characterized.
CH3
H
H
H
a
b
c
d
600
580
580
590
87b
55c
46c
0
0
CH3/H H/CH3
10c
21b
38b
CH3 CH3/H H/CH3
CH3 CH3
H
a Based on isolated material. b As a 1:1 mixture of (E)- and (Z)-isomers.
c Exclusively (E)-isomer.
(9) For leading references on musk odorants, see: (a) Fra´ter, G.;
Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633. (b) Fra´ter, G.;
Lamparsky, D. In Perfumes: Art, Science and Technology; Mu¨ller, P. M.,
Lamparsky, D., Eds.; Elsevier: London, New York, 1991; Chapter 20, pp
533-555. (c) Ohloff, G. Riechstoffe und Geruchssinn. Die Molekulare Welt
der Du¨fte; Springer: Berlin, 1990; Chapter 9, pp 195-219. (d) Mookherjee,
B. D.; Wilson, R. A. In Fragrance Chemistry: The Science of the Sense of
Smell; Theimer, E. T., Ed.; Academic Press: New York, 1982; Chapter
12, pp 433-494.
structure 1d, DGPTI of 3-(isopropenyl)cyclododecanone (3a)
at 600 °C produced 4-methylcyclotetradec-4-enone (4a) as
(11) Compounds 3a-d were prepared in excellent yields (90-98%) by
conjugate 1,4-addition of the corresponding freshly prepared vinyllithium
reagents and cuprous iodide in ether at -78 °C, see: (a) Leonard, J.;
Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A. Tetrahedron 1995, 51,
12843. (b) Linstrumelle, G.; Krieger, J. K.; Whitesides, G. M. Org. Synth.
1976, 55, 103.
(10) Decrease in yield might be explained by side reactions taking place
in the kugelrohr oven (static conditions) during the evaporation process,
which requires higher temperatures for the rather high-boiling substrate 1f.
4212
Org. Lett., Vol. 5, No. 22, 2003

a 2:1 mixture of (E)- and (Z)-isomers (87%) that could easily
be separated by column chromatography or crystallization
from hexane. In remarkable contrast, a methyl substituent
at the terminal position of the vinyl moiety such as that
present in 3b,c led to the corresponding ring-expanded cyclic
ketones 4b,c (55 and 46%, respectively) only in (E)-
configuration along with open-chain methyl ketones 5b,c (10
and 21%, respectively), which are valuable intermediates in
synthesis but undesired products in the current study.
Interestingly, no 5,6-dihydro-2H-pyrane derivatives formed
via intramolecular hetero Diels-Alder reaction could be
detected.12 The starting materials 3b and 3c, respectively,
were mixtures of (E)- and (Z)-isomers. However, both pure
isomers react to give exclusively the corresponding (E)-
cycloalkenones 4b and 4c, respectively. Hydrogenation of
4b quantitatively afforded (()-normuscone. An additional
methyl group at the recombination center affected, as
expected, the course of the reaction: thermal isomerization
of 3-(2-methyl-1-propenyl)cyclododecanone (3d) at 590 °C
afforded only the thermodynamically most favorable open-
chain diene 5d (38%) besides a considerable amount of
recovered starting material.13 It seems that in this case, the
formed diradical of type b only undergoes recombination to
the starting material and disproportionation to the observed
diene 5d.14
Scheme 2. Diradical-Mediated Formation of a Cyclic Allene
6.15 DGPTI at 540 °C provided the extraordinary cyclic allene
7 in 56% yield (based on recovered starting material), which
showed in its IR spectrum a characteristic absorption at 1962
cm-1.16 In comparison with the vinyl analogues, rather low
temperatures were necessary for optimal conversion. More
elevated temperatures, however, resulted in the formation
of open-chain products and additional low-boiling side
products, which were not further characterized. In summary,
we have demonstrated the first example of a ring expansion
reaction of 3-vinyl/ethinyl-substituted medium- and large-
ring cycloalkanones to the isomeric bishomologous γ,δ-
unsaturated cyclic ketones by means of DGPTI. Moreover,
this method provides a novel strategy for the synthesis of
functionalized macrocyclic systems. Further synthetic studies
of DGPTI processes involving other substrates are in
progress.
These results demonstrate that substrates bearing a 1-pro-
penyl substituent adversely effect the facility of this reaction.
Furthermore, it could be established that the methyl substit-
uents on the vinyl moiety are transferred to the ring-expanded
products as corresponding â- and γ-substituents, respectively.
Finally, we have extended our investigations by varying
the C2-insertion unit starting from 3-ethinylcyclododecanone
Acknowledgment. This work was generously supported
by the Swiss National Science Foundation (SNF).
Supporting Information Available: Experimental condi-
tions and complete spectral data for all products of the ring
expansion reaction 2a-f, 4a-d, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Brouard, C.; Pornet, J.; Miginiac, L. Synth. Commun. 1994, 21, 3047.
(13) At temperatures below 590 °C, almost no conversion occurred,
whereas higher temperatures gave rise to a broad variety of low-boiling
products.
(14) In agreement with this finding, first experiments with optically active
(Z)-3b gave racemic 4b as well as racemic starting material (details will be
provided in an upcoming publication).
OL035700Y
(15) (a) Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson, T. J. Org. Chem.
1997, 62, 182. (b) Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson, T. J.
Org. Chem. 1993, 58, 7238.
(16) Johnson, R. P. Chem. ReV. 1989, 89, 1111.
Org. Lett., Vol. 5, No. 22, 2003
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