Diene-Transmissive Diels-Alder Sequences with Benzynes

Article abstract of DOI:10.1021/acs.orglett.9b02807

Diene-transmissive Diels-Alder (DTDA) sequences are extraordinarily powerful processes for the generation of fused bicyclic systems. Nonetheless, only stable dienophiles have previously been deployed. Herein we report DTDA sequences with a variety of substituted [3]dendralenes in the first study to deploy arynes as dienophiles. We demonstrate the one-flask generation of complex, aromatic-ring-containing, multicyclic systems of relevance to medicinal chemistry. These synthetic operations provide numerous successful examples of the otherwise challenging and rarely reported intermolecular Diels-Alder reaction of acyclic 1,3-butadienes with arynes, which is made possible due to the exalted reactivity of dendralenic dienes.

Full text of DOI:10.1021/acs.orglett.9b02807

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diene-Transmissive Diels−Alder Sequences with Benzynes
Josemon George, Jas S. Ward, and Michael S. Sherburn*
Research School of Chemistry, Australian National University, Canberra, Australian Capital Territory 2601, Australia
S
* Supporting Information
ABSTRACT: Diene-transmissive Diels−Alder (DTDA) sequences are extraordinarily powerful processes for the generation of
fused bicyclic systems. Nonetheless, only stable dienophiles have previously been deployed. Herein we report DTDA sequences
with a variety of substituted [3]dendralenes in the first study to deploy arynes as dienophiles. We demonstrate the one-flask
generation of complex, aromatic-ring-containing, multicyclic systems of relevance to medicinal chemistry. These synthetic
operations provide numerous successful examples of the otherwise challenging and rarely reported intermolecular Diels−Alder
reaction of acyclic 1,3-butadienes with arynes, which is made possible due to the exalted reactivity of dendralenic dienes.
cyclic sp2-rich hydrocarbons are excellent precursors for
Athe step-economic generation of multicyclic systems.
Dendralenes are particularly prominent in this field because
they serve as multidienes in interconnected sequences of [4 +
2] cycloadditions.1,2 The simplest cross-conjugated hydro-
carbon, [3]dendralene, behaves as a double diene, reacting
successively with two dienophiles in a so-called diene-
transmissive Diels−Alder (DTDA) reaction sequence.3 In
DTDA sequences of [3]dendralenes, the first [4 + 2]
cycloaddition is generally faster than the second, which allows
the use of two different dienophiles.4 Despite their obvious
power and potential, DTDA sequences are by no means
generalized processes because little in the way of dienophile
variation has been investigated.1,3,5,6 Herein we deploy
dendralenes for the first time in DTDA sequences with
benzynes. In addition to significantly broadening the scope of
the extraordinarily powerful (four covalent bonds, two rings
formed) DTDA sequence, this investigation also demonstrates
Figure 1. Proposed two-fold Diels−Alder sequence and selected
clinically used substances containing a carbo-/heteroannelated tetralin
core.
the rapid construction of novel, medicinal-chemistry-relevant
structures.
Specifically, this work shows that a substituted [3]-
dendralene 1 undergoes an intermolecular Diels−Alder
reaction with (a substituted) benzyne 2 to generate 2-vinyl-
1,4-dihydronaphthalenes 3, which, in turn, undergoes an
intermolecular Diels−Alder reaction with a range of
dienophiles 4 to furnish new carbo- and heteroannelated
tetralins 5. Diverse substitution of the tricyclic framework is
within reach using this approach, a feature made pertinent by
the privileged position of these systems in medicinal chemistry
(Figure 1).7
With diversely substituted [3]dendralenes available through
a short and efficient two-step synthesis from aldehydes,8 we set
about testing the feasibility of intermolecular cycloadditions to
benzynes. Our confidence was fueled by the knowledge that
[3]dendralenes are reactive dienes.1,3,4 Nonetheless, our
Received: August 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02807
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Organic Letters
Letter
Table 1. Aryne Additions to Internally-Substituted
[3]Dendralenes 1 Generate 2-Vinyl-1,4-
dihydronaphthalenes 3
Table 2. One-Flask, Two-Fold Cycloadditions to
Substituted [3]Dendralenes Involving First an Aryne, Then
an Electron-Poor Alkene, Alkyne, or Azo-Compound
a
a
Dienophile
a
Unless otherwise specified, yields refer to isolated products from the
n-BuLi method: To a solution of dendralene 1 and benzyne precursor
2c (1.0 mol equiv) in PhMe at 0 °C was added n-BuLi (1.2 mol
b
equiv) dropwise over 5 min. To a solution of dendralene 1 and
benzyne precursor 2a or 2b (1.5 mol equiv) in MeCN at 23 °C was
c
added CsF (6 mol equiv). To a solution of dendralene 1 and benzyne
precursor 2a or 2b (2 to 3 mol equiv) in THF at −20 °C was added
d
TBAF (3.5 mol equiv). Procedure a was followed but with benzyne
precursor 2d (3.0 mol equiv) and n-BuLi (3.2 mol equiv).
