Intramolecular Diels-Alder reactions of cyclopropenone ketals

Article abstract of DOI:10.1021/ol101375a

(Equation Presented). The first intramolecular cycloaddition reactions of cyclopropenone ketals with tethered electron-deficient, electron-rich, and neutral 1-substituted dienes are reported, constituting inverse electron demand, normal, and neutral Diels

Full text of DOI:10.1021/ol101375a

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3540-3543
Intramolecular Diels-Alder Reactions of
Cyclopropenone Ketals
Paresma R. Patel and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
boger@scripps.edu
Received June 16, 2010
ABSTRACT
The first intramolecular cycloaddition reactions of cyclopropenone ketals with tethered electron-deficient, electron-rich, and neutral 1-substituted
dienes are reported, constituting inverse electron demand, normal, and neutral Diels-Alder reactions, that provide exclusively the exo [4 +
2] cycloaddition products without the intervention of [1 + 2], [3 + 2], or [3 + 4] cycloadducts in reactions whose courses do not depend on
the reaction conditions, the diene activating substituent, or the nature of the tethering.
TheexaminationandanticipatedexploitationoftheDiels-Alder
reactions of the parent unsubstituted cyclopropenone ketals
led to the discovery of the reversible thermal generation of
π-delocalized singlet vinylcarbenes from cyclopropenone
ketals.1 This resulted in the disclosure of the thermal [1 +
2],2 [3 + 2],3 and [3 + 4]4 cycloaddition reactions of singlet
π-delocalized vinylcarbenes that complement the [4 + 2]5
cycloaddition reactions of the cyclopropenone ketals them-
selves providing a rich series of reactions whose course could
be controlled by a combination of the choice of substrate
and the reaction conditions (Figure 1).1,6 A key element to
emerge from these studies was the capability of cyclopro-
(1) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6695.
(2) (a) Boger, D. L.; Brotherton, C. E. Tetrahedron Lett. 1984, 25, 5611.
(b) Tokuyama, H.; Yamada, T.; Nakamura, E. Synlett 1993, 589.
(3) (a) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1984, 106,
805. (b) Boger, D. L.; Brotherton, C. E.; Georg, G. I. Tetrahedron Lett.
1984, 25, 5615. (c) Boger, D. L.; Brotherton, C. E.; Georg, G. I. Org. Synth.
1987, 65, 32. (d) Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1988, 53,
3408.
Figure 1. Intermolecular reactions of cyclopropenone ketals.
penone ketals to participate in normal, inverse electron
demand, or neutral Diels-Alder reactions with equal facility.
Although a well-founded explanation of this behavior can
be derived from a FMO analysis of the reactions,5b it is also
(4) (a) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1985, 50, 3425.
(b) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6713.
(5) (a) Albert, R. M.; Butler, G. B. J. Org. Chem. 1977, 42, 674. (b)
Boger, D. L.; Brotherton, C. E. Tetrahedron 1986, 42, 2777. (c) Boger,
D. L.; Zhu, Y. J. Org. Chem. 1994, 59, 3453. (d) Boger, D. L.; Takahashi,
K. J. Am. Chem. Soc. 1995, 117, 12452. (e) Boger, D. L.; Ichikawa, S.;
Jiang, H. J. Am. Chem. Soc. 2000, 122, 12169. For a [5 + 2] cycloaddition,
see: (f) Delgado, A.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2002, 4,
3091.
(6) Reviews: (a) Boger, D. L.; Brotherton-Pleiss, C. E. In AdVances in
Cycloaddition, Vol. 2; Curran, D. P., Ed.; JAI Press: Stamford, CT, 1990;
pp 147-219. (b) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV. 2003,
103, 1295.
10.1021/ol101375a  2010 American Chemical Society
Published on Web 07/08/2010

