Formal [2 + 2 + 2] cycloaddition strategy based on an intramolecular propargylic ene reaction/diels-alder cycloaddition cascade

Article abstract of DOI:10.1021/ja1053829

A formal, metal-free, [2 + 2 + 2] cycloaddition strategy is described based on a cascade of two pericyclic processes. The first step involves an intramolecular propargylic ene reaction of a 1,6-diyne to generate a vinylallene, which then reacts in an inter- or intramolecular Diels-Alder reaction with an alkenyl or alkynyl dienophile. Reactions involving unsymmetrical alkenyl and alkynyl dienophiles proceed with good to excellent regioselectivity, and the diastereoselectivity in the Diels-Alder step is also high, with endo cycloadducts produced as the exclusive products of the reaction. In the case of alkynyl dienophiles, [4 + 2] cycloaddition initially generates an isotoluene-type intermediate that isomerizes to the isolated aromatic product upon exposure to a catalytic amount of DBU at room temperature. The mechanism of several earlier fully intramolecular related transformations have been shown to involve an analogous process rather than the diradical-mediated pathways proposed previously.

Full text of DOI:10.1021/ja1053829

Published on Web 07/22/2010
Formal [2 + 2 + 2] Cycloaddition Strategy Based on an Intramolecular
Propargylic Ene Reaction/Diels-Alder Cycloaddition Cascade
Julia M. Robinson, Takeo Sakai, Katsuhiko Okano, Takafumi Kitawaki, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 19, 2010; E-mail: danheisr@mit.edu
intramolecular Diels-Alder reaction with an alkenyl or alkynyl
Abstract: A formal, metal-free, [2 + 2 + 2] cycloaddition strategy
is described based on a cascade of two pericyclic processes.
The first step involves an intramolecular propargylic ene reaction
of a 1,6-diyne to generate a vinylallene, which then reacts in an
inter- or intramolecular Diels-Alder reaction with an alkenyl or
alkynyl dienophile. Reactions involving unsymmetrical alkenyl and
alkynyl dienophiles proceed with good to excellent regioselectivity,
and the diastereoselectivity in the Diels-Alder step is also high,
with endo cycloadducts produced as the exclusive products of
the reaction. In the case of alkynyl dienophiles, [4 + 2] cycload-
dition initially generates an isotoluene-type intermediate that
isomerizes to the isolated aromatic product upon exposure to a
catalytic amount of DBU at room temperature. The mechanism
of several earlier fully intramolecular related transformations have
been shown to involve an analogous process rather than the
diradical-mediated pathways proposed previously.
dienophile.3 The efficacy of the propargylic-type ene reaction in
this sequence is noteworthy. Although the intramolecular ene
reaction is a well established process,4 very few examples have
been reported involving propargylic rather than allylic hydrogen
atoms.5,6 Overall, this two-stage pericyclic cascade sequence
provides rapid access to highly functionalized alkylidenecyclohex-
ane derivatives. When alkynes are employed as dienophiles, the
initial products are isotoluene derivatives7 that are easily isomerized
to aromatic products upon exposure to base.
Scheme 2 presents representative examples of the formal
[2 + 2 + 2] cycloaddition involving N-methylmaleimide as a
dienophile and illustrating the effect of variations in the 1,6-diyne
tether on the facility of the propargylic ene reaction.8 Good yields
are obtained using only 1 equiv of the dienophile, in contrast to
most cases of the metal-catalyzed bimolecular [2 + 2 + 2] process.