Scheme 1. Sequential 1,4-Nucleophilic Addition/
Electrophilic Substitution of a 1,3-Butadiene
a
Unless otherwise specified, yields refer to isolated products 5 from
THF solutions of dendralenes 1 through a one-pot method involving
successive additions of (i) 2a or 2b (3 mol equiv) and TBAF (3.5 mol
equiv), then (ii) MeOH, CaCO3, and Dowex 50WX8-400 resin, then
(iii) N-methylmaleimide (4a), N-phenyltriazoline-2,5-dione (4b), or
b
dimethylacetylenedicarboxylate (4c) (6 mol equiv). Isolated yield
from 2-vinyl-1,4-dihydronaphthalene 3.
enthusiasm was curtailed somewhat by the paucity of
successful Diels−Alder reactions between benzynes and acyclic
B
DOI: 10.1021/acs.orglett.9b02807
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Organic Letters
Letter
1,4-addition polymerizations of dienes23 and dendralenes24 are
known, but to our knowledge, 1,4-addition/substitution is
without precedent for unsaturated hydrocarbons.25 Attempts
to generalize this three-component, two C−C bond-forming
process are underway.
Scheme 2. Step Economic Synthesis of a 7-Arylangucycline
A significant contributing factor to the relatively low isolated
yields of 2-vinyl-1,4-dihydronaphthalenes 3 (Table 1) relates
to difficulties with product isolation. The separation of target
product 3 from unreacted dendralene 1 and benzyne side
products was nontrivial, particularly when all were hydro-
carbons.26 To circumvent this issue, we performed a second
cycloaddition to semicyclic diene 3 with a nonhydrocarbon
dienophile in the same reaction flask: We reasoned that the
functionality in this double adduct would facilitate its isolation,
hence simultaneously improving step economy and increasing
isolated yields. The successful realization of this hypothesis is
depicted in Table 2.27 Thus [3]dendralenes with the
substituent types listed in Table 1, along with additional
substrates carrying an internal, electron-poor aromatic ring (→
5c) or an indole (→ 5g) and dendralenes with phenyl groups
at the terminal sites (→ 5j, k), undergo one-flask DTDA
sequences involving an aryne as the initial dienophile and N-
methylmaleimide (NMM), N-phenyltriazoline-2,5-dione
(PTAD), or dimethylacetylenedicarboxylate (DMAD28) as
the representative second dienophile. The carbo-/heteroanne-
lated tetralin products of these three component reactions29
are isolated in highly respectable yields, considering that up to
six new stereocenters, four new covalent bonds, and a new
octalin ring system are generated in one operation.
dienes in the literature. In fact, we could locate only eight
publications reporting examples of this process, most of which
describe only one or two examples.9−16 Collectively, these
reports indicate: (a) 1,4-Disubstituted-1,3-butadienes are the
best performers,8,12,13 (b) unsubstituted diene termini can be
problematic, giving rise to competing [2 + 2] cycloaddition
products,9,10 (c) 2-methyl-1,3-butadienes can be challenging
due to competing Alder ene reactions,7,9 and (d) the
elimination of CO2/N2 from ortho-benzendiazonium carbox-
ylate (BDC) is the preferred method of benzyne gener-
ation.11−13
Of the various methods of aryne generation, TBAF/2-
trimethylsilyl-benzene-1-trifluoromethanesulfonate gave the
best outcome in the one-flask process. For optimal yields,
Kishi’s method30 of TBAF workup was deployed in situ prior
to the addition of the second dienophile to the reaction
mixture, and an excess of the second dienophile was used. In
most cases, the second cycloaddition proceeds with (within the
limits of detection) complete π-diastereofacial selectivity, with
the dienophile avoiding the side of the 2-vinyl-1,4-dihydro-
naphthalene 3 that carries the substituents (R/R1; Table 2).
Complete endo-selectivity is also seen in cases involving NMM
as the dienophile.