intuitively easy to understand on the basis of the release of
cyclopropene ring strain energy (ca. 25 kcal/mol) in the
course of the [4 + 2] cycloaddition reactions that supersedes
the electronic features of the reactions. In preceding studies,
only the intermolecular cycloaddition reactions were exam-
ined with a focus on understanding the underlying mecha-
nistic questions posed by the observed reactions.1,6 Herein,
we report the examination of the first intramolecular [4 +
2] cycloaddition reactions of cyclopropenone ketals with
tethered, 1-substituted dienes that permit an assessment of
the impact of the substrate tethering on the reaction course
conducted with the intention of providing additional mecha-
nistic insights into these unique thermal reactions. A key
question we wished to address was whether the cyclopro-
penone ketal tethering to a 1-substituted diene would lead
to competitive intervention of cycloaddition reactions of a
thermally generated π-delocalized singlet vinylcarbene.7
Analogous to the intermolecular reactions that provide only
the products of an exo selective [4 + 2] cycloaddition with
1-substituted dienes,1,5 the intramolecular variants were found
to only provide the analogous exo Diels-Alder products
without the intervention of [1 + 2], [3 + 2], or [3 + 4]
cycloadducts in reactions that do not depend on the reaction
conditions, the diene activating substituent, or the nature of
the tethering.
Scheme 1
even at 25 °C, reacted distinguishably and expectedly faster
than the substrate 5a containing a four atom linker, the
nonpolar solvent benzene proved to be more effective than
the more polar aprotic solvent CH2Cl2, and warming (45-60
°C) the solutions containing either 4a or 5a only led to
formation of the Diels-Alder products faster, but without
the detection of carbene derived addition products. Impor-
tantly, both substrates proved to be superb participants in
the intramolecular Diels-Alder reaction providing a single
(exo) diastereomer.
Without efforts at optimization, a series of additional
substrates 6a-9a containing the three atom straight chain
alkyl linker were examined that bear an alternative electron-
withdrawing substituent (-CN), a conjugated aryl substituent
(-Ph), no substituent representing an unactivated diene
(-H), or an electron-donating substituent (-OBn) reflecting
the full spectrum of potential 1-substituted dienes (Scheme
2). In many instances, the [4 + 2] cycloaddition reaction
proceeded with such facility that the products were observed
to form under conditions used to install or purify the diene,
making it difficult to secure pure substrate and to accurately
monitor the rate of product formation. Nonetheless, we could
qualitatively establish that both 6a and 9a (R ) CN or OBn),
constituting either an electron-deficient or electron-rich diene,
react at similar rates and slightly faster than either 7a or 8a
(R ) Ph or H). Thus, similar to observations made in the
study of the intermolecular reactions,1,5 a tethered cyclo-
propenone ketal participates equally well in an exo diaste-
reoselective intramolecular normal or inverse electron de-
mand Diels-Alder reaction. Moreover, it even effectively
reacts with unactivated dienes (e.g., 8a) that typically are
difficult to employ in a conventional Diels-Alder reaction
and does so under remarkably mild reaction conditions (C6H6,
45 °C, 12 h, 72%).
Substrates that explore two variations on the linking tether
(alkyl or aryl) were examined.8 Although not discussed in
detail herein, alkyl substitution favors thermal cleavage of
the cyclopropenone ketal 1 to provide the 2-substituted
π-delocalized singlet vinylcarbene 2, whereas aryl substitu-
tion favors a regioselective ring-opening reaction to provide
the 3-substituted π-delocalized singlet vinylcarbene 3 po-
tentially increasing the rate of its subsequent cycloaddition
reaction with the type of substrates explored herein (eq 1).6,7,9
The intramolecular Diels-Alder reaction was examined
in greatest detail with the substrates 4a and 5a bearing an
alkyl cyclopropenone ketal substituent, a straight chain three
or four atom alkyl tether, and an electron-withdrawing
1-ethoxycarbonyl substituent on the tethered diene that could
activate the system for trap of a thermally generated
π-delocalized singlet vinylcarbene (Scheme 1).
Substrate 4a bearing the three atom linker, which under-
went the intramolecular [4 + 2] cycloaddition effectively
(7) Patel, P. R.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 8527.
(8) Although not the topic of this communication, the substrate prepara-
tions (Supporting Information) revealed the robust nature of the cyclopro-
penone ketal, indicating that it can be carried through a range of reactions
(e.g., Bu4NF, CrO3-pyr2 or TPAP, Wittig reaction, Negishi coupling) that
may otherwise appear challenging.
Notably, the unsubstituted alkyl chains used to link the
dienophile with the diene in the substrates above do not
represent the most effective tethering strategy and may be
viewed as a series that significantly challenges the reaction
(9) Tokuyama, H.; Isaka, M.; Nakamura, E. J. Am. Chem. Soc. 1992,
114, 5523
.
Org. Lett., Vol. 12, No. 15, 2010
3541

