Stereospecific synthesis of dienones via a torquoselective retro-nazarov reaction

Article abstract of DOI:10.1021/ol050657v

(Chemical Equation Presented) Enol ethers are cleaved via a three-step sequence involving cycloaddition with dichloroketene, ring expansion with diazomethane, and a base-mediated retro-Nazarov reaction. The latter conrotatory process proceeds torquoselect

Full text of DOI:10.1021/ol050657v

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1881-1883
Stereospecific Synthesis of Dienones
via a Torquoselective Retro-Nazarov
Reaction
Michael Harmata,* Dong Reyoul Lee, and Charles L. Barnes
Department of Chemistry, UniVersity of Missouri-Columbia, Columbia, Missouri 65211
harmatam@missouri.edu
Received March 28, 2005
ABSTRACT
Enol ethers are cleaved via a three-step sequence involving cycloaddition with dichloroketene, ring expansion with diazomethane, and a
base-mediated retro-Nazarov reaction. The latter conrotatory process proceeds torquoselectively and stereospecifically in accord with theoretical
predictions.
We recently reported the first examples of the retro-Nazarov
reaction. In our original work, treatment of a 2-bromocy-
clopentanone such as 1 with triethylamine (TEA) in refluxing
trifluoroethanol (TFE) resulted in the formation of a dienone,
presumably via a retro-electrocyclization of the cyclopentenyl
oxyallylic cation 5, in other words, a retro-Nazarov reaction
(Scheme 1).1
Scheme 1
We have examined this process computationally and are
using the results to guide us in formulating guidelines
involving the kind of substituents flanking the cleaving bond
that will inhibit or promote the reaction.2 We pursued an
experimental study that showed that an alkoxy group was
sufficient to promote the reaction, as shown in eq 1. Thus,
treatment of 7 with TEA in refluxing TFE afforded 8 in 51%
yield, a result of a retro-Nazarov reaction followed by a
conjugate addition. However, a single aryl or even several
alkyl groups flanking the cleaving bond did not promote the
reaction.2 An aryl group and an alkyl group flanking the
cleaving bond resulted in retro-Nazarov reaction (eq 2).
One of the predictions based on our calculations was that
the retro-Nazarov reaction would be torquoselective. This
(1) Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328.
(2) Harmata, M.; Schreiner, P. R.; Lee, D. R.; Kirchhoefer, P. L. J Am.
Chem. Soc. 2004, 126, 10954.
10.1021/ol050657v CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/07/2005

Table 1. Retro-Nazarov Reactions of cis-3,4-Disubstituted
Cyclopentenones
prediction was in line with work by Houk on related
electrocyclic processes.3 This report documents that the retro-
Nazarov reaction is torquoselective and that the process is
not just mechanistically interesting. It can be used to prepare
compounds not easily accessible by other means.
We initially decided to prepare a set of appropriate
substrates using the general approach shown in Scheme 2.
Scheme 2
a 1-Adamantyl. b Z:E ratio of enol ethers was 93:7 by NMR analysis.
c Numbers in parentheses are average yields per step. d A 7% yield of the
E isomer was also isolated. NMR analysis of the crude product indicated
a 91:9 ratio of Z:E isomers.
Cycloaddition of dichloroketene to an enol ether would lead
to a dichlorocyclobutanone. Ring expansion with diaz-
omethane would then afford a dichlorocyclopentanone, which
would be subjected to treatment with base to effect the retro-
Nazarov reactions. At the outset of the work, it was not clear
how the presence of a chloro substituent in the oxyallylic
cation would affect the retro-electrocyclization, but it turned
out to be inconsequential.
already been described.7 Purification of intermediates was
generally not performed and quoted yields include all three
steps. Reactions were conducted in refluxing hexafluoroiso-
propanol (HFIP) in the presence of 2,2,6,6-tetramethylpip-
eridine (TMP) as base.8
According to our computational predictions,2 cis enol
ethers should undergo conrotatory ring opening to place the
alkoxy group on the outside of the transition structure to
give a dienone with two (Z)-alkenes. The basis for this
preference has been discussed in the context of cyclobutene
ring openings3a as as well as cyclopentenyl cation ring
openings,3b and the concept should be general.
As illustrated in entries 1-11 of Table 1, we found that
our procedure produced single diastereomers of products.
The coupling constant for the protons on carbons 4 and 5
on the dienone were in the range of 11.5-11.6 Hz. This
was at the high end of a cis coupling constant and the low
end of a trans coupling constant. We were nevertheless
confident in our assignment, since dienones that we had
Our results using cis enol ethers are shown in Table 1.
Dichloroketene was generated via reductive elimination of
trichloroacetyl chloride in the presence of an appropriate enol
ether.4 The latter were in general formed by the isomerization
of the corresponding allylic ethers or by reduction of ynol
ethers.5,6 Details are given in Supporting Information. The
ring expansion of cyclobutanones using diazomethane had
(3) (a) Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc.
Chem. Res. 1996, 29, 471. (b) Kallel, E. A.; Houk, K. N. J. Org. Chem.
1989, 54, 6006.
(4) (a) Nebois, P.; Greene, A. E. J. Org. Chem. 1996, 61, 5210. (b) Mehta,
G.; Rao, H. S. P. Synth. Commun. 1985, 15, 991. (c) Brady, W. T.
Tetrahedron 1981, 37, 2949.
(5) Evans, D. A.; Andrews, G. C.; Buckwalter, B. J. Am. Chem. Soc.
1974, 96, 5560.
(6) Kann, N.; Bernards, V.; Greene, A. E. Org. Synth. 1997, 74, 13.
(7) Greene, A. E.; Depre´s, J.-P. J. Am. Chem. Soc. 1979, 101, 4003.
(8) These reaction conditions have largely superseded those involving
triethylamine in refluxing trifluoroethanol.
1882
Org. Lett., Vol. 7, No. 9, 2005