A final example, which extends the methodology to a more
elaborate product structure, is depicted in Scheme 2.31 Thus
the reaction of 2-vinyl-1,4-dihydronaphthalene 3e with para-
benzoquinone 4d, followed by the stereoselective two-fold
Luche reduction and O-methylation, gives pentacycle 9,
containing both the tetracarbocyclic framework of angucycline
antibiotics32 and the tricyclic aryltetralin unit of antineoplastic
lignans such as podophyllotoxin and its derivatives33 (Figure
1).
In summary, the first Diels−Alder additions of arynes to
dendralenes have been performed. These reactions have been
sequenced with a second [4 + 2] cycloaddition in a one-flask
operation to rapidly create complex multicyclic systems. This
study significantly extends knowledge on aryne cycloaddition
chemistry to acyclic dienes, processes that are poorly
represented in the literature. Evidently, the enhanced diene
reactivity of dendralenes is a contributing factor to their
success in benzyne Diels−Alder additions. It is noteworthy that
in contrast with 1,3-butadienes, dendralenes 1 provide
reasonable yields from benzyne [4 + 2] cycloadditions
irrespective of the presence or absence of terminal 1,3-
butadiene substituents. The structures generated through this
Table 1 reports the results of [4 + 2] cycloadditions of in-
situ-generated benzyne, 3,6-dimethoxybenzyne, and 4,5-
dimethoxybenzyne with [3]dendralenes 1a−h, which carry a
single substituent at the internal carbon. In contrast with the
most recent literature findings of acyclic diene−benzyne
cycloadditions, for which the BDC method is superior,11−13
the acyclic diene units of substituted [3]dendralenes undergo
the highest yielding reactions with n-BuLi/1,2-dibromoben-
zene and fluoride/2-trimethylsilyl-benzene-1-trifluoromethane-
sulfonate.17 Table 1 presents successful aryne additions to
[3]dendralenes carrying acyclic and cyclic alkyl, alkynyl, and
diversely substituted aromatic substituents. The 2-vinyl-1,4-
dihydronaphthalene products 3 are poorly represented in the
literature.18 This is surprising considering their significant
potential for further elaboration into multicyclic structures.19,20
We selected one set of conditions for aryne generation/
cycloaddition based on those developed by Coe and
coworkers, who report a 89% yield for a reaction between
cyclopentadiene, 1,2-dibromobenzene, and n-BuLi (1:1:1
stoichiometry) performed on a 100 g scale.21 Under the
same conditions, [3]dendralenes gave modest yields by
comparison, and hence optimization experiments were under-
taken. One attempt involved the replacement of PhMe with
THF as the solvent, which led to an intriguing and
unprecedented result: None of the expected benzyne addition
product of dendralene 1a was observed, but instead a product
with two additional n-butyl units and one less CC bond, 6-
Z, was isolated in ca. 20% yield. A 60% yield of this product
was obtained in the absence of 1,2-dibromobenzene but with
added n-bromobutane (Scheme 1).22 We presume that the
nucleophilic addition of n-BuLi to either terminus of a 1,3-
butadiene moiety of 1a generates the pentadienyl-lithium 7a or
the phenylpropenyl-lithium 7b, which undergoes the nucleo-
philic substitution of bromobutane. Organolithium-initiated
C
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(3) Bradford, T. A.; Payne, A. D.; Willis, A. C.; Paddon-Row, M. N.;
Sherburn, M. S. Practical Synthesis And Reactivity Of [3]Dendralene.
J. Org. Chem. 2010, 75, 491−494.
(4) Sherburn, M. S. Preparation And Synthetic Value Of π-Bond-
Rich Branched Hydrocarbons. Acc. Chem. Res. 2015, 48, 1961−1970.
(5) Green, N. J.; Saglam, M. F.; Sherburn, M. S. Synthesis of
Dendralenes. In Cross Conjugation: Modern Dendralene, Radialene and
Fulvene Chemistry; Hopf, H., Sherburn, M. S., Eds.; Wiley-VCH, 2016;
pp 1−38.
(6) (a) Newton, C. G.; Sherburn, M. S. Cross-Conjugation in
Synthesis. In Cross Conjugation: Modern Dendralene, Radialene and
Fulvene Chemistry; Hopf, H., Sherburn, M. S., Eds.; Wiley-VCH, 2016;
pp 413−444. (b) Hong, B.-C. Constructing Molecular Complexity
and Diversity by Cycloaddition Reactions of Fulvenes. In Cross
Conjugation: Modern Dendralene, Radialene and Fulvene Chemistry;
Hopf, H., Sherburn, M. S., Eds.; Wiley-VCH, 2016; pp 249−300.
