Intramolecular [1 + 2] and [3 + 2] cycloaddition reactions of cyclopropenone ketals

Article abstract of DOI:10.1021/ja103933n

The first intramolecular thermal reactions of cyclopropenone ketals are reported and the work examined substrates tethered to an electron-deficient olefin bearing a single electron-withdrawing substituent. Whereas the intermolecular variants of the reacti

Full text of DOI:10.1021/ja103933n

Published on Web 06/08/2010
Intramolecular [1 + 2] and [3 + 2] Cycloaddition 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
Received January 21, 2010; E-mail: boger@scripps.edu
The disclosure of the reversible thermal generation of π-delocalized
singlet vinylcarbenes from cyclopropenone ketals first emerged from
an examination of the cycloaddition reactions of the parent unsubsti-
tuted cyclopropenone ketals.1 This resulted in the discovery of the
thermal [1 + 2],2 [3 + 2],3 and [3 + 4]4 cycloaddition reactions of
singlet π-delocalized vinylcarbenes, which complement the [4 + 2]5
cycloaddition reactions of the cyclopropenone ketals themselves,
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
Substrates exploring two variations on the tether (alkyl or aryl)
were examined.8 The most remarkable combination of structural
features that impacted the reactivity was observed with substrates
1a-5a bearing an aldehyde- or ketone-substituted electron-deficient
olefin and an aryl cyclopropenone ketal substituent built into the
linking tether (Scheme 1).
Scheme 1
Figure 1. Generation and intermolecular cycloaddition reactions of a
π-delocalized singlet vinylcarbene.
A key element that emerged from the studies was the reversibility
of the thermal π-delocalized singlet vinylcarbene generation that insures
its eventual productive trapping by an electron-deficient substrate. In
preceding studies, only intermolecular cycloadditions had been ex-
amined, with a focus on understanding the underlying mechanistic
questions posed by the observed reactions.1,6 Herein, we report the
first intramolecular thermal cycloaddition reactions of cyclopropenone
ketals that permit the nature of the substrate tethering and the
stereoelectronic (orbital alignment) features of the reactions to control
the reaction course, providing additional mechanistic insights into these
unique thermal reactions. Examined herein are the reactions of a
cyclopropenone ketal tethered to an electron-deficient olefin bearing
a single electron-withdrawing substituent. Whereas the intermolecular
reactions provide only the olefin addition products derived from an
endo-selective [1 + 2] cycloaddition,2 the intramolecular variants
provide either [1 + 2] or [3 + 2] cycloadducts in reactions that depend
on the reaction conditions, the alkene activating substituent, and the
nature of the tethering. In addition to providing key mechanistic insights
into the thermal [3 + 2] cycloaddition, they were also found to proceed
under conditions that reflect the ease and regioselectivity of the
cyclopropenone ketal cleavage7 for π-delocalized singlet vinylcarbene
generation.
Simply warming a solution of 1a in toluene at 80 °C for 12 h
directly provided the [3 + 2] cycloadduct 1b in good yield (70%)
as a single diastereomer whose structure and stereochemistry were
confirmed by X-ray analysis9 (Scheme 1). Extension of the tether
by one carbon (2a), resulting in a four- versus three-atom linker,
similarly provided the [3 + 2] cycloadduct 2b (X-ray9) directly in
good yield (60%, 16 h, 80 °C). Further substitution of the electron-
deficient olefin with a methyl group (substrates 3a and 4a) resulted
in diastereospecific generation of the [3 + 2] cycloadducts 3b and
4b, respectively, with good conversion (88 and 60%, 12-16 h, 80
°C) as single diastereomers (X-ray9) in which the stereochemistry
of the substrate olefin was maintained in the product. Similarly,
the ketone substrate 5a directly provided the [3 + 2] cycloadduct
5b in excellent yield (77%) under comparable mild thermal reaction
conditions (100 °C, 8 h; Scheme 1). The reaction course observed
with substrates 1a-5a is remarkable in two respects. First, the
reactions directly provide the [3 + 2] cycloadducts under mild
thermal reaction conditions and likely entail an intermediate thermal
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C O M M U N I C A T I O N S
vinylcyclopropane rearrangement that proceeds with unprecedented
ease.10 Just as significantly, the intramolecular tethering of the
substrates precludes the otherwise preferred intermolecular carbonyl
addition of the thermally generated π-delocalized singlet
vinylcarbene.3b Representative of this preference, the intermolecular
reaction of the phenyl-substituted cyclopropenone ketal 6 with
methyl vinyl ketone (7) cleanly provides only the carbonyl addition
product 8 (80 °C, 2 h, 68%) without the detection of olefin addition
products, despite the propensity of the electrophilic double bond
of 7 to dominate its reactivity (Scheme 1).
