Diradical-promoted (n + 2 - 1) ring expansion: An efficient reaction for the synthesis of macrocyclic ketones

Article abstract of DOI:10.1021/ol048701e

(Chemical Equation Presented) A diradical-promoted (n + 2 - 1) ring expansion reaction based on vinyl side chain insertion (+2C) and decarbonylation (-1C) has been developed. Flash vacuum pyrolysis (FVP) of medium- and large-ring 2-trimethylsilyloxy-2-vinyl-cycloalkanones at 500-600°C affords the one-carbon ring-expanded cycloalkanones in good yields. Methyl groups on the vinyl moiety are transformed regiospecifically as corresponding α- and β-substituents, respectively. 2-Ethynyl precursor analogues react in a manner similar to give α,β-unsaturated cyclic ketones.

Full text of DOI:10.1021/ol048701e

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3179-3181
Diradical-Promoted (n + 2 − 1) Ring
Expansion: An Efficient Reaction for
the Synthesis of Macrocyclic Ketones
Georg Ru1edi,* Matthias A. Oberli, Matthias Nagel,† and Hans-Ju1rgen Hansen
Organisch-chemisches Institut der UniVersita¨t, 8057 Zu¨rich, Switzerland
georg@access.unizh.ch
Received July 7, 2004
ABSTRACT
A diradical-promoted (n + 2 − 1) ring expansion reaction based on vinyl side chain insertion (+2C) and decarbonylation (−1C) has been
developed. Flash vacuum pyrolysis (FVP) of medium- and large-ring 2-trimethylsilyloxy-2-vinyl-cycloalkanones at 500−600 °C affords the one-
carbon ring-expanded cycloalkanones in good yields. Methyl groups on the vinyl moiety are transformed regiospecifically as corresponding
r- and â-substituents, respectively. 2-Ethynyl precursor analogues react in a manner similar to give r,â-unsaturated cyclic ketones.
The design and development of synthetic methods providing
access to functionalized macrocyclic target molecules by
means of free-radical-mediated ring expansion represents a
major challenge in contemporary organic synthesis.1 Among
these processes the class of reactions running through
diradical intermediates is very sparsely populated. Apart
from the well-established vinylcyclopropane-to-cyclopentene
rearrangement2 only very few examples involving confor-
mationally or otherwise constrained substrates have been
reported so far.3 Considering the significance of function-
alized medium- and large-ring carbocyclic systems, we have
initiated a program directed at developing diradical-mediated
ring expansion reactions by means of flash vacuum pyrolysis
(FVP). These investigations have thus far produced funda-
mentally new two-4 and three-carbon ring expansions5
suitable for the synthesis of such compounds. In continuation
of these studies, we describe herein a remarkable one-carbon
ring expansion and its application to the synthesis of muscone
and related macrocyclic ketones.
Recently, we have reported that 1-vinylcycloalkanols (1a)
undergo clean homolysis of the weakest single bond when
submitted to FVP at 650 °C (Scheme 1).4a,b Recombination
within the generated diradical intermediate 2a provided the
two-carbon ring-expanded ketones 3a in good-to-excellent
yields.6 On the basis of this finding, we envisioned that
2-hydroxy-2-vinylcycloalkanones (1b) having an adjacent
carbonyl group would react in a similar manner to give an
open-chain R-hydroxyallyl ω-acyl intermediate 2b, which
under the high thermal impact would immediately loose
carbon monoxide. Driven by ring strain release gained by
† Current address: Swiss Federal Laboratories for Materials Testing and
Research (EMPA), CH-8600 Du¨bendorf, Switzerland.
(1) For reviews, see: (a) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93,
2091. (b) Yet, L. Tetrahedron 1999, 55, 9649. (c) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2224.
(2) For a recent review, see: Baldwin, J. E. Chem. ReV. 2003, 103, 1197.
(3) (a) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078. (b)
Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3517. (c) Muthuramu,
K.; Sundari, B.; Ramamurthy, V. J. Org. Chem. 1983, 48, 4482. (d) Sarobe,
M.; Kwint, H. C.; Fleer, T.; Hevenith, R. W. A.; Jenneskens, L. W.;
Vlietstra, E. J.; Van Lenthe, J. H.; Wesseling, J. Eur. J. Org. Chem. 1999,
5, 1191. (e) Paquette, L. A.; Zhao, Z.; Gallou, F.; Liu, J. J. Am. Chem. Soc.
2000, 122, 1540. (f) von Doering, W.; Cheng, Y.; Lee, K.; Lin, Z. J. Am.
Chem. Soc. 2002, 124, 11642.
(4) (a) Nagel, M.; Fra´ter, G.; Hansen, H.-J. Synlett 2002, 275. (b) Nagel,
M.; Fra´ter, G.; Hansen, H.-J. Synlett 2002, 280. (c) Ru¨edi, G.; Nagel, M.;
Hansen, H.-J. Org. Lett. 2003, 5, 4211.
(5) (a) Ru¨edi, G.; Hansen, H.-J. Tetrahedron Lett. 2004, 45, 5143. (b)
Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Org. Lett. 2004, 6, in press.
(6) In a recent paper, we provided evidence that vinyl insertion occurs
via open-chain diradical intermediate states, rather than via formally
disallowed 1,3-sigmatropoic shifts; see: Ru¨edi, G.; Hansen, H.-J. HelV.
Chim. Acta 2004, 87, 1628.
10.1021/ol048701e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/10/2004