Scheme 2
Scheme 3
potential. Substitution on the linking chain or introduction
of unsaturation into the linking chain is often used to further
accelerate the rate of such intramolecular reactions. One such
series that contains a substituted linking alkyl chain was
examined in the course of our studies as a result of the
approach used to prepare the tethered substrates (Scheme
3). Lithiation of the parent cyclopropenone ketal 10 followed
by addition to the aldehydes 11 and 12 containing an
unsubstituted and unactivated diene provided the substrates
13a and 14a containing a three and four atom alkyl linker
bearing a secondary alcohol substituent. Substrate 13a with
the three atom linker now participated in the intramolecular
exo Diels-Alder reaction at room temperature even though
it represents the reaction of an unactivated diene (benzene,
14 h, 91%) to provide the product 13b in superb yield and
as a single detectable diastereomer. Substrate 14a, containing
the longer four atom alkyl linker, provided the product 14b
derived from exo selective [4 + 2] cycloaddition with the
unactivated diene, but as a 2:1 mixture of alcohol diastere-
omers in good yield (80%, benzene, 60 °C, 18 h). Efforts to
extend this approach to the preparation of substrates contain-
ing activated 1-substituted dienes (R ) CO2Et or CN) and a
three atom linker failed to provide the isolated substrates
and simply provided the resulting subsequent exo Diels-Alder
products 17b and 18b as single detectable diastereomers.
Cycloadduct 18b was obtained as a crystalline product whose
structure and stereochemistry were established with a single
crystal X-ray structure determination10 that served to confirm
the assignments made herein based on spectroscopic properties.
To date, we have briefly examined a single example of a
tethered 1-substituted electron-deficient diene bearing an ethoxy-
carbonyl group (ethyl ester) and incorporating an aryl cyclo-
propenone ketal substituent in the linking tether (Scheme 4).
In initial efforts to potentially observe competitive cycloadducts
derived from the thermally generated π-delocalized singlet
vinylcarbene (see 3, eq 1), substrate 19 was warmed in toluene
at 80 °C (12 h) under conditions demonstrated to lead to
reversible carbene formation7 but was found to provide only 20
(69%) derived from the intramolecular exo Diels-Alder reaction.
Scheme 4
Finally, and representative of the synthetic utility of the
intramolecular [4 + 2] cycloaddition reaction, the cycloadduct
4b was converted to the tropone 24 in 3 steps (Scheme 5). Thus,
Scheme 5
(10) A single crystal X-ray structure determination of 18b confirmed
the structural and stereochemical assignment (CCDC763497). A single
crystal X-ray structure determination of 24 confirmed the structural
assignment (CCDC763498).
3542
Org. Lett., Vol. 12, No. 15, 2010

regioselective bromohydrin formation (NBS, THF-H2O, 80%),
alcohol oxidation to the ketone 22 (DMP, pyr, 85%), and
base-catalyzed elimination of HBr and in situ enolization
(DBU, CH2Cl2, 0 °C, 45 min, 83%), resulting in rearrange-
ment of the intermediate norcaradiene to the corresponding
cycloheptatrienone ketal and subsequent tautomerization,
provided the crystalline tropone 24, whose structure was
confirmed with a single crystal X-ray structure determina-
tion.10
the reaction conditions, the diene activating substituent, or
the nature of the tethering. Significantly, the reactions
proceed without the intervention or trap of thermally gener-
ated π-delocalized singlet vinylcarbenes in [1 + 2], [3 +
2], or [3 + 4] cycloaddition reactions.7
Acknowledgment. We gratefully acknowledge the finan-
cial support of the National Institutes of Health (CA042056)
and the Skaggs Institute for Chemical Biology. We thank
Dr. Raj Chadha (The Scripps Research Institute) for the
X-ray crystal structures. P.R.P. is a Skaggs Fellow.
The first intramolecular cycloaddition reactions of cyclo-
propenone ketals with tethered electron-rich, electron-
deficient, and neutral 1-substituted dienes were reported and
constitute normal, inverse electron demand and neutral
Diels-Alder reactions that proceed under mild reaction
conditions and provide exclusively the exo [4 + 2] cycload-
dition products in reactions whose course do not depend on
Supporting Information Available: Full experimental
details, compound characterizations, and two X-ray structures
are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL101375A
Org. Lett., Vol. 12, No. 15, 2010
3543