Highlighting the unique reactivity of 1a-5a, substrate 9 incorporat-
ing a nitrile-substituted electron-deficient olefin cleanly provided
cyclopropane 11 (94%) upon reaction at 80 °C in toluene for 16 h,
affording the product derived from an endo [1 + 2] cycloaddition of
the thermally generated singlet π-delocalized vinylcarbene and hy-
drolysis of the ketene acetal 10 upon aqueous workup (eq 1). Moreover,
warming either a solution of 10 (generated in situ at 80 °C, 16 h) or
a solution of 9 in toluene at 170 °C (8 h, 72%) directly provided the
[3 + 2] cycloadduct 12 (X-ray9) arising from initial [1 + 2]
cycloaddition of the thermally generated singlet π-delocalized vinyl-
carbene followed by vinylcyclopropane rearrangement. In addition to
defining the mechanism responsible for the [3 + 2] cycloaddition
reaction of such substrates, the comparison of 1a-5a with 9
underscores the remarkable activating properties of the aldehyde or
ketone substituent for the ensuing vinylcyclopropane rearrangement.10
2] cycloadduct 15, whereas warming a solution of substrate 13 at 175
°C for only a brief period (10 min) provided the [1 + 2] cycloadduct
14 (70%) along with only a small amount of the [3 + 2] cycloadduct
15 (8%). Collectively, these results indicate that the initial vinylcy-
clopropane [1 + 2] cycloadduct is an intermediate en route to the [3
+ 2] cycloadduct 15. In view of the diastereospecific reactions of 3a
and 4a, it should also be noted that the partial loss of stereochemistry
with the [3 + 2] cycloadduct 15, as well as 12, may reflect partial
epimerization of the products under the thermal conditions rather than
definitive evidence of a stepwise vinylcyclopropane rearrangement,
since warming a solution of pure 15 to 170 °C led to slow epimerization
(8:1 dr at 1 h). Finally, kinetic trapping of the π-delocalized
vinylcarbene generated from 13 (C6H6/MeOH, 90 °C, 2 h) revealed
regioselective cleavage preferentially leading to 22 that result from
phenyl stabilization of its allyl cation and contribute to the facility of
the cycloaddition reactions.
Scheme 2
Similarly, substrates 13 and 16 bearing an ethyl ester substituent
on the tethered olefin selectively provided the endo [1 + 2] cycload-
ducts 14 (95%) and 17 (67%), respectively, as single diastereomers
when warmed at 80 °C for 16 h in toluene (Scheme 2). The reaction
of substrate 16 with the longer four- versus three-atom linker (13) was
slower but effective (67 vs 95%), and substitution of the double bond
with an additional methyl substituent (19) did not alter the course or
endo diastereoselectivity of the reaction, exclusively providing 20
(74%) containing a quaternary center incapable of epimerization. Only
a trace of the [3 + 2] cycloadduct 15 (<4%) was detected under the
conditions (80 °C, 16 h) that provided 14 (Scheme 2). Upon reaction
at 170 °C for 8 h in toluene, 13 and 16 cleanly provided the
corresponding [3 + 2] cycloadducts 15 and 18 in 80% (7:1 dr) and
55% (>20-30:1 dr), respectively. In the case of 13, where the reaction
was examined in detail, warming the intermediate vinylcyclopropane
generated in situ (80 °C, 16 h) at 170 °C (8 h) also provided the [3 +
Analogous to the behavior of 1a-4a, substrate 23 bearing an
alkyl-substituted cyclopropenone ketal, a straight-chain alkyl tether,
and an aldehyde-substituted electron-deficient olefin directly provided
a single diastereomer (X-ray9) of the [3 + 2] cycloadduct 24 (53%)
but required more vigorous reaction conditions (170 °C, xylene, 16 h)
(Scheme 3). The effect of the alkyl tethering was examined in detail
with the ethyl ester substrates 25 and 28. Because of the lower
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C O M M U N I C A T I O N S
reactivity, it was more difficult to develop conditions that cleanly
provided only the initial [1 + 2] cycloadducts. Thus, 25 and 28
provided the products 26 and 29, respectively, in more modest
conversions and required higher temperatures and longer reaction times
