Intermolecular [4+2] cycloadditions of a reactive cyclopentadienone

Article abstract of DOI:10.1002/ejoc.200600173

A reactive cyclopentadienone gives Diels-Alder cycloadducts with a variety of dienes in high yield and often with extremely high levels of regio- and stereoselectivity. The high degree of generality of this reaction suggests it will be of use in organic s

Full text of DOI:10.1002/ejoc.200600173

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600173
Intermolecular [4+2] Cycloadditions of a Reactive Cyclopentadienone
Michael Harmata*[a] and Maria G. Gomes[a]
Keywords: Cyclopentadienone / Cycloaddition / Deantiaromatization / Diels–Alder reactions
A reactive cyclopentadienone gives Diels–Alder cycload-
ducts with a variety of dienes in high yield and often with
extremely high levels of regio- and stereoselectivity. The
high degree of generality of this reaction suggests it will be
of use in organic synthesis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
We recently reported the generation of cyclopenta-
dienones from 2-bromocyclopentenones by treatment of the
latter with triethylamine in refluxing trifluoroethanol (TFE)
(Scheme 1).[1]
Scheme 1. Formation of a cyclopentadienone dimer.
Eager to apply this “new”[2] approach to cyclopen-
tadienones in some fashion, we became generally interested
in exploring antiaromatic intermediates as a driving force
in organic reactions, a concept we have termed “deanti-
aromatization”. This idea led to our discovery of an elec-
trocyclic reaction of cyclopentadienones illustrated in
Scheme 2.[3] In searching for another application of cyclo-
pentadienones, we became very excited by the reports by
Gavina[4] and by Fuchs,[5] in which it was shown that a reac-
tive cyclopentadienone could be a competent dienophile in
a [4+2] cycloaddition (Diels–Alder) process.
Common knowledge suggests that reactive cyclopen-
tadienones dimerize very rapidly.[6] Indeed, a number of
strategies have been developed to combat this problem in
the form of syntheses of relatively stable, monomeric cyclo-
pentadienones that are competent dienophiles and dienes in
[4+2] cycloaddition reactions.[7] Fuchs’s paper presented a
small number of intriguing examples that suggested that
such special precautions need not be taken. For example,
treatment of either 8 or 9 with tripropylamine in benzene at
50 °C in the presence of 5 equiv. of 2,3-dimethylbutadiene
Scheme 2. Electrocyclization of a cyclopentadienone.
afforded 10 in 84% and 71% yield, respectively (Scheme 3).
Unlike the corresponding cyclobutadiene,[8] attempts to
perform an intramolecular version of this reaction were un-
successful. To the best of our knowledge, there has been no
subsequent or related work on this chemistry. We saw an
opportunity to exploit our cyclopentadienone chemistry
and further explore the scope of this elegant and mild cyclo-
pentadienone cycloaddition process. We report our prelimi-
nary results herein.
Scheme 3. Fuchs’s cyclopentadienone cycloaddition.
We began our study simply by attempting to generate
a cyclopentadienone from 11.[9] Of several sets of reaction
conditions studied, we found that the treatment of 11 with
2 equiv. of triethylamine in toluene at reflux for 1 h afforded
the decarbonylated dimer (DCD), the indanone 14, in 71%
[a] Department of Chemistry, University of Missouri – Columbia,
Columbia, Missouri 65211, USA
Fax: +1-573-882-2754
E-mail: harmatam@missouri.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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M. Harmata, M. G. Gomes
SHORT COMMUNICATION
yield.[10] The reaction presumably proceeded through the while cycloaddition is competitive with dimerization. The
pathway shown in Scheme 4, in which cyclopentadienone lower yields in THF may reflect starting material or prod-
formation was followed by dimerization and decarbonyl- uct decomposition over the longer time course of the reac-
ation to afford the indanone 14.
tion. For 2,3-dimethylbutadiene, the difference in yield be-
tween the two solvents is about 10%. However, as shown in
the case of cyclopentadiene, cycloaddition reactions of 11
can proceed well in THF (Table 2, Entry 4). The reaction
with cyclohexadiene clearly benefited from a change from
THF to toluene (Table 2, Entries 5–6).
