Strain-activated diels-alder trapping of 1,2-cyclohexadienes: Intramolecular capture by pendent furans

Article abstract of DOI:10.1021/acs.orglett.9b02085

Intramolecular [4 + 2] cycloaddition reactions of substituted 1,2-cyclohexadienes with pendent furans enables the synthesis of complex tetracyclic scaffolds in a single step under mild conditions. All Diels-Alder cycloadducts were obtained as single diast

Full text of DOI:10.1021/acs.orglett.9b02085

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strain-Activated Diels−Alder Trapping of 1,2-Cyclohexadienes:
Intramolecular Capture by Pendent Furans
Verner A. Lofstrand,† Kyle C. McIntosh,† Yaseen A. Almehmadi, and F. G. West*
Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada
S
* Supporting Information
ABSTRACT: Intramolecular [4 + 2] cycloaddition reactions of
substituted 1,2-cyclohexadienes with pendent furans enables the
synthesis of complex tetracyclic scaffolds in a single step under mild
conditions. All Diels−Alder cycloadducts were obtained as single
diastereomers, assigned as the endo isomer. Substrates were easily
assembled via Stork−Danheiser alkylation of 3-ethoxy-2-bromocyclohex-
2-enone to accommodate a range of tethers and furan traps. Cleavage of
enol acetate moieties resulted in room-temperature Diels−Alder
cycloreversion to tethered furyl cyclohexenones.
Scheme 1. Intermolecular (a) vs Intramolecular (b; This
Work) Diels−Alder Trapping of Cyclic Allenes
iels−Alder cycloadditions involving furans as 1,3-diene
partners provide access to synthetically versatile
D
oxabicycloheptene scaffolds but are complicated by the
energetic costs of breaking aromaticity, which require heating
or Lewis acid activation of the dienophile.1 Intramolecular
Diels−Alder cycloadditions of furans (IMDAF) have been
studied extensively and applied to a number of natural
products targets.2 A further challenge is the potential for
retrograde cycloaddition to regenerate the heteroaromatic
reactant,3 an issue that has been overcome through the use of
high-pressure reaction conditions.4
Bond angle strain can provide potent activation of otherwise
relatively inert functionalities. Well-known reactive intermedi-
ates based on strained unsaturated rings such as arynes and
cyclohexynes have been established as valuable synthetic
building blocks that undergo Diels−Alder cycloaddition and
various ionic processes under mild conditions.5 The corre-
sponding cyclic allenes have recently become attractive
alternatives as reactants in strain-driven cycloadditions;6
although less strained than cyclohexynes, 1,2-cyclohexadienes
still exhibit a high degree of bond angle strain, estimated at ca.
32 kcal/mol.7 Moreover, the distribution of unsaturation over
three contiguous carbon atoms raises interesting regioselectiv-
ity issues, and the intrinsic chirality of cyclic allenes suggests
their possible mobilization in asymmetric synthesis. Notably,
acyclic allenes have proven to be unusually good dienophiles in
IMDAF reactions,8 prompting us to explore the corresponding
strain-activated cyclic allenes in this process.
One challenge associated with methodology employing
transient cyclic allenes is their propensity for dimerization to
afford tricyclic bis(alkylidene)cyclobutanes (Scheme 1).9
Effective Diels−Alder reaction with furan and related 1,3-
dienes often requires a large excess of the trapping reagent.10
We have found that some stable 1,3-dipoles can be used in
comparatively smaller excesses,6b and Garg and co-workers
have made comparable observations.6a,c Another strategy to
enhance trapping efficiency for reactive intermediates is
intramolecularity. In this case, a furan linked to one terminus
of the cyclic allene by a suitable tether (e.g., 1) would be
expected to undergo fast unimolecular Diels−Alder reaction to
afford 2.11 Here, we describe a general route to such
intermediates and their stereoselective conversion to complex
tetracyclic products under mild conditions.
Of the various reported methods for generation of 1,2-
cyclohexadienes, fluoride-induced elimination of allylic silanes
bearing leaving groups on the adjacent sp2 carbon was selected
for this study due to its mild conditions.12 Installation of the
furan-bearing tether could be accomplished via a Stork−
Danheiser-type transposition13 using 2-bromo-3-ethoxycyclo-
Received: June 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hexanone 3 and organolithium reagents 4, prepared from the
corresponding iodides 5 (Scheme 2). The resulting enones
solution in THF) in CH3CN at rt), resulting in rapid
consumption and formation of cycloadducts 2a−j in moderate
to good yields and in all cases as single diastereomers (Table 1;
Scheme 2. Construction of Furan-Tethered Substrates via
Stork−Danheiser Transposition
Table 1. Allene Generation and Intramolecular Diels−Alder
a
Trapping
b
substrate
R1
R2/R3
R4
X
n
yield (%)
c,d
1a
1b
1c
1d
1e
1f
Me
Ph
H/H
H/H
H/H
H/H
H/Me
Me/H
H/H
H/H
H/H
H
H
H
Me
H
H
Et
H
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
NBn
1
1
2
1
1
1
1
1
1
65 (46)
49
Me
Me
Me
Me
Me
Me
Me
21
62
62
64
47
40
79
d
1g
1h
1i
N(furfuryl)
a
Standard procedure: compound 1 was dissolved in CH3CN (0.02
M), and a 5 equiv solution of Bu4NF in THF (1 M) was added
dropwise. After consumption of 1 (1 h), the reaction mixture was
concentrated and purified by flash chromatography to furnish 2.
6a−f were subjected to silylcuprate conjugate addition,
followed by capping of the enolate oxygen with either an
acetyl or a benzoyl group. Through this short sequence, allene
precursors 1a−g could be obtained, allowing exploration of the
effect of furan substitution pattern, tether length, and enol-
capping group.
b
Yield values are for isolated product after chromatographic
c
d
purification. Yield for gram-scale reaction. For these examples,
CsF (5 equiv) was used in place of Bu4NF.
Two additional substrates with nitrogen-containing tethers
were also prepared (Scheme 3). In this case, chloromethyl-
Scheme 3. Preparation of Additional Furan-Tethered
Substrates with an Amine-Containing Tether and Lacking
Alkene Oxygenation
eq 1). In accounting for the remaining material, no evidence of
[2 + 2] dimerization was seen; however, reactions were
typically complicated by the presence of uncharacterizable
polar side products, which may result from polar trapping of
allene intermediates by trace amounts of water14 or reaction
with the THF in which the Bu4NF was dissolved.15 The
relative configuration of the cycloadducts was assigned on a
preliminary basis to be the endo diastereomers shown, in
analogy to the intermolecular examples (e.g., Scheme 1). This
assignment is supported by the consistent observation of a
1
single upfield proton in the H NMR spectra resulting from
anisotropic shielding of the axial cyclohexene proton on C12
by the nearby dihydrofuran π system (Figure 1), a spectral
feature that has been observed by others.10,16 Single-crystal X-
ray diffraction analysis of cycloadduct 2f confirmed this
stereochemical assignment, allowing the generalization of this
relative configuration to other products due to their close
spectral analogy.
In addition to the complete diastereoselectivity, the Diels−
Alder cycloaddition occurred only between the furan diene and
the proximal allene π bond to form the angularly fused
skeleton. No evidence was seen for the alternative
regiochemical outcome to afford the isomers 7 (see Figure
1). Electronic deactivation of the distal π bond by carboxylate
ester substitution may be partially responsible, though
observation of the same regiochemistry in the case of substrate
1j (eq 1) shows that other factors such as tether length also
lithium was used in the Stork−Danheiser sequence, followed
by displacement of the chloride with either N-benzylfurfuryl-
amine or bis(furfuryl)amine to afford 6g,h. Conjugate addition
of PhMe2Si and enolate trapping with Ac2O then furnished
1h,i. Finally, a substrate lacking any oxygen substitution on the
allene precursor was prepared. In this short route, cyclo-
hexanone 6a was subjected to Luche reduction and conversion
of the alcohol to the corresponding carbonate, followed by
direct displacement of the allylic carbonate with silylcuprate,14
to afford 1j.
Substrates 1a−j were then subjected to desilylation
conditions (5 equiv of tetrabutylammonium fluoride (1 M
B
DOI: 10.1021/acs.orglett.9b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Unexpected Retro-Diels−Alder Reaction of Enol
Acetate Cleavage Products
Figure 1. Characteristic upfield 1H NMR chemical shift of endo
cycloadducts, shown for 2f, ORTEP structure of 2f with H12ax
labeled, and alternative regiochemical outcome (7) not observed.
contribute to this selectivity. Indeed, a much lower yield in the
case of a four-carbon tether (substrate 1c) indicates the
importance of proximity of the furan diene to the transient
allene.
Replacement of the acetate moiety on the allene with
benzoate (substrate 1b) led to reduced yields of cycloadduct,
and methyl substitution around the furan ring (substrates 1c−
e) had a minimal effect. Incorporation of a nitrogen atom in
the tether (substrates 1h,i) was tolerated, although much
higher yields were seen in the case of the bis(furfuryl) amine
1i, as expected due to the greater likelihood of one of the
furans encountering the allene. Finally, on a gram-scale the
yield of the reaction is slightly diminished.
Cycloadducts 2a−i possess a masked enolate moiety
adjacent to the bridging ether oxygen atom of the dihydrofuran
embedded in a strained tetracyclic skeleton, and we wondered
whether this relationship could be exploited for the controlled
modification of cycloadducts via an elimination process. In the
event, treatment of 2g with K2CO3 in MeOH failed to afford
tricyclic alcohol 8g (Scheme 4).
molecular Diels−Alder reactions to completion with no
competing cycloreversion.
Here, we have described the first intramolecular trapping of
6-membered cyclic allenes via Diels−Alder cycloaddition using
pendent furans. Substrates are available via a short sequence,
and allene generation takes place under mild and convenient
conditions. In all cases, cycloadducts were isolated as single
(endo) diastereomers, and no evidence was seen for alternative
regiochemistry in the cycloaddition. The dihydrofuran moiety
is subject to regioselective opening with the assistance of the
masked enolate remaining after addition to the nonoxygenated
bond of the allene. Other intramolecular trapping processes
and further synthetic elaboration of the polycyclic scaffolds
available through this methodology will be described else-
where.
Instead, we observed clean formation of furan-tethered
cyclohexenone 10g. We attribute this surprising result to retro-
Diels−Alder reaction of intermediate 9g, arising from
protonation of the intermediate enolate derived from 2g. To
test the generality of this process, we subjected 2f to the same
conditions, which once again afforded the retro-[4 + 2] adduct
(10f) as the main product. We examined cleavage of the enol
acetate to the enolate under anhydrous conditions (excess
MeLi/−78 °C) using cycloadduct 2i. In this case, we
hypothesized that in the absence of an in situ proton source
the originally sought elimination might occur. However, once
again we saw exclusive reaction through the retro-[4 + 2]
pathway to afford 10i in quantitative yield, presumably via
enolate protonation during aqueous workup, followed by rapid
cycloreversion. The generality of this outcome indicates a
Diels−Alder equilibrium that strongly favors the diene and
dienophile reactants. Concerted cycloreversions of oxanorbor-
nenes to furans under mild conditions are sensitive to
substituent effects,17 and in this case, the strain resident in
the tetracyclic adducts 2 may contribute to a lower activation
barrier. At this juncture, however, we cannot rule out
alternative mechanistic pathways via stepwise heterolytic
cleavage, as shown for 9g. Computational studies currently
underway should yield additional insights. Moreover, the
distinct reactivity of 9 vs 2 highlights the critical role of the
high-energy cyclic allene intermediates in driving the intra-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02085.
Experimental procedures, compound data, crystal
1
structure, H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1895480 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fwest@ualberta.ca.
ORCID
(13) (a) Stork, G.; Danheiser, R. L. J. J. Org. Chem. 1973, 38, 1775−
1776. Recent examples: (b) Peng, F.; Danishefsky, S. J. J. Am. Chem.
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F. G. West: 0000-0001-7419-2314
Author Contributions
†V.A.L. and K.C.M. contributed equally.
Notes
The authors declare no competing financial interest.
(15) Hydrogen transfer by THF to strained benzyne intermediates
has been observed: Niu, D.; Willoughby, P. H.; Woods, B. P.; Baire,
B.; Hoye, T. R. Nature 2013, 501, 531−534.
ACKNOWLEDGMENTS
■
(16) Nendel, M.; Tolbert, L. M.; Herring, L. E.; Islam, Md. N.;
Houk, K. N. J. Org. Chem. 1999, 64, 976−983.
We thank Dr. R. McDonald (University of Alberta X-ray
Crystallography Facility) for obtaining the X-ray crystal
structure of 2f. Acknowledgment is made to the donors of
the American Chemical Society Petroleum Research Fund for
support of this work. We also thank the Natural Science and
Engineering Research Council of Canada (NSERC) for partial
support and King Abdulaziz University (KAU) for a
postgraduate scholarship (Y.A.A.).
(17) Fell, J. S.; Lopez, S. A.; Higginson, C. J.; Finn, M. G.; Houk, K.
N. Org. Lett. 2017, 19, 4504−4507.
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DOI: 10.1021/acs.orglett.9b02085
Org. Lett. XXXX, XXX, XXX−XXX