In an effort to determine whether the product ratio could
be shifted to the desired one-carbon ring expansion product
7, the effect of the reaction temperature and the role of a
protecting group were investigated (Table 1). A temperature
Scheme 1
Table 1. Temperature and Protecting Group Effects
entry
R
T (°C) 7 (% yield) 8 (% yield) 9 (% yield)
1
2
3
4
5
6
7
8
9
H
H
H
TMS
TMS
TMS
TMS
TMS
TMS
500
560
600
520
540
560
580
600
480
26
38
46
48a
59a
68a
75a
73a
31a
28
26
22
44
27
5
0
0
0
0
0
0
48a
36a
25a
14a
6a
passing to increasingly large ring systems the resulting
R-hydroxyallyl ω-alkyl diradical 4 would ring expand to an
enol ether precursor, from which the cyclic ketone 5 would
be derived by an overall (n + 2 - 1) ring expansion.
We started our investigations with 2-hydroxy-2-vinylcy-
clododecanone (6a), which was readily prepared by vinyl-
magnesium bromide addition to cyclododecane-1,2-dione.7
As illustrated in Scheme 2, FVP of 6a at 500 °C and 2-4
51a
a After treatment of the crude silylenonl ether precursor with 1% HCl in
EtOH.
increase from 500 to 560 °C was found to be only marginally
beneficial. The unwanted 1,4-diketone 8 proved to be rather
unaffected while the yield of 9 decreased in favor of 7 (entry
2). As depicted in Scheme 2, the higher yield of 7 may be
ascribed to decarbonylation of initially formed 1,2-dione 9
under increasingly high reactor temperatures (g560 °C).9
This effect was found to be even more pronounced at 600
°C (entry 3).10
Scheme 2. FVP of 2-Hydroxy-2-vinylcylcododecanone 6a
To suppress competing C2-C3 bond breakage the tertiary
alcohol functionality was protected with a TMS group.
Hence, subjecting silyl ether 6b to FVP at 520 °C provided
upon hydrolysis (1% HCl in EtOH) of the resulting silylenol
ether intermediates a 1:1 mixture of 7 and 8 in 96% combined
yield with no traces of 9 (entry 4).11 Gradually increasing
the temperature by 20 °C steps eventually led to a value of
580 °C at which the conversion to cyclotridecanone (2) was
found be optimal (entry 7). On the other hand 1,4-diketone
8 could be obtained in 51% yield when the reaction was
conducted at 480 °C (entry 9).12 This finding suggested that
the formation of 7 might also involve decarbonylation of
the initially formed silylenol ether precursor of 8. Indeed,
FVP of an independently synthesized sample of (E/Z)-4-
trimethylsilyloxycyclotetradec-3-enone (8′) at 600 °C af-
forded upon hydrolysis cyclotridecanone (7) in 60% yield,
whereas FVP at 480 °C resulted in essentially no reaction.
× 10-2 mbar produced three products, 7-9, in 98%
combined yield (GC). Apart from the expected one-carbon
ring-expanded cyclotridecanone 7 (26%), the other compo-
nents turned out to be 14-membered 1,4-dione 8 (28%) and
1,2-dione 9 (44%), respectively. Apparently, the formation
of 8 involves the insertion of the vinyl moiety in diradical
intermediate 2b before CO can leave the molecule. On the
other hand, the additional five-membered ring, formed by
the intramolecular hydrogen bridge in 2-hydroxy ketone 6a,8
makes the C1-C2 bond breakage a bit more difficult, thus
allowing for partial C2-C3 cleavage to give 1,2-dione 9.
(7) In connection with this study, we have developed a practical and
user-friendly method for the selenium-free one-step preparation of 1,2-
diketones by treating the corresponding cycloalkanones with sodium nitrite
and HCl in THF at low temperatures.
With optimized conditions in hand, the next issue to be
addressed was the effect of the ring size on the (n + 2 - 1)
(8) The 1H NMR showed a low field shifted singlet at 4.19 ppm
accounting for a OH group being part of a hydrogen bridge.
3180
Org. Lett., Vol. 6, No. 18, 2004