prepared earlier2 and that were expected to possess the E
configuration had vicinal coupling constants between the
corresponding protons of 15.1-16.2 Hz, strongly supporting
a trans relationship.
Table 2. Retro-Nazarov Reaction of trans-3,4-Disubstituted
Cyclopentenones
After considerable effort with several systems, we were
able to produce very nice crystals of the product from entry
8 of Table 1. The crystal structure of this compound proved
our stereochemical assignment and it is this structure, along
with our NMR data, which we used to make stereochemical
assignments of all the other compounds.
We were interested in examining the stereospecificity of
this reaction. Entry 12 of Table 1 suggests that the reaction
may be stereospecific, but the ratio of isomers in the products
and starting materials do not correlate perfectly. We think
this may be due to inherent errors in such measurements.
We decided to examine several configurationally pure E enol
ethers and examine the outcome of the retro-Nazarov reaction
derived from such species. The results are shown in Table
2.
a Cyclohexyl. b 1-Adamantyl. c E:Z ratio of enol ethers was 79:21 by
NMR. NMR analysis of the crude product indicated a 81:19 ratio of E:Z
isomers. d Numbers in parentheses are average yields per step. e An 8.6%
yield of the Z isomer was also isolated.
In all cases, only single diastereomers of dienone products
were detected by NMR in crude reaction mixtures. Thus,
starting with enol ethers that were pure E by NMR resulted
in products that were pure E by NMR. Stereochemical
assignments of the 4,5-double bond were made on the basis
of coupling constants (15.1-16.2 Hz). An X-ray structure
was obtained for the product of entry 3 in Table 2. The enol
ether E/Z mixture shown in entry 5 of Table 2 gave a good
correlation withthe products derived from the retro-Nazarov
reaction sequence (79:29 vs 81:19, E:Z). We thus conclude
that this reaction is both torquoselective and stereospecific.
produced are in progress, and new results will be reported
in due course.
Acknowledgment. We thank the National Science Foun-
dation for support of this work. Fluorinated solvents used in
this study were a gift from Halocarbon Products Corporation,
to whom we are grateful. We also thank referees for valuable
suggestions.
In summary, we have demonstrated a stereospecific and
torquoselective cleavage of enol ethers via a process that
includes a retro-Nazarov reaction. The synthesis of the
product dienones would not be trivial by other methods and
the process represents the stereoselective synthesis of both
di- and trisubstituted alkenes in a single molecule. Further
studies of this process and application of the products
Supporting Information Available: Experimental pro-
cedures, spectral data, and crystallographic data in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL050657V
Org. Lett., Vol. 7, No. 9, 2005
1883