Products are obtained as predominantly Z isomers, as expected for
cycloadditions in which bond formation to the central carbon of
the allene moiety occurs preferentially trans to the R1 substituent
on the terminal carbon of the allene (Scheme 1).9 In the case of
these ene reactions involving unactivated alkynes as enophiles,
efficient reaction generally requires temperatures in the range
[2 + 2 + 2] Cycloadditions provide rapid access to polysubsti-
tuted six-membered rings. The most prominent variant of this
powerful strategy is the transition-metal-catalyzed process in which
three alkynes combine to form benzenoid aromatic products.1
Although the fully intramolecular metal-catalyzed cotrimerization
is generally an efficient process, the bimolecular variant involving
the reaction of an R,ω-diyne with a third acetylene suffers from
several limitations. Often a large excess of the third alkyne must
be employed due to its competitive trimerization, and reactions in
which the third alkyne is unsymmetrical frequently proceed with
poor regioselectivity.2
Scheme 2. Formal [2 + 2 + 2] Cycloadditions with
N-Methylmaleimide as Dienophile
Herein we describe a formal, metal-free, bimolecular [2 + 2 +
2] cycloaddition strategy based on a cascade of two pericyclic
processes (Scheme 1). The first step involves an intramolecular
propargylic ene-type reaction of a 1,6-diyne to generate a vinylallene
of type 2. The vinylallene is necessarily in an s-cis conformation,
rendering it highly reactive in the second step, an inter- or
Scheme 1. Propargylic Ene Reaction/Diels-Alder Cycloaddition
Cascade
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C O M M U N I C A T I O N S
Table 1. Formal [2 + 2 + 2] Cycloadditions with Alkenyl
Dienophiles
acrylate, and butynone, yields are slightly improved by carrying
out the tandem process in the presence of small amounts of BHT
as a radical inhibitor. No competition from [4 + 2] arenyne12 or
“ynone”13 type cycloadditions was observed in cases with G ) Ph
or CO2Me (Table 1, entries 2-4). Reactions involving unsym-
metrical alkenyl and alkynyl dienophiles proceed smoothly with
good to excellent regioselectivity in the Diels-Alder step as
observed previously for cycloadditions of vinylallenes.3 Diastereo-
selectivity in the Diels-Alder step is also high, and endo cycload-
ducts are observed as the exclusive products of the reaction (Table
1, entries 2-6).14 Finally, in the case of alkynyl dienophiles (Table
2), [4 + 2] cycloaddition initially generates an isotoluene-type
intermediate that isomerizes to the isolated aromatic product upon
exposure to a catalytic amount of DBU at room temperature.
Table 2. Formal [2 + 2 + 2] Cycloadditions with Alkynyl
Dienophiles
a Isolated yield of products purified by chromatography. b The
regioisomeric Diels-Alder product was isolated in 6% yield.
Fully intramolecular “cyclotrimerizations” of triynes constitute
one of the most useful variants of the transition-metal-catalyzed
process, providing efficient access to angularly fused polycyclic
systems. Several examples of purely thermal [2 + 2 + 2]
cycloadditions of triynes have been reported prior to our work.
Notably, in 1999 Kociolek and Johnson reported that the gas phase
thermolysis of 1,6,11-dodecatriyne at 500-600 °C and 0.01 Torr
affords a hexahydroindacene [2 + 2 + 2] cycloadduct together with
derived dehydrogenation products in 35% combined yield.15
Johnson proposed a stepwise mechanism to account for this process
in which bond formation initially occurs between two alkynes to
generate a 1,4-diradical which is then trapped by the third alkyne
to directly produce an aromatic ring. An analogous diradical
mechanism was proposed by Parsons et al. to account for an
interesting cyclization of enediynes discovered in their laboratory.16
More recently, Ley and co-workers have reported the cyclotrim-
erization of triyne 22 carried out in DMF either by heating at 200
a Isolated yield of products purified by chromatography. b Mixture of
Z and E isomers (86:14). c The regioisomeric Diels-Alder product was
isolated in 11% yield. d Reaction at reflux for 21 h gave 12 in 68%
yield. e Mixture of Z and E isomers (92:8). f Mixture of Z and E isomers
(93:7). g Mixture of Z and E isomers (90:10). h Mixture of Z and E
isomers (81:19).
150-160 °C.10 Thermolysis in the absence of dienophiles leads to
the formation of vinylallene dimers which are obtained as complex
mixtures of regio- and stereoisomers.11
Further examples demonstrating the scope of the bimolecular
version of this formal [2 + 2 + 2] cycloaddition strategy are shown
in Tables 1 and 2. As expected, propargylic ene reactions involving
diynes bearing electron-withdrawing groups proceed under milder
conditions and in these cases the tandem ene reaction/Diels-Alder
cascade can be carried out in refluxing toluene (Table 1, entries 2
and 4-6, Table 2, entry 3). In reactions involving MVK, methyl
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C O M M U N I C A T I O N S
°C or by using focused microwave heating.17 Ley et al. reported
the isolation of an intermediate that they identified as 27, leading
to the proposal of the mechanism outlined in Scheme 3 involving
several unusual strained and reactive intermediates.
We have repeated the thermolysis of 22 and obtained unequivocal
evidence that the intermediate formed in this reaction is not 27,
but rather the isomeric triene 2818 (Scheme 4), the product expected
if the reaction proceeds via a sequential propargylic ene/[4 + 2]
cycloaddition cascade mechanism rather than the pathway proposed
by Ley and co-workers as outlined in Scheme 3. In addition, we
have also found that cyclotrimerization of the related substrate 30
leads to the formation of diene 31 (the product predicted by our
pericyclic cascade mechanism), rather than the isomeric diene 32
reported by Ley et al. as the product of this reaction (Scheme 5).17
Acknowledgment. We thank the National Institutes of Health
(GM 28273), Merck Research Laboratories, Daiichi Sankyo Co.,
and Boehringer Ingelheim Pharmaceuticals for generous financial
support. J.R. was supported in part by National Science Foundation
and AstraZeneca Graduate Fellowships. T.S. was supported in part
by a Research Fellowship of the Japan Society for the Promotion
of Science (JSPS) for Young Scientists.
Supporting Information Available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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Scheme 3. Mechanism Proposed (Ref 17) for Thermal Cyclo-
trimerization of 22
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Scheme 4. Cyclotrimerization of Triyne 22
(6) As our study neared completion, Roglans et al. reported three related
examples of a fully intramolecular propargylic ene/intramolecular Diels-
Alder process involving 15-membered macrocyclic triaza triynes and
enediynes: Gonza´lez, I.; Pla-Quintana, A.; Roglans, A.; Dachs, A.; Sola`,
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a Conditions: (a) 160 °C, 14 h, toluene. (b) Add 0.1 equiv of TsOH-
H2O, 60 °C, 3 h; 56% total overall yield after reduction of indene byproduct
(H2, Pd/C, MeOH, rt).
(8) For full details on the synthesis of the 1,6-diyne cycloaddition substrates,
see the Supporting Information.
(9) E/Z stereochemistry was assigned by differential nOe experiments. See
Supporting Information for details.
Scheme 5. Cyclotrimerization of 30
(10) Attempts to extend the intramolecular propargylic ene reaction to 1,7-diynes
were not successful. Unreacted starting material was recovered after
prolonged heating at 200 °C (see Supporting Information for further details).
Note that in contrast to intramolecular ene reactions of 1,6-dienes, similar
reactions involving 1,7-dienes require higher temperatures and proceed in
low yield.4
(11) For the isolation and characterization of products generated by dimerization
of the vinylallene produced by thermolysis of 16, see the Supporting
Information.
(12) Reviewed in Wessig, P.; Mu¨ller, G. Chem. ReV. 2008, 108, 2051.
(13) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
(14) Stereochemical assignments are based on nOe experiments and analysis
of 1H NMR coupling constants. For details, see Supporting Information.
(15) Kociolek, M. G.; Johnson, R. P. Tetrahedron Lett. 1999, 40, 4141.
(16) Parsons, P. J.; Waters, A. J.; Walter, D. S.; Board, J. J. Org. Chem. 2007,
72, 1395.
In summary, this study establishes the utility of a bimolecular
propargylic ene reaction/Diels-Alder cascade as a method for
achieving formal, thermal [2 + 2 + 2] cycloadditions leading to
functionalized polycyclic compounds. The mechanisms of several
earlier fully intramolecular related transformations appear to involve
an analogous pericyclic cascade process rather than the diradical-
mediated pathways proposed previously. Further studies are
underway in our laboratory aimed at developing additional syntheti-
cally useful variants of this [2 + 2 + 2] strategy.
(17) Saaby, S.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 3365.
(18) The structure of 28 was assigned based on NMR studies. For details, see
Supporting Information.
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