ring expansion reaction. Toward this end, a series of cyclic
2-trimethylsilyloxy-2-vinyl precursors 10a-c was submitted
to FVP (Table 2, entries 1-3). The reactions proceeded
tionality for an isopropenyl group resulted in slightly lower
yield, providing a 5:1 mixture of 2-methylcyclotridecanone
(11f) and 2-methylcyclotetradecane-1,4-dione (12f) (entry 6).
Best results were obtained in the case of 10g, which upon
FVP at 580 °C and subsequent hydrolysis produced 2,3-
dimethylcyclotridecanone 11g in 81% yield (entry 7). In
remarkable contrast to previous studies, the gem-dimethyl
group on the recombination center in substrate 10h did not
adversely affect the course of the reaction in terms of
producing open chain disproportionation products via in-
tramolecular hydrogen abstraction.16 Instead, the desired 3,3-
dimethyl ketone 11h was formed in 70% yield accompanied
with its 1,4-dione counterpart 12h (14%) (entry 8).
Table 2. Ring Size and Substituent Effects
A final study was directed at whether 2-ethynyl analogue
13 might react under FVP in a similar manner to yield the
corresponding R,â-unsaturated ketones. As illustrated in
Scheme 3, pyrolysis of 13 at 540 °C produced a 1:1 mixture
T
11
12
entry
n
R1
R2
R3
(°C)a (% yield) (% yield)
1
2
3
4
5
6
7
8
10
11
15
12
14
12
12
12
a
b
c
d
e
f
H
H
H
H
H
CH3
H
H
H
H
H
H
590
580
560
560
570
580
580
580
63
71
70
71
73
60
81c
70
12
17
18
15
19
12
11c
14
b
b
CH3/H H/CH3
CH3/H H/CH3
Scheme 3
H
H
b
g
h
CH3 CH3/H H/CH3
CH3 CH3
H
a Optimized temperature. b Substrate used as a 1:1 mixture of (E/Z)-
isomers. c Obtained as a 1:1 mixture of diastereoisomers.
equally well to give after hydrolysis of the crude product
mixtures the one-carbon ring-expanded ketones 11a-c in
good yields (63-71%) along with their respective 1,4-
diketone counterparts 12a-c (12-18%). Given the good
performance and the ready availability of the 12-membered
parent system 6b, the influence of substituents on the vinyl
side chain was investigated with selected substrates 10d-h
bearing variable 1-alkenyl groups in the 2-position.13 Replac-
ing the vinyl moiety with a 1-propenyl group had little effect
on the efficiency of the reaction (entries 4 and 5). It is
noteworthy to state that FVP of the 14-membered substrate
10e followed by hydrolysis of the silylenol ether intermediate
directly afforded the valuable musk odorant (()-muscone
(11e) in 73% yield.14 Given the ready accessibility of 10e,
this sequence represents a short and very efficient synthesis
of this natural product from low-priced C-12 starting
material.15 On the other hand, exchanging the vinyl func-
of (E/Z)-2-cyclotridecenone (14) in 55% yield (based on
recovered material). The spectroscopic data provided no
evidence for the presence of unsaturated dione side products.
Although the conversion rate could be increased at elevated
temperatures, the yield of 14 decreased as a result of the
formation of low-boiling side products, which were not
further characterized.
To conclude, we have developed a conceptually new one-
carbon ring expansion reaction providing access to specif-
ically substituted cycloalkanones based on a diradical cascade
mechanism. In view of the ready availability of appropriately
substituted substrates, this sequence represents a short and
very efficient route to naturally occurring macrocyclic musks
such as, e.g., (()-muscone, as well as a variety of synthetic
analogues from cheap C-12 starting compounds. Further
studies are in progress.
(9) As a control experiment 1,2-dione 9 was subjected to FVP at 600
°C to give 7 (67%), doubly decarbonylated cyclododecane (16%), and
unreacted starting material (10%). In contrast, 9 remained unaffected when
treated at temperatures below 540 °C.
(10) The lower overall yield may be attributed to double decarbonylation
and dehydration.
(11) The initially formed silylenol ether compounds were each obtained
as 1:1 mixture of E/Z-isomers.
(12) Lower temperatures gave rise to incomplete conversion.
(13) Compounds 10d-h were prepared in good yields by addition of
the corresponding 1-alkenylmagnesium bromide reagent to the appropriate
1,2-diketone, followed by silylation.
(14) For recent reviews on macrocyclic musks, see: (a) Fra´ter, G.;
Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633. (b) Williams, A.
S. Synthesis 1999, 1707. (c) Fra´ter, G.; Bajgrowicz, J. A.; Denis, C.; Kraft,
P. Angew. Chem., Int. Ed. 2000, 39, 2980.
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 compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048701E
(15) Precursor 10e was obtained on a multigram scale from low-priced
cyclododecanone through a five-step synthesis in ca. 60% overall yield.
For details, see refs 4a,b and 6.
(16) Recent examples: (a) Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Org.
Lett. 2003, 5, 2691. (b) Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Org. Lett.
2003, 5, 4211. (c) Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Synlett 2003, 1210.
Org. Lett., Vol. 6, No. 18, 2004
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