(120 °C, 40 h vs 80 °C, 16 h) for observation of the initial endo [1 +
2] cycloaddition. However, warming a solution of 25 at the higher
reaction temperature of 180 °C (o-Cl2C6H4, 8 h) cleanly provided the
corresponding [3 + 2] cycloadduct 27 in good yield (70%) (Scheme
3). Terminating this latter reaction conducted at the higher reaction
temperature (180 °C) at shorter reaction times (4 and 1 h) led to
isolation of increasing amounts of the [1 + 2] cycloadduct 26 (25 and
55%, respectively) with accompanying lower conversions to 27 (63
and 21%, respectively) indicating that the reaction proceeds by initial
[1 + 2] cycloaddition of the thermally generated π-delocalized singlet
vinylcarbene followed by vinylcyclopropane rearrangement to provide
27. Because of the higher reaction temperatures required for the initial
[1 + 2] cycloaddition in this series, it was not possible to define
conditions that cleanly provided the [1 + 2] cycloadducts without
significant generation of the [3 + 2] products. Responsible in part for
this behavior, kinetic trapping of the π-delocalized singlet vinylcarbene
derived from 25 (C6H6/MeOH, 90 °C, 2 h) revealed preferential
regioselective cleavage to provide isomer 30, requiring the reversible
and slower occasional generation of 31 for productive partitioning into
the reaction cascade (Scheme 3). In contrast, direct conversion to the
[3 + 2] cycloadducts occurred cleanly, although it required the higher
reaction temperature (180 °C) and proceeded at rates and conversions
comparable to those for the phenyl-tethered substrates.
The first study defining the scope of the intramolecular cycload-
dition reactions of cyclopropenone ketals tethered to olefins bearing a
single electron-withdrawing substituent has been described herein,
which explored the cyclopropenone ketal substitution, two variations
of the linking tether (alkyl or aryl), and the impact of the olefin electron-
withdrawing substituent. The most effective combination of structural
features was observed with substrates bearing an aldehyde- or ketone-
substituted electron-deficient olefin and an aryl cyclopropenone ketal
substituent built into the linking tether. Unlike the intermolecular
reactions, such substrates not only now participated in olefin addition
reactions rather than the otherwise preferred carbonyl addition reactions
by virtue of the constraints imposed by the linking tether, but they
were also found to directly provide [3 + 2] cycloadducts in excellent
yields under mild thermal reaction conditions (80-100 °C). Less
activated substrates bearing an ester- or nitrile-substituted olefin
provided intermediate cyclopropanes derived from endo [1 + 2]
cycloaddition of the thermally generated singlet π-delocalized vinyl-
carbene under mild thermal conditions (80-100 °C) or cleanly
provided the [3 + 2] cycloadducts at higher reaction temperatures
(170-180 °C) required to promote the intermediate vinylcyclopropane
rearrangement. In addition to defining a two-step mechanism leading
to the [3 + 2] cycloaddition products, the cycloaddition cascade of
the aldehyde and ketone substrates was found to entail vinylcyclo-
propane rearrangements that proceed with unprecedented ease.10
Examination of additional intramolecular cycloaddition reactions of
cyclopropenone ketals and the exploitation of the remarkable facility
(80 °C) with which the intramolecular [3 + 2] cycloaddition of a
thermally generated π-delocalized singlet vinylcarbene proceeds with
selected substrates are in progress.
Scheme 3
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA042056) and the
Skaggs Institute for Chemical Biology. P.R.P. is a Skaggs Fellow.
Supporting Information Available: Full experimental details and
crystallographic data (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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minor diastereomer of 12, CCDC773876; 24, CCDC776317.
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