Interestingly, 1,2-dialkylbutadienes react with 11 to af-
ford cycloadducts as single regio- and stereoisomers
(Table 2, Entries 7–12). Especially attractive among the ex-
amples in Table 2 is that in Entry 12. The product bears the
carbocyclic skeleton of a steroid, marking the methodology
as a potential entry to this important class of compounds.
The stereochemistry of DA-22 was established by NMR
studies, particularly NOESY spectra. The appropriate inter-
actions that led to the stereochemical assignment shown
were observed. This suggests an endo approach of the diene
to the cyclopentadienone and is entirely consistent with
other structural data (vide infra).
Results with 1-substituted butadienes were somewhat
mixed. Piperylene gave a poor yield of cycloadduct, though
the product was a single isomer (Table 2, Entry 13). This
result may simply stem from the volatility of the diene.
Thus, when 10 equiv. of diene were used and the reaction
was conducted in a sealed tube, DA-23 was obtained in a
yield of 71 %, along with 14% of the DCD 14. Related aryl-
substituted systems performed better, affording regiochem-
ically and stereochemically clean products (Table 2, Entries
14 and 16). Interestingly, it appears that 2-substituted
dienes can react well with 11 to give cycloadducts, but with
virturally no regioselectivity (Table 2, Entry 15). Further
studies of this phenomenon are in progress.
Scheme 4. Generation of a cyclopentadienone from 11.
To evaluate [4+2] cycloadditions of 11, experiments using
2,3-dimethylbutadiene as a test substrate were conducted.
The results are shown in Table 1. We initially looked at se-
veral solvents using 5 equiv. of triethylamine (TEA) as base.
It appeared that toluene and THF were the most effective.
To this point, little effort has been put into varying the con-
centration, but more than doubling the concentration of the
reaction in THF essentially afforded the same yield of cy-
cloadduct. Stronger bases such as DBU proved too potent
and apparently destroyed the starting material. The hin-
dered base 2,2,6,6-tetramethylpiperidine (TMP) afforded
the product in THF, but the yield was considerably lower
than when TEA was used. Given these results, we decided
to pursue cycloadditions using TEA as base in toluene or
THF as the reaction solvent.
Table 1. Optimization of the reaction between 11 and 2,3-dimethyl-
butadiene via 12.[a]
The importance of electronic effects on the course of the
reaction could be gleaned from studies of other 1-substi-
tuted dienes. For example, 1-methoxybutadiene and the cor-
responding TBS silyl ether gave clean cycloadducts in excel-
lent yield (Table 2, Entries 17–19). However, with com-
pound 29 under essentially the same conditions, only a 30%
yield of the Diels–Alder adduct DA-29 was observed, the
major product being the DCD 14 (41%). The lower reactiv-
ity of the diene could be circumvented by increasing its con-
centration. Thus, when 5 equiv. of 29 was used, the yield of
the cycloadduct DA-29 improved to 72% (Table 2, Entry
21). Similar results were realized with compound 30
(Table 2, Entries 22–23). The structure of the cycloadduct
DA-30 was established by X-ray analysis.[11]
Good yields of cycloadducts were obtained with the
dienes 31–34. Interestingly, we had some problems in using
Danishefsky’s diene 31. The reaction benefited greatly from
the inclusion of 20 mol-% of triethylamine hydrobromide.
The reasons behind this are not clear, and we are still at-
tempting to improve the cycloaddition process with this
diene and understand the effect of additives on the yield.
Entry Base (equiv.)
Solvent
MeCN
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
TEA (5)
TEA (5)
TEA (5)
TEA (5)
TEA (5)
TEA (5)
TEA (3)
TEA (3)
DBU (3)
DBU (3)
TMP (3)
35
70
255
40
210
90
160
160
20
14
70
22
1.4-dioxane
54
[b]
22[c]
61
2-butanone
acetone
toluene
THF
22
84
73
THF
71[d]
[e]
9
10
11
toluene
2-butanone
THF
[e]
43
[a] All reactions were conducted at the reflux temperature of the
solvent unless otherwise noted at a concentration of 0.04  with
respect to 11. [b] 1-Butyl-3-methylimidazolium tetrafluoroborate.
[c] Reaction conducted at 85 °C. [d] Reaction conducted at a con-
centration of 0.1 . [e] Decomposition of starting material.
In general, the results suggest that the reaction proceeds The dienyl sulfide 33 performed very well in the cycload-
better in toluene than in THF. It appears that cyclopen- dition. The structure of the cycloadduct was established by
tadienone generation is more rapid in refluxing toluene, X-ray analysis of the corresponding sulfone, produced in
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Intermolecular [4+2] Cycloadditions of a Reactive Cyclopentadienone
SHORT COMMUNICATION
Table 2. [4+2] Cycloaddtion reactions of cyclopentadienone 12.
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M. Harmata, M. G. Gomes
SHORT COMMUNICATION
Table 2. (continued).
1
[a] Plus 26% of 14. [b] The ratio of regioisomers was 1:1 based on H NMR analysis. [c] Th = 2-thienyl. [d] Plus 41% of 11. [e] Plus 35%
of 11. [f] Plus 10% of 11. [g] This reaction was run in the presence of 20 mol-% of triethylamine hydrobromide.
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Intermolecular [4+2] Cycloadditions of a Reactive Cyclopentadienone
SHORT COMMUNICATION
74% yield by oxidation of DA-33 with mCPBA.[11] The that can participate in these and related cycloaddition reac-
stereostructures of other cycloadducts, if not secured with tions. We are presently exploring these possibilities and the
NOE data, were assigned based on the X-ray data we ob- application of the methodology to total synthesis. Results
tained. Thus far, all data appear to be consistent with our will be reported in due course.
assignments.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the cycloaddition reaction, char-
acterization data for the cycloadducts and copies of proton and
How does the reaction really proceed? We attempted to
perform the reaction without base. Cycloaddition between
11 and the dienes 15 or 31 in the absence of base in re- carbon NMR spectra.
fluxing THF or benzene resulted in the recovery of starting
material (41–75%) with no evidence for the formation of a
cycloadduct of any kind. This fact, along with the forma-
Acknowledgments
tion of 14 in the presence of base but absence of diene,
This work was supported by the National Science Foundation to
strongly suggests the formation of 12 as the reactive inter-
mediate in these reactions.
whom we are grateful. We thank Dr. Charles L. Barnes for the
acquisition of X-ray data.
Diels–Alder reactions between two dienes are interesting
in that one can ask which diene is the 2π component (dieno-
phile) and which is the 4π component (diene). Recent calcu-
lations suggest that both dienes can serve this function
simultaneously resulting in a single transition state that bi-
furcates to produce two different products which are sepa-
rated by a Cope rearrangement.[12] This is illustrated in
Scheme 5 with butadiene. We carried out the reaction be-
tween 28 and 11 at room temperature (toluene, 7 d) in the
hope of isolating a structure like DA-36Ј. Only the cycload-
duct DA-28 was formed in 53% yield. We are continuing to
study the mechanistic aspects of this reaction.
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[9] Details of the synthesis of this compound will be published
elsewhere.
[10] The indanone was formed as a 10:1 mixture of isomers accord-
ing to the 1H NMR spectrum of the crude reaction mixture.
We believe the minor isomer is a constitutional isomer arising
from a highly, but not completely, regioselective cycloaddition.
[11] CCDC-297302 (DA-30), and -297303 (sulfone of DA-33) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[12] a) P. Quadrelli, S. Romano, L. Toma, P. Caramella, J. Org.
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P. Quadrelli, L. Toma, J. Am. Chem. Soc. 2002, 124, 1130.
Received: February 27, 2006
Scheme 5. Possible paths for the formation of cycloadducts.
In summary, we have shown that a reactive cyclopen-
tadienone can be an effective partner in highly regioselec-
tive and stereoselective [4+2] cycloadditions with certain
dienes. Along with the work by Fuchs, this demonstrates
that a variety of cyclopentadienone precursors will gen-
erally give rise to cyclopentadienones under mild conditions
Published Online: March 31, 2006
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