(7) A small selection of the many approved and investigational drugs
containing substituted tetralins includes: sertralines, steroidal estro-
gens and nonsteroidal estrogens such as nafoxidine and lasofoxifene,
opiates, podophyllotoxin and derivatives such as etoposide and
teniposide, doxorubicins and tetracyclines, tetryzoline, quinagolide,
rotigotine, palonosetron, ecopipam, PF-03882845, nirogacestat,
fosdagrocorat, ORG-25935, palovarotene, and dihydrexidine.
(8) George, J.; Ward, J. S.; Sherburn, M. S. A General Synthesis of
Dendralenes. Chem. Sci. 2019, submitted.
new DTDA sequence are suggestive of those found in
biologically active compounds. In some cases, these new
structures represent hybrids of natural products and drug
molecules,34 which have obvious potential for exploitation
outside of synthetic chemistry. Extensions of these studies to
unsymmetrically substituted dienophiles and applications of
these concepts in target syntheses are underway.
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.9b02807.
Experimental procedures, characterization data and
nuclear magnetic resonance spectra, and crystallographic
data for X-ray crystal structures (PDF)
Accession Codes
CCDC 1922951−1922955 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
(9) Wittig, G.; Duerr, H. Dehydrobenzene And Acyclic Dienes.
Liebigs Ann. 1964, 672, 55−62.
(10) Jones, M., Jr.; Levin, R. H. Stereochemistry Of The [2 + 2] And
[2 + 4] Cycloadditions Of Benzyne. J. Am. Chem. Soc. 1969, 91,
6411−15.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.sherburn@anu.edu.au
ORCID
(11) Crews, P.; Beard, J. Cycloadditions Of Benzyne With Cyclic
Olefins. Competition Between [2 + 4], Ene, And [2 + 2] Reaction
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Pentadiene. J. Org. Chem. 1975, 40, 1355−6.
Jas S. Ward: 0000-0001-9089-9643
Michael S. Sherburn: 0000-0001-5098-0703
Author Contributions
(13) Schmidt, R. R.; Angerbauer, R. A New Entry To Naphthalene
Oxides. Angew. Chem., Int. Ed. Engl. 1979, 18, 304−305.
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15029.
The manuscript was written through contributions of all
authors. J.S.W. performed the X-ray structure analyses. All
authors have given approval to the final version of the
manuscript.
(15) Chen, Z.; Shou, W.; Wang, Y. One-Pot Synthesis Of 1,4-
Diarylnaphthalenes Via A Wittig-Horner Reaction/[4 + 2] Cyclo-
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Notes
The authors declare no competing financial interest.
(16) Intramolecular examples: (a) Buszek, K. R. First Intramolecular
Benzyne Diels-Alder Reaction With An Acyclic Diene. Unusual Effect
Of Diene Geometry On The Course Of The Reaction. Tetrahedron
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R. L. Intramolecular [4 + 2] Cycloadditions Of Benzynes With
Conjugated Enynes, Arenynes, And Dienes. Org. Lett. 2005, 7, 3917−
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Leads To An Effective Class Of Bifunctional Linchpins Uniting Anion
Relay Chemistry (ARC) With Benzyne Reactivity. Proc. Natl. Acad.
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Suzuki, K. 2-Bromo-6-(chlorodiisopropylsilyl)phenyl Tosylate As An
Efficient Platform For Intramolecular Benzyne-Diene [4 + 2]
Cycloaddition. Chem. Sci. 2019, 10, 3840−3850.
(17) The BDC method gave mixtures of single and two-fold addition
products in lower yields than the other methods, with low recoveries
and no other discernible products. We attribute the poor mass
balances of tractable products to polymer formation. Polymers might
be generated through acid-catalyzed decomposition from traces of
acid remaining from the preparation of BDC, perhaps accelerated by
the higher reaction temperatures used in this procedure.
(18) (a) Okazaki, E.; Okamoto, R.; Shibata, Y.; Noguchi, K.; Tanaka,
K. Rhodium-Catalyzed Cascade Reactions Of Dienynes Leading To
Substituted Dihydronaphthalenes And Naphthalenes. Angew. Chem.,
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ACKNOWLEDGMENTS
■
This work was supported by the Australian Research Council
(DP160104322). We thank Dr. Jotham Coe (Pfizer) for
suggestions, Ms. Madison Sowden (ANU) for performing
preliminary experiments with BDC, Dr. Michael Gardiner
(ANU) and Dr. Paul Carr (ANU) for assistance with single-
crystal X-ray analyses, and Dr. Hideki Onagi (ANU) for
assistance with nuclear magnetic resonance and high-perform-
ance liquid chromatography (HPLC) analyses. Molecular
structures from single-crystal X-ray analyses were visualized
using CYLview 1